CN112079826B - Steroid synthetase inhibitor and treatment application thereof - Google Patents
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Abstract
The invention discloses a steroid synthetase inhibitor and treatment application thereof, belonging to the field of medicines. The compounds which can be used as medicaments provided by the invention have the effect of inhibiting steroid synthase, have high inhibition rate and can be used as medicaments for treating hormone-dependent diseases.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a steroid synthetase inhibitor and a treatment application thereof.
Background
Steroid hormones are important endogenous regulatory factors in human bodies and are widely involved in various physiological and pathological effects. Once its biosynthesis and signal sensing and transmission process are changed, it can cause various serious diseases. The steroid synthase is a key factor of the biosynthesis of the steroid hormones, and the inhibition of the steroid synthase can directly reduce the concentration of the steroid hormones, thereby treating related diseases.
Mineralocorticoids, represented by aldosterone, can regulate renal tubular function, control the dynamic balance of potassium ions, sodium ions and water, and thus regulate blood volume and blood pressure. Recent studies have shown that aldosterone is a potent inflammatory factor, is capable of inducing reactive oxygen species, and can upregulate the expression of a variety of fibrosis-inducing factors, including PAI. Aldosterone with too high concentration has direct relation with congestive heart failure, refractory hypertension, chronic nephropathy, diabetic nephropathy, hyperaldosteronism, cardio-renal fibrosis, cardio-renal syndrome, metabolic syndrome and other diseases. The aldosterone synthase (CYP11B2) is a key enzyme in aldosterone biosynthesis, and inhibition of the aldosterone synthase can effectively reduce aldosterone level, thereby treating related diseases.
Cortisone is an important glucocorticoid in the human body and can widely regulate immune response, stress response, sugar and lipid metabolism. Abnormal hypersecretion of cortisone due to tumors that occur in the hypothalamus-pituitary-adrenal gland is called cushing's syndrome. High levels of cortisone are also directly associated with metabolic syndrome, insulin resistance, obesity, type II diabetes. 11 beta hydroxylase (CYP11B1) is a key enzyme in cortisone biosynthesis, and inhibition of the 11 beta hydroxylase can effectively reduce cortisone levels and further treat related diseases.
Estrogens and androgens regulate physiological functions such as osteogenic and osteoclastic balance, cardiovascular function, muscle homeostasis, etc., in addition to maintaining normal sex characteristics and functions. However, the excessive concentration of estrogen and androgen is closely related to the occurrence and development of breast cancer and prostate cancer respectively. CYP19 and CYP17 are key enzymes in estrogen and androgen biosynthesis, respectively, and inhibition thereof can effectively reduce estrogen and androgen levels, thereby treating related diseases.
Bile acid is an endogenous steroid secreted by the liver, forms chylomicron in the small intestine to help fat absorption, is a potential signal factor, and can widely regulate and control the synthesis and metabolism of sugar and fat, inflammation, fibrosis and other pathological processes. CYP7A1 and CYP8B1 are key enzymes in bile acid biosynthesis, can regulate liver function and organism metabolism by intervening, and are potential targets for treating diseases such as non-alcoholic fatty liver disease, fatty liver, liver cirrhosis, hepatic fibrosis and the like.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The present invention aims to provide a class of steroid synthase inhibitors and therapeutic applications thereof to solve the above technical problems.
The invention is realized by the following steps:
a class of compounds useful as pharmaceuticals comprising at least one of the following compounds:
wherein:
z is C, N, O or S;
a ═ O, S, N, or C; but not the same element at the same time;
R 1 ，R 2 and R 3 Each independently selected from the group consisting of:
hydrogen, deuterium, halogen, hydrocarbon group, hydrocarbyloxy group, aryl group, nitro group, nitroso group, amino group, ureido group, ester group, hydroxyl group, carboxyl group, sulfonic group, haloformyl group, carbamoyl group, aldehyde group, cyano group, aryloxy group, mercapto group, thioether, carbonyl group, sulfonyl fluoride, CF 3 、SF 5 Optionally substituted or unsubstituted piperazinyl, morpholinyl, optionally substituted or unsubstituted pyridyl, optionally substituted or unsubstituted pyrrolinyl, oxime, hydrazone, optionally substituted hydrocarbyl, optionally substituted hydrocarbyloxy, optionally substituted NHC 1 -C 8 Alkyl, optionally substituted or unsubstituted-S- (-C) 1 -C 8 Alkyl), optionally substituted or unsubstituted-SO 2 -(-C 1 -C 8 Alkyl), optionally substituted or unsubstituted-SO 2 -NH-(-C 1 -C 8 Alkyl), optionally substituted or unsubstituted-NH-SO 2 -(-C 1 -C 8 Alkyl), -CO 2 R 4 、-NR 5 R 6 and-CO-NR 5 R 6 ；
R 4 Independently selected from the group consisting of: optionally substituted or unsubstituted-C 1 -C 8 Alkyl, optionally substituted or unsubstituted-C 2 -C 8 Alkenyl, optionally substituted or unsubstituted-C 2 -C 8 Alkynyl, optionally substituted or unsubstituted-C 3 -C 8 Cycloalkyl, optionally substituted or unsubstituted-C 3 -C 8 Cycloalkenyl, optionally substituted or unsubstituted 3-to 8-membered heterocycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl;
R 5 and R 6 Each independently selected from hydrogen, optionally substituted or unsubstituted-C 1 -C 8 -alkyl, optionally substituted or unsubstituted-C 2 -C 8 -alkenyl, optionally substituted or unsubstituted-C 2 -C 8 -alkynyl, optionally substituted or unsubstituted-C 3 -C 8 -cycloalkyl, -C (O) R 4 、-S(O) 2 R 4 、-S(O) 2 NHR 4 Optionally substituted or unsubstituted-C 1 -C 8 Alkoxy, and R 5 And R 6 A heterocyclic ring formed with the attached nitrogen;
x is 0, 1 or 2; y is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4.
In the above formula, the parent nucleus means: removal of the substituent R 1 、R 2 And R 3 ，
The remainder of the nitrogen-containing heterocycle.
A is O, S, N or C; but not both are the same element. A is a plurality of in the structural general formula at the same time, and can not be carbon at the same time or sulfur at the same time.
