Pyridine derivatives and their use in medicine

Abstract

The present application relates to compounds of formula (I) and their use in medicine, the compounds being useful in the treatment of tumors

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 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl, the C 3-8 Heterocyclic alkyl groups contain 1 to 4 heteroatoms selected from N, O, and S;

[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 by one or more substituents selected from halogens, hydroxyl groups and cyano groups;

[0010] A is a 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is a 4- to 12-membered monocyclic ring, a 5- to 12-membered spirocyclic ring, a 4- to 12-membered fused ring, or a 4- to 12-membered bridged ring, and the 4- to 12-membered heterocycle contains 1 to 4 heteroatoms selected from N, O, and S;

[0011] R2 represents H and C. 1-6 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 to 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 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;

[0012] n is 1 or 2.

[0013] 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.

[0014] In one or more embodiments, the C 3-8 Heterocyclic alkyl groups or 4 to 12-membered heterocycles contain 1, 2, 3 or 4 heteroatoms selected from N, O and S.

[0015] In one or more embodiments, R1 is

[0016] In one or more embodiments, L is -CH2-, -CH(CH3)-, or -CD2-.

[0017] In one or more embodiments, A is...

[0018] In one or more embodiments, R2 is oxecyclopentyl, oxecyclohexyl, azircyclobutyl, methyl, ethyl, or propyl; wherein the oxecyclopentyl, oxecyclohexyl, azircyclobutyl, methyl, ethyl, or propyl is optionally substituted by one or more substituents selected from methyl, methoxy, and hydroxyl.

[0019] In one or more embodiments, the compound is:

[0020]

[0021] 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.

[0022] In one or more embodiments, the halogen is F, Cl, or Br.

[0023] One or more embodiments of this application provide a pharmaceutical composition comprising:

[0024] (1) The above-mentioned compounds of this application or their pharmaceutically acceptable salts or stereoisomers;

[0025] (2) Optional one or more other active ingredients; and

[0026] (3) Acceptable carriers and / or excipients for the drug.

[0027] One or more embodiments of this application provide compounds of general formula (I') or their stereoisomers:

[0028]

[0029] in:

[0030] 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;

[0031] L is selected from -NH-, -CO-, or -(CR) L1 R L2 ) n -;

[0032] 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;

[0033] 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.

[0034] 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 3-8Heterocyclic 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;

[0035] n is 1 or 2.

[0036] One or more embodiments of this application provide compounds or stereoisomers of the general formula (I”):

[0037]

[0038] in:

[0039] R1 is selected from H, halogens, and 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;

[0040] L is selected from -NH-, -CO-, or -(CR) L1 R L2 ) n -;

[0041] 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;

[0042] 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.

[0043] 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 C1-6 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;

[0044] n is 1 or 2.

[0045] One or more embodiments of this application provide compounds or stereoisomers of the general formula (I”'):

[0046]

[0047] in:

[0048] R1 is selected from C 1-6 alkyl;

[0049] L is selected from -NH-, -CO-, or -(CR) L1 R L2 ) n -;

[0050] 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;

[0051] 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.

[0052] 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, C3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups;

[0053] n is 1 or 2.

[0054] One or more embodiments of this application provide compounds of general formula (II') or their stereoisomers:

[0055]

[0056] in:

[0057] R1 is selected from C 1-6 alkyl;

[0058] L is selected from -NH-, -CO-, or -(CR) L1 R L2 ) n -;

[0059] 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;

[0060] X1 and X2 are each independently selected from CR X Or N;

[0061] R X Selected from H, hydroxyl, cyano or C 1-6 alkyl;

[0062] When X1 and X2 are both N, R a 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;

[0063] 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;

[0064] 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 3-8Heterocyclic 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;

[0065] m can be 1, 2, or 3;

[0066] n is 1 or 2.

[0067] One or more embodiments of this application provide compounds of general formula (III') 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] 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;

[0074] R2 is selected from C5-6 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;

[0075] n is 1 or 2.

[0076] m is 0, 1, 2, or 3

[0077] One or more embodiments of this application provide compounds of general formula (III”) or their stereoisomers:

[0078]

[0079] in:

[0080] R1 is selected from C 1-6 alkyl;

[0081] L is selected from -NH-, -CO-, or -(CR) L1 R L2 ) n -;

[0082] 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;

[0083] 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;

[0084] n is 1 or 2.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0091] The carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I mentioned in the groups and compounds described in this application include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen mentioned in the groups and compounds described in this application 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 15N, 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.

[0092] "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.

[0093] "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.

[0094] "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.

[0095] "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.

[0096] "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.

[0097] "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 ring 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.

