WO2021018165A1 - Pyridine benzamide derivative, preparation method for same, and medicinal applications thereof - Google Patents

Abstract

The present disclosure relates to a pyridine benzamide derivative, a preparation method for same, and medicinal applications thereof. Specifically, the present disclosure relates to the pyridine benzamide derivative as represented by formula (I), the preparation method therefor, a pharmaceutical composition containing the derivative, and uses thereof serving as a therapeutic agent and specifically serving as an Na_V inhibitor in treating and/or relieving pain and pain-related diseases. The substituents of formula (I) are as defined in the description.

Description

Pyridine benzamide derivatives, preparation method thereof and application in medicine Technical field

The present disclosure belongs to the field of medicine, and relates to a pyridine benzamide derivative represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and a therapeutic agent, especially a Na _V inhibitor in Use in preparing medicines for treating and/or reducing pain and pain-related diseases.

Background technique

Pain is a complex physical and psychological activity and one of the most common symptoms in clinical practice. The International Association for Pain Research defines pain as "an unpleasant feeling and emotional feeling, accompanied by substantial or potential tissue damage, which is a subjective feeling." Pain can be used as a warning signal to remind the body to pay attention to potential dangers, and has an indispensable protective effect on the body's normal life activities. At the same time, pain is also a common clinical symptom. After the external stimulus that caused the pain disappears, strong or long-lasting pain can cause disorders of physiological functions and seriously affect the quality of life of the living body. Statistics show that about one-fifth of people in the world suffer from moderate to severe chronic pain.

Pain originates from nociceptors in the peripheral nervous system. This is a kind of free nerve endings, which are widely distributed in the skin, muscles, joints and visceral tissues of the whole body. It can convert the thermal, mechanical or chemical stimulation felt into nerve impulses (action potentials) and pass them through Incoming nerve fibers are transmitted to the body part of the dorsal root ganglia (DRG), and finally transmitted to the higher nerve center, causing pain. The generation and conduction of action potentials in neurons relies on voltage-gated sodium channels (Na _V ) on the cell membrane. When the cell membrane is depolarized, the sodium ion channel is activated and the channel opens, causing the influx of sodium ions, further depolarizing the cell membrane, leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity is helpful for the treatment and relief of pain.

Na _V is a type of transmembrane ion channel protein. These proteins consist of an alpha subunit with a molecular weight of 260kD and a beta subunit with a molecular weight of 30-40kD. According to the different α subunits, it can be divided into 9 subtypes, Na _V ll ~ Na _V 1.9. Different subtypes show different tissue distribution and electrophysiological and pharmacological characteristics. According to whether it can be effectively inhibited by nanomolar tetrodotoxin (TTX), sodium ion channels are classified into TTX sensitive (TTX-S) and TTX insensitive (TTX-R). Among them, Na _V 1.1, Na _V 1.2, Na _V 1.3, and Na _V 1.7 are TTX-S type, and the coding genes are located in human chromosome 2q23-24, and they are expressed in large amounts in neurons. Na _V 1.5, Na _V 1.8 and Na _V 1.9 are TTX-R type, and the coding gene is located on human chromosome 3p21-24. Among them, Na _V 1.5 is mainly present in cardiomyocytes, and Na _V 1.8 and Na _V 1. 9 are present in the peripheral nervous system. Both Na _V 1.4 and Na _V 1.6 are TTX-S type, which are abundant in skeletal muscle and central nervous system respectively. Local anesthetic lidocaine for pain by inhibiting Na _V. Non-selective Na _V inhibitors, such as lamotrigine, lacosamide, and mexiletine have been successfully used to treat chronic pain.

Na _V 1.8 is of TTX-R type, and the coding gene is SCN10A. It mainly exists in trigeminal ganglion neurons and DRG neurons, and has electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Na _V 1.8, the rise of action potential is mainly composed of Na _V 1.8 current. In some models of neuropathic pain, nerve damage will increase the expression level of Na _V 1.8 in axons and neuron cell bodies. The use of Na _V 1.8 antisense oligonucleotides can significantly relieve pain while reducing the expression of Na _V 1.8. After carrageenan was injected into the paws of rats, the expression of Na _V 1.8 in DRG neurons increased. Na _V 1.8 knockout mice cannot show normal visceral inflammation pain. After the human Na _V 1.8 gene has a functional gain mutation, it will cause peripheral neuralgia. Based on a series of animal experiments and human genetic evidence, selective inhibition of Na _V 1.8 has the potential to become a new type of analgesic therapy, which can be used for the treatment of inflammatory pain, nerve pain, postoperative pain, cancer pain and other types of pain.

Due to the lack of subtype selectivity, Na _V inhibitors used in clinical practice can inhibit sodium channels expressed in the heart and central nervous system, so the therapeutic window is narrow and the application range is limited. Na _V 1.8 is mainly distributed in the peripheral nervous system, so selective inhibition of Na _V 1.8 can effectively reduce side effects. Necessary to develop higher activity, better selectivity, better pharmacokinetic properties, fewer side effects of inhibitors of Na _V 1.8.

Summary of the invention

The purpose of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or Mixture form or its pharmaceutically acceptable salt:

among them:

Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^{1 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic and heterocyclylalkyl;

R ^{2 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, -CH ₂ OR ^w , cycloalkyl and heterocyclic group; R ^{w is} selected From hydrogen atom, alkyl group, -C(O)R ⁶ , -S(O) ₂ OH, -S(O) ₂ O ^- Q ⁺ , -PO(OH) ₂ , -PO(OH)O ^- Q ⁺ and _{^{-PO (O -) 2 W 2+}} ; Q + is a monovalent pharmaceutically acceptable cation; W ²⁺ cation is a pharmaceutically acceptable divalent;

R ^{3 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyloxy, -OR ⁵ , Cycloalkyl and heterocyclyl; the alkyl and alkoxy are optionally further substituted by one or more substituents selected from halogen, alkyl, hydroxy, cycloalkyl and heterocyclyl;

R ^{4 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy and hydroxyalkyl;

R ^{5 is} selected from hydrogen atom, alkyl group, hydroxyl group, cycloalkyl group and heterocyclic group;

R ^{6 is} selected from alkyl, alkoxy, alkenyl, carboxyl and -C(O)O ^- M ⁺ , wherein said alkyl, alkoxy and alkenyl are optionally further selected from hydroxyl, amino, carboxyl And -C(O)O ^- M ⁺ substituted by one or more substituents; M ⁺ is a pharmaceutically acceptable monovalent cation;

n is 0, 1, 2, 3, 4 or 5; and

m is 0, 1, 2 or 3.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{6 is} selected from alkyl, alkoxy, alkenyl, carboxy and carboxylate, wherein the alkyl, alkoxy and alkenyl are any Optionally, it is further substituted with one or more substituents selected from hydroxyl, amino, carboxyl and carboxylate.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II), or a tautomer, meso, racemate, enantiomer, Diastereoisomers, or their mixtures or their pharmaceutically acceptable salts:

