A selective parp1 inhibitor and uses thereof

Abstract

A selective parp1 inhibitor and uses thereof

Description

Technical Field

[0001] This invention relates to a selective PARP1 inhibitor or its stereoisomer and its pharmaceutical applications. Background Technology

[0002] PARPs (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 / 2 inhibitors have been successfully marketed, they still commonly cause hematological and gastrointestinal side effects, 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 / 2 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] The purpose of this invention is to provide a selective PARP1 inhibitor or its stereoisomers, pharmaceutical compositions thereof, and their pharmaceutical applications.

[0004] This invention provides a compound of general formula (I) or its stereoisomer:

[0005]

[0006] in:

[0007] A is

[0008] R a0 Selected from halogens, C 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group, the C 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, 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;

[0009] R a1 Selected from H, halogen or C1-6 Alkyl, the C 1-6 Alkyl groups may optionally be further selected from one or more halogens or C 1-6 Alkyl substituents;

[0010] L a1 L a2 L a3 Each is independently N or CR L ;

[0011] R L Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0012] L is selected from -NH-, -CO-, or -(CR1R2). n -;

[0013] R1 and R2 are each 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;

[0014] B 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. The 4- to 12-membered heterocycle may contain 1 to 4 heteroatoms selected from N, O, or S, and may optionally be further divided by one or more R atoms. b replace;

[0015] R b Selected from H, hydroxyl, cyano 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;

[0016] Or, any two R b It can form 3 to 8-membered rings;

[0017] C is

[0018] X1, X2, and X3 are each independently selected from CH or N. When X1 or X2 is CH, it can be optionally further substituted with a halogen. When X3 is selected from N, X1 and X2 cannot be CH at the same time.

[0019] R3 and R4 are each independently selected from H, halogen, cyano, or C. 1-6 alkyl;

[0020] Rc Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups may optionally be further distinguished by one or more groups selected from D, halogen, hydroxyl, cyano, NR. c1 R c2 C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups;

[0021] R c1 R c2 Each is independently selected from H or C 1-6 alkyl;

[0022] n is 1 or 2;

[0023] The conditions are:

[0024] The compound represented by general formula (I) is not

[0025] The compound of general formula (I) may optionally be further substituted with one or more deuterium atoms.

[0026] This invention provides a compound or a stereoisomer thereof, wherein the compound is selected from compounds represented by general formula (II) or stereoisomers thereof:

[0027]

[0028] in:

[0029] R a0 Selected from halogens, C 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group, the C 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, 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;

[0030] R a1Selected from H, halogen or C 1-6 Alkyl, the C 1-6 Alkyl groups may optionally be further selected from one or more halogens or C 1-6 Alkyl substituents;

[0031] Z1 and Z2 are each independently N or CR L ;

[0032] R L Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0033] L is selected from -NH-, -CO-, or -(CR1R2). n -;

[0034] R1 and R2 are each 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;

[0035] B 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. The 4- to 12-membered heterocycle may contain 1 to 4 heteroatoms selected from N, O, or S, and may optionally be further divided by one or more R atoms. b replace;

[0036] R b Selected from H, hydroxyl, cyano 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;

[0037] Or, any two R b It can form 3 to 8-membered rings;

[0038] C is

[0039] X1, X2, and X3 are each independently selected from CH or N. When X1 or X2 is CH, it can be optionally further substituted with a halogen. When X3 is selected from N, X1 and X2 cannot be CH at the same time.

[0040] R3 and R4 are each independently selected from H, halogen, cyano, or C. 1-6 alkyl;

[0041] R c Selected from H, C 1-6 Alkyl, C1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups may optionally be further distinguished by one or more groups selected from D, halogen, hydroxyl, cyano, NR. c1 R c2 C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups;

[0042] R c1 R c2 Each is independently selected from H or C 1-6 alkyl;

[0043] n is 1 or 2;

[0044] The compound of general formula (II) may optionally be further substituted with one or more deuterium atoms.

[0045] The compounds or stereoisomers thereof provided by this invention:

[0046] in:

[0047] A is

[0048] R a0 Selected from C 1-6 Alkyl, C 3-8 cycloalkyl or C 2-6 alkenyl, the C 1-6 Alkyl, C 3-8 cycloalkyl or C 2-6 The alkenyl group may optionally be further selected by one or more elements chosen from halogens or C. 1-6 Alkyl substituents;

[0049] L a1 L a2 L a3 Each is independently N or CR L ;

[0050] R L Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0051] L is -(CR1R2) n -;

[0052] R1 and R2 are each 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;

[0053] B 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. The 4- to 12-membered heterocycle may contain 1 to 4 heteroatoms selected from N, O, or S, and may optionally be further divided by one or more R atoms. b replace;

[0054] R b For 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 halogens or cyano groups;

[0055] Or, any two R b It can form 3 to 8-membered rings;

[0056] C is

[0057] X1, X2, and X3 are each independently selected from CH or N. When X1 or X2 is CH, it can be optionally further substituted with a halogen. When X3 is selected from N, X1 and X2 cannot be CH at the same time.

[0058] R3 and R4 are each independently selected from H, halogen, cyano, or C. 1-6 alkyl;

[0059] R c Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups may optionally be further surrounded by one or more elements selected from D, halogen, hydroxyl, and NR. c1 R c2 C 1-6 Alkyl or C 3-8 Substituents of heterocyclic alkyl groups;

[0060] R c1 R c2 Each is independently selected from H or C 1-6 alkyl;

[0061] n is 1 or 2;

[0062] The conditions are:

[0063] The compound represented by general formula (I) is not

[0064] The compound may optionally be further substituted with one or more deuterium atoms.

[0065] The compound or its stereoisomer provided by this invention:

[0066] in:

[0067] A is

[0068] R a0 Selected from C 1-6 Alkyl, C 3-8 cycloalkyl or C 2-6 alkenyl, the C 1-6 Alkyl, C 3-8 cycloalkyl or C 2-6 The alkenyl group may optionally be further selected by one or more elements chosen from halogens or C. 1-6 Alkyl substituents;

[0069] L a1 L a2 L a3 Each can be independently represented as CH or N;

[0070] L is -(CR1R2) n -;

[0071] R1 and R2 are each independently H or C. 1-6 alkyl;

[0072] B 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. The 4- to 12-membered heterocycle may contain 1 to 4 heteroatoms selected from N, O, or S, and may optionally be further divided by one or more R atoms. b replace;

[0073] R b For 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 halogens or cyano groups;

[0074] Or, any two R b It can form 3 to 8-membered rings;

[0075] C is

[0076] X1, X2, and X3 are each independently selected from CH or N. When X1 or X2 is CH, it can be optionally further substituted with a halogen. When X3 is selected from N, X1 and X2 cannot be CH at the same time.

[0077] R3 and R4 are each independently selected from H, halogen, cyano, or C. 1-6 alkyl;

[0078] R c Selected from H, C 1-6 Alkyl or C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be further selected from D, halogen or C. 1-6 Alkyl substituents;

[0079] n is 1 or 2;

[0080] The conditions are:

[0081] The compound represented by general formula (I) is not

[0082] The compound may optionally be further substituted with one or more deuterium atoms.

[0083] The compound or stereoisomer provided by this invention is selected from compounds or stereoisomers of general formula (III):

[0084]

[0085] Ra2 is C 1-6 Alkyl or C 3-8 cycloalkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens;

[0086] R d Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or C 3-8 Heterocyclic alkyl groups may optionally be further surrounded by one or more elements selected from D, halogen, hydroxyl, or C. 1-6 Alkyl substituents;

[0087] The compound represented by general formula (III) may optionally be further substituted with one or more deuterium atoms.

[0088] The compounds or stereoisomers thereof described in this invention are selected from compounds represented by general formula (IV) or their stereoisomers:

[0089]

[0090] Ra3 is C 1-6 Alkyl or C 3-8 cycloalkyl;

[0091] R e Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 The heterocyclic alkyl group may optionally be further substituted with one or more substituents selected from hydroxyl groups;

[0092] The compound represented by general formula (IV) may optionally be further substituted with one or more deuterium atoms.

[0093] The compound or its stereoisomer provided by this invention:

[0094] in:

[0095] A is

[0096] R a0 C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens;

[0097] L a1 L a2 L a3 Each can be independently represented as CH or N;

[0098] L is -(CR1R2) n -;

[0099] R1 and R2 are each independently H or C. 1-3 alkyl;

[0100] B is

[0101] C is

[0102] R b For 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 halogens or cyano groups;

[0103] Or, any two R b It can form 3 to 8-membered rings;

[0104] R c For H or C 1-6 alkyl;

[0105] n is 1 or 2;

[0106] m is 0, 1, or 2;

[0107] The compound may optionally be further substituted with one or more deuterium atoms.

[0108] The compounds or stereoisomers thereof provided by this invention are selected from:

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115] The compound may optionally be further substituted with one or more deuterium atoms.

[0116] One or more embodiments of the present invention provide a pharmaceutical composition comprising:

[0117] (1) The compound or its stereoisomer of the present invention;

[0118] (2) One or more other active ingredients selected by choice; and

[0119] (3) Pharmaceutically acceptable carriers and / or excipients.

[0120] One or more embodiments of the present invention provide the use of the compounds of the present invention or their stereoisomers or pharmaceutical compositions thereof in the preparation of a medicament for treating cancer.

[0121] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0122] 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.

[0123] "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, 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 various branched isomers thereof; when the alkyl group is substituented, it may optionally be further substituted by one or more substituents.

[0124] "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.

[0125] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which can be a 3- to 10-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 20-membered polycyclic system, preferably with 3 to 10 carbon atoms, and more preferably 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 substituted, it may optionally be further substituted with 0 or more substituents.

[0126] "Heterocyclic alkyl" refers to a substituted or unsubstituted saturated non-aromatic cyclic group, which can be a 3- to 8-membered monocyclic, 4- to 12-membered bicyclic, or 10- to 15-membered tricyclic system, and contains 1 to 3 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. The selectively substituted N or S 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 epoxyethyl, aziridine, oxacyclobutyl, aziridine, 1,3-dioxolanecycloyl, 1,4-dioxolanecycloyl, 1,3-dioxahexacycloyl, aziridine, 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.

[0127] "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.

[0128] "Alynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing 1 to 3 carbon-carbon triple bonds and composed of 2 to 20 carbon atoms, preferably an alkynyl group with 2 to 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, pentyne-1-yl, pentyne-2-yl, hexyn-1-yl, 1-heptyne-1-yl, heptyne-3-yl, heptyne-4-yl, octyne-3-yl, nonyne-3-yl, decantyne-4-yl, undecyn-3-yl, and dodecanyne-4-yl. The alkynyl group may optionally be further substituted by 0 to 4 substituents selected from F, Cl, Br, I, alkyl, alkoxy, straight-chain alkenyl, straight-chain alkynyl, amino, nitro, cyano, mercapto, amide, carbocyclic or heterocyclic groups.

[0129] "Heterocycle" or "heterocyclic group" 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 that 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 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms selectively substituted 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 fused ring, a bridged ring, or a spirocycle. The "heterocyclic group" or "heterocycle" may optionally be further substituted by one or more substituents.

[0130] When the terms "alkyl", "alkoxy", "alkenyl", "alkynyl", "heterocyclic", "heterocyclic", "cycloalkyl" or "heterocyclic alkyl" mentioned above are substituted, they may optionally 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 R q5 =NR q6 -C(=O)OC 1-6 Alkyl group, -OC (=O)C 1-6Alkyl, -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 it may be replaced by a =O substituent; Rq 1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; Rq 2 、Rq 3 Selected from H or C 1-6 Alkyl; Rq 4 Rq5 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, wherein the ring may contain one or more heteroatoms selected from N, O or S.

[0131] "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.

[0132] "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.

[0133] "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.

[0134] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0135] "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

[0136] 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.

[0137] 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).

[0138] MS measurements were performed using Agilent 6120B (ESI) and Agilent 6120B (APCI);

[0139] 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.

[0140] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0141] Intermediate 1

[0142] 2-Fluoro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 1

[0143] 2-fluoro-N-methyl-4-(piperazin-1-yl)benzamide

[0144]

[0145] first step:

[0146] 4-(3-fluoro-4-(methylcarbamoyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 1c

[0147] tert-butyl 4-(3-fluoro-4-(methylcarbamoyl)phenyl)piperazine-1-carboxylate

[0148] Dissolve 1a (2 g, 8.62 mmol) and 1b (1.77 g, 9.48 mmol) in 15 mL of toluene, then add palladium acetate (194 mg, 0.86 mmol) and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (537 mg, 0.86 mmol). After the addition is complete, the reaction is carried out under nitrogen protection at 120 °C for 16 h. After the reaction is complete, 20 mL of water and ethyl acetate (3 × 30 mL) are added for extraction three times. The organic phase is collected, concentrated under reduced pressure, and then purified by column chromatography (PE:EA = 2:1-1:2) to obtain crude product 1c. Step 2:

[0149] 2-Fluoro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 1

[0150] 2-fluoro-N-methyl-4-(piperazin-1-yl)benzamide

[0151] Add 1c to 15 mL of 1,4-dioxane hydrochloric acid solution (4 M), stir and react at room temperature for 16 h. After the reaction is complete, filter the reaction system and collect the filter cake to obtain intermediate 1 (white solid, 1.4 g, yield 69%).

[0152] 1 H NMR(400MHz,DMSO-d6)δ9.67(dr s,1H),8.58(dr s,1H),7.81(t,J=8.6Hz,1H),7.12-6.93(m,2H),3.60-3.56(m,4H),2.97(d,J=2.6Hz,3H),3.12-3.09(m,4H).

[0153] LCMSm / s = 238.30 [M+1].

