DNA-pk selective inhibitors and methods of making and using the same

Abstract

The present application relates to a kind of DNA-PK selective inhibitors shown in formula (I) and preparation method and purposes thereof.The purposes include the purposes of compound of formula (I) in the preparation of the drug for treating the disease related to DNA-PK.In preparation process, by substitution, reduction, cyclization and alkylation etc., a series of reactions, obtain the compound of the present application.

Description

[0001] Cross-referencing

[0002] This application claims Chinese Patent Application No. 202010708897.9, filed July 20, 2020, entitled "DNA-PK Selective Inhibitor and its Preparation Method and Use", Chinese Patent Application No. 202010998179.X, filed September 18, 2020, entitled "DNA-PK Selective Inhibitor and its Preparation Method and Use", Chinese Patent Application No. 202011298735.9, filed November 18, 2020, entitled "DNA-PK Selective Inhibitor and its Preparation Method and Use", and Chinese Patent Application No. 202011298735.9, filed December 2020. The priority of Chinese Patent Application No. 202011424931.6, filed on August 8, 2021, entitled "DNA-PK Selective Inhibitor and Preparation Method and Use Thereof", Chinese Patent Application No. 202110181140.3, filed on February 9, 2021, entitled "DNA-PK Selective Inhibitor and Preparation Method and Use Thereof", and Chinese Patent Application No. 202110617681.6, filed on June 3, 2021, entitled "DNA-PK Selective Inhibitor and Preparation Method and Use Thereof", is hereby invoked in its entirety. Technical Field

[0003] This invention relates to compounds that selectively inhibit the activity of DNA-PK proteins, methods for preparing these compounds and their salts, and methods for treating DNA-PK-mediated diseases (including cancer) using such compounds and salts. Background Technology

[0004] DNA-dependent protein kinases (DNA-PKs) are serine and threonine protein kinases that are activated upon binding to DNA. DNA-PKs are trimers formed by the polymerization of a heterodimer consisting of a catalytic subunit (DNA-PKcs, 470 kDa) and two regulatory subunits (Ku70 and Ku80) upon contact with broken DNA. DNA-PKcs is a member of the phosphatidylinositol-3 kinase family and participates in various biochemical processes, including the repair of DNA double-strand breaks (DSBs), signal transduction of programmed cell death, gene surveillance, and maintenance of telomere structure (FASEBJ, 2005, 19(7):704-715). Radiation and many anticancer drugs can directly or indirectly act on DNA or DNA metabolic processes, leading to DNA damage and triggering a series of cellular responses, including DNA repair. The result of this repair is increased cell survival, which is one of the mechanisms by which tumor cells resist radiotherapy and chemotherapy. Inhibiting the repair of these DNA damages can improve the sensitivity of cells to radiotherapy and chemotherapy (Int J Hyperthermia, 2008, 24(1):17-29.). Among DNA damages, DNA double-strand breaks (DSBs) are the most fatal, and the repair of DSBs is mainly carried out through DNA-dependent protein kinase DNA-PK-dominated nonhomologous end-joining (NHEJ) (Cell Res, 2008, 18(1):114-124.). In addition to playing a major role in the repair of DSBs, DNA-PK also plays other roles:

[0005] 1) V(D)J chain rearrangement of immunoglobulins and T cell receptors, such as the deletion of DNA-PKcs or Ku protein, can lead to severe combined immunodeficiency (SCID) in mammalian cells.

[0006] 2) Maintaining telomere structure stability; lack of Ku or DNA-PKcs can lead to genomic instability, delayed cell growth, and premature aging.

[0007] 3) DNA-PKcs are serine / threonine kinases and members of the PI-3-K (Phospha tidy lino sitol-3-kinase) kinase family (which also includes ATM, ATR, etc.). They also play a role in cell signal transduction and cell cycle functions after DNA damage. (Int J Radiat Oncol Biol Phys, 2005, 61(3):915-921.)

[0008] A range of factors can induce DNA double-strand breaks, including chemotherapy, radiotherapy, and PARP inhibitors such as olaparib. DNA-PK inhibitors have the potential to sensitize these therapies. DNA-PK inhibitors can also serve as effective monotherapy, particularly for endogenous DNA damage in tumor cells where other DNA repair pathways are absent. Currently, several DNA-PK selective inhibitors have entered clinical trials globally, with two drugs already in Phase II clinical trials; however, no such drugs have yet been marketed, and the demand for these drugs remains unmet. The DNA-PK selective inhibitor provided by this invention exhibits high activity, strong resistance to drug resistance, and few clinical side effects, effectively enhancing the sensitivity to radiotherapy and chemotherapy in tumor treatment, and possesses significant economic value and application prospects. Summary of the Invention

[0009] This invention provides a DNA-PK selective inhibitor, which is a compound of general formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof. This invention also provides a series of compounds represented by general formula (I) and their pharmaceutically acceptable salts, solvates, polymorphs, or isomers, pharmaceutical compositions comprising these compounds, and methods of treating diseases with such compounds.

[0010] In one aspect, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof.

[0011]

[0012] in,

[0013] Y is

[0014] Ring A is a 6-10 aryl group or a 5-12 heteroaryl group.

[0015] Ring B is a 3-12 membered carbon ring or a 4-12 membered heterocyclic ring. The sulfur (S) on ring B may optionally be oxidized, and the carbon ring or heterocyclic ring may optionally be fused with a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring.

[0016] The C ring is a 5-12 membered heteroaryl ring.

[0017] Z is -N(R)-, O, or S.

[0018] X2 is either CR2 or N.

[0019] X1 represents CRR4, O, S, NR6.

[0020] R1 represents H and C. 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12-membered heterocycloalkyl, 6-10-membered aryl, or 5-12-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be replaced by halogens, -CN, -OH, -NH2, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution,

[0021] R7 and R8 are each independently selected from halogens, CN, -OH, -NH2, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl and -NR-C 1-6 Alkyl groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be replaced by halogens, -CN, -OH, -NH2, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution,

[0022] m and n are each independently 0, 1, 2, or 3.

[0023] R3 is either R5 or -X3-R5.

[0024] R4 is either R6 or -X3-R6.

[0025] X3 can be independently -O-, -S-, or -NR-.

[0026] R5 and R6 are each independently selected from H, halogens, -CN, -OH, -NH2, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl and -NR-C 1-6 Alkyl groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be replaced by halogens, -CN, -OH, -NH2, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution, or

[0027] R5 and R6 combine to form -(CH2). p -X-(CH2) q -, or R5 and Y connected together -(CH2) p -X-(CH2) q - where X is a bond, -CR=CR-, -CO-CR=CR-, -C≡C-, -CO-C≡C-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)2NR-, -N(R)-, -CO-, -C(O)NR-, -C(O)O-, 6-10 arylene, 5-12 heteroarylene, 3-12 carbon ring, or 3-12 heterocycle, and -(CH2). p -X-(CH2) q CH2 in - and the said arylene, heteroarylene, carbocyclic and heterocyclic groups may optionally be replaced by halogens, -CN, -OH, -NH2, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl, or -NR-C 1-6Alkyl substitution,

[0028] p and q are each independently 0, 1, 2, 3, or 4, and p + q is 1, 2, 3, 4, 5, or 6.

[0029] R2 is selected from H, halogens, CH2F, CHF2, CF3, -OH, -NH2, CN, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl group, -(CH2) 1-6 -CN, -(CH2) 1-6 -OC 1-6 Alkyl group, -(CH2) 1-3 -OH, -CHO, -(CO)NH2, -(CO)NHR, -(CO)OR, and -NR-C 1-6 Alkyl groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be replaced by halogens, -CN, -OH, -NH2, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution,

[0030] R is independently H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be replaced by halogens, -CN, -OH, -NH2, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC1-6 Alkyl, or -NR-C 1-6 Alkyl substitution;

[0031] In some implementations, Y is

[0032] In some embodiments, ring B is a 3-12 membered carbon ring or a 4-12 membered heterocycle, and the S on ring B may optionally be oxidized;

[0033] In another aspect, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof.

[0034]

[0035] in,

[0036] Ring A is a 6-10 aryl group or a 5-12 heteroaryl group.

[0037] Ring B is a 3-12 membered carbon ring or a 4-12 membered heterocyclic ring. The sulfur (S) on ring B may optionally be oxidized, and the carbon ring or heterocyclic ring may optionally be fused with a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring.

[0038] Z is -N(R)-, O, or S.

[0039] X2 is either CR2 or N.

[0040] X1 represents CRR4, O, S, NR6.

[0041] R1 represents H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12-membered heterocycloalkyl, 6-10-membered aryl, or 5-12-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be replaced by halogens, -CN, -OH, -NH2, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution,

[0042] R7 and R8 are each independently selected from halogens, CN, -OH, -NH2, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl and -NR-C 1-6 Alkyl groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be replaced by halogens, -CN, -OH, -NH2, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution,

[0043] m and n are each independently 0, 1, 2, or 3.

[0044] R3 is either R5 or -X3-R5.

[0045] R4 is either R6 or -X3-R6.

[0046] X3 can be independently -O-, -S-, or -NR-.

[0047] R5 and R6 are each independently selected from H, halogens, -CN, -OH, -NH2, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl, or -NR-C 1-6 Alkyl groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be replaced by halogens, -CN, -OH, -NH2, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution, or

[0048] R5 and R6 combine to form -(CH2). p -X-(CH2) q -, or R5 and Y connected together -(CH2) p -X-(CH2) q - where X is a bond, -CR=CR-, -CO-CR=CR-, -C≡C-, -CO-C≡C-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)2NR-, -N(R)-, -CO-, -C(O)NR-, -C(O)O-, 6-10 arylene, 5-12 heteroarylene, 3-12 carbon ring, or 3-12 heterocycle, and -(CH2). p -X-(CH2) q CH2 in - and the said arylene, heteroarylene, carbocyclic and heterocyclic groups may optionally be replaced by halogens, -CN, -OH, -NH2, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution,

[0049] p and q are each independently 0, 1, 2, 3, or 4, and p + q is 1, 2, 3, 4, 5, or 6.

[0050] R2 is selected from H, halogens, CH2F, CHF2, CF3, -OH, -NH2, CN, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl group, -(CH2) 1-6 -CN, -(CH2) 1-6 -OC 1-6 Alkyl group, -(CH2)1-3 -OH, -CHO, -(CO)NH2, -(CO)NHR, -(CO)OR, and -NR-C 1-6 Alkyl groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be replaced by halogens, -CN, -OH, -NH2, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution,

[0051] R is independently H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be replaced by halogens, -CN, -OH, -NH2, -S(O)R, -S(O)2R, -S(O)2NR-C 1-6 alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OC 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution;

[0052] In some embodiments, the B ring is a 3-12 membered carbon ring or a 4-12 membered hetero ring, and the S on the B ring may optionally be oxidized;

[0053] In another aspect, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof.

[0054]

[0055] in,

[0056] Ring A is a 6-10 aryl group or a 5-12 heteroaryl group.

[0057] Ring B is C 3-8 Cycloalkyl or 4-12 membered heterocycles, with the sulfur on the B ring optionally oxidized.

[0058] Z is either O or S.

[0059] X2 is either CR2 or N.

[0060] X1 is CRR4, O, S, or NR6.

[0061] R1 represents H and C. 1-6 Alkyl, or C 3-8 Cycloalkyl groups, wherein the alkyl group and the cycloalkyl group may optionally be converted by halogen, -CN, -OH, -NH2, -OC 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution,

[0062] R7 and R8 are each independently selected from halogen, CN, and C. 1-6 Alkyl, -OC 1-6 Alkyl and -NR-C 1-6 Alkyl groups, which may optionally be converted to halogen, -CN, -OH, -NH2, or -OC. 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution,

[0063] m and n are each independently 0, 1, 2, or 3.

[0064] R3 is either R5 or -X3-R5.

[0065] R4 is either R6 or -X3-R6.

[0066] X3 can be independently -O-, -S-, or -NR-.

[0067] R5 and R6 are each independently selected from H and C. 1-6 Alkyl groups, or R5 and R6 linked together to form -(CH2). p -X-(CH2) q - where X is a bond, -CH=CH-, -CO-CH=CH-, -O-, -S, -N(R)-, -CO-, -C(O)NR-, -C(O)O-, 6-10 arylene, 5-12 heteroarylene, or 3-12 heterocycle, and -(CH2). p -X-(CH2) q - The CH2 in - can optionally be replaced by halogen or C 1-6 Alkyl substitution,

[0068] p and q are each independently 0, 1, 2, 3, or 4, and p + q is 1, 2, 3, 4, 5, or 6.

[0069] R2 is selected from H, halogens, CH2F, CHF2, CF3, -OH, -NH2, CN, C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl group, -(CH2) 1-6 -CN, -(CH2) 1-6 -OC 1-6 Alkyl group, -(CH2) 1-3 -OH, -CHO, -(CO)NH2, -(CO)NHR, -(CO)OR, and -NR-C 1-6 alkyl.

[0070] R is H or C 1-6 alkyl;

[0071] In some implementations,

[0072] Ring A is a 6-10 aryl group or a 5-12 heteroaryl group.

[0073] Ring B is a 4-12 membered heterocycle, and the sulfur on ring B can be optionally oxidized.

[0074] Z is either O or S.

[0075] X2 is either CR2 or N.

[0076] X1 is CRR4, O, S, or NR6.

[0077] R1 represents H and C. 1-6 Alkyl, or C 3-8 Cycloalkyl groups, wherein the alkyl group and the cycloalkyl group may optionally be converted by halogen, -CN, -OH, -NH2, -OC 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution,

[0078] R7 and R8 are each independently selected from halogen, CN, and C. 1-6 Alkyl, -OC 1-6 Alkyl and -NR-C 1-6 Alkyl groups, which may optionally be converted to halogen, -CN, -OH, -NH2, or -OC. 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution,

[0079] m and n are each independently 0, 1, 2, or 3.

[0080] R3 is either R5 or -X3-R5.

[0081] R4 is either R6 or -X3-R6.

[0082] X3 can be independently -O-, -S-, or -NR-.

[0083] R5 and R6 are each independently selected from H and C. 1-6 Alkyl groups, or R5 and R6 linked together to form -(CH2). p -X-(CH2) q - where X is a bond, -O-, -S, -N(R)-, -CO-, -C(O)NR-, -C(O)O-, 6-10 arylene, 5-12 heteroarylene, or 3-12 heterocycle, and -(CH2). p -X-(CH2) q The CH2 in - can optionally be replaced by halogens,

[0084] p and q are each independently 0, 1, 2, 3, or 4, and p + q is 1, 2, 3, 4, 5, or 6.

[0085] R2 is selected from H, halogens, CHF2, CF3, -OH, -NH2, CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl group, -(CH2) 1-6 -CN, -(CH2) 1-6 -OC 1-6 Alkyl group, -(CH2) 1-3 -OH, -CHO, -(CO)NH2, -(CO)NHR, -(CO)OR, and -NR-C 1-6 alkyl.

[0086] R is H or C 1-6 alkyl.

[0087] In some implementations,

[0088] Ring A is C 6-10 aryl or C 5-12 Mixed aromatics,

[0089] Ring B is C 4-12 Heterocyclic rings

[0090] Z is either O or S.

[0091] X2 is either CR2 or N.

[0092] X1 is CRR4, O, S, or NR6.

[0093] R1 is H or C 1-6 Alkyl groups, which may optionally be converted to halogen, -CN, -OH, -NH2, or -OC. 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution;

[0094] R7 and R8 are each independently selected from halogen, CN, and C. 1-6 Alkyl, -OC 1-6 Alkyl and -NR-C 1-6 Alkyl groups, which may optionally be converted to halogen, -CN, -OH, -NH2, or -OC. 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution,

[0095] m and n are each independently 0, 1, 2, or 3.

[0096] R3 is either R5 or -X3-R5.

[0097] R4 is either R6 or -X3-R6.

[0098] X3 can be -O-, -S-, or -NR-.

[0099] R5 and R6 are each independently selected from H and C. 1-6 Alkyl groups, or R5 and R6 linked together to form -(CH2). p -X-(CH2) q -, where X is a bond, -O-, -S, -N(R)-, -CO-, -C(O)NR-, -C(O)O-, C 6-10 Alpha-aryl, C 5-12 heteroaryl, or C 3-12 Heterocyclic rings

[0100] p and q are each independently 0, 1, 2, 3, or 4, and p + q is 1, 2, 3, 4, 5, or 6.

[0101] R2 is selected from H, halogens, CHF2, CF3, -OH, -NH2, CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl group, -(CH2) 1-6 -CN, -(CH2) 1-6 -OC 1-6 Alkyl and -NR-C 1-6 alkyl.

[0102] R is H or C 1-6 alkyl.

[0103] In some implementations, X is -CH=CH- or -CO-CH=CH-, and R2 is CH2F;

[0104] In some implementations, ring A is C 6-10 aryl or C 5-12 Mixed aromatics,

[0105] Ring B is C 4-12 Heterocyclic rings;

[0106] X2 is N,

[0107] X1 represents CRR4, O, S, NR6. or,

[0108] X2 is CR2.

[0109] X1 represents O, S, NR6. Other functional groups are as defined above;

[0110] In some implementations, R5 and R6 are each independently selected from H and C. 1-6 Alkyl groups, or R5 and R6 linked together to form -(CH2). p -X-(CH2) q - where X is a bond, -O-, -S, -N(R)-, -CO-, -C(O)NR-, -C(O)O-, 6-10 arylene, 5-12 heteroarylene, or 3-12 heterocycle;

[0111] In some implementations, R5 and R6 are each independently selected from H or C. 1-6 When alkyl, R2 is selected from halogen, CH2F, CHF2, CF3, -OH, -NH2, CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl group, -(CH2) 1-6 -CN, -(CH2) 1-6 -OC 1-6 Alkyl, or -NR-C 1-6 alkyl,

[0112] When R5 and R6 are bonded together, they form -(CH2). p -X-(CH2) q When - R2 is selected from H, halogens, CHF2, CF3, -OH, -NH2, CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl group, -(CH2) 1-6 -CN, -(CH2) 1-6 -OC 1-6 Alkyl and -NR-C 1-6 alkyl,

[0113] R is H or C 1-6 alkyl;

[0114] In some embodiments, R2 is selected from H, halogens, CHF2, CF3, -OH, -NH2, CN, C 1-6 Alkyl, -OC 1-6 Alkyl group, -(CH2) 1-3 -CN, -(CH2) 1-3 -OC 1-6 Alkyl group, -(CH2) 1-3 -OH, -CHO, -(CO)NH2, -(CO)OR, and -NR-C 1-6 Alkyl group, where R is H or C 1-6 Alkyl group; preferably, R2 is selected from H, halogen, CHF2, CF3, CN, C. 1-6 Alkyl group and -(CO)NH2; more preferably, R2 is selected from halogen, CHF2, CF3, CN, C 1-6 Alkyl groups and -(CO)NH2;

[0115] In some implementations, when When R2 is selected from halogens, CH2F, CHF2, CF3, -OH, -NH2, CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl group, -(CH2) 1-6 -CN, -(CH2) 1-6 -OC 1-6 Alkyl and -NR-C 1-6 alkyl,

[0116] R is H or C 1-6 alkyl;

[0117] In some implementations, R1 is C 1-6 Alkyl or C 3-8 Cycloalkyl groups, wherein the alkyl group and the cycloalkyl group may optionally be converted by halogen, -CN, -OH, -NH2, C 2-6 alkynyl group, -OC 1-6 Alkyl, or -NR-C 1-6 Alkyl substitution, where R is H or C 1-6 Alkyl groups, preferably, the alkyl and cycloalkyl groups may optionally be substituted with halogens or -CN;

[0118] In some implementations, R1 is C 1-6 alkyl;

[0119] In some implementations, R1 is CD3;

[0120] In some embodiments of the present invention, the compounds of the present invention are selected from:

[0121]

[0122]

[0123]

[0124]

[0125] Or its pharmaceutically acceptable salts, solvates, polymorphs or isomers.

[0126] It should be noted that the compounds and salts described in this specification can exist in solvated and unsolvated forms; the atoms of these compounds and salts described in this specification can exist as their isotopes; and the compounds and salts described in this specification can exist in optically active or racemic forms with the aid of one or more asymmetric carbon atoms.

[0127] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof; in some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient; in some embodiments, the pharmaceutical composition of the present invention further comprises other drugs for treating cancer; in some embodiments, the other drugs for treating cancer are selected from chemotherapeutic drugs or PARP inhibitors.

[0128] On the other hand, the present invention provides a method for treating a DNA-PK-related disease, the method comprising administering to a subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a pharmaceutical composition thereof;

[0129] In another aspect, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts, solvates, polymorphs, or tautomers thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for treating diseases related to DNA-PK.

[0130] In some embodiments of the present invention, the DNA-PK-related disease is cancer; preferably, the cancer is colorectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, small cell lung cancer, or non-small cell lung cancer. Invention Details

[0132] Exemplary embodiments utilizing the principles of the invention are set forth in the following detailed description of the invention. The features and advantages of the invention can be better understood by referring to the following summary of the invention.

[0133] It should be understood that the scope of protection of each aspect of the present invention is determined by the claims, and the methods and structures within the scope of these claims, as well as their equivalents, are all within the scope of these claims.

[0134] Unless otherwise defined, all technical terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent applications, and publications cited in this document are incorporated herein in their entirety through reference.

[0135] It should be understood that the above summary and the following detailed description are exemplary and explanatory, and not intended to limit any subject matter of the invention. Unless otherwise specified, the singular form includes the plural form. Unless otherwise specified, the use of "or" or "or" means "and / or". Furthermore, the use of the term "comprising" and other forms such as "including," "containing," and "containing" are not limiting.

[0136] Some chemical terms

[0137] The terms “optional,” “optional,” or “optionally” mean that the event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally substituted alkyl” means “unsubstituted alkyl” or “substituted alkyl.” Furthermore, the optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or any level between monosubstituted and fully substituted (e.g., -CH2CHF2, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution mode that is spatially impossible and / or cannot be synthesized is introduced.

[0138] Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, nuclear magnetic resonance, high-performance liquid chromatography, infrared and ultraviolet / visible spectroscopy, and pharmacological methods, are employed. Unless specifically defined herein, the terminology, experimental procedures, and techniques used herein in analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and patient treatment. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of reagent kits, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein are generally carried out according to conventional methods well known in the art, based on descriptions in several summary and more specific documents cited and discussed herein. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0139] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0140] As used in this article, the terms "group" and "chemical group" refer to a specific part or functional group of a molecule. Chemical groups are often considered as chemical entities that are embedded in or attached to a molecule.

[0141] Some of the chemical groups named here can be represented by abbreviated notations to indicate the total number of carbon atoms. For example, C 1-6 An alkyl group describes an alkyl group that, as defined below, has a total of 1 to 6 carbon atoms. The abbreviated notation indicates the total number of carbon atoms, excluding carbon atoms on possible substituents.

[0142] The terms “halogen,” “halogenated,” or “halogenated” refer to bromine, chlorine, fluorine, or iodine.

[0143] The compounds of the present invention may contain one or more (e.g., one, two, three, or four) isotopic substitutions. For example, in said compounds, H may be any isotopic form, including 1 H, 2 H (D or deuterium) and 3 H (T or tritium); C can be any isotopic form, including 12 C 13 C and 14 C and O can be any isotopic form, including 16 O and 18 O etc.

[0144] As used herein, the terms "aromatic," "aromatic ring," "aromatic," "aromatic," and "aromatic ring" refer to a planar ring or ring portion of one or more rings having a delocalized electronic conjugated system containing 4n+2 electrons, where n is an integer. Aromatic rings can be formed from 5, 6, 7, 8, 9, or more atoms. Aromatic compounds can be optionally substituted and can be monocyclic or polycyclic with fused rings.

[0145] The term "heteroatom" or "heteroatom" as used herein, alone or as part of other components, refers to an atom other than carbon and hydrogen. Heteroatoms are independently selected from, but not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. In embodiments where 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.

[0146] The term “dense” or “dense ring” as used alone or in combination in this article refers to a ring structure in which two or more rings share one or more bonds.

[0147] The term “spiral” or “spiroring” as used alone or in combination in this article refers to a ring structure in which two or more rings share one or more atoms.

[0148] The term "alkyl" as used alone or in combination herein refers to a monovalent saturated hydrocarbon with optional substituted straight or optional substituted branched chains having 1-12 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, and connected to other parts of the molecule by single bonds, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, etc.

[0149] As used alone or in combination herein, the term "alkenyl" refers to a monovalent hydrocarbon group of optional substituted straight or optional substituted branched form, having one or more C=C double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The double bonds in these groups may be in cis or trans conformations and should be understood to include both isomers. Examples include, but are not limited to, vinyl (CH=CH2), 1-propenyl (CH2CH=CH2), isopropenyl (C(CH3)=CH2), butenyl, and 1,3-butadienyl. When alkenyl as defined herein appears in numerical ranges, for example, "C2-C6 alkenyl" or "C 2-6 "Alkenyl" refers to an alkenyl group that can be composed of 2, 3, 4, 5, or 6 carbon atoms. In this article, alkenyl also includes cases where no numerical range is specified.

[0150] The term "alkynyl" as used alone or in combination herein refers to an optionally substituted straight-chain or branched monovalent hydrocarbon group having one or more C≡C triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl. When alkynyl as defined herein is accompanied by a numerical range, such as "C2-C6 alkynyl" or "C 2-6 "Alynyl" refers to an alkynyl group that can be composed of 2, 3, 4, 5, or 6 carbon atoms. In this article, alkynyl also includes cases where no numerical range is specified.

[0151] The term "aryl" refers to a fully carbon monocyclic or fused ring having a fully conjugated π-electron system, having 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms. The aryl group can be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, sulfonyl, sulfinyl, phosphoryl, and heterocyclic groups. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthraceneyl.

[0152] The term “aryl” as used alone or in combination in this article refers to a divalent group derived from a monovalent aryl group as defined above.

[0153] The term "heteroaryl" refers to a monocyclic or fused ring with 5-12 ring atoms, having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, of which 1, 2, 3, or 4 are selected from N, O, and S, and the remaining ring atoms are C, and possessing a fully conjugated π-electron system. Heteroaryl groups can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl, and heterocyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, and triazineyl.

[0154] The term “hybrid aryl” as used alone or in combination in this article refers to a divalent group derived from a monovalent heteroaryl group as defined above.

[0155] The term “cycloalkyl” as used alone or in combination herein refers to an optionally substituted monovalent saturated hydrocarbon ring comprising 3 to about 15 cyclic carbon atoms or 3 to about 10 cyclic carbon atoms, and may also include other non-cyclic carbon atoms as substituents (e.g., methylcyclopropyl).

[0156] The term "carbon ring" refers to a structure consisting of a covalently closed ring of carbon, which can be saturated or partially unsaturated. A carbon ring can be formed by 3, 4, 5, 6, 7, 8, 9, or more atoms. The distinction between a carbon ring and a heterocycle lies in the fact that the ring skeleton of a heterocycle contains at least one atom different from carbon. The term "carbon ring" as used herein can refer to a monocyclic or polycyclic ring, including spirocyclic, fused, and bridged rings. Carbon rings can be arbitrarily substituted. Preferably, a "carbon ring" as used herein contains about 5 to about 20, 5 to 10, 5-8, or 5-6 cyclic atoms in its skeleton.

[0157] The terms "heterocyclic" and "heterocyclic alkyl" as used alone or in combination herein refer to aliphatic heterocycles, which may be saturated or partially unsaturated. When the number of carbon atoms in a heterocycle is indicated herein (e.g., C...),... 3-6 Heterocyclic rings, wherein at least one non-carbon atom (heteroatom) must be present. For example, "C 3-6 The nomenclature of "heterocycle" refers only to the number of carbon atoms in the ring, not the total number of atoms in the ring. For example, the nomenclature of "4-6 membered heterocycle" refers to the total number of atoms contained in the ring (i.e., a four-, five-, or six-membered ring, wherein at least one atom is a carbon atom, at least one atom is a heteroatom, and the remaining 2-4 atoms are either carbon atoms or heteroatoms). For heterocycles having two or more heteroatoms, the two or more heteroatoms may be the same or different from each other. The "heterocycle" in this document can be a monocyclic or polycyclic ring, and polycyclic heterocycles include spirocyclic, fused, and bridged rings. Heterocycles can be arbitrarily substituted. The "heterocycle" in this document preferably contains about 5 to about 20, 5 to 10, 5-8, or 5-6 skeletal ring atoms.

[0158] The term "polymorph" or "polymorphism" as used in this invention refers to the fact that the compounds of this invention have multiple crystal lattice forms. Some compounds of this invention may have more than one crystal form, and this invention covers all polymorphs or mixtures thereof.

[0159] Intermediate compounds and polymorphs of the compounds of this invention are also within the scope of this invention.

[0160] Unless otherwise specified, the olefin double bonds contained in the compounds of this invention include E and Z isomers.

[0161] It should be understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be R or S configurations. Some compounds of the present invention may also exhibit cis-trans isomerism, which will be apparent to those skilled in the art. It should be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers, as well as mixtures thereof, including racemic mixtures. These isomers can be isolated from mixtures thereof by implementing or modifying known methods, such as chromatography and recrystallization techniques, or they can be prepared separately from suitable isomers of their intermediates.

[0162] The term “pharmaceutically acceptable salt” as used in this article includes both salts with added acid salts and salts with added alkali salts.

[0163] "Pharmaceutically acceptable salts" refer to salts that retain the biological potency and properties of the free base of a compound, are not biologically or otherwise undesirable, and are formed with inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids, such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, decanoic acid, hexanoic acid, carbonic acid, cinnamic acid, citric acid, etc. "Pharmaceutically acceptable base salts" refer to salts that retain the biological potency and properties of the free acid of a compound, and are not biologically or otherwise undesirable. These salts are prepared by reacting a free acid with an inorganic or organic base. Salts formed by reacting with an inorganic base include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and manganese salts.

[0164] Organic bases that form salts include, but are not limited to, primary amines, secondary amines, tertiary amines, and cyclic amines, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purines, piperazine, piperidine, choline, and caffeine. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0165] Crystallization often produces solvates of the compounds of this invention. As used herein, the term "solvate" refers to a combination of one or more molecules of the compounds of this invention and one or more solvent molecules.

