WO2022166990A1 - Combinaison pharmaceutique antitumorale - Google Patents

Combinaison pharmaceutique antitumorale Download PDF

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WO2022166990A1
WO2022166990A1 PCT/CN2022/075561 CN2022075561W WO2022166990A1 WO 2022166990 A1 WO2022166990 A1 WO 2022166990A1 CN 2022075561 W CN2022075561 W CN 2022075561W WO 2022166990 A1 WO2022166990 A1 WO 2022166990A1
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substituted
unsubstituted
group
alkyl
amino
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Chinese (zh)
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杨财广
董泽
徐洪蛟
王传辉
黄悦
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中国科学院上海药物研究所
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings

Definitions

  • the present invention relates to the field of pharmaceutical compounds, and specifically, the present invention provides a combination of an FTO inhibitor represented by formula (I) and an immune checkpoint inhibitor for the treatment of solid tumors.
  • tumors can weaken and evade immune T cells.
  • tumors can express aggressive molecules on the cell surface that bind T cells and thereby inhibit the killing activity of T cells. These molecules are called immune checkpoints, such as PD. -1 and CTLA-4. Inhibiting immune checkpoint molecules to regulate the body's immune system is the core of tumor immunotherapy.
  • Tumor immunotherapy stimulates the recognition of the immune system by modulating T cell receptor signaling or using natural biomolecules and monoclonal antibodies to relevant tumor antigens.
  • the immune checkpoint inhibitor anti-PD-1/PD-L1 antibody has shown good efficacy in various advanced solid tumors such as melanoma and renal cancer, and its objective response rate (ORR) is about 10 in different solid tumors. %-40%, with the highest in malignant melanoma (about 36%-53%).
  • ORR objective response rate
  • anti-PD-1/PD-L1 antibody alone has not achieved the expected efficacy in many cancer patients, especially for patients with advanced colorectal cancer. Therefore, it is urgent to find small molecule compounds that can be combined with PD-1 or PD-L1 antibodies and enhance their efficacy.
  • m 6 A modification affects tumor antigen-specific T cell immune responses by regulating lysosomal cathepsin translation efficiency of dendritic cells.
  • m 6 A demethylase FTO its inhibitor can change the abundance of m 6 A in tumor cells, so as to improve the efficiency of tumor antigen-specific T cell immune response.
  • the present invention provides a type of FTO inhibitor, which can achieve the purpose of anti-tumor by being used in combination with an immune checkpoint inhibitor PD-1 or PD-L1 antibody.
  • the object of the present invention is to provide a pharmaceutical combination containing an FTO inhibitor suitable for tumor treatment.
  • the first aspect of the present invention provides a compound represented by the following formula (I), and the use of a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
  • M is selected from the group consisting of CR'2 , NH, O or S;
  • X has the structure shown in the following formula: carboxyl group, O-substituted or unsubstituted hydroxamic acid group, substituted or unsubstituted C2 - C12 ester group, substituted or unsubstituted amide group (C(O) NH2 ), substituted or unsubstituted 3-12-membered heterocyclyl;
  • Y is selected from the group consisting of substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted 3-12 membered heterocyclyl;
  • the compound of formula (I) is used together with an immune checkpoint inhibitor to prepare a pharmaceutical composition for treating or preventing solid tumors.
  • R a and R b are each independently selected from the group consisting of halogen, -OH, CN, NO 2 , NH 2 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted of C 1 -C 6 alkoxy;
  • R c , R d are each independently selected from the group consisting of H, halogen, -OH, CN, NO 2 , NH 2 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy.
  • the compound of formula (I) has the structure shown in the following formula (II):
  • a 1 , A 2 , A 3 , A 4 are each independently CR' or N;
  • R 0 is selected from the group consisting of hydrogen, hydroxy, substituted or unsubstituted C 1 -C 10 alkyl
  • R a , R b are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl (including monocyclic, polycyclic , bridged ring structure), substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl;
  • n is selected from the group consisting of 0, 1, 2, 3 or 4;
  • R x , R y are each independently selected from the group consisting of halogen, substituted or unsubstituted C 1 -C 4 alkyl;
  • Het is selected from the group consisting of substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 4-7 membered saturated heterocyclyl, substituted or unsubstituted 3-12 membered heterocyclyl;
  • the R 0 has the structure shown in the following formula:
  • R a , R b are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl (including monocyclic, polycyclic, bridged ring structure), substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl;
  • described Het is selected from the following group: substituted or unsubstituted pyridine, substituted or unsubstituted tetrazolium, substituted or unsubstituted triazole, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrimidine, substituted or unsubstituted tetrazolium Unsubstituted pyrazoles, substituted or unsubstituted isoxazoles, substituted or unsubstituted morpholines, substituted or unsubstituted thiomorpholines, substituted or unsubstituted piperidines, substituted or unsubstituted piperazines, substituted or unsubstituted or unsubstituted oxetane, substituted or unsubstituted thietane, substituted or unsubstituted azetidine.
  • described Het is selected from the following group:
  • the A 2 and A 3 are each independently CR'.
  • the A 1 , A 2 , A 3 , and A 4 are each independently CR'.
  • the R' has the structure shown in the following formula:
  • R" is H or a substituted or unsubstituted C1-C6 alkyl group.
  • the compound of formula (I) is selected from the following group:
  • the solid tumor is selected from the group consisting of melanoma, lung cancer, colon cancer, renal cancer, pancreatic cancer, lung cancer, and osteosarcoma.
  • Figure 1 shows that after the compounds of the present invention Dac51, Dac258, Dam62, and Dam128 treat tumor cells, the m 6 A abundance changes in a concentration-dependent manner with FTO inhibitors.
  • Figure 2 shows the improvement of tumor growth and body weight change of the compound Dam59 of the present invention in combination with anti-PD-L1 antibody in tumor-bearing mice.
  • Figure 4 shows the improvement of tumor growth and body weight change in tumor-bearing mice when the compound Dam60 of the present invention is combined with anti-PD-1 antibody.
