CN109206446B

CN109206446B - Substituted boron-containing compound and pharmaceutical composition containing same

Info

Publication number: CN109206446B
Application number: CN201811344179.7A
Authority: CN
Inventors: 王义汉; 刘志强
Original assignee: Shenzhen Targetrx Inc
Current assignee: Shenzhen Targetrx Inc
Priority date: 2017-11-14
Filing date: 2018-11-13
Publication date: 2021-08-03
Anticipated expiration: 2038-11-13
Also published as: CN109206446A; WO2019096113A1

Abstract

The invention provides a substituted boron-containing compound, a pharmaceutical composition containing the compound and an application of the compound, wherein the boron-containing compound is a compound shown as a formula (I), or a pharmaceutically acceptable salt, a prodrug, a hydrate or a solvent compound, a polymorphism, a stereoisomer or an isotopic variant thereof. The compounds of the present invention are useful in the treatment and/or prevention of infections and a variety of diseases associated with inflammation.

Description

Substituted boron-containing compound and pharmaceutical composition containing same

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a substituted boron-containing compound, a composition containing the compound and application of the compound. More particularly, the present invention relates to certain deuterium substituted 5- (4-cyanophenoxy) -1, 3-dihydro-1-hydroxy-2, 1-benzoxaboroles which are useful in the treatment and/or prevention of diseases associated with infection or inflammation and which have superior pharmacokinetic properties.

Background

Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are second messengers in cells and play an important role in cell signaling. When an external signal (neurotransmitter, hormone, light, odor, etc.) acts on a receptor on a cell membrane, a nucleotide cyclase is activated to act on Adenosine Triphosphate (ATP) and Guanosine Triphosphate (GTP) to generate cAMP and cGMP, respectively. They act as second messengers, regulating cellular functions through adenylate (guanylate) protein kinases (cAK or cGK). cAK and cGK are both composed of a catalytic subunit and a regulatory subunit. The cyclic nucleotides bind to the regulatory subunit, releasing a catalytic subunit, which phosphorylates the protein, causing a biological effect within the cell. Phosphodiesterases (PDEs) can specifically take cAMP and cGMP as substrates, and catalyze hydrolysis to generate inactive 5 '-AMP and 5' -GMP. The concentration of intracellular cyclic nucleotides is mainly determined by the balance between synthesis of nucleotide cyclase and hydrolysis of PDEs. PDEs inhibitors regulate the functions of tissues and organs by inhibiting the activity of PDEs and increasing the concentration of cAMP and cGMP in cells.

PDEs can be isolated by ion exchange chromatography and classified according to their amino acid sequence, enzyme kinetic characteristics, catalytic and regulatory properties, substrate specificity, cell distribution and sensitivity to inhibitors. To date, there are at least 11 gene families (PDE 1-PDE 11) reported in PDEs, each family having 20-25% homology, each family including multiple subfamilies encoded by different genes, each family having 70-80% homology with each other and participating in different signal transduction pathways. Studies have shown that the pharmacological effects of PDEs inhibitors on target organs are mainly two-fold: (1) directly inhibiting the activity of PDEs and improving the intracellular level of cyclic nucleotide; (2) feedback inhibitory effect on PDEs activity. Wherein, the PDE4 inhibitor has obvious anti-inflammatory, antiallergic, antiplatelet activation, and anti-infective effects.

Crisabolone, also known as AN2728 and PF-06930164 and chemically known as 5- (4-cyanophenoxy) -1, 3-dihydro-1-hydroxy-2, 1-benzoxaborole, is a novel non-steroidal phosphodiesterase 4(PDE-4) inhibitor developed by Anacor pharmaceuticals, now available from Pfizer, for use as a topical treatment for mild to moderate allergic dermatitis in patients 2 years and older, and was approved by the united states Food and Drug Administration (FDA) for marketing on 2016, 12 months, 14 days.

Accordingly, there remains a need in the art to develop compounds that are useful as PDE4 inhibitors and that have better pharmacodynamics/pharmacokinetics. The invention provides a novel PDE4 inhibitor which is deuterated and modified by taking Crisabiole as a parent compound, and undesirable metabolites are reduced or eliminated through a deuteration strategy; increasing the half-life of the parent compound; reducing the number of doses required to achieve the desired effect; reducing the number of doses required to achieve the desired effect; increase the formation of active metabolites, if any; reducing the production of harmful metabolites in specific tissues; resulting in a more effective drug and/or a safer drug for multidrug administration (whether or not the multidrug administration is intended).

Disclosure of Invention

In view of the above technical problems, the present invention discloses a novel deuterium-substituted boron-containing compound, a composition comprising the same, and uses thereof, which have better pharmacodynamic/pharmacokinetic properties and are useful for treating and/or preventing conditions associated with infection or inflammation.

In contrast, the invention adopts the following technical scheme:

in a first aspect of the invention, there is provided a compound of formula (I):

wherein,

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、X¹and X²Each independently selected from hydrogen or deuterium;

with the proviso that R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、X¹And X²At least one of which is deuterated or deuterium;

or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate, polymorph, stereoisomer, or isotopic variant thereof.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient. In a specific embodiment, the compounds of the present invention are provided in an effective amount in the pharmaceutical composition. In particular embodiments, the compounds of the present invention are provided in a therapeutically effective amount. In particular embodiments, the compounds of the present invention are provided in a prophylactically effective amount.

In another aspect, the present invention provides a method for preparing the pharmaceutical composition as described above, comprising the steps of: pharmaceutically acceptable excipients are mixed with the compounds of the present invention to form pharmaceutical compositions.

In another aspect, the present invention provides a method of treating and/or preventing an infection in a subject in need thereof, the method comprising administering to the subject an effective dose of a compound of the present invention. In particular embodiments, the infection is selected from: chloromycehia, paronychia, erysipelas-like, onychomycosis, gonorrhea, swimming pool granuloma, larva migration crawl rash, leprosy, contagious deep pustule nodule, milker nodule, herpetic whitlow, acute bacterial periunguium, chronic periunguium, sporotrichosis, syphilis, cutaneous wart tuberculosis, tularemia, daphnia, periungual and digital hypothyroid warts, shingles, nail dystrophy, skin diseases, psoriasis, pustular psoriasis, alopecia areata, impetigo parakeratosis, contact dermatitis, Mendel-de's syndrome, dermatitis planati, lichen planus, idiopathic disease in lichen, lichen glossus, lichen striatus, inflammatory linear verrucous epidermal nevus, bald top, pemphigus, bullous pemphigoid, acquired epidermolysis epidermidis, darier's disease, pityriasis rubra pilaris, palmoplantar's, contact eczema, erythema multiformis, erythematoides rubrum, papulosa, peri, periunguis, perionychomalosis, periunguium, ichthyosis, papyriosis, papyriasis, papyriosis, papyriasis, papyriosis, papyriasis, papyriosis, papyriasis, papyriosis, papyriasis, papyriosis, papyriasis, Scabies, Barzex syndrome, systemic scleroderma, systemic lupus erythematosus, chronic lupus erythematosus, dermatomyositis, sporotrichosis, fungal keratitis, diffuse ocular mycosis, endogenous ocular mycosis, keloid blastomycosis, foot mycosis, sarcoidosis, tinea versicolor, tinea corporis, tinea cruris, tinea pedis, tinea barbae, tinea capitis, microsporidiosis, otomycosis, tinea flavum, chromomycosis, and tinea imbricata. In particular embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In particular embodiments, the compound is administered chronically.

