Pyridine derivatives and their use in medicine

Abstract

Compounds of formula (I) and their use in medicine, the compounds being useful in the treatment of tumours

Description

Technical Field

[0001] This application relates to pyridine derivatives and their pharmaceutical applications. Background Technology

[0002] PARP (poly(ADP-ribose) polymerases) are a class of poly-ADP-ribose polymerases that catalyze the poly-ADP-ribosylation of various proteins. This process plays a crucial role in many cellular processes, including DNA damage repair, transcriptional regulation, chromatin remodeling, and remodeling. Currently, although several PARP1 / PARP2 inhibitors have been successfully marketed, side effects, such as hematological and gastrointestinal side effects, are still prevalent in clinical practice, whether used alone or in combination, limiting their clinical application. Therefore, developing safer and more effective PARP inhibitors remains a pressing clinical challenge. A series of studies have shown that, compared to PARP1 / PARP2 inhibitors, highly selective PARP1 inhibitors offer better efficacy and lower toxicity, potentially reducing the potential risks of current PARP drugs, broadening their clinical application, and improving patients' quality of life. Summary of the Invention

[0003] One of the purposes of this application is to provide pyridine derivatives or their pharmaceutically acceptable salts or stereoisomers, as well as pharmaceutical compositions comprising the above compounds, and their use in medicine.

[0004] One or more embodiments of this application provide compounds of formula (I) or pharmaceutically acceptable salts or stereoisomers thereof:

[0005]

[0006] in

[0007] R1 is C 1-6 alkyl;

[0008] L is -NH-, -CO-, or -(CR) L1 R L2 ) n -;

[0009] R L1 R L2 Each independently is H or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogens, hydroxyl groups and cyano groups;

[0010] R3 can be H, halogen, hydroxyl, cyano, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8cycloalkyl or C 3-8 Heterocyclic alkyl; the C 3-8 The heterocyclic alkyl group comprises 1-4 heteroatoms selected from N, O, and S; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 The heterocyclic alkyl group is optionally surrounded by one or more groups selected from H, halogen, hydroxyl, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups;

[0011] R2 is C 1-4 Alkyl, C 5-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl; the C 3-8 The heterocyclic alkyl group comprises 1-4 heteroatoms selected from N, O, and S; the C 5-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups are optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl and C 3-8 Substituents of heterocyclic alkyl groups; when R2 is C 1-4 When alkyl, the C 1-4 The alkyl group is selected from one or more hydroxyl groups and C. 1-6 Substitution of alkoxy groups;

[0012] n is 1 or 2;

[0013] m can be 0, 1, 2, or 3.

[0014] In one or more embodiments, the compound of formula (I) is substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) deuterium.

[0015] In one or more embodiments, the C 3-8 Heteroalkyl groups contain 1, 2, 3 or 4 heteroatoms selected from N, O and S.

[0016] In one or more embodiments, the compound has the structure of formula (II):

[0017]

[0018] in

[0019] R1 is C 1-6 alkyl;

[0020] L is -NH-, -CO-, or -(CR) L1 R L2 ) n -;

[0021] R L1 R L2 Each independently is H or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogens, hydroxyl groups and cyano groups;

[0022] R2 is C 1-4 Alkyl, C 5-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl; the C 3-8 The heterocyclic alkyl group comprises 1-4 heteroatoms selected from N, O, and S; the C 5-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups are optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl and C 3-8 Substituents of heterocyclic alkyl groups; when R2 is C 1-4 When alkyl, the C 1-4 The alkyl group is selected from one or more hydroxyl groups and C. 1-6 Substitution of alkoxy groups;

[0023] n is 1 or 2.

[0024] In one or more embodiments, the compound of formula (II) is substituted with one or more deuterium atoms.

[0025] In one or more embodiments, the compound of formula (I) is substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) deuterium.

[0026] In one or more embodiments, R1 is an ethyl group.

[0027] In one or more embodiments, L is -CH2- or -CD2-.

[0028] In one or more embodiments, R3 is H, -CH3, -CD3, -OCH3, or -Cl.

[0029] In one or more embodiments, R2 is cyclobutyl, oxecyclopentyl, oxecyclohexyl, azircyclobutyl, methyl, ethyl, or propyl; wherein the cyclobutyl, oxecyclopentyl, oxecyclohexyl, azircyclobutyl, methyl, ethyl, or propyl is optionally substituted by one or more substituents selected from methyl, methoxy, and hydroxyl.

[0030] In one or more embodiments, the compound is:

[0031]

[0032]

[0033]

[0034] In one or more embodiments, the above-described compound is substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) deuterium.

[0035] In one or more embodiments, the halogen is F, Cl, or Br.

[0036] One or more embodiments of this application provide a pharmaceutical composition comprising:

[0037] (1) The above-mentioned compounds of this application or their pharmaceutically acceptable salts or stereoisomers;

[0038] (2) Optional one or more other active ingredients; and

[0039] (3) Acceptable carriers and / or excipients for the drug.

[0040] One or more embodiments of this application provide compounds of general formula (I') or their stereoisomers:

[0041]

[0042] in:

[0043] R1 is selected from C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S;

[0044] L is selected from -NH-, -CO-, or -(CR) L1 R L2 ) n -;

[0045] R L1 R L2 Each is independently selected from H or C1-6 Alkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogen, hydroxyl or cyano groups;

[0046] A is a 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is selected from 4- to 12-membered monocyclic rings, 5- to 12-membered spirocyclic rings, 4- to 12-membered fused rings or 4- to 12-membered bridged rings, and the 4- to 12-membered heterocycle may contain 1 to 4 heteroatoms selected from N, O or S.

[0047] R2 is selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups may optionally be further selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, etc. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups;

[0048] n is 1 or 2.

[0049] One or more embodiments of this application provide compounds or stereoisomers thereof represented by general formula (I”):

[0050]

[0051] in:

[0052] R1 is selected from H, halogens, C 2-6 alkenyl or C 2-6 alkynyl group, the C 2-6 alkenyl or C 2-6 The alkynyl group may optionally be further selected by one or more halogens or C 1-6 Alkyl substituents;

[0053] L is selected from -NH-, -CO-, or -(CR) L1 R L2 ) n -;

[0054] R L1 R L2 Each is independently selected from H or C 1-6 Alkyl, the C 1-6The alkyl group may optionally be further substituted with one or more substituents selected from halogen, hydroxyl or cyano groups;

[0055] A is a 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is selected from 4- to 12-membered monocyclic rings, 5- to 12-membered spirocyclic rings, 4- to 12-membered fused rings or 4- to 12-membered bridged rings, and the 4- to 12-membered heterocycle may contain 1 to 4 heteroatoms selected from N, O or S.

[0056] R2 is selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups may optionally be further selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, etc. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups;

[0057] n is 1 or 2.

[0058] One or more embodiments of this application provide compounds or stereoisomers of the general formula (I”'):

[0059]

[0060] in:

[0061] R1 is selected from C 1-6 alkyl;

[0062] L is selected from -NH-, -CO-, or -(CR) L1 R L2 ) n -;

[0063] R L1 R L2 Each is independently selected from H or C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogen, hydroxyl or cyano groups;

[0064] A is a 7- to 12-membered heterocycle, wherein the 7- to 12-membered heterocycle is selected from 7- to 12-membered monocyclic rings, 7- to 12-membered spirocyclic rings, 7- to 12-membered fused rings, or 7- to 12-membered bridged rings, and the 7- to 12-membered heterocycle may contain 1 to 4 heteroatoms selected from N, O, or S.

[0065] R2 is selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups may optionally be further selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, etc. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups;

[0066] n is 1 or 2.

[0067] One or more embodiments of this application provide compounds of general formula (II') or their stereoisomers:

[0068]

[0069] in:

[0070] R1 is selected from C 1-6 alkyl;

[0071] L is selected from -NH-, -CO-, or -(CR) L1 R L2 ) n -;

[0072] R L1 R L2 Each is independently selected from H or C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogen, hydroxyl or cyano groups;

[0073] X1 and X2 are each independently selected from CR X Or N;

[0074] R X Selected from H, hydroxyl, cyano or C 1-6 alkyl;

[0075] When X1 and X2 are both N, Ra Selected from hydroxyl, cyano, =O or C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from hydroxyl, halogen or cyano groups;

[0076] When either X1 or X2 is CR X At that time, R a Selected from H, hydroxyl, cyano, =O or C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from hydroxyl, halogen or cyano groups;

[0077] R2 is selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups may optionally be further selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, etc. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups;

[0078] m can be 1, 2, or 3;

[0079] n is 1 or 2.

[0080] One or more embodiments of this application provide compounds of general formula (III') or their stereoisomers:

[0081]

[0082] in:

[0083] R1 is selected from C 1-6 alkyl;

[0084] L is selected from -NH-, -CO-, or -(CR) L1 R L2 ) n -;

[0085] R L1 R L2 Each is independently selected from H or C 1-6 Alkyl, the C 1-6The alkyl group may optionally be further substituted with one or more substituents selected from halogen, hydroxyl or cyano groups;

[0086] R3 is selected from H, halogen, hydroxyl, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 The heterocyclic alkyl group may optionally be further surrounded by one or more groups selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups;

[0087] R2 is selected from C 5-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups may optionally be further selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, etc. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups;

[0088] n is 1 or 2.

[0089] m is 0, 1, 2, or 3

[0090] One or more embodiments of this application provide compounds of general formula (III”) or their stereoisomers:

[0091]

[0092] in:

[0093] R1 is selected from C 1-6 alkyl;

[0094] L is selected from -NH-, -CO-, or -(CR) L1 R L2 ) n -;

[0095] R L1 R L2 Each is independently selected from H or C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogen, hydroxyl or cyano groups;

[0096] R2 is selected from C 5-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups, the C 3-8 Heterocyclic alkyl groups may contain 1 to 4 heteroatoms selected from N, O, or S; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups may optionally be further selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, etc. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups;

[0097] n is 1 or 2.

[0098] One or more embodiments of this application provide the use of the above-described compounds of this application, or their pharmaceutically acceptable salts or stereoisomers, or the above-described pharmaceutical compositions, in the preparation of antitumor or anticancer drugs.

[0099] One or more embodiments of this application provide the above-described compounds of this application or their pharmaceutically acceptable salts or stereoisomers or the above-described pharmaceutical compositions, which are used as pharmaceuticals.

[0100] One or more embodiments of this application provide a method for treating / preventing cancer using the above-described compound or its pharmaceutically acceptable salt or stereoisomer or the above-described pharmaceutical composition.