  • substituted refers to the substitution of one or more hydrogen atoms on a group with a substituent selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy group, halogen, hydroxyl, carboxyl group (-COOH), C 1 -C 10 aldehyde group, C 2 -C 10 acyl group, C 2 -C 10 ester group, amino group, phenyl group; the described Phenyl includes unsubstituted phenyl or substituted phenyl with 1-3 substituents selected from: halogen, C 1 -C 10 alkyl, cyano, OH, nitro, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, amino.
  • C 1 -C 6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy , isobutoxy, sec-butoxy, tert-butoxy, or similar groups.
  • carbonyl C 1 -C 6 alkyl refers to a group in the form of "-COO-straight or branched chain alkyl of 1 to 6 carbon atoms", such as carbonyl-methyl, carbonyl-ethyl, carbonyl- propyl, carbonyl-isopropyl, carbonyl-butyl, carbonyl-isobutyl, carbonyl-sec-butyl, carbonyl-tert-butyl, or the like.
  • C 6 -C 12 aryl refers to aryl groups having 6 to 12 carbon atoms, including monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, or the like.
  • 3-12 membered heterocyclyl refers to a 3- to 12-membered ring system substituted with one or more heteroatoms selected from O, S, N, or P, saturated or unsaturated (including aromatic) ring systems group, such as pyridyl, thienyl, piperidinyl, or similar groups, preferably a 4-9 membered heterocyclic group.
  • halogen refers to F, Cl, Br and I.
  • the terms “comprising”, “comprising” or “including” mean that the various ingredients can be used together in the mixture or composition of the present invention.
  • the terms “consisting essentially of” and “consisting of” are encompassed by the term “comprising”.
  • the term "pharmaceutically acceptable” ingredients refers to substances that are suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation and allergy), ie, have a reasonable benefit/risk ratio.
  • the term "effective amount" refers to an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect.
  • the precise effective amount for a subject depends on the size and health of the subject, the nature and extent of the disorder, and the therapeutic agent and/or combination of therapeutic agents selected for administration. Therefore, it is useless to prespecify the exact effective amount. However, for a given situation, routine experimentation can be used to determine the effective amount, as is the judgment of the clinician.
  • substituted refers to the replacement of one or more hydrogen atoms on a group with a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted Substituted or halogenated C2-C6 acyl, unsubstituted or halogenated C1-C6 alkyl-hydroxy.
  • each chiral carbon atom can optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.
  • the term "compounds of the present invention” refers to compounds of formula I.
  • the term also includes the various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (I).
  • prodrug refers to a pharmaceutically acceptable metabolic precursor of a compound of the present invention, which can be converted to a compound of the biologically active compound of the present invention under physiological conditions or by solvolysis.
  • a prodrug may be inactive when administered to an individual in need thereof, but be converted in vivo to an active compound of the present invention.
  • Prodrugs are typically rapidly transformed in vivo to yield the parent compounds of the invention, eg, by hydrolysis in blood.
  • Prodrug compounds generally provide the advantages of solubility, histocompatibility or sustained release in mammalian organisms.
  • the FTO inhibitor compound is used in combination with the immune checkpoint inhibitor, thereby achieving a synergistic effect.
  • the FTO inhibitor is a compound represented by the following formula (I), and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof:
  • a 1 , A 2 , A 3 , A 4 are each independently CR' or N;
  • M is selected from the group consisting of CR'2 , NH, O or S;
  • X has the structure shown in the following formula: carboxyl group, hydroxamic acid group, substituted or unsubstituted C 2 -C 12 ester group, substituted or unsubstituted amide group (C(O)NH 2 ), substituted or unsubstituted 3 -12-membered heterocyclyl;
  • Y is selected from the group consisting of substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted 3-12 membered heterocyclyl;
  • R a , R b , R c , R d are each independently selected from the group consisting of H, halogen, -OH, CN, NO 2 , NH 2 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted Substituted C 1 -C 6 alkoxy;
  • substitution means that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen atom, carbonyl ( O), carboxyl, hydroxyl, amino, nitro, cyano, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 amido, C 2 -C 12 ester group, substituted or unsubstituted C 1 -C 10 alkane base, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted five-membered or Six-membered heteroaryl, 3-12-membered heterocyclic, 3-12-membered cycloalkyl, preferably C 1 -C 6 alkyl, hal
  • Preferred compounds have structures as shown in the Examples herein.
  • the pharmaceutical combination of the present invention has excellent inhibitory activity on tumor cell proliferation
  • Pharmaceutical combinations of inhibitors can be used to treat, prevent and alleviate diseases caused by tumor cell proliferation.
  • the compounds of the present invention can be used to treat the following diseases: melanoma, lung cancer, colon cancer and other cancers.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 5 to 500 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the present invention provides the use of a compound of formula (I) and an immune checkpoint inhibitor in combination to treat tumors.
  • the method can effectively inhibit the proliferation of tumor cells at a very low dosage, and compared with the two used alone , resulting in a clear synergistic effect.
  • the first step 30g (120mmol, 1.2eq) of o-iodobenzoic acid, 24g (100mmol, 1.0eq) of 2,6-dichloro-4-bromoaniline, 24g (100mmol, 1.0eq) of triethylamine (150mmol, 1.5eq) and anhydrous copper acetate 9g (5.0mmol, 0.5eq) was dissolved in 500mL of DMF, heated to 120°C under argon protection and reacted for 24 hours, after the reaction was completed.
  • Step 2 Dissolve 3.6 g of 2-(4-bromo-2,6-dichlorophenyl)amino)benzoic acid in 200 mL of absolute ethanol, add 20 mL of concentrated sulfuric acid to it under cooling in an ice-water bath, and heat to 100 The reaction was refluxed at °C for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, concentrated by rotary evaporation to remove ethanol, 100 mL of water was added to the system, and neutralized with saturated sodium carbonate until no bubbles were generated. The organic phase was extracted with ethyl acetate 50 mL ⁇ 3, and the organic phases were combined and washed with saturated brine for 10 mL ⁇ 3.
