Fused bicyclic compounds, processes for their preparation and their use in medicine

Abstract

The present disclosure relates to fused bicyclic compounds, methods for their preparation and their use in medicine. In particular, the present disclosure relates to a fused bicyclic compound of general formula (I), methods for their preparation, pharmaceutical compositions containing such compounds and their use as therapeutic agents, in particular as PARP1 inhibitors and for the treatment and / or prevention of cancer.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a fused bicyclic compound, its preparation method, and its pharmaceutical applications. In particular, this disclosure relates to fused bicyclic compounds of general formula (I), their preparation methods, pharmaceutical compositions containing such compounds, and their use as PARP1 inhibitors and for the treatment and / or prevention of cancer. Background Technology

[0002] Poly(ADP-ribose) polymerase 1 (PARP1), first reported over 50 years ago, has since been found to play crucial roles in DNA repair, maintaining genome integrity, and regulating various metabolic and signal transduction processes. PARP1 catalyzes the transfer of ADP-ribose residues from NAD+ to target substrates, constructing a poly(ADP-ribose) (PAR) chain. The formation and clearance of PAR chains occur in almost all eukaryotic cells.

[0003] ADP-ribosylation is a post-translational modification of proteins widely present in various physiological and pathological processes. It refers to the binding of one or more ADP-ribose units to a specific site on a protein under the catalysis of an enzyme. PARP1 is the first member of the PARP superfamily, which consists of proteins homologous to PARP1 and currently has 17 members, four of which (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 catalyzes the movement of the poly(ADP-ribosyl) (PAR) chain toward target proteins. This post-translational modification, called poly-ADP-ribosylation (PARylation), mediates the recruitment of other DNA repair factors to the DNA damage site. After completing this recruitment, PARP auto-PARylation triggers the release of bound PARP from the DNA, allowing access to other DNA repair proteins to complete the repair. Therefore, PARP binding to the damaged site, its catalytic activity, and its eventual release from the DNA are all crucial steps in how cancer cells respond to DNA damage induced by chemotherapy and radiotherapy.

[0005] Inhibiting PARP family 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 with harmful alterations in the key tumor suppressor proteins BRCA1 or BRCA2, which are involved in double-strand DNA break (DSB) repair via harmful recombination (HR), are selectively sensitive to small molecules such as inhibitors of the PARP family of DNA repair enzymes. These tumors have insufficient homologous recombination repair (HRR) pathways and rely on the survival function of PARP enzymes. Although PARP inhibitor therapy primarily targets BRCA-mutated cancers, PARP inhibitors have been clinically tested in non-BRCA-mutated tumors that exhibit homologous recombination deficiency (HRD).

[0006] Compared to other PARP1 / 2 inhibitors, PARP inhibitors with enhanced selectivity for PARP1 can exhibit improved efficacy and reduced toxicity. We believe that strong selective inhibition of PARP1 will lead to PARP1 capture on DNA, resulting in DNA double-strand breaks (DSBs) through the collapse of the replication fork in S phase. PARP1-DNA capture is an effective mechanism for selectively killing tumor cells with HRD.

[0007] Therefore, there is an urgent clinical need for effective and safe PARP inhibitors, especially PARP inhibitors that are selective for PARP1.

[0008] The currently published patent applications for PARP inhibitors include WO2021013735A1, WO2009053373A1, WO2008107478A1, and WO2021260092A1. Summary of the Invention

[0009] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0010]

[0011] in:

[0012] Ring A is a heteroaryl group;

[0013] Ring B is aryl or heteroaryl;

[0014] G 2 For CR 6a Or nitrogen atoms;

[0015] G 3 For CR 6b Or nitrogen atoms;

[0016] R 0 R 1a R 6aand R 6b They may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b hydroxyl group, -C(O)R 8a -C(O)OR 8a -C(O)NR 7a R 7b -S(O) p R 8a cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b The substance is substituted by one or more substituents selected from hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

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

[0018] Each R 3 They may be the same or different, and each is independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7e R 7f hydroxyl group, -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 groups are each independently and optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9c R 9d The substance is substituted by one or more substituents selected from hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0019] R 7a R 7b R 7c R 7d R 7e R 7f R 9a R 9b R 9c and R9d The same or different, and each independently selected from hydrogen atoms, alkyl, hydroxyalkyl, cycloalkyl, and heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are each independently optionally substituted by one or more substituents selected from halogens, alkyl, alkoxy, haloalkyl, and haloalkoxy; or

[0020] R 7a and R 7b Together with the attached nitrogen atom, it forms a heterocyclic group, or R 7c and R 7d Together with the attached nitrogen atom, it forms a heterocyclic group, or R 7e and R 7f Together with the attached nitrogen atom, it forms a heterocyclic group, or R 9a and R 9b Together with the attached nitrogen atom, it forms a heterocyclic group, or R 9c and R 9d Together with the attached nitrogen atom, a heterocyclic group is formed, wherein the formed heterocyclic group is optionally substituted by 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 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, hydroxyalkyl, cycloalkyl and heterocyclic groups, wherein each of the alkyl, cycloalkyl and heterocyclic groups is independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

[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 can be 0, 1, 2 or 3.

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

[0029] In some embodiments of this 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 atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 7c R 7d , hydroxyl and hydroxyalkyl, R 7c R 7d m and n are as defined in general formula (I).

[0030] In some embodiments of this 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 this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, ring B is a phenyl or a 6-membered heteroaryl; more preferably, ring B is a pyridyl.

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

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

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

[0035] In some embodiments of this 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 this 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]

[0038] in:

[0039] X and Y may be the same or different, and each is independently a nitrogen atom or a CR atom. 2a ;

[0040] R 2a Selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 7c R 7d hydroxyl and hydroxyalkyl;

[0041] R 0 R 1a R 6a R 6b R 7c R 7d R 3 , n and t are as defined in general formula (I).

[0042] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein each R 3 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, cyano, -NR 7e R 7f hydroxyl group, -C(O)R 8b -C(O)OR 8b and -C(O)NR 7e R 7f R 8b R 7e 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.

[0043] In some embodiments of this disclosure, the compound represented by general formula (I) or 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 Haloalkyl, C1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl; preferably, R 6a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; more preferably, R 6a It is a hydrogen atom.

