Nitrogen-containing heterocyclic compounds, their preparation method and medical applications

Abstract

The present invention relates to a nitrogen-containing heterocyclic compound, its preparation method and its pharmaceutical application. Specifically, the present invention relates to a nitrogen-containing heterocyclic compound represented by the general formula (IM), its preparation method and a pharmaceutical composition containing the compound, as well as its use as a therapeutic agent, in particular its use as a PARP1 inhibitor and in the preparation of a medicament for treating and / or preventing cancer. JPEG2024519188000081.jpg43170

Description

[Technical field]

[0001] The present disclosure belongs to the pharmaceutical field and relates to a nitrogen-containing heterocyclic compound, its preparation method and its pharmaceutical application. In particular, the present disclosure relates to a nitrogen-containing heterocyclic compound represented by general formula (IM), its preparation method and pharmaceutical composition containing the compound, and its use as a PARP1 inhibitor and in the preparation of a medicament for treating and / or preventing cancer. [Background technology]

[0002] Since its first report over 50 years ago, poly(ADP-ribose) polymerase 1 (PARP1) has gradually been found to play important roles in DNA repair, maintaining genome integrity, and regulating various metabolic and signaling processes. PARP1 can catalyze the transfer of ADP-ribose residues from NAD+ to target substrates to build poly(ADP-ribose) (PAR) chains. The formation and removal of PAR chains occurs in almost all eukaryotic cells.

[0003] ADP-ribosylation is a post-translational modification of proteins that is widely present in various physiological and pathological processes and refers to the attachment of one or more ADP-ribose units to specific sites of proteins under the catalysis of enzymes. PARP1 is the first member of the PARP superfamily, which consists of proteins with homology to PARP1 and currently has 17 members, of which four (PARP1, PARP2, PARP5A and PARP5B) can synthesize PAR chains. Many of the other enzymes in the family can only build a single ADP-ribose unit and are therefore classified as mono(ADP-ribosyl)ases (MARs).

[0004] PARP1 and PARP2 have been extensively studied due to their role in DNA damage repair. PARP1 is activated by DNA breaks and functions as a catalyst for poly(ADP-ribose) (PAR) chains to target proteins. Such post-translational modification, called polyadenosine diphosphate ribosylation (PARylation), can mediate the recruitment of other DNA repair factors to DNA lesions. After this recruitment mission is completed, PARP automatically PARylates, triggering the release of bound PARP from DNA, allowing access to other DNA repair proteins to complete the repair. Thus, the binding of PARP to the damage site, its catalytic activity, and eventual release from DNA are all critical steps in cancer cells responding to DNA damage caused by chemotherapeutic agents and radiation therapy.

[0005] Inhibition of PARP family enzymes has been used as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. A large amount of preclinical and clinical studies have shown that tumor cells with deleterious alterations of the key tumor suppressor proteins BRCA1 or BRCA2, involved in double-stranded DNA break (DSB) repair by deleterious recombination (HR), are selectively sensitive to small molecules, inhibitors of the DNA repair enzyme PARP family. Such tumors have insufficient homologous recombination repair (HRR) pathways and depend on the survival function of PARP enzymes. Although PARP inhibitor therapy is primarily directed at BRCA-mutated cancers, PARP inhibitors have already been in clinical trials in non-BRCA-mutated tumors, which showed homologous recombination deficiency (HRD).

[0006] Compared with other PARP1 / 2 inhibitors, PARP inhibitors with improved selectivity for PARP1 may have improved efficacy and reduced toxicity. It is believed that selective and strong inhibition of PARP1 traps PARP1 on DNA, causing DNA double-strand breaks (DSBs) due to the collapse of replication forks in the S phase. PARP1-DNA trapping is an effective mechanism for selectively killing tumor cells with HRD.

[0007] Therefore, there is an urgent clinical need for effective and safe PARP inhibitors, especially PARP inhibitors that are selective for PARP1.

[0008] Currently, related patent applications that have already been published include WO2021013735A1, WO2021260092A1, WO2009053373A1, WO2008107478A1, etc. Summary of the Invention

[0009] The present disclosure aims to provide a compound represented by general formula (IM) or a medicamentable salt thereof: [ka] Among them, X and Y are homologous or different, and each independently (CR 4a R 4b ) m , N.R. 5 (CR 4c R 4d ) r , C(O)NR 5 , N.R. 5 C(O), C(O) and O(CR 4e R 4f ) n Selected from R 4a , R 4b , R 4c , R 4d , R 4e and R 4f are identical or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 5 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; G 1 , G 2 and G 3are homologous or different, and each independently represents CR 6 or a nitrogen atom, R 0 , R 1 and R 6 are identical or different and each independently represent a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, -NR 7a R 7b , hydroxy group, -C(O)R 8 , -C(O)OR 8 , -C(O)NR 7a R 7b , -S(O) p R 8 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally selected from halogen, oxo group, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, -NR 9a R 9b , substituted with one or more substituents selected from a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; Each R 2 are identical or different and each independently represent a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, an oxo group, a cyano group, -NR 7a R 7b , a hydroxy group and a hydroxyalkyl group; Each R 3 are identical or different and each independently represent a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, -NR 7a R 7b , hydroxy group, -C(O)R 8 , -C(O)OR 8 , -C(O)NR 7a R 7b , -S(O) p R 8, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally selected from halogen, oxo group, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, -NR 9a R 9b , substituted with one or more substituents selected from a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 7a , R 7b , R 9a and R 9b are identical or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group and the heterocyclyl group are each independently optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkoxy group, a haloalkyl group and a haloalkoxy group; Or, R 7a and R 7b forms a heterocyclyl group together with the nitrogen atom to which it is linked, and R 9a and R 9b together with the nitrogen atom to which it is linked form a heterocyclyl group, the heterocyclyl group being optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 8 is selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, and a haloalkoxy group; p is 0, 1 or 2; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; r is 0, 1, 2, 3 or 4; s is 0, 1, 2, 3 or 4, and t is 0, 1, 2, or 3.

[0010] In some embodiments of the present disclosure, the compound represented by the above general formula (IM) or a medicamentable salt thereof is a compound represented by general formula (I) or a medicamentable salt thereof. [ka] Among them, X and Y are homologous or different, and each independently (CR 4a R 4b ) m , N.R. 5 (CR 4c R 4d ) r , C(O)NR 5 , N.R. 5 C(O), C(O) and O(CR 4e R 4f ) n Selected from R 4a , R 4b , R 4c , R 4d , R 4e and R 4f are identical or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 5 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; G 1 , G 2 and G 3 are homologous or different, and each independently represents CR 6 or a nitrogen atom, R 1 and R 6are identical or different and each independently represent a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, -NR 7a R 7b , hydroxy group, -C(O)R 8 , -C(O)OR 8 , -C(O)NR 7a R 7b , -S(O) p R 8 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally selected from halogen, oxo group, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, -NR 9a R 9b , substituted with one or more substituents selected from a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; Each R 2 are identical or different and each independently represent a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, an oxo group, a cyano group, -NR 7a R 7b , a hydroxy group and a hydroxyalkyl group; Each R 3 are identical or different and each independently represent a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, -NR 7a R 7b , hydroxy group, -C(O)R 8 , -C(O)OR 8 , -C(O)NR 7a R 7b , -S(O) p R 8, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally selected from halogen, oxo group, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, -NR 9a R 9b , substituted with one or more substituents selected from a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 7a , R 7b , R 9a and R 9b are identical or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group and the heterocyclyl group are each independently optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkoxy group, a haloalkyl group and a haloalkoxy group; Or, R 7a and R 7b forms a heterocyclyl group together with the nitrogen atom to which it is linked, and R 9a and R 9b together with the nitrogen atom to which it is linked form a heterocyclyl group, the heterocyclyl group being optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 8 is selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, and a haloalkoxy group; p is 0, 1 or 2; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; r is 0, 1, 2, 3 or 4; s is 0, 1, 2, 3 or 4, and t is 0, 1, 2, or 3.

[0011] In some embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (I) or a medicamentable salt thereof, wherein X is (CR 4a R 4b ) m or C(O), of which R 4a , R 4b and m are as defined in general formula (IM), and preferably X is CH 2 , C.H. 2 CH 2 and C(O).

[0012] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (IM), general formula (I), or a medicamentable salt thereof, wherein Y is O(CR 4e R 4f ) n or NR 5 (CR 4c R 4d ) r Of these, R 4c , R 4d , R 4e , R 4f , R 5 , n and r are as defined in general formula (IM), and preferably Y is O, OCH 2 , NH and NCH 3 Selected from.

[0013] In some embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (I) or a medicamentable salt thereof, wherein X is (CR 4a R 4b ) m or C(O) and Y is O(CR 4e R 4f ) n or NR 5 (CR 4c R4d ) r and preferably, X is (CR 4a R 4b ) m , and Y is O(CR 4e R 4f ) n or X is (CR 4a R 4b ) m , and Y is NR 5 (CR 4c R 4d ) r or X is C(O) and Y is NR 5 (CR 4c R 4d ) r Of these, R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 5 , m, n and r are as defined in general formula (IM), more preferably XY is CH 2 O, C.H. 2 OCH 2 , C.H. 2 CH 2 O, C(O)NH, CH 2 NH and CH 2 NCH 3 Selected from.

[0014] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (IM), general formula (I), or a medicamentable salt thereof, wherein R 4c and R 4d are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl groups and C 1-6 haloalkyl groups, preferably R 4c and R 4d are both hydrogen atoms.

[0015] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (IM), general formula (I), or a medicamentable salt thereof, wherein R 4e and R4f are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl groups and C 1-6 haloalkyl groups, preferably R 4e and R 4f are both hydrogen atoms.

[0016] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (IM) or a medicamentable salt thereof, wherein R 0 is a hydrogen atom, halogen, C 1-6 Alkyl groups and C 1-6 haloalkyl groups, preferably R 0 is a hydrogen atom or a halogen atom, and more preferably, R 0 is a hydrogen atom or F, and most preferably, R 0 is a hydrogen atom.

[0017] In some embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (I) or a medicamentable salt thereof is a compound represented by general formula (II-1) or a medicamentable salt thereof. [ka] Among them, X is (CR 4a R 4b ) m and G 1 ~G 3 , R 1 ~R 3 , R 4a , R 4b , s, t, m and n are as defined in general formula (IM).

[0018] In some embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (I) or a medicamentable salt thereof is a compound represented by general formula (II-2) or a medicamentable salt thereof. [ka] Among them, X is (CR 4a R 4b ) m or C(O), G 1 ~G 3 , R 1 ~R 3 , R 4a , R 4b , R 5 , s, t, m and r are as defined in general formula (IM).

[0019] In some embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (I), general formula (II-1), general formula (II-2), or a medicamentable salt thereof, wherein each R 2 are the same or different, and each independently represents a halogen, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl Groups and C 1-6 haloalkoxy groups.

[0020] In some embodiments of the present disclosure, the compound is represented by the above general formula (IM), general formula (I), general formula (II-1), or general formula (II-2), or a medicamentable salt thereof, wherein s is 0.

[0021] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (IM), general formula (I), general formula (II-1), or general formula (II-2) or a medicamentous salt thereof, wherein 1 is CH, G 2 is a nitrogen atom, and G 3 is CR 6 or G 1 and G 2 are both CH and G 3 is a nitrogen atom, or G 1 is a nitrogen atom, G 2 is CH and G 3 is CR 6 and preferably, G 1 is CH, G 2 is a nitrogen atom, and G 3 is CR6 Of these, R 6 is as defined in general formula (IM).

[0022] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (IM), general formula (I), general formula (II-1), or general formula (II-2) or a medicamentous salt thereof, wherein 1 is CH, G 2 is a nitrogen atom, and G 3 is CR 6 or G 1 and G 2 are both CH and G 3 is a nitrogen atom, or G 1 is a nitrogen atom, G 2 is CH and G 3 is CR 6 Of these, R 6 is as defined in general formula (IM), preferably G 1 is CH, G 2 is a nitrogen atom, and G 3 is CR 6 or G 1 is a nitrogen atom, G 2 is CH and G 3 is CR 6 Of these, R 6 is as defined in general formula (IM).

