CN116462688A - Aromatic condensed ring derivative and preparation method and application thereof - Google Patents

Aromatic condensed ring derivative and preparation method and application thereof Download PDF

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Publication number
CN116462688A
CN116462688A CN202310063347.XA CN202310063347A CN116462688A CN 116462688 A CN116462688 A CN 116462688A CN 202310063347 A CN202310063347 A CN 202310063347A CN 116462688 A CN116462688 A CN 116462688A
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alkyl
group
cancer
cycloalkyl
alkoxy
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程超英
邵林江
张盼盼
张衡
叶成
钱文建
陈磊
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Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
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Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The present invention relates to a substitutionAromatic condensed ring derivatives, a preparation method thereof and a pharmaceutical composition containing the derivatives are applied to medicine. In particular, the invention relates to a substituted aromatic condensed ring derivative shown in a general formula (I), a preparation method and pharmaceutically acceptable salts thereof, and application thereof as a therapeutic agent, in particular to an HPK1 inhibitor, wherein the definition of each substituent in the general formula (I) is the same as that in the specification.

Description

Aromatic condensed ring derivative and preparation method and application thereof
Technical Field
The invention relates to an aromatic condensed ring derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative as a therapeutic agent, in particular to an HPK1 inhibitor.
Background
Hematopoietic progenitor kinase (HPK 1, also known as MAP4K 1) is a mammalian Ste 20-like serine/threonine kinase, which belongs to the family of mitogen-activated protein kinases (MAP 4K) mainly in hematopoietic stem cells, and it has been found that this family includes the other 5 members MAP4K2, MAP4K3, MAP4K4, MAP4K5, MAP4K6, as an expression product of the gene MAP4K 1. HPK1 is a protein of 97kDa in relative molecular weight, and is largely divided into 3 regions, the N-terminal Ste 20-like kinase region, the C-terminal kinase region and the middle 4 proline-rich regions (P1, P2, P3 and P4), which normally interact with the adaptor proteins containing SH2/SH3 regions, activating the transduction of a range of signal pathways.
When HPK1 is activated by a variety of upstream signaling factors, including epidermal growth factor, prostaglandin E2, tumor growth factor, erythropoietin, T cell receptors, B cell receptors, etc., a series of biological cascades are triggered. HPK1 can also interact with the adaptor protein SLP-76 family, CARD11, GRB2 family, CRK family and the like in the downstream signaling pathway to activate the JNK/SAPK signaling pathway of hematopoietic stem cells, thereby back-regulating the T cell pathway. Therefore, HPK1 is involved in regulating cell proliferation and apoptosis, and plays an important role in immunosuppression.
HPK1 acts as a kinase regulating immunosuppression and is a reverse regulator of T cell receptor, when T cell receptor is activated, HPK1 in cytoplasm recruits to the vicinity of cell membrane, activated HPK1 phosphorylates linker protein SLP76, activated SLP76 acts as docking site for T cell regulatory inhibitor protein 14-3-3, multiple proteins combine to form SLP76 complex, SLP76 complex induces ubiquitination degradation, finally leading to instability of T cell receptor signaling complex, thereby down regulating T cell signaling pathway and T cell proliferation.
However, T cells participate in an important process of anti-tumor immunity, and the antigen receptor of the T cells recognizes specific antibodies on tumor cells to directly kill the tumor cells; or indirectly kill tumor cells by activating macrophages and secreting other lymphokines. Therefore, inhibition of HPK1 can proliferate T cells and activate T cell signaling pathways, further enhancing tumor killing and inhibiting tumor growth. Since HPK1 plays an important role in immunomodulation, HPK1 can be used as a research direction for treating inflammatory responses, autoimmune diseases (e.g., systemic lupus erythematosus, psoriasis) and malignant tumors (e.g., acute myelogenous leukemia, bladder epithelial cancer, colon cancer, pancreatic cancer).
Even though only two compounds are currently in clinical use as inhibitors against the HPK1 target, CFI-402411 (second phase) from Treadwell and BGB-15025 (first phase) from baji shenzhou, respectively, but facing the tumor, the field of fight is not in progress, and medical workers are not in the hope of being in the position of being in the arms, more and more medical companies have been added to this campaign today, such as Nimbus Therapeutics and aro medicine. The HPK1 inhibitor is taken as a research direction of a comparison front, and immune response related to T cells is brought about when tumors are treated, so that the HPK1 inhibitor which is safer and more effective is needed to be found, the risk in the treatment process is reduced, and the pain of patients is reduced.