[0166] The solvent can be water, in which case the solvate is a hydrate. Alternatively, it can be an organic solvent. Therefore, the compounds of this invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, etc., and the corresponding solvated forms. The compounds of this invention can be true solvates, but in other cases, they may simply retain water or a mixture of water and some other solvents by chance. The compounds of this invention can react in a solvent or precipitate or crystallize in a solvent. The solvates of the compounds of this invention are also included within the scope of this invention.

[0167] As used herein, the term "pharmaceutical composition" refers to a formulation containing the compounds of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (such as humans). Such a medium includes all pharmaceutically acceptable carriers.

[0168] As used in this article, the term "acceptable" in relation to formulations, compositions, or ingredients means that it does not have a lasting harmful effect on the overall health of the treated subject.

[0169] As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., that the substance can be administered to an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0170] "Pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, auxiliaries, deodorants, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administrative departments for use in humans and domesticated animals.

[0171] As used herein, the terms “subject,” “patient,” “object,” or “individual” refer to an individual suffering from a disease, disorder, or symptom, including both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans; non-human primates (e.g., chimpanzees and other apes and monkeys); livestock such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0172] The term "treatment" as used in this article refers to the treatment of relevant diseases or conditions in mammals, particularly humans, including...

[0173] (i) To prevent mammals, especially those previously exposed to a disease or condition but not yet diagnosed with it, from developing the corresponding disease or condition.

[0174] (ii) To suppress a disease or symptom, that is, to control its development;

[0175] (iii) To alleviate the disease or symptom, that is, to make the disease or symptom subside;

[0176] (iv) Relieve symptoms caused by disease or illness.

[0177] The terms “disease” and “symptom” used in this article may be used interchangeably or have different meanings, because some specific diseases or symptoms do not yet have known causative factors (so the cause of the disease is still unclear), so they cannot be recognized as diseases but can only be regarded as unwanted conditions or syndromes. These syndromes have more or less some specific symptoms that have been confirmed by clinical researchers.

[0178] As used herein, the terms "effective amount," "therapeutic effective amount," or "pharmaceutical effective amount" refer to an amount of at least one drug or compound that, when taken, is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. The result may be a reduction and / or relief of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition containing the compounds disclosed herein that is clinically necessary to provide significant symptom relief. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation testing.

[0179] As used herein, the terms “administration,” “application,” “dosage,” etc., refer to methods that deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), local administration, and rectal administration. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0180] The anticancer treatment described herein may be useful as a monotherapy, or may include conventional surgery, radiotherapy, or chemotherapy in addition to the administration of a compound having formula (I); or a combination of such other therapies. Such conventional surgery, radiotherapy, or chemotherapy may be administered simultaneously, sequentially, or separately with a compound having formula (I) for treatment.

[0181] Preparation of the compounds of the present invention

[0182] The following reaction route illustrates a method for preparing the compounds of the present invention.

[0183] It should be understood that, in the following description, the combination of substituents and / or variables of the molecular formula is permitted only in the case of forming a stable compound.

[0184] Those skilled in the art will also understand that, in the processes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. These functional groups include hydroxyl, amino, mercapto, and carboxyl groups. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butylmethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable amino, amidine, and guanidine protecting groups include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable mercapto protecting groups include -C(O)-R" (R" represents alkyl, aryl, or arylalkyl), p-methoxybenzyl, triphenylmethyl, etc. Suitable carboxyl protecting groups include alkyl, aryl, or arylalkyl esters. Protecting groups can be added or removed using standard techniques known to those skilled in the art. Example

[0185] The following non-limiting embodiments are merely illustrative and do not limit the invention in any way.

[0186] Unless otherwise specified, temperatures are in Celsius. Reagents were purchased from commercial suppliers such as Sinopharm Chemical Reagents Beijing Co., Ltd., Alfa Aesar, or Beijing Bailingwei Technology Co., Ltd., and these reagents are ready for use without further purification, unless otherwise specified.

[0187] Unless otherwise specified, the following reactions are carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or argon, or using a drying tube; the reaction flask is fitted with a rubber diaphragm to allow for the addition of substrates and reagents via syringe; glassware is dried by drying and / or heating.

[0188] Unless otherwise specified, column chromatography purification used 200-300 mesh silica gel from Qingdao Ocean Chemical Plant; preparative thin-layer chromatography used thin-layer chromatography silica gel pre-plates (HSGF254) produced by Yantai Chemical Industry Research Institute; MS determination was performed using a ThermoLCQ Fleet (ESI) liquid chromatography-mass spectrometry system; optical rotation determination was performed using an SGW-3 automatic polarimeter from Shanghai Shenguang Instrument Co., Ltd.

[0189] NMR data ( 1 H NMR was performed using a Varian instrument at 400 MHz. Solvents used for NMR data included CDCl3, CD3OD, D2O, and DMSO-d6, with tetramethylsilane (0.00 ppm) or residual solvents as the reference (CDCl3: 7.26 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm). When indicating peak shape diversity, the following abbreviations are used to represent different peak shapes: s (singleton), d (doublet), t (triplet), q (quartet), m (multiplex), br (broad peak), dd (double doublet), dt (double triplet). If coupling constants are given, they are expressed in Hertz (Hz).

[0190] Abbreviations:

[0191]

[0192]

[0193] Intermediate 1: 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-nitrile

[0194]

[0195] Step 1: 4-((2-chloro-5-nitropyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-nitrile

[0196] 2,4-Dichloro-5-nitropyrimidine (1.94 g) and triethylamine (1.01 g) were dissolved in tetrahydrofuran (50 mL), and 4-aminotetrahydro-2H-pyran-4-onitrile (1.26 g) was slowly added under ice bath conditions. The reaction mixture was heated to room temperature and stirred overnight. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (200 mL), extracted with ethyl acetate (100 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 (V:V)) to give a white solid (1.9 g).

[0197] Step 2: 4-((5-amino-2-chloropyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-nitrile

[0198] At room temperature, 1.5 g of reduced iron powder was added to a 30 mL solution of 4-((2-chloro-5-nitropyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-onitrile (1.9 g) in acetic acid. The reaction mixture was then heated to 45 °C and stirred for 2 hours. After cooling, the reaction mixture was poured into ice water and extracted with 100 mL of ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to give a white solid (1.3 g).

[0199] Step 3: 4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile

[0200] The 4-((5-amino-2-chloropyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-onitrile (1.3 g) and CDI (1.3 g) from step 2 were dissolved in tetrahydrofuran (50 mL). The mixture was heated to 65 °C and stirred for 2 hours under nitrogen protection. After cooling, the reaction solution was poured into water (150 mL). The reaction solution was extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 (V:V)) to obtain a pale yellow solid (1 g).

[0201] Step 4: 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-nitrile

[0202] At 0°C, 200 mg of 60% (mineral oil) sodium hydride was slowly added to a 20 mL DMF solution of 1 g of 4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (DMF) obtained in step 3. After the addition was complete, the mixture was stirred at 0°C for 0.5 hours. Subsequently, 1.41 g of iodomethane was slowly added to the reaction solution. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride aqueous solution and stirred continuously until a yellow precipitate was formed. The precipitate was filtered and dried to obtain a yellow solid (900 mg).

[0203] Intermediate 2: 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one (synthesized according to the method described in patent CN110177791A1)

[0204]

[0205] Intermediate 3: 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione

[0206]

[0207] At room temperature, the intermediate 22-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (269 mg) was dissolved in xylene (30 mL), and phosphorus pentasulfide (300 mg) was added. The reaction mixture was then heated to reflux and stirred for 2 hours. After cooling to room temperature, the reaction mixture was evaporated to dryness, and the residue was purified by column chromatography (elution: petroleum ether: ethyl acetate = 2:1 (V:V)) to give a pale yellow solid (100 mg).

[0208] Intermediate 4: 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (synthesized according to the method described in patent CN110177791A1)

[0209]

[0210] Intermediate 5: 2-chloro-7-methyl-9-morpholino-7,9-dihydro-8H-purine-8-one

[0211]

[0212] Based on the synthetic route of intermediate 1, intermediate 5 was obtained by replacing 4-aminotetrahydro-2H-pyran-4-nitrile with morpholino-4-amine as the starting material through four steps.

[0213] Intermediates 6-11: The following intermediates 6-11 are all synthesized according to the method described in patent WO2019 / 238929A1.

[0214] Intermediate 6: 2-chloro-7-methyl-9-(piperidin-4-yl)-7,9-dihydro-8H-purine-8-one

[0215]

[0216] Intermediate 7: 2-chloro-9-(4-hydroxycyclohexyl)-7-methyl-7,9-dihydro-8H-purine-8-one

[0217]

[0218] Intermediate 8: 7-methylquinoline-6-amine

[0219]

[0220] Intermediate 9: 7-Methylmorpholine-6-amine

[0221]

[0222] Intermediate 10: 7-methylquinoxaloline-6-amine

[0223]

[0224] Intermediate 11: 2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one

[0225]

[0226] Intermediate 11 is obtained according to the method described in patent (US2012 / 172347A1).

[0227] Intermediate 12: 2-chloro-9-(4-(2-methoxyethyl)tetrahydro-2H-pyran-4-yl)-7-methyl-7,9-dihydro-8H-purin-8-one

[0228]

[0229] Step 1: Methyl 4-(2-methoxyethyl)tetrahydro-2H-pyran-4-carboxylate

[0230] Methyl tetrahydro-2H-pyran-4-carboxylic acid (1.44 g) was dissolved in tetrahydrofuran (30 mL). Under nitrogen protection, a 1M tetrahydrofuran solution (15 mL) of LHMDS was slowly added at 0 °C and maintained for 0.5 hours. Subsequently, 1-bromo-3-methoxypropane (1.44 g) was added, and the reaction mixture was slowly heated to room temperature and stirred overnight. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (200 mL) and extracted with ethyl acetate (100 mL). The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 (V:V)) to obtain a colorless oil (1.2 g).

[0231] Step 2: 4-(2-methoxyethyl)tetrahydro-2H-pyran-4-carboxylic acid

[0232] At room temperature, 10 mL of 1 M lithium hydroxide aqueous solution was added to a methanol (20 mL) solution of methyl 4-(2-methoxyethyl)tetrahydro-2H-pyran-4-carboxylate (1.2 g), and the reaction was stirred for 1 hour. 1 M dilute hydrochloric acid was slowly added to the reaction mixture to adjust the pH to 5, and then the solution was extracted with 100 mL of ethyl acetate. The extract was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a white solid (900 mg).

[0233] Step 3: 4-(2-methoxyethyl)tetrahydro-2H-pyran-4-amine

[0234] Dissolve 900 mg of 4-(2-methoxyethyl)tetrahydro-2H-pyran-4-carboxylic acid and DPPA (1.5 g) from step 2 in DMF (50 mL). Slowly add 1 mL of triethylamine at room temperature and stir for 1 hour. Add 0.5 mL of water to the system, then heat to 80 °C under nitrogen protection and stir for 2 hours. After cooling, pour the reaction solution into water (150 mL). Extract the reaction solution with ethyl acetate, wash the extract with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 (V:V)) to obtain a pale yellow solid (200 mg).

[0235] Steps 4, 5, 6, and 7, following the method described in Intermediate 1, replace 4-aminotetrahydro-2H-pyran-4-amine with 4-(2-methoxyethyl)tetrahydro-2H-pyran-4-amine to obtain Intermediate 12.

[0236] Intermediate 13: 1-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-4-oxocyclohexane-1-carbamate

[0237]

[0238] Step 1: 8-Amino-1,4-dioxazo[4.5]decane-8-carbamate

[0239] Tetraisopropyl titanate (5.68 g) was added to a saturated ethanol solution of ammonia (50 mL) under nitrogen protection, followed by the slow addition of 1,4-dioxazo[4.5]dec-8-one (1.56 g). The reaction mixture was stirred at room temperature for 2 hours, then cooled to -5°C and TMSCN (1.1 g) was added. The reaction mixture was maintained at this temperature for 3 hours, then left at room temperature overnight. The reaction was quenched with water (2 mL), the system was filtered, the filtrate was collected and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (V:V)) to obtain the target compound (0.91 g).

[0240] Step 2: 8-((2-chloro-5-nitropyrimidin-4-yl)amino)-1,4-dioxa[4.5]decane-8-carbamate

[0241] 2,4-Dichloro-5-nitropyrimidine (0.97 g) and triethylamine (1.01 g) were dissolved in tetrahydrofuran (50 mL), and 8-amino-1,4-dioxazo[4.5]decane-8-carbamate (0.91 g) was slowly added under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (200 mL), extracted with ethyl acetate (100 mL), dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1 (V:V)) to give a yellow solid (1.5 g).

[0242] Step 3: 8-((5-amino-2-chloropyrimidin-4-yl)amino)-1,4-dioxaspiro[4.5]decane-8-carbamate

[0243] At room temperature, 1.8 g of reduced iron powder was added to a 50 mL acetic acid solution of 1.5 g of 8-((2-chloro-5-nitropyrimidin-4-yl)amino)-1,4-dioxa[4.5]decane-8-carbamate. The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through diatomaceous earth and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 10:1 (V:V)) to obtain a white solid (1.2 g).

[0244] Step 4: 8-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)-1,4-dioxa[4.5]decane-8-carbonitrile 8-((5-amino-2-chloropyrimidin-4-yl)amino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.2 g) and CDI (1.4 g) from Step 3 were dissolved in tetrahydrofuran (30 mL). The mixture was heated to 65 °C and stirred for 2 hours under nitrogen protection. After cooling to room temperature, the reaction solution was poured into water (100 mL). The reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (V:V)) to obtain a white solid (1.1 g).

[0245] Step 5: 8-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-1,4-dioxa[4.5]decane-8-carbamate

[0246] At 0°C, 210 mg of 60% (mineral oil) sodium hydride was slowly added to a 20 mL DMF solution of 1.1 g of 8-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)-1,4-dioxa[4.5]decane-8-carbamate obtained in step 4. After the addition was complete, the mixture was stirred at 0°C for 10 minutes. Subsequently, 1.0 g of iodomethane was slowly added to the reaction solution. After 1 hour, the reaction solution was poured into a saturated ammonium chloride aqueous solution and stirred continuously. A white precipitate was formed. The precipitate was filtered and dried to obtain the target compound (950 mg).

[0247] Step 6: 1-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-4-oxocyclohexane-1-carbamate

[0248] At 0°C, 4M hydrochloric acid (10 mL) was slowly added to a dioxane (20 mL) solution of 950 mg of 9-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-1,4-dioxa[4.5]decane-8-carbamate. After the addition was complete, the mixture was stirred for 10 hours. The reaction solution was then diluted with 100 mL of sodium bicarbonate aqueous solution and stirred continuously. A white precipitate was formed. The solid was filtered and dried to obtain the target compound (600 mg).

[0249] Intermediate 14: 2-chloro-9-((1r,4r)-4-hydroxycyclohexyl)-7-methyl-7,9-dihydro-8H-purine-8-one (synthesized according to the method described in patent WO2019 / 238929A1)

[0250]

[0251] Intermediate 15: 2-chloro-9-((1s,4s)-4-hydroxycyclohexyl)-7-methyl-7,9-dihydro-8H-purine-8-one (synthesized according to the method described in patent WO2019 / 238929A1)

[0252]

[0253] Intermediate 16: 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidine-4-carbamate

[0254]

[0255] Step 1: 4-((2-chloro-5-nitropyrimidin-4-yl)amino)-4-cyanopiperidin-1-carboxylic acid tert-butyl ester

[0256] 2,4-Dichloro-5-nitropyrimidine (0.97 g) and triethylamine (1.01 g) were dissolved in tetrahydrofuran (50 mL), and 4-amino-4-cyanopiperidin-1-carboxylic acid tert-butyl ester (1.13 g) was slowly added under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (200 mL), extracted with ethyl acetate (100 mL), and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1 (V:V)) to give a yellow solid (1.7 g).

[0257] Step 2: 4-((5-amino-2-chloropyrimidin-4-yl)amino)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester

[0258] At room temperature, 1.9 g of reduced iron powder was added to a 50 mL solution of 1.7 g of 4-((2-chloro-5-nitropyrimidin-4-yl)amino)-4-cyanopiperidin-1-carboxylic acid tert-butyl ester (tert-butyl ester). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through diatomaceous earth and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution: dichloromethane:methanol = 10:1 (V:V)) to give a white solid (1.3 g).

[0259] Step 3: 4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester. The 4-((5-amino-2-chloropyrimidin-4-yl)amino)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester (1.3 g) and CDI (1.5 g) from Step 2 were dissolved in tetrahydrofuran (50 mL). The mixture was heated to 65 °C and stirred for 2 hours under nitrogen protection. After cooling to room temperature, the reaction solution was poured into water (100 mL). The reaction solution was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (V:V)) to obtain a white solid (1.2 g).

[0260] Step 4: 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-4-cyanopiperidin-1-carboxylic acid tert-butyl ester

[0261] At 0°C, 200 mg of 60% (mineral oil) sodium hydride was slowly added to a 20 mL DMF solution of 1.2 g of 4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)-4-cyanopiperidin-1-carboxylic acid tert-butyl ester (DMF) obtained in step 3. After the addition was complete, the mixture was stirred at 0°C for 10 minutes. Subsequently, 1.0 g of iodomethane was slowly added to the reaction solution. After 1 hour, the reaction solution was poured into a saturated ammonium chloride aqueous solution and stirred continuously. A white precipitate was formed. The precipitate was filtered and dried to obtain the target compound (990 mg).

[0262] Step 5: 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidine-4-carbamate

[0263] At 0°C, 4M hydrochloric acid (20 mL) was slowly added to a dioxane (20 mL) solution of 990 mg of tert-butyl 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-4-cyanopiperidin-1-carboxylic acid. After the addition was complete, the mixture was stirred for 10 hours. The reaction solution was then neutralized to pH 8 with a saturated sodium bicarbonate aqueous solution, resulting in a white precipitate. The solid was filtered and dried to obtain the target compound (500 mg).

[0264] Intermediate 17: 9-((1r,4r)-4-aminocyclohexyl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one

[0265]

[0266] Intermediate 17 was synthesized using the same method as intermediate 16.

[0267] Intermediate 18: 9-((1s,4s)-4-aminocyclohexyl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one

[0268]

[0269] Intermediate 18 was synthesized using the same method as intermediate 16.

[0270] Intermediate 18-1: 2-chloro-7-methyl-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purine-8-one

[0271]

[0272] Intermediate 18-1 was synthesized using the same method as intermediate 16.

[0273] Intermediate 19: 2-chloro-7-methyl-9-(6-oxopyridin[3.3]heptane-2-yl)-7,9-dihydro-8H-purine-8-one

[0274]

[0275] Intermediate 19 was synthesized using the same method as intermediate 1.

[0276] Intermediate 20: 2-chloro-7-methyl-9-(3-oxocyclobutyl)-7,9-dihydro-8H-purine-8-one

[0277]

[0278] Intermediate 20 was synthesized using the same method as intermediate 1.

[0279] Intermediate 21: 2'-chloro-5'-methylspirocyclic [piperidine-4,7'-pyrrolo[3,2-d]pyrimidine]-6'(5'H)-one trifluoroacetate

[0280]

[0281] Step 1: Under nitrogen protection, 2,4-dichloro-5-nitropyrimidin-4-yl)piperidine-1,4-dicarboxylate was dissolved in tetrahydrofuran (20 mL), and LHMDS (2 mL 1M THF solution) was slowly added in an ice bath. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction was then quenched with acetic acid (0.5 mL). The reaction mixture was concentrated under reduced pressure, and the residue (350 mg) was used directly in the next step without purification.

[0282] Step 2: 2'-Chloro-6'-O-5',6'-Dihydrospirocyclic [piperidine-4,7'-pyrrolo[3,2-d]pyrimidine]-1-carboxylic acid tert-butyl ester

[0283] At room temperature, 0.5 g of reduced iron powder was slowly added to a 20 mL acetic acid solution of 350 mg of 1-(tert-butyl)-4-methyl-4-(2-chloro-5-nitropyrimidin-4-yl)piperidine-1,4-dicarboxylate in step one. The reaction was then stirred at 40 °C for 12 hours. The reaction solution was filtered through diatomaceous earth and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution: dichloromethane:methanol = 20:1 (V:V)) to obtain a white solid (130 mg).

[0284] Step 3: 2'-Chloro-5'-methyl-6'-oxo-5',6'-dihydrospirocyclic [piperidine-4,7'-pyrrolo[3,2-d]pyrimidine]-1-carboxylic acid tert-butyl ester

[0285] At 0°C, 60% (mineral oil) sodium hydride (30 mg) was slowly added to a DMF (5 mL) solution of 130 mg of 2'-chloro-6'-oxy-5',6'-dihydrospirocyclic [piperidine-4,7'-pyrrolo[3,2-d]pyrimidine]-1-carboxylic acid tert-butyl ester (DMF). After the addition was complete, the mixture was stirred at 0°C for 10 minutes. Subsequently, 100 mg of iodomethane was slowly added to the reaction solution. After 1 hour, the reaction solution was poured into a saturated ammonium chloride aqueous solution (30 mL) and stirred continuously. A white precipitate was formed. The precipitate was filtered and dried to obtain the target compound (110 mg).

[0286] Step 4: 2'-Chloro-5'-methylspirocyclic [piperidine-4,7'-pyrrolo[3,2-d]pyrimidine]-6'(5'H)-ketone trifluoroacetate

[0287] At room temperature, 110 mg of 2'-chloro-5'-methyl-6'-oxo-5',6'-dihydrospirocyclic [piperidine-4,7'-pyrrolo[3,2-d]pyrimidine]-1-carboxylic acid tert-butyl ester was dissolved in 10 mL of dichloromethane. Trifluoroacetic acid (3 mL) was then slowly added to the reaction solution. After 1 hour, the reaction solution was concentrated under reduced pressure to obtain the target compound (100 mg).

[0288] Intermediate 22: 2-chloro-7-(methyl-d3)-9-(4-oxocyclohexyl)-7,9-dihydro-8H-purine-8-one

[0289]

[0290] At 0°C, 60% (mineral oil) sodium hydride (600 mg) was slowly added to a DMF (100 mL) solution of 2-chloro-9-(4-oxocyclohexyl)-7,9-dihydro-8H-purin-8-one (2.67 g). After the addition was complete, the mixture was stirred at 0°C for 0.5 hours. Subsequently, iodomethane (1.41 g) was slowly added to the reaction solution. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride aqueous solution and stirred continuously until a white precipitate was formed. The precipitate was filtered and dried to obtain a white solid (2.5 g).

[0291] Intermediate 23: 2-((7-methyl-6-nitroquinoline-4-yl)oxy)ethane-1-amine trifluoroacetate

[0292]

[0293] Step 1: tert-butyl(2-((7-methyl-6-nitroquinoline-4-yl)oxy)ethyl)carbamate

[0294] At 0°C, DIAD (306 mg) was slowly added dropwise to a THF solution of 7-methyl-6-nitroquinoline-4-ol (204 mg), tert-butyl (2-hydroxyethyl) carbamate (320 mg), and triphenylphosphine (526 mg) in 30 mL. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 12 hours. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to give a pale yellow solid (300 mg).

[0295] Step 2: 2-((7-methyl-6-nitroquinoline-4-yl)oxy)ethane-1-amine trifluoroacetate

[0296] At 0°C, tert-butyl(2-((7-methyl-6-nitroquinoline-4-yl)oxy)ethyl)carbamate (300 mg) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was slowly added. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue (250 mg) was used directly in the next reaction without purification.

[0297] Intermediate 24: 2-Chloro-7-ethyl-9-(4-oxocyclohexyl)-7,9-dihydro-8H-purine-8-one

[0298]

[0299] At 0°C, 60% sodium hydride (600 mg, mineral oil) was slowly added to a DMF (100 mL) solution of 2-chloro-9-(4-oxocyclohexyl)-7,9-dihydro-8H-purine-8-one (2.67 g). After the addition was complete, the mixture was stirred at 0°C for 0.5 hours. Subsequently, 1.58 g of iodoethane was slowly added to the reaction solution. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride aqueous solution and stirred continuously until a white precipitate was formed. The precipitate was filtered and dried to obtain a white solid (2.3 g).

[0300] Example 1: 4-(7-methyl-2-(((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino))-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-nitrile

[0301]

[0302] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 47-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (30 mg), RuPhosPd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL). The reaction flask was purged with nitrogen three times and heated to 100 °C with stirring for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (35 mg).

[0303] 1 H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.77(s,1H),8.35(s,1H),8.18(s,1H),7.68(s,1H),3.87- 3.93(m,2H),3.52-3.69(m,2H),3.28(s,3H),2.68-2.76(m,2H),2.57-2.64(m,2H),2.35(s,3H).

[0304] Example 2: 7-Methyl-2-(((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro)-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione

[0305]

[0306] Under nitrogen protection, intermediates 32-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione (57 mg), 47-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (30 mg), RuPhos PdG3 (18 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) and heated to 100 °C with stirring for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (15 mg).

[0307] 1 H NMR(400MHz,DMSO-d6)δ9.03(s,1H),9.01(s,1H),8.42(s,1H),8.36(s,1H),7.70(s,1H),5.05-5.15(m,1H)3.92( dd,J=11.6Hz,4.0Hz,2H),3.64(s,3H),3.38(t,J=11.6Hz,2H),2.56-2.67(m,2H),2.35(s,3H),1.61-1.68(m,2H).

[0308] Example 3: 7-Methyl-2-(((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-morpholino-7,9-dihydro-8H-purine-8-one

[0309]

[0310] Under nitrogen protection, intermediates 52-chloro-7-methyl-9-morpholino-7,9-dihydro-8H-purine-8-one (54 mg), 47-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), and the mixture was heated to 100 °C and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (33 mg).

[0311] 1 H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.82(s,1H),8.34(s,1H),8.05(s,1H), 7.67(s,1H),3.66-3.72(m,4H),3.32-3.38(m,4H),3.25(s,3H),2.36(s,3H).

[0312] Example 4: 4-(7-methyl-2-((7-methylquinoline-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-nitrile

[0313]

[0314] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 87-methylquinoline-6-amine (32 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), and the mixture was heated to 100 °C and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (43 mg).

[0315] 1 H NMR (400MHz, DMSO-d6) δ8.68-8.72(m,2H),8.26(s,1H),8.25(s,1H),8.15(d,J=8.0Hz,1H),7.81(s,1H),7.39(dd,J=7.6H z, 4.4Hz, 1H), 3.85-3.92 (m, 2H), 3.57 (t, J = 11.6Hz, 2H), 3.29 (s, 3H), 2.71-2.80 (m, 2H), 2.59-2.66 (m, 2H), 2.47 (s, 3H).

[0316] Example 5: 4-(7-methyl-2-((7-methyl-cenline-6-yl)amino)-8-oxo7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-nitrile

[0317]

[0318] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 97-methylcenolin-6-amine (32 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) and heated to 100 °C with stirring for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (23 mg).

[0319] 1 H NMR (400MHz, DMSO-d6) δ9.12(d,J=5.6Hz,1H),8.85(s,1H),8.48(s,1H),8.35(s,1H),8.22(s,1H),7.91(d,J=6.0H z,1H),3.92-3.99(m,2H),3.61(t,J=11.2Hz,2H),3.33(s,3H),2.76-2.83(m,2H),2.62-2.68(m,2H),2.59(s,3H).

[0320] Example 6: 4-(7-methyl-2-((7-methylquinoxalo-6-yl)amino)-8-oxo7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carboxynitrile

[0321]

[0322] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 107-methylquinoxalin-6-amine (32 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), and the mixture was heated to 100 °C and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (27 mg).

[0323] 1 H NMR (400MHz, DMSO-d6) δ8.78(s,1H),8.77(d,J=2.0Hz,1H),8.71(d,J=2.0Hz,1H),8.48(s,1H),8.30(s,1 H),7.87(s,1H),3.92-3.98(m,2H),3.61(t,J=11.2Hz,2H),3.32(s,3H),2.67-2.84(m,4H),2.53(s,3H).

[0324] Example 7: 4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocyclooctane-2 8 -ketone

[0325]

[0326] Step 1: 1-(3-bromopropoxy)-2-chloro-4-methyl-5-nitrobenzene

[0327] At 0°C, DIAD (2.2 g) was slowly added dropwise to a toluene (20 mL) solution of 2-chloro-4-methyl-5-nitrophenol (1.87 g), 3-bromo-1-propanol (1.39 g), and triphenylphosphine (3.96 g). After the addition was complete, the mixture was brought to room temperature and stirred for 12 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 30:1 (V:V)) to obtain a white oily substance (2.1 g).

[0328] Step 2: 2-Chloro-9-(1-(3-(2-chloro-4-methyl-5-nitrophenoxy)propyl)piperidin-4-yl)-7-methyl-7,9-dihydro-8H-purine-8-one

[0329] Under nitrogen protection, 1-(3-bromopropoxy)-2-chloro-4-methyl-5-nitrobenzene (307 mg), intermediate 6 (300 mg), and potassium carbonate (276 mg) were dissolved in DMF (20 mL), heated to 100 °C, and stirred for 2 hours. The reaction solution was cooled to room temperature and poured into ice water, where a solid was produced. The solid was filtered and dried to obtain a pale yellow solid (300 mg).

[0330] Step 3: 9-(1-(3-(5-amino-2-chloro-4-methylphenoxy)propyl)piperidin-4-yl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one

[0331] At room temperature, 0.5 g of reduced iron powder was added to a 15 mL acetic acid solution of 300 mg of 2-chloro-9-(1-(3-(2-chloro-4-methyl-5-nitrophenoxy)propyl)piperidin-4-yl)-7-methyl-7,9-dihydro-8H-purine-8-one. The mixture was then heated to 45 °C and stirred for 2 hours. After cooling, the reaction solution was poured into 50 mL of water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (200 mg).