[0023] In some embodiments of the present disclosure, the compound is represented by the above general formula (IM), general formula (I), general formula (II-1), or general formula (II-2), or a medicamentable salt thereof, wherein t is 1 or 2, and preferably t is 1.

[0024] In some embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (I), general formula (II-1), general formula (II-2), or a medicamentable salt thereof, wherein R 3 is halogen, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C1-6 Hydroxyalkyl group, cyano group, -NR 7a R 7b , hydroxy group, -C(O)R 8 , -C(O)OR 8 and -C(O)NR 7a R 7b Preferably, R 3 -C(O)NR 7a R 7b Of these, R 7a , R 7b and R 8 is as defined in general formula (IM), more preferably R 3 -C(O)NHCH 3 It is.

[0025] In some embodiments of the present disclosure, the compound is represented by the above general formula (IM), general formula (I), general formula (II-1), or general formula (II-2), or a medicamentable salt thereof, wherein m is 1 or 2.

[0026] In some embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (I), general formula (II-1), general formula (II-2), or a medicamentable salt thereof, wherein R 4a and R 4b are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl groups and C 1-6 haloalkyl groups, preferably R 4a and R 4b are both hydrogen atoms.

[0027] In some embodiments of the present disclosure, the compound is represented by the above general formula (IM), general formula (I), general formula (II-2), or a medicamentable salt thereof, wherein r is 0 or 1, and preferably r is 0.

[0028] In some embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (I), general formula (II-1) or a medicamentable salt thereof is a compound represented by general formula (III-1) or a medicamentable salt thereof. [ka] Among them, m1 is 0 or 1, R 1 , R 6 , R 7a , R 7b and n are as defined in general formula (IM).

[0029] In some embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (I), general formula (II-1), or general formula (III-1) or a medicamentable salt thereof is a compound represented by general formula (III-1-A) or a medicamentable salt thereof. [ka] Among them, m1 is 0 or 1, R 1 , R 6 , R 7a , R 7b and n are as defined in general formula (IM).

[0030] In some embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (I), general formula (II-2) or a medicamentable salt thereof is a compound represented by general formula (III-2) or a medicamentable salt thereof. [ka] Among them, X is CH 2 or C(O), R 1 , R 5 , R 6 , R 7a and R 7b is as defined in general formula (IM).

[0031] In some embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-1-A), general formula (III-2), or a medicamentable salt thereof, wherein R 1 is a hydrogen atom, halogen, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy groups and C 1-6 hydroxyalkyl groups, preferably R 1 is C 1-6 More preferably, R 1 is an ethyl group.

[0032] In some embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-1-A), general formula (III-2), or a medicamentable salt thereof, wherein R 6 is a hydrogen atom, halogen, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy groups and C 1-6 hydroxyalkyl groups, preferably R 6 is a hydrogen atom.

[0033] In some embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-1-A), general formula (III-2), or a medicamentable salt thereof, wherein R 7a and R 7b are identical or different, and each independently represents a hydrogen atom, C 1-6 Alkyl group, C 1-6 is selected from the group consisting of a hydroxyalkyl group, a 3- to 8-membered cycloalkyl group, and a 3- to 8-membered heterocyclyl group, preferably R 7a and R 7bare identical or different, and each independently represents a hydrogen atom or C 1-6 More preferably, R 7a is a hydrogen atom, R 7b is a methyl group.

[0034] In some embodiments of the present disclosure, the compound is represented by the above general formula (IM), general formula (I), general formula (II-1), general formula (III-1), general formula (III-1-A), or a medicamentable salt thereof, wherein n is 0 or 1.

[0035] In some embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (I), general formula (II-2), general formula (III-2), or a medicamentable salt thereof, wherein R 5 is a hydrogen atom or C 1-6 is an alkyl group, preferably R 5 is a hydrogen atom or a methyl group.

[0036] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (IM) or a medicamentable salt thereof, wherein X is (CR 4a R 4b ) m or C(O), Y is O(CR 4e R 4f ) n or NR 5 (CR 4c R 4d ) r and G 1 is CH, G 2 is a nitrogen atom, and G 3 is CR 6 or G 1 is a nitrogen atom, G 2 is CH and G 3 is CR 6 and R 0 is a hydrogen atom or a halogen atom, and R 1 is C 1-6 is an alkyl group, R 3 -C(O)NR 7a R 7b and R 4a , R4b , R 4c , R 4d , R 4e and R 4f are both hydrogen atoms, and R 5 is a hydrogen atom or C 1-6 is an alkyl group, R 6 is a hydrogen atom, and R 7a and R 7b are identical or different, and each independently represents a hydrogen atom or C 1-6 m is 1 or 2, n is 0 or 1, r is 0 or 1, s is 0, and t is 1.

[0037] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein X is (CR 4a R 4b ) m or C(O) and Y is O(CR 4e R 4f ) n or NR 5 (CR 4c R 4d ) r and G 1 is CH, G 2 is a nitrogen atom, and G 3 is CR 6 or G 1 and G 2 is CH and G 3 is a nitrogen atom, or G 1 is a nitrogen atom, G 2 is CH and G 3 is CR 6 and R 1 is a hydrogen atom, halogen, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy groups and C 1-6 hydroxyalkyl groups, R 3 -C(O)NR 7a R 7b and R 4a , R 4b , R 4c , R 4d, R 4e and R 4f are both hydrogen atoms, and R 5 is a hydrogen atom or C 1-6 is an alkyl group, R 6 is a hydrogen atom, halogen, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy groups and C 1-6 hydroxyalkyl groups, R 7a and R 7b are identical or different, and each independently represents a hydrogen atom, C 1-6 Alkyl group, C 1-6 It is selected from a hydroxyalkyl group, a 3- to 8-membered cycloalkyl group, and a 3- to 8-membered heterocyclyl group, m is 1 or 2, n is 0 or 1, r is 0 or 1, s is 0, and t is 1 or 2.

[0038] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (II-1) or a medicamentable salt thereof, wherein X is (CR 4a R 4b ) m and G 1 is CH, G 2 is a nitrogen atom, and G 3 is CR 6 and R 1 is C 1-6 is an alkyl group, R 3 -C(O)NR 7a R 7b and R 4a and R 4b are both hydrogen atoms, and R 6 is a hydrogen atom, and R 7a and R 7b are identical or different, and each independently represents a hydrogen atom, C 1-6 Alkyl group, C 1-6 It is selected from a hydroxyalkyl group, a 3- to 8-membered cycloalkyl group, and a 3- to 8-membered heterocyclyl group, s is 0, t is 1, m is 1 or 2, and n is 0 or 1.

[0039] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (II-2) or a medicamentable salt thereof, wherein X is (CR 4a R 4b ) m or C(O), G 1 is CH, G 2 is a nitrogen atom, and G 3 is CR 6 and R 1 is C 1-6 is an alkyl group, R 3 -C(O)NR 7a R 7b and R 4a and R 4b are both hydrogen atoms, and R 5 is a hydrogen atom or C 1-6 is an alkyl group, R 6 is a hydrogen atom, and R 7a and R 7b are identical or different, and each independently represents a hydrogen atom, C 1-6 Alkyl group, C 1-6 It is selected from a hydroxyalkyl group, a 3- to 8-membered cycloalkyl group, and a 3- to 8-membered heterocyclyl group, s is 0, t is 1, m is 1 or 2, and r is 0.

[0040] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (III-1) or general formula (III-1-A) or a medicamentable salt thereof, wherein R 1 is C 1-6 is an alkyl group, R 6 is a hydrogen atom, and R 7a and R 7b are identical or different, and each independently represents a hydrogen atom or C 1-6 It is an alkyl group, m1 is 0 or 1, and n is 0 or 1.

[0041] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (III-2) or a medicamentable salt thereof, wherein X is CH 2 or C(O), R 1 is C 1-6 is an alkyl group, R 5 is a hydrogen atom or C1-6 is an alkyl group, R 6 is a hydrogen atom, and R 7a and R 7b are identical or different, and each independently represents a hydrogen atom or C 1-6 It is an alkyl group.

[0042] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0043] Another aspect of the present disclosure relates to a compound represented by the general formula (IMa) or a salt thereof. [ka] Among them, t is 1, 2 or 3; X, Y, R 2 , R 3 and s are as defined for compounds of general formula (IM).

[0044] Another aspect of the present disclosure relates to a compound represented by general formula (II-1a) or a salt thereof. [ka] Among them, X, R 2 , R 3 , s, t and n are as defined for the compound of general formula (II-1).

[0045] Another aspect of the present disclosure relates to a compound represented by general formula (II-2a) or a salt thereof. [ka] Among them, X, R 2 , R 3 , R 5 , s, t and r are as defined for the compound of general formula (II-2).

[0046] Another aspect of the present disclosure relates to a compound represented by general formula (III-1a) or a salt thereof. [ka] Among them, m1 is 0 or 1, R 7a , R 7b and n are as defined for the compound of general formula (III-1).

[0047] Another aspect of the present disclosure relates to a compound represented by general formula (III-1-Aa) or a salt thereof. [ka] Among them, m1 is 0 or 1, R 7a , R 7b and n are as defined for the compound of general formula (III-1-A).

[0048] Another aspect of the present disclosure relates to a compound represented by general formula (III-2a) or a salt thereof. [ka] Among them, X, R 5 , R 7a and R 7b is as defined in general formula (III-2).

[0049] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0050] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (IM) or a medicamentable salt thereof, the method comprising: [ka] nucleophilic substitution reaction of a compound of general formula (IMa) or a salt thereof (preferably the hydrochloride salt) with a compound of general formula (IMb) to obtain a compound of general formula (IM) or a medicamentable salt thereof, Among them, L is a halogen atom, preferably a chlorine atom; X, Y, G 1 ~G 3 , R 0 ~R 3 , s and t are as defined in general formula (IM).

[0051] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (I) or a medicamentable salt thereof, the method comprising: [ka] nucleophilic substitution reaction of a compound of general formula (IMa) or a salt thereof (preferably the hydrochloride salt) with a compound of general formula (V) to obtain a compound of general formula (I) or a medicamentable salt thereof, Among them, L is a halogen atom, preferably a chlorine atom; X, Y, G 1 ~G 3 , R 1 ~R 3 , s and t are as defined in general formula (I).

[0052] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a medicamentable salt thereof, the method comprising: [ka] A method of the present invention comprising the steps of: reacting a compound of general formula (II-1a) or a salt thereof (preferably the hydrochloride salt) with a compound of general formula (V) to obtain a compound of general formula (II-1) or a medicamentable salt thereof; Among them, L is a halogen atom, preferably a chlorine atom; X, G 1 ~G 3 , R 1 ~R 3 , s, t and n are as defined in general formula (II-1).

[0053] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-2) or a medicamentable salt thereof, the method comprising: [ka] A method of the present invention comprising the steps of: reacting a compound of general formula (II-2a) or a salt thereof (preferably the hydrochloride salt) with a compound of general formula (V) to obtain a compound of general formula (II-2) or a medicamentable salt thereof, Among them, L is a halogen atom, preferably a chlorine atom; X, G 1 ~G 3 , R 1 ~R 3 , R 5 , s, t and r are as defined in general formula (II-2).

[0054] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (III-1) or a medicamentable salt thereof, the method comprising: [ka] A method comprising the steps of: reacting a compound of general formula (III-1a) or a salt thereof (preferably the hydrochloride salt) with a compound of general formula (VI) to obtain a compound of general formula (III-1) or a medicamentable salt thereof; Among them, m1 is 0 or 1, L is a halogen atom, preferably a chlorine atom; R 1 , R 6 , R 7a , R 7b and n are as defined in general formula (III-1).

