A thyroid hormone receptor β agonist compound and its preparation method and application

Abstract

The present invention provides a thyroid hormone receptor β (TRβ) agonist compound, a preparation method and an application thereof. The compound and the pharmaceutically acceptable salts, esters, amides or carbamates, as well as isomers, racemates, prodrugs, co-crystallized complexes or solvates of the compound can be used as thyroid hormone receptor β agonists, and the prepared thyroid hormone receptor β agonist has a good activation effect on wild-type and mutant thyroid hormone receptor β, has a weak effect or basically no effect on thyroid hormone receptor α (TRα) and prolyl hydroxylase (PHD2) targets, and has good selectivity. Therefore, the compound can be used in the prevention or treatment of thyroid hormone receptor β-mediated related diseases.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical medicine, and relates to a thyroid hormone receptor β agonist compound, a preparation method and application thereof, and in particular to a highly selective and anti-mutation thyroid hormone receptor β agonist, a preparation method and application thereof. Background Art

[0002] Thyroid hormone receptors (TRs) are members of the nuclear receptor (NR) superfamily, with two major forms, TRα and TRβ, transcribed from THRA (NR1A1, chromosome 17) and THRB (NR1A2, chromosome 3), respectively. Over the past two decades, much of the work on thyroid hormone receptor β-selective compounds has focused on analogs of T3, such as GC-1, GC-24, KB2115, MB07811, MGL3196.

[0003] Among them, MGL3196 was reported to have only 28-fold beta subtype selectivity in in vitro functional assays and has been considered a highly selective compound. Fortunately, MGL3196 achieved liver selectivity, thus avoiding the side effects of low-selective thyroid hormone receptor beta agonists on the heart and bones. The difficulty in improving selectivity lies in the fact that there is only one amino acid difference in the ligand binding domain (LBD), namely TRα-Ser277 and its corresponding TRβ-Asn331. Although many thyroid hormone receptor beta agonists have been reported, it is difficult to break through the selectivity because the skeleton structure is too simple. At the same time, resistance to thyroid hormone beta (RTHβ) is a syndrome characterized by reduced responsiveness of peripheral tissues to thyroid hormone (TH), which is mainly caused by thyroid hormone beta mutations.

[0004] Hypothyroidism is associated with decreased brain development, increased body weight, decreased body temperature, decreased heart rate, and increased plasma total cholesterol and low-density lipoprotein (LDL) cholesterol. Children with hyperthyroidism experience tachycardia, irregular heartbeat, increased body temperature, fatigue and anxiety, muscle wasting, osteoporosis, and increased stature. Despite the adverse effects of high thyroid hormone levels, efforts are ongoing to develop molecules that can exert beneficial effects, such as lowering serum LDL cholesterol levels, increasing basal metabolic rate, and reducing body weight. Diseases or conditions associated with thyroxine receptor beta include: hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, familial hypercholesterolemia, dyslipidemia, atherosclerosis, NASH, obesity, thyroid hormone resistance (RTH), replacement therapy for elderly subjects with hypothyroidism and risk of cardiovascular complications, diabetes, depression, osteoporosis (especially in combination with bone resorption inhibitors), goiter, thyroid cancer, cardiovascular disease or congestive heart failure, glaucoma and skin diseases, psychiatric disorders such as attention deficit hyperactivity disorder, depression, mental retardation and cognitive dysfunction, etc.

[0005] CN110507655A discloses a drug for treating thyroid hormone receptor-mediated diseases, namely FG-4592 (roxadustat). FG-4592 is a multi-target compound, which can be used to treat anemia as an oral hypoxia-inducible factor prolyl hydroxylase (HIF-PHD2) inhibitor. This invention reports that FG-4592 has an activating effect on both thyroid hormone receptor α and β, but its subtype selectivity is limited.

[0006] Therefore, it is desirable in the art to develop a thyroid hormone receptor β agonist with high selectivity and resistance to mutation to specifically treat thyroid hormone receptor β-related diseases while avoiding the cardiovascular and other side effects caused by thyroid hormone receptor α. Summary of the invention

[0007] In view of the shortcomings of the prior art, the object of the present invention is to provide a thyroid hormone receptor β agonist compound and its preparation method and application. The thyroid hormone receptor β agonist prepared by the compound has high selectivity for thyroid hormone receptor β subtypes, and also has an activating effect on mutant thyroid hormone receptor β, and can specifically treat related diseases.

[0008] To achieve this object, the present invention adopts the following technical solutions:

[0009] In a first aspect, the present invention provides a thyroid hormone receptor β agonist compound, characterized in that the compound has a structure as shown in Formula I;

[0010]

[0011] wherein R1 is selected from any one of C1-C4 alkyl, alkoxy chain or cycloalkoxy, cyano or halogen; R2 is selected from any one of hydroxyl, alkoxy, amino, substituted amino, glycine, glycine derivatives, alanine, phosphate group, phosphate substitution, imidazole or imidazole substitution; R3 and R7 are independently selected from any one of C1-C4 alkyl, alkoxy chain or halogen; R4 and R6 are independently selected from any one of substituted or unsubstituted benzyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenethyl, C1-C4 alkyl, cyano, nitro, halogen or trifluoromethyl; R5 is selected from any one of substituted or unsubstituted phenyl, substituted or unsubstituted five-membered heterocyclic ring, substituted or unsubstituted six-membered heterocyclic ring, substituted or unsubstituted phenoxy, substituted or unsubstituted benzoyl, substituted or unsubstituted benzyl, substituted or unsubstituted styryl, substituted or unsubstituted phenylethynyl, C1-C4 alkyl, halogen, cyano or trifluoromethyl;

[0012] Preferably, R5 and R6 form a saturated or unsaturated polysubstituted or unsubstituted heterocyclic ring or a bridged ring; R6 and R7 form a saturated or unsaturated polysubstituted or unsubstituted heterocyclic ring or a bridged ring.

[0013] In the present invention, the compounds represented by Formula I include: (1) salts or solvates of compounds suitable for use in medicine, wherein the counterions or bound solvents in the salts or solvates are pharmaceutically acceptable; (2) salts and solvates containing non-pharmaceutically acceptable counterions or bound solvents, for example, used as intermediates in the preparation of compounds of Formula I and pharmaceutically acceptable salts, solvates and physiologically functional derivatives. The term "physiologically functional derivative" refers to, for example, chemical derivatives of compounds of Formula I that have the same physiological function as the free compounds of Formula I by being converted into the free compounds of Formula I in vivo; according to the present invention, the physiologically functional derivatives include esters, amides or carbamates, preferably esters or amides.

[0014] As a preferred technical solution of the present invention, the compound has a structure as shown in Formula II;

[0015]

[0016] Wherein, X is selected from -CH2-, -O-, -CO-, -CONH, -CH=CH-, ethynyl or -S(O) m-, wherein m represents 0 or 2; R1 is selected from any one of C1-C4 alkyl, alkoxy chain, cyano or halogen; R3 is selected from any one of C1-C4 alkyl, alkoxy chain or halogen; R7 is selected from any one of C1-C4 alkyl, alkoxy chain or halogen; R8 is selected from H, halogen, C1-C4 alkyl, CN-, NO2-, CF3- or alkoxy chain;

[0017] As a preferred technical solution of the present invention, the compound has a structure as shown in Formula III;

[0018]

[0019] In the formula, R1 is selected from any one of C1-C4 alkyl, alkoxy chain, cyano or halogen; R9 is selected from any one of C1-C4 alkyl, alkoxy chain, cyano or halogen; R 10 Any one selected from C1-C4 alkyl, alkoxy chain, cyano or halogen;

[0020] Preferably, the compound includes any one of the following compounds, salts, esters, amides or carbamates thereof:

[0021]

[0022]

[0023]

[0024] In a second aspect, the present invention provides a thyroid hormone receptor β agonist, which comprises: the compound described in the first aspect and a pharmaceutically acceptable salt, ester, amide or carbamate, as well as a pharmaceutically acceptable isomer, racemate, prodrug, co-crystallized complex or solvate, etc.

[0025] The term "isomer" refers to compounds with the same chemical composition but different spatial arrangements of atoms or groups, mainly including diastereomers and enantiomers. Among them, "diastereomer" refers to a stereoisomer with two or more asymmetric centers and whose molecules are not mirror images of each other; "enantiomer" refers to two non-superimposable mirror images of a compound. An equimolar mixture of two enantiomers is called a "racemic mixture" or "racemate".

[0026] The term "prodrug" includes compounds with moieties that can be metabolized in vivo. Typically, prodrugs are metabolized in vivo to active drugs by esterases or other mechanisms. These prodrugs can be prepared in situ during the final separation and purification of the compound, or the purified compound can be reacted with a suitable esterifying agent in acid form or at the hydroxyl group, respectively.

[0027] As a preferred technical solution of the present invention, the target of the thyroid hormone receptor β agonist is wild-type or mutant thyroid hormone receptor β.

[0028] Preferably, the mutant thyroid hormone receptor β includes but is not limited to any one or a combination of at least two of V264D, A268D, R282S, V283A, M310T, E311K, S314C, A317T, R320C, N331D, G332E, G332R, L346F, L346V, H435L, R438H, F459C or F459L, which cause thyroid hormone resistance syndrome (RTH).

[0029] In a third aspect, the present invention further provides a method for preparing an isoquinoline compound in which the substituent R1 is an alkoxy group (i.e., the compound in which the substituent R1 is an alkoxy group in the first aspect), the preparation method comprising:

[0030] by and the alcohol corresponding to the substituent R1 as a raw material, dibromohydantoin, dichlorohydantoin, N-bromosuccinimide or N-chlorosuccinimide is added to react to obtain an isoquinoline compound in which the substituent R1 is an alkoxy group

[0031] Preferably, the reaction temperature is 0°C to 30°C, for example, it can be 0°C, 5°C, 10°C, 15°C, 18°C, 20°C, 26°C, 28°C or 30°C.

[0032] Preferably, the reaction time is 5 min to 2 h, for example, 5 min, 20 min, 40 min, 60 min, 1.2 h, 1.5 h, 1.6 h, 1.8 h or 2 h.

[0033] Preferably, the reaction is represented by the following reaction formula:

[0034]

[0035] In a fourth aspect, the present invention further provides a method for preparing the compound as described in the first aspect or the thyroid hormone receptor β agonist as described in the second aspect, wherein the preparation method is represented by the following reaction formula:

[0036]

[0037] The reagents and reaction conditions added in each step are as follows:

[0038] Step 1: N, N-dimethylformamide, various substituted phenols, cuprous bromide, acetylacetone, argon, potassium carbonate, 120°C, 30h+, 50%-80%; Step 2: xylene, benzyltriethylammonium chloride, boron trifluoride-ether, dichlorothionyl, argon, 120°C, 10h; ethanol, 1h, 90%-98%; Step 3: N, N-dimethylformamide, methyl 2-(4-methylphenylsulfonyl)acetate, potassium iodide, carbonate Potassium, 50℃, 3h; 5M ethanol / sodium ethoxide, 4h, 55%-62%; Step 4: See the synthesis method when R1 is a different substituent; Step 5: 2-methoxyethanol, 1,8-diazabicycloundec-7-ene, glycine or 2-aminoisobutyric acid or 2-amino-N-methylacetamide, 110℃, 4h-5h, 50%-95%; or ethanol, sodium hydroxide aqueous solution, 75℃, 3h, 80%-85%;

[0039] Preferably, the preparation method uses the following reaction formula to prepare the compound in which R1 is methyl:

[0040]

[0041] The reagents and reaction conditions added in each step are as follows:

[0042] First, acetic acid, tetramethylmethanediamine, 0℃-80℃, 16h, 80%; second, acetic anhydride, 0℃-120℃, 20h; dichloromethane, sodium bicarbonate, 0℃; morpholine, 0℃-rt, 60%; then, palladium carbon, hydrogen, ethyl acetate, sodium carbonate, 60℃-68℃, 85%;

[0043] Preferably, the preparation method adopts the following reaction formula to prepare the compound in which R1 is an alkoxy group or a halogen group:

[0044]

[0045] Dichloromethane or alcohol, 1,3-dibromo-5,5-dimethylhydantoin or 1,3-dichloro-5,5-dimethylhydantoin or NBS or NCS, 0℃-rt, 50%-95%;

[0046] Preferably, the preparation method uses the following reaction formula to prepare the compound in which R1 is a cyano group:

[0047]

[0048] N-methylpyrrolidone, cuprous cyanide, 130℃, 4h, 78%.

[0049] The present invention can synthesize the pharmaceutically acceptable salts of the present invention from the compounds of the present invention containing a basic part or an acidic part by conventional chemical methods. Usually, the salts of the basic compounds are prepared by reacting with a suitable inorganic or organic acid in a suitable solvent or a combination of multiple solvents. Similarly, the salts of the acidic compounds are formed by reacting with a suitable inorganic or organic base.

