Condensed bicyclic compound, preparation method thereof and application of fused bicyclic compound in medicine

Abstract

The invention relates to a fused bicyclic compound, a preparation method thereof and application of the fused bicyclic compound in medicine. Specifically, the invention relates to a fused bicyclic compound as shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a therapeutic agent, especially application of the compound as a PARP1 inhibitor and application of the compound in treatment and / or prevention of cancers. # imgabs0 #

Description

Condensed bicyclic compound, preparation method thereof and application thereof in medicine Technical Field

[0001] The present disclosure relates to the field of medicine and relates to a fused bicyclic compound, a method for preparing the same, and its use in medicine. In particular, the present disclosure relates to a fused bicyclic compound represented by general formula (I), a method for preparing the same, a pharmaceutical composition containing the same, and its use as a PARP1 inhibitor and for treating and / or preventing cancer. Background Art

[0002] Poly(ADP-ribose) polymerase 1 (PARP1) was first described over 50 years ago and has since been found to play a crucial role in DNA repair, maintaining genomic integrity, and regulating various metabolic and signal transduction processes. PARP1 catalyzes the transfer of an ADP-ribose residue from NAD+ to its target substrate, forming a poly(ADP-ribose) (PAR) chain. PAR chain formation and clearance occurs in nearly all eukaryotic cells.

[0003] ADP-ribosylation is a post-translational modification of proteins that is widely present in various physiological and pathological processes. It refers to the incorporation of one or more ADP-ribose units into specific sites on proteins under the catalysis of an enzyme. PARP1 is the first member of the PARP superfamily, which consists of proteins with homology to PARP1. There are currently 17 members of the superfamily, of which four (PARP1, PARP2, PARP5A, and PARP5B) are capable of synthesizing PAR chains. Most other enzymes in the family can only construct a single ADP-ribose unit and are therefore classified as mono(ADP-ribosyl)ases (MARs).

[0004] PARP1 and PARP2 have been extensively studied for their roles in DNA damage repair. PARP1 is activated by DNA damage and acts to catalyze the attachment of poly(ADP-ribose) (PAR) chains to target proteins. This post-translational modification, called poly-ADP-ribosylation (PARylation), mediates the recruitment of other DNA repair factors to DNA damage. Once this recruitment mission is completed, PARP autoPARylation triggers the release of bound PARP from DNA, allowing access to other DNA repair proteins to complete the repair. Therefore, the binding of PARP to damaged sites, its catalytic activity, and ultimately its release from DNA are all important steps in the response of cancer cells to DNA damage caused by chemotherapeutic agents and radiation therapy.

[0005] Inhibition of the PARP family of enzymes has been used as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Numerous preclinical and clinical studies have shown that tumor cells harboring deleterious alterations in BRCA1 or BRCA2, key tumor suppressor proteins involved in the repair of double-stranded DNA breaks (DSBs) through deleterious recombination (HR), are selectively sensitive to small molecule inhibitors of the PARP family of DNA repair enzymes. These tumors have deficient homologous recombination repair (HRR) pathways and rely on the PARP enzymes for their survival function. Although PARP inhibitor therapy is primarily targeted at BRCA-mutated cancers, PARP inhibitors have been clinically tested in non-BRCA-mutated tumors that exhibit homologous recombination deficiency (HRD).

[0006] PARP inhibitors with enhanced selectivity for PARP1 may have improved efficacy and reduced toxicity compared to other PARP1 / 2 inhibitors. We believe that selective and potent inhibition of PARP1 will lead to PARP1 trapping on DNA, causing DNA double-strand breaks (DSBs) by collapsing replication forks during S phase. PARP1-DNA trapping is an effective mechanism for selectively killing tumor cells with HRD.

[0007] Therefore, effective and safe PARP inhibitors are urgently needed clinically, especially PARP inhibitors that are selective for PARP1.

[0008] The patent applications for PARP inhibitors that have been disclosed include WO2021013735A1, WO2009053373A1, WO2008107478A1, WO2021260092A1, etc.

[0009] Summary of the Invention

[0010] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0011] in:

[0012] Ring A is a heteroaryl group;

[0013] Ring B is aryl or heteroaryl;

[0014] G 2 CR 6a or nitrogen atoms;

[0015] G 3 CR 6b or nitrogen atoms;

[0016] R 0 、R 1a 、R 6a and R 6b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b , hydroxyl, -C(O)R 8a 、-C(O)OR 8a 、-C(O)NR 7a R 7b 、-S(O) p R 8a , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0017] Each R 2 are the same or different and are each independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 7c R 7d , hydroxyl and hydroxyalkyl;

[0018] Each R 3 are the same or different and are each 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, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9c R 9d , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0019] 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 hydrogen, alkyl, hydroxyalkyl, cycloalkyl and heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy; or

[0020] R 7a and R 7b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, or R 7c and R 7d Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, or R 7e and R 7f Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, or R 9a and R 9b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, or R 9c and R 9d Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the formed heterocyclic group is optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0021] R 8a and R 8b are the same or different and are each independently selected from hydrogen, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally substituted with one or more substituents selected from halogen, an alkyl group, an alkoxy group, a haloalkyl group and a haloalkoxy group;

[0022] p is 0, 1, or 2;

[0023] q is 0, 1, or 2;

[0024] m is 0, 1, or 2;

[0025] n is 0, 1, or 2;

[0026] s is 0, 1, 2, 3, or 4; and

[0027] t is 0, 1, 2, or 3.

[0028] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered or 6-membered heteroaryl group containing at least one nitrogen atom; in some embodiments, ring A is selected from pyrazolyl, thienyl and imidazolyl; in some embodiments, ring A is pyrazolyl.

[0029] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from Preferably, for More preferably, for Among them, R 2a Selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 7c R 7d , hydroxyl and hydroxyalkyl, R 7c 、R 7d , m and n are as defined in the general formula (I).

[0030] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2; preferably, m is 1.

[0031] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably, ring B is a phenyl group or a 6-membered heteroaryl group; more preferably, ring B is a pyridyl group.

[0032] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein G 2 CR 6a , R 6a As defined in general formula (I).

[0033] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein G 3 CR 6b , R 6b As defined in general formula (I).

[0034] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein G 2 CR 6a , R 6a As defined in formula (I); and / or G 3 CR 6b , R 6b As defined in general formula (I).

[0035] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein s is 0 or 1; preferably, s is 0.

[0036] 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:

[0037] in:

[0038] X and Y are the same or different and are each independently a nitrogen atom or CR 2a ;

[0039] R 2a Selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 7c R 7d , hydroxyl and hydroxyalkyl;

[0040] R 0 、R 1a 、R 6a 、R 6b 、R 7c 、R 7d 、R 3 , n and t are as defined in the general formula (I).

[0041] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof, wherein each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, 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 , R 8b 、R7e and R 7f As defined in general formula (I); preferably, R 3 -C(O)NR 7e R 7f , R 7e and R 7f As defined in general formula (I); more preferably, R 3 It is -C(O)NHCH3.

[0042] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 6a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; preferably, R 6a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 More preferably, R 6a A hydrogen atom.

[0043] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 6b Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; preferably, R 6b Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 More preferably, R 6b A hydrogen atom.