In another aspect, the present invention provides a method of treating and/or preventing a disease associated with inflammation in a subject in need thereof, the method comprising administering to the subject an effective dose of a compound of the present invention. In particular embodiments, the disease associated with inflammation is selected from the group consisting of arthritis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, neurodegenerative disorders, congestive heart failure, stroke, aortic stenosis, renal failure, lupus, pancreatitis, allergy, fibrosis, anemia, atherosclerosis, metabolic diseases, bone diseases, cardiovascular diseases, chemotherapy/chemotherapy-associated complications, type I diabetes, type II diabetes, liver diseases, gastrointestinal disorders, ophthalmic diseases, allergic conjunctivitis, diabetic retinopathy, schungen syndrome, uveitis, pulmonary diseases, kidney diseases, dermatitis, HIV-associated cachexia, brain diseases, ankylosing spondylitis, leprosy, anemia, and fibromyalgia. In a specific embodiment, said neurodegenerative disorder is selected from members of alzheimer's disease and parkinson's disease. In particular embodiments, the inflammatory bowel disease is selected from a member of the group consisting of crohn's disease or ulcerative colitis. In a specific embodiment, the gastrointestinal complication is diarrhea. In particular embodiments, the liver disease is a member selected from the group consisting of autoimmune hepatitis, hepatitis c, primary biliary cirrhosis, primary sclerosing cholangitis, and fulminant liver failure. In a specific embodiment, the gastrointestinal disorder is a member selected from the group consisting of celiac disease and non-specific colitis. In a specific embodiment, the pulmonary disease is a member selected from the group consisting of allergic rhinitis, asthma, chronic obstructive pulmonary disease, chronic granulomatous inflammation, cystic fibrosis, and sarcoidosis. In a specific embodiment, the cardiovascular disease is a member selected from the group consisting of atherosclerotic heart disease, congestive heart failure, and restenosis. In a specific embodiment, the kidney disease is a member selected from the group consisting of glomerulonephritis and vasculitis. In particular embodiments, the compound is administered topically.

Detailed Description

Definition of

Herein, "deuterated", unless otherwise specified, means that one or more hydrogens of a compound or group are replaced with deuterium; deuterium can be mono-, di-, poly-, or fully substituted. The terms "deuterated one or more" and "deuterated one or more" are used interchangeably.

Herein, unless otherwise specified, "non-deuterated compound" means a compound containing deuterium at an atomic ratio of deuterium not higher than the natural deuterium isotope content (0.015%).

The invention also includes isotopically-labeled compounds, equivalent to those disclosed herein as the original compound. Examples of isotopes that can be listed as compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively²H，³H，¹³C，¹⁴C，¹⁵N，¹⁷O，¹⁸O，³¹P，³²P，³⁵S，¹⁸F and³⁶and (4) Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, wherein isotopes or other isotopic atoms containing such compounds are within the scope of the present invention. Certain isotopically-labelled compounds of the invention, e.g.³H and¹⁴among these, the radioactive isotope of C is useful in tissue distribution experiments of drugs and substrates. Tritium, i.e.³H and carbon 14, i.e.¹⁴C, itThe preparation and detection of the compounds are easy, and the compounds are the first choice among isotopes. Isotopically labeled compounds can be prepared by conventional methods by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents using the protocols set forth in the examples.

The compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of "stereoisomeric" forms, e.g., enantiomeric and/or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from mixtures by methods known to those skilled in the art, including: chiral High Pressure Liquid Chromatography (HPLC) and the formation and crystallization of chiral salts; alternatively, preferred isomers may be prepared by asymmetric synthesis.

As used herein, the term "compounds of the present invention" refers to compounds of formula (I). The term also includes pharmaceutically acceptable salts, prodrugs, hydrates or solvate compounds, polymorphs, stereoisomers or isotopic variations of the compounds of formula (I).

As used herein, the term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, the pharmaceutically acceptable salts are described in detail by Berge et al in J.pharmaceutical Sciences (1977)66: 1-19.

Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Salts formed using methods conventional in the art, e.g., ion exchange methods, are also included. Other pharmaceutically acceptable salts include: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cypionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, picrate, etc, Stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, pentanoates, and the like. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄And (3) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like. Other pharmaceutically acceptable salts include, if appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed with counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

The term "solvate" refers to a complex of a compound of the present invention coordinated to solvent molecules in a specific ratio. "hydrate" refers to a complex formed by coordination of a compound of the present invention with water.

The term "prodrug" includes a class of compounds which may be biologically active or inactive in nature and which, when administered by an appropriate method, undergo a metabolic or chemical reaction in the human body to convert it to a compound of formula (I), or a salt or solution of a compound of formula (I). Such prodrugs include, but are not limited to, the following compounds: amino acid residues or polypeptide chains consisting of one or more (e.g. 2, 3 or 4) amino acid residues are covalently linked via an amide or ester bond to a free amino, hydroxyl or carboxyl group of a compound of the invention. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids commonly represented by 3 letter symbols, but also include 4-hydroxyproline, hydroxylysine, Demosine, isodemosine, 3-methylhistidine, norvaline, ornithine, and azathionine. Other types of prodrugs are also included. For example, the free carboxyl groups may be derivatized as amides or alkyl esters. As described in Advanced Drug Delivery Reviews 1996,19,115, the free hydroxyl group is derivatized using groups including, but not limited to, hemisuccinate, phosphate, dimethylaminoacetate, and phosphoryloxymethoxycarbyl groups. Carbamate prodrugs of hydroxy and amino groups, as well as carbonate prodrugs, sulfonates and sulfates of hydroxy groups, are also included. Also included are derivatization of hydroxyl groups such as (acyloxy) methyl and (acyloxy) ethyl ethers, wherein the acyl group may be an alkyl ester, optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups, or wherein the acyl group is an amino acid ester as described above. Prodrugs of this type are described in the following documents: med. chem.1996,39,10. the free amine can also be derivatized to an amide, sulfonamide or phosphoramide. All of these other moieties may incorporate groups including, but not limited to, ether, amine, and carboxylic acid functional groups.

The term "polymorphs" refers to the different arrangements of chemical drug molecules, typically expressed as the presence of the drug material in a solid state. One drug can exist in a plurality of crystal form substances, and different crystal forms of the same drug can be dissolved and absorbed in vivo differently, so that the dissolution and release of the preparation can be influenced.

As used herein, the term "subject" includes, but is not limited to: a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an older adult)) and/or a non-human animal, e.g., a mammal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a cow, a pig, a horse, a sheep, a goat, a rodent, a cat, and/or a dog. In some embodiments, the subject is a human. In other embodiments, the subject is a non-human animal.

"disease," "disorder," and "condition" are used interchangeably herein.

As used herein, unless otherwise specified, the term "treatment" includes the effect that occurs when a subject has a particular disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or delays or slows the progression of the disease, disorder or condition ("therapeutic treatment"), and also includes the effect that occurs before the subject begins to have the particular disease, disorder or condition ("prophylactic treatment").

Generally, an "effective amount" of a compound is an amount sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the present invention may vary depending on the following factors: for example, biological goals, pharmacokinetics of the compound, the disease being treated, mode of administration, and the age, health, and condition of the subject. An effective amount includes both therapeutically and prophylactically therapeutically effective amounts.

As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves the overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of other therapeutic agents.

As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with a disease, disorder, or condition, or to prevent recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic efficacy of other prophylactic agents.

"combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention. For example, a compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously with another therapeutic agent in a single unit dosage form.

Compound (I)

The present invention provides benzimidazole compounds of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate, polymorph, stereoisomer, or isotopic variant thereof:

wherein,

with the proviso that R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、X¹And X²At least one of which is deuterated or deuterium.

As a preferred embodiment of the present invention, the compound of formula (I) contains at least one deuterium atom, more preferably two deuterium atoms, more preferably three deuterium atoms, more preferably four deuterium atoms, more preferably five deuterium atoms, more preferably six deuterium atoms, more preferably seven deuterium atoms, more preferably eight deuterium atoms, more preferably nine deuterium atoms.