In a preferred embodiment of the present invention, the mother core is selected from the group consisting of:
3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one, 3, 4-dihydrobenzo [ e][1,3]Oxazazem
-5(1H) -one, 4, 5-dihydrobenzo [ d][1,2]Oxazazem
-1(2H) -one, 3, 4-dihydrobenzo [ f][1,4]Sulfoazazepine
-5(2H) -one, 3, 4-dihydrobenzo [ e][1,3]Sulfoazazepine
-5(1H) -one, 4, 5-dihydrobenzo [ d][1,2]Thiazepine
-1(2H) -one, 1,2,3, 4-tetrahydro-5H-benzo [ e][1,4]Diaza derivatives
-5-one, 2,3,4, 5-tetrahydro-1H-benzo [ e][1,3]Diaza derivatives
-1-one, 2,3,4, 5-tetrahydro-1H-benzo [ d][1,2]Diaza derivatives
-1-one, 1-dioxo-3, 4-dihydro-2H-benzo [ b ]][1,4,5]Oxathiazepine
1, 1-dioxo-2, 3-dihydro-5H-benzo [ e ]][1,4,3]Oxathiazepine
1, 1-dioxo-4, 5-dihydro-2H-benzo [ d ]][1,3,2]Oxathiazepine
1, 1-dioxo-3, 4-dihydro-2H-benzo [ f][1,5,2]Dithioazepines
1, 1-dioxo-2, 3-dihydro-5H-benzo [ f][1,4,2]Dithioazepines
1, 1-dioxo-4, 5-dihydro-2H-benzo [ d ]][1,3,2]Dithioazepines
1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f][1,2,5]Thiodiazepines
1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f][1,2,4]Thiodiazepines
1, 1-dioxo-2, 3,4, 5-tetrahydrobenzo [ f][1,2,3]Thiodiazepines
4, 5-dihydrobenzo [ f ]][1,4]Sulfoazazepine
-3(2H) -one, 4, 5-dihydro-3H-benzo [ e][1,4]Diaza derivatives
-3-keto, 4, 5-dihydrobenzo [ f ][1,4]Oxazazem
-3(2H) -one, 1,2,4, 5-tetrahydro-3H-benzo [ e][1,4]Diaza derivatives
-3-keto, 3-dioxo-4, 5-dihydrobenzo [ d ]][1,2,6]Thiodiazepines
3, 3-dioxo-1, 2,4, 5-tetrahydrobenzo [ d ]][1,2,6]Thiodiazepines
3, 3-dioxo-4, 5-dihydro-2H-benzo [ d ]][1,6,2]Dithioazepines
3, 3-dioxo-4, 5-dihydro-2H-benzo [ f][1,3,4]Oxathiazepine
。
In a preferred embodiment of the present invention, R is 1 ，R 2 And R 3 Each optionally substituted with 1 to 3 substituents of the group consisting of: halogen, -CH 3 、-CF 3 、-CBr 3 、-CCl 3 、-OCF 3 、-CN、-NH 2 、-OH、-CH 2 N(CH 3 ) 2 、-C(O)CH 3 、-SO 2 -、-NH-SO 2 -, acyl, acylamino, optionally substituted-NH- (C) 1 -C 6 ) Alkyl, optionally substituted-NH- (C) 1 -C 6 ) Alkyl radical- (C) 1 -C 6 ) Alkoxy, optionally substituted-SO 2 -(C 1 -C 6 ) Alkyl, optionally substituted-SO 2 -NH-(C 1 -C 6 ) Alkyl, optionally substituted-NH-SO 2 -(C 1 -C 6 ) Alkyl, optionally substituted 3-to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted-C 1 -C 8 Alkyl, optionally substituted-C 1 -C 8 Alkenyl, optionally substituted-C 3 -C 8 -cycloalkyl, optionally substituted-C 3 -C 8 Cycloalkenyl radical and optionally substituted-C 1 -C 8 An alkoxy group.
Further, R 1 ，R 2 And R 3 Each optionally substituted with 1 to 3 substituents of the group consisting of:
fluorine, -CH 3 、-CF 3 and-CN.
In the preferred embodiment of the present invention, when m is >At 1 time, a plurality of R 1 Are connected into a ring structure; when n is>At 1 time, a plurality of R 2 Are connected into a ring structure; when y is>At 1 time, a plurality of R 3 Are connected into a ring structure.
Further, when R is 3 When in the ortho position to N, R 3 Is hydrogen or deuterium.
In a preferred embodiment of the present invention, the nitrogen-containing heterocycle is a five-membered heterocycle, a six-membered heterocycle, or a fused heterocycle;
preferably, the five-membered heterocyclic ring is pyrrole, thiazole, imidazole or pyrazole, the six-membered heterocyclic ring is pyridine, pyridazine or pyrimidine, and the fused heterocyclic ring is quinoline, isoquinoline, purine, pyrrolopyridine, furopyridine, thienopyridine, imidazopyridine, oxazolopyridine, thiazolopyridine, dihydropyrrolopyridine, dihydrofuropyridine, dihydrothienopyridine, dihydroimidazopyridine, pyrrolopyrimidine, furopyrimidine, thienopyrimidine, imidazopyrimidine, oxazolopyrimidine, thiazolopyrimidine, dihydropyrrolopyrimidine, dihydrofuropyrimidine, dihydrothienopyrimidine, dihydroimidazopyrimidine, dihydrooxazolopyrimidine, dihydrothiazolopyrimidine, imidazopyrimidine, imidazotriazine, pyrrolotriazine, dihydroimidazotriazine, dihydropyrrolotriazine.
In other embodiments, the heterocyclic ring may be an 8-to 10-membered fused heterocyclic ring.
Further, the compound which can be used as a medicament is any one of the following compounds:
8-fluoro-4- (4-methyl-3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8-fluoro-4- (3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8- (N, N-dimethyl) -4- (3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8- (N, N-dimethyl) -4- (5-methyl-3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8- (N, N-dimethyl) -4- (5-fluoro-3-pyridinyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8- (N, N-dimethyl) -4- (5-chloro-3-pyridinyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8- (N, N-dimethyl) -4- (4-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8- (N, N-dimethyl) -4- (3-methyl-4-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8- (N, N-dimethyl) -4- (3-fluoro-4-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8- (N, N-dimethyl) -4- (3-chloro-4-pyridinyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8- (N, N-dimethyl) -4- (5-methoxy-3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8- (N, N-dimethyl) -4- (4-methyl-3-pyridyl) -3, 4-dihydrobenzo [ f ][1,4]Oxazazem
-5(2H) -one, 8- (N, N-dimethyl) -4- (4-chloro-3-pyridinyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8- (N, N-dimethyl) -4- (4-cyano-3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 3- (8- (N, N-dimethyl) -5-oxo-2, 3-dihydrobenzo [ f)][1,4]Oxazazem
-4(5H) -isonicotinic acid methyl ester, 3- (8- (N, N-dimethyl) -5-oxo-2, 3-dihydrobenzo [ f [ ]][1,4]Oxazazem
-4(5H) -nicotinic acid methyl ester, 8- (N, N-dimethyl) -4- (5-acetyl-3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8- (N, N-dimethyl) -4- (4-trifluoromethyl-3-pyridinyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8- (N, N-dimethyl) -4- (5-trifluoromethyl-3-pyridinyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8- (N, N-dimethyl) -4- (5)-nitrile-3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8-morpholinyl-4- (4-nitrile-3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8-piperazinyl-4- (4-cyano-3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8- (4-methylpiperazino) -4- (4-nitrile-3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, 8- (4-acetylpiperazinyl) -4- (4-cyano-3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem 
-5(2H) -one, 8-piperidinyl-4- (4-cyano-3-pyridinyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazepine
-5(2H) -one and 8-pyrrolinyl-4- (4-cyano-3-pyridyl) -3, 4-dihydrobenzo [ f [ -E][1,4]Oxazazem
-5(2H) -one.
In other embodiments, the pharmaceutically acceptable salts of the above compounds that can be used as drugs, "pharmaceutically acceptable salts" include pharmaceutically acceptable salts of inorganic or organic acids; the inorganic acid salt is preferably sulfate, sulfite, hydrochloride, hydrobromide, nitrate, phosphate, dihydrogen phosphate; the organic acid salt is preferably acetate, maleate, fumarate, succinate, citrate, p-toluenesulfonate, tartrate, formate, propionate, heptanoate, oxalate, benzoate, malonate, succinate, maleate, hydroxybutyrate, citrate, methanesulfonate, benzenesulfonate, lactate or mandelate.
