Parp1 inhibitors

Abstract

The present application provides a class of PARP1 inhibitors represented by formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof. The present application also provides a preparation method of the compound, a pharmaceutical composition comprising the compound, and the role of the compound in the prevention and treatment of cancer, ischemic disease or neurodegenerative disease.

Description

[0001] This application claims priority to Chinese application 202211668333.2 filed on December 23, 2022, and Chinese application 202311484011.7 filed on November 08, 2023, which are incorporated herein by reference in their entirety. Technical Field

[0002] This invention relates to a new class of PARP1 inhibitors, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof. The invention also relates to methods for preparing said compounds, pharmaceutical compositions comprising said compounds, and the role of said compounds in the prevention and treatment of PARP1-mediated diseases such as cancer. Background Technology

[0003] ADP-ribosylation is an enzymatic reaction that breaks down the substrate nicotinamide adenine dinucleotide (NAD+) into nicotinamide and an ADP ribose group, which is then covalently linked to a receptor protein. ADP ribosylation is a common and reversible post-translational modification of proteins, playing a crucial role in a range of biological processes, including DNA damage repair, cell proliferation and differentiation, metabolism, and stress response.

[0004] Poly(ADP-ribose) polymerase (PARP) is a family of proteins that catalyze the ribosylation of ADP. PARP1 is one of the most widely studied and important members of this family. It is highly expressed in cells and responds rapidly, quickly catalyzing and modifying DNA repair factors and interacting with them to participate in various DNA repair processes. In normal cells, single-strand breaks in DNA can be repaired through base excision. PARP1 uses NAD+ as a substrate, binds to the damage site through its zinc finger domain to change its conformation, and catalyzes the transfer of ADP-ribose groups, ultimately completing single-strand repair. In cancer cells with double-strand breaks (DSB), DNA breaks are mainly repaired through homologous recombination (HR). BRCA1 and BRCA2 are key proteins mediating HR. In cancer cells with BRCA1 / 2 mutations, PARP1 function is also inhibited, causing obstruction of the main DNA repair pathway and ultimately leading to cell death. This is the synthetic lethal effect that has been well-validated in clinical practice. Therefore, PARP1 has become a highly sought-after target for cancer therapy.

[0005] In recent years, four small-molecule PARP inhibitors (PARPi) have been approved by the US FDA for cancer treatment: olaparib, niraparib, rucaparib, and telazoparib. These drugs have demonstrated good clinical efficacy in treating patients with BRCA1 / 2-mutated ovarian and / or breast cancer, and have also shown very promising results in other BRCA-mutated cancers, including prostate and pancreatic cancer.

[0006] Recent studies have suggested that the mechanism of action of PARP1 can be attributed to two distinct but interconnected mechanisms. First, by inhibiting the catalytic activity of PARP1, these PARP1 inhibitors block the synthesis of the PAR chain, thereby inhibiting poly(ADP-ribosylation) and blocking PARP1-mediated DNA damage repair signaling. Second, PARP inhibitors may also induce PARP1 trapping, leading to DNA double-strand breaks and ultimately killing cancer cells. When PARP1 itself undergoes PARylation, it detaches from the DNA damage site due to steric hindrance and charge repulsion of the PAR chain. However, treatment with PARP inhibitors blocks PARP1 self-modification, causing PARP1 to become trapped at the DNA damage site. The long-term presence of the PARP-DNA complex occupies the DNA damage site and interferes with subsequent DNA replication, leading to replication fork arrest and subsequent double-strand DNA damage, ultimately causing cell death. However, PARP1 trapping occurs concurrently with the inhibition of PARP1 catalytic activity. Therefore, the inhibition of PARP1 catalytic activity and PARP1 capture caused by PARP inhibitors are functionally completely different but intrinsically related.

[0007] Based on the synthetic lethal mechanism, cell lines carrying BRCA1 / 2 mutations or homologous recombination deficiency (HRD) are highly sensitive to PARP inhibitors, providing a very broad therapeutic safety window. However, because some normal cells in the body, such as myeloid-derived cells, are often in a state of rapid proliferation, DNA damage is inevitable. Furthermore, many enrolled patients have germline mutations, leading to varying degrees of hematologic toxicity when using approved non-selective PARP1 / 2 inhibitors, including anemia, neutropenia, and thrombocytopenia. Grade III or IV hematologic toxicity often results in dose reduction, discontinuation, or interruption of treatment, severely impacting the therapeutic efficacy of PARP inhibitors.

[0008] On the other hand, there is a potential basis for synergistic effects when chemotherapy drugs and PARP inhibitors are used in combination. However, because chemotherapy drugs inhibit rapidly proliferating cells while also having strong hematologic toxicity, the combined use of the two can lead to an additive effect of hematologic toxicity, which greatly limits the combined use of PARP inhibitors.

[0009] Studies have shown that anemia caused by PARP inhibitors may be mainly due to the inhibition of PARP2 (Farrés J, et al. Cell Death Differ. 2015 Jul; 22(7):1144-57.). Currently marketed PARP inhibitors all have inhibitory activity on both PARP1 and PARP2. If highly selective PARP1 inhibitors can be developed to reduce the inhibition of PARP2, it may be possible to avoid the anemia toxicity caused by existing PARP1 / 2 inhibitors. WO2021013735A1 discloses a series of selective PARP1 inhibitors, such as AZD5305.

[0010]

[0011] Therefore, developing more highly selective PARP1 inhibitors has significant clinical application value, and there is a demand for such inhibitors in this field. Summary of the Invention

[0012] This invention targets PARP1 and develops a new class of small molecule inhibitors that can be used to treat various cancers.

[0013] The compounds of this invention target PARP1, exhibiting excellent PARP1 inhibitory activity and selectivity, thereby avoiding anemia toxicity. Simultaneously, the compounds of this invention possess different volumes of distribution (reducing neutrophil and platelet toxicity) and different trapping activities (facilitating dosage adjustment), maintaining the clinical efficacy of PARP1 / 2 inhibitors while reducing hematologic toxicity, thus enabling further combination therapy of highly selective PARP1 inhibitors with chemotherapy drugs.

[0014] In one aspect, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof:

[0015]

[0016] in,

[0017] L1 is selected from CRR', O, S, NH, -C(O)-, -S(O)- or -S(O)2-;

[0018] R and R' are independently selected from H, D, halogens, and C. 1-6 Alkyl or C1-6 Halogenated alkyl groups;

[0019] A is selected from CR A Or N;

[0020] E is selected from CR E Or N;

[0021] G is selected from CR G Or N;

[0022] R A R E and R G Independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -LC 3-10 Cycloalkyl or -L-3-10 membered heterocyclic groups;

[0023] R1 is selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic, -LC 6-10 aryl or -L-5-10 heteroaryl, optionally surrounded by 1, 2 or 3 R groups 1s replace;

[0024] R 1s Independently selected from H, D, halogen, CN, OR a SR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0025] It can be represented as a single bond or a double bond;

[0026] M1 is selected from N, C, or CR5;

[0027] M2 is either N or CR6;

[0028] R5 and R6 are independently selected from H, D, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0029] R4 is independently selected from H, D, halogens, CN, =O, OR a SR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 4s replace;

[0030] Alternatively, R4, located adjacent to M1, together with R2 and the atoms connected to them, forms C. 5-7 Cycloalkyl or 5-7 membered heterocyclic groups, or R4 located ortho to M1 together with Z3 and the atoms they are attached to form C. 5-7 Cycloalkyl or 5-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 4s replace;

[0031] R 4s Independently selected from H, D, halogens, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups;

[0032] n is 0, 1, 2, 3 or 4;

[0033] Z1 is selected from CR7 or N;

[0034] Z2 is selected from CR8 or N;

[0035] Z3 is selected from CR9 or N;

[0036] R2, R7, R8, and R9 are independently selected from H, D, halogens, CN, and OR. a SR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 2s replace;

[0037] R 2sIndependently selected from H, D, halogens, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups;

[0038] R3 is selected from H, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic, -LC 6-10 aryl or -L-5-10 heteroaryl, optionally surrounded by 1, 2 or 3 R groups 3s replace;

[0039] R 3s Independently selected from H, D, halogen, CN, OR a SR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0040] L represents a chemical bond, C represents a chemical bond. 1-6 Alkylene, C 2-6 imide or C 2-6 The ynyl group, optionally surrounded by 1, 2, or 3 atoms selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 Group substitution of the alkynyl group;

[0041] R a R b and R c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclic groups; or R b R c Together with the atoms they connect, they form 5-10 membered heterocyclic groups;

[0042] The aforementioned groups are optionally deuterated, up to and including complete deuteration.

[0043] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant, or mediator.

[0044] In another aspect, the present invention provides the use of the compounds or pharmaceutical compositions of the present invention in the preparation of medicaments for treating and / or preventing PARP-mediated diseases; preferably, the PARP is PARP1.

[0045] In another aspect, the present invention provides a method for treating and / or preventing PARP-mediated diseases in a subject, comprising administering the subject a compound of the present invention or a pharmaceutical composition of the present invention; preferably, the PARP is PARP1.

[0046] In another aspect, the present invention provides compounds or pharmaceutical compositions of the present invention for the treatment and / or prevention of PARP-mediated diseases; preferably, the PARP is PARP1.

[0047] In specific implementations, the present invention is used to treat and / or prevent cancer, ischemic diseases, and neurodegenerative diseases.

[0048] In another specific implementation, the cancer lacks the HR-dependent DNA DSB repair pathway.

[0049] In another specific embodiment, the cancer has a BRCA1 or BRCA2 defective phenotype.

[0050] In another specific embodiment, the present invention is used to treat and / or prevent the following cancers: breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, and lung cancer.

[0051] definition

[0052] Chemical definition

[0053] The definitions of specific functional groups and chemical terms are described in more detail below.

[0054] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0055] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl, C 1-3 Alkyl and C 1-2 Alkyl groups are preferred. C 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C" is used in conjunction with the preceding text. 1-6 "Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0056] “C 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl groups are preferred. C 2-6 Examples of alkenyl groups include: vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and so on. The term "C" is used in conjunction with these groups. 2-6 "Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0057] “C 2-6"Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 The alkynyl group is preferred. C 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), etc. The term "C" is used in conjunction with other alkynyl groups. 2-6 "Alkyne" also includes heteroyne, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0058] “C 1-6 "Alkylene" refers to the removal of C 1-6 The alkyl group is a divalent group formed by the other hydrogen atom of the alkyl group, and can be substituted or unsubstituted. In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylenes are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0059] “C 2-6 "Alkenyl" refers to the group that has been de-carbonied. 2-6 The other hydrogen atom of the alkenyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 2-4Alkenyl groups are particularly preferred. Exemplary unsubstituted alkenyl groups include, but are not limited to, vinylidene (-CH=CH-) and propenylidene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenyl groups, such as alkenyl groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylidene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylidene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), etc.

[0060] “C 2-6 "Iso-ynyl group" refers to the group with the C group removed. 2-6 The other hydrogen atom of the alkynyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 2-4 The ethynyl group is particularly preferred. Exemplary ethynyl groups include, but are not limited to: ethynyl group (-C≡C-), substituted or unsubstituted propynyl group (-C≡CCH2-), etc.

[0061] “C 0-6 "alkylene" refers to chemical bonds and the aforementioned "C" 1-6 Alkylene", "C" 0-4 "alkylene" refers to chemical bonds and the aforementioned "C" 1-4 Alkylene".

[0062] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0063] Therefore, "C" 1-6 "Halogenated alkyl" refers to the above "C 1-6 "alkyl" is substituted with one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl groups are particularly preferred, and C4 groups are more preferred. 1-3 Halogenated alkyl, more preferably C 1-2 Halogenated alkyl groups. Exemplary alkyl halogenated groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The alkyl halogenated group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0064] “C 1-6"Deuterated alkyl" refers to the above "C 1-6 "alkyl" is substituted with one or more deuterium groups. In some embodiments, C 1-4 Deuterated alkyl groups are particularly preferred, and C4 groups are more preferred. 1-2 Deuterated alkyl, more preferably C 1-2 Deuterated alkyl groups. Exemplary deuterated alkyl groups include, but are not limited to: -CD3, -CHD2, -CH2D, -CHDCH2D, -CH2CD3, -CD2CD3, etc. The deuterated alkyl group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0065] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 cyclic carbon atoms and zero heteroatoms, optionally containing 1, 2, or 3 double or triple bonds. In some embodiments, C 5-10 cycloalkyl, C 3-7 cycloalkyl and C 3-6 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-7 cycloalkyl and C 5-6 Cycloalkyl groups. Cycloalkyl groups also include ring systems in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the bonding point is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Cycloalkyl groups also include the aforementioned cycloalkyl ring in which substituents on any non-adjacent carbon atoms are linked to form a bridged ring, together forming a polycyclic alkane sharing two or more carbon atoms. Cycloalkyl groups also include the aforementioned cycloalkyl ring in which substituents on the same carbon atom are linked to form a ring, together forming a polycyclic alkane sharing one carbon atom. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), etc. The cycloalkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0066] “C 3-10 "Cycloalkylene" refers to the alkylene oxide that has had C removed. 3-10 The cycloalkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 5-10 Cycloalkylene, C 5-7 Cycloalkylene, C 3-7 Cycloalkylene, C 3-6 Cycloalkylene and C 3-4Cycloalkylene compounds are particularly preferred, especially cyclopropylene compounds.