[0101] One or more embodiments of this application provide a method for treating / preventing tumors or cancer, comprising using the above-described compounds of this application, or their pharmaceutically acceptable salts or stereoisomers, or the above-described pharmaceutical compositions, on a subject in need of such treatment.

[0102] One or more embodiments of this application provide a method for inhibiting PARP1 and / or PARP2, comprising using the above-described compounds of this application, or their pharmaceutically acceptable salts or stereoisomers, or the above-described pharmaceutical compositions, on a subject in need of doing so.

[0103] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0104] The carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I involved in the groups and compounds described in this invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0105] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8), more preferably an alkyl group with 1 to 6 carbon atoms, and even more preferably an alkyl group with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched isomers; when the alkyl group is substituented, it may optionally be further substituted by one or more substituents.

[0106] "Alkoxy" refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. The definition of alkyl is the same as that of "alkyl" as described above.

[0107] "Alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, composed of 2 to 20 carbon atoms, preferably alkenyl groups with 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably alkenyl groups with 2 to 8 carbon atoms, and even more preferably alkenyl groups with 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3-yl. The alkenyl group may optionally be further replaced by one or more substituents.

[0108] "Alynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, composed of 2 to 20 carbon atoms, preferably an alkynyl group with 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, more preferably an alkynyl group with 2 to 8 carbon atoms, and even more preferably an alkynyl group with 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, penyn-1-yl, penyn-2-yl, hexyn-1-yl, 1-heptyne-1-yl, heptyne-3-yl, heptyne-4-yl, octyne-3-yl, nonyn-3-yl, decanyn-4-yl, undecyn-3-yl, and dodecanyn-4-yl. The ethynyl group may optionally be further substituted with one or more substituents.

[0109] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5- to 8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system. It can be a bridged ring or a spirocyclic ring. Non-limiting examples include phenyl and naphthyl. The aryl group may optionally be further substituted by one or more substituents.

[0110] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S, preferably 5- to 8-membered heteroaryl. The 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms selectively substituted in the ring of the heteroaryl can be oxidized to various oxidation states. The heteroaryl group can be attached to a heteroatom or a carbon atom. The heteroaryl group can be a bridged ring or a spiro ring. Non-limiting examples include cyclopyridyl, furanyl, thiophenyl, pyranyl, pyrrolidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, and pyrrolopyridyl. The heteroaryl group may optionally be further substituted with one or more substituents.

[0111] "Carbocyclic group" or "carbocyclic" refers to a saturated or unsaturated aromatic ring or non-aromatic ring. When it is an aromatic ring, its definition is the same as that of "aryl" above; when it is a non-aromatic ring, it can be a monocyclic ring of 3 to 10 members (e.g., 3, 4, 5, 6, 7, 8, 9, 10 members), a bicyclic ring of 4 to 12 members (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 members), or a tricyclic system of 10 to 15 members (e.g., 10, 11, 12, 13, 14, 15 members). It can be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. The “carbocyclic group” or “carbocyclic” may optionally be further substituted by one or more substituents.

[0112] "Heterocyclic group" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl" above. When it is a non-aromatic heterocycle, it can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. The selectively substituted 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms in the ring of the "heterocyclic group" or "heterocycle" can be oxidized to various oxidation states; the "heterocyclic group" or "heterocycle" can be attached to a heteroatom or a carbon atom; the "heterocyclic group" or "heterocycle" can be a bridged ring or a spirocycle. Non-limiting examples of the "heterocyclic group" or "heterocycle" include epoxyethyl, epoxypropyl, azirropropyl, oxacyclobutyl, azirrobutyl, thioheterobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxhexacycloyl, azirroheptyl, oxacycloheptyl, thioheterobutyl, oxazorphinyl, diazorphinyl, thioazorphinyl, pyridinyl, piperidinyl, homopiperidinyl, and furan. Thiophene, pyranyl, N-alkylpyrrole, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxylalkyl, 1,3-dithiaalkyl, dihydrofuranyl, dithiapentanecycloyl, tetrahydrofuranyl, tetrahydrothiopheneyl, tetrahydropyranyl, tetrahydrothiaranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidyl Azolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolyl, imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3] [1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptyl. The “heterocyclic group” or “heterocycle” may optionally be further substituted with one or more substituents.

[0113] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which can be a monocyclic ring of 3 to 10 members (e.g., 3, 4, 5, 6, 7, 8, 9, 10 members), a bicyclic ring of 4 to 12 members (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 members), or a polycyclic system of 10 to 20 members (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 members), preferably with 3 to 10 carbon atoms, more preferably with 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cyclohepttrienyl, etc. When the cycloalkyl group is substituted, it may optionally be further substituted by one or more substituents.

[0114] "Heterocyclic alkyl" refers to a substituted or unsubstituted saturated non-aromatic cyclic group, which can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. The 1, 2, or 3 N or S atoms selectively substituted in the ring of the "heterocyclic alkyl" can be oxidized to various oxidation states; the "heterocyclic alkyl" can be attached to a heteroatom or a carbon atom; the "heterocyclic alkyl" can be a bridged ring or a spirocyclic ring. Non-limiting examples of “heterocyclic alkyl” include epoxide ethyl, aziridine propyl, oxacyclobutyl, aziridine butyl, 1,3-dioxolanecycloyl, 1,4-dioxolanecycloyl, 1,3-dioxahexacycloyl, aziridine heptyl, piperidinyl, piperinyl, morpholinyl, thiomorpholinyl, 1,3-dithiaalkyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, aziridine[3.2.1]octyl, aziridine[5.2.0]nonyl, oxacyclo[5.3.1.1]dodecyl, aziridine, and oxaspiro[3.3]heptyl.

[0115] When the terms "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclic", "carbocyclic", "heterocyclic", "cycloalkyl", "heterocyclic", or "heterocyclic" mentioned above are substituted, they may be further replaced by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 Alkylamino, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -NR q4 Rq5 =NR q6 -C(=O)OC 1-6 Alkyl group, -OC (=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 3-8 Heterocyclic alkyl, -C(=O)OC 3-8 Heterocyclic alkyl groups, -OC (=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 2-6 alkenyl or -NHC(=O)C 2-6 The alkynyl group is replaced by a substituent, and the substituent C is described in the figure. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 Heterocyclic alkyl groups or -NHC(=O)C 3-8 The cycloalkyl group may optionally be further surrounded by one to three elements selected from OH, F, Cl, Br, I, C. 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or replaced by the =O substituent; R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; Rq2 R q3 Selected from H or C 1-6 Alkyl; wherein, R q4 R q5 Selected from H, C 1-6 Alkyl group, -NH (C=NR) q1 )NR q2 R q3 -S(=O)2NR q2 R q3 -C(=O)R q1 Or -C(=O)NR q2 R q3 The C mentioned therein 1-6 The alkyl group may optionally be further influenced by one or more elements selected from OH, F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 heteroaryl, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups; or R q4 With R q5 The N atom forms a 3- to 8-membered heterocycle, which may contain one or more heteroatoms selected from N, O or S.

[0116] Halogens include F, Cl, Br and I.

[0117] "Pharmaceutical-acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0118] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0119] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0120] "Excipients" are inert substances added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0121] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0122] "Optional," "optionally," "selectively," or "selectively" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "selectively alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group. Detailed Implementation

[0123] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0124] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using Bruker Avance III 400 and Bruker Avance 300 NMR spectrometers. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0125] MS measurements were performed using Agilent 6120B (ESI) and Agilent 6120B (APCI);

[0126] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.20mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm-0.5mm in diameter.

[0127] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0128] Example 1

[0129] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-((1R,3R)-3-hydroxycyclobutyl)pyridineamide compound 1

[0130] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1R,3R)-3-hydroxycyclobutyl)picolinamide

[0131]

[0132] first step

[0133] 4-(6-((1R,3R)-3-hydroxycyclobutyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 1c

[0134] tert-butyl 4-(6-(((1R,3R)-3-hydroxycyclobutyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0135] 5-Bromo-N-((1R,3R)-3-hydroxycyclobutyl)pyridine amide compound 1a (1.2 g, 4.43 mmol) and (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester compound 1b (823 mg, 4.43 mmol) were dissolved in toluene (15 mL). Palladium acetate (purchased from Huajieming Biotechnology, 95.6 mg, 0.43 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (purchased from Chengdu Aester Chemical Technology Co., Ltd., 265.2 mg, 0.43 mmol) were added. The reaction system was purged with nitrogen and reacted in an oil bath at 120 °C for 4 h. The reaction was quenched with water (20 mL), extracted with ethyl acetate (3 × 30 mL), and the organic phase was collected, evaporated to dryness, and analyzed by column chromatography (PE:EA = 2:1) to give compound 1c (white solid, 1.3 g, yield 78%).

[0136] 1 H NMR(400MHz,DMSO-d6)δ8.56(d,1H),8.28(d,1H),7.82(d,1H),7.41(dd,1H),4.99(d,1H),4.48 (q,1H),4.28(q,1H),3.47(t,4H),3.31(dd,4H),2.36-2.26(m,2H),2.12(ddd,2H),1.42(s,9H).

[0137] LC-MS m / z(ESI)=377.46[M+1].

[0138] Step 2

[0139] N-((1R,3R)-3-hydroxycyclobutyl)-5-(piperazin-1-yl)pyridineamide 1d

[0140] N-((1R,3R)-3-hydroxycyclobutyl)-5-(piperazin-1-yl)picolinamide

[0141] Compound 1c was dissolved in hydrochloric acid-1,4-dioxane solution (purchased from Anaiji Chemical, 4M, 15mL), and the reaction was stirred at room temperature for 8 hours. The reaction solution was filtered and the filter cake was collected to give compound 1d (white solid, 1.1g, yield 94%).

[0142] LC-MS m / z(ESI)=265.33[M+1].

[0143] Step 3

[0144] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-((1R,3R)-3-hydroxycyclobutyl)pyridineamide compound 1

[0145] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1R,3R)-3-hydroxycyclobutyl)picolinamide

[0146] Compound 1d (35.9 mg, 0.13 mmol) and compound 1e (36.7 mg, 0.13 mmol) were dissolved in acetonitrile (5 mL), and N,N-diisopropylethylamine (purchased from Shanghai Maclean Biochemical Technology Co., Ltd., 84 mg, 1.5 mmol) was added. The mixture was reacted at 70 °C for 3 h, and the reaction solution was evaporated to dryness. The crude product was separated by column chromatography (MeOH:DCM = 1:60 to 1:15) to give compound 1 (white solid, 36 mg, yield 62%).