[0098] "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 replaced by one or more substituents.

[0099] "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.

[0100] "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.

[0101] "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.

[0102] 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.

[0103] Halogens include F, Cl, Br and I.

[0104] "Pharmaceutical-acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of this application 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.

[0105] "Pharmaceutical composition" means a mixture of one or more compounds described in this application, their pharmaceutically acceptable salts or prodrugs, and other chemical components, wherein "other chemical components" means pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0106] "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.

[0107] "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.

[0108] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0109] "Optional" or "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

[0110] The following embodiments illustrate the technical solutions of this application in detail, but the scope of protection of this application includes, but is not limited to, these embodiments.

[0111] 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).

[0112] MS measurements were performed using Agilent 6120B (ESI) and Agilent 6120B (APCI);

[0113] 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.

[0114] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0115] Example 1

[0116] 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-methylpyridineamide compound 1

[0117] 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0118]

[0119] first step

[0120] 6-Formyl-5-nitronicotinic acid ethyl ester 1b

[0121] ethyl 6-formyl-5-nitronicotinate

[0122] Ethyl 6-methyl-5-nitronicotinic acid 1a (purchased from Jiangsu Aikon Biomedical R&D Co., Ltd., 10 g, 45.6 mmol) and selenium dioxide (7.6 g, 68.4 mmol) were dissolved in dioxane (100 mL) and refluxed at 110 °C for 4 h. After the reaction was complete, the mixture was hot filtered, and the filtrate was concentrated under reduced pressure and column chromatography was performed to obtain compound 1b (yellow solid, 9.7 g, yield 90%).

[0123] LC-MS m / z(ESI)=225.10[M+1].

[0124] Step 2

[0125] 6-(2-bromo-3-ethoxy-3-oxopropane-1-en-1-yl)-5-nitronicotinic acid ethyl ester 1c

[0126] ethyl 6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)-5-nitronicotinate

[0127] Ethyl 2-bromo-2-(diethoxyphosphoryl)ethyl acetate (purchased from Shanghai Mairui Chemical Technology Co., Ltd., 20 g, 66.6 mmol) was dissolved in tetrahydrofuran (100 mL). Sodium hydroxide (1.6 g, 66.6 mmol) was slowly added at -78 °C, and the temperature was slowly raised to 40 °C for 10 min. Then, the temperature was lowered to -78 °C and a tetrahydrofuran solution of 1b (9.7 g, 44.4 mmol) was slowly added dropwise. After reacting for 15 min, a saturated ammonium chloride aqueous solution (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and concentrated under reduced pressure. Column chromatography was used to obtain 1c (yellow solid, 13 g, yield 81%, E / Z = 10:3).

[0128] 1H NMR (400MHz, DMSO-d6) δ9.42(d,1H),9.23(d,0.3H),8.86(d,1H),8.80(d,0.3H),8.61(s,1H),7.89(s,0. 3H),4.46-4.38(m,2.6H),4.34(q,2H),4.16(q,0.6H),1.39-1.34(m,3.9H),1.32(t,3H),1.08(t,0.9H).

[0129] LC-MS m / z(ESI)=373.00[M+1].

[0130] Step 3

[0131] 5-Amino-6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)nicotinic acid ethyl ester 1d

[0132] ethyl 5-amino-6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)nicotinate

[0133] Compound 1c (13 g, 34.8 mmol) was dissolved in acetic acid (130 mL), iron powder (5.8 g, 104.5 mmol) was added, and the reaction was carried out at room temperature for 2 h. The reaction was quenched by adding distilled water (100 mL), and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and concentrated under reduced pressure to give compound 1d (yellow solid, 10 g, yield 83%).

[0134] LC-MS m / z(ESI)=343.00[M+1].

[0135] Step 4

[0136] 1e of ethyl 7-bromo-6-oxo-5,6-dihydro-1,5-naphthyl-3-carboxylate

[0137] ethyl 7-bromo-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate

[0138] Compound 1d (10 g, 29.1 mmol) was placed in a reaction flask, and a solution of hydrogen bromide in acetic acid (100 mL) was added under nitrogen protection. The reaction was carried out at 50 °C for 4 h, and then concentrated under reduced pressure. The reaction was quenched with a saturated sodium bicarbonate aqueous solution (100 mL), extracted with ethyl acetate (50 mL × 3), concentrated under reduced pressure, and column chromatography was used to obtain compound 1e (yellow solid, 2 g, yield 23%).

[0139] 1H NMR (400MHz, DMSO-d6) δ12.54(s,1H),8.88(d,1H),8.51(s,1H),8.14(d,1H),4.37(q,2H),1.35(t,3H).