Wherein, ring A, R ¹ , R ³ , R ⁴ , m and n are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Isomer, or its mixture form or its pharmaceutically acceptable salt, which is the compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, non- Enantiomers, or their mixture forms or their pharmaceutically acceptable salts:

Wherein, R ¹ , R ² , R ³ , R ⁴ , m and n are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Or a pharmaceutically acceptable salt thereof, wherein R ² is a hydrogen atom or -CH ₂ OR ^w ; R ^{w is} as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Isomer, or its mixture form or its pharmaceutically acceptable salt, which is a compound represented by general formula (III), or its tautomer, meso, racemate, enantiomer, Diastereoisomers, or their mixtures or their pharmaceutically acceptable salts:

Wherein, R ¹ , R ³ , R ⁴ , m and n are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IV), or a tautomer, meso, racemate, enantiomer, Diastereoisomers, or their mixtures or their pharmaceutically acceptable salts:

Wherein, R ¹ , R ³ , m and n are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IVG), or a tautomer, meso, racemate, enantiomer, Diastereoisomers, or their mixtures or their pharmaceutically acceptable salts:

Wherein: R ^w is selected from _{-PO (OH) 2, -PO (} OH) O - Q + and _{^{-PO (O -) 2 W 2+}} ; Q + is a monovalent pharmaceutically acceptable cation; W ²⁺ pharmaceutically Acceptable divalent cation;

R ¹ , R ³ , m and n are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a compound, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{3 is the} same or different, and each is independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a cycloalkyloxy group, and a cycloalkyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a compound, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 2.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (V), or a tautomer, meso, racemate, enantiomer, Diastereoisomers, or their mixtures or their pharmaceutically acceptable salts:

among them,

R ^3a and R ^{3b are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, -OR ⁵ , cycloalkyl and heterocycle The alkyl group is optionally further substituted with a substituent selected from halogen, hydroxy, cycloalkyl and heterocyclyl;

Preferably, R ^3a and R ^{3b are the} same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a cycloalkyloxy group and a cycloalkyl group;

The R ¹ , R ⁵ and m are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a compound, a mixture thereof, or a pharmaceutically acceptable salt thereof, R ¹ is a hydrogen atom or an alkyl group, preferably a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is -CH ₂ OR ^w , and R ^{w is} selected from a hydrogen atom, an alkyl group, -C(O)R ⁶ , and -S(O) ₂ OH ^{_{, -S (O) 2 O -}} Q +, -PO (OH) 2, -PO (OH) O - Q + and _{^{-PO (O -) 2 W 2+}} ; Q + is a pharmaceutically acceptable monovalent cation ; W ²⁺ is a pharmaceutically acceptable divalent cation; R ^{6 is} as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Q ⁺ and M ^{+ are the} same or different, and are each independently a quaternary ammonium ion and an alkali metal ion; preferably Na ⁺ or K ⁺ ; W ²⁺ is The alkaline earth metal ion is preferably Mg ²⁺ or Ca ²⁺ .

Typical compounds of the present disclosure include but are not limited to:

Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof.

Another aspect of the present disclosure relates to the compound represented by general formula (I-IA) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or Its mixture form or its pharmaceutically acceptable salt:

It can be used as an intermediate for preparing the compound represented by general formula (I-I),

among them:

R ^a is alkyl, preferably C ₁ -C ₆ alkyl, more preferably methyl; ring ^{A, R 1, R 3,} R 4, m and n are as in formula (I) as defined above.

Another aspect of the present disclosure relates to the compound represented by the general formula (IIIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form or its pharmaceutically acceptable salt:

It can be used as an intermediate for preparing the compound represented by general formula (III),

among them:

R ^a is an alkyl group, preferably a C ₁ -C ₆ alkyl group, more preferably a methyl group; R ¹ , R ³ , R ⁴ , m and n are as defined in the general formula (III).

Another aspect of the present disclosure relates to the compound represented by the general formula (IVA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form or its pharmaceutically acceptable salt:

It can be used as an intermediate for preparing the compound represented by general formula (IV),

among them:

R ^a is an alkyl group, preferably a C ₁ -C ₆ alkyl group, more preferably a methyl group; R ¹ , R ³ , m and n are as defined in the general formula (IV).

Another aspect of the present disclosure relates to the compound represented by the general formula (VA) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form or its pharmaceutically acceptable salt:

It can be used as an intermediate for preparing compounds of general formula (V),

among them:

R ^a is an alkyl group, preferably a C ₁ -C ₆ alkyl group, more preferably a methyl group; R ¹ , R ^3a , R ^3b and m are as defined in the general formula (V).

The compound represented by the general formula (IIIA) or (IVA) or (VA) or its tautomers, mesosomes, racemates, enantiomers, diastereomers , Or its mixture form or its pharmaceutically acceptable salt, wherein each group can be as defined in the general formula (I) or (II) or (III) or (IV) or (V).

Typical compounds of general formula (I-IA), (IIIA), (IVA), (VA) in the present disclosure include but are not limited to:

Another aspect of the present disclosure relates to a preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of general formula (I-IA) are reacted under acidic conditions to obtain compounds of general formula (I-I),

The reagents that provide acidic conditions are preferably pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid and methanesulfonic acid, more preferably pyridine hydrobromide; wherein ^Ra is an alkyl group, preferably C ₁ -C ₆ Alkyl group is more preferably methyl; ring A, R ¹ , R ³ , R ⁴ , m, n are as defined in general formula (II).

Another aspect of the present disclosure relates to a pharmaceutical composition containing a therapeutically effective amount of the compound represented by the general formula (I) of the present disclosure or its tautomer, mesosome, racemate, enantiomer Isomers, diastereomers or mixtures thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure also relates to a compound represented by the general formula (I) of the present disclosure or its tautomer, mesosome, racemate, enantiomer, diastereomer, or Use of the mixture form or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same in preparing a medicament for inhibiting a voltage-gated sodium channel of a subject, wherein the voltage-gated sodium channel is preferably Na _V 1.8.

The present disclosure also relates to a compound represented by the general formula (I) of the present disclosure or its tautomer, mesosome, racemate, enantiomer, diastereomer, or Its mixture form or its pharmaceutically acceptable salt or pharmaceutical composition containing it is prepared for the treatment and/or alleviation of pain or pain-related diseases, multiple sclerosis, Char-Martin-Tusan syndrome, incontinence Or the use of arrhythmia drugs. The pain described therein may be chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain or idiopathic pain.

The present disclosure also relates to a method for inhibiting a voltage-gated sodium channel in a subject, the method comprising administering a compound represented by the general formula (I) of the present disclosure or a tautomer, mesoisomer thereof to a patient in need thereof Isomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts or pharmaceutical compositions containing them, wherein the voltage-gated sodium channel is preferably Na _V 1.8.

The present disclosure also relates to a method of treating and/or alleviating pain or pain-related diseases, multiple sclerosis, Char-Martin-Tuson syndrome, incontinence or arrhythmia, the method comprising administering to a patient in need thereof The compound represented by the general formula (I) of the present disclosure, or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its forms or Medicinal salts or pharmaceutical compositions containing them. The pain described therein may be chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain or idiopathic pain.

