CN106518768B - Acrylic acid derivative, preparation method and medical application thereof - Google Patents

Acrylic acid derivative, preparation method and medical application thereof Download PDF

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CN106518768B
CN106518768B CN201610814214.1A CN201610814214A CN106518768B CN 106518768 B CN106518768 B CN 106518768B CN 201610814214 A CN201610814214 A CN 201610814214A CN 106518768 B CN106518768 B CN 106518768B
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methyl
compound
reaction
pyran
cancer
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CN106518768A (en
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杨方龙
王春飞
王阳
何明勋
胡齐悦
贺峰
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The invention relates to acrylic acid derivatives, a preparation method thereof and application thereof in medicines. In particular, the invention relates to acrylic acid derivatives shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivatives, and application of the derivatives as estrogen receptor modulators to treatment of estrogen receptor-mediated or estrogen receptor-dependent diseases or symptoms, wherein the diseases are particularly preferably breast cancer. Wherein, each substituent group in the general formula (I) is the same as the definition in the specification.

Description

Acrylic acid derivative, preparation method and medical application thereof
Technical Field
The invention belongs to the field of medicines, and relates to an acrylic acid derivative, a preparation method thereof and application thereof in medicines. In particular, the invention relates to acrylic acid derivatives shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivatives, and application of the derivatives as estrogen receptor modulators to treatment of estrogen receptor-mediated or estrogen receptor-dependent diseases or symptoms, wherein the diseases are particularly preferably breast cancer.
Background
Through long-term basic research and clinical monitoring, people find that diseases such as breast cancer, ovarian cancer, osteoporosis, schizophrenia, senile dementia and the like are closely related to the abnormity of estrogen signal pathways. Estrogens are steroid hormones secreted by the endocrine system and play important roles in the reproductive system, bone tissue, cardiovascular system, immune system and central nervous system. The estrogen signaling system plays an important role in regulating cell growth, differentiation and apoptosis. The occurrence and development of estrogen-dependent tumors such as breast cancer, ovarian cancer, endometrial cancer and the like are closely related to estrogen. Currently, the main chemotherapy for breast cancer is with antiestrogens such as Tamoxifen (Tamoxifen), but Tamoxifen exhibits estrogen agonist properties in the uterus and has stimulatory effects on cancer cells in the uterus. Due to these serious side effects, it is imperative to find new safe and effective treatments.
An important protein of the estrogen signaling pathway is the Estrogen Receptor (ER), which is a steroid hormone receptor, a ligand-activated transcription factor belonging to the nuclear receptor superfamily, and comprises two subtypes: ER α (found in 1950) and ER β (found in 1996), respectively, encoded by different genes. ER α and ER β show a high degree of similarity at the amino acid level, with a similarity of up to 97% in the DNA binding domain and 56% in the ligand binding domain, however, only a low homology of 24% at the N-terminus. ER comprises 6 structural domains (A-F) and consists of 4 main functional regions, the functional region of the N-terminal A/B domain has a ligand-independent transcription activation functional region AF-1, AF-1 has constitutive activation activity, the transcription of a target gene is activated through the action of a basal transcription factor, a reactivation factor and other transcription factors, the region has a plurality of phosphorylation sites, and the function of AF-1 depends on protein phosphorylation in literature. The C domain constituting the DNA Binding Domain (DBD) is highly conserved, contains 2 zinc finger domains, and is capable of specifically binding to the target DNA, while it plays an important role in receptor dimerization. The D domain is a hinge region, connecting the DBD and the ligand domain (LBD), and is less conserved (homology between two subtypes is only 30%). The C-terminal E domain constitutes a Ligand Binding Domain (LBD) that determines specific binding of ER to ligands such as estrogen, SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor down-regulator), and the like. LBD has ligand-dependent transcriptional activation function area AF-2, and with AF-1 to function in cooperation with ER receptor activation target gene transcription. Meanwhile, LBD has a strong dimerization interface and can still function without a ligand, so that LBD is a key site for receptor dimerization.
ER α is distributed primarily in the uterus, ovaries, testes, pituitary, kidney, epididymis, and adrenal glands, while ER β is distributed primarily in the prostate, ovaries, lungs, bladder, brain, and blood vessels. Since either full agonists or full antagonists have more serious side effects, the study of SERMs has been ongoing. By "selective" is meant that the SERM behaves as an agonist in certain tissues such as bone, liver, ER β focal region of the cardiovascular system, and as an antagonist in other tissues such as breast. It may be an agonist or antagonist in the uterus (more prominent region of ER α). The currently marketed SERMs include Tamoxifen (Tamoxifen), Raloxifene (Raloxifene), Bazedoxifene (Bazedoxifene), Toremifene (Tormeifene), and the like, but the research finds that the currently marketed SERMs still have serious side effects, such as endometrial hyperplasia, polyps, endometrial cancer and the like caused by long-term administration of Tamoxifen and Toremifene, and the common side effects of Raloxifene include hot flashes, leg pain, breast tenderness, venous embolism and the like. Therefore, research and development of novel compounds remain problems to be solved urgently.
The SERD and the SERM can compete with estrogen to bind to an estrogen receptor and block the activation of a downstream gene promoter by the ER receptor, and meanwhile, the SERD can also promote the rapid quantitative degradation of the ER receptor in tissues and aggravate the blockage of an ER receptor signal pathway. Compared to SERMs, SERDs also have a specific gene expression profile, showing antagonist effects in breast cancer.
Published selective estrogen receptor-mediated modulator patent applications include WO2014165723, WO2014151899, WO2014141292, WO2014135834 and WO 2014106848.
To achieve better therapeutic effect and meet the market demand, we hope to develop a new generation of efficient and low-toxicity SERD for estrogen signaling pathway. The invention provides a novel structural SERD, and finds that the compound with the structure has good activity and shows excellent ER receptor antagonism.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I) or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt thereof,
Figure BDA0001111876800000021
wherein:
ring A is selected from cycloalkyl, fused ring alkyl, bridged cycloalkyl and heterocyclyl;
R1each of which is the same OR different and is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR5、-C(O)R5、-C(O)OR5、-S(O)mR5and-NR6R7(ii) a Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R2each of which is the same OR different and is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR5、-C(O)R5、-C(O)OR5、-S(O)mR5and-NR6R7(ii) a Wherein said alkyl, haloalkyl, alkoxyOptionally further substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R3selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR5、-C(O)R5、-C(O)OR5、-S(O)mR5and-NR6R7(ii) a Wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R4selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxy, amino, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R5、-C(O)OR5and-NR6R7(ii) a Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R5selected from the group consisting of hydrogen atoms, alkyl groups, alkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein said alkyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of alkyl groups, halogen groups, hydroxy groups, amino groups, nitro groups, cyano groups, alkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;
R6and R7Each of which is the same or different and is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkaneOxy, hydroxyalkyl, hydroxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
m is 0, 1 or 2; and is
n is 0, 1,2, 3,4 or 5;
q is 0, 1,2, 3 or 4.
In a preferred embodiment of the invention, the compounds of the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is1Selected from hydrogen atoms and alkyl groups.
In a preferred embodiment of the invention, the compounds of the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is2Selected from hydrogen atoms and halogens.
In a preferred embodiment of the invention, the compounds of the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is3Selected from hydrogen atoms and halogens.
In a preferred embodiment of the invention, the compounds of the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is4Selected from hydrogen atoms.
In a preferred embodiment of the invention, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of
Figure BDA0001111876800000041
Preference is given to
Figure BDA0001111876800000042
Figure BDA0001111876800000043
In a preferred embodiment of the present invention, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,
Figure BDA0001111876800000044
wherein:
x is selected from carbon atom and oxygen atom;
R1～R4n and q are as defined in formula (I).
Typical compounds of formula (I) include, but are not limited to:
Figure BDA0001111876800000051
Figure BDA0001111876800000061
Figure BDA0001111876800000071
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.
The present invention further provides a compound represented by the general formula (III):
Figure BDA0001111876800000072
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
r is selected from alkyl and cycloalkyl;
ring A, R1～R4Q and n are as defined in formula (I).
The present invention further provides a process for the preparation of a compound according to general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
Figure BDA0001111876800000081
hydrolyzing the compound of the general formula (III) under alkaline conditions to obtain a compound of a general formula (I);
wherein:
ring A, R, R1～R4Q and n are as defined in formula (III).
Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of each of the above formulae or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The invention also relates to a method for preparing the pharmaceutical composition, which comprises mixing the compound shown in the general formula or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form of the compound or the pharmaceutically acceptable salt with a pharmaceutically acceptable carrier, diluent or excipient.
The invention further relates to a compound shown in the general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, and an application of the compound in preparing estrogen receptor modulators.
The invention further relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of a disease or disorder mediated or dependent on estrogen receptors. Wherein the estrogen receptor mediated or dependent disease or condition is selected from the group consisting of cancer, Central Nervous System (CNS) deficiencies, cardiovascular system deficiencies, blood system deficiencies, immune and inflammatory diseases, susceptibility to infection, metabolic deficiencies, neurological deficiencies, psychiatric deficiencies, and reproductive deficiencies. Wherein the cancer may be breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumors, ovarian tumors, hemophilia, and leukemia; preferably breast cancer, ovarian cancer, endometrial cancer, prostate cancer or cervical cancer; more preferably breast cancer; the Central Nervous System (CNS) deficiency may be alcoholism or migraine; the cardiovascular system defect can be aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension; the blood system defect may be deep vein thrombosis; the immune and inflammatory diseases can be Graves' disease, arthritis, multiple sclerosis, liver cirrhosis; the infection susceptibility may be hepatitis b, chronic liver disease; the metabolic defect may be cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis; the neurological deficit can be alzheimer's disease, parkinson's disease, migraine, vertigo; the mental deficiency may be anorexia nervosa, Attention Deficit Hyperactivity Disorder (ADHD), dementia, major depressive disorder, psychosis; and the reproductive defect may be endometriosis, infertility, or the like.
The invention further relates to a compound of the general formula (I) according to the invention or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of a disease or disorder mediated or dependent on estrogen receptors. Wherein the estrogen receptor mediated or dependent disease or condition is selected from the group consisting of cancer, Central Nervous System (CNS) deficiencies, cardiovascular system deficiencies, blood system deficiencies, immune and inflammatory diseases, susceptibility to infection, metabolic deficiencies, neurological deficiencies, psychiatric deficiencies, and reproductive deficiencies. Wherein the cancer may be breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumors, ovarian tumors, hemophilia, and leukemia; preferably breast cancer, ovarian cancer, endometrial cancer, prostate cancer or cervical cancer; more preferably breast cancer; the Central Nervous System (CNS) deficiency may be alcoholism or migraine; the cardiovascular system defect can be aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension; the blood system defect may be deep vein thrombosis; the immune and inflammatory diseases can be Graves' disease, arthritis, multiple sclerosis, liver cirrhosis; the infection susceptibility may be hepatitis b, chronic liver disease; the metabolic defect may be cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis; the neurological deficit can be alzheimer's disease, parkinson's disease, migraine, vertigo; the mental deficiency may be anorexia nervosa, Attention Deficit Hyperactivity Disorder (ADHD), dementia, major depressive disorder, psychosis; and the reproductive defect may be endometriosis, infertility, or the like.
