CN113527179A

CN113527179A - Chain hydrocarbon substituted isoindoline-1, 3-diketone PDE4 inhibitor and pharmaceutical application thereof

Info

Publication number: CN113527179A
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: 2021-10-22
Anticipated expiration: 2041-04-12
Also published as: CN113527179B

Abstract

The invention relates to a compound shown in formula I, and racemate, stereoisomer, tautomer, isotopic marker, solvate, polymorph, ester, prodrug or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, a preparation method thereof, and medical application thereof, wherein the structure of the formula I is as follows:

Description

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

the application is filed on 13.4.2020 of China intellectual Property office, and has patent application number 202010287739.0, entitled "inhibitor of chain hydrocarbon substituted isoindoline-1, 3-diketone PDE4 and pharmaceutical use thereof", priority of prior application. The entire disclosure of this application is incorporated by reference into this application.

Technical Field

The invention belongs to the field of pharmaceutical compounds, and particularly relates to a PDE4 inhibitor of a chain hydrocarbon substituted (S) -2- [1- (3-alkoxy-4-alkoxy phenyl) -2-alkyl sulfonyl ethyl ] -4-amide substituent-containing isoindoline-1, 3-diketone compound (I) and a pharmaceutical application thereof.

Background

Cyclic adenosine monophosphate (cAMP) acts as a second messenger with a rather significant impact and role in biological processes. It has been found that the lack or inactivation of cyclic adenosine monophosphate in asthma, obstructive pulmonary disease, inflammation and other diseases contributes to these diseases (Lowe and Cheng, Drugs of the Future, 17 (9): 799-807, 1992), and that the increase in cyclic adenosine monophosphate levels in inflammatory leukocytes inhibits the release of inflammatory mediators including TNF- α and NF- κ B, while the increase in cyclic adenosine levels also leads to the relaxation of airway smooth muscle.

The major biological mechanism of cyclic adenosine inactivation is due to disruption of cyclic adenosine monophosphate (Beavo and Reitsnyder, Trends in pharm., 11: 150-155, 1990) levels by the family of cyclic nucleotide Phosphodiesterases (PDEs). There are 11 families of PDE members known, and inhibition of PDE4(PDE IV) type has a significant effect on cyclic adenosine monophosphate elevation and inflammatory mediator release (Verghes et al, Journal of pharmacy and Experimental Therapeutics, 272(3) stages 1313-1320, 1995). Therefore, selective inhibition of organic compounds of PDE4 has the potential to inhibit airway inflammation, promote airway smooth muscle relaxation, and treat skin inflammation.

Inhibition of the PDE4 enzyme 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 immune stimulators. 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 inducing and exacerbating role in many diseases. When administered to mammals or humans, TNF- α causes or aggravates inflammation, fever, cardiovascular effects, hemorrhage, and acute reactions similar to those seen in acute infections and shock states.

Arthritis, arthritic conditions (e.g. osteoarthritis and rheumatoid arthritis), inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), sepsis, Psoriasis (Psoriasisis), Atopic Dermatitis (AD), contact Dermatitis and Chronic Obstructive Pulmonary Disease (COPD), chronic pneumonia, Acute Respiratory Distress Syndrome (ARDS), Vitiligo (Vitigo), Prurigo (Prurigo Nodularis), Vulvodynia (Vulvodynia), fibrotic diseases, cachexia, autoimmune diseases, rheumatoid Spondylitis (angiosing spondinitis), osteoporosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, Multiple Sclerosis (Multiple Sclerosis, MS), Discoid Lupus Erythematosus (Discoid Lupus erythematosis), systemic Lupus Erythematosus, radiation injury, high alveolar injury (Tracey et al, p. 1987, Natasa. 664, et al.: Hinahw 662 and et al, in 1990, circ. shock, stage 30: page 279-292 (endotoxic shock); millar et al, 1989, Lancet, stage 2: page 712-: page 1400-1405 (adult respiratory distress syndrome); bertolini et al, 1986, Nature, stage 319: 516-; pignet et al, 1990, Nature, stage 344: 245-247, Bissonnette et al, 1989, Inflammation, phase 13: 329 pages 339 and Baughman et al, 1990, j.lab.clin.med., 115: pages 36-42 (chronic pneumonia); elliot et al, 1995, int.j.pharmac., stage 17: page 141-145 (rheumatoid arthritis); von Dullemen et al, 1995, Gastroenterology, stage 109: inflammatory diseases such as 129-135 (Crohn's disease)) are widespread and problematic diseases in which alpha-tumor necrosis factor plays a critical role. Inhibition of alpha-tumor necrosis factor has been shown to effectively block chronic and acute inflammatory responses in animal models of inflammatory disease.

