CN113527179B

CN113527179B - Chain hydrocarbon substituted isoindoline-1, 3-diketone PDE4 inhibitor and pharmaceutical application thereof

Info

Publication number: CN113527179B
Application number: CN202110389365.8A
Authority: CN
Inventors: 朱加望; 姚瑶
Original assignee: Suzhou Puzheng Pharmaceutical Co ltd
Current assignee: Suzhou Puzheng Pharmaceutical Co ltd
Priority date: 2020-04-13
Filing date: 2021-04-12
Publication date: 2023-07-07
Anticipated expiration: 2041-04-12
Also published as: CN113527179A

Abstract

The invention relates to a compound shown in a formula I, racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, ester, prodrug or pharmaceutically acceptable salt thereof, a preparation method of the compound and a medical application of the compound, wherein the formula I has the following structure:

Description

Chain hydrocarbon substituted isoindoline-1, 3-diketone PDE4 inhibitor and pharmaceutical application thereof

the application requires priority of the prior application, which is filed by 4/13/2020 to the China national intellectual property agency, and has the patent application number of 202010287739.0 and the name of 'chain hydrocarbon substituted isoindoline-1, 3-dione PDE4 inhibitor and the pharmaceutical application thereof'. The entirety of this application is incorporated by reference into this application.

Technical Field

The invention belongs to the field of pharmaceutical compounds, and in particular relates to a PDE4 inhibitor of chain hydrocarbon substituted (S) -2- [1- (3-alkoxy-4-alkoxy phenyl) -2-alkylsulfonylethyl ] -4-isoindoline-1, 3-dione compound (I) containing amide substituent groups and pharmaceutical application thereof.

Background

Cyclic adenosine monophosphate (cAMP) plays a fairly significant role and role in biological processes as a second messenger. It was found that the absence or inactivation of cyclic adenylate in asthma, pulmonary obstructive disorders, inflammation and the like contributes to these diseases (Lowe and Cheng, drugs of the Future,17 (9): pages 799-807, 1992), whereas the increase in cyclic adenylate levels in inflammatory leukocytes inhibits the release of inflammatory mediators including TNF- α and NF- κB, while the increase in cyclic adenylate levels also leads to the relaxation of airway smooth muscle.

The main biological mechanism of cyclic adenylate inactivation is due to the destruction of cyclic nucleotide Phosphodiesterase (PDE) family by cyclic adenylate (Beavo and Reitsnyder, trends in Pharm., 11: pages 150-155, 1990). It is known that there are 11 PDE member family enzymes, and inhibition of PDE4 (PDE IV) type has a significant effect on the elevation of cyclic adenosine and the release of inflammatory mediators (Verghes et al, journal ofPharmacology and Experimental Therapeutics,272 (3: pages 1313-1320, 1995). Thus, organic compounds that selectively inhibit PDE4 have the potential to inhibit airway inflammation, promote airway smooth muscle relaxation, and treat skin inflammation.

Inhibition of PDE4 enzymes may block the activity or production of certain cytokines including alpha-tumor necrosis factor (TNF-alpha). alpha-tumor necrosis factor is a cytokine that is released primarily by mononuclear phagocytes in response to immunostimulants. TNF- α is capable of promoting most cellular processes such as differentiation, recruitment, proliferation, and protein degradation. At low levels, TNF- α has a protective effect against infectious agents, tumors and tissue damage, but TNF- α plays an inductive and exacerbating role in many diseases. Inflammation, fever, cardiovascular effects, bleeding and acute responses similar to those occurring during acute infection and shock phases are caused or exacerbated when TNF-alpha is administered to a mammal or human.

Arthritis, arthritic conditions (e.g., osteoarthritis and rheumatoid arthritis), enteritis (e.g., crohn's disease and ulcerative colitis), sepsis, psoriasis (Psoriasis), atopic dermatitis (Atopic Dermatitis, AD), contact dermatitis and Chronic Obstructive Pulmonary Disease (COPD), chronic pneumonia, acute respiratory distress syndrome (Acute Respiratory Distress Syndrome, ARDS), vitiligo (Vitiligo), prurigo (Prurigo Nodularis), vulvodynia (Vulvodynia), fibrotic diseases, cachexia, autoimmune diseases, rheumatoid spondylitis (Ankylosing Spondylitis), osteoporosis, crohn's disease, ulcerative colitis, enteritis, multiple sclerosis (Multiple Sclerosis, MS), discoid lupus erythematosus (Discoid Lupus Erythematosus), systemic lupus erythematosus, radiation injury, high oxygen alveolar injury (Tracey et al, 1987, nature, 330: pages 662-664 and Hinshaw et al, 1990, circ. Shock, 30: 279-292 (endotoxin shock); millar et al, 1989, lancet,2 pages 712-714 and Ferrai-Baliviera et al, 1989, arch. Surg.,124 pages 1400-1405 (adult respiratory distress syndrome), bertolini et al, 1986, nature,319 pages 516-518, pignet et al, 1990, nature,344 pages 245-247, bissonete et al, 1989, information, 13 pages 329-339 and Baughman et al, 1990, J.Lab. Clin. Med.,115 pages 36-42 (chronic pneumonia), elliot et al, 1995, int. J.Pharmac, 17 pages 141-145 (rheumatoid arthritis), von Dumen et al, 1995, gastroenterology, 109: 129-135 (Crohn's disease)) are common problematic diseases in which alpha-tumor necrosis factor plays a critical role. Whereas inhibition of alpha-tumor necrosis factor is seen to be effective in blocking both chronic and acute inflammatory responses in animal models of inflammatory disease.

A number of small molecule inhibitors have been found to be capable of treating inflammatory diseases involving alpha-tumor necrosis factor (see review by Lowe, 1998, exp. Opin. Ther. Patents, 8: pages 1309-1332). This class of molecules is the substituted phenethyl sulfones described in U.S. Pat. nos. 6020358, 6962940, and WO0134606A1, WO0025777, WO2012083153, WO2018157779A1, WO0134604, WO2012083153, WO 20. Apremilast is disclosed in patent US2003187052, and the same family of Chinese patents are CN1652772, CN1965823, CN101683334, CN03811093.8.

Since PDE4 enzymes are proteins found in multiple sites and tissues in humans including the central nervous system, it has also been found clinically that the prior art of PDE4 inhibitor drugs has serious side effects including vomiting, heart, vomiting, causing depression and gastrointestinal symptoms. The adoption of local administration is a practical and selective method for avoiding the side effects of the medicines, and safer and more effective disease treatment is realized. Further enhancement of the biological activity of the PDE4 inhibitor action of the substituted isoindoline-1, 3-diones and improvement of the physical properties, in particular the lipophilicity, of the pharmaceutically active compounds may expand the beneficial use of such inhibitors for topical administration.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides a compound shown in a formula I and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, prodrugs or pharmaceutically acceptable salts thereof:

wherein R is a 5,6, or 7 substituent, independently can be a C1-C16 hydrocarbyl (including alkyl, alkenyl, alkynyl), C3-C7 cycloalkyl, or H, halogen, cyano, wherein alkyl, alkenyl, alkynyl can optionally be a substituted or unsubstituted chain or cyclic group, wherein the substituents can independently be selected from halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 alkylthio, and the like; r at different positions independently can form a ring;

m is 1,2, or 3; n is 0 or 1;

R ¹ is C1-C3 alkyl or C1-C3 haloalkyl, or is C3-C6 cycloalkyl; r is R ² Is C1-C5 alkyl or C1-C5 haloalkyl, or is C3-C6 cycloalkyl; r1 and R2 independently may form a 5,6, 7 ring;

R ³ is C1-C5 alkyl or C1-C5 haloalkyl, or is C3-C6 cycloalkyl; r is R ⁴ Is C1-C12 alkyl or C3-C6 cycloalkyl, wherein alkyl and cycloalkyl are optionally substituted with halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, or C1-C3 alkylthio, etc.

According to an embodiment of the invention, the compound of formula I is further selected from the following formula II:

wherein R is a 5,6, or 7 substituent, independently can be a C3-C10 hydrocarbyl (including alkyl, alkenyl, alkynyl), C3-C7 cycloalkyl, or H, halogen, cyano, wherein alkyl, alkenyl, alkynyl can optionally be a substituted or unsubstituted chain or cyclic group, wherein the substituents can independently be selected from halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 alkylthio, and the like; r at different positions independently can form a ring; m is 1,2, or 3;

According to an embodiment of the invention, the compound of formula I is further selected from the following formula III:

Wherein R is a 5,6, or 7 substituent, independently can be a C5-C8 hydrocarbyl (including alkyl, alkenyl, alkynyl), C3-C7 cycloalkyl, or H, halogen, cyano, wherein alkyl, alkenyl, alkynyl can optionally be a substituted or unsubstituted chain or cyclic group, wherein the substituents can independently be selected from halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 alkylthio, and the like; m is 1,2, or 3;

R ⁴ is C1-C5 alkyl or C3-C6 cycloalkyl, wherein alkyl and cycloalkyl are optionally substituted with halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, or C1-C3 alkylthio, etc.

According to an embodiment of the present invention, illustrative, non-limiting specific examples of the compounds of formula I (including formula II-III) and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, prodrugs or pharmaceutically acceptable salts thereof are shown below:

the invention also provides a preparation method of the compound shown in the formula I (including formulas II-III) and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, prodrugs or pharmaceutically acceptable salts thereof, but not limited to the method described below. All starting materials are based on the radical characteristics of the target molecule according to the rules of the general formula and are prepared by schemes in these routes, by methods well known to those of ordinary skill in the art of organic chemistry or are purchased directly. The compounds of the present invention may be synthesized by combining the methods described below with synthetic methods known in the art of synthetic organic chemistry or modifications thereof as will be appreciated by those skilled in the art. One skilled in the art will recognize that depending on the particular target structure, one or more of the following schemes may optionally be employed in combination, or any combination of steps in one or more of the schemes may be employed to arrive at a synthetic scheme.

The preparation method of the compound shown in the formula I comprises the following steps: under proper conditions, the substituted benzoic acid raw material I-1 (R' is halogen, alkane, carboxyl, cyano, amino or nitro, and t is an integer between 1 and 5) is synthesized and converted into anhydride I-2, and further reacts with amine intermediate I-3 to generate substituted isoindoline-1, 3-dione I-4, and under proper conditions, the steps of protecting group loading, protecting group removing, substituting, condensing, reductive amination or hydrolysis are carried out to obtain the compound shown in the formula I. Specifically, the synthesis can be performed with reference to the following further schemes.

The preparation of the compounds of the invention may comprise one or more of the following general steps according to known synthetic methods, such as WO 2016169533. Further synthetic route to intermediate sulfonylethylamine I-3 (11):

the raw material substituted benzoate 1 is subjected to para-position phenol group protection to obtain 2, meta-position etherification to obtain 3, and para-position deprotection of the phenol group to obtain 4. Similar etherification is carried out to the para-position 5, the ester is reduced to the alcohol 6 and oxidized to the intermediate aldehyde 7. The further reaction can smoothly obtain methanesulfonyl styrene 8, the further alkylation can obtain alkylsulfonyl styrene 9, the amination reaction can be carried out on the product 10, and the (S) -1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonyl ethylamine 11 can be obtained by a method of chiral resolution or separation of benzophenone.

In addition, raw benzonitrile 12 can be converted into a benzophenone 14 intermediate through an intermediate 13, reduced into alcohol 15 and dehydrated to obtain methanesulfonyl styrene 8, so that chiral 1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethylamine 11 can be obtained through further chemical conversion.

Para-position alkylation of dihydroxyl substituted benzophenone 24 provides 17, further alkylation provides dialkoxy benzophenone 18, bromination provides bromobenzophenone 19, thioetherification provides intermediate 20, and two paths of intermediate 11 are provided through 21, 22 and 23.

Wherein the R is ¹ ，R ² ，R ³ X is selected from halogen as defined in formula I above.

