WO2023198060A1

WO2023198060A1 - Pharmaceutical combination of proteasome inhibitor and anti-pd-1 antibody

Info

Publication number: WO2023198060A1
Application number: PCT/CN2023/087619
Authority: WO
Inventors: 丁大伟; 于鼎; 王训强; 汤少男
Original assignee: 正大天晴药业集团股份有限公司
Priority date: 2022-04-12
Filing date: 2023-04-11
Publication date: 2023-10-19

Abstract

The present application belongs to the technical field of medicines, and relates to a pharmaceutical combination of a proteasome inhibitor and an anti-PD-1 antibody. Specifically, the present application relates to a pharmaceutical combination of compounds of formula (I') of the present disclosure, prodrugs thereof or pharmaceutically acceptable salts thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, and the use thereof in preventing or treating solid tumors.

Description

Drug combinations of proteasome inhibitors and anti-PD-1 antibodies

Cross-references to related applications

This disclosure claims priority and rights to the following Chinese patent applications filed with the State Intellectual Property Office of China, the contents of which are incorporated herein by reference in their entirety: Chinese Patent No. 202210378911.2 filed on April 12, 2022 Apply.

Technical field

The present disclosure belongs to the field of medical technology and relates to a pharmaceutical combination of a proteasome inhibitor and an anti-PD-1 antibody. Specifically, it relates to the pharmaceutical combination of the compound of formula I' of the present disclosure, its prodrug or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or its antigen-binding fragment and its use in the prevention or treatment of solid tumors.

Background technique

The ubiquitin-proteasome pathway is an important pathway for degrading intracellular proteins. Proteins are ubiquitinated through interactions with ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin ligases. The ubiquitinated-labeled proteins are catalyzed by 26S protease. recognized and degraded by the body. The 26S proteasome is composed of two parts: the 20S core particle and the 19S regulatory particle. Tumor cells are more sensitive to protein homeostasis due to their proliferation needs. Proteasome inhibitors inhibit the ubiquitin-proteasome pathway, leading to the accumulation of polyubiquitination-labeled proteins and affecting related signaling pathways, ultimately inducing tumor cells. The purpose of apoptosis.

WO2018157820A1 discloses compounds of formula I and other compounds, and WO2020025037A1 discloses compounds of formula II and other compounds, which are proteasome inhibitors.

PD-1 (programmed death-1, programmed death receptor 1) is a key immune checkpoint receptor expressed by activated T lymphocytes and B lymphocytes, and its ligands include at least PD-L1 and PD-L2. PD-L1 (Programmed death-ligand1), also known as CD274 or B7-H1, is a ligand of PD-1. The combination of PD-1 and PD-L1 mediates co-inhibitory signals of T cell activation, inhibits the killing function of T cells, and plays a negative regulatory role in the human immune response. Chinese patent document CN106977602A discloses an anti-PD-1 monoclonal antibody 14C12H1L1. This monoclonal antibody can very effectively block the combination of PD1 and PDL1 and shows good anti-tumor activity.

The biggest challenge encountered in the process of tumor immunotherapy is poor efficacy due to tumor immune tolerance and escape. The combination of small molecule anti-tumor compounds and anti-PD-1/PD-L1 antibodies is used to try to break the body's already existing The established immune tolerance to tumor cells has important theoretical significance and application value.

Contents of the invention

In one aspect, the present disclosure provides a pharmaceutical combination comprising a compound of formula I', an ester thereof or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof,

in,

Ring A is selected from phenyl or 5-10 membered heteroaryl;

Each R ¹ is independently selected from halogen, CN, OH, NH ₂ , C _1-6 alkyl or C _1-6 heteroalkyl, wherein the C _1-6 alkyl or C _1-6 heteroalkyl is either Optionally substituted with one or more groups selected from halogen, OH or _NH ;

n is selected from 0, 1, 2, 3, 4 or 5;

R ² and R ³ are each independently selected from H or C _1-6 alkyl.

In some embodiments, Ring A is selected from phenyl or 5-6 membered heteroaryl. In some embodiments, Ring A is selected from phenyl or pyridyl.

In some embodiments, each R ¹ is independently selected from halogen, CN, OH, NH ₂ , C _1-3 alkyl, or C _1-3 alkoxy. In some embodiments, each ^R1 is independently selected from fluorine or CN.

In some embodiments, n is selected from 1 or 2.

In some embodiments, R ² and R ³ are each independently selected from H.

In some embodiments, the compound of Formula I', its ester or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of Formula I, Formula I-1, Formula I-2 or Formula I-3, its ester or a pharmaceutically acceptable salt thereof. Take it with a grain of salt

On the other hand, the present disclosure provides a kit comprising a pharmaceutical combination, specifically comprising 1) a compound of formula I', its ester or a pharmaceutically acceptable salt thereof; 2) an anti-PD-1 antibody or its antigen binding fragment,

Also included are: instructions for use of the compound of formula I', its ester or a pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody or its antigen-binding fragment.

In some embodiments, the ester of the compound of Formula I' is a prodrug form of the compound of Formula I'.

In some embodiments, the ester of the compound of Formula I' is the malate ester of the compound of Formula I'. In some embodiments, the ratio of the number of molecules of the compound of formula I' to malic acid in the malic acid ester of the compound of formula I' is selected from 1:1.

In some embodiments, the malate ester of the compound of Formula I' is a prodrug form of the compound of Formula I'.

In some embodiments, the ester structure of the compound of Formula I' or the malate ester structure of the compound of Formula I' is selected from the group consisting of compounds of Formula II, Formula II-1, Formula II-2 or Formula II-3

In one aspect, the present disclosure provides a pharmaceutical combination comprising a compound of Formula I (or Formulas I-1 to I-3), an ester thereof or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof,

On the other hand, the present disclosure provides a kit, which includes a pharmaceutical combination, specifically including 1) a compound of formula I (or formulas I-1 to I-3), an ester thereof or a pharmaceutically acceptable salt thereof; 2 ) anti-PD-1 antibody or antigen-binding fragment thereof,

Also included: instructions for use of the compound of formula I (or formula I-1 to I-3), its ester or a pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody or its antigen-binding fragment,

In some embodiments, the ester of a compound of Formula I (or Formulas I-1 to I-3) is a prodrug form of a compound of Formula I (or Formulas I-1 to I-3).

In some embodiments, the ester of the compound of Formula I (or Formulas I-1 to I-3) is the malate ester of the compound of Formula I (or Formulas I-1 to I-3). In some embodiments, the molecular number ratio of the compound of Formula I (or Formula I-1 to I-3) and malic acid in the ester of the compound of Formula I (or Formula I-1 to I-3) is selected from 1:1 .

In some embodiments, the malate ester of the compound of Formula I (or Formulas I-1 to I-3) is a prodrug form of the compound of Formula I (or Formulas I-1 to I-3).

In some embodiments, the ester of the compound of Formula I is a compound of Formula II

In some embodiments, the ester of the compound of Formula I-1 is a compound of Formula II-1

In some embodiments, the ester of the compound of Formula I-2 is a compound of Formula II-2

In some embodiments, the ester of the compound of Formula I-3 is a compound of Formula II-3

On the other hand, the present disclosure provides a pharmaceutical combination comprising a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.

On the other hand, the present disclosure provides a kit comprising 1) a compound of formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof; 2) an anti-PD-1 antibody or an antigen-binding fragment thereof , and 3) Instructions for use of a compound of formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 and heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, wherein said LCDR1, LCDR2, and LCDR3 Containing the amino acid sequences shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 respectively, the HCDR1, HCDR2 and HCDR3 respectively include SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO: The amino acid sequence shown in 6.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 and heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3, said light chain complementarity determining regions LCDR1, LCDR2 and LCDR3. LCDR2 and LCDR3 are respectively composed of the amino acid sequences shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3. The heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3 are respectively composed of SEQ ID NO:4, SEQ ID NO:4. The amino acid sequence composition shown in ID NO:5 and SEQ ID NO:6.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that has more than 85% (including 86%, 87%, 88%, 89%, Light chain variable region and amino acid sequence 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 8 The amino acid sequence shown has more than 85% (including 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical heavy chain variable region.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region with an amino acid sequence set forth in SEQ ID NO:7 and a heavy chain variable region with an amino acid sequence set forth in SEQ ID NO:8. Change area.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that has more than 85% (including 86%, 87%, 88%, 89%, A light chain and amino acid sequence that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to that shown in SEQ ID NO: 10 The amino acid sequence has more than 85% (including 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical heavy chain.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain with an amino acid sequence set forth in SEQ ID NO:9 and a heavy chain with an amino acid sequence set forth in SEQ ID NO:10.

In some embodiments, the anti-PD-1 antibody is 14C12H1L1.

In other embodiments, the anti-PD-1 antibody is Nivolumab, Pembrolizumab, Toripalimab (JS-001), Sintilimab (IBI308), Camrelizumab (Camrelizumab), Tislelizumab (BGB-A317), Balstilimab (Balstilimab), Genosumab (GB226), LZM009, HLX10, AK103 (HX008 ), CS1003, SCT-I10A, F520, SG001 or cepalizumab (GLS-010).

In some embodiments, the pharmaceutical combination includes: a compound of formula I (or formula I-1 to I-3), an ester thereof (for example, a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof; and 14C12H1L1 or an antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination includes: a compound of Formula I (or Formulas I-1 to I-3) or its malate ester (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof; and 14C12H1L1 or an antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination includes: a compound of Formula I (or Formulas I-1 to I-3) or a pharmaceutically acceptable salt thereof; and 14C12H1L1 or an antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination includes: a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof; and 14C12H1L1 or an antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination contains a compound of formula I (or formula I-1 to I-3), or its ester (for example, formula II (or II-1 to II-3) in the range of 0.5 mg to 8.5 mg. ) compound) or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination includes 0.5 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg or the compound of formula I (or formula I-1 to I-3) or its ester (for example, the compound of formula II (or II-1 to II-3) within the range formed by any of the above values ) or its pharmaceutically acceptable salt.

In some embodiments, the pharmaceutical combination contains a compound of formula I (or formula I-1 to I-3), its ester (for example, formula II (or II-1 to II-3) in the range of 0.8mg-8.0mg ) compound) or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination contains 0.8 mg, 1.2 mg, 1.6 mg, 2.0 mg, 2.4 mg, 2.8 mg, 3.2 mg, 3.6 mg, 4.0 mg, 4.4 mg, 4.8 mg, 5.2 mg, 5.6 mg, 6.0 mg, 6.4 mg, 6.8 mg, 7.2 mg, 7.6 mg, 8.0 mg or a compound of formula I (or formulas I-1 to I-3) or a pharmaceutically acceptable salt thereof within the range formed by any of the above values.

In some embodiments, the pharmaceutical combination contains a compound of Formula I (or Formulas I-1 to I-3) or a pharmaceutically acceptable salt thereof in an amount of 4.0 mg to 8 mg. In some embodiments, the pharmaceutical combination contains a compound of Formula I (or Formulas I-1 to I-3) or a pharmaceutically acceptable salt thereof in an amount of 5.0 mg to 6 mg. In some embodiments, the pharmaceutical combination contains a compound of Formula I (or Formulas I-1 to I-3) or a pharmaceutically acceptable salt thereof in an amount of 4.0 mg to 5.6 mg. In some embodiments, the pharmaceutical combination contains a compound of Formula I (or Formulas I-1 to I-3) or a pharmaceutically acceptable salt thereof in an amount of 4.0 mg, 4.8 mg or 5.6 mg.

