CN113121417A - Novel piperidine derivative and pharmaceutical application thereof - Google Patents

Abstract

The present disclosure relates to a novel piperidine derivative and pharmaceutical use thereof. Specifically, the compound shown as the formula I or the medicinal salt or the stereoisomer thereof is providedThe compounds have PDE4B1 or PDE4D3 inhibitory activity and can be used for treating or preventing diseases related to PDE4, such as inflammatory diseases, diabetes or allergic diseases, and the definition of each group in formula I is consistent with the specification.

Description

Novel piperidine derivative and pharmaceutical application thereof

Technical Field

The disclosure belongs to the field of medicine, and relates to a novel piperidine derivative and a medicinal application thereof.

Background

3 ', 5' -cyclic adenosine monophosphate (cAMP) and 3 ', 5' -cyclic guanosine monophosphate (cGMP) which are intracellular signal transducers (second messengers) are decomposed into inactive 5 '-AMP and 5' -GMP, respectively, by a hydrolase called Phosphodiesterase (PDE). The PDE isozymes inactivating them are not uniformly present in the living body, but show differences in cell distribution, tissue distribution, etc., and are present in the living body at a unique position of an organ.

Up to now, 11 families of PDE1-PDE11 (Currentopinion in Cell Biology,12,174-179(2000)) have been identified, while the PDE4 family can be divided into 4 subtypes, PDE4A, PDE4B, PDE4C and PDE4D, each subtype having multiple subtypes, e.g. 3 subtypes of PDE4B, depending on the different gene codings. With the 3 PDE4 subtypes PDE4A, PDE4B and PDE4D being expressed most, and PDE4C being expressed little or no. PDE4B is the strongest known PDE4 inflammatory factor, and inhibition of PDE4D is strongly associated with side effects.

PDE4 inhibitors are known to be broadly divided into non-selective PDE4 inhibitors and selective PDE4 inhibitors.

Non-selective PDE4 inhibitors such as theophylline, although effective in dilating bronchi, some of the adverse effects of theophylline such as central nervous stimulation, arrhythmia and diuretic effects are also associated with adenosine receptor antagonism.

Selective PDE4 inhibitors are classified as first-generation selective inhibitors such as rolipram, second-generation selective inhibitors such as roflumilast, cilomilast and others, where roflumilast is active on the three subtypes PDE4A, PDE4B and PDE4D, in addition to being slightly less effective at inhibiting PDE 4C. Roflumilast can reduce inflammation of lungs, resist oxygen stress, effectively relieve fibrosis of lungs, enhance the cleaning capacity of mucosa and remodeling of airways and the like, and then has serious adverse effects which are mainly manifested by diarrhea, weight loss, nausea, atrial fibrillation, exacerbation of mental diseases and the like, wherein the adverse effects are related to selective inhibition of different PDE4 subtypes by a PDE4 inhibitor.

Until now, selective inhibitors of PDE4 still do not achieve absolute specific inhibition of PDE4B, greatly limiting the clinical utility of this class of drugs. On the other hand, a PDE4 inhibitor with high homology with cAMP is constructed by carrying out structural modification based on cAMP, so that the selectivity of the PDE4 inhibitor is improved, the drug effect is increased, and meanwhile, the toxic and side effects are reduced.

In addition, PDE4 inhibitors are known from patent documents CN1468219A, CN1203058C, US5602173, US7649095, WO93/19747 and WO 93/19749.

Disclosure of Invention

The disclosure provides compounds of formula (I),

or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer or tautomer thereof,

wherein R is¹Selected from hydrogen or nitrile groups;

R²is selected from C_3-7CycloalkanesA group of C_3-7Cycloalkyl substituted with halogen or haloalkyl;

R³selected from alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with one or more groups selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxy or halogen;

R⁴and R⁵Each independently selected from hydrogen, halogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with one or more groups selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxy, halogen, or R is⁴、R⁵Together with their adjacent carbon atoms form a 5-to 12-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, preferably a 6-to 8-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, which carbocyclic, heterocyclic, aromatic or heteroaromatic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, amino, oxo, carboxy, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁶selected from hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl or-NHOH groups, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl groups being optionally substituted with one or more groups selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl or halogen;

x is methylene optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, alkoxy or cycloalkyl;

n and m are integers of 1-4 (including 1,2, 3 or 4).

Some embodiments provide R in the compound of formula (I)⁶Selected from hydroxy, C_1-8Alkyl (e.g. methyl, ethyl, isopropyl, phenyl, C)_1-4Phenyl substituted with alkyl, etc.), C_1-8Alkoxy (e.g., methoxy, ethoxy, isopropyl, etc.) or-NHOH, said C_1-8Alkyl or C_1-8The alkoxy group is optionally substituted with one or more substituents selected from aryl and heteroaryl.

In some embodiments, the compound of formula (I) is as follows:

wherein R is¹～R⁵M is as defined for the compound of formula (I),

some embodiments provide R in the compound of formula (I)²Is C substituted by 1-3 fluorine atoms_3-7A cycloalkyl group.

Some embodiments provide R in the compound of formula (I)²C substituted by haloalkyl_3-7Cycloalkyl, said haloalkyl being difluoromethyl, trifluoromethyl or 1, 1-difluoroethyl.

Some embodiments provide R in the compound of formula (I)²Selected from, but not limited to:

further, it may be optionally and independently selected from C on a ring carbon atom_1-6Alkyl (including methyl, ethyl, isopropyl, etc.), C_1-6Alkyloxy (including methoxy, ethoxy, isopropoxy, etc.), C_3-7Cycloalkyl (including cyclopropyl, cyclopentyl, cyclohexyl, etc.) optionally and independently substituted on the ring nitrogen by a substituent selected from C_1-6Alkyl, -COR', -S (O)₂R'、-CON(R')₂、C_3-7A cycloalkyl group is substituted by a cycloalkyl group,

r' is selected from hydrogen, hydroxy, alkyl (e.g. C)_1-8Alkyl), alkoxy (e.g. C)_1-8Alkoxy group), acyl group (C)_3-6Alkanoyl including but not limited to acetyl, formyl),Aryl (e.g. phenyl, methylphenyl) or heteroaryl (e.g. pyridyl), said alkyl, alkoxy, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen (e.g. fluorine, chlorine or bromine), alkyl (e.g. C)_1-8Alkyl, including but not limited to methyl, ethyl or isopropyl), cycloalkyl (e.g. C)_3-7Cycloalkyl groups, including but not limited to cyclopropyl or cyclopentyl), alkoxy (e.g. C)_1-8Alkoxy including but not limited to methoxy, ethoxy, isopropyl, etc.), oxy, hydroxy, nitro, nitrile.

