Biphenyl olefin compound as well as pharmaceutical composition and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a biphenyl olefin compound, a pharmaceutical composition of the biphenyl olefin compound and application of the biphenyl olefin compound in disease treatment medicines. The invention provides a compound shown as a formula I, and a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof. Experiments prove that the compound provided by the invention has a better drug effect and higher safety, and shows an excellent PD-L1 inhibition effect.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a biphenyl olefin compound and a pharmaceutical composition and application thereof. Background Art

[0002] With the deepening of research into cancer treatment, cancer immunotherapy has been increasingly used to treat advanced malignancies. Immune checkpoint inhibitors are revolutionizing the treatment options and expectations for cancer patients. The success of targeting the T cell immune checkpoint receptors PD-1 / PD-L1 demonstrates the importance of immune regulation. The PD-1 / PD-L1 pathway is one of the inhibitory signaling pathways in the immune system. The PD-1 receptor is expressed on the surface of human T cells. When activated, it inhibits T cell activity and weakens the immune response. PD-L1 is a ligand that specifically binds to PD-1, secreted by the human body to prevent overly strong immune responses that can lead to autoimmune diseases. To evade T cell detection, tumor cells upregulate PD-L1 expression, inhibiting T cell activity and achieving immune escape.

[0003] PD-1 / PD-L1 immune checkpoint inhibitors inhibit this pathway, increasing T cell activity and achieving the goal of treating cancer. These drugs have two modes of action: one, known as a PD-1 inhibitor, reduces the binding of PD-L1 to PD-1 by binding to PD-1. The other, known as a PD-L1 inhibitor, reduces the binding of PD-L1 to PD-1 by binding to PD-L1. However, almost all immune checkpoint inhibitors on the market are monoclonal antibodies, which are expensive to produce and result in high prices for the finished drugs.

[0004] Although a series of PD-L1 inhibitors have been disclosed in recent years, there is still a need to discover and develop compounds with new chemical structures, better efficacy and better safety.

[0005] In view of this, the present invention is proposed. Summary of the Invention

[0006] The present invention designs a general compound having a biphenyl olefin functional group, and finds that the biphenyl olefin compound exhibits excellent PD-L1 inhibitory effect.

[0007] The present invention provides a compound as shown in Formula I or I', its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0008]

[0009]

[0010] Wherein, X1, X2 and X3 are each independently a nitrogen atom, CR X1 , CR X2 , CR X3 ;

[0011] X4, X5, X6, X7, X8, X9, X 10 、X 11 、X 12 Each independently is a nitrogen atom, CR X4 , CR X5 , CR X6 , CR X7 , CR X8 , CR X9 , CR X10 , CR X11 , CR X12 ;

[0012] Z is a carbon atom or a nitrogen atom;

[0013] R X1 、R X2 、R X3 、R X4 、R X5 、R X6 、R X7 、R X8 、R X9 、R X10 、R X11 、R X12 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, hydroxy, hydroxy-substituted alkyl, alkoxy, deuterated alkyloxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, or alkynyl;

[0014] m = 0, 1, 2, 3, 4;

[0015] n = 0, 1, 2, 3, 4;

[0016] q=0, 1, 2, 3, 4.

[0017] n = 0, 1, 2, 3, 4;

[0018] q=0, 1, 2, 3, 4.

[0019] The present invention also provides a pharmaceutical composition comprising a therapeutically effective dose of the above compound or its stereoisomers, tautomers or pharmaceutically acceptable salts and a pharmaceutically acceptable carrier.

[0020] The present invention provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of PD-1 / PD-L1 inhibitor drugs.

[0021] The present invention proposes the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 12 in the preparation of a medicament for treating or preventing a tumor disease; the tumor disease is melanoma, lung cancer, liver cancer, basal cell carcinoma, kidney cancer, myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, rectal cancer, head and neck cancer, peritoneal tumor, fallopian tube cancer, endometrial cancer, esophageal cancer, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer and thyroid cancer.

[0022] The technical solution provided by the embodiment of the present invention has the following advantages compared with the existing technology:

[0023] The present invention provides a novel compound having an unsaturated alkane functional group, which has better efficacy and exhibits excellent PD-L1 inhibitory effect.

[0024] The compounds provided by the embodiments of the present invention have better safety. Detailed Description of the Invention

[0026] All technical and scientific terms used in this specification have the same meanings as commonly understood by those skilled in the art.