[0147] 1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.53(d,1H),8.40(d,1H),8.27(d,1H),7.81(d,1H),7.75(s,1H),7.63(d,1H),7.39(dd,1H) ,5.00(d,1H),4.47(q,1H),4.28(d,1H),3.65(s,2H),3.33(s,4H),2.59-2.52(m,6H),2.30(ddd,2H),2.11(ddt,2H),1.18(t,3H).

[0148] LC-MS m / z(ESI)=463.55[M+1].

[0149] Example 2

[0150] (R)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester compound 2

[0151] tert-butyl(R)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate

[0152]

[0153]

[0154] first step

[0155] (R)-5-bromo-N-(tetrahydrofuran-3-yl)pyridineamide 2b

[0156] (R)-5-bromo-N-(tetrahydrofuran-3-yl)picolinamide

[0157] Compound 2a (2 g, 9.9 mmol) was dissolved in dichloromethane (20 mL). Under ice-water bath conditions, a solution of (R)-tetrahydrofuran-3-amine, HATU (3.5 g, 14.8 mmol), and triethylamine (2 mL) was added dropwise. The reaction was carried out at room temperature for 90 minutes. After the reaction was completed, the solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 2b (yellow solid, 1.9 g, yield 80%).

[0158] LC-MS m / z(ESI)=270.10[M+1].

[0159] Step 2

[0160] (R)-4-(6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 2c

[0161] tert-butyl(R)-4-(6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0162] Following the synthetic method of compound 1c, compound 2c (white solid, 2.5 g, yield 89%) was obtained.

[0163] 1 H NMR (400MHz, DMSO-d6) δ8.43-8.34(m,2H),8.27(d,1H),7.81(d,1H),7.65(d,1H),4.51-4.38(m,1H),3.83(ddd, 2H),3.71(td,1H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,4H),2.14(dtd,1H),1.99-1.85(m,1H),1.49(s,9H).

[0164] LC-MS m / z(ESI)=377.21[M+1].

[0165] Step 3

[0166] (R)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide 2d

[0167] (R)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide

[0168] Following the synthetic method of compound 1d, compound 2d (white solid, 1.6 g, yield 83%) was obtained.

[0169] LC-MS m / z(ESI)=277.16[M+1].

[0170] Step 4

[0171] (R)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester compound 2

[0172] tert-butyl(R)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate

[0173] Following the same synthetic method as compound 1, compound 2 (white solid, 19 mg, yield 42%) was obtained.

[0174] 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.43-8.34(m,2H),8.27(d,1H),7.83(d,1H),7.74(d,1H),7.62(d,1H),7.39(dd,1H),4.51-4.38(m,1 H),3.83(ddd,2H),3.71(td,1H),3.64(s,2H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,6H),2.14(dtd,1H),1.99-1.85(m,1H),1.18(q,4H).

[0175] LC-MS m / z(ESI)=463.24[M+1].

[0176] Example 3

[0177] (S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide compound 3

[0178] (S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide

[0179]

[0180] first step

[0181] (S)-5-bromo-N-(tetrahydrofuran-3-yl)pyridineamide 3a

[0182] (S)-5-bromo-N-(tetrahydrofuran-3-yl)picolinamide

[0183] Following the synthetic method of compound 2b, compound 3a (yellow solid, 1.7 g, yield 77%) was obtained.

[0184] LC-MS m / z(ESI)=270.10[M+1].

[0185] Step 2

[0186] (S)-4-(6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 3b

[0187] tert-butyl(S)-4-(6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0188] Following the synthetic method of compound 1c, compound 3b (white solid, 1.1 g, yield 82%) was obtained.

[0189] 1 H NMR (400MHz, DMSO-d6) δ8.43-8.34(m,2H),8.27(d,1H),7.81(d,1H),7.65(d,1H),4.51-4.38(m,1H),3.83(ddd, 2H),3.71(td,1H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,4H),2.14(dtd,1H),1.99-1.85(m,1H),1.49(s,9H).

[0190] LC-MS m / z(ESI)=377.21[M+1].

[0191] Step 3

[0192] (S)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide 3c

[0193] (S)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide

[0194] Following the synthetic method of compound 1d, compound 3c (white solid, 1.2 g, yield 82%) was obtained.

[0195] LC-MS m / z(ESI)=277.16[M+1].

[0196] Step 4

[0197] (S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide compound 3

[0198] (S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide

[0199] Following the same synthetic method as compound 1, compound 3 (white solid, 19 mg, yield 42%) was obtained.

[0200] 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.43-8.34(m,2H),8.27(d,1H),7.83(d,1H),7.74(d,1H),7.62(d,1H),7.39(dd,1H),4.51-4.38(m,1 H),3.83(ddd,2H),3.71(td,1H),3.64(s,2H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,6H),2.14(dtd,1H),1.99-1.85(m,2H),1.18(t,3H).

[0201] LC-MS m / z(ESI)=463.24[M+1].

[0202] Example 4

[0203] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)pyridineamide compound 4

[0204] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)picolinamide

[0205]

[0206] first step

[0207] 4-(6-((2-methoxyethyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 4b

[0208] tert-butyl 4-(6-((2-methoxyethyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0209] Following the synthetic method of compound 1c, compound 4b (white solid, 1.7 g, yield 67%) was obtained.

[0210] LC-MS m / z(ESI)=365.45[M+1].

[0211] Step 2

[0212] N-(2-Methoxyethyl)-5-(piperazin-1-yl)pyridineamide 4c

[0213] N-(2-methoxyethyl)-5-(piperazin-1-yl)picolinamide

[0214] Following the synthetic method of compound 1d, compound 4c (white solid, 1.4 g, yield 89%) was obtained.

[0215] LC-MS m / z(ESI)=265.33[M+1].

[0216] Step 3

[0217] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)pyridineamide compound 4

[0218] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)picolinamide

[0219] Following the same synthetic method as compound 1, compound 4 (white solid, 41 mg, yield 67%) was obtained.

[0220] 1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),8.68(s,1H),8.62(s,1H),8.39(d,J1H),8.35(s,1H),7.89(d,1H),7.81(d,1H),7.50( s,1H),4.56(s,2H),4.10(d,2H),3.62-3.54(m,4H),3.27-3.14(m,2H),3.26(s,3H),3.14(d,2H),2.57(s,4H),1.20(d,3H).

[0221] LC-MS m / z(ESI)=451.54[M+1].

[0222] Example 5

[0223] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)pyridineamide compound 5

[0224] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide

[0225]

[0226] first step

[0227] 4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 5a

[0228] tert-butyl 4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0229] Following the synthetic method of compound 1c, compound 5a (white solid, 1.2 g, yield 67%) was obtained.

[0230] 1H NMR(400MHz,DMSO-d6)δ8.31(dd,2H),7.85(d,1H),7.42(dd,1H),4.84(d,1H),3.76(tt, 1H),3.47(t,4H),3.31(ddd,4H),3.13(ddd,1H),2.69(s,1H),1.42(s,9H),1.05(d,3H).

[0231] LC-MS m / z(ESI)=365.45[M+1].

[0232] Step 2

[0233] N-(2-hydroxypropyl)-5-(piperazin-1-yl)pyridineamide 5b

[0234] N-(2-hydroxypropyl)-5-(piperazin-1-yl)picolinamide

[0235] Following the synthetic method of compound 1d, compound 5b (white solid, 910 mg, yield 96%) was obtained.

[0236] LC-MS m / z(ESI)=265.33[M+1].

[0237] Step 3

[0238] 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)pyridineamide compound 5

[0239] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide

[0240] Following the synthetic method of compound 1, compound 5 (white solid, 60 mg, yield 68%) was obtained.

[0241] LC-MS m / z(ESI)=451.54[M+1].

[0242] Example 6

[0243] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxyethyl)pyridineamide compound 6

[0244] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxyethyl)picolinamide

[0245]

[0246] first step

[0247] 5-Bromo-N-(2-hydroxyethyl)pyridineamide 6a

[0248] 5-bromo-N-(2-hydroxyethyl)picolinamide

[0249] Following the synthetic method of compound 2b, compound 6a (yellow solid, 1.7 g, yield 77%) was obtained.

[0250] LC-MS m / z(ESI)=244.98[M+1].

[0251] Step 2

[0252] 4-(6-((2-hydroxyethyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 6b

[0253] tert-butyl 4-(6-((2-hydroxyethyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0254] Following the synthetic method of compound 1c, compound 6b (white solid, 1.9 g, yield 86%) was obtained.

[0255] 1 H NMR (400MHz, DMSO-d6) δ8.30(d,1H),7.68(d,1H),7.49-7.12(m,2H),5.25(s,1H),3.12(dd,6H),2.75-2.52(m,6H),1.50(s,9H).

[0256] LC-MS m / z(ESI)=351.20[M+1].

[0257] Step 3

[0258] N-(2-hydroxyethyl)-5-(piperazin-1-yl)pyridineamide 6c

[0259] N-(2-hydroxyethyl)-5-(piperazin-1-yl)picolinamide

[0260] Following the synthetic method of compound 1d, compound 6c (white solid, 1.2 g, yield 81%) was obtained.

[0261] LC-MS m / z(ESI)=250.14[M+1].

[0262] Step 4

[0263] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxyethyl)pyridineamide compound 6

[0264] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-

[0265] hydroxyethyl)picolinamide

[0266] Compound 1e (21.3 mg, 0.08 mmol), compound 6c (22.0 mg, 0.09 mmol), and N,N-diisopropylethylamine (51.6 mg, 0.4 mmol) were dissolved in acetonitrile (4 mL) and reacted at 80 °C for 4 h. The reaction solution was concentrated under reduced pressure, and compound 6 (white solid, 16 mg, yield 46%) was obtained by preparative chromatography.

[0267] 1 H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.49-8.31(m,2H),8.27(d,1H),7.83(d,1H),7.75(q,1H),7.62(d, 1H),7.44-7.32(m,1H),4.82(t,1H),3.64(s,2H),3.49(q,2H),3.33(dd,6H),2.54(td,6H),1.17(t,3H).

[0268] LC-MS m / z(ESI)=437.22[M+1].

[0269] Example 7

[0270] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-((1s,3s)-3-hydroxycyclobutyl)pyridineamide compound 7

[0271] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1s,3s)-3-hydroxycyclobutyl)picolinamide

[0272]

[0273] first step

[0274] 4-(6-((1s,3s)-3-hydroxycyclobutyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 7b

[0275] tert-butyl 4-(6-(((1s,3s)-3-hydroxycyclobutyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0276] Following the synthetic method of compound 1c, compound 7b (white solid, 1.1 g, yield 76%) was obtained.

