CN114195786A - Preparation and application of novel FXR (FXR) small molecule agonist - Google Patents

Preparation and application of novel FXR (FXR) small molecule agonist Download PDF

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CN114195786A
CN114195786A CN202010988285.XA CN202010988285A CN114195786A CN 114195786 A CN114195786 A CN 114195786A CN 202010988285 A CN202010988285 A CN 202010988285A CN 114195786 A CN114195786 A CN 114195786A
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赵一爽
张振伟
吴国辉
汪鹏
杨生生
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Kaisi Kaidi Shanghai Pharmaceutical Technology Co ltd
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Abstract

The invention discloses an FXR (farnesoid X receptor) micromolecule agonist and a preparation method thereof, and the structure of the FXR micromolecule agonist is shown as a formula I. Wherein, the definition of each substituent is described in the specification. The compound has the advantages of high FXR agonistic activity, simple synthesis, easily obtained raw materials and the likeCan be used for treating FXR related diseases.

Description

Preparation and application of novel FXR (FXR) small molecule agonist
Technical Field
The invention belongs to the field of medicines, and relates to preparation and application of non-steroidal compounds serving as FXR agonists. In particular to a preparation method of organic small molecular compounds capable of being used as FXR agonists, enantiomers, diastereomers, tautomers, racemates, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, and application thereof in preparing drugs for treating FXR related diseases.
Background
Farnesoid X receptor (Farnesoid X receptor) is a member of the nuclear receptor superfamily, belongs to ligand-dependent nuclear transcription factors, and is mainly expressed in systems such as liver, intestinal tract, kidney, bile duct and the like; FXR is also called bile acid receptor because it can be activated by endogenous ligand bile acid and participates in important links such as bile acid metabolism and cholesterol metabolism. FXR may be directly involved in regulating the expression of over 300 genes including lipid metabolism, carbohydrate metabolism, inflammation, fibrosis, liver regeneration, cell differentiation and proliferation, etc. In natural environment, the ligand comprises primary bile acid chenodeoxycholic acid, secondary cholic acid lithocholic acid, deoxycholic acid and the like. For example, FXR activated by endogenous ligand bile acid plays an important role in Triglyceride (TG) metabolism, and can regulate and control key enzymes, lipoproteins, and corresponding receptors involved in TG metabolism, thereby achieving steady-state equilibrium of TG content in liver and circulating blood. Therefore, up to now, many FXR synthetic ligand molecules have been applied to metabolic diseases such as liver.
FXR agonist molecules have shown superior clinical efficacy in the treatment of liver diseases such as Primary Biliary Cirrhosis (PBC), Primary Sclerosing Cholangitis (PSC) and nonalcoholic steatohepatitis (NASH). To date, the FXR agonist molecule obeticholic acid (OCA), which will be the first approved molecule to market, has been shown to significantly improve various metabolic symptoms, such as lowering liver fat content, reducing inflammatory response, and inhibiting liver fibrosis. However, OCA is increasingly showing a number of clinical short plates, such as causing itching, decreasing high-density lipoprotein (HDLc), increasing low-density lipoprotein (LDLc), etc. Therefore, in the aspect of clinical requirements, new FXR agonist molecules with good clinical effect and low toxic and side effects are urgently needed to appear.
In addition, research has confirmed that FXR is closely related to the development and development of tumors. FXR plays a role as an oncogene suppressor in a variety of tumors. For example, in hepatocellular carcinoma and rectal cancer, FXR is in a low-expression state, and after FXR is activated, the progress of liver cancer or rectal cancer is remarkably inhibited by inhibiting the activity of beta-catenin. Recent studies have shown that, in bile duct cancer, OCA, which is an agonist of FXR, can significantly inhibit proliferation, migration, clonogenic and the like of intrahepatic bile duct cells.
Furthermore, FXR agonists serve as a new antiviral drug candidate and studies have shown that FXR ligands can serve as a new therapeutic strategy for the inhibition of Hepatitis B Virus (HBV) replication. FXR agonists inhibit HBV surface antigen synthesis, inhibit replication of HBV DNA and RNA, and most importantly, inhibit HBV cccDNA production. In the case of Hepatitis C Virus (HCV), the FXR agonist GW4064 may inhibit HCV entry into hepatic tissue cells in an indirect manner. Therefore, the FXR agonist molecules also have great prospects in development of antiviral drugs.
In conclusion, a novel FXR agonist molecule which is simple in preparation method and good in inhibition effect is not available in the field.
Disclosure of Invention
The invention aims to provide a novel FXR agonist molecule which is simple in preparation method and good in inhibition effect.
In a first aspect of the present invention, there is provided a compound represented by formula I, or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, prodrug thereof, or a pharmaceutically acceptable salt thereof.
Figure BDA0002689977030000021
Wherein,
ar is selected from the group consisting of: substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted 5-9 membered heteroaromatic ring (including monocyclic or fused ring, containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen);
R1selected from: substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted 5-9 membered heterocyclic ring (containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen);
R21、R22、R23each independently selected from the group consisting of: hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C1-C6An alkoxy group;
w is selected from the group consisting of: hydrogen or deuterium;
v is selected from the group consisting of: hydrogen or deuterium;
u is selected from the group consisting of: o or NH;
x is selected from the group consisting of: o, NH, CH2Or CHR2Wherein R is2Selected from the group consisting of: deuterium, substituted or unsubstituted C1-C6Alkyl radical, C3-C6A cycloalkyl group;
y is selected from the group consisting of: o, NH, CH2Or CHR3Wherein R is3Selected from the group consisting of: deuterium, substituted or unsubstituted C1-C6Alkyl radical, C3-C6A cycloalkyl group;
wherein said substitution means that one or more hydrogen atoms on the group are each independently replaced by a substituent selected from the group consisting of: deuterium, halogen, halogeno C1-C6Alkyl, halo C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C3-C6Cycloalkoxy, cyano or nitro.
In another preferred embodiment, Ar is selected from the group consisting of: substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted 5-9 membered heteroaromatic ring wherein the aryl or heteroaryl substituents are selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, or trifluoromethoxy.
In another preferred embodiment, R21、R22、R23Each independently selected from the group consisting of: hydrogen, halogen, halogeno C1-C6Alkyl, halo C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6An alkoxy group.
In another preferred embodiment, R is1Selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl or cyclopentyl.
In another preferred embodiment, R is21、R22、R23Each independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, or trifluoromethoxy.
In another preferred embodiment, Ar is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-7 membered heteroaromatic ring (including monocyclic or fused ring, containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen).
In another preferred embodiment, Ar is selected from the group consisting of substituted or unsubstituted groups selected from: a benzene ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a furan ring, a thiophene ring, a pyrrole ring, a thiazole ring, or an imidazole ring.
In another preferred embodiment, R is1Selected from the group consisting of: substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted cyclopropyl.
In another preferred embodiment, Ar is a substituted or unsubstituted benzene ring.
In another preferred embodiment, Ar is selected from the group consisting of: 2, 5-dichlorophenyl group, 2-methylphenyl group, 2-trifluoromethylphenyl group, 2-trifluoromethoxyphenyl group.
In another preferred embodiment, said X is selected from: o, NH, CH2Or CHR2Wherein R is2Selected from the group consisting of: deuterium, substituted or unsubstituted C1-C6Alkyl radical, C3-C6A cycloalkyl group; the Y is selected from: o, NH, CH2Or CHR2Wherein R is2Selected from the group consisting of: deuterium, substituted or unsubstituted C1-C6Alkyl radical, C3-C6A cycloalkyl group.