[0140] LC-MS m / z(ESI)=297.00[M+1].

[0141] Step 5

[0142] 7-Cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyl-3-carboxylic acid ethyl ester 1f

[0143] ethyl 7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate

[0144] Compound 1e (400 mg, 1.3 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (purchased from Chengdu Dingdang Times Pharmaceutical Technology Co., Ltd., 328 mg, 0.40 mmol), potassium carbonate (745 mg, 5.4 mmol), and cyclopropylboronic acid (Hangzhou Aikon Biotechnology Co., Ltd., 231 mg, 2.7 mmol) were dissolved in dioxane (4 mL), refluxed at 110 °C for 8 h, quenched with water (5 mL), extracted with ethyl acetate (5 mL × 3), and purified by concentrated column chromatography under reduced pressure to obtain compound 1f (yellow solid, 270 mg, yield 77%).

[0145] 1 H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.85(d,1H),8.12(d,1H),7.46(s,1H ),4.36(q,2H),2.25-2.12(m,1H),1.34(t,3H),1.02(dt,2H),0.90(dt,2H).

[0146] LC-MS m / z(ESI)=259.10[M+1].

[0147] Step 6

[0148] 1g of 3-cyclopropyl-7-(hydroxymethyl)-1,5-naphthidium-2(1H)-one

[0149] 3-cyclopropyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one

[0150] Compound 1f (270 mg, 1 mmol) was dissolved in tetrahydrofuran (2 mL), and a tetrahydrofuran solution of lithium aluminum hydride (purchased from Anaiji Chemical, 2 mL, 2 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 (1 mL) was added. The mixture was concentrated under reduced pressure and column chromatography was performed to obtain compound 1 g (yellow solid, 100 mg, yield 44%).

[0151] 1 H NMR(400MHz,DMSO-d6)δ11.92(s,1H),8.35(d,1H),7.59(d,1H),7.41(s,1H ),5.45(t,1H),4.60(d,2H),2.16-2.09(m,1H),0.96(dt,2H),0.82(dt,2H).

[0152] LC-MS m / z(ESI)=217.10[M+1].

[0153] Step 7

[0154] 7-(bromomethyl)-3-cyclopropyl-1,5-naphthidium-2(1H)-one 1h

[0155] 7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one

[0156] 1 g (100 mg, 0.46 mmol) of compound and triphenylphosphine (purchased from Shanghai Adamas Reagent Co., Ltd., 242 mg, 0.92 mmol) were dissolved in dichloromethane (1 mL). A solution of carbon tetrabromide (purchased from Anaiji Chemical, 306 mg, 0.92 mmol) in dichloromethane (0.5 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 compound 1 h (yellow solid, 100 mg, yield 78%).

[0157] LC-MS m / z(ESI)=279.00[M+1].

[0158] Step 8

[0159] 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-methylpyridineamide compound 1

[0160] 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0161] Compound 1h (100 mg, 0.36 mmol), N-methyl-5-(piperazin-1-yl)pyridinecarboxamide 1i (Jiangsu Yaoze Pharmaceutical Technology Co., Ltd., 86 mg, 0.39 mmol), and N,N-diisopropylethylamine (230 mg, 1.8 mmol) were dissolved in acetonitrile (4 mL) and reacted at 80 °C for 4 h. The reaction solution was concentrated under reduced pressure and preparatively chromatographically to obtain compound 1 (white solid, 40 mg, yield 27%).

[0162] 1 H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.40(d,1H),8.38(d,1H),8.26(d,1H),7.82(d,1H),7.60(d,1H),7.42(s,1H),7.38(dd, 1H),3.63(s,2H),2.34-3.31(s,4H),2.77(d,3H),2.56-2.53(d,4H),2.19-2.09(m,1H),0.99-0.91(m,2H),0.84-0.76(m,2H).

[0163] LC-MS m / z(ESI)=419.20[M+1].

[0164] Example 2

[0165] (R)-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthidin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide compound 2

[0166] (R)-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide

[0167]

[0168] Compound 2a (22.08 mg, 0.08 mmol) and compound 1h (22.32 mg, 0.08 mmol) were dissolved in acetonitrile (5 mL), and N,N-diisopropylethylamine (purchased from Shanghai Maclean Biochemical Technology Co., Ltd., 51.7 mg, 0.4 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 2 (white solid, 26 mg, yield 71%).

[0169] 1 H NMR(400MHz,DMSO-d6)δ12.13(s,1H),8.38(d,2H),8.27(s,1H),7.83(d,1H) ,7.60(s,1H),7.40(d,2H),4.47-4.42(m,1H),3.87-3.79(m,2H),3.73-3.68( m,1H),3.63(s,2H),3.59-3.55(m,1H),3.43-3.37(m,4H),2.56-2.54(m,4H) ,2.17-2.09(m,2H),1.97-1.91(m,1H),0.99-0.93(m,2H),0.82-0.80(m,2H).

