Benzamide compound, pharmaceutical composition and application

Abstract

The invention discloses a benzamide compound, a pharmaceutical composition and application. The benzamide compound has a structure as shown in the following formula: # imgabs0 #, wherein R1 and R2 are respectively and independently selected from aryl, heteroaryl or heterocyclic radical; r3 and R4 are respectively and independently selected from any one of hydrogen, halogen, trifluoromethyl, cyano, nitryl, hydroxyl, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, heterocyclic group substituted C1-C6 alkoxy, C3-C8 naphthenic base, aryl, heteroaryl and heterocyclic group; x is selected from CH2, NH, O, CO or S; n is selected from 0, 1, 2, 3 or 4. The benzamide compound, namely the V2R antagonist, provided by the invention has the advantages of high activity, high selectivity and simplicity in synthesis, has a good curative effect on in-vitro and in-vivo autosomal dominant polycystic kidney disease models, and has great optimization potential in the field of being used as a lead compound for treating ADPKD.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical compounds, and in particular relates to a benzamide compound, a pharmaceutical composition and uses thereof. Background Art

[0002] Arginine vasopressin (AVP) is a naturally occurring neurohormone released in the brain and blood. AVP plays an important role in regulating water, blood pressure, and the secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland, and exerts its physiological and behavioral effects by binding to specific G protein-coupled receptors in the central nervous system and certain peripheral sites or tissues. In the brain, AVP regulates circadian rhythms, promotes learning and memory in the hippocampus, and plays an important role in regulating social behavior in neurobehavioral disorders through its actions in limbic circuits.

[0003] Three distinct AVP receptor subtypes have been identified on a pharmacological and functional basis: V 1a 、V 1b and V2. These receptors are located in the liver, blood vessels (coronary arteries, renal vessels, cerebral vessels), platelets, kidneys, uterus, adrenal glands, pancreas, central nervous system or pituitary gland. AVP is involved in the regulation of a variety of functions, such as cardiovascular, liver, pancreatic, antidiuretic and platelet aggregation effects, as well as its effects on the central and peripheral nervous systems and uterine bulbs. The effects produced by AVP receptors depend on their location. V 1a Receptors are found throughout the limbic system and cortex of the brain and are distributed in the smooth muscle of blood vessels, the uterus, and the myocardium. 1b V2 receptors are also distributed in the limbic system and pituitary gland. V2 receptors are located in the collecting ducts of the nephrons in the kidneys and have become a target for the treatment of cardiovascular diseases. Inhibition of arginine vasopressin receptors can produce a series of physiological effects.

[0004] Studies have shown that arginine vasopressin receptor antagonists play a positive role in the prevention and treatment of hypertension, Reye's syndrome, dysmenorrhea, premature birth, adrenocorticotropic hormone secretion disorder, adrenal hyperplasia, depression, chronic congestive heart failure, cirrhosis, antidiuretic hormone secretion disorder syndrome or chronic heart failure, cirrhosis, hyponatremia caused by antidiuretic hormone secretion disorder and autosomal dominant polycystic kidney disease. The development of conivaptan and tolvaptan has become a hot topic in the research and development of drugs for the treatment of the above diseases. These compounds have antagonistic activity against arginine vasopressin receptors and can therefore be used to treat the above diseases.

[0005] Autosomal dominant polycystic kidney disease (ADPKD, hereinafter referred to as polycystic kidney disease) is a common hereditary kidney disease with a prevalence of between 1 / 1000 and 1 / 2500. ADPKD can develop during the embryonic period and is characterized by the formation of fluid-filled renal cysts in the renal tubules and collecting ducts, which continue to proliferate and expand, damaging the normal renal parenchyma. This cyst-induced renal insufficiency can last for decades and eventually lead to end-stage renal disease (ESRD). In addition, ADPKD can also induce a series of complications, such as hypertension, acute / chronic pain, hematuria, cyst infection, and kidney stones, which bring great pain to patients' daily lives.

[0006] Since ADPKD is a genetic defect disease, the selection of its drug targets is very difficult. Therefore, there are very few effective therapeutic drugs available on the market, and related research is still in its infancy. Based on the pathogenesis of ADPKD, the current research on its drug targets generally focuses on pathways that can regulate cell proliferation and fluid secretion, such as aquaporin-2 (AQP2), V2 receptor (Vasopressin-2 receptor, V2R), somatostatin receptor (SSTR), human epidermal growth factor receptor 2 (ErbB-2), integrin-linked kinase (ILK), etc. Inhibition of AQP2 can significantly inhibit the expansion of vesicles caused by fluid secretion, but the inhibitory effect on cell proliferation induced by ADPKD is not obvious, and it may cause cystic tumor lesions. SSTR acts on G i Signaling pathways, somatostatin analogs such as octreotide can activate this receptor and inhibit the formation of vesicles, however, the use of such drugs can lead to dysregulation of hormone secretion and significant side effects, making clinical application difficult. ErbB-2 and ILK-mediated signaling pathways can both regulate cell proliferation, so ErbB-2 and ILK are potential targets, and their therapeutic effects on ADPKD still need to be verified. Chinese herbal extracts such as Ganoderma lucidum triterpenes and quercetin also have certain therapeutic effects on ADPKD, but the specific mechanism of action and adverse reactions need further study.

[0007] V2R antagonists can alleviate disease progression by downregulating intracellular cAMP (cyclic adenosine monophosphate) levels. Tolvaptan (OPC41061) is a V2R antagonist and is currently the only drug approved by the FDA (U.S. Food and Drug Administration) for the treatment of ADPKD. However, tolvaptan is hepatotoxic and is only recommended for patients with rapidly progressive ADPKD. Currently, the structural diversity of V2R antagonists is poor, and most V2R antagonists are based on aromatic ring nitrogen modified from tolvaptan. It is generally believed that there is a lack of aromatic ring nitrogen Such structures will cause the compounds to lose their binding affinity or selectivity to V2R, which limits the development of new skeletons. Therefore, it is necessary to develop new non-benzoazepine V2R antagonists to alleviate the occurrence of ADPKD. Summary of the invention

[0008] The main purpose of the present invention is to provide a benzamide compound, a pharmaceutical composition and use to overcome the deficiencies of the prior art.

[0009] In order to achieve the above-mentioned invention object, the technical solution adopted by the present invention includes:

[0010] An embodiment of the present invention provides a benzamide compound, wherein the benzamide compound has a structure as shown in formula (I):

[0011]

[0012] wherein R1 and R2 are each independently selected from aryl, heteroaryl or heterocyclic, wherein aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one selected from halogen, trifluoromethyl, cyano, nitro, hydroxyl, amino, carboxyl, carboxymethyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The substituent of the cycloalkyl group is substituted; R3 and R4 are each independently selected from any one of hydrogen, halogen, trifluoromethyl, cyano, nitro, hydroxyl, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy substituted with heterocyclic group, C3-C8 cycloalkyl, aryl, heteroaryl, and heterocyclic group;

[0013] X is selected from CH2, NH, O, CO or S; n is selected from 0, 1, 2, 3 or 4.

[0014] The embodiment of the present invention further provides a pharmaceutical composition, which includes the aforementioned benzamide compound, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0015] The present invention also provides the aforementioned benzamide compounds, their stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions for use in the preparation of drugs for preventing and / or treating diseases related to arginine vasopressin V. 1a Receptor, arginine vasopressin V 1b The invention relates to a drug for treating diseases related to the arginine vasopressin V2 receptor, the sympathetic nervous system or the renin-angiotensin-aldosterone system.