The present disclosure also relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof or The pharmaceutically acceptable salt or the pharmaceutical composition containing the same is used as a medicament, and the medicament is preferably used for the treatment and/or alleviation of pain or pain-related diseases, multiple sclerosis, and Sha-Mar-Tusan The use of syndrome, incontinence or arrhythmia, wherein the pain is preferably chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain or idiopathic pain.

The present disclosure also relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof or or a pharmaceutically acceptable salt thereof a pharmaceutical composition, for use as a drug that inhibits voltage-gated sodium channels subject, wherein said voltage-gated sodium channels preferably Na _V 1.8.

The present disclosure also relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof or Use of its pharmaceutically acceptable salt or pharmaceutical composition containing it for the treatment and/or alleviation of pain or pain-related diseases, multiple sclerosis, Xia-Martin-Tusan syndrome, incontinence or arrhythmia , Wherein the pain is preferably chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain or idiopathic pain.

The neuropathic pain described in the present disclosure is preferably selected from the group consisting of trigeminal neuralgia, postherpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuralgia, burn syndrome, post-amputation pain, pain after spinal cord injury, phantom Pain, painful neuroma, traumatic neuroma, Morton neuroma, nerve crush injury, spinal canal stenosis, carpal tunnel syndrome, nerve root pain, sciatica, nerve avulsion, brachial plexus avulsion, complexity Regional pain syndrome, neuralgia caused by drug therapy, neuralgia caused by cancer chemotherapy, neuralgia caused by antiretroviral therapy, primary small fiber neuropathy, primary sensory neuralgia, and trigeminal autonomic headache .

The musculoskeletal pain described in the present disclosure is preferably selected from osteoarthritis pain, back pain, cold pain, burning pain and toothache.

The intestinal pain described in the present disclosure is preferably selected from inflammatory bowel disease pain, Crohn's disease pain or intestinal pain caused by interstitial cystitis.

The inflammatory pain described in the present disclosure is preferably selected from rheumatoid arthritis pain and vulvar pain.

The idiopathic pain described in the present disclosure is preferably fibromyalgia.

The active compound can be prepared in a form suitable for administration by any appropriate route, and the active compound is preferably in a unit dose form, or a form in which the patient can self-administer in a single dose. The expression mode of the unit dose of the compound or composition of the present disclosure can be tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, regenerating powder or liquid preparation.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants, excipients Wait. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions. Such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, In order to provide pleasing and delicious medicinal preparations. The tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

Oral preparations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient is mixed with a water-soluble carrier or oil vehicle.

Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions can be formulated by suspending the active ingredients in vegetable oil or mineral oil. Oil suspensions may contain thickeners. Sweetening and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

By adding water, dispersible powders and granules suitable for water suspension can provide active ingredients and dispersing or wetting agents, suspending agents or one or more preservatives for mixing. Suitable dispersing or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweetening agents, flavoring agents and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.

The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase can be vegetable oil or mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable solvents or solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. The sterile injection preparation may be a sterile injection oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion can be injected into the patient's bloodstream by local mass injection. Alternatively, it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.

The pharmaceutical composition of the present disclosure may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixed oil can be used. In addition, fatty acids can also be used to prepare injections.

The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug.

As is well known to those skilled in the art, the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient , The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best mode of treatment such as the mode of treatment, the daily dosage of compound (I) or the amount of pharmaceutically acceptable salt The type can be verified according to the traditional treatment plan. As a general guide, a suitable unit dose can be 0.1-1000 mg.

Detailed description of the invention

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing 1 to 6 carbon atoms An alkyl group of carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers. More preferred is a lower alkyl group containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point. The substituents are preferably independently selected from H atom, D atom, halogen, and alkane. Is substituted by one or more substituents in the group, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl and cycloalkyl are as defined herein. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from H atom, D atom, halogen, alkyl, and alkoxy , Haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl substituted by one or more substituents.

The term "alkylene" refers to a saturated linear or branched aliphatic hydrocarbon group, which has 2 residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms, more preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH ₂ -), 1,1-ethylene (-CH(CH ₃ )-), 1,2-ethylene (-CH ₂ -) CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3-propylene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), etc. The alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy Substituted by one or more substituents in the group, cycloalkylthio, heterocycloalkylthio and oxo.

The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, hydroxyl groups, It is substituted by one or more substituents among hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above. The alkynyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, hydroxyl groups, It is substituted by one or more substituents among hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 (E.g. 3, 4, 5, 6, 7, or 8) carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.

The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but none of the rings have complete conjugate Π electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the ring and the ring, the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete Conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure The ring together is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably phenylcyclopentyl, tetrahydronaphthyl.

Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, sulfur, S( O) and S(O) ₂ heteroatoms, but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 (for example, 3, 4, 5, 6, 7 or 8) ring atoms, of which 1-3 are heteroatoms ; More preferably contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl and so on. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between 5- to 20-membered monocyclic rings, in which one or more ring atoms are selected from nitrogen, oxygen, sulfur, and S (O) and S(O) ₂ heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiro atoms between the ring and the ring, the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclic groups include:

The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, S(O) and S(O) ₂ , and the rest of the ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, S(O) and S(O) ₂ and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

The heterocyclyl ring includes the heterocyclic group (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the group is The structures linked together are heterocyclic groups, non-limiting examples of which include:

Wait.

The heterocyclyl ring includes the heterocyclic group (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the group is The structures linked together are heterocyclic groups, non-limiting examples of which include:

The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.

The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated π-electron system, preferably 6 to 10 members, such as benzene Base and naphthyl. The aryl ring includes the aryl ring as described above fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include :

The aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, and alkyl groups. One or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl are substituted.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl groups are preferably 5 to 10 members, more preferably 5 members or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, Imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes the aforementioned heteroaryl group fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include :

Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.

The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein alkyl and heterocyclyl are as defined above.

The term "cycloalkyloxy" refers to cycloalkyl-O-, where cycloalkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.

The term "hydroxy" refers to the -OH group.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to the -OH group.

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "carbonyl" refers to C=O.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

The term "pharmaceutically acceptable monovalent cation" (Q ⁺ ) includes quaternary ammonium ions (such as N ⁺ (R ^y ) ₄ , where R ^y is H or C ₁ -C ₄ alkyl), alkali metal ions (such as potassium, Sodium, lithium ion), dicyclohexylamine ion and N-methyl D-reduced glucosamine ion.