[0170] LC-MS m / z(ESI)=475.24[M+1].

[0171] Example 3

[0172] 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxyethyl)pyridineamide compound 3

[0173] 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxyethyl)picolinamide

[0174]

[0175] Following the same synthetic method as compound 2, compound 3 (white solid, 31 mg, yield 76%) was obtained.

[0176] 1H NMR(400MHz,DMSO-d6)δ11.90(s,1H),8.41-8.33(m,2H),8.28(d,1H),7.83(d,1H),7.60(d,1H),7.42(s,1H),7.41-7.38(m,1H),4.79(t,1H) ,3.63(s,2H),3.49(q,2H),3.37-3.35(m,2H),3.34-3.32(m,4H),2.56 -2.53(m,4H),2.18-2.12(m,1H),1.01-0.93(m,2H),0.85-0.80(m,2H).

[0177] LC-MS m / z(ESI)=449.22[M+1].

[0178] Example 4

[0179] 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)pyridineamide compound 4

[0180] 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)picolinamide

[0181]

[0182] Following the same synthetic method as compound 2, compound 4 (white solid, 28 mg, yield 74%) was obtained.

[0183] 1 H NMR(400MHz,DMSO-d6)δ11.90(s,1H),8.36(d,2H),8.28(d,1H),7.83(d,1H),7.60(s,1H),7.45-7.37(m,2H),3.63(s,2H),3.46-3.4 2(m,4H),3.39-3.35(t,2H),3.33-3.10(m,2H),3.26(s,3H),2.56-2.53(m,4H),2.18-2.11(m,1H),0.99-0.94(m,2H),0.85-0.79(m, 2H).

[0184] LC-MS m / z(ESI)=463.24[M+1].

[0185] Example 5

[0186] (R)-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthidin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)pyridineamide compound 5

[0187] (R)-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide

[0188]

[0189] Following the same synthetic method as compound 2, compound 5 (white solid, 29 mg, yield 76%) was obtained.

[0190] 1 H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.41–8.34(m,2H),7.80(d,1H),7.60(s,1 H),7.48(d,1H),7.42(s,1H),4.50-4.42(m,1H),3.92–3.77(m,2H),3.74-3.70(m ,1H),3.66(s,2H),3.59(dd,1H),2.96-2.93(m,4H),2.60-2.56(m,4H),2.51(s, 3H),2.22–2.10(m,2H),1.97-1.89(m,1H),0.99-0.94(m,2H),0.85–0.79(m,2H).

[0191] LC-MS m / z(ESI)=489.25[M+1].

[0192] Example 6

[0193] (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 6

[0194] (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

[0195]

[0196]

[0197] first step

[0198] 3-Cyclopropyl-7-(hydroxymethyl-d2)-1,5-naphthidium-2(1H)-one 6a

[0199] 3-cyclopropyl-7-(hydroxymethyl-d2)-1,5-naphthyridin-2(1H)-one

[0200] Following the same synthesis method as 1g, lithium aluminum tetradeuterium was used instead of lithium aluminum tetrahydrogen to obtain 6a (white solid, 700g, yield 58%).

[0201] LC-MS m / z(ESI)=219.1[M+1].

[0202] Step 2

[0203] 7-(bromomethyl-d2)-3-cyclopropyl-1,5-naphthidium-2(1H)-one 6b

[0204] 7-(bromomethyl-d2)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one

[0205] Following the 1h synthesis method, 6b (white solid, 310 mg, yield 69%) was obtained.

[0206] LC-MS m / z(ESI)=281.1[M+1].

[0207] Step 3

[0208] (R)-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthidin-3-yl)methyl-d2)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyridineamide compound 6

[0209] (R)-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d2)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide

[0210] Following the same synthetic method as compound 2, compound 6 (white solid, 26 mg, yield 49%) was obtained.

[0211] 1 H NMR(400MHz,DMSO-d6)δ12.13(s,1H),8.38(d,2H),8.27(s,1H),7.83(d, 1H),7.60(s,1H),7.40(d,2H),4.47-4.42(m,1H),3.87-3.79(m,2H),3.73 -3.68(m,1H),3.59-3.55(m,1H),3.43-3.37(m,4H),2.56-2.54(m,4H),2. 17-2.09(m,2H),1.97-1.91(m,1H),0.99-0.93(m,2H),0.82-0.80(m,2H).

