WO2022194287A1 - Bicyclic pyridinone compound and use thereof - Google Patents

Abstract

Disclosed are a bicyclic pyridinone compound and the use thereof, and particularly disclosed are a compound as shown in formula (I) and a pharmaceutically acceptable salt thereof.

Description

Bicyclic pyridones and their applications

This application claims the following priority

CN202110299530.0, application date: March 19, 2021;

CN202110443443.8, application date: April 23, 2021.

technical field

The present invention relates to a class of bicyclic pyridone compounds and applications thereof, and specifically discloses a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.

Background technique

Thyroid hormones play an important role in growth, differentiation, development and maintaining metabolic balance. Its physiological action is carried out through thyroid hormone receptors. Thyroid hormone (THR) has two subtypes: THRα and THRβ. THRα is mainly distributed in the brain, heart and skeletal muscle, and can control the heart rate. THRβ is widely distributed in various tissues, mainly in liver, brain, and less in heart. It is involved in energy metabolism and is the main receptor for lipid metabolism and glucose metabolism. In the past decades, a variety of THRβ agonists have been developed for the treatment of dyslipidemia, non-alcoholic fatty liver and non-alcoholic steatohepatitis and other metabolic diseases, such as: GC-1, KB141, KB2115 and so on. However, skeletal and cardiac side effects have hindered its further development, such as KB2115 being stopped in Phase 3 clinical studies due to cartilage damage found in dogs). These side effects are thought to be due to agonism of the THRα isoform and are therefore expected to be avoided by improving target selectivity and liver tissue selectivity. The representative variety of this strategy is MGL-3196, which has entered the third clinical phase, and its safety and efficacy have been further confirmed. Therefore, the development of thyroid hormone analogs with liver tissue distribution specificity and thyroid hormone receptor subtype selectivity is of great clinical value.

Based on literature (J.Med.Chem.2014,57,3912-3923) reports, the structure of THRβ agonist MGL-3196 is as follows:

SUMMARY OF THE INVENTION

The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

in,

R ₁ is independently selected from H and C _1-3 alkyl optionally substituted with ₁ , 2 or 3 _Ra ;

R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, C _1-3 alkyl and C _1-3 alkoxy, said C _1-3 alkyl and C _1-3 alkoxy is optionally substituted with ₁ , 2 or 3 R _b ;

L is selected from -O-, -C(=O)-, -S-, -S(=O) ₂ , -S(=O) _- , -C(R4) _2- and

Each R ₄ is independently selected from H, C _1-3 alkyl and C _1-3 alkoxy, and said C _1-3 alkyl and C _1-3 alkoxy are optionally separated by 1, 2 or 3 R _c substitution;

Ring A is selected from phenyl, 5-6 membered heteroaryl,

The phenyl group, the 5- to 6-membered heteroaryl group,

optionally substituted with 1, 2 or 3 _Rd ;

n and m are independently selected from 0, 1 and 2;

R _a , R _b and R _c are each independently selected from F, Cl, Br and I;

Each R _d is independently selected from F, Cl, Br, I, =O, =NC _1-3 alkoxy, C _1-3 alkyl and C _1-3 alkoxy, the =NC _1-3 alkoxy, C _1-3 alkyl and C _1-3 alkoxy are optionally substituted with 1, 2 or 3 R;

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-, -S(=O) ₂ , -S(=O) _- , -C(R4 ) ₂ - and

The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

in,

R ₁ is independently selected from H and C _1-3 alkyl optionally substituted with ₁ , 2 or 3 _Ra ;

R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, C _1-3 alkyl and C _1-3 alkoxy, said C _1-3 alkyl and C _1-3 alkoxy is optionally substituted with ₁ , 2 or 3 R _b ;

