CN117624154A - Bicyclic pyridone compounds and application thereof - Google Patents

Bicyclic pyridone compounds and application thereof Download PDF

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CN117624154A
CN117624154A CN202311769408.0A CN202311769408A CN117624154A CN 117624154 A CN117624154 A CN 117624154A CN 202311769408 A CN202311769408 A CN 202311769408A CN 117624154 A CN117624154 A CN 117624154A
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independently selected
compound
och
alkyl
alkoxy
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张盛彬
于涛
吴成德
刘金鑫
黎健
陈曙辉
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Medshine Discovery Inc
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

A dicyclopyridone compound and application thereof, in particular discloses a compound shown in a formula (I) and pharmaceutically acceptable salts thereof.

Description

Bicyclic pyridone compounds and application thereof
The patent application is a divisional application of a patent application with the application number of 202280016736.0, the application date of the patent application is 2022, 03 and 18, and the patent application is named as a double-ring pyridone compound and application thereof.
The present application claims priority as follows
CN202110299530.0, filing date: 2021, 03, 19;
CN202110443443.8, filing date: 2021, 04, 23.
Technical Field
The invention relates to a bicyclic pyridone compound and application thereof, and in particular discloses a compound shown in a formula (I) and pharmaceutically acceptable salts thereof.
Background
Thyroid hormones play an important role in growth, differentiation, development and maintenance of metabolic balance. Its physiological action is via thyroid hormone receptors. Thyroid Hormone (THR) has two subtypes: thrα and thrβ. Thrα is distributed mainly in brain, heart and skeletal muscle, and can control heart rate. Thrβ is widely distributed in various tissues, mainly in the liver, brain, and less in the heart. It is involved in energy metabolism and is the primary receptor for lipid metabolism and sugar metabolism. Over the past decades, a variety of thrβ agonists have been developed for the treatment of metabolic diseases such as dyslipidemia, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, for example: GC-1, KB141, KB2115, and the like. However skeletal and cardiac side effects have prevented their further development, e.g., KB2115 stopped the three-phase clinical study due to cartilage damage found in dogs). These side effects are thought to be due to agonism of the thrα subtype and thus are desirably avoided by increasing target selectivity and liver tissue selectivity. A representative variety of this strategy is MGL-3196, which has entered clinical stage three, and safety and efficacy have been further demonstrated. Therefore, the development of thyroid hormone analogs with high liver tissue distribution specificity and thyroid hormone receptor subtype selectivity has great clinical value.
Based on literature (j.med.chem.2014, 57, 39123923) it is reported that the thrβ agonist MGL-3196 has the structure:
disclosure of Invention
The invention provides a compound shown as a formula (I) or pharmaceutically acceptable salt thereof,
wherein,
R 1 independently selected from H and C 1-3 Alkyl, said C 1-3 Alkyl is optionally substituted with 1,2 or 3R a Substitution;
R 2 and R is 3 Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CN、C 1-3 Alkyl and C 1-3 Alkoxy group, the C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1,2 or 3R b Substitution;
l is selected from-O-, -C (=O)、-S-、-S(＝O) 2 、-S(＝O)-、-C(R 4 ) 2 -sum of
Each R is 4 Are respectively and independently selected from H, C 1-3 Alkyl and C 1-3 Alkoxy group, the C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1,2 or 3R c Substitution;
ring A is selected from phenyl, 5-6 membered heteroaryl, and,And->Said phenyl, 5-6 membered heteroaryl, -/->And->Optionally by 1,2 or 3R d Substitution;
n and m are each independently selected from 0, 1 and 2;
R a 、R b and R is c Each independently selected from F, cl, br and I;
each R is d Are independently selected from F, cl, br, I, =o, =n-C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Alkoxy, said = N-C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1,2 or 3R;
r is independently selected from F, cl, br and I;
when ring a is phenyl or 6 membered heteroaryl, L is selected from-C (=o) -, -S (=o) 2 、-S(＝O)-、-C(R 4 ) 2 -sum of
The invention provides a compound shown as a formula (I) or pharmaceutically acceptable salt thereof,
wherein,
R 1 independently selected from H and C 1-3 Alkyl, said C 1-3 Alkyl is optionally substituted with 1,2 or 3R a Substitution;
R 2 and R is 3 Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CN、C 1-3 Alkyl and C 1-3 Alkoxy group, the C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1,2 or 3R b Substitution;
l is selected from-O-, -C (=O) -, -S (=O) 2 、-S(＝O)-、-C(R 4 ) 2 -sum of
R4 is independently selected from H, C 1-3 Alkyl and C 1-3 Alkoxy group, the C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1,2 or 3R c Substitution;
ring A is selected from phenyl, 5-6 membered heteroaryl, and,And->Said phenyl, 5-6 membered heteroaryl, -/->And->Optionally by 1,2 or 3R d Substitution;
n and m are each independently selected from 0, 1 and 2;
R a 、R b and R is c Each independently selected from F, cl, br and I;
R d independently selected from F, cl, br, I, =o, =n-C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Alkoxy, said = N-C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1,2 or 3R;
r is independently selected from F, cl, br and I.