The preparation method of the compound used as the medicine comprises the following steps:
firstly, reacting corresponding substituted aromatic amine, aromatic phenol, aromatic mercaptan and other raw materials with corresponding halogenated carboxylic ester, hydrolyzing the obtained product in an aqueous solution of lithium hydroxide to obtain a carboxylic acid intermediate I, then closing the ring in the environment of trifluoroacetic acid and trifluoroacetic anhydride to obtain a fused ring aromatic cyclic ketone intermediate II, reacting the fused ring aromatic cyclic ketone intermediate II with hydroxylamine hydrochloride to obtain an oxime intermediate III, then carrying out BECKMANN rearrangement to obtain an amide intermediate IV, and reacting the amide intermediate IV with corresponding bromine compound of a nitrogen-containing heterocyclic ring or boric acid in an alkaline environment catalyzed by copper or palladium to obtain a target compound V;
The polycyclic aromatic hydrocarbon cyclic ketone intermediate II is 7-fluoro-chroman-4-one, the oxime intermediate III is 7-fluoro-chroman-4-oxime, and the amide intermediate IV is 8-fluoro-3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one, or 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one.
The substituted nitrogen-containing heterocycle is halogen substituted heterocycle, methoxy substituted heterocycle, halogen methoxy substituted heterocycle, alkyl substituted heterocycle, nitrile substituted heterocycle, halogen nicotinate substituted heterocycle, acyl substituted heterocycle, halogen acyl substituted heterocycle or halogen alkyl substituted heterocycle;
preferably, the substituted nitrogen-containing heterocycle is 3-bromo-4-methylpyridine, 3-bromopyridine, 3-bromo-5-fluoropyridine, 3-bromo-5-chloropyridine, 4-bromo-3-methylpyridine, 4-bromo-3-fluoropyridine, 4-bromo-3-chloropyridine, 3-bromo-5-methoxypyridine, 3-bromo-4-cyanopyridine, 3-bromo-nicotinic acid methyl ester, 3-bromo-5-acetylpyridine, 3-bromo-4-trifluoromethylpyridine or 3-bromo-5-cyanopyridine.
The invention also provides application of the compound serving as a medicament in preparation of a steroid synthetase inhibitor.
Further, the steroid synthase inhibitor is a steroid biosynthetic enzyme inhibitor.
Further, the steroid biosynthetic enzyme is at least one of the following enzymes: aldosterone synthase (CYP11B2), cortisone biosynthetic enzymes, estrogen synthase, androgen synthase, and bile acid biosynthetic enzymes.
Preferably, the aldosterone synthase is CYP11B 2; the cortisone biosynthetic enzyme is CYP11B1(11 beta hydroxylase); the estrogen synthase is CYP 19; androgen synthase CYP 17; the bile acid biosynthetic enzyme is CYP7A1 and/or CYP8B 1.
In other embodiments, the pharmaceutical compounds provided herein are not limited to the inhibitory uses of the several steroid synthases described above.
The invention also provides the application of the compound which can be used as a medicine in the preparation of medicines for treating hormone-dependent diseases, wherein the hormone-dependent diseases comprise at least one of the following diseases:
congestive heart failure, hypertension, chronic kidney disease, diabetic nephropathy, hyperaldosteronism, cardiac fibrosis, renal syndrome, metabolic syndrome, cushing's syndrome, insulin resistance, obesity, type II diabetes, breast cancer, prostate cancer, ovarian cancer, cervical cancer, diabetic foot, diabetic eye disease, diabetic ulcers, renal failure, non-alcoholic fatty liver disease, fatty liver, cirrhosis, liver fibrosis, liver cancer, pancreatic cancer, cholangiocarcinoma, colon cancer, rectal cancer.
A medicament for the treatment of hormone dependent diseases, which comprises a compound useful as a medicament;
Preferably, the medicament for treating the hormone-dependent diseases further comprises pharmaceutically acceptable additives or auxiliary materials, and preferably, the dosage form of the pharmaceutical composition is selected from tablets, pills, powders, suspensions, gels, emulsions, creams, granules, nanoparticles, capsules, suppositories, injections, sprays and injections.
A pharmaceutical composition comprising a compound that is pharmaceutically acceptable;
preferably, the pharmaceutical composition further comprises a combination drug/therapy, which is a combination of the disclosed pharmaceutical compound and at least one of the following drugs/therapies:
chemotherapeutic agents, radiation therapy, photosensitizers, photothermics, immunotherapy, androgen receptor antagonists and function modulators, estrogen receptor antagonists and function modulators, sugar hormone receptor antagonists and function modulators, salt hormone receptor antagonists and function modulators, FXR agonists, antagonists and function modulators, GPR30 agonists, antagonists and function modulators, TGR agonists, antagonists and function modulators, GLP receptor agonists, antagonists and function modulators, FGF receptor agonists, antagonists and function modulators, thyroxine receptor agonists, antagonists and function modulators, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, and TGF receptor agonists, antagonists and function modulators.
The above-mentioned combination drugs may have the same mechanism of action as the compound of the present invention or may have different mechanisms of action.
The invention has the following beneficial effects:
the invention provides a steroid synthetase inhibitor which has the function of inhibiting steroid synthetase and high inhibition rate and can be used for preparing medicaments for treating hormone-dependent diseases.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a scheme for the synthesis of compounds.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The features and properties of the present invention are described in further detail below with reference to examples.
The first general method comprises the following steps: the corresponding amino product is prepared by adopting a method of substituting fluorine by amino. The method comprises the following steps:
the fluoro intermediate (20mmol), the corresponding amine (40mmol), potassium carbonate (44mmol) were suspended in DMSO (20mL) and stirred at 100 ℃ for 16 h. After cooling to room temperature, the reaction mixture was added to cold water (100mL) and extracted twice with 100mL of ethyl acetate, and the organic phase was then washed with saturated brine (100mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Purification on silica gel column (petroleum ether/ethyl acetate 1/2) gave the corresponding amine-based product.
The general method II comprises the following steps: amide is introduced into substituted pyridine to obtain corresponding pyridine substituted product. Which comprises the following steps:
reacting the corresponding 3, 4-dihydrobenzo [ f ]][1,4]Oxazazem
-5(2H) -one (22mmol), the corresponding substituted pyridine (22mmol), and potassium carbonate (132mmol), cuprous iodide (11mmol), N-diethyl-1, 2-ethylenediamine (15.4mmol) were suspended in dioxane (60mL) and stirred at 120 ℃ for 16H. After cooling to room temperature, the reaction mixture was added to cold water (100mL) and extracted with ethyl acetate (100mL × 2), and the organic phase was then washed with saturated brine (100mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Purification on silica gel column (petroleum ether/ethyl acetate 1/3) gave the corresponding pyridine substituted product.
Example 1
This example provides a preparation method of intermediate 1(3- (3-fluorophenoxy) propionic acid), and this example uses 3-fluorophenol shown in fig. 1 as a raw material, and in other examples, any one of the analogues may be selected as a reaction raw material.
3-fluorophenol (10.0g,89mmol), methyl 3-bromopropionate (15.8g,95mmol) and potassium carbonate (30.8g,223mmol) were stirred in 100 ml of tetrahydrofuran at 70 ℃ for 16 h. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure and extracted twice with 300 ml of ethyl acetate/water (1: 1). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give a yellow solid. This was suspended in 200 ml of an aqueous lithium hydroxide solution and stirred at room temperature for 5 hours. The reaction mixture was extracted twice with 300 ml of ethyl acetate/water (1: 1). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 14.3 g of a yellow solid with a yield of 87.5%.
Example 2
This example provides a method for preparing intermediate 2 (7-fluoro-chroman-4-one), which uses 3- (3-fluorophenoxy) propionic acid prepared in example 1 as a starting material, and any one of the analogues may be selected as a starting material in other examples.