[0050] Therefore, the pharmaceutically acceptable salts of the compounds described in the present invention include: conventional non-toxic salts formed by the reaction of the basic compounds of the present invention and inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid or nitric acid, etc.) or organic acids (e.g., acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid or trifluoroacetic acid, etc.). If the compounds of the present invention are acidic, then the salts prepared by pharmaceutically acceptable non-toxic bases include inorganic bases (including aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts or zinc salts, etc.) and organic bases (salts of primary, secondary and tertiary amines).

[0051] In a fifth aspect, the present invention further provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises the thyroid hormone beta receptor agonist as described in the first aspect. Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. Preferably, the pharmaceutically acceptable excipient comprises any one or a combination of at least two of an excipient, a diluent, a carrier, a flavoring agent, a binder or a filler.

[0052] Although the active ingredient can be administered alone, it is preferably present in a pharmaceutical preparation or composition. Therefore, the present invention provides a pharmaceutical composition comprising any one of the above compounds or a pharmaceutically acceptable ester, amide, solvate or salt thereof, including a salt of the ester or amide and a solvate of the ester, amide or salt, and a pharmaceutically acceptable excipient.

[0053] Preferably, the administration route of the pharmaceutical composition includes any one of intravenous injection, intramuscular injection, oral administration, inhalation administration, sublingual administration, rectal administration, vaginal administration, intracisternal administration, intrathecal administration, lumbar puncture administration, urethral administration, intradermal injection, intraperitoneal administration or transdermal administration. Typical but non-limiting examples of the administration route include oral, parenteral, intraperitoneal, intravenous, transdermal, sublingual, intramuscular, rectal, oral, intranasal, liposome and the like.

[0054] The pharmaceutical composition of the present invention may be in liquid, semi-liquid or solid form, and is formulated in a manner suitable for the route of administration used. As a preferred technical solution of the present invention, the dosage form of the pharmaceutical composition includes any one of tablets, capsules, granules, bulk powders, injections or freeze-dried powder injections. The oral pharmaceutical composition may be solid, gel or liquid; examples of solid preparations include but are not limited to tablets, capsules, granules and bulk powders. These preparations may optionally contain binders, diluents, disintegrants, lubricants, glidants, sweeteners and flavoring agents. Examples of binders include but are not limited to microcrystalline cellulose, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste; examples of lubricants include but are not limited to talc, starch, magnesium stearate, calcium stearate, stearic acid; examples of diluents include but are not limited to lactose, sucrose, starch, mannitol, dicalcium phosphate; examples of glidants include but are not limited to silicon dioxide; examples of disintegrants include but are not limited to cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar and carboxymethyl cellulose.

[0055] The pharmaceutical composition of the present invention is administered parenterally, generally by injection, including subcutaneous, intramuscular or intravenous injection. The injection can be prepared in any conventional form, such as a liquid solution or suspension, a solid form suitable for dissolving or suspending in a liquid before injection, or an emulsion. Examples of pharmaceutically acceptable carriers that can be used for the injection of the present invention include, but are not limited to, aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifiers, chelating agents, and other pharmaceutically acceptable substances. Examples of aqueous carriers include sodium chloride injection, Ringer's injection, isotonic glucose injection, sterile water injection, glucose and lactated Ringer's injection; examples of non-aqueous carriers include fixed oils of plant origin, cottonseed oil, corn oil, sesame oil, and peanut oil; examples of antimicrobial agents include metacresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, etc.; examples of isotonic agents include sodium chloride and glucose; buffers include phosphates and citrates.

[0056] The pharmaceutical composition of the present invention can also be prepared as a sterile lyophilized powder injection by dissolving the compound in a sodium phosphate buffer solution containing glucose or other suitable excipients, then aseptically filtering the solution under standard conditions, followed by freeze drying to obtain the desired preparation.

[0057] As a preferred technical solution of the present invention, the pharmaceutical composition also includes a therapeutic agent. The compound of the present invention can be used in combination with one or more other regulators and / or thyroid receptor ligands or one or more other suitable therapeutic agents.

[0058] Preferably, the therapeutic agent comprises any one of anti-non-alcoholic fatty liver agents, lipid-lowering agents, anti-atherosclerotic agents, anti-hypothyroidism agents, anti-diabetic agents, anti-cholesterol / lipid degrading agents, anti-osteoporosis agents, anti-obesity agents, growth promoters, anti-inflammatory agents, antianxiety agents, antidepressants, antihypertensive agents, cardiac glycosides, appetite suppressants, bone resorption inhibitors, thyroid mimetic agents, anabolic agents, anti-tumor agents or retinoids, or a combination of at least two thereof.

[0059] Examples of suitable hypolipidemic agents for use in combination with the compounds of the present invention include: acyl-CoA cholesterol acyltransferase (ACAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, cholesterol ester transfer protein (CETP) inhibitors, ileal bile acid transporter (IBAT) inhibitors, any cholesterol absorption inhibitors, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, squalene synthetase inhibitors, bile acid sequestrants, peroxisome proliferator-activated receptor-alpha agonists, peroxisome proliferator-activated receptor-delta agonists, peroxisome proliferator-activated receptor-gamma / delta agonists, any peroxisome proliferator-activated receptor-alpha / delta agonists, niacin or a derivative thereof, and thiazolidinedione or a derivative thereof.

[0060] Examples of suitable hypolipidemic agents for use in combination with the compounds of the present invention also include ezetimibe, various statins (eg, simvastatin, atorvastatin, rosuvastatin, cerivastatin, etc.), fenofibrate, gemfibrozil, and bezafibrate.

[0061] Examples of suitable antidiabetic agents for use in combination with the compounds of the present invention include biguanides, glucosidase inhibitors, insulin, meglitinides, sulfonylureas, biguanide / glibenclamide combinations, thiazolidinediones, peroxisome proliferator-activated receptor-alpha agonists, peroxisome proliferator-activated receptor-delta agonists, peroxisome proliferator-activated receptor-gamma / delta agonists, any peroxisome proliferator-activated receptor-alpha / delta agonists, SGLT1, 2 or 3 inhibitors, glycogen phosphorylase inhibitors, fatty acid binding protein inhibitors, glucagon-like peptide-1, glucocorticoid antagonists, and dipeptidyl peptidase IV inhibitors.

[0062] Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include aP2 inhibitors, peroxisome proliferator-activated receptor-gamma agonists, peroxisome proliferator-activated receptor-delta agonists, beta-3 adrenergic agonists, L750355 or CP331648 or other known beta-3 agonists, lipase inhibitors, serotonin (and dopamine) reuptake inhibitors, asoxetine, other thyroid receptor beta drugs, CB-1 antagonists or anorectics.

[0063] Examples of suitable anti-cholesterol / lipid degrading agents for use in combination with the compounds of the present invention include acyl-CoA cholesterol acyltransferase (ACAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, cholesterol ester transfer protein (CETP) inhibitors, ileal bile acid transporter (IBAT) inhibitors, any cholesterol absorption inhibitors, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, squalene synthetase inhibitors, bile acid sequestrants.

[0064] In a sixth aspect, the present invention also provides use of the compound described in the first aspect, the thyroid hormone receptor β agonist described in the second aspect, or the pharmaceutical composition described in the fourth aspect in the preparation of a method for preventing or treating thyroid hormone receptor-related diseases.

[0065] The present invention provides a compound with isoquinoline as the parent nucleus as described above, which has high selectivity and activity against mutant thyroid hormone receptor β ligands. Therefore, the compound can be used to treat diseases and conditions related to thyroid hormone receptors, especially diseases or conditions with high selectivity of thyroid hormone receptor β agonists and anti-mutant thyroid hormone receptor β agonists as indications. In particular, the compound of the present invention can be used to treat diseases or conditions related to metabolic dysfunction or dependent on T3-regulated gene expression.

[0066] Clinical conditions for which the use of agonists or partial agonists is indicated include, but are not limited to: hypothyroidism, subclinical hyperthyroidism, nontoxic goiter, atherosclerosis, NASH, thyroid hormone resistance (RTH), thyroid replacement therapy (e.g., in the elderly), malignant tumor cells that include thyroid receptors, papillary or follicular carcinoma, maintenance of muscle strength and function (e.g., in the elderly), reversal or prevention of decline or age-related functional impairment in the elderly, treatment of the catabolic side effects of glucocorticoids, prevention and / or treatment of decreased bone mass, bone density or bone growth, treatment of chronic fatigue syndrome, acceleration of complex fractures. Healing, joint replacement, eating disorders (e.g., anorexia), treatment of obesity and growth retardation associated with obesity, treatment of depression, nervousness, irritability, and tension, treatment of decreased mental energy and low self-esteem, improvement of cognitive function, treatment of catabolism associated with lung dysfunction and respiratory dependence, treatment of neo-function disorders, lowering of blood pressure, avoidance of ventricular dysfunction or prevention of reperfusion events, treatment of hyperinsulinemia, stimulation of osteoblasts, bone remodeling and cartilage growth, regulation of feeding, treatment of insulin resistance in mammals, NIDDM, treatment of insulin resistance in the heart, treatment of congestive heart failure, treatment of musculoskeletal injuries, improvement of overall lung function, skin diseases or conditions.

[0067] The compounds of the invention find particular application in the treatment or prevention of hypothyroidism, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, familial hypercholesterolemia, dyslipidemia, atherosclerosis, NASH, obesity, thyroid hormone resistance (RTH), replacement therapy for elderly subjects with hypothyroidism at risk for cardiovascular complications, diabetes, depression, osteoporosis (particularly in combination with bone resorption inhibitors), goiter, thyroid cancer, cardiovascular disease or congestive heart failure, glaucoma and skin diseases.

[0068] The compounds of the invention are particularly useful in the treatment or prevention of hypothyroidism, hypercholesterolemia, dyslipidemia or any other lipid disorder manifested by an imbalance in blood or tissue lipid levels, resistance to thyroid hormone (RTH), atherosclerosis, NASH, obesity, diabetes.

[0069] The present invention also provides the use of the compound shown in the above formula I or its pharmaceutically acceptable ester, amide, solvate or salt, including the salt of the ester or amide and the solvate of the ester, amide or salt, in the preparation of a medicament for treating or preventing a thyroid hormone receptor-mediated condition. The clinical conditions mediated by thyroid hormone receptor beta agonists that can be treated with the methods of the present invention are as described above.

[0070] Compared with the prior art, the present invention has the following beneficial effects:

[0071] The present invention provides a class of novel structural compounds that can be used as thyroid hormone receptor β agonists, which can selectively stimulate thyroid hormone receptor β, have no or very weak thyroid hormone receptor α agonism, and have no or very weak PHD2 target activity, and also have a good activation effect on mutant thyroid hormone receptor β;

[0072] The compound of formula I or the pharmaceutical composition thereof provided by the present invention can be used to prepare drugs for treating or preventing hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, familial hypercholesterolemia, dyslipidemia, atherosclerosis, NASH, obesity, thyroid hormone resistance (RTH), replacement therapy for elderly subjects with hypothyroidism and risk of cardiovascular complications, diabetes, depression, osteoporosis (especially in combination with bone resorption inhibitors), goiter, thyroid cancer, cardiovascular disease or congestive heart failure, glaucoma and skin diseases, and has broad application prospects.

[0073] At the same time, the present invention introduces various alkoxy groups into the 1'-isoquinoline mother nucleus in an innovative way, and the 1'-alkoxy substituted isoquinoline mother nucleus can be obtained quickly and in high yield simply by changing different solvents. Moreover, the structure of this type of compound is stable, the synthesis method is simple, and it is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0074] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0075] Example 1 2-(4-Hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamide)-2-methylpropanoic acid

[0076] Step 1: Synthesis of 5-phenoxyisobenzofuran-1(3H)-one

[0077]

[0078] 5-Bromophthalide (2.13 g, 10 mmol), phenol (1.21 g, 12 mmol), cuprous bromide (0.28 g, 2 mmol), acetylacetone (0.22 g, 2 mmol), potassium carbonate (1.71 g, 12 mmol) were added to 40 mL of N, N-dimethylformamide solvent, the gas was replaced three times, argon was protected, and stirred at 120 ° C for 30 h. TLC was used to detect the reaction. After the reaction was completed, ethyl acetate (100 mL), saturated brine (30 mL) and dilute hydrochloric acid (1 mol, 10 mL) were added to the reaction, shaken, and repeated three times. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE: EA = 30: 1, v / v) to obtain the target product as a white solid (1.61 g, yield: 70%). 1H NMR (500MHz, DMSO-d6) δ7.84 (d, J = 8.3Hz, 1H), 7.50 (t, J = 7.9Hz, 2H), 7.29 (t, J = 7.4Hz, 1H), 7.23-7.08 (m, 4H), 5.33 (s, 2H).