[0055] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (III-1-A) or a medicamentable salt thereof, the method comprising: [ka] A method comprising the steps of: reacting a compound of general formula (III-1-Aa) or a salt thereof (preferably the hydrochloride salt) with a compound of general formula (VI) by nucleophilic substitution to obtain a compound of general formula (III-1-A) or a medicamentable salt thereof, Among them, m1 is 0 or 1, L is a halogen atom, preferably a chlorine atom; R 1 , R 6 , R 7a , R 7b and n are as defined in general formula (III-1-A).

[0056] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (III-2) or a medicamentable salt thereof, the method comprising: [ka] A method comprising the steps of: reacting a compound of general formula (III-2a) or a salt thereof (preferably the hydrochloride salt) with a compound of general formula (VI) to obtain a compound of general formula (III-2) or a medicamentable salt thereof; Among them, L is a halogen atom, preferably a chlorine atom; X, R1 , R 5 , R 6 , R 7a and R 7b is as defined in general formula (III-2).

[0057] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure as set forth in general formula (IM), general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-1-A), general formula (III-2) and Table A or a medicamentable salt thereof, and one or more pharma-ceutically acceptable vectors, diluents or excipients.

[0058] The present disclosure further relates to the use of a compound as shown in general formula (IM), general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-1-A), general formula (III-2) and Table A or a medicamentable salt thereof, or a pharmaceutical composition containing same, in the preparation of a PARP1 inhibitor.

[0059] The present disclosure further relates to the use of a compound as shown in general formula (IM), general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-1-A), general formula (III-2) and Table A or a medicament salt thereof, or a pharmaceutical composition comprising same, in the preparation of a medicament for treating and / or preventing cancer.

[0060] The present disclosure further relates to a method of inhibiting PARP1, comprising administering to a patient in need thereof an inhibitory effective amount of a compound as set forth in general formula (IM), general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-1-A), general formula (III-2) and Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising same.

[0061] The present disclosure further relates to a method for treating and / or preventing cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (IM), general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-1-A), general formula (III-2) and Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising same.

[0062] The present disclosure further relates to a compound of general formula (IM), general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-1-A), general formula (III-2) and Table A, or a medicamentable salt thereof, or a pharmaceutical composition containing same, for use as a medicament.

[0063] The present disclosure further relates to a compound as shown in general formula (IM), general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-1-A), general formula (III-2) and Table A, or a medicamentable salt thereof, or a pharmaceutical composition containing the same, for use as a PARP1 inhibitor.

[0064] The present disclosure further relates to a compound as shown in general formula (IM), general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-1-A), general formula (III-2) and Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising same, for use in the treatment and / or prevention of cancer.

[0065] Cancers described in this disclosure include breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer (e.g., colon and rectal cancer), lung cancer, kidney cancer, liver cancer (e.g., hepatocellular carcinoma), cervical cancer, endometrial cancer, myeloma (e.g., multiple myeloma), leukemia (e.g., acute leukemia, chronic leukemia, myeloblastic leukemia, myelofibrosis, erythroleukemia), lymphoma (e.g., diffuse large B-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoid malignancies of T-cell or B-cell origin, follicular lymphoma), acoustic neuroma, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, bronchial carcinoma, sarcoma (e.g., chondrosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, myxosarcoma, osteogenic sarcoma, , rhabdomyosarcoma), chordoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, hemangioendothelioma, ependymoma, epithelial carcinoma, esophageal cancer (also called esophageal carcinoma), primary thrombocytosis, Ewing's sarcoma, testicular cancer, glioma, heavy chain disease, hemangioblastoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, glioma, NUT midline carcinoma, glioma, bone cancer, nasopharyngeal carcinoma, oral cancer, thyroid cancer, pineal tumor, polycythemia vera, retinoblastoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, Waldenstrom's macroglobulinemia and Wilms' tumor, preferably, the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer and lung cancer.

[0066] The active compound can be prepared in a suitable form for administration by any suitable route, and the composition of the present disclosure can be prepared by one or more pharma- ceutically acceptable vectors in a conventional manner. Thus, the active compound of the present disclosure can be prepared in various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation administration. The compound of the present disclosure can be prepared in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injection solutions, dispersible powders or granules, suppositories, tablets for external application, or syrups.

[0067] As a general guideline, it is preferred that the active compound be in a unit dose form or in a form that the patient can self-administer as a single agent. The unit dose of the compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, bottled liquid, drug powder, granule, topical tablet, suppository, reconstituted powder or liquid formulation. A suitable unit dose may be 0.1 to 1000 mg.

[0068] The pharmaceutical composition according to the present disclosure may contain one or more additives in addition to the active compound, and the additives are selected from components such as fillers (diluents), binders, wetting agents, disintegrants, or excipients. The composition may contain 0.1 to 99% by weight of the active compound, depending on the method of administration.

[0069] The tablets contain the active ingredient and non-toxic medicamentous excipients suitable for mixing in the preparation of tablets. These excipients may be inert diluents, granulating agents, disintegrating agents, binding agents and lubricants. The tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over an extended period of time.

[0070] Oral formulations may be provided by soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or with a water-soluble vector or oil-based solvent.

[0071] Aqueous suspensions contain the active substances and mixing excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0072] Oily suspensions can be prepared by suspending the active ingredient in vegetable oil or mineral oil.Oily suspensions can contain thickening agents.In order to provide a palatable preparation, the above-mentioned sweeteners and flavorings can be added.These compositions can be preserved by adding antioxidants.

[0073] The pharmaceutical compositions according to the present disclosure may be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may contain sweeteners, flavoring agents, preservatives and antioxidants. Such formulations may also contain demulcents, preservatives, colorants and antioxidants.

[0074] The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable solvents or vehicles that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injectable solution or microemulsion can be injected into the patient's bloodstream by local injection of large amounts. Alternatively, it is preferable to administer the solutions and microemulsions in a manner that allows a constant cyclic concentration of the compounds of the present disclosure to be maintained. To maintain such a constant concentration, a continuous intravenous administration device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

[0075] The pharmaceutical composition according to the present disclosure may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension may be prepared according to known techniques using the above-mentioned suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension prepared in a non-toxic diluent or solvent that is parenterally acceptable. Sterile fixed oils may also be conveniently used as a solvent or suspension medium. Any fixed oil for formulation may be used for this purpose. Fatty acids may also be used to prepare an injectable.

[0076] The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid in the rectum, and therefore melts in the rectum to release the drug.

[0077] The compounds of the present disclosure can be administered by adding water to prepare dispersible powders and granules in aqueous suspension. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, and one or more preservatives.

[0078] As is well known to those skilled in the art, the dosage of a drug depends on many factors, including but not limited to the activity of the specific compound used, the patient's age, the patient's weight, the patient's physical condition, the patient's behavior, the patient's diet, the administration time, the administration method, the excretion rate, the composition of the drug, the severity of the disease, etc., and the optimal treatment method, such as the treatment mode, the daily dosage of the compound or the type of medicinal salt, can be verified according to conventional treatment plans. Explanation of terms

[0079] Unless specifically stated to the contrary, terms used in the specification and claims have the following meanings.

[0080] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group that is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 1-12 alkyl group), more preferably an alkyl group containing 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 6-methylhexyl, 7-methylhexyl, 8-methylhexyl, 9-methylhexyl, 10-methylhexyl, 11-methylhexyl, 12-methylhexyl, 13-methylhexyl, 14-methylhexyl, 15-methylhexyl, 16-methylhexyl, 17-methylhexyl, 18-methylhexyl, 19-methylhexyl, 22-methylhexyl, 23-methylhexyl, 24-methylhexyl, 25-methylhexyl, 26-methylhexyl, 27-methylhexyl, 28-methylhexyl, 29-methylhexyl, 30-methylhexyl, 31-methylhexyl, 32-methylhexyl, 33-methylhexyl, 34-methylhexyl, 35-methylhexyl, 36-methylhexyl, 37-methylhexyl, 38-methylhexyl, 39-methylhexyl, 40-methylhexyl, 41-methylhexyl, 42-methylhexyl, 43-methylhexyl, 44-methylhexyl, 45-methylhex Examples of such groups include 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. An alkyl group may be substituted or unsubstituted and, if substituted, may be substituted at any available attachment point, the substituents being optionally one or more selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.

[0081] The term "alkylene group" refers to a saturated, straight or branched chain aliphatic hydrocarbon group, the residue derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane, and is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably having from 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 1-12 alkylene group), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 A non-limiting example of an alkylene group is methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 Alkylene groups can be substituted or unsubstituted and, if substituted, can be substituted at any available linkage site, with the substituents optionally being one or more selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0082] The term "alkenyl group" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, of which the alkyl group is defined as above, and preferably an alkenyl group having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 2-12 alkenyl group), more preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 alkenyl groups). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. The alkenyl group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

[0083] The term "alkynyl group" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, of which alkyl group is defined above. Preferably, the alkynyl group has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 2-12 alkynyl group), more preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 alkynyl groups). Non-limiting examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. The alkynyl group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more selected from alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0084] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., 3 to 12-membered cycloalkyl group), preferably 3 to 8 carbon atoms (i.e., 3 to 8-membered cycloalkyl group), and more preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl group). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups, and the like, and polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups, and bridged cycloalkyl groups.

[0085] The term "spirocycloalkyl group" refers to a polycyclic group having 5 to 20 members, in which the monocyclic rings share one carbon atom (called a spiro atom), which may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into monospirocycloalkyl groups or polyspirocycloalkyl groups (e.g., bisspirocycloalkyl groups), and are preferably monospirocycloalkyl groups and bisspirocycloalkyl groups. More preferably, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups are: [ka] Includes.

[0086] The term "fused cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, and in which one or more rings may contain one or more double bonds, preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). Depending on the number of rings, it can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused cycloalkyl groups, preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused cycloalkyl groups. Non-limiting examples of fused cycloalkyl groups are: [ka] Includes.

[0087] The term "bridged cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). Depending on the number of rings that constitute it, it can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups are: [ka] The cycloalkyl rings include the above cycloalkyl groups (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, in which the ring connected to the parent structure is a cycloalkyl group, non-limiting examples of which are: [ka] etc., but preferably [ka] It is.

[0088] Cycloalkyl groups may be substituted or unsubstituted and, if substituted, may be substituted at any available attachment point, with the substituents being preferably independently and optionally one or more selected from halogen, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.

[0089] The term "alkoxy group" refers to -O-(alkyl group), where alkyl group is defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy and butoxy groups. An alkoxy group may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.

[0090] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic ring substituent containing 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl group), in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which sulfur may optionally be substituted with an oxo group (i.e., to form a sulfoxide or sulfone), but does not include -OO-, -OS- or -SS- ring moieties, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms (i.e., a 3- to 12-membered heterocyclyl group), of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms, more preferably it contains 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) ring atoms (i.e., a 3- to 8-membered heterocyclyl group), of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms, more preferably it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms, and most preferably it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyl groups include spiroheterocyclyl groups, fused heterocyclyl groups, and bridged heterocyclyl groups.

[0091] The term "spiroheterocyclyl group" refers to a 5-20 membered polycyclic heterocyclyl group in which the monocyclic rings share one atom (referred to as a spiro atom), in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally substituted with an oxo group (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6-14 membered (i.e., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (i.e., a 6-14 membered spiroheterocyclyl group), and more preferably 7-10 membered (e.g., 7, 8, 9 or 10 membered) (i.e., a 7-10 membered spiroheterocyclyl group). Depending on the number of spiro atoms shared between the rings, spiroheterocyclyl groups are divided into monospiroheterocyclyl groups or polyspiroheterocyclyl groups (e.g., bisspiroheterocyclyl groups), preferably monospiroheterocyclyl groups and bisspiroheterocyclyl groups. More preferably, 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospiroheterocyclyl groups. Non-limiting examples of spiroheterocyclyl groups are: [ka] Includes.