[0016] Compared with the prior art, the beneficial effects of the present invention are as follows: the novel benzamide compound (i.e., V2R antagonist) proposed in the present invention does not contain the generally believed key active group of V2R antagonists, an aromatic ring azepine structure, while still having high activity selectivity and simple synthesis; at the same time, the compound N-(4-((4-fluorophenyl)(2-morpholinoethyl)carbamoyl)-2-hydroxyphenyl)-[1,1′-biphenyl]-2-carboxamide has the highest activity, and its water solubility and selectivity are significantly higher than tolvaptan, and can be used as a lead compound for the treatment of ADPKD. DETAILED DESCRIPTION

[0017] In view of the defects of the prior art, the inventor of this case has proposed the technical solution of the present invention after long-term research and extensive practice. The technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0018] Specifically, as one aspect of the technical solution of the present invention, a benzamide compound involved has a structure as shown in formula (I):

[0019]

[0020] wherein R1 and R2 are each independently selected from aryl, heteroaryl or heterocyclic, wherein aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one selected from halogen, trifluoromethyl, cyano, nitro, hydroxyl, amino, carboxyl, carboxymethyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The substituent of the cycloalkyl group is substituted; R3 and R4 are each independently selected from any one of hydrogen, halogen, trifluoromethyl, cyano, nitro, hydroxyl, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy substituted with a heterocyclic group, C3-C8 cycloalkyl, aryl, heteroaryl, and heterocyclic group;

[0021] X is selected from CH2, NH, O, CO or S; n is selected from 0, 1, 2, 3 or 4.

[0022] In some preferred embodiments, R1 in formula (I) is selected from phenyl or pyridine, wherein the phenyl group is unsubstituted or substituted at the 3-position or 4-position by any one of fluoro, chloro, methyl, trifluoromethyl, methoxy, hydroxy, carboxyl, and carboxymethyl.

[0023] In some preferred embodiments, R2 in formula (I) is selected from phenyl, 3-chlorophenyl, pyridyl, morpholinyl or pyranyl, and is not limited thereto.

[0024] In some preferred embodiments, R3 in formula (I) is selected from 3-hydroxy, 3-methoxy or 3-(4-(4-methylpiperazin-1-yl)butoxy), and is not limited thereto.

[0025] In some preferred embodiments, R4 in formula (I) is selected from 2-substituted methyl, ethyl, isopropyl, phenyl, morpholinyl, pyrrolyl or piperidinyl, and is not limited thereto.

[0026] In some preferred embodiments, in formula (I), X is selected from CH2, CO or O, and n is selected from 0, 1 or 2.

[0027] In some preferred embodiments, the benzamide compound comprises any one or more combinations of the following compounds:

[0028] 1) N-(4-((2-phenoxyethyl)(phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0029] 2) N-(4-((2-(3-chlorophenoxy)ethyl)(phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0030] 3) N-(4-((2-phenoxyethyl)(pyridin-4-yl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0031] 4) N-(4-((3-morpholinyl-3-oxopropyl)(phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0032] 5) N-(4-((3-morpholinopropyl)(phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0033] 6) N-(4-(phenethyl(phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0034] 7) N-(4-((2-morpholinyl-2-oxoethyl)(phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0035] 8) N-(4-((2-morpholinylethyl)(phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0036] 9) N-(4-(Benzyl(phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0037] 10) N-(4-(phenyl((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0038] 11) N-(4-(diphenylcarbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0039] 12) N-(4-(Benzyl(pyridin-2-yl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0040] 1 3) N-(4-(Benzyl(pyridin-3-yl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0041] 14) N-(4-(Benzyl(pyridin-4-yl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0042] 15) N-(4-(Benzyl(2-hydroxyphenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0043] 16) N-(4-(Benzyl(3-hydroxyphenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0044] 17) N-(4-(Benzyl(4-hydroxyphenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0045] 18) 4-(4-([1,1′-biphenyl]-2-carboxamido)-N-benzylbenzamido)benzoic acid;

[0046] 19) methyl 4-(4-([1,1′-biphenyl]-2-carboxamido)-N-benzylbenzamido)benzoate;

[0047] 20) N-(4-(Benzyl(4-fluorophenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0048] 21) N-(4-(Benzyl(4-chlorophenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0049] 22) N-(4-(Benzyl(p-tolyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0050] 23) N-(4-(Benzyl(4-(trifluoromethyl)phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0051] 24) N-(4-(Benzyl(4-methoxyphenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0052] 25) N-(4-(Benzyl(3-fluorophenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0053] 26) N-(4-(Benzyl(3-chlorophenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0054] 27) N-(4-(Benzyl(m-tolyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0055] 28) N-(4-(Benzyl(3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0056] 29) N-(4-(Benzyl(3-methoxyphenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0057] 30) N-(4-(Benzyl(phenyl)carbamoyl)-2-(4-(4-methylpiperazin-1-yl)butoxy)phenyl)-[1,1′-biphenyl]-2-carboxamide;

[0058] 31) N-(4-(Benzyl(phenyl)carbamoyl)-2-methoxyphenyl)-[1,1′-biphenyl]-2-carboxamide;

[0059] 32) N-(4-(Benzyl(phenyl)carbamoyl)-2-hydroxyphenyl)-[1,1′-biphenyl]-2-carboxamide;

[0060] 33) N-Benzyl-N-(4-fluorophenyl)-4-(2-methylbenzamido)benzamide;

[0061] 34) N-Benzyl-4-(2-ethylbenzamido)-N-(4-fluorophenyl)benzamide;

[0062] 35) N-Benzyl-N-(4-fluorophenyl)-4-(2-isopropylbenzamido)benzamide;

[0063] 36) N-(4-(Benzyl(4-fluorophenyl)carbamoyl)-2-hydroxyphenyl)-[1,1′-biphenyl]-2-carboxamide;

[0064] 37) N-Benzyl-N-(4-fluorophenyl)-3-hydroxy-4-(2-morpholinylbenzamido)benzamide;

[0065] 38) N-Benzyl-N-(4-fluorophenyl)-3-hydroxy-4-(2-(pyrrolidin-1-yl)benzamido)benzamide;

[0066] 39) N-Benzyl-N-(4-fluorophenyl)-3-hydroxy-4-(2-(pyridin-2-yl)benzamido)benzamide;

[0067] 40) N-(4-((4-fluorophenyl)((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-2-hydroxyphenyl)-[1,1′-biphenyl]-2-carboxamide;

[0068] 41) N-(4-((4-fluorophenyl)(2-morpholinoethyl)carbamoyl)-2-hydroxyphenyl)-[1,1′-biphenyl]-2-carboxamide;

[0069] 42) N-(4-((4-Fluorophenyl)(pyridin-3-ylmethyl)carbamoyl)-2-hydroxyphenyl)-[1,1′-biphenyl]-2-carboxamide.

[0070] Another aspect of the embodiments of the present invention further provides a pharmaceutical composition, which includes the aforementioned benzamide compound, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0071] Another aspect of the present invention also provides the aforementioned benzamide compounds, their stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions for the preparation of a method for preventing and / or treating diseases related to arginine vasopressin V. 1a Receptor, arginine vasopressin V 1b The invention relates to a drug for treating diseases related to the arginine vasopressin V2 receptor, the sympathetic nervous system or the renin-angiotensin-aldosterone system.

[0072] In some preferred embodiments, the arginine vasopressin V 1a Receptor, arginine vasopressin V 1bDiseases associated with the vasopressin receptor, arginine vasopressin V2 receptor, sympathetic nervous system, or renin-angiotensin-aldosterone system include hypertension, Reye's syndrome, dysmenorrhea, premature labor, impaired corticotropin-releasing hormone secretion, adrenal hyperplasia, depression, chronic congestive heart failure, cirrhosis, syndrome of impaired antidiuretic hormone secretion, hyponatremia caused by chronic heart failure / cirrhosis / impaired antidiuretic hormone secretion, or polycystic kidney disease.

