WO2024032410A1 - 哌嗪类化合物和pd-1抑制剂或pd-l1抑制剂的组合物以及其治疗肿瘤的用途 - Google Patents

哌嗪类化合物和pd-1抑制剂或pd-l1抑制剂的组合物以及其治疗肿瘤的用途 Download PDF

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WO2024032410A1
WO2024032410A1 PCT/CN2023/110231 CN2023110231W WO2024032410A1 WO 2024032410 A1 WO2024032410 A1 WO 2024032410A1 CN 2023110231 W CN2023110231 W CN 2023110231W WO 2024032410 A1 WO2024032410 A1 WO 2024032410A1
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alkyl
independently
component
heterocyclic ring
halogens
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French (fr)
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朱钰沁
魏用刚
楚洪柱
叶飞
苏桂转
孙毅
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成都百裕制药股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings

Definitions

  • This application belongs to the field of medical technology and relates to drug combinations that can be used for anti-tumor. Specifically, the present application relates to compositions based on piperazine compounds and PD-1 inhibitor antibodies or PD-L1 inhibitors and their use in treating tumors.
  • PD 1, Pdcd 1 or CD279 is a 55KD receptor protein related to the CD28/CTLA4 costimulatory/inhibitory receptor family. Cancer cells express the PD 1 ligand PDL1, which they use to evade the host immune system. Marketed PD 1 inhibitors can significantly extend the overall survival of patients by interfering with tumor immunosuppression mechanisms. However, this treatment method can only induce responses in some patients, or some patients may have a good response when first taking the drug. , but the efficacy decreases or disappears after taking the medicine for a period of time. Therefore, new and improved therapies are urgently needed to enhance the therapeutic efficacy of existing therapies.
  • the applicant's PCT application PCT/CN2022/094124 records the use of a piperazine derivative for the treatment of cancer.
  • the compound described in the specification has high selectivity and significant inhibitory activity on PARP7.
  • it was unexpectedly found that the piperazine derivative combined with a PD-1 inhibitor antibody can significantly improve the anti-tumor effect of the PD-1 inhibitor antibody or PD-L1 inhibitor antibody.
  • the present invention provides a composition of a piperazine compound and a PD-1 inhibitor antibody or a PD-L1 inhibitor antibody and its use for treating tumors.
  • component A is a PD-1 inhibitor antibody or a PD-L1 inhibitor antibody
  • component B is a compound of formula (I) or its pharmaceutical composition.
  • X 1 is NH, O or a 4- to 6-membered heterocyclic ring, which contains 1 to 3 heteroatoms selected from N and O;
  • X 2 is O or single bond
  • X 3 and X 4 are each independently C or N;
  • R 1a and R 1b are each independently H, D or C 1-6 alkyl; or R 1a and R 1b and the attached carbon atom form a 3 to 5-membered cycloalkyl group;
  • R 2a and R 2b are each independently H, D or C 1-6 alkyl; or R 2a and R 2b and the attached carbon atom form a 3 to 5-membered cycloalkyl group;
  • R 3 is H, D, C 1-6 alkyl, halogen or cyano, and the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • R 4 and R 5 are each independently H, D or C 1-6 alkyl; or R 4 and R 5 and the attached carbon atom form a 3 to 5-membered cycloalkyl group;
  • R 10 is each independently C 1-6 alkyl, C 1-6 alkoxy, CONR 10a R 10b , halogen, cyano, S(O) 2 R 10c , SR 10d or 3 to 5-membered cycloalkyl,
  • the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by 1 to 3 halogens;
  • R 10a , R 10b , R 10c , and R 10d are each independently H, D or C 1-6 alkyl;
  • R a is C 1-6 alkyl, C 3-5 cycloalkyl, halogen or cyano, and the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • B is a 5 to 10-membered carbocyclic ring or heterocyclic ring, and the heterocyclic ring contains 1 to 3 heteroatoms selected from N, O and S;
  • C is a 5- to 6-membered heterocyclic ring, and the heterocyclic ring contains 1 to 3 N heteroatoms;
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2 or 3.
  • Component A is a PD-1 inhibitor antibody
  • component B is a compound of formula (I) or a pharmaceutically acceptable salt or steric compound thereof. Isomers or deuterated products, of which:
  • X 1 is NH, O or a 4- to 6-membered heterocyclic ring, which contains 1 to 3 heteroatoms selected from N and O;
  • X 2 is O or single bond
  • X 3 and X 4 are each independently C or N;
  • R 1a and R 1b are each independently H, D or C 1-6 alkyl
  • R 2a and R 2b are each independently H, D or C 1-6 alkyl; or R 2a and R 2b and the attached carbon atom form a 3 to 5-membered cycloalkyl group;
  • R 3 is H, D, C 1-6 alkyl, halogen or cyano, and the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • R 4 and R 5 are each independently H, D or C 1-6 alkyl; or R 4 and R 5 and the attached carbon atom form a 3 to 5-membered cycloalkyl group;
  • R 6 and R 7 are each independently H, D or C 1-6 alkyl
  • R 10 is each independently C 1-6 alkyl, C 1-6 alkoxy, CONR 10a R 10b , halogen, cyano, S(O) 2 R 10c , SR 10d or 3 to 5-membered cycloalkyl,
  • the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by 1 to 3 halogens;
  • R 10a , R 10b , R 10c , and R 10d are each independently H, D or C 1-6 alkyl;
  • R a is C 1-6 alkyl, C 3-5 cycloalkyl, halogen or cyano, and the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • B is a 5- to 6-membered carbocyclic ring or heterocyclic ring, and the heterocyclic ring contains 1 to 3 heteroatoms selected from N, O and S;
  • C is a 5- to 6-membered heterocyclic ring, and the 5- to 6-membered heterocyclic ring contains 1 to 3 N heteroatoms;
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2 or 3.