[0067] "3-10 membered heterocyclic groups" refer to saturated or unsaturated groups of 3- to 10 membered non-aromatic ring systems having a ring carbon atom and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally contains 1, 2, or 3 double or triple bonds. In heterocyclic groups containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. In some embodiments, a 5-10 membered heterocyclic group is preferred, which is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 3-7 membered heterocyclic group is preferred, which is a 3-7 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; a 5-7 membered heterocyclic group is preferred, which is a 5-7 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 3-6 membered heterocyclic group is preferred, which is a 3-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 4-6 membered heterocyclic group is preferred, which is a 4-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; and a 5-6 membered heterocyclic group is preferred, which is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Heterocyclic groups also include ring systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the linking point is on the heterocyclic ring; or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Heterocyclic groups also include the aforementioned heterocyclic ring in which substituents on any non-adjacent carbon or nitrogen atom are linked to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclic groups also include the aforementioned heterocyclic ring in which substituents on the same carbon atom are linked to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxetane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxetane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolylyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: pyrazolylyl, dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiohexane, and dioxane. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. Heterocyclic groups also include those that share one or two atoms with a cycloalkyl, heterocyclic, aryl, or heteroaryl group to form a bridged or spirocyclic ring, wherein the shared atom may be a carbon or nitrogen atom, provided the valence allows. Heterocyclic groups also include those that can be optionally substituted with one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0068] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0069] "5-10-membered heteroaryl" refers to a group comprising a 4n+2 aromatic ring system of a 5-10-membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms (e.g., having 6 or 10 shared π electrons arranged in a ring), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6-membered heteroaryl is particularly preferred, which is a 4n+2 aromatic ring system of a 5-6-membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl or pyridoneyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azirmonoheptatrienyl, oxazirmonoheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinel. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, zenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0070] The divalent groups formed by removing one hydrogen atom from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined above are collectively referred to as "subunits". Cyclic groups such as cycloalkyl, heterocyclic, aryl, and heteroaryl are collectively referred to as "cyclogroups".

[0071] The alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0072] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bb C(=O)N(R bb )2、-C(=NR bb )R aa -C(=NR) bb OR aa -OC(=NR) bb )R aa -OC(=NR) bb OR aa -C(=NR) bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa -NR bb SO2R aa -SO2N(R) bb )2、-SO2R aa -SO2OR aa -OSO2R aa-S(=O)R aa -OS(=O)R aa 、-Si(R aa )3、-OSi(R aa 3. -C(=S)N(R) bb )2、-C(=O)SR aa -C(=S)SR aa -SC(=S)SR aa -SC(=O)SR aa -OC(=O)SR aa -SC(=O)OR aa -SC(=O)R aa -P(=O)2R aa -OP(=O)2R aa -P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0073] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa=NR bb or = NOR cc replace;

[0074] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0075] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0076] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups.dd Group substitution;

[0077] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee )3、-OSi(R ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee-C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently marked by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0078] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0079] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0080] R gg Each of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6 Alkyl)3, -C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC (=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0081] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0082] Other definitions

[0083] The term "cancer" includes, but is not limited to, the following cancers: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor), Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma); Urogenital tract: Kidneys (adenocarcinoma, Wilms' tumor, lymphoma, leukemia), Bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), Prostate (adenocarcinoma, sarcoma), Testes (seminomatous cyst, teratoma, embryonal carcinoma, teratoma), Choriocarcinoma, Sarcoma, Stromal cell carcinoma, Fibroma, Fibroadenoma, Adenomatous tumor, Lipoma); Liver: Hepatocellular carcinoma, Bile duct carcinoma, Hepatoblastoma, Angiosarcoma, Hepatocellular adenoma, Hemangioma; Bile duct: Gallbladder carcinoma, Ampullary carcinoma, Bile duct carcinoma; Bone: Osteosarcoma, Fibrosarcoma, Malignant fibrous histiocytoma, Chondrosarcoma, Ewing's sarcoma, Malignant lymphoma (reticular cell sarcoma), Multiple myeloma, Malignant giant cell tumor, Chondromalacia, Chronic osteocartilaginous osteophytes. Exostoses, benign chondromas, chondroblastomas, fibrochondromas, chondromyxomas, osteoid osteomas, and giant cell tumors; Nervous system: Skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pineal tumors), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors); Spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecology: Uterus (endometrial cancer), Cervix (cervical cancer, precancerous cervical dysplasia, etc.), Ovary (ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), Granulosarcoma, Sertoli stromal cell tumor, dysgerminoma, malignant teratoma), Vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), Fallopian tube (cancer);Hematology: Blood disorders (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), follicular lymphoma, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin disorders: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland disorders: neuroblastoma.

[0084] In one implementation, the term "cancer" includes, but is not limited to, the following cancers: breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, and lung cancer.

[0085] As used herein, the term “treatment” refers to reversing, alleviating, inhibiting, or preventing the progression of an obstacle or condition to which the term applies, or one or more symptoms of such an obstacle or condition. The noun “treatment” as used herein also refers to the action of the verb “to treat,” as defined above.

[0086] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of the present invention.

[0087] Pharmaceutically acceptable base addition salts are those formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, and calcium. Suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, and procaine.

[0088] The base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the required base in a conventional manner to form a salt. The free acid can be regenerated by contacting the salt form with an acid in a conventional manner and then separating the free acid. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents; however, for the purposes of this invention, the salts are equivalent to their respective free acids.

[0089] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides prepared from inorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, gluconate, lactobionate, laurylsulfonate, and hydroxyethanesulfonate. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, and aliphatic and aromatic sulfonic acids. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, naphthates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates. Pharmaceutically acceptable salts may include alkali metal and alkaline earth metal-based cations, such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. It also covers salts of amino acids, such as arginine salts, gluconates, galacturons, etc. (see, for example, Berge S. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0090] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0091] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0092] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0093] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0094] Unless otherwise stated, the term "therapeuticly effective amount" of a compound as used herein is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. Therapeuticly effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic effects of other therapeutic agents.

[0095] Unless otherwise stated, the “preventively effective amount” of a compound as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount sufficient to prevent recurrence of a disease, disorder, or condition. The preventively effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in the prevention of a disease, disorder, or condition. The term “preventively effective amount” may include amounts that improve overall prevention or enhance the preventive effect of other preventive agents.

[0096] The term "combination" and related terms refer to the simultaneous or sequential administration of the compounds of the present invention and other therapeutic agents. For example, the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form. Attached Figure Description

[0097] Figure 1 This is the effect curve of the compound of the present invention on PARP1 / 2-DNA capture over 2 hours.

[0098] Figure 2 The time-effect curves of the compounds of this invention on PARP1 / 2-DNA capture at different time points are shown.

[0099] Figure 3 The effect of the compound of the present invention on tumor volume changes in subcutaneous xenografts in MDA-MB-436 mice.

[0100] Figure 4 The compound of this invention induced DLD-1BRCA2 in three different experiments. - / - Apoptosis.

[0101] Figure 5 The expression of cleaved Caspase-3 and Caspase-3 proteins in tumor tissue.

[0102] Figure 6 The effect of the compound of Example 4 and the reference AZD5305 on cleaved Caspase-3 protein in tumor tissue at the same dose (*, p<0.05, no statistically significant difference between other groups by one-way ANOVA). Detailed Implementation

[0103] In this document, “compounds of the present invention” refers to compounds of formula (I), formula (II), etc., pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof.

[0104] In this document, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood (unless otherwise stated) that all optical isomers and mixtures thereof are included. Furthermore, unless otherwise specified, all isomers included in this invention may have carbon-carbon double bonds in the forms of Z and E. Regarding compounds existing in different tautomeric forms, a single compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.

[0105] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:

[0106]

[0107] in,

[0108] L1 is selected from CRR', O, S, NH, -C(O)-, -S(O)- or -S(O)2-;

[0109] R and R' are independently selected from H, D, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0110] A is selected from CRA Or N;

[0111] E is selected from CR E Or N;

[0112] G is selected from CR G Or N;

[0113] R A R E and R G Independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -LC 3-10 Cycloalkyl or -L-3-10 membered heterocyclic groups;

[0114] R1 is selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic, -LC 6-10 aryl or -L-5-10 heteroaryl, optionally surrounded by 1, 2 or 3 R groups 1s replace;

[0115] R 1s Independently selected from H, D, halogen, CN, OR a SR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0116] It can be represented as a single bond or a double bond;

[0117] M1 is selected from N, C, or CR5;

[0118] M2 is either N or CR6;

[0119] R5 and R6 are independently selected from H, D, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0120] R4 is independently selected from H, D, halogens, CN, =O, OR a SR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 4s replace;

[0121] Alternatively, R4, located adjacent to M1, together with R2 and the atoms connected to them, forms C. 5-7 Cycloalkyl or 5-7 membered heterocyclic groups, or R4 located ortho to M1 together with Z3 and the atoms they are attached to form C. 5-7 Cycloalkyl or 5-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 4s replace;

[0122] R 4s Independently selected from H, D, halogens, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups;

[0123] n is 0, 1, 2, 3 or 4;

[0124] Z1 is selected from CR7 or N;

[0125] Z2 is selected from CR8 or N;

[0126] Z3 is selected from CR9 or N;

[0127] R2, R7, R8, and R9 are independently selected from H, D, halogens, CN, and OR. a SR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 2s replace;

[0128] R 2s Independently selected from H, D, halogens, CN, C 1-6 Alkyl, C 1-6Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups;

[0129] R3 is selected from H, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic, -LC 6-10 aryl or -L-5-10 heteroaryl, optionally surrounded by 1, 2 or 3 R groups 3s replace;

[0130] R 3s Independently selected from H, D, halogen, CN, OR a SR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0131] L represents a chemical bond, C represents a chemical bond. 1-6 Alkylene, C 2-6 imide or C 2-6 The ynyl group, optionally surrounded by 1, 2, or 3 atoms selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 Group substitution of the alkynyl group;

[0132] R a R b and R c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclic groups; or R b R c Together with the atoms they connect, they form 5-10 membered heterocyclic groups;

[0133] The aforementioned groups are optionally deuterated, up to and including complete deuteration.

[0134] L1

[0135] In one embodiment, L1 is CRR', for example CH2; in another embodiment, L1 is O; in another embodiment, L1 is S; in another embodiment, L1 is NH; in another embodiment, L1 is -C(O)-; in another embodiment, L1 is -S(O)-; in another embodiment, L1 is -S(O)2-.

[0136] In one more specific embodiment, L1 is selected from CRR', O, S, NH or -C(O)-; in another more specific embodiment, L1 is CRR' or -C(O)-; in another more specific embodiment, L1 is CRR'; in another more specific embodiment, L1 is CH2.

[0137] R and R'

[0138] In one embodiment, R is H; in another embodiment, R is D; in yet another embodiment, R is a halogen; in yet another embodiment, R is C. 1-6 Alkyl, such as C 1-3 Alkyl; in another embodiment, R is C 1-6 Halogenated alkyl groups, such as C 1-3 Halogenated alkyl groups.

[0139] In one embodiment, R' is H; in another embodiment, R' is D; in yet another embodiment, R' is a halogen; in yet another embodiment, R' is C. 1-6 Alkyl, such as C 1-3 Alkyl; in another embodiment, R' is C 1-6 Halogenated alkyl groups, such as C 1-3 Halogenated alkyl groups.

[0140] In a more specific implementation, R and R' are independently selected from H, D, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl group; in another, more specific embodiment, R and R' are independently selected from H, D, C. 1-3 Alkyl or C 1-3 Halogenated alkyl; in another more specific embodiment, R and R' are independently H or D; in another more specific embodiment, R and R' are H.

[0141] A, E and G

[0142] In one implementation, A is CR A In another implementation, A is N.

[0143] In one implementation, E is CRE In another implementation, E is N.

[0144] In one implementation, G is CR G In another implementation, G is N.

[0145] In one more specific embodiment, A is N; in another more specific embodiment, E is CR. E In another, more specific implementation, G is CR G In another, more specific implementation, for

[0146] R A R E and R G

[0147] In one implementation, R A H; in another embodiment, R A For D; in another implementation, R A It is a halogen; in another embodiment, R A CN; in another embodiment, R A For -L-OR a OR is preferred a In another implementation, R A -L-SR a SR is preferred a In another implementation, R A -L-NR b R c NR is preferred. b R c In another implementation, R A C 1-6 Alkyl; in another embodiment, R A C 1-6 Halogenated alkyl; in another embodiment, R A C 2-6 alkenyl; in another embodiment, R A C 2-6 Alkyne group; in another embodiment, R A For -LC 3-10 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R A It is an -L-3-10 membered heterocyclic group, preferably a 3-10 membered heterocyclic group, and more preferably a 3-7 membered heterocyclic group.

[0148] In one implementation, R E H; in another embodiment, R E For D; in another implementation, R E It is a halogen; in another embodiment, R E CN; in another embodiment, R E For -L-OR a OR is preferred a In another implementation, R E -L-SR a SR is preferred a In another implementation, R E -L-NR b R c NR is preferred. b R c In another implementation, R E C 1-6 Alkyl; in another embodiment, R E C 1-6 Halogenated alkyl; in another embodiment, R E C 2-6 alkenyl; in another embodiment, R E C 2-6 Alkyne group; in another embodiment, R E For -LC 3-10 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R E It is an -L-3-10 membered heterocyclic group, preferably a 3-10 membered heterocyclic group, and more preferably a 3-7 membered heterocyclic group.