A number of small molecule inhibitors have been found to be able to treat inflammatory diseases involving alpha-tumor necrosis factor (reviewed in Lowe, 1998, Exp. Opin. Ther. patents, stage 8: 1309-1332). This class of molecules is the substituted phenethyl sulfones described in US patents 6020358, US69629, and WO0134606a1, WO0025777, WO2012083153, WO2018157779a1, WO0134604, WO2012083153, WO 20. Apremilast is disclosed in patent US2003187052, chinese patents of the same family CN1652772, CN1965823, CN101683334, CN 03811093.8.

Because the PDE4 enzyme is a protein found in many parts and tissues of the human body, including the central nervous system, it has been found clinically that there are serious side effects of drugs in the prior art of PDE4 inhibitor drugs, including nausea, vomiting, depression and gastrointestinal disorders. The use of topical administration is a practical alternative to avoid the side effects of these drugs, leading to safer and more effective treatment of the disease. Further enhancement of the biological activity of substituted isoindoline-1, 3-dione PDE4 inhibitors and improvement of the physical properties, especially lipophilicity, of the pharmaceutically active compounds may extend the beneficial use of such inhibitors in topical administration.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides a compound shown as formula I, and racemate, stereoisomer, tautomer, isotopic marker, solvate, polymorph, ester, prodrug or pharmaceutically acceptable salt thereof:

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

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

R¹is C1-C3 alkyl or C1-C3 haloalkyl, or is C3-C6 cycloalkyl; r²Is C1-C5 alkyl or C1-C5 haloalkyl, or is C3-C6 cycloalkyl; independently R1 and R2 may form a 5, 6, 7 ring cyclic;

R³is C1-C5 alkyl or C1-C5 haloalkyl, or is C3-C6 cycloalkyl; r⁴Is C1-C12 alkyl or C3-C6 cycloalkyl, wherein the 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, and can be independently C3-C10 hydrocarbyl (including alkyl, alkenyl, alkynyl), C3-C7 cycloalkyl, or H, halogen, cyano, wherein alkyl, alkenyl, alkynyl can be optionally substituted or unsubstituted chain or cyclic groups, and wherein the substituent can be independently selected from halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 alkylthio, etc.; r at independently different positions may form a cyclic group; 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, and can be independently C5-C8 hydrocarbyl (including alkyl, alkenyl, alkynyl), C3-C7 cycloalkyl, or H, halogen, cyano, wherein alkyl, alkenyl, alkynyl can be optionally substituted or unsubstituted chain or cyclic groups, and wherein the substituent can be independently selected from halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 alkylthio, etc.; m is 1, 2, or 3;

R⁴is C1-C5 alkyl or C3-C6 cycloalkyl, wherein the 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 embodiments of the present invention, among the compounds of formula I (including formulae II-III) and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, prodrugs, or pharmaceutically acceptable salts thereof, illustrative, non-limiting specific examples of compounds of formula I are as follows:

the invention also provides a preparation method of the compound shown in the formula I (including the formulas II to III) and racemate, stereoisomer, tautomer, isotopic marker, solvate, polymorph, ester, prodrug or pharmaceutically acceptable salt thereof, but not limited to the methods described below. All starting materials are prepared or purchased directly according to the general rules of the target molecule and by protocols in these routes, methods well known to those of ordinary skill in the art of organic chemistry. The compounds of the invention can be synthesized by combining the methods described below with synthetic methods known in the art of synthetic organic chemistry or variations thereon as recognized 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 combined, or any of one or more of the schemes may be combined to provide a synthetic scheme.