  • component A is a PD-1 inhibitor antibody
  • component B is a compound of formula (I-1) or a pharmaceutically acceptable salt thereof , stereoisomers or deuterated products:
  • X 1 is NH or a 4- to 6-membered heterocyclic ring, which contains 1 to 3 heteroatoms selected from N and O;
  • X 2 is O
  • X 3 and X 4 are each independently C or N;
  • R 1a and R 1b are each independently H, D or C 1-6 alkyl
  • R 2a and R 2b are each independently H, D or C 1-6 alkyl
  • R 3 is H, D, C 1-6 alkyl or halogen, and the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • R 4 and R 5 are each independently H, D or C 1-6 alkyl
  • R 6 and R 7 are each independently H, D or C 1-6 alkyl
  • R 10 is C 1-6 alkyl, C 1-6 alkoxy, cyano or SR 10d , and the C 1-6 alkyl, C 1-6 alkoxy is optionally substituted by 1 to 3 halogens ;
  • R 10d is H, D or C 1-6 alkyl
  • B is a 5- to 6-membered carbocyclic ring or heterocyclic ring, and the heterocyclic ring contains 1 to 3 heteroatoms selected from N, O and S;
  • C is a 5- to 6-membered heterocyclic ring, and the 5- to 6-membered heterocyclic ring contains 1 to 3 N heteroatoms;
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3.
  • component A is a PD-1 inhibitor antibody
  • component B is a compound of formula (I-2) or a pharmaceutically acceptable salt thereof , stereoisomers or deuterated products:
  • X 1 is NH
  • X 2 is O
  • R 1a and R 1b are each independently H, D or C 1-6 alkyl
  • R 2a and R 2b are each independently H, D or C 1-6 alkyl
  • R 3 is H, D, C 1-6 alkyl or halogen, and the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • R 4 and R 5 are each independently H, D or C 1-6 alkyl
  • R 6 and R 7 are each independently H, D or C 1-6 alkyl
  • R 10 is C 1-6 alkyl, C 1-6 alkoxy, cyano or SR 10d , and the C 1-6 alkyl, C 1-6 alkoxy is optionally substituted by 1 to 3 halogens ;
  • R 10d is H, D or C 1-6 alkyl
  • B is a 5- to 6-membered carbocyclic ring or heterocyclic ring, and the heterocyclic ring contains 1 to 3 heteroatoms selected from N, O and S;
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3.
  • component A is a PD-1 inhibitor antibody
  • component B is a compound of formula (I-2) or a pharmaceutically acceptable salt thereof , stereoisomers or deuterated products, wherein:
  • X 1 is NH
  • X 2 is O
  • R 1a and R 1b are each independently H, D or C 1-6 alkyl
  • R 2a and R 2b are each independently H, D or C 1-6 alkyl
  • R 3 is H, D, C 1-6 alkyl or halogen, and the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • R 4 and R 5 are each independently H, D or C 1-6 alkyl
  • R 6 and R 7 are each independently H, D or C 1-6 alkyl
  • R 10 is C 1-6 alkyl, cyano, or SR 10d , and the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • R 10d is H, D or C 1-6 alkyl
  • B is a 5- to 6-membered carbocyclic ring or heterocyclic ring, and the heterocyclic ring contains 1 to 3 heteroatoms selected from N, O and S;
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3.
  • component A is a PD-1 inhibitor antibody
  • component B is a compound of formula (I-2) or a pharmaceutically acceptable salt thereof , stereoisomers or deuterated products, wherein:
  • X 1 is selected from NH
  • X 2 is selected from O;
  • R 1a and R 1b are each independently selected from H, D or C 1-6 alkyl
  • R 2a and R 2b are each independently selected from H, D or C 1-6 alkyl
  • R 3 is H, D, C 1-6 alkyl or halogen, and the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • R 4 and R 5 are each independently H or D;
  • R 6 and R 7 are each independently H or D;
  • R 8 and R 9 are each independently H or D;
  • R 10 is CF 3 or SR 10d ;
  • R 10d is H, D or C 1-6 alkyl
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3.
  • component A is a PD-1 inhibitor antibody
  • component B is a compound of formula (I-2) or a pharmaceutically acceptable salt thereof , stereoisomers or deuterated products, wherein:
  • X 1 is selected from NH
  • X 2 is selected from O;
  • R 1a and R 1b are each independently selected from H, D or C 1-3 alkyl
  • R 2a and R 2b are each independently selected from H, D or C 1-3 alkyl
  • R 3 is selected from H, D or CF 3 ;
  • R 4 and R 5 are each independently selected from H or D;
  • R 6 and R 7 are each independently selected from H or D;
  • R 8 and R 9 are each independently selected from H or D;
  • R 10 is CF 3 ;
  • n 1, 2 or 3;
  • n 0, 1 or 2.
  • component A is a PD-1 inhibitor antibody
  • component B is a compound of formula (I-3) or a pharmaceutically acceptable salt thereof , stereoisomers or deuterated products:
  • X 1 is NH or a 4- to 6-membered heterocyclic ring, which contains 1 to 3 heteroatoms selected from N and O;
  • X 2 is O
  • R 1a and R 1b are each independently H, D or C 1-6 alkyl
  • R 2a and R 2b are each independently H, D or C 1-6 alkyl
  • R 4 and R 5 are each independently H, D or C 1-6 alkyl
  • R 6 and R 7 are each independently H, D or C 1-6 alkyl
  • R 10 is C 1-6 alkyl, C 1-6 alkoxy, cyano or SR 10d , and the C 1-6 alkyl, C 1-6 alkoxy is optionally substituted by 1 to 3 halogens ;
  • R 10d is H, D or C 1-6 alkyl
  • B is a 5- to 6-membered carbocyclic ring or heterocyclic ring, and the heterocyclic ring contains 1 to 3 heteroatoms selected from N, O and S;
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3.
  • component A is a PD-1 inhibitor antibody
  • component B is a compound of formula (I-3) or a pharmaceutically acceptable salt thereof , stereoisomers or deuterated products, wherein:
  • X 1 is NH or a 4- to 6-membered heterocyclic ring, which contains 1 to 3 heteroatoms selected from N and O;
  • X 2 is O
  • R 1a and R 1b are each independently H, D or C 1-3 alkyl
  • R 2a and R 2b are each independently H, D or C 1-3 alkyl
  • R 4 and R 5 are each independently H, D or C 1-3 alkyl
  • R 6 and R 7 are each independently H, D or C 1-3 alkyl
  • R 10 is C 1-6 alkyl, cyano or SR 10d , and the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • R 10d is H, D or C 1-6 alkyl
  • n 1, 2 or 3;
  • n 0, 1 or 2.