[0149] In one implementation, R G H; in another embodiment, R G For D; in another implementation, R G It is a halogen; in another embodiment, R G CN; in another embodiment, R G For -L-OR a OR is preferred a In another implementation, R G -L-SR a SR is preferred a In another implementation, R G -L-NR b R c NR is preferred. b Rc In another implementation, R G C 1-6 Alkyl; in another embodiment, R G C 1-6 Halogenated alkyl; in another embodiment, R G C 2-6 alkenyl; in another embodiment, R G C 2-6 Alkyne group; in another embodiment, R G For -LC 3-10 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R G It is an -L-3-10 membered heterocyclic group, preferably a 3-10 membered heterocyclic group, and more preferably a 3-7 membered heterocyclic group.

[0150] In a more specific implementation, R A R E and R G Independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 3-7 Cycloalkyl or -L-3-7-membered heterocyclic group; in another more specific embodiment, R A R E and R G Independently selected from H, D, halogen, CN, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; in another more specific embodiment, R A R E and R G Independently selected from H, D, halogens, and C 1-6 Alkyl or C 1-6 Halogenated alkyl; in another, more specific embodiment, R A R E and R G Independently H or D; in another, more specific implementation, R A R E and R G For H.

[0151] R1

[0152] In one embodiment, R1 is H; in another embodiment, R1 is D; in yet another embodiment, R1 is a halogen; in another embodiment, R1 is CN; in yet another embodiment, R1 is -L-OR a OR is preferred a In another implementation, R1 is -L-SR a SR is preferred a In another implementation, R1 is -L-NR b R c NR is preferred. b R c In another embodiment, R1 is C 1-6 Alkyl, such as Me, such as Et; in another embodiment, R1 is C 1-6 Halogenated alkyl; in another embodiment, R1 is C 2-6 Alkenyl; in another embodiment, R1 is C 2-6 Alkyne group; in another embodiment, R1 is -LC 3-10 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, R1 is a -L-3-10-membered heterocyclic group, preferably a 3-10-membered heterocyclic group, preferably a 3-7-membered heterocyclic group; in another embodiment, R1 is a -LC 6-10 Aryl, preferably C 6-10 Aryl, preferably phenyl; in another embodiment, R1 is -L-5-10 heteroaryl, preferably 5-10 heteroaryl, preferably 5-6 heteroaryl; in another embodiment, R1 is optionally surrounded by 1, 2 or 3 R... 1s replace.

[0153] In a more specific embodiment, R1 is selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic, -LC 6-10 Aryl or -L-5-10 heteroaryl; in another more specific embodiment, R1 is selected from H, D, halogen, CN, OR a NR b R c C 1-6 Alkyl, C1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; in another more specific embodiment, R1 is selected from H, D, halogen, CN, OR a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; in another more specific embodiment, R1 is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; preferably selected from H, D, and C. 1-6 Alkyl or C 1-6 Haloalkyl; in another, more specific embodiment, R1 is C 1-6 Alkyl or C 1-6 Halogenated alkyl group; preferably Et.

[0154] R 1s

[0155] In one implementation, R 1s H; in another embodiment, R 1s For D; in another implementation, R 1s It is a halogen; in another embodiment, R 1s CN; in another embodiment, R 1s OR a In another implementation, R 1s For SR a In another implementation, R 1s For NR b R c In another implementation, R 1s C 1-6 Alkyl; in another embodiment, R 1s C 1-6 Halogenated alkyl; in another embodiment, R 1s C 2-6 alkenyl; in another embodiment, R 1s C 2-6 Alkyne group; in another embodiment, R 1s C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R 1s It is a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group; in another embodiment, R 1s C 6-10 Aryl, preferably phenyl; in another embodiment, R 1sIt is a 5-10 nucleotide heteroaryl group, preferably a 5-6 nucleotide heteroaryl group.

[0156] In a more specific implementation, R 1s Independently selected from H, D, halogen, CN, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; in another more specific embodiment, R 1s Independently selected from H, D, halogens, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; in another more specific embodiment, R 1s Independently selected from H, D, halogens, and C 1-6 Alkyl or C 1-6 Halogenated alkyl; in another, more specific embodiment, R 1s Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0157]

[0158] In one implementation method It is a single bond; in another embodiment, It is a double bond.

[0159] M1 and M2

[0160] In one embodiment, M1 is N; in another embodiment, M1 is C; in yet another embodiment, M1 is CR5.

[0161] In one implementation, M2 is N; in another implementation, M2 is CR6.

[0162] In one more specific embodiment, M1 is selected from N or CR5; in another more specific embodiment, M1 is N; in another more specific embodiment, M2 is N; in another more specific embodiment... for

[0163] R5 and R6

[0164] In one embodiment, R5 is H; in another embodiment, R5 is D; in yet another embodiment, R5 is a halogen; in yet another embodiment, R5 is C.1-6 Alkyl; in another embodiment, R5 is C 1-6 Halogenated alkyl groups.

[0165] In one embodiment, R6 is H; in another embodiment, R6 is D; in yet another embodiment, R6 is a halogen; in yet another embodiment, R6 is C. 1-6 Alkyl; in another embodiment, R6 is C 1-6 Halogenated alkyl groups.

[0166] In a more specific implementation, R5 and R6 are independently selected from H, D, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl; in another more specific embodiment, R5 and R6 are H or D; in another more specific embodiment, R5 and R6 are H.

[0167] R4

[0168] In one embodiment, R4 is H; in another embodiment, R4 is D; in yet another embodiment, R4 is a halogen; in another embodiment, R4 is CN; in yet another embodiment, R4 is =O; in yet another embodiment, R4 is OR. a In another embodiment, R4 is SR. a In another embodiment, R4 is NR. b R c In another embodiment, R4 is C 1-6 Alkyl; in another embodiment, R4 is C 1-6 Halogenated alkyl; in another embodiment, R4 is C 3-7 Cycloalkyl; in another embodiment, R4 is a 3-7 membered heterocyclic group; in another embodiment, R4 is optionally surrounded by 1, 2 or 3 R groups. 4s replace.

[0169] In one implementation, R4, located adjacent to M1, together with R2 and the atoms connected to them, forms C. 5-7 Cycloalkyl; in another embodiment, R4 at the position adjacent to M1, together with R2 and the atoms they are attached to, forms a 5-7 membered heterocyclic group; in another embodiment, R4 at the position adjacent to M1, together with Z3 and the atoms they are attached to, forms a C 5-7 Cycloalkyl; in another embodiment, R4 located ortho to M1, together with Z3 and the atoms they are connected to, forms a 5-7 membered heterocyclic group; in another embodiment, the ring structure formed by R4 and R2 or Z3 is optionally surrounded by 1, 2 or 3 R... 4s replace.

[0170] In a more specific embodiment, R4 is independently selected from H, D, halogen, CN, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; in another more specific embodiment, R4 is independently selected from H, D, halogen, CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; in another more specific embodiment, R4 is independently selected from H, D, halogen, C. 1-6 Alkyl or C 1-6 Halogenated alkyl group; in another, more specific embodiment, R4 is independently selected from H, D, C. 1-6 Alkyl or C 1-6 Halogenated alkyl; in another more specific embodiment, R4 is independently H or D; in another more specific embodiment, R4 is H.

[0171] In a more specific embodiment, R4 located adjacent to M1, together with R2 and the atoms connected to them, forms a 5-7 membered heterocyclic group, or R4 located adjacent to M1, together with Z3 and the atoms connected to them, forms a 5-7 membered heterocyclic group; in another more specific embodiment, R4 located adjacent to M1, together with R2 and the atoms connected to them, forms a 5-7 membered heterocyclic group.

[0172] R 4s

[0173] In one implementation, R 4s H; in another embodiment, R 4s For D; in another implementation, R 4s It is a halogen; in another embodiment, R 4s CN; in another embodiment, R 4s C 1-6 Alkyl; in another embodiment, R 4s C 1-6 Halogenated alkyl; in another embodiment, R 4s C 3-7 cycloalkyl; in another embodiment, R 4s It is a 3-7 membered heterocyclic group.

[0174] In a more specific implementation, R 4s Independently selected from H, D, halogens, and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0175] n

[0176] In one implementation, n is 0; in another implementation, n is 1; in another implementation, n is 2; in another implementation, n is 3; in another implementation, n is 4.

[0177] In one more specific implementation, n is selected from 0, 1, or 2; in another more specific implementation, n is 0.

[0178] Z1, Z2 and Z3

[0179] In one implementation, Z1 is CR7; in another implementation, Z1 is N.

[0180] In one implementation, Z2 is CR8; in another implementation, Z2 is N.

[0181] In one implementation, Z3 is CR9; in another implementation, Z3 is N.

[0182] In one more specific embodiment, Z1 is N; in another more specific embodiment, Z2 is CR8; in another more specific embodiment, Z3 is CR9; in another more specific embodiment... for

[0183] R7, R8 and R9

[0184] In one embodiment, R7 is H; in another embodiment, R7 is D; in yet another embodiment, R7 is a halogen; in another embodiment, R7 is CN; in yet another embodiment, R7 is OR. a In another implementation, R7 is SR. a In another implementation, R7 is NR. b R c In another embodiment, R7 is C 1-6 Alkyl; in another embodiment, R7 is C 1-6 Halogenated alkyl; in another embodiment, R7 is C 3-7 Cycloalkyl; in another embodiment, R7 is a 3-7 membered heterocyclic group, optionally surrounded by 1, 2, or 3 R groups. 2s replace.

[0185] In one embodiment, R8 is H; in another embodiment, R8 is D; in yet another embodiment, R8 is a halogen; in another embodiment, R8 is CN; in yet another embodiment, R8 is OR. aIn another implementation, R8 is SR. a In another implementation, R8 is NR. b R c In another embodiment, R8 is C 1-6 Alkyl; in another embodiment, R8 is C 1-6 Halogenated alkyl; in another embodiment, R8 is C 3-7 Cycloalkyl; in another embodiment, R8 is a 3-7 membered heterocyclic group, optionally surrounded by 1, 2, or 3 R groups. 2s replace.

[0186] In one embodiment, R9 is H; in another embodiment, R9 is D; in yet another embodiment, R9 is a halogen; in another embodiment, R9 is CN; in yet another embodiment, R9 is OR. a In another embodiment, R9 is SR. a In another embodiment, R9 is NR. b R c In another embodiment, R9 is C 1-6 Alkyl; in another embodiment, R9 is C 1-6 Halogenated alkyl; in another embodiment, R9 is C 3-7 Cycloalkyl; in another embodiment, R9 is a 3-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 2s replace.

[0187] In a more specific embodiment, R7, R8, and R9 are independently selected from H, D, halogens, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; in another more specific embodiment, R7, R8, and R9 are independently selected from H, D, halogen, C. 1-6 Alkyl or C 1-6 Haloalkyl; in another, more specific embodiment, R7, R8, and R9 are independently selected from H, D, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl; in another more specific embodiment, R7, R8 and R9 are independently H or D; in another more specific embodiment, R7, R8 and R9 are H.

[0188] R2

[0189] In one embodiment, R2 is H; in another embodiment, R2 is D; in yet another embodiment, R2 is a halogen, such as F; in another embodiment, R2 is CN; in yet another embodiment, R2 is OR.a In another embodiment, R2 is SR. a In another embodiment, R2 is NR. b R c In another embodiment, R2 is C 1-6 Alkyl; in another embodiment, R2 is C 1-6 Halogenated alkyl; in another embodiment, R2 is C 3-7 Cycloalkyl; in another embodiment, R2 is a 3-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 2s replace.

[0190] In a more specific embodiment, R2 is selected from H, D, halogen, CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; in another more specific embodiment, R2 is selected from H, D, halogen, CN, C. 1-6 Alkyl or C 1-6 Haloalkyl; in another, more specific embodiment, R2 is selected from H, D, halogen, C. 1-6 Alkyl or C 1-6 Alkyl halide; in another more specific embodiment, R2 is selected from H, D or halogen; in another more specific embodiment, R2 is H or F.

[0191] In a more specific embodiment, R2 is a halogen, preferably F, Cl or Br, with F being the most preferred.

[0192] R 2s

[0193] In one implementation, R 2s H; in another embodiment, R 2s For D; in another implementation, R 2s It is a halogen; in another embodiment, R 2s CN; in another embodiment, R 2s C 1-6 Alkyl; in another embodiment, R 2s C 1-6 Halogenated alkyl; in another embodiment, R 2s C 3-7 cycloalkyl; in another embodiment, R 2s It is a 3-7 membered heterocyclic group.

[0194] In a more specific implementation, R 2s Independently selected from H, D, halogens, and C 1-6 Alkyl or C1-6 Halogenated alkyl groups.

[0195] R3

[0196] In one implementation, R3 is H; in another implementation, R3 is -L-OR. a OR is preferred a For example, OMe; in another implementation, R3 is -L-SR a SR is preferred a In another implementation, R3 is -L-NR b R c NR is preferred. b R c In another embodiment, R3 is C 1-6 Alkyl, such as Me; in another embodiment, R3 is C. 1-6 Haloalkyl; in another embodiment, R3 is C 2-6 Alkenyl; in another embodiment, R3 is C 2-6 Alkyne group; in another embodiment, R3 is -LC 3-10 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, R3 is a -L-3-10-membered heterocyclic group, preferably a 3-10-membered heterocyclic group, preferably a 3-7-membered heterocyclic group; in another embodiment, R3 is a -LC 6-10 Aryl, preferably C 6-10 Aryl, preferably phenyl; in another embodiment, R3 is -L-5-10 heteroaryl, preferably 5-10 heteroaryl, preferably 5-6 heteroaryl; in another embodiment, R3 is optionally surrounded by 1, 2 or 3 R... 3s Replacement, for example, R3 is C 1-6 Deuterated alkyl groups, such as CD3.