[0154] Intermediate 2

[0155] 7-(bromomethyl)-3-ethyl-1,5-naphthidine-2(1H)-one intermediate 2

[0156] 7-(bromomethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0157]

[0158] Intermediate 2 was prepared according to the synthesis method of intermediate 14 in patent WO2021013735, m / z(ES) + [M] + =267.

[0159] Intermediate 3

[0160] 2-Fluoro-N-(methyl-d3)-4-(piperazin-1-yl)benzamide intermediate 3

[0161] 2-fluoro-N-(methyl-d3)-4-(piperazin-1-yl)benzamide

[0162]

[0163] Following the preparation method of intermediate 1, intermediate 3 (white solid, 1.5 g, yield 75%) was obtained.

[0164] 1 H NMR(400MHz,DMSO-d6)δ9.54(dr s,1H),7.83(d,J=4.8Hz,1H),7.59(t,J=8.8Hz,1H),6.87–6.85(m,1H),6.83(s,1H),3.60–3.45(m,4H),3.18–3.13(m,4H).

[0165] LCMSm / s = 241.20 [M+1].

[0166] Intermediate 4

[0167] 2-Fluoro-4-(piperazin-1-yl)benzamide intermediate 4

[0168] 2-fluoro-4-(piperazin-1-yl)benzamide

[0169]

[0170] Following the preparation method of intermediate 1, intermediate 4 (white solid, 1.4 g, yield 70%) was obtained.

[0171] 1 H NMR (400MHz, DMSO-d6) δ9.85 (dr s, 2H), 7.90 (t, J = 8.9Hz, 1H), 7.33-7.03 (m, 2H), 6.85 (s, 1H), 3.84-3.68 (m, 4H), 3.28-3.19 (m, 4H).

[0172] LCMSm / s = 224.10 [M+1].

[0173] Intermediate 5

[0174] 2-Chloro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 5

[0175] 2-chloro-N-methyl-4-(piperazin-1-yl)benzamide

[0176]

[0177] Following the preparation method of intermediate 1, intermediate 5 (white solid, 1.5 g, yield 73%) was obtained.

[0178] LCMSm / s = 254.10 [M+1].

[0179] Intermediate 6

[0180] 4-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-2-fluoro-N-methylbenzamide intermediate 6

[0181] 4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-fluoro-N-methylbenzamide

[0182]

[0183] Following the preparation method of intermediate 1, intermediate 6 (white solid, 1.4 g, yield 86%) was obtained.

[0184] 1 H NMR(400MHz,DMSO-d6)δ9.45(dr s,1H),8.33(dr s,1H),7.62(t,J=9.0Hz,1H),6.62-6.59(m,1H),6.58–6.51(m,1H),3.65-3.62(m,2H),3.45- 3.39(m,2H),3.31-3.28(m,2H),2.75(d,J=4.5Hz,3H),2.58–2.52(m,1H),1.47-1.44(m,1H).

[0185] LCMSm / s = 250.1 [M+1].

[0186] Intermediate 7

[0187] N-Cyclopropyl-2-fluoro-4-(piperazin-1-yl)benzamide intermediate 7

[0188] N-cyclopropyl-2-fluoro-4-(piperazin-1-yl)benzamide

[0189]

[0190] Following the preparation method of intermediate 1, intermediate 7 (brown solid, 1.4 g, yield 81%) was obtained.

[0191] 1 H NMR(400MHz,DMSO-d6)δ9.73(dr s,1H),8.69(dr s,1H),7.95(t,J=8.4Hz,1H),7.64-7.28(m,2H),3.56-3.50(m,4H),2.8 1-2.77(m,1H),3.18-3.15(m,4H),0.68-0.64(m,2H),0.56-0.51(m,2H).

[0192] LCMSm / s = 264.1 [M+1].

[0193] Intermediate 8

[0194] 3-Fluoro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 8

[0195] 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide

[0196]

[0197] Following the preparation method of intermediate 1, intermediate 8 (white solid, 1.2 g, yield 85%) was obtained.

[0198] 1 H NMR (400MHz, DMSO-d6) δ9.56 (s, 1H), 8.50 (d, J = 3.1Hz, 1H), 7.67 (s, 1H), 7.63 (s, 1H) ,7.13(t,J=8.7Hz,1H),4.42-4.36(m,4H),3.23-3.18(m,4H),2.75(d,J=3.1Hz,3H).

[0199] LCMSm / s = 238.1 [M+1].

[0200] Intermediate 9

[0201] (R)-2-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide intermediate 9

[0202] (R)-2-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide

[0203]

[0204] Following the preparation method of intermediate 1, intermediate 9 (white solid, 2.1 g, yield 87%) was obtained.

[0205] 1 H NMR (400MHz, DMSO-d6) δ9.56(s,1H),8.07(dd,J=7.0,2.9Hz,1H),7.90(dd,J=8.0,4.6Hz,1H),7.55(dt,J=21.6,9.0Hz,2H),4.25(t,J=6.7H z,1H),3.84-3.77(m,2H),3.76-3.64(m,4H),3.52(d,J=4.5Hz,4H),3.48(t,J=6.3Hz,2H),2.12(dq,J=12.8,7.7Hz,1H),1.93-1.81(m,1H).

[0206] LCMSm / s = 294.3 [M+1].

[0207] Intermediate 10

[0208] (S)-2-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide intermediate 10

[0209] (S)-2-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide

[0210]

[0211]

[0212] Following the preparation method of intermediate 1, intermediate 10 (white solid, 1.7 g, yield 89%) was obtained.

[0213] 1 H NMR (400MHz, DMSO-d6) δ9.54(s,1H),8.06(dd,J=7.0,2.9Hz,1H),7.90(dd,J=8.0,4.6Hz,1H),7.54(dt,J=21.6,9.0Hz,2H),4.24(t,J=6.7H z,1H),3.82-3.74(m,2H),3.77-3.66(m,4H),3.52(d,J=4.5Hz,4H),3.48(t,J=6.3Hz,2H),2.11(dq,J=12.8,7.7Hz,1H),1.92-1.80(m,1H).

[0214] LCMSm / s = 294.3 [M+1].

[0215] Intermediate 11

[0216] 4-(3,6-diazabicyclo[3.1.1]heptane-6-yl)-2-fluoro-N-methylbenzamide intermediate 11

[0217] 4-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-fluoro-N-methylbenzamide

[0218]

[0219] Following the preparation method of intermediate 1, intermediate 11 (white solid, 1.2 g, yield 70%) was obtained.

[0220] 1 H NMR(400MHz,DMSO-d6)δ9.46(dr,1H),8.35(dr,1H),7.65(m,1H),6.62-6.58(m,1H),6.43–6.40(m,1H),4.3 8-4.33(m,2H),3.81–3.64(m,2H),3.31-3.21(M,2H),2.73(d,3H),2.67–2.59(m,1H),1.55(d,J=8.7Hz,1H).

[0221] LCMSm / s = 250.10 [M+1].

[0222] Intermediate 12

[0223] 2-Chloro-6-fluoro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 12

[0224] 3-2-chloro-6-fluoro-N-methyl-4-(piperazin-1-yl)benzamide

[0225]

[0226] Following the preparation method of intermediate 1, intermediate 12 (yellow solid, 630 mg, yield 83%) was obtained.

[0227] 1H NMR (400MHz, DMSO-d6) δ9.57(s,1H),8.42(q,J=4.6Hz,1H),6.91-6.86(m,2H),3.57–3.48(m,4H),3.18-3.05(m,4H),2.72(d,J=4.6Hz,3H).

[0228] LCMSm / s = 272.1 [M+1]

[0229] Intermediate 13

[0230] 2,3,5,6-Tetrafluoro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 13

[0231] 2,3,5,6-tetrafluoro-N-methyl-4-(piperazin-1-yl)benzamide

[0232]

[0233] Following the preparation method of intermediate 1, intermediate 13 (yellow solid, 91 mg, yield 31%) was obtained.

[0234] 1 H NMR (400MHz, DMSO-d6) δ9.57(s,1H),8.69(q,J=4.8Hz,1H),3.45-3.43(m,2H),3.20-3.17(m,2H),2.96-2.94(m,4H),1.43(d,J=4.8Hz,3H).

[0235] LCMSm / s = 292.1 [M+1].

[0236] Intermediate 14

[0237] 3-Bromo-2,5,6-trifluoro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 14

[0238] 3-bromo-2,5,6-trifluoro-N-methyl-4-(piperazin-1-yl)benzamide

[0239]

[0240] Intermediate 14 (yellow solid, 187 mg, yield 63%) was obtained according to the preparation method of intermediate 1.

[0241] 1H NMR (400MHz, DMSO-d6) δ9.57 (s, 1H), 8.51 (q, J = 4.8Hz, 1H), 2.96-2.94 (m, 4H), 2.79-2.76 (m, 4H), 1.43 (d, J = 4.8Hz, 3H).

[0242] LCMSm / s = 352.0 [M+1].

[0243] Intermediate 15

[0244] (S)-2-fluoro-N-methyl-4-(3-methylpiperazin-1-yl)benzamide intermediate 15

[0245] (S)-2-fluoro-N-methyl-4-(3-methylpiperazin-1-yl)benzamide

[0246]

[0247]

[0248] Following the preparation method of intermediate 1, intermediate 15 (yellow solid, 480 mg, yield 85%) was obtained.

[0249] 1 H NMR(400MHz, DMSO-d6)δ9.60(s,1H),7.85(q,J=4.8Hz,1H),7.59(t,J=8.8Hz,1H),6.90–6.81(m,2H), 3.97–3.86(m,2H),3.36–3.23(m,2H),3.13–2.87(m,3H),2.74(d,J=4.8Hz,3H),1.30(d,J=6.5Hz,3H).

[0250] LCMSm / s = 252.2 [M+1].

[0251] Intermediate 16

[0252] (R)-2-fluoro-N-methyl-4-(3-methylpiperazin-1-yl)benzamide intermediate 16

[0253] (R)-2-fluoro-N-methyl-4-(3-methylpiperazin-1-yl)benzamide

[0254]

[0255] Following the preparation method of intermediate 1, intermediate 16 (yellow solid, 460 mg, yield 81%) was obtained.

[0256] 1 H NMR(400MHz, DMSO-d6)δ9.75(S,2H),7.87(q,J=4.7Hz,1H),7.58(t,J=8.8Hz,1H),6.90–6.78(m,2H), 4.76(d,J=4.7Hz,3H),3.96-3.87(m,2H),3.33–3.13(m,3H),3.02-2.92(m,2H),1.31(d,J=6.4Hz,3H).

[0257] LCMSm / s = 252.2 [M+1].

[0258] Intermediate 17

[0259] (S)-4-(3-(cyanomethyl)piperazin-1-yl)-2-fluoro-N-methylbenzamide intermediate 17

[0260] (S)-4-(3-(cyanomethyl)piperazin-1-yl)-2-fluoro-N-methylbenzamide

[0261]

[0262]

[0263] Following the preparation method of intermediate 1, intermediate 17 (yellow solid, 1.1 g, yield 85%) was obtained.

[0264] 1 H NMR(400MHz, DMSO-d6)δ9.81(s,1H),7.88q,J=4.5Hz,1H),7.64-7.59(m,1H),6.93–6.80(m,2H),4.00–3.85( m,2H),3.73-3.69(m,2H),3.39-3.35(m,1H),3.25–3.15(m,2H),3.13(d,J=6.3Hz,2H),2.75(d,J=4.5Hz,3H).

[0265] LCMSm / s = 277.1 [M+1].

[0266] Intermediate 18

[0267] (R)-2-fluoro-4-(3-(hydroxymethyl)piperazin-1-yl)-N-methylbenzamide intermediate 18

[0268] (R)-2-fluoro-4-(3-(hydroxymethyl)piperazin-1-yl)-N-methylbenzamide

[0269]

[0270] Following the preparation method of intermediate 1, intermediate 18 (yellow solid, 210 mg, yield 61%) was obtained.

[0271] LCMSm / s = 268.1 [M+1].

[0272] Intermediate 19

[0273] (S)-2-fluoro-4-(3-(hydroxymethyl)piperazin-1-yl)-N-methylbenzamide intermediate 19

[0274] (S)-2-fluoro-4-(3-(hydroxymethyl)piperazin-1-yl)-N-methylbenzamide

[0275]

[0276] Following the preparation method of intermediate 1, intermediate 19 (yellow solid, 240 mg, yield 67%) was obtained.

[0277] LCMSm / s = 268.1 [M+1].

[0278] Intermediate 20

[0279] 2-Cyano-N-methyl-4-(piperazin-1-yl)benzamide intermediate 20

[0280] 2-cyano-N-methyl-4-(piperazin-1-yl)benzamide

[0281]

[0282] Following the preparation method of intermediate 1, intermediate 20 (yellow solid, 920 mg, yield 87%) was obtained.

[0283] LCMSm / s = 245.1 [M+1].

[0284] Intermediate 21

[0285] 3-Fluoro-N-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide intermediate 21

[0286] 3-fluoro-N-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide

[0287]

[0288] first step:

[0289] 4-(2-fluoro-4-(methylcarbamoyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 21b

[0290] tert-butyl 4-(2-fluoro-4-(methylcarbamoyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0291] Dissolve 8a (500 mg, 2.17 mmol) and 21a (610 mg, 1.98 mmol) in 15 mL of 1,4-dioxane, then add tetra(triphenylphosphine)palladium (231 mg, 0.20 mmol) and cesium carbonate (968 mg, 2.97 mmol). After the addition is complete, the reaction system is protected with nitrogen and reacted at 120 °C. After 16 h, the reaction is complete. Extract the mixture three times with 20 mL of water and ethyl acetate (3 × 30 mL). Collect the organic phase, concentrate under reduced pressure, and then purify by column chromatography (PE:EA = 2:1-1:2) to obtain crude 21b.