The term "pharmaceutically acceptable divalent cations" (W ²⁺ ) includes alkaline earth metal ions, such as calcium, magnesium ions, and divalent aluminum ions; also includes amino acid cations, such as arginine, lysine, ornithine Equal monovalent or divalent ions. The pharmaceutically acceptable divalent cation (W ²⁺ ) can be replaced by two pharmaceutically acceptable monovalent cations (Q ⁺ ). The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, with the structure of the present disclosure, in addition to replacing hydrogen with "deuterium" or "tritium", or replacing fluorine with ¹⁸ F-fluorine label ( ¹⁸ F isotope), or enriching with ¹¹ C-, ¹³ C- or ¹⁴ C- Compounds in which carbon atoms ( ¹¹ C-, ¹³ C- or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C- or ¹⁴ C- isotopes) replace carbon atoms are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies. Deuterated compounds can generally retain activity comparable to that of non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements) ). The various deuterated forms of the compounds of formula (I) in this disclosure are expressed as each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the compound of formula (I) in deuterated form with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques using deuterated reagents. Deuterated reagents include but are not limited to deuterated borane and tri-deuterated. Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.

"Optional" or "optionally" means that the event or environment described later can but does not necessarily occur, and the description includes the occasion where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present disclosure. Such salt is safe and effective when used in the body of a mammal, and has due biological activity.

For drugs or pharmacologically active agents, the term "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.

Synthetic method of the compound of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

Option One

The method for preparing the compound represented by general formula (I-I) or its pharmaceutically acceptable salt of the present disclosure includes the following steps:

Compounds of general formula (I-IA) are reacted under acidic conditions to obtain compounds of general formula (I-I),

Wherein, R ^a is alkyl, preferably C ₁ -C ₆ alkyl, more preferably methyl; ring ^{A, R 1, R 3,} R 4, m, n the general formula (II) as defined above.

Option II

The preparation method of the compound represented by the general formula (III) or the pharmaceutically acceptable salt thereof of the present disclosure includes the following steps:

The compound of general formula (IIIA) is reacted under acidic conditions to obtain the compound of general formula (III),

Wherein, R ^a is alkyl, preferably C ₁ -C ₆ alkyl, more preferably ^{methyl; R 1, R 3, R} 4, m, n the general formula (III) as defined above.

third solution

The preparation method of the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof of the present disclosure includes the following steps:

The compound of general formula (IVA) is reacted under acidic conditions to obtain the compound of general formula (IV),

Wherein, R ^a is alkyl, preferably C ₁ -C ₆ alkyl, more preferably ^{methyl; R 1, R 3, m} , n general formula (IV) as defined above.

Option Four

The method for preparing the compound represented by general formula (V) or its salt in the present disclosure includes the following steps:

The compound of general formula (VA) is reacted under acidic conditions to obtain the compound of general formula (V),

Wherein, R ^a is alkyl, preferably C ₁ -C ₆ alkyl, more preferably ^{methyl; R 1, R 3, m} , n the general formula (V) as defined above.

The reagents that provide acidic conditions in the above scheme include but are not limited to pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably pyridine hydrobromide.

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, acetonitrile, pyridine, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl Sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide and mixtures thereof.

Detailed ways

The present disclosure is further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present disclosure.

Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methylsilane (TMS).

For MS measurement, Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid-mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.

Chiral HPLC analysis and determination use Agilent 1260 DAD high performance liquid chromatograph.

The HPLC preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

For chiral preparation, Shimadzu LC-20AP preparative chromatograph was used.

CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm～0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm ~0.5mm.

The silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The average value of ₅₀ measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

The known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Darui Chemicals and other companies.

There is no special description in the examples, and the reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.

The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.

The hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.

The microwave reaction uses the CEM Discover-S 908860 microwave reactor.

There is no special description in the examples, and the solution refers to an aqueous solution.

There are no special instructions in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

The monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC). The developing reagent used in the reaction, the eluent system of column chromatography used in the purification of the compound and the developing reagent system of thin-layer chromatography include: A: Dichloromethane/methanol system; B: n-hexane/ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

Example 1

5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzene Formamide 1

first step

5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid 1b

Under an argon atmosphere, 2,2,6,6-tetramethylpiperidine (19.2 g, 135.93 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was added to 200 mL of tetrahydrofuran. Cool down to 0°C, add n-butyl lithium (1.6M, 85.1mL) dropwise, control the temperature to be lower than 3°C, complete the addition in about 45 minutes, and react at 0°C for 1 hour. The temperature was lowered to -78°C, 1-chloro-4-fluoro-2-(trifluoromethyl)benzene 1a (18g, 90.66mmol, Shanghai Titan Technology Co., Ltd.) was added dropwise, and the reaction was carried out for 3 hours. Add excess dry ice, naturally heat to 0°C, and add 150 mL ice water. Separate the liquids, adjust the pH to 5-6 with 2N dilute hydrochloric acid, extract with 50 mL of ethyl acetate, and concentrate the organic phase under reduced pressure. The crude product was washed with n-hexane (50 mL), and then purified with developing solvent system A by thin layer chromatography to obtain the title compound 1b (15 g), yield: 68%.

MS m/z(ESI): 241.1[M-1].

Second step

5-chloro-2-fluoro-4-(trifluoromethyl)benzoyl chloride 1c

Compound 1b (8.0 g, 33 mmol) was dissolved in 10 mL of thionyl chloride and reacted at 80° C. for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound 1c (8.60 g), which was directly used in the next reaction without purification.

third step

5-chloro-2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide 1d

The crude compound 1c (8.60g, 32.98mmol) and 2-methoxypyridine-4-amine (4.90g, 39.5mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) were dissolved in 80mL of dichloromethane, and pyridine (11g, 139mmol), react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and purified by thin-layer chromatography with the developing solvent system A to obtain the title compound 1d (10 g), yield: 87%.

MS m/z(ESI): 349.0[M+1].

the fourth step

5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide 1e

Compound 1d (100mg, 0.29mmol), 4-fluoro-2-methylphenol (37mg, 0.29mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) and cesium carbonate (141mg, 0.43mmol) were added to N,N-dimethyl Methyl formamide (3 mL) was reacted at 100°C for 2 hours. After cooling to room temperature, the reaction solution was filtered with Celite to obtain a filtrate containing the title compound 1e, which was used directly in the next step without purification.

the fifth step

5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzene Formamide 1

Pyridine hydrobromide (92 mg, 0.57 mmol, Shanghai Adamas Co., Ltd.) was added to the reaction solution containing compound 1e, and reacted at 100°C for 1 hour. The reaction solution was filtered with diatomaceous earth, and the filtrate was purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor 2, elution system: trifluoroacetic acid, water, acetonitrile) to obtain the title compound 1 (100 mg), yield: 99% .

MS m/z(ESI): 441.0[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.42 (s, 1H), 10.72 (s, 1H), 8.06 (s, 1H), 7.35 (d, 1H), 7.22 (d, 1H), 7.10- 7.08 (m, 3H), 6.76 (d, 1H), 6.38 (dd, 1H), 2.16 (s, 3H).