  • component A is a PD-1 inhibitor antibody
  • component B is a compound of formula (I-3) or a pharmaceutically acceptable salt thereof , stereoisomers or deuterated products, wherein:
  • X 1 is NH
  • X 2 is O
  • R 1a and R 1b are each independently H, D or C 1-3 alkyl
  • R 2a and R 2b are each independently H or D;
  • R 4 and R 5 are each independently H or D;
  • R 6 and R 7 are each independently H or D;
  • R 8 and R 9 are each independently H or D;
  • R 10 is CF 3 ;
  • n 1, 2 or 3;
  • n 0, 1 or 2.
  • component A is a PD-1 inhibitor antibody
  • component B is selected from the compounds shown below or their pharmaceutically acceptable salts, stereo Isomers or deuterated products:
  • Component A is Pembrolizumab, Nivolumab, Serplulimab, Pidilide Pidilizumab, Lambrolizumab, Atezolizumab, Toripalimab, Sintilimab, Tislelizumab Tislelizumab, Camrelizumab, Penpulimab, Zimberelimab, Envafolimab, Sugemalimab ), Dostarlimab, Cadonilimab, Cemiplimab, Retifanlimab, BMS-986213, HX-008, Geptanolimab, Palolizumab ( Prolgolimab), socazolimab, avelumab, adebrelimab, or durvalumab.
  • the pharmaceutical combination includes the above-mentioned component A and the above-mentioned component B, and one or more pharmaceutically acceptable excipients, diluents or carriers.
  • the total daily dose of component B is selected from 50-1500 mg, preferably 100-1000 mg, more preferably 400-800 mg, with the amount of free base as the measured value.
  • the invention relates to the use of the pharmaceutical combination to treat or prevent solid tumors.
  • the solid tumor is selected from the group consisting of non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, hormone receptor positive (HR+) breast cancer, PARP7 amplified advanced solid tumor, Colon cancer or lung cancer, preferably colon cancer or lung cancer, more preferably colon cancer.
  • the above-mentioned component A and the above-mentioned component B are administered simultaneously.
  • the above-mentioned component A and the above-mentioned component B are administered sequentially.
  • component A is administered first and then component B, or component B is administered first and then component A is administered.
  • Administration intervals can be hours, days, weeks or months.
  • the above-mentioned component A is administered by intravenous administration, and the administration frequency is twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, every Once a month, once every 3-6 months, preferably twice a week, once a week, once every two weeks or once every three weeks.
  • the above-mentioned component B is administered orally, and the frequency of administration is three times a day, twice a day, once a day, once every two days, once every three days, once every four days, or every five days.
  • the frequency of administration is three times a day, twice a day, once a day, once every two days, once every three days, once every four days, or every five days.
  • the compounds of the present invention combined with PD-1 inhibitors or PD-L1 inhibitors have better in vivo anti-tumor effects than PD-1 inhibitors or PD-L1 inhibitors alone, and demonstrate good safety and tolerance. receptive nature. It shows that the pharmaceutical combination of the present invention has significant synergistic effect.
  • Figure 1 is the structural formula of compound 1.
  • Figure 2 shows the tumor volume growth curve of tumor-bearing mice.
  • Figure 3 shows the body weight change rate of tumor-bearing mice.
  • compound 1 is compound 1 of PCT application PCT/CN2022/094124, and compound 1 is prepared according to its preparation method.
  • Colon cancer cell CT26 was purchased from ATCC. The culture conditions were DMEM medium plus 10% fetal calf serum and 1% penicillin-streptomycin, and cultured in a cell culture incubator containing 5% CO2 at 37°C. When the cells are in the exponential growth phase, trypsinize, collect cells, count, and inoculate.
  • the CT26 cell suspension was subcutaneously inoculated into the right flank of the mice, with 1 ⁇ 10 6 cells/mouse and an inoculation volume of 0.1 mL.
  • the tumor grows to about 30-80mm3 , 32 animals are screened and enrolled; according to the size of the tumor, they are divided into 4 groups according to the S-shaped grouping method, with 8 animals in each group.
  • the day of grouping was set as experimental day 0 (PG-D0), and administration began on day 1. Please see Table 1 for the group dosing schedule.
  • ig refers to intragastric administration
  • ip refers to intraperitoneal administration
  • BID refers to twice daily administration
  • BIW refers to twice weekly administration.
  • V 1/2 ⁇ a ⁇ b 2 , where a and b represent the long diameter and short diameter of the tumor respectively.
  • mice were weighed at least twice a week. ?
  • compound 1 combined with anti-PD-1 antibody has better in vivo anti-tumor effect than anti-PD-1 antibody alone, and shows good safety and tolerability. It shows that the pharmaceutical combination of the present invention has significant synergistic effect.

