WO2024041643A1

WO2024041643A1 - Fused tricyclic compound, preparation method therefor, and medical use thereof

Info

Publication number: WO2024041643A1
Application number: PCT/CN2023/114986
Authority: WO
Inventors: 李心; 沈峰; 董怀德; 贺峰
Original assignee: 江苏恒瑞医药股份有限公司; 上海恒瑞医药有限公司
Priority date: 2022-08-25
Filing date: 2023-08-25
Publication date: 2024-02-29

Abstract

The present disclosure relates to a fused tricyclic compound, a preparation method therefor, and medical use thereof. Specifically, the present disclosure relates to a fused tricyclic compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and use thereof as a therapeutic agent, and particularly, to use thereof as a PARP1 inhibitor and use thereof in the preparation of a medicament for treating and/or preventing cancer.

Description

Fused tricyclic compounds, their preparation methods and their applications in medicine

Technical field

The present disclosure belongs to the field of medicine and relates to a fused tricyclic compound, its preparation method and its application in medicine. In particular, the present disclosure relates to fused tricyclic compounds represented by general formula (I), their preparation methods and pharmaceutical compositions containing such compounds, as well as their use as PARP1 inhibitors and their preparation for treatment and/or or use in drugs to prevent cancer.

Background technique

Poly(ADP-ribose)polymerase 1 (PARP1) was first reported more than 50 years ago and has since been gradually discovered to play an important role in DNA repair, maintenance of genome integrity, and regulation of various metabolisms and signal transductions. process plays an important role. PARP1 can catalyze the transfer of ADP ribose residues from NAD+ to the target substrate to build a poly(ADP-ribose), PAR) chain. The formation and clearance of PAR chains occurs in almost all eukaryotic cells.

ADP-ribosylation is a post-translational modification of proteins that is widely present in various physiological and pathological processes. It refers to the binding of one or more ADP-ribose units to specific sites on proteins under the catalysis of enzymes. PARP1 is the first member of the PARP superfamily, which consists of proteins with homology to PARP1. There are currently 17 members, four of which (PARP1, PARP2, PARP5A and PARP5B) can synthesize PAR chains. Most other enzymes in the family can only build a single ADP-ribose unit and are therefore classified as mono(ADP-ribosyl)ases (MARs), i.e.

PARP1 and PARP2 have been extensively studied for their roles in DNA damage repair. PARP1 is activated by DNA damage and functions to catalyze poly(ADP-ribose) (PAR) strands to target proteins. This post-translational modification, called poly-ADP-ribosylation (PARylation), mediates the recruitment of other DNA repair factors to DNA damage. Upon completion of this recruitment task, PARP auto-PARylation triggers the release of bound PARP from DNA, allowing access to other DNA repair proteins to complete repair. Therefore, the binding of PARP to damaged sites, its catalytic activity and eventual release from DNA are all important steps in the response of cancer cells to DNA damage caused by chemotherapeutic agents and radiotherapy.

Inhibition of PARP family enzymes has been used as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Extensive preclinical and clinical studies have shown that tumor cells harboring deleterious alterations of BRCA1 or BRCA2, key tumor suppressor proteins involved in double-stranded DNA break (DSB) repair through deleterious recombination (HR), are selectively sensitive to small molecules. Inhibitor of the PARP family of DNA repair enzymes. These tumors are deficient in the homologous recombination repair (HRR) pathway and rely on the survival function of PARP enzymes. Although PARP inhibitor therapy has primarily targeted BRCA-mutated cancers, PARP inhibitors have been clinically tested in non-BRCA-mutated tumors that exhibit homologous recombination deficiency (HRD).

PARP inhibitors with improved selectivity for PARP1 compared with other PARP1/2 inhibitors with improved efficacy and reduced toxicity. We believe that selective strong inhibition of PARP1 will lead to trapping of PARP1 on DNA, leading to DNA double-strand breaks (DSBs) through the collapse of replication forks in S phase. PARP1-DNA trapping is an efficient mechanism to selectively kill tumor cells with HRD.

Therefore, there is an urgent clinical need for effective and safe PARP inhibitors, especially PARP inhibitors that are selective for PARP1.

The relevant patent applications that have been published are WO2021013735A1, WO2021260092A1, WO2009053373A1, WO2008107478A1, etc.

Contents of the invention

The purpose of this disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

in:

Y is O or NR ⁵ ;

R ⁵ is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group;

G ³ is CR ⁶ or N;

R ⁰ , R ^1a , R ^1b , R ^1c and R ⁶ are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, cyano group, -NR ^7a R ^7b , hydroxyl group, -C(O)R ^8a , -C(O)OR ^8a , -C(O)NR ^7a R ^7b , -S(O) _p R ^8a , cycloalkyl group, heterocyclyl group , aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of halogen, oxo, alkyl, Substituted by one or more substituents of alkoxy, haloalkyl, haloalkoxy, cyano, -NR ^9a R ^9b , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl ;

Each R ² and R ⁴ are the same or different, and are each independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, -NR ^7c R ^7d , hydroxyl, hydroxyalkyl , cycloalkyl, heterocyclyl, aryl and heteroaryl;

Each R ³ is the same or different, and each is independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR ^7e R ^7f , hydroxyl, -C(O)R ^8b , -C(O)OR ^8b , -C(O)NR ^7e R ^7f , -S(O) _q R ^8b , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl group , alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -Substituted with one or more substituents of -NR ^9c R ^9d , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , R ^7f , R ^9a , R ^9b , R ^9c and R ^9d are the same or different, and each is independent is selected from the group consisting of hydrogen atoms, alkyl groups, hydroxyalkyl groups, cycloalkyl groups and heterocyclyl groups, wherein the alkyl groups, cycloalkyl groups and heterocyclyl groups are each independently selected from the group consisting of halogen, alkyl, alkoxy Substituted with one or more substituents among haloalkyl, haloalkyl and haloalkoxy; or

R ^7a and R ^7b together with the attached nitrogen atom form a heterocyclyl group, or R ^7c and R ^7d together with the attached nitrogen atom form a heterocyclyl group, or R ^7e and R ^7f together with the attached nitrogen atom form a heterocyclyl group, Either R ^9a and R ^9b together with the connected nitrogen atom form a heterocyclyl group, or R ^9c and R ^9d together with the connected nitrogen atom form a heterocyclyl group, and the formed heterocyclic group is optionally selected from halogen, oxo One or more of base, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by substituents;

R ^8a and R ^8b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are each independently selected Optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

p is 0, 1 or 2;

q is 0, 1 or 2;

s is 0, 1, 2, 3 or 4;

t is 0, 1, 2, or 3; and

v is 0, 1, 2, 3 or 4.

In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof:

in:

Y, G ³ , R ⁰ , R ^1a , R ^1b , R ^1c , R ² , R ³ , R ⁴ , s, t and v are as defined in general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein Y is O.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom or a C _1-6 alkyl group; Preferably, R ⁵ is a hydrogen atom or a methyl group.

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein each R ³ is the same or different, and each is independently selected from Halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, cyano, -NR ^7e R ^7f , hydroxyl , -C(O)R ^8b , -C(O)OR ^8b and -C(O)NR ^7e R ^7f , wherein R ^7e , R ^7f and R ^8b are as defined in general formula (I); preferably, each R ³ is the same or different, and each is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl and -C(O)NR ^7e R ^7f , wherein R ^7e and R ^7f are as in the general formula (I) as defined in; more preferably, R ³ is -C(O)NR ^7e R ^7f , where R ^7e and R ^7f As defined in general formula (I); most preferably, ^R3 is -C(O) _NHCH3 .

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein t is 1 or 2; preferably, t is 1.

