CN111825701A - Tricyclic FXR modulator compounds containing benzothiazole - Google Patents

Tricyclic FXR modulator compounds containing benzothiazole Download PDF

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CN111825701A
CN111825701A CN202010300950.1A CN202010300950A CN111825701A CN 111825701 A CN111825701 A CN 111825701A CN 202010300950 A CN202010300950 A CN 202010300950A CN 111825701 A CN111825701 A CN 111825701A
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孙颖慧
姚金锁
闵汪洋
解博文
刘希杰
李红娟
路畅
张喜全
杨玲
徐宏江
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
Shouyao Holdings Beijing Co Ltd
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Lianyungang Runzhong Pharmaceutical Co Ltd
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Abstract

The application belongs to the field of pharmaceutical chemistry, relates to a tricyclic FXR (FXR) regulator compound containing benzothiazole, and particularly provides a compound containing benzothiopheneTricyclic compounds of formula (I) of azoles, processes for their preparation and their use in the preparation of medicaments for the treatment of FXR-related diseases.

Description

Tricyclic FXR modulator compounds containing benzothiazole
Technical Field
The invention belongs to the field of medicinal chemistry, and provides a tricyclic compound containing benzothiazole, a preparation method thereof, and application thereof in preparing medicaments for treating FXR related diseases.
Background
Farnesoid X Receptor (FXR) is one of the members of the superfamily of nuclear receptors that regulate metabolism and is usually highly expressed in organs such as the liver, small intestine, kidney and adrenal gland. It was initially discovered that it was slightly activated by farnesyl ester at physiological level and was thus named, and it was soon discovered that certain specific types of bile acids (e.g. chenodeoxycholic acid, lithocholic acid, deoxycholic acid, etc.) could bind to the Ligand-binding domain (LBD) of FXR as physiological ligands, causing a change in the steric configuration of the receptor, allowing it to form heterodimers with the retinoid receptor (RXR). The FXR/RXR heterodimer can bind to a specific DNA sequence of a chromosome, plays a role of a transcription regulatory factor, regulates and controls the transcription expression of a series of downstream genes such as an alpha-Fetoprotein Transcription Factor (FTF), a Small Heterodimer Partner (SHP), Cholesterol 7 alpha hydroxylase (CYP 7 alpha 1), Ileal bile acid binding protein (I-BABP) and the like, and finally regulates cholic acid metabolism and Cholesterol metabolism. Activation of FXR inhibits bile acid synthesis by two complementary mechanisms. In the liver, when the bile acid level is too high, the bile acid can be used as a physiological ligand to be combined with FXR to stimulate the expression of SHP, and the SHP can form a dimer with LRH-1 or LXP alpha to inactivate the two transcription regulation factors, so that the gene transcription of CYP7 alpha 1 is inhibited, and the expression of CYP7 alpha 1 protein is reduced. The decrease in the expression level of CYP7 alpha 1, which is a rate-limiting enzyme in cholesterol synthesis, can decrease the synthesis of cholesterol in vivo and, in turn, the synthesis of bile acids. Meanwhile, in small intestine tissues outside the liver, FXR activation can induce transcriptional expression of endocrine hormone FGF19, FGF19 can enter portal circulation after being secreted and then is combined with an FGFR4 receptor on the liver, and combination of FGF9 and FGFR4 can activate an MAPK signal pathway in the liver, so that expression of CYP7 alpha 1 protein is reduced, and synthesis of bile acid is reduced through another pathway. Besides, after the FXR is combined with bile acid, the FXR can also induce the transcription expression of BABP, enhance the reabsorption of bile and enhance the liver-intestine circulation of the bile acid. FXR can also regulate expression of bile acid carrier MRP2 and bile salt export pump BSEP, promote bile export, and inhibit bile intake. Through a series of actions, the FXR activation can regulate and control the synthesis, transportation and metabolism of bile acid, reduce the accumulation of bile acid in the liver, relieve the liver burden and reduce the occurrence of fatty liver.
In addition, studies have shown that FXR activation can inhibit the expression of some key genes (e.g., SREBP-1c, etc.) involved in adipogenesis and triglyceride synthesis in the liver, regulate insulin sensitivity in peripheral tissues, and thus lower plasma triglyceride and blood glucose levels.
Non-alcoholic steatohepatitis (NASH) is a metabolic disease caused by multiple factors, and is mainly characterized by liver fat accumulation, inflammation, liver cell balloon-like lesion, liver fibrosis and the like. Based on basic research and some clinical researches, the FXR activation is expected to play a role in reducing liver steatosis, inflammation and fibrosis in NASH patients, so that the development of FXR agonists and the activation of FXR physiological functions have become popular fields for the research and development of new NASH medicines in recent years.
