WO2022012509A1 - 一种作为可透脑的btk或her2抑制剂的化合物及其制备方法与用途 - Google Patents
一种作为可透脑的btk或her2抑制剂的化合物及其制备方法与用途 Download PDFInfo
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Definitions
- the present invention relates to the technical field of medicine, in particular to a compound of BTK or HER2 protein kinase inhibitor with good brain penetration and a preparation method and application thereof.
- BTK Bruton's tyrosine kinase
- the Tec family is the second largest family of human non-receptor kinases after the Src family, and its main members include BTK, BMX (etk), ITK, TEC and TXK (RLK).
- BTK was identified as a defective protein in human X-linked agammaglobulinemia (XLA).
- XLA X-linked agammaglobulinemia
- BTK is a key regulator of B cell receptor (BCR) signal transduction pathway, plays an important role in B cell activation, proliferation, differentiation and survival, and is closely related to a variety of B cell tumors and autoimmune diseases.
- BCR B cell receptor
- the BTK structure contains 5 main domains, namely the PH domain (Pleckstrin homology), the TH domain (Tec homology), the SH3 domain (Src homology 3), the SH2 domain (Src homology 2) and the SH1 domain ( Src homology1).
- Activation (phosphorylation) of BTK occurs initially in the activation loop in the SH1 domain, and further activation occurs in the SH2 and SH3 domains that contain major autophosphorylation sites; these SH domains also contain BTK for nucleocytoplasmic shuttling Required nuclear localization signal (NLS) and nuclear export sequence (NES).
- NLS nucleocytoplasmic shuttling Required nuclear localization signal
- NES nuclear export sequence
- BTK plays an irreplaceable role in the generation of B lymphocytes. It can control the development and differentiation of B cells by activating positive cell cycle regulators and differentiation factors, and can also regulate pro-apoptotic and anti-apoptotic proteins. expression to control B cell survival and proliferation. Sustained activation of BTK is a prerequisite for the development of chronic lymphocytic leukemia (CLL); abnormal BCR-BTK signaling promotes the survival of activated B-cell subtypes in diffuse large B-cell lymphoma (DLBCL). Gain-of-function mutations in BTK have also been identified in colorectal cancer, acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML). It can be seen that the abnormal activation of BTK-dependent pathway has been proved to be closely related to the occurrence and development of various tumors.
- CLL chronic lymphocytic leukemia
- ALL acute lymphoblastic leukemia
- CML chronic myeloid leukemia
- the currently approved irreversible BTK inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib, all selectively bind to the cysteine residue of BTK.
- Cys-481 forms an irreversible covalent bond and inhibits BTK activity to achieve the purpose of treating related diseases.
- a subset of cancer patients will develop resistance to first-generation BTK inhibitors, creating a new unmet clinical need.
- Studies have shown that the BTK-C481S mutation is one of the main drug resistance mechanisms associated with this. Therefore, drugs that can target and inhibit the BTK-C481S mutation are expected to provide new treatment options.
- ARQ-531 is an orally bioavailable, potent, and reversible dual inhibitor of wild-type and C481S-mutated BTK; preliminary clinical results of ARQ-531 demonstrate its efficacy in patients with C481S-mutated BTK.
- PCNSL central nervous system lymphoma
- HD-MTX high-dose methotrexate
- WBRT whole brain Radiotherapy
- the median OS of this program can reach 30 to 50 months.
- this regimen can lead to severe neurotoxicity, and the toxicity increases with the patient's age and radiation dose, manifested as memory loss, cognitive impairment, gait disturbance, dementia and other symptoms, which seriously affect the patient's quality of life.
- Some studies have also investigated the efficacy and inferiority of autologous hematopoietic stem cell transplantation and whole-brain radiotherapy in PCNSL consolidation therapy. Regardless of the treatment option, the prognosis is poor.
- BBB blood brain barrier
- conventional immunochemotherapy is difficult to penetrate and the efficacy is poor.
- the efficacy of drugs for the treatment of primary or secondary CNS invasion depends on their distribution in the brain after crossing the blood-brain barrier. Only lipophilic molecules can easily pass through the BBB by passive diffusion.
- Conventional immunochemotherapy such as rituximab is a single drug.
- the cloned antibody has a large molecular weight and is difficult to penetrate the blood-brain barrier, so it cannot exert its full curative effect.
- BTK Bruton's tyrosine kinase
- MYD88 and CD79B are involved in the BCR pathway, and MYD88 and CD79B are often the main mutations in the BCR signaling pathway in central nervous system lymphomas.
- PCNSL The diagnosis of PCNSL is based on the WHO2008 classification, and the results of immunohistochemistry must be obtained.
- the main markers include all B cell markers (CD19, CD20, PAX5), BCL6, MUM1/IRF4 and CD10.
- the NCCN Guidelines for Central Nervous System Malignancies (2020.V1) recommend BTKi for relapsed and refractory PCNSL.
- a first-generation irreversible BTK inhibitor (Tirabrutinib) has been approved for the treatment of this disease in foreign countries, but the drug has weak activity on BTK protein, high clinical dose (480mg once a day), obvious side effects, poor patient compliance, and There is a risk of developing drug resistance due to the C481S mutation after taking it for a period of time.
- BTK inhibitors can also be used for autoimmune diseases such as rheumatoid arthritis, multiple sclerosis (MS), psoriasis and other autoimmune diseases.
- autoimmune diseases such as rheumatoid arthritis, multiple sclerosis (MS), psoriasis and other autoimmune diseases.
- MS multiple sclerosis
- psoriasis a soriasis .
- the pathogenesis of multiple sclerosis is directly related to the lesions of the brain.
- the global multiple sclerosis drugs market size was valued at USD 25.0 billion in 2019 and is expected to reach USD 40.66 billion in 2027, growing at a CAGR of 7.1% during the forecast period.
- the annual cost of treatment for MS is $28,000.
- BTK As a key kinase in the B cell receptor signaling pathway, BTK is important for the development and function of immune cells involved in the pathological process of MS, such as B lymphocytes, macrophages, and microglia. Therefore, BTK inhibitors are expected to provide novel therapeutic options for the treatment of autoimmune diseases such as MS.
- HER2 human epidermal growth factor receptor-2
- ERBB2 human epidermal growth factor receptor-2
- HER2 protein is a transmembrane protein with tyrosine protein kinase activity and belongs to one of the members of the EGFR family. It is overexpressed in a variety of cancers, including breast, ovarian, and gastric cancers, among others.
- HER2 mediates cell growth, differentiation and survival and can promote the aggressive spread of cancer cells.
- HER2+ tumors are more aggressive than HER2-negative cancers and are associated with shorter survival times, worse overall survival, higher risk of recurrence, and CNS disease (brain metastases).
- CNS disease brain metastases.
- breast cancer is the number one cancer killer of women worldwide, with the highest morbidity and mortality.
- the incidence of breast cancer in my country ranks first among female malignant tumors, reaching 43/100,000.
- the growth rate of breast cancer incidence in China is twice the global average growth rate (an increase of more than 300,000 per year), ranking first in the world.
- Patients with HER2-positive breast cancer with brain metastases have no effective therapy and have a high mortality rate (10 deaths per 100,000 people from breast cancer.
- Tukysa is a small molecule oral tyrosine kinase inhibitor (TKI) with excellent target selectivity for HER2.
- BTD breakthrough therapy designation
- the drug also obtained fast track designation and orphan drug designation in 2017.
- trastuzumab and capecitabine for the treatment of patients with locally advanced, unresectable or trastuzumab, pertuzumab, T-DM1 (ado-trastuzumab emtansine) previously Patients with metastatic (including those with brain metastases) HER2-positive breast cancer.
- the present application provides a compound as a BTK inhibitor or a HER2 inhibitor and a preparation method and use thereof.
- the compound provided by the present invention can be used as a BTK protein kinase inhibitor or a HER2 protein kinase inhibitor, and has higher Inhibitory activity, etc.
- the present invention provides a compound having the structure shown in formula I or a tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, which is pharmaceutically acceptable.
- a 1 , A 2 , A 3 , A 4 , A 5 , and A 6 are independently selected from CR 5 or nitrogen (N); and A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 are among at least one of them is N;
- M is selected from substituted or unsubstituted saturated hydrocarbon group or heterosaturated hydrocarbon group, substituted or unsubstituted unsaturated cyclic group or heterocyclic group, substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl;
- the substituted groups are independently selected from aryl or heteroaryl substituted by any group, alkyl or heteroalkyl, cycloalkyl or heterocycloalkyl, unsaturated cyclic or heterocyclic, phenoloxy , halogen, hydroxyl, cyano, amino, ester, nitro, mercapto, amide, sulfonyl, phosphoryl, alkyl phosphoryl, alkyl sulfone, alkyl sulfoxide; further, the substitution The group of is aryl or heteroaryl substituted by any group, more preferably phenyl substituted by any group;
- Q is selected from CR 10 R 11 , NR 12 , oxygen (O), sulfur (S), S(O), S(O) 2 ;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 are each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted Cycloalkyl or heterocycloalkyl, substituted or unsubstituted unsaturated cyclic or heterocyclic, substituted or unsubstituted aryl or heteroaryl, hydroxyl, cyano, amino, ester, nitro, mercapto, Amido, sulfonyl, phosphoryl, alkyl oxyphosphorus, alkyl sulfone, alkyl sulfoxide; or R 3 , R 4 together with the carbon atoms to which they are attached form a substituted or unsubstituted C3-C10 cycloalkyl group or heterocycloalkyl; the substituted substituent is selected from halogen, hydroxyl, cyan
- n is selected from an integer from 0 to 3.
- the compounds described in the present invention are in any form with the structure of formula I, including tautomers, mesomers, racemates, enantiomers, diastereomers or their mixture forms, pharmaceutical above acceptable hydrates, solvates or salts, etc.
- substitution from is generally a juxtaposition of or.
- the position of R 2 is not limited, preferably at the para position of R 1 .
- the substitution can be mono-substitution or multi-substitution (eg, di-substitution, tri-substitution), and the specific substitution position is not particularly limited.
- Said unsubstituted saturated hydrocarbon group includes unsubstituted alkyl group and unsubstituted cycloalkyl group; said heterocyclic group, heteroaryl group and other groups are wherein one or more carbon atoms can be replaced by heteroatoms,
- the atoms are atoms other than carbon (C), oxygen, sulfur, nitrogen, phosphorus (P), and the like.
- the above-mentioned halogen includes fluorine (F), chlorine (Cl), bromine (Br) and the like, and is preferably fluorine or chlorine.
- the above-mentioned "C3-C10" is an integer whose number of carbon atoms is selected from 3 to 10, and similar expressions below will not be repeated.
- the bridge atom is connected to the ring system formed by chemical bonds (as shown in the following formula), which means that the bridge atom can be connected to any connectable C atom on the ring, which can form any spiro ring or bridge ring structure compound.
- the following formula indicates that the bridge atom Q can be connected to any C atom on the six-membered ring that can be connected to the bridge atom, that is, it is connected to the same C atom to form a spiro compound, for example, the bridge atom is connected to the No. 2 C atom or They are all connected with C atom No. 3, etc.; they are connected with different C atoms to form bridged ring compounds, such as bridge atoms are connected with C atoms No. 1 and No. 4 or C atoms No. 2 and No. 4 respectively, etc.;
- the compound has the structure shown in formula II or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, and is pharmaceutically acceptable.
- R 1 is selected from hydrogen, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 heteroalkane base, substituted or unsubstituted C3-C6 heterocycloalkyl; further, R 1 is selected from hydrogen, amino, methyl, ethyl, methoxy, cyano, trifluoromethyl, isopropyl, cyclopropyl base; further, R 1 is selected from hydrogen (H), amino (NH 2 ), methyl (CH 3 );
- R 2 is selected from hydrogen, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, Substituted or unsubstituted C3-C6 heterocycloalkyl; further, R 2 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, cyano, trifluoromethyl, isopropyl, cyclopropyl; further, R 2 is selected from hydrogen, chlorine, methyl;
- R 3 , R 4 are selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3 -C6 heterocycloalkyl; or R 3 and R 4 together with the carbon atoms to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl or a heterocycloalkyl containing N and O atoms;
- R 3 , R 4 are selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl or R 3 , R 4 and the carbon atoms to which they are attached together form cyclopropyl, azetidine, aza Cyclopentyl, azacyclohexyl, oxetanyl, oxolane, oxhexyl;
- R 6 is selected from hydrogen, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, Substituted or unsubstituted C3-C6 heterocycloalkyl; further, R 6 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy; Further, R 6 is selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl, methoxy, trifluoromethoxy, difluoromethoxy; further R 6 is hydrogen or fluorine.
- R 7 is selected from substituted or unsubstituted aryl, substituted or unsubstituted pyridyl, wherein the substituted substituent is independently selected from halogen, hydroxyl, amino, cyano, alkyl, heteroalkyl, cycloalkane further, the substituents are independently selected from fluorine, chlorine, bromine, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3 -C6 heterocycloalkyl; further, the substituents are independently selected from fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, deuterium Substituted methoxy, cyclopropyl, cyclopropylmethoxy, ethyl, isopropyl, isobutyl; wherein the number of the substituents is an integer between 0-5;
- X is selected from and other acceptable linking groups.
- R 9 and R 13 are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl; R 9 and R 13 and their connected carbon atoms together form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted C3-C6 heterocycloalkyl containing N or O; further, independently selected from Hydrogen, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, isobutyl, R 9 and R 13 and their attached carbon atoms together form cyclopropyl, more Further, it is selected from hydrogen, fluorine, deuterium, chlorine, methyl, hydroxyl, and amino
- the compounds have the structures shown in Formula III and Formula IV, or their tautomers, mesomers, racemates, enantiomers, and diastereomers Forms or mixtures thereof, pharmaceutically acceptable hydrates, solvates or salts:
- R 1 , R 2 , R 3 , R 4 , R 6 , and X are as described above; m, n, and n1 are also as described above; for example, X is Wait.
- n2 is selected from 0, 1, 2, 3, 4;
- R 8 is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl; further, R 8 is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl; further, the substituents are independently selected from hydrogen, fluorine, chlorine , bromine, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, deuterated methoxy, cyclopropyl, cyclopropylmethoxy, ethyl, isopropyl, Isobutyl; wherein the number of the substituents is an integer between 0-5 (including the endpoint); multiple substituents can be the same or different; in formula IV, the connection position of the substituted or unsubstit
- the N-containing fused ring in formula II-IV can be used instead, the single bonds at both ends are connecting bonds.
- the single bond with a curved line represents a connecting bond.
- R 1 is amino
- R 2 is hydrogen or chlorine
- R 6 is hydrogen or mono-substituted fluorine
- R 7 is substituted or unsubstituted phenyl or pyridyl
- X the main structure of an ether or an amide and the amide nitrogen is connected to R 7.
- n is 0 or 1
- m is 0 or 2
- R 3 and R 4 are both hydrogen, methyl or cyclopropyl with the carbon atom to which they are attached.
- the structure of the compound described in this application is selected from one of the following (wherein, the one with a single bond at one end is a methyl group, as shown in formula 5 of compound 5); more preferably formula 2, formula 5, formula 34, formula 42, formula 89, formula 100, formula 101, formula 103, formula 106, formula 109, formula 111, formula 114, formula 116, formula 118, formula 121, formula 125, formula 130, formula 145, formula 146, formula 152, These compounds of formula 155 have better properties:
- the present invention provides a pharmaceutical composition, the active ingredient of which is selected from one of the aforementioned compounds or their stereoisomers, solvates, hydrates, pharmaceutically acceptable salts or co-crystals or a combination of two or more.
- the present invention has no particular limitation on the formulation type and the like of the pharmaceutical composition.
- the present invention provides the use of the aforementioned compound or its stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal in the preparation of a protein kinase inhibitor; further, the kinase inhibitor is BTK inhibitors or HER2 inhibitors.
- the present invention provides the use of the aforementioned compound or its stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal in the preparation of a medicament for treating diseases caused by overexpression of BTK kinase or HER2 kinase .
- the present invention provides the aforementioned compounds or their stereoisomers, solvates, hydrates, pharmaceutically acceptable salts or co-crystals in the preparation for the treatment of autoimmune diseases, inflammatory diseases, thromboembolic diseases, allergies Use in the medicament of any one or more of , infectious diseases, proliferative disorders and cancer.
- the disease can be selected from: arthritis, rheumatoid arthritis, urticaria, vitiligo, organ transplant rejection, ulcerative colitis, Crohn's disease, dermatitis, asthma, Sjögren's syndrome, systemic lupus erythematosus , multiple sclerosis, idiopathic thrombocytopenic purpura, rash, anti-neutrophil cytoplasmic antibody vasculitis, pemphigus, pemphigus vulgaris, chronic obstructive pulmonary disease, psoriasis; cell lymphoma, ovarian cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, hepatocellular carcinoma, gastric cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, Melanoma, bladder cancer, biliary tract cancer, kidney cancer, pancreatic cancer, lymphoma, hair
- ARQ-531 In the prior art, the inhibitory activity of ARQ-531 still needs to be improved, and its inhibitory activity on TMD8, REC-1 and other cells is poor, resulting in problems such as excessive clinical dose and high side effects. In addition, ARQ-531 has poor selectivity and high inhibitory activity on TEC and EGFR, which can easily lead to side effects such as bleeding, diarrhea, and eczema. Furthermore, its pharmacokinetics are not ideal. Preclinical studies have shown that PK In the experiment, the bioavailability was only 38%. That is, ARQ-531 has great room for improvement in terms of inhibitory activity, selectivity, and pharmacokinetics.
- a first-generation irreversible BTK inhibitor (Tirabrutinib) has been approved for the treatment of this disease in foreign countries, but the drug has weak activity on BTK protein, high clinical dose (480mg once a day), obvious side effects, poor patient compliance, and There is a risk of developing drug resistance due to the C481S mutation after taking it for a period of time. There are two main reasons for the high clinical dose of the drug. First, the activity of the compound is weak, and more importantly, the drug has a low blood-brain barrier permeability, and a larger dose is required to achieve the drug that penetrates the blood-brain barrier. effective concentration. Tirabrutinib has great room for improvement in terms of inhibitory activity, pharmacokinetics, and brain penetration rate.
- Tucatinib is a small molecule oral tyrosine kinase inhibitor (TKI) with excellent target selectivity for HER2.
- BTD breakthrough therapy designation
- the drug also obtained fast track designation and orphan drug designation in 2017.
- trastuzumab and capecitabine for the treatment of patients with locally advanced, unresectable or trastuzumab, pertuzumab, T-DM1 (ado-trastuzumab emtansine) previously Metastatic (including with brain metastases) HER2-positive breast cancer patients was approved by the U.S. Food and Drug Administration (FDA) on April 17, 2020.
- FDA U.S. Food and Drug Administration
- the compound powder can be dissolved in 100% DMSO to prepare a 10 mM stock solution; cryopreserved in the dark at -20 degrees.
- test compounds were tested at a concentration of 1 ⁇ M, diluted to 100-fold final concentration in 100% DMSO solution in 384source plates, and compounds were diluted 3-fold to 10 concentrations.
- experiments such as liver microsome stability, rat PK, rat brain penetration rate, and pharmacodynamic model were also carried out by using the compounds in the examples of the present invention.
- the compound of the present invention Compared with the existing clinical drug (ARQ-531), the compound of the present invention, as a BTK protein kinase inhibitor, has advantages in BTK, BTK (C481S) inhibitory activity, liver microsome stability, rat pharmacokinetics, and toxicity. .