Disclosure of Invention
Aiming at the technical problems, the invention provides an aromatic condensed ring derivative shown in a general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:
wherein:
ring a is selected from:
in the case of double bonds, G is selected from CR 1 ；X 1 、X 2 、X 3 、X 4 Each independently selected from CR x Or N;
when a single bond is formed, G is selected from C=O, X 1 Selected from NR x ，X 2 、X 3 、X 4 Each independently selected from CR x Or N;
R x selected from hydrogen atom, hydroxy, halogen, alkyl, cyano, alkoxy, cycloalkyl, heterocyclyl or-NR 8 R 9 Wherein said alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally further substituted with one or more groups selected from halogen, amino, hydroxy, cyano, alkoxy or-NR 8 R 9 Is substituted by a substituent of (2);
R 1 selected from the group consisting of hydrogen atoms, hydroxy groups, cyano groups, alkoxy groups, cycloalkyl groups,Heterocyclyl, aryl, heteroaryl, -S (O) r R 10 、-C(O)OR 10 、-C(O)R 10 、-S(O) r NR 8 R 9 、-C(O)NR 8 R 9 or-NHC (O) R 10 Wherein said alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from halogen, amino, hydroxy, cyano or alkoxy;
R 2 selected from alkyl, -S (O) r R 10 、-S(O) r NR 8 R 9 、-C(O)R 10 、-C(O)NR 8 R 9 、-NHC(O)R 10 or-P (O) R 8 R 9 Wherein said alkyl is optionally further substituted with one or more substituents selected from halogen, amino, hydroxy, cyano or alkoxy;
R 3 and R is 5 The same or different, each independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, cyano, or alkoxy;
R 4 selected from the group consisting of hydrogen, halogen, amino, hydroxy, cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, cyano, or alkoxy;
R 6 And R is 7 The same or different are each independently selected from a hydrogen atom or an alkyl group;
R 8 and R is 9 The same or different, are each independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkylGroup, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or-NR 12 C(O)R 13 Is substituted by a substituent of (2);
alternatively, R 8 And R is 9 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more of N, O or S (O) r And said 4-8 membered heterocyclic group is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclic group,
Aryl, heteroaryl, =o, -C (O) R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or-NR 12 C(O)R 13 Is substituted by a substituent of (2);
R 10 each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl group, heteroaryl group, =o, -C (O) R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or-NR 12 C(O)R 13 Is substituted by a substituent of (2);
R 11 、R 12 and R is 13 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate;
n is 0,1 or 2;
r is 0,1 or 2.
In a preferred embodiment of the present invention, a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (II):
wherein: G. x is X 1 ～X 4 、R 2 ～R 4 The definition of (C) is as described in the general formula (I).
In a preferred embodiment of the present invention, a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (III):
wherein: r is R x 、R 1 、R 3 And R is 4 The definition of (C) is as described in the general formula (I).
In a preferred embodiment of the invention, a compound of formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
Selected from:
wherein: r is R x And R is 1 ～R 4 The definition of (C) is as described in the general formula (II).
In a preferred embodiment of the invention, a compound of formula (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
R 1 selected from-C (O) OR 10 ；
Rx is selected from alkyl or-NR 8 R 9 Wherein said alkyl is optionally further substituted with-NR 8 R 9 Substituted;
R 8 and R is 9 Each independently selected from a hydrogen atom or an alkyl group;
R 10 selected from alkyl groups.
In a preferred embodiment of the invention, a compound of formula (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
R 1 selected from-C (O) OR 10 ；
Rx is selected from-NR 8 R 9 Or (b)
R 8 Selected from hydrogen atoms;
R 9 selected from alkyl groups;
R 10 selected from methyl, ethyl or isopropyl.
In a preferred embodiment of the invention, a compound of formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
selected from:
R 1 selected from the group consisting of hydrogen atom, alkoxy group, cyano group, -SR 10 、-SO 2 R 10 、-C(O)R 10 or-NHC (O) R 10 ；
R 10 Selected from alkyl or cycloalkyl;
R x and R is 2 The definition of (C) is as described in the general formula (II).
In a preferred embodiment of the invention, a compound of formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
selected from:
R 2 selected from alkyl, -SO 2 R 10 、-SO 2 NR 8 R 9 、-C(O)R 10 、-C(O)NR 8 R 9 or-P (O) R 8 R 9 Wherein said alkyl is optionally further substituted with-NR 8 R 9 Substituted;
R 8 and R is 9 Each independently selected from a hydrogen atom or an alkyl group;
R 10 selected from alkyl or cycloalkyl;
R x and R is 2 The definition of (C) is as described in the general formula (II).
In a preferred embodiment of the invention, a compound of formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
selected from:
R 2 selected from the group consisting of
R 1 And R is x The definition of (C) is as described in the general formula (II).
In a preferred embodiment of the invention, a compound of formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
selected from:
R 2 selected from-SO 2 R 10 、-SO 2 NR 8 R 9 、-C(O)NR 8 R 9 、-C(O)R 10 or-P (O) R 8 R 9 ；
R 8 And R is 9 Each independently selected from hydrogen, methyl, ethyl or isopropyl;
R 10 selected from methyl, ethyl, isopropyl or cyclopropyl;
R x and R is 1 The definition of (C) is as described in the general formula (II).
In a preferred embodiment of the invention, the compounds of formula (I) are selected from:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Note that: if there is a difference between the drawn structure and the name given to the structure, the drawn structure will be given greater weight.
The present invention provides a pharmaceutical composition comprising an effective amount of a compound according to any one of the general formulas (I), (II) or (III), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.
The invention provides an application of a compound shown in a general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing an HPK1 inhibitor.
The invention also provides a use of a compound of formula (I), (II) or (III), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease mediated by HPK1, wherein the disease mediated by HPK1 is preferably an inflammatory, autoimmune or tumour, wherein the autoimmune disease is preferably systemic lupus erythematosus or psoriasis; wherein the tumour is selected from acute myelogenous leukemia, bladder epithelial cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, blastoma, retinoblastoma, sarcoma, prostate cancer, cholangiocarcinoma, oesophageal cancer, stomach cancer, liver cancer, glioma, cervical cancer, ovarian cancer, head and neck cancer and multiple myeloma.