As a preferred embodiment of the present invention, the deuterium isotope content of deuterium at the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 99%.

Specifically, in the present invention R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、X¹And X²The deuterium isotope content in each deuterated position is at least 5%, preferably greater than 10%, more preferably greater than 15%, more preferably greater than 20%, more preferably greater than 25%, more preferably greater than 30%, more preferably greater than 35%, more preferably greater than 40%, more preferably greater than 45%, more preferably greater than 50%, more preferably greater than 55%, more preferably greater than 60%, more preferably greater than 65%, more preferably greater than 70%, more preferably greater than 75%, more preferably greater than 80%, more preferably greater than 85%, more preferably greater than 90%, more preferably greater than 95%, more preferably greater than 99%.

In another embodiment, R of the compound of formula (I)¹、R²、R³、R⁴、R⁵、R⁶、R⁷、X¹And X²At least one of the deuterium containing groups, preferably two deuterium containing groups, more preferably three deuterium containing groups, more preferably four deuterium containing groups, more preferably five deuterium containing groups, more preferably six deuterium containing groups, more preferably seven deuterium containing groups, more preferably eight deuterium containing groups, and more preferably nine deuterium containing groups. In particular, the compounds of formula (I) contain at least one, two, three, four, five, six, seven, eight, nine deuterium atoms.

As a preferred embodiment of the present invention, R¹、R²、R³And R⁴Each independently selected from hydrogen or deuterium.

In another preferred embodiment, R¹And R²Is deuterium.

In another preferred embodiment, R³And R⁴Is deuterium.

As a preferred embodiment of the present invention, R⁵、R⁶And R⁷Each independently from hydrogen or deuterium.

In another preferred embodiment, R⁵And R⁶Is deuterium.

As a preferred embodiment of the present invention, X¹And X²Each independently from hydrogen or deuterium.

In another preferred embodiment, X¹Is deuterium.

In another preferred embodiment, X²Is deuterium.

In another preferred embodiment, X¹And X²Is deuterium.

In a particular embodiment, "R¹、R²、R³、R⁴、R⁵、R⁶And R⁷Each independently selected from hydrogen or deuterium "comprising R¹Selected from hydrogen or deuterium, R²Selected from hydrogen or deuterium, R³Selected from hydrogen or deuterium, and so on, up to R⁷Selected from hydrogen or deuterium. More specifically, includes R¹Is hydrogen, R¹Is deuterium, R²Is hydrogen, R²Is deuterium, R³Is hydrogen, R³Deuterium is used by analogy, until R⁷Is hydrogen, R⁷Is a technical scheme of deuterium.

In a particular embodiment, "X¹And X²Each independently selected from hydrogen or deuterium "including X¹Selected from hydrogen or deuterium, R²Selected from hydrogen or deuterium. More specifically, including X¹Is hydrogen, X¹Is deuterium, X²Is hydrogen, X²Is a technical scheme of deuterium.

As a preferred embodiment of the present invention, the present invention relates to a compound of formula (I) wherein R³、R⁴And R⁷Selected from hydrogen, R¹、R²、R⁵、R⁶、X¹And X²Each independently selected from hydrogen or deuterium, with the proviso that the compound contains at least one deuterium.

As a preferred embodiment of the present invention, the present invention relates to a compound of formula (I) wherein R¹-R⁴And R⁷Selected from hydrogen, R⁵、R⁶、X¹And X²Each independently selected from hydrogen or deuterium, with the proviso that the compound contains at least one deuterium.

As a preferred embodiment of the present invention, the present inventionThe invention relates to a compound of formula (I), wherein R¹-R⁴、R⁷And X¹Selected from hydrogen, R⁵、R⁶And X²Each independently selected from hydrogen or deuterium, with the proviso that the compound contains at least one deuterium.

As a preferred embodiment of the present invention, the present invention relates to a compound of formula (I) wherein R¹-R⁴、R⁷、X¹And X²Selected from hydrogen, R⁵And R⁶Each independently selected from hydrogen or deuterium, with the proviso that the compound contains at least one deuterium.

As a preferred embodiment of the present invention, the present invention relates to a compound of formula (I) wherein R⁵And R⁶Selected from deuterium, R¹-R⁴、X¹And X²Each independently selected from hydrogen or deuterium.

As a preferred embodiment of the present invention, the present invention relates to a compound of formula (I) wherein R⁵And R⁶Selected from deuterium, R³、R⁴And R⁷Selected from hydrogen, R¹、R²、X¹And X²Each independently selected from hydrogen or deuterium.

As a preferred embodiment of the present invention, the compound is selected from the group consisting of:

in another preferred embodiment, the compound does not include non-deuterated compounds.

Pharmaceutical compositions and methods of administration

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of an active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an active ingredient. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of an active ingredient.

The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 0.5-2000mg of a compound of the invention per dose, more preferably, 1-500mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.

"pharmaceutically acceptable excipient" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

The compositions of the invention may be administered orally, topically, parenterally, by inhalation or spray, or rectally in unit dosage forms containing conventional pharmaceutically acceptable excipients. It is further understood that the optimal mode of administration may be a combination of methods. Particularly preferably, the pharmaceutical composition is administered orally in the form of pills, capsules, elixirs, syrups, troches, tablets, and the like. The term parenteral as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injections, and the like, or infusion techniques.

Pharmaceutical formulations containing the compounds of the present invention are preferably in a form suitable for oral use, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, hard or soft capsules or syrups or elixirs.

Solid dosage forms for oral administration include capsules, tablets, pills and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or solubilizers, for example, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert release agents conventionally employed in the art, such as water or other solvents, solubilizing agents and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils, or mixtures of these materials.

In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Topical formulations

In a preferred embodiment, the method of the invention may be applied by topical application of the compounds of the invention.

The compositions of the present invention comprise a fluid or semi-solid vehicle which may include, but is not limited to, polymers, thickeners, buffers, neutralizers, chelating agents, preservatives, surfactants or emulsifiers, antioxidants, waxes or oils, emollients, sunscreens, and solvents or mixed solvent systems. A solvent or mixed solvent system is important for shaping because she primarily dissolves the drug. Despite the difficulty in adding solvents to the formulation, optimal solvents or solvent systems are able to maintain clinically relevant levels of the drug in solution. The topical compositions used in the subject invention can be formulated into a variety of product types. They include, but are not limited to, lotions, creams, gels, sticks, sprays, ointments, pastes, foams, mousses, and cleansers. These product types can include several types of carrier systems, including but not limited to particles, nanoparticles, and liposomes. If desired, disintegrating agents such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate may be added.

Formulations lotions for application to the skin, nail, hair, claw or hoof surface without abrasion are typically liquid or semi-liquid formulations in which a solid fine powder, wax or liquid is dispersed. Lotions typically contain suspending agents to produce better dispersions and compounds such as methylcellulose, sodium carboxymethylcellulose, and the like, for localizing and maintaining contact of the active agent to the skin, nails, hair, claws, or hooves.

Creams containing the active agent delivered according to the invention are viscous liquids or semi-solids, either oil-in-water or water-in-oil. Cream bases are water-washable and comprise an oil phase, an emulsifier and an aqueous phase.

Gelling agents may also be used in conjunction with the present invention. As will be appreciated by those skilled in the art of topical pharmaceutical formulations, gels are semi-solid. The single-solid phase comprises organic macromolecules substantially homogeneously distributed in a carrier liquid, which is typically water and may be a solvent or a mixture of solvents.

Ointments, which are semisolid formulations, are generally based on petrolatum or other petrolatum derivatives. The ointment base should be inert, stable, non-irritating and non-sensitizing with respect to the carrier or vehicle.