[0197] In a more specific implementation, R3 is selected from H, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic, -LC 6-10 aryl or -L-5-10 heteroaryl; in another more specific embodiment, R3 is selected from H, OR a NR b R c C 1-6 Alkyl, C1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; in another more specific embodiment, R3 is selected from H, OR a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; in another more specific embodiment, R3 is selected from H, OR a C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Deuterated alkyl; in another, more specific embodiment, R3 is selected from OR a C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Deuterated alkyl; in another more specific embodiment, R3 is selected from Me, CD3 or OMe.

[0198] In a more specific implementation, R3 is selected from C. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Deuterated alkyl; in another, more specific embodiment, R3 is C 1-6 Deuterated alkyl; in another more specific embodiment, R3 is selected from Me and CD3; in another more specific embodiment, R3 is CD3.

[0199] R 3s

[0200] In one implementation, R 3s H; in another embodiment, R 3s For D; in another implementation, R 3s It is a halogen; in another embodiment, R 3s CN; in another embodiment, R 3s OR a In another implementation, R 3s For SR a In another implementation, R 3s For NR b R c In another implementation, R 3s C 1-6 Alkyl; in another embodiment, R 3s C 1-6 Halogenated alkyl; in another embodiment, R 3s C 2-6alkenyl; in another embodiment, R 3s C 2-6 Alkyne group; in another embodiment, R 3s C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R 3s It is a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group; in another embodiment, R 3s C 6-10 Aryl, preferably phenyl; in another embodiment, R 3s It is a 5-10 nucleotide heteroaryl group, preferably a 5-6 nucleotide heteroaryl group.

[0201] In a more specific implementation, R 3s Independently selected from H, D, halogen, CN, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; in another more specific embodiment, R 3s Independently selected from H, D, halogens, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; in another more specific embodiment, R 3s Independently selected from H, D, halogens, and C 1-6 Alkyl or C 1-6 Halogenated alkyl; in another, more specific embodiment, R 3s Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0202] L

[0203] In one embodiment, L is a chemical bond; in another embodiment, L is C. 1-6 Alkylene; in another embodiment, L is C 2-6 Ideonyl; in another embodiment, L is C 2-6 Alynyl group; in another embodiment, L is optionally composed of 1, 2, or 3 groups selected from H, D, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is substituted; in another embodiment, L is optionally replaced by one, two, or three groups selected from H, D, halogen, C.1-6 Alkyl or C 1-6 Substitution of alkyl groups with haloalkyl groups.

[0204] In a more specific embodiment, L is independently selected from chemical bonds or C. 1-6 Alkylene, optionally composed of one, two, or three atoms selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Substitution of alkyl groups with haloalkyl groups.

[0205] R a R b and R c

[0206] In one implementation, R a R b and R c H is independent; in another implementation, R a R b and R c Independently for C 1-6 Alkyl, such as Me; in another embodiment, R a R b and R c Independently for C 1-6 Halogenated alkyl; in another embodiment, R a R b and R c Independently for C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R a R b and R c Independently, it is a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group; in another embodiment, R b R c Together with the atoms they are connected to, they form 5-10 membered heterocyclic groups, preferably 5-7 membered heterocyclic groups.

[0207] In a more specific implementation, R a R b and R c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; in another more specific embodiment, R a R b and R c Each is independently selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl; in another, more specific embodiment, Ra R b and R c For H or Me; in another, more specific implementation, R a R b and R c For Me; in another, more specific implementation, R b R c Together with the atoms they connect, they form 5-7 membered heterocyclic groups.

[0208] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof of ring A can be combined with L1, R, R', A, E, G, R A R E R G R1, R 1s M1, M2, R5, R6, R4, R 4s ,n,Z1,Z2,Z3,R2,R7,R8,R9,R 2s R3, R 3s L, R a R b and R c This invention involves combining any of the technical solutions or any combination thereof. The present invention aims to include combinations of all these technical solutions; however, due to space limitations, they will not be listed individually.

[0209] In a more specific embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:

[0210]

[0211] in,

[0212] L1 is selected from CRR', O, S, NH, -C(O)-, -S(O)- or -S(O)2-;

[0213] R and R' are independently selected from H, D, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0214] A is selected from CR A Or N;

[0215] E is selected from CR E Or N;

[0216] G is selected from CR G Or N;

[0217] R A R E and R G Independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -LC 3-10 Cycloalkyl or -L-3-10 membered heterocyclic groups;

[0218] R1 is selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic, -LC 6-10 aryl or -L-5-10 heteroaryl, optionally surrounded by 1, 2 or 3 R groups 1s replace;

[0219] R 1s Independently selected from H, D, halogen, CN, OR a SR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0220] It can be represented as a single bond or a double bond;

[0221] M1 is selected from N, C, or CR5;

[0222] M2 is either N or CR6;

[0223] R5 and R6 are independently selected from H, D, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0224] R4 is independently selected from H, D, halogens, CN, =O, OR a SR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 4s replace;

[0225] Alternatively, R4, located adjacent to M1, together with R2 and the atoms connected to them, forms C. 5-7 Cycloalkyl or 5-7 membered heterocyclic groups, or R4 located ortho to M1 together with Z3 and the atoms they are attached to form C. 5-7 Cycloalkyl or 5-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 4s replace;

[0226] R 4s Independently selected from H, D, halogens, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups;

[0227] n is 0, 1, 2, 3 or 4;

[0228] Z1 is selected from CR7 or N;

[0229] Z2 is selected from CR8 or N;

[0230] Z3 is selected from CR9 or N;

[0231] R2, R7, R8, and R9 are independently selected from H, D, halogens, CN, and OR. a SR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 2s replace;

[0232] R 2s Independently selected from H, D, halogens, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups;

[0233] R3 is selected from H, -L-OR a -L-SR a -L-NRb R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic, -LC 6-10 aryl or -L-5-10 heteroaryl, optionally surrounded by 1, 2 or 3 R groups 3s replace;

[0234] R 3s Independently selected from H, D, halogen, CN, OR a SR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0235] L represents a chemical bond, C represents a chemical bond. 1-6 Alkylene, C 2-6 imide or C 2-6 The ynyl group, optionally surrounded by 1, 2, or 3 atoms selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 Group substitution of the alkynyl group;

[0236] R a R b and R c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclic groups; or R b R c Together with the atoms they connect, they form 5-10 membered heterocyclic groups;

[0237] The aforementioned groups are optionally deuterated, up to and including complete deuteration.

[0238] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is selected from CRR', O, S, NH or -C(O)-; preferably CRR' or -C(O)-; preferably CRR'; preferably CH2.

[0239] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R and R' are independently selected from H, D, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; preferably selected from H, D, and C. 1-3 Alkyl or C 1-3 Halogenated alkyl group; preferably H or D; preferably H.

[0240] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein A is N;

[0241] Preferably, E is CR E ;

[0242] Preferably, G is CR G ;

[0243] Preferably, for

[0244] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R A R E and R G Independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 3-7 Cycloalkyl or -L-3-7-membered heterocyclic group; preferably selected from H, D, halogen, CN, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7Cycloalkyl or 3-7 membered heterocyclic groups; preferably selected from H, D, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl group; preferably H or D; preferably H.

[0245] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R1 is selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic, -LC 6-10 Aryl or -L-5-10 heteroaryl; preferably selected from H, D, halogen, CN, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; preferably selected from H, D, halogen, CN, OR a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; preferably selected from H, D, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; preferably selected from H, D, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl group; preferably Et.

[0246] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R 1s Independently selected from H, D, halogen, CN, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10Aryl or 5-10 heteroaryl groups; preferably selected from H, D, halogens, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; preferably selected from H, D, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; preferably selected from H, D, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0247] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein M1 is selected from N or CR5, preferably N;

[0248] Preferably, M2 is N;

[0249] Preferably, for

[0250] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R5 and R6 are independently selected from H, D, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl group; preferably H or D; preferably H.

[0251] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R4 is independently selected from H, D, halogen, CN, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; preferably selected from H, D, halogens, CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; preferably selected from H, D, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; preferably selected from H, D, and C. 1-6 Alkyl or C 1-6 Haloalkyl; preferably H or D; preferably H;

[0252] Preferably, n is 0, 1, or 2, and more preferably 0.

[0253] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R4 at the position adjacent to M1, together with R2 and the atoms connected thereto, forms a 5-7 membered heterocyclic group, or R4 at the position adjacent to M1, together with Z3 and the atoms connected thereto, forms a 5-7 membered heterocyclic group;

[0254] Preferably, R4, located adjacent to M1, together with R2 and the atoms they are connected to form a 5-7 membered heterocyclic group.

[0255] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R 4s Independently selected from H, D, halogens, and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0256] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Z1 is N;

[0257] Preferably, Z2 is CR8;

[0258] Preferably, Z3 is CR9;

[0259] Preferably, for

[0260] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R7, R8, and R9 are independently selected from H, D, halogen, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; preferably selected from H, D, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; preferably selected from H, D, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl group; preferably H or D; preferably H.

[0261] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R2 is selected from H, D, halogen, CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; preferably selected from H, D, halogens, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; preferably selected from H, D, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl group; preferably selected from H, D or halogen; preferably H or F.

[0262] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R 2s Independently selected from H, D, halogens, and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0263] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R3 is selected from H, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic, -LC 6-10 Aryl or -L-5-10 heteroaryl; preferably selected from H, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; preferably selected from H, OR a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; preferably selected from H, OR a C 1-6 Alkyl, C 1-6 Halogenated alkyl or C1-6 Deuterated alkyl groups; preferably selected from OR a C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Deuterated alkyl group; preferably selected from Me, CD3 or OMe.

[0264] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R 3s Independently selected from H, D, halogen, CN, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; preferably selected from H, D, halogens, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; preferably selected from H, D, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; preferably selected from H, D, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0265] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein L is independently selected from chemical bonds or C 1-6 Alkylene, optionally composed of 1, 2, or 3 atoms selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Substitution of alkyl groups with haloalkyl groups.

[0266] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R a R b and R c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; preferably selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably C 1-6Alkyl or C 1-6 Halogenated alkyl group; preferably H or Me; more preferably Me;

[0267] Or R b R c Together with the atoms they connect, they form 5-7 membered heterocyclic groups.

[0268] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, having the following structural formula:

[0269]

[0270] The groups are defined as above.

[0271] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein...

[0272] R1 is selected from H, D, halogen, CN, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl groups, optionally bound by 1, 2 or 3 R groups. 1s replace;

[0273] R2 is selected from H, D, halogens, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 2s replace;

[0274] R3 is selected from H, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl groups, optionally bound by 1, 2 or 3 R groups. 3s replace;

[0275] R4 is selected from H, D, halogens, CN, and C. 1-6 Alkyl, C 1-6Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 4s replace;

[0276] Alternatively, R4, located at the N-ortho position connected to pyridine, together with R2 and the atoms they are connected to, form a 5-7 membered heterocyclic group;

[0277] R 1s and R 3s Each is independently selected from H, D, halogen, CN, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0278] R 2s and R 4s Each is independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0279] n is 0, 1, 2, 3 or 4;

[0280] R a R b and R c Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclic groups; or R b R c Together with the atoms they connect, they form 5-7 membered heterocyclic groups;

[0281] The aforementioned groups are optionally deuterated, up to and including complete deuteration.

[0282] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein...

[0283] R1 is selected from H, D, halogen, CN, OR a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 1s replace;

[0284] R2 is selected from H, D, halogens, CN, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups, optionally surrounded by 1, 2, or 3 R groups. 2s replace;

[0285] R3 is selected from H, OR a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 3s replace;

[0286] R4 is selected from H, D, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups, optionally surrounded by 1, 2, or 3 R groups. 4s replace;

[0287] R 1s and R 3s Each is independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups;

[0288] R 2s and R 4s Each is independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0289] n is 0, 1, 2, 3 or 4;

[0290] R a Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0291] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein...

[0292] R1 is selected from H, D, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0293] R2 is selected from H, D, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0294] R3 is selected from H, OR a C 1-6 Alkyl, C 1-6Halogenated alkyl or C 1-6 Deuterated alkyl groups;

[0295] R4 is selected from H, D, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0296] n is 0, 1, 2, 3 or 4;

[0297] R a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0298] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein...

[0299] R1 is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, preferably Et;

[0300] R2 is selected from H, D or halogens, preferably H or F;

[0301] R3 is selected from OR a C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Deuterated alkyl groups, preferably selected from Me, CD3, or OMe;

[0302] R4 is either H or D, preferably H;

[0303] n can be 0, 1, or 2, preferably 0;

[0304] R a C 1-6 Alkyl or C 1-6 Haloalkyl groups, preferably Me;

[0305] Preferably, R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Deuterated alkyl groups, preferably C464-246 ... 1-6 Deuterated alkyl groups, preferably selected from Me and CD3, with CD3 being the most preferred;

[0306] Preferably, R2 is a halogen, preferably F, Cl or Br, with F being the most preferred.

[0307] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein the compound is selected from the following:

[0308]

[0309]

[0310] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0311] The compounds of this invention can exist as tautomers. Tautomers are functional group isomers that arise from the rapid movement of an atom between two positions in a molecule. Tautomers are a special type of functional group isomer. A pair of tautomers can interconvert, but usually the more stable isomer is the dominant form. The most important examples are enol and keto tautomers.