To a mixed solution of 3- (3-fluorophenoxy) propionic acid (5.0g,27.1mmol) in 25 ml of trifluoroacetic acid was added dropwise trifluoroacetic anhydride (5.7g,27.1mmol), and the resulting reaction mixture was stirred at room temperature for 5 hours, followed by addition of saturated Na 2 CO 3 The solution was adjusted to pH 8 and then extracted twice with 300 ml ethyl acetate/water (1: 1). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give a white solid (2.8g, yield 62.1%). 1 H-NMR(400MHz,DMSO-d 6 ):δ＝7.81-7.85(m,1H),6.92-6.95(m,2H),4.57(t,J＝4.8Hz,2H),2.79(t,J＝4.8Hz,2H)。
Example 3
This example provides a method for preparing intermediate 3 (7-fluoro-chroman-4-oxime), and this example uses 7-fluoro-chroman-4-one prepared in example 2 as a starting material, and in other examples, any one of the analogues may be selected as a starting material for the reaction.
After addition of sodium bicarbonate (22.8g,270mmol) to a solution of 7-fluoro-chroman-4-one (15g,90mmol) and hydroxylamine hydrochloride (12.6g,180mmol) in dry ethanol (50mL) at room temperature, the reaction mixture is heated at 90 ℃ under reflux for 16 h. After cooling to room temperature, the solid was removed by filtration and the filter cake was washed with ethanol, the filtrate was concentrated and purified with silica gel column (petroleum ether/ethyl acetate: 10/1) to give off-white solid (15g, yield 92%).
Example 4
This example provides intermediate 4 (8-fluoro-3, 4-dihydrobenzo [ f)][1,4]Oxazazepine
-5(2H) -one) starting from 7-fluoro-chroman-4-oxime as obtained in example 3. In other embodiments, any one of the analogs can be selected as the reaction starting material.
7-fluoro-chroman-4-oxime (15g,83mmol) was suspended in polyphosphoric acid (20mL) and stirred at 110 ℃ for 4 hours. After cooling to room temperature, the reaction mixture was poured into cold water, the solid was filtered off, adjusted to pH 8 with sodium bicarbonate and extracted with ethyl acetate (300mL × 2), the organic phase was then washed with saturated brine (300mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Purification on silica gel column (petroleum ether/ethyl acetate 3/1) gave a yellow solid (6.3g, 42% yield).
Example 5
This example provides intermediate 5(8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one) from example 4][1,4]Oxazazem
-5(2H) -ketone is used as raw material. In other embodiments, any one of the analogs can be selected as the reaction starting material.
According to general procedure one, 8-fluoro-3, 4-dihydrobenzo [ f ] is used ][1,4]Oxazazepine
-5(2H) -one (3.75g,20mmol), dimethylamine hydrochloride (3.37g,40mmol), potassium carbonate (6.3g,44 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate 1/2) to give a white solid (1.7g, 40% yield).
Example 6
This example provides the compound 1 (8-fluoro-4- (4-methyl-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one) from example 4][1,4]Oxazazem
-5(2H) -ketone is used as raw material. In other embodiments, any one of the analogs can be selected as the reaction starting material.
According to general method two, 8-fluoro-3, 4-dihydrobenzo [ f ] is used][1,4]Oxazazem
-5(2H) -one (4.0g,22mmol), 3-bromo-4-methylpyridine (3.78g,22mmol), potassium carbonate (18.2g,132mmol), cuprous iodide (2.08g,11mmol), N, N-diethyl-1, 2-ethylenediamine (1.37g,15.4 mmol). The crude product was purified on a silica gel column (petroleum ether/ethyl acetate-1/3) to give a white solid (2.9g, 48% yield). To obtain the compound 1 (8-fluoro-4- (4-methyl-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):273.27[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.46(s,1H),8.42(d,J＝4.8Hz,1H),7.84-7.80(q,1H),7.38(d,J＝5.2Hz,1H),7.11-7.06(m,1H),7.02-6.99(dd,J＝2.4Hz,2.8Hz,1H),4.52-4.48(m,2H),3.89-3.92(m,2H),2.22(s,3H)。
Example 7
According to general method two, 8-fluoro-3, 4-dihydrobenzo [ f ] is used][1,4]Oxazazem
-5(2H) -one (0.15g,0.8mmol), 3-bromopyridine (0.13g,0.8mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified on a silica gel column (petroleum ether/ethyl acetate-1/3) to give a yellow solid (52mg, yield 24%). To obtain the compound 2 (8-fluoro-4- (3-pyridyl) -3, 4-dihydrobenzo [ f) ][1,4]Oxazazepine
-5(2H) -one).
MS(m/s):259.25[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.66(s,1H),8.50(d,J＝4Hz,1H),7.88-7.79(m,2H),7.51-7.48(q,1H),7.10-7.06(m,1H),7.01-6.98(q,1H),4.54(t,J＝5Hz,2H),3.99(t,J＝5Hz,2H)。
Example 8
This example provides the compound 3(8- (N, N-dimethyl) -4- (3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one) preparation, this example being 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f ] prepared as in example 5][1,4]Oxazazem
-5(2H) -ketone is used as raw material. In other embodiments, any one of the analogs can be selected as the reaction starting material. According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.7mmol), 3-bromopyridine (0.114g,0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). Silica gel for crude productColumn purification (petroleum ether/ethyl acetate 1/3) gave a light yellow solid (555mg, yield 26.7%). To obtain the compound 3(8- (N, N-dimethyl) -4- (3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):284.33[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.62(d,J＝2.4Hz,1H),8.44-8.43(m,1H),7.83-7.80(m,1H),7.60(d,J＝8.8Hz,1H),7.47-7.43(m,1H),6.55-6.52(m,1H),6.26(d,J＝2.4Hz,1H),4.43(t,J＝4.8Hz,2H),3.95(t,J＝5Hz,2H),2.97(s,6H)。
Example 9
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.7mmol), 3-bromo-4-methyl-pyridine (0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate 1/3) to give a pale yellow solid (58mg, yield 26.8%). To obtain the compound 4(8- (N, N-dimethyl) -4- (5-methyl-3-pyridyl) -3, 4-dihydrobenzo [ f) ][1,4]Oxazazepine
-5(2H) -one).
MS(m/s):298.35[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.41(d,J＝2.4Hz,1H),8.29(d,J＝1.2Hz,1H),7.64(s,1H),7.59(d,J＝8.8Hz,1H),6.55-6.52(m,1H),6.26(d,J＝2.4Hz,1H),4.42(t,J＝4.8Hz,2H),3.92(t,J＝5Hz,2H),2.97(s,6H),2.32(s,3H)。
Example 10
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazepine
-5(2H) -one (0.15g,0.7mmol), 3-bromo-5-fluoropyridine (0.7mmol), carbonPotassium (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate-1/3) to give a white solid (51mg, yield 23.3%). To obtain the compound 5(8- (N, N-dimethyl) -4- (5-fluoro-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):302.32[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.56(d,J＝1.6Hz,1H),8.47(d,J＝2.4Hz,1H),7.92-7.88(m,1H),7.61(d,J＝8.8Hz,1H),6.54(dd,J＝2.4Hz,2.4Hz,1H),6.26(d,J＝2.8Hz,1H),4.44(t,J＝5Hz,2H),3.98(t,J＝5Hz,2H),2.97(s,6H)。
Example 11
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.7mmol), 3-bromo-5-chloropyridine (0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified on a silica gel column (petroleum ether/ethyl acetate 1/3) to give a grey solid (56mg, yield 24.2%). To obtain the compound 6(8- (N, N-dimethyl) -4- (5-chloro-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):318.77[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.62(d,J＝2Hz,1H),8.50(d,J＝2.4Hz,1H),8.06(t,J＝2.2Hz,1H),7.62(d,J＝9.2Hz,1H),6.54(dd,J＝2.4Hz,2.4Hz,1H),6.25(d,J＝2.4Hz,1H),4.44(t,J＝4.8Hz,2H),3.98(t,J＝5Hz,2H),2.97(s,6H)。
Example 12
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.7mmol), 3-bromopyridine (0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate 1/3) to give a white solid (50mg, yield 24.1%). To obtain the compound 7(8- (N, N-dimethyl) -4- (4-pyridyl) -3, 4-dihydrobenzo [ f) ][1,4]Oxazazem
-5(2H) -one).