The present invention further relates to a method of treating a disease or disorder mediated or dependent on an estrogen receptor, comprising administering to a patient in need thereof a therapeutically effective dose of a compound of the present invention of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof. The method has remarkable therapeutic effect and less side effects. Wherein the estrogen receptor mediated or dependent disease or condition is selected from the group consisting of cancer, Central Nervous System (CNS) deficiencies, cardiovascular system deficiencies, blood system deficiencies, immune and inflammatory diseases, susceptibility to infection, metabolic deficiencies, neurological deficiencies, psychiatric deficiencies, and reproductive deficiencies. Wherein the cancer may be breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumors, ovarian tumors, hemophilia, and leukemia; preferably breast cancer, ovarian cancer, endometrial cancer, prostate cancer or cervical cancer; more preferably breast cancer; the Central Nervous System (CNS) deficiency may be alcoholism or migraine; the cardiovascular system defect can be aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension; the blood system defect may be deep vein thrombosis; the immune and inflammatory diseases can be Graves' disease, arthritis, multiple sclerosis, liver cirrhosis; the infection susceptibility may be hepatitis b, chronic liver disease; the metabolic defect may be cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis; the neurological deficit can be alzheimer's disease, parkinson's disease, migraine, vertigo; the mental deficiency may be anorexia nervosa, Attention Deficit Hyperactivity Disorder (ADHD), dementia, major depressive disorder, psychosis; and the reproductive defect may be endometriosis, infertility, or the like.
Another aspect of the present invention relates to a compound represented by the general formula (I) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, as a medicament for treating cancer. It shows outstanding therapeutic effect and less side effects in treating cancer, wherein the cancer may be selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia; preferably breast cancer, ovarian cancer, endometrial cancer, prostate cancer or cervical cancer; more preferably breast cancer.
Another aspect of the present invention relates to a method for treating cancer, which comprises administering to a patient in need thereof a therapeutically effective dose of a compound of the present invention represented by general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof. The method shows outstanding therapeutic effects and fewer side effects, wherein the cancer can be selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia; preferably breast cancer, ovarian cancer, endometrial cancer, prostate cancer or cervical cancer; more preferably breast cancer.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binding agents, for example starch, gelatin, polyvinylpyrrolidone or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water soluble taste masking substances such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose, or time extending substances such as ethyl cellulose, cellulose acetate butyrate may be used.
Oral formulations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water soluble carrier, for example polyethylene glycol, or an oil vehicle, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyethylene oxide sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene oxide sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl paraben, one or more colouring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrative of the examples given above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyethylene oxide sorbitol monooleate. The emulsions may also contain sweetening agents, flavouring agents, preservatives and antioxidants. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions of the present invention may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding to a mixture of water and glycerol. The injection solution or microemulsion may be injected into the bloodstream of a patient by local bulk injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.
The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally-acceptable non-toxic diluent or solvent, for example as a solution in 1, 3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health condition of the patient, the patient's integument, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like; in addition, the optimal treatment regimen, such as the mode of treatment, the daily amount of compound (I) of the formula or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:
Figure BDA0001111876800000131
the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:
Figure BDA0001111876800000132
the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:
Figure BDA0001111876800000141
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like; preferably phenyl and cyclopentyl, tetrahydronaphthyl. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably 3 to 6 ring atoms, of which 1-2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, with tetrahydropyranyl, piperidinyl, pyrrolidinyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of spiro heterocyclic groups include:
Figure BDA0001111876800000142
the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure BDA0001111876800000151
the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure BDA0001111876800000152
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
Figure BDA0001111876800000153
and the like.
The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure BDA0001111876800000161
the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferred is pyrazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure BDA0001111876800000162
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to the group-NH2。
The term "cyano" refers to — CN.
The term "nitro" means-NO2。
The term "carboxy" refers to-C (O) OH.
The term "haloalkyl" refers to an alkyl group in which a hydrogen atom is replaced with one or more halogen atoms.
The term "haloalkoxy" refers to an alkoxy group in which a hydrogen atom is replaced by one or more halogen atoms.
The term "carboxylate" refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
The term "acyl halide" refers to a compound containing a group that is-C (O) -halogen.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
Synthesis of the Compounds of the invention
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
the invention relates to a method for preparing a compound shown in a general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof, which comprises the following steps:
Figure BDA0001111876800000181
scheme one
Reacting the compound of the general formula (I-A) with an aldehyde derivative under low-temperature alkaline conditions to obtain a compound of the general formula (I-B), wherein the alkali reagent for the reaction is preferably n-butyllithium; the obtained compound of the general formula (I-B) is subjected to oxidation reaction at normal temperature to obtain a compound of the general formula (I-C), and the oxidant under the condition is preferably Daes-Martin oxidant; the obtained compound of the general formula (I-C) is subjected to cross type McMurry coupling reaction with zinc powder, titanium tetroxide and cyclic ketone derivatives under the heating condition to obtain a compound of the general formula (I-D); reacting the obtained compound of the general formula (I-D) with acrylate under high-temperature alkaline conditions to obtain a compound of a general formula (III), wherein a basic reagent of the reaction is preferably triethylamine, and catalysts of the reaction are preferably palladium acetate and tri (o-tolyl) phosphine; the resulting compound of formula (III) is hydrolyzed under basic conditions to give the compound of formula (I), the alkaline reagents of the reaction being preferably lithium hydroxide and sodium hydroxide.
The compounds of the invention of the general formula (I) can also be prepared as follows:
Figure BDA0001111876800000191
scheme two
Reacting the compound of the general formula (I-A) with an aldehyde derivative under low-temperature alkaline conditions to obtain a compound of the general formula (I-E), wherein the alkali reagent for the reaction is preferably n-butyllithium; the obtained compound of the general formula (I-E) is subjected to oxidation reaction at normal temperature to obtain a compound of the general formula (I-F), and the oxidant under the condition is preferably Daes-Martin oxidant; removing benzyl from the obtained compound of the general formula (I-F) under heating to obtain a compound of the general formula (I-G), wherein hydrogen and palladium carbon are preferably used as reducing agents for the reaction; the obtained compound of the general formula (I-G) is subjected to cross type McMurry coupling reaction with zinc powder, titanium tetroxide and cyclic ketone derivatives under the heating condition to obtain a compound of the general formula (I-H); reacting the obtained compound with the general formula (I-H) with trifluoromethanesulfonic anhydride under an ice-bath alkaline condition to obtain a compound of the general formula (I-I), wherein triethylamine is preferably used as a basic reagent for the reaction; obtaining a compound of the general formula (I-I), and reacting the compound with acrylate to obtain a compound of the general formula (III), wherein a basic reagent of the reaction is preferably triethylamine, and a catalyst of the reaction is preferably palladium acetate and tri (o-tolyl) phosphine; the resulting compound of formula (III) is hydrolyzed under basic conditions to give the compound of formula (I), the alkaline reagents of the reaction being preferably lithium hydroxide and sodium hydroxide.
The reagents that provide basic conditions include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, or potassium tert-butoxide, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, or cesium carbonate, sodium hydroxide, and lithium hydroxide.
Conditions that provide acidity include, but are not limited to, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid.
The reducing agent includes but is not limited to Fe powder, Zn powder, H2Sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or lithium aluminum hydride.
The oxidant used includes, but is not limited to, hydrogen peroxide, potassium permanganate, dess-martin oxidant, oxygen, ozone, potassium dichromate, and manganese dioxide.
Solvents used include, but are not limited to: acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1, 4-dioxane, water or N, N-dimethylformamide.
Wherein:
x is selected from halogen;
ring A, R1～R4R, q and n are as defined in formula (I).
Detailed Description
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
Examples
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).
Average inhibition rate of kinase and IC50The values were determined with a NovoStar microplate reader (BMG, Germany).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc), Darri Chemicals, and the like.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a developing solvent system of: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: the volume ratio of acetone and solvent is adjusted according to the polarity of the compound. The eluent system for column chromatography and the developing agent system for thin-layer chromatography used for purifying compounds comprise: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.
Example 1
(E) -3- (4- (cyclohexylidene (1H-indazol-5-yl) methyl) phenyl) acrylic acid
Figure BDA0001111876800000211
First step of
(4-bromophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanol
5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 1a (500mg, 1.8mmol, prepared by the well-known method "Journal of Organic Chemistry,2009,74(16), 6331-6334") was dissolved in 20mL of tetrahydrofuran, cooled to-78 deg.C, n-butyllithium (0.8mL, 1.98mmol) was added dropwise, the reaction was stirred for 5 minutes, 3mL of a pre-prepared solution of p-bromobenzaldehyde (300mg, 1.62mmol) in tetrahydrofuran was added dropwise, and the reaction was stirred at-78 deg.C for 2 hours. After the reaction was completed, the reaction was quenched with 10mL of a saturated ammonium chloride solution, extracted with ethyl acetate (50mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product (4-bromophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanol 1B (200mg, colorless oil) in yield: 28.7 percent.
MS m/z(ESI):387.0[M+1]
Second step of
(4-bromophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone
(4-bromophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanol 1B (200mg, 0.52mmol) was dissolved in 10mL of dichloromethane, dess-martin oxidant (657mg, 1.55mmol) was added, reaction was performed at 25 ℃ for 12 hours, after completion of the reaction, 10mL of water was added, extraction was performed with ethyl acetate (30 mL. times.2), the organic layer was washed with water (20 mL. times.2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product (4-bromophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 1c (160mg, white solid), the yield was 80%.
MS m/z(ESI):301.0[M+1]
The third step
5- ((4-bromophenyl) (cyclohexylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole
A zinc powder (135mg, 2.08mmol) was dispersed in 10mL of tetrahydrofuran, titanium tetrachloride (190mg, 1.04mmol) was added dropwise, heating and refluxing were carried out for 2 hours, a solution of 10mL of a prepared tetrahydrofuran solution of (4-bromophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 1c (100mg, 0.26mmol) and cyclohexanone (77mg, 0.78mmol) was added dropwise, and the reaction was stirred for 1 hour. After completion of the reaction, it was naturally cooled, the reaction solution was poured into a 10% aqueous solution of potassium carbonate, extracted with ethyl acetate (50mL × 3), the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 5- ((4-bromophenyl) (cyclohexylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 1d (45mg, yellow solid) in yield: 38.5 percent.