[0292] Step Two:

[0293] 3-Fluoro-N-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide intermediate 21

[0294] 3-fluoro-N-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide

[0295] 21b was added to 15 mL of 1,4-dioxane hydrochloric acid solution (4 M), and the mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was filtered, and the filter cake was collected to obtain intermediate 21 (white solid, 465 mg, yield 84%).

[0296] LCMSm / s = 235.1 [M+1].

[0297] Intermediate 22

[0298] N-Methyl-4-(piperazin-1-yl)benzamide intermediate 22

[0299] N-methyl-4-(piperazin-1-yl)benzamide

[0300]

[0301] Following the preparation method of intermediate 1, intermediate 22 (yellow solid, 1 g, yield 69%) was obtained.

[0302] 1 H NMR (400MHz, DMSO-d6) δ9.68(dr,1H),8.46(d,1H),7.78(d,2H),7.00(d,2H),3.51–3.38(m,4H),3.23–3.20(m,4H),2.74(d,3H).

[0303] LCMSm / s = 220.10 [M+1].

[0304] Intermediate 23

[0305] 2,5-Difluoro-aza-methyl-4-(piperazin-1-yl)benzamide intermediate 23

[0306] 2,5-difluoro-N-methyl-4-(piperazin-1-yl)benzamide

[0307]

[0308] Following the preparation method of intermediate 1, intermediate 23 (white solid, 1.8 g, yield 84%) was obtained.

[0309] 1 H NMR (400MHz, DMSO-d6) δ9.36 (s, 1H), 8.14-8.04 (m, 1H), 7.44 (dd, J = 13.3, 6.7Hz, 1H), 7.04 (d d,J=12.5,7.1Hz,1H),3.57-3.43(m,4H),3.36(dd,J=6.6,3.7Hz,4H),2.76(d,J=4.5Hz,3H).

[0310] LCMSm / s = 256.27 [M+1].

[0311] Intermediate 24

[0312] 2,5-Difluoro-aza-methyl-4-(piperazin-1-yl)benzamide intermediate 24

[0313] 2,5-difluoro-N-methyl-4-(piperazin-1-yl)benzamide

[0314]

[0315] Following the preparation method of intermediate 1, intermediate 24 (white solid, 1.1 g, yield 86%) was obtained.

[0316] 1 H NMR (400MHz, DMSO-d6) δ9.39(s,1H),8.19(dq,J=6.2,3.9Hz,1H),7.39(td,J=8.3,7.8,2.0Hz,1H),6.97(td,J=8 .5,8.0,1.8Hz,1H),3.58(d,J=11.6Hz,2H),3.37(d,J=4.6Hz,2H),3.23(q,J=4.7Hz,4H),2.76(d,J=4.6Hz,3H).

[0317] LCMSm / s = 256.27 [M+1].

[0318] Intermediate 25

[0319] Nitrogen-(2-(dimethylamino)ethyl)-2-fluoro-4-(piperazin-1-yl)benzamide intermediate 25

[0320] N-(2-(dimethylamino)ethyl)-2-fluoro-4-(piperazin-1-yl)benzamide

[0321]

[0322] Following the preparation method of intermediate 1, intermediate 25 (white solid, 1.4 g, yield 89%) was obtained.

[0323] LCMSm / s = 295.37 [M+1].

[0324] Intermediate 26

[0325] 2-Fluoro-N-(oxetane-3-yl)-4-(piperazin-1-yl)benzamide intermediate 26

[0326] 2-fluoro-N-(oxetan-3-yl)-4-(piperazin-1-yl)benzamide

[0327]

[0328] Following the preparation method of intermediate 1, intermediate 26 (white solid, 1.1 g, yield 84%) was obtained.

[0329] 1 H NMR(400MHz, DMSO-d6)δ9.43(s,1H),7.76–7.69(m,1H),7.63(t,J=8.8Hz,1H),7.06(dd,J=23.5,12.7Hz,1H),6.8 9(d,J=2.5Hz,1H),4.52(d,J=33.3Hz,8H),4.16(q,J=6.4Hz,1H),3.79–3.74(m,2H),3.48(dd,J=11.0,6.5Hz,2H).

[0330] LCMSm / s = 280.32 [M+1].

[0331] Intermediate 27

[0332] 2-Fluoro-nitro-(1-methylazacyclobutane-3-yl)-4-(piperazin-1-yl)benzamide intermediate 27

[0333] 2-fluoro-N-(1-methylazetidin-3-yl)-4-(piperazin-1-yl)benzamide

[0334]

[0335] Following the preparation method of intermediate 1, intermediate 27 (white solid, 1.2 g, yield 87%) was obtained.

[0336] LCMSm / s = 293.36 [M+1].

[0337] Intermediate 28

[0338] 2-Fluoro-nitro-(2-methoxyethyl)-4-(piperazin-1-yl)benzamide intermediate 28

[0339] 2-fluoro-N-(2-methoxyethyl)-4-(piperazin-1-yl)benzamide

[0340]

[0341] Following the preparation method of intermediate 1, intermediate 28 (white solid, 1.7 g, yield 83%) was obtained.

[0342] 1H NMR(400MHz, DMSO-d6)δ9.48(s,1H),7.89–7.80(m,1H),7.60(t,J=8.8Hz,1H),6.86(d,J=2.5Hz,1H),6.8 3(q,J=2.2Hz,1H),3.54(t,J=5.3Hz,4H),3.41(qd,J=8.3,3.0Hz,4H),3.26(s,3H),3.16(t,J=5.1Hz,4H).

[0343] LCMSm / s = 282.33 [M+1].

[0344] Intermediate 29

[0345] 2-Fluoro-nitro-(2-hydroxyethyl)-4-(piperazin-1-yl)benzamide intermediate 29

[0346] 2-fluoro-N-(2-hydroxyethyl)-4-(piperazin-1-yl)benzamide

[0347]

[0348]

[0349] Following the preparation method of intermediate 1, intermediate 29 (white solid, 1.4 g, yield 81%) was obtained.

[0350] 1 H NMR(400MHz, DMSO-d6)δ9.48(s,1H),7.89–7.80(m,1H),7.60(t,J=8.8Hz,1H),6.86(d,J=2.5Hz,1H),6.8 3(q,J=2.2Hz,1H),5.14(s,1H),3.54(t,J=5.3Hz,4H),3.41(qd,J=8.3,3.0Hz,4H),3.16(t,J=5.1Hz,4H).

[0351] LCMSm / s = 268.30 [M+1].

[0352] Intermediate 30

[0353] 3-Fluoro-nitro-(2-methoxyethyl)-4-(piperazin-1-yl)benzamide intermediate 30

[0354] 3-fluoro-N-(2-methoxyethyl)-4-(piperazin-1-yl)benzamide

[0355]

[0356] Following the preparation method of intermediate 1, intermediate 30 (white solid, 1.5 g, yield 81%) was obtained.

[0357] LCMSm / s = 282.15 [M+1].

[0358] Intermediate 31

[0359] 3-Fluoro-N-((1s,3s)-3-hydroxycyclobutyl)-4-(piperazin-1-yl)benzamide intermediate 31

[0360] 3-fluoro-N-((1s,3s)-3-hydroxycyclobutyl)-4-(piperazin-1-yl)benzamide

[0361]

[0362] Following the preparation method of intermediate 1, intermediate 31 (white solid, 430 mg, yield 83%) was obtained.

[0363] LCMSm / s = 294.15 [M+1].

[0364] Intermediate 32

[0365] 3-Fluoro-N-((1r,3r)-3-hydroxycyclobutyl)-4-(piperazin-1-yl)benzamide intermediate 32

[0366] 3-fluoro-N-((1r,3r)-3-hydroxycyclobutyl)-4-(piperazin-1-yl)benzamide

[0367]

[0368] Following the preparation method of intermediate 1, intermediate 32 (white solid, 370 mg, yield 86%) was obtained.

[0369] LCMSm / s = 294.15 [M+1].

[0370] Intermediate 33

[0371] 3-Fluoro-N-(2-hydroxy-2-methylpropyl)-4-(piperazin-1-yl)benzamide intermediate 33

[0372] 3-fluoro-N-(2-hydroxy-2-methylpropyl)-4-(piperazin-1-yl)benzamide

[0373]

[0374] Following the preparation method of intermediate 1, intermediate 33 (white solid, 1.1 g, yield 91%) was obtained.

[0375] 1 H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.30(t,1H),7.73(q,1H),7.70(d,1H),7.1 5(t,1H),5.09(s,1H),3.36–3.30(m,4H),3.27(s,2H),3.23(d,4H),1.08(s,6H).

[0376] LCMSm / s = 296.36 [M+1].

[0377] Intermediate 34

[0378]

[0379] 3-Fluoro-N-methyl-4-(piperidin-4-yl)benzamide intermediate 34

[0380] 3-fluoro-N-methyl-4-(piperidin-4-yl)benzamide

[0381]

[0382] first step:

[0383] 3-Fluoro-N-methyl-4-(piperidin-4-yl)benzamide intermediate 34

[0384] 3-fluoro-N-methyl-4-(piperidin-4-yl)benzamide

[0385] Intermediate 21 (150 mg, 2.17 mmol), ammonium formate (120 mg, 1.98 mmol), and 10% Pd / C (150 mg) were dissolved in 3 mL of anhydrous methanol. The reaction system was placed at 80 °C for 5 hours. After filtration, the filtrate was collected and concentrated under reduced pressure to obtain intermediate 34 (white solid, 170 mg, yield 82%).

[0386] LCMSm / s = 237.13 [M+1].

[0387] Intermediate 35

[0388] (S)-3-fluoro-N-(2-hydroxypropyl)-4-(piperazin-1-yl)benzamide intermediate 35

[0389] (S)-3-fluoro-N-(2-hydroxypropyl)-4-(piperazin-1-yl)benzamide

[0390]

[0391] Following the preparation method of intermediate 1, intermediate 35 (white solid, 1.3 g, yield 94%) was obtained.

[0392] LCMSm / s = 282.15 [M+1].

[0393] Intermediate 36

[0394] (R)-3-fluoro-N-(2-hydroxypropyl)-4-(piperazin-1-yl)benzamide intermediate 36

[0395] (R)-3-fluoro-N-(2-hydroxypropyl)-4-(piperazin-1-yl)benzamide

[0396]

[0397] Following the preparation method of intermediate 1, intermediate 36 (white solid, 0.9 g, yield 85%) was obtained.

[0398] LCMSm / s = 282.15 [M+1].

[0399] Intermediate 37

[0400] N-(2-hydroxyethyl)-6-(piperazin-1-yl)nicotinamide intermediate 37

[0401] N-(2-hydroxyethyl)-6-(piperazin-1-yl)nicotinamide

[0402]

[0403]

[0404] Following the preparation method of intermediate 1, intermediate 37 (white solid, 0.8 g, yield 82%) was obtained.

[0405] LCMSm / s = 251.14 [M+1].

[0406] Intermediate 38

[0407] 3-Chloro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 38

[0408] 3-chloro-N-methyl-4-(piperazin-1-yl)benzamide

[0409]

[0410] Following the preparation method of intermediate 1, intermediate 38 (white solid, 1.2 g, yield 77%) was obtained.

[0411] LCMSm / s = 254.10 [M+1].

[0412] Intermediate 39

[0413] 4-Fluoro-N-((1-hydroxycyclopropyl)methyl)-4-(piperazin-1-yl)benzamide intermediate 39

[0414] 4-fluoro-N-((1-hydroxycyclopropyl)methyl)-4-(piperazin-1-yl)benzamide

[0415]

[0416] Following the preparation method of intermediate 1, intermediate 39 (white solid, 0.9 g, yield 85%) was obtained.

[0417] LCMSm / s = 294.15 [M+1].

[0418] Intermediate 40

[0419] 7-(bromomethyl)-3-cyclopropyl-1,5-naphthidine-2(1H)-one intermediate 40

[0420] 7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one

[0421]

[0422] first step

[0423] Ethyl 6-formyl-5-nitronicotinate 40b

[0424] ethyl 6-formyl-5-nitronicotinate

[0425] Ethyl 6-methyl-5-nitronicotinic acid 40a (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 40b (yellow solid, 9.7 g, yield 90%).

[0426] LC-MSm / z(ESI) = 225.10[M+1].

[0427] Step 2

[0428] 6-(2-bromo-3-ethoxy-3-oxopropane-1-en-1-yl)-5-nitronicotinic acid ethyl ester 40c

[0429] ethyl 6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)-5-nitronicotinate

[0430] 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 40b (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 40c (yellow solid, 13 g, yield 81%, E / Z = 10:3).

[0431] 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).

[0432] LC-MSm / z(ESI) = 373.00 [M+1].

[0433] Step 3

[0434] 5-Amino-6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)nicotinic acid ethyl ester 40d

[0435] ethyl 5-amino-6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)nicotinate

[0436] Compound 40c (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 40d (yellow solid, 10 g, yield 83%).

[0437] LC-MSm / z(ESI) = 343.00 [M+1].

[0438] Step 4

[0439] 40e of ethyl 7-bromo-6-oxo-5,6-dihydro-1,5-naphthyl-3-carboxylate

[0440] ethyl 7-bromo-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate

[0441] Compound 40d (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 40e (yellow solid, 2 g, yield 23%).

[0442] 1 H 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).

[0443] LC-MSm / z(ESI) = 297.00 [M+1].

[0444] Step 5

[0445] 40f of 7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyl-3-carboxylic acid ethyl ester

[0446] ethyl 7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate

[0447] Compound 40e (400 mg, 1.3 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride 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 give compound 40f (yellow solid, 270 mg, yield 77%).