[0073] In some preferred embodiments, the pharmaceutically acceptable salt is a salt formed by the benzamide compound and an inorganic acid and / or an organic acid.

[0074] Furthermore, the inorganic acid includes any one or more combinations of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, but is not limited thereto.

[0075] Furthermore, the organic acid includes any one or more combinations of citric acid, lactic acid, malic acid, gluconic acid, tartaric acid, adipic acid, acetic acid, succinic acid, fumaric acid, ascorbic acid, itaconic acid, methanesulfonic acid, and benzenesulfonic acid, but is not limited thereto.

[0076] Unless otherwise indicated, the chemical compounds used in the above formulae have their usual meanings.

[0077] In the present invention, unless otherwise specified, "alkyl" refers to a linear or branched monovalent saturated hydrocarbon group having up to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. Similarly, "C 1-6 The "C" in "alkyl" 1-6 " refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched chain. Substituted alkyl is an alkyl group containing one or more substituents in place of hydrogen, for example 1, 2 or 3 substituents up to the number of hydrogen present on the unsubstituted alkyl group. If not otherwise specified, suitable substituents for alkyl groups may be selected from halogen, CN, oxo, hydroxy, C 1-4 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, amino, (C 1-4 alkyl)amino, di(C 1-4 Alkyl)amino, C 1-4 Alkylthio, C 1-4 Alkylsulfonyl, -C(=O)-C 1-4 Alkyl, COOH, COO(C 1-4alkyl), -O(C=O)-C 1-4 Alkyl, -NHC(=O)C 1-4 Alkyl and -NHC(=O)OC 1-4 wherein, for substituted cycloalkyl or phenyl, the substituents are up to three groups selected from Me, Et, -OMe, -OEt, CF3, halogen, CN, OH and NH2.

[0078] In the present invention, unless otherwise indicated, the term "alkoxy" refers to alkyl-O-, wherein alkyl is as defined above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. Typically, the alkoxy group has 1-6 carbons, more typically 1-4 carbon atoms.

[0079] In the present invention, unless otherwise specified, the term "heterocyclyl" refers to a saturated or partially unsaturated but non-aromatic heterocyclic group, and may be monocyclic or polycyclic (in the case of polycyclic, especially bicyclic, tricyclic or spirocyclic); and has 3 to 14, more usually 4 to 10, most preferably 5 or 6 ring atoms; wherein one or more, preferably one to four, especially one or two ring atoms are heteroatoms independently selected from O, S and N (the remaining ring atoms are carbon). Even if described as, for example, C 5-6 Atomic ring, then heterocycle contains at least one heteroatom as ring atom, other ring atoms are carbon, and have described number of ring atoms, for example, 5-6 in this example. Preferably, heterocyclic radical has one or two such heteroatoms as ring atoms, and preferably, heteroatoms are not directly connected to each other. Unless otherwise indicated, bonding ring (i.e., ring connected to target formula) preferably has 4-12, particularly 5-7 ring atoms. Heterocyclic group can be fused to aromatic ring, provided that the atom of heterocyclic group connected to target chemical formula is not aromatic. Heterocyclic group can be connected to target formula by heteroatom (usually nitrogen) or carbon atom on heterocyclic group. Heterocyclic radical can include condensed ring or bridged ring and spirocycle, and as long as one ring of polycyclic heterocyclic group contains heteroatom as ring atom. This heterocyclic radical can be connected to any heteroatom or carbon atom to form stable structure. Examples of these heterocyclic groups include, but are not limited to, tetrahydrofuran (THF) group, dihydrofuranyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dioxanyl, 1,3-dithianyl, oxathianyl, thiomorpholinyl, and the like.

[0080] In the present invention, unless otherwise stated, the term "aryl" refers to an aromatic hydrocarbon group having 6-14 carbon atoms in the ring portion. Typically, an aryl group is a monocyclic, bicyclic or tricyclic aromatic group having 6-14 carbon atoms, typically 6-10 carbon atoms, such as a phenyl or naphthyl group. In addition, the term "aryl" as used herein refers to an aromatic substituent, which may be a single aromatic ring, or a plurality of aromatic rings fused together. Non-limiting examples include phenyl, naphthyl and 1,2,3,4-tetrahydronaphthyl, provided that the tetrahydronaphthyl group is connected to the target molecular formula via the carbon of the aromatic ring of the tetrahydronaphthyl group. Unless otherwise stated, a preferred aryl group is a phenyl group.

[0081] In the present invention, unless otherwise indicated, the term "heteroaryl" refers to a 5-14-membered monocyclic or bicyclic or tricyclic aromatic ring system having 1 to 8 heteroatoms as ring atoms, the remaining ring atoms being carbon, and the heteroatoms being selected from N, O and S. Typically, heteroaryl is a 5-10-membered ring system, particularly a 5-6-membered monocyclic or 8-10-membered bicyclic group. Heteroaryl can be attached to any heteroatom or carbon atom to form a stable structure. Examples of heteroaryl include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adenine, quinolyl or isoquinolyl.

[0082] The term "substituted" or "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents. Typical substituents include, but are not limited to, halogen (F, Cl, Br or I), C 1-8 Alkyl, C 3-12 Cycloalkyl, -OR1, -SR1, =O, =S, -C(O)R1, -C(S)R1, =NR1, -C(O)OR1, -C(S)OR1, -NR1R1, -C(O)NR1R1, cyano, nitro, -S(O)2R1, -OS(O2)OR1, -OS(O)2R1, -OP(O)(OR1)(OR2); wherein R1 and R2 are independently selected from -H, C 1-6 Alkyl, C 1-6 In some embodiments, the substituents are independently selected from the group comprising -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH3, -SC2H5, formaldehyde, -C(OCH3), cyano, nitro, -CF3, -OCF3, amino, dimethylamino, methylthio, sulfonyl and acetyl.

[0083] The compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.

[0084] The above-described formula (I) does not precisely define the stereostructure of a certain position of the compound. The present invention includes all stereoisomers of the compound shown in formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. In the synthetic process for preparing such compounds, or in the process of racemization or epimerization known to those skilled in the art, the obtained product may be a mixture of stereoisomers. When the compound shown in formula (I) exists as tautomers, unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0085] When the compound shown in formula (I) and its pharmaceutically acceptable salt exist solvate or polymorph, the present invention includes any possible solvate and polymorph. The type of solvent forming the solvate is not particularly limited, as long as the solvent is pharmaceutically acceptable. For example, similar solvents such as water, ethanol, propanol, acetone can be adopted.

[0086] Therefore, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound shown in formula (I) or its stereoisomer, tautomer, polymorph, solvate, pharmaceutically acceptable salt, or prodrug thereof. The compound shown in formula (I) or its pharmaceutically acceptable salt, in combination with one or more other therapeutically active compounds, is also included in the pharmaceutical composition of the present invention.

[0087] In the present invention, the term "composition" refers to a product comprising a specified amount of each specified component, and any product produced directly or indirectly by a combination of specified amounts of each specified component. Therefore, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods for preparing the compounds of the present invention are also part of the present invention. In addition, some crystalline forms of the compounds may exist in polymorphic forms, and such polymorphic forms are included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates also fall within the scope of the present invention.

[0088] The pharmaceutical composition provided by the present invention includes a compound shown in formula (I) (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable excipient and other optional therapeutic components or adjuvants. Although in any given case, the most suitable mode of administration of the active ingredient depends on the specific subject, subject property and severity of the disease to be administered, the pharmaceutical composition of the present invention includes a pharmaceutical composition suitable for oral, rectal, local and parenteral (including subcutaneous administration, intramuscular injection, intravenous administration) administration. The pharmaceutical composition of the present invention can be conveniently prepared in unit dosage forms known in the art and any preparation method known in the pharmaceutical field.