MS m/z(ESI):453.0[M+1]
The fourth step
(E) -methyl 3- (4- (cyclohexylidene (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methyl) phenyl) acrylate
Dissolving 5- ((4-bromophenyl) (cyclohexylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 1d (45mg, 0.1mmol), methyl acrylate (26mg, 0.3mmol), tri (o-tolyl) phosphine (3mg, 0.011mmol), triethylamine (30mg, 0.3mmol), and palladium acetate (2mg, 0.006mmol) in 1mL of N, N-dimethylformamide, microwave-reacting at 140 ℃ for 1 hour, after the reaction is finished, naturally cooling, adding 20mL of water, extracting with ethyl acetate (30 mL. times.2), washing the organic layer with water (10 mL. times.3), drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a crude title product (E) -3- (4- (cyclohexylidene (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) Methyl) phenyl) acrylic acid methyl ester 1e (45mg, yellow oil), the product was used in the next reaction without purification.
MS m/z(ESI):457.2[M+1]
The fifth step
(E) -methyl 3- (4- (cyclohexylidene (1H-indazol-5-yl) methyl) phenyl) acrylate
Crude methyl (E) -3- (4- (cyclohexylidene (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methyl) phenyl) acrylate 1E (45mg, 0.1mmol) was dissolved in 2mL of ethanol, 0.2mL of a 5N hydrogen chloride dioxane solution was added, and the reaction was stirred at 70 ℃ for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, adjusted to pH ≈ 9 with saturated sodium bicarbonate solution, extracted with ethyl acetate (30mL × 2), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude title product, methyl (E) -3- (4- (cyclohexylidene (1H-indazol-5-yl) methyl) phenyl) acrylate 1f (37mg, yellow oily substance), which was directly subjected to the next reaction without purification.
MS m/z(ESI):373.1[M+1]
The sixth step
(E) -3- (4- (cyclohexylidene (1H-indazol-5-yl) methyl) phenyl) acrylic acid
Crude methyl (E) -3- (4- (cyclohexylidene (1H-indazol-5-yl) methyl) phenyl) acrylate 1f (37mg, 0.1mmol) was dissolved in 6mL of a mixed solution of tetrahydrofuran and ethanol (V: V ═ 1:1), lithium hydroxide monohydrate (80mg, 2mmol) was added, the reaction mixture was stirred at 25 ℃ for 12 hours, after the reaction was completed, the reaction mixture was concentrated under reduced pressure, pH was adjusted to approximately 3 with 1N hydrochloric acid, extraction was performed with ethyl acetate (30mL × 3), the organic layer was dried over anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography using developer system a to give title product (E) -3- (4- (cyclohexylidene (1H-indazol-5-yl) methyl) phenyl) acrylic acid 1(10mg, a white solid), the yield thereof was found to be 28.6%.
MS m/z(ESI):359.2[M+1]
1H NMR(400MHz,DMSO-d6):δ13.02(brs,1H),12.32(brs,1H),8.05(s,1H),7.65-7.61(m,2H),7.57-7.53(m,2H),7.45(d,1H),7.24(d,2H),7.14(dd,1H),6.48(d,1H),2.53-2.43(m,2H),2.33-2.24(m,2H),1.96-1.89(m,2H),1.59-1.55(m,2H),1.50-1.41(m,2H).
Example 2
(E) -3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -2, 6-difluorophenyl) acrylic acid
Figure BDA0001111876800000231
Figure BDA0001111876800000241
First step of
(4- (benzyloxy) -3, 5-difluorophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanol
5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 1a (1.87g, 6.65mmol) is dissolved in 30mL of tetrahydrofuran, 2.5M n-butyllithium (3.0mL, 7.32mmol) is added dropwise at-78 deg.C, stirring is performed for 10 minutes after the addition is completed, 5mL of a solution of 4- (benzyloxy) -3, 5-difluorobenzaldehyde 2a (1.65g, 6.65mmol, prepared by the method disclosed in patent application WO 2014069963) in tetrahydrofuran, which is prepared by raising the temperature to 25 deg.C naturally, and the reaction is stirred for 12 hours. After the reaction was completed, the reaction was quenched by adding 20mL of saturated ammonium chloride solution, extracted with ethyl acetate (20mL × 3), the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product (4- (benzyloxy) -3, 5-difluorophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanol 2B (1.78g, yellow viscous substance), yield: and 59.3 percent.
Second step of
(4- (benzyloxy) -3, 5-difluorophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone
(4- (benzyloxy) -3, 5-difluorophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanol 2B (1.78g, 3.95mmol) was dissolved in 40mL of dichloromethane, dess-martin oxidant (3.35g, 7.90mmol) was added, the reaction mixture was reacted at 25 ℃ for 12 hours, after the completion of the reaction, the reaction mixture was concentrated under reduced pressure, 30mL of a saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (30 mL. times.3), the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with an eluent system B to give the title product (4- (benzyloxy) -3, 5-difluorophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 2c (1.17g, yellow solid), yield 66%.
The third step
(3, 5-difluoro-4-hydroxyphenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone
To 45mL of ethanol was added (4- (benzyloxy) -3, 5-difluorophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 2c (1.17g, 3.3mmol), 150mg of 10% palladium on carbon was added, hydrogen was substituted three times, and the reaction was stirred at 40 ℃ for 60 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product (3, 5-difluoro-4-hydroxyphenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 2d (540mg, white solid) in yield: 46.0 percent.
The fourth step
2, 6-difluoro-4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenol
Zinc powder (1.04g, 16mmol) was added to 20mL tetrahydrofuran, titanium tetrachloride (0.88mL, 8mmol) was added, the mixture was refluxed for 2 hours, cooled to 0 ℃, lithium aluminum hydride (152mg, 4mmol) was added, the mixture was stirred for 10 minutes in an ice bath, triethylamine (0.56mL, 4mmol) was added, the mixture was refluxed for 1 hour, 5mL of a solution of (3, 5-difluoro-4-hydroxyphenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 2d and 3,3,5, 5-tetramethylcyclohexanone (469mg, 3mmol) in tetrahydrofuran were added, and the mixture was refluxed for 2 hours. After the reaction was completed, 20mL of water was added, extraction was performed with ethyl acetate (20mL × 2), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title product 2, 6-difluoro-4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenol 2e (350mg, pale yellow solid) in a yield of 72.9%.
The fifth step
2, 6-difluoro-4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyltriflate
2, 6-difluoro-4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenol 2e (210mg, 0.437mmol) was dissolved in 10mL of dichloromethane, triethylamine (88mg, 0.874mmol) was added, trifluoromethanesulfonic anhydride (185mg, 0.656mmol) was added under ice bath, the reaction was stirred at 25 ℃ for 12 hours, after completion of the reaction, 10mL of water was added, dichloromethane extraction (10 mL. times.2) was performed, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 2, 6-difluoro-4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) Yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyltriflate 2f (260mg, white solid), yield: 97.4 percent.
The sixth step
(E) -methyl 3- (2, 6-difluoro-4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylate
2, 6-difluoro-4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyltrifluoromethanesulfonate 2f (130mg, 0.2mmol), 0.3mL of methyl acrylate, triethylamine (101mg, 1mmol), and bis (triphenylphosphine) palladium dichloride (15mg, 0.02mmol) were added to 1mL of N, N-dimethylformamide and reacted with a microwave at 140 ℃ for 1.5 hours under an argon atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure, 10mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with an eluent system B to give the title product methyl (E) -3- (2, 6-difluoro-4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylate 2g (30mg, yellow solid) in 27.2% yield.
Seventh step
(E) -methyl 3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -2, 6-difluorophenyl) acrylate
2g (30mg, 0.05mmol) of methyl (E) -3- (2, 6-difluoro-4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylate was dissolved in 5mL of ethanol, 0.5mL of 4M solution of hydrogen chloride in 1, 4-dioxane was added, and the reaction was stirred at 60 ℃ for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, 10mL of a saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (10mL × 3), the organic layer was dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain a crude title product of (E) -methyl 3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -2, 6-difluorophenyl) acrylate (2H (25mg, white solid), which was directly subjected to the next reaction without purification.
Eighth step
(E) -3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -2, 6-difluorophenyl) acrylic acid
Dissolving crude methyl (E) -3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -2, 6-difluorophenyl) acrylate in 4mL of methanol for 2H (25mg, 0.05mmol), adding 1mL of 2N sodium hydroxide solution, stirring at 25 ℃ for reaction for 12 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure, adding 10mL of water, adjusting the pH to 2-3 with 1N hydrochloric acid, extracting with ethyl acetate (10 mL. times.3), drying the organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the obtained residue with a developing reagent system A by thin layer chromatography to obtain the title product (E) -3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -2, 6-difluorophenyl) acrylic acid 2(20mg, white solid), yield 83.3%.
MS m/z(ESI):451.4[M+1]
1H NMR(400MHz,DMSO-d6):δ13.05(bs,2H),8.15(s,1H),7.29-7.50(m,6H),6.65(d,1H),2.01(s,2H),1.88(s,2H),1.27(s,2H),0.91(d,12H).
Example 3
(E) -3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -3, 5-difluorophenyl) acrylic acid
Figure BDA0001111876800000271
First step of
(4-bromo-2, 6-difluorophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanol
5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 1a (560mg, 2mmol) is dissolved in 10mL of diethyl ether, 2.5M n-butyllithium (1.7mL, 2.2mmol) is added dropwise at-78 deg.C, stirring is completed for 10 minutes, 2mL of a 4-bromo-2, 6-difluorobenzaldehyde (442mg, 2mmol) solution in diethyl ether is added dropwise, the temperature is raised to 25 deg.C naturally, and the reaction is stirred for 60 hours. After the reaction was completed, the reaction was quenched by adding 10mL of saturated ammonium chloride solution, extracted with ethyl acetate (10mL × 3), the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product (4-bromo-2, 6-difluorophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanol 3a (500mg, white solid), yield: 59.1 percent.
Second step of
(4-bromo-2, 6-difluorophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone
(4-bromo-2, 6-difluorophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanol 3a (470mg, 1.11mmol) was dissolved in 10mL of dichloromethane, followed by addition of dess-martin oxidant (942mg, 2.22mmol) and reaction at 25 ℃ for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, 10mL of a saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (10mL × 3), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product (4-bromo-2, 6-difluorophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 3B (350mg, white solid) in a yield of 75.6%.