Formulations useful in the present invention also include sprays. Sprays generally provide the active agent in an aqueous and/or alcoholic solution, which can be aerosolized on the skin, nails, hair, claws, or hooves for delivery. Such sprays include those configured to provide a concentration of the active agent solution at the site of administration after delivery, for example the spray solution may consist essentially of an alcohol or other volatile-like liquid in which the drug or active agent may be dissolved. Upon delivery to the skin, nail, hair, paw or hoof, the carrier evaporates, leaving a concentrated active agent on the site of administration.

The topical pharmaceutical compositions may also contain a suitable solid or gel phase carrier. Examples of such carriers include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers. Such as polyethylene glycols.

Topical pharmaceutical compositions may also contain suitable emulsifying agents, i.e., agents that enhance or facilitate mixing and suspending of the oil-in-water or water-in-oil. The emulsifier used herein may consist of a single emulsifier or may be a nonionic, anionic, cationic or amphoteric surfactant or a mixture of two or more such surfactants; preference is given here to using nonionic or anionic emulsifiers.

The topical pharmaceutical composition may also comprise a suitable emollient. Emollients are substances used to prevent or slow down dryness and to protect the skin, nails, hair, claws or hooves. Useful emollients include, but are not limited to, cetyl alcohol, isopropyl myristate, stearyl alcohol, and the like.

The topical pharmaceutical compositions may also contain suitable antioxidants, i.e., substances known to inhibit oxidation. Antioxidants suitable for use in the present invention include, but are not limited to, butylated hydroxytoluene, ascorbic acid, butylated hydroxyanisole, thiodipropionic acid, tocopherols, and the like, including pharmaceutically acceptable salts and esters of these compounds.

The topical pharmaceutical composition may also contain a suitable preservative. Preservatives are compounds which are added to pharmaceutical preparations and which act as antimicrobial agents. Among the preservatives known in the art to be effective and acceptable in parenteral formulations are benzalkonium chloride, benzethonium chloride, chlorhexidine, phenol, m-cresol, benzyl alcohol, methyl paraben, propyl paraben, chlorobutanol, o-cresol, p-cresol, chlorocresol, phenylmercuric nitrate, thimerosal, benzoic acid, and various mixtures thereof.

The topical pharmaceutical composition may also contain a suitable chelating agent to complex with metal cations that do not pass through the lipid bilayer. Examples of suitable chelating agents include ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis (. beta. -aminoethyl ether) -N, N, N ', N' -tetraacetic acid (EGTA) and the tetrapotassium salt of 8-amino-2 [ (2-amino-5-methylphenoxy) methyl ] -6-methoxyquinoline-N, N, N ', N' -tetraacetic acid (QUIN-2).

The topical composition may also contain a suitable neutralizing agent for adjusting the pH of the formulation to within a pharmaceutically acceptable range.

The topical composition may also contain a suitable viscosity enhancing agent. These ingredients are diffusible compounds that are capable of increasing the viscosity of a polymer-containing solvent through the interaction of an active agent with the polymer.

The topical composition may also comprise a suitable nail penetration enhancer or one or more suitable solvents.

In addition, compounds can be delivered using a sustained release system, such as a translucent matrix of a solid hydrophobic polymer containing the therapeutic agent.

The topical treatment regimen applied according to the present invention comprises applying the composition directly to the application site of the skin, nails, hair, claws or hooves, once to several times daily.

The formulations of the present invention may be used to treat, ameliorate or prevent conditions or disorders associated with bacterial infection, acne, inflammation, and the like.

Additional active agent

The following are examples that may be added to the topical formulations of the present invention.

Anti-inflammatory agents include, but are not limited to, menthol, chlorosulfone, aloe, hydrocortisone, and the like.

Vitamins include, but are not limited to, vitamin B, vitamin E, vitamin a, vitamin D, and the like, and vitamin derivatives.

Anti-aging agents include, but are not limited to, niacinamide, retinol and retinoid derivatives, AHA, ascorbic acid, lipoic acid, coenzyme Q10, beta hydroxy acids, salicylic acid, copper binding peptides, Dimethylaminoethyl (DAEA), and the like.

Agents effective in controlling or altering keratosis include, but are not limited to, tretinoin and adapalene.

Administration of drugs

In general, administration is by any acceptable means of administration of the active agent for similar applications. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration and rate of excretion, the severity of the particular disease undergoing therapy and the judgment of the prescribing clinician. Administration may be once daily or twice daily or up to 3 or 4 times daily.

The dosage for systemic administration to a patient is usually in the range of 0.1-1000 mg/day, preferably 1-500 mg/day, more preferably 10-200 mg/day, even more preferably 100-200 mg/day. The usual dosage ranges stated are 50-91mg/m in respect of the body surface area of the patient²The day is.

Therapeutic indications for the Compounds of the invention

The present invention also relates to a method of treating and/or preventing an infection in a subject, comprising administering to said subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, polymorph, stereoisomer or isotopic variant thereof, or a pharmaceutical composition according to the present invention. In one embodiment, the method relates to the treatment and/or prevention of the following infections: chloromycehia, paronychia, erysipelas-like, onychomycosis, gonorrhea, swimming pool granuloma, larva migration crawl rash, leprosy, contagious deep pustule nodule, milker nodule, herpetic whitlow, acute bacterial periunguium, chronic periunguium, sporotrichosis, syphilis, cutaneous wart tuberculosis, tularemia, daphnia, periungual and digital hypothyroid warts, shingles, nail dystrophy, skin diseases, psoriasis, pustular psoriasis, alopecia areata, impetigo parakeratosis, contact dermatitis, Mendel-de's syndrome, dermatitis planati, lichen planus, idiopathic disease in lichen, lichen glossus, lichen striatus, inflammatory linear verrucous epidermal nevus, bald top, pemphigus, bullous pemphigoid, acquired epidermolysis epidermidis, darier's disease, pityriasis rubra pilaris, palmoplantar's, contact eczema, erythema multiformis, erythematoides rubrum, papulosa, peri, periunguis, perionychomalosis, periunguium, ichthyosis, papyriosis, papyriasis, papyriosis, papyriasis, papyriosis, papyriasis, papyriosis, papyriasis, papyriosis, papyriasis, papyriosis, papyriasis, Scabies, Barzex syndrome, systemic scleroderma, systemic lupus erythematosus, chronic lupus erythematosus, dermatomyositis, sporotrichosis, fungal keratitis, diffuse ocular mycosis, endogenous ocular mycosis, keloid blastomycosis, foot mycosis, sarcoidosis, tinea versicolor, tinea corporis, tinea cruris, tinea pedis, tinea barbae, tinea capitis, microsporidiosis, otomycosis, tinea flavum, chromomycosis, and tinea imbricata, etc.

The present invention also relates to a method of treating and or preventing a disease associated with inflammation in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, polymorph, stereoisomer or isotopic variant thereof, or a pharmaceutical composition according to the present invention. In one embodiment, the method relates to the treatment and/or prevention of the following inflammatory conditions: arthritis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, neurodegenerative disorders, congestive heart failure, stroke, aortic stenosis, renal failure, lupus, pancreatitis, allergy, fibrosis, anemia, atherosclerosis, metabolic diseases, bone diseases, cardiovascular diseases, chemotherapy/chemotherapy-related complications, type I diabetes, type II diabetes, liver diseases, gastrointestinal disorders, ophthalmic diseases, allergic conjunctivitis, diabetic retinopathy, schungren syndrome, uveitis, pulmonary diseases, kidney diseases, dermatitis, HIV-related cachexia, brain diseases, ankylosing spondylitis, leprosy, anemia, and fibromyalgia.