L is selected from -O-, -C(=O)-, -S-, -S(=O) ₂ , -S(=O) _- , -C(R4) _2- and

R ₄ is independently selected from H, C _1-3 alkyl and C _1-3 alkoxy, said C _1-3 alkyl and C _1-3 alkoxy optionally surrounded by 1, 2 or 3 R _c replace;

Ring A is selected from phenyl, 5-6 membered heteroaryl,

The phenyl group, the 5- to 6-membered heteroaryl group,

optionally substituted with 1, 2 or 3 _Rd ;

n and m are independently selected from 0, 1 and 2;

R _a , R _b and R _c are each independently selected from F, Cl, Br and I;

R _d is independently selected from F, Cl, Br, I, =O, =NC _1-3 alkoxy, C _1-3 alkyl and C _1-3 alkoxy, the =NC _1-3 alkoxy group, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1, 2 or 3 R;

R is independently selected from F, Cl, Br and I.

The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

in,

R ₁ is independently selected from H and C _1-3 alkyl optionally substituted with ₁ , 2 or 3 _Ra ;

R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, C _1-3 alkyl and C _1-3 alkoxy, said C _1-3 alkyl and C _1-3 alkoxy is optionally substituted with ₁ , 2 or 3 R _b ;

L is selected from O, -C(R ₄ ) ₂ and

R ₄ is independently selected from H, C _1-3 alkyl and C _1-3 alkoxy, said C _1-3 alkyl and C _1-3 alkoxy optionally surrounded by 1, 2 or 3 R _c replace;

Ring A is selected from phenyl, 5-6 membered heteroaryl,

The phenyl group, the 5- to 6-membered heteroaryl group,

optionally substituted with 1, 2 or 3 _Rd ;

n and m are independently selected from 0, 1 and 2;

R _a , R _b and R _c are each independently selected from F, Cl, Br and I;

R _d is independently selected from F, Cl, Br, I, =O, =NC _1-3 alkoxy, C _1-3 alkyl and C _1-3 alkoxy, the =NC _1-3 alkoxy group, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1, 2 or 3 R;

R is independently selected from F, Cl, Br and I.

In some embodiments of the present invention, the above R ₁ is independently selected from H and CH ₃ , said CH ₃ is optionally substituted with 1, 2 or 3 _Ra , and other variables are as defined in the present invention.

In some aspects of the present invention, the above R ₁ is independently selected from H, CH ₃ and CF ₃ , and other variables are as defined in the present invention.

In some embodiments of the present invention, the above R ₂ and R ₃ are independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, CH ₃ and OCH ₃ , and the CH ₃ and OCH ₃ are optional Substituted by 1, 2 or 3 _Ra , other variables are as defined in the present invention.

In some embodiments of the present invention, the above R ₂ and R ₃ are independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ and OCH ₃ , and other variables are as defined in the present invention.

In some aspects of the present invention, the above R ₄ is independently selected from H, CH ₃ , OCH ₃ and OCH ₂ CH ₃ , and said CH ₃ , OCH ₃ and OCH ₂ CH ₃ are optionally surrounded by 1, 2 or 3 R _c Instead, other variables are as defined in the present invention.

In some aspects of the present invention, the above R ₄ is independently selected from H, CH ₃ , OCH ₃ and OCH ₂ CH ₃ , and other variables are as defined in the present invention.

In some aspects of the present invention, the above L is selected from -O-, _-CH2- , -C( _{OCH2CH3 ) 2-} and

Other variables are as defined in the present invention.

In some aspects of the present invention, the above R _d is independently selected from F, Cl, Br, I, =O, =NO-CH ₃ , =NO-CH ₂ CH ₃ , CH ₃ , OCH ₃ and OCH ₂ CH ₃ , Said =NO- _CH3 , =NO- _CH2CH3 , _CH3 , _OCH3 and _OCH2CH3 are optionally substituted with 1, ₂ or ₃ R, other variables are as defined in the present invention.