- the compound of the present invention as a BTK protein kinase inhibitor, has the advantages of BTK, BTK (C481S) inhibitory activity, cell activity, liver microsome stability, rat pharmacokinetics, rat blood-brain barrier. It has advantages in terms of transmittance and so on.
- the HER2 inhibitor compound of the present invention is comparable to the existing marketed drug Tucatinib in terms of HER2 inhibitory activity, BT474 cell activity and NCI-N87 cell activity; it is significantly better than the rat pharmacokinetics and rat blood-brain barrier permeability. Tucatinib.
- a number of target compounds are designed and synthesized.
- the specific preparation process can be shown in the following formula.
- Intermediate A also known as boronic acid or boronic acid ester compound shown in The bromide shown in the formula
- intermediate C the intermediate shown in formula C
- intermediate C is prepared by coupling commercially available boronic acid A or self-made boronic acid ester A and self-made bromide B under palladium catalysis, and intermediate C is deprotected to obtain the example compound.
- the compound of the present invention has obvious improvement in the inhibitory activity of BTK and BTK(C481S), the stability of liver microsomes and the pharmacokinetics in rats.
- the embodiment of the present invention provides an intermediate compound for preparing the aforementioned BTK inhibitor or HER2 inhibitor, which has the following structure:
- R 1 , R 2 , R 3 , R 4 , m, n are as described above; for example:
- the embodiment of the present invention provides another intermediate compound for preparing the aforementioned BTK inhibitor or HER2 inhibitor, which has the following structure; further, the following structure compound can be used in the preparation of blood-brain barrier permeable drugs:
- Fig. 1 is the test result of drug effect model of some compounds of the present invention TMD8;
- Fig. 2 is the test result of drug effect model of some compounds of the present invention TMD8;
- Fig. 3 is the test result of drug effect model of some compounds of the present invention DOHH-2-Luc in brain tumor;
- Figure 4 is a fluorescent photo of the test results of the drug effect model of some compounds of the present invention DOHH-2-Luc in the brain tumor.
- the structures of the compounds were determined by mass spectrometry (MS) or nuclear magnetic resonance ( 1 H NMR) equipment.
- room temperature refers to between 10°C and 25°C.
- the chemical abbreviations have the following meanings:
- DMF N,N-dimethylformamide
- DIEA N,N-diisopropylethylamine
- HATU O-(7-azabenzotriazol-1-yl)-N,N,N';-tetramethylurea hexafluorophosphate
- DCM dichloromethane
- TEA triethylamine
- TBDPSCl lithium bistrimethylsilylamide
- 9-BBN 9-borabicyclo[3.3.1]nonane
- Dess-Martin Dess-Martin oxidant
- DME ethylene glycol dimethyl ether
- TosMIC p-methylbenzenesulfonylmethylisonitrile
- t-BuOK potassium tert-butoxide
- Dibal-H diisobutylaluminum hydride
- THF tetrahydrofuran
- NBS N-bromosuccinimide
- TBAF tetrabutylammonium fluoride
- DMSO dimethyl sulfoxide
- LDA lithium diisopropylamide
- HBTU benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate
- NMP N-methylpyrrolidone
- BAST bis(2-methoxyethyl)aminosulfur trifluoride
- PMDTA pentamethyldiethylenetriamine
- DMA N,N-dimethylacetamide
- dppf 1,1'-bis(diphenylphosphino)ferrocene
- Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium;
- TsCl 4-toluenesulfonyl chloride
- DMAP 4-dimethylaminopyridine
- PDC pyridine dichromate
- DIAD diisopropyl azodicarboxylate
- NCS N-chlorosuccinimide
- reaction liquid was replaced with nitrogen, and then heated to 140° C. to stir the reaction overnight.
- reaction system was cooled to room temperature, water was added, extracted three times with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, evaporated in vacuo, and purified by silica gel column to obtain 800 mg of product A-2-3, yield: 38%.
- reaction solution was stirred at room temperature and reacted overnight.
- the reaction solution was filtered with suction, and the filtrate was added to silica gel and mixed with a sample, and then purified by silica gel column to obtain 600 mg of product A-3-3, yield: 43%.
- the method for synthesizing A-3 refers to the method for synthesizing A-2 from A-2-3.
- the synthesis method of A-4 refers to the synthesis method of A-2 from A-2-3.
- the synthesis method of A-13 refers to the synthesis method of A-2 from A-2-1.
- the synthesis method of A-14 refers to the synthesis method of A-2 from A-2-2.
- the synthesis method of A-15 refers to the synthesis method of A-2 from A-2-3.
- the synthesis method of A-16 refers to the synthesis method of A-13 from A-13-1.
- the synthesis method of A-17 refers to the synthesis method of A-2 from A-2-3.
- the synthesis method of A-18-3 refers to the synthesis method of A-15-1 from A-2-3.
- the synthesis method of A-18 refers to the synthesis method of A-2 from A-2-2.
- reaction solution was quenched by adding saturated aqueous ammonium chloride solution, extracted twice with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered and spin-dried to obtain 535 mg of product A-21-1, yield : 100%.
- the product was used in the next step without further purification.
- the synthesis method of A-21 refers to the synthesis method of A-2 from A-2-3.
- the synthesis method of A-26-2 refers to the synthesis method of A-18-2 from A-18-1.
- reaction solution was quenched by adding water, extracted twice with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous Na 2 SO 4 , evaporated in vacuo and purified by silica gel column to obtain 219 mg of product A-26 in a yield of 219 mg. : 52%.
- reaction solution was quenched by adding saturated aqueous ammonium chloride solution, extracted twice with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, evaporated in vacuo, and purified by silica gel column to obtain 630 mg of product A-27-2, yield: 68 %.
- the synthesis method of A-27 refers to the synthesis method of A-2 from A-2-3.
- the synthesis method of A-28 refers to the synthesis method of A-2 from A-2-3.
- reaction solution was stirred at room temperature for 1 hour, the reaction solution was quenched by adding saturated aqueous ammonium chloride solution, extracted twice with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, evaporated in vacuo, and purified by silica gel column to obtain 612 mg of product A-29-2, yield: 50%.
- the method for synthesizing A-29 refers to the method for synthesizing A-27 from A-21-1.
- the synthesis method of A-30 refers to the synthesis method of A-2 from A-2-3.
- the method for synthesizing A-31 refers to the method for synthesizing A-2 from A-2-3.
- the compound p-bromoiodobenzene (876 mg, 3.10 mmol) and tetrahydrofuran (10 mL) were added to the reaction flask, the reaction solution was replaced with nitrogen, and cooled to -70°C in a dry ice/ethanol bath.
- To the reaction solution was added dropwise n-butyllithium (2.5M, 1.24 mL, 3.10 mmol), and after stirring for 30 minutes, a solution of A-34-2 (600 mg, 2.81 mmol) in tetrahydrofuran (3 mL) was added dropwise to the reaction solution. After dropping, the reaction solution was slowly warmed to room temperature for 1 hour.
- reaction solution was quenched by adding water, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, evaporated in vacuo, and purified by silica gel column to obtain 360 mg of product A-34-3, yield: 41%.
- the synthesis method of A-34 refers to the synthesis method of A-2 from A-2-3.
- the synthesis method of A-35-2 refers to the synthesis method of A-34-3 from A-34-2.
- the synthesis method of A-35-3 refers to the synthesis method of A-29-3 from A-29-2.
- the synthesis method of A-35 refers to the synthesis method of A-2 from A-2-3.
- reaction solution was heated to 80°C and reacted for 5 hours.
- the reaction solution was cooled, poured into water, extracted twice with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated in vacuo, and purified by preparative silica gel plate to obtain 62 mg of product A-40, yield : 60%.
- the method for synthesizing A-48 refers to the method for synthesizing A-2 from A-2-3.
- the synthesis method of A-54 refers to the synthesis method of A-2 from A-2-3.
- reaction solution was quenched with dilute hydrochloric acid, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, evaporated in vacuo, and purified by silica gel column to obtain 430 mg of product A-55-3, yield: 41%.
- the synthesis method of A-55 refers to the synthesis method of A-2 from A-2-1.
- the method for synthesizing A-56 refers to the method for synthesizing A-55 from A-55-2.
- the synthesis method of A-60 refers to the synthesis method of A-2 from A-2-3.
- the organic phase was extracted 3 times with an aqueous sodium carbonate solution, the aqueous phase was adjusted to pH 3 with dilute hydrochloric acid, the precipitated solid was filtered off with suction, washed with water, the filter cake was collected, and dried in vacuo to obtain 2.0 g of product A-64-2, yield: 81%.
- the product was used in the next step without further purification.
- the synthesis method of A-64-3 refers to the synthesis method of A-2 from A-2-3.
- the synthesis method of A-68 refers to the synthesis method of A-2 from A-2-3.
- the synthesis method of A-69 refers to the synthesis method of A-1 from A-1-1 and A-1-2.
- the synthesis method of A-70 refers to the synthesis method of A-2 from A-2-3.
- the synthesis method of A-71 refers to the synthesis method of A-54 from A-54-1.
- the synthesis method of A-73 refers to the synthesis method of A-2 from A-2-3.
- reaction solution was quenched with dilute hydrochloric acid, extracted three times with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to obtain 1.00 g of product A-74-2, yield: 74%.
- the product was used in the next step without further purification.
- reaction solution was stirred at room temperature overnight.
- the reaction solution was poured into water, extracted 6 times with ethyl acetate, the organic phases were combined, evaporated in vacuo, and purified by silica gel column to obtain 254 mg of product A-74-4, yield: 42%.
- the synthesis method of A-74 refers to the synthesis method of A-17 from A-17-1.
- the synthesis method of A-75-1 refers to the synthesis method of A-34-2 from A-34-1.
- reaction solution was quenched with dilute hydrochloric acid, extracted twice with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated in vacuo to obtain 538 mg of product A-75-2, yield: 100%.
- the product was used in the next step without further purification.
- the synthesis method of A-75 refers to the synthesis method of A-73 from A-21-1.
- the synthesis method of A-76 refers to the synthesis method of A-2 from A-2-3.
- the synthesis method of A-77-3 refers to the synthesis method of A-34-3 from A-34-1.
- the synthesis method of A-77 refers to the synthesis method of A-73 from A-21-1.
- the synthesis method of A-78-2 refers to the synthesis method of A-34-2 from A-34-1.
- reaction liquid was replaced with nitrogen, and heated to 110° C. to react overnight.
- the reaction solution was cooled, poured into water, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, evaporated in vacuo, and purified by silica gel column to obtain 473 mg of product A-78-3, yield: 100%.
- the synthesis method of A-78-4 refers to the synthesis method of A-34-3 from A-34-2.
- the synthesis method of A-78 refers to the synthesis method of A-73 from A-21-1.
- Dichloromethane (5 mL) was added to the reaction flask, nitrogen was replaced, the dry ice/acetonitrile bath was cooled to -40°C, titanium tetrachloride (1453 mg, 7.66 mmol) was added, and then dimethylzinc in toluene solution (1M) was slowly added dropwise. , 7.7 mL, 7.7 mmol), the addition was completed, and the reaction was incubated for 30 minutes.
- a solution of compound A-21-1 500 mg, 1.91 mmol) in dichloromethane (3 mL) was added dropwise to the reaction solution, the addition was completed, the reaction was incubated for 1 hour, and then slowly warmed to room temperature and stirred overnight.
- reaction solution was quenched by adding water, extracted twice with dichloromethane, the organic phases were combined, washed with water, evaporated in vacuo, and purified by silica gel column to obtain 326 mg of product A-82-1, yield: 62%.
- the method for synthesizing A-82 refers to the method for synthesizing A-2 from A-2-3.
- reaction flask To the reaction flask was added p-bromoiodobenzene (1.71 g, 6.03 mmol) and tetrahydrofuran (15 mL), nitrogen was replaced, the dry ice/ethanol bath was cooled to -70 ° C, and then n-butyllithium (2.5 M, 2.4 mL, 6.03 mmol), the addition was completed, and the reaction was incubated for 30 minutes.
- A-101-1 (1.00 g, 5.74 mmol) was weighed and dissolved in tetrahydrofuran (5 mL), and added dropwise to the reaction solution. After 10 minutes, the reaction solution was slowly warmed to room temperature.
- reaction solution was quenched by adding water, extracted twice with ethyl acetate, the organic phases were combined, washed with water, evaporated in vacuo, and purified by silica gel column to obtain 1.4 g of product A-101-2, yield: 73%.
- the synthesis method of A-101 refers to the synthesis method of A-2 from A-2-3.
- A-101-2 550 mg, 1.66 mmol
- dichloromethane 6 mL
- DAST 402 mg, 2.49 mmol
- the reaction solution was quenched by adding aqueous sodium bicarbonate solution, extracted twice with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, evaporated in vacuo, and purified by silica gel preparation plate to obtain 410 mg of product A-102, yield: 74%.
- the synthesis method of A-102 refers to the synthesis method of A-2 from A-2-3.
- A-103-1 500 mg, 1.50 mmol
- aqueous hydrobromic acid 5 mL
- sodium nitrite 645 mg, 9.35 mmol
- CuBr 2.69 g, 18.75 mmol
- hydrobromic acid aqueous solution 5 mL
- the reaction solution was diluted with water, extracted twice with ethyl acetate, the organic phases were combined, washed with water, evaporated in vacuo, and purified by silica gel column to obtain 620 mg of product A-103-2, yield: 89%.
- the method for synthesizing A-103 refers to the method for synthesizing A-2 from A-2-3.
- reaction solution was poured into water, the reaction solution was extracted twice with ethyl acetate, combined, washed twice with water, then washed with saturated NaCl solution, and finally dried with anhydrous Na 2 SO 4 , and directly evaporated in vacuo to obtain 6.68 g of product B-1-2, the product was used in the next step without purification.
- reaction solution was poured into water, extracted twice with ethyl acetate, combined, washed twice with water, washed with saturated NaCl solution, directly added with silica gel and mixed with the sample, and then purified by silica gel column to obtain 6.49 g of product B-1-3. Step yield: 100%.
- reaction solution was poured into saturated NH 4 Cl solution (350 mL), extracted twice with ethyl acetate, combined, added with silica gel to mix samples, and then purified by silica gel column to obtain 2.27 g of product B-1-5 (TLC showed two spots) , Yield: 34%.
- reaction solution was poured into water, extracted twice with ethyl acetate, combined, washed twice with water, then washed with saturated NaCl solution, added with silica gel to mix samples, and then purified by silica gel column to obtain 1.94 g of product B-1-8 ( TLC shows two dots). Yield: 78%.
- reaction solution was poured into NaHCO 3 solution (4.5g NaHCO 3 /30mL H 2 O) to quench, extracted twice with ethyl acetate, combined, then washed twice with water, then with saturated NaCl solution, and finally with anhydrous Na Drying over 2 SO 4 gave 680 mg of product B-1-9 after direct vacuum evaporation (TLC showed two spots). Yield: 89.0%.
- B-1-B is prepared by reacting B-1-10-B with ammonia water by the method of synthesizing B-1-A.
- reaction solution was cooled to room temperature, added to ice water, adjusted to pH 3 with concentrated HCl, extracted twice with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound B- 2-2 was a colorless oil (37.6 g, 83%).
- reaction solution was added to saturated NaHCO 3 solution, extracted with ethyl acetate, the organic phases were combined, the organic phases were back-washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of compound B-2-16, which was not further purification.
- B-3-1 was prepared by referring to the method of literature (Angew.Chem.Int.Ed.2020,59,7161-7167).
- the method for preparing B-3 from B-3-3 refers to the method for preparing B-2 from B-2-14.
- reaction solution was added to water, adjusted with dilute hydrochloric acid, extracted twice with ethyl acetate, the organic phases were combined, washed with water, washed with saturated NaCl solution, concentrated to dryness under reduced pressure, and purified by silica gel column to obtain compound B-5-1 (550 mg, 78%) .
- Compound B-6-1 was oxidized with PDC (refer to the synthesis of B-2-14 from B-2-13) to prepare B-6-2.
- reaction solution was poured into aqueous ammonium chloride solution to quench, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, concentrated to dryness under reduced pressure, and purified by silica gel preparation plate to obtain 22 mg of compound B-6-4 in a yield of 22 mg. : 28%.
- the method for preparing B-6 from B-6-4 refers to the method for preparing B-2 from B-2-17.
- the method for preparing B-7 from B-7-1 refers to the method for preparing B-2 from B-2-17.
- the method for preparing B-8 from B-8-2 refers to the method for preparing B-1-A(B) from B-1-3.
- B-9-2 is condensed with B-1-7, closed, and brominated to obtain B-9.
- the specific method refers to the method for preparing B-1-10-A(B) from B-1-7.
- B-10-1 is prepared by adding bromine on NBS and then ammonolysis to prepare B-10.
- the specific method refers to the method for preparing B-1-A(B) from B-1-9.
- reaction flask To the reaction flask was added compound B-1-B (205 mg, 0.362 mmol), A-1 (161 mg, 0.471 mmol), Na 2 CO 3 (77 mg, 0.724 mmol), PdCl 2 (dppf) (20 mg), dioxygen Hexacyclic (6 mL) and water (2 mL) were replaced with nitrogen, and the mixture was heated to 95° C. for 2.5 h. TLC showed that the reaction was complete. The reaction solution was diluted with ethyl acetate, directly added with silica gel to mix samples, and then purified by silica gel column to obtain 182 mg of product C-1-B, yield: 72%.
- the structure of the product was characterized by nuclear magnetic resonance and mass spectrometry, and the results are as follows:
- 1-A was prepared using A-1 and B-1-A by the method for synthesizing 1-B.
- the structure of the product was characterized by nuclear magnetic resonance and mass spectrometry, and the results are as follows:
- 2-A was prepared by reacting A-5 with B-1-A by the method of synthesizing 1-B.
- the structure of the product was characterized by nuclear magnetic resonance and mass spectrometry, and the results are as follows:
- Compound 2-A was resolved by SFC to give 2-A-P1 (first peak) and 2-A-P2 (last peak).
- 2-B was prepared by reacting A-5 with B-1-B by the method of synthesizing 1-B.
- the structure of the product was characterized by nuclear magnetic resonance and mass spectrometry, and the results are as follows:
- Compound 1-B was prepared by method 3, using Compound different intermediate system having 4 to 119, with which it is shown in an intermediate number, structural formula, the MS and 1 H-NMR data shown in Table 13.
- the structure of the product was characterized by nuclear magnetic resonance and mass spectrometry, and the results are as follows:
- Compound 1-B was prepared by method 3, using Compound different intermediate system 121 to 138, with its intermediate number, structural formula, the MS and 1 H-NMR data shown in Table 14.
- Test Example 1 In vitro BTK Inhibition Kinase Activity Test
- test compound concentration gradient the test compound concentration was 1 ⁇ M, diluted in 384source plate into 100-fold final concentration 100% DMSO solution, 3-fold diluted compound, 10 concentrations.
- dispenser Echo 550 to transfer 250nL 100-fold final concentration of compound to the destination plate OptiPlate-384F;
- Conversion%_sample is the conversion rate reading of the sample
- Conversion%_min the mean value of the negative control wells, representing the conversion rate readings of the wells without enzymatic activity
- Conversion%_max the mean ratio of the positive control wells, representing the conversion rate readings of the wells without compound inhibition .
- IC50 A ⁇ 5nM; 5nM ⁇ B ⁇ 20nM; 20nM ⁇ C ⁇ 100nM; 100nM ⁇ D ⁇ 1000nM; E>1000nM.