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R ^1b is selected from hydrogen atom, halogen, C _1-6 Alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy and C _1-6 hydroxyalkyl; preferably, R ^1b is selected from hydrogen atom, halogen, C _1-6 Alkyl and C _1-6 haloalkyl; more preferably, R ^1b is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R ^1c is selected from hydrogen atom, halogen, C _1-6 Alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy and C _1-6 hydroxyalkyl; preferably, R ^1c is selected from hydrogen atom, halogen, C _1-6 Alkyl and C _1-6 haloalkyl; more preferably, R ^1c is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R ^1b is a hydrogen atom; and/or R ^1c is hydrogen atom.

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein s is 0 or 1; preferably, s is 0.

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein v is 0 or 1; preferably, v is 0.

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein s is 0; and/or v is 0.

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein each R ² is the same or different, and each is independently selected from Halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; preferably, each R ² is the same or different, and each is independently selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl.

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein each R ⁴ is the same or different, and each is independently selected from Halogen, C _1-6 alkyl and C _1-6 haloalkyl.

In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

in:

G ³ , R ⁰ , R ^1a , R ^7e and R ^7f are as defined in general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1) or general formula (II) or a pharmaceutically acceptable salt thereof is of general formula (II-1 ) or a pharmaceutically acceptable salt thereof:

in:

G ³ , R ⁰ , R ^1a , R ^7e and R ^7f are as defined in general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, Wherein G ³ is N or CH; Preferably, G ³ is N.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, Wherein R ⁶ is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy and C _1-6 hydroxyalkyl; preferably , R ⁶ is selected from hydrogen atom, halogen, C _1-6 alkyl group and C _1-6 haloalkyl group; more preferably, R ⁶ is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, Wherein R ⁰ is selected from hydrogen atom, halogen, C _1-6 alkyl group and C _1-6 haloalkyl group; preferably, R ⁰ is a hydrogen atom or halogen; more preferably, R ⁰ is a hydrogen atom or F.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, Wherein R ^1a is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy and C _1-6 hydroxyalkyl; preferably , R ^1a is C _1-6 alkyl; more preferably, R ^1a is methyl or ethyl.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R ^7e and R ^7f are the same or different, and are each independently selected from a hydrogen atom, C _1-6 alkyl, C _1-6 hydroxyalkyl, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclyl; Preferably, R ^7e and R ^7f are the same or different, and each is independently a hydrogen atom or a C _1-6 alkyl group; more preferably, R ^7e is a hydrogen atom, and R ^7f is a C _1-6 alkyl group; most preferably , R ^7e is a hydrogen atom, and R ^7f is a methyl group.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, Wherein R ^7e is a hydrogen atom or a C _1-6 alkyl group; and/or R ^7f is a hydrogen atom or a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein Y is O; G ³ is CR ⁶ or N; R ⁶ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ⁰ is hydrogen atom or halogen; R ^1a is C _1-6 alkyl; R ^1b is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ^1c is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; s is 0 or 1; R ² is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl; v is 0 or 1; R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl; t is 1 or 2; each R ³ is the same or different, and each is independently selected From halogen, C _1-6 alkyl, C _1-6 haloalkyl and -C(O)NR ^7e R ^7f ; and R ^7e and R ^7f are the same or different, and each is independently a hydrogen atom or C _1-6 alkyl base.

In some embodiments of the present disclosure, the compound represented by general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein G ³ is N or CH; R ⁰ is a hydrogen atom or Halogen; R ^1a is a C _1-6 alkyl group; and R ^7e is a hydrogen atom, and R ^7f is a C _1-6 alkyl group.

Table A Typical compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to compounds represented by general formula (Ia) or salts thereof:

in:

Y, R ² , R ³ , R ⁴ , s, v and t are as defined in general formula (I).

Another aspect of the present disclosure relates to compounds represented by general formula (I-1a) or salts thereof:

in:

Y, R ² , R ³ , R ⁴ , s, v and t are as defined in general formula (I-1).

Another aspect of the present disclosure relates to compounds represented by general formula (IIa) or salts thereof:

in:

R ^7e and R ^7f are as defined in general formula (II).

Another aspect of the present disclosure relates to a compound represented by general formula (II-1a) or a salt thereof:

in:

R ^7e and R ^7f are as defined in general formula (II-1).

Table B Typical intermediate compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

A nucleophilic substitution reaction occurs between a compound of general formula (Ia) or a salt thereof (preferably hydrochloride) and a compound of general formula (Ib) or a salt thereof, to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen, preferably a chlorine atom;

Y, G ³ , R ⁰ , R ^1a , R ^1b , R ^1c , R ² , R ³ , R ⁴ , s, v and t are as defined in general formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:

A nucleophilic substitution reaction occurs between a compound of general formula (I-1a) or a salt thereof (preferably a hydrochloride) and a compound of general formula (Ib) or a salt thereof to obtain a compound of general formula (I-1) or a pharmaceutically acceptable compound thereof of salt;

in:

L is a halogen, preferably a chlorine atom;

Y, G ³ , R ⁰ , R ^1a , R ^1b , R ^1c , R ² , R ³ , R ⁴ , s, v and t are as defined in the general formula (I-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

A nucleophilic substitution reaction occurs between a compound of general formula (IIa) or a salt thereof (preferably a hydrochloride) and a compound of general formula (IIb) or a salt thereof, to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen, preferably a chlorine atom;

G ³ , R ⁰ , R ^1a , R ^7e and R ^7f are as defined in general formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

A nucleophilic substitution reaction occurs between a compound of general formula (II-1a) or a salt thereof (preferably hydrochloride) and a compound of general formula (IIb) or a salt thereof to obtain a compound of general formula (II-1) or a pharmaceutically acceptable compound thereof of salt;

in:

L is a halogen, preferably a chlorine atom;

G ³ , R ⁰ , R ^1a , R ^7e and R ^7f are as defined in general formula (II-1).

Another aspect of the present disclosure relates to a pharmaceutical composition, which contains the general formula (I), the general formula (I-1), the general formula (II), the general formula (II-1) of the present disclosure and the table The compound represented by A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure further relates to compounds represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A, or pharmaceutically acceptable salts thereof, or compounds including the same Use of pharmaceutical compositions in the preparation of PARP1 inhibitors.

The present disclosure further relates to compounds represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A, or pharmaceutically acceptable salts thereof, or compounds including the same Use of a pharmaceutical composition in the preparation of a medicament for the treatment and/or prevention of diseases or conditions mediated by PARP1.

The present disclosure further relates to compounds represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A, or pharmaceutically acceptable salts thereof or medicaments including the same Use of the composition for the preparation of a medicament for the treatment and/or prevention of cancer.

The present disclosure further relates to a method of inhibiting PARP1, which includes administering to a patient in need an effective amount of inhibitory amounts of Formula (I), Formula (I-1), Formula (II), Formula (II-1) and Table 1 The compound represented by A, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same.

The present disclosure further relates to a method of treating and/or preventing a disease or disorder mediated by PARP1, which comprises administering to a patient in need an inhibitory effective amount of Formula (I), Formula (I-1), Formula (II ), the compound represented by general formula (II-1) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same.

The present disclosure further relates to a method of treating and/or preventing cancer, which comprises administering to a patient in need a therapeutically effective amount of Formula (I), Formula (I-1), Formula (II), Formula (II- 1) and the compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same.

The present disclosure further relates to a compound shown in general formula (I), general formula (I-1), general formula (II), general formula (II-1) and table A or a pharmaceutically acceptable salt thereof, or a compound including Pharmaceutical compositions thereof, which are used as medicines.

The present disclosure further relates to a compound shown in general formula (I), general formula (I-1), general formula (II), general formula (II-1) and table A or a pharmaceutically acceptable salt thereof, or a compound including Pharmaceutical compositions thereof for use as PARP1 inhibitors.

The present disclosure further relates to a compound shown in general formula (I), general formula (I-1), general formula (II), general formula (II-1) and table A or a pharmaceutically acceptable salt thereof, or a compound including Pharmaceutical compositions thereof for the treatment and/or prevention of diseases or conditions mediated by PARP1.

The present disclosure further relates to a compound shown in general formula (I), general formula (I-1), general formula (II), general formula (II-1) and table A or a pharmaceutically acceptable salt thereof, or a compound including Pharmaceutical compositions thereof for the treatment and/or prevention of cancer.