Disclosure of Invention
The present application relates to a compound of formula I or a pharmaceutically acceptable salt thereof:
Figure BDA0002453959550000021
wherein the content of the first and second substances,
R1is selected from C1-6Alkyl or C3-10Cycloalkyl radical, said C1-6Alkyl or C3-10Cycloalkyl is optionally substituted with 1-3 halogens, OH or CN;
R2selected from halogen, CN, NH2、C1-6Alkyl radical, C1-6Alkoxy radical, C3-10Cycloalkyl radical, C3-10Cycloalkyloxy, -NHC1-6Alkyl or-N (C)1-6Alkyl radical)2Said C is1-6Alkyl radical, C1-6Alkoxy radical, C3-10Cycloalkyl, or C3-10Cycloalkoxy optionally substituted by 1-3 halogens, CN, NH2Or OH substitution;
n is selected from 1,2, 3 or 4;
R31or R32Each independently selected from H, -CO2H、-CO2C1-6Alkyl and OH are takenSubstituted C1-6Alkyl-, -CONH2、-CONHC1-6Alkyl or-CON (C)1-6Alkyl radical)2；
Ring A is selected from 3-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, ring A is optionally substituted with 1-3R, each independently selected from halogen, CN, OH, NH2、C1-6Alkyl or C1-6An alkoxy group.
In some embodiments, the above R1Is selected from C1-3Alkyl or C3-6Cycloalkyl radical, said C1-3Alkyl or C3-6Cycloalkyl is optionally substituted with 1-3 halogens, OH or CN; in some embodiments, the above R1Is selected from C3-4Cycloalkyl radical, said C3-4Cycloalkyl is optionally substituted with 1-3 of F, Cl, Br, OH or CN; in some embodiments, the above R1Is selected from C3-4A cycloalkyl group; in some embodiments, the above R1Selected from cyclopropyl.
In some embodiments, the above R2Selected from halogen, CN, NH2、C1-3Alkyl radical, C1-3Alkoxy radical, C3-6Cycloalkyl radical, C3-6Cycloalkyloxy, -NHC1-3Alkyl or-N (C)1-3Alkyl radical)2Said C is1-3Alkyl radical, C1-3Alkoxy radical, C3-6Cycloalkyl radical, C3-6Cycloalkyloxy optionally substituted with 1-3 halogens, CN, NH2Or OH substitution; in some embodiments, the above R2Selected from F, Cl, Br, C1-3Alkyl or C1-3Alkoxy radical, said C1-3Alkyl or C1-3Alkoxy is optionally substituted with 1-3 of F, Cl or Br; in some embodiments, the above R2Selected from F, Cl, Br, methyl substituted by 1-3 of F, Cl and Br or methoxy substituted by 1-3 of F, Cl and Br; in some embodiments, the above R2Selected from chlorine, trifluoromethyl or trifluoromethoxy.
In some embodiments, n is selected from 1,2 or 3; in some embodiments, the above n is selected from 1 or 2.
In some embodiments, n is selected from 1 or 2, and R is2Ortho to the C atom to which the isoxazole is attached.
In some embodiments, R31Or R32Each independently selected from H, -CO2H、-CO2C1-3Alkyl, OH substituted C1-3Alkyl-, -CONH2、-CONHC1-3Alkyl or-CON (C)1-3Alkyl radical)2。
In some embodiments, R31Is selected from H.
In some embodiments, R32Is selected from-CO2H。
In some embodiments, ring a above is selected from 3-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S; in some embodiments, ring a above is selected from 4-, 5-, 6-, 7-membered heterocycloalkyl, said ring a containing 1 or 2 heteroatoms selected from N, O or S; in some embodiments, the above ring a is selected from 5-or 6-membered heterocycloalkyl, said ring a containing 1 or 2O atoms. Wherein the substituents of ring A are as defined above.
In some embodiments, the heteroatom of ring a above is in a position directly attached to a benzene ring C atom.
In some embodiments, each R is independently selected from halogen, CN, OH, NH2、C1-3Alkyl or C1-3An alkoxy group; in some embodiments, each R is independently selected from F, Cl, Br, CN, OH, or NH2(ii) a In some embodiments, each R is independently selected from the group consisting of F, Cl, Br; in some embodiments, each of the above R is independently selected from F.