[0448] 1H 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).

[0449] LC-MSm / z(ESI) = 259.10[M+1].

[0450] Step 6

[0451] 3-Cyclopropyl-7-(hydroxymethyl)-1,5-naphthidium-2(1H)-one 40g

[0452] 3-cyclopropyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one

[0453] Compound 40f (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 ethyl acetate (1 mL) was added. The mixture was concentrated under reduced pressure and column chromatography was performed to obtain compound 40 g (yellow solid, 100 mg, yield 44%).

[0454] 1H 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).

[0455] LC-MSm / z(ESI) = 217.10[M+1].

[0456] Step 7

[0457] 7-(bromomethyl)-3-cyclopropyl-1,5-naphthidine-2(1H)-one intermediate 40

[0458] 7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one

[0459] 40 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 intermediate 40 of compound (yellow solid, 100 mg, yield 78%).

[0460] LC-MSm / z(ESI) = 279.00 [M+1].

[0461] Intermediate 41

[0462] (R)-6-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)nicotinamide intermediate 41

[0463] (R)-6-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)nicotinamide

[0464]

[0465]

[0466] Following the preparation method of intermediate 1, intermediate 35 (white solid, 0.4 g, yield 87%) was obtained.

[0467] LCMSm / s = 277.16 [M+1].

[0468] Intermediate 42

[0469] N-Methyl-4-(piperazin-1-yl)pyridine amide intermediate 42

[0470] N-methyl-4-(piperazin-1-yl)picolinamide

[0471]

[0472] Intermediate 42 (yellow solid, 500 mg, yield 74%) was obtained according to the preparation method of intermediate 1.

[0473] LCMSm / s = 221.28 [M+1].

[0474] Intermediate 43

[0475] N-Methyl-5-(piperazin-1-yl)pyrazin-2-carboxamide intermediate 43

[0476] N-methyl-5-(piperazin-1-yl)pyrazine-2-carboxamide

[0477]

[0478] Following the preparation method of intermediate 1, intermediate 43 (yellow solid, 1.1 g, yield 72%) was obtained.

[0479] LCMSm / s = 222.26 [M+1].

[0480] Intermediate 44

[0481] 5-Fluoro-N-methyl-6-(piperazin-1-yl)nicotinamide intermediate 44

[0482] 5-fluoro-N-methyl-6-(piperazin-1-yl)nicotinamide

[0483]

[0484]

[0485] Following the preparation method of intermediate 1, intermediate 44 (yellow solid, 530 mg, yield 78%) was obtained.

[0486] LCMSm / s = 239.12 [M+1].

[0487] Intermediate 45

[0488] 3,5-Difluoro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 45

[0489] 3,5-difluoro-N-methyl-4-(piperazin-1-yl)benzamide

[0490]

[0491] Following the preparation method of intermediate 1, intermediate 45 (white solid, 1.4 g, yield 69%) was obtained.

[0492] 1H NMR (400MHz, DMSO-d6) δ9.40(s,1H),8.60(q,1H),7.58(s,1H),7.55(s,1H),3.46–3.36(m,4H),3.20–3.11(m,4H),2.76(d,3H).

[0493] LCMSm / s = 256.10 [M+1].

[0494] Intermediate 46

[0495] 2-Chloro-5-fluoro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 46

[0496] 2-chloro-5-fluoro-N-methyl-4-(piperazin-1-yl)benzamide

[0497]

[0498] Following the same method described above, intermediate 46 (white solid, 1.5 g, yield 75%) was obtained.

[0499] 1 H NMR (400MHz, DMSO-d6) δ9.49(s,1H),8.32(q,1H),7.32(d,1H),7.15(d,1H),3.39–3.26(m,4H),3.24–3.16(m,4H),2.72(d,3H).

[0500] LCMSm / s = 272.10 [M+1].

[0501] Intermediate 47

[0502] 2,6-Dichloro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 47

[0503] 2,6-dichloro-N-methyl-4-(piperazin-1-yl)benzamide

[0504]

[0505] Following the same method described above, intermediate 47 (white solid, 1.4 g, yield 70%) was obtained.

[0506] 1H NMR (400MHz, DMSO-d6) δ9.47(s,1H),8.39(q,1H),7.06(s,2H),3.55–3.45(m,4H),3.18–3.09(m,4H),2.72(d,3H).

[0507] LCMSm / s = 288.10 [M+1].

[0508] Intermediate 48

[0509] 7-(bromomethyl)-3-methyl-1,5-naphthidine-2(1H)-one intermediate 48

[0510] 7-(bromomethyl)-3-methyl-1,5-naphthyridin-2(1H)-one

[0511]

[0512] Intermediate 48 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 LCMSm / s = 253.10 [M+1].

[0513] Intermediate 49

[0514] (R)-3-chloro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide intermediate 49

[0515] (R)-3-chloro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide

[0516]

[0517] Following the preparation method of intermediate 1, intermediate 49 (white solid, 1.3 g, yield 94%) was obtained.

[0518] LCMSm / s = 310.7 [M+1].

[0519] Intermediate 50

[0520] 3-Chloro-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-4-(piperazin-1-yl)benzamide intermediate 50

[0521] 3-chloro-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-4-(piperazin-1-yl)benzamide

[0522]

[0523]

[0524] Following the preparation method of intermediate 1, intermediate 50 (white solid, 1.6 g, yield 94%) was obtained.

[0525] LCMSm / s = 326.1 [M+1].

[0526] Intermediate 51

[0527] 3-Chloro-N-(3-methyltetrahydrofuran-3-yl)-4-(piperazin-1-yl)benzamide intermediate 51

[0528] 3-chloro-N-(3-methyltetrahydrofuran-3-yl)-4-(piperazin-1-yl)benzamide

[0529]

[0530] Following the preparation method of intermediate 1, intermediate 51 (white solid, 1.1 g, yield 92%) was obtained.

[0531] LCMSm / s = 324.1 [M+1].

[0532] Intermediate 52

[0533] N-(3-oxazolylcyclo[3.1.0]hexane-6-yl)-3-chloro-4-(piperazin-1-yl)benzamide intermediate 52

[0534] N-(3-oxabicyclo[3.1.0]hexan-6-yl)-3-chloro-4-(piperazin-1-yl)benzamide

[0535]

[0536] Following the preparation method of intermediate 1, intermediate 52 (white solid, 1.3 g, yield 91%) was obtained.

[0537] LCMSm / s = 322.1 [M+1].

[0538] Example 1

[0539] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-methylbenzamide compound 1

[0540] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-methylbenzamide

[0541]

[0542] Intermediate 2 (100 mg, 0.37 mmol) and intermediate 1 (98 mg, 0.41 mmol) were dissolved in 5 mL of acetonitrile, and then N,N-diisopropylethylamine (241.5 mg, 1.9 mmol) was added. The reaction was carried out under nitrogen protection at 70 °C for 3 h until the reaction was completed. The crude product was concentrated under reduced pressure and then purified by column chromatography (MeOH:DCM = 1:60 to 1:15) to give compound 1 (white solid, 50 mg, yield: 32%).

[0543] 1 H NMR (400MHz, DMSO-d6) δ11.85 (s, 1H), 8.40 (d, J = 2.0Hz, 1H), 8.22 (dr s,1H),7.75(s,1H),7.62(s,1H),7.56(t,J=9.0Hz,1H),6.82-6.72(m,2H),3.64(s,2H ),3.29-3.26(m,4H),2.74(d,J=4.5Hz,3H),2.54-2.51(m,6H),1.18(t,J=7.4Hz,3H).

[0544] LCMSm / s = 424.50 [M+1].

[0545] Example 2

[0546] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(methyl-D3)benzamide compound 2

[0547] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(methyl-d3)benzamide

[0548]

[0549] Compound 2 (white solid, 100 mg, yield: 62%) was prepared according to the method of compound 1.

[0550] 1 H NMR (400MHz, DMSO-d6) δ11.85 (s, 1H), 8.40 (d, J = 1.9Hz, 1H), 7.75 (dr s,1H),7.73(d,J=5.6Hz,1H),7.62(d,J=1.9Hz,1H),7.56(t,J=9.0Hz,1H),6.81–6. 70(m,2H),3.63(s,2H),3.29–3.26(m,4H),2.59–2.51(m,6H),1.18(t,J=7.4Hz,3H).

[0551] LCMSm / s = 427.20 [M+1].

[0552] Example 3

[0553] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-2-fluorobenzamide compound 3

[0554] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluorobenz amide

[0555]

[0556] Compound 3 (white solid, 5 mg, yield: 7%) was prepared according to the method of compound 1.

[0557] 1 H NMR (400MHz, DMSO-d6) δ11.85(s,1H),8.40(d,J=1.9Hz,1H),7.75(s,1H),7.62(d,J=1.6Hz,1H),7.59(d,J=9.0Hz,1H),7.32(dr s,1H),7.20(dr s,1H),6.83–6.67(m,2H),3.64(s,2H),3.32-3.27(m,4H),2.54-2.50(m,6H),1.18(t,J=7.4Hz,3H).

[0558] LCMSm / s = 410.20 [M+1].

[0559] Example 4

[0560] 2-Chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-methylbenzamide compound 4

[0561] 2-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylbenzamide

[0562]

[0563] Compound 4 (white solid, 50 mg, yield: 30%) was prepared according to the method of compound 1.

[0564] LCMSm / s = 440.20 [M+1].

[0565] Example 5

[0566] 4-(6-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-2-fluoro-N-methylbenzamide compound 5

[0567] 4-(6-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-fluoro-N-methylbenzamide

[0568]

[0569] Compound 5 (white solid, 18 mg, yield: 23%) was prepared according to the method of compound 1.

[0570] 1 H NMR (400MHz, DMSO-d6) δ12.01(s,1H),8.53(s,1H),7.90–7.53(m,4H),6.76–6. 47(m,2H),3.88-3.61(m,4H),3.21-3.12(m,4H)2.77(s,3H),2.62–2.51(m,3H),

[0571] 1.29-1.25 (m, 1H), 1.15 (s, 3H).

[0572] LCMSm / s = 436.20 [M+1].

[0573] Example 6

[0574] N-Cyclopropyl-4-(4-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-2-fluorobenzamide compound 6

[0575] N-cyclopropyl-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluorobenzamide

[0576]

[0577] Compound 6 (white solid, 18 mg, yield: 6%) was prepared according to the method of compound 1.

[0578] 1 H NMR (400MHz, DMSO-d6) δ11.72 (s, 1H), 8.39 (d, J = 1.8Hz, 1H), 7.85 (s, 1H),

[0579] 7.75(d,J=5.4Hz,1H),7.68(d,J=1.8Hz,1H),7.47(t,J=8.9Hz,1H),6.81-6.70(m,2H),3.63(s,2H),3.27-3. 24(m,4H),2.80-2.77(m,1H),2.56-2.55(m,6H),1.17(t,J=7.5Hz,3H).0.68-0.65(m,2H),0.53-0.50(m,2H).

[0580] LCMSm / s = 450.2 [M+1].

[0581] Example 7

[0582] 4-(4-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide compound 7

[0583] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide

[0584]

[0585] Compound 7 (white solid, 50 mg, yield: 78%) was prepared according to the method of compound 1.

[0586] 1 H NMR (400MHz, DMSO-d6) δ11.86(s,1H),8.40(s,1H),8.33(q,J=4.1Hz,1H),7.75(s,1H),7.68–7.52(m,3H),7.05(t,J=8.6H z,1H),3.65(s,2H),3.14-3.08(m,4H),2.75(d,J=4.1Hz,3H),2.59–2.55(m,4H),2.54-2.51(m,2H),1.18(t,J=7.4Hz,3H).

[0587] LCMSm / s = 424.2[M+1]

[0588] Example 8

[0589] (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(tetrahydrofuran-3-yl)benzamide compound 8

[0590] (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(tetrahydrofuran-3-yl)benzamide

[0591]

[0592] Compound 8 (white solid, 40 mg, yield: 82%) was prepared according to the method of compound 1.

[0593] 1H NMR (400MHz, DMSO-d6) δ11.82(s,1H),8.40(d,J=1.8Hz,1H),7.96(dd,J=6.7,3.6Hz,1H),7.75 (s,1H),7.62(s,1H),7.49(t,J=8.8Hz,1H),6.82-6.69(m,2H),4.40(d,J=5.6Hz,1H),3.81(td ,J=9.5,6.8Hz,2H),3.73-3.66(m,1H),3.64(s,2H),3.53(dd,J=8.8,4.4Hz,1H),3.28(s,4H), 2.54(d,J=8.3Hz,6H),2.17-2.06(m,1H),1.87(dd,J=12.2,5.8Hz,1H),1.18(t,J=7.4Hz,3H).

[0594] LCMSm / s = 480.5 [M+1].

[0595] Example 9

[0596] (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(tetrahydrofuran-3-yl)benzamide compound 9

[0597] (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(tetrahydrofuran-3-yl)benzamide

[0598]

[0599] Compound 9 (white solid, 46 mg, yield: 84%) was prepared according to the method of compound 1.

[0600] 1H NMR (400MHz, DMSO-d6) δ11.85(s,1H),8.40(d,J=1.9Hz,1H),7.96(dd,J=6.6,3.5Hz,1H),7.75( s,1H),7.62(d,J=1.8Hz,1H),7.49(t,J=8.8Hz,1H),6.80-6.70(m,2H),4.39(d,J=6.1Hz,1H),3 .85-3.77(m,2H),3.73-3.67(m,1H),3.63(s,2H),3.53(dd,J=8.8,4.4Hz,1H),3.27(d,J=5.4Hz ,4H),2.59-2.51(m,6H),2.18-2.06(m,1H),1.85(dq,J=12.5,6.2Hz,1H),1.18(t,J=7.4Hz,3H).