In some aspects of the present invention, the above R _d is independently selected from F, Cl, Br, I, =O, =NO-CH ₃ , =NO-CH ₂ CH ₃ , CH ₃ , OCH ₃ and OCH ₂ CH ₃ , Other variables are as defined in the present invention.

In some aspects of the present invention, the above-mentioned ring A is selected from

said

Optionally substituted with 1, 2 or 3 _Rd , other variables are as defined herein.

In some aspects of the present invention, the above-mentioned ring A is selected from

Other variables are as defined in the present invention.

In some aspects of the present invention, the above-mentioned ring A is selected from

Other variables are as defined in the present invention.

There are still some solutions of the present invention which are obtained by any combination of the above variables.

The present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,

The present invention also provides following synthetic method:

method 1:

Method 2:

Method 3:

Method 4:

The present invention also provides following test method:

Cytochrome P450 Isozyme Inhibitory Study

Purpose:

The inhibitory effect of test compounds on the activity of human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) was determined.

Experimental operation:

First, dilute the test compound (10.0 mM) to prepare a working solution (100× final concentration) with a concentration of 1.00 mM. At the same time, prepare P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (with mida) Zolam as the probe substrate) and CYP3A4 (with testosterone as the probe substrate)) positive inhibitors and their specific probe substrate working solution; human liver microsomes stored in a refrigerator below -60 ℃ Thawed on ice, after all human liver microsomes were dissolved, diluted with PB to prepare a working solution of a certain concentration (0.127mg/ml). First add 20.0μL of probe substrate to the reaction plate (add 20.0μL of PB to Blank wells), then add 158μL of human liver microsome working solution to the reaction plate, and place the reaction plate on ice for later use; Add 2.00 μL test compound (N=1) and specific inhibitor (N=2) to the corresponding wells, add the corresponding organic solvent to the no inhibitor (test compound or positive inhibitor) group, and test compound control sample The organic phase of the positive control sample was 1:1DMSO:MeOH and 1:9DMSO:MeOH respectively; after pre-incubating in a 37°C water bath for 10min, 20.0μL of coenzyme factor (NADPH) solution was added to the reaction plate. The CYP3A4 metabolic reaction of the probe substrate, the reaction time is 3 minutes; the CYP2C19 reaction using (S)-mephenytoin as the probe substrate and the CYP2D6 reaction using dextromethorphan as the probe substrate, the reaction time is 20 400 μL of pre-cooled acetonitrile solution (internal standard containing 200 ng/mL Tolbutamide and Labetalol) was added to terminate the reaction; the reaction plate was placed on a shaker, shaken and mixed for 10 min; then at 4°C, Centrifuge at 4000 rpm for 20 min; add 200 μL of supernatant to 100 μL of water for sample dilution; finally seal the plate, shake, shake well, and perform LC/MS/MS detection.

In vivo pharmacodynamic studies

Purpose:

The in vivo efficacy of the compounds to be tested was detected by using a rat model induced by dietary cholesterol cholic acid.

experimental method:

Male SD rats aged 9-10 weeks were selected and acclimated for 3-7 days after arriving at the facility. During the acclimation period, the animals' health status was observed daily and normal feed was provided. After the adaptation period, the vehicle control group and the test compound group were fed with high cholesterol (1.5% cholesterol and 0.5% bile acid) feed for modeling, and the vehicle was 0.5% sodium carboxymethyl cellulose + 0.2% Tween 80 aqueous solution, The rats in the blank control group continued to be fed with normal chow. After the rats were fed a high cholesterol diet for two weeks, blood was collected, and serum was separated to detect LDL-C levels. The hypercholesterolemic model rats were randomly divided into groups according to serum LDL-C levels, and then administered orally once a day for 7 consecutive days. One week after administration, the serum of rats was collected to detect the level of LDL-C to evaluate the efficacy of the drug.

Definition and Explanation

Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without specific definitions, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat 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 compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat 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, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.

The pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.

The compounds of the present 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 isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

Unless otherwise indicated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.

Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.

Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.

Unless otherwise specified, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.

Use solid wedge keys unless otherwise specified

and wedge-dotted keys

Indicate the absolute configuration of a stereocenter, using a straight solid key

and straight dashed keys

Indicate the relative configuration of the stereocenter, with a wavy line

Represents a solid wedge key

or wedge-dotted key

or with wavy lines

Represents a straight solid key

and straight dashed keys

Unless otherwise specified, when there is a double bond structure in the compound, such as carbon-carbon double bond, carbon-nitrogen double bond and nitrogen-nitrogen double bond, and each atom on the double bond has two different substituents attached (including nitrogen atom) In the double bond, a lone pair of electrons on the nitrogen atom is regarded as a substituent for its connection), if a wavy line is used between the atom on the double bond and its substituent in the compound

If connected, it means the (Z) isomer, (E) isomer or a mixture of both isomers of the compound. For example, the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2) The following formula (B) indicates that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or exists in two forms of formula (B-1) and formula (B-2) exists as a mixture of isomers. The following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of two isomers of formula (C-1) and formula (C-2) exists in the form of a mixture.

Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature. A chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

Unless otherwise indicated, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer" or "enriched in one enantiomer" refer to one of the isomers or pairs The enantiomer content is less than 100%, and the isomer or enantiomer content 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 terms "isomeric excess" or "enantiomeric excess" refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .

Optically active (R)- and (S)-isomers, as well as 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 present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art The diastereoisomers were resolved and the pure enantiomers recovered. In addition, separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).

The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or C-14 ( ¹⁴ C). For another example, deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

The terms "optional" or "optionally" mean 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 in which it does not. .

The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable. When the substituent is oxygen (ie =O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.

The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.

When any variable (eg, 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 0-2 Rs, the group may optionally be substituted with up to two Rs, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

When the number of a linking group is 0, such as -(CRR) ₀ -, it means that the linking group is a single bond.

When one of the variables is selected from a single bond, it means that the two groups connected to it are directly connected, for example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.

When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.

When the listed linking group does not indicate its direction of attachment, the direction of attachment is arbitrary, for example,

The linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right.

It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.

Combinations of the 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 attachable sites, any one or more sites in the group can be linked to other groups by chemical bonds. When the connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group. The chemical bond connecting the site to other groups can be represented by straight solid line bonds

straight dotted key

or wavy lines

express. For example, a straight solid bond in -OCH ₃ indicates that it is connected to other groups through the oxygen atom in this group;

The straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;

The wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;

Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least

These 4 connection methods, even if the H atom is drawn on -N-, but

still includes

The group in this connection method is only that when one chemical bond is connected, the H at the site will be correspondingly reduced by one to become the corresponding monovalent piperidinyl group.

Unless otherwise specified, the term "C _1-3 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C _1-3 alkyl group includes C _1-2 and C _2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) . Examples of _C1-3 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 " _C1-3alkoxy " refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom. The C _1-3 alkoxy group includes C _1-2 , C _2-3 , C ₃ and C ₂ alkoxy and the like. Examples of C _1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

Unless otherwise specified, the terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" are used interchangeably in the present invention, and the term "5-6 membered heteroaryl" means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) _p , p is 1 or 2). A 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2- -pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

Unless otherwise specified, _Cn-n+m or _Cn - _Cn+m includes any particular instance of n to n+ _m carbons, eg _C1-12 includes _C1 , _C2 , C3, C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , and C ₁₂ , also including any range from n to n+ _m , eg C _1-12 includes 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.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from 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, also including any one range from n to n+m, for example, 3-12-membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.

The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is:

After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.

The solvent used in the present invention is commercially available. The present 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 dimethyl sulfoxide; EtOAc for ethyl acetate; EtOH for ethanol; MeOH for methanol; r.t. for room temperature; O/N for overnight; THF for tetrahydrofuran; TFA for trifluoroacetic acid; DIPEA for diisopropylethylamine; TEA for triethylamine.

