Selective PARP1 inhibitors and their uses

Abstract

Selective PARP1 inhibitors and their applications. The present invention provides a compound represented by the general formula (IA), and its stereoisomers, pharma- ceutically acceptable salts or deuterated compounds. It also provides a pharmaceutical composition comprising the compound or its stereoisomer, and the application of the compound and pharmaceutical composition in the preparation of antitumor drugs. [Formula 1] JPEG2024540600000101.jpg24169

Description

Detailed Description of the Invention

[0001] [Technical Field] The present invention relates to selective PARP1 inhibitors or stereoisomers thereof and their use in medicine. [Background technology] PARP (poly(ADP-ribose) polymerase) is an enzyme that catalyzes the poly(ADP-ribosylation) of various proteins. This process plays an important role in many intracellular processes, including DNA damage repair, transcriptional regulation, and chromatin reorganization and remodeling. Currently, several PARP1 / 2 inhibitors are commercially available. However, whether used alone or in combination, PARP1 / 2 inhibitors have common side effects in the blood and gastrointestinal tract, limiting their clinical application. Therefore, the development of safer and more effective PARP inhibitors remains an urgent clinical challenge. A series of studies have shown that highly selective PARP1 inhibitors exhibit superior efficacy and lower toxicity compared with PARP1 / 2 inhibitors. Therefore, highly selective PARP1 inhibitors are expected to mitigate the potential risks associated with existing clinical PARP inhibitors, broaden their clinical application, and improve patients' quality of life. Summary of the Invention The present invention provides a selective PARP1 inhibitor or its stereoisomer, and its pharmaceutical composition, and its use in medicine. The compounds described herein have high selectivity and significant inhibitory activity against PARP1, and therefore exhibit better efficacy and lower toxicity. Furthermore, the applicant has found through research that these compounds can penetrate the blood-brain barrier. Therefore, the compounds described herein or their stereoisomers and pharmaceutical compositions thereof can also be used to treat brain tumors.

[0002] One or more embodiments of the present invention provide compounds represented by the general formula (IA), or a stereoisomer, pharmaceutically acceptable salt, or deuterated compound thereof:

[0003] [ka]

[0004] where R1 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or C 3-8 heterocycloalkyl, C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O, or S; R0 is H, halogen or C 1-6 alkyl, wherein C 1-6 The alkyl is optionally further substituted with one or more substituents selected from halogen; X1, X2, and X3 each independently represent N or CR X and at least one of X1, X2, and X3 is selected from N; R X is H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl; L is selected from CH2; A is a 4- to 12-membered heterocycle selected from a 4- to 12-membered monocyclic ring, a 5- to 12-membered spiro ring, a 4- to 12-membered fused ring, or a 4- to 12-membered bridged ring, wherein said 4- to 12-membered heterocycle optionally contains 1 to 4 heteroatoms selected from N, O, or S; structural fragment

[0005] [ka]

[0006] teeth,

[0007] [ka]

[0008] Selected from; R 2b may be the same or different; R 2c may be the same or different; R 2d may be the same or different; R 2e may be the same or different; R 2f may be the same or different; R 2b , R 2c and R 2f are each independently CN, halogen, OR 2a , C 1-6 alkyl or a 4- to 12-membered heterocycle, wherein C 1-6 The alkyl and 4- to 12-membered heterocycles are optionally substituted with halogen, OH and C 1-3 alkyl, and said 4- to 12-membered heterocycle may contain 1 to 4 heteroatoms selected from N, O or S; R 2d and R 2e are each independently CN, halogen, OR 2a and C 1-6 alkyl, wherein C 1-6 The alkyl is optionally further substituted with one or more substituents selected from halogen or OH; R 2a is H, C 1-6 Alkyl, (CH2) n C 3-8 Cycloalkyl or (CH2) n C 3-8 heterocycloalkyl, wherein said C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O, or S, and the C 1-6 The alkyl is optionally further substituted with one or more substituents selected from halogen; Z1, Z2, and Z3 are each independently selected from N or C, and at least two of Z1, Z2, and Z3 are selected from N; n is selected from 0, 1, 2 or 3; b is selected from 1, 2 or 3; c is selected from 1, 2 or 3; d is selected from 2 or 3; e is selected from 1, 2 or 3; f is selected from 1 or 2, however The compound of general formula (IA) is not a compound of general formula (IA):

[0009] [ka]

[0010] In a preferred embodiment, the structural unit

[0011] [ka]

[0012] teeth,

[0013] [ka]

[0014] Selected from; R1 is C 1-6 Alkyl, C 2-6 Alkenyl or C 3-8 cycloalkyl; R0 is selected from halogens; A is,

[0015] [ka]

[0016] Selected from; R 2b may be the same or different, and R 2b are each independently CN, halogen, or C 1-3 Alkoxy, C 1-3 alkyl or a 4- to 12-membered heterocycle, wherein said C 1-3 Alkyl, C 1-3 The alkoxy and 4- to 12-membered heterocycles are optionally substituted with halogen, OH and C 1-3 further substituted with one or more substituents selected from alkyl; R 2c is CN; R 2d is CN or a halogen; R 2f is CN; R 2e may be the same or different, and R 2e are each independently CN, halogen, or OR 2a and C 1-6 alkyl, C 1-6 The alkyl is optionally further substituted with one or more substituents selected from halogen or OH; R 2a is C 1-3 Alkyl or

[0017] [ka]

[0018] Selected from C 1-3 The alkyl is optionally further substituted with one or more substituents selected from halogen; p is selected from 0 or 1; q is selected from 1 or 2;

[0019] In a further preferred embodiment, the structural unit

[0020] [ka]

[0021] teeth,

[0022] [ka]

[0023] Selected from; R1 is C 1-6 Alkyl or C 3-8 cycloalkyl; A is,

[0024] [ka]

[0025] R 2e may be the same or different, and R 2e are each independently CN, OR 2a or C 1-3 alkyl, wherein C 1-3 The alkyl is optionally further substituted with one or more substituents selected from halogen; R 2a is C 1-3 Alkyl or

[0026] [ka]

[0027] wherein C is selected from 1-3 The alkyl is optionally further substituted with one or more substituents selected from halogen.

[0028] In a further preferred embodiment, R 2b CN, halogen, C 1-3 alkyl or a 5-membered heterocycle, wherein said C 1-3 The alkyl and 5-membered heterocycle may optionally be halogen and C 1-3 further substituted with one or more substituents selected from alkyl; R2e is selected from CN.

[0029] In a further preferred embodiment, R 2b is selected from CN.

[0030] One or more embodiments of the present invention provide compounds represented by general formula (I) or stereoisomers thereof:

[0031] [ka]

[0032] where: R1 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or C 3-8 heterocycloalkyl, C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O, or S; X1, X2 and X3 each independently represent N or CR X Selected from; R X is H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl; L is selected from CH2; A is a 4- to 12-membered heterocycle selected from a 4- to 12-membered monocyclic ring, a 5- to 12-membered spiro ring, a 4- to 12-membered fused ring, or a 4- to 12-membered bridged ring, wherein said 4- to 12-membered heterocycle optionally contains 1 to 4 heteroatoms selected from N, O, or S; R2 may be the same or different, and each R2 is independently CN, halogen, OR 2a or C 1-6 alkyl; R 2a is H, C 1-6 Alkyl, (CH2)n C 3-8 Cycloalkyl or (CH2) n C 3-8 heterocycloalkyl, wherein C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S, and C 1-6 The alkyl is optionally further substituted with one or more substituents selected from halogen; Z may be the same or different, and each Z is independently selected from CH or N; m is selected from 1, 2, or 3; n is selected from 0, 1, 2, or 3; however The compound represented by general formula (I) is not a compound represented by the formula:

[0033] [ka]

[0034] One or more embodiments of the present invention provide compounds represented by general formula (I) or stereoisomers thereof:

[0035] [ka]

[0036] where R1 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or C 3-8 heterocycloalkyl, C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O, or S; X1, X2 and X3 each independently represent N or CR X Selected from; R X is H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C1-6 Alkoxy or C 3-8 cycloalkyl; L is selected from CH2; A is a 4- to 12-membered heterocycle selected from a 4- to 12-membered monocyclic ring, a 5- to 12-membered spiro ring, a 4- to 12-membered fused ring, or a 4- to 12-membered bridged ring, wherein said 4- to 12-membered heterocycle optionally contains 1 to 4 heteroatoms selected from N, O, or S; R2 may be the same or different, and each R2 is independently CN, halogen, OR 2a or C 1-6 alkyl, wherein said C 1-6 The alkyl is optionally further substituted with one or more substituents selected from halogen or hydroxyl; R 2a is H, C 1-6 Alkyl, (CH2) n C 3-8 Cycloalkyl or (CH2) n C 3-8 heterocycloalkyl, wherein said C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S, and C 1-6 The alkyl is optionally further substituted with one or more substituents selected from halogen; Z may be the same or different, and each Z is independently selected from CH or N; m is selected from 1, 2, or 3; n is selected from 0, 1, 2, or 3; however The compound represented by general formula (I) is not a compound represented by the formula:

[0037] [ka]

[0038] One or more embodiments of the present invention provide compounds represented by general formula (II) or stereoisomers thereof:

[0039] [ka]

[0040] where R1 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or C 3-8 heterocycloalkyl, wherein C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O, or S; R0 is H, halogen or C 1-6 alkyl, wherein C 1-6 The alkyl may optionally be a halogen or a C 1-6 further substituted with one or more substituents selected from alkyl; X1 and X2 each independently represent N or CR X Selected from; R X is H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl; L is selected from CH2; A is a 4- to 12-membered heterocycle selected from a 4- to 12-membered monocyclic ring, a 5- to 12-membered spiro ring, a 4- to 12-membered fused ring, or a 4- to 12-membered bridged ring, wherein said 4- to 12-membered heterocycle optionally contains 1 to 4 heteroatoms selected from N, O, or S; B is selected from a 6-membered aryl or heteroaryl, wherein said heteroaryl may contain 1 to 4 heteroatoms selected from N; R2 may be the same or different, and each R2 is independently CN, halogen, OR 2a or C 1-6 alkyl; R 2a is H, C 1-6 Alkyl, (CH2) n C3-8 Cycloalkyl or (CH2) n C 3-8 heterocycloalkyl, wherein C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O, or S, and the C 1-6 The alkyl is optionally further substituted with one or more substituents selected from halogen; Z may be the same or different, and each Z is independently selected from CH or N; m is selected from 1, 2, or 3; n is selected from 0, 1, 2 or 3.

[0041] In one or more embodiments of the invention, the compound of the invention is selected from:

[0042] [ka] JPEG0007762306000019.jpg224169JPEG0007762306000020.jpg134169

[0043] One or more embodiments of the present invention provide a pharmaceutical composition comprising: (1) A compound of the present invention or a stereoisomer thereof; (2) optionally, one or more additional active ingredients; and (3) A pharmaceutically acceptable carrier and / or excipient.

[0044] One or more embodiments of the present invention provide the use of a compound of the present invention or a stereoisomer thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for treating cancer.