The invention provides a compound shown as a formula (I) or pharmaceutically acceptable salt thereof,
wherein,
R 1 independently selected from H and C 1-3 Alkyl, said C 1-3 Alkyl is optionally substituted with 1,2 or 3R a Substitution;
R 2 and R is 3 Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CN、C 1-3 Alkyl and C 1-3 Alkoxy group, the C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1,2 or 3 Rb;
l is selected from O, -C (R) 4 ) 2 And
R 4 independently selected from H, C 1-3 Alkyl and C 1-3 Alkoxy group, the C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1,2 or 3R c Substitution;
ring A is selected from phenyl, 5-6 membered heteroaryl, and,And->Said phenyl, 5-6 membered heteroaryl, -/->And->Optionally by 1,2 or 3R d Substitution;
n and m are each independently selected from 0, 1 and 2;
R a 、R b and R is c Each independently selected from F, cl, br and I;
R d independently selected from F, cl, br, I, =o, =n-C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Alkoxy, said = N-C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1,2 or 3R;
r is independently selected from F, cl, br and I.
In some aspects of the invention, R is as described above 1 Independently selected from H and CH 3 The CH is 3 Optionally by 1,2 or 3R a Instead, the other variables are as defined herein.
In some aspects of the invention, R is as described above 1 Independently selected from H, CH 3 And CF (compact F) 3 The other variables are as defined herein.
In some aspects of the invention, R is as described above 2 And R is 3 Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CN、CH 3 And OCH 3 The CH is 3 And OCH 3 Optionally by 1,2 or 3R a Instead, the other variables are as defined herein.
In some aspects of the invention, R is as described above 2 And R is 3 Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CN、CH 3 、CH 2 F、CHF 2 、CF 3 And OCH 3 The other variables are as defined herein.
In some aspects of the invention, R is as described above 4 Independently selected from H, CH 3 、OCH 3 And OCH 2 CH 3 The CH is 3 、OCH 3 And OCH 2 CH 3 Optionally by 1,2 or 3R c Instead, the other variables are as defined herein.
In some embodiments of the invention, R4 is independently selected from H, CH 3 、OCH 3 And OCH 2 CH 3 The other variables are as defined herein.
In some embodiments of the invention, L is selected from the group consisting of-O-, -CH 2 -、-C(OCH 2 CH 3 ) 2 -sum ofThe other variables are as defined herein.
In some aspects of the invention, rd is independently selected from F, cl, br, I, =o, =n-O-CH 3 、＝N-O-CH 2 CH 3 、CH 3 、OCH 3 And OCH 2 CH 3 The = N-O-CH 3 、＝N-O-CH 2 CH 3 、CH 3 、OCH 3 And OCH 2 CH 3 Optionally substituted with 1,2 or 3R, and the other variables are as defined herein.
In some aspects of the invention, R is as described above d Independently selected from F, cl, br, I, =o, =n-O-CH 3 、＝N-O-CH 2 CH 3 、CH 3 、OCH 3 And OCH 2 CH 3 The other variables are as defined herein.
In some embodiments of the invention, the ring A is selected from And->Said-> Optionally substituted with 1,2 or 3 Rd, and the other variables are as defined herein.
In some embodiments of the invention, the ring A is selected from The other variables are as defined herein.
In some embodiments of the invention, the ring A is selected from The other variables are as defined herein.
Still other embodiments of the present invention are derived from any combination of the variables described above.
The invention also provides a compound shown in the following formula or pharmaceutically acceptable salt thereof,
the invention also provides the following synthesis method: method 1:
method 2:
method 3:
method 4:
the invention also provides a testing method as follows:
cytochrome P450 isoenzyme inhibition studies
The purpose of the experiment is as follows:
the inhibitory effect of the test compound on the activity of human liver microsomal cytochrome P450 isozymes (CYP 1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3 A4) was measured.