[0027] Table 1:

[0028]

[0029]

[0030] The term "alkyl" refers herein to a saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, and further refers to a saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. The term includes straight and branched hydrocarbon groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, etc. Alkyl groups described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acyloxy, amide, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkyloxy, heterocyclooxy, aryloxy, heteroaryloxy, aryl or heteroaryl.

[0031] The term "aryl" herein refers to a 6-10 membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings with adjacent pairs of carbon atoms) group having a conjugated π electron system. The aryl group can be covalently attached to the defined chemical structure at any carbon atom that produces a stable structure. The aryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

[0032] The term "heterocyclyl" refers to a ring system containing a nitrogen atom or an oxygen atom, and the ring system can be "parallel" to aromatic and non-aromatic ring systems, or linked to other ring systems through a "spiro carbon atom".

[0033] The term "heteroaryl" as used herein refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O, or S. The term can have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, etc.), wherein the fused rings may or may not be aromatic groups containing heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. The heteroaryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, acyloxy, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

[0034] The term "alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms and at least one alkenyl unsaturated site in this article, and further refers to an alkenyl group having 2 to 6 carbon atoms and at least one alkenyl unsaturated site. Non-limiting examples of alkenyl include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, etc. Alkenyl described herein can be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkyloxy, sulfydryl, alkylthiol, deuterated alkylthiol, sulfone, sulfoxide, amino, silicon, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester.

[0035] The term "alkynyl" herein refers to an alkyl group having 2 to 8 carbon atoms in which two adjacent carbon atoms are linked by a triple bond, and further refers to an alkynyl group having 2 to 6 carbon atoms and having at least one alkynyl unsaturation site, wherein the alkyl group is as defined herein. Alkynyl refers to an unsaturated alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. Alkynyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkylthio, deuterated alkylthio, sulfone, sulfoxide, amino, silicon, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, and ester.

[0036] The present invention provides a compound as shown in Formula I, its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0037]

[0038] Wherein, X1, X2 and X3 are each independently a nitrogen atom, CR X1 , CR X2 , CR X3 ;

[0039] X4, X5, X6, X7, X8, X9, X 10 、X 11 、X 12 Each independently is a nitrogen atom, CR X4 , CR X5 , CR X6 , CR X7 , CR X8 , CR X9 , CR X10 , CR X11 , CR X12 ;

[0040] Z is a carbon atom or a nitrogen atom;

[0041] R X1 、R X2 、R X3 、R X4 、R X5 、R X6 、R X7 、R X8 、R X9 、R X10 、RX11 、R X12 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, hydroxy, hydroxy-substituted alkyl, alkoxy, deuterated alkyloxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, or alkynyl;

[0042] m = 0, 1, 2, 3, 4;

[0043] n = 0, 1, 2, 3, 4;

[0044] q=0, 1, 2, 3, 4.

[0045] The present invention provides a compound as shown in Formula I', its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0046]

[0047] Wherein, X1, X2 and X3 are each independently a nitrogen atom, CR X1 , CR X2 , CR X3 ;

[0048] X4, X5, X6, X7, X8, X9, X 10 、X 11 、X 12 Each independently is a nitrogen atom, CR X4 , CR X5 , CR X6 , CR X7 , CR X8 , CR X9 , CR X10 , CR X11 , CR X12 ;

[0049] Z is a carbon atom or a nitrogen atom;

[0050] R X1 、R X2 、R X3 、R X4 、R X5 、R X6 、R X7 、R X8 、RX9 、R X10 、R X11 、R X12 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, hydroxy, hydroxy-substituted alkyl, alkoxy, deuterated alkyloxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, or alkynyl;

[0051] m = 0, 1, 2, 3, 4;

[0052] n = 0, 1, 2, 3, 4;

[0053] q=0, 1, 2, 3, 4.

[0054] As an improvement of the embodiment of the present invention, in the general formula I and the general formula I', X4 is a nitrogen atom or CR X4 , X5 is a nitrogen atom or CR X5 , X6 is a nitrogen atom or CR X6 , X7 is a nitrogen atom or CR X7 , X8 is a nitrogen atom or CR X8 , X9 is a nitrogen atom or CR X9 , X 10 is a nitrogen atom or CR X10 , X 11 is a nitrogen atom or CR X11 , X 12 is a nitrogen atom or CR 12 ; R X1 、R X2 、R X3 、R X4 、R X5 、R X6 、R X7 、R X8 、R X9 、R X10 、R X11 、R X12 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R9 、R 10 、R 11 、R 12 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C3-C8 cycloalkyl, hydroxy, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkyloxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, C2-C8 alkenyl, or C2-C8 alkynyl.