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Abstract

本申请涉及哌嗪类化合物和PD-1抑制剂抗体或PD-L1抑制剂抗体的组合以及其治疗肿瘤的用途。

Description

哌嗪类化合物和PD-1抑制剂或PD-L1抑制剂的组合物以及其治疗肿瘤的用途 技术领域
本申请属于医药技术领域，涉及可用于抗肿瘤的药物组合。具体的，本申请涉及基于哌嗪类化合物和PD-1抑制剂抗体或PD-L1抑制剂的组合物以及其治疗肿瘤的用途。
背景技术
程序性死亡1蛋白(PD 1、Pdcd 1或CD279)是一种与CD28/CTLA4共刺激/抑制受体家族相关的55KD受体蛋白。癌细胞表达PD 1的配体PD L1，它们借此避开宿主免疫系统。已上市的PD 1抑制剂通过干扰肿瘤免疫抑制机制能够显著延长患者的总生存期，然而，该种治疗方法只能在部分患者中引起应答，或者某些患者可能在首次用药时有良好的反应，但用药一段时间后疗效下降或消失。因此，亟待新的和改进的疗法以增强现有疗法的治疗效果。
发明内容
本申请人的PCT申请PCT/CN2022/094124记载了一种哌嗪衍生物在用于治疗癌症的用途，其中，说明书中描述的化合物对PARP7具有高度的选择性和显著的抑制活性。在后续的研究中意外发现，该哌嗪衍生物联合PD-1抑制剂抗体能够显著提高PD-1抑制剂抗体或PD-L1抑制剂抗体的抗肿瘤效果。
因此，本发明在于提供一种哌嗪类化合物和PD-1抑制剂抗体或PD-L1抑制剂抗体的组合物以及其治疗肿瘤的用途。
本发明的一个或多个实施方式提供至少两种组分的药物组合，组分A为PD-1抑制剂抗体或PD-L1抑制剂抗体，组分B为式(I)的化合物或者其药学上可接受的盐、立体异构体或氘代物：
其中：
X1为NH、O或4至6元杂环，所述4至6元杂环包含1至3个选自N和O的杂原子；
X2为O或单键；
X3、X4各自独立地为C或N；
R1a、R1b各自独立地为H、D或C1-6烷基；或者R1a、R1b与相连的碳原子形成3至5元环烷基；
R2a、R2b各自独立地为H、D或C1-6烷基；或者R2a、R2b与相连的碳原子形成3至5元环烷基；
R3为H、D、C1-6烷基、卤素或氰基，所述C1-6烷基任选地被1至3个卤素取代；
R4、R5各自独立地为H、D或C1-6烷基；或者R4、R5与相连的碳原子形成3至5元环烷基；
R6、R7各自独立地为H、D或C1-6烷基；或者R6、R7与相连的碳原子形成C＝O；
R8、R9各自独立地为H、D或C1-6烷基；或者R8、R9与相连的碳原子形成C＝O；或者R8与R9与相连的碳原子形成3至5元环烷基；
R10各自独立地为C1-6烷基、C1-6烷氧基、CONR10aR10b、卤素、氰基、S(O)2R10c、SR10d或3至5元环烷基，所述C1-6烷基、C1-6烷氧基任选地被1至3个卤素取代；
R10a、R10b、R10c、R10d各自独立地为H、D或C1-6烷基；
A为Ra为C1-6烷基、C3-5环烷基、卤素或氰基，所述C1-6烷基任选地被1至3个卤素取代；
B为5至10元的碳环或杂环，所述杂环包含1至3个选自N、O和S的杂原子；
C为5至6元杂环，所述杂环包含1至3个N杂原子；
m为1、2或3；
n为0、1、2或3；
p为0、1、2或3。
本发明的一个或多个实施方式提供至少两种组分的药物组合，组分A为PD-1抑制剂抗体，组分B为式(I)的化合物或者其药学上可接受的盐、立体异构体或氘代物，其中：
X1为NH、O或4至6元杂环，所述4至6元杂环包含1至3个选自N和O的杂原子；
X2为O或单键；
X3、X4各自独立地为C或N；
R1a、R1b各自独立地为H、D或C1-6烷基；
R2a、R2b各自独立地为H、D或C1-6烷基；或者R2a、R2b与相连的碳原子形成3至5元环烷基；
R3为H、D、C1-6烷基、卤素或氰基，所述C1-6烷基任选地被1至3个卤素所取代；
R4、R5各自独立地为H、D或C1-6烷基；或者R4、R5与相连的碳原子形成3至5元环烷基；
R6、R7各自独立地为H、D或C1-6烷基；
R8、R9各自独立地为H、D或C1-6烷基；或者R8、R9与相连的碳原子形成C＝O；
R10各自独立地为C1-6烷基、C1-6烷氧基、CONR10aR10b、卤素、氰基、S(O)2R10c、SR10d或3至5元环烷基，所述C1-6烷基、C1-6烷氧基任选地被1至3个卤素取代；
R10a、R10b、R10c、R10d各自独立地为H、D或C1-6烷基；
A为Ra为C1-6烷基、C3-5环烷基、卤素或者氰基，所述C1-6烷基任选地被1至3个卤素取代；
B为5至6元的碳环或杂环，所述杂环包含1至3个选自N、O和S的杂原子；
C为5至6元杂环，所述5至6元杂环包含1至3个N杂原子；
m为1、2或3；
n为0、1、2或3；
p为0、1、2或者3。
本发明的一个或多个实施方式提供至少两种组分的药物组合，组分A为PD-1抑制剂抗体，组分B为式(I-1)的化合物或者其药学上可接受的盐、立体异构体或氘代物：
其中：
X1为NH或4至6元杂环，所述4至6元杂环包含1至3个选自N和O的杂原子；
X2为O；
X3、X4各自独立地为C或N；
R1a、R1b各自独立地为H、D或C1-6烷基；
R2a、R2b各自独立地为H、D或C1-6烷基；
R3为H、D、C1-6烷基或卤素，所述C1-6烷基任选地被1至3个卤素取代；
R4、R5各自独立地为H、D或C1-6烷基；
R6、R7各自独立地为H、D或C1-6烷基；
R8、R9各自独立地为H、D或C1-6烷基；或者R8与R9与相连的碳原子形成C＝O；
R10为C1-6烷基、C1-6烷氧基、氰基或SR10d，所述C1-6烷基、C1-6烷氧基任选地被1至3个卤素取代；
R10d为H、D或C1-6烷基；
A为
B为5至6元碳环或杂环，所述杂环包含1至3个选自N、O和S的杂原子；
C为5至6元杂环，所述5至6元杂环包含1至3个N杂原子；
m为1、2或3；
n为0、1、2或3。
本发明的一个或多个实施方式提供至少两种组分的药物组合，组分A为PD-1抑制剂抗体，组分B为式(I-2)的化合物或者其药学上可接受的盐、立体异构体或氘代物：