[0601] LCMSm / s = 480.5 [M+1].

[0602] Example 10

[0603] 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-aza-methylbenzamide compound 10

[0604] 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide

[0605]

[0606] first step

[0607] 6-Formyl-5-nitronitroethyl ester 10B

[0608] ethyl 6-formyl-5-nitronicotinat

[0609] Compound 10A of ethyl 6-methyl-5-nitronicotinic acid (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 subjected to column chromatography to obtain compound 10B (yellow solid, 9.7 g, yield 90%).

[0610] LC-MSm / z(ESI) = 225.10[M+1].

[0611] Step 2

[0612] 6-(2-bromo-3-ethoxy-3-propoxy-1-en-1-yl)-5-nitronicotinic acid ethyl ester 10C

[0613] ethyl 6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)-5-nitronicotinate

[0614] 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 10B (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 10C (yellow solid, 13 g, yield 81%, E / Z = 10:3).

[0615] 1 H 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).

[0616] LC-MSm / z(ESI) = 373.00 [M+1].

[0617] Step 3

[0618] 5-Amino-6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)nicotinic acid ethyl ester 10D

[0619] ethyl 5-amino-6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)nicotinate

[0620] Compound 10C (13 g, 34.8 mmol) was dissolved in acetic acid (130 mL), and iron powder (5.8 g, 104.5 mmol) was added. The reaction was carried out at room temperature for 2 h, and then distilled water (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (100 mL × 3), and the organic phases were combined and concentrated under reduced pressure to give compound 10D (yellow solid, 10 g, yield 83%).

[0621] LC-MSm / z(ESI) = 343.00 [M+1].

[0622] Step 4

[0623] 7-Bromo-6-oxo-5,6-dihydro-1,5-naphthyl-3-carboxylic acid ethyl ester 10E

[0624] ethyl 7-bromo-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate

[0625] Compound 10D (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 10E (yellow solid, 2 g, yield 23%).

[0626] 1 H 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).

[0627] LC-MSm / z(ESI) = 297.00 [M+1].

[0628] Step 5

[0629] 7-Cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyl-3-carboxylic acid ethyl ester 10F

[0630] ethyl 7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate

[0631] Compound 10E (400 mg, 1.3 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride 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 10F (yellow solid, 270 mg, yield 77%).

[0632] 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).

[0633] LC-MSm / z(ESI) = 259.10[M+1].

[0634] Step 6

[0635] 3-Cyclopropyl-7-(hydroxymethyl)-1,5-naphthidium-2(1-hydro)-one 10g

[0636] 3-cyclopropyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one

[0637] Compound 10F (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 used to obtain compound 10G (yellow solid, 100 mg, yield 44%).

[0638] 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).

[0639] LC-MSm / z(ESI) = 217.10[M+1].

[0640] Step 7

[0641] 7-(bromomethyl)-3-cyclopropyl-1,5-naphthidium-2(1-hydro)-one 10H

[0642] 7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one

[0643] Compound 10G (100 mg, 0.46 mmol) 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 conditions. 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 10H (yellow solid, 100 mg, yield 78%).

[0644] LC-MSm / z(ESI) = 279.00 [M+1].

[0645] Step 8

[0646] 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-aza-methylbenzamide compound 10

[0647] 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide

[0648] Compound 10H (100 mg, 0.36 mmol), intermediate 8, N,N-diisopropylethylamine (230 mg, 1.8 mmol), of 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide (93 mg, 0.39 mmol), was dissolved in acetonitrile (4 mL). The reaction was carried out at 80 °C for 4 h. The reaction solution was concentrated under reduced pressure and preparatively chromatographically to give compound 10 (white solid, 40 mg, yield 27%).

[0649] 1H NMR (400MHz, DMSO-d6) δ11.88(s,1H),8.37(d,1H),8.35–8.31(m,1H),7.64–7.53(m,3H),7.41(s,1H),7.05(t,1H),3. 63(d,2H),3.12–3.09(m,4H),2.75(d,3H),2.57–2.54(m,4H),2.19–2.11(m,1H),1.02–0.92(m,2H),0.87–0.74(m,2H).

[0650] LC-MSm / z(ESI)=436.20[M+1].

[0651] Example 11

[0652] 4-(4-((7-ethyl-2,6-dioxy-1,2,5,6-tetrahydro-1,5-naphthidin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide compound 11

[0653] 4-(4-((7-ethyl-2,6-dioxo-1,2,5,6-tetrahydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide

[0654]

[0655]

[0656] first step

[0657] (5-Acetyl-7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl acetate 11B

[0658] (5-acetyl-7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methylacetate

[0659] Compound 11A (1.02 g, 5 mmol; prepared according to the synthesis method of intermediate 13 in patent WO2021013735, LC-MS m / s = 205.1 [M+1]) and acetic anhydride (10.2 g, 100 mmol) were added to a 100 mL reaction flask and stirred in an oil bath at 100 °C for 8 h under a nitrogen atmosphere. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure and separated by column chromatography (PE:EA = 5:1) to obtain compound 11B (pale yellow solid, 1.15 g, yield 80%).

[0660] LC-MSm / s = 289.1 [M+1].

[0661] Step 2

[0662] 3-Ethyl-7-(hydroxymethyl)-1,5-dihydro-1,5-naphthidine-2,6-dione 11C

[0663] 3-ethyl-7-(hydroxymethyl)-1,5-dihydro-1,5-naphthyridine-2,6-dione

[0664] Take a 50 mL reaction flask, dry it, add compound 11B (1.15 g, 4 mmol) and 10 mL of dichloromethane, replace with nitrogen, add m-chloroperoxybenzoic acid (756 mg, 4.4 mmol) in portions under ice-water bath conditions, allow to return to room temperature naturally, stir and react for 5 h, monitor the reaction for completeness by TLC, add saturated sodium bicarbonate aqueous solution (20 mL), extract with dichloromethane (3 × 20 mL), combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure to remove organic solvent. Add acetic anhydride (10 mL), reflux and stir for 2 h, add distilled water (8 mL), continue reflux and stir for 2 h, concentrate under reduced pressure to remove organic solvent, add methanol (20 mL) and potassium carbonate (2.76 g, 20 mmol), stir at room temperature for 1 h, filter, wash the filter cake with methanol, collect the filtrate, concentrate under reduced pressure to remove organic solvent, separate the crude product by reversed-phase column chromatography to obtain compound 11C (brown solid, 310 mg, yield 35%).

[0665] 1 H NMR (400MHz, DMSO-d6) δ10.50(s,2H),6.94(d,1H),6.73(s,1H),5.37(t,1H),4.20(dd,2H),2.35(qd,2H),1.08(t,3H).

[0666] LC-MSm / s = 221.1[M+1].

[0667] Step 3

[0668] 3-(bromomethyl)-7-ethyl-1,5-dihydro-1,5-naphthidine-2,6-dione 11D

[0669] 3-(bromomethyl)-7-ethyl-1,5-dihydro-1,5-naphthyridine-2,6-dione

[0670] Compound 11C (310 mg, 1.41 mmol) and triphenylphosphine (739 mg, 2.82 mmol, purchased from Shanghai Adamas Reagent Co., Ltd.) were dissolved in dichloromethane (5 mL). Carbon tetrabromide (933 mg, 2.82 mmol, purchased from Anaiji Chemical) in dichloromethane (2 mL) was added under ice-water bath conditions. The reaction was carried out for 0.5 h. The reaction solution was concentrated under reduced pressure and then subjected to column chromatography to obtain compound 11D (yellow solid, 160 mg, yield 40%).

[0671] 1 H NMR (400MHz, DMSO-d6) δ10.22(s,2H),6.99(s,1H),6.73(s,1H),3.97(d,2H),2.33(qd,2H),1.08(t,3H).

[0672] LC-MSm / s = 283.0 [M+1].

[0673] Step 4

[0674] 4-(4-((7-ethyl-2,6-dioxy-1,2,5,6-tetrahydro-1,5-naphthidin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide compound 11

[0675] 4-(4-((7-ethyl-2,6-dioxo-1,2,5,6-tetrahydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide

[0676] Compound 11D (100 mg, 0.35 mmol), intermediate 8 (93 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 give compound 11 (white solid, 31 mg, yield 27%).

[0677] 1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),10.52(s,1H),8.28(s,1H),7.63(dd,1H),7.31(dd,1H),6.96 –6.60(m,3H),4.13(d,2H),3.08(t,4H),2.81(s,3H),2.56(d,3H),2.49–2.22(m,2H),1.15(t,3H).

[0678] LC-MSm / s = 440.2 [M+1].

[0679] Example 12

[0680] 4-(3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)

[0681] 2-Fluoro-nitro-methylbenzamide compound 12

[0682] 4-(3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-fluoro-N-methylbenzamide

[0683]

[0684] Compound 12 (white solid, 50 mg, yield: 47%) was prepared according to the method of compound 1.

[0685] 1 H NMR (400MHz, DMSO-d6) δ11.77(s,1H),8.14(s,1H),7.75-7.72(m,1H),7.70(s,1H),7.54(t,1H),7.46(s,1H),6.36(s,1H),6.34(s,1H),4. 33-4.32(m,2H),3.59(s,2H),3.04-3.01(m,2H),2.82–2.69(m,5H),2 .55-2.52(m,2H),1.99-1.97(m,1H),1.23-1.21(m,1H),1.17(t,3H).

[0686] LCMSm / s = 436.20 [M+1].

[0687] Example 13

[0688] 2-Chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-6-fluoro-aza-methylbenzamide compound 13

[0689] 2-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylbenzamide

[0690]

[0691] Following the method for compound 1, compound 13 was obtained (white solid, 17.7 mg, yield: 42%).

[0692] 1 H NMR (400MHz, DMSO-d6) δ11.86(s,1H),8.40(s,1H),8.36(q,J=4.6Hz,1H),7.75(s,1H),7.62(s,1H),6.82(s,1H),6.78-6.76 (m,1H),3.62(s,2H),3.28-3.22(m,4H),3.16-3.12(m,2H),2.71(d,J=4.6Hz,3H),2.57–2.51(m,4H),1.18(t,J=7.4Hz,3H).

[0693] 19 F NMR(377MHz,DMSO-d6)δ-113.43(s).

[0694] LCMSm / s = 458.2 [M+1].

[0695] Example 14

[0696] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-2,3,5,6-tetrafluoro-nitro-methylbenzamide compound 14

[0697] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2,3,5,6-tetrafluoro-N-methylbenzamide

[0698]

[0699] Following the method for compound 1, compound 14 (white solid, 6.5 mg, yield: 41%) was obtained.

[0700] 1 H NMR (400MHz, DMSO-d6) δ11.85(s,1H),8.68(d,J=4.6Hz,1H),8.39(s,1H),7.75(s,1H),7.62(s,1H),3.65(s,2 H),3.27-3.22(s,4H),2.76(d,J=4.6Hz,3H),2.57-2.54(m,4H),2.54(d,J=7.4Hz,2H),1.18(t,J=7.4Hz,3H).

[0701] 19 F NMR (377MHz, DMSO-d6) δ-144.07 (dd, J=22.8, 8.3Hz), -150.60 (dd, J=22.8, 8.3Hz).

[0702] LCMSm / s = 478.2 [M+1].

[0703] Example 15

[0704] 4-Bromo-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-2,5,6-trifluoro-N-methylbenzamide compound 15

[0705] 3-bromo-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2,5,6-trifluoro-N-methylbenzamide

[0706]

[0707] Following the method for compound 1, compound 15 (white solid, 15.3 mg, yield: 44%) was obtained.

[0708] 1H NMR (400MHz, DMSO-d6) δ11.85(s,1H),8.53(q,J=4.6Hz,1H),8.38(s,1H),7.74(s,1H),7.63(s,1H),3.60(s ,2H),3.15-3.10(m,4H),3.05-2.99(m,4H),2.77(d,J=4.6Hz,3H),2.57–2.52(m,2H),1.18(d,J=7.4Hz,3H).

[0709] 19 F NMR(377MHz, DMSO-d6)δ-117.65(d,J=11.5Hz),-133.54(d,J=25.6Hz),

[0710] -143.13 (dd, J = 25.6, 11.5 Hz).

[0711] LCMSm / s = 538.1 [M+1].

[0712] Example 16

[0713] (S)-4-(4-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthid-3-yl)methyl)-3-methylpiperazin-1-yl)-2-fluoro-aziro-methylbenzamide compound 16

[0714] (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazin-1-yl)-2-fluoro-N-methylbenzamide

[0715]

[0716] Following the method for compound 1, compound 16 (white solid, 43 mg, yield: 46%) was obtained.

[0717] 1 H NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.54(q,J=4.4Hz,1H),7.95-7.59(m,5H),6.84(s,1H),3.64-3.60(m,4H),3.18– 3.12(m,4H),2.95-2.87(m,1H),2.74(d,J=4.4Hz,3H),2.59–2.53(m,2H),1.46(d,J=6.5Hz,3H),1.18(t,J=8.0Hz,3H).

[0718] 19 F NMR(377MHz,DMSO-d6)δ-111.44.

[0719] LCMSm / s = 438.2 [M+1].

[0720] Example 17

[0721] (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)-3-methylpiperazin-1-yl)-2-fluoro-nitro-methylbenzamide compound 17

[0722] (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazin-1-yl)-2-fluoro-N-methylbenzamide

[0723]

[0724] Following the method for compound 1, compound 17 (white solid, 41 mg, yield: 43%) was obtained.