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

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

the raw material substituted benzoate 1 is subjected to para-phenolic group protection to obtain 2, meta-etherification is performed to obtain 3, and para-deprotection is performed to obtain 4. Similar etherification of para-substitution 5 reduces the ester to alcohol 6 and oxidation to intermediate aldehyde 7. Further reaction can successfully obtain mesyl styrene 8, further alkylation can obtain alkyl sulfonyl styrene 9, amination reaction can give product 10, and (S) -1- (3-alkoxy-4-alkoxy phenyl) -2-alkyl sulfonyl ethylamine 11 can be obtained by a benzophenone chiral resolution or separation method.

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

P-alkylation of dihydroxy-substituted benzophenone 24 to obtain 17, further alkylation to produce dialkoxy benzophenone 18, bromination reaction to obtain bromobenzophenone 19, thioetherification to obtain intermediate 20, and synthesis of intermediate 11 by two routes of 21, 22 and 23.

Wherein, R is¹，R²，R³As defined for formula I above, X is selected from halogen.

The corresponding chiral compound can be isolated from its racemic compound by techniques known in the art. Examples include, but are not limited to, the formation of chiral salts, the use of chiral and high performance liquid chromatography "HPLC", and the formation and crystallization of chiral salts. See, e.g., Jacques, j. et al, eneriomers, Racemates and solutions (Wiley-Interscience, new york, 1981); wilen, s.h. et al, Tetrahedron, stage 33: 2725 (1977); eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, New York, 1962) and Wilen, S.H., Tables of solving Agents and Optical solutions, p.268 (E.L.Eliel, Notre Dame university Press, Notre Dame, IN, 1972).

Specific examples chiral amino acid salts of (S) -2- (3-alkoxy-4-alkoxyphenyl) -1- (alkylsulfonyl) -eth-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 invention, the compounds of the invention can be synthesized by selecting the following synthetic route (see WO2018157779a 1):

scheme 1:

nitrifying o-methylbenzoic acid 24 to obtain 25, oxidizing to obtain 26 substituted phthalic acid, acid anhydrizing to obtain 27 halogenated 4-nitrobenzoic anhydride, further reacting with 1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethylamine 11 in acetic acid to obtain 27 halogenated (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-nitroisoindoline-1, 3-dione 28, further reducing nitro to obtain 29 intermediate, acylating to 30, and Suzuki or Sonogashira reacting to obtain 30 long-chain hydrocarbon substituted (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-acylamidoisoindoline Indole-1, 3-dione II.

Wherein, R¹，R²，R³，R⁴M is as defined above for formula I, X is selected from halogen (Cl, Br, I).

Scheme 2:

halo-3-nitrobenzoic anhydride 27 and nitro-reduced intermediate 31, 4-acylated phthalic anhydride 32, further reacted with 1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethylamine 11 in acetic acid to give halogenated (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-amidoisoindoline-1, 3-dione 30, further reacted by Suzuki reaction or Sonogashira reaction to give long-chain hydrocarbon substituted (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-amidoisoindoline-1, 3-diketo II.

Scheme 3:

hydrocarbon 4 nitrobenzoic anhydride 33, further reaction with 1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethylamine 11 in acetic acid to obtain hydrocarbon (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-nitroisoindoline-1, 3-dione 34, reduction of nitro group to obtain intermediate (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-aminoisoindoline-1, 3-dione 35, acylation to obtain (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4 Acylaminoisoindoline-1, 3-dione II.

Wherein, R¹，R²，R³，R⁴M is as defined above for formula I.

Scheme 4:

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

Wherein, R¹，R²，R³，R⁴And m is as defined above for formula II.

Scheme 5:

ammoniation of 4-nitrobenzoic anhydride 27 gives 38, Mitsunobu reaction with alcohol 39 also gives intermediate 28, which is subjected to Suzuki reaction or Sonogashira reaction to give intermediate 34, which is further reduced to give amine 35, which is acylated to give the chain hydrocarbon-substituted (S) -2- [1- (3-alkoxy-4-alkoxyphenyl) -2-alkylsulfonylethyl ] -4-acylamidoisoindoline-1, 3-dione II.