[0277] LC-MS m / z(ESI)=377.46[M+1].

[0278] Step 2

[0279] N-((1s,3s)-3-hydroxycyclobutyl)-5-(piperazin-1-yl)pyridineamide 7c

[0280] N-((1s,3s)-3-hydroxycyclobutyl)-5-(piperazin-1-yl)picolinamide

[0281] Following the synthetic method of compound 1d, compound 7c (white solid, 0.9 g, yield 92%) was obtained.

[0282] LC-MS m / z(ESI)=277.16[M+1].

[0283] Step 3

[0284] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-((1s,3s)-3-hydroxycyclobutyl)pyridineamide compound 7

[0285] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1s,3s)-3-hydroxycyclobutyl)picolinamide

[0286] Following the synthetic method of compound 1, compound 7 (white solid, 41 mg, yield 59%) was obtained.

[0287] 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.39(d,2H),8.27(d,1H),7.83-7.73(m,2H),7.62(s,1H),7.39(dd,1H),5.03(d,1H) ,3.94-3.78(m,2H),3.65(s,2H),3.34-3.31(m,4H),2.56-2.53(m,6H),2.50-2.44(m,2H),1.98-1.85(m,2H),1.18(t,3H).

[0288] LC-MS m / z(ESI)=463.24[M+1].

[0289] Example 8

[0290] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxy-2-methylpropyl)pyridineamide compound 8

[0291] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxy-2-methylpropyl)picolinamide

[0292]

[0293] first step

[0294] 5-Bromo-N-(2-hydroxy-2-methylpropyl)pyridineamide 8a

[0295] 5-bromo-N-(2-hydroxy-2-methylpropyl)picolinamide

[0296] Following the synthetic method of compound 2b, compound 8a (yellow solid, 1.4 g, yield 71%) was obtained.

[0297] LC-MS m / z(ESI)=274.13[M+1].

[0298] Step 2

[0299] 4-(6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 8b

[0300] tert-butyl 4-(6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0301] Following the synthetic method of compound 1c, compound 8b (white solid, 1.1 g, 92% yield) was obtained.

[0302] LC-MS m / z(ESI)=379.47[M+1].

[0303] Step 3

[0304] N-(2-hydroxy-2-methylpropyl)-5-(piperazin-1-yl)pyridineamide 8c

[0305] N-(2-hydroxy-2-methylpropyl)-5-(piperazin-1-yl)picolinamide

[0306] Following the synthetic method of compound 1d, compound 8c (white solid, 920 mg, yield 89%) was obtained.

[0307] LC-MS m / z(ESI)=279.3[M+1].

[0308] Step 4

[0309] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-2-hydroxy-2-methylpropyl)pyridineamide compound 8

[0310] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-

[0311] hydroxy-2-methylpropyl)picolinamide

[0312] Following the synthetic method of compound 6, compound 8 (white solid, 27 mg, yield 53%) was obtained.

[0313] 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.40(d,1H),8.31(d,1H),8.20(t,1H),7.84(d,1H),7.75(s,1H),7.63(d,1H ),7.41(dd,1H),4.70(s,1H),3.65(s,2H),3.35(s,4H),3.23(d,2H),2.59-2.52(m,6H),1.18(t,3H),1.08(s,6H).

[0314] LC-MS m / z(ESI)=465.5[M+1].

[0315] Example 9

[0316] (S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropane-2-yl)pyridineamide compound 9

[0317] (S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropan-2-yl)picolinamide

[0318]

[0319] first step

[0320] (S)-5-bromo-N-(1-hydroxypropane-2-yl)pyridineamide 9a

[0321] (S)-5-bromo-N-(1-hydroxypropan-2-yl)picolinamide

[0322] Following the synthetic method of compound 2b, compound 9a (yellow solid, 1.3 g, yield 76%) was obtained.

[0323] LC-MS m / z(ESI)=259.00[M+1].

[0324] Step 2

[0325] (S)-4-(6-((1-hydroxypropan-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 9b

[0326] tert-butyl(S)-4-(6-((1-hydroxypropan-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carbamoyl

[0327] Following the synthetic method of compound 1c, compound 9b (white solid, 1.2 g, yield 91%) was obtained.

[0328] LC-MS m / z(ESI)=365.21[M+1].

[0329] Step 3

[0330] (S)-N-(1-hydroxypropan-2-yl)-5-(piperazin-1-yl)pyridineamide 9c

[0331] (S)-N-(1-hydroxypropan-2-yl)-5-(piperazin-1-yl)picolinamide

[0332] Following the synthetic method of compound 1d, compound 9c (white solid, 860 mg, yield 88%) was obtained.

[0333] LC-MS m / z(ESI)=279.3[M+1].

[0334] 1 H NMR(400MHz,DMSO-d6)δ9.53(s,1H),8.37-8.29(m,1H),8.04(d,1H),7.63(dd,1H),3.99 (dt,1H),3.77-3.58(m,4H),3.43(qd,2H),3.21-3.10(m,6H),1.19(t,1H),1.14(d,3H).

[0335] Step 4

[0336] (S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropane-2-yl)pyridineamide compound 9

[0337] (S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropan-2-yl)picolinamide

[0338] Following the synthetic method of compound 6, compound 9 (white solid, 23 mg, yield 54%) was obtained.

[0339] 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.39(d,1H),8.27(d,1H),8.10(d,1H),7.84(d,1H),7.74(s,1H),7.62(d,1H),7. 38(dd,1H),4.86(t,1H),3.98(ddt,1H),3.63(s,2H),3.43(dq,2H),3.32(t,4H),2.58-2.52(m,6H),1.22-1.08(m,6H).

[0340] LC-MS m / z(ESI)=465.5[M+1].

[0341] Example 10

[0342] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropane-2-yl)pyridineamide compound 10

[0343] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropan-2-yl)picolinamide

[0344]

[0345] first step

[0346] (R)-5-bromo-N-(1-hydroxypropane-2-yl)pyridineamide 10a

[0347] (R)-5-bromo-N-(1-hydroxypropan-2-yl)picolinamide

[0348] Following the synthetic method of compound 2b, compound 10a (yellow solid, 1.4 g, yield 76%) was obtained.

[0349] LC-MS m / z(ESI)=259.00[M+1].

[0350] Step 2

[0351] (R)-4-(6-((1-hydroxypropan-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 10b

[0352] tert-butyl(R)-4-(6-((1-hydroxypropan-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0353] Following the synthetic method of compound 1c, compound 10b (white solid, 1.1 g, 90% yield) was obtained.

[0354] LC-MS m / z(ESI)=365.21[M+1].

[0355] Step 3

[0356] (R)-N-(1-hydroxypropan-2-yl)-5-(piperazin-1-yl)pyridineamide 10c

[0357] (R)-N-(1-hydroxypropan-2-yl)-5-(piperazin-1-yl)picolinamide

[0358] Following the synthetic method for compound 1d, compound 10c (white solid, 840 mg, yield 83%) was obtained.

[0359] LC-MS m / z(ESI)=279.3[M+1].

[0360] 1 H NMR(400MHz,DMSO-d6)δ9.53(s,1H),8.37-8.29(m,1H),8.04(d,1H),7.63(dd,1H),3.99 (dt,1H),3.77-3.58(m,4H),3.43(qd,2H),3.21-3.10(m,6H),1.19(t,1H),1.14(d,3H).

[0361] Step 4

[0362] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropane-2-yl)pyridineamide compound 10

[0363] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-hydroxypropan-2-yl)picolinamide

[0364] Following the synthetic method of compound 6, compound 10 (white solid, 27 mg, yield 62%) was obtained.

[0365] 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.39(d,1H),8.27(d,1H),8.10(d,1H),7.84(d,1H),7.74(s,1H),7.62(d,1H),7. 38(dd,1H),4.86(t,1H),3.98(ddt,1H),3.63(s,2H),3.43(dq,2H),3.32(t,4H),2.58-2.52(m,6H),1.22-1.08(m,6H).

[0366] LC-MS m / z(ESI)=465.5[M+1].

[0367] Example 11

[0368] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)pyridineamide compound 11

[0369] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide

[0370]

[0371]

[0372] first step

[0373] (R)-4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 11b

[0374] tert-butyl(R)-4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0375] Following the synthetic method of compound 1c, compound 11b (white solid, 1.1 g, yield 81%) was obtained.

[0376] 1 H NMR(400MHz,DMSO-d6)δ8.31(dd,2H),7.85(d,1H),7.42(dd,1H),4.84(d,1H),3.76(tt, 1H),3.47(t,4H),3.31(ddd,4H),3.13(ddd,1H),2.69(s,1H),1.42(s,9H),1.05(d,3H).

[0377] LC-MS m / z(ESI)=365.45[M+1].

[0378] Step 2

[0379] (R)-N-(2-hydroxypropyl)-5-(piperazin-1-yl)pyridineamide 11c

[0380] (R)-N-(2-hydroxypropyl)-5-(piperazin-1-yl)picolinamide

[0381] Following the synthetic method of compound 1d, compound 11c (white solid, 902 mg, yield 92%) was obtained.

[0382] LC-MS m / z(ESI)=265.33[M+1].

[0383] Step 3

[0384] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)pyridineamide compound 11

[0385] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide

[0386] Following the synthetic method of compound 1, compound 11 (white solid, 42 mg, yield 72%) was obtained.

[0387] 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.40(d,1H),8.35-8.24(m,2H),7.84(d,1H),7.75(s,1H),7.63(d,1H),7.40(dd,1H),4.8 5(d,1H),3.75(p,1H),3.65(s,2H),3.33(s,4H),3.32-3.27(m,1H),3.13(dt,1H),2.59-2.52(m,6H),1.18(t,3H),1.04(d,3H).

[0388] LC-MS m / z(ESI)=451.54[M+1].

[0389] Example 12

[0390] (S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)pyridineamide compound 12

[0391] (S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide

[0392]

[0393] first step

[0394] (S)-4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 12b

[0395] tert-butyl(S)-4-(6-((2-hydroxypropyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0396] Following the synthetic method of compound 1c, compound 12b (white solid, 1.3 g, yield 84%) was obtained.

[0397] LC-MS m / z(ESI)=365.45[M+1].

[0398] Step 2

[0399] (S)-N-(2-hydroxypropyl)-5-(piperazin-1-yl)pyridineamide 12c

[0400] (S)-N-(2-hydroxypropyl)-5-(piperazin-1-yl)picolinamide

[0401] Following the synthetic method of compound 1d, compound 12c (white solid, 1.1 g, 94% yield) was obtained.