  • the third step 2-((4-bromo-2,6-dichlorophenyl)amino)ethyl benzoate 3.0g (8.0mmol, 1.0eq), 3,5-dimethylpyrazole-4- Pinacol borate 2.13g (9.6mmol, 1.2eq), Pd(dppf)Cl 2 584mg (0.8mmol, 0.1eq), Potassium carbonate 1.68g (12.0mmol, 1.5eq) dissolved in 1,4-dioxane In 160 mL of a mixed solvent of ring and water, the mixture was heated to 100°C and reacted for 24 hours.
  • Step 4 Dissolve 1.10g (2.7mmol, 1.0eq) of ethyl 2-((2,6-dichloro-4-(3,5-dimethylpyrazole)phenyl)amino)benzoate in tetrahydrofuran
  • a mixed solvent of 13.5 mL and 27 mL of absolute ethanol under cooling in an ice-water bath, a solution of 540 mg (13.5 mmol, 5.0 eq) of sodium hydroxide in 7 mL of water was slowly added dropwise. The reaction was heated to 45 °C overnight.
  • the system was cooled to room temperature, concentrated to remove the organic solvent, added with 20 mL of water, placed in an ice-water bath, adjusted to pH 3 with 2M dilute hydrochloric acid, and the resulting suspension was stirred at room temperature for 30 min. . After suction filtration, the solid was washed with water to obtain 930 mg of the target product, 2-((2,6-dichloro-4-(3,5-dimethylpyrazole)phenyl)amino)benzoic acid as a white solid.
  • the first and second reactions were prepared according to the synthetic procedure of Dac51.
  • the system was cooled to room temperature, concentrated to remove the organic solvent, added with 20 mL of water, placed in an ice-water bath, adjusted to pH 3 with 2M dilute hydrochloric acid, and the resulting suspension was stirred at room temperature for 30 min. After suction filtration, the solid was washed with water to obtain 930 mg of the target product, 2-((2,6-dichloro-4-(3-methylpyrazole)phenyl)amino)benzoic acid as a white solid.
  • the fifth step in a 10mL round-bottom flask, add 2-((2,6-dichloro-4-(pyrazole)phenyl)amino)benzoic acid 71mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol) , 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), hydroxylamine hydrochloride 17mg (0.24 mmol, 1.2eq) were successively added to the above system, and the resulting mixed system was added at 45 °C reaction. TLC detection, the raw material consumption was completed.
  • the fifth step in a 10mL round bottom flask, add 2-((2,6-dichloro-4-(3,5-dimethylpyrazole)phenyl)amino)benzoic acid 71mg (0.2mmol, 1.0eq ), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), ammonium chloride 14mg (0.24mmol, 1.2 eq), the resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic operation of Dac51.
  • the fifth step in a 10mL round bottom flask, add 2-((2,6-dichloro-4-(3,5-dimethylpyrazole)phenyl)amino)benzoic acid 71mg (0.2mmol, 1.0eq ), 114 mg (0.3 mmol, 1.5 eq) of HATU, dissolved in 4.0 mL of anhydrous DMF at room temperature, stirred for 5 min, and 77 mg (0.6 mmol, 3.0 eq) of DIEA, 18 mg (0.24 mmol) of 3-aminopropanol were sequentially added to the above system , 1.2eq), the resulting mixed system was reacted at 45 ° C for 2 hours.
  • the fifth step in a 10mL round bottom flask, add 2-((2,6-dichloro-4-(3,5-dimethylpyrazole)phenyl)amino)benzoic acid 71mg (0.2mmol, 1.0eq ), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), N,N-diethylaminoethylenedi Amine 28mg (0.24mmol, 1.2eq), the resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic operation of Dac51.
  • the fifth step in a 10mL round bottom flask, add 2-((2,6-dichloro-4-(3,5-dimethylpyrazole)phenyl)amino)benzoic acid 71mg (0.2mmol, 1.0eq ), 114 mg (0.3 mmol, 1.5 eq) of HATU, dissolved in 4.0 mL of anhydrous DMF at room temperature, stirred for 5 min, and 77 mg (0.6 mmol, 3.0 eq) of DIEA, 18 mg (0.24 mmol) of 3-aminopropanol were sequentially added to the above system , 1.2eq), the resulting mixed system was reacted at 45 ° C for 2 hours.
  • the first step 29.8g (120mmol, 1.2eq) of o-iodobenzoic acid, 22.8g (100mmol, 1.0eq) of 2,6-diethyl-4-bromoaniline, 22.8g (100mmol, 1.0eq) of triethylamine (150mmol, 1.5eq) and no 9.1 g (5.0 mmol, 0.5 eq) of water copper acetate was dissolved in 360 mL of DMF, heated to 120° C. for 24 h under argon protection, and the reaction was completed.
  • Step 2 Dissolve 10.4 g of 2-(4-bromo-2,6-diethylphenyl)amino)benzoic acid in 300 mL of absolute ethanol, add 30 mL of concentrated sulfuric acid to it under cooling in an ice-water bath, and heat to The reaction was refluxed at 100°C for 12 hours. After the reaction, the reaction system was cooled to room temperature, concentrated by rotary evaporation to remove ethanol, 100 mL of water was added to the system, and neutralized with saturated sodium carbonate until no bubbles were generated. The organic phase was extracted with ethyl acetate 50 mL ⁇ 3, and the organic phases were combined and washed with saturated brine for 10 mL ⁇ 3.
  • the fourth step dissolve 650 mg (1.7 mmol, 1.0 eq) of ethyl 2-((2,6-diethyl-4-(3,5-dimethylisoxazole)phenyl)amino)benzoate in A solution of 199 mg (8.3 mmol, 5.0 eq) of lithium hydroxide in 2 mL of water was slowly added dropwise to a mixed solvent of 4 mL of tetrahydrofuran and 8 mL of anhydrous ethanol under ice-water bath cooling. The reaction was heated to 45°C overnight.