Preferably, the disease or disorder mediated by PARP1 of the present disclosure is cancer.

Preferably, the cancer described in the present disclosure is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer (such as colon cancer and rectal cancer), lung cancer, kidney cancer, liver cancer (such as hepatocellular carcinoma), Cervical cancer, endometrial cancer, myeloma (such as multiple myeloma), leukemia (such as acute leukemia, chronic leukemia, myelogenous leukemia, myelofibrosis, erythroleukemia), lymphoma (such as diffuse large B-cell lymphoma) , Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoid malignancies of T-cell or B-cell origin, follicular lymphoma), acoustic neuroma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer , bronchial carcinoma, sarcomas (such as chondrosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, myxosarcoma, osteogenic sarcoma, rhabdomyosarcoma), chordoma, choriocarcinoma, craniopharyngioma, cyst gland carcinoma, embryonal carcinoma, hemangioendothelioma, ependymoma, epithelial carcinoma, esophageal cancer (also known as esophageal cancer), essential thrombocythemia, Ewing's tumor, testicular cancer, glioma, heavy chain disease, adult Hemangiocytoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, neuroblastoma, NUT midline carcinoma, glioma, bone cancer, nasopharyngeal carcinoma, oral cancer, thyroid cancer, Pineal tumor, polycythemia vera, retinoblastoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, synovoma, sweat gland carcinoma, Waldenström's macroglobulinemia, and VIL MS tumor; preferably, the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer and lung cancer.

Preferably, the cancer cells of the cancer described in the present disclosure are BRCA1 or BRCA2 deficient, preferably BRCA2 deficient.

Preferably, the cancer cells of the cancer described in the present disclosure are defective in BRCA1 or BRCA2, preferably BRCA2.

The active compounds may be prepared in a form suitable for administration by any appropriate route and the compositions of the present disclosure may be formulated by conventional means using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compounds of the present disclosure may also be formulated as tablets, hard or soft capsules, water Dosage forms include liquid or oily suspension, emulsion, injection, dispersible powder or granule, suppository, lozenge or syrup.

As a general guide, the active compounds are preferably in unit dosage form, or in such form that the patient may self-administer a single dose. The unit dosage form of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder or liquid preparation. A suitable unit dose may be 0.1 to 1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients wait. Depending on the method of administration, the composition may contain from 0.1 to 99% by weight of active compound.

Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.

Oral formulations may also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or in which the active ingredient is mixed with a water-soluble carrier or oil vehicle.

Aqueous suspensions contain the active substances and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

Oil suspensions can be formulated by suspending the active ingredient in vegetable oil, or mineral oil. Oil suspensions may contain thickening agents. Sweetening and flavoring agents as described above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be vegetable oil, or mineral oil or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants. Such preparations may also contain demulcents, preservatives, coloring agents and antioxidants.

Pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. Sterile injectable preparations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oily phase. Injectable solutions or microemulsions may be injected into the patient's bloodstream by local mass injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains constant circulating concentrations of the compounds of the present disclosure. To maintain this constant concentration, continuous intravenous drug delivery devices can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

Pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents such as those mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a nontoxic parenterally acceptable diluent or solvent. In addition, sterile fixed oil can be conveniently used as the solvent or suspending medium. For this purpose, any blend of fixed oils can be used. In addition, fatty acids are also prepared as injectables.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore dissolve in the rectum to release the drug.

Compounds of the present disclosure may be administered by adding water to prepare water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including, but not limited to, the activity of the specific compound used, the patient's age, the patient's weight, the patient's health, and the patient's behavior. , patient's diet, administration time, administration method, excretion rate, combination of drugs, severity of disease, etc.; in addition, the best treatment method such as treatment mode, daily dosage of compounds or pharmaceutically acceptable salts Types can be verified based on traditional treatment regimens.

Terminology

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

The term "alkyl" refers to a saturated linear or branched aliphatic hydrocarbon group having 1 to 20 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e. C _1-20 alkyl). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, C _1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (ie, C _1-6 alkyl group). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group is as defined above and has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C _1-20 alkylene group). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C _1-12 alkylene group), and more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C _1-6 alkylene group ). Non-restrictive Examples include: -CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -CH ₂ CH ₂ -, -CH(CH ₂ CH ₃ )-, -CH ₂ CH(CH ₃ )-, -CH ₂ C(CH ₃ ) ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, etc. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment. The substituent is preferably selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, where the alkyl group is as defined above and has 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e. C _2-12 alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C _2-6 alkenyl group). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from the group consisting of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, where the alkyl group is as defined above and has 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e. C _2-12 alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, C _2-6 alkynyl group). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment. The substituents are preferably selected from the group consisting of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment. The substituent is preferably selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e. 3 to 20 membered cycloalkyl). The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered cycloalkyl group), and more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered cycloalkyl group). ), most preferably cycloalkyl groups having 3 to 6 ring atoms (i.e., 3 to 6 membered cycloalkyl groups).

Non-limiting examples of the monocyclic cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and cycloheptyl , cycloheptatrienyl and cyclooctyl, etc.

The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

The term "spirocycloalkyl" refers to a polycyclic system in which one carbon atom (called a spiro atom) is shared between the rings. The ring may contain one or more double bonds, or the ring may contain one or more atoms selected from nitrogen, Heteroatoms of oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxoated, that is, to form sulfoxide or sulfone, but does not include -O-O-, -O-S - or -S-S-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, which has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e. 5 to 20 membered spirocycloalkyl). The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered spirocycloalkyl group), and more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spirocycloalkyl group). membered spirocycloalkyl). The spirocycloalkyl group includes a single spirocycloalkyl group and a multi-spirocycloalkyl group (such as a double spirocycloalkyl group, etc.), preferably a single spirocycloalkyl group or a double spirocycloalkyl group, and more preferably a 3-membered/4-membered, 3-membered or 3-membered spirocycloalkyl group. Yuan/5 Yuan, 3 Yuan/6 Yuan, 4 Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/3 Yuan, 5 Yuan/4 Yuan, 5 Yuan/5 Yuan, 5 Yuan/ 6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan Single spirocycloalkyl. Non-limiting examples include:

Its connection point can be at any position;

wait.

The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with a heterocyclic cycloalkyl group. One or more of the cyclic groups, aryl groups or heteroaryl groups are condensed, wherein the point of attachment is on a single-ring cycloalkyl group, which may contain one or more double bonds in the ring, and has 5 to 20 (for example, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e. 5 to 20 membered fused ring alkyl group). The fused ring alkyl group is preferably a fused ring alkyl group having 6 to 14 ring atoms (ie, a 6 to 14-membered fused ring alkyl group), and more preferably a fused ring alkyl group having 7 to 10 ring atoms (ie, a 7 to 10 membered ring alkyl group). fused ring alkyl group). The fused cycloalkyl group includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl , more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan , 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 One-membered/5-membered or 7-membered/6-membered bicyclic fused cycloalkyl group. Non-limiting examples include:

, its connection point can be at any position; wait.

The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings. The ring may contain one or more double bonds and has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie, 5 to 20 membered bridged cycloalkyl). The bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e., a 6- to 14-membered bridged cycloalkyl group), and more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e., a 7 to 10-membered bridged cycloalkyl group). bridged cycloalkyl). The bridged cycloalkyl group includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl . Non-limiting examples include:

Its connection point can be anywhere.

Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from the group consisting of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkyl One of oxygen, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclyl) or a polycyclic heterocyclic system (i.e., polycyclic heterocyclyl), which contains at least one ring (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxogenated, that is, to form sulfoxide or sulfone, but not including -O-O-, -O-S- or -S-S-), and having 3 to 20 (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e. 3 to 20 membered heterocyclyl). The heterocyclyl group is preferably a heterocyclyl group having 3 to 12 ring atoms (i.e. a 3 to 12 membered heterocyclyl group); further preferably a heterocyclyl group having 3 to 8 ring atoms (i.e. a 3 to 8 membered heterocyclyl group) ); more preferably a heterocyclyl group with 3 to 6 ring atoms (i.e. a 3 to 6 membered heterocyclyl group); most preferably a heterocyclyl group with 5 or 6 ring atoms (i.e. a 5 or 6 membered heterocyclyl group).