The corresponding chiral compounds can be isolated from their racemic compounds by the prior art. Examples include, but are not limited to, formation of chiral salts, use of chiral and high performance liquid chromatography "HPLC", and formation and crystallization of chiral salts. See, e.g., jacques, j. Et al, enantomers, racemates and Resolutions (Wiley-Interscience, new York, 1981); wilen, s.h. et al, tetrahedron, 33: 2725 (1977); eliel, e.l., stereochemistry of Carbon Compounds (McGraw-Hill, new york, 1962) and Wilen, s.h., tables of Resolving Agents and Optical Resolutions, page 268 (e.l. Eliel, university press, note Dame, IN 1972).

Specific examples of chiral amino acid salts of (S) -2- (3-alkoxy-4-alkoxyphenyl) -1- (alkylsulfonyl) -ethan-2-ylamine 11 include, but are not limited to, salts with the L isomer of an amino acid or the L isomer of an acylated amino acid.

According to an embodiment of the present invention, the compounds of the present invention may be synthesized by the following synthetic route (see WO2018157779 A1):

synthetic route 1:

the halo o-methylbenzoic acid 24 is subjected to nitration reaction to obtain 25, oxidation reaction to obtain substituted phthalic acid 26, acid anhydride reaction to obtain halo 4-nitrobenzoic anhydride 27, further reaction with 1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethylamine 11 in acetic acid to obtain halo (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-nitroisoindoline-1, 3-dione 28, further reduction of nitro to obtain intermediate 29, acylation to 30, and formation of long chain hydrocarbon substituted (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-acylaminoisoindoline-1, 3-dione II by Suzuki reaction or Sonogashira reaction.

Wherein R, R ¹ ，R ² ，R ³ ，R ⁴ M is as defined for formula I above and X is selected from halogen (Cl, br, I).

Synthetic route 2:

halo-3-nitrobenzoanhydride 27 and nitro reduction intermediate 31, 4-acylated benzoic anhydride 32 are further reacted with 1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethylamine 11 in acetic acid to give halo (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-amidoisoindoline-1, 3-dione 30, which is further reacted by Suzuki or Sonogashira reactions to give long chain hydrocarbon substituted (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-amidoisoindoline-1, 3-dione II.

Synthetic route 3:

the hydrocarbon 4 nitrobenzoanhydride 33 is further reacted with 1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethylamine 11 in acetic acid to give the hydrocarbon (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-nitroisoindoline-1, 3-dione 34, reduction of the nitro group gives the intermediate (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-aminoisoindoline-1, 3-dione 35, and acylation gives (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-acylaminoisoindoline-1, 3-dione II.

Wherein R, R ¹ ，R ² ，R ³ ，R ⁴ M is as defined for formula I above.

Synthetic route 4:

acylation of the hydro-4-aminobenzoic anhydride 36 gives intermediate 37 which is further reacted with 1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethylamine 11 in acetic acid to give the hydro-chain substituted (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-amidoisoindoline-1, 3-dione II.

Wherein R, R ¹ ，R ² ，R ³ ，R ⁴ M is as defined for formula II above.

Synthetic route 5:

the 4-nitrobenzoanhydride 27 is aminated to give 38, and is subjected to Mitsunobu reaction with alcohol 39 to give intermediate 28, which is then subjected to Suzuki reaction or Sonogashira reaction to give intermediate 34, which is further reduced to give amino 35, and the acylation reaction to give the chain-hydrocarbon-substituted (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-amidoisoindoline-1, 3-dione II.

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Wherein R, R ¹ ，R ² ，R ³ ，R ⁴ M is as defined for formula II above.

Synthetic route 6:

bromination of the hydrocarbon (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-aminoisoindoline-1, 3-dione 35 gives 39, cyanation gives cyano compound 40, reduction gives 4-aminomethyl substituent intermediate 41, and acylation gives the hydrocarbon-substituted (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4- (aminomethyl) isoindoline-1, 3-dione.

Wherein R, R ¹ ，R ² ，R ³ ，R ⁴ M is as defined for formula I above.

The present invention further provides a pharmaceutical composition comprising a compound of formula I as described herein, and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, prodrugs or pharmaceutically acceptable salts thereof.

In some embodiments, the pharmaceutical compositions of the present invention further comprise a therapeutically effective amount of a compound of formula I of the present invention, and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

The carrier in the pharmaceutical composition is "acceptable" in that it is compatible with the active ingredient of the composition (and preferably, is capable of stabilizing the active ingredient) and is not deleterious to the subject being treated. One or more solubilizing agents can be employed as pharmaceutical excipients for delivery of the active compound.

The invention further provides the use of a compound of formula I, as well as racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, prodrugs or pharmaceutically acceptable salts thereof, or said pharmaceutical composition for the manufacture of a medicament for inhibiting PDE4 enzyme.

The invention further provides the use of the compound of formula I, and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, prodrugs or pharmaceutically acceptable salts thereof, or said pharmaceutical composition for the manufacture of a medicament for use in the treatment of a disease involving modulation of intracellular cAMP levels.

The invention further provides the use of the compound of formula I, and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, prodrugs or pharmaceutically acceptable salts thereof, or the pharmaceutical composition thereof, in the manufacture of a medicament for inhibiting TNF- α or inhibiting NF- κb production.

According to embodiments of the present invention, the conditions ameliorated by PDE4 inhibition by a PDE 4-inhibiting agent include, but are not limited to, asthma, inflammation (e.g., inflammation due to reperfusion), chronic or acute obstructive pulmonary disease, chronic or acute pneumonia, covid-19 and like viral-induced lung disease, enteritis, crohn's disease, psoriasis, psoriatic arthritis, bechet's, or colitis.

In a particular method of the invention, a compound of the invention or a pharmaceutically acceptable polymorph, prodrug, salt, solvate, hydrate or clathrate thereof is administered in combination with at least one other therapeutic agent.

The unit dosage forms of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular or arterial), or transdermal administration to a patient, as well as topical administration in the form of a topical or inhalant. Dosage forms include, but are not limited to: tablets, caplets, capsules, e.g., soft elastic gelatin capsules, cachets, lozenges (troches), dispersions, suppositories, ointments, pastes (cataplasms), mud, powders, dressings, creams, plasters, solutions, patches, aerosols (e.g., nasal sprays or inhalants), gels, dry powder inhalants, liquid dosage forms suitable for oral or transmucosal administration to a patient, including suspensions (e.g., aqueous or nonaqueous suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs, liquid dosage forms suitable for parenteral administration to a patient, and sterile solid dosage forms (e.g., crystalline or amorphous solids) that are reconfigurable to provide liquid dosage forms suitable for parenteral administration to a patient. It will be apparent to those skilled in the art that the specific dosage forms encompassed by the present invention vary in all respects. See, e.g., remington' sPharmaceutical Sciences,18 edition, mack publication, easton PA (1990).

Term interpretation:

unless otherwise indicated, the radical and term definitions recited in the specification and claims of this application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combined group definitions and structures of compounds should fall within the scope of the description herein.

The term "halogen" refers to F, cl, br and I. In other words, F, cl, br, and I may be described as "halogen" in the present specification.

The optional substitution by substituents described herein encompasses both unsubstituted and substituted by one or more substituents, e.g. "optionally substituted by one, two or more R" means that it may be unsubstituted or substituted by one, two or more R.

The term "hydrocarbon group" includes saturated or unsaturated, linear or branched chain or cyclic hydrocarbon groups of the type selected from alkyl groups, alkenyl groups, alkynyl groups and the like, the number of carbon atoms of the hydrocarbon groups (alkyl groups, alkenyl groups, alkynyl groups) preferably being 1 to 12, further preferred ranges being 1 to 8,1 to 5,1 to 3 and the like may specifically include, but are not limited to, the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 1-ethylvinyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the hydrocarbyl (including alkyl, alkenyl, alkynyl) moiety in other terms also meets this definition.

The term "cycloalkyl" includes "C _3-12 Cycloalkyl "is understood to mean a saturated or unsaturated monovalent mono-or bicyclic ring having 3 to 12 carbon atoms, preferably C _3-8 Cycloalkyl, more preferably C _3-6 Cycloalkyl groups. For example C _3-8 Cycloalkyl is understood to mean a saturated or unsaturated monovalent mono-or bicyclic ring having 3, 4, 5, 6, 7 or 8 carbon atoms. The C is _3-12 Cycloalkyl may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as tetralin or decalin.

The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of the present invention that is sufficient to achieve the intended use, including but not limited to the treatment of a disease as defined below. The therapeutically effective amount may vary depending on the following factors: the intended use (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, the manner of administration, and the like, can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the particular compound selected, the regimen based on, whether to administer in combination with other compounds, the timing of administration, the organization of administration, and the physical delivery system carried.

The term "solvates" are those forms of the compounds of the invention which form complexes in the solid or liquid state by complexation with solvent molecules. Hydrates are a specific form of solvate in which complexation is with water. In the present invention, the preferred solvate is a hydrate. Further, pharmaceutically acceptable solvates (hydrates) of the compounds of the general formula I according to the invention refer to co-crystals and clathrates of compound I with water or other solvents of one or more molecules of stoichiometry. Solvents that may be used for the solvates include, but are not limited to: water, methanol, ethanol, ethylene glycol and acetic acid.

The term "prodrug" or "prodrug" means a compound that is converted in vivo to a compound represented by the general formula or a specific compound described above. Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. Prodrugs of the invention may be esters, and in the present invention esters may be phenyl esters, aliphatic esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters as prodrugs. For example, one compound of the invention comprises a hydroxy/carboxy group, i.e., it can be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent.

Advantageous effects

The compounds of the present invention are capable of inhibiting PDE4 enzyme responses, increasing cAMP levels or inhibiting factors such as TNF-alpha, thus effectively treating Psoriasis (Psoriasis), psoriatic arthritis, scalp Psoriasis, bechet's, atopic dermatitis (Atopic Dermatitis, AD), vitiligo (Vititigo), seborrheic dermatitis, obstructive pulmonary disease (COPD), acute pneumonia (ARDS), covid-19-induced pulmonary disease and respiratory inflammatory diseases. The compound has outstanding biological enzyme PDE4 inhibition activity, and physical, mechanical and in vivo metabolic properties of the compound are more suitable for topical administration of special preparation forms such as external medicine, inhalant and the like.

Detailed Description

The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.

Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.

EXAMPLE 1 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4- (gamma-chlorobutyramido) -5-hexylisoindoline-1, 3-dione

Synthesis of Compounds 1-2: compound 1-1 (5 g,23.25mmol,1 eq) was added in portions to fuming nitric acid (1.47 g,23.25mmol,16mL,1 eq) at 0deg.C, and after addition, stirred further for 1h at 0deg.C to form a yellow suspension. The mixture was stirred and poured into ice water (100 mL), the suspension was filtered, the filter cake was washed with water (30 mL), the filter cake was dissolved in ethyl glycolate (100 mL), and Na was used ₂ SO ₄ Drying and vacuum concentrating. Yellow solid compound 1-2 (5.3 g, crude) was obtained.

Synthesis of Compounds 1-3: compound 1-2 (5.3 g,6.73mmol,1 eq) was dissolved in H ₂ To O (60 mL), naOH (2.42 g,60.53mmol,9 eq) was added, the temperature was raised to 80℃and KMnO was added in portions over 3 hours ₄ (25.51 g,161.42mmol,24 eq), stirring for 30 min, suction filtration, washing the solid with hot water (30 ml. Times.3), cooling the aqueous phase with ice water, adjusting pH=2 with 2M HCl, extraction with ethyl acetate (100 ml. Times.2), washing the combined organic phases with saturated brine, washing the combined organic phases with Na ₂ SO ₄ After drying, filtration and concentration gave compound 1-3 (1.9 g, crude) as a yellow solid.

Synthesis of Compounds 1-4: compounds 1 to 3 (1.9 g,3.93mmol,1 eq) were dissolved in Ac ₂ O (21.80 g,213.54mmol,20mL,54.33 eq) was stirred at 140℃for 16 hours and concentrated to give compound 1-4 (1.6 g, crude) as a pale brown solid.

Synthesis of Compounds 1-5: compounds 1-4 (1.6 g,3.53mmol,1 eq) and 11a (1.54 g,5.65mmol,1.6 eq) were dissolved in AcOH (20 mL) and stirred at 120℃for 18 h. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate 10/1-1:1) to obtain yellow solid compound 1-5 (1.2 g, crude product).