Example 2

5-chloro-2-(2-ethyl-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzene Formamide 2

first step

4-fluoro-2-(1-hydroxyethyl)phenol 2b

Dissolve 5-fluoro-2-hydroxyacetophenone 2a (4.9g, 31.8mmol, Shanghai Beide Pharmaceutical Co., Ltd.) in ethanol (20mL), slowly add sodium borohydride (1.8g, 47.57mmol) in batches, and stir. React for 1 hour. The reaction solution was concentrated under reduced pressure, ethyl acetate (50 mL) and water (50 mL) were added, and 2M dilute hydrochloric acid was added dropwise to adjust the pH to 5-6. Liquid separation, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The organic phase was concentrated under reduced pressure to obtain the title compound 2b (4.5 g), yield: 91%.

MS m/z(ESI): 155[M-1].

Second step

2-ethyl-4-fluorophenol 2c

Compound 2b (6g, 38.4mmol) was dissolved in dichloromethane (40mL), cooled to 0°C, trifluoroacetic acid (23g, 201.7mmol, 15mL) was added, and triethylsilane (14g, 120.4mmol, 19.2mL) was added dropwise ), react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, dichloromethane (50 mL) and water (50 mL) were added, and the layers were separated. The organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The organic phase was concentrated under reduced pressure to obtain the title compound 2c (6.1 g). The crude product was directly used in the next reaction without purification.

MS m/z(ESI): 139.1 [M-1].

third step

5-chloro-2-(2-ethyl-4-fluorophenoxy)-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide 2d

Compound 1d (100 mg, 0.29 mmol), compound 2c (62 mg, 0.44 mmol) and cesium carbonate (141 mg, 0.44 mmol) were added to N,N-dimethylformamide (3 mL) and reacted at 80°C for 1 hour. After cooling to room temperature, the reaction solution was filtered through Celite to obtain a filtrate containing the title compound 2d, which was used directly in the next step without purification. MS m/z(ESI): 468.9[M+1].

the fourth step

5-chloro-2-(2-ethyl-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzene Formamide 2

Pyridine hydrobromide (92 mg, 0.57 mmol, Shanghai Adamas Co., Ltd.) was added to the reaction solution containing compound 2d and reacted at 100°C for 1 hour. The reaction solution was concentrated under reduced pressure and purified by thin-layer chromatography with the developing solvent system A to obtain the title compound 2 (99 mg), yield: 76%.

MS m/z(ESI): 455.0[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.32 (s, 1H), 10.69 (s, 1H), 8.06 (s, 1H), 7.33-7.32 (d, 1H), 7.24-7.22 (d, 1H) ), 7.11-7.10 (m, 3H), 6.74 (s, 1H), 6.37-6.35 (dd, 1H), 2.57-2.54 (t, 2H), 1.09-1.06 (t, 3H).

Example 3

5-chloro-2-(2-cyclopropyl-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl) Benzamide 3

first step

2-cyclopropyl-4-fluorophenol 3b

The compound 2-bromo-4-fluorophenol 3a (1.77g, 9.3mmol, Shanghai Bi De Pharmaceutical Technology Co., Ltd.), potassium phosphate (6.89g, 32.5mmol), tricyclohexylphosphine (260mg, 0.92mmol), cyclopropyl Boric acid (1.20 g, 14 mmol) was added to a mixed solution of toluene (40 mL) and water (2 mL), and replaced with argon three times. Add palladium acetate (105 mg, 0.46 mmol), and replace with argon three times. React at 100°C for 16 hours. The reaction solution was concentrated under reduced pressure, and purified by thin-layer chromatography with developing solvent system A to obtain the title compound 3b (990 mg), yield: 70%.

Second step

5-chloro-2-(2-cyclopropyl-4-fluorophenoxy)-N-(2-methoxypyridin-4-yl)-4-trifluoromethyl)benzamide 3c

Compound 1d (100 mg, 0.29 mmol), compound 3b (52 mg, 0.34 mmol) and cesium carbonate (187 mg, 0.57 mmol) were added to N,N-dimethylformamide (3 mL) and reacted at 80°C for 1 hour. After cooling to room temperature, the reaction solution was filtered with Celite to obtain a filtrate containing the title compound 3c, which was used directly in the next step without purification.

third step

5-chloro-2-(2-cyclopropyl-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl) Benzamide 3

Pyridine hydrobromide (92 mg, 0.57 mmol, Shanghai Adamas Co., Ltd.) was added to the reaction solution containing compound 3c, and reacted at 100°C for 1 hour. The reaction solution was filtered with diatomaceous earth, and the filtrate was prepared by high performance liquid chromatography (Waters 2767-SQ Detecor 2, elution system: trifluoroacetic acid, water, acetonitrile) to obtain the title compound 3 (40 mg), yield: 30%.

MS m/z(ESI): 465.0[M-1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.44 (s, 1H), 10.74 (s, 1H), 8.07 (s, 1H), 7.38 (d, 1H), 7.18-7.14 (m, 1H), 7.09-7.03 (m, 2H), 6.87 (dd, 1H), 6.80 (s, 1H), 6.41 (dd, 1H), 2.01-1.94 (m, 1H), 0.88-0.83 (m, 2H), 0.72- 0.68 (m, 2H).

Example 4

5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl) Benzamide 4

Using the synthetic route of Example 1, the fourth step raw material 4-fluoro-2-methylphenol was replaced with the compound 4-fluoro-2-methoxyphenol (Shaoyuan Technology (Shanghai) Co., Ltd.) to prepare the title compound 4 (60mg).

MS m/z(ESI): 456.8[M+1].

¹ H NMR(400MHz,DMSO-d ₆ )δ8.00(s,1H),7.33-7.31(m,1H),7.28-7.26(m,1H),7.15(dd,1H),6.96(s,1H) ), 6.90-6.86 (m, 1H), 6.76 (s, 1H), 6.40-6.38 (m, 1H), 3.75 (s, 3H).

Example 5

5-chloro-2-(2-ethoxy-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl) Benzamide 5

first step

1-bromo-2-ethoxy-4-fluorobenzene 5b

Dissolve 2-bromo-5-fluorophenol 5a (2g, 10.5mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) in N,N-dimethylformamide (10mL), add iodoethane (2g, 12.8mmol) , Shanghai Titan Technology Co., Ltd.), potassium carbonate (2.9g, 21mmol), react at room temperature for 16 hours. Add ethyl acetate (50 mL) and water (30 mL), and separate the layers. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The organic phase was concentrated under reduced pressure and purified by thin-layer chromatography with the developing solvent system B to obtain the title compound 5b (2.29 g), yield: 100%.

