WO2022214009A1 - High-activity hpk1 kinase inhibitor - Google Patents

High-activity hpk1 kinase inhibitor Download PDF

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Publication number
WO2022214009A1
WO2022214009A1 PCT/CN2022/085446 CN2022085446W WO2022214009A1 WO 2022214009 A1 WO2022214009 A1 WO 2022214009A1 CN 2022085446 W CN2022085446 W CN 2022085446W WO 2022214009 A1 WO2022214009 A1 WO 2022214009A1
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Prior art keywords
alkyl
compound
pharmaceutically acceptable
stereoisomer
acceptable salt
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PCT/CN2022/085446
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French (fr)
Chinese (zh)
Inventor
陈宇锋
时永强
武朋
温俏冬
杨寒
吕萌
刘灿丰
陈凯旋
王友平
何南海
Original Assignee
杭州阿诺生物医药科技有限公司
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Priority to CN202280013620.1A priority Critical patent/CN116888100A/en
Publication of WO2022214009A1 publication Critical patent/WO2022214009A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms

Definitions

  • the present invention relates to a heterocyclic compound, in particular to a highly active HPK1 kinase inhibitor and use thereof.
  • HPK1 a member of the MAP4K family, is mainly expressed in cells of the hematopoietic system and acts as an intracellular negative regulator of T cell proliferation and signaling.
  • the adaptor protein SLP-76 in the cytoplasm is recruited to the lipid membrane TCR complex, providing binding sites for signal transduction-related kinases to achieve TCR-mediated signal transmission and induce T cell activation.
  • HPK1 is activated by phosphorylation by the tyrosine kinases Lck and Zap70, and is involved in the regulation of T cell receptor protein interactions.
  • HPK1 phosphorylates the Ser376 site of the adaptor protein SLP-76, so that SLP-76 binds to the scaffold protein 14-3-3 ⁇ and is degraded by the proteasome, and this effect reduces the binding of SLP-76 to signal transduction-related kinases It blocked TCR signal transduction, which in turn inhibited T cell activation and proliferation.
  • HPK1 is also involved in regulating the maturation and activation of dendritic cells (DCs), especially inhibiting the expression of T-cell activation-related proteins such as CD80, CD86 and MHC complexes in DCs, thereby affecting DC regulation
  • DCs dendritic cells
  • T-cell activation-related proteins such as CD80, CD86 and MHC complexes
  • the role of T cell activation; the presentation of tumor antigens by activated DCs and the mutual cooperation between DCs and T cells is one of the most important links in the anti-tumor immune system.
  • immunosuppressive molecules such as PGE2 and TGF- ⁇ in the tumor microenvironment, and the immunosuppressive effects mediated by these factors are also related to HPK1.
  • small-molecule compounds that specifically target and inhibit HPK1 can improve T cell function, enhance DC cell function, and at the same time reverse the tumor immunosuppressive microenvironment. effect.
  • the present invention has unexpectedly discovered a compound of formula (I) and a pharmaceutically acceptable salt thereof or a stereoisomer thereof having HPK1 kinase inhibitory activity. Accordingly, in a first aspect, the present invention provides a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
  • X represents N or CR 10 ;
  • R 1 represents hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogenated C 3 -C 6 cycloalkyl, halogen, cyano or -C (O)NH 2 ;
  • R 2 represents hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, -(C 0 -C 6 alkylene)(C 3 -C 8 )cycloalkyl , -(C 0 -C 6 alkylene) (4-8 membered) heterocycloalkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl (C 0 -C 6 ) alkylene)oxy, (4-8 membered)heterocycloalkyl(C 0 -C 6 alkylene)oxy;
  • R 3 represents hydrogen or C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, hydroxy (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl , 4-8 membered heterocycloalkyl;
  • R 4 represents hydrogen or C 1 -C 6 alkyl; and the C 1 -C 6 alkyl may be optionally substituted with a substituent selected from halogen, -OR a , -SR a , -P(O )R a R b , -S(O) 2 R a , -S(O)(NH)R a , -S(O)R a , -S(O) 2 NR a R b , -C(O) NR a R b , -C(O)OH, -OC(O)NR a R b , -NR a C(O) R b , -NR a S(O) 2 R b ;
  • R 5 and R 5' each independently represent hydrogen, C 1 -C 6 alkyl, (C 2 -C 6 )alkenyl, halogen, halogenated C 1 -C 6 alkyl or hydroxy (C 1 -C 6 alkane) base);
  • R 5 and R 5' together form a 3-6 membered ring with the carbon atom connected to it, and the ring can also optionally contain 0, 1 or 2 heteroatoms selected from N, O, S;
  • R 6 and R 6' each independently represent hydrogen, C 1 -C 6 alkyl, (C 2 -C 6 )alkenyl, halogen, halogenated C 1 -C 6 alkyl, hydroxy (C 1 -C 6 alkane) base);
  • R 6 and R 6' together form a 3-6 membered ring with the carbon atom connected to it, and the ring can also optionally contain 0, 1 or 2 heteroatoms selected from N, O, and S;
  • p 1 or 2;
  • R 7 and R 7' each independently represent hydrogen, C 1 -C 6 alkyl, (C 2 -C 6 )alkenyl, halogen, halogenated C 1 -C 6 alkyl, hydroxy (C 1 -C 6 alkane) base);
  • R 7 and R 7' together form a 3-6 membered ring with the carbon atom connected to it, and the ring can also optionally contain 0, 1 or 2 heteroatoms selected from N, O, and S;
  • A' represents CR a or N
  • B represents CR b ;
  • A' represents CHR a
  • B represents CHR b or does not exist
  • R 8 and R 9 each independently represent hydrogen or C 1 -C 6 alkyl; or R 8 and R 9 may together with W 1 and W 2 form a 3-6 membered ring;
  • W 1 means C, W 2 means CH or N;
  • R M and R N each independently represent hydrogen or C 1 -C 6 alkyl
  • R 10 represents hydrogen, halogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, -(C 0 -C 6 alkylene)(C 3 -C 8 )cycloalkyl, - (C 0 -C 6 alkylene) 4-10 membered heterocycloalkyl, -(C 0 -C 6 alkylene) (C 6 -C 10 ) aryl, -(C 0 -C 6 alkylene ) 5-10 membered heteroaryl,
  • R 10 may together with the adjacent R 2 form (5-10 membered) cycloalkyl or 5-10 membered heterocycloalkyl;
  • cycloalkyl, heterocycloalkyl, aryl, heteroaryl as defined above it may be optionally substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: (C 1 -C 6 ) alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, -(C 1 -C 6 alkylene) -O-(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, halo(C 3 -C 8 )cycloalkyl, halogen, -CN, oxo, -NR a R b , -OR a , -SR a , -(C 1 -C 6 alkylene) hydroxyl, -C(O)R a , -N(R a )C(O)R a ,
  • R a and R b each independently represent hydrogen, C 1 -C 6 alkyl, hydroxyl (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl;
  • n 0, 1 or 2, respectively.
  • W represents
  • o each independently represents 0 or 1;
  • R 8 represents hydrogen or C 1 -C 6 alkyl
  • R 9 each independently represents hydrogen or C 1 -C 6 alkyl
  • R 8 together with adjacent R 9 and the carbon atoms to which they are attached form a 3-6 membered ring;
  • W 2 , RM and RN are as described above.
  • W represents or
  • o each independently represents 0 or 1;
  • R 8 represents hydrogen or C 1 -C 6 alkyl
  • R 9 each independently represents hydrogen or C 1 -C 6 alkyl
  • R 8 together with adjacent R 9 and the carbon atoms to which they are attached form a 3-6 membered ring;
  • W 2 , RM and RN are as described in claim 1 .
  • W is an aromatic heterocycle, preferably an aromatic lactam.
  • W is a saturated heterocycle, preferably a saturated lactam.
  • the ring W represents
  • the ring W represents W represents
  • R 1 represents hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyano or -C(O)NH 2 ; more preferably, R 1 represents hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • R 2 represents hydroxyl, (C 1 -C 6 )alkyl, -(C 0 -C 6 alkylene) (C 3 -C 8 )cycloalkyl, -( C 0 -C 6 alkylene) (4-8 membered) heterocycloalkyl, (C 1 -C 6 )alkoxy; more preferably, R 2 represents C 1 -C 6 alkyl, C 1 -C 6alkoxy or C3 - C6cycloalkyl .
  • R 3 represents hydrogen or C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl; more preferably, R 3 represents hydrogen or C 1 -C 6 alkyl.
  • R 4 represents hydrogen or C 1 -C 6 alkyl; and the C 1 -C 6 alkyl can be optionally substituted by a substituent selected from the following: halogen, - OR a , -SR a , -P(O)R a R b , -S(O) 2 R a , -S(O)(NH)R a , -S(O)R a , -S(O) 2NR a R b , -C(O)NR a R b , -C(O)OH; more preferably, R 4 represents hydrogen or C 1 -C 6 alkyl.
  • R 5 and R 5' each independently represent hydrogen, halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
  • R 6 and R 6′ each independently represent hydrogen, halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
  • R 7 and R 7' each independently represent hydrogen, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl or hydroxyl (C 1 -C 6 alkyl).
  • R 8 represents hydrogen or C 1 -C 6 alkyl.
  • R 9 represents hydrogen or C 1 -C 6 alkyl.
  • R 10 represents hydrogen, halogen, (C 1 -C 6 )alkyl, -(C 0 -C 6 alkylene) (C 3 -C 8 )cycloalkyl, -(C 0 -C 6 alkylene)4-10 membered heterocycloalkyl; more preferably, R 10 represents hydrogen, halogen or (C 1 -C 6 )alkyl.
  • R M represents hydrogen or C 1 -C 6 alkyl.
  • R a and R b each independently represent hydrogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
  • the compounds of the present invention have the following structure:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of a compound or pharmaceutical composition of the present invention in the preparation of a medicament for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.
  • the present invention also provides the use of a compound of the present invention for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.
  • salts, solvates and hydrates of a compound are alternative existing forms of the compound, and they can all be converted into the compound under certain conditions.
  • a compound When referring to a compound, it generally includes its pharmaceutically acceptable salts, and further includes its solvates and hydrates.
  • prodrugs, metabolites and nitrogen oxides thereof are generally also included.
  • the pharmaceutically acceptable salts of the present invention can be formed using, for example, the following inorganic or organic acids:
  • “Pharmaceutically acceptable salts” refers to salts that, within the scope of sound medical judgment, are suitable for use in contact with humans and lower levels of and other animal tissues, without undue toxicity, irritation, allergic reactions, etc., can be called a reasonable benefit/risk ratio.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent, as outlined below. For example, the free base functionality can be reacted with a suitable acid.
  • suitable pharmaceutically acceptable salts thereof may include metal salts, such as alkali metal salts (eg, sodium or potassium salts); and alkaline earth metal salts (eg, calcium or magnesium salts) .
  • metal salts such as alkali metal salts (eg, sodium or potassium salts); and alkaline earth metal salts (eg, calcium or magnesium salts) .
  • pharmaceutically acceptable non-toxic acid addition salts are amino groups with inorganic acids (eg, hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric) or organic acids (eg, acetic, oxalic, maleic, tartaric, citric acid, succinic acid or malonic acid), or by using other methods in the art such as ion exchange.
  • salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, Camphorsulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerin Phosphate, gluconate, hernisulfate, heptanoate, caproate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malic acid salt, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectic acid Salt, pers
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Other pharmaceutically acceptable salts include, where appropriate, nontoxic ammonium salts, quaternary ammonium salts, and ammonium cations formed with counter ions, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower Alkyl sulfonates and aryl sulfonates.
  • the pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving a compound of the present invention in a water-miscible organic solvent (eg, acetone, methanol, ethanol, and acetonitrile), adding thereto an excess of an organic acid or inorganic An aqueous acid solution to precipitate the salt from the resulting mixture, the solvent and remaining free acid removed therefrom, and the precipitated salt isolated.
  • a water-miscible organic solvent eg, acetone, methanol, ethanol, and acetonitrile
  • the precursors or metabolites described in the present invention may be those known in the art, as long as the precursors or metabolites can be metabolized in vivo to form the target compound.
  • “prodrugs” refer to those prodrugs of the compounds of the present invention which, within the scope of sound medical judgment, are suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic response, etc., Have a reasonable benefit/risk ratio and be valid for its intended use.
  • prodrug refers to a compound that is rapidly transformed in vivo to yield the parent compound of the above formula, eg, by in vivo metabolism, or N-demethylation of a compound of the present invention.
  • Solvate as used herein means a physical association of a compound of the present invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In certain instances, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be capable of isolation. Solvent molecules in a solvate may exist in regular and/or disordered arrangements. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate” encompasses both solution phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • the "stereoisomerism" mentioned in the present invention is divided into conformational isomerism and configurational isomerism.
  • Configurational isomerism can also be divided into cis-trans isomerism and optical isomerism (ie optical isomerism).
  • cis-trans isomerism ie optical isomerism
  • optical isomerism ie optical isomerism
  • Stepoisomer means when the compounds of the present invention contain one or more asymmetric centers and are thus available as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers.
  • the compounds of the present invention have asymmetric centers, each of which produces two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereoisomeric mixtures and pure or partially pure compounds .
  • the compounds described herein may exist in tautomeric forms having different points of attachment of the hydrogen through displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention.
  • Enantiomers, diastereomers, racemates, mesomers, cis-trans isomers, tautomers, geometric isomers, epimers of all compounds of formula (I) Constructs and mixtures thereof, etc., are all included in the scope of the present invention.
  • Isotopic derivatives of the present invention refer to molecules in which compounds are isotopically labeled in this patent.
  • Isotopes commonly used as isotopic labels are: hydrogen isotopes, 2 H and 3 H; carbon isotopes: 11 C, 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotopes: 18 F; iodine isotopes: 123 I and 125 I; nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S.
  • isotopically labeled compounds can be used to study the distribution of medicinal molecules in tissues.
  • deuterium 3 H and carbon 13 C are more widely used because of their ease of labeling and detection. Substitution of certain heavy isotopes, such as deuterium ( 2 H), can enhance metabolic stability, prolong half-life and thus provide therapeutic advantages for the purpose of reducing dosage.
  • Isotopically-labeled compounds are generally synthesized from labeled starting materials, and their synthesis is accomplished using known synthetic techniques as for non-isotopically-labeled compounds.
  • the present invention also provides the use of the compound of the present invention in the preparation of a medicament for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.
  • the present invention provides a pharmaceutical composition for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, comprising the present invention compound as active ingredient.
  • the present invention provides a method for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, comprising: A mammal in need thereof is administered a compound of the present invention.
  • inflammatory, autoimmune, and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis , other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related disorders, psoriasis, eczema, dermatitis, atopic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS) , pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjögren's syndrome, autoimmune thyroid disease, urticaria (rubella), multiple sclerosis
  • cancers or tumors may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer , colon cancer, familial adenomatous polyposis cancer, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as Glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neurona
  • therapeutic agents for the treatment of inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, steroidal drugs (eg, prednisone, prednisone, methylhydroponil) sone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNF ⁇ agents (eg, etanercept, infliximab, adalix monoclonal antibodies, etc.), calcineurin inhibitors (eg, tacrolimus, pimecrolimus, etc.), and antihistamines (eg, diphenhydramine, hydroxyzine, loratadine, ebaz) Cetirizine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one therapeutic agent selected from them may be included in the pharmaceutical composition of the present invention.
  • steroidal drugs
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an active ingredient in an effective amount ranging from 0.1 to 2,000 mg/kg body weight/day, in mammals including humans (about 70 kg body weight), Preferably from 1 to 1,000 mg/kg body weight/day, and administered in single or 4 divided doses per day, or on/off schedule.
  • the dosage of the active ingredient can be adjusted according to a number of relevant factors, such as the condition of the subject to be treated, the type and severity of the disease, the rate of administration, and the opinion of the physician. In some cases, amounts less than the above doses may be appropriate. An amount greater than the above dose may be used if it does not cause adverse side effects and the amount may be administered in divided doses per day.
  • the present invention also provides a method for preventing and/or treating tumors, cancer, viral infections, organ transplant rejection, neurodegenerative diseases, attention-related diseases or autoimmune diseases, comprising A compound of the present invention or a pharmaceutical composition of the present invention is administered to a mammal in need thereof.
  • compositions of the present invention may be formulated according to any of conventional methods into dosage forms such as tablets, granules, powders for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes, intratumoral injection) , capsules, syrups, emulsions, microemulsions, solutions or suspensions.
  • the compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis, using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or by variations thereof known to those skilled in the art.
  • Compounds of the present invention were synthesized. Preferred methods include, but are not limited to, those described below. Reactions are carried out in a solvent or solvent mixture suitable for the kit materials used and for the transformation being effected.
  • Those skilled in the art of organic synthesis will understand that the functionality present on the molecule is consistent with the proposed transformation. This sometimes requires the discretion to alter the order of synthetic steps or starting materials to obtain the desired compounds of the invention.
  • the present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, and which may be isolated as a mixture of isomers or as separate isomeric forms.
  • the compounds of the present invention can be isolated in optically active or racemic forms.
  • the compounds of the present invention may exist in various tautomeric forms in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are thereby rearranged. It is to be understood that all tautomeric forms that may exist are encompassed by the present invention.
  • the definitions of the substituents of the present invention are each independent rather than interrelated, for example, for R a (or R a ') in a substituent, it is independent in the definitions of different substituents .
  • selecting a definition for Ra (or Ra ') in one substituent does not mean that Ra (or Ra ') has the same definition in other substituents.
  • NR a R a ' when the definition of R a (or R a ') is selected from hydrogen, it does not mean that in -C(O)-NR In a R a ', R a (or R a ') must be hydrogen.
  • substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halo, hydroxy, alkane oxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine groups (wherein the 2 amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio group, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylthiocarbonyl, alkylthiocarbonyl, alkylthiocarbonyl, alkylthio
  • alkyl or “alkylene” as used herein are intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms.
  • C1 - C6 alkyl means an alkyl group having 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (eg n-propyl and isopropyl), butyl (eg n-butyl, isobutyl, tert-butyl) and Pentyl (eg n-pentyl, isopentyl, neopentyl).
  • alkenyl refers to a straight or branched chain hydrocarbon group containing one or more double bonds and usually 2 to 20 carbon atoms in length.
  • C2-C6 alkenyl contains two to six carbon atoms.
  • Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
  • alkynyl refers to a straight or branched chain hydrocarbon group containing one or more triple bonds and usually 2 to 20 carbon atoms in length.
  • C2 - C6alkynyl contains two to six carbon atoms.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like.
  • alkoxy refers to -O-alkyl.
  • C 1 -C 6 alkoxy (or alkyloxy) is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), and t-butoxy.
  • alkylthio or “thioalkoxy” represents an alkyl group, as defined above, having the indicated number of carbon atoms attached through a sulfur bridge; eg, methyl-S- and ethyl-S-.
  • aryl alone or as part of a larger moiety such as “aralkyl”, “aralkoxy” or “aryloxyalkyl”, refers to a single ring having a total of 5 to 12 ring members , bicyclic or tricyclic ring systems, wherein at least one ring in the system is aromatic and wherein each ring in the system contains from 3 to 7 ring members.
  • aryl refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene base.
  • aralkyl or "arylalkyl” refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, and the like. A fused aryl group can be attached to another group at a suitable position on the cycloalkyl or aromatic ring. For example, dashed lines drawn from a ring system indicate that the bond may be attached to any suitable ring atom.
  • cycloalkyl refers to a monocyclic or bicyclic cyclic alkyl group, preferably having 3 to 8 ring members.
  • a monocyclic cyclic alkyl group refers to a C3 - C8 cyclic alkyl group, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl.
  • Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl".
  • Bicyclic cyclic alkyl groups include bridged, spiro or fused ring cycloalkyl groups.
  • cycloalkenyl refers to a monocyclic or bicyclic cyclic alkenyl group, preferably having 3 to 8 ring members.
  • Monocyclic cyclic alkenyl refers to C3 - C8 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornyl.
  • Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl".
  • Bicyclic cyclic alkenyl groups include bridged, spiro or fused ring cyclic alkenyl groups.
  • Halo or halogen includes fluorine, chlorine, bromine and iodine.
  • Haloalkyl is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with 1 or more halogens, preferably 1, 2 or 3 halogens.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoroethyl propyl and heptachloropropyl.
  • haloalkyl groups also include "fluoroalkyl groups" intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (preferably 1 to 6 carbon atoms) substituted with 1 or more fluorine atoms.
  • Haloalkoxy or "haloalkyloxy” means a haloalkyl group, as defined above, having the indicated number of carbon atoms (preferably 1 to 6 carbon atoms) attached through an oxygen bridge.
  • haloC1 - C6alkoxy is intended to include C1 , C2 , C3, C4 , C5 , C6 haloalkoxy .
  • haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy.
  • haloalkylthio or “thiohaloalkoxy” represents a haloalkyl group as defined above having the indicated number of carbon atoms (preferably 1 to 6 carbon atoms) attached through a sulfur bridge; eg trifluoromethyl base-S- and pentafluoroethyl-S-.
  • C x1 -C x2 is used when referring to some substituent groups, which means that the number of carbon atoms in the substituent groups may be x1 to x2.
  • C 0 -C 8 indicates that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • C 1 -C 8 indicates that the group contains 1, 2, 3 , 4, 5, 6, 7 or 8 carbon atoms
  • C 2 -C 8 means the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • C 3 -C 8 means the group
  • the group contains 3, 4, 5, 6, 7 or 8 carbon atoms
  • C 4 -C 8 means the group contains 4, 5, 6, 7 or 8 carbon atoms
  • C 0 -C 6 means the A group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms
  • C 1 -C 6 means the group contains 1, 2, 3, 4, 5 or 6 carbon atoms
  • C 2 -C 6 indicates that the group contains 2, 3, 4, 5 or 6 carbon atoms
  • C3 - C6
  • x1-x2 membered ring is used when referring to cyclic groups (eg, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), which refers to the ring atoms of the group The number may be x1 to x2.
  • cyclic groups eg, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl
  • the 3-12 membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 3-6 membered ring means that the cyclic group can be a 3, 4, 5 or 6 membered ring, and the number of ring atoms can be 3, 4, 5 or 6 ; 3-8 membered ring means that the cyclic group can be a 3, 4, 5, 6, 7 or 8 membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7 or 8; 3-9 Ring member means that the cyclic group can be a 3, 4, 5, 6, 7, 8 or 9 membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8 or 9; 4-7 Ring member means that the cyclic group can be 4, 5, 6 or 7 membered ring, and the number of ring atoms can be 4, 5, 6 or 7; 5-8 membered ring means that the cyclic
  • the ring atoms may be carbon atoms or heteroatoms, eg heteroatoms selected from N, O and S.
  • the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, eg selected from N, O and S of heteroatoms.
  • the one or more halogens may each be independently selected from fluorine, chlorine, bromine, and iodine.
  • heteroaryl means a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, 12-membered Aromatic polycyclic heterocycles, which are fully unsaturated, partially unsaturated, and which contain carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and include Any of the following polycyclic groups wherein any heterocycle as defined above is fused to a benzene ring. Nitrogen and sulfur heteroatoms can optionally be oxidized. Nitrogen atoms are substituted or unsubstituted (ie, N or NR, where R is H or, if defined, another substituent).
  • Heterocycles can be attached to their pendant groups at any heteroatom or carbon atom that results in a stable structure.
  • the heterocyclyl groups described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable.
  • the nitrogens in the heterocycle may be optionally quaternized.
  • the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in the heterocycle is not greater than one.
  • heterocycle it is intended to include heteroaryl groups.
  • heteroaryl groups include, but are not limited to, acridinyl, azetidinyl, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxanyl azolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carboline, chromanyl, chromenyl, cinnoline, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2, 3-b] tetrahydrofuranyl, furanyl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-
  • heteroaryl may also include biaryl structures formed by the above-defined “aryl” and a monocyclic “heteroaryl”, such as, but not limited to, "-phenylbipyridyl-", “- Phenylbipyrimidinyl”, “-pyridylbiphenyl”, “-pyridylbipyrimidinyl-”, “-pyrimidinylbiphenyl-”; wherein the present invention also includes fused rings containing, for example, the above heterocycles and Spiro compounds.
  • heterocycloalkyl refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes spiroheterocycles or bridged heterocycloalkyls.
  • Monocyclic heterocycloalkyl refers to a 3-8 membered cyclic alkyl system containing at least one saturated or unsaturated but non-aromatic alkyl group selected from O, N, S, P.
  • a bicyclic heterocycloalkyl system refers to a heterocycloalkyl group fused to a phenyl group, or a cycloalkyl group, or a cycloalkenyl group, or a heterocycloalkyl group, or a heteroaryl group.
  • bridged cycloalkyl refers to polycyclic compounds that share two or more carbon atoms. It can be divided into bicyclic bridged cyclic hydrocarbons and polycyclic bridged cyclic hydrocarbons.
  • the former consists of two alicyclic rings sharing more than two carbon atoms; the latter is a bridged cyclic hydrocarbon consisting of three or more rings.
  • spirocycloalkyl refers to polycyclic hydrocarbons in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings.
  • bridged heterocyclic group refers to a polycyclic compound sharing two or more carbon atoms, and the ring contains at least one atom selected from O, N and S. It can be divided into bicyclic bridged heterocycles and polycyclic bridged heterocycles.
  • heterospirocyclyl refers to polycyclic hydrocarbons in which a single carbon atom (called a spiro atom) is shared between single rings, and the ring contains at least one atom selected from O, N and S.
  • substituted means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valences are maintained and the substitution results in a stable compound.
  • nitrogen atoms eg, amines
  • these nitrogen atoms can be converted to N-oxides by treatment with oxidizing agents (eg, mCPBA and/or hydrogen peroxide) to obtain other compounds of the present invention .
  • oxidizing agents eg, mCPBA and/or hydrogen peroxide
  • both shown and claimed nitrogen atoms are considered to encompass both the shown nitrogen and its N-oxides to obtain the derivatives of the present invention.
  • any variable occurs more than once in any composition or formula of a compound, its definition at each occurrence is independent of its definition at each other occurrence.
  • the group may be optionally substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R.
  • substituents and/or variables are only permissible if such combinations result in stable compounds.
  • patient refers to an organism treated by the methods of the present invention.
  • organisms preferably include, but are not limited to, mammals (eg, murine, simian/monkey, equine, bovine, porcine, canine, feline, etc.) and most preferably refer to humans.
  • the term "effective amount” means the amount of a drug or agent (ie, a compound of the invention) that will elicit the biological or medical response of a tissue, system, animal or human, eg, sought by a researcher or clinician.
  • therapeutically effective amount means an amount that results in improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or a reduction in the incidence of a disease, as compared to a corresponding subject not receiving such amounts or the rate of progression of the disease.
  • An effective amount can be administered in one or more administrations, administrations or doses and is not intended to be limited by a particular formulation or route of administration. The term also includes within its scope an amount effective to enhance normal physiology.
  • treating includes any effect that results in amelioration of a condition, disease, disorder, etc., eg, alleviation, reduction, modulation, amelioration or elimination, or amelioration of symptoms thereof.
  • pharmaceutically acceptable refers to those compounds, substances, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without unduly toxic, irritating sexual, allergic reactions and/or other problems or complications and are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutical substance, composition or vehicle such as a liquid or solid filler, diluent, excipient, manufacturing aid (eg lubricants, talc, magnesium stearate, calcium stearate or zinc stearate or stearic acid) or a solvent encapsulating material which is involved in carrying or transporting a subject compound from one organ or part of the body to another organ or part of the body.
  • manufacturing aid eg lubricants, talc, magnesium stearate, calcium stearate or zinc stearate or stearic acid
  • solvent encapsulating material which is involved in carrying or transporting a subject compound from one organ or part of the body to another organ or part of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • composition means a composition comprising a compound of the present invention and at least one other pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” refers to a medium generally accepted in the art for delivering a biologically active agent to an animal, particularly a mammal, including (ie) adjuvants, excipients or vehicles such as diluents, preservatives , fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating and dispersing agents, depending on The mode of administration and the nature of the dosage form.
  • acceptable refers to a formulation component or active ingredient that does not have undue deleterious effects on the health of the general target of treatment.
  • cancer refers to an abnormal growth of cells that is uncontrollable and, under certain conditions, is capable of metastasizing (spreading). Cancers of this type include, but are not limited to, solid tumors (eg, bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (eg, thyroid), prostate , skin (melanoma), or blood tumor (eg, nonleukemic leukemia).
  • solid tumors eg, bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (eg, thyroid), prostate , skin (melanoma), or blood tumor (eg, nonleukemic leukemia).
  • co-administration refers to the administration of several selected therapeutic agents to a patient, administered in the same or different administrations at the same or different times.
  • enhancing refers to the ability of a desired result to be increased or prolonged, either in potency or duration.
  • the term “enhancer” refers to the drug's ability to increase or prolong the potency or duration of the drug in the system.
  • potency value refers to the ability to maximize the ability of another therapeutic agent in an ideal system.
  • immune disease refers to a disease or condition of an adverse or deleterious response to an endogenous or exogenous antigen.
  • the result is usually the dysfunction of cells, or the destruction and dysfunction of the cells, or the destruction of organs or tissues that may produce immune symptoms.
  • subject or “patient” includes mammals and non-mammals.
  • Mammals include, but are not limited to, mammals: humans, non-human primates such as orangutans, apes and monkeys; agricultural animals such as cattle, horses, goats, sheep, pigs; livestock such as rabbits, dogs; laboratory animals including rodents, Such as rats, mice and guinea pigs.
  • Non-mammalian animals include, but are not limited to, birds, fish, and the like.
  • the selected mammal is a human.
  • treatment include alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of a disease or symptom, Such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing and/or treating symptoms caused by a disease or symptom.
  • a compound or pharmaceutical composition when administered, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, conditions may be attributable to or associated with the administration.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, ear canal , nasal administration and topical administration.
  • parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary, ventricular, intraperitoneal, intralymphatic, and intranasal.
  • the compounds described herein are administered locally rather than systemically.
  • the depot formulation is administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is administered by a targeted drug delivery system.
  • liposomes encapsulated by organ-specific antibodies In this particular embodiment, the liposomes are selectively targeted to specific organs and absorbed.
  • the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the present invention formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally a one or more of the other therapeutic agents described above.
  • the compounds of the present invention may be administered for any of the above uses by any suitable means, eg orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingual; buccal; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (eg, in sterile injectable aqueous or non-aqueous solutions or suspensions liquid); nasally, including administration to nasal membranes, such as by inhalation spray; topically, such as in cream or ointment; or rectally, such as in suppository; or by intratumoral injection.
  • suitable means eg orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions
  • Pharmaceutically acceptable carriers are formulated according to a number of factors within the purview of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to which the composition containing the active agent is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media and various solid and semisolid dosage forms.
  • Such carriers may include many different ingredients and additives in addition to the active agent, which are included in the formulation for various reasons known to those skilled in the art, such as stabilizing the active agent, binders, and the like.
  • suitable pharmaceutical carriers and factors involved in carrier selection can be found in a number of readily available sources such as Allen L.V.Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012 ), Pharmaceutical Press.
  • dosage regimens for the compounds of the present invention will vary depending on known factors, such as the pharmacodynamic properties of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition and weight of the recipient. nature and extent of symptoms; type of concomitant treatment; frequency of treatment; route of administration, renal and hepatic function of the patient, and desired effect.
  • the daily oral dose of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably, when used for the indicated effect Typically from about 0.1 mg/day to about 250 mg/day.
  • the most preferred intravenous dose should be from about 0.01 mg/kg/minute to about 10 mg/kg/minute.
  • the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
  • the compounds are usually in the form of suitable pharmaceutical diluents, excipients or carriers (herein) appropriately selected according to the intended form of administration (eg, oral tablets, capsules, elixirs and syrups) and consistent with conventional pharmaceutical practice. are administered in the form of a mixture of drug carriers).
  • Dosage forms suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit.
  • the active ingredient will generally be present in an amount of about 0.1-95% by weight, based on the total weight of the composition.
  • a typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and packaged into size 1 gelatin capsules.
  • a typical injectable formulation can be prepared by aseptically placing at least one compound of the invention (250 mg) in a vial, aseptically lyophilizing and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline to produce an injectable formulation.
  • compositions comprising, either alone or in combination with a pharmaceutical carrier, a therapeutically effective amount of at least one compound of the present invention as an active ingredient.
  • the compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (eg, anticancer agents or other pharmaceutically active substances).
  • the compounds of the present invention (which may be used in a suitable hydrated form) and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art.
  • the actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response, composition, and mode of administration for a particular patient, without being toxic to the patient.
  • the dose level selected will depend on a variety of factors, including the activity of the particular compound of the invention or its ester, salt or amide employed; the route of administration; the time of administration; the rate of excretion of the particular compound employed; the rate and extent of absorption duration of treatment; other drugs, compounds and/or substances used in combination with the particular compound used; factors well known in the medical arts such as age, sex, weight, condition, general health and previous medical history of the patient being treated.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition.
  • a physician or veterinarian may initiate a dose of a compound of the present invention used in a pharmaceutical composition at a level lower than that required and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the present invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect.
  • Such an effective dose will generally depend on the factors discussed above.
  • oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of the invention for patients will range from about 0.01 to about 50 mg/kg body weight/day.
  • an effective daily dose of the active compound may be administered separately in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form.
  • the dosing is once a day.
  • kits/Product Packaging are preferred to administer the compounds in the form of a pharmaceutical formulation (composition).
  • Kits/product packaging are also described herein for use in the treatment of the above-mentioned indications. These kits may consist of a transporter, a pack, or a case of containers, which may be divided into compartments to accommodate one or more containers, such as vials, test tubes, and the like, each container containing the a single component of the method described above. Suitable containers include bottles, vials, syringes and test tubes, among others. Containers are made of acceptable materials such as glass or plastic.
  • the container may contain one or more of the compounds described herein, which may be present as pharmaceutical components or in admixture with other ingredients described herein.