[0312] Those skilled in the art will understand that organic compounds can form complexes with solvents, react in the solvent, or precipitate or crystallize out of the solvent. These complexes are called "solvates." When the solvent is water, the complex is called a "hydrate." This invention covers all solvates of the compounds of this invention.

[0313] The term "solvent" refers to a compound or its salt that is bound to a solvent and formed typically by a solvent decomposition reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvent" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0314] The term "hydrate" refers to a compound that is bound to water. Typically, it is determined by the ratio of the number of water molecules contained in the hydrate to the number of molecules of the compound in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0315] The compounds of this invention can be in amorphous or crystalline forms (polymorphs). Furthermore, the compounds of this invention can exist in one or more crystalline forms. Therefore, this invention encompasses all amorphous or crystalline forms of the compounds of this invention within its scope. The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates) with a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

[0316] The present invention also includes isotopically labeled compounds (isotopic variants) that are equivalent to those described in formula (I), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e.14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0317] Furthermore, prodrugs are also included in the context of this invention. As used herein, the term "prodrug" refers to a compound which is converted in vivo, for example, by hydrolysis in the blood, into its active form having a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series, Vol. 14; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; and D. Fleisher, S. Ramon, and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs," Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which is incorporated herein by reference.

[0318] A prodrug is any covalently bonded compound of the present invention that, when administered to a patient, releases the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in a manner that allows the modification to produce the parent compound through conventional operation or in vivo cleavage. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or thiol group is bonded to any group, which, when administered to a patient, can cleave to form a hydroxyl, amino, or thiol group. Thus, representative examples of prodrugs include (but are not limited to) acetate / amide, formate / amide, and benzoate / amide derivatives of formula (I) with hydroxyl, thiol, and amino functional groups. Additionally, in the case of carboxylic acids (-COOH), esters, such as methyl esters, ethyl esters, etc., can be used. The ester itself may be active and / or hydrolyzable under in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that readily decompose in the body to release the parent acid or its salt.

[0319] The present invention also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, or excipient thereof. All such forms are subject to the present invention.

[0320] Pharmaceutical Compositions and Kits

[0321] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as the "active component") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the compound of the present invention.

[0322] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0323] Suitable formulations for administering the compounds of the present invention will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, sugar lozenges, solutions (particularly for injection (subcutaneous, intravenous, intramuscular) and infusion), elixirs, syrups, capsules, emulsions, inhalers, or dispersible powders. The content of one or more pharmaceutically active compounds should range from 0.1 to 90 wt%, preferably 0.5 to 50 wt%, of the composition as a whole, i.e., an amount sufficient to achieve the dosage range specified below. If necessary, the specified dosage may be administered several times daily.

[0324] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0325] Dosage

[0326] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0327] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0328] When used to prevent the conditions described in this invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0329] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0330] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active component through the body; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active component, while a bolus dose delivered directly to a vein (e.g., via IV intravenous infusion) allows for a more rapid delivery, causing the concentration of the active component in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV intravenous infusion, thereby providing a steady-state concentration of the active component in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0331] Oral compositions may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, the compositions are provided in unit dose form for the purpose of precise dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active substance and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dose forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is typically a smaller component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients useful for forming the desired dosage form, as well as processing aids.

[0332] For oral dosage, a typical regimen is one to five oral doses daily, particularly two to four oral doses, typically three oral doses. Using these dosage regimens, each dose provides approximately 0.01 to approximately 20 mg / kg of the compound of the invention, with preferred doses each providing approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0333] To provide blood levels similar to or lower than those achieved with an injection dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0334] From approximately 1 to approximately 120 hours, especially 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain adequate steady-state levels, a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may also be administered. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0335] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers, as well as buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavorings.

[0336] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously described, in such compositions, the active compound is typically a smaller component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0337] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are well known in the art and generally include other components to enhance stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of this invention.

[0338] The compounds of this invention can also be administered via transdermal devices. Therefore, transdermal drug delivery can be achieved using reservoirs or porous membrane types, or patches with various solid matrices.

[0339] The above-described components for oral, injectable, or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0340] The compounds of this invention can also be administered in a sustained-release form or from a sustained-release drug delivery system. Descriptions of representative sustained-release materials can be found at Remington's Pharmaceutical Sciences.

[0341] This invention also relates to pharmaceutically acceptable formulations of the compounds of this invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, respectively, composed of 6, 7, and 8 α-1,4-linked glucose units, optionally including one or more substituents on the linked sugar moieties, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfonyl ether substituted groups. In some embodiments, the cyclodextrin is a sulfonyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0342] Indications

[0343] For tumors lacking HR-dependent DNA DSB repair pathways or other DNA repair mechanisms, the development of highly selective PARP1 inhibitors could provide therapeutic benefits to a large number of cancer patients. The compounds in this invention exert their therapeutic effect by highly selectively negatively regulating PARP1 activity within tumor cells, particularly tumor cells lacking HR-dependent DNA DSB repair pathways or other DNA repair mechanisms, or various tumor cells with BRCA1 or BRCA2 deficiency phenotypes.

[0344] In some embodiments, the PARP1 inhibitors described in this invention can treat a variety of cancers, ischemic diseases, and neurodegenerative diseases.

[0345] More specifically, these compounds can be used to treat: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, etc.), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, etc.), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, etc.), stomach (tumors, lymphoma, leiomyosarcoma, etc.), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma, etc.), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, etc.), Kaposi's sarcoma, leiomyosarcoma, hemangioma, and lipoma. Tumors: neurofibroma, fibroma, etc.); colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma, etc.); genitourinary tract: kidneys (adenocarcinoma, nephroblastoma, etc.), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, etc.), prostate (adenocarcinoma, sarcoma, etc.), testes (seminomatous seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma, etc.); liver: hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma, etc.; bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma, etc.). Multiple myeloma, malignant giant cell tumors, chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromycinoma, osteoid osteoma, and giant cell tumor of bone; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, etc.), Meninges (meningioma, meningeal sarcoma, glioma, etc.), Brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumors (pineal tumor, etc.), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, etc.), Spinal cord neurofibroma, meningioma, glioma, sarcoma, etc.; Gynecology: Uterus (endometrial cancer, etc.), Cervix (cervical cancer, precancerous cervical dysplasia). (etc.), ovaries (ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, etc.), granulosa cell tumor, supporting stromal cell tumor, dysgerminoma, malignant teratoma, etc.), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma, etc.), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma, etc.), fallopian tube cancer, etc.; hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), follicular lymphoma, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, etc.), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), etc.;Skin: Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, etc.; Adrenal glands: Neuroblastoma, etc.

[0346] More specifically, these compounds can be used to treat: breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancers, gastrointestinal cancers (such as stomach cancer and colorectal cancer), and lung cancer.

[0347] combination therapy

[0348] The PARP1 inhibitors described in this invention can be used in combination with other drugs to treat cancer, and include at least one target drug / cell activity modulator, including CDK4 / 6 inhibitors, MAT2A inhibitors, MAPK1 / MAPK3 inhibitors, Type I PRMT inhibitors, EGFR inhibitors, SHP2 inhibitors, pan-KRAS inhibitors, KRASG12C inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, Bcl-2 inhibitors, SOS1 inhibitors, PARP inhibitors, MALT1 inhibitors, MALT2 inhibitors, BTK inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, DNA methyltransferase (DNMT) inhibitors, EZH1 / 2 inhibitors, EZH2 inhibitors, Menin-MLL inhibitors, IDH1 inhibitors, IDH2 inhibitors, IDH1 / 2 inhibitors, chemotherapy drugs (e.g., carboplatin), radiotherapy, STING agonists, or immune checkpoint inhibitors / modulators, etc.

[0349] Example

[0350] The raw materials or reagents used in this article are commercially available or prepared by synthetic methods commonly known in the art.

[0351] Example 1

[0352] 5-(4-((8-amino-7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-N-methylpyridineamide

[0353]

[0354] Step 1

[0355] Intermediate 1 (2.00 g) was dissolved in toluene (14.0 mL), and 1-Boc-piperazine (1.72 g), cesium carbonate (9.05 g), 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (432 mg), and bis(dibenzylacetone)palladium (133 mg) were added. After the addition was complete, the reaction mixture was stirred at 100 °C for 12 hours. LCMS (RT = 1.700 min) showed that the starting material was completely consumed. After cooling, the reaction mixture was filtered through diatomaceous earth. Water (15.0 mL) and ethyl acetate (20.0 mL, 10.0 mL) were added to the filtrate for extraction. The organic phase was washed with saturated sodium chloride solution (10.0 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oily intermediate 2 (3.00 g, crude product).

[0356] LCMS(ESI) m / z: 322.0 [M+H] + .

[0357] Step Two

[0358] Intermediate 2 (3.00 g) was dissolved in methanol (21.0 mL), and methylamine solution (7.25 g, 40% purity) was added. After the addition was complete, the reaction mixture was stirred at 20 °C for 4 hours. LCMS (RT = 1.376 min) showed that the starting material was completely consumed. The reaction was quenched by adding dilute hydrochloric acid (20.0 mL, 2 M), and extracted with dichloromethane (20.0 mL, 10.0 mL). The organic phase was washed with saturated sodium chloride solution (20.0 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oily intermediate 3 (2.90 g, crude product).

[0359] LCMS(ESI) m / z: 321.2 [M+H] + .

[0360] Step 3

[0361] Intermediate 3 (2.90 g) was dissolved in hydrochloric acid / methanol (21.0 mL, 4 M). After the addition was complete, the reaction mixture was stirred at 20 °C for 2 hours. TLC (petroleum ether / ethyl acetate = 0 / 1, product: R) f =0.02, Raw material: R f =0.43) indicates that the raw materials were completely consumed. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was added to methyl ether (4.00 mL) and purified by stirring to obtain a yellow oily intermediate 4 (2.00 g, yield 86.0%, HCl).

[0362] Step Four

[0363] Intermediate 5 (5.00 g) was dissolved in toluene (35.0 mL), and ethyl butyrate (5.87 g, 6.74 mL) and potassium tert-butoxide (8.50 g) were added. After the addition was complete, the reaction mixture was stirred at 50 °C for 2 hours. LCMS (RT = 1.355 min) showed that the starting material was completely consumed. After cooling the reaction mixture, water (15.0 mL) and ethyl acetate (20.0 mL, 15.0 mL) were added for extraction. The organic phase was washed with saturated sodium chloride solution (15.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily intermediate 6 (3.00 g, yield 31.2%).

[0364] LCMS(ESI) m / z: 268.0 [M+H] + .

[0365] Step 5

[0366] Intermediate 6 (3.00 g) was dissolved in dioxane (18.0 mL) and methanol (3.00 mL), followed by the addition of triethylamine (3.40 g, 4.67 mL) and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloromethane (456 mg). After the addition was complete, the reaction mixture was stirred at 80 °C for 12 hours under a carbon monoxide atmosphere (50 Psi). LCMS (RT = 1.213 min) showed complete consumption of the starting material. After cooling, the reaction mixture was filtered through diatomaceous earth. The filtrate was extracted with water (10.0 mL) and ethyl acetate (10.0 mL, 8.00 mL). The organic phase was washed with saturated sodium chloride solution (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid intermediate 7 (2.00 g, crude product).

[0367] LCMS(ESI) m / z: 248.1 [M+H] + .

[0368] Step Six

[0369] Intermediate 7 (2.30 g) was dissolved in dichloromethane (15.0 mL), and diisobutylaluminum hydride (13.9 mL, 1 M) was added at -78 °C. After the addition was complete, the reaction mixture was stirred at 20 °C for 1 hour. LCMS (RT = 0.58 min) showed that the starting material was completely consumed. Water (10.0 mL) and dichloromethane (10.0 mL, 8.00 mL) were added to the reaction mixture for extraction. The organic phase was washed with saturated sodium chloride solution (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (HPLC) (column: Phenomenex C18 250*50 mm*10 μm; mobile phase: [water (ammonia)-acetonitrile]; B%: 3%-30%, 20 min) to obtain yellow solid intermediate 8 (300 mg, yield 14.7%).

[0370] LCMS(ESI) m / z: 220.1 [M+H] + .

[0371] Step Seven

[0372] Intermediate 8 (80.0 mg) was dissolved in dichloromethane (2.00 mL), and thionyl chloride (217 mg, 132 μL) was added at 0 °C. After the addition was complete, the reaction mixture was stirred at 20 °C for 2 hours. LCMS (RT = 1.43 min) showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give a yellow solid intermediate 9 (80.0 mg, yield 92.2%).

[0373] LCMS(ESI) m / z: 238.0 [M+H] + .

[0374] Step 8

[0375] Intermediate 9 (80.0 mg) and intermediate 4 (111 mg, HCl) were dissolved in N,N-dimethylformamide (1.00 mL), and potassium carbonate (139 mg) was added. After the addition was complete, the reaction mixture was stirred at 60 °C for 2 hours. LCMS (RT = 1.287 min) showed that the starting materials were completely consumed. After cooling the reaction mixture, water (3.00 mL) and ethyl acetate (5.00 mL, 3.00 mL) were added for extraction. The organic phase was washed with saturated sodium chloride solution (5.00 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (HPLC) (column: Phenomenex luna C18 80*40 mm*3 μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 5%-35%, 7 min) to obtain the white solid compound of Example 1 (74.3 mg, purity 100%, HCl).