[0044] In some embodiments of this disclosure, the compound represented by general formula (I) or 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 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl; preferably, R 6b Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; more preferably, R 6b It is a hydrogen atom.

[0045] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 6a It is a hydrogen atom; and / or R 6b It is a hydrogen atom.

[0046] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (II) or its pharmaceutically usable salt is used, wherein t is 1 or 2; preferably 1.

[0047] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:

[0048]

[0049] in:

[0050] X and Y may be the same or different, and each is independently a nitrogen atom or a CR atom. 2a ;

[0051] R 2a Selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 7c R 7d hydroxyl and hydroxyalkyl;

[0052] R 0 R 1a R 7c R 7d R7e R 7f And n is as defined in general formula (I).

[0053] In some embodiments of this disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2; preferably, n is 1.

[0054] In some embodiments of this disclosure, the compound represented by general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein X is a nitrogen atom.

[0055] In some embodiments of this disclosure, the compound represented by general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein Y is CR 2a R 2a As defined in general formula (II); preferably, Y is CH.

[0056] In some embodiments of this disclosure, the compound represented by general formula (II) or general formula (III) or its pharmaceutically acceptable salt, wherein X is a nitrogen atom; and / or Y is CH.

[0057] In some embodiments of this disclosure, the compound represented by 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 Haloalkyl, C 1-6 Halogenated alkoxy groups 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.

[0058] In some embodiments of this disclosure, the compound represented by 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 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl; preferably, R 2a Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Hydroxyalkyl; preferably, R 2a It is a hydrogen atom.

[0059] In some embodiments of this disclosure, the compound represented by 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 Halogenated alkyl; preferably, R 0 It is a hydrogen atom or a halogen; more preferably, R 0 It is a halogen; most preferably, R 0 It is F.

[0060] In some embodiments of this disclosure, the compound represented by 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 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl; preferably, R 1a C 1-6 Alkyl; more preferably, R 1a It is a methyl group.

[0061] In some embodiments of this disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 7e and R 7f They may be the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups; preferably, R 7e and R 7f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 7e and R 7f They may be the same or different, and each is independently a hydrogen atom or a methyl group.

[0062] In some embodiments of this disclosure, the compound represented by general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein for Preferably, for Among them, R 2a And n is as defined in general formula (II).

[0063] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, R 0 It is a hydrogen atom or a halogen; R 1a C 1-6Alkyl; R 6a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; 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 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0064] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, R 0 It is a halogen; R 1a C 1-6 Alkyl group; n is 1; X is a nitrogen atom; Y is CH; and R 7e and R 7f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0065] Table A lists typical compounds disclosed herein, including but not limited to:

[0066]

[0067] Another aspect of this disclosure relates to compounds of general formula (IIa) or salts thereof:

[0068]

[0069] in:

[0070] R 3 -C(O)NR 7e R 7f ;

[0071] t is 1, 2, or 3;

[0072] X, Y, R 7e R 7f And n is as defined in general formula (II).

[0073] Another aspect of this disclosure relates to compounds of general formula (IIIa) or salts thereof:

[0074]

[0075] in:

[0076] X, Y, R 7e R 7f And n is as defined in general formula (III).

[0077] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0078]

[0079]

[0080] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0081]

[0082] A compound of general formula (Ia) or a salt thereof (preferably a hydrochloride salt) undergoes a nucleophilic substitution reaction with a compound of general formula (Ib) to give a compound of general formula (I) or a pharmaceutically usable salt thereof;

[0083] in:

[0084] L is a halogen, preferably Br;

[0085] 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 general formula (I).

[0086] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0087]

[0088] A compound of general formula (IIa) or a salt thereof (preferably a hydrochloride salt) undergoes a nucleophilic substitution reaction with a compound of general formula (IIb) to give a compound of general formula (II) or a pharmaceutically usable salt thereof;

[0089] in:

[0090] L is a halogen, preferably Br;

[0091] X, Y, R 0 R 1a R 3 R 6a R 6b, t and n are as defined in general formula (II).

[0092] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0093]

[0094] A compound of general formula (IIIa) or a salt thereof (preferably a hydrochloride salt) undergoes a nucleophilic substitution reaction with a compound of general formula (IIIb) to give a compound of general formula (III) or a pharmaceutically usable salt thereof;

[0095] in:

[0096] L is a halogen, preferably Br;

[0097] X, Y, R 0 R 1a R 7e R 7f And n is as defined in general formula (III).

[0098] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (II) or formula (III) of this disclosure and a pharmaceutically acceptable salt thereof as shown in Table A, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0099] This disclosure further relates to the use of compounds of general formula (I), general formula (II) or general formula (III) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of PARP1 inhibitors.

[0100] This disclosure further relates to the use of compounds of general formula (I), general formula (II) or general formula (III) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated by PARP1.

[0101] This disclosure further relates to the use of compounds of general formula (I), general formula (II) or general formula (III) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of cancer, essential thrombocythemia, or polycythemia vera.

[0102] This disclosure further relates to a method of inhibiting PARP1, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (II), or formula (III) and the compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound.

[0103] This disclosure further relates to a method of treating and / or preventing diseases or conditions mediated by PARP1, comprising administering to a desired patient an 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 thereof.

[0104] This disclosure further relates to a method of treating and / or preventing cancer, essential thrombocythemia, or polycythemia vera, comprising administering to a patient 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.

[0105] This disclosure further relates to a compound of general formula (I), general formula (II) or general formula (III) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicine.

[0106] This disclosure further relates to a compound of general formula (I), general formula (II) or general formula (III) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a PARP1 inhibitor.

[0107] This 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 thereof, for the treatment and / or prevention of diseases or conditions mediated by PARP1.

[0108] This disclosure further relates to a compound of general formula (I), general formula (II) or general formula (III) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, used as a medicament for the treatment and / or prevention of cancer, essential thrombocythemia, or polycythemia vera.

[0109] Preferably, the PARP1-mediated disease or condition described in this disclosure is cancer.