In another aspect, some embodiments provide R in the compound of formula (I)³Is selected from C_1-8Alkyl (e.g. methyl, ethyl or isopropyl) or C_3-7Cycloalkyl (e.g. cyclopropyl or cyclopentyl), said C_1-8Alkyl or C_3-7Cycloalkyl optionally substituted by one or more groups selected from C_1-8Alkyl (e.g. methyl, ethyl or isopropyl), C_3-7Cycloalkyl (e.g. cyclopropyl or cyclopentyl), halogen (e.g. fluorine, chlorine or bromine), C_1-8Alkoxy (e.g., methoxy, ethoxy, isopropyl, etc.), C_3-7Heterocyclyl (e.g., pyridyl, pyrrolyl), aryl (e.g., phenyl, methylphenyl), or heteroaryl (e.g., pyridyl).

In some embodiments, R in the compound of formula (I)³Selected from difluoromethyl, trifluoromethyl, 1-difluoroethyl.

In some embodiments, the compounds of formula (I) are as follows:

wherein R is¹～R²，R⁴～R⁵M is as defined for the compound of formula (I).

In other embodiments, there are provided compounds of formula (I) wherein R is⁴And R⁵Each independently selected from hydrogen and C_1-8Alkyl (e.g. methyl, ethyl, isopropyl, phenyl, C)_1-4Phenyl substituted with alkyl, etc.), or R⁴、R⁵Together with their adjacent carbon atoms form a 6-to 8-membered carbocyclic or heterocyclic ring, optionally substituted with one or more substituents selected from alkyl (e.g. methyl, ethyl, isopropyl), halogen (e.g. fluorine, chlorine or bromine), hydroxy (-OH), nitro, cyano, alkoxy (e.g. C)_1-8Alkoxy, including but not limited to methoxy, ethoxy, isopropyl, etc.) with one or more substituents.

In some embodiments, R in the compound of formula (I)⁴And R⁵Selected from hydrogen.

In some embodiments, R in the compound of formula (I)⁴And R⁵Each independently selected from methyl, ethyl or isopropyl, optionally substituted with halogen, such as fluorine, chlorine or bromine.

In some embodiments, R in the compound of formula (I)⁴And R⁵Together with their adjacent carbon atoms form a 6-to 8-membered carbocyclic ring, including but not limited to, cyclopropane, cyclobutane, cyclopentane.

Typical compounds of formula (I) include, but are not limited to:

or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof.

In some embodiments, the present disclosure provides that the compound of formula (I) is selected from:

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides a pharmaceutical composition comprising at least one therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

In some embodiments, the unit dose of the pharmaceutical composition is from 0.001mg to 1000 mg.

In certain embodiments, the pharmaceutical composition comprises 0.01 to 99.99% of the aforementioned compound, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1-99.9% of the aforementioned compound. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of the aforementioned compound. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of the aforementioned compound. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of the aforementioned compound.

In certain embodiments, the pharmaceutical composition comprises from 0.01% to 99.99% of a pharmaceutically acceptable carrier, diluent or excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable carrier, diluent or excipient.

In another aspect, the present disclosure also provides a method for treating or preventing asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatic diseases by administering to the patient a therapeutically effective amount of the compound of formula (I) or the pharmaceutical composition of the foregoing.

Further, diseases such as asthma, obstructive pulmonary disease, septicemia, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, and rheumatism are related to phosphodiesterase 4(PDE 4).

Also provided in this disclosure is a method of treating or preventing a disease associated with PDE4 by administering to the patient a therapeutically effective amount of a compound of formula (I) as described above or a pharmaceutical composition as described above.

In some embodiments, diseases associated with PDE4 include inflammatory diseases (asthma, obstructive pulmonary disease, septicemia, nephritis, etc.), diabetes, allergic diseases (allergic rhinitis, allergic conjunctivitis, etc.), autoimmune diseases (ulcerative enteritis, rheumatism), and the like.

The present disclosure also relates to the use of the compound of the above scheme or the pharmaceutical composition of the foregoing in the preparation of a medicament for treating or preventing asthma, obstructive pulmonary disease, septicemia, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatic diseases.

Further, diseases such as asthma, obstructive pulmonary disease, septicemia, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, and rheumatism are related to phosphodiesterase 4(PDE 4).

The present disclosure also relates to the use of a compound described in the above scheme or a pharmaceutical composition of the foregoing in the manufacture of a medicament for the treatment or prevention of a disease associated with PDE 4.

In some embodiments, diseases associated with PDE4 include inflammatory diseases (asthma, obstructive pulmonary disease, septicemia, nephritis, etc.), diabetes, allergic diseases (allergic rhinitis, allergic conjunctivitis, etc.), autoimmune diseases (ulcerative enteritis, rheumatism), and the like.

In another aspect, the pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic or organic salts, and the compounds described in this disclosure are reacted with an acid, such as trifluoroacetic acid, selected from, but not limited to, acetic acid, hydrochloric acid, salicylic acid, malic acid, ascorbic acid, phosphoric acid, citric acid, benzoic acid, or fumaric acid, to form the corresponding salts.

In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride salt thereof.

The disclosed compounds may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.

Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).

In the chemical structure of the compounds described in the present disclosure, a bond

Denotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structure

Can be that

Or

Or at the same time contain

And

two configurations.

In another aspect, the hydrogen in the functional group of the compounds described in the present disclosure is deuterated, resulting in corresponding deuterated compounds that retain selectivity and potential comparable to hydrogen analogs; deuterium bonds are more stable, making the "ADME", i.e. "pharmacokinetics", different, thereby providing clinically beneficial effects.

Pharmacokinetics refers to the processes of absorption (absorption), distribution (distribution), metabolism (metabolism) and excretion (excretion) of exogenous chemicals by the body. Process for preparing compounds of formula I

The preparation of compounds of formula I from known or readily prepared starting materials according to methods known to those skilled in the art of organic synthesis is shown below and summarized in the following scheme. Alternative synthetic routes and similar structures will be apparent to those skilled in the art of organic synthesis.

The scheme is as follows:

interpretation of terms:

a "pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifying agent that has been approved by the U.S. food and drug administration for use in humans or livestock animals.

"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups having 1 to 12 carbon atoms are preferred, and alkyl groups having 1 to 6 carbon atoms are more preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, various branched isomers thereof, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxy, or halogen.

"alkenyl" includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups. E.g. "C_2-6Alkenyl "denotes alkenyl having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl, and 4-hexenyl. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxy, or halogen.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, halo, hydroxy, amino, oxo, carboxy, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)_m(where m is an integer from 0 to 2) but does not include the ring portion of-O-, O-S-or-S-the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. Non-limiting examples of "heterocyclyl" include:

and so on.