[0055] As an improvement of the embodiment of the present invention, in Formula I and Formula I',

[0056] R X1 、R X2 、R X3 、R X4 、R X5 、R X6 、R X7 、R X8 、R X9 、R X10 、R X11 、R X12 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 Each is independently hydrogen, deuterium, halogen, C1-C3 alkyl, deuterated C1-C3 alkyl, halogenated C1-C3 alkane, C3-C6 cycloalkyl, hydroxy, hydroxy-substituted C1-C3 alkyl, C1-C3 alkoxy, deuterated C1-C3 alkyloxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, C2-C4 alkenyl, C2-C4 alkynyl;

[0057] m=1;

[0058] n=1;

[0059] q=1, 2, 3.

[0060] As an improvement to an embodiment of the present invention, in the general formula I and the general formula I', X1 is -CH2=.

[0061] As an improvement to an embodiment of the present invention, in the general formula I and the general formula I', X2 is -CH2=.

[0062] As an improvement to an embodiment of the present invention, in the general formula I and the general formula I', X3 is a nitrogen atom or -CH2=.

[0063] As an improvement to an embodiment of the present invention, in Formula I and Formula I', Z is a nitrogen atom.

[0064] As an improvement of the embodiment of the present invention, in the general formula I and the general formula I', R 1 、R 2 At the same time it is a hydrogen atom.

[0065] As an improvement of the embodiment of the present invention, in the general formula I and the general formula I', R 3 、R 4 Each independently represents hydrogen or hydroxy substituted C1-C3 alkyl, further optionally, R 3 、R 4 are each independently hydrogen, -CH 2 -OH, -CH 2 -CH 2 -OH, -CH 2 -CH 2 -CH 2 -OH.

[0066] As an improvement of the embodiment of the present invention, in the general formula I and the general formula I', R 5 、R 6 、R 7 、R 8 A hydrogen atom.

[0067] As an improvement to the embodiment of the present invention, in the general formula I and the general formula I', m=1.

[0068] As an improvement to the embodiment of the present invention, in the general formula I and the general formula I', n=1.

[0069] As an improvement to the embodiment of the present invention, in the general formula I and the general formula I', q=1, 2, 3, and further optionally, q=1.

[0070] As an improvement of the embodiment of the present invention, in the general formula I and the general formula I', X4 is CR X4 Optional, R X4 is a hydrogen atom or a C1-C6 alkyl group, R X4 It is a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, or an isopropyl group.

[0071] As an improvement to an embodiment of the present invention, in the general formula I and the general formula I', X5 is -CH=.

[0072] As an improvement of an embodiment of the present invention, in the general formula I and the general formula I', X6 is -CH=.

[0073] As an improvement to an embodiment of the present invention, in the general formula I and the general formula I', X8 is -CH=.

[0074] As an improvement of an embodiment of the present invention, in the general formula I and the general formula I', X9 is -CH=.

[0075] As an improvement of the embodiment of the present invention, in the general formula I and the general formula I', X 10 It is -CH=.

[0076] As an improvement of the embodiment of the present invention, in the general formula I and the general formula I', X 11 It is -CH=.

[0077] As an improvement of the embodiment of the present invention, in the general formula I and the general formula I', X 12 It is -CH=.

[0078] The present invention provides a compound as shown in Formula II, its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0079]

[0080] Wherein, X1, X2 and X3 are each independently a nitrogen atom, CR X1 , CR X2 , CR X3 ;

[0081] R X1 、R X2 、R X3 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, hydroxy, hydroxy-substituted alkyl, alkoxy, deuterated alkyloxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, or alkynyl;

[0082] m = 0, 1, 2, 3, 4;

[0083] n = 0, 1, 2, 3, 4;

[0084] q=0, 1, 2, 3, 4.