Synthesis of Compounds 1-6: compounds 1-5 (1.2 g,1.50mmol,1 eq.) PdCl ₂ (PPh ₃ ) ₂ (210.83 mg, 300.37. Mu. Mol,0.2 eq), cuI (57.21 mg, 300.37. Mu. Mol,0.2 eq), DIEA (582.31 mg,4.51mmol, 784.78. Mu.L, 3 eq) and 1-hexyne (370.11 mg,4.51mmol, 506.99. Mu.L, 3 eq) were dissolved in DMF (12 mL) and the reaction mixture was taken in N ₂ Stirring was carried out at 60℃for 18 hours under an atmosphere, water (15 mL) and ethyl acetate (20 mL) were added to the reaction system, extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ Drying, filtering, concentrating to obtain crude product, and subjecting to column chromatography (SiO) ₂ PE: etOAc=10:1 to 1:1) afforded compound 1-6 (376 mg, 47.36%) as a yellow solid.

Compounds 1to 6 ¹ H-NMR(400MHz,CDCl ₃ )δ＝7.87(d,J＝8.0Hz,1H),7.81(d,J＝8.0Hz,1H),7.11-7.06(m,2H),6.83(d,J＝8.4Hz,1H),5.86(dd,J＝4.4,10.4Hz,1H),4.50(dd,J＝10.4,14.0Hz,1H),4.10(q,J＝7.2Hz,2H),3.87-3.84(m,3H),3.70(dd,J＝4.4,14.4Hz,1H),2.89-2.84(m,3H),2.44(t,J＝7.2Hz,2H),1.62-1.56(m,2H),1.49-1.41(m,5H),0.97-0.91(m,3H).

Synthesis of Compounds 1-7: compounds 1-6 (370.00 mg, 700.00. Mu. Mol,1 eq) were dissolved in methanol (10 mL), pd/C (100 mg,10% purity) was added under nitrogen, displaced 3 times with hydrogen under vacuum, and stirred at 60℃for 16 hours under hydrogen (50 Psi) atmosphere. The reaction was filtered through celite to remove solids, the filter cake was washed with EtOAc, concentrated and purified by prep-HPLC (formic acid system) to give compounds 1-7 (128 mg, yield 36.38%) and compounds 1-7A (25 mg, yield 7.13%).

Compounds 1 to 7 ¹ H-NMR(400MHz,CDCl ₃ )δ＝7.25(br s,1H),7.15-7.07(m,3H),6.82(d,J＝8.0Hz,1H),5.83(dd,J＝5.2,9.6Hz,1H),5.28(s,2H),4.52(dd,J＝9.2,14.4Hz,1H),4.10(q,J＝7.2Hz,2H),3.84(s,3H),3.79(dd,J＝5.2,14.4Hz,1H),2.80(s,3H),2.51(t,J＝8.0Hz,2H),1.64-1.58(m,2H),1.46(t,J＝7.2Hz,3H),1.35-1.29(m,6H),0.90-0.87(m,3H).

Compounds 1 to 7A ¹ H-NMR(400MHz,CDCl ₃ )δ＝7.43(d,J＝7.2Hz,1H),7.16-7.10(m,3H),6.84(d,J＝8.4Hz,1H),6.36-6.30(m,1H),6.26-6.18(m,1H),5.85(dd,J＝5.2,9.6Hz,1H),5.36(s,2H),4.52(dd,J＝9.6,14.4Hz,1H),4.12(q,J＝7.2Hz,2H),3.85(s,3H),3.80(dd,J＝4.8,14.4Hz,1H),2.81(s,3H),2.30-2.23(m,2H),1.51-1.447(m,5H),1.43-1.35(m,2H),0.97-0.92(m,3H).

Synthesis of example 1:

compounds 1 to 7 (40 mg, 79.58. Mu. Mol,1 eq) and chlorobutyryl chloride (11.22 mg, 79.58. Mu. Mol, 8.91. Mu.L, 1 eq) were dissolved in DCE (2 mL) and DIEA (10.29 mg, 79.58. Mu. Mol, 13.86. Mu.L, 1 eq) was added to the reaction solution and stirred at 50℃for 3 hours. The reaction solution was dried by spin-drying and purified by prep-HPLC (formic acid system) to give example 1 (14.04 mg, 29.06% yield) as a white solid.

¹ H-NMR(400MHz,CDCl ₃ )δ＝7.94(br s,1H),7.65-7.57(m,2H),7.07(d,J＝2.0Hz,1H),7.09(s,1H),6.83(d,J＝8.4Hz,1H),5.85(dd,J＝4.4,10.0Hz,1H),4.51(dd,J＝10.4,14.4Hz,1H),4.10(q,J＝6.8Hz,2H),3.85(s,3H),3.74(dd,J＝4.4,14.4Hz,1H),3.69(t,J＝6.4Hz,2H),2.84(s,3H),2.74-2.60(m,4H),2.24(quin,J＝6.8Hz,2H),1.63-1.56(m,2H),1.46(t,J＝7.2Hz,3H),1.28(br s,6H),0.92-0.82(m,3H).

LCMS:607.0([M+H] ⁺ ).

EXAMPLE 2 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4- (gamma-chlorobutyramido) -5-hexene (-1) yl isoindoline-1, 3-dione

Compounds 1-7A (20.00 mg, 39.95. Mu. Mol,1 eq) and chlorobutyryl chloride (6.20 mg, 43.95. Mu. Mol, 4.92. Mu.L, 1.1 eq) were dissolved in DCE (2 mL) and DIEA (5.16 mg, 39.95. Mu. Mol, 6.96. Mu.L, 1 eq) was added to the reaction solution and stirred at 50℃for 16 hours. The reaction mixture was dried by spin-drying and purified by prep-HPLC (formic acid system) to give example 2 (5.13 mg, 21.22% yield) as a white solid.

¹ H-NMR(400MHz,CDCl ₃ )δ＝8.03(br s,1H),7.83(d,J＝7.6Hz,1H),7.62(d,J＝7.6Hz,1H),7.11-7.06(m,2H),6.83(d,J＝8.8Hz,1H),6.42-6.28(m,2H),5.85(dd,J＝4.4,10.4Hz,1H),4.51(br dd,J＝10.4,14.4Hz,1H),4.10(q,J＝6.8Hz,2H),3.85(s,3H),3.77-3.62(m,3H),2.83(s,3H),2.69(br s,2H),2.23(quin,J＝7.2Hz,4H),1.50-1.43(m,5H),1.40-1.33(m,2H),0.96-0.87(m,3H).

LCMS:605.1([M+H] ⁺ ).

EXAMPLE 3 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-cyclopropylamido-5-octylisoindoline-1, 3-dione

Synthesis of Compound 3-2: compound 3-1 5-bromo-2-methyl-3-nitrobenzoic acid (20 g,76.91mmol,1 eq.) was dissolved in H ₂ O (20 mL), naOH (9.23 g,230.73mmol,3 eq) was added, the temperature was raised to 80℃and KMnO was added in portions over 3 hours ₄ (97.24 g,615.29mmol,8 eq.) and after addition stirring is continued for 30min at 80 ℃, suction filtration and washing of the filter cake with hot water (300 ml. Times.3). The aqueous phase was cooled with ice water, ph=1 adjusted with 2M HCl, extracted with EtOAc (400 ml x 3), the combined organic phases were washed with saturated brine, and dried over Na ₂ SO ₄ After drying, filtration and concentration gave compound 3-2 (5 g, yield 22.42%) as a yellow solid.

¹ H-NMR(400MHz，DMSO-d ₆ )δ＝13.98(br s,2H),8.52(d,J＝2.0Hz,1H),8.33(d,J＝2.0Hz,1H).

Synthesis of Compound 3-3: compound 3-2 (5 g,17.24mmol,1 eq.) was dissolved in Ac ₂ O (20 mL) was stirred at 140℃for 16 hours. The reaction mixture was dried by spin to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate 100/0to 1/1) to give 3-3 (4.5 g, crude product) as a yellow solid.

Synthesis of Compounds 3-4: compound 3-3 (4 g,14.71mmol,1 eq) and compound 11a (4.02 g,14.71mmol,1 eq.) are dissolved in AcOH (80 mL) and stirred at 120℃for 16 hours. The reaction solution was dried by spin to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate 100/0to 1/1) to give 3-4 (2.9 g, yield 37.40%) as a yellow solid.

¹ H-NMR(400MHz，CDCl ₃ )δ＝8.24(d,J＝1.6Hz,1H),8.21(d,J＝1.6Hz,1H),7.13-7.06(m,2H),6.84(d,J＝7.6Hz,1H),5.91(dd,J＝11.2,4.4Hz,1H),4.57(dd,J＝14.4,11.2Hz,1H),4.14-4.07(m,2H),3.85(s,3H),3.66(dd,J＝14.4,4.0Hz,1H),2.91(s,3H),1.47(t,J＝7.2Hz,3H).

Synthesis of Compounds 3-5: compound 3-4 (400.00 mg, 758.52. Mu. Mol,1 eq), pdCl ₂ (PPh ₃ ) ₂ (106.48 mg, 151.70. Mu. Mol,0.2 eq), cuI (28.89 mg, 151.70. Mu. Mol,0.2 eq), DIEA (294.09 mg,2.28mmol, 396.35. Mu.L, 3 eq) and 1-octyne (417.93 mg,3.79mmol,5 eq) were dissolved in DMF (4 mL) and the reaction mixture was taken up in N ₂ Stirring at 60deg.C for 16 hr under atmospheric conditions, adding water (10 mL) into the reaction system, ethyl acetate (10 mL x 3) extraction, combining organic phases, washing with saturated brine, washing with Na ₂ SO ₄ Drying, filtering, concentrating to obtain crude product, and subjecting to column chromatography (SiO) ₂ Petroleum ether, ethyl acetate 100:1-1:1) to afford compound 3-5 as a yellow solid (130 mg, 30.79% yield).

¹ H-NMR(400MHz CDCl ₃ )δ＝7.13-7.07(m,3H),6.85-6.80(m,2H),5.82(dd,J＝9.6,5.2Hz,1H),5.15(s,2H),4.49(dd,J＝14.4,9.6Hz,1H),4.10(d,J＝7.2Hz,2H),3.84(s,3H),3.78(dd,J＝14.4,5.2Hz,1H),2.80(s,3H),2.39(t,J＝7.2Hz,2H),1.63-1.56(m,2H),1.46(t,J＝7.2Hz,3H),1.32-1.30(m,3H),0.88-0.87(m,4H).

Synthesis of Compounds 3-6: compound 3-5 (130 mg, 233.55. Mu. Mol,1 eq) was dissolved in EtOAc (15 mL), pd/C (140 mg, 10%) was added under nitrogen, replaced 3 times with hydrogen under vacuum, and stirred at 60℃for 16 hours under an atmosphere of hydrogen (50 Psi). The reaction was filtered through celite to remove solids, the filter cake was washed with EtOAc, and the filtrate was dried to give compound 3-6 (100 mg, 80.68%) as a yellow solid.

¹ H-NMR(400MHz CDCl ₃ )δ＝7.14-7.08(m,2H),7.00-6.96(m,1H),6.82(d,J＝8.4Hz,1H),6.62(s,1H),5.82(dd,J＝5.2,9.6Hz,1H),5.30(s,1H),5.12(s,2H),4.51(dd,J＝14.8,9.6Hz,1H),4.11(q,J＝7.2Hz,2H),3.84(s,3H),3.79(dd,J＝14.8,5.2Hz,1H),2.80(s,3H),2.57(t,J＝7.6Hz,2H),2.05-1.98(m,1H),1.57(br s,2H),1.46(t,J＝7.2Hz,3H),1.26(br d,J＝6.8Hz,8H),0.89-0.86(m,3H).

Synthesis of example 3:

compounds 3-6 (10 mg, 18.84. Mu. Mol,1 eq) and cyclopropylchloride (9.85 mg, 94.22. Mu. Mol, 8.56. Mu.L, 5 eq.) were dissolved in DCE (1 mL) and DIEA (19.48 mg, 150.75. Mu. Mol, 26.26. Mu.L, 8 eq.) was added to the reaction solution and stirred at 90℃for 2 hours. The reaction mixture was dried by spin-drying and purified by prep-HPLC (formic acid system) to give example 3 (8.2 mg, yield 72.68%) as a white solid.