In another preferred embodiment, the compound is selected from the group consisting of:
Figure BDA0002689977030000031
in another preferred embodiment, the compound of formula (I) has the structure shown below:
Figure BDA0002689977030000032
in a second aspect of the invention, there is provided a process for the preparation of a compound according to the first aspect of the invention, said process comprising: preparing a compound of formula I by a process selected from the group consisting of those described in scheme one, scheme two or scheme three:
route one:
Figure BDA0002689977030000041
(a') reacting a compound of formula VIII with a compound of formula XI under basic conditions to form a compound of formula XV;
(b') reacting the compound of formula XV with hydroxylamine hydrochloride to produce a compound of formula XVI;
(c') reacting the compound shown in the general formula XVI under the action of phosgene, triphosgene or carbonyl diimidazole to generate the compound shown in the general formula I,
wherein, X is NH,y is O, R1、R21、R22、R23Ar, W, V, U are as defined in the first aspect of the invention;
and a second route:
Figure BDA0002689977030000042
(a') reacting the compound of formula VIII with a compound of formula XIV under basic conditions to form a compound of formula XVII;
(b') reacting the compound of formula XVII with hydrazine hydrate under the action of a base to produce a compound of formula XVIII;
(c') reacting the compound of formula XVIII under the action of phosgene, triphosgene or carbonyldiimidazole to form a compound of formula I;
wherein X is O, Y is NH, R1、R21、R22、R23Ar, W, V, U are as defined in the first aspect of the invention;
and a third route:
Figure BDA0002689977030000051
(a') reacting the compound of formula XVII with thionyl chloride in the presence of a trace amount of N, N-dimethylformamide to form a compound of formula XIX;
(b' ") reacting the compound of formula XIX with glycinamide under the action of a base to form a compound of formula XX;
(c') reacting the compound shown in the general formula XX under the action of phosphorus oxychloride to generate the compound shown in the general formula I,
wherein X is NH and Y is CH2，R1、R21、R22、R23Ar, W, V, U are as defined in the first aspect of the invention.
In another preferred embodiment, the compound of formula VIII is prepared by the following steps:
Figure BDA0002689977030000052
(a) reacting a compound shown as a general formula II of substituted benzaldehyde serving as an initial raw material with hydroxylamine hydrochloride under the action of alkali to obtain an intermediate, and chlorinating the intermediate by using N-chlorosuccinimide (NCS) to obtain a compound shown as a general formula III;
(b) then reacting the compound shown in the general formula III with corresponding 3-oxo-propionic ester to obtain a compound shown in a general formula IV;
(c) reducing ester in the compound shown in the general formula IV into corresponding alcohol under the action of a reducing agent, brominating to generate a compound shown in V,
(d) reacting the compound shown in the general formula V with the compound shown in the formula VI under a basic condition to obtain a compound shown in the general formula VII;
(e) reacting the compound shown in the general formula VII under the action of trifluoroacetic acid to obtain a compound shown in a general formula VIII;
in the formulae, R1、R21、R22、R23Ar, W, V, U are as defined in the first aspect of the invention.
In another preferred embodiment, the compound of formula XI is prepared by the following steps:
Figure BDA0002689977030000061
(f) reacting the compound shown in the general formula IX with sodium thiocyanate under the action of liquid bromine or with tetrabutyl ammonium thiocyanate under the action of benzyl trimethyl ammonium bromide to obtain a compound shown in the general formula X;
(g) and (3) reacting the compound shown in the general formula X with cuprous bromide, cupric bromide, cuprous chloride or cupric chloride under the action of tert-butyl nitrite to obtain the compound shown in the general formula XI.
In the formulae, R21、R22、R23Is as defined in the first aspect of the invention.
The compounds of formula XIV are prepared by the following steps:
Figure BDA0002689977030000062
(h) reacting the compound shown in the general formula XII with sodium thiocyanate under the action of liquid bromine or tetrabutyl ammonium thiocyanate under the action of benzyl trimethyl ammonium bromide to obtain a compound shown in the general formula XIII;
(i) and (3) reacting the compound shown in the general formula XIII with cuprous bromide, cupric bromide, cuprous chloride or cupric chloride under the action of tert-butyl nitrite to obtain the compound shown in the general formula XIV.
In the formulae, R21、R22、R23Is as defined in the first aspect of the invention.
In another preferred embodiment, when the product has optical isomers, the product is prepared by using the raw materials with corresponding optical configurations.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula I as described in the first aspect of the present invention, or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, metabolite, prodrug, pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
In a fourth aspect of the present invention, there is provided a use of a compound represented by general formula I according to the first aspect of the present invention, or an enantiomer, a diastereomer, a tautomer, a racemate, a hydrate, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof, for preparing a pharmaceutical composition for treating a disease or disorder associated with FXR activity or expression.
In another preferred embodiment, said FXR related disease is selected from the group consisting of: bile acid metabolism, carbohydrate metabolism, lipid metabolism, inflammation, and/or diseases associated with liver fibrosis processes.
In another preferred example, the FXR-related disease is nonalcoholic fatty liver disease (NASH), Primary Biliary Cirrhosis (PBC), Primary Sclerosing Cholangitis (PSC), gallstones, nonalcoholic cirrhosis, liver fibrosis, cholestatic liver disease, hyperlipidemia, hypercholesterolemia, or diabetes.
In another preferred embodiment, the pharmaceutical composition is used as an FXR agonist.
In another preferred embodiment, the pharmaceutical composition is used for reducing serum levels of ALP, ALT, AST, TBA.
In another preferred embodiment, the pharmaceutical composition is used for reducing the content of hydroxyproline in liver tissues.
In another preferred embodiment, the pharmaceutical composition is used for down-regulating the expression of alpha-SMA and Col1 alpha 1mRNA in liver tissue.
In another preferred embodiment, the pharmaceutical composition is used for inhibiting the synthesis of HBV surface antigens, inhibiting the replication of HBV DNA and RNA, and inhibiting the production of HBV cccDNA.
In another preferred embodiment, the pharmaceutical composition is used for reducing the collagen content in the liver.
In another preferred embodiment, the pharmaceutical composition is prepared by the following method: the compound of the formula I is mixed with pharmaceutically acceptable auxiliary materials (such as excipient, diluent and the like) to prepare tablets, capsules, granules, syrups and the like for oral administration.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor of the application researches extensively and deeply and develops a class of non-steroidal compounds capable of being used as FXR agonists, and the non-steroidal compounds have the exciting ability on FXR at a molecular level and a cell level, and the research shows that the compounds can reduce the levels of ALP, ALT, AST and TBA in serum, reduce the content of hydroxyproline in liver tissues, regulate the expression of a-SMA and Col1 a 1mRNA in the liver tissues, reduce the content of collagen in the liver, inhibit the synthesis of HBV surface antigen, inhibit the replication of HBV DNA and RNA and inhibit the generation of HBV cccDNA. The compound has the advantages of high FXR agonistic activity, simplicity in synthesis, easiness in obtaining raw materials and the like, and can be used for preparing medicines for treating FXR related diseases. On the basis of this, the present invention has been completed.
Term(s) for
In the present invention, unless otherwise specified, the terms used have the ordinary meanings well known to those skilled in the art.
In the present invention, the halogen is F, Cl, Br or I.
In the present invention, the term "C1-C6" means having 1, 2, 3, 4, 5, or 6 carbon atoms, "C3-C6" means having 3, 4, 5, or 6 carbon atoms, and so on.