  • the container may have a sterile outlet (eg, the container may be an IV pack or bottle, the stopper being pierced by a hypodermic needle).
  • kits may carry a compound, along with instructions for use, labeling, or operating instructions as described herein.
  • a typical kit may include one or more containers, each containing one or more materials (such as reagents, or concentrated stock solutions, and/ or equipment). These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, dispensers, bags, containers, vials and/or tubes, with a list of contents and/or instructions for use, and instructions for the inner packaging. The entire set of instructions is to be included.
  • materials include, but are not limited to, buffers, diluents, filters, needles, syringes, dispensers, bags, containers, vials and/or tubes, with a list of contents and/or instructions for use, and instructions for the inner packaging. The entire set of instructions is to be included.
  • Labels can be displayed on or closely associated with the container.
  • the presence of a label on a container means that the letters, numbers or other features of the label are affixed, molded, or engraved on the container; the label may also appear in a container box or shipping box containing a variety of containers, such as in product inserts.
  • a label may be used to indicate a specific therapeutic use of the contents.
  • the label may also indicate instructions for use of the contents, such as described in the above method.
  • the unit in the weight volume percentage in the present invention is well known to those skilled in the art, for example, it refers to the weight of the solute in 100 ml of the solution. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Methods and materials for preferred embodiments described herein are provided for illustrative purposes only.
  • the raw materials and reagents used in the present invention are all known products, which can be synthesized according to methods known in the art, or can be obtained by purchasing commercially available products. None of the commercially available reagents were used without further purification.
  • Room temperature refers to 20-30°C.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L.
  • microwave reaction use Initiator+ microwave reactor.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the measurement of LC-MS was performed using a Thermo liquid mass spectrometer (UltiMate 3000+MSQ PLUS).
  • a Thermo high pressure liquid chromatograph (UltiMate 3000) was used.
  • Preparative Reversed Phase Chromatography A Thermo (UltiMate 3000) Preparative Reversed Phase Chromatograph was used.
  • Fast column chromatography uses AIJER (FS-9200T) automatic column passing machine, and silica gel prepacked column uses Santai Prepacked columns.
  • the thin layer chromatography silica gel plate is made of Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications of the thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
  • the first step 1-methyl-3,5-dinitropyridin-2-one Int-1a (1.0 g, 5.02 mmol) was dissolved in methanol (50 mL), followed by adding ammonia methanol solution (7 mol/L, 8.61 mL, 60.27 mmol) and 1-methylpiperidin-4-one Int-1b (625 mg, 5.52 mmol).
  • the reaction mixture was heated to 50°C and stirred for 5 hours. After cooling to room temperature, it was left to stand for 48 hours, the reaction solution was concentrated under reduced pressure, and the residue was added with ethyl acetate (50 mL), followed by filtration.
  • the second step The compound Int-1c (1.0 g) obtained in the previous step was dissolved in methanol (30 mL), 10% Pd-C (400 mg) was added, and the reaction was carried out at room temperature for 6 hours under a hydrogen atmosphere. The palladium carbon was removed by filtration, and the filtrate was concentrated to obtain Int-1d as a yellow solid (800 mg, yield 94.70%).
  • the third step Compound Int-1d (100 mg, 0.61 mmol) was dissolved in acetic acid (3 mL), N-bromosuccinimide (109 mg, 0.61 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to quench the reaction until no bubbles were generated, the aqueous phase was extracted with methanol/dichloromethane (1/20, 50 mL ⁇ 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound Int-1e (38 mg, 25% yield).
  • the first step Compound Int-1e (100 mg, 0.41 mmol) and trimethylcyclotriboroxane (148 mg, 1.19 mmol) were dissolved in dioxane (1.5 mL) and water (0.15 mL), and carbonic acid was added Potassium (171 mg, 1.24 mmol), Pd(dppf)Cl2 (30 mg , 0.041 mmol). After the reaction system was replaced with nitrogen, it was heated to 140° C. with a microwave and stirred for 1 hour. The reaction was cooled to room temperature, the reaction mixture was filtered through celite, and the filtrate was concentrated.
  • the first step Compound Int-1e (350 mg, 1.45 mmol) and potassium vinyl trifluoroborate (387 mg, 2.89 mmol) were dissolved in 1,4-dioxane (1.5 mL) and water (0.15 mL), Potassium carbonate (399 mg, 2.89 mmol) and Pd(dppf)Cl2 (105 mg , 0.14 mmol) were added. After the reaction system was replaced with nitrogen, it was heated to 120° C. with a microwave reactor and stirred for 1 hour.
  • the first step Compound Int-1e (100mg, 0.41mmol) was dissolved in a mixed solvent of toluene (3mL) and water (0.3mL), cyclopropylboronic acid (42mg, 0.49mmol), potassium phosphate (306mg, 1.45 mmol), tricyclohexylphosphine (23 mg, 0.082 mmol) and palladium acetate (9 mg, 0.041 mmol). After the reaction system was replaced with nitrogen, it was heated to 100°C and stirred for 18 hours.
  • N-tert-butoxycarbonyl-4-piperidinone Int-6a (4.4 g, 22.1 mmol) and 1-methyl-3,5-dinitro-2-pyridone Int-1a (4.0 g, 20.1 mmol) was dissolved in methanol (150 mL) and ammonia in methanol (7N, 34.4 mL, 240.8 mmol) was added. Stir at 60°C for 6 hours under nitrogen protection. The reaction solution was cooled to room temperature, and stirring was continued for 2 days.
  • the third step Compound Int-6c (3.7 g, 14.8 mmol) was dissolved in DMF (20 mL), and N-bromosuccinimide (2.78 g, 15.6 mmol) and acetic acid (370 mg) were added. The reaction mixture was stirred at room temperature for 2 hours and completed by LCMS. Water (100 mL) was added, the aqueous phase (150 mL*3) was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography to obtain a yellow solid Int- 6d (3.6 g, 74% yield). ESI-MS (m/z): 328.2 [M+H] + .
  • the fourth step Compound Int-6d (500 mg, 1.53 mmol) was dissolved in methanol (5 mL), and sodium methoxide methanol solution (5N, 0.33 mL, 1.65 mmol) was added. The reaction mixture was heated to 100°C with microwave and stirred for 3 hours. The reaction was cooled to room temperature, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography to obtain Int-6 as a yellow solid (330 mg, yield 77%). ESI-MS (m/z): 280.2 [M+H] + .
  • Compound 1 was prepared by the following steps:
  • the first step 2,4,5-trichloropyrimidine 1a (57 mg, 0.31 mmol) and 3-(aminomethyl)-1-methyl-1,2-dihydropyridin-2-one hydrochloride 1b (50 mg, 0.28 mmol) and dissolved in isopropanol (2 mL) and N,N-diisopropylethylamine (85 mg, 0.65 mmol, 0.11 mL) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction solution was filtered, the solid was washed with isopropanol, and dried to obtain a white solid 1c (62 mg, yield 75%). ESI-MS (m/z): 285.2 [M+H] + .
  • the second step Compound 1c (62 mg, 0.21 mmol) and Int-1 (42 mg, 0.21 mmol) were dissolved in 1,4-dioxane (5 mL), and BrettPhos Pd G3 (19 mg, 0.021 mmol) was added, BrettPhos (23 mg, 0.043 mmol) and cesium carbonate (141 mg, 0.43 mmol), the reaction system was heated to 100° C. and stirred for 18 hours after replacing nitrogen. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated.
  • Compound 6 was prepared by the following steps:
  • Step 1 To a suspension of sodium hydride (202 mg, 5.06 mmol, content 60%) in DMF (5 mL) at 0°C in an ice bath and nitrogen atmosphere, compound 6a (500 mg, 3.37 mmol) in DMF (5 mL) was added solution. After stirring for 30 minutes, iodomethane (718 mg, 5.06 mmol, 0.31 mL) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, and washed with water and saturated brine in this order.
  • Second step Compound 6b (230 mg, 1.42 mmol) was dissolved in methanol (5 mL), Raney Ni (0.5 mL, aqueous suspension) and ammonia (0.5 mL) were added. The mixture was stirred at room temperature under an atmosphere of hydrogen (hydrogen balloon) for 16 hours. The reaction solution was filtered with celite, the filter cake was washed with methanol, and the filtrate was concentrated to obtain compound 6c (200 mg), which was directly used in the next reaction. ESI-MS (m/z): 167.1 [M+H] + .
  • the fourth step Compound 6d (71 mg, 0.22 mmol) and Int-1 (40 mg, 0.20 mmol) were dissolved in 1,4-dioxane (4 mL), cesium carbonate (202 mg, 0.62 mmol) was added, BrettPhos ( 22 mg, 0.041 mmol) and BrettPhos Pd G3 (18 mg, 0.020 mmol). After the reaction system was replaced with nitrogen, it was heated to 100°C and stirred for 16 hours.
  • the first step Compound 9a (700 mg, 5.83 mmol) was dissolved in DMF (10 mL), cesium carbonate (2.28 g, 6.99 mmol) was added, and then iodoethane (1.36 g, 8.74 mmol, 0.70 mL) was added dropwise, and the reaction was carried out. The mixture was stirred at room temperature overnight. The reaction solution was diluted with water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • Second step Compound 9b (100 mg, 0.67 mmol) was dissolved in methanol (5 mL), Raney Ni (0.3 mL, aqueous suspension) and ammonia (1 mL) were added. The mixture was stirred at room temperature under a hydrogen atmosphere (hydrogen balloon) overnight. The reaction solution was filtered with celite, the filter cake was washed with methanol, and the filtrate was concentrated to obtain compound 9c (100 mg), which was directly used in the next reaction.
  • the third step Compound 9c (100 mg) was dissolved in isopropanol (5 mL), and N,N-diisopropylethylamine (169 mg, 1.31 mmol, 0.23 mL) and 2,4,5-trichloropyrimidine were added 1a (180 mg, 0.98 mmol), the reaction mixture was stirred at room temperature overnight. The reaction solution was filtered, and the filter cake was washed with isopropanol and dried to obtain 9d (100 mg) as a white solid.
  • ESI-MS (m/z): 299.2 [M+H] + .
  • Compound 19 was prepared by the following steps:
  • the second step The crude 19a obtained in the previous step (300 mg) was dissolved in acetonitrile (5 mL), and p-toluenesulfonic acid monohydrate (323 mg, 1.70 mmol) was added. The reaction mixture was warmed to 70°C and stirred for 2 hours. The reaction solution was concentrated to obtain a crude product of compound 19 (240 mg), 20 mg of which was purified by reverse-phase preparative HPLC to obtain compound 19 (1 mg).
  • Compound 21 was prepared by the following steps:
  • Step 1 Dissolve 3-bromo-2-hydroxy-5-methylpyridine 21a (200mg, 1.06mmol) in tetrahydrofuran (5mL), add NaH (50mg, 1.28mmol, content 60%) at 0°C, The reaction solution was stirred for 30 minutes. Iodomethane (227 mg, 1.60 mmol) was added dropwise to the reaction solution, and the reaction solution was further stirred at 0°C for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • the third step Compound 21c (120 mg, 0.81 mmol) was dissolved in methanol (5 mL) and ammonia water (0.5 mL), Raney Nickel (0.3 mL, aqueous suspension) and BOC anhydride (212 mg, 0.97 mmol) were added, and the mixture was Stir overnight at room temperature under a hydrogen atmosphere (hydrogen balloon). The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was dissolved in 4N hydrochloric acid dioxane solution (5 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain the crude product of compound 21d, which was directly used in the next reaction. ESI-MS (m/z): 153.8 [M+H] + .
  • the fifth step Compound 21e (50mg, 0.17mmol) and Int-1 (36mg, 0.18mmol) were dissolved in 1,4-dioxane (5mL), BrettPhos G3Pd (15mg, 17umol), BrettPhos (9mg , 17umol) and cesium carbonate (109mg, 0.34mmol).
  • the reaction system was replaced with nitrogen and then heated to 100°C and stirred overnight. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated.
  • Compound 23 was prepared by the following steps:
  • Step 1 Dissolve 3-bromo-2-hydroxy-4-methylpyridine 23a (200mg, 1.06mmol) in tetrahydrofuran (5mL), add NaH (50mg, 1.28mmol, content 60%) at 0°C, The reaction solution was stirred for 30 minutes. Iodomethane (227 mg, 1.60 mmol) was added dropwise to the reaction solution, and the reaction solution was further stirred at 0°C for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • the third step Compound 23c (143 mg, 0.97 mmol) was dissolved in methanol (5 mL) and ammonia water (0.5 mL), Raney Nickel (0.3 mL, aqueous suspension) and BOC anhydride (253 mg, 1.16 mmol) were added, and the mixture was Stir overnight at room temperature under a hydrogen atmosphere (hydrogen balloon). The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was dissolved in 4N hydrochloric acid dioxane solution (5 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain the crude product of compound 23d, which was directly used in the next reaction. ESI-MS (m/z): 153.5 [M+H] + .
  • the fifth step Compound 23e (50mg, 0.17mmol) and Int-1 (32mg, 0.17mmol) were dissolved in 1,4-dioxane (5mL), BrettPhos G3Pd (15mg, 17umol), BrettPhos (9mg , 17umol) and cesium carbonate (109mg, 0.34mmol).
  • the reaction system was replaced with nitrogen and then heated to 100°C and stirred overnight. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated.
  • Compound 24 was prepared by the following steps:
  • the first step compound 3-(hydroxymethyl)pyrrolidin-2-one 24a (258 mg, 2.24 mmol), phthalimide (362 mg, 2.4, 7 mmol) and triphenylphosphine (646 mg, 2.47 mmol) mmol) was dissolved in THF (5 mL), and diisopropyl azodicarboxylate (498 mg, 2.47 mmol, 0.48 mL) was slowly added dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction was complete by LCMS. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain white solid 24b (335 mg, yield 61%). ESI-MS (m/z): 245.5 [M+H] + .
  • the fourth step Compound 24d (54 mg, 0.20 mmol) and Int-1 (40 mg, 0.20 mmol) were dissolved in 1,4-dioxane (4 mL), cesium carbonate (134 mg, 0.41 mmol) was added, BrettPhos ( 22 mg, 0.041 mmol) and BrettPhos Pd G3 (18 mg, 0.020 mmol). After the reaction system was replaced with nitrogen, it was heated to 110°C and stirred for 16 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated, and the residue was purified by preparative thin layer chromatography to obtain the crude product, which was then separated by reverse preparative HPLC to obtain compound 24 (17 mg, yield 20%).
  • Compound 27 was prepared by the following steps:
  • the first step Compound 27a (500 mg, 4.06 mmol) was dissolved in DMF (5 mL), cesium carbonate (1.59 g, 4.87 mmol) and methyl iodide (692 mg, 4.87 mmol) were added under ice bath at 0 °C, and the reaction rose to Stir at room temperature for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL*2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • the sixth step Compound Int-1 (20 mg, 0.10 mmol) and compound 27f (31 mg, 0.10 mmol) were dissolved in 1,4-dioxane (3 mL), cesium carbonate (67 mg, 0.20 mmol) was added, BrettPhos (11 mg, 0.020 mmol) and BrettPhos Pd G3 (9 mg, 0.010 mmol). The reaction mixture was replaced with nitrogen and then heated to 100°C with stirring for 18 hours.
  • Test Example 1 Detection of the ability of compounds to inhibit HPK1 kinase activity (Method 1)
  • the required reagents are as follows
  • the specific operations are as follows: configure the enzymatic reaction system buffer (10mM MOPS, pH 7.2, 5mM ⁇ -glycerol-phosphate, 10mM MgCl2, 0.8mM EDTA, 2mM EGTA, 0.1mM DTT); test compounds (1mM in DMSO) Compound stock solution) was diluted with buffer to a maximum concentration of 60uM (containing 6% DMSO), and prepared a 60 ⁇ M concentration starting with a 5-fold dilution with a buffer containing 6% DMSO for a total of 8 point gradient concentrations of compounds; then The HPK1 kinase was diluted to 30 nM with buffer.
  • reaction substrate (10 ⁇ M MBP and 20 ⁇ M ATP dissolved in distilled water)
  • reaction substrate 10 ⁇ M MBP and 20 ⁇ M ATP dissolved in distilled water
  • the enzymatic reaction activity was detected by ADP-Glo Kinase Assay Kit, ADP - Glo Kinase Assay Kit assays are performed according to the kit's operating instructions. Data are described using the compound's median inhibitory concentration IC50.
  • Test Example 2 Detection of agonistic ability of compounds to secrete cytokine interleukin-2 (IL-2) by Jurkat cells (Method 2)
  • the required reagents and cells are as follows
  • the specific operations are as follows: dissolve the compound powder to 10 mM with DMSO, add 2 ⁇ l of the compound to 998 ⁇ l of RPMI 1640 medium (both in this test containing 10% FBS), and vortex to mix the highest concentration point.
  • the compound solution was gradually diluted 3-fold with 0.2% DMSO medium for a total of 8 concentration points.
  • the control was treated with RPMI 1640 medium solution containing 0.1% DMSO.
  • 1 ⁇ 105 Jurkat E6-1 cells were added to each well of a Corning 96-well cell culture plate (Cat. No. 3599), followed by an equal volume of compound dilutions.
  • the control group was added RPMI 1640 medium containing 0.2% DMSO, and placed in 37 Incubate for 1 h in a cell incubator (Thermo Fisher Scientific, model: 3111). Then, the final concentrations of 1 ⁇ g/ml Anti-human CD3 Antibody and 1 ⁇ g/ml Anti-human CD28 Antibody were added and incubated in a 37°C cell incubator for 24 hours.
  • Human IL-2 DuoSet ELISA KIT was used to detect the IL-2 content in the cell supernatant, and the Human IL-2 DuoSet ELISA detection was carried out according to the operating instructions of the kit. Data are described as the highest fold ratio of the stimulation signal of the compound to the signal of 0.1% DMSO.
  • Test Example 3 Detection of the agonistic ability of compounds to secrete cytokine interleukin-2 (IL-2) by human PBMC cells (Method 3)
  • the required reagents are as follows
  • human PBMCs were taken out from liquid nitrogen according to standard operations, thawed and thawed in a water bath at 37°C, resuspended in RPMI 1640 medium (both containing 10% FBS in this test), and washed twice by centrifugation. ; Human PBMC cells were subsequently resuspended in RPMI 1640 medium for later use.
  • the compound powder was dissolved to 10 mM with DMSO, and 2 ⁇ l of the compound was added to 998 ⁇ l of RPMI 1640 medium, and the highest concentration point was obtained after vortexing and mixing.
  • the compound solution was gradually diluted 3-fold with 0.2% DMSO medium for a total of 8 concentration points.
  • the control was treated with RPMI 1640 medium solution containing 0.1% DMSO.
  • 1 ⁇ 105 human PBMC cells were added to each well of a Corning 96-well cell culture plate (Cat. No. 3599), followed by an equal volume of compound diluents.
  • RPMI 1640 medium containing 0.2% DMSO was added, and the cells were placed at 37°C.
  • the cells were incubated in a cell incubator (Thermo Fisher Scientific, model: 3111) for 1 h.
  • the final concentrations of 0.01 ⁇ g/ml Anti-human CD3 Antibody and 1 ⁇ g/ml Anti-human CD28 Antibody were added, and incubated at 37°C for 24h.
  • Human IL-2 DuoSet ELISA KIT was used to detect the IL-2 content in the cell supernatant, and the Human IL-2 DuoSet ELISA detection was carried out according to the operating instructions of the kit. Data are described as the highest fold ratio of the stimulation signal of the compound to the signal of 0.1% DMSO.

Abstract

Provided are a compound, which has a structure of formula (I) and is capable of inhibiting HPK1 kinase activity, and a pharmaceutical composition comprising the compound. Further provided is the use of the compound in the prevention and/or treatment of cancers, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

Description

一种高活性的HPK1激酶抑制剂A highly active HPK1 kinase inhibitor
本申请要求于2021年4月8日提交到中国国家知识产权局的发明名称为“一种高活性的HPK1激酶抑制剂”的中国专利申请202110378424.1的优先权，其内容通过引用以整体并入本文。This application claims the priority of Chinese Patent Application No. 202110378424.1 filed on April 8, 2021 with the State Intellectual Property Office of the People's Republic of China, entitled "A Highly Active HPK1 Kinase Inhibitor", the contents of which are hereby incorporated by reference in their entirety. .
技术领域technical field
本发明涉及一种杂环化合物，具体地涉及一种高活性的HPK1激酶抑制剂及其用途。The present invention relates to a heterocyclic compound, in particular to a highly active HPK1 kinase inhibitor and use thereof.
背景技术Background technique
HPK1是MAP4K家族的成员之一，主要在造血***细胞中表达，并且充当T细胞增殖和信号传导的细胞内负调节物。抗原刺激T细胞后促使胞浆中的接头蛋白SLP-76被招募到脂膜TCR复合体上，为信号转导相关激酶提供结合位点来实现TCR介导的信号传递而诱导T细胞激活。在这一过程中HPK1被酪氨酸激酶Lck和Zap70磷酸化而激活，参与调节T细胞受体蛋白相互作用。HPK1通过磷酸化接头蛋白SLP-76的Ser376位点，使得SLP-76与支架蛋白14-3-3ε结合进而通过蛋白酶体被降解，而这一效应使得SLP-76与信号转导相关激酶结合减少而阻断了TCR信号转导，继而抑制T细胞激活和增值。另一方面，HPK1还参与了调控树突状细胞(DC)的成熟及激活，特别是抑制了DC细胞中协助T细胞激活相关蛋白如CD80，CD86及MHC复合物等的表达，进而影响DC调节T细胞激活的作用；而活化的DC对肿瘤抗原的呈递及DC和T细胞的相互协作是抗肿瘤免疫***中最重要的环节之一。此外在肿瘤微环境中存在大量免疫抑制性的分子如PGE2和TGF－β，这些因子介导的免疫抑制作用也与HPK1有重要联系。总体而言，特异性靶向抑制HPK1的小分子化合物可以改善T细胞功能，增强DC细胞功能并同时逆转肿瘤免疫抑制微环境，通过多途径来发挥增强抗肿瘤免疫效应，从而实现发挥抑制肿瘤生长的作用。HPK1, a member of the MAP4K family, is mainly expressed in cells of the hematopoietic system and acts as an intracellular negative regulator of T cell proliferation and signaling. After antigen stimulation of T cells, the adaptor protein SLP-76 in the cytoplasm is recruited to the lipid membrane TCR complex, providing binding sites for signal transduction-related kinases to achieve TCR-mediated signal transmission and induce T cell activation. In this process, HPK1 is activated by phosphorylation by the tyrosine kinases Lck and Zap70, and is involved in the regulation of T cell receptor protein interactions. HPK1 phosphorylates the Ser376 site of the adaptor protein SLP-76, so that SLP-76 binds to the scaffold protein 14-3-3ε and is degraded by the proteasome, and this effect reduces the binding of SLP-76 to signal transduction-related kinases It blocked TCR signal transduction, which in turn inhibited T cell activation and proliferation. On the other hand, HPK1 is also involved in regulating the maturation and activation of dendritic cells (DCs), especially inhibiting the expression of T-cell activation-related proteins such as CD80, CD86 and MHC complexes in DCs, thereby affecting DC regulation The role of T cell activation; the presentation of tumor antigens by activated DCs and the mutual cooperation between DCs and T cells is one of the most important links in the anti-tumor immune system. In addition, there are a large number of immunosuppressive molecules such as PGE2 and TGF-β in the tumor microenvironment, and the immunosuppressive effects mediated by these factors are also related to HPK1. Overall, small-molecule compounds that specifically target and inhibit HPK1 can improve T cell function, enhance DC cell function, and at the same time reverse the tumor immunosuppressive microenvironment. effect.
因此，现有技术中仍迫切需要有效的HPK1激酶活性抑制剂，以便为抗肿瘤提供更多有效的选择。Therefore, there is still an urgent need for effective inhibitors of HPK1 kinase activity in the prior art, in order to provide more effective options for anti-tumor.
发明内容SUMMARY OF THE INVENTION
本发明意外发现了一种具有抑制HPK1激酶活性的式(I)化合物以及其药学上可接受的盐或其立体异构体。因此，在第一个方面，本发明提供了具有式(I)结构的化合物或其药学上可接受的盐或其立体异构体：The present invention has unexpectedly discovered a compound of formula (I) and a pharmaceutically acceptable salt thereof or a stereoisomer thereof having HPK1 kinase inhibitory activity. Accordingly, in a first aspect, the present invention provides a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
Figure PCTCN2022085446-appb-000001
Figure PCTCN2022085446-appb-000001
其中in
X表示N或者CR 10； X represents N or CR 10 ;
R 1表示氢、C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基、卤代C 3-C 6环烷基、卤素、氰基或-C(O)NH 2； R 1 represents hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogenated C 3 -C 6 cycloalkyl, halogen, cyano or -C (O)NH 2 ;
R 2表示氢、卤素、羟基、(C 1-C 6)烷基、(C 2-C 6)烯基、-(C 0-C 6亚烷基)(C 3-C 8)环烷基、-(C 0-C 6亚烷基)(4-8元)杂环烷基、(C 1-C 6)烷氧基、(C 3-C 8)环烷基(C 0-C 6亚烷基)氧基、(4-8元)杂环烷基(C 0-C 6亚烷基)氧基； R 2 represents hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, -(C 0 -C 6 alkylene)(C 3 -C 8 )cycloalkyl , -(C 0 -C 6 alkylene) (4-8 membered) heterocycloalkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl (C 0 -C 6 ) alkylene)oxy, (4-8 membered)heterocycloalkyl(C 0 -C 6 alkylene)oxy;
R 3表示氢或C 1-C 6烷基、C 3-C 6烯基、C 3-C 6环烷基、羟基(C 1-C 6烷基)、卤代C 1-C 6烷基、4-8元杂环烷基； R 3 represents hydrogen or C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, hydroxy (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl , 4-8 membered heterocycloalkyl;
R 4表示氢或C 1-C 6烷基；并且所述C 1-C 6烷基可以任意地被选自以下的取代基所取代：卤素、-OR a、-SR a、-P(O)R aR b、-S(O) 2R a、-S(O)(NH)R a、-S(O)R a、-S(O) 2NR aR b、-C(O)NR aR b、-C(O)OH、-OC(O)NR aR b、-NR aC(O)R b、-NR a S(O) 2R b； R 4 represents hydrogen or C 1 -C 6 alkyl; and the C 1 -C 6 alkyl may be optionally substituted with a substituent selected from halogen, -OR a , -SR a , -P(O )R a R b , -S(O) 2 R a , -S(O)(NH)R a , -S(O)R a , -S(O) 2 NR a R b , -C(O) NR a R b , -C(O)OH, -OC(O)NR a R b , -NR a C(O) R b , -NR a S(O) 2 R b ;
R 5和R 5’各自独立地表示氢、C 1-C 6烷基、(C 2-C 6)烯基、卤素、卤代C 1-C 6烷基或羟基(C 1-C 6烷基)； R 5 and R 5' each independently represent hydrogen, C 1 -C 6 alkyl, (C 2 -C 6 )alkenyl, halogen, halogenated C 1 -C 6 alkyl or hydroxy (C 1 -C 6 alkane) base);
或者R 5与R 5’一起与与之相连的碳原子形成3-6元环，该环中还可以任意地含有0、1或2个选自N、O、S的杂原子； Or R 5 and R 5' together form a 3-6 membered ring with the carbon atom connected to it, and the ring can also optionally contain 0, 1 or 2 heteroatoms selected from N, O, S;
R 6和R 6’各自独立地表示氢、C 1-C 6烷基、(C 2-C 6)烯基、卤素、卤代C 1-C 6 烷基、羟基(C 1-C 6烷基)； R 6 and R 6' each independently represent hydrogen, C 1 -C 6 alkyl, (C 2 -C 6 )alkenyl, halogen, halogenated C 1 -C 6 alkyl, hydroxy (C 1 -C 6 alkane) base);
或者R 6与R 6’一起与与之相连的碳原子形成3-6元环，该环中还可以任意地含有0、1或2个选自N、O、S的杂原子； Or R 6 and R 6' together form a 3-6 membered ring with the carbon atom connected to it, and the ring can also optionally contain 0, 1 or 2 heteroatoms selected from N, O, and S;
p表示1或者2；p represents 1 or 2;
R 7和R 7’各自独立地表示氢、C 1-C 6烷基、(C 2-C 6)烯基、卤素、卤代C 1-C 6烷基、羟基(C 1-C 6烷基)； R 7 and R 7' each independently represent hydrogen, C 1 -C 6 alkyl, (C 2 -C 6 )alkenyl, halogen, halogenated C 1 -C 6 alkyl, hydroxy (C 1 -C 6 alkane) base);
或者R 7与R 7’一起与与之相连的碳原子形成3-6元环，该环中还可以任意地含有0、1或2个选自N、O、S的杂原子； Or R 7 and R 7' together form a 3-6 membered ring with the carbon atom connected to it, and the ring can also optionally contain 0, 1 or 2 heteroatoms selected from N, O, and S;
W表示
Figure PCTCN2022085446-appb-000002
W means
Figure PCTCN2022085446-appb-000002
其中，A表示
Figure PCTCN2022085446-appb-000003
Among them, A means
Figure PCTCN2022085446-appb-000003
Figure PCTCN2022085446-appb-000004
表示该环中含有单键或双键；
Figure PCTCN2022085446-appb-000004
Indicates that the ring contains a single bond or a double bond;
当A与A’之间的化学键为双键时，A’表示CR a或N，B表示CR b； When the chemical bond between A and A' is a double bond, A' represents CR a or N, and B represents CR b ;
当A与A’之间的化学键为单键时，A’表示CHR a，B表示CHR b或者不存在； When the chemical bond between A and A' is a single bond, A' represents CHR a , B represents CHR b or does not exist;
R 8和R 9各自独立地表示氢或C 1-C 6烷基；或者R 8与R 9可以与W 1和W 2一起构成3-6元环； R 8 and R 9 each independently represent hydrogen or C 1 -C 6 alkyl; or R 8 and R 9 may together with W 1 and W 2 form a 3-6 membered ring;
W 1表示C，W 2表示CH或N； W 1 means C, W 2 means CH or N;
R M和R N各自独立地表示氢或C 1-C 6烷基； R M and R N each independently represent hydrogen or C 1 -C 6 alkyl;
R 10表示氢、卤素、(C 1-C 6)烷基、(C 2-C 6)烯基、-(C 0-C 6亚烷基)(C 3-C 8)环烷基、-(C 0-C 6亚烷基)4-10元杂环烷基、-(C 0-C 6亚烷基)(C 6-C 10)芳基、-(C 0-C 6亚烷基)5-10元杂芳基， R 10 represents hydrogen, halogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, -(C 0 -C 6 alkylene)(C 3 -C 8 )cycloalkyl, - (C 0 -C 6 alkylene) 4-10 membered heterocycloalkyl, -(C 0 -C 6 alkylene) (C 6 -C 10 ) aryl, -(C 0 -C 6 alkylene ) 5-10 membered heteroaryl,
或者，当X表示CR 10时，R 10可以与相邻的R 2一起形成(5-10元)环烷基或者5-10元杂环烷基； Alternatively, when X represents CR 10 , R 10 may together with the adjacent R 2 form (5-10 membered) cycloalkyl or 5-10 membered heterocycloalkyl;
对于上述定义的环烷基、杂环烷基、芳基、杂芳基而言，其可以任意地被选自以下的0、1、2或3个取代基所取代：(C 1-C 6)烷基、(C 2-C 6)烯基、卤代(C 1-C 6)烷基、卤代(C 1-C 6)烷氧基、-(C 1-C 6亚烷基)-O-(C 1-C 6)烷基、(C 3-C 8)环烷基、卤代(C 3-C 8)环烷基、卤素、-CN、氧代、-NR aR b、-OR a、-SR a、-(C 1-C 6亚烷基)羟基、-C(O)R a、-N(R a)C(O)R a、-NR aC(O)OR a、-NR aSO 2R a、-C(O)OR a、-C(O)N R aR b、-S(O) 2N R aR b、-S(O)R a、-S(O) 2R a、-P(O)R aR b； For cycloalkyl, heterocycloalkyl, aryl, heteroaryl as defined above, it may be optionally substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: (C 1 -C 6 ) alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, -(C 1 -C 6 alkylene) -O-(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, halo(C 3 -C 8 )cycloalkyl, halogen, -CN, oxo, -NR a R b , -OR a , -SR a , -(C 1 -C 6 alkylene) hydroxyl, -C(O)R a , -N(R a )C(O)R a , -NR a C(O) OR a , -NR a SO 2 R a , -C(O)OR a , -C(O)N R a R b , -S(O) 2 N R a R b , -S(O)R a , -S (O) 2 R a , -P(O)R a R b ;
R a、R b各自独立地表示氢、C 1-C 6烷基、羟基(C 1-C 6烷基)、卤代C 1-C 6烷基； R a and R b each independently represent hydrogen, C 1 -C 6 alkyl, hydroxyl (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl;
m、n分别表示0、1或2。m and n represent 0, 1 or 2, respectively.
在本发明的一个技术方案中，W表示
Figure PCTCN2022085446-appb-000005
In a technical solution of the present invention, W represents
Figure PCTCN2022085446-appb-000005
其中，A表示
Figure PCTCN2022085446-appb-000006
Among them, A means
Figure PCTCN2022085446-appb-000006
Figure PCTCN2022085446-appb-000007
表示该环中含有单键或双键；
Figure PCTCN2022085446-appb-000007
Indicates that the ring contains a single bond or a double bond;
o各自独立地表示0或者1；o each independently represents 0 or 1;
R 8表示氢或C 1-C 6烷基； R 8 represents hydrogen or C 1 -C 6 alkyl;
R 9各自独立地表示氢或C 1-C 6烷基； R 9 each independently represents hydrogen or C 1 -C 6 alkyl;
或者R 8与相邻的R 9以及与它们相连的碳原子一起构成3-6元环； Or R 8 together with adjacent R 9 and the carbon atoms to which they are attached form a 3-6 membered ring;
W 2、R M、R N如前所述。 W 2 , RM and RN are as described above.
