CN117396482A - Wnt pathway inhibitor compound - Google Patents

Wnt pathway inhibitor compound Download PDF

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Publication number
CN117396482A
CN117396482A CN202380010281.6A CN202380010281A CN117396482A CN 117396482 A CN117396482 A CN 117396482A CN 202380010281 A CN202380010281 A CN 202380010281A CN 117396482 A CN117396482 A CN 117396482A
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halo
compound
alkyl
cycloalkyl
formula
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陈宇锋
武朋
陈凯旋
金超凡
王友平
陈可可
陈梦
何南海
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Hangzhou Arnold Biomedical Technology Co ltd
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Hangzhou Arnold Biomedical Technology Co ltd
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Priority claimed from PCT/CN2023/109227 external-priority patent/WO2024022365A1/en
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Abstract

The invention relates to a Wnt channel inhibitor compound shown in a formula (I), a pharmaceutical composition containing the compound and application of the compound in preventing and/or treating cancers, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

Description

Wnt pathway inhibitor compound
Technical Field
The invention relates to a heterocyclic compound, in particular to a high-activity Wnt channel inhibitor and application thereof.
Background
The Wnt/beta-catenin signal transduction pathway is a pathway conserved in biological evolution. In normal somatic cells, β -catenin acts only as a cytoskeletal protein complex with E-cadherein at the cell membrane to maintain cell adhesion of the isotype and prevent cell migration. When the Wnt signal channel is not activated, the beta-catenin in cytoplasm is phosphorylated and forms a beta-catenin degradation complex with APC, axin, GSK3 beta and the like, so that the ubiquitin system is started to degrade the beta-catenin through a proteasome way, and the beta-catenin in cytoplasm is maintained at a lower level. When the cell is stimulated by Wnt signals, the Wnt protein is combined with a specific receptor Frizzled protein on a cell membrane, the activated Frizzled receptor recruits an intracellular disheveled protein, the degradation activity of a beta-catenin degradation complex formed by GSK3 beta and other proteins is inhibited, and the beta-catenin protein in a free state in cytoplasm is stabilized. The stably accumulated beta-catenin in cytoplasm enters the nucleus and then binds with LEF/TCF transcription factor family to start the transcription of downstream target genes (such as c-myc, c-jun, cyclin D1, etc.). Overactivation of the Wnt/β -catenin signaling pathway is closely associated with the occurrence of a variety of cancers (including colon, stomach, breast, etc.). For example, abnormal activation of Wnt canonical signaling pathway and nuclear accumulation of β -catenin protein are widely present in colorectal cancer, and proliferation of cancers such as colon cancer can be inhibited by inhibiting Wnt signaling pathway activity. Mutations of APC exist in more than 85% of colorectal cancers, and the mutated APC blocks the phosphorylation degradation of beta-catenin to induce the occurrence of colorectal cancers. In addition, the mutation of Axin and the mutation of beta-catenin can cause the intracellular aggregation of beta-catenin and activate Wnt/beta-catenin channels.
While inhibition of the Wnt signaling pathway is known to be effective in preventing and/or treating cancer, tumors, inflammatory diseases, autoimmune diseases, and immune-mediated diseases, there is currently no satisfactory effective Wnt pathway inhibitor compound in the art. Thus, there is a need in the art to investigate effective Wnt pathway inhibitor compounds.
Disclosure of Invention
In one aspect, the present invention provides a compound that inhibits Wnt pathway activity having the structure of formula (I):
wherein,
R 1 、R 2 each independently represents hydrogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl, 4-8 membered heterocycloalkyl, halo 4-8 memberedHeterocycloalkyl, - (C) 1 -C 6 ) Alkylene OR a (C) 1 -C 6 ) Alkylene OR a 、-(C 1 -C 6 ) Alkylene SR a (C) 1 -C 6 ) Alkylene SR a Or R 1 、R 2 Together with the carbon atoms to which they are attached, form a 3-8 membered ring, which ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O and S;
R 3 representation (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl, or R 3 And R is 1 Or R is 2 Together form a 4-7 membered ring, which may optionally contain 0 or 1 heteroatom selected from O and S;
W 6 Represents CR 6 Or N;
R 6 each independently represents hydrogen, halogen, cyano, (C) 1 -C 3 ) Alkyl, halo (C) 1 -C 3 ) An alkyl group;
cy represents a 5-12 membered aromatic heterocycle optionally containing 1, 2, 3 or 4 heteroatoms, each independently selected from N, O and S, and the ortho position of Cy to the-O-linkage is unsubstituted or substituted with hydrogen;
R 1 ' represents hydrogen, halogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl, (C) 3 -C 8 ) Heterocycloalkyl, halo (C) 3 -C 8 ) Heterocyclylalkyl, -OR a (ii) halo OR a 、-SR a (ii) -halogenated SR a ；
R 2 ' represents hydrogen, halogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl, (C) 3 -C 8 ) Heterocycloalkyl, halo (C) 3 -C 8 ) Heterocyclylalkyl, -OR a (ii) halo OR a 、-SR a (ii) -halogenated SR a ；
R 3 ' represents hydrogen, halogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl, (C) 3 -C 8 ) Heterocycloalkyl, halo (C) 3 -C 8 ) Heterocyclylalkyl, -OR a (ii) halo OR a 、-SR a (ii) -halogenated SR a ；
Each m independently represents 0, 1 or 2;
R a each independently represents hydrogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl groups.
In one aspect, cy in the structure of formula (I) is a 5-membered heteroaryl ring or a 6-membered heteroaryl ring. More preferably, cy is pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl or pyrrolyl.
In yet another aspect, the compound of formula (I) is as shown in formula (II):
wherein,
the dotted ring indicates that the ring in which it is located is an aromatic ring;
W 1 represents CR 1 ' or N;
W 2 represents CR 2 ' or N;
W 3 represents CR 3 ' or N;
W 4 represents CH or N;
W 5 represents CH or N;
R 1 、R 2 、R 3 、R 6 、W 6 、R 1 ’、R 2 ’、R 3 ’、R a m is as defined in claim 1. More preferably, the formula (II) isThe compounds are shown below:
in another aspect, the compound of formula (I) is as shown in formula (III):
wherein,
the dotted ring indicates that the ring in which it is located is an aromatic ring;
W 1 ' represents CH, N or NH;
W 2 ' represents CR 2 ', N or NR 2 ’；
W 3 ' represents CR 3 ', N or NR 3 ’；
W 4 ' represents CH, N or NH;
R 1 、R 2 、R 3 、R 6 、W 6 、R 1 ’、R 2 ’、R 3 ’、R a m is as defined in claim 1.
More preferably, the compound of formula (III) is as follows:
in one aspect, R 1 、R 2 Each independently represents hydrogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl, 4-8 membered heterocycloalkyl, halo 4-8 membered heterocycloalkyl, - (C) 1 -C 6 ) Alkylene OR a (C) 1 -C 6 ) Alkylene OR a The method comprises the steps of carrying out a first treatment on the surface of the Preferably hydrogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) An alkyl group.
In one aspect, R 3 Is (C) 1 -C 6 ) An alkyl group.
In one aspect, W 6 Is CR (CR) 6 。
In one aspect, R 6 Is hydrogen.
In one aspect, R 1 ' represents hydrogen, halogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl groups. More preferably, R 1 ' represents halo (C) 1 -C 6 ) An alkyl group.
In one aspect, R 2 ' represents hydrogen, halogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl groups. More preferably, R 2 ' represents hydrogen or halogen.
In one aspect, R 3 ' represents halogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl, -OR a (ii) halo OR a 、-SR a (ii) -halogenated SR a . Preferably, R 3 ' represents halogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl groups. More preferably, R 3 ' represents halo (C) 1 -C 6 ) Alkyl or halo (C) 3 -C 8 ) Cycloalkyl groups.
In some preferred aspects, the invention provides a compound having the structure:
further, the invention also provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt, an isotope derivative or a stereoisomer thereof.
Further, the invention also provides application of the compound or pharmaceutically acceptable salt, isotopic derivative, stereoisomer or the pharmaceutical composition of the invention in preparing medicines for preventing and/or treating cancers, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases. It is particularly noted that, in this context, when referring to "compounds" of the structures of formulae (I) to (III), stereoisomers, diastereomers, enantiomers, racemic mixtures, and isotopic derivatives thereof are also generally contemplated.
It is well known to those skilled in the art that salts, solvates, hydrates of a compound are alternative forms of the compound, which can all be converted into the compound under certain conditions, and therefore, particular attention is paid herein to the compounds of the formulae (I) to (III), generally also including pharmaceutically acceptable salts thereof, and further including solvates and hydrates thereof.
Similarly, when a compound is referred to herein, prodrugs, metabolites, and nitrogen oxides thereof are also generally included.
Pharmaceutically acceptable salts according to the invention may be formed using, for example, the following mineral or organic acids: by "pharmaceutically acceptable salt" is meant a salt which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like commensurate with 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 by reacting the free base or free acid with a suitable reagent alone, as outlined below. For example, the free base function may be reacted with a suitable acid. Examples of pharmaceutically acceptable inorganic acid addition salts are salts of amino groups with inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric) or organic acids (e.g., acetic, oxalic, maleic, tartaric, citric, succinic or malonic) or by using other methods in the art such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, sodium alginate, ascorbate, aspartic acid salts, benzenesulfonate salts, benzoate salts, bisulfate salts, borate salts, butyric acid salts, camphoric acid salts, citric acid salts, cyclopentanepropionate salts, digluconate salts, dodecylsulfate salts, ethanesulfonate salts, formate salts, fumaric acid salts, glucoheptonate salts, glycerophosphate salts, gluconate salts, southern sulfate salts, heptanoate salts, caproate salts, hydroiodic acid salts, 2-hydroxy-ethanesulfonate salts, lactobionate salts, lactate salts, laurate salts, lauryl sulfate salts, malate salts, maleate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, oxalate salts, palmitate salts, pamoate salts, pectate salts, persulfates, 3-phenylpropionate salts, phosphate salts, bitter salts, pivalate salts, propionate salts, stearate salts, succinate salts, sulfate salts, tartrate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, and the like. Representative alkali or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed with counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate.
The pharmaceutically acceptable salts of the invention may be prepared by conventional methods, for example by dissolving the compounds of the invention in a water miscible organic solvent (e.g. acetone, methanol, ethanol and acetonitrile), adding thereto an excess of an organic or inorganic acid aqueous solution to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then isolating the precipitated salt.
The precursors or metabolites of the invention may be precursors or metabolites well known in the art, as long as the precursors or metabolites are converted into compounds by in vivo metabolism. For example, "prodrugs" refer to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to produce the parent compound of the formula described above, for example by metabolism in vivo, or N-demethylation of a compound of the invention.
"solvate" as used herein means a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In some cases, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be isolated. The solvent molecules in the solvate may be present in a regular arrangement and/or in a disordered arrangement. The solvate may comprise a stoichiometric or non-stoichiometric solvent molecule. "solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolamides. Solvation methods are well known in the art.