[0332] Step 4: 4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7H-5-oxa-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocyclooctane-2 8 -ketone

[0333] Under nitrogen protection, 9-(1-(3-(5-amino-2-chloro-4-methylphenoxy)propyl)piperidin-4-yl)-2-chloro-7-methyl-7,9-dihydro-8H-purin-8-one (47 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (65 mg) were dissolved in dioxane (10 mL), heated to 100 °C, and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to give the target compound (13 mg).

[0334] 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.17(s,1H),7.97(s,1H),7.15(s,1H),4.24-4.32(m,1H),4.06(t,J=5.2Hz,2 H), 3.30 (s, 3H), 2.70-2.88 (m, 4H), 2.60 (t, J = 6.4Hz, 2H), 2.18-2.29 (m, 5H), 1.77-1.85 (m, 2H), 1.55-1.60 (m, 2H).

[0335] Example 8: 2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocyclooctane-2 8 -ketone

[0336]

[0337] The compound was synthesized using the synthesis method of Example 7, which used alternative phenols as starting materials.

[0338] 1H NMR(400MHz, DMSO-d6)δ8.43(s,1H),8.14(s,1H),7.34-7.50(br,1H),7.09(d,J=8.0Hz,1H),6.70-6.77(m,1H),4.38-4 .51(m,1H),4.16-4.24(m,2H),2.98-3.45(m,7H),2.57-2.71(m,2H),2.17(s,3H),1.82-1.99(m,4H),1.64-1.76(m,2H).

[0339] Example 9: 2 7 4 6 -dimethyl-2 8 -Oxyto-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocyclooctane-4 4 -Nitrile

[0340]

[0341] The compound was synthesized using an alternative phenol as a starting material according to the synthesis method of Example 7.

[0342] 1 H NMR(400MHz,DMSO-d6)δ8.56(s 1H),8.28(s,1H),8.24(s,1H),7.42(s,1H),4.26-4.35(m,1H),4.19(t,J=5.2Hz,2H),3.32(s,3H),2.69 -2.88(m,4H),2.56-2.62(m,2H),2.26(s,3H),2.15-2.24(m,2H),1.82-1.90(m,2H),1.60-1.67(m,2H).

[0343] Example 10: Methyl 4-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)piperidine-1-carboxylate

[0344]

[0345] At room temperature, intermediates 62-chloro-7-methyl-9-(piperidin-4-yl)-7,9-dihydro-8H-purin-8-one (268 mg) and methyl chloroformate (95 mg) were dissolved in dichloromethane (20 mL), and triethylamine (200 mg) was slowly added while stirring for 2 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (V:V)) to give methyl 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidin-1-carboxylate (100 mg).

[0346] Under nitrogen protection, the above-mentioned methyl 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidine-1-carboxylate (66 mg), intermediate 47-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (33 mg).

[0347] 1 HNMR(400MHz,DMSO-d6)δ9.03(s,1H),8.66(s,1H),8.34(s,1H),8.04(s,1H),7.65(s,1H),4.28-4.39(m,1 H),3.99-4.15(m,2H),3.56(s,3H),3.26(s,3H),2.76-2.96(m,2H),2.22-2.35(m,5H),1.68-1.74(m,2H).

[0348] Example 11: 2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocyclodecane-2 8 -ketone

[0349]

[0350] The compound was synthesized using the synthetic method of Example 7, with alternative phenols and suitable bromo fatty alcohols as starting materials.

[0351] 1 H NMR(400MHz, DMSO-d6)δ8.15(s,1H),7.87(s,1H),7.84(s,1H),6.99(d,J=8.0Hz,1H),6.41-6.46(m,1H),4.05-4.16(m,1H),3.93-3.98(m,2H),3 .29(s,3H),2.83-2.92(m,2H),2.50-2.64(m,2H),2.28-2.35(m,2H),2. 19(s,3H),1.96(t,J=11.6Hz,2H),1.52-1.70(m,6H),1.38-1.48(m,2H).

[0352] Example 12: 4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocycloheptane-2 8 -ketone

[0353]

[0354] The compound was synthesized using alternative phenols and bromo fatty alcohols as starting materials according to the synthesis method of Example 7.

[0355] 1 H NMR(400MHz,DMSO-d6)δ8.24(s,1H),8.18(s,1H),8.13(s,1H),7.16(s,1H),4.31-4.40(m,1H),4.2 3-4.30(m,2H),3.29(s,3H),2.99-3.04(m,2H),2.64-2.86(m,6H),2.22(s,3H),1.38-1.45(m,2H).

[0356] Example 13: 4-(7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-nitrile

[0357]

[0358] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 6-methylbenzo[c][1,2,5]thiadiazol-5-amine (32 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (13 mg).

[0359] 1 H NMR(400MHz,DMSO)δ8.67(s,1H),8.45(s,1H),8.31(s,1H),7.87(s,1H),3.92-3.99(m,2H ), 3.61 (t, J = 11.2Hz, 2H), 3.32 (s, 3H), 2.76-2.83 (m, 2H), 2.66-2.72 (m, 2H), 2.50 (s, 3H).

[0360] Example 14: 4-(2-((1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-nitrile

[0361]

[0362] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 5-amino-1,4-dimethylpyridin-2(1H)-one (28 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (35 mg).

[0363] 1H NMR (400MHz, DMSO) δ8.32(s,1H),8.07(s,1H),7.61(s,1H),6.24(s,1H),3.86-3.93(m,2H),3.57(t ,J=10.8Hz,2H),3.34(s,3H),3.25(s,3H),2.69-2.76(m,2H),2.55(d,J=12.8Hz,2H),1.98(s,3H).

[0364] Example 15: 2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5,9-dioxo-3-aza-2(9,2)-purine-4(1,3)-benzal-1(1,4)-cyclohexane-2 8 -ketone

[0365]

[0366] The compound was synthesized using the synthesis method of Example 7, which employed alternative phenols, suitable bromo fatty alcohols, and intermediate 7 as starting materials.

[0367] 1 H NMR (400MHz, DMSO) δ8.13(s,1H),7.93(s,1H),7.81(d,J=2.0Hz,1H),6.99(d,J=8.0Hz,1H),6.49(dd,J=8.0Hz,2.0Hz,1H),4.07-4. 17(m,3H),3.46-3.54(m,3H),3.29(s,3H),2.41-2.54(m,2H),2.19(s,3H),1.93-2.04(m,2H),1.81-1.90(m,2H),1.41-1.56(m,4H).

[0368] Example 16: 1 7 ,3 6 -Dimethyl-1 8 ,1 9 -dihydro-1 7 H-4-oxa-2-aza-1(2,9)-purine-3(1,3)-benzocyclodecane-1 8 -ketone

[0369]

[0370] Step 1: 4-((6-bromohexyl)oxy)-1-methyl-2-nitrobenzene

[0371] At 0°C, DIAD (2.2 g) was slowly added dropwise to a toluene (20 mL) solution of 4-methyl-3-nitrophenol (1.53 g), 6-bromohexanol (2.0 g), and triphenylphosphine (3.96 g). After the addition was complete, the mixture was brought to room temperature and stirred for 12 hours. The solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 30:1 (V:V)) to obtain a pale yellow oil (2.0 g).

[0372] Step 2: 2-Chloro-7-methyl-9-(6-(4-methyl-3-nitrophenoxy)hexyl)-7,9-dihydro-8H-purine-8-one

[0373] The above-mentioned 4-((6-bromohexyl)oxy)-1-methyl-2-nitrobenzene (300 mg), intermediate 112-chloro-7-methyl-7,9-dihydro-8H-purine-8-one (184 mg), and potassium carbonate (276 mg) were dissolved in DMF (10 mL), heated to 100 °C and stirred for 3 hours. After cooling to room temperature, the reaction solution was poured into ice water, and a solid was produced. The solid was filtered and dried, and used directly in the next step without purification (350 mg).

[0374] Step 3: 9-(6-(3-amino-4-methylphenoxy)hexyl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one

[0375] At room temperature, 0.5 g of reduced iron powder was added to a 15 mL acetic acid solution of 350 mg of 2-chloro-7-methyl-9-(6-(4-methyl-3-nitrophenoxy)hexyl)-7,9-dihydro-8H-purine-8-one (350 mg), and the mixture was then heated to 45 °C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was poured into 50 mL of water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to give a pale yellow solid (220 mg).

[0376] Step 4: 1 7 ,3 6 -Dimethyl-1 8 ,1 9 -dihydro-1 7 H-4-oxa-2-aza-1(2,9)-purine-3(1,3)-benzocyclodecane-1 8 -ketone

[0377] Under nitrogen protection, the above-mentioned 9-(6-(3-amino-4-methylphenoxy)hexyl)-2-chloro-7-methyl-7,9-dihydro-8H-purin-8-one (39 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (65 mg) were dissolved in dioxane (10 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 30:1 (V:V)) to obtain the target compound (15 mg).

[0378] 1 H NMR (400MHz, DMSO) δ8.13(s,1H),7.97(d,J=2.4Hz,1H),7.94(s,1H),6.97(d,J=8.4Hz,1H),6.39(dd,J=8.4Hz,2 .4Hz,1H),4.03-4.07(m,2H),3.68-3.73(m,2H),3.29(s,3H),2.20(s,3H),1.71-1.82(m,4H),1.37-1.52(m,4H).

[0379] Example 17: 4 4 -Fluorine-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocyclooctane-2 8 -ketone

[0380]

[0381] The compound was synthesized using an alternative phenol as a starting material according to the synthesis method of Example 7.

[0382] 1 H NMR (400MHz, DMSO-d6) δ8.08-8.15(m,3H),6.99(d,J=12.0Hz,1H),4.20-4.31(m,1H),4.12(t,J=4.8Hz,2H),3.29( s,3H),2.85-2.92(m,2H),2.58-2.78(m,4H),2.28-2.39(m,2H),2.21(s,3H),1.96-1.82(m,2H),1.47-1.54(m,2H).

[0383] Example 18: 7-Methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[0384]

[0385] Under nitrogen protection, intermediate 2: 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (54 mg), 6-methylbenzo[c][1,2,5]thiadiazole-5-amine (32 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (33 mg).

[0386] 1 H NMR(400MHz,DMSO)δ8.56(s,1H),8.50(s,1H),8.21(s,1H),7.86(s,1H),4.38-4.49(m,1H), 3.92-3.98(m,2H),3.40(t,J=11.2Hz,2H),3.31(s,3),2.48-2.58(m,5H),1.64-1.71(m,2H).

[0387] Example 19: 7-Methyl-2-((5-methyl-[1,2,5]thiadiazol[3,4-b]pyridin-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[0388]

[0389] Under nitrogen protection, intermediate 2: 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (54 mg), 5-methyl-[1,2,5]thiadiazole[3,4-b]pyridine-6-amine (33 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (28 mg).

[0390] 1H NMR (400MHz, DMSO) δ8.88(s,1H),8.82(s,1H),8.22(s,1H),4.39-4.50(m,1H),3.93-3.97(m, 2H), 3.40 (t, J = 11.6Hz, 2H), 3.32 (s, 3H), 2.79 (s, 3H), 2.47-2.57 (m, 2H), 1.65-1.72 (m, 2H).

[0391] Example 20: 4-(7-methyl-2-((5-methyl-[1,2,5]thiadiazol[3,4-b]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-nitrile

[0392]

[0393] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 5-methyl-[1,2,5]thiadiazole[3,4-b]pyridine-6-amine (33 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (19 mg).

[0394] 1 H NMR(400MHz,DMSO)δ9.02(s,1H),8.73(s,1H),8.33(s,1H),3.92-3.99(m, 2H), 3.57-3.64(m,2H),3.32(s,3H),2.74-2.82(m,5H),2.65-2.71(m,2H).

[0395] Example 21: 7-Methyl-2-((6-methylpyridin[2,3-b]pyrazin-7-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[0396]

[0397] Under nitrogen protection, intermediate 2: 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (54 mg), 6-methylpyridin[2,3-b]pyrazin-7-amine (32 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (22 mg).

[0398] 1 H NMR(400MHz,DMSO)δ8.96(s,1H),8.90(s,1H),8.86(s,2H),8.22(s,1H),4.40-4.50(m,1H),3.91-3 .98(m,2H),3.39(t,J=12.0Hz,2H),3.32(s,3H),2.80(s,3H),2.47-2.58(m,2H),1.64-1.71(m,2H).

[0399] Example 22: 4-(7-methyl-2-((6-methylpyridin[2,3-b]pyrazin-7-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-nitrile

[0400]

[0401] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 6-methylpyridin [2,3-b]pyrazine-7-amine (32 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (21 mg).

[0402] 1 H NMR (400MHz, DMSO) δ9.09(s,1H),8.88(s,2H),8.82(s,1H),8.34(s,1H),3.92-3.99(m,2H),3.58-3.64(m,2H),3.33(s,3H),2.67-2.82(m,7H).

[0403] Example 23: 7-Methyl-2-((7-methylimidazol[1,2-b]pyridazin-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[0404]

[0405] Under nitrogen protection, intermediate 2: 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (54 mg), 7-methylimidazolium[1,2-b]pyridazine-6-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (18 mg).

[0406] 1 H NMR (400MHz, DMSO) δ9.33(s,1H),8.07(s,1H),7.97(s,1H),7.89(s,1H),7.59(d,J=1.2Hz,1H),4.30-4.41(m ,1H),3.88-3.93(m,2H),3.31-3.35(m,2H),3.28(s,3H),2.23(s,3H),1.58-1.65(m,2H),1.20-1.27(m,2H).

[0407] Example 24: 4-(7-methyl-2-((8-methyl-4-oxo-4H-pyridin[1,2-a]pyrimidin-7-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-nitrile

[0408] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 7-amino-8-methyl-4H-pyridin[1,2-a]pyrimidin-4-one (35 mg), RuPhos PdG3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (32 mg).

[0409] 1H NMR (400MHz, DMSO) δ9.36 (s, 1H), 8.89 (s, 1H), 8.28 (s, 1H), 8.19 (d, J = 6.0Hz, 1H), 7.62 (s, 1H), 6.25 (d,J=6.0Hz,1H),3.91-3.97(m,2H),3.54-3.61(m,2H),3.31(s,3H),2.66-2.72(m,4H),2.47(s,3H).

[0410] Example 25: 9-(4-(2-methoxyethyl)tetrahydro-2H-pyran-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one

[0411]

[0412] Under nitrogen protection, intermediates 122-chloro-9-(4-(2-methoxyethyl)tetrahydro-2H-pyran-4-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (65 mg), 47-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL). The reaction flask was purged with nitrogen three times and heated to 100 °C with stirring for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (45 mg).

[0413] 1 H NMR(400MHz,DMSO-d6)δ8.95(s,1H),8.55(s,1H),8.34(s,1H),8.08(s,1H),7.68(s,1H),3.54-3.62(m,2 H),3.34-3.41(m,2H),3.16-3.25(m,7H),2.87(s,3H),2.32(s,3H),1.98-2.03(m,2H),1.58-1.66(m,2H).

[0414] Example 26: 4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocycloheptane-28 7-Diketone

[0415]

[0416] The compound was synthesized using the synthesis method of Example 7, with alternative phenols and bromoacetyl chloride as starting materials.

[0417] 1 H NMR (400MHz, DMSO-d6) δ8.21(s,1H),7.88(s,1H),7.82(s,1H),7.17(s,1H),5.02-5.12(m,2H),4.60-4.71(m,1H),4.16-4.23(m ,1H),3.72-3.80(m,1H),3.29(s,3H),2.72-2.90(m,2H),2.27-2.42(m,2H),2.23(s,3H),1.78-1.86(m,1H),1.57-1.65(m,1H).

[0418] Example 27: 4 4 -Chloride-2 7 -Methyl-2 8 ,2 9 -dihydro-2 7 H-5-O-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocycloheptane-2 8 -ketone

[0419]

[0420] The compound was synthesized using the synthetic method of Example 7, with alternative phenols and bromoethanol as starting materials.

[0421] 1 H NMR (400MHz, DMSO-d6) δ8.55(d,J=2.8Hz,1H),7.89(s,1H),7.20(d,J=8.8Hz,1H),7.11(s,1H),6.43(dd,J=8.8Hz,2.8Hz,1H), 4.51-4.60(m,1H),4.36-4.40(m,2H),3.40(s,3H),3.21-3.25(m,2H),2.94-3.03(m,4H),2.81-2.86(m,2H),1.61-1.64(m,2H).

[0422] Example 28: 4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,29 -dihydro-2 7 H-5-O-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocyclohexane-2 8 6-Diketone

[0423]

[0424] The compound was synthesized using the synthesis method of Example 7, with alternative phenols and CDI as starting materials.

[0425] 1 H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.60(s,1H),8.15(s,1H),7.19(s,1H),4.64-4.75(m,1H),4.02-4.09(m,1H),3.87-3.9 6(m,1H),3.26-3.36(m,4H),3.06-3.15(m,1H),2.40-2.52(m,1H),2.13-2.28(m,4H),1.82-1.90(m,1H),1.62-1.74(m,1H).

[0426] Example 29: 2-(2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-7-yl)acetonitrile

[0427]

[0428] Step 1: 2-(2-chloro-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-7-yl)acetonitrile

[0429] At 0 °C, 60% (mineral oil) sodium hydride (80 mg) was slowly added to a DMF (10 mL) solution of 2-chloro-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (254 mg). After the addition was complete, the mixture was stirred at 0 °C for 0.5 hours. Subsequently, bromoacetonitrile (150 mg) was slowly added to the reaction solution. After the reaction was complete, the reaction solution was poured into a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (77 mg).

[0430] Step 2: 2-(2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-7-yl)acetonitrile

[0431] Under nitrogen protection, the above-mentioned 2-(2-chloro-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-7-yl)acetonitrile (58 mg), intermediate 47-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (30 mg), RuPhosPdG3 (20 mg), and cesium carbonate (160 mg) were dissolved in dioxane (10 mL). The reaction flask was purged with nitrogen three times and heated to 100 °C with stirring for 3 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (45 mg).

[0432] 1 HNMR(400MHz,DMSO-d6)δ9.05(s,1H),8.82(s,1H),8.36(s,1H),8.20(s,1H),7.69(s,1H),5.06(s,2H),4.34-4.43 (m,1H),3.92(dd,J=11.6Hz,4.0Hz,2H),3.37(t,J=11.6Hz,2H),2.40-2.50(m,2H),2.35(s,3H),1.64-1.72(m,2H).

[0433] Example 30: 7-Methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-9-(1-trihydro-2H-thiophen-4-yl)-7,9-dihydro-8H-purine-8-one

[0434]

[0435] Under nitrogen protection, 2-chloro-7-methyl-9-(1-tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purin-8-one (obtained using 4-aminotetrahydro-2H-thiopyran-1-oxide as a starting material, following the synthesis method of intermediate 1) (60 mg), intermediate 47-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (43 mg).

[0436] 1 H NMR(400MHz,DMSO-d6)δ9.03(s,0.5H),9.01(s,0.5H),8.65(s,0.5H),8.60(s,0.5H),8. 35(s,0.5H),8.33(s,0.5H),8.05(s,0.5H),8.03(s,0.5H),7.68(s,0.5H),7.65(s,0.5H) ,4.32-4.47(m,1H),3.30-3.36(m,1H),3.26(s,1.5H),3.25(s,1.5H),2.94-3.14(m,2H), 2.76-2.86(m,2H),2.48-2.60(m,1H),2.34(s,3H),1.95-2.04(m,1H),1.69-1.77(m,1H).

[0437] Example 31: 4-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)piperidin-1-carbamate

[0438]

[0439] At room temperature, intermediates 62-chloro-7-methyl-9-(piperidin-4-yl)-7,9-dihydro-8H-purin-8-one (268 mg) and cyanogen bromide (110 mg) were dissolved in THF (20 mL), and triethylamine (200 mg) was slowly added while stirring for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (V:V)) to give 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidin-1-carbamate (120 mg). Under nitrogen protection, the above-mentioned 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidine-1-carbamate (59 mg), intermediate 47-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (30 mg), RuPhos PdG3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (36 mg).

[0440] 1 HNMR(400MHz,DMSO-d6)δ9.04(s,1H),8.67(s,1H),8.33(s,1H),8.05(s,1H),7.67(s,1H),4.22-4.35(m,1 H),3.42-3.50(m,2H),3.26(s,3H),3.10-3.22(m,2H),2.44-2.56(m,2H),2.35(s,3H),1.69-1.79(m,2H).

[0441] Example 32: 2 7 4 2 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,4)-phenylcyclononane-2 8 -ketone

[0442]

[0443] The compound was synthesized using an alternative phenol as a starting material according to the synthesis method of Example 7.

[0444] 1H NMR (400MHz, DMSO-d6) δ8.46(s,1H),7.98(s,1H),6.96(d,J=8.4Hz,1H),6.85(s,1H),6.78(d,J=7.6Hz,1H),4.04-4.20(m,2 H),3.77-4.03(m,1H),3.22(s,3H),2.52-2.79(m,2H),2.04-2.30(m,4H),2.01(s,3H),1.58-1.78(m,4H),1.28-1.56(m,4H).

[0445] Example 33: 9-(1,3-dimethoxypropane-2-yl)-7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one

[0446]

[0447] Under nitrogen protection, 2-chloro-9-(1,3-dimethoxypropane-2-yl)-7-methyl-7,9-dihydro-8H-purine-8-one (obtained by the same method as intermediate 1) (58 mg), intermediate 47-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to give the target compound (43 mg).

[0448] 1 H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.63(s,1H),8.34(s,1H),8.08(s,1H),7.68(s,1H),4.63-4.70( m, 1H), 3.87 (t, J = 9.6Hz, 2H), 3.56 (dd, J = 10.4Hz, 5.6Hz, 2H), 3.28 (s, 3H), 3.16 (s, 6H), 2.35 (s, 3H).

[0449] Example 34: 7-Methyl-2-((3-methyl-3H-imidazol[4,5-c]pyridin-2-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[0450]

[0451] Under nitrogen protection, intermediate 2: 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (54 mg), 3-methyl-3H-imidazolium[4,5-c]pyridine-2-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (13 mg).

[0452] 1 H NMR (400MHz, DMSO-d6) δ8.50-8.66(m,1H),8.23(d,J=4.8Hz,1H),8.13(s,1H),7.37(d,J=4.8Hz,1H),4.3 7-4.52(m,1H),3.89-4.02(m,2H),3.60(s,3H),3.37-3.52(m,5H),2.47-2.59(m,2H),1.57-1.70(m,2H).

[0453] Example 35: 7-Cyclopropyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[0454]

[0455] Step 1: 2-Chloro-7-cyclopropyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[0456] At room temperature, cyclopropylboronic acid (100 mg), copper acetate (20 mg), and pyridine (160 mg) were added sequentially to a solution of 2-chloro-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (254 mg) in 1,2-dichloroethane (10 mL). The mixture was stirred for 12 hours after the addition was complete. After the reaction was complete, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (150 mg).

[0457] Step 2: 7-Cyclopropyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[0458] Under nitrogen protection, the above-mentioned 2-chloro-7-cyclopropyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (60 mg), intermediate 47-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (160 mg) were dissolved in dioxane (10 mL). The reaction flask was purged with nitrogen three times and heated to 100 °C with stirring for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (45 mg).

[0459] 1 H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.66(s,1H),8.33(s,1H),8.02(s,1H),7.67(s,1H),4.28-4.40(m,1H),3.86-3.9 7(m,2H),3.34-3.42(m,2H),2.83-2.91(m,1H),2.39-2.52(m,2H),2.35(s,3H),1.56-1.68(m,2H),0.80-0.99(m,4H).

[0460] Example 36: 2-((1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[0461]

[0462] Under nitrogen protection, intermediate 2: 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (54 mg), 5-amino-1,4-dimethylpyridin-2(1H)-one (28 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), and the mixture was heated to 100 °C and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (15 mg).

[0463] 1H NMR (400MHz, DMSO-d6) δ8.21(s,1H),7.94(s,1H),7.62(s,1H),6.23(s,1H),4.29-4.38(m,1H),3.92(dd,J=11.6Hz,4.4H z,2H),3.37(t,J=11.6Hz,2H),3.35(s,3H),3.23(s,3H),2.41-2.51(m,2H),1.98(s,3H),1.60(dd,J=12.4Hz,2.4Hz,2H).

[0464] Example 37: 13,20-Dimethyl-1,5,10,15,17,20,23-heptaazapentacyclo[14.5.2.2] 2,5 .1 10, 14 .0 19,22 [Hexacarbon-12,14(24),16,18,22-penten-11,21-dione]

[0465]

[0466] The compound was synthesized using the synthesis method of Example 7, which used alternative nitropyridinones as starting materials.

[0467] 1 H NMR(400MHz,DMSO-d6)δ8.49(s,1H),8.16(s,1H),7.86(s,1H),6.24(s,1H),4.21-4.30(m,1H),3.80-3.8 6(m,2H),3.26-3.32(m,5H),2.82-2.88(m,2H),2.62-2.73(m,2H),2.17-2.28(m,5H),1.49-1.69(m,6H).

[0468] Example 38: 4-(7-methyl-2-((6-methylimidazolium[1,2-a]pyridin-7-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0469]

[0470] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 6-methylimidazolium[1,2-a]pyridine-7-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (41 mg).

[0471] 1 H NMR (400MHz, DMSO) δ8.59-8.71(m,2H),8.14(s,1H),7.76-7.92(m,1H),7.36-7.55(m,1H),6.68-6.82(m,1 H),3.81-3.92(m,2H),3.46-3.60(m,2H),3.27(s,3H),2.65-2.78(m,2H),2.52-2.61(m,2H),2.24(s,3H).

[0472] Example 39: 4-(2-((4-chloro-7-methylquinoline-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbaonitrile

[0473]

[0474] Under nitrogen protection, intermediate 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 4-chloro-7-methylquinoline-6-amine (synthesized according to the method described in patent WO2019 / 238929A1) (38 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (31 mg).

[0475] 1H NMR (400MHz, DMSO) δ8.80 (s, 1H), 8.63 (d, J = 4.4Hz, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 7.91 (s, 1H), 7.60 (d,J=4.4Hz,1H),3.84-3.92(m,2H),3.51-3.60(m,2H),3.31(s,3H),2.62-2.80(m,4H),2.50(s,3H).

[0476] Example 40: 4-(2-((4-methoxy-7-methylquinoline-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0477]

[0478] Under nitrogen protection, intermediate 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 4-methoxy-7-methylquinoline-6-amine (synthesized according to the method described in patent WO2019 / 238929A1) (38 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (45 mg).

[0479] 1 H NMR (400MHz, DMSO) δ8.67(s,1H),8.55(d,J=4.8Hz,1H),8.34(s,1H),8.23(s,1H),7.74(s,1H),6.88(d,J=5 .2Hz,1H),3.97(s,3H),3.81-3.88(m,2H),3.52-3.60(m,2H),3.30(s,3H),2.62-2.77(m,4H),2.44(s,3H).

[0480] Example 41: 4-(7-methyl-2-((7-methyl-[1,2,4]triazol[4,3-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0481]

[0482]

[0483] Step 1: 7-Methyl-[1,2,4]triazole[4,3-a]pyridine-6-amine

[0484] Under nitrogen protection, 6-bromo-7-methyl-[1,2,4]triazole[4,3-a]pyridine (212 mg), RuPhos Pd G3 (84 mg), benzophenone imine (182 mg), and cesium carbonate (650 mg) were dissolved in toluene (15 mL), heated to 100 °C, and stirred for 12 hours. After cooling to room temperature, the mixture was filtered, and the solid was washed with dichloromethane. The filtrate was then concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (30 mL). 1 M dilute hydrochloric acid (10 mL) was slowly added, and stirring was continued for 1 hour. Saturated sodium bicarbonate solution was added to the system until the pH was neutral. Then, ethyl acetate was added for extraction, and the organic phase was evaporated to dryness. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to give 7-methyl-[1,2,4]triazole[4,3-a]pyridine-6-amine (103 mg).

[0485] Step 2: 4-(7-methyl-2-((7-methyl-[1,2,4]triazol[4,3-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0486] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 7-methyl-[1,2,4]triazol[4,3-a]pyridine-6-amine (30 mg), RuPhos PdG3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to obtain the target compound (44 mg).

[0487] 1 H NMR (400MHz, DMSO) δ9.07(s,1H),8.77(s,1H),8.35(s,1H),8.18(s,1H),7.68(s,1H),3.87-3. 94(m,2H),3.52-3.60(m,2H),3.28(s,3H),2.68-2.76(m,2H),2.58-2.64(m,2H),2.35(s,3H).

[0488] Example 42: 4 4 -Chloro-6,6-difluoro-2 7 4 6-dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocycloheptane-2 8 7-Diketone

[0489]

[0490] The compound was synthesized using the synthetic method of Example 7, with alternative phenols and ethyl difluorobromoacetate as starting materials.

[0491] 1 H NMR(400MHz,DMSO-d6)δ8.34(s,1H),8.20(s,1H),7.96-7.98(m,1H),7.33(s,1H),4.68-4.77(m,1H),4.11-4.22(m,2H),3.41-3.4 8(m,1H),3.30(s,3H),2.96-3.04(m,1H),2.50-2.68(m,1H),2.46-2.53(m,1H),2.26(s,3H),1.94-2.02(m,1H),1.68-1.75(m,1H).

[0492] Example 43: 4-(7-methyl-2-((2-methyl-1,8-naphthidin-3-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0493]

[0494]

[0495] Step 1: 2-Methyl-1,8-naphthidine-3-amine

[0496] 2-Methyl-1,8-naphthyl-3-carboxylic acid (188 mg) and DPPA (300 mg) were dissolved in toluene (20 mL). Triethylamine (0.5 mL) was slowly added at room temperature and stirred for 1 hour. 0.5 mL of water was added to the system, and the mixture was then heated to 80 °C and stirred for 2 hours under nitrogen protection. After cooling to room temperature, the reaction solution was poured into water (150 mL). The reaction solution was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1 (V:V)) to give a pale yellow solid (60 mg).

[0497] Step 2: 4-(7-methyl-2-((2-methyl-1,8-naphthid-3-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0498] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 2-methyl-1,8-naphthidium-3-amine (32 mg), RuPhos PdG3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (41 mg).