Non-limiting examples of the monocyclic heterocyclyl include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl , thiomorpholinyl and homopiperazinyl, etc.

The polycyclic heterocyclyl group includes spiroheterocyclyl group, fused heterocyclyl group and bridged heterocyclyl group.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic system in which the rings share one atom (called a spiro atom). The ring may contain one or more double bonds, and the ring contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, But does not include -O-O-, -O-S- or -S-S-), provided that it contains at least one monocyclic heterocyclyl group and the point of attachment is on the monocyclic heterocyclyl group, which has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie, 5 to 20 membered spiroheterocyclyl). The spiroheterocyclyl group is preferably a spiroheterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroheterocyclyl group), and more preferably a spiroheterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclyl group). 1-membered spiroheterocyclyl). The spiroheterocyclyl group includes a single spiroheterocyclyl group and a polyspiroheterocyclyl group (such as a double spiroheterocyclyl group, etc.), preferably a single spiroheterocyclyl group or a double spiroheterocyclyl group, more preferably 3-membered/4-membered, 3-membered or 3-membered spiroheterocyclyl. Yuan/5 Yuan, 3 Yuan/6 Yuan, 4 Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/3 Yuan, 5 Yuan/4 Yuan, 5 Yuan/5 Yuan, 5 Yuan/ 6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan Single spiroheterocyclyl. Non-limiting examples include:

wait.

The term "fused heterocyclyl" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between the rings. The ring may contain one or more double bonds, and the ring may contain at least one (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, but not Including -OO-, -OS- or -SS-), which is a monocyclic heterocyclyl fused with one or more monocyclic heterocyclyl groups, or a monocyclic heterocyclyl group with a cycloalkyl, aryl or heteroaryl group. One or more of the radicals are fused, wherein the point of attachment is on the monocyclic heterocyclyl radical, and there are 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19 or 20) ring atoms (i.e. 5 to 20 membered fused heterocyclyl). The fused heterocyclyl group is preferably a fused heterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused heterocyclyl group), and more preferably a fused heterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclyl group). fused heterocyclic group). The fused heterocyclyl group includes bicyclic and polycyclic fused heterocyclyl groups (such as tricyclic fused heterocyclyl group, tetracyclic fused heterocyclyl group, etc.), preferably bicyclic fused heterocyclyl group or tricyclic fused heterocyclyl group, more preferably 3 Yuan/4 Yuan, 3 Yuan/5 Yuan, 3 Yuan/6 Yuan, 4 Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/3 Yuan, 5 Yuan/4 Yuan, 5 Yuan/ 5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan Or 7-membered/6-membered bicyclic fused heterocyclyl. Non-limiting examples include:

wait.

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic system that shares two atoms that are not directly connected between the rings. The ring may contain one or more double bonds, and the ring contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, but not including -O-O-, -O-S- or -S-S-), which has 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e. 5 to 20 membered bridged heterocyclyl). The bridged heterocyclyl group is preferably a bridged heterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclyl group), and more preferably a bridged heterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered bridged heterocyclyl group). Yuan-bridged heterocyclyl). According to the number of constituent rings, it can be divided into bicyclic bridged heterocyclyl and polycyclic bridged heterocyclyl (such as tricyclic bridged heterocyclyl, tetracyclic bridged heterocyclyl, etc.), preferably bicyclic bridged heterocyclyl or tricyclic bridged heterocyclyl. base. Non-limiting examples include:

wait.

Heterocyclyl may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituent is preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkyl. One of oxygen, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.

The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aryl) or a polycyclic aromatic ring system (i.e., a polycyclic aryl) having a conjugated π electron system, having 6 to 14 (e.g., 6 , 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e. 6 to 14 membered aryl group). The aryl group is preferably an aryl group having 6 to 10 ring atoms (ie, 6 to 10 membered aryl group). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc. The polycyclic aryl group also includes phenyl and heterocyclyl or ring One or more of the alkyl groups are fused, or the naphthyl group is fused to one or more of the heterocyclyl or cycloalkyl groups, where the point of attachment is on the phenyl or naphthyl group, and in this case the ring The number of atoms continues to refer to the number of ring atoms in the polycyclic aromatic ring system. Non-limiting examples include:

wait.

Aryl groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment. The substituents are preferably selected from D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups. or Multiple.

The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., polycyclic heteroaryl) with a conjugated π electron system, which contains at least one (For example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo-substituted, i.e. Forms sulfoxides or sulfones, but not -O-O-, -O-S-, or -S-S-), which have 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ) ring atoms (i.e. 5 to 14 membered heteroaryl). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl group), and more preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl group). ).

Non-limiting examples of the monocyclic heteroaryl include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl , pyrazolyl, triazolyl, tetrazolyl, furazyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (such as etc.), pyrazinyl, pyridazinyl, etc.

Non-limiting examples of the polycyclic heteroaryl include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene base, quinazolinyl, benzothiazolyl, carbazolyl, etc. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aryl groups, wherein the point of attachment is on the aromatic ring, and in this case, the number of ring atoms continues to represent a polycyclic heteroaryl ring The number of ring atoms in the system. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused to one or more of cycloalkyl or heterocyclyl, wherein the point of attachment is on the monocyclic heteroaromatic ring, and in this case, the ring The number of atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

wait.

Heteroaryl groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment. The substituents are preferably selected from D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkyl groups. One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "amino protecting group" refers to an easily removable group introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), watmethoxycarbonyl (Fmoc), allyl Oxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthalyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), Trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.

The term "hydroxyl protecting group" refers to an easily removable group introduced on a hydroxyl group to block or protect the hydroxyl group for reactions on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyl Dimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

The term "cycloalkyloxy" refers to cycloalkyl-O-, where cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to aryl-O-, where aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, where heteroaryl is as defined above.

The term "alkylthio" refers to alkyl-S-, where alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, where alkyl is as defined above.

The term "methylene" refers to = _CH2 .

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to -OH.

The term "mercapto" refers to -SH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "oxo" or "oxo" refers to "=O".

The term "carbonyl" refers to C=O.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, where alkyl and cycloalkyl are as defined above.

Compounds of the present disclosure may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers that have the same structure but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformational isomers and their mixtures (e.g. racemates, mixtures of diastereomers) . Additional asymmetric atoms may be present for substituents in the compounds of the present disclosure. All such stereoisomers, as well as mixtures thereof, are included within the scope of this disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer. An isomer of a certain compound of the present disclosure can be prepared through asymmetric synthesis or chiral auxiliaries, or when the molecule contains basic functional groups (such as amino) or acidic functional groups (such as carboxyl), and appropriate optical Reactive acids or bases form diastereomeric salts, and then the diastereoisomers are resolved by conventional methods known in the art to obtain pure isomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.

In the chemical structure of the compounds described in this disclosure, the bond Indicates that the configuration is not specified, i.e. if there are chiral isomers in the chemical structure, the bond can be or both Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E forms are included.

The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, either as single isomers or as mixtures of said tautomers in any proportion. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactam, and the like. An example of a lactam-lactam equilibrium is shown below:

When referring to pyrazolyl, it should be understood to include either one of the following two structures or a mixture of two tautomers:

All tautomeric forms are within the scope of the present disclosure, and the naming of a compound does not exclude any tautomeric form.

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom with the same atomic number but a different atomic mass. Examples of isotopes that may be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, and the like, such as ² H (deuterium, D), respectively. ³ H (tritium, T), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, 18 O, ³² p, ³³ p, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ ^F , ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I and ¹³¹ I, etc., preferably deuterium.

Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of the drug. All variations in the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, where the replacement of deuterium can be partial or complete. The replacement of partial deuterium means that at least one hydrogen is replaced by at least one deuterium.

Compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D", that position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e. At least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (ie, at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (ie, at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (ie, at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (ie, at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (ie, at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (ie, at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (ie, at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (ie, at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (ie, at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (ie, at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (ie, at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (ie, at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (ie, at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

"Optionally" or "optionally" means that the subsequently described event or circumstance may but does not necessarily occur, which includes both the occurrence or non-occurrence of the event or circumstance. For example, "alkyl optionally substituted by halogen or cyano" includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

"Substituted" or "substituted" means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents. A person skilled in the art will be able to determine possible or impossible substitutions without undue effort (either experimentally or theoretically). For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond, such as an alkene.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or a pharmaceutically acceptable salt thereof, and other chemical components, as well as other ingredients such as pharmaceutically acceptable carriers and excipients. The purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.

In some embodiments, the unit dosage of the pharmaceutical composition is 0.001 mg-1000 mg.

In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof. In certain embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof. In certain embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof.

In certain embodiments, the pharmaceutical composition contains 0.01% to 99.99% of pharmaceutically acceptable excipients, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

"Pharmaceutically acceptable salts" refer to salts of compounds of the present disclosure, which may be selected from inorganic salts or organic salts. This type of salt is safe and effective when used in mammals, and has due biological activity. They can be prepared individually during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of a therapeutically effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate therapeutically effective amount in an individual case can be determined by those skilled in the art based on routine experiments.

As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and/or dosage forms which, within the scope of reasonable medical judgment, are suitable for contact with patient tissue without undue toxicity, irritation, allergic reactions or other problems or complications, has a reasonable benefit/risk ratio, and is effective for the intended use.

As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is intended that the parameter may vary by ±10%, and is sometimes more preferably within ±5%. As those skilled in the art will appreciate, when a parameter is not critical, numbers are generally given for purposes of illustration only and not limitation.

Synthetic methods of compounds of the present disclosure

In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

Option One

The present disclosure discloses a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, which method includes the following steps:

A nucleophilic substitution reaction occurs between a compound of general formula (Ia) or a salt thereof (preferably a hydrochloride) and a compound of general formula (Ib) or a salt thereof under alkaline conditions, optionally in the presence of a catalyst, to obtain the general formula ( The compound of I) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen, preferably a chlorine atom;

Option II

The present disclosure discloses a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, which method includes the following steps:

A nucleophilic substitution reaction occurs between a compound of general formula (I-1a) or a salt thereof (preferably a hydrochloride) and a compound of general formula (Ib) or a salt thereof under alkaline conditions, optionally in the presence of a catalyst, to obtain the general formula Compounds of formula (I-1) or pharmaceutically acceptable salts thereof;

in:

L is a halogen, preferably a chlorine atom;

third solution

The present disclosure discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, which method includes the following steps:

The compound of general formula (IIa) or a salt thereof (preferably hydrochloride) and the compound of general formula (IIb) or a salt thereof undergo a nucleophilic substitution reaction under basic conditions, optionally in the presence of a catalyst, to obtain the general formula ( II) compound or a pharmaceutically acceptable salt thereof;

in:

L is a halogen, preferably a chlorine atom;

G ³ , R ⁰ , R ^1a , R ^7e and R ^7f are as defined in general formula (II).

Option 4

The present disclosure discloses a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, which method includes the following steps:

A nucleophilic substitution reaction occurs between a compound of general formula (II-1a) or a salt thereof (preferably a hydrochloride) and a compound of general formula (IIb) or a salt thereof under basic conditions, optionally in the presence of a catalyst, to obtain the general formula Compounds of formula (II-1) or pharmaceutically acceptable salts thereof;

in:

L is a halogen, preferably a chlorine atom;

G ³ , R ⁰ , R ^1a , R ^7e and R ^7f are as defined in general formula (II-2).

The reagents that provide alkaline conditions include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, and diisopropylamine. Lithium amide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; the inorganic bases include but are not limited to sodium hydride, potassium phosphate, Sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably N,N-diisopropylethylamine.

The catalyst for the above nucleophilic substitution reaction is sodium iodide or potassium iodide, preferably sodium iodide.

The above reaction is preferably carried out in a solvent, and the solvents used include but are not limited to: N-methylpyrrolidone, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum Ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2- Dibromoethane and its mixtures.

Detailed ways

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR is measured using Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M. The measurement solvents are deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD). , the internal standard is tetramethylsilane (TMS).

MS was measured using Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS).

waters ACQuity UPLC-QD/SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)

THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q Exactive)

High performance liquid chromatography (HPLC) analysis used Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatography.

Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.

High-performance liquid phase preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

Chiral preparation uses Shimadzu LC-20AP preparative chromatograph.

CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm~0.2mm. The specifications used for thin layer chromatography separation and purification products are 0.4mm. ~0.5mm.

Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200~300 mesh silica gel as the carrier.

The average kinase inhibition rate and IC ₅₀ value were measured using NovoStar microplate reader (BMG Company, Germany).

The known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.

There are no special instructions in the examples, and the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1L.

The hydrogen atmosphere refers to the reaction bottle connected to a hydrogen balloon with a volume of about 1L.

The pressurized hydrogenation reaction uses Parr 3916EKX hydrogenator and Clear Blue QL-500 hydrogen generator or HC2-SS hydrogenator.

The hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.

The microwave reaction uses CEM Discover-S 908860 microwave reactor.

There is no special explanation in the examples, and the solution refers to an aqueous solution.

There are no special instructions in the examples. The reaction temperature is room temperature, which is 20°C to 30°C.

The reaction progress in the embodiment is monitored by thin layer chromatography (TLC). The developing agent used in the reaction, the column chromatography eluent system and the thin layer chromatography developing agent system used to purify the compound include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Example 1

(R)-3-((3-ethyl-8-fluoro-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)methyl)-N-methyl-1 ,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepine-9-methyl Amide 1

first step

(R)-tert-butyl 3-(((6-bromo-3-fluoropyridin-2-yl)methoxy)methyl)piperazine-1-carboxylate 1c

6-Bromo-2-(bromomethyl)-3-fluoropyridine 1b (2.5g, 9.29mmol, prepared by the method disclosed in Preparation Example 6 on page 12 of the patent application "WO2016077161A1") and (R )-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester 1a (2.25g, 10.40mmol, Shanghai Hanhong) was dissolved in tetrahydrofuran (30mL), and sodium hydride (812.5mg, 21.20 mmol, 60% purity), the reaction was stirred for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 1c (3g, yield: 79.8%).

MS m/z(ESI):404.1[M+1].

Step 2

(R)-3-(((6-(ethoxycarbonyl)-3-fluoropyridin-2-yl)methoxy)methyl)piperazine-1-carboxylic acid tert-butyl ester 1d

Compound 1c (2g, 4.94mmol) was dissolved in N,N-dimethylformamide (20mL) and ethanol (10mL) To the mixed solvent, add bis(triphenylphosphine)palladium dichloride (0.52g, 740.8μmol) and N,N-diisopropylethylamine (1.52g, 15mmol), stir and react at 100°C for 14 hours in a carbon monoxide atmosphere. After cooling, add ethyl acetate (100 mL) to dilute, wash with water and saturated sodium chloride solution in sequence, collect the organic phase, dry over anhydrous sodium sulfate, filter to remove the desiccant, and the filtrate is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography. Purification with eluent system B gave the title compound 1d (1.5 g, yield: 76.2%).

MS m/z(ESI):398.2[M+1].

third step

3-(tert-butyl)9-ethyl(R)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1, 4] Oxaazepine-3,9(4H)-dicarboxylate 1e

Dissolve compound 1d (4g, 10.06mmol) in N,N-dimethylacetamide (20mL), add N,N-diisopropylethylamine (4g, 30.9mmol), and react under microwave at 140°C for 6 hours. The liquid was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 1e (2.3 g, yield: 60%).