Experimental operation:
firstly, diluting a tested compound (10.0 mM), preparing a working solution (100 times the final concentration), wherein the working solution concentration is 1.00mM, and simultaneously preparing working solutions of positive inhibitors and specific probe substrates of P450 isozymes (CYP 1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (using midazolam as a probe substrate) and CYP3A4 (using testosterone as a probe substrate) respectively; the human liver microsomes stored in a refrigerator below-60 ℃ are placed on ice for thawing, and when the human liver microsomes are completely dissolved, PB is used for dilution, so that working solution (0.127 mg/m 1) with a certain concentration is prepared. Firstly, adding 20.0 mu L of probe substrate into a reaction plate (20.0 mu LPB is added into a Blank hole), then adding 158 mu L of human liver microsome working solution into the reaction plate, and placing the reaction plate on ice for standby; at this point 2.00 μl of test compound (n=1) and specific inhibitor (n=2) were added to the corresponding wells, no inhibitor (test compound or positive inhibitor) group was added to the corresponding organic solvent, and the test compound control sample and positive control sample organic phases were 1:1 DMSO: meOH and 1:9 DMSO: meOH; after pre-incubation in a 37 ℃ water bath for 10min, 20.0 μl of coenzyme factor (NADPH) solution was added to the reaction plate for 3 min for the CYP3A4 metabolic reaction with midazolam as probe substrate; CYP2C19 reaction with (S) -mefenadine as a probe substrate and CYP2D6 reaction with dextromethorphan as a probe substrate are carried out for 20 minutes, and the rest reactions are all carried out for 10 minutes; then 400. Mu.L of pre-chilled acetonitrile solution (containing 200ng/mL of Tolbutamide and Labetalol internal standard) was added to terminate the reaction; placing the reaction plate in a shaking table, and uniformly mixing for 10min; then centrifuging at 4 ℃ and 4000rpm for 20min; 200 mu L of supernatant is added into 100 mu L of water to dilute the sample; finally sealing the plates, oscillating, shaking uniformly, and carrying out LC/MS/MS detection.
In vivo pharmacodynamic studies
The purpose of the experiment is as follows:
and detecting the in vivo efficacy of the compound to be detected by using a rat model induced by cholesterol cholic acid added with feed.
The experimental method comprises the following steps:
male SD rats 9-10 weeks old were selected and adapted 3-7 days after reaching the facility. During the acclimation period, animals were observed daily for health and provided normal feed. After the adaptation period is finished, the solvent control group and the tested compound group are fed with high cholesterol (1.5% cholesterol and 0.5% cholic acid) feed for molding, the solvent is 0.5% sodium carboxymethyl cellulose+0.2% Tween 80 aqueous solution, and rats in the blank control group are continuously fed with normal feed. After two weeks of feeding rats with high cholesterol diet, blood was collected and serum was isolated to detect LDL-C levels. High cholesterol model rats were randomized according to serum LDL-C levels and then orally administered for 7 consecutive days once daily. One week after administration, serum from rats was collected to detect LDL-C levels and the efficacy was evaluated.
Definition and description
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The term "pharmaceutically acceptable" as used herein 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.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts including acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.
Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.
Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" is caused by the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely.
Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers of a molecule having two or more chiral centers and having a non-mirror relationship between the molecules.
Unless otherwise indicated, "(+)" means dextrorotation, "(-)" means levorotatory, "(±)" means racemization.
Unless otherwise indicated, with solid wedge bondsAnd wedge-shaped dotted bond->Representing the absolute configuration of a solid centre, using straight solid keys +.>And straight dotted bond->Representing the relative configuration of the stereo centers, using wavy lines +.>Representing a wedge solid key +.>Or wedge-shaped dotted bond->Or by wave lines->Representing a straight solid line key->And straight dotted bond->
Unless otherwise indicated, when there is a double bond structure in a compound, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is attached to two different substituents (of the double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is considered as one substituent to which it is attached), if a wavy line is used between the atom on the double bond and its substituent in the compoundThe term "attached" means the (Z) isomer, (E) isomer or a mixture of both isomers of the compound. The compound represented by the following formula (A) exists in the form of a single isomer of formula (A-1) or formula (A-2) or in the form of a mixture of two isomers of formula (A-1) and formula (A-2); the compound represented by the following formula (B) exists in the form of a single isomer of the formula (B-1) or the formula (B-2)In the form of a mixture of two isomers of formula (B-1) and formula (B-2). The following formula (C) represents that the compound exists as a single isomer of formula (C-1) or formula (C-2) or as a mixture of both isomers of formula (C-1) and formula (C-2).
Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to the fact that at room temperature, different functional group isomers are in dynamic equilibrium and are capable of rapid interconversion. If tautomers are possible (e.g., in solution), chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as proton tautomers) (prototropic tautomer) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence isomer (valance tautomer) includes the interconversion by recombination of some of the bond-forming electrons. A specific example of where keto-enol tautomerization is the interconversion between two tautomers of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one.
Unless otherwise indicated, the terms "enriched in one isomer", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100% and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or enantiomers. For example, where one isomer or enantiomer is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomer excess (ee value) is 80%.
Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods well known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).
The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite For example, deuterium can be substituted for hydrogen to form a deuterated drug, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, so that the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life of the drug and the like compared with the non-deuterated drug. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, which may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =o), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on the aromatic group.
The term "optionally substituted" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.
When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.
When the number of one linking group is 0, such as- (CRR) 0 -it is meant that the linking group is a single bond.
When one of the variables is selected from a single bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in A-L-Z represents a single bond, it is indicated that the structure is actually A-Z.
When a substituent is absent, it is meant that the substituent is absent, e.g., X in A-X is absent, meaning that the structure is actually A. When the listed substituents do not indicate which atom is attached to the substituted group, such substituents may be bonded through any atom thereof, for example, a pyridyl group may be attached to the substituted group as a substituent through any carbon atom on the pyridine ring.
When the exemplified linking group does not indicate its linking direction, its linking direction is arbitrary, for example,the linking group L is-M-W-, in which case-M-W-may be a group in which the linking rings A and B are linked in the same direction as the reading order from left to right>It is also possible to connect the ring A and the ring B in the opposite direction to the reading order from left to right>Combinations of such linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
Unless otherwise specified, when a group has one or more bondable sites, any one or more of the sites of the group may be bonded to other groups by chemical bonds. When the connection mode of the chemical bond is not positioned and the H atoms exist in the connectable site, the number of the H atoms of the site can be correspondingly reduced to be changed into the corresponding valence group along with the number of the connected chemical bond when the chemical bond is connected. The chemical bond of the site and other groups can be a straight solid line bondStraight dotted line key->Or wave line->And (3) representing. For example-OCH 3 The straight solid line bond in (a) represents the connection to other groups through the oxygen atom in the group; />The straight dashed bonds in (a) represent the attachment to other groups through both ends of the nitrogen atom in the group; />The wavy line means that the carbon atoms at positions 1 and 2 in the phenyl group are attached to other groups;it means that any of the ligatable sites on the piperidinyl group may be attached to other groups by 1 chemical bond, including at leastThese 4 connection forms, even though the H atom is depicted on-N-, are +.>Still include->The group of this linkage is only when 1 chemical bond is linked, the H at this site will be correspondingly reduced by 1 to the corresponding monovalent piperidinyl group.
Unless otherwise specified, the term "C 1-3 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C is 1-3 Alkyl includes C 1-2 And C 2-3 Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
Unless otherwise specified, the term "C 1-3 Alkoxy "means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through one oxygen atom. The C is 1-3 Alkoxy includes C 1-2、 C 2-3 、C 3 And C 2 Alkoxy groups, and the like. C (C) 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
The terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" are used interchangeably herein unless otherwise specified, the term "5-6 membered heteroaryl" meaning a monocyclic group having a conjugated pi-electron system consisting of 5 to 6 ring atoms, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms. Wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p P is 1 or 2). The 5-6 membered heteroaryl group may be attached to the remainder of the molecule through a heteroatom or carbon atom. The 5-6 membered heteroaryl groups include 5-and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1, 2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furanyl (including 2-furanyl, 3-furanyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 4-pyridyl, etc.), pyrimidyl (including 2-pyridyl, 4-pyrimidyl, etc.), or pyrimidine (including 2-pyridyl, 4-pyridyl, etc.).
Unless otherwise specified, C n-n+m Or C n -C n+m Comprising any one of the specific cases of n to n+m carbons, e.g. C 1-12 Comprises C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 、C 11 And C 12 Also included is any one of the ranges n to n+m, e.g. C 1-12 Comprises C 1-3、 C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 And C 9-12 Etc.; similarly, n-membered to n+m-membered means that the number of atoms on the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and any one of n to n+m is also included, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-8-membered ring, 6-10-membered ring, and the like.
The compounds of the invention may be structurally verified by conventional methods well known to those skilled in the art if the invention relates to the absolute nature of the compoundsFor configuration, the absolute configuration can be confirmed by means conventional in the art. For example, single crystal x-ray diffraction (SXRD), the grown single crystal is collected from diffraction intensity data using a Bruker D8 vent diffractometer, and the light source is cukα radiation, scanning:after scanning and collecting the relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by a direct method (Shellxs 97).