其中：
X1为NH；
X2为O；
R1a、R1b各自独立地为H、D或C1-6烷基；
R2a、R2b各自独立地为H、D或C1-6烷基；
R3为H、D、C1-6烷基或卤素，所述C1-6烷基任选地被1至3个卤素取代；
R4、R5各自独立地为H、D或C1-6烷基；
R6、R7各自独立地为H、D或C1-6烷基；
R8、R9各自独立地为H、D或C1-6烷基；或者R8和R9与其相连的碳原子形成C＝O；
R10为C1-6烷基、C1-6烷氧基、氰基或SR10d，所述C1-6烷基、C1-6烷氧基任选地被1至3个卤素取代；
R10d为H、D或C1-6烷基；
A为
B为5至6元的碳环或杂环，所述杂环包含1至3个选自N、O和S的杂原子；
m为1、2或3；
n为0、1、2或3。
本发明的一个或多个实施方式提供至少两种组分的药物组合，组分A为PD-1抑制剂抗体，组分B为式(I-2)的化合物或者其药学上可接受的盐、立体异构体或氘代物，其中：
X1为NH；
X2为O；
R1a、R1b各自独立地为H、D或C1-6烷基；
R2a、R2b各自独立地为H、D或C1-6烷基；
R3为H、D、C1-6烷基或卤素，所述C1-6烷基任选地被1至3个卤素取代；
R4、R5各自独立地为H、D或C1-6烷基；
R6、R7各自独立地为H、D或C1-6烷基；
R8、R9各自独立地为H、D或C1-6烷基，或者R8与R9与相连的碳原子形成C＝O；
R10为C1-6烷基、氰基、或SR10d，所述C1-6烷基任选地被1至3个卤素取代；
R10d为H、D或C1-6烷基；
A为
B为5至6元的碳环或杂环，所述杂环包含1至3个选自N、O和S的杂原子；
m为1、2或3；
n为0、1、2或3。
本发明的一个或多个实施方式提供至少两种组分的药物组合，组分A为PD-1抑制剂抗体，组分B为式(I-2)的化合物或者其药学上可接受的盐、立体异构体或氘代物，其中：
X1选自NH；
X2选自O；
R1a、R1b各自独立地选自H、D或C1-6烷基；
R2a、R2b各自独立地选自H、D或C1-6烷基；
R3为H、D、C1-6烷基或卤素，所述C1-6烷基任选地被1至3个卤素取代；
R4、R5各自独立地为H或D；
R6、R7各自独立地为H或D；
R8、R9各自独立地为H或D；
R10为CF3或SR10d；
R10d为H、D或C1-6烷基；
A为
B为
m为1、2或3；
n为0、1、2或3。
本发明的一个或多个实施方式提供至少两种组分的药物组合，组分A为PD-1抑制剂抗体，组分B为式(I-2)的化合物或者其药学上可接受的盐、立体异构体或氘代物，其中：
X1选自NH；
X2选自O；
R1a、R1b各自独立地选自H、D或C1-3烷基；
R2a、R2b各自独立地选自H、D或C1-3烷基；
R3选自H、D或者CF3；
R4、R5各自独立地选自H或D；
R6、R7各自独立地选自H或D；
R8、R9各自独立地选自H或D；
R10为CF3；
A为
B为
m为1、2或3；
n为0、1或2。
本发明的一个或多个实施方式提供至少两种组分的药物组合，组分A为PD-1抑制剂抗体，组分B为式(I-3)的化合物或者其药学上可接受的盐、立体异构体或氘代物：
其中：
X1为NH或4至6元杂环，所述4至6元杂环包含1至3个选自N和O的杂原子；
X2为O；
R1a、R1b各自独立地为H、D或C1-6烷基；
R2a、R2b各自独立地为H、D或C1-6烷基；
R4、R5各自独立地为H、D或C1-6烷基；
R6、R7各自独立地为H、D或C1-6烷基；
R8、R9各自独立地为H、D或C1-6烷基；或者R8、R9与相连的碳原子形成C＝O；
R10为C1-6烷基、C1-6烷氧基、氰基或SR10d，所述C1-6烷基、C1-6烷氧基任选地被1至3个卤素取代；
R10d为H、D或C1-6烷基；
A为
B为5至6元的碳环或杂环，所述杂环包含1至3个选自N、O和S的杂原子；
m为1、2或3；
n为0、1、2或3。
本发明的一个或多个实施方式提供至少两种组分的药物组合，组分A为PD-1抑制剂抗体，组分B为式(I-3)的化合物或者其药学上可接受的盐、立体异构体或氘代物，其中：
X1为NH或4至6元杂环，所述4至6元杂环包含1至3个选自N和O的杂原子；
X2为O；
R1a、R1b各自独立地为H、D或C1-3烷基；
R2a、R2b各自独立地为H、D或C1-3烷基；
R4、R5各自独立地为H、D或C1-3烷基；
R6、R7各自独立地为H、D或C1-3烷基；
R8、R9各自独立地为H、D或C1-3烷基；或者R8与R9与相连的碳原子形成C＝O；
R10为C1-6烷基、氰基或SR10d，所述C1-6烷基任选地被1至3个卤素取代；
R10d为H、D或C1-6烷基；
A为
B为
m为1、2或3；
n为0、1或2。
本发明的一个或多个实施方式提供至少两种组分的药物组合，组分A为PD-1抑制剂抗体，组分B为式(I-3)的化合物或者其药学上可接受的盐、立体异构体或氘代物，其中：
X1为NH；
X2为O；
R1a、R1b各自独立地为H、D或C1-3烷基；
R2a、R2b各自独立地为H或D；
R4、R5各自独立地为H或D；
R6、R7各自独立地为H或D；
R8、R9各自独立地为H或D；
R10为CF3；
A为
B为
m为1、2或3；
n为0、1或2。
本发明的一个或多个实施方式提供至少两种组分的药物组合，组分A为PD-1抑制剂抗体，组分B选自以下所示的化合物或者其药学上可接受的盐、立体异构体或氘代物：




本发明的一个或多个实施方式提供至少两种组分的药物组合，组分A为派姆单抗(Pembrolizumab)、纳武单抗(Nivolumab)、斯鲁利单抗(Serplulimab)、皮地利珠单抗(Pidilizumab)、兰伯丽珠单抗(Lambrolizumab)、阿特珠单抗(Atezolizumab)、特瑞普利单抗(Toripalimab)、信迪利单抗(Sintilimab)、替雷利珠单抗(Tislelizumab)、卡瑞利珠单抗(Camrelizumab)、派安普利单抗(Penpulimab)、赛帕利单抗(Zimberelimab)、恩沃利单抗(Envafolimab)、舒格利单抗(Sugemalimab)、多塔利单抗(Dostarlimab)、 卡度尼利单抗(Cadonilimab)、西米普利单抗(Cemiplimab)、瑞弗利单抗(Retifanlimab)、BMS-986213、HX-008、杰诺单抗(Geptanolimab)、帕洛利单抗(Prolgolimab)、索卡佐利单抗(Socazolimab)、阿维鲁单抗(Avelumab)、阿得贝利单抗(Adebrelimab)或者度伐利尤单抗(Durvalumab)。