MS(m/s):284.33[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.53(d,J＝6.4Hz,2H),7.64-7.59(m,3H),6.57(dd,J＝2.4Hz,2.4Hz,1H),6.34(d,J＝2.8Hz,1H),4.43(t,J＝5Hz,2H),4.09(t,J＝5.2Hz,2H),3.03(s,6H)。
Example 13
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.7mmol), 4-bromo-3-methylpyridine (0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate-1/3) to give a yellow solid (55mg, yield 25.4%). To obtain the compound 8(8- (N, N-dimethyl) -4- (3-methyl-4-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):298.35[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.50(t,J＝8.2Hz,2H),7.60(d,J＝9.2Hz,1H),7.30(d,J＝4.4Hz,1H),6.54(dd,J＝2.8Hz,2.4Hz,1H),6.27(d,J＝2.8Hz,1H),4.35(t,J＝5Hz,2H),3.86(t,J＝4.8Hz,2H),2.97(s,6H),2.15(s,3H).
Example 14
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.7mmol), 4-bromo-3-fluoropyridine (0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate-1/3) to give a yellow solid (55mg, yield 25.1%). To obtain the compound 9(8- (N, N-dimethyl) -4- (3-fluoro-4-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):302.32[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.63(d,J＝2.4Hz,1H),8.47(d,J＝5.2Hz,1H),7.60(d,J＝8.8Hz,1H),7.56(q,1H),6.54(dd,J＝2.4Hz,2.8Hz,1H),6.26(d,J＝2.4Hz,1H),4.37(t,J＝4.8Hz,2H),3.94(t,J＝5Hz,2H),2.98(s,6H).
Example 15
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.7mmol), 4-bromo-3-chloropyridine (0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate-1/3) to give a yellow solid (54mg, yield 23.4%). To obtain the compound 10(8- (N, N-dimethyl) -4- (3-chloro-4-pyridyl) -3, 4-dihydrobenzo [ f) ][1,4]Oxazazepine
-5(2H) -one).
MS(m/s):318.77[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.74(s,1H),8.59(d,J＝5.2Hz,1H),7.64(d,J＝8.8Hz,1H),7.54(d,J＝5.2Hz,1H),6.54(dd,J＝2.4Hz,2.8Hz,1H),6.25(d,J＝2.4Hz,1H),4.40(t,J＝4.6Hz,2H),3.88(t,J＝4.8Hz,2H),2.97(s,6H).
Example 16
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.7mmol), 3-bromo-5-methoxypyridine (0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate 1/3) to give a yellow solid (52mg, yield 22.8%). To obtain the compound 11(8- (N, N-dimethyl) -4- (5-methoxy-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):314.35[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.22(d,J＝2Hz,1H),8.18(d,J＝2.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.44(t,J＝2.2Hz,1H),6.54(dd,J＝2.4Hz,2.4Hz,1H),6.26(d,J＝2.4Hz,1H),4.43(t,J＝5Hz,2H),3.94(t,J＝4.8Hz,2H),3.85(s,3H),2.97(s,6H).
Example 17
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.7mmol), 3-bromo-4-methoxypyridine (0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate-1/3) to give a yellow solid (57mg, yield 26.4%). To obtain the compound 12(8- (N, N-dimethyl) -4- (4-methyl-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):298.35[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.41(s,1H),8.38(d,J＝5.2Hz,1H),7.62(d,J＝9.2Hz,1H),7.35(d,J＝5.2Hz,1H),6.54(dd,J＝2.4Hz,2.4Hz,1H),6.27(d,J＝2.8Hz,1H),4.39(d,J＝3.6Hz,2H),3.84(t,J＝4.8Hz,2H),2.97(s,6H),2.19(s,3H).
Example 18
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem 
-5(2H) -one (0.15g,0.7mmol), 3-bromo-4-chloropyridine (0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate-1/3) to give a yellow solid (59mg, yield 25.5%). To obtain the compound 13(8- (N, N-dimethyl) -4- (4-chloro-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):318.77[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.58(s,1H),8.48(d,J＝3.6Hz,1H),7.71(s,1H),7.68(t,J＝4.2Hz,1H),6.57(dd,J＝2.8Hz,2.8Hz,1H),6.34(d,J＝2.8Hz,1H),4.50(t,J＝4.8Hz,2H),3.92(t,J＝4.6Hz,2H),3.03(s,6H).
Example 19
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.7mmol), 3-bromo-4-cyanopyridine (0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate-1/3) to give a yellow solid (58mg, yield 25.9%). To obtain the compound 14(8- (N, N-dimethyl) -4- (4-nitrile-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):309.33[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.86(s,1H),8.75(d,J＝4.8Hz,1H),7.97(d,J＝4.8Hz,1H),7.66(d,J＝9.2Hz,1H),6.56(dd,J＝2.4Hz,2.8Hz,1H),6.27(d,J＝2.4Hz,1H),4.46(t,J＝4.6Hz,2H),4.02(t,J＝4.6Hz,2H),2.98(s,6H).
Example 20
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.7mmol), 3-bromo-isonicotinic acid methyl ester (0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate-1/3) to give a yellow solid (54mg, yield 21.8%). To obtain the compound 15(3- (8- (N, N-dimethyl) -5-oxo-2, 3-dihydrobenzo [ f) ][1,4]Oxazazepine
-4(5H) -isonicotinic acid methyl ester).
MS(m/s):342.36[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.71(s,1H),8.67(d,J＝4.8Hz,1H),7.72(d,J＝4.8Hz,1H),7.61(d,J＝8.8Hz,1H),6.52(dd,J＝2.4Hz,2.8Hz,1H),6.25(d,J＝2.8Hz,1H),4.52(t,J＝4.6Hz,2H),3.95(t,J＝4.6Hz,2H),3.73(s,3H),2.97(s,6H).
Example 21
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.7mmol), 3-bromo-nicotinic acid methyl ester (0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate 1/3) to give a white solid (50mg, yield 20.1%). To obtain the compound 16(3- (8- (N, N-dimethyl) -5-oxo-2, 3-dihydrobenzo [ f)][1,4]Oxazazem
-4(5H) -nicotinic acid methyl ester).
MS(m/s):342.36[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.94(d,J＝2Hz,1H),8.86(d,J＝2.4Hz,1H),8.32(t,J＝2.2Hz,1H),7.64(d,J＝8.8Hz,1H),6.54(dd,J＝2.8Hz,2.4Hz,1H),6.26(d,J＝2.4Hz,1H),4.46(t,J＝4.8Hz,2H),4.01(t,J＝4.8Hz,2H),3.91(s,3H),2.97(s,6H).
Example 22
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.7mmol), 3-bromo-5-acetylpyridine (0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate-1/3) to give a yellow solid (51mg, yield 21.6%). To obtain the compound 17(8- (N, N-dimethyl) -4- (5-acetyl-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):326.36[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.99(d,J＝1.6Hz,1H),8.84(d,J＝2.4Hz,1H),8.26(t,J＝2Hz,1H),7.64(d,J＝8.8Hz,1H),6.55(dd,J＝2.8Hz,2.4Hz,1H),6.27(d,J＝2.4Hz,1H),4.46(t,J＝4.8Hz,2H),4.01(t,J＝4.8Hz,2H),2.98(s,6H),2.66(s,3H).