[0044] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 6a is a hydrogen atom; and / or R 6b A hydrogen atom.

[0045] In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein t is 1 or 2; preferably 1.

[0046] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:

[0047] in:

[0048] X and Y are the same or different and are each independently a nitrogen atom or CR 2a ;

[0049] R 2a Selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 7c R 7d , hydroxyl and hydroxyalkyl;

[0050] R 0 、R 1a 、R 7c 、R 7d 、R 7e 、R 7f and n are as defined in the general formula (I).

[0051] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2; preferably, n is 1.

[0052] In some embodiments of the present disclosure, in the compound represented by formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, X is a nitrogen atom.

[0053] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (III) or a pharmaceutically acceptable salt thereof, wherein Y is CR 2a , R 2a As defined in formula (II); preferably, Y is CH.

[0054] In some embodiments of the present disclosure, the compound represented by formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein X is a nitrogen atom; and / or Y is CH.

[0055] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 2 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; preferably, each R 2 The same or different, and each independently selected from C 1-6 Alkyl and C 1-6 Hydroxyalkyl.

[0056] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2a Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; preferably, R 2a Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Hydroxyalkyl; preferably, R 2a A hydrogen atom.

[0057] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 0 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 preferably, R 0 is a hydrogen atom or a halogen; more preferably, R 0 is halogen; most preferably, R 0 For F.

[0058] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 1a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; preferably, R 1a C 1-6 Alkyl; More preferably, R 1a It is a methyl group.

[0059] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 7e and R 7f are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, C 1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group; preferably, R 7e and R 7f The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; More preferably, R 7e and R 7f are the same or different and are each independently a hydrogen atom or a methyl group.

[0060] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (III) or a pharmaceutically acceptable salt thereof, wherein for Preferably, for Among them, R 2a and n are as defined in general formula (II).

[0061] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, R 0 is a hydrogen atom or a halogen; R 1a C 1-6 Alkyl; R 6a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 6b Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; n is 1; X is a nitrogen atom; Y is CR 2a , R 2a Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Hydroxyalkyl; t is 1; R 3 -C(O)NR 7e R 7f , and R 7e and R 7f The same or different, and each independently a hydrogen atom or a C 1-6 alkyl.

[0062] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, R 0 is halogen; R 1a C 1-6 alkyl; n is 1; X is a nitrogen atom; Y is CH; and R 7e and R 7f The same or different, and each independently a hydrogen atom or a C 1-6 alkyl.

[0063] Table A Typical compounds of the present disclosure include, but are not limited to:

[0064] Another aspect of the present disclosure relates to a compound represented by general formula (IIa) or a salt thereof:

[0065] in:

[0066] R 3 -C(O)NR 7eR 7f ;

[0067] t is 1, 2, or 3;

[0068] X, Y, R 7e 、R 7f and n are as defined in general formula (II).

[0069] Another aspect of the present disclosure relates to a compound represented by general formula (IIIa) or a salt thereof:

[0070] in:

[0071] X, Y, R 7e 、R 7f and n are as defined in general formula (III).

[0072] Table B Typical intermediate compounds disclosed herein include, but are not limited to:

[0073] 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:

[0074] A compound of general formula (Ia) or a salt thereof (preferably hydrochloride) undergoes a nucleophilic substitution reaction with a compound of general formula (Ib) to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof;

[0075] in:

[0076] L is halogen, preferably Br;

[0077] G 2 , G 3 , Ring A, Ring B, R 0 、R 1a 、R 2 、R 3 , s, t, m and n are as defined in the general formula (I).

[0078] 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:

[0079] A compound of general formula (IIa) or a salt thereof (preferably hydrochloride) undergoes a nucleophilic substitution reaction with a compound of general formula (IIb) to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof;

[0080] in:

[0081] L is halogen, preferably Br;

[0082] X, Y, R 0 、R 1a 、R 3 、R 6a 、R 6b , t and n are as defined in the general formula (II).

[0083] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0084] A compound of formula (IIIa) or a salt thereof (preferably hydrochloride) undergoes a nucleophilic substitution reaction with a compound of formula (IIIb) to obtain a compound of formula (III) or a pharmaceutically acceptable salt thereof;

[0085] in:

[0086] L is halogen, preferably Br;

[0087] X, Y, R 0 、R 1a 、R 7e 、R 7f and n are as defined in general formula (III).

[0088] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of Formula (I), Formula (II) or Formula (III) and Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0089] The present disclosure further relates to the use of compounds represented by formula (I), formula (II) or formula (III) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of PARP1 inhibitors.

[0090] The present disclosure further relates to the use of compounds represented by formula (I), formula (II) or formula (III) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and / or preventing diseases or conditions mediated by PARP1.

[0091] The present disclosure further relates to the use of compounds represented by formula (I), formula (II) or formula (III) and shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and / or preventing cancer, essential thrombocythemia or polycythemia vera.

[0092] The present disclosure further relates to a method for inhibiting PARP1, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II) or formula (III) and shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0093] The present disclosure further relates to a method for treating and / or preventing diseases or conditions mediated by PARP1, comprising administering to a patient in need thereof an inhibitory effective amount of a compound of formula (I), formula (II) or formula (III) and shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0094] The present disclosure further relates to a method for treating and / or preventing cancer, essential thrombocythemia, or polycythemia vera, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), or formula (III) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0095] The present disclosure further relates to a compound represented by formula (I), formula (II) or formula (III) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0096] The present disclosure further relates to a compound represented by formula (I), formula (II) or formula (III) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a PARP1 inhibitor.

[0097] The present disclosure further relates to a compound of formula (I), formula (II) or formula (III) and shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for treating and / or preventing diseases or conditions mediated by PARP1.

[0098] The present disclosure further relates to a compound of formula (I), formula (II) or formula (III) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for treating and / or preventing cancer, essential thrombocythemia or polycythemia vera.

[0099] Preferably, the disease or disorder mediated by PARP1 according to the present disclosure is cancer.

[0100] Preferably, the cancer of 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, myeloid 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, bile duct cancer, bladder cancer, brain cancer, bronchial cancer, sarcoma (such as chondrosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, myxosarcoma, osteoblastic sarcoma, Rhabdomyosarcoma, Ewing's tumor), chordoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, hemangioendothelioma, ependymoma, epithelial carcinoma, esophageal cancer (also known as esophageal cancer), testicular cancer, glioma, heavy chain disease, hemangioblastoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, neuroblastoma, NUT midline cancer, glioma, bone cancer, nasopharyngeal cancer, oral cancer, thyroid cancer, pinealoma, retinoblastoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, Waldenstrom's macroglobulinemia and Wilms' tumor; the sarcoma is preferably Ewing's tumor; preferably, the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer and lung cancer.

[0101] Preferably, the cancer cells of the cancer described in the present disclosure are BRCA1 or BRCA2 deficient, preferably BRCA2 deficient.

[0102] Preferably, the cancer cells of the cancers described in the present disclosure are deficient in BRCA1 or BRCA2, preferably deficient in BRCA2.