Compounds are named according to conventional nomenclature in the art or are used

Software naming, commercially available compounds use supplier catalog names.

technical effect

The compound of the present invention has significant THRβ activity and selectivity; the compound of the present invention has excellent pharmacokinetic properties; the compound of the present invention has no drug-drug interaction; the compound of the present invention can significantly reduce the level of plasma LDL-C in rats.

Description of drawings

Figure 1: Prediction of the binding mode of compound A to MGL-3196;

Figure 2: Prediction of the binding mode of compound B to MGL-3196;

Figure 3: Prediction of the binding mode of compound C to MGL-3196;

Figure 4: Prediction of the binding mode of Compound D to MGL-3196.

Detailed ways

The present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. For those skilled in the art, various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention. will be obvious.

Calculation example 1

Molecular docking process: by using Maestro (

GlideSP[1] and default options in version 2017-2). MGL-3196 was chosen as the docking template. To prepare the protein, hydrogen atoms were added using the protein preparation wizard module of Maestro [2] and the OPLS3 force field was used. For the preparation of ligands, 3D structures were generated and energy minimization was performed using LigPrep [3]. Generated using ligand centroids in the 1Q4X crystal structure

Docking grid. Through Induced Fit Docking, the amino acid side chain within the 5A range of the constrained ligand center moves in the B factor range to generate a complex model. The ligands are then removed and the example compounds are placed during the molecular docking process. The interaction types of protein receptors and ligands were analyzed, and then reasonable docking conformations were selected and saved according to the calculated docking scrore and globalStrain values. The binding mode of compound AD to MGL-3196 is shown in 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 present invention has good binding with THRβ protein. The compounds of the present invention occupy the binding pocket of THRβ and thyroxine. The binding pocket is a closed, hydrophobic pocket composed of multi-layer α-helices, and above the pocket is a positive band composed of three arginines (Arg282, Arg316 and Arg320). Electric sub pocket. The 6-azauracil acidic group of the original reference compound MGL-3196 is bound in this sub-pocket, the cyano group forms hydrogen bonds with Arg316, the carbonyl and nitrogen atoms of 6-azauracil form hydrogen bonds with Arg320, and the pyridazine group forms hydrogen bonds with Arg320. The carbonyl oxygen of the ketone forms a hydrogen bond with His435. The benzene ring in the middle, the pyridazinone and the isopropyl group at the end can all form hydrophobic interactions with the surrounding amino acids. The 1,2,4-oxadiazolin-5-one polar head of the compound of the present invention is combined in this sub-pocket, and also forms a hydrogen bond with three arginines, improving the angle of dichlorobenzene through amides, making it easier to Forming a halogen bond with Phe272, the carbonyl or hydroxyl group at the tail can form a hydrogen bond through interaction with His435, and the ring effectively provides hydrophobic interactions. Has better selectivity.

Example 1

synthetic route:

Step 1: Synthesis of compound WX001-2

In a dry reaction flask, successively added WX001-1 (5g, 37.85mmol, 1eq), 1,4-dioxane (50mL), 1-cyclohexyl-2-morpholinoethylcarbodiimide to Tosylate (6.75g, 41.63mmol, 1.1eq) and DBU (6.34g, 41.63mmol, 6.27mL, 1.1eq), the reaction system was warmed to 80°C and stirred for 2 hours. After the reaction was completed, water (100 mL) was added to dilute, 1N HCl was added to adjust the pH to 3-4, ethyl acetate (3*100 mL) 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 obtain WX001-2. ¹ H NMR (400 MHz, deuterated chloroform) δ 4.51 (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 (1g, 6.32mmol, 1eq), water (2mL), ethanol (10mL) and lithium hydroxide monohydrate (318.49mg, 7.59mmol, 2eq) were added in sequence, and the reaction was adjusted to Stir at 20°C for 1 hour. After the reaction was completed, water (20 mL) was added to the reaction solution to dilute, 2M hydrochloric acid was added to adjust the pH to 4-6, ethyl acetate (30 mL*3) was added for extraction, and the organic phase was collected after separation. Add 2M hydrochloric acid to the aqueous phase to adjust the pH to 1, add ethyl acetate (30mL*3) for extraction, add chloroform:isopropanol=3:1 (30mL*18) for extraction, collect the organic phase after separation, anhydrous sodium sulfate Dry and concentrate under reduced pressure to obtain WX001-3.