[0725] 1 H NMR (400MHz, DMSO-d6) δ11.82(s,1H),8.40(d,J=4.7Hz,1H),7.75(s,2H),7.62(s,1H),7.55(t,J=8.9Hz,1H),6.82–6.68 (m,2H),3.64-3.58(m,4H),3.15–3.11(m,4H),2.93-2.84(m,1H),2.74(d,J=4.7Hz,3H),2.58–2.51(m,2H),1.17(m,6H).

[0726] 19 F NMR(377MHz,DMSO-d6)δ-111.57.

[0727] LCMSm / s = 438.2 [M+1]

[0728] Example 18

[0729] (S)-4-(3-(cyanomethyl)-4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-2-fluoro-aziro-methylbenzamide compound 18

[0730] (S)-4-(3-(cyanomethyl)-4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)

[0731] piperazin-1-yl)-2-fluoro-N-methylbenzamide

[0732]

[0733] Following the method for compound 1, compound 18 (white solid, 39 mg, yield: 45%) was obtained.

[0734] 1 H NMR (400MHz, DMSO-d6) δ11.81(s,1H),8.47(q,J=4.4Hz,1H),8.27(s,1H),7.91-7.63(m,3H),6.91-6.83(m,2H),3.65(s,2H ),3.33–3.27(m,4H),3.13-3.09(m,4H),2.91-2.86(m,1H),2.73(d,J=4.4Hz,3H),2.59–2.53(m,2H),1.17(t,J=7.8Hz,3H).

[0735] 19 F NMR(377MHz,DMSO-d6)δ-111.53.

[0736] LCMSm / s = 463.2 [M+1].

[0737] Example 19

[0738] (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)-3-(hydroxymethyl)piperazin-1-yl)-2-fluoro-aziro-methylbenzamide compound 19

[0739] (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-(hydroxymethyl)pipe razin-1-yl)-2-fluoro-N-methylbenzamide

[0740]

[0741] Following the method for compound 1, compound 19 (white solid, 42 mg, yield: 43%) was obtained.

[0742] 1 H NMR (400MHz, DMSO-d6) δ11.81(s,1H),8.42(q,J=4.6Hz,1H),7.76(s,2H),7.65(s,1H),7.57(t,J=9.0Hz,1H),6.80–6.67(m,2H),4.77(t ,J=5.2Hz,1H),3.78–3.43(m,6H),3.05–2.94(m,4H),2.75(d,J=4.6Hz,3H),2.70-2.68(m,1H),2.56-2.53(m,2H),1.18(t,J=7.4Hz,3H).

[0743] 19 F NMR(377MHz,DMSO-d6)δ-111.56.

[0744] LCMSm / s = 454.2 [M+1].

[0745] Example 20

[0746] (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)-3-(hydroxymethyl)piperazin-1-yl)-2-fluoro-aziro-methylbenzamide compound 20

[0747] (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-(hydroxymethyl)piperazin-1-yl)-2-fluoro-N-methylbenzamide

[0748]

[0749] Following the method for compound 1, compound 20 (white solid, 46 mg, yield: 45%) was obtained.

[0750] 1H NMR (400MHz, DMSO-d6) δ11.83(s,1H),8.41(q,J=4.7Hz,1H),7.75(s,2H),7.64(s,1H),7.57(t,J=8.9Hz,1H),6.79–6.67(m,2H),4.79(t ,J=5.2Hz,1H),3.83–3.40(m,6H),3.07-2.99(m,4H),2.74(d,J=4.7Hz,3H),2.71-2.67(m,1H),2.57–2.52(m,2H),1.17(t,J=7.4Hz,3H).

[0751] LCMSm / s = 454.2 [M+1].

[0752] Example 21

[0753] 2-Cyano-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-methylbenzamide compound 21

[0754] 2-cyano-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylbenzamide

[0755]

[0756] Following the method for compound 1, compound 21 (white solid, 43 mg, yield: 44%) was obtained.

[0757] 1 H NMR (400MHz, DMSO-d6) δ11.85(s,1H),9.62(s,1H),8.40(q,J=4.7Hz,1H),7.91(d,J=8.5Hz,1H),7.75(s,2H),7.2 7–7.18(m,2H),3.64(s,2H),3.09-3.87(m,4H),2.75(d,J=4.7Hz,3H),2.54-2.51(m,6H),1.18(t,J=7.4Hz,.3H).

[0758] LCMSm / s = 431.2 [M+1].

[0759] Example 22

[0760] 4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-N-methylbenzamide compound 22

[0761] 4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-N-methylbenzamide

[0762]

[0763] Following the method for compound 1, compound 22 (white solid, 39 mg, yield: 46%) was obtained.

[0764] 1 H NMR (400MHz, DMSO-d6) δ11.85(s,1H),8.51(q,J=4.5Hz,1H),8.41(s,1H),7.75(s,1H),7.70–7.57(m,3H),7.49–7.41(m,1H) ,6.08(s,1H),3.71(s,2H),3.14-3.12(m,2H),2.77(d,J=4.5,3H),2.69-2.64(m,2H),2.58–2.51(m,4H),1.18(d,J=7.5,3H).

[0765] 19 F NMR(377MHz,DMSO-d6)δ-114.94.

[0766] LCMSm / s = 421.2 [M+1].

[0767] Example 23

[0768] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-methylbenzamide compound 23

[0769] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylbenzamide

[0770]

[0771] Following the method for compound 1, compound 23 (white solid, 100 mg, yield: 70%) was obtained.

[0772] 1 H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.40(d,1H),8.13(q,1H),7.75(d,1H),7.72–7.67(m,2H),7.62( d,1H),6.97–6.90(m,2H),3.64(s,2H),3.27–3.24(m,4H),2.73(d,3H),2.57–2.52(m,6H),1.18(t,3H).

[0773] LCMSm / s = 406.20 [M+1].

[0774] Example 24

[0775] (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-nitro-(tetrahydrofuran-3-yl)benzamide compound 24

[0776] (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

[0777]

[0778]

[0779] first step

[0780] (R)-4-bromo-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide 24B

[0781] (R)-4-bromo-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

[0782] Compound 24A (2 g, 9.9 mmol) was dissolved in dichloromethane (20 mL). Under ice-water bath conditions, (R)-tetrahydrofuran-3-amine (1.73 g, 19.8 mmol), HATU (3.5 g, 14.8 mmol), and triethylamine (2 mL) were added dropwise. The reaction was carried out at room temperature for 90 min. After the reaction was completed, the solution was concentrated under reduced pressure and purified by column chromatography to obtain 24B (yellow solid, 2.1 g, yield 78%).

[0783] LC-MSm / z(ESI) = 287.10[M+1].

[0784] Step 2

[0785] (R)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 24C

[0786] tert-butyl

[0787] (R)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate

[0788] Following the synthetic method of compound 1c, compound 24C (white solid, 1.8 g, yield 88%) was synthesized and isolated.

[0789] 1 H NMR(400MHz,DMSO-d6)δ8.36(dd,1H),7.80(d,1H),7.74(d,1H),7.62(d,1H),3.23–3.03(m,4H),2.8 6-2.71(m,3H),2.67–2.42(m,4H),2.49–2.29(m,2H),2.23(dt,1H),1.95–1.83(m,1H),1.50(s,9H).

[0790] LC-MSm / z(ESI) = 394.12 [M+1].

[0791] Step 3

[0792] (R)-3-Fluoro-4-(piperazin-1-yl)-nitro-(tetrahydrofuran-3-yl)benzamide 24D

[0793] (R)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide

[0794] Following the synthetic method for intermediate 1, compound 24D (white solid, 1.0 g, yield 81%) was synthesized and isolated.

[0795] LC-MSm / z(ESI) = 294.15[M+1].

[0796] Step 4

[0797] (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-nitro-(tetrahydrofuran-3-yl)benzamide compound 24

[0798] (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

[0799] Following the synthetic method of compound 1, compound 24 (white solid, 26 mg, yield 54%) was synthesized and isolated.

[0800] 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.40(dd,1H),8.00–7.48(m,5H),7.05(t,1H),4.41(dtt,1H),3.96–3.48( m,6H),3.23–3.00(m,4H),2.64–2.39(m,4H),2.13(dtd,1H),1.96–1.81(m,1H),1.37–1.21(m,2H),1.18(t,3H).

[0801] Example 25

[0802] (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-nitro-(tetrahydrofuran-3-yl)benzamide compound 25

[0803] (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

[0804]

[0805] first step

[0806] (S)-4-bromo-3-fluoro-nitro-(tetrahydrofuran-3-yl)benzamide 25A

[0807] (S)-4-bromo-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

[0808] Following the synthetic method of compound 24B, compound 25A (yellow solid, 2.3 g, yield 82%) was synthesized and isolated.

[0809] LC-MSm / z(ESI) = 287.10[M+1].

[0810] Step 2

[0811] (S)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 25B

[0812] tert-butyl

[0813] (S)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate

[0814] Following the synthetic method of compound 1c, compound 25B (white solid, 2.5 g, yield 89%) was synthesized and isolated.

[0815] 1 H NMR(400MHz,DMSO-d6)δ8.36(dd,1H),7.80(d,1H),7.74(d,1H),7.62(d,1H),3.23–3.03(m,4H),2.8 6-2.71(m,3H),2.67–2.42(m,4H),2.49–2.29(m,2H),2.23(dt,1H),1.95–1.83(m,1H),1.50(s,9H).

[0816] LC-MSm / z(ESI) = 394.12 [M+1].

[0817] Step 3

[0818] (S)-3-Fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide 25C

[0819] (S)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide

[0820] Following the synthetic method for intermediate 1, compound 25C (white solid, 1.6 g, yield 83%) was synthesized and isolated.

[0821] LC-MSm / z(ESI) = 294.15[M+1].

[0822] Step 4

[0823] (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-nitro-(tetrahydrofuran-3-yl)benzamide compound 25

[0824] (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

[0825] Following the synthetic method of compound 1, compound 25 (white solid, 19 mg, yield 42%) was synthesized and isolated.

[0826] 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.40(dd,1H),8.00–7.48(m,5H),7.05(t,1H),4.41(dtt,1H),3.96–3.48 (m,6H),3.23–3.00(m,4H),2.64–2.39(m,4H),2.13(dtd,1H),1.96–1.81(m,1H),1.37–1.21(m,2H),1.18(t,3H)

[0827] Example 26

[0828] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide compound 26

[0829] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide

[0830]

[0831] first step

[0832] 4-Bromo-3-fluoro-N-(2-hydroxyethyl)benzamide 26A

[0833] 4-bromo-3-fluoro-N-(2-hydroxyethyl)benzamide

[0834] Following the synthetic method of compound 24B, compound 26A (yellow solid, 2.5 g, yield 82%) was synthesized and isolated.

[0835] LC-MSm / z(ESI) = 261.98 [M+1].

[0836] Step 2

[0837] 4-(2-Fluoro-4-((2-hydroxyethyl)carbamoyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 26B

[0838] tert-butyl 4-(2-fluoro-4-((2-hydroxyethyl)carbamoyl)phenyl)piperazine-1-carboxylate

[0839] Following the synthetic method of compound 1c, compound 26B (white solid, 2.2 g, yield 83%) was synthesized and isolated.

[0840] 1 H NMR (400MHz, DMSO-d6) δ8.35(d,1H),7.78(d,1H),7.42–7.12(m,2H),5.41(s,1H),3.15(s,6H),2.65–2.42(m,6H),1.51(s,9H).

[0841] LC-MSm / z(ESI) = 394.12 [M+1].

[0842] Step 3

[0843] 3-Fluoro-4-(piperazin-1-yl)-nitro-(tetrahydrofuran-3-yl)benzamide 26C

[0844] 3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide

[0845] Following the synthetic method for intermediate 1, compound 26C (white solid, 1.6 g, yield 83%) was synthesized and isolated.

[0846] LC-MSm / z(ESI) = 254.12[M+1].

[0847] Step 4

[0848] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide compound 26

[0849] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide

[0850] Following the synthetic method of compound 1, compound 26 (white solid, 19 mg, yield 42%) was synthesized and isolated.

[0851] 1 H NMR(400MHz,DMSO-d6)δ8.41(d,1H),8.17(d,1H),7.75(d,1H),7.64(d,1H),7.42–7.14(m ,2H),5.25(s,1H),4.44(d,2H),3.69(s,3H),3.19(s,6H),2.69–2.51(m,7H),1.17(t,3H).

[0852] Example 27

[0853] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-2-fluoro-nitro-(2-hydroxyethyl)benzamide compound 27

[0854] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(2-hydroxyethyl)benzamide

[0855]

[0856] Compound 27 (white solid, 42 mg, yield: 74%) was prepared according to the method of compound 1.

[0857] 1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.40(s,1H),7.75(s,1H),7.69(s,1 H),7.62(s,1H),7.58(d,J=9.0Hz,1H),6.79(d,J=9.4Hz,1H),6.74(d,J=1 5.3Hz,1H),4.74(t,J=5.4Hz,1H),3.63(d,J=4.6Hz,2H),3.47(t,J=5.6Hz ,2H),3.29(d,J=4.8Hz,8H),2.54(d,J=8.1Hz,4H),1.18(t,J=7.4Hz,3H).

[0858] LCMSm / s = 454.52 [M+1].

[0859] Example 28

[0860] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(2-methoxyethyl)benzamide compound 28

[0861] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(2-methoxyethyl)benzamide

[0862]

[0863] Compound 28 (white solid, 42 mg, yield: 74%) was prepared according to the method of compound 1.

[0864] 1 H NMR (400MHz, DMSO-d6) δ11.85(s,1H),8.40(d,J=1.8Hz,1H),7.75(s,1H),7.73(s,1H),7.62(d,J=1.8Hz,1H),7.57(t,J=9.0Hz,1H),6.79(dd,J= 8.8,2.4Hz,1H),6.77–6.71(m,1H),3.64(s,2H),3.46–3.34(m,6H),3.28 (d,J=5.4Hz,4H),3.26(s,3H),2.57–2.52(m,4H),1.18(t,J=7.4Hz,3H).