[0103] The active compound can be formulated into a form suitable for administration by any appropriate route, and the compositions of the present disclosure can be formulated using one or more pharmaceutically acceptable carriers by conventional methods. Thus, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous), inhalation or insufflation. The compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

[0104] As a general guide, the active compound is preferably in a unit dosage form, or in a form that a patient can self-administer as a single dose. A unit dosage form of a compound or composition of the present disclosure may be a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation. Suitable unit dosage forms may range from 0.1 to 1000 mg.

[0105] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0106] Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients, granulating agents, disintegrants, binders, and lubricants. Tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period of time.

[0107] Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.

[0108] Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, dispersing agents, 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.

[0109] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding antioxidants.

[0110] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavorings, preservatives, and antioxidants. Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.

[0111] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. The injectable solution or microemulsion may be administered into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous pump.

[0112] Pharmaceutical compositions of the present disclosure may be in the form of sterile water for injection or oil suspensions for intramuscular and subcutaneous administration. The suspensions may be prepared using suitable dispersants or wetting agents and suspending agents as described above according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral, nontoxic diluents or solvents. In addition, sterile fixed oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixed oil may be used. In addition, fatty acids may also be used to prepare injections.

[0113] The disclosed compounds can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0114] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by adding water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0115] 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 following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0116] Terminology

[0117] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0118] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 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 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Non-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-dimethylpentyl, 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 chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available attachment point. The substituent is preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0119] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 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 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylene can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. The substituents are preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0120] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, etc. Alkenyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0121] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0122] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment, with the substituent preferably being selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0123] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., a monocyclic cycloalkyl) or a polycyclic ring system (i.e., a 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., a 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), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered cycloalkyl group), and most preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3- to 6-membered cycloalkyl group).

[0124] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

[0125] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0126] The term "spiroalkyl" refers to a polycyclic ring system having a common carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds within the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized to form nitrogen oxides; the sulfur may be optionally oxoed to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroalkyl). The spiroalkyl preferably has 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroalkyl), and more preferably has 7 to 10 ring atoms (i.e., a 7- to 10-membered spiroalkyl). The spirocycloalkyl group includes a monospirocycloalkyl group and a polyspirocycloalkyl group (such as a bispirocycloalkyl group, etc.), preferably a monospirocycloalkyl group or a bispirocycloalkyl group, more preferably a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospirocycloalkyl group. Non-limiting examples include:

[0127] Its connection point can be at any position;

[0128] wait.

[0129] The term "fused cycloalkyl" refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls, or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused cycloalkyl). The fused cycloalkyl is preferably a fused cycloalkyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused cycloalkyl), more preferably a fused cycloalkyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered fused cycloalkyl). The fused cycloalkyl group includes bicyclic fused cycloalkyl groups and polycyclic fused cycloalkyl groups (such as tricyclic fused cycloalkyl groups, tetracyclic fused cycloalkyl groups, etc.), preferably bicyclic fused cycloalkyl groups or tricyclic fused cycloalkyl groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused cycloalkyl groups. Non-limiting examples include: , whose connection points can be at any position; wait.

[0130] The term "bridged cycloalkyl" refers to a full carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., a 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., a 6 to 14-membered bridged cycloalkyl), more preferably a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., a 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0131] Its connection point can be at any position.

[0132] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0133] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) containing at least one (e.g., 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 oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-) in the ring, 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., a 3- to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group); and most preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group).

[0134] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0135] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0136] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl). The spiro heterocyclic radical preferably has a spiro heterocyclic radical (i.e., a 6 to 14 yuan spiro heterocyclic radical) of 6 to 14 ring atoms, more preferably a spiro heterocyclic radical (i.e., a 7 to 10 yuan spiro heterocyclic radical) with 7 to 10 ring atoms. The spiro heterocyclic radical includes monospiro heterocyclic radical and polyspiro heterocyclic radical (such as dispiro heterocyclic radical etc.), preferably monospiro heterocyclic radical or dispiro heterocyclic radical, 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 yuan / 6 yuan monospiro heterocyclic radical. Non-limiting examples include:

[0137] wait.

[0138] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclyl). The fused heterocyclic radical preferably has a fused heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic radical), more preferably a fused heterocyclic radical of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic radical). The fused heterocyclic radical includes bicyclic and polycyclic fused heterocyclic radicals (such as tricyclic fused heterocyclic radicals, tetracyclic fused heterocyclic radicals, etc.), preferably bicyclic fused heterocyclic radicals or tricyclic fused heterocyclic radicals, 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 yuan / 6 yuan bicyclic fused heterocyclic radicals. Non-limiting examples include:

[0139] wait.

[0140] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclic group). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group). According to the number of constituent rings, heterocyclic groups can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0141] wait.

[0142] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclic group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.

[0143] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., a polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., a 6- to 14-membered aromatic group). The aryl group is preferably an aromatic group having 6 to 10 ring atoms (i.e., a 6- to 10-membered aromatic group). The monocyclic aromatic group is, for example, a phenyl group. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc. The polycyclic aromatic group also includes a phenyl group fused with one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused with one or more heterocyclic groups or cycloalkyl groups, wherein the connection point is on the phenyl group or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:

[0144] wait.

[0145] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0146] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl). The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl), more preferably a heteroaryl having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl).

[0147] The monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

[0148] The polycyclic heteroaryl groups include, but are not limited to, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more aromatic groups, wherein the point of attachment is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more cycloalkyl or heterocyclic groups, wherein the point of attachment is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

[0149] wait.

[0150] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0151] The term "amino protecting group" refers to a group that is easily removed and introduced onto an amino group in order to keep the amino group unchanged while reacting other parts of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, and the like.

[0152] The term "hydroxy protecting group" refers to a group that is easily removed and is introduced on a hydroxy group to block or protect the hydroxy group while reacting on other functional groups of the compound. Non-limiting examples include trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0153] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0154] The term "heterocyclyloxy" refers to a heterocyclyl-O- group in which heterocyclyl is as defined above.

[0155] The term "aryloxy" refers to an aryl-O- group in which the aryl group is as defined above.

[0156] The term "heteroaryloxy" refers to a heteroaryl-O- group in which heteroaryl is as defined above.

[0157] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0158] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0159] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0160] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0161] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0162] The term "methylidene" refers to =CH2.

[0163] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0164] The term "hydroxy" refers to -OH.

[0165] The term "mercapto" refers to -SH.

[0166] The term "amino" refers to -NH2.

[0167] The term "cyano" refers to -CN.

[0168] The term "nitro" refers to -NO2.

[0169] The term "oxo" or "oxo" refers to "=0".

[0170] The term "carbonyl" refers to C=O.

[0171] The term "carboxy" refers to -C(O)OH.

[0172] 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.

[0173] The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers having identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0174] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

[0175] 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 easily converted from one isomeric form to another. It includes all possible tautomers, that is, in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. An example of a lactam-lactim equilibrium is shown below:

[0176] For example, when referring to pyrazolyl, it is understood to include either of the following two structures or a mixture of two tautomers:

[0177] All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

[0178] 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 having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium, D), 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.

[0179] Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0180] Compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D," are understood to have an abundance of deuterium at that position 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 for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

[0181] "Optional" or "optionally" means that the event or circumstances described subsequently may but need not occur, and includes both situations in which the event or circumstances occur and do not occur. For example, "alkyl optionally (optionally) substituted with halogen or cyano" includes both situations in which the alkyl is substituted with halogen or cyano and situations in which the alkyl is not substituted with halogen and cyano.