- T0, T5, T10, T20, T30, T60 and NCF60 samples To the wells of T0, T5, T10, T20, T30, T60 and NCF60 samples, add 10 ⁇ L test or reference working solution and 80 ⁇ L microsomal working solution (liver microsomal protein concentration is 0.5 mg/mL), Add only the microsomal working solution to the Blank60 well, and then place the samples Blank60, T5, T10, T20, T30 and T60 except for T0 and NCF60 in a 37°C water bath and pre-incubate for about 10 minutes;
- test compound was administered orally (10 mg/kg, 3 per group) to SD rats for pharmacokinetic study.
- the test compound was dissolved in 5% DMSO+10% solutol+85% saline, And after vortexing for 1-2min, ultrasonic for 5-10min, it was prepared into a colorless, transparent and clear dosing solution. Animals were fasted overnight before oral dosing and resumed feeding 4 hours after dosing. After oral administration of SD rats, the pharmacokinetic samples were collected through orbital blood collection. Three whole blood samples were collected at each time point, and the collection volume was about 0.2-0.3 mL.
- the blood samples were placed on ice immediately after collection, and the plasma was centrifuged within 15 minutes (centrifugation conditions: 8000 rpm, 1 minute, room temperature). The collected plasma was stored at –20°C until analysis. Take 20 ⁇ L of plasma sample into a 1.6 mL 96-well deep-well plate, add 200 ⁇ L of working internal standard solution (without adding internal standard and add the same volume of solvent), vortex for 1 min, centrifuge at 5800 rpm for 10 min, take 100 ⁇ L The supernatant was added to a 96-well injection plate and analyzed by LC-MS/MS injection.
- Cells were cultured in 1640 medium, 10% inactivated FBS and 1% double antibody were added, and cultured at 37°C and 5% CO 2 .
- the cells are routinely cultured until the cell saturation is 80%-90%, and the cells are harvested when the number reaches the requirement.
- the compounds to be tested were diluted with DMSO to prepare a stock solution with a final concentration of 20 mM for later use.
- Blank control wells were cells plus 0.5% DMSO, as high reading control wells.
- IC 50 was calculated with GraphPad Prism 8 software , and the IC 50 (half inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula. The results are as follows:
- Table 18 Inhibitory activity of some compounds of the present invention on TMD8 cell proliferation
- Table 19 Inhibitory activity of some compounds of the present invention on DOHH2 cell proliferation
- Table 20 Inhibitory activity of some compounds of the present invention on BT474 cell proliferation
- Table 21 Proliferation inhibitory activity of some compounds of the present invention on NCI-N87 cells
- 2 ⁇ kinase substrate and ATP mixture with 1 ⁇ kinase reaction buffer, 2 ⁇ Her2 kinase substrate is 2 ⁇ M TK-substrate-biotin and 4 ⁇ M ATP.
- Table 22 HER2 kinase inhibitory activity of some compounds of the present invention
- the pharmacokinetics of each test compound was studied by single oral administration in SD rats at a dose of 10 mg/kg, 9 animals in each group.
- the test compound was dissolved in 5% DMSO+10% solutol+85% saline, vortexed for 1-2 min, and sonicated for 5-10 min to prepare a colorless, transparent and clear dosing solution. Animals were fasted overnight before administration, and 3 SD rats were taken 1h, 2h, and 4h after administration, and about 0.2-0.3 mL of blood was collected from the orbit. The blood samples were placed on ice immediately after collection, and the plasma was centrifuged within 15 minutes (centrifugation conditions: 8000 rpm, 1 minute, room temperature).
- the collected plasma was stored at –20°C until analysis.
- the cerebrospinal fluid and brain tissue were collected immediately after blood collection. Cerebrospinal fluid was extracted by dural puncture with a micro-injector under direct vision. After chloral hydrate anesthesia, the head was fixed, the back hair was cut off, and a transverse incision (2cm) was cut at the connection line between the two ears. The muscle layer of the neck and skull base was scraped open to expose the foramen magnum. With a 100 ⁇ l microinjector, about 100 ⁇ l of cerebrospinal fluid was taken and stored at –20°C before analysis.
- the rats were then killed immediately, decapitated, and the brain tissue was dissected out, the surface capillaries were stripped, weighed, and 3 times the volume of ice-cold physiological saline was added, homogenized by a homogenizer for 1 min, and stored at –20°C before analysis.
- a homogenizer for 1 min, and stored at –20°C before analysis.
- Fig. 1 and Fig. 2 The results are shown in Fig. 1 and Fig. 2; according to Fig. 1, according to the pharmacodynamic model of subcutaneously transplanted tumor in TMD8 mice, under the same 10 mg/kg dose condition, the two compounds of Example 118 and Example 89-P1 were used for tumorigenic effects. The inhibitory effect is significantly better than that of the clinical phase II drug ARQ-531 and the marketed drug ibrutinib. According to Figure 2, the pharmacodynamic model of TMD8 mice subcutaneously transplanted tumor, under the same 20mg/kg dose condition,
- Example 111-P1 and Example 125 on tumor were significantly better than that of Tirabrutinib.
- TGI of Example 111-P1 was 93%, which was nearly 2 times that of Tirabrutinib, almost completely controlled the growth of the tumor, and the drug efficacy advantage was very obvious.
- the brain locator uses the brain locator to locate at a distance of about 0.5-1.0mm above the coronal line and about 2mm to the right of the sagittal line and drill a hole with a 1mL syringe needle, insert the micro-injector vertically to a depth of 3mm at the positioning point, and slowly inject (about 1 minute) DOHH-2-luc tumor cells were suspended in 3 ⁇ 10 5 /2 ⁇ L and the needle was retained for 1 minute. After the needle was withdrawn, the needle hole was quickly sealed with bone wax, and the wound was sutured with a stapler. About the 7th day after tumor inoculation, animals were randomly divided into 5 groups of 5 animals according to their body weight and the optical signal intensity of the tumor site.
- D-luciferin 15mg/mL, 5 ⁇ L/g according to the body weight of the experimental animal
- the animals were subjected to inhalation anesthesia with 1%-2% isoflurane, and 10 minutes after the injection of D-luciferin, IVIS Lumina III Imaging the animals.
- the data were analyzed and processed using the in vivo imaging software Living Image software (Perkin Elmer), and the optical signal intensity within the ROI (regions of interest) of each animal was calculated.
- Figure 4 shows the fluorescence images of all the tested animals after imaging.
- the image represents the tumor size in the brain by color and area size. The redder the color, the larger the tumor. It can be seen from the pictures that at the same dose, Example 111-P1 and Example 125 have very good inhibitory effects on tumors, and there is almost no red area, indicating that the intracerebral tumors of these two groups of animals are very small; while the model group and Tirabrutinib All animals in the group had large red areas, indicating a large tumor.
- the compounds of the present invention as BTK protein kinase inhibitors have the structure of formula I, preferably the structure of formula II; they have strong inhibitory effects on wild-type BTK and mutant BTK (C481S), and have good inhibitory effects.
- Pharmacokinetic properties can be used to prepare drugs for treating diseases caused by overexpression of BTK kinase. Some of these compounds are significantly better than the marketed BTK inhibitors Ibrutinib, Tirabrutinib and ARQ-531 in phase II clinical trials in TMD8 subcutaneous tumor model experiments.
- Some of the compounds of the present invention are obviously superior to the marketed drugs Tirabrutinib and Tucatinib in terms of blood-brain barrier permeability, liver microsome stability, and pharmacokinetics.
- the pharmacodynamics of some compounds were very good, which also verified the brain-penetrating data. It can be used for preparing medicines for treating diseases caused by overexpression of BTK or HER2 kinase, especially brain diseases.
- the aforementioned compounds of the present invention or their stereoisomers, solvates, hydrates, pharmaceutically acceptable salts or co-crystals can be used to prepare and treat autoimmune diseases, inflammatory diseases, thromboembolic diseases, allergies, Drugs for any one or more of infectious diseases, proliferative disorders and cancer are expected to provide new and better treatment options.
Abstract
一种作为BTK抑制剂或HER2抑制剂的化合物及其制备方法与用途,所述化合物具有式II所示结构或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、药学上可接受的水合物、溶剂化物或盐。本发明的BTK蛋白质激酶抑制剂对野生型BTK和突变的BTK(C481S)都有很强的抑制活性,部分化合物具有很高的透脑率;本发明的HER2抑制剂具有较好的HER2激酶抑制活性、很高的血脑屏障透过率;且本发明化合物具有良好的药代动力学性质,有很好的应用前景。
Description