In the present invention, the term "alkyl" denotes a saturated linear or branched hydrocarbon moiety, for example the term "C1-C6 alkyl" means a straight or branched chain alkyl group having 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like; ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are preferred.
In the present invention, the term "alkoxy" denotes the group-O- (C1-C6 alkyl). For example, the term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.
In the present invention, the term "cycloalkyl" denotes a saturated cyclic hydrocarbon moiety, for example the term "C3-C6 cycloalkyl" refers to a cyclic alkyl group having 3 to 6 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
In the present invention, the term "cycloalkoxy" denotes cycloalkyl-O-, cycloalkyl being as defined above.
In the present invention, the term "aryl" denotes a hydrocarbyl moiety comprising one or more aromatic rings. Examples of aryl groups include, but are not limited to, phenyl (Ph), naphthyl, pyrenyl, fluorenyl, anthracenyl, and phenanthrenyl.
In the present invention, the term "heteroaryl" denotes a moiety comprising one or more aromatic rings having at least one heteroatom (e.g. N, O or S). Examples of heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolinyl, isoquinolinyl, indolyl and the like.
Unless otherwise specified, alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, and heteroaryl groups described herein are substituted and unsubstituted groups. Possible substituents on alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, and heteroaryl groups include, but are not limited to: hydroxy, amino, nitro, nitrile, halogen, C1-C6Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, C3-C20Cycloalkyl radical, C3-C20Cycloalkenyl radical, C1-C20Heterocycloalkyl radical, C1-C20Heterocycloalkenyl, C1-C6Alkoxy, aryl, heteroaryl, heteroaryloxy, C1-C10Alkylamino radical, C1-C20Dialkylamino, arylamino, diarylamino, C1-C10Alkylsulfamoyl, arylsulfamoyl, C1-C10Alkylimino radical, C1-C10Alkylsulfimidyl, arylsulfimidyl, mercapto, C1-C10Alkylthio radical, C1-C10Alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidino, ureido, cyano, acyl, thioacyl, acyloxy, carboxyl and carboxylate groups. In another aspect, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups can also be fused to each other.
In the invention, the substitution is mono-substitution or multi-substitution, and the multi-substitution is di-substitution, tri-substitution, tetra-substitution or penta-substitution. By disubstituted is meant having two substituents and so on.
The pharmaceutically acceptable salts of the present invention may be salts of anions with positively charged groups on the compounds of formula I. Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methylsulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate or maleate. Similarly, salts may be formed from cations with negatively charged groups on the compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium ions, such as tetramethylammonium.
In another preferred embodiment, "pharmaceutically acceptable salt" refers to a salt of a compound of formula I with an acid selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid and the like; or a sodium, potassium, calcium, aluminum or ammonium salt of a compound of formula I with an inorganic base; or methylamine salt, ethylamine salt or ethanolamine salt formed by the compound in the general formula I and organic base.
In another preferred embodiment, in the compound, Ar and R1、R21、R22、R23Any of, W, V, X, Y, and Z are each independently the corresponding group in the specific compound described in the examples.
The compounds of the present invention have asymmetric centers, chiral axes and chiral planes, and can exist in the form of racemates, R-isomers or S-isomers. The person skilled in the art is able to obtain the R-isomer and/or the S-isomer by resolution of the racemate by means of customary technical measures.
Preparation method
The preparation method of the compound shown in the general formula I comprises the following synthetic route:
route one:
Figure BDA0002689977030000091
the preparation method comprises the following steps:
(a) reacting a compound shown as a general formula II of aryl formaldehyde with hydroxylamine hydrochloride under the action of alkali to obtain an intermediate, and chlorinating the intermediate by using N-chlorosuccinimide (NCS) to obtain a compound shown as a general formula III;
(b) then reacting the compound shown in the general formula III with corresponding 3-oxo-propionic ester under the action of alkali to obtain a compound shown in a general formula IV;
(c) reducing ester in the compound shown in the general formula IV into corresponding alcohol under the action of a reducing agent, and then carrying out bromination to generate a compound shown in V;
(d) reacting the compound shown in the general formula V with the compound shown in the general formula VI under the action of alkali to obtain a compound shown in the general formula VII;
(e) reacting the compound shown in the general formula VII under the action of trifluoroacetic acid to obtain a compound shown in a general formula VIII;
(a') reacting a compound represented by the general formula VIII with a compound represented by the general formula XI under the action of a base to obtain a compound represented by the general formula XV;
(b') reacting the compound of formula XV with hydroxylamine hydrochloride under the action of a base to produce a compound of formula XVI;
(c') reacting the compound shown in the general formula XVI under the action of phosgene, triphosgene or carbonyl diimidazole to generate the compound shown in the general formula I.
Wherein the compound of formula XI is prepared by the following steps:
Figure BDA0002689977030000092
(f) reacting the compound shown in the general formula IX with sodium thiocyanate under the action of liquid bromine or with tetrabutyl ammonium thiocyanate under the action of benzyl trimethyl ammonium bromide to obtain a compound shown in the general formula X;
(g) then reacting the compound shown in the general formula X with cuprous bromide, cupric bromide, cuprous chloride or cupric chloride under the action of tert-butyl nitrite to obtain a compound shown in the general formula XI;
line 2
Figure BDA0002689977030000101
The compounds of formula VIII can also be prepared by reference to line 1, and further comprising the following steps:
(h) reacting the compound shown in the general formula XII with sodium thiocyanate under the action of liquid bromine or tetrabutyl ammonium thiocyanate under the action of benzyl trimethyl ammonium bromide to obtain a compound shown in the general formula XIII;
(i) then reacting the compound shown in the general formula XIII with cuprous bromide, cupric bromide, cuprous chloride or cupric chloride under the action of tert-butyl nitrite to obtain a compound shown in the general formula XIV;
(a') reacting the compound of formula VIII with a compound of formula XIV under the action of a base to form a compound of formula XVII;
(b') reacting the compound of formula XVII with hydrazine hydrate under the action of a base to produce a compound of formula XVIII;
(c') reacting the compound of formula XVIII under the action of phosgene, triphosgene or carbonyldiimidazole to form the compound of formula I
Line 3
Figure BDA0002689977030000102
The compounds of the general formula XVII can also be prepared with reference to line 2, which comprises the following steps:
(a') reacting the compound of formula XVII with thionyl chloride in the presence of a trace amount of N, N-dimethylformamide to form a compound of formula XIX;
(b' ") reacting the compound of formula XIX with glycinamide under the action of a base to form a compound of formula XX;
(c') reacting the compound shown in the general formula XX under the action of phosphorus oxychloride to generate the compound shown in the general formula I.
Wherein R is1、R21、R22、R23Ar, W, V, U, X and Y are as defined above.
Pharmaceutical compositions and therapeutic uses thereof
The compound provided by the invention can be used alone, or can be mixed with pharmaceutically acceptable auxiliary materials (such as excipient, diluent and the like) to be prepared into tablets, capsules, granules, syrups and the like for oral administration. The pharmaceutical composition can be prepared according to a conventional method in pharmacy. The pharmaceutical composition of the present invention comprises the active ingredient in a safe and effective amount range, and a pharmaceutically acceptable carrier.
The active ingredient refers to the compound of the formula I.
The active ingredient and the pharmaceutical composition are used for preparing the medicine for treating FXR related diseases. The invention
The "active ingredient" and pharmaceutical compositions are useful as FXR agonists. In another preferred embodiment, said active ingredient can be used for the preparation of a medicament for the prevention and/or treatment of diseases modulated by FXR agonists.
"safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of active ingredient per dose, more preferably, 10-200mg of active ingredient per dose. Preferably, said "dose" is a tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being combined with the active ingredients of the present invention and with each other without significantly diminishing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like)) Gelatin, talc, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as propylene glycol, glycerin, mannitol, sorbitol, etc.)
Figure BDA0002689977030000111
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include 5 (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and the like.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like. In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the invention may be administered alone or in combination with other therapeutic agents, such as hypolipidemic agents.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 20 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures for which specific conditions are not indicated in the following examples are generally carried out according to conventional conditions (e.g.as described in Sambrook et al, molecular cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989)) or according to the conditions as recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
The instruments used and the main experimental materials were as follows:
the reagents and anhydrous solvents used were purchased from commercial companies in China and used as received unless otherwise specified;1h and13c NMR was performed using a BrukeraM-400 and Varian Mercury plus-400 NMR spectrometer using an Agilent6230 mass spectrometer, and 200-mesh 300-mesh column chromatography silica gel (Qingdao Seisakusho), HSGF254 TLC plate (Nicoti Seisakusho chemical research institute).
The compounds of the present invention are prepared according to any method selected from the following scheme 1, scheme 2 and scheme 3, using suitable starting materials:
line 1
Figure BDA0002689977030000121
Line 2
Figure BDA0002689977030000131
Line 3
Figure BDA0002689977030000132
Synthesis of intermediate VIII-1:
Figure BDA0002689977030000133
aqueous potassium carbonate (3N, 182mmol) was added dropwise to a stirring solution of hydroxylamine hydrochloride (182mmol) in ethanol (100mL) at 0 deg.C, 2, 6-dichlorobenzaldehyde II-1(20g, 114mmol) was dissolved in 100mL of ethanol and then added to the hydroxylamine solution, the temperature was raised to 90 deg.C, and the reaction was carried out for two hours. The mixture was allowed to cool to room temperature and then concentrated to a solid. Water/ethanol (1000mL/100mL) solution was added and the solid was broken up by stirring, filtered and dried overnight under vacuum at 50 ℃ to give the intermediate compound (18.4 g). This intermediate was dissolved in N, N-dimethylformamide (50mL), and a solution of N-chlorosuccinimide (97mmol) in N, N-dimethylformamide (100mL) was added dropwise at 0 ℃ and stirred overnight. The reaction solution was poured into ice water at 0 ℃ and then extracted with methyl t-butyl ether (200 mL each time, 3 times in total), the organic phases were washed with saturated brine, and the combined organic phases were concentrated to give a crude product. To a flask containing the crude product was added n-hexane (600mL), stirred with a magneton, filtered, and the solid was dried under vacuum (30 ℃ C.) to give intermediate III-1(18.3g, 73% yield).1H NMR(400MHz,CDCl3)δ7.43–7.39(m,2H),7.39–7.33(m,1H)。
Triethylamine (8.2g)Was added to methyl 3-cyclopropyl-3-oxopropanoate (82mmol), and the mixture was stirred for 30 minutes. Then, it was cooled to 10 ℃ and a solution of III-1(18.3g, 82mmol) in anhydrous ethanol (80mL) was added dropwise thereto (inner temperature not exceeding 30 ℃ C.), and the reaction was allowed to proceed overnight at room temperature. The reaction was diluted with ethyl acetate (100mL), washed with water, and the aqueous phase was extracted with ethyl acetate (100mL each, 3 times). The organic phases were mixed, washed with saturated brine, the combined organic phases were concentrated. To the concentrate was added 100mL of ether and stirred, and the solvent was removed in vacuo to give the product IV-1 as a solid (21.6g, 84% yield).1H NMR(400MHz,CDCl3)δ7.43–7.39(m,2H),7.39–7.33(m,1H),3.72(s,3H),2.21–2.09(m,1H),1.35–1.28(m,2H),1.25–1.18(m,2H)；MS(ESI,m/z)：312[M+H]+。
IV-1(21.6g, 69mmol) was dissolved in tetrahydrofuran (140mL), cooled to 0 deg.C, a toluene solution of diisobutylaluminum hydride (1.5M,102mL) was slowly added dropwise to the solution, and the reaction was stirred at room temperature for 6 h. Slowly pouring the reaction liquid into ice water, adding 1M hydrochloric acid aqueous solution to adjust the pH to be about 2, extracting with ethyl acetate (100mL each time, three times), combining organic phases, concentrating, and performing column chromatography to obtain intermediate alcohol; this intermediate and triphenylphosphine (59mmol) were dissolved in dichloromethane (60mL), cooled to 0 deg.C, and a solution of carbon tetrabromide (62mmol) in dichloromethane (60mL) was added dropwise under nitrogen, and reacted at room temperature for 4 h. The solvent was removed from the reaction mixture to give an oil, which was subjected to column chromatography to give intermediate V-1(15.3g, 96% yield).1H NMR(400MHz,CDCl3)δ7.49–7.44(m,2H),7.43–7.37(m,1H),4.25(d,J＝1.3Hz,2H),2.21–2.09(m,1H),1.35–1.28(m,2H),1.25–1.18(m,2H)；MS(ESI,m/z)：346[M+H]+。
At 0 ℃ inward-N-BOC-3-hydroxy-8-azabicyclo [3.2.1 ]]To a solution of octane VI-1(1.48g, 6.5mmol) in dry tetrahydrofuran (20mL) was added potassium tert-butoxide (6.5mmol), and the mixture was stirred for 30 minutes, then a solution of V-1(4.3mmol) in dry tetrahydrofuran (5mL) was added dropwise and reacted for 8 hours. Water (20mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL each time for 3 times), and the organic phase was washed with saturated brine, and the organic phases were combined, concentrated, and subjected to column chromatography to give intermediate VII-1(1.44 g). Intermediate VII-1(1.44g,2.9mmol) was dissolved in dichloromethane (8mL), cooled to 0 deg.C, trifluoroacetic acid (8mL) was added dropwise and stirred at room temperature for 3 h. The solvent was removed under vacuum, and ethyl acetate (20mL) was added to dissolve, and the solution was washed with 2N sodium hydroxide solution and saturated brine, and the solvent was removed to give intermediate VIII-1(638mg, yield 56%).1H NMR(400MHz,CDCl3)δ7.42–7.39(m,2H),7.36–7.31(m,1H),4.27–4.18(m,2H),4.10–3.96(m,2H),3.53(t,J＝4.8Hz,1H),2.16–2.07(m,1H),1.91–1.69(m,6H),1.64(d,J＝14.4Hz,2H),1.26–1.22(m,2H),1.14–1.08(m,2H)；MS(ESI,m/z)：393[M+H]+。