The third step
5- ((4-bromo-2, 6-difluorophenyl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole
Zinc powder (839mg, 12.9mmol) was added to 20mL of tetrahydrofuran, titanium tetrachloride (0.71mL, 6.46mmol) was added, the mixture was refluxed for 2 hours, cooled to 0 ℃, lithium aluminum hydride (123mg, 3.23mmol) was added, the mixture was stirred for 10 minutes in ice bath, triethylamine (0.45mL, 3.23mmol) was added, the mixture was refluxed for 1 hour, and 5mL of a solution of (4-bromo-2, 6-difluorophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 3b (340mg, 0.807mmol) and 3,3,5, 5-tetramethylcyclohexanone (374mg, 2.42mmol) in tetrahydrofuran were added and refluxed for 2 hours. After the reaction was completed, 20mL of water was added to quench the reaction, extracted with ethyl acetate (10mL × 3), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title product 5- ((4-bromo-2, 6-difluorophenyl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 3c (120mg, colorless viscous) in 27.3% yield.
The fourth step
(E) -methyl 3- (3, 5-difluoro-4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylate
5- ((4-bromo-2, 6-difluorophenyl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 3c (120mg, 0.221mmol), 0.25mL of methyl acrylate, triethylamine (67mg, 0.663mmol), palladium acetate (2.98mg, 0.0133mmol), and tris (o-tolyl) phosphine (8.07mg, 0.0265mmol) were added to 0.5mL of N, N-dimethylformamide and reacted with a microwave at 150 ℃ for 1.5 hours under an argon atmosphere. After the reaction was completed, 10mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title product methyl (E) -3- (3, 5-difluoro-4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) acrylate 3d (50mg, colorless viscous substance) in 41.7% yield.
The fifth step
(E) -methyl 3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -3, 5-difluorophenyl) acrylate
Methyl (E) -3- (3, 5-difluoro-4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylate 3d (50mg, 0.1mmol) was dissolved in 5mL of ethanol, 0.5mL of 4M solution of hydrogen chloride in 1, 4-dioxane was added, and the reaction was stirred at 60 ℃ for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, 10mL of a saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (10mL × 3), the organic layer was dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain a crude title product of (E) -methyl 3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -3, 5-difluorophenyl) acrylate 3E (46mg, white solid), which was directly subjected to the next reaction without purification.
The sixth step
(E) -3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -3, 5-difluorophenyl) acrylic acid
Dissolving crude methyl (E) -3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -3, 5-difluorophenyl) acrylate 3E (46mg, 0.1mmol) in 5mL of methanol, adding 0.5mL of 15% sodium hydroxide solution, stirring at 25 ℃ for reaction for 12 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure, adding 10mL of water, adjusting the pH to 2-3 with 2N hydrochloric acid, extracting with ethyl acetate (10 mL. times.3), concentrating the organic phase under reduced pressure, purifying the obtained residue with high performance liquid chromatography to obtain the title product (E) -3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -3, 5-difluorophenyl) acrylic acid 3(40mg, white solid), yield 88.9%.
MS m/z(ESI):451.4[M+1]
1H NMR(400MHz,DMSO-d6):δ13.07(bs,2H),8.05(s,1H),7.41-7.56(m,5H),7.18(d,1H),6.60(d,1H),1.99(s,2H),1.84(s,2H),1.30(s,2H),0.90(d,12H).
Example 4
(E) -3- (4- ((3-fluoro-1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylic acid
Figure BDA0001111876800000291
First step of
(4-bromophenyl) (3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanol
5-bromo-3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 4a (600mg, 2mmol, prepared by the method disclosed in patent application "WO 2012037411") was added to 8mL of anhydrous ethanol, 2.5M n-butyllithium (0.8mL, 2mmol) was added at-78 ℃, stirred for 10 minutes at-78 ℃, a solution of 2mL of p-bromobenzaldehyde (388mg, 2.1mmol) in anhydrous ethanol was added dropwise, the mixture was allowed to naturally rise to 25 ℃ and stirred for 12 hours. After the reaction was completed, the reaction was quenched with 10mL of water, extracted with ethyl acetate (10mL × 3), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title product (4-bromophenyl) (3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanol 4B (590mg, white solid), yield: 72.8 percent.
Second step of
(4-bromophenyl) (3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone
(4-bromophenyl) (3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanol 4b (1.34g, 3.31mmol) was dissolved in 25mL of dichloromethane, and dess-martin oxidant (2.81g, 6.61mmol) was added to react at 25 ℃ for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 10mL of a saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (10mL × 3), the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product (4-bromophenyl) (3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 4c (950mg, white solid) in 71.2% yield.
The third step
5- ((4-bromophenyl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole
Zinc powder (520mg, 8mmol) was added to 10mL tetrahydrofuran, titanium tetrachloride (0.44mL, 4mmol) was added, the mixture was refluxed for 2 hours, cooled to 0 ℃, lithium aluminum hydride (0.44mL, 4mmol) was added, the mixture was stirred for 10 minutes in an ice bath, triethylamine (0.28mL, 2mmol) was added, the mixture was refluxed for 1 hour, 2mL of a solution of (4-bromophenyl) (3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 4c (200mg, 0.5mmol) and 3,3,5, 5-tetramethylcyclohexanone (231mg, 1.5mmol) in tetrahydrofuran was added, and the reaction was refluxed for 1 hour. After the reaction was completed, 10mL of water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate (10mL × 3), and the organic phase was concentrated under reduced pressure to give a crude title product, 5- ((4-bromophenyl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 4d (270mg, colorless viscous substance), which was directly subjected to the next reaction without purification.
The fourth step
(E) -methyl 3- (4- ((3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylate
5- ((4-bromophenyl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 4d (210mg, 0.5mmol), 0.75mL of methyl acrylate, triethylamine (151mg, 1.5mmol), palladium acetate (6.75mg, 0.03mmol), and tri (o-tolyl) phosphine (18.25mg, 0.06mmol) were added to 1.5mL of N, N-dimethylformamide and reacted with a microwave at 150 ℃ for 1.5 hours. After the reaction was completed, 10mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product methyl (E) -3- (4- ((3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) acrylate 4E (140mg, white solid) in 52.8% yield.
The fifth step
(E) -methyl 3- (4- ((3-fluoro-1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylate
Methyl (E) -3- (4- ((3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylate 4E (140mg, 0.264mmol) was dissolved in 4.5mL of ethanol, 0.5mL of a 4N solution of hydrogen chloride in 1, 4-dioxane was added, and the reaction was stirred at 50 ℃ for 60 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, 10mL of a saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (10mL × 3), the organic layer was dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain a crude title product of (E) -methyl 3- (4- ((3-fluoro-1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylate 4f (150mg, colorless viscous substance), which was directly subjected to the next reaction without purification.
The sixth step
(E) -3- (4- ((3-fluoro-1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylic acid
Dissolving crude methyl (E) -3- (4- ((3-fluoro-1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylate 4f (150mg, 0.336mmol) in 5mL of methanol, adding 1mL of 2N sodium hydroxide solution, stirring at 25 ℃ for reaction for 12 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure, adding 10mL of water, adjusting the pH to 2-3 with 1N hydrochloric acid, extracting with ethyl acetate (10 mL. times.3), concentrating the organic phase under reduced pressure, purifying the obtained residue with a developing solvent system A by thin layer chromatography to obtain a title product (E) -3- (4- ((3-fluoro-1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylic acid 4(60 mg), yellow solid), yield 41.3%.
MS m/z(ESI):433.4[M+1]
1H NMR(400MHz,DMSO-d6):δ12.50(s,1H),12.35(bs,1H),7.61(d,2H),7.46-7.52(m,2H),7.40(m,1H),7.20-7.26(m,3H),6.47(m,1H),1.93(d,4H),1.28(s,2H),0.90(d,12H).
Example 5
(E) -3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylic acid
Figure BDA0001111876800000311
First step of
5- ((4-bromophenyl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole
Zinc powder (270mg, 4.16mmol) was added to 10mL of tetrahydrofuran, titanium tetrachloride (394mg, 2.08mmol) was added, the mixture was refluxed for 2 hours, cooled to 0 ℃, lithium aluminum hydride (39mg, 1.04mmol) was added, the mixture was stirred for 10 minutes in ice bath, triethylamine (101mg, 1.04mmol) was added, the mixture was refluxed for 1 hour, 2mL of a prepared tetrahydrofuran solution of (4-bromophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 1c (100mg, 0.26mmol) and 3,3,5, 5-tetramethylcyclohexanone (111mg, 0.72mmol) was added, and the reaction was refluxed for 1 hour. After the reaction was completed, 10mL of water was added to quench the reaction, filtered, extracted with ethyl acetate (10mL × 3), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title product 5- ((4-bromophenyl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 5a (150mg, white solid) in 76.5% yield.
MS m/z(ESI):507.1[M+1]
Second step of
(E) -methyl 3- (4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylate
5- ((4-bromophenyl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 5a (150mg, 0.3mmol), methyl acrylate (127mg, 1.48mmol), triethylamine (91mg, 0.9mmol), palladium acetate (4mg, 0.016mmol), and tri (o-tolyl) phosphine (1.0mg, 0.033mmol) were added to 1mL of N, N-dimethylformamide, and microwave-reacted at 150 ℃ for 1.5 hours. After the reaction was completed, 10mL of water was added, extraction was performed with ethyl acetate (30mL × 2), the organic phase was washed with water (10mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product methyl (E) -3- (4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylate 5B (80mg, white solid) in 52.3% yield.
MS m/z(ESI):513.3[M+1]
The third step
(E) -methyl 3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylate
Methyl (E) -3- (4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylate 5b (80mg, 0.156mmol) was dissolved in 4mL of ethanol, 0.5mL of a 4M solution of 1, 4-dioxane was added, and the reaction was stirred at 60 ℃ for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude title product of methyl (E) -3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylate 5c (67mg, yellow oil), which was directly subjected to the next reaction without purification.
The fourth step
(E) -3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylic acid
Crude methyl (E) -3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylate 5c (67mg, 0.156mmol) was dissolved in 2mL of methanol and 2mL of tetrahydrofuran, 0.78mL of 1N lithium hydroxide was added, the reaction was stirred at 25 ℃ for 12 hours, after the completion of the reaction, the reaction mixture was concentrated under reduced pressure, pH was adjusted to 5 with 1N hydrochloric acid, extraction was performed with ethyl acetate (30 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography developed reagent system A to give the title product (E) -3- (4- ((1H-indazol-5-yl) (3,3,5, 5-tetramethylcyclohexylidene) methyl) phenyl) acrylic acid 5(20mg, white solid), yield 31.3%.
MS m/z(ESI):415.4[M+1]
1H NMR(400MHz,DMSO-d6):δ13.02(brs,1H),12.32(brs,1H),8.03(s,1H),7.62(d,2H),7.57-7.53(m,2H),7.46(d,1H),7.24(d,2H),7.14(dd,1H),6.48(d,1H),1.97(d,4H),1.30(s,2H),0.92(d,12H).