¹ H-NMR(400MHz，CDCl ₃ )δ＝9.60(s,1H),8.58(s,1H),7.30(s,1H),7.12-7.08(m,2H),6.86-6.82(m,1H),5.86(dd,J＝10.4,4.4Hz,1H),4.55(dd,J＝14.4,10.4Hz,1H),4.11(q,J＝6.8Hz,2H),3.85(s,3H),3.74(dd,J＝14.4,4.4Hz,1H),2.86(s,3H),2.69-2.64(m,2H),1.67-1.58(m,3H),1.47(t,J＝7.2Hz,3H),1.26(br d,J＝12.4Hz,10H),1.12(quin,J＝3.6Hz,2H),0.97-0.91(m,2H),0.89-0.84(m,3H)

LCMS:599.1[M+H] ⁺ .

EXAMPLE 4 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-acetamidomethyl-7-pentylisoindoline-1, 3-dione

Example 4 was synthesized via scheme 6.

LCMS:545.1([M+H] ⁺ ).

EXAMPLE 5 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4- (gamma-chlorobutyramide) -7-pentylisoindoline-1, 3-dione

Synthesis of Compound 5-2: compound 5-1 (21.19 g,109.75mmol,1 eq) and compound 11a (30 g,109.75mmol,1 eq) were dissolved in HOAc (500 mL) and stirred at 120℃for 16 hours. The reaction solution was dried by spin to give a crude product which was purified by column chromatography (petroleum ether: ethyl acetate 100/0-1:1) to give Compound 5-2 (43.3 g, yield 89.98%) as a yellow solid.

¹ H-NMR(400MHz,CDCl ₃ )δ＝8.13-8.07(m,2H),7.92-7.86(m,1H),7.15-7.09(m,2H),6.84(d,J＝8.0Hz,1H),5.93(dd,J＝4.0,10.8Hz,1H),4.58(dd,J＝10.8,14.4Hz,1H),4.15-4.07(m,2H),3.85(s,3H),3.70(dd,J＝4.4,14.4Hz,1H),2.90(s,3H),1.47(t,J＝7.2Hz,3H).

Synthesis of Compound 5-3: compound 5-2 (50.00 g,111.15mmol,1 eq) was dissolved in EtOAc (400 mL), pd/C (9 g, 10%) was added under nitrogen, replaced 3 times with hydrogen under vacuum and stirred at 60℃for 12 hours under an atmosphere of hydrogen (50 Psi). The reaction was filtered through celite to remove the solids, the filter cake was washed with EtOAc, and the filtrate was dried to give compound 5-3 (4 g, 85.73% yield) as a yellow solid.

¹ H-NMR(400MHz,CDCl ₃ )δ＝7.37(dd,J＝7.2,8.4Hz,1H),7.13-7.10(m,2H),7.10-7.08(m,1H),6.83-6.78(m,2H),5.83(dd,J＝4.8,9.8Hz,1H),5.20(s,2H),4.54-4.47(m,1H),4.12-4.06(m,2H),3.83(s,3H),3.78(dd,J＝5.2,14.8Hz,1H),2.79(s,3H),1.47-1.42(m,3H).

Synthesis of Compounds 5-4: compound 5-3 (47.4 g,113.27mmol,1 eq) was dissolved in ethyl acetate (500 mL), NBS (20.16 g,113.27mmol,1 eq) was added, stirred at 25℃for 16 hours, the reaction mixture was dried by spin to give crude product which was purified by column chromatography (petroleum ether: ethyl acetate 100/0-1:1) to give compound 5-4 (26.52 g, yield 42.07%) as a yellow solid.

¹ H-NMR(400MHz,CDCl ₃ )δ＝7.44(d,J＝8.4Hz,1H),7.16-7.08(m,2H),6.84(d,J＝8.0Hz,1H),6.71(d,J＝8.4Hz,1H),5.86(dd,J＝4.4,10.4Hz,1H),5.55-5.15(m,2H),4.55(dd,J＝10.4,14.4Hz,1H),4.15-4.02(m,2H),3.86(s,3H),3.77(dd,J＝4.8,14.4Hz,1H),2.85(s,3H),1.47(t,J＝7.2Hz,3H).

Synthesis of Compounds 5-5: compound 5-4 (13.98 g,28.11mmol,1 eq), cs ₂ CO ₃ (27.47 g,84.33mmol,3 eq.) pentylboronic acid (6.52 g,56.22mmol,2 eq.) was dissolved in dioxane (150 mL) and water (30 mL), in N ₂ Pd (dppf) Cl was added under ambient atmosphere ₂ (4.11 g,5.62mmol,0.2 eq) under nitrogen at 60℃for 18 hours, the reaction concentrated, added water (50 mL) and ethyl acetate (50 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases combined, washed with saturated brine, and concentrated in vacuo, taken up in water, and dried over sodium chloride ₂ SO ₄ Drying, filtering, concentrating to obtainThe crude product was purified by column chromatography (SiO) ₂ Petroleum ether, ethyl acetate 100/0-1:1) to afford compound 5-5 (4.78 g, 34.80% yield) as a yellow solid.

¹ H-NMR(400MHz,CDCl ₃ )δ＝7.18(d,J＝8.4Hz,1H),7.16-7.10(m,2H),6.83(d,J＝8.4Hz,1H),6.75(d,J＝8.4Hz,1H),5.83(dd,J＝5.2,9.6Hz,1H),5.14(s,2H),4.50(dd,J＝9.6,14.4Hz,1H),4.16-4.09(m,2H),3.85(s,3H),3.83-3.78(m,1H),3.64(t,J＝6.8Hz,1H),2.96-2.86(m,2H),2.83-2.76(m,3H),1.62-1.57(m,2H),1.46(t,J＝7.2Hz,3H),1.38-1.27(m,4H),0.94-0.85(m,3H)

Synthesis of example 5

Compound 5-5 (4.04 g,8.27mmol,1 eq) and chlorobutyryl chloride (2.33 g,16.54mmol,1.85mL,2 eq) were dissolved in DCE (80 mL), DIEA (4.27 g,33.07mmol,5.76mL,4 eq) was added and stirred at 90℃for 3 hours. The reaction solution was dried by spin drying, saturated NaHCO was added ₃ (20 mL) aqueous solution and DCM (20 mL), dichloromethane (3X 20 mL) extracts, and the combined organic phases are washed with saturated brine, and dried over Na ₂ SO ₄ Drying, filtering, concentrating to obtain crude product, and subjecting to column chromatography (SiO) ₂ Petroleum ether ethyl acetate 1/0-1:1) to afford example 5 as a yellow solid (4.12 g, ee 96.7%, yield 84.01%).

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.58(s,1H),8.63(d,J＝8.8Hz,1H),7.43(d,J＝8.8Hz,1H),7.13-7.08(m,2H),6.88-6.82(m,1H),5.86(dd,J＝4.8,10.0Hz,1H),4.53(dd,J＝10.4,14.4Hz,1H),4.12(q,J＝7.2Hz,2H),3.85(s,3H),3.75(dd,J＝4.8,14.4Hz,1H),3.66(t,J＝6.4Hz,2H),3.03-2.94(m,2H),2.85(s,3H),2.66(t,J＝7.2Hz,2H),2.22(quin,J＝6.8Hz,2H),1.65-1.57(m,2H),1.47(t,J＝7.2Hz,3H),1.36-1.30(m,4H),0.91-0.86(m,3H).

LCMS:593.1([M+H] ⁺ ).

EXAMPLE 6 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-cyclopropylamide-7-pentylisoindoline-1, 3-dione

Synthesis of Compound 6-2:

compound 5-4 (200 mg, 402.12. Mu. Mol,1 eq), pdCl ₂ (PPh ₃ ) ₂ (56.45 mg, 80.42. Mu. Mol,0.2 eq), cuI (15.32 mg, 80.42. Mu. Mol,0.2 eq), DIEA (155.91 mg,1.21mmol, 210.12. Mu.L, 3 eq) and 1-pentyne (273.91 mg,4.02mmol, 394.69. Mu.L, 10 eq) were dissolved in DMF (2 mL) and the reaction mixture was taken up in N ₂ Stirring at 60deg.C for 16 hr under atmospheric conditions, adding water (5 mL) into the reaction system, extraction with ethyl acetate (5 mL. Times.3), combining the organic phases, washing with saturated brine, and washing with Na ₂ SO ₄ Drying, filtering, concentrating to obtain crude product, and subjecting to column chromatography (SiO) ₂ Petroleum ether is purified by ethyl acetate 1/0-1:1 to obtain yellow solid compound 6-2 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl ethyl]-4-amino-6- [ pent-1-ynyl]Isoindoline-1, 3-dione (98 mg, yield 50.29%).

¹ H-NMR(400MHz CDCl ₃ )δ＝7.36(d,J＝8.4Hz,1H),7.15-7.10(m,2H),6.82(d,J＝8.8Hz,1H),6.74(d,J＝8.4Hz,1H),5.84(dd,J＝9.6,5.2Hz,1H),5.32(d,J＝13.2Hz,2H),4.48(dd,J＝14.4,9.2Hz,1H),4.14-4.08(m,2H),3.84(s,3H),3.84-3.79(m,1H),2.81-2.77(m,3H),2.46(t,J＝7.2Hz,2H),1.67(sxt,J＝7.2Hz,2H),1.46(t,J＝7.2Hz,3H),1.08(t,J＝7.2Hz,3H).

Synthesis of Compound 6-3:

compound 6-2 (98 mg, 202.24. Mu. Mol,1 eq) was dissolved in EtOAc (10 mL), pd/C (100 mg, 10%) was added under nitrogen, replaced 3 times with hydrogen under vacuum, and stirred at 60℃for 16 hours under an atmosphere of hydrogen (50 Psi). The reaction was filtered through celite to remove solids, the filter cake was washed with EtOAc, and the filtrate was dried to give compound 6-3 (60 mg, 60.72% yield) as a yellow solid.

¹ H-NMR(400MHz CDCl ₃ )δ＝7.20-7.10(m,3H),6.83(d,J＝8.4Hz,1H),6.75(d,J＝8.4Hz,1H),5.84(dd,J＝9.2,5.2Hz,1H),5.14(s,2H),4.50(dd,J＝14.8,9.6Hz,1H),4.11(q,J＝6.8Hz,2H),3.85-3.84(m,3H),3.84-3.79(m,1H),2.93-2.88(m,2H),2.78(s,3H),1.62-1.55(m,2H),1.46(t,J＝7.2Hz,3H),1.35-1.28(m,4H),0.91-0.85(m,3H).

Synthesis of example 6:

compound 6-3 (12.5 mg, 25.58. Mu. Mol,1 eq.) and cyclopropylchloride (13.37 mg, 127.92. Mu. Mol, 11.63. Mu.L, 5 eq.) are dissolved in DCE (1 mL) and DIEA (26.45 mg, 204.67. Mu. Mol, 35.65. Mu.L, 8 eq.) is added and stirred at 90℃for 2 hours. The reaction solution was dried by spin-drying and purified by prep-HPLC (formic acid system) to give example 6 (5 mg, yield 35.11%) as a white solid.

¹ H-NMR(400MHz，CDCl ₃ )δ＝9.76(s,1H),8.63(d,J＝8.8Hz,1H),7.41(d,J＝8.8Hz,1H),7.14-7.08(m,2H),6.88-6.81(m,1H),5.87(dd,J＝10.0,4.8Hz,1H),4.53(dd,J＝14.4,10.0Hz,1H),4.12(q,J＝7.2Hz,2H),3.85(s,3H),3.76(dd,J＝14.4,4.4Hz,1H),3.01-2.94(m,2H),2.84(s,3H),1.67-1.58(m,3H),1.47(t,J＝7.2Hz,3H),1.37-1.27(m,4H),1.15-1.07(m,2H),0.96-0.84(m,5H).