[0182] "Substitution" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. Those skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0183] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0184] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0185] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0186] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0187] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. They can be prepared during the final isolation and purification of the compound, or separately 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 and organic acids.

[0188] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" 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, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate therapeutically effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0189] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0190] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0191] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustrative purposes only and are not limiting.

[0192] Synthesis method of the disclosed compound

[0193] In order to achieve the purpose of this disclosure, the present disclosure adopts the following technical solutions:

[0194] Option 1

[0195] The present invention discloses a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0196] A compound of general formula (Ia) or a salt thereof (preferably a hydrochloride) undergoes a nucleophilic substitution reaction with a compound of general formula (Ib) under alkaline conditions, optionally in the presence of a catalyst, to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof;

[0197] in:

[0198] L is halogen, preferably Br;

[0199] G 2 , G 3 , Ring A, Ring B, R 0 、R 1a 、R 2 、R 3 , s, t, m and n are as defined in the general formula (I).

[0200] Option 2

[0201] The present invention discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0202] A compound of general formula (IIa) or a salt thereof (preferably a hydrochloride) undergoes a nucleophilic substitution reaction with a compound of general formula (IIb) under alkaline conditions, optionally in the presence of a catalyst, to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof;

[0203] in:

[0204] L is halogen, preferably Br;

[0205] X, Y, R 0 、R 1a 、R 3 、R 6a 、R 6b , t and n are as defined in the general formula (II).

[0206] Option 3

[0207] The present invention discloses a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0208] A compound of general formula (IIIa) or a salt thereof (preferably a hydrochloride) undergoes a nucleophilic substitution reaction with a compound of general formula (IIIb) under alkaline conditions, optionally in the presence of a catalyst, to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof;

[0209] in:

[0210] L is halogen, preferably Br;

[0211] X, Y, R 0 、R 1a 、R 7e 、R 7f and n are as defined in general formula (III).

[0212] The base providing alkaline conditions includes organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, 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.

[0213] The catalyst for the above nucleophilic substitution reaction is sodium iodide or potassium iodide, preferably sodium iodide.

[0214] The above reaction is preferably carried out in a solvent, and the solvent used includes but is 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 mixtures thereof. DETAILED DESCRIPTION

[0215] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0216] Example

[0217] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0218] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0219] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector)

[0220] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q Exactive)

[0221] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC1200VWD and Waters HPLC e2695-2489.

[0222] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0223] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0224] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0225] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0226] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0227] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0228] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0229] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0230] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0231] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0232] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0233] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0234] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0235] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0236] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0237] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0238] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, and D: dichloromethane / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0239] Example 1

[0240] 5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methyl-2-pyridinecarboxamide 1

[0241] first step

[0242] tert-Butyl 2-(6-(methoxycarbonyl)pyridin-3-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate 1c

[0243] Methyl 5-bromopyridine-2-carboxylate 1b (200 mg, 925.78 μmol, Shanghai Shaoyuan) and tert-butyl 2,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5(4H)-carboxylate 1a (290 mg, 1.38 mmol, Shanghai Bidex) were dissolved in 1,4-dioxane (5 mL). Cuprous iodide (35 mg, 183.77 μmol), (1S,2S)-(+)-1,2-cyclohexanediamine (21 mg, 183.90 μmol), and cesium carbonate (301 mg, 923.82 μmol) were added. Under nitrogen, the mixture was heated to 120°C and stirred for 14 hours. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System A to afford the title compound 1c (205 mg, 64.3% yield).

[0244] MS m / z(ESI):345.2[M+1].

[0245] Step 2

[0246] tert-Butyl 2-(6-(methylaminocarbonyl)pyridin-3-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate 1d

[0247] Compound 1c (200 mg, 580.8 μmol) was dissolved in 15 mL of 1 M methylamine ethanol solution and stirred for 48 hours. The reaction solution was concentrated under reduced pressure to give the crude title compound 1d (190 mg, yield: 95.2%), which was directly used for the next reaction without purification.

[0248] MS m / z(ESI):344.2[M+1].

[0249] Step 3

[0250] 5-(5,6-Dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methyl-2-pyridinecarboxamide hydrochloride 1e

[0251] The crude compound 1d (140 mg, 407.7 μmol) was dissolved in dichloromethane (2 mL), and 1 mL of 4 M hydrochloric acid in dioxane was added. The mixture was stirred for 0.5 h. The reaction solution was concentrated under reduced pressure to give the crude title compound 1e (110 mg, yield: 96.5%), which was used directly in the next step without purification.

[0252] MS m / z(ESI):244.2[M+1].

[0253] Step 4

[0254] 5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methyl-2-pyridinecarboxamide 1

[0255] The crude compound 1e (51 mg, 182 μmol), 7-(bromomethyl)-8-fluoro-3-methylquinoxaline-2(1H)-one 1f (50 mg, 184 μmol, prepared by the method disclosed in Intermediate 29 on page 14 of the specification of patent application "US20220009901A1"), N,N-diisopropylethylamine (119 mg, 920 μmol), and sodium iodide (5.5 mg, 36 μmol) were dissolved in acetonitrile (5 mL) and reacted at 80°C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL / min) to obtain the title compound 1 (15mg, yield: 18.7%).

[0256] MS m / z(ESI):434.2[M+1].

[0257] 1 H NMR (500MHz, DMSO-d6): δ9.06(s,1H),8.74(s,1H),8.38(d,1H),8.31(d,1H),8.09(d ,1H),7.53(d,1H),4.11(d,2H),3.84(s,2H),3.79(s,2H),2.82(t,3H),2.42(d,3H).

[0258] Example 2

[0259] 6-Fluoro-5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpyridine-2-carboxamide

[0260] first step

[0261] 6-amino-5-(5-(tert-butoxycarbonyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridine-2-carboxylic acid 2b

[0262] Compound 1a (271.7 mg, 1.3 mmol, Shanghai Shaoyuan) and methyl 5-bromo-6-aminopyridine-2-carboxylate 2a (200 mg, 865.6 μmol, Shanghai Bid) were dissolved in dimethyl sulfoxide (6 mL), and cuprous iodide (33 mg, 173.1 μmol), L-proline (20 mg, 173.1 μmol), and cesium carbonate (564 mg, 1.73 mmol) were added. The atmosphere was replaced with nitrogen and stirred in a microwave oven at 120°C for 2 hours. After the reaction solution was cooled to room temperature, it was filtered through diatomaceous earth and the filtrate was analyzed by high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: water (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-40%, flow rate: 30mL / min) to obtain the title compound 2b (50mg, yield: 16.7%).

[0263] MS m / z(ESI):344.4[M-1].

[0264] Step 2

[0265] 2-(2-amino-6-(methylcarbamoyl)pyridin-3-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid tert-

[0266] Butyl ester 2c

[0267] Compound 2b (20 mg, 57.9 μmol) was dissolved in 2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (37.4 mg, 289.5 μmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (33 mg, 86.9 μmol), and methylamine hydrochloride (5.9 mg, 86.8 μmol) were added under ice-cooling. The mixture was stirred at room temperature for 16 hours. Water was added to dilute the reaction solution, and the mixture was extracted with ethyl acetate (5 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to give the crude title compound 2c (20 mg).