[0376] LCMS(ESI) m / z: 422.2 [M+H] + ;

[0377] 1 H NMR (400MHz, DMSO-d6) δppm 1.01 (t, J = 7.32Hz, 3H), 2.53-2.59 (m, 2H), 2.77-2.87 (m, 3H), 3.17-3.55 (m, 6H), 4.02-4.18 (m, 2H), 4.52 (br s,2H),,7.47-7.58(m,1H)7.73(d,J=1.60Hz,1H),7.86-7.99(m,1H),8.29-8.41(m,1H),8.50(br d,J=4.80Hz,1H),8.61-8.70(m,1H),11.18-11.30(m,1H),11.32-11.51(m,1H).

[0378] Example 2

[0379] 5-(4-((8-amino-7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-6-fluoro-N-methoxypyridine amide

[0380]

[0381] Step 1

[0382] Intermediate 10 (14.0 g) was dissolved in acetonitrile (140 mL), and silver fluoride (II) (24.6 g) was added. After the addition was complete, the reaction mixture was stirred at 20 °C for 12 hours. TLC (petroleum ether / ethyl acetate = 2 / 1, product: R) f =0.54, Raw material: R f =0.43) indicates that the raw materials were completely consumed. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica, petroleum ether / ethyl acetate = 50 / 1-1 / 1) to give yellow solid intermediate 11 (9.30 g, yield 61.3%).

[0383] Step Two

[0384] Intermediate 11 (4.30 g) was dissolved in toluene (43 mL), and 1-tert-butyloxycarbonyl-piperazine (4.11 g), cesium carbonate (19.4 g), 2-biscyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (857 mg) and bis(dibenzylacetone)palladium (504 mg) were added. After the addition was complete, the reaction mixture was stirred at 100 °C for 12 hours. TLC (petroleum ether / ethyl acetate = 2 / 1, product: R) f =0.24, Raw material: Rf =0.54) indicates that the raw materials were completely consumed. After cooling, the reaction solution was filtered through diatomaceous earth. Water (50.0 mL) and ethyl acetate (50.0 mL, 30.0 mL) were added to the filtrate for extraction. The organic phase was washed with saturated sodium chloride solution (30.0 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica, petroleum ether / ethyl acetate = 50 / 1-0 / 1) to give a yellow solid intermediate 12 (2.70 g, yield 43.3%).

[0385] 1 H NMR (400MHz, CDCl3) δppm 1.49 (s, 9H) 3.15-3.26 (m, 4H) 3.56-3.67 (m, 4H) 3.96 (s, 3H) 7.23-7.27 (m, 1H) 7.97 (dd, J=8.00, 1.06Hz, 1H).

[0386] Step 3

[0387] Intermediate 12 (2.70 g) was dissolved in tetrahydrofuran (14.0 mL), methanol (2.70 mL), and water (7.00 mL). Lithium hydroxide (700 mg) was added, and the reaction mixture was stirred at 20 °C for 12 hours after the addition was complete. TLC (petroleum ether / ethyl acetate = 1 / 1, product: R) f =0.02, Raw material: R f =0.43) indicates that the raw materials were completely consumed. The reaction was quenched by adding dilute hydrochloric acid (10.0 mL, 2 M) to the reaction solution, and extracted by adding ethyl acetate (30.0 mL, 20.0 mL). The organic phase was washed with saturated sodium chloride solution (20.0 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give yellow oily intermediate 13 (2.10 g, yield 81.1%).

[0388] 1 H NMR (400MHz, CDCl3) δppm 1.35-1.60 (m, 9H) 2.63-3.13 (m, 4H) 3.28-3.68 (m, 4H) 6.81-7.16 (m, 1H) 7.65-8.00 (m, 1H).

[0389] Step Four

[0390] Intermediate 13 (700 mg) was dissolved in N,N-dimethylformamide (7.00 mL), and N,N-diisopropylethylamine (556 mg, 749 μL), methoxyamine hydrochloride (179 mg), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphonate (818 mg) were added. After the addition was complete, the reaction mixture was stirred at 20 °C for 12 hours. TLC (petroleum ether / ethyl acetate = 1 / 1, product: R) f =0.24, Raw material: R f =0.02) indicates that the raw materials were completely consumed. Water (10.0 mL) and ethyl acetate (10.0 mL, 8.00 mL) were added to the reaction solution for extraction. The organic phase was washed with saturated sodium chloride solution (10.0 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give yellow solid intermediate 14 (500 mg, yield 65.5%).

[0391] Step 5

[0392] Intermediate 14 (100 mg) was dissolved in hydrochloric acid / methanol (2.00 mL, 4 M). After the addition was complete, the reaction mixture was stirred at 20 °C for 2 hours. TLC (petroleum ether / ethyl acetate = 1 / 1, product: R) f =0.02, Raw material: R f =0.43) indicates that the raw materials were completely consumed. The reaction solution was concentrated under reduced pressure to give a yellow solid intermediate 15 (50.0 mg, yield 69.6%, HCl).

[0393] Step Six

[0394] Intermediate 9 (50.0 mg) and intermediate 15 (56.3 mg, HCl) were dissolved in N,N-dimethylformamide (1.00 mL), and N,N-diisopropylethylamine (81.5 mg) was added. After the addition was complete, the reaction mixture was stirred at 60 °C for 2 hours. LCMS (RT = 0.892 min) showed that the starting materials were completely consumed. After cooling the reaction mixture, water (3.00 mL) and ethyl acetate (5.00 mL, 3.00 mL) were added for extraction. The organic phase was washed with saturated sodium chloride solution (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (column: Phenomenex luna C18 80*30mm*3um; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 5%-35%, 8min) to obtain the white solid compound of Example 2 (13.0 mg, purity 96.4%, HCl).

[0395] LCMS(ESI) m / z: 456.1 [M+H] + ;

[0396] 1 H NMR (400MHz, DMSO-d6) δppm 1.01 (t, J = 7.20Hz, 3H) 2.56 (br.s, 2H) 3.13-3.33 (m, 6H) 3.67 (s, 3H) 3.73 (br.d, J = 12.0Hz, 2H) 4.54 (br.s, 2H) 6.36-6.50 (m, 1H) 7.65-7.74 (m, 2H) 7.88 (d, J=8.00Hz, 1H) 8.52 (br.s, 1H) 10.51 (br.d, J=3.60Hz, 1H) 11.24 (br.s, 1H) 11.82 (s, 1H).

[0397] Examples 3 and 4 were synthesized using the same experimental methods as Examples 1 and 2.

[0398] Example 3

[0399] 5-(4-((8-amino-7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridineamide

[0400]

[0401] LCMS(ESI) m / z: 440.1 [M+H] + ;

[0402] 1 H NMR (400MHz, DMSO-d6) δppm 1.01 (t, J = 7.20Hz, 3H) 2.54-2.58 (m, 2H) 2.74-2.82 (m, 3H) 3.14-3.38 (m, 6H) 3.72 (br.d, J = 12.0Hz, 2H) 4.54 (br.s, 2H) 6.31-6 .53 (m, 1H) 7.65-7.73 (m, 2H) 7.89 (d, J=7.80Hz, 1H) 8.43-8.48 (m, 1H) 8.50-8.55 (m, 1H) 10.28-10.68 (m, 1H) 11.25 (br.s, 1H).

[0403] Example 4

[0404] 5-(4-((8-amino-7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl-d3)pyridineamide

[0405]

[0406] LCMS(ESI) m / z: 443.1 [M+H] + ;

[0407] 1 H NMR (400MHz, DMSO-d6) δppm 0.96-1.05(m,3H)2.29-2.41(m,4H)2.54(br.s,2H)3.11-3.25(m,4H)3.63-3.80(m,2H)4.54(br.s,2H)6.42(br. s, 2H) 7.68-7.72 (m, 1H) 7.89 (d, J=8.00Hz, 1H) 8.42 (s, 1H) 8.51 (br.s, 1H) 10.28-10.54 (m, 1H) 11.24 (br.s, 1H).

[0408] Inhibitory effect of compound 1 on PARP1 / PARP2 enzyme activity

[0409] PARP1 / PARP2 enzyme activities were detected using a chemiluminescence method. First, histone (Active Motif, 81126) was incubated in 384-well plates for 2 hours. Then, different dilutions of the example compounds and either PARP1 working solution (Abcam, ab279663) or PARP2 working solution (BPS, 80502) were added. Max control wells contained only PARP1 or PARP2 working solution, while Min control wells contained only assay buffer. The plates were incubated at room temperature for 15 minutes, followed by the addition of biotin-labeled substrate NAD. + (BPS, 80610) After incubation at room temperature for 2 hours, the ADP riboyl group of the substrate remained biotinylated on the histone after enzyme catalysis. Streptavidin-HRP solution (Abcam, AB7403) was added to develop biotin color, and the values ​​were read on an EnSight (PE) instrument. The inhibition rate was calculated using the fluorescence values ​​of the Max and Min wells. A dose-response curve was fitted using GraphPad Prism 5 software to obtain the IC50 of each compound on the enzyme activity. 50 value.

[0410] The results are shown in Table 1 below. Examples 1, 2, 3, and 4 showed dose-dependent inhibition of PARP1 enzyme, with significant inhibitory activity reaching picomolar concentration levels, similar to the reference compounds AZD5305 and Olaparib. Regarding PARP2 selectivity, Example 1 showed 3 times better selectivity than the reference AZD5305, while Examples 2, 3, and 4 showed similar selectivity to the reference AZD5305. Compared to the currently marketed PARP1 compound Olaparib, Examples 1, 2, 3, and 4 significantly improved PARP2 selectivity while maintaining inhibition of PARP1 enzyme activity, with selectivity increases ranging from 16 to 83 times.

[0411] Table 1 shows the inhibitory effects of compounds on PARP1 / PARP2 enzyme activity.

[0412]

[0413] Experiment Example 2: Compounds induce the DNA capture ability of PARP1 / PARP2

[0414] The DNA capture capacity of PARP1 / PARP2 was detected using HTRF (homogeneous time-resolved fluorescence). First, PARP1 (BPS, 80501) or PARP2 (BPS, 80502) was labeled with Mabanti GST-Tb crypate (Cisbio, 61GSTTLA). Damaged DNA-labeled probes (Generay) were added, along with different concentrations of the example compounds. 50 μL of MAZD2281 was added to the Max control wells, and medium buffer was added to the Min wells. After incubation at room temperature for 1 hour, the substrate NAD+ was added. + (Sigma, 10127965001) After 10 minutes of incubation, PARP exhibits enzymatic activity, causing it to be released from the damaged DNA. At this stage, only a fluorescence signal with an emission wavelength of 615 nm can be detected. When PARP is inhibited, it is induced to bind to the damaged DNA, causing energy transfer. Two emission wavelengths can then be detected: one is the fluorescence signal emitted by the damaged DNA probe itself at 615 nm, and the other is the fluorescence signal emitted at 665 nm due to energy transfer after PARP binds to the damaged DNA. The fluorescence ratio of 665 nm to 615 nm represents the amount of PARP-captured DNA complex. The capture capacity induced by each compound was calculated using the fluorescence values ​​of the Max and Min wells. The dose-response curve was fitted using the analysis software GraphPad Prism 5 to obtain the EC5 value of each compound's PARP enzyme DNA capture capacity. 50Value (required concentration to achieve 50% capture).

[0415] The results are shown in Table 2 below. Examples 1, 2, 3, and 4 induced PARP to capture DNA at single-digit nanomolar concentrations, demonstrating significant capture ability similar to the reference compound AZD53305 and superior to Olaparib. Regarding PARP2 selectivity, Example 3 achieved a 64-fold selectivity, similar to the reference AZD5305; Examples 1, 2, and 4 achieved approximately 100-fold selectivity, superior to the reference AZD5305. Compared to the currently marketed PARP1 compound Olaparib, Examples 1, 2, 3, and 4 significantly improved PARP1 activity and PARP2 selectivity, with activity increasing by 3-7 times and selectivity by 213-333 times.

[0416] Table 2. DNA capture ability of PARP induced by the compounds

[0417]

[0418] Experimental Example 3: Inhibitory effect of compound on PARP1 / PARP2 enzyme activity at the cellular level

[0419] The inhibitory effects of the compounds on PARP1 / PARP2 enzyme activity at the cellular level were detected using high-content imaging. A549WT, PARP1-KO, and PARP2-KO cell lines were self-established. After cell resuscitation and stabilization, a sufficient number of cells were collected, and 100 μL of cell suspension was seeded into 96-well plates. The next day, serially diluted concentrations of the example compounds were added. Max control wells received only buffer, while Min control wells received 500 nM AZD5305 (A549WT and PARP2-KO cell lines) or 1 μM AZD2281 (PARP1-KO cell line). Incubation was performed for 1.5 hours (A549WT and PARP2-KO cell lines) or 2 hours (PARP1-KO cell line). Remove the supernatant and incubate with 0.4 mM H2O2 for 10 minutes (A549 WT and PARP2-KO cell lines) or 1.5 mM H2O2 for 15 minutes (PARP1-KO cell line) to induce significant DNA damage. Remove the supernatant, fix with 4% paraformaldehyde for 20 minutes, then treat with 0.5% Triton X-100 for 20 minutes to increase cell membrane permeability. Incubate with 3% BSA for 1 hour to avoid nonspecific binding. Add the primary antibody Poly(ADP-ribose) monoclonal antibody (CST, 83732S) diluted 1:500 and incubate overnight. Then add the secondary antibody Goat anti-Rabbit IgG, diluted 1:500. TMIncubate with 488 (Invitrogen, A-11034) for 1 hour. Add 50 μL of DAPI (Invitrogen, R37606) to stain cell nuclei for 30 minutes. Wash twice with PBS, then incubate in OPERETTA CLASSES. TM Cells were photographed on a PE (polyepidermal imager) in non-confocal mode under a 20x water objective, with five regions photographed for each well. For data analysis, DAPI-stained nuclei were used to distinguish between the nucleus and cytoplasm, and the average intensity of Alexa 488 in the nuclei of each well was calculated. The inhibition rate was calculated using the fluorescence values ​​from the Max and Min wells, and dose-response curves were fitted using GraphPad Prism 5 software to determine the IC50 of each compound on enzyme activity. 50 value.