[0045] In another aspect, one or more embodiments of the present invention relate to a compound of the present invention or a stereoisomer thereof, or a pharmaceutical composition of the present invention, for use in treating cancer.

[0046] In another aspect, one or more embodiments of the present invention relate to a method for treating cancer, the method comprising administering a therapeutically effective amount of a compound of the present invention or a stereoisomer thereof, or a pharmaceutical composition of the present invention.

[0047] Unless stated to the contrary, terms used in the specification and claims have the following meanings.

[0048] Carbon, hydrogen, oxygen, sulfur, nitrogen, F, Cl, Br, and I associated with the groups and compounds described herein each include their isotopes, and carbon, hydrogen, oxygen, sulfur, or nitrogen associated with the groups and compounds of the present invention are optionally further substituted with one or more of their corresponding isotopes, where the isotopes of carbon include: 12 C. 13 C and 14 C, isotopes of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), and tritium (T, also known as superheuterium), and isotopes of oxygen include 16 O. 17 O and 18 O is included, and the sulfur isotopes are 32 S, 33 S, 34 S and 36 It contains S, and the nitrogen isotopes are: 14 N and 15 It contains N, and the fluorine isotopes are: 17 F and 19 It contains F, and the chlorine isotopes are: 35 Cl and 37 It contains Cl, and the isotopes of bromine are: 79 Br and 81 Contains Br.

[0049] "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 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-chain isomers thereof. When substituted, alkyl may be optionally further substituted with one or more substituents.

[0050] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which may be a 3- to 10-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 20-membered polycyclic ring system, preferably having 3 to 10 ring carbon atoms, more preferably 3 to 8 ring 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 cycloheptatrienyl. When substituted, cycloalkyl may be optionally further substituted with zero or more substituents.

[0051] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic cyclic group. Heterocycloalkyl may be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, containing 1 to 3 heteroatoms selected from N, O, or S, and is preferably a 3- to 8-membered heterocyclyl. The optionally substituted N and S in the ring of a "heterocycloalkyl" may be oxidized to various oxidation states; a "heterocycloalkyl" may be linked to a heteroatom or carbon atom; and a "heterocycloalkyl" may be a bridged or spiro ring. Non-limiting examples of "heterocycloalkyl" include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptanyl.

[0052] "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, and 10) carbon-carbon double bonds and composed of 2 to 20 carbon atoms, preferably an alkenyl containing 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably an alkenyl containing 2 to 8 carbon atoms, and even more preferably an alkenyl containing 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, and buten-2-yl. , Pe Alkenyl may be optionally further substituted with one or more substituents.

[0053] "Alkynyl" 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 alkynyl containing 2 to 12 carbon atoms, more preferably alkynyl containing 2 to 8 carbon atoms, and even more preferably alkynyl containing 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, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, and dodecyn-4-yl. The alkynyl may be optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, alkyl, alkoxy, straight chain alkenyl, straight chain alkynyl, amino, nitro, cyano, mercapto, amido, carbocyclyl, or heterocyclyl.

[0054] "Heterocycle" or "heterocyclyl" refers to a saturated or unsaturated aromatic heterocycle or non-aromatic heterocycle. When the "heterocycle" or "heterocyclyl" is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl" above. When the "heterocycle" or "heterocyclyl" is a non-aromatic heterocycle, the "heterocycle" or "heterocyclyl" can be a 3- to 10-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10-, 11-, 12-, 13-, 14-, or 15-membered) tricyclic ring system containing 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, or S, and is preferably a 3- to 8-membered heterocyclyl. One to four (e.g., one, two, three, or four) optionally substituted N and S atoms in the ring of a "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; a "heterocyclyl" or "heterocycle" can be linked to a heteroatom or a carbon atom; and a "heterocyclyl" or "heterocycle" can be a fused, bridged, or spirocyclic ring. A "heterocyclyl" or "heterocycle" can be optionally further substituted with one or more substituents.

[0055] "Aryl" refers to a substituted or unsubstituted aromatic ring. An aryl may be a 5- to 8-membered (e.g., 5-, 6-, 7-, or 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10-, 11-, 12-, 13-, 14-, or 15-membered) tricyclic ring system, and may be a bridged or spirocyclic ring. Non-limiting examples include phenyl and naphthyl. An aryl may optionally be further substituted with one or more substituents.

[0056] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring. Heteroaryl may be a 3- to 8-membered (e.g., 3-, 4-, 5-, 6-, 7-, or 8-membered) monocyclic ring containing 1 to 6 (e.g., 1, 2, 3, 4, 5, and 6) heteroatoms selected from N, O, or S, and is preferably a 5- to 8-membered heteroaryl. Heteroaryl can be linked to a heteroatom or carbon atom, and may be a bridged or spirocyclic ring. Non-limiting examples include pyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, and imidazolyl. Heteroaryl is optionally further substituted with one or more substituents.

[0057] When substituted, the above "alkyl", "alkenyl", "alkynyl", "heterocycle", "heterocyclyl", "cycloalkyl", "heterocycloalkyl", "aryl" or "heteroaryl" may optionally be substituted with 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, -NR q4 R q5 , =NR q6 , -C(=O)OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 , C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, 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 Heterocycloalkyl, -C(=O)OC 3-8 Heterocycloalkyl, -OC(=O)C3-8 Cycloalkyl, -C(=O)OC 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 2-6 Alkenyl or -NHC(=O)C 2-6 alkynyl, wherein the substituent C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, 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 Heterocycloalkyl or -NHC(=O)C 3-8 Cycloalkyl is optionally substituted with OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 or ═O; R q1 is C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 aryl; R q2 and R q3 is H or C 1-6 alkyl; R q4 and R q5 is H, C 1-6 Alkyl, -NH(C=NR q1 )NR q2 R q3 , -S(=O)2NR2 q2 Rq3 , -C(=O)R q1 or -C(=O)NR q2 R q3 Selected from C 1-6 Alkyl is optionally OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 Heteroaryl, C 3-8 Cycloalkyl or C 3-8 heterocycloalkyl; or R q4 , R q5 and N atoms form a 3- to 8-membered heterocyclic ring, and the ring may contain one or more heteroatoms selected from N, O, or S.

[0058] A "pharmaceutical composition" refers to a mixture of one or more compounds of the invention or pharmaceutically acceptable salts or prodrugs thereof with other chemical components, where "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0059] "Carrier" refers to a substance that is not significantly irritating to an organism and does not eliminate the biological activity and properties of the compound being administered.

[0060] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycol, diluents, granulating agents, lubricants, adhesives, and disintegrating agents.

[0061] "Stereoisomer" refers to an isomer resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0062] "Optional" or "optionally," "optional," or "selectively" means that the subsequently described event or circumstance may, but need not, occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl may, but need not, be present, and includes instances where the heterocyclyl is substituted with alkyl and instances where the heterocyclyl is not substituted with alkyl. Detailed Description of the Embodiments The technical solutions of the present invention are illustrated in more detail in the following examples, but the protection scope of the present invention is not limited thereto.

[0063] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are 10 -6 The values ​​are given in units of ppm. NMR was determined using a Bruker Avance III 400 and a Bruker Avance 300 nuclear magnetic resonance spectrometer; the solvents for the determination were deuterated dimethyl sulfoxide (DMSO-d), deuterated chloroform (CDCl), and deuterated methanol (CD3OD); and the internal standard was tetramethylsilane (TMS).

[0064] MS is measured on Agilent 6120B (ESI) and Agilent 6120B (APCI); Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used as thin-layer chromatography silica gel plates. The silica gel plate specifications for thin-layer chromatography (TLC) are 0.15mm-0.20mm, and the specifications for separating and purifying products by thin-layer chromatography are 0.4mm-0.5mm.

[0065] In column chromatography, Yantai Yellow Sea silica gel (200-300 mesh silica gel) is commonly used as a carrier.

[0066] Example 1 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile (Compound 1)

[0067] [ka]

[0068] [ka]

[0069] Step 1 tert-Butyl 4-(4-cyano-2-fluorophenyl)piperazine-1-carboxylate (1c) 4-Bromo-3-fluorobenzonitrile (1a, 1 g, 5.00 mmol) and tert-butyl piperazine-1-carboxylate (1b, 838 mg, 4.5 mmol) were dissolved in toluene (15 mL), followed by the addition of palladium acetate (112 mg, 0.5 mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (311 mg, 0.5 mmol). The reaction flask was purged with nitrogen and then incubated in an oil bath pan at 120 °C for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 5:1) to give compound 1c (yellow solid, 1.4 g, yield: 92%).

[0070] LCMS m / s=306.15[M+1].

[0071] Step 2: 3-Fluoro-4-(piperazin-1-yl)benzonitrile (1d) Compound 1c (1.4 g, 4.60 mmol) was added to a 1,4-dioxane solution of hydrogen chloride (4 M, 15 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filter cake was collected to give compound 1d (yellow solid, 880 mg, 94% yield).

[0072] 1 H NMR (400MHz, DMSO-d6) δ9.58 (s, 1H), 7.69 (dd, J=13.4, 2.0Hz, 1H), 7.63-7.54 (m, 2H), 3.53-3.51 (m, 4H), 3.15-3.12 (m, 4H).

[0073] LCMS m / s=205.10[M+1].

[0074] Step 3: 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile (Compound 1) Compound 1e (white solid, 5 g, yield: 76%) was prepared according to the synthesis method of intermediate 14 in patent WO2021013735, and LCMS m / s=267 [M+1] was obtained.

[0075] Compound 1d (100 mg, 0.49 mmol) and compound 1e (130 mg, 0.49 mmol) were dissolved in acetonitrile (5 mL), and N,N-diisopropylethylamine (316 mg, 2.45 mmol) was added. The reaction system was purged with nitrogen and then reacted in an oil bath at 70 °C for 3 hours. The resulting solution was concentrated under reduced pressure to obtain the crude product. This was purified by column chromatography (MeOH:DCM = 1:60 to 1:15) to obtain compound 1 (white solid, 139 mg, yield: 73%).

[0076] 1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.40(d,J=1.8Hz,1H),7.77-7.67(m,2H),7.63-7.54(m,2H) ,7.12(t,J=8.7Hz,1H),3.64(s,2H),3.21-3.17(m,4H),2.57-2.53(m,6H),1.18(t,J=7.4Hz,3H).

[0077] LCMS m / s=392.2[M+1].

[0078] Example 2 7-((4-(3,5-difluoropyridin-2-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Compound 2)

[0079] [ka]

[0080] [ka]

[0081] Step 1 tert-Butyl 4-(3,5-difluoropyridin-2-yl)piperazine-1-carboxylate (2c) Intermediate 2c (yellow solid, 1.8 g, yield: 85%) was prepared according to the synthesis of intermediate 1c.

[0082] 1 H NMR (400MHz, DMSO-d6) δ8.11 (d, 1H), 7.82 (ddd, 1H), 3.45-3.43 (m, 4H), 3.26-3.23 (m, 4H), 1.41 (s, 9H).

[0083] LCMS m / s=300.10[M+1].

[0084] Step 2 1-(3,5-difluoropyridin-2-yl)piperazine (2d) Intermediate 2d (yellow solid, 1.1 g, yield: 92%) was prepared according to the synthesis of intermediate 1d.