[0110] Preferably, the cancers described in this disclosure are 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, T-cell or B-cell lymphoid malignancies, 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), and others. The cancers include rhabdomyosarcoma, Ewing's tumor, chordoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, hemangioendothelioma, ependymoma, epithelial carcinoma, esophageal cancer, testicular cancer, glioma, heavy chain disease, hemangioblastoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, neuroblastoma, midline carcinoma of NUT, glioma, bone cancer, nasopharyngeal carcinoma, oral cancer, thyroid cancer, pineal tumor, retinoblastoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, synovoma, sweat gland carcinoma, Waldenström 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.

[0111] Preferably, the cancer cells of the cancer described in this disclosure are BRCA1 or BRCA2 deficient, with BRCA2 deficient being more preferred.

[0112] Preferably, the cancer cells of the cancer described in this disclosure have defective BRCA1 or BRCA2, more preferably BRCA2.

[0113] The active compounds can be formulated into forms suitable for administration via any appropriate route, using one or more pharmaceutically acceptable carriers through conventional methods. Therefore, the active compounds of this disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or blow-through administration. The compounds of this 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.

[0114] As a general guideline, the active compound is preferably expressed in a unit dose manner, or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition may be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation. Suitable unit doses may range from 0.1 to 1000 mg.

[0115] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0116] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These 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, thus providing sustained release over a longer period.

[0117] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0118] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions, used for mixing. These 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 sweeteners.

[0119] Oil suspensions are prepared by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0120] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. 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, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0121] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0122] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral-acceptable, non-toxic diluents or solvents. Furthermore, sterile fixative oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil may be used. Additionally, fatty acids may also be used to prepare injectable formulations.

[0123] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0124] The compounds disclosed herein can be administered by adding water to prepare water-soluble dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, or one or more preservatives.

[0125] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0126] Terminology Explanation

[0127] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0128] 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., C2). 1-20 Alkyl group). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-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 their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0129] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylenes). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkylenes, more preferably alkylenes having 1 to 6 carbon atoms (i.e., C16-164 ... 1-6Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents are preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0130] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described 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 atoms). 2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point. Substituents are preferably selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0131] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C64). 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. The substituent is preferably selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0132] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. The substituent is preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0133] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic carbocyclic ring (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl). The cycloalkyl is preferably a cycloalkyl having 3 to 12 ring atoms (i.e., 3 to 12 membered cycloalkyl), more preferably a cycloalkyl having 3 to 8 ring atoms (i.e., 3 to 8 membered cycloalkyl), and most preferably a cycloalkyl having 3 to 6 ring atoms (i.e., 3 to 6 membered cycloalkyl).

[0134] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0135] The polycyclic alkyl groups include: spirocyclic alkyl, fused cyclic alkyl, and bridged cyclic alkyl.

[0136] The term "spirocycloalkyl" refers to a polycyclic system in which rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that it contains at least one full carbon ring with a bonding point on that full carbon ring, having 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., 5 to 20-membered spirocycloalkyl). The spirocycloalkyl is preferably a spirocycloalkyl having 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), more preferably a spirocycloalkyl having 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocyclic alkyl group includes monospirocyclic alkyl and polyspirocyclic alkyl (such as bispirocyclic alkyl, etc.), preferably monospirocyclic alkyl or bispirocyclic alkyl, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5 or 7 / 6 monospirocyclic alkyl. Non-limiting examples include:

[0137] Its connection point can be anywhere;

[0138] wait.

[0139] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. This system is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group. The ring may contain one or more double bonds 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., 5 to 20-membered fused cycloalkyl groups). The fused cycloalkyl group is preferably a fused cycloalkyl group having 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl groups), and more preferably a fused cycloalkyl group having 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl groups). The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.), preferably bicyclic fused cyclic alkyl groups or tricyclic fused cyclic alkyl groups, more preferably ternary / quadrivalent, ternary / pentary, ternary / hexavalent, quadrivalent / quadrivalent, quadrivalent / pentary, quadrivalent / hexavalent, pentary / pentary ... or pentary / pentary bicyclic fused cyclic alkyl groups. Non-limiting examples include: Its connection point can be anywhere; wait.

[0140] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and the ring may contain one or more double bonds 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., 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl is preferably a bridged cycloalkyl having 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), more preferably a bridged cycloalkyl having 7 to 10 carbon atoms (i.e., 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 or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0141] Its connection point can be anywhere.

[0142] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0143] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered heterocyclic groups). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclic group); more 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).

[0144] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0145] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0146] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that at least one monocyclic heterocyclic group is present and the bonding point 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., 5 to 20-membered spiroheterocyclic groups). The spiroheterocyclic group is preferably a spiroheterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclic group), more preferably a spiroheterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclic group). The spiroheterocyclic group includes monospirocyclic and polyspirocyclic groups (such as bispirocyclic groups), preferably monospirocyclic or bispirocyclic, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6 monospirocyclic. Non-limiting examples include:

[0147] wait.

[0148] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The ring may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). It is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic heterocyclic group 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., 5 to 20 membered fused heterocyclic groups). The fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), more preferably a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably bicyclic or tricyclic fused heterocyclic 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 heterocyclic groups. Non-limiting examples include:

[0149] wait.

[0150] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly connected atoms are shared between the rings. The rings may contain one or more double bonds, and the rings contain at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). The system 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 with 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), and more preferably a bridged heterocyclic group with 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group). Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), with bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups being preferred. Non-limiting examples include:

[0151] wait.

[0152] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0153] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6 to 14-membered aryl). The aryl is preferably an aryl having 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). The monocyclic aryl is, for example, phenyl. Non-limiting examples of the polycyclic aryl include naphthyl, anthraceneyl, phenanthrene, etc. The polycyclic aryl further includes fusion of the phenyl with one or more heterocyclic groups or cycloalkyl groups, or fusion of the naphthyl with one or more heterocyclic groups or cycloalkyl groups, wherein the bonding point is on the phenyl 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 including:

[0154] wait.

[0155] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0156] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, wherein the ring contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5 to 14-membered heteroaryl). The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., 5 to 10-membered heteroaryl), more preferably a heteroaryl having 5 or 6 ring atoms (i.e., 5 or 6-membered heteroaryl).

[0157] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, etc.