Wherein, R¹，R²，R³，R⁴And m is as defined above for formula II.

Scheme 6:

bromination reaction is carried out on (S) -2- [1- (3-alkoxy-4-alkoxy phenyl) -2-alkyl sulfonyl ethyl ] -4-amino isoindoline-1, 3-diketone 35 to obtain 39, cyanation reaction is carried out to obtain a cyano compound 40, reduction is carried out to obtain a 4-amino methyl substituent group intermediate 41, and acylation reaction is carried out to obtain chain hydrocarbon substituted (S) -2- [1- (3-alkoxy-4-alkoxy phenyl) -2-alkyl sulfonyl ethyl ] -4- (amide methyl) isoindoline-1, 3-diketone.

Wherein, R¹，R²，R³，R⁴M is as defined above for formula I.

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 thereof 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 thereof or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

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

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

The invention further provides the use of a compound of formula I, and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, prodrugs or pharmaceutically acceptable salts thereof, or of said pharmaceutical composition, for the manufacture of a medicament for the treatment of diseases related to the 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 the production of NF- κ B.

According to an embodiment of the invention, the condition that the medicament inhibiting PDE4 ameliorates by inhibiting PDE4 includes, but is not limited to, asthma, inflammation (e.g., due to reperfusion), chronic or acute obstructive pulmonary disease, chronic or acute pneumonia, viral-induced lung disease such as Covid-19, inflammatory bowel disease, crohn's disease, psoriasis, psoriatic arthritis, Bechet's disease, or colitis.

In particular methods 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 form. Dosage forms include, but are not limited to: tablets, caplets, capsules, such as soft elastic gelatin capsules, cachets, lozenges (troches), dispersions, suppositories, ointments, pastes (cataplasms), plasters, 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 patients, including suspensions (e.g., aqueous or non-aqueous suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs, liquid dosage forms suitable for parenteral administration to patients, and sterile solid dosage forms (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to patients. It will be apparent to those skilled in the art that the specific dosage forms encompassed by the present invention vary in various respects. See, for example, Remington's pharmaceutical Sciences, 18 th edition, Mack publishing, Easton PA (1990).

Interpretation of terms:

unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination should fall within the scope of the present specification.

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 with a substituent described herein covers the absence of substitution as well as substitution with one or more substituents, e.g., "optionally substituted with one, two or more R" means that it may be unsubstituted (unsubstituted) or substituted with one, two or more R.

The term "hydrocarbon group" includes a saturated or unsaturated, straight-chain or branched chain or cyclic hydrocarbon group, the type of the hydrocarbon group may be selected from alkyl, alkenyl, alkynyl and the like, the number of carbon atoms of the hydrocarbon group (alkyl, alkenyl, alkynyl) is preferably 1to 12, and a further preferred range is 1to 8, 1to 5, 1to 3 and the like, and specifically may include but is not limited to the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 1-ethylethenyl, 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; hydrocarbyl (including alkyl, alkenyl, alkynyl) moieties in other terms also conform to this definition.

The term "cycloalkyl" includes "C_3-12Cycloalkyl "is understood to mean a saturated or unsaturated monovalent monocyclic or bicyclic ring having 3 to 12 carbon atoms, preferably C_3-8Cycloalkyl, more preferably C_3-6A cycloalkyl group. E.g. C_3-8Cycloalkyl is understood to mean a saturated or unsaturated monovalent monocyclic or bicyclic ring having 3, 4, 5, 6, 7 or 8 carbon atoms. Said C is_3-12Cycloalkyl groups may be monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic, such as tetralin or decalin.

The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of the present invention sufficient to effect 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 application (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 and the mode of administration, etc., 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 dosage regimen to be followed, whether to administer it in combination with other compounds, the timing of administration, the tissue to be administered and the physical delivery system carried.

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

The term "prodrug", or "prodrug" refers to a compound that is converted in vivo to a compound of the general formula or a particular compound. Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrugs of the present invention may be esters, and esters useful as prodrugs in the present invention are esters of benzene, aliphatic, acyloxymethyl, carbonate, carbamate and amino acids. For example, a compound of the present invention comprises a hydroxy/carboxy group, i.e., it may be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent.