Example 6
(E) -3- (4- ((1H-indazol-5-yl) (1H-inden-2 (3H) -ylidene) methyl) phenyl) acrylic acid
Figure BDA0001111876800000331
First step of
5- ((4-bromophenyl) (1H-inden-2 (3H) -ylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole
Zinc powder (416mg, 6.4mmol) was added to 15mL tetrahydrofuran, titanium tetrachloride (0.35mL, 3.2mmol) was added, the reaction was refluxed for 2 hours, cooled to 0 ℃, lithium aluminum hydride (61mg, 1.6mmol) was added, stirred for 10 minutes in ice bath, triethylamine (0.22mL, 1.6mmol) was added, the reaction was refluxed for 1 hour, and 3mL of a solution of (4-bromophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 1c (154.1mg, 0.4mmol) and 2-indanone (158mg, 1.2mmol) in tetrahydrofuran were added and refluxed for 1 hour. After the reaction was completed, the reaction solution was cooled to 0 ℃,20 mL of water was added to quench the reaction, extracted with ethyl acetate (80mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 5- ((4-bromophenyl) (1H-inden-2 (3H) -ylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 6a (100mg, colorless solid) in 50% yield.
MS m/z(ESI):487.1[M+1]
Second step of
(E) -methyl 3- (4- ((1H-inden-2 (3H) -ylidene) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methyl) phenyl) acrylate
5- ((4-bromophenyl) (1H-inden-2 (3H) -ylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 6a (100mg, 0.2mmol), 1mL of methyl acrylate, triethylamine (0.3mL, 2.0mmol), palladium acetate (4.5mg, 0.02mmol), and tri (o-tolyl) phosphine (6.2mg, 0.02mmol) were added to 2mL of N, N-dimethylformamide, and microwave-reacted at 150 ℃ for 1.5 hours. After the reaction was completed, 30mL of water was added, and extraction was performed with ethyl acetate (60mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product methyl (E) -3- (4- ((1H-indene-2 (3H) -ylidene) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methyl) phenyl) acrylate 6B (65mg, colorless oil) in 35% yield.
MS m/z(ESI):491.2[M+1]
The third step
(E) -methyl 3- (4- ((1H-indazol-5-yl) (1H-inden-2 (3H) -ylidene) methyl) phenyl) acrylate
Methyl (E) -3- (4- ((1H-inden-2 (3H) -ylidene) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methyl) phenyl) acrylate 6b (35mg, 0.071mmol) was dissolved in 4mL of ethanol, 0.5mL of 4M hydrogen chloride 1, 4-dioxane solution was added, and the reaction was stirred at 60 ℃ for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and dissolved in 20mL of dichloromethane, concentrated under reduced pressure, and then 20mL of dichloromethane was added, three drops of triethylamine were added, and concentrated under reduced pressure to obtain a crude title product, methyl (E) -3- (4- ((1H-indazol-5-yl) (1H-indene-2 (3H) -ylidene) methyl) phenyl) acrylate 6c (25mg, brown oil), which was directly subjected to the next reaction without purification.
MS m/z(ESI):407.3[M+1]
The fourth step
(E) -3- (4- ((1H-indazol-5-yl) (1H-inden-2 (3H) -ylidene) methyl) phenyl) acrylic acid
Crude methyl (E) -3- (4- ((1H-indazol-5-yl) (1H-inden-2 (3H) -ylidene) methyl) phenyl) acrylate 6c (25mg, 0.06mmol) was dissolved in 3mL of methanol, 0.5mL of 2N sodium hydroxide solution was added, the reaction was stirred at 25 ℃ for 12 hours, after the completion of the reaction, the reaction mixture was concentrated under reduced pressure, 10mL of water was added, pH was adjusted to about 3 with 2N hydrochloric acid, extraction was performed with ethyl acetate (30 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product (E) -3- (4- ((1H-indazol-5-yl) (1H-inden-2 (3H) -ylidene) methyl) phenyl) acrylic acid 6(10mg, white solid), yield 41%.
MS m/z(ESI):393.3[M+1]
1H NMR(400MHz,DMSO-d6):δ13.40(bs,1H),12.36(bs,1H),8.27(d,1H),8.23(s,1H),7.89(s,1H),7.45(d,1H),7.41-7.43(m,4H),7.33-7.40(m,5H),6.33(d,1H),3.21-3.26(m,4H).
Example 7
(E) -3- (4- ((1r,3r) -adamantan-2-ylidene (1H-indazol-5-yl) methyl) phenyl) acrylate
Figure BDA0001111876800000351
First step of
5- ((1r,3r) -adamantan-2-ylidene (4-bromophenyl) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole
Zinc powder (520mg, 8mmol) was added to 20mL tetrahydrofuran, titanium tetrachloride (0.44mL, 4mmol) was added, the mixture was refluxed for 2 hours, cooled to 0 ℃, lithium aluminum hydride (76mg, 2mmol) was added, the mixture was stirred for 10 minutes in an ice bath, triethylamine (0.28mL, 2mmol) was added, the mixture was refluxed for 1 hour, 5mL of a prepared tetrahydrofuran solution of (4-bromophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 1c (193mg, 0.5mmol) and (1r,3r,5r,7r) -adamantan-2-one (220mg, 1.5mmol) were added, and the reaction was refluxed for 1 hour. After the reaction was completed, 20mL of water was added to quench the reaction, extracted with ethyl acetate (10mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 5- ((1r,3r) -adamantan-2-ylidene (4-bromophenyl) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 7a (200mg, white solid) in 80% yield.
Second step of
(E) -methyl 3- (4- ((1r,3r) -adamantan-2-ylidene (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methyl) phenyl) acrylate
5- ((1r,3r) -adamantan-2-ylidene (4-bromophenyl) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 7a (200mg, 0.4mmol), 0.5mL methyl acrylate, triethylamine (121mg, 1.2mmol), palladium acetate (5.4mg, 0.024mmol), and tri (o-tolyl) phosphine (13.4mg, 0.044mmol) were added to 1.5mL N, N-dimethylformamide and microwave-reacted at 150 ℃ for 1.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, 10mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product methyl (E) -3- (4- ((1r,3r) -adamantan-2-ylidene (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methyl) acrylate 7B (150mg, white solid) in 73.9% yield.
The third step
(E) -methyl 3- (4- ((1r,3r) -adamantan-2-ylidene (1H-indazol-5-yl) methyl) phenyl) acrylate
Methyl (E) -3- (4- ((1r,3r) -adamantan-2-ylidene (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methyl) phenyl) acrylate 7b (150mg, 0.29mmol) was dissolved in 5mL ethanol, 0.5mL of 4N hydrogen chloride 1, 4-dioxane solution was added, and the reaction was stirred at 60 ℃ for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude title product, methyl (E) -3- (4- ((1r,3r) -adamantan-2-ylidene (1H-indazol-5-yl) methyl) phenyl) acrylate 7c (140mg, white solid), which was directly subjected to the next reaction without purification.
The fourth step
(E) -3- (4- ((1r,3r) -adamantan-2-ylidene (1H-indazol-5-yl) methyl) phenyl) acrylic acid
Dissolving crude (E) -3- (4- ((1r,3r) -adamantan-2-ylidene (1H-indazol-5-yl) methyl) phenyl) methyl acrylate 7c (120mg, 0.28mmol) in 5mL of methanol, adding 1mL of 2N sodium hydroxide solution, stirring at 25 ℃ for reaction for 12 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure, adding 10mL of water, adjusting the pH to 2-3 with 1N hydrochloric acid, extracting with ethyl acetate (10 mL. times.3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the obtained residue by high performance liquid chromatography to obtain a target product (E) -3- (4- ((1r,3r) -adamantan-2-ylidene (1H-indazol-5-yl) methyl) phenyl) acrylic acid 7(100 mg), white solid), yield 86.2%.
MS m/z(ESI):411.4[M+1]
1H NMR(400MHz,DMSO-d6):δ12.75(bs,2H),8.01(s,1H),7.44-7.60(m,5H),7.13(d,2H),7.05(d,1H),2.69(d,2H),1.95(s,2H),1.77-1.83(m,10H).
Example 8
(E) -3- (4- (bicyclo [3.3.1] nonan-9-ylidene (1H-indazol-5-yl) methyl) phenyl) acrylic acid
Figure BDA0001111876800000361
Figure BDA0001111876800000371
First step of
5- (bicyclo [3.3.1] nonan-9-ylidene (4-bromophenyl) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole
Zinc powder (270mg, 4.16mmol) was added to 10mL of tetrahydrofuran, titanium tetrachloride (394mg, 2.08mmol) was added, the reaction refluxed for 2 hours, cooled to 0 deg.C, lithium aluminum hydride (39mg, 1.04mmol) was added, the mixture was stirred for 10 minutes in ice bath, triethylamine (101mg, 1.04mmol) was added, the reaction refluxed for 1 hour, and 2mL of a solution of (4-bromophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 1c (100mg, 0.26mmol) and bicyclo [3.3.1] nonan-9-one (107mg, 0.78mmol, Aldrich Chemical Company) in tetrahydrofuran were added and refluxed for 1 hour. After the reaction was completed, 10mL of water was added to quench the reaction, filtered, extracted with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 5- (bicyclo [3.3.1] nonan-9-ylidene (4-bromophenyl) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 8a (100mg, white solid) in 78% yield.
MS m/z(ESI):493.1[M+1]
Second step of
(E) -methyl 3- (4- (bicyclo [3.3.1] nonan-9-ylidene (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methyl) phenyl) acrylate
5- (bicyclo [3.3.1] nonan-9-ylidene (4-bromophenyl) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 8a (100mg, 0.2mmol), methyl acrylate (86mg, 1.0mmol), triethylamine (61mg, 0.6mmol), palladium acetate (3mg, 0.012mmol), and tri (o-tolyl) phosphine (7mg, 0.022mmol) were added to 1mL of N, N-dimethylformamide and reacted with a microwave at 140 ℃ for 1.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, 10mL of water was added, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product (E) -methyl 3- (4- (bicyclo [3.3.1] nonan-9-ylidene (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methyl) acrylate 8B (100mg, yellow oil) with a yield of 98.7%.
MS m/z(ESI):497.3[M+1]
The third step
(E) -methyl 3- (4- (bicyclo [3.3.1] nonan-9-ylidene (1H-indazol-5-yl) methyl) phenyl) acrylate
Methyl (E) -3- (4- (bicyclo [3.3.1] nonan-9-ylidene (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methyl) phenyl) acrylate 8b (100mg, 0.2mmol) was dissolved in 2mL of ethanol, 0.2mL of 5N hydrogen chloride 1, 4-dioxane solution was added, and the reaction was stirred at 70 ℃ for 0.5 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude title product of (E) -methyl 3- (4- (bicyclo [3.3.1] nonan-9-ylidene (1H-indazol-5-yl) methyl) phenyl) acrylate 8c (100mg, yellow oil), which was directly subjected to the next reaction without purification.