[0420] The results are shown in Table 3. The compounds in the examples all showed dose-dependent inhibition of enzyme activity in both the A549WT and PARP2-KO cell lines, with significant inhibitory activity. Example 4 reached a single-digit nanomolar concentration with similar inhibitory activity, indicating that the cellular enzyme activity mainly originates from PARP1. Examples 1, 2, 3, and 4 showed similar inhibitory activity against PARP1 compared to the reference AZD5305. The compounds in the examples all showed relatively weak inhibitory activity in the A549PARP1-KO cell line. Examples 2, 3, and 4 showed no enzyme activity inhibition at the highest concentration of 40 μM, indicating that after PARP1 knockout, the compounds in the examples did not significantly inhibit PARylation at the cellular level, and their inhibitory effect on enzymes other than PARP1 was not significant. Compared to the reference AZD5305, Examples 1 and 2 showed similar selectivity, while Examples 3 and 4 showed a selectivity fold greater than 3-6 times higher than the reference AZD5305, demonstrating better selectivity.

[0421] Table 3 shows the inhibitory effects of compounds on PARP1 / PARP2 enzyme-mediated parylation activity at the cellular level.

[0422]

[0423]

[0424] Experiment Example 4: Test of the antiproliferative activity of the compound against tumor cells

[0425] The anti-proliferative assay of the compounds against tumor cells was performed using the most widely used ATP concentration detection method. The MDA-MB-231 and MDA-MB-436 cell lines were both derived from ATCC, DLD-1 human colorectal adenocarcinoma epithelial cells, and DLD-1BRCA2 cells. - / -Cells were obtained from Horizon. Cells were resuscitated and, once stabilized, collected with a viable cell count greater than 90%. 450-500 cells were seeded into 384-well plates. The next day, serially diluted compounds from the example were added. Max wells received only buffer, and Min wells received 50 μM AZD2281. Incubation was performed for 7 days. On the 8th day, [the following was added]... Reagent (Promega, G7573), incubated at room temperature for 30 minutes, and values ​​were read on Envision (PE). Inhibition rates were calculated using the fluorescence values ​​of the Max and Min wells. Dose-response curves were fitted using GraphPadPrism 5 software to determine the IC50 of each compound on enzyme activity. 50 value.

[0426] The results are shown in Table 4 below. In both the BRCA1-mutated MDA-MB-436 human triple-negative breast cancer cell line and the BRCA1-normal MDA-MB-231 human triple-negative breast cancer cell line, the compounds in the examples exhibited dose-dependent anti-proliferative activity against the BRCA1-mutated MDA-MB-436. Examples 2, 3, and 4 all showed inhibitory activity against this cancer cell line at single-digit nanomolar concentrations, similar to the reference AZD5305. For the BRCA1-normal MDA-MB-231, Examples 1, 2, and 4 showed no inhibitory activity against cell proliferation at the highest concentration of 10 μM, consistent with the reference AZD5305. Example 3 showed a low IC50 value. 50 At 7.4 μM, Examples 1, 2, 3, and 4 demonstrated significant selectivity in BRCA1-mutant cell lines and normal BRCA1 cells, with selection folds reaching hundreds or thousands of times. Compared to the commercially available PARPi Olaparib, Examples 1, 2, 3, and 4 showed 18-235-fold increased antiproliferative activity against BRCA1-mutant MDA-MB-436 and 55-530-fold increased selectivity against PARP2, significantly enhancing both PARP1 inhibitory activity and PARP2 selectivity.

[0427] As shown in Table 5, in the BRCA2-mutated DLD-1BRCA2 - / -In the BRCA2-normal DLD-1 human colorectal adenocarcinoma epithelial cell line, the compounds in the examples all exhibited dose-dependent antiproliferative activity against BRCA2-mutant cell lines. Examples 2, 3, and 4 showed inhibitory activity against cancer cell proliferation at single-digit nanomolar concentrations, similar to the reference AZD5305. For the BRCA2-normal DLD-1 cell line, Examples 1, 2, 3, and 4 showed no inhibitory activity against cell proliferation at the highest concentration of 10 μM, consistent with the reference AZD5305. This indicates that Examples 1, 2, 3, and 4 showed significant selectivity in both BRCA2-mutant and BRCA2-normal cell lines, with selection folds reaching hundreds or thousands of times.

[0428] The antiproliferative activity of the compounds in BRCA1-mutated and normal, and BRCA2-mutated and normal cancer cell lines, as demonstrated by the examples, indicates that the compounds possess strong antiproliferative activity against target cells and are targeted and safe for clinical treatment.

[0429] Table 4. Antiproliferative activity of compounds against BRCA1-mutated and BRCA1-normal cancer cells.

[0430]

[0431]

[0432] Table 5. Antiproliferative activity of compounds against BRCA2-mutated and BRCA2-normal cancer cells.

[0433]

[0434] By combining enzymatic activities at both the molecular and cellular levels, PARP was induced to capture damaged DNA and exert anti-proliferative activity against cancer cells. Examples 1, 2, 3, and 4 exhibited excellent selective inhibitory activity against PARP1 and anti-proliferative capacity against target cells. They were significantly superior to the marketed PARP1 olparib in both PARP1 activity and PARP2 selectivity. Compared with the reference compound AZD5305, they showed a significant improvement in PARP1 selectivity at the cellular level.

[0435] Experimental Example 5: Pharmacokinetic Study of Mice After Single Dosage

[0436] Male CD-1 mice were used as test animals to determine the plasma drug concentration of the compound and evaluate pharmacokinetic parameters after a single dose. Healthy adult male CD-1 mice were selected. The candidate compound was added to 10% DMSO, vortexed and sonicated until fully dissolved. Then, 30% PEG400 was added, vortexed and sonicated, and 60% double-distilled water was added to prepare a clear solution for later use. Mice were administered 2 mg / kg intravenously and 10 mg / kg orally. Whole blood was collected at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration to prepare plasma. After sample processing, drug concentration was analyzed by LC-MS / MS, and pharmacokinetic parameters were calculated.

[0437] The results are shown in Table 6 below, indicating that the compound of Example 1 has good bioavailability and good pharmacokinetic properties.

[0438] Table 6. Pharmacokinetic parameters of the compounds in CD-1 mice.

[0439]

[0440] The above experiments demonstrate that the compounds of this invention exhibit high selectivity in inhibiting PARP1 enzyme, with inhibitory activity at both the PARP1 and cellular levels 10-100 times greater than that against PARP2 enzyme. This higher selectivity is expected to result in greater clinical safety, fewer toxic side effects, and easier patient acceptance, thus enhancing its medical value.

[0441] Selectivity of compound 6 to PARP family members PARP3, 5a, 6, 7, and 11

[0442] The activities of PARP family enzymes were detected using a chemiluminescence method. First, histone (Active Motif, 81126) was incubated in a 384-well plate for 2 hours.

[0443] Different dilutions of the example compounds and PARP3 working solution (BPS, 80503) were added. Max control wells were added only with the respective PARP working solutions, and Min control wells were added only with the assay buffer. The mixtures were incubated at room temperature for 15 minutes, followed by the addition of the biotin-labeled substrate NAD. + (BPS, 80610), PARP3 activating DNA (Generay), incubated at room temperature for 2 hours. After the substrate is catalyzed by the enzyme, the ADP riboyl group binds to the histone and still carries the biotin label. Striptigin-HRP solution (Abcam, ab7403) is added to make biotin develop color, and the value is read on the EnSight (PE) instrument.

[0444] Different dilutions of the example compounds and PARP5a working solution (BPS, 80504) were added. Max control wells were added only with the respective PARP working solutions, and Min control wells were added only with the assay buffer. The mixtures were incubated at room temperature for 15 minutes, followed by the addition of the biotin-labeled substrate NAD. + (BPS, 80610), incubated at room temperature for 2 hours. After the substrate is catalyzed by the enzyme, the ADP riboyl group binds to the histone and still carries the biotin label. Striptigin-HRP solution (Abcam, ab7403) is added to make biotin develop color, and the value is read on the EnSight (PE) instrument.

[0445] Different dilutions of the example compounds and PARP6 working solution (BPS, 80506) were added. Max control wells contained only the respective PARP working solution, and Min control wells contained only the assay buffer. The mixtures were incubated at room temperature for 15 minutes, followed by the addition of the biotin-labeled substrate NAD. + (BPS, 80610), incubated at room temperature for 2 hours. After the substrate is catalyzed by the enzyme, the ADP riboyl group binds to the histone and still carries the biotin label. Striptigin-HRP solution (Abcam, ab7403) is added to make biotin develop color, and the value is read on the EnSight (PE) instrument.

[0446] Using the PARP7 Chemiluminescent assay kit (BPS, 79729), different dilutions of the example compounds and PARP7 working solution (BPS, 80527) were added. Max control wells contained only the PARP working solution, and Min control wells contained only the assay buffer. The mixture was incubated at room temperature for 15 minutes. Then, the substrate mixture provided by the assay kit (BPS, 78371) was added, and the mixture was incubated at room temperature for 1 hour. After enzyme catalysis, the ADP riboyl groups of the substrates bound to histones, still bearing the biotin label. Treptavidin-HRP solution (BPS, 80611) was added to develop the biotin color, and the values ​​were read on an EnSight (PE) instrument.

[0447] The PARP11 Chemiluminescent assay kit (BPS, 80561) was used. Different dilutions of the example compounds and PARP11 working solution (BPS, 80511) were added. The Max control wells were added only with the PARP working solution, and the Min control wells were added only with the assay buffer. The mixture was incubated at room temperature for 15 minutes. The substrate mixture provided by the assay kit (BPS, 78371) was then added, and the mixture was incubated at room temperature for 1 hour. After the substrate was catalyzed by the enzyme, the ADP riboyl group was bound to histone and still carried the biotin label. Treptavidin-HRP solution (BPS, 80611) was added to develop the biotin color, and the values ​​were read on the EnSight (PE) instrument.

[0448] The inhibition rate was calculated using the fluorescence values ​​of the Max and Min wells. Dose-response curves were fitted using the analysis software GraphPad Prism 5 to determine the IC50 of each compound on enzyme activity. 50 value.

[0449] The results are shown in Table 7 below. Example 4 showed weaker inhibitory effects on all PARP enzymes than on PARP1 enzyme activity. The values ​​in parentheses in Table 7 represent the ratios to PARP1 enzyme activity. Compared with the commercially available PARPi Olaparib, Example 4 showed significantly improved selectivity for all PARP enzymes except for slightly weaker selectivity for PARP11. Compared with the reference AZD5305, Example 4 showed significantly improved selectivity for all tested PARP enzymes.

[0450] Example 4 illustrates that it is a PARP1-specific selective inhibitor, which is superior to AZD5305 in selectivity against PARP3, PARP5a, PARP6, PARP7 and PARP11, especially in its selective advantage against PARP11; and superior to Olaparib in selectivity against PARP3, PARP5a, PARP6 and PARP7, especially in its selective advantage against PARP3.

[0451] Table 7. Inhibition of PARP3 / PARP5a / PARP6 / PARP7 / PARP11 enzyme activity by compounds (nM)

[0452]

[0453] Example 7: Effect of compound 7 on the induction of PARP1 / 2 on DNA capture in FP experiments

[0454] To further explore the effects of Example 4 on PARP1-DNA and PARP2-DNA capture, and the differences between them, fluorescence polarization (FP) was used for further evaluation. The PARP1 / 2 enzymes bind to the fluorescently labeled DNA to form a larger complex, resulting in slower rotation of the fluorescently labeled DNA and thus emitting a higher polarization value. This effect was observed after the addition of NAD+. + Subsequently, PARP1 / 2 enzymes undergo self-ribosylation and accumulate negative charges. When the negative charge accumulates to a certain level, it causes the fluorescently labeled DNA to dissociate, resulting in faster rotation of the fluorescently labeled DNA and a decrease in polarization intensity. Adding a PARP inhibitor affects PARP-DNA capture, and the degree of this effect can be detected by changes in polarization intensity. First, 25 nL of different concentrations of the compound were transferred to 384-well plates at 1000-fold final concentrations. 25 nL of 100% DMSO was added to the Min and Max wells, followed by 5 μL of enzyme solution containing 10 nM PARP1 (BPS, 80501) and 1 nM FAM-PARP1-DNA (Generay, customized) or 10 nM PARP2 (BPS, 80502) and 1 nM FAM-PARP2-DNA (Generay, customized). The plates were centrifuged at 1000 rpm for 1 minute, then incubated at room temperature for 30 minutes. Finally, 5 μL of 1 mM NAD+ substrate was added. + (MCE,HY-B0445), add 5 μL of 1 mM NAD substrate to the min well. + Add Assay buffer to the Max well, centrifuge at 1000 rpm for 1 minute, react at 25°C, and test at the following different time points:

[0455] For PARP1 capture test readings (Envision) at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 30 hours, 48 ​​hours and 54 hours.

[0456] For PARP2 capture test plate reader readings at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours and 48 hours.

[0457] The induced capture capacity of the compounds was calculated using the fluorescence values ​​of the Max and Min wells. Dose-response curves were fitted using the analysis software GraphPadPrism 5 to determine the EC5 values ​​of each compound's ability to induce PARP enzyme DNA capture. 50 value.