[0089] In fact, according to conventional drug mixing technology, the compound shown in formula (I) of the present invention, or a drug precursor, or a metabolite, or a pharmaceutically acceptable salt, can be used as an active ingredient and mixed with a drug carrier to form a pharmaceutical composition. The drug carrier can take a variety of forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention can be a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention can be in the form of a powder, granule, solution, aqueous suspension, non-aqueous liquid, water-in-oil emulsion, or oil-in-water emulsion. In addition, in addition to the common dosage forms mentioned above, the compound shown in formula (I) or its pharmaceutically acceptable salt can also be administered by controlled release and / or delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with a carrier constituting one or more essential components. Generally, the pharmaceutical composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of the two. In addition, the product can be easily prepared into a desired appearance.

[0090] In the present invention, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, etc. and combinations thereof, as known to those skilled in the art (see, e.g., Remington: The Science and Practice of Pharmacy, 22nd edition). In addition to any conventional carriers that are incompatible with the active ingredient, their use in therapeutic or pharmaceutical compositions is also contemplated. The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that induces a biological or medical response in a subject, for example, an amount sufficient to reduce one or more symptoms, alleviate a symptom, slow or delay disease progression, or prevent a disease, etc. In a non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, effectively prevents or treats a disease associated with arginine vasopressin V 1a Receptor, arginine vasopressin V 1b receptors, arginine vasopressin V2 receptors, sympathetic nervous system, or renin-angiotensin-aldosterone system-related diseases.

[0091] Specifically, the drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier. Solid carriers include, but are not limited to, lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid. Liquid carriers include, but are not limited to, syrup, peanut oil, olive oil and water. Gas carriers include, but are not limited to, carbon dioxide and nitrogen. When preparing oral pharmaceutical preparations, any pharmaceutically convenient medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, colorants, etc. can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, adhesives, disintegrants, etc. can be used for oral solid preparations such as powders, capsules and tablets. Considering the ease of administration, tablets and capsules are preferred for oral preparations, and solid pharmaceutical carriers are used here. Optionally, tablet coating can use standard aqueous preparation or non-aqueous preparation technology.

[0092] Tablets containing the compounds or pharmaceutical compositions of the present invention can be formed by compression or molding, and optionally, can be made into tablets together with one or more auxiliary ingredients or adjuvants. The active ingredient is mixed in a free-flowing form such as powder or granules with a binder, lubricant, inert diluent, surfactant or dispersant, and compressed in a suitable machine to obtain compressed tablets. The powdered compound or pharmaceutical composition is wetted with an inert liquid diluent and then molded in a suitable machine to obtain molded tablets. Tablets can be film-coated or enteric-coated according to methods known in the art. Preferably, each tablet contains about 0.05 mg to 5 g of active ingredient, and each cachet or capsule contains about 0.05 mg to 5 g of active ingredient. For example, a formulation intended for oral administration to humans contains about 0.5 mg to about 5 g of active ingredient, compounded with suitable and conveniently metered auxiliary materials, which account for about 5% to 95% of the total amount of the pharmaceutical composition. Dosage unit forms generally contain from about 1 mg to about 2 g of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

[0093] The pharmaceutical composition of the present invention can be an aqueous isotonic solution or suspension for some injectable compositions, and suppositories are advantageously prepared from fat emulsions or suspensions. The compositions can be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts for regulating osmotic pressure and / or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulation or coating methods, respectively, and contain about 0.1-75% or about 1-50% of active ingredients.

[0094] The pharmaceutical composition of the present invention can be a suitable composition for transdermal administration comprising an effective amount of the compound of the present invention and a suitable carrier. Suitable carriers for transdermal delivery include absorbable pharmacologically acceptable solvents to help pass through the host skin. For example, the transdermal device is in the form of a bandage, which comprises a backing member, a reservoir containing the compound and optionally a carrier, optionally a rate-controlling barrier to deliver the compound to the host skin at a controlled and predetermined rate over a long period of time, and a means of fixing the device to the skin.

[0095] The pharmaceutical composition of the present invention can be suitable compositions for topical application (e.g., skin and eyes) including aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, for example, for delivery by aerosol, etc. These local delivery systems can relate to, for example, inhalation or intranasal applications applicable to the treatment of influenza and can contain solubilizers, stabilizers, tension enhancers, buffers and preservatives. With or without a suitable propellant, they can be conveniently delivered in the form of dry powder (separately, as a mixture, for example, a dry blend with lactose, or mixed component particles, for example, with phospholipids) from a dry powder inhaler or delivered in the form of an aerosol spray from a pressurized container, pump, sprayer, atomizer or atomizer.

[0096] For a human subject of about 50-70 kg, the unit dose of the pharmaceutical composition of the present invention or combination may contain about 1-1000 mg active ingredient (one or more), or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg active ingredient. The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof depends on the type, body weight, age, and individual condition of the subject, the disorder or disease treated, or its severity. A physician, clinician, or veterinarian of ordinary skill can easily determine the effective amount of each active ingredient necessary for preventing, treating, or inhibiting the progression of a condition or disease.

[0097] Generally, the dosage level of the drug for treating the conditions or discomforts shown above is about 0.01 mg / kg body weight to 150 mg / kg body weight per day, or 0.5 mg to 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergies / asthma, diseases and disorders of the immune system, and diseases and disorders of the central nervous system (CNS) are effectively treated at a dosage level of 0.01 mg / kg body weight to 50 mg / kg body weight per day, or 0.5 mg to 3.5 g per patient per day. However, it is understood that lower or higher doses than those described above may be required. The specific dosage level and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health status, sex, diet, administration time, administration route, excretion rate, drug combination, and the severity of the specific disease being treated.

[0098] The following examples are intended to illustrate the present invention and should not be construed as limiting it. Temperatures are given in degrees Celsius. If not otherwise mentioned, all evaporations are carried out under reduced pressure, typically between about 15 mmHg and 100 mmHg (about 20-133 mbar). The structures of final products, intermediates and raw materials are confirmed by standard analytical methods such as microanalysis and spectroscopic features such as MS, IR, NMR. All parts and percentages of the present invention are calculated by weight, and all temperatures are degrees Celsius. The compounds of the present invention can be obtained from commercial sources or can be synthesized by the following conventional methods using commercially available raw materials and reagents. The abbreviations used in the present invention are conventional abbreviations in the art. Some abbreviations in the present invention are listed as follows:

[0099] abbreviation

[0100] MS mass spectrometry

[0101] IR Infrared absorption spectroscopy

[0102] NMR Nuclear Magnetic Resonance Spectroscopy

[0103] HRMS High Resolution Mass Spectrometry

[0104] ESI Electrospray Ion Source

[0105] Tolvaptan

[0106] EA Ethyl acetate

[0107] PE Petroleum Ether

[0108] DCM Methyl Chloroform

[0109] MeOH Methanol

[0110] LiAIH4 Lithium Aluminum Tetrahydride

[0111] DMF N,N-Dimethylformamide

[0112] K2CO3 Potassium carbonate

[0113] TEA Triethylamine

[0114] THF Tetrahydrofuran

[0115] Pd / C Palladium / Carbon

[0116] CDCl3 deuterated chloroform

[0117] DMSO Methyl sulfoxide

[0118] g

[0119] kg kilogram

[0120] mL milliliters

[0121] mmol millimole

[0122] nm nanometer

[0123] μm micrometer

[0124] μM nanomoles per liter (micromoles per liter)

[0125] nM Molarity (nanomoles per liter)

[0126] M Molar concentration (mole per liter)

[0127] ℃ Celsius

[0128] h hour

[0129] min

[0130] V2R vasopressin-2 receptor

[0131] AC eukaryotic adenylate cyclase

[0132] Forskolin Adenylate Cyclase Activator

[0133] ADPKD Autosomal dominant polycystic kidney disease

[0134] Compound 1-42 in the specific embodiment of the present invention is a novel benzamide compound. In view of the large number of compound types protected by the present invention, the applicant only lists some of the compounds, and the other compounds can achieve the following technical effects (compounds 1-42).