[0158] Non-limiting examples of the polycyclic heteroaryl groups include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aryl groups, wherein the connecting point 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 heteroaryl ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the connecting point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include:

[0159] wait.

[0160] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0161] The term "amino protecting group" refers to a group that is easily removed from the amino group, introduced onto the amino group to ensure that the amino group remains unchanged during reactions at other sites of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), triphenylmethyl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.

[0162] The term "hydroxyl protecting group" refers to a group introduced onto a hydroxyl group that is easily removed, used to block or protect the hydroxyl group so that reactions can occur 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.

[0163] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

[0164] The term “heterocyclic oxy group” refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

[0165] The term "aryloxy group" refers to aryl-O-, where the aryl group is as defined above.

[0166] The term “heteroaryloxy” refers to heteroaryl-O-, where the heteroaryl group is as defined above.

[0167] The term "alkylthio" refers to alkyl-S-, where the alkyl group is as defined above.

[0168] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0169] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0170] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0171] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0172] The term "methyl-xyl" refers to =CH2.

[0173] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0174] The term "hydroxyl group" refers to -OH.

[0175] The term "thiol" refers to -SH.

[0176] The term "amino" refers to -NH2.

[0177] The term "cyano" refers to -CN.

[0178] The term "nitro" refers to -NO2.

[0179] The term "oxo" or "oxo group" refers to "=O".

[0180] The term "carbonyl" refers to C=O.

[0181] The term "carboxyl group" refers to -C(O)OH.

[0182] The term "carboxylic acid ester group" 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.

[0183] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this 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. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0184] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0185] The compounds disclosed herein can exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. An example of a lactam-lactamimide in equilibrium is shown below:

[0186]

[0187] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0188]

[0189] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0190] The compounds disclosed herein include all suitable isotopic derivatives 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 may be introduced into the compounds of this 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 Grade I, with deuterium as the preferred grade.

[0191] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0192] In the compounds disclosed herein, when a position is specifically designated as "deuterium" or "D", that position should be understood to indicate that the abundance of deuterium is at least 1000 times greater than the native abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the native abundance of deuterium (i.e., at least 15% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the native abundance of deuterium (i.e., at least 30% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the native abundance of deuterium (i.e., at least 45% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural deuterium abundance (i.e., at least 50.1% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural deuterium abundance (i.e., at least 52.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural deuterium abundance (i.e., at least 60% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural deuterium abundance (i.e., at least 67.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural deuterium abundance (i.e., at least 75% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural deuterium abundance (i.e., at least 82.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural deuterium abundance (i.e., at least 90% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural deuterium abundance (i.e., at least 95% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural deuterium abundance (i.e., at least 97% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural deuterium abundance (i.e., at least 99% deuterium doping). In some implementations, the abundance of deuterium in each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium doping).

[0193] "Optionally" or "optionally" means that the event or environment described below may but not necessarily occur, including both the occurrence and non-occurrence of the event or environment. For example, "optionally (optionally) alkyl group substituted with halogen or cyano" includes cases where the alkyl group is substituted with halogen or cyano and cases where the alkyl group is not substituted with halogen or cyano.

[0194] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0195] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0196] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0197] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution.

[0198] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0199] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0200] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0201] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0202] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0203] When the term "about" is applied to parameters such as pH, concentration, and temperature, it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations.

[0204] The method for synthesizing the compounds disclosed herein

[0205] In order to achieve the purpose of this disclosure, the following technical solution is adopted:

[0206] Option 1

[0207] The present disclosure discloses a method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0208]

[0209] A compound of general formula (Ia) or a salt thereof (preferably a hydrochloride salt) undergoes a nucleophilic substitution reaction with a compound of general formula (Ib) under basic conditions, optionally in the presence of a catalyst, to give a compound of general formula (I) or a pharmaceutically usable salt thereof.

[0210] in:

[0211] L is a halogen, preferably Br;

[0212] 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 general formula (I).

[0213] Option 2

[0214] The present disclosure discloses a method for preparing the compound of formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0215]

[0216] A compound of general formula (IIa) or a salt thereof (preferably a hydrochloride salt) undergoes a nucleophilic substitution reaction with a compound of general formula (IIb) under basic conditions, optionally in the presence of a catalyst, to give a compound of general formula (II) or a pharmaceutically usable salt thereof.

[0217] in:

[0218] L is a halogen, preferably Br;

[0219] X, Y, R 0 R 1a R 3 R 6a R 6b , t and n are as defined in general formula (II).

[0220] Option 3

[0221] A method for preparing the compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0222]

[0223] A compound of general formula (IIIa) or a salt thereof (preferably a hydrochloride salt) undergoes a nucleophilic substitution reaction with a compound of general formula (IIIb) under basic conditions, optionally in the presence of a catalyst, to give a compound of general formula (III) or a pharmaceutically usable salt thereof.

[0224] in:

[0225] L is a halogen, preferably Br;

[0226] X, Y, R 0 R 1a R7e R 7f And n is as defined in general formula (III).

[0227] The alkaline conditions provided include organic and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, 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. N,N-diisopropylethylamine is preferred.

[0228] The catalyst for the above nucleophilic substitution reaction is sodium iodide or potassium iodide, preferably sodium iodide.

[0229] The above reaction is preferably carried out in a solvent, which 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 Implementation

[0230] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0231] Example

[0232] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0233] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0234] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector)

[0235] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO QExactive)

[0236] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0237] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0238] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0239] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0240] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0241] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0242] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0243] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0244] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0245] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0246] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0247] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0248] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0249] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0250] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0251] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0252] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0253] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC 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 compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0254] Example 1

[0255] 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

[0256]

[0257] first step

[0258] 2-(6-(methoxycarbonyl)pyridin-3-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid tert-butyl ester 1c

[0259] Methyl 5-bromopyridine-2-carboxylic acid ester 1b (200 mg, 925.78 μmol, Shanghai Shaoyuan), 2,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid tert-butyl ester 1a (290 mg, 1.38 mmol, Shanghai Bide) were dissolved in 1,4-dioxane (5 mL), and 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 protection, the mixture was heated to 120 °C and stirred for 14 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 1c (205 mg, yield: 64.3%).