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:

and the like.

The ring carbon atoms of the heterocycloalkyl group can be oxo (functionalized as a carbonyl group). Illustrative examples of such heterocycloalkyl groups are: .

The term "5-to 8-membered monocyclic cycloalkyl" refers to monocyclic cycloalkyl groups having 5 to 8 ring atoms, including 5-, 6-, 7-or 8-membered ring atoms. The term "5 to 8 membered monocyclic heterocycloalkyl" refers to monocyclic heterocycloalkyl having 5 to 8 ring atoms, including 5, 6, 7 or 8 membered ring atoms, at least one ring atom being selected from other than carbon atoms, such as nitrogen, oxygen or sulfur. The term "8-to 12-membered bicyclic cycloalkyl" refers to bicyclic cycloalkyl having 8 to 12 ring atoms, including 8-, 10-, or 12-membered ring atoms. The term "8 to 12 membered bicyclic heterocycloalkyl" refers to bicyclic heterocycloalkyl having 8 to 12 ring atoms, including 8, 10 or 12 membered ring atoms, at least one ring atom being selected from other than carbon, such as nitrogen, oxygen or sulfur. Unless otherwise indicated, cycloalkyl, heterocycloalkyl groups may be substituted.

The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, halo, hydroxy, amino, oxo, carboxy, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl.

"alkynyl" includes branched and straight chain alkynyl groups having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups, or if the specified number of carbon atoms is specified, that particular number is intended. For example, ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl groups.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, halo, hydroxy, amino, oxo, oxy, carboxy, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably phenyl.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12-membered, more preferably 5-or 6-membered. For example. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazine, thiadiazole

And so on.

The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, halo, hydroxy, amino, oxo, carboxy, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, halo, hydroxy, amino, oxo, carboxy, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "haloalkyl" refers to an alkyl group as defined above substituted with one or more halogen atoms as defined above. Preferably, the haloalkyl group can be a monohaloalkyl group, a dihaloalkyl group, or a polyhaloalkyl group including perhaloalkyl groups. The monohaloalkyl group may have one iodine atom, bromine atom, chlorine atom or fluorine atom. The dihaloalkyl and polyhaloalkyl groups may be substituted with two or more of the same halogen atoms or a combination of different halogen atoms. Unless set forth or recited to the contrary, all haloalkyl groups described or claimed in this disclosure may be straight or branched chain, substituted or unsubstituted.

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

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

The term "amino" refers to the group-NH₂。

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

The term "oxo" refers to an ═ O substituent.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

Which are known in the art to protect reactive groups (including, without limitation, hydroxyl and amino groups) from side reactions during the synthetic process. Hydroxy and amino groups protected with a protecting group are referred to herein as "protected hydroxy" and "protected amino", respectively. Protecting groups are typically used selectively and/or orthogonally to protect sites during reaction of other reactive sites and can then be removed while leaving the unprotected group intact or taking part in further reactions. Protecting Groups as known in the art are generally described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of "hydroxy protecting groups" include, but are not limited to, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2, 4-dinitrophenyl, benzyl, 2, 6-dichlorobenzyl, diphenyl-methyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyl-diphenylsilyl (TBDPS), triphenylsilyl, benzoylformate, acetate, chloroacetate, trichloroacetate, trifluoroacetate, pivalate, benzoate, p-benzoate, 9-fluorenylmethylcarbonate, pivaloate, p-chlorobenzoate, benzylate, Mesylate and tosylate. Examples of "amino protecting groups" include, but are not limited to, carbamate protecting groups such as 2-trimethyl-silylethoxycarbonyl (Teoc), 1-methyl-1- (4-biphenyl) -ethoxy-carbonyl (Bpoc), tert-Butoxycarbonyl (BOC), allyloxycarbonyl (Al loc), 9-fluorenylmethyloxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); amide protecting groups such as formyl, acetyl, trichloroacetyl, benzoyl and nitrophenylacetyl; sulfonamide-protecting groups, such as 2-nitrobenzenesulfonyl; and imine and cyclic imine protecting groups, such as phthalimido and dithiasuccinyl.

"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

The compounds of the present disclosure may contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined as (R) -or (S) -or (D) -or (L) -for amino acids according to absolute stereochemistry. The present disclosure includes all possible isomers as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R) -and (S) -or (D) -and (L) -isomers can be prepared using chiral synthons or chiral reagents, or can be prepared using conventional methods such as chromatography and fractional crystallization. Conventional methods for the preparation/separation of the individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC). When a compound described herein contains an olefinic double bond or other center of geometric asymmetry, unless otherwise indicated, it is meant that the compound includes both E and Z geometric isomers. Moreover, all tautomeric forms are also intended to be included.

"stereoisomers" refers to compounds of the same atomic composition bonded by the same bond but having different three-dimensional structures, which are not interchangeable. Various stereoisomers and mixtures thereof are contemplated in the present disclosure and include "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other.

"tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. Tautomers of any of the compounds are included in the present disclosure.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Experimental procedures, in which specific conditions are not noted in the examples of the present disclosure, are generally performed under conventional conditions, or under conditions recommended by manufacturers of raw materials or commercial products. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10^-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated Methanol (Methanol-d)₄) Internal standard is Tetramethylsilane (TMS).

HPLC measurements were performed using a Waters 2795 AllianceHT LC high pressure liquid chromatograph, a Waters 2996 Photodiode Array Detector UV Detector, a Thermo Accucor Polar Premium C1850 @ 4.6mm 2.6um chromatography column.

MS is measured by a Waters Micromass Quattro micro API triple quadrupole mass spectrometer, scanning is carried out in a positive/negative ion mode, and the mass scanning range is 120-1300.

The silica gel plate for thin layer chromatography is HSGF254 silica gel plate of cigarette platform yellow sea, and the silica gel plate for Thin Layer Chromatography (TLC) is 0.2mm + -0.03 mm, and the specification of the product for thin layer chromatography separation and purification is 0.4mm-0.5 mm.

The flash column purification system used either Combiflash Rf150(TELEDYNE ISCO) or Isolara one (Biotage).

The forward column chromatography generally uses 200-300 mesh or 300-400 mesh silica gel of the Titan yellow sea as a carrier, or uses a hyperpure normal phase silica gel column (40-63 μm, 60g, 24g, 40g, 120g or other specifications) pre-filled by Santai in Changzhou.

Known starting materials in this disclosure can be synthesized by or according to methods known in the art, or can be purchased from companies such as Shanghai Tantan science, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoshi Chemical technology (Accela ChemBio Inc), Biddy medicine, and the like.

In the examples, the reactions were all carried out under a nitrogen atmosphere without specific indication.