The invention also provides an application of the compound shown in the general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicines for treating inflammation, autoimmune diseases or tumors, wherein the autoimmune diseases are preferably systemic lupus erythematosus or psoriasis; wherein the tumour is selected from acute myelogenous leukemia, bladder epithelial cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, blastoma, retinoblastoma, sarcoma, prostate cancer, cholangiocarcinoma, oesophageal cancer, stomach cancer, liver cancer, glioma, cervical cancer, ovarian cancer, head and neck cancer and multiple myeloma.
The pharmaceutical formulations of the present invention may be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocular, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intradermal, intraperitoneal, subcutaneous, subcuticular or by inhalation. Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
The formulations of the present invention are suitably presented in unit-dose form and may be prepared by any method well known in the pharmaceutical arts. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form can vary depending upon the host treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form generally refers to the amount of compound that is capable of producing a therapeutic effect.
Dosage forms for topical or transdermal administration of the compounds of the present invention may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be admixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants which may be required.
When the compounds of the invention are administered to humans and animals in the form of a medicament, the compounds may be provided alone or in the form of a pharmaceutical composition containing the active ingredient in combination with a pharmaceutically acceptable carrier, for example 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient.
Examples of pharmaceutically acceptable carriers include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) Polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; (21) Cyclodextrins, e.g., targeting ligands attached to nanoparticles, e.g., accursinTM; and (22) other non-toxic compatible substances used in pharmaceutical formulations, such as polymer-based compositions.
Examples of pharmaceutically acceptable antioxidants include, but are not limited to: (1) Water-soluble antioxidants such as ascorbic acid, cysteamine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) Oil-soluble antioxidants such as ascorbyl palmitate, butylated Hydroxyanisole (BHA), butylated Hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelators such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like. Solid dosage forms (e.g., capsules, dragees, powders, granules and the like) may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) Fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) Binders, such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and/or acacia; (3) humectants, such as glycerin; (4) Disintegrants, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) an absorption accelerator, such as a quaternary ammonium compound; (7) Humectants, such as cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) a colorant. Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizing agents and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Suspensions, in addition to the active compounds, may also contain suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
In addition to the active compounds, ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
In addition to the active compounds, the powders and sprays can also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. The spray may contain other conventional propellants such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons such as butane and propane.
Detailed description of the invention
Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:
"alkyl" when taken as a group or part of a group is meant to include C 1 -C 20 Straight chain or branched aliphatic hydrocarbon groups. Preferably C 1 -C 10 Alkyl, more preferably C 1 -C 6 An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentylAnd cyclopentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.
"cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocycles. Preferably C 3 -C 12 Cycloalkyl, more preferably C 3 -C 8 Cycloalkyl, most preferably C 3 -C 6 Cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred. Cycloalkyl groups may be optionally substituted or unsubstituted.
"spirocycloalkyl" refers to a 5 to 18 membered, two or more cyclic structure, and monocyclic polycyclic groups sharing one carbon atom (called spiro atom) with each other, containing 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro group, a double spiro group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, preferably single spiro group and double spirocycloalkyl group, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.
"fused ring alkyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of "fused ring alkyl" include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, decalinyl, or tetradecahydrophenanthryl.
"bridged cycloalkyl" means an aromatic system having 5 to 18 members, containing two or more cyclic structures, sharing two all-carbon polycyclic groups with one another that are not directly attached to a carbon atom, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron, preferably 6 to 12 members, more preferably 7 to 10 members. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1 s,4 s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1 s,5 s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1 r,5 r) -bicyclo [3.3.2] decyl.
"heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more of the ring-forming atoms are heteroatoms, such as oxygen, nitrogen, sulfur, and the like, and include monocyclic, polycyclic, fused, bridged, and spiro heterocyclic groups. Preferably having a 5 to 7 membered single ring or a 7 to 10 membered double or triple ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulphur.
Examples of "monocyclic heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, piperazinyl, hexahydropyrimidinyl,
the monocyclic heterocyclic group may be substituted or unsubstituted.
"spiroheterocyclyl" refers to a 5-to 18-membered, two or more cyclic structure, polycyclic group having single rings sharing one atom with each other, which ring may contain 1 or more double bonds, but no ring has a completely conjugated pi-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) r (wherein r is selected from 0, 1 or 2) and the remainderThe ring atom is carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multiple spiro heterocyclic group according to the number of common spiro atoms between rings, and preferably a single spiro heterocyclic group and a double spiro heterocyclic group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5 ] ]Decyl, 2-oxa-7-azaspiro [4.4 ]]Nonyl, 7-oxaspiro [3.5 ]]Nonyl, 5-oxaspiro [2.4 ]]Heptyl group,
The spiroheterocyclyl groups may be substituted or unsubstituted.
"fused heterocyclyl" refers to a polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered, 5-membered/6-membered or 5-membered/7-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrrolo [3,4-c ]]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0 ]]Hexyl, octahydrobenzo [ b ]][1,4]Dioxin (dioxane),
The fused heterocyclic group may be substituted or unsubstituted.
"bridged heterocyclyl" means a 5 to 14 membered, 5 to 18 membered, polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more of the rings may contain one One or more double bonds, but none of the rings has a completely conjugated pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2]Octyl, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, 2-azabicyclo [3.3.2]And (3) a decyl group.
The bridged heterocyclic group may be substituted or unsubstituted.
"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably aryl is C 6 -C 10 Aryl, more preferably aryl is phenyl and naphthyl, most preferably naphthyl. Aryl groups may be substituted or unsubstituted.