Preferably the neurodegenerative disorder is selected from alzheimer's disease and parkinson's disease; inflammatory bowel disease is selected from crohn's disease or ulcerative colitis; the gastrointestinal complication is diarrhea; the liver disease is selected from autoimmune hepatitis, hepatitis C, primary biliary cirrhosis, primary sclerosing cholangitis and fulminant liver failure; the gastrointestinal disorder is selected from celiac disease and nonspecific colitis; the pulmonary disease is selected from allergic rhinitis, asthma, chronic obstructive pulmonary disease, chronic granulomatous inflammation, cystic fibrosis, and sarcoidosis; cardiovascular disease is selected from the group consisting of atherosclerotic heart disease, congestive heart failure and restenosis; the kidney disease is selected from glomerulonephritis and vasculitis.

The compounds of the present invention have a number of advantages over the non-deuterated compounds known in the prior art. The advantages of the invention include: first, the compounds and compositions of the present invention provide a more advantageous therapeutic tool for the treatment of infection and inflammation related disorders. Second, the metabolism of the compound in the organism is improved, giving the compound better pharmacokinetic parameters. In this case, the dosage can be varied and a long acting formulation formed, improving the applicability. Thirdly, the medicine concentration of the compound in the animal body is improved, and the medicine curative effect is improved. Fourth, certain metabolites are inhibited, increasing the safety of the compounds.

Examples

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Parts and percentages are parts and percentages by weight unless otherwise indicated.

In general, in the preparative schemes, each reaction is usually carried out in an inert solvent at a temperature ranging from room temperature to reflux temperature (e.g., from 0 ℃ to 100 ℃, preferably from 0 ℃ to 80 ℃). The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 24 hours.

Example 15- (4-Cyanophenoxy) -1, 3-dihydro-1-hydroxy-3-d-2, 1-benzoxaborole (Compound L-1) preparation.

The synthesis was carried out using the following route:

step 1 Synthesis of Compound 3

Compound 1(2.0g, 16.5mmol), compound 2(3.3g, 16.5mmol) and potassium carbonate (3.4g, 24.8mmol) were added sequentially to a solution of DMF (20ml) and the reaction was stirred at 100 ℃ for about 10h and the plates analyzed until the starting material reaction was complete. The reaction solution was cooled to room temperature, quenched with water (15ml), extracted with ethyl acetate (30ml × 2), the organic phase was washed with saturated sodium chloride 2 times, the organic phase was collected, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (eluent: petroleum ether/ethyl acetate (v/v) ═ 10:1) to give 3.8g of a white solid product in 76% yield.

Step 2 Synthesis of Compound 4

Under the condition of 0 ℃, NaBD₄(0.16g, 3.97mmol) was slowly added to a solution of Compound 3(1.0g, 3.31mmol) in methanol (15ml) and the reaction was continued for 0.5 h. The reaction was quenched by the addition of 1M hydrochloric acid (10ml), extracted with dichloromethane (20 ml. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed to give 0.9g of a white solid product in 90% yield.

Step 3 Synthesis of Compound 5

Compound 4(0.90g, 3.0mmol), 3, 4-dihydro-2H-pyran (0.30g, 3.56mmol), and pyridinium p-toluenesulfonate (PPTS, 0.075g, 0.30mmol) were added in this order to a solution of dichloromethane (20ml) and stirred at room temperature for 10H. The reaction was quenched with water (10ml), extracted with dichloromethane (15ml × 2), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (eluent: ethyl acetate/petroleum ether (v/v) ═ 1:30) to give 1.0g of a colorless oil, yield 87%.

Step 4 Synthesis of Compound L-1

Adding compound 5(0.3g, 0.77mmol) into anhydrous tetrahydrofuran (15ml) under nitrogen atmosphere, cooling the solution to-78 ℃, then slowly adding n-butyl lithium solution (0.34ml, 2.5mol/L) dropwise, continuing to react at-78 ℃ for 1h after dropwise addition, adding trimethyl borate ester (0.12g, 1.15mmol) once again, naturally raising the reaction solution to room temperature after addition for 10h, adding hydrochloric acid (5ml, 6mol/L), stirring for 2h, adding water (10ml) to quench the reaction, extracting dichloromethane (15ml multiplied by 2), combining organic phases, drying anhydrous sodium sulfate, removing solvent, and performing column separation on the concentrated solution (eluent: ethyl acetate/petroleum ether (v/v) ═ 1:3) to obtain 60mg of white solid product with 31% yield. LC-MS (APCI) M/z 253.12(M +1)⁺。¹H NMR(400MHz,DMSO-d₆)δ9.22(s,1H),7.86(d,J＝8.9Hz,2H),7.81(d,J＝8.0Hz,1H),7.16(dd,J＝5.4,3.5Hz,3H),7.10(dd,J＝8.0,1.8Hz,1H),4.96(s,1H).

Example 25- (4-cyanophenoxy) -1, 3-dihydro-1-hydroxy-2, 1-benzoxaborole-4, ₂preparation of 6-d (Compound L-2).

The synthesis was carried out using the following route:

step 1 Synthesis of Compound 6

At 0 deg.C, adding NaBH₄(0.22g, 5.97mmol) was slowly added dropwise to a solution of Compound 2(1.0g, 4.98mmol) in methanol (15ml), and the reaction was continued for 0.5h after the addition was complete. The reaction was quenched by the addition of 1M hydrochloric acid (10ml), extracted with dichloromethane (20 ml. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed to give 0.93g of a white solid product in 92% yield.

Step 2 Synthesis of Compound 7

Compound 6(1.3g, 6.4mmol) and deuterated sodium hydroxide (NaOD, 0.32g, 7.7mmol) were added to a heavy water (15ml) solution in this order, the reaction solution was stirred at 180 ℃ with a microwave for 1.5 hours, the reaction solution was cooled to room temperature, the pH of the reaction solution was adjusted to about 5 with 1M hydrochloric acid, extraction was performed with ethyl acetate (30ml × 2), the organic phase was washed with saturated sodium chloride 2 times, the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed to obtain 1.1g of a white solid product with a yield of 84%.

Step 3 Synthesis of Compound 8

Compound 1(0.78g, 6.44mmol), compound 7(1.1g, 5.37mmol) and potassium carbonate (1.1g, 8.05mmol) were added sequentially to a solution of DMF (20ml) and the reaction was stirred at 100 ℃ for about 10h and the plates analyzed until the starting material reaction was complete. The reaction solution was cooled to room temperature, quenched with water (15ml), extracted with ethyl acetate (30ml × 2), the organic phase was washed with saturated sodium chloride 2 times, the organic phase was collected, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (eluent: petroleum ether/ethyl acetate (v/v) ═ 10:1) to give 1.2g of a white solid product, yield 74%.

Step 4 Synthesis of Compound 9

Compound 8(1.2g, 3.92mmol), 3, 4-dihydro-2H-pyran (0.40g, 4.71mmol), and pyridinium p-toluenesulfonate (PPTS, 0.10g, 0.4mmol) were successively added to a dichloromethane (20ml) solution, and stirred at room temperature for 10 hours. The reaction was quenched with water (10ml), extracted with dichloromethane (15ml × 2), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (eluent: ethyl acetate/petroleum ether (v/v) ═ 1:30) to give 1.3g of a colorless oil, yield 85%.