[0865] LCMSm / s = 468.55 [M+1].

[0866] Example 29

[0867] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-2-fluoro-aza-(1-methylazacyclobutane-3-yl)benzamide compound 29

[0868] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(1-methylazetidin-3-yl)benzamide

[0869]

[0870] Compound 29 (white solid, 11 mg, yield: 63%) was prepared according to the method of compound 1.

[0871] 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.59–8.50(m,2H),7.80(s,1H),7.76(s,1H),7.64(td,J=8.9,2.8Hz,1H),6.95–6.84(m,2H),4.8 5–4.71(m,1H),4.53–4.29(m,4H),4.09(d,J=40.8Hz,4H),3.22(s,4H),2.88(dd,J=7.4,4.7Hz,3H),2.60(s,4H),1.19(t,J=7.4Hz,3H).

[0872] LCMSm / s = 479.57 [M+1].

[0873] Example 30

[0874] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-2-fluoro-nitro-(oxoalkyl-3-yl)benzamide compound 30

[0875] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(oxetan-3-yl)benzamide

[0876]

[0877] Compound 30 (white solid, 17 mg, yield: 64%) was prepared according to the method of compound 1.

[0878] 1 H NMR(400MHz,DMSO-d6)δ11.93(s,1H),9.37(s,1H),8.43(s,1H),7.75(s,1H), 7.66(d,J=8.0Hz,2H),6.84–6.73(m,2H),4.85(t,J=5.6Hz,1H),4.42–4.21(m, 2H),4.18(q,J=7.1,6.3Hz,2H),3.59(ddt,J=10.0,7.4,3.3Hz,4H),3.45(d,J =15.0Hz,2H),3.11(qd,J=7.4,4.1Hz,2H),2.56(s,4H),1.17(t,J=7.4Hz,3H).

[0879] LCMSm / s = 466.53 [M+1].

[0880] Example 31

[0881] N-(2-(dimethylamino)ethyl)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-2-fluorobenzamide compound 31

[0882] N-(2-(dimethylamino)ethyl)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluorobenzamide

[0883]

[0884] Compound 31 (white solid, 16 mg, yield: 57%) was prepared according to the method of compound 1.

[0885] 1H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.59(d,J=1.8Hz,1H),8.24(d,J=5.8Hz,1H),7.82(d,J=5.2Hz,2H),7.66(t,J=8.8Hz,1H),6.93–6.85(m, 2H),4.76(s,2H),3.78(d,J=6.4Hz,2H),3.52(d,J=5.7Hz,6H),3.22(d, J=5.4Hz,4H),3.08(s,6H),2.59(t,J=7.4Hz,2H),1.18(d,J=7.3Hz,3H).

[0886] LCMSm / s = 481.59 [M+1].

[0887] Example 32

[0888] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-2-fluoro-nitro-(oxoalkyl-3-yl)benzamide compound 32

[0889] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro-N-(oxetan-3-yl)benzamide

[0890]

[0891] Compound 32 (white solid, 68 mg, yield: 72%) was prepared according to the method of compound 1.

[0892] 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.40(d,J=1.9Hz,1H),8.06–7.99(m,1H),7.75(s,1H),7.61(d,J=1.8Hz,1H),7.39(dd,J=13.5,6.8Hz ,1H),6.89(dd,J=12.7,7.1Hz,1H),3.64(s,2H),3.13(t,J=4.8Hz,4H),2.75(d,J=4.5Hz,3H),2.54(d,J=8.5Hz,6H),1.18(t,J=7.4Hz,3H).

[0893] LCMSm / s = 442.48 [M+1].

[0894] Example 33

[0895] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-2,5-difluoro-nitro-methylbenzamide compound 33

[0896] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2,5-difluoro-N-methylbenzamide

[0897]

[0898] Compound 33 (white solid, 57 mg, yield: 64%) was prepared according to the method of compound 1.

[0899] 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.37(d,J=1.9Hz,1H),8.06–7.99(m,1H),7.75(s,1H),7.61(d,J=1.8Hz,1H),7.29(dd,J=13.5,6.8Hz ,1H),6.89(dd,J=12.7,7.1Hz,1H),3.64(s,2H),3.13(t,J=4.8Hz,4H),2.75(d,J=4.5Hz,3H),2.54(d,J=8.5Hz,6H),1.18(t,J=7.4Hz,3H).

[0900] LCMSm / s = 442.48 [M+1].

[0901] Example 34

[0902] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-methoxyethyl)benzamide compound 34

[0903] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-methoxyethyl)benzamide

[0904]

[0905] Compound 34 (white solid, 36 mg, yield: 68%) was prepared according to the method of compound 1.

[0906] 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.43(t,J=5.3Hz,1H),8.40(d,J=1.8Hz,1H),7.75(s,1H),7.66–7.58(m,3H),7.05( t,J=8.7Hz,1H),3.64(s,2H),3.44-3.38(m,4H),3.25(s,3H),3.16–3.08(m,4H),2.60–2.52(m,6H),1.18(t,J=7.4Hz,3H).

[0907] LCMSm / s = 468.23 [M+1].

[0908] Example 35

[0909] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-((1s,3s)-3-hydroxycyclobutyl)benzamide compound 35

[0910] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-((1s,3s)-3-hydroxycyclobutyl)benzamide

[0911]

[0912] Compound 35 (white solid, 41 mg, yield: 65%) was prepared according to the method of compound 1.

[0913] 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.44(s,1H),8.40(d,J=1.8Hz,1H),7.75(s,1H),7.67–7.60(m,3H),7.04(t,J=8.8Hz,1H),5.10(d,J=5 .5Hz,1H),3.90–3.80(m,2H),3.65(s,2H),3.17-3.11(m,4H),2.59–2. 52(m,6H),1.92-1.85(m,2H),1.28–1.23(m,2H),1.18(t,J=7.4Hz,3H).

[0914] 19 F NMR(377MHz,DMSO-d6)δ-122.18.

[0915] LCMSm / s = 480.23 [M+1].

[0916] Example 36

[0917] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-((1r,3r)-3-hydroxycyclobutyl)benzamide compound 36

[0918] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-((1r,3r)-3-hydroxycyclobutyl)benzamide

[0919]

[0920] Compound 36 (white solid, 44 mg, yield: 68%) was prepared according to the method of compound 1.

[0921] 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.45(d,J=6.8Hz,1H),8.40(d,J=1.8Hz,1H),7.75(s,1H),7.64-7.60(m,3H),7.05(t,J=8.7Hz,1H),5.02(d ,J=5.3Hz,1H),4.45–4.26(m,2H),3.65(s,2H),3.19–3.08(m,4H),2.58- 2.53(m,6H),2.27-2.21(m,2H),2.16-2.09m,2H),1.18(t,J=7.4Hz,3H).

[0922] LCMSm / s = 480.23 [M+1].

[0923] Example 37

[0924] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-methoxyethyl)benzamide compound 37

[0925] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-methoxyethyl)benzamide

[0926]

[0927] Compound 37 (white solid, 32 mg, yield: 84%) was prepared according to the method of compound 1.

[0928] 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.40(d,1H),8.19(t,1H),7.75(d,1H),7.66(d,1H),7.65–7.60(m,2H), 7.06(t,1H),4.56(s,1H),3.65(s,2H),3.22(d,2H),3.11(d,4H),2.61–2.51(m,6H),1.18(t,3H),1.07(s,6H).

[0929] LCMSm / s = 482.57 [M+1].

[0930] Example 38

[0931] (S)-4-(4-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide compound 38

[0932] (S)-4-(4-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

[0933]

[0934] first step

[0935] 7-Chloro-6-oxo-5,6-dihydro-1,5-naphthyl-3-carboxylic acid ethyl ester 38A

[0936] ethyl 7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate

[0937] Intermediate 10D (1 g, 2.9 mmol) was added to a 1,4-dioxane hydrochloride solution (10 mL, 4 mol / L) at room temperature and reacted at 80 °C for 16 hours. After the reaction was completed, the mixture was filtered to obtain 38A (yellow solid, 700 mg, yield 95%).

[0938] LC-MSm / z(ESI) = 253.00 [M+1].

[0939] Step 2

[0940] 3-Chloro-7-(hydroxymethyl)-1,5-naphthidium-2(1H)-one 38B

[0941] 3-chloro-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one

[0942] Following the synthetic method of compound 10G, intermediate 38B (yellow solid, 500 mg, yield 85%) was obtained.

[0943] 1 H NMR (400MHz, DMSO-d6) δ12.50(dr,1H),8.45(d,1H),8.27(d,1H),7.68(d,1H),5.53(dr,1H),4.64(d,2H).

[0944] LC-MSm / z(ESI) = 211.00[M+1].

[0945] Step 3

[0946] 7-(bromomethyl)-3-chloro-1,5-naphthidium-2(1H)-one 38C

[0947] 7-(bromomethyl)-3-chloro-1,5-naphthyridin-2(1H)-one

[0948] Following the synthetic method of compound 10H, intermediate 38C (yellow solid, 400 mg, yield 62%) was obtained.

[0949] LC-MSm / z(ESI) = 273.00 [M+1].

[0950] Step 4

[0951] (S)-4-(4-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide compound 38

[0952] (S)-4-(4-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

[0953] Compound 38 (white solid, 20 mg, yield: 20%) was prepared according to the method of compound 1.

[0954] 1 H NMR(400MHz,DMSO-d6)δ11.89(dr,1H),8.46(d,1H),8.41(d,1H),7.80–7.48(m,3H), 7.44(s,1H),6.79(d,1H),4.42(dtt,1H),3.96–3.50(m,6H),3.25–3.01(m,4H),2.64–

[0955] 2.39(m,2H),2.12(dtd,1H),1.94–1.81(m,1H),1.38–1.22(m,2H).

[0956] LCMSm / s = 486.20 [M+1].

[0957] Example 39

[0958] 4-(4-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)3-fluoro-N-(2-hydroxyethyl)benzamide compound 39

[0959] 4-(4-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide

[0960]

[0961] Compound 39 (white solid, 25 mg, yield: 28%) was prepared according to the method of compound 1.

[0962] 1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.47(d,1H),8.40(d,1H),7.79(d,1H),7.70(d,1H),7.60(t,1H), 7.58(d,1H),6.75(d,1H),4.74(t,1H),3.63(d,2H),3.47(t,2H),3.29–3.18(m,6H),2.54–2.48(m,4H).

[0963] LCMSm / s = 460.20 [M+1].

[0964] Example 40

[0965] 4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperidin-4-yl)-3-fluoro-N-methylbenzamide compound 40

[0966] 4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperidin-4-yl)-3-fluoro-N-methylbenzamide

[0967]

[0968] Compound 40 (white solid, 28 mg, yield: 81%) was prepared according to the method of compound 1.

[0969] 1 H NMR (400MHz, DMSO-d6) δ11.85(s,1H),8.46(d,1H),8.39(s,1H),7.75(s,1H),7.68–7.51(m,3H),7.44(t,1H),3. 61(s,2H),2.93-2.82(m,3H),2.77(d,3H),2.56-2.52(m,2H),2.14-2.10(m,2H),1.75-1.72(m,4H),1.18(t,3H).

[0970] LCMSm / s = 423.21 [M+1].

[0971] Example 41

[0972] (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxypropyl)benzamide compound 41

[0973] (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxypropyl)benzamide

[0974]

[0975] Compound 41 (white solid, 42 mg, yield: 77%) was prepared according to the method of compound 1.

[0976] 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.40(d,1H),8.32(t,1H),7.75(d,1H),7.65-7.60(m,3H),7.05(t,1H),4.73(d,1 H),3.80–3.72(m,1H),3.65(s,2H),3.18-3.14(m,2H),3.12-3.10(m,4H),2.60–2.52(m,6H),1.18(t,3H),1.04(d,3H).

[0977] LCMSm / s = 468.23 [M+1].

[0978] Example 42

[0979] (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxypropyl)benzamide compound 42

[0980] (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxypropyl)benzamide

[0981]

[0982] Compound 42 (white solid, 54 mg, yield: 82%) was prepared according to the method of compound 1.

[0983] 1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.40(d,1H),8.31(t,1H),7.75(d,1H),7.64-7.60(m,3H),7.05(t,1H),4.73(d,1 H),3.80–3.71(m,1H),3.65(s,2H),3.18-3.14(m,2H),3.12-3.10(m,4H),2.60–2.52(m,6H),1.18(t,3H),1.04(d,3H).

[0984] LCMSm / s = 468.23 [M+1].

[0985] Example 43

[0986] 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxyethyl)nicotinamide compound 43

[0987] 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydrox yethyl)nicotinamide

[0988]

[0989] Compound 43 (white solid, 44 mg, yield: 73%) was prepared according to the method of compound 1.

[0990] 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.40(d,1H),8.31(t,1H),7.75(d,1H),7.64-7.60(m,3H),7.05(t,1H),4.73(d,1H),3 .80–3.71(m,1H),3.65(s,2H),3.18-3.14(m,2H),3.12-3.10(m,4H),2.60–2.52(m,6H),1.18(t,3H),1.04(d,J=6.2Hz,3H).

[0991] LCMSm / s = 437.22 [M+1].

[0992] Example 44

[0993] 4-Chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-methylbenzamide compound 44

[0994] 4-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylbenzamide

[0995]

[0996] Compound 44 (white solid, 49 mg, yield: 88%) was prepared according to the method of compound 1.