[0260] MS m / z(ESI): 345.2 [M+1].

[0261] Step 2

[0262] 2-(6-(methylaminocarbonyl)pyridin-3-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid tert-butyl ester 1d

[0263] Compound 1c (200 mg, 580.8 μmol) was dissolved in 15 mL of 1 M methylamine in ethanol, and the mixture was stirred for 48 hours. The reaction solution was concentrated under reduced pressure to obtain crude title compound 1d (190 mg, yield: 95.2%). The product was directly used for the next reaction without purification.

[0264] MS m / z(ESI): 344.2 [M+1].

[0265] Step 3

[0266] 5-(5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)-N-methyl-2-pyridinecarboxamide hydrochloride 1e

[0267] The crude compound 1d (140 mg, 407.7 μmol) was dissolved in dichloromethane (2 mL), and 1 mL of 4 M dioxane hydrochloride solution was added. The mixture was stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 1e (110 mg, yield: 96.5%). The product was used directly in the next step of the reaction without purification.

[0268] MS m / z(ESI):244.2[M+1].

[0269] Step 4

[0270] 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

[0271] Crude compound 1e (51 mg, 182 μmol), 7-(bromomethyl)-8-fluoro-3-methylquinoxalin-2(1H)-one 1f (50 mg, 184 μmol, prepared by the method disclosed on page 14, Intermediate 29 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). The mixture was reacted at 80 °C for 5 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs) for analysis. 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 title compound 1 (15mg, yield: 18.7%).

[0272] MS m / z(ESI):434.2[M+1].

[0273] 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).

[0274] Example 2

[0275] 6-Fluoro-5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalo-6-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpyridin-2-carboxamide 2

[0276]

[0277] first step

[0278] 6-Amino-5-(5-(tert-butoxycarbonyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridine-2-carboxylic acid 2b

[0279] Compound 1a (271.7 mg, 1.3 mmol, Shanghai Shaoyuan) and methyl 5-bromo-6-aminopyridine-2-carboxylic acid ester 2a (200 mg, 865.6 μmol, Shanghai Bide) were dissolved in dimethyl sulfoxide (6 mL). 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 mixture was purged with nitrogen and stirred in a microwave at 120 °C for 2 hours. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth. The filtrate was analyzed by high-performance liquid chromatography (Waters-2545, column: YMCTriart-Exrs). C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-40%, flow rate: 30mL / min) to obtain title compound 2b (50mg, yield: 16.7%).

[0280] MS m / z(ESI): 344.4 [M-1].

[0281] Step 2

[0282] 2-(2-amino-6-(methylcarbamoyl)pyridin-3-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid tertiary

[0283] Butyl ester 2c

[0284] Compound 2b (20 mg, 57.9 μmol) was dissolved in 2 mL of N,N-dimethylformamide. Under ice bath conditions, N,N-diisopropylethylamine (37.4 mg, 289.5 μmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (33 mg, 86.9 μmol), and methylamine hydrochloride (5.9 mg, 86.8 μmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water and 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 obtain the crude title compound 2c (20 mg).

[0285] MS m / z(ESI): 359.2 [M+1].

[0286] Step 3

[0287] 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-6-fluoro-N-methylpyridine-2-carboxamide 2d

[0288] The crude compound 2c (20 mg, 55.8 μmol) was dissolved in a pyridine hydrogen fluoride complex (1 mL), and sodium nitrite (46.2 mg, 669.6 μmol) was added. After reacting for 1 hour, the mixture was quenched with water. Impurities were removed by extraction with dichloromethane ester (5 mL). After filtration through the aqueous phase, the mixture 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 20%-35%, flow rate: 30 mL / min) to obtain the title compound 2d (14.5 mg, yield: 99%).

[0289] MS m / z(ESI):262.2[M+1].

[0290] Step 4

[0291] 6-Fluoro-5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalo-6-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpyridin-2-carboxamide 2

[0292] 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). The mixture was reacted at 80 °C for 0.5 h. The reaction solution was concentrated under reduced pressure. 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 title compound 2 (2 mg, yield: 8%).

[0293] MS m / z(ESI):452.2[M+1].

[0294] 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).

[0295] Example 3

[0296] 3-Fluoro-5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalo-6-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpyridin-2-carboxamide 3

[0297]

[0298] Using the synthetic route in Example 1, the starting compound 1b of the first step was replaced with methyl 5-bromo-3-fluoropyridine-2-carboxylate (Nanjing Yaoshi) to obtain the title compound 3 (39 mg, yield: 17.3%).

[0299] MS m / z(ESI):452.2[M+1].

[0300] 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).

[0301] Example 4

[0302] 5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-5,6-dihydro-4H-thieno[2,3-c]pyrrolo-2-yl)-N-methylpyridine-2-carboxamide 4

[0303]

[0304] first step

[0305] 3-(bromomethyl)thiophene-2-carboxylic acid methyl ester 4b

[0306] Methyl 3-methylthiophene-2-carboxylate 4a (9.5 g, 60.8 mmol, Shanghai Bide) and N-bromosuccinimide (11.9 g, 66.9 mmol) were dissolved in carbon tetrachloride (80 mL), purged with nitrogen, and azobisisobutyronitrile (2 g, 12.1 mmol) was added at 70 °C. The mixture was stirred for 3 hours, cooled to room temperature, and saturated sodium carbonate solution was added. The mixture was extracted with dichloromethane (100 mL × 3), and the organic phases were combined. The mixture was 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 elution system C to give the title compound 4b (10.2 g, yield: 71.3%).

[0307] Step 2

[0308] 3-(aminomethyl)thiophene-2-carboxylic acid methyl ester 4c

[0309] Compound 4b (11.5 g, 48.9 mmol) was dissolved in 7 M ammonia-methanol solution (70 mL), stirred for 2 hours, concentrated under reduced pressure, and the residue was slurried with diethyl ether (50 mL), filtered, the filter cake was washed with diethyl ether, and dried to obtain crude title compound 4c (6.6 g, yield: 78.8%).

[0310] Step 3

[0311] 4,5-Dihydro-6H-thieno[2,3-c]pyrrolo-6-one 4d

[0312] 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 residue was washed successively with water and saturated sodium chloride solution. The organic phase was collected, 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 elution system C to give the title compound 4d (1.3 g, yield: 25.1%).