In some embodiments, the above ring a is selected from the following structures:
Figure BDA0002453959550000031
Figure BDA0002453959550000032
in some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula I', or a pharmaceutically acceptable salt thereof:
Figure BDA0002453959550000033
wherein R is1、R2、R31、R32N and ring A are as defined above for compounds of formula I.
In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, described above is selected from a compound of formula II, or a pharmaceutically acceptable salt thereof:
Figure BDA0002453959550000034
wherein the content of the first and second substances,
X1、X3or X4Are each independently selected from-NH-, -N (R) -, O, S, -CH2-, -CH (R) -, or-C (RR) -; x2Selected from a single bond, -NH-, O, S, or-CH2-；
R、R1、R2、R32And n is as defined above for compounds of formula I.
In some embodiments, the aforementioned X1、X3Or X4Each independently selected from O, S, -CH2-, -CH (R) -or-C (RR) -.
In some embodiments, the aforementioned X1Or X4Each independently selected from O, S or-CH2-; in some embodiments, the aforementioned X1Or X4Each independently selected from O or-CH2-。
In some embodiments, the aforementioned X3Is selected from-CH2-or-c (rr) -; in some embodiments, the aforementioned X3Is selected from-CH2-or-C (RR) -, wherein R is each independently selected from F, Cl, Br, CN, OH or NH2(ii) a In some embodiments, the aforementioned X3Is selected from-CH2-or-c (rr) -wherein R is each independently selected from F, Cl, Br; in some embodiments, the aforementioned X3Is selected from-CH2-or-CF2-。
In some embodiments, the aforementioned X2Selected from single bond or-CH2-。
In some embodiments, the compound of formula II, or a pharmaceutically acceptable salt thereof, described above is selected from a compound of formula II', or a pharmaceutically acceptable salt thereof:
Figure BDA0002453959550000041
wherein R is1、R2、R32、n、X1、X2、X3Or X4As defined above for compounds of formula II.
In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, described above is selected from a compound of formula III, or a pharmaceutically acceptable salt thereof:
Figure BDA0002453959550000042
X1、X3or X4Are each independently selected from-NH-, -N (R) -, O, S, -CH2-, -CH (R) -, or-C (RR) -; x2
Selected from a single bond, -NH-, O, S, or-CH2-；
R、R2And n is as defined above for compounds of formula I;
optionally, X1、X2、X3Or X4As defined above for compounds of formula II.
In some embodiments, the compound of formula III, or a pharmaceutically acceptable salt thereof, described above is selected from a compound of formula III', or a pharmaceutically acceptable salt thereof:
Figure BDA0002453959550000043
wherein R is2、n、X1、X2、X3Or X4As defined above for the compound of formula III.
The present application provides the following compounds, or pharmaceutically acceptable salts thereof:
Figure BDA0002453959550000044
Figure BDA0002453959550000051
the present application provides the following compounds, or pharmaceutically acceptable salts thereof:
Figure BDA0002453959550000052
in another aspect, the present application also provides a pharmaceutical composition comprising a compound of formula I, formula I ', formula II ', formula III ' of the present application, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions of the present application further comprise a pharmaceutically acceptable excipient.
In another aspect, the present application provides a method for treating various diseases related to farnesoid X receptor, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound represented by formula I, formula I ', formula II ', formula III ', or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In another aspect, the present application also provides the use of a compound of formula I, formula I ', formula II ', formula III ', or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application in the manufacture of a medicament for the treatment of various disorders associated with the farnesoid X receptor.
In another aspect, the present application also provides the use of a compound of formula I, formula I ', formula II ', formula III ', or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application in the treatment of various disorders associated with the farnesoid X receptor.
In another aspect, the present application also provides a compound of formula I, formula I ', formula II ', formula III ', or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described above, for treating a variety of disorders associated with the farnesoid X receptor.
In some embodiments, the farnesoid X receptor-associated various diseases are selected from the group consisting of liver function impairment due to non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, primary biliary cholangitis, cholestatic liver disease, chronic liver disease, hepatitis C infection, alcoholic liver disease, liver fibrosis, Primary Sclerosing Cholangitis (PSC), gallstones, biliary atresia, lower urinary tract symptoms and Benign Prostatic Hyperplasia (BPH), ureteral stones, obesity, type ii diabetes, atherosclerosis, arteriosclerosis, hypercholesterolemia, and hyperlipidemia; preferably non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, primary biliary cholangitis, Primary Sclerosing Cholangitis (PSC), liver fibrosis, or biliary atresia.