Example 23
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem 
-5(2H) -one (0.15g,0.7mmol), 3-bromo-4-trifluoromethylpyridine (0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate 1/3) to give a white solid (59mg, yield 11%). Is prepared byCompound 18(8- (N, N-dimethyl) -4- (4-trifluoromethyl-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):352.32[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.84(s,1H),8.82(d,J＝2Hz,1H),7.86(d,J＝5.2Hz,1H),7.66(d,J＝9.2Hz,1H),6.52(dd,J＝2.4Hz,2.4Hz,1H),6.25(d,J＝2.8Hz,1H),4.56-4.51(m,1H),4.42-4.37(m,1H),4.88-4.83(m,2H),2.97(s,6H).
Example 24
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.7mmol), 3-bromo-5-trifluoromethylpyridine (0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethylenediamine (0.051g,0.48 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate-1/3) to give a yellow solid (52mg, yield 20.4%). To obtain the compound 19(8- (N, N-dimethyl) -4- (5-trifluoromethyl-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):352.32[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.93(d,J＝2.4Hz,1H),8.83(s,1H),8.30(s,1H),7.65(d,J＝8.8Hz,1H),6.55(dd,J＝2.8Hz,2.4Hz,1H),6.26(d,J＝2.4Hz,1H),4.47(t,J＝4.8Hz,2H),4.03(t,J＝4.8Hz,2H),2.98(s,6H).
Example 25
According to general procedure two, using 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.7mmol), 3-bromo-5-cyanopyridine (0.7mmol), potassium carbonate (0.69g,4.8mmol), cuprous iodide (0.078g,0.64mmol), N, N-diethyl-1, 2-ethane Diamine (0.051g,0.48mmol) was synthesized. The crude product was purified by silica gel column (petroleum ether/ethyl acetate 1/3) to give a white solid (55mg, yield 15%). To obtain the compound 20(8- (N, N-dimethyl) -4- (5-nitrile-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):309.33[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.96(d,J＝2.8Hz,1H),8.87(d,J＝2Hz,1H),8.41(t,J＝2.2Hz,1H),7.63(d,J＝9.2Hz,1H),6.55(dd,J＝2.4Hz,2.8Hz,1H),6.26(d,J＝2.4Hz,1H),4.46(t,J＝4.8Hz,2H),4.00(t,J＝5Hz,2H),2.97(s,6H).
Example 26
According to general procedure one, use is made of 8-fluoro-4- (4-methyl-3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.55mmol), morpholine (0.096g,1.1 mmol). The crude product was purified on a silica gel column (petroleum ether/ethyl acetate 1/2) to give a white solid (53mg, 28.5%). To obtain the compound 21 (8-morpholinyl-4- (4-nitrile-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):340.39[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.42(s,1H),8.39(d,J＝4.8Hz,1H),7.64(t,J＝4.6Hz,1H),7.36(d,J＝4.8Hz,1H),6.78(d,J＝8.8Hz,1H),6.53(s,1H),4.42(brs,2H),3.85(t,J＝4.4Hz,2H),3.72(t,J＝4.4Hz,4H),3.23(t,J＝4.4Hz,4H),2.19(s,3H).
Example 27
According to general procedure one, use is made of 8-fluoro-4- (4-methyl-3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.55mmol), piperazine (1.1 mmol). Purifying the crude product with silica gel columnConversion (petroleum ether/ethyl acetate: 1/2) gave a yellow solid (51mg, 27.4%). To prepare the compound 22 (8-piperazinyl-4- (4-nitrile-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):339.40[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.41(s,1H),8.38(d,J＝5.2Hz,1H),7.62(d,J＝9.2Hz,1H),7.36(d,J＝4.8Hz,1H),6.75(dd,J＝2.4Hz,2.8Hz,1H),6.48(d,J＝2.4Hz,1H),4.41(s,2H),3.85(t,J＝4.8Hz,2H),3.17(t,J＝4.8Hz,4H),2.80(t,J＝4.8Hz,4H),2.19(s,3H).
Example 28
According to general procedure one, use is made of 8-fluoro-4- (4-methyl-3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem 
-5(2H) -one (0.15g,0.55mmol), 4-methylpiperazine (1.1 mmol). The crude product was purified by silica gel column (petroleum ether/ethyl acetate 1/2) to give a white solid (57mg, 29.3%). To obtain the compound 23(8- (4-methylpiperazino) -4- (4-nitrile-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):353.43[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.41(s,1H),8.39(d,J＝4.8Hz,1H),7.62(d,J＝8.8Hz,1H),7.35(d,J＝4.8Hz,1H),6.77(dd,J＝1.6Hz,2.0Hz,1H),6.51(d,J＝1.6Hz,1H),4.41(brs,2H),3.85(t,J＝4.6Hz,2H),3.26(t,J＝4.4Hz,4H),2.42(t,J＝4.6Hz,4H),2.21(s,3H),2.19(s,3H).
Example 29
According to general procedure one, use is made of 8-fluoro-4- (4-methyl-3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.55mmol), 4-acetylpiperazine (1.1 mmol). Silica gel for crude productColumn purification (petroleum ether/ethyl acetate 1/2) gave a white solid (59mg, 21.4%). To prepare the compound 24(8- (4-acetylpiperazinyl) -4- (4-nitrile-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):381.44[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.42(s,1H),8.39(d,J＝4.8Hz,1H),7.65(d,J＝4.4Hz,1H),7.36(d,J＝5.2Hz,1H),6.79(dd,J＝2.4Hz,2.4Hz,1H),6.54(d,J＝2.4Hz,1H),4.43(brs,2H),3.85(t,J＝4.8Hz,2H),3.57(t,J＝5.2Hz,4H),3.31-3.25(m,4H),2.19(s,3H),2.04(s,3H).
Example 30
According to general procedure one, use is made of 8-fluoro-4- (4-methyl-3-pyridyl) -3, 4-dihydrobenzo [ f][1,4]Oxazazem
-5(2H) -one (0.15g,0.55mmol), piperidine (1.1 mmol). The crude product was purified on a silica gel column (petroleum ether/ethyl acetate 1/2) to give a yellow solid (53mg, 28.5%). To prepare the compound 25 (8-piperidyl-4- (4-nitrile-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):338.42[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.41(s,1H),8.38(d,J＝4.8Hz,1H),7.61(d,J＝8.8Hz,1H),7.34(d,J＝4.8Hz,1H),6.74(dd,J＝2.8Hz,2.4Hz,1H),6.48(d,J＝2Hz,1H),4.41(d,J＝2.4Hz,2H),3.85(t,J＝4.8Hz,2H),3.29(s,4H),2.19(s,3H),1.57(s,6H).
Example 31
According to general procedure one, use is made of 8-fluoro-4- (4-methyl-3-pyridyl) -3, 4-dihydrobenzo [ f ][1,4]Oxazazem
-5(2H) -one (0.15g,0.55mmol), pyrroline (1.1 mmol). The crude product is purified by silica gel column (petroleum ether/ethyl acetate)Ethyl acetate 1/2) yielded a white solid (58mg, 16%). To obtain the compound 26 (8-pyrrolinyl-4- (4-nitrile-3-pyridyl) -3, 4-dihydrobenzo [ f)][1,4]Oxazazem
-5(2H) -one).