[0402] LC-MS m / z(ESI)=265.33[M+1].

[0403] Step 3

[0404] (S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)pyridineamide compound 12

[0405] (S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)picolinamide

[0406] Following the synthetic method of compound 1, compound 12 (white solid, 37 mg, yield 76%) was obtained.

[0407] 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.40(d,1H),8.35-8.20(m,2H),7.84(d,1H),7.75(d,1H),7.62(d,1H),7.40(dd,1H),4.84 (d,1H),3.75(ddd,1H),3.65(s,2H),3.33(d,4H),3.32-3.28(m,1H),3.13(ddd,1H),2.61-2.51(m,6H),1.18(t,3H),1.04(d,3H).

[0408] LC-MS m / z(ESI)=451.54[M+1].

[0409] Example 13

[0410] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyridinecarboxamide compound 13

[0411] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)picolinamide

[0412]

[0413] first step

[0414] 4-(6-((tetrahydro-2H-pyran-4-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 13b

[0415] tert-butyl 4-(6-((tetrahydro-2H-pyran-4-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0416] Following the synthetic method of compound 1c, compound 13b (white solid, 1.1 g, yield 82%) was obtained.

[0417] LC-MS m / z(ESI)=389.25[M+1].

[0418] Step 2

[0419] N-Cyclohexyl-5-(piperazin-1-yl)pyridinecarboxamide 13c

[0420] N-cyclohexyl-5-(piperazin-1-yl)picolinamide

[0421] Following the synthetic method of compound 1d, compound 13c (white solid, 1.0 g, yield 91%) was obtained.

[0422] LC-MS m / z(ESI)=288.20[M+1].

[0423] Step 3

[0424] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyridinecarboxamide compound 13

[0425] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)picolinamide

[0426] Following the synthetic method of compound 1, compound 13 (white solid, 32 mg, yield 74%) was obtained.

[0427] 1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.68(s,1H),8.33(s,2H),7.93-7.78(m,3H),7.48(d,1H),4.52(s,2H),4.12-3.92(m,3H) ,3.91-3.82(m,2H),3.63-3.56(m,2H),3.34-3.17(m,4H),3.15-3.08(m,2H),2.59-2.54(m,2H),1.75-1.58(m,4H),1.19(t,3H).

[0428] LC-MS m / z(ESI)=477.25[M+1].

[0429] Example 14

[0430] 3-Ethyl-7-((4-(6-(3-hydroxyazacyclobutane-1-carbonyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthidium-2(1H)-one compound 14

[0431] 3-ethyl-7-((4-(6-(3-hydroxyazetidine-1-carbonyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0432]

[0433] first step

[0434] 4-(6-(3-hydroxyazacyclobutane-1-carbonyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 14b

[0435] tert-butyl 4-(6-(3-hydroxyazetidine-1-carbonyl)pyridin-3-yl)piperazine-1-carboxylate

[0436] Following the synthetic method of compound 1c, compound 14b (white solid, 1.1 g, yield 87%) was obtained.

[0437] 1 H NMR(400MHz,DMSO-d6)δ8.29(d,1H),7.79(d,1H),7.38(dd,1H),5.66(d,1H),4.72(dd,1H), 4.54–4.37(m,1H),4.30–4.11(m,2H),3.74(dd,1H),3.45(d,4H),3.31(d,4H),1.42(s,9H).

[0438] LC-MS m / z(ESI)=363.43[M+1].

[0439] Step 2

[0440] (3-hydroxyazacyclobutane-1-yl)(5-(piperazin-1-yl)pyridin-2-yl)methyl ketone 14c

[0441] (3-hydroxyazetidin-1-yl)(5-(piperazin-1-yl)pyridin-2-yl)methanone

[0442] Following the synthetic method of compound 1d, compound 14c (white solid, 1.1 g, 94% yield) was obtained.

[0443] LC-MS m / z(ESI)=265.33[M+1].

[0444] Step 3

[0445] 3-Ethyl-7-((4-(6-(3-hydroxyazacyclobutane-1-carbonyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthidium-2(1H)-one compound 14

[0446] 3-ethyl-7-((4-(6-(3-hydroxyazetidine-1-carbonyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0447] Following the synthetic method of compound 1, compound 14 (white solid, 37 mg, yield 76%) was obtained.

[0448] 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.40(d,1H),8.27(d,1H),7.78(d,1H),7.75(d,1H),7.62(d,1H),7.36(dd,1H),5.67(d,1H ),4.76–4.65(m,1H),4.46(tdd,1H),4.32–4.14(m,2H),3.81–3.68(m,1H),3.64(s,2H),3.33(d,4H),2.54(qd,6H),1.18(t,3H).

[0449] LC-MS m / z(ESI)=449.53[M+1].

[0450] Example 15

[0451] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)pyridineamide compound 15

[0452] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide

[0453]

[0454] first step

[0455] (R)-4-(2-methyl-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 15b

[0456] tert-butyl(R)-4-(2-methyl-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0457] Following the synthetic method of compound 1c, compound 15b (white solid, 1.3 g, yield 84%) was obtained.

[0458] LC-MS m / z(ESI)=391.23[M+1].

[0459] Step 2

[0460] (R)-6-methyl-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide 15c

[0461] (R)-6-methyl-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide

[0462] Following the synthetic method of compound 1d, compound 15c (white solid, 1.1 mg, yield 89%) was obtained.

[0463] LC-MS m / z(ESI)=291.17[M+1].

[0464] Step 3

[0465] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)pyridineamide compound 15

[0466] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide

[0467] Following the synthetic method of compound 1, compound 15 (white solid, 26 mg, yield 77%) was obtained.

[0468] 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.41(s,1H),8.38(d,1H),7.80(d,1H),7.7 5(s,1H),7.63(s,1H),7.48(d,1H),4.49-4.44(m,1H),3.90–3.79(m,2H),3.74-3. 70(m,1H),3.67(s,2H),3.61-3.58(m,1H),2.96-2.94(m,4H),2.64–2.59(m,4H),2 .57-2.53(m,2H),2.50(s,3H),2.22–2.11(m,1H),2.05–1.84(m,1H),1.18(t,3H).

[0469] LC-MS m / z(ESI)=477.25[M+1].

[0470] Example 16

[0471] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-6-methoxy-N-(tetrahydrofuran-3-yl)pyridineamide compound 16

[0472] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methoxy-N-(tetrahydrofuran-3-yl)picolinamide

[0473]

[0474] first step

[0475] tert-Butyl(R)-4-(4-methoxy-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate 16b

[0476] tert-butyl(R)-4-(4-methoxy-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0477] Following the synthetic method of compound 1c, compound 16b (yellow solid, 1.2 g, yield 79%) was obtained.

[0478] LC-MS m / z(ESI)=407.48[M+1].

[0479] Step 2

[0480] (R)-4-methoxy-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide 16c

[0481] (R)-4-methoxy-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide

[0482] Following the synthetic method of compound 1d, compound 16c (white solid, 920 mg, yield 86%) was obtained.

[0483] LC-MS m / z(ESI)=307.37[M+1].

[0484] Step 3

[0485] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-6-methoxy-N-(tetrahydrofuran-3-yl)pyridineamide compound 16

[0486] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methoxy-N-(tetrahydrofuran-3-yl)picolinamide

[0487] Following the synthetic method of compound 1, compound 16 (white solid, 56 mg, yield 76%) was obtained.

[0488] 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.40(d,1H),8.12(d,1H),7.75(s,1H),7.62(d,1H),7.55(d,1H),7.25(d,1H),4.52–4.40(m,1H),3.9 9(s,3H),3.86(qd,2H),3.71(td,1H),3.64(s,2H),3.60(dd,1H),3.1 0(s,4H),2.54(t,6H),2.17(dtd,1H),2.02–1.84(m,1H),1.18(t,3H).

[0489] LC-MS m / z(ESI)=493.58[M+1].

[0490] Example 17

[0491] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-6-(methyl-d3)-N-(tetrahydrofuran-3-yl)pyridineamide compound 17

[0492] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-(methyl-d3)-N-(tetrahydrofuran-3-yl)picolinamide

[0493]

[0494] first step

[0495] 5-Fluoro-6-(methyl-d3)pyridinecarboxylate methyl ester 17b

[0496] methyl 5-fluoro-6-(methyl-d3)picolinate

[0497] A 100 mL reaction flask was dried and purged with N2. Under N2 conditions, methyl 6-bromo-5-fluoropyridinecarboxylate (17a, 10 mmol), methylboronic acid-d3 (11 mmol), Pd(dppf)Cl2 (0.5 mmol), K2CO3 (20 mmol), and 1,4-dioxane (50 mL) were added. The mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the filtrate was collected by filtration, the solvent was removed by rotary evaporation, and the compound 17b was obtained by column chromatography (colorless oil, 70% yield).

[0498] LC-MS m / z(ESI)=173.2[M+1].

[0499] Step 2

[0500] 4-(6-(methoxycarbonyl)-2-(methyl-d3)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 17c

[0501] tert-butyl 4-(6-(methoxycarbonyl)-2-(methyl-d3)pyridin-3-yl)piperazine-1-carboxylate

[0502] A 50 mL reaction flask was dried and purged with N2. Under N2 conditions, 17b (5 mmol), K2CO3 (15 mmol), piperazine-1-carboxylic acid tert-butyl ester (10 mmol), and 20 mL DMF were added. The mixture was stirred at 120 °C for 12 hours. After the reaction was complete, 100 mL of water was added, and the mixture was extracted three times with EA. The combined organic phases were dried over Na2SO4, and the solvent was removed by rotary evaporation. Compound 17c (white solid, yield 63%) was obtained by chromatography.

[0503] LC-MS m / z(ESI)=339.2[M+1].

[0504] Step 3

[0505] tert-Butyl(R)-4-(2-(methyl-d3)-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate 17d

[0506] tert-butyl(R)-4-(2-(methyl-d3)-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0507] Following the synthetic method of compound 1c, compound 17c (yellow solid, 1.2 g, yield 80%) was obtained.

[0508] LC-MS m / z(ESI)=394.2[M+1].

[0509] Step 4

[0510] (R)-6-(methyl-d3)-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide 17e

[0511] (R)-6-(methyl-d3)-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide

[0512] Following the synthetic method of compound 1d, compound 17e (yellow solid, 1.2 g, yield 80%) was obtained.

[0513] LC-MS m / z(ESI)=294.2[M+1].