"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 8-to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, and the like,
Heteroaryl groups may be substituted or unsubstituted.
"alkoxy" refers to a group of (alkyl-O-). Wherein alkyl is as defined herein. C (C) 1 -C 6 Is preferably selected. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
"hydroxy" refers to an-OH group.
"halogen" refers to fluorine, chlorine, bromine and iodine.
"amino" means-NH 2 。
"cyano" refers to-CN.
"nitro" means-NO 2 。
"benzyl" means-CH 2 -phenyl.
"carboxy" means-C (O) OH.
"carboxylate" refers to-C (O) O-alkyl or-C (O) O-cycloalkyl, wherein alkyl, cycloalkyl are as defined above.
"DMSO" refers to dimethyl sulfoxide.
"TFA" refers to trifluoroacetic acid.
"Ts" refers to p-toluenesulfonyl.
"Tf" refers to p-trifluoromethylbenzenesulfonyl.
The term "leaving group", or "leaving group", is used in the term nucleophilic substitution reaction and elimination reaction as an atom or functional group that is released from a larger molecule in a chemical reaction. In nucleophilic substitution reactions, the reactant that is attacked by a nucleophile is referred to as a substrate (substrate), and the atom or group of atoms that breaks away from a pair of electrons in the substrate molecule is referred to as a leaving group. Groups that accept electrons easily and bear a strong negative charge are good leaving groups. The smaller the pKa of the leaving group conjugate acid, the easier the leaving group will be to disengage from the other molecule. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to be bound to other atoms, and the tendency to exist in anionic (or charge neutral leaving group) form is enhanced. Common leaving groups include, but are not limited to, halogen, methanesulfonyl, -OTs, -OTf, or-OH.
"substituted" means that one or more, preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"substituted" or "substituted" as used herein, unless otherwise indicated, means that the group may be substituted with one or more groups selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =o, -C (O) R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or-NR 12 C(O)R 13 Is substituted by a substituent of (2);
R 11 、R 12 and R is 13 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, and carboxylate.
The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (attopiomers) and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.
Unless otherwise indicated, the structures described herein also include all stereoisomers (e.g., diastereomers, enantiomers and atropisomers and geometric (conformational) isomeric forms of such structures, e.g., the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.
"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain the original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds represented by the general formula (I) may be metal salts, amine salts with suitable acids.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
Synthesis method of compound of the invention
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
the present invention provides a process for the preparation of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which process comprises:
the compound of the general formula (IA) and the compound of the general formula (IB) are subjected to coupling reaction under the condition of a catalyst and under the condition of alkalinity to obtain the compound of the general formula (I);
wherein:
x is selected from leaving groups selected from halogen or OTf;
ring A, R 3 -R 7 And n is as defined in formula (I).
The catalyst is preferably dibenzylidene acetone dipalladium;
the reagent providing alkalinity is preferably cesium carbonate.
Detailed Description
The invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.
Examples
The preparation of representative compounds represented by formula (I) and related structural identification data are presented in the examples. It must be noted that the following examples are given by way of illustration and not by way of limitation. 1 The H NMR spectrum was determined with a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation method: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and, unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, all of which are used without further purification and, unless otherwise indicated, commercially available manufacturers include, but are not limited to, aldrich Chemical Company, ABCR GmbH & co.kg, acros Organics, praise chemical technology limited, and vision chemical technology limited, etc.
CD 3 OD: deuterated methanol.
CDCl 3 : deuterated chloroform.
DMSO-d 6 : deuterated dimethyl sulfoxide.
The nitrogen atmosphere is defined as the reaction flask being connected to a nitrogen balloon of about 1L volume.
The examples are not particularly described, and the solution in the reaction is an aqueous solution.
Purifying the compound by using a silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: methylene chloride and methanol systems; c: dichloromethane: ethyl acetate; the volume ratio of the solvent is different according to the polarity of the compound, and can be adjusted by adding a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine.
Example 1
2-((5-(2-aminopropan-2-yl)-8-(methylthio)-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-
dihydro-5H-pyrano[4,3-b]pyridin-5-one
2- ((5- (2-aminoisopropyl-2-yl) -8- (methylsulfanyl) -2, 7-naphthyridin-3-yl) amino) -7, 7-dimethyl-7, 8-dihydro-5H-pyran
[4,3-b ] pyridin-5-one
First step
4-bromo-6-chloro-2,7-naphthyridin-1(2H)-one
4-bromo-6-chloro-2, 7-naphthyridin-1 (2H) -one
6-chloro-2, 7-naphthyridin-1 (2H) -one 1a (3 g,16.61 mmol) and N-bromosuccinimide (3.55 g,19.93 mmol) were added sequentially to N, N-dimethylformamide (30 mL) and stirring continued for 2 hours at 20 ℃. LC-MS detects that the reaction of the raw materials is finished. The reaction solution was poured into ice water to precipitate a large amount of a earthy yellow solid, which was filtered, and the cake was washed twice with water, and dried to give 4-bromo-6-chloro-2, 7-naphthyridin-1 (2H) -one 1b (3.7 g,14.26mmol,85.83% yield).