[0135] The structural formula and detailed preparation method of compound 3 are as follows.

[0136]

[0137] Example 1

[0138] Preparation of N-(4-((2-phenoxyethyl)(pyridin-4-yl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide (Compound 3)

[0139] Step 1: Preparation of 2-phenoxy-N-(pyridin-4-yl)acetamide (Intermediate I):

[0140]

[0141] 4-Aminopyridine (0.10 g, 1.06 mmol) was dissolved in DCM, TEA (0.19 mL, 1.38 mmol) was added dropwise at 0°C, and 2-phenoxyacetyl chloride (0.16 mL, 1.17 mmol) was added dropwise after stirring for 30 minutes. The mixture was stirred at room temperature for 45 minutes. The reaction of the raw material was completed after TLC monitoring. The mixture was extracted with DCM (50 mL×3). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The solid residue was purified by silica gel column chromatography (PE: EA=1:2) to obtain white foamy intermediate I (0.2357 g, yield: 97.4%).

[0142] 1 H NMR (400MHz, CDCl3) δ8.55 (d, J=6.4Hz, 2H), 8.41 (s, 1H), 7.56 (d, J=6.4Hz, 2H) , 7.39-7.33 (m, 2H), 7.09 (t, J=7.4Hz, 1H), 7.00 (d, J=8.8Hz, 2H), 4.63 (s, 2H).

[0143] Step 2: Preparation of N-(2-phenoxyethyl)pyridin-4-amine (Intermediate II):

[0144]

[0145] Intermediate I (0.05 g, 0.22 mmol) was dissolved in anhydrous THF (40 mL), and a THF solution of LiAlH4 (0.025 g, 0.66 mmol) was added dropwise under nitrogen protection. After the addition was completed, the mixture was refluxed for 2 hours. Ice water was added to the reaction solution, and then filtered with suction. The filtrate was extracted with DCM, the organic phases were combined, washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The solid residue was purified by silica gel column chromatography (EA: PE = 2: 1, DCM: PE: MeOH = 5: 2: 1) to obtain a white foamy intermediate II (0.30 g, yield: 63.6%).

[0146] 1 H NMR (400MHz, CDCl3) δ8.21 (d, J=5.6Hz, 2H), 7.33-7.28 (m, 2H), 6.99 (tt, J=7.4, 1.1Hz, 1H ), 6.94-6.89 (m, 2H), 6.52 (d, J=5.6Hz, 2H), 4.17 (t, J=5.2Hz, 2H), 3.59 (q, J=5.2Hz, 2H).

[0147] Step 3: Preparation of 4-nitro-N-(2-phenoxyethyl)-N-(pyridin-4-yl)benzamide (Intermediate III):

[0148]

[0149] N-(2-phenoxyethyl)pyridin-4-amine (0.075 g, 0.35 mmol) was dissolved in DCM, TEA (0.097 mL, 0.70 mmol) was added dropwise at 0°C, and a DCM solution of 4-nitrobenzoyl chloride (0.16 g, 1.17 mmol) was added dropwise after stirring for 30 minutes. The mixture was stirred at room temperature for 6 hours. The reaction of the raw material was completed by TLC monitoring. The mixture was extracted with DCM (50 mL×3). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The solid residue was purified by silica gel column chromatography (PE: EA=1:3) to obtain yellow foamy intermediate III (0.066 g, yield: 51.9%).

[0150] 1 H NMR (400MHz, CDCl3) δ8.51-8.46(m, 2H), 8.11-8.04(m, 2H), 7.51-7.44(m, 2H), 7.33-7.26(m, 2H) , 7.09-7.05 (m, 2H), 6.97 (tt, J=7.4, 1.0Hz, 1H), 6.83 (dq, J=7.8, 1.0Hz, 2H), 4.42-4.27 (m, 4H).

[0151] Step 4: Preparation of 4-amino-N-(2-phenoxyethyl)-N-(pyridin-4-yl)benzamide (Intermediate IV):

[0152]

[0153] 4-Nitro-N-(2-phenoxyethyl)-N-(pyridin-4-yl)benzamide (0.03 g, 0.083 mmol) and 10% Pd / C (0.012 g) were put into a reaction bottle, MeOH was added under N2 protection, and the reaction was carried out under hydrogen for 7 hours. The reaction of the raw materials was completed after TLC monitoring. Pd / C was removed by filtration, and the solvent was evaporated under reduced pressure to obtain yellow foamy intermediate IV (0.021 g, yield: 76.3%).

[0154] 1 H NMR (400MHz, CDCl3) δ8.42(m,2H), 7.28-7.26(m, 1H), 7.26-7.23(m, 2H), 7.19-7.13(m, 2H), 7.07(m , 2H), 6.94 (t, J=7.8Hz, 1H), 6.87-6.80 (m, 2H), 6.46-6.41 (m, 2H), 4.40-4.25 (m, 4H), 3.89 (s, 2H).

[0155] Step 5: Preparation of N-(4-((2-phenoxyethyl)(pyridin-4-yl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide (Compound 3):

[0156]

[0157] 4-Amino-N-(2-phenoxyethyl)-N-(pyridin-4-yl)benzamide (0.027 g, 0.08 mmol) was dissolved in DCM, TEA (0.022 mL, 0.16 mmol) was added dropwise at 0°C, and a DCM solution of 2-phenylbenzoyl chloride (0.026 g, 0.12 mmol) was added dropwise after stirring for 30 minutes. The mixture was stirred at room temperature for 6 hours, extracted with DCM (50 mL×3), the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The solid residue was purified by silica gel column chromatography (PE: EA = 1: 5) to obtain white foamy compound 3 (0.01 g, yield: 24.3%).

[0158] 1 H NMR (400MHz, CDCl3) δ 8.46-8.39 (m, 2H), 7.87 (d, J=7.6Hz, 1H), 7.55 (td, J=7.6, 1.4Hz, 1H), 7.48 (td, J=7.6, 1.4Hz, 1H), 7.45-7.32 (m, 6H), 7.31-7. 27 (m, 1H), 7.25 (d, J = 1.8Hz, 1H), 7.19 (d, J = 8.4Hz, 2H), 7.06-7.00 (m, 2H) , 6.99-6.91 (m, 3H), 6.88 (s, 1H), 6.86-6.80 (m, 2H), 4.31 (m, J=4.0Hz, 4H).

[0159] Basically according to the method described in Example 1, compounds 1-5, 7, 8, 10, 40, and 41 as shown in Table 1 were prepared using the corresponding intermediates.

[0160] Example 2

[0161] Preparation of N-benzyl-N-(4-fluorophenyl)-3-hydroxy-4-(2-(pyridin-2-yl)benzamido)benzamide (Compound 39):

[0162]

[0163] Step 1: Preparation of N-benzyl-4-fluoroaniline (Intermediate V):

[0164]

[0165] 4-Fluoroaniline (0.50 g, 4.50 mmol) was dissolved in DMF, K2CO3 and KI were added, benzyl bromide was added during stirring, the temperature was raised to 80°C and stirred overnight, extracted with EA, the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the solid residue was purified by silica gel column chromatography (PE / EA=10:1) to separate the light yellow transparent liquid intermediate V (0.38 g, yield: 42.0%).

[0166] 1 H NMR (400MHz, CDCl3) δ7.41-7.31(m, 4H), 7.31-7.26(m, 1H), 6.92-6.82(m, 2H), 4.29(s, 2H), 3.93(s, 1H).