[0268] MS m / z(ESI):359.2[M+1].

[0269] Step 3

[0270] 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-6-fluoro-N-methylpyridine-2-carboxamide 2d

[0271] The crude compound 2c (20 mg, 55.8 μmol) was dissolved in hydrogen fluoride pyridine complex (1 mL), and sodium nitrite (46.2 mg, 669.6 μmol) was added. After reacting for 1 hour, the reaction was quenched with water, and impurities were removed by extraction with dichloromethane (5 mL). The aqueous phase was filtered and purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 20%-35%, flow rate: 30 mL / min) to give the title compound 2d (14.5 mg, yield: 99%).

[0272] MS m / z(ESI):262.2[M+1].

[0273] Step 4

[0274] 6-Fluoro-5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpyridine-2-carboxamide

[0275] Compound 2d (14.5 mg, 55.5 μmol), compound 1f (15 mg, 55.5 μmol), N,N-diisopropylethylamine (36 mg, 277.5 μmol), and sodium iodide (2.1 mg, 13.8 μmol) were dissolved in acetonitrile (2 mL) and reacted at 80°C for 0.5 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 2 (2 mg, yield: 8%).

[0276] MS m / z(ESI):452.2[M+1].

[0277] 1 H NMR (500MHz, DMSO-d6): δ12.42(s,1H),8.70(d,1H),8.45(d,1H),8.09–8.04(m,2H),7.5 3(d,1H),7.36(s,1H),4.11(s,2H),3.85(s,2H),3.81(s,2H),2.82(d,3H),2.42(s,3H).

[0278] Example 3

[0279] 3-Fluoro-5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpyridine-2-carboxamide

[0280] The synthetic route in Example 1 was used to replace the first step raw material compound 1b with 5-bromo-3-fluoropyridine-2-carboxylic acid methyl ester (Nanjing Yaoshi) to obtain the title compound 3 (39 mg, yield: 17.3%).

[0281] MS m / z(ESI):452.2[M+1].

[0282] 1 H NMR (500MHz, DMSO-d6): δ12.48(s,1H),8.94(d,1H),8.62(d,1H),8.40(s,1H),8.23(dd,1H) ,7.54(d,1H),7.37(t,1H),4.11(s,2H),3.85(s,2H),3.81(s,2H),2.79(d,3H),2.43(s,3H).

[0283] Example 4

[0284] 5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-N-methylpyridine-2-carboxamide

[0285] first step

[0286] Methyl 3-(bromomethyl)thiophene-2-carboxylate 4b

[0287] Methyl 3-methylthiophene-2-carboxylate 4a (9.5 g, 60.8 mmol, Shanghai Bidex) and N-bromosuccinimide (11.9 g, 66.9 mmol) were dissolved in carbon tetrachloride (80 mL) and replaced with nitrogen. Azobisisobutyronitrile (2 g, 12.1 mmol) was added at 70°C and stirred for 3 hours. The reaction solution was cooled to room temperature and saturated sodium carbonate solution was added. The mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent C to give the title compound 4b (10.2 g, yield: 71.3%).

[0288] Step 2

[0289] Methyl 3-(aminomethyl)thiophene-2-carboxylate 4c

[0290] Compound 4b (11.5 g, 48.9 mmol) was dissolved in 7 M ammonia methanol solution (70 mL). The mixture was stirred for 2 hours and then concentrated under reduced pressure. Ether (50 mL) was added to the residue for slurrying. The mixture was filtered and the filter cake was washed with ether. After drying, the crude title compound 4c (6.6 g, yield: 78.8%) was obtained.

[0291] Step 3

[0292] 4,5-Dihydro-6H-thieno[2,3-c]pyrrol-6-one 4d

[0293] The crude compound 4c (6.6 g, 38.5 mmol) was dissolved in methanol (50 mL) and ethanol (50 mL), and potassium carbonate (6.4 g, 46.3 mmol) was added. The mixture was reacted at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). The mixture was washed with water and saturated sodium chloride solution in that order. The organic phase was collected and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to give the title compound 4d (1.3 g, yield: 25.1%).

[0294] MS m / z(ESI):140.2[M+1].

[0295] Step 4

[0296] 2-Bromo-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one 4e

[0297] Compound 4d (0.5 g, 3.6 mmol) was dissolved in water (7 mL) and acetic acid (9 mL), and bromine (632.3 mg, 4 mmol) was added dropwise under ice-bath. The reaction mixture was stirred and maintained at the temperature for 3 hours. Water was added to the reaction solution, and the mixture was neutralized with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to give the crude title compound 4e (800 mg). The product was used directly in the next reaction without purification.

[0298] MS m / z(ESI):217.9[M+1].

[0299] Step 5

[0300] tert-Butyl 2-bromo-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-carboxylate 4f

[0301] Crude compound 4e (1 g, 4.6 mmol), 4-dimethylaminopyridine (282.4 mg, 2.3 mmol), and triethylamine (1.4 g, 13.8 mmol) were mixed in dichloromethane (30 mL). Di-tert-butyl dicarbonate (2 g, 9.2 mmol) was added and stirred for 16 hours. The reaction solution was washed with saturated sodium bicarbonate solution. The organic phase was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent C to give the title compound 4f (1.2 g, yield: 82.2%). MS m / z (ESI): 262.1 [M-55].

[0302] Step 6

[0303] tert-Butyl 2-bromo-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-carboxylate 4g

[0304] Compound 4f (500 mg, 1.57 mmol) was dissolved in tetrahydrofuran (10 mL), and 1 M borane tetrahydrofuran complex (7.9 mL) was slowly added dropwise under a nitrogen atmosphere in an ice bath. After completion of the addition, the temperature was raised to 40°C and the reaction was allowed to react for 16 hours. The reaction solution was cooled to room temperature, and a small amount of methanol and water were added, followed by stirring at 70°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give 4 g of the title compound (300 mg, yield: 62.7%).

[0305] Step 7

[0306] tert-Butyl 2-(6-(methylcarbamoyl)pyridin-3-yl)-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-carboxylate 4i

[0307] Compound 4g (250 mg, 821.8 μmol), (6-(methylcarbamoyl)pyridin-3-yl)boronic acid 4h (177.5 mg, 986.2 μmol, Shanghai Bidex), potassium carbonate (226.8 mg, 1.6 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (120.3 mg, 164.4 μmol) were mixed in 1,4-dioxane (30 mL) and water (6 mL), replaced with nitrogen, and reacted at 90°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 4i (220 mg, yield: 74.4%).

[0308] MS m / z(ESI):360.2[M+1].

[0309] Step 8

[0310] 5-(5,6-Dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-N-methylpyridine-2-carboxamide hydrochloride 4j

[0311] Compound 4i (50 mg, 139.1 μmol) was dissolved in dichloromethane (3 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to give the crude title compound 4j (40 mg). The product was used directly in the next reaction without purification.

[0312] MS m / z(ESI):260.3[M+1].