[0499] 1 H NMR (400MHz, DMSO) δ8.99 (s, 1H), 8.86 (dd, J = 4.4Hz, 2.0Hz, 1H), 8.64 (s, 1H), 8.25-8.27 (m, 2H), 7.50 (dd, J = 8 -7.6Hz,4.4Hz,1H),3.86-3.93(m,2H),3.53-3.61(m,2H),3.31(s,3H),2.68-2.78(m,5H),2.58-2.65(m,2H).

[0500] Example 44: 4-(7-methyl-2-((7-methylquinazolin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0501]

[0502] Under nitrogen protection, intermediate 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 7-methylquinazoline-6-amine (synthesized according to the method described in patent WO2019 / 238929A1) (32 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (39 mg).

[0503] 1H NMR(400MHz,DMSO)δ9.36(s,1H),9.09(s,1H),8.84(s,1H),8.45(s,1H),8.28(s,1H),7.83(s,1H),3 .88-3.94(m,2H),3.54-3.62(m,2H),3.31(s,3H),2.74-2.82(m,2H),2.58-2.64(m,2H),2.53(s,3H).

[0504] Example 45: 2-((7-chloro-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[0505]

[0506] Under nitrogen protection, intermediates 22-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (54 mg), 7-chloro-[1,2,4]triazol[1,5-a]pyridine-6-amine (synthesized according to the method described for intermediate 4 in patent WO2019 / 238929A1) (34 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (18 mg).

[0507] 1 H NMR(400MHz,DMSO)δ10.19(s,1H),8.29(s,1H),7.95(s,1H),7.85(s,1H),7.37(s,1H),4.52-4.61(m,1H ), 4.15 (dd, J = 11.6Hz, 4.4Hz, 2H), 3.51-3.59 (m, 2H), 3.43 (s, 3H), 2.72-2.82 (m, 2H), 1.71-1.77 (m, 2H).

[0508] Example 46: 4-(2-((7-chloro-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0509]

[0510] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 7-chloro-[1,2,4]triazol[1,5-a]pyridine-6-amine (34 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (39 mg).

[0511] 1 H NMR(400MHz,DMSO)δ10.04(s,1H),8.30(s,1H),8.03(s,1H),7.86(s,1H),7.37 (s,1H),4.10-4.17(m,2H),3.89-3.95(m,2H),3.43(s,3H),2.77-2.87(m,4H).

[0512] Example 47: 4-(7-methyl-2-((7-methylbenzothiazol-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0513]

[0514] Step 1: 7-Methylbenzothiazole-6-amine

[0515] Under nitrogen protection, 6-bromo-7-methylbenzo[d]thiazole (228 mg), RuPhos PdG3 (80 mg), benzophenone imine (182 mg), and cesium carbonate (650 mg) were dissolved in toluene (10 mL), heated to 100 °C, and stirred for 5 hours. After cooling to room temperature, the mixture was filtered, the solid was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), and 1 M dilute hydrochloric acid (10 mL) was slowly added. Stirring continued for 1 hour, and then saturated sodium bicarbonate solution was added until the pH was neutral. Extraction with ethyl acetate was performed, and the organic phase was evaporated to dryness. The residue was purified by column chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give 7-methylbenzothiazole-6-amine (73 mg).

[0516] Step 2: 4-(7-methyl-2-((7-methylbenzothiazol-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0517] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 7-methylbenzothiazol-6-amine (33 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (37 mg).

[0518] 1 H NMR (400MHz, DMSO) δ9.25(s,1H),8.93(s,1H),8.12(s,1H),7.84(d,J=8.4Hz,1H),7.61(d,J=8.4Hz,1H) ,3.82-3.92(m,2H),3.46-3.60(m,2H),3.33(s,3H),2.65-2.76(m,2H),2.50-2.59(m,2H),2.41(s,3H).

[0519] Example 48: 4-(7-methyl-2-((6-methylbenzo[d][1,3]dioxin-5-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0520]

[0521] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 6-methylbenzo[d][1,3]dioxane-5-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (45 mg).

[0522] 1H NMR (400MHz, DMSO) δ8.40(s,1H),8.07(s,1H),6.95(s,1H),6.74(s,1H),5.92(s,2H),3.86-3. 92(m,2H),3.53-3.61(m,2H),3.25(s,3H),2.68-2.77(m,2H),2.54-2.61(m,2H),2.07(s,3H).

[0523] Example 49: 4-(7-methyl-2-((7-methylbenzothiazol-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0524]

[0525] Step 1: 7-Methylbenzothiazole-6-amine

[0526] Under nitrogen protection, 6-bromo-7-methylbenzo[d]thiazole (228 mg), RuPhos PdG3 (80 mg), benzophenone imine (182 mg), and cesium carbonate (650 mg) were dissolved in toluene (10 mL), heated to 100 °C, and stirred for 5 hours. After cooling to room temperature, the mixture was filtered, the solid was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), and 1 M dilute hydrochloric acid (10 mL) was slowly added. Stirring continued for 1 hour, and then saturated sodium bicarbonate solution was added until the pH was neutral. Extraction with ethyl acetate was performed, and the organic phase was evaporated to dryness. The residue was purified by column chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain 5-methylbenzothiazole-6-amine (40 mg).

[0527] Step 2: 4-(7-methyl-2-((7-methylbenzothiazol-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0528] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 7-methylbenzothiazol-6-amine (33 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (31 mg).

[0529] 1H NMR (400MHz, DMSO) δ9.25(s,1H),8.93(s,1H),8.12(s,1H),7.84(d,J=8.4Hz,1H),7.61(d,J=8.4Hz,1H) ,3.82-3.92(m,2H),3.46-3.60(m,2H),3.33(s,3H),2.65-2.76(m,2H),2.50-2.59(m,2H),2.41(s,3H).

[0530] Example 50: 4-(7-methyl-2-((6-methylpyrazol[1,5-a]pyrimidin-5-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0531]

[0532] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 6-methylpyrazol[1,5-a]pyrimidin-5-amine (32 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (22 mg).

[0533] 1 H NMR (400MHz, DMSO) δ9.39(s,1H),8.75(s,1H),8.33(s,1H),7.90(d,J=2.0Hz,1H),6.15(d,J=2.0Hz,1H) ,3.89-3.95(m,2H),3.54-3.62(m,2H),3.33(s,3H),2.82-2.91(m,2H),2.61-2.67(m,2H),2.34(s,3H).

[0534] Example 51: 4-(7-methyl-2-((3-methyl-1,5-naphthidin-2-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0535]

[0536] Step 1: 3-Methyl-1,5-naphthidine-2-amine

[0537] Under nitrogen protection, 3-bromo-1,5-naphthidine-2-amine (224 mg), PdCl2 (dppf) (90 mg), trimethylcycloborane (250 mg), and potassium carbonate (278 mg) were dissolved in dioxane (20 mL) and water (5 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the reaction solution was poured into water (100 mL), extracted with ethyl acetate, and the organic phase was evaporated to dryness. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to obtain 3-methyl-1,5-naphthidine-2-amine (90 mg).

[0538] Step 2: 4-(7-methyl-2-((3-methyl-1,5-naphthidin-2-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0539] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 3-methyl-1,5-naphthidine-2-amine (32 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (10 mL), heated to 100 °C, and stirred for 3 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (49 mg).

[0540] 1 H NMR (400MHz, DMSO) δ9.42(s,1H),8.73(d,J=3.2Hz,1H),8.30(s,1H),8.11(s,1H),8.01(d,J=8.8Hz,1H),7.58(dd,J=8 .8Hz,4.0Hz,1H),3.82-3.89(m,2H),349-3.57(m,2H),3.32(s,3H),2.79-2.88(m,2H),2.58-2.65(m,2H),2.45(s,3H).

[0541] Example 52: 4-(7-methyl-2-((7-methylpyridin[2,3-b]pyrazin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0542]

[0543] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 7-methylpyridine[2,3-b]pyrazine-6-amine (32 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (14 mg).

[0544] 1 H NMR(400MHz,DMSO)δ9.64(s,1H),8.85(s,1H),8.72(s,1H),8.36(s,1H),8.18(s,1H) ,3.86-3.96(m,2H),3.50-3.61(m,2H),3.34(s,3H),2.70-2.90(m,4H),2.47(s,3H).

[0545] Example 53: 4-(2-((4,7-dimethylquinoline-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0546]

[0547] Step 1: 4,7-Dimethylquinoline-6-amine

[0548] Under nitrogen protection, 4-chloro-7-methylquinoline-6-amine (192 mg), PdCl2 (dppf) (90 mg), trimethylcycloboroxane (250 mg), and potassium carbonate (278 mg) were dissolved in dioxane (20 mL) and water (5 mL), heated to 100 °C, and stirred for 4 hours. After cooling to room temperature, the reaction solution was poured into water (100 mL), extracted with ethyl acetate, dried the organic phase, evaporated to dryness, and the residue was purified by column chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain 3-methyl-1,5-naphthyl-2-amine (100 mg).

[0549] Step 2: 4-(2-((4,7-dimethylquinoline-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0550] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 4,7-dimethylquinoline-6-amine (34 mg), RuPhos PdG3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (10 mL), heated to 100 °C, and stirred for 3 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (37 mg).

[0551] 1 H NMR (400MHz, DMSO) δ8.74(s,1H),8.57(d,J=4.4Hz,1H),8.20(s,1H),8.16(s,1H),7.81(s,1H),7.23(d,J=4.4 Hz,1H),3.81-3.88(m,2H),3.50-3.57(m,2H),3.29(s,3H),2.70-2.79(m,2H),2.54-2.61(m,5H),2.43(s,3H).

[0552] Example 54: 2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-4(6,4)-quinoline-2(9,2)-purine-1(4,1)-piperidinecycloheptane-2 8 -ketone

[0553]

[0554] The compound was synthesized using 7-methyl-6-nitroquinoline-4-phenol as the starting material according to the synthesis method of Example 7.

[0555] 1 H NMR (400MHz, DMSO) δ8.96(s,1H),8.49(d,J=4.8Hz,1H),8.20(s,1H),8.05(s,1H),7.71(s,1H),6.93(d,J=5.2Hz,1H),4.31-4.40 (m,2H),4.18-4.30(m,1H),3.32(s,3H),2.90-3.03(m,4H),2.76-2.89(m,2H),2.52(s,3H),2.38-2.50(m,2H),1.56-1.66(m,2H).

[0556] Example 55: 4 4 -Fluorine-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocycloheptane-2 8 -ketone

[0557]

[0558] The compound was synthesized using the synthesis method of Example 7, which used alternative phenols as starting materials.

[0559] 1 H NMR (400MHz, DMSO) δ8.25(s,1H),8.17(s,1H),8.03(d,J=8.0Hz,1H),7.02(d,J=12.4Hz,1H),4.26-4.51(m, 3H),3.31(s,3H),3.12-3.30(m,2H),2.81-3.11(m,4H),2.67-2.81(m,2H),2.21(s,3H),1.49-1.69(m,2H).

[0560] Example 56: 4-(2-((4-methoxy-7-methylquinazoline-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0561]

[0562] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 4-methoxy-7-methylquinazoline-6-amine (38 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (48 mg).

[0563] 1H NMR(400MHz,DMSO)δ8.76(s,1H),8.63(s,1H),8.42(s,1H),8.27(s,1H),7.74(s,1H),4.07 (s,3H),3.84-3.92(m,2H),3.54-3.61(m,2H),3.31(s,3H),2.62-2.79(m,4H),2.48(s,3H).

[0564] Example 57: 4-(7-methyl-2-((6-methyl-[1,2,5]thiadiazol[3,4-b]pyridin-5-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0565]

[0566] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 6-methyl-[1,2,5]thiadiazole[3,4-b]pyridine-5-amine (33 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (17 mg).

[0567] 1 H NMR(400MHz,DMSO)δ9.62(s,1H),8.41(s,1H),8.16(s,1H),3.90-3.98(m,2H),3. 56-3.63(m,2H),3.35(s,3H),2.85-2.94(m,2H),2.68-2.76(m,2H),2.47(s,3H).

[0568] Example 58: 4 4 -Fluorine-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3,5-diaza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocycloheptane-2 8 -ketone

[0569]

[0570] The compound was synthesized using 2-fluoro-4-methyl-5-nitroaniline as the starting material, following the synthesis method of Example 7.

[0571] 1 H NMR (400MHz, DMSO) δ8.19 (s, 1H), 8.02 (s, 1H), 7.56 (d, J = 8.4Hz, 1H), 6.86 (d, J = 12.0Hz, 1H), 5.63-5. 70(br,1H),4.52-4.65(m,1H),3.20-3.53(m,11H),2.72-2.86(m,2H),2.16(s,3H),1.74-1.86(m,2H).

[0572] Example 59: 2 7 4 5 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2(9,2)-purine-4(4,2)-pyrimidine-1(4,1)-piperidinecycloheptane-2 8 -ketone

[0573]

[0574] The compound was synthesized using 5-methylcytosine as the starting material, following the synthesis method of Example 7.

[0575] 1 H NMR (400MHz, DMSO) δ8.73(s,1H),8.34(s,1H),8.09(s,1H),4.51-4.63(m,1H),4.40-4.47(m,2H),3. 74-3.88(m,2H),3.35(s,3H),3.13-3.22(m,4H),2.78-2.95(m,2H),2.18(s,3H),1.67-1.82(m,2H).

[0576] Example 60: 4-(7-methyl-2-((5-methylbenzothiazol-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbaonitrile

[0577]

[0578] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 5-methylbenzothiazol-6-amine (33 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (34 mg).

[0579] 1 H NMR(400MHz,DMSO)δ9.19(s,1H),8.70(s,1H),8.36(s,1H),8.19(s,1H),7.89(s,1H),3.86-3. 92(m,2H),3.52-3.59(m,2H),3.28(s,3H),2.67-2.75(m,2H),2.56-2.63(m,2H),2.37(s,3H).

[0580] Example 61: 4-(2-((5,7-dimethylquinoline-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0581]

[0582] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 5,7-dimethylquinoline-6-amine (34 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (25 mg).

[0583] 1H NMR (400MHz, DMSO) δ8.80 (s, 1H), 8.76 (s, 1H), 8.40 (d, J = 7.6Hz, 1H), 8.03 (s, 1H), 7.74 (s, 1H), 7.41-7.48 (m, 1H), 3.56-3.90(m,2H),3.32-3.52(m,2H),3.23(s,3H),2.50-2.74(m,2H),2.44(s,3H),2.31(s,3H),1.35-1.64(m,2H).

[0584] Example 62: 4-(7-methyl-2-((8-methylquinoline-7-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0585]

[0586] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 8-methylquinoline-7-amine (32 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (26 mg).

[0587] 1 H NMR (400MHz, DMSO) δ8.97(s,1H),8.84(dd,J=4.0Hz,1.6Hz,1H),8.24(dd,J=8.4Hz,1.6Hz,1H),8.17(s,1H),7.81(d,J=8.8Hz,1H),7.71(d,J=9 .2Hz,1H),7.40(dd,J=8.4Hz,4.0Hz,1H),3.83-3.91(m,2H),3.50-3.58 (m,2H),3.28(s,3H),2.68-2.76(m,2H),2.62(s,3H),2.54-2.61(m,2H).

[0588] Example 63: 4-(2-((7-fluoro-5-methylquinoline-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbaonitrile

[0589]

[0590]

[0591] Step 1: 6-Bromo-7-fluoro-5-methylquinoline

[0592] Concentrated H₂SO₄ (13.7 g) was slowly added to glycerol (8.63 g) while maintaining the temperature below 70 °C. Then, 4-bromo-3-fluoro-5-methylaniline (6.1 g) was added, and the mixture was heated to 85 °C and stirred for 40 minutes. Potassium iodide (0.30 g), iodine (0.34 g), and water (1.50 mL) were added, and the mixture was heated to 135 °C and stirred for 4 hours. The mixture was cooled to room temperature, quenched on ice, and filtered through diatomaceous earth. The filtrate was adjusted to pH 7 with ammonia and extracted thoroughly with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography to obtain 6-bromo-7-fluoro-5-methylquinoline (1.5 g) and its isomer 6-bromo-5-fluoro-7-methylquinoline (1.1 g).

[0593] Step 2: 7-Fluoro-5-methylquinoline-6-amine

[0594] Under nitrogen protection, 6-bromo-7-fluoro-5-methylquinoline (240 mg), RuPhos PdG3 (80 mg), benzophenone imine (182 mg), and cesium carbonate (650 mg) were dissolved in toluene (10 mL), heated to 100 °C, and stirred for 5 hours. After cooling to room temperature, the mixture was filtered, and the solid was washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (30 mL). 1 M dilute hydrochloric acid (10 mL) was slowly added, and stirring continued for 1 hour. Saturated sodium bicarbonate solution was added to the system until the pH was neutral. The mixture was extracted with ethyl acetate, and the organic phase was evaporated to dryness. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to obtain 7-fluoro-5-methylquinoline-6-amine (120 mg).

[0595] Step 3: 4-(2-((7-fluoro-5-methylquinoline-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0596] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 7-fluoro-5-methylquinoline-6-amine (35 mg), RuPhos PdG3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (42 mg).

[0597] 1 HNMR(400MHz,DMSO)δ9.01(s,1H),8.85(d,J=2.8Hz,1H),8.47(d,J=8.4Hz,1H),8.07(s,1H),7.63(d,J=10.8Hz,1H),7.51(dd ,J=8.8Hz,4.4Hz,1H),3.74-3.83(m,2H),3.43-3.53(m,2H),3.25(s,3H),2.61-2.71(m,2H),2.53(s,3H),2.46-2.52(m,2H).

[0598] Example 64: 4-(2-((5-fluoro-7-methylquinoline-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbaonitrile

[0599]

[0600] The target compound (30 mg) was synthesized in two steps using 6-bromo-5-fluoro-7-methylquinoline obtained in step one of Example 63 as the starting material.

[0601] 1 H NMR (400MHz, DMSO) δ8.92(s,1H),8.86(dd,J=4.0Hz,1.2Hz,1H),8.36(d,J=8.4Hz,1H),8.10(s,1H),7.76(s,1H),7.51(dd, J=8.4Hz, 4.0Hz, 1H), 3.70-3.78 (m, 2H), 3.41-3.48 (m, 2H), 3.26 (s, 3H), 2.59-2.68 (m, 2H), 2.44-2.50 (m, 2H), 2.41 (s, 3H).

[0602] Example 65: 4-(2-((2,2-difluoro-6-methylbenzo[d][1,3]dioxane-5-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0603]

[0604] Step 1: 2,2-Difluoro-6-methylbenzo[d][1,3]dioxin-5-amine

[0605] Under nitrogen protection, 250 mg of 5-bromo-2,2-difluoro-6-methylbenzo[d][1,3]dioxane, 80 mg of RuPhosPdG3, 182 mg of benzophenone imine, and 650 mg of cesium carbonate were dissolved in 10 mL of toluene. The mixture was heated to 100 °C and stirred for 5 hours. After cooling to room temperature, the mixture was filtered, and the solid was washed with dichloromethane. The filtrate was then concentrated under reduced pressure. The residue was dissolved in 30 mL of tetrahydrofuran, and 10 mL of 1 M dilute hydrochloric acid was slowly added. The mixture was stirred for 1 hour, and saturated sodium bicarbonate solution was added until the pH was neutral. The mixture was extracted with ethyl acetate, and the organic phase was evaporated to dryness. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to give 95 mg of 2,2-difluoro-6-methylbenzo[d][1,3]dioxin-5-amine.

[0606] Step 2: 4-(2-((2,2-difluoro-6-methylbenzo[d][1,3]dioxane-5-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0607] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 2,2-difluoro-6-methylbenzo[d][1,3]dioxin-5-amine (38 mg), RuPhosPdG3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (36 mg).

[0608] 1 H NMR(400MHz,DMSO)δ7.90(s,1H),7.69(s,1H),6.90(s,1H),6.58(s,1H),4.03 -4.10(m,2H),3.82-3.90(m,2H),3.37(s,3H),2.72-2.82(m,4H),2.29(s,3H).

[0609] Example 66: 4-(7-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0610]

[0611] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-amine (31 mg), RuPhos PdG3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (43 mg).

[0612] 1 H NMR (400MHz, DMSO) δ8.34(s,1H),8.07(s,1H),6.91(s,1H),6.64(s,1H),4.16(s,4H),3.87-3. 93(m,2H),3.54-3.62(m,2H),3.25(s,3H),2.69-2.77(m,2H),2.56-2.63(m,2H),2.05(s,3H).

[0613] Example 67: 4-(7-methyl-2-((7-methylbenzo[b][1,4]dioxin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0614]

[0615] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 7-methylbenzo[b][1,4]dioxin-6-amine (33 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (27 mg).

[0616] 1H NMR (400MHz, DMSO) δ8.41(s,1H),8.11(s,1H),6.87(s,1H),6.53(s,1H),6.13(s,2H),3.89-3. 96(m,2H),3.55-3.63(m,2H),3.26(s,3H),2.69-2.77(m,2H),2.57-2.63(m,2H),2.03(s,3H).

[0617] Example 68: 4-(2-((8-fluoro-7-methylquinoline-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbaonitrile

[0618]

[0619] Following Example 63, the target compound (20 mg) was synthesized in three steps using 4-bromo-2-fluoro-3-methylaniline as the starting material.

[0620] 1 H NMR (400MHz, DMSO) δ8.93 (s, 1H), 8.76 (dd, J = 4.4Hz, 1.6Hz, 1H), 8.25 (s, 1H), 8.22 (d, J = 8.4Hz, 1H), 8.08 (s, 1H), 7.49 (dd, J = 8. 4Hz, 4.4Hz, 1H), 3.85-3.92 (m, 2H), 3.52-3.60 (m, 2H), 3.30 (s, 3H), 2.70-2.79 (m, 2H), 2.58-2.64 (m, 2H), 2.36 (d, J = 2.4Hz, 3H).

[0621] Example 69: 4-(2-((7-(difluoromethyl)quinoline-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0622]

[0623] Following Example 63, the target compound (22 mg) was synthesized in three steps using 4-bromo-3-(difluoromethyl)aniline as the starting material.

[0624] 1H NMR (400MHz, DMSO) δ8.95(s,1H),8.86(d,J=2.8Hz,1H),8.34(s,1H),8.29(d,J=8.4Hz,1H),8.24(s,1H),8.18(s,1H),7.57(dd,J=8 .4Hz, 4.4Hz, 1H), 7.45 (t, J = 54.2Hz, 1H), 3.84-3.91 (m, 2H), 3.52-3.59 (m, 2H), 3.31 (s, 3H), 2.68-2.77 (m, 2H), 2.56-2.62 (m, 2H).

[0625] Example 70: 2 7 4 5 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2(9,2)-purine-4(4,2)-pyridine-1(4,1)-piperidinecycloheptane-2 8 -ketone

[0626]

[0627] The compound was synthesized using 2-bromo-5-methyl-4-nitropyridine as the starting material, following the synthesis method of Example 7.

[0628] 1 H NMR(400MHz,DMSO)δ8.45(s,1H),8.26(s,1H),8.02(s,1H),7.80(s,1H),4.35-4.45(m,1H),4.26 -4.32(m,2H),3.32(s,3H),3.07-3.15(m,2H),2.62-2.88(m,6H),2.18(s,3H),1.37-1.45(m,2H).

[0629] Example 71: 4-(7-(methyl-d3)-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0630]

[0631] Following Example 1, CD3I (deuterated iodomethane) was used instead of CH3I as a substitute raw material in the synthesis of intermediate 1, and the target compound (33 mg) was obtained through two steps.

[0632] 1H NMR(400MHz,DMSO)δ9.06(s,1H),8.76(s,1H),8.35(s,1H),8.18(s,1H),7.67(s,1H),3 .87-3.93(m,2H),3.52-3.60(m,2H),2.68-2.76(m,2H),2.58-2.64(m,2H),2.35(s,3H).

[0633] Example 72: 4-(7-(methyl-d3)-2-((7-methylquinoline-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0634]

[0635] Following Example 71, the target compound (34 mg) was obtained by catalytic coupling reaction using 7-methylquinoline-6-amine as a substitute amine.

[0636] 1 H NMR (400MHz, DMSO) δ8.69-8.71(m,2H),8.26(s,1H),8.25(s,1H),8.14-8.17(m,1H),7.81(s,1H),7.39(dd,J =8.4Hz,4.0Hz,1H),3.85-3.92(m,2H),3.53-3.60(m,2H),2.72-2.79(m,2H),2.59-2.65(m,2H),2.47(s,3H).

[0637] Example 73: 4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-Thia-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocycloheptane-2 8 -ketone

[0638]

[0639] The compound was synthesized using 2-chloro-4-methyl-5-nitrobenzenethiol as a starting material, following the synthesis method of Example 7.

[0640] 1H NMR(400MHz,DMSO)δ8.23(s,1H),7.88(s,1H),7.20(s,1H),6.86(s,1H),4.47-4.58(m,1H),3.41(s,3H),3.21 (t,J=7.2Hz,2H),3.12-3.19(m,2H),3.09(t,J=7.2Hz,2H),2.82-2.97(m,4H),2.29(s,3H),1.47-1.55(m,2H).

[0641] Example 74: 5 4 -Chloride-3 7 5 6 -Dimethyl-3 8 ,3 9 -dihydro-3 7 H-6-O-4-aza-3(9,2)-purine-2(1,4)-piperidine-1,5(1,3)-dibenzocycloheptane-3 8 -ketone

[0642]

[0643] The compound was synthesized using 2-chloro-4-methyl-5-nitrophenol and 3-bromobenzyl bromide as starting materials, following the synthesis method of Example 7.

[0644] 1 H NMR (400MHz, DMSO) δ7.79(s,1H),7.43(s,1H),7.31(s,1H),7.12(s,1H),7.09(t,J=8.0Hz,1H),6.86-6.90(m,1H),6.50(d,J=7.6Hz,1H),5.27(s ,1H),5.24(s,2H),4.64-4.74(m,1H),4.05-4.13(m,2H),3.39(s,3H),3. 27(t,J=13.6Hz,2H),2.59-2.72(m,2H),2.22(s,3H),1.61-1.69(m,2H).

[0645] Example 75: 4-(7-methyl-2-((6-methyl-[1,2,4]triazol[1,5-a]pyridin-7-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0646]

[0647] Step 1: (E)-N'-(4-iodo-5-methylpyridin-2-yl)-N,N-dimethylformamide

[0648] At room temperature, 2.34 g of 4-iodo-5-methylpyridin-2-amine was dissolved in 50 mL of toluene, and 4.0 mL of 1,1-dimethoxy-N,N-dimethylmethylamine was added. The reaction mixture was stirred under reflux for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 2.5 g of the title compound as a yellow solid.

[0649] Step 2: (E)-N-hydroxy-N'-(4-iodo-5-methylpyridin-2-yl)formamide

[0650] At room temperature, hydroxylamine hydrochloride (1.4 g) was added to (E)-N'-(4-iodo-5-methylpyridin-2-yl)-N,N-dimethylformamide (2.5 g) in MeOH (50 mL). The reaction mixture was stirred under reflux for 2 hours, cooled to room temperature, poured into water, and extracted with EtOAc (100 mL). The extract was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (2 g) as a yellow solid.

[0651] Step 3: 7-Iodo-6-methyl-[1,2,4]triazole[1,5-a]pyridine

[0652] At 0 °C, 2,2,2-trifluoroacetic anhydride (2.1 g) was added to (E)-N-hydroxy-N'-(4-iodo-5-methylpyridin-2-yl)carboxamide (2 g) in THF (50 mL). The reaction mixture was stirred at room temperature for 18 hours and then concentrated. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was evaporated to dryness. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 50:1 (V:V)) to give the title compound (1.2 g).

[0653] Step 4: 6-Methyl-[1,2,4]triazole[1,5-a]pyridine-7-amine

[0654] Under nitrogen protection, 259 mg of 7-iodo-6-methyl-[1,2,4]triazole[1,5-a]pyridine, 80 mg of RuPhos Pd G3, 182 mg of benzophenone imine, and 650 mg of cesium carbonate were dissolved in 10 mL of toluene. The mixture was heated to 100 °C and stirred for 7 hours. After cooling to room temperature, the mixture was filtered, and the solid was washed with dichloromethane. The filtrate was then concentrated under reduced pressure, and the residue was dissolved in 30 mL of tetrahydrofuran. 1 M dilute hydrochloric acid (10 mL) was slowly added, and the mixture was stirred for 1 hour. Saturated sodium bicarbonate solution was added to the system until the pH was neutral. The mixture was extracted with ethyl acetate, and the organic phase was evaporated to dryness. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 10:1 (V:V)) to give 90 mg of 6-methyl-[1,2,4]triazole[1,5-a]pyridine-7-amine.

[0655] Step 5: 4-(7-methyl-2-((6-methyl-[1,2,4]triazol[1,5-a]pyridin-7-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0656] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 6-methyl-[1,2,4]triazol[1,5-a]pyridine-7-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to obtain the target compound (56 mg).

[0657] 1 H NMR (400MHz, DMSO) δ8.71(s,1H),8.68(s,1H),8.33(s,1H),8.27(s,1H),8.24(s,1H),3.95-4. 01(m,2H),3.58-3.67(m,2H),3.32(s,3H),2.75-2.84(m,2H),2.67-2.73(m,2H),2.34(s,3H).

[0658] Example 76: 7-Methyl-2-((6-methyl-[1,2,4]triazol[1,5-a]pyridin-7-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[0659]

[0660] Under nitrogen protection, intermediate 2: 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (54 mg), 6-methyl-[1,2,4]triazol[1,5-a]pyridine-7-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (43 mg).

[0661] 1 H NMR(400MHz,DMSO)δ8.70(s,1H),8.53(s,1H),8.39(s,1H),8.23(s,2H),4.38-4.50(m,1H),3.90-4 .01(m,2H),3.40(t,J=11.2Hz,2H),3.32(s,3H),2.44-2.58(m,2H),2.36(s,3H),1.62-1.72(m,2H).

[0662] Example 77: 4-(7-(methyl-d3)-2-((6-methyl-[1,2,4]triazol[1,5-a]pyridin-7-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0663]

[0664] Following Example 71, the target compound (44 mg) was obtained by catalytic coupling reaction using 6-methyl-[1,2,4]triazole[1,5-a]pyridine-7-amine as a substitute amine.