[0079] Step 2: Synthesis of methyl 2-(chloromethyl)-4-phenoxybenzoate

[0080]

[0081] Take a 15mL sealed tube and add 5-phenoxyisobenzofuran-1(3H)-one (2.26g, 10mmol) and benzyltriethylammonium chloride (0.45g, 0.2mmol). Place under Ar2, add 5ml of ultra-dry xylene, ultrasonicate for 30s, place the sealed tube in an ice bath, drop 0.24mL of boron trifluoride ether and 2mL of dichlorothionyl, stir at 120℃ for 10h. Cool to below zero, add 5mL of methanol, stir at room temperature for 1h. TLC detection reaction. After the reaction is completed, ethyl acetate (150mL) and saturated brine (30mL) are added to the reaction, shake, and repeat three times. Separate the organic layer, dry with anhydrous Na2SO4, and concentrate in vacuo. Purify the crude product by silica gel column chromatography (PE:EA=50:1, v / v) to obtain the target product as a viscous liquid (2.49g, yield: 95%). 1H NMR (500MHz, DMSO-d6) δ7.94 (d, J = 8.7Hz, 1H), 7.50-7.45 (m, 2H), 7.29-7.24 (m, 1H), 7. 23(d,J=2.6Hz,1H),7.14(m,2H),7.00(dd,J=8.7,2.6Hz,1H),5.08(s,2H),3.84(s,3H).

[0082] Step 3: Synthesis of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate

[0083]

[0084] Add 2-(chloromethyl)-4-phenoxybenzoic acid methyl ester (2.73g, 10mmol), p-toluenesulfonylglycine methyl ester (2.87g, 11.8mmol), KI (0.33g, 2mmol), potassium carbonate (1.27g, 12mmol) to 20mL of DMF solvent and stir at 50℃ for 3h. At room temperature, add 6.5mL of 5M CH3OH / CH3ONa dropwise and stir at room temperature for 4h. TLC detection reaction. After the reaction is completed, dilute hydrochloric acid is adjusted to acidity. Ethyl acetate (100mL) and saturated brine (30mL) are added to the reaction, shaken, and repeated three times. The organic layer is separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product is purified by silica gel column chromatography (PE:EA=30:1, v / v) to obtain the target product as a white solid (1.71g, yield: 58%). 1H NMR (500MHz, DMSO-d6) δ11.61(s,1H),8.73(s,1H),8.31(d,J=9.0Hz,1H),7.60(dd,J=9.0,2 .4Hz, 1H), 7.50 (t, J = 7.9Hz, 3H), 7.29 (t, J = 7.4Hz, 1H), 7.21 (d, J = 7.9Hz, 2H), 3.97 (s, 3H).

[0085] Step 4: Synthesis of methyl 1-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate

[0086]

[0087] Take a 15mL sealed tube, add 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (2.95g, 10mmol) and 8mL acetic acid. Place in an ice bath, drop tetramethylmethanediamine (1.53g, 15mmol), and stir at 80℃ for 20h. TLC detection reaction. After the reaction is completed, add NaHCO3 to remove acid. Add ethyl acetate (150mL) and saturated brine (30mL) to the reaction, shake, and repeat three times. Separate the organic layer, dry with anhydrous Na2SO4, and concentrate in vacuo. Purify the crude product by silica gel column chromatography (PE:EA=15:1, v / v) to obtain the target product as a white solid (2.81g, yield: 80%). 1H NMR (500MHz, DMSO-d6) δ11.65(s,1H),8.34(d,J=9.1Hz,1H),7.92(d,J=2.3Hz,1H),7.56(dd,J=9.1,2.3Hz,1H ),7.51(t,J=7.9Hz,2H),7.29(t,J=7.4Hz,1H),7.22(d,J=7.8Hz,2H),3.98(s,3H),3.71(s,2H),2.09(s,6H).

[0088] Step 5: Synthesis of methyl 1-(acetoxymethyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate

[0089]

[0090] Take a 48mL sealed tube, add 1-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (3.52g, 10mmol) and 15mL acetic acid. Place under ice bath conditions, drop acetic anhydride (4.08g, 40mmol), and stir at 120℃ for 20h. TLC detection reaction. Add DCM under ice bath conditions and add NaHCO3 in batches to remove acid. Finally, add 5mL morpholine, stir under ice bath conditions for 30min, and stir at room temperature for 1h. After the reaction is completed, ethyl acetate (150mL) and saturated brine (30mL) are added to the reaction, shaken, and repeated three times. The organic layer is separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product is purified by silica gel column chromatography (PE:EA=20:1, v / v) to obtain the target product as a white solid (3.12g, yield: 85%). 1HNMR(500MHz,DMSO-d6)δ11.67(s,1H),8.39(d,J=9.1Hz,1H),7.63(dd,J=9.1,2.3Hz,1H),7.50(t ,J=7.9Hz,3H),7.29(t,J=7.4Hz,1H),7.21(d,J=8.4Hz,2H),5.35(s,2H),3.97(s,3H),1.97(s,3H).

[0091] Step 6: Synthesis of methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate

[0092]

[0093] 1-(Acetoxymethyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (1.82g, 5mmol) and 10% Pd / C (250mg) were added to 10mL of ethyl acetate solvent, the gas was replaced three times, hydrogen was reacted, and the mixture was stirred at 60-68°C for 24h. The reaction was detected by TLC. After the reaction was completed, diatomaceous earth was passed, and ethyl acetate (100mL) and saturated brine (30mL) were added to the reaction, shaken, and repeated three times. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE:EA) to obtain the target product as a white solid (1.42g, yield: 92%). 1H NMR (500MHz, DMSO-d6) δ11.51(s,1H),8.35(d,J=9.0Hz,1H),7.61(d,J=2.2Hz,1H),7.55(dd,J=9.0,2. 2Hz, 1H), 7.50 (t, J = 7.9Hz, 2H), 7.28 (t, J = 7.4Hz, 1H), 7.20 (d, J = 8.2Hz, 2H), 3.97 (s, 3H), 2.66 (s, 3H).

[0094] Step 7: Synthesis of 2-(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamide)-2-methylpropanoic acid

[0095]

[0096] 4-Hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (0.309g, 1mmol), 2-methylalanine (0.310g, 3mmol), 1,8-diazabicycloundec-7-ene (0.456g, 3mmol) were added to 10mL of 2-methoxyethanol solvent and stirred at 110°C for 5h. TLC was used to monitor the reaction. After the reaction was completed, ethyl acetate (100mL), saturated brine (30mL) and 10mL of dilute hydrochloric acid were added to the reaction, shaken, and repeated three times. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE:EA) to obtain the target product as a white solid (0.311g, yield: 82%). 1H NMR (500MHz, DMSO-d6) δ13.20(s,1H),12.87(s,1H),8.83(s,1H),8.30(d,J=9.0Hz,1H),7.62(d,J=2.0Hz,1H),7.55( dd,J=9.0,2.2Hz,1H),7.49(t,J=7.9Hz,2H),7.27(t,J=7.4Hz,1H),7.20(d,J=7.9Hz,2H),2.71(s,3H),1.62(s,6H).

[0097] Example 2 (4-Hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine

[0098]

[0099] The synthesis method is the same as that in Example 1, white solid, yield 89%. 1H NMR (500MHz, DMSO-d6) δ13.58 (s, 1H), 12.80 (s, 1H), 9.29 (t, J = 5.3 Hz, 1H), 8.77 (s, 1H), 8.30 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.54 (s, 1H), 7.51 (t, J = 7.5 Hz, 2H), 7.29 (t, J = 7.1 Hz, 1H), 7.22 (d, J = 7.9 Hz, 2H), 4.04 (d, J = 5.6 Hz, 2H).

[0100] Example 3 (4-Hydroxy-1-methoxy-7-phenoxyisoquinoline-3-carbonyl)glycine

[0101] Step 1: 4-Hydroxy-1-methoxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester

[0102]

[0103] Add 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (0.30 g, 1 mmol) to 15 mL of methanol solvent. Place in an ice bath, add dibromohydantoin (0.16 g, 0.55 mmol) in batches, and stir at room temperature for 10 min. TLC detection reaction. After the reaction is completed, ethyl acetate (100 mL) and saturated brine (30 mL) are added to the reaction, shaken, and repeated three times. The organic layer is separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product is purified by silica gel column chromatography (PE: EA = 40: 1, v / v) to obtain the target product as a white solid (0.31 g, yield: 95%). 1H NMR (500MHz, DMSO-d6) δ11.36(s,1H),8.29(d,J=9.0Hz,1H),7.65(dd,J=9.0,1.6Hz,1H),7.52(t, J=7.6Hz,2H),7.38(s,1H),7.31(t,J=7.2Hz,1H),7.23(d,J=8.2Hz,2H),3.96(s,3H),3.94(s,3H).

[0104] Step 2: Synthesis of (4-hydroxy-1-methoxy-7-phenoxyisoquinoline-3-carbonyl)glycine

[0105]

[0106] The synthesis method is the same as that in Example 1, white solid, yield 82%. 1H NMR (500MHz, DMSO-d6) δ 13.10 (s, 1H), 12.88 (s, 1H), 8.92 (t, J = 3.2 Hz, 1H), 8.25 (d, J = 9.0 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.41 (s, 1H), 7.30 (t, J = 7.3 Hz, 1H), 7.22 (d, J = 7.7 Hz, 2H), 4.03 (s, 3H), 4.01 (d, J = 6.1 Hz, 2H).

[0107] Example 4 (1-ethoxy-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) glycine

[0108]

[0109] The synthesis method is the same as that in Example 3, white solid, yield 80%. 1H NMR (500MHz, DMSO-d6) δ13.05 (s, 1H), 12.77 (s, 1H), 8.92 (t, J = 6.1 Hz, 1H), 8.24 (d, J = 9.0 Hz, 1H), 7.61 (dd, J = 9.0, 2.5 Hz, 1H), 7.52-7.49 (m, 3H), 7.29 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 7.8 Hz, 2H), 4.53 (q, J = 7.0 Hz, 2H), 4.04 (d, J = 6.1 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H).

[0110] Example 5 (4-Hydroxy-1-isopropoxy-7-phenoxyisoquinoline-3-carbonyl)glycine

[0111]

[0112] The synthesis method is the same as that in Example 3, white solid, yield 93%. 1H NMR (500MHz, DMSO-d6) δ13.05 (s, 1H), 12.81 (s, 1H), 8.88 (t, J = 6.0 Hz, 1H), 8.23 ​​(d, J = 9.0 Hz, 1H), 7.57 (dd, J = 9.0, 2.4 Hz, 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.49 (t, J = 7.9 Hz, 2H), 7.27 (t, J = 7.4 Hz, 1H), 7.18 (d, J = 7.9 Hz, 2H), 5.62 (dt, J = 12.2, 6.1 Hz, 1H), 4.04 (d, J = 6.0 Hz, 2H), 1.33 (d, J = 6.1 Hz, 6H).

[0113] Example 6 (1-chloro-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine

[0114] Step 1: Synthesis of methyl 1-chloro-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate

[0115]

[0116] Add 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (0.30 g, 1 mmol) to 15 mL of DCM solvent. Place in an ice bath, add dichlorohydantoin (0.29 g, 1.5 mmol) in batches, and stir at room temperature for 1 h 30 min. TLC detects the reaction. After the reaction is completed, ethyl acetate (100 mL) and saturated brine (30 mL) are added to the reaction, shaken, and repeated three times. The organic layer is separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product is purified by silica gel column chromatography (PE: EA = 40: 1, v / v) to obtain the target product as a white solid (0.25 g, yield: 75%). 1H NMR(500MHz,DMSO-d6)δ11.56(s,1H),8.41(d,J=9.1Hz,1H),7.71(dd,J=9.1,2.4Hz,1H),7.6 1-7.51(m,2H),7.46(d,J=2.4Hz,1H),7.33(t,J=7.4Hz,1H),7.30-7.22(m,2H),3.97(s,3H).

[0117] Step 2: Synthesis of (1-chloro-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine

[0118]

[0119] The synthesis method is the same as that in Example 3, white solid, yield 70%. 1H NMR (500MHz, DMSO-d6) δ13.67 (s, 1H), 12.87 (s, 1H), 9.16 (t, J = 6.1 Hz, 1H), 8.37 (d, J = 9.1 Hz, 1H), 7.70 (dd, J = 9.1, 2.4 Hz, 1H), 7.56-7.51 (m, 2H), 7.50 (d, J = 2.4 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.29-7.24 (m, 2H), 4.02 (d, J = 6.1 Hz, 2H).

[0120] Example 7 (1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine

[0121]

[0122] The synthesis method is the same as that in Example 6, white solid, yield 76%. 1H NMR (500MHz, DMSO-d6) δ13.67 (s, 1H), 12.84 (s, 1H), 9.16 (t, J = 6.2 Hz, 1H), 8.37 (t, J = 6.3 Hz, 1H), 7.71 (dd, J = 8.8, 2.1 Hz, 1H), 7.58-7.44 (m, 3H), 7.34 (t, J = 7.2 Hz, 1H), 7.27 (d, J = 7.9 Hz, 2H), 4.03 (d, J = 5.7 Hz, 2H).