[0085] 1 H NMR (400MHz, DMSO-d6) δ9.46 (dr, 1H), 8.15 (d, 1H), 7.88 (ddd, 1H), 3.55-3.52 (m, 4H), 3.20-3.16 (m, 4H).

[0086] LCMS m / s=200.10[M+1].

[0087] Step 3 7-((4-(3,5-difluoropyridin-2-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Compound 2) Compound 2 (white solid, 40 mg, yield: 40%) was prepared according to the synthesis method for compound 1.

[0088] 1 H NMR(600MHz,DMSO-d6)δ11.84(s,1H),8.40(d,1H),8.09(d,1H),7.78(ddd,1H),7.75 (s,1H),7.62(d,1H),3.64(s,2H),3.32-3.30(m,4H),2.57-2.52(m,6H),1.18(t,3H).

[0089] LCMS m / s=386.20[M+1].

[0090] Example 3 3-Ethyl-7-((4-(5-fluoropyridin-2-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (Compound 3)

[0091] [ka]

[0092] [ka]

[0093] Step 1 tert-Butyl 4-(5-fluoropyridin-2-yl)piperazine-1-carboxylate (3c) Intermediate 3c (yellow solid, 2 g, yield: 90%) was prepared according to the synthesis of intermediate 1c.

[0094] 1 H NMR (400MHz, DMSO-d6) δ 8.10 (d, 1H), 7.53 (ddd, 1H), 6.89 (dd, 1H), 3.41 (s, 8H), 1.41 (s, 9H).

[0095] LCMS m / s=282.20[M+1].

[0096] Step 2 1-(5-fluoropyridin-2-yl)piperazine (3d) Intermediate 3d (yellow solid, 1.2 g, yield: 92%) was prepared according to the synthesis of intermediate 1d.

[0097] 1 H NMR (400MHz, DMSO-d6) δ9.55 (dr, 1H), 8.15 (d, 1H), 7.64 (td, 1H), 7.02 (dd, 1H), 3.72-3.69 (m, 4H), 3.21-3.01 (m, 4H).

[0098] LCMS m / s=182.20[M+1].

[0099] Step 3 3-Ethyl-7-((4-(5-fluoropyridin-2-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (Compound 3) Compound 3 (white solid, 50 mg, 45% yield) was prepared according to the synthesis of compound 1.

[0100] 1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.39(d,1H),8.08(d,1H),7.74(s,1H),7.62(d,1H),7.49(dd d,1H),6.86(dd,1H),3.62(s,2H),3.48-3.38(m,4H),2.53(q,2H),2.50-2.46(m,4H),1.17(t,3H).

[0101] LCMS m / s=368.20[M+1].

[0102] Example 4 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinonitrile (Compound 4)

[0103] [ka]

[0104] [ka]

[0105] Step 1 tert-Butyl 4-(6-cyanopyridin-3-yl)piperazine-1-carboxylate (4c) Intermediate 4c (yellow solid, 1.3 g, yield: 88%) was prepared according to the synthesis of intermediate 1c.

[0106] LCMS m / s=289.16[M+1].

[0107] Step 2 5-(Piperazin-1-yl)picolinonitrile (4d) Intermediate 4d (yellow solid, 1.0 g, yield: 91%) was prepared according to the synthesis of intermediate 1d.

[0108] LCMS m / s=189.10[M+1].

[0109] Step 3 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinonitrile (Compound 4) Compound 4 (white solid, 47 mg, yield: 51%) was prepared according to the synthesis of compound 1.

[0110] 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.42(d,J=3.0Hz,1H),8.40(d,J=1.9Hz,1H),7.79-7.72(m,2H),7.61( s,1H),7.36(dd,J=8.9,3.0Hz,1H),3.64(s,2H),3.43-3.40(m,4H),2.58-2.51(m,6H),1.18(t,J=7.4Hz,3H).

[0111] LCMS m / s=375.16[M+1].

[0112] Example 5 7-((4-(6-(2,2-difluoroethoxy)pyridin-3-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Compound 5)

[0113] [ka]

[0114] [ka]

[0115] Step 1 tert-Butyl 4-(6-(2,2-difluoroethoxy)pyridin-3-yl)piperazine-1-carboxylate (5c) Intermediate 5c (yellow solid, 1.4 g, yield: 84%) was prepared according to the synthesis of intermediate 1c.

[0116] 1H NMR(400MHz,DMSO-d6)δ7.80(d,J=3.0Hz,1H),7.51(dd,J=9.0,3.0Hz,1H),6.83(d,J=9.0Hz,1H),6.35(tt, J=54.9,3.6Hz,1H),4.47(td,J=15.0,3.7Hz,2H),3.45(t,J=5.1Hz,4H),3.01(t,J=5.2Hz,4H),1.41(s,9H).

[0117] LCMS m / s=344.37[M+1].

[0118] Step 2 1-(6-(2,2-difluoroethoxy)pyridin-3-yl)piperazine (5d) Intermediate 5d (yellow solid, 1.2 g, yield: 93%) was prepared according to the synthesis of intermediate 1d.

[0119] 1 H NMR(400MHz,DMSO-d6)δ9.46(s,1H),7.85(d,J=3.0Hz,1H),7.56(dd,J=9.0,3.1Hz,1H),7.09 (s,1H),6.51-6.22(m,1H),4.53-4.46(m,2H),3.31(dd,J=6.6,3.7Hz,4H),3.21-3.17(m,4H).

[0120] LCMS m / s=244.26[M+1].

[0121] Step 3 7-((4-(6-(2,2-difluoroethoxy)pyridin-3-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Compound 5) Compound 5 (white solid, 63 mg, yield: 64%) was prepared according to the synthesis of compound 1.

[0122] 1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.39(d,J=1.8Hz,1H),7.77(d,J=3.0H z,1H),7.75(s,1H),7.62(d,J=1.8Hz,1H),7.49(dd,J=9.0,3.1Hz,1H),6.80( d,J=9.0Hz,1H),6.35(tt,J=55.0,3.7Hz,1H),4.46(td,J=15.0,3.7Hz,2H), 3.64(s,2H),3.08(t,J=4.7Hz,4H),2.58-2.52(m,6H),1.18(t,J=7.4Hz,3H).

[0123] LCMS m / s=430.47M+1].

[0124] Example 6 3-Ethyl-7-((4-(6-((tetrahydrofuran-3-yl)methoxy)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (Compound 6)

[0125] [ka]

[0126] [ka]

[0127] Step 1 tert-Butyl 4-(6-((tetrahydrofuran-3-yl)methoxy)pyridin-3-yl)piperazine-1-carboxylate (6c) Intermediate 6c (yellow solid, 1.1 g, yield: 87%) was prepared according to the synthesis of intermediate 1c.

[0128] 1H NMR(400MHz,DMSO-d6)δ7.78(d,J=3.0Hz,1H),7.46(dd,J=9.0,3.0Hz,1H),6.73(d,J=9.0Hz,1H),4.68(dd,J=7.9,6.0Hz,2H),4.12-4.10(m ,2H),3.89(dd,J=6.5,4.8Hz,2H),3.45(t,J=5.0Hz,4H),3.36(dd,J=7.9,6.4Hz,1H),2.98(t,J=5.1Hz,4H),1.94-1.87(m,2H),1.41(s,9H).

[0129] LCMS m / s=364.46[M+1].

[0130] Step 2 1-(6-((tetrahydrofuran-3-yl)methoxy)pyridin-3-yl)piperazine (6d) Intermediate 6d (yellow solid, 904 mg, yield: 90%) was prepared according to the synthesis of intermediate 1d.

[0131] 1 H NMR(400MHz,DMSO-d6)δ9.46(s,1H),7.78(d,J=3.0Hz,1H),7.46(dd,J=9.0,3.0Hz,1H),6.73(d,J=9.0Hz,1H),4.68(dd,J=7.9,6.0Hz,2H), 4.12-4.10(m,2H),3.89(dd,J=6.5,4.8Hz,2H),3.45(t,J=5.0Hz,4H),3.36(dd,J=7.9,6.4Hz,1H),2.98(t,J=5.1Hz,4H),1.94-1.87(m,2H).

[0132] LCMS m / s = 264.34[M+1].

[0133] Step 3 3-Ethyl-7-((4-(6-((tetrahydrofuran-3-yl)methoxy)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (Compound 6) Compound 6 (white solid, 41 mg, yield: 59%) was prepared according to the synthesis method of compound 1.

[0134] 1 H NMR(400MHz,DMSO-d6)δ11.94(s,1H),8.92(s,1H),8.67(s,1H),7.87(s,1H),7.84(s,1H) ),7.47(d,J=8.9Hz,1H),6.76(d,J=9.1Hz,1H),4.54(s,1H),4.25-4.00(m,2H),3.79-3. 71(m,2H),3.67-3.56(m,6H),3.44(s,1H),3.24(s,1H),3.06(s,2H),2.67-2.51(m,4H), 1.99(ddd,J=15.3,7.8,4.1Hz,1H),1.61(dq,J=13.3,6.8Hz,1H),1.19(t,J=7.4Hz,3H).

[0135] LCMS m / s=450.56[M+1].

[0136] Example 7 3-Ethyl-7-((4-(6-(oxetan-3-ylmethoxy)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (Compound 7)

[0137] [ka]

[0138] [ka]

[0139] Step 1 tert-Butyl 4-(6-(oxetan-3-ylmethoxy)pyridin-3-yl)piperazine-1-carboxylate (7c) Intermediate 7c (yellow solid, 1.9 g, yield: 89%) was prepared according to the synthesis of intermediate 1c.

[0140] 1H NMR(400MHz,DMSO-d6)δ7.78(d,J=3.0Hz,1H),7.46(dd,J=9.0,3.0Hz,1H),6.73(d,J=9.0Hz,1H),4.68(dd,J=7.9,6.0Hz ,2H),4.39(dd,J=6.5,4.8Hz,4H),3.45(t,J=5.0Hz,4H),3.36(dd,J=7.9,6.4Hz,1H),2.98(t,J=5.1Hz,4H),1.41(s,9H).

[0141] LCMS m / s=350.43[M+1].

[0142] Step 2 1-(6-(oxetan-3-ylmethoxy)pyridin-3-yl)piperazine (7d) Intermediate 7d (yellow solid, 1.4 g, yield: 86%) was prepared according to the synthesis of intermediate 1d.

[0143] LCMS m / s=250.31[M+1].

[0144] Step 3 3-Ethyl-7-((4-(6-(oxetan-3-ylmethoxy)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (Compound 7) Compound 7 (white solid, 37 mg, yield: 63%) was prepared according to the synthesis of compound 1.

[0145] 1 H NMR(400MHz,DMSO-d6)δ11.94(s,1H),8.92(s,1H),8.67(s,1H),7.87(s,1H),7.84(s,1H),7.47(d,J=8.9Hz,1H),6.76(d,J=9.1Hz,1H),4. 54(s,1H),4.39(dd,J=6.5,4.8Hz,4H),3.67-3.56(m,6H),3.44(s,1H),3.24(s,1H),3.06(s,H),2.67-2.51(m,4H),1.19(t,J=7.4Hz,3H).