[0665] 1 H NMR(400MHz,DMSO)δ8.71(s,1H),8.68(s,1H),8.33(s,1H),8.27(s,1H),8.24(s,1H),3 .94-4.02(m,2H),3.58-3.67(m,2H),2.74-2.84(m,2H),2.66-2.74(m,2H),2.34(s,3H).

[0666] Example 78: 4-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carboxamide

[0667]

[0668] At room temperature, 30 mg of 4-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate was dissolved in 10 mL of THF, 1 mL of 1 M NaOH was added, and the mixture was heated to 50 °C and stirred for 2 hours. After cooling to room temperature, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane:methanol = 10:1 (V:V)) to obtain the target compound (17 mg).

[0669] 1 H NMR(400MHz,DMSO)δ8.93(s,1H),8.55(s,1H),8.33(s,1H),8.10(s,1H),7.66(s,1H),7.33(s,1H),7.13(s, 1H),3.62-3.70(m,2H),3.38-3.48(m,2H),3.25(s,3H),2.97-3.06(m,2H),2.32(s,3H),2.01-2.11(m,2H).

[0670] Example 79: 4-(7-methyl-2-((5-methylbenzo[d]oxazol-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0671]

[0672] Step 1: 5-Methylbenzo[d]oxazol-6-amine

[0673] Under nitrogen protection, 6-bromo-5-methylbenzo[d]oxazole (212 mg), RuPhos PdG3 (80 mg), benzophenone imine (182 mg), and cesium carbonate (650 mg) were dissolved in toluene (10 mL), heated to 100 °C, and stirred for 5 hours. After cooling to room temperature, the mixture was filtered, the solid was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), and 1 M dilute hydrochloric acid (10 mL) was slowly added. Stirring continued for 1 hour, and then saturated sodium bicarbonate solution was added until the pH was neutral. The mixture was extracted with ethyl acetate, and the organic phase was evaporated to dryness. The residue was purified by column chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain 5-methylbenzo[d]oxazole-6-amine (50 mg).

[0674] Step 2: 4-(7-methyl-2-((5-methylbenzo[d]oxazol-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0675] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 5-methylbenzo[d]oxazol-6-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 3 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to give the target compound (33 mg).

[0676] 1 H NMR (400MHz, DMSO) δ8.62(s,1H),8.57(s,1H),8.17(s,1H),7.95(s,1H),7.58(s,1H),3.86-3. 92(m,2H),3.52-3.60(m,2H),3.28(s,3H),2.69-2.79(m,2H),2.56-2.63(m,2H),2.32(s,3H).

[0677] Example 80: (E)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-Thia-3-aza-2(9,2)-purine-4(6,3)-[1,2,4]triazole[4,3-a]pyridine-1(4,1)-piperidinecycloheptane-2 8 -ketone

[0678]

[0679] The compound was synthesized using 7-methyl-6-nitro-[1,2,4]triazole[4,3-a]pyridine-3-thiol as the starting material, following the synthesis method of Example 7.

[0680] 1H NMR(400MHz,DMSO)δ8.83(s,1H),8.70(s,1H),8.01(s,1H),7.49(s,1H),3.72-3.83(m,1H),3.21(s,3H),3 .08-3.14(m,2H),2.59-2.72(m,4H),2.25(s,3H),1.72-1.87(m,2H),1.63-1.71(m,2H),1.24-1.33(m,2H).

[0681] Example 81: 4-(7-methyl-2-((6-methylbenzothiazol-5-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0682]

[0683] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 6-methylbenzothiazol-5-amine (33 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (47 mg).

[0684] 1 H NMR (400MHz, DMSO) δ9.24(s,1H),8.67(s,1H),8.25(s,1H),8.17(s,1H),7.92(s,1H),3.85-3. 92(m,2H),3.52-3.60(m,2H),3.28(s,3H),2.70-2.79(m,2H),2.58-2.65(m,2H),2.35(s,3H).

[0685] Example 82: 4-(7-(fluoromethyl)-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0686]

[0687] Following Example 1, in the synthesis of intermediate 1, fluoroiodomethyl ether was used instead of CH3I and cesium carbonate was used instead of sodium hydride as a base to obtain the target compound (13 mg) through two steps.

[0688] 1 H NMR(400MHz,DMSO)δ9.50(s,1H),8.26(s,1H),8.14(s,1H),7.58(s,1H),6.82(s,1H),5.9 0(d,J=53.6Hz,2H),4.07-4.14(m,2H),3.84-3.92(m,2H),2.73-2.83(m,4H),2.49(s,3H).

[0689] Example 83: 4-(7-(fluoromethyl)-2-((7-methylquinoline-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate

[0690]

[0691] Following Example 75, the target compound (16 mg) was obtained by catalytic coupling reaction using 7-methylquinoline-6-amine as a substitute amine.

[0692] 1 H NMR (400MHz, DMSO) δ8.75(dd,J=4.0Hz,1.6Hz,1H),8.63(s,1H),8.14-8.19(m,2H),7.93(s,1H),7.34(dd,J=8.0Hz,4 .0Hz,1H),7.14(s,1H),5.89(d,J=53.6Hz,2H),4.04-4.10(m,2H),3.84-3.91(m,2H),2.76-2.86(m,4H),2.57(s,3H).

[0693] Example 84: 7-Methyl-2-((7-methyl-[1,2,4]triazol[4,3-a]pyridin-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[0694]

[0695] Under nitrogen protection, intermediate 2: 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (54 mg), 7-methyl-[1,2,4]triazol[4,3-a]pyridine-6-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (34 mg).

[0696] 1 H NMR(400MHz,DMSO)δ9.08(s,1H),8.65(s,1H),8.34(s,1H),8.05(s,1H),7.67(s,1H),4.33-4.43(m,1H),3.92 (dd,J=11.2Hz,4.0Hz,2H),3.33-3.42(m,2H),3.27(s,3H),2.41-2.54(m,2H),2.36(s,3H),1.60-1.68(m,2H).

[0697] Example 85: 4-(7-(methyl-d3)-2-((7-methyl-[1,2,4]triazol[4,3-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0698]

[0699] Following Example 71, the target compound (24 mg) was obtained by catalytic coupling reaction using 7-methyl-[1,2,4]triazole[4,3-a]pyridine-6-amine as a substitute amine.

[0700] 1 H NMR(400MHz,DMSO)δ9.58(s,1H),8.26(s,1H),7.97(s,1H),7.57(s,1H),6.68 (s,1H),4.08-4.13(m,2H),3.86-3.92(m,2H),2.75-2.85(m,4H),2.49(s,3H).

[0701] Example 86: (E)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7H-3-aza-2(9,2)-purine-4(6,3)-[1,2,4]triazole[4,3-a]pyridine-1(4,1)-piperidinecyclohexane-2 8 6-Diketone

[0702]

[0703]

[0704] Step 1: Methyl 2-(7-methyl-6-nitro-[1,2,4]triazol[4,3-a]pyridin-3-yl)acetate

[0705] At room temperature, 1.68 g of 2-hydrazino-4-methyl-5-nitropyridine and 1.18 g of monomethyl malonate were dissolved in 50 mL of toluene, and 3.1 g of phosphorus oxychloride was added. The reaction mixture was stirred at 90 °C for 12 hours. After cooling to room temperature, the reaction was quenched with methanol, the reaction solution was concentrated under reduced pressure, evaporated to dryness, and the residue was purified by column chromatography (eluent: dichloromethane:methanol = 50:1 (V:V)) to give the title compound (1.2 g).

[0706] Step 2: 2-(7-methyl-6-nitro-[1,2,4]triazol[4,3-a]pyridin-3-yl)acetic acid

[0707] At room temperature, methyl 2-(7-methyl-6-nitro-[1,2,4]triazol[4,3-a]pyridin-3-yl)acetate (1.2 g) was dissolved in MeOH (30 mL), and 1 M lithium hydroxide aqueous solution (30 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, and the pH of the system was adjusted to 4 with 1 M dilute hydrochloric acid aqueous solution, resulting in precipitation. The solid was filtered and dried to give the title compound (900 mg).

[0708] Step 3: 2-Chloro-7-methyl-9-(1-(2-(7-methyl-6-nitro-[1,2,4]triazol[4,3-a]pyridin-3-yl)acetyl)piperidin-4-yl)-7,9-dihydro-8H-purine-8-one

[0709] At 0 °C, 900 mg of 2-(7-methyl-6-nitro-[1,2,4]triazol[4,3-a]pyridin-3-yl)acetic acid, 1.1 g of intermediate 6,2-chloro-7-methyl-9-(piperidin-4-yl)-7,9-dihydro-8H-purine-8-one, and 2.9 g of HATU were dissolved in DMF (30 mL), and 1.5 mL of DIEA was added. The reaction mixture was stirred at room temperature for 12 hours, then poured into water (100 mL) with constant stirring. The precipitate was collected and filtered to give the title compound (1.5 g).

[0710] Step 4: 9-(1-(2-(6-amino-7-methyl-[1,2,4]triazol[4,3-a]pyridin-3-yl)acetyl)piperidin-4-yl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one)

[0711] At room temperature, 1.6 g of reduced iron powder was added to a 50 mL acetic acid solution of 1.5 g of 2-chloro-7-methyl-9-(1-(2-(7-methyl-6-nitro-[1,2,4]triazol[4,3-a]pyridin-3-yl)acetyl)piperidin-4-yl)-7,9-dihydro-8H-purine-8-one (1.5 g). The reaction was stirred at room temperature for 2 hours. The reaction solution was filtered through diatomaceous earth and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution: dichloromethane:methanol = 10:1 (V:V)) to give a white solid (1.21 g).

[0712] Step 5: (E)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3-aza-2(9,2)-purine-4(6,3)-[1,2,4]triazole[4,3-a]pyridine-1(4,1)-piperidinecyclohexane-2 8 6-Diketone

[0713] Under nitrogen protection, 9-(1-(2-(6-amino-7-methyl-[1,2,4]triazol[4,3-a]pyridin-3-yl)acetyl)piperidin-4-yl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one (46 mg), RuPhos PdG3 (9 mg), and cesium carbonate (65 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to obtain the target compound (16 mg).

[0714] 1 H NMR(400MHz,DMSO-d6)8.93(s,1H),8.72(s,1H),7.98(s,1H),7.54(s,1H),4.28-4.70(m,2H),3.93-4.13(m,2H), 3.73(d,J=16.0Hz,1H),3.15-3.24(m,4H),2.74-2.88(m,1H),2.25(s,3H),1.38-1.59(m,2H),0.79-0.90(m,2H).

[0715] Example 87: 4-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carboxylic acid

[0716]

[0717] At room temperature, 50 mg of 7-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carboxamide from Example 784 was dissolved in 5 mL of dioxane, 1 mL of 2 M KOH aqueous solution was added, and the mixture was heated to 90 °C and stirred for 12 hours. After cooling to room temperature, the pH of the system was adjusted to 5 with 1 M dilute hydrochloric acid aqueous solution. The reaction solution was then evaporated to dryness under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to obtain the target compound (10 mg).

[0718] 1 H NMR(400MHz,DMSO-d6)8.96(s,1H),8.67(s,1H),8.36(s,1H),8.13(s,1H),7.68(s,1H),3.60-3 .67(m,2H),3.48-3.55(m,2H),3.27(s,3H),2.92-3.01(m,2H),2.32(s,3H),2.01-2.09(m,2H).

[0719] Example 88: (E)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3-aza-2(9,2)-purine-4(6,3)-[1,2,4]triazole[4,3-a]pyridine-1(4,1)-piperidinecycloheptane-2 8 7-Diketone

[0720]

[0721] The compound was synthesized using monomethyl succinate as a starting material, following the synthesis method of Example 86.

[0722] MS(ESI) m / z 434.17(M+H) +

[0723] Example 89: (1) 1 r,1 4r)-4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5,8-dioxo-3-aza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[0724]

[0725]

[0726] Step 1: 2-((1r,4r)-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)cyclohexyl)oxy)ethyl acetate

[0727] 2-Chloro-9-((1r,4r)-4-hydroxycyclohexyl)-7-methyl-7,9-dihydro-8H-purin-8-one (283 mg) and rhodium dimer acetate (9 mg) were dissolved in dichloromethane (20 mL) at room temperature. Ethyl diazonate (8 mL, 15% toluene solution) was added, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane:methanol = 30:1 (V:V)) to give the title compound (184 mg).

[0728] Step 2: 2-Chloro-9-((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)-7-methyl-7,9-dihydro-8H-purine-8-one

[0729] At -78°C, 184 mg of ethyl acetate 2-((1r,4r)-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexyl)oxy)ethyl acetate was dissolved in toluene (20 mL), and 3 mL of 1 MDI BAL-H toluene solution was added. The reaction mixture was heated to room temperature and stirred for 12 hours. The reaction solution was poured into water, and the pH of the system was adjusted to 3 with 1 M dilute hydrochloric acid aqueous solution. Ethyl acetate was added for extraction, the organic phase was separated and concentrated under reduced pressure, evaporated to dryness, and the residue was purified by column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (114 mg).

[0730] Step 3: 2-Chloro-9-((1r,4r)-4-(2-(2,4-dimethyl-5-nitrophenoloxy)ethoxy)cyclohexyl)-7-methyl-7,9-dihydro-8H-purine-8-one

[0731] At 0 °C, DIAD (140 mg) was slowly added dropwise to a toluene (20 mL) solution of 2-chloro-9-((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)-7-methyl-7,9-dihydro-8H-purin-8-one (114 mg), 2-chloro-4-methyl-5-nitrophenol (65 mg), and triphenylphosphine (190 mg). After the addition was complete, the mixture was brought to room temperature and stirred for 12 hours. Methanol (2 mL) was added to the reaction mixture and stirred for 1 hour. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution: petroleum ether: ethyl acetate = 1:1 (V:V)) to give a pale yellow solid (140 mg).

[0732] Step 4: 9-((1r,4r)-4-(2-(5-amino-2,4-dimethylphenoxy)ethoxy)cyclohexyl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one

[0733] At room temperature, 150 mg of reduced iron powder was added to a 10 mL acetic acid solution of 140 mg of 2-chloro-9-((1r,4r)-4-(2-(2,4-dimethyl-5-nitrophenoloxy)ethoxy)cyclohexyl)-7-methyl-7,9-dihydro-8H-purine-8-one (140 mg). The mixture was stirred at room temperature for 2 hours, filtered through diatomaceous earth, and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution: dichloromethane:methanol = 10:1 (V:V)) to give a white solid (100 mg).

[0734] Step 5: (1) 1 r,1 4 r)-4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5,8-dioxo-3-aza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[0735] Under nitrogen protection, 9-((1r,4r)-4-(2-(5-amino-2,4-dimethylphenoxy)ethoxy)cyclohexyl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one (44 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (65 mg) were dissolved in dioxane (10 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to obtain the target compound (26 mg).

[0736] MS(ESI) m / z 430.15(M+H) +

[0737] Example 90: (S)-4 4 -Chloride-2 7 4 6 ,7-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocycloheptane-2 8 -ketone

[0738]

[0739] The compound was synthesized using intermediate 6 and a suitable haloalcohol as starting materials, following the synthetic method of Example 89.

[0740] 1 H NMR (400MHz, DMSO-d6)8.38-8.44(m,1H),7.88-7.91(m,1H),7.14(s,1H),6.92-6.96(m,1H),4.31-4.62(m,2H),3.61- 3.82(m,1H),3.41(s,1.5H),3.40(s,1.5H),2.42-3.23(m,5H),2.26(s,3H),1.50-1.68(m,3.5H),0.98-1.25(m,3.5H).

[0741] Example 91: 9-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one

[0742]

[0743] At -78°C, 42 mg of 4-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carboxylic acid was dissolved in 10 mL of THF, and 15 mg of LAH was added. The reaction mixture was heated to room temperature and stirred for 2 hours. The reaction solution was poured into water, and the pH of the system was adjusted to 3 with 1 M dilute hydrochloric acid aqueous solution. Ethyl acetate was added for extraction, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (12 mg).

[0744] 1 H NMR(400MHz,DMSO-d6)9.48(s,1H),8.24(s,1H),7.89(s,1H),7.56(s,1H),6.63(s,1H),4.1 1(s,2H),3.76-3.81(m,4H),3.38(s,3H),3.26-3.34(m,2H),2.47(s,3H),1.85-1.92(m,2H).

[0745] Example 92: (1) 1 r,1 4 r)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5,8-dioxo-3-aza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexosecyclooctane-2 8 -ketone

[0746]

[0747] The compound was synthesized using intermediate 13 and a suitable nitrophenol as starting materials, following the synthesis method of Example 89.

[0748] 1 H NMR (400MHz, DMSO-d6)8.44-8.58(m,1H),8.35(s,1H),8.20(s,1H),7.98(s,1H),7.80(s,1H),6.86-6.98(m,1H),4.15-4.50(m ,4H),3.74-4.02(m,2H),3.30(s,3H),2.56-2.73(m,2H),2.53(s,3H),1.88-2.04(m,2H),1.68-1.83(m,2H),1.10-1.38(m,2H).

[0749] Example 93: 4-(2-((4-amino-7-methylquinazoline-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0750]

[0751] Step 1: 2-Amino-4-methyl-5-nitrobenzene

[0752] 300 mg of 2-fluoro-4-methyl-5-nitrobenzenenitrile and 10 mL of ammonia-ethanol saturated solution were placed in a sealed tube, heated to 80 °C and stirred for 3 hours. After cooling to room temperature, a precipitate was formed when the reaction solution was poured into water (30 mL). The solid was filtered and dried to give the title compound (180 mg).

[0753] Step 2: 7-Methyl-6-nitroquinazoline-4-amine

[0754] A solution of 180 mg of 2-amino-4-methyl-5-nitrobenzene in 10 mL of formamide was heated to 180 °C and stirred for 8 hours. After cooling to room temperature, the reaction solution was poured into water, and a precipitate was formed. The solid was filtered and dried to give the title compound (120 mg).

[0755] Step 3: 7-Methylquinazoline-4,6-diamine

[0756] At room temperature, 250 mg of reduced iron powder was added to a 10 mL solution of 120 mg of 7-methyl-6-nitroquinazolin-4-amine in acetic acid. The reaction mixture was stirred at room temperature for 12 hours. The reaction solution was filtered through diatomaceous earth and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 10:1 (V:V)) to obtain a white solid (100 mg).

[0757] Step 4: 4-(2-((4-amino-7-methylquinazoline-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0758] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 7-methylquinazoline-4,6-diamine (35 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were sequentially added to a flask containing dioxane (20 mL). The reaction flask was purged with nitrogen three times and heated to 100 °C with stirring for 2 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to obtain the target compound (23 mg).

[0759] 1 H NMR(400MHz,DMSO-d6)8.82(s,1H),8.27(s,1H),8.22(s,1H),8.18(s,1H),7.53(s,2H),7.4 9(s,1H),3.78-3.85(m,2H),3.46-3.55(m,2H),3.29(s,3H),2.56-2.70(m,4H),2.36(s,3H).

[0760] Example 94: 7-(methyl-d3)-2-((6-methyl-[1,2,4]triazol[1,5-a]pyridin-7-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[0761]

[0762] Following Example 71, the target compound (33 mg) was synthesized in two steps using CD3I (deuterated iodomethane) instead of CH3I as a substitute raw material.

[0763] 1 H NMR(400MHz,DMSO-d6)8.71(s,1H),8.54(s,1H),8.40(s,1H),8.21-8.25(m,2H),4.39-4.49(m,1H),3.9 5(dd,J=11.6Hz,4.0Hz,2H),3.40(t,J=11.6Hz,2H),2.44-5.57(m,2H),2.36(s,3H),1.63-1.71(m,2H).

[0764] Example 95: (1) 1 r,1 4 r)-4 4 -Chloride-2 7 4 6 -dimethyl-28 ,2 9 -dihydro-2 7 H-5-oxa-3,8-diaza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexaneoctadecane-2 8 -ketone

[0765]

[0766] Step 1: 2-Chloro-7-methyl-9-(4-oxocyclohexyl)-7,9-dihydro-8H-purine-8-one

[0767] 2-Chloro-9-((1r,4r)-4-hydroxycyclohexyl)-7-methyl-7,9-dihydro-8H-purine-8-one (566 mg) was dissolved in dichloromethane (20 mL) at room temperature, and Dess-Martin oxidant (900 mg) was slowly added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane (100 mL), and the organic phase was separated, dried, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 30:1 (V:V)) to give the title compound (530 mg).

[0768] Step 2: 2-Chloro-9-((1r,4r)-4-((2-hydroxyethyl)amino)cyclohexyl)-7-methyl-7,9-dihydro-8H-purine-8-one

[0769] At 0 °C, 530 mg of 2-chloro-7-methyl-9-(4-oxocyclohexyl)-7,9-dihydro-8H-purine-8-one and ethanolamine (250 mg) were dissolved in 30 mL of dichloromethane, and 200 mg of acetic acid and 900 mg of sodium triacetoxyborohydride were added sequentially. The reaction mixture was stirred at room temperature for 12 hours, the reaction solution was poured into water, and extracted with dichloromethane. The organic phase was separated and concentrated under reduced pressure. After evaporation to dryness, the residue was purified by column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (200 mg) and its isomer (190 mg).

[0770] Step 3: tert-butyl((1r,4r)-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexyl)(2-hydroxyethyl)carbamate

[0771] At 0 °C, (Boc)₂O (200 mg) was slowly added dropwise to a solution of 2-chloro-9-((1r,4r)-4-((2-hydroxyethyl)amino)cyclohexyl)-7-methyl-7,9-dihydro-8H-purine-8-one (200 mg) in dichloromethane (20 mL). After the addition was complete, the mixture was brought to room temperature and stirred for 12 hours. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution: petroleum ether: ethyl acetate = 1:1 (V:V)) to give the title compound (170 mg).

[0772] Step 4: tert-butyl((1r,4r)-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexyl)(2-(2,4-dimethyl-5-nitrophenoxy)ethyl)carbamate

[0773] At 0 °C, DIAD (200 mg) was slowly added dropwise to a toluene (20 mL) solution of tert-butyl((1r,4r)-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexyl)(2-hydroxyethyl)carbamate (170 mg), 2-chloro-4-methyl-5-nitrophenol (100 mg), and triphenylphosphine (263 mg). After the addition was complete, the mixture was brought to room temperature and stirred for 12 hours. Methanol (2 mL) was added to the reaction mixture and stirred for 1 hour. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution: petroleum ether: ethyl acetate = 1:1 (V:V)) to give a pale yellow solid (150 mg).

[0774] Step 5: 9-((1r,4r)-4-((2-(5-amino-2,4-dimethylphenoxy)ethyl)amino)cyclohexyl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one

[0775] At room temperature, 200 mg of reduced iron powder was added to a 15 mL acetic acid solution of tert-butyl((1r,4r)-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexyl)(2-(2,4-dimethyl-5-nitrophenoxy)ethyl)carbamate (150 mg). The mixture was stirred at room temperature for 12 hours. The reaction solution was filtered through diatomaceous earth and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution: dichloromethane:methanol = 10:1 (V:V)) to give a white solid (90 mg).

[0776] Step 6: (1) 1 r,1 4 r)-4 4 -Chloride-2 7 4 6 -dimethyl-2 8,2 9 -dihydro-2 7 H-5-oxa-3,8-diaza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexaneoctadecane-2 8 -ketone

[0777] Under nitrogen protection, 9-((1r,4r)-4-((2-(5-amino-2,4-dimethylphenoxy)ethyl)amino)cyclohexyl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one (45 mg), RuPhos PdG3 (9 mg), and cesium carbonate (65 mg) were dissolved in dioxane (10 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to obtain the target compound (11 mg).

[0778] 1 HNMR(400MHz, CDCl3)8.50(s,1H),7.90(s,1H),7.12(s,1H),6.96(s,1H),4.71-4.78(m,2H),4.53-4.65(m,1H),3.72-3.80(m, 1H),3.48-3.55(m,2H),3.40(s,3H),2.74-2.86(m,2H),2.42-2.52(m,2H),2.28(s,3H),2.03-2.13(m,2H),1.80-1.94(m,2H).

[0779] Example 96: (1) 1 s,1 4 s)-4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3,8-diaza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexaneoctadecane-2 8 -ketone

[0780]

[0781] The isomer obtained in the second step of the synthesis method of Example 95 was used to synthesize the compound (21 mg).

[0782] 1H NMR(400MHz, CDCl3)8.43(s,1H),7.88(s,1H),7.13(s,1H),6.86(s,1H),4.31-4.42(m,3H),3.41 (s,3H),2.95-3.07(m,3H),2.80-2.93(m,2H),2.26(s,3H),1.94-2.08(m,2H),1.54-1.71(m,4H).

[0783] Example 97: 7-(methyl-d3)-2-((7-methyl-[1,2,4]triazol[4,3-a]pyridin-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[0784]

[0785] Following Example 94, the target compound (43 mg) was synthesized using 7-methyl-[1,2,4]triazole[4,3-a]pyridine-6-amine.

[0786] 1 H NMR(400MHz,DMSO-d6)9.09(s,1H),8.81(s,1H),8.58(s,1H),8.05(s,1H),7.60(s,1H),4.34-4.44(m,1H), 3.94(dd,J=11.6Hz,3.6Hz,2H),3.39(t,J=11.6Hz,2H),2.42-2.55(m,2H),2.309s,3H),1.60-1.67(m,2H).

[0787] Example 98: (R)-4 4 -Chloride-2 7 4 6 ,6-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocycloheptane-2 8 -ketone

[0788]

[0789] The compound was synthesized using intermediate 6 and a suitable haloalcohol as starting materials, following the synthetic method of Example 89.

[0790] 1H NMR(400MHz, CDCl3)8.26(s,1H),7.91(s,1H),7.16(s,1H),6.98(s,1H),4.44-4.66(m,2H ),3.60-4.02(m,2H),3.41(s,3H),2.50-3.32(m,8H),2.27(s,3H),1.65(d,J=5.2Hz,3H).

[0791] Example 99: (E)-4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-O-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocyclononane-7-ene-2 8 ,9-Diketone

[0792]

[0793] The compound was synthesized using intermediates 6 and 4-bromocrotonic acid as starting materials, following the synthesis method of Example 89.

[0794] 1 H NMR (400MHz, DMSO-d6)8.42(s,1H),8.17(s,1H),7.88(s,1H),7.21(s,1H),6.43(d,J=6.4Hz,1H),5.14-5.20(m,1H),4.32-4.44(m,2H),3.85-3 .94(m,1H),3.30(s,3H),3.07(d,J=7.6Hz,2H),2.50-2.59(m,1H),2.27 -2.44(m,2H),2.17-2.27(m,4H),1.68-1.76(m,1H),1.52-1.59(m,1H).

[0795] Example 100: 1-Methyl-4-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)piperidin-4-carbamate

[0796]

[0797] Step 1: 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-1-methylpiperidin-4-carbamate

[0798] At 0 °C, 60% (mineral oil) sodium hydride (80 mg) was slowly added to a DMF (10 mL) solution of 292 mg of 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidine-4-carbamate (292 mg). After the addition was complete, the mixture was stirred at 0 °C for 10 minutes. Subsequently, 0.15 g of iodomethane was slowly added to the reaction solution at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (90 mg).

[0799] Step 2: 1-Methyl-4-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)piperidin-4-carbamate

[0800] Under nitrogen protection, 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-1-methylpiperidin-4-carbamate (62 mg), 7-methyl-[1,2,4]triazol[1,5-a]pyridine-6-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were sequentially added to a flask containing dioxane (20 mL). The reaction flask was purged with nitrogen three times and heated to 100 °C with stirring for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to obtain the target compound (53 mg).

[0801] 1 H NMR(400MHz,DMSO-d6)9.06(s,1H),8.75(s,1H),8.35(s,1H),8.17(s,1H),7.67(s,1H ),3.27(s,3H),2.73-2.82(m,2H),2.58-2.71(m,4H),2.35(s,3H),2.10-2.25(m,5H).

[0802] Example 101: 1-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)-4-oxocyclohexane-1-carbamate

[0803]

[0804] Under nitrogen protection, intermediate 131-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-4-oxocyclohexane-1-carbamate (61 mg), 7-methyl-[1,2,4]triazol[1,5-a]pyridine-6-amine (30 mg), RuPhosPdG3 (9 mg), and cesium carbonate (130 mg) were sequentially added to a flask containing dioxane (20 mL). The reaction flask was purged with nitrogen three times, heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (43 mg).

[0805] 1 H NMR(400MHz,DMSO-d6)9.05(s,1H),8.79(s,1H),8.35(s,1H),8.20(s,1H),7.68(s,1H ),3.30(s,3H),3.18-3.27(m,2H),2.71-2.81(m,2H),2.36-2.45(m,4H),2.34(s,3H).

[0806] Example 102: 4-amino-1-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)cyclohexane-1-carbamate

[0807]

[0808] 1-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)-4-oxocyclohexane-1-carbamate (42 mg) and ammonium formate (30 mg) were dissolved in tetrahydrofuran (20 mL), and sodium cyanoborohydride (30 mg) was added and stirred for 12 hours. The reaction solution was poured into water and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to give the target compound (23 mg).

[0809] 1H NMR(400MHz,DMSO-d6)9.09(s,0.6H),9.04(s,0.4H),8.77(s,0.4H),8.75(s,0.6H),8.35(s,0 .4H),8.34(s,0.6H),8.20(s,0.4H),8.18(s,0.6H),7.68(s,0.4H),7.67(s,0.6H),3.28(s,3H) ,3.22-3.27(m,1H),2.97-3.05(m,0.6H),2.62-2.80(m,1.4H),2.40-2.52(m,1H),2.36(s,1.8 H),2.35(s,1.2H),2.10-2.21(m,1H),1.85-1.93(m,1H),1.65-1.74(m,1H),1.38-1.52(m,2H).

[0810] Example 103: (1s,4s)-4-hydroxy-1-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)cyclohexane-1-carbamate

[0811]

[0812] 1-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)-4-oxocyclohexane-1-carbamate (42 mg) was dissolved in methanol (5 mL), and sodium borohydride (20 mg) was added and stirred for 1 hour. The reaction solution was poured into water and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to obtain the target compound (17 mg) and its isomers.