Step 3: Synthesis of Compound WX001-4

In a dry reaction flask, sequentially add WX001-3 (100mg, 768.88μmol, 1eq), THF (1mL), oxalyl chloride (117.11mg, 922.66μmol, 80.77μL, 1.2eq) and DMF (5.62mg, 76.89μmol, 5.92 μL, 0.1 eq), stirred at 20°C for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain WX001-4.

Step 4: Synthesis of Compound WX001-7

In a dry reaction flask, sequentially add WX001-5 (5g, 24.62mmol, 1eq), WX001-6 (5.83g, 32.75mmol, 1.33eq), N,N-dimethylacetamide (50mL) and cesium carbonate (16.04 g, 49.24 mmol, 2 eq), heated to 80° C. and stirred for 10 hours. After the reaction was completed, water (100 mL) was added for dilution, ethyl acetate (100 mL*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 obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 2:1) to obtain WX001-7. ¹ H NMR (400 MHz, deuterated chloroform) δ 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, add NaOH (16.25g, 406.24mmol, 20eq), water (70mL), DMSO (70mL), WX001-7 (7g, 20.31mmol, 1eq), warm to 120°C, and stir for 2 hours. After the reaction was completed, water (100 mL) was added for dilution, ethyl acetate (100 mL*3) was added for extraction, and the organic phase was collected after separation. The organic phase was successively dried with saturated saline solution (100 mL*3), anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 2:1) to obtain WX001-8. ¹ H NMR (400 MHz, deuterated chloroform) δ 6.67 (s, 2H), 2.84-2.52 (m, 4H), 1.93-1.71 (m, 4H).

Step 6: Synthesis of Compound WX001

In a dry reaction flask, add WX001-8 (150.34mg, 460.91μmol, 1eq), THF (2mL), TEA (139.92mg, 1.38mmol, 192.46μL, 3eq) and WX001-4 (102.67mg, 691.36μmol) in turn , 1.5eq) in THF (2mL) and stirred at 20°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX80*40mm*3μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 10 %-40%, 8 minutes) to get WX001. ¹ H NMR (400 MHz, deuterated methanol) δ 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 [MH] ^- .

Example 2

synthetic route:

Step 1: Synthesis of compound WX002-2

In a dry reaction flask, sequentially add WX002-1 (1.18g, 7.97mmol, 2.6eq), WX001-8 (1g, 3.07mmol, 1eq), DMF (10mL) and TEA (620.46mg, 6.13mmol, 853.45μL) , 2eq), the temperature was raised to 100 °C and stirred for 10 hours. After the reaction was completed, water (50 mL) was added to make slurry, filtered, and the filter cake was washed with water (10 mL*2) and concentrated under reduced pressure to obtain WX002-2. ¹ H NMR (400MHz, deuterated chloroform) δ 9.46 (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, add WX002-2 (300mg, 654.60μmol, 1eq), DMF (12mL), potassium carbonate (180.95mg, 1.31mmol, 2eq) and methyl iodide (185.83mg, 1.31mmol, 81.50μL) in turn, 2eq), stirred for 10 hours at 20°C. After the reaction is complete, add water (20mL) to dilute, add ethyl acetate (20mL*3) for extraction, collect the organic phase after separation, successively use saturated brine solution (20mL*3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain Crude. The crude product was purified by column chromatography (DCM:MeOH=20:1) to give WX002-3. ¹ H NMR (400MHz, deuterated chloroform) δ8.04-7.96(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, add WX002-3 (290 mg, 613.99 μmol, 1 eq), THF (3 mL) and hydrazine hydrate (108.48 mg, 1.84 mmol, 105.32 μL, 85% purity, 3 eq) in turn, and the temperature was raised to 40°C, Stir for 3 hours. After the reaction was completed, the reaction solution was quenched by adding ammonium chloride aqueous solution (10 mL), and extracted with ethyl acetate (20 mL*3). Dry and concentrate under reduced pressure to obtain 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) δ 6.68 (s, 2H), 3.58-3.43 (m, 3H), 2.77-2.55 (m, 4H), 1.81 (br t, J=2.8 Hz, 4H).