[0123] Example 8 4-Hydroxy-7-phenoxyisoquinoline-3-carboxylic acid

[0124]

[0125] Add 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (0.295 g, 1 mmol) to 20 mL of ethanol and drop an excess of sodium hydroxide aqueous solution. Stir at 75 ° C for 3 h. TLC reaction was detected. After the reaction was completed, dilute hydrochloric acid was added to neutralize the excess sodium hydroxide. Ethyl acetate (150 mL) and saturated brine (30 mL) were added to the reaction, shaken, and repeated three times. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography to obtain the target product as a white solid (0.251 g, yield: 92%). 1H NMR(500MHz,DMSO-d6)δ8.70(s,1H),8.43(d,J=8.9Hz,1H),7.77(s,1H),7.73(d, J=8.9Hz, 1H), 7.51 (t, J=7.8Hz, 2H), 7.31 (t, J=7.3Hz, 1H), 7.22 (d, J=7.9Hz, 2H).

[0126] Example 9 4-Hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid

[0127]

[0128] The synthesis method is the same as that of Example 8, white solid, yield 92%. 1H NMR (500 MHz, DMSO-d6) δ 8.43 (d, J = 9.0 Hz, 1H), 7.77 (d, J = 1.7 Hz, 1H), 7.66 (dd, J = 9.0, 1.9 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 7.9 Hz, 2H), 2.88 (s, 3H).

[0129] Example 10 Methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate

[0130]

[0131] The synthesis method is the same as that in Example 1, white solid, yield 92%. 1H NMR (500MHz, DMSO-d6) δ11.51 (s, 1H), 8.35 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 9.0, 2.2 Hz, 1H), 7.50 (t, J = 7.9 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 8.2 Hz, 2H), 3.97 (s, 3H), 2.66 (s, 3H).

[0132] Example 11 (1-ethoxy-4-hydroxy-7-(4-phenoxyphenoxy)isoquinoline-3-carbonyl)glycine

[0133]

[0134] The synthesis method is the same as that in Example 3, white solid, yield 82%. 1H NMR (500MHz, DMSO-d6) δ 13.05 (s, 1H), 12.80 (s, 1H), 8.91 (t, J = 5.9 Hz, 1H), 8.23 ​​(d, J = 9.0 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.47 (s, 1H), 7.41 (t, J = 7.5 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.16 (t, J = 8.0 Hz, 3H), 7.05 (d, J = 7.8 Hz, 2H), 4.53 (q, J = 6.9 Hz, 2H), 4.04 (d, J = 6.0 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H).

[0135] Example 12 (1-ethoxy-4-hydroxy-7-(naphthalen-1-yloxy)isoquinoline-3-carbonyl)glycine

[0136]

[0137] The synthesis method is the same as that in Example 3, white solid, yield 79%. 1H NMR (500MHz, DMSO-d6) δ 13.05 (s, 1H), 12.80 (s, 1H), 8.90 (t, J = 6.0 Hz, 1H), 8.25 (d, J = 9.0 Hz, 1H), 8.04 (dd, J = 16.1, 8.3 Hz, 2H), 7.88 (d, J = 8.3 Hz, 1H), 7.70-7.53 (m, 4H), 7.50 (s, 1H), 7.27 (d, J = 7.5 Hz, 1H), 4.49 (q, J = 6.9 Hz, 2H), 4.04 (d, J = 6.0 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H).

[0138] Example 13 (1-ethoxy-4-hydroxy-7-(3-phenoxyphenoxy)isoquinoline-3-carbonyl)glycine

[0139]

[0140] The synthesis method is the same as in Example 3, white solid, yield 85%. 1H NMR (500MHz, DMSO-d6) δ13.04 (s, 1H), 12.76 (s, 1H), 8.91 (t, J = 5.8 Hz, 1H), 8.22 (d, J = 8.9 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.54 (s, 1H), 7.47 (t, J = 8.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2 H),7.16(t,J=7.3Hz,1H),7.08(d,J=7.9Hz,2H),6.92(d,J=8.1Hz,1H),6.88(d,J=8.2H z, 1H), 6.81 (s, 1H), 4.54 (q, J = 6.9Hz, 2H), 4.04 (d, J = 5.9Hz, 2H), 1.38 (t, J = 7.0Hz, 3H).

[0141] Example 14 (7-(3-benzylphenoxy)-1-ethoxy-4-hydroxyisoquinoline-3-carbonyl)glycine

[0142]

[0143] The synthesis method is the same as in Example 3, white solid, yield 82%. 1H NMR (500MHz, DMSO-d6) δ13.04 (s, 1H), 12.78 (s, 1H), 8.91 (t, J = 5.9 Hz, 1H), 8.22 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.47 (s, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.32-7.22 ( m,4H),7.19(t,J=7.1Hz,1H),7.14(d,J=7.6Hz,1H),7.08(s,1H),7.00(d,J=8.0Hz,1 H), 4.52 (q, J = 7.0Hz, 2H), 4.04 (d, J = 6.0Hz, 2H), 3.98 (s, 2H), 1.35 (t, J = 7.0Hz, 3H).

[0144] Example 15 (7-(4-(tert-butyl)phenoxy)-1-ethoxy-4-hydroxyisoquinoline-3-carbonyl)glycine

[0145]

[0146] The synthesis method is the same as that in Example 3, white solid, yield 80%. 1H NMR (500MHz, DMSO-d6) δ13.04 (s, 1H), 12.81 (s, 1H), 8.89 (t, J = 6.0 Hz, 1H), 8.22 (d, J = 9.0 Hz, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.50-7.48 (m, 3H), 7.10 (d, J = 8.4 Hz, 2H), 4.52 (q, J = 7.0 Hz, 2H), 4.03 (d, J = 6.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H), 1.31 (s, 9H).

[0147] Example 16 (4-hydroxy-1-(2-methoxyethoxy)-7-phenoxyisoquinoline-3-carbonyl)glycine

[0148]

[0149] The synthesis method is the same as that in Example 3, white solid, yield 80%. 1H NMR (500MHz, DMSO-d6) δ13.08 (s, 1H), 12.81 (s, 1H), 8.97 (t, J = 6.2 Hz, 1H), 8.24 (d, J = 9.0 Hz, 1H), 7.61 (dd, J = 9.0, 2.5 Hz, 1H), 7.55-7.43 (m, 3H), 7.28 (t, J = 7.4 Hz, 1H), 7.22-7.16 (m, 2H), 4.60 (t, J = 6.2 Hz, 2H), 4.02 (d, J = 6.2 Hz, 2H), 3.70 (t, J = 4.6 Hz, 2H), 3.27 (s, 3H).

[0150] Example 17 (1-cyclobutyloxy-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine

[0151]

[0152] The synthesis method is the same as Example 3, white solid, yield 80%. 1H NMR(500MHz,DMSO-d6)δ13.03(s,1H),12.82(s,1H),8.73(t,J=6.1Hz,1H),8 .23(d,J=9.0Hz,1H),7.59(dd,J=9.0,2.5Hz,1H),7.53-7.47(m,3H),7.29(t, J=7.4Hz,1H),7.22-7.17(m,2H),5.42(p,J=7.3Hz,1H),4.06(d,J=6.1Hz,2H) ,2.59-2.52(m,2H),2.14-1.98(m,2H),1.81-1.79(m,1H),1.72-1.61(m,1H).

[0153] Example 18 (1-(cyclohexyloxy)-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine

[0154]

[0155] The synthesis method is the same as that in Example 3, white solid, yield 81%. 1H NMR (500MHz, DMSO-d6) δ 13.05 (s, 1H), 12.84 (s, 1H), 8.82 (t, J = 5.5 Hz, 1H), 8.22 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.54-7.44 (m, 3H), 7.28 (t, J = 7.3 Hz, 1H), 7.20 (d, J = 7.7 Hz, 2H), 5.43-5.41 (s, 1H), 4.04 (d, J = 5.7 Hz, 2H), 1.88-1.86 (s, 2H), 1.78-1.28 (m, 8H).

[0156] Example 19 (1-(cyclohexyloxy)-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine

[0157] Step 1: Synthesis of methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate

[0158]

[0159] Add 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (0.37 g, 1 mmol) to 10 mL of NMP solvent. Add CuCN (0.11 g, 1.2 mmol) and stir at 130 ° C for 4 h. TLC reaction was detected. After the reaction was completed, ethyl acetate (100 mL) and saturated brine (30 mL) were added to the reaction, shaken, and repeated three times. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography to obtain the target product as a white solid (0.22 g, yield: 70%). 1H NMR (500MHz, DMSO-d6) δ8.46(d,J=9.2Hz,1H),7.76(dd,J=9.2,2.4Hz,1H),7.58-7.64(m,2H),7.38(t,J=7.4Hz,1H),7.35-7.27(m,3H),4.00(s,3H). MS(ESI)m / z forC18H12N2O4(M+H)+calcd 319.07, found 319.1.

[0160] Step 2: Synthesis of (1-(cyclohexyloxy)-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine

[0161]

[0162] The synthesis method is the same as that in Example 3, white solid, yield 82%. 1H NMR (500MHz, DMSO-d6) δ14.44 (s, 1H), 12.86 (s, 1H), 9.50 (t, J = 3.2 Hz, 1H), 8.42 (d, J = 9.1 Hz, 1H), 7.74 (d, J = 9.1 Hz, 1H), 7.56 (t, J = 7.4 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.33 (s, 1H), 7.30 (d, J = 7.8 Hz, 2H), 4.04 (d, J = 5.9 Hz, 2H).

[0163] Example 20 (1-(Cyclopentyloxy)-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine

[0164]

[0165] The synthesis method is the same as that in Example 3, white solid, yield 80%. 1H NMR (500MHz, DMSO-d6) δ 13.03 (s, 1H), 12.83 (s, 1H), 8.85 (t, J = 5.8 Hz, 1H), 8.23 ​​(d, J = 8.9 Hz, 1H), 7.96 (s, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.51-7.48 (m, 3H), 7.28 (t, J = 7.3 Hz, 1H), 7.19 (d, J = 7.8 Hz, 2H), 5.72-5.70 (m, 1H), 4.05 (d, J = 5.8 Hz, 2H), 2.04-2.02 (m, 2H), 1.69-1.60 (m, 6H).

[0166] Example 21 (7-(3-benzoylphenoxy)-1-ethoxy-4-hydroxyisoquinoline-3-carbonyl)glycine

[0167]

[0168] The synthesis method is the same as that in Example 3, white solid, yield 82%. 1H NMR (500MHz, DMSO-d6) δ 13.07 (s, 1H), 12.80 (s, 1H), 8.93 (t, J = 5.7 Hz, 1H), 8.26 (d, J = 8.9 Hz, 1H), 7.77 (d, J = 7.6 Hz, 2H), 7.68 (t, J = 7.9 Hz, 3H), 7.61 (d, J = 8.5 Hz, 2H), 7.55 (t, J = 7.5 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 4.55 (q, J = 6.9 Hz, 2H), 4.04 (d, J = 5.9 Hz, 2H), 1.38 (t, J = 6.9 Hz, 3H).

[0169] Example 22 (7-(4-benzylphenoxy)-1-ethoxy-4-hydroxyisoquinoline-3-carbonyl)glycine

[0170]

[0171] The synthesis method is the same as that in Example 3, white solid, yield 80%. 1H NMR (500MHz, DMSO-d6) δ13.04 (s, 1H), 12.79 (s, 1H), 8.89 (t, J = 6.0 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.57 (d, J = 9.1 Hz, 1H), 7.44 (s, 1H), 7.34-7.30 (m, 4H), 7.26 (d, J = 7.3 Hz, 2H), 7.21 (t, J = 7.1 Hz, 1H), 7.11 (d, J = 8.3 Hz, 2H), 4.51 (q, J = 7.0 Hz, 2H), 4.04 (d, J = 6.0 Hz, 2H), 3.99 (s, 2H), 1.34 (t, J = 7.0 Hz, 3H).

[0172] Example 23 (7-(3-cyanophenoxy)-1-ethoxy-4-hydroxyisoquinoline-3-carbonyl)glycine

[0173]

[0174] The synthesis method is the same as that in Example 3, white solid, yield 82%. 1H NMR (500MHz, DMSO-d6) δ 13.07 (s, 1H), 12.80 (s, 1H), 8.94 (t, J = 5.7 Hz, 1H), 8.27 (d, J = 8.9 Hz, 1H), 7.73-7.71 (m, 2H), 7.78-7.74 (m, 2H), 7.60 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 4.55 (q, J = 6.7 Hz, 2H), 4.05 (d, J = 6.0 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H).