MS m/z(ESI):378.2[M+1].

the fourth step

(R)-9-(methylaminocarbonyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4] Oxaazepine-3(4H)-carboxylic acid tert-butyl ester 1f

Compound 1e (600 mg, 1.58 mmol) was dissolved in 5 mL of 1M ethanol solution of methylamine, and the reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 1f (570 mg). The product was directly used in the next reaction without purification.

MS m/z(ESI):363.2[M+1].

the fifth step

(R)-N-Methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4] Oxaazepine-9-carboxamide hydrochloride 1g

The crude compound 1f (140 mg, 386.2 μmol) was dissolved in dichloromethane (3 mL), 1 mL of 4M dioxane hydrochloride solution was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 1 g of the crude title compound (110 mg). , the product was directly used in the next reaction without purification.

MS m/z(ESI):263.2[M+1].

Step 6

4-Amino-6-chloro-5-fluoronicotinic aldehyde 1i

Dissolve 4-amino-6-chloro-3-pyridinecarboxaldehyde 1h (500mg, 3.1935mmol, Shanghai Bide) in N,N-dimethylformamide (DMF) (8mL) and acetonitrile (8mL), add 1 -Chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (selectfluor) (1.35g, 3.83mmol, Shanghai Bide), under nitrogen protection 80 The reaction was carried out at ℃ for 2 hours. The reaction solution was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 1i (200 mg, yield: 35.8%).

MS m/z(ESI):175.2[M+1].

Step 7

7-Chloro-3-ethyl-8-fluoro-1,6-naphthyridin-2(1H)-one 1j

Compound 1i (165 mg, 945.23 μmol) was dissolved in dichloromethane (10 mL), and n-butyryl chloride (300 mg, 2.81 mmol, Shaoyuan, Shanghai) and N, N-diisopropylethylamine (610.8 mg, 4.72 mmol), 4-dimethylaminopyridine (116.4 mg, 945.2 μmol), and reacted naturally for 14 hours after returning to room temperature. The reaction solution was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title compound. 1j (70 mg, yield: 32.6%).

MS m/z(ESI):227.2[M+1].

Step 8

3-ethyl-8-fluoro-7-(hydroxymethyl)-1,6-naphthyridin-2(1H)-one 1k

Compound 1j (70 mg, 308.8 μmol), (tributyltin) methanol (300 mg, 934.3 μmol, Shanghai Leyan) were dissolved in 1,4-dioxane (5 mL), and chloro(2-dicyclohexylphosphino- 2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)(XPhos Pd G2) (50 mg, 63.6 μmol, Shaoyuan, Shanghai), under nitrogen protection, raise the temperature to 100°C and stir for 14 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 1k (16 mg, yield: 23.3%).

MS m/z(ESI):223.2[M+1].

Step 9

7-(Chloromethyl)-3-ethyl-8-fluoro-1,6-naphthyridin-2(1H)-one 1l

Dissolve compound 1k (16 mg, 72 μmol) in thionyl chloride (1 mL), raise the temperature to 100°C and stir for 1 hour. The reaction solution is concentrated under reduced pressure to obtain the crude title compound 1l (17 mg). The product is directly carried to the next step without purification. reaction.

MS m/z(ESI):241.2[M+1].

Step 10

Dissolve crude compound 1g (22mg, 71.6μmol), crude compound 1l (16mg, 66μmol), N,N-diisopropylethylamine (25mg, 193μmol), sodium iodide (5mg, 33μmol) in acetonitrile (1mL) , reacted at 80°C for 5 hours. After the reaction solution was concentrated under reduced pressure, the residue was analyzed by high performance liquid chromatography (Waters-2545, chromatographic column: SharpSil-T C18, 30*150mm, 5μm; mobile phase: water phase (10mmol/L (Ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL/min), the title compound 1 (5 mg, yield: 16.1%) was purified.

MS m/z(ESI):467.2[M+1].

¹ H NMR (500MHz, CD ₃ OD): δ8.65(d,1H),7.96-7.89(m,2H),7.47(dd,1H),3.97(dd,1H),3.89(d,2H), 3.84(dd,1H),3.39(q,3H),2.94(s,3H),2.89(dd,2H),2.84-2.77(m,1H),2.70-2.59(m,4H),1.29(td, 4H).

Example 2

(R)-N-Methyl-3-((3-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)methyl)-1,2,3 ,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepine-9-carboxamide 2

first step

7-Chloro-3-methyl-1,6-naphthyridin-2(1H)-one 2a

Compound 1h (500 mg, 3.19 mmol) was dissolved in dichloromethane (20 mL), and propionyl chloride (887 mg, 9.58 mmol, Sinopharm) and N, N-diisopropylethylamine (2.07 g, 16 mmol) were added under an ice-water bath. 4-Dimethylaminopyridine (79 mg, 641 μmol), react naturally for 14 hours at room temperature, add water to the reaction solution, dilute with dichloromethane (15 mL × 3), combine the organic phases, wash with saturated sodium chloride, anhydrous sulfuric acid Dry over sodium, remove the desiccant by filtration, and concentrate the filtrate under reduced pressure. Add methanol (2 mL) to the residue to make a slurry, filter, wash the filter cake with methanol (2 mL) and dry to obtain the crude title compound 2a (250 mg). The product is directly processed without purification. Next reaction.

MS m/z(ESI):195.2[M+1].

Step 2

7-(hydroxymethyl)-3-methyl-1,6-naphthyridin-2(1H)-one 2b

Dissolve crude compound 2a (250 mg, 1.28 mmol), (tributyltin) methanol (800 mg, 2.49 mmol, Shanghai Leyan) in 1,4-dioxane (6 mL), add chloro(2-dicyclohexylphosphine) -2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)(XPhos Pd G2 ) (102 mg, 130 μmol, Shaoyuan, Shanghai), under nitrogen protection, raise the temperature to 100°C and stir for 14 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 2b (70 mg, yield: 28.6%).

MS m/z(ESI):191.2[M+1].

third step

7-(Chloromethyl)-3-methyl-1,6-naphthyridin-2(1H)-one 2c

Compound 2b (20 mg, 105 μmol) was dissolved in thionyl chloride (3 mL), and 1 drop of N,N-dimethylethane was added. amide, the temperature was raised to 60°C and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 2c (30 mg). The product was directly subjected to the next reaction without purification.

MS m/z(ESI):209.2[M+1].

the fourth step

Dissolve crude compound 1g (23mg, 76.2μmol), crude compound 2c (15mg, 66μmol), N,N-diisopropylethylamine (28mg, 216μmol), sodium iodide (2.5mg, 16μmol) in acetonitrile (1mL ), reacted at 80°C for 5 hours, the reaction solution was concentrated under reduced pressure, and the residue was analyzed by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30*150mm, 5μm; mobile phase: water phase (10mmol/ L ammonium bicarbonate) and acetonitrile (gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL/min) was purified to obtain the title compound 2 (4 mg, yield: 12.8%).

MS m/z(ESI):435.2[M+1].

¹ H NMR (500MHz, CD ₃ OD): δ8.73(s,1H),7.94-7.90(m,2H),7.51-7.46(m,2H),4.14-4.10(m,1H),3.90-3.87 (m,1H),3.82-3.75(m,2H),3.52-3.49(m,1H),3.47-3.45(m,2H),2.95(s,3H),2.85-2.83(m,1H),2.76 -2.73(m,1H),2.69-2.66(m,1H),2.62-2.59(m,1H),2.23(s,3H),2.07-2.03(m,1H),1.64-1.61(m,1H) .

Example 3

(R)-3-((8-fluoro-3-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)methyl)-N-methyl-1 ,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepine-9-methyl Amide 3

Adopt the synthetic route in Example 2, replace the first step raw material compound 1h with compound 1i, and prepare the title compound 3 (6 mg, yield: 10%)

MS m/z(ESI):453.2[M+1].