本发明的一个或多个实施方式中，该药物组合包含上述组分A和上述组分B，以及一种或多种可药用的赋型剂、稀释剂或载体。
本发明的一个或多个实施方式中，所述的组分B每日总剂量选自50-1500mg，优选100-1000mg，更优选400-800mg，以游离碱的量为测量值。
本发明的一个或多个实施方式中，本发明涉及该药物组合治疗或预防实体瘤的用途。
本发明的一个或多个实施方式中，所述实体瘤选自非小细胞肺癌、头颈部鳞癌、食管鳞癌、激素受体阳性(HR+)乳腺癌、PARP7扩增的晚期实体瘤、结肠癌或肺癌，优选结肠癌或肺癌，更优选结肠癌。
本发明的一个或多个实施方式中，上述组分A和上述组分B同时给予。
本发明的一个或多个实施方式中，上述组分A和上述组分B依次给予。例如先给予组分A，再给予组分B，或者先给予组分B，再给予组分A。施用间隔可以为数小时，数天，数周或数月。
本发明的一个或多个实施方式中，上述组分A通过静脉内给药给予，给药频率为每周两次、每周一次、每二周一次、每三周一次、每四周一次、每月一次、每3-6个月一次，优选每周两次、每周一次、每二周一次或每三周一次。
本发明的一个或多个实施方式中，上述组分B口服给予，给药频率为每天三次、每天两次、每天一次、每两天一次、每三天一次、每四天一次、每五天一次、每六天一次、每周一次、每二周一次、每三周一次、每四周一次，优选每天两次或每天一次。
本发明的优点
本发明的化合物联用PD-1抑制剂或PD-L1抑制剂，较PD-1抑制剂或PD-L1抑制剂单用具有更好的体内抗肿瘤效应，且体现出良好的安全性和耐受性。表明本发明药物组合具有显著协同效果。
附图说明
图1为化合物①的结构式。
图2显示荷瘤小鼠肿瘤体积生长曲线。
图3显示荷瘤小鼠体重变化率。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果，旨在帮助阅读者更好地理解本发明的实质和特点，不作为对本案可实施范围的限定。
下面结合附图对本发明做进一步详细描述：
实施例中化合物①为PCT申请PCT/CN2022/094124的化合物1，化合物①按照其制备方法制备得到。
CT26小鼠荷瘤模型中的药效试验
1、实验步骤
1.1细胞培养
结肠癌细胞CT26购自ATCC，培养条件为DMEM培养基中加10％胎牛血清以及1％青链霉素，于37℃、含5％CO2的细胞培养箱中培养。当细胞呈指数生长期时，胰酶消化、收集细胞，计数，接种。
1.2分组及给药
BALB/c小鼠实验室环境适应后，CT26细胞悬液于小鼠右肋部皮下接种，1×106细胞/只，接种体积为0.1mL。待肿瘤生长至30-80mm3左右时，筛选32只动物入组；根据肿瘤体积大小按S形分组法分为4组，每组8只。分组当天设为实验第0天(PG-D0)，给药开始于第1天。分组给药方案详见表1。
表1 给药方案

注：i.g.指灌胃给药；i.p.指腹腔给药；BID：指每天两次给药；BIW:指每周两次给药。
2、测定方法
2.1肿瘤体积
每周2次用游标卡尺测量肿瘤直径，计算肿瘤体积，绘制肿瘤生长曲线，肿瘤体积 (V)计算公式为：
V＝1/2×a×b2，其中a、b分别表示肿瘤长径、短径。
2.2小鼠体重
药物治疗周期内，每周至少称量2次小鼠体重。？
3、实验结果
如图2、图3所示，化合物①联用anti-PD-1抗体，较anti-PD-1抗体单用具有更好的体内抗肿瘤效应，且体现出良好的安全性和耐受性。表明本发明药物组合具有显著协同效果。
本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，上述实施方案是示例性的，不能理解为对本发明的限制，对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。

Claims (19)

  1. 至少两种组分的药物组合，组分A为PD-1抑制剂抗体或PD-L1抑制剂抗体，组分B为式(I)的化合物或者其药学上可接受的盐、立体异构体或氘代物：
    其中：
    X1为NH、O或4至6元杂环，所述4至6元杂环包含1至3个选自N和O的杂原子；
    X2为O或单键；
    X3、X4各自独立地为C或N；
    R1a、R1b各自独立地为H、D或C1-6烷基；或者R1a、R1b与相连的碳原子形成3至5元环烷基；
    R2a、R2b各自独立地为H、D或C1-6烷基；或者R2a、R2b与相连的碳原子形成3至5元环烷基；
    R3为H、D、C1-6烷基、卤素或氰基，所述C1-6烷基任选地被1至3个卤素取代；
    R4、R5各自独立地为H、D或C1-6烷基；或者R4、R5与相连的碳原子形成3至5元环烷基；
    R6、R7各自独立地为H、D或C1-6烷基；或者R6、R7与相连的碳原子形成C＝O；
    R8、R9各自独立地为H、D或C1-6烷基；或者R8、R9与相连的碳原子形成C＝O；或者R8与R9与相连的碳原子形成3至5元环烷基；
    R10各自独立地为C1-6烷基、C1-6烷氧基、CONR10aR10b、卤素、氰基、S(O)2R10c、SR10d或3至5元环烷基，所述C1-6烷基、C1-6烷氧基任选地被1至3个卤素取代；
    R10a、R10b、R10c、R10d各自独立地为H、D或C1-6烷基；
    A为Ra为C1-6烷基、C3-5环烷基、卤素或氰基，所述C1-6烷基任选地被1至3个卤素取代；
    B为5至10元的碳环或杂环，所述杂环包含1至3个选自N、O和S的杂原子；