在本发明的一个技术方案中，W表示
Figure PCTCN2022085446-appb-000008
或者
Figure PCTCN2022085446-appb-000009
In a technical solution of the present invention, W represents
Figure PCTCN2022085446-appb-000008
or
Figure PCTCN2022085446-appb-000009
Figure PCTCN2022085446-appb-000010
表示该环中含有单键或双键；
Figure PCTCN2022085446-appb-000010
Indicates that the ring contains a single bond or a double bond;
o各自独立地表示0或者1；o each independently represents 0 or 1;
R 8表示氢或C 1-C 6烷基； R 8 represents hydrogen or C 1 -C 6 alkyl;
R 9各自独立地表示氢或C 1-C 6烷基； R 9 each independently represents hydrogen or C 1 -C 6 alkyl;
或者R 8与相邻的R 9以及与它们相连的碳原子一起构成3-6元环； Or R 8 together with adjacent R 9 and the carbon atoms to which they are attached form a 3-6 membered ring;
W 2、R M、R N如权利要求1所述。 W 2 , RM and RN are as described in claim 1 .
在本发明的一个方案中，W为芳香杂环，优选为芳香内酰胺。In one embodiment of the present invention, W is an aromatic heterocycle, preferably an aromatic lactam.
在本发明的一个方案中，W为饱和杂环，优选为饱和内酰胺。In one embodiment of the present invention, W is a saturated heterocycle, preferably a saturated lactam.
在本发明的优选技术方案中，其中环W表示
Figure PCTCN2022085446-appb-000011
Figure PCTCN2022085446-appb-000012
或者
Figure PCTCN2022085446-appb-000013
Figure PCTCN2022085446-appb-000014
In the preferred technical solution of the present invention, wherein the ring W represents
Figure PCTCN2022085446-appb-000011
Figure PCTCN2022085446-appb-000012
or
Figure PCTCN2022085446-appb-000013
Figure PCTCN2022085446-appb-000014
在本发明的进一步优选技术方案中，环W表示
Figure PCTCN2022085446-appb-000015
Figure PCTCN2022085446-appb-000016
In a further preferred technical solution of the present invention, the ring W represents
Figure PCTCN2022085446-appb-000015
Figure PCTCN2022085446-appb-000016
在本发明的进一步优选技术方案中，环W表示W表示
Figure PCTCN2022085446-appb-000017
Figure PCTCN2022085446-appb-000018
In a further preferred technical solution of the present invention, the ring W represents W represents
Figure PCTCN2022085446-appb-000017
Figure PCTCN2022085446-appb-000018
在本发明的优选技术方案中，其中，R 1表示氢、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、氰基或-C(O)NH 2；更优选地，R 1表示氢、卤素、C 1-C 6烷基或C 1-C 6卤代烷基。 In a preferred technical solution of the present invention, wherein, R 1 represents hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyano or -C(O)NH 2 ; more preferably, R 1 represents hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
在本发明的优选技术方案中，其中，R 2表示羟基、(C 1-C 6)烷基、-(C 0-C 6亚烷基)(C 3-C 8)环烷基、-(C 0-C 6亚烷基)(4-8元)杂环烷基、(C 1-C 6)烷氧基；更优选地，R 2表示C 1-C 6烷基、C 1-C 6烷氧基或C 3-C 6环烷基。 In the preferred technical solution of the present invention, wherein, R 2 represents hydroxyl, (C 1 -C 6 )alkyl, -(C 0 -C 6 alkylene) (C 3 -C 8 )cycloalkyl, -( C 0 -C 6 alkylene) (4-8 membered) heterocycloalkyl, (C 1 -C 6 )alkoxy; more preferably, R 2 represents C 1 -C 6 alkyl, C 1 -C 6alkoxy or C3 - C6cycloalkyl .
在本发明的优选技术方案中，其中，R 3表示氢或C 1-C 6烷基、C 3-C 6环烷基、卤代C 1-C 6烷基；更优选地，R 3表示氢或C 1-C 6烷基。 In a preferred technical solution of the present invention, wherein, R 3 represents hydrogen or C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl; more preferably, R 3 represents hydrogen or C 1 -C 6 alkyl.
在本发明的优选技术方案中，其中，R 4表示氢或C 1-C 6烷基；并且所述C 1-C 6烷基可以任意地被选自以下的取代基所取代：卤素、-OR a、-SR a、-P(O)R aR b、-S(O) 2R a、-S(O)(NH)R a、-S(O)R a、-S(O) 2NR aR b、-C(O)NR aR b、-C(O)OH；更优选地，R 4表示氢或C 1-C 6烷基。 In the preferred technical solution of the present invention, wherein, R 4 represents hydrogen or C 1 -C 6 alkyl; and the C 1 -C 6 alkyl can be optionally substituted by a substituent selected from the following: halogen, - OR a , -SR a , -P(O)R a R b , -S(O) 2 R a , -S(O)(NH)R a , -S(O)R a , -S(O) 2NR a R b , -C(O)NR a R b , -C(O)OH; more preferably, R 4 represents hydrogen or C 1 -C 6 alkyl.
在本发明的优选技术方案中，其中，R 5、R 5’各自独立地表示氢、卤素、C 1-C 6 烷基或卤代C 1-C 6烷基。 In a preferred technical solution of the present invention, wherein, R 5 and R 5' each independently represent hydrogen, halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
在本发明的优选技术方案中，其中，R 6、R 6’各自独立地表示氢、卤素、C 1-C 6烷基或卤代C 1-C 6烷基。 In a preferred technical solution of the present invention, wherein, R 6 and R 6′ each independently represent hydrogen, halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
在本发明的优选技术方案中，其中，R 7、R 7’各自独立地表示氢、卤素、C 1-C 6烷基、卤代C 1-C 6烷基或羟基(C 1-C 6烷基)。 In a preferred technical solution of the present invention, wherein, R 7 and R 7' each independently represent hydrogen, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl or hydroxyl (C 1 -C 6 alkyl).
在本发明的优选技术方案中，其中，R 8表示氢或C 1-C 6烷基。 In a preferred technical solution of the present invention, wherein, R 8 represents hydrogen or C 1 -C 6 alkyl.
在本发明的优选技术方案中，其中，R 9表示氢或C 1-C 6烷基。 In a preferred technical solution of the present invention, wherein, R 9 represents hydrogen or C 1 -C 6 alkyl.
在本发明的优选技术方案中，其中，R 10表示氢、卤素、(C 1-C 6)烷基、-(C 0-C 6亚烷基)(C 3-C 8)环烷基、-(C 0-C 6亚烷基)4-10元杂环烷基；更优选地，R 10表示氢、卤素或者(C 1-C 6)烷基。 In a preferred technical solution of the present invention, wherein, R 10 represents hydrogen, halogen, (C 1 -C 6 )alkyl, -(C 0 -C 6 alkylene) (C 3 -C 8 )cycloalkyl, -(C 0 -C 6 alkylene)4-10 membered heterocycloalkyl; more preferably, R 10 represents hydrogen, halogen or (C 1 -C 6 )alkyl.
在本发明的优选技术方案中，其中，R M表示氢或C 1-C 6烷基。 In the preferred technical solution of the present invention, wherein, R M represents hydrogen or C 1 -C 6 alkyl.
在本发明的优选技术方案中，其中，R a、R b各自独立地表示氢、C 1-C 6烷基或卤代C 1-C 6烷基。 In a preferred technical solution of the present invention, R a and R b each independently represent hydrogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
优选地，本发明的化合物具有以下结构：Preferably, the compounds of the present invention have the following structure:
Figure PCTCN2022085446-appb-000019
Figure PCTCN2022085446-appb-000019
Figure PCTCN2022085446-appb-000020
Figure PCTCN2022085446-appb-000020
Figure PCTCN2022085446-appb-000021
Figure PCTCN2022085446-appb-000021
Figure PCTCN2022085446-appb-000022
Figure PCTCN2022085446-appb-000022
Figure PCTCN2022085446-appb-000023
Figure PCTCN2022085446-appb-000023
Figure PCTCN2022085446-appb-000024
Figure PCTCN2022085446-appb-000024
Figure PCTCN2022085446-appb-000025
Figure PCTCN2022085446-appb-000025
Figure PCTCN2022085446-appb-000026
Figure PCTCN2022085446-appb-000026
Figure PCTCN2022085446-appb-000027
Figure PCTCN2022085446-appb-000027
此外，本发明还提供了一种药物组合物，其包含本发明所述的化合物以及药学上可用的载体。In addition, the present invention also provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier.
此外，本发明还提供了一种本发明的化合物或者药物组合物在制备用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的药物中的用途。In addition, the present invention also provides the use of a compound or pharmaceutical composition of the present invention in the preparation of a medicament for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.
此外，本发明还提供了一种本发明的化合物用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的用途。In addition, the present invention also provides the use of a compound of the present invention for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.
特别注意的是，在本文中，当提及具有特定结构式的“化合物”时，一般地还涵盖其立体异构体、非对映异构体、对映异构体、外消旋混合物和同位素衍生物。It is particularly noted that in this text, when referring to a "compound" having a specific structural formula, its stereoisomers, diastereomers, enantiomers, racemic mixtures and isotopes are generally also encompassed derivative.
本领域技术人员公知，一种化合物的盐、溶剂合物、水合物是化合物的替代性存在形式，它们都可以在一定条件下转化为所述化合物，因此，特别注意的是在本文中当提到一种化合物时，一般地还包括它的可药用盐，进而还包括其溶剂合物和水合物。It is well known to those skilled in the art that salts, solvates and hydrates of a compound are alternative existing forms of the compound, and they can all be converted into the compound under certain conditions. When referring to a compound, it generally includes its pharmaceutically acceptable salts, and further includes its solvates and hydrates.
相似地，在本文中当提到一种化合物时，一般地还包括其前药、代谢产物和氮氧化物。Similarly, when referring to a compound herein, prodrugs, metabolites and nitrogen oxides thereof are generally also included.
本发明所述的可药用盐可使用例如以下的无机酸或有机酸而形成：“可药用盐”是指这样的盐，在合理的医学判断范围内，其适用于接触人和较低等动物的组织，而没有不适当的毒性、刺激性、过敏反应等，称得上合理的受益/风险比。可以在本发明化合物的最终分离和纯化期间原位制备所述盐，或单独通过将游离碱或游离酸与合适的试剂反应制备所述盐，如下概述。例如，游离碱官能团可以与合适的酸反应。此外，当本发明的化合物带有酸性部分时，其合适的可药用盐可包括金属盐，例如碱金属盐(如钠盐或钾盐)；和碱土金属盐(如钙盐或镁盐)。可药用的无毒酸加成盐的示例是氨基与无机酸(例如，盐酸、氢溴酸、磷酸、硫酸和高氯酸)或有机酸(例如，醋酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐，或通过使用现有技术中的其他方法如离子交换形成的盐。其他可药用盐包括己二酸盐、海藻酸钠、抗坏血酸盐、天门冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、hernisulfate、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。代表性碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐等。其他可药用盐包括(适当时)无毒铵盐、季铵盐和用反离子形成的铵阳离子，例如，卤化物、氢氧化物、羧酸盐、硫酸盐、磷酸盐、硝酸 盐、低级烷基磺酸盐和芳基磺酸盐。The pharmaceutically acceptable salts of the present invention can be formed using, for example, the following inorganic or organic acids: "Pharmaceutically acceptable salts" refers to salts that, within the scope of sound medical judgment, are suitable for use in contact with humans and lower levels of and other animal tissues, without undue toxicity, irritation, allergic reactions, etc., can be called a reasonable benefit/risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent, as outlined below. For example, the free base functionality can be reacted with a suitable acid. In addition, when the compounds of the present invention bear an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts, such as alkali metal salts (eg, sodium or potassium salts); and alkaline earth metal salts (eg, calcium or magnesium salts) . Examples of pharmaceutically acceptable non-toxic acid addition salts are amino groups with inorganic acids (eg, hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric) or organic acids (eg, acetic, oxalic, maleic, tartaric, citric acid, succinic acid or malonic acid), or by using other methods in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, Camphorsulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerin Phosphate, gluconate, hernisulfate, heptanoate, caproate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malic acid salt, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectic acid Salt, persulfate, 3-phenylpropionate, phosphate, bitter salt, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluene Sulfonate, undecanoate, valerate, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, nontoxic ammonium salts, quaternary ammonium salts, and ammonium cations formed with counter ions, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower Alkyl sulfonates and aryl sulfonates.
本发明的可药用盐可通过常规方法制备，例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈)，向其中添加过量的有机酸或无机酸水溶液，以使得盐从所得混合物中沉淀，从中除去溶剂和剩余的游离酸，然后分离所沉淀的盐。The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving a compound of the present invention in a water-miscible organic solvent (eg, acetone, methanol, ethanol, and acetonitrile), adding thereto an excess of an organic acid or inorganic An aqueous acid solution to precipitate the salt from the resulting mixture, the solvent and remaining free acid removed therefrom, and the precipitated salt isolated.
本发明所述的前体或代谢物可以是本领域公知的前体或代谢物，只要所述的前体或代谢物可通过体内代谢转化形成目标化合物即可。例如“前药”是指本发明化合物的那些前药，在合理的医学判断范围内，其适用于接触人和更低等动物的组织，而没有不适当的毒性、刺激性、过敏反应等，称得上合理的受益/风险比并且对其预期用途有效。术语“前药”是指在体内迅速经转化产生上述式的母体化合物的化合物，例如通过在体内代谢，或本发明化合物的N-去甲基化。The precursors or metabolites described in the present invention may be those known in the art, as long as the precursors or metabolites can be metabolized in vivo to form the target compound. For example, "prodrugs" refer to those prodrugs of the compounds of the present invention which, within the scope of sound medical judgment, are suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic response, etc., Have a reasonable benefit/risk ratio and be valid for its intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to yield the parent compound of the above formula, eg, by in vivo metabolism, or N-demethylation of a compound of the present invention.
本发明所述的“溶剂合物”意指本发明化合物与一个或多个溶剂分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中，例如当一个或多个溶剂分子纳入结晶固体的晶格中时，溶剂化物将能够被分离。溶剂化物中的溶剂分子可按规则排列和/或无序排列存在。溶剂合物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂合物。示例性溶剂合物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。"Solvate" as used herein means a physical association of a compound of the present invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In certain instances, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be capable of isolation. Solvent molecules in a solvate may exist in regular and/or disordered arrangements. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
本发明所述的“立体异构”分为构象异构和构型异构，构型异构还可分为顺反异构和旋光异构(即光学异构)，构象异构是指具有一定构型的有机物分子由于碳、碳单键的旋转或扭曲而使得分子各原子或原子团在空间产生不同的排列方式的一种立体异构现象，常见的有烷烃和环烷烃类化合物的结构，如环己烷结构中出现的椅式构象和船式构象。“立体异构体”是指当本发明化合物含有一个或多个不对称中心，因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物有不对称中心，每个不对称中心会产生两个光学异构体，本发明的范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。本发明所述的化合物可以以互变异构体形式存在，其通过一个或多个双键位移而具有不同的氢的连接点。例如，酮和它的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都包括在本发明的化合物中。所有式(I)化合物的对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等，均包括在本 发明范围中。The "stereoisomerism" mentioned in the present invention is divided into conformational isomerism and configurational isomerism. Configurational isomerism can also be divided into cis-trans isomerism and optical isomerism (ie optical isomerism). A certain configuration of organic molecules due to the rotation or distortion of carbon and carbon single bonds, a stereoisomerism phenomenon in which each atom or atomic group of the molecule has different arrangements in space. The common structures of alkane and cycloalkane compounds Such as the chair conformation and boat conformation appearing in the cyclohexane structure. "Stereoisomer" means when the compounds of the present invention contain one or more asymmetric centers and are thus available as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers. The compounds of the present invention have asymmetric centers, each of which produces two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereoisomeric mixtures and pure or partially pure compounds . The compounds described herein may exist in tautomeric forms having different points of attachment of the hydrogen through displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. Enantiomers, diastereomers, racemates, mesomers, cis-trans isomers, tautomers, geometric isomers, epimers of all compounds of formula (I) Constructs and mixtures thereof, etc., are all included in the scope of the present invention.
本发明的“同位素衍生物”是指在本专利中化合物被同位素标记的分子。通常用作同位素标记的同位素是：氢同位素， 2H和 3H；碳同位素： 11C、 13C和 14C；氯同位素： 35Cl和 37Cl；氟同位素： 18F；碘同位素： 123I和 125I；氮同位素： 13N和 15N；氧同位素： 15O、 17O和 18O和硫同位素 35S。这些同位素标记化合物可以用来研究药用分子在组织中的分布情况。尤其是氘 3H和碳 13C，由于它们容易标记且方便检测，运用更为广泛。某些重同位素，比如重氢( 2H)，的取代能增强代谢的稳定性，延长半衰期从而达到减少剂量的目而提供疗效优势的。同位素标记的化合物一般从已被标记的起始物开始，用已知的合成技术如同合成非同位素标记的化合物一样来完成其合成。 "Isotopic derivatives" of the present invention refer to molecules in which compounds are isotopically labeled in this patent. Isotopes commonly used as isotopic labels are: hydrogen isotopes, 2 H and 3 H; carbon isotopes: 11 C, 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotopes: 18 F; iodine isotopes: 123 I and 125 I; nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotopically labeled compounds can be used to study the distribution of medicinal molecules in tissues. In particular, deuterium 3 H and carbon 13 C are more widely used because of their ease of labeling and detection. Substitution of certain heavy isotopes, such as deuterium ( 2 H), can enhance metabolic stability, prolong half-life and thus provide therapeutic advantages for the purpose of reducing dosage. Isotopically-labeled compounds are generally synthesized from labeled starting materials, and their synthesis is accomplished using known synthetic techniques as for non-isotopically-labeled compounds.
本发明还提供了本发明化合物在制备用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的药物中的用途。The present invention also provides the use of the compound of the present invention in the preparation of a medicament for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.
此外，本发明提供了用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的药物组合物，其包含本发明化合物作为活性成分。Furthermore, the present invention provides a pharmaceutical composition for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, comprising the present invention compound as active ingredient.
此外，本发明提供了一种用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的方法，其包括向有此需要的哺乳动物施用本发明化合物。In addition, the present invention provides a method for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, comprising: A mammal in need thereof is administered a compound of the present invention.
炎症性疾病、自身免疫性疾病和免疫介导性疾病的代表性实例可包括但不限于，关节炎、类风湿性关节炎、脊柱关节炎、痛风性关节炎、骨关节炎、幼年型关节炎、其他关节炎性病症、狼疮、***性红斑狼疮(SLE)、皮肤相关疾病、银屑病、湿疹、皮炎、过敏性皮肤炎、疼痛、肺病、肺部炎症、成人呼吸窘迫综合征(ARDS)、肺结节病、慢性肺部炎症性疾病、慢性阻塞性肺病(COPD)、心血管疾病、动脉粥样硬化、心肌梗塞、充血性心力衰竭、心肌缺血再灌注损伤、炎性肠病、克罗恩病、溃疡性结肠炎、肠易激综合征、哮喘、干燥综合征、自身免疫甲状腺疾病、荨麻疹(风疹)、多发性硬化、硬皮症、器官移植排斥、异种移植、特发性血小板减少性紫癜(ITP)、帕金森病、阿尔兹海默病、糖尿病相关疾病、炎症、***性疾病、过敏性鼻炎、过敏性支气管炎、过敏性鼻窦炎、白血病、淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、骨髓瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性髓性白血病(AML)、慢性髓性白血病(CML)、毛细胞白血病、何杰金氏病、非何杰金淋巴瘤、多发性骨髓瘤、骨髓增生异常综 合征(MDS)、骨髓增生性肿瘤(MPN)、弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤。Representative examples of inflammatory, autoimmune, and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis , other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related disorders, psoriasis, eczema, dermatitis, atopic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS) , pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjögren's syndrome, autoimmune thyroid disease, urticaria (rubella), multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic Thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B cell lymphoma, T-cell lymphoma, myeloma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Ho Jie King's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.
癌症或肿瘤的代表性实例可包括但不限于，皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、***癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、***状甲状腺癌、肾癌、肾实质癌、卵巢癌、***、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、***癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、***瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤。Representative examples of cancers or tumors may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer , colon cancer, familial adenomatous polyposis cancer, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as Glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia ( ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, Osteosarcoma, chondrosarcoma, sarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, or plasmacytoma.
用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂的代表性实例可包括但不限于，甾体药物(例如，强的松、氢化波尼松、甲基氢化波尼松、可的松、羟基可的松、倍他米松、***等)、甲氨蝶呤、来氟米特、抗TNFα剂(例如，依那西普、英夫利昔单抗、阿达利单抗等)、钙调神经磷酸酶抑制剂(例如，他克莫司、吡美莫司等)和抗组胺药(例如，苯海拉明、羟嗪、氯雷他定、依巴斯汀、酮替芬、西替利嗪、左西替利嗪、非索非那定等)，并且选自其中的至少一种治疗剂可包含于本发明药物组合物中。Representative examples of therapeutic agents for the treatment of inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, steroidal drugs (eg, prednisone, prednisone, methylhydroponil) sone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα agents (eg, etanercept, infliximab, adalix monoclonal antibodies, etc.), calcineurin inhibitors (eg, tacrolimus, pimecrolimus, etc.), and antihistamines (eg, diphenhydramine, hydroxyzine, loratadine, ebaz) Cetirizine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one therapeutic agent selected from them may be included in the pharmaceutical composition of the present invention.
本发明的化合物或其可药用盐可作为活性成分通过口服或肠胃外施用，其有效量的范围为在哺乳动物包括人(体重约70kg)的情况下0.1至2,000mg/kg体重/天、优选1至1,000mg/kg体重/天，并且每天以单次或4次分次剂量，或者遵循/不遵循预定时间施用。活性成分的剂量可根据多个相关因素(例如待治疗对象的情况、疾病类型和严重性、施用速率和医生意见)进行调整。在某些情况下，小于以上剂量的量可能是合适的。如果不引起有害的副作用则可使用大于以上剂量的量并且该量可以每天以分次剂量施用。The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an active ingredient in an effective amount ranging from 0.1 to 2,000 mg/kg body weight/day, in mammals including humans (about 70 kg body weight), Preferably from 1 to 1,000 mg/kg body weight/day, and administered in single or 4 divided doses per day, or on/off schedule. The dosage of the active ingredient can be adjusted according to a number of relevant factors, such as the condition of the subject to be treated, the type and severity of the disease, the rate of administration, and the opinion of the physician. In some cases, amounts less than the above doses may be appropriate. An amount greater than the above dose may be used if it does not cause adverse side effects and the amount may be administered in divided doses per day.
除此之外，本发明还提供了一种预防和/或***、癌症、病毒感染、器官移植排斥、神经退行性疾病、注意力相关疾病或自身免疫性疾病的方法，其包 括向有此需要的哺乳动物施用本发明的化合物或本发明的药物组合物。In addition, the present invention also provides a method for preventing and/or treating tumors, cancer, viral infections, organ transplant rejection, neurodegenerative diseases, attention-related diseases or autoimmune diseases, comprising A compound of the present invention or a pharmaceutical composition of the present invention is administered to a mammal in need thereof.
可根据常规方法中的任何一种将本发明药物组合物配制成用于口服施用或肠胃外施用(包括肌内、静脉内和皮下途径、瘤内注射)的剂型，例如片剂、颗粒、粉末、胶囊、糖浆、乳剂、微乳剂、溶液或混悬液。The pharmaceutical compositions of the present invention may be formulated according to any of conventional methods into dosage forms such as tablets, granules, powders for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes, intratumoral injection) , capsules, syrups, emulsions, microemulsions, solutions or suspensions.
本发明描述示例性实施方案的过程中，本发明的其它特征将变得显而易见，给出所述实施方案用于说明本发明而不意欲成为其限制，以下实施例使用本发明所公开的方法制备、分离和表征。Other features of this invention will become apparent in the course of describing exemplary embodiments of this invention, which are given to illustrate the invention and not to limit it, and the following examples were prepared using the methods disclosed in this invention. , isolation and characterization.
可以用有机合成领域的技术人员已知的多种方式来制备本发明的化合物，可使用下述方法以及有机合成化学领域中已知的合成方法或通过本领域技术人员所了解的其变化形式来合成本发明化合物。优选方法包括但不限于下文所述的这些。在适用于所使用试剂盒材料和适用于所实现转变的溶剂或溶剂混合物中实施反应。有机合成领域的技术人员将理解，分子上存在的官能性与所提出的转变一致。这有时需要加以判断改变合成步骤的顺序或原料以获得期望的本发明化合物。The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis, using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or by variations thereof known to those skilled in the art. Compounds of the present invention were synthesized. Preferred methods include, but are not limited to, those described below. Reactions are carried out in a solvent or solvent mixture suitable for the kit materials used and for the transformation being effected. Those skilled in the art of organic synthesis will understand that the functionality present on the molecule is consistent with the proposed transformation. This sometimes requires the discretion to alter the order of synthetic steps or starting materials to obtain the desired compounds of the invention.
具体实施方式Detailed ways
术语the term
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。Unless otherwise stated, terms used in the present application, including the specification and claims, are defined as follows. It must be noted that, in the specification and the appended claims, the singular form "a" includes the plural unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology were used unless otherwise stated. In this application, the use of "or" or "and" means "and/or" unless stated otherwise.
在说明书和权利要求书中，给定化学式或名称应涵盖所有立体和光学异构体及其中存在上述异构体的外消旋物。除非另外指明，否则所有手性(对映异构体和非对映异构体)和外消旋形式均在本发明范围内。所述化合物中还可存在C＝C双键、C＝N双键、环***等的许多几何异构体，且所有上述稳定异构体均涵盖于本发明内。本发明描述了本发明化合物的顺式-和反式-(或E-和Z-)几何异构体，且其可分离成异构体的混合物或分开的异构体形式。本发明化合物可以光学活性或外消旋形式加以分离。用于制备本发明化合物和其中制备的中间体的所有方法均视为本发明的部分。在制备对映异构体或非对映异构体产物时，其可通过常规方法(例如通过色谱或分段结晶)进行分离。取决于方法条件，以游离(中性)或盐形式获得本发明的终产物。这些终产物的游离形式和盐均在本发明的范围内。如 果需要的话，则可将化合物的一种形式转化成另一种形式。可将游离碱或酸转化成盐；可将盐转化成游离化合物或另一种盐；可将本发明异构体化合物的混合物分离成单独的异构体。本发明化合物、其游离形式和盐可以多种互变异构体形式存在，其中氢原子转置到分子的其它部分上且由此分子的原子之间的化学键发生重排。应当理解的是，可存在的所有互变异构体形式均包括在本发明内。In the specification and claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates in which such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the present invention. Numerous geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc. may also exist in the compounds, and all such stable isomers are encompassed by the present invention. The present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, and which may be isolated as a mixture of isomers or as separate isomeric forms. The compounds of the present invention can be isolated in optically active or racemic forms. All methods used to prepare the compounds of the present invention and intermediates prepared therein are considered part of this invention. In the preparation of enantiomeric or diastereomeric products, they can be separated by conventional methods, eg by chromatography or fractional crystallization. Depending on the process conditions, the final product of the invention is obtained in free (neutral) or salt form. Both free forms and salts of these final products are within the scope of the present invention. If desired, one form of a compound can be converted into another. Free bases or acids can be converted into salts; salts can be converted into free compounds or another salt; mixtures of isomeric compounds of the present invention can be separated into individual isomers. The compounds of the present invention, their free forms and salts, may exist in various tautomeric forms in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are thereby rearranged. It is to be understood that all tautomeric forms that may exist are encompassed by the present invention.
除非另有定义，本发明的取代基的定义是各自独立而非互相关联的，例如对于取代基中R a(或者R a’)而言，其在不同的取代基的定义中是各自独立的。具体而言，对于R a(或者R a’)在一种取代基中选择一种定义时，并不意味着该R a(或者R a’)在其他取代基中都具有该相同的定义。更具体而言，例如(仅列举非穷举)对于NR aR a’中，当R a(或者R a’)的定义选自氢时，其并不意味着在-C(O)-NR aR a’中，R a(或者R a’)必然为氢。 Unless otherwise defined, the definitions of the substituents of the present invention are each independent rather than interrelated, for example, for R a (or R a ') in a substituent, it is independent in the definitions of different substituents . Specifically, selecting a definition for Ra (or Ra ') in one substituent does not mean that Ra (or Ra ') has the same definition in other substituents. More specifically, for example (to list only non-exhaustive) for NR a R a ', when the definition of R a (or R a ') is selected from hydrogen, it does not mean that in -C(O)-NR In a R a ', R a (or R a ') must be hydrogen.
除非另有定义，否则当取代基被标注为“任意取代的”时，所述取代基选自例如以下取代基，诸如烷基、环烷基、芳基、杂环基、卤素、羟基、烷氧基、氧代、烷酰基、芳基氧基、烷酰基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺基团(其中2个氨基取代基选自烷基、芳基或芳基烷基)、烷酰基氨基、芳酰基氨基、芳烷酰基氨基、取代的烷酰基氨基、取代的芳基氨基、取代的芳烷酰基氨基、硫基、烷基硫基、芳基硫基、芳基烷基硫基、芳基硫羰基、芳基烷基硫羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、磺酰氨基例如-SO 2NH 2、取代的磺酰氨基、硝基、氰基、羧基、氨基甲酰基例如-CONH 2、取代的氨基甲酰基例如-CONH烷基、-CONH芳基、-CONH芳基烷基或在氮上具有两个选自烷基、芳基或芳基烷基的取代基的情况、烷氧基羰基、芳基、取代的芳基、胍基、杂环基，例如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯烷基、哌啶基、吗啉基、哌嗪基、高哌嗪基等和取代的杂环基。 Unless otherwise defined, when a substituent is annotated as "optionally substituted", the substituent is selected from, for example, substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halo, hydroxy, alkane oxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine groups (wherein the 2 amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio group, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamido such as -SO 2 NH2 , substituted sulfonamido, nitro, cyano, carboxyl, carbamoyl such as -CONH2 , substituted carbamoyl such as -CONH alkyl, -CONH aryl, -CONH arylalkyl or at nitrogen In the case of having two substituents selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclic groups such as indolyl, imidazolyl, Furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, etc. and substituted heterocyclyl.
本文使用的术语“烷基”或“亚烷基”意欲包括具有指定碳原子数的支链和直链饱和脂族烃基团。例如，“C 1-C 6烷基”表示具有1个至6个碳原子的烷基。烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基、叔丁基)和戊基(例如正戊基、异戊基、新戊基)。 The terms "alkyl" or "alkylene" as used herein are intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, " C1 - C6 alkyl" means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (eg n-propyl and isopropyl), butyl (eg n-butyl, isobutyl, tert-butyl) and Pentyl (eg n-pentyl, isopentyl, neopentyl).
术语“烯基”表示含一个或多个双键且通常长度为2至20个碳原子的直链或支链的烃基。例如，“C2-C6烯基”含有两个至六个碳原子。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and usually 2 to 20 carbon atoms in length. For example, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
术语“炔基”表示含一个或多个三键且通常长度为2至20个碳原子的直链或 支链的烃基。例如，“C 2-C 6炔基”含有两个至六个碳原子。代表性炔基包括但不限于例如乙炔基、1-丙炔基、1-丁炔基等。 The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing one or more triple bonds and usually 2 to 20 carbon atoms in length. For example, "C2 - C6alkynyl " contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like.
术语“烷氧基”或“烷基氧基”是指-O-烷基。“C 1-C 6烷氧基”(或烷基氧基)意欲包括C 1、C 2、C 3、C 4、C 5、C 6烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)和叔丁氧基。类似地，“烷基硫基”或“硫代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的烷基；例如甲基-S-和乙基-S-。 The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C 1 -C 6 alkoxy" (or alkyloxy) is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group, as defined above, having the indicated number of carbon atoms attached through a sulfur bridge; eg, methyl-S- and ethyl-S-.
术语“羰基”是指由碳和氧两种原子通过双键连接而成的有机官能团(C＝O)。The term "carbonyl" refers to an organic functional group (C=O) composed of two atoms, carbon and oxygen, linked by a double bond.
术语“芳基”，单独或作为较大部分诸如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”的部分，是指具有总计5至12个环成员的单环、二环或三环的环***，其中所述***中的至少一个环为芳族的且其中所述***中的每个环含有3至7个环成员。在本发明的某些实施方案中，“芳基”是指芳族环***，其包括但不限于苯基、联苯基、茚满基、1-萘基、2-萘基和四氢萘基。术语“芳烷基”或“芳基烷基”是指连接至芳基环的烷基残基。非限制性实例包括苄基、苯乙基等。稠合的芳基可在环烷基环或芳族环的合适位置上连接至另一基团。例从环***中画出的虚线表明键可连接至任意合适的环原子。The term "aryl", alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a single ring having a total of 5 to 12 ring members , bicyclic or tricyclic ring systems, wherein at least one ring in the system is aromatic and wherein each ring in the system contains from 3 to 7 ring members. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene base. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, and the like. A fused aryl group can be attached to another group at a suitable position on the cycloalkyl or aromatic ring. For example, dashed lines drawn from a ring system indicate that the bond may be attached to any suitable ring atom.
术语“环烷基”是指单环或二环的环状烷基，优选具有3至8个环成员。单环的环状烷基指C 3-C 8的环状烷基，包括但不限于环丙基、环丁基、环戊基、环己基和降莰烷基。支化环烷基诸如1-甲基环丙基和2-甲基环丙基包括在“环烷基”的定义中。二环的环状烷基包括桥环、螺环或融合环的环烷基。 The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group, preferably having 3 to 8 ring members. A monocyclic cyclic alkyl group refers to a C3 - C8 cyclic alkyl group, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Bicyclic cyclic alkyl groups include bridged, spiro or fused ring cycloalkyl groups.