The term "stereoisomers" as used herein is divided into conformational isomerism and configurational isomerism, which may be also divided into cis-trans isomerism and optical isomerism (i.e. optical isomerism), and conformational isomerism refers to a stereoisomerism phenomenon that an organic molecule with a certain configuration makes each atom or group of molecules generate different arrangement modes in space due to rotation or twisting of carbon and carbon single bonds, and commonly includes structures of alkane and cycloalkane compounds, such as chair-type conformations and boat-type conformations, which occur in cyclohexane structures. "stereoisomers" means that when a compound of the invention contains one or more asymmetric centers, it is useful as racemate and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the invention have asymmetric centers, each of which produces two optical isomers, and the scope of the invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The compounds described herein may exist in tautomeric forms having different points of attachment of hydrogen through displacement of one or more double bonds. For example, the ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. All enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of the compounds of formula (I) to (III) are included within the scope of the present invention.
The term "isotopically-labeled" as used herein refers to molecules wherein the compound is isotopically labeled. Isotopes commonly used as isotopic labels are: the hydrogen isotope is selected from the group consisting of, 2 h and 3 h is formed; carbon isotopes: 11 C, 13 c and C 14 C, performing operation; chlorine isotopes: 35 cl and Cl 37 Cl; fluorine isotopes: 18 f, performing the process; iodine isotopes: 123 i and 125 i, a step of I; nitrogen isotopes: 13 n and 15 n; oxygen isotopes: 15 O, 17 o and 18 isotopes of O and sulfur 35 S, S. These isotopically-labeled compounds can be used to study the distribution of a pharmaceutical molecule in a tissue. In particular deuterium 3 H and carbon 13 C, because they are easily labeled and conveniently detected, the application is wider. Certain heavy isotopes, such as heavy hydrogen @, for example 2 H) The substitution can enhance the metabolic stability and prolong the half-life period, thereby achieving the aim of reducing the dosage and providing curative effect advantages. Isotopically-labeled compounds generally begin with a starting material that has been labeled, and are synthesized using known synthetic techniques like synthesizing non-isotopically-labeled compounds.
The invention also provides the use of the compounds of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of cancer, tumour, inflammatory disease, autoimmune disease or immune mediated disease.
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 compound of the present invention as an active ingredient. The pharmaceutical composition may optionally comprise a pharmaceutically acceptable carrier.
Furthermore, 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 administering to a mammal in need thereof a compound of the present invention.
Representative examples of inflammatory, autoimmune and immune-mediated diseases may include but are not limited to, arthritis, rheumatoid arthritis, spinal arthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic Lupus Erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung disease, pulmonary inflammation, adult Respiratory Distress Syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory diseases, chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia reperfusion injury, inflammatory bowel disease, crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, sjogren's syndrome, autoimmune thyroid disease urticaria (rubella), multiple sclerosis, scleroderma, organ transplant rejection, xenograft, 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 Lymphoblastic Leukemia (CLL), acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), hairy cell leukemia, hodgkin's disease, non-hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), diffuse large B-cell lymphoma and follicular lymphoma.
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, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharynx cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral nerve ectodermal tumors hodgkin's lymphoma, non-hodgkin's lymphoma, burkitt's lymphoma, acute Lymphoblastic Leukemia (ALL), chronic Lymphocytic Leukemia (CLL), acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gall bladder carcinoma, bronchogenic carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choriocarcinoma, seminoma, rhabdomyosarcoma, craniopharyngeal pipe carcinoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, ewing's sarcoma, or plasmacytoma.
The compounds of the present invention or pharmaceutically acceptable salts thereof may provide enhanced anticancer effects when administered in combination with additional anticancer agents or immune checkpoint inhibitors for the treatment of cancer or tumors.
Representative examples of anticancer agents for the treatment of cancer or tumors may include, but are not limited to, cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, gonadorelin analog, megestrol, prednisone, dexamethasone, prednisone, thalidomide, interferon alpha calcium folinate, sirolimus lipidates, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, britinib, cabotinib, ceridinib, crenolanib, crizotinib, dabrafenib, dacatinib, danarotinib, dasatinib, multi-vitamin tinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, enotinib, imatinib, triamcinolone acetonide, dacatinib, dacalotinib, and pharmaceutical compositions thereof iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momellotinib, mo Tisha, lenatinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, picilinib, ponatinib, quinartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, secatinib, saridegib, sorafenib, sunitinib, tiratinib, tivantinib, tivozanib, tofacitinib, trimitinib, vandetanib, velipine, vemurafenib, sevelipinib, sorafenib, and the like, velmoroxydine, volasentib, alemtuzumab, bevacizumab, belantuotuzumab Shan Kangwei, katuzumab, cetuximab, denouzumab, gemtuzumab, ipilimumab, nituzumab, ofatuzumab, panitumumab, rituximab, tositumomab, trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and/or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, anti-CTLA-4 antibodies, or any combination thereof.
The compounds of the present invention or pharmaceutically acceptable salts thereof may provide enhanced therapeutic effects when administered in combination with additional therapeutic agents for the treatment of inflammatory, autoimmune and immune-mediated diseases.
Representative examples of therapeutic agents for the treatment of inflammatory, autoimmune, and immune-mediated diseases may include, but are not limited to, steroidal drugs (e.g., prednisone, hydroprednisone, methyl hydroprednisone, cortisone, hydroxy cortisone, betamethasone, dexamethasone, and the like), methotrexate, leflunomide, anti-tnfα agents (e.g., etanercept, infliximab, ada Li Shan resistance, and the like), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, and the like), and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, and the like), and at least one or more therapeutic agents selected therefrom may be included in the pharmaceutical compositions of the present invention.
The compound of the present invention or a pharmaceutically acceptable salt thereof may be administered orally or parenterally as an active ingredient in an effective amount ranging from 0.1 to 2,000mg/kg body weight/day, preferably 1 to 1,000mg/kg body weight/day in the case of mammals including humans (body weight of about 70 kg), and administered in divided doses, single or 4 times daily, or with/without following a predetermined time. The dosage of the active ingredient may 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 dosages may be suitable. An amount greater than the above dosage may be used if it does not cause deleterious side effects and may be administered in divided doses per day.
In addition, the present invention provides a method for preventing and/or treating a tumor, cancer, viral infection, organ transplant rejection, neurodegenerative disease, attention-related disease or autoimmune disease, comprising administering to a mammal in need thereof a compound of the present invention or a pharmaceutical composition of the present invention.
The pharmaceutical compositions of the present invention may be formulated according to any of the conventional methods into dosage forms for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes, intratumoral injection), such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions or suspensions.
The pharmaceutical compositions of the invention for oral administration can be prepared by mixing the active ingredient with, for example, the following carriers: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents and diluents.
Examples of carriers employed in the pharmaceutical compositions for injectable administration of the present invention may be water, salt solutions, dextrose-like solutions (glucose), alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents and emulsifiers.
Other features of the present invention will become apparent in the course of describing exemplary embodiments of the invention, which are presented to illustrate the invention and are not intended to be limiting thereof, the following examples being prepared, isolated and characterized using the methods disclosed herein.
The compounds of the present invention may be prepared in a variety of ways known to those skilled in the art of organic synthesis, and may be synthesized using the methods described below as well as synthetic methods known in the art of organic synthetic chemistry or by variations thereof as will be appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the kit materials used and for the transformation to be effected. Those skilled in the art of organic synthesis will understand that the functionalities present on the molecule are consistent with the proposed transformations. This sometimes requires judgment to change the order or starting materials of the synthesis steps to obtain the desired compounds of the invention.
Drawings
Figure 1 shows the effect of compound 1 on the growth of human colon carcinoma cell Colo205 xenograft tumor.
Detailed Description
Terminology
The terms used in the present application, including the specification and claims, are defined as follows, unless otherwise indicated. Conventional methods of mass spectrometry, nuclear magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used, if not otherwise indicated. In this application, the use of "or" and "means" and/or "unless otherwise indicated.
In the description and claims, a given formula or name shall encompass all stereoisomers and optical isomers thereof, as well as racemates in which the above isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Various geometric isomers of c=c double bonds, c=n double bonds, ring systems, etc. may also be present in the compounds, and all such stable isomers are contemplated within 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 separated into mixtures of isomers or separate isomeric forms. The compounds of the invention may be isolated in optically active or racemic forms. All processes for preparing the compounds of the invention and intermediates prepared therein are considered part of the present invention. When preparing the enantiomeric or diastereomeric products, they can be separated by conventional methods, for example by chromatography or fractional crystallization. Depending on the process conditions, the end products of the invention are obtained in free (neutral) or salt form. Both the free form and the salt of these end products are within the scope of the invention. If desired, one form of the compound may be converted to another form. The free base or acid may be converted to a salt; the salt may be converted to the free compound or another salt; mixtures of the isomeric compounds of the invention may be separated into the individual isomers. The compounds of the invention, free forms and salts thereof, may exist in various tautomeric forms in which hydrogen atoms are transposed to other parts of the molecule and thereby the chemical bonds between the atoms of the molecule are rearranged. It is to be understood that all tautomeric forms that may exist are included within the invention.
Unless otherwise defined, the definition of substituents of the invention are each independent of, and not interrelated with, each other, e.g., by way of example, and not by way of exhaustive, in one aspect, R for a substituent a (or R) a ') which are independent of each other in the definition of the different substituents. Specifically, for R a (or R) a ' when a definition is selected in a substituent, it does not mean that R a (or R) a ') have the same definition in all other substituents. More specifically, for example (by way of non-exhaustive list) for NR a R a In' when R a (or R) a Where the definition of') is selected from hydrogen, it is not meant to be in-C (O) -NR a R a In' R a (or R) a ') is necessarily hydrogen. In another aspect, when more than one R is present in a substituent a (or R) a ') at the same time, these R a (or R) a ') are also independent of each other. For example, in the substituent- (CR) a R a’ ) m -O-(CR a R a’ ) n In the case where m+n is 2 or more, m+n R's therein a (or R) a ') are independent of each other and may have the same or different meanings.
Unless otherwise defined, when a substituent is noted as "optionally substituted", the substituent is selected from, for example, substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein 2 amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkylamino, substituted alkanoylamino, substituted arylamino, substituted aralkylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, for example, -SO 2 NH 2 Substituted sulphonylamino, nitro, cyano, carboxyl, carbamoyl, e.g. -CONH 2 Substituted carbamoyl such as-CONH alkyl, -CONH aryl, -CONH arylalkyl or where there are two substituents on the nitrogen selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclyl such as indolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl and the like and substituted heterocyclyl.
The term "alkyl" or "alkylene" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, "C 1 -C 6 Alkyl "meansAlkyl groups having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). In this context, alkyl is preferably alkyl having 1 to 6, more preferably having 1 to 4 carbon atoms.
The term "alkenyl" denotes a straight or branched hydrocarbon radical containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. For example, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. In this context, alkenyl groups are preferably C 2 -C 6 Alkenyl groups.
The term "alkynyl" denotes a straight or branched hydrocarbon radical containing one or more triple bonds and typically ranging in length from 2 to 20 carbon atoms. For example, "C 2 -C 6 Alkynyl "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. In this context, alkynyl is preferably C 2 -C 6 Alkynyl groups.