Step 4: Synthesis of Compound WX002

In a dry reaction flask, add WX002-4 (150mg, 440.91μmol, 1eq), THF (2mL), TEA (133.85mg, 1.32mmol, 184.11μL, 3eq) and WX001-4 (98.22mg, 661.37μmol, 1.5 eq) in THF (2 mL) at 20°C and stirred for 1 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (column: Gemini-NX80*40mm*3μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; % acetonitrile: 15%-45%, 8 minutes) to obtain WX002. ¹ H NMR (400MHz, deuterated methanol) δ 7.93(s, 2H), 3.48(s, 3H), 2.79-2.73(m, 2H), 2.61-2.55(m, 2H), 1.86(br t, J = 3.1 Hz, 4H). MS-ESI m/z: 450.1 [MH] ^- .

biological test

Experiment 1: Test of the activation activity of the compounds of the present invention on thyroid hormone receptors at the cellular level

Experimental principle:

This experiment uses ThermoFisher developed

TR alpha/beta-UAS-bla HEK 293T Cell-based Assay method, the principle is that TR alplha-UAS-bla HEK 293T Cell and TR beta-UAS-bla HEK 293T Cell express β-lactamase, this reporter gene is controlled In the upstream UAS sequence, when the compound enters the cell and binds to THR, the receptor binds to the DNA-binding region to form a complete GAL4 dimer, using the GAL4-UAS system to activate the expression of β-lactamase and decompose the substrate CCF4- AM (coumarin), the product generates fluorescence at 447 nm under excitation at 409 nm. If β-lactamase is not expressed, under excitation at 409 nm, it directly generates fluorescence at 520 nm by FRET. By detecting the ratio of the two fluorescence ( 447nm/520nm) to determine the binding of the compound to the protein, so as to calculate the EC ₅₀ of the compound.

experimental method:

Compounds were transferred to a 384-well plate using an ECHO liquid workstation, with 10 gradient concentrations per compound, 3-fold dilution, and double wells. Plate 1.5×10 ⁴ cells (TR beta-UAS-bla HEK 293T Cell) or 1.0×10 ⁴ cells (TR alpha-UAS-bla HEK 293T Cell) in 384-well plates. HEK 293T-TR beta was incubated in a 37°C incubator for 16 hours, HEK 293T-TR alpha was incubated for 22 hours, LiveBLAzer ^TM -FRET B/G(CCF4-AM) substrate was added to the cell plate, and incubated at room temperature in the dark for 2 hours. The Flexstation 3 instrument was used to detect the product under excitation at 409nm, and the fluorescence value of 460nm/530nm wavelength was emitted. By detecting the ratio of the two fluorescence (460nm/530nm), the software Graphpad Prism was used to calculate the EC ₅₀ of the compound.

Table 1 THRα and THRβ activity of each example

compound	THRαEC 50 (nM), maximal agonistic capacity	THRβEC 50 (nM), maximal agonistic capacity
WX002	11524, 29%	4151, 85%

Conclusion: The compounds of the present invention have significant THRβ activity and selectivity.