Step 5 Synthesis of Compound L-2

Adding compound 9(0.5g, 1.28mmol) into anhydrous tetrahydrofuran (15ml) under nitrogen atmosphere, cooling the solution to-78 ℃, then slowly adding n-butyl lithium solution (0.61ml, 2.5mol/L) dropwise, continuing to react at-78 ℃ for 1h after dropwise addition, adding trimethyl borate ester (0.20g, 1.92mmol) once again, naturally raising the reaction solution to room temperature after addition for 10h, adding hydrochloric acid (6ml, 6mol/L), stirring for 2h, adding water (10ml) to quench the reaction, extracting with dichloromethane (15ml multiplied by 2), combining organic phases, drying with anhydrous sodium sulfate, removing solvent, and performing column separation on the concentrated solution (eluent: ethyl acetate/petroleum ether (v/v) ═ 1:3) to obtain 85mg of white solid product with the yield of 26%. LC-MS (APCI) M/z 254.07(M +1)⁺。¹H NMR(400MHz,DMSO-d₆)δ9.22(s,1H),7.85(d,J＝8.9Hz,2H),7.79(s,1H),7.14(d,J＝8.9Hz,2H),4.96(s,2H).

Example 35- (4-cyanophenoxy) -1, 3-dihydro-1-hydroxy-2, 1-benzoxaborole-3, ₂preparation of 3-d (Compound L-3).

The synthesis was carried out using the following route:

step 1 Synthesis of Compound 11

At 0 deg.C, mixing LiAlD₄(0.21g, 5.19mmol) was slowly added to a solution of Compound 10(1.0g, 4.33mmol) in tetrahydrofuran (15ml) and the reaction was continued for 0.5 h. The reaction was quenched by the addition of 1M hydrochloric acid (10ml), extracted with dichloromethane (20 ml. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed to give 0.8g of a white solid product in 78% yield.

Step 2 Synthesis of Compound 12

Compound 1(0.57g, 4.68mmol), compound 11(0.8g, 3.90mmol) and potassium carbonate (0.80g, 5.85mmol) were added sequentially to a solution of DMF (20ml) and the reaction was stirred at 100 ℃ for about 10h and the plates analyzed until the starting material reaction was complete. The reaction solution was cooled to room temperature, quenched with water (15ml), extracted with ethyl acetate (30ml × 2), the organic phase was washed with saturated sodium chloride 2 times, the organic phase was collected, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (eluent: petroleum ether/ethyl acetate (v/v) ═ 10:1) to give 0.86g of a white solid product with a yield of 71%.

Step 3 Synthesis of Compound 13

Compound 12(0.86g, 2.81mmol), 3, 4-dihydro-2H-pyran (0.28g, 3.37mmol), and pyridinium p-toluenesulfonate (PPTS, 0.07g, 0.3mmol) were successively added to a dichloromethane (20ml) solution, and stirred at room temperature for 10 hours. The reaction was quenched with water (10ml), extracted with dichloromethane (15ml × 2), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (eluent: ethyl acetate/petroleum ether (v/v): 1:30) to give 0.82g of a colorless oil with a yield of 75%.

Step 4 Synthesis of Compound L-3

Adding the compound 13(0.4g, 1.02mmol) into an anhydrous tetrahydrofuran (15ml) solution under a nitrogen atmosphere, cooling the solution to-78 ℃, then slowly dropwise adding an n-butyllithium solution (0.50ml, 2.5mol/L), continuously reacting for 1h at-78 ℃ after dropwise adding is finished, adding trimethyl borate (0.16g, 1.54mmol) once again, and reacting the reaction solution after the dropwise adding is finishedThen the reaction was allowed to warm to room temperature for 10h, hydrochloric acid (6ml, 6mol/L) was added, the reaction was stirred for 2h, water (10ml) was added to quench the reaction, dichloromethane (15ml × 2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (eluent: ethyl acetate/petroleum ether (v/v) ═ 1:3) to give 55mg of a white solid product, yield 21%. LC-MS (APCI) M/z 254.13(M +1)⁺。¹H NMR(500MHz,DMSO-d₆)δ9.20(s,1H),7.84(d,J＝8.7Hz,2H),7.78(d,J＝8.0Hz,1H),7.14(d,J＝8.5Hz,3H),7.09(dd,J＝8.0,2.0Hz,1H).

Example 45- (4-cyanophenoxy) -1, 3-dihydro-1-hydroxy-2, 1-benzoxaborole-3, ₃preparation of 4,6-d (Compound L-4).

The synthesis was carried out using the following route:

step 1 Synthesis of Compound 14

Under the condition of 0 ℃, NaBD₄(0.23g, 5.97mmol) was slowly added dropwise to a solution of Compound 2(1.0g, 4.98mmol) in methanol (15ml) and the reaction was continued for 0.5 h. The reaction was quenched by the addition of 1M hydrochloric acid (10ml), extracted with dichloromethane (20 ml. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed to give 0.94g of a white solid product in 93% yield.

Step 2 Synthesis of Compound 15

Compound 14(1.0g, 4.90mmol) and NaOD (0.24g, 5.88mmol) were added to a solution of heavy water (15ml) in this order, the reaction solution was stirred at microwave 180 ℃ for 1.5 hours, the reaction solution was cooled to room temperature, pH 5 was adjusted with 1M hydrochloric acid, extraction was performed with ethyl acetate (30ml × 2), the organic phase was washed with saturated sodium chloride again for 2 times, the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed to give 0.76g of a white solid product with a yield of 77%.

Step 3 Synthesis of Compound 16

Compound 1(0.43g, 3.50mmol), compound 15(0.6g, 2.91mmol) and potassium carbonate (0.61g, 4.37mmol) were added sequentially to a solution of DMF (20ml) and the reaction was stirred at 100 ℃ for about 10h and the plates analyzed until the starting material reaction was complete. The reaction solution was cooled to room temperature, quenched with water (15ml), extracted with ethyl acetate (30ml × 2), the organic phase was washed with saturated sodium chloride 2 times, the organic phase was collected, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (eluent: petroleum ether/ethyl acetate (v/v) ═ 10:1) to give 0.6g of a white solid product in 68% yield.

Step 4 Synthesis of Compound 17

Compound 16(0.50g, 1.63mmol), 3, 4-dihydro-2H-pyran (0.17g, 1.95mmol), and pyridinium p-toluenesulfonate (PPTS, 0.04g, 0.17mmol) were successively added to a dichloromethane (20ml) solution, and stirred at room temperature for 10 hours. The reaction was quenched with water (10ml), extracted with dichloromethane (15ml × 2), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (eluent: ethyl acetate/petroleum ether (v/v) ═ 1:30) to give 0.52g of a colorless oil with a yield of 81%.

Step 5 Synthesis of Compound L-4

Under nitrogen atmosphere, compound 17(0.3g, 0.77mmol) was added to anhydrous tetrahydrofuran (15ml) solution, the solution was cooled to-78 ℃, then n-butyllithium solution (0.34ml, 2.5mol/L) was slowly added dropwise, reaction was continued at-78 ℃ for 1h after completion of dropwise addition, trimethylborate (0.12g, 1.15mmol) was added once more, the reaction solution was naturally warmed to room temperature for reaction for 10h after completion of addition, hydrochloric acid (5ml, 6mol/L) was added, stirring was carried out for 2h, water (10ml) was added to quench the reaction, dichloromethane (15ml × 2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (eluent: ethyl acetate/petroleum ether (v/v) ═ 1:3) to give 50mg of white solid product, yield 26%. LC-MS (APCI) M/z 255.09(M +1)⁺。¹H NMR(400MHz,DMSO-d₆)δ9.21(s,1H),7.85(d,J＝8.9Hz,2H),7.79(s,1H),7.14(d,J＝8.9Hz,2H),4.94(s,1H).

₂Example 55- (4-Cyanophenoxy-2, 6-d) -1, 3-dihydro-1-hydroxy-2, 1-benzoxaborole Preparation of diene (Compound L-5).