In some embodiments, the pharmaceutical combination contains a compound of formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof (in the form of formula II (or II-1 to II-3) Compound weight).

In some embodiments, the pharmaceutical combination includes 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 The compound of formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof (formula II (or II-1～II-3) compound weight).

In some embodiments, the pharmaceutical combination contains a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof in an amount of 5.0 mg to 7.0 mg. In some embodiments, the pharmaceutical combination contains a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof in an amount of 5.0 mg, 6.0 mg or 7.0 mg. In some embodiments, the pharmaceutical combination contains a compound of formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof in an amount of 6.0 mg.

In some embodiments, the pharmaceutical combination contains a compound of Formula II or a pharmaceutically acceptable salt thereof in the range of 1.0 mg to 10 mg (based on the weight of the compound of Formula II).

In some embodiments, the pharmaceutical combination contains approximately 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.1 mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 7.0mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 8.0mg, 8.5mg, 8.6mg, 8.7mg, 8.8mg, 8.9mg, 9.0mg , 9.5 mg, 10 mg or a range of the formula II compound or a pharmaceutically acceptable salt thereof (based on the weight of the formula II compound) within the range formed by any of the above values.

In some embodiments, the pharmaceutical combination includes an amount of about 5.5 mg to about 9.5 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II). In some embodiments, the pharmaceutical combination contains a compound of Formula II in an amount of approximately 6.0 mg to 9.0 mg. or a pharmaceutically acceptable salt thereof (based on the weight of the compound of formula II). In some embodiments, the pharmaceutical combination includes an amount of approximately 6.3 mg, 7.5 mg, or 8.8 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II). In some embodiments, the pharmaceutical combination includes an amount of approximately 7.5 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II).

In some embodiments, the pharmaceutical combination contains about 10 mg to about 1000 mg of an anti-PD-1 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination contains about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, approximately 1000 mg, or a range of any of the above values of an anti-PD-1 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination contains approximately 50-350 mg of anti-PD-1 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination contains approximately 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination of the present disclosure contains: 4.0 mg-5.6 mg of the compound of Formula I (or Formula I-1 to I-3) or its malate ester, or its pharmaceutically acceptable salt; and 50-350 mg of anti-PD-1 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination of the present disclosure includes: 5.0 mg to 7.0 mg (such as 6 mg) of a compound of formula II (or II-1 to II-3); and 50 mg to 350 mg of an anti-PD-1 antibody or its Antigen-binding fragments.

In some embodiments, the pharmaceutical combination of the present disclosure includes: 5.0 mg, 6.0 mg or 7.0 mg of a compound of formula II (or II-1 to II-3); and 100 mg or 200 mg of an anti-PD-1 antibody or its Antigen-binding fragments.

In some embodiments, the pharmaceutical combination of the present disclosure includes a compound of formula I (or formula I-1 to I-3), an ester thereof (for example, a compound of formula II (or II-1 to II-3)) or a pharmaceutical composition thereof. The weight ratio of the above acceptable salt and anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of 4 mg: 100 mg, 4.4 mg: 100 mg, 4.8 mg: 100 mg, 5.2 mg: 100 mg, 5.6 mg: 100 mg, 6.0 mg: 100 mg, 4 mg : 200mg, 4.4mg: 200mg, 4.8mg: 200mg, 5.2mg: 200mg, 5.6mg: 200mg, 6.0mg: 200mg or the range formed by any of the above values.

In some embodiments, the pharmaceutical combination of the present disclosure includes a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof (in the form of a compound of Formula II (or II-1 to II-3) By weight) and the anti-PD-1 antibody or antigen-binding fragment thereof (approximately) the weight ratio is selected from 5 mg: 100 mg, 5.5 mg: 100 mg, 6 mg: 100 mg, 6.1 mg: 100 mg, 6.2 mg: 100 mg, 6.3 mg: 100 mg, 6.4 mg: 100mg, 6.5mg: 100mg, 7mg: 100mg, 7.1mg: 100mg, 7.2mg: 100mg, 7.3mg: 100mg, 7.4mg: 100mg, 7.5mg: 100mg, 7.6mg: 100mg, 7.7mg: 100mg, 7.8mg : 100mg, 7.9mg: 100mg, 8.0mg: 100mg, 8.5mg: 100mg, 8.6mg: 100mg, 8.7mg: 100mg, 8.8mg: 100mg, 8.9mg: 100mg, 9.0mg: 100mg, 9.1mg: 100mg, 9.2mg : 100mg, 9.3mg: 100mg, 9.4mg: 100mg, 9.5mg: 100mg, 5mg: 200mg, 5.5mg: 200mg, 6mg: 200mg, 6.1mg: 200mg, 6.2mg: 200mg, 6.3mg: 200mg, 6.4mg: 200mg , 6.5mg: 200mg, 7mg: 200mg, 7.1mg: 200mg, 7.2mg: 200mg, 7.3mg: 200mg, 7.4mg: 200mg, 7.5mg: 200mg, 7.6mg: 200mg, 7.7mg: 200mg, 7.8mg: 200mg, 7.9mg: 200mg, 8.0mg: 200mg, 8.5mg: 200mg, 8.6mg: 200mg, 8.7mg: 200mg, 8.8mg: 200mg, 8.9mg: 200mg, 9.0mg: 200mg, 9.1mg: 200mg, 9.2mg: 200mg, 9.3mg: 200mg, 9.4mg: 200mg, 9.5mg: 200mg or the range formed by any of the above values.

In some embodiments, the drug combination is a fixed combination or a non-fixed combination.

In some embodiments, the pharmaceutical combination is a fixed combination. In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.

In some embodiments, the compound of formula I (or formula I-1 to I-3), its ester (such as the compound of formula II (or II-1 to II-3)) or its pharmaceutically acceptable The accepted salt and the anti-PD-1 antibody or antigen-binding fragment thereof (eg, 14C12H1L1 or antigen-binding fragment thereof) are present in the same pharmaceutical composition.

In some embodiments, the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen thereof) in the fixed combination binding fragment) present in the same pharmaceutical composition.

In some embodiments, the pharmaceutical combination is a non-fixed combination.

In some embodiments, the compound of formula I (or formula I-1 to I-3), its ester (such as the compound of formula II (or II-1 to II-3)) or its pharmaceutical The acceptable salt and the anti-PD-1 antibody or antigen-binding fragment thereof (eg, 14C12H1L1 or antigen-binding fragment thereof) are each in the form of a pharmaceutical composition.

In some embodiments, the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or its Antigen-binding fragments) are each in the form of a pharmaceutical composition.

In some embodiments, the compound of formula I (or formula I-1 to I-3), its ester (such as the compound of formula II (or II-1 to II-3)) or its pharmaceutical Acceptable salts and anti-PD-1 antibodies or antigen-binding fragments thereof (e.g., 14C12H1L1 or antigen-binding fragments thereof) are each in the form of pharmaceutical compositions, and compounds of Formula I (or Formulas I-1 to I-3), esters thereof ( For example, a pharmaceutical composition of formula II (or compound II-1 to II-3) or a pharmaceutically acceptable salt thereof and a pharmaceutical combination of an anti-PD-1 antibody or an antigen-binding fragment thereof (for example, 14C12H1L1 or an antigen-binding fragment thereof) items may or may not exist in the same medicine bag.

The present disclosure also aims to at least provide a pharmaceutical package, which contains individually packaged pharmaceutical compositions in independent containers, wherein one container contains a compound of formula I (or formulas I-1 to I-3), A pharmaceutical composition of an ester thereof (such as a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof, and comprising an anti-PD-1 antibody or an antigen-binding fragment thereof in a second container ( For example, pharmaceutical compositions of 14C12H1L1 or antigen-binding fragments thereof).

In some embodiments, medicaments of compounds of Formula I (or Formulas I-1 to I-3), esters thereof (e.g., compounds of Formula II (or II-1 to II-3)) or pharmaceutically acceptable salts thereof The composition is selected from solid pharmaceutical compositions. In some specific embodiments, the pharmaceutical composition of the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is selected from solid pharmaceutical compositions. In some specific embodiments, the solid pharmaceutical composition is selected from tablets or capsules.

In some specific embodiments, the pharmaceutical composition of an anti-PD-1 antibody or antigen-binding fragment thereof (eg, 14C12H1L1 or antigen-binding fragment thereof) is selected from the group consisting of liquid pharmaceutical compositions. In some specific embodiments, the liquid pharmaceutical composition is selected from injectable solutions.

In some embodiments, the compound of Formula I (or Formula I-1 to I-3), its ester (such as the compound of Formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof can Apply once every day, apply twice daily, apply once every two days, apply once every three days, apply once every four days, apply once every five days, apply once every six days, apply once every week, apply every two weeks Apply once, once every three weeks, twice every three weeks, or three times every three weeks.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or antigen-binding fragment thereof) can be administered once every day, once every two days, once every three days, once every four days , apply once every five days, once every six days, once every week, once every two weeks, or once every three weeks.

In some embodiments, the drug combination is treated every 14 days (2 weeks), 21 days (3 weeks), or 28 days (4 weeks). In some embodiments, the drug combination is administered in a treatment cycle every 21 days (3 weeks).

In some embodiments, the pharmaceutical combination is administered 1, 2, 3 or 4 times per treatment cycle with a compound of Formula I (or Formulas I-1 to I-3), its ester (e.g. Formula II ( or compound II-1 to II-3) or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula I (or Formula I-1 to I-3), or an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)) is administered 2 or 3 times per treatment cycle or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)) or a pharmaceutical thereof is administered twice per treatment cycle. with an acceptable salt. In some embodiments, the compound of Formula I (or Formula I-1 to I-3), its ester (e.g., Formula II (or II-1 to II -3) compound) or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination is administered 1, 2, 3 or 4 times per treatment cycle. Formula II (or II-1 to II-3) compound or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula II (or II-1 to II-3), or a pharmaceutically acceptable salt thereof, is administered two or three times per treatment cycle. In some embodiments, a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is administered twice per treatment cycle. In some embodiments, the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is administered once on day 1 and day 8 of each treatment cycle.

In some embodiments, compounds of Formula I (or Formulas I-1 to I-3), esters thereof (e.g., compounds of Formula II (or II-1 to II-3)) or pharmaceutically acceptable salts thereof can be used in the morning. Take orally on an empty stomach; optionally, at least 1 hour before or 2 hours after a meal.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof (eg, 14C12H1L1 or antigen-binding fragment thereof) is administered once, twice, or three times per treatment cycle. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof (eg, 14C12H1L1 or antigen-binding fragment thereof) is administered once per treatment cycle. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof (eg, 14C12H1L1 or antigen-binding fragment thereof) is administered intravenously on Day 1 (D1) of each treatment cycle, administered once per treatment cycle. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or antigen-binding fragment thereof) is administered intravenously on Day 1 (D1) of each treatment cycle. Note time is 60±10min. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or antigen-binding fragment thereof) is administered intravenously on Day 1 (D1) of each treatment cycle. The injection time is 60±10min, and the maximum medication time should not exceed 24 months.