MS m/z(ESI):413.2[M+1]
The fourth step
(E) -3- (4- (bicyclo [3.3.1] nonan-9-ylidene (1H-indazol-5-yl) methyl) phenyl) acrylic acid
Crude methyl (E) -3- (4- (bicyclo [3.3.1] nonane-9-ylidene (1H-indazol-5-yl) methyl) phenyl) acrylate 8c (100mg, 0.2mmol) was dissolved in 2mL of tetrahydrofuran and 4mL of methanol, 0.6mL of 1N lithium hydroxide solution was added, the reaction mixture was stirred at 25 ℃ for 12 hours, after the completion of the reaction, the reaction mixture was concentrated under reduced pressure, pH was adjusted to 5 with 1N hydrochloric acid, extraction was performed with ethyl acetate (30 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the resulting residue was purified by thin layer chromatography with eluent A to give the title product (E) -3- (4- (bicyclo [3.3.1] nonane-9-ylidene (1H-indazol-5-yl) methyl) phenyl) acrylic acid 8(10mg, white solid), yield 12.5%.
MS m/z(ESI):399.3[M+1]
1H NMR(400MHz,DMSO-d6):δ1.30-1.37(m,3H),1.42-1.46(m,2H),1.61-1.68(m,3H),1.76-1.85(m,4H),2.43-2.47(m,2H),6.48(d,1H),7.12(d,1H),7.27(d,2H),7.45(d,1H),7.51-7.54(m,2H),7.59-7.63(m,2H),8.01(s,1H),12.35(brs,1H),13.00(brs,1H).
Example 9
(E) -3- (4- ((1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) -3, 5-difluorophenyl) acrylic acid
Figure BDA0001111876800000381
Figure BDA0001111876800000391
First step of
5- ((4-bromo-2, 6-difluorophenyl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole
Zinc powder (1.04g, 16mmol) was added to 20mL of tetrahydrofuran, titanium tetrachloride (0.88mL, 8mmol) was added, the reaction was refluxed for 2 hours, cooled to 0 ℃, added with lithium aluminum hydride (152mg, 4mmol), stirred for 10 minutes in ice bath, added with triethylamine (0.56mL, 4mmol), refluxed for 1 hour, 5mL of a prepared tetrahydrofuran solution of (4-bromo-2, 6-difluorophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 3b (421mg, 1mmol) and 2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -one (469mg, 3mmol, prepared by the method disclosed in patent application "WO 2062018589") was added and reacted for 1 hour under reflux. After the reaction was completed, 20mL of water was added to quench the reaction, extracted with ethyl acetate (10mL × 3), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title product 5- ((4-bromo-2, 6-difluorophenyl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 9a (220mg, white solid) in 40.4% yield.
Second step of
(E) -methyl 3- (3, 5-difluoro-4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylate
5- ((4-bromo-2, 6-difluorophenyl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 9a (120mg, 0.22mmol), 0.25mL of methyl acrylate, triethylamine (67mg, 0.66mmol), palladium acetate (2.98mg, 0.0133mmol), and tri (o-tolyl) phosphine (8.07mg, 0.0265mmol) were added to 0.5mL of N, N-dimethylformamide and microwave-reacted at 150 ℃ for 1.5 hours. After the reaction was completed, 10mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title product methyl (E) -3- (3, 5-difluoro-4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylate 9B (88mg, colorless viscous substance) in yield of 72.7%.
The third step
(E) -methyl 3- (4- ((1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) -3, 5-difluorophenyl) acrylate
Methyl (E) -3- (3, 5-difluoro-4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylate 9b (88mg, 0.16mmol) was dissolved in 5mL of ethanol, 0.5mL of a 4M solution of hydrogen chloride 1, 4-dioxane was added, and the reaction was stirred at 60 ℃ for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, 10mL of a saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (10mL × 3), the organic layer was dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain a crude title product, methyl (E) -3- (4- ((1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) -3, 5-difluorophenyl) acrylate 9c (80mg, white solid), which was directly subjected to the next reaction without purification.
The fourth step
(E) -3- (4- ((1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) -3, 5-difluorophenyl) acrylic acid
Dissolving crude methyl (E) -3- (4- ((1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) -3, 5-difluorophenyl) acrylate 9c (80mg, 0.17mmol) in 5mL of methanol, adding 0.5mL of 15% sodium hydroxide solution, stirring at 25 ℃ for reaction for 12 hours, after the reaction is completed, concentrating the reaction solution under reduced pressure, adding 10mL of water, adjusting the pH to 2-3 with 2N hydrochloric acid, extracting with ethyl acetate (10 mL. times.3), concentrating the organic phase under reduced pressure, and purifying the resulting residue by high performance liquid chromatography to obtain the title product (E) -3- (4- ((1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) Methyl) -3, 5-difluorophenyl) acrylic acid 9(40mg, white solid), yield 51.5%.
MS m/z(ESI):453.4[M+1]
1H NMR(400MHz,DMSO-d6):δ13.08(bs,1H),12.60(bs,1H),8.06(s,1H),7.49-7.58(m,5H),7.18(d,1H),6.65(d,1H),2.24(s,2H),2.05(s,2H),1.14(d,12H).
Example 10
(E) -3- (4- ((1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylic acid
Figure BDA0001111876800000401
First step of
5- ((4-bromophenyl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole
Zinc powder (520mg, 8mmol) was added to 20mL tetrahydrofuran, titanium tetrachloride (0.44mL, 4mmol) was added, the reaction was refluxed for 2 hours, cooled to 0 ℃, lithium aluminum hydride (76mg, 2mmol) was added, the mixture was stirred for 10 minutes in an ice bath, triethylamine (0.28mL, 2mmol) was added, the reaction was refluxed for 1 hour, 5mL of a prepared tetrahydrofuran solution of (4-bromophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 1c (193mg, 0.5mmol) and 2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -one (200mg, 1.28mmol) were added, and the reaction was refluxed for 1 hour. After the reaction was completed, 10mL of water was added to quench the reaction, extracted with ethyl acetate (10mL × 3), the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 5- ((4-bromophenyl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 10a (190mg, white solid) in 74.5% yield.
Second step of
(E) -methyl 3- (4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylate
5- ((4-bromophenyl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 10a (140mg, 0.275mmol), 0.5mL of methyl acrylate, triethylamine (108mg, 1.06mmol), palladium acetate (4.8mg, 0.0213mmol), and tris (o-tolyl) phosphine (12mg, 0.039mmol) were added to 1.5mL of N, N-dimethylformamide and microwave-reacted at 150 ℃ for 1.5 hours. After the reaction was completed, 10mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product methyl (E) -3- (4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylate 10B (60mg, white solid) in 42.5% yield.
The third step
(E) -methyl 3- (4- ((1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylate
Methyl (E) -3- (4- ((1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylate 10b (100mg, 0.19mmol) was dissolved in 5mL of ethanol, 0.5mL of 4N hydrogen chloride 1, 4-dioxane solution was added, and the reaction was stirred at 60 ℃ for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, 10mL of a saturated sodium bicarbonate solution was added, ethyl acetate was extracted (10mL × 3), and the organic phase was concentrated under reduced pressure to obtain a crude title product of (E) -methyl 3- (4- ((1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylate 10c (100mg, yellow solid), which was directly subjected to the next reaction without purification.
The fourth step
(E) -3- (4- ((1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylic acid
Dissolving crude (E) -3- (4- ((1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylic acid methyl ester 10c (100mg, 0.232mmol) in 10mL of methanol and 10mL of dichloromethane, adding 3mL of 2N sodium hydroxide solution, stirring and reacting at 25 ℃ for 48 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure, adding 10mL of water, adjusting the pH to 2-3 with 1N hydrochloric acid, extracting with ethyl acetate (10 mL. times.3), concentrating the organic phase under reduced pressure, purifying the obtained residue with an eluent system B by silica gel column chromatography to obtain a title product (E) -3- (4- ((1H-indazol-5-yl) (2,2,6, 6-Tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylic acid 10(50mg, white solid) yield 51.5%.
MS m/z(ESI):417.4[M+1]
1H NMR(400MHz,DMSO-d6):δ13.03(bs,1H),12.37(bs,1H),8.03(s,1H),7.46-7.63(m,5H),7.25(d,1H),7.14(d,1H),6.47(d,1H),2.18(d,4H),1.15(d,12H).
Example 11
(E) -3- (4- ((E) - (3, 4-dihydronaphthalen-1 (2H) -ylidene) (1H-indazol-5-yl) methyl) phenyl) acrylic acid
Figure BDA0001111876800000421
First step of
(E) -5- ((4-bromophenyl) (3, 4-dihydronaphthalen-1 (2H) -ylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole
Zinc powder (832mg, 12.8mmol) was added to 30mL tetrahydrofuran, titanium tetrachloride (0.70mL, 6.4mmol) was added, the reaction was refluxed for 2 hours, cooled to 0 ℃, lithium aluminum hydride (122mg, 3.2mmol) was added, stirred for 10 minutes in ice bath, triethylamine (0.44mL, 3.2mmol) was added, the reaction was refluxed for 1 hour, and a pre-prepared solution of 6mL (4-bromophenyl) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 1c (308.2mg, 0.8mmol) and 3, 4-dihydronaphthalen-1 (2H) -one (350mg, 2.4mmol, Shao-Tuo chemical science) in tetrahydrofuran was added and refluxed for 1 hour. After the reaction was completed, 10mL of water was added to quench the reaction, extracted with ethyl acetate (10mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product (E) -5- ((4-bromophenyl) (3, 4-dihydronaphthalen-1 (2H) -ylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 11a (200mg, white viscous substance) in 50% yield.
MS m/z(ESI):499.3[M+1]
Second step of
(E) -methyl 3- (4- ((E) - (3, 4-dihydronaphthalen-1 (2H) -ylidene) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methyl) phenyl) acrylate
(E) -5- ((4-bromophenyl) (3, 4-dihydronaphthalen-1 (2H) -ylidene) methyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 11a (150mg, 0.3mmol), 1.5mL of methyl acrylate, 0.9mL of triethylamine, palladium acetate (6.6mg, 0.01mmol), and tri (o-tolyl) phosphine (9.3mg, 0.03mmol) were added to 2mL of N, N-dimethylformamide and microwave-reacted at 140 ℃ for 1.5 hours. After the reaction was completed, 30mL of water was added, and extraction was performed with ethyl acetate (60mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product methyl (E) -3- (4- ((E) - (3, 4-dihydronaphthalen-1 (2H) -ylidene) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methyl) phenyl) acrylate 11B (52mg, colorless oil) in 35% yield.