[0167] Step 2: Preparation of N-benzyl-N-(4-fluorophenyl)-3-methoxy-4-nitrobenzamide (Intermediate VI):

[0168]

[0169] N-Benzyl-4-fluoroaniline (0.38 g, 1.89 mmol) was dissolved in DCM, and TEA (1.31 mL, 9.45 mmol) was added dropwise at 0°C. After stirring for 30 minutes, a DCM solution of 3-methoxy-4-nitrobenzoyl chloride (0.45 g, 2.08 mmol) was added dropwise. The mixture was stirred at room temperature for 6 hours. The reaction of the raw material was completed as monitored by TLC. The mixture was extracted with DCM (50 mL×3). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The solid residue was purified by silica gel column chromatography (PE: EA = 10: 1, 5: 1) to give white foamy intermediate VI (0.30 g, yield: 41.5%).

[0170] 1 H NMR (400MHz, CDCl3) δ7.61 (d, J=8.4Hz, 1H), 7.35-7.26 (m, 5H), 7.10 (d, J=1.6Hz, 1H), 6.89 (d, J=8.2Hz, 5H), 5.08 (s, 2H), 3.82 (s, 3H).

[0171] Step 3: Preparation of 4-amino-N-benzyl-N-(4-fluorophenyl)-3-methoxybenzamide (Intermediate VII):

[0172]

[0173] N-Benzyl-N-(4-fluorophenyl)-3-methoxy-4-nitrobenzamide (0.30 g, 0.79 mmol) and 10% Pd / C (0.060 g) were put into a reaction bottle, MeOH was added under Ar protection, and the reaction was carried out under hydrogen for 12 hours. The reaction of the raw materials was completed after TLC monitoring. Pd / C was removed by filtration, and the solvent was evaporated under reduced pressure to obtain white foamy intermediate VII (0.23 g, yield: 83.1%).

[0174] 1 H NMR (400MHz, CDCl3) δ7.32-7.26(m, 4H), 7.25-7.22(m, 1H), 6.96-6.83(m, 5H) , 6.75 (m, 1H), 6.4l (dd, J=8.2, 0.8Hz, 1H), 5.08 (s, 2H), 3.67 (d, J=0.8Hz, 3H).

[0175] Step 4: Preparation of N-benzyl-N-(4-fluorophenyl)-3-methoxy-4-(2-(pyridin-2-yl)benzamido)benzamide (Intermediate VIII):

[0176]

[0177] 4-Amino-N-benzyl-N-(4-fluorophenyl)-3-methoxybenzamide (0.10 g, 0.29 mmol) was dissolved in DCM, TEA (0.20 mL, 1.43 mmol) was added dropwise at 0°C, and a DCM solution of 2-(pyridin-2-yl)benzoyl chloride (0.07 g, 0.31 mmol) was added dropwise after stirring for 30 minutes. The mixture was stirred at room temperature for 6 hours, extracted with DCM (50 mL×3), the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The solid residue was purified by silica gel column chromatography (PE: EA=2:1) ​​to obtain white foamy compound 3 (0.09 g, yield: 57.7%).

[0178] 1 H NMR (400MHz, CDCl3) δ8.58 (d, J=5.2Hz, 1H), 8.20 (d, J=8.4Hz, 1H), 8.07 (s, 1H), 7.73 (d, J=7.4Hz, 1H), 7.64 (dd, J=8.6, 6.4Hz, 2H), 7.56 (td, J=7.6, 1.4Hz, 1H), 7.54-7.44 (m, 2H), 7.34-7.27 (m, 4H), 7.19 (dd, J=7.4, 4.9Hz, 1H), 6.90-6.79 (m, 6H), 5.08 (s, 2H), 3.56 (s, 3H).

[0179] Step 5: Preparation of N-benzyl-N-(4-fluorophenyl)-3-hydroxy-4-(2-(pyridin-2-yl)benzamido)benzamide (Compound 39)

[0180]

[0181] N-Benzyl-N-(4-fluorophenyl)-3-methoxy-4-(2-(pyridin-2-yl)benzamido)benzamide (0.04 g, 0.08 mmol) was placed in a reaction bottle, DCM was added under Ar environment, BBr3 was added under ice bath, stirred at room temperature for 16 hours, extracted with DCM (50 mL×3), the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the solid residue was purified by silica gel column chromatography (PE: EA=1:2) to obtain white foamy compound 3 (0.023 g, yield: 58.5%)

[0182] 1 H NMR (400MHz, CDCl3) δ9.07 (s, 1H), 8.51 (d, J = 4.7Hz, 1H), 7.84 (td, J = 7.6, 1.8Hz, 1H), 7.72 (d, J = 7.4Hz, 1H), 7.58 (d, J = 7.8Hz, 1H), 7.5 5-7.44 (m, 3H), 7.37-7.27 (m, 4H), 7.24 (d, J=8.0Hz, 2H), 7.19 (d, J=8.2Hz, 1H), 6.78 (d, J=6.6Hz, 4H), 6.73-6.64 (m, 2H), 5.03 (s, 2H).

[0183] Basically according to the method described in Example 2, compounds 6, 9, 11-39, 42 as shown in Table 1 were prepared using the corresponding intermediates.

[0184] Table 1

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197] Example 3 V2 receptor affinity experiment

[0198] This experiment uses fluorescence based methods. In this experiment, the Ki of the test compound is obtained by detecting the SB fluorescence intensity after the V2R fluorescent ligand with a final concentration of 6.3nM binds to the V2R expressed by the cell at different concentrations of the test compound (Table 2). Under the conditions of this experiment, the specific binding of the V2R fluorescent ligand to V2R in the system cannot be directly measured, and it is indirectly obtained from the total binding and nonspecific binding: SB = TB-NSB.

[0199] The specific method is as follows: the TB signal at each concentration of V2R fluorescent ligand is obtained by detecting at 620nm and 665nm by a multifunctional microplate reader after the binding and dissociation of the V2R fluorescent ligand with the V2R expressed by the SNAP-tagged HEK293-hV2R cell reaches a state of equilibrium; the NSB signal at each concentration of V2R fluorescent ligand is obtained by detecting at 620nm and 665nm by a multifunctional microplate reader after the binding and dissociation of the test compound with a final concentration of 100μM with the V2R expressed by the cells reaches a state of equilibrium, that is, after the compound fully antagonizes the V2R in the system, and the nonspecific binding of the V2R fluorescent ligand in the system with the system other than V2R is detected by a multifunctional microplate reader.

[0200] The specific operation steps are as follows: dilute the test compound to a final concentration of 1×10 -6 -1×10 -12The prepared compounds, the test compound solution with a final concentration of 100 μM, the Tag-lite assay buffer (1×) with 1% DMSO content, and the V2R fluorescent ligand with a final concentration of 6.3 nM were transferred to a 384-well plate in sequence, mixed with the labeled SNAP-tagged HEK293-hV2R cell, and incubated at 37°C for 2 hours. After the incubation time, the experimental results were detected at 620 nm and 665 nm in a multifunctional microplate reader. After the detection, the SB fluorescence ratio was calculated using the formula "fluorescence intensity at 665 nm / fluorescence intensity at 620 nm 10000". When the concentration of the test compound in the system is the lowest, the V2R fluorescent ligand with a final concentration of 6.3 nM reaches a binding and dissociation equilibrium with the cell-expressed V2R, and the ratio of SB fluorescence intensity measured at 620 nm and 665 nm is taken as 100%. The SB fluorescence ratios of the V2R fluorescent ligand with a final concentration of 6.3 nM and V2R that reach a binding and dissociation equilibrium at different concentrations of each test compound are normalized.

[0201] Using One Site-Fit K in Graphpad Prism 7.0 i Model analysis of the K of the test compound i value.