In some embodiments, the administration of a compound of Formula I (or Formula I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof The treatment is based on a treatment cycle of 3 weeks (21 days), with administration once on the 1st day and once on the 8th day. In some embodiments, the administration of the compound of formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is 3 weeks (21 days) as a treatment cycle, with day 1 and day 8 Apply once each.

In some embodiments, wherein the anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or antigen-binding fragment thereof) is administered in a treatment cycle of 3 weeks (21 days), on day 1 of each treatment cycle ( D1) Anti-PD-1 antibody or antigen-binding fragment thereof is administered intravenously. That is, the anti-PD-1 antibody or antigen-binding fragment thereof (eg, 14C12H1L1 or antigen-binding fragment thereof) is administered at a frequency of once every 3 weeks (q3w).

In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle, and the drug administered in a single treatment cycle includes: 10 mg to 16 mg of a compound of formula I or formula I', an ester thereof, or a pharmaceutically acceptable salt thereof ; and 10-1000mg anti-PD-1 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle, which (drug administered in a single treatment cycle) contains approximately: 10-20 mg of Formula I (or Formulas I-1 to I-3) The compound, its ester (such as the compound of formula II (or formula II-1 ~ II-3)) or its pharmaceutically acceptable salt (based on the weight of the compound of formula II (or formula II-1 ~ II-3)); and 10-1000 mg anti-PD-1 antibody or antigen-binding fragment thereof (eg, 14C12H1L1 or antigen-binding fragment thereof).

In some embodiments, the drug combination is suitable for administration in a single treatment cycle, which (drug administered in a single treatment cycle) contains approximately: 10 mg, 10.6 mg, 11.6 mg, 12.3 mg, 12.4 mg, 12.5 mg, 12.6mg, 13.6mg, 14.6mg, 14.7mg, 14.8mg, 14.9mg, 15.0mg, 15.1mg, 15.2mg, 15.3mg, 15.4mg, 15.5mg, 16.6mg, 16.8mg, 17.0mg, 17.2mg, 17.4mg , 17.5 mg, 17.6 mg, 17.8 mg or 18 mg of the compound of formula I (or formula I-1 to I-3), its ester (such as the compound of formula II (or II-1 to II-3)) or its pharmaceutical Acceptable salts (based on the weight of the compound of Formula II (or Formula II-1 to II-3)); and about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, or a range of anti-PD-1 antibodies or antigen-binding fragments thereof (e.g., 14C12H1L1 or antigen-binding fragments thereof) formed by any of the above values.

In some embodiments, the drug combination is suitable for administration in a single treatment cycle, which (drugs administered in a single treatment cycle) Approximately containing: 12.0 mg-18.0 mg of the compound of formula I (or formula I-1 to I-3), its ester (such as the compound of formula II (or II-1 to II-3)) or its pharmaceutically acceptable Salt (based on the weight of the compound of Formula II (or Formula II-1 to II-3)); and 50-350 mg of anti-PD-1 antibody or antigen-binding fragment thereof (eg, 14C12H1L1 or antigen-binding fragment thereof).

In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle, which (drug administered in a single treatment cycle) contains approximately: 12.6 mg, 15 mg or 17.6 mg of Formula I (or Formula I-1 to I-3) compound, its ester (such as formula II (or formula II-1 ~ II-3) compound) or its pharmaceutically acceptable salt (based on formula II (or formula II-1 ~ II-3) compound weight (calculated); and 100 mg or 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or antigen-binding fragment thereof).

In some embodiments, the pharmaceutical combination is administered each time a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)) or its The pharmaceutically acceptable salt (based on the weight of the compound of formula II (or formula II-1 to II-3)) is 6.0 mg-9 mg (for example, 7.5 mg), each time the anti-PD-1 antibody or antigen-binding fragment thereof is administered ( For example, 14C12H1L1 or its antigen-binding fragment) is 100 mg-200 mg.

In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, which (drug administered within a single treatment cycle) includes: 10 mg to 16 mg of a compound of formula I (or formulas I-1 to I-3) , its ester (such as formula II (or II-1 ~ II-3) compound) or its pharmaceutically acceptable salt; and 10-1000 mg anti-PD-1 antibody or its antigen-binding fragment (such as 14C12H1L1 or its antigen-binding fragment ).

In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle, which (a drug administered in a single treatment cycle) comprises: 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg or 16 mg of Formula I (or Compounds of formulas I-1 to I-3), esters thereof (such as compounds of formula II (or II-1 to II-3)) or pharmaceutically acceptable salts thereof; and about 100 mg, about 150 mg, about 200 mg, about 250 mg , about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg or an anti-PD-1 antibody or an antigen-binding fragment thereof within a range formed by any of the above values (e.g. 14C12H1L1 or its antigen-binding fragment).

In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, which (drug administered within a single treatment cycle) includes: 10 mg to 14 mg of a compound of formula I (or formulas I-1 to I-3) , its ester (such as formula II (or II-1 ~ II-3) compound or its pharmaceutically acceptable salt; and 50-350 mg anti-PD-1 antibody or its antigen-binding fragment (such as 14C12H1L1 or its antigen-binding fragment) .

In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle, which (drug administered in a single treatment cycle) comprises: 10 mg, 11 mg, 12 mg, 13 mg or 14 mg of Formula I (or Formula I-1 to I-3) Compounds, esters thereof (for example, compounds of Formula II (or II-1 to II-3) or pharmaceutically acceptable salts thereof; and 100 mg or 200 mg of anti-PD-1 antibodies or antigen-binding fragments thereof (for example, 14C12H1L1 or Antigen-binding fragments thereof). In some embodiments, the pharmaceutical combination, each time a compound of Formula I (or Formulas I-1 to I-3), its ester (e.g., Formula II (or II-1 to II-3) is administered ) compound or a pharmaceutically acceptable salt thereof is 5 mg-8 mg, and each administration of the anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or antigen-binding fragment thereof) is 100 mg-200 mg. In some embodiments, the Pharmaceutical combination, the compound of formula I (or formula I-1 to I-3), its ester (such as the compound of formula II (or II-1 to II-3) or its pharmaceutically acceptable salt) is 5mg-7mg per administration (e.g., 6 mg), the anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or antigen-binding fragment thereof) is 200 mg per administration.

In some embodiments, the pharmaceutical combination is administered every 21 days as a treatment cycle in the following manner: the compound of formula I, its ester (such as the compound of formula II) or its pharmaceutical composition is administered once on day 1 and day 8. The above acceptable salts are 5 mg, 5.5 mg, 6 mg, 6.5 mg or 7 mg/time, and the anti-PD-1 antibody or its antigen-binding fragment (such as 14C12H1L1 or its antigen-binding fragment) is administered once on the first day, 200 mg/time.

In some embodiments, the drug combination is administered every 21 days as a treatment cycle in the following manner: the compound of formula I, its ester (for example, the compound of formula II (compound or its pharmaceutical composition) is administered once on day 1 and day 8). The above acceptable salts are 5 mg, 6 mg or 7 mg/time, and the anti-PD-1 antibody or its antigen-binding fragment (such as 14C12H1L1 or its antigen-binding fragment) is administered once on the first day, 200 mg/time.

In some embodiments, the pharmaceutical combination, the compound of Formula II is administered at a dosage of 5 mg to 8 mg, and 14C12H1L1 is administered at a dosage of 100 mg to 200 mg.

In some embodiments, the pharmaceutical combination, the compound of Formula II is administered at a dose of 5 mg to 7 mg per administration, and the 14C12H1L1 is administered at a dose of is 200mg.

In some embodiments, the pharmaceutical combination is administered every 21 days as a treatment cycle in the following manner: the compound of formula II or a pharmaceutically acceptable salt thereof is administered once on day 1 and day 8. The compound of formula II is administered once on day 1 and day 8. Each administration dose is 5 mg-8 mg, and the anti-PD-1 antibody or its antigen-binding fragment (such as 14C12H1L1 or its antigen-binding fragment) is administered once on day 1. Each administration dose of 14C12H1L1 is 100 mg-200 mg.

In some embodiments, the pharmaceutical combination is administered every 21 days as a treatment cycle in the following manner: the compound of formula II or a pharmaceutically acceptable salt thereof is administered once on day 1 and day 8. The compound of formula II is administered once on day 1 and day 8. Each administration dose is 5mg-7mg. 14C12H1L1 or its antigen-binding fragment is administered once on day 1. Each administration dose of 14C12H1L1 is 200mg.

In some embodiments, the pharmaceutical combination is administered every 21 days as a treatment cycle in the following manner: the compound of formula II is administered once on day 1 and day 8, and the dosage of compound of formula II per administration is 5 mg, 5.5 mg, 6 mg, 6.5 mg or 7 mg, 14C12H1L1 is administered once on Day 1, with 14C12H1L1 administered at a dose of 200 mg.

In some embodiments, the pharmaceutical combination is administered every 21 days as a treatment cycle in the following manner: the compound of formula II is administered once on day 1 and day 8, and the dosage of compound of formula II is 5 mg and 6 mg each time. Or 7 mg, 14C12H1L1 administered once on Day 1, 14C12H1L1 administered at a dose of 200 mg. In some embodiments, the pharmaceutical combination is administered in a dosage of 0.5 mg or 2 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a dosage of 10 mL:100 mg per administration.

In some embodiments, the pharmaceutical combination contains a compound of formula I (or formula I-1 to I-3), an ester thereof (for example, a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable compound thereof. The salt and the anti-PD-1 antibody or antigen-binding fragment thereof (eg, 14C12H1L1 or antigen-binding fragment thereof) are administered in single or multiple doses, respectively. In some embodiments, the pharmaceutical combination contains a compound of formula I (or formula I-1 to I-3), an ester thereof (for example, a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable compound thereof. The salt and the anti-PD-1 antibody or antigen-binding fragment thereof (eg, 14C12H1L1 or antigen-binding fragment thereof) are administered separately in a single dose. In some embodiments, the pharmaceutical combination contains a compound of formula I (or formula I-1 to I-3), an ester thereof (for example, a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable compound thereof. The salt and the anti-PD-1 antibody or antigen-binding fragment thereof (eg, 14C12H1L1 or antigen-binding fragment thereof) are administered separately in multiple doses.

On the other hand, the present disclosure also provides the use of the pharmaceutical combination of the present disclosure in the preparation of a medicament for treating tumors. The present disclosure also provides methods of treating tumors comprising administering to an individual in need thereof an effective amount of a pharmaceutical combination of the present disclosure. The present disclosure also provides pharmaceutical combinations for treating tumors. The present disclosure also provides the use of the pharmaceutical combination of the present disclosure for treating tumors.

The present disclosure also provides a method of treating a subject suffering from a tumor, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I (or Formulas I-1 to I-3) of the present disclosure, which A pharmaceutical combination of an ester (eg, a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.

On the other hand, the present disclosure provides a kit comprising 1) a compound of formula I (or formula I-1 to I-3), an ester thereof (for example, a compound of formula II (or II-1 to II-3)) or Pharmaceutically acceptable salts thereof; 2) anti-PD-1 antibodies or antigen-binding fragments thereof (such as 14C12H1L1 or antigen-binding fragments thereof), and 3) compounds of formula I (or formulas I-1 to I-3) and esters thereof Instructions for the use of (for example, a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof (for example, 14C12H1L1 or an antigen-binding fragment thereof) for the treatment of tumors .