  • the fifth step in a 10mL round bottom flask, add 2-((2,6-diethyl-4-(3,5-dimethylisoxazole)phenyl)amino)benzoic acid 73mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), ammonium chloride 14mg (0.24mmol) were sequentially added to the above system , 1.2eq), the resulting mixed system was reacted at 45 ° C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic operation of Dam128.
  • the fifth step in a 10mL round bottom flask, add 2-((2,6-dichloro-4-(3,5-dimethylpyrazole)phenyl)amino)benzoic acid 71mg (0.2mmol, 1.0eq ), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), N,N-diethylaminoethylenedi Amine 28mg (0.24mmol, 1.2eq), the resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first and second reactions were prepared according to the synthetic procedure for Dam128.
  • the third step 2-(4-bromo-2,6-diethylphenyl)amino)ethyl benzoate 1.13g (3.0mmol, 1.0eq), pyridine-4-boronic acid 443mg (3.6mmol, 1.2eq) ), catalyst Pd(dppf)Cl 2 220mg (0.3mmol, 0.1eq), potassium carbonate 828mg (6.0mmol, 1.5eq) dissolved in a mixed solvent of dioxane and water 160mL (4:1/v:v) , heated to 100 °C for 24 hours.
  • Step 4 Dissolve 775 mg (2.1 mmol, 1.0 eq) of ethyl 2-((2,6-diethyl-4-pyridine)phenyl)amino)benzoate in a mixed solvent of 4 mL of tetrahydrofuran and 8 mL of anhydrous ethanol 249 mg (10.5 mmol, 5.0 eq) of a solution of lithium hydroxide in 2 mL of water was slowly added dropwise thereto under ice-water bath cooling. The reaction was heated to 45°C overnight.
  • the fifth step in a 10mL round bottom flask, add 2-((2,6-diethyl-4-pyridine)phenyl)amino)benzoic acid 69mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq) and ammonium chloride 14mg (0.24mmol, 1.2eq) were successively added to the above system, and the resulting mixed system was at 45 °C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic operation of Dam159.
  • the fifth step in a 10mL round bottom flask, add 2-((2,6-diethyl-4-pyridine)phenyl)amino)benzoic acid 69mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in 4.0mL of anhydrous DMF at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq) and methylamine hydrochloride 16mg (0.24mmol, 1.2eq) were added to the above system successively, and the resulting mixed system The reaction was carried out at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic operation of Dam159.
  • the fifth step in a 10mL round bottom flask, add 2-((2,6-diethyl-4-pyridine)phenyl)amino)benzoic acid 69mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), N,N-diethylaminoethylenediamine 28mg (0.24mmol, 1.2eq) were successively added to the above system ), the resulting mixed system was reacted at 45 °C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic operation of Dam159.
  • the fifth step in a 10mL round bottom flask, add 2-((2,6-diethyl-4-pyridine)phenyl)amino)benzoic acid 69mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), N,N-dimethylaminoethylenediamine 21mg (0.24mmol, 1.2eq) were added to the above system successively ), the resulting mixed system was reacted at 45 °C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic operation of Dam159.
  • the fifth step in a 10mL round bottom flask, add 2-((2,6-diethyl-4-pyridine)phenyl)amino)benzoic acid 69mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in 4.0mL of anhydrous DMF at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq) and 2-aminoethanol 15mg (0.24mmol, 1.2eq) were added to the above system successively, and the resulting mixed system was The reaction was carried out at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic operation of Dam128.
  • the fifth step in a 10mL round bottom flask, add 2-((2,6-diethyl-4-(3,5-dimethylisoxazole)phenyl)amino)benzoic acid 73mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), hydroxylamine hydrochloride 17mg (0.24mmol, 1.2eq), the resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic operation of Dam159.
  • the fifth step in a 10mL round bottom flask, add 2-((2,6-diethyl-4-pyridine)phenyl)amino)benzoic acid 69mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in 4.0mL of anhydrous DMF at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq) and hydroxylamine hydrochloride 17mg (0.24mmol, 1.2eq) were added to the above system successively, and the resulting mixed system was heated at 45°C React for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic operation of Dam128.
  • the fifth step in a 10mL round bottom flask, add 2-((2,6-diethyl-4-(3,5-dimethylisoxazole)phenyl)amino)benzoic acid 73mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), hydroxylamine hydrochloride 17mg (0.24mmol, 1.2eq), the resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step 30.7g (124mmol, 1.2eq) of o-iodobenzoic acid, 22.7g (103mmol, 1.0eq) of 2-chloro-6-methyl-4-bromoaniline, 15.7g (155mmol, 1.5eq) of triethylamine ) and 9.3 g (51.5 mmol, 0.5 eq) of anhydrous copper acetate were dissolved in 372 mL of DMF, heated to 120° C. under argon protection and reacted for 24 h, after the reaction was completed.
  • the second step dissolve 32 g of 2-(4-bromo-2-chloro-6-methylphenyl) amino) benzoic acid in 300 mL of absolute ethanol, add 50 mL of concentrated sulfuric acid to it, and heat to The reaction was refluxed at 100°C for 12 hours. After the reaction, the reaction system was cooled to room temperature, concentrated by rotary evaporation to remove ethanol, 100 mL of water was added to the system, and neutralized with saturated sodium carbonate until no bubbles were generated. The organic phase was extracted with ethyl acetate 50 mL ⁇ 3, and the organic phases were combined and washed with saturated brine for 20 mL ⁇ 3.
  • the third step 2-(4-bromo-2-chloro-6-methylphenyl)amino)ethyl benzoate 2.7g (7.3mmol, 1.0eq), 3,5-dimethylisoxazole- 4-boronic acid 1.2g (8.8mmol, 1.2eq), catalyst Pd(dppf)Cl 2 534mg (0.73mmol, 0.1eq), potassium carbonate 2.1g (14.6mmol, 2.0eq) dissolved in a mixture of dioxane and water In 37 mL of solvent (4:1/v:v), the mixture was heated to 100°C and reacted for 24 hours.