术语“环烯基”是指单环或二环的环状烯基，优选具有3至8个环成员。单环的环状烯基指C 3-C 8的环状烯基，包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基和降莰烯基。支化环烯基诸如1-甲基环丙烯基和2-甲基环丙烯基包括在“环烯基”的定义中。二环的环状烯基包括桥环、螺环或融合环的环状烯基。 The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl group, preferably having 3 to 8 ring members. Monocyclic cyclic alkenyl refers to C3 - C8 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornyl. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyl groups include bridged, spiro or fused ring cyclic alkenyl groups.
“卤代”或“卤素”包括氟、氯、溴和碘。“卤代烷基”意欲包括具有指定碳原子数且取代有1个或多个卤素(优选1个、2个或3个卤素)的支链和直链饱和脂族烃基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。卤代烷基的实例还包括意欲包括具有指定碳原子数(优选1至6个碳原子)且取代有1个或多个氟原子的支链和直链饱和脂族烃基团的“氟烷基”。"Halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with 1 or more halogens, preferably 1, 2 or 3 halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoroethyl propyl and heptachloropropyl. Examples of haloalkyl groups also include "fluoroalkyl groups" intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (preferably 1 to 6 carbon atoms) substituted with 1 or more fluorine atoms.
“卤代烷氧基”或“卤代烷基氧基”表示具有指定数量碳原子(优选1至6个碳原子)的经氧桥连接的如上文所定义的卤代烷基。例如，“卤代C 1-C 6烷氧基”意欲包括C 1、C 2、C 3、C 4、C 5、C 6卤代烷氧基。卤代烷氧基的实例包括但不限于三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。类似地，“卤代烷基硫基”或“硫代卤代烷氧基”表示具有指定数量碳原子(优选1至6个碳原子)的经硫桥连接的如上文所定义的卤代烷基；例如三氟甲基-S-和五氟乙基-S-。 "Haloalkoxy" or "haloalkyloxy" means a haloalkyl group, as defined above, having the indicated number of carbon atoms (preferably 1 to 6 carbon atoms) attached through an oxygen bridge. For example, " haloC1 - C6alkoxy " is intended to include C1 , C2 , C3, C4 , C5 , C6 haloalkoxy . Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group as defined above having the indicated number of carbon atoms (preferably 1 to 6 carbon atoms) attached through a sulfur bridge; eg trifluoromethyl base-S- and pentafluoroethyl-S-.
本公开内容中，当提到一些取代基团时使用C x1-C x2的表述，这表示所述取代基团中的碳原子数可以是x1至x2个。例如，C 0-C 8表示所述基团含有0、1、2、3、4、5、6、7或8个碳原子，C 1-C 8表示所述基团含有1、2、3、4、5、6、7或8个碳原子，C 2-C 8表示所述基团含有2、3、4、5、6、7或8个碳原子，C 3-C 8表示所述基团含有3、4、5、6、7或8个碳原子，C 4-C 8表示所述基团含有4、5、6、7或8个碳原子，C 0-C 6表示所述基团含有0、1、2、3、4、5或6个碳原子，C 1-C 6表示所述基团含有1、2、3、4、5或6个碳原子，C 2-C 6表示所述基团含有2、3、4、5或6个碳原子，C 3-C 6表示所述基团含有3、4、5或6个碳原子。 In the present disclosure, the expression C x1 -C x2 is used when referring to some substituent groups, which means that the number of carbon atoms in the substituent groups may be x1 to x2. For example, C 0 -C 8 indicates that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and C 1 -C 8 indicates that the group contains 1, 2, 3 , 4, 5, 6, 7 or 8 carbon atoms, C 2 -C 8 means the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C 3 -C 8 means the group The group contains 3, 4, 5, 6, 7 or 8 carbon atoms, C 4 -C 8 means the group contains 4, 5, 6, 7 or 8 carbon atoms, and C 0 -C 6 means the A group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C 1 -C 6 means the group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C 2 -C 6 indicates that the group contains 2, 3, 4, 5 or 6 carbon atoms and C3 - C6 indicates that the group contains 3, 4, 5 or 6 carbon atoms.
本公开内容中，当提到环状基团(例如芳基、杂芳基、环烷基和杂环烷基)时使用“x1-x2元环”的表述，这表示该基团的环原子数可以是x1至x2个。例如，所述3-12元环状基团可以是3、4、5、6、7、8、9、10、11或12元环，其环原子数可以是3、4、5、6、7、8、9、10、11或12个；3-6元环表示该环状基团可以是3、4、5或6元环，其环原子数可以是3、4、5或6个；3-8元环表示该环状基团可以是3、4、5、6、7或8元环，其环原子数可以是3、4、5、6、7或8个；3-9元环表示该环状基团可以是3、4、5、6、7、8或9元环，其环原子数可以是3、4、5、6、7、8或9个；4-7元环表示该环状基团可以是4、5、6或7元环，其环原子数可以是4、5、6或7个；5-8元环表示该环状基团可以是5、6、7或8元环，其环原子数可以是5、6、7或8个；5-12元环表示该环状基团可以是5、6、7、8、9、10、11或12元环，其环原子数可以是5、6、7、8、9、10、11或12个；6-12元环表示该环状基团可以是6、7、8、9、10、11或12元环，其环原子数可以是6、7、8、9、10、11或12个。所述环原子可以是碳原子或杂原子，例如选自N、O和S的杂原子。当所述环是杂环时，所述杂环可以含有1、2、3、4、5、6、7、8、9、10或更多个环杂原子，例如选自N、O和S的杂原子。In this disclosure, the expression "x1-x2 membered ring" is used when referring to cyclic groups (eg, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), which refers to the ring atoms of the group The number may be x1 to x2. For example, the 3-12 membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 3-6 membered ring means that the cyclic group can be a 3, 4, 5 or 6 membered ring, and the number of ring atoms can be 3, 4, 5 or 6 ; 3-8 membered ring means that the cyclic group can be a 3, 4, 5, 6, 7 or 8 membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7 or 8; 3-9 Ring member means that the cyclic group can be a 3, 4, 5, 6, 7, 8 or 9 membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8 or 9; 4-7 Ring member means that the cyclic group can be 4, 5, 6 or 7 membered ring, and the number of ring atoms can be 4, 5, 6 or 7; 5-8 membered ring means that the cyclic group can be 5, 6, 7 or 8 membered ring, the number of ring atoms can be 5, 6, 7 or 8; 5-12 membered ring means that the cyclic group can be 5, 6, 7, 8, 9, 10, 11 or 12-membered ring, the number of ring atoms can be 5, 6, 7, 8, 9, 10, 11 or 12; 6-12-membered ring means that the cyclic group can be 6, 7, 8, 9, 10, 11- or 12-membered ring, the number of ring atoms may be 6, 7, 8, 9, 10, 11 or 12. The ring atoms may be carbon atoms or heteroatoms, eg heteroatoms selected from N, O and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, eg selected from N, O and S of heteroatoms.
本公开内容中，一个或更多个卤素可以各自独立地选自氟、氯、溴和碘。In the present disclosure, the one or more halogens may each be independently selected from fluorine, chlorine, bromine, and iodine.
术语“杂芳基”意指稳定的3元、4元、5元、6元、或7元芳香单环或芳香二环或7元、8元、9元、10元、11元、12元芳香多环杂环，其为完全不饱和的、部分不饱和的，且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子；且包括任何以下多环基团，其中上文所定义的任意杂环与苯环稠合。氮和硫杂原子可任选地被氧化。氮原子为取代的或未取代的(即N或NR，其中R为H或如果被定义，则为另一取代基)。杂环可在得到稳定结构的任何杂原子或碳原子处连接至其侧基。如果所得化合物是稳定的，则本文所述的杂环基可在碳或氮原子上被取代。杂环中的氮可任选地被季铵化。优选地，当杂环中S和O原子的总数超过1时，则这些杂原子彼此不相邻。优选地，杂环中S和O原子的总数不大于1。当使用术语“杂环”时，其意欲包括杂芳基。芳杂基的实施例包括但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并***基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、假吲哚基(indolenyl)、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、萘嵌间二氮杂苯基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基和呫吨基、喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、异吲哚基、二氢吲哚基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢-喹啉基、2,3-二氢-苯并呋喃基、色满基、1,2,3,4-四氢-喹喔啉基和1,2,3,4- 四氢-喹唑啉基。术语“杂芳基”还可以包括由上述所定义的“芳基”与单环“杂芳基”所形成的联芳基结构，例如但不限于“-苯基联吡啶基-”、“-苯基联嘧啶基”、“-吡啶基联苯基”、“-吡啶基联嘧啶基-”、“-嘧啶基联苯基-”；其中本发明还包括含有例如上述杂环的稠环和螺环化合物。The term "heteroaryl" means a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, 12-membered Aromatic polycyclic heterocycles, which are fully unsaturated, partially unsaturated, and which contain carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and include Any of the following polycyclic groups wherein any heterocycle as defined above is fused to a benzene ring. Nitrogen and sulfur heteroatoms can optionally be oxidized. Nitrogen atoms are substituted or unsubstituted (ie, N or NR, where R is H or, if defined, another substituent). Heterocycles can be attached to their pendant groups at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable. The nitrogens in the heterocycle may be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than one. When the term "heterocycle" is used, it is intended to include heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, acridinyl, azetidinyl, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxanyl azolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carboline, chromanyl, chromenyl, cinnoline, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2, 3-b] tetrahydrofuranyl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridyl, indolenyl, indolyl, Indolyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, iso Quinolinyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, naphthyl, octahydroisoquinoline base, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl , oxazolidinyl, oxazolyl, oxazolopyridyl, oxazolidinyl, rylene, oxindole, pyrimidinyl, phenanthridine, phenanthroline, phenazinyl , phenothiazinyl, phenoxthiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinone, 4-piperidinone, piperonyl, pteridyl, purinyl, Pyranyl, pyrazinyl, pyrazolidine, pyrazolinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl , pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidone, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinuclidine, quinoxalinyl, quinuclidinyl, Tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4- Thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthyl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, thienooxa azolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4 - Triazolyl and xanthyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indoline, 1H-indazolyl, benzo Imidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3 - Dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl. The term "heteroaryl" may also include biaryl structures formed by the above-defined "aryl" and a monocyclic "heteroaryl", such as, but not limited to, "-phenylbipyridyl-", "- Phenylbipyrimidinyl", "-pyridylbiphenyl", "-pyridylbipyrimidinyl-", "-pyrimidinylbiphenyl-"; wherein the present invention also includes fused rings containing, for example, the above heterocycles and Spiro compounds.
本文使用的术语“杂环烷基”指的是一个单环杂环烷基体系，或为一个二环杂环烷基体系，同时还包括螺杂环或桥杂环烷基。单环的杂环烷基指的是3-8元、且至少含一个选自O、N、S、P的饱和或不饱和但不为芳香性的环状烷基体系。二环杂环烷基体系指的是一个杂环烷基稠合到一个苯基、或一个环烷基、或一个环烯基、或一个杂环烷基、或一个杂芳基。The term "heterocycloalkyl" as used herein refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes spiroheterocycles or bridged heterocycloalkyls. Monocyclic heterocycloalkyl refers to a 3-8 membered cyclic alkyl system containing at least one saturated or unsaturated but non-aromatic alkyl group selected from O, N, S, P. A bicyclic heterocycloalkyl system refers to a heterocycloalkyl group fused to a phenyl group, or a cycloalkyl group, or a cycloalkenyl group, or a heterocycloalkyl group, or a heteroaryl group.
本文使用的术语“桥环烷基”指的是共用两个或两个以上碳原子的多环化合物。可分为二环桥环烃及多环桥环烃。前者由两个脂环共用两个以上碳原子所构成；后者是由三个以上的环组成的桥环烃。The term "bridged cycloalkyl" as used herein refers to polycyclic compounds that share two or more carbon atoms. It can be divided into bicyclic bridged cyclic hydrocarbons and polycyclic bridged cyclic hydrocarbons. The former consists of two alicyclic rings sharing more than two carbon atoms; the latter is a bridged cyclic hydrocarbon consisting of three or more rings.
本文使用的术语“螺环烷基”指的是单环之间共用一个碳原子(称螺原子)的多环烃。The term "spirocycloalkyl" as used herein refers to polycyclic hydrocarbons in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings.
本文使用的术语“桥环杂基”指的是共用两个或两个以上碳原子的多环化合物，该环中至少含一个选自O、N、S原子。可分为二环桥环杂环及多环桥杂环。The term "bridged heterocyclic group" as used herein refers to a polycyclic compound sharing two or more carbon atoms, and the ring contains at least one atom selected from O, N and S. It can be divided into bicyclic bridged heterocycles and polycyclic bridged heterocycles.
本文使用的术语“杂螺环基”指的是单环之间共用一个碳原子(称螺原子)的多环烃，该环中至少含一个选自O、N、S原子。The term "heterospirocyclyl" as used herein refers to polycyclic hydrocarbons in which a single carbon atom (called a spiro atom) is shared between single rings, and the ring contains at least one atom selected from O, N and S.
本文中所用的术语“取代”意指至少一个氢原子被非氢基团替代，条件是维持正常化合价且所述取代得到稳定的化合物。本文所用的环双键为在两个相邻环原子之间形成的双键(例如C＝C、C＝N或N＝N)。The term "substituted" as used herein means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valences are maintained and the substitution results in a stable compound. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (eg, C=C, C=N, or N=N).
在本发明化合物上存在氮原子(例如胺)的情形下，可通过使用氧化剂(例如mCPBA和/或过氧化氢)进行处理来将这些氮原子转化成N-氧化物以获得本发明的其它化合物。因此，所显示和要求保护的氮原子视为均涵盖所显示氮及其N-氧化物以获得本发明衍生物。Where nitrogen atoms (eg, amines) are present on the compounds of the present invention, these nitrogen atoms can be converted to N-oxides by treatment with oxidizing agents (eg, mCPBA and/or hydrogen peroxide) to obtain other compounds of the present invention . Accordingly, both shown and claimed nitrogen atoms are considered to encompass both the shown nitrogen and its N-oxides to obtain the derivatives of the present invention.
当任何变量在化合物的任何组成或式中出现一次以上时，其每次出现时的定义均独立于其在其它每种情况下出现时的定义。因此，例如如果显示基团取代有0-3个R，则所述基团可任选地取代有至多三个R基团，且在每次出现时R独立地选自R的定义。此外，取代基和/或变量的组合仅在上述组合可产生稳定的化合物时才容许存在。When any variable occurs more than once in any composition or formula of a compound, its definition at each occurrence is independent of its definition at each other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R groups, the group may be optionally substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R. Furthermore, combinations of substituents and/or variables are only permissible if such combinations result in stable compounds.
本文使用的术语“患者”是指通过本发明的方法进行治疗的有机体。这类有机体优选包括但不限于哺乳动物(例如鼠类、猿/猴、马、牛、猪、犬、猫等)且最优选是指人类。The term "patient" as used herein refers to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (eg, murine, simian/monkey, equine, bovine, porcine, canine, feline, etc.) and most preferably refer to humans.
本文使用的术语“有效量”意指将会引起例如研究人员或临床医师所寻求的组织、***、动物或人的生物学或医学响应的药物或药剂(即本发明化合物)的量。此外，术语“治疗有效量”意指这样的量：与未接受上述量的相应受试者相比，所述量导致改善的治疗、治愈、预防或减轻疾病、病症或副作用，或降低在疾病或病症的进展速度。有效量可以一个或多个给药、施用或剂量给予且不意欲被特定的制剂或给药途径限制。该术语还包括在其范围内的增强正常生理机能的有效量。As used herein, the term "effective amount" means the amount of a drug or agent (ie, a compound of the invention) that will elicit the biological or medical response of a tissue, system, animal or human, eg, sought by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means an amount that results in improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or a reduction in the incidence of a disease, as compared to a corresponding subject not receiving such amounts or the rate of progression of the disease. An effective amount can be administered in one or more administrations, administrations or doses and is not intended to be limited by a particular formulation or route of administration. The term also includes within its scope an amount effective to enhance normal physiology.
本文使用的术语“治疗”包括导致改善病症、疾病、障碍等的任何效果，例如减轻、减少、调节、改善或消除，或改善其症状。As used herein, the term "treating" includes any effect that results in amelioration of a condition, disease, disorder, etc., eg, alleviation, reduction, modulation, amelioration or elimination, or amelioration of symptoms thereof.
术语“药用”在本文中用于指如下那些化合物、物质、组合物和/或剂型：在合理医学判断的范围内，其适于与人类和动物的组织接触使用而无过高毒性、刺激性、过敏反应和/或其它问题或并发症，并与合理的益处/风险比相称。The term "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without unduly toxic, irritating sexual, allergic reactions and/or other problems or complications and are commensurate with a reasonable benefit/risk ratio.
本文使用的短语“药用载体”意指药用物质、组合物或媒介物，诸如液体或固体填充剂、稀释剂、赋形剂、制造助剂(例如润滑剂、滑石、硬脂酸镁、硬脂酸钙或硬脂酸锌或硬脂酸)或溶剂包囊物质，其涉及将主题化合物从一个器官或身体的部分携带或运送至另一个器官或身体的部分。每种载体在与制剂的其它成分相容和对患者无害的意义上必须是“可接受的”。The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutical substance, composition or vehicle such as a liquid or solid filler, diluent, excipient, manufacturing aid (eg lubricants, talc, magnesium stearate, calcium stearate or zinc stearate or stearic acid) or a solvent encapsulating material which is involved in carrying or transporting a subject compound from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
术语“药物组合物”意指包含本发明化合物与至少一种其它药用载体的组合物。“药用载体”是指本领域中通常接受用于将生物活性剂递送至动物(具体为哺乳动物)的介质，包括(即)佐剂、赋形剂或媒介物，诸如稀释剂、防腐剂、填充剂、流动调控剂、崩解剂、润湿剂、乳化剂、悬浮剂、增甜剂、矫味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂，这取决于给药模式和剂型的性质。The term "pharmaceutical composition" means a composition comprising a compound of the present invention and at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering a biologically active agent to an animal, particularly a mammal, including (ie) adjuvants, excipients or vehicles such as diluents, preservatives , fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating and dispersing agents, depending on The mode of administration and the nature of the dosage form.
特定药学及医学术语Certain Pharmacy and Medical Terms
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。The term "acceptable", as used herein, refers to a formulation component or active ingredient that does not have undue deleterious effects on the health of the general target of treatment.
术语“癌症”，如本文所用，指一种不能控制的细胞的异常生长，并且在某种条件下能够转移(传播)。这种类型的癌症包括但不限于，实体肿瘤(如膀胱、肠、脑、胸、子宫、心脏、肾、肺、淋巴组织(淋巴瘤)、卵巢、胰腺或其它内分泌器 官(如甲状腺)、***、皮肤(黑色素瘤)或血液瘤(如非白血性白血病)。The term "cancer", as used herein, refers to an abnormal growth of cells that is uncontrollable and, under certain conditions, is capable of metastasizing (spreading). Cancers of this type include, but are not limited to, solid tumors (eg, bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (eg, thyroid), prostate , skin (melanoma), or blood tumor (eg, nonleukemic leukemia).
术语“联合给药”或其类似术语，如本文所用，指将几种所选的治疗药物给一个病人用药，以相同或不同的给药方式在相同或不同的时间给药。The term "co-administration" or similar terms, as used herein, refers to the administration of several selected therapeutic agents to a patient, administered in the same or different administrations at the same or different times.
术语“增强”或“能增强”，如本文所用，指预期的结果能够在效价或是持续时间方面都有增加或延长。因此，在增强药物的治疗效果方面，术语“能增强”指药物在***中有提高或延长效价或持续时间的能力。本文所用的“增效值”，指在理想的***中，能够最大限度地的增强另外一个治疗药物的能力。The term "enhancing" or "enhancing", as used herein, refers to the ability of a desired result to be increased or prolonged, either in potency or duration. Thus, in enhancing the therapeutic effect of a drug, the term "enhancer" refers to the drug's ability to increase or prolong the potency or duration of the drug in the system. As used herein, "potentiation value" refers to the ability to maximize the ability of another therapeutic agent in an ideal system.
术语“免疫性疾病”指对内源性或外源性抗原产生的不良或有害反应的疾病或症状。结果通常会造成细胞的功能障碍、或因此而破坏并造成机能障碍、或破坏可能产生免疫症状的器官或组织。The term "immune disease" refers to a disease or condition of an adverse or deleterious response to an endogenous or exogenous antigen. The result is usually the dysfunction of cells, or the destruction and dysfunction of the cells, or the destruction of organs or tissues that may produce immune symptoms.
术语“试剂盒”与“产品包装”是同义词。The terms "kit" and "product packaging" are synonymous.
术语“受试者”或“病人”包括哺乳动物和非哺乳动物。哺乳动物包括但不限于，哺乳类：人、非人灵长类如猩猩、猿及猴类；农业动物如牛、马、山羊、绵羊、猪；家畜如兔、狗；实验动物包括啮齿类，如大鼠、小鼠及豚鼠等。非哺乳类动物包括但不限于，鸟、鱼等。在一优选例中，所选哺乳动物是人。The term "subject" or "patient" includes mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as orangutans, apes and monkeys; agricultural animals such as cattle, horses, goats, sheep, pigs; livestock such as rabbits, dogs; laboratory animals including rodents, Such as rats, mice and guinea pigs. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In a preferred embodiment, the selected mammal is a human.
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防和/或治疗由疾病或症状引起的征兆。The terms "treatment", "course of treatment" or "therapy" as used herein include alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of a disease or symptom, Such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing and/or treating symptoms caused by a disease or symptom.
如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或断续给药，可以归因于或与给药有关的情况。As used herein, a compound or pharmaceutical composition, when administered, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, conditions may be attributable to or associated with the administration.
给药途径Route of administration
适合的给药途径包括但不限于，口服、静脉注射、直肠、气雾剂、非肠道给药、眼部给药、肺部给药、经皮给药、***给药、耳道给药、鼻腔给药及局部给药。此外，仅作举例说明，肠道外给药，包括肌肉注射、皮下注射、静脉注射、髓内注射、心室注射、腹膜内注射、***内注射、及鼻内注射。Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, ear canal , nasal administration and topical administration. In addition, by way of example only, parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary, ventricular, intraperitoneal, intralymphatic, and intranasal.
在一方面，此处描述的化合物给药方式是局部的而不是全身性的给药方式。 在特定的具体实施例中，长效制剂通过植入给药(例如皮下或肌肉)或通过肌肉注射。此外，在另一具体化实施例中，药物通过靶向药物给药***来给药。例如，由器官特异性抗体包裹的脂质体。在这种具体实施例中，所述脂质体被选择性的导向特定器官并吸收。In one aspect, the compounds described herein are administered locally rather than systemically. In certain specific embodiments, the depot formulation is administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in another embodiment, the drug is administered by a targeted drug delivery system. For example, liposomes encapsulated by organ-specific antibodies. In this particular embodiment, the liposomes are selectively targeted to specific organs and absorbed.
药物组合物和剂量Pharmaceutical composition and dosage
本发明还提供药用组合物，其包含治疗有效量的与一种或多种药用载体(添加剂)和/或稀释剂一起配制的一种或多种本发明的化合物，和任选的一种或多种上述其它治疗剂。可通过任意合适方式给予本发明化合物以用于任意上述用途，例如口服，诸如片剂、丸剂、粉剂、颗粒剂、酏剂、酊剂、悬浮液(包括纳米悬浮液、微悬浮液、喷雾干燥的分散液)、糖浆和乳液；经舌下；含服；经肠胃外，诸如通过皮下、静脉内、肌内或胸骨内注射或输注技术(例如以无菌可注射水性或非水性溶液或悬浮液形式)；经鼻，包括向鼻膜给药，诸如通过吸入喷雾；局部，诸如以乳膏剂或软膏剂形式；或经直肠，诸如以栓剂形式；或经瘤内注射。它们可单独给药，但通常使用基于所选给药途径和标准药学实践选择的药物载体给药。The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the present invention formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally a one or more of the other therapeutic agents described above. The compounds of the present invention may be administered for any of the above uses by any suitable means, eg orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingual; buccal; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (eg, in sterile injectable aqueous or non-aqueous solutions or suspensions liquid); nasally, including administration to nasal membranes, such as by inhalation spray; topically, such as in cream or ointment; or rectally, such as in suppository; or by intratumoral injection. They can be administered alone, but are usually administered using a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
根据本领域技术人员认识范围内的诸多因素来调配药用载体。这些因素包括，但不限于：所调配活性剂的类型和性质；含有活性剂的组合物所要给药的受试者；组合物的预期给药途径；及所靶向的治疗适应症。药用载体包括水性和非水性液体介质及各种固体和半固体剂型。Pharmaceutically acceptable carriers are formulated according to a number of factors within the purview of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to which the composition containing the active agent is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media and various solid and semisolid dosage forms.
上述载体可包括除活性剂外的诸多不同成分和添加剂，上述其它成分出于本领域技术人员公知的各种原因包括于制剂中，例如稳定活性剂、粘合剂等。关于合适的药用载体和载体选择中所涉及的因素的描述可参见多个容易获得的来源，例如Allen L.V.Jr.et al.Remington:The Science and Practice of Pharmacy(2 Volumes),22nd Edition(2012),Pharmaceutical Press。Such carriers may include many different ingredients and additives in addition to the active agent, which are included in the formulation for various reasons known to those skilled in the art, such as stabilizing the active agent, binders, and the like. A description of suitable pharmaceutical carriers and factors involved in carrier selection can be found in a number of readily available sources such as Allen L.V.Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012 ), Pharmaceutical Press.
当然，本发明化合物的剂量方案取决于已知因素而有所变化，诸如具体药剂的药效学特性及其给药模式和途径；接受者的物种、年龄、性别、健康状况、医学病状和重量；症状的性质和程度；同时治疗的种类；治疗频率；给药途径、患者的肾和肝功能及期望效应。根据一般指导，当用于指定效应时，各活性成分的日口服剂量应为约0.001mg/天至约10-5000mg/天，优选地为约0.01mg/天至约1000mg/天，且最优选地为约0.1mg/天至约250mg/天。在恒速输注期间，静脉内最优选剂量应为约0.01mg/kg/分钟至约10mg/kg/分钟。本发明化合物可以单一日 剂量给药，或可以每日两次、三次或四次的分开剂量给药总日剂量。Of course, dosage regimens for the compounds of the present invention will vary depending on known factors, such as the pharmacodynamic properties of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition and weight of the recipient. nature and extent of symptoms; type of concomitant treatment; frequency of treatment; route of administration, renal and hepatic function of the patient, and desired effect. According to general guidance, the daily oral dose of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably, when used for the indicated effect Typically from about 0.1 mg/day to about 250 mg/day. During constant rate infusion, the most preferred intravenous dose should be from about 0.01 mg/kg/minute to about 10 mg/kg/minute. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
所述化合物通常以与根据预期给药形式(例如口服片剂、胶囊剂、酏剂和糖浆剂)适当地选择且与常规药学实践相符合的合适药物稀释剂、赋形剂或载体(在本文中统称为药物载体)的混合物形式进行给药。The compounds are usually in the form of suitable pharmaceutical diluents, excipients or carriers (herein) appropriately selected according to the intended form of administration (eg, oral tablets, capsules, elixirs and syrups) and consistent with conventional pharmaceutical practice. are administered in the form of a mixture of drug carriers).
适于给药的剂型(药物组合物)可含有约1毫克至约2000毫克活性成分/剂量单位。在这些医药组合物中，以组合物的总重量计，活性成分通常将以约0.1-95重量％的量存在。Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1-95% by weight, based on the total weight of the composition.
用于口服给药的典型胶囊剂含有至少一种本发明化合物(250mg)、乳糖(75mg)和硬脂酸镁(15mg)。使该混合物穿过60目网筛，并包装成1号明胶胶囊。A typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and packaged into size 1 gelatin capsules.
典型的可注射制剂可如下制备：以无菌方式将至少一种本发明化合物(250mg)置于瓶中、以无菌方式冻干并密封。为进行使用，将瓶内容物与2mL生理盐水混合，以产生可注射制剂。A typical injectable formulation can be prepared by aseptically placing at least one compound of the invention (250 mg) in a vial, aseptically lyophilizing and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline to produce an injectable formulation.
本发明范围包括(单独或与药物载体组合)包含治疗有效量的至少一种本发明化合物作为活性成分的药物组合物。任选地，本发明化合物可单独使用、与本发明其它化合物组合使用或与一种或多种其它治疗剂(例如抗癌剂或其它药学活性物质)组合使用。Within the scope of the present invention are pharmaceutical compositions comprising, either alone or in combination with a pharmaceutical carrier, a therapeutically effective amount of at least one compound of the present invention as an active ingredient. Optionally, the compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (eg, anticancer agents or other pharmaceutically active substances).
不考虑所选择的给药路径，通过本领域技术人员已知的常规方法来将本发的化合物(其可以合适的水合形式使用)和/或本发明的药物组合物配制成药用剂量形式。Regardless of the chosen route of administration, the compounds of the present invention (which may be used in a suitable hydrated form) and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art.
可改变活性成分在本发明的药物组合物中的实际剂量水平，从而获得对于实现特定患者的期望的治疗响应、组成和给药模式有效的而对患者无毒的活性成分量。The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response, composition, and mode of administration for a particular patient, without being toxic to the patient.
选定的剂量水平会取决于多种因素，包括所用的本发明的特定化合物或其酯、盐或酰胺的活性；给药路径；给药时间；所用的特定化合物的***速率；吸收速率和程度；治疗的持续时间；与所用的特定化合物组合使用的其它药物、化合物和/或物质；所治疗的患者的年龄、性别、重量、状况、一般健康和先前的医学史等医学领域公知的因素。The dose level selected will depend on a variety of factors, including the activity of the particular compound of the invention or its ester, salt or amide employed; the route of administration; the time of administration; the rate of excretion of the particular compound employed; the rate and extent of absorption duration of treatment; other drugs, compounds and/or substances used in combination with the particular compound used; factors well known in the medical arts such as age, sex, weight, condition, general health and previous medical history of the patient being treated.
具有本领域普通技术的医生或兽医可容易地确定并开出有效量的所需药物组合物。例如，为了达到所期望的治疗效果，医师或兽医可在低于所需的水平开始药物组合物中所用的本发明化合物的较量，并逐步增加剂量直至实现所期望的 效果。通常，合适日剂量的本发明化合物将是有效产生治疗效果的最低剂量的化合物的量。此种有效剂量通常取决于上述因素。通常，口服、静脉内、脑室内和皮下剂量的用于患者的本发明化合物的范围为约0.01至约50mg/kg体重/天。如果需要的话，有效日剂量的活性化合物可以两个、三个、四个、五个、六个或更多个亚剂量在一天当中的适当的间隔分别给药，任选地呈单位剂型形式。在本发明的某些方面中，服药为每天一次给药。A physician or veterinarian having ordinary skill in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, in order to achieve the desired therapeutic effect, a physician or veterinarian may initiate a dose of a compound of the present invention used in a pharmaceutical composition at a level lower than that required and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a compound of the present invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors discussed above. Typically, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of the invention for patients will range from about 0.01 to about 50 mg/kg body weight/day. If desired, an effective daily dose of the active compound may be administered separately in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form. In certain aspects of the invention, the dosing is once a day.
虽然本发明化合物可单独给药，但优选以药物制剂(组合物)形式给予化合物。试剂盒/产品包装Although the compounds of the present invention may be administered alone, it is preferred to administer the compounds in the form of a pharmaceutical formulation (composition). Kit/Product Packaging
为了用于上述适应症的治疗，试剂盒/产品包装也在此进行描述。这些试剂盒可以由输送器、药包或容器盒组成，容器盒可被划分成多格，以容纳一种或多种容器，如管形瓶、试管及类似物等，每个容器中包含所述方法中的单独一种成分。合适的容器包括瓶子，管形瓶，注射器和试管等。容器由可接受的玻璃或塑料等材料制作而成。Kits/product packaging are also described herein for use in the treatment of the above-mentioned indications. These kits may consist of a transporter, a pack, or a case of containers, which may be divided into compartments to accommodate one or more containers, such as vials, test tubes, and the like, each container containing the a single component of the method described above. Suitable containers include bottles, vials, syringes and test tubes, among others. Containers are made of acceptable materials such as glass or plastic.
举例来讲，容器可装有一种或多种在此所述的化合物，化合物可能以药物组分形式存在，也可能与在本文中所述的其它成分组成混合物体存在。容器可有一个无菌输出口(例如容器可为静脉输液包或瓶，瓶塞可被皮下注射器针头刺破)。这样的试剂盒可带有一种化合物，及本文中所述的使用方法的说明、标签或操作说明。For example, the container may contain one or more of the compounds described herein, which may be present as pharmaceutical components or in admixture with other ingredients described herein. The container may have a sterile outlet (eg, the container may be an IV pack or bottle, the stopper being pierced by a hypodermic needle). Such kits may carry a compound, along with instructions for use, labeling, or operating instructions as described herein.
一个典型的试剂盒可包括一种或多种容器，为适应商业推广和使用者对化合物使用的需求，每个容器装有一种或多种材料(如试剂，也可以是浓缩的母液，和/或器械)。这些材料包括但不局限于缓冲液，稀释液，滤器，针头，注射器，输送器，包，容器，瓶和/或试管，附有内容清单和/或使用说明书，内置包装也附有说明书。整套的说明都要包括在内。A typical kit may include one or more containers, each containing one or more materials (such as reagents, or concentrated stock solutions, and/ or equipment). These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, dispensers, bags, containers, vials and/or tubes, with a list of contents and/or instructions for use, and instructions for the inner packaging. The entire set of instructions is to be included.
标签可显示在容器上或与容器紧密相关。标签出现在容器上即指标签字母、数字或其它特征被粘贴、铸模、刻在容器上；标签也可出现在装有多种容器的容器盒或运输盒内，如在产品插页中。一个标签可用来提示内容物的某种特定治疗用途。标签也可标示内容物使用说明，诸如在上述方法中描述的。Labels can be displayed on or closely associated with the container. The presence of a label on a container means that the letters, numbers or other features of the label are affixed, molded, or engraved on the container; the label may also appear in a container box or shipping box containing a variety of containers, such as in product inserts. A label may be used to indicate a specific therapeutic use of the contents. The label may also indicate instructions for use of the contents, such as described in the above method.