MS m/z(ESI):505.3[M+1]
The third step
(E) -methyl 3- (4- ((E) - (3, 4-dihydronaphthalen-1 (2H) -ylidene) (1H-indol-5-yl) methyl) phenyl) acrylate
Methyl (E) -3- (4- ((E) - (3, 4-dihydronaphthalen-1 (2H) -ylidene) (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methyl) phenyl) acrylate 11b (60mg, 0.12mmol) was dissolved in 4mL of ethanol, 0.5mL of 4M hydrogen chloride 1, 4-dioxane solution was added, and the reaction was stirred at 60 ℃ for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give a crude title product of (E) -methyl 3- (4- ((E) - (3, 4-dihydronaphthalen-1 (2H) -ylidene) (1H-indol-5-yl) methyl) phenyl) acrylate 11c (50mg, colorless oil), which was directly subjected to the next reaction without purification.
The fourth step
(E) -3- (4- ((E) - (3, 4-dihydronaphthalen-1 (2H) -ylidene) (1H-indazol-5-yl) methyl) phenyl) acrylic acid
Dissolving crude methyl (E) -3- (4- ((E) - (3, 4-dihydronaphthalene-1 (2H) -ylidene) (1H-indol-5-yl) methyl) phenyl) acrylate 11c (50mg, 0.12mmol) in 5mL of methanol, adding 1mL of 2N sodium hydroxide solution, stirring at 25 ℃ for reaction for 3 hours, after the reaction is completed, concentrating the reaction solution under reduced pressure, adding 10mL of water, adjusting the pH to 2-3 with 1N hydrochloric acid, extracting with ethyl acetate (10 mL. times.3), concentrating the organic phase under reduced pressure, purifying the resulting residue with silica gel column chromatography using an eluent system B to obtain the title product (E) -3- (4- ((E) - (3, 4-dihydronaphthalene-1 (2H) -ylidene) (1H-indazol-5-yl) methyl) phenyl) acrylic acid 11(15 mg), yellow solid), yield 31.2%.
MS m/z(ESI):407.3[M+1]
1H NMR(400MHz,DMSO-d6):δ13.40(bs,1H),12.35(bs,1H),8.32(d,1H),8.24(s,1H),8.01(s,1H),7.45-7.56(m,5H),7.25-7.38(m,5H),6.37(d,1H),2.76-2.79(t,2H),1.91-1.97(t,2H),1.86-1.89(m,2H).
Example 12
(E) -3- (4- ((3-fluoro-1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylic acid
Figure BDA0001111876800000441
First step of
5- ((4-bromophenyl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) -3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole
Zinc powder (5.20g, 80mmol) was added to 100mL tetrahydrofuran, titanium tetrachloride (4.4mL, 40mmol) was added, the reaction was refluxed for 2 hours, cooled to 0 ℃, lithium aluminum hydride (750mg, 20mmol) was added, the mixture was stirred for 10 minutes in an ice bath, triethylamine (2.8mL, 20mmol) was added, the reaction was refluxed for 1 hour, and a solution of 10mL of (4-bromophenyl) (3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) methanone 4c (2.02g, 5mmol) and 2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -one (2.34g, 15mmol) in tetrahydrofuran was added and refluxed for 1 hour. After the reaction was completed, 50mL of water was added to quench the reaction, extracted with ethyl acetate (50mL × 3), the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 5- ((4-bromophenyl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) -3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 12a (2.35g, yellow dope) in 89.0% yield.
Second step of
(E) -methyl 3- (4- ((3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylate
5- ((4-bromophenyl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) -3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole 12a (2.25g, 4.28mmol), 4mL of methyl acrylate, triethylamine (1.79mL, 12.84mmol), palladium acetate (58mg, 0.256mmol), and tri (o-tolyl) phosphine (156mg, 0.513mmol) were added to 10mL of N, N-dimethylformamide and microwave-reacted at 150 ℃ for 1.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title product methyl (E) -3- (4- ((3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylate 12B (1.15g, pale yellow solid) in 50% yield.
The third step
(E) -methyl 3- (4- ((3-fluoro-1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylate
Methyl (E) -3- (4- ((3-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylate 12b (1.15g, 2.16mmol) was dissolved in 15mL of ethanol, 3mL of a 4N solution of hydrogen chloride 1, 4-dioxane was added, and the reaction was stirred at 60 ℃ for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, 10mL of a saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (10mL × 3), the organic layer was dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain a crude title product, methyl (E) -3- (4- ((3-fluoro-1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylate 12c (1.10g, yellow solid), which was directly subjected to the next reaction without purification.
The fourth step
(E) -3- (4- ((3-fluoro-1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylic acid
Dissolving crude (E) -methyl 3- (4- ((3-fluoro-1H-indazol-5-yl) (2,2,6, 6-tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylate 12c (1.10g, 2.16mmol) in 10mL of methanol and 2mL of dichloromethane, adding 2mL of 4N sodium hydroxide solution, stirring at 25 ℃ for reaction for 12 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure, adding 20mL of water, adjusting the pH to 2-3 with 6N hydrochloric acid, extracting with ethyl acetate (10 mL. times.3), concentrating the organic phase under reduced pressure, purifying the obtained residue with a developing reagent system A by thin layer chromatography to obtain a title product (E) -3- (4- ((3-fluoro-1H-indazol-5-yl) (2,2,6, 6-Tetramethyldihydro-2H-pyran-4 (3H) -ylidene) methyl) phenyl) acrylic acid 12(350mg, white solid) yield 37.3%.
MS m/z(ESI):435.4[M+1]
1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),7.63(d,2H),7.55(d,1H),7.50(s,1H),7.42(d,1H),7.26(d,2H),7.22(d,1H),6.48(d,1H),2.16(d,4H),1.14(d,12H).
Biological evaluation
The present invention is further illustrated below with reference to test examples, which are not intended to limit the scope of the present invention.
Test example 1 inhibition of ER Activity by Compounds of the present invention
1. Purpose of experiment
The compounds of the present invention have an inhibitory effect on the activity of ER (estrogen receptor), thereby blocking the binding of the complex of E and ER to ERE (estrogen responsive element), which in turn blocks the expression of downstream luciferase protein.
The inhibitory effect of in vitro compounds on the binding of E to ER was tested by the following method.
The purpose of this experiment was to test the inhibitory effect of compounds on E binding to ER, according to IC50Size compounds were evaluated for in vitro activity.
2. Experimental materials and instruments
2.1 Experimental instruments
Name of instrument Supply company Model number
Victor3 PE 1420-012
Micro-oscillator Linbel of the city of Haiman MH-I
96-well plate Corning 3599
Votex Corning LSE
Reinin Mettle Toledo EDP3-plus
50ml centrifuge tube Corning 430828
2.2 materials of the experiment
Name of reagent Supply company Goods number
ONE-GloTM luciferase assay System Promega E6110
Steady-Glo luciferase assay system Promega E2510
Beta-estradiol Sigma E2758
MEM Hyclone SH30024.01B
Fetal Bovine Serum (FBS) Corning 35-076-CV
Fetal bovine serum-sterile filtration Moregate FBSF
G418, sulfate salt Enzo ALX-380-013-G005
Sodium pyruvate solution Sigma S8636-100ML
Non-essential amino acid solution Sigma M7145-100ML
Penicillin-streptomycin solution Hyclone SV30010
DMSO Shanghai Taitan chemistry G75927B
Deionized water Shanghai Hengrui medicine Self-made
ERE-pGL4.17 Jinzhi Biotechnology Ltd Synthesis of
3. Experimental procedure
3.1 obtaining of ERE/MCF-7 monoclonal cell strain:
the ERE-pGL4.17 plasmid was transformed into MCF-7 cell line (TCTU 74, ATCC) by adding G418 to the medium and selecting ERE/MCF-7 monoclonal cell lines in 96-well cell culture plates.
3.2 inhibition of E and ER activity by Compounds:
ERE/MCF-7 monoclonal cell lines were cultured using complete medium (57 mL FBS, 5.7mL sodium pyruvate solution, 5.7mL non-essential amino acid solution, and 2.85mL 100mg/mL G418 in 500mL EME mixed well) and passaged every 3 days. The day before the experiment, cells were cultured in incomplete medium (57 mL of CS-FBS, 5.7mL of sodium pyruvate solution, 5.7mL of non-essential amino acid solution and 2.85mL of 100mg/mL G418 in 500mL of EME, mixed well). 96-well plates (Corning, #3599) were plated at 20,000 cells/well and cultured overnight to 100% confluence. The following day, the medium was discarded from the cell culture plate and 90. mu.l/well of compound dilution (50mL of ERE-luciferase/MCF-7 incomplete medium, 5uL of 1. mu.M β -estradiol monomer (E2758, Sigma) was added to the well of the cell culture plate and mixed well). Another new 96-well plate was added with 95. mu.l/well of the compound dilution. 5ul of a 20mM stock solution of the compound was added to 95. mu.l of DMSO and mixed to obtain a first concentration point, 10. mu.l of the first concentration point was added to 90. mu.l of DMSO and mixed to obtain a second concentration point, and the mixture was sequentially diluted to obtain 7 concentration points. Adding 5uL of the prepared compound into 95 uL of compound diluent, adding 10uL of the diluted compound into a cell culture plate to enable the final concentration of the compound to be 10000, 1000, 100, 10, 1, 0.1 and 0.01nM, placing the cell culture plate added with the compound into a 37 ℃ incubator, culturing for 5 hours, discarding cell culture solution, adding 50 uL of luciferase substrate prepared in each hole, placing the cell culture plate for 10-15 minutes in a dark place at room temperature, reading a chemiluminescence signal value in Victor3, and processing the read data by using software.
4. Test results
Inhibition of E binding to ER by Compounds of the invention IC was determined by the above assay50The values are shown in Table 1.
TABLE 1 inhibitory Effect of the Compounds of the present invention on the Activity of E and ER IC50
Example numbering IC50(nM)
3 2.81
4 0.83
5 1.22
9 0.62
10 0.29
12 0.98
And (4) conclusion: the compound has obvious inhibition effect on the combination of E and ER.
Test example 2 inhibitory Effect of the Compound of the present invention on the proliferation of MCF7 cells
1. Purpose of experiment
The aim of this experiment was to test the inhibitory effect of the compounds of the invention on the proliferation of MCF7 cells by the ATP method, according to IC50Size compounds were evaluated for in vitro activity.