LCMS:557.1([M+H] ⁺ ).

EXAMPLE 7 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-acetamide-7-pentene (-1) ylisoindoline-1, 3-dione

Synthesis of example 7:

compound 6-2 (180 mg, 371.47. Mu. Mol,1.0 eq.) was dissolved in Ac ₂ O (1 mL) was stirred for 3 hours, the reaction was dried by spin-drying and purified by prep-HPLC (formic acid system) to give example 7 as a white solid (119 mg, 60.8% yield).

¹ H-NMR(400MHz DMSO-δ ₆ )δ＝9.77(s,1H),8.46(d,J＝8.7Hz,1H),7.74(d,J＝8.7Hz,1H),7.08(d,J＝1.9Hz,1H),7.03–6.93(m,2H),5.79(dd,J＝10.4,4.3Hz,1H),4.35(dd,J＝14.3,10.5Hz,1H),4.17(dd,J＝14.3,4.4Hz,1H),4.04(d,J＝7.0Hz,2H),3.75(s,3H),3.04(s,3H),2.49(d,J＝6.9Hz,2H),2.22(s,3H),1.62(p,J＝7.2Hz,2H),1.34(t,J＝7.0Hz,3H),1.06(t,J＝7.4Hz,3H).

LCMS:527.2([M+H] ⁺ ).

EXAMPLE 8 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-decanoamide-7-pentene (-1) yl isoindoline-1, 3-dione

Synthesis by way of example 3

¹ H-NMR(400MHz，CDCl ₃ )δ＝9.47(s,1H),8.79(d,J＝8.4Hz,1H),7.74–7.59(m,1H),7.48(d,J＝7.2Hz,1H),7.11(dd,J＝5.9,2.1Hz,2H),6.84(d,J＝8.9Hz,1H),5.87(dd,J＝10.4Hz,4.4Hz,1H),4.62-4.47(m,1H),4.17-4.05(m,2H),3.85(s,3H),3.73(s,1H),2.86(s,3H),2.46(d,J＝7.5Hz,2H),1.84-1.69(m,2H),1.50-1.44(m,3H),1.43-1.17(m,12H),0.94-0.75(m,3H).

LCMS:573.6([M+H] ⁺ ).

EXAMPLE 9 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-acetamide-7-pentylisoindoline-1, 3-dione

Synthesis by way of example 3

¹ H-NMR(400MHz DMSO-δ6)δ＝9.70(s,1H),8.35(d,J＝8.6Hz,1H),7.62(d,J＝8.6Hz,1H),7.09(d,J＝1.8Hz,1H),7.03-6.92(m,2H),5.78(dd,J＝10.4,4.3Hz,1H),4.37(dd,J＝14.3Hz,10.5Hz,1H),4.15(dd,J＝14.3Hz,4.4Hz,1H),4.03(q,J＝7.0Hz,2H),3.75(s,3H),3.02(s,3H),2.99–2.92(m,2H),2.19(s,3H),1.57(p,J＝7.3Hz,2H),1.38-1.25(m,7H),0.87(t,J＝6.9Hz,3H).

LCMS:531.2([M+H] ⁺ ).

EXAMPLE 10 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-butyramide-7-pentylisoindoline-1, 3-dione

Synthesis by way of example 3

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.54(s,1H),8.66(d,J＝8.4Hz,1H),7.42(d,J＝8.4Hz,1H),7.15-7.06(m,2H),6.84(d,J＝8.8Hz,1H),5.85(dd,J＝4.4,10.0Hz,1H),4.52(dd,J＝10.4,14.4Hz,1H),4.11(q,J＝6.8Hz,2H),3.85(s,3H),3.76(dd,J＝4.4,14.4Hz,1H),3.03-2.94(m,2H),2.84(s,3H),2.42(t,J＝7.6Hz,2H),1.78(qd,J＝7.2,14.8Hz,2H),1.62-1.57(m,2H),1.47(t,J＝7.2Hz,3H),1.37-1.28(m,4H),1.02(t,J＝7.2Hz,3H),0.94-0.82(m,3H).

LCMS:559.1([M+H] ⁺ ).

EXAMPLE 11 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-isovaleramide-7-butylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.52(s,1H),8.67(d,J＝8.4Hz,1H),7.42(d,J＝8.8Hz,1H),7.14-7.08(m,2H),6.85(d,J＝8.4Hz,1H),5.85(dd,J＝4.8,10.0Hz,1H),4.52(dd,J＝10.0,14.4Hz,1H),4.11(q,J＝7.2Hz,2H),3.85(s,3H),3.77(dd,J＝4.8,14.4Hz,1H),3.03-2.93(m,2H),2.83(s,3H),2.34-2.28(m,2H),2.28-2.19(m,1H),1.64-1.58(m,2H),1.47(t,J＝7.2Hz,3H),1.37-1.29(m,4H),1.03(d,J＝6.4Hz,6H),0.92-0.85(m,3H).

LCMS:573.1([M+H] ⁺ ).

EXAMPLE 12 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-hexanamide-7-butylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.54(br s,1H),8.66(br d,J＝8.4Hz,1H),7.42(br d,J＝8.8Hz,1H),7.19-7.03(m,2H),6.84(br d,J＝8.4Hz,1H),5.85(br dd,J＝4.0,9.2Hz,1H),4.58-4.44(m,1H),4.18-4.04(m,2H),3.85(s,3H),3.76(br dd,J＝4.0,14.4Hz,1H),2.98(br t,J＝7.2Hz,2H),2.84(s,3H),2.44(br t,J＝7.2Hz,2H),1.75(br s,2H),1.60(br s,2H),1.47(br t,J＝6.8Hz,3H),1.35(br d,J＝16.4Hz,8H),0.95-0.85(m,6H).

LCMS:587.1([M+H] ⁺ ).

EXAMPLE 13 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-propionamide-7-pentylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.56(s,1H),8.66(d,J＝8.8Hz,1H),7.42(d,J＝8.8Hz,1H),7.15-7.06(m,2H),6.84(d,J＝8.8Hz,1H),5.85(dd,J＝4.8,10.0Hz,1H),4.52(dd,J＝10.0,14.4Hz,1H),4.15-4.08(m,2H),3.85(s,3H),3.76(dd,J＝4.8,14.4Hz,1H),3.02-2.94(m,2H),2.84(s,3H),2.48(q,J＝7.6Hz,2H),1.63-1.58(m,2H),1.47(t,J＝7.2Hz,3H),1.33-1.25(m,7H),0.89-0.86(m,3H).

LCMS:545.1([M+H] ⁺ ).

EXAMPLE 14 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-acetamide-7-tridecylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.53(s,1H),8.64(d,J＝8.8Hz,1H),7.42(d,J＝8.8Hz,1H),7.15-7.06(m,2H),6.85(d,J＝8.8Hz,1H),5.86(dd,J＝4.4,10.0Hz,1H),4.53(dd,J＝10.4,14.4Hz,1H),4.12(q,J＝7.2Hz,2H),3.85(s,3H),3.75(dd,J＝4.8,14.4Hz,1H),2.98(dd,J＝6.4,8.8Hz,2H),2.85(s,3H),2.25(s,3H),1.63-1.57(m,2H),1.47(t,J＝7.2Hz,3H),1.33-1.18(m,20H),0.91-0.85(m,3H).

LCMS:643.3([M+H] ⁺ ).

EXAMPLE 15 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-cyclopropylamide-7-tridecylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.76(s,1H),8.63(d,J＝8.8Hz,1H),7.40(d,J＝8.8Hz,1H),7.15-7.08(m,2H),6.85(d,J＝8.8Hz,1H),5.87(dd,J＝4.4,10.0Hz,1H),4.53(dd,J＝10.4,14.4Hz,1H),4.12(q,J＝6.8Hz,2H),3.85(s,3H),3.76(dd,J＝4.8,14.4Hz,1H),2.97(br t,J＝7.6Hz,2H),2.84(s,3H),1.68-1.57(m,3H),1.47(t,J＝7.2Hz,3H),1.36-1.23(m,20H),1.13-1.09(m,2H),0.92(br dd,J＝3.2,7.6Hz,2H),0.88(br t,J＝6.8Hz,3H).

LCMS:669.2([M+H] ⁺ ).

EXAMPLE 16 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-butyramide-7-nonylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.55(s,1H),8.67(d,J＝8.8Hz,1H),7.42(d,J＝8.8Hz,1H),7.14-7.08(m,2H),6.85(d,J＝8.8Hz,1H),5.85(dd,J＝4.8,10.0Hz,1H),4.52(dd,J＝10.0,14.4Hz,1H),4.12(q,J＝7.2Hz,2H),3.85(s,3H),3.76(dd,J＝4.8,14.4Hz,1H),2.98(dd,J＝6.8,8.8Hz,2H),2.84(s,3H),2.43(t,J＝7.6Hz,2H),1.79(sxt,J＝7.6Hz,2H),1.64-1.57(m,2H),1.47(t,J＝7.2Hz,3H),1.32-1.18(m,12H),1.03(t,J＝7.6Hz,3H),0.89-0.86(m,3H).

LCMS:615.2([M+H] ⁺ ).

EXAMPLE 17 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-cyclopropylamide-7-nonylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.76(s,1H),8.62(d,J＝8.8Hz,1H),7.40(d,J＝8.8Hz,1H),7.15-7.08(m,2H),6.85(d,J＝8.8Hz,1H),5.87(dd,J＝4.8,10.0Hz,1H),4.53(dd,J＝10.0,14.4Hz,1H),4.12(q,J＝7.2Hz,2H),3.85(s,3H),3.77(dd,J＝4.8,14.4Hz,1H),3.03-2.92(m,2H),2.84(s,3H),1.67-1.57(m,3H),1.47(t,J＝7.2Hz,3H),1.33-1.23(m,12H),1.14-1.08(m,2H),0.95-0.90(m,2H),0.89-0.86(m,3H).

LCMS:613.1([M+H] ⁺ ).

EXAMPLE 18 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-propionamide-7-nonylisoindoline-1, 3-dione

/>

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.56(s,1H),8.66(d,J＝8.8Hz,1H),7.42(d,J＝8.8Hz,1H),7.14-7.07(m,2H),6.84(d,J＝8.8Hz,1H),5.85(dd,J＝4.8,10.0Hz,1H),4.52(dd,J＝10.0,14.4Hz,1H),4.11(q,J＝7.2Hz,2H),3.85(s,3H),3.76(dd,J＝4.8,14.4Hz,1H),2.98(dd,J＝6.8,8.4Hz,2H),2.84(s,3H),2.48(q,J＝7.6Hz,2H),1.61-1.56(m,2H),1.47(t,J＝7.2Hz,3H),1.34-1.21(m,15H),0.87(t,J＝6.8Hz,3H)

LCMS:601.2([M+H] ⁺ ).

EXAMPLE 19 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-propionamide-7-tridecylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.56(s,1H),8.66(d,J＝8.8Hz,1H),7.42(d,J＝8.8Hz,1H),7.16-7.06(m,2H),6.84(d,J＝8.8Hz,1H),5.85(dd,J＝4.4,10.0Hz,1H),4.52(dd,J＝10.0,14.4Hz,1H),4.11(q,J＝7.2Hz,2H),3.85(s,3H),3.76(dd,J＝4.8,14.4Hz,1H),2.98(dd,J＝6.8,8.8Hz,2H),2.84(s,3H),2.48(q,J＝7.6Hz,2H),1.62(br s,2H),1.47(t,J＝7.2Hz,2H),1.49-1.43(m,3H),1.37-1.23(m,23H),0.90-0.84(m,3H)

LCMS:657.3([M+H] ⁺ ).

EXAMPLE 20 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4- (gamma-chlorobutyramide) -7-hexylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.58(s,1H),8.63(d,J＝8.4Hz,1H),7.43(d,J＝8.8Hz,1H),7.11(br d,J＝4.4Hz,2H),6.85(br d,J＝8.8Hz,1H),5.86(br dd,J＝4.4,10.0Hz,1H),4.53(br dd,J＝10.4,14.4Hz,1H),4.12(q,J＝6.8Hz,2H),3.85(s,3H),3.75(br dd,J＝4.4,14.4Hz,1H),3.66(t,J＝6.4Hz,2H),2.99(br t,J＝7.6Hz,2H),2.85(s,3H),2.66(br t,J＝7.2Hz,2H),2.22(quin,J＝6.6Hz,2H),1.64-1.57(m,2H),1.47(t,J＝7.2Hz,3H),1.34-1.25(m,6H),0.90-0.84(m,3H)

LCMS:607.1([M+H] ⁺ ).