The term "alkoxy" or "alkyloxy" refers to an-O-alkyl group. "C 1 -C 6 Alkoxy "(or alkyloxy) is intended to include C 1 、C 2 、C 3 、C 4 、C 5 、C 6 An alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. In this context, alkoxy groups are preferably alkoxy groups having 1 to 6, more preferably having 1 to 4 carbon atoms. Similarly, "alkylthio" or "thio" means an alkyl group as defined above having the indicated number of carbon atoms attached via a sulfur bridge; such as methyl-S-and ethyl-S-.
The term "carbonyl" refers to an organofunctional group (c=o) formed by the double bond connection of two atoms of carbon and oxygen.
The term "aryl", alone or as part of a larger moiety such as "aralkyl", "arylalkoxy" or "aryloxyalkyl", refers to a monocyclic, bicyclic or tricyclic ring system having a total of 5 to 12 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 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 tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring, non-limiting examples of which include benzyl, phenethyl, and the like. The fused aryl group may be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring. The dashed lines drawn from the ring system indicate that the bond may be attached to any suitable ring atom.
The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group. Monocyclic cyclic alkyl means C 3 -C 8 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". The cyclic alkyl group of the bicyclic ring includes bridged, spiro or fused ring cycloalkyl groups. In this context, cycloalkyl is preferably C 3 -C 6 Cycloalkyl groups.
The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl. Monocyclic cyclic alkenyl means C 3 -C 8 Cyclic alkenyl groups of (c) including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornenyl. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyl includes bridged, spiro, or fused cyclic alkenyl.
"halo" or "halogen" includes fluoro, chloro, bromo and iodo. "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with 1 or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl groups also include "fluoroalkyl groups" intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with 1 or more fluorine atoms.
"haloalkoxy" or "haloalkyloxy" means an oxygen-bridged haloalkyl as defined above having the indicated number of carbon atoms. For example, "halo C 1 -C 6 Alkoxy "is intended to include C 1 、C 2 、C 3 、C 4 、C 5 、C 6 Haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" means a thio-bridged haloalkyl as defined above having the indicated number of carbon atoms; such as trifluoromethyl-S-and pentafluoroethyl-S-.
In the present disclosure, C is used when referring to some substituents x1 -C x2 This means that the number of carbon atoms in the substituent group may be x1 to x 2. For example, C 0 -C 8 Represents that the radical contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C 1 -C 8 Representing that the radicals contain 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C 2 -C 8 Representing that the radicals contain 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C 3 -C 8 Representing that the radicals contain 3, 4, 5, 6, 7 or 8 carbon atoms, C 4 -C 8 Representing that the radicals contain 4, 5, 6, 7 or 8 carbon atoms, C 0 -C 6 Represents that the radical contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C 1 -C 6 Representing that the radicals contain 1, 2, 3, 4, 5 or 6 carbon atoms, C 2 -C 6 Representing that the radicals contain 2, 3, 4, 5 or 6 carbon atoms, C 3 -C 6 Meaning that the group contains 3, 4, 5 or 6 carbon atoms.
In the present disclosure, the expression "x1-x2 membered ring" is used when referring to a cyclic group (e.g., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), which means that the number of ring atoms of the group can be x1 to x 2. For example, the 3-12 membered cyclic group may be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, the number of ring atoms of which may be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; the 3-6 membered ring represents that the cyclic group may be a 3, 4, 5 or 6 membered ring, and the number of ring atoms may be 3, 4, 5 or 6; the 3-8 membered ring represents that the cyclic group may be a 3, 4, 5, 6, 7 or 8 membered ring, and the number of ring atoms may be 3, 4, 5, 6, 7 or 8; the 3-9 membered ring represents that the cyclic group may be a 3, 4, 5, 6, 7, 8 or 9 membered ring, and the number of ring atoms may be 3, 4, 5, 6, 7, 8 or 9; the 4-7 membered ring represents that the cyclic group may be a 4, 5, 6 or 7 membered ring, and the number of ring atoms may be 4, 5, 6 or 7; the 5-8 membered ring represents that the cyclic group may be a 5, 6, 7 or 8 membered ring, and the number of ring atoms may be 5, 6, 7 or 8; the 5-12 membered ring represents that the cyclic group may be a 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms may be 5, 6, 7, 8, 9, 10, 11 or 12; the 6-12 membered ring means that the cyclic group may be a 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms may be 6, 7, 8, 9, 10, 11 or 12. The ring atom may be a carbon atom or a heteroatom, for example a heteroatom selected from N, O and S. When the ring is a heterocyclic ring, the heterocyclic ring may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, for example heteroatoms selected from N, O and S.
In the present disclosure, the one or more halogens may each be independently selected from fluorine, chlorine, bromine, and iodine.
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 heterocycle which is fully unsaturated or partially unsaturated and which contains carbon atoms and 1,2,3 or 4 heteroatoms independently selected from N, O and S; and includes any of the following polycyclic groups wherein any of the heterocycles defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom is substituted or unsubstituted (i.e., N or NR, where R is H or another substituent if defined). The heterocycle may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclyl groups described herein may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is no greater than 1. When the term "heterocycle" is used, it is intended to include heteroaryl. Examples of aryl radicals include, but are not limited to, acridinyl, azetidinyl, azepinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazole, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromen, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b ] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolyl (indolenyl), indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinyl (atinoyl), isobenzofuranyl, isochromanyl isoindazolyl, isoindolinyl, isoindolyl, isoquinolyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, naphthyridinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinonyl, 2H-pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazinyl, 1,2, 4-thiadiazinyl, 1,2, 5-thiadiazinyl, 1,3, 4-thiadiazinyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl and xanthenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 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 from "aryl" and monocyclic "heteroaryl" as defined above, such as, but not limited to "-phenyl bipyridyl-", "-phenyl bipyrimidinyl", "-pyridinyl biphenyl", "-pyridinyl bipyrimidinyl-", "-pyrimidinyl biphenyl-"; wherein the invention also includes fused and spiro compounds containing, for example, the above-described heterocycles.
The term "heterocycloalkyl" as used herein refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes spiroheterocycles or bridged heterocycloalkyl groups. A monocyclic heterocycloalkyl group refers to a 3-8 membered, saturated or unsaturated, but not aromatic, cyclic alkyl system containing at least one heteroatom selected from O, N, S and P. Bicyclic heterocycloalkyl system refers to a bicyclic system formed by a heterocycloalkyl fused to a phenyl, or a cycloalkyl, or a cycloalkenyl, or a heterocycloalkyl, or a heteroaryl.
The term "bridged cycloalkyl" as used herein refers to polycyclic compounds sharing two or more carbon atoms. Can be classified into bicyclic bridged ring hydrocarbons and polycyclic bridged ring hydrocarbons. The former is composed of two alicyclic rings sharing more than two carbon atoms; the latter is a bridged cyclic hydrocarbon consisting of three or more rings.
The term "spirocycloalkyl" as used herein refers to a polycyclic hydrocarbon having a single ring of carbon atoms in common with each other (referred to as spiro atoms).
The term "bridged ring hetero group" as used herein refers to a polycyclic compound having a common two or more carbon atoms, the ring having at least one heteroatom selected from O, N and S atoms. Can be divided into two-ring bridged heterocyclic rings and multiple-ring bridged heterocyclic rings.
The term "heterospirocyclic" as used herein refers to a polycyclic hydrocarbon having a single ring with a single carbon atom (referred to as the spiro atom) in common, the ring containing at least one heteroatom selected from O, N and S atoms.
The term "substituted" as used herein means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that the normal valence is maintained and that the substitution results in a stable compound. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., c= C, C =n or n=n).
In the case where nitrogen atoms (e.g., amines) are present on the compounds of the present invention, these nitrogen atoms may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxide) to obtain other compounds of the present invention. Thus, the nitrogen atoms shown and claimed are considered to both encompass the nitrogen shown and its N-oxides to obtain the derivatives of the invention.
When any variable occurs more than one time in any composition or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3R, then the group may optionally be substituted with up to three R groups, and R is independently selected at each occurrence from the definition of R. Furthermore, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
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 (e.g., murine, simian, monkey, horse, bovine, porcine, canine, feline, etc.) and most preferably refer to humans.
The term "effective amount" as used herein means the amount of a drug or pharmaceutical agent (i.e., a compound of the present invention) that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means an amount of: such amounts result in improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, as compared to a corresponding subject not receiving such amounts. An effective amount may be administered in one or more administrations, or dosages and is not intended to be limited to a particular formulation or route of administration. The term also includes within its scope an effective amount to enhance normal physiological function.
The term "treatment" as used herein includes any effect that results in an improvement in a condition, disease, disorder, etc., such as a reduction, decrease, modulation, improvement or elimination, or improvement of symptoms thereof.
The term "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and/or dosage forms which are: it is suitable for use in contact with human and animal tissue without undue toxicity, irritation, allergic response, and/or other problems or complications commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment.
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 (e.g., lubricant, talc, magnesium stearate, calcium or zinc stearate, or stearic acid), or solvent encapsulating material, which involves carrying or transporting the subject compound from one organ or body part to another organ or body part. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
The term "pharmaceutical composition" means a composition comprising a compound of the invention and at least one other pharmaceutically acceptable carrier. "pharmaceutically acceptable carrier" refers to a medium commonly accepted in the art for delivery of biologically active agents to animals, particularly mammals, and includes (i.e., adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow control agents, disintegrants, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, antibacterial agents, antifungal agents, lubricants, and dispersing agents, depending upon the mode of administration and the nature of the dosage form.
Specific pharmaceutical and medical terminology
The term "acceptable" as used herein, means that a prescription component or active ingredient does not unduly adversely affect the health of the general therapeutic objective.
The term "cancer", as used herein, refers to an abnormal growth of cells that is not controllable and is capable of metastasis (transmission) under certain conditions. Cancers of this type include, but are not limited to, solid tumors (e.g., bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas, or other endocrine organ (e.g., thyroid), prostate, skin (melanoma), or hematological tumors (e.g., non-leukemia).
The term "co-administration" or similar terms, as used herein, refers to administration of several selected therapeutic agents to a patient, administered at the same or different times, in the same or different modes of administration.
The term "enhance" or "potentiating," as used herein, means that the intended result can be increased or prolonged in either efficacy or duration. Thus, in enhancing the therapeutic effect of a drug, the term "capable of enhancing" refers to the ability of the drug to increase or prolong the efficacy or duration of the drug in the system. As used herein, "potentiating value" means that the ability of another therapeutic agent to be maximally enhanced in an ideal system.
The term "immunological disorder" refers to a disease or condition that produces an adverse or detrimental response to an endogenous or exogenous antigen. As a result, the cells are often dysfunctional, or thus destroyed and dysfunctional, or destroy organs or tissues that may develop immune symptoms.
The term "kit" is synonymous with "product package".
The term "subject" or "patient" includes mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as gorillas, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, pigs; domestic animals such as rabbits and dogs; laboratory animals include rodents such as rats, mice, guinea pigs, and the like. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In a preferred aspect, the mammal selected is a human.
The terms "treat," "course of treatment," or "therapy" as used herein include alleviation, inhibition, or amelioration of symptoms or conditions of a disease; inhibit the occurrence of complications; improving or preventing underlying metabolic syndrome; inhibiting the occurrence of a disease or condition, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing the disease or symptom to subside; alleviating complications caused by diseases or symptoms, or preventing and/or treating signs caused by diseases or symptoms.