MS m/z(ESI)：260.3[M+H] +
Second step
4-bromo-1,6-dichloro-2,7-naphthyridine
4-bromo-1, 6-dichloro-2, 7-naphthyridine
4-bromo-6-chloro-2, 7-naphthyridin-1 (2H) -one 1b (500 mg,1.93 mmol) was added to phosphorus oxychloride (3.40 g,22.16mmol,5 mL) and stirring was continued for 3 hours at 110℃under nitrogen. LC-MS monitoring, cooling the reaction solution to room temperature after the reaction of the raw materials is completed, concentrating under reduced pressure, adding ice blocks into the residue for quenching, adding 50mL of saturated sodium bicarbonate solution, adjusting the pH to be slightly alkaline, extracting with dichloromethane (50 mL multiplied by 2), washing with saturated saline (50 mL), drying with anhydrous sodium sulfate, filtering and concentrating to obtain 4-bromo-1, 6-dichloro-2, 7-naphthyridine 1c (500 mg,1.80mmol,93.36% yield).
MS m/z(ESI)：281.1[M+H] +
Third step
4-bromo-6-chloro-1-(methylthio)-2,7-naphthyridine
4-bromo-6-chloro-1- (methylthio) -2, 7-naphthyridine
4-bromo-1, 6-dichloro-2, 7-naphthyridine 1c (1 g,3.60 mmol), sodium methyl mercaptide (1.26 g,3.60mmol,20% purity) were added sequentially to N, N-dimethylformamide (10 mL), and stirring was continued under nitrogen at 25℃for 12 hours. LC-MS monitors that the reaction of the raw materials is completed, the reaction solution is added into 200mL of ice water, a large amount of earthy yellow solid is precipitated, the mixture is filtered, a filter cake is washed twice by water, and the mixture is dried to obtain 4-bromo-6-chloro-1- (methylthio) -2, 7-naphthyridine 1d (900 mg,3.11mmol,86.38% yield).
MS m/z(ESI)：290.3[M+H] +
Fourth step
6-chloro-4-(1-ethoxyvinyl)-1-(methylthio)-2,7-naphthyridine
6-chloro-4- (1-ethoxyvinyl) -1- (methylthio) -2, 7-naphthyridine
4-bromo-6-chloro-1- (methylthio) -2, 7-naphthyridine 1d (1 g,3.45 mmol), tributyl (1-ethoxyethylene) tin (2.49 g,6.91 mmol), tetrakis (triphenylphosphine) palladium (199.52 mg, 172.66. Mu. Mol) were added sequentially to toluene (10 mL) and stirring was continued for 3 hours at 80℃under nitrogen. LC-MS monitors that the reaction of the raw materials is completed, water is added, then ethyl acetate is used for extraction, and the obtained residue is further separated and purified by silica gel column chromatography (eluent: system A) to obtain 6-chloro-4- (1-ethoxyvinyl) -1- (methylthio) -2, 7-naphthyridine 1e (660 mg,2.35mmol,68.07% yield).
MS m/z(ESI)：281.5[M+H] +
Fifth step
1-(6-chloro-1-(methylthio)-2,7-naphthyridin-4-yl)ethan-1-one
1- (6-chloro-1- (methylsulfanyl) -2, 7-naphthyridin-4-yl) ethan-1-one
6-chloro-4- (1-ethoxyvinyl) -1- (methylthio) -2, 7-naphthyridine 1e (660 mg,2.35 mmol) and concentrated hydrochloric acid (0.7 mL) were added sequentially to tetrahydrofuran (7 mL), and stirring was continued under nitrogen at 0deg.C for 3 hours. LC-MS monitors the completion of the reaction of the starting materials, the reaction solution was poured into 50mL of water, the pH was adjusted to be weakly alkaline by adding a saturated sodium bicarbonate solution, extracted with ethyl acetate (25 mL. Times.2), dried, concentrated under reduced pressure to give 1- (6-chloro-1- (methylthio) -2, 7-naphthyridin-4-yl) ethan-1-one 1f (500 mg,1.98mmol,84.17% yield).
MS m/z(ESI)：253.1[M+H] +
Sixth step
2-(6-chloro-1-(methylthio)-2,7-naphthyridin-4-yl)propan-2-ol
2- (6-chloro-1- (methylsulfanyl) -2, 7-naphthyridin-4-yl) propan-2-ol
1- (6-chloro-1- (methylthio) -2, 7-naphthyridin-4-yl) ethan-1-one 1f (500 mg,1.98 mmol) and methylmagnesium bromide (5 mL,1mol/L, THF) were added sequentially to tetrahydrofuran (5 mL) and stirring was continued under nitrogen at 0deg.C for 5 hours. LC-MS monitors the completion of the reaction of the starting materials, water was added, extraction was performed with ethyl acetate, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: system A) to give 1g (200 mg, 744.15. Mu. Mol,37.61% yield) of 2- (6-chloro-1- (methylthio) -2, 7-naphthyridin-4-yl) propan-2-ol.
MS m/z(ESI)：269.1[M+H] +
Seventh step
4-(2-azidopropan-2-yl)-6-chloro-1-(methylthio)-2,7-naphthyridine
4- (2-azidopropan-2-yl) -6-chloro-1- (methylsulfanyl) -2, 7-naphthyridine
1g (100 mg, 372.08. Mu. Mol) of 2- (6-chloro-1- (methylsulfanyl) -2, 7-naphthyridin-4-yl) propan-2-ol was added to methylene chloride (3 mL), and azido trimethylsilane (111.25 mg, 967.40. Mu. Mol) and boron trifluoride diethyl ether (110.90 mg, 781.36. Mu. Mol) were slowly added thereto, and stirring was continued at room temperature under nitrogen atmosphere for 12 hours. LC-MS monitors the completion of the reaction of the starting materials, water was added, followed by extraction with ethyl acetate, and the combined organic phases were concentrated under reduced pressure, and the resulting residue was further separated and purified by column chromatography on silica gel (eluent: system A) to give 4- (2-azidopropan-2-yl) -6-chloro-1- (methylthio) -2, 7-naphthyridine for 1h (80 mg, 272.32. Mu. Mol,73.19% yield).