EXAMPLE 21 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4- (gamma-chlorobutyramide) -7-heptylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.58(s,1H),8.63(br d,J＝8.4Hz,1H),7.42(br d,J＝8.8Hz,1H),7.11(brs,2H),6.85(br d,J＝8.8Hz,1H),5.86(br dd,J＝4.4,10.0Hz,1H),4.53(br dd,J＝10.4,14.0Hz,1H),4.12(q,J＝6.8Hz,2H),3.85(s,3H),3.75(br dd,J＝4.4,14.4Hz,1H),3.66(br t,J＝6.0Hz,2H),3.07-2.91(m,2H),2.85(s,3H),2.65(br t,J＝7.2Hz,2H),2.22(quin,J＝6.5Hz,2H),1.58(br d,J＝6.4Hz,2H),1.47(br t,J＝6.8Hz,3H),1.34-1.23(m,8H),0.87(br t,J＝6.4Hz,3H).

LCMS:621.1([M+H] ⁺ ).

EXAMPLE 22 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4- (gamma-chlorobutyramide) -7-octylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.58(s,1H),8.63(d,J＝8.8Hz,1H),7.42(d,J＝8.8Hz,1H),7.11(dd,J＝2.4,4.4Hz,2H),6.88-6.82(m,1H),5.86(dd,J＝4.4,10.0Hz,1H),4.53(dd,J＝10.4,14.4Hz,1H),4.12(q,J＝7.2Hz,2H),3.85(s,3H),3.75(dd,J＝4.8,14.4Hz,1H),3.66(t,J＝6.4Hz,2H),3.03-2.91(m,2H),2.85(s,3H),2.66(t,J＝7.2Hz,2H),2.22(quin,J＝6.8Hz,2H),1.64-1.56(m,2H),1.47(t,J＝7.2Hz,3H),1.35-1.23(m,10H),0.87(t,J＝6.8Hz,3H).

LCMS:635.1([M+H] ⁺ ).

EXAMPLE 23 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-propionamide-6-hexylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝8.00(br s,1H),7.60(q,J＝7.6Hz,2H),7.11-7.05(m,2H),6.83(d,J＝7.6Hz,1H),5.85(dd,J＝4.8,10.0Hz,1H),4.51(dd,J＝9.6,14.4Hz,1H),4.10(q,J＝7.2Hz,2H),3.85(s,3H),3.75(dd,J＝4.4,14.4Hz,1H),2.83(s,3H),2.71-2.63(m,2H),2.51(q,J＝7.2Hz,2H),1.60-1.56(m,2H),1.46(t,J＝7.2Hz,3H),1.32-1.25(m,9H),0.90-0.84(m,3H).

LCMS:559([M+H] ⁺ ).

EXAMPLE 24 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4- (gamma-chlorobutyramide) -7-pentylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.63(s,1H),8.65(d,J＝8.8Hz,1H),7.44(d,J＝8.8Hz,1H),7.15-7.07(m,2H),6.85(d,J＝8.8Hz,1H),5.86(dd,J＝4.4,10.4Hz,1H),4.53(dd,J＝10.4,14.4Hz,1H),4.12(q,J＝7.2Hz,2H),3.88(t,J＝6.4Hz,2H),3.85(s,3H),3.75(dd,J＝4.4,14.4Hz,1H),3.03-2.95(m,2H),2.91(t,J＝6.4Hz,2H),2.85(s,3H),1.64-1.56(m,2H),1.47(t,J＝7.2Hz,3H),1.37-1.29(m,4H),0.93-0.85(m,3H).

LCMS:579([M+H] ⁺ ).

EXAMPLE 25 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4- (chloroacetamide) -7-pentylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝10.57(s,1H),8.64(d,J＝8.4Hz,1H),7.46(d,J＝8.8Hz,1H),7.17-7.09(m,2H),6.85(d,J＝8.0Hz,1H),5.87(dd,J＝4.8,10.0Hz,1H),4.53(dd,J＝10.4,14.4Hz,1H),4.21(s,2H),4.16-4.09(m,2H),3.85(s,3H),3.77(dd,J＝4.8,14.4Hz,1H),3.04-2.98(m,2H),2.84(s,3H),1.63-1.59(m,2H),1.47(t,J＝6.8Hz,3H),1.36-1.31(m,4H),0.91-0.87(m,3H)

LCMS:587([M+Na] ⁺ ).

EXAMPLE 26 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-chloroacetamide-7-butylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝10.57(s,1H),8.64(d,J＝8.4Hz,1H),7.46(d,J＝8.8Hz,1H),7.17-7.10(m,2H),6.85(d,J＝8.4Hz,1H),5.87(dd,J＝4.8,10.0Hz,1H),4.53(dd,J＝9.6,14.4Hz,1H),4.21(s,2H),4.17-4.08(m,2H),3.85(s,3H),3.77(dd,J＝4.8,14.4Hz,1H),3.05-2.98(m,2H),2.85(s,3H),1.65-1.57(m,2H),1.50-1.45(m,2H),1.42-1.35(m,2H),0.94(t,J＝7.2Hz,3H)

LCMS:551([M+H] ⁺ ).

EXAMPLE 27 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4- (gamma-chlorobutyramide) -7-butylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.59(s,1H),8.63(d,J＝8.8Hz,1H),7.43(d,J＝8.8Hz,1H),7.15-7.07(m,2H),6.85(d,J＝8.8Hz,1H),5.86(dd,J＝4.4,10.0Hz,1H),4.53(dd,J＝10.0,14.4Hz,1H),4.12(q,J＝7.2Hz,2H),3.86(s,3H),3.75(dd,J＝4.8,14.4Hz,1H),3.67(t,J＝6.4Hz,2H),3.04-2.96(m,2H),2.85(s,3H),2.66(t,J＝7.2Hz,2H),2.22(quin,J＝6.8Hz,2H),1.63-1.56(m,2H),1.47(t,J＝7.2Hz,3H),1.43-1.34(m,2H),0.93(t,J＝7.2Hz,3H).

LCMS:579([M+H] ⁺ ).

EXAMPLE 28 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-fluoroacetamide-7-pentylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )＝10.34(br d,J＝4.4Hz,1H),8.65(d,J＝8.4Hz,1H),7.46(d,J＝8.8Hz,1H),7.16-7.10(m,2H),6.84(d,J＝8.8Hz,1H),5.86(dd,J＝4.4,10.0Hz,1H),5.04-4.86(m,2H),4.54(dd,J＝10.0,14.4Hz,1H),4.12(q,J＝7.2Hz,2H),3.85(s,3H),3.75(dd,J＝4.4,14.4Hz,1H),3.01(dd,J＝6.8,8.8Hz,2H),2.85(s,3H),1.67-1.59(m,2H),1.47(t,J＝7.2Hz,3H),1.39-1.32(m,4H),0.93-0.87(m,3H).

LCMS:571([M+Na] ⁺ ).

EXAMPLE 29 (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-alkylsulfonylethyl ] -4-propenamide-7-pentylisoindoline-1, 3-dione

¹ H-NMR(400MHz,CDCl ₃ )δ＝9.73(s,1H),8.73(d,J＝8.8Hz,1H),7.45(d,J＝8.8Hz,1H),7.11(qd,J＝2.0,4.4Hz,2H),6.85(d,J＝8.8Hz,1H),6.50-6.43(m,1H),6.36-6.27(m,1H),5.90-5.83(m,2H),4.53(dd,J＝10.4,14.4Hz,1H),4.12(q,J＝6.8Hz,2H),3.85(s,3H),3.76(dd,J＝4.4,14.4Hz,1H),3.03-2.96(m,2H),2.85(s,3H),1.66-1.57(m,2H),1.47(t,J＝7.2Hz,3H),1.38-1.31(m,4H),0.92-0.85(m,3H)

LCMS:543([M+H] ⁺ ).

Example 30:

synthesis of Compound 30-2:

compound 5-5 (200 mg, 0.309 mmol,1.0 eq) was dissolved in DCM (7 mL) and DIEA (158 mg,1.228mmol,3.0 eq) and compound 30-1 (111.77 mg,0.818mmol,2.0 eq) were added and stirred at room temperature for 1 hour. The reaction mixture was quenched with water, extracted with water (10 mL), and the combined organic phases were washed with brine, dried over Na ₂ SO ₄ Drying, filtering, concentrating to obtain crude product, and subjecting to column chromatography (SiO) ₂ Petroleum ether, ethyl acetate 1/0-1:1) to afford compound 30-2 (150 mg, 62.5% yield).

1H-NMR(400MHz,DMSO)δ10.10(s,1H),8.42(d,J＝8.6Hz,1H),7.64(d,J＝8.6Hz,1H),7.12(d,J＝1.8Hz,1H),6.97(dt,J＝16.7,5.1Hz,2H),5.77(dd,J＝10.1,4.6Hz,1H),4.76(s,2H),4.34(dd,J＝14.3,10.2Hz,1H),4.16(dd,J＝14.4,4.7Hz,1H),4.03(d,J＝7.1Hz,2H),3.74(s,3H),3.00(s,3H),2.98–2.89(m,2H),2.24(s,3H),1.66–1.47(m,2H),1.33(d,J＝6.9Hz,3H),1.30–1.22(m,4H),0.85(t,J＝6.8Hz,3H).

Synthesis of example 30:

compound 30-2 (150 mg,0.255mmol,1.0 eq) was dissolved in THF (5 mL) and H ₂ To O (2.5 mL), naOH (2.5 g) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with water (20 mL), ethyl acetate (20 mL. Times.2), and the organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ Drying, filtering, concentrating to obtain crude product, and performing prep-TLC (SiO) ₂ Methylene chloride methanol=10: 1) Purification gave example 30 (43.86 mg, 31.49% yield).

1H NMR(400MHz,DMSO)δ10.66(s,1H),8.65(d,J＝8.6Hz,1H),7.64(d,J＝8.7Hz,1H),7.08(d,J＝1.9Hz,1H),6.98(dt,J＝19.0,5.2Hz,2H),6.32(t,J＝5.6Hz,1H),5.77(dd,J＝10.3,4.4Hz,1H),4.35(dd,J＝14.3,10.5Hz,1H),4.15(dd,J＝14.3,4.5Hz,1H),4.09–3.98(m,4H),3.74(s,3H),3.02(d,J＝5.9Hz,3H),2.99–2.88(m,2H),1.66–1.41(m,2H),1.35–1.23(m,7H),0.85(t,J＝6.9Hz,3H).

LCMS:(M+H) ⁺ :547.

Example 31:

synthesis of Compound 31-2:

compound 31-1 (1.0 g,11.1mmol,1.0 eq) was dissolved in DCM (15 mL) and added at 0deg.C (COCl) ₂ (1.8 g,14.4mmol,1.3 eq) followed by a catalytic amount of DMF (0.1 mL) was stirred at room temperature for 18 hours. The reaction solution was used directly in the next step.

Synthesis of example 31:

compound 5-5 (100 mg,0.20mmol,1.0 eq) was dissolved in DCM (5 mL) and DIEA (400 mg,3.05mmol,5.0 eq) and compound 31-2 (1.0 mL) were added and stirred at room temperature for 2 hours. The reaction mixture was extracted with water (10 mL), ethyl acetate (20 mL. Times.2), and the organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ After drying, filtration and concentration, the crude product was purified by prep-HPLC (formic acid system) to give example 31 (15.28 mg, 10% yield).