Second step

2-ethoxy-4-fluorophenol 5c

Compound 5b (5.6 g, 25.6 mmol) and triisopropyl borate (6.25 g, 33.2 mmol, Shanghai Titan Technology Co., Ltd.) were added to tetrahydrofuran (80 mL). Under an argon atmosphere, the temperature was lowered to -78°C, and n-butyllithium (1.6M, 38.2mmol, 23.9mL) was slowly added dropwise, and the addition was completed in 20 minutes. It was naturally warmed to room temperature and stirred overnight. The temperature was lowered to 0° C., 50 mL of methanol was added to quench the reaction, and hydrogen peroxide (30 wt%, 20 mL) and 10% sodium hydroxide solution (50 mL) were added dropwise, and stirred for 30 minutes. After the addition was completed, saturated sodium chloride solution (400 mL) was added and extracted with ethyl acetate (200 mL×3). The organic phase was washed with saturated sodium bicarbonate solution (150 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by thin-layer chromatography with developing solvent system B to obtain the title compound 5c (3.5g), yield: 87%.

third step

5-chloro-2-(2-ethoxy-4-fluorophenoxy)-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide 5d

Compound 1d (100 mg, 0.29 mmol), compound 5c (69 mg, 0.44 mmol) and cesium carbonate (141 mg, 0.44 mmol) were added to N,N-dimethylformamide (3 mL) and reacted at 80°C for 1 hour. After cooling to room temperature, the reaction solution was filtered through Celite to obtain a filtrate containing the title compound 5d, which was used directly in the next step without purification. MS m/z(ESI): 485.1[M+1].

the fourth step

5-chloro-2-(2-ethoxy-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl) Benzamide 5

Pyridine hydrobromide (92 mg, 0.57 mmol, Shanghai Adamas Co., Ltd.) was added to the reaction solution containing compound 5d, and reacted at 100°C for 1 hour. The reaction solution was filtered with diatomaceous earth, and the filtrate was purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: trifluoroacetic acid, water, acetonitrile) to obtain the title compound 5 (73mg), yield: 35% .

MS m/z(ESI): 470.9[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.00 (s, 1H), 7.38-7.25 (m, 2H), 7.12 (dd, 1H), 7.01 (s, 1H), 6.90-6.80 (m, 1H) ), 6.76 (s, 1H), 6.39 (d, 1H), 4.04 (q, 2H), 1.12 (t, 3H).

Example 6

5-chloro-2-(2-cyclopropoxy-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl )Benzamide 6

first step

1-Bromo-2cyclopropoxy-4-fluorobenzene 6b

The compound 2-bromo-5-fluorophenol 6a (2g, 10.5mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), cyclopropyl bromide (5g, 41.3mmol, Shanghai Titan Technology Co., Ltd.), cesium carbonate (7g , 21.5mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), potassium iodide (180mg, 1.1mmol) were added to N,N-dimethylformamide (10mL). Placed in a microwave reactor and reacted at 130°C for 1.5 hours. The reaction solution was cooled to room temperature, ethyl acetate (20 mL) was added, and washed with water (20 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by thin-layer chromatography with the developing solvent system A to obtain the title compound 6b (3.0 g), yield: 70%.

Second step

2-Cyclopropoxy-4-fluorophenol 6c

Compound 6b (1.85 g, 8 mmol) and triisopropyl borate (1.96 g, 10.4 mmol, Shanghai Titan Technology Co., Ltd.) were added to tetrahydrofuran (20 mL). Under an argon atmosphere, the temperature was lowered to -78°C, and n-butyllithium (1.6M, 7.5mL, 12mmol) was slowly added dropwise, and the addition was completed in 20 minutes. Warm to room temperature naturally and stir overnight. The temperature was cooled to 0°C, 50 mL of methanol was added to quench the reaction, and hydrogen peroxide (30 wt%, 11 mL) and 10% sodium hydroxide solution (50 mL) were added dropwise. After the addition was completed, a saturated sodium chloride solution (400 mL) was added, and the mixture was extracted with ethyl acetate (200 mL×3). The organic phase was washed with saturated sodium bicarbonate solution (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by thin layer chromatography with the developing solvent system B to obtain the title compound 6c (1.0 g). Yield: 74%.

third step

5-chloro-2-(2-cyclopropoxy-4-fluorophenoxy)-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide 6d

Compound 1d (100 mg, 0.29 mmol), compound 6c (74 mg, 0.44 mmol) and cesium carbonate (141 mg, 0.44 mmol) were added to N,N-dimethylformamide (3 mL) and reacted at 80°C for 1 hour. After cooling to room temperature, the reaction solution was filtered with Celite to obtain a filtrate containing the title compound 6d, which was used directly in the next step without purification. MS m/z(ESI): 497.1 [M+1].

the fourth step

5-chloro-2-(2-cyclopropoxy-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl )Benzamide 6

Pyridine hydrobromide (92 mg, 0.57 mmol, Shanghai Adamas Co., Ltd.) was added to the reaction solution containing compound 6d, and reacted at 100°C for 1 hour. The reaction solution was filtered with diatomaceous earth, and the filtrate was prepared by high performance liquid chromatography (Waters 2767-SQ Detecor 2, elution system: trifluoroacetic acid, water, acetonitrile) to obtain the title compound 6 (85 mg), yield: 40%.

MS m/z(ESI): 482.9[M+1].

¹ H NMR(400MHz,DMSO-d ₆ )δ10.63(s,1H),8.00(s,1H),7.37-7.22(m,3H),6.95(s,1H),6.93-6.85(m,1H) ), 6.76 (s, 1H), 6.39 (d, 1H), 3.98-3.90 (m, 1H), 0.80-0.70 (m, 2H), 0.50-0.40 (m, 2H).

Example 7

(4-(5-Chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoyl)-2-oxopyridine-1(2H)-yl) Methyl dihydrogen phosphate 7

first step

5-chloro-N-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4 -(Trifluoromethyl)benzamide 7a

Compound 1 (370mg, 0.84mmol) and chloromethyl formate (325mg, 2.52mmol, Shanghai Anaiji Chemical Co., Ltd.) were placed in N,N-dimethylformamide (0.3mL) and dichloromethane (3.5mL )in. Stir at room temperature for 4 hours under nitrogen atmosphere. Add ethyl acetate (50 mL) and wash with saturated sodium bicarbonate solution (10 mL×3) and saturated sodium chloride solution (10 mL×3) respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 7a (410 mg).

MS m/z(ESI): 488.9[M+1].

Second step

((4-(5-Chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridine-1(2H)- Base) methyl di-tert-butyl phosphate 7b

Compound 7a (410mg, 0.84mmol) was dissolved in N,N-dimethylformamide (5mL), and di-tert-butyl phosphate potassium salt (417mg, 1.68mmol, Shanghai Beide Pharmaceutical Technology Co., Ltd.), tetrabutyl Ammonium iodide (28mg, 0.084mmol, Sinopharm Chemical Reagent Co., Ltd.), reacted at 70°C for 3 hours. Add ethyl acetate (50 mL), wash with water (10 mL×3) and saturated sodium chloride solution (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 7b (555 mg).

MS m/z(ESI): 662.1[M-1].

third step

4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoyl)-2-oxopyridine-1(2H)-yl)methane Dihydrogen phosphate 7

Compound 7b (555 mg, 0.1 mmol) was dissolved in a mixed solvent of acetonitrile (3.3 mL), acetic acid (3.3 mL) and water (3.3 mL), and reacted at 70°C for 1 hour. The reaction solution was concentrated under reduced pressure and purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 7 (170 mg).