As used herein, a compound or pharmaceutical composition, upon administration, may result in an improvement in a disease, symptom, or condition, particularly an improvement in severity, delay of onset, slow progression, or decrease in duration. Whether stationary or temporary, continuous or intermittent, may be due to or associated with administration.
Route of administration
Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, auditory canal, nasal, and topical. Further, by way of example only, parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary, ventricular, intraperitoneal, intralymphatic, and intranasal.
In one aspect, the administration of the compounds described herein is topical rather than systemic. In particular embodiments, the depot is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in another specific 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 a specific organ and absorbed.
Pharmaceutical composition and dosage
The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the invention, and optionally one or more other therapeutic agents described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. The compounds of the invention may be administered by any suitable means for any of the above uses, for example, orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingual delivery; is taken orally; parenteral, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., in the form of sterile injectable aqueous or nonaqueous solutions or suspensions); transnasally, including administration to the nasal membrane, such as by inhalation spray; topical, such as in the form of a cream or ointment; or rectally, such as in the form of suppositories; or intratumoral injection. They may be administered alone, but are typically administered using a drug carrier selected based on the chosen route of administration and standard pharmaceutical practice.
Pharmaceutical carriers are formulated according to a number of factors within the purview of one skilled in the art. These factors include, but are not limited to: the type and nature of the active agent formulated; a subject to whom the active agent-containing composition is to be administered; the intended route of administration of the composition; and targeted therapeutic indications. Pharmaceutically acceptable carriers include aqueous and nonaqueous liquid media and various solid and semi-solid pharmaceutically acceptable carriers.
The carrier may include a number of different ingredients and additives in addition to the active agent, such other ingredients being included in the formulation for a variety of reasons known to those skilled in the art, such as stabilizers, binders, and the like. For a description of suitable pharmaceutical carriers and the factors involved in carrier selection, see a number of readily available sources, for example, allen l.v. jr.et al remington: the Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), pharmaceutical Press.
Of course, the dosage regimen of the compounds of the invention will vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health condition, medical condition and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; treatment frequency; the route of administration, the renal and hepatic function of the patient, and the desired effect. According to general guidelines, when used for the indicated effects, the daily oral dosage 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 from about 0.1 mg/day to about 250 mg/day. During constant infusion, the most preferred dosage for intravenous administration should be about 0.01 mg/kg/min to about 10 mg/kg/min. 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 typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration (e.g., oral tablets, capsules, elixirs and syrups) and consistent with conventional pharmaceutical practices.
Dosage forms suitable for administration (pharmaceutical compositions) may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will typically be present in an amount of about 0.1 to 95% by weight, based on the total weight of the composition.
Typical capsules for oral administration contain 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.
Typical injectable formulations can be prepared as follows: at least one compound of the invention (250 mg) is placed in a bottle in a sterile manner, lyophilized in a sterile manner and sealed. For use, the vial contents were mixed with 2mL of physiological saline to produce an injectable formulation.
The scope of the present invention includes pharmaceutical compositions (alone or in combination with a pharmaceutical carrier) comprising 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 (e.g., anticancer agents or other pharmaceutically active substances).
Regardless of the route of administration selected, the compounds of the invention (which may be used in a suitable hydrated form) and/or the pharmaceutical compositions of the 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 may be varied to achieve amounts of the active ingredient that are effective to achieve the desired therapeutic response, composition and mode of administration for a particular patient, but which are non-toxic to the patient.
The selected dosage level will depend on a variety of factors including the activity of the particular compound of the invention or an ester, salt or amide thereof employed; a route of administration; administration time; the rate of excretion of the particular compound being used; the rate and extent of absorption; duration of treatment; other drugs, compounds and/or substances used in combination with the particular compound used; the age, sex, weight, condition, general health and previous medical history of the patient being treated.
A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, to achieve a desired therapeutic effect, a physician or veterinarian may begin the relative amounts of the compound of the invention used in the pharmaceutical composition at a level less than that required and step up the dosage until the desired effect is achieved. In general, a suitable daily dose of a compound of the invention will be the amount of the compound at the lowest dose effective to produce a therapeutic effect. Such effective dosages will generally depend on the factors described above. Generally, oral, intravenous, intraventricular and subcutaneous dosages of the compounds of the invention for patients range from about 0.01 to about 50mg/kg body weight/day. If desired, an effective daily dose of the active compound may be administered separately at appropriate intervals throughout the day in two, three, four, five, six or more sub-doses, optionally in unit dosage form. In certain aspects of the invention, the administration is once daily.
Although the compounds of the present invention may be administered alone, it is preferable to administer the compounds in the form of a pharmaceutical formulation (composition).
Kit/product package
For use in the treatment of the above indications, the kit/product package is also described herein. These kits may consist of a conveyor, a pack or a container box which may be divided into multiple compartments to hold one or more containers, such as vials, tubes and the like, each of which contains a separate one of the components of the method. Suitable containers include bottles, vials, syringes, test tubes, and the like. The container is made of acceptable glass or plastic materials.
For example, the container may contain one or more of the compounds described herein, possibly in the form of pharmaceutical compounds, and possibly in the form of a mixture with other ingredients described herein. The container may have a sterile outlet (e.g., the container may be an iv bag or vial, and the vial stopper may be pierced by a hypodermic needle). Such kits may contain a compound, as well as instructions, tags, or instructions for use as described herein.
A typical kit may include one or more containers, each containing one or more materials (e.g., reagents, or concentrated mother liquor, and/or equipment) to accommodate commercial popularization and use of the compound by the user. Such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, conveyors, bags, containers, bottles and/or tubes with a content list and/or instructions for use, and with instructions for packaging. The complete set of instructions is included.
The label may be displayed on or closely associated with the container. The appearance of a label on a container means that the label letters, numbers or other features are affixed, molded, engraved on the container; the label may also be present in a container box or shipping box containing a variety of containers, such as in a product insert. A label may be used to indicate a particular therapeutic use of the contents. The label may also indicate instructions for use of the content, such as described in the methods above.
All of the features described in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps in any method or process so described, may be present in any combination, unless certain features or steps are mutually exclusive in the same combination.
The above-mentioned features of the invention, or of the embodiments, may be combined in any desired manner. All of the features disclosed in this specification may be combined with any combination of the features disclosed in this specification, and the various features disclosed in this specification may be substituted for any alternative feature serving the same, equivalent or similar purpose. The disclosed features are thus merely representative of general examples of equivalent or similar features, unless specified otherwise.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer. All percentages, ratios, proportions, or parts are by weight unless otherwise indicated.
The units in weight volume percent are well known to those skilled in the art and refer, for example, to the weight of solute (g) in 100 milliliters of solution. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
Examples
Universal procedure
When the preparation route is not included, the raw materials and reagents used in the present invention are known products, and can be synthesized according to the methods known in the art, or can be obtained by purchasing commercial products. The commercial reagents used were all used without further purification.
Room temperature refers to 20-30 ℃.
The reaction examples are not particularly described, and the reactions are all carried out under nitrogen atmosphere. The nitrogen atmosphere is defined as the reaction flask being attached to a balloon of about 1L of nitrogen.
The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times. The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L.
Microwave reaction is usedInitiator + microwave reactor.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was determined using (Bruker Assetnd TM 500) nuclear magnetic resonance apparatus, the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard is Tetramethylsilane (TMS). The following abbreviations are used for multiplicity of NMR signals: s=singlet, brs=broad, d=doublet, t=triplet, m=multiplet. Coupling constants are listed as J values, measured in Hz.
LC-MS was determined using a Thermo liquid chromatography apparatus (UltiMate 3000+MSQ PLUS). HPLC was determined using a Thermo high pressure liquid chromatograph (UltiMate 3000). Reverse phase preparative chromatography a Thermo (UltiMate 3000) reverse phase preparative chromatograph was used. Quick column chromatography using Ai Jieer (FS-9200T) automatic column passing machine, silica gel pre-packed column using SantaiAnd (5) preassembling the column. The specification of the thin layer chromatography separation and purification product adopted by the smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate is 0.4 mm-0.5 mm.