本申请要求于2020年07月15日提交中国专利局、申请号为202010679776.6、发明名称为“一种作为BTK抑制剂的化合物及其制备方法与用途”的中国专利申请的优先权,并且要求于2020年11月25日提交中国专利局、申请号为202011337022.9、发明名称为“一种作为BTK抑制剂的化合物及其制备方法与用途”的中国专利申请的优先权,其全部内容通过引用结合在本申请中。
本发明涉及医药技术领域,特别是涉及一种具有良好透脑性的BTK或HER2蛋白质激酶抑制剂的化合物及其制备方法与用途。
布鲁顿酪氨酸蛋白激酶(BTK)是非受体蛋白酪酸激酶Tec家族的成员,主要表达于多种造血细胞系。Tec家族是人类非受体激酶中仅次于Src家族的第2大家族,其主要成员包括BTK、BMX(etk)、ITK、TEC和TXK(RLK)。在1993年,BTK被确定为人X-连锁无丙种球蛋白血症(X-1inked agammaglobulinemia,XLA)中的缺陷蛋白。BTK是B细胞受体(BCR)信号转导通路的关键调节因子,在B细胞激活、增殖、分化和存活过程中有着重要的作用,与多种B细胞肿瘤及自身免疫性疾病密切相关。
BTK结构中包含5个主要结构域,分别是PH结构域(Pleckstrin homology),TH结构域(Tec homology),SH3结构域(Src homology 3),SH2结构域(Src homology 2)和SHl结构域(Src homology1)。BTK的活化(磷酸化)最初发生在SHl结构域中的活化环中,进一步的活化发生在包含主要自磷酸化位点的SH2及SH3结构域中;这些SH结构域也包含BTK进行核质穿梭所需要的核定位信号(NLS)及核输出序列(NES)。
BTK在B淋巴细胞的生成过程中起着不可替代的作用,其可以通过激活细胞周期正向调控因子和分化因子来控制B细胞的发育、分化,也能通过调节促凋亡和抗凋亡蛋白的表达来控制B细胞的存活和增殖。BTK的持续激活是慢性淋巴细胞白血病(CLL)发展的一个先决条件;BCR-BTK信号传递异常会促进弥漫性大B细胞淋巴瘤(DLBCL)中活化B细胞亚型的存活。BTK功能 获得型突变也已在大肠癌、急性淋巴细胞白血病(ALL)、慢性粒细胞白血病(CML)中得到确证。可见,BTK依赖型通路的异常激活被证明与多种肿瘤的发生发展密切相关。
目前已批准上市的不可逆BTK抑制剂,如伊布替尼(Ibrutinib)、阿卡替尼(acalabrutinib)、赞布替尼(Zanubrutinib),都是可选择性地与BTK的半胱氨酸残基(Cys-481)形成不可逆的共价键结合,抑制BTK活性达到治疗相关疾病的目的。然而,一部分癌症患者会对第一代BTK抑制剂产生耐药,从而出现未满足的新的临床需求。有研究表明,BTK-C481S突变是与此相关的主要耐药机制之一,因此,能够靶向抑制BTK-C481S突变型的药物有望提供新的治疗方案。例如,ARQ-531就是一种口服生物可用的、有效的、可逆的野生型和C481S突变的BTK双重抑制剂;ARQ-531初期临床结果表明了其对C481S突变的BTK患者的有效性。
原发中枢神经系统淋巴瘤(PCNSL)年发病率约为0.47/10万,中国每年有超过1万人患病。经过几十年的治疗发展,截至目前,一线治疗方案以大剂量甲氨蝶呤(high-dose methotrexate,HD-MTX)为基础诱导化疗,实现影像学完全缓解(complete response,CR),全脑放疗(whole-brain radiotherapy,WBRT)作为巩固治疗,此方案中位OS可达30~50个月。但该方案会导致严重神经毒性,且毒性随着病人年龄和放疗剂量增加而增加,表现为记忆力下降、认知功能损伤、步态障碍、痴呆等症状,严重影响病人生活质量。也有研究探讨了自体造血干细胞移植与全脑放疗在PCNSL巩固治疗中的疗效优劣性,结果显示两者并无差异,需指出的是,全脑放疗对于患者的脑功能具有不可逆性的损伤。不论哪种治疗方案,预后都很差。
由于血脑屏障(blood brain barrier,BBB)的存在,常规免疫化疗难以渗透,疗效较差。治疗原发性或继发性CNS侵犯的药物疗效取决于其通过血脑屏障后在大脑中的分布,仅亲脂性分子能被动扩散轻易穿过BBB,常规免疫化疗如利妥昔单抗属于单克隆抗体,分子量较大,难以穿透血脑屏障,故无法发挥全部疗效。
随着PCNSL的发病机制越来越被深入研究,近年来针对BCR通路分子特异性靶向药物的突破性进展给这类患者带来新的治疗选择。Bruton’s酪氨酸激酶(BTK)是一种连接BCR信号通路和NF-κB信号通路的激酶,是治疗 ABC-DLBCL抑制的基本靶点,BTK抑制剂是一种选择性的药物,可直接作用于BCR通路中MYD88和CD79B,而中枢神经系统淋巴瘤中BCR信号通路突变常常是以MYD88和CD79B为主。根据WHO2008分类诊断PCNSL,并且必须要免疫组化的结果,主要标记包括所有的B细胞标志(CD19,CD20,PAX5)、BCL6、MUM1/IRF4和CD10。中枢神经系统恶性肿瘤NCCN指南(2020.V1)中推荐BTKi应用于复发难治PCNSL。
2020年3月,BTK抑制剂Velexbru(Tirabrutinib hydrochloride)在日本获得批准,用于治疗复发性或难治性原发性中枢神经系统淋巴瘤(PCNSL),Velexbru是全球第一个被批准用于治疗复发性或难治性PCNSL的BTK抑制剂。结果显示,经Velexbru治疗后,52.9%的患者得到了有效缓解。Tirabrutinib在复发/难治中枢神经系统淋巴瘤中的I/II期研究,共纳入44例复发/难治性CNSL,第1阶段使用3+3剂量递增设计,接受320和480mg的tirabrutinib每日一次治疗(QD),在28天内评估剂量限制性毒性(DLT);第2阶段在禁食条件下给予480mg tirabrutinib QD;结果显示:与320mg相比,480mg患者的ORR和PFS均更优,ORR:320mg vs 480mg vs 480mg(禁食条件)=60%vs 100%vs 52.9%,PFS:320mg vs 480mg vs 480mg(禁食条件)为2.1vs.11.1vs 5.8个月。但与320mg组相比,480mg(禁食组)的ORR较低可能是由于患者特征的差异造成的。Tirabrutinib各剂量下血浆中药物浓度相当;Tirabrutinib在4个不同时间点,相比320mg,480mg组CSF谷浓度较高,脑脊液浓度随血药浓度的增加而增加;可见中枢神经系统淋巴瘤疗效与BTKi在脑脊液(CSF)中的药物浓度相关。
PCNSL的治疗药物有限,PFS及OS远未达到预期。国外已经有一代不可逆BTK抑制剂(Tirabrutinib)批准用于该病的治疗,但该药物对BTK蛋白活性较弱、临床剂量过高(480mg每天一次)、副作用明显,病人的顺应性较差,且存在服用一段时间后会由于C481S突变而产生耐药的风险。
研究显示,BTK抑制剂还可用于自身免疫性疾病如类风湿性关节炎、多发性硬化症(MS)、银屑病等自身免疫性疾病。其中多发性硬化症的发病原理与脑部的病变有直接的关系。2019年,全球多发性硬化症药物市场规模为250亿美元,预计2027年将达到406.6亿美元,预测期间复合年增长率将为7.1%。临床和经济研究数据显示,MS的年治疗费用为28,000美元。BTK作为B细胞受体信号通路中的一个关键激酶,对B淋巴细胞、巨噬细胞及小胶质细胞 等参与MS病理过程的免疫细胞的发育和功能都很重要。因此,BTK抑制剂有望为MS等自身免疫性疾病的治疗提供新颖的治疗选择。
HER2(人表皮生长因子受体-2)也称ERBB2,位于17号染色体,属于原癌基因。其编码产物HER2蛋白是具有酪氨酸蛋白激酶活性的跨膜蛋白,属于EGFR家族成员之一。它在多种癌症中过度表达,包括乳腺癌、卵巢癌和胃癌等等。HER2介导细胞生长,分化和存活,能促进癌细胞的侵袭性扩散。
大约有15%至20%的乳腺癌是HER2阳性(HER2+)。与HER2阴性癌症相比,HER2+肿瘤更具攻击性,并与较短的生存时间、较差的总体存活率、更高的复发风险以及中枢神经系统疾病(脑转移)有关。大约30%至50%的HER2+乳腺癌患者会随着时间的推移发生脑转移。
2018年GLOBOCAN统计报告显示,全球乳腺癌新增人数接近210万例,发病率为27.5/10万,占所有种类肿瘤发病人数的11.6%。从全球新增发病人数和死亡人数的对比情况来看,乳腺癌是全球女性的第一大癌症杀手,其发病率和死亡率均最高。我国乳腺癌发病率位居女性恶性肿瘤的第一位,高达43/10万。2018年中国乳腺癌新增接近36.8万例,乳癌药金额达400亿元。中国乳腺癌发病率的增速是全球平均增速的两倍(每年增加30余万),在全球排第一。HER2阳性的乳腺癌脑转移患者任无有效疗法,死亡率居高不下(每10万人中有10位死于乳腺癌。
Tukysa(tucatinib)是一种小分子口服酪氨酸激酶抑制剂(TKI),对HER2具有优秀的靶向选择性。2019年曾被FDA授予突破性疗法资格(BTD),除了获得突破性疗法资格,该药物还于2017年获得快速通道资格、孤儿药资格。与曲妥珠单抗和卡培他滨联联用,用于治疗接受过曲妥珠单抗、帕妥珠单抗、T-DM1(ado-trastuzumab emtansine)治疗的局部晚期、不可切除性或转移性(包括伴有脑转移)HER2阳性乳腺癌患者。
发明内容
有鉴于此,本申请提供一种作为BTK抑制剂或HER2抑制剂的化合物及其制备方法与用途,本发明提供的化合物可用作BTK蛋白质激酶抑制剂或HER2蛋白质激酶抑制剂,具有较高的抑制活性等特点。
本发明提供一种化合物,具有式I所示结构或其互变异构体、内消旋体、 外消旋体、对映异构体、非对映异构体或其混合物形式、药学上可接受的水合物、溶剂化物或盐:
其中:A
1、A
2、A
3、A
4、A
5、A
6分别独立选自C-R
5或氮(N);而且A
1、A
2、A
3、A
4、A
5、A
6中至少有一个为N;
M选自取代或非取代的饱和烃基或杂饱和烃基,取代或非取代的不饱和环基或杂环基,取代或非取代的单环、双环或三环芳基或杂芳基;其中所述取代的基团分别独立选自被任意基团取代的芳基或杂芳基、烷基或杂烷基、环烷基或杂环烷基、不饱和环基或杂环基、酚氧基、卤素、羟基、氰基、氨基、酯基、硝基、巯基、酰胺基、磺酰基、磷酰基、烷基氧磷基、烷基砜基、烷基亚砜基;进一步地,所述取代的基团为被任意基团取代的芳基或杂芳基,更优选为被任意基团取代的苯基;
Q选自C-R
10R
11、N-R
12、氧(O)、硫(S)、S(O)、S(O)
2;
R
1、R
2、R
3、R
4、R
5、R
10、R
11、R
12分别独立选自氢、氘、卤素、取代或非取代的烷基或杂烷基、取代或非取代的环烷基或杂环烷基、取代或非取代的不饱和环基或杂环基、取代或非取代的芳基或杂芳基、羟基、氰基、氨基、酯基、硝基、巯基、酰胺基、磺酰基、磷酰基、烷基氧磷基、烷基砜基、烷基亚砜基;或R
3、R
4与其相连的碳原子一起组成取代或非取代的C3-C10环烷基或杂环烷基;所述取代的取代基选自卤素、羟基、氰基、氨基、巯基、硝基、羧基、羟氨基、烷基、环烷基、杂烷基、杂环烷基、芳基、杂芳基、酯基、酰基、酰胺基、磺酰基、磷酰基;
m选自0到6的整数;n选自0到3的整数。
本发明所述的化合物为具有式I结构的任意形式,包括互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、药学上可接受 的水合物、溶剂化物或盐等。
在本申请中,“选自”一般是或的并列关系。式I所示结构中,A
1、A
2、A
3、A
4、A
5、A
6中优选有三个或四个为N;R
2的位置不限,优选在R
1对位。在本申请中,所述的取代可以是单取代或多取代(例如二取代、三取代),具体取代位置没有特殊限定。所述非取代的饱和烃基包括非取代的烷基和非取代的环烷基;所述的杂环基、杂芳基等基团是其中的一个或多个碳原子可以被杂原子替代,杂原子是相对碳(C)之外的氧、硫、氮、磷(P)等原子。另外,上述的卤素包括氟(F)、氯(Cl)、溴(Br)等,优选为氟或氯。上述的“C3-C10”为碳原子数选自3到10的整数,以下类似表述不再赘述。
在本申请中,桥原子用化学键连接到环上形成的环体系(如下式所示),代表桥原子可与环上任意可连接的C原子相连接,即可形成任意螺环或桥环结构化合物。例如,下式表示桥原子Q可与六元环上任意的可连接桥原子的C原子相连接,即与相同C原子相连接形成螺环化合物,如桥原子都与2号C原子相连接或都与3号C原子相连接等;与不同C原子相连形成桥环化合物,如桥原子分别与1、4号C原子或2、4号C原子相连接等;
作为优选,所述化合物具有式II所示结构或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、药学上可接受的水合物、溶剂化物或盐:
其中,R
1选自氢、卤素、羟基、氰基、氨基、取代或非取代的C1-C6烷基、取代或非取代的C3-C6环烷基、取代或非取代的C1-C6杂烷基、取代或 非取代的C3-C6杂环烷基;进一步地,R
1选自氢、氨基、甲基、乙基、甲氧基、氰基、三氟甲基、异丙基、环丙基;更进一步地,R
1选自氢(H)、氨基(NH
2)、甲基(CH
3);
R
2选自氢、卤素、羟基、氰基、氨基、取代或非取代的C1-C6烷基、取代或非取代的C3-C6环烷基、取代或非取代的C1-C6杂烷基、取代或非取代的C3-C6杂环烷基;进一步地,R
2选自氢、氟、氯、溴、甲基、乙基、甲氧基、氰基、三氟甲基、异丙基、环丙基;更进一步地,R
2选自氢、氯、甲基;
R
3、R
4选自氢、取代或非取代的C1-C6烷基、取代或非取代的C3-C6环烷基、取代或非取代的C1-C6杂烷基、取代或非取代的C3-C6杂环烷基;或R
3、R
4与其相连的碳原子一起组成取代或非取代的C3-C6环烷基或含有N、O原子的杂环烷基;
进一步地,R
3、R
4选自氢、甲基、乙基、异丙基、环丙基或R
3、R
4与其相连的碳原子一起组成环丙基、氮杂环丁基、氮杂环戊基、氮杂环已基、氧杂环丁基、氧杂环戊基、氧杂环已基;
R
6选自氢、卤素、羟基、氰基、氨基、取代或非取代的C1-C6烷基、取代或非取代的C3-C6环烷基、取代或非取代的C1-C6杂烷基、取代或非取代的C3-C6杂环烷基;进一步地,R
6选自氢、卤素、氰基、取代或非取代的C1~C3烷基、取代或非取代的C1~C3烷氧基;进一步地,R
6选自氢、氟、氯、溴、三氟甲基、甲基、甲氧基、三氟甲氧基、二氟甲氧基;更进一步地R
6为氢或氟。
m选自0、1、2、3;n选自0、1、2;n1选自0、1、2、3、4;
R
7选自取代或非取代的芳基、取代或非取代的吡啶基,其中,所述取代的取代基独立地选自卤素、羟基、氨基、氰基、烷基、杂烷基、环烷基、杂环烷基;进一步地,所述取代基独立地选自氟、氯、溴、氰基、氨基、C1~C3烷基、C1-C3烷氧基、C3~C6环烷基、C3-C6杂环烷基;更进一步地,所述取代基独立地选自氟、氯、溴、氰基、三氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、氘代甲氧基、环丙基、环丙甲氧基、乙基、异丙基、异丁基;其中所述取代基的个数为0-5之间的整数;
X选自
等可接受的连接基团。在一些实施例中,X为
其中,R
9、R
13独立地选自氢、卤素、羟基、氨基、氰基、C1~C3烷基、C1-C3烷氧基、C3~C6环烷基、C3-C6杂环烷基;R
9与R
13及其所连碳原子共同组成取代或非取代的C3~C6环烷基或含有N或O的取代或非取代的C3-C6杂环烷基;进一步地,独立地选自氢、氟、氯、氰基、甲基、乙基、异丙基、环丙基、三氟甲基、异丁基、R
9与R
13及其所连碳原子共同组成环丙基,更进一步地,选自氢、氟、氘、氯、甲基、羟基、氨基。具体地,X可为:
其中,X为
的所有化合物可作为透脑BTK抑制剂或HER2抑制剂,更优地是,R
9、R
13均选自氟。
在本申请一些实施例中,所述化合物具有式III、式IV所示结构,或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、药学上可接受的水合物、溶剂化物或盐:
式III-式IV中,n2选自0、1、2、3、4;
R
8独立地选自氢、卤素、羟基、氨基、氰基、烷基、杂烷基、环烷基、杂环烷基;进一步地,R
8独立地选自氢、氟、氯、溴、氰基、氨基、C1~C3烷基、C1-C3烷氧基、C3~C6环烷基、C3-C6杂环烷基;更进一步地,所述取代基独立地选自氢、氟、氯、溴、氰基、三氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、氘代甲氧基、环丙基、环丙甲氧基、乙基、异丙基、异丁基;其中所述取代基的个数为0-5之间的整数(包括端点);多个取代基可以相同也可以不同;式IV中,取代或非取代吡啶基的连接位置不限,可以连接在N的邻位。
本申请一些实施例中,式II-式IV中含N稠环可用
替代,其两端单键是连接键。此外,式II-式IV的X结构中,有弯曲线的单键代表连接键。R
6的位置不限;n1优选为0、1或2。n=0时是五元环;n为1时是六元环,以此类推。
作为优选,式II-式IV中,R
1为氨基,R
2为氢或氯,R
6为氢或单取代的氟;式II中R
7为取代或未取代的苯基或吡啶基;X主要为醚或酰胺结构且酰胺的氮与R
7相连。作为优选,n为0或1,m为0或2,R
3和R
4均为氢、甲基或与所连接的碳原子组成环丙基。
具体地,本申请所述化合物结构选自如下之一(其中,有一端单键形式的是甲基,如化合物5的式5所示);进一步优选为式2、式5、式34、式42、式89、式100、式101、式103、式106、式109、式111、式114、式116、式118、式121、式125、式130、式145、式146、式152、式155所示的这些化合物,性能较佳:
本发明提供一种药用组合物,该药用组合物活性成分选自前文所述的化合物或其立体异构体、溶剂化物、水合物、药学上可接受的盐或共晶中的一种或两种以上的组合。此外,本发明对所述药物组合物的制剂类型等没有特殊限制。
本发明提供前文所述的化合物或其立体异构体、溶剂化物、水合物、药学上可接受的盐或共晶在制备蛋白质激酶抑制剂中的用途;进一步地,所述激酶抑制剂为BTK抑制剂或HER2抑制剂。或者,本发明提供前文所述的化合物或其立体异构体、溶剂化物、水合物、药学上可接受的盐或共晶在制备治疗BTK激酶或HER2激酶过度表达所致疾病的药物中的用途。
本发明提供前文所述的化合物或其立体异构体、溶剂化物、水合物、药学上可接受的盐或共晶在制备用于治疗自身免疫性疾病、炎性疾病、血栓栓塞疾病、过敏症、感染性疾病、增生性病症和癌症中的任意一种或多种疾病的药物中的用途。
进一步地,所述疾病可选自:关节炎、类风湿性关节炎、荨麻疹、白癜风、器官移植排斥、溃疡性结肠炎、克罗恩病、皮炎、哮喘、干燥综合征、系统性红斑狼疮、多发性硬化、特发性血小板减少性紫癜、皮疹、抗嗜中性白细胞胞质抗体血管炎、天胞疮、寻常性天疱疮、慢性阻塞性肺疾病、银屑病;乳腺癌、套细胞淋巴瘤、卵巢癌、食道癌、喉癌、成胶质细胞瘤、成神经细胞瘤、胃癌、肝细胞癌、胃癌、胶质瘤、子宫内膜癌、黑色素瘤、肾癌、膀胱癌、黑色素瘤、膀胱癌、胆道癌、肾癌、胰腺癌、淋巴瘤、毛细胞癌、鼻咽癌、咽癌、大肠癌、直肠癌、脑和中枢神经系统癌症、宫颈癌、前列腺癌、睾丸癌、泌尿生殖道癌、肺癌、非小细胞肺癌、小细胞癌、肺腺癌、骨癌、结肠癌、腺瘤、胰腺癌、腺癌、甲状腺癌、滤泡性癌、霍奇金白血病、支气管癌、甲状腺癌、子宫体癌、子宫颈癌、多发性骨髓瘤、急性髓细胞源性白血病、慢性髓细胞源性白血病、淋巴细胞白血病、慢性淋巴样白血病、骨髓性白血病、非霍奇金淋巴瘤、原发性巨球蛋白血症。
现有技术中,ARQ-531的抑制活性仍有待提升,其对TMD8、REC-1等细胞抑制活性较差,导致临床剂量过大,副作用较高等问题。另外,ARQ-531的选择性也较差,对TEC、EGFR有较高的抑制活性,容易导致出血、腹泻、湿疹等副作用;再者其药代也不太理想,临床前研究表明,犬PK实验中,生物利用度仅38%。即,ARQ-531在抑制活性、选择性、药代方面都有较大的提升空间。
PCNSL的治疗药物有限,PFS及OS远未达到预期。国外已经有一代不可逆BTK抑制剂(Tirabrutinib)批准用于该病的治疗,但该药物对BTK蛋白活性较弱、临床剂量过高(480mg每天一次)、副作用明显,病人的顺应性较差,且存在服用一段时间后会由于C481S突变而产生耐药的风险。该药物临床剂量高的原因主要有两个,一是该化合物的活性较弱,更重要的是该药物的血脑屏障透过率低,需要更大的剂量才能达到透过血脑屏障的药物的起效浓度。Tirabrutinib在抑制活性、药代、透脑率方面都有很大的提升空间。
Tucatinib是一种小分子口服酪氨酸激酶抑制剂(TKI),对HER2具有优秀的靶向选择性。2019年曾被FDA授予突破性疗法资格(BTD),除了获得突破性疗法资格,该药物还于2017年获得快速通道资格、孤儿药资格。与曲妥珠单抗和卡培他滨联联用,用于治疗接受过曲妥珠单抗、帕妥珠单抗、T-DM1(ado-trastuzumab emtansine)治疗的局部晚期、不可切除性或转移性(包括伴 有脑转移)HER2阳性乳腺癌患者,于2020年4月17日获得美国食品药品监督管理局(FDA)批准上市。该药物临床剂量大,每天两次,300mg一次,副作用明显。文献资料显示,Tucatinib在小鼠中的透脑率不到5%。Tucatinib在药代、透脑率方面有很大的提升空间。