Example 1 synthesis:
Figure BDA0002689977030000151
intermediate IX-1(16.8g, 142.3mmol), tetrabutylammonium thiocyanate (142.3mmol), benzyltrimethylammonium bromide (142.3mmol) were added to a round bottom flask and dichloromethane (140mL) was added under nitrogen and allowed to react at room temperature for three days. And adding water into the reaction liquid for quenching, adding a saturated sodium bicarbonate solution to adjust the reaction system to be neutral, extracting by ethyl acetate, combining organic phases, concentrating, and performing column chromatography to obtain an intermediate X-1(2.5g, yield 10%). MS (ESI, m/z): 176[ M + H]+。
X-1(2.5g, 14.3mmol), cuprous bromide (22mmol) and acetonitrile (50mL) were added to a three-necked round bottom flask and stirred, tert-butyl nitrite (2.9mmol) was slowly added dropwise under nitrogen, and the mixture was heated to 30 ℃ for reaction for 48 hours. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, the combined organic phases concentrated and subjected to column chromatography to give intermediate XI-1(2.12g, 62% yield). MS (ESI, m/z): 239[ M + H]+。
Intermediate VIII-1(0.43g, 1.09mmol), intermediate XI-1(1.09mmol), cesium carbonate (1.6mmol) were added to a round bottom flask, N-dimethylacetamide (5mL) was added under nitrogen, and the mixture was heated to 60 ℃ for 12 hours. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, the combined organic phases concentrated and subjected to column chromatography to give intermediate XV-1(0.55g, 91% yield). MS (ESI, m/z): 551[ M + H ]]+。
Intermediate XV-1(0.55g, 1mmol), hydroxylamine hydrochloride (2.6mmol) and absolute ethanol (10mL) were added to a three-necked round bottom flask and stirred, triethylamine (2.6mmol) was slowly added dropwise under nitrogen protection, and the mixture was heated to 90 ℃ for 12 hours. The reaction solution was cooled to room temperature, quenched with water, evaporated to remove ethanol, extracted with ethyl acetate, the combined organic phases concentrated, and subjected to column chromatography to give intermediate XVI-1(0.58g, yield 99%). MS (ESI, m/z): 584[ M + H ]]+。
Intermediate XVI-1(0.58g, 0.99mmol), N, N' -carbonyldiimidazole (1.2mmol), 1, 4-dioxane (5mL) was charged to a round-bottomed flask, followed by 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (1.2mmol) was heated to 100 ℃ for 4 hours. The reaction was cooled to room temperature, diluted with water (5mL), adjusted to pH 2 with 1M aqueous hydrochloric acid, extracted with ethyl acetate, the organic phases combined, washed with saturated brine, the combined organic phases concentrated to give the crude product, which was then subjected to column chromatography to give the final product 1 as a white solid (0.28g yield 64%).1H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.70–7.61(m,3H),7.60–7.53(m,2H),4.28(s,2H),4.21(s,br,2H),3.55–3.48(m,1H),2.39–2.29(m,1H),2.03–1.91(m,2H),1.88–1.79(m,4H),1.78–1.64(m,2H),1.19–1.03(m,4H)；MS(ESI,m/z)：610[M+H]+。
Synthesis of example 2:
Figure BDA0002689977030000152
the preparation of example 2 proceeds from compound XII-1 via scheme 2, which follows:
Figure BDA0002689977030000161
intermediate XII-1(6g, 35.6mmol), tetrabutylammonium thiocyanate (35.6mmol), benzyltrimethylammonium bromide (35.6mmol) were added to a round bottom flask, dichloromethane (50mL) was added under nitrogen and allowed to react at room temperature for three days. Adding water to the reaction solution for quenching, and adding saturated waterThe reaction system was adjusted to neutral with sodium bicarbonate solution, extracted with ethyl acetate, the combined organic phases were concentrated and subjected to column chromatography to give intermediate XIII-1(2.62g, yield 32%). MS (ESI, m/z): 227[ M + H ]]+。
XIII-1(2.62g, 11.6mmol), cuprous bromide (17.9mmol) and acetonitrile (30mL) were added to a three-necked round-bottomed flask and stirred, tert-butyl nitrite (2.32mmol) was slowly added dropwise under nitrogen, and the mixture was heated to 30 ℃ for reaction for 48 hours. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, the combined organic phases concentrated and subjected to column chromatography to give intermediate XIV-1(2.35g, yield 70%). MS (ESI, m/z): 290[ M + H ]]+。
Intermediate VIII-1(0.34g, 0.86mmol), intermediate XIV-1(0.86mmol), and cesium carbonate (1.3mmol) were added to a round-bottomed flask, N-dimethylacetamide (5mL) was added under nitrogen, and the mixture was heated to 60 ℃ for 12 hours. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, the combined organic phases concentrated and subjected to column chromatography to give intermediate XVII-1(0.5g, 96% yield). MS (ESI, m/z): 602[ M + H]+。
Intermediate XVII-1(0.5g, 0.83mmol), hydrazine hydrate (20.6mmol), and absolute ethanol (10mL) were added to a three-necked round-bottomed flask, stirred, and heated to 90 ℃ under nitrogen for 48 hours. The reaction mixture was cooled to room temperature, quenched with water, evaporated to remove ethanol, extracted with ethyl acetate, the combined organic phases concentrated, and subjected to column chromatography to give intermediate XVIII-1(0.28g, yield 56%). MS (ESI, m/z): 602[ M + H]+。
Intermediate XVIII-1(0.21g, 0.35mmol), N, N' -carbonyldiimidazole (0.42mmol), 1, 4-dioxane (2mL) was charged into a round-bottomed flask, and 1, 8-diazabicyclo [5.4.0 ] was added under nitrogen]Undec-7-ene (0.42mmol) was heated to 100 ℃ for 4 hours. The reaction was cooled to room temperature, diluted with water (5mL), adjusted to pH 2 with 1M aqueous hydrochloric acid, extracted with ethyl acetate, the organic phases combined, washed with saturated brine, the combined organic phases concentrated and the crude product obtained was chromatographed to give the final product 2 as a white solid (0.18g yield 82%).1H NMR(400MHz,d-DMSO)δ7.77(s,1H),7.64–7.62(m,2H),7.59–7.52(m,1H),7.31–7.28(m,1H),4.25(s,2H),4.15(s,2H),3.49(s,1H),1.97–1.93(m,2H),1.77–1.67(m,6H),1.57(s,2H),1.18–1.02(m,4H)；MS(ESI,m/z)：628[M+H]+。
Synthesis of example 3:
Figure BDA0002689977030000162
preparation of example 3 starting from 4-amino-3-fluorobenzoic acid methyl ester XII-2 the intermediate XVII-1 of reference example 2 was prepared to give intermediate XVII-2, which was then prepared via scheme 3, as follows:
Figure BDA0002689977030000171