  • the fourth step 911mg (2.37mmol, 1.0eq) of ethyl 2-((2-chloro-6-methyl-4-(3,5-dimethylisoxazole))phenyl)amino)benzoate It was dissolved in a mixed solvent of 8 mL of tetrahydrofuran and 16 mL of absolute ethanol, and a solution of 284 mg (11.9 mmol, 5.0 eq) of lithium hydroxide in 4 mL of water was slowly added dropwise to it under ice-water bath cooling. The reaction was heated to 45°C overnight.
  • Step 5 In a 10mL round-bottomed flask, add 72mg (0.2 mg of 2-((2-chloro-6-methyl-4-(3,5-dimethylisoxazole))phenyl)amino)benzoic acid mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), hydroxylamine hydrochloride 17mg (0.24 mmol, 1.2eq), the resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first and second steps are prepared according to the synthetic operation of Dam106.
  • the third step 2-(4-bromo-2-chloro-6-methylphenyl)amino)ethyl benzoate 1.1g (3.0mmol, 1.0eq), pyridine-4-boronic acid 443mg (3.6mmol, 1.2g) eq), catalyst Pd(dppf)Cl 2 220mg (0.3mmol, 0.1eq), potassium carbonate 828mg (6.0mmol, 1.5eq) dissolved in a mixed solvent of dioxane and water 15mL (4:1/v:v) , heated to 100 °C for 24 hours.
  • Step 4 Dissolve 734 mg (2.0 mmol, 1.0 eq) of ethyl 2-((2-chloro-6-methyl-4-pyridine)phenyl)amino)benzoate in a mixture of 8 mL of tetrahydrofuran and 16 mL of anhydrous ethanol In the solvent, under ice-water bath cooling, a solution of 240 mg (10 mmol, 5.0 eq) of lithium hydroxide in 4 mL of water was slowly added dropwise thereto. The reaction was heated to 45°C overnight.
  • the fifth step in a 10mL round bottom flask, add 2-((2-chloro-6-methyl-4-pyridine)phenyl)amino)benzoic acid 68mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol) , 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), hydroxylamine hydrochloride 17mg (0.24mmol, 1.2eq) were added to the above system in turn, the resulting mixed system was at 45 °C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic operation of Dac406.
  • the fifth step in a 10mL round bottom flask, add 2-((2-chloro-6-methyl-4-pyridine)phenyl)amino)benzoic acid 68mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol) , 1.5eq), dissolved in 4.0mL of anhydrous DMF at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq) and ammonium chloride 14mg (0.24mmol, 1.2eq) were added to the above system in turn, and the resulting mixed system was The reaction was carried out at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first and second reactions were prepared according to the synthetic procedure of Dac406.
  • Step 5 In a 10mL round-bottomed flask, add 72mg (0.2 mg of 2-((2-chloro-6-methyl-4-(3,5-dimethylisoxazole))phenyl)amino)benzoic acid mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), N,N-di Ethylaminoethylenediamine 18mg (0.24mmol, 1.2eq), the resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • Step 5 In a 10mL round-bottomed flask, add 72mg (0.2 mg of 2-((2-chloro-6-methyl-4-(3,5-dimethylisoxazole))phenyl)amino)benzoic acid mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), 3-aminopropanol were added to the above system successively 18mg (0.24mmol, 1.2eq), the resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the fifth step in a 10mL round bottom flask, add 2-((2-chloro-6-methyl-4-pyridine)phenyl)amino)benzoic acid 68mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol) , 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), N,N-diethylaminoethylenediamine 24mg (0.24mmol, 1.2 eq), the resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first and second reactions were prepared according to the synthetic procedure of Dac406.
  • Step 5 In a 10mL round-bottomed flask, add 72mg (0.2 mg of 2-((2-chloro-6-methyl-4-(3,5-dimethylisoxazole))phenyl)amino)benzoic acid mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), hydroxylamine hydrochloride 14mg (0.24mg) were successively added to the above system mmol, 1.2eq), the resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first and second reactions were prepared according to the synthetic procedure of Dac406.
  • the first step o-iodobenzoic acid 30g (120mmol, 1.2eq), 2,6-diisopropyl-4-bromoaniline 25.6g (100mmol, 1.0eq), triethylamine (150mmol, 1.5eq) and no 9 g (5.0 mmol, 0.5 eq) of water copper acetate was dissolved in 500 mL of DMF, heated to 120° C. under argon protection and reacted for 24 h, after the reaction was completed.
  • the third step 2-(4-bromo-2,6-diisopropylphenyl)amino)ethyl benzoate 1.2g (3.0mmol, 1.0eq), pyridine-4-boronic acid 443mg (3.6mmol, 1.2g) eq), catalyst Pd(dppf)Cl 2 220mg (0.3mmol, 0.1eq), potassium carbonate 828mg (6.0mmol, 1.5eq) dissolved in a mixed solvent of dioxane and water 15mL (4:1/v:v) , heated to 100 °C for 24 hours.
  • Step 4 Dissolve 748 mg (2.0 mmol, 1.0 eq) of ethyl 2-((2,6-diisopropyl-4-pyridylphenyl)amino)benzoate in a mixed solvent of 4 mL of tetrahydrofuran and 8 mL of anhydrous ethanol 240 mg (10 mmol, 5.0 eq) of lithium hydroxide in 2 mL of water was slowly added dropwise thereto under ice-water bath cooling. The reaction was heated to 45°C overnight.
  • the fifth step in a 10mL round bottom flask, add 2-((2,6-diisopropyl-4-pyridylphenyl)amino)benzoic acid 75mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq) and ammonium chloride 14mg (0.24mmol, 1.2eq) were successively added to the above system, and the resulting mixed system was at 45 °C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step 29.8g (120mmol, 1.2eq) of o-iodobenzoic acid, 20.4g (100mmol, 1.0eq) of 2-fluoro-6-methyl-4-bromoaniline, 15.2g (150mmol, 1.5eq) of triethylamine ) and 9.1 g (50 mmol, 0.5 eq) of anhydrous copper acetate were dissolved in 360 mL of DMF, heated to 120 °C under argon protection and reacted for 24 h, after the reaction was completed.