The synthesis was carried out using the following route:

step 1 Synthesis of Compound 18

Compound 1(3.0g, 27.0mmol) and deuterated hydrochloric acid (1.1g, 29.7mmol) are added into a heavy water (15ml) solution in sequence, the reaction solution is stirred at 180 ℃ by microwave for reaction for 0.5h, the reaction solution is cooled to room temperature, the pH value is adjusted to about 7 by using a sodium carbonate solution, ethyl acetate (30ml × 2) is used for extraction, the organic phase is washed by saturated sodium chloride for 2 times, the organic phase is collected, anhydrous sodium sulfate is dried, the solvent is removed, and 2.8g of reddish brown liquid is obtained, wherein the yield is 93%.

Step 2 Synthesis of Compound 19

Compound 18(2.0g, 17.7mmol) and hydrochloric acid (20ml, 2mmol) are added to a water (15ml) solution in sequence, the solution is stirred, the temperature of the solution is reduced to 0 ℃, then sodium nitrite (10ml, 1.5g, 21.2mmol) aqueous solution is slowly dropped, reaction is continued at 0 ℃ for 1h after the addition is finished, potassium iodide (10ml, 4.4g, 26.5mmol) aqueous solution is dropped, the temperature is naturally raised to room temperature for reaction for 4h after the addition is finished, after the reaction is finished, ethyl acetate (30ml multiplied by 2) is used for extraction, an organic phase is washed by saturated sodium chloride for 2 times, the organic phase is collected, dried by anhydrous sodium sulfate, the solvent is removed, and concentrated solution is subjected to column separation (eluent: petroleum ether) to obtain 2.6g of colorless liquid with the yield of 65%.

Step 3 Synthesis of Compound 20

Compound 19(3.0g, 13.4mmol), zinc cyanide (3.2g, 26.8mmol), tetrakistriphenylphosphine palladium (1.54g, 1.34mmol) were added to a solution of anhydrous DMF (80ml) under nitrogen, the solution was allowed to warm to 120 ℃ for 5h, the reaction was quenched with water (50ml), extracted with dichloromethane (50 ml. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (eluent: petroleum ether) to give 0.7g of an oil in 42% yield.

Step 4 Synthesis of Compound 21

Compound 20(1.2g, 9.75mmol), Compound 2(2.0g, 9.75mmol) and potassium carbonate (2.10g, 14.6mmol) were added sequentially to a solution of DMF (20ml) and the reaction was stirred at 100 ℃ for about 10h and the plates analyzed until the starting material reaction was complete. The reaction solution was cooled to room temperature, quenched with water (15ml), extracted with ethyl acetate (30ml × 2), the organic phase was washed with saturated sodium chloride 2 times, the organic phase was collected, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (eluent: petroleum ether/ethyl acetate (v/v) ═ 10:1) to give 2.1g of a white solid product with a yield of 70%.

Step 5 Synthesis of Compound 22

At 0 deg.C, adding NaBH₄(0.24g, 5.92mmol) was slowly added dropwise to a solution of Compound 21(1.5g, 4.93mmol) in methanol (15ml) and the reaction was continued for 0.5 h. The reaction was quenched by the addition of 1M hydrochloric acid (10ml), extracted with dichloromethane (20 ml. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed to give 1.4g of a white solid product in 94% yield.

Step 6 Synthesis of Compound 23

Compound 22(1.0g, 3.27mmol), 3, 4-dihydro-2H-pyran (0.33g, 3.92mmol), and pyridinium p-toluenesulfonate (PPTS, 0.08g, 0.33mmol) were successively added to a dichloromethane (20ml) solution, and stirred at room temperature for 10 hours. The reaction was quenched with water (10ml), extracted with dichloromethane (15ml × 2), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (eluent: ethyl acetate/petroleum ether (v/v) ═ 1:30) to give 1.1g of a colorless oil, yield 86%.

Step 7 Synthesis of Compound L-5

Under nitrogen atmosphere, adding compound 23(0.5g, 1.28mmol) into anhydrous tetrahydrofuran (15ml), cooling to-78 deg.C, slowly adding n-butyllithium solution (0.61ml, 2.5mol/L), and continuing to react at-78 deg.CAfter the reaction solution is naturally raised to room temperature for 10 hours after the addition of trimethylborate (0.20g, 1.92mmol) is added once again for 1 hour, hydrochloric acid (6ml, 6mol/L) is added, the reaction solution is stirred for 2 hours, water (10ml) is added to quench the reaction, dichloromethane (15ml multiplied by 2) is extracted, organic phases are combined, dried by anhydrous sodium sulfate, a solvent is removed, and a concentrated solution is subjected to column separation (eluent: ethyl acetate/petroleum ether (v/v) ═ 1:3) to obtain 95mg of a white solid product with the yield of 29 percent. LC-MS (APCI) M/z 254.19(M +1)⁺。¹H NMR(400MHz,DMSO-d₆)δ9.22(s,1H),7.79(d,J＝7.9Hz,1H),7.14(s,3H),7.09(d,J＝8.1Hz,1H),4.96(s,2H).

And (4) testing the biological activity.

(1) Kinase inhibition

Reagents and consumables:

PDE4D2TR-FRET Assay Kit (BPS bioscience, cat # 60707), Cyclic-3 ', 5' -AMP (Sigma, cat # A6885), Tris (amresco, cat # T0497), BSA (Perkin Elmer, cat # CR84-100), magnesium chloride (Sigma, cat # M1028), Tween-20(Solarbio, cat # T8220), dithiothreitol (Invitrogen, cat # P2325), DMSO (Sigma, cat # D8418), 96-well plate (Nunc, cat # 249944), 384-well plate (Greiner, cat # 784075).

The specific experimental method comprises the following steps:

PDE4D2 inhibitor activity was determined using the PDE4D2TR-FRET Assay Kit using the AMP-Glo method

Compound preparation: test compounds were dissolved in DMSO to make 10mM stock. Then, the mother liquor was diluted to 2mM, and then diluted in DMSO with a 3-fold concentration gradient for 10 doses to obtain a working solution.

PDE4D2 enzyme activity assay: 2.5uL of 2 × PDE4D2 enzyme solution (4 pg/. mu.L) was transferred to a lateral plate with 25nL of pre-diluted compounds at various concentrations and mixed for 10 minutes at room temperature in a sealed manner, each concentration being double-well. Wherein negative and positive controls were set: negative is blank control and positive is Rolipram. mu.L of a previously prepared 2 × Cyclic-3 ', 5' -AMP (2. mu.M) solution was added to the reaction system and incubated at room temperature for 60 minutes. After which 5. mu.L of AMP glo reagent was added and incubation continued for 60 minutes at room temperature. After the reaction, 10. mu.L of AMP detection reagent was added, and incubation was carried out at room temperatureAfter 60 minutes of incubation, enzyme activity is detected by an Evnvision microplate reader, the enzyme activity is measured in the presence of the compound with each concentration, and the inhibitory activity of the compound with different concentrations on the enzyme activity is calculated. Then fitting the inhibitory activity of the enzyme activity of the compounds with different concentrations according to a four-parameter equation and Graphpad 5.0 software, and calculating IC₅₀The value is obtained.

The compounds of the invention and the non-deuterated compound Crisabiole were tested in the above kinase inhibition assay and found to have more potent or comparable activity against PDE4D2 kinase. The results of the inhibition of kinases by representative example compounds are summarized in table 1 below.

Table 1:

EXAMPLES Compounds	PDE4D2IC₅₀(nM)
		Crisaborole	1.32
L-1	1.25
		L-2	1.06
L-3	1.35
		L-4	1.29
L-5	1.45

(2) Metabolic stability evaluation

Microsome experiment: human liver microsomes: 0.5mg/mL, Xenotech; coenzyme (NADPH/NADH): 1mM, Sigma Life science; magnesium chloride: 5mM, 100mM phosphate buffer (pH 7.4).

Preparing a stock solution: an amount of the compound of example was weighed out finely and dissolved in DMSO to 5mM each.