[0175] Example 24 (1-ethoxy-4-hydroxy-7-(3-(trifluoromethyl)phenoxy)isoquinoline-3-carbonyl)glycine

[0176]

[0177] The synthesis method is the same as that in Example 3, white solid, yield 80%. 1H NMR (500MHz, DMSO-d6) δ13.05 (s, 1H), 12.78 (s, 1H), 8.92 (t, J = 5.7 Hz, 1H), 8.26 (d, J = 8.9 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.64-7.60 (m, 3H), 7.55 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 4.53 (q, J = 6.9 Hz, 2H), 4.05 (d, J = 6.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H).

[0178] Example 25 (7-([1,1'-biphenyl]-4-yloxy)-1-ethoxy-4-hydroxyisoquinoline-3-carbonyl)glycine

[0179]

[0180] The synthesis method is the same as Example 3, white solid, yield 80%. 1H NMR(500MHz,DMSO-d6)δ13.07(s,1H),12.80(s,1H),8.92(t,J=5.9Hz,1H),8.2 6(d,J=9.0Hz,1H),7.78(d,J=7.9Hz,2H),7.70(d,J=7.7Hz,2H),7.65(d,J=9.0 Hz,1H),7.59(s,1H),7.48(t,J=7.4Hz,2H),7.38(t,J=7.3Hz,1H),7.27(d,J=7 .9Hz, 2H), 4.54 (q, J = 7.0Hz, 2H), 4.05 (d, J = 5.9Hz, 2H), 1.36 (t, J = 7.0Hz, 3H).

[0181] Example 26 (1-ethoxy-4-hydroxy-7-(3-isopropylphenoxy)isoquinoline-3-carbonyl)glycine

[0182]

[0183] The synthesis method is the same as in Example 3, white solid, yield 80%. 1H NMR (500MHz, DMSO-d6) δ13.04 (s, 1H), 12.80 (s, 1H), 8.89 (t, J = 5.9 Hz, 1H), 8.22 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.50 (s, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 7.7Hz,1H),7.10(s,1H),6.97(d,J=8.0Hz,1H),4.51(q,J=7.0Hz,2H),4.04(d,J=5. 9Hz, 2H), 2.93 (dt, J = 13.7, 6.8Hz, 1H), 1.34 (t, J = 7.0Hz, 3H), 1.21 (d, J = 6.8Hz, 6H).

[0184] Example 27 (7-([1,1'-biphenyl]-3-yloxy)-1-ethoxy-4-hydroxyisoquinoline-3-carbonyl)glycine

[0185]

[0186] The synthesis method is the same as that in Example 3, white solid, yield 82%. 1H NMR (500MHz, DMSO-d6) δ 13.06 (s, 1H), 12.77 (s, 1H), 8.91 (t, J = 6.0 Hz, 1H), 8.25 (d, J = 9.0 Hz, 1H), 7.70 (d, J = 7.7 Hz, 2H), 7.64 (d, J = 9.0 Hz, 1H), 7.60-6.55 (m, 3H), 7.51-7.43 (m, 3H), 7.39 (t, J = 7.3 Hz, 1H), 7.18 (d, J = 6.4 Hz, 1H), 4.53 (q, J = 7.0 Hz, 2H), 4.04 (d, J = 6.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H).

[0187] Example 28 ((1-ethoxy-4-hydroxy-7-(4-isopropylphenoxy)isoquinoline-3-carbonyl)glycine

[0188]

[0189] The synthesis method is the same as that in Example 3, white solid, yield 82%. 1H NMR (500MHz, DMSO-d6) δ 13.04 (s, 1H), 12.80 (s, 1H), 8.89 (t, J = 5.9 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 4.52 (q, J = 7.0 Hz, 2H), 4.04 (d, J = 6.0 Hz, 2H), 2.94 (dt, J = 13.8, 6.9 Hz, 1H), 1.35 (t, J = 7.0 Hz, 3H), 1.23 (d, J = 6.9 Hz, 6H).

[0190] Example 29 (1-ethoxy-4-hydroxy-7-(naphthalen-2-yloxy)isoquinoline-3-carbonyl)glycine

[0191]

[0192] The synthesis method is the same as Example 3, white solid, yield 82%. 1H NMR(500MHz,DMSO-d6)δ13.07(s,1H),12.79(s,1H),8.91(t,J=6.0Hz,1H),8.27( d,J=9.0Hz,1H),8.06(d,J=8.9Hz,1H),7.98(d,J=7.9Hz,1H),7.89(d,J=8.0Hz,1 H),7.67(d,J=9.0Hz,1H),7.64(s,1H),7.59(s,1H),7.57-7.48(m,2H),7.42(d,J =8.9Hz, 1H), 4.52 (q, J = 7.0Hz, 2H), 4.05 (d, J = 6.0Hz, 2H), 1.32 (t, J = 7.0Hz, 3H).

[0193] Example 30 (7-(3-(tert-butyl)phenoxy)-1-ethoxy-4-hydroxyisoquinoline-3-carbonyl)glycine

[0194]

[0195] The synthesis method is the same as that in Example 3, white solid, yield 82%. 1H NMR (500MHz, DMSO-d6) δ 13.04 (s, 1H), 12.79 (s, 1H), 8.89 (t, J = 6.0 Hz, 1H), 8.23 ​​(d, J = 9.0 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.51 (s, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.25 (s, 1H), 6.97 (d, J = 8.0 Hz, 1H), 4.51 (q, J = 7.0 Hz, 2H), 4.04 (d, J = 6.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H), 1.30 (s, 9H).

[0196] Example 31 (7-(3,5-difluoro-4-methoxyphenoxy)-1-ethoxy-4-hydroxyisoquinoline-3-carbonyl)glycine

[0197]

[0198] The synthesis method is the same as that in Example 3, white solid, yield 91%. 1H NMR (500MHz, DMSO-d6) δ 13.07 (s, 1H), 12.83 (s, 1H), 8.92 (t, J = 5.8 Hz, 1H), 8.24 (d, J = 8.9 Hz, 1H), 7.61 (d, J = 10.2 Hz, 1H), 7.59 (s, 1H), 6.97 (d, J = 5.6 Hz, 1H), 6.92 (dd, J = 10.8, 5.6 Hz, 1H), 4.56 (q, J = 6.9 Hz, 2H), 4.04 (d, J = 5.9 Hz, 2H), 3.87 (s, 3H), 1.39 (t, J = 6.9 Hz, 3H).

[0199] Example 32 (4-hydroxy-1-methoxy-7-(4-(2-phenylpropan-2-yl)phenoxy)isoquinoline-3-carbonyl)glycine

[0200]

[0201] The synthesis method is the same as that in Example 3, white solid, yield 82%. 1H NMR (500MHz, DMSO-d6) δ 13.06 (s, 1H), 12.81 (s, 1H), 8.94 (t, J = 5.6 Hz, 1H), 8.22 (d, J = 8.9 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.42 (s, 1H), 7.35-7.24 (m, 6H), 7.18 (t, J = 6.9 Hz, 1H), 7.09 (d, J = 7.8 Hz, 2H), 4.07 (s, 3H), 4.05 (d, J = 6.1 Hz, 2H), 1.68 (s, 6H).

[0202] Example 33 (7-(4-cyanophenoxy)-1-ethoxy-4-hydroxyisoquinoline-3-carbonyl)glycine

[0203]

[0204] The synthesis method is the same as that in Example 3, white solid, yield 81%. 1H NMR (500MHz, DMSO-d6) δ13.07 (s, 1H), 12.81 (s, 1H), 8.94 (t, J = 6.0 Hz, 1H), 8.28 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 8.7 Hz, 2H), 7.84-7.57 (m, 2H), 7.28 (d, J = 8.7 Hz, 2H), 4.55 (q, J = 7.0 Hz, 2H), 4.05 (d, J = 6.1 Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H).

[0205] Example 34 (7-(3-benzylphenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0206]

[0207] The synthesis method is the same as Example 3, white solid, yield 81%. 1H NMR(500MHz,DMSO-d6)δ13.06(s,1H),12.80(s,1H),8.94(t,J=5.9Hz,1H),8.2 2(d,J=9.0Hz,1H),7.60(d,J=9.0Hz,1H),7.44-7.38(m,2H),7.30(t,J=7.3Hz, 2H),7.25(d,J=7.4Hz,2H),7.20(t,J=7.0Hz,1H),7.15(d,J=7.6Hz,1H),7.10( s, 1H), 7.02 (d, J = 8.0Hz, 1H), 4.05 (d, J = 6.0Hz, 2H), 4.03 (s, 3H), 3.98 (s, 2H).

[0208] Example 35 (4-hydroxy-1-methoxy-7-(naphthalen-2-yloxy)isoquinoline-3-carbonyl)glycine

[0209]

[0210] The synthesis method is the same as that in Example 3, white solid, yield 72%. 1H NMR (500MHz, DMSO-d6) δ 13.08 (s, 1H), 12.77 (s, 1H), 8.94 (t, J = 6.0 Hz, 1H), 8.27 (d, J = 9.0 Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.74-7.65 (m, 2H), 7.59-7.51 (m, 2H), 7.47 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 4.05 (d, J = 6.0 Hz, 2H), 4.00 (s, 3H).

[0211] Example 36 (4-hydroxy-7-(3-isopropylphenoxy)-1-methoxyisoquinoline-3-carbonyl)glycine

[0212]

[0213] The synthesis method is the same as that in Example 3, white solid, yield 84%. 1H NMR (500MHz, DMSO-d6) δ 13.05 (s, 1H), 12.78 (s, 1H), 8.93 (t, J = 6.0 Hz, 1H), 8.28 (s, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 1.5 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.09 (s, 1H), 6.99 (d, J = 8.1 Hz, 1H), 4.05 (d, J = 6.0 Hz, 2H), 4.03 (s, 3H), 2.93 (dt, J = 13.7, 6.9 Hz, 1H), 1.22 (d, J = 6.9 Hz, 6H).

[0214] Example 37 (1-chloro-4-hydroxy-7-(3-isopropylphenoxy)isoquinoline-3-carbonyl)glycine

[0215]

[0216] The synthesis method is the same as that in Example 3, white solid, yield 72%. 1H NMR (500MHz, DMSO-d6) δ13.56 (s, 1H), 9.12 (t, J = 5.7 Hz, 1H), 8.34 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.50 (s, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.15 (s, 1H), 7.04 (d, J = 7.9 Hz, 1H), 4.03 (d, J = 5.9 Hz, 2H), 2.94 (dt, J = 13.6, 6.7 Hz, 1H), 1.22 (d, J = 6.7 Hz, 6H).

[0217] Example 38 (1-chloro-4-hydroxy-7-(3-phenoxyphenoxy)isoquinoline-3-carbonyl)glycine

[0218]

[0219] The synthesis method is the same as that in Example 6, white solid, yield 72%. 1H NMR (500MHz, DMSO-d6) δ12.78 (s, 1H), 8.38 (d, J = 8.7 Hz, 1H), 8.17 (t, J = 5.4 Hz, 1H), 7.69 (s, 1H), 7.54 (d, J = 9.1 Hz, 1H), 7.42-7.37 (m, 3H), 7.15 (t, J = 7.0 Hz, 1H), 7.09-7.05 (m, 2H), 6.91 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.80 (s, 1H), 4.35 (d, J = 5.4 Hz, 2H).

[0220] Example 39 (7-(4-benzoylphenoxy)-1-ethoxy-4-hydroxyisoquinoline-3-carbonyl)glycine

[0221]

[0222] The synthesis method is the same as that in Example 3, white solid, yield 75%. 1H NMR (500MHz, DMSO-d6) δ13.07 (s, 1H), 12.81 (s, 1H), 8.95 (t, J = 5.9 Hz, 1H), 8.29 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.75 (d, J = 7.6 Hz, 2H), 7.73-7.64 (m, 3H), 7.58 (t, J = 7.3 Hz, 2H), 7.27 (d, J = 7.7 Hz, 2H), 4.55 (q, J = 6.9 Hz, 2H), 4.05 (d, J = 5.9 Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H).

[0223] Example 40 7-(4-Benzoyl-2,6-dimethylphenoxy)-4-hydroxy-1-methoxy-N-(2-(methylamino)-2-oxoethyl)isoquinoline-3-carboxamide

[0224]

[0225] The synthesis method is the same as that in Example 3, white solid, yield 78%. 1H NMR (500MHz, DMSO-d6) δ13.11 (s, 1H), 8.86 (t, J = 6.0 Hz, 1H), 8.27 (d, J = 9.0 Hz, 1H), 7.96 (d, J = 4.4 Hz, 1H), 7.81 (d, J = 7.4 Hz, 2H), 7.72 (t, J = 7.4 Hz, 1H), 7.66 (s, 2H), 7.61 (t, J = 7.7 Hz, 2H), 7.18 (d, J = 2.3 Hz, 1H), 4.03 (s, 3H), 3.94 (d, J = 6.0 Hz, 2H), 2.63 (d, J = 4.6 Hz, 3H), 2.16 (s, 8H).