2. Experimental reagents and materials
Figure BDA0001111876800000471
Figure BDA0001111876800000481
3. Experimental methods
Add 100. mu.L of MCF7 cell suspension to a 96-well cell culture plate at a density of 5X 104Cells/ml, medium 10% FBS EMEM, 96-well plate peripheral only added 100u l 10% FBS EMEM medium. The plates were incubated in an incubator for 24 hours (37 ℃, 5% CO)2). After 24 hours of cell attachment, the medium was discarded and 90 μ L of 2% FBS EMEM medium and 10 μ L of test compound at different concentrations were added to each well, two duplicate wells per compound. Will be provided withThe plates were incubated in an incubator (37 ℃, 5% CO)2) After 72 hours of incubation, 50. mu.l of mixed Cell Titer-Glo (10ml of buffer added to the corresponding substrate-filled brown bottle) was added to each well, mixed well with shaking, and allowed to stand at room temperature for 10 minutes. 100 μ l of the sample was added to the corresponding wells of a white opaque 96-well plate and chemiluminescence was detected using a microplate reader (Victor3, PE).
4. Data analysis
Data were processed and analyzed using Graphpad Prism 5. See table 2 for results.
TABLE 2 IC of inhibitory Effect of the Compounds of the invention on MCF7 cell proliferation50
Figure BDA0001111876800000482
Figure BDA0001111876800000491
And (4) conclusion: the compound of the invention has obvious inhibition effect on MCF7 cell proliferation.
Test example 3 degradation of ER α by Compounds of the invention
1. Purpose of experiment
The compounds of the invention were tested for their ability to cause ER α degradation and the method was used to determine the ability of the compounds of the invention to degrade ER α.
2. Experimental materials and instruments
BioTek Synergy HT plate reader
MCF-7 cell line (TCHU 74, ATCC)
ERαDuoset Kit(#DYC5715E，R&D System)
3. Experimental methods
MCF-7 cells were cultured in DMEM/F-12+ 10% FBS medium.
On the first day of the experiment, MCF-7 was resuspended in DMEM/F-12 medium plus 10% charcoal treated FBS and seeded at 50000 cells/well in 48-well plates for 22-24 hours.
The next day of the experiment, the test compound was diluted into the culture medium and added to a 48-well plate; the ER α capture antibody was diluted to 1 μ g/ml with PBS, added to a 96-well plate at 100 μ l/well, sealed and coated overnight at room temperature.
On day three of the experiment, the coated 96-well plates were washed 2 times with PBS, 110 ul/well blocking solution (1% BSA in PBS) was added and blocked for 1 hour at room temperature. The 48-well plate was washed 1 time with PBS, the residual liquid was aspirated off, 60ul of lysis buffer (6M urea, 1mM EDTA, 0.5% Triton X-100, 1mM PMSF, Protease Inhibitor cocktail) was added to each well and lysed on ice for 15 minutes, and then diluent (1mM EDTA, 0.5% Triton X-100 in PBS) was added; transferring the lysate after cell dilution into a 96-well sealed plate by 100ul per well, and incubating for 2 hours at room temperature; washing the plate with washing solution (PBST) for 4 times, adding diluted primary antibody, incubating for 1 hour, washing the 96-well plate for 4 times, adding secondary antibody, and incubating for 30 minutes; after washing the plate with washing solution, TMB was added for color development for 15 minutes, and the reaction was stopped with 1M sulfuric acid to read the light absorption at 450 nm.
4. Test results
IC determined by degradation of ER alpha by Compounds of the invention50The values are shown in Table 3.
TABLE 3 IC of the degradation of ER α by the Compounds of the invention50Value of
Figure BDA0001111876800000492
Figure BDA0001111876800000501
And (4) conclusion: the compound of the invention has obvious degradation effect on ER alpha.
Pharmacokinetic evaluation
Test example 4 pharmacokinetic testing of nude mice with the compounds of examples 4 and 12 of the invention
1. Abstract
BALB/C nude mice are used as test animals, and the drug concentration in blood plasma of the BALB/C nude mice at different times after gastric lavage of the compound of the embodiment is determined by an LC/MS/MS method. The pharmacokinetic behavior of the compounds of the invention in BALB/C nude mice was studied and their pharmacokinetic profile was evaluated.
2. Test protocol
2.1 test drugs
Compounds of examples 4 and 12
2.2 test animals
BALB/C nude mice 18, female, purchased from shanghai siepal-bikei laboratory animals ltd, animal production license number: SCXK (Shanghai) 2008-0016.
2.3 pharmaceutical formulation
Weighing a proper amount of sample, adding 9% PEG400, 0.5% Tween 80, 0.5% PVP and 90% 0.5% CMC aqueous solution, sequentially adding, and performing ultrasonic treatment to obtain 0.5mg/ml suspension.
Note:
PEG 400: polyethylene glycol 400
CMC-Na: sodium carboxymethylcellulose
PVP: polyvinylpyrrolidone K30
2.4 administration
BALB/C nude mice 18, female, divided into 2 groups on average; after fasting overnight, the administration was effected by gavage in a volume of 0.2ml/10 g.
3. Operation of
BALB/C nude mice 18, female, divided into 2 groups on average; after fasting overnight, gavage and intravenous administration were performed, respectively. The gavage group was collected at 0.1ml (3 animals per time point) at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0h after administration, placed in heparinized tubes, centrifuged at 3500rpm for 10min to separate plasma, and stored at-20 ℃.
And (3) determining the content of the compound to be tested in the plasma of BALB/C nude mice after the intragastric administration of different compounds by an LC/MS/MS method.
4. Results of pharmacokinetic parameters of nude mice
The pharmacokinetic parameters for the compounds of examples 4 and 12 of the invention are as follows:
Figure BDA0001111876800000511
and (4) conclusion: the compound of the invention has good drug absorption and obvious drug absorption effect.
Test example 5 rat pharmacokinetic testing of the Compounds of examples 3,5, 9 and 10 of the invention
1. Abstract
The drug concentrations in plasma of SD rats at various times after intragastric administration of the compounds of examples 3,5, 9 and 10 were determined by LC/MS/MS method using SD rats as test animals. The pharmacokinetic behavior of the compounds of the invention in SD rats was studied and evaluated for their pharmacokinetic profile.
2. Test protocol
2.1 test drugs
Compounds of examples 3,5, 9 and 10
2.2 test animals
Healthy adult SD rats 16, female, purchased from shanghai sipel-bikeka laboratory animals ltd, animal production license number: SCXK (Shanghai) 2008-0016.
2.3 pharmaceutical formulation
Weighing a proper amount of sample, adding 0.5% CMC-Na, and carrying out ultrasonic treatment to prepare 0.5mg/ml suspension.
2.4 administration
Healthy adult SD rats 16, females, were divided into 4 groups and were each gavaged overnight at an administration volume of 5 ml/kg.
3. Operation of
The gavage group was administered at 0.1ml per 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0h before and after administration, collected from the orbit, placed in heparinized tubes, centrifuged at 3500rpm for 10 minutes to separate plasma, stored at-20 ℃, and taken 2h after administration.
The LC/MS/MS method is used for measuring the content of the compound to be measured in the plasma of SD rats after the intragastric administration of different compounds.
4. Results of pharmacokinetic parameters in rats
The pharmacokinetic parameters of the compounds of examples 3,5, 9, 10 of the invention are as follows:
Figure BDA0001111876800000512
Figure BDA0001111876800000521
and (4) conclusion: the compound of the invention has good drug absorption and obvious drug absorption effect.

Claims (16)

1. A compound of the general formula (I):
Figure FDA0002921182580000011
or a pharmaceutically acceptable salt thereof,
wherein:
ring A is selected from
Figure FDA0002921182580000012
R1Each of which is the same or different and is independently selected from a hydrogen atom, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy and halogen;
R2each of which is the same or different and is independently selected from a hydrogen atom, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy and halogen;
R3selected from hydrogen atoms, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy and halogen;
R4selected from hydrogen atoms and C1-6An alkyl group;
n is 0, 1,2, 3,4 or 5;
q is 0, 1,2, 3 or 4.
2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1Selected from hydrogen atoms and C1-6An alkyl group.
3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R2Selected from hydrogen atoms and halogens.
4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R3Selected from hydrogen atoms and halogens.
5. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (II):
Figure FDA0002921182580000021
or a pharmaceutically acceptable salt thereof,
wherein:
x is selected from carbon atom and oxygen atom;
R1～R4n and q are as defined in claim 1.
6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the compound is selected from:
Figure FDA0002921182580000022
7. a compound:
Figure FDA0002921182580000031
8. a compound of the general formula (III):
Figure FDA0002921182580000032
or a pharmaceutically acceptable salt thereof,
wherein:
r is selected from C1-6Alkyl and C3-6A cycloalkyl group;
ring A is selected from
Figure FDA0002921182580000033
R1Each of which is the same or different and is independently selected from a hydrogen atom, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy and halogen;
R2each of which is the same or different and is independently selected from a hydrogen atom, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy and halogen;
R3selected from hydrogen atoms, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy and halogen;
R4selected from hydrogen atoms and C1-6An alkyl group;
n is 0, 1,2, 3,4 or 5;
q is 0, 1,2, 3 or 4.
9. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, comprising the steps of:
Figure FDA0002921182580000041
hydrolyzing the compound of the general formula (III) under alkaline conditions to obtain a compound of a general formula (I);
wherein:
r is as defined in claim 8;
ring A, R1～R4N and qAs defined in claim 1.
10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and a compound of claim 7, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
11. Use of a compound of general formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and a compound of claim 7 or a pharmaceutical composition according to claim 10 for the preparation of an estrogen receptor modulator.
12. Use of a compound of formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and a compound according to claim 7 or a pharmaceutical composition according to claim 10 for the manufacture of a medicament for the treatment of an estrogen receptor mediated or dependent disease or condition.
13. The use according to claim 12, wherein the estrogen receptor mediated or dependent disease or condition is selected from the group consisting of cancer, central nervous system deficiencies, cardiovascular system deficiencies, blood system deficiencies, immune and inflammatory diseases, susceptibility to infection, metabolic deficiencies, neurological deficiencies, psychiatric deficiencies and reproductive deficiencies.
14. The use according to claim 13, wherein the cancer is selected from the group consisting of breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumors, hemophilia, and leukemia.
15. The use according to claim 14, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, prostate cancer and cervical cancer.
16. The use according to claim 14, wherein the cancer is breast cancer.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103189361A (en) * 2010-09-16 2013-07-03 亚拉冈制药公司 Estrogen receptor modulators and use thereof
CN104220426A (en) * 2012-03-20 2014-12-17 塞拉根制药公司 Estrogen receptor modulators and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103189361A (en) * 2010-09-16 2013-07-03 亚拉冈制药公司 Estrogen receptor modulators and use thereof
CN104220426A (en) * 2012-03-20 2014-12-17 塞拉根制药公司 Estrogen receptor modulators and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"dentification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts";Andiliy Lai, et al.;《J. Med. Chem》;20150416;第58卷(第12期);4888-4904 *

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