intermediate XVII-2(0.57g, 0.95mmol), toluene (5mL) was added to a round-bottomed flask, then N, N-dimethylformamide (0.02mL) and thionyl chloride (1mL) were added under nitrogen, and the mixture was heated to 110 ℃ for 1 hour. The reaction mixture was concentrated, and the resulting crude product, intermediate XIX-2(0.3g), was used directly in the next reaction. MS (ESI, m/z): 606[ M + H]+。
Crude intermediate XVII-2 (0.3g), glycinamide (64mg, 0.58mmol) and acetonitrile (5mL) were added to a round bottom flask, followed by triethylamine (0.58mmol) under nitrogen and heated to 40 ℃ for 2 hours. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, the combined organic phases concentrated and subjected to column chromatography to give intermediate XX-2(0.25g, 81% yield). MS (ESI, m/z): 644[ M + H ]]+。
Intermediate XX-2(0.25g, 0.48mmol), 1, 4-dioxane (5mL) was added to a round bottom flask, then phosphorus oxychloride (1mL) was added under nitrogen, and the mixture was heated to 100 ℃ for reaction for 3 hours. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, the combined organic phases concentrated and subjected to column chromatography to give the final product, white solid 3(0.04g, yield 13%).1H NMR(400MHz,d-DMSO)δ8.06(s,1H),7.69–7.62(m,2H),7.61–7.49(m,2H),4.28(s,2H),4.24(s,br,2H),4.16(s,br,2H),3.55–3.50(m,1H),2.39–2.29(m,1H),2.02–1.92(m,2H),1.89–1.70(m,6H),1.19–1.05(m,4H)；MS(ESI,m/z)：626[M+H]+。
Synthesis of example 4:
Figure BDA0002689977030000172
the synthetic route of example 4 is as follows:
Figure BDA0002689977030000181
starting from a raw material III-1, synthesizing a compound VIII-2 by replacing 3-cyclopropyl-3-oxopropanoic acid methyl ester with methyl isobutyrylacetate according to a synthetic method for synthesizing an intermediate VIII-1, and then preparing 4 through a route 1, wherein:
the yield of the white solid is 21 percent,1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.65–7.63(m,3H),7.59–7.52(m,2H),4.20(s,4H),3.47(s,1H),3.38(t,J＝6.8Hz,1H),1.96-1.91(m,2H),1.82(s,4H),1.69(d,J＝14.8Hz,2H),1.32(d,J＝7.2Hz,6H).；MS(ESI,m/z)：612[M+H]+。
synthesis of example 5:
Figure BDA0002689977030000182
the synthetic route of example 5 is as follows:
Figure BDA0002689977030000191
starting from a raw material III-1, synthesizing a compound VIII-3 by replacing 3-cyclopropyl-3-oxopropanoic acid methyl ester with 3-cyclobutyl-3-oxopropanoic acid methyl ester according to the synthesis method for synthesizing an intermediate VIII-1, and then preparing 5 through a scheme 1, wherein:
the yield of the white solid 5 percent is 19 percent,1H NMR(400MHz,DMSO-d6)δ8.19(s,1H),7.67-7.65(m,3H),7.60–7.53(m,2H),4.30(s,1H),4.21–4.15(m,2H),3.63–3.61(m,2H),2.26–1.83(m,11H),1.80–1.76(m,3H),1.65(d,J＝14.8Hz,1H).MS(ESI,m/z)：624[M+H]+。
synthesis of example 6:
Figure BDA0002689977030000192
the synthetic route of example 6 is as follows:
Figure BDA0002689977030000193
compound XI-2 was synthesized starting from starting material IX-2 following the synthetic procedure for the synthesis of intermediate XI-1, substituting 4-aminobenzonitrile with 4-amino-2-methylbenzonitrile, followed by preparation of 6 via scheme 1, wherein:
the yield of the white solid 5 percent is 20 percent,1H NMR(400MHz,DMSO-d6)δ7.69–7.61(m,2H),7.61–7.53(m,1H),7.51–7.39(m,2H),4.28(s,2H),4.22(br,s,1H),3.50–3.42(m,1H),3.28–3.21(m,2H),2.55(s,3H),2.38–2.31(m,1H),2.02–1.91(m,2H),1.87–1.78(m,4H),1.76–1.67(m,2H),1.19–1.06(m,4H).MS(ESI,m/z)：625[M+H]+。
synthesis of example 7:
Figure BDA0002689977030000201
the synthetic route of example 7 is as follows:
Figure BDA0002689977030000202
compound XI-3 is synthesized starting from raw material IX-3 according to the synthesis of synthesis intermediate XI-1, replacing 4-aminobenzonitrile with 4-amino-3-chlorobenzonitrile, followed by scheme 1 to afford 7, wherein:
the yield of the white solid 7 is 21 percent,1H NMR(400MHz,d-DMSO)δ8.18(s,1H),7.75(s,1H),7.69–7.62(m,2H),7.61–7.55(m,1H),4.28(s,2H),4.19(s,br,2H),3.55-3.49(m,1H),2.38–2.32(m,1H),1.99–1.92(m,2H),1.89–1.72(m,6H),1.19–1.05(m,4H)；MS(ESI,m/z)：644[M+H]+。
synthesis of example 8:
Figure BDA0002689977030000203
the synthetic route of example 8 is as follows:
Figure BDA0002689977030000211
compound XI-4 is synthesized starting from starting material IX-4 by the synthetic method for the synthesis of intermediate XI-1, replacing 4-aminobenzonitrile with 4-amino-3-fluorobenzonitrile, followed by scheme 1 to afford 8, wherein:
the yield of the white solid is 8 percent and 24 percent,1H NMR(400MHz,d-DMSO)δ8.06(s,1H),7.69–7.62(m,2H),7.61–7.49(m,2H),4.28(s,2H),4.24(s,br,2H),3.55–3.50(m,1H),2.39-2.29(m,1H),2.02–1.92(m,2H),1.89–1.70(m,6H),1.19–1.05(m,4H)；MS(ESI,m/z)：628[M+H]+。
synthesis of example 9:
Figure BDA0002689977030000212
the synthetic route for example 9 is as follows:
Figure BDA0002689977030000213
preparation of 9 via scheme 1 starting from starting material III-2, wherein:
the yield of the white solid is 9 percent,1H NMR(400MHz,d-DMSO)δ8.18(s,1H),7.74–7.62(m,2H),7.57–7.46(m,1H),7.33–7.24(m,2H),4.31(s,2H),4.19(s,br,2H),3.56–3.50(m,1H),2.35–2.29(m,1H),2.05–1.91(m,2H),1.89–1.65(m,6H),1.16–1.04(m,4H)；MS(ESI,m/z)：578[M+H]+。
synthesis of example 10:
Figure BDA0002689977030000221
the synthetic route of example 10 is as follows:
Figure BDA0002689977030000222
starting from starting material III-3, preparation via scheme 1 yields 10, where:
the yield of the white solid is 10 percent and 28 percent,1H NMR(400MHz,d-DMSO)δ8.18(s,1H),7.73–7.62(m,1H),7.59–7.48(m,3H),7.44–7.29(m,2H),4.35(s,2H),4.21(s,br,2H),3.58–3.53(m,1H),2.36–2.29(m,1H),2.05–1.91(m,2H),1.89–1.65(m,6H),1.16–1.04(m,4H)；
MS(ESI,m/z)：560[M+H]+。
synthesis of example 11:
Figure BDA0002689977030000223
the synthetic route for example 11 is as follows:
Figure BDA0002689977030000231
preparation of 11 via scheme 1 starting from starting material III-4, wherein:
the yield of the white solid is 11 percent,1H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.92–7.89(m,1H),7.85–7.71(m,2H),7.69-7.52(m,3H),4.25(s,2H),4.21(s,br,2H),3.55–3.46(m,1H),2.38–2.24(m,1H),2.02–1.90(m,2H),1.89–1.68(m,6H),1.19-1.04(m,4H).
MS(ESI,m/z)：610[M+H]+。
synthesis of example 12:
Figure BDA0002689977030000232
the synthetic route for example 12 is as follows:
Figure BDA0002689977030000241
preparation of 12 via scheme 1 starting from starting material III-5, wherein:
the yield of the white solid is 12 percent and 19 percent,1H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.80–7.59(m,3H),7.58–7.50(m,3H),4.35(s,2H),4.21(s,br,2H),3.60–3.48(m,1H),2.38–2.24(m,1H),2.05–1.92(m,2H),1.91–1.65(m,6H),1.18–1.02(m,4H).