Definition of
The following terms used in the present application have the following meanings, unless otherwise specified. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
As used herein, when the ring a forms a fused ring structure with benzene, if the C atom of benzene is a ring-forming atom of the ring a group, the C atoms are common C atoms.
When a covalent bond in some structural unit or group is not attached to a particular atom in this application, it is meant that the covalent bond can be attached to any atom in the structural unit or group, as long as the valence bond attachment rules are not violated.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., ═ O), meaning that two hydrogen atoms are substituted, oxo does not occur on the aryl.
The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For exampleEthyl "optionally" substituted by halogen means that ethyl may be unsubstituted (CH)2CH3) Monosubstituted (e.g. CH)2CH2F) Polysubstituted (e.g. CHFCH)2F、CH2CHF2Etc.) or completely substituted (CF)2CF3). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.
Herein Cm-nIt is the moiety that has an integer number of carbon atoms in the given range. E.g. "C1-6By "is meant that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. E.g. C1-3Meaning that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 2R, then there are separate options for each R.
When the number of one linking group is 0, e.g. - (CH)2)0-, indicates that the linking group is a covalent bond.
When one of the variables is selected from a covalent bond, it means that the two groups to which it is attached are directly linked, for example, in A-L '-Z where L' represents a covalent bond, it means that the structure is actually A-Z.
When a substituent's bond is cross-linked to two atoms on a ring, such substituent may be bonded to any atom on the ring. For example, a structural unit
Figure BDA0002453959550000071
Meaning that it may be substituted at any position on the cyclohexyl or cyclohexadiene.
The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "alkyl" refers to a group of formula CnH2n+1A hydrocarbon group of (1). The alkyl group may beAre straight chain or branched. For example, the term "C1-6Alkyl "means an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio groups have the same definitions as above. Also for example, the term "C1-3Alkyl "refers to alkyl groups containing 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).
The term "alkoxy" refers to-O-alkyl.
The term "cycloalkyl" refers to a carbon ring that is fully saturated and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1 ] n]Heptyl), bicyclo [2.2.2]Octyl, adamantyl, bicyclo [1.1.1]Pent-1-yl, and the like. E.g. C3-4Cycloalkyl groups include cyclopropyl and cyclobutyl.
The term "heterocycloalkyl" refers to a cyclic group that is fully saturated or partially unsaturated and may exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 10 membered ring (or 3 to 7 membered ring) containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxiranyl, thietanyl, cycloazenyl, non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thiabutinyl, examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, examples of tetrahydropyrazolyl, 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thialkyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, and examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, thiepanyl. Monocyclic heterocycloalkyl groups having 5 or 6 ring atoms are preferred.
The term "treating" means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease condition, but has not yet been diagnosed as having the disease condition;
(ii) inhibiting the disease or disease state, i.e., arresting its development;
(iii) alleviating the disease or condition, i.e., causing regression of the disease or condition.
The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art with their own knowledge and this disclosure.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like can be mentioned.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
The term "pharmaceutically acceptable adjuvants" refers to those adjuvants which do not have a significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
The words "comprise" or "comprise" and variations thereof such as "comprises" or "comprising," are to be understood in an open, non-exclusive sense, i.e., "including but not limited to.
The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, wherein the proton can migrate between two ring nitrogens. Valence tautomers include interconversion by recombination of some of the bonding electrons.
The present application also includes isotopically-labeled compounds of the present application, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as respectively2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I and36cl, and the like.
Certain isotopically-labelled compounds of the present application (e.g. with3H and14c-labeled ones) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation)3H) And carbon-14 (i.e.14C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as15O、13N、11C and18f can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
In addition, heavier isotopes are used (such as deuterium (i.e., deuterium)2H) Substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium, all such forms of the compounds being encompassed within the scope of the present application.
The compounds of the present application may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.
The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These adjuvants enable the compounds of the present application to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.
Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid adjuvants, optionally the mixture obtained is milled, if desired with further suitable adjuvants, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
Therapeutic dosages of the compounds of the present application may be determined, for example, by: the particular use of the treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the present application in the pharmaceutical composition may not be fixed, depending on a variety of factors including dosage, chemical properties (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present application can be provided for parenteral administration by a physiological buffered aqueous solution containing about 0.1-10% w/v of the compound. Some typical dosage ranges are from about 1. mu.g/kg to about 1g/kg body weight/day. In certain embodiments, the dosage range is from about 0.01mg/kg to about 100mg/kg body weight/day. The dosage will likely depend on such variables as the type and extent of progression of the disease or disorder, the general health status of the particular patient, the relative biological efficacy of the selected compound, the excipient formulation and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application.