[0085] The present invention provides a compound as shown in Formula II', its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0086]

[0087] Wherein, X1, X2 and X3 are each independently a nitrogen atom, CR X1 , CR X2 , CR X3 ;

[0088] X4, X5, X6, X7, X8, X9, X 10 、X 11 、X 12 Each independently is a nitrogen atom, CR X4 , CR X5 , CR X6 , CR X7 , CR X8 , CR X9 , CR X10 , CR X11 , CR X12 ;

[0089] Z is a carbon atom or a nitrogen atom;

[0090] R X1 、R X2 、R X3 、R X4 、R X5 、R X6 、R X7 、R X8 、R X9 、R X10 、R X11 、R X12 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, hydroxy, hydroxy-substituted alkyl, alkoxy, deuterated alkyloxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, or alkynyl;

[0091] m = 0, 1, 2, 3, 4;

[0092] n = 0, 1, 2, 3, 4;

[0093] q=0, 1, 2, 3, 4.

[0094] As an improvement of the embodiment of the present invention, in Formula II and Formula II',

[0095] R X1 、R X2 、R X3 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C3-C8 cycloalkyl, hydroxy, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkyloxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, C2-C8 alkenyl, C2-C8 alkynyl;

[0096] R X1 、R X2 、R X3 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19Each is independently hydrogen, deuterium, halogen, C1-C3 alkyl, deuterated C1-C3 alkyl, halogenated C1-C3 alkane, C3-C6 cycloalkyl, hydroxy, hydroxy-substituted C1-C3 alkyl, C1-C3 alkoxy, deuterated C1-C3 alkyloxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, C2-C4 alkenyl, C2-C4 alkynyl;

[0097] m=1;

[0098] n=1;

[0099] q=1, 2, 3.

[0100] As an improvement of the embodiment of the present invention, in Formula II and Formula II', X1 is CH2;

[0101] As an improvement of the embodiment of the present invention, in Formula II and Formula II', X2 is CH2;

[0102] As an improvement of the embodiment of the present invention, in the general formula II and the general formula II', X3 is a nitrogen atom or CH2;

[0103] As an improvement of the embodiment of the present invention, in Formula II and Formula II', R 1 、R 2 At the same time, it is a hydrogen atom;

[0104] As an improvement of the embodiment of the present invention, in Formula II and Formula II', R 3 、R 4 Each independently represents hydrogen or hydroxy substituted C1-C3 alkyl; optionally, R 3 、R 4 Each is independently hydrogen, -CH2-OH, -CH2-CH2-OH, -CH2-CH2-CH2-OH.

[0105] As an improvement of the embodiment of the present invention, in Formula II and Formula II', R 5 、R 6 、R 7 、R 8 At the same time, it is a hydrogen atom;

[0106] As an improvement of the embodiment of the present invention, in Formula II and Formula II', R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 At the same time, it is a hydrogen atom;

[0107] As an improvement of the embodiment of the present invention, in Formula II and Formula II', R 19 is a hydrogen atom or a C1-C6 alkyl group. 19 A hydrogen atom, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group can be used.

[0108] The present invention provides the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts:

[0109]

[0110] In embodiments of the present invention, compounds of the present invention having the same molecular formula but different properties or sequences of their atomic bonds or different spatial arrangements of their atoms are referred to as "isomers". Isomers having different spatial arrangements of atoms are referred to as "stereoisomers". All isomers of the compounds described herein (e.g., cis-, trans-, or diastereomers) alone or in any mixture thereof are encompassed within the scope of the embodiments of the present invention. All of these forms include enantiomers, diastereomers, cis, trans, syn, anti, tautomers, and mixtures thereof. Stereoisomeric mixtures (e.g., mixtures of diastereomers) can be separated into their corresponding isomers using suitable separation methods in a known manner.

[0111] In embodiments of the present invention, the pharmaceutically acceptable salts of Formula I, Formula I', Formula II, and Formula II' compounds may include acid addition salts and basic salts. Suitable acid addition salts are formed by acids that can form non-toxic salts. For example, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclohexanesulfonate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, sucrose salt, stearate, succinate, tannate, and tartrate. Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.

[0112] The present invention also provides a pharmaceutical composition comprising a therapeutically effective dose of the above-mentioned compound or its stereoisomers, tautomers or pharmaceutically acceptable salts and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention can be prepared by methods known in the art. The pharmaceutical composition used in the present invention can be formulated according to conventional methods using one or more pharmaceutically acceptable carriers, which include excipients and adjuvants, which facilitate processing of the active compound into a pharmaceutically usable preparation. Suitable formulations depend on the selected route of administration. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore encompassed by the scope of the present invention. The pharmaceutical composition of the embodiments of the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and the compounds of the embodiments of the present invention can be present in suitable solid or liquid carriers or diluents. The pharmaceutical composition of the present invention can also be stored in suitable sterile equipment for injection or infusion. Generally, the amount of active ingredient in the pharmaceutical composition is 0.01% to 99% by weight of the pharmaceutical composition.