In yet another aspect, the present disclosure provides compounds of formula I (or formulas I-1 to I-3), esters thereof (such as compounds of formula II (or II-1 to II-3)) or pharmaceutically acceptable salts thereof, or Use of its pharmaceutical composition in the preparation of drugs for treating solid tumors. The present disclosure also provides methods of treating solid tumors, comprising administering to an individual in need thereof an effective amount of a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., Formula II (or II-1 to II- 3) compound) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. The present disclosure also provides compounds of Formula I (or Formulas I-1 to I-3), esters thereof (such as compounds of Formula II (or II-1 to II-3)) or pharmaceutically acceptable compounds thereof for the treatment of solid tumors. salts or pharmaceutical compositions thereof. The present disclosure also provides compounds of formula I (or formulas I-1 to I-3), esters thereof (such as compounds of formula II (or II-1 to II-3)) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof For the treatment of solid tumors way.

In some embodiments, the ester of the compound of Formula I (or Formulas I-1 to I-3) is the malate ester of the compound of Formula I (or Formulas I-1 to I-3). In some embodiments, the molecular number ratio of the compound of formula I (or formula I-1 to I-3) and malic acid in the ester of the compound of formula I is selected from 1:1.

In some embodiments, the ester of the compound of Formula I (or Formula I-1 to I-3) is a compound of Formula II (or II-1 to II-3)

In some embodiments, the compound of formula I (or formula I-1 to I-3), its ester (for example, the compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof or its The dosage of the pharmaceutical composition per administration is selected from the group consisting of 0.5 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg or any of the above values.

In some embodiments, the compound of formula I (or formula I-1 to I-3), its ester (for example, the compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof or its The dosage of the pharmaceutical composition per administration is selected from the group consisting of 0.8 mg, 1.2 mg, 1.6 mg, 2.0 mg, 2.4 mg, 2.8 mg, 3.2 mg, 3.6 mg, 4.0 mg, 4.4 mg, 4.8 mg, 5.2 mg, 5.6 mg, 6.0 mg, 6.4mg, 6.8mg, 7.2mg, 7.6mg, 8.0mg or the range formed by any of the above values.

In some embodiments, the dosage of each administration of the compound of formula II (or II-1 to II-3), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, is selected from the group consisting of 1.0 mg, 1.5 mg, 2.0 mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 4.5mg, 5.0mg, 5.5mg, 6.0mg, 6.5mg, 7.0mg, 7.5mg, 8.0mg, 8.5mg, 9.0mg, 9.5mg, 10mg or any of the above values range of formation.

In some embodiments, the dosage per administration of the compound of formula II (or II-1 to II-3), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, is selected from 5 mg to 7 mg. In some embodiments, the pharmaceutical combination, wherein each dose of the compound of formula II (or II-1 to II-3), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, is selected from 5 mg, 6 mg or 7mg.

In some embodiments, a treatment cycle is every 21 days (3 weeks) or 28 days (4 weeks).

In some embodiments, the compound of Formula I (or Formula I-1 to I-3), its ester (e.g., the compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof is administered. As follows: A treatment cycle of 3 weeks (21 days) is used, once on the 1st day and once on the 8th day. Alternatively, in some embodiments, compounds of Formula I (or Formulas I-1 to I-3), esters thereof (e.g., compounds of Formula II (or II-1 to II-3)), or pharmaceutically acceptable compounds thereof The application method of salt is: a treatment cycle of 3 weeks (21 days) is used, and it is administered once on the 1st day, the 8th day, and the 15th day.

In some embodiments, the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.5 mg or 2 mg (based on the weight of the compound of Formula II).

In some embodiments, the pharmaceutical combination contains a compound of formula I (or formula I-1 to I-3), an ester thereof (for example, a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable compound thereof. The salts are administered in single or multiple doses.

In some embodiments, the tumor is selected from solid tumors. In some embodiments, the tumor is selected from advanced solid tumors. In some embodiments, the tumor or advanced solid tumor is selected from advanced malignant solid tumors. In some embodiments, the tumor, advanced solid tumor or advanced malignant solid tumor is selected from lung cancer. In some embodiments, the tumor, advanced solid tumor or advanced malignant solid tumor is selected from advanced or locally advanced lung cancer. In some embodiments, the tumor, advanced solid tumor or advanced malignant solid tumor is selected from metastatic, recurrent and/or refractory lung cancer. In some embodiments, the tumor, advanced solid tumor, advanced malignant solid tumor or lung cancer is selected from the group consisting of lung cancer with a mutation in the EGFR cancer driver gene. In some embodiments, the tumor, advanced solid tumor, advanced malignant solid tumor, or lung cancer is selected from tumor in situ of lung cancer. In some embodiments, the tumor, advanced solid tumor, advanced malignant solid tumor or lung cancer is selected from the group consisting of lung cancer in situ with a CC1ORTTA-EGFR-DEL cancer driver gene mutation.

In some embodiments, the tumor is selected from lung adenocarcinoma. In some embodiments, the tumor is selected from EGFR driven lung adenocarcinoma.

In some embodiments, the tumor is selected from the group consisting of advanced progressive/metastatic solid tumors confirmed by histopathology and/or cytology.

In some embodiments, the patient/individual has a tumor for which standard treatment is not available, or has disease progression or is intolerant to standard treatment. In some embodiments, the patient/individual wherein the tumor is demonstrated to have at least one measurable lesion according to RECIST 1.1 criteria.

In some embodiments, the patient/individual has a tumor that has progressed following or is intolerant to targeted therapy.

In some embodiments, the patient/individual whose tumor has progressed after prior treatment with an ALK inhibitor or is intolerant to it.

In some embodiments, wherein the tumor has a patient/individual ECOG score: 0-2 points. In some embodiments, the patient/individual with the tumor is expected to survive for more than 3 months.

In some embodiments, the patient/individual with the tumor has good major organ function and meets the following criteria:

(1) Routine blood examination standards (no blood transfusion, no correction with hematopoietic stimulating factor drugs or other medical support treatment within 14 days before the examination):

a) Hemoglobin (HGB) ≥ 90g/L;

b) Neutrophil absolute value (NEUT) ≥1.5×109/L;

c) Platelet count (PLT) ≥100×109/L;

(2) Blood biochemical tests must meet the following standards:

a) Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN);

b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN. If there is liver metastasis, ALT and AST <5×ULN;

c) Creatinine clearance rate (CCR) ≥ 50ml/min (estimated according to the Cockcroft-Gault formula);

(3) Urine routine: urine protein <2+ (when the baseline urine protein is ≥2+, a 24-hour urine protein quantitative test should be performed within 7 days, and only when the urine protein is <1g can be selected);

(4) The coagulation function test must meet the following requirements: prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR) ≤ 1.5 × ULN;

(5) Thyroid function test: thyroid stimulating hormone (TSH) ≤ ULN; if abnormal, T3 and T4 levels should be examined. If T3 and T4 levels are normal, you can be selected;

(6) Cardiac color ultrasound evaluation: left ventricular ejection fraction (LVEF) ≥50%.

Compounds of formula I, their esters or pharmaceutically acceptable salts thereof (formulas I-1 to I-3 are similar)

As used in this disclosure, the compound of formula I has the following structural formula and is prepared by referring to the method disclosed in WO2018157820A1,

As used in this disclosure, the ester of the compound of formula I is the compound of formula II, which is the prodrug form of the compound of formula I and is prepared by referring to the method disclosed in WO2020025037A1:

As used in this disclosure, the compound of Formula I includes its free compound, its ester form, and its pharmaceutically acceptable salts. The non-salt forms or salts are all included in the protection scope of this disclosure.

In some embodiments, the compound of formula I, its ester (eg, the compound of formula II) or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, and the single dose of the pharmaceutical composition is 0.5 mg to 50 mg of the pharmaceutical composition. , preferably a pharmaceutical composition with a single dose of 0.5mg-10mg.

In some embodiments, the compound of formula II or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, and the single dose of the pharmaceutical composition is a pharmaceutical composition of 0.5 mg to 50 mg, preferably a single dose of 0.5 mg, 1 mg , 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg , 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg or the above A pharmaceutical composition within the range formed by any value; preferably a single dose is 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg or a pharmaceutical composition within the range formed by any of the above values; more preferably A single dose is a pharmaceutical composition in the range of 0.5 mg and 2 mg or any of the above values.

The method of administration can be comprehensively determined based on the activity, toxicity and patient tolerance of the drug.

In some embodiments of the present disclosure, the pharmaceutical composition of the compound of Formula I, its ester (eg, the compound of Formula II) or a pharmaceutically acceptable salt thereof further contains pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, binders, disintegrating agents agents, lubricants, etc. In some embodiments of the present disclosure, the pharmaceutical compositions include, but are not limited to, formulations suitable for oral, parenteral, topical administration. In some embodiments, the pharmaceutical composition is a formulation suitable for oral administration. In some embodiments, the pharmaceutical composition is a solid formulation suitable for oral administration. In some embodiments, the pharmaceutical compositions include, but are not limited to, tablets and capsules.

In some embodiments of the present disclosure, the pharmaceutical composition is a solid pharmaceutical composition.

In some embodiments of the present disclosure, the pharmaceutical composition of a compound of Formula I, an ester thereof (e.g., a compound of Formula II), or a pharmaceutically acceptable salt thereof is a compound of Formula I, an ester thereof (e.g., a compound of Formula II), or a pharmaceutical composition thereof. Solid pharmaceutical compositions of pharmaceutically acceptable salts.

In some embodiments of the present disclosure, the pharmaceutical composition of a compound of Formula I, an ester thereof (e.g., a compound of Formula II), or a pharmaceutically acceptable salt thereof is a compound of Formula I, an ester thereof (e.g., a compound of Formula II), or a pharmaceutical composition thereof. Capsules of pharmaceutically acceptable salt.

The pharmaceutical composition of the present disclosure can be manufactured using methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets or The core of the sugar coating. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

14C12H1L1

As used in this disclosure, 14C12H1L1 is an anti-PD-1 monoclonal antibody, and its sequence and structure can be found in the literature (CN106977602A). In the 14C12H1L1, LCDR1 contains the sequence QDINTY (SEQ ID NO: 1), LCDR2 contains the sequence RAN (SEQ ID NO: 2), LCDR3 contains the sequence LQYDEFPLT (SEQ ID NO: 3), HCDR1 contains the sequence GFAFSSYD (SEQ ID NO: 4), and HCDR2 contains the sequence ISGGGRYT (SEQ ID NO:5), and HCDR3 contains the sequence ANRYGEAWFAY (SEQ ID NO:6).

It will be understood by those skilled in the art that, unless otherwise specified, the term "CDR" or "complementarity determining region" of a given antibody or region thereof (e.g., variable region) should be understood to encompass definitions defined by any one of the known schemes complementarity determining region. Although the present disclosure has shown the CDR sequence of 14C12H1L1, however, when it comes to defining an antibody with a specific CDR sequence, the scope of the antibody encompasses any numbering system definition (such as AbM, Kabat, Chothia, IMGT or Contact as known in the art). An antibody defined by the CDR sequence of one or more of the following definitions:

The amino acid sequence of the light chain variable region of 14C12H1L1 is:

The amino acid sequence of the heavy chain variable region of 14C12H1L1 is:

The amino acid sequence of the light chain of 14C12H1L1 is:

The amino acid sequence of the heavy chain of 14C12H1L1 is:

In some embodiments, the 14C12H1L1 is in the form of a pharmaceutical composition, and the single dose of the pharmaceutical composition is a pharmaceutical composition of 50 mg to 500 mg, and the preferred single dose is 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg. , 450mg, 500mg or a pharmaceutical composition within the range formed by any of the above values. In some embodiments, the 14C12H1L1 is in the form of a pharmaceutical composition, and a single dose of the pharmaceutical composition is 100 mg of the pharmaceutical composition.