[0212] LC-MS m / z(ESI)=477.2[M+1].

[0213] Bioevaluation

[0214] 1. PARP1 and PARP2 activity inhibition assay

[0215] 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:

[0216] (1) Coat the 96-well plate overnight with 1× histone mixture (50 μL / well);

[0217] (2) Discard the coating solution; add 200 μL of blocking buffer 3 to each well and incubate at room temperature for 90 min;

[0218] (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.

[0219] (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;

[0220] (5) Discard the liquid, wash 3 times with PBST; add 100 μL of ELISA ECL Substrate A / B mixture (50 μL each);

[0221] (6) Microplate reader test results, IC50 analysis was performed using GraphPad Prism 8. 50 The calculation.

[0222] The results showed that the compound of this application has significant inhibitory activity against PARP1 and good selectivity relative to PARP2.

[0223] 2. PARP1 / PARP2 trapping experiment:

[0224] 2.1 PARP1 trapping test:

[0225] (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);

[0226] (2) Prepare 4×DSB DNA probe-1 (purchased from Generay) with buffer and add 4 μL / well to a 384-well plate;

[0227] (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;

[0228] (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;

[0229] (5) The results were obtained by TR-FRET detection, curve fitting was performed using GraphPad 5.0, and IC50 was calculated.

[0230] 2.2 PARP2 trapping test:

[0231] (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 Greiner, catalog number: 784075);

[0232] (2) Prepare 4×PARP2probe2 (purchased from Generay) with buffer solution and add 4 μL / well to a 384-well plate;

[0233] (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;

[0234] (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;

[0235] (5) The results were obtained by TR-FRET detection, curve fitting was performed using GraphPad 5.0, and IC50 was calculated.

[0236]

[0237] 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.

[0238] The results show that the compound of this application has significant inhibitory activity against PARP1 trapping and good selectivity relative to PARP2 trapping.

[0239] 3. DLD1 BRCA2- / - Cell proliferation inhibition assay

[0240] 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).

[0241] 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).

[0242] 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.

[0243] Compound 1 2.00

[0244] The results showed that the compound of this application had a significant inhibitory effect on the proliferation of DLD1 BRCA2- / - cells.

[0245] 4. MDA-MB-436 cell proliferation inhibition experiment

[0246] 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).

[0247] 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).

[0248] The detection results were curve-fitted using GraphPad Prism 8 and the IC was calculated. 50 .

[0249] Compare with Example 2 ＞10000 Compound 1 4.96 Compound 4 24.68

[0250] Note: Comparative Example 2 is compound 62 of patent WO200905337, which was obtained according to the preparation method of compound 62.

[0251] The results showed that the compound of this application had a significant inhibitory effect on the proliferation of MDA-MB-436 cells.

[0252] 5. Pharmacokinetics in mice

[0253] (1) Experimental animals: ICR male rats, 5-6 weeks old, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0254] (2) Preparation of test substance: Accurately weigh appropriate amounts of reference example 1 and compound 1, and prepare a 0.3 mg / mL clear solution. The solvent is 5% DMSO + 30% HP-β-CD.

[0255] (3) Animal drug administration and blood collection: Each mouse was administered 3 mg / kg by gavage to control example 1 and compound 1, respectively, with 3 mice in each group. Blood was collected at 10 time points: before drug administration (0 h), 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after drug administration, with 0.1 mL of blood collected through the orbital venous plexus. The blood samples were centrifuged at 2000g for 10 min at 4℃, and the plasma was collected for subsequent testing.

[0256] (4) The concentration of the original drug in plasma was determined by LC-MS / MS, and the main pharmacokinetic parameters were calculated using the Winnolin 8.2 non-compartmental model.

[0257]

[0258] 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.

[0259] The results showed that the compound of this application exhibited significantly better pharmacokinetic characteristics than the control in mice.

[0260] This application specification provides a detailed description of specific implementation schemes. Those skilled in the art should recognize that the above implementation schemes are exemplary and should not be construed as limiting this application. For those skilled in the art, without departing from the principles of this application, several improvements and modifications can be made to this application, and the resulting technical solutions also fall within the protection scope of the claims of this application.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: (I) in: R1 is ; L stands for -CH2-; A is ; R2 is methyl, ethyl, or propyl; Optionally, the compound of formula (I) is substituted with one or more deuterium atoms.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is an ethyl group.

3. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: Optionally, the compound is substituted with one or more deuterium atoms.

4. A pharmaceutical composition comprising: (1) The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof; (2) Optional one or more other active ingredients; and (3) Acceptable carriers and / or excipients for the drug.

5. Use of the compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 4, in the preparation of an antitumor drug.

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