[0202] Table 2 V2 receptor affinity experiment

[0203]

[0204] Note: The cell line used in this experiment is the human embryonic kidney 293 cell line that highly expresses the human V2R protein carrying a fluorescent group (SNAP-tagged HEK293 V2R high expression cell, SNAP-tagged HEK293-hV2R cell).

[0205] Example 4 Equilibrium Solubility Measurement

[0206] In this experiment, the concentration of the compound was determined by ultraviolet spectroscopy. Excessive compounds were added to 400 μL of water, incubated at 37°C for 24 hours to reach equilibrium, filtered with a 0.22 μm PVDF membrane (Merck Chemical, Shanghai), and then the concentration of the compound was determined by ultraviolet spectroscopy. The results in Table 3 show that the water solubility of compound 41 is much higher than that of tolvaptan, reaching 14 times.

[0207] Table 3 Equilibrium solubility measurements

[0208]

[0209] Example 5 V1a Receptor affinity assay

[0210] This experiment uses the radioligand substitution assay to detect the V at a final concentration of 2.6 nM at different concentrations of the test compound. 1a R radioligand and cell-expressed V 1a The radioactivity intensity after R binding is obtained to obtain the K i .

[0211] CHOhV containing 5 μg protein 1a Aliquots of R cell membranes were placed in a total volume of 250 uL of buffer (50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 10 mM MgCl2, 0.1 mg / mL bacitracin, and 1 mg / mL BSA) and incubated at 37°C for 1 h. 3 The substitution experiment of compound 41 was carried out in the presence of [H]-vasopressin. Nonspecific binding was determined in the presence of 10 μM conivaptan. The cell solution was added to a 96-well filter plate, and the incubation was terminated by rapid vacuum filtration using a cell harvester to separate bound and free radioligands. The filter was then washed 3 times with ice Tris-HCl buffer (50 mM, pH 7.4). The radioactivity bound by the filter was determined by a MicroBeta-2450 scintillation counter using a 96-well filter plate. The K of the test compound was analyzed using Graphpad Prism7.0 i The results in Table 4 show that the affinity of compound 41 for V2R is much higher than that for V 1a R, whose selectivity for V2R is about V 1a R is 194 times higher than Tolvaptan; 1a R has a selectivity of 123 times for V2R, which is much lower than that of compound 41.

[0212] Table 4 Effect of Compound 41 on V2R and V 1a Selective detection of R

[0213]

[0214] Example 6 Vesicle Experiment

[0215] MDCK cells were used to form vesicles similar to those in polycystic kidney disease under the action of the AC enzyme agonist forskolin, the occurrence and development of the disease were simulated, and the test compounds were administered to observe the effects of the test compounds on the vesicles.

[0216] Specific operations:

[0217] 1. Cell culture

[0218] MDCK cells were cultured at 37°C and 5% CO2 in DMEM F12 medium (available from Kangmei Co., Ltd.), with 10% fetal bovine serum and 1% double antibody added. After three days of cell culture, when the growth area was about 80-90%, the next step of the experiment was started.

[0219] 2. Prepare the matrix gel (single well) according to the following formula:

[0220]

[0221] 3. Digested cells were added to 24-well plates

[0222] While the Matrigel was recooling, the MDCK cells were digested and counted.

[0223] After the matrix gel was prepared, the well plate was placed in the incubator to stabilize for 90 minutes, and then 1.5 ml of cell culture medium containing 10 μM Forsklin and corresponding concentrations of drugs was added to each well, and the cells were divided into control group, AMPK agonist (1 μM) group, AMPK agonist (3 μM) group, and AMPK agonist (10 μM) group. The cells were cultured for 12 days, the medium was changed every 12 hours, and photos were taken on the 4th, 6th, 8th, 10th, and 12th days. The photo area was selected and specific vesicles were tracked.

[0224] On the 12th day, the vesicle diameters were compared to evaluate the effects of the test compounds. The experimental results are shown in Table 5.

[0225] Table 5 MDCK vesicle experiment

[0226]

[0227] The results of the vesicle experiment showed that compared with the control group, this type of compound can significantly inhibit the development of vesicles in polycystic kidney disease.

[0228] Example 7 Tissue Embryonic Kidney Experiment

[0229] The kidneys of 13.5-day embryonic rats were placed in transwells, and vesicles similar to those in polycystic kidney disease were formed under the stimulation of 80-Br-cAMP. The occurrence and development of the disease were simulated, and the test compounds were administered to observe the effects of the test compounds on the kidneys.

[0230] Embryonic kidney culture: Embryonic kidneys were cultured at 37°C and 5% CO2. The culture medium was DMEM F12 (available from Kangmei.com), with 80-Br-cAMP, insulin, transferrin, sodium selenite and double antibody added, and drugs of corresponding concentrations added, divided into control groups. The culture was continued for 6 days, with the medium changed every 12 hours, and photographed on days 2, 4, and 6.

[0231] On the 6th day, the vesicle areas were compared to evaluate the effects of the test compounds. The experimental results are shown in Table 6.

[0232] Table 6 Tissue embryo kidney experiment

[0233]

[0234] Example 8 Polycystic Kidney Mouse Experiment

[0235] This type of compound has an antagonistic effect on arginine vasopressin receptors, which can inhibit the action of cAMP in the body, thereby inhibiting the occurrence and development of polycystic kidney disease. In this experiment, Pkd1 gene knockout mice were used to evaluate the efficacy of this type of compound.

[0236] Specific operations:

[0237] 1. Mouse number and gene identification: 3 days after birth, the mice were marked by clipping their toes and placed in pre-labeled EP tubes. After the toes were cut and boiled, PCR was performed and then agarose electrophoresis was used for gene identification.

[0238] 2. Prepare the corresponding drug: Use an electronic balance to accurately weigh the corresponding weight of the drug and place it in a new EP tube. Then use a pipette to add the corresponding amount of HPMC to prepare the drug of the required concentration. (Take 5mg / kg compound 41 as an example, weigh 2.5mg compound 41, add 500ul HPMC, vortex for 30s (to suspend most of the drug), then ultrasonicate for 15-20 minutes to crush the large pieces of drug, and vortex for 30s again.

[0239] 3. Dosing for mice: Dosing begins on the 6th or 5th day after birth (if the mouse is underweight, dosing begins on the 6th day, otherwise dosing begins on the 5th day), and the dosing time is fixed (e.g. 9 a.m.). Pinch the target mouse (back) with the index finger and thumb, weigh it, and use a microinjector to draw the corresponding amount of medicine, insert the injector from the middle of the bulge on the mouse's back (between the thumb and index finger), and perform subcutaneous injection.

[0240] 4. Mouse tissue extraction: Seven days after administration, the mice were killed and weighed accurately. The laparotomy was performed, and the left kidney was removed and weighed accurately. The kidney was placed in the horizontal line and photographed. After completion, it was placed in a numbered ep tube and temporarily stored on ice. The right kidney was then removed, weighed and photographed under the same conditions, and stored in a numbered ep tube in paraformaldehyde. The liver was removed and temporarily stored in an ep tube on ice. After the operation was completed, the liver and left kidney were stored in a -80 degree refrigerator.

[0241] 5. Data processing: Calculate the total weight of the left and right kidneys, kidney specific gravity, etc. The experimental results are shown in Table 7.

[0242] Table 7 Polycystic kidney mouse experiment

[0243]

[0244] The results of animal experiments showed that compared with the control group, this type of compound significantly delayed the occurrence and development of polycystic kidney disease, that is, this type of compound has a therapeutic effect on polycystic kidney disease.

[0245] The above experiments show that this type of compound can effectively inhibit the occurrence and development of vesicles and slow down the progression of polycystic kidney disease by antagonizing arginine vasopressin receptors. Therefore, this type of compound has potential use in treating polycystic kidney disease.