¹ H NMR (500MHz, CDCl ₃ ):9.59(br,1H),8.60(br,1H),8.07-8.06(m,1H),7.88-7.85(m,1H),7.71(s,1H),7.31 (s,1H),4.99-4.88(m,2H),3.94(s,2H),3.85-3.84(m,2H),3.39-3.31(m,4H),3.02-3.00(m,3H),2.87 -2.85(m,1H),2.64-2.63(m,2H),2.32(s,3H).

Example 4

(R)-3-((8-fluoro-3-methyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)-N-methyl-1,2,3, 4,4a,5-Hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepine-9-carboxamide 4

first step

(2-Amino-4-bromo-3-fluorophenyl)methanol 4b

Dissolve 2-amino-4-bromo-3-fluorobenzoic acid 4a (10g, 42.7mmol, Shanghai Bide) in tetrahydrofuran (100mL), add dropwise 1M lithium aluminum hydride solution in tetrahydrofuran (85mL), and stir for 4 hours. , add sodium sulfate decahydrate to the reaction solution in an ice bath to quench, filter through diatomaceous earth, wash the filter cake with ethyl acetate, and concentrate the filtrate under reduced pressure to obtain the crude title compound 4b (6.4g). The product is directly processed without purification. Proceed to the next step of the reaction.

MS m/z(ESI):220.2[M+1].

Step 2

N-(3-bromo-2-fluoro-6-(hydroxymethyl)phenyl)propionamide 4c

Dissolve crude compound 4b (600 mg, 2.7 mmol) in tetrahydrofuran (10 mL), add propionyl chloride (504 mg, 5.4 mmol, Sinopharm), triethylamine (600 mg, 6 mmol), and 4-dimethylaminopyridine (79 mg, 641μmol), naturally return to room temperature and react for 14 hours. Add water to the reaction solution, extract with ethyl acetate (15mL×3), combine the organic phases, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, filter to remove the desiccant and the filtrate The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 4c (366 mg, yield: 48.6%).

MS m/z(ESI):276.2[M+1].

third step

N-(3-bromo-2-fluoro-6-formylphenyl)propionamide 4d

Dissolve oxalyl chloride (135 mg, 1.1 mmol) in dichloromethane (5 mL), add dimethyl sulfoxide (168 mg, 2.1 mmol) at -78°C, maintain the temperature and stir for 0.5 hours, then add compound 4c (211 mg, 764 μmol) dropwise. Dichloromethane (2mL) solution, react at -78°C for 1 hour, add triethylamine (310mg, 3.1μmol), naturally return to room temperature and react for 1 hour, add water to the reaction solution, and extract with dichloromethane (5mL×3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain crude title compound 4d (220 mg). The product was directly subjected to the next reaction without purification.

MS m/z(ESI):274.2[M+1].

the fourth step

7-Bromo-8-fluoro-3-methylquinolin-2(1H)-one 4e

Compound 4d (220 mg, 802 μmol) was dissolved in N,N-dimethylacetamide (10 mL), cesium carbonate (1.32 g, 4.05 mmol) was added, the temperature was raised to 100°C, and the reaction was stirred for 3 hours. The reaction solution was cooled to room temperature and then filtered. , the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 4e (100 mg, yield: 48.6%).

MS m/z(ESI):255.2[M+1].

the fifth step

Using the second to fourth steps of the synthetic route in Example 2, replacing the raw material compound 2a in the second step with compound 4e, the title compound 4 (10 mg, yield: 31.2%) was obtained.

MS m/z(ESI):452.2[M+1].

¹ H NMR (500MHz, CD ₃ OD): δ7.93(d,1H),7.84(t,1H),7.48(d,1H),7.42(d,1H),7.31(dd,1H),4.99- 4.90(m,2H),4.01(dd,1H),3.85(dd,1H),3.80(d,2H),3.41(dp,3H),2.95(s,3H),2.87-2.80(m,1H) ,2.76-2.70(m,1H),2.65-2.53(m,2H),2.23(d,3H).

biological evaluation

The present disclosure will be further described and explained below in conjunction with test examples, but these test examples are not meant to limit the scope of the present disclosure.

Test example 1, cell proliferation experiment

The following method evaluates the inhibitory effect of the disclosed compounds on the proliferation of DLD1 cells, DLD1 ^BRCA2-/- and MDA-MB-436 cells by detecting intracellular ATP content and based on the IC ₅₀ size. The experimental method is briefly described as follows:

1. Experimental materials and instruments

1. DLD1, human colon cancer tumor cells (Nanjing Kebai, CBP60037)

2. DLD1 ^BRCA2-/- , human BRCA2 gene knockout colon cancer tumor cells (Creative biogene, CSC-RT0015)

3. MDA-MB-436, human breast cancer cells (ATCC, HTB-130)

4. Fetal bovine serum (GIBCO, 10091-148)

5. CellTite-Glo reagent (Promega, G7573)

6. 96-well cell culture plate (corning, 3903)

7. Trypsin (invitrogen, 25200-072)

8. Microplate reader (BMG, PHERAsta)

9. Cell counter (Shanghai Ruiyu Biotechnology Co., Ltd., IC1000)

2. Experimental steps

DLD1 cells were cultured in RPMI-1640 medium containing 10% FBS and passaged 2 to 3 times a week with a passage ratio of 1:6 or 1:8. During passage, trypsinize the cells and transfer them to a centrifuge tube, centrifuge at 1200 rpm for 3 minutes, discard the supernatant medium residue, and add fresh medium to resuspend the cells. Add 180 μL of cell suspension to the 96-well cell culture plate at a density of 2.78 × 10 ³ cells/mL. Only 180 μL of complete culture medium is added to the periphery of the 96-well plate.

DLD1 ^BRCA2-/- cells were cultured in RPMI-1640 medium containing 10% FBS and passaged 2 to 3 times a week with a passage ratio of 1:6 or 1:8. During passage, trypsinize the cells and transfer them to a centrifuge tube, centrifuge at 1200 rpm for 3 minutes, discard the supernatant medium residue, and add fresh medium to resuspend the cells. Add 180 μL of cell suspension to the 96-well cell culture plate with a density of 8.34×10 ³ cells/mL. Only 180 μL of complete culture medium is added to the periphery of the 96-well plate.

MDA-MB-436 cells were cultured in Leibovitz's L-15 medium containing 10% FBS, 10 μg/mL insulin, and 16 μg/mL glutathione, and were passaged 2 to 3 times a week, with a passage ratio of 1:3 or 1: 5. During passage, trypsinize the cells and transfer them to a centrifuge tube, centrifuge at 1200 rpm for 3 minutes, discard the supernatant medium residue, and add fresh medium to resuspend the cells. Add 180 μL of cell suspension to the 96-well cell culture plate with a density of 8.34×10 ³ cells/mL. Only 180 μL of complete culture medium is added to the periphery of the 96-well plate.

The culture plates were incubated in an incubator for 24 hours (37°C, 5% _CO2 ).

Dilute the sample to be tested with DMSO to 2mM, and dilute it 3 times to 10 concentrations, and set blank and control wells. Take 5 μL of the solution of the compound to be tested prepared with a gradient concentration and add it to 95 μL of fresh culture medium. Then add 20 μL of the above drug-containing culture medium solution to the culture plate. The culture plates were incubated for 6 days in an incubator (37°C, 5% _CO2 ). In a 96-well cell culture plate, add 90 μL CellTiter-Glo reagent to each well and place it at room temperature in the dark for 5-10 minutes. Read the chemiluminescence signal value in PHERAstar. The data is processed using GraphPad software. The results are shown in Table 1.

Table 1 Inhibitory effects of the disclosed compounds on the proliferation of DLD1, DLD1 ^BRCA2-/- and MDA-MB-436 cells

Conclusion: The disclosed compound has a good inhibitory effect on the proliferation of DLD1 ^BRCA2-/- and MDA-MB-436 cells.

Test Example 2. Determination of binding activity of compounds of the present disclosure to PARP1 and PARP2

In vitro PARP1 and PARP2 binding activities were tested by the following methods.