[0313] MS m / z(ESI): 140.2 [M+1].

[0314] Step 4

[0315] 2-Bromo-4,5-dihydro-6H-thieno[2,3-c]pyrrolo-6-one 4e

[0316] Compound 4d (0.5 g, 3.6 mmol) was dissolved in water (7 mL) and acetic acid (9 mL). Bromine (632.3 mg, 4 mmol) was added dropwise under ice bath conditions. The mixture was stirred and kept at the same temperature for 3 hours. Water was added to the reaction mixture, 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 obtain the crude title compound 4e (800 mg). The product was used directly in the next reaction without purification.

[0317] MS m / z(ESI):217.9[M+1].

[0318] Step 5

[0319] 2-Bromo-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-carboxylic acid tert-butyl ester 4f

[0320] The 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), and di-tert-butyl dicarbonate (2 g, 9.2 mmol) was added. The mixture was stirred for 16 hours. The reaction solution was washed with saturated sodium bicarbonate solution, and the organic phase was collected. The 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 4f (1.2 g, yield: 82.2%). MS m / z (ESI): 262.1 [M-55].

[0321] Step 6

[0322] 4g of 2-bromo-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-carboxylic acid tert-butyl ester

[0323] 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 the addition was complete, the temperature was raised to 40 °C and the reaction was carried out for 16 hours. The reaction solution was cooled to room temperature, and a small amount of methanol and water were added. The mixture was stirred 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 the title compound 4 g (300 mg, yield: 62.7%).

[0324] Step 7

[0325] 2-(6-(methylcarbamoyl)pyridin-3-yl)-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-carboxylic acid tert-butyl ester 4i

[0326] 4 g (250 mg, 821.8 μmol) of compound, 4 h (177.5 mg, 986.2 μmol, Shanghai Bide) of (6-(methylcarbamoyl)pyridin-3-yl)boronic acid, 226.8 mg (1.6 mmol) of potassium carbonate, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (120.3 mg, 164.4 μmol) were mixed in 30 mL of 1,4-dioxane and 6 mL of water. The mixture was purged with nitrogen and reacted at 90 °C for 16 h. 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%).

[0327] MS m / z(ESI): 360.2 [M+1].

[0328] Step 8

[0329] 5-(5,6-dihydro-4H-thieno[2,3-c]pyrrolo-2-yl)-N-methylpyridine-2-carboxamide hydrochloride 4j

[0330] Compound 4i (50 mg, 139.1 μmol) was dissolved in dichloromethane (3 mL), and a 1,4-dioxane solution of 4M hydrogen chloride (3 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 4j (40 mg). The product was used directly in the next step of the reaction without purification.

[0331] MS m / z(ESI):260.3[M+1].

[0332] Step 9

[0333] 5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-5,6-dihydro-4H-thieno[2,3-c]pyrrolo-2-yl)-N-methylpyridine-2-carboxamide 4

[0334] 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. After the reaction solution was concentrated under reduced pressure, 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 obtain the title compound 4 (20 mg, yield: 33%).

[0335] MS m / z(ESI): 450.2 [M+1].

[0336] 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).

[0337] Example 5

[0338] (±)-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-carboxamide5

[0339]

[0340] first step

[0341] (±)-2-(6-(methoxycarbonyl)pyridin-3-yl)-6-methyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid benzyl ester 5b

[0342] 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 using the literature "Bioorganic and Medicinal The compound was prepared by the method disclosed in 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 with 1,4-dioxane (4 mL), purged with nitrogen, heated to 120 °C and stirred for 16 hours. After the reaction solution was cooled to room temperature, it was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system D to give the title compound 5b (racemic mixture) (176 mg, yield: 96.8%).

[0343] MS m / z(ESI): 393.2 [M+1].

[0344] Step 2

[0345] (±)-6-methyl-2-(6-(methylcarbamoyl)pyridin-3-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid benzyl ester 5c

[0346] Compound 5b (176 mg, 448.5 μmol) was dissolved in 30% methylamine ethanol solution (1.5 mL), stirred for 16 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system D to give the title compound 5c (racemic mixture) (188 mg, yield: 107%).

[0347] MS m / z(ESI): 392.2 [M+1].

[0348] Step 3

[0349] (±)-N-methyl-5-(6-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridine-2-carboxamide 5d

[0350] Compound 5c (188 mg, 480.3 μmol) was dissolved in dichloromethane (2 mL). A solution of 33% hydrogen bromide in acetic acid (3.5 g, 14.3 mmol) was added under a nitrogen atmosphere at 0 °C. The mixture was stirred for 30 minutes while maintaining the temperature. The reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform, and 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 (racemic mixture) (127 mg, yield: 102%).

[0351] MS m / z(ESI):258.2[M+1].

[0352] Step 4

[0353] (±)-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-carboxamide5

[0354] 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). The mixture was reacted at 80 °C for 3 hours. The reaction solution was concentrated under reduced pressure. 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 title compound 5 (racemic mixture) (25 mg, yield: 31.9%).

[0355] MS m / z(ESI):448.2[M+1].

[0356] 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).

[0357] Example 6

[0358] 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-methylpyridin-2-carboxamide 6

[0359]

[0360]

[0361] first step

[0362] 6-(methylcarbamoyl)nicotinic acid methyl ester 6b

[0363] 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 was complete, the reaction was continued for 16 hours. The reaction solution was concentrated under reduced pressure to obtain crude title compound 6b (3.8 g). The product was used directly in the next reaction without purification.

[0364] MS m / z(ESI): 195.2 [M+1].

[0365] Step 2

[0366] 5-(hydroxymethyl)-N-methylpyridine-2-carboxamide 6c

[0367] 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 mixture was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure. 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%).

[0368] MS m / z(ESI):167.2[M+1].

[0369] Step 3

[0370] 5-Formyl-N-methylpyridine-2-carboxamide 6d

[0371] 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, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 6d (50 mg). The product was used directly in the next reaction without purification.

[0372] MS m / z(ESI): 165.2 [M+1].