[0092] The term "fused heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more of the rings optionally containing one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be oxidized (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It is preferably 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (i.e., a 6-14 membered fused heterocyclyl group), and more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members) (i.e., a 7-10 membered fused heterocyclyl group). Depending on the number of rings, it can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused heterocyclyl groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused heterocyclyl groups. Non-limiting examples of fused heterocyclyl groups are: [ka] Includes.

[0093] The term "bridged heterocyclyl group" refers to a 5-14 membered polycyclic heterocyclyl group in which any two rings share two atoms that are not directly linked, and may contain one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally substituted with an oxo group (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It is preferably 6-14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (i.e., a 6-14 membered bridged heterocyclyl group), and more preferably 7-10 membered (e.g., 7, 8, 9 or 10 membered) (i.e., a 7-10 membered bridged heterocyclyl group). Depending on the number of rings that they consist of, they can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged heterocyclyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups are: [ka] Includes.

[0094] The heterocyclyl rings include the above heterocyclyl groups (including monocyclic, spiro, fused and bridged heterocyclic rings) fused to an aryl, heteroaryl or cycloalkyl ring, in which the ring connected to the parent structure is a heterocyclyl group, non-limiting examples of which are: [ka] etc.

[0095] The heterocyclyl group may be substituted or unsubstituted and, if substituted, may be substituted at any available attachment point, and the substituents are preferably one or more selected from halogen, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.

[0096] The term "aryl group" refers to a 6-14 membered all carbon monocyclic or fused polycyclic (fused polycyclic rings are rings that share adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6-10 membered, such as phenyl and naphthyl groups. The aryl rings include those fused to a heteroaryl, heterocyclyl or cycloalkyl ring, in which the ring connected to the parent structure is an aryl ring, non-limiting examples of which are: [ka] Includes.

[0097] The aryl group may be substituted or unsubstituted and, if substituted, may be substituted at any available attachment point, and said substituents are preferably one or more selected from halogen, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups. The term "heteroaryl group" refers to a heteroaromatic system containing 1-4 (e.g. 1, 2, 3, and 4) heteroatoms and 5-14 ring atoms, of which the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5-10 membered (e.g. 5, 6, 7, 8, 9, or 10 membered) (i.e., 5-10 membered heteroaryl group), more preferably 5 or 6 membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes the above heteroaryl group fused to an aryl group, heterocyclyl group, or cycloalkyl ring, of which the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which are: [ka] Includes.

[0098] Heteroaryl groups may be substituted or unsubstituted and, if substituted, may be substituted at any available point of attachment and the substituents are preferably one or more selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

[0099] The above cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups include residues derived by removing one hydrogen atom from a parent ring atom or two hydrogen atoms from the same parent ring atom or two different ring atoms, i.e., "divalent cycloalkyl groups", "divalent heterocyclyl groups", "arylene groups" and "heteroarylene groups".

[0100] The term "amino-protecting group" refers to a group that protects an amino group with a group that is easily removed so that the amino group is not altered when other parts of the molecule react. Non-limiting examples include (trimethylsilicon)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl. These groups can be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, and nitro groups.

[0101] The term "hydroxy protecting group" generally refers to a hydroxy derivative that is used to block or protect a hydroxy group and react with other functional groups of a compound. For example, the hydroxy protecting group may be preferably a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilane group (TBS), a tert-butyldiphenylsilyl group, a methyl group, a tert-butyl group, a benzyl group, a methoxymethyl group (MOM), an ethoxyethyl group, a formyl group, a acetyl group, a benzoyl group, or a p-nitrobenzoyl group.

[0102] The term "cycloalkyloxy" refers to a cycloalkyl-O- group, in which the cycloalkyl group is as defined above.

[0103] The term "heterocyclyloxy" refers to a heterocyclyl-O- group, in which the heterocyclyl group is as defined above.

[0104] The term "aryloxy group" refers to an aryl-O- group, in which the aryl group is defined above.

[0105] The term "heteroaryloxy group" refers to a heteroaryl-O- group, in which the heteroaryl group is as defined above.

[0106] The term "alkylthio group" refers to an alkyl-S- group, in which the alkyl group is as defined above.

[0107] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

[0108] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0109] The term "deuterated alkyl group" refers to an alkyl group substituted with one or more deuterium atoms, wherein the alkyl group is as defined above.

[0110] The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group is as defined above.

[0111] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0112] The term "hydroxy group" refers to --OH.

[0113] The term "mercapto" refers to -SH.

[0114] The term "amino group" means -NH 2 Refers to...

[0115] The term "cyano" refers to -CN.

[0116] The term "nitro group" means -NO 2 Refers to...

[0117] The term "oxo group" or "oxo" refers to "=O".

[0118] The term "carbonyl group" refers to C=O.

[0119] The term "carboxy" refers to -C(O)OH.

[0120] The term "carboxylic acid ester group" refers to a -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are defined above.

[0121] The compounds of the present disclosure may have specific stereoisomeric forms. The term "stereoisomer" refers to isomers that have the same structure but differ in the spatial arrangement of atoms. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in the compounds of the present disclosure may have other asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. Single isomers of certain compounds of the present disclosure can be prepared by asymmetric synthesis or chiral auxiliaries, or, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxy group), by forming a diastereomeric salt with an appropriate optically active acid or base, and then carrying out diastereomeric resolution by conventional methods known in the art to obtain the pure isomers. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0122] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and in which the isomeric form is easily converted from one to the other. It includes all possible tautomers, i.e., exists in the form of a single isomer or in the form of a mixture of said tautomers in any ratio. Non-limiting examples include keto-enol, imine-enamine, lactam-lactim, etc. An example of a lactam-lactim equilibrium is as follows: [ka]

[0123] For example, reference to a pyrazolyl group should be understood to include any one or a mixture of the two tautomers of the following two structures: [ka]

[0124] All tautomeric forms are within the scope of the disclosure, and the naming of a compound does not exclude any tautomeric form.

[0125] The compounds of the present disclosure include their isotopic derivatives. The term "isotopic derivative" refers to a compound having a structure according to the present disclosure, which differs only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure according to the present disclosure, in which hydrogen is replaced by "deuterium" or "tritium" or fluorine is replaced by 18 F-fluorine labeling ( 18 F isotope) or the carbon atom is 11 C-, 13 C-, or 14 C-rich carbon ( 11 C-, 13 C- or 14 C-carbon label, 11 C-, 13 C- or 14Compounds in which the hydrogen atom is replaced by a C-isotope) are within the scope of the present disclosure. Such compounds may be used, for example, as analytical tools or probes in bioassays, or as imaging tracers for in vivo diagnosis of disease, or as tracers in pharmacodynamic, pharmacokinetic, or receptor studies. Among them, deuterated forms of compounds allow each available hydrogen atom linked to a carbon atom to be independently replaced with a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds by referring to the relevant literature. When preparing deuterated forms of compounds, commercially available deuterated starting materials may be used, or they may be synthesized by conventional techniques with deuterated reagents, including, but not limited to, deuterated borane, tritium borane tetrahydrofuran solution, lithium aluminum deuteride, deuterated iodoethane, deuterated iodomethane, and the like. Deuterated compounds can generally retain activity comparable to non-deuterated compounds, and when deuteration is at a certain site, they can obtain better metabolic stability and some therapeutic advantages. Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxicity and side effects, increasing drug stability, improving therapeutic efficacy, and extending the biological half-life of drugs.All isotopic variations of the compounds according to the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.Each available hydrogen atom connected to a carbon atom can be independently replaced with a deuterium atom, of which the replacement of deuterium can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced with at least one deuterium.

[0126] In the chemical structures of the compounds described in this disclosure, [ka] " bond indicates that no configuration is specified, i.e., if chiral isomers are present in the chemical structure, [ka] The bond " [ka] " or " [ka] " or " [ka] " and " [ka] " may include both types of arrangements at the same time.

[0127] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not. For example, "C optionally substituted with a halogen or cyano group" 1-6 By "alkyl group" is meant that halogen or cyano groups may or may not be present, and this description includes cases where the alkyl group is substituted with halogen or cyano groups and cases where the alkyl group is not substituted with halogen and cyano groups.

[0128] "Substituted" refers to one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in a group being independently replaced with a corresponding number of substituents. A person skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, an amino group or a hydroxy group having a free hydrogen may be unstable if it is attached to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0129] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein or their medicamentous salts or prodrugs with other chemical components, and other components such as pharmaceutical acceptable vectors and excipients. The pharmaceutical composition is intended to facilitate administration to a living body and contribute to the absorption of the active ingredient to further exert biological activity.

[0130] "Pharmaceutical salt" refers to a salt of a compound according to the present disclosure, which may be selected from inorganic salts or organic salts. Such salts have the desired biological activity while being safe and effective when used in a mammalian body. The salts may be prepared separately during the final isolation and purification process of the compound, or by reacting a suitable group with a suitable base or acid. In general, bases for forming pharmaceutical acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonium. In general, acids for forming pharmaceutical acceptable salts include inorganic acids and organic acids.

[0131] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a dose of the drug or agent sufficient to achieve, or at least partially achieve, a desired effect. The effective amount is human-determined and depends on the age and general condition of the subject, and also on the specific active agent, and the appropriate effective amount for an individual can be determined by one of ordinary skill in the art through routine testing.

[0132] As used herein, the term "pharmacologically acceptable" means that these compounds, materials, compositions and / or dosage forms are, within the scope of reasonable medical judgment, applicable to contact with the tissues of a patient without undue toxicity, irritation, allergic response or other problem or complication, and are effective for the desired use, with a reasonable benefit / risk ratio.

[0133] As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly indicates otherwise.

[0134] The term "about" when applied to parameters such as pH, concentration, temperature, etc., indicates that the parameter may vary within ±10%, and in some cases, more preferably within ±5%. As will be appreciated by those skilled in the art, when a parameter is not critical, generally, numbers are given merely for illustration, not limitation. Methods for synthesizing compounds according to the present disclosure

[0135] In order to achieve the objectives of the present disclosure, the present disclosure adopts the following technical solutions: Technical proposal 1

[0136] A process for preparing a compound of general formula (IM) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] nucleophilic substitution reaction of a compound of general formula (IMa) or a salt thereof (preferably the hydrochloride salt) with a compound of general formula (IMb) under basic conditions, optionally in the presence of a catalyst, to obtain a compound of general formula (IM) or a medicamentable salt thereof, Among them, L is a halogen atom, preferably a chlorine atom; X, Y, G 1 ~G 3 , R 0 ~R 3 , s and t are as defined in general formula (IM). Technical proposal 2

[0137] A method for preparing a compound of general formula (I) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] nucleophilic substitution reaction of a compound of general formula (IMa) or a salt thereof (preferably the hydrochloride salt) with a compound of general formula (V) under basic conditions, optionally in the presence of a catalyst, to obtain a compound of general formula (I) or a medicamentable salt thereof, Among them, L is a halogen atom, preferably a chlorine atom; X, Y, G 1 ~G 3 , R 1 ~R 3 , s and t are as defined in general formula (I). Technical proposal 3

[0138] A method for preparing a compound of general formula (II-1) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The method comprises the steps of: reacting a compound of general formula (II-1a) or a salt thereof (preferably the hydrochloride salt) with a compound of general formula (V) under basic conditions and optionally in the presence of a catalyst to obtain a compound of general formula (II-1) or a medicamentable salt thereof; Among them, L is a halogen atom, preferably a chlorine atom; X, G 1 ~G 3 , R 1 ~R 3 , s, t and n are as defined in general formula (II-1). Technical proposal 4

[0139] A method for preparing a compound of general formula (II-2) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The method comprises the steps of: subjecting a compound of general formula (II-2a) or a salt thereof (preferably the hydrochloride salt) to a nucleophilic substitution reaction with a compound of general formula (V) under basic conditions, optionally in the presence of a catalyst, to obtain a compound of general formula (II-2) or a medicamentable salt thereof; Among them, L is a halogen atom, preferably a chlorine atom; X, G 1 ~G 3 , R 1 ~R 3 , R 5 , s, t and r are as defined in general formula (II-2). Technical proposal 5

[0140] A method for preparing a compound of general formula (III-1) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The method comprises the steps of: reacting a compound of general formula (III-1a) or a salt thereof (preferably the hydrochloride salt) with a compound of formula (VI) under basic conditions and optionally in the presence of a catalyst to obtain a compound of general formula (III-1) or a medicamentable salt thereof; Among them, m1 is 0 or 1, L is a halogen atom, preferably a chlorine atom; R 1 , R 6 , R 7a , R 7b and n are as defined in general formula (III-1). Technical proposal 6

[0141] A method for preparing a compound of general formula (III-1-A) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The method comprises the steps of: reacting a compound of general formula (III-1-Aa) or a salt thereof (preferably the hydrochloride salt) with a compound of general formula (VI) under basic conditions and optionally in the presence of a catalyst to obtain a compound of general formula (III-1-A) or a medicamentable salt thereof, Among them, m1 is 0 or 1, L is a halogen atom, preferably a chlorine atom; R 1 , R 6 , R 7a , R 7b and n are as defined in general formula (III-1-A). Technical proposal 7

[0142] A method for preparing a compound of general formula (III-2) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The method comprises the steps of: reacting a compound of general formula (III-2a) or a salt thereof (preferably the hydrochloride salt) with a compound of formula (VI) under basic conditions and optionally in the presence of a catalyst to obtain a compound of general formula (III-2) or a medicamentable salt thereof, Among them, L is a halogen atom, preferably a chlorine atom; X, R 1 , R 5 , R 6 , R 7a and R 7b is as defined in general formula (III-2).