In some embodiments, the 14C12H1L1 is in the form of a pharmaceutical composition comprising 14C12H1L1, a buffer, an isotonicity regulator/stabilizer, and a surfactant. In a specific embodiment, the 14C12H1L1 is in the form of a pharmaceutical composition comprising 14C12H1L1, sodium acetate trihydrate, glacial acetic acid, sorbitol, and polysorbate 80.

In some embodiments, the pharmaceutical composition of 14C12H1L1 is a water-soluble injection, and the water-soluble injection includes but is not limited to a water-soluble preparation that has not been lyophilized or a water-soluble preparation reconstituted with lyophilized powder. In other embodiments, the pharmaceutical composition of 14C12H1L1 is a lyophilized formulation. The freeze-dried preparation refers to a preparation prepared by an aqueous solution undergoing a freeze-drying process. Freeze-drying is a stabilization process in which the substance is first frozen, then the amount of solvent is reduced by sublimation (primary drying process), and then the amount of solvent is reduced by desorption. (secondary drying process) until the amount of solvent no longer supports biological activity or chemical reactions.

It should be understood that for each of the above technical solutions and embodiments, the present disclosure also includes a technical solution in which the "compound of formula I (or formula I-1 to I-3)" is replaced by a "compound of formula I'", as well as It includes a technical solution of replacing the "compound of formula II (or II-1 to II-3)" with "ester of the compound of formula I'".

definition

Unless otherwise stated, the following terms used in this disclosure have the following meanings. A particular term should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in accordance with its ordinary meaning in the art. Where a trade name appears in this disclosure, it is intended to refer to its corresponding trade name, composition, or active ingredient thereof.

In the present disclosure, unless otherwise stated, the weight of the corresponding compound is based on the weight of the free acid compound, such as the weight of the compound of formula I (or formula I-1 to I-3), further such as formula I (or formula I- Each dose of the compound 1 to I-3), its ester (such as the compound of formula II (or II-1 to II-3)) or its pharmaceutically acceptable salt or its pharmaceutical composition is selected from 0.5 mg, 1.5 mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 4.5mg, 5.0mg, 5.5mg, 6.0mg, 6.5mg, 7.0mg, 7.5mg, 8.0mg, 8.5mg or the range formed by any of the above values , wherein the dosage is based on the weight of the compound of Formula I (or Formula I-1 to I-3); for another example, in some embodiments, the pharmaceutical combination, the dosage of the compound of Formula II is 5mg-8mg each time, and the dosage of 14C12H1L1 is 5mg-8mg each time. The dosage is 100 mg-200 mg, and the dosage of each administration of the compound of formula II is also based on the weight of the free acid form of the compound of formula II, that is, the compound of formula I.

As used herein, the term "antibody" refers to an antigen-binding protein having at least one antigen-binding domain. Antibodies and fragments thereof of the present disclosure may be whole antibodies or any fragments thereof. Thus, the antibodies and fragments thereof of the present disclosure include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof. Examples of antibodies and antigen-binding fragments thereof include monospecific antibodies, bispecific antibodies, multispecific antibodies, Fab fragments, Fab' fragments, F(ab)' ₂ fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv) and other antibody fragments known in the art. Anti-PD-1 antibodies or antigen-binding fragments thereof of the present disclosure may be of the IgG1, IgG2, IgG3, or IgG4 isotype. The term "isotype" refers to the class of antibody encoded by the heavy chain constant region genes. In some embodiments, the anti-PD-1 antibodies or antigen-binding fragments thereof of the present disclosure are of the IgG1 or IgG4 isotype. Anti-PD-1 antibodies or antigen-binding fragments thereof of the present disclosure can be derived from any species, including, but not limited to, mouse, rat, rabbit, primate, llama, and human. The anti-PD-1 antibodies or antigen-binding fragments thereof of the present disclosure may be murine antibodies, chimeric antibodies, humanized antibodies, or fully human antibodies. Unless otherwise stated, "antibodies" in this disclosure include entire antibodies and any antigen-binding fragments (or "antigen-binding portions") or single chains thereof. A conventional "whole antibody" is a glycoprotein containing two heavy (H) chains and two light (L) chains linked by disulfide bonds. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region consists of three domains, namely CH1, CH2 and CH3. Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The light chain constant region consists of one domain, CL. VH and VL can also be divided into hypervariable regions, namely complementarity determining regions (CDR), and framework regions (FR) with relatively conserved sequences. Each VH and VL are composed of three CDRs and four FRs respectively, from the amino end to the carboxyl end: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The constant region of an antibody can mediate binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (Clq) of the classical complement system. Meanwhile, as is understood by those skilled in the art, special "whole antibodies", such as Nanobodies, have only heavy (H) chains and no light (L) chains.

An "antigen-binding fragment" or "antibody-binding portion" of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding an antigen (eg, PD-1). It has been demonstrated that the antigen-binding function of an antibody can be performed by fragments of the entire antibody. Examples encompassed by the term "antigen-binding portion/fragment" of an antibody include: (i) Fab fragments: monovalent fragments consisting of VL, _VH , CL and CH1 domains; ₍ ii) F(ab') ₂ fragments , a bivalent fragment containing two Fab fragments connected by a disulfide bridge in the hinge region; (iii) Fd fragment consisting of VH and CH1 domains; (iv) Fv consisting of VL and VH domains of an antibody single arm Fragments; (v) dAb fragments consisting of VH domains (see Ward et al., Nature. 341:544-546 (1989)); (vi) isolated complementarity determining regions (CDRs); and (vii) Nanobodies , a heavy chain variable region containing a single variable domain and two constant domains. In addition, although the two domains VL and VH of the Fv fragment are encoded by different genes, recombinant methods can be used to connect VH and VL into a single protein chain through synthetic linkers, in which VL and VH pair to form a monovalent molecule (called a single-chain Fv (scFv); see, for example, Bird et al., Science. 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85:5879-5883 (1988)). These single chain antibodies are also encompassed by the term antigen-binding portion/fragment. Furthermore, recombinant polypeptides, fusion proteins and immunoconjugates comprising such antigen-binding portions/fragments are also encompassed by the term antigen-binding portions/fragments.

The term "humanized antibody" refers to an antibody in which the antigen-binding site is derived from a non-human species and the variable region framework is derived from human immunoglobulin sequences. Humanized antibodies may contain substitutions in the framework regions such that the framework may not be an exact copy of the expressed human immunoglobulin or germline gene sequence.

"Isolated antibody" means an antibody that is substantially free of other antibodies with different antigenic specificities (e.g., an isolated antibody that specifically binds PD-1/PD-L1 is substantially free of other antibodies that specifically bind other than Antibodies to antigens other than PD-1/PD-L1). However, an isolated antibody that specifically binds PD-1/PD-L1 may have cross-reactivity with other antigens, such as PD-1/PD-L1 molecules from different species. Furthermore, isolated antibodies may be substantially free of other cellular material and/or chemicals.

As used herein, the term "sequence identity" or "percent identity" in the comparison of two nucleic acids or polypeptides means that when measured using a nucleotide or amino acid residue sequence comparison algorithm or by visual inspection, Maximum correspondence is compared and aligned when they are similar or have a specific percentage of identical sequences. That is to say, the identity of nucleotide or amino acid sequences can be defined by the ratio that maximizes the number of identical nucleotides or amino acids when comparing two or more nucleotide or amino acid sequences. , and gaps are added as necessary to achieve a consistent ratio of the number of nucleotides or amino acids in the alignment to the total number of nucleotides or amino acids in the alignment.

As used herein, sequence identity between two or more polynucleotides or polypeptides can be determined by aligning the nucleotide or amino acid sequences of the polynucleotides or polypeptides and aligning the aligned The number of positions in a polynucleotide or polypeptide that contain the same nucleotide or amino acid residue is scored and compared to the number of positions in the aligned polynucleotide or polypeptide that contain different nucleotides or amino acid residues. Polynucleotides may differ at one position, for example, by containing different nucleotides or deleting nucleotides. Polypeptides may differ at one position, for example, by containing a different amino acid or missing an amino acid. Sequence identity can be calculated by dividing the number of positions containing identical nucleotides or amino acid residues by the total number of amino acid residues in the polynucleotide or polypeptide. For example, it can be divided by the number of positions containing the same nucleotide or amino acid residue. Percent identity is calculated as the total number of nucleotides or amino acid residues in a polynucleotide or polypeptide multiplied by 100.

Illustratively, as used herein, two or more sequences or subsequences have at least 40%, 50%, 60% when compared and aligned with maximum correspondence using sequence comparison algorithms or as measured by visual inspection. , 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% "sequence identity" of nucleotide or amino acid residues sex” or “percent identity”. The determination/calculation of "sequence identity" or "percent identity" can be based on any suitable region of the sequence. For example, a region of at least about 10 residues in length, a region of at least about 20 residues in length, a region of at least about 50 residues in length, a region of at least about 100 residues in length, a region of at least about 200 residues in length. region, or a region of at least about 400 residues in length. In certain embodiments, the sequences are substantially identical throughout the entire length of either or both compared biopolymers (that is, nucleic acids or polypeptides).

The term "treating" means administering a compound or formulation of the present disclosure to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) To inhibit a disease or disease state, that is, to arrest its progression;

(ii) Alleviation of a disease or condition, i.e. resolution of the disease or condition.

The term "prevention" means the administration of a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with said disease, and includes: preventing a disease or disease state from occurring in a mammal, particularly when Such mammals are susceptible to the disease state but have not yet been diagnosed as having the disease state.

As used herein, the term "systemic treatment" refers to treatment in which drug substances are delivered through the bloodstream to reach and affect cells throughout the body.

As used herein, the term "subject" includes mammals such as rodents, felines, canines, and primates. Preferably, the subject according to the present disclosure is a human.

The term "administering" or "administering" or "administering" means the physical introduction of a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art.

As used herein, an "adverse event" (AE) is any adverse and generally unintentional or undesirable sign (including abnormal laboratory findings), symptom, or disease associated with the use of a medical treatment. For example, adverse events may be associated with activation of the immune system or expansion of immune system cells (eg, T cells) in response to treatment. A medical treatment can have one or more associated AEs, and each AE can have the same or different severity levels. References to methods that "modify adverse events" refer to treatment embodiments that reduce the incidence and/or severity of one or more AEs associated with the use of different treatment embodiments.

"Dosing interval" as used herein refers to the amount of time that elapses between each administration of a formulation disclosed herein to a subject (which may be two consecutive administrations or two administrations separated by two administrations). Dosing intervals can thus be indicated as ranges.

The use of the term "fixed dose" with respect to the compositions of the present disclosure means that two or more different antibodies in a single composition are present in said composition in a specific (fixed) ratio to each other. In certain embodiments, the fixed dose is based on the weight of the antibody (eg, mg). In certain embodiments, the fixed dose is based on the concentration of the antibody (eg, mg/ml). In certain embodiments, the ratio of mg first antibody:mg second antibody is at least about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1: 6. About 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1: 60. About 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200: 1. About 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50: 1. About 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5: 1. About 4:1, about 3:1 or about 2:1. For example, a 3:1 ratio of primary antibody to secondary antibody may mean that the vial may contain approximately 240 mg of primary antibody and 80 mg of secondary antibody, or approximately 3 mg/ml of primary antibody and 1 mg/ml of secondary antibody. .