The synthesis method of some intermediates in the invention is as follows:
intermediate 1
Intermediate 1 was prepared by the following steps:
the first step: compound Int-1a (5.0 g,28.09 mmol), int-1b (5.61 g,36.51 mmol) and sodium bicarbonate (7.08 g,84.26 mmol) were dissolved in ethanol (50 mL) and water (5 mL) and the reaction was heated at reflux overnight. LCMS monitoring of the reverse After completion, cool to room temperature, suction filter, wash the filter cake with water, and dry to give Int-1 (5.0 g, 78% yield) as an off-white solid. ESI-MS (m/z): 227.4[ M+H ]] + 。
Intermediate 2
Intermediate 2 was prepared by the following steps:
the first step: sodium hydrogen (1.59 g,39.64mmol, 60%) was added to a two-necked flask equipped with anhydrous tetrahydrofuran (10 mL), placed in an ice-water bath, and compound Int-2a (5.0 g,26.43 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) and slowly added dropwise to the reaction solution. The addition of deuterated iodomethane (4.02 g,27.75 mmol) was started after 30 minutes and was slowly allowed to warm to room temperature after completion of the addition and stirred overnight. After completion of LCMS monitoring, the reaction was cooled to 0 ℃, quenched by slow dropwise addition of saturated aqueous ammonium chloride, extracted with ethyl acetate, and dried in organic phase to give Int-2b as a yellow oil (5.0 g, 91% yield). ESI-MS (m/z): 207.2[ M+H ]] + 。
And a second step of: int-2b (5.0 g,24.24 mmol) was dissolved in methanol (50 mL), placed in an ice-water bath, and thionyl chloride (8.65 g,72.73 mmol) was slowly added dropwise, and after the addition was completed, the reaction was allowed to proceed to room temperature and then allowed to proceed to 60℃overnight. After completion of the LCMS reaction, the reaction mixture was concentrated to give Int-2c (3.0 g, 79% yield) as a yellow oil. ESI-MS (m/z): 157.2[ M+H ] ] + 。
And a third step of: compound Int-1a (2.0 g,11.23 mmol), int-2c (3.17 g,20.22 mmol) and sodium bicarbonate (2.83 g,33.70 mmol) were dissolved in ethanol (20 mL) and water (2 mL) and the reaction was refluxed overnight. After completion of LCMS monitoring the reaction, cooled to room temperature, suction filtered, the filter cake washed with water and then dried to give Int-2 (1.4 g, 54% yield) as an off-white solid. ESI-MS (m/z): 230.3[ M+H ]] + 。
Intermediate 3
Intermediate 3 was prepared by the following steps:
the first step: sodium hydrogen (237 mg,5.90mmol, 60% by weight) was added to a two-necked flask equipped with anhydrous tetrahydrofuran (5 mL), the flask was placed in an ice-water bath, and Compound Int-3a (300 mg,1.48 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and slowly added dropwise to the reaction solution. After 30 minutes, the addition of deuterated iodomethane (470 mg,2.95 mmol) was started, and after completion of the addition, the mixture was slowly warmed to room temperature and stirred overnight. LCMS monitored the end of the reaction, cooled to 0 ℃, quenched by slow dropwise addition of saturated aqueous ammonium chloride, extracted with ethyl acetate, and dried in organic phase to give Int-3b as a yellow oil (312 mg, 96% yield). ESI-MS (m/z): 221.6[ M+H ]] + 。
And a second step of: int-3b (312 mg,1.42 mmol) was dissolved in methanol (5 mL), placed in an ice-water bath, and thionyl chloride (505 mg,4.25 mmol) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was warmed to room temperature and then to 70℃for overnight reaction. After completion of the LCMS monitoring reaction, the reaction was concentrated to give Int-3c as a yellow oil (180 mg, 84% yield). ESI-MS (m/z): 135.4[ M+H ] ] + 。
And a third step of: compound Int-3c (180 mg,1.05 mmol) and compound 4d (200 mg,0.95 mmol) were dissolved in tetrahydrofuran (5 mL), and N, N-diisopropylamine (371 mg,2.88 mmol) was added. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the end of the reaction. The reaction solution was diluted with water, extracted with ethyl acetate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give Int-3d (105 mg, reaction yield 35%) as an off-white solid. ESI-MS (m/z): 306.5[ M+H ]] + 。
Fourth step: compound Int-3d (105 mg, 345 umol) was dissolved in glacial acetic acid (2 mL), and iron powder (77 mg,1.37 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. LCMS monitored reaction completion and the residue was filtered off with celiteThe residue was washed with ethyl acetate, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give compound Int-3 (81 mg, reaction yield 96%). ESI-MS (m/z): 244.4[ M+H ]] + 。
Intermediate 4
Intermediate 4 was prepared by the following steps:
the first step: compound Int-4a (1.01 g,5 mmol) and potassium hydroxide (842 mg,15 mmol) were dissolved in anhydrous dimethyl sulfoxide (10 mL), followed by dropwise addition of deuterated iodomethane (1.59 g,11 mmol) to the reaction solution. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the end of the reaction. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product of Compound Int-4b (1.0 g, yield 84%). ESI-MS (m/z): 236.3[ M+H ] ] + 。
And a second step of: compound Int-4b (1.0 g,4.25 mmol) was dissolved in dioxane hydrochloride solution (4M, 10 mL). The reaction was stirred at room temperature for 4 hours. LCMS monitored the end of the reaction. The reaction solution was concentrated under reduced pressure to give a crude product of Compound Int-4c (720 mg). ESI-MS (m/z): 136.1[ M+H ]] + 。
And a third step of: compound Int-4c (720 mg,4.19 mmol) and compound Int-3d (872 mg,4.19 mmol) were dissolved in tetrahydrofuran (10 mL), and N, N-diisopropylamine (1.62 g,12.57 mmol) was added. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the end of the reaction. The reaction mixture was diluted with water, filtered, and the filter cake was washed with water and dried to give Int-4d (993 mg, 77% yield in two steps) as an off-white solid. ESI-MS (m/z): 307.2[ M+H ]] + 。
Fourth step: compound Int-4d (306 mg,1 mmol) and potassium carbonate (207 mg,1.5 mmol) were dissolved in methanol (10 mL), sodium dithionite (871 mg,5 mmol) was dissolved in water and added dropwise to the reactionAnd (5) applying liquid. The reaction solution was stirred at room temperature for 15 minutes. LCMS monitored complete reaction of starting material. Dioxahexacyclic hydrochloride solution (4M, 1.25 mL) was added to the reaction solution. The reaction mixture was stirred at room temperature for 8 hours. The methanolic ammonia solution was added dropwise to the reaction solution, the pH of the reaction solution was adjusted to 10, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give compound Int-4 (30 mg, yield 13%). ESI-MS (m/z): 242.3[ M+H ] ] + 。
Intermediate 5
Intermediate 5 was prepared by the following steps:
the first step: compound Int-5a (500 mg,3.86 mmol), 6-fluoro-nicotinonitrile Int-5b (518.39 mg,4.25 mmol) and cesium carbonate (1.89 g,5.79 mmol) were dissolved in acetonitrile (10 mL) and stirred overnight at room temperature. LCMS monitored the end of the reaction. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give 5c (680 mg, yield 76%) as a yellow oil. ESI-MS (m/z): 232.4[ M+H ]] + 。
And a second step of: compound Int-5c (680 mg,2.94 mmol) and Raney Nickel (0.5 mL, aqueous suspension) were dissolved and dispersed in methanol (10 mL) and aqueous ammonia (1 mL), the gas was evacuated with a hydrogen balloon, and stirred overnight at room temperature. LCMS monitored the end of the reaction, the reaction was diluted with methanol, the celite filtrate was filtered off with suction, the organic phase was concentrated and purified by column chromatography on silica gel (dichloromethane/methanol=10/1) to give Int-5 as a yellow oil (220 mg, 31% yield). ESI-MS (m/z): 236.4[ M+H ]] + 。
Intermediate 6
Intermediate 6 was prepared by the following steps:
the first step: compound Int-1a (500 mg,2.81 mmol) and compound Int-6a (602 mg,3.65 mmol) were dissolved in ethanol (20 mL) and water (2 mL), followed by addition of sodium bicarbonate (707 mg,8.34 mmol), and the reaction solution was heated to 80℃and stirred for 16 hours. After the reaction solution was cooled to room temperature, water (12 mL) was added to the reaction solution, and the mixture was filtered to give Int-6 (385 mg, yield 57%) as an off-white solid, ESI-MS (m/z): 239.4[ M+H ] ] + 。
Intermediate 7
Intermediate 7 was prepared by the following steps:
the first step: 2- (trifluoromethyl) pyrimidin-5-ol Int-7a (1.0 g,6.09 mmol), 6-fluoro-nicotinonitrile Int-5b (1.01 g,7.31 mmol) and cesium carbonate (3.97 g,12.19 mmol) were dissolved in DMF (10 mL) and stirred overnight at 80 ℃. LCMS monitored the end of the reaction. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give Int-7b (1.3 g, yield 80%) as a yellow oil.
And a second step of: compound Int-7b (1.3 g,4.88 mmol) and Raney Nickel (0.5 mL, aqueous suspension) were dissolved and dispersed in methanol (10 mL) and aqueous ammonia (1 mL), the gas was evacuated with a hydrogen balloon, and stirred overnight at room temperature. LCMS was monitored for reaction completion, the reaction was diluted with methanol, the celite was filtered off with suction, and the organic phase was concentrated to give Int-7 as a yellow oil (700 mg, 53% yield))。ESI-MS(m/z):271.3[M+H] + 。
Intermediate 8
Intermediate 8 was prepared by the following steps:
the first step: 6- (trifluoromethyl) pyridin-3-ol Int-8a (1.0 g,6.13 mmol) was dissolved in dimethyl sulfoxide (10 mL), cesium carbonate (2.0 g,6.13 mmol) was added, after stirring at room temperature for 30 minutes 2-fluoropyridine-5-carbaldehyde Int-8b (1.53 g,12.26 mmol) was added and the reaction mixture continued stirring for 2 hours to terminate the reaction. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography to give the product Int-8c (1.5 g, yield 91%). 1 HNMR(500MHz,DMSO-d6)δ10.04(s,1H),8.79-8.70(m,2H),8.37(dd,J＝8.6,2.3Hz,1H),8.05(d,J＝1.0Hz,2H),7.42(d,J＝8.6Hz,1H)。
And a second step of: compound Int-8c (1.53 g,5.70 mmol) was dissolved in ethanol (5 mL), hydroxylamine hydrochloride (792 mg,11.41 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction was concentrated to give crude oxime, redissolved in acetic acid (5 mL), zinc powder (1.94 g,29.66 mmol) was added and stirred at room temperature for 2 hours and the reaction was complete by LCMS. The reaction mixture was filtered, the filtrate was concentrated to remove most of the acetic acid, diluted with ethyl acetate, and then basified with NaOH solution (2N) to ph=11. The mixture was filtered, and the filtrate was concentrated to give Compound Int-8 (1.3 g) which was used directly in the next reaction. ESI-MS (m/z): 270.5[ M+H ]] + 。
Intermediate 9
Intermediate 9 was prepared by the following steps:
the first step: compound Int-9a (500 mg,3.83 mmol), 6-fluoro-nicotinonitrile Int-5b (514.47 mg,4.21 mmol) and cesium carbonate (1.87 g,5.75 mmol) were dissolved in acetonitrile (10 mL) and stirred overnight at room temperature. LCMS monitored the end of the reaction. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give Int-9b (630 mg, yield 70%) as a yellow oil. ESI-MS (m/z): 233.4[ M+H ]] + 。
And a second step of: compound Int-9b (630 mg,2.71 mmol) and Raney Nickel (0.5 mL, aqueous suspension) were dissolved and dispersed in methanol (10 mL) and aqueous ammonia (1 mL), the gas was evacuated with a hydrogen balloon, and stirred overnight at room temperature. LCMS monitored the end of the reaction, the reaction was diluted with methanol, the celite filtrate was filtered off with suction, the organic phase was concentrated and purified by column chromatography on silica gel (dichloromethane/methanol=10/1) to give Int-9 as a yellow oil (200 mg, 31% yield). ESI-MS (m/z): 237.4[ M+H ] ] + 。
Intermediate 10
Intermediate 10 is prepared by the steps of:
the first step: 2- (methylthio) -5-hydroxypyrimidine Int-10a (300 mg,2.11 mmol) was dissolved in acetonitrile (5 mL), cesium carbonate (1.37 g,4.22 mmol) was added, and after stirring at room temperature for 30 minutes 2-fluoropyridine-5-carbaldehyde Int-8b (316 mg,2.53 mmol) was added and the reaction mixture stirred overnight. LCMS monitored the end of the reaction. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was passed through a silica gel columnPurification by chromatography (petroleum ether/ethyl acetate=3/1) gave Int-10b (511 mg, 97% yield) as a yellow solid. ESI-MS (m/z): 248.5[ M+H ]] + 。
And a second step of: compound Int-10b (400 mg,1.62 mmol) and 3, 4-dimethoxybenzylamine (405 mg,2.43 mmol) were dissolved in dichloromethane (5 mL) and methanol (0.5 mL), and after stirring at room temperature for 2 hours, sodium borohydride acetate (2.06 g,9.71 mmol) was added and the reaction mixture was stirred overnight. LCMS monitored the end of the reaction. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give Int-10c as a yellow liquid (630 mg, yield 98%). ESI-MS (m/z): 399.4[ M+H ]] + 。
And a third step of: compound Int-10c (630 mg,1.58 mmol), di-tert-butyl dicarbonate (345 mg,1.58 mmol) and triethylamine (235 mg,2.37 mmol) were dissolved in dichloromethane (5 mL) and after stirring at room temperature for 2 hours, LCMS monitored the reaction. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give Int-10d (402 mg, yield 51%) as a yellow oil. ESI-MS (m/z): 499.4[ M+H ] ] + 。
Fourth step: compound Int-10d (402 mg,0.86 mmol) was added to trifluoroacetic acid (1.5 mL), stirred overnight at room temperature, and the reaction was monitored by LCMS. The reaction solution was diluted with water, the solution was adjusted to ph=8 with sodium hydroxide, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give Int-10 as a yellow oil (80 mg, yield 39%). ESI-MS (m/z): 249.4[ M+H ]] + 。
The synthesis method of the compound of the embodiment is as follows:
example 1
(S) -4,7, 8-trimethyl-2- (((6- ((2- (trifluoromethyl) pyrimidin-5-yl) oxo) pyridin-3-yl) methyl) amino) -7, 8-dihydropteridine
-6 (5H) -ones
Example 1 was prepared by the following steps:
the first step: compound Int-1 (50 mg,220.59 umol) and compound Int-7 (77.49 mg,286.77 umol) were dissolved in n-butanol (2 mL), and p-toluenesulfonic acid monohydrate (3.89 mg,27 umol) was added thereto, and the reaction mixture was stirred under microwave conditions at 160℃for 3 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to give 1 (21.43 mg, yield 21%) as a white solid. ESI-MS (m/z): 461.2[ M+H ]] + ； 1 H NMR(500MHz,DMSO-d6)δ10.35(s,1H),9.06(s,2H),8.20(d,J＝2.3Hz,1H),7.99(dd,J＝8.5,2.4Hz,2H),7.29(d,J＝8.4Hz,1H),4.55(d,J＝6.0Hz,2H),4.23(d,J＝6.9Hz,1H),3.07(s,3H),2.24(s,3H),1.36(d,J＝6.9Hz,3H).