[0146] LCMS m / s=436.53[M+1].

[0147] Example 8 3-Ethyl-7-((4-(6-(hydroxymethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (Compound 8)

[0148] [ka]

[0149] [ka]

[0150] Step 1 tert-Butyl 4-(6-(hydroxymethyl)pyridin-2-yl)piperazine-1-carboxylate (8c) Intermediate 8c (yellow solid, 1.7 g, yield: 82%) was prepared according to the synthesis of intermediate 1c.

[0151] 1 H NMR (400MHz, DMSO-d6) δ7.74(d,1H),7.41(dd,1H),6.95(d,1H),5.33(t,1H),4.68(dd,2H),3.45(t,4H),2.98(t,4H),1.41(s,9H).

[0152] LCMS m / s=294.17[M+1].

[0153] Step 2 (6-(piperazin-1-yl)pyridin-2-yl)methanol (8d) Intermediate 8d (yellow solid, 1.2 g, yield: 87%) was prepared according to the synthesis of intermediate 1d.

[0154] LCMS m / s=194.12[M+1].

[0155] Step 3 3-Ethyl-7-((4-(6-(hydroxymethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (Compound 8) Compound 8 (white solid, 27 mg, yield: 55%) was prepared according to the synthesis method of compound 1.

[0156] 1 H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.92(s,1H),8.67(s,1H),7.87(s,1H),7.84(s,1H),7.47(d,1H),7 .09(d,1H),5.64(t,1H),4.68(dd,2H),3.45(t,4H),3.06(s,2H),2.98(t,4H),2.43(dd,2H),1.19(t,3H).

[0157] LCMS m / s=436.53[M+1].

[0158] Example 9 3-Ethyl-7-((4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (Compound 9)

[0159] [ka]

[0160] [ka]

[0161] Step 1 tert-Butyl 4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (9b) Intermediate 9b (yellow solid, 1.3 g, yield: 82%) was prepared according to the synthetic method for intermediate 1c.

[0162] LCMS m / s=332.34[M+1].

[0163] Step 2 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine (9c) Intermediate 9c (yellow solid, 900 mg, yield: 89%) was prepared according to the synthesis of intermediate 1d.

[0164] 1 H NMR (400MHz, DMSO-d6) δ9.73 (s, 1H), 8.45 (d, 1H), 7.90 (dd, 1H), 7.08 (d, 1H), 3.91 (t, 4H), 3.14 (p, 4H).

[0165] LCMS m / s=232.22[M+1].

[0166] Step 3 3-Ethyl-7-((4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (Compound 9) Compound 9 (white solid, 23 mg, yield: 71%) was prepared according to the synthesis of compound 1.

[0167] 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.40(d,2H), .79(dd,1H),7.75(d,1H),7.62(d,1H),6.95(d,1H),3.64(d,6H),2.55(td,2H),2.48(t,4H),1.18(t,3H).

[0168] LCMS m / s=418.44[M+1].

[0169] Example 10 7-((4-(5-chloropyridin-2-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Compound 10)

[0170] [ka]

[0171] [ka]

[0172] Step 1 tert-Butyl 4-(5-chloropyridin-2-yl)piperazine-1-carboxylate (10b) Intermediate 10b (yellow solid, 1.2 g, yield: 80%) was prepared according to the synthesis of intermediate 1c.

[0173] LCMS m / s=298.78[M+1].

[0174] Step 2 1-(5-chloropyridin-2-yl)piperazine (10c) Intermediate 10c (yellow solid, 930 mg, yield: 82%) was prepared according to the synthesis of intermediate 1d.

[0175] LCMS m / s=198.67[M+1].

[0176] Step 3 7-((4-(5-chloropyridin-2-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Compound 10) Compound 10 (white solid, 46 mg, 74% yield) was prepared according to the synthesis of compound 1.

[0177] 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.39(d,1H),8.10(d,1H),7.75(d,1H),7.64-7.54 (m,2H),6.86(d,1H),3.62(s,2H),3.48(t,4H),2.55(td,2H),2.48(t,4H),1.18(t,3H).

[0178] LCMS m / s=384.88[M+1].

[0179] Example 11 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile (Compound 11)

[0180] [ka]

[0181] [ka]

[0182] Step 1 Ethyl 6-formyl-5-nitronicotinate (11b) Ethyl 6-methyl-5-nitronicotinate (11a, purchased from Jiangsu Aikang Biopharmaceutical R&D Co., Ltd., 10 g, 45.6 mmol) and selenium dioxide (7.6 g, 68.4 mmol) were dissolved in dioxane (100 mL). The mixture was refluxed at 110°C for 4 hours. After the reaction was completed, the reaction mixture was filtered while hot. The filtrate was concentrated under reduced pressure and subjected to column chromatography to obtain compound 11b (yellow solid, 9.7 g, yield: 90%).

[0183] LC-MS m / z(ESI)=225.10[M+1].

[0184] Step 2 Ethyl 6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)-5-nitronicotinate (11c) Ethyl 2-bromo-2-(diethoxyphosphoryl)acetate (purchased from Meriya (Shanghai) Chemical Technology Co., Ltd., 20 g, 66.6 mmol) was dissolved in tetrahydrofuran (100 mL), and sodium hydride (1.6 g, 66.6 mmol) was slowly added at -78 °C. The resulting mixture was slowly heated to 40 °C and reacted for 10 min. After cooling to -78 °C, a solution of 11b (9.7 g, 44.4 mmol) in tetrahydrofuran was slowly added dropwise. The mixture was reacted for 15 min, then quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, concentrated under reduced pressure, and subjected to column chromatography to give 11c (yellow solid, 13 g, yield: 81%, E / Z = 10:3).

[0185] 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). LC-MS m / z(ESI)=373.00[M+1].

[0186] Step 3 Ethyl 5-amino-6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)nicotinate (11d) Compound 11c (13 g, 34.8 mmol) was dissolved in acetic acid (130 mL) and iron powder (5.8 g, 104.5 mmol) was added. The mixture was reacted at room temperature for 2 hours, quenched with distilled water (100 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phase was concentrated under reduced pressure to give compound 11d (yellow solid, 10 g, yield: 83%).

[0187] LC-MS m / z(ESI)= 343.00[M+1].

[0188] Step 4 Ethyl 7-bromo-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (11e) Compound 11d (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 a nitrogen atmosphere. The mixture was reacted at 50°C for 4 hours and then concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution (100 mL) was added. The resulting solution was extracted with ethyl acetate (50 mL x 3), concentrated under reduced pressure, and subjected to column chromatography to obtain compound 11e (yellow solid, 2 g, yield: 23%).

[0189] 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).

[0190] LC-MS m / z(ESI)=297.00[M+1].

[0191] Step 5 Ethyl 7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (11f) Compound 11e (400 mg, 1.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (Chengdu Dingdang Times Pharmaceutical Technology Co., Ltd., 328 mg, 0.40 mmol), potassium carbonate (745 mg, 5.4 mmol), and cyclopropylboronic acid (ACON Biotech (Hangzhou) Co., Ltd., 231 mg, 2.7 mmol) were dissolved in dioxane (4 mL). The resulting mixture was refluxed at 110 °C for 8 hours, quenched with water (5 mL), extracted with ethyl acetate (5 mL × 3), concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 11f (yellow solid, 270 mg, yield: 77%).

[0192] 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).

[0193] LC-MS m / z(ESI)=259.10[M+1].

[0194] Step 6 3-Cyclopropyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one (11g) Compound 11f (270 mg, 1 mmol) was dissolved in tetrahydrofuran (2 mL), and a solution of lithium aluminum hydride in tetrahydrofuran (purchased from Energy Chemical, 2 mL, 2 mmol) was slowly added dropwise in an ice-water bath. After the dropwise addition, the resulting solution was stirred for 10 minutes. Ethyl acetate (1 mL) was added, and the resulting mixture was concentrated under reduced pressure and purified by column chromatography to give compound 11g (yellow solid, 100 mg, yield: 44%).

[0195] 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).

[0196] LC-MS m / z(ESI)=217.10[M+1].

[0197] Step 7 7-(Bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one (11h) Compound 11g (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 Energy Chemical Co., Ltd., 306 mg, 0.92 mmol) in dichloromethane (0.5 mL) was added in an ice-water bath, and the mixture was reacted for 0.5 hours. The reaction solution was concentrated under reduced pressure and then subjected to column chromatography to obtain compound 11h (yellow solid, 100 mg, yield: 78%).

[0198] LC-MS m / z(ESI)=279.00[M+1].

[0199] Step 8 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile (Compound 11) Compound 11h (100 mg, 0.36 mmol), compound 1d (86 mg, 0.39 mmol), and N,N-diisopropylethylamine (230 mg, 1.8 mmol) were dissolved in acetonitrile (4 mL), and the resulting mixture was reacted at 80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure and separated by prep-HPLC to give compound 11 (white solid, 40 mg, yield: 27%).

[0200] 1 H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.37(d,1H),7.69(dd,1H),7.61-7.54(m,2H),7.41(s,1H),7.12( t,1H),3.63(s,2H),3.18(t,4H),2.54(t,4H),2.18-2.09(m,1H),1.00-0.92(m,2H),0.85-0.80(m,2H).

[0201] LC-MS m / z(ESI)=404.46[M+1].

[0202] Example 12 3-Cyclopropyl-7-((4-(5-fluoropyridin-2-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (Compound 12)

[0203] [ka]

[0204] [ka]

[0205] Compound 12 was synthesized in the same manner as compound 11. The reaction mixture was concentrated under reduced pressure and separated by prep-HPLC to obtain compound 12 (white solid, 12 mg, yield: 24%).

[0206] 1 H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.37(d,1H),8.08(d,1H),7.60(d,1H),7.50(td,1H),7.41(s,1H),6 .86(dd,1H),3.61(s,2H),3.42(t,4H),2.49-2.43(m,4H),2.14(tt,1H),1.01-0.91(m,2H),0.82(dd,2H).

[0207] LC-MS m / z(ESI)=380.44[M+1].

[0208] Example 13 6-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)nicotinonitrile (Compound 13)

[0209] [ka]

[0210] [ka]

[0211] The synthesis method of compound 13 was the same as that of compound 11. The reaction solution was concentrated under reduced pressure and separated by prep-HPLC to obtain compound 13 (white solid, 16 mg, yield: 22%).

[0212] 1 H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.47(d,1H),8.37(d,1H),7.84(dd,1H),7.59(d,1H),7.41(s,1H), 6.92(d,1H),3.66(t,4H),3.61(s,2H),2.46(t,4H),2.13(ddt,1H),1.00-0.91(m,2H),0.86-0.76(m,2H).

[0213] LC-MS m / z(ESI)=387.46[M+1].

[0214] Example 14 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinonitrile (Compound 14)

[0215] [ka]

[0216] [ka]

[0217] Step 1 tert-Butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate (14b) Intermediate 14b (yellow solid, 1.2 g, yield: 85%) was prepared according to the synthesis of intermediate 1c.

[0218] LCMS m / s=289.16[M+1].