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

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The hydrogen was produced by QPH-1L model hydrogen generator, Shanghai Quanpu scientific instruments.

The nitrogen atmosphere or the hydrogen atmosphere is usually evacuated, and nitrogen or hydrogen is charged, and the operation is repeated 3 times.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: n-heptane/ethyl acetate system, C: in the petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

The following acronyms are used throughout the invention:

the following acronyms are used throughout the invention:

DMSO dimethyl sulfoxide

DMF dimethyl formamide

DIPEA N, N-diisopropylethylamine

HOBT 1-hydroxybenzotriazole

EDCI 1-ethyl-3 (3-dimethylpropylamine) carbodiimide

THF tetrahydrofuran

TMSCN Trimethylcyanosilane

PPh₃Triphenylphosphine

Ni(COD)₂Bis- (1, 5-cyclooctadiene) nickel

Examples

Preparation of key intermediates

Preparation of intermediate 3- (benzyloxy) -4- (difluoromethoxy) benzaldehyde (1)

4- (difluoromethoxy) -3-Hydroxybenzaldehyde (37.60g, 200.0mmol) was dissolved in tetrahydrofuran (200ml), potassium carbonate (55.28g, 400.0mmol) and benzyl bromide (44.19g, 260.0mmol) were added sequentially at room temperature, stirred at 70 ℃ until the reaction was complete, cooled, filtered, the filtrate was concentrated under reduced pressure, and intermediate 1(52.89g, yield 95.1%) was obtained by silica gel column chromatography (n-heptane/ethyl acetate system ═ 5:1) as a colorless oil, ms (esi) M/z 279.1[ M + H M/z 279.1 ]]⁺。

Preparation of intermediate (3- (benzyloxy) -4- (difluoromethoxy) phenyl) methanol (2)

Intermediate 3- (benzyloxy) -4- (difluoromethoxy) benzaldehyde (1, 52.89g, 190.2mmol) was dissolved in methanol (250ml), sodium borohydride (7.20g, 190.2mmol) was added portionwise at 0 ℃, stirring was performed at 0 ℃ until the reaction was complete, a saturated ammonium chloride solution was added to quench the reaction, extraction was performed with ethyl acetate, the reaction was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated under reduced pressure, and chromatography was performed on a silica gel column (n-heptane/ethyl acetate system ═ 2:1) to obtain intermediate 2(49.23g, yield 92.4%), a colorless oil, ms esi (esi) M/z 281.1[ M + H ] 281.1]⁺。

Preparation of intermediate 2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) acetonitrile (3)

Intermediate (3- (benzyloxy) -4- (difluoromethoxy) phenyl) methanol (2, 28.00g, 100.0mmol) was dissolved in dichloromethane (150ml), thionyl chloride (16.65g, 140.0mmol) was slowly added dropwise at room temperature, stirred at room temperature until the reaction was complete, and concentrated under reduced pressure to give intermediate 3. Dissolving intermediate 3 in anhydrous toluene (150ml), adding TMSCN (39.68, 400.0mmol) and PPh respectively at room temperature under the protection of nitrogen₃(5.24g, 20.0mmol) and Ni (COD)₂(5.50g, 20.0mmol), reaction stirred at 60 ℃, cooled, concentrated under reduced pressure and chromatographed on silica gel (n-heptane/ethyl acetate system 2:1) to give intermediate 3(26.25g, yield 90.8%) as a white solid powder, ms (esi) M/z 290.2[ M + H esi ]]⁺。

Preparation of intermediate 4- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester (4)

Intermediate 2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) acetonitrile (3, 26.25g, 90.8mmol) was dissolved in N, N-dimethylformamide (250ml) and 60% was added portionwise at 0 deg.CSodium hydrogen (5.45g, 227.0mmol) was added and stirred for 0.5H, followed by addition of tert-butyl N, N-bis (2-chloroethyl) carbamate (32.98g, 136.2mmol), gentle warming to room temperature with continued stirring to completion, quenching with saturated ammonium chloride solution, extraction with ethyl acetate, combining the organic phases, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and chromatography on silica gel column (N-heptane/ethyl acetate system ═ 2:1) to give intermediate 4(31.54g, yield 75.8%), white solid powder, ms (esi) M/z 459.2[ M + H459.2 ] ("M + H459.2")]⁺。

Preparation of intermediate 4- (3- (benzyloxy) -4-methoxyphenyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester (5)

Referring to the synthesis of intermediate 4, starting from 2- (3- (benzyloxy) -4-methoxyphenyl) acetonitrile, intermediate 5 was obtained (yield 76.3%), as a white solid powder, ms (esi) M/z 423.5[ M + H []⁺。

Preparation of intermediate ethyl 2- (4- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -4-cyanopiperidin-1-yl) acetate (6)

Intermediate 4- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester (4, 31.54g, 68.8mmol) was dissolved in dichloromethane (300ml), trifluoroacetic acid (67ml) was slowly added dropwise at room temperature, and the reaction was stirred at room temperature for 0.5 hour, and the reaction was concentrated under reduced pressure to give a solid. The solid was dissolved in acetonitrile (300ml), ethyl bromoacetate (22.84g, 137.6mmol) and potassium carbonate (38.04g, 275.2mmol) were added at room temperature, the reaction was stirred until completion, filtered, the filtrate was concentrated under reduced pressure, and intermediate 5(26.92g, yield 88.1%) was obtained by silica gel column chromatography (n-heptane/ethyl acetate system ═ 2:1) to obtain a white solid powder, ms (esi) M/z 445.2[ M + H445.2 ] (M + esi)]⁺。

Preparation of intermediate ethyl 2- (4- (3- (benzyloxy) -4-methoxyphenyl-4-cyanopiperidin-1-yl) acetate (7)

With reference to the synthesis of intermediate 6, starting from intermediate 5, intermediate 7 (yield 85.7%) was obtained as a white solid powder, MS (ESI) M/z 409.2[ M + H ]]⁺。

Preparation of intermediate ethyl 2- (4-cyano-4- (4- (difluoromethoxy) -3-hydroxyphenyl) piperidin-1-yl) acetate (8)

Intermediate ethyl 2- (4- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -4-cyanopiperidin-1-yl) acetate (6, 26.92g, 60.6mmol) was dissolved in methanol (300ml), 10% palladium on carbon (2.69g) was added at room temperature, the reaction was stirred at 1atm until completion, the filtrate was filtered, the filtrate was concentrated under reduced pressure, and silica gel column chromatography (dichloromethane/methanol system ═ 20:1) was performed to give intermediate 6(18.45g, yield 85.7%), white solid powder, ms (esi) M/z 355.3[ M + h.]⁺。