"Programmed death receptor-1 (PD-1)" means an immunosuppressive receptor belonging to the CD28 family. PD-1 is mainly expressed on previously activated T cells in the body and binds two ligands, PD-L1 and PD-L2. The term "PD-1" as used herein includes human PD-1 (hPD-1), variants, isoforms and species homologs of hPD-1, and analogs that share at least one epitope in common with hPD-1.

"Programmed death ligand-1 (PD-L1)" is one of two cell surface glycoprotein ligands for PD-1 (the other is PD-L2), which downregulates T cells after binding to PD-1 Activation and cytokine secretion.

"Subject" includes any human or non-human animal. The term "non-human animals" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In certain embodiments, the subject is a human. The terms "subject," "subject," and "patient" are used interchangeably in certain contexts herein.

A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of a disease or promotes regression of a disease Regression is evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free phases, or the prevention of impairment or disability caused by disease afflictions. The ability of therapeutic agents to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by in vitro assays to determine the activity of the agent.

As an example for treating tumors, a therapeutically effective amount of an anti-cancer agent may inhibit cell growth or tumor growth by at least About 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80%. In other embodiments of the present disclosure, tumor regression may be observed for a period of at least about 7 days, at least about 10 days, at least about 14 days, at least about 20 days, at least about 40 days, or at least about 60 days. Despite these ultimate measures of therapeutic effectiveness, the evaluation of immunotherapeutic agents must also consider “immune-related” response patterns.

"Immune-related" response patterns refer to clinical response patterns frequently observed in cancer patients treated with immunotherapeutic agents that produce anti-tumor effects by inducing cancer-specific immune responses or by altering innate immune processes. This response pattern is characterized by a beneficial therapeutic effect after an initial increase in tumor burden or the appearance of new lesions, which in the evaluation of conventional chemotherapeutic agents would be classified as disease progression and would be synonymous with drug failure. Therefore, appropriate evaluation of immunotherapeutic agents may require long-term monitoring of the effects of these agents on the target disease.

A therapeutically effective amount of a drug includes a "prophylactically effective amount" which is when administered alone or in combination with an antineoplastic agent to a subject at risk of developing cancer (e.g., a subject with a premalignant condition) or a subject at risk of recurrence of cancer The amount of any drug that inhibits the occurrence or recurrence of cancer. In certain embodiments, the prophylactically effective amount completely prevents the development or recurrence of cancer. "Inhibiting" the occurrence or recurrence of cancer means reducing the likelihood of the occurrence or recurrence of cancer, or completely preventing the occurrence or recurrence of cancer.

A "recurrent" cancer is a cancer that grows back at the original site or at a distant site after responding to initial treatment, such as surgery. A "locally recurrent" cancer is a cancer that appears after treatment in the same location as a previously treated cancer.

"Metastatic" cancer is cancer that has spread from one part of the body, such as the lungs, to another part of the body.

Use of alternative embodiments (eg, "or") should be understood to refer to either, both, or any combination of the alternative embodiments. The indefinite article "a" or "an" as used herein shall be understood to mean "one or more/one or more" of any enumerated or enumerated components.

The terms "about," "approximately," or "substantially comprise" mean a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined or composition, that is, the limitations of the measurement system. For example, "about," "approximately," or "substantially including" may mean within 1 or more than 1 standard deviation as is practiced in the art. Alternatively, "about" or "substantially comprising" may refer to a range that differs by up to 10% or 20% (ie, ±10% or ±20%) from the parameter or value modified thereby. For example, about 3 mg may include any number between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%). Furthermore, particularly with regard to biological systems or processes, the term may refer up to an order of magnitude or up to 5 times a numerical value. When a specific value or composition is provided in the specification and claims of the present disclosure, the meaning of "about" or "substantially comprising" should be assumed to be within an acceptable error range for that specific value or composition unless stated otherwise.

As used herein, the terms "about once a week,""about once every two weeks," or any other similar dosing interval term refer to approximations. "About once a week" may include every 7 days ± 1 day, that is, every 6 days to every 8 days. “Approximately every two weeks” may include every 14 days ± 3 days, i.e., every 11 days to every 17 days. Similar approximations apply, for example, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, and about once every 12 weeks. In certain embodiments, a dosing interval of about every 6 weeks or about every 12 weeks means that the first dose can be administered on any day of the first week, and then on any day of the sixth or twelfth week, respectively. Administer the second dose on any day. In other embodiments, a dosing interval of about every 6 weeks or about every 12 weeks means administering the first dose on a specific day of the first week (e.g., Monday), and then on a specific day of the first week or 12 weeks, respectively. The second dose is administered on the same day at twelve weeks (i.e., Monday). Similar principles apply to phrases including, but not limited to, "about once every 2 weeks,""about once a month," etc.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" includes salts of a base ion with a free acid or an acid ion with a free base.

The term "prodrug" is intended to include any covalently bound carrier that releases the active parent drug of the invention in vivo when such prodrug is administered to a mammalian subject. The prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a manner that the modification is cleaved to the parent compound during routine manipulation or in vivo.

The term "fixed combination" means that the active components (eg, anti-PD-1 antibody or compound of formula I) are administered simultaneously to a subject in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or preparation.

The term "non-fixed combination" refers to the administration of two or more active components as independent entities (such as pharmaceutical compositions, preparations) to a subject simultaneously, concurrently or sequentially without specific time limits, wherein the administration to the subject The active ingredient reaches a therapeutically effective dose level. Examples of non-fixed combinations include cocktail therapy, for example, administration of three or more active ingredients. In non-fixed combinations, the individual active ingredients may be packaged, sold or administered as entirely separate pharmaceutical compositions. The "non-fixed combination" also includes the combined use of "fixed combinations" between "fixed combinations" or "fixed combinations" with any one or more independent entities of the active ingredients.

As used herein, "combination" or "used in combination" means that two or more active substances may be administered to a subject together in a mixture, simultaneously as a single formulation, or sequentially in any order as a single formulation.

The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present disclosure (eg, anti-PD-1 antibody or compound of Formula I) or a pharmaceutical combination thereof and pharmaceutically acceptable excipients. The purpose of pharmaceutical compositions is to facilitate administration to a subject of a compound of the present disclosure or a pharmaceutical combination thereof.

The term "synergistic effect" refers to the effect produced by two or more components (e.g., an anti-PD-1 antibody or a compound of Formula I) (e.g., inhibition or alleviation of lung or colon cancer (symptoms), specifically, for example, inhibition of colon cancer growth, or Alleviating colon cancer symptoms, inhibiting lung cancer growth, or alleviating lung cancer symptoms) is a simple additive effect greater than the effects of the ingredients administered alone.

Unless specifically stated otherwise, singular terms include plural terms and plural terms include the singular term. The word "a" or "an" means "at least one" or "at least one" unless specifically stated otherwise. The use of "or" means "and/or" unless stated otherwise.

In this document, unless stated otherwise, the terms "comprises, including and containing" or equivalents are open-ended expressions, meaning that in addition to the listed elements, components and steps, other unspecified elements, components, and steps may also be encompassed. Ingredients and Procedures.

The term "single dose" refers to the smallest packaging unit containing a certain amount of medicine. For example, if there are seven capsules in a box of medicine, each capsule is a single dose; or each bottle of injection is a single dose.

The term "multiple doses" consists of a plurality of single doses.

Mode of administration

The following content does not limit the administration mode of the pharmaceutical combination of the present disclosure.

The components in the pharmaceutical combination of the present disclosure may be formulated separately, or part or all of them may be formulated together. In one embodiment, The pharmaceutical combinations of the present disclosure may be formulated into pharmaceutical compositions suitable for single or multiple administration.

The components in the pharmaceutical combination of the present disclosure may be administered individually, or part or all thereof may be administered together. The components of the pharmaceutical combinations of the present disclosure may be administered substantially simultaneously, or some or all thereof may be administered substantially simultaneously.

The components of the pharmaceutical combinations of the present disclosure may be administered individually, or part or all thereof, together, by any suitable route, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). ). In some embodiments, the components of the pharmaceutical combinations of the present disclosure may be administered individually, or part or all of them may be administered together orally or by injection, such as intravenously or intraperitoneally.

The components in the pharmaceutical combination of the present disclosure may be suitable dosage forms each independently, or part or all of them together, including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, enteric capsules, etc.). capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or parenteral administration dosage form of sustained-release preparations.

The components in the pharmaceutical combination of the present disclosure may be each independently, or some or all of them may together contain pharmaceutically acceptable carriers and/or excipients.

Pharmaceutical combinations of the present disclosure may also include additional therapeutic agents. In one embodiment, the additional therapeutic agent may be a cancer therapeutic agent known in the art.

Technical effect

The compounds of formula I′ (specifically, formula I, etc.), their esters (such as compounds of formula II (or II-1 to II-3)) or pharmaceutically acceptable salts thereof disclosed in the present disclosure can exert therapeutic effects on solid tumors such as lung cancer. , has good pharmacokinetic properties, small adverse reactions, good tolerance, and good medicinal value.

The drug combination of the present disclosure can exert curative effect on solid tumors such as lung cancer; and compared with single drugs, the drug combination of the present disclosure shows an enhanced effect, has a synergistic effect, has good pharmacokinetic properties, has small adverse reactions, and is tolerant. It has good receptivity and good medicinal value.

The "clinical benefits" of the disclosed drug combination include, but are not limited to: prolongation of progression-free survival (PFS), prolongation of overall survival (OS), improvement of objective response rate (ORR), disease control rate ( DCR) is improved, the number and/or severity of adverse reactions is reduced, the distant metastasis rate and local control rate are reduced, etc.

Description of the drawings

Figure 1 Relative tumor burden in mice;

Figure 2 Relative tumor area of mice.

Detailed ways

The present disclosure will be further described below with reference to specific embodiments. However, these embodiments in the present disclosure are only used for illustration and do not limit the scope of the present disclosure. Likewise, this disclosure is not limited to any specific preferred embodiments described herein. Those skilled in the art should understand that equivalent substitutions or corresponding improvements made to the technical features of the present disclosure still fall within the protection scope of the present disclosure. Unless otherwise specified, the reagents used in the following examples are all commercially available products, and the solutions can be prepared using conventional techniques in the art.

Table 1 Abbreviation list

“14C12H1L1 injection” refers to an injectable medical preparation containing the monoclonal antibody 14C12H1L1, which is usually administered to patients via intravenous infusion. In specific embodiments, the expression "14C12H1L1 injection, 200 mg/time" can be understood in the usual manner in the art as a water-soluble injection medical preparation containing 200 mg of 14C12H1L1 administered to the patient each time.

Example 1

Formation of lung cancer orthotopic tumors in transgenic mice that induce CC10RTTA-EGFR-DEL cancer driver gene mutations: CC10RTTA-EGFR-DEL transgenic mice (hereinafter referred to as EGFR-DEL mice) were used for treatment. When mice are fed doxycycline (DOX) food when they are 6 weeks old, tumors can form in the lungs about 1-2 months later.