[0313] Step 9

[0314] 5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-N-methylpyridine-2-carboxamide

[0315] The crude compound 4j (40 mg, 139 μmol), compound 1f (43.9 mg, 162 μmol), N,N-diisopropylethylamine (174.4 mg, 1.3 mmol), and sodium iodide (20.2 mg, 135 μmol) were dissolved in acetonitrile (5 mL) and reacted at 90°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 4 (20 mg, yield: 33%).

[0316] MS m / z(ESI):450.2[M+1].

[0317] 1 H NMR (500MHz, CDCl3): δ8.86(d,1H),8.73-8.70(m,1H),8.14-8.12(m,1H),8.01(d,1H),7.57(s,1H) ,7.53(d,1H),7.39-7.36(m,2H),4.03(s,2H),4.01(s,2H),3.88(s,2H),2.82(s,3H),2.42(m,3H).

[0318] Example 5

[0319] (±)-5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-6-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpyridine-2-carboxamide 5

[0320] first step

[0321] (±)-2-(6-(Methoxycarbonyl)pyridin-3-yl)-6-methyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid benzyl ester 5b

[0322] Compound 1b (100 mg, 462.9 μmol) and (±)-6-methyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid benzyl ester 5a (111 mg, 431.4 μmol) were prepared by the method of “Bioorganic and Medicinal Chemistry, 2018, vol. 26, #8, p. 2107-2150), cuprous iodide (18 mg, 94.5 μmol), potassium phosphate (197 mg, 928.1 μmol), and trans-N,N'-dimethyl-1,2-cyclohexanediamine (27 mg, 189.8 μmol, Shanghai Titan) were mixed in 1,4-dioxane (4 mL), replaced with nitrogen, and heated to 120°C with stirring for 16 hours. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System D to give the title compound 5b (racemate) (176 mg, yield: 96.8%).

[0323] MS m / z(ESI):393.2[M+1].

[0324] Step 2

[0325] (±)-6-Methyl-2-(6-(methylcarbamoyl)pyridin-3-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid benzyl ester 5c

[0326] Compound 5b (176 mg, 448.5 μmol) was dissolved in 30% ethanolic methylamine solution (1.5 mL) and stirred for 16 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent System D to give the title compound 5c (racemate) (188 mg, yield: 107%).

[0327] MS m / z(ESI):392.2[M+1].

[0328] Step 3

[0329] (±)-N-methyl-5-(6-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridine-2-carboxamide 5d

[0330] Compound 5c (188 mg, 480.3 μmol) was dissolved in dichloromethane (2 mL). A 33% solution of hydrogen bromide in acetic acid (3.5 g, 14.3 mmol) was added under a nitrogen atmosphere at 0°C. The mixture was stirred at the same temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. Chloroform was added to the residue to dissolve it. A small amount of N,N-diisopropylethylamine was added. After concentration under reduced pressure, the residue was purified by silica gel column chromatography using eluent system A to give the title compound 5d (racemate) (127 mg, yield: 102%).

[0331] MS m / z(ESI):258.2[M+1].

[0332] Step 4

[0333] (±)-5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-6-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpyridine-2-carboxamide 5

[0334] Compound 5d (45 mg, 174.9 μmol), compound 1f (48 mg, 177 μmol), N,N-diisopropylethylamine (45 mg, 348.1 μmol), and sodium iodide (5 mg, 22 μmol) were dissolved in acetonitrile (2 mL) and reacted at 80°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 5 (racemate) (25 mg, yield: 31.9%).

[0335] MS m / z(ESI):448.2[M+1].

[0336] 1 H NMR (500MHz, DMSO-d6): δ9.06(d,1H),8.73(q,1H),8.35(s,1H),8.32(dd,1H),8.10(d,1H),7.54(d,1H),7.36(t,1 H),4.22(d,1H),4.04–3.96(m,2H),3.88(d,1H),3.58(d,1H),3.38(d,1H),2.83(d,3H),2.42(s,3H),1.43(d,3H).

[0337] Example 6

[0338] 5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-N-methylpyridine-2-carboxamide

[0339] first step

[0340] 6-(Methylcarbamoyl)nicotinate methyl ester 6b

[0341] Dimethyl 2,5-pyridinedicarboxylate 6a (4 g, 20.5 mmol, Shanghai Titan) and anhydrous magnesium chloride (973.5 mg, 10.2 mmol) were dissolved in tetrahydrofuran (50 mL). After stirring for 30 minutes, 30% methylamine ethanol solution (3.2 g, 30.74 mmol) was slowly added dropwise. After the addition, the reaction was continued for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 6b (3.8 g). The product was used directly in the next step without purification.

[0342] MS m / z(ESI):195.2[M+1].

[0343] Step 2

[0344] 5-(Hydroxymethyl)-N-methylpyridine-2-carboxamide 6c

[0345] The crude compound 6b (4 g, 20.6 mmol) was dissolved in methanol (30 mL), and sodium borohydride (3.9 g, 103 mmol) was added. The reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to give the title compound 6c (1.6 g, yield: 48.4%).

[0346] MS m / z(ESI):167.2[M+1].

[0347] Step 3

[0348] 5-Formyl-N-methylpyridine-2-carboxamide 6d

[0349] Compound 6c (50 mg, 300.8 μmol) was dissolved in dichloromethane (3 mL), and manganese dioxide (523 mg, 6 mmol) was added. The mixture was stirred for 5 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound 6d (50 mg). The product was used directly in the next step without purification.

[0350] MS m / z(ESI):165.2[M+1].

[0351] Step 4

[0352] tert-Butyl 2-(6-(methylcarbamoyl)pyridin-3-yl)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate 6f

[0353] The crude compound 6d (50 mg, 304.6 μmol), (3R,4S)-rel-3,4-diaminopyrrolidine-1-carboxylic acid tert-butyl ester 6e (79.7 mg, 396 μmol, Shanghai Bidex), iodine (116 mg, 456.9 μmol), and potassium carbonate (126.1 mg, 913.7 μmol) were dissolved in tert-butanol (12 mL), replaced with nitrogen, and reacted at 70°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 6f (80 mg, yield: 76%).

[0354] MS m / z(ESI):346.4[M+1].

[0355] Step 5

[0356] tert-Butyl 2-(6-(methylcarbamoyl)pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate 6g

[0357] Oxalyl chloride (165.4 mg, 1.3 mmol) was dissolved in anhydrous dichloromethane (5 mL), and dimethyl sulfoxide (190 mg, 2.4 mmol) was added at -78°C. After stirring for 30 minutes, a dichloromethane solution (2 mL) of compound 6f (200 mg, 579 μmol) was added. Stirring was continued for 30 minutes, and triethylamine (584.8 mg, 5.8 mmol) was added. The reaction was returned to room temperature and stirred for 2 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 6g (80 mg, yield: 40.2%).

[0358] MS m / z(ESI):344.2[M+1].

[0359] Step 6

[0360] N-Methyl-5-(1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)pyridine-2-carboxamide hydrochloride 6h

[0361] Compound 6g (80 mg, 233 μmol) was dissolved in dichloromethane (4 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (4 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to give the crude title compound 6h (65 mg). The product was used directly in the next reaction without purification.

[0362] MS m / z(ESI):244.3[M+1].