[0514] Step 5

[0515] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-6-(methyl-d3)-N-(tetrahydrofuran-3-yl)pyridineamide

[0516] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-(methyl-d3)-N-(tetrahydrofuran-3-yl)picolinamide

[0517] Following the synthetic method of compound 1, compound 17 (yellow solid, 17 g, yield 39%) was obtained.

[0518] 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.41(s,1H),8.38(d,1H),7.80(d,1H),7 .75(s,1H),7.63(s,1H),7.48(d,1H),4.49-4.44(m,1H),3.90–3.79(m,2H),3. 74-3.70(m,1H),3.67(s,2H),3.61-3.58(m,1H),2.96-2.94(m,4H),2.64–2.59 (m,4H),2.57-2.53(m,2H),2.22–2.11(m,1H),2.05–1.84(m,1H),1.18(t,3H).

[0519] LC-MS m / z(ESI)=480.3[M+1].

[0520] Example 18

[0521] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl-d2)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide compound 18

[0522] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d2)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide

[0523]

[0524]

[0525] first step

[0526] 3-Ethyl-7-(hydroxymethyl-d2)-1,5-naphthidium-2(1H)-one 18b

[0527] 3-ethyl-7-(hydroxymethyl-d2)-1,5-naphthyridin-2(1H)-one

[0528] Compound 18a (2.7 g, 9 mmol) was dissolved in tetrahydrofuran (10 mL), and a tetrahydrofuran solution of lithium aluminum tetradeuterium (purchased from Anaiji Chemical, 18 mL, 18 mmol) was slowly added dropwise under an ice-water bath. After the addition was complete, the mixture was stirred for 10 min, and then ethyl acetate (5 mL) was added. The mixture was concentrated under reduced pressure and column chromatography was used to obtain 18b (white solid, 1.2 g, yield 63%).

[0529] LC-MS m / z(ESI)=207.2[M+1].

[0530] Step 2

[0531] 7-(bromomethyl-d2)-3-ethyl-1,5-naphthidium-2(1H)-one 18c

[0532] 7-(bromomethyl-d2)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0533] Compound 18b (430 mg, 2 mmol) and triphenylphosphine (purchased from Shanghai Adamas Reagent Co., Ltd., 2183 mg, 4 mmol) were dissolved in dichloromethane (5 mL). Carbon tetrabromide (purchased from Anaiji Chemical, 1.3 g, 4 mmol) in dichloromethane (2 mL) was added under ice-water bath. The reaction was allowed to proceed for 0.5 h. The reaction solution was concentrated under reduced pressure and then subjected to column chromatography to obtain 18c (white solid, 450 mg, yield 80%).

[0534] LC-MS m / z(ESI)=269.1[M+1].

[0535] Step 3

[0536] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl-d2)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide compound 18

[0537] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d2)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide

[0538] Following the synthetic method of compound 1, compound 18 (white solid, 46 mg, yield 49%) was obtained.

[0539] 1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.43-8.34(m,2H),8.27(d,1H),7.83(d,1H),7.74(d,1H),7.62(d,1H),7.39(dd,1H),4.51-4.3 8(m,1H),3.83(ddd,2H),3.71(td,1H),3.56(dd,1H),3.33(d,3H),2.58-2.50(m,6H),2.14(dtd,1H),1.99-1.85(m,1H),1.18(q,4H).

[0540] LC-MS m / z(ESI)=465.3[M+1].

[0541] Example 19

[0542] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl-d2)piperazin-1-yl)-6-(methyl-d3)-N-(tetrahydrofuran-3-yl)pyridineamide compound 19

[0543] (R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d2)piperazin-1-yl)-6-(methyl-d3)-N-(tetrahydrofuran-3-yl)picolinamide

[0544]

[0545] Following the synthetic method of compound 1, compound 19 (white solid, 28 mg, yield 41%) was obtained.

[0546] 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.41(s,1H),8.38(d,1H),7.80(d,1H ),7.75(s,1H),7.63(s,1H),7.48(d,1H),4.49-4.44(m,1H),3.90–3.79(m, 2H),3.74-3.70(m,1H),3.61-3.58(m,1H),2.96-2.94(m,4H),2.64–2.59(m ,4H),2.57-2.53(m,2H),2.22–2.11(m,1H),2.05–1.84(m,1H),1.18(t,3H).

[0547] LC-MS m / z(ESI)=482.3[M+1].

[0548] Example 20

[0549] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-methylpyridineamide compound 20

[0550] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-methylpicolinamide

[0551]

[0552] first step

[0553] 5-Bromo-6-methylpyridinecarboxylate methyl ester 20b

[0554] methyl 5-bromo-6-methylpicolinate

[0555] 20a (2 g, 9.26 mmol) was dissolved in methanol (20 mL), and then thionyl chloride (20 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction flask was refluxed in an oil bath at 80 °C for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, the pH was adjusted to neutral with saturated sodium carbonate solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried, filtered, and concentrated under reduced pressure to give 20b (yellow solid, 2 g, yield 94%).

[0556] 1 H NMR (400MHz, DMSO-d6) δ8.20(d,1H),7.78(d,1H),3.86(s,3H),2.62(s,3H).

[0557] LC-MS m / z(ESI)=229.90[M+1].

[0558] Step 2

[0559] 4-(6-(methoxycarbonyl)-2-methylpyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 20c

[0560] tert-butyl 4-(6-(methoxycarbonyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate

[0561] 20b (2 g, 8.70 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.78 g, 9.56 mmol), RuPhos Pd G3 (364 mg, 0.44 mmol), and cesium carbonate (11 g, 34.8 mmol) were dissolved in dioxane (40 mL) and refluxed at 110 °C for 4 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried, filtered, concentrated under reduced pressure, and separated by silica gel (200-300 mesh) column chromatography (DCM:EA = 3-1) to give 20c (white solid, 2.2 g, 75% yield).

[0562] LC-MS m / z(ESI)=336.20[M+1].

[0563] Step 3

[0564] 5-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-6-methylpyridinecarboxylic acid 20d

[0565] 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-methylpicolinic acid

[0566] 20c (2.2 g, 6.5 mmol) was dissolved in (tetrahydrofuran:methanol:water = 1:1:1, 20 mL), and lithium hydroxide (0.78 g, 32.7 mmol) was added. The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the organic phase was concentrated under reduced pressure, extracted with ethyl acetate (10 mL * 2), and the aqueous phase was collected. The pH was adjusted to 2-3 with 1 M hydrochloric acid, and the mixture was stirred for 30 minutes. A large amount of solid precipitated, which was filtered, and the filter cake was collected. After drying, 20d (yellow solid, 2 g, yield 95%) was obtained.

[0567] LC-MS m / z(ESI)=322.20[M+1].

[0568] Step 4

[0569] 4-(6-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamoyl)-2-methylpyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 20e

[0570] tert-butyl 4-(6-(((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamoyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate

[0571] Following the synthetic method of compound 2b, compound 20e (white solid, 150 mg, yield 95%) was obtained.

[0572] 1 H NMR(400MHz,DMSO-d6)δ8.31(d,1H),7.82(d,1H),7.50(d,1H),4.25(p,1H),4.22-4.17(m,1H),3.95(dd d,2H),3.64(dd,1H),3.50-3.48(m,4H),3.13-3.07(m,2H),2.89-2.87(m,4H),2.52(s,3H),1.42(s,9H).

[0573] LC-MS m / z(ESI)=407.20[M+1].

[0574] Step 5

[0575] N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-methyl-5-(piperazin-1-yl)pyridineamide 20f

[0576] N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-methyl-5-(piperazin-1-yl)picolinamide

[0577] Following the synthetic method of compound 1d, compound 20f (white solid, 110 mg, yield 97%) was obtained.

[0578] LC-MS m / z(ESI)=307.20[M+1].

[0579] Step 6

[0580] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-methylpyridineamide compound 20

[0581] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-methylpicolinamide

[0582] Following the synthetic method of compound 6, compound 20 (white solid, 40 mg, yield 46%) was synthesized and isolated.

[0583] 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.41(s,1H),8.29(d,1H),7.81(d,1H),7.75(s,1H),7.62(s,1H),7.49(d,1H),5.34(d,1H),4.25–4. 22(m,1H),4.21–4.16(m,1H),3.94(ddd,2H),3.67(s,2H),3.63(dd,1H),3.51(dd,1H),2.96–2.93(m,4H),2.64–2.51(m,9H),1.18(t,3H).

[0584] LC-MS m / z(ESI)=493.20[M+1].

[0585] Example 21

[0586] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(3-methyltetrahydrofuran-3-yl)pyridineamide compound 21

[0587] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(3-methyltetrahydrofuran-3-yl)picolinamide

[0588]

[0589] first step

[0590] 4-(2-Methyl-6-((3-methyltetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 21a

[0591] tert-butyl 4-(2-methyl-6-((3-methyltetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0592] Following the synthetic method of compound 2b, compound 21a (white solid, 140 mg, 90% yield) was obtained.

[0593] 1 H NMR(400MHz,DMSO-d6)δ8.23(s,1H),7.80(d,1H),7.50(d,1H),3.96(d,1H),3.84–3.77(m,2H),3.63(d,1H) ,3.80–3.48(m,4H),2.88–2.86(m,4H),2.52(s,3H),2.40(dt,1H),1.95(dt,1H),1.47(s,3H),1.42(s,9H).

[0594] LC-MS m / z(ESI)=405.20[M+1].

[0595] Step 2

[0596] 6-Methyl-N-(3-methyltetrahydrofuran-3-yl)-5-(piperazin-1-yl)pyridineamide 21b

[0597] 6-methyl-N-(3-methyltetrahydrofuran-3-yl)-5-(piperazin-1-yl)picolinamide

[0598] Following the synthetic method of compound 1d, compound 21b (white solid, 100 mg, yield 95%) was obtained.

[0599] LC-MS m / z(ESI)=305.20[M+1].

[0600] Step 3

[0601] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(3-methyltetrahydrofuran-3-yl)pyridineamide compound 21

[0602] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(3-methyltetrahydrofuran-3-yl)picolinamide

[0603] Following the synthetic method of compound 6, compound 21 (white solid, 35 mg, yield 40%) was synthesized and isolated.

[0604] 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.41(s,1H),8.21(s,1H),7.79(d,1H),7.75(s,1H),7.62(s,1H),7.49(d,1H),3.96(d,1H),3.85–3. 76(m,2H),3.67(s,2H),3.62(d,1H),2.96–2.93(m,4H),2.65–2.51(m ,9H),2.43–2.35(m,1H),2.01–1.90(m,1H),1.47(s,3H),1.18(t,3H).