[0219] Step 2 6-(Piperazin-1-yl)picolinonitrile (14c) Intermediate 14c (yellow solid, 1.1 g, yield: 90%) was prepared according to the synthesis of intermediate 1d.

[0220] 1 H NMR (400MHz, DMSO-d6) δ9.59(s,1H), 8.54(d,1H), 7.95(dd,1H), 7.03(d,1H), 3.91(t,4H), 3.15(t,4H).

[0221] LCMS m / s=189.10[M+1].

[0222] Step 3 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinonitrile (Compound 14) Compound 14 (white solid, 43 mg, yield: 65%) was prepared according to the synthesis of compound 1.

[0223] 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.47(d,1H),8.39(d,1H),7.84(dd,1H),7.74(s,1H),7.62(s, 1H),6.93(d,1H),3.67-3.65(m,4H),3.63(s,2H),2.58-2.52(m,2H),2.48-2.44(m,4H),1.17(t,3H).

[0224] LCMS m / s=375.19[M+1].

[0225] Example 15 3-Ethyl-7-((4-(5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (Compound 15)

[0226] [ka]

[0227] [ka]

[0228] Step 1 tert-Butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (15b) 5-Bromo-2-fluoropyridine (15a, 1 g, 5.71 mmol) and tert-butyl piperazine-1-carboxylate (1b, 1.17 g, 4.5 mmol) were dissolved in dimethyl sulfoxide (20 mL) and potassium carbonate (1.18 g, 8.57 mmol) was added. The mixture in the reaction flask was reacted in an oil bath at 120 °C for 8 hours, and then quenched with water (60 mL). The precipitated solid was filtered, and the filter cake was washed with water (3 mL × 2) and dried to give compound 15b (yellow solid, 1.7 g, 87% yield).

[0229] LCMS m / s=342.07[M+1].

[0230] Step 2 tert-Butyl 4-(5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)piperazine-1-carboxylate (15c) tert-Butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (15b, 1.7 g, 5.00 mmol) and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (1.14 g, 5.50 mmol) were dissolved in 1,4-dioxane (20 mL). Methanesulfonato(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (430.25 mg, 0.5 mmol) and cesium carbonate (3.26 g, 10.0 mmol) were added. The reaction flask was purged with nitrogen, and the mixture was reacted in an oil bath at 120 °C for 16 h. The mixture was then quenched with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined and concentrated under reduced pressure, and the crude product was purified by column chromatography (PE:EA=3:1) to give Compound 15c (yellow solid, 1.5 g, yield: 88%).

[0231] LCMS m / s=344.20[M+1].

[0232] Step 3 1-(5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)piperazine (15d) Compound 15c (1.5 g, 4.37 mmol) was added to a 1,4-dioxane solution of hydrogen chloride (4 M, 15 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filter cake was collected to give compound 15d (yellow solid, 902.62 mg, 85% yield).

[0233] LCMS m / s=244.15[M+1].

[0234] Step 4 3-Ethyl-7-((4-(5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (Compound 15) Compound 15d (121.50 mg, 0.50 mmol) and compound 1e (133.00 mg, 0.50 mmol) were dissolved in acetonitrile (5 mL) and N,N-diisopropylethylamine (316 mg, 2.50 mmol) was added. After purging the reaction system with nitrogen, the mixture was reacted in an oil bath at 70 °C for 3 hours. The resulting solution was concentrated under reduced pressure to obtain the crude product. This was purified by column chromatography (MeOH:DCM = 1:60 to 1:15) to obtain compound 15 (white solid, 160.96 mg, yield: 75%). 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.41(d,1H),8.25(d,1H),7.75(s,1H ),7.69(dd,1H),7.63(s,1H),7.43(s,1H),6.92(d,1H),6.34(s,1H),3.81(s ,3H),3.64(s,2H),3.59-3.52(m,4H).92(d,1H),6.34(s,1H),3.81(s,3H),3 .64(s,2H),3.59-3.52(m,4H),3.36-3.33(m,4H),2.56(d,2H),1.18(t,3H).

[0235] LCMS m / s=430.23[M+1].

[0236] Example 16 6-(4-((2-ethyl-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)nicotinonitrile (Compound 16)

[0237] [ka]

[0238] [ka]

[0239] Step 1 tert-Butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate (16b) Intermediate 6b (yellow solid, 1.2 g, yield: 85%) was prepared according to the synthetic method for intermediate 1c.

[0240] LCMS m / s=289.16[M+1].

[0241] Step 2 6-(Piperazin-1-yl)nicotinonitrile (16c) Intermediate 16c (yellow solid, 1.1 g, yield: 90%) was prepared according to the synthesis of intermediate 1d.

[0242] 1 H NMR (400MHz, DMSO-d6) δ9.59(s,1H), 8.54(d,1H), 7.95(dd,1H), 7.03(d,1H), 3.91(t,4H), 3.15(t,4H).

[0243] LCMS m / s=189.10[M+1].

[0244] Step 3 6-(4-((2-ethyl-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)nicotinonitrile (Compound 16) Compound 16d (white solid, 5 g, yield: 76%) was prepared according to the synthesis method of intermediate 66 in patent WO2021260092, and LCMS m / s=286.00 [M+1] was obtained.

[0245] Compound 16 (white solid, 52 mg, yield: 63%) was prepared according to the synthesis of compound 1.

[0246] 1H NMR(400MHz,DMSO-d6)δ12.66(s,1H),8.55(s,1H),7.96(d,1H),7.66(d,1H),7.38(t,1H), 7.03(d,1H),4.58-4.39(m,4H),3.55(s,2H),3.33-2.99(m,4H),2.84(q,2H),1.22(t,3H).

[0247] LCMS m / s=394.17[M+1].

[0248] Example 17 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyrazine-2-carbonitrile (Compound 17)

[0249] [ka]

[0250] [ka]

[0251] Step 1 tert-Butyl-4-(5-cyanopyrazin-2-yl)piperazine-1-carboxylate (17b) Intermediate 17b (yellow solid, 1.3 g, yield: 75%) was prepared according to the synthesis of intermediate 1c.

[0252] LCMS m / s=290.15[M+1].

[0253] Step 2 5-(Piperazin-1-yl)pyrazine-2-carbonitrile (17c) Intermediate 17c (yellow solid, 0.9 g, yield: 90%) was prepared according to the synthesis of intermediate 1d.

[0254] LCMS m / s=190.10[M+1].

[0255] Step 3 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyrazine-2-carbonitrile (Compound 17) Compound 17 (white solid, 23 mg, yield: 61%) was prepared according to the synthesis of compound 1.

[0256] 1 H NMR(400MHz,DMSO)δ11.89(s,1H),8.75(s,2H),8.37(d,1H),7.59(d,1H),7.41(s,1H), 3.84(t,4H),3.62(s,2H),2.46(t,4H),1.22(dt,1H),1.01-0.92(m,2H),0.82(dt,2H).

[0257] LCMS m / s=388.19[M+1].

[0258] Example 18 6-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridazine-3-carbonitrile (Compound 18)

[0259] [ka]

[0260] [ka]

[0261] Step 1 tert-Butyl-4-(6-cyanopyridazin-3-yl)piperazine-1-carboxylate (18b) Intermediate 18b (yellow solid, 1.5 g, yield: 80%) was prepared according to the synthesis of intermediate 1c.

[0262] LCMS m / s=290.15[M+1].

[0263] Step 2 6-(Piperazin-1-yl)pyridazine-3-carbonitrile (18c) Intermediate 18c (yellow solid, 1.1 g, yield: 88%) was prepared according to the synthetic method for intermediate 1d.

[0264] LCMS m / s=190.10[M+1].

[0265] Step 3 6-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridazine-3-carbonitrile (Compound 18) Compound 18 (white solid, 23 mg, yield: 61%) was prepared according to the synthesis of compound 1.

[0266] 1 H NMR(400MHz,DMSO)δ11.89(s,1H),8.55(d,1H),8.39(d,1H),7.77-7.74(m,1H),7.70(dd,1H),7.65 (d,1H),3.64(s,2H),3.53(dd,4H),2.54(d,4H),1.34(t,1H),1.17-1.08(m,2H),0.91-0.81(m,2H).

[0267] LCMS m / s=388.19[M+1].

[0268] Example 19 2-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyrimidine-5-carbonitrile (Compound 19)

[0269] [ka]

[0270] [ka]

[0271] Step 1 tert-Butyl-4-(5-cyanopyrimidin-2-yl)piperazine-1-carboxylate (19b) Intermediate 19b (yellow solid, 1.1 g, yield: 74%) was prepared according to the synthesis of intermediate 1c.

[0272] LCMS m / s=290.15[M+1].

[0273] Step 2 2-(Piperazin-1-yl)pyrimidine-5-carbonitrile (19c) Intermediate 19c (yellow solid, 0.8 g, yield: 89%) was prepared according to the synthesis of intermediate 1d.

[0274] LCMS m / s=190.10[M+1].

[0275] Step 3 2-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyrimidine-5-carbonitrile (Compound 19) Compound 19 (white solid, 23 mg, yield: 61%) was prepared according to the synthesis of compound 1.

[0276] 1 H NMR(400MHz,DMSO)δ11.89(s,1H),8.78(s,2H),8.34(d,1H),7.57(d,1H),7.43(s,1H),3.93-3. 81(m,4H),3.61(s,2H),2.43-2.28(m,4H),1.21(dt,1H),1.01-0.94(m,2H),0.83-0.79(m,2H).

[0277] LCMS m / s=388.19[M+1].

[0278] Example 21 3-Ethyl-7-((4-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (Compound 21)

[0279] [ka]

[0280] [ka]

[0281] Step 1 tert-Butyl-4-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)piperazine-1-carboxylate (21a) Intermediate 21a (yellow solid, 330 mg, yield: 64%) was prepared according to the synthesis of intermediate 20d.

[0282] LCMS m / s=345.20[M+1].

[0283] Step 2 1-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)piperazine (21b) Intermediate 21b (yellow solid, 120 mg, yield: 61%) was prepared according to the synthesis of intermediate 1d.

[0284] LCMS m / s=244.15[M+1].

[0285] Step 3 3-Ethyl-7-((4-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (Compound 21) Compound 21 (white solid, 30 mg, yield: 71%) was prepared according to the synthesis of compound 1.

[0286] 1H NMR(400MHz,DMSO)δ11.86(s,1H),8.41(s,1H),8.34(s,1H),8.02(s,1H),7.74-7.69(m,3H),7.64 (s,1H),6.84(d,1H),3.84(s,3H),3.64-3.47(m,6H),2.68-2.62(m,4H),1.99(t,2H),1.23(s,3H).

[0287] LCMS m / s=429.24[M+1].

[0288] Example 22 7-((4-(5-(1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Compound 22)

[0289] [ka]

[0290] [ka]

[0291] Step 1 tert-Butyl 4-(5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate (22b) Intermediate 22b (white solid, 8.4 g, yield: 76%) was prepared according to the synthesis of intermediate 4c.

[0292] LCMS m / s=322.17[M+1].