Preparation of intermediate ethyl 2- (4-cyano-4- (3-hydroxy-4-methoxyphenyl) piperidin-1-yl) acetate (9)

With reference to the synthesis of intermediate 8, starting from intermediate 7, intermediate 9 (yield 88.2%) was obtained as a white solid powder, MS (ESI) M/z 319.4[ M + H ]]⁺。

Preparation of intermediate ethyl 2- (4-cyano-4- (3- ((3, 3-difluorocyclobutyl) methoxy) -4- (difluoromethoxy) phenyl) piperidin-1-yl) acetate (10)

Ethyl 2- (4-cyano-4- (4- (difluoromethoxy) -3-hydroxyphenyl) piperidin-1-yl) acetate intermediate (8, 1.78g, 5.0mmol) was dissolved in N, N-dimethylformamide (15ml), methyl 1- (3, 3-difluorocyclobutyl) -4-methylbenzenesulfonate (2.07g, 7.5mmol) and potassium carbonate (2.10g, 15.0mmol) were added at room temperature, respectively, and stirred at 100 ℃ until the reaction was completed, cooled, quenched by addition of a saturated sodium chloride solution, extracted with ethyl acetate, the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography (N-heptane/ethyl acetate system ═ 5:1) to give intermediate 10(2.05g, yield 88.5%), a colorless oil, MS (ESI) M/z 459.2[ M + H ]]⁺。

Intermediate (11): preparation of ethyl 2- (4-cyano-4- (4- (difluoromethoxy) -3- ((1-fluorocyclopropyl) methoxy) phenyl) piperidin-1-yl) acetate

Referring to the synthesis of intermediate 10, starting from intermediate 8 and methyl 4-methyl-1-fluorocyclophenylbenzenesulfonate, intermediate 11 was obtained (yield 72.1%), as a colorless oil, MS (ESI) M/z 427.2[ M + H)]⁺。

Preparation of intermediate ethyl 2- (4-cyano-4- (3- (2-cyclopropylethoxy) -4- (difluoromethoxy) phenyl) piperidin-1-yl) acetate (12)

Referring to the synthesis of intermediate 10, starting from intermediate 8 and 2-cyclopropylethyl 4-methylbenzenesulfonate, intermediate 12 was obtained (95.3% yield) as a colorless oil, MS (ESI) M/z 423.5[ M + H ]]⁺。

Preparation of intermediate ethyl 2- (4-cyano-4- (4- (difluoromethoxy) -3- (4-phenoxybutoxy) phenyl) piperidin-1-yl) acetate (13)

Referring to the synthesis of intermediate 10, starting from intermediate 8 and 4-bromobutoxybenzene, intermediate 13 was obtained (yield 91.9%) as a colorless oil, MS (ESI) M/z 503.6[ M + H ]]⁺。

Preparation of intermediate ethyl 2- (4-cyano-4- (3- (((1-fluorocyclopropyl) methoxy) -4-methoxyphenyl) piperidin-1-yl) acetate (14)

Referring to the synthesis of intermediate 10, starting from intermediate 9 and methyl 4-methyl-1-fluorocyclophenylbenzenesulfonate, intermediate 14 was obtained (yield 89.1%), as a colorless oil, MS (ESI) M/z 391.5[ M + H ]]⁺。

Preparation of intermediate ethyl 2- (4-cyano-4- (3- (((3, 3-difluorocyclobutyl) methoxy) -4-methoxyphenyl) piperidin-1-yl) acetate (15)

Referring to the synthesis of intermediate 10, starting from intermediate 9 and methyl 1- (3, 3-difluorocyclobutyl) -4-methylbenzenesulfonate, intermediate 15 was obtained (yield 90.4%) as a colorless oil, MS (ESI) M/z 423.4[ M + H423.4 ]]⁺。

Preparation of intermediate 2- (4-cyano-4- (3- ((3, 3-difluorocyclobutyl) methoxy) -4- (difluoromethoxy) phenyl) piperidin-1-yl) acetic acid (16)

Intermediate ethyl 2- (4-cyano-4- (3- ((3, 3-difluorocyclobutyl) methoxy) -4- (difluoromethoxy) phenyl) piperidin-1-yl) acetate (10, 2.05g, 4.5mmol) was dissolved in a methanol/tetrahydrofuran/water mixed solution (150ml, V_Methanol/V_{Tetrahydrofuran (THF)}/V_{Water (W)}3:1:1), lithium hydroxide (0.95g, 22.5mmol) was added at room temperature, stirred until the reaction was complete, concentrated under reduced pressure to no methanol and tetrahydrofuran, then water was added until the solid was dissolved, 1N HCL solution was added to pH 3, filtered, and the filter cake was dried to give intermediate 16(1.75g, yield 90.3%) as a white solid powder.

¹H NMR(400MHz,DMSO-d₆)δ7.32(d,J＝2.2Hz,1H),7.30-7.25(m,1H),7.19(dd,J＝8.4,2.2Hz,1H),7.09(s,0.43H),6.91(s,0.20H),4.19(d,J＝5.7Hz,2H),3.36(s,2H),3.11(d,J＝12.0Hz,2H),2.80-2.53(m,8H),2.29-2.05(m,3H)。MS(ESI)m/z 429.4[M-H]⁺。

Preparation of intermediate 2- (4-cyano-4- (4- (difluoromethoxy) -3- ((1-fluorocyclopropyl) methoxy) phenyl) piperidin-1-yl) acetic acid (17)

Referring to the synthesis method of intermediate 16, intermediate 17 (yield 87.5%) was obtained as a white solid powder starting from intermediate 11.

¹H NMR(400MHz,DMSO-d₆)δ7.35-7.27(m,2H),7.20(dd,J＝8.4,2.2Hz,1H),7.13(s,0.47H),6.94(s,0.22H),4.47(d,J＝22.6Hz,2H),3.21(s,2H),3.10-3.00(m,2H),2.67-2.54(m,2H),2.16-2.10(m,4H),1.25-1.07(m,2H),1.01-0.81(m,2H)。MS(ESI)m/z 397.3[M-H]⁺。

Preparation of intermediate 2- (4-cyano-4- (3- (2-cyclopropylethoxy) -4- (difluoromethoxy) phenyl) piperidin-1-yl) acetic acid (18)

Referring to the synthesis of intermediate 16, intermediate 12 was used as the starting material to obtain intermediate 18 (yield 90.7%), white solid powder,¹H NMR(400MHz,DMSO-d₆)δ7.33-7.22(m,2H),7.15(dd,J＝8.4,2.2Hz,1H),7.09(s,0.45H),6.91(s,0.21H),4.18(t,J＝6.5Hz,2H),3.28(s,2H),3.28-3.02(m,2H),2.67-2.60(m,2H),2.21-2.04(m,4H),1.68(q,J＝6.6Hz,2H),0.94-0.80(m,1H),0.52-0.41(m,2H),0.21-0.12(m,2H)。MS(ESI)m/z 393.4[M-H]⁺。

preparation of intermediate 2- (4-cyano-4- (4- (difluoromethoxy) -3- (4-phenoxybutoxy) phenyl) piperidin-1-yl) acetic acid (19)