[0363] Step 7

[0364] 5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-N-methylpyridine-2-carboxamide

[0365] The crude compound 6h (65 mg, 233 μmol), compound 1f (86.9 mg, 320 μmol), N,N-diisopropylethylamine (318.7 mg, 2.4 mmol), and sodium iodide (37 mg, 246.6 μmol) were dissolved in acetonitrile (5 mL) and reacted at 90°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 6 (5 mg, yield: 4.6%).

[0366] MS m / z(ESI):434.2[M+1].

[0367] 1 H NMR (500MHz, CDCl3): δ12.89(s,2H),9.11(s,1H),8.80-8.77(m,1H),8.35-8.33(m,1H),8.05(d,1H) ),7.53(d,1H),7.39-7.36(m,1H),4.12(s,2H),3.93(s,2H),3.79(s,2H),2.82(s,3H),2.42(m,3H).

[0368] Example 7

[0369] 4-Fluoro-5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrrolidone

[0370] Oxazol-2(4H)-yl)-N-methylpyridine-2-carboxamide 7

[0371] first step

[0372] tert-Butyl 2-(4-fluoro-6-(methoxycarbonyl)pyridin-3-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate

[0373] Methyl 5-bromo-4-fluoropyridine-2-carboxylate 7a (1.75 g, 7.5 mmol, prepared by the method disclosed in Example 12 on page 53 of the specification of patent application "WO2023051716"), compound 1a (1.56 g, 7.5 mmol, Shanghai Bidex) were dissolved in 1,4-dioxane (40 mL), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (593.7 mg, 747.7 μmol), potassium phosphate (3.2 g, 15 mmol), and the reaction mixture was heated to 120 ° C and stirred under nitrogen for 14 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-40%, flow rate: 30 mL / min) to give the title compound 7b (50 mg, yield: 1.8%).

[0374] MS m / z(ESI):363.4[M+1].

[0375] Step 2

[0376] 4-Fluoro-5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpyridine-2-carboxamide 7

[0377] The synthetic route in Example 1 was used to replace the second step raw material compound 1c with compound 7b to obtain the title compound 7 (2 mg, yield: 12.4%).

[0378] MS m / z(ESI):452.4[M+1].

[0379] 1H NMR (500MHz, DMSO-d6): δ12.48(s,1H),9.04(d,1H),8.89(d,1H),8.03(d,2H),7.54( d,1H),7.39(d,1H),4.11(s,2H),3.87(s,2H),3.82(s,2H),2.83(d,3H),2.43(s,3H).

[0380] Biological evaluation

[0381] The present disclosure is further described and explained below in conjunction with test examples, but these test examples are not intended to limit the scope of the present disclosure.

[0382] Test Example 1: Cell Proliferation Experiment

[0383] The following method detects the intracellular ATP content according to IC 50 Evaluation of the effect of the disclosed compounds on DLD1 cells, DLD1 BRCA2- / - The experimental method is briefly described as follows:

[0384] 1. Experimental Materials and Instruments

[0385] 1. DLD1, human colon cancer cells (Nanjing Kebai, CBP60037)

[0386] 2. DLD1 BRCA2- / - Human BRCA2 gene knockout colon cancer tumor cells (Creative biogene, CSC-RT0015)

[0387] 3. MDA-MB-436, human breast cancer cells (ATCC, HTB-130)

[0388] 4. Fetal bovine serum (GIBCO, 10091-148)

[0389] 5. CellTite-Glo reagent (Promega, G7573)

[0390] 6. 96-well cell culture plate (corning, 3903)

[0391] 7. Pancreatin (Invitrogen, 25200-072)

[0392] 8. Microplate reader (BMG, PHERAsta)

[0393] 9. Cell counter (Shanghai Ruiyu Biotechnology Co., Ltd., IC1000)

[0394] 2. Experimental steps

[0395] DLD1 cells were cultured in RPMI-1640 medium containing 10% FBS and passaged 2-3 times a week at a passage ratio of 1:6 or 1:8. During passage, cells were trypsinized and transferred to a centrifuge tube. Centrifuged at 1200 rpm for 3 minutes, the supernatant was discarded, and fresh medium was added to resuspend the cells. 180 μL of cell suspension was added to a 96-well cell culture plate at a density of 2.78 × 10 3 cells / mL, and only 180 μL of complete culture medium was added to the periphery of the 96-well plate.

[0396] DLD1 BRCA2- / - Cells were cultured in RPMI-1640 medium supplemented with 10% FBS and passaged 2-3 times a week at a subculture ratio of 1:6 or 1:8. During subculture, cells were trypsinized and transferred to a centrifuge tube. Centrifuged at 1200 rpm for 3 minutes, the supernatant was discarded, and fresh medium was added to resuspend the cells. 180 μL of the cell suspension was added to a 96-well cell culture plate at a density of 8.34 × 10 3 cells / mL, and only 180 μL of complete culture medium was added to the periphery of the 96-well plate.

[0397] MDA-MB-436 cells were cultured in Leibovitz's L-15 medium supplemented with 10% FBS, 10 μg / mL insulin, and 16 μg / mL glutathione. The cells were passaged 2-3 times per week at a subculture ratio of 1:3 or 1:5. During subculture, the cells were trypsinized and transferred to a centrifuge tube. The cells were centrifuged at 1200 rpm for 3 minutes, the supernatant was discarded, and fresh medium was added to resuspend the cells. 180 μL of the cell suspension was added to a 96-well cell culture plate at a density of 8.34 × 10 3 cells / mL, and only 180 μL of complete culture medium was added to the periphery of the 96-well plate.

[0398] The culture plate was incubated in an incubator (37° C., 5% CO 2 ) for 24 hours.

[0399] The sample to be tested was diluted to 2 mM with DMSO and diluted 3 times in sequence to 10 concentrations, and blank and control wells were set. 5 μL of the test compound solution prepared into a gradient concentration was added to 95 μL of fresh culture medium. 20 μL of the above-mentioned drug-containing culture medium solution was then added to the culture plate. The culture plate was incubated in an incubator for 6 days (37°C, 5% CO2). In a 96-well cell culture plate, 90 μL of CellTiter-Glo reagent was added to each well and placed in the dark at room temperature for 5-10 minutes. The chemiluminescence signal value was read in PHERAstar and the data was processed using GraphPad software. The results are shown in Table 1.

[0400] Table 1 Effects of the compounds disclosed herein on DLD1, DLD1 BRCA2- / -and the inhibitory effect on MDA-MB-436 cell proliferation

[0401] Conclusion: The compounds disclosed herein have an effect on DLD1 BRCA2- / - It has a good inhibitory effect on the proliferation of MDA-MB-436 cells.

[0402] Test Example 2: Determination of the Binding Activity of the Disclosed Compounds to PARP1 and PARP2

[0403] The in vitro PARP1 and PARP2 binding activities were tested by the following method.