  • the first step 20.2g (100mmol, 1.0eq) of 2-chloro-5-nitrobenzoic acid, 26.5g (110mmol, 1.1eq) of 2,6-dichloro-4-bromoaniline, 28.8g of sodium tert-butoxide (300mmol, 3.0eq) was dissolved in 500mL of DMF, heated to 80°C under argon protection and reacted for 24 hours, after the reaction was completed. Cooled to room temperature, adjusted pH with 2M dilute hydrochloric acid, a yellow solid was precipitated, suction filtered, and washed with water to obtain 28.0 g of the target product, a yellow solid.
  • the fourth step 2-((2,6-dichloro-4-(3,5-dimethylisoxazole) phenyl) amino)-5-nitrobenzoic acid ethyl ester 1.3g (2.9mmol, 1.0eq), zinc powder 943mg (14.5mmol, 5.0eq), ammonium formate 1.8g (29.0mmol, 10.0eq) was dissolved in DMF 58mL, heated to 45°C, reacted overnight, water was added to the system, EA extraction, silica gel column After chromatographic separation, 1.22 g of ethyl 2-((2,6-dichloro-4-(3,5-dimethylisoxazole)phenyl)amino)-5-aminobenzoate was obtained as a yellow target product.
  • Step 5 Dissolve 79mg (0.55mmol, 1.1eq) of monoethyl fumarate, 228mg (0.6mmol, 1.2eq) of HATU in DMF (4mL), stir for 5min, and add 194mg (1.5mg) of DIEA to the above system in turn. mmol, 3.0eq), 2-((2,6-dichloro-4-(3,5-dimethylisoxazole)phenyl)amino)-5-aminobenzoic acid ethyl ester 210mg (0.5mmol, 1.0 eq), the resulting mixed system was reacted at 45 °C. TLC detection, the raw material consumption was completed. An ice-water mixture was added to the system, and a yellow solid was precipitated, which was filtered off with suction and washed with water to obtain the target product, Dac258 (180 mg) as a yellow solid.
  • the fourth step Compound Dac258 55mg (0.1mmol, 1.0eq) was dissolved in a mixed solvent of tetrahydrofuran (2mL) and absolute ethanol (4mL), and lithium hydroxide 24mg (1.0mmol, 10.0eq) was slowly added dropwise thereto. solution in water (1 mL). The reaction was heated to 45°C overnight. After the reaction was completed, the system was cooled to room temperature, concentrated to remove the organic solvent, water was added, and 2M dilute hydrochloric acid was added to adjust the pH to 3. The obtained suspension was stirred at room temperature for 30 min. After suction filtration, the solid was washed with water to obtain the target product Dac58 (46 mg).
  • the third step 2-(4-bromo-2,6-diisopropylphenyl)amino)ethyl benzoate 1.2g (3.0mmol, 1.0eq), morpholine 313mg (3.6mmol, 1.2eq), BINAP 224mg (0.36mmol, 0.12eq) catalyst Pd(OAc) 2 68mg (0.3mmol, 0.1eq), potassium carbonate 828mg (6.0mmol, 1.5eq) was dissolved in 15mL of toluene, heated to 110 °C and reacted for 24 hours.
  • the third step 1.2g (3.0mmol, 1.0eq) of ethyl 2-(4-bromo-2-fluoro-6-methylphenyl)amino)benzoate, 313mg (3.6mmol, 1.2eq) of morpholine, BINAP 224mg (0.36mmol, 0.12eq) catalyst Pd(OAc) 2 68mg (0.3mmol, 0.1eq), potassium carbonate 828mg (6.0mmol, 1.5eq) was dissolved in 15mL of toluene, heated to 110 °C and reacted for 24 hours.
  • Step 4 Dissolve 720 mg (2.0 mmol, 1.0 eq) of ethyl 2-(2-fluoro-6-methyl-4-morpholine)amino)benzoate in a mixed solvent of 4 mL of tetrahydrofuran and 8 mL of anhydrous ethanol, Under ice-water bath cooling, a solution of 240 mg (10 mmol, 5.0 eq) of lithium hydroxide in 2 mL of water was slowly added dropwise thereto. The reaction was heated to 45°C overnight.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic method of Dam266.
  • the first step and the second step are prepared according to the synthetic method of Dac51.
  • the third step 2-(4-bromo-2,6-dichlorophenyl)amino)ethyl benzoate 3.0g (8.0mmol, 1.0eq), triazole boronic acid 1.1g (8.8mmol, 1.2eq), Catalyst Pd(dppf)Cl 2 534mg (0.73mmol, 0.1eq), potassium carbonate 2.1g (14.6mmol, 2.0eq) was dissolved in a mixed solvent of dioxane and water 37mL (4:1/v:v), Heated to 100°C and reacted for 24 hours.
  • the fourth step 927 mg (2.37 mmol, 1.0 eq) of ethyl 2-((2-chloro-6-methyl-4-(5-methyltriazole))phenyl)amino)benzoate was dissolved in tetrahydrofuran A solution of 284 mg (11.9 mmol, 5.0 eq) of lithium hydroxide in 4 mL of water was slowly added dropwise to a mixed solvent of 8 mL and 16 mL of anhydrous ethanol under cooling in an ice-water bath. The reaction was heated to 45°C overnight.
  • the fifth step in a 10mL round bottom flask, add 2-((2-chloro-6-methyl-4-(5-methyltriazole))phenyl)amino)benzoic acid 72mg (0.2mmol, 1.0 eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), hydroxylamine hydrochloride 17mg (0.24mmol, 1.2 eq), the resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step and the second step are prepared according to the synthetic method of Dac51.