[0293] Step 2 tert-Butyl 4-(5-(hydrazinecarbonyl)pyridin-2-yl)piperazine-1-carboxylate (22c) Intermediate 22b (2.0 g, 6.2 mmol) was added to hydrazine hydrate (3.2 g, 62 mmol), and the mixture was reacted in an oil bath at 80 °C for 24 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure, and the residue was dissolved in 50 mL of ethyl acetate. The organic phase was washed with water, dried over NaSO, and evaporated under reduced pressure to remove the solvent, yielding crude 22c (yellow solid, 820 mg, yield: 83%).

[0294] LCMS m / s=322.18[M+1].

[0295] Step 3 tert-Butyl 4-(5-(1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperazine-1-carboxylate (22d) Intermediate 22c (500 mg, 1.6 mmol) was added to 50 mL of triethyl orthoformate, and the resulting mixture was heated to 150°C and reacted for 48 hours. After completion of the reaction, the crude product was purified by silica gel chromatography (PE / EA = 3 / 1) to obtain Intermediate 22d (colorless oil, 210 mg, yield: 39%).

[0296] Step 4 2-(6-(piperazin-1-yl)pyridin-3-yl)-1,3,4-oxadiazole (22e) Intermediate 22e (yellow solid, 82 mg, yield: 86%) was prepared according to the synthesis of intermediate 1d.

[0297] Step 5 7-((4-(5-(1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Compound 22) Compound 22 (white solid, 42 mg, yield: 81%) was prepared according to the synthesis of compound 1.

[0298] 1H NMR(400MHz,DMSO)δ11.86(s,1H),9.24(s,1H),8.70(d,1H),8.41(d,1H),8.05(dd,1H),7.75 (s,1H),7.63(s,1H),7.00(d,1H),3.65(d,6H),3.32(s,4H),2.58-2.52(m,2H),1.18(t,3H).

[0299] LCMS m / s=418.19[M+1]. Example 23 7-((4-(6-(difluoromethyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Compound 23)

[0300] [ka]

[0301] [ka]

[0302] Step 1 tert-Butyl 4-(6-(difluoromethyl)pyridin-3-yl)piperazine-1-carboxylate (23b) 5-Bromo-2-fluoromethylpyridine (23a, 2 g, 9.61 mmol) and tert-butyl piperazine-1-carboxylate (1b, 1.79 mg, 9.61 mmol) were dissolved in toluene (30 mL), followed by the addition of palladium acetate (215 mg, 0.96 mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (598 mg, 0.96 mmol). The reaction flask was purged with nitrogen, and the mixture was reacted in an oil bath at 120 °C for 16 h. The mixture was then quenched with water (40 mL) and extracted with ethyl acetate (6 × 30 mL). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 5:1) to give compound 23b (yellow solid, 1.89 g, 63% yield).

[0303] LCMS m / s=314.16[M+1].

[0304] Step 2: 1-(6-(difluoromethyl)pyridin-3-yl)piperazine (23c) Compound 23b (1.89 g, 6.03 mmol) was added to a 1,4-dioxane solution of hydrogen chloride (4 M, 63.3 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filter cake was collected to give compound 23c (yellow solid, 1.96 g, 94% yield).

[0305] LCMS m / s=214.11[M+1].

[0306] Step 3: 7-((4-(6-(difluoromethyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Compound 23) Compound 1e (white solid, 5 g, yield: 76%) was prepared according to the synthesis method of intermediate 14 in patent WO2021013735, and LCMS m / s=267 [M+1] was obtained.

[0307] Compound 23c (100 mg, 0.46 mmol) and compound 1e (83 mg, 0.37 mmol) were dissolved in acetonitrile (5 mL), and N,N-diisopropylethylamine (181 mg, 1.40 mmol) was added. After purging the reaction system with nitrogen, the mixture was reacted in an oil bath at 70 °C for 3 hours. The resulting solution was concentrated under reduced pressure to obtain the crude product. This was purified by column chromatography (MeOH:DCM = 1:60 to 1:15) to obtain compound 23 (white solid, 65 mg, yield: 34%).

[0308] 1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.42-8.38(m,1H),8.35(d,J=2.7Hz,1H),7.75(s,1H),7.62(s,1H),7.49(d,J=8.8 Hz,1H),7.44-7.39(m,1H),6.95-6.65(m,1H),3.64(s,2H),3.32-3.27(m,4H),2.59-2.51(m,6H),1.18(t,J=7.4Hz,3H).

[0309] LCMS m / s=400.02[M+1].

[0310] Example 24 7-((4-(5-(difluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Compound 24)

[0311] [ka]

[0312] [ka]

[0313] Step 1 tert-Butyl 4-(5-(difluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (24b) Intermediate 24b (yellow solid, 1.8 g, yield: 85%) was prepared according to the synthesis of intermediate 1c.

[0314] LCMS m / s=314.16[M+1].

[0315] Step 2 1-(5-(difluoromethyl)pyridin-2-yl)piperazine (24c) Intermediate 24d (yellow solid, 1.1 g, yield: 92%) was prepared according to the synthesis of intermediate 1d.

[0316] LCMS m / s=214.11[M+1].

[0317] Step 3 7-((4-(5-(difluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Compound 24) Compound 24 (white solid, 30 mg, yield: 43%) was prepared according to the synthesis of compound 1.

[0318] 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.42-8.38(m,1H),8.34(d,J=2.7Hz,1H),7.75(s,1H),7.62(s,1H),7.48(d,J=8.8 Hz,1H),7.44-7.39(m,1H),6.97-6.67(m,1H),3.65(s,2H),3.34-3.29(m,4H),2.60-2.52(m,6H),1.18(t,J=7.4Hz,3H).

[0319] LCMS m / s=400.19[M+1].

[0320] Example 25 7-((4-(5-(difluoromethoxy)pyridin-2-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Compound 25)

[0321] [ka]

[0322] [ka]

[0323] Step 1 tert-Butyl 4-(5-(difluoromethoxy)pyridin-2-yl)piperazine-1-carboxylate (25b) Intermediate 25b (red-brown solid, 2.35 g, yield: 79%) was prepared according to the synthesis of intermediate 1c.

[0324] LCMS m / s=330.16[M+1].

[0325] Step 2 1-(5-(difluoromethoxy)pyridin-2-yl)piperazine (25c) Intermediate 25c (yellow solid, 2.2 g, yield: 95%) was prepared according to the synthesis of intermediate 1d.

[0326] LCMS m / s=230.10[M+1].

[0327] Step 3 7-((4-(5-(difluoromethoxy)pyridin-2-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Compound 25) Compound 25 (brown solid, 75 mg, yield: 41%) was prepared according to the synthesis of compound 1.

[0328] 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.40(d,J=1.4Hz,1H),8.01(d,J=2.9Hz,1H),7.75(s,1H),7.62(s,1H),7.47-7.41(m,1H),7.1 4(d,J=74.3Hz,1H),6.89-6.85(m,1H),3.62(s,2H),3.49-3.44(m,4H),2.57-2.50(m,4H),2.48-2.44(m,2H),1.18(t,J=7.4Hz,3H).

[0329] LCMS m / s=416.18[M+1].

[0330] Example 26 6-(4-((7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)nicotinonitrile (Compound 26)

[0331] [ka]

[0332] [ka]

[0333] Step 1 tert-Butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate (26b) Intermediate 26b (brown solid, 2.47 g, yield: 75%) was prepared according to the synthesis of intermediate 1c.

[0334] LCMS m / s=289.16[M+1].

[0335] Step 2 6-(Piperazin-1-yl)nicotinonitrile (26c) Intermediate 26c (yellow solid, 2.1 g, yield: 92%) was prepared according to the synthesis of intermediate 1d.

[0336] LCMS m / s=189.11[M+1].

[0337] Step 3 6-(4-((7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)nicotinonitrile (Compound 26) Compound 26d was prepared according to patent WO2021013735A1.

[0338] Compound 26 (white solid, 88 mg, yield: 33%) was prepared according to the synthesis of compound 1.

[0339] 1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.47(d,J=2.3Hz,1H),8.38(d,J=1.6Hz,1H),7.86-7.80(m,2H) ,7.61(s,1H),6.92(d,J=9.2Hz,1H),3.69-3.64(m,4H),3.62(s,2H),2.49-2.45(m,4H),2.13(s,3H).

[0340] LCMS m / s=361.17[M+1].

[0341] Example 27 2-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)thiazole-5-carbonitrile (Compound 27)

[0342] [ka]

[0343] [ka]

[0344] Step 1 tert-Butyl 4-(5-cyanothiazol-2-yl)piperazine-1-carboxylate (27b) 2-Bromothiazole-5-nitrile (27a, 1 g, 5.30 mmol) and tert-butyl piperazine-1-carboxylate (1b, 1.08 g, 5.82 mmol) were dissolved in toluene (15 mL) and palladium acetate (119 mg, 0.53 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (330 mg, 0.53 mmol), and cesium carbonate (6.9 g, 21.3 mmol) were added. The reaction flask was purged with nitrogen, and the mixture was reacted in an oil bath at 120 °C for 16 h. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 5:1) to give compound 27b (yellow solid, 1.5 g, 96% yield).

[0345] 1 H NMR (400MHz, DMSO-d6) δ8.05 (s, 1H), 3.57-3.51 (m, 4H), 3.50-3.43 (m, 4H), 1.42 (s, 9H).

[0346] LCMS m / s=294.10[M+1].

[0347] Step 2 2-(Piperazin-1-yl)thiazole-5-carbonitrile (Compound 27c) Compound 27b (1.5 g, 5 mmol) was added to a 1,4-dioxane solution of hydrogen chloride (4 M, 15 mL), and the mixture was stirred at room temperature for 2 hours to allow the reaction to proceed. The reaction mixture was filtered, and the filter cake was collected to give compound 27c (yellow solid, 900 mg, 91% yield).

[0348] LCMS m / s=194.10[M+1].

[0349] Step 3 2-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)thiazole-5-carbonitrile (Compound 27) Compound 1e (white solid, 5 g, yield: 76%) was prepared according to the synthesis method of intermediate 14 in patent WO2021013735, and LCMS m / s=267 [M+1] was obtained.

[0350] Compound 27c (100 mg, 0.51 mmol) and compound 1e (123 mg, 0.46 mmol) were dissolved in acetonitrile (5 mL) and N,N-diisopropylethylamine (297 mg, 2.3 mmol) was added. The reaction mixture was purged with nitrogen and then reacted in an oil bath at 90 °C for 3 hours. The resulting solution was concentrated under reduced pressure to obtain the crude product. This was then purified by column chromatography (MeOH:DCM = 1:60 to 1:15) to obtain compound 27 (white solid, 100 mg, yield: 57%).

[0351] 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.39(d,1H),8.03(s,1H),7.75(s,1H), 7.60(d,1H),3.65(s,2H),3.60-3.50(m,4H),2.54-2.52(m,6H),1.17(t,3H).

[0352] LCMS m / s = 381.20 [M+1].