在本说明书中被描述的所有特征(包括任何所述的权利要求、摘要和图),和/或任何方法或过程中涉及的所有步骤，均有可能以任意一种组合存在，除非某些特征或步骤在同一组合中是相互排斥的。All features described in this specification (including any stated claims, abstract and figures), and/or all steps involved in any method or process, may be present in any combination, unless certain features Or steps are mutually exclusive in the same combination.
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。The above features mentioned in the present invention or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in this specification can be used in combination with any composition, and each feature disclosed in the specification can be replaced by any alternative features that serve the same, equivalent or similar purpose. Therefore, unless otherwise stated, the disclosed features are only general examples of equivalent or similar features.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions or in accordance with the conditions suggested by the manufacturer. All percentages, ratios, ratios, or parts are by weight unless otherwise indicated.
本发明中的重量体积百分比中的单位是本领域技术人员所熟知的，例如是指在100毫升的溶液中溶质的重量。除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。The unit in the weight volume percentage in the present invention is well known to those skilled in the art, for example, it refers to the weight of the solute in 100 ml of the solution. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Methods and materials for preferred embodiments described herein are provided for illustrative purposes only.
实施例Example
通用过程Generic process
未包括制备途径时，本发明所用原料与试剂均为已知产品，可以按照本领域已知的方法合成，或者可通过购买市售产品获得。使用的市售试剂均不需进一步纯化。When the preparation route is not included, the raw materials and reagents used in the present invention are all known products, which can be synthesized according to methods known in the art, or can be obtained by purchasing commercially available products. None of the commercially available reagents were used without further purification.
室温是指20-30℃。Room temperature refers to 20-30°C.
如反应实施例中无特殊说明，则反应均在氮气氛下进行。氮气氛是指反应瓶连接一个约1L的氮气气球。Unless otherwise specified in the reaction examples, the reactions were all carried out under nitrogen atmosphere. Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L.
氢化反应通常抽真空，充入氢气，反复操作3次。氢气氛是指反应瓶连接一个约1L的氢气气球。The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times. Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L.
微波反应使用
Figure PCTCN2022085446-appb-000028
Initiator+微波反应器。 microwave reaction use
Figure PCTCN2022085446-appb-000028
Initiator+ microwave reactor.
本发明化合物的结构是通过核磁共振(NMR)和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用(Bruker Ascend TM 500型)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl 3),氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。以下简写用于NMR信号的多重性：s＝单峰，brs＝宽峰，d＝二重峰，t＝三重峰，m＝多重峰。耦合常数以J值列出， 以Hz测量。 The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" 6 > (ppm). NMR was measured using a (Bruker Ascend TM 500 type) nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and internal standard. For tetramethylsilane (TMS). The following abbreviations are used for the multiplicity of NMR signals: s=singlet, brs=broad, d=doublet, t=triplet, m=multiplet. Coupling constants are listed in J values, measured in Hz.
LC-MS的测定使用Thermo液质联用仪(UltiMate 3000+MSQ PLUS)。HPLC的测定使用Thermo高压液相色谱仪(UltiMate 3000)。反相制备色谱使用Thermo(UltiMate 3000)反相制备色谱仪。快速柱层析使用艾杰尔(FS-9200T)自动过柱机，硅胶预装柱使用三泰
Figure PCTCN2022085446-appb-000029
预装柱。薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。 The measurement of LC-MS was performed using a Thermo liquid mass spectrometer (UltiMate 3000+MSQ PLUS). For the HPLC measurement, a Thermo high pressure liquid chromatograph (UltiMate 3000) was used. Preparative Reversed Phase Chromatography A Thermo (UltiMate 3000) Preparative Reversed Phase Chromatograph was used. Fast column chromatography uses AIJER (FS-9200T) automatic column passing machine, and silica gel prepacked column uses Santai
Figure PCTCN2022085446-appb-000029
Prepacked columns. The thin layer chromatography silica gel plate is made of Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications of the thin layer chromatography separation and purification products are 0.4mm ~ 0.5mm.
本发明中一些中间体的合成方法如下：The synthetic methods of some intermediates in the present invention are as follows:
中间体1Intermediate 1
Figure PCTCN2022085446-appb-000030
Figure PCTCN2022085446-appb-000030
中间体1由以下步骤制备：Intermediate 1 was prepared by the following steps:
Figure PCTCN2022085446-appb-000031
Figure PCTCN2022085446-appb-000031
第一步：将1-甲基-3,5-二硝基吡啶-2-酮Int-1a(1.0g,5.02mmol)溶于甲醇(50mL)中，依次加入氨甲醇溶液(7mol/L，8.61mL,60.27mmol)和1-甲基哌啶-4-酮Int-1b(625mg,5.52mmol)。反应混合物加热至50℃搅拌5小时。冷却至室温后静置48小时，减压浓缩反应液，残余物加入乙酸乙酯(50mL)后过滤。滤液减压浓缩后得到红色固体Int-1c(1.0g)，直接用于下一步反应。ESI-MS (m/z):194.4[M+H] +； 1H NMR(500MHz,DMSO-d 6)δ9.14(d,J＝2.5Hz,1H),8.36(d,J＝2.5Hz,1H),3.64(s,2H),3.02(t,J＝6.0Hz,2H),2.74(t,J＝6.0Hz,2H),2.39(s,3H)。 The first step: 1-methyl-3,5-dinitropyridin-2-one Int-1a (1.0 g, 5.02 mmol) was dissolved in methanol (50 mL), followed by adding ammonia methanol solution (7 mol/L, 8.61 mL, 60.27 mmol) and 1-methylpiperidin-4-one Int-1b (625 mg, 5.52 mmol). The reaction mixture was heated to 50°C and stirred for 5 hours. After cooling to room temperature, it was left to stand for 48 hours, the reaction solution was concentrated under reduced pressure, and the residue was added with ethyl acetate (50 mL), followed by filtration. The filtrate was concentrated under reduced pressure to obtain Int-1c (1.0 g) as a red solid, which was directly used in the next reaction. ESI-MS (m/z): 194.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.14 (d, J=2.5 Hz, 1 H), 8.36 (d, J=2.5 Hz) , 1H), 3.64(s, 2H), 3.02(t, J=6.0Hz, 2H), 2.74(t, J=6.0Hz, 2H), 2.39(s, 3H).
第二步：将上一步得到的化合物Int-1c(1.0g)溶于甲醇(30mL)中，加入10％Pd-C(400mg)，在氢气氛围下室温反应6小时。过滤除去钯碳，滤液浓缩得到黄色固体Int-1d(800mg，收率94.70％)。ESI-MS(m/z):164.2[M+H] +。 The second step: The compound Int-1c (1.0 g) obtained in the previous step was dissolved in methanol (30 mL), 10% Pd-C (400 mg) was added, and the reaction was carried out at room temperature for 6 hours under a hydrogen atmosphere. The palladium carbon was removed by filtration, and the filtrate was concentrated to obtain Int-1d as a yellow solid (800 mg, yield 94.70%). ESI-MS (m/z): 164.2 [M+H] + .
第三步：将化合物Int-1d(100mg,0.61mmol)溶于醋酸(3mL)中，加入N-溴代丁二酰亚胺(109mg,0.61mmol)，反应混合物在室温下搅拌1小时。加入饱和碳酸氢钠水溶液淬灭反应直至不产生气泡，水相用甲醇/二氯甲烷(1/20,50mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤浓缩得到化合物Int-1e(38mg，收率25％)。ESI-MS(m/z):242.3[M+H] +； 1H NMR(500MHz,DMSO-d 6)δ6.77(s,1H),5.25(s,2H),3.37(s,2H),2.69(t,J＝6.0Hz,2H),2.60(t,J＝6.0Hz,2H),2.32(s,3H)。 The third step: Compound Int-1d (100 mg, 0.61 mmol) was dissolved in acetic acid (3 mL), N-bromosuccinimide (109 mg, 0.61 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to quench the reaction until no bubbles were generated, the aqueous phase was extracted with methanol/dichloromethane (1/20, 50 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound Int-1e (38 mg, 25% yield). ESI-MS (m/z): 242.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d 6 ) δ 6.77 (s, 1H), 5.25 (s, 2H), 3.37 (s, 2H) , 2.69(t, J=6.0Hz, 2H), 2.60(t, J=6.0Hz, 2H), 2.32(s, 3H).
第四步：将化合物Int-1e(37mg,0.15mmol)溶于甲醇(1mL)中，加入碘化亚铜(3mg，0.015mmol)，1，10-菲啰啉(3mg，0.03mmol)和碳酸铯(99mg,0.30mmol)。反应混合物置换氮气后用微波加热至100℃搅拌2小时。反应冷却至室温，浓缩反应液，残余物用制备型薄层层析纯化(甲醇/二氯甲烷/三乙胺＝1/10/0.1)得到黄色固体Int-1(20mg，收率67％)。ESI-MS(m/z):194.5[M+H] +； 1H NMR(500MHz,DMSO-d 6)δ6.54(s,1H),4.68(s,2H),3.80(s,3H),3.30(s,2H),2.64(t,J＝5.6Hz,2H),2.59(t,J＝5.7Hz,2H),2.31(s,3H)。 The fourth step: Compound Int-1e (37mg, 0.15mmol) was dissolved in methanol (1mL), cuprous iodide (3mg, 0.015mmol), 1,10-phenanthroline (3mg, 0.03mmol) and carbonic acid were added. Cesium (99 mg, 0.30 mmol). The reaction mixture was replaced with nitrogen and heated to 100°C with microwave and stirred for 2 hours. The reaction was cooled to room temperature, the reaction solution was concentrated, and the residue was purified by preparative thin layer chromatography (methanol/dichloromethane/triethylamine=1/10/0.1) to obtain a yellow solid Int-1 (20 mg, yield 67%) . ESI-MS (m/z): 194.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d 6 ) δ 6.54 (s, 1H), 4.68 (s, 2H), 3.80 (s, 3H) , 3.30(s, 2H), 2.64(t, J=5.6Hz, 2H), 2.59(t, J=5.7Hz, 2H), 2.31(s, 3H).
中间体2Intermediate 2
Figure PCTCN2022085446-appb-000032
Figure PCTCN2022085446-appb-000032
中间体2由以下步骤制备：Intermediate 2 was prepared by the following steps:
Figure PCTCN2022085446-appb-000033
Figure PCTCN2022085446-appb-000033
第一步：将化合物Int-1e(230mg,0.94mmol)溶于乙醇(2mL)中，加入碘化亚铜(18mg,0.095mmol)，1，10-菲啰啉(34mg,0.18mmol)和碳酸铯(619mg,1.90mmol)。反应混合物置换氮气后用微波加热至100℃搅拌5小时。反应冷却至室温，过滤，滤液浓缩，残余物用硅胶柱层析纯化(甲醇/二氯甲烷/三乙胺＝1/50/0.1)得到黄色固体Int-2(113mg，收率57％)。ESI-MS(m/z):208.5[M+H] +。 The first step: Compound Int-1e (230mg, 0.94mmol) was dissolved in ethanol (2mL), cuprous iodide (18mg, 0.095mmol), 1,10-phenanthroline (34mg, 0.18mmol) and carbonic acid were added Cesium (619 mg, 1.90 mmol). The reaction mixture was heated to 100°C by microwave and stirred for 5 hours after displacing nitrogen. The reaction was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methanol/dichloromethane/triethylamine=1/50/0.1) to give yellow solid Int-2 (113 mg, yield 57%). ESI-MS (m/z): 208.5 [M+H] + .
中间体3Intermediate 3
Figure PCTCN2022085446-appb-000034
Figure PCTCN2022085446-appb-000034
中间体3由以下步骤制备：Intermediate 3 was prepared by the following steps:
Figure PCTCN2022085446-appb-000035
Figure PCTCN2022085446-appb-000035
第一步：将化合物Int-1e(100mg，0.41mmol)和三甲基环三硼氧烷(148mg，1.19mmol)溶于二氧六环(1.5mL)和水(0.15mL)中，加入碳酸钾(171mg，1.24mmol)，Pd(dppf)Cl 2(30mg,0.041mmol)。反应体系置换氮气后用微波加热至140℃搅拌1小时。反应冷却至室温，反应混合物用硅藻土过滤，滤液浓缩。残余物用硅胶柱层析纯化(甲醇/二氯甲烷＝1/20)得到黄色固体Int-3(50mg，收率68％)。ESI-MS(m/z):178.6[M+H] +。 The first step: Compound Int-1e (100 mg, 0.41 mmol) and trimethylcyclotriboroxane (148 mg, 1.19 mmol) were dissolved in dioxane (1.5 mL) and water (0.15 mL), and carbonic acid was added Potassium (171 mg, 1.24 mmol), Pd(dppf)Cl2 (30 mg , 0.041 mmol). After the reaction system was replaced with nitrogen, it was heated to 140° C. with a microwave and stirred for 1 hour. The reaction was cooled to room temperature, the reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (methanol/dichloromethane=1/20) to obtain Int-3 as a yellow solid (50 mg, yield 68%). ESI-MS (m/z): 178.6 [M+H] + .
中间体4Intermediate 4
Figure PCTCN2022085446-appb-000036
Figure PCTCN2022085446-appb-000036
中间体4由以下步骤制备：Intermediate 4 was prepared by the following steps:
Figure PCTCN2022085446-appb-000037
Figure PCTCN2022085446-appb-000037
第一步：将化合物Int-1e(350mg,1.45mmol)和乙烯基三氟硼酸钾(387mg,2.89mmol)溶于1,4-二氧六环(1.5mL)和水(0.15mL)中，加入碳酸钾(399mg,2.89mmol)和Pd(dppf)Cl 2(105mg,0.14mmol)。反应体系置换氮气后用微波反应器加热至120℃搅拌1小时。反应冷却至室温后，用硅藻土过滤，滤液浓缩，残留物用柱层析分离(甲醇/二氯甲烷＝1/20)得到黄色固体Int-4a(136mg,收率49％)。ESI-MS(m/z):190.7[M+H] +； 1H NMR(500MHz,CDCl 3)δ6.85(dd,J＝17.2,11.0Hz,1H),6.66(s,1H),6.16(dd,J＝17.3,1.9Hz,1H),5.49(dd,J＝11.0,1.9Hz,1H),3.67-3.63(m,2H),3.55(s,2H),3.00(t,J＝6.1Hz,2H),2.80(t,J＝6.1Hz,2H),2.49(s,3H)。 The first step: Compound Int-1e (350 mg, 1.45 mmol) and potassium vinyl trifluoroborate (387 mg, 2.89 mmol) were dissolved in 1,4-dioxane (1.5 mL) and water (0.15 mL), Potassium carbonate (399 mg, 2.89 mmol) and Pd(dppf)Cl2 (105 mg , 0.14 mmol) were added. After the reaction system was replaced with nitrogen, it was heated to 120° C. with a microwave reactor and stirred for 1 hour. After the reaction was cooled to room temperature, it was filtered through celite, the filtrate was concentrated, and the residue was separated by column chromatography (methanol/dichloromethane=1/20) to obtain yellow solid Int-4a (136 mg, yield 49%). ESI-MS (m/z): 190.7 [M+H] + ; 1 H NMR (500 MHz, CDCl 3 ) δ 6.85 (dd, J=17.2, 11.0 Hz, 1H), 6.66 (s, 1H), 6.16 (dd,J=17.3,1.9Hz,1H),5.49(dd,J=11.0,1.9Hz,1H),3.67-3.63(m,2H),3.55(s,2H),3.00(t,J=6.1 Hz, 2H), 2.80 (t, J=6.1 Hz, 2H), 2.49 (s, 3H).
第二步：将化合物Int-4a(60mg,0.31mmol)溶于甲醇(5mL)中，加入10％钯碳(20mg)，混合物在氢气氛围下室温搅拌1小时。反应液用硅藻土过滤，滤液浓缩得到中间体4(37mg,收率61％)。ESI-MS(m/z):192.7[M+H] +。 The second step: Compound Int-4a (60 mg, 0.31 mmol) was dissolved in methanol (5 mL), 10% palladium on carbon (20 mg) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain Intermediate 4 (37 mg, yield 61%). ESI-MS (m/z): 192.7 [M+H] + .
中间体5Intermediate 5
Figure PCTCN2022085446-appb-000038
Figure PCTCN2022085446-appb-000038
中间体5由以下步骤制备：Intermediate 5 was prepared by the following steps:
Figure PCTCN2022085446-appb-000039
Figure PCTCN2022085446-appb-000039
第一步：将化合物Int-1e(100mg,0.41mmol)溶于甲苯(3mL)和水(0.3mL) 的混合溶剂中，加入环丙基硼酸(42mg,0.49mmol)，磷酸钾(306mg,1.45mmol)，三环己基膦(23mg,0.082mmol)和醋酸钯(9mg,0.041mmol)。反应体系置换氮气后加热至100℃搅拌18小时。反应冷却至室温后，反应液用硅藻土过滤，滤液浓缩，残留物用柱层析分离(甲醇/二氯甲烷＝1/20)得到黄色固体Int-5(61mg，收率72％)。ESI-MS(m/z):204.2[M+H] +。 The first step: Compound Int-1e (100mg, 0.41mmol) was dissolved in a mixed solvent of toluene (3mL) and water (0.3mL), cyclopropylboronic acid (42mg, 0.49mmol), potassium phosphate (306mg, 1.45 mmol), tricyclohexylphosphine (23 mg, 0.082 mmol) and palladium acetate (9 mg, 0.041 mmol). After the reaction system was replaced with nitrogen, it was heated to 100°C and stirred for 18 hours. After the reaction was cooled to room temperature, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was separated by column chromatography (methanol/dichloromethane=1/20) to obtain yellow solid Int-5 (61 mg, yield 72%). ESI-MS (m/z): 204.2 [M+H] + .
中间体6Intermediate 6
Figure PCTCN2022085446-appb-000040
Figure PCTCN2022085446-appb-000040
中间体6由以下步骤制备：Intermediate 6 was prepared by the following steps:
Figure PCTCN2022085446-appb-000041
Figure PCTCN2022085446-appb-000041
第一步：将N-叔丁氧羰基-4-哌啶酮Int-6a(4.4g，22.1mmol)和1-甲基-3，5-二硝基-2-吡啶酮Int-1a(4.0g，20.1mmol)溶于甲醇(150mL)中，加入氨甲醇溶液(7N，34.4mL，240.8mmol)。氮气保护下60℃搅拌6小时。反应液降至室温，继续搅拌2天。LCMS监测反应结束，反应液浓缩，加入乙酸乙酯(150mL)，搅拌半小时后过滤，滤液浓缩得到黄色固体Int-6b(5.1g，产率91％)。ESI-MS(m/z):280.1[M+H] +。 The first step: N-tert-butoxycarbonyl-4-piperidinone Int-6a (4.4 g, 22.1 mmol) and 1-methyl-3,5-dinitro-2-pyridone Int-1a (4.0 g, 20.1 mmol) was dissolved in methanol (150 mL) and ammonia in methanol (7N, 34.4 mL, 240.8 mmol) was added. Stir at 60°C for 6 hours under nitrogen protection. The reaction solution was cooled to room temperature, and stirring was continued for 2 days. The reaction was monitored by LCMS, the reaction solution was concentrated, ethyl acetate (150 mL) was added, stirred for half an hour, filtered, and the filtrate was concentrated to obtain yellow solid Int-6b (5.1 g, yield 91%). ESI-MS (m/z): 280.1 [M+H] + .
第二步：将化合物Int-6b(5.0g，17.9mmol)，溶于甲醇(50mL)中，加入10％钯/碳(500mg)。混合物在氢气氛围下(氢气球)室温搅拌16小时。反应结束后，反应液过滤，滤液浓缩得到淡黄色固体Int-6c(3.7g，产率84％)。ESI-MS(m/z):250.2[M+H] +。 The second step: Compound Int-6b (5.0 g, 17.9 mmol) was dissolved in methanol (50 mL), and 10% palladium/carbon (500 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere (hydrogen balloon) for 16 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated to obtain Int-6c (3.7 g, yield 84%) as a light yellow solid. ESI-MS (m/z): 250.2 [M+H] + .
第三步：将化合物Int-6c(3.7g，14.8mmol)溶于DMF(20mL)中，加入N-溴代丁二酰亚胺(2.78g，15.6mmol)和醋酸(370mg)。反应混合物室温搅拌2小时，LCMS监测反应结束。加水(100mL)，用乙酸乙酯萃取水相(150mL*3)，有机相合并，饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，残余物后通过硅胶柱层析分离得到黄色固体Int-6d(3.6g，产率74％)。ESI-MS(m/z):328.2[M+H] +。 The third step: Compound Int-6c (3.7 g, 14.8 mmol) was dissolved in DMF (20 mL), and N-bromosuccinimide (2.78 g, 15.6 mmol) and acetic acid (370 mg) were added. The reaction mixture was stirred at room temperature for 2 hours and completed by LCMS. Water (100 mL) was added, the aqueous phase (150 mL*3) was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography to obtain a yellow solid Int- 6d (3.6 g, 74% yield). ESI-MS (m/z): 328.2 [M+H] + .
第四步：将化合物Int-6d(500mg，1.53mmol)溶于甲醇(5mL)中，加入甲醇钠甲醇溶液(5N，0.33mL，1.65mmol)。反应混合物用微波加热至100℃搅拌3小时。反应冷至室温，反应液浓缩，残余物通过硅胶柱层析分离得到黄色固体Int-6(330mg，产率77％)。ESI-MS(m/z):280.2[M+H] +。 The fourth step: Compound Int-6d (500 mg, 1.53 mmol) was dissolved in methanol (5 mL), and sodium methoxide methanol solution (5N, 0.33 mL, 1.65 mmol) was added. The reaction mixture was heated to 100°C with microwave and stirred for 3 hours. The reaction was cooled to room temperature, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography to obtain Int-6 as a yellow solid (330 mg, yield 77%). ESI-MS (m/z): 280.2 [M+H] + .
实施例1Example 1
3-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-1-甲基吡啶-2(1H)-酮3-(((5-Chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) pyrimidin-4-yl)amino)methyl)-1-methylpyridin-2(1H)-one
Figure PCTCN2022085446-appb-000042
Figure PCTCN2022085446-appb-000042
化合物1由以下步骤制备：Compound 1 was prepared by the following steps:
Figure PCTCN2022085446-appb-000043
Figure PCTCN2022085446-appb-000043
第一步：将2，4，5-三氯嘧啶1a(57mg，0.31mmol)和3-(氨基甲基)-1-甲基-1,2-二氢吡啶-2-酮盐酸盐1b(50mg，0.28mmol)和溶于异丙醇(2mL)中，加入N，N-二异丙基乙胺(85mg，0.65mmol,0.11mL)。反应混合物在室温下搅拌18小时。过滤反应液，固体用异丙醇洗，干燥得到白色固体1c(62mg，收率75％)。ESI-MS(m/z):285.2[M+H] +。 The first step: 2,4,5-trichloropyrimidine 1a (57 mg, 0.31 mmol) and 3-(aminomethyl)-1-methyl-1,2-dihydropyridin-2-one hydrochloride 1b (50 mg, 0.28 mmol) and dissolved in isopropanol (2 mL) and N,N-diisopropylethylamine (85 mg, 0.65 mmol, 0.11 mL) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction solution was filtered, the solid was washed with isopropanol, and dried to obtain a white solid 1c (62 mg, yield 75%). ESI-MS (m/z): 285.2 [M+H] + .
第二步：将化合物1c(62mg，0.21mmol)和Int-1(42mg，0.21mmol)溶于1，4-二氧六环(5mL)中，加入BrettPhos Pd G3(19mg，0.021mmol)，BrettPhos(23mg，0.043mmol)和碳酸铯(141mg，0.43mmol)，反应体系置换氮气后加热至100℃搅拌18小时。待反应液冷却至室温，反应液用硅藻土过滤，滤液浓缩。残留用硅胶柱层析纯化(甲醇/二氯甲烷＝1/30)得到粗产品，再用反向制备HPLC分离得到白色固体1(25mg,收率26％)。ESI-MS(m/z):442.3[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.00(s,1H),7.86(s,1H),7.69-7.61(m,2H),7.56(s,1H),7.08(d,J＝6.8Hz,1H),6.19(t,J＝6.8Hz,1H),4.37(d,J＝5.9Hz,2H),3.86(s,3H),3.50(s,3H),3.12(s,2H),2.70(t,J＝6.0Hz,2H),2.60(t,J＝5.9Hz,2H),2.33(s,3H)。 The second step: Compound 1c (62 mg, 0.21 mmol) and Int-1 (42 mg, 0.21 mmol) were dissolved in 1,4-dioxane (5 mL), and BrettPhos Pd G3 (19 mg, 0.021 mmol) was added, BrettPhos (23 mg, 0.043 mmol) and cesium carbonate (141 mg, 0.43 mmol), the reaction system was heated to 100° C. and stirred for 18 hours after replacing nitrogen. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (methanol/dichloromethane=1/30) to obtain a crude product, which was then separated by reverse-phase preparative HPLC to obtain white solid 1 (25 mg, yield 26%). ESI-MS (m/z): 442.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.86 (s, 1H), 7.69-7.61 (m, 2H) ),7.56(s,1H),7.08(d,J＝6.8Hz,1H),6.19(t,J＝6.8Hz,1H),4.37(d,J＝5.9Hz,2H),3.86(s,3H ), 3.50(s, 3H), 3.12(s, 2H), 2.70(t, J=6.0Hz, 2H), 2.60(t, J=5.9Hz, 2H), 2.33(s, 3H).
实施例2Example 2
3-(((5-氯-2-((2-乙氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-1-甲基吡啶-2(1H)-酮3-(((5-Chloro-2-((2-ethoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) pyrimidin-4-yl)amino)methyl)-1-methylpyridin-2(1H)-one
Figure PCTCN2022085446-appb-000044
Figure PCTCN2022085446-appb-000044
用Int-2替代实施例1第二步中的Int-1，用类似的方法和反应步骤，可以得到化合物2。ESI-MS(m/z):456.1[M+H] +； 1HNMR(500MHz,DMSO-d6)δ8.00(s,1H), 7.87(s,1H),7.69(t,J＝5.9Hz,1H),7.64(dd,J＝6.7,2.0Hz,1H),7.48(s,1H),7.12-7.06(m,1H),6.18(t,J＝6.8Hz,1H),4.38(d,J＝5.9Hz,2H),4.30(q,J＝7.0Hz,2H),3.50(s,3H),3.09(s,2H),2.67(d,J＝5.9Hz,2H),2.59(d,J＝5.7Hz,2H),2.32(s,3H),1.32(t,J＝7.0Hz,3H)。 Substituting Int-2 for Int-1 in the second step of Example 1, and using similar methods and reaction steps, compound 2 can be obtained. ESI-MS (m/z): 456.1[M+H] + ; 1 HNMR (500MHz, DMSO-d6) δ 8.00(s, 1H), 7.87(s, 1H), 7.69(t, J=5.9Hz ,1H),7.64(dd,J＝6.7,2.0Hz,1H),7.48(s,1H),7.12-7.06(m,1H),6.18(t,J＝6.8Hz,1H),4.38(d, J=5.9Hz, 2H), 4.30(q, J=7.0Hz, 2H), 3.50(s, 3H), 3.09(s, 2H), 2.67(d, J=5.9Hz, 2H), 2.59(d, J=5.7Hz, 2H), 2.32 (s, 3H), 1.32 (t, J=7.0Hz, 3H).
实施例3Example 3
3-(((2-((2-乙氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)甲基)-1-甲基吡啶-2(1H)-酮3-(((2-((2-Ethoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino)-5-( Trifluoromethyl)pyrimidin-4-yl)amino)methyl)-1-methylpyridin-2(1H)-one
Figure PCTCN2022085446-appb-000045
Figure PCTCN2022085446-appb-000045
用2，4-二氯-5-三氟甲基嘧啶替代实施例1第一步中的2，4，5-三氯嘧啶1a，然后用Int-2替代实施例1第二步中的Int-1，用类似的方法和反应步骤，可以得到化合物3。ESI-MS(m/z):490.2[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.23(s,1H),7.95(s,1H),7.76(s,1H),7.64(dd,J＝6.7,2.0Hz,1H),7.59(br s,1H),7.02(d,J＝7.0Hz,1H),6.19(t,J＝6.8Hz,1H),4.40(d,J＝5.6Hz,2H),4.30(q,J＝7.0Hz,2H),3.50(s,3H),3.10(br s,2H),2.69(t,J＝5.9Hz,2H),2.59(t,J＝5.9Hz,2H),2.33(s,3H),1.31(t,J＝7.0Hz,3H)。 Substitute 2,4-dichloro-5-trifluoromethylpyrimidine for 2,4,5-trichloropyrimidine 1a in the first step of Example 1, and then substitute Int-2 for Int in the second step of Example 1 -1, Compound 3 can be obtained by a similar method and reaction procedure. ESI-MS (m/z): 490.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ 8.23(s, 1H), 7.95(s, 1H), 7.76(s, 1H), 7.64(dd,J=6.7,2.0Hz,1H),7.59(br s,1H),7.02(d,J=7.0Hz,1H),6.19(t,J=6.8Hz,1H),4.40(d, J=5.6Hz, 2H), 4.30(q, J=7.0Hz, 2H), 3.50(s, 3H), 3.10(br s, 2H), 2.69(t, J=5.9Hz, 2H), 2.59(t , J=5.9Hz, 2H), 2.33 (s, 3H), 1.31 (t, J=7.0Hz, 3H).
实施例4Example 4
5-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)吡啶-2(1H)-酮5-(((5-Chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) pyrimidin-4-yl)amino)methyl)pyridin-2(1H)-one
Figure PCTCN2022085446-appb-000046
Figure PCTCN2022085446-appb-000046
用5-(氨基甲基)-1，2-二氢吡啶-2-酮替代实施例1第一步中的3-(氨基甲基)-1-甲基-1,2-二氢吡啶-2-酮盐酸盐1b，用类似的方法和反应步骤，可以得到化合物 4。ESI-MS(m/z):428.2[M+H] +； 1H NMR(500MHz,DMSO-d6)δ7.99(s,1H),7.96(s,1H),7.74(s,1H),7.68(t,J＝5.9Hz,1H),7.40(dd,J＝9.4,2.6Hz,1H),7.20(br s,1H),6.27(d,J＝9.4Hz,1H),4.29(d,J＝5.6Hz,2H),3.88(s,3H),3.34-3.30(m,2H),2.74(t,J＝5.8Hz,2H),2.63(t,J＝5.9Hz,2H),2.33(s,3H)。 Substitute 5-(aminomethyl)-1,2-dihydropyridin-2-one for 3-(aminomethyl)-1-methyl-1,2-dihydropyridine- 2-keto hydrochloride 1b, compound 4 can be obtained by a similar method and reaction procedure. ESI-MS (m/z): 428.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ 7.99(s, 1H), 7.96(s, 1H), 7.74(s, 1H), 7.68(t, J=5.9Hz, 1H), 7.40(dd, J=9.4, 2.6Hz, 1H), 7.20(br s, 1H), 6.27(d, J=9.4Hz, 1H), 4.29(d, J=5.6Hz, 2H), 3.88(s, 3H), 3.34-3.30(m, 2H), 2.74(t, J=5.8Hz, 2H), 2.63(t, J=5.9Hz, 2H), 2.33( s, 3H).
实施例5Example 5
3-(((5-氯-2-((2,6-二甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-1-甲基吡啶-2(1H)-酮3-(((5-Chloro-2-((2,6-dimethyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino)pyrimidine-4 -yl)amino)methyl)-1-methylpyridin-2(1H)-one
Figure PCTCN2022085446-appb-000047
Figure PCTCN2022085446-appb-000047
用Int-3替代实施例1第二步中的Int-1，用类似的方法和反应步骤，可以得到化合物5。ESI-MS(m/z):426.2[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.36(s,1H),7.91(s,1H),7.63(dd,J＝6.8,2.0Hz,1H),7.50-7.40(m,2H),7.08-6.96(m,1H),6.18(t,J＝6.8Hz,1H),4.29(d,J＝5.9Hz,2H),3.47(s,3H),3.19(s,2H),2.76(t,J＝6.0Hz,2H),2.62(t,J＝6.0Hz,2H),2.31(s,3H),2.30(s,3H)。 Substituting Int-3 for Int-1 in the second step of Example 1, and using similar methods and reaction steps, compound 5 can be obtained. ESI-MS (m/z): 426.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.91 (s, 1H), 7.63 (dd, J=6.8 ,2.0Hz,1H),7.50-7.40(m,2H),7.08-6.96(m,1H),6.18(t,J=6.8Hz,1H),4.29(d,J=5.9Hz,2H),3.47 (s,3H),3.19(s,2H),2.76(t,J=6.0Hz,2H),2.62(t,J=6.0Hz,2H),2.31(s,3H),2.30(s,3H) .
实施例6Example 6
3-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-1,4,6-三甲基吡啶-2(1H)-酮3-(((5-Chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) pyrimidin-4-yl)amino)methyl)-1,4,6-trimethylpyridin-2(1H)-one
Figure PCTCN2022085446-appb-000048
Figure PCTCN2022085446-appb-000048
化合物6由以下步骤制备：Compound 6 was prepared by the following steps:
Figure PCTCN2022085446-appb-000049
Figure PCTCN2022085446-appb-000049
第一步：在0℃冰浴和氮气氛围下，向氢化钠(202mg，5.06mmol,含量60％)的DMF(5mL)悬浊液中加入化合物6a(500mg，3.37mmol)的DMF(5mL)溶液。搅拌30分钟后，加入碘甲烷(718mg，5.06mmol，0.31mL)，混合物在室温下搅拌16小时。反应液用乙酸乙酯稀释，依次用水和饱和食盐水洗涤。有机相用无水硫酸钠干燥，过滤浓缩，残余物用硅胶柱层析分离(石油醚/乙酸乙酯＝1/1)得到黄色固体6b(230mg，收率42％)。ESI-MS(m/z):163.1[M+H] +。 Step 1: To a suspension of sodium hydride (202 mg, 5.06 mmol, content 60%) in DMF (5 mL) at 0°C in an ice bath and nitrogen atmosphere, compound 6a (500 mg, 3.37 mmol) in DMF (5 mL) was added solution. After stirring for 30 minutes, iodomethane (718 mg, 5.06 mmol, 0.31 mL) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, and washed with water and saturated brine in this order. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain yellow solid 6b (230 mg, yield 42%). ESI-MS (m/z): 163.1 [M+H] + .