Before treatment, the size and severity of tumors in EGFR-DEL mice were recorded by computer tomography (CT). And the mice with lung tumors were divided into four groups, namely the normal saline control group (vehicle), the formula II compound treatment group, the 14C12H1L1 treatment group, and the formula II compound + 4C12H1L1 combined treatment group.

Dosing method:

Compound of formula II, taken orally, once every two days, 7mg/kg/time;

14C12H1L1, intraperitoneal injection, once every two days, 10mg/kg/time.

A two-week drug treatment was carried out simultaneously according to the aforementioned administration method and dosage. On the 7th and 14th days of treatment, the changes in the lung tumors of the mice were recorded through computed tomography.

After the treatment, the mice were euthanized, and the lung tissues were dissected and paraffin sections were prepared. HE staining of paraffin sections and microscopic observation of pathological changes in mouse lung cancer tissues after drug treatment were performed.

Results and analysis:

From the results of CT scans, it can be found that after two weeks of treatment (including the control group and the treatment group), the infiltration area of lung tumors in mice in the control group increased to varying degrees; compared with the control group, 14C12H1L1 monotherapy can The infiltration of lung tumors in mice was slightly reduced; the single drug treatment of the compound of formula II could significantly reduce the infiltration of lung tumors in mice, which was reduced by about 50-80% compared with before treatment; and the compound of formula II combined with 14C12H1L1 treatment reduced tumor infiltration The inhibition is more obvious, reduced by about 80-90% compared with before treatment; especially for mice with lighter lung tumor burden, whether it is compound II alone or combined with 14C12H1L1 treatment, it can be inhibited after two weeks of administration. The lung tumors have almost completely disappeared. It shows that the compound of formula II has a significant therapeutic effect on mouse lung cancer orthotopic tumors with EGFR-DEL driver gene mutation (EGFR gene exon 19 deletion), and combined with 14C12H1L1 can further enhance the therapeutic effect (see Figure 1 for details) .

After 2 weeks of treatment (including the control group and the treatment group), part of the lungs were removed for formalin fixation, paraffin embedding, sectioning, H&E staining, and microscopic observation and photography. Pathological analysis showed that the lungs of control mice had highly heterogeneous nuclear morphology, an increased ratio of nuclei to cytoplasm, and highly disordered arrangement of tumor cells along the alveoli, all of which indicated the malignant nature of lung cancer. In sharp contrast, high intratumoral spaces and thickened alveolar walls were detected in the lungs of mice treated with the compound of formula II and the compound of formula II combined with 14C12H1L1, indicating that the area occupied by the initial tumor had undergone dramatic changes. of reshaping. Furthermore, heterogeneity in nuclear morphology and nuclear to cytoplasmic ratio were significantly milder in the lungs of mice treated with the compound of Formula II combined with 14C12H1L1. These results pathologically confirmed the anti-tumor effect of the compound of formula II and the compound of formula II combined with 14C12H1L1 (see Figure 2 for details).

Example 2

2.1 Selection criteria:

1. Subjects voluntarily join this study and sign the informed consent form;

2. Age: ≥18 years old (when signing the informed consent form); gender is not limited;

3. Subjects with advanced progressive/metastatic solid tumors confirmed by histopathology and/or cytology;

4. There is no standard treatment plan, or the disease has progressed or is intolerant after receiving standard treatment in the past;

5. Confirmed to have at least one measurable lesion according to RECIST1.1 standards;

6.ECOG score: 0-2 points;

7. The expected survival period is more than 3 months;

8. The main organs function well and meet the following standards:

a) Hemoglobin (HGB) ≥ 90g/L;

b) Neutrophil absolute value (NEUT) ≥1.5×109/L;

c) Platelet count (PLT) ≥100×109/L;

(2) Blood biochemical tests must meet the following standards:

a) Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN);

b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN. If there is liver metastasis, ALT and AST < 5 × ULN;

(6) Cardiac color ultrasound evaluation: left ventricular ejection fraction (LVEF) ≥50%;

9. Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study period and within 6 months after the end of the study; have a negative serum pregnancy test within 7 days before study enrollment , and must be non-lactating subjects; women of childbearing age include premenopausal women and women within 2 years after menopause. Male subjects should agree to use birth control measures during the study period and for 6 months after the end of the study period.

2.2 Therapeutic drugs:

Formula II compound capsules: specifications 0.5mg, 2mg, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

14C12H1L1 injection: specification 10ml: 100mg, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

2.3 Dosage regimen

plan 1:

Capsules of compound of formula II: administered once on the 1st and 8th days of each treatment cycle, 5 mg each time (based on the weight of compound of formula I), every 3 weeks is a treatment cycle, taken orally in the morning on an empty stomach (before meals) Take at least 1 hour or at least 2 hours after eating);

14C12H1L1 injection: administered once every 3 weeks (i.e. administered once on the first day of each cycle), every 3 weeks is a treatment cycle, 200mg/time, administered by intravenous infusion. The infusion time is 60±10min.

Scenario 2:

Capsules of compound of formula II: administered once on the 1st and 8th days of each treatment cycle, 6 mg (based on the weight of compound of formula I) each time, every 3 weeks is a treatment cycle, taken orally in the morning on an empty stomach (before meals) Take at least 1 hour or at least 2 hours after eating);

Option 3:

Capsules of compound of formula II: administered once on the 1st and 8th days of each treatment cycle, 7 mg (based on the weight of compound of formula I) each time, every 3 weeks is a treatment cycle, taken orally in the morning on an empty stomach (before meals) Take at least 1 hour or at least 2 hours after eating);

2.3 Efficacy evaluation

The patient's efficacy evaluation criteria are based on RECIST1.1 (Response Evaluation Criteria for Solid Tumors).

Efficacy evaluation indicators include but are not limited to: objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Descriptive statistics were used for ORR and DCR to describe the ORR, DCR and corresponding 95% CI of each group. CI was calculated using the Clopper-pearson method. For PFS, OS and DOR, the Kaplan-Meier method was used to calculate the median progression-free survival, median overall survival and median duration of response, and provide 95% confidence intervals to draw survival curves.

The incidence and severity of adverse events (AEs) were also assessed.

2.4 Treatment results

The compound of Formula II combined with 14C12H1L1 can safely and effectively treat solid tumors (especially lung cancer), improve the clinical benefits of patients, relieve and control the patient's condition, and slow down the progression of the disease. Specific exemplary results are as follows:

Claims

A pharmaceutical combination comprising a compound of formula I', its ester or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or antigen-binding fragment thereof,

in,

Ring A is selected from phenyl or 5-10 membered heteroaryl;

Each R 1 is independently selected from halogen, CN, OH, NH 2 , C 1-6 alkyl or C 1-6 heteroalkyl, wherein the C 1-6 alkyl or C 1-6 heteroalkyl is either Optionally substituted with one or more groups selected from halogen, OH or NH ;

n is selected from 0, 1, 2, 3, 4 or 5;

R 2 and R 3 are each independently selected from H or C 1-6 alkyl.
The pharmaceutical combination according to claim 1, wherein Ring A is selected from phenyl or 5-6 membered heteroaryl;

Alternatively, Ring A is selected from phenyl or pyridyl;

Optionally, each R 1 is independently selected from halogen, CN, OH, NH 2 , C 1-3 alkyl or C 1-3 alkoxy;

Alternatively, each R 1 is independently selected from fluorine or CN;

Optionally, n is selected from 1 or 2.
The pharmaceutical combination according to claim 1 or 2, wherein the compound of formula I', its ester or a pharmaceutically acceptable salt thereof is selected from formula I, formula I-1, formula I-2 or formula I-3 compound, its ester or a pharmaceutically acceptable salt thereof,
A pharmaceutical combination comprising a compound of formula I, its ester or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or antigen-binding fragment thereof,
A kit comprising the pharmaceutical combination according to any one of claims 1 to 4, further comprising a compound of Formula I or Formula I', its ester or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or its antigen Instructions for use with combined fragments.
The pharmaceutical combination or kit according to any one of claims 1 to 5, wherein the ester of the compound of Formula I or Formula I-1 to I-3 is the malate ester of the compound of Formula I or Formula I';

Optionally, the ratio of the number of molecules of the compound of Formula I or Formula I' to malic acid in the ester of the compound of Formula I or Formula I' is selected from 1:1;

Optionally, wherein the ester of a compound of formula I or formula I' is a compound of formula II
The pharmaceutical combination or kit according to any one of claims 1 to 6, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 and heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3, the LCDR1, LCDR2 and LCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3, the HCDR1, HCDR2 and HCDR3 respectively comprise SEQ ID NO:4, The amino acid sequence shown in SEQ ID NO:5 and SEQ ID NO:6;

Optionally, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region having more than 85% identity with the amino acid sequence shown in SEQ ID NO:7 and a light chain variable region with the amino acid sequence shown in SEQ ID NO:8 A heavy chain variable region with an amino acid sequence of more than 85% identity;

Optionally, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region with an amino acid sequence as shown in SEQ ID NO:7 and a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:8 ;

Optionally, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain with more than 85% identity to the amino acid sequence shown in SEQ ID NO: 9 and an amino acid sequence shown in SEQ ID NO: 10 85% identical heavy chain;

Optionally, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain with an amino acid sequence as shown in SEQ ID NO: 9 and a heavy chain with an amino acid sequence as shown in SEQ ID NO: 10;

Optionally, the anti-PD-1 antibody is 14C12H1L1.
The pharmaceutical combination or kit according to any one of claims 1 to 7, wherein the anti-PD-1 antibody is 14C12H1L1, nivolumab, pembrolizumab, toripalimab, sintilizumab monoclonal antibody, camrelizumab, tislelizumab, batilizumab, jenosumab, LZM009, HLX10, AK103, CS1003, SCT-I10A, F520, SG001, or cepalizumab.
The pharmaceutical combination or kit according to any one of claims 1 to 8, said pharmaceutical combination comprising: a compound of Formula I or Formulas I-1 to I-3, its ester or a pharmaceutically acceptable salt thereof; and 14C12H1L1 or antigen-binding fragments thereof;

Alternatively, the pharmaceutical combination includes: a compound of Formula I or Formulas I-1 to I-3, or its malate ester, or a pharmaceutically acceptable salt thereof; and 14C12H1L1 or its antigen-binding fragment;

Optionally, the pharmaceutical combination contains a compound of Formula I or Formulas I-1 to I-3, its ester or a pharmaceutically acceptable salt thereof in the range of 0.5 mg to 8.5 mg;

Or, the pharmaceutical combination includes 0.5mg, 1.5mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 4.5mg, 5.0mg, 5.5mg, 6.0mg, 6.5mg, 7.0mg, 7.5mg , 8.0 mg, 8.5 mg, or a compound of Formula I or Formula I-1 to I-3, its ester or a pharmaceutically acceptable salt thereof within the range formed by any of the above values;

Alternatively, the pharmaceutical combination contains a compound of Formula I or Formulas I-1 to I-3, its ester or a pharmaceutically acceptable salt thereof in the range of 0.8 mg to 8.0 mg;

Or, the pharmaceutical combination includes 0.8mg, 1.2mg, 1.6mg, 2.0mg, 2.4mg, 2.8mg, 3.2mg, 3.6mg, 4.0mg, 4.4mg, 4.8mg, 5.2mg, 5.6mg, 6.0mg , 6.4 mg, 6.8 mg, 7.2 mg, 7.6 mg, 8.0 mg or a compound of Formula I or Formula I-1 to I-3 within the range formed by any of the above values, or a pharmaceutically acceptable salt thereof;