MS(m/s):324.39[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.41(s,1H),8.38(d,J＝4.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.35(d,J＝4.8Hz,1H),6.38(dd,J＝2.4Hz,2.4Hz,1H),6.12(d,J＝2.4Hz,1H),4.39(d,J＝2.4Hz,2H),3.84(t,J＝4.8Hz,2H),3.28(t,J＝6.6Hz,4H),2.19(s,3H),1.97-1.94(m,4H)。
Experimental example 1
An assay for CYP17 inhibitory activity was performed. Human CYP17 and rat NADPH-P450 are co-expressed in Escherichia coli, and after the Escherichia coli enters a logarithmic growth phase, the Escherichia coli is cracked and centrifuged at 5000rpm to obtain a supernatant. 100nM pregnenolone and the appropriate concentration of test compound (compounds 1-26 and Abiraterone, Fadrazole, Anastrozole) were added thereto, incubated at 37 deg.C for 2 hours, quenched with ethyl acetate, and then quantified by HPLC at 260nM for substrate and product, and the inhibition and IC50 values were calculated.
Experimental example 2
An assay for CYP19 inhibitory activity was performed. Adding testosterone 100nM and compound to be tested with appropriate concentration into human placenta extract, incubating at 37 deg.C for 30 min, adding ethyl acetate for quenching, quantifying substrate and product at 260nM by HPLC, and calculating inhibition rate and IC 50 The value is obtained.
Experimental example 3
An assay for CYP11B1 inhibitory activity was performed.
Human CYP11B1 and rat NADPH-P450 gene are transfected into V79 cells by lentivirus, and a puromycin resistance gene is used for screening to obtain a stable transgenic cell strain. Diluting cells in logarithmic growth phase, removing about 104 cells for colonization, adding a 96-well plate, adding a compound to be tested with a proper concentration for preincubation for 2 hours, adding 10nM of deoxycrtisone to start catalytic reaction, continuously incubating for 30 minutes, adding ethyl acetate to quench, and then performing HPLC (high performance liquid chromatography) on a substrate at 260nM And product quantification, calculation of inhibition and IC 50 The value is obtained.
Experimental example 4
An assay for CYP11B2 inhibitory activity was performed.
Human CYP11B2 and rat NADPH-P450 gene are transfected into V79 cells by lentivirus, and a puromycin resistance gene is used for screening to obtain a stable transgenic cell strain. Diluting cells in logarithmic growth phase, removing about 104 cells for field planting, adding a compound to be detected with appropriate concentration, pre-incubating for 2 hours, adding deoxycrtisone 10nM to start catalytic reaction, incubating for 1 hour, adding ethyl acetate to quench, quantifying substrate and product at 260nM by HPLC, and calculating inhibition rate and IC 50 The value is obtained.
Experimental example 5
An assay for CYP8B1 inhibitory activity was performed.
Human CYP8B1 and rat NADPH-P450 gene are transfected into V79 cells by lentivirus, and a puromycin resistance gene is used for screening to obtain a stable transgenic cell strain. Diluting cells in logarithmic growth phase, removing about 104 cells for field planting, adding a compound to be detected with appropriate concentration, pre-incubating for 2 hours, adding deoxycrtisone 10nM to start catalytic reaction, incubating for 1 hour, adding ethyl acetate to quench, quantifying substrate and product at 260nM by HPLC, and calculating inhibition rate and IC 50 The value is obtained.
Experimental example 6
An assay for CYP7a1 inhibitory activity was performed.
Human CYP7A1 and rat NADPH-P450 gene are transfected into V79 cells by lentivirus, and a puromycin resistance gene is used for screening to obtain a stable transgenic cell strain. Diluting cells in logarithmic growth phase, removing about 104 cells for field planting, adding a compound to be detected with appropriate concentration, pre-incubating for 2 hours, adding deoxycrtisone 10nM to start catalytic reaction, incubating for 1 hour, adding ethyl acetate to quench, quantifying substrate and product at 260nM by HPLC, and calculating inhibition rate and IC 50 The value is obtained.
The measurement results are shown in Table 1.
TABLE 1 inhibition and IC 50 The value is obtained.
***IC 50 <100nM**IC 50 <500nM*IC 50 <1000nM。
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (19)
1. A compound capable of being used as a medicine is characterized by being selected from the following compounds:
formula IV
；
Wherein:
a is O;
R 1 And R 3 Each independently selected from the group consisting of:
hydrogen, deuterium, halogen, aryl, nitro, nitroso, amino, ureido, ester, hydroxyl, carboxyl, sulfonic, haloformyl, carbamoyl, aldehyde, cyano, aryloxy, mercapto, thioether, carbonyl, sulfonyl fluoride, CF 3 、SF 5 Optionally unsubstituted piperazinyl, morpholinyl, optionally unsubstituted pyridyl, optionally unsubstituted pyrrolinyl, oxime, hydrazone, optionally unsubstituted-NHC 1 -C 8 Alkyl, optionally unsubstituted-S- (-C) 1 -C 8 Alkyl), optionally unsubstituted-SO 2 -(-C 1 -C 8 Alkyl), optionally unsubstituted-SO 2 -NH-(-C 1 -C 8 Alkyl), optionally unsubstituted-NH-SO 2 -(-C 1 -C 8 Alkyl), -CO 2 R 4 、-NR 5 R 6 and-CO-NR 5 R 6 ；
R 2 Selected from hydrogen;
R 4 independently selected from the group consisting of: optionally unsubstituted-C 1 -C 8 Alkyl, optionally unsubstituted-C 2 -C 8 Alkenyl, optionally unsubstituted-C 2 -C 8 Alkynyl, optionally unsubstituted-C 3 -C 8 Cycloalkyl, optionally unsubstituted-C 3 -C 8 Cycloalkenyl and optionally unsubstituted 3 to 8 membered heterocycloalkyl;
R 5 and R 6 Each independently selected from hydrogen, optionally unsubstituted-C 1 -C 8 -alkyl, optionally unsubstituted-C 2 -C 8 -alkenyl, optionally unsubstituted-C 2 -C 8 -alkynyl, optionally unsubstituted-C 3 -C 8 -cycloalkyl, -C (O) R 4 、-S(O) 2 R 4 、-S(O) 2 NHR 4 And optionally unsubstituted-C 1 -C 8 An alkoxy group;
y is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4.
2. The pharmaceutical compound of claim 1, wherein R is 1 And R 3 Each optionally substituted with 1 to 3 substituents of the group consisting of: halogen, -CH 3 、-CF 3 、-SF 5 、-CCl 3 、-OCF 3 、-CN、-NH 2 、-OH、-CH 2 N(CH 3 ) 2 、-C(O)CH 3 、-SO 2 -、-NHSO 2 -、-SO 2 F. Acyl, acylamino, optionally-NH- (C) 1 -C 6 ) Alkyl, optionally-NH- (C) 1 -C 6 ) Alkyl radical- (C) 1 -C 6 ) Alkoxy, optionally-SO 2 -(C 1 -C 6 ) Alkyl, optionally-SO 2 -NH-(C 1 -C 6 ) Alkyl, optionally-NH-SO 2 -(C 1 -C 6 ) Alkyl, optionally 3-to 12-membered heterocycloalkyl, optionally-C 1 -C 8 Alkyl, optionally-C 1 -C 8 Alkenyl, optionally-C 3 -C 8 -cycloalkyl, optionally-C 3 -C 8 Cycloalkenyl radical and optionally-C 1 -C 8 An alkoxy group.
3. A pharmaceutical compound according to claim 2, wherein R is 1 And R 3 Each optionally substituted with 1 to 3 substituents of the group consisting of:
fluorine, -CH 3 、-CF 3 and-CN.