MS m/zESI): 550.9[M+1].

¹ H NMR (400MHz, CD ₃ OD) δ 7.92 (s, 1H), 7.78 (d, 1H), 7.10-6.99 (m, 5H), 6.58-6.58 (m, 1H), 5.63 (d, 2H) ,2.21(s,3H).

Comparative example 1

2-(4-Fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide

It was synthesized by referring to the disclosed synthetic route of Example 10 in patent application WO2014120808.

Test case:

Biological evaluation

Test Example 1. Determination of the inhibitory activity of the compound of the present disclosure on Nav1.8

The purpose of the experiment is to investigate the effect of the compound on the Na _V 1.8 ion channel in an in vitro experiment, and the Na _V 1.8 ion channel is stably expressed on HEK293 cells. After the Na _V 1.8 current is stable, comparing the Na _V 1.8 current before and after the compound application, the influence of the compound on the Na _V 1.8 ion channel can be obtained.

1. Experimental materials and instruments

1) Patch clamp amplifier: patch clamp PC-505B (WARNER instruments)/MultiClamp 700A (Axon instrument)

2) Digital-to-analog converter: Digidata 1440A (Axon CNS)/Digidata 1550A (Axon instruments)

3) Micro-manipulator: MP-225 (SUTTER instrument)

4) Inverted microscope: TL4 (Olympus)

5) Glass microelectrode drawing instrument: PC-10 (NARISHIGE)

6) Microelectrode glass capillary: B12024F (Wuhan Micro-Exploration Scientific Instrument Co., Ltd.)

7) Dimethyl sulfoxide (DMSO): D2650 (Sigma-Aldrich)

8) Tetrodotoxin (TTX): AF3014 (Affix Scientific)

9) HEK293 cells (Cell Bank of Chinese Academy of Sciences, catalog number GNHu18)

2. Experimental steps

2.1 Reagent preparation

The reagents for preparing intracellular and extracellular fluids were purchased from Sigma (St. Louis, MO) except for NaOH and KOH used for acid-base titration. Extracellular fluid of: NaCl, 137mM; KCl, 4mM ; CaCl 2, 1.8mM; MgCl 2, 1mM; HEPES, 10mM; glucose, 10mM; pH 7.4 (NaOH titration). The intracellular fluid is aspartic acid, 140 mM; MgCl ₂ , 2 mM; EGTA 11 mM; HEPES, 10 mM; pH 7.2 mM (CsOH titration). All test compound and control compound solutions contained 1 μM TTX.

The storage concentration of the test compound is 9 mM, dissolved in dimethyl sulfoxide (DMSO). Re-dissolve in the extracellular fluid on the day of the test and prepare the required concentration.

2.2 Manual patch clamp test process

1) After the compound is formulated into a solution with a specified concentration, the drug solution is added to each pipeline in order from low to high concentration, and each pipeline is marked.

2) Transfer the cells to the perfusion tank, apply positive pressure in the electrode, touch the electrode tip to the cell, adjust the three-way valve of the suction device to a three-way state, and then apply negative pressure to the electrode to form a high resistance seal between the electrode and the cell Pick up. Continue to apply negative pressure to rupture the cell membrane and form a current path.

3) After the cell rupture current is stabilized, perfusion of different concentrations is performed sequentially. If the current is stable for at least one minute, the next concentration can be changed for perfusion. The perfusion time for each concentration does not exceed five minutes.

4) Cleaning the perfusion tank: Rinse according to the concentration of the drug solution from high to low, and rinse for 20 seconds for each concentration of the drug solution. Finally, rinse with extracellular fluid for 1 minute.

2.3 Test voltage equation (rest state) and results

Clamp the cell at -80mV, and then depolarize it to 10mV with a square wave lasting 10 milliseconds to obtain a Na _V 1.8 current. This procedure is repeated every 5 seconds. Detect the maximum current induced by the square wave, after it stabilizes, perfuse the test compound, and calculate the blocking strength when the reaction stabilizes.

3. Data analysis

Data collection and analysis used pCLAMP 10 (Molecular Devices, Union City, CA). Current stability means that the current changes within a limited range over time. Dose-effect relationship between the steady current value by plotting the drug concentration gradient dilution series and its role in the generation of HEK293 / Nav1.8, Nav1.8 inhibitory activity on the drug ion channel (IC ₅₀₎ is calculated in turn.

The inhibitory activity of the compounds of the present disclosure on Nav1.8 was determined by the above test, and the measured IC ₅₀ value is shown in Table 1.

Table 1 The IC _{50 of the} compounds of the present disclosure for inhibition of Nav1.8 channel activity

Example number	IC 50 (nM)
1	0.78
2	0.74
3	3.1
4	5.07
5	0.66
6	1.87
Comparative example 1	17

Conclusion: The compounds in the present disclosure have a significant inhibitory effect on the activity of the Nav1.8 channel.

Pharmacokinetic evaluation

Test Example 2. Pharmacokinetic test of the compound of the present disclosure

1. Summary

Using rats as the test animals, the LC/MS/MS method was used to determine the drug concentration in plasma at different times after the rats were given the compound of Example 7 by intragastric administration. To study the pharmacokinetic behavior of the compound of the present disclosure in rats and evaluate its pharmacokinetic characteristics.

2. Test plan

2.1 Experimental drugs

Example 7 compound.

2.2 Experimental animals

4 healthy adult SD rats were divided into 1 group, half male and half male, and the source was Medicilon.

2.3 Drug preparation

Weigh a certain amount of medicine, add 5% DMSO, 5% Tween 80 and 90% normal saline to prepare a colorless and clear solution of 0.2 mg/mL.

2.4 Administration

SD rats were fasted overnight and then given by gavage. The dose was 2.0 mg/kg and the volume was 10.0 mL/kg.

3. Operation

Rats were intragastrically administered the compound of Example 7, and 0.2 mL of blood was collected from the orbit before and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours after the administration, and placed in an EDTA-K2 anticoagulation test tube. Centrifuge for 1 minute at 4°C, 10,000 rpm, and operate on wet ice during the whole process. Plasma is separated within 1 hour, stored at -20°C, and eaten 2 hours after administration.

Determine the content of the test compound in rat plasma after gavage of different concentrations of drugs: Take 30μL of rat plasma at each time after administration, add 150μL MeOH (containing 100ng/mL camptothecin), vortex to mix 1 After centrifugation for 7 minutes (18000g), 8μL of supernatant was taken from the plasma sample for LC/MS/MS analysis.

After intragastric administration of the compound of Example 7 to rats, the compound of Example 7 was basically not detected, and the compound detected was the compound of Example 1.

4. Results of pharmacokinetic parameters

The pharmacokinetic parameters of the compounds of the present disclosure are shown in Table 2 below.

Table 2 Pharmacokinetic parameters of the compound of Example 7

Conclusion: The above research results confirm that the compound of Example 7 is transformed into the compound of Example 1 in rats and has good pharmacokinetic activity.