Alternatively, the pharmaceutical combination contains a compound of Formula II or a pharmaceutically acceptable salt thereof in the range of 1.0 mg to 10 mg (based on the weight of the compound of Formula II);

Or, the pharmaceutical combination includes 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg , 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg or a compound of formula II or a pharmaceutically acceptable salt thereof in the range formed by any of the above values (based on the weight of the compound of formula II);

Alternatively, the pharmaceutical combination contains a compound of formula II or a pharmaceutically acceptable salt thereof in an amount of 5.0 mg to 7.0 mg;

Alternatively, the pharmaceutical composition contains a compound of formula II or a pharmaceutically acceptable salt thereof in an amount of 5.0 mg, 6.0 mg or 7.0 mg;

Optionally, the pharmaceutical combination contains about 10 mg to about 1000 mg of anti-PD-1 antibody or antigen-binding fragment thereof;

Alternatively, the pharmaceutical combination contains about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg Or anti-PD-1 antibodies or antigen-binding fragments thereof within the range formed by any of the above values;

Alternatively, the pharmaceutical combination contains approximately 50-350 mg of anti-PD-1 antibody or antigen-binding fragment thereof;

Alternatively, the pharmaceutical combination contains approximately 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof;

Alternatively, the pharmaceutical combination includes: 5.0 mg to 7.0 mg of the compound of formula I or its malate ester, or its pharmaceutically acceptable salt; and 50 to 350 mg of anti-PD-1 antibody or antigen-binding fragment thereof;

Optionally, the pharmaceutical combination includes a compound of formula I, its ester or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or its antigen-binding fragment in a weight ratio selected from the group consisting of 4 mg: 100 mg, 4.4 mg: 100 mg, and 4.8 mg. : 100mg, 5.2mg: 100mg, 5.6mg: 100mg, 6.0mg: 100mg, 4mg: 200mg, 4.4mg: 200mg, 4.8mg: 200mg, 5.2mg: 200mg, 5.6mg: 200mg, 6.0mg: 200mg or any of the above values the scope of formation;

Alternatively, the pharmaceutical combination includes a compound of Formula II or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II) and an anti-PD-1 antibody or an antigen-binding fragment thereof in a weight ratio selected from the group consisting of 5 mg: 100 mg and 5.5 mg: 100 mg. , 6mg: 100mg, 6.1mg: 100mg, 6.2mg: 100mg, 6.3mg: 100mg, 6.4mg: 100mg, 6.5mg: 100mg, 7mg: 100mg, 7.1mg: 100mg, 7.2mg: 100mg, 7.3mg: 100mg, 7.4 mg: 100mg, 7.5mg: 100mg, 7.6mg: 100mg, 7.7mg: 100mg, 7.8mg: 100mg, 7.9mg: 100mg, 8.0mg: 100mg, 8.5mg: 100mg, 8.6mg: 100mg, 8.7mg: 100mg, 8.8 mg: 100mg, 8.9mg: 100mg, 9.0mg: 100mg, 9.1mg: 100mg, 9.2mg: 100mg, 9.3mg: 100mg, 9.4mg: 100mg, 9.5mg: 100mg, 5mg: 200mg, 5.5mg: 200mg, 6mg: 200mg, 6.1mg: 200mg, 6.2mg: 200mg, 6.3mg: 200mg, 6.4mg: 200mg, 6.5mg: 200mg, 7mg: 200mg, 7.1mg: 200mg, 7.2mg: 200mg, 7.3mg: 200mg, 7.4mg: 200mg , 7.5mg: 200mg, 7.6mg: 200mg, 7.7mg: 200mg, 7.8mg: 200mg, 7.9mg: 200mg, 8.0mg: 200mg, 8.5mg: 200mg, 8.6mg: 200mg, 8.7mg: 200mg, 8.8mg: 200mg , 8.9mg: 200mg, 9.0mg: 200mg, 9.1mg: 200mg, 9.2mg: 200mg, 9.3mg: 200mg, 9.4mg: 200mg, 9.5mg: 200mg or the range formed by any of the above values.
The pharmaceutical combination or kit according to any one of claims 1 to 9, wherein the pharmaceutical combination is a fixed combination or a non-fixed combination;

Optionally, the compounds of Formula I or Formulas I-1 to I-3, their esters or pharmaceutically acceptable salts thereof and the anti-PD-1 antibody or antigen-binding fragment thereof in the fixed combination are present in the same pharmaceutical composition. ;

Optionally, the compounds of Formula I or Formulas I-1 to I-3, their esters or pharmaceutically acceptable salts thereof and the anti-PD-1 antibody or antigen-binding fragment thereof in the non-fixed combination are each in the form of a pharmaceutical composition form;

Optionally, the compounds of Formula I or Formulas I-1 to I-3, their esters or pharmaceutically acceptable salts thereof and the anti-PD-1 antibody or antigen-binding fragment thereof in the non-fixed combination are each in the form of a pharmaceutical composition form, and the pharmaceutical composition of the compound of Formula I or Formula I-1 to I-3, its ester or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of the anti-PD-1 antibody or its antigen-binding fragment are present or absent. in the same medicine bag.
The pharmaceutical combination or kit according to any one of claims 1 to 10, the pharmaceutical composition of the compound of formula I or formula I-1 to I-3, its ester or its pharmaceutically acceptable salt is selected from the group consisting of solid pharmaceutical combinations thing;

Optionally, the solid pharmaceutical composition is selected from tablets or capsules;

Optionally, the pharmaceutical composition of the anti-PD-1 antibody or antigen-binding fragment thereof is selected from a liquid preparation composition;

Optionally, the liquid formulation composition is selected from injectable solutions.
The pharmaceutical combination or kit according to any one of claims 1 to 11, the compound of formula I or formula I-1 to I-3, its ester or its pharmaceutically acceptable salt can be administered once a day, every Apply twice a day, apply once every two days, apply once every three days, apply once every four days, Apply every five days, every six days, every week, every two weeks, every three weeks, twice every three weeks, or three times every three weeks;

Optionally, the anti-PD-1 antibody or antigen-binding fragment thereof can be administered once every day, once every two days, once every three days, once every four days, once every five days, once every six days. Apply once, once every week, once every two weeks, or once every three weeks.
The pharmaceutical combination or kit according to any one of claims 1 to 12, wherein every 14, 21 or 28 days of the pharmaceutical combination constitutes a treatment cycle;

Alternatively, the drug combination is a treatment cycle every 21 days;

Optionally, the pharmaceutical combination is administered once, twice, three times or four times in each cycle with a compound of Formula I or Formulas I-1 to I-3, its ester or a pharmaceutically acceptable salt thereof;

Alternatively, administer a compound of Formula I or Formulas I-1 to I-3, its ester or a pharmaceutically acceptable salt thereof 2 or 3 times per cycle;

Alternatively, administer the compound of Formula I or Formulas I-1 to I-3, its ester or its pharmaceutically acceptable salt twice in each cycle;

Alternatively, administer the compound of Formula I or Formula I-1 to I-3, its ester or its pharmaceutically acceptable salt once on the 1st day and the 8th day of each cycle;

Optionally, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once, twice, or three times per cycle;

Alternatively, administer an anti-PD-1 antibody or antigen-binding fragment thereof once per cycle;

Optionally, administered once per cycle, the anti-PD-1 antibody or antigen-binding fragment thereof is administered intravenously on Day 1 (D1) of each cycle;

Optionally, the pharmaceutical combination is suitable for administration in a single treatment cycle, and the drug administered in a single treatment cycle includes: 10 mg-16 mg of a compound of formula I or formulas I-1 to I-3, an ester thereof or a pharmaceutically acceptable compound thereof. an acceptable salt; and 10-1000 mg of anti-PD-1 antibody or antigen-binding fragment thereof.
The use of the pharmaceutical combination or kit according to any one of claims 1 to 13 in the preparation of drugs for treating tumors.
A method of treating tumors, which includes administering an effective amount of the pharmaceutical combination or kit according to any one of claims 1-14 to an individual in need.
The pharmaceutical combination or kit according to any one of claims 1-15 for treating tumors.
Use of the pharmaceutical combination or kit according to any one of claims 1 to 16 for treating tumors.
The use of a compound of formula I, its ester or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of solid tumors,
A method of treating solid tumors, comprising administering to an individual in need thereof an effective amount of a compound of formula I, an ester thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof,
A compound of formula I, its ester or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the treatment of solid tumors,
The use of a compound of formula I, its ester or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the treatment of solid tumors,
The use, method or compound of formula I, its ester or a pharmaceutically acceptable salt thereof or its pharmaceutical composition according to any one of claims 18 to 21, wherein the ester of the compound of formula I is malic acid of the compound of formula I ester;

Optionally, the molecular number ratio of the compound of formula I to malic acid in the ester of the compound of formula I is selected from 1:1;

Optionally, the ester of the compound of formula I is a compound of formula II
The use, method or compound of formula I, its ester or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof according to any one of claims 18 to 22, wherein the compound of formula I, its ester or its pharmaceutically acceptable salt The dosage per administration of the salt or pharmaceutical composition thereof is selected from the group consisting of 0.5 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5mg, 8.0mg, 8.5mg or the range formed by any of the above values;

Alternatively, the dosage for each administration of the compound of formula I, its ester or its pharmaceutically acceptable salt or its pharmaceutical composition is selected from the group consisting of 0.8 mg, 1.2 mg, 1.6 mg, 2.0 mg, 2.4 mg, 2.8 mg, 3.2 mg, 3.6mg, 4.0mg, 4.4mg, 4.8mg, 5.2mg, 5.6mg, 6.0mg, 6.4mg, 6.8mg, 7.2mg, 7.6mg, 8.0mg or the range formed by any of the above values;

Alternatively, the dose of the compound of formula II, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, is selected from the group consisting of 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, and 4.5 mg. , 5.0mg, 5.5mg, 6.0mg, 6.5mg, 7.0mg, 7.5mg, 8.0mg, 8.5mg, 9.0mg, 9.5mg, 10mg or the range formed by any of the above values (based on the weight of the compound of formula II);

Optionally, the compound of formula I, its ester or a pharmaceutically acceptable salt thereof may be administered once every day, twice every day, once every two days, once every three days, once every four days, Apply every five days, every six days, every week, every two weeks, or every three weeks;

Optionally, every 21 (3 weeks) days or 28 (4 weeks) days is a treatment cycle;

Optionally, the administration treatment of the compound of formula I, its ester or its pharmaceutically acceptable salt is based on a cycle of 3 weeks (21 days), and is administered once on the 1st day and the 8th day.
The use, method, pharmaceutical combination, kit, or compound of formula I, its ester or its pharmaceutically acceptable salt or its pharmaceutical composition according to any one of claims 14-23, wherein the tumor is selected from solid tumors ; Alternatively, the tumor is selected from advanced solid tumors;

Optionally, the tumor or advanced solid tumor is selected from advanced malignant solid tumors;

Optionally, the tumor, advanced solid tumor or advanced malignant solid tumor is selected from lung cancer;

Optionally, the tumor, advanced solid tumor, advanced malignant solid tumor or lung cancer is selected from lung cancer with an EGFR cancer driver gene mutation.