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
The solvent used in the present invention is commercially available. The invention adopts the following abbreviations: aq represents water; eq represents equivalent, equivalent; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N, N-dimethylformamide; DMSO represents dimethylsulfoxide; etOAc represents ethyl acetate; etOH stands for ethanol; meOH represents methanol; r.t. stands for room temperature; O/N stands for overnight; THF represents tetrahydrofuran; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine; TEA stands for triethylamine.
Compounds are either prepared according to the general nomenclature of the art or are usedSoftware naming, commercial compounds are referred to by vendor catalog names.
Technical effects
The compound has obvious THRbeta activity and selectivity; the compounds of the invention have excellent pharmacokinetic properties; the compounds of the present invention have no drug-drug interactions; the compounds of the present invention significantly reduce plasma LDL-C levels in rats.
Drawings
Fig. 1: prediction of the binding pattern of Compound A with MGL-3196;
fig. 2: prediction of the binding pattern of compound B with MGL-3196;
fig. 3: prediction of the binding pattern of compound C with MGL-3196;
fig. 4: compound D and MGL-3196 binding patterns were predicted.
Detailed Description
The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention.
Calculation example 1
Molecular docking process: by using MaestroGlideSP [1 ] in version 2017-2)]And default options. MGL-3196 was chosen as the docking template. For the preparation of proteins Maestro [2 ] was used]The protein preparation of (2) adds hydrogen atoms to the guide module and uses the OPLS3 force field. For ligand preparation, 3D structures were generated and energy minimization was performed using LigPrep [3]. Ligand cardiogenesis using 1Q4X crystal structure->And (5) butting the grids. By indictFitDocking, the amino acid side chains within 5A of the ligand center are constrained to move in the B factor range, creating a complex model. The ligand is then removed and the example compound is placed during molecular docking. The type of interaction of the protein receptor with the ligand is analyzed, and then a reasonable docking conformation is selected and preserved based on the calculated docking score and globalsain values. The binding mode of the compounds A-D and MGL-3196 is shown in the accompanying figures 1-4.
[1]Glide，LLC，New York，NY，2017.
[2]Maestro，LLC，New York，NY，2017.
[3]LigPrep，LLC，New York，NY，2017.
Conclusion: the compound of the invention has better combination with THR beta protein. The compound occupies a binding pocket of THRbeta and thyroxine, which is a closed, hydrophobic pocket consisting of multiple layers of alpha helices, above which is a positively charged sub-pocket consisting of three arginines (Arg 282, arg316 and Arg 320). The 6-azauracil acid group of the original reference compound MGL-3196 is bound in this sub-pocket, cyano groups form hydrogen bonds with Arg316, carbonyl groups and nitrogen atoms of 6-azauracil form hydrogen bonds with Arg320, and carbonyl oxygen of pyridazinone forms hydrogen bonds with His 435. The middle benzene ring, the terminal pyridazinone and the isopropyl group all can form hydrophobic interactions with surrounding amino acids. The polar head of the compound 1,2, 4-oxadiazolin-5-ketone is combined in the sub-pocket, and also forms hydrogen bonds with three arginines, so that dichlorobenzene angles are improved through amide, halogen bonds are more easily formed with Phe272, carbonyl or hydroxyl at the tail can form hydrogen bonds through interaction with His435, and the ring effectively provides hydrophobic interaction. Has better selectivity.
Example 1
The synthetic route is as follows:
step 1: synthesis of Compound WX001-2
In a dry reaction flask, WX001-1 (5 g,37.85mmol,1 eq), 1, 4-dioxane (50 mL), 1-cyclohexyl-2-morpholinoethyl carbodiimide p-toluenesulfonate (6.75 g,41.63mmol,1.1 eq) and DBU (6.34 g,41.63mmol,6.27mL,1.1 eq) were added in sequence, the reaction was warmed to 80℃and stirred for 2 hours. After completion of the reaction, water (100 mL) was added for dilution, 1N HCl was added for pH adjustment to 3-4, ethyl acetate (3 x 100 mL) was added for extraction, and the organic phase was collected after separation. The organic phase was washed with saturated brine solution (100 ml×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give WX001-2. 1 H NMR (400 MHz, deuterated chloroform) δ4.51 (q, j=7.1 hz, 2H), 1.45 (t, j=7.1 hz, 3H).