[0605] LC-MS m / z(ESI)=491.30[M+1].

[0606] Example 22

[0607] N-(3-oxazolylcyclohexane-6-yl)-5-(4-((7-ethyl-6-oxy-5,6-dihydro-1,5-naphthidin-3-yl)methyl)piperazin-1-yl)-6-methylpyridineamide compound 22

[0608] N-(3-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methylpicolinamide

[0609]

[0610] first step

[0611] 4-(6-((3-oxazolylcyclo[3.1.0]hexane-6-yl)carbamoyl)-2-methylpyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 22a

[0612] tert-butyl 4-(6-((3-oxabicyclo[3.1.0]hexan-6-yl)carbamoyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate

[0613] Following the synthetic method of compound 2b, compound 22a (white solid, 110 mg, yield 81%) was obtained.

[0614] 1 H NMR(400MHz,DMSO-d6)δ8.45(d,1H),7.78(d,1H),7.49(d,1H),3.86(s,1H),3.84(s,1H),3.63(s,1H),3.62( s,1H),3.49–2.40(m,4H),2.93–2.84(m,4H),2.60–2.58(m,1H),2.52(s,3H),1.98–1.97(m,2H),1.42(s,9H).

[0615] LC-MS m / z(ESI)=403.20[M+1].

[0616] Step 2

[0617] N-(3-oxeheno[3.1.0]hexane-6-yl)-6-methyl-5-(piperazin-1-yl)pyridineamide 22b

[0618] N-(3-oxabicyclo[3.1.0]hexan-6-yl)-6-methyl-5-(piperazin-1-yl)picolinamide

[0619] Following the synthetic method of compound 1d, compound 22b (white solid, 80 mg, yield 96%) was obtained.

[0620] LC-MS m / z(ESI)=303.20[M+1].

[0621] Step 3

[0622] N-(3-oxazolylcyclohexane-6-yl)-5-(4-((7-ethyl-6-oxy-5,6-dihydro-1,5-naphthidin-3-yl)methyl)piperazin-1-yl)-6-methylpyridineamide compound 22

[0623] N-(3-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methylpicolinamide

[0624] Following the synthetic method of compound 6, compound 22 (white solid, 30 mg, yield 42%) was synthesized and isolated.

[0625] 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.44(d,1H),8.41(s,1H),7.78(d,1H),7.75(s,1H),7.62(s,1H),7.48(d,1H),3. 85(d,2H),3.67(s,2H),3.62(d,2H),2.94–2.91(m,4H),2.61–2.53(m,7H),2.48(s,3H),1.97–1.96(m,2H),1.18(t,3H).

[0626] LC-MS m / z(ESI)=489.20[M+1].

[0627] Example 23

[0628] (R)-6-chloro-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthidin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide compound 23

[0629] (R)-6-chloro-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide

[0630]

[0631] first step

[0632] 5-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-6-chloropyridinecarboxylic acid 23b

[0633] 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloropicolinic acid

[0634] Following the synthesis method of 1c, 23b (white solid, 700 mg, yield 68%) was obtained.

[0635] LC-MS m / z(ESI)=342.1[M+1].

[0636] Step 2

[0637] tert-Butyl(R)-4-(2-chloro-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate 23c

[0638] tert-butyl(R)-4-(2-chloro-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0639] Following the synthesis method of 2b, 23c (white solid, 340 mg, yield 53%) was obtained.

[0640] LC-MS m / z(ESI)=411.2[M+1].

[0641] Step 3

[0642] (R)-6-chloro-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide 23d

[0643] (R)-6-chloro-5-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide

[0644] Following the same synthesis method as 1d, 23d (white solid, 170 mg, yield 67%) was obtained.

[0645] LC-MS m / z(ESI)=311.2[M+1].

[0646] Step 4

[0647] (R)-6-chloro-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthidin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide compound 23

[0648] (R)-6-chloro-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide

[0649] Following the synthetic method of compound 1, compound 23 (white solid, 23 mg, yield 55%) was obtained.

[0650] 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.40(d,2H),7.93(d,1H),7.74(s,1H),7.69–7.55(m,2H),4.45(dt,1H),3.83( ddd,2H),3.74–3.55(m,4H),3.49(t,2H),3.10(t,2H),2.65–2.54(m,6H),2.15(tq,1H),1.93(ddd,1H),1.17(t,3H).

[0651] LC-MS m / z(ESI)=497.2[M+1].

[0652] Example 24

[0653] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(3-methyltetrahydrofuran-3-yl)pyridineamide compound 24

[0654] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(3-methyltetrahydrofuran-3-yl)picolinamide

[0655]

[0656] first step

[0657] 5-Bromo-N-(3-methyltetrahydrofuran-3-yl)pyridineamide 24a

[0658] 5-bromo-N-(3-methyltetrahydrofuran-3-yl)picolinamide

[0659] Following the synthetic method of compound 2b, compound 24a (yellow solid, 1.4 g, yield 71%) was obtained.

[0660] LC-MS m / z(ESI)=286.14[M+1].

[0661] Step 2

[0662] 4-(6-((3-methyltetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 24b

[0663] tert-butyl 4-(6-((3-methyltetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0664] Following the synthetic method of compound 1c, compound 24b (white solid, 1.1 g, 92% yield) was obtained.

[0665] LC-MS m / z(ESI)=390.48[M+1].

[0666] Step 3

[0667] N-(3-Methyltetrahydrofuran-3-yl)-5-(piperazin-1-yl)pyridineamide 24c

[0668] N-(3-methyltetrahydrofuran-3-yl)-5-(piperazin-1-yl)picolinamide

[0669] Following the synthetic method for compound 1d, compound 24c (white solid, 920 mg, yield 89%) was obtained.

[0670] LC-MS m / z(ESI)=291.37[M+1].

[0671] Step 4

[0672] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(3-methyltetrahydrofuran-3-yl)pyridineamide compound 24

[0673] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(3-methyltetrahydrofuran-3-yl)picolinamide

[0674] Following the synthetic method of compound 6, compound 24 (white solid, 27 mg, yield 53%) was obtained.

[0675] LC-MS m / z(ESI)=477.58[M+1].

[0676] Example 25

[0677] N-(2-oxazolylcyclohexane-6-yl)-5-(4-((7-ethyl-6-oxy-5,6-dihydro-1,5-naphthidin-3-yl)methyl)piperazin-1-yl)pyridineamide compound 25

[0678] N-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide

[0679]

[0680] first step

[0681] N-(2-oxazolylcyclo[3.1.0]n-hexane-6-yl)-5-bromopiperidineamide 25a

[0682] N-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-bromopicolinamide

[0683] Following the synthetic method of compound 2b, compound 25a (yellow solid, 1.1 g, yield 74%) was obtained.

[0684] LC-MS m / z(ESI)=284.13[M+1].

[0685] Step 2

[0686] 4-(6-((2-oxazolylcyclo[3.1.0]hexane-6-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 25b

[0687] tert-butyl 4-(6-((2-oxabicyclo[3.1.0]hexan-6-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0688] Following the synthetic method of compound 1c, compound 25b (white solid, 900 mg, yield 91%) was obtained.

[0689] LC-MS m / z(ESI)=389.47[M+1].

[0690] Step 3

[0691] N-(2-oxazolylcyclo[3.1.0]hexane-6-yl)-5-(piperazin-1-yl)pyridineamide 25c

[0692] N-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-(piperazin-1-yl)picolinamide

[0693] Following the synthetic method of compound 1d, compound 25c (white solid, 670 mg, yield 81%) was obtained.

[0694] LC-MS m / z(ESI)=289.35[M+1].

[0695] Step 4

[0696] N-(2-oxazolylcyclohexane-6-yl)-5-(4-((7-ethyl-6-oxy-5,6-dihydro-1,5-naphthidin-3-yl)methyl)piperazin-1-yl)pyridineamide compound 25

[0697] N-(2-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide

[0698] Following the synthetic method of compound 6, compound 25 (white solid, 27 mg, yield 53%) was obtained.

[0699] LC-MS m / z(ESI)=475.57[M+1].

[0700] Example 26

[0701] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)pyridineamide compound 26

[0702] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)picolinamide

[0703]

[0704] first step

[0705] 5-Bromo-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)pyridineamide 26a

[0706] 5-bromo-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)picolinamide

[0707] Following the synthetic method of compound 2b, compound 26a (yellow solid, 1.1 g, yield 76%) was obtained.

[0708] LC-MS m / z(ESI)=288.11[M+1].

[0709] Step 2

[0710] 4-(6-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 26b

[0711] tert-butyl 4-(6-(((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0712] Following the synthetic method of compound 1c, compound 26b (white solid, 900 mg, yield 92%) was obtained.

[0713] LC-MS m / z(ESI)=393.46[M+1].

[0714] Step 3

[0715] N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-5-(piperazin-1-yl)pyridineamide 26c

[0716] N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-5-(piperazin-1-yl)picolinamide

[0717] Following the synthetic method for compound 1d, compound 26c (white solid, 640 mg, yield 89%) was obtained.

[0718] LC-MS m / z(ESI)=293.46[M+1].

[0719] Step 4

[0720] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)pyridineamide compound 26

[0721] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)picolinamide

[0722] Following the synthetic method of compound 6, compound 26 (white solid, 46 mg, yield 42%) was obtained.

[0723] LC-MS m / z(ESI)=479.55[M+1].

[0724] Example 27

[0725] (R)-5-(4-((7-methyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide compound 27

[0726] (R)-5-(4-((7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide

[0727]

[0728] 27a was prepared by using triethyl-2-phosphonopropyl ester instead of triethyl-2-butylpropylene ester according to the synthesis method of intermediate 14 in patent WO2021013735, with LCMS m / s = 253.10 [M+1].

[0729] Compound 27 (white solid, 31 mg, yield: 74%) was prepared according to the method of compound 1.

[0730] 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.50(d,1H),8.40(d,1H),7.83(d,1H),7.85-7.76(m,2H),7.32(d,1H),7.18(d,1H),4.48-4.3 6(m,1H),3.87-3.79(m,2H),3.75–3.63(m,3H),3.56(dd,1H),3.06(s,4H),2.58(s,4H),2.13(d,3H),2.09(d,1H),1.94–1.85(m,1H).

[0731] LCMS m / s = 449.53 [M+1].