[0813] 1 H NMR(400MHz,DMSO-d6)9.05(s,1H),8.73(s,1H),8.34(s,1H),8.16(s,1H),7.67(s,1H),4.60(s ,1H),3.74-3.82(m,1H),3.28(s,3H),2.80-2.82(m,2H),2.30-2.42(m,5H),1.59-1.75(m,4H).

[0814] Example 104: (1s,4s)-4-hydroxy-1-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)cyclohexane-1-carbamate

[0815]

[0816] The target compound was the isomer of Example 103 (14 mg).

[0817] 1 H NMR(400MHz, DMSO-d6)9.08(s,1H),8.74(s,1H),8.35(s,1H),8.17(s,1H),7.67(s,1H),4.80(d,J=5.2Hz,1H),3.33 -3.47(m,1H),3.27(s,3H),2.57-2.65(m,2H),2.48-2.56(m,2H),2.35(s,3H),1.83-1.92(m,2H),1.39-1.52(m,2H).

[0818] Example 105: 4-(7-(methyl-d3)-2-((7-methyl-[1,2,4]triazol[4,3-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0819]

[0820] Following Example 71, the target compound (34 mg) was obtained by catalytic coupling reaction using 7-methyl-[1,2,4]triazole[4,3-a]pyridine-6-amine as a substitute amine.

[0821] 1 H NMR(400MHz, CDCl3)9.38(s,1H),8.80(s,1H),8.00(s,1H),7.59(s,1H),6.74(s,1H),4 .07-4.13(m,2H),3.83-3.92(m,2H),2.84-2.92(m,2H),2.62-2.69(m,2H),2.46(s,3H).

[0822] Example 106: 9-(4-ethyltetrahydro-2H-pyran-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one

[0823]

[0824] Step 1: 4-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-aminocarboxaldehyde

[0825] At room temperature, 82 mg of 919-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one was dissolved in dichloromethane (20 mL), and 100 mg of Dess-Martin oxidant was slowly added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane (100 mL), and the organic phase was separated, dried, and concentrated under reduced pressure. The crude product (60 mg) was used directly in the next step without purification.

[0826] Step 2: 9-(4-ethyltetrahydro-2H-pyran-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one

[0827] At 0 °C, dimethyl (1-diazo-2-oxopropyl)phosphonate (40 mg) was dissolved in methanol (10 mL), and potassium carbonate (70 mg) and 4-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-aminocarboxaldehyde (60 mg) were added sequentially. The reaction mixture was heated to room temperature and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, evaporated to dryness, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to obtain the target compound (14 mg).

[0828] 1 H NMR(400MHz, CDCl3)9.83(s,1H),8.31(s,1H),7.76-8.02(m,2H),6.76(s,1H),3. 89-4.02(m,4H),3.39(s,3H),2.77-2.83(m,3H),2.62-2.72(m,2H),2.52(s,3H).

[0829] Example 107: 9-(4-(fluoromethyl)tetrahydro-2H-pyran-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one

[0830]

[0831] Step 1: tert-butyl(7-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)(7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)carbamate

[0832] At room temperature, 82 mg of 9-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one was dissolved in 20 mL of dichloromethane. Di-tert-butyl dicarbonate (100 mg), triethylamine (100 mg), and DMAP (10 mg) were added to the mixture sequentially, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 50 mL of saturated sodium bicarbonate aqueous solution and extracted with 100 mL of dichloromethane. The organic phase was separated, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 30:1 (V:V)) to obtain the target compound (100 mg).

[0833] Step 2: tert-butyl(9-(4-(fluoromethyl)tetrahydro-2H-pyran-4-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)(7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)carbamate

[0834] At 0 °C, 100 mg of tert-butyl(7-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)(7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)carbamate was dissolved in 15 mL of THF, and 150 mg of diethylaminotrifluoride was added. The reaction mixture was heated to 50 °C and stirred for 12 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (50 mL) and extracted with dichloromethane (100 mL). The organic phase was separated, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 30:1 (V:V)) to obtain the target compound (60 mg).

[0835] Step 3: 9-(4-(fluoromethyl)tetrahydro-2H-pyran-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one

[0836] At 0 °C, tert-butyl(9-(4-(fluoromethyl)tetrahydro-2H-pyran-4-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)(7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)carbamate (60 mg) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1.5 mL) was added. The reaction mixture was heated to room temperature and stirred for 2 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (100 mL) and extracted with dichloromethane (100 mL). The organic phase was separated, dried, and concentrated under reduced pressure. The reaction solution was concentrated under vacuum, evaporated to dryness, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (33 mg).

[0837] 1 H NMR(400MHz, CDCl3)9.60(s,1H),8.33(s,1H),7.80-7.97(m,2H),6.64(s,1H),4.71(d,J=47.2H z,2H),3.87-3.93(m,2H),3.62-3.68(m,2H),3.34-3.42(m,5H),2.50(s,3H),1.94-2.02(m,2H).

[0838] Example 108: 2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3,5-diaza-4(6,4)-quinazoline-2(9,2)-purine-1(4,1)-piperidinecycloheptane-2 8 -ketone

[0839]

[0840] Step 1: N-(2,2-dimethoxyethyl)-7-methyl-6-nitroquinazolin-4-amine

[0841] 7-Methyl-6-nitroquinazolin-4-amine (0.204 g) and 2-bromo-1,1-dimethoxyethane (0.170 g) were dissolved in DMF (30 mL), and anhydrous potassium carbonate (0.280 g) was slowly added at room temperature. The reaction mixture was heated to 80 °C and stirred for 2 hours. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (200 mL), extracted with ethyl acetate (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution: petroleum ether: ethyl acetate = 1:1 (V:V)) to give a yellow solid (0.20 g).

[0842] Step 2: 2-((7-methyl-6-nitroquinazolin-4-yl)amino)acetaldehyde

[0843] The above-mentioned N-(2,2-dimethoxyethyl)-7-methyl-6-nitroquinazolin-4-amine (200 mg) was dissolved in 4M hydrochloric acid (20 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a pale yellow solid (150 mg).

[0844] Step 3: 2-Chloro-7-methyl-9-(1-(2-((7-methyl-6-nitroquinazolin-4-yl)amino)ethyl)piperidin-4-yl)-7,9-dihydro-8H-purine-8-one

[0845] At 0 °C, 134 mg of 2-chloro-7-methyl-9-(4-oxocyclohexyl)-7,9-dihydro-8H-purine-8-one and 123 mg of 2-(7-methyl-6-nitroquinazolin-4-yl)amino)acetaldehyde were dissolved in 50 mL of THF, and 300 mg of sodium triacetoxyborohydride was added. The reaction mixture was heated to room temperature and stirred for 12 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was separated and concentrated under reduced pressure. After evaporation to dryness, the residue was purified by column chromatography (eluent: dichloromethane:methanol = 15:1 (V:V)) to give the title compound (140 mg).

[0846] Step 4: 9-(1-(2-((6-amino-7-methylquinazoline-4-yl)amino)ethyl)piperidin-4-yl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one)

[0847] At room temperature, 0.2 g of reduced iron powder was added to a 15 mL acetic acid solution of 140 mg of 2-chloro-7-methyl-9-(1-(2-(((7-methyl-6-nitroquinazolin-4-yl)amino)ethyl)piperidin-4-yl)-7,9-dihydro-8H-purine-8-one. The mixture was then heated to 45 °C and stirred for 2 hours. After cooling, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution: dichloromethane:methanol = 10:1 (V:V)) to obtain the title compound (100 mg).

[0848] Step 5: 2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3,5-diaza-4(6,4)-quinazoline-2(9,2)-purine-1(4,1)-piperidinecycloheptane-2 8 -ketone

[0849] Under nitrogen protection, 9-(1-(2-((6-amino-7-methylquinazoline-4-yl)amino)ethyl)piperidin-4-yl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one (47 mg), RuPhos PdG3 (9 mg), and cesium carbonate (65 mg) were dissolved in dioxane (10 mL), heated to 100 °C, and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to give the target compound (14 mg).

[0850] 1 H NMR(400MHz, CDCl3)8.90(s,1H),8.53(s,1H),8.09-8.17(br,1H),7.96(s,1H),7.67(s,1H),7.31(s,1H),4.53-4.63(m,1H),3.58-3.63( m,2H),3.44(s,3H),2.96-3.01(m,2H),2.93(t,J=6.0Hz,2H),2.52-2.61(m,5H),1.89-1.93(m,2H),1.19-1.31(m,1H),0.81-0.83(m,1H).

[0851] Example 109: 1-Methyl-4-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)piperidin-4-carbamate

[0852]

[0853] Following Example 100, the target compound (44 mg) was obtained by catalytic coupling reaction using 7-methylquinoline-6-amine as a substitute amine.

[0854] 1 H NMR (400MHz, CDCl3)8.75(dd,J=4.4Hz,1.6Hz,1H),8.68(s,1H),8.17(dd,J=8.4Hz,1.6Hz,1H),7.99(s,1H),7.91( s,1H),7.32(dd,J=8.4Hz,4.4Hz,1H),7.07(s,1H),3.40(s,3H),2.81-2.99(m,6H),2.49-2.49(m,5H),2.37(s,3H).

[0855] Example 110: (1) 3 R)-4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2(9,2)-purine-1(3,1)-pyrrolidine-4(1,3)-benzocycloheptane-2 8 -ketone

[0856]

[0857] Following the synthesis method of intermediate 16 and Example 7, the target compound (34 mg) was synthesized using tert-butyl(R)-3-aminopyrrolidine-1-carboxylate as the starting material.

[0858] 1 H NMR(400MHz, CDCl3)9.21(s,1H),7.89(s,1H),7.07(s,1H),6.89-6.95(br,1H),5.06-5.14(m,1H),4.30-4.36(m,1H),4.17-4 .23(m,1H),3.83-3.88(m,1H),3.41(s,3H),3.19-3.28(m,2H),2.64-2.69(m,1H),2.49(t,J=10.0Hz,1H),2.11-2.36(m,6H).

[0859] Example 111: 4 4 -Chloride-2 7 4 6 -dimethyl-2 8-Oxyto-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocycloheptane-1 4 -Carbide

[0860]

[0861] Following the synthesis method of Example 7, the target compound (23 mg) was synthesized using intermediate 16 as a starting material.

[0862] 1 H NMR(400MHz, CDCl3)8.46(s,1H),7.93(s,1H),7.13(s,1H),6.86(s,1H),4.09(t,J=4.4Hz,2H),3.58(td, J=12.4Hz, 4.4Hz, 2H), 3.40 (s, 3H), 2.96-3.03 (m, 2H), 2.83-2.92 (m, 4H), 2.27 (s, 3H), 2.04-2.09 (m, 2H).

[0863] Example 112: 4-(hydroxyimino)-1-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbamate

[0864]

[0865] Example 1011-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)-4-oxocyclohexane-1-carbamate (42 mg) and hydroxylamine hydrochloride (20 mg) were refluxed in ethanol (10 mL) for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (34 mg).

[0866] 1 HNMR(400MHz, CDCl3)9.58(s,1H),8.27(s,1H),7.97(s,1H),7.58(s,1H),7.07-7.14(br,1H),6 .69(s,1H),3.43-3.50(m,1H),3.41(s,3H),2.63-2.92(m,6H),2.49(s,3H),2.35-2.44(m,1H).

[0867] Example 113: 2-(4-(7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purine-9-yl)piperidin-1-yl)acetonitrile

[0868]

[0869] The target compound (39 mg) was synthesized following the procedure described in Example 31.

[0870] 1 H NMR(400MHz, CDCl3)9.09(s,1H),8.63(s,1H),8.33(s,1H),8.04(s,1H),7.67(s,1H),4.10-4.19(m,1H),3.72 (s,2H),3.26(s,3H),2.86-2.92(m,2H),2.46-2.57(m,2H),2.36(s,3H),2.19-2.28(m,2H),1.68-1.75(m,2H).

[0871] Example 114: 2 7 4 7 -dimethyl-2 8 -Oxyto-2 8 ,2 9 -dihydro-2 7 H-8-O-3,5-diaza-4(6,4)-quinazolin-2(9,2)-purine-1(1,4)-cyclohexane-1 1 -Carbide

[0872]

[0873] The compound was synthesized using 7-methyl-6-nitroquinazoline-4-amine as the starting material, following the synthesis method of Example 108.

[0874] 1H NMR(400MHz, CDCl3)8.16(s,1H),7.96(s,1H),7.83(s,1H),7.61(s,1H),6 .82-6.99(br,1H),4.56(d,J=14.0Hz,1H),4.32-4.39(m,1H),3.69-3.80( m,2H),3.32(s,3H),2.75-2.92(m,2H),2.36(s,3H),2.18-2.26(m,1H),2. 01-2.09(m,1H),1.88-1.98(m,1H),1.44-1.62(m,3H),1.10-1.20(m,1H).

[0875] Example 115: (E)-4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-O-3-aza-2(9,2)-purine-1(4,1)-piperidine-4(1,3)-benzocyclononane-7-ene-2 8 -ketone

[0876]

[0877] The synthetic compound was prepared using (E)-1,4-dibromo-2-ene according to the method described in Example 7.

[0878] 1 H NMR (400MHz, CDCl3)8.34-8.58(br,1H),7.87(s,1H),7.17(s,1H),6.97(s,1H),6.25(d,J=6.4Hz,1H),4.52-4.76(m,1H),4. 30-4.44(m,1H),3.40(s,3H),2.96-3.16(m,2H),2.79-2.91(m,2H),2.19-2.67(m,7H),1.57-1.78(m,3H),0.79-0.85(m,1H).

[0879] Example 116: (1 3 S)-4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2(9,2)-purine-1(3,1)-piperidine-4(1,3)-benzocycloheptane-28 -ketone

[0880]

[0881] The compound was synthesized using (S)-tert-butyl-3-aminopiperidine-1-carboxylate according to the synthesis method of Example 110.

[0882] 1 HNMR(400MHz, CDCl3)8.33(s,1H),7.86(s,1H),7.12(s,1H),6.81(s,1H),4.64-4.74(m,1H),4.35-4.44(m,1H),4.11-4.19(m,1H),3.42-3 .51(m,1H),3.36(s,3H),3.23-3.31(m,1H),2.92-3.06(m,2H),2.76- 2.89(m,2H),2.57-2.71(m,1H),2.16-2.26(m,4H),1.60-1.78(m,2H).

[0883] Example 117: (1) 1 s,1 4 s)-4 4 -Fluorine-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3,8-diaza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexaneoctadecane-2 8 -ketone

[0884]

[0885] The compound (25 mg) was synthesized using 2-fluoro-4-methyl-5-nitrophenol, following the synthesis method of Example 95.

[0886] 1H NMR (400MHz, DMSO-d6)8.98-9.07(br,2H),8.43(s,1H),8.17(s,1H),7.95(d,J=8.8Hz,1H),7.10(d,J=12.8Hz,1H),4.51-4.57(m,2H),4. 35-4.47(m,1H),3.40-3.47(m,2H),3.29(s,3H),2.44-2.60(m,3H),2 .24(s,3H),2.16-2.23(m,2H),1.86-1.95(m,2H),1.46-1.58(m,2H).

[0887] Example 118: (1 1 r,1 4 r)-4 4 -Fluorine-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3,8-diaza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[0888]

[0889] The compound (10 mg) was synthesized using 2-fluoro-4-methyl-5-nitrophenol, following the synthesis method of Example 95.

[0890] 1 H NMR (400MHz, DMSO-d6)8.17(s,1H),8.11(s,1H),7.85(d,J=8.0Hz,1H),7.01(d,J=13.2Hz,1H),4.0 5-4.20(m,3H),3.28(s,3H),2.57-2.78(m,5H),2.20(s,3H),1.76-1.86(m,2H),1.32-1.54(m,4H).

[0891] Example 119: 3 4 -Chloride-1 7 ,3 6 -Dimethyl-1 8 ,1 9 -dihydro-1 7 H-4-O-2-aza-1(2,9)-purine-3(1,3)-benzocyclononane-1 8 -ketone

[0892]

[0893] The compound was synthesized according to the synthesis method of Example 16.

[0894] 1 H NMR(400MHz, CDCl3)7.88(s,1H),7.79(s,1H),7.14(s,1H),6.69-6.82(br,1H),4.15-4.19(m,2H),3.9 1(t,J=6.8Hz,2H),3.41(s,3H),2.22(s,3H),2.04-2.13(m,2H),1.84-1.92(m,2H),1.34-1.42(m,2H).

[0895] Example 120: (1) 1 s,1 4 s)-4 4 -Chloride-2 7 4 6 ,8-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3,8-diaza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[0896]

[0897] At room temperature, Example 96 (1 1 s,1 4 s)-4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3,8-diaza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexaneoctadecane-2 8 - Ketone (43 mg) and potassium carbonate (42 mg) were dissolved in DMF (10 mL), and iodomethane (40 mg) was slowly added to the solution. The reaction mixture was stirred at room temperature for 24 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with ethyl acetate (30 mL), the organic phase was separated and washed with saturated brine (50 mL), dried and concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to give the title compound (14 mg).

[0898] 1H NMR(400MHz, CDCl3)8.48(s,1H),7.87(s,1H),7.12(s,1H),6.84-7.10(br,1H),4.25-4.46(m, 3H),3.41(s,3H),2.70-3.03(m,4H),2.06-2.42(m,9H),1.45-1.62(m,2H),0.98-1.18(m,2H).

[0899] Example 121: (1 1 s,1 4 s)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3,5,8-triaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[0900]

[0901]

[0902] Step 1: N-(2,2-diethoxyethyl)-7-methyl-6-nitroquinoline-4-amine

[0903] 4-Chloro-7-methyl-6-nitroquinoline (2.22 g) and 2,2-diethoxyethane-1-amine (1.33 g) were dissolved in DMF (50 mL), and anhydrous potassium carbonate (2.8 g) was slowly added at room temperature. The reaction mixture was heated to 60 °C and stirred for 2 hours. After cooling, the reaction mixture was poured into a saturated ammonium chloride aqueous solution (200 mL), extracted with ethyl acetate (100 mL), washed with saturated brine and dried over sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:3 (V:V)) to give a yellow solid (2.1 g).

[0904] Step 2: 2-((7-methyl-6-nitroquinoline-4-yl)amino)acetaldehyde

[0905] The above-mentioned N-(2,2-diethoxyethyl)-7-methyl-6-nitroquinoline-4-amine (2.1 g) was dissolved in 4M hydrochloric acid (20 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a pale yellow solid (1.4 g).

[0906] Step 3: 2-Chloro-7-methyl-9-((1s,4s)-4-((2-((7-methyl-6-nitroquinoline-4-yl)amino)ethyl)amino)cyclohexyl)-7,9-dihydro-8H-purine-8-one

[0907] At 0 °C, 2-((7-methyl-6-nitroquinoline-4-yl)amino)acetaldehyde (245 mg) and intermediate 18:9-((1s,4s)-4-aminocyclohexyl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one (282 mg) were dissolved in THF (50 mL), and sodium triacetoxyborohydride (500 mg) was added. The reaction mixture was heated to room temperature and stirred for 12 hours. The reaction solution was poured into water, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was purified by column chromatography (elution: dichloromethane:methanol = 15:1 (V:V)) to give the title compound (170 mg).

[0908] Step 4: 9-((1s,4s)-4-((2-((6-amino-7-methylquinoline-4-yl)amino)ethyl)cyclohexyl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one

[0909] At room temperature, 0.3 g of reduced iron powder was added to a 15 mL acetic acid solution of 170 mg of 2-chloro-7-methyl-9-((1s,4s)-4-((2-(((7-methyl-6-nitroquinoline-4-yl)amino)ethyl)amino)cyclohexyl)-7,9-dihydro-8H-purine-8-one. The mixture was then heated to 45 °C and stirred for 2 hours. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution: dichloromethane:methanol = 10:1 (V:V)) to give the title compound (110 mg).

[0910] Step 5: (1) 1 s,1 4 s)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3,5,8-triaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[0911] Under nitrogen protection, 9-((1s,4s)-4-((2-(((6-amino-7-methylquinoline-4-yl)amino)ethyl)cyclohexyl)-2-chloro-7-methyl-7,9-dihydro-8H-purin-8-one (48 mg), RuPhos PdG3 (9 mg), and cesium carbonate (65 mg) were dissolved in dioxane (10 mL), heated to 100 °C, and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to give the target compound (19 mg).

[0912] 1 H NMR (400MHz, DMSO-d6)8.57(s,1H),8.36(d,J=6.0Hz,1H),8.25(s,1H),8.20(s,1H),7.68(s,1H),6.68(d,J=6.0Hz,1H),4.08-4.1 8(m,1H),3.47-3.54(m,2H),3.32(s,3H),2.82-2.94(m,3H),2.55-2.66(m,2H),2.52(s,3H),1.80-1.88(m,2H),1.49-1.61(m,4H).

[0913] Example 122: 4-(2-((3-amino-7-methyl-[1,2,4]triazol[4,3-a]pyridin-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0914]

[0915] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 7-methyl-[1,2,4]triazol[4,3-a]pyridine-3,6-diamine (33 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL). The reaction flask was purged with nitrogen three times and heated to 100 °C with stirring for 3 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to obtain the target compound (9 mg).

[0916] 1H NMR(400MHz,DMSO-d6)8.61(s,1H),8.53(s,1H),8.12(s,1H),7.18(s,1H),5.82(s,2H),3.86-3 .92(m,2H),3.51-3.59(m,2H),3.26(s,3H),2.67-2.75(m,2H),2.54-2.61(m,2H),2.22(s,3H).

[0917] Example 123: (1 1 r,1 4 r)-4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3,9-diaza-2(9,2)-purine-4(1,3)-benzene-1(1,4)-cyclohexane-2 8 -ketone

[0918]

[0919] The compound (17 mg) was synthesized following the synthetic method of Example 95.

[0920] 1 H NMR (400MHz, DMSO-d6)8.70-9.24(br,2H),8.47(s,1H),8.23(s,1H),8.05(s,1H),7.28(s,1H),4.31-4.41(m,1H),4.08(t,J=4.8Hz, 2H),3.36-3.46(m,1H),3.31(s,3H),3.19-3.26(m,2H),2.52-2.66(m,2H),2.13-2.32(m,7H),1.86-1.96(m,2H),1.51-1.64(m,2H).

[0921] Example 124: (1 1 s,1 4 s)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexane-2 8 -ketone

[0922]

[0923] The cost compound (25 mg) was synthesized using intermediate 18 and 7-methyl-6-nitroquinoline-4-ol, following the synthetic method of Example 95.

[0924] 1 H NMR (400MHz, DMSO-d6)8.59(s,1H),8.50(d,J=5.2Hz,1H),8.25(s,1H),7.92(s,1H),7.77(s,1H),6.91(d,J=4.8Hz,1H),4.33(t,J=4 .4Hz,2H),4.18-4.27(m,1H),3.33(s,3H),2.87-2.99(m,3H),2.53(s,3H),2.42-2.49(m,2H),1.90-1.99(m,2H),1.51-1.62(m,4H).

[0925] Example 125: (1 1 r,1 4 r)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexane-2 8 -ketone

[0926]

[0927] The cost compound (15 mg) was synthesized using intermediate 17 and 7-methyl-6-nitroquinoline-4-ol, following the synthetic method of Example 95.

[0928] 1 H NMR (400MHz, DMSO-d6)8.54(d,J=4.8Hz,1H),8.30(s,1H),8.20(s,1H),7. 97(s,1H),7.80(s,1H),6.95(d,J=4.8Hz,1H),4.42-4.49(m,2H),4.18-4.3 0(m,1H),3.46-3.56(m,1H),3.32(s,3H),3.16-3.26(m,2H),2.56-2.69(m, 2H),2.53(s,3H),1.91-2.01(m,2H),1.71-1.79(m,2H),1.16-1.18(m,2H).

[0929] Example 126: 2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-7-(2-propyl-1-ynyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[0930]

[0931] 2-Chloro-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (255 mg) and 3-bromopropane-1-yne (119 mg) were dissolved in THF (20 mL) at room temperature. Triethylamine (200 mg) was slowly added and the mixture was heated to reflux with stirring for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (V:V)) to give 2-chloro-7-(propane-2-yne-1-yl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (70 mg). Under nitrogen protection, the above-mentioned 2-chloro-7-(prop-2-yn-1-yl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (58 mg), intermediate 47-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (16 mg).

[0932] MS(ESI) m / z 405.21(M+H) +

[0933] Example 127: 7-Methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro-2H-thiophen-4-yl)-7,9-dihydro-8H-purine-8-one

[0934]

[0935] Step 5: (1) 1 s,1 4 s)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7H-3,5,8-triaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[0936] Under nitrogen protection, intermediates 18-12-chloro-7-methyl-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purin-8-one (57 mg), 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (65 mg) were dissolved in dioxane (10 mL), heated to 100 °C, and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (49 mg).

[0937] 1 H NMR(400MHz,DMSO-d6)9.05(s,1H),8.65(s,1H),8.34(s,1H),8.04(s,1H),7.67(s,1H),4.10-4 .20(m,1H),3.26(s,3H),2.64-2.79(m,4H),2.48-2.55(m,2H),2.35(s,3H),1.96-2.03(m,2H).

[0938] Example 128: 9-(1,1-dioxytetrahydro-2H-thiopyran-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one

[0939]

[0940] At 0°C, 40 mg of 7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro-2H-thiophen-4-yl)-7,9-dihydro-8H-purine-8-one was dissolved in dichloromethane (5 mL), and 50 mg of m-chloroperoxybenzoic acid was added. The reaction mixture was heated to room temperature and stirred for 12 hours. The reaction solution was poured into a saturated aqueous sodium thiosulfate solution (5 mL), extracted with ethyl acetate, and the organic phase was separated and washed with a saturated aqueous sodium bicarbonate solution (5 mL). The organic phase was dried and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (30 mg).

[0941] MS(ESI) m / z 429.11(M+H)+

[0942] Example 129: 9-(1-imino-1-hexahydro-1λ) 6 -thiapyran-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one

[0943]

[0944] At room temperature, 40 mg of 7-methyl-2-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro-2H-thiophen-4-yl)-7,9-dihydro-8H-purine-8-one, 100 mg of iodophenyldiacetic acid, and 40 mg of ammonium acetate were added to 20 mL of ethanol and stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to give the title compound (10 mg).

[0945] MS(ESI) m / z 428.25(M+H) +

[0946] Example 130: 5'-Methyl-2'-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-2,3,5,6-tetrahydrospiro[pyran-4,7'-pyrrolo[3,2-d]pyrimidine]-6'(5'H)-one

[0947]

[0948] Step 1: Methyl 4-(2-chloro-5-nitropyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxylic acid

[0949] 2,4-Dichloro-5-nitropyrimidine (194 mg) and tetrahydro-2H-pyran-4-carboxylic acid methyl ester (144 mg) were dissolved in tetrahydrofuran (10 mL), and LHMDS (1.5 mL 1 M tetrahydrofuran solution) was slowly added under ice bath conditions. The reaction mixture was brought to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue (330 mg) was used directly in the next step without purification.

[0950] Step 2: At room temperature, 0.25 g of reduced iron powder was added to a 20 mL acetic acid solution of methyl 4-(2-chloro-5-nitropyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxylic acid (330 mg) from Step 1. The reaction was then stirred at room temperature for 12 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution: dichloromethane:methanol = 20:1 (V:V)) to obtain a white solid (150 mg).

[0951] Step 3: 2'-Chloro-5'-methyl-2,3,5,6-tetrahydrospiro[pyran-4,7'-pyrrolo[3,2-d]pyrimidine]-6'(5'H)-one

[0952] At 0°C, 60% (mineral oil) sodium hydride (40 mg) was slowly added to a DMF (10 mL) solution of 150 mg of 2'-chloro-2,3,5,6-tetrahydrospiro[pyran-4,7'-pyrrolo[3,2-d]pyrimidine]-6'(5'H)-one at 0°C. After the addition was complete, the mixture was stirred at 0°C for 10 minutes. Then, 141 mg of iodomethane was slowly added to the reaction solution. After 1 hour, the reaction solution was poured into a saturated ammonium chloride aqueous solution and stirred continuously. A white precipitate was formed. The precipitate was filtered and dried to obtain the target compound (140 mg).

[0953] Step 4: 5'-Methyl-2'-((7-methyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-2,3,5,6-tetrahydrospiro[pyran-4,7'-pyrrolo[3,2-d]pyrimidine]-6'(5'H)-one

[0954] Under nitrogen protection, 2'-chloro-5'-methyl-2,3,5,6-tetrahydrospiro[pyran-4,7'-pyrrolo[3,2-d]pyrimidin]-6'(5'H)-one (51 mg), intermediate 47-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (30 mg), RuPhosPd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL). The reaction flask was purged with nitrogen three times and heated to 100 °C with stirring for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (45 mg).

[0955] 1H NMR(400MHz,DMSO-d6)9.11(s,1H),8.85(s,1H),8.35(s,1H),8.13(s,1H),7.69(s,1H ),3.83-3.99(m,4H),3.11(s,3H),2.36(s,3H),1.75-1.84(m,2H),1.60-1.68(m,2H).

[0956] Example 131: 4-(2-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[0957]

[0958] Under nitrogen protection, intermediates 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (59 mg), 7-methyl-[1,2,4]triazol[4,3-a]pyridine-3,6-diamine (32 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (10 mL). The reaction flask was purged with nitrogen three times and heated to 100 °C with stirring for 3 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (49 mg).

[0959] 1 H NMR(400MHz, CDCl3)9.67(s,1H),7.98(s,1H),7.70(s,1H),6.77(s,1H),4.09-4.13( m,2H),3.86-3.93(m,2H),3.42(s,3H),2.76-2.84(m,4H),2.66(s,3H),2.53(s,3H).