The chemical reactions of the embodiments herein are carried out in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.
An important consideration in the art of synthetic route planning is the selection of suitable protecting Groups for reactive functional Groups (e.g., amino Groups as used herein), for example, reference may be made to Greene's Protective Groups in organic Synthesis (4th Ed.) Hoboken, New Jersey: John Wiley & Sons, Inc.
In some embodiments, the compounds of the present application may be prepared by one of ordinary skill in the art of organic synthesis using methods common in the art, with reference to the following routes:
Figure BDA0002453959550000101
wherein R is2、n、X1、X2、X3Or X4As defined above.
For clarity, the invention is further illustrated by examples, which do not limit the scope of the application. All reagents used herein were commercially available and used without further purification.
Detailed Description
Intermediate 1: synthesis of 4, 7-dibromo- [1,3] dioxolane benzo [1,2-d ] thiazole
Figure BDA0002453959550000102
Step 1: synthesis of 7-bromobenzo [ d ] [1,3] dioxol-4-amine
Figure BDA0002453959550000103
To a solution of benzo [ d ] [1,3] dioxol-4-amine (1.0g) in N, N-dimethylformamide (20mL) was slowly added dropwise a solution of N-bromosuccinimide (1.4g) in N, N-dimethylformamide (10.0mL) at 0 ℃ and the reaction was continued at 0 ℃ for 1.0 hour after completion of the dropwise addition. The reaction solution was poured into 100mL of water, extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with saturated brine (100mL × 2) and dried over anhydrous sodium sulfate, filtered, and the ethyl acetate was removed by rotary evaporation, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate ═ 8:1) to give 7-bromobenzo [ d ] [1,3] dioxol-4-amine (1.2 g).
1H NMR(400MHz,CDCl3)：6.78(1H,d,J＝8.8Hz),6.2(1H,d,J＝8.8Hz),5.99(2H,s),3.42-3.76(2H,brs)。
Step 2: synthesis of 4-bromo- [1.3] dioxolo [4',5':5,6] benzo [1,2-d ] thiazol-7-amine
Figure BDA0002453959550000111
To a solution of 7-bromobenzo [ d ] [1,3] dioxol-4-amine (1.2g) and potassium thiocyanate (2.2g) in acetic acid (20mL) was slowly added dropwise a solution of bromine (0.3mL) in acetic acid (10.0mL) at room temperature, and the reaction was continued for 12 hours after the completion of the dropwise addition. The reaction mixture was poured into 200mL of water, extracted with ethyl acetate (50 mL. times.3), the organic phases were combined, the organic phase was washed with saturated brine (100 mL. times.2) and dried over anhydrous sodium sulfate, filtered and rotary evaporated to remove ethyl acetate, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate. RTM. 4:1) to give 4-bromo- [1.3] dioxolo [4',5':5,6] benzo [1,2-d ] thiazol-7-amine (1.4 g).
And step 3: synthesis of 4, 7-dibromo- [1,3] dioxolo [4',5':5,6] benzo [1,2-d ] thiazole
Figure BDA0002453959550000112
To a solution of 4-bromo- [1.3] dioxolo [4',5':5,6] benzo [1,2-d ] thiazol-7-amine (0.56g) and copper bromide (0.52g) in acetonitrile (20mL) at 0 ℃ was slowly added dropwise a solution of isoamyl nitrite (0.6mL) in acetonitrile (5.0mL), and after completion of the addition, the reaction mixture was slowly warmed to room temperature and the reaction was continued for 8.0 hours. The reaction mixture was poured into 100mL of water, extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with saturated brine (50mL × 2) and dried over anhydrous sodium sulfate, filtered and the ethyl acetate was removed by rotary evaporation, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate: 8:1) to give 4, 7-dibromo- [1,3] dioxolo [4',5':5,6] benzo [1,2-d ] thiazole (0.58 g).