[0353] Example 28 2-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)thiazole-4-carbonitrile (Compound 28)

[0354] [ka]

[0355] [ka]

[0356] Step 1 tert-Butyl 4-(4-cyanothiazol-2-yl)piperazine-1-carboxylate (compound 28b) 2-Bromothiazole-4-nitrile (28a, 1 g, 5.30 mmol) and tert-butyl piperazine-1-carboxylate (1b, 1.08 g, 5.82 mmol) were dissolved in toluene (15 mL), and palladium acetate (119 mg, 0.53 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (330 mg, 0.53 mmol), and cesium carbonate (6.9 g, 21.3 mmol) were added. The reaction flask was purged with nitrogen, and the mixture was reacted in an oil bath at 120 °C for 16 h. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 5:1) to give compound 28b (yellow solid, 100 mg, 6% yield).

[0357] 1 H NMR (400MHz, DMSO-d6) δ8.00 (s, 1H), 3.44 (s, 8H), 1.42 (s, 10H).

[0358] LCMS m / s=294.10[M+1].

[0359] Step 2 2-(Piperazin-1-yl)thiazole-4-carbonitrile (Compound 28c) Compound 28b (100 mg, 0.33 mmol) was added to a 1,4-dioxane solution of hydrogen chloride (4 M, 2 mL) and stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filter cake was collected to give compound 28c (yellow solid, 60 mg, yield: 92%).

[0360] LCMS m / s=194.10[M+1].

[0361] Step 3 2-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)thiazole-4-carbonitrile Lu(Compound 28) Compound 28c (60 mg, 0.31 mmol) and compound 1e (91 mg, 0.34 mmol) were dissolved in acetonitrile (5 mL) and N,N-diisopropylethylamine (219 mg, 1.7 mmol) was added. The reaction system was purged with nitrogen and then reacted in an oil bath at 90 °C for 3 hours. The resulting solution was concentrated under reduced pressure to obtain the crude product. This was then purified by column chromatography (MeOH:DCM = 1:60 to 1:15) to obtain compound 28 (white solid, 50 mg, yield: 38%).

[0362] 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.39(d,1H),7.98(s,1H),7.74(s,1H), 7.60(d,1H),3.64(s,2H),3.55-3.39(m,4H),2.54-2.52(m,6H),1.17(t,3H).

[0363] LCMS m / s=381.20[M+1].

[0364] Example 29 7-((4-(6-(difluoromethoxy)pyridin-3-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Compound 29)

[0365] [ka]

[0366] [ka]

[0367] Step 1 tert-Butyl 4-(6-(difluoromethoxy)pyridin-3-yl)piperazine-1-carboxylate (compound 29b) 5-Bromo-2-(difluoromethoxy)pyridine (29a, 500 mg, 2.23 mmol) and tert-butyl piperazine-1-carboxylate (1b, 457 mg, 2.45 mmol) were dissolved in toluene (10 mL), and palladium acetate (50 mg, 0.22 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (137 mg, 0.22 mmol), and cesium carbonate (2.9 g, 8.92 mmol) were added. The reaction flask was purged with nitrogen, and the mixture was then reacted in an oil bath at 120 °C for 16 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 5:1) to give compound 29b (yellow solid, 700 mg, 95% yield).

[0368] 1 H NMR (400MHz, DMSO-d6) δ7.89(d,1H),7.58(dd,1H),7.56(t,1H),6.98(d,1H),3.47-3.44(m,4H),3.14-3.03(m,4H),1.42(s,9H).

[0369] LCMS m / s=329.20[M+1].

[0370] Step 2 1-(6-(difluoromethoxy)pyridin-3-yl)piperazine (compound 29c) Compound 29b (700 mg, 2.13 mmol) was added to a 1,4-dioxane solution of hydrogen chloride (4 M, 4 mL), and the mixture was stirred at room temperature for 2 hours to react. The reaction mixture was filtered, and the filter cake was collected to give compound 29c (yellow solid, 450 mg, yield: 92%).

[0371] LCMS m / s=229.10[M+1].

[0372] Step 3 7-((4-(6-(difluoromethoxy)pyridin-3-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Compound 29) Compound 29c (50 mg, 0.22 mmol) and compound 1e (52 mg, 0.20 mmol) were dissolved in acetonitrile (5 mL) and N,N-diisopropylethylamine (129 mg, 1.0 mmol) was added. The reaction system was purged with nitrogen and then reacted in an oil bath at 90 °C for 3 hours. The resulting solution was concentrated under reduced pressure to obtain the crude product. This was then purified by column chromatography (MeOH:DCM = 1:60 to 1:15) to obtain compound 29 (white solid, 20 mg, yield: 25%).

[0373] 1 H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.40(d,1H),7.87(d,1H),7.75(s,1H),7.62(s,1H),7.57(d d,1H),7.54(t,1H),6.96(d,1H),3.64(s,2H),3.22-3.07(m,4H),2.56-2.53(m,6H),1.18(t,3H).

[0374] LCMS m / s=416.20[M+1].

[0375] Biological Testing 1. PARP1 and PARP2 enzyme activity inhibition experiments In this experiment, the inhibition of the enzymatic activity of PARP1 and PARP2 by test compounds was detected using the PARP1 Chemiluminescence Assay (BPS, Catalog No. 80551) and the PARP2 Chemiluminescence Assay (BPS, Catalog No. 80552), respectively. The specific experimental procedure was as follows: After coating a 96-well plate with a histone mixture overnight, blocking buffer was added and the plate was incubated at room temperature for 90 minutes. Then, test compounds, PARP enzyme, and biotinylated substrate were added, and the mixture was incubated at room temperature for 1 hour. After this incubation, streptavidin-labeled HRP was added, and the resulting mixture was incubated at room temperature for 30 minutes. Finally, a mixture of ELISA ECL substrates A and B was added, and bioluminescence was immediately detected using a microplate reader. IC 50Values ​​were calculated using GraphPad Prism8 software.

[0376] As a result, the compounds of the present invention had significant biological inhibitory activity against PARP1 and showed better selectivity for PARP1 than for PARP2.

[0377] 2. PARP1 and PARP2 Trapping Experiments 2.1 PARP1 trapping experiments First, PARP1 (BPS, catalog number: 80501) and MAb anti-GST-Tb cryptate (cisbio, catalog number: 61GSTTL) were added to a 384-well plate, followed by DSB DNA probe-1 (Generay) and test compounds. The resulting mixture was incubated at room temperature for 45 minutes. NAD (Sigma, catalog number: 10127965001) was then added, and the resulting mixture was incubated at room temperature for 10 minutes. TR-FRET signals were detected using Envision2105 (PerkinElmer). IC 50 The values ​​were calculated using GraphPad Prism 8 software, and the results are shown in Table 1.

[0378] 2.2 PARP2 trapping experiments First, PARP2 (BPS, catalog number: 80502) and MAb anti-GST-Tb cryptate (cisbio, catalog number: 61GSTTL) were added to a 384-well plate, followed by PARP2 probe 2 (Generay) and the test substance. The resulting mixture was incubated at room temperature for 45 minutes. NAD (Sigma, catalog number: 10127965001) was then added, and the resulting mixture was incubated at room temperature for 10 minutes. Finally, the TR-FRET signal was detected using an Envision 2105 (PerkinElmer). IC 50 The values ​​were calculated using GraphPad Prism 8 software, and the results are shown in Table 1.

[0379] [Table 1]

[0380] The above results demonstrate that the compounds of the present invention have significant inhibitory activity against PARP1 trapping and have better selectivity for PARP1 trapping than for PARP2 trapping.

[0381] 3. Cell proliferation inhibition experiment 3.1 DLD-1 BRCA2 - / - Cell proliferation inhibition experiment Human colon adenocarcinoma-derived epithelial cell line DLD-1 BRCA2 - / - (Horizon Discovery, Catalog No. HD105-007) were cultured in RPMI-1640 medium containing 10% FBS, 1% penicillin-streptomycin solution, 1% LG, and 0.1 mg / mL hygromycin at 37°C and 5% CO2. One thousand DLD-1 BRCA2 cells were counted by cell counting. - / - Cells were seeded into each well of a 96-well plate and cultured overnight. The next day, test compounds (2-fold gradient dilutions, starting from the highest dose of 10 μM, for a total of 9 gradient concentrations) were added. Additionally, blank control wells containing the same concentration of DMSO were also set up. After culturing the cells at 37°C and 5% CO2 for 7 days, CellTiter-Glo® reagent was added, and chemiluminescence values ​​were measured using a microplate reader. IC 50 The values ​​were calculated using GraphPad Prism 8 software, and the results are shown in Table 2.

[0382] [Table 2]

[0383] The results show that the compounds of the present invention inhibit the DLD1 BRCA2 - / - It was shown to have a significant inhibitory effect on cell proliferation.

[0384] 3.2 MDA-MB-436 cell proliferation inhibition experiment Human breast cancer cell line MDA-MB-436 (supplied by ATCC, Cat. #HTB-130) was cultured in L15 medium containing 10% FBS and 1% penicillin-streptomycin solution at 37°C and 5% CO2. Four hundred MDA-MB-436 cells were seeded into each well of a 384-well plate by cell counting and cultured overnight. The following day, test compounds (3-fold gradient dilutions, starting from the highest dose of 10 μM, for a total of 10 gradient concentrations) were added. Additionally, blank control wells containing 0.1% DMSO were also set up. After culturing the cells at 37°C and 5% CO2 for 7 days, the detection solution from the Celltiter Glo assay kit was added, and chemiluminescence values ​​were measured using a microplate reader. IC 50 The values ​​were calculated using GraphPad Prism 8 software, and the results are shown in Table 3.

[0385] [Table 3]

[0386] The results showed that the compounds of the present invention had significant inhibitory effects on the proliferation of MDA-MB-436 cells.

[0387] 4. Bidirectional permeability evaluation using MDCK-MDR1 cell model In this experiment, MDCK-MDR1 cells were cultured in a 96-well transwell plate as a monolayer. Transport buffer containing 1 μM test compound was added to the appropriate apical or basolateral well, and transport buffer containing DMSO was added to the appropriate receiving well. After 2 hours of incubation at 37°C, the cell plate was removed, and samples (50 μL each) were collected from the apical and basolateral wells and transferred to a new 96-well plate. Acetonitrile was then added to precipitate proteins. The samples were analyzed by LC-MS / MS to determine the concentration of the test compound. This concentration data was used to calculate the apparent permeability coefficients for transport from the apical to the basolateral and basolateral to the apical side of the monolayer, and the efflux rates were calculated. The integrity of the monolayer was assessed by Lucifer Yellow leakage after 2 hours of incubation. The permeation results of the test compounds in MDCK-MDR1 cell monolayers are shown in Table 4.

[0388] [Table 4]

[0389] The above results show that the compounds of the present invention have higher cell membrane permeability and lower efflux rates than the comparative examples.

[0390] 5. Pharmacokinetic studies in mice The appropriate amount of test compound was precisely weighed and prepared as a 0.1 mg / mL solution in 30% DMSO and 30% HP-β-CD for intravenous injection. The test compound was also prepared as a 0.1 mg / mL solution in 0.5% MC for intragastric administration. Healthy adult male ICR mice were fasted overnight and then intravenously injected (0.5 mg / kg) with the test compound or intragastrically administered (1 mg / kg). Blood (anticoagulated with heparin sodium) was collected from the forelimb vein at different time points (0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours) after administration. Blood samples were centrifuged at 6800 g for 10 minutes at 4°C to obtain plasma. All samples were stored at -80°C for further testing. Plasma drug concentrations were measured by LC-MS / MS, and major pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0. The results are shown in Table 5.