[0143] The reagents for providing the basic conditions include organic bases and inorganic bases, the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium ethylate, sodium tert-butoxide and potassium tert-butoxide, preferably N,N-diisopropylethylamine, and the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide.

[0144] The catalyst for the above nucleophilic substitution reaction is sodium iodide or potassium iodide, preferably sodium iodide.

[0145] The reaction is preferably carried out in a solvent, and the solvents used include, but are not limited to, N-methylpyrrolidone, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethylsulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane, and mixtures thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0146] The present disclosure will be further described below with reference to examples, but these examples are not intended to limit the scope of the present disclosure. Working Example

[0147] The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are within the range of 10 -6 The unit of concentration is expressed in ppm. The NMR measurement was performed using a nuclear magnetic resonance spectrometer Bruker AVANCE-400 or Bruker AVANCE NEO 500M, and the measurement solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) and the internal standard was tetramethylsilane (TMS).

[0148] For the MS measurements, a liquid chromatograph mass spectrometer Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS (manufacturer: Agilent, MS model number: 6110 / 6120 Quadrupole MS) was used.

[0149] Waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model number: waters ACQuity Qda Detector / waters SQ Detector) and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model number: THERMO Q Exactive) were used.

[0150] For high performance liquid chromatography (HPLC) analysis, liquid chromatographs Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 were used.

[0151] For chiral HPLC analysis, a high performance liquid chromatograph Agilent 1260 DAD was used.

[0152] For preparative high performance liquid chromatography, preparative chromatographs Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 were used.

[0153] For chiral separation, a preparative chromatograph Shimadzu LC-20AP was used.

[0154] Combiflash Rf200 (TELEDYNE ISCO) was used as the CombiFlash high-speed preparative chromatograph.

[0155] As the silica gel plate for thin layer chromatography, Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate is used, the specification of the silica gel plate used for thin layer chromatography (TLC) is 0.15-0.2 mm, and the specification for separating and purifying the product by thin layer chromatography is 0.4-0.5 mm.

[0156] For silica gel column chromatography, 200-300 mesh silica gel manufactured by Yantai Huanghai Silica Gel was generally used as the vector.

[0157] Kinase mean inhibition rate and IC 50 The values ​​were measured using a NovoStar plate reader (BMG, Germany).

[0158] Known starting materials according to the present disclosure may be synthesized by or according to methods known in the art or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), Darui Chemicals, etc.

[0159] Unless otherwise noted in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0160] An argon or nitrogen atmosphere refers to an argon or nitrogen balloon of approximately 1 L volume connected to the reaction flask.

[0161] Hydrogen atmosphere refers to a hydrogen balloon of approximately 1 L volume attached to the reaction flask.

[0162] For the pressurized hydrogenation reaction, a Parr 3916EKX hydrogenation apparatus and a Seiran QL-500 hydrogen generator or an HC2-SS hydrogenation apparatus were used.

[0163] The hydrogenation reaction was generally carried out by repeating the process of evacuating and refilling with hydrogen three times.

[0164] A CEM Discover-S 908860 microwave reactor was used for microwave reactions.

[0165] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0166] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20 to 30°C.

[0167] In the examples, thin layer chromatography (TLC) was used to monitor the progress of the reaction. The developing solvent used in the reaction, the eluent system of column chromatography for purifying the compound, and the developing solvent system of thin layer chromatography included A: dichloromethane / methanol system, and the volume ratio of the solvent was adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of basic or acidic reagent such as triethylamine and acetic acid.

[0168] Example 1 (±)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-formamide 1 [ka]

[0169] Step 1 Methyl 5-bromo-6-fluoropicolinate 1b Compound 5-bromopyridine-2-carboxylate methyl 1a (2.0 g, 9.25 mmol, Shanghai Shaoyuan) was dissolved in acetonitrile (50 mL), and silver difluoride (4.7 g, 32.22 mmol) was added. The mixture was stirred under nitrogen atmosphere for 14 hours. The reaction solution was filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 1b (1.8 g, yield: 83%). MS m / z (ESI): 233.9[M+1].

[0170] Step 2 (±)-tert-Butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate 1d Compound (±)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl 1c (2 g, 9.24 mmol, Shanghai Bide) was dissolved in dichloromethane (30 mL), and imidazole (1.3 g, 19.09 mmol) and tert-butyldimethylsilyl chloride (2.17 g, 14.39 mmol) were added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain title compound 1d (1.9 g, yield: 62.1%). MS m / z (ESI): 331.2 [M+1].

[0171] Step 3 (±)-tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(2-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate 1e Compound 1b (300 mg, 1.28 mmol) and compound 1d (635 mg, 1.92 mmol) were dissolved in 1,4-dioxane (15 mL), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (107 mg, 127.78 μmol) and cesium carbonate (1.0 g, 3.06 mmol) were added, and the mixture was reacted at 110 ° C. for 14 hours in a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 1e (290 mg, yield: 46.7%). MS m / z (ESI): 484.2 [M+1].

[0172] Step 4 (±)-3-(tert-butyl) 8-methyl 1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate 1f Compound 1e (290 mg, 599.61 μmol) was dissolved in tetrahydrofuran (6 mL), 3 mL of 1 M tetrabutylammonium fluoride in tetrahydrofuran was added, and the mixture was reacted with stirring for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 1f (200 mg, yield: 95.2%), which was used in the next reaction without purification. MS m / z (ESI): 350.2[M+1].

[0173] Step 5 (±)-8-(Methylaminocarbonyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylate tert-butyl 1g The crude product, compound 1f (200 mg, 572.44 μmol), was dissolved in ethanol (5 mL), and 1.13 mL of a 1 M ethanol solution of methylamine was added. The mixture was reacted with stirring for 14 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 1g (190 mg, yield: 95.4%). MS m / z (ESI): 349.2[M+1].

[0174] Step 6 (±)-N-Methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-formamide hydrochloride 1H Compound 1g (50 mg, 143.5 μmol) was dissolved in dioxane (2 mL), 1 mL of 4 M hydrochloric acid in dioxane was added, and the mixture was reacted with stirring for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 1h (35 mg, yield: 98.2%), which was used in the next reaction without purification. MS m / z (ESI): 249.2[M+1].

[0175] Step 7 (±)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-formamide 1 The crude product, compound 1h (30 mg, 134.72 μmol), compound 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one 1i (33 mg, 132.91 μmol, prepared by the method disclosed in Example 4 on page 15 of the specification of patent application "WO2021013735A1"), N,N-diisopropylethylamine (174 mg, 1.34 mmol), and sodium iodide (4 mg, 26.68 μmol) were dissolved in acetonitrile (3 mL) and reacted at 80° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T The title compound 1 (4 mg, yield: 6.8%) was obtained by purification using C18, 30 × 150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient blend ratio: acetonitrile 35-45%, flow rate: 30 mL / min). MS m / z (ESI): 435.2[M+1]. 1 H NMR (500 MHz, CDCl 3 ): δ 10.11 (s, 1H), 8.53 (d, 1H), 7.86 (s, 1H), 7.81 (d, 1H), 7.61 (d, 1H), 7.58-7.54 (m, 1H), 7.10 (d, 1H), 4.37 (dd, 1H), 4.17 (dd, 1H), 3.76 (d, 1H), 3.73-3.65 (m, 2H), 3.40-3.30 (m, 1H), 3.09-3.02 (m, 1H), 2.99 (d, 2H), 2.89 (dt, 1H), 2.80-2.68 (m, 2H), 2.41 (td, 1H), 2.25 (t, 1H), 2.03 (d, 1H), 1.98 (t, 1H), 1.33 (t, 3H).

[0176] Example 2 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-formamide 2 [ka]

[0177] Step 1 (R)-tert-Butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate 2b Compound (3R)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl 2a (4.2g, 19.4mmol, Shanghai Bide) was dissolved in dichloromethane (100mL), triethylamine (117mg, 38.9mmol), tert-butyldimethylsilyl chloride (2.17g, 14.39mmol), 4-dimethylaminopyridine (3.94g, 0.94mmol) were added, and the reaction was carried out under stirring for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 2b (6g, yield: 93%). MS m / z (ESI): 331.2 [M+1].

[0178] Step 2 (R)-tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(2-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate 2c Compound 1b (1.3 g, 5.55 mmol) and compound 2b (2.02 g, 6.1 mmol) were dissolved in 1,4-dioxane (15 mL), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (464 mg, 554.7 μmol) and cesium carbonate (3.6 g, 11.1 mmol) were added, and the mixture was reacted at 110 ° C. for 14 hours in a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 2c (1 g, yield: 37.2%). MS m / z (ESI): 484.2 [M+1].

[0179] Step 3 3-(tert-Butyl)8-methyl(R)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate 2d Compound 2c (1 g, 2.06 mmol) was dissolved in tetrahydrofuran (6 mL), and 6 mL of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added. The mixture was reacted for 2 hours with stirring. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 2d (722 mg, yield: 99%). The product was used in the next reaction without purification. MS m / z (ESI): 350.2[M+1].

[0180] Step 4 (R)-tert-butyl 8-(methylaminocarbonyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylate 2e The crude product, compound 2d (722 mg, 2.06 mmol), was dissolved in 10 mL of a 1 M ethanol solution of methylamine and reacted with stirring for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 2e (700 mg, yield: 97%), which was used in the next reaction without purification. MS m / z (ESI): 349.2[M+1].

[0181] Step 5 (R)-N-Methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-formamide hydrochloride 2f Compound 2e (700 mg, 2 mmol) was dissolved in dichloromethane (5 mL), 2 mL of 4 M hydrochloric acid in dioxane was added, and the mixture was reacted with stirring for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 2f (570 mg, yield: 99%), which was used in the next reaction without purification. MS m / z (ESI): 249.2[M+1].

[0182] Step 6 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-formamide 2 The crude product, compound 2f (66 mg, 265.82 μmol), compound 1i (60 mg, 269.4 μmol), and N,N-diisopropylethylamine (180.7 mg, 1.4 mmol) were dissolved in acetonitrile (5 mL), a catalytic amount of sodium iodide was added, and the mixture was reacted at 80 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30 × 150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient blending ratio: acetonitrile 35 to 45%, flow rate: 30 mL / min) to obtain the title compound 2 (33 mg, yield: 28.1%). MS m / z (ESI): 435.2[M+1]. 1 H NMR (500 MHz, CD 3OD): δ 8.48 (d,1H), 7.82 (s, 1H), 7.76 (d,1H), 7.61 (d,1H), 7.23 (d,1H), 4.39 (dd,1H), 4.11 (dd,1H), 3.84-3.67 (m, 3H), 3.26 (d, 1H), 3.04 (d,1H), 2.95 (dt,1H), 2.89 (d, 4H), 2.66 (q,2H), 2.41-2.33 (m, 1H), 1.96 (t,1H), 1.27 (t,3H).