[0960] Example 132: (1 1 s,1 4 s)-4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,9-diaza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexanecyclononane-2 8 -ketone

[0961]

[0962] Step 1: tert-butyl (3-(2,4-dimethyl-5-nitrophenoxy)propyl)carbamate

[0963] At 0°C, DIAD (300 mg) was slowly added dropwise to a toluene (20 mL) solution of 2-chloro-4-methyl-5-nitrophenol (187 mg), tert-butyl (3-hydroxypropyl)carbamate (175 mg), and triphenylphosphine (526 mg). After the addition was complete, the mixture was brought to room temperature and stirred for 12 hours. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 (V:V)) to give a pale yellow solid (250 mg).

[0964] Step 2: 3-(2,4-dimethyl-5-nitrophenoxy)propane-1-amine trifluoroacetate

[0965] At 0°C, tert-butyl (3-(2,4-dimethyl-5-nitrophenoxy)propyl)carbamate (200 mg) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was slowly added. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue (190 mg) was used directly in the next reaction without purification.

[0966] Step 3: 2-Chloro-9-((1s,4s)-4-((3-(2-chloro-4-methyl-5-nitrophenoxy)propyl)amino)cyclohexyl)-7-methyl-7,9-dihydro-8H-purine-8-one

[0967] At 0 °C, 190 mg of 3-(2,4-dimethyl-5-nitrophenoxy)propane-1-amine trifluoroacetate and 140 mg of 2-chloro-7-methyl-9-(4-oxocyclohexyl)-7,9-dihydro-8H-purine-8-one (140 mg) were dissolved in 30 mL of THF, and 500 mg of sodium triacetoxyborohydride was added. The reaction mixture was heated to room temperature and stirred for 12 hours. The reaction solution was poured into water, extracted with dichloromethane, and the organic phase was separated and concentrated under reduced pressure. After evaporation to dryness, the residue was purified by column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (100 mg) and its trans isomer (90 mg).

[0968] Step 4: 9-((1s,4s)-4-((3-(5-amino-2-chloro-4-methylphenoxy)propyl)amino)cyclohexyl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one

[0969] At room temperature, 200 mg of reduced iron powder was added to a 10 mL acetic acid solution of 100 mg of 2-chloro-9-((1s,4s)-4-((3-(2-chloro-4-methyl-5-nitrophenoxy)propyl)amino)cyclohexyl)-7-methyl-7,9-dihydro-8H-purine-8-one (100 mg). The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through diatomaceous earth and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution: dichloromethane:methanol = 10:1 (V:V)) to give a white solid (60 mg).

[0970] Step 5: (1) 1 s,1 4 s)-4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,9-diaza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexanecyclononane-2 8 -ketone

[0971] Under nitrogen protection, 9-((1s,4s)-4-((3-(5-amino-2-chloro-4-methylphenoxy)propyl)amino)cyclohexyl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one (48 mg), RuPhos PdG3 (4 mg), and cesium carbonate (65 mg) were dissolved in dioxane (10 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (V:V)) to obtain the target compound (31 mg).

[0972] 1 H NMR (400MHz, DMSO-d6)8.17(s,1H),8.09(s,1H),7.92(s,1H),7.18(s,1H),4.20(t,J=5.6Hz,2H),4.06-4.16(m,1H),3. 30(s,3H),2.76-2.81(m,1H),2.58-2.68(m,4H),2.22(s,3H),1.76-1.86(m,4H),1.40-1.54(m,4H),1.30-1.36(m,1H).

[0973] Example 133: (1 1 r,1 4 r)-2 7 4 7 -dimethyl-28 ,2 9 -dihydro-2 7 H-3,5,8-triaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[0974]

[0975] The compound (10 mg) was synthesized following the synthetic method of Example 121.

[0976] 1 H NMR(400MHz,DMSO-d6)9.87(s,1H),9.59(s,2H),8.76(s,1H),8.52(s,1H),8.17(s,1H),7.77(s,1H),6.88(s,1H),4.01- 4.21(m,4H),3.68-3.82(m,1H),3.28(s,3H),2.40-2.65(m,6H),1.94-2.06(m,2H),1.66-1.78(m,2H),1.32-1.48(m,2H).

[0977] Example 134: (1 1 S, 1 4 S,6R)-4 4 -Chloride-2 7 4 6 ,6-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[0978]

[0979] The compound (25 mg) was synthesized following the synthetic method of Example 132.

[0980] 1 H NMR(400MHz,DMSO-d6)8.28(s,1H),8.17(s,1H),7.94(s,1H),7.02-7.42(m,1H),4.26-4.42(m,1H),4 .11-4.22(m,1H),3.30(s,3H),2.70-2.94(m,3H),2.23(s,3H),1.76-1.99(m,2H),1.14-1.72(m,9H).

[0981] Example 135: (1 1 s,1 4 s)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-4(6,4)-quinazolin-2(9,2)-purine-1(1,4)-cyclohexane-2 8 -ketone

[0982]

[0983] The compound (15 mg) was synthesized following the synthetic method of Example 132.

[0984] 1 H NMR(400MHz,DMSO-d6)8.89(s,1H),8.21(s,1H),8.12(s,1H),8.10(s,1H),7.54(s,1H),4.61-4.72(m,2H),4.10-4.16(m,1H),3.98-4 .07(m,1H),3.84-3.94(m,1H),3.64-3.70(m,1H),3.27(s,3H),2.39(s,3H),1.92-1.97(m,2H),1.66-1.80(m,2H),1.40-1.51(m,4H).

[0985] Example 136: (1 1 r,1 4 r)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-4(6,4)-quinazolin-2(9,2)-purine-1(1,4)-cyclohexane-2 8 -ketone

[0986]

[0987] The compound (11 mg) was synthesized following the synthetic method of Example 132.

[0988] 1H NMR(400MHz,DMSO-d6)8.86(s,1H),8.63(s,1H),8.21(s,1H),7.79(s,1H),4.41-4.56(m,3H),3.4 9-3.58(m,3H),3.44(s,3H),2.62(s,3H),2.53-2.59(m,2H),2.28-2.34(m,2H),1.94-2.03(m,4H).

[0989] Example 137: (1 1 S, 1 4 S, 7R)-4 4 -Chloride-2 7 4 6 ,7-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[0990]

[0991] The compound (21 mg) was synthesized following the synthetic method of Example 132.

[0992] 1 H NMR(400MHz,DMSO-d6)8.54(s,1H),7.87(s,1H),7.11(s,1H),6.85(s,1H),4.32-4.48(m,2H),3.72-3.97(m,1H),3.4 1(s,3H),2.91-3.20(m,3H),2.64-2.80(m,1H),2.25(s,3H),2.01-2.11(m,1H),1.44-1.84(m,6H),1.04-1.20(m,3H).

[0993] Example 138: (1 1 S, 1 4 S,6R)-4 4 -Chloride-2 7 4 6 ,6-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[0994]

[0995] The compound (31 mg) was synthesized following the synthetic method of Example 132.

[0996] 1 H NMR (400MHz, DMSO-d6)8.32(s,1H),8.16(s,1H),7.90(s,1H),7.17(s,1H),4.25-4.33(m,1H),4.11-4.20(m,1H),3.30( s,3H),2.76-2.90(m,4H),2.53-2.64(m,1H),2.22(s,3H),1.78-1.87(m,2H),1.30-1.62(m,5H),1.21(d,J=6.0Hz,3H).

[0997] Example 139: (1 1 s,1 4 s)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,9-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclononane-2 8 -ketone

[0998]

[0999] The compound (19 mg) was synthesized following the synthetic method of Example 132.

[1000] 1 H NMR (400MHz, DMSO-d6)8.63(d,J=5.6Hz,1H),8.56(s,1H),8.01-8.14(br,1H),7.95(s,1H),6.99(s,1H),6.88(d,J=4.8Hz,1H),4.68-4.75(m,2 H),4.21-4.32(m,1H),3.43(s,3H),3.06-3.28(m,3H),2.54(s,3H),2.4 0-2.50(m,4H),2.21-2.34(m,2H),1.88-1.96(m,2H),1.73-1.86(m,2H).

[1001] Example 140: 2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-27 H-5-oxo-3,8-diaza-4(6,4)-quinoline-2(9,2)-purine-1,9(1,3)-bicyclobutane-2 8 -ketone

[1002]

[1003] The compound (9 mg) was synthesized using intermediate 19 as a substitute starting material, following the synthesis method of Example 132.

[1004] 1 H NMR(400MHz,DMSO-d6)8.74(d,J=5.2Hz,1H),8.30(s,1H),8.02(s,1H),7.83(s,1 H),6.97(s,1H),6.84(d,J=5.2Hz,1H),4.82-4.87(m,1H),4.55-4.64(m,2H),3.6 4-3.70(m,1H),3.47-3.51(m,1H),3.27-3.42(m,5H),2.94-3.06(m,2H),2.49-2. 58(m,4H),2.41(dd,J=12.4Hz,8.8Hz,1H),2.26-2.33(m,1H),2.14-2.24(m,2H).

[1005] Example 141: 2-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(4-ethynyltetrahydro-2H-pyran-4-yl)-7-methyl-7,9-dihydro-8H-purine-8-one

[1006]

[1007] Step 1: 4-(2-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-aminocarboxaldehyde

[1008] At room temperature, 84 mg of 4-(2-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate from Example 131 was dissolved in 10 mL of 80% formic acid aqueous solution. Raney-Ni (100 mg) was slowly added to the solution, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate and washed with 100 mL of saturated sodium bicarbonate aqueous solution. The organic phase was separated, dried, and concentrated under reduced pressure. The crude product (60 mg) was used directly in the next step without purification.

[1009] Step 2: 2-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(4-ethynyltetrahydro-2H-pyran-4-yl)-7-methyl-7,9-dihydro-8H-purine-8-one

[1010] At 0°C, dimethyl (1-diazo-2-oxopropyl)phosphonate (200 mg) was dissolved in methanol (10 mL), and potassium carbonate (280 mg) was added. The mixture was stirred for 10 minutes. Then, 4-(2-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-aminocarboxaldehyde (60 mg dissolved in 2 mL THF) was added. The reaction mixture was heated to room temperature and stirred for 1 hour. After filtration, the mother liquor was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to obtain the target compound (24 mg).

[1011] 1 H NMR(400MHz,DMSO-d6)8.93(s,1H),8.60(s,1H),8.10(s,1H),7.51(s,1H),3.71-3.77(m,2H),3 .58-3.65(m,3H),3.25(s,3H),2.60-2.66(m,2H),2.52-2.58(m,2H),2.39(s,3H),2.32(s,3H).

[1012] Example 142: (1 1 s,1 3 s)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7H-5-oxo-3,8-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,3)-cyclobutyrylcyclooctane-2 8 -ketone

[1013]

[1014] The compound (12 mg) was synthesized using intermediate 20 as a substitute starting material, following the synthesis method of Example 132.

[1015] 1 H NMR(400MHz, CDCl3)9.09(s,1H),8.57(d,J=4.8Hz,1H),7.95(s,1H),7.85(s,1H),7.32(s,1H),6.64(d,J=5.2Hz,1H),5.1 8-5.26(m,1H),4.86-4.94(m,1H),4.27(t,J=4.4Hz,2H),3.42(s,3H),3.12-3.21(m,4H),2.58(s,3H),2.41-2.48(m,2H).

[1016] Example 143: (1 1 R, 1 4 R, 7S)-2 7 4 7 ,7-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[1017]

[1018] The compound (22 mg) was synthesized following the synthetic method of Example 132.

[1019] 1H NMR (400MHz, CDCl3)8.73(s,1H),8.57(d,J=5.2Hz,1H),7.95(s,1H),7.92(s,1H),7.35(s,1H ),6.72(d,J=5.2Hz,1H),4.40-4.48(m,1H),4.24(dd,J=8.4Hz,2.8Hz,1H),3.92-3.97(m,1H), 3.47-3.56(m,1H),3.44(s,3H),3.25-3.30(m,1H),2.56-2.67(m,4H),2.42-2.54(m,1H),2.28 -2.34(m,1H),1.91-1.98(m,2H),1.70-1.81(m,2H),1.54-1.63(m,1H),1.16(d,J=6.0Hz,3H).

[1020] Example 144: (1 1 S, 1 4 S, 7R)-4 4 -Chloride-2 7 4 6 ,7-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[1021]

[1022] The compound (32 mg) was synthesized following the synthetic method of Example 132.

[1023] 1 H NMR(400MHz, CDCl3)8.54(s,1H),7.87(s,1H),7.11(s,1H),6.85(s,1H),4.31-4.50(m,2H),3.71-3.94(m, 1H),3.41(s,3H),2.88-3.18(m,2H),2.64-2.80(m,1H),2.25(s,3H),1.46-1.87(m,7H),1.01-1.34(m,4H).

[1024] Example 145: 3 4 -Chloride-1 5 ,3 6 -Dimethyl-1 6 ,1 7 -dihydro-1 5H-4-oxa-2-aza-1(2,7)-pyrrolo[3,2-d]pyrimidine-7(4,1)-piperidine-3(1,3)-benzohepta-1 6 -ketone

[1025]

[1026] The compound (23 mg) was synthesized using intermediate 21, following the synthetic method of Example 121.

[1027] 1 H NMR(400MHz, CDCl3)9.07-9.26(br,1H),7.90(s,1H),7.09(s,1H),6.88(s,1H),4.41-4.49(m,2H ),3.55-3.68(m,2H),3.20-3.32(m,5H),2.66-2.81(m,2H),2.20-2.36(m,5H),1.65-1.74(m,2H).

[1028] Example 146: (1 1 S, 1 4 S,6R)-2 7 4 7 ,6-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[1029]

[1030] The compound (26 mg) was synthesized following the synthetic method of Example 132.

[1031] 1 H NMR(400MHz, CDCl3)8.57(d,J=5.2Hz,1H),8.56(s,1H),7.92(s,1H),7.87( s,1H),7.12(s,1H),6.71(d,J=5.2Hz,1H),4.79-4.87(m,1H),4.35-4.43(m ,1H),3.42(s,3H),3.04-3.13(m,2H),2.65-2.76(m,2H),2.55(s,3H),2.16 -2.34(m,3H),1.85-1.92(m,1H),1.51-1.79(m,4H),1.49(d,J=6.4Hz,3H).

[1032] Example 147: 4 4 -Chloride-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-2(9,2)-purine-4(1,3)-benzene-1,9(1,3)-dicyclobutane-2 8 -ketone

[1033]

[1034] The compound (26 mg) was synthesized using intermediate 19 as a substitute starting material, following the synthesis method of Example 132.

[1035] MS(ESI) m / z 441.03(M+H) +

[1036] Example 148: (1 1 R, 1 4 R,6S)-2 7 4 7 ,6-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[1037]

[1038] The compound (41 mg) was synthesized following the synthetic method of Example 132.

[1039] 1 H NMR(400MHz, CDCl3)8.58(d,J=5.2Hz,1H),8.57(s,1H),7.96(s,1H),7.93( s,1H),7.15(s,1H),6.76(d,J=5.2Hz,1H),4.87-4.96(m,1H),4.36-4.45(m ,1H),3.43(s,3H),3.10-3.15(m,2H),2.69-2.78(m,2H),2.56(s,3H),2.26 -2.32(m,2H),1.90-1.98(m,1H),1.56-1.82(m,4H),1.52(d,J=5.6Hz,3H).

[1040] Example 149: (1 1 S, 1 4S, 7R)-2 7 4 7 ,7-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[1041]

[1042] The compound (32 mg) was synthesized following the synthetic method of Example 132.

[1043] 1 H NMR(400MHz, DMSO-d6)8.60(s,1H),8.50(d,J=5.2Hz,1H),8.26(s,1H),7.88(s,1H),7.78 (s,1H),6.92(d,J=5.2Hz,1H),4.30-4.34(m,1H),4.18-4.28(m,1H),3.73-3.80(m,1H),3. 34(s,3H),3.22-3.28(m,1H),3.06-3.13(m,1H),2.53(s,3H),2.28-2.42(m,2H),2.13-2. 17(m,1H),1.66-1.82(m,2H),1.54-1.64(m,2H),1.37-1.48(m,1H),1.01(d,J=6.0Hz,3H).

[1044] Example 150: 7-Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(4-(prop-1-yn-1-yl)tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[1045]

[1046] Step 1: 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-aminocarboxaldehyde

[1047] At room temperature, intermediate 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-onitrile (294 mg) was dissolved in 80% formic acid aqueous solution (5 mL), and Raney-Ni (100 mg) was slowly added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate aqueous solution (100 mL). The organic phase was separated, dried, and concentrated under reduced pressure. The crude product (150 mg) was used directly in the next step without purification.

[1048] Step 2: 2-Chloro-9-(4-ethynyltetrahydro-2H-pyran-4-yl)-7-methyl-7,9-dihydro-8H-purin-8-one

[1049] At 0 °C, 100 mg of dimethyl (1-diazo-2-oxopropyl)phosphonate was dissolved in 10 mL of methanol, and 140 mg of potassium carbonate was added, followed by stirring for 10 minutes. Then, 150 mg of 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-aminocarboxaldehyde (dissolved in 4 mL of THF) was added. The reaction mixture was heated to room temperature and stirred for 1 hour. After filtration, the mother liquor was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (59 mg).

[1050] Step 3: 2-Chloro-7-methyl-9-(4-(prop-1-yn-1-yl)tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one

[1051] At 0 °C, 59 mg of 2-chloro-9-(4-ethynyltetrahydro-2H-pyran-4-yl)-7-methyl-7,9-dihydro-8H-purin-8-one was dissolved in 5 mL of dry THF. LDA (0.4 mL, 1 MtHF solution) was slowly added, and the reaction mixture was stirred at 0 °C for 0.5 h. Then, 70 mg of iodomethane was slowly added, and stirring continued for 1 h. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with 20 mL of ethyl acetate. The organic phase was separated, dried, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (31 mg).

[1052] Step 4: 7-Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(4-(prop-1-yn-1-yl)tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-one

[1053] Under nitrogen protection, 2-chloro-7-methyl-9-(4-(prop-1-yn-1-yl)tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (31 mg), 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (15 mg), RuPhos Pd G3 (4 mg), and cesium carbonate (65 mg) were dissolved in dioxane (5 mL). The reaction flask was purged with nitrogen three times and heated to 100 °C with stirring for 3 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (19 mg).

[1054] 1 H NMR(400MHz,DMSO-d6)9.17(s,1H),8.62(s,1H),8.34(s,1H),8.12(s,1H),7.67(s,1H),3.70-3.75(m ,2H),3.59-3.65(m,2H),3.25(s,3H),2.57-2.64(m,2H),2.48-2.54(m,2H),2.37(s,3H),1.79(s,3H).

[1055] Example 151: 9-(4-hydroxybicyclo[2.2.2]octane-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one

[1056]

[1057] Under nitrogen protection, 2-chloro-9-(4-hydroxybicyclo[2.2.2]octane-1-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (obtained by the same method as intermediate 1) (62 mg), intermediate 47-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (44 mg).

[1058] 1 H NMR(400MHz,DMSO-d6)9.09(s,1H),8.53(s,1H),8.34(s,1H),8.03(s,1H),7.67(s ,1H),4.35(s,1H),3.19(s,3H),2.38-2.46(m,6H),2.36(s,3H),1.49-1.66(m,6H).

[1059] Example 152: (1) 1 r,1 4 r)-4 4 -Fluorine-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,9-diaza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexanecyclononane-2 8 -ketone

[1060]

[1061] The compound (22 mg) was synthesized following the synthetic method of Example 132.

[1062] 1 HNMR(400MHz, CDCl3)8.46(d,J=8.0Hz,1H),7.86(s,1H),6.92(d,J=12.0Hz,1H),6.84(s,1H),4.40-4.48(m,1H),4.19(t,J=5.2Hz,2H),3.4 0(s,3H),3.07-3.16(m,1H),3.03(t,J=5.2Hz,2H),2.72-2.83(m,2H), 2.29(s,3H),2.12-2.20(m,2H),1.88-2.03(m,4H),1.23-1.38(m,3H).

[1063] Example 153: (1) 1 s,1 4 s)-4 4 -Fluorine-2 7 4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,9-diaza-2(9,2)-purine-4(1,3)-benzo-1(1,4)-cyclohexanecyclononane-2 8 -ketone

[1064]

[1065] The compound (29 mg) was synthesized following the synthetic method of Example 132.

[1066] 1 HNMR(400MHz, CDCl3)8.41(d,J=8.4Hz,1H),7.87(s,1H),6.89(d,J=12.4Hz,1H),6.86(s,1H),4.29-4.39(m ,3H),3.40(s,3H),2.86-3.10(m,3H),2.60-2.70(m,2H),2.27(s,3H),1.97-2.23(m,4H),1.62-1.78(m,4H).

[1067] Example 154: 3 4 -Chloride-1 7 ,3 6 -Dimethyl-1 8 ,1 9 -dihydro-1 7 H-4-oxo-2-aza-1(2,9)-purine-3(1,3)-benzocyclooctane-1 8 -ketone

[1068]

[1069] The compound (20 mg) was synthesized following the method described in Example 16.

[1070] 1 H NMR(400MHz, CDCl3)7.83(s,1H),7.82(s,1H),7.30-7.68(br,1H),7.13(s,1H),4.24-4.28(m ,2H),3.91(t,J=5.2Hz,2H),3.41(s,3H),2.32-2.40(m,2H),2.25(s,3H),1.81-1.88(m,2H).

[1071] Example 155: 7-Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(2-oxospiro[3,3]heptane-6-yl)-7,9-dihydro-8H-purine-8-one

[1072]

[1073] Under nitrogen protection, 2-chloro-7-methyl-9-(2-oxaspiro[3.3]heptane-6-yl)-7,9-dihydro-8H-purine-8-one (obtained by the same method as intermediate 1) (56 mg), intermediate 47-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (54 mg).

[1074] 1 H NMR(400MHz, CDCl3)9.45(s,1H),8.31(s,1H),7.84(s,1H),7.65(s,1H),4.73-4.79( m,3H),4.66(s,2H),3.40(s,3H),3.10-3.15(m,2H),2.67-2.72(m,2H),2.53(s,3H).

[1075] Example 156: (R)-9-(chroman-4-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine-8-one

[1076]

[1077] Under nitrogen protection, (R)-2-chloro-9-(chroman-4-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (obtained by the same method as intermediate 1) (63 mg), intermediate 47-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (30 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100 °C, and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to obtain the target compound (44 mg).

[1078] 1H NMR(400MHz,DMSO-d6)8.84(s,1H),8.59(s,1H),8.34(s,1H),8.09(s,1H),7.60(s,1H),7.00-7.05(m,1H),6.69-6.76(m,2H),6.62(d, J=8.0Hz,1H),5.58-5.62(m,1H),4.32-4.37(m,1H),4.14-4.20(m,1H),3.37(s,3H),2.69-2.79(m,1H),2.15(s,3H),2.09-2.14(m,1H).

[1079] Example 157: 1 7 ,3 7 -Dimethyl-3 8 ,3 9 -dihydro-3 7 H-10-oxo-2,7-diaza-1(6,4)-quinoline-3(2,9)-purinecyclodecane-3 8 -ketone

[1080]

[1081] Following the synthesis methods of intermediate 1 and Example 7, the target compound (14 mg) was synthesized using tert-butyl (3-aminopropyl) carbamate as the starting material.

[1082] 1 H NMR(400MHz,DMSO-d6)8.67(s,1H),8.44-8.56(m,2H),8.21(s,1H),7.71(s,1H),6.76-6.84(m,1H),4.25-4.37 (m,2H),3.72-3.82(m,2H),3.30(s,3H),3.15-3.24(m,2H),2.92-3.06(m,2H),1.88(s,3H),1.05-1.20(m,2H).

[1083] Example 158: (1 1 S, 1 4 s, 6 1 S, 6 3 s)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,7-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexane-6(1,3)-cyclobutylcycloheptane-2 8 -ketone

[1084]

[1085] Step 1: tert-butyl ((1s,3s)-3-((7-methyl-6-nitroquinoline-4-yl)oxy)cyclobutyl)carbamate

[1086] At 0 °C, DIAD (306 mg) was slowly added dropwise to a THF solution of 7-methyl-6-nitroquinoline-4-ol (204 mg), tert-butyl ((1r,3r)-3-hydroxycyclobutyl)carbamate (187 mg), and triphenylphosphine (526 mg) in 30 mL. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 12 hours. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to give a pale yellow solid (310 mg).

[1087] Step 2: (1s,3s)-3-((7-methyl-6-nitroquinoline-4-yl)oxy)cyclobutane-1-amine trifluoroacetate

[1088] At 0°C, tert-butyl((1s,3s)-3-((7-methyl-6-nitroquinoline-4-yl)oxy)cyclobutyl)carbamate (310 mg) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was slowly added. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue (270 mg) was used directly in the next reaction without purification.

[1089] Step 3: 2-Chloro-7-methyl-9-((1S,4S)-4-((1S,3S)-3-((7-methyl-6-nitroquinoline-4-yl)oxy)cyclobutyl)cyclohexyl)-7,9-dihydro-8H-purine-8-one

[1090] At 0 °C, 141 mg of 2-chloro-7-methyl-9-(4-oxocyclohexyl)-7,9-dihydro-8H-purine-8-one and 170 mg of (1s,3s)-3-((7-methyl-6-nitroquinolin-4-yl)oxy)cyclobutane-1-amine trifluoroacetate were dissolved in 50 mL of THF, and 300 mg of sodium triacetoxyborohydride was added. The reaction mixture was stirred at room temperature for 12 hours, and the reaction solution was poured into a saturated aqueous sodium bicarbonate solution. Ethyl acetate was added for extraction, the organic phase was separated and concentrated under reduced pressure, evaporated to dryness, and the residue was purified by column chromatography (eluent: dichloromethane:methanol = 10:1 (V:V)) to give the title compound (140 mg) and its isomer (110 mg).

[1091] Step 4: 9-((1S,4S)-4-((1S,3S)-3-((6-amino-7-methylquinoline-4-yl)oxy)cyclobutyl)amino)cyclohexyl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one

[1092] At room temperature, 0.2 g of reduced iron powder was added to a 15 mL acetic acid solution of 140 mg of 2-chloro-7-methyl-9-((1S,4S)-4-((1S,3S)-3-((7-methyl-6-nitroquinoline-4-yl)oxy)cyclobutyl)cyclohexyl)-7,9-dihydro-8H-purine-8-one. The mixture was then heated to 45 °C and stirred for 2 hours. After cooling, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 5:1 (V:V)) to obtain the title compound (90 mg).

[1093] Step 5: (1) 1 S, 1 4 s, 6 1 S, 6 3 s)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,7-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexane-6(1,3)-cyclobutylcycloheptane-2 8 -ketone

[1094] Under nitrogen protection, 51 mg of 9-((1S,4S)-4-((1S,3S)-3-((6-amino-7-methylquinoline-4-yl)oxy)cyclobutyl)amino)cyclohexyl)-2-chloro-7-methyl-7,9-dihydro-8H-purine-8-one, 9 mg of RuPhos Pd G3, and 65 mg of cesium carbonate were dissolved in dioxane (10 mL), heated to 100 °C, and stirred for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to give the target compound (21 mg).

[1095] 1H NMR(400MHz, DMSO-d6)8.60(s,1H),8.48(d,J=5.2Hz,1H),8.24(s,1H),8. 09(s,1H),7.76(s,1H),6.51(d,J=5.2Hz,1H),4.91-4.96(m,1H),4.14-4.2 4(m,1H),3.34(s,3H),3.22-3.29(m,1H),2.74-2.86(m,3H),2.58-2.70(m, 2H),2.52(s,3H),1.84-1.91(m,2H),1.73-1.81(m,2H),1.47-1.50(m,4H).

[1096] Example 159: 2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diazo-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-benzocyclooctyl-2 8 -ketone

[1097]

[1098] Following the synthesis method of intermediate 1 and Example 158, the target compound (17 mg) was synthesized using tert-butyl (4-aminophenyl)carbamate as the starting material.

[1099] 1 H NMR (400MHz, DMSO-d6)8.48(d,J=4.8Hz,1H),8.21(s,1H),8.12(s,1H),8.04(s,1H),7.69(s,1H),7.13(d,J=8. 8Hz,1H),6.86-6.88(m,3H),5.53-5.60(m,1H),4.36-4.42(m,2H),3.64-3.71(m,2H),3.39(s,3H),2.48(s,3H).

[1100] Example 160: (1 1 R, 1 4 s,8S)-2 7 4 7 ,8-trimethyl-2 8 ,2 9 -dihydro-27H-5-oxo-3,9-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclononane-2 8 -ketone

[1101]

[1102] The compound (29 mg) was synthesized following the synthetic method of Example 158.

[1103] 1 H NMR (400MHz, CDCl3)8.78(s,1H),8.57(d,J=2.8Hz,1H),7.92(s,1H),7.90(s,1H),7. 01(s,1H),6.68(d,J=4.8Hz,1H),4.65-4.71(m,1H),4.37-4.43(m,1H),4.20-4.29(m ,1H),3.43(s,3H),2.09-3.08(m,2H),2.64-2.76(m,1H),2.53(s,3H),2.34-2.46(m, 1H), 2.10-2.18 (m, 1H), 1.98-2.08 (m, 1H), 1.58-1.95 (m, 6H), 1.11 (d, J = 5.2Hz, 3H).

[1104] Example 161: (1 1 s,1 4 s)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane-2 8 7-Diketone

[1105]

[1106] The compound (13 mg) was synthesized using ethyl 2-hydroxyacetate, following the synthetic method of Example 95.

[1107] 1H NMR(400MHz, DMSO-d6)9.02(s,1H),8.02(s,1H),7.88(d,J=8.0Hz,1H),7.72(s,1H),7.4 8(s,1H),6.19(d,J=4.4Hz,1H),6.00(d,J=8.0Hz,1H),5.17(d,J=17.2Hz,1H),4.80(d,J= 17.2Hz,1H),3.82-3.90(m,1H),3.62-3.67(m,1H),3.23(s,3H),2.12-2.21(m,4H),1.91- 2.02(m,1H),1.57-1.64(m,1H),1.37-1.51(m,3H),1.22-1.32(m,1H),1.08-1.17(m,1H).

[1108] Example 162: 9-(4-ethynyltetrahydro-2H-pyran-4-yl)-7-methyl-2-((7-methylquinolin-6-yl)amino)-7,9-dihydro-8H-purine-8-one

[1109]

[1110] The compound (43 mg) was synthesized using the starting material from Example 4, following the synthesis method of Example 141.