MS(ESI,m/z)：626[M+H]+。
synthesis of example 13:
Figure BDA0002689977030000242
the synthetic route for example 13 is as follows:
Figure BDA0002689977030000251
prepared by route 1 starting from starting material III-6 to 13, wherein:
the yield of the white solid is 13 percent,1H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.70–7.63(m,1H),7.58–7.51(m,1H),7.45–7.24(m,4H),4.35–4.10(m,4H),3.58–3.49(m,1H),2.37–2.25(m,1H),2.21(s,3H),2.05–1.94(m,2H),1.92–1.73(m,6H),1.19–1.03(m,4H).
MS(ESI,m/z)：556[M+H]+。
synthesis of example 14:
Figure BDA0002689977030000252
the synthetic route for example 14 is as follows:
Figure BDA0002689977030000261
prepared by route 1 starting from starting material III-7 to 14, wherein:
the yield of the white solid is 14 percent,1H NMR(400MHz,d-DMSO)δ8.74(d,J＝5.2Hz,2H),8.20(s,1H),7.72(d,J＝5.2Hz,2H),7.66(d,J＝8.4Hz,1H),7.55(d,J＝8.4Hz,1H),4.51(s,2H),4.29(s,2H),3.72(s,1H),2.38–2.34(m,1H),2.11–2.06(m,2H),2.01–1.91(m,6H),1.13–1.11(m,2H),1.06–1.05(m,2H).
MS(ESI,m/z)：543[M+H]+。
synthesis of example 15:
Figure BDA0002689977030000262
the synthetic route for example 15 is as follows:
Figure BDA0002689977030000271
starting from a raw material III-1, replacing diisobutyl aluminum hydride synthetic compound intermediate VIII-10 with deuterated lithium aluminum hydride according to the synthetic method of the synthetic intermediate VIII-1, and then preparing 15 through a route 1, wherein:
white solid 15 (yield 58%).1H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.70–7.61(m,3H),7.60–7.53(m,2H),4.21(s,br,2H),3.55–3.48(m,1H),2.39–2.29(m,1H),2.03–1.91(m,2H),1.88–1.79(m,4H),1.78–1.64(m,2H),1.19–1.03(m,4H)；MS(ESI,m/z)：612[M+H]+。
Synthesis of example 16:
Figure BDA0002689977030000272
the synthetic route for example 16 is as follows:
Figure BDA0002689977030000281
preparation of intermediate VIII-1 starting from V-1 gives VIII-11, which is prepared by scheme 1 to give 16, wherein:
white solid 16 (yield 21%),1H NMR(400MHz,d-DMSO)δ.8.18(s,1H),7.72–7.60(m,3H),7.59–7.51(m,2H),4.20–3.85(m,2H),3.66–3.20(m,2H),2.95–2.48(m,1H),2.29–2.03(m,1H),2.02–1.88(m,2H),1.78–1.69(m,4H),1.66–1.43(m,2H),1.19–1.03(m,4H)
MS(ESI,m/z)：609[M+H]+。
pharmacological test example:
a method for detecting FXR agonistic activity of a compound based on a reporter gene activity assay:
1.1 construction and preparation of plasmids pGAL4-FXR-LBD and pG5-Luc
pGAL4-FXR-LBD and pG5-Luc plasmids used by a reporter gene detection system are constructed according to a conventional molecular cloning method. The method mainly comprises the following steps: inserting the FXR (NM-001206979.2) cDNA sequence corresponding to the FXR-LBD (212-476AA) amino acid sequence into BamHI and NotI enzyme cutting sites of pGAL4 vector by using PCR technology to obtain pGAL 4-FXR-LBD; pG5-Luc and phRL-TK plasmids were given to Shanghai pharmaceutical research institute of Chinese academy of sciences; by using CaCl2The plasmid was transformed into DH 5. alpha. E.coli, further cultured and amplified, and then purified with a plasmid extraction kit (TIANGEN, # D107) to obtain the corresponding plasmid DNA.
1.2 plasmid cotransfection of HEK293T cells and Compound treatment
HEK293T cells were transfected at 1X 10 the day before plasmid transfection4Density of/well was seeded in 96-well plates. According to the transfection reagent Fu
Figure BDA0002689977030000282
HD (Promega, # E2311) instructions for cell transfection. The main steps areComprises the following steps: using one well as an example, the plasmids pGAL4-FXR-LBD, pG5-Luc and phRL-TK were added to 10uL of Opti-MEM in a ratio of 20ng, 50ng and 5ngTMMix well in I medium (Gibco, # 11058021); then add 0.25uL of Fu
Figure BDA0002689977030000283
HD, standing for 5min at room temperature after uniformly mixing; this 10uL mixture was then added to the wells containing 100uL of medium. 6h after cell cotransfection, the compound was diluted in 3-fold gradient with 1uM as the highest concentration, and added to the cell culture medium in 10 concentrations for 24h, and 2 multiple wells in total, with LJN452 compound as the positive control.
1.3Dual-Glo Luciferase assay
Cells were treated with compound for 24h, followed by Dual-
Figure BDA0002689977030000291
The Luciferase Assay System (Promega, # E2940) was used for the Assay. The method mainly comprises the following steps: 50uL of culture medium was aspirated from each well, and 50uL of Dual-
Figure BDA0002689977030000292
Shaking Luciferase reagent at room temperature for 10 min; taking 80uL of the lysis reaction solution to a white opaque optiPlate-96 pore plate, and detecting the luminescence signal value (Firefly-Luc) of Firefly luciferase (Firefly luciferase) by using an MD i3x multifunctional microplate reader; then adding 40uL Dual-
Figure BDA0002689977030000293
Stop&
Figure BDA0002689977030000294
Shaking the reagent at room temperature for 10 min; the luminescence signal value (Renilla-Luc) of Renilla luciferase (Renilla luciferase) was detected using an MD i3x multi-functional microplate reader. The ratio of Firefly-Luc/Renilla-Luc was used as the FXR activating activity of the compound, the ratio of the solvent DMSO group was used for normalization, a dose-response curve was fitted with four parameters using GraphPad prism6.0 software, and EC was calculated50The value is obtained.
2. Results
The experimental data show that the compounds all have certain FXR agonistic activity, wherein the EC of the examples 1, 2, 4, 7, 8 and 1650All values are less than 10nM, in particular EC of example 850Values of less than 5nM, very strong FXR agonistic activity. The FXR agonist activity data for each example are shown in table 1.
FXR agonistic Activity of the Compounds of Table 1
Test sample FXR cellular level Activity EC50(nM)
Example 1 ＊＊＊
Example 2 ＊＊＊
Example 3 ＊＊
Example 4 ＊＊＊
Example 5 ＊
Example 6 ＊＊
Example 7 ＊＊＊
Example 8 ＊＊＊＊
Example 9 ＊＊
Example 10 ＊＊
Example 11 ＊＊
Example 12 ＊＊
Example 13 ＊
Example 14 ＊
Example 15 ＊＊＊
Example 16 ＊＊＊
LJN452 ＊＊＊
＊＊＊＊:EC50(nM)<5；＊＊＊:5<EC50(nM)<10；＊＊:10<EC50(nM)<50；
＊:50<EC50(nM)
Pharmacological experiment example two:
in vitro anti-HBV activity of compound detected based on human primary hepatocyte (PHH) in vitro infection model
1. Method of producing a composite material
1.1HBV Virus infects human primary hepatocytes to establish HBV in vitro infection model and compound treatment
After culturing hepg2.2.15 cells in DMEM containing 10% FBS for 72h, D-type HBV was collected and concentrated in the culture broth and its viral titer was determined by quantitative PCR. Human primary hepatocytes (purchased from Reid liver disease research Co., Ltd.) frozen in liquid nitrogen were thawed, and the cell density was adjusted to 6X 105Cells/ml, and plated in 48-well plates at 220uL per well (approximately 1.3X 10)5Individual cell), placed in 5% CO2Incubated overnight at 37 ℃. Day 2, D-type HBV was added to PHH cells at a ratio of 800 genome equivalents/cell; on day 3, compound treatment was started, compound at 10uM concentration, 3 replicates, and treatment continued for 8 days, with compound-containing medium changed every 2 days, with DMSO as negative control.