Experiment 2: In vivo pharmacokinetic study

Pharmacokinetic study of oral and intravenous injection of WX002 in mice

Male C57BL/6 mice were selected, and the test substances were administered according to Table 2.

Table 2. Administration and Blood Collection of 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 pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA). The experimental results are shown in Table 3 and Table 4:

Table 3. Pharmacokinetic Results of Compounds of the Invention by Intravenous Administration

Table 4. Pharmacokinetic Results of Compounds of the Invention by Oral Administration

Conclusion: The compounds of the present invention have good pharmacokinetic properties.

Claims (13)

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

   

   in,

   R ₁ is independently selected from H and C _1-3 alkyl optionally substituted with ₁ , 2 or 3 _Ra ;

   R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, C _1-3 alkyl and C _1-3 alkoxy, said C _1-3 alkyl and C _1-3 alkoxy is optionally substituted with ₁ , 2 or 3 R _b ;

   L is selected from -O-, -C(=O)-, -S-, -S(=O) ₂ , -S(=O) _- , -C(R4) _2- and

   

   Each R ₄ is independently selected from H, C _1-3 alkyl and C _1-3 alkoxy, and said C _1-3 alkyl and C _1-3 alkoxy are optionally separated by 1, 2 or 3 R _c substitution;

   Ring A is selected from phenyl, 5-6 membered heteroaryl,

   

   The phenyl group, the 5- to 6-membered heteroaryl group,

   

   optionally substituted with 1, 2 or 3 _Rd ;

   n and m are independently selected from 0, 1 and 2;

   R _a , R _b and R _c are each independently selected from F, Cl, Br and I;

   Each R _d is independently selected from F, Cl, Br, I, =O, =NC _1-3 alkoxy, C _1-3 alkyl and C _1-3 alkoxy, the =NC _1-3 alkoxy, C _1-3 alkyl and C _1-3 alkoxy are optionally substituted with 1, 2 or 3 R;

   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-, -S(=O) ₂ , -S(=O) _- , -C(R4 ) ₂ - and

   
2. The compound of claim ₁ , or a pharmaceutically acceptable salt thereof, wherein R1 is independently selected from H and _CH3 , wherein _CH3 is optionally substituted with 1, 2 or 3 _Ra .
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R ₁ is independently selected from H, CH ₃ and CF ₃ .
4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R ₂ and R ₃ are independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, _CH3 and _OCH3 optionally substituted with ₁ , 2 or _{3 Ra} .
5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, CH ₃ , CH ₂ F, _CHF2 , _CF3 and _OCH3 .
6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ₄ is independently selected from H, CH ₃ , OCH ₃ and OCH ₂ CH ₃ , the CH ₃ , OCH ₃ and _OCH2CH3 is optionally substituted with 1, 2 or _{3 Rcs} .
7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R ₄ is independently selected from H, CH ₃ , OCH ₃ and OCH ₂ CH ₃ .
8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein L is selected from -O-, -CH ₂ -, -C(OCH ₂ CH ₃ ) ₂ - and

   
9. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R _d is independently selected from F, Cl, Br, I, =O, =NO-CH ₃ , =NO-CH ₂ CH ₃ , CH ₃ , OCH ₃ and OCH ₂ CH ₃ , the =NO-CH ₃ , =NO-CH ₂ CH ₃ , CH ₃ , OCH ₃ and OCH ₂ CH ₃ are optionally 1, 2 or 3 R replaced.
10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R _d is independently selected from F, Cl, Br, I, =O, =NO-CH ₃ , =NO-CH ₂ CH ₃ , CH ₃ , _OCH3 and _{OCH2CH3 .}
11. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from

    

    

    said

    

    

    Optionally substituted with 1, 2 or 3 _Rd .
12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from

    

    
13. A compound of the formula or a pharmaceutically acceptable salt thereof,

    

    

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