Advantageous effects

The compounds of the present invention can inhibit the reaction of PDE4 enzyme, increase cAMP level or inhibit factors such as TNF-alpha, thereby effectively treating Psoriasis (Psoriasisis), psoriatic arthritis, scalp Psoriasis, Bechet's disease, Atopic Dermatitis (Atomic Dermatitis, AD), Vitiligo (Vitilo), seborrheic Dermatitis, obstructive pulmonary disease (COPD), acute pneumonia (ARDS), pulmonary diseases caused by Covid-19 and respiratory inflammatory diseases. The compound of the invention has outstanding inhibitory activity of the biological enzyme PDE4, and the physical, mechanical and in vivo metabolic properties of the compound are more suitable for the special preparation forms of topical administration such as external application and inhalant.

Detailed Description

The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

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

Synthesis of Compounds 1-2: compound 1-1(5g,23.25mmol,1eq) was added portionwise to 0 ℃ fuming nitric acid (1.47g,23.25mmol,16mL,1eq), which after addition was stirred for a further 1h at 0 ℃ to form a yellow suspension. The mixture was poured into ice water (100mL) with stirring, the suspension filtered, the filter cake washed with water (30mL), the filter cake dissolved in ethyl glycolate (100mL) over Na₂SO₄Drying and vacuum concentrating. Compound 1-2 was obtained as a yellow solid (5.3g, crude).

Synthesis of Compounds 1-3: dissolve Compound 1-2(5.3g,6.73mmol,1eq) in H₂To O (60mL), NaOH was added(2.42g,60.53mmol,9eq), warmed to 80 ℃ and KMnO added portionwise over 3 hours₄(25.51g,161.42mmol,24eq) after addition, stirring for a further 30min, suction filtration, washing the solid with hot water (30mL × 3), cooling the aqueous phase with ice water, adjusting the pH to 2 with 2M HCl, extraction with ethyl acetate (100mL × 2), combining the organic phases, washing with saturated brine, washing with Na₂SO₄After drying, filtration and concentration gave compound 1-3(1.9g, crude) as a yellow solid.

Synthesis of Compounds 1-4: dissolve compound 1-3(1.9g,3.93mmol,1eq) in Ac₂O (21.80g,213.54mmol,20mL,54.33eq), stirred at 140 ℃ for 16 h and concentrated to give compound 1-4 as a light brown solid (1.6g, crude).

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

Synthesis of Compounds 1-6: compound 1-5(1.2g,1.50mmol,1eq), PdCl₂(PPh₃)₂(210.83mg, 300.37. mu. mol,0.2eq), CuI (57.21mg, 300.37. mu. mol,0.2eq), DIEA (582.31mg,4.51mmol, 784.78. mu.L, 3eq) and 1-hexyne (370.11mg,4.51mmol, 506.99. mu.L, 3eq) were dissolved in DMF (12mL) and the reaction solution was N (N-N), and₂stirring at 60 deg.C for 18 hr under the atmosphere, adding water (15mL) and ethyl acetate (20mL), extracting with ethyl acetate (30 mL. times.3), mixing organic phases, washing with saturated brine, and purifying with Na₂SO₄Drying, filtering, concentrating to obtain crude product, and performing column chromatography (SiO)₂PE: EtOAc ═ 10:1to 1:1) purification afforded compounds 1-6(376mg, 47.36% yield) as yellow solids.

Of Compounds 1to 6¹H-NMR(400MHz,CDCl₃)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(370.00mg, 700.00. mu. mol,1eq) were dissolved in methanol (10mL), Pd/C (100mg, 10% purity) was added under nitrogen atmosphere, replaced 3 times with hydrogen under vacuum, and stirred at 60 ℃ for 16 hours under hydrogen (50Psi) 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 afford compounds 1-7(128mg, 36.38% yield) and compounds 1-7A (25mg, 7.13% yield).

Of compounds 1to 7¹H-NMR(400MHz,CDCl₃)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).