[0183] Example 3 (±)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxyazepane-9-formamide 3 [ka]

[0184] Step 1 (±)-3-(hydroxymethyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate tert-butyl 3a Compound 1c (5 g, 23.1 mmol) was dissolved in N,N-dimethylformamide (50 mL), and anhydrous potassium carbonate (4.8 g, 34.7 mmol) and 4-methoxychlorobenzyl (4 g, 25.54 mmol) were added and reacted at 60°C for 72 hours. The reaction solution was filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 3a (7 g, yield: 90%). MS m / z (ESI): 337.2[M+1].

[0185] Step 2 (±)-3-(((6-bromo-3-fluoropyridin-2-yl)methoxy)methyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate tert-butyl 3c Compound 6-bromo-2-(bromomethyl)-3-fluoropyridine 3b (1.94 g, 7.21 mmol, prepared according to the method disclosed in Preparation Example 6 on page 12 of the specification of patent application "WO2016077161A1"), compound 3a (2.2 g, 6.59 mmol) was dissolved in N,N-dimethylformamide (20 mL), sodium hydride (0.36 g, 9 mmol, 60% purity) was added, and the mixture was reacted with stirring for 1 hour, and then quenched by adding water, and extracted with dichloromethane (30 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 3c (1.84 g, yield: 53.6%). MS m / z (ESI): 524.2[M+1].

[0186] Step 3 (±)-3-((3-fluoro-6-(methoxycarbonyl)pyridin-2-yl)methoxy)methyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate tert-butyl 3d Compound 3c (1.84 g, 3.50 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide (3 mL) and ethanol (2 mL), bis(triphenylphosphino)palladium dichloride (0.55 g, 783.59 μmol), N,N-diisopropylethylamine (1.1 g, 10.87 mmol) were added, and the mixture was reacted under stirring at 90 ° C. for 3 hours in a carbon monoxide atmosphere. After cooling, ethyl acetate (100 mL) was added to dilute the mixture, and the mixture was washed with water and saturated sodium chloride solution in order. The organic phase was collected, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 3d (1.1 g, yield: 60.57%). MS m / z (ESI): 504.2[M+1].

[0187] Step 4 (±)-3-(((3-fluoro-6-(methoxycarbonyl)pyridin-2-yl)methoxy)methyl)piperazine-1-carboxylate tert-butyl 3e Compound 3d (0.4 g, 772.81 μmol) was dissolved in a mixed solvent of water (3 mL) and acetonitrile (3 mL), and cerium ammonium nitrate (2.11 g, 3.86 mmol) was added. The mixture was replaced with hydrogen gas and reacted with stirring for 14 hours. The mixture was neutralized by adding saturated aqueous sodium bicarbonate solution (10 mL), filtered, and the filtrate was extracted with ethyl acetate (10 mL × 3). The organic phase was collected, washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 3e (120 mg, yield: 40%). MS m / z (ESI): 384.2[M+1].

[0188] Step 5 (±)-3-(tert-butyl) 9-methyl 1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxyazepane-3,9(4H)-dicarboxylate 3f Compound 3e (300 mg, 754.8 μmol) was dissolved in N,N-dimethylacetamide (2 mL), N,N-diisopropylethylamine (300 mg, 2.32 mmol) was added, and the mixture was reacted in a microwave at 140° C. for 1.5 hours. After cooling the reaction solution, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 3f (130 mg, yield: 45.6%). MS m / z (ESI): 364.2[M+1]. Then, following the synthesis route in Example 1, the starting compound 1f in step 5 was replaced with compound 3f to give the title compound 3 (7.5 mg, yield: 14.6%). MS m / z (ESI): 449.2[M+1]. 1H NMR (500 MHz, CD 3OD): δ 8.51 (d, 1H), 7.93 (d, 1H), 7.86 (s, 1H), 7.79 (d, 1H), 7.50 (d, 1H), 4.99 (t, 2H), 4.85 (d, 1H), 4.08 (dd, 2H), 3.87 (dd, 1H), 3.81-3.71 (m, 2H), 3.46 (ddd, 2H), 2.95 (s, 3H), 2.86- 2.78 (m, 1H), 2.75-2.61 (m, 3H), 2.57 (dd, 1H), 1.31 (t, 3H).

[0189] Example 4 (±)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-d]pyrido[2,3-b][1,4]oxyazepane-9-formamide 4 [ka]

[0190] Step 1 (±)-tert-Butyl 3-(2-((6-bromo-3-fluoropyridin-2-yl)oxy)ethyl)piperazine-1-carboxylate 4c Compound 2,6-dibromo-3-fluoropyridine 4a (1.0 g, 3.92 mmol, Shanghai Bide) and compound (±)-3-(2-hydroxyethyl)piperazine-1-carboxylate tert-butyl 4b (900 mg, 3.90 mmol, Jiangsu Aikang) were dissolved in tetrahydrofuran (20 mL), potassium tert-butoxide (880 mg, 7.84 mmol) was added, and the mixture was reacted with stirring for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 4c (1 g, yield: 63%). MS m / z (ESI): 404.2[M+1].

[0191] Step 2 (±)-9-Bromo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-d]pyrido[2,3-b][1,4]oxyazepane-3-carboxylate tert-butyl ester 4d Compound 4c (40 mg, 98.9 μmol) was dissolved in N,N-dimethylacetamide (2 mL), N,N-diisopropylethylamine (38 mg, 294 μmol) was added, and the mixture was reacted in a microwave at 140° C. for 2 hours. The reaction solution was cooled and then concentrated under reduced pressure to obtain the title compound 4d (38 mg, yield: 99%) as a crude product, which was used in the next reaction without purification. MS m / z (ESI): 384.2[M+1].

[0192] Step 3 (±)-3-(tert-Butyl) 9-methyl 1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-d]pyrido[2,3-b][1,4]oxyazepane-3,9-dicarboxylate 4e The crude product, compound 4d (100 mg, 247.3 μmol), was dissolved in a mixed solvent of N,N-dimethylacetamide (2 mL) and methanol (5 mL), and palladium acetate (17 mg, 75.72 μmol), triethylamine (125 mg, 1.23 mmol), and 1,3-bis(diphenylphosphino)propane (30 mg, 72.72 μmol) were added. The mixture was reacted at 80° C. for 14 hours in a carbon monoxide atmosphere. The reaction solution was cooled and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 4e (40 mg, yield: 42.1%). MS m / z (ESI): 364.2 [M+1]. Then, according to the synthesis route in Example 1, the raw material compound 1f in step 5 was replaced with compound 4e to obtain the title compound 4 (130 mg, yield: 52.1%). MS m / z (ESI): 449.2[M+1]. 1H NMR (500 MHz, CDCl 3): δ 11.38 (s, 1H), 8.57 (d, 1H), 7.90 (q, 1H), 7.70 (d, 1H), 7.68 (d, 1H), 7.68-7.62 (m, 1H), 7.19 (d, 1H), 4.46 (ddd, 1H), 4.28 (ddd, 1H),3.73 (s, 2H), 3.68 (dd, 1H), 3.68-3.52 (m, 2H), 3.02 (d, 3H), 2.89-2.82 (m, 1H), 2.78 (qd, 2H), 2.68 (ddd, 1H), 2.57 (ddd, 1H), 2.34 (ddd, 1H), 2.21-2.00 (m, 2H), 1.35 (t, 3H).

[0193] Example 5 (±)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-5-oxo-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]pyrido[2,3-e]pyrazine-8-formamide 5 [ka]

[0194] Step 1 (±)-8-Bromo-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]pyrido[2,3-e]pyrazine-3-carboxylate benzyl 5b Compound (±)-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]pyrido[2,3-e]pyrazine-3-carboxylate benzyl 5a (566 mg, 1.67 mmol, obtained by preparing according to the method disclosed in Example 7 on page 6 of the specification of patent application "US4138564A") was dissolved in dichloromethane (20 mL), and N-bromosuccinimide (297.7 mg, 1.67 mmol) was added in several portions under ice bath. After the addition was completed, the temperature was kept as it was and the reaction was carried out for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 5b (343 mg, yield: 35.8%). MS m / z (ESI): 417.2[M+1].

[0195] Step 2 (±)-3-Benzyl 8-methyl 5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]pyrido[2,3-e]pyrazine-3,8-dicarboxylate 5c Compound 5b (335.00 mg, 802.86 μmol) was dissolved in methanol (5 mL) and N,N-dimethylformamide (5 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (327.55 mg, 401.40 μmol) and triethylamine (812.41 mg, 8.02 mmol) were added. The mixture was purged with carbon monoxide three times and stirred at 70°C for 14 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30 x 150 mm, 5 µm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient blending ratio: acetonitrile 35 to 45%, flow rate: 30 mL / min) to obtain the title compound 5c (20 mg, yield: 6.2%). MS m / z (ESI): 397.2[M+1].

[0196] Step 3 (±)-8-(Methylaminocarbonyl)-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]pyrido[2,3-e]pyrazine-3-carboxylate benzyl 5d The crude product, compound 5c (20 mg, 48.7 μmol), was dissolved in ethanol (5 mL), and 5 mL of a 1 M ethanol solution of methylamine was added. The mixture was reacted with stirring for 14 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 5d (18 mg, yield: 93.4%). The product was directly used in the next reaction without purification. MS m / z (ESI): 396.2 [M+1].

[0197] Step 4 (±)-N-Methyl-5-oxo-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]pyrido[2,3-e]pyrazine-8-formamide 5e The crude product, compound 5d (20 mg, 50.58 μmol), was dissolved in 2 mL of 30% hydrobromic acid / acetic acid solution and reacted with stirring for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 5e (10 mg, yield: 75%), which was directly used in the next reaction without purification. MS m / z (ESI): 262.2 [M+1].

[0198] Step 5 (±)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-5-oxo-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]pyrido[2,3-e]pyrazine-8-formamide 5 Compound 5e (11 mg, 42.1 μmol), compound 1i (10 mg, 44.9 μmol), N,N-diisopropylethylamine (29 mg, 224.3 μmol), sodium iodide (2 mg, 13 μmol) were dissolved in acetonitrile (3 mL) and reacted at 80 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30 × 150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient blending ratio: acetonitrile 35 to 45%, flow rate: 30 mL / min) to obtain the title compound 5 (3 mg, yield: 14.9%). MS m / z (ESI): 448.2[M+1]. 1H NMR (500 MHz, CD 3 OD): δ 8.56 (d, 1H), 7.84 (s, 1H), 7.77 (d, 1H), 7.71 (d, 1H), 7.24 (d, 1H), 5.34 (t, 2H), 3.89-3.79 (m, 3H), 2.93 (s, 1H), 2.67 (q, 2H), 2.41-2.26 (m, 2H), 2.19 (t, 2H), 1.64-1.57 (m, 2H), 0.90 (t, 3H).

[0199] Example 6 (±)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]pyrido[2,3-e]pyrazine-8-formamide 6 [ka]

[0200] Step 1 (±)-3-Benzyl 8-methyl 1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]pyrido[2,3-e]pyrazine-3,8-dicarboxylate 6a Compound 5c (7 mg, 17.65 μmol) was dissolved in tetrahydrofuran (1 mL), 0.2 mL of 1 M borane tetrahydrofuran solution was added, and the mixture was heated to 40° C. and reacted for 1 hour. After the reaction was completed, methanol was added and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography using developing solvent system A to obtain the title compound 6a (4 mg, yield: 59.2%). MS m / z (ESI): 383.2[M+1]. Then, according to the synthetic route in Example 5, the raw material compound 5c in step 3 was replaced with compound 6a to obtain the title compound 6 (1 mg, yield: 21.6%). MS m / z (ESI): 434.2[M+1]. 1H NMR (500 MHz, CDCl 3 ): δ 9.38 (s, 1H), 8.51 (s, 1H), 7.85 (s, 1H), 7.63 (s, 1H), 7.54-7.45 (m, 2H), 7.07 (d, 1H), 6.86 (d, 1H), 4.72 (s, 1H), 3.77-3.59 (m, 3H), 3.44-3.33 (m, 2H), 3.28-3.19 (m, 1H), 3.07-2.87 (m, 4H), 2.85-2.65 (m, 3H), 2.25 (td, 2H), 0.90 (dt, 3H).