[0113] The compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be administered clinically to mammals (including humans) via oral, nasal, dermal, pulmonary, or gastrointestinal routes. The preferred route of administration is oral. The preferred daily dose is 0.5 to 200 mg / kg body weight, taken once or in divided doses. Regardless of the method of administration, the optimal dose for each individual should be determined based on the specific treatment. Typically, a low dose is started and the dose is gradually increased until the most appropriate dose is found. The effective dose of the active ingredient used may vary depending on the compound used, the mode of administration, and the severity of the disease being treated. However, satisfactory results are generally achieved when the compounds of the present invention are administered at a dose of about 1 to 300 mg / kg of animal body weight per day, preferably in 1 to 3 divided doses per day, or in a sustained-release form. For most large mammals, the total daily dose is about 5 to 1000 mg, preferably about 10 to 500 mg. Dosage forms suitable for oral administration contain about 1 to 200 mg of the active compound intimately mixed with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as required by the exigencies of the therapeutic situation.

[0114] The present invention also provides an embodiment of the present invention for use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a PD-1 / PD-L1 inhibitor drug.

[0115] The embodiments of the present invention also provide the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a tumor disease; the tumor disease is melanoma, lung cancer, liver cancer, basal cell carcinoma, kidney cancer, myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, rectal cancer, head and neck cancer, peritoneal tumor, fallopian tube cancer, endometrial cancer, esophageal cancer, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer and thyroid cancer.

[0116] The embodiments of the present invention also provide methods for treating or preventing a disease or condition, which include administering an effective amount of a compound comprising an embodiment of the present invention or a pharmaceutically acceptable salt thereof to an individual. The compound of the present invention or its pharmaceutical composition can be administered orally, parenterally, topically, rectally, mucosally or intestinally. Parenteral administration includes indirect injection to produce a systemic effect or direct injection to the affected site. Topical administration includes treatment of the skin or organs (such as eyes or ears) that can be easily reached by topical application. Transdermal delivery is also included to produce a systemic effect. Rectal administration includes the form of suppositories. Preferred routes of administration are oral and parenteral. BRIEF DESCRIPTION OF THE DRAWINGS

[0117] Figure 1 is the inhibition curve of compound 1;

[0118] Figure 2 is the inhibition curve of compound 3;

[0119] Figure 3 The body weight change curves of compound 1 and compound 3 during the dosing period. DETAILED DESCRIPTION

[0120] The present invention is further illustrated by the following examples, but the present invention is not limited thereto. Throughout this application, various examples of the compounds and methods of the present invention are mentioned herein. The present invention is not limited to these examples. The following examples are merely provided to provide methods for practicing the present invention and are not intended to limit the scope of the present invention in any way.

[0121] The compounds provided herein can be prepared by standard synthetic methods known in the art, and this specification provides general methods for preparing the compounds of the present invention. Starting materials can generally be obtained commercially or prepared by methods well known to those skilled in the art.

[0122] The compounds of the present invention and corresponding preparation methods are further explained and listed below by way of examples and preparations. It should be understood that although typical or preferred reaction conditions are given in the specific examples, other reaction conditions may also be used by those skilled in the art. Optimum reaction conditions may vary with the specific reaction used.

[0123] Compound preparation

[0124] Example 1:

[0125]

[0126] first step:

[0127] To a 5 ml single-necked bottle, SM-1 (150 mg), SM-2 (211 mg), Na2CO3 (160 mg), 1,4-dioxane (1.5 mL), and H2O (0.15 mL) were added. The mixture was protected by nitrogen and stirred at room temperature. Pd(dppf)Cl2 (44 mg) was added. The mixture was protected by nitrogen and the temperature was increased. The reaction was kept at 80°C for 23 h. The reaction was stopped and cooled to room temperature. Ethyl acetate (2 mL) was added to the reaction solution. The system was washed twice with water (2 mL each time); then washed once with saturated brine (2 mL), the organic phase was collected, and dried over anhydrous Na2SO4; the organic phase was collected, concentrated to dryness at 45°C, and purified by Flash chromatography to obtain a brown oil IM-1-1 (125 mg).