[0226] Example 41 (1-ethoxy-4-hydroxy-7-(3-(phenylethynyl)phenoxy)isoquinoline-3-carbonyl)glycine

[0227]

[0228] The synthesis method is the same as that in Example 3, white solid, yield 72%. 1H NMR (500MHz, DMSO-d6) δ 13.06 (s, 1H), 12.80 (s, 1H), 8.92 (t, J = 5.4 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.57-7.52 (m, 4H), 7.44 (d, J = 13.8 Hz, 3H), 7.33 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 4.54 (q, J = 6.8 Hz, 2H), 4.05 (d, J = 5.9 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H).

[0229] Example 42 (1-ethoxy-4-hydroxy-7-(3-phenylethoxy)isoquinoline-3-carbonyl)glycine

[0230]

[0231] The synthesis method is the same as in Example 3, white solid, yield 80%. 1H NMR (500MHz, DMSO-d6) δ13.06 (s, 1H), 12.78 (s, 1H), 8.90 (t, J = 5.7 Hz, 1H), 8.22 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.49 (s, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.25 (t, J = 7.1 Hz, 1H) z,2H),7.20(d,J=7.4Hz,2H),7.18-7.09(m,2H),7.03(s,1H),6.99(d,J=8.1Hz,1H),4 .53(q,J=6.8Hz,2H),4.04(d,J=5.7Hz,2H),2.89-2.92(m,4H),1.36(t,J=6.9Hz,3H).

[0232] Example 43 (4-hydroxy-1-methoxy-7-(naphthalen-1-yloxy)isoquinoline-3-carbonyl)glycine

[0233]

[0234] The synthesis method is the same as that in Example 3, white solid, yield 72%. 1H NMR (500MHz, DMSO-d6) δ 13.07 (s, 1H), 12.74 (s, 1H), 8.92 (t, J = 5.8 Hz, 1H), 8.28 (d, J = 9.0 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.61 (q, J = 7.7 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.37-7.30 (m, 2H), 4.03 (d, J = 6.1 Hz, 2H), 3.97 (s, 3H).

[0235] Example 44 (7-(4-(tert-butyl)phenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0236]

[0237] The synthesis method is the same as that in Example 3, white solid, yield 82%. 1H NMR (500MHz, DMSO-d6) δ 13.04 (s, 1H), 12.70 (s, 1H), 8.91 (t, J = 5.9 Hz, 1H), 8.20 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.41 (s, 1H), 7.11 (d, J = 8.4 Hz, 2H), 4.05 (d, J = 6.0 Hz, 2H), 4.02 (s, 3H), 7.41 (s, 9H).

[0238] Example 45 (7-(3-cyanophenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0239]

[0240] The synthesis method is the same as that in Example 3, white solid, yield 82%. 1H NMR (500MHz, DMSO-d6) δ 13.06 (s, 1H), 12.77 (s, 1H), 8.95 (t, J = 5.9 Hz, 1H), 8.25 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 5.4 Hz, 2H), 7.66 (dd, J = 17.6, 9.0 Hz, 2H), 7.54 (d, J = 8.3 Hz, 1H), 7.50 (s, 1H), 4.05 (d, J = 6.0 Hz, 2H), 4.03 (s, 3H).

[0241] Example 46 (7-(4-cyanophenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0242]

[0243] The synthesis method is the same as that in Example 3, white solid, yield 80%. 1H NMR (500MHz, DMSO-d6) δ 13.08 (s, 1H), 12.71 (s, 1H), 8.98 (t, J = 5.8 Hz, 1H), 8.29 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 9.0 Hz, 1H), 7.64 (s, 1H), 7.31 (d, J = 8.2 Hz, 2H), 4.05 (d, J = 6.0 Hz, 2H), 4.03 (s, 3H).

[0244] Example 47 (4-hydroxy-1-methoxy-7-(3-(trifluoromethyl)phenoxy)isoquinoline-3-carbonyl)glycine

[0245]

[0246] The synthesis method is the same as that in Example 3, white solid, yield 80%. 1H NMR (500MHz, DMSO-d6) δ13.06 (s, 1H), 12.80 (s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 8.26 (d, J = 8.9 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.64 (t, J = 10.5 Hz, 2H), 7.56 (s, 1H), 7.54-7.46 (m, 2H), 4.05 (d, J = 6.0 Hz, 2H), 4.03 (s, 3H).

[0247] Example 48 (4-hydroxy-1-methoxy-7-(3-nitrophenoxy)isoquinoline-3-carbonyl)glycine

[0248]

[0249] The synthesis method is the same as that in Example 3, white solid, yield 78%. 1H NMR (500MHz, DMSO-d6) δ 13.07 (s, 1H), 12.73 (s, 1H), 8.97 (t, J = 6.0 Hz, 1H), 8.27 (d, J = 9.0 Hz, 1H), 8.27 (d, J = 9.0 Hz, 1H), 8.10 (dd, J = 8.2, 1.1 Hz, 1H), 7.94 (s, 1H), 7.76 (t, J = 8.2 Hz, 1H), 7.67 (t, J = 7.8 Hz, 2H), 7.58 (d, J = 2.1 Hz, 1H), 4.05 (d, J = 6.0 Hz, 2H), 4.03 (s, 3H).

[0250] Example 49 (4-hydroxy-1-methoxy-7-(4-phenoxyphenoxy)isoquinoline-3-carbonyl)glycine

[0251]

[0252] The synthesis method is the same as that in Example 3, white solid, yield 84%. 1H NMR (500MHz, DMSO-d6) δ 13.05 (s, 1H), 12.78 (s, 1H), 8.94 (t, J = 5.8 Hz, 1H), 8.23 ​​(d, J = 8.9 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.44-7.40 (m, 3H), 7.24 (d, J = 8.0 Hz, 2H), 7.17-7.13 (m, 3H), 7.07 (d, J = 7.8 Hz, 2H), 4.05 (d, J = 6.1 Hz, 2H), 4.02 (s, 3H).

[0253] Example 50 (7-(4-benzylphenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0254]

[0255] The synthesis method is the same as that in Example 3, white solid, yield 84%. 1H NMR (500MHz, DMSO-d6) δ13.04 (s, 1H), 8.92 (t, J = 6.0 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.59 (dd, J = 9.0, 2.4 Hz, 1H), 7.39 (s, 1H), 7.35-7.27 (m, 6H), 7.21 (t, J = 7.1 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 4.05 (d, J = 6.1 Hz, 2H), 4.02 (s, 3H), 3.99 (s, 2H).

[0256] Example 51 (7-(4-benzoylphenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0257]

[0258] The synthesis method is the same as that in Example 3, white solid, yield 80%. 1H NMR (500MHz, DMSO-d6) δ 13.09 (s, 1H), 12.79 (s, 1H), 8.98 (t, J = 6.0 Hz, 1H), 8.29 (d, J = 8.9 Hz, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 7.8 Hz, 2H), 7.69 (dd, J = 15.6, 8.1 Hz, 2H), 7.65 (s, 1H), 7.58 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 4.07 (s, 3H), 4.05 (d, J = 6.1 Hz, 2H).

[0259] Example 52 (7-(3-benzylphenoxy)-1-chloro-4-hydroxyisoquinoline-3-carbonyl)glycine

[0260]

[0261] The synthesis method is the same as that in Example 6, white solid, yield 74%. 1H NMR (500MHz, DMSO-d6) δ13.60 (s, 1H), 9.12 (t, J = 6.0 Hz, 1H), 8.33 (d, J = 9.0 Hz, 1H), 7.67 (dd, J = 9.0, 2.0 Hz, 1H), 7.46-7.42 (m, 2H), 7.31-7.22 (m, 4H), 7.19 (d, J = 7.3 Hz, 2H), 7.14 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 4.03 (d, J = 6.0 Hz, 2H), 3.99 (s, 2H).

[0262] Example 53 (7-([1,1'-biphenyl]-4-yloxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0263]

[0264] The synthesis method is the same as that in Example 3, white solid, yield 82%. 1H NMR (500MHz, DMSO-d6) δ 13.06 (s, 1H), 12.84 (s, 1H), 8.94 (t, J = 6.0 Hz, 1H), 8.25 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 7.7 Hz, 2H), 7.66 (d, J = 9.0 Hz, 1H), 7.48 (t, J = 7.5 Hz, 3H), 7.38 (t, J = 7.3 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 4.05 (d, J = 6.0 Hz, 2H), 4.03 (s, 3H).

[0265] Example 54 (7-(4-benzyl-2,6-dimethylphenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0266]

[0267] The synthesis method is the same as that in Example 3, white solid, yield 84%. 1H NMR (500MHz, DMSO-d6) δ 13.05 (s, 1H), 12.81 (s, 1H), 8.90 (t, J = 5.2 Hz, 1H), 8.22 (d, J = 9.0 Hz, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.37-7.26 (m, 4H), 7.22 (t, J = 6.5 Hz, 1H), 7.09 (s, 3H), 4.03 (d, J = 5.7 Hz, 2H), 4.00 (s, 3H), 3.94 (s, 2H), 2.03 (s, 6H).

[0268] Example 55 (4-hydroxy-1-methoxy-7-(4-phenylethoxy)isoquinoline-3-carbonyl)glycine

[0269]

[0270] The synthesis method is the same as that in Example 3, white solid, yield 83%. 1H NMR (500MHz, DMSO-d6) δ 13.06 (s, 1H), 12.81 (s, 1H), 8.94 (t, J = 5.7 Hz, 1H), 8.23 ​​(d, J = 9.0 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.36 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 7.4 Hz, 2H), 7.24 (d, J = 7.2 Hz, 2H), 7.19 (t, J = 7.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 4.03 (d, J = 5.7 Hz, 2H), 4.00 (s, 3H), 2.94-2.86 (m, 4H).

[0271] Example 56 (7-(2,6-dimethylphenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0272]

[0273] The synthesis method is the same as that in Example 3, white solid, yield 82%. 1H NMR (500MHz, DMSO-d6) δ13.06 (s, 1H), 12.81 (s, 1H), 8.89 (t, J = 5.4 Hz, 1H), 8.23 ​​(d, J = 9.0 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.24 (d, J = 7.3 Hz, 2H), 7.22-7.15 (m, 1H), 7.07 (s, 1H), 4.03 (d, J = 5.9 Hz, 2H), 4.00 (s, 3H), 2.08 (s, 6H).

[0274] Example 57 (7-(3,5-bis(trifluoromethyl)phenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0275]

[0276] The synthesis method is the same as that in Example 3, white solid, yield 70%. 1H NMR (500MHz, DMSO-d6) δ 13.09 (s, 1H), 12.85 (s, 1H), 8.96 (t, J = 5.7 Hz, 1H), 8.30 (t, J = 10.0 Hz, 1H), 7.98 (d, J = 10.6 Hz, 1H), 7.90 (d, J = 11.1 Hz, 1H), 7.71 (dd, J = 20.3, 11.3 Hz, 1H), 4.07 (d, J = 5.7 Hz, 2H), 4.05 (s, 3H).

[0277] Example 58 (7-(4-benzoyl-2,6-dimethylphenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0278]

[0279] The synthesis method is the same as that in Example 3, white solid, yield 78%. 1H NMR (500MHz, DMSO-d6) δ 13.07 (s, 1H), 12.81 (s, 1H), 8.93 (t, J = 5.3 Hz, 1H), 8.26 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 7.4 Hz, 2H), 7.71 (t, J = 7.2 Hz, 1H), 7.65 (s, 2H), 7.60 (t, J = 7.1 Hz, 3H), 7.18 (s, 1H), 4.05 (d, J = 6.1 Hz, 2H), 4.02 (s, 3H), 2.16 (s, 6H).

[0280] Example 59 (7-(2,6-difluorophenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0281]

[0282] The synthesis method is the same as that in Example 3, white solid, yield 75%. 1H NMR (500MHz, DMSO-d6) δ13.06 (s, 1H), 12.85 (s, 1H), 8.95 (t, J = 5.6 Hz, 1H), 8.24 (d, J = 8.9 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.51-7.44 (m, 1H), 7.40 (t, J = 8.2 Hz, 2H), 7.33 (s, 1H), 4.05 (d, J = 6.1 Hz, 2H), 4.02 (s, 3H).

[0283] Example 60 (1-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine

[0284]

[0285] The synthesis method is the same as that in Example 1, white solid, yield 87%. 1H NMR (500MHz, DMSO-d6) δ13.63 (s, 1H), 10.57 (s, 1H), 10.25 (t, J = 5.7 Hz, 1H), 8.37 (d, J = 9.0 Hz, 1H), 7.67 (s, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 7.19 (d, J = 7.8 Hz, 2H), 4.94 (s, 2H), 4.06 (d, J = 5.9 Hz, 2H), 2.92 (s, 6H).