[1111] 1 H NMR (400MHz, DMSO-d6)8.70(dd,J=4.4Hz,1.2Hz,1H),8.60(s,1H),8.32(s,1H),8.20(s,1H),8.12(d,J=7.6Hz,1H),7.81(s,1H),7.40(dd ,J=8.0Hz,4.4Hz,1H),3.72-3.79(m,2H),3.71(s,1H),3.59-3.68(m,2H),3.28(s,3H),2.67-2.75(m,2H),2.51-2.61(m,2H),2.48(s,3H).

[1112] Example 163: 1 5 ,3 7 -Dimethyl-1 6 ,1 7 -dihydro-1 5 H-4-oxa-2,7-diaza-3(6,4)-quinazolin-1(2,7)-pyrrolo[3,2-d]pyrimidine-8(1,4)-cyclohexane-1 6 -ketone

[1113]

[1114] The compound (33 mg) was synthesized using methyl 1,4-dioxospiro[4.5]decane-8-carboxylate as a starting material, following the synthesis methods of Examples 130 and 158.

[1115] 1 H NMR(400MHz, DMSO-d6)9.74(s,1H),8.49(d,J=5.6Hz,1H),8.43(s,1H),8.26(s,1H),7.70(s,1H),6.84(d,J=4.8Hz,1H),4.23-4.28(m,2H), 3.15(s,3H),3.07-3.13(m,1H),2.98-3.04(m,2H),2.54(s,3H),2.12- 2.24(m,2H),1.99-2.08(m,2H),1.82-1.91(m,2H),1.48-1.56(m,2H).

[1116] Example 164: (1 1 s,1 4 s)-4 7 -Methyl-2 7 -(methyl-d3)-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[1117]

[1118] Step 1: 2-Chloro-7-(methyl-d3)-9-((1s,4s)-4-((2-((7-methyl-6-nitroquinoline-4-yl)oxy)ethyl)amino)cyclohexyl)-7,9-dihydro-8H-purine-8-one

[1119] At 0 °C, intermediates 222-chloro-7-(methyl-d3)-9-(4-oxocyclohexyl)-7,9-dihydro-8H-purine-8-one (141 mg) and intermediate 232-((7-methyl-6-nitroquinolin-4-yl)oxy)ethane-1-amine trifluoroacetate (180 mg) were dissolved in THF (50 mL), and sodium triacetoxyborohydride (300 mg) was added. The reaction mixture was heated to room temperature and stirred for 12 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was separated and concentrated under reduced pressure. After evaporation to dryness, the residue was purified by column chromatography (elution: dichloromethane:methanol = 10:1 (V:V)) to give the title compound (150 mg) and its isomer (100 mg).

[1120] Step 2: 9-((1s,4s)-4-((2-((6-amino-7-methylquinoline-4-yl)oxy)ethyl)amino)cyclohexyl)-2-chloro-7-(methyl-d3)-7,9-dihydro-8H-purine-8-one

[1121] At room temperature, 0.2 g of reduced iron powder was added to a 15 mL acetic acid solution of 150 mg of 2-chloro-7-(methyl-d3)-9-((1s,4s)-4-((2-(((7-methyl-6-nitroquinoline-4-yl)oxy)ethyl)amino)cyclohexyl)-7,9-dihydro-8H-purine-8-one) and stirred for 2 hours. After cooling, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 5:1 (V:V)) to obtain the title compound (100 mg).

[1122] Step 3: (1) 1 s,1 4 s)-4 7 -Methyl-2 7 -(methyl-d3)-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[1123] Under nitrogen protection, 9-((1s,4s)-4-((2-(((6-amino-7-methylquinoline-4-yl)oxy)ethyl)amino)cyclohexyl)-2-chloro-7-(methyl-d3)-7,9-dihydro-8H-purin-8-one (49 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (65 mg) were dissolved in dioxane (10 mL), heated to 100 °C, and stirred for 3 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1 (V:V)) to give the target compound (31 mg).

[1124] 1 H NMR (400MHz, DMSO-d6)8.60(s,1H),8.50(d,J=5.2Hz,1H),8.25(s,1H),7.92(s,1H),7.77(s,1H),6.91(d,J=5.2Hz,1H),4.33 (t,J=4.8Hz,2H),4.19-4.28(m,1H),2.88-2.96(m,3H),2.53(s,3H),2.45-2.50(m,1H),1.84-1.98(m,3H),1.52-1.62(m,4H).

[1125] Example 165: (1 1 s,1 4 s)-4 7 -Methyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[1126]

[1127] The compound (11 mg) was synthesized using 2-chloro-9-(4-oxocyclohexyl)-7,9-dihydro-8H-purine-8-one as a starting material, following the synthetic method of Example 164.

[1128] 1H NMR (400MHz, DMSO-d6)11.25(s,1H),8.65(s,1H),8.56(d,J=5.6Hz,1H),8.05(s,1H),7.92(s,1H),7.80(s,1H),7.02(d,J=5 .2Hz,1H),4.47-4.55(m,2H),4.18-4.28(m,1H),3.25-3.48(m,6H),2.50-2.57(m,2H),2.09-2.18(m,2H),1.71-1.88(m,4H).

[1129] Example 166: (1 1 R, 1 4 R, 7S)-4 7 ,7-Dimethyl-2 7 -(methyl-d3)-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[1130]

[1131] The compound (41 mg) was synthesized using tert-butyl (S)-(1-hydroxypropane-2-yl)carbamate as a starting material, following the synthetic method of Example 164.

[1132] 1 H NMR (400MHz, DMSO-d6)8.59(s,1H),8.49(d,J=5.2Hz,1H),8.25(s,1H),7.85(s,1H),7.77(s,1H),6.89(d,J=5.2Hz,1H),4.17-4.30(m,2H),3.72 -3.77(m,1H),3.04-3.11(m,1H),2.53(s,3H),2.09-2.48(m,4H),1.64-1 .82(m,2H),1.53-1.62(m,2H),1.35-1.46(m,1H),0.98(d,J=6.0Hz,3H).

[1133] Example 167: 4-(2-((2,7-dimethyl-[1,2,4]triazol[1,5-a]pyridin-6-yl)amino)-7-(methyl-d3)-8-oxy-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[1134]

[1135] Following Example 71, the target compound (44 mg) was obtained by catalytic coupling reaction using 2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine as a substitute amine.

[1136] 1 H NMR(400MHz,DMSO-d6)8.90(s,1H),8.74(s,1H),8.16(s,1H),7.53(s,1H),3.87-3.93(m ,2H),3.52-3.60(m,2H),2.68-2.76(m,2H),2.57-2.63(m,2H),2.40(s,3H),2.32(s,3H).

[1137] Example 168: (1 1 S, 1 4 s, 6 1 S, 6 3 s)-4 7 -Methyl-2 7 -(methyl-d3)-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3,7-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexane-6(1,3)-cyclobutylcycloheptane-2 8 -ketone

[1138]

[1139] Following Example 158, intermediate 22 was used as a substitute to obtain the target compound (24 mg).

[1140] 1 H NMR(400MHz, DMSO-d6)8.60(s,1H),8.49(d,J=4.0Hz,1H),8.24(s,1H),8.07(s,1H),7.76(s,1H),6.51(d,J=4.0Hz,1H),4.90-4.97(m ,1H),4.14-4.24(m,1H),2.76-2.87(m,4H),2.58-2.70(m,2H),2.52(s,3H),1.84-1.91(m,2H),1.74-1.82(m,2H),1.47-1.58(m,4H).

[1141] Example 169: 2-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(4-ethynyltetrahydro-2H-pyran-4-yl)-7-(methyl-d3)-7,9-dihydro-8H-purine-8-one

[1142]

[1143] The compound (13 mg) was synthesized using the starting material from Example 167, following the synthesis method of Example 141.

[1144] 1 H NMR(400MHz,DMSO-d6)8.93(s,1H),8.61(s,1H),8.11(s,1H),7.52(s,1H),3.72-3.78(m,2H),3 .60-3.65(m,2H),3.58(s,1H),2.60-2.67(m,2H),2.51-2.59(m,2H),2.40(s,3H),2.32(s,3H).

[1145] Example 170: (1 1 R, 1 4 r, 6 1 S, 6 3 s)-4 7 -Methyl-2 7 -(methyl-d3)-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,7-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexane-6(1,3)-cyclobutylcycloheptane-2 8 -ketone

[1146]

[1147] Following Example 158, intermediate 22 was used as a substitute to obtain the target compound as an isomer of Example 168 (14 mg).

[1148] 1H NMR (400MHz, DMSO-d6)8.53(d,J=4.8Hz,1H),8.32(s,1H),8.15(s,1H),8.08(s,1H),7.78(s,1H),6.63(d,J=5.2Hz,1H),4.77-4.84(m,1H),4.05- 4.15(m,1H),3.52-3.61(m,1H),3.07-3.17(m,1H),2.90-2.99(m,2H),2. 43-2.54(m,5H),2.08-2.17(m,2H),1.58-1.76(m,4H),1.21-1.34(m,2H).

[1149] Example 171: (1 1 s,1 4 s)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,10-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclodecane-2 8 -ketone

[1150]

[1151] The compound (21 mg) was synthesized using 4-(N-tert-butoxycarbonylamino)-1-butanol as a substitute starting material, following the synthetic method of Example 158.

[1152] 1 H NMR (400MHz, DMSO-d6)8.53(d,J=5.6Hz,1H),8.17-8.19(m,2H),8.14(s,1H),7.74(s,1H),6.98(d,J=5.6Hz,1H),4.40-4.44(m,2H),3.91-3.99(m ,1H),3.37(s,3H),2.54-2.59(m,1H),2.41-2.46(m,2H),2.36(s,3H),2. 25-2.35(m,2H),1.84-1.92(m,2H),1.51-1.60(m,4H),1.29-1.47(m,4H).

[1153] Example 172: (1 1 R, 1 4 r, 6 1 S, 6 3 s)-2 7 4 7 -dimethyl-28 ,2 9 -dihydro-2 7 H-5-oxo-3,7-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexane-6(1,3)-cyclobutylcycloheptane-2 8 -ketone

[1154]

[1155] Referring to Example 158, the trans isomer obtained in the third step of Synthesis Example 158 was reduced and coupled to obtain the target compound (17 mg).

[1156] 1 H NMR(400MHz, DMSO-d6)9.31-9.66(br,2H),8.56(d,J=5.2Hz,1H),8.32(s,1H ),8.19(s,1H),8.18(s,1H),7.81(s,1H),6.67(d,J=5.2Hz,1H),4.93-5.00( m,1H),4.18-4.28(m,1H),3.96-4.03(m,1H),3.59-3.68(m,1H),3.18-3.37( m,7H),2.50(s,3H),2.38-2.46(m,2H),2.08-2.16(m,2H),1.67-1.81(m,4H).

[1157] Example 173: (1 1 S, 1 4 s,8R)-2 7 4 7 ,8-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,9-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclononane-2 8 -ketone

[1158]

[1159] The compound (29 mg) was synthesized using Boc-(S)-3-amino-1-butanol as a substitute starting material, following the synthetic method of Example 158.

[1160] 1H NMR(400MHz, DMSO-d6)8.59(s,1H),8.50(d,J=5.2Hz,1H),8.21(s,1H),8.19(s,1H) ,7.73(s,1H),6.85(s,1H),4.59-4.66(m,1H),4.30-4.37(m,1H),3.98-4.06(m,1H), 3.33(s,3H),2.82-2.94(m,2H),2.48-2.58(m,4H),2.14-2.25(m,1H),1.99-2.06(m, 1H), 1.77-1.97 (m, 3H), 1.54-1.74 (m, 4H), 1.36-1.47 (m, 1H), 0.93 (d, J = 6.0Hz, 3H).

[1161] Example 174: (1 1 R, 1 4 r,8R)-2 7 4 7 ,8-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,9-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclononane-2 8 -ketone

[1162]

[1163] Referring to Example 173, the trans isomer obtained in the third step of Synthesis Example 173 was reduced and coupled to obtain the target compound (20 mg).

[1164] 1 H NMR(400MHz,DMSO-d6)8.54(d,J=5.2Hz,1H),8.51(s,1H),8.23(s,1H),8.20(s,1 H),7.78(s,1H),6.88(d,J=5.2Hz,1H),4.58-4.67(m,1H),4.44-4.52(m,1H),4.16 -4.26(m,1H),3.38-3.64(m,3H),3.33(s,3H),2.50-2.65(m,4H),2.35-2.45(m,2H ),1.84-2.15(m,4H),1.71-1.80(m,1H),1.39-1.59(m,2H),1.27(d,J=6.0Hz,3H).

[1165] Example 175: (1 1 s,1 4s)-4 7 -Methyl-2 7 -(methyl-d3)-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,9-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclononane-2 8 -ketone

[1166]

[1167] The compound (23 mg) was synthesized using 4-(N-tert-butoxycarbonylamino)-1-propanol as a substitute starting material, following the synthetic method of Example 158.

[1168] 1 H NMR (400MHz, DMSO-d6)8.61(s,1H),8.59(d,J=4.8Hz,1H),7.90(s,1H),7.86(s,1H),6.91(s,1H),6.70(d,J=4.8Hz,1H),4.52- 4.55(m,2H),4.17-4.26(m,1H),2.80-2.88(m,3H),2.44-2.56(m,5H),2.15-2.23(m,2H),1.97-2.04(m,2H),1.56-1.81(m,4H).

[1169] Example 176: (1 1 r,1 4 r)-4 7 -Methyl-2 7 -(methyl-d3)-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,9-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclononane-2 8 -ketone

[1170]

[1171] Referring to Example 175, the trans isomer obtained in the third step of Synthesis Example 175 was reduced and coupled to obtain the target compound (10 mg).

[1172] 1H NMR (400MHz, DMSO-d6)8.67(s,1H),8.58(d,J=5.6Hz,1H),7.91(s,1H),7.87(s,1H),7.13(s,1H),6.70(d,J=5.6Hz,1H),4.51-4.55(m,2H),4.3 7-4.46(m,1H),3.22-3.30(m,1H),2.97-3.01(m,2H),2.72-2.84(m,2H) ,2.57(s,3H),2.06-2.16(m,4H),1.86-1.94(m,2H),1.21-1.34(m,2H).

[1173] Example 177: (1 1 s,1 4 s)-2 7 4 7 3-Trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[1174]

[1175] At 0℃, towards (1 1 s,1 4 s)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diazo-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane-2 8 60% (mineral oil) sodium hydride (8 mg) was slowly added to a DMF (5 mL) solution of ketone (45 mg), and the mixture was stirred at 0 °C for 10 minutes after the addition was complete. Then, iodomethane (28 mg) was slowly added to the reaction solution. After 1 hour, the reaction solution was poured into a saturated ammonium chloride aqueous solution and stirred continuously. A white precipitate was formed. The precipitate was filtered, washed with water, and dried to obtain the target compound (35 mg).

[1176] 1H NMR (400MHz, DMSO-d6)8.65(d,J=5.2Hz,1H),8.22(s,1H),8.12(s,1H),7.81(s,1H),7.09(d,J=5.2Hz,1H),4.16-4.96(m ,2H),3.79-3.88(m,1H),3.33(s,3H),3.25(s,3H),2.70-2.80(m,2H),2.56-2.63(m,1H),2.24(s,3H),0.90-1.90(m,8H).

[1177] Example 178: (1 1 s,1 4 s)-2 7 -Ethyl-4 7 -Methyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,8-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane-2 8 -ketone

[1178]

[1179] The compound (53 mg) was synthesized using intermediate 24 as a substitute starting material, following the synthesis method of Example 158.

[1180] 1 H NMR (400MHz, CDCl3)8.67(s,1H),8.61(d,J=5.2Hz,1H),7.97(s,1H),7.90(s,1H),7.37(s,1H),6.73(d,J=5.2Hz,1H),4.38-4.50 (m,3H),3.94(q,J=7.2Hz,2H),3.11-3.16(m,3H),2.51-2.62(m,5H),2.15-2.22(m,2H),1.70-1.80(m,4H),1.38(t,J=7.2Hz,3H).

[1181] Example 179: (1's, 4's)-7', 7'-dimethylspirocyclic [cyclopropane-1,7'-5-oxo-3,8-diaza-4(6,4)-quinoline-2(9,2)-purine-1(1,4)-cyclohexanecyclooctane]-8'-one

[1182]

[1183] The compound (38 mg) was synthesized using tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate as a substitute starting material, following the synthesis method of Example 158.

[1184] 1 H NMR (400MHz, DMSO-d6)9.04(s,1H),8.46(d,J=5.2Hz,1H),8.23(s,1H),8.12(s,1H),7.72(s,1H),6.98(d,J=5.2Hz,1H),4.29(s,2H),4.08-4.18(m ,1H),3.33(s,3H),2.91-2.98(m,1H),2.68-2.81(m,2H),2.52(s,3H),1. 92-2.00(m,1H),1.77-1.86(m,2H),1.49-1.62(m,4H),0.60-0.70(m,4H).

[1185] Example 180: 4-(2-((2-ethyl-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate)

[1186]

[1187] Step 1: 2-Ethyl-7-methyl-6-nitro-[1,2,4]triazolo[1,5-a]pyridine

[1188] Under nitrogen protection, 2-chloro-4-methyl-5-nitropyridine (172 mg), 5-ethyl-1,3,4-thiadiazol-2-amine (130 mg), and DIEA (260 mg) were dissolved in toluene (20 mL), heated to 130 °C, and stirred for 48 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (50 mg).

[1189] Step 2: 2-Ethyl-7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine

[1190] At room temperature, 0.3 g of reduced iron powder was added to a 5 mL acetic acid solution of 50 mg of 2-ethyl-7-methyl-6-nitro-[1,2,4]triazolo[1,5-a]pyridine, and the mixture was then heated to 40 °C and stirred for 1 hour. After cooling, the reaction solution was poured into 50 mL of water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1 (V:V)) to give the title compound (38 mg).

[1191] Step 3: 4-(2-((2-ethyl-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[1192] Under nitrogen protection, the above-mentioned 2-ethyl-7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (18 mg), intermediate 14-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)tetrahydro-2H-pyran-4-carbamate (29 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (65 mg) were dissolved in dioxane (10 mL), heated to 100 °C, and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (33 mg).

[1193] 1 H NMR(400MHz, CDCl3)9.39(s,1H),7.93(s,1H),7.45(s,1H),6.64(s,1H),4.06-4.13(m,2H),3.84-3. 92(m,2H),3.40(s,3H),2.92(q,J=7.2Hz,2H),2.74-2.86(m,4H),2.45(s,3H),1.41(t,J=7.2Hz,3H).

[1194] Example 181: 4-(2-((2-isopropyl-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[1195]

[1196] The compound (20 mg) was synthesized using 5-isopropyl-1,3,4-thiadiazole-2-amine as a substitute starting material, following the synthetic method of Example 180.

[1197] 1 H NMR(400MHz,DMSO-d6)8.93(s,1H),8.75(s,1H),8.16(s,1H),7.54(s,1H),3.88-3.94(m,2H),3.53-3.60(m,2 H), 3.28 (s, 3H), 3.05-3.14 (m, 1H), 2.67-2.76 (m, 2H), 2.59-2.66 (m, 2H), 2.32 (s, 3H), 1.30 (d, J = 7.2Hz, 6H).

[1198] Example 182: (1 1 S, 1 4 s, 6 1 S, 6 4 s)-2 7 4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3,7-diaza-4(6,4)-quinoline-2(9,2)-purine-1,6(1,4)-dicyclohexylcycloheptane-2 8 -ketone

[1199]

[1200] The compound (25 mg) was synthesized using trans-4-BOC-aminocyclohexanol as a substitute starting material, following the synthetic method of Example 158.

[1201] 1 H NMR(400MHz, DMSO-d6)8.58(d,J=4.8Hz,1H),8.15(s,2H),7.93(s,1H),7.74(s,1H),6.99(d,J=4.8Hz,1H),4.86-4 .92(m,1H),3.91-4.00(m,1H),3.29(s,3H),3.14-3.20(m,1H),2.71-2.84(m,1H),2.37(s,3H),1.30-1.74(m,16H).

[1202] Example 183: 4-(2-((2-cyclopropyl-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)tetrahydro-2H-pyran-4-carbamate

[1203]

[1204] The compound (22 mg) was synthesized using 5-cyclopropyl-1,3,4-thiadiazole-2-amine as a substitute starting material, following the synthetic method of Example 180.

[1205] 1 H NMR(400MHz, CDCl3)9.33(s,1H),7.93(s,1H),7.40(s,1H),6.68(s,1H),4.02-4.14(m,2H),3.82-3.94(m, 2H),3.40(s,3H),2.70-2.86(m,4H),2.44(s,3H),2.12-2.25(m,1H),0.98-1.14(m,2H),0.78-0.92(m,2H).

[1206] Example 184: 3-(2-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)-8-oxeheno[3.2.1]octane-3-carbamate

[1207]

[1208] Step 1: 3-Amino-8-oxoheterocyclic [3.2.1]octane-3-carbamate

[1209] Tetraisopropyl titanate (5.68 g) was added to a saturated ethanol solution of ammonia (50 mL) under nitrogen protection, followed by the slow addition of 1,4-dioxazo[4.5]dec-8-one (1.26 g). The reaction mixture was stirred at room temperature for 2 hours, then cooled to -5°C and TMSCN (1.1 g) was added. The reaction mixture was maintained at this temperature for 2 hours, then left at room temperature overnight. The reaction was quenched with water (2 mL), the system was filtered, the filtrate was collected and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (V:V)) to obtain the target compound (0.81 g).

[1210] Step 2: (1R,5S)-3-((2-chloro-5-nitropyrimidin-4-yl)amino)-8-oxehenocyclic[3.2.1]octane-3-carbamate

[1211] 2,4-Dichloro-5-nitropyrimidine (1.1 g) and triethylamine (1.01 g) were dissolved in tetrahydrofuran (50 mL), and 3-amino-8-oxehedgeane[3.2.1]octane-3-carbamate (0.81 g) was slowly added under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (200 mL), extracted with ethyl acetate (100 mL), dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1 (V:V)) to give a yellow solid (1.2 g).

[1212] Step 3: (1R,5S)-3-((5-amino-2-chloropyrimidin-4-yl)amino)-8-oxehenocyclic[3.2.1]octane-3-carbamate

[1213] At room temperature, 1.5 g of reduced iron powder was added to a 50 mL acetic acid solution of 1R,5S)-3-((2-chloro-5-nitropyrimidin-4-yl)amino)-8-oxehedgeane[3.2.1]octane-3-carbamate (1.2 g). The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through diatomaceous earth and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution: dichloromethane:methanol = 10:1 (V:V)) to obtain a white solid (1.0 g).

[1214] Step 4: 3-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)-8-oxoheterocyclic[3.2.1]octane-3-carbamate

[1215] The (1R,5S)-3-((5-amino-2-chloropyrimidin-4-yl)amino)-8-oxoheterocyclic [3.2.1]octane-3-carbamate (1.0 g) and CDI (1.3 g) from step 3 were dissolved in tetrahydrofuran (30 mL), heated to 60 °C and stirred for 2 hours under nitrogen protection, cooled to room temperature, and the reaction solution was poured into water (100 mL). The reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (V:V)) to obtain a white solid (900 mg).

[1216] Step 5: 3-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-8-oxoheterocyclic[3.2.1]octane-3-carbamate

[1217] At 0°C, 210 mg of 60% (mineral oil) sodium hydride was slowly added to a 20 mL DMF solution of 900 mg of 3-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)-8-oxoheterocyclic [3.2.1]octane-3-carbamate (600 mg) obtained in step 4. After the addition was complete, the mixture was stirred at 0°C for 10 minutes. Subsequently, 0.7 g of iodomethane was slowly added to the reaction solution. After 1 hour, the reaction solution was poured into a saturated ammonium chloride aqueous solution and stirred continuously. A white precipitate was formed. The precipitate was filtered and dried to obtain the target compound (750 mg).

[1218] Step 6: 3-(2-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-8-oxo-7,8-dihydro-9H-purine-9-yl)-8-oxeheno[3.2.1]octane-3-carbamate

[1219] Under nitrogen protection, the above-mentioned 3-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-8-oxacyclo[3.2.1]octane-3-carbamate (32 mg), 2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (16 mg), RuPhos Pd G3 (9 mg), and cesium carbonate (65 mg) were dissolved in dioxane (10 mL), heated to 100 °C, and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (V:V)) to give the target compound (23 mg).

[1220] MS(ESI) m / z 446.31(M+H) +

[1221] Bioactivity experiment

[1222] DNA-PK compound bioactivity assay method

[1223] 1. In vitro enzymatic activity assay of the compound against DNA-PK

[1224] In this patent, the IC50 value of the compound's inhibition of DNA-PK enzymatic activity was determined using time-resolved fluorescence resonance energy transfer (TR-FRET). The compound was serially diluted 10-fold with 100% DMSO starting at 1 mM (totaling 7 concentrations). 2 μL of each concentration was added to 48 μL of reaction buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM DTT, 0.01% Brij-35, and 1 mM EGTA pH 8.0) and mixed thoroughly. Add 2.5 μL of the diluted compound to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), then add 5 μL of DNA-PK (Full-length, final concentration 5 nM), centrifuge to mix, and then add 2.5 μL of ATP (final concentration 2 μM) and Fluorescein-p53 Substrate mixture (final concentration 2 μM, purchased from Thermo) to start the reaction. The total reaction volume is 10 μL. Incubate the 384-well plate at 23°C for 2 hours, then add 10 μL of... The reaction was terminated with a mixture of Tb-antiphospho-p53[pSer15]antibody (final concentration 2 nM, purchased from Thermo) and EDTA (final concentration 10 mM). After incubation for another 1 hour, fluorescence values ​​were read on an Envision (purchased from PerkinElmer) microscope (excitation at 340 nm, detection of emission at 520 nm and 490 nm, the ratio of which is the enzyme activity signal). The enzymatic activity signal of DNA-PK was measured at 7 concentrations for each compound, and the IC50 value of the compound was calculated using GraphPadPrism software. Enzymatic activities of some examples are shown in Table 1.

[1225] Table 1. Enzyme activity data from some examples

[1226] Example 56 0.118 Example 72 0.073 Example 85 0.099 Example 117 0.277 Example 124 0.121 Example 131 0.146 Example 139 0.750 Example 141 0.389 Example 143 0.147 Example 158 0.087 Example 159 0.148 Example 164 0.166 Example 166 0.160 Example 167 0.179 Example 168 0.122 Example 169 0.297

[1227] 2. Assay of the proliferative activity of the compound in MDA-MB-468 cells

[1228] This patent describes a detection method for the inhibition of cell proliferation in human breast cancer cells MDA-MB-468 under the combined use of a DNA-PK inhibitor and the chemotherapeutic drug Doxorubicin. The specific method is as follows: Human breast cancer cells MDA-MB-468 were cultured in RPMI-1640 medium (purchased from Biological Industries, BI) with 10% fetal bovine serum (FBS, purchased from Hyclone) and 1% penicillin / streptomycin antibiotics (P / S, purchased from Life Technology) at 37°C and 5% CO2. The day before the compound detection, MDA-MB-468 cells were seeded at a concentration of 1000 cells / 190 μL / well in 96-well plates (#3917, purchased from Corning). After 24 hours, Doxorubicin was added to a final concentration of 10 nM (DMSO final concentration 0.1%). The test compound was serially diluted 3-fold with 100% DMSO, starting at 10 mM (total of 10 concentrations). 2 μL of each concentration was then added to 48 μL of RPMI-1640 medium for further dilution. 5 μL of each diluted concentration was added to the prepared cell suspension. The compound and cells were incubated together in a cell culture incubator for 120 h (5 days). After aspirating the medium, 25 μL of Cell-TiterGlo (G7570, purchased from Promega) reagent was added, and the cells were incubated again for 5-10 minutes. Fluorescence values ​​were then read using a CLARIO starPlus (purchased from BMG) microplate reader. The IC50 value of the compound's inhibitory effect on cell proliferation was calculated using GraphPad Prism software. The specific compound's cell activity data (IC50) in the examples are shown below. 50 The cell activity (nM) was all below 2000, indicating good cell proliferation inhibition activity. Cell activity from some examples is shown in Table 2.

[1229] Table 2. Cell viability data from some examples

[1230]

[1231]

[1232] 3. Pharmacokinetic data of the compound:

[1233] Male SD rats were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. Rats were divided into groups of three and orally administered a suspension of the test sample (5 mg / kg, suspension of 0.5% HPMC and 0.1% Tween 80 in H2O). Animals were fasted overnight before the experiment, from 10 hours before administration to 4 hours after administration. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After anesthesia with isoflurane using a small animal anesthesia machine, 0.3 mL of whole blood was collected through the fundus venous plexus and placed in heparin anticoagulant tubes. The samples were centrifuged at 4000 rpm for 5 min at 4℃. Plasma was transferred to centrifuge tubes and stored at -80℃ until analysis. Protein precipitation was used to extract the plasma samples, and the extract was analyzed by LC / MS. See Table 3.

[1234] Table 3. Pharmacokinetic data of some compounds

[1235]

[1236]

[1237] Industrial applicability

[1238] This invention provides a DNA-PK selective inhibitor, its preparation, and its uses. The invention also provides a series of compounds represented by general formula (I) and their pharmaceutically acceptable salts, solvates, polymorphs, or isomers, pharmaceutical compositions comprising these compounds, and methods for treating diseases with such compounds. The DNA-PK selective inhibitor provided by this invention exhibits high activity, strong drug resistance, and few clinical side effects, and can effectively enhance the sensitivity to radiotherapy and chemotherapy in tumor treatment, possessing good economic value and application prospects.

Claims

1. Any one of the following compounds, in combination with other drugs used to treat breast cancer, can be used to prepare a treatment for breast cancer. Use in drugs for adenocarcinoma, wherein the compound is: ， The other drug mentioned for treating breast cancer is the chemotherapy drug Doxorubicin.

2. A pharmaceutical composition for treating breast cancer, comprising the compound according to claim 1. The drug and chemotherapy drug Doxorubicin.

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