MS m/z(ESI)：293.1[M+H] +
Eighth step
2-((5-(2-azidopropan-2-yl)-8-(methylthio)-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-
dihydro-5H-pyrano[4,3-b]pyridin-5-one
2- ((5- (2-azidopropyl-2-yl) -8- (methylsulfanyl) -2, 7-naphthyridin-3-yl) amino) -7, 7-dimethyl-7, 8-dihydro-5H-pyran [4,3- ]
b ] pyridin-5-ones
4- (2-azidopropan-2-yl) -6-chloro-1- (methylthio) -2, 7-naphthyridine (80.00 mg, 272.32. Mu. Mol), 2-amino-7, 7-dimethyl-8H-pyran [4,3-b ] pyridin-5-one 1j (52.34 mg, 272.32. Mu. Mol, prepared with reference to WO 2021146370A 1), tris-dibenzylideneacetone dipalladium (24.94 mg, 27.23. Mu. Mol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (31.51 mg, 54.46. Mu. Mol), cesium carbonate (266.18 mg, 816.95. Mu. Mol) were added sequentially to 1, 4-dioxane (3 mL) and stirring was continued under nitrogen-protected microwave conditions at 125℃for 1 hour. LC-MS monitors the completion of the reaction of the starting materials, water was added, ethyl acetate extraction, the combined organic phases were concentrated under reduced pressure and the resulting residue was further isolated and purified by column chromatography on silica gel (eluent: system B) to give 2- ((5- (2-azidopropyl-2-yl) -8- (methylsulfanyl) -2, 7-naphthyridin-3-yl) amino) -7, 7-dimethyl-7, 8-dihydro-5H-pyran [4,3-B ] pyridin-5-one 1i (75 mg, 166.84. Mu. Mol,61.27% yield).
MS m/z(ESI):450.2[M+1]
Ninth step
2-((5-(2-aminopropan-2-yl)-8-(methylthio)-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one
2- ((5- (2-aminoisopropyl-2-yl) -8- (methylsulfanyl) -2, 7-naphthyridin-3-yl) amino) -7, 7-dimethyl-7, 8-dihydro-5H-pyran [4,3-b ] pyridin-5-one
2- ((5- (2-azidopropyl-2-yl) -8- (methylsulfanyl) -2, 7-naphthyridin-3-yl) amino) -7, 7-dimethyl-7, 8-dihydro-5H-pyran [4,3-b ] pyridin-5-one 1i (70 mg, 155.72. Mu. Mol), zinc powder (50.91 mg, 778.59. Mu. Mol), glacial acetic acid (46.76 mg, 778.59. Mu. Mol) were added sequentially to tetrahydrofuran (3 mL) and stirring was continued under hydrogen protection at 25℃for 2 hours. After completion of the reaction, the LC-MS was monitored, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, saturated sodium bicarbonate solution (50 mL) was added to the residue, ethyl acetate was extracted (25 mL. Times.2) twice, the organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and the resulting residue was concentrated by filtration to give 2- ((5- (2-aminoisopropyl-2-yl) -8- (methylthio) -2, 7-naphthyridin-3-yl) amino) -7, 7-dimethyl-7, 8-dihydro-5H-pyran [4,3-b ] pyridin-5-one 1 (15 mg, 33.65. Mu. Mol,21.61% yield) by HPLC.
MS m/z(ESI):424.2[M+1]
1 H NMR(400MHz,Chloroform-d)δ9.47(s,1H),9.42(s,1H),8.52(s,1H),8.27(d,J＝8.6Hz,1H),8.08(s,1H),7.20(d,J＝8.6Hz,1H),3.18(s,2H),2.74(s,3H),1.82(s,6H).
Biological evaluation
Test example 1 test of the Compounds of the invention for HPK1 kinase inhibitory Activity
The following methods were used to determine the extent of inhibition of recombinant human HPK1 kinase activity by the compounds of the invention under in vitro conditions. The method uses ADP-Glo from Promega company TM Kinase Assay kit (cat. V9102). The kit is a luminescent kinase detection kit and is used for detecting the content of ADP generated by kinase reaction, the content of ADP is positively correlated with kinase activity, and the inhibition of the compound on HPK1 kinase activity is reflected by measuring the content of ADP. For detailed experimental procedures reference is made to the kit instructions.