¹ H-NMR(400MHz,CDCl ₃ )δ10.47(s,1H),8.70(d,J＝8.4Hz,1H),7.45(d,J＝8.4Hz,1H),7.14-7.12(m,2H),6.85(d,J＝8.4Hz,1H),5.88(q,J＝4.8Hz,1H),4.52-4.47(m,1H),4.13-4.12(m,2H),4.06(d,J＝1.0Hz,2H),3.85(s,3H),3.81(dd,J＝5.2Hz,14.4Hz,1H),3.58(s,3H),2.99(t,J＝8.0Hz,2H),2.82(s,3H),1.48(t,J＝10.2Hz,4H),1.35-1.32(m,5H),1.26(s,1H),0.92-0.87(m,3H).

LCMS:(M+H) ⁺ :561.

Example 32

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Synthesis of Compound 32-1:

compound 5-4 (2 g,4.12mmol,1.0 eq) was dissolved in acetic anhydride (9 mL) and stirred at 110℃for 2 hours. The reaction solution was concentrated to give a residue, which was slurried with methyl tert-butyl ether/ethyl acetate (20 mL/10 mL), and the cake was washed with methyl tert-butyl ether by filtration to give compound 32-1 (1.8 g,3.34mmol, yield 80.99%).

Synthesis of Compound 32-3:

compound 32-2 (8.05 g,69.30mmol,1.0 eq) was dissolved in THF (100 mL) and LiAlD was added at 0deg.C ₄ (3.2 g,41.98mmol,1.1 eq) was gradually warmed to room temperature and stirred for 5 hours. The reaction was quenched with ethyl acetate (4 mL), concentrated, the solid was suspended in ethyl acetate (100 mL) at 0 ℃, cold water (80 mL) was added in small amounts, the pH of the solution was adjusted to 1 with 2M HCl and extracted with ethyl acetate (60 mL x 2). The organic phases were combined and washed with saturated brine, followed by Na ₂ SO ₄ After drying, filtration was carried out, and compound 32-3 (5.13 g,56.89mmol, yield 82.11%) was concentrated.

Synthesis of Compound 32-4:

HBr (14.62 g,40% purity,72.26mmol,1.27 eq) was dissolved in H ₂ SO ₄ (3.64 mL) was added compound 32-3 (5.13 g,56.89mmol,1 eq) and stirred at 120℃for 2 hours. The reaction mixture was quenched with water (500 mL), extracted with 100mL x 3 of ethyl acetate, the organic phases combined and washed with brine, and dried over Na ₂ SO ₄ After drying, filtration and concentration gave compound 32-4 (1.79 g,11.69mmol, 20.56% yield).

Synthesis of Compound 32-5:

will B ₂ Pin ₂ (3.199g,12.64mmol,1.5eq)、CuI(160mg,0.84mmol,0.1eq)、LiO ^t Bu (1.349 g,16.86mmol,2 eq) in tetrahydrofuran (10 mL) was added compound 32-4 (1.29 g,8.42mmol,1 eq) and stirred at room temperature under nitrogen for 16 hours. The reaction solution was filtered, and the crude product was concentrated to obtain compound 32-5 (1.28 g,6.39mmol, yield 75.96%) by purification through column chromatography (silica, hexane: ethyl acetate=100:1 to 50:1).

Synthesis of Compound 32-6:

compound 32-5 (400 mg,1.99mmol,1.0 eq) was dissolved in tolueneAlcohol (5 mL) was added to KHF ₂ (4.5 mL,19.99mmol,4.5M,10 eq) was stirred at room temperature for 16 hours. The reaction solution was concentrated to give a crude product, which was dissolved in hot acetone (10 mL) and filtered, the combined filtrates were concentrated to 4mL, diethyl ether (10 mL) was added, and the precipitated white solid was filtered, and the filter cake was dried to give compound 32-6 (260 mg,1.44mmol, yield 72.36%).

Synthesis of Compound 32-7:

compound 32-6 (260 mg,1.44mmol,1.0 eq) was dissolved in acetonitrile/water (2 mL/1 mL) and trimethoxychlorosilane (268 mg,4.31mmol,3 eq) was added and stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL x 2), the organic phases combined and washed with saturated brine, and dried over Na ₂ SO ₄ After drying, filtration and concentration gave compound 32-7 (30 mg,0.25mmol, 17.66% yield).

Synthesis of example 32:

compound 32-7 (30 mg,0.25mmol,2 eq) was dissolved in dioxane (0.5 mL) and compound 32-1 (68.5 mg,0.127mmol,1 eq) K was added ₂ CO ₃ (52.6 mg, 0.3831 mmol,3 eq) and Pd (dppf) Cl ₂ (4.6 mg, 6.35. Mu. Mol,0.05 eq) was stirred under nitrogen at 100℃for 4 hours. The reaction mixture was extracted with water (10 mL) and ethyl acetate (3 mL. Times.2), and the organic phases were combined, washed with saturated brine, and dried over Na ₂ SO ₄ After drying, filtration and concentration the crude product was purified by prep-HPLC (formic acid system) to give example 32 (24.87 mg,0.047mmol, 36.81% yield).

¹ H NMR(400MHz,CDCl ₃ )δ9.53(s,1H),8.64(d,J＝8Hz,1H),7.42(d,J＝8Hz,1H),7.10(s,2H),6.85(d,J＝8Hz,1H),5.86(m,1H),4.53(m,1H),4.11(q,2H),3.85(s,3H),3.74(m,1H),2.85(s,3H),2.25(s,3H),1.47(t,3H),1.36–1.31(m,4H),1.26(d,J＝4Hz,2H),0.88(t,3H).

LCMS:(M+H) ⁺ :533.3

Example 33:

synthesis of Compound 33-2: compound 33-1 (1 g,5.88mmol, 1)eq) is dissolved in H ₂ SO ₄ (3.75 mL) HNO was added ₃ (1.48 g,23.51mmol,1.06mL,4 eq). The reaction solution was stirred at 100℃for 3 hours. The reaction mixture was slowly poured into ice water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined and washed with saturated brine, and dried over Na ₂ SO ₄ After drying, filtration and concentration, the crude product was purified by column chromatography to give compound 33-2 (970 mg,4.08mmol, yield 69.37%).

LCMS(ESI+):m/z 258.9(M+1+46) ⁺

Synthesis of Compound 33-3: compound 33-2 (970 mg,4.53mmol,1 eq) was dissolved in acetic anhydride (15 mL) and stirred at 120℃for 2 h. The reaction solution was concentrated to give crude compound 33-3 (88 mg,4.53mmol, yield 99.96%) which was used directly in the next step.

Synthesis of Compound 33-4: compound 11a (1.36 g,4.98mmol,1.1 eq) and compound 33-3 (88 mg,4.53mmol,1 eq) were dissolved in AcOH (15 mL) and stirred at 120℃for 16 h. The reaction mixture was concentrated to give a crude product which was purified by column chromatography (petroleum ether: ethyl acetate 10/1 to 4:1) to give compound 33-4 (680 mg,1.51mmol, yield 33.27%).

LCMS(ESI+):m/z 451.5(M+1) ⁺ :

Synthesis of Compound 33-5: compound 33-4 (580 mg,1.28mmol,1 eq) was dissolved in ethyl acetate (5 mL), pd/C (100 mg,7.71mmol, purity 10%) was added under hydrogen atmosphere and stirred under hydrogen (15 psi) at 50℃for 3 hours. The reaction solution was concentrated by filtration to give compound 33-5 (520 mg,1.23mmol, yield 96.03%).

LCMS(ESI+):m/z 451.5(M+1) ⁺

Synthesis of Compound 33-6: compound 33-5 (520 mg,1.23mmol,1 eq) was dissolved in ethyl acetate (10 mL), NBS (219.59 mg,1.23mmol,1 eq) was added, stirred at 25℃for 4 hours, extracted with water (30 mL) and ethyl acetate (3X 30 mL), the organic phases were combined and washed with saturated brine, and the mixture was washed with Na ₂ SO ₄ Drying, filtering, concentrating to obtain crude product, and subjecting to column chromatography (SiO) ₂ Petroleum ether, ethyl acetate 100/0-1:1) to afford compound 33-6 (534 mg,1.07mmol, 86.67% yield).

LCMS(ESI+):m/z 499.6(M+1) ⁺

Synthesis of Compound 33-7: compound 33-6 (534 mg,1.07mmol,1 eq) was dissolved in acetic anhydride (190.33 mg,1.86mmol,174.61uL,1.74 eq), the reaction was stirred at 120℃for 3 hours, and the reaction was concentrated to give crude compound 33-7 (450 mg,831.17umol, yield 77.73%).

Synthesis of Compound 33-8: compound 33-7 (100 mg,184.70 mol,1 eq), cuI (7.04 mg,36.94 mol,0.2 eq), pd (PPh ₃ ) ₂ Cl ₂ (25.93 mg,36.94 mol,0.2 eq), DIEA (71.61 mg,554.11 mol,96.52uL,3 eq) and 1-pentyne (125.81 mg,1.85mmol,181.29uL,10 eq) were dissolved in DMF (4 mL) and the reaction mixture was taken up in N ₂ Stirring at 60deg.C for 16 hr under atmospheric conditions, adding water (5 mL) into the reaction system, extraction with ethyl acetate (5 mL. Times.3), combining the organic phases, washing with saturated brine, and washing with Na ₂ SO ₄ Drying, filtering, concentrating to obtain crude product, and subjecting to column chromatography (SiO) ₂ Petroleum ether was purified with ethyl acetate 1/0-1:1 to give compound 33-8 (75 mg,141.88umol, 76.82% yield).

LCMS(ESI+):m/z 529.4(M+1) ⁺

Synthesis of example 33: compound 33-8 (75 mg,141.88umol,1 eq) was dissolved in EtOAc (5 mL), pd/C (160 mg,141.88umol,10% purity) was added under nitrogen, displaced 3 times with hydrogen under vacuum, and stirred at 50℃for 16 hours under a hydrogen (15 Psi) atmosphere. The reaction was filtered through celite to remove solids, the filter cake was washed with EtOAc, and the filtrate was spin-dried to give crude product which was purified by prep-HPLC (formic acid system) to give example 33 (19 mg,35.67umol, 25.14% yield).

¹ H NMR(400MHz,DMSO-d6)δ0.85(s,3H),1.22-1.36(m,7H),1.44-1.66(m,2H),2.17(s,3H),2.95(t,J＝7.15Hz,2H),3.01(s,3H)3.73(s,3H),4.01(d,J＝6.85Hz,2H),4.08-4.19(m,1H),4.28-4.41(m,1H),5.76(d,J＝5.99Hz,1H),6.89-7.01(m,2H),7.07(s,1H)9.68(s,1H).

LCMS(ESI+):m/z 533.1(M+1) ⁺

Examples 34 to 54

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Examples of biological Activity of Compounds

cLogP value calculation:

compound cLogP is one of the methods for evaluating the lipophilicity of compounds. A high cLogP value indicates that the compound is more lipophilic and tends to penetrate the lipid layer of the human body more passively (by the principle of compound concentration diffusion). Compound CLogP values are shown in the following table:

numbering of compounds	CLog P
		Example 0	1.4606
Example 5	4.9966
		Example 9	4.0756
Example 13	4.6046
		Example 32	4.0756
Example 33	4.0756

Note that: example 0 in this invention represents the control drug apremilast.

Inhibition assay of the pde4d3 enzyme:

materials and instruments:

PDE4D3 TR-FRET assay kit (BPS, cat.60701):
	PDE4D3 recombinases
FAM-Cyclic-3′,5′-AMP
	PDE buffers
Tb donor
	Adhesive agent
Binding buffer A
	Binding buffer B
Black plate(VWR62408-936)
	SpectraMax M4 multimode reader

Measurement conditions:

reagent preparation:

FAM substrate: a20. Mu.M stock of FAM substrate was diluted to 200nM with PDE test buffer. 12.5. Mu.L of diluted substrate was added to each well.

A compound: test compounds were first dissolved in DMSO to a stock solution of 10 mM. mu.L of the compound stock solution was added to 45. Mu.L of DMSO to prepare a 1mM dilution. mu.L of 1mM diluent was then added to 45. Mu.L of PDE test buffer to prepare a gradient dilution start point. Then, the mixture was diluted in a gradient 9 times by adding 5. Mu.L of the above-mentioned solution to 15. Mu.L of PDE test buffer, thereby preparing working solutions of 10 concentrations of the compound. The compound was added to the wells at 2.5. Mu.L/well.