第二步：将化合物6b(230mg，1.42mmol)溶于甲醇(5mL)中，加入Raney Ni(0.5mL,水混悬液)和氨水(0.5mL)。混合物在氢气(氢气球)氛围下室温搅拌16小时。反应液用硅藻土过滤，滤饼用甲醇洗，滤液浓缩得到化合物6c(200mg)，直接用于下一步反应。ESI-MS(m/z):167.1[M+H] +。 Second step: Compound 6b (230 mg, 1.42 mmol) was dissolved in methanol (5 mL), Raney Ni (0.5 mL, aqueous suspension) and ammonia (0.5 mL) were added. The mixture was stirred at room temperature under an atmosphere of hydrogen (hydrogen balloon) for 16 hours. The reaction solution was filtered with celite, the filter cake was washed with methanol, and the filtrate was concentrated to obtain compound 6c (200 mg), which was directly used in the next reaction. ESI-MS (m/z): 167.1 [M+H] + .
第三步：将化合物6c(135mg)溶于异丙醇(2mL)中，加入N，N-二异丙基乙胺(159mg，1.23mmol，0.21mL)和2，4，5-三氯嘧啶1a(150mg，0.81mmol)，混合物在室温下搅拌16小时。浓缩反应液，残留物用硅胶柱层析分离(二氯甲烷/甲醇＝10/1)得到白色固体6d(130mg)。ESI-MS(m/z):313.2[M+H] +。 The third step: Compound 6c (135 mg) was dissolved in isopropanol (2 mL), and N,N-diisopropylethylamine (159 mg, 1.23 mmol, 0.21 mL) and 2,4,5-trichloropyrimidine were added 1a (150 mg, 0.81 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain 6d (130 mg) as a white solid. ESI-MS (m/z): 313.2 [M+H] + .
第四步：将化合物6d(71mg，0.22mmol)和Int-1(40mg，0.20mmol)溶于1，4-二氧六环(4mL)中，加入碳酸铯(202mg，0.62mmol)，BrettPhos(22mg， 0.041mmol)和BrettPhos Pd G3(18mg，0.020mmol)。反应体系置换氮气后加热至100℃搅拌16小时。待反应液冷却至室温，反应液浓缩，残留物用制备薄层层析纯化(二氯甲烷/甲醇＝10/1)得到粗产品，再用反向制备HPLC分离得到化合物6(10mg，收率10％)。ESI-MS(m/z):470.2[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.07(s,1H),7.94(s,1H),7.69(s,1H),7.07(br s,1H),6.05(s,1H),4.44(d,J＝5.5Hz,2H),3.88(s,3H),3.46-3.40(m,5H),2.75(br s,2H),2.65(t,J＝5.5Hz,2H),2.34(s,3H),2.30(s,3H),2.12(s,3H)。 The fourth step: Compound 6d (71 mg, 0.22 mmol) and Int-1 (40 mg, 0.20 mmol) were dissolved in 1,4-dioxane (4 mL), cesium carbonate (202 mg, 0.62 mmol) was added, BrettPhos ( 22 mg, 0.041 mmol) and BrettPhos Pd G3 (18 mg, 0.020 mmol). After the reaction system was replaced with nitrogen, it was heated to 100°C and stirred for 16 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane/methanol=10/1) to obtain a crude product, which was then separated by reverse preparative HPLC to obtain compound 6 (10 mg, yield 10%). ESI-MS (m/z): 470.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ 8.07(s, 1H), 7.94(s, 1H), 7.69(s, 1H), 7.07(br s,1H),6.05(s,1H),4.44(d,J=5.5Hz,2H),3.88(s,3H),3.46-3.40(m,5H),2.75(br s,2H) , 2.65(t, J=5.5Hz, 2H), 2.34(s, 3H), 2.30(s, 3H), 2.12(s, 3H).
实施例7Example 7
3-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-4,6-二甲基吡啶-2(1H)-酮3-(((5-Chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) Pyrimidin-4-yl)amino)methyl)-4,6-lutidine-2(1H)-one
Figure PCTCN2022085446-appb-000050
Figure PCTCN2022085446-appb-000050
用3-(氨基甲基)-4,6-二甲基-1,2-二氢吡啶-2-酮替代实施例1第一步中的3-(氨基甲基)-1-甲基-1,2-二氢吡啶-2-酮盐酸盐1b，用类似的方法和反应步骤，可以得到化合物7。ESI-MS(m/z):456.0[M+H] +； 1HNMR(500MHz,DMSO-d6)δ11.59(br s,1H),8.09(s,1H),7.94(s,1H),7.69(s,1H),7.20(br s,1H),5.89(s,1H),4.42(br s,2H),3.89(s,3H),3.42(s,2H),2.75(br s,2H),2.65(br s,2H),2.34(s,3H),2.12(s,6H)。 Substitute 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one for 3-(aminomethyl)-1-methyl- 1,2-Dihydropyridin-2-one hydrochloride 1b, compound 7 can be obtained by a similar method and reaction procedure. ESI-MS(m/z): 456.0[M+H] + ; 1 HNMR (500MHz, DMSO-d6)δ11.59(br s,1H),8.09(s,1H),7.94(s,1H), 7.69(s, 1H), 7.20(br s, 1H), 5.89(s, 1H), 4.42(br s, 2H), 3.89(s, 3H), 3.42(s, 2H), 2.75(br s, 2H ), 2.65(br s, 2H), 2.34(s, 3H), 2.12(s, 6H).
实施例8Example 8
4-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)吡啶-2(1H)-酮4-(((5-Chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) pyrimidin-4-yl)amino)methyl)pyridin-2(1H)-one
Figure PCTCN2022085446-appb-000051
Figure PCTCN2022085446-appb-000051
用4-(氨基甲基)-1,2-二氢吡啶-2-酮替代实施例1第一步中的3-(氨基甲基)-1-甲基 -1,2-二氢吡啶-2-酮盐酸盐1b，用类似的方法和反应步骤，可以得到化合物8。ESI-MS(m/z):428.1[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.01(s,1H),7.90(s,1H),7.83(t,J＝6.1Hz,1H),7.62(s,1H),7.31(d,J＝6.7Hz,1H),6.11(dd,J＝6.8,1.7Hz,1H),6.08(s,1H),4.41(d,J＝5.8Hz,2H),3.86(s,3H),3.22(s,2H),2.71(t,J＝5.9Hz,2H),2.61(t,J＝5.9Hz,2H),2.33(s,3H)。 Substitute 4-(aminomethyl)-1,2-dihydropyridin-2-one for 3-(aminomethyl)-1-methyl-1,2-dihydropyridine- 2-keto hydrochloride 1b, compound 8 can be obtained by a similar method and reaction procedure. ESI-MS (m/z): 428.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.90 (s, 1H), 7.83 (t, J=6.1 Hz, 1H), 7.62(s, 1H), 7.31(d, J=6.7Hz, 1H), 6.11(dd, J=6.8, 1.7Hz, 1H), 6.08(s, 1H), 4.41(d, J ＝5.8Hz, 2H), 3.86(s, 3H), 3.22(s, 2H), 2.71(t, J＝5.9Hz, 2H), 2.61(t, J＝5.9Hz, 2H), 2.33(s, 3H) ).
实施例9Example 9
3-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-1-乙基吡啶-2(1H)-酮3-(((5-Chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) Pyrimidine-4-yl)amino)methyl)-1-ethylpyridin-2(1H)-one
Figure PCTCN2022085446-appb-000052
Figure PCTCN2022085446-appb-000052
化合物9由以下步骤制备：Compound 9 was prepared by the following steps:
Figure PCTCN2022085446-appb-000053
Figure PCTCN2022085446-appb-000053
第一步：将化合物9a(700mg，5.83mmol)溶于DMF(10mL)中，加入碳酸铯(2.28g，6.99mmol)，然后滴加碘乙烷(1.36g，8.74mmol，0.70mL)，反应混合物在室温下搅拌过夜。反应液加水稀释，用乙酸乙酯萃取水相。有机相合并，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离(石 油醚/乙酸乙酯＝1/1)得到白色固体9b(730mg，收率84％)。ESI-MS(m/z):149.4[M+H] +； 1HNMR(500MHz,Chloroform-d)δ7.80(dd,J＝7.0,2.0Hz,1H),7.57(dd,J＝7.0,2.0Hz,1H),6.28(t,J＝7.0Hz,1H),4.05(q,J＝7.0Hz,2H),1.40(t,J＝7.0Hz,3H)。 The first step: Compound 9a (700 mg, 5.83 mmol) was dissolved in DMF (10 mL), cesium carbonate (2.28 g, 6.99 mmol) was added, and then iodoethane (1.36 g, 8.74 mmol, 0.70 mL) was added dropwise, and the reaction was carried out. The mixture was stirred at room temperature overnight. The reaction solution was diluted with water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain 9b (730 mg, yield 84%) as a white solid. ESI-MS (m/z): 149.4 [M+H] + ; 1 H NMR (500 MHz, Chloroform-d) δ 7.80 (dd, J=7.0, 2.0 Hz, 1 H), 7.57 (dd, J=7.0, 2.0Hz, 1H), 6.28 (t, J=7.0Hz, 1H), 4.05 (q, J=7.0Hz, 2H), 1.40 (t, J=7.0Hz, 3H).
第二步：将化合物9b(100mg，0.67mmol)溶于甲醇(5mL)中，加入Raney Ni(0.3mL，水混悬液)和氨水(1mL)。混合物在氢气氛围下(氢气球)室温搅拌过夜。反应液用硅藻土过滤，滤饼用甲醇洗，滤液浓缩得到化合物9c(100mg)，直接用于下一步反应。Second step: Compound 9b (100 mg, 0.67 mmol) was dissolved in methanol (5 mL), Raney Ni (0.3 mL, aqueous suspension) and ammonia (1 mL) were added. The mixture was stirred at room temperature under a hydrogen atmosphere (hydrogen balloon) overnight. The reaction solution was filtered with celite, the filter cake was washed with methanol, and the filtrate was concentrated to obtain compound 9c (100 mg), which was directly used in the next reaction.
第三步：将化合物9c(100mg)溶于异丙醇(5mL)中，加入N，N-二异丙基乙胺(169mg，1.31mmol，0.23mL)和2，4，5-三氯嘧啶1a(180mg，0.98mmol)，反应混合物在室温下搅拌过夜。反应液过滤，滤饼用异丙醇洗，干燥得到白色固体9d(100mg)。ESI-MS(m/z):299.2[M+H] +。 The third step: Compound 9c (100 mg) was dissolved in isopropanol (5 mL), and N,N-diisopropylethylamine (169 mg, 1.31 mmol, 0.23 mL) and 2,4,5-trichloropyrimidine were added 1a (180 mg, 0.98 mmol), the reaction mixture was stirred at room temperature overnight. The reaction solution was filtered, and the filter cake was washed with isopropanol and dried to obtain 9d (100 mg) as a white solid. ESI-MS (m/z): 299.2 [M+H] + .
第四步：将化合物9d(50mg，0.16mmol)和Int-1(32mg，0.16mmol)溶于1，4-二氧六环(5mL)中，加入碳酸铯(108mg，0.33mmol)，BrettPhos(9mg，0.016mmol)和BrettPhos Pd G3(15mg，0.016mmol)。反应体系置换氮气后加热至100℃搅拌过夜。待反应液冷却至室温，反应液浓缩，残留物用制备薄层层析纯化(二氯甲烷/甲醇＝10/1)得到粗产品，再用反向制备HPLC分离得到化合物9(8mg，收率11％)。ESI-MS(m/z):456.1[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.00(s,1H),7.91(s,1H),7.66-7.62(m,2H),7.56(s,1H),7.08(dd,J＝7.0,2.0Hz,1H),6.20(t,J＝7.0Hz,1H),4.39(d,J＝6.0Hz,2H),3.98(q,J＝7.0Hz,2H),3.85(s,3H),3.18(s,2H),2.70(t,J＝6.0Hz,2H),2.60(t,J＝6.0Hz,2H),2.32(s,3H),1.25(t,J＝7.0Hz,3H)。 The fourth step: Compound 9d (50 mg, 0.16 mmol) and Int-1 (32 mg, 0.16 mmol) were dissolved in 1,4-dioxane (5 mL), cesium carbonate (108 mg, 0.33 mmol) was added, BrettPhos ( 9 mg, 0.016 mmol) and BrettPhos Pd G3 (15 mg, 0.016 mmol). The reaction system was replaced with nitrogen and then heated to 100°C and stirred overnight. After the reaction solution was cooled to room temperature, the reaction solution was concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane/methanol=10/1) to obtain a crude product, which was then separated by reverse preparative HPLC to obtain compound 9 (8 mg, yield 11%). ESI-MS (m/z): 456.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.91 (s, 1H), 7.66-7.62 (m, 2H ), 7.56(s, 1H), 7.08(dd, J=7.0, 2.0Hz, 1H), 6.20(t, J=7.0Hz, 1H), 4.39(d, J=6.0Hz, 2H), 3.98(q , J＝7.0Hz, 2H), 3.85(s, 3H), 3.18(s, 2H), 2.70(t, J＝6.0Hz, 2H), 2.60(t, J＝6.0Hz, 2H), 2.32(s , 3H), 1.25 (t, J=7.0Hz, 3H).
实施例10Example 10
3-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-1,5,6-三甲基吡啶-2(1H)-酮3-(((5-Chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) pyrimidin-4-yl)amino)methyl)-1,5,6-trimethylpyridin-2(1H)-one
Figure PCTCN2022085446-appb-000054
Figure PCTCN2022085446-appb-000054
用2-羟基-3-氰基-5,6-二甲基吡啶替代实施例9第一步中的3-氰基-2-羟基-4,6-二甲基吡啶，用类似的方法和反应步骤，可以得到化合物10。ESI-MS(m/z):470.1[M+H] +； 1HNMR(500MHz,DMSO-d6)δ7.98(s,1H),7.93(s,1H),7.58(t,J＝6.0Hz,1H),7.56(s,1H),6.94(s,1H),4.36(d,J＝6.0Hz,2H),3.86(s,3H),3.52(s,3H),3.19(s,2H),2.71(t,J＝6.0Hz,2H),2.60(t,J＝6.0Hz,2H),2.33(s,3H),2.27(s,3H),1.99(s,3H)。 Substituting 2-hydroxy-3-cyano-5,6-lutidine for 3-cyano-2-hydroxy-4,6-lutidine in the first step of Example 9, using a similar method and In the reaction step, compound 10 can be obtained. ESI-MS (m/z): 470.1 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.93 (s, 1H), 7.58 (t, J=6.0 Hz ,1H),7.56(s,1H),6.94(s,1H),4.36(d,J=6.0Hz,2H),3.86(s,3H),3.52(s,3H),3.19(s,2H) , 2.71(t, J=6.0Hz, 2H), 2.60(t, J=6.0Hz, 2H), 2.33(s, 3H), 2.27(s, 3H), 1.99(s, 3H).
实施例11Example 11
3-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)吡啶-2(1H)-酮3-(((5-Chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) pyrimidin-4-yl)amino)methyl)pyridin-2(1H)-one
Figure PCTCN2022085446-appb-000055
Figure PCTCN2022085446-appb-000055
用3-(氨基甲基)吡啶-2(1H)-酮替代实施例1第一步中的3-(氨基甲基)-1-甲基-1,2-二氢吡啶-2-酮盐酸盐1b，用类似的方法和反应步骤，可以得到化合物11。ESI-MS(m/z):428.3[M+H] +； 1H NMR(500MHz,DMSO-d6)δ11.68(br s,1H),8.00(s,1H),7.90(s,1H),7.65-7.62(m,1H),7.56(s,1H),7.33-7.28(m,1H),7.13-7.09(m,1H),6.15(t,J＝6.6Hz,1H),4.35(d,J＝5.9Hz,2H),3.86(s,3H),3.17(s,2H),2.69(d,J＝5.9Hz,2H),2.60(d,J＝5.7Hz,2H),2.33(s,3H)。 Substitute 3-(aminomethyl)pyridin-2(1H)-one for the 3-(aminomethyl)-1-methyl-1,2-dihydropyridin-2-one salt in the first step of Example 1 Compound 11 can be obtained using a similar method and reaction procedure for the acid salt 1b. ESI-MS(m/z): 428.3[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ 11.68(br s, 1H), 8.00(s, 1H), 7.90(s, 1H) ,7.65-7.62(m,1H),7.56(s,1H),7.33-7.28(m,1H),7.13-7.09(m,1H),6.15(t,J＝6.6Hz,1H),4.35(d , J＝5.9Hz, 2H), 3.86(s, 3H), 3.17(s, 2H), 2.69(d, J＝5.9Hz, 2H), 2.60(d, J＝5.7Hz, 2H), 2.33(s , 3H).
实施例12Example 12
3-(((5-氯-2-((2-环丙基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-1-甲基吡啶-2(1H)-酮3-(((5-Chloro-2-((2-cyclopropyl-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) pyrimidin-4-yl)amino)methyl)-1-methylpyridin-2(1H)-one
Figure PCTCN2022085446-appb-000056
Figure PCTCN2022085446-appb-000056
用Int-5替代实施例1第二步中的Int-1，用类似的方法和反应步骤，可以得到化合物12。ESI-MS(m/z):452.2[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.55(s,1H),7.90(s,1H),7.62(dd,J＝6.7,2.0Hz,1H),7.36(t,J＝6.0Hz,1H),7.34(s,1H),6.97(d,J＝6.9Hz,1H),6.15(t,J＝6.8Hz,1H),4.29(d,J＝6.0Hz,2H),3.46(s,3H),3.20(s,2H),2.71(t,J＝6.0Hz,2H),2.61(t,J＝6.0Hz,2H),2.31(s,3H),2.23-2.12(m,1H),0.85-.075(m,4H)。 Substituting Int-5 for Int-1 in the second step of Example 1, and using similar methods and reaction steps, compound 12 can be obtained. ESI-MS (m/z): 452.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.90 (s, 1H), 7.62 (dd, J=6.7 ,2.0Hz,1H),7.36(t,J＝6.0Hz,1H),7.34(s,1H),6.97(d,J＝6.9Hz,1H),6.15(t,J＝6.8Hz,1H), 4.29(d,J＝6.0Hz,2H),3.46(s,3H),3.20(s,2H),2.71(t,J＝6.0Hz,2H),2.61(t,J＝6.0Hz,2H), 2.31(s, 3H), 2.23-2.12(m, 1H), 0.85-.075(m, 4H).
实施例13Example 13
3-(((5-氯-2-((2-乙基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-1-甲基吡啶-2(1H)-酮3-(((5-Chloro-2-((2-ethyl-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino)pyrimidine -4-yl)amino)methyl)-1-methylpyridin-2(1H)-one
Figure PCTCN2022085446-appb-000057
Figure PCTCN2022085446-appb-000057
用Int-4替代实施例1第二步中的Int-1，用类似的方法和反应步骤，可以得到化合物13。ESI-MS(m/z):440.2[M+H] +； 1HNMR(500MHz,DMSO-d6)δ8.36(s,1H),7.89(s,1H),7.62(dd,J＝6.8,2.0Hz,1H),7.37(d,J＝6.0Hz,1H),7.36(s,1H),6.98(d,J＝6.9Hz,1H),6.16(t,J＝6.8Hz,1H),4.27(d,J＝6.0Hz,2H),3.46(s,3H),3.22(s,2H),2.78(t,J＝6.0Hz,2H),2.69-2.61(m,4H),2.32(s,3H),1.07(t,J＝7.5Hz,3H)。 Substituting Int-4 for Int-1 in the second step of Example 1, and using similar methods and reaction steps, compound 13 can be obtained. ESI-MS (m/z): 440.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.89 (s, 1H), 7.62 (dd, J=6.8, 2.0Hz, 1H), 7.37(d, J＝6.0Hz, 1H), 7.36(s, 1H), 6.98(d, J＝6.9Hz, 1H), 6.16(t, J＝6.8Hz, 1H), 4.27 (d, J＝6.0Hz, 2H), 3.46(s, 3H), 3.22(s, 2H), 2.78(t, J＝6.0Hz, 2H), 2.69-2.61(m, 4H), 2.32(s, 3H), 1.07 (t, J=7.5Hz, 3H).
实施例14Example 14
3-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-1-甲基吡咯烷-2-酮3-(((5-Chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) pyrimidin-4-yl)amino)methyl)-1-methylpyrrolidin-2-one
Figure PCTCN2022085446-appb-000058
Figure PCTCN2022085446-appb-000058
用3-(氨基甲基)-1-甲基吡咯烷-2-酮替代实施例1第一步中的3-(氨基甲基)-1-甲基-1,2-二氢吡啶-2-酮盐酸盐1b，用类似的方法和反应步骤，可以得到化合物14。ESI-MS(m/z):432.3[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.13(s,1H),7.96(s,1H),7.61(s,1H),7.38-7.33(m,1H),3.88(s,3H),3.65-3.58(m,1H),3.50-3.40(m,3H),3.27-3.24(m,2H),2.79-2.73(m,6H),2.66-2.62(m,2H),2.34(s,3H),2.08-2.02(m,1H),1.78-1.72(m,1H)。 Substitute 3-(aminomethyl)-1-methylpyrrolidin-2-one for 3-(aminomethyl)-1-methyl-1,2-dihydropyridine-2 in the first step of Example 1 - Ketone hydrochloride 1b, compound 14 can be obtained by a similar method and reaction procedure. ESI-MS (m/z): 432.3[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ 8.13(s, 1H), 7.96(s, 1H), 7.61(s, 1H), 7.38-7.33(m, 1H), 3.88(s, 3H), 3.65-3.58(m, 1H), 3.50-3.40(m, 3H), 3.27-3.24(m, 2H), 2.79-2.73(m, 6H) ), 2.66-2.62(m, 2H), 2.34(s, 3H), 2.08-2.02(m, 1H), 1.78-1.72(m, 1H).
实施例15Example 15
5-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)吡咯烷-2-酮5-(((5-Chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) pyrimidin-4-yl)amino)methyl)pyrrolidin-2-one
Figure PCTCN2022085446-appb-000059
Figure PCTCN2022085446-appb-000059
用5-氨甲基-2-吡咯烷酮替代实施例1第一步中的3-(氨基甲基)-1-甲基-1,2-二氢吡啶-2-酮盐酸盐1b，用类似的方法和反应步骤，可以得到化合物15。ESI-MS(m/z):418.4[M+H] +； 1HNMR(500MHz,DMSO-d6)δ8.10(s,1H),7.95(s,1H),7.75(br s,1H),7.67(s,1H),7.27(t,J＝5.9Hz,1H),3.89(s,3H),3.82-3.77(m,1H),3.53-3.47(m,1H),3.41(s,2H),3.36-3.30(m,1H),2.75(t,J＝5.9Hz,2H),2.64(t,J＝6.3Hz,2H),2.34(s,3H),2.13-2.03(m,3H),1.78-1.71(m,1H)。 Substitute 5-aminomethyl-2-pyrrolidone for 3-(aminomethyl)-1-methyl-1,2-dihydropyridin-2-one hydrochloride 1b in the first step of Example 1, and use similar According to the method and reaction steps, compound 15 can be obtained. ESI-MS(m/z): 418.4[M+H] + ; 1 HNMR (500MHz, DMSO-d6)δ8.10(s,1H),7.95(s,1H),7.75(br s,1H), 7.67(s, 1H), 7.27(t, J=5.9Hz, 1H), 3.89(s, 3H), 3.82-3.77(m, 1H), 3.53-3.47(m, 1H), 3.41(s, 2H) ,3.36-3.30(m,1H),2.75(t,J＝5.9Hz,2H),2.64(t,J＝6.3Hz,2H),2.34(s,3H),2.13-2.03(m,3H), 1.78-1.71 (m, 1H).
实施例16Example 16
3-(((2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)-5-甲基嘧啶-4-基)氨基)甲基)-1-甲基吡啶-2(1H)-酮3-(((2-((2-Methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino)-5-methyl pyrimidin-4-yl)amino)methyl)-1-methylpyridin-2(1H)-one
Figure PCTCN2022085446-appb-000060
Figure PCTCN2022085446-appb-000060
用2，4-二氯-5-甲基嘧啶替代实施例1第一步中的2，4，5-三氯嘧啶1a，用类似的方法和反应步骤，可以得到化合物16。ESI-MS(m/z):422.3[M+H] +； 1HNMR(500MHz,DMSO-d6)δ8.19(s,1H),7.74(s,1H),7.63(dd,J＝6.8,1.9Hz,1H),7.35(br s,1H),7.31(br s,1H),7.15(d,J＝6.8Hz,1H),6.19(t,J＝6.8Hz,1H),4.41(d,J＝5.9Hz,2H),3.96-3.85(m,5H),3.52(s,3H),3.30-3.22(m,2H),2.91(br s,2H),2.74(br s,2H),2.49(s,3H),2.02(s,3H)。 Substituting 2,4-dichloro-5-methylpyrimidine for 2,4,5-trichloropyrimidine 1a in the first step of Example 1, and using a similar method and reaction procedure, compound 16 can be obtained. ESI-MS (m/z): 422.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.74 (s, 1H), 7.63 (dd, J=6.8, 1.9Hz, 1H), 7.35(br s, 1H), 7.31(br s, 1H), 7.15(d, J=6.8Hz, 1H), 6.19(t, J=6.8Hz, 1H), 4.41(d, J=5.9Hz, 2H), 3.96-3.85(m, 5H), 3.52(s, 3H), 3.30-3.22(m, 2H), 2.91(br s, 2H), 2.74(br s, 2H), 2.49 (s, 3H), 2.02 (s, 3H).
实施例17Example 17
3-(((5-氟-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-1-甲基吡啶-2(1H)-酮3-(((5-Fluoro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) pyrimidin-4-yl)amino)methyl)-1-methylpyridin-2(1H)-one
Figure PCTCN2022085446-appb-000061
Figure PCTCN2022085446-appb-000061
用2，4-二氯-5-氟嘧啶替代实施例1第一步中的2，4，5-三氯嘧啶1a，用类似的方法和反应步骤，可以得到化合物17。ESI-MS(m/z):426.3[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.03(s,1H),8.00-7.91(m,2H),7.64(dd,J＝6.7,2.0Hz,1H),7.43(s,1H),7.19(dd,J＝7.0,1.8Hz,1H),6.19(t,J＝6.8Hz,1H),4.37(d,J＝5.9Hz,2H),3.87(s,3H),3.50(s,3H),3.47(br s,2H),2.88(br s,2H),2.79(t,J＝5.8Hz,2H),2.49(s,3H)。 Substituting 2,4-dichloro-5-fluoropyrimidine for 2,4,5-trichloropyrimidine 1a in the first step of Example 1, and using a similar method and reaction procedure, compound 17 can be obtained. ESI-MS (m/z): 426.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.03 (s, 1H), 8.00-7.91 (m, 2H), 7.64 (dd, J =6.7,2.0Hz,1H),7.43(s,1H),7.19(dd,J=7.0,1.8Hz,1H),6.19(t,J=6.8Hz,1H),4.37(d,J=5.9Hz ,2H),3.87(s,3H),3.50(s,3H),3.47(br s,2H),2.88(br s,2H),2.79(t,J＝5.8Hz,2H),2.49(s, 3H).
实施例18Example 18
4-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-1-甲基吡啶-2(1H)-酮4-(((5-Chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) pyrimidin-4-yl)amino)methyl)-1-methylpyridin-2(1H)-one
Figure PCTCN2022085446-appb-000062
Figure PCTCN2022085446-appb-000062
用4-(氨基甲基)-1-甲基-1,2-二氢吡啶-2-酮替代实施例1第一步中的3-(氨基甲基)-1-甲基-1,2-二氢吡啶-2-酮盐酸盐1b，用类似的方法和反应步骤，可以得到化合物33。ESI-MS(m/z):442.3[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.01(s,1H),7.89(s,1H),7.84(t,J＝5.5Hz,1H),7.66-7.60(m,2H),6.17-6.13(m,2H),4.41(d,J＝5.9Hz,2H),3.85(s,3H),3.37(s,3H),3.21(br s,2H),2.71(t,J＝5.3Hz,2H),2.61(t,J＝5.7Hz,2H),2.33(s,3H)。 Substitute 4-(aminomethyl)-1-methyl-1,2-dihydropyridin-2-one for 3-(aminomethyl)-1-methyl-1,2 in the first step of Example 1 - Dihydropyridin-2-one hydrochloride 1b, compound 33 can be obtained by a similar method and reaction procedure. ESI-MS (m/z): 442.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.89 (s, 1H), 7.84 (t, J=5.5 Hz,1H),7.66-7.60(m,2H),6.17-6.13(m,2H),4.41(d,J=5.9Hz,2H),3.85(s,3H),3.37(s,3H),3.21 (br s, 2H), 2.71 (t, J=5.3 Hz, 2H), 2.61 (t, J=5.7 Hz, 2H), 2.33 (s, 3H).
实施例19Example 19
3-(((5-氯-2-((2-甲氧基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-1-甲基吡啶-2(1H)-酮3-(((5-Chloro-2-((2-methoxy-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino)pyrimidin-4-yl )amino)methyl)-1-methylpyridin-2(1H)-one
Figure PCTCN2022085446-appb-000063
Figure PCTCN2022085446-appb-000063
化合物19由以下步骤制备：Compound 19 was prepared by the following steps:
Figure PCTCN2022085446-appb-000064
Figure PCTCN2022085446-appb-000064
第一步：将化合物1b(244mg，0.85mmol)和Int-7(200mg，0.71mmol)溶于1，4-二氧六环(5mL)中，加入碳酸铯(700mg，2.15mmol)，BrettPhos(76mg，0.14mmol)和BrettPhos Pd G3(64mg，0.071mmol)。反应体系置换氮气后加热至120℃搅拌16小时。待反应液冷却至室温，浓缩反应液，残留物用硅胶柱层析纯化(二氯甲烷/甲醇＝20/1)得到化合物19a粗品(300mg)，直接用于下一步反应。ESI-MS(m/z):528.1[M+H] +。 The first step: Compound 1b (244 mg, 0.85 mmol) and Int-7 (200 mg, 0.71 mmol) were dissolved in 1,4-dioxane (5 mL), cesium carbonate (700 mg, 2.15 mmol) was added, BrettPhos ( 76 mg, 0.14 mmol) and BrettPhos Pd G3 (64 mg, 0.071 mmol). After the reaction system was replaced with nitrogen, it was heated to 120°C and stirred for 16 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain the crude compound 19a (300 mg), which was directly used in the next reaction. ESI-MS (m/z): 528.1 [M+H] + .
第二步：将上一步得到的19a粗品(300mg)溶于乙腈(5mL)中，加入对甲苯磺酸一水合物(323mg，1.70mmol)。反应混合物升温至70℃搅拌2小时。反应液浓缩，得到化合物19的粗品(240mg)，取其中20mg用反向制备HPLC纯化得到化合物19(1mg)。ESI-MS(m/z):428.3[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.00(s,1H),7.84(s,1H),7.69-7.60(m,2H),7.53(s,1H),7.09(d,J＝6.9Hz,1H),6.18(t,J＝6.8Hz,1H),4.37(d,J＝5.9Hz,2H),3.85(s,3H),3.52(s,2H),3.49(s,3H),2.96(t,J＝5.8Hz,2H),2.59(t,J＝5.8Hz,2H)。 The second step: The crude 19a obtained in the previous step (300 mg) was dissolved in acetonitrile (5 mL), and p-toluenesulfonic acid monohydrate (323 mg, 1.70 mmol) was added. The reaction mixture was warmed to 70°C and stirred for 2 hours. The reaction solution was concentrated to obtain a crude product of compound 19 (240 mg), 20 mg of which was purified by reverse-phase preparative HPLC to obtain compound 19 (1 mg). ESI-MS (m/z): 428.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.84 (s, 1H), 7.69-7.60 (m, 2H ), 7.53(s, 1H), 7.09(d, J＝6.9Hz, 1H), 6.18(t, J＝6.8Hz, 1H), 4.37(d, J＝5.9Hz, 2H), 3.85(s, 3H ), 3.52(s, 2H), 3.49(s, 3H), 2.96(t, J=5.8Hz, 2H), 2.59(t, J=5.8Hz, 2H).
实施例20Example 20
2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)-4-(((1-甲基-2-羰基-1,2-二氢吡啶-3-基)甲基)氨基)嘧啶-5-甲腈2-((2-Methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino)-4-(((1-methyl yl-2-carbonyl-1,2-dihydropyridin-3-yl)methyl)amino)pyrimidine-5-carbonitrile
Figure PCTCN2022085446-appb-000065
Figure PCTCN2022085446-appb-000065
用2，4-二氯-5-氰基嘧啶替代实施例1第一步中的2，4，5-三氯嘧啶1a，用类似的方法和反应步骤，可以得到化合物20。ESI-MS(m/z):433.2[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.38(s,1H),8.24-8.19(m,1H),8.16(s,1H),7.71(s,1H),7.63-7.60(m,1H),6.98-6.94(m,1H),6.15-6.12(m,1H),4.16(d,J＝6.1Hz,2H),3.85(s,3H),3.47(s,3H),3.14(br s,2H),2.73(d,J＝6.1Hz,2H),2.63-2.60(m,2H),2.33(s,3H)。 Substituting 2,4-dichloro-5-cyanopyrimidine for 2,4,5-trichloropyrimidine 1a in the first step of Example 1, and using a similar method and reaction procedure, compound 20 can be obtained. ESI-MS (m/z): 433.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.24-8.19 (m, 1H), 8.16 (s, 1H) ), 7.71(s, 1H), 7.63-7.60(m, 1H), 6.98-6.94(m, 1H), 6.15-6.12(m, 1H), 4.16(d, J=6.1Hz, 2H), 3.85( s, 3H), 3.47 (s, 3H), 3.14 (br s, 2H), 2.73 (d, J=6.1 Hz, 2H), 2.63-2.60 (m, 2H), 2.33 (s, 3H).