Step 2: synthesis of Compound WX001-3
In a dry reaction flask, WX001-2 (1 g,6.32mmol,1 eq), water (2 mL), ethanol (10 mL) and lithium hydroxide monohydrate (318.49 mg,7.59mmol,2 eq) were added in sequence and the reaction was stirred for 1 hour at 20deg.C. After the reaction was completed, water (20 mL) was added to the reaction mixture to dilute the mixture, 2M hydrochloric acid was added to adjust the pH to 4 to 6, ethyl acetate (30 ml×3) was added to extract the mixture, and an organic phase was collected after separation. To the aqueous phase was added 2M hydrochloric acid to adjust pH to 1, extracted with ethyl acetate (30 ml x 3), chloroform: isopropyl alcohol=3:1 (30 ml×18) extraction, separating the liquid, collecting the organic phase, drying over anhydrous sodium sulfate, concentrating under reduced pressure to obtain WX001-3.
Step 3: synthesis of Compound WX001-4
In a dry reaction flask, WX001-3 (100 mg, 768.88. Mu. Mol,1 eq), THF (1 mL), oxalyl chloride (117.11 mg, 922.66. Mu. Mol, 80.77. Mu.L, 1.2 eq) and DMF (5.62 mg, 76.89. Mu. Mol, 5.92. Mu.L, 0.1 eq) were added in this order and stirred at 20℃for 1 hour. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure to give WX001-4.
Step 4: synthesis of Compound WX001-7
In a dry reaction flask, WX001-5 (5 g,24.62mmol,1 eq), WX001-6 (5.83 g,32.75mmol,1.33 eq), N, N-dimethylacetamide (50 mL) and cesium carbonate (16) were added sequentially04g,49.24mmol,2 eq), warmed to 80℃and stirred for 10 hours. After completion of the reaction, water (100 mL) was added for dilution, ethyl acetate (100 mL x 3) was added for extraction, and the organic phase was collected after separation. The organic phase was washed successively with saturated brine solution (100 ml×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=1:0 to 2:1) to give WX001-7. 1 H NMR (400 MHz, deuterated chloroform) delta 6.66 (s, 2H), 2.87-2.83 (m, 2H), 2.77-2.69 (m, 2H), 1.92-1.88 (m, 4H).
Step 5: synthesis of Compound WX001-8
In a dry reaction flask, naOH (16.25 g,406.24mmol,20 eq) and water (70 mL), DMSO (70 mL), WX001-7 (7 g,20.31mmol,1 eq) were added, warmed to 120℃and stirred for 2 hours. After completion of the reaction, water (100 mL) was added for dilution, ethyl acetate (100 mL x 3) was added for extraction, and the organic phase was collected after separation. The organic phase was dried over saturated aqueous saline (100 ml x 3), anhydrous sodium sulfate and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=1:0 to 2:1) to give WX001-8. 1 H NMR (400 MHz, deuterated chloroform) delta 6.67 (s, 2H), 2.84-2.52 (m, 4H), 1.93-1.71 (m, 4H).
Step 6: synthesis of Compound WX001
A solution of WX001-8 (150.34 mg, 460.91. Mu. Mol,1 eq), THF (2 mL), TEA (139.92 mg,1.38mmol, 192.46. Mu.L, 3 eq) and WX001-4 (102.67 mg, 691.36. Mu. Mol,1.5 eq) in THF (2 mL) were added in this order and stirred at 20℃for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by a high performance liquid chromatography (column: phenomenex Gemini-NX 80. Times.40 mM. Times.3 μm; mobile phase: water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile%: 10% -40%,8 minutes) to give WX001. 1 H NMR (400 MHz, deuterated methanol) delta 7.92 (s, 2H), 2.79-2.74 (m, 2H), 2.59-2.54 (m, 2H), 1.89-1.85 (m, 4H). MS-ESI m/z:436.4[ M-H ]] - 。
Example 2
The synthetic route is as follows:
step 1: synthesis of Compound WX002-2
In a dry reaction flask, WX002-1 (1.18 g,7.97mmol,2.6 eq), WX001-8 (1 g,3.07mmol,1 eq), DMF (10 mL) and TEA (620.46 mg,6.13mmol, 853.45. Mu.L, 2 eq) were added sequentially, warmed to 100deg.C and stirred for 10 hours. After the reaction was completed, water (50 mL) was added to the mixture to slurry, and the mixture was filtered, washed with cake water (10 ml×2) and concentrated under reduced pressure to obtain WX002-2. 1 H NMR (400 MHz, deuterated chloroform) δ9.46 (br s, 1H), 7.99 (dd, j=3.0, 5.4hz, 2H), 7.85 (dd, j=3.1, 5.4hz, 2H), 7.60 (s, 2H), 2.77 (br s, 2H), 2.63 (br s, 2H), 1.89-1.84 (m, 4H).