[0732] Bioevaluation

[0733] 1. PARP1 and PARP2 activity inhibition assay

[0734] The inhibitory activities of the compounds against PARP1 and PARP2 were detected by chemiluminescence assays (PPAR1: Chemiluminescent assay, purchased from BPS Bioscience, catalog number: 80551) and PARP2: Chemiluminescence assay (PPAR2: Chemiluminescent assay, purchased from BPS Bioscience, catalog number: 80552), respectively. The results were quantified using chemiluminescence, and the specific experimental protocol is as follows:

[0735] (1) Coat the 96-well plate overnight with 1× histone mixture (50 μL / well);

[0736] (2) Discard the coating solution; add 200 μL of blocking buffer 3 to each well and incubate at room temperature for 90 min;

[0737] (3) Discard the blocking solution and wash twice with PBST; add 25 μL of the master mixture (containing 2.5 μL of 10×PARP buffer, 2.5 μL of 10×PARP Assay mixture, 5 μL of activated DNA, and 15 μL of ddH2O), 5 μL of inhibitor (initially 10 μM, diluted 1:5 to 8 concentrations), and 20 μL of enzyme (2 ng / μL); incubate at room temperature for 1 hour.

[0738] (4) Discard the liquid, wash twice with PBST; add 50 μL of streptavidin-HRP blocking buffer 3 (diluted 50 times); incubate at room temperature for 30 min;

[0739] (5) Discard the liquid, wash 3 times with PBST; add 100 μL of ELISA ECL Substrate A / B mixture (50 μL each);

[0740] (6) Microplate reader test results, IC50 analysis was performed using GraphPad Prism 8. 50 The calculation.

[0741] The results show that the compounds of the present invention have significant inhibitory activity against PARP1 and good selectivity relative to PARP2.

[0742] 2. PARP1 / PARP2 trapping experiment:

[0743] 2.1 PARP1 trapping test:

[0744] (1) Prepare a mixture of 4×PARP1 (purchased from BPS Bioscience, catalog number: 80501) and Mabanti GST-Tb (purchased from cisbio, catalog number: 61GSTTLA) using buffer solution, and add 4 μL of the mixture to a 384-well plate (purchased from Greiner, catalog number: 784075);

[0745] (2) Prepare 4×DSB DNA probe-1 (purchased from Generay) with buffer and add 4 μL / well to a 384-well plate;

[0746] (3) Add 4 μL / well of inhibitor to the 384-well plate (initial concentration is 10 μM, diluted 10 times at a ratio of 1:5) and incubate at room temperature for 1 h;

[0747] (4) Prepare 4×NAD with buffer (purchased from Sigma, catalog number: 10127965001), add 4 μL / well to a 384-well plate, and incubate at room temperature for 10 min;

[0748] (5) The results were obtained by TR-FRET detection, curve fitting was performed using GraphPad 5.0, and IC50 was calculated.

[0749] 2.2 PARP2 trapping test:

[0750] (1) Prepare a mixture of 4×PARP2 (purchased from BPS Bioscience, catalog number: 80502) and Mabanti GST-Tb (purchased from cisbio, catalog number: 61GSTTLA) using buffer solution, and add 4 μL of the mixture to a 384-well plate (purchased from G reiner, catalog number: 784075);

[0751] (2) Prepare 4×PARP2probe2 (purchased from Generay) with buffer solution and add 4 μL / well to a 384-well plate;

[0752] (3) Add 4 μL / well of inhibitor to the 384-well plate (initial concentration is 10 μM, diluted 10 times at a ratio of 1:5) and incubate at room temperature for 45 min;

[0753] (4) Prepare 4×NAD with buffer (purchased from Sigma, catalog number: 10127965001), add 4 μL / well to a 384-well plate, and incubate at room temperature for 10 min;

[0754] (5) The results were obtained by TR-FRET detection, curve fitting was performed using GraphPad 5.0, and IC50 was calculated.

[0755]

[0756] Note: Comparative Example 1 is compound 25 of J.Med.Chem (2021), 64(19), 14498–14512, which was obtained according to the preparation method of compound 25.

[0757] The results show that the compounds of the present invention have significant inhibitory activity against PARP1 trapping and good selectivity relative to PARP2 trapping.

[0758] 3. DLD1 BRCA2- / - Cell proliferation inhibition assay

[0759] DLD-1 BRCA2(- / -) cells (purchased from Horizon Discovery Ltd.) were cultured in 1640 medium (10% FBS, 1% PS) at 37°C and 5% CO2. When the cells reached the logarithmic growth phase, they were resuspended and diluted to 15,000 cells / mL with 1640 medium. Using an Echo pipette, 40 nL of the test compound (final concentrations of 10 μM, 2 μM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, and 0.00512 nM) were added to each well of a 384-well PerkinElmer plate; each concentration gradient was performed in duplicate, with control group 1 (containing 0.1% DMSO) and control group 2 (blank medium). Subsequently, 40 μL (600 cells) of cell suspension was added to each well of the 384-well white plate (PerkinElmer) (control group 2 did not add cells).

[0760] The 384-well plates were incubated in a CO2 incubator (37℃, 5% CO2) for 7 days. After incubation, the plates were removed and allowed to stand at room temperature for 30 minutes. 20 μL of Celltiter Glo assay solution was added to each well, and the plates were shaken for 2 minutes and then allowed to stand at room temperature for 30 minutes. The chemiluminescence values ​​were measured using a microplate reader (PerkinElmer; EnVision).

[0761] Curve fitting and IC calculation using GraphPad Prism 8.0 50 The results of the ELISA reader were analyzed using a GraphPad Prism 8 for IC50 analysis. 50 The calculation.

[0762] Compound numbering <![CDATA[IC of DLD1 BRCA2- / - cells 50 (nM)]]> Compound 1 11.61 Compound 2 9.84 Compound 3 5.49 Compound 4 5.38 Compound 6 11.00 Compound 7 10.98

[0763] The results showed that the compound of the present invention had a significant inhibitory effect on the proliferation of DLD1 BRCA2- / - cells.

[0764] 4. MDA-MB-436 cell proliferation inhibition experiment

[0765] MDA-MB-436 cells (supplier ATCC) were cultured in DMEM medium (10% FBS, 1% PS) at 37°C and 5% CO2. When the cells reached the logarithmic growth phase, they were resuspended in DMEM medium and diluted to 1500 cells / ml. 40 μL of the test compound (final concentrations of 10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, and 0.00512 nM) were added to each well of a 384-well plate; each concentration gradient was replicated in duplicate, with control group 1 (containing 0.1% DMSO) and control group 2 (blank medium). Subsequently, 40 μL of cell suspension was added to each well of the 384-well plate (control group 2 did not contain cells).

[0766] The 384-well plates were incubated in an incubator (37℃, 5% CO2) for 7 consecutive days. Then, the plates were removed and allowed to stand at room temperature for 30 minutes. 30 μL of Celltiter Glo assay kit solution was added to each well, and the plates were shaken for 3 minutes and then allowed to stand at room temperature for 30 minutes. The chemiluminescence values ​​were measured using a microplate reader (PerkinElmer; EnVision).

[0767] The detection results were curve-fitted using GraphPad Prism 8 and the IC was calculated. 50 .

[0768] Compound numbering <![CDATA[IC of MDA-MB-436 cells 50 (nM)]]> Compare with Example 2 ＞10000 Compound 1 28.95 Compound 2 10.51 Compound 3 16.41 Compound 4 8.02 Compound 5 19.07 Compound 6 9.81 Compound 7 18.33 Compound 9 35.67 Compound 11 10.68 Compound 12 15.75 Compound 13 37.30 Compound 15 1.83 Compound 20 6.86 Compound 22 39.97 Compound 23 44.83 Compound 25 2.01

[0769] Note: Comparative Example 2 is compound 62 of patent WO200905337, which was obtained according to the preparation method of compound 62.

[0770] The results showed that the compound of the present invention had a significant inhibitory effect on the proliferation of MDA-MB-436 cells.

[0771] This invention specification provides a detailed description of specific embodiments. Those skilled in the art should recognize that the above embodiments are exemplary and should not be construed as limiting the invention. For those skilled in the art, various improvements and modifications can be made to the invention without departing from its principles, and the resulting technical solutions also fall within the scope of protection of the claims of this invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I) in R1 is C 1-6 alkyl; L is -(CR) L1 R L2 ) n -; R L1 R L2 Each independently is H or C 1-6 alkyl; R3 represents H, halogen, or C. 1-6 Alkyl or C 1-6 Alkoxy; R2 is C 1-4 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl; the C 3-8 The heterocyclic alkyl group comprises 1-4 heteroatoms selected from N and O; the C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups are optionally surrounded by one or more molecules selected from hydroxyl and C. 1-4 Alkyl substituents; when R2 is C 1-4 When alkyl, the C 1-4 Alkyl groups are formed by one or more carbon atoms. 1-6 Substitution of alkoxy groups; n is 1; m is 0 or 1; Optionally, the compound of formula (I) is substituted with one or more deuteriums; Formula (I) does not contain the following compounds: 、 、 、 、 、 、 、 、 、 、 。 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (II): Equation (II) in R1 is C 1-6 alkyl; L is -(CR) L1 R L2 ) n -; R L1 R L2 Each independently is H or C 1-6 alkyl; R2 is C 1-4 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl; the C 3-8 The heterocyclic alkyl group comprises 1-4 heteroatoms selected from N and O; the C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups are optionally surrounded by one or more molecules selected from hydroxyl and C. 1-4 Alkyl substituents; when R2 is C 1-4 When alkyl, the C 1-4 Alkyl groups are formed by one or more carbon atoms. 1-6 Substitution of alkoxy groups; n is 1; Optionally, the compound of formula (II) is substituted with one or more deuterium atoms.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is an ethyl group.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is -CH2- or -CD2-.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is H, -CH3, -CD3, -OCH3 or -Cl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is cyclobutyl, oxecyclopentyl, oxecyclohexyl, azircyclobutyl, methyl, ethyl, or propyl; wherein the cyclobutyl, oxecyclopentyl, oxecyclohexyl, azircyclobutyl, methyl, ethyl, or propyl is optionally substituted by one or more substituents selected from methyl and methoxy.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the halogen is F, Cl or Br.

8. A compound or a pharmaceutically acceptable salt thereof, said compound being: , , , , , , , , , , , , , , , , , , , or ; The compound is optionally substituted with one or more deuterium atoms.

9. A pharmaceutical composition comprising: (1) The compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof; (2) Optional one or more other active ingredients; and (3) Drug-acceptable excipients.

10. The pharmaceutical composition of claim 9, wherein the excipient is a carrier.

11. Use of the compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 9 or 10, in the preparation of an antitumor drug, wherein the antitumor drug is an inhibitor of PARP1 and / or PARP2.

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