[0391] [Table 5]

[0392] The above results demonstrate that the compounds of the present invention exhibit significantly superior pharmacokinetic properties in mice compared to the comparative compounds.

[0393] 6. Detection of Compound Distribution in Rat Brain Tissue The appropriate amount of test compound was precisely weighed and prepared as a 0.2 mg / mL solution in 0.5% MC. Healthy adult male SD rats were fasted overnight and then intragastrically administered with the test compound (1 mg / kg) or a blank vehicle. Blood was collected from the retro-orbital venous plexus at different time points after administration (anticoagulated with EDTA-K2). The animals were then sacrificed and brain tissue samples were collected. Blood samples were separated by centrifugation at 6000 g at 4°C for 5 minutes to obtain plasma. All samples were stored at -80°C for further analysis. The drug concentration in brain tissue was measured by LC-MS / MS. Brain tissue samples were homogenized prior to measurement. Key pharmacokinetic parameters were calculated using the Winnolin 8.3 noncompartmental model.

[0394] The results of the above test showed that the compounds of the present invention exhibit good blood-brain barrier permeability.

[0395] 7. Pharmacodynamic study of DLD-1 BRCA2- / - tumors Human colon adenocarcinoma-derived epithelial cells DLD-1 BRCA2- / - were cultured in RPMI-1640 medium containing 10% FBS and 1% penicillin-streptomycin solution. When cell confluence reached 80%-90%, the cells were digested, centrifuged, and counted. Matrigel and the cell suspension were uniformly mixed at a 1:1 ratio, and the resulting mixture was inoculated into the right flank of BALB / c nude mice at a dose of 5 × 10 cells. 6 The tumors were subcutaneously inoculated into mice with an inoculation volume of 0.2 mL. 3 When tumors reached the size (zigzag pattern), mice were divided into six groups (8 mice per group): vehicle, Comparative Example 1 (0.1 mpk, 1 mpk, and 10 mpk), and Compound 14 (1 mpk and 10 mpk). The test compounds were prepared with 0.5% MC and administered intragastrically at a dose of 10 mL / kg once daily for a total of 28 days. During the administration period, tumor volume and body weight were measured twice weekly, and tumor growth curves and mouse body weight change curves were plotted. Blood was collected from the orbital venous plexus of the mice at different time points (0, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours) after the final administration and centrifuged to obtain plasma. Drug concentrations in the plasma were then measured. At the final administration, tumors were excised from the mice 1 hour, 6 hours, and 24 hours after administration, crushed, and the drug concentrations in the tumors were measured.

[0396] The results of the test showed that the compounds of the present application had higher concentrations in tumor tissues compared to the comparative examples, and that the compounds of the present application had significantly superior efficacy in transplanted tumor models compared to the comparative examples.

[0397] Specific embodiments are described in detail in the specification of the present invention. Those skilled in the art should realize that the above-mentioned embodiments are examples and cannot be understood as limiting the present invention. Those skilled in the art can make some improvements and modifications to the present invention without departing from the principle of the present invention, and the technical solutions obtained based on these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A compound represented by general formula (IA), or a stereoisomer, a pharmaceutically acceptable salt or a deuterated compound thereof: 【Chemistry 1】 In the formula: R １ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl or C ３－８ heterocycloalkyl, wherein C ３－８ The heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O, or S; R ０ is H, halogen or C １－６ alkyl, wherein C １－６ The alkyl is optionally further substituted with one or more substituents selected from halogen; X 1 and X ３ is CR Ｘ and X 2 is selected from N, or X 1 is selected from N and X 2 and X 3 are selected from CR X ; R Ｘ is H or C １－６ alkyl; L is CH ２ Selected from: A is 【Chemistry 2】 Selected from: structural fragment 【Transformation 3】 teeth 【Chemistry 4】 Selected from: R ２ｂ may be the same or different; R ２ｃ may be the same or different; R ２ｄ may be the same or different; R ２ｅ may be the same or different; R ２ｆ may be the same or different; R ２ｂ , R ２ｃ and R ２ｆ are each independently CN, halogen, OR ２ａ , C １－６ alkyl or a 4- to 12-membered heterocycle, wherein C １－６ The alkyl and 4- to 12-membered heterocycles are optionally substituted with halogen, OH and C １－３ alkyl, and said 4- to 12-membered heterocycle optionally contains 1 to 4 heteroatoms selected from N, O, or S; R ２ｄ and R ２ｅ are each independently CN, halogen, OR ２ａ and C １－６ alkyl, wherein C １－６ The alkyl is optionally further substituted with one or more substituents selected from halogen or OH; R ２ａ is H, C １－６ Alkyl, (CH ２ ) ｎ C ３－８ Cycloalkyl or (CH ２ ) ｎ C ３－８ heterocycloalkyl, wherein said C ３－８ Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S, and said C １－６ The alkyl is optionally further substituted with one or more substituents selected from halogen; Z １ , Z ２ and Z ３ are each independently selected from N or C; Z １ , Z ２ and Z ３ at least two of are selected from N; n is selected from 0, 1, 2 or 3; b is selected from 1, 2 or 3; c is selected from 1, 2 or 3; d is selected from 2 or 3; e is selected from 1, 2 or 3; f is selected from 1 or 2; however The compound represented by general formula (IA) is not a compound represented by the following formula: 【Transformation 5】 。

2. Structural Unit 【Transformation 6】 teeth, 【Transformation 7】 Selected from: R １ is C １－６ Alkyl, C ２－６ alkenyl or C ３－８ cycloalkyl; R ０ is selected from halogens; R ２ｂ may be the same or different, R ２ｂ are each independently CN, halogen, C １－３ Alkoxy, C １－３ alkyl or a 4- to 12-membered heterocycle, wherein said C １－３ Alkyl, C １－３ The alkoxy and 4- to 12-membered heterocycles are optionally substituted with halogen, OH and C １－３ alkyl, and said 4- to 12-membered heterocycle optionally contains 1 to 4 heteroatoms selected from N, O, or S; R ２ｃ is CN; R ２ｄ is CN or halogen; R ２ｆ is CN; R ２ｅ may be the same or different, R ２ｅ are each independently CN, halogen, OR ２ａ and C １－６ alkyl, wherein C １－６ The alkyl is optionally further substituted with one or more substituents selected from halogen or OH; R ２ａ is C １－３ Alkyl or 【Transformation 8】 and C is selected from １－３ The alkyl is optionally further substituted with one or more substituents selected from halogen; p is selected from 0 or 1; q is selected from 1 or 2; 10. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt or deuterated compound thereof.

3. Structural Unit 【Chemistry 9】 teeth, 【Chemistry 10】 Selected from: R １ is C １－６ Alkyl or C ３－８ cycloalkyl; A is, 【Chemistry 11】 Selected from: R ２ｅ may be the same or different, R ２ｅ are each independently CN, OR ２ａ or C １－３ alkyl, wherein C １－３ The alkyl is optionally further substituted with one or more substituents selected from halogen; R ２ａ is C １－３ Alkyl or 【Chemistry 12】 and C is selected from １－３ The alkyl is optionally further substituted with one or more substituents selected from halogen; 3. The compound of claim 2, or a stereoisomer, pharmaceutically acceptable salt or deuterated compound thereof.

4. R ２ｂ CN, halogen, C １－３ alkyl or a 5-membered heterocycle, １－３ The alkyl and 5-membered heterocycle are optionally substituted with halogen and C １－３ alkyl, and said 5-membered heterocycle optionally contains 1 to 4 heteroatoms selected from N, O or S; R ２ｅ is selected from CN; 4. The compound of claim 3, or a stereoisomer, pharmaceutically acceptable salt or deuterated compound thereof.

5. R ２ｂ 5. The compound of claim 4, or a stereoisomer, pharmaceutically acceptable salt or deuterated compound thereof, wherein is selected from CN.

6. A compound represented by the following general formula (I) or a stereoisomer thereof: 【Chemistry 13】 During the ceremony, R １ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl or C ３－８ heterocycloalkyl; ３－８ The heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O, or S; X 1 and X ３ is CR Ｘ and X 2 is selected from N; R Ｘ is H or C １－６ alkyl; L is CH ２ Selected from: A is a 6-membered monocyclic heterocycle or a 9-membered spiro heterocycle, wherein said heterocycle optionally contains two N atoms; R ２ may be the same or different, R ２ are each independently CN, halogen, OR ２ａ or C １－６ alkyl; R ２ａ is H, C １－６ Alkyl, (CH ２ ) ｎ C ３－８ Cycloalkyl or (CH ２ ) ｎ C ３－８ heterocycloalkyl, wherein C ３－８ Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S; C １－６ The alkyl is optionally further substituted with one or more substituents selected from halogen; Z may be the same or different, and each Z is independently selected from CH or N; m is selected from 1, 2 or 3; n is selected from 0, 1, 2 or 3; however The compound represented by general formula (I) is not a compound represented by the following formula: 【Chemistry 14】 。

7. A compound represented by general formula (II) or a stereoisomer thereof: 【Chemistry 15】 During the ceremony, R １ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl or C ３－８ heterocycloalkyl, wherein C ３－８ The heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O, or S; R ０ is H, halogen or C １－６ alkyl, C １－６ The alkyl may optionally be a halogen or a C １－６ further substituted with one or more substituents selected from alkyl; X １ and X ２ are each independently CR Ｘ Selected from: R Ｘ is H or C １－６ alkyl; L is CH ２ Selected from: A is a 6-membered monocyclic heterocycle or a 9-membered spiro heterocycle, wherein said heterocycle optionally contains two N atoms; B is selected from a 6-membered aryl or a 6-membered heteroaryl, wherein said heteroaryl may contain 1 to 2 heteroatoms selected from N; R ２ may be the same or different, R ２ are each independently CN, halogen, OR ２ａ or C １－６ alkyl; R ２ａ is H, C １－６ Alkyl, (CH ２ ) ｎ C ３－８ Cycloalkyl or (CH ２ ) ｎ C ３－８ heterocycloalkyl, wherein C ３－８ Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S, and said C １－６ The alkyl is optionally further substituted with one or more substituents selected from halogen; m is selected from 1, 2 or 3; n is selected from 0, 1, 2 or 3;

8. A compound or a stereoisomer thereof selected from the following compounds: 【Chemistry 16】 【change】 【change】

9. (1) A compound according to any one of claims 1 to 5, or a stereoisomer thereof, a pharmaceutically acceptable salt or a deuterated compound thereof, or a compound according to any one of claims 6 to 8, or a stereoisomer thereof; (2) optionally, one or more additional active ingredients; and (3) Pharmaceutically acceptable carriers and / or excipients A pharmaceutical composition comprising:

10. Use of a compound according to any one of claims 1 to 5 or a stereoisomer thereof, a pharmaceutically acceptable salt or a deuterated compound thereof, or a compound according to any one of claims 6 to 8 or a stereoisomer thereof in the preparation of an antitumor drug.

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