Step 2: synthesis of Compound WX002-3
In a dry reaction flask, WX002-2 (300 mg, 654.60. Mu. Mol,1 eq), DMF (12 mL), potassium carbonate (180.95 mg,1.31mmol,2 eq) and methyl iodide (185.83 mg,1.31mmol, 81.50. Mu.L, 2 eq) were added in this order and stirred at 20℃for 10 hours. After the reaction was completed, water (20 mL) was added for dilution, ethyl acetate (20 ml×3) was added for extraction, and after separation, the organic phase was collected, and dried sequentially with saturated saline solution (20 ml×3), anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM: meOH=20:1) to give WX002-3. 1 H NMR (400 MHz, deuterated chloroform) delta 8.04-7.96 (m, 2H), 7.90-7.80 (m, 2H), 7.60 (s, 2H), 3.53 (s, 3H), 2.80-2.58 (m, 4H), 1.90-1.78 (m, 4H).
Step 3: synthesis of Compound WX002-4
In a dry reaction flask, WX002-3 (290 mg, 613.99. Mu. Mol,1 eq), THF (3 mL) and hydrazine hydrate (108.48 mg,1.84mmol, 105.32. Mu.L, 85% purity, 3 eq) were added in this order, warmed to 40℃and stirred for 3 hours. After the reaction was completed, the reaction mixture was quenched with aqueous ammonium chloride (10 mL), extracted with ethyl acetate (20 ml×3), and the organic phase was collected after separation, followed by sequential extraction with saturated aqueous saline solution(10 ml. Times.3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product. The crude product was purified by thin layer chromatography on silica gel plate (DCM: meOH=20:1) to give WX002-4. 1 H NMR (400 MHz, deuterated chloroform) delta 6.68 (s, 2H), 3.58-3.43 (m, 3H), 2.77-2.55 (m, 4H), 1.81 (brt, j=2.8 hz, 4H).
Step 4: synthesis of Compound WX002
A solution of WX002-4 (150 mg, 440.91. Mu. Mol,1 eq), THF (2 mL), TEA (133.85 mg,1.32mmol, 184.11. Mu.L, 3 eq) and WX001-4 (98.22 mg, 661.37. Mu. Mol,1.5 eq) in THF (2 mL) were added sequentially to the dried reaction flask, and stirred at 20℃for 1 hour. After the reaction is completed, the reaction solution is decompressed and concentrated to obtain a crude product. Purifying the crude product by preparing high performance liquid chromatography column (chromatographic column: gemini-NX 80X 40mM X3 μm; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile%: 15% -45%,8 minutes) to obtain WX002. 1 H NMR (400 MHz, deuterated methanol) delta 7.93 (s, 2H), 3.48 (s, 3H), 2.79-2.73 (m, 2H), 2.61-2.55 (m, 2H), 1.86 (brt, j=3.1 hz, 4H). MS-ESI m/z:450.1[ M-H ]]-。
Biological testing
Experiment one: test of the activation Activity of the Compounds of the invention on thyroid hormone receptors at the cellular level
Experimental principle:
the experiment was developed using a thermo FisherThe TR alpha/beta-UAS-bla HEK 293T Cell-based Assay method is based on the principle that TR-alpha-UAS-bla HEK 293T Cell and TR-beta-UAS-bla HEK 293T Cell express beta-lactamase, the reporter gene is controlled by an upstream UAS sequence, when a compound enters cells to be combined with THR, a receptor is combined with a DNA binding region to form a complete GAL4 dimer, the GAL4-UAS system is utilized to activate beta-lactamase expression, a decomposition substrate CCF4-AM (coumarin) is decomposed, fluorescence with 447nm wavelength is generated by the product under the excitation of 409nm, if beta-lactamase is not expressed, fluorescence with 520nm wavelength is generated directly through FRET under the excitation of 409nm, and the ratio of the fluorescence (447 nm/520 nm) is detected to judge the compound and the proteinBinding, thus calculating the EC of the compound 50 。
The experimental method comprises the following steps:
compounds were transferred to 384 well plates using an ECHO liquid station, 10 gradient concentrations of each compound, 3-fold dilution, double multiplexed wells. Spread 1.5×10 4 Individual cells (TR beta-UAS-bla HEK 293T Cell) or 1.0X10 4 Individual cells (TR alpha-UAS-bla HEK 293T Cell) were plated in 384 well plates. HEK 293T-TR beta was incubated in an incubator at 37℃for 16 hours and HEK 293T-TR alpha was incubated for 22 hours, liveBLAzer TM The FRETB/G (CCF 4-AM) substrate is added into the cell plate, incubated for 2 hours at normal temperature under the dark condition, a Flexstation 3 instrument is used for detecting the fluorescence value of the product with the wavelength of 460nm/530nm under the excitation action of 409nm, and the EC of the compound is calculated by detecting the ratio of two fluorescence values (460 nm/530 nm) by using software Graphpad Prism 50 。
Table 1 THRα and THRβ Activity of the examples
Compounds of formula (I) THRαEC 50 Maximum agonistic ability (nM) THRβEC 50 Maximum agonistic ability (nM)
WX002 11524，29％ 4151，85％
Conclusion: the compounds of the present invention have significant thrβ activity and selectivity.