[0997] 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.59–8.25(m,2H),7.86(d,1H),7.76(d,2H),7.66–7.5 7(m,1H),7.18(d,1H),3.66(s,2H),3.05(s,4H),2.75(d,3H),2.64–2.51(m,6H),1.19(q,3H).

[0998] LCMSm / s = 440.18 [M+1].

[0999] Example 45

[1000] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-((1-hydroxycyclopropyl)methyl)benzamide compound 45

[1001] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-((1-hydroxycyclopropyl)methyl)benzamide

[1002]

[1003] Compound 45 (white solid, 37 mg, yield: 71%) was prepared according to the method of compound 1.

[1004] 1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.70(t,1H),8.40(d,1H),7.75(s,1H),7.71–7.56(m,3H),7.08(t,1H), 4.37–3.98(m,5H),3.65(s,2H),3.23–3.05(m,4H),2.62–2.51(m,4H),2.46(t,2H),1.42(s,2H),0.94(t,3H).

[1005] LCMSm / s = 480.56 [M+1].

[1006] Example 46

[1007] 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-methoxyethyl)benzamide compound 46

[1008] 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-methoxyethyl)benzamide

[1009]

[1010] Compound 46 (white solid, 34 mg, yield: 65%) was prepared according to the method of compound 1.

[1011] 1 H NMR (400MHz, DMSO-d6) δ11.90(s,1H),8.43(t,1H),8.37(d,1H),7.69–7.53(m,3H),7.41(s,1H),7.04(t,1H),3. 62(s,2H),3.41(dd,4H),3.25(s,3H),3.10(t,4H),2.55(t,4H),2.13(tt,1H),0.96(dt,2H),0.86–0.72(m,2H).

[1012] LCMSm / s = 480.23 [M+1].

[1013] Example 47

[1014] (R)-4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide compound 47

[1015] (R)-4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

[1016]

[1017] Compound 47 (white solid, 33 mg, yield: 64%) was prepared according to the method of compound 1.

[1018] 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.41(t,1H),8.37(dd,1H),7.65–7.51(m,3H),7.41(s,1H),7.04(t,1H),4.43(dtt,1H),3.92–3.44(m,3 H),3.21–3.00(m,4H),2.64–2.39(m,3H),2.13(dtd,1H),1.96–1.81(m ,1H),1.33–1.20(m,2H),1.15(t,3H).0.95(dt,2H),0.85–0.70(m,2H).

[1019] LCMSm / s = 492.23 [M+1].

[1020] Example 48

[1021] 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide compound 48

[1022] 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide

[1023]

[1024] Compound 48 (white solid, 31 mg, yield: 62%) was prepared according to the method of compound 1.

[1025] 1 H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.46–8.27(m,2H),7.68–7.56(m,3H),7.42(s,1H),7.05(t,1H),4.74(t,1H),3.6 3(s,2H),3.48(dd,2H),3.29(d,2H),2.56(t,4H),2.20–2.07(m,2H),1.23(s,3H),1.02–0.90(m,2H),0.87–0.74(m,2H).

[1026] LCMSm / s = 466.22 [M+1].

[1027] Example 49

[1028] (R)-6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)nicotinamide compound 49

[1029] (R)-6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)nicotinamide

[1030]

[1031] Compound 49 (white solid, 41 mg, yield: 65%) was prepared according to the method of compound 1.

[1032] 1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.60(d,1H),8.40(d,1H),8.28(d,1H),7.97 (dd,1H),7.75(s,1H),7.62(d,1H),6.84(d,1H),4.47–4.38(m,1H),3.86-3.81(m, 2H),3.72-3.66(m,1H),3.63(s,2H),3.61-3.59(m,4H),3.56-3.52(m,1H),2.59–2 .52(m,2H),2.49-2.47(m,4H),2.19–2.07(m,1H),1.94–1.83(m,1H),1.18(t,3H).

[1033] LCMSm / s = 463.24 [M+1].

[1034] Example 50

[1035] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-methylpyrazine-2-carboxamide compound 50

[1036] 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpyrazine-2-carboxamide

[1037]

[1038] Following the method for compound 1, compound 50 (white solid, 37 mg, yield: 76%) was obtained.

[1039] 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.59(d,1H),8.40(d,1H),8.34(d,1H),8.26(d,1H),7.7 5(s,1H),7.62(d,1H),3.70(t,4H),3.65(s,2H),2.77(d,3H),2.58–2.51(m,6H),1.18(t,3H).

[1040] LCMSm / s = 408.48 [M+1].

[1041] Example 51

[1042] 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-5-fluoro-N-methylnicotinamide compound 51

[1043] 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-5-fluoro-N-methylnicotinamide

[1044]

[1045] Following the method for compound 1, compound 51 (white solid, 31 mg, yield: 67%) was obtained.

[1046] 1 H NMR (400MHz, DMSO-d6) δ8.52–8.32(m,3H),7.92–7.52(m,4H),3.59(d,6H),3.17(d,2H),2.76(d,3H),2.52(s,4H),1.18(t,3H).

[1047] LCMSm / s = 404.49 [M+1].

[1048] Example 52

[1049] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-3,5-difluoro-N-methylbenzamide compound 52

[1050] 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3,5-difluoro-N-methylbenzamide

[1051]

[1052] Following the method for compound 1, compound 52 (white solid, 50 mg, yield: 32%) was obtained.

[1053] 1H NMR(400MHz,DMSO-d6)δ11.84(s,1H),8.45(q,1H),8.39(d,H),7.74(d,1H),7.63(d,1H),7.50(s ,1H),7.47(s,1H),3.64(s,2H),3.23-3.17(m,4H),2.75(d,3H),2.57-2.51(m,6H),1.18(t,3H).

[1054] LCMSm / s = 442.20 [M+1].

[1055] Example 53

[1056] 2-Chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-5-fluoro-N-methylbenzamide compound 53

[1057] 2-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-5-fluoro-N-methylbenzamide

[1058]

[1059] Following the method for compound 1, compound 53 (white solid, 40 mg, yield: 45%) was obtained.

[1060] 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.40(s,1H),8.27–8.22(m,1H),7.75(s,1H),7.61(s,1H),7.2 6(d,1H),7.03(d,1H),3.65(s,2H),3.11–3.05(m,4H),2.72(d,3H),2.63–2.52(m,6H),1.18(t,3H).

[1061] LCMSm / s = 458.20 [M+1].

[1062] Example 54

[1063] 2,6-Dichloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-methylbenzamide compound 54

[1064] 2,6-dichloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylbenzamide

[1065]

[1066] Following the method for compound 1, compound 54 (white solid, 15 mg, yield: 14%) was obtained.

[1067] 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.39(d,1H),8.37–8.31(m,1H),7.75(s,1H),7.61(d,1 H),6.96(s,2H),3.63(s,2H),3.27–3.21(m,4H),2.71(d,3H),2.58–2.51(m,6H),1.18(t,3H).

[1068] LCMSm / s = 474.10 [M+1].

[1069] Example 55

[1070] (R)-3-chloro-4-(4-((7-methyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide compound 55

[1071] (R)-3-chloro-4-(4-((7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide

[1072]

[1073] Compound 55 (white solid, 36 mg, yield: 67%) was prepared according to the method of compound 1.

[1074] 1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.50(d,1H),8.40(d,1H),7.93(d,1H),7.85–7.76(m,2H),7.62(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).

[1075] LCMSm / s = 482.98 [M+1].

[1076] Example 56

[1077] 3-Chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)benzamide compound 56

[1078] 3-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)benzamide

[1079]

[1080] Compound 56 (white solid, 30 mg, yield: 62%) was prepared according to the method of compound 1.

[1081] 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.55–8.30(m,2H),7.93(d,1H),7.80(dd,1H),7.75(s,1H),7.62(s,1H),7.19(d,1H),5.27(d, 1H),4.18(d,2H),3.98(dd,1H),3.89(dd,1H),3.66(s,2H),3.61(dd,1H),3.52(dd,1H),3.06(s,4H),2.58-2.50(m,6H),1.18(t,3H).

[1082] LCMSm / s = 512.21 [M+1].

[1083] Example 57

[1084] 3-Chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)benzamide compound 57

[1085] 3-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)benzamide

[1086]

[1087] Compound 57 (white solid, 34 mg, yield: 71%) was prepared according to the method of compound 1.

[1088] 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.56–8.31(m,2H),7.91(d,1H),7.80(dd,1H),7.76(s,1H),7.61(s,1H),7.15(d,1H),4.18(d, 2H),3.98(dd,1H),3.89(dd,1H),3.66(s,2H),3.61(dd,1H),3.52(dd,1H),3.06(s,4H),2.58-2.50(m,6H),1.39(s,3H)1.18(t,3H).

[1089] LCMSm / s = 510.22 [M+1].

[1090] Example 58

[1091] N-(3-oxazolylcyclo[3.1.0]hexane-6-yl)-3-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)benzamide compound 58

[1092] N-(3-oxabicyclo[3.1.0]hexan-6-yl)-3-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)benzamide

[1093]

[1094] Compound 58 (white solid, 30 mg, yield: 58%) was prepared according to the method of compound 1.

[1095] 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.50–8.37(m,2H),7.86(d,1H),7.81–7.70(m,2H),7.62(s,1H),7.1 9(d,1H),3.85(d,2H),3.72–3.52(m,4H),3.06(s,4H),2.69–2.53(m,7H),1.90–1.83(m,2H),1.18(t,3H).

[1096] LCMSm / s = 508.20 [M+1].

[1097] Biological experiments

[1098] 1. PARP1 / PARP2 trapping experiment procedure:

[1099] 1.1 PARP1 trapping experiment:

[1100] (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);

[1101] (2) Prepare 4×DSB DNA probe-1 (purchased from Generay) with buffer and add 4 μL / well to a 384-well plate;

[1102] (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;

[1103] (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;

[1104] (5) Results were obtained using TR-FRET detection, curve fitting was performed using GraphPad 5.0, and IC analysis was conducted. 50 The calculation.

[1105] 1.2 PARP2 trapping experiment:

[1106] (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);

[1107] (2) Prepare 4×PARP2 probe2 (purchased from Generay) with buffer solution and add 4 μL / well to a 384-well plate;

[1108] (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;

[1109] (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;

[1110] (5) Results were obtained using TR-FRET detection, curve fitting was performed using GraphPad 5.0, and IC analysis was conducted. 50 The calculation.

[1111]

[1112] Note: Comparative Example 1 is compound 25 of J.Med.Chem(2021),64(19)14498–14512, which was prepared according to its preparation method.

[1113] Conclusion: The compounds of this invention exhibit significant inhibitory activity against PARP1 trapping and good selectivity relative to PARP2 trapping.

[1114] 2. PARP1 and PARP2 activity inhibition test

[1115] The inhibitory activities of the compounds against PARP1 and PARP2 were detected using the PARP1 chemiluminescent assay (purchased from BPS Bioscience, catalog number: 80551) and the PARP2 chemiluminescent assay (purchased from BPS Bioscience, catalog number: 80552), respectively. The results were quantified using chemiluminescence. The specific experimental protocol is as follows:

[1116] (1) Coat the 96-well plate overnight with 1×histone mixture (50 μL / well);

[1117] (2) Discard the coating solution; add Blocking buffer 3 (200 μL) to each well and incubate at room temperature for 90 min;

[1118] (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 h;

[1119] (4) Discard the liquid, wash twice with PBST; add 50 μL of Streptavidin-HRP (Blockingbuffer 3 diluted 50 times); incubate at room temperature for 30 min;

[1120] (5) Discard the liquid, wash 3 times with PBST; add 100μL of ELISA ECL Substrate A / B mix (50μL each);

[1121] (6) Microplate reader test results, IC50 analysis was performed using GraphPad Prism 8. 50 The calculation.

[1122] The results show that the compounds of the present invention have significant inhibitory activity against PARP1 and good selectivity relative to PARP2.

[1123] 3. DLD1 BRCA2- / - Cell proliferation inhibition assay

[1124] 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) was 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).

[1125] 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).

[1126] GraphPadPrism 8.0 for curve fitting and IC 50 Calculation. Microplate reader results were analyzed using GraphPad Prism8 for IC50 analysis. 50 The calculation.

[1127]

[1128] The results showed that the compound of the present invention had a significant inhibitory effect on the proliferation of DLD1 BRCA2- / - cells.

[1129] 4. MDA-MB-436 cell proliferation inhibition experiment

[1130] 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).

[1131] The 384-well plates were incubated in an incubator (37℃, 5% CO2) for 7 consecutive days. Then, the plates were removed and incubated 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 incubated at room temperature for 30 minutes. The chemiluminescence values ​​were measured using a microplate reader (PerkinElmer; EnVision).

[1132] The detection results were used for curve fitting and IC analysis using GraphPad Prism 8. 50 The calculation.

[1133]

[1134] Comparative Example 2 was prepared according to the synthesis method of compound 62 in patent WO2009053373A.

[1135] The results showed that the compound of the present invention had a significant inhibitory effect on the proliferation of MDA-MB-436 cells.

[1136] 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 or a stereoisomer thereof, wherein the compound is selected from compounds represented by general formula (IV) or stereoisomers thereof: Ra3 is C 1-6 alkyl; R e Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 Heterocyclic alkyl groups, optionally further substituted with one or more substituents selected from hydroxyl groups.

2. A compound or its stereoisomers, wherein the compound is selected from:

3. A pharmaceutical composition comprising: (1) The compound or its stereoisomer as claimed in claim 1 or 2; (2) One or more other active ingredients may be selected; as well as (3) Pharmaceutically acceptable carriers and / or excipients.

4. Use of the pharmaceutical composition of claim 3 or the compound or stereoisomer of claim 1 or 2 in the preparation of an antitumor drug.

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