Referring to the synthesis of intermediate 16, intermediate 13 was used as a starting material to obtain intermediate 19 (yield 95.1%), which was a white solid powder,¹H NMR(400MHz,DMSO-d₆)δ7.37-7.22(m,4H),7.16(dd,J＝8.4,2.1Hz,1H),7.11(s,0.45H),6.99-6.89(m,3H),4.19(d,J＝5.8Hz,2H),4.10-4.03(m,2H),3.28(s,2H),3.16-2.96(m,2H),2.66-2.62(m,2H),2.20-2.01(m,4H),1.94-1.88(m,4H)。MS(ESI)m/z 473.2[M-H]⁺。

preparation of intermediate 2- (4-cyano-4- (3- (((1-fluorocyclopropyl) methoxy) -4-methoxyphenyl) piperidin-1-yl) acetic acid (20)

Referring to the synthesis of intermediate 16, intermediate 14 was used as the starting material to obtain intermediate 20 (yield 83.4%) as a white solid powder.

¹H NMR(400MHz,DMSO-d₆)δ7.11(dd,J＝6.3,2.3Hz,2H),7.07-7.03(m,1H),4.34(d,J＝22.7Hz,2H),3.82(s,3H),3.27(s,2H),3.10-3.00(m,3H),2.66-2.58(m,2H),2.17-1.97(m,4H),1.21-1.06(m,2H),0.95-0.84(m,2H)。MS(ESI)m/z 361.4[M-H]⁺。

Preparation of intermediate 2- (4-cyano-4- (3- (((3, 3-difluorocyclobutyl) methoxy) -4-methoxyphenyl) piperidin-1-yl) acetic acid (21)

Referring to the synthesis method of intermediate 16, intermediate 21 (yield 86.1%) was obtained as a white solid powder starting from intermediate 15.

¹H NMR(400MHz,Methanol-d₄)δ7.20-7.07(m,3H),4.17(d,J＝6.9Hz,2H),4.05(s,2H),3.86(s,3H),3.55-3.45(m,1H),2.85-2.80(m,2H),2.80-2.68(m,2H),2.65-2.55(m,4H),2.55-2.35(m,4H)。MS(ESI)m/z 393.3[M-H]⁺。

Preparation of intermediate 2- (4-cyano-4- (3- ((3, 3-difluorocyclobutyl) methoxy) -4- (difluoromethoxy) phenyl) piperidin-1-yl) -N- (2-methoxypropan-2-yl) oxyacetamide (22)

Intermediate 2- (4-cyano-4- (3- ((3, 3-difluorocyclobutyl) methoxy) -4- (difluoromethoxy) phenyl) piperidin-1-yl) acetic acid (16, 1.75g, 4.1mmol) was dissolved in N, N-dimethylformamide (60ml), O- (2-methoxypropan-2-yl) hydroxylamine (0.78g, 6.2mmol), HOBt (1.11g, 8.2mmol), EDCI (1.57g, 8.2mmol) and DIPEA (2.65g, 20.5mmol) were added at room temperature, respectively, after completion of the reaction, a saturated sodium chloride solution was added to quench the reaction, ethyl acetate was extracted 3 times, the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and then subjected to silica gel column chromatography (ethyl acetate system) to obtain intermediate 22(1.26g, yield 59.8%) colorless oil, MS (ESI) M/z 518.5[ M + H%]⁺。

Preparation of intermediate 2- (4-cyano-4- (4- (difluoromethoxy) -3- ((1-fluorocyclopropyl) methoxy) phenyl) piperidin-1-yl) -N- (((2-methoxypropan-2-yl) oxy) acetamide (23)

Referring to the synthesis of intermediate 22, starting from intermediate 17, intermediate 23 was obtained (yield 62.1%) as a colorless oil, MS (ESI) M/z 486.5[ M + H ]]⁺。

Preparation of intermediate 2- (4-cyano-4- (3- (2-cyclopropylethoxy) -4- (difluoromethoxy) phenyl) piperidin-1-yl) -N- ((2-methoxypropan-2-yl) oxy) acetamide (24)

Referring to the synthesis of intermediate 22, starting from intermediate 18, intermediate 24 was obtained (yield 65.6%), as a colorless oil, MS (ESI) M/z 482.5[ M + H ]]⁺。

Preparation of intermediate 2- (4-cyano-4- (4- (difluoromethoxy) -3- (4-phenoxybutoxy) phenyl) piperidin-1-yl) -N- ((2-methoxypropan-2-yl) oxy) acetamide (25)

Referring to the synthesis of intermediate 22, starting from intermediate 19, intermediate 25 was obtained (yield 84.3%) as a colorless oil, MS (ESI) M/z 562.6[ M + H ]]⁺。

Preparation of intermediate 2- (4-cyano-4- (3- (((1-fluorocyclopropyl) methoxy) -4-methoxyphenyl) piperidin-1-yl) -N- ((2-methoxypropan-2-yl) oxy) acetamide (26)

Referring to the synthesis of intermediate 22, starting from intermediate 20, intermediate 26 was obtained (yield 73.8%), as a colorless oil, MS (ESI) M/z 450.2[ M + H ]]⁺。

Preparation of intermediate 2- (4-cyano-4- (3- ((3, 3-difluorocyclobutyl) methoxy) -4-methoxyphenyl) piperidin-1-yl) -N- ((2-methoxypropan-2-yl) oxy) acetamide (27)

Referring to the synthesis of intermediate 22, starting from intermediate 21, intermediate 27 was obtained (yield 70.8%), as a colorless oil, MS (ESI) M/z 482.5[ M + H ]]⁺。

Example 1:2- (4-cyano-4- (3- ((3, 3-difluorocyclobutyl) methoxy) -4- (difluoromethoxy) phenyl) piperidin-1-yl) -N-hydroxyacetamide hydrochloride

Intermediate 2- (4-cyano-4- (3- ((3, 3-difluorocyclobutyl) methoxy) -4- (difluoromethoxy) phenyl) piperidin-1-yl) -N- (2-methoxypropan-2-yl) oxyacetamide (22, 1.26g, 2.4mmol) was dissolved in ethanol (20ml), and 2N HCl solution (20ml) was added dropwise at room temperature, followed by stirring until the reaction was completed, filtration and drying of the filter cake to obtain the objective compound 1(0.74g, yield 69.4%).