Example 2
(S) -4, 7-dimethyl-8- (methyl-d 3) -2- (((6- ((2- (trifluoromethyl) pyrimidin-5-yl) oxo) pyridin-3-yl) methyl) amino) -7, 8-dihydro-pteridin-6 (5H) -one
Example 2 was prepared by the following steps:
the first step: compound Int-2 (100 mg, 435.39. Mu. Mol) and compound Int-7 (152.94 mg, 566.00. Mu. Mol) were dissolved in n-butanol (2 mL), and p-toluenesulfonic acid monohydrate (8.27 mg, 43.54. Mu. Mol) was added thereto, and the reaction mixture was stirred under microwave conditions at 160℃for 3 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to give 2 (38.22 mg, yield 18%) as a white solid. ESI-MS (m/z): 464.2[ M+H ]] + ； 1 H NMR(500MHz,DMSO-d6)δ9.80(s,1H),9.03(s,2H),8.12(d,J＝2.2Hz,1H),7.92(dd,J＝8.5,2.2Hz,1H),7.22(d,J＝8.5Hz,1H),6.97(t,J＝6.4Hz,1H),4.47-4.28(m,2H),3.98(q,J＝6.8Hz,1H),2.11(s,3H),1.17(d,J＝6.8Hz,3H).
Example 3
(S) -4-methyl-2- (((6- ((2- (trifluoromethyl) pyrimidin-5-yl) oxo) pyridin-3-yl) methyl) amino) -6a,7,8, 9-tetrahydropyrrolo [2,1-H ] pteridin-6 (5H) -one
Example 3 was prepared by the following steps:
the first step: compound Int-6 (80 mg,335.19 umol) and compound Int-7 (117.74 mg,435.74 umol) were dissolved in n-butanol (2 mL), and p-toluenesulfonic acid monohydrate (6.37 mg,33.52 umol) was added, and the reaction mixture was stirred under microwave conditions at 160℃for 3 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to give 3 (99.37 mg, yield 62%) as a white solid. ESI-MS (m/z): 473.2[ M+H ]] + ； 1 H NMR(500MHz,DMSO-d6)δ9.74(s,1H),9.03(d,J＝1.9Hz,2H),8.12(d,J＝2.4Hz,1H),7.92(dd,J＝8.5,2.4Hz,1H),7.21(d,J＝8.4Hz,1H),6.98(t,J＝6.4Hz,1H),4.46-4.26(m,2H),4.02-3.92(m,1H),3.60-3.48(m,1H),3.44-3.35(m,1H),2.19-2.14(m,1H),2.10(s,3H),1.99-1.79(m,3H).
Example 4
4',8' -dimethyl-2 '- (((6- ((2- (trifluoromethyl) pyrimidin-5-yl) oxo) pyridin-3-yl) methyl) amino) -5',8 '-dihydro-6'H-spiro [ cyclopropan-1, 7 '-pteridine ] -6' -one
Example 4 was prepared by the following steps:
the first step: sodium hydrogen (1.59 g,39.76mmol, 60% by weight) was added to a two-necked flask equipped with anhydrous tetrahydrofuran (20 mL), placed in an ice-water bath, and Compound Int-4a (2 g,9.94 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and slowly added dropwise to the reaction solution. After 30 minutes, methyl iodide (3.53 g,24.85 mmol) was added dropwise, and the mixture was slowly warmed to room temperature and stirred overnight. LCMS monitored the end of the reaction, cooled to 0 ℃, quenched by slow dropwise addition of saturated aqueous ammonium chloride, extracted with ethyl acetate and dried in organic phase to give 4a as a yellow oil (1.7 g, 79% yield). ESI-MS (m/z): 216.2[ M+H ]] + 。
And a second step of: 4a (1.7 g,7.90 mmol) was dissolved in methanol (5 mL), placed in an ice-water bath, thionyl chloride (2.82 g,23.69 mmol) was slowly added dropwise, and after the addition was completed, the reaction was allowed to warm to room temperature and then allowed to warm to 70℃overnight. After completion of the LCMS monitoring reaction, the reaction was concentrated to give 4b as a yellow solid (1.2 g, 91% yield). ESI-MS (m/z): 130.2[ M+H ]] + 。
And a third step of: compound Int-3d (500 mg,2.40 mmol) and compound 4b (597.17 mg,3.61 mmol) were dissolved in tetrahydrofuran (10 mL), and N, N-diisopropylethylamine (1.26 mL,7.20 mmol) was added. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the end of the reaction. The reaction solution was diluted with water, extracted with ethyl acetate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give 4c (200 mg, reaction yield 27%) as a yellow oil. ESI-MS (m/z): 301.3[ M+H ] ] + 。
Fourth step: compound 4c (200 mg,665.12 umol) and compound Int-7 (270.21 mg,215.67 umol) were dissolved in N, N-dimethylformamide (5 mL), and N, N-diisopropylethylamine (27.89 mg,2.00 mmol) was added. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the end of the reaction. The reaction solution was diluted with water, extracted with ethyl acetate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give compound 4d (300 mg, yield 84%). ESI-MS (m/z): 535.2[ M+H ]] + 。
Fifth step: compound 4d (250 mg, 467.7)7 umol) was dissolved in methanol (5 mL), palladium on carbon (5.68 mg,46.78 umol) was added, and the reaction system was replaced with hydrogen. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the end of the reaction, the residue was filtered through celite, the reaction concentrated under reduced pressure, and the residue purified by Prep-HPLC to give 4 as a white solid (24.02 mg, 10% yield). ESI-MS (m/z): 473.2[ M+H ]] + ； 1 H NMR(500MHz,DMSO-d6)δ9.87(s,1H),9.03(s,2H),8.11(d,J＝2.3Hz,1H),7.91(dd,J＝8.4,2.2Hz,1H),7.22(d,J＝8.4Hz,1H),7.10-6.90(m,1H),4.36(d,J＝6.4Hz,2H),2.72(s,3H),2.11(s,3H),1.37-1.20(m,2H),1.20-1.07(m,2H).
Example 5
4' -methyl-8 ' - (methyl-d 3) -2' - (((6- ((2- (trifluoromethyl) pyrimidin-5-yl) oxo) pyridin-3-yl) methyl) amino) -5',8' -dihydro
-6'H-spiro [ cyclopropane-1, 7' -pteridine ] -6' -one
Example 5 was obtained by reference to the synthetic method of example 4. ESI-MS (m/z): 476.7[ M+H ]] + ； 1 H NMR(500MHz,DMSO-d6)δ9.88(s,1H),9.04(s,2H),8.12(d,J＝2.3Hz,1H),7.92(dd,J＝8.4,2.4Hz,1H),7.23(d,J＝8.4Hz,1H),7.00(t,J＝6.3Hz,1H),4.37(d,J＝6.3Hz,2H),2.12(s,3H),1.31-1.24(m,2H),1.18-1.08(m,2H).
Example 6
4, 7-trimethyl-8- (methyl-d 3) -2- (((6- ((2- (trifluoromethyl) pyrimidin-5-yl) oxo) pyridin-3-yl) methyl) amino) -7, 8-dihydro-pteridin-6 (5H) -one
Example 6 was prepared by the following steps:
the first step: by combining compound Int-3 (55 mg,225 umol) and Compound Int-7 (73 mg,270 umol) were dissolved in n-butanol (2 mL), and p-toluenesulfonic acid monohydrate (3.89 mg,27 umol) was added, and the reaction mixture was stirred under microwave conditions at 160℃for 3 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to give 6 (24 mg, yield 21%) as a white solid. ESI-MS (m/z): 478.6[ M+H ]] + ； 1 H NMR(500MHz,DMSO-d6)δ9.80(s,1H),9.04(s,2H),8.13(d,J＝2.3Hz,1H),7.93(dd,J＝8.4,2.4Hz,1H),7.23(d,J＝8.4Hz,1H),6.99(t,J＝6.2Hz,1H),4.38(d,J＝6.3Hz,2H),2.13(s,3H),1.32(s,6H).