The experimental procedure is briefly described as follows: test compounds were first dissolved in DMSO to prepare stock solutions, and then buffer (20 mM MgCl) was prepared according to the buffer formulation provided in the reagent instructions 2 50. Mu.M DTT,0.1mg/ml BSA,40mM Tris,pH7.4), and the final concentration of the test compound in the reaction system was in the range of 1000nM to 0.02nM. The reaction was performed in 384-well microwell plates, first the compound and recombinant human HPK1 protein (final concentration 1 ng/. Mu.L, available from Signalchem, cat. No. M23-11G-10) were added to the wells, and incubated at room temperature for 5 minutes, followed by addition of ATP solution (from ADP-Glo) to the reaction solution TM Kinase Assay kit component V915A, final concentration 10. Mu.M) and substrate MBP (final concentration 0.2. Mu.g/. Mu.L, available from Signalchem, cat. M42-51N) were incubated with shaking for 60 minutes at room temperature. Subsequently, 5. Mu.L of ADP-Glo Reagent was added to the reaction system, and incubation was continued at room temperature with shaking for 40 minutes. Then 10 μ L Kinase Detection Reagent was added to the reaction and incubation was continued at room temperature for 30 minutes with shaking. After the incubation, the chemiluminescent intensity value of each well was measured in a luminometer in the luminometer mode. The percent inhibition of the compounds at each concentration was calculated by comparison with the ratio of the luminescence intensity of the control group (0.1% dmso) and nonlinear regression analysis was performed on the number-inhibition at the compound concentration by GraphPad Prism 5 software to obtain the IC of the compounds 50 The values are shown in Table 1.
TABLE 1 IC50 data for compounds of the invention inhibiting HPK1 kinase activity
As can be seen from Table 1, the compounds of the present invention have a better inhibition of HPK1 kinase.
Test example 2 determination of the inhibitory Activity of the Compounds of the invention against p-SLP 76S 376 in Jurkat cells
The following method was used to determine the p-SLP 76S 376 inhibitory activity of the compounds of the present invention on Jurkat cells. The method uses a Phospho-SLP-76 (Ser 376) cell kit (product number 63ADK076 PEG) from Cisbio, and the detailed experimental procedure can be referred to the kit instructions. Jurkat cells were purchased from the China academy of sciences of Shanghai life sciences center for cell resources.
The experimental procedure is briefly described as follows: jurkat cells were cultured in RPMI 1640 complete medium containing 10% fetal bovine serum, 100U penicillin, 100. Mu.g/mL streptomycin and 1mM Sodium Pyruvate. 8uL Jurkat cells (100000 per well) were plated in 384 well plates and the medium was complete and incubated in a 5% CO2 incubator at 37 ℃. Dissolving a test compound in DMSO to prepare a 10mM stock solution, diluting with RPMI 1640 complete medium, adding 2uL of RPMI 1640 complete medium containing the test compound with corresponding concentration into each well, and placing the test compound in a cell culture box for culture for 1 hour, wherein the final concentration of the test compound in the system is 10000nM-0.01 nM; subsequently, 2ul of Anti-human CD3 (5 ug/ml) was added and incubated in a cell incubator for 30 minutes; then 4uL of lysate was added for 45 min, finally 4uL of Phospho-SLP-76Cryptate antibody and Phospho-SLP-76d2 anti-ibody were added and incubated overnight at room temperature. Fluorescence intensities at excitation wavelengths of 304nM were measured on an microplate reader in TF-FRET mode, with emission wavelengths of 620nM and 665nM for each well, and the fluorescence intensity ratio for each well 665/620 was calculated. The percent inhibition of the test compounds at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group (0.1% DMSO) and nonlinear regression analysis was performed by GraphPad Prism 5 software with the test compound concentration log-inhibition to obtain compound IC 50 The values are shown in Table 2.
TABLE 2 IC of the inhibitory Activity of the inventive Compounds against p-SLP 76S 376 in Jurkat cells 50 Data
Examples numbering IC 50 (nM)
1 77.99
As can be seen from Table 2, the compounds of the present invention have a good inhibitory effect on p-SLP 76S 376 in Jurkat cells.
Test example 3 ICR mouse pharmacokinetic study of the Compound of the invention
1. Purpose of experiment
The pharmacokinetic characteristics of the compound of the invention in mice were studied by measuring the drug concentration in plasma of compound 1 administered by intragastric administration by LC/MS method using ICR mice as test animals.
2. Experimental protocol
2.1 experimental drugs and animals;
compounds of the invention
ICR mice, male, 29.7-34.6 g, purchased from Peking Vitre Liwa laboratory animal technologies Co.
2.2 pharmaceutical formulation
Weighing a proper amount of medicine, sequentially adding DMA, cremophor EL and 5% GS, and uniformly mixing by ultrasonic vortex to prepare a 1mg/mL administration preparation. Wherein DMA: cremophor EL 5% gs=5:10:85 (v/v/v).
2.3 administration of drugs
ICR mice, the test compound(s) were gavaged (9) and fed (PO, administered at a dose of 10mg/kg, administered at a volume of 10 mL/kg) after an overnight fast for 4 hours.
3. Operation of
About 0.1mL of blood was collected via orbital veins before and after administration for 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours, and heparin sodium was anticoagulated. After blood sample collection, the plasma was centrifuged (centrifugation conditions: 1500g,10 min). The collected plasma was stored at a temperature of-40 to-20℃prior to analysis.
LC-MS/MS was used to determine the amount of test compound in the plasma of mice following intragastric administration.
4. Pharmacokinetic parameter results
The pharmacokinetic parameters of the compounds of the invention are shown in the following table.
TABLE 3 pharmacokinetic results
Conclusion: the compounds of the present invention have good pharmacokinetic properties.