¹H NMR(400MHz,DMSO-d₆)δ7.43-7.26(m,2H),7.24-7.10(m,1.35H),6.95(s,0.17H),4.40(s,0.43H),4.19(d,J＝5.7Hz,2H),4.02(s,1H),3.87-3.57(m,2H),2.85-2.53(m,10H)。

MS(ESI)m/z 446.2[M+H]⁺。

Example 2: 2- (4-cyano-4- (4- (difluoromethoxy) -3- ((1-fluorocyclopropyl) methoxy) phenyl) piperidin-1-yl) -N-hydroxyacetamide hydrochloride

The synthesis method of example 1 was followed, and intermediate 23 was used as a starting material to obtain the objective compound 2 (yield 85.8%).

¹H NMR(400MHz,DMSO-d₆)δ7.40-7.30(m,2H),7.25-7.15(m,1.46H),6.98(s,0.23H),4.53-4.38(m,2H),4.11-3.61(m,5H),3.46-3.29(m,2H),1.21-1.13(m,2H),0.94-0.89(m,2H)。

MS(ESI)m/z 414.3[M+H]⁺。

Example 3:2- (4-cyano-4- (3- (((1-fluorocyclopropyl) methoxy) -4-methoxyphenyl) piperidin-1-yl) -N-hydroxyacetamide

The synthesis method of example 1 was followed, and intermediate 26 was used as a starting material to obtain target compound 5 (yield 69.8%).

¹H NMR(400MHz,Methanol-d₄)δ7.37(d,J＝2.3Hz,1H),7.32(d,J＝8.4Hz,1H),7.25(dd,J＝8.5,2.3Hz,1H),6.86(t,J＝75.0Hz,1H),4.53-4.41(m,3H),4.09(s,1H),4.00-3.80(m,2H),3.70-3.48(m,2H),2.68-2.48(m,4H),1.26-1.14(m,2H),0.96-0.91(m,2H)。

MS(ESI)m/z 378.4[M+H]⁺。

Example 4: 2- (4-cyano-4- (3- ((3, 3-difluorocyclobutyl) methoxy) -4-methoxyphenyl) piperidin-1-yl) -N-hydroxyacetamide

The synthesis method of example 1 was followed, and intermediate 27 was used as a starting material to obtain target compound 6 (yield 70.1%).

¹H NMR(400MHz,Methanol-d₄)δ7.32(d,J＝8.2Hz,2H),7.23(dd,J＝8.5,2.3Hz,1H),6.81(t,J＝74.5Hz,1H),4.45(s,0.59H),4.21(d,J＝5.3Hz,2H),4.08(s,1H),4.00-3.80(m,2H),3.70-3.50(m,2H),2.83-2.65(m,3H),2.65-2.50(m,6H)。

MS(ESI)m/z 410.1[M+H]⁺。

Biological evaluation

The present disclosure is further described and explained below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1In vitro PDE4B enzyme activity assay: IMAP FP-based analytical method detection

1. Experimental Material

Material	Brand	Goods number/model
			PDE4B1	BPS	60041
Trequinsin	Sigma	T2057
			384-well plate	Perkin Elmer	6007279
IMAP FP IPP Explorer Kit	MOLECULAR DEVICES	R8124

2. Experimental procedure

Compounds were diluted in DMSO in 5-fold gradients to give different concentrations (10000nM, 2000nM, 400nM, 80nM, 16nM, 3.2nM, 0.64nM, 0.128nM, 0.0256nM, 0.005 nM). 200 μ L of different concentrations of compound were added to 384 well plates (n 2) and 2 portions of 200 μ L DMSO were added simultaneously to 384 well plates (n 2) as blanks; 10 μ L of 0.025 μ g/mL PDE4B1 enzyme solution (formulated with 1mM 5 IMAP Reaction buffer and 1mM DTT) was then added to the 384 well plates, and 10 μ L of a blank buffer without PDE4B1 enzyme was added to one of the blanks, incubated with shaking at room temperature for 15 minutes, followed by 10 μ L of 0.1 μ M FAM cAMP solution (formulated with 1mM 5 IMAP Reaction buffer and 1mM DTT), 60 μ L of detection solution (formulated with 0.5625mM 5 IMAP Progressive Binding buffer A, 0.1875mM 5 IMAP Progressive Binding buffer B and 0.75mM beads) was added after 30 minutes of shaking at room temperature, and data was collected after 60 minutes of shaking at room temperature. The formula for calculating the inhibition rate is as follows: inhibition ratio M/(M-M)_control) 100, x; calculating IC according to the fitted curve of concentration and inhibition rate₅₀The value is obtained. Rofluwster and AN-2728 were used as positive controls in this experiment.

In vitro inhibition of PDE4B1 enzymatic Activity by the examples of the present disclosure IC was determined by the above assay₅₀The values are shown in Table 1.

TABLE 1

Test example 2Cell in vitro activity experiment, using LPS to induce PBMC cells, detecting TNF-alpha release

1. Experimental Material

Material	Brand	Goods number/model
			LPS	Sigma	L4391
Human TNF-αElisa kit	Neobioscience	EHC103a.96
			CellTiter-Glo Cell viability assay	Promega	G7572
Multifunctional enzyme mark instrument	PerkinElmer	EnVision 2105
			Automatic cell counter	Shanghai Rui Yu	Countstar Medical
Desk type refrigerated centrifuge	THERMO	ST40R
			Carbon dioxide incubator	THERMO	3111
Biological safety cabinet	ESCO	AC2-6S1
			Microscope	Olympus	CKX53

2. Experimental procedure

mu.L of different concentrations of compound (10mM, 1mM, 0.1mM, 0.01mM, 0.001mM, 0.0001mM, 0.00001mM) in DMSO was diluted 10-fold with PBMC complete Medium (RPMI 1640Medium + 10% inactivated FBS + 1. Penicillin Streptomyces) and DMSO was used as a blank. Fresh PBMC 400g were centrifuged for 7 minutes, the supernatant was discarded, resuspended to a cell density of 1.25E6/mL using 14mL PBMC complete medium, 160 μ L was added to a 96-well plate (n ═ 2), followed by 20 μ L of compound dilutions at different concentrations, vortexed, incubated at 37 ℃ for 1 hour, followed by 20 μ L LPS (40ng/mL), homogenized, and incubated at 37 ℃ for 18 hours. After the cell culture is finished, 400g is centrifuged for 5 minutes, 100 mu L of supernatant is added into a 96-well plate and stored at minus 80 ℃ to be tested for the content of TNF-alpha. The remaining cells were added with 100. mu.L CellTiter-Glo reagent, centrifuged at 400g for 10 minutes at room temperature, and the viability of the cells was calculated using the Envision reading.