[0128] Step 2:

[0129] To a 5 mL single-necked flask, add intermediate IM-1-1 (125 mg), N,N-dimethylacetamide (1.25 mL), and Na2CO3 (61 mg), and stir at room temperature for 10 minutes. Add methyl bromoacetate (65 mg), and stir at room temperature for 14 hours. Add ethyl acetate (3.5 mL) to the reaction solution, and wash with water three times (3 mL each time); the organic phase is then washed once with saturated brine (3 mL); the organic phase is collected and dried over anhydrous Na2SO4; the organic phase is dried at 40°C and purified by Flash chromatography to obtain a yellow oil IM-1-2 (102 mg).

[0130] Step 3:

[0131] IM-1-2 (95 mg) was added to a 5 ml single-necked flask, and tetrahydrofuran (2 mL) was stirred. NaOH (14 mg) and H2O (0.38 mL) were added and stirred at room temperature for 3 h. 1 M hydrochloric acid (10 drops) was added to adjust the pH to about 4. The reaction solution was concentrated to dryness at 40 ° C. Methanol (3 mL) was added to dissolve the residue, filtered, and the product was prepared by preparative chromatography. The organic phase was concentrated and the aqueous phase was lyophilized to obtain 30 mg of compound 1. 1 H NMR (DMSO-d6, 600MHz) δ: 7.09~6.60(m,12H), 4.01(Br.s,2H), 3.61(Br.s,2H), 3.30~3, 20(m,4H), 2.77(s,3H).

[0132] Example 2:

[0133]

[0134] first step:

[0135] To a 5 mL single-necked bottle, SM-1 (100 mg), SM-3 (142 mg), Na2CO3 (107 mg), 1,4-dioxane (1 mL), and H2O (0.1 mL) were added. The mixture was protected by nitrogen and stirred at room temperature. Pd(dppf)Cl2 (30 mg) was added. The mixture was protected by nitrogen and the temperature was raised. The reaction was kept at 80°C for 17 h. The reaction was stopped and cooled to room temperature. Ethyl acetate (2 mL) was added to the reaction solution. The system was washed twice with water (2 mL each time); then washed once with saturated brine (2 mL), the organic phase was collected, and dried over anhydrous Na2SO4; the organic phase was collected, concentrated to dryness at 45°C, and purified by Flash chromatography to obtain a brown oil (70 mg).

[0136] Step 2:

[0137] To a 5 mL single-necked bottle, IM-2-1 (70 mg), N,N-dimethylacetamide (0.7 mL), and Na2CO3 (34 mg) were added, and the mixture was stirred at room temperature for 10 minutes. Methyl bromoacetate (36 mg) was added, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate (3 mL) was added to the reaction solution, and the mixture was washed with water three times (3 mL) each time; the organic phase was then washed once with saturated brine (3 mL); the organic phase was collected and dried over anhydrous Na2SO4; the organic phase was dried at 40°C and purified by Flash chromatography to give a yellow oil (47 mg).

[0138] Step 3:

[0139] IM-2-2 (47 mg) was added to a 5 mL single-necked flask, and tetrahydrofuran (1 mL) was stirred. NaOH (7 mg) and H2O (0.19 mL) were added and stirred at room temperature for 3 h. 1 M hydrochloric acid (8 drops) was added to adjust the pH to about 4. The reaction solution was concentrated to dryness at 40 ° C. Methanol (2 mL) was added to dissolve the residue, filtered, and the product was prepared by preparative chromatography. The organic phase was concentrated and the aqueous phase was lyophilized to obtain 17 mg of compound 3. 1 H NMR (DMSO-d6, 600MHz) δ: 7.09~6.61(m,12H), 4.00(Br.s,2H), 3.63(Br.s,2H), 3.31~3, 25(m,4H), 2.78(s,3H).

[0140] Experimental Example 1

[0141] This experimental example is used to illustrate the inhibitory activity of PD-1 / PD-L1 protein-protein interaction:

[0142] Experimental purpose: Use the PD-1 / PD-L1 binding assay kit (CISBIO) to detect the activity of the PD-1 / PD-L1 interaction inhibitors of the example compounds of the present invention.

[0143] Experimental materials: PD-1 / PD-L1 binding assay kits purchased from CISBIO; 96-well plates: purchased from CISBIO.

[0144] Testing instrument: Perkin Elmer, model: EnVision.

[0145] Test compound: Dissolve in DMSO and dilute with diluent buffer; DMSO concentration should not exceed 0.5%.