Claims (17)

1. A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
wherein:
ring a is selected from:
in the case of double bonds, G is selected from CR 1 ；X 1 、X 2 、X 3 、X 4 Each independently selected from CR x Or N;
when a single bond is formed, G is selected from C=O, X 1 Selected from NR x ，X 2 、X 3 、X 4 Each independently selected from CR x Or N;
R x selected from hydrogen atom, hydroxy, halogen, alkyl, cyano, alkoxy, cycloalkyl, heterocyclyl or-NR 8 R 9 Wherein said alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally further substituted with one or more groups selected from halogen, amino, hydroxyRadicals, cyano radicals, alkoxy radicals or-NR 8 R 9 Is substituted by a substituent of (2);
R 1 selected from the group consisting of hydrogen, hydroxy, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (O) r R 10 、-C(O)OR 10 、-C(O)R 10 、-S(O) r NR 8 R 9 、-C(O)NR 8 R 9 or-NHC (O) R 10 Wherein said alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from halogen, amino, hydroxy, cyano or alkoxy;
R 2 Selected from alkyl, -S (O) r R 10 、-S(O) r NR 8 R 9 、-C(O)R 10 、-C(O)NR 8 R 9 、-NHC(O)R 10 or-P (O) R 8 R 9 Wherein said alkyl is optionally further substituted with one or more substituents selected from halogen, amino, hydroxy, cyano or alkoxy;
R 3 and R is 5 The same or different, each independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, cyano, or alkoxy;
R 4 selected from the group consisting of hydrogen, halogen, amino, hydroxy, cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, cyano, or alkoxy;
R 6 and R is 7 The same or different are each independently selected from a hydrogen atom or an alkyl group;
R 8 and R is 9 The same or different, each independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein The alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or-NR 12 C(O)R 13 Is substituted by a substituent of (2);
alternatively, R 8 And R is 9 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more of N, O or S (O) r And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or-NR 12 C(O)R 13 Is substituted by a substituent of (2);
R 10 each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl group, heteroaryl group, =o, -C (O) R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or-NR 12 C(O)R 13 Is substituted by a substituent of (2);
R 11 、R 12 and R is 13 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, and ring Substituents for alkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate groups;
n is 0,1 or 2;
r is 0,1 or 2.
2. The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (II):
wherein: G. x is X 1 ～X 4 、R 2 ～R 4 Is defined as in claim 1.
3. A compound according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (III):
wherein: r is R x 、R 1 、R 3 And R is 4 Is defined as in claim 1.
4. The compound of claim 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
selected from:
wherein: r is R x And R is 1 ～R 4 Is defined as in claim 2.
5. A compound according to claim 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 1 selected from-C (O) OR 10 ；
Rx is selected from alkyl or-NR 8 R 9 Wherein said alkyl is optionally further substituted with-NR 8 R 9 Substituted;
R 8 and R is 9 Each independently selected from a hydrogen atom or an alkyl group;
R 10 Selected from alkyl groups.
6. The compound of claim 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
rx is selected from-NR 8 R 9 Or (b)
R 8 Selected from hydrogen atoms;
R 9 selected from alkyl groups;
R 10 selected from methyl, ethyl or isopropyl.
7. A compound according to claim 4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 1 selected from the group consisting of hydrogen atom, alkoxy group, cyano group, -SR 10 、-SO 2 R 10 、-C(O)R 10 or-NHC (O) R 10 ；
R 10 Selected from alkyl or cycloalkyl groups.
8. A compound according to claim 4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 2 selected from alkyl, -SO 2 R 10 、-SO 2 NR 8 R 9 、-C(O)R 10 、-C(O)NR 8 R 9 or-P (O) R 8 R 9 Wherein said alkyl is optionally further substituted with-NR 8 R 9 Substituted;
R 8 and R is 9 Each independently selected from a hydrogen atom or an alkyl group;
R 10 selected from alkyl or cycloalkyl groups.
9. The compound of claim 8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 2 selected from the group consisting of
10. The compound of claim 8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 2 selected from-SO 2 R 10 、-SO 2 NR 8 R 9 、-C(O)NR 8 R 9 、-C(O)R 10 or-P (O) R 8 R 9 ；
R 8 And R is 9 Each independently selected from hydrogen, methyl, ethyl or isopropyl;
R 10 selected from methyl, ethyl, isopropyl or cyclopropyl.
11. The compound according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is:
12. a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
13. Use of a compound according to any one of claims 1 to 11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, for the preparation of an HPK1 inhibitor.
14. Use of a compound according to any one of claims 1 to 11, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, for the manufacture of a medicament for the treatment of a disease mediated by HPK1, wherein the disease mediated by HPK1 is preferably an inflammation, autoimmune disease or tumour, wherein the autoimmune disease is preferably systemic lupus erythematosus or psoriasis.
15. The use of claim 14, wherein the tumor is selected from the group consisting of acute myelogenous leukemia, bladder epithelial cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, blastoma, retinoblastoma, sarcoma, prostate cancer, cholangiocarcinoma, esophageal cancer, gastric cancer, liver cancer, glioma, cervical cancer, ovarian cancer, head and neck cancer, and multiple myeloma.
16. Use of a compound according to any one of claims 1 to 11, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, for the manufacture of a medicament for the treatment of inflammation, autoimmune diseases or neoplasms, wherein the autoimmune diseases are preferably systemic lupus erythematosus or psoriasis.
17. The use of claim 16, wherein the tumor is selected from the group consisting of acute myelogenous leukemia, bladder epithelial cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, blastoma, retinoblastoma, sarcoma, prostate cancer, cholangiocarcinoma, esophageal cancer, gastric cancer, liver cancer, glioma, cervical cancer, ovarian cancer, head and neck cancer, and multiple myeloma.
CN202310063347.XA 2022-01-20 2023-01-16 Aromatic condensed ring derivative and preparation method and application thereof Pending CN116462688A (en)

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