1H NMR(400MHz,CDCl3)：7.42(1H,s),6.24(2H,s)。
Synthesis of the following intermediates with reference to the synthetic procedure shown for intermediate 1
Figure BDA0002453959550000113
The following intermediates were synthesized with reference to the synthetic procedure shown in WO2012087519
Figure BDA0002453959550000114
Figure BDA0002453959550000121
Example 1: synthesis of 7- ((1R,3R,5S) -3- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -8-azabicyclo [3.2.1] oct-8-yl) - [1,3] dioxolo [4',5':5,6] benzo [1,2-d ] thiazole-4-carboxylic acid
Figure BDA0002453959550000122
Step 1: synthesis of 4-bromo-7- ((1R,3R,5S) -3- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -8-azabicyclo [3.2.1] oct-8-yl) - [1,3] dioxolo [4',5':5,6] benzo [1,2-d ] thiazole
Figure BDA0002453959550000123
To a solution of 4- (((1R,3R,5S) -8-azabicyclo [3.2.1] oct-3-yloxy) methyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazole (0.25g) and 4, 7-dibromo- [1,3] dioxolo [4',5':5,6] benzo [1,2-d ] thiazole (0.22g) in N, N-dimethylformamide (20mL) was added potassium carbonate (0.21g) with stirring, and the mixture was heated to 60 ℃ for 2.0 hours. The reaction solution was poured into 100mL of water, extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, washed with saturated brine (50 mL. times.3) and dried over anhydrous sodium sulfate, filtered and the ethyl acetate was removed by rotary evaporation, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate. RTM.4: 1) to give 4-bromo-7- ((1R,3R,5S) -3- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -8-azabicyclo [3.2.1] oct-8-yl) - [1,3] dioxolo [4',5':5,6] benzo [1,2-d ] thiazole (0.35 g).
1H NMR(400MHz,CDCl3)：7.49-7.55(2H,m),7.35-7.41(2H,m),7.15(1H,s),6.10(2H,s),4.32(2H,s),4.19-4.28(2H,m),3.52(1H,t,J＝4.4Hz),2.04-2.13(3H,m),1.85-1.97(4H,m),1.72(2H,d,J＝14.8Hz),1.20-1.25(2H,m),1.08-1.13(2H,m)。
Step 2: synthesis of 4-cyano-7- ((1R,3R,5S) -3- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -8-azabicyclo [3.2.1] oct-8-yl) - [1,3] dioxolo [4',5':5,6] benzo [1,2-d ] thiazole
Figure BDA0002453959550000131
4-bromo-7- ((1R,3R,5S) -3- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -8-azabicyclo [3.2.1] oct-8-yl) - [1,3] dioxolo [4',5':5,6] benzo [1,2-d ] thiazole (0.35g), zinc cyanide (0.15g) and tetratriphenylphosphine palladium (0.03g) were added to N, N-dimethylformamide (50mL) in this order under nitrogen, and the mixture was heated to 110 ℃ under nitrogen for 8.0 hours. The reaction solution was cooled to room temperature, poured into 100mL of water, extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, washed with saturated brine (50 mL. times.3) and dried over anhydrous sodium sulfate, filtered and rotary-evaporated to remove ethyl acetate, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate. RTM. 4:1) to give 4-cyano-7- ((1R,3R,5S) -3- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -8-azabicyclo [3.2.1] oct-8-yl) - [1,3] dioxolo [4',5':5,6] benzo [1,2-d ] thiazole (0.23 g).
And step 3: synthesis of 7- ((1R,3R,5S) -3- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -8-azabicyclo [3.2.1] oct-8-yl) - [1,3] dioxolo [4',5':5,6] benzo [1,2-d ] thiazole-4-carboxylic acid
Figure BDA0002453959550000132
To a solution of 4-cyano-7- ((1R,3R,5S) -3- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -8-azabicyclo [3.2.1] oct-8-yl) - [1,3] dioxolo [4',5':5,6] benzo [1,2-d ] thiazole (0.23g) in methanol and water (4:1,25mL) was added sodium hydroxide (0.06g), and the mixture was heated under reflux for 12.0 hours. The reaction mixture was cooled to room temperature and then the pH of the reaction mixture was adjusted to 5 with 1N hydrochloric acid, the mixture was concentrated, cooled to room temperature, filtered and dried under vacuum to give 7- ((1R,3R,5S) -3- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -8-azabicyclo [3.2.1] oct-8-yl) - [1,3] dioxolo [4',5':5,6] benzo [1,2-d ] thiazole-4-carboxylic acid (0.11 g).