1.2 collecting cell culture supernatant to detect HBV DNA, hepatitis B virus surface antigen (HBsAg) and hepatitis B virus e antigen (HBeAg)
Cell culture supernatants were collected after day 8 of compound treatment and tested for HBV DNA, HBeAg and HBsAg, respectively. DNA was extracted from 100ul of cell culture supernatant according to the QIAamp 96DNA Blood Kit (QIAGEN, #51161) instructions; and (3) qPCR (quantitative polymerase chain reaction) quantitative detection of the content of the HBV DNA by taking the HBV plasmid DNA as a standard substance. HBsAg and HBsAg were detected according to the ELISA kit instructions. The method is briefly described as follows: the samples were first diluted 8-fold (15ul cell supernatant +105ul PBS); then respectively taking 50ul of standard substance, adding the sample and the reference substance into a detection plate, then adding 50ul of enzyme conjugate into each hole, and incubating for 60 minutes at 37 ℃; washing the plate with washing liquor, then sucking to dry, then adding 50ul of premixed luminescent substrate, incubating for 10 minutes at room temperature in a dark place, and finally measuring the luminescent value by an enzyme-linked immunosorbent assay.
1.3CCK-8 test of the Effect of Compounds on cell viability
Cell viability was determined according to the CCK-8 kit instructions, the procedure is briefly as follows: after the compound treatment day 8, after the cell culture supernatant was collected, 180ul of fresh medium and 20ul of CCK-8 were added to each well, mixed well, incubated at 37 ℃ for 2.5 hours, and the absorbance (450nm/650nm) was measured with an enzyme reader.
1.4 data processing
The calculation is carried out according to the following formulas respectively:
HBV DNA inhibition rate ═ (1-compound HBV DNA copy number/DMSO control HBV DNA copy number) × 100%;
HBsAg inhibition rate ═ 1-HBsAg (IU/ml for sample)/HBsAg (IU/ml) for DMSO control) × 100%;
HBeAg inhibition ═ 100% (1-HBeAg (PEIU/ml for sample)/DMSO control HBeAg (PEIU/ml)) ×;
cell viability ═ 100% (signal value for sample-signal value for media control)/(signal value for DMSO control-signal value for media control).
2. Results
The specific experimental results of the HBV DNA inhibition rate, HBsAg inhibition rate, HBeAg inhibition rate and cell viability of the compounds in an in vitro model of primary hepatocytes (PHH) infected with HBV are shown in the following table.
Figure BDA0002689977030000301
Figure BDA0002689977030000311
Inhibition% < 50; inhibition% 50; a: the concentration of the compound was 0.5uM
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A compound of formula I, or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, prodrug, or a pharmaceutically acceptable salt thereof:
Figure FDA0002689977020000011
wherein,
ar is selected from the group consisting of: substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted 5-9 membered heteroaromatic ring (including monocyclic or fused ring, containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen);
R1selected from: substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted 5-9 membered heterocyclic ring (containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen);
R21、R22、R23each independently selected from the group consisting of: hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C1-C6An alkoxy group;
w is selected from the group consisting of: hydrogen or deuterium;
v is selected from the group consisting of: hydrogen or deuterium;
u is selected from the group consisting of: o or NH;
x is selected from the group consisting of: o, NH, CH2Or CHR2Wherein R is2Selected from the group consisting of: deuterium, substituted or unsubstituted C1-C6Alkyl radical, C3-C6A cycloalkyl group;
y is selected from the group consisting of: o, NH, CH2Or CHR3Wherein R is3Selected from the group consisting of: deuterium, substituted or unsubstituted C1-C6Alkyl radical, C3-C6A cycloalkyl group;
wherein said substitution means that one or more hydrogen atoms on the group are each independently replaced by a substituent selected from the group consisting of: deuterium, halogen, halogeno C1-C6Alkyl, halo C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radicals、C3-C6Cycloalkoxy, cyano or nitro.
2. The compound of claim 1, wherein Ar is selected from the group consisting of: substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted 5-9 membered heteroaromatic ring wherein the aryl or heteroaryl substituents are selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, or trifluoromethoxy.
3. A compound of claim 1 wherein R is1Selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl or cyclopentyl.
4. A compound of claim 1 wherein R is21、R22、R23Each independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, or trifluoromethoxy.
5. The compound of claim 1, wherein X is selected from the group consisting of: o, NH, CH2Or CHR2Wherein R is2Selected from the group consisting of: deuterium, substituted or unsubstituted C1-C6Alkyl radical, C3-C6A cycloalkyl group; the Y is selected from: o, NH, CH2Or CHR2Wherein R is2Selected from the group consisting of: deuterium, substituted or unsubstituted C1-C6Alkyl radical, C3-C6A cycloalkyl group.
6. The compound of claim 1, wherein said compound is selected from the group consisting of:
Figure FDA0002689977020000021
7. a process for the preparation of a compound according to claim 1, which comprises: preparing a compound of formula I by a process selected from the group consisting of those described in scheme one, scheme two or scheme three:
route one:
Figure FDA0002689977020000022
(a') reacting a compound of formula VIII with a compound of formula XI under basic conditions to form a compound of formula XV;
(b') reacting the compound of formula XV with hydroxylamine hydrochloride to produce a compound of formula XVI;
(c') reacting the compound shown in the general formula XVI under the action of phosgene, triphosgene or carbonyl diimidazole to generate the compound shown in the general formula I,
wherein X is NH, Y is O, R1、R21、R22、R23Ar, W, V and U are defined as in claim 1;
and a second route:
Figure FDA0002689977020000031
(a') reacting the compound of formula VIII with a compound of formula XIV under basic conditions to form a compound of formula XVII;
(b') reacting the compound of formula XVII with hydrazine hydrate under the action of a base to produce a compound of formula XVIII;
(c') reacting the compound of formula XVIII under the action of phosgene, triphosgene or carbonyldiimidazole to form a compound of formula I;
wherein X is O, Y is NH, R1、R21、R22、R23Ar, W, V, U are as defined in claim 1；
And a third route:
Figure FDA0002689977020000032
(a') reacting the compound of formula XVII with thionyl chloride in the presence of a trace amount of N, N-dimethylformamide to form a compound of formula XIX;
(b' ") reacting the compound of formula XIX with glycinamide under the action of a base to form a compound of formula XX;
(c') reacting the compound shown in the general formula XX under the action of phosphorus oxychloride to generate the compound shown in the general formula I,
wherein X is NH and Y is CH2，R1、R21、R22、R23Ar, W, V and U are defined as in claim 1.
8. A pharmaceutical composition comprising a compound of formula I according to claim 1, or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, metabolite, prodrug, pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
9. Use of a compound of formula I according to claim 1, or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, prodrug or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of a disease or condition associated with FXR activity or expression.
10. The use according to claim 9, wherein the FXR related disease is selected from the group consisting of: bile acid metabolism, carbohydrate metabolism, lipid metabolism, inflammation, and/or diseases associated with liver fibrosis processes.
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