Preparation of phosphate buffer (100mM, pH 7.4): 150mL of 0.5M potassium dihydrogenphosphate and 700mL of 0.5M dipotassium hydrogenphosphate solution prepared in advance were mixed, the pH of the mixture was adjusted to 7.4 with the 0.5M dipotassium hydrogenphosphate solution, diluted 5-fold with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer solution (100mM) containing 100mM potassium phosphate and 3.3mM magnesium chloride at a pH of 7.4.

NADPH regenerating system solution (containing 6.5mM NADP, 16.5mM G-6-P, 3U/mL G-6-P D, 3.3mM magnesium chloride) was prepared and placed on wet ice before use.

Preparing a stop solution: acetonitrile solution containing 50ng/mL propranolol hydrochloride and 200ng/mL tolbutamide (internal standard). 25057.5 mu L of phosphate buffer solution (pH7.4) is taken to a 50mL centrifuge tube, 812.5 mu L of human liver microsome is respectively added and mixed evenly, and liver microsome dilution liquid with the protein concentration of 0.625mg/mL is obtained.

Incubation of the samples: the stock solutions of the corresponding compounds were diluted to 0.25mM each with an aqueous solution containing 70% acetonitrile, and used as working solutions. 398. mu.L of each human liver microsome dilution was added to a 96-well plate (N2), 2. mu.L of each 0.25mM working solution, and mixed well.

Determination of metabolic stability: 300. mu.L of pre-cooled stop solution was added to each well of a 96-well deep-well plate and placed on ice as a stop plate. The 96-well incubation plate and the NADPH regeneration system are placed in a 37 ℃ water bath box, shaken at 100 rpm and pre-incubated for 5 min. 80. mu.L of the incubation solution was taken out of each well of the incubation plate, added to the stop plate, mixed well, and supplemented with 20. mu.L of NADPH regenerating system solution as a 0min sample. Then 80. mu.L of NADPH regenerating system solution was added to each well of the incubation plate, the reaction was started, and the timer was started. The reaction concentration of the corresponding compound was 1. mu.M, and the protein concentration was 0.5 mg/mL. When the reaction was carried out for 10min, 30 min and 90min, 100. mu.L of each reaction solution was added to the stop plate and vortexed for 3min to terminate the reaction. The stop plates were centrifuged at 5000 Xg for 10min at 4 ℃. And (3) taking 100 mu L of supernatant to a 96-well plate in which 100 mu L of distilled water is added in advance, mixing uniformly, and performing sample analysis by adopting LC-MS/MS.

And (3) data analysis: and detecting peak areas of the corresponding compound and the internal standard through an LC-MS/MS system, and calculating the peak area ratio of the compound to the internal standard. The slope is determined by plotting the natural logarithm of the percentage of compound remaining against time and calculating t according to the following formula_1/2And CL_intWhere V/M is equal to 1/protein concentration.

The compound of the invention and the compound without deuteration are simultaneously tested and compared to evaluate the metabolic stability of the compound in human liver microsomes. The half-life and intrinsic hepatic clearance as indicators of metabolic stability are shown in table 2. The experimental results show that: compared with the compound Crisabiole without deuteration, the compound of the invention can obviously improve the metabolic stability.

Table 2:

(3) pharmacokinetic experiment of rat

6 male Sprague-Dawley rats, 7-8 weeks old, weighing about 210g, were divided into 2 groups of 3 per group and compared for pharmacokinetic differences by intravenous or oral administration of a single dose of compound (10 mg/kg oral).

Rats were fed with standard feed and given water. Fasting began 16 hours prior to the experiment. The drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the orbit at 0.083 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr and 24 hr post-dose.

The rats were briefly anesthetized after ether inhalation and 300 μ L of blood was collected from the orbit into a test tube. In the test tube there was 30. mu.L of 1% heparin salt solution. Before use, the tubes were dried overnight at 60 ℃. After completion of blood collection at the last time point, rats were sacrificed after ether anesthesia.

Immediately after blood collection, the tubes were gently inverted at least 5 times to ensure mixing and then placed on ice. The blood samples were centrifuged at 5000rpm for 5 minutes at 4 ℃ to separate the plasma from the erythrocytes. Pipette 100 μ L of plasma into a clean plastic centrifuge tube, designating the name of the compound and the time point. Plasma was stored at-80 ℃ before analysis. The concentration of the compounds of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.

Experiments show that the compound has better pharmacokinetic property in animals, thereby having better pharmacodynamics and treatment effect.

The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.

Claims

1. A compound, wherein the compound is selected from the following compounds, or pharmaceutically acceptable salts thereof:

2. a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 2, in the manufacture of a medicament for the treatment and/or prevention of a disease associated with infection or inflammation.

4. The use according to claim 3, wherein the infection-related disease is selected from chloromycetis, paronychia, erysipelas, onychomycosis, gonorrhea, swimming pool granuloma, larva migration crawl rash, leprosy, contagious deep pustular nodule, milker nodule, blepharitis felis, acute bacterial periunguium, chronic periunguium, sporotrichosis, syphilis, cutaneous wart tuberculosis, tularemia, periungual and subungual warts, shingles, nail dystrophy, skin disease, psoriasis, pustular psoriasis, alopecia areata, impetigo-keratosis, contact dermatitis, sauter's syndrome, acropsoriatic dermatitis, lichen planus, idiopathic atrophy in lichen, lichen glossus, lichen striatus, inflammatory linear epidermoid nevus verrucosus, baldness, pemphigoid, epidermolysis bullosa acquisita, epidermolysis bullosa, lichen planus, Darier's disease, pityriasis rubra pilaris, palmoplantar keratosis, contact eczema, erythema multiforme, scabies, Pazex syndrome, systemic scleroderma, systemic lupus erythematosus, chronic lupus erythematosus, dermatomyositis, sporotrichosis, fungal keratitis, diffuse ocular mycosis, endogenous ocular mycosis, keloid blastomycosis, podomycosis, sarcoidosis, tinea versicolor, tinea corporis, tinea cruris, tinea pedis, tinea barbae, tinea capitis, microsporosis nigra, otomycosis, xanthomycosis pigmentosa, and tinea imbricata.

5. The use according to claim 3, wherein the disease associated with inflammation is selected from the group consisting of arthritis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, neurodegenerative disorders, congestive heart failure, stroke, aortic stenosis, renal failure, lupus, pancreatitis, allergy, fibrosis, anemia, atherosclerosis, metabolic diseases, bone diseases, cardiovascular diseases, chemotherapy/chemotherapy-related complications, type I diabetes, type II diabetes, liver diseases, gastrointestinal disorders, ophthalmic diseases, allergic conjunctivitis, diabetic retinopathy, Scherger's syndrome, uveitis, pulmonary diseases, kidney diseases, dermatitis, HIV-related cachexia, brain diseases, ankylosing spondylitis, leprosy, anemia, and fibromyalgia.

6. The use according to claim 5, wherein said neurodegenerative disorder is selected from members of the group consisting of Alzheimer's disease and Parkinson's disease; said inflammatory bowel disease is selected from a member of Crohn's disease or ulcerative colitis; the gastrointestinal complication is diarrhea; the liver disease is a member selected from autoimmune hepatitis, hepatitis c, primary biliary cirrhosis, primary sclerosing cholangitis, and fulminant liver failure; the gastrointestinal disorder is a member selected from the group consisting of celiac disease and non-specific colitis; the pulmonary disease is a member selected from the group consisting of allergic rhinitis, asthma, chronic obstructive pulmonary disease, chronic granulomatous inflammation, cystic fibrosis, and sarcoidosis; said cardiovascular disease is a member selected from the group consisting of arteriosclerotic heart disease, congestive heart failure and restenosis; and the kidney disease is a member selected from the group consisting of glomerulonephritis and vasculitis.