实施例21Example 21
3-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-1,5-二甲基吡啶-2(1H)-酮3-(((5-Chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) Pyrimidine-4-yl)amino)methyl)-1,5-lutidine-2(1H)-one
Figure PCTCN2022085446-appb-000066
Figure PCTCN2022085446-appb-000066
化合物21由以下步骤制备：Compound 21 was prepared by the following steps:
Figure PCTCN2022085446-appb-000067
Figure PCTCN2022085446-appb-000067
第一步：将3-溴-2-羟基-5-甲基吡啶21a(200mg，1.06mmol)溶于四氢呋喃(5mL)中，在0℃下加入NaH(50mg，1.28mmol，含量60％)，反应液搅拌30分钟。将碘甲烷(227mg，1.60mmol)滴加至反应液中，反应液在0℃下继续搅拌2小时。反应液用饱和氯化铵水溶液淬灭，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯＝5/3)得到化合物21b(200mg，收率93％)。ESI-MS(m/z):202.5[M+H] +。 Step 1: Dissolve 3-bromo-2-hydroxy-5-methylpyridine 21a (200mg, 1.06mmol) in tetrahydrofuran (5mL), add NaH (50mg, 1.28mmol, content 60%) at 0°C, The reaction solution was stirred for 30 minutes. Iodomethane (227 mg, 1.60 mmol) was added dropwise to the reaction solution, and the reaction solution was further stirred at 0°C for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/3) to obtain compound 21b (200 mg, yield 93%). ESI-MS (m/z): 202.5 [M+H] + .
第二步：将化合物21b(180mg，0.89mmol)溶于DMF(5mL)中，加入Pd(PPh 3) 4(103mg，0.09mmol)和Zn(CN) 2(105mg，0.89mmol)，反应体系置换氮气后用微波加热至130℃反应4小时。待反应液冷却至室温，反应液用硅藻土过滤，滤液浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯＝5/4)得到白色固体21c(122mg，收率92％)。ESI-MS(m/z):149.4[M+H] +。 The second step: Compound 21b (180 mg, 0.89 mmol) was dissolved in DMF (5 mL), Pd(PPh 3 ) 4 (103 mg, 0.09 mmol) and Zn(CN) 2 (105 mg, 0.89 mmol) were added, and the reaction system was replaced After nitrogen, the reaction was heated to 130°C by microwave for 4 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/4) to obtain 21c (122 mg, yield 92%) as a white solid. ESI-MS (m/z): 149.4 [M+H] + .
第三步：将化合物21c(120mg，0.81mmol)溶于甲醇(5mL)和氨水(0.5mL)中，加入Raney Nickel(0.3mL，水混悬液)和BOC酸酐(212mg，0.97mmol)， 混合物在氢气氛围下(氢气球)下室温搅拌过夜。反应液用硅藻土过滤，滤液浓缩。将残余物溶于4N盐酸二氧六环溶液(5mL)中，反应液在室温下搅拌1小时。反应液浓缩得到化合物21d的粗品，直接用于下一步反应。ESI-MS(m/z):153.8[M+H] +。 The third step: Compound 21c (120 mg, 0.81 mmol) was dissolved in methanol (5 mL) and ammonia water (0.5 mL), Raney Nickel (0.3 mL, aqueous suspension) and BOC anhydride (212 mg, 0.97 mmol) were added, and the mixture was Stir overnight at room temperature under a hydrogen atmosphere (hydrogen balloon). The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was dissolved in 4N hydrochloric acid dioxane solution (5 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain the crude product of compound 21d, which was directly used in the next reaction. ESI-MS (m/z): 153.8 [M+H] + .
第四步：将上一步得到的化合物21d粗品和2，4，5-三氯嘧啶1a(169mg，0.92mmol)溶于i-PrOH(5mL)中，加入N，N-二异丙基乙基胺(357mg，2.76mmol)，反应液在90℃下搅拌过夜。待反应液冷却至室温，反应液浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯＝5/4)得到白色固体21e(98mg，收率36％)。ESI-MS(m/z):300.2[M+H] +。 The fourth step: The crude compound 21d obtained in the previous step and 2,4,5-trichloropyrimidine 1a (169 mg, 0.92 mmol) were dissolved in i-PrOH (5 mL), and N,N-diisopropylethyl was added. Amine (357 mg, 2.76 mmol), the reaction was stirred at 90°C overnight. After the reaction solution was cooled to room temperature, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/4) to obtain 21e (98 mg, yield 36%) as a white solid. ESI-MS (m/z): 300.2 [M+H] + .
第五步：将化合物21e(50mg，0.17mmol)和Int-1(36mg，0.18mmol)溶于1，4-二氧六环(5mL)中，加入BrettPhos G3Pd(15mg，17umol)，BrettPhos(9mg，17umol)和碳酸铯(109mg，0.34mmol)。反应体系置换氮气后加热至100℃搅拌过夜。待反应液冷却至室温，反应液用硅藻土过滤，滤液浓缩。残余物用制备性薄层层析纯化(石油醚/乙酸乙酯＝1/1)得到化合物21的粗品，粗品用反向制备HPLC纯化得到化合物21(6mg，收率8％)。ESI-MS(m/z):456.2[M+H] +。 1H NMR(500MHz,DMSO-d 6)δ7.99(s,1H),7.89(s,1H),7.62(t,J＝6.0Hz,1H),7.57(s,1H),7.43(s,1H),6.97(s,1H),4.37(d,J＝5.8Hz,2H),3.86(s,3H),3.45(s,3H),3.16(s,2H),2.70(t,J＝5.7Hz,2H),2.60(t,J＝5.9Hz,2H),2.33(s,3H),1.96(s,3H)。 The fifth step: Compound 21e (50mg, 0.17mmol) and Int-1 (36mg, 0.18mmol) were dissolved in 1,4-dioxane (5mL), BrettPhos G3Pd (15mg, 17umol), BrettPhos (9mg , 17umol) and cesium carbonate (109mg, 0.34mmol). The reaction system was replaced with nitrogen and then heated to 100°C and stirred overnight. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate = 1/1) to obtain the crude product of compound 21, which was purified by reverse phase preparative HPLC to obtain compound 21 (6 mg, yield 8%). ESI-MS (m/z): 456.2 [M+H] + . 1 H NMR (500MHz, DMSO-d 6 )δ7.99(s,1H),7.89(s,1H),7.62(t,J=6.0Hz,1H),7.57(s,1H),7.43(s,1H) 1H), 6.97(s, 1H), 4.37(d, J=5.8Hz, 2H), 3.86(s, 3H), 3.45(s, 3H), 3.16(s, 2H), 2.70(t, J=5.7 Hz, 2H), 2.60 (t, J=5.9 Hz, 2H), 2.33 (s, 3H), 1.96 (s, 3H).
实施例22Example 22
3-(((2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-1-甲基吡啶-2(1H)-酮3-(((2-((2-Methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino)pyrimidine-4- yl)amino)methyl)-1-methylpyridin-2(1H)-one
Figure PCTCN2022085446-appb-000068
Figure PCTCN2022085446-appb-000068
用2，4-二氯嘧啶替代实施例1第一步中的2，4，5-三氯嘧啶1a，用类似的方法和反应步骤，可以得到化合物22。ESI-MS(m/z):408.3[M+H] +； 1HNMR(500MHz,DMSO-d6)δ8.08(br s,1H),7.83(d,J＝5.8Hz,1H),7.68(br s,1H),7.63(dd,J＝6.7,1.9Hz,1H),7.28(s,1H),7.19(br s,1H),6.19(t,J＝6.8Hz,1H),6.10(br s,1H),4.30(br s,2H),3.88(s,3H),3.49(s,3H),3.19(br s,2H),2.70(t,J＝6.6Hz,2H),2.62(t,J＝5.7Hz,2H),2.33(s,3H)。 Substituting 2,4-dichloropyrimidine for 2,4,5-trichloropyrimidine 1a in the first step of Example 1, and using similar methods and reaction steps, compound 22 can be obtained. ESI-MS (m/z): 408.3[M+H] + ; 1 HNMR (500MHz, DMSO-d6) δ 8.08 (br s, 1H), 7.83 (d, J=5.8Hz, 1H), 7.68 ( br s,1H),7.63(dd,J=6.7,1.9Hz,1H),7.28(s,1H),7.19(br s,1H),6.19(t,J=6.8Hz,1H),6.10(br s, 1H), 4.30(br s, 2H), 3.88(s, 3H), 3.49(s, 3H), 3.19(br s, 2H), 2.70(t, J＝6.6Hz, 2H), 2.62(t , J=5.7Hz, 2H), 2.33 (s, 3H).
实施例23Example 23
3-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-1,4-二甲基吡啶-2(1H)-酮3-(((5-Chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) Pyrimidin-4-yl)amino)methyl)-1,4-lutidine-2(1H)-one
Figure PCTCN2022085446-appb-000069
Figure PCTCN2022085446-appb-000069
化合物23由以下步骤制备：Compound 23 was prepared by the following steps:
Figure PCTCN2022085446-appb-000070
Figure PCTCN2022085446-appb-000070
第一步：将3-溴-2-羟基-4-甲基吡啶23a(200mg，1.06mmol)溶于四氢呋喃(5mL)中，在0℃下加入NaH(50mg，1.28mmol，含量60％)，反应液搅拌30分钟。将碘甲烷(227mg，1.60mmol)滴加至反应液中，反应液在0℃下继续搅拌2小时。反应液用饱和氯化铵水溶液淬灭，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯＝5/3)得到黄色油23b(210mg，收率98％)。ESI-MS(m/z):202.5[M+H] +。 Step 1: Dissolve 3-bromo-2-hydroxy-4-methylpyridine 23a (200mg, 1.06mmol) in tetrahydrofuran (5mL), add NaH (50mg, 1.28mmol, content 60%) at 0°C, The reaction solution was stirred for 30 minutes. Iodomethane (227 mg, 1.60 mmol) was added dropwise to the reaction solution, and the reaction solution was further stirred at 0°C for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/3) to obtain 23b as a yellow oil (210 mg, yield 98%). ESI-MS (m/z): 202.5 [M+H] + .
第二步：将化合物23b(210mg，1.04mmol)溶于DMF(5mL)中，加入Pd(PPh 3) 4(120mg，0.11mmol)和Zn(CN) 2(122mg，1.04mmol)，反应体系置换氮气后用微波加热至130℃反应4小时。待反应液冷却至室温，反应液用硅藻土过滤，滤液浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯＝5/4)得到白色固体23c(143mg，收率92％)。ESI-MS(m/z):149.4[M+H] +。 The second step: Compound 23b (210 mg, 1.04 mmol) was dissolved in DMF (5 mL), Pd(PPh 3 ) 4 (120 mg, 0.11 mmol) and Zn(CN) 2 (122 mg, 1.04 mmol) were added, and the reaction system was replaced After nitrogen, the reaction was heated to 130°C by microwave for 4 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/4) to obtain 23c (143 mg, yield 92%) as a white solid. ESI-MS (m/z): 149.4 [M+H] + .
第三步：将化合物23c(143mg，0.97mmol)溶于甲醇(5mL)和氨水(0.5mL)中，加入Raney Nickel(0.3mL，水混悬液)和BOC酸酐(253mg，1.16mmol)，混合物在氢气氛围下(氢气球)下室温搅拌过夜。反应液用硅藻土过滤，滤液浓缩。将残余物溶于4N盐酸二氧六环溶液(5mL)中，反应液在室温下搅拌1小时。反应液浓缩得到化合物23d的粗品，直接用于下一步反应。ESI-MS(m/z):153.5[M+H] +。 The third step: Compound 23c (143 mg, 0.97 mmol) was dissolved in methanol (5 mL) and ammonia water (0.5 mL), Raney Nickel (0.3 mL, aqueous suspension) and BOC anhydride (253 mg, 1.16 mmol) were added, and the mixture was Stir overnight at room temperature under a hydrogen atmosphere (hydrogen balloon). The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was dissolved in 4N hydrochloric acid dioxane solution (5 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain the crude product of compound 23d, which was directly used in the next reaction. ESI-MS (m/z): 153.5 [M+H] + .
第四步：将上一步得到的化合物23d粗品和2，4，5-三氯嘧啶(176mg，0.96mmol)溶于i-PrOH(5mL)中，加入DIEA(372mg，2.88mmol)，反应液在90℃下搅拌过夜。待反应液冷却至室温，反应液浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯＝5/4)得到白色固体23e(161mg，收率56％)。ESI-MS(m/z):300.2[M+H] +。 The fourth step: The crude compound 23d obtained in the previous step and 2,4,5-trichloropyrimidine (176 mg, 0.96 mmol) were dissolved in i-PrOH (5 mL), DIEA (372 mg, 2.88 mmol) was added, and the reaction solution was Stir overnight at 90°C. After the reaction solution was cooled to room temperature, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/4) to obtain 23e (161 mg, yield 56%) as a white solid. ESI-MS (m/z): 300.2 [M+H] + .
第五步：将化合物23e(50mg，0.17mmol)和Int-1(32mg，0.17mmol)溶于1,4-二氧六环(5mL)中，加入BrettPhos G3Pd(15mg，17umol)，BrettPhos(9mg，17umol)和碳酸铯(109mg，0.34mmol)。反应体系置换氮气后加热至100℃搅拌过夜。待反应液冷却至室温，反应液用硅藻土过滤，滤液浓缩。残余物用制备性薄层层析纯化(石油醚/乙酸乙酯＝1/1)得到化合物23的粗品，粗品用反向制备HPLC纯化得到化合物23(7mg，收率9％)。ESI-MS(m/z):456.1[M+H] +； 1H NMR(500MHz,DMSO-d 6)δ8.07(s,1H),7.95(s,1H),7.71(s,1H),7.56(d,J＝6.9Hz,1H),7.14(t,J＝5.4Hz,1H),6.12(d,J＝7.0Hz,1H),4.47(d,J＝5.4Hz,2H),3.88(s,3H),3.43(s,5H),2.76(t,J＝5.8Hz,2H),2.65(t,J＝5.9Hz, 2H),2.34(s,3H),2.16(s,3H)。 The fifth step: Compound 23e (50mg, 0.17mmol) and Int-1 (32mg, 0.17mmol) were dissolved in 1,4-dioxane (5mL), BrettPhos G3Pd (15mg, 17umol), BrettPhos (9mg , 17umol) and cesium carbonate (109mg, 0.34mmol). The reaction system was replaced with nitrogen and then heated to 100°C and stirred overnight. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to obtain the crude product of compound 23, which was purified by reverse phase preparative HPLC to obtain compound 23 (7 mg, yield 9%). ESI-MS (m/z): 456.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.07 (s, 1H), 7.95 (s, 1H), 7.71 (s, 1H) ,7.56(d,J＝6.9Hz,1H),7.14(t,J＝5.4Hz,1H),6.12(d,J＝7.0Hz,1H),4.47(d,J＝5.4Hz,2H),3.88 (s, 3H), 3.43(s, 5H), 2.76(t, J=5.8Hz, 2H), 2.65(t, J=5.9Hz, 2H), 2.34(s, 3H), 2.16(s, 3H) .
实施例24Example 24
3-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)吡咯烷-2-酮3-(((5-Chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) pyrimidin-4-yl)amino)methyl)pyrrolidin-2-one
Figure PCTCN2022085446-appb-000071
Figure PCTCN2022085446-appb-000071
化合物24由以下步骤制备：Compound 24 was prepared by the following steps:
Figure PCTCN2022085446-appb-000072
Figure PCTCN2022085446-appb-000072
第一步：将化合物3-(羟甲基)吡咯烷-2-酮24a(258mg，2.24mmol)，邻苯二甲酰亚胺(362mg2.4，7mmol)和三苯基膦(646mg，2.47mmol)溶解于THF(5mL)中，0℃下缓慢滴加偶氮二甲酸二异丙酯(498mg，2.47mmol，0.48mL)。反应混合物升至室温搅拌18小时，LCMS检测反应完全。反应液浓缩，残余物用硅胶柱层析纯化得到白色固体24b(335mg，收率61％)。ESI-MS(m/z):245.5[M+H] +。 The first step: compound 3-(hydroxymethyl)pyrrolidin-2-one 24a (258 mg, 2.24 mmol), phthalimide (362 mg, 2.4, 7 mmol) and triphenylphosphine (646 mg, 2.47 mmol) mmol) was dissolved in THF (5 mL), and diisopropyl azodicarboxylate (498 mg, 2.47 mmol, 0.48 mL) was slowly added dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction was complete by LCMS. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain white solid 24b (335 mg, yield 61%). ESI-MS (m/z): 245.5 [M+H] + .
第二步：将化合物24b(335mg，1.37mmol)溶于乙醇(5mL)中，加入水合 肼((171mg，2.74mmol，0.17mL，含量80％)。反应混合物升至85℃搅拌2小时后冷至室温。反应液过滤，滤液浓缩得到化合物24c粗品(156mg)，直接用于下一步反应。The second step: compound 24b (335 mg, 1.37 mmol) was dissolved in ethanol (5 mL), and hydrazine hydrate ((171 mg, 2.74 mmol, 0.17 mL, content 80%) was added. The reaction mixture was raised to 85° C. and stirred for 2 hours and then cooled. The reaction solution was filtered, and the filtrate was concentrated to obtain a crude product of compound 24c (156 mg), which was directly used in the next reaction.
第三步：将上一步得到的化合物24c粗品(156mg)和2，4，5-三氯嘧啶1a(501mg，2.73mmol)溶于i-PrOH(5mL)中，加入DIPEA(529mg，4.10mmol)。反应混合物在室温搅拌18小时。反应液浓缩。残余物用硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1)得到白色固体24d(300mg，收率84％)。ESI-MS(m/z):261.2[M+H] +。 The third step: The crude compound 24c obtained in the previous step (156 mg) and 2,4,5-trichloropyrimidine 1a (501 mg, 2.73 mmol) were dissolved in i-PrOH (5 mL), and DIPEA (529 mg, 4.10 mmol) was added. . The reaction mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain 24d as a white solid (300 mg, yield 84%). ESI-MS (m/z): 261.2 [M+H] + .
第四步：将化合物24d(54mg，0.20mmol)和Int-1(40mg，0.20mmol)溶于1，4-二氧六环(4mL)中，加入碳酸铯(134mg，0.41mmol)，BrettPhos(22mg，0.041mmol)和BrettPhos Pd G3(18mg，0.020mmol)。反应体系置换氮气后加热至110℃搅拌16小时。待反应液冷却至室温，浓缩反应液，残留物用制备薄层层析纯化得到粗产品，再用反向制备HPLC分离得到化合物24(17mg，收率20％)。ESI-MS(m/z):418.2[M+H] +； 1HNMR(500MHz,DMSO-d6)δ8.15(s,1H),7.96(s,1H),7.74(br s,1H),7.61(s,1H),7.35-7.31(m,1H),3.88(s,3H),3.65-3.59(m,1H),3.48-3.37(m,3H),3.21-3.11(m,2H),2.74(t,J＝5.9Hz,2H),2.69-2.61(m,3H),2.34(s,3H),2.14-2.06(m,1H),1.85-1.76(m,1H)。 The fourth step: Compound 24d (54 mg, 0.20 mmol) and Int-1 (40 mg, 0.20 mmol) were dissolved in 1,4-dioxane (4 mL), cesium carbonate (134 mg, 0.41 mmol) was added, BrettPhos ( 22 mg, 0.041 mmol) and BrettPhos Pd G3 (18 mg, 0.020 mmol). After the reaction system was replaced with nitrogen, it was heated to 110°C and stirred for 16 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated, and the residue was purified by preparative thin layer chromatography to obtain the crude product, which was then separated by reverse preparative HPLC to obtain compound 24 (17 mg, yield 20%). ESI-MS(m/z): 418.2[M+H] + ; 1 HNMR (500MHz, DMSO-d6)δ8.15(s,1H),7.96(s,1H),7.74(br s,1H), 7.61(s, 1H), 7.35-7.31(m, 1H), 3.88(s, 3H), 3.65-3.59(m, 1H), 3.48-3.37(m, 3H), 3.21-3.11(m, 2H), 2.74 (t, J=5.9 Hz, 2H), 2.69-2.61 (m, 3H), 2.34 (s, 3H), 2.14-2.06 (m, 1H), 1.85-1.76 (m, 1H).
实施例25Example 25
4-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)甲基)哌啶-2-酮4-(((5-Chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino) pyrimidin-4-yl)amino)methyl)piperidin-2-one
Figure PCTCN2022085446-appb-000073
Figure PCTCN2022085446-appb-000073
用4-(氨基甲基)哌啶-2-酮替代实施例1第一步中的3-(氨基甲基)-1-甲基-1,2-二氢吡啶-2-酮盐酸盐1b，用类似的方法和反应步骤，可以得到化合物25。ESI-MS (m/z):432.2[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.07(s,1H),7.94(s,1H),7.64(s,1H),7.43(s,1H),7.39(t,J＝5.9Hz,1H),3.88(s,3H),3.41(s,2H),3.31-3.27(m,2H),3.21-3.14(m,1H),3.10-3.03(m,1H),2.75(t,J＝5.9Hz,2H),2.64(t,J＝5.9Hz,2H),2.34(s,3H),2.23-2.15(m,2H),1.94-1.83(m,1H),1.81-1.74(m,1H),1.36-1.27(m,1H)。 Replacing 3-(aminomethyl)-1-methyl-1,2-dihydropyridin-2-one hydrochloride in the first step of Example 1 with 4-(aminomethyl)piperidin-2-one 1b, using a similar method and reaction procedure, compound 25 can be obtained. ESI-MS (m/z): 432.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ 8.07(s, 1H), 7.94(s, 1H), 7.64(s, 1H), 7.43(s, 1H), 7.39(t, J=5.9Hz, 1H), 3.88(s, 3H), 3.41(s, 2H), 3.31-3.27(m, 2H), 3.21-3.14(m, 1H) ,3.10-3.03(m,1H),2.75(t,J＝5.9Hz,2H),2.64(t,J＝5.9Hz,2H),2.34(s,3H),2.23-2.15(m,2H), 1.94-1.83 (m, 1H), 1.81-1.74 (m, 1H), 1.36-1.27 (m, 1H).
实施例26Example 26
3-(((2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)甲基)-1-甲基吡啶-2(1H)-酮3-(((2-((2-Methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalen-3-yl)amino)-5-( Trifluoromethyl)pyrimidin-4-yl)amino)methyl)-1-methylpyridin-2(1H)-one
Figure PCTCN2022085446-appb-000074
Figure PCTCN2022085446-appb-000074
用2，4-二氯-5-三氟甲基嘧啶替代实施例1第一步中的2，4，5-三氯嘧啶1a，用类似的方法和反应步骤，可以得到化合物26。ESI-MS(m/z):476.2[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.23(s,1H),8.06(s,1H),7.74(s,1H),7.64(d,J＝6.5Hz,1H),7.57(br s,1H),7.01(d,J＝6.8Hz,1H),6.19(t,J＝6.8Hz,1H),4.39(d,J＝5.2Hz,2H),3.84(s,3H),3.50(s,3H),3.12(s,2H),2.71(d,J＝6.9Hz,2H),2.60(t,J＝5.9Hz,2H),2.33(s,3H)。 Substituting 2,4-dichloro-5-trifluoromethylpyrimidine for 2,4,5-trichloropyrimidine 1a in the first step of Example 1, and using a similar method and reaction procedure, compound 26 can be obtained. ESI-MS (m/z): 476.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ 8.23(s, 1H), 8.06(s, 1H), 7.74(s, 1H), 7.64(d,J＝6.5Hz,1H),7.57(br s,1H),7.01(d,J＝6.8Hz,1H),6.19(t,J＝6.8Hz,1H),4.39(d,J＝ 5.2Hz, 2H), 3.84(s, 3H), 3.50(s, 3H), 3.12(s, 2H), 2.71(d, J=6.9Hz, 2H), 2.60(t, J=5.9Hz, 2H) , 2.33(s, 3H).
实施例27Example 27
(R)-3-(1-((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氢-1,6-二氮杂萘-3-基)氨基)嘧啶-4-基)氨基)乙基)-1-甲基吡啶-2(1H)-酮(R)-3-(1-((5-Chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalene- 3-yl)amino)pyrimidin-4-yl)amino)ethyl)-1-methylpyridin-2(1H)-one
Figure PCTCN2022085446-appb-000075
Figure PCTCN2022085446-appb-000075
化合物27由以下步骤制备：Compound 27 was prepared by the following steps:
Figure PCTCN2022085446-appb-000076
Figure PCTCN2022085446-appb-000076
第一步：将化合物27a(500mg，4.06mmol)溶于DMF(5mL)中，在0℃冰浴下加入碳酸铯(1.59g，4.87mmol)和碘甲烷(692mg，4.87mmol)，反应升至室温搅拌16小时。待反应完全后，反应混合物加水(50mL)稀释，用乙酸乙酯(40mL*2)萃取。合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离(石油醚/乙酸乙酯＝2/1)得到白色固体化合物27b(290mg，收率52％)。 1H NMR(500MHz,CDCl 3)δ10.37(s,1H),8.04(dd,J＝7.0.4.5Hz,1H),7.63(dd,J＝6.5,2,0Hz,1H),6.32(t,J＝7.0Hz,1H),3.64(s,3H)。 The first step: Compound 27a (500 mg, 4.06 mmol) was dissolved in DMF (5 mL), cesium carbonate (1.59 g, 4.87 mmol) and methyl iodide (692 mg, 4.87 mmol) were added under ice bath at 0 °C, and the reaction rose to Stir at room temperature for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL*2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain compound 27b (290 mg, yield 52%) as a white solid. 1 H NMR (500MHz, CDCl 3 ) δ 10.37 (s, 1H), 8.04 (dd, J=7.0.4.5Hz, 1H), 7.63 (dd, J=6.5, 2, 0Hz, 1H), 6.32 (t , J=7.0Hz, 1H), 3.64 (s, 3H).
第二步：将化合物27b(200mg，1.46mmol)溶于DCE(5mL)中，加入碳酸铯(950mg，2.92mmol)和S-叔丁基亚磺酰胺(212mg，1.75mmol)，混合物在65℃下搅拌16小时。待反应完全后，反应混合物加水(30mL)稀释，用乙酸乙酯(30mL*2)萃取。合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得到淡黄色油状化合物27c(330mg，收率94％)。ESI-MS(m/z):241.4[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.71(s,1H),8.15(dd,J＝6.0.2.0Hz,1H),8.05(dd,J＝6.5,2,5Hz,1H),6.41(t,J＝7.0Hz,1H),3.52(s,3H),1.15(s,9H)。 The second step: Compound 27b (200 mg, 1.46 mmol) was dissolved in DCE (5 mL), cesium carbonate (950 mg, 2.92 mmol) and S-tert-butylsulfinamide (212 mg, 1.75 mmol) were added, and the mixture was heated at 65 °C under stirring for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL*2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 27c (330 mg, yield 94%) as a pale yellow oil. ESI-MS (m/z): 241.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.15 (dd, J=6.0.2.0 Hz, 1H), 8.05 (dd, J=6.5, 2, 5Hz, 1H), 6.41 (t, J=7.0Hz, 1H), 3.52 (s, 3H), 1.15 (s, 9H).
第三步：将化合物27c(35mg，0.14mmol)溶于DCM(3mL)中，氮气保护下于-78℃加入甲基溴化镁(1mol/L in THF，0.29mL)，混合物在-78℃下搅拌2小时。待反应完全后，加入饱和氯化铵溶液(20mL)淬灭反应，混合物用乙酸乙酯(20mL*2)萃取。合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得到淡黄色油状化合物27d(30mg，收率80％)。ESI-MS(m/z):257.5[M+H] +； 1H NMR(500MHz,DMSO-d6)δ7.61(dd,J＝7.0.2.0Hz,1H),7.46(dd,J＝6.5,2,0Hz,1H),6.25-6.20(m,1H),5.68(d,J＝10.5Hz,1H),4.42-4.37(m,1H), 3.44(s,3H),1.29(d,J＝6.5Hz,3H),1.10(s,9H)。化合物27d新生成的手性中心的立体构型假定为R-型。 The third step: Compound 27c (35 mg, 0.14 mmol) was dissolved in DCM (3 mL), methylmagnesium bromide (1 mol/L in THF, 0.29 mL) was added under nitrogen protection at -78 °C, and the mixture was heated at -78 °C under stirring for 2 hours. After the reaction was completed, saturated ammonium chloride solution (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL*2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 27d (30 mg, yield 80%) as a pale yellow oil. ESI-MS (m/z): 257.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 7.61 (dd, J=7.0.2.0 Hz, 1 H), 7.46 (dd, J=6.5 ,2,0Hz,1H),6.25-6.20(m,1H),5.68(d,J＝10.5Hz,1H),4.42-4.37(m,1H), 3.44(s,3H),1.29(d,J = 6.5Hz, 3H), 1.10 (s, 9H). The stereoconfiguration of the newly formed chiral center of compound 27d is assumed to be R-form.
第四步：将化合物27d(30mg，0.11mmol)溶于MeOH(2mL)中，加入盐酸二氧六环溶液(4mol/L，0.12mL)，反应混合物在室温下搅拌2小时。待反应完全后，反应液浓缩得白色固体化合物27e(22mg，收率99％)。ESI-MS(m/z):153.1[M+H] +。 The fourth step: Compound 27d (30 mg, 0.11 mmol) was dissolved in MeOH (2 mL), dioxane hydrochloride solution (4 mol/L, 0.12 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a white solid compound 27e (22 mg, yield 99%). ESI-MS (m/z): 153.1 [M+H] + .
第五步：将化合物27e(22mg，0.11mmol)溶于异丙醇(2mL)中，加入2，4，5-三氯嘧啶1a(32mg，0.17mmol)和N，N-二异丙基乙胺(30mg，0.23mmol)。反应混合物在室温下搅拌16小时。待反应完全后，反应液浓缩，残留物用制备薄层层析纯化(石油醚/乙酸乙酯＝1/1)得到白色固体化合物27f(31mg,收率88％)。ESI-MS(m/z):299.1[M+H] +。 The fifth step: Compound 27e (22 mg, 0.11 mmol) was dissolved in isopropanol (2 mL), 2,4,5-trichloropyrimidine 1a (32 mg, 0.17 mmol) and N,N-diisopropylethyl acetate were added. Amine (30 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to obtain white solid compound 27f (31 mg, yield 88%). ESI-MS (m/z): 299.1 [M+H] + .
第六步：将化合物Int-1(20mg，0.10mmol)和化合物27f(31mg，0.10mmol)溶于1，4-二氧六环(3mL)中，加入碳酸铯(67mg，0.20mmol)，BrettPhos(11mg，0.020mmol)和BrettPhos Pd G3(9mg，0.010mmol)。反应混合物置换氮气后加热至100℃搅拌18小时。反应液用硅藻土过滤，滤液浓缩，残留物用制备薄层层析纯化(二氯甲烷/甲醇＝10/1)得到粗产品，再用反向制备HPLC分离得到白色固体化合物27(3mg，收率6％)。ESI-MS(m/z):299.1[M+H] +； 1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.99(s,1H),7.67-7.63(m,1H),7.57(s,1H),7.53(d,J＝8.4Hz,1H),7.37-7.33(m,1H),6.26-6.19(m,1H),5.35-5.26(m,1H),3.87(s,3H),3.49(s,3H),3.45-3.43(m,2H),2.77-2.71(m,2H),2.68-2.60(m,2H),2.37(s,3H),1.44(d,J＝6.8Hz,3H)。 The sixth step: Compound Int-1 (20 mg, 0.10 mmol) and compound 27f (31 mg, 0.10 mmol) were dissolved in 1,4-dioxane (3 mL), cesium carbonate (67 mg, 0.20 mmol) was added, BrettPhos (11 mg, 0.020 mmol) and BrettPhos Pd G3 (9 mg, 0.010 mmol). The reaction mixture was replaced with nitrogen and then heated to 100°C with stirring for 18 hours. The reaction solution was filtered with celite, the filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane/methanol=10/1) to obtain a crude product, which was then separated by reverse preparative HPLC to obtain a white solid compound 27 (3 mg, yield 6%). ESI-MS (m/z): 299.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.99 (s, 1H), 7.67-7.63 (m, 1H) ), 7.57(s, 1H), 7.53(d, J=8.4Hz, 1H), 7.37-7.33(m, 1H), 6.26-6.19(m, 1H), 5.35-5.26(m, 1H), 3.87( s, 3H), 3.49(s, 3H), 3.45-3.43(m, 2H), 2.77-2.71(m, 2H), 2.68-2.60(m, 2H), 2.37(s, 3H), 1.44(d, J=6.8Hz, 3H).
根据以上实施例描述的合成路线和中间体的合成方法，制备得到了以下实施例。According to the synthetic route and the synthetic method of the intermediate described in the above examples, the following examples were prepared.