  • the third step 2-(4-bromo-2,6-dichlorophenyl)amino)ethyl benzoate 3.0g (8.0mmol, 1.0eq), 3,5-dimethyltriazole-4 - Boric acid 1.2g (8.8mmol, 1.2eq), catalyst Pd(dppf)Cl 2 534mg (0.73mmol, 0.1eq), potassium carbonate 2.1g (14.6mmol, 2.0eq) dissolved in a mixed solvent of dioxane and water 37mL (4:1/v:v), heated to 100°C and reacted for 24 hours.
  • the fourth step 893mg (2.37mmol, 1.0eq) of ethyl 2-((2-chloro-6-methyl-4-(3,5-dimethyltriazole))phenyl)amino)benzoate It was dissolved in a mixed solvent of 8 mL of tetrahydrofuran and 16 mL of absolute ethanol, and a solution of 284 mg (11.9 mmol, 5.0 eq) of lithium hydroxide in 4 mL of water was slowly added dropwise to it under ice-water bath cooling. The reaction was heated to 45°C overnight.
  • the fifth step in a 10mL round bottom flask, add 2-((2-chloro-6-methyl-4-(3,5-dimethyltriazole))phenyl)amino)benzoic acid 72mg (0.2 mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), hydroxylamine hydrochloride 17mg (0.24 mmol, 1.2eq), the resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic method of Dac105.
  • the fifth step in a 10mL round bottom flask, add 2-((2-chloro-6-methyl-4-(3,5-dimethyltriazole))phenyl)amino)benzoic acid 72mg (0.2 mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), hydroxylamine hydrochloride 17mg (0.24 mmol, 1.2eq), the resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic method of Dac105.
  • the third step 2-(4-bromo-2-chloro-6-methylphenyl)amino)ethyl benzoate 2.7g (7.3mmol, 1.0eq), 3,5-dimethyltriazole- 4-boronic acid 1.2g (8.8mmol, 1.2eq), catalyst Pd(dppf)Cl 2 534mg (0.73mmol, 0.1eq), potassium carbonate 2.1g (14.6mmol, 2.0eq) dissolved in a mixture of dioxane and water In 37 mL of solvent (4:1/v:v), the mixture was heated to 100°C and reacted for 24 hours.
  • the fifth step in a 10mL round bottom flask, add 2-((2-chloro-6-methyl-4-(3,5-dimethyltriazole))phenyl)amino)benzoic acid 72mg (0.2 mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq), dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), ammonium chloride 14mg ( 0.24mmol, 1.2eq), the resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step and the second step are prepared according to the synthetic method of Dac51.
  • the third step 2-(4-bromo-2-chloro-6-methylphenyl)amino)ethyl benzoate 2.7g (7.3mmol, 1.0eq), tetrazolium-5-boronic acid 1.2g (8.8g) mmol, 1.2eq), catalyst Pd(dppf)Cl 2 534mg (0.73mmol, 0.1eq), potassium carbonate 2.1g (14.6mmol, 2.0eq) dissolved in a mixed solvent of dioxane and water 37mL (4:1/ In v:v), the reaction was heated to 100° C. for 24 hours.
  • the fourth step 830 mg (2.37 mmol, 1.0 eq) of ethyl 2-((2-chloro-6-methyl-4-(tetrazolium))phenyl)amino)benzoate was dissolved in 8 mL of tetrahydrofuran and anhydrous A solution of 284 mg (11.9 mmol, 5.0 eq) of lithium hydroxide in 4 mL of water was slowly added dropwise to a mixed solvent of 16 mL of ethanol under ice-water bath cooling. The reaction was heated to 45°C overnight.
  • the fifth step in a 10mL round bottom flask, add 2-((2-chloro-6-methyl-4-(tetrazolium))phenyl)amino)benzoic acid 70mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq) was dissolved in 4.0mL of anhydrous DMF at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq) and hydroxylamine hydrochloride 17mg (0.24mmol, 1.2eq) were added to the above system in turn, the resulting The mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic method of Dac111.
  • the fifth step in a 10mL round bottom flask, add 2-((2-chloro-6-methyl-4-(tetrazolium))phenyl)amino)benzoic acid 70mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq) was dissolved in 4.0mL of anhydrous DMF at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq) and ammonium chloride 14mg (0.24mmol, 1.2eq) were sequentially added to the above system, The resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic method of Dac111.
  • the fifth step in a 10mL round bottom flask, add 2-((2-chloro-6-methyl-4-(tetrazolium))phenyl)amino)benzoic acid 72mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq) was dissolved in 4.0mL of anhydrous DMF at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), N,N-diethylamino-1,4- Butanediamine 35mg (0.24mmol, 1.2eq), the resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic method of Dac111.
  • the fifth step in a 10mL round bottom flask, add 2-((2-chloro-6-methyl-4-(tetrazolium))phenyl)amino)benzoic acid 72mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq) was dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), 3-aminopropanol 18mg (0.24mmol, 1.2eq) were added to the above system in turn ), the resulting mixed system was reacted at 45 °C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic method of Dac111.
  • the fifth step in a 10mL round bottom flask, add 2-((2-chloro-6-methyl-4-(tetrazolium))phenyl)amino)benzoic acid 72mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq) was dissolved in anhydrous DMF 4.0mL at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq), N,N-diethylethylenediamine 24mg ( 0.24mmol, 1.2eq), the resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first and second steps are prepared according to the synthetic method of Dac406.
  • the third step 2-(4-bromo-2-chloro-6-methylphenyl)amino)ethyl benzoate 2.7g (7.3mmol, 1.0eq), tetrazolium-5-boronic acid 1.2g (8.8g) mmol, 1.2eq), catalyst Pd(dppf)Cl 2 534mg (0.73mmol, 0.1eq), potassium carbonate 2.1g (14.6mmol, 2.0eq) dissolved in a mixed solvent of dioxane and water 37mL (4:1/ In v:v), the reaction was heated to 100° C. for 24 hours.