PDE4D3: 0.054. Mu.L PDE4D3 recombinase stock is added to 1500. Mu.L PDE buffer and added to all compound wells and positive control wells at 10. Mu.L/well. To the substrate control wells 10. Mu.L PDE test buffer was added.

Binding liquid: 3750. Mu.L of binding buffer A and 3750. Mu.L of binding buffer B were taken and mixed well. Then 150. Mu.L of adhesive was added and mixed well. 7.5. Mu.L of Tb donor was added and mixed well. Add to all wells at 50 μl/well.

And (3) data processing:

FRET＝(S ₅₂₀ -(Tb ₅₂₀ ×S ₄₉₀ /Tb ₄₉₀ ))×1000/S ₄₉₀

S ₅₂₀ read value of =520 nm sample

S ₄₉₀ Read at 490nm for sample

Tb ₅₂₀ Read value of =Tb only 520nm

Tb ₄₉₀ Read at Tb only 490 nm.

％Inhibition rate＝(FRET _P -FRET _S )/(FRET _P -FRET _Sub )×100％

FRET _S Sample FRET

FRET _P ＝pOSITIVE control FRET

FRET _Sub =substrate control FRET.

Inhibition assay of the pde4a1 enzyme:

materials and instruments:

PDE4A1 kit (BPS, cat.60340)
	PDE4A1 recombinases
FAM-Cyclic-3′,5′-AMP
	PDE buffers
Adhesive agent
	Binding buffer
Adhesive diluent (cAMP)
	Black plate
Envision 2104 multi-tag reader (Perkinelmer)

Measurement conditions:

reagent preparation:

FAM substrate: 25. Mu.L of FAM substrate stock was added to 2500. Mu.L of PDE test buffer. 25. Mu.L of diluted substrate was added to each well.

A compound: test compounds were first dissolved in DMSO to a stock solution of 10 mM. mu.L of the compound stock solution was added to 45. Mu.L of DMSO to prepare a 1mM dilution. mu.L of 1mM diluent was then added to 45. Mu.L of PDE test buffer to prepare a gradient dilution start point. Then, the mixture was diluted in a gradient 9 times by adding 5. Mu.L of the above-mentioned solution to 15. Mu.L of PDE test buffer, thereby preparing working solutions of 10 concentrations of the compound. Added to the compound wells at 5. Mu.L/well.

PDE4A1: PDE4A1 stock was diluted 100-fold to a concentration of 4.9 ng/. Mu.L, then 1.8. Mu.L of the dilution was added to 2200. Mu.L PDE test buffer and added to all compound wells and positive control wells at 20. Mu.L/well. 20. Mu.L PDE test buffer was added to the substrate control wells.

Binding liquid: mu.L of the binding buffer was added to 9.5mL of the adhesive diluent and mixed well. Add to all wells at 100 μl/well.

And (3) data processing:

Inhibition rate＝(FP _P -FP _S )/(FP _P -FP _Sub )×100％

FP _S sample FP

FP _P Positive control FP

FP _Sub =substrate control FP.

Inhibition assay of the pde4b2 enzyme:

materials and instruments:

PDE4B2 kit (BPS, cat.60343)
	PDE4B2 recombinases
FAM-Cyclic-3′,5′-AMP
	PDE buffers
Adhesive agent
	Binding buffer
Adhesive diluent (cAMP)
	Black plate
Envision 2104 multi-tag reader (Perkinelmer)

Measurement conditions:

reagent preparation:

PDE4B2: PDE4B2 stock was diluted 100-fold to a concentration of 5.2 ng/. Mu.L, then 3.2. Mu.L of the dilution was added to 2200. Mu.L PDE test buffer and added to all compound wells and positive control wells at 20. Mu.L/well. 20. Mu.L PDE test buffer was added to the substrate control wells.

Binding liquid: mu.L of adhesive was added to 9.5mL of adhesive diluent and mixed well. Add to all wells at 100 μl/well.

And (3) data processing:

％Inhibition rate＝(FP _P -FP _S )/(FP _P -FP _Sub )×100％

FP _S sample FP

FP _P Positive control FP

FP _Sub =substrate control FP.

Inhibition assay of the pde4c1 enzyme:

materials and instruments:

PDE4C1 kit (BPS, cat.60384)
	PDE4C1 recombinases
FAM-Cyclic-3′,5′-AMP
	PDE buffers
Adhesive agent
	Binding buffer
Adhesive diluent (cAMP)
	Black plate
Envision 2104 multi-tag reader (Perkinelmer)

Measurement conditions:

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reagent preparation:

FAM substrate: 12.5. Mu.L of FAM substrate stock solution was added to 1250. Mu.L of PDE test buffer. 12.5. Mu.L of diluted substrate was added to each well.

PDE4C1: PDE4C1 stock was diluted 100-fold to a concentration of 3.2 ng/. Mu.L, then 13.75. Mu.L of the dilution was added to 1100. Mu.L of LPDE test buffer and added to all compound wells and positive control wells at 10. Mu.L/well. 10 μ LPDE assay buffer was added to the substrate control wells.

Binding liquid: mu.L of adhesive was added to 5mL of adhesive dilution and mixed well. Add to all wells at 50 μl/well.

And (3) data processing:

％Inhibition rate＝(FP _P -FP _S )/(FP _P -FP _Sub )×100％

FP _S sample FP

FP _P Positive control FP

FP _Sub =substrate control FP.

6. Experimental results show that the compounds of the examples of the present invention have an inhibitory effect on PDE4, with representative compounds exemplified as follows:

IC of PDE4D3 ₅₀ Table:

the above biological activity is a+ <5nM; a is 5-10nM; b is 10-50nM; c is 50-200nM; d is greater than 200nM; . The embodiments of the present invention have been described, but the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Note that: example 0 in this invention represents the control drug apremilast.

IC of PDE4A1 ₅₀ Table:

numbering of compounds	PDE4A1(nM)
		Example 0	B
Example 5	A
		Example 9	A
Example 13	B
		Example 32	A
Example 33	A

The above biological activity is A <100nM; b is 100-200nM; . The embodiments of the present invention have been described, but the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Note that: example 0 in this invention represents the control drug apremilast.

IC of PDE4B2 ₅₀ Table:

numbering of compounds	PDE4B2(nM)
		Example 0	B
Example 5	A
		Example 9	A
Example 13	B
		Example 32	A
Example 33	A

The above biological activity is A <100nM; b is 100-200nM; the embodiments of the present invention have been described, but the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Note that: example 0 in this invention represents the control drug apremilast.

IC of PDE4C1 ₅₀ Table:

the above biological activity is A <200nM; b is 200-500nM; . The embodiments of the present invention have been described, but the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

And (3) injection: example 0 in this invention represents the control drug apremilast.

Determination of the Selective inhibition Activity of PDE1, 2, 3, 5, 7, 10 and 11 enzymes

The selective specificity of compounds for PDE4 was evaluated by measuring the concentration of a single compound. Such as PDE1a enzyme, PDE1c enzyme, PDE2a enzyme, PDE3b enzyme, PDE5a1 enzyme, PDE7a enzyme, PDE7b enzyme, PDE10a1 enzyme and PDE11a4 enzyme. The selective inhibition of PDE1C, PDE2A, PDE3B, PDE A1, PDE7A, PDE10A1 enzyme activity by the different compounds at concentrations of 10 μm and 1 μm, respectively, is shown in the following table:

inhibition of PDE1C (%)

Compounds of formula (I)	1μM	10μM
			Example 0	7.77	37.15
Example 5	8.26	30.84
			Example 6	0	17.97
Example 7	6.80	26.47
			Example 9	0.49	30.60
Example 13	5.34	51.72
			Example 24	3.89	34.48
Example 25	3.89	33.75
			Example 27	12.14	67.53
Example 28	1.46	24.77
			Example 29	4.13	25.98

Inhibition of PDE2A (%)

Compounds of formula (I)	1μM	10μM
			Example 0	2.95	2.35
Example 5	0.83	9.01
			Example 6	0	3.41
Example 7	0.08	2.65
			Example 9	5.83	12.18
Example 13	0.08	13.85
			Example 24	0	7.79
Example 25	20.36	13.39
			Example 27	0	8.10
Example 28	0	5.83
			Example 29	7.19	15.82

Inhibition of PDE3B (%)

Compounds of formula (I)	1μM	10μM
			Example 0	2.44	1.56
Example 5	0.06	-0.69
			Example 6	0.94	-0.44
Example 7	1.81	0.06
			Example 9	5.44	0.81
Example 13	3.31	0.94
			Example 24	0	-0.81
Example 25	0	0.19
			Example 27	0	-1.31
Example 28	3.69	6.44
			Example 29	0	-1.94

Inhibition of PDE5A1 (%)

Compounds of formula (I)	1μM	10μM
			Example 0	3.97	2.65
Example 5	0.66	8.39
			Example 6	34.22	34.00
Example 7	0	-2.87
			Example 9	1.99	5.74
Example 13	14.13	20.31
			Example 24	0	11.48
Example 25	0	8.17
			Example 27	0	8.14
Example 28	0	4.16
			Example 29	5.72	12.99

Inhibition of PDE7A (%)

Compounds of formula (I)	1μM	10μM
			Example 0	9.41	11.07
Example 5	0	1.94
			Example 6	0	13.83
Example 7	3.87	15.49
			Example 9	20.75	44.54
Example 13	0	9.96
			Example 24	0	4.15
Example 25	4.98	24.62
			Example 27	2.21	14.66
Example 28	0.55	10.51
			Example 29	17.43	19.92

Inhibition of PDE10A1 (%)

Compounds of formula (I)	1μM	10μM
			Example 0	0	-2.75
Example 5	2.21	5.46
			Example 6	4.84	-16.18
Example 7	0	1.30
			Example 9	0	10.09
Example 13	16.31	-26.73
			Example 24	6.04	11.44
Example 25	3.02	11.10
			Example 27	11.86	1.01
Example 28	29.06	0.04
			Example 29	0	16.13

Note that: example 0 in this invention represents the control drug apremilast.

8. Inhibition assay for inflammatory factors TNF-alpha, IL-2, INF-gamma

Determination of human peripheral blood mononuclear cells LPS/SEB-induced TNF- α, IL-2, INF- γ:

1. after thawing the purchased PBMC frozen cells at 37℃they were transferred to RMPI1640 medium at 37℃with 5% CO ₂ Culturing in an incubator overnight.

2. The next day, according to 2X 10 ⁵ cells/well were plated at 100 μl per well.

3. Test compounds were serially diluted 3-fold. The final drug concentration was 3000,1000,333.33,111.11,37.04,12.35,4.12,1.37,0.46nM.

4. LPS stimulation was added to each well at a final concentration of 10ng/ml.

5. 7℃，5％CO ₂ Culturing in an incubator overnight.

6. On the third day, cell culture supernatants were collected and cytokine determination was performed using MSD method.

Experimental results show that the compound of the embodiment of the invention has the effect of inhibiting inflammatory factors such as TNF-alpha, IL-2, IFN-gamma and the like. Representative compounds are exemplified below:

the compounds of the present invention have significantly improved activity in inhibiting the expression of inflammatory-related factors.

Note that: example 0 in this invention represents the control drug apremilast.

The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. The following compounds or pharmaceutically acceptable salts thereof:

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

3. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 2 or 3 in the manufacture of a medicament for inhibiting PDE4 enzyme.

5. The use according to claim 4, wherein the PDE 4-inhibiting drug is selected from the group consisting of inflammation.

6. The use according to claim 4, wherein the PDE4 inhibiting drug is selected from the group consisting of asthma, inflammation due to reperfusion, chronic or acute obstructive pulmonary disease, enteritis, psoriasis, behcet's disease.

7. The use according to claim 4, wherein the PDE 4-inhibiting drug is selected from chronic or acute pneumonia, crohn's disease or colitis.

8. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 2 or 3 for the manufacture of a medicament for use in the treatment of a disease involving modulation of intracellular cAMP levels.

9. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 2 or 3 in the manufacture of a medicament for inhibiting TNF- α or NF- κb production.