[0146] Experimental process: Use PD-1 / PD-L1binding assay kits. Set up negative group, positive group and drug-treated group, with 2 replicates in each group. For the positive control group, 2 μL diluent was added to the 96-well plate; 4 μL PD-L1 and 4 μL PD-1 diluted according to the instructions were added to the negative control group; 6 μL diluent and 4 μL PD-L1 were added to the 96-well plate; for the drug-treated group, 2 μL of the test compound (I), 4 μL PD-L1 and 4 μL PD-1 were added to the 96-well plate in sequence. Seal the plate with a sealing film, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 15 minutes. Then, Anti-Tag-Eu3 diluted in Buffer was added. + Mix equal volumes of Anti-tag-XL665, then add 10 μL of the mixture to each well, seal the plate, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 2 hours. Remove the plate seal, read the fluorescence intensity at 665 nm and 615 nm using EnVision, and calculate the IC value of the compound using Graphpad. 50 .

[0147] The inhibition curves of compound 1 and compound 3 are shown in Figure 2. Figure 1 and Figure 2 As shown, IC 50 The experimental results are shown in Table 2.

[0148] Table 2: Blocking effect of the compounds of the present invention on hPD-1 / hPD-L1

[0149] Example Compound No. <![CDATA[IC 50 (nM)]]> 1 8.77 3 20.13 BMS202 77.01

[0150] The above data show that the compound of the present invention has significant inhibitory activity on PD-1 / PD-L1 protein-protein interaction, and its inhibitory activity is better than that of BMS202.

[0151] Experimental Example 2

[0152] This experimental example is used to illustrate the preliminary safety of the compound:

[0153] Test samples: Compound 1 and Compound 3.

[0154] Animal species and number: Balb / c mice; 6 mice per group (half male and half female);

[0155] Administration: oral gavage;

[0156] Animal grouping and administration dosage: vehicle blank group, compound 1 group, compound 3 group, the dosage was gradually increased according to the dosage escalation rule shown in Table 3.

[0157] Dosage frequency: once a day for 8 consecutive days.

[0158] The specific test process is shown in Table 3:

[0159] Table 3

[0160] Group Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 solvent group / / / / / / / / Compound 1 10 mg / kg 50 mg / kg 80 mg / kg 100mg / kg 120 mg / kg 140 mg / kg 160 mg / kg 200mg / kg Compound 3 group 10 mg / kg 50 mg / kg 80 mg / kg 100mg / kg 120 mg / kg 140 mg / kg 160 mg / kg 200mg / kg

[0161] Experimental results: During the administration period of Compound 1 and Compound 3, the animals in all dose groups had normal water intake and food intake, normal activities and body weight. The body weight change curves were as follows: Figure 3 shown.

[0162] The experimental results showed no obvious abnormal changes in body weight, suggesting that the maximum tolerated dose of Compound 1 and Compound 3 is greater than 200 mg / kg.

[0163] The foregoing description is intended only to provide specific embodiments of the present invention, which will enable those skilled in the art to understand and implement the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not intended to be limited to the embodiments described herein, but is to be construed in the widest manner consistent with the principles and novel features disclosed herein.

Claims

1. A compound as shown in formula I or I', its stereoisomers, tautomers or pharmaceutically acceptable salts, in, X1, X2 and X3 are each independently a nitrogen atom, CR X1 , CR X2 , CR X3 ; X4, X5, X6, X7, X8, X9, X 10 、X 11 、X 12 Each independently is a nitrogen atom, CR X4 , CR X5 , CR X6 , CR X7 , CR X8 , CR X9 , CR X10 , CR X11 , CR X12 ; Z is a carbon atom or a nitrogen atom; R X1 、R X2 、R X3 、R X4 、R X5 、R X6 、R X7 、R X8 、R X9 、R X10 、R X11 、R X12 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, hydroxy, hydroxy-substituted alkyl, alkoxy, deuterated alkyloxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, or alkynyl; m＝0、1、2、3、4； n＝0、1、2、3、4； q＝0、1、2、3、4。 2. The compound according to claim 1, its stereoisomers, tautomers or pharmaceutically acceptable salts, characterized in that X4 is a nitrogen atom or CR X4 , X5 is a nitrogen atom or CR X5 , X6 is a nitrogen atom or CR X6 , X7 is a nitrogen atom or CR X7 , X8 is a nitrogen atom or CR X8 , X9 is a nitrogen atom or CR X9 , X 10 is a nitrogen atom or CR X10 , X 11 is a nitrogen atom or CR X11 , X 12 is a nitrogen atom or CR 12 ; Optional, R X1 、R X2 、R X3 、R X4 、R X5 、R X6 、R X7 、R X8 、R X9 、R X10 、R X11 、R X12 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C3-C8 cycloalkyl, hydroxy, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkyloxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, C2-C8 alkenyl, C2-C8 alkynyl; Optional, R X1 、R X2 、R X3 、R X4 、R X5 、R X6 、R X7 、R X8 、R X9 、R X10 、R X11 、R X12 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 Each is independently hydrogen, deuterium, halogen, C1-C3 alkyl, deuterated C1-C3 alkyl, halogenated C1-C3 alkane, C3-C6 cycloalkyl, hydroxy, hydroxy-substituted C1-C3 alkyl, C1-C3 alkoxy, deuterated C1-C3 alkyloxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, C2-C4 alkenyl, C2-C4 alkynyl; Optional, m=1; Optional, n=1; Optional, q=1, 2, 3.