[0404] 1. Experimental Materials and Instruments

[0405] 1. PARP1 recombinant protein (Sino Biological, Cat. No. 11040-H08B);

[0406] 2. PARP2 recombinant protein (BPS, Cat. No. 80502)

[0407] 3. Fluorescent probe (prepared using compound CAS No. 1380359-84-1, Shanghai Hengrui);

[0408] 4. 384-well plate (Corning, 3575)

[0409] 5. Microplate reader PHERAstar FS (BMG Labtech)

[0410] 2. Experimental steps

[0411] 8 μL of binding buffer was added to each well of a 384-well plate. The fluorescent probe was dissolved in dimethyl sulfoxide and diluted to the desired concentration. The fluorescent probe prepared in dimethyl sulfoxide was then diluted 20-fold in binding buffer (50 mM Tris-HCl pH 8.0, 50 mM NaCl, 1 mM MgCl2, 0.1 mM EDTA, 0.01% IGEPAL) and 2 μL was added to each well. The test compound was dissolved in dimethyl sulfoxide and diluted to the desired concentration range according to the experimental requirements. The compound prepared in dimethyl sulfoxide was then diluted 20-fold in binding buffer and 2 μL was added to each well. PARP1 or PARP2 protein was diluted to the desired concentration in binding buffer and 8 μL / well was added to a black 384-well plate. After mixing, the plate was incubated at 25°C for 40 minutes. Signals were read using the FP program in a PHERAstar FS microplate reader. Data were processed using GraphPad software.

[0412] The PARP1 and PARP2 binding inhibitory activities of the disclosed compounds were determined by the above assays, and the IC 50 See Table 2 for values.

[0413] Table 2 Inhibitory activity of the disclosed compounds on PARP1 and PARP2 binding

[0414] Conclusion: The disclosed compounds have selective inhibitory effects on PARP1.

[0415] Test Example 3 PARP1 enzyme activity assay

[0416] The following in vitro screening assay is used to determine the inhibitory effect of the disclosed compounds on PARP1 enzyme activity.

[0417] The following experiments were conducted using a PARP1 Chemiluminescent Assay Kit (BPS, 80551, Lot# 211124-K) to determine the inhibitory effect of compounds on PARP1 enzyme activity. The key to the PARP1 Chemiluminescent Assay Kit is the use of biotinylated NAD+. By measuring the intensity of the chemiluminescent signal, the NAD+ content in the reaction system can be determined. + The level of PARP1 was determined by the test compound, thereby calculating the degree of inhibition of PARP1 enzyme activity by the test compound.

[0418] For detailed experimental procedures and the preparation of the reagents used, such as histone mixture, master mixture, assay buffer, and ELISA ECL substrate, please refer to the instructions of the PARP1 chemiluminescence test kit.

[0419] The experimental steps are briefly described as follows: 96-well flat-bottom plates were coated with a histone mixture overnight at 4°C. Blocking buffer 3 was used for 90 minutes at room temperature. 20 μl of 2 ng / μl PARP1 enzyme was added to each well, along with 25 μl of the master mixture. Test compounds were dissolved in dimethyl sulfoxide (DMSO), diluted with buffer to the desired concentration, and 5 μl was added to each well. After mixing, the mixture was incubated at room temperature for 1 hour, followed by the addition of streptavidin-conjugated horseradish peroxidase and incubation at room temperature for 30 minutes. Finally, a 1:1 mixture of ECL Substrate A and ECL Substrate B was added. Chemiluminescence signals were detected using PHERAstar, and data were processed using GraphPad software to calculate the inhibitory rate of PARP1 activity.

[0420] IC of the compound 50 The inhibition rate at different concentrations can be calculated.

[0421] Conclusion: The disclosed compounds have significant inhibitory activity on the proliferation of PARP1 kinase.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is a heteroaryl group; Ring B is aryl or heteroaryl; G 2 CR 6a or nitrogen atoms; G 3 CR 6b or nitrogen atoms; R 0 、R 1a 、R 6a and R 6b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b , hydroxyl, -C(O)R 8a 、-C(O)OR 8a 、-C(O)NR 7a R 7b 、-S(O) p R 8a , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R 2 are the same or different and are each independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 7c R 7d , hydroxyl and hydroxyalkyl; Each R 3 are the same or different and are each 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, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9c R 9d , hydroxy, 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 hydrogen, alkyl, hydroxyalkyl, cycloalkyl and heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy; or R 7a and R 7b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, or R 7c and R 7d Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, or R 7e and R 7f Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, or R 9a and R 9b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, or R 9c and R 9d Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group formed is optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkyl substituted by one or more substituents selected from oxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 8a and R 8b are the same or different and are each independently selected from hydrogen, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally substituted with one or more substituents selected from halogen, an alkyl group, an alkoxy group, a haloalkyl group and a haloalkoxy group; p is 0, 1, or 2; q is 0, 1, or 2; m is 0, 1, or 2; n is 0, 1, or 2; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, or 3.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is selected from pyrazolyl, thienyl and imidazolyl; preferably, ring A is pyrazolyl.

3. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein m is 1. 4 . The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , wherein ring B is pyridyl.

5. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein G 2 CR 6a , R 6a As defined in claim 1; and / or G 3 CR 6b , R 6b As defined in claim 1.

6. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof: in: X and Y are the same or different and are each independently a nitrogen atom or CR 2a ; R 2a Selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 7c R 7d , hydroxyl and hydroxyalkyl; R 0 、R 1a 、R 6a 、R 6b 、R 7c 、R 7d 、R 3 , n and t are as defined in claim 1. 7 . The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , wherein n is 1.

8. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to claim 6 or 7, wherein X is a nitrogen atom; and / or Y is CH.

9. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 3 -C(O)NR 7e R 7f ; where R 7e and R 7f As defined in claim 1.

10. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 6a is a hydrogen atom; and / or R 6b A hydrogen atom.

11. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 0 is a hydrogen atom or a halogen.

12. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 1a C 1-6 alkyl.

13. A compound or a pharmaceutically acceptable salt thereof, which is selected from any one of the following compounds:

14. A compound represented by general formula (IIa) or a salt thereof: in: R 3 -C(O)NR 7e R 7f ; t is 1, 2, or 3; X, Y, R 7e 、R 7f and n as defined in claim 6.

15. A compound or a salt thereof, which is selected from any one of the following compounds:

16. A method for preparing the compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, the method comprising: A compound of general formula (Ia) or a salt thereof (preferably hydrochloride) undergoes a nucleophilic substitution reaction with a compound of general formula (Ib) to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof; in: L is halogen, preferably Br; G 2 , G 3 , Ring A, Ring B, R 0 、R 1a 、R 2 、R 3 , s, t, m and n are as defined in claim 1.

17. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

18. Use of the compound represented by general formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 in the preparation of a PARP1 inhibitor.

19. Use of a compound represented by the general formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the preparation of a medicament for treating and / or preventing cancer, essential thrombocythemia or polycythemia vera; the cancer is preferably selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, cervical cancer, endometrial cancer, myeloma, leukemia, lymphoma, acoustic neuroma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, bronchial cancer, sarcoma, chordoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, Embryonic carcinoma, hemangioendothelioma, ependymoma, epithelial carcinoma, esophageal cancer, testicular cancer, glioma, heavy chain disease, hemangioblastoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, neuroblastoma, NUT midline cancer, bone cancer, nasopharyngeal cancer, oral cancer, thyroid cancer, pinealoma, retinoblastoma, sebaceous gland cancer, seminoma, skin cancer, squamous cell carcinoma, synovioma, sweat gland cancer, Waldenstrom's macroglobulinemia and Wilms' tumor; the sarcoma is preferably Ewing's tumor; preferably, the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer and lung cancer.

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