[0201] Example 7 (±)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,6-dimethyl-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]pyrido[2,3-e]pyrazine-8-formamide 7 [ka]

[0202] Step 1 (±)-6-Methyl-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]pyrido[2,3-e]pyrazine-3-carboxylate benzyl 7a Compound 5a (1.50g, 4.43mmol) was dissolved in tetrahydrofuran (10mL), sodium hydride (265.96mg, 6.64mmol, 60% purity) was added under ice bath, and the mixture was allowed to react with stirring for 0.5 hours after returning to room temperature. Then, iodomethane (1.88g, 13.24mmol) was added under ice bath and the mixture was allowed to react with stirring for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 7a (940mg, yield: 60.2%). MS m / z (ESI): 353.2[M+1].

[0203] Step 2 (±)-8-Bromo-6-methyl-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]pyrido[2,3-e]pyrazine-3-carboxylate benzyl 7b Compound 7a (620 mg, 1.75 mmol) was dissolved in dichloromethane (10 mL), and N-bromosuccinimide (313.15 mg, 1.75 mmol) was added in portions under ice bath. After the addition was completed, the temperature was kept as it was and the reaction was continued for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 7b (660 mg, yield: 86.9%). MS m / z (ESI): 431.2 [M+1].

[0204] Step 3 (±)-3-Benzyl 8-methyl 6-methyl-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]pyrido[2,3-e]pyrazine-3,8-dicarboxylate 7c Compound 7b (220 mg, 510.1 μmol) was dissolved in methanol (5 mL) and N,N-dimethylformamide (5 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (208.1 mg, 255 μmol) and triethylamine (516.1 mg, 5.1 mmol) were added. The mixture was substituted with carbon monoxide three times and reacted at 70°C for 14 hours with stirring. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 7c (180 mg, yield: 86.1%). MS m / z (ESI): 411.2[M+1].

[0205] Step 4 (±)-3-Benzyl 8-methyl 6-methyl-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]pyrido[2,3-e]pyrazine-3,8-dicarboxylate 7d Compound 7c (80 mg, 194.92 μmol) was dissolved in tetrahydrofuran (4 mL), 2 mL of 1 M borane tetrahydrofuran solution was added, and the mixture was heated to 50° C. and reacted for 1 hour. After the reaction was completed, methanol was added and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 7d (61 mg, yield: 78.9%). MS m / z (ESI): 397.2[M+1]. Then, following the synthetic route in Example 5, the starting compound 5c in step 3 was replaced with compound 7d to give the title compound 7 (5.4 mg, yield: 8%). MS m / z (ESI): 448.2[M+1]. 1H NMR (500 MHz, CDCl 3): δ 10.58 (s, 1H), 8.52 (s, 1H), 7.87 (s, 1H), 7.73 (d, 1H), 7.66 (s, 1H), 7.48 (d, 1H), 6.78 (d, 1H), 3.80-3.65 (m, 2H), 3.62 (d, 1H), 3.40-3.22 (m, 3H), 3.10 (s, 3H), 3.03 (d, 3H), 2.96-2.82 (m, 2H), 2.74 (q, 2H), 2.40 (t, 1H), 2.09-1.90 (d, 2H), 1.37-1.31 (m, 3H).

[0206] Example 8 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxyazepane-9-formamide 8 [ka]

[0207] Step 1 (R)-tert-butyl 3-(((6-bromo-3-fluoropyridin-2-yl)methoxy)methyl)piperazine-1-carboxylate 8b Compound 3b (2.5g, 9.29mmol) and compound (R)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl 8a (2.25g, 10.40mmol, Shanghai Hanhong) were dissolved in tetrahydrofuran (30mL), sodium hydride (812.5mg, 21.20mmol, 60% purity) was added under ice bath, and the mixture was reacted with stirring for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 8b (3g, yield: 79.8%). MS m / z (ESI): 404.1[M+1].

[0208] Step 2 (R)-tert-butyl 3-(((6-(ethoxycarbonyl)-3-fluoropyridin-2-yl)methoxy)methyl)piperazine-1-carboxylate 8c Compound 8b (2 g, 4.94 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide (20 mL) and ethanol (10 mL), and bis(triphenylphosphino)palladium dichloride (0.52 g, 740.8 μmol) and N,N-diisopropylethylamine (1.52 g, 15 mmol) were added, and the mixture was reacted under stirring at 100 ° C. for 14 hours in a carbon monoxide atmosphere. After cooling, ethyl acetate (100 mL) was added to dilute the mixture, and the mixture was washed with water and saturated sodium chloride solution in order. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 8c (1.5 g, yield: 76.2%). MS m / z (ESI): 398.2[M+1].

[0209] Step 3 3-(tert-Butyl) 9-ethyl (R)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxyazepane-3,9(4H)-dicarboxylate 8d Compound 8c (4 g, 10.06 mmol) was dissolved in N,N-dimethylacetamide (20 mL), N,N-diisopropylethylamine (4 g, 30.9 mmol) was added, and the mixture was reacted at 140° C. for 6 hours in a microwave oven. After cooling the reaction mixture, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 8d (2.3 g, yield: 60%). MS m / z (ESI): 378.2[M+1].

[0210] Step 4 (R)-9-(Methylaminocarbonyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxyazepane-3(4H)-carboxylate tert-butyl 8e Compound 8d (600 mg, 1.58 mmol) was dissolved in 5 mL of a 1 M ethanol solution of methylamine and reacted with stirring for 14 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 8e (570 mg, yield: 98%), which was used in the next reaction without purification. MS m / z (ESI): 363.2[M+1].

[0211] Step 5 (R)-N-Methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxyazepane-9-formamide hydrochloride 8f The crude product, Compound 8e (140 mg, 386.2 μmol), was dissolved in dichloromethane (3 mL), and 1 mL of a 4 M solution of hydrochloric acid in dioxane was added. The mixture was reacted with stirring for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title Compound 8f (110 mg, yield: 95%). The product was used in the next reaction without purification. MS m / z (ESI): 263.2[M+1].

[0212] Step 6 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxyazepane-9-formamide 8 The crude product, compound 8f (570 mg, 1.9 mol), compound 1i (430 mg, 1.93 mol), and N,N-diisopropylethylamine (1.5 g, 11.6 mmol) were dissolved in acetonitrile (30 mL), sodium iodide (30 mg, 200 μmol) was added, and the mixture was reacted at 80 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30 × 150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient blending ratio: acetonitrile 30 to 45%, flow rate: 30 mL / min) to obtain the title compound 8 (5.4 mg, yield: 8%). MS m / z (ESI): 449.2[M+1]. 1H NMR (500 MHz, CD 3 OD): δ 8.51 (d, 1H), 7.93 (d, 1H), 7.86 (s, 1H), 7.79 (d, 1H), 7.50 (d, 1H), 4.99 (t, 2H), 4.85 (d, 1H), 4.08 (dd, 2H), 3.87 (dd, 1H), 3.81-3.71 (m, 2H), 3.46 (ddd, 2H), 2.95 (s, 3H), 2.86- 2.78 (m, 1H), 2.75-2.61 (m, 3H), 2.57 (dd, 1H), 1.31 (t, 3H).

[0213] Example 9 (R)-3-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxyazepane-9-formamide 9 [ka]

[0214] Step 1 7-(Chloromethyl)-8-fluoro-3-methylquinoxalin-2(1H)-one 9b Compound 9a (100 mg, 480 μmol, prepared by the method disclosed in intermediate 17 on page 35 of the specification of patent application "WO2021260093 A1") was dissolved in dichloromethane (4 mL), phosphorus oxychloride (3 mL) was added, and the mixture was reacted with stirring for 14 hours. The reaction solution was concentrated under reduced pressure, and ice water was added to precipitate a solid. The solid was filtered, and the filter cake was washed with water and then dried to obtain the crude product, the title compound 9b (90 mg). The product was used in the next reaction as it was without purification. MS m / z (ESI): 227.2[M+1].

[0215] Step 2 (R)-3-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxyazepane-9-formamide 9 The crude product, compound 9b (136 mg, 601 μmol), compound 8f (255 mg, 601 μmol), N,N-diisopropylethylamine (233 mg, 1.8 mmol), and sodium iodide (18 mg, 125.6 μmol) were dissolved in acetonitrile (3 mL) and reacted at 80 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs, Prep 30 × 150 mm, 5 μm, C18, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient blending ratio: acetonitrile 35 to 45%, flow rate: 30 mL / min) to obtain the title compound 9 (40 mg, yield: 14.6%). MS m / z (ESI): 453.2[M+1]. 1 H NMR (500 MHz, CD 3OD): δ 7.93 (d, 1H), 7.57 (d, 1H), 7.48 (d, 1H), 7.40 (t, 1H), 4.97 (d, 1H), 4.91 (s, 1H), 4.01 (dd, 1H), 3.85 (dd, 1H), 3.80 (s, 2H), 3.41 (td, 3H), 2.95 (s, 3H), 2.83 (dq, 1H), 2.73 (dd, 1H), 2.60 (ddd, 2H), 2.53 (s, 3H).

[0216] Example 10 (R)-3-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-formamide 10 [ka] Following the synthesis route in Example 2, the starting compound 1i in step 6 was replaced with compound 9b to give the title compound 10 (84 mg, yield: 30.5%). MS m / z (ESI): 439.2[M+1]. 1 H NMR (500 MHz, CD 3 OD): δ 7.63 (d, 1H), 7.57 (d, 1H), 7.41 (t, 1H), 7.25 (d, 1H), 4.42 (dd, 1H), 4.13 (t, 1H), 3.80 (d, 3H), 3.29 (s, 3H), 3.08 (d, 1H), 3.00 (d, 1H), 2.94-2.85 (m, 4H), 2.53 (s, 3H). Biological evaluation

[0217] The present disclosure will be further described and explained below in conjunction with test examples, but these test examples are not intended to limit the scope of the present disclosure. Test Example 1: Cell proliferation experiment

[0218] The following method measures IC by detecting intracellular ATP content. 50 DLD1 cells, DLD1 BRCA2- / - The inhibitory effect on the proliferation of MDA-MB-436 cells was evaluated. The experimental method is briefly described as follows. 1. Experimental materials and equipment

[0219] 1. DLD1, human colon cancer tumor cells (Nanjing Kebai, CBP60037) 2. DLD1 BRCA2- / - , human BRCA2 gene knockout colon cancer tumor cells (Creative biogene, CSC-RT0015) 3. MDA-MB-436, human breast cancer cells (ATCC, HTB-130) 4. Fetal bovine serum (GIBCO, 10091-148) 5. CellTite-Glo Reagent (Promega, G7573) 6. 96-well cell culture plate (corning, 3903) 7. Pancreatin (Invitrogen, 25200-072) 8. Plate reader (BMG, PHERAsta) 9. Cell Counter (Shanghai Rui

number

[0220] DLD1 cells were cultured in RPMI-1640 medium containing 10% FBS and passaged 2 to 3 times a week with a passage ratio of 1:6 or 1:8. During passage, the cells were digested with pancreatin, transferred to a centrifuge tube, centrifuged at 1200 rpm for 3 minutes, the supernatant medium residue was discarded, and fresh medium was added to resuspend the cells. 180 μL of the cell suspension was added to a 96-well cell culture plate, and the cells were cultured at a density of 2.78 × 10 3 cells / mL and 180 μL of complete medium alone was added to the periphery of the 96-well plate.