Example 7
4,7,7,8-tetramethyl-2- (((6- ((2- (trifluoromethyl) pyrimidin-5-yl) oxo) pyridin-3-yl) methyl) amino) -7, 8-dihydro-pteridin-6 (5H) -one
Example 7 was prepared by the following steps:
the first step: sodium hydrogen (275 mg,6.89mmol, 60%) was added to a two-necked flask equipped with anhydrous tetrahydrofuran (5 mL), placed in an ice-water bath, and compound 7a (350 mg,1.72 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and slowly added dropwise to the reaction solution. After 30 minutes, methyl iodide (365 mg,2.58 mmol) was added dropwise, and the mixture was slowly warmed to room temperature and stirred overnight. LCMS monitored the reaction to completion, cooled to 0 ℃, quenched by slow dropwise addition of saturated aqueous ammonium chloride, extracted with ethyl acetate and dried in organic phase to give 7b as a yellow oil (370 mg, 98% yield). ESI-MS (m/z): 218.7[ M+H ] ] + 。
And a second step of: 7b (370 mg,1.70 mmol) was dissolved in methanol (5 mL), placed in an ice-water bath, and thionyl chloride (405 mg,3.41 mmol) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was warmed to room temperature and then to 70℃for overnight reaction. After completion of the LCMS monitoring reaction, the reaction mixture was concentrated to give 7c (200 mg, 86% yield) as a yellow oil。ESI-MS(m/z):132.7[M+H] + 。
And a third step of: compound 7c (200 mg,1.19 mmol) and compound Int-3d (225 mg,1.08 mmol) were dissolved in tetrahydrofuran (5 mL) and N, N-diisopropylamine (420 mg,3.25 mmol) was added. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the end of the reaction. The reaction solution was diluted with water, extracted with ethyl acetate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) as a white solid for 7d (70 mg, reaction yield 21%). ESI-MS (m/z): 303.3[ M+H ]] + 。
Fourth step: compound 7d (70 mg,231 umol) and compound Int-7 (75 mg,278 umol) were dissolved in tetrahydrofuran (5 mL), and N, N-diisopropylamine (90 mg,694 umol) was added. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the end of the reaction. The reaction solution was diluted with water, extracted with ethyl acetate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give compound 7e (90 mg, yield 72%). ESI-MS (m/z): 538.7[ M+H ] ] + 。
Fifth step: compound 7e (90 mg,177 umol) was dissolved in methanol (5 mL), palladium on carbon (10 mg,89 umol) was added, and the reaction system was replaced with hydrogen. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the end of the reaction, the residue was filtered through celite, the reaction concentrated under reduced pressure, and the residue purified by Prep-HPLC to give 7 as a white solid (21 mg, 25% yield). ESI-MS (m/z): 475.7[ M+H ]] + ； 1 H NMR(500MHz,DMSO-d6)δ9.82(s,1H),9.04(s,2H),8.13(d,J＝2.3Hz,1H),7.93(dd,J＝8.4,2.4Hz,1H),7.23(d,J＝8.4Hz,1H),7.00(t,J＝6.3Hz,1H),4.38(d,J＝6.3Hz,2H),2.94(s,3H),2.14(s,3H),1.33(s,6H)。
Example 8
(S) -2- (((6- ((2-chloropyrimidin-5-yl) oxo) pyridin-3-yl) methyl) amino) -4,7, 8-trimethyl-7, 8-dihydropteridin-6 (5H) -one
Example 8 was prepared by the following steps:
the first step: compound Int-1 (50.00 mg,220.59 umol) and compound Int-9 (67.87 mg,286.77 umol) were dissolved in n-butanol (2 mL), and p-toluenesulfonic acid monohydrate (4.19 mg,22.06 umol) was added thereto, and the reaction mixture was stirred under microwave conditions at 160℃for 3 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to give 8 (10.69 mg, yield 11%) as a white solid. ESI-MS (m/z): 427.6[ M+H ]] + ； 1 H NMR(500MHz,DMSO-d6)δ9.82(s,1H),8.78(s,2H),8.10(d,J＝2.3Hz,1H),7.89(dd,J＝8.5,2.4Hz,1H),7.17(d,J＝8.5Hz,1H),6.98(t,J＝6.3Hz,1H),4.42-4.30(m,2H),3.99(q,J＝6.8Hz,1H),2.91(s,3H),2.11(s,3H),1.18(d,J＝6.8Hz,3H).
Example 9
(S) -4,7, 8-trimethyl-2- (((6- ((6- (trifluoromethyl) pyridin-3-yl) oxo) pyridin-3-yl) methyl) amino) -7, 8-dihydro-pteridin-6 (5H) -one
Example 9 was prepared by the following steps:
the first step: compound Int-1 (50.00 mg,220.59 umol) and compound Int-8 (77.02 mg,286.77 umol) were dissolved in n-butanol (2 mL), and p-toluenesulfonic acid monohydrate (4.19 mg,22.06 umol) was added thereto, and the reaction mixture was stirred under microwave conditions at 160℃for 3 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to give 9 (64.26 mg, yield 63%) as a white solid. ESI-MS (m/z): 460.6[ M+H ] ] + ； 1 H NMR(500MHz,DMSO-d6)δ9.80(s,1H),8.62(s,1H),8.12(s,1H),7.95(d,J＝8.6Hz,1H),7.89(d,J＝8.4Hz,1H),7.85(d,J＝8.6Hz,1H),7.15(d,J＝8.5Hz,1H),6.95(t,J＝6.3Hz,1H),4.46-4.28(m,2H),3.98(q,J＝6.9Hz,1H),2.91(s,3H),2.11(s,3H),1.17(d,J＝6.8Hz,3H).
Example 10
(S) -2- (((6- ((6-chloropyridin-3-yl) oxo) pyridin-3-yl) methyl) amino) -4,7, 8-trimethyl-7, 8-dihydropteridin-6 (5H) -one
Example 10 was prepared by the following steps:
the first step: compound Int-1 (50.00 mg,220.59 umol) and compound Int-5 (67.58 mg,286.77 umol) were dissolved in n-butanol (2 mL), and p-toluenesulfonic acid monohydrate (4.19 mg,22.06 umol) was added thereto, and the reaction mixture was stirred under microwave conditions at 160℃for 3 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to give 10 (49.62 mg, yield 52%) as a white solid. ESI-MS (m/z): 426.6[ M+H ]] + ； 1 H NMR(500MHz,Chloroform-d)δ8.19(d,J＝2.9Hz,1H),8.06(d,J＝2.4Hz,1H),7.70(dd,J＝8.4,2.5Hz,1H),7.42(dd,J＝8.6,2.9Hz,1H),7.27(d,J＝8.6Hz,1H),6.88(d,J＝8.4Hz,1H),5.34(s,1H),4.54-4.39(m,2H),4.00(q,J＝6.9Hz,1H),2.95(s,3H),2.15(s,3H),1.33(d,J＝6.9Hz,3H).
The following examples can be obtained according to the synthetic routes and synthetic methods of intermediates described in the above examples.
Comparative example 1
(S)-2-(((6-(4-fluorophenoxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6
(5H)-one
Comparative example 1 was obtained by referring to the method of synthesizing compound 54 described in patent WO 2019209757. ESI-MS (m/z): 409.8[ M+H ]] + ； 1 H NMR(500MHz,DMSO-d6)δ9.80(s,1H),8.07(d,J＝2.3Hz,1H),7.79(dd,J＝8.6,2.3Hz,1H),7.28–7.18(m,2H),7.18–7.08(m,2H),7.01–6.88(m,2H),4.44–4.26(m,2H),3.98(q,J＝6.9Hz,1H),2.91(s,3H),2.11(s,3H),1.17(d,J＝6.7Hz,3H).
Comparative example 2
(S)-2-(((6-(4-fluorophenoxy)pyridin-3-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5
H)-one
Comparative example 2 was obtained by referring to the method of synthesizing compound 56 described in patent WO 2019209757. ESI-MS (m/z): 395.7[ M+H ]] + ； 1 H NMR(500MHz,Chloroform-d)δ8.11(d,J＝2.3Hz,1H),7.66(dd,J＝8.5,2.4Hz,1H),7.19(s,1H),7.03–6.96(m,4H),6.77(d,J＝8.4Hz,1H),4.54–4.38(m,2H),4.01(q,J＝6.9Hz,1H),2.97(s,3H),1.38(dd,J＝6.9,1.3Hz,3H).
Biological screening and results of Wnt pathway inhibitors
Test example 1: construction of Colo205-LUC-TCF/LEF-M1 reporter cell line
Colo205 cell line (Proc. Natl. Acad. Sci. Cell bank, cat#TCHu102) was purchased from Proc. Natl. Acad. Sci. Cell bank, amplified and subcultured, and then transfected with a luciferase reporter plasmid (Promega) driven by TCF/LEF transcription factor by lipo3000 liposome transfection in the exponential growth phase of cells. The plasmid carries a resistance gene, and can be used for resistance screening. Transfection was performed in 10cm dishes using conventional complete medium without resistance. After 2 days, the medium with resistance was changed and the culture was continued. The resistant medium was then changed every 2 days and the suspension cells were discarded, and the original medium was centrifuged to remove cells and debris and was then retained as an adaptive medium. After the cells had grown up the dishes, the cells were digested, counted and passaged into 96-well plates to average the number of cells contained in each well to 1.5 cells/well, using adaptation medium at the time of passaging. The remaining cells were frozen. After 4 hours of culture after passage, the cells were allowed to adhere, and then the cell numbers of each well were observed under a microscope. Only 1 cell per well was labeled, which was a monoclonal well. Then, the culture medium was changed every 2 days for normal culture, and observation was performed. The pre-monoclonal cells have wells that continue to grow, and are labeled 2 times, and can be replaced with normal medium with resistance. When cells in a monoclonal well grow over a 96-well plate well, they are digested and passaged to a 24-well culture plate, after the 24-well plate grows over, passaged to 1 96-well plate and 1 6-well plate, wherein 96-well plate cells are passaged to at least 6-well, wherein 3-well are added with a known Wnt inhibitor, and the other 3-well are not treated. After 24 hours, the 96-well plate cells were added with a fluorescent detection reagent to detect the fluorescence intensity. Cell lines in which fluorescence expression was not present in the treatment and post-fluorescence reduction was inhibited were selected and further cultured. The Colo205-LUC-TCF/LEF-M1 cell line is one of the cell lines screened by the screening method, the growth curve, the cell morphology and the cell growth state of the cell line are similar to those of original Colo205 cells, the ratio of the fluorescent signals treated by adding the inhibitor to the fluorescent signals not treated by the inhibitor is large in all the cell lines, and the ratio can be inhibited by 4-5 times at 4h, so that the cell line is completely suitable for screening Wnt inhibitors in the later period.
Test example 2: detection of Colo205-LUC-TCF/LEF M1 reporter cell line inhibition Capacity by Compounds
The Colo205-LUC-TCF/LEF M1 cell strain is a report tool cell for stably transfecting pGL4.49-LUC2-TCF/LEF vectors, the beta-catenin Wnt channel is continuously activated, after an inhibitor is added, the Wnt channel is inhibited, the expression level of firefly luciferase regulated by TCF/LEF cis elements on the vectors is reduced, and after a detection substrate is added subsequently, the detected optical signal is correspondingly reduced, so that the inhibition effect of the compound is detected.
100. Mu.L of the highest concentration was added to each well of a 96-well cell culture plateCompound concentration was 3-fold gradient diluted at 20 μm. 10000 stably reporter-transfected colo205 cells and 100. Mu.L medium were then inoculated into each well, with corresponding treatments as positive and negative control wells. Cells were placed in 5% CO 2 After 4 hours of incubation at 37℃in a cell incubator for 4 hours, the culture medium was removed, 100. Mu.L of a reagent (Promega) containing a corresponding firefly luciferase substrate was added to each well, and the luciferase reporter gene activity was measured. The luminescence intensity was read in full wavelength mode with SpectraMax. The IC of each compound was calculated from the light signal intensity of DMSO-treated cells alone as positive control and the light signal intensity of cell-free wells as negative control 50 Is a concentration of (3). The Colo205 reporter assay data are summarized in Table 1 below.
IC of the Table 1 Compounds against Colo205-LUC-TCF/LEF reporter inhibition 50 Value of
Test example 3: proliferation inhibition assay of compounds on Wnt mutant cell lines (Colo 205, DU4475, NCI-H929 and HepG 2) and non-Wnt mutant cell lines (Hela and RKO)
The cell lines used in the experiments were those in which the Wnt pathway was continuously activated and which proliferated as Wnt pathway dependent Colo205, DU4475, NCI-H929 and HepG2 cell lines; whereas normally Wnt pathway is not activated and HELA and RKO cell lines whose proliferation is independent of Wnt pathway are used as control cell lines, it was judged that the inhibition of Wnt dependent proliferation by the compounds of the invention is not due to other non-specific toxicities.