1. Experimental materials and instruments

1. PARP1 recombinant protein (Yiqiao Shenzhou, product number 11040-H08B);

2. PARP2 recombinant protein (BPS, Cat. No. 80502)

3. Fluorescent probe (self-made using compound with CAS number 1380359-84-1, Shanghai Hengrui);

4. 384-well plate (Corning, 3575)

5. Microplate reader PHERAstar FS (BMG Labtech)

2. Experimental steps

Add 8 μL of binding buffer to each well of the 384-well plate; dissolve the fluorescent probe in dimethyl sulfoxide, dilute to the corresponding concentration, and then dilute the fluorescent probe prepared with dimethyl sulfoxide 20 times in the binding buffer (50mM Tris-HCl pH 8.0, 50mM NaCl, 1mM MgCl ₂ , 0.1mM EDTA, 0.01% IGEPAL), add 2 μL to each well; dissolve the test compound in dimethyl sulfoxide, and dilute to each concentration gradient according to experimental needs, and then Dilute the compounds of each concentration prepared with dimethyl sulfoxide 20 times into the binding buffer, and add 2 μL to each well; dilute the PARP1 or PARP2 protein to the corresponding concentration with the binding buffer, add 8 μL/well to a black 384-well plate, and mix After homogenization, incubate at 25°C for 40 minutes. Read the signal value using the FP program in the microplate reader PHERAstar FS. Data were processed using GraphPad software.

The PARP1 and PARP2 binding inhibitory activities of the disclosed compounds were measured through the above tests, and the measured IC ₅₀ values are shown in Table 2.

Table 2 The binding inhibitory activity of the disclosed compounds on PARP1 and PARP2

Conclusion: The disclosed compounds have selective inhibitory effects on PARP1.

Test Example 3 PARP1 enzyme activity measurement experiment

The following in vitro screening assay is used to determine the inhibitory effect of compounds of the present disclosure on PARP1 enzymatic activity.

The experiments described below were used to determine the inhibitory effect of the disclosed compounds on PARP1 enzyme activity by using a PARP1 Chemiluminescent Assay Kit (BPS, 80551, Lot #211124-K). The key to the PARP1 chemiluminescence detection kit is the use of biotinylated NAD+. By measuring the intensity of the chemiluminescence signal, the level of NAD ⁺ in the reaction system can be known, thereby calculating the degree of inhibition of PARP1 enzyme activity by the test compound.

For the detailed operation of the experiment and the preparation of the reagents used, such as Histone mixture, Master mixture, Assay buffer and ELISA ECL Substrate, etc., please refer to PARP1 Chemiluminescence test kit instructions.

The experimental steps are briefly described as follows: Coat a 96-well flat-bottomed plate with Histone mixture and incubate at 4 overnight. Block with blocking buffer 3 at room temperature for 90 minutes. Add 20 μl of 2ng/μl PARP1 enzyme to each well of the well plate, and add 25 μl of Master mixture to each well. Test compounds were dissolved in dimethyl sulfoxide, then diluted with buffer to the concentration required for the experiment, and 5 μl was added to each well of the well plate. After mixing, incubate at room temperature for 1 hour, then add streptavidin-labeled horseradish peroxidase and incubate at room temperature for 30 minutes. Finally, a 1:1 mixture of ECL Substrate A and ECL Substrate B was added, and the chemiluminescence signal was detected using PHERAstar. The data was processed with GraphPad software to calculate the inhibitory rate of the compound on PARP1 enzyme activity.

The IC ₅₀ value of a compound can be calculated from the inhibition rate at different concentrations.

Conclusion: The disclosed compounds have significant inhibitory activity on the proliferation of PARP1 kinase.

Claims

A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

in:

Y is O or NR 5 ;

R 5 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group;

G 3 is CR 6 or N;

R 0 , R 1a , R 1b , R 1c and R 6 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, cyano group, -NR 7a R 7b , hydroxyl group, -C(O)R 8a , -C(O)OR 8a , -C(O)NR 7a R 7b , -S(O) p R 8a , cycloalkyl group, heterocyclyl group , aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of halogen, oxo, alkyl, Substituted by one or more substituents of alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl ;

Each R 2 and R 4 are the same or different, and are each independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, -NR 7c R 7d , hydroxyl, hydroxyalkyl , cycloalkyl, heterocyclyl, aryl and heteroaryl;

Each R 3 is the same or different, and each is independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7e R 7f , hydroxyl, -C(O)R 8b , -C(O)OR 8b , -C(O)NR 7e R 7f , -S(O) q R 8b , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl group , alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -Substituted with one or more substituents of -NR 9c R 9d , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 9a , R 9b , R 9c and R 9d are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a ring Alkyl and heterocyclyl, wherein each of the alkyl, cycloalkyl and heterocyclyl is independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl and haloalkoxy Substituted by a substituent; or

R 7a and R 7b together with the attached nitrogen atom form a heterocyclyl group, or R 7c and R 7d together with the attached nitrogen atom form a heterocyclyl group, or R 7e and R 7f together with the attached nitrogen atom form a heterocyclyl group, Either R 9a and R 9b together with the connected nitrogen atom form a heterocyclyl group, or R 9c and R 9d together with the connected nitrogen atom form a heterocyclyl group, and the formed heterocyclic group is optionally selected from halogen, oxo in radical, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents;

R 8a and R 8b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group, wherein the alkyl group, cycloalkyl group and heterocyclyl group are each independently selected Optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

p is 0, 1 or 2;

q is 0, 1 or 2;

s is 0, 1, 2, 3 or 4;

t is 0, 1, 2 or 3; and

v is 0, 1, 2, 3 or 4.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Y is O.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 3 is -C(O)NR 7e R 7f , wherein R 7e and R 7f are as claimed in claim 1 defined in.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 1b is a hydrogen atom; and/or R 1c is a hydrogen atom.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein s is 0; and/or v is 0.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which is a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof :

in:

G 3 , R 0 , R 1a , R 7e and R 7f are as defined in claim 1 .
The compound represented by general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein G3 is CH or N.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 0 is a hydrogen atom or halogen.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 1a is a C 1-6 alkyl group.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 7e is a hydrogen atom or a C 1-6 alkyl group; and/or R 7f is Hydrogen atom or C 1-6 alkyl group.
The compound represented by general formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, which is selected from any of the following compounds:
A compound represented by general formula (Ia) or a salt thereof:

in:

Y, R2 , R3 , R4 , s, v and t are as defined in claim 1.
The compound represented by the general formula (Ia) according to claim 12 or a salt thereof, which is selected from:
A method for preparing the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, the method comprising:

A nucleophilic substitution reaction occurs between a compound of general formula (Ia) or a salt thereof (preferably a hydrochloride) and a compound of general formula (Ib) or a salt thereof, to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen, preferably a chlorine atom;

Y, G 3 , R 0 , R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , s, v and t are as defined in claim 1 .
A pharmaceutical composition containing a compound represented by general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical Acceptable carriers, diluents or excipients.
Use of the compound represented by general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 15 in the preparation of a PARP1 inhibitor.
The compound represented by the general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 15 is used for the treatment and/or prevention of cancer. uses in medicines.
The use according to claim 17, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, cervical cancer, endometrial cancer, bone marrow Tumor, leukemia, lymphoma, acoustic neuroma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, bronchial carcinoma, sarcoma, chordoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, vascular endothelial cell tumour, ependymoma, epithelial cancer, esophageal cancer, essential thrombocythemia, Ewing's tumor, testicular cancer, glioma, heavy chain disease, hemangioblastoma, medullary carcinoma, medulloblastoma, melanoma Tumor, meningioma, mesothelioma, neuroblastoma, NUT midline cancer, glioma, bone cancer, nasopharyngeal cancer, oral cancer, thyroid cancer, pineal tumor, polycythemia vera, retinoblastoma , sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, Waldenström macroglobulinemia and Wilms'tumor; preferably, the cancer is selected from the group consisting of breast cancer cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, colorectal cancer, and lung cancer.