在本发明实施例的体外BTK抑制及HER2抑制激酶活性试验中,可将所述化合物粉末溶解在100%DMSO中,配制成10mM储存液;-20度避光冻存。在激酶反应过程中,受试化合物测试浓度为1μM,在384source板中稀释成100倍终浓度的100%DMSO溶液,3倍稀释化合物,10个浓度。并且,本发明实施例采用所述化合物还进行了肝微粒体稳定性、大鼠PK、大鼠透脑率、药效模型等实验。与现有临床药物(ARQ-531)相比,本发明作为BTK蛋白质激酶抑制剂的化合物,在BTK、BTK(C481S)抑制活性,肝微粒体稳定性、大鼠药代方面、毒性方面具有优势。与现有上市药物Tirabrutinib相比,本发明作为BTK蛋白质激酶抑制剂的化合物,在BTK、BTK(C481S)抑制活性、细胞活性、肝微粒体稳定性、大鼠药代方面、大鼠血脑屏障透过率等方面具有优势。本发明的HER2抑制剂化合物,在HER2抑制活性、BT474细胞活性、NCI-N87细胞活性方面与现有已上市药物Tucatinib相当;在大鼠药代及大鼠血脑屏障透过率方面明显优于Tucatinib。
本发明实施例通过设计并合成了多个目标化合物,具体的制备过程可如下式所示,中间体A(也称式A所示的硼酸或硼酸酯类化合物)、中间体B(式B所示的溴代物)进行Suzuki反应合成中间体C(式C所示中间体),再脱保护得到式II所示结构的化合物。具体的实施例中,由市售的硼酸A或自制的硼酸酯A与自制的溴代物B在钯催化下偶联制得中间体C,中间体C脱保护得到实施例化合物。相比于临床二期药物ARQ-531,本发明该化合物在BTK及BTK(C481S)的抑制活性、肝微粒体稳定性、大鼠药代方面均有明显的提高。
此外,本发明实施例以下合成方法简便,收率较高。
本发明实施例提供一种制备前文所述BTK抑制剂或HER2抑制剂的中间体化合物,具有如下所示结构:
本发明实施例提供制备前文所述BTK抑制剂或HER2抑制剂的另一中间体化合物,具有如下所示结构;进一步地,如下所示结构化合物可应用于制备可透过血脑屏障药物中:
图1为本发明部分化合物TMD8药效模型测试结果;
图2为本发明部分化合物TMD8药效模型测试结果;
图3为本发明部分化合物DOHH-2-Luc脑内瘤药效模型测试结果;
图4为本发明部分化合物DOHH-2-Luc脑内瘤药效模型测试结果荧光照 片。
下面对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
为了进一步理解本申请,下面结合实施例对本申请提供的可作为BTK蛋白质激酶抑制剂的化合物及其制备方法与用途进行具体地描述。
本发明实施例中,化合物的结构是通过质谱(MS)或核磁共振(
1H NMR)设备来确定的。术语“室温”是指10℃~25℃之间。化学缩写简称具有以下意义:
DMF:N,N-二甲基甲酰胺;DIEA:N,N-二异丙基乙胺;
HATU:O-(7-氮杂苯并三唑-1-基)-N,N,N';-四甲基脲六氟磷酸盐;
PdCl
2(dppf):[1,1'-双(二苯基膦基)二茂铁]二氯化钯;
DCM:二氯甲烷;TEA:三乙胺;TBDPSCl:双三甲基硅基胺基锂;
9-BBN:9-硼双环[3.3.1]壬烷;Dess-Martin:戴斯-马丁氧化剂;
DME:乙二醇二甲醚;TosMIC:对甲基苯磺酰甲基异腈;
t-BuOK:叔丁醇钾;Dibal-H:二异丁基氢化铝;THF:四氢呋喃;
NBS:N-溴代丁二酰亚胺;TBAF:四丁基氟化铵;DMSO:二甲基亚砜;
LDA:二异丙基氨基锂;
HBTU:苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐;
NMP:N-甲基吡咯烷酮;BAST:双(2-甲氧基乙基)氨基三氟化硫;
PMDTA:五甲基二乙烯三胺;DMA:N,N-二甲基乙酰胺;
dppf:1,1'-双(二苯基膦)二茂铁;Pd
2(dba)
3:三(二亚苄基丙酮)二钯;
TsCl:4-甲苯磺酰氯;DMAP:4-二甲氨基吡啶;PDC:重铬酸吡啶;
DIAD:偶氮二甲酸二异丙酯;NCS:N-氯代丁二酰亚胺。
中间体A-1的制备:
向反应瓶中加入化合物A-1-1(5.0g,53.1mmol),DMF(50mL),A-1-2(11.6g,53.1mmol)和DIEA(20.6g,159.3mmol),反应液氮气置换,冷却至0℃,分批加入HATU(24.2g,63.7mmol),该反应混合物缓慢升至室温并搅拌反应过夜,TLC显示原料反应完全。向反应体系中加水,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗涤,无水Na
2SO
4干燥,真空蒸发后,通过硅胶柱纯化得到11.9g产物A-1-3,收率:76%。
向反应瓶中加入化合物A-1-3(5.0g,16.9mmol),二氧六环(50mL),双联频哪醇硼酸酯(5.2g,20.3mmol)和乙酸钾(2.5g,25.4mmol),反应液氮气置换,向反应液中加入PdCl
2(dppf)(500mg,0.68mmol),反应液再次氮气置换,该反应混合物加热至90℃搅拌过夜,TLC显示原料反应完全。反应体系冷却后,直接加入硅胶拌样,然后通过硅胶柱纯化得粗品,粗品用石油醚打浆,得到3.4g产物A-1,收率:62%。
中间体A-2的制备:
向反应瓶中加入化合物A-2-1(2.0g,11.8mmol)和二氧六环(20mL),冰 水浴冷却。向反应液中滴加双氧水(20mL,30%),然后反应液室温搅拌过夜,停止反应。向反应体系中加水,用乙酸乙酯萃取4次,有机相合并,水洗,饱和食盐水洗涤,真空蒸发后,通过硅胶柱纯化得到1.6g产物A-2-2,收率:96%。
向反应瓶中加入化合物A-2-2(1.00g,7.04mmol),DMF(20mL),对溴碘苯(1.99g,7.04mmol),四丁基溴化铵(230mg,0.704mmol),磷酸钾(2.99g,14.1mmol)和碘化亚铜(140mg,0.704mmol),反应液氮气置换,然后加热至140℃搅拌反应过夜。反应体系冷却至室温,加水,用乙酸乙酯萃取3次,有机相合并,水洗,饱和食盐水洗涤,真空蒸发后,通过硅胶柱纯化得到800mg产物A-2-3,收率:38%。
向反应瓶中加入化合物A-2-3(800mg,2.69mmol),二氧六环(16mL),双联频哪醇硼酸酯(821mg,3.23mmol)和乙酸钾(528mg,5.38mmol),反应液氮气置换,向反应液中加入PdCl
2(dppf)(80mg,0.109mmol),反应液再次氮气置换,该反应混合物加热至80℃搅拌16小时。反应体系冷却后,直接加入硅胶拌样,然后通过硅胶柱纯化得到520mg产物A-2,收率:56%。
中间体A-3的制备:
向反应瓶中加入化合物A-3-1(1.28g,10.5mmol),DCM(40mL),A-3-2(1.0g,5.2mmol),Cu(OAc)
2(945mg,5.2mmol),TEA(1.58g,15.6mmol)和4A分子筛(1.66g),反应液室温搅拌反应过夜。反应液抽滤,滤液加入硅胶拌样,然后通过硅胶柱纯化得到600mg产物A-3-3,收率:43%。
A-3的合成方法参照由A-2-3合成A-2的方法。
中间体A-4的制备:
向反应瓶中加入化合物A-4-1(1.06g,6.3mmol),DMF(10mL),A-3-2(1.0g,5.2mmol)和碳酸钾(1.45g,10.5mmol),反应液加热至100℃搅拌反应过夜,TLC显示原料反应完全。向反应体系中加水,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗涤,无水Na
2SO
4干燥,真空蒸发后,得到1.8g产物A-4-2,收率:100%。产物无需纯化直接用于下一步。
A-4的合成方法参照由A-2-3合成A-2的方法。
下列化合物通过制备以上中间体的方法,利用市售的相应原料合成制得。
表1:中间体A-5至A-12的结构及合成
中间体A-13的制备:
向反应瓶中加入化合物A-13-1(1.00g,5.55mmol),THF(15mL)和硼酸三异丙酯(1.25g,6.66mmol),反应液冷却至-70℃,向反应液中滴加LDA(2M,3.3mL,6.6mmol)。滴毕,反应液缓慢升至室温,加入稀盐酸淬灭反应,用 乙酸乙酯萃取两次,有机相合并,饱和食盐水洗涤,旋干,残渣硅胶柱纯化得到838mg产物A-13-2,收率:67%。
A-13的合成方法参照由A-2-1合成A-2的方法。
中间体A-14的制备:
向反应瓶中加入化合物A-14-1(500mg,3.90mmol),乙腈(5mL),碳酸钾(647mg,4.68mmol)和氘代碘甲烷(566mg,3.90mmol),反应液加热至50℃搅拌过夜。反应液倒入水中,用稀盐酸调酸,用乙酸乙酯萃取两次,有机相合并,饱和食盐水洗涤,旋干,残渣硅胶柱纯化得到432mg产物A-14-2,收率:76%。
A-14的合成方法参照由A-2-2合成A-2的方法。
中间体A-15的制备:
向反应瓶中加入化合物A-2-3(500mg,1.68mmol)和二氯甲烷(8mL),反 应液冷却至-70℃,向反应液中滴加三溴化硼的二氯甲烷溶液(1M,5mL,5.0mmol),滴毕,保温反应2小时。反应液加水淬灭,用二氯甲烷萃取两次,有机相合并,旋干,残渣硅胶柱纯化得到390mg产物A-15-1,收率:82%。
向反应瓶中加入化合物A-15-1(200mg,0.706mmol),DMF(2mL),溴代环丙烷(171mg,1.41mmol),碳酸铯(276mg,0.847mmol)和碘化钠(53mg,0.353mmol),反应液加热至150℃反应15小时。反应液倒入水中,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗,旋干,残渣硅胶柱纯化得到121mg产物A-15-2,收率:53%。
A-15的合成方法参照由A-2-3合成A-2的方法。
中间体A-16的制备:
A-16的合成方法参照由A-13-1合成A-13的方法。
中间体A-17的制备:
向反应瓶中加入化合物A-17-1(250mg,1.76mmol),二氯甲烷(5mL),对溴苯硼酸(706mg,3.52mmol),醋酸铜(320mg,1.76mmol),吡啶(418mg,5.28mmol)和4A分子筛(粉末状,500mg),反应液在大气环境下室温搅拌两天,向反应液中直接加入硅胶旋干拌样,硅胶柱纯化得到367mg产物A-17-2,收率:70%。
A-17的合成方法参照由A-2-3合成A-2的方法。
中间体A-18的制备:
向反应瓶中加入化合物A-18-1(500mg,2.44mmol),甲苯(10mL),环丙基硼酸(315mg,3.66mmol),磷酸钾(1036mg,4.88mmol),三环己基膦(68mg,0.244mmol),醋酸钯(30mg)和水(0.5mL)。反应液氮气置换,加热至100℃反应过夜。反应液冷却后直接加硅胶旋干拌样,经硅胶柱纯化得到316mg产物A-18-2,收率:78%。
A-18-3的合成方法参照由A-2-3合成A-15-1的方法。
A-18的合成方法参照由A-2-2合成A-2的方法。
下列化合物通过制备以上中间体的方法,利用市售的相应原料合成制得。
表2:中间体A-19和A-20的结构及合成
中间体A-21的制备:
向反应瓶中加入化合物A-21-1(500mg,1.91mmol)和四氢呋喃(8mL),反应液氮气置换,冰盐浴冷却,向反应液中滴加甲基溴化镁(1M四氢呋喃溶液,2.3mL,2.3mmol),滴毕,升至室温反应1小时。反应液加饱和氯化铵水溶液淬灭,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤旋干得到535mg产物A-21-1,收率:100%。产物无需进一步纯化直接用于下一步。
A-21的合成方法参照由A-2-3合成A-2的方法。
中间体A-22的制备:
A-2的合成参照文献Journal of Medicinal Chemistry,2020,vol.63,#10,5102-5118。
下列化合物通过制备以上中间体的方法,利用市售的相应原料合成制得。
表3:中间体A-23至A-25的结构及合成
中间体A-26的制备:
A-26-2的合成方法参照由A-18-1合成A-18-2的方法。
向反应瓶中加入化合物A-26-2(500mg,2.57mmol),甲醇(8mL)和氢氧化钠水溶液(1M,5.1mL,5.1mmol),反应液室温反应过夜。反应液加水稀释,稀盐酸调酸,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤旋干得到440mg产物A-26-3,收率:95%。产物无需进一步纯化直接用于下一步。
向反应瓶中加入化合物A-26-3(200mg,1.11mmol),DMF(2mL),4-氨基苯硼酸频哪醇酯(268mg,1.22mmol)和DIEA(430mg,3.33mmol)。向反应液中一次性加入HATU(633mg,1.67mmol),混合物室温反应过夜。反应液加水淬灭,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗涤,无水Na
2SO
4干燥,真空蒸发后,通过硅胶柱纯化得到219mg产物A-26,收率:52%。
中间体A-27的制备:
向反应瓶中加入化合物A-21-1(1000mg,3.83mmol),S-叔丁基亚磺酰胺(511mg,4.21mmol)和1,4-二氧六环(10mL),反应液氮气置换,向反应液中加入钛酸四乙酯(2184mg,9.58mmol)。反应液加热至100℃搅拌5小时。反应液冷却,加水淬灭,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗,真空蒸发后,通过硅胶柱纯化得到882mg产物A-27-1,收率:63%。
向反应瓶中加入化合物A-27-1(882mg,2.42mmol)和四氢呋喃(14mL),反应液氮气置换,冰盐浴冷却,向反应液中滴加甲基溴化镁(1M四氢呋喃溶液,2.9mL,2.9mmol),滴毕,升至室温反应1小时。反应液加饱和氯化铵水溶液淬灭,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗,真空蒸发后,通过硅胶柱纯化得到630mg产物A-27-2,收率:68%。
向反应瓶中加入化合物A-27-2(630mg,1.66mmol)和甲醇(10mL),然后加入氯化氢的1,4-二氧六环溶液(4M,6mL)。反应液室温反应1小时后减压浓缩干。残渣加水,用氢氧化钠水溶液调碱,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗涤,真空蒸发后,通过硅胶柱纯化得到371mg产物A-27-3,收率:81%。
A-27的合成方法参照由A-2-3合成A-2的方法。
中间体A-28的制备:
A-28的合成方法参照由A-2-3合成A-2的方法。
中间体A-29的制备:
向反应瓶中加入化合物A-29-1(1000mg,5.17mmol)和四氢呋喃(10mL),反应液氮气置换,冰水浴冷却。向反应液中滴加异丙基氯化镁(1M四氢呋喃溶液,6.2mL,6.2mmol)。滴毕,反应液升至室温搅拌1小时,向反应液中滴加对氟苯甲醛(770mg,6.20mmol)的四氢呋喃(4mL)溶液。滴毕,反应液室温搅拌1小时,反应液加饱和氯化铵水溶液淬灭,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗,真空蒸发后,通过硅胶柱纯化得到612mg产物A-29-2,收率:50%。
向反应瓶中加入化合物A-29-2(612mg,2.56mmol),二氯甲烷(12mL)和Dess-Martin氧化剂(1632mg,3.85mmol),反应液室温反应1小时,TLC显示反应完全。向反应液直接加入硅胶旋干拌样,硅胶柱纯化得到495mg产物A-29-3,收率:82%。
A-29的合成方法参照由A-21-1合成A-27的方法。
中间体A-30的制备:
向反应瓶中加入化合物A-30-1(500mg,2.92mmol),乙腈(5mL),对溴苯酚(607mg,3.51mmol)和碳酸钾(485mg,3.51mmol),反应液加热至70℃搅拌过夜。反应液冷却,抽滤,乙酸乙酯洗涤,滤液真空蒸发后,通过硅胶柱纯化得到742mg产物A-30-2,收率:97%。
A-30的合成方法参照由A-2-3合成A-2的方法。
中间体A-31的制备:
向反应瓶中加入化合物A-31-1(500mg,2.82mmol),5-溴-2-氯嘧啶(546mg,2.82mmol)和N-甲基吡咯烷酮(5mL),反应液加热至150℃搅拌2小时。反应液冷却,加水稀释,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗,真空蒸发后,通过硅胶柱纯化得到580mg产物A-31-2,收率:62%。
A-31的合成方法参照由A-2-3合成A-2的方法。
下列化合物通过制备以上中间体的方法,利用市售的相应原料合成制得。
表4:中间体A-32至A-33的结构及合成
中间体A-34的制备:
向反应瓶中加入化合物A-34-1(500mg,2.94mmol),DMF(5mL),二甲羟胺盐酸盐(344mg,3.53mmol)和DIEA(1520mg,11.8mmol)。搅拌下向反应液中一次性加入HBTU(1449mg,3.82mmol)。反应液室温搅拌过夜,反应液倒入水中,用乙酸乙酯萃取4次,有机相合并,饱和食盐水洗,真空蒸发后,通过硅胶柱纯化得到600mg产物A-34-2,收率:96%。
向反应瓶中加入化合物对溴碘苯(876mg,3.10mmol)和四氢呋喃(10mL),反应液氮气置换,干冰/乙醇浴冷却至-70℃。向反应液中滴加正丁基锂(2.5M,1.24mL,3.10mmol),搅拌30分钟后,向反应液中滴加A-34-2(600mg,2.81mmol)的四氢呋喃(3mL)溶液。滴毕,反应液缓慢升至室温反应1小时。反应液加水淬灭,用乙酸乙酯萃取两次,有机相合并,饱和食盐水洗,真空蒸发后,通过硅胶柱纯化得到360mg产物A-34-3,收率:41%。
A-34的合成方法参照由A-2-3合成A-2的方法。
中间体A-35的制备:
A-35-2的合成方法参照由A-34-2合成A-34-3的方法。
A-35-3的合成方法参照由A-29-2合成A-29-3的方法。
A-35的合成方法参照由A-2-3合成A-2的方法。
下列化合物通过制备以上中间体的方法,利用市售的相应原料合成制得。
表5:中间体A-36至A-39的结构及合成
中间体A-40的制备:
向反应瓶中加入化合物A-38(100mg,0.309mmol),DMF(1mL),碘甲烷(48mg,0.340mmol)和碳酸钾(51mg,0.371mmol)。反应液加热至80℃反应5小时。反应液冷却,倒入水中,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗,无水硫酸钠干燥,真空蒸发后,通过制备硅胶板纯化得到62mg产物A-40,收率:60%。
下列化合物通过制备以上中间体的方法,利用市售的相应原料合成制得。
表6:中间体A-41至A-47的结构及合成
中间体A-48的制备:
向反应瓶中加入化合物A-15-1(200mg,0.706mmol),DMF(4mL)和二氟氯乙酸钠(215mg,1.41mmol),反应液氮气置换,加热至100℃反应6小时。反应液冷却,倒入水中,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗,真空蒸发后,通过硅胶柱纯化得到128mg产物A-48-1,收率:54%。
A-48的合成方法参照由A-2-3合成A-2的方法。
下列化合物通过制备以上中间体的方法,利用市售的相应原料合成制得。
表7:中间体A-49至A-53的结构及合成
中间体A-54的制备:
向反应瓶中加入化合物A-54-1(500mg,3.89mmol),5-溴-2-氯嘧啶(752mg,3.89mmol),DMF(5mL)和碳酸钾(645mg,4.67mmol),反应液加热至100℃反应4小时。反应液冷却,倒入水中,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗,真空蒸发后,通过硅胶柱纯化得到511mg产物A-54-2,收率:46%。
A-54的合成方法参照由A-2-3合成A-2的方法。
中间体A-55的制备:
向反应瓶中加入化合物A-55-1(1.00g,7.35mmol),Pd/C(10%,200mg)和甲醇(25mL),反应液氢气置换,然后在氢气压力(气球)下搅拌过夜。反应液抽滤,滤液直接旋干得到1.00g产物A-55-2,收率:99%。产物无需纯化直接用于下一步。
向反应瓶中加入化合物A-55-2(800mg,5.79mmol)和四氢呋喃(10mL),反应液氮气置换,干冰/乙醇浴冷却至-70℃。向反应液中滴加正丁基锂(2.5M,2.8mL,6.95mmol),搅拌30分钟后,向反应液中滴加硼酸三甲酯(723mg,6.95mmol)的四氢呋喃(3mL)溶液。滴毕,反应液缓慢升至室温反应30分钟。反应液用稀盐酸淬灭,用乙酸乙酯萃取两次,有机相合并,饱和食盐水洗,真空蒸发后,通过硅胶柱纯化得到430mg产物A-55-3,收率:41%。
A-55的合成方法参照由A-2-1合成A-2的方法。
中间体A-56的制备:
向反应瓶中加入化合物A-56-1(500mg,3.90mmol),二溴甲烷(1018mg,5.85mmol),DMF(8mL)和碳酸钾(1348mg,9.75mmol),反应液加热至100℃反应4小时。反应液冷却,倒入水中,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗,真空蒸发后,通过硅胶柱纯化得到320mg产物A-56-2,收率:59%。
A-56的合成方法参照由A-55-2合成A-55的方法。
下列化合物通过制备以上中间体的方法,利用市售的相应原料合成制得。
表8:中间体A-57至A-59的结构及合成
中间体A-60的制备:
向反应瓶中加入化合物A-60-1(500mg,3.31mmol),对溴苯酚(685mg,3.96mmol),NMP(10mL)和碳酸铯(3.20g,9.90mmol),反应液加热至80℃反应过夜。反应液冷却,倒入水中,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗,真空蒸发后,通过硅胶柱纯化得到830mg产物A-60-2,收率:82%。
A-60的合成方法参照由A-2-3合成A-2的方法。
下列化合物通过制备以上中间体的方法,利用市售的相应原料合成制得。
表9:中间体A-61至A-63的结构及合成
中间体A-64的制备:
向反应瓶中加入化合物A-64-1(1.192g,8.05mmol),溴苯(10.1g,64.3mmol)和三氯化铝(2.15g,16.1mmol),反应液氮气置换,加热至90℃反应3小时。反应液冷却,倒入稀盐酸中,用二氯甲烷萃取3次,有机相合并。有机相用碳酸钠水溶液萃取3次,水相用稀盐酸调酸至pH 3,析出固体抽滤,水洗,滤饼收集,真空干燥得到2.0g产物A-64-2,收率:81%。产物无需进一步纯化直接用于下一步。
A-64-3的合成方法参照由A-2-3合成A-2的方法。
向反应瓶中加入化合物A-64-3(200mg,0.57mmol),DMF(3mL),氯化铵(152mg,2.85mmol)和DIEA(220mg,1.71mmol)。搅拌下向反应液中一次性加入HBTU(324mg,0.85mmol)。反应液室温搅拌过夜,反应液倒入水中,用乙酸乙酯萃取3次,有机相合并,饱和食盐水洗,真空蒸发后,通过硅胶制备板纯化得到70mg产物A-64,收率:35%。
下列化合物通过制备以上中间体的方法,利用市售的相应原料合成制得。
表10:中间体A-65至A-67的结构及合成
中间体A-68的制备:
向反应瓶中加入化合物A-68-1(200mg,1.39mmol),对溴苯酚(361mg,2.09mmol),NMP(2mL)和碳酸钾(384mg,2.78mmol),反应液加热至180℃反应8小时。反应液冷却,倒入水中,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗,无水硫酸钠干燥,真空蒸发后,通过硅胶制备板纯化得到60mg产物A-68-2,收率:15%。
A-68的合成方法参照由A-2-3合成A-2的方法。
中间体A-69的制备:
A-69的合成方法参照由A-1-1和A-1-2合成A-1的方法。
中间体A-70的制备:
向反应瓶中加入化合物A-21-1(200mg,0.766mmol),三乙基硅烷(267mg,2.31mmol),二氯甲烷(4mL)和三氟甲磺酸(35mg,0.231mmol),反应液室温搅拌过夜。反应液倒入水中,用乙酸乙酯萃取两次,有机相合并,真空蒸发后,通过硅胶柱纯化得到190mg产物A-70-1,收率:100%。
A-70的合成方法参照由A-2-3合成A-2的方法。
中间体A-71的制备:
A-71的合成方法参照由A-54-1合成A-54的方法。
中间体A-72的制备:
向反应瓶中加入化合物A-72-2(2.00g,8.06mmol),DMF(15mL),A-72-1(1.31g,8.06mmol),DIEA(3.12g,24.2mmol)和HATU(4.60g,12.1mmol)。反应液加热至60℃反应过夜。反应液冷却,倒入水中,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗,真空蒸发后,通过硅胶柱纯化得到1.56g产物A-72,收率:49%。
中间体A-73的制备:
向反应管中加入化合物A-21-1(300mg,1.15mmol)和BAST(3mL),反应管密封,加热至90℃反应过夜。反应液冷却,倒入水中,用乙酸乙酯萃取两次,有机相合并,饱和食盐水洗,无水硫酸钠干燥,真空蒸发后,通过硅胶制备版纯化得到270mg产物A-73-1,收率:83%。
A-73的合成方法参照由A-2-3合成A-2的方法。
中间体A-74的制备:
向反应瓶中加入化合物A-74-1(1.00g,7.93mmol),PMDTA(1.44g,8.32mmol)和四氢呋喃(10mL),反应液氮气置换,干冰/乙醇浴冷却至-70℃。向反应液中滴加正丁基锂(2.5M,3.3mL,8.30mmol),保温搅拌2小时后,向反应液中小心加入干冰,反应液缓慢升至室温。反应液用稀盐酸淬灭,用二氯甲烷萃取3次,有机相合并,饱和食盐水洗,无水硫酸钠干燥,真空蒸发后得到1.00g产物A-74-2,收率:74%。产物未进一步纯化直接用于下一步。
向反应瓶中加入化合物A-74-2(800mg,4.70mmol)和二氯甲烷(8mL),反应液氮气置换,冰水浴冷却。向反应液中滴加三溴化硼的二氯甲烷溶液(17%,27.7g,18.8mmol)。滴毕,反应液升至室温反应30分钟,重新用冰水浴冷却,缓慢滴加甲醇淬灭反应,反应液直接真空蒸发后,通过硅胶柱纯化得到560mg产物A-74-3,收率:76%。
向反应瓶中加入化合物A-74-3(560mg,3.59mmol),DMF(5mL),甲胺醇溶液(30%,557mg,5.38mmol),DIEA(1392mg,10.8mmol)和HATU(1775mg,4.67mmol)。反应液室温搅拌过夜。反应液倒入水中,用乙酸乙酯萃取6次,有机相合并,真空蒸发后,通过硅胶柱纯化得到254mg产物A-74-4,收率:42%。
A-74的合成方法参照由A-17-1合成A-17的方法。
中间体A-75的制备:
A-75-1的合成方法参照由A-34-1合成A-34-2的方法。
向反应瓶中加入化合物A-75-1(500mg,1.91mmol)和四氢呋喃(8mL),反应液氮气置换,冰盐浴冷却。向反应液中滴加苯基溴化镁的四氢呋喃溶液(1M,2.3mL,2.3mmol),滴毕,反应液缓慢升至室温搅拌1小时。反应液用稀盐酸淬灭,用乙酸乙酯萃取2次,有机相合并,水洗,饱和食盐水洗,无水硫酸钠干燥,真空蒸发后得到538mg产物A-75-2,收率:100%。产物未进一步纯化直接用于下一步。
A-75的合成方法参照由A-21-1合成A-73的方法。
中间体A-76的制备:
向反应瓶中加入化合物A-76-1(200mg,1.10mmol),对溴苯酚(228mg,1.32mmol),NMP(2mL)和碳酸铯(538mg,1.65mmol),反应液加热至80℃反应过夜。反应液冷却,倒入水中,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗,真空蒸发后,通过硅胶柱纯化得到280mg产物A-76-2,收率:76%。
向反应瓶中加入化合物A-76-2(200mg,0.597mmol),甲醇钠(161mg,2.98mmol)和NMP(2mL),反应液加热至80℃反应过夜。反应液冷却,倒入水中,用乙酸乙酯萃取两次,有机相合并,水洗,饱和食盐水洗,真空蒸发后,通过硅胶柱纯化得到116mg产物A-76-3,收率:56%。
A-76的合成方法参照由A-2-3合成A-2的方法。
中间体A-77的制备:
A-77-3的合成方法参照由A-34-1合成A-34-3的方法。
A-77的合成方法参照由A-21-1合成A-73的方法。
中间体A-78的制备:
A-78-2的合成方法参照由A-34-1合成A-34-2的方法。
向反应瓶中加入化合物A-78-2(474mg,1.73mmol),氰化锌(305mg,2.59mmol),DMA(5mL),锌粉(47mg),dppf(94mg)和Pd
2(dba)
3(94mg),反应液氮气置换,加热至110℃反应过夜。反应液冷却,倒入水中,用乙酸乙酯萃取两次,有机相合并,饱和食盐水洗,真空蒸发后,通过硅胶柱纯化得到473mg产物A-78-3,收率:100%。
A-78-4的合成方法参照由A-34-2合成A-34-3的方法。
A-78的合成方法参照由A-21-1合成A-73的方法。
下列化合物通过制备以上中间体的方法,利用市售的相应原料合成制得。
表11:中间体A-79至A-81的结构及合成
中间体A-82的制备:
向反应瓶中加入二氯甲烷(5mL),氮气置换,干冰/乙腈浴冷却至-40℃,加入四氯化钛(1453mg,7.66mmol),然后缓慢滴加二甲基锌的甲苯溶液(1M,7.7mL,7.7mmol),加毕,保温反应30分钟。向反应液中滴加化合物A-21-1(500mg,1.91mmol)的二氯甲烷(3mL)溶液,加毕,保温反应1小时,然后缓慢升至室温搅拌过夜。反应液加水淬灭,用二氯甲烷萃取两次,有机相合并,水洗,真空蒸发后,通过硅胶柱纯化得到326mg产物A-82-1,收率:62%。
A-82的合成方法参照由A-2-3合成A-2的方法。
下列化合物通过制备以上中间体的方法,利用市售的相应原料合成制得。
表12:中间体A-83至A-100的结构及合成
中间体A-101的制备:
向反应瓶中加入对溴碘苯(1.71g,6.03mmol)和四氢呋喃(15mL),氮气置换,干冰/乙醇浴冷却至-70℃,然后缓慢滴加正丁基锂(2.5M,2.4mL,6.03mmol),加毕,保温反应30分钟。称取A-101-1(1.00g,5.74mmol)溶于四氢呋喃(5mL),滴加到反应液中,10分钟后,反应液缓慢升至室温。反应液加水淬灭,用乙酸乙酯萃取两次,有机相合并,水洗,真空蒸发后,通过硅胶柱纯化得到1.4g产物A-101-2,收率:73%。
A-101的合成方法参照由A-2-3合成A-2的方法。
中间体A-102的制备:
向反应瓶中加入A-101-2(550mg,1.66mmol)和二氯甲烷(6mL),氮气置换,冰浴下加入DAST(402mg,2.49mmol),保温反应2小时。反应液加碳酸氢钠水溶液淬灭,用二氯甲烷萃取两次,有机相合并,无水硫酸钠干燥,真空蒸发后,通过硅胶制备板纯化得到410mg产物A-102,收率:74%。
A-102的合成方法参照由A-2-3合成A-2的方法。
中间体A-103的制备:
向反应瓶中加入A-103-1(500mg,1.50mmol)和氢溴酸水溶液(5mL),冰浴冷却,加入亚硝酸钠(645mg,9.35mmol),然后保温反应20分钟。向反应液中加入CuBr(2.69g,18.75mmol)的氢溴酸水溶液(5mL),反应液缓慢升至室温反应3小时。反应液加水稀释,用乙酸乙酯萃取两次,有机相合并,水洗,真空蒸发后,通过硅胶柱纯化得到620mg产物A-103-2,收率:89%。
向反应瓶中加入A-103-2(200mg,0.43mmol)和四氢呋喃(5mL),氮气置换,干冰/乙醇浴冷却至-70℃,然后缓慢滴加正丁基锂(2.5M,0.17mL,0.43mmol),加毕,保温反应1小时。反应液加稀盐酸淬灭,用乙酸乙酯萃取两次,有机相合并,无水硫酸钠干燥,真空蒸发后得到170mg粗品A-103-3,粗品未纯化直接用于下一步。
A-103的合成方法参照由A-2-3合成A-2的方法。
中间体B-1的制备:
向反应瓶中加入化合物B-1-1(2.00g,17.5mmol),咪唑(1.43g,21.0mmol),DMF溶液(10mL),反应液氮气置换,冰水浴加TBDPSCl(5.30g,19.3mmol),滴毕,撤冰,该反应混合物室温搅拌16h,TLC显示反应完全。将反应液倒入水中,反应液用乙酸乙酯萃取两次,合并,再用水洗两次,之后用饱和NaCl溶液洗涤,最后用无水Na
2SO
4干燥,直接真空蒸发后得到6.68g产物B-1-2,产物未纯化直接用于下一步。
向反应瓶中加入B-1-2(6.68g,18.9mmol)的四氢呋喃溶液(35mL),反应液氮气置换,冰水浴下滴加9-BBN(0.5M,91mL),滴毕,该反应混合物室温搅拌16h,TLC显示原料反应完全。反应液再次用冰水浴冷却,缓慢加入10%NaOH溶液(24mL)和30%H
2O
2溶液(12mL),继续搅拌1h,TLC显示中间体反应完全。将反应液倒入水中,用乙酸乙酯萃取两次,合并,之后用水洗两次,饱和NaCl溶液洗涤,直接加入硅胶拌样,然后通过硅胶柱纯化得到6.49g产物B-1-3,两步收率:100%。
向反应瓶中加入化合物B-1-3(6.49g,17.5mmol)的二氯甲烷溶液(50mL),反应液氮气置换,冰水浴向反应瓶中加入Dess-Martin氧化剂(11.14g,26.3mmol),搅拌1.5h,TLC显示反应完全。直接加入硅胶拌样,然后通过硅胶柱 纯化得到6.45g产物B-1-4,收率:100%。
向反应瓶中加入化合物B-1-4(6.45g,17.5mmol),乙醇(926mg,20.1mmol),DME(60mL)和TosMIC(3.92g,20.1mmol),氮气置换,冰水浴冷却。向反应液中加入t-BuOK(3.83g,34.1mmol),搅拌30min后慢慢升至室温,继续搅拌1.5h。TLC显示原料反应完全。将反应液倒入饱和NH
4Cl溶液(350mL),用乙酸乙酯萃取两次,合并,加入硅胶拌样,然后通过硅胶柱纯化得到2.27g产物B-1-5(TLC显示两个点),收率:34%。
向反应瓶中加入B-1-5(2.27g,5.97mmol)的二氯甲烷溶液(35mL),反应液氮气置换,干冰-乙醇浴冷却,向反应液中慢慢滴加Dibal-H(1M,9mL),在此温度下搅拌1.5h,TLC显示反应完全,将反应液加入到冷的稀盐酸(1M,10mL)搅拌至无气泡后再加入DCM萃取两次,合并有机相,用饱和NaCl溶液洗涤,最后用无水Na
2SO
4干燥,反应液直接真空蒸发后得到2.22g产物B-1-6。收率:97%。
向反应瓶中加入化合物B-1-6(2.22g,5.81mmol),THF(60mL),水(30mL)和K
2CO
3(4.82g,34.8mmol),然后分批加入KMnO
4(3.67g,23.2mmol),反应液室温搅拌反应30min。TLC显示原料反应完全,向反应液中加入稀盐酸调酸,再加入NaHSO
3溶液至反应液无色,用乙酸乙酯萃取两次,有机相合并,用饱和NaCl溶液洗涤,最后用无水Na
2SO
4干燥,反应液直接真空蒸发后得到1.89g产物B-1-7。收率:82%。
向反应瓶中加入化合物B-1-7(1.89g,4.74mmol),3-氯吡嗪-2-甲胺二盐酸盐(1.03g,4.74mmol)和DMF(20mL),氮气置换,冰水浴下冷却,向反应液加入HATU(2.16g,5.69mmol)和DIEA(3.06g,23.7mmol)。反应液搅拌反应30min后撤冰,室温继续搅拌30min。TLC显示原料反应完全。将反应液倒入水中,用乙酸乙酯萃取两次,合并,之后用水洗两次,再用饱和NaCl溶液洗涤,加入硅胶拌样,然后通过硅胶柱纯化得到1.94g产物B-1-8(TLC显示两个点)。收率:78%。
向反应瓶中加入化合物B-1-8(790mg,1.51mmol),DMF(0.8mL)和乙酸乙酯(8mL),氮气置换,冰水浴下向反应液中滴加三氯氧磷(1.39g,9.08mmol),反应液搅拌1h。TLC显示原料反应完全。将反应液倒入NaHCO
3溶液(4.5g NaHCO
3/30mL H
2O)淬灭,用乙酸乙酯萃取两次,合并,之后用水洗两次,再用饱和NaCl溶液洗涤,最后用无水Na
2SO
4干燥,直接真空蒸发后 得到680mg产物B-1-9(TLC显示两个点)。收率:89.0%。
向反应瓶中加入B-1-9(680mg,1.34mmol)的DMF溶液(7mL),反应液氮气置换,冰水浴下加NBS(287mg,1.61mmo),搅拌40min,TLC显示反应完全。将反应液倒入水中淬灭,用乙酸乙酯萃取两次,合并,之后用水洗两次,再用饱和NaCl溶液洗涤,加入硅胶拌样,然后通过硅胶柱纯化得到298mg产物B-1-10-A(TLC上极性小的点,先出)和339mg产物B-1-10-B(TLC上极性大的点,后出)。总收率:81%。
向闷罐中加入化合物B-1-10-A(298mg,0.509mmol),氨水(6mL),正丁醇溶液(3mL),反应瓶密封,加热至95℃搅拌16h。反应液冷却,真空旋干,然后通过硅胶柱纯化得到184mg产物B-1-A,收率:64%。
用合成B-1-A的方法利用B-1-10-B与氨水反应制得B-1-B。
中间体B-2的制备:
称取NaH(8.56g,357mmol)悬浮于无水THF(80mL),升温至40-45℃,滴加化合物B-2-1(22.85g,149mmol)的THF溶液,滴毕,保持该温度搅拌反应15分钟。滴加丙烯酸乙酯的THF溶液,加毕,继续反应15min。将反应液冷却至室温后加入冰水中,浓HCl调pH至3,加乙酸乙酯萃取两次,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,柱层析纯化得化合物B-2-2为无色油状(37.6g,83%)。
将化合物B-2-2(37.6g,120mmol),氯化钠(20.97g,359mmol)加入到DMSO(170mL)和H
2O(5mL)中于160℃反应1.7h。反应液冷却,加入冰水中,加乙酸乙酯萃取,无水硫酸钠干燥有机相,过滤,减压浓缩。柱层析纯化得化合物B-2-3为无色油状(21.6g,75%)。
称取化合物B-2-3(21.6g,89.2mmol),乙二醇(6.64g,107mmol)和对甲苯磺酸-水合物(169mg,0.89mmol)加入甲苯(180mL)中,于120℃分水回流4h。反应液冷却,加入到饱和NaHCO
3水溶液中,加乙酸乙酯萃取,无水硫酸钠干燥有机相,过滤,减压浓缩,柱层析纯化得化合物B-2-4为浅黄色液体(23.7g,93%)。
称取LAH(6.47g,166mmol)于三口瓶中,加入无水THF(150mL),氮气置换,冰-盐浴冷却下滴加化合物B-2-4(23.7g,82.8mmol)的THF(100mL)溶液,滴加完毕后缓慢升至室温反应5h。冰水浴下向反应中缓慢滴加H
2O/THF(1:1,30mL),再加入5N氢氧化钠水溶液(8mL),室温搅拌过夜。向反应瓶中加入DCM/MeOH(5:1,250mL)稀释反应液,过滤,用DCM/MeOH(5:1)淋洗。向滤液中加入50g硅胶,搅拌15min,过滤,淋洗。滤液减压浓缩得化合物B-2-5(16.7g,99%)。
称取化合物B-2-5(16.7g,82.6mmol)于反应瓶中,加入吡啶(100mL),冰水浴下加入TsCl(34.6g,182mmol),室温搅拌过夜。反应液加乙酸乙酯稀释,用10%的柠檬酸溶液及饱和氯化钠洗,无水硫酸钠干燥有机相,过滤,减压浓缩。所得粗品用乙醇打浆,得化合物B-2-6为白色固体(35g,83%)。
称取化合物B-2-6(35g,68.5mmol)于反应瓶中,加入1N HCl溶液(260mL)和THF(300mL)于80℃反应5h。反应液加乙酸乙酯萃取,水洗有机相,无水硫酸钠干燥,过滤,减压浓缩。柱层析纯化得化合物B-2-7(26.2g,82%)。
向反应瓶中加入化合物1,3-二噻烷(2.1g,17.4mmol),无水THF(40mL),氮气置换,干冰-乙醇浴冷却下滴加正丁基锂(2.5M,8.5mL),滴毕升至0℃反 应1h。干冰-乙醇浴冷却后,滴加化合物B-2-7(6.5g,13.9mmol)的THF溶液,滴毕升至室温反应1h。将反应液加入饱和NH
4Cl溶液中淬灭,加乙酸乙酯萃取,无水硫酸钠干燥有机相,过滤,减压浓缩。柱层析纯化得化合物B-2-8(6.77g,83%)。