[0373] Step 4

[0374] 2-(6-(methylcarbamoyl)pyridin-3-yl)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5(1H)-tert-butyl carboxylate 6f

[0375] 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 Bide), iodine (116 mg, 456.9 μmol), and potassium carbonate (126.1 mg, 913.7 μmol) were dissolved in tert-butanol (12 mL), purged 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%).

[0376] MS m / z(ESI): 346.4 [M+1].

[0377] Step 5

[0378] 6g of 2-(6-(methylcarbamoyl)pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylic acid tert-butyl ester

[0379] Oxaloyl chloride (165.4 mg, 1.3 mmol) was dissolved in anhydrous dichloromethane (5 mL). Dimethyl sulfoxide (190 mg, 2.4 mmol) was added at -78 °C, and the mixture was stirred for 30 minutes. Then, a dichloromethane solution (2 mL) of compound 6f (200 mg, 579 μmol) was added, and the mixture was stirred for another 30 minutes. Triethylamine (584.8 mg, 5.8 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, 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 using eluent system A to give the title compound 6 g (80 mg, yield: 40.2%).

[0380] MS m / z(ESI): 344.2 [M+1].

[0381] Step 6

[0382] N-Methyl-5-(1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)pyridine-2-carboxamide hydrochloride 6h

[0383] 6 g (80 mg, 233 μmol) of compound was dissolved in dichloromethane (4 mL), and 4 M hydrogen chloride solution of 1,4-dioxane (4 mL) was added. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain crude title compound 6h (65 mg). The product was used directly in the next step of the reaction without purification.

[0384] MS m / z(ESI):244.3[M+1].

[0385] Step 7

[0386] 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-methylpyridin-2-carboxamide 6

[0387] 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 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 obtain the title compound 6 (5 mg, yield: 4.6%).

[0388] MS m / z(ESI):434.2[M+1].

[0389] 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).

[0390] Example 7

[0391] 4-Fluoro-5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalo-6-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyridine

[0392] 7-Azazole-2(4H)-yl)-N-methylpyridine-2-carboxamide

[0393]

[0394] first step

[0395] 2-(4-fluoro-6-(methoxycarbonyl)pyridin-3-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid tert-butyl ester

[0396] 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 patent application "WO2023051716"), compound 1a (1.56 g, 7.5 mmol, Shanghai Biotech) 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), and potassium phosphate (3.2 g, 15 mmol). The mixture was heated to 120 °C and stirred for 14 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-40%, flow rate: 30mL / min) to give title compound 7b (50mg, yield: 1.8%).

[0397] MS m / z(ESI): 363.4 [M+1].

[0398] Step 2

[0399] 4-Fluoro-5-(5-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalo-6-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpyridin-2-carboxamide 7

[0400] Using the synthetic route in Example 1, the starting material 1c in the second step was replaced with compound 7b to obtain title compound 7 (2 mg, yield: 12.4%).

[0401] MS m / z(ESI):452.4[M+1].

[0402] 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).

[0403] Biological evaluation

[0404] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0405] Test Example 1: Cell Proliferation Experiment

[0406] The following method detects intracellular ATP levels and, based on IC50... 50 Size evaluation of the disclosed compounds on DLD1 cells, DLD1 BRCA2- / - The inhibitory effect on the proliferation of MDA-MB-436 cells was investigated. The experimental methods are briefly described below:

[0407] I. Experimental Materials and Instruments

[0408] 1. DLD1, human colon cancer tumor cells (Nanjing Kebai, CBP60037)

[0409] 2. DLD1 BRCA2- / - Human BRCA2 gene knockout colon cancer cells (Creative biogene, CSC-RT0015)

[0410] 3. MDA-MB-436, human breast cancer cells (ATCC, HTB-130)

[0411] 4. Fetal bovine serum (GIBCO, 10091-148)

[0412] 5. CellTite-Glo reagent (Promega, G7573)

[0413] 6. 96-well cell culture plate (corning, 3903)

[0414] 7. Pancreatic enzyme (invitrogen, 25200-072)

[0415] 8. Microplate reader (BMG, Pherasta)

[0416] 9. Cell counter (Shanghai Ruiyu Biotechnology Co., Ltd., IC1000)

[0417] II. Experimental Procedure

[0418] DLD1 cells were cultured in RPMI-1640 medium containing 10% FBS, passaged 2-3 times per week at a passage ratio of 1:6 or 1:8. During passage, cells were digested with trypsin and transferred to centrifuge tubes, centrifuged at 1200 rpm for 3 minutes, the supernatant was discarded, and the cells were resuspended in fresh medium. 180 μL of the cell suspension was added to each 96-well cell culture plate, at a density of 2.78 × 10⁻⁶ cells / well. 3 Cells / mL, add only 180 μL of complete culture medium to the periphery of the 96-well plate.

[0419] DLD1 BRCA2- / - Cells were cultured in RPMI-1640 medium containing 10% FBS, passaged 2-3 times per week at a passage ratio of 1:6 or 1:8. During passage, cells were digested with trypsin and transferred to centrifuge tubes, centrifuged at 1200 rpm for 3 minutes, the supernatant was discarded, and the cells were resuspended in fresh medium. 180 μL of the cell suspension was added to each 96-well cell culture plate, resulting in a density of 8.34 × 10⁻⁶ cells / well. 3 Cells / mL, add only 180 μL of complete culture medium to the periphery of the 96-well plate.

[0420] MDA-MB-436 cells were cultured in Leibovitz's L-15 medium containing 10% FBS, 10 μg / mL insulin, and 16 μg / mL glutathione, and passaged 2–3 times per week at a passage ratio of 1:3 or 1:5. During passage, cells were digested with trypsin and transferred to centrifuge tubes, centrifuged at 1200 rpm for 3 minutes, and the supernatant was discarded. The cells were resuspended in fresh medium. 180 μL of the cell suspension was added to each 96-well cell culture plate, resulting in a density of 8.34 × 10⁻⁶ cells / well. 3 Cells / mL, add only 180 μL of complete culture medium to the periphery of the 96-well plate.

[0421] The culture plates were incubated in an incubator for 24 hours (37°C, 5% CO2).