  • the fourth step 848 mg (2.37 mmol, 1.0 eq) of ethyl 2-((2-chloro-6-methyl-4-(tetrazolium))phenyl)amino)benzoate was dissolved in 8 mL of tetrahydrofuran and anhydrous A solution of 284 mg (11.9 mmol, 5.0 eq) of lithium hydroxide in 4 mL of water was slowly added dropwise to a mixed solvent of 16 mL of ethanol under ice-water bath cooling. The reaction was heated to 45°C overnight.
  • the fifth step in a 10mL round bottom flask, add 2-((2-chloro-6-methyl-4-(tetrazolium))phenyl)amino)benzoic acid 72mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq) was dissolved in 4.0mL of anhydrous DMF at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq) and hydroxylamine hydrochloride 17mg (0.24mmol, 1.2eq) were added to the above system in turn, the resulting The mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • the first step, the second step, the third step and the fourth step are prepared according to the synthetic method of Dac118.
  • the fifth step in a 10mL round bottom flask, add 2-((2-chloro-6-methyl-4-(tetrazolium))phenyl)amino)benzoic acid 72mg (0.2mmol, 1.0eq), HATU 114mg (0.3mmol, 1.5eq) was dissolved in 4.0mL of anhydrous DMF at room temperature, stirred for 5min, DIEA 77mg (0.6mmol, 3.0eq) and ammonium chloride 14mg (0.24mmol, 1.2eq) were sequentially added to the above system, The resulting mixed system was reacted at 45°C for 2 hours. TLC detection, the raw material consumption was completed.
  • FTO enzyme activity inhibition reaction system is as follows: 50mM Tris ⁇ HCl, pH 7.5, 0.3 ⁇ M FTO, 1 ⁇ M 39nt-m 6 A modified double-stranded DNA, 300 ⁇ M 2OG, 280 ⁇ M (NH 4 ) 2 Fe(SO 4 ) 2 , 2mM L -Ascorbic Acid and compounds of different concentrations, incubated at room temperature for 2 hours, slowly heated at 65°C for inactivation, and annealed to double-stranded DNA by adding 1 ⁇ M 39nt antisense DNA. Take 8ul of the reaction solution and digest the double-stranded substrate with the methylation-sensitive enzyme DpnII.
  • the digested samples were detected by 15% non-denaturing polyacrylamide electrophoresis, and photographed under the gel imaging system after Gel-Red staining.
  • the obtained bands were read for the inhibition rate in grayscale, and the IC 50 for inhibiting the demethylation activity of FTO was evaluated for the compounds with better inhibition rate. The results are shown in the following table.
  • Solid tumor cell lines such as the melanoma cell line B16-OVA, the lung cancer cell line LLC, and the colon cancer cell line MC38 were cultured separately, seeded at a density of 1000 cells per well in a 96-well plate, and placed in a 37°C CO 2 incubator. Incubate the cells until they adhere to the wall, add different compounds and continue to culture for 72h, add 10uL of MTT solution to each well, continue to incubate for 4h, detect the absorbance value at 490nm, calculate the inhibition rate with the DMSO group as the control, and focus on the cells with better inhibition rate. Compounds were evaluated for cell proliferation inhibitory activity IC50 , and the results are shown in the table below.
  • Tumor cells were seeded in a 6cm culture dish at a certain density, the compound was added the next day (the concentration was set according to the IC 50 value of MTT), and after 48-72 hours of treatment, the cell culture medium was removed, and 1 mL of TRIzol reagent was added to it, and the cells were collected. Lyse, pipette into RNase free tube, and incubate on ice for 5 min to completely separate nucleoprotein complexes; add 200 ⁇ L of chloroform to lyse, vortex for 15 s, incubate; centrifuge for layers.
  • mice 5-week-old C57BL/6 strain mice with a body weight of 18-20 g were selected.
  • tumor cells MC38 were cultured.
  • the candidate compounds Dam59 and Dam159 were respectively dissolved in DMSO to prepare a 20 mM stock solution and diluted with PBS.
  • the content of DMSO in the finally obtained dosing solution was 20%, which was ready for use.
  • the candidate compounds Dam59 (2 mg/kg) and Dam159 (0.5 mg/kg) were injected by intraperitoneal administration from the 10th, 11th, and 12th days, respectively.
  • On days 13 and 16 100 mg/kg of antibody PD-L1 and antibody negative control IgG were injected intraperitoneally. Tumor volume and mouse body weight were measured every two days. The results are shown in Fig. 2 and Fig. 3 , when used in combination with the antibody PD-L1, the compounds of the present invention exhibited obvious synergistic effects.
  • mice 5-week-old C57BL/6 strain mice with a body weight of 18-20 g were selected.
  • tumor cells MC38 were cultured.
  • the candidate compound Dam60 was dissolved in DMSO, and a 20 mM stock solution was prepared and diluted with PBS. The content of DMSO in the finally obtained dosing solution was 20%, which was ready for use.
  • the candidate compound Dam60 (1 mg/kg) was injected by intraperitoneal administration from day 7, 8, and 9, respectively. On days 10 and 12, 100 mg/kg of antibody PD-1 and antibody negative control IgG were injected intraperitoneally. Tumor volume and mouse body weight were measured every two days. The results are shown in FIG. 4 , when the compound is used in combination with the antibody PD-1, the compound of the present invention exhibits an obvious synergistic effect.

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Abstract

La présente invention concerne un inhibiteur FTO d'acide formique 2-(phénoxy substitué)aromatique, son procédé de préparation et son utilisation, et concerne en particulier un composé représenté par la formule (I), et l'utilisation d'un sel pharmaceutiquement acceptable, un hydrate, un solvate ou un promédicament de celui-ci. Le composé peut être utilisé en combinaison avec un inhibiteur de point de contrôle immunitaire pour traiter des tumeurs solides, telles que le mélanome, le cancer du poumon, le cancer du côlon, le cancer du rein, le cancer du pancréas, le cancer du poumon et l'ostéosarcome.
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