[0246] In addition, the inventors of this case also referred to the aforementioned embodiments and conducted experiments with other raw materials, process operations, and process conditions described in this specification, and obtained relatively ideal results.

[0247] It should be understood that the technical solution of the present invention is not limited to the above-mentioned specific implementation cases. Any technical deformation made according to the technical solution of the present invention without departing from the scope of protection of the purpose of the present invention and the claims shall fall within the protection scope of the present invention.

Claims

1. A benzamide compound, characterized in that: The benzamide compound has a structure as shown in formula (I): wherein R1 and R2 are each independently selected from aryl, heteroaryl or heterocyclic, wherein aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one selected from halogen, trifluoromethyl, cyano, nitro, hydroxyl, amino, carboxyl, carboxymethyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The substituent of the cycloalkyl group is substituted; R3 and R4 are each independently selected from any one of hydrogen, halogen, trifluoromethyl, cyano, nitro, hydroxyl, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy substituted with a heterocyclic group, C3-C8 cycloalkyl, aryl, heteroaryl, and heterocyclic group; X is selected from CH2, NH, O, CO or S; n is selected from 0, 1, 2, 3 or 4.

2. The benzamide compound according to claim 1, characterized in that: In formula (I), R1 is selected from phenyl or pyridine, wherein the phenyl group is unsubstituted or substituted at the 3-position or 4-position by any one of fluoro, chloro, methyl, trifluoromethyl, methoxy, hydroxy, carboxyl, and carboxymethyl; and / or, in formula (I), R2 is selected from phenyl, 3-chlorophenyl, pyridyl, morpholinyl or pyranyl; and / or, in formula (I), R3 is selected from 3-hydroxy, 3-methoxy or 3-(4-(4-methylpiperazin-1-yl)butoxy); And / or, in formula (I), R4 is selected from 2-substituted methyl, ethyl, isopropyl, phenyl, morpholinyl, pyrrolyl or piperidinyl.

3. The benzamide compound according to claim 1, characterized in that: In formula (I), X is selected from CH2, CO or O, and n is selected from 0, 1 or 2.

4. The benzamide compound according to claim 1, characterized in that: The benzamide compounds include any one or more combinations of the following compounds: 1) N-(4-((2-phenoxyethyl)(phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 2) N-(4-((2-(3-chlorophenoxy)ethyl)(phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 3) N-(4-((2-phenoxyethyl)(pyridin-4-yl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 4) N-(4-((3-morpholinyl-3-oxopropyl)(phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 5) N-(4-((3-morpholinopropyl)(phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 6) N-(4-(phenethyl(phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 7) N-(4-((2-morpholinyl-2-oxoethyl)(phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 8) N-(4-((2-morpholinylethyl)(phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 9) N-(4-(Benzyl(phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 10) N-(4-(phenyl((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 11) N-(4-(diphenylcarbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 12) N-(4-(Benzyl(pyridin-2-yl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 13) N-(4-(Benzyl(pyridin-3-yl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 14) N-(4-(Benzyl(pyridin-4-yl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 15) N-(4-(Benzyl(2-hydroxyphenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 16) N-(4-(Benzyl(3-hydroxyphenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 17) N-(4-(Benzyl(4-hydroxyphenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 18) 4-(4-([1,1′-biphenyl]-2-carboxamido)-N-benzylbenzamido)benzoic acid; 19) methyl 4-(4-([1,1′-biphenyl]-2-carboxamido)-N-benzylbenzamido)benzoate; 20) N-(4-(Benzyl(4-fluorophenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 21) N-(4-(Benzyl(4-chlorophenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 22) N-(4-(Benzyl(p-tolyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 23) N-(4-(Benzyl(4-(trifluoromethyl)phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 24) N-(4-(Benzyl(4-methoxyphenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 25) N-(4-(Benzyl(3-fluorophenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 26) N-(4-(Benzyl(3-chlorophenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 27) N-(4-(Benzyl(m-tolyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 28) N-(4-(Benzyl(3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 29) N-(4-(Benzyl(3-methoxyphenyl)carbamoyl)phenyl)-[1,1′-biphenyl]-2-carboxamide; 30) N-(4-(Benzyl(phenyl)carbamoyl)-2-(4-(4-methylpiperazin-1-yl)butoxy)phenyl)-[1,1′-biphenyl]-2-carboxamide; 31) N-(4-(Benzyl(phenyl)carbamoyl)-2-methoxyphenyl)-[1,1′-biphenyl]-2-carboxamide; 32) N-(4-(Benzyl(phenyl)carbamoyl)-2-hydroxyphenyl)-[1,1′-biphenyl]-2-carboxamide; 33) N-Benzyl-N-(4-fluorophenyl)-4-(2-methylbenzamido)benzamide; 34) N-Benzyl-4-(2-ethylbenzamido)-N-(4-fluorophenyl)benzamide; 35) N-Benzyl-N-(4-fluorophenyl)-4-(2-isopropylbenzamido)benzamide; 36) N-(4-(Benzyl(4-fluorophenyl)carbamoyl)-2-hydroxyphenyl)-[1,1′-biphenyl]-2-carboxamide; 37) N-Benzyl-N-(4-fluorophenyl)-3-hydroxy-4-(2-morpholinylbenzamido)benzamide; 38) N-Benzyl-N-(4-fluorophenyl)-3-hydroxy-4-(2-(pyrrolidin-1-yl)benzamido)benzamide; 39) N-Benzyl-N-(4-fluorophenyl)-3-hydroxy-4-(2-(pyridin-2-yl)benzamido)benzamide; 40) N-(4-((4-fluorophenyl)((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-2-hydroxyphenyl)-[1,1′-biphenyl]-2-carboxamide; 41) N-(4-((4-fluorophenyl)(2-morpholinoethyl)carbamoyl)-2-hydroxyphenyl)-[1,1′-biphenyl]-2-carboxamide; 42) N-(4-((4-Fluorophenyl)(pyridin-3-ylmethyl)carbamoyl)-2-hydroxyphenyl)-[1,1′-biphenyl]-2-carboxamide.

5. A pharmaceutical composition, characterized in that It comprises the benzamide compound described in any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. The benzamide compound according to any one of claims 1 to 4, its stereoisomer or its pharmaceutically acceptable salt or the pharmaceutical composition according to claim 5 for the preparation of a drug for preventing and / or treating arginine vasopressin V 1a Receptor, arginine vasopressin V 1b The invention relates to a drug for treating diseases related to the arginine vasopressin V2 receptor, the sympathetic nervous system or the renin-angiotensin-aldosterone system.

7. The use according to claim 6, characterized in that: Arginine vasopressin V 1a Receptor, arginine vasopressin V 1b Diseases associated with the vasopressin receptor, arginine vasopressin V2 receptor, sympathetic nervous system, or renin-angiotensin-aldosterone system include hypertension, Reye's syndrome, dysmenorrhea, premature labor, impaired corticotropin-releasing hormone secretion, adrenal hyperplasia, depression, chronic congestive heart failure, cirrhosis, syndrome of impaired antidiuretic hormone secretion, hyponatremia caused by chronic heart failure / cirrhosis / impaired antidiuretic hormone secretion, or polycystic kidney disease.

8. The use according to claim 6, characterized in that: The pharmaceutically acceptable salt is a salt formed by the benzamide compound and an inorganic acid and / or an organic acid.

9. The use according to claim 8, characterized in that: The inorganic acid includes any one or more combinations of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.

10. The use according to claim 8, characterized in that: The organic acid includes any one or more combinations of citric acid, lactic acid, malic acid, gluconic acid, tartaric acid, adipic acid, acetic acid, succinic acid, fumaric acid, ascorbic acid, itaconic acid, methanesulfonic acid, and benzenesulfonic acid.

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