[0286] Example 61 (4-hydroxy-1-methoxy-7-(3,4,5-trimethylphenoxy)isoquinoline-3-carbonyl)glycine

[0287]

[0288] The synthesis method is the same as that in Example 3, white solid, yield 92%. 1H NMR (500MHz, DMSO-d6) δ13.04 (s, 1H), 12.85 (s, 1H), 8.91 (t, J = 5.5 Hz, 1H), 8.19 (d, J = 9.0 Hz, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.35 (s, 1H), 6.84 (s, 2H), 4.04 (d, J = 6.0 Hz, 2H), 4.01 (s, 3H), 2.25 (s, 6H), 2.13 (s, 3H).

[0289] Example 62 (4-hydroxy-7-(4-isopropyl-3-methylphenoxy)-1-methoxyisoquinoline-3-carbonyl)glycine

[0290]

[0291] The synthesis method is the same as that in Example 3, white solid, yield 82%. 1H NMR (500MHz, DMSO-d6) δ 13.04 (s, 1H), 12.85 (s, 1H), 8.92 (t, J = 5.8 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.41 (s, 1H), 7.32 (d, J = 9.0 Hz, 1H), 6.97 (s, 2H), 4.04 (d, J = 9.5 Hz, 2H), 4.03 (s, 3H), 3.11 (dt, J = 13.5, 6.7 Hz, 1H), 2.31 (s, 1H), 1.20 (d, J = 6.8 Hz, 6H).

[0292] Example 63 (4-hydroxy-1-methoxy-7-((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)isoquinoline-3-carbonyl)glycine

[0293]

[0294] The synthesis method is the same as that in Example 3, white solid, yield 81%. 1H NMR (500MHz, DMSO-d6) δ 13.04 (s, 1H), 12.85 (s, 1H), 8.92 (t, J = 6.0 Hz, 1H), 8.22 (d, J = 9.0 Hz, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.29 (s, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 4.04 (d, J = 6.1 Hz, 2H), 4.02 (s, 3H), 2.79-2.76 (m, 2H), 2.53-2.51 (m, 2H), 1.72-1.68 (m, 4H).

[0295] Example 64 (1-ethoxy-7-(2-fluorophenoxy)-4-hydroxyisoquinoline-3-carbonyl)glycine

[0296]

[0297] The synthesis method is the same as that in Example 3, white solid, yield 72%. 1H NMR (500MHz, DMSO-d6) δ 13.06 (s, 1H), 12.85 (s, 1H), 8.92 (t, J = 5.9 Hz, 1H), 8.24 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.49 (t, J = 8.2 Hz, 1H), 7.42 (s, 1H), 7.41-7.30 (m, 3H), 4.52 (q, J = 7.0 Hz, 2H), 4.03 (d, J = 6.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H).

[0298] Example 65 (7-([1,1'-biphenyl]-3-yloxy)-1-chloro-4-hydroxyisoquinoline-3-carbonyl)glycine

[0299]

[0300] The synthesis method is the same as that in Example 6, white solid, yield 79%. 1H NMR (500MHz, DMSO-d6) δ12.86 (s, 1H), 8.35 (d, J = 9.0 Hz, 1H), 8.21 (t, J = 6.0 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.58-7.48 (m, 3H), 7.45 (t, J = 7.4 Hz, 2H), 7.37 (d, J = 7.5 Hz, 2H), 7.12 (d, J = 6.9 Hz, 1H), 4.31 (d, J = 5.2 Hz, 2H).

[0301] Example 66 (7-(4-benzoyl-2,6-dimethylphenoxy)-1-ethoxy-4-hydroxyisoquinoline-3-carbonyl)glycine

[0302]

[0303] The synthesis method is the same as that in Example 3, white solid, yield 90%. 1H NMR (500MHz, DMSO-d6) δ 13.06 (s, 1H), 12.79 (s, 1H), 8.89 (t, J = 5.9 Hz, 1H), 8.24 (d, J = 8.9 Hz, 1H), 7.80 (d, J = 7.3 Hz, 2H), 7.71 (t, J = 7.0 Hz, 1H), 7.64 (s, 2H), 7.60 (t, J = 7.2 Hz, 2H), 7.49 (d, J = 9.0 Hz, 1H), 7.32 (s, 1H), 4.53 (d, J = 6.8 Hz, 2H), 4.04 (d, J = 5.0 Hz, 2H), 2.16 (s, 6H), 1.37 (t, J = 6.6 Hz, 3H).

[0304] Example 67 (4-hydroxy-1-methoxy-7-((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)isoquinoline-3-carbonyl)glycine

[0305]

[0306] The synthesis method is the same as that in Example 3, white solid, yield 80%. 1H NMR (500MHz, DMSO-d6) δ 13.04 (s, 1H), 12.82 (s, 1H), 8.92 (s, 1H), 8.20 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.38 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.88 (s, 1H), 4.03 (d, J = 6.1 Hz, 2H), 4.02 (s, 3H), 2.75-2.71 (m, 4H), 1.76-1.72 (m, 4H).

[0307] Example 68 (7-(5-cyano-2-methylphenoxy)-1-ethoxy-4-hydroxyisoquinoline-3-carbonyl)glycine

[0308]

[0309] The synthesis method is the same as that in Example 3, white solid, yield 78%. 1H NMR (500MHz, DMSO-d6) δ13.05 (s, 1H), 12.83 (s, 1H), 8.92 (t, J = 6.1 Hz, 1H), 8.24 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.64-7.53 (m, 3H), 7.46 (d, J = 2.4 Hz, 1H), 4.53 (q, J = 7.0 Hz, 2H), 4.04 (d, J = 6.1 Hz, 2H), 2.28 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H).

[0310] Example 69 (1-ethoxy-4-hydroxy-7-(5-isopropyl-2-methylphenoxy)isoquinoline-3-carbonyl)glycine

[0311]

[0312] The synthesis method is the same as in Example 3, white solid, yield 86%. 1H NMR (500MHz, DMSO-d6) δ13.04 (s, 1H), 12.79 (s, 1H), 8.89 (t, J = 5.9 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.53 (dd, J = 9.0, 2.3 Hz, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H) ,7.11(d,J=7.7Hz,1H),7.02(s,1H),4.50(q,J=7.0Hz,2H),4.03(d,J=6.0Hz,2H),2. 88(dt,J=13.6,6.8Hz,1H),2.11(s,3H),1.33(t,J=7.0Hz,3H),1.18(d,J=6.9Hz,6H).

[0313] Example 70 (7-(4-(3,5-dimethylbenzoyl)-2,6-dimethylphenoxy)-1-ethoxy-4-hydroxyisoquinoline-3-carbonyl)glycine

[0314]

[0315] The synthesis method is the same as that in Example 3, white solid, yield 80%. 1H NMR (500MHz, DMSO-d6) δ13.06 (s, 1H), 12.79 (s, 1H), 8.90 (t, J = 6.1 Hz, 1H), 8.24 (d, J = 9.0 Hz, 1H), 7.61 (s, 2H), 7.50 (d, J = 2.5 Hz, 1H), 7.37 (s, 2H), 7.35-7.29 (m, 2H), 4.53 (q, J = 7.0 Hz, 2H), 4.03 (d, J = 6.1 Hz, 2H), 2.37 (s, 6H), 2.16 (s, 6H), 1.36 (t, J = 7.0 Hz, 3H).

[0316] Example 71 (7-(2,6-dimethyl-4-(3-methylbenzoyl)phenoxy)-1-ethoxy-4-hydroxyisoquinoline-3-carbonyl)glycine

[0317]

[0318] The synthesis method is the same as that in Example 3, white solid, yield 78%. 1H NMR (500MHz, DMSO-d6) δ 13.07 (s, 1H), 12.79 (s, 1H), 8.90 (t, J = 6.1 Hz, 1H), 8.24 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 9.1 Hz, 3H), 7.56 (d, J = 7.4 Hz, 1H), 7.55-7.45 (m, 3H), 7.32 (d, J = 2.4 Hz, 1H), 4.53 (q, J = 7.0 Hz, 2H), 4.03 (d, J = 6.1 Hz, 2H), 2.42 (s, 3H), 2.16 (s, 6H), 1.37 (t, J = 7.0 Hz, 3H).

[0319] Example 72 (1-ethoxy-7-(2-fluoro-5-(trifluoromethyl)phenoxy)-4-hydroxyisoquinoline-3-carbonyl)glycine

[0320]

[0321] The synthesis method is the same as that in Example 3, white solid, yield 72%. 1H NMR (500MHz, DMSO-d6) δ 13.08 (s, 1H), 12.79 (s, 1H), 8.94 (t, J = 6.1 Hz, 1H), 8.26 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 7.3 Hz, 1H), 7.77-7.73 (m, 1H), 7.66 (dd, J = 9.0, 2.5 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 4.54 (q, J = 7.0 Hz, 2H), 4.03 (d, J = 6.1 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H).

[0322] Example 73 (1-ethoxy-7-(2-fluoro-5-(trifluoromethyl)phenoxy)-4-hydroxyisoquinoline-3-carbonyl)glycine

[0323]

[0324] The synthesis method is the same as that in Example 3, white solid, yield 77%. 1H NMR (500MHz, DMSO-d6) δ 13.07 (s, 1H), 12.79 (s, 1H), 8.91 (t, J = 6.1 Hz, 1H), 8.23 ​​(d, J = 9.0 Hz, 1H), 7.69 (s, 2H), 7.64 (t, J = 9.0 Hz, 1H), 7.49 (d, J = 9.1 Hz, 1H), 7.45 (d, J = 5.4 Hz, 2H), 7.33 (s, 1H), 4.53 (q, J = 7.0 Hz, 2H), 4.03 (d, J = 5.8 Hz, 2H), 2.17 (s, 6H), 1.36 (t, J = 6.9 Hz, 3H).

[0325] Example 74 (7-(2,6-dimethyl-4-(3-methylbenzoyl)phenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0326]

[0327] The synthesis method is the same as in Example 3, white solid, yield 80%. 1H NMR (500MHz, DMSO-d6) δ13.07 (s, 1H), 12.80 (s, 1H), 8.94 (t, J = 6.0 Hz, 1H), 8.26 (d, J = 9.0 Hz, 1H), 7.68-7.59 (m, 4H), 7.56 (d, J = 7.3 Hz, 1H), 7.53-7.46 (m, 2H), 7.17 (s, 1H), 4.04 (d, J = 6.1 Hz, 2H), 4.02 (s, 3H), 2.42 (s, 3H), 2.15 (s, 6H).

[0328] Example 75 (7-(4-(3,5-dimethylbenzoyl)-2,6-dimethylphenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0329]

[0330] The synthesis method is the same as that in Example 3, white solid, yield 81%. 1H NMR (500MHz, DMSO-d6) δ 13.06 (s, 1H), 12.82 (s, 1H), 8.93 (t, J = 6.0 Hz, 1H), 8.25 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 11.4 Hz, 2H), 7.59 (d, J = 2.5 Hz, 1H), 7.37 (s, 2H), 7.31 (s, 1H), 7.17 (s, 1H), 4.04 (d, J = 5.9 Hz, 2H), 4.02 (s, 3H), 2.36 (s, 6H), 2.15 (s, 6H).

[0331] Example 76 (7-(4-(3,5-difluorobenzoyl)-2,6-dimethylphenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0332]

[0333] The synthesis method is the same as that in Example 3, white solid, yield 70%. 1H NMR (500MHz, DMSO-d6) δ 13.09 (s, 1H), 12.83 (s, 1H), 8.92 (t, J = 6.1 Hz, 1H), 8.26 (d, J = 9.0 Hz, 1H), 7.70 (s, 2H), 7.62 (t, J = 9.0 Hz, 1H), 7.52-7.35 (m, 2H), 7.19 (s, 1H), 4.03 (d, J = 6.1 Hz, 2H), 4.02 (s, 3H), 2.16 (s, 6H).

[0334] Example 77 (1-ethoxy-7-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoxy)-4-hydroxyisoquinoline-3-carbonyl)glycine

[0335]

[0336] The synthesis method is the same as that in Example 3, white solid, yield 72%. 1H NMR (500MHz, DMSO-d6) δ13.06 (s, 1H), 12.81 (s, 1H), 8.90 (t, J = 6.0 Hz, 1H), 8.23 ​​(d, J = 9.0 Hz, 1H), 7.66 (s, 2H), 7.50 (dd, J = 9.0, 2.5 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.20 (d, J = 10.8 Hz, 1H), 7.11 (d, J = 8.7 Hz, 2H), 4.53 (q, J = 7.0 Hz, 2H), 4.03 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.16 (s, 6H), 1.36 (t, J = 4.9 Hz, 3H).