The Colo205, du4475, NCI-H929, hepG2, HELA and RKO cell lines cultured in the respective media were treated in the logarithmic phase, the cells were collected to prepare uniform cell suspensions of known concentration, and then the cell suspensions were added to 96-well cell culture plates to make each wellThe cell number is 1000. Placing 5% CO 2 The cells are cultured in a cell incubator at 37 ℃ for 20-24 hours. The following day, the 3-fold gradient of the compound which had been completely dissolved was added to each cell culture well to give a final maximum concentration of 20. Mu.M in the cell culture well, and the culture was continued for 96 hours. The assay was performed using a Promega cell viability assay, the more cell proliferation the stronger the final signal intensity. The detection instrument is in SpectraMax, full wavelength mode. Wells with DMSO alone served as positive control wells and wells without cells inoculated served as negative control wells, and IC of each compound for Wnt continuous activation or proliferation inhibition of proliferation dependent cells was calculated 50 Value, and IC for proliferation inhibition of Wnt-unactivated or proliferation-independent cells 50 The inhibition of Wnt pathway and the toxic effect on normal cells were evaluated. The results are shown in Table 2 below.
IC of the compounds of Table 2 for inhibition of proliferation of Wnt mutant cell lines 50 Value of
NT represents undetected
The results show that the compound has remarkable inhibitory activity on mutant cell strains Colo205, DU4475, NCI-H929 and HepG2, but basically has no remarkable inhibitory activity on Hela and RKO cell strains, which shows that the compound has remarkable Wnt-dependent proliferation inhibition effect.
Test example 4: evaluation of the present compounds in terms of mouse pharmacokinetics
1. Experimental materials
ICR mice: male, 25-35g, purchased from Shanghai Style laboratory animal Co.
Reagent: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), solutol HS-15, ultrapure water, methanol, acetonitrile, formic acid, propranolol (internal standard), tolbutamide (internal standard), ICR mouse blank plasma (EDTA-K2 anticoagulation)
Instrument: SCIEX LC-MS/MS (Exion LC, QTRAP 6500 Plus liquid chromatography-mass spectrometer)
2. Experimental method
Weighing a certain amount of the compounds of examples 1, 2, 3, 5, 6, 9 and 10 and the compound of the comparative example 1, respectively dissolving the compounds with DMSO of 5% volume, adding other corresponding solvents (see table 3) to prepare a clear solution, taking 100 mu L of blood from an eye socket 15min, 30min, 1h, 2h, 4h, 8h and 24h (5 min are taken by intravenous administration group) after intravenous or intragastric administration of a mouse, placing the blood into an EDTA-K2 anticoagulation centrifuge tube, centrifuging (4 ℃) for 10min within 30min, separating blood plasma, and preserving at-80 ℃ to be tested.
A fixed amount of the compound was precisely weighed and dissolved to 2 mg/ml with DMSO to prepare a stock solution. Accurately sucking a proper amount of compound stock solution, diluting with acetonitrile-water (8:2) solution to prepare a standard series solution, accurately sucking 1 μl of the standard series solution, adding 19 μl of mouse blank plasma, and mixing to obtain a series of concentration plasma matrix standard curves. After accurate aspiration of 20. Mu.L of each of the dosed mouse plasma samples, 400. Mu.L of acetonitrile solution containing an internal standard (propranolol 50ng/ml, tolbutamide 100 ng/ml) was added, vortexed for 5min at 4000rpm for 10min, 200. Mu.L of the supernatant was taken, 200. Mu.L of ultrapure water was added, and after mixing, the mixture was analyzed by LC-MS/MS.
3. Data processing
After LC-MS measurement of blood concentration, pharmacokinetic parameters were calculated using WinNonlin 8.1 software, non-compartmental model, and the results are shown in Table 3.
Table 3 compound mouse pharmacokinetic parameters
Solvent a:5% DMSO+10% PEG-400+10% Solutol+75% H 2 O
B：5％DMSO+10％PEG 400+85％H 2 O
C：5％DMSO+20％Solutol+75％H 2 O
The above results show that the highest blood concentration (Cmax) and the area under the absorption curve (AUC) of the compound of the present invention after oral absorption administration by mice are both significantly better than those of the control. This suggests that the novel structural features have the ability to improve and enhance oral absorption characteristics.
Test example 5: tumor growth inhibition test of Compound 1 (W421) on Colo205 mouse Xenograft model
The present study was evaluated for in vivo antitumor activity of compound 1 in a BALB/c Nude mice engraftment model of human colon cancer cells Colo 205.
The female BALB/c Nude mice are inoculated with human colon cancer cells Colo205 subcutaneously, and a Colo205 BALB/c Nude mice transplantation tumor model is established. When the tumor grows to an average tumor volume of 100mm 3 After left and right, tumor-bearing mice were divided into 4 groups by random grouping according to tumor volume size: solvent treatment control, 1.5mg/kg compound 1, 3mg/kg compound 1 and 10mg/kg compound 1. Compound 1 was orally administered once a Day for 15 days of the dosing cycle, tumor volumes were measured every other Day (fig. 1), day15 weighed and tumor volumes were measured (table 4).
Table 4 Compound 1 inhibits human colon carcinoma cell Colo205 tumor volume in vivo (day 15)
a. Mean ± SEM.
b. Tumor growth inhibition was determined by T/C (TRTV/CRTV) (TRTV: treatment group mean RTV; CRTV: vehicle control group mean RTV; RTV = Vt/V0, V0 being the tumor volume of the animal when grouped, vt being the tumor volume of the animal after treatment).
c.p values were calculated based on tumor volume, and comparisons among groups were analyzed using one-way ANOVA, if the variance alignment test p >0.05, dunnett was chosen, otherwise Games-Howell was chosen.
The results in fig. 1 and table 4 show that the compounds of the present invention, in particular compound 1, have a significant in vivo function of inhibiting the Colo205 tumor volume of human colon cancer cells.

Claims (21)

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof:
wherein,
R 1 、R 2 each independently represents hydrogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl, 4-8 membered heterocycloalkyl, halo 4-8 membered heterocycloalkyl, - (C) 1 -C 6 ) Alkylene OR a (C) 1 -C 6 ) Alkylene OR a 、-(C 1 -C 6 ) Alkylene SR a (C) 1 -C 6 ) Alkylene SR a Or R 1 、R 2 Together with the carbon atoms to which they are attached, form a 3-8 membered ring, which ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O and S;
R 3 representation (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl, or R 3 And R is 1 Or R is 2 Together form a 4-7 membered ring, which may optionally contain 0 or 1 heteroatom selected from O and S;
W 6 represents CR 6 Or N;
R 6 each independently represents hydrogen, halogen, cyano, (C) 1 -C 3 ) Alkyl, halo (C) 1 -C 3 ) An alkyl group;
cy represents a 5-12 membered aromatic heterocycle optionally containing 1, 2, 3 or 4 heteroatoms, each independently selected from N, O and S, and the ortho position of Cy to the-O-linkage is unsubstituted or substituted with hydrogen;
R 1 ' represents hydrogen, halogen, (C) 1 -C 6 ) Alkyl group,Halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl, (C) 3 -C 8 ) Heterocycloalkyl, halo (C) 3 -C 8 ) Heterocyclylalkyl, -OR a (ii) halo OR a 、-SR a (ii) -halogenated SR a ；
R 2 ' represents hydrogen, halogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl, (C) 3 -C 8 ) Heterocycloalkyl, halo (C) 3 -C 8 ) Heterocyclylalkyl, -OR a (ii) halo OR a 、-SR a (ii) -halogenated SR a ；
R 3 ' represents hydrogen, halogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl, (C) 3 -C 8 ) Heterocycloalkyl, halo (C) 3 -C 8 ) Heterocyclylalkyl, -OR a (ii) halo OR a 、-SR a (ii) -halogenated SR a ；
Each m independently represents 0, 1 or 2;
R a each independently represents hydrogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl groups.
2. The compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, according to claim 1, wherein Cy is a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring.
3. A compound of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof according to any one of the preceding claims, wherein Cy is pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl or pyrrolyl.
4. The compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof of claim 1, wherein the compound of formula (I) is represented by formula (II):
wherein,
the dotted ring indicates that the ring in which it is located is an aromatic ring;
W 1 represents CR 1 ' or N;
W 2 represents CR 2 ' or N;
W 3 represents CR 3 ' or N;
W 4 represents CH or N;
W 5 represents CH or N;
R 1 、R 2 、R 3 、R 6 、W 6 、R 1 ’、R 2 ’、R 3 ’、R a m is as defined in claim 1.
5. The compound having the structure of formula (II) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof of claim 4, wherein the compound of formula (II) is as follows:
6. the compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof of claim 1, wherein the compound of formula (I) is as shown in formula (III):
wherein,
the dotted ring indicates that the ring in which it is located is an aromatic ring;
W 1 ' represents CH, N or NH;
W 2 ' represents CR 2 ', N or NR 2 ’；
W 3 ' represents CR 3 ', N or NR 3 ’；
W 4 ' represents CH, N or NH;
R 1 、R 2 、R 3 、R 6 、W 6 、R 1 ’、R 2 ’、R 3 ’、R a m is as defined in claim 1.
7. The compound having the structure of formula (III) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof of claim 6, wherein the compound of formula (III) is as follows:
8. A compound of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in any one of the preceding claims, wherein R 1 、R 2 Each independently represents hydrogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl, 4-8 membered heterocycloalkyl, halo 4-8 membered heterocycloalkyl, - (C) 1 -C 6 ) Alkylene OR a (C) 1 -C 6 ) Alkylene groupOR a The method comprises the steps of carrying out a first treatment on the surface of the More preferably hydrogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) An alkyl group.
9. A compound of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in any one of the preceding claims, wherein R 3 Is (C) 1 -C 6 ) An alkyl group.
10. A compound of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in any one of the preceding claims, wherein W is 6 Is CR (CR) 6 。
11. A compound of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in any one of the preceding claims, wherein R 6 Is hydrogen.
12. A compound of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in any one of the preceding claims, wherein R 1 ' represents hydrogen, halogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl groups.
13. The compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof of claim 11, wherein R 1 ' represents halo (C) 1 -C 6 ) An alkyl group.
14. A compound of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in any one of the preceding claims, wherein R 2 ' represents hydrogen, halogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl group,(C 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl groups.
15. The compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof of claim 13, wherein R 2 ' represents hydrogen or halogen.
16. A compound of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in any one of the preceding claims, wherein R 3 ' represents halogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl, -OR a (ii) halo OR a 、-SR a (ii) -halogenated SR a 。
17. The compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof of claim 15, wherein R 3 ' represents halogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl groups.
18. A compound of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in any one of the preceding claims, wherein R 3 ' represents halo (C) 1 -C 6 ) Alkyl or halo (C) 3 -C 8 ) Cycloalkyl groups.
19. A compound or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein the compound has the structure:
20. a pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, and optionally a pharmaceutically acceptable carrier.
21. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof or a pharmaceutical composition according to claim 20 for the manufacture of a medicament for the prevention and/or treatment of cancer, tumour, inflammatory disease, autoimmune disease or immune mediated disease.
CN202380010281.6A 2022-07-28 2023-07-26 Wnt pathway inhibitor compound Pending CN117396482A (en)

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CN202210924700 2022-07-28
CN2022109247004 2022-07-28
PCT/CN2023/109227 WO2024022365A1 (en) 2022-07-28 2023-07-26 Wnt pathway inhibitor compound

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CN117396482A true CN117396482A (en) 2024-01-12

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