[0422] The test samples were diluted to 2 mM with DMSO, and then serially diluted 3-fold to obtain 10 concentrations, with blank and control wells provided. 5 μL of the prepared gradient concentration test compound solutions were added to 95 μL of fresh culture medium. Then, 20 μL of the above drug-containing culture medium solution was added to the culture plate. The culture plate was incubated for 6 days (37℃, 5% CO2). In a 96-well cell culture plate, 90 μL of CellTiter-Glo reagent was added to each well, and the plate was incubated at room temperature in the dark for 5–10 min. The chemiluminescence signal values ​​were read using Pherastar, and the data were processed using GraphPad software. The results are shown in Table 1.

[0423] Table 1. The effects of the disclosed compounds on DLD1 and DLD1 BRCA2- / -Inhibitory effect on the proliferation of MDA-MB-436 cells

[0424]

[0425] Conclusion: The disclosed compound is effective against DLD1. BRCA2- / - It has a good inhibitory effect on the proliferation of MDA-MB-436 cells.

[0426] Test Example 2: Determination of the binding activity of the disclosed compounds on PARP1 and PARP2.

[0427] The in vitro PARP1 and PARP2 binding activity was tested using the following methods.

[0428] I. Experimental Materials and Instruments

[0429] 1. PARP1 recombinant protein (Sino Biotech, catalog number 11040-H08B);

[0430] 2. PARP2 recombinant protein (BPS, catalog number 80502)

[0431] 3. Fluorescent probe (made in-house using a compound with CAS number 1380359-84-1, Shanghai Hengrui);

[0432] 4. 384-well plate (Corning, 3575)

[0433] 5. Pherastar FS microplate reader (BMG Labtech)

[0434] II. Experimental Procedure

[0435] Add 8 μL of binding buffer to each well of a 384-well plate; dissolve the fluorescent probe in dimethyl sulfoxide (DMSO) and dilute to the appropriate concentration. Then, dilute the DMSO-prepared fluorescent probe 20-fold in binding buffer (50 mM Tris-HCl pH 8.0, 50 mM NaCl, 1 mM MgCl2, 0.1 mM EDTA, 0.01% IGEPA), adding 2 μL to each well; dissolve the test compound in DMSO and dilute to various concentration gradients as needed. Then, dilute each concentration of the compound prepared in DMSO 20-fold in binding buffer, adding 2 μL to each well; dilute PARP1 or PARP2 protein to the appropriate concentration using binding buffer, adding 8 μL / well to a black 384-well plate, mixing thoroughly, and incubating at 25°C for 40 minutes. Read the signal values ​​using the FP program in the Pherastar FS microplate reader. Data were processed using GraphPad software.

[0436] The PARP1 and PARP2 binding inhibitory activities of the disclosed compounds were determined by the above experiments, and the measured IC50 values ​​were... 50 The values ​​are shown in Table 2.

[0437] Table 2 shows the inhibitory activity of the compounds disclosed in this study on PARP1 and PARP2 binding.

[0438]

[0439] Conclusion: The compound disclosed herein exhibits selective inhibition of PARP1.

[0440] Test Example 3: PARP1 Enzyme Activity Assay

[0441] The following in vitro screening assays are used to determine the inhibitory effect of the compounds disclosed herein on PARP1 enzyme activity.

[0442] The following experiments used a PARP1 chemiluminescence assay kit (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 chemiluminescence assay kit is the use of biotinylated NAD+. By measuring the intensity of the chemiluminescent signal, the amount of NAD+ in the reaction system can be determined. + The level of the test compound was used to calculate the degree of inhibition of PARP1 enzyme activity.

[0443] For detailed experimental procedures and preparation of reagents such as histone mixture, master mixture, assay buffer, and ELISA ECL Substrate, please refer to the PARP1 chemiluminescence assay kit instructions.

[0444] The experimental procedure is briefly described as follows: A 96-well plate was coated with histone mixture and incubated overnight at 4°C. Blocking buffer 3 was used to block the plate for 90 minutes at room temperature. 20 μl of 2 ng / μl PARP1 enzyme and 25 μl of Master mixture were added to each well. The test compound was dissolved in dimethyl sulfoxide and then diluted with buffer to the required concentration, with 5 μl added to each well. After mixing, the plate was incubated at room temperature for 1 hour, followed by the addition of streptavidin-labeled 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 the data were processed using GraphPad software to calculate the inhibition rate of the compound on PARP1 enzyme activity.

[0445] IC of the compound50 The value can be calculated from the inhibition rate at different concentrations.

[0446]

[0447] Conclusion: The compound disclosed herein has significant inhibitory activity against the proliferation of PARP1 kinase.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is a pyrazol group; Ring B is pyridinyl; G 2 For CH; G 3 For CH; R 0 It is a halogen; R 1a C 1-6 alkyl; Each R 3 They may be the same or different, and each is independently selected from halogens and -C(O)NR. 7e R 7f ; R 7e R 7f They may be the same or different, and each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl; m is 1; n is 1; s is 0; and t can be 0, 1, 2 or 3.

2. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (II) or a pharmaceutically acceptable salt thereof is: in: X is a nitrogen atom; Y represents CH; R 6a It is a hydrogen atom; R 6b It is a hydrogen atom; R 0 R 1a R 3 , n and t are as defined in claim 1.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 It is either F or C(O)NHCH3.

4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein t is 0, 1 or 2.

5. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 0 It is F.

6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1a It is a methyl group.

7. A compound or a pharmaceutically acceptable salt thereof, selected from any of the following compounds: 。 8. A compound of general formula (IIa) or a salt thereof: in: R 3 -C(O)NR 7e R 7f ; t is 1; X is N; Y represents CH; n is 1; R 7e R 7f They may be the same or different, and each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl.

9. A method for preparing a compound of 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 undergoes a nucleophilic substitution reaction with a compound of general formula (Ib) to give a compound of general formula (I) or a pharmaceutically usable salt thereof; in: L represents a halogen; 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.

10. The method according to claim 9, wherein the salt of the general formula (Ia) is a hydrochloride.

11. The method of claim 9, wherein L is Br.

12. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

13. Use of the compound of general formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, in the preparation of a PARP1 inhibitor.

14. Use of the compound of general formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, in the preparation of a medicament for the treatment and / or prevention of colorectal cancer or breast cancer.

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