Adding 20 mu L of recovered cell supernatant into a 96-well plate (n is 2), adding 140 mu L of standard substance diluent which is used as a blank control, using the standard substance as a standard control, sealing the plate, incubating for 90 minutes at 37 ℃, washing the plate for 5 times, adding 100 mu L of biotinylated antibody working solution (adding biotinylated antibody diluent into blank holes), sealing the plate, incubating for 60 minutes at 37 ℃, washing the plate for 5 times, adding 100 mu L of enzyme conjugate working solution (adding enzyme conjugate diluent into blank holes), sealing the plate, incubating for 30 minutes at 37 ℃, washing the plate for 5 times, adding 100 mu L of chromogenic substrate TMB, incubating for 15 minutes at 37 ℃ in a dark place, adding 100 mu L of reaction termination solution, shaking and mixing uniformly, reading OD (OD) by using an enzyme reader₄₅₀The value is obtained. Rofluwster and AN-2728 were used as positive controls in this experiment.

Effect of the presently disclosed examples on TNF- α Release from LPS-induced PBMC cells the IC determined by the above assay₅₀The values are shown in Table 2.

TABLE 2

Numbering	IC50(nM)
		AN-2728	470.6
Roflumilast	1.004
		Example 1	0.636
Example 2	0.384
		Example 3	2.189
Example 4	2.641

Test example 3Cell in vitro activity experiment, in which the amount of cAMP is detected by using the PBMC cells after Prostagladin E2 induction inhibition

1. Experimental Material

2. Experimental procedure

mu.L of different concentrations of compound (10mM, 1mM, 0.1mM, 0.01mM, 0.001mM, 0.0001mM, 0.00001mM) in DMSO was diluted 10-fold with PBMC complete Medium (RPMI 1640Medium + 10% inactivated FBS + 1. Penicillin Streptomyces) and DMSO was used as a blank. Fresh PBMC 400g were centrifuged for 7 min, supernatant discarded, resuspended in 14mL PBMC complete medium to a cell density of 1.25E6/mL, 160. mu.L was added to a 96 well plate (n ═ 2), followed by 20. mu.L of compound dilutions at different concentrations, vortexed, incubated at 37 ℃ for 1 hr, followed by 20. mu.L of PEG2 (100. mu.M), homogenized, incubated at 37 ℃ for 1 hr, after cell culture was complete, 400g was centrifuged for 5 min, 10. mu.L of supernatant was added to a 384 well plate (n ═ 2), followed by 5. mu.L of Anti-cAMP-Cryptate working solution (1.1mL of ddH)₂Prepared by dissolving Anti-cAMP-Cryptate in O), and 5. mu.L of cAMP-d2 working solution (1.1mL of ddH) was added again₂O-soluble cAMP-d₂Formulation) and plates were sealed and incubated at room temperature for 1 hour and the values at 665nm and 620nm wavelength were read. Rofluwster and AN-2728 were used as positive controls in this experiment.

Measured IC₅₀The values are shown in Table 3.

TABLE 3

Numbering	IC50(μM)
		AN-2728	31.66
Roflumilast	0.0977
		Example 1	0.36
Example 2	1.95
		Example 3	0.11
Example 4	0.13

And (4) conclusion: the examples of the disclosure all exhibit comparable or good biological activity in cell experiments as the positive compound roflumilast.

Claims (10)

1. A compound of the formula (I),

or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer or tautomer, or deutero-derivative thereof,

wherein R is¹Selected from hydrogen or nitrile groups;

R²is selected from C_3-7Cycloalkyl radical, said C_3-7Cycloalkyl substituted with halogen or haloalkyl;

R³selected from alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with one or more groups selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxy or halogen;

R⁴and R⁵Each independently selected from hydrogen, halogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with one or more groups selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxy, halogen, or R is⁴、R⁵Together with their adjacent carbon atoms form a 5-to 12-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, preferably a 6-to 8-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, which carbocyclic, heterocyclic, aromatic or heteroaromatic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, amino, oxo, carboxy, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁶selected from hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl or-NHOH groups, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl groups being optionally substituted with one or more groups selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl or halogen;

x is methylene optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, alkoxy or cycloalkyl;

n and m are integers of 1-4.

2. The compound of claim 1, wherein R⁶Selected from hydroxy, C_1-8Alkyl radical, C_1-8Alkoxy or-NHOH group, said C_1-8Alkyl or C_1-8The alkoxy group is optionally substituted with one or more substituents selected from aryl and heteroaryl.

3. A compound according to claim 1 or 2, which is of formula (I)

4. The compound of claim 3, wherein R²Selected from:

which may optionally and independently be selected from C on a ring carbon atom_1-6Alkyl (including methyl, ethyl, isopropyl, etc.), C_1-6Alkyloxy (including methoxy, ethoxy, isopropoxy, etc.), C_3-7Cycloalkyl (including cyclopropyl, cyclopentyl, cyclohexyl, etc.) optionally and independently substituted on the ring nitrogen by a substituent selected from C_1-6Alkyl, -COR', -S (O)₂R'、-CON(R')₂、C_3-7A cycloalkyl group is substituted by a cycloalkyl group,

r' is selected from hydrogen, hydroxyl, alkyl, alkoxy, acyl, aryl or heteroaryl, and the alkyl, alkoxy, aryl or heteroaryl is optionally substituted by one or more groups selected from halogen, alkyl, cycloalkyl, alkoxy, oxy, hydroxyl, nitro and nitrile.

5. The compound of any one of claims 1-4, wherein R³Is selected from C_1-8Alkyl or C_3-7Cycloalkyl radical, said C_1-8Alkyl or C_3-7Cycloalkyl optionally substituted by one or more groups selected from C_1-8Alkyl radical, C_3-7Cycloalkyl, halogen, C_1-8Alkoxy radical, C_3-7Heterocyclyl, aryl or heteroaryl, preferably difluoromethyl, trifluoromethyl, 1-difluoroethyl.

6. The compound of any one of claims 1-5, wherein R⁴And R⁵Each independently selected from hydrogen and C_1-8Alkyl, or R⁴、R⁵Together with their adjacent carbon atoms form a 6-to 8-membered carbocyclic or heterocyclic ring, which carbocyclic or heterocyclic ring is optionally substituted by one or more substituents selected from alkyl, halogen, hydroxy, nitro, cyano, alkoxy.

7. The compound of any one of claims 1-6, selected from:

or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer, or deuteron thereof.

8. The compound of claim 1, selected from:

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier, diluent or excipient.

10. Use of a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the treatment or prophylaxis of asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis or rheumatic diseases, further wherein said asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis or rheumatic diseases are preferably associated with phosphodiesterase 4.