[0221] DLD1 BRCA2- / - The cells were cultured in RPMI-1640 medium containing 10% FBS and passaged 2 to 3 times a week with a passage ratio of 1:6 or 1:8. During passage, the cells were digested with pancreatin, transferred to a centrifuge tube, centrifuged at 1200 rpm for 3 minutes, the supernatant medium residue was discarded, and fresh medium was added to resuspend the cells. 180 μL of the cell suspension was added to a 96-well cell culture plate, and the cells were cultured at a density of 8.34 × 10 3 cells / mL and 180 μL of complete medium alone was added to the periphery of the 96-well plate.

[0222] MDA-MB-436 cells were cultured in Leibovitz's L-15 medium containing 10% FBS, 10 μg / mL insulin, and 16 μg / mL glutathione, and passaged 2-3 times a week at a passage ratio of 1:3 or 1:5. During passage, the cells were digested with pancreatin, transferred to a centrifuge tube, and centrifuged at 1200 rpm for 3 minutes. The supernatant medium residue was discarded, and fresh medium was added to resuspend the cells. 180 μL of the cell suspension was added to a 96-well cell culture plate, and the cells were cultured at a density of 8.34 × 10 3 cells / mL and 180 μL of complete medium alone was added to the periphery of the 96-well plate.

[0223] The culture plate was incubated in an incubator (37°C, 5% CO 2 ).

[0224] The samples to be measured were diluted to 2 mM with DMSO, and then diluted three-fold to 10 concentrations to set up blank and control wells. 5 μL of the compound solutions to be measured prepared at gradient concentrations were taken and added to 95 μL of fresh medium. Then, 20 μL of the above drug-containing medium solution was added to the culture plate. The culture plate was incubated in an incubator (37° C., 5% CO 2 In a 96-well cell culture plate, 90 μL of CellTiter-Glo reagent was added to each well and incubated at room temperature in the dark for 5 to 10 min. The chemiluminescence signal was read using a PHERAstar and the data was processed using GraphPad software. The results are shown in Table 1.

[0225] [Table 3]

[0226] Conclusion: The compounds disclosed herein have the potential to inhibit DLD1 BRCA2- / - And it has good inhibitory effect on the proliferation of MDA-MB-436 cells. Test Example 2: Measurement of binding activity of compounds according to the present disclosure to PARP1 and PARP2

[0227] In vitro PARP1, PARP2 binding activity was tested by the following method. 1. Experimental materials and equipment

[0228] 1. PARP1 recombinant protein (Yiqiao Shenzhou, product number 11040-H08B) 2. PARP2 Recombinant Protein (BPS, Product No. 80502) 3. Fluorescent probe (self-made using the compound with CAS number 1380359-84-1, Shanghai Hengrui) 4. 384-well plate (Corning, 3575) 5. Plate Reader PHERAstar FS (BMG Labtech) II. Experimental Procedure

[0229] Add 8 μL of binding buffer to each well of a 384-well plate, dissolve the fluorescent probe in dimethyl sulfoxide and dilute it to the corresponding concentration, and then add the fluorescent probe prepared in dimethyl sulfoxide to the binding buffer (50 mM Tris-HCl pH 8.0, 50 mM NaCl, 1 mM MgCl 2 , 0.1 mM EDTA, 0.01% IGEPAL) and add 2 μL to each well. Test compounds were dissolved in dimethyl sulfoxide and diluted to each concentration gradient according to the experimental needs. Compounds of each concentration prepared in dimethyl sulfoxide were further diluted 20 times in binding buffer and add 2 μL to each well. PARP1 or PARP2 protein was diluted to the corresponding concentration with binding buffer and added at 8 μL / well.

number

[0230] The PARP1 and PARP2 binding inhibitory activity of the compounds according to the present disclosure was measured by the above test. 50 The values ​​are shown in Table 2.

[0231] [Table 4]

[0232] Conclusion: The compounds disclosed herein have selective inhibitory activity against PARP1.

Claims

1. A compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof, 【Chemical 1】 wherein, X and Y are the same or different and each independently is (CR ４ａ R ４ｂ ), NR ｍ (CR ５ R ４ｃ R ４ｄ ), C(O)NR ｒ , NR ５ C(O), C(O) and O(CR ５ R ４ｅ R ４ｆ ), ｎ selected from R ４ａ 、 R ４ｂ 、 R ４ｃ 、 R ４ｄ 、 R ４ｅ and R ４ｆ are the same or different and each independently is selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, R ５ is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, G １ , G ２ and G ３ are the same or different and each independently is CR ６ or a nitrogen atom, R ０ 、 R １ and R ６ are the same or different and each independently is a hydrogen atom, halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, cyano group, -NR ７ａ R ７ｂ , hydroxy group, -C(O)R ８ , -C(O)OR ８ , -C(O)NR ７ａ R ７ｂ , -S(O) ｐ R ８ , cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently optionally substituted with one or more substituents selected from halogen, oxo group, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, -NR ９ａ R ９ｂ , hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, Each R ２ is the same or different and each independently is halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, an oxo group, a cyano group, -NR ７ａ R ７ｂ , selected from a hydroxy group and a hydroxyalkyl group, Each R ３ is the same or different and each independently is halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, -NR ７ａ R ７ｂ , a hydroxy group, -C(O)R ８ , -C(O)OR ８ , -C(O)NR ７ａ R ７ｂ , -S(O) ｐ R ８ , a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ９ａ R ９ｂ , a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group R ７ａ 、 R ７ｂ 、 R ９ａ and R ９ｂ are the same or different and each independently is selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are each independently optionally substituted with one or more substituents selected from halogen, an alkyl group, an alkoxy group, a haloalkyl group and a haloalkoxy group, Alternatively, R ７ａ and R ７ｂ form a heterocyclyl group together with the linking nitrogen atom, and R ９ａ and R ９ｂ form a heterocyclyl group together with the linking nitrogen atom, and the formed heterocyclyl group is optionally substituted with one or more substituents selected from halogen, oxo group, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group. R ８ is selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group and a haloalkoxy group, p is 0, 1 or 2, m is 0, 1, 2, 3 or 4, n is 0, 1, 2, 3 or 4, r is 0, 1, 2, 3 or 4, s is 0, 1, 2, 3 or 4, and t is 0, 1, 2 or 3, A compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof.

2. X is (CR ４ａ R ４ｂ ) ｍ or C(O), wherein R ４ａ , R ４ｂ and m are as defined in claim 1, A compound represented by the general formula (IM) according to Claim 1 or a pharmaceutically acceptable salt thereof.

3. Y is O(CR ４ｅ R ４ｆ ), ｎ or NR ５ (CR ４ｃ R ４ｄ ), ｒ wherein R ４ｃ R ４ｄ R ４ｅ R ４ｆ R ５ , n and r are as defined in claim 1. A compound represented by the general formula (IM) according to Claim 1 or a pharmaceutically acceptable salt thereof.

4. A compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof, 【Chemical Formula 2】 wherein, X is (CR ４ａ R ４ｂ ) ｍ and G １ to G ３ , R １ to R ３ , R ４ａ , R ４ｂ , s, t, m and n are as defined in claim 1 A compound represented by the general formula (IM) according to Claim 1 or a pharmaceutically acceptable salt thereof.

5. A compound represented by the general formula (IM) according to Claim 1 or a pharmaceutically acceptable salt thereof, wherein s is 0.

6. G １ is CH, G ２ is a nitrogen atom, and G ３ is CR ６ or G １ and G ２ are both CH, and G ３ is a nitrogen atom, or G １ is a nitrogen atom, G ２ is CH, and G ３ is CR ６ wherein, R ６ is as defined in claim 1, A compound represented by the general formula (IM) according to Claim 1 or a pharmaceutically acceptable salt thereof.

7. R ３ is halogen, C １－６ alkyl group, C １－６ alkoxy group, C １－６ haloalkyl group, C １－６ haloalkoxy group, C １－６ hydroxyalkyl group, cyano group, -NR ７ａ R ７ｂ , hydroxy group, -C(O)R ８ , -C(O)OR ８ and -C(O)NR ７ａ R ７ｂ selected from, preferably, R ３ is -C(O)NR ７ａ R ７ｂ , wherein, R ７ａ , R ７ｂ and R ８ are as defined in claim 1, A compound represented by the general formula (IM) according to Claim 1 or a pharmaceutically acceptable salt thereof.

8. A compound represented by the general formula (III-1) or the general formula (III-1-A) or a pharmaceutically acceptable salt thereof, [Chemical 3] or 【Chemical Formula 4】 wherein, m1 is 0 or 1, R １ 、R ６ 、R ７ａ 、R ７ｂ and n are as defined in claim 1, A compound represented by the general formula (IM) according to Claim 1 or a pharmaceutically acceptable salt thereof.

9. R １ is selected from a hydrogen atom, a halogen, C １－６ alkyl group, C １－６ alkoxy group, C １－６ haloalkyl group, C １－６ haloalkoxy group and C １－６ hydroxyalkyl group A compound represented by the general formula (IM) according to Claim 1 or a pharmaceutically acceptable salt thereof.

10. R ６ is selected from a hydrogen atom, a halogen, C １－６ alkyl group, C １－６ alkoxy group, C １－６ haloalkyl group, C １－６ haloalkoxy group and C １－６ hydroxyalkyl group A compound represented by the general formula (IM) according to Claim 1 or a pharmaceutically acceptable salt thereof.

11. R ７ａ and R ７ｂ are the same or different and each independently is a hydrogen atom, C １－６ alkyl group, C １－６ hydroxyalkyl group, a 3- to 8-membered cycloalkyl group and a 3- to 8-membered heterocyclyl group selected from A compound represented by the general formula (IM) according to Claim 1 or a pharmaceutically acceptable salt thereof.

12. A compound represented by the general formula (IM) according to Claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

13. 【Chemical Formula 5】 【Chemical Formula 6】 A compound represented by the general formula (IM) according to Claim 1 or a pharmaceutically acceptable salt thereof, which is any one selected from the following compounds.

14. A compound represented by the general formula (IMa) or a salt thereof, [Chemical Formula 7] wherein, t is 1, 2 or 3, X, Y, R ２ , R ３ and s are as defined in claim 1, A compound represented by the general formula (IMa) or a salt thereof.

15. 【Chemical Formula 8】 【Chemical Formula 9】 A compound represented by the general formula (IMa) according to Claim 14 or a salt thereof, which is selected from the following.

16. A method for preparing a compound represented by the general formula (IM) according to Claim 1 or a pharmaceutically acceptable salt thereof, 【Chemical Formula 10】 A compound of general formula (IMa) or a salt thereof (preferably hydrochloride) is subjected to a nucleophilic substitution reaction with a compound of general formula (IMb) to obtain a compound of general formula (IM) or a pharmaceutically acceptable salt thereof, wherein, L is halogen, preferably a chlorine atom, X, Y, G １ ~G ３ , R ０ ~R ３ , s and t are as defined in claim 1, Method.

17. A compound represented by general formula (IM) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vectors, diluents or excipients, Pharmaceutical composition.

18. Use of a compound represented by general formula (IM) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of a PARP1 inhibitor, Use.

19. Use of a compound represented by general formula (IM) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing cancer, Use.

20. The cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, cervical cancer, endometrial cancer, myeloma, leukemia, lymphoma, acoustic neuroma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, bronchial cancer, sarcoma, chordoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, hemangioendothelioma, epithelioma, epithelial cancer, esophageal cancer, essential thrombocythemia, Ewing's sarcoma, testicular cancer, glioma, heavy chain disease, hemangioblastoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, glioma, NUT midline carcinoma, glioma, bone cancer, nasopharyngeal cancer, oral cancer, thyroid cancer, pinealoma, polycythemia vera, retinoblastoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, Waldenström macroglobulinemia and Wilms' tumor, preferably, the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer and lung cancer, Use according to claim 19.

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