    C为5至6元杂环，所述杂环包含1至3个N杂原子；
    m为1、2或3；
    n为0、1、2或3；
    p为0、1、2或3。
  2. 根据权利要求1所述的药物组合，其中所述组分B为式(I)的化合物或者其药学上可接受的盐、立体异构体或氘代物，其中：
    X1为NH、O或4至6元杂环，所述4至6元杂环包含1至3个选自N和O的杂原子；
    X2为O或单键；
    X3、X4各自独立地为C或N；
    R1a、R1b各自独立地为H、D或C1-6烷基；
    R2a、R2b各自独立地为H、D或C1-6烷基；或者R2a、R2b与相连的碳原子形成3至5元环烷基；
    R3为H、D、C1-6烷基、卤素或氰基，所述C1-6烷基任选地被1至3个卤素所取代；
    R4、R5各自独立地为H、D或C1-6烷基；或者R4、R5与相连的碳原子形成3至5元环烷基；
    R6、R7各自独立地为H、D或C1-6烷基；
    R8、R9各自独立地为H、D或C1-6烷基；或者R8、R9与相连的碳原子形成C＝O；
    R10各自独立地为C1-6烷基、C1-6烷氧基、CONR10aR10b、卤素、氰基、S(O)2R10c、SR10d或3至5元环烷基，所述C1-6烷基、C1-6烷氧基任选地被1至3个卤素取代；
    R10a、R10b、R10c、R10d各自独立地为H、D或C1-6烷基；
    A为Ra为C1-6烷基、C3-5环烷基、卤素或者氰基，所述C1-6烷基任选地被1至3个卤素取代；
    B为5至6元的碳环或杂环，所述杂环包含1至3个选自N、O和S的杂原子；
    C为5至6元杂环，所述5至6元杂环包含1至3个N杂原子；
    m为1、2或3；
    n为0、1、2或3；
    p为0、1、2或者3。
  3. 根据权利要求2所述的药物组合，其中所述组分B为式(I-1)所示的化合物或者其药学上可接受的盐、立体异构体或氘代物，其中：
    其中：
    X1为NH或4至6元杂环，所述4至6元杂环包含1至3个选自N和O的杂原子；
    X2为O；
    X3、X4各自独立地为C或N；
    R1a、R1b各自独立地为H、D或C1-6烷基；
    R2a、R2b各自独立地为H、D或C1-6烷基；
    R3为H、D、C1-6烷基或卤素，所述C1-6烷基任选地被1至3个卤素取代；
    R4、R5各自独立地为H、D或C1-6烷基；
    R6、R7各自独立地为H、D或C1-6烷基；
    R8、R9各自独立地为H、D或C1-6烷基；或者R8与R9与相连的碳原子形成C＝O；
    R10为C1-6烷基、C1-6烷氧基、氰基或SR10d，所述C1-6烷基、C1-6烷氧基任选地被1至3个卤素取代；
    R10d为H、D或C1-6烷基；
    A为
    B为5至6元碳环或杂环，所述杂环包含1至3个选自N、O和S的杂原子；
    C为5至6元杂环，所述5至6元杂环包含1至3个N杂原子；
    m为1、2或3；
    n为0、1、2或3。
  4. 根据权利要求3所述的药物组合，其中所述组分B为式(I-2)所示的化合物或者其药学上可接受的盐、立体异构体或氘代物，其中：
    其中：
    X1为NH；
    X2为O；
    R1a、R1b各自独立地为H、D或C1-6烷基；
    R2a、R2b各自独立地为H、D或C1-6烷基；
    R3为H、D、C1-6烷基或卤素，所述C1-6烷基任选地被1至3个卤素取代；
    R4、R5各自独立地为H、D或C1-6烷基；
    R6、R7各自独立地为H、D或C1-6烷基；
    R8、R9各自独立地为H、D或C1-6烷基；或者R8和R9与其相连的碳原子形成C＝O；
    R10为C1-6烷基、C1-6烷氧基、氰基或SR10d，所述C1-6烷基、C1-6烷氧基任选地被1至3个卤素取代；
    R10d为H、D或C1-6烷基；
    A为
    B为5至6元的碳环或杂环，所述杂环包含1至3个选自N、O和S的杂原子；
    m为1、2或3；
    n为0、1、2或3。
  5. 根据权利要求4所述的药物组合，其中所述组分B为式(I-2)所示的化合物或者其药学上可接受的盐、立体异构体或氘代物，其中：
    X1为NH；
    X2为O；
    R1a、R1b各自独立地为H、D或C1-6烷基；
    R2a、R2b各自独立地为H、D或C1-6烷基；
    R3为H、D、C1-6烷基或卤素，所述C1-6烷基任选地被1至3个卤素取代；
    R4、R5各自独立地为H、D或C1-6烷基；
    R6、R7各自独立地为H、D或C1-6烷基；
    R8、R9各自独立地为H、D或C1-6烷基，或者R8与R9与相连的碳原子形成C＝O；
    R10为C1-6烷基、氰基、或SR10d，所述C1-6烷基任选地被1至3个卤素取代；
    R10d为H、D或C1-6烷基；
    A为
    B为5至6元的碳环或杂环，所述杂环包含1至3个选自N、O和S的杂原子；
    m为1、2或3；
    n为0、1、2或3。
  6. 根据权利要求5所述的药物组合，其中所述组分B为式(I-2)所示的化合物或者其药学上可接受的盐、立体异构体或氘代物，其中：
    X1选自NH；
    X2选自O；
    R1a、R1b各自独立地选自H、D或C1-6烷基；
    R2a、R2b各自独立地选自H、D或C1-6烷基；
    R3为H、D、C1-6烷基或卤素，所述C1-6烷基任选地被1至3个卤素取代；
    R4、R5各自独立地为H或D；
    R6、R7各自独立地为H或D；
    R8、R9各自独立地为H或D；
    R10为CF3或SR10d；
    R10d为H、D或C1-6烷基；
    A为
    B为
    m为1、2或3；
    n为0、1、2或3。
  7. 根据权利要求6所述的药物组合，其中所述组分B为式(I-2)所示的化合物或者其药学上可接受的盐、立体异构体或氘代物，其中：