向反应瓶中加入化合物B-2-8(6.77g,11.5mmol),NaOH(1.38g,34.6mmol),THF(170mL)于70℃回流过夜。将反应液冷却至室温,加水,乙酸乙酯萃取,无水硫酸钠干燥有机相,过滤,减压浓缩。柱层析纯化得化合物B-2-9(3.7g,77%)。
向反应瓶中加入化合物B-2-9(3.7g,8.92mmol),乙腈(50mL)和水(12.5mL),冰水浴下加入NBS(5.56g,31.2mmol),加毕,移至室温反应3h。将反应液加入饱和NaHCO
3溶液中,加乙酸乙酯萃取,合并有机相,饱和NaCl溶液反洗有机相,无水硫酸钠干燥,过滤,减压浓缩得化合物B-2-10粗品,未进一步纯化。
将上述所得化合物B-2-10粗品加乙醇溶解,冰水浴下加入NaBH4(508mg,13.4mmol),移至室温反应1h。将反应液加入饱和NH
4Cl溶液中淬灭,加入乙酸乙酯萃取,无水硫酸钠干燥有机相,过滤,减压浓缩。柱层析纯化得化合物B-2-11(2.66g,两步收率91%)。
向反应瓶中加入化合物B-2-11(2.56g,7.84mmol),DMAP(287mg,2.35mmol),咪唑(1.06g,15.7mmol)和DMF(15mL),再加入TBDPSCl(2.59g,9.41mmol)于室温反应0.5h。将反应液加入水中,加乙酸乙酯萃取,合并有机相,饱和NaCl溶液反洗有机相,无水硫酸钠干燥,过滤,减压浓缩。柱层析纯化得化合物B-2-12(4.0g,90%)。
向反应瓶中加入化合物B-2-12(4.0g,7.08mmol)和甲醇(120mL),室温搅拌下加入Mg(1.89g,77.9mmol),30分钟后,反应剧烈放热,反应搅拌过夜。将反应液加入饱和NH
4Cl溶液中,加入乙酸乙酯萃取,无水硫酸钠干燥有机相,过滤,减压浓缩。柱层析纯化得化合物B-2-13(2.4g,83%)。
向反应瓶中加入化合物B-2-13(2.4g,5.85mmol)和DMF(30mL),冰水浴下加入PDC(6.6g,17.6mmol),加毕,移至室温反应2h。向反应瓶中加入乙酸乙酯稀释反应液,加水萃取,合并有机相,饱和NaCl溶液反洗有机相,无水硫酸钠干燥,过滤,减压浓缩。柱层析纯化得化合物B-2-14(1.99g,80%)。
向反应瓶中加入化合物B-2-14(1.99g,4.69mmol),3-氯吡嗪-2-甲胺二 盐酸盐(1.02g,4.69mmol)和DMF(10mL),再向反应液加入HBTU(2.13g,5.62mmol)和DIEA(2.42g,18.8mmol),室温反应1h。将反应液加入水中,用乙酸乙酯萃取两次,合并有机相,用饱和NaCl溶液反洗,无水硫酸钠干燥,过滤,减压浓缩。柱层析纯化得化合物B-2-15(1.99g,77%)。
向反应瓶中加入化合物B-2-15(1.59g,2.89mmol),加入DCM(30mL)溶解,氮气保护,冰水浴下加入吡啶(1.83g,23.1mmol)和三氟甲磺酸酐(4.89g,17.3mmol),加毕,移至室温反应4h。将反应液加入到饱和NaHCO
3溶液中,加乙酸乙酯萃取,合并有机相,饱和NaCl溶液反洗有机相,无水硫酸钠干燥,过滤,减压浓缩得化合物B-2-16粗品,未进一步纯化。
将上述所得化合物B-2-16粗品溶于DMF(8mL),加入NBS(566mg,3.18mmol)于室温反应0.5h。将反应液加入到NaHCO
3溶液中,加乙酸乙酯萃取,合并有机相,饱和NaCl溶液反洗有机相,无水硫酸钠干燥,过滤,减压浓缩。柱层析纯化得化合物B-2-17(1.43g,两步收率81%)。
向闷罐中加入化合物B-2-17(1.43g,2.34mmol),氨水(20mL),正丁醇(8mL),反应体系加热至95℃,搅拌16h。将反应液真空旋干,柱层析纯化得化合物B-2(1.2g,87%)。
中间体B-3的制备:
B-3-1参照文献(Angew.Chem.Int.Ed.2020,59,7161-7167)方法制得。
向反应瓶中加入化合物B-3-1(1.25g,6.71mmol),咪唑(548mg,8.06mmol)和DMF(12mL),再加入TBDPSCl(1.94g,7.05mmol)于室温反应过夜。将反应液加入水中,用乙酸乙酯萃取两次,合并有机相,水洗,饱和NaCl溶液洗,无水硫酸钠干燥,过滤,减压浓缩得化合物B-3-2(2.85g,100%)。未进一步纯化。
将化合物B-3-2(2.85g,6.71mmol)溶于乙醇(25mL),加入氢氧化钠(403mg,10.1mmol)的水溶液(10mL)。反应液加热至60℃反应过夜。反应液冷却,加入水中,稀盐酸调酸,用乙酸乙酯萃取两次,合并有机相,水洗, 饱和NaCl溶液洗,无水硫酸钠干燥,过滤,减压浓缩得化合物B-3-3(2.53g,95%)。未进一步纯化。
用B-3-3制备B-3的方法参照由B-2-14制备B-2的方法。
中间体B-4的制备:
向反应瓶中加入化合物B-4-1(100mg,0.383mmol),B-1-3(170mg,0.460mmol),三苯基膦(251mg,0.958mmol)和THF(2mL),反应液氮气置换,加热至60℃。向反应液中滴加DIAD(194mg,0.958mmol),保温反应过夜。反应液冷却,减压浓缩干,硅胶柱纯化得化合物B-4-A(52mg,极性小的点)和B-4-B(140mg,极性大的点,含杂质三苯氧膦)。总收率:82%。
中间体B-5的制备:
向反应瓶中加入化合物B-1-3(500mg,1.35mmol),TEA(273mg,2.70mmol),DCM(5mL)和对甲苯磺酰氯(309mg,1.62mmol),反应液室温搅拌2h,TLC显示几乎无反应。向反应液中加入DMAP(198mg,1.62mmol),反应过夜。反应液加入水中,稀盐酸调酸,用乙酸乙酯萃取两次,合并有机相,水洗,饱和NaCl溶液洗,减压浓缩干,硅胶柱纯化得化合物B-5-1(550mg,78%)。
向反应瓶中加入化合物B-5-1(200mg,0.381mmol),3-溴-4-氯-1H-吡唑并[4,3-C]吡啶(89mg,0.381mmol),碳酸铯(149mg,0.457mmol)和DMA(2mL),反应液加热至100℃搅拌过夜。反应液冷却,加入水中,用乙酸乙酯萃取两次,合并有机相,水洗,饱和NaCl溶液洗,减压浓缩干,硅胶制备板纯 化得化合物B-5-2(60mg,27%)。
向封管中加入化合物B-5-2(60mg,0.103mmol),氨水(2mL),正丁醇(1mL),反应体系加热至100℃,搅拌过夜。反应液冷却,真空旋干,硅胶制备板纯化得化合物B-5(38mg,66%)。
中间体B-6的制备:
向反应瓶中加入化合物B-1-10-B(200mg,0.342mmol),THF(3mL)和TBAF(1M,0.7mL,0.7mmol),反应液室温搅拌4h,反应液直接硅胶制备板纯化得化合物B-6-1(108mg,91%)。
化合物B-6-1用PDC氧化(参照由B-2-13合成B-2-14)制得B-6-2。
向反应瓶中加入化合物B-6-2(90mg,0.25mmol),碳酸钾(69mg,0.50mmol),DMF(1mL)和碘甲烷(53mg,0.374mmol),反应液室温搅拌过夜。反应液加入水中,用乙酸乙酯萃取两次,合并有机相,水洗,饱和NaCl溶液洗,无水硫酸钠干燥,抽滤,减压浓缩干,硅胶制备板纯化得化合物B-6-3(80mg,85%)。
向反应瓶中加入化合物B-6-3(80mg,0.21mmol)和THF(2mL),氮气置换,冰水浴冷却。向反应液中加入钛酸四异丙酯(28mg,0.10mmol),然后缓慢滴加乙基溴化镁(0.6mL,0.6mmol,1M)。滴毕,反应液升至室温搅拌过夜。反应液倒入氯化铵水溶液中淬灭,用乙酸乙酯萃取两次,有机相合并,用饱和 食盐水洗涤,减压浓缩干,硅胶制备板纯化得22mg化合物B-6-4,收率:28%。
用B-6-4制备B-6的方法参照由B-2-17制备B-2的方法。
中间体B-7的制备:
向反应瓶中加入化合物B-6-3(100mg,0.267mmol)和THF(2mL),氮气置换,冰水浴冷却。向反应液中滴加甲基溴化镁(0.8mL,0.8mmol,1M)。滴毕,反应液升至室温搅拌过夜。反应液倒入氯化铵水溶液中淬灭,用乙酸乙酯萃取两次,有机相合并,用饱和食盐水洗涤,减压浓缩干,硅胶制备板纯化得65mg化合物B-7-1,收率:65%。
用B-7-1制备B-7的方法参照由B-2-17制备B-2的方法。
中间体B-8的制备:
向反应瓶中加入化合物B-8-1(CAS:652-67-5,1.00g,6.84mmol),咪唑(559mg,8.21mmol)和DMF(15mL),再加入TBDPSCl(1.88g,6.84mmol),室温反应过夜。将反应液倒入水中,用乙酸乙酯萃取两次,合并有机相,水洗,饱和NaCl溶液洗,减压浓缩后硅胶柱纯化得化合物B-8-2(1.63g,62%)。
用B-8-2制备B-8的方法参照由B-1-3制备B-1-A(B)的方法。
中间体B-9的制备:
向反应瓶中加入化合物B-9-1(8.0g,76.1mmol),二氧六环(120mL)和RaneyNi(约1g),反应液氢气置换,在氢气袋压力下加热至90℃搅拌反应过夜,TLC显示原料基本反应完全。反应液冷却,抽滤,滤液减压旋干得到8.3g产物B-9-2,收率:100%。产物未纯化直接用于下一步。
B-9-2与B-1-7缩合、关环、上溴制得B-9,具体方法参照由B-1-7制备B-1-10-A(B)的方法。
中间体B-10的制备:
向反应瓶中加入化合物B-1-9(200mg,0.395mmol)和四氢呋喃(3mL),反应液氮气置换,干冰/乙醇浴冷却至-70℃,向反应液中滴加正丁基锂(2.5M,0.19mL,0.474mmol)。滴毕,保温反应30分钟。向反应液中滴加碘甲烷(112mg,0.790mmol),滴毕,反应液缓慢升至室温。加入氯化铵水溶液淬灭反应,用乙酸乙酯萃取两次,合并有机相,减压浓缩干,柱层析纯化得B-10-1(160mg,78%)。
B-10-1用NBS上溴,再氨解制得B-10,具体方法参照由B-1-9制备B-1-A(B)的方法。
实施例1:化合物1的制备
向反应瓶中加入化合物B-1-B(205mg,0.362mmol),A-1(161mg,0.471mmol),Na
2CO
3(77mg,0.724mmol),PdCl
2(dppf)(20mg),二氧六环(6mL)和水(2mL),氮气置换,升至95℃反应2.5h,TLC显示反应完全。反应液用乙酸乙酯稀释,直接加入硅胶拌样,然后通过硅胶柱纯化得到182mg产物C-1-B,收率:72%。
向反应瓶中加入化合物C-1-B(182mg,0.260mmol)和四氢呋喃(4mL),向反应液中加入TBAF(1M,0.39mL),反应液室温搅拌反应1.5h。TLC显示反应完全。反应液直接通过制备硅胶板(DCM/MeOH=15/1)纯化,得到70mg产物1-B,收率:58%。
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ1.56-1.60(1H,m),1.94-2.07(2H,m),2.20-2.25(1H,m),3.28-3.31(1H,m),3.38-3.42(2H,m),3.47-3.51(1H,m),3.77(1H,dd,J=11.8Hz,3.2Hz),4.11(1H,dd,J=11.8Hz,1.8Hz),4.59(1H,t,J=5.8Hz),6.03(2H,brs),7.07(1H,d,J=5.0Hz),7.20(1H,ddd,J=7.4Hz,4.9Hz,1.0Hz),7.63(2H,dd,J=10.4Hz,5.4Hz),7.85-7.90(1H,m),7.98-8.02(2H,m),8.21(1H,d,J=8.4Hz),8.41-8.43(1H,m),10.97(1H,s).
MS(ESI)m/z(M+H)
+:463.0。
用合成1-B的方法利用A-1与B-1-A制得1-A。
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ1.38-1.50(1H,m),1.73-1.75(1H,m),1.80-1.92(1H,m),2.12-2.15(1H,m),3.36-3.47(3H,m),3.62(1H,t,J=11.0Hz),4.07-4.10(1H,m),4.69(1H,t,J=5.5Hz),6.02(2H,s),7.07(1H,d,J=5.0Hz),7.20(1H,dd,J=6.9Hz,5.2Hz),7.61(1H,t,J=7.9Hz),7.76(1H,d,J=5.0Hz),7.83-7.91(1H,m),7.95-8.04(2H,m),8.21(1H,d,J=8.4Hz),8.42(1H,d,J=3.8Hz),10.97(1H,s).
MS(ESI)m/z(M+H)
+:463.1。
实施例2:化合物2的制备
用合成1-B的方法利用A-5与B-1-A反应制得2-A。
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ1.41-1.51(1H,m),1.50-1.78(1H,m),1.85-1.97(1H,m),2.13-2.15(1H,m),3.35-3.49(4H,m),3.65(1H,t,J=11.0Hz),4.10(1H,ddd,J=11.0Hz,3.6Hz,1.6Hz),4.69(1H,t,J=5.6Hz),6.13(2H,brs),7.09(1H,d,J=4.9Hz),7.19(1H,dd,J=6.9Hz,5.2Hz),7.76(3H,dd,J=9.5Hz,6.7Hz),7.83-7.90(1H,m),8.16(2H,d,J=8.4Hz),8.23(1H,d,J=8.4Hz),8.41(1H,dd,J=4.8Hz,1.0Hz),10.84(1H,s).
MS(ESI)m/z(M+H)
+:445.2。
化合物2-A用SFC拆分得到2-A-P1(先出峰)和2-A-P2(后出峰)。
制备SFC条件:
Instrument:SFC-80(Thar,Waters)
Column:CHIRALCEL OJ(30*250mm 5μm)(Daicel)
Column temperature:35℃
Mobile phase:A=CO
2 Co-Solvent B=ETOH
Cycle Time:12.5min Run Time:21min
用合成1-B的方法利用A-5与B-1-B反应制得2-B。
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ1.58-1.63(1H,m),1.95-2.02(1H,m),2.08-2.17(1H,m),2.24-2.28(1H,m),3.39-3.51(4H,m),3.78(1H,dd,J=11.7,3.2Hz),4.10(1H,d,J=10.1Hz),4.60(1H,t,J=5.2Hz),6.14(2H,brs),7.09(1H,d,J=4.9Hz),7.18(1H,dd,J=6.9Hz,5.3Hz),7.63(1H,d,J=5.0Hz),7.76(2H,d,J=8.3Hz),7.84-7.88(1H,m),8.16(2H,d,J=8.3Hz),8.23(1H,d,J=8.3Hz),8.41(1H,dd,J=4.8Hz,1.0Hz),10.84(1H,s).
MS(ESI)m/z(M+H)
+:445.2。
实施例3:化合物3的制备
向反应瓶中加入化合物2-B(50mg,0.113mmol),NCS(16.5mg,0.124mmol)和冰乙酸(1mL),反应液加热至80℃反应2h。反应液减压浓缩干,加入碳酸氢钠水溶液,用乙酸乙酯萃取两次,有机相合并,饱和氯化钠水溶液洗涤,无水硫酸钠干燥,抽滤,减压浓缩干,通过硅胶制备板纯化得到28mg产物3,收率:52%。
MS(ESI)m/z(M+H)
+:479.2。
实施例4~119:化合物4~119的制备
用制备化合物1-B或3的方法,采用不同的中间体制得化合物4~119,其所用中间体编号、结构式、MS及
1H-NMR数据如表13所示。
表13:实施例4~119的结构、MS及
1H-NMR数据
实施例120:化合物120的制备
向反应瓶中加入化合物B-1-4(3.10g,8.41mmol),甲醇(31mL),羟胺盐酸盐(1.17g,16.8mmol)和乙酸钠(2.07g,25.2mmol)。反应液室温搅拌过夜。倒入水中,用乙酸乙酯萃取两次,有机相合并,饱和食盐水洗,减压浓缩干,然后通过硅胶柱纯化得到1.90g产物120-1,收率:59%。
向反应瓶中加入化合物120-1(1.90g,4.95mmol)和四氢呋喃(20mL), 冰浴冷却,向反应液中分批加入四氢铝锂(376mg,9.91mmol)。反应液升至室温反应3h。反应液重新冰浴冷却,缓慢依次滴加水(380mg),15%NaOH水溶液(380mg),水(1.14g)淬灭反应。所得混悬液抽滤,DCM/MeOH(10/1)洗涤,滤液减压浓缩干,然后通过硅胶柱纯化得到200mg产物120-2,收率:31%。
向反应瓶中加入化合物2,4-二氯-3-硝基吡啶(294mg,1.52mmol),DMF(2mL),120-2(200mg,1.52mmol)和三乙胺(231mg,2.29mmol)。反应液室温搅拌4h。反应液倒入水中,用乙酸乙酯萃取3次,有机相合并,饱和食盐水洗,无水硫酸钠干燥,过滤,减压浓缩干得到464mg产物120-3,收率:100%。产物未进一步纯化。
向反应瓶中加入化合物120-3(464mg,1.61mmol),异丙醇(5mL),双-(4-甲氧基苄基)-胺(415mg,1.61mmol)和三乙胺(212mg,2.10mmol)。反应液加热至95℃搅拌4h。反应液冷却,减压浓缩干,然后通过硅胶柱纯化得到540mg产物120-4,收率:66%。
向反应瓶中加入化合物120-4(388mg,0.76mmol),DMF(4mL),咪唑(78mg,1.14mmol),DMAP(10mg,0.076mmol)和叔丁基二苯基氯硅烷(210mg,0.76mmol)。反应液加热至60℃搅拌过夜。TLC显示原料剩余很多。向反应液中补加咪唑(150mg),DMAP(40mg)和叔丁基二苯基氯硅烷(100mg),升温至80℃反应2h。继续向反应液中补加叔丁基二苯基氯硅烷(200mg),2h后TLC显示反应完全。反应液冷却,倒入水中,用乙酸乙酯萃取3次,有机相合并,饱和食盐水洗,无水硫酸钠干燥,过滤,减压浓缩干,然后通过硅胶柱纯化得到650mg产物120-5,收率:100%。
向反应瓶中加入化合物120-5(650mg,0.87mmol),甲醇/冰乙酸(5mL/5mL)和铁粉(486mg,8.7mmol)。反应液室温搅拌4h。反应液缓慢倒入NaHCO
3水溶液中,用乙酸乙酯萃取两次,有机相合并,饱和食盐水洗,无水硫酸钠干燥,过滤,减压浓缩干得到612mg产物120-6,收率:98%。产物未进一步纯化。
向反应瓶中加入化合物120-6(612mg,0.85mmol),乙腈(6mL)和N,N'-羰基二咪唑(280mg,1.71mmol)。反应液加热至80℃搅拌过夜。反应液冷却,减压浓缩干,然后通过硅胶柱纯化得到470mg产物120-7,收率:74%。
向反应瓶中加入化合物120-7(470mg,0.63mmol),二氯甲烷(15mL), 4-苯氧基苯基硼酸(271mg,1.27mmol),醋酸酮(115mg,0.63mmol),4A分子筛(500mg)和三乙胺(192mg,1.90mmol)。反应液室温搅拌36h。反应液垫硅藻土抽滤,乙酸乙酯洗涤,滤液减压浓缩干,然后通过硅胶柱纯化得到240mg产物120-8,收率:41%。
向反应瓶中加入化合物120-8(260mg,0.29mmol),二氯甲烷(4mL)和三氟乙酸(4mL)。反应液加热至50℃搅拌3h。反应液冷却,减压浓缩干,加入NaHCO
3水溶液,用乙酸乙酯萃取两次,有机相合并,饱和食盐水洗,无水硫酸钠干燥,过滤,减压浓缩。残渣用四氢呋喃(2mL)溶解,加入TBAF(1M,0.2mL),室温搅拌1h。反应液直接硅胶制备板纯化得到40mg产物120,收率:30%。
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ1.37-1.53(1H,m),1.56-1.71(1H,m),1.81-1.95(1H,m),2.12-2.29(1H,m),2.34-2.44(4H,m),3.40-3.54(1.5H,m),3.59-3.70(1H,m),3.77-4.02(1H,m),4.17-4.39(1H,m),4.71(0.5H,t,J=5.7Hz),4.76-4.83(2H,m),6.94(0.5H,d,J=5.6Hz),7.13(4H,t,J=8.5Hz),7.18-7.25(1.5H,m),7.40-7.48(4H,m),7.74(1H,t,J=5.6Hz).