1H NMR(400MHz,DMSO-d6)：12.74(1H,s),7.74(1H,s),7.66-7.73(2H,m),7.57-7.64(2H,m),6.17(2H,s),4.38(2H,s),4.16-4.31(2H,m),3.57-3.63(1H,m),2.35-2.42(1H,m),1.98-2.07(2H,m),1.82-1.94(4H,m),1.78(2H,d,J＝14.2Hz),1.09-1.23(4H,m)。
The following examples are synthesized by reference to the procedure set forth in example 1
Figure BDA0002453959550000141
Figure BDA0002453959550000151
Experimental example 1 determination of FXR activation activity by compounds:
HepG2 cells are human liver cancer cells, FXR (Farnesoid X Receptor ) is a bile acid-activated nuclear Receptor, and fxre (FXR response element) is the response element of FXR. We constructed a HepG2 cell line overexpressing both the FXR and FXRE-luciferase reporter genes. A screening method of FXR activation activity of the compound in FXRE/FXR/HepG2 cells is established by adopting a Brigh-Glo luciferase detection system (Promega) of Promega company.
FXRE/FXR/HepG2 cells were cultured in 75cm of DMEM (Biological Industries) medium containing 10% fetal bovine serum (Biological Industries) and 0.2mg/ml G418(Merck)2Culturing was carried out in a plastic tissue culture flask (Corning) (37 ℃, 95% air and 5% CO)2) And passage 2-3 times a week.
The cells were seeded at 40000 cells/well (195. mu.L) in a 96-well cell culture plate (Corning) and cultured in a cell culture incubator. The next day the test compound was added: compounds were diluted in DMSO in 5-fold gradients starting at 10mM (in DMSO) for 10 concentrations, 2. mu.L of each was added to 48. mu.L of serum-free DMEM medium, and finally 5. mu.L of the diluted compounds was added to the cell-seeded plates. The final concentration of DMSO in the cell culture broth was 0.1%, and the final concentration of the test compound was 0.00512 nM-10. mu.M.
Co-incubating the compound and cells in an incubator for 40 hours, adding a Brigh-Glo luciferase detection reagent, reading a chemiluminescence signal by envision (Perkin Elmer), processing data by GraphPad Prism software, and calculating to obtain the semi-activation concentration of the compound to FXR in the cells, namely EC50The value is obtained.
Figure BDA0002453959550000161
。
Experimental example 2 pharmacokinetic data
Male SD rats are from Beijing Wittingle laboratory animal technology, Inc., the rats are grouped into 3 groups, and the suspension (5mg/kg, solvent: 1.0% CMC-Na, 0.25% Tween 80, 0.05% dimethicone aqueous solution) of the sample to be tested is respectively orally taken for single gavage. Animals were fasted overnight prior to the experiment, with the fasting time ranging from 10 hours prior to dosing to 4 hours post-dosing. Blood was collected at 0.25, 0.5, 1,2, 4, 6, 8, and 24 hours post-dose. After isoflurane anesthesia by using a small animal anesthesia machine, 0.3mL of whole blood is collected through an eyeground venous plexus, the whole blood is placed in a heparin anticoagulation tube, a sample is centrifuged at 4000rpm and 4 ℃ for 5 minutes, and the plasma is transferred to a centrifuge tube and stored at-80 ℃ until analysis. Samples from plasma were extracted using protein precipitation and the extracts were analyzed by LC/MS/MS.
Figure BDA0002453959550000162
。

Claims (10)

1. A compound of formula I:
Figure FDA0002453959540000011
wherein the content of the first and second substances,
R1is selected from C1-6Alkyl or C3-10Cycloalkyl radical, said C1-6Alkyl orC3-10Cycloalkyl is optionally substituted with 1-3 halogens, OH or CN;
R2selected from halogen, CN, NH2、C1-6Alkyl radical, C1-6Alkoxy radical, C3-10Cycloalkyl radical, C3-10Cycloalkyloxy, -NHC1-6Alkyl or-N (C)1-6Alkyl radical)2Said C is1-6Alkyl radical, C1-6Alkoxy radical, C3-10Cycloalkyl, or C3-10Cycloalkoxy optionally substituted by 1-3 halogens, CN, NH2Or OH substitution;
n is selected from 1,2, 3 or 4;
R31or R32Each independently selected from H, -CO2H、-CO2C1-6Alkyl, OH substituted C1-6Alkyl-, -CONH2、-CONHC1-6Alkyl or-CON (C)1-6Alkyl radical)2；
Ring A is selected from 3-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, ring A is optionally substituted with 1-3R, each independently selected from halogen, CN, OH, NH2、C1-6Alkyl or C1-6An alkoxy group.