Figure PCTCN2022085446-appb-000077
Figure PCTCN2022085446-appb-000077
Figure PCTCN2022085446-appb-000078
Figure PCTCN2022085446-appb-000078
Figure PCTCN2022085446-appb-000079
Figure PCTCN2022085446-appb-000079
Figure PCTCN2022085446-appb-000080
Figure PCTCN2022085446-appb-000080
Figure PCTCN2022085446-appb-000081
Figure PCTCN2022085446-appb-000081
Figure PCTCN2022085446-appb-000082
Figure PCTCN2022085446-appb-000082
Figure PCTCN2022085446-appb-000083
Figure PCTCN2022085446-appb-000083
HPK1抑制剂生物学筛选和结果Biological Screening and Results of HPK1 Inhibitors
试验例1：化合物对HPK1激酶活性抑制能力的检测(方法1)Test Example 1: Detection of the ability of compounds to inhibit HPK1 kinase activity (Method 1)
所需使用试剂如下The required reagents are as follows
Figure PCTCN2022085446-appb-000084
Figure PCTCN2022085446-appb-000084
实验步骤Experimental procedure
具体操作如下：配置酶促反应体系缓冲液(10mM MOPS，pH 7.2，5mM β-glycerol-phosphate，10mM MgCl2，0.8mM EDTA，2mM EGTA，0.1mM DTT)；将测试的化合物(配于DMSO中1mM的化合物储液)用缓冲液稀释至为60uM最高浓度(包含6％DMSO)，并配置60μM浓度起始用包含6％DMSO的缓冲液进行5倍稀释共计8个点的梯度浓度的化合物；随后使用缓冲液将HPK1激酶稀释至30nM。在Greiner 384孔微孔板(货号：784075)中每孔加入2μl的HPK1激酶稀释液，对照孔中补充2μl缓冲液；短暂离心后在反应孔中加入1μl的稀释化合物，对照孔中加入1μl包含6％DMSO的缓冲液；短暂离心后置于25℃恒温孵育箱(上海一恒科学仪器有限公司，货号：LRH-150)中孵育20min。在每孔中加入3μl反应底物(溶解于蒸馏水中的10μM MBP和20μM ATP)，短暂离心后置于25℃恒温孵育箱中孵育60min，采用ADP-Glo Kinase Assay Kit检测酶促反应活性，ADP-Glo Kinase Assay Kit检测都依据试剂盒的操作说明进行。数据采用化合物的半数抑制浓度IC50描述。The specific operations are as follows: configure the enzymatic reaction system buffer (10mM MOPS, pH 7.2, 5mM β-glycerol-phosphate, 10mM MgCl2, 0.8mM EDTA, 2mM EGTA, 0.1mM DTT); test compounds (1mM in DMSO) Compound stock solution) was diluted with buffer to a maximum concentration of 60uM (containing 6% DMSO), and prepared a 60 μM concentration starting with a 5-fold dilution with a buffer containing 6% DMSO for a total of 8 point gradient concentrations of compounds; then The HPK1 kinase was diluted to 30 nM with buffer. Add 2 μl of HPK1 kinase dilution to each well of a Greiner 384-well microplate (Cat. No. 784075), and add 2 μl of buffer to control wells; add 1 μl of diluted compound to reaction wells after brief centrifugation, and add 1 μl of control wells containing 6% DMSO buffer; briefly centrifuged and then placed in a 25°C constant temperature incubator (Shanghai Yiheng Scientific Instrument Co., Ltd., product number: LRH-150) for 20 min. Add 3 μl of reaction substrate (10 μM MBP and 20 μM ATP dissolved in distilled water) to each well, centrifuge briefly and then incubate in a constant temperature incubator at 25°C for 60 min. The enzymatic reaction activity was detected by ADP-Glo Kinase Assay Kit, ADP - Glo Kinase Assay Kit assays are performed according to the kit's operating instructions. Data are described using the compound's median inhibitory concentration IC50.
化合物编号Compound number IC50(nM)IC50(nM) 化合物编号Compound number IC50(nM)IC50(nM)
11 <0.1<0.1 22 8888
33 45.7345.73 55 18.5218.52
66 2.62.6 77 <0.1<0.1
88 5.435.43 99 16.1216.12
1010 98.5498.54 1111 4.984.98
1313 82.5982.59 1414 18.9918.99
1616 34.4234.42 1717 82.8282.82
1919 8.528.52 21twenty one 94.7594.75
23twenty three 0.160.16 24twenty four 0.710.71
2525 33.9933.99 2626 1.351.35
2727 1.921.92 2828 18.3518.35
2929 19.4319.43 3030 29.7829.78
3131 11.8011.80 3232 0.850.85
3333 13.5613.56 3434 43.5143.51
3535 42.2842.28 3636 3.443.44
3737 8.038.03 3838 12.8212.82
3939 19.0119.01 4040 2.062.06
4242 81.0681.06 4343 4.264.26
4444 0.480.48 4545 29.4029.40
4646 44.9744.97 4747 20.9720.97
4848 17.9417.94 4949 5.785.78
5050 9.679.67 5151 14.6114.61
5252 9.009.00 5353 2.692.69
试验例2：化合物对Jurkat细胞分泌细胞因子白介素-2(IL-2)激动能力的检测(方法2)Test Example 2: Detection of agonistic ability of compounds to secrete cytokine interleukin-2 (IL-2) by Jurkat cells (Method 2)
所需使用试剂及细胞如下The required reagents and cells are as follows
实验试剂：Experimental reagents:
试剂reagent 品牌brand 货号article number 保存条件Storage Conditions
RPMI1640RPMI1640 BIBI 01-100-1ACS01-100-1ACS 4℃4℃
FBSFBS BIBI 04-002-1A04-002-1A -80℃-80℃
BSABSA AmrescoAmresco 0332-1KG0332-1KG 4℃4℃
磷酸盐缓冲溶液Phosphate buffer solution BIBI 02-024-1ACS02-024-1ACS 4℃4℃
Tween-20Tween-20 SolarbioSolarbio T8220T8220 RTRT
Anti-human CD3 AntibodyAnti-human CD3 Antibody invitrogeninvitrogen 16-0037-8516-0037-85 4℃4℃
Anti-human CD28 AntibodyAnti-human CD28 Antibody invitrogeninvitrogen 16-0289-8516-0289-85 4℃4℃
Human IL-2 DuoSet ELISAHuman IL-2 DuoSet ELISA R&DR&D DY202DY202 4℃4℃
实验细胞：Experimental cells:
细胞cell 细胞类型cell type 品牌brand
Jurkat E6-1Jurkat E6-1 人T淋巴细胞白血病细胞human T-lymphocytic leukemia cells 中科院细胞库Chinese Academy of Sciences Cell Bank
实验步骤Experimental procedure
具体操作如下：将化合物粉末用DMSO溶解至10mM，取2μl化合物加入到998μl RPMI 1640培养基(此试验中均含10％FBS)中，涡旋混匀后为最高浓度点。用0.2％DMSO培养基3倍逐渐稀释化合物溶液，共8个浓度点。以含浓度为0.1％DMSO的RPMI 1640培养基溶液处理作为对照。在康宁96孔细胞培养板(货号：3599)中每孔加入1×105Jurkat E6-1细胞，随后加入等量体积的化合物稀释液，对照组加入含0.2％DMSO的RPMI 1640培养基，置于37℃细胞培养箱(Thermo Fisher Scientific，型号：3111)孵育1h。随后加入终浓度为1μg/ml Anti-human CD3 Antibody和1μg/ml Anti-human CD28 Antibody抗体，置于37℃细胞培养箱孵育24h。采用Human IL-2 DuoSet ELISA KIT检测细胞上清液中的IL-2含量，Human IL-2 DuoSet ELISA检测依据试剂盒的操作说明进行。数据采用化合物的刺激信 号与0.1％DMSO的信号的最高倍数比值描述。The specific operations are as follows: dissolve the compound powder to 10 mM with DMSO, add 2 μl of the compound to 998 μl of RPMI 1640 medium (both in this test containing 10% FBS), and vortex to mix the highest concentration point. The compound solution was gradually diluted 3-fold with 0.2% DMSO medium for a total of 8 concentration points. The control was treated with RPMI 1640 medium solution containing 0.1% DMSO. 1 × 105 Jurkat E6-1 cells were added to each well of a Corning 96-well cell culture plate (Cat. No. 3599), followed by an equal volume of compound dilutions. The control group was added RPMI 1640 medium containing 0.2% DMSO, and placed in 37 Incubate for 1 h in a cell incubator (Thermo Fisher Scientific, model: 3111). Then, the final concentrations of 1 μg/ml Anti-human CD3 Antibody and 1 μg/ml Anti-human CD28 Antibody were added and incubated in a 37°C cell incubator for 24 hours. Human IL-2 DuoSet ELISA KIT was used to detect the IL-2 content in the cell supernatant, and the Human IL-2 DuoSet ELISA detection was carried out according to the operating instructions of the kit. Data are described as the highest fold ratio of the stimulation signal of the compound to the signal of 0.1% DMSO.
Figure PCTCN2022085446-appb-000085
Figure PCTCN2022085446-appb-000085
Figure PCTCN2022085446-appb-000086
Figure PCTCN2022085446-appb-000086
试验例3：化合物对人PBMC细胞分泌细胞因子白介素-2(IL-2)激动能力的检测(方法3)Test Example 3: Detection of the agonistic ability of compounds to secrete cytokine interleukin-2 (IL-2) by human PBMC cells (Method 3)
所需使用试剂如下The required reagents are as follows
试剂reagent 品牌brand 货号article number 保存条件Storage Conditions
RPMI1640RPMI1640 BIBI 01-100-1ACS01-100-1ACS 4℃4℃
FBSFBS BIBI 04-002-1A04-002-1A -80℃-80℃
BSABSA AmrescoAmresco 0332-1KG0332-1KG 4℃4℃
磷酸盐缓冲溶液Phosphate buffer solution BIBI 02-024-1ACS02-024-1ACS 4℃4℃
Tween-20Tween-20 SolarbioSolarbio T8220T8220 RTRT
Anti-human CD3 AntibodyAnti-human CD3 Antibody invitrogeninvitrogen 16-0037-8516-0037-85 4℃4℃
Anti-human CD28 AntibodyAnti-human CD28 Antibody invitrogeninvitrogen 16-0289-8516-0289-85 4℃4℃
Human IL-2 DuoSet ELISAHuman IL-2 DuoSet ELISA R&DR&D DY202DY202 4℃4℃
实验细胞来源信息：Experimental cell source information:
Figure PCTCN2022085446-appb-000087
Figure PCTCN2022085446-appb-000087
实验步骤Experimental procedure
具体操作如下：人PBMC按照标准操作从液氮中取出后，置于37℃水浴锅中解冻复苏，将细胞用RPMI 1640培养基(此试验中均含10％FBS)重悬，离心洗涤两次；随后将人PBMC细胞重悬于RPMI 1640培养基中备用。将化合物粉末用DMSO溶解至10mM，取2μl化合物加入到998μl RPMI 1640培养基中，涡旋混匀后为最高浓度点。用0.2％DMSO培养基3倍逐渐稀释化合物溶液，共8个浓度点。以含浓度为0.1％DMSO的RPMI 1640培养基溶液处理作为对照。在康宁96孔细胞培养板(货号：3599)中每孔加入1×105人PBMC细胞，随后加入等量体积的化合物稀释液，对照组加入含0.2％DMSO的RPMI 1640培养基，置于37℃细胞培养箱(Thermo Fisher Scientific，型号：3111)孵育1h。随后加入终浓度为0.01μg/ml Anti-human CD3 Antibody和1μg/ml Anti-human CD28 Antibody抗体，置于37℃细胞培养箱孵育24h。采用Human IL-2 DuoSet ELISA KIT检测细胞上清液中的IL-2含量，Human IL-2 DuoSet ELISA检测依据试剂盒的操作说明进行。数据采用化合物的刺激信号与0.1％DMSO的信号的最高倍数比值描述。The specific operations are as follows: human PBMCs were taken out from liquid nitrogen according to standard operations, thawed and thawed in a water bath at 37°C, resuspended in RPMI 1640 medium (both containing 10% FBS in this test), and washed twice by centrifugation. ; Human PBMC cells were subsequently resuspended in RPMI 1640 medium for later use. The compound powder was dissolved to 10 mM with DMSO, and 2 μl of the compound was added to 998 μl of RPMI 1640 medium, and the highest concentration point was obtained after vortexing and mixing. The compound solution was gradually diluted 3-fold with 0.2% DMSO medium for a total of 8 concentration points. The control was treated with RPMI 1640 medium solution containing 0.1% DMSO. 1×105 human PBMC cells were added to each well of a Corning 96-well cell culture plate (Cat. No. 3599), followed by an equal volume of compound diluents. For the control group, RPMI 1640 medium containing 0.2% DMSO was added, and the cells were placed at 37°C. The cells were incubated in a cell incubator (Thermo Fisher Scientific, model: 3111) for 1 h. Then, the final concentrations of 0.01μg/ml Anti-human CD3 Antibody and 1μg/ml Anti-human CD28 Antibody were added, and incubated at 37°C for 24h. Human IL-2 DuoSet ELISA KIT was used to detect the IL-2 content in the cell supernatant, and the Human IL-2 DuoSet ELISA detection was carried out according to the operating instructions of the kit. Data are described as the highest fold ratio of the stimulation signal of the compound to the signal of 0.1% DMSO.
Figure PCTCN2022085446-appb-000088
Figure PCTCN2022085446-appb-000088
Figure PCTCN2022085446-appb-000089
Figure PCTCN2022085446-appb-000089
上述结果表明，本发明化合物可以使IL-2显著增加。The above results show that the compounds of the present invention can significantly increase IL-2.

Claims (27)

  1. 具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物或其立体异构体：A compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof:
    Figure PCTCN2022085446-appb-100001
    Figure PCTCN2022085446-appb-100001
    其中in
    X表示N或者CR 10； X represents N or CR 10 ;
    R 1表示氢、C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基、卤代C 3-C 6环烷基、卤素、氰基或-C(O)NH 2； R 1 represents hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogenated C 3 -C 6 cycloalkyl, halogen, cyano or -C (O)NH 2 ;
    R 2表示氢、卤素、羟基、(C 1-C 6)烷基、(C 2-C 6)烯基、-(C 0-C 6亚烷基)(C 3-C 8)环烷基、-(C 0-C 6亚烷基)(4-8元)杂环烷基、(C 1-C 6)烷氧基、(C 3-C 8)环烷基(C 0-C 6亚烷基)氧基或(4-8元杂环烷基)(C 0-C 6亚烷基)氧基； R 2 represents hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, -(C 0 -C 6 alkylene)(C 3 -C 8 )cycloalkyl , -(C 0 -C 6 alkylene) (4-8 membered) heterocycloalkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl (C 0 -C 6 ) alkylene)oxy or (4-8 membered heterocycloalkyl)(C 0 -C 6 alkylene)oxy;
    R 3表示氢或C 1-C 6烷基、C 3-C 6烯基、C 3-C 6环烷基、羟基(C 1-C 6烷基)、卤代C 1-C 6烷基、4-8元杂环烷基； R 3 represents hydrogen or C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, hydroxy (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl , 4-8 membered heterocycloalkyl;
    R 4表示氢或C 1-C 6烷基；并且所述C 1-C 6烷基可以任意地被选自以下的取代基所取代：卤素、-OR a、-SR a、-P(O)R aR b、-S(O) 2R a、-S(O)(NH)R a、-S(O)R a、-S(O) 2NR aR b、-C(O)NR aR b、-C(O)OH、-OC(O)NR aR b、-NR aC(O)R b、-NR aS(O) 2R b； R 4 represents hydrogen or C 1 -C 6 alkyl; and the C 1 -C 6 alkyl may be optionally substituted with a substituent selected from halogen, -OR a , -SR a , -P(O )R a R b , -S(O) 2 R a , -S(O)(NH)R a , -S(O)R a , -S(O) 2 NR a R b , -C(O) NR a R b , -C(O)OH, -OC(O)NR a R b , -NR a C(O) R b , -NR a S(O) 2 R b ;
    R 5和R 5’各自独立地表示氢、C 1-C 6烷基、C 2-C 6烯基、卤素、卤代C 1-C 6烷基或羟基(C 1-C 6烷基)； R 5 and R 5' each independently represent hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halogen, halogenated C 1 -C 6 alkyl or hydroxy (C 1 -C 6 alkyl) ;
    或者R 5与R 5’一起与与之相连的碳原子形成3-6元环，该环中还可以任意地含有0、1或2个选自N、O、S的杂原子； Or R 5 and R 5' together form a 3-6 membered ring with the carbon atom connected to it, and the ring can also optionally contain 0, 1 or 2 heteroatoms selected from N, O, S;
    R 6和R 6’各自独立地表示氢、C 1-C 6烷基、C 2-C 6烯基、卤素、卤代C 1-C 6烷基或羟基(C 1-C 6烷基)； R 6 and R 6' each independently represent hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halogen, halogenated C 1 -C 6 alkyl or hydroxy (C 1 -C 6 alkyl) ;
    或者R 6与R 6’一起与与之相连的碳原子形成3-6元环，该环中还可以任意地含有0、1或2个选自N、O、S的杂原子； Or R 6 and R 6' together form a 3-6 membered ring with the carbon atom connected to it, and the ring can also optionally contain 0, 1 or 2 heteroatoms selected from N, O, and S;
    p表示1或者2；p represents 1 or 2;
    R 7和R 7’各自独立地表示氢、C 1-C 6烷基、C 2-C 6烯基、卤素、卤代C 1-C 6烷基或羟基(C 1-C 6烷基)； R 7 and R 7' each independently represent hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halogen, halogenated C 1 -C 6 alkyl or hydroxy (C 1 -C 6 alkyl) ;
    或者R 7与R 7’一起与与之相连的碳原子形成3-6元环，该环中还可以任意地含有0、1或2个选自N、O、S的杂原子； Or R 7 and R 7' together form a 3-6 membered ring with the carbon atom connected to it, and the ring can also optionally contain 0, 1 or 2 heteroatoms selected from N, O, and S;
    W表示
    Figure PCTCN2022085446-appb-100002
    W means
    Figure PCTCN2022085446-appb-100002
    其中A表示
    Figure PCTCN2022085446-appb-100003
    where A means
    Figure PCTCN2022085446-appb-100003
    Figure PCTCN2022085446-appb-100004
    表示该环中含有单键或双键；
    Figure PCTCN2022085446-appb-100004
    Indicates that the ring contains a single bond or a double bond;
    当A与A’之间的化学键为双键时，A’表示CR a或N，B表示CR b； When the chemical bond between A and A' is a double bond, A' represents CR a or N, and B represents CR b ;
    当A与A’之间的化学键为单键时，A’表示CHR a，B表示CHR b或者不存在； When the chemical bond between A and A' is a single bond, A' represents CHR a , B represents CHR b or does not exist;
    R 8和R 9各自独立地表示氢或C 1-C 6烷基；或者R 8与R 9可以与W 1和W 2一起构成3-6元环； R 8 and R 9 each independently represent hydrogen or C 1 -C 6 alkyl; or R 8 and R 9 may together with W 1 and W 2 form a 3-6 membered ring;
    W 1表示C，W 2表示CH或N； W 1 means C, W 2 means CH or N;
    R M和R N各自独立地表示氢或C 1-C 6烷基； R M and R N each independently represent hydrogen or C 1 -C 6 alkyl;
    R 10表示氢、卤素、(C 1-C 6)烷基、(C 2-C 6)烯基、-(C 0-C 6亚烷基)(C 3-C 8)环烷基、-(C 0-C 6亚烷基)4-10元杂环烷基、-(C 0-C 6亚烷基)(C 6-C 10)芳基或-(C 0-C 6亚烷基)5-10元杂芳基， R 10 represents hydrogen, halogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, -(C 0 -C 6 alkylene)(C 3 -C 8 )cycloalkyl, - (C 0 -C 6 alkylene) 4-10 membered heterocycloalkyl, -(C 0 -C 6 alkylene) (C 6 -C 10 ) aryl or -(C 0 -C 6 alkylene ) 5-10 membered heteroaryl,
    或者，当X表示CR 10时，R 10可以与相邻的R 2一起形成5-10元环烷基或者5-10元杂环烷基； Alternatively, when X represents CR 10 , R 10 may together with the adjacent R 2 form a 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl;
    其中，R a、R b各自独立地表示氢、C 1-C 6烷基、羟基(C 1-C 6烷基)或卤代C 1-C 6烷基； wherein, R a and R b each independently represent hydrogen, C 1 -C 6 alkyl, hydroxyl (C 1 -C 6 alkyl) or halogenated C 1 -C 6 alkyl;
    m、n分别表示0、1或2。m and n represent 0, 1 or 2, respectively.
  2. 如权利要求1所述的化合物或其药学上可接受的盐、同位素衍生物或其立体异构体，其中，The compound of claim 1 or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein,
    W表示
    Figure PCTCN2022085446-appb-100005
    W means
    Figure PCTCN2022085446-appb-100005
    其中，A表示
    Figure PCTCN2022085446-appb-100006
    Among them, A means
    Figure PCTCN2022085446-appb-100006
    Figure PCTCN2022085446-appb-100007
    表示该环中含有单键或双键；
    Figure PCTCN2022085446-appb-100007
    Indicates that the ring contains a single bond or a double bond;
    o各自独立地表示0或者1；o each independently represents 0 or 1;
    R 8表示氢或C 1-C 6烷基； R 8 represents hydrogen or C 1 -C 6 alkyl;
    R 9各自独立地表示氢或C 1-C 6烷基； R 9 each independently represents hydrogen or C 1 -C 6 alkyl;
    或者R 8与相邻的R 9以及与它们相连的碳原子一起构成3-6元环； Or R 8 together with adjacent R 9 and the carbon atoms to which they are attached form a 3-6 membered ring;
    W 2、R M、R N如权利要求1所述。 W 2 , RM and RN are as described in claim 1 .
  3. 如权利要求2所述的化合物或其药学上可接受的盐、同位素衍生物或其立体异构体，其中，The compound of claim 2 or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein,
    W表示
    Figure PCTCN2022085446-appb-100008
    或者
    Figure PCTCN2022085446-appb-100009
    W means
    Figure PCTCN2022085446-appb-100008
    or
    Figure PCTCN2022085446-appb-100009
    Figure PCTCN2022085446-appb-100010
    表示该环中含有单键或双键；
    Figure PCTCN2022085446-appb-100010
    Indicates that the ring contains a single bond or a double bond;
    o各自独立地表示0或者1；o each independently represents 0 or 1;
    R 8表示氢或C 1-C 6烷基； R 8 represents hydrogen or C 1 -C 6 alkyl;
    R 9各自独立地表示氢或C 1-C 6烷基； R 9 each independently represents hydrogen or C 1 -C 6 alkyl;
    或者R 8与相邻的R 9以及与它们相连的碳原子一起构成3-6元环； Or R 8 together with adjacent R 9 and the carbon atoms to which they are attached form a 3-6 membered ring;
    W 2、R M、R N如权利要求1所述。 W 2 , RM and RN are as described in claim 1 .
  4. 如权利要求3所述的化合物或其药学上可接受的盐、同位素衍生物或其立体异构体，其中，W为芳香杂环。The compound of claim 3 or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein W is an aromatic heterocycle.
  5. 如权利要求3所述的化合物或其药学上可接受的盐、同位素衍生物或其立体异构体，其中，W为饱和杂环。The compound of claim 3 or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein W is a saturated heterocycle.
  6. 如权利要求1所述的化合物或其药学上可接受的盐、同位素衍生物或其立体异构体，其中环W表示
    Figure PCTCN2022085446-appb-100011
    Figure PCTCN2022085446-appb-100012
    或者
    Figure PCTCN2022085446-appb-100013
    Figure PCTCN2022085446-appb-100014
    The compound of claim 1 or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein ring W represents
    Figure PCTCN2022085446-appb-100011
    Figure PCTCN2022085446-appb-100012
    or
    Figure PCTCN2022085446-appb-100013
    Figure PCTCN2022085446-appb-100014
  7. 如权利要求6所述的化合物或其药学上可接受的盐、同位素衍生物或其立体异构体，其中环W表示
    Figure PCTCN2022085446-appb-100015
    Figure PCTCN2022085446-appb-100016
    The compound of claim 6 or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein ring W represents
    Figure PCTCN2022085446-appb-100015
    Figure PCTCN2022085446-appb-100016
    Figure PCTCN2022085446-appb-100017
    Figure PCTCN2022085446-appb-100017
  8. 如权利要求7所述的化合物或其药学上可接受的盐、同位素衍生物或其立体异构体，其中环W表示
    Figure PCTCN2022085446-appb-100018
    The compound of claim 7 or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein ring W represents
    Figure PCTCN2022085446-appb-100018
  9. 如前述任一权利要求所述的化合物或其药学上可接受的盐、同位素衍生物或其立体异构体，其中，R 1表示氢、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、氰基或-C(O)NH 2。 The compound of any preceding claim, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein R 1 represents hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyano or -C(O) NH2 .
  10. 如权利要求9所述的化合物或其药学上可接受的盐同位素衍生物或其立体异构体，其中，R 1表示氢、卤素、C 1-C 6烷基或者C 1-C 6卤代烷基。 The compound of claim 9 or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 1 represents hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl .
  11. 如前述任一权利要求所述的化合物或其药学上可接受的盐同位素衍生物或其立体异构体，其中，R 2表示羟基、(C 1-C 6)烷基、-(C 0-C 6亚烷基)(C 3-C 8)环烷基、-(C 0-C 6亚烷基)(4-8元)杂环烷基、(C 1-C 6)烷氧基。 The compound of any preceding claim, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 2 represents hydroxy, (C 1 -C 6 )alkyl, -(C 0 - C 6 alkylene) (C 3 -C 8 )cycloalkyl, -(C 0 -C 6 alkylene)(4-8 membered)heterocycloalkyl, (C 1 -C 6 )alkoxy.
  12. 如权利要求11所述的化合物或其药学上可接受的盐、同位素衍生物或其立体异构体，其中，R 2表示C 1-C 6烷基、C 1-C 6烷氧基或C 3-C 6环烷基。 The compound of claim 11 or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein R 2 represents C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 6 cycloalkyl.
  13. 如前述任一权利要求所述的化合物或其药学上可接受的盐同位素衍生物或其立体异构体，其中，R 3表示氢或C 1-C 6烷基、C 3-C 6环烷基、卤代C 1-C 6烷基； The compound of any preceding claim, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 3 represents hydrogen or C 1 -C 6 alkyl, C 3 -C 6 cycloalkane base, halogenated C 1 -C 6 alkyl;
  14. 如权利要求13所述的化合物或其药学上可接受的盐、同位素衍生物或其立体异构体，其中，R 3表示氢或C 1-C 6烷基。 The compound of claim 13 or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein R 3 represents hydrogen or C 1 -C 6 alkyl.
  15. 如前述任一权利要求所述的化合物或其药学上可接受的盐同位素衍生物或其立体异构体，其中，R 4表示氢或C 1-C 6烷基；并且所述C 1-C 6烷基可以任意地被选自以下的取代基所取代：卤素、-OR a、-SR a、-P(O)R aR b、-S(O) 2R a、-S(O)(NH)R a、-S(O)R a、-S(O) 2NR aR b、-C(O)NR aR b、-C(O)OH。 The compound of any preceding claim, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 4 represents hydrogen or C 1 -C 6 alkyl; and the C 1 -C 6Alkyl can be optionally substituted by a substituent selected from the group consisting of halogen, -OR a , -SR a , -P(O)R a R b , -S(O) 2 R a , -S(O) (NH)R a , -S(O)R a , -S(O) 2 NR a R b , -C(O)NR a R b , -C(O)OH.
  16. 如权利要求15所述的化合物或其药学上可接受的盐、同位素衍生物或其立体异构体，其中，R 4表示氢或C 1-C 6烷基。17、如前述任一权利要求所述的化合物或其药学上可接受的盐同位素衍生物或其立体异构体，其中，R 5、R 5’各自独立地表示氢、卤素、C 1-C 6烷基或卤代C 1-C 6烷基。 The compound of claim 15 or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein R 4 represents hydrogen or C 1 -C 6 alkyl. 17. The compound of any preceding claim, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 5 , R 5' each independently represent hydrogen, halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
  17. 如前述任一权利要求所述的化合物或其药学上可接受的盐同位素衍生物或其立体异构体，其中，R 6、R 6’各自独立地表示氢、卤素、C 1-C 6烷基或卤代C 1-C 6烷基。 The compound of any preceding claim, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 6 , R 6′ each independently represent hydrogen, halogen, C 1 -C 6 alkane or halogenated C 1 -C 6 alkyl.
  18. 如前述任一权利要求所述的化合物或其药学上可接受的盐同位素衍生物或其立体异构体，，其中，R 7、R 7’各自独立地表示氢、卤素、C 1-C 6烷基、卤代C 1-C 6烷基或羟基(C 1-C 6烷基)。20、.如前述任一权利要求所述的化合物或其药学上可接受的盐同位素衍生物或其立体异构体，其中，R 8表示氢或C 1-C 6烷基。 The compound of any preceding claim, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 7 and R 7' each independently represent hydrogen, halogen, C 1 -C 6 Alkyl, halogenated C1 - C6 alkyl or hydroxy ( C1 - C6 alkyl). 20. The compound of any preceding claim, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R8 represents hydrogen or C1 - C6 alkyl.
  19. 如前述任一权利要求所述的化合物或其药学上可接受的盐同位素衍生物或其立体异构体，其中，R 9表示氢或C 1-C 6烷基。 A compound as claimed in any preceding claim, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 9 represents hydrogen or C 1 -C 6 alkyl.
  20. 如前述任一权利要求所述的化合物或其药学上可接受的盐同位素衍生物或其立体异构体，其中，R 10表示氢、卤素、(C 1-C 6)烷基、-(C 0-C 6亚烷基)(C 3-C 8)环烷基、-(C 0-C 6亚烷基)4-10元杂环烷基。 The compound of any preceding claim, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 10 represents hydrogen, halogen, (C 1 -C 6 )alkyl, -(C 0 - C6alkylene )(C3 - C8 )cycloalkyl, -( C0 - C6alkylene )4-10 membered heterocycloalkyl.
  21. 如权利要求22所述的化合物或其药学上可接受的盐同位素衍生物或其立体异构体，其中，R 10表示氢、卤素或者(C 1-C 6)烷基。 The compound of claim 22, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 10 represents hydrogen, halogen or (C 1 -C 6 )alkyl.
  22. 如前述任一权利要求所述的化合物或其药学上可接受的盐同位素衍生物或其立体异构体，其中，R M表示氢或C 1-C 6烷基。 A compound as claimed in any preceding claim, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R M represents hydrogen or C 1 -C 6 alkyl.
  23. 如前述任一权利要求所述的化合物或其药学上可接受的盐同位素衍生物或其立体异构体，其中，R a、R b各自独立地表示氢、C 1-C 6烷基或卤代C 1-C 6烷基。 The compound of any preceding claim, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R a , R b each independently represent hydrogen, C 1 -C 6 alkyl or halo Substituted C 1 -C 6 alkyl.
  24. 化合物，具有以下结构：A compound with the following structure:
    Figure PCTCN2022085446-appb-100019
    Figure PCTCN2022085446-appb-100019
    Figure PCTCN2022085446-appb-100020
    Figure PCTCN2022085446-appb-100020
    Figure PCTCN2022085446-appb-100021
    Figure PCTCN2022085446-appb-100021
    Figure PCTCN2022085446-appb-100022
    Figure PCTCN2022085446-appb-100022
    Figure PCTCN2022085446-appb-100023
    Figure PCTCN2022085446-appb-100023
    Figure PCTCN2022085446-appb-100024
    Figure PCTCN2022085446-appb-100024
    Figure PCTCN2022085446-appb-100025
    Figure PCTCN2022085446-appb-100025
    Figure PCTCN2022085446-appb-100026
    Figure PCTCN2022085446-appb-100026
    Figure PCTCN2022085446-appb-100027
    Figure PCTCN2022085446-appb-100027
  25. 药物组合物，其包含权如前述任一权利要求所述的化合物或其药学上可接受的盐、同位素衍生物或其立体异构体，以及药学上可用的载体。A pharmaceutical composition comprising a compound as claimed in any preceding claim, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, and a pharmaceutically acceptable carrier.
  26. 权利要求1-26任一项所述的化合物或其药学上可接受的盐、同位素衍生物、立体异构体或者权利要求27所述的药物组合物在制备用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的药物中的用途。The compound of any one of claims 1-26 or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer or the pharmaceutical composition of claim 27 is prepared for the prevention and/or treatment of cancer, Use in the medicament of tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.
  27. 如权利要求1-26所述的化合物或其药学上可接受的盐、同位素衍生物或其立体异构体用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的用途。The compounds of claims 1-26 or their pharmaceutically acceptable salts, isotopic derivatives or stereoisomers thereof for preventing and/or treating cancer, tumors, inflammatory diseases, autoimmune diseases or immune mediators Use in leading diseases.
PCT/CN2022/085446 2021-04-08 2022-04-07 High-activity hpk1 kinase inhibitor WO2022214009A1 (en)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2004056807A1 (en) * 2002-12-20 2004-07-08 Pfizer Products Inc. Pyrimidine derivatives for the treatment of abnormal cell growth
CN1665789A (en) * 2002-06-28 2005-09-07 山之内制药株式会社 Diaminopyrimidinecarboxa mide derivative
US20050256111A1 (en) * 2004-05-14 2005-11-17 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
CN110678466A (en) * 2017-03-30 2020-01-10 豪夫迈·罗氏有限公司 Naphthyridines as HPK1 inhibitors
CN112243439A (en) * 2018-06-13 2021-01-19 百济神州有限公司 Pyrrolo [2,3-B ] pyridines or pyrrolo [2,3-B ] pyrazines as HPK1 inhibitors and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1665789A (en) * 2002-06-28 2005-09-07 山之内制药株式会社 Diaminopyrimidinecarboxa mide derivative
WO2004056807A1 (en) * 2002-12-20 2004-07-08 Pfizer Products Inc. Pyrimidine derivatives for the treatment of abnormal cell growth
US20050256111A1 (en) * 2004-05-14 2005-11-17 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
CN110678466A (en) * 2017-03-30 2020-01-10 豪夫迈·罗氏有限公司 Naphthyridines as HPK1 inhibitors
CN112243439A (en) * 2018-06-13 2021-01-19 百济神州有限公司 Pyrrolo [2,3-B ] pyridines or pyrrolo [2,3-B ] pyrazines as HPK1 inhibitors and uses thereof

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