MS(ESI)m/z(M+H)
+:433.2。
实施例121~138:化合物121~138的制备
用制备化合物1-B或3的方法,采用不同的中间体制得化合物121~138,其所用中间体编号、结构式、MS及
1H-NMR数据如表14所示。
表14:实施例121~138的结构、MS及
1H-NMR数据
药效试验
试验例1:体外BTK抑制激酶活性试验
1:化合物配制
将化合物粉末溶解在100%DMSO中,配制成10mM储存液。-20度避光冻存。
2:激酶反应过程
(1)配制1×Kinase buffer;
(2)化合物浓度梯度的配制:受试化合物测试浓度为1μM,在384source板中稀释成100倍终浓度的100%DMSO溶液,3倍稀释化合物,10个浓度。使用分液器Echo 550向目的板OptiPlate-384F转移250nL 100倍终浓度的化合物;
(3)用1×Kinase buffer配制2.5倍终浓度的激酶溶液;
(4)在化合物孔和阳性对照孔分别加10μL的2.5倍终浓度的激酶溶液;在阴性对照孔中加10μL的1×Kinase buffer;
(5)1000rpm离心30秒,反应板振荡混匀后室温孵育10分钟;
(6)用1×Kinase buffer配制5/3倍终浓度的ATP和Kinase substrate2的 混合溶液;
(7)加入15μL的5/3倍终浓度的ATP和底物的混合溶液,起始反应;
(8)将384孔板1000rpm离心30秒,振荡混匀后室温孵育10分钟;
(9)加入30μL终止检测液停止激酶反应,1000rpm离心30秒,振荡混匀;
(10)用Caliper EZ Reader读取转化率。
3:数据分析
计算公式:
其中:Conversion%_sample是样品的转化率读数;Conversion%_min:阴性对照孔均值,代表没有酶活孔的转化率读数;Conversion%_max:阳性对照孔比值均值,代表没有化合物抑制孔的转化率读数。
拟合量效曲线
以浓度的log值作为X轴,百分比抑制率为Y轴,采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线,从而得出各个化合物对酶活性的IC50值。
计算公式是Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))。
本发明化合物对BTK野生型和BTK突变型C481S激酶抑制活性见表15:
IC50:A≤5nM;5nM<B≤20nM;20nM<C≤100nM;100nM<D≤1000nM;E>1000nM。
表15:本发明化合物对BTK及BTK-C481S激酶抑制活性
“\”代表未做此项测试。
试验例2:肝微粒体稳定性实验
1:向T0,T5,T10,T20,T30,T60和NCF60样品孔位中,加入10μL供试品或对照品工作液和80μL微粒体工作液(肝微粒体蛋白浓度为0.5mg/mL),在Blank60孔位中只添加微粒体工作液,然后将除T0和NCF60外的样品Blank60、T5、T10、T20、T30和T60放置于37℃水浴锅中,预孵育大约10分钟;
2:T0样品中先加入300μL的终止液(containing 200ng/mL tolbutamide and 200ng/mL labetalol的乙腈溶液)后再添加10μL NADPH再生体系工作液;
3:孵育板Blank60、T5、T10、T20、T30和T60预孵育结束后,每个样品孔内添加10μL NADPH再生体系工作液以启动反应,NCF60样品孔中加入10μL 100mM磷酸钾缓冲液;
4:孵育适当时间(如5、10、20、30和60分钟)后,分别在Blank60、T5、T10、T20、T30、T60和NCF60板的每个供试品样品孔和对照品样品孔中,加入300μL的终止液以终止反应。
5:所有样品板摇匀并在4000rpm离心20分钟,分别取100μL供试品或对照品上清液稀释到300μL纯水中,用于LC-MS/MS分析。
6:数据分析,根据一级消除动力学计算T
1/2和CL
int(mic)(μL/min/mg)值,一级消除动力学方程式为:
人和大鼠肝微粒体稳定性测试结果见表16:
表16:本发明化合物肝微粒体稳定性测试结果
试验例3:药代动力学测试
各受试化合物分别以口服(10mg/kg,每组3只)给药方式单次给予SD大鼠进行药代动力学研究,受试化合物使用5%DMSO+10%solutol+85%saline溶解,并经涡旋1-2min,超声5-10min之后配制成无色透明澄清给药溶液。口服给药前动物需禁食过夜,并于给药4小时后恢复给食。SD大鼠经口服给药后,经眼眶采血采集药代动力学样本,采集时间点为:给药后0.25h、0.5h、1h、2h、2.5h、3h、4h、6h、8h、10h,每个时间点采集3个全血样本,采集量约0.2~0.3mL。血液样本采集后立即置于冰上,于15分钟之内离心分离血浆(离心条件:8000rpm,1分钟,室温)。收集的血浆分析前存放于–20℃。取20μL血浆样品至1.6mL的96孔深孔板中,加入200μL的工作内标溶液(空白不加内标补加相同体积的溶媒),涡旋混合1min,5800转/分钟离心10min,取100μL上清液加入到96孔进样板中,经LC-MS/MS进样分析。
本发明部分化合物的药代动力学测试结果如下表17所示:
表17 本发明部分化合物的药代动力学测试结果
试验例4:体外细胞增殖抑制活性测试
1:细胞培养
细胞培养于1640培养基中,加10%灭活FBS和1%双抗,置于37℃、5%CO
2条件下培养。
2:细胞铺板
(1)细胞常规培养至细胞饱和度为80%-90%,数量到达要求时,收取细胞。
(2)用相应的培养基重悬,计数,配制成合适密度的细胞悬液。
(3)将细胞悬液加入96孔板,每孔100μL。
(4)细胞在37℃,5%CO
2培养箱中培养过夜。
3:化合物的准备
(1)待测化合物分别用DMSO稀释配成终浓度为20mM母液备用。
(2)将母液用DMSO从20mM稀释10倍到2mM,然后从2mM开始3倍稀释9个浓度。
(3)空白对照孔为细胞加0.5%DMSO,作为高读值对照孔。
(4)无细胞只有培养基的孔作为低读值对照孔。
4:化合物处理细胞
(1)细胞铺板24小时以后,化合物单独作用,每孔补99μL的生长培养基,然后加入1μL步骤4.3a)b)c)准备的化合物,轻轻震荡确保混合均匀,然后放入37℃,5%CO
2培养箱中。
(2)将细胞板放置培养箱72小时。
5:CTG方法检测
(1)将细胞待测板放置室温平衡30分钟,每孔弃掉100μL培养基。
(2)每孔加100μL CTG试剂(CelltiterGlo试剂盒),放置快速振荡器振荡2分钟,室温避光放置30分钟。
(3)用Envision仪器读取化学发光信号值。
6:数据分析
用GraphPad Prism 8 software计算IC
50,利用以下非线性拟合公式来得到化合物的IC
50(半数抑制浓度),结果如下表:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)*HillSlope))
X:化合物浓度log值,Y:抑制率(%inhibition)
抑制率(%inhibition)=(高读值对照读数-化合物孔读值)/(高读值对照读数-低读值对照读数)*100
表18:本发明部分化合物对TMD8细胞增殖抑制活性
表19:本发明部分化合物对DOHH2细胞增殖抑制活性
表20:本发明部分化合物对BT474细胞增殖抑制活性
表21:本发明部分化合物对NCI-N87细胞增殖抑制活性
实施例 | NCI-N87IC50(nm) |
130 | 100.3 |
142 | 106.2 |
145 | 37.5 |
146 | 82.0 |
152 | 43.4 |
Tucatinib | 26.0 |
试验例5:HER2激酶活性测试
1,Her2激酶测试步骤
1)制备1×激酶反应缓冲液:1倍体积的5×激酶反应缓冲液和4倍体积的水,1mM二硫苏糖醇,5mM氯化镁,1mM氯化锰,12.5mM SEB。
2)用Echo 550向反应板(784075,Greiner)每孔中转移稀释好的化合物工作液100nl。用封板膜封住反应板,1000g离心1分钟。
3)用1×激酶反应缓冲液配制1ng/μL Her2激酶溶液。
4)向反应板中每孔加入5μL上述配制的激酶溶液。用封板膜封住板子1000g离心1分钟,室温放置10分钟。
5)用1×激酶反应缓冲液配制2×激酶底物和ATP混合液,2×Her2激酶底物为2μM TK-substrate-biotin和4μM ATP。
6)向反应板中加入5μL 2×TK-substrate-biotin和ATP混合液,1000g离心30秒,开始反应。
7)Her2激酶测试室温反应50分钟。
8)用HTRF检测缓冲液配制Sa-XL 665(125nM)和TK-antibody-Cryptate混合液。
9)每孔加入10μL Sa-XL 665和TK-antibody-Cryptate混合液,1000g离心30秒,室温反应1小时。
10)用Envision 2104读615nm(Cryptate)和665nm(XL665)的荧光信号。
2,数据分析
1)抑制百分率计算如下:
2)计算IC50以及拟合化合物量效曲线:
用GraphPad 6.0,利用以下非线性拟合公式来得到化合物的IC50。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X:化合物浓度log值;Y:化合物抑制百分率
表22:本发明部分化合物对HER2激酶抑制活性
实施例 | HER2IC50(nm) |
130 | 4.35 |
145 | 1.69 |
146 | 3.92 |
152 | 4.19 |
155 | 9.44 |
Tucatinib | 3.00 |
试验例6:血脑屏障透过性测试
各受试化合物分别用SD大鼠进行单次口服给药药代动力学研究,剂量为10mg/kg,每组9只动物。受试化合物使用5%DMSO+10%solutol+85%saline溶解,并经涡旋1-2min,超声5-10min之后配制成无色透明澄清给药溶液。给药前动物禁食过夜,SD大鼠在给药后1h、2h、4h,各取3只大鼠,经眼眶采约0.2~0.3mL的血液。血液样本采集后立即置于冰上,于15分钟之内离心分离血浆(离心条件:8000rpm,1分钟,室温)。收集的血浆分析前存放于–20℃。采血后立即取其脑脊液及脑组织。脑脊液以直视下微量进样器经硬脊膜穿刺抽取脑脊液法抽取,水合氯醛麻醉后,固定头颅,剪去背毛,于两耳根的连线处剪开一横切口(2cm),钝性刮开颈部及颅底的肌肉层,暴露出枕骨大孔,持100μl微量进样器,取大约100μl左右的脑脊液,分析前存放于–20℃。随后立即处死大鼠,断头,将脑组织剖解出来,剥离表面毛细血管,称重,加入3倍量的冰凉的生理盐水,匀浆机匀浆1min,分析前存放于–20℃。分别取20μL血浆样品、脑匀浆样品,分别加入200μL的工作内标溶液(空白不加内标补加相同体积的溶媒),涡旋混合1min,13500转/分钟离心10min,取100μL上清液,经LC-MS/MS进样分析。取20μL脑脊液样品,加入60μL的工作内标溶液(空白不加内标补加相同体积的溶媒),涡旋混合1min,13500转/分钟离心10min,取50μL上清液,经LC-MS/MS进样分析。
表23:本发明部分化合物血脑屏障透过率测试结果
试验例7:TMD8药效模型测试
人弥漫性大B淋巴瘤TMD8细胞体外单层培养,培养条件为RPMI1640培养基中加10%胎牛血清,100U/mL青霉素和100μg/mL链霉素,37℃5%CO
2孵箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80%-90%,数量到达要求时,收取细胞,计数,接种。将0.2ml(1x10
7个)TMD8细胞(加基质胶,体积比为1:1)皮下接种于每只小鼠的右后背, 肿瘤平均体积达到约137mm
3时开始分组给药。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为:V=0.5a×b
2,a和b分别表示肿瘤的长径和短径。
结果参见图1和图2;根据图1,TMD8小鼠皮下移植瘤药效模型来看,在相同的10mg/kg的剂量条件下,实施列118、实施例89-P1两个化合物对肿瘤的抑制效果明显优于临床二期药物ARQ-531及上市药物依布替尼。根据图2,TMD8小鼠皮下移植瘤药效模型来看,在相同的20mg/kg的剂量条件下,
实施例111-P1、实施例125对肿瘤的抑制效果明显优于Tirabrutinib。尤其是实施例111-P1,在肿瘤抑瘤率方面,实施例111-P1的TGI为93%,是Tirabrutinib的近2倍,几乎完全控制住肿瘤的生长,药效优势非常明显。
试验例8:DOHH-2-Luc脑内瘤药效模型测试
1,细胞培养
用含有10%胎牛血清和500ng/mL嘌呤霉素的RPMI 1640培养基在37℃、5%CO
2的培养箱中对DOHH-2-luc肿瘤细胞进行体外培养。每隔2至3天补液或更换培养基,传代次数不超过4-5次。将处于对数生长期的肿瘤细胞用于体内肿瘤的接种。
2,肿瘤细胞的接种与分组
将动物肌肉注射舒泰麻醉后,俯卧固定在操作台上,对其头顶部皮肤分别用碘酒和75%酒精消毒,沿着头部中线切开皮肤约0.5cm,暴露冠状线和矢状线,利用脑定位仪在距离冠状线偏上约0.5-1.0mm,矢状线偏右约2mm处定位并用1mL注射器针头钻一孔,在定位处将微量进样器垂直插入深至3mm,缓慢注入(约1分钟)DOHH-2-luc肿瘤细胞3×10
5/2μL悬液并留针1分钟,拔针后迅速用骨蜡将针孔密封,并用钉皮器缝合伤口。肿瘤接种后大约第7天,根据动物体重和肿瘤部位光学信号强度,将动物随机分为5组,每组5只。
3,影像学分析
使用小动物活体成像系统IVIS Lumina III(Perkin Elmer)根据小鼠状态对其每周成像1-2次,监测小鼠肿瘤细胞接种部位生物光学影像(bioluminescence imaging,BLI,unit:photons/s)信号强度,作为评估肿瘤生长和药效的主要指标,具体操作如下:
小鼠腹腔注射D-luciferin(15mg/mL,依实验动物体重按5μL/g)后,使 用1%-2%的异氟烷对动物进行吸入式麻醉,注射D-luciferin10分钟后,使用IVIS Lumina III对动物进行成像。使用活体成像软件Living Image software(Perkin Elmer)对数据进行分析处理,计算每只动物ROI(regions of interest)内光学信号强度。
结果参见图3、图4;根据图3,在小鼠脑内DOHH2肿瘤模型研究中,相同的30mg/kg(BID)的剂量条件下,实施例111-P1、实施例125对肿瘤的抑制效果明显优于Tirabrutinib,药效优势非常明显,且给药21天没有发现任何副作用。
图4为所有受试动物成像后的荧光图,该图以颜色及区域大小来表示脑内的肿瘤大小,颜色越红,说明肿瘤越大。从图片可以看出,同等剂量下,实施例111-P1、实施例125对肿瘤的抑制效果非常好,几乎没有红色区域,说明这两个组动物的脑内肿瘤很小;而模型组及Tirabrutinib组的所有动物均有大片红色区域,说明肿瘤很大。
由以上实施例可知,本发明作为BTK蛋白质激酶抑制剂的化合物具有式I结构,优选具有式II结构;对野生型BTK和突变的BTK(C481S)都有很强的抑制作用,且具有良好的药代动力学性质,可用于制备治疗BTK激酶过度表达所致疾病的药物。其中部分化合物在TMD8皮下瘤药效模型实验中明显优于已上市BTK抑制剂Ibrutinib、Tirabrutinib及处于临床二期的ARQ-531。
本发明部分化合物在血脑屏障透过率、肝微粒体稳定性、药代等方面明显优于已上市的药物Tirabrutinib和Tucatinib。在DOHH-2-Luc脑内药效模型中,部分化合物的药效非常好,也验证了透脑的数据。可用于制备治疗BTK或HER2激酶过度表达所致疾病,尤其是脑部疾病的药物。
本发明前文所述的化合物或其立体异构体、溶剂化物、水合物、药学上可接受的盐或共晶,可用于制备治疗自身免疫性疾病、炎性疾病、血栓栓塞疾病、过敏症、感染性疾病、增生性病症和癌症中的任意一种或多种疾病的药物,有望提供新的良好的治疗方案。
以上所述仅是本发明的优选实施方式,应当指出,对于使本技术领域的专业技术人员,在不脱离本发明技术原理的前提下,是能够实现对这些实施例的多种修改的,而这些修改也应视为本发明应该保护的范围。
Claims (10)
- 一种作为BTK抑制剂或HER2抑制剂的化合物,其特征在于,具有式II所示结构或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、药学上可接受的水合物、溶剂化物或盐:其中,R 1选自氢、卤素、羟基、氰基、氨基、取代或非取代的C1-C6烷基、取代或非取代的C3-C6环烷基、取代或非取代的C1-C6杂烷基、取代或非取代的C3-C6杂环烷基;进一步地,R 1选自氢、氨基、甲基、乙基、甲氧基、氰基、三氟甲基、异丙基、环丙基;更进一步地,R 1选自氢、氨基、甲基;R 2选自氢、卤素、羟基、氰基、氨基、取代或非取代的C1-C6烷基、取代或非取代的C3-C6环烷基、取代或非取代的C1-C6杂烷基、取代或非取代的C3-C6杂环烷基;进一步地,R 2选自氢、氟、氯、溴、甲基、乙基、甲氧基、氰基、三氟甲基、异丙基、环丙基;更进一步地,R 2选自氢、氯、甲基;R 3、R 4选自氢、取代或非取代的C1-C6烷基、取代或非取代的C3-C6环烷基、取代或非取代的C1-C6杂烷基、取代或非取代的C3-C6杂环烷基;或R 3、R 4与其相连的碳原子一起组成取代或非取代的C3-C6环烷基或含有N、O原子的杂环烷基;进一步地,R 3、R 4选自氢、甲基、乙基、异丙基、环丙基或R 3、R 4与其相连的碳原子一起组成环丙基、氮杂环丁基、氮杂环戊基、氮杂环已基、氧杂环丁基、氧杂环戊基、氧杂环已基;R 6选自氢、卤素、羟基、氰基、氨基、取代或非取代的C1-C6烷基、取代或非取代的C3-C6环烷基、取代或非取代的C1-C6杂烷基、取代或非取代的C3-C6杂环烷基;进一步地,R 6选自氢、卤素、氰基、取代或非取代的C1~C3 烷基、取代或非取代的C1~C3烷氧基;进一步地,R 6选自氢、氟、氯、溴、三氟甲基、甲基、甲氧基、三氟甲氧基、二氟甲氧基;更进一步地R 6为氢或氟;m选自0、1、2、3;n选自0、1、2;n1选自0、1、2、3、4;R 7选自取代或非取代的芳基、取代或非取代的吡啶基,其中,所述取代的取代基独立地选自卤素、羟基、氨基、氰基、烷基、杂烷基、环烷基、杂环烷基;进一步地,所述取代基独立地选自氟、氯、溴、氰基、氨基、C1~C3烷基、C1-C3烷氧基、C3~C6环烷基、C3-C6杂环烷基;更进一步地,所述取代基独立地选自氟、氯、溴、氰基、三氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、氘代甲氧基、环丙基、环丙甲氧基、乙基、异丙基、异丁基;其中所述取代基的个数为0-5之间的整数;
- 根据权利要求1所述的化合物,其特征在于,具有式III、式IV所示结构,或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、药学上可接受的水合物、溶剂化物或盐:其中,n2选自0、1、2、3、4;R 8独立地选自氢、卤素、羟基、氨基、氰基、烷基、杂烷基、环烷基、杂环烷基;进一步地,R 8独立地选自氢、氟、氯、溴、氰基、氨基、C1~C3烷基、C1-C3烷氧基、C3~C6环烷基、C3-C6杂环烷基;更进一步地,所述取 代基独立地选自氢、氟、氯、溴、氰基、三氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、氘代甲氧基、环丙基、环丙甲氧基、乙基、异丙基、异丁基;其中所述取代基的个数为0-5之间的整数。
- 一种药用组合物,其特征在于,该药用组合物活性成分选自权利要求1-3任一所述的化合物或其立体异构体、溶剂化物、水合物、药学上可接受的盐或共晶中的一种或两种以上的组合。
- 权利要求1-3任意一项所述的化合物或其立体异构体、溶剂化物、水合物、药学上可接受的盐或共晶在制备蛋白质激酶抑制剂中的用途;进一步地,所述激酶抑制剂为BTK抑制剂或HER2抑制剂。
- 权利要求1-3任意一项所述的化合物或其立体异构体、溶剂化物、水合物、药学上可接受的盐或共晶在制备治疗BTK激酶或HER2激酶过度表达所致疾病的药物中的用途。
- 权利要求1-3任意一项所述的化合物或其立体异构体、溶剂化物、水合物、药学上可接受的盐或共晶在制备用于治疗自身免疫性疾病、炎性疾病、血栓栓塞疾病、过敏症、感染性疾病、增生性病症和癌症中的任意一种或多种疾病的药物中的用途。
- 根据权利要求8所述的用途,其特征在于,所述疾病选自:关节炎、类风湿性关节炎、荨麻疹、白癜风、器官移植排斥、溃疡性结肠炎、克罗恩病、皮炎、哮喘、干燥综合征、系统性红斑狼疮、多发性硬化、特发性血小板减少性紫癜、皮疹、抗嗜中性白细胞胞质抗体血管炎、天胞疮、寻常性天疱疮、慢性阻塞性肺疾病、银屑病;乳腺癌、套细胞淋巴瘤、卵巢癌、食道癌、喉癌、成胶质细胞瘤、成神经细胞瘤、胃癌、肝细胞癌、胃癌、胶质瘤、子宫内膜癌、黑色素瘤、肾癌、膀胱癌、黑色素瘤、膀胱癌、胆道癌、肾癌、胰腺癌、淋巴瘤、毛细胞癌、鼻咽癌、咽癌、大肠癌、直肠癌、脑和中枢神经系统癌症、宫颈癌、前列腺癌、睾丸癌、泌尿生殖道癌、肺癌、非小细胞肺癌、小细胞癌、 肺腺癌、骨癌、结肠癌、腺瘤、胰腺癌、腺癌、甲状腺癌、滤泡性癌、霍奇金白血病、支气管癌、甲状腺癌、子宫体癌、子宫颈癌、多发性骨髓瘤、急性髓细胞源性白血病、慢性髓细胞源性白血病、淋巴细胞白血病、慢性淋巴样白血病、骨髓性白血病、非霍奇金淋巴瘤、原发性巨球蛋白血症。
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