[0458] The results are shown in Table 8 and Figure 1As shown, taking the 2-hour time point as an example, Example 4 showed a 48-fold increase in the ability to induce PARP1-DNA capture compared to the marketed PARPi Olaparib, and similar activity to the reference AZD5305. Example 4 showed almost no ability to capture PARP2-DNA, similar to the reference AZD5305; while the marketed PARPi Olaparib showed similar capture of PARP2-DNA as PARP1-DNA, with no selectivity.

[0459] This demonstrates that Example 4 exhibits PARP1 selectivity significantly higher than that of PARP2. It is expected to significantly reduce the blood toxicity induced by PARP2.

[0460] As shown in Table 8 and Figure 2 As shown, further comparisons were made between Example 4 and the reference AZD5305 regarding their ability to capture PARP1-DNA. Over time, the activity of Example 4 was maintained for more than 54 hours, and at 54 hours, its activity was 14 times stronger than that of the reference AZD5305. This suggests potentially better anti-tumor proliferative activity.

[0461] Table 8. Effects of compounds on PARP1 / 2-DNA capture

[0462]

[0463]

[0464] Example 8: Antitumor effect of compound on mouse model of human breast cancer cell MDA-MB-436 xenograft

[0465] To further validate Example 4 in vivo, a mouse subcutaneous xenograft model was established using the BRCA1-mutated MDA-MB-436 cell line. Human breast cancer MDA-MB-436 cells (ATCC, HTB-130) were cultured in vitro as a monolayer under the following conditions: L-15 medium supplemented with 10% fetal bovine serum, 1% penicillin-streptomycin solution, and 0.01 mg / mL bovine insulin, incubated at 37°C in a CO2-free incubator. Cells were passaged twice a week using trypsin-EDTA digestion. When cell saturation reached 80%-90%, cells were harvested, counted, and 0.2 mL of 1×10⁻⁶ cells was added. 7 One MDA-MB-436 cell was subcutaneously seeded into the right posterior dorsal region of each mouse (PBS:Matrigel = 1:1). The average tumor volume reached 152 mm. 3 The mice were started to be administered drugs at a certain time, with the day designated as Day 0. Tumor volume and mouse weight were monitored twice a week for 28 days.

[0466] The tumor diameter was measured using vernier calipers. The formula for calculating tumor volume is: V = 0.5a × b 2, where a and b represent the long and short diameters of the tumor, respectively. The tumor-suppressing efficacy of the compound is evaluated using the relative tumor shrinkage rate Reg%. Reg% reflects the rate at which the tumor volume shrinks after treatment. Reg% = (V0 - V t ) / V0×100%, where V0 is the tumor volume measured at the time of group administration (i.e., d0), V t The tumor volume at a particular measurement.

[0467] The compound response criteria in mouse models are derived from mRECIST (Revised Solid Tumor Response Criteria) (Gao et al., 2015), and are defined as follows:

[0468] CR (complete remission): Best Response <-95% and Best Avg Response <-40%;

[0469] Partial remission (PR): Best Response < -50% and Best Avg Response < -20%;

[0470] SD (Stable Disease): Best Response <35% and Best Avg Response <30%;

[0471] PD (Disease Progression): Other Categories;

[0472] ORR% equals the sum of the percentages of complete remission (CR) and partial remission (PR).

[0473] Statistical analysis was performed using Prism software, including the mean (mean) and standard error (SEM) of tumor volume at each time point for each group. For statistical analysis of TV, the raw TV data from each measurement were used to compare differences between groups. Two-way ANOVA was used to include both drug administration and time factors in the analysis, and Tukey's multiple comparisons test was applied. A p-value < 0.05 was considered statistically significant.

[0474] The results are as follows Figure 3 As shown, at the same dose, both Example 4 and the reference AZD5305 promoted tumor regression. Example 4 achieved a greater degree of tumor regression than the reference AZD5305, with an ORR of 60%, while the reference ORR was 20%.

[0475] This indicates that in the human breast cancer MDA-MB-436 mouse subcutaneous xenograft model, the anti-tumor growth effect of Example 4 was superior to that of the reference AZD5305.

[0476] Example 9: The apoptosis-promoting effect of compound on BRCA2-deficient cell lines

[0477] Mechanism analysis of the antiproliferative effect of the compound on BRCA-mutated tumors, and flow cytometry analysis of the compound's effect on apoptosis in BRCA2-mutated cell lines. BRCA2-deficient human colon cancer DLD-1 cells (ATCC, HTB-130) were cultured adherently in RPMI 1640 medium supplemented with 1% fetal bovine serum and 100 μg / mL hygromycin B. Once the cells entered the logarithmic growth phase, they were harvested and placed in 6-well plates (600,000 cells per well) and incubated overnight at 37°C / 5% CO2. Different concentrations of the compound were added to each well for incubation. After 7 days, the cells were harvested and placed in 96-well plates. 195 μL of Annexin V-FITC binding buffer was added to each well to resuspend the cells, followed by 5 μL of Annexin V-FITC (beyotime, C1052). The mixture was gently mixed and incubated at room temperature for 30 minutes. The cells were washed twice with PBS, centrifuged at 300g for 5 minutes, and 500 μL of PBS was added to each well for reselection. Finally, 5 μL of [the compound name is missing here, likely a continuation of the previous sentence] was added to each well. Gently mix with PI (beyotime, C1052), stain at room temperature for 30 minutes, wash once with PBS, centrifuge at 300g for 5 minutes, resuspend cells in 500μL PBS, and transfer 300μL of cells to a flow cytometry tube for analysis (BD Bioscience, FACSVerse). Analyze the data collected by the flow cytometer using FlowJo software.

[0478] Apoptosis Analysis: Drag the apoptotic sample into FlowJo and double-click the raw data to open the graph window. Select FSC-A for the X-axis and SSC-A for the Y-axis. Analyze the apoptotic cells using the cell population shown in the above figure. Cell debris is not analyzed. In the SSC / FSC graph, double-click "Analyzed Cell Population," select FITC for the X-axis to represent Annexin V-FITC, and PerCP for the Y-axis to represent PI. Use the quadrature gate tool to delineate live and apoptotic cells. Annexin V positive cells are apoptotic, Annexin V positive and PI negative cells are early apoptotic cells, and Annexin V positive and PI positive cells are late apoptotic cells. Use PRISM for plotting and analysis. Statistical analysis uses two-way ANOVA to include different compounds and concentrations in the analysis. Tukey's multiple comparisons test is applied, and p < 0.05 is considered statistically significant.

[0479] The results are as follows Figure 4As shown, three replicate experiments were conducted. Example 4 induced apoptosis rates higher than the reference AZD5305 at different concentrations, with some concentrations showing statistically significant differences. This suggests that Example 4 was superior to the reference AZD5305 in inducing apoptosis in BRCA2-deficient human colon cancer DLD-1 cells.

[0480] Experimental Example 10: The apoptosis-promoting effect of compound on BRCA1-mutated human breast cancer xenografts

[0481] To further validate the pro-apoptotic effects of the compounds in vivo, the changes in cleaved caspase-3 in subcutaneous xenograft tissue of MDA-MB-436 mice were detected by Western blotting. After 10 days of treatment with different compounds, animals were euthanized 0.25 hours and 24 hours after the last administration, and tumor tissue was collected for analysis. The flash-frozen tumor tissue was placed on dry ice, and 350 μL of complete cell lysis buffer (containing 1% protease inhibitor and phosphatase inhibitor) was added. The tissue was lysed using a tissue grinder for 5 minutes, and the lysate was placed on ice for 30 minutes. The tissue was centrifuged at 12,000 rpm and 4°C for 10 minutes, and the supernatant was transferred to a new 1.5 mL centrifuge tube. Protein quantification was performed using a BCA quantitative kit. Based on the quantification results, the sample protein concentration was adjusted to 2 μg / μL, and LDS loading buffer (4X) and sample reducing agent (10X) were added. The sample was heated at 100°C for 10 minutes. For Western blotting, load 10 μL of protein into each well of an SDS-PAGE gel and incubate at 80 V for 30 minutes; then perform electrophoresis at 120 V for 90 minutes. Transfer the membrane using an iBlot2 transfer kit and transfer apparatus for 7 minutes. Cut the membrane to the molecular weight of the protein to be detected. Wash the membrane three times with 1xTBST for 5 minutes each time. Add the primary antibodies Cleaved Caspase-3 (Asp175)(5A1E) Rabbit mAb (CST, 9664), Caspase-3 Antibody (CST, 9662), and β-Actin Antibody (CST, 4967) and incubate overnight at 4°C. Wash the membrane three times with 1xTBST for 10 minutes each time. Add the secondary antibody Goat anti-Rabbit IgG-HRP (Thermopolymer). Fisher (31462), incubated at room temperature for 1 hour, washed three times with 1xTBST for 10 minutes each time, added HRP substrate from the WestFemto ultrasensitive chemiluminescence kit, and chemiluminescence was performed. The chemiluminescence was detected and photographed on a Tanon 5200 Multi instrument. Quantitative analysis was performed using Alpha View software to relatively quantify the density intensity of the immunoblot spectral bands. β-Actin, a housekeeping protein, was used to check the consistency of sample loading in the immunoblot assay. The density intensity of the cleaved caspase-3 band was standardized by comparing it with the density intensity of the total caspase-3 band, and then the relative density intensity of cleaved caspase-3 in the Vehicle control group was set to 1 for plotting the relative expression levels of cleaved caspase-3 in each treatment group.The values ​​were analyzed graphically using Prism software, including the mean and standard error (SEM) of the relative expression levels of cleaved caspase-3 at each time point for each group. Differences between groups were compared, and one-way ANOVA was used for comparisons among multiple groups. For unequal variances (significant differences in F-values), the Games-Howell test was applied. If no significant difference was found in the F-values, Tukey's multiple comparisons test was used. A p-value < 0.05 was considered statistically significant.

[0482] The results are as follows Figure 5 and Figure 6 As shown, Example 4 promoted the increase of cleaved caspase-3 in subcutaneous xenograft tissue of MDA-MB-436 mice, with a greater increase than the reference AZD5305 at 0.25 hours and 24 hours after the last administration. This suggests that in vivo tumors of BRCA1-mutated MDA-MB-436 mice, Example 4 has a better effect on promoting tumor cell apoptosis than the reference AZD5305, which is consistent with its better tumor-suppressing effect.

[0483] In summary, the compound of this invention is a highly selective PARP1 inhibitor, exhibiting superior tumor growth inhibition compared to AZD5305 in the BRCA1 MDA-MB-436 human breast cancer tumor model. This advantage is further confirmed by comparisons of its promotion of PARP1-DNA capture and its induction of apoptosis. Compared to marketed PARP inhibitors, it significantly improves selectivity for PARP2, and compared to the reference AZD5305, it significantly improves selectivity for other PARP families. This suggests that the compound of this invention, as described in Example 4, holds promise as a safer and more effective highly selective PARP1 inhibitor, providing higher quality treatment options for clinical patients.

[0484] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A compound of formula (II), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, having the following structural formula: (II) in, R1 is selected from H, D, halogen, CN, OR a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 1s replace; R2 is selected from H, D, halogens, CN, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups, optionally surrounded by 1, 2, or 3 R groups. 2s replace; R3 is selected from H, OR a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 3s replace; R4 is selected from H, D, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups, optionally surrounded by 1, 2, or 3 R groups. 4s replace; R 1s and R 3s Each is independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; R 2s and R 4s Each is independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; n is 0, 1, 2, 3 or 4; R a Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; The aforementioned groups are optionally deuterated, up to and including complete deuteration.

2. The compound of formula (II) of claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein, R1 is selected from H, D, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R2 is selected from H, D, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R3 is selected from H, OR a C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Deuterated alkyl groups; R4 is selected from H, D, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; n is 0, 1, 2, 3 or 4; R a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

3. The compound of formula (II) of claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein, R1 is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R2 is selected from H, D, or halogens; R3 is selected from OR a C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Deuterated alkyl groups; R4 is either H or D; n is 0, 1, or 2; R a C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

4. The compound of formula (II) of claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein, R1 is Et; R2 is either H or F; R3 is selected from Me, CD3, or OMe; R4 is H; n is 0; R a For Me.

5. The compound of formula (II) of claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein, R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Deuterated alkyl groups; R2 is a halogen.

6. The compound of formula (II) of claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein, R3 is C 1-6 Deuterated alkyl groups, R2 can be F, Cl, or Br.

7. The compound of formula (II) of claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein, R3 is selected from Me and CD3; R2 is F.

8. The compound of formula (II) of claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein, R3 is CD3.

9. The compound of formula (II) of claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein, The compound is selected from the following: 。 10. A pharmaceutical composition comprising a compound of any one of claims 1-9, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier, adjuvant or mediator, optionally other therapeutic agents.

11. Use of any compound of claims 1-9, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the pharmaceutical composition of claim 10 in the preparation of a medicament for the treatment or prevention of PARP-mediated diseases.

12. The use of claim 11, wherein the PARP is PARP1.

13. The use of claim 11 or 12, wherein the disease is selected from cancer, ischemic diseases, and neurodegenerative diseases.

14. The use of claim 13, wherein the cancer lacks the HR-dependent DNA DSB repair pathway.

15. The use of claim 13, wherein the cancer has a BRCA1 or BRCA2 defective phenotype.

16. The use of claim 13, wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, and lung cancer.

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