4. The pharmaceutical compound of claim 1, wherein R is 3 When in the ortho position to N, R 3 Is hydrogen or deuterium.
5. The pharmaceutical compound of claim 1, wherein the pharmaceutical compound is any one of the following compounds:
8-fluoro-4- (4-methyl-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] azepine-5 (2H) -one, 8-fluoro-4- (3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] azepine-5 (2H) -one, 8- (N, N-dimethyl) -4- (3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one, 8- (N, N-dimethyl) -4- (5-methyl-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] azepine-5 (2H) -one, 8- (N, N-dimethyl) -4- (5-fluoro-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] azepine-5 (2H) -one, 8- (N, N-dimethyl) -4- (5-chloro-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one, 8- (N, N-dimethyl) -4- (3-methyl-4-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one, 8- (N, N-dimethyl) -4- (3-fluoro-4-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one, 8- (N, N-dimethyl) -4- (3-chloro-4-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one, 8- (N, N-dimethyl) -4- (5-methoxy-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one, b, 8- (N, N-dimethyl) -4- (4-methyl-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one, 8- (N, N-dimethyl) -4- (4-chloro-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one, 8- (N, N-dimethyl) -4- (4-cyano-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one, 3- (8- (N, N-dimethyl) -5-oxo-2, 3-dihydrobenzo [ f ] [1,4] oxazepine-4 (5H) -isonicotinic acid methyl ester, 3- (8- (N, N-dimethyl) -5-oxo-2, 3-dihydrobenzo [ f ] [1,4] oxazepine-4 (5H) -nicotinic acid methyl ester, 8- (N, N-dimethyl) -4- (5-acetyl-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one, 8- (N, N-dimethyl) -4- (4-trifluoromethyl-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one, b, 8- (N, N-dimethyl) -4- (5-trifluoromethyl-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one, 8- (N, N-dimethyl) -4- (5-cyano-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one, 8-morpholinyl-4- (4-cyano-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one, 8-piperazinyl-4- (4-cyano-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one, 8- (4-methylpiperazino) -4- (4-cyano-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one, 8- (4-acetylpiperazinyl) -4- (4-cyano-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one, 8-piperidinyl-4- (4-cyano-3-pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one, and 8-pyrrolinyl-4- (4-cyano-3-pyridone) Pyridyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one.
6. The pharmaceutically acceptable salt of the compound as a medicine in claim 1, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable inorganic acid salt or organic acid salt; the inorganic acid salt is selected from sulfate, sulfite, hydrochloride, hydrobromide, nitrate, phosphate and dihydrogen phosphate.
7. The pharmaceutically acceptable salt of a pharmaceutical compound according to claim 6, wherein the organic acid salt is acetate, maleate, fumarate, succinate, citrate, p-toluenesulfonate, tartrate, formate, propionate, heptanoate, oxalate, benzoate, malonate, succinate, maleate, hydroxybutyrate, citrate, methanesulfonate, benzenesulfonate, lactate or mandelate.
8. A process for the preparation of a pharmaceutical compound according to any one of claims 1 to 7, comprising the steps of:
firstly, corresponding substituted aromatic phenol is used as a raw material to react with corresponding methyl bromocarboxylate, the obtained product is hydrolyzed in aqueous solution of lithium hydroxide to obtain a carboxylic acid intermediate I, then, the ring closure is carried out in the environment of trifluoroacetic acid and trifluoroacetic anhydride to obtain a fused ring aromatic cyclic ketone intermediate II, the fused ring aromatic cyclic ketone intermediate II is reacted with hydroxylamine hydrochloride to obtain an oxime intermediate III, then, BECKMANN rearrangement is carried out to obtain an amide intermediate IV, and the amide intermediate IV is reacted with a bromide of a corresponding nitrogen-containing heterocyclic ring in an alkaline environment catalyzed by copper or palladium to obtain a target compound V;
9. The method for preparing according to claim 8, characterized in that it comprises: the fused ring aromatic hydrocarbon cyclic ketone intermediate II is 7-fluoro-chroman-4-one, the oxime intermediate III is 7-fluoro-chroman-4-oxime, and the amide intermediate IV is 8-fluoro-3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one, or 8- (N, N-dimethyl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepine-5 (2H) -one.
10. Use of a compound according to any one of claims 1 to 7 as a medicament in the manufacture of a steroid synthase inhibitor.
11. Use according to claim 10, characterized in that the steroid synthase is at least one of the following enzymes: aldosterone synthase, cortisone biosynthetic enzymes, estrogen synthase, androgen synthase, and bile acid biosynthetic enzymes.
12. The use of claim 11, wherein said aldosterone synthase is CYP11B2, said cortisone biosynthetic enzyme is CYP11B 1; the estrogen synthase is CYP 19; the androgen synthase CYP 17; the bile acid biosynthetic enzyme is CYP7A1 and/or CYP8B 1.
13. Use of a compound according to any one of claims 1 to 7 as a medicament for the manufacture of a medicament for the treatment of an hormone dependent disorder selected from at least one of the following disorders:
Congestive heart failure, hypertension, chronic kidney disease, diabetic nephropathy, hyperaldosteronism, cardiac fibrosis, renal fibrosis, cardiorenal syndrome, metabolic syndrome, cushing's syndrome, insulin resistance, obesity, type II diabetes, breast cancer, prostate cancer, ovarian cancer, cervical cancer, diabetic foot, diabetic eye disease, diabetic ulcer, renal failure, fatty liver, cirrhosis, liver fibrosis, liver cancer, pancreatic cancer, cholangiocarcinoma, colon cancer, rectal cancer.
14. The use according to claim 13, wherein the hormone dependent disorder is selected from non-alcoholic fatty liver disease.
15. A medicament for the treatment of hormone dependent diseases, comprising a pharmaceutically acceptable compound according to any one of claims 1 to 7.
16. The agent for treating hormone-dependent disorder according to claim 15, further comprising pharmaceutically acceptable additives or adjuvants.
17. The drug for treating hormone-dependent diseases according to claim 16, wherein the dosage form is selected from the group consisting of tablets, pills, powders, suspensions, gels, emulsions, creams, granules, nanoparticles, capsules, suppositories, injections, sprays and injections.
18. A pharmaceutical composition comprising a pharmaceutically acceptable compound according to any one of claims 1 to 7.
19. The pharmaceutical composition of claim 18, further comprising a combination drug/therapy, wherein the combination drug/therapy is at least one of the following drugs:
chemotherapeutic agents, radiation therapy, photosensitizers, photothermics, immunotherapy, androgen receptor antagonists and function modulators, estrogen receptor antagonists and function modulators, sugar hormone receptor antagonists and function modulators, salt hormone receptor antagonists and function modulators, FXR agonists, antagonists and function modulators, GPR30 agonists, antagonists and function modulators, TGR agonists, antagonists and function modulators, GLP receptor agonists, antagonists and function modulators, FGF receptor agonists, antagonists and function modulators, thyroxine receptor agonists, antagonists and function modulators, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, and TGF receptor agonists, antagonists and function modulators.
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| CN113913507A (en) * | 2021-10-29 | 2022-01-11 | 温州医科大学附属第一医院 | Application of CCL3 protein as biomarker for evaluating non-alcoholic fatty liver disease inflammation level and disease progression |
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| CA2672286A1 (en) * | 2006-12-18 | 2008-06-26 | Novartis Ag | Organic compounds |
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| WO2008076860A1 (en) * | 2006-12-18 | 2008-06-26 | Novartis Ag | 4-imidazolyl-1,2,3,4-tetrahydroquinoline derivatives and their use as aldosterone/11-beta-hydroxylase inhibitors |
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| JP2013540145A (en) * | 2010-10-21 | 2013-10-31 | ウニベルシテート デス ザールランデス | Selective CYP11B1 inhibitor for the treatment of cortisol-dependent diseases |
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