    X1选自NH；
    X2选自O；
    R1a、R1b各自独立地选自H、D或C1-3烷基；
    R2a、R2b各自独立地选自H、D或C1-3烷基；
    R3选自H、D或者CF3；
    R4、R5各自独立地选自H或D；
    R6、R7各自独立地选自H或D；
    R8、R9各自独立地选自H或D；
    R10为CF3；
    A为
    B为
    m为1、2或3；
    n为0、1或2。
  8. 根据权利要求1所述的药物组合，其中所述组分B为式(I-3)所示的化合物或者其药学上可接受的盐、立体异构体或氘代物，其中：
    其中：
    X1为NH或4至6元杂环，所述4至6元杂环包含1至3个选自N和O的杂原子；
    X2为O；
    R1a、R1b各自独立地为H、D或C1-6烷基；
    R2a、R2b各自独立地为H、D或C1-6烷基；
    R4、R5各自独立地为H、D或C1-6烷基；
    R6、R7各自独立地为H、D或C1-6烷基；
    R8、R9各自独立地为H、D或C1-6烷基；或者R8、R9与相连的碳原子形成C＝O；
    R10为C1-6烷基、C1-6烷氧基、氰基或SR10d，所述C1-6烷基、C1-6烷氧基任选地被1至3个卤素取代；
    R10d为H、D或C1-6烷基；
    A为
    B为5至6元的碳环或杂环，所述杂环包含1至3个选自N、O和S的杂原子；
    m为1、2或3；
    n为0、1、2或3。
  9. 根据权利要求8所述的药物组合，其中所述组分B为式(I-3)所示的化合物或者其药学上可接受的盐、立体异构体或氘代物，其中：
    X1为NH或4至6元杂环，所述4至6元杂环包含1至3个选自N和O的杂原子；
    X2为O；
    R1a、R1b各自独立地为H、D或C1-3烷基；
    R2a、R2b各自独立地为H、D或C1-3烷基；
    R4、R5各自独立地为H、D或C1-3烷基；
    R6、R7各自独立地为H、D或C1-3烷基；
    R8、R9各自独立地为H、D或C1-3烷基；或者R8与R9与相连的碳原子形成C＝O；
    R10为C1-6烷基、氰基或SR10d，所述C1-6烷基任选地被1至3个卤素取代；
    R10d为H、D或C1-6烷基；
    A为
    B为
    m为1、2或3；
    n为0、1或2。
  10. 根据权利要求9所述的药物组合，其中所述组分B为式(I-3)所示的化合物或者其药学上可接受的盐、立体异构体或氘代物，其中：
    X1为NH；
    X2为O；
    R1a、R1b各自独立地为H、D或C1-3烷基；
    R2a、R2b各自独立地为H或D；
    R4、R5各自独立地为H或D；
    R6、R7各自独立地为H或D；
    R8、R9各自独立地为H或D；
    R10为CF3；
    A为
    B为
    m为1、2或3；
    n为0、1或2。
  11. 根据权利要求1至10中任一项所述的药物组合，其中所述组分B选自以下所示的化合物或者其药学上可接受的盐、立体异构体或氘代物：





  12. 根据权利要求1所述的药物组合，其中所述组分A为派姆单抗(Pembrolizumab)、纳武单抗(Nivolumab)、斯鲁利单抗(Serplulimab)、皮地利珠单抗(Pidilizumab)、兰伯丽珠单抗(Lambrolizumab)、阿特珠单抗(Atezolizumab)、特瑞普利单抗(Toripalimab)、信迪利单抗(Sintilimab)、替雷利珠单抗(Tislelizumab)、卡瑞利珠单抗(Camrelizumab)、派安普利单抗(Penpulimab)、赛帕利单抗(Zimberelimab)、恩沃利单抗(Envafolimab)、舒格利单抗(Sugemalimab)、多塔利单抗(Dostarlimab)、卡度尼利单抗(Cadonilimab)、西米普利单抗(Cemiplimab)、瑞弗利单抗(Retifanlimab)、BMS-986213、HX-008、杰诺单抗(Geptanolimab)、帕洛利单抗(Prolgolimab)、索卡佐利单抗(Socazolimab)、阿维鲁单抗(Avelumab)、阿得贝利单抗(Adebrelimab)或者度伐利尤单抗(Durvalumab)。
  13. 根据权利要求1至12中任一项所述的至少两种组分的药物组合，包含权利要求12所述的组分A和权利要求1至11中任一项所述的组分B，以及一种或多种可药用的赋型剂、稀释剂或载体。
  14. 根据权利要求1至13中任一项所述的药物组合，其中所述的组分B每日总剂量选自50-1500mg，优选100-1000mg，更优选400-800mg，以游离碱的量为测量值。
  15. 权利要求1至14中任一项中所述的药物组合在治疗或预防实体瘤的用途。
  16. 根据权利要求15所述的用途，其特征在于，权利要求12所述的组分A和权利要求1至11中任一项所述的组分B同时给予。
  17. 根据权利要求15所述的用途，其特征在于，权利要求12所述的组分A和权利要求1至11中任一项所述的组分B依次给予。
  18. 根据权利要求15至17中任一项所述的用途，其特征在于，权利要求12所述的组分A通过静脉内给药给予，给药频率为每周两次、每周一次、每二周一次、每三周一次、每四周一次、每月一次、每3-6个月一次，优选每周两次、每周一次、每二周一次或每三周一次。
  19. 根据权利要求15至17中任一项所述的用途，其特征在于，权利要求1至11中任一项所述的组分B口服给予，给药频率为每天两次或每天一次。
PCT/CN2023/110231 2022-08-09 2023-07-31 哌嗪类化合物和pd-1抑制剂或pd-l1抑制剂的组合物以及其治疗肿瘤的用途 WO2024032410A1 (zh)

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