3. The compound according to claim 1 or 2, its stereoisomer, tautomer or pharmaceutically acceptable salt, characterized in that: X1 is -CH2=; Optionally, X2 is -CH2=; Optionally, X3 is a nitrogen atom or -CH2=; Optionally, Z is a nitrogen atom; Optional, R 1 、R 2 is a hydrogen atom; Optional, R 3 、R 4 Each is independently hydrogen, hydroxyl substituted C1-C3 alkyl; Optional, R 5 、R 6 、R 7 、R 8 is a hydrogen atom; Optional, X4 for CR X4 ; Optional, R X4 is a hydrogen atom or a C1-C6 alkyl group; Optionally, X5 is -CH=; Optionally, X6 is -CH=; Optionally, X8 is -CH=; Optionally, X9 is -CH=; Optional, X 10 For -CH=; Optional, X 11 For -CH=; Optional, X 12 For -CH=; Optional, m=1; Optional, n=1; Optional, q=1, 2, 3.

4. A compound of formula II or II', its stereoisomers, tautomers or pharmaceutically acceptable salts, in, X1, X2 and X3 are each independently a nitrogen atom, CR X1 , CR X2 , CR X3 ; R X1 、R X2 、R X3 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, hydroxy, hydroxy-substituted alkyl, alkoxy, deuterated alkyloxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, or alkynyl; m＝0、1、2、3、4； n＝0、1、2、3、4； q＝0、1、2、3、4。 5. The compound according to claim 4, its stereoisomers, tautomers or pharmaceutically acceptable salts, characterized in that R X1 、R X2 、R X3 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C3-C8 cycloalkyl, hydroxy, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkyloxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, C2-C8 alkenyl, C2-C8 alkynyl; Optional, R X1 、R X2 、R X3 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 Each is independently hydrogen, deuterium, halogen, C1-C3 alkyl, deuterated C1-C3 alkyl, halogenated C1-C3 alkane, C3-C6 cycloalkyl, hydroxy, hydroxy-substituted C1-C3 alkyl, C1-C3 alkoxy, deuterated C1-C3 alkyloxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, C2-C4 alkenyl, C2-C4 alkynyl; Optional, m=1; Optional, n=1; Optional, q=1, 2, 3.

6. The compound according to claim 4 or 5, its stereoisomer, tautomer or pharmaceutically acceptable salt, characterized in that: X1 is CH2; Optionally, X2 is CH2; Optionally, X3 is a nitrogen atom or CH2; Optional, R 1 、R 2 is a hydrogen atom; Optional, R 3 、R 4 Each is independently hydrogen, hydroxyl substituted C1-C3 alkyl; Optional, R 5 、R 6 、R 7 、R 8 is a hydrogen atom; Optional, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 is a hydrogen atom; Optional, R 19 a hydrogen atom or a C1-C6 alkyl group.

7. The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts, 8. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 7 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in the preparation of a PD-1 / PD-L1 inhibitor drug.

10. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, in the preparation of a medicament for treating or preventing a tumor disease; the tumor disease is melanoma, lung cancer, liver cancer, basal cell carcinoma, kidney cancer, myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, rectal cancer, head and neck cancer, peritoneal tumor, fallopian tube cancer, endometrial cancer, esophageal cancer, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer and thyroid cancer.

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