[0337] Example 78 (7-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0338]

[0339] The synthesis method is the same as that in Example 3, white solid, yield 88%. 1H NMR (500MHz, DMSO-d6) δ 13.08 (s, 1H), 12.88 (s, 1H), 8.92 (t, J = 6.0 Hz, 1H), 8.26 (d, J = 9.0 Hz, 1H), 7.67 (s, 2H), 7.60 (dd, J = 9.1, 2.4 Hz, 1H), 7.19 (t, J = 6.8 Hz, 2H), 7.13 (s, 1H), 4.03 (d, J = 6.1 Hz, 2H), 4.02 (s, 3H), 3.86 (s, 3H), 2.16 (s, 6H).

[0340] Example 79 (1-ethoxy-7-(4-(3-fluorobenzoyl)-2,6-dimethylphenoxy)-4-hydroxyisoquinoline-3-carbonyl)glycine

[0341]

[0342] The synthesis method is the same as that in Example 3, white solid, yield 78%. 1H NMR (500MHz, DMSO-d6) δ 13.06 (s, 1H), 12.80 (s, 1H), 8.90 (t, J = 6.1 Hz, 1H), 8.23 ​​(d, J = 9.0 Hz, 1H), 7.69-7.63 (m, 3H), 7.62 (t, J = 6.5 Hz, 1H), 7.57 (d, J = 9.1 Hz, 2H), 7.49 (dd, J = 9.0, 2.5 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 4.53 (d, J = 7.0 Hz, 2H), 4.03 (d, J = 6.1 Hz, 2H), 2.16 (s, 6H), 1.36 (t, J = 7.0 Hz, 3H).

[0343] Example 80 (7-(4-(3-fluorobenzoyl)-2,6-dimethylphenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carbonyl)glycine

[0344]

[0345] The synthesis method is the same as that in Example 3, white solid, yield 78%. 1H NMR (500MHz, DMSO-d6) δ13.08 (s, 1H), 12.86 (s, 1H), 8.93 (t, J = 6.1 Hz, 1H), 8.26 (d, J = 9.0 Hz, 1H), 7.67 (s, 2H), 7.66-7.52 (m, 4H), 7.18 (d, J = 2.3 Hz, 1H), 4.04 (d, J = 6.1 Hz, 2H), 4.02 (s, 3H), 2.16 (s, 6H).

[0346] Example 81 ((7-(4-benzoyl-2,6-dimethylphenoxy)-4-hydroxyisoquinoline-3-carbonyl)glycine

[0347]

[0348] The synthesis method is the same as in Example 3, yellow solid, yield 70%. 1H NMR (500MHz, DMSO-d6) δ13.60 (s, 1H), 12.80 (s, 1H), 9.30 (t, J = 5.6 Hz, 1H), 8.75 (s, 1H), 8.33 (d, J = 9.1 Hz, 1H), 7.83 (d, J = 7.2 Hz, 2H), 7.71 (t, J = 7.4 Hz, 1H), 7.69-7.57 (m, 5H), 7.27 (d, J = 1.7 Hz, 2H), 4.02 (d, J = 6.0 Hz, 2H), 2.18 (s, 6H).

[0349] Example 82 N-(2-amino-2-oxoethyl)-7-(4-benzoyl-2,6-dimethylphenoxy)-4-hydroxy-1-methoxyisoquinoline-3-carboxamide

[0350]

[0351] The synthesis method is the same as in Example 3, yellow solid, yield 70%. 1H NMR (500MHz, DMSO-d6) δ13.15 (s, 1H), 8.80 (t, J = 5.8 Hz, 1H), 8.26 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 7.5 Hz, 2H), 7.71 (t, J = 7.4 Hz, 1H), 7.69-7.57 (m, 5H), 7.52 (s, 1H), 7.17 (s, 2H), 4.02 (s, 3H), 3.94 (d, J = 5.8 Hz, 2H), 2.16 (s, 6H).

[0352] Comparative Example 1 (4-Hydroxyisoquinoline-3-carbonyl)glycine

[0353]

[0354] The synthesis method is the same as in Example 2, white solid, yield 80%. 1H NMR (500 MHz, DMSO-d6) δ 13.57 (s, 1H), 12.83 (s, 1H), 9.34 (s, 1H), 8.87 (t, J = 3.6 Hz, 1H), 8.27 (d, J = 7.6 Hz, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.96-7.71 (m, 2H), 4.06 (d, J = 5.8 Hz, 2H).

[0355] Comparative Example 2 (4-Hydroxyisoquinoline-3-carbonyl)glycine

[0356]

[0357] The synthesis method is the same as that in Example 3, white solid, yield 92%. 1H NMR (500 MHz, DMSO-d6) δ 13.03 (s, 1H), 12.81 (s, 1H), 9.00 (t, J = 5.8 Hz, 1H), 8.20 (t, J = 8.2 Hz, 2H), 7.89 (t, J = 7.6 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 4.12 (s, 3H), 4.06 (d, J = 6.0 Hz, 2H).

[0358] Comparative Example 3 (1-chloro-4-hydroxyisoquinoline-3-carbonyl)glycine

[0359]

[0360] The synthesis method is the same as in Example 6, white solid, yield 75%. 1H NMR (500 MHz, DMSO-d6) δ 13.62 (s, 1H), 9.20 (t, J = 5.8 Hz, 1H), 8.35-8.20 (m, 2H), 8.02-7.98 (m, 2H), 4.05 (d, J = 6.0 Hz, 2H).

[0361] Performance Testing

[0362] In vitro activity experiments were conducted on the prepared compounds, comparative positive drugs T3, MGL-3196, and FG-4592: AlphaScreen detection technology was used to verify the activation ability of the above compounds on TRα, TRβ and mutant proteins; TSA detection technology was used to verify the stabilizing effect of the above compounds on PHD2 protein.

[0363] The AlphaScreen kit (Perkin-Elmer) can be used to detect the ability of ligands to regulate the recruitment of coactivator peptides with various motifs after binding to TR LBD protein. The reaction system of this experiment is 20-80nM receptor LBD protein, 20nM biotinylated cofactor peptide, 5μg / mL donor and acceptor microbeads, buffer (25mM Hepes, 100mM NaCl and 0.1mg / mL bovine serum albumin, pH7.0). This technology has been widely used in drug development based on the interaction between nuclear receptors and ligands.

[0364] The polypeptide with N-terminal biotinylation is SRC2-3, and its sequence is QEPVSPKKKENALLRYLLDKDDTKD.

[0365] TSA experiment: Dilute each component to the corresponding concentration, then add 20μL of reaction system, which includes 2μL protein, 2μL SYPRO Orange fluorescent dye, 10μL compound, 2μL buffer, and 4μL deionized water. Mix thoroughly and add to a 96-well reaction plate. Centrifuge at room temperature for 1min and incubate on ice for 30min. Place the incubated 96-well reaction plate into a Real-time PCR instrument, with a starting temperature of 30℃ and an end temperature of 80℃. Read once every 5 seconds, and increase the temperature by 0.3℃ each time. This experiment can efficiently detect the ability of small molecules to bind and stabilize proteins.

[0366] The results of the positive drugs T3, MGL-3196, and FG-4592 were compared using AlphaScreen detection technology. The verification results are shown in Tables 1 and 2;

[0367] Table 1

[0368]

[0369]

[0370] Note: 1): AlphaScreen experiment, EC 50 The unit is: nM.

[0371] 2) Activation fold of TRα / β protein: Example: In the 1 μM AlphaScreen experiment, its activity on TRα / β is the ratio of the activity of the negative control DMSO.

[0372] 3): TSA experiment, the unit of ΔT is: ℃.

[0373] 4): NA, No Activity; NT, Not Tested.

[0374] Table 2

[0375] Compound No. <![CDATA[EC 50 TRβ(H435A)]]> <![CDATA[EC 50 TRβ(H435Y)]]> <![CDATA[EC 50 TRβ(H435R)]]> T3 997.1 1529.0 NA MGL-3196 NA 567.0 NA Embodiment 70 NA NA 5277.0 Embodiment 71 NA NA 2386.0 Embodiment 77 NA NA 2925.0 Embodiment 78 NA 695.7 1344.0

[0376] Note: 1) In AlphaScreen experiment, the unit of EC50 is nM.

[0377] 4): NA, No Activity.

[0378] FG-4592 is a multi-target drug, while Examples 70, 71, 77, and 78 in the table only show TRβ agonism, and have no activity on TRα and PHD2; they have a greater advantage over the positive drugs T3, MGL-3196, and the lead compound FG-4592, and achieve a selective TRβ agonist. Structurally, Examples 70, 71, 77, and 78 are all benzophenone-substituted isoquinoline derivatives, which are very different from the isoquinoline parent nucleus of FG-4592. Subsequently, we tested the activity of some compounds against the H435 mutant. The results showed that compared with the positive drugs T3 and MGL-3196, they showed obvious advantages against the H435R mutant.

[0379] From the comparative examples, it can be seen that the compounds having the structure shown in the present invention have great advantages in preparing thyroid hormone β receptor agonists. For comparative examples 1, 2 and 3, which are quite different, they are inactive or have weak activity against TRβ, TRα and PHD2.

[0380] In summary, the thyroid hormone β receptor agonist provided by the present invention has a good activation effect on wild-type and mutant thyroid hormone β receptors, has a weaker effect or basically no effect on thyroid hormone α receptor and PHD2 targets, and has good selectivity. Therefore, the compound can be used in the prevention or treatment of thyroid hormone receptor β-mediated related diseases.

[0381] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention shall fall within the protection scope and disclosure scope of the present invention. SEQUENCE LISTING <110> Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences <120> A thyroid hormone receptor β agonist compound and its preparation method and application <130> 20210806 <160> 1 <170> PatentIn version 3.3 <210> 1 <211> 25 <212> PRT <213> Artificial sequence <400> 1 Gln Glu Pro Val Ser Pro Lys Lys Lys Glu Asn Ala Leu Leu Arg Tyr 1 5 10 15 Leu Leu Asp Lys Asp Asp Thr Lys Asp 20 25

Claims

1. A thyroid hormone receptor β agonist compound, characterized in that The compound is selected from any one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. A use of a thyroid hormone receptor β agonist compound, characterized in that: Use of the compound in preparing a thyroid hormone receptor β agonist; The compound is selected from the compounds according to claim 1.

3. A use of a thyroid hormone receptor β agonist compound, characterized in that: Use of the compound in preparing a thyroid hormone receptor β agonist; The compound is selected from any one of the following compounds: 、 、 、 。 4. The use according to claim 2 or 3, characterized in that: The target of the thyroid hormone receptor β agonist is wild-type thyroid hormone receptor β and / or mutant thyroid hormone receptor β.

5. The use according to claim 4, characterized in that: The mutant thyroid hormone receptor β is selected from any one of V264D, A268D, R282S, V283A, M310T, E311K, S314C, A317T, R320C, N331D, G332E, G332R, L346F, L346V, H435R, R438H, F459C or F459L, or a combination of at least two thereof.

6. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the thyroid hormone receptor β agonist compound as claimed in claim 1 and pharmaceutically acceptable excipients.

7. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutically acceptable excipient is selected from any one of a diluent, a flavoring agent, a binder or a filler, or a combination of at least two thereof.

8. The pharmaceutical composition according to claim 6, characterized in that The dosage form of the pharmaceutical composition is selected from any one of tablets, capsules, granules, bulk powders, injections or lyophilized powder injections.

9. The pharmaceutical composition according to claim 6, characterized in that The administration route of the pharmaceutical composition is selected from any one of intravenous injection, intramuscular injection, oral administration, inhalation administration, sublingual administration, rectal administration, vaginal administration, intracisternal administration, intrathecal administration, lumbar puncture administration, urethral administration, intradermal injection, intraperitoneal administration or transdermal administration.

10. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition also includes a therapeutic agent.

11. The pharmaceutical composition according to claim 10, characterized in that The therapeutic agent is selected from any one or a combination of at least two of anti-nonalcoholic fatty liver agents, lipid-lowering agents, anti-atherosclerotic agents, anti-diabetic agents, anti-cholesterol / lipid degradation agents, anti-osteoporosis agents, anti-obesity agents, growth promoters, anti-inflammatory agents, antianxiety agents, antidepressants, antihypertensive agents, cardiac glycosides, appetite suppressants, bone resorption inhibitors, thyroid mimetic agents, anabolic agents, anti-tumor agents or retinoids.

12. Use of the compound according to claim 1 or the pharmaceutical composition according to any one of claims 6 to 11 in the preparation of a medicament for preventing or treating a thyroid hormone receptor β-related disease.

13. The use according to claim 12, characterized in that: The thyroid hormone receptor β-related diseases include diseases that are dependent on T3-regulated gene expression.

14. The use according to claim 12, characterized in that: The thyroid hormone receptor β-related disease is selected from hypercholesterolemia, hypertriglyceridemia, atherosclerosis, NASH, obesity, thyroid hormone resistance, diabetes, ataxia, depression, cognitive dysfunction, attention deficit hyperactivity disorder, osteoporosis, goiter, hypothyroidism, thyroid cancer, congestive heart failure, glaucoma or skin disease.

Images