Claims (21)

1. A compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable Salt used:

   

   among them:

   Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

   R ^{1 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic and heterocyclylalkyl;

   R ^{2 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, -CH ₂ OR ^w , cycloalkyl and heterocyclic group; R ^{w is} selected From hydrogen atom, alkyl group, -C(O)R ⁶ , -S(O) ₂ OH, -S(O) ₂ O ^- Q ⁺ , -PO(OH) ₂ , -PO(OH)O ^- Q ⁺ and _{^{-PO (O -) 2 W 2+}} ; Q + is a monovalent pharmaceutically acceptable cation; W ²⁺ cation is a pharmaceutically acceptable divalent;

   R ^{3 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyloxy, -OR ⁵ , Cycloalkyl and heterocyclyl; the alkyl and alkoxy are optionally further substituted by one or more substituents selected from halogen, alkyl, hydroxy, cycloalkyl and heterocyclyl;

   R ^{4 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy and hydroxyalkyl;

   R ^{5 is} selected from hydrogen atom, alkyl group, cycloalkyl group and heterocyclic group;

   R ^{6 is} selected from alkyl, alkoxy, alkenyl, carboxyl and -C(O)O ^- M ⁺ , wherein said alkyl, alkoxy and alkenyl are optionally further selected from hydroxyl, amino, carboxyl And -C(O)O ^- M ⁺ substituted by one or more substituents; M ⁺ is a pharmaceutically acceptable monovalent cation;

   n is 0, 1, 2, 3, 4 or 5; and

   m is 0, 1, 2 or 3.
2. The compound represented by the general formula (I) according to claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt:

   

   Wherein, ring A, R ¹ , R ³ , R ⁴ , m and n are as defined in claim 1.
3. The compound represented by the general formula (I) according to claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt:

   

   Wherein, R ¹ , R ² , R ³ , R ⁴ , m and n are as defined in claim 1.
4. The compound represented by the general formula (I) according to claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form or a pharmaceutically acceptable salt thereof, wherein R ² is a hydrogen atom or -CH ₂ OR ^w ; R ^{w is} as defined in claim 1.
5. The compound represented by the general formula (I) according to any one of claims 1 to 4, or its tautomer, meso, racemate, enantiomer, diastereomer Structure, or its mixture form or its pharmaceutically acceptable salt, which is a compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, Diastereoisomers, or their mixtures or their pharmaceutically acceptable salts:

   

   Wherein, R ¹ , R ³ , R ⁴ , m and n are as defined in claim 1.
6. The compound represented by the general formula (I) according to any one of claims 1 to 5 or its tautomer, meso, racemate, enantiomer, diastereomer A structure, or a mixture thereof or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IV) or a tautomer, meso, racemate, enantiomer, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

   

   Wherein, R ¹ , R ³ , m and n are as defined in claim 1.
7. The compound represented by the general formula (I) according to any one of claims 1, 3 and 4, or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, or mixtures thereof or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (IVG) or tautomers, mesoisomers, racemates, enantiomers Forms, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:

   

   Wherein: R ^w is selected from _{-PO (OH) 2, -PO (} OH) O - Q + and _{^{-PO (O -) 2 W 2+}} ; Q + is a monovalent pharmaceutically acceptable cation; W ²⁺ pharmaceutically Acceptable divalent cation;

   R ¹ , R ³ , m, and n are as defined in claim 1.
8. The compound represented by the general formula (I) according to any one of claims 1 to 7 or its tautomer, meso, racemate, enantiomer, diastereomer A structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{3 is the} same or different, and each is independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a cycloalkyloxy group, and a cycloalkyl group .
9. The compound represented by the general formula (I) according to any one of claims 1 to 8 or its tautomer, meso, racemate, enantiomer, diastereomer A structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 2.
10. The compound represented by the general formula (I) according to any one of claims 1 to 9 or its tautomer, meso, racemate, enantiomer, diastereomer A structure, or a mixture thereof or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (V) or a tautomer, meso, racemate, enantiomer, Diastereoisomers, or their mixtures or their pharmaceutically acceptable salts:

    

    among them,

    R ^3a and R ^{3b are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, -OR ⁵ , cycloalkyl and heterocycle The alkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxy, cycloalkyl and heterocyclyl;

    Preferably, R ^3a and R ^{3b are the} same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a cycloalkyloxy group and a cycloalkyl group;

    R ¹ , R ⁵ and m are as defined in claim 1.
11. The compound represented by the general formula (I) according to any one of claims 1 to 10, or a tautomer, meso, racemate, enantiomer, or diastereomer thereof In the form of a structure, a mixture thereof, or a pharmaceutically acceptable salt thereof, R ¹ is a hydrogen atom or an alkyl group, preferably a hydrogen atom.
12. The compound represented by the general formula (I) according to any one of claims 1, 3, and 7 or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein Q ⁺ and M ^{+ are the} same or different, and are each independently a quaternary ammonium salt ion and an alkali metal ion; preferably Na ⁺ or K ⁺ ; W ²⁺ is an alkaline earth metal ion, preferably Mg ²⁺ or Ca ²⁺ .
13. The compound represented by the general formula (I) according to any one of claims 1 to 12 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or its mixture form or its pharmaceutically acceptable salt, is selected from any of the following compounds:

    
14. A compound represented by the general formula (I-IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or Medicinal salt:

    

    Wherein, R ^a is alkyl, preferably C ₁ -C ₆ alkyl, more preferably methyl; ring ^{A, R 1, R 3,} R 4, m, n are defined as claimed in claim 1.
15. The compound represented by the general formula (I-IA) according to claim 14 or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or In the form of a mixture or a pharmaceutically acceptable salt thereof, it is selected from any of the following compounds:

    

    
16. A method for preparing a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its forms or The method of medicinal salt, the method includes:

    

    Compounds of general formula (I-IA) are reacted under acidic conditions to obtain compounds of general formula (I-I),

    Wherein, R ^a is alkyl, preferably C ₁ -C ₆ alkyl, more preferably methyl;

    Ring A, R ¹ , R ³ , R ⁴ , m, and n are as defined in claim 2.
17. A pharmaceutical composition containing a therapeutically effective amount of the compound represented by the general formula (I) according to any one of claims 1 to 13 or its tautomer, mesosome, or racemate Isomers, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
18. The compound represented by the general formula (I) according to any one of claims 1 to 13 or its tautomer, meso, racemate, enantiomer, diastereomer Use of the construct, its mixture form or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 17 in the preparation of a medicament for inhibiting voltage-gated sodium channels in a subject.
19. The use according to claim 18, wherein the voltage-gated sodium channel is Na _V 1.8.
20. The compound represented by the general formula (I) according to any one of claims 1 to 13 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or its mixture form or its pharmaceutically acceptable salt or the pharmaceutical composition according to claim 17 is used in the preparation of the treatment and/or alleviation of pain or pain-related diseases, multiple sclerosis, Xia-horse-figure three Use in medicines for the syndrome, incontinence or arrhythmia.
21. The use according to claim 20, wherein the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, and idiopathic pain.