2. A compound of formula I according to claim 1, wherein R is1Is selected from C1-3Alkyl or C3-6Cycloalkyl radical, said C1-3Alkyl or C3-6Cycloalkyl is optionally substituted with 1-3 halogens, OH or CN;
or, wherein R1R is as defined above1Is selected from C3-4Cycloalkyl radical, said C3-4Cycloalkyl is optionally substituted with 1-3 of F, Cl, Br, OH or CN;
or, wherein R1Is selected from C3-4A cycloalkyl group;
or, wherein R is as defined above1Selected from cyclopropyl.
3. A compound of formula I according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2Selected from halogen, CN, NH2、C1-3Alkyl radical, C1-3Alkoxy radical, C3-6Cycloalkyl radical, C3-6Cycloalkyloxy, -NHC1-3Alkyl or-N (C)1-3Alkyl radical)2Said C is1-3Alkyl radical, C1-3Alkoxy radical, C3-6Cycloalkyl radical, C3-6Cycloalkyloxy optionally substituted with 1-3 halogens, CN, NH2Or OH substitution;
or, wherein R2Selected from F, Cl, Br, C1-3Alkyl or C1-3Alkoxy radical, said C1-3Alkyl or C1-3Alkoxy is optionally substituted with 1-3 of F, Cl or Br;
or, wherein R2Selected from F, Cl, Br, methyl substituted by 1-3 of F, Cl and Br or methoxy substituted by 1-3 of F, Cl and Br;
or, wherein R2Selected from chloro, trifluoromethyl or trifluoromethoxy;
optionally, said n is selected from 1,2 or 3;
or, wherein n is selected from 1 or 2, optionally R2Ortho to the C atom to which the isoxazole is attached.
4. A compound of formula I according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R31Or R32Each independently selected from H, -CO2H、-CO2C1-3Alkyl, OH substituted C1-3Alkyl-, -CONH2、-CONHC1-3Alkyl or-CON (C)1-3Alkyl radical)2；
Or, wherein R31Is selected from H;
or, wherein R32Is selected from-CO2H。
5. A compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from 3-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S;
or wherein ring a is selected from 4-, 5-, 6-, 7-membered heterocycloalkyl, said ring a containing 1 or 2 heteroatoms selected from N, O or S;
or, wherein ring a is selected from 5-or 6-membered heterocycloalkyl, said ring a containing 1 or 2O atoms, wherein the substituents of ring a are as defined in claim 1, optionally the heteroatoms of ring a are in a position directly attached to the C atom of the phenyl ring;
wherein the substituents of the above ring A are as defined in claim 1;
alternatively, ring a is selected from the following structures:
Figure FDA0002453959540000021
6. a compound of formula I according to any one of claims 1 to 5, wherein R is each independently selected from halogen, CN, OH, NH2、C1-3Alkyl or C1-3An alkoxy group;
or, wherein R is independently selected from F, Cl, Br, CN, OH or NH2。
7. A compound of formula I according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, selected from compounds of formula I ', formula II ', formula III or formula III ', or a pharmaceutically acceptable salt thereof:
Figure FDA0002453959540000022
wherein a compound of formula II, formula II ', formula III or formula III' or a pharmaceutically acceptable salt thereof, said X1、X3Or X4Are each independently selected from-NH-, -N (R) -, O, S, -CH2-, -CH (R) -, or-C (RR) -; x2Selected from a single bond, -NH-, O, S, or-CH2-；
Or, wherein X1、X3Or X4Each independently selected from O, S, -CH2-, -CH (R) -, or-C (RR) -;
or, wherein X is as defined above1Or X4Each independently selected from O, S or-CH2-；
Or, wherein X3Is selected from-CH2-or-c (rr) -;
or, wherein X3Is selected from-CH2-or-C (RR) -, wherein R is each independently selected from F, Cl, Br, CN, OH or NH2；
Or, wherein X3Is selected from-CH2-or-CF2-；
Or, wherein X2Selected from single bond or-CH2-。
8. The following compounds or pharmaceutically acceptable salts thereof:
Figure FDA0002453959540000031
alternatively, the following compounds or pharmaceutically acceptable salts thereof:
Figure FDA0002453959540000032
9. a pharmaceutical composition comprising a compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof.
10. Use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment of various disorders associated with the farnesoid X receptor.
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Title
DAVID C, TULLY;PAUL V, RUCKER;DONATELLA, CHIANELLI;JENNIFER, WILLIAMS;AGNES, VIDAL;PHIL B, ALPER;DANIEL, MUTNICK;BADRY, BURSULAYA;: "Discovery of Tropifexor (LJN452), a Highly Potent Non-Bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH).", JOURNAL OF MEDICINAL CHEMISTRY *

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