WO2022214009A1 - Inhibiteur de la kinase hpk1 à haute activité - Google Patents

Inhibiteur de la kinase hpk1 à haute activité 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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English (en)
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/zh
Publication of WO2022214009A1 publication Critical patent/WO2022214009A1/fr

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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.

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Abstract

L'invention concerne un composé qui a une structure de formule (I) et qui est capable d'inhiber l'activité de la kinase HPK1, ainsi qu'une composition pharmaceutique comprenant ce composé. L'invention concerne en outre l'utilisation dudit composé dans la prévention et/ou le traitement de cancers, de tumeurs, de maladies inflammatoires, de maladies auto-immunes ou de maladies à médiation immunitaire.
PCT/CN2022/085446 2021-04-08 2022-04-07 Inhibiteur de la kinase hpk1 à haute activité WO2022214009A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056807A1 (fr) * 2002-12-20 2004-07-08 Pfizer Products Inc. Derives de pyrimidine destines au traitement de la croissance cellulaire anormale
CN1665789A (zh) * 2002-06-28 2005-09-07 山之内制药株式会社 二氨基嘧啶酰胺衍生物
US20050256111A1 (en) * 2004-05-14 2005-11-17 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
CN110678466A (zh) * 2017-03-30 2020-01-10 豪夫迈·罗氏有限公司 作为hpk1抑制剂的二氮杂萘类
CN112243439A (zh) * 2018-06-13 2021-01-19 百济神州有限公司 作为hpk1抑制剂的吡咯并[2,3-b]吡啶或吡咯并[2,3-b]吡嗪及其用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1665789A (zh) * 2002-06-28 2005-09-07 山之内制药株式会社 二氨基嘧啶酰胺衍生物
WO2004056807A1 (fr) * 2002-12-20 2004-07-08 Pfizer Products Inc. Derives de pyrimidine destines au traitement de la croissance cellulaire anormale
US20050256111A1 (en) * 2004-05-14 2005-11-17 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
CN110678466A (zh) * 2017-03-30 2020-01-10 豪夫迈·罗氏有限公司 作为hpk1抑制剂的二氮杂萘类
CN112243439A (zh) * 2018-06-13 2021-01-19 百济神州有限公司 作为hpk1抑制剂的吡咯并[2,3-b]吡啶或吡咯并[2,3-b]吡嗪及其用途

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