Experiment II: in vivo pharmacokinetic studies
Pharmacokinetic study of oral and intravenous administration of WX002 in mice
Male C57BL/6 mice were selected and administered according to Table 2.
TABLE 2 administration and blood sampling of the compounds of the invention
Whole blood was collected for a certain period of time, plasma was prepared, drug concentration was analyzed by LC-MS/MS method, and drug substitution parameters were calculated by Phoenix WinNonlin software (Pharsight, USA). The experimental results are shown in tables 3 and 4:
TABLE 3 pharmacokinetic results of intravenous administration of the compounds of the invention
TABLE 4 pharmacokinetic results of the compounds of the invention by oral administration
Conclusion: the compounds of the present invention have good pharmacokinetic properties.

Claims (10)

1. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,
wherein,
R 1 independently selected from H and C 1-3 Alkyl, said C 1-3 Alkyl is optionally substituted with 1,2 or 3R a Substitution;
R 2 and R is 3 Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CN、C 1-3 Alkyl and C 1-3 Alkoxy group, the C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1,2 or 3R b Substitution;
l is selected from-O-, -C (=O) -, -S (=O) 2 、-S(＝O)-、-C(R 4 ) 2 -sum of
Each R4 is independently selected from H, C 1-3 Alkyl and C 1-3 Alkoxy group, the C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1,2 or 3R c Substitution;
ring A is selected from phenyl, 5-6 membered heteroaryl, and,The phenyl group, the 5-to 6-membered heteroaryl group,Optionally substituted with 1,2 or 3 Rd;
n and m are each independently selected from 0, 1 and 2;
R a 、R b and R is c Each independently selected from F, cl, br and I;
each R is d Are independently selected from F, cl, br, I, =o, =n-C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Alkoxy, said = N-C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1,2 or 3R;
r is independently selected from F, cl, br and I;
when ring a is phenyl or 6 membered heteroaryl, L is selected from-C (=o) -, -S (=o) 2 、-S(＝0)-、-C(R 4 ) 2 -sum of
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Independently selected from H and CH 3 The CH is 3 Optionally by 1,2 or 3R a Substitution;
preferably, R 1 Independently selected from H, CH 3 And CF (compact F) 3 。
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 And R is 3 Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CN、CH 3 And OCH 3 The CH is 3 And OCH 3 Optionally by 1,2 or 3R a Substitution;
preferably, R 2 And R is 3 Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CN、CH 3 、CH 2 F、CHF 2 、CF 3 And OCH 3 。
4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 Independently selected from H, CH 3 、OCH 3 And OCH 2 CH 3 The CH is 3 、OCH 3 And OCH 2 CH 3 Optionally by 1,2 or 3R c Substitution;
preferably, R 4 Independently selected from H, CH 3 、OCH 3 And OCH 2 CH 3 。
5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is selected from-O-, -CH 2 -、-C(OCH 2 CH 3 ) 2 -sum of
6. According to claim 1 or 2The compound or a pharmaceutically acceptable salt thereof, wherein R d Independently selected from F, cl, br, I, =o, =n-O-CH 3 、＝N-O-CH 2 CH 3 、CH 3 、OCH 3 And OCH 2 CH 3 The = N-O-CH 3 、＝N-O-CH 2 CH 3 、CH 3 、OCH 3 And OCH 2 CH 3 Optionally substituted with 1,2 or 3R.
7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R d Independently selected from F, cl, br, I, =o, =n-O-CH 3 、＝N-O-CH 2 CH 3 、CH 3 、OCH 3 And OCH 2 CH 3 。
8. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from The said Optionally substituted with 1,2 or 3 Rd.
9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from
10. A compound of the formula or a pharmaceutically acceptable salt thereof,
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