Of Compounds 1-7A¹H-NMR(400MHz,CDCl₃)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 1to 7(40mg, 79.58. mu. mol,1eq) and chlorobutyryl chloride (11.22mg, 79.58. mu. mol, 8.91. mu.L, 1eq) were dissolved in DCE (2mL) and DIEA (10.29mg, 79.58. mu. mol, 13.86. mu.L, 1eq) was added to the reaction mixture, which was stirred at 50 ℃ for 3 hours. The reaction was spun dry and purified by prep-HPLC (formic acid system) to give example 1(14.04mg, 29.06% yield) as a white solid.

¹H-NMR(400MHz,CDCl₃)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-chlorobutanamido) -5-hexen (-1) ylisoindoline-1, 3-dione

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

¹H-NMR(400MHz,CDCl₃)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-cyclopropylamino-5-octylisoindoline-1, 3-dione

Synthesis of Compound 3-2: the compound 3-15-bromo-2-methyl-3-nitrobenzoic acid (20g,76.91mmol,1eq.) was dissolved in H₂O (20mL), NaOH (9.23g,230.73mmol,3eq) was added, the temperature was raised to 80 ℃ and KMnO was added in portions over 3 hours₄(97.24g,615.29mmol,8eq.) after addition, stirring was continued at 80 ℃ for 30min, suction filtration was performed and the filter cake was washed with hot water (300mL × 3). The aqueous phase was cooled with ice water, the pH adjusted to 1 with 2M HCl, extracted with EtOAc (400mL × 3), the organic phases combined and washed with saturated brine, over Na₂SO₄Drying, filtering, and concentrating to obtain yellow solidCompound 3-2(5g, 22.42% yield).

¹H-NMR(400MHz，DMSO-d₆)δ＝13.98(br s,2H),8.52(d,J＝2.0Hz,1H),8.33(d,J＝2.0Hz,1H).

Synthesis of Compounds 3-3: dissolve compound 3-2(5g,17.24mmol,1eq.) in Ac₂O (20mL), and stirred at 140 ℃ for 16 hours. The reaction solution was spin-dried to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate 100/0to 1/1) to obtain 3-3(4.5g, crude product) as a yellow solid.

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

¹H-NMR(400MHz，CDCl₃)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(400.00mg, 758.52. mu. mol,1eq), PdCl₂(PPh₃)₂(106.48mg, 151.70. mu. mol,0.2eq), CuI (28.89mg, 151.70. mu. mol,0.2eq), DIEA (294.09mg,2.28mmol, 396.35. mu.L, 3eq) and 1-octyne (417.93mg,3.79mmol,5eq) were dissolved in DMF (4mL) and the reaction solution was stirred in N₂Stirring at 60 deg.C for 16 hr, extracting with water (10mL) and ethyl acetate (10mL x 3), mixing organic phases, washing with saturated brine, and adding Na₂SO₄Drying, filtering, concentrating to obtain crude product, and performing column chromatography (SiO)₂Petroleum ether and ethyl acetate 100: 1-1: 1) to obtain yellow solid compound 3-5(130mg, yield 30.79%).

¹H-NMR(400MHz CDCl₃)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(130mg, 233.55. mu. mol,1eq) was dissolved in EtOAc (15mL), Pd/C (140mg, 10%) was added under nitrogen atmosphere, replaced 3 times with hydrogen under vacuum, and stirred at 60 ℃ for 16 hours under hydrogen (50Psi) 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 compound 3-6 as a yellow solid (100mg, 80.68% yield).

¹H-NMR(400MHz CDCl₃)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(10mg, 18.84. mu. mol,1eq.) and propionyl chloride (9.85mg, 94.22. mu. mol, 8.56. mu.L, 5eq.) were dissolved in DCE (1mL) and DIEA (19.48mg, 150.75. mu. mol, 26.26. mu.L, 8eq.) was added to the reaction and stirred at 90 ℃ for 2 hours. The reaction was spun dry and purified by prep-HPLC (formic acid system) to give example 3(8.2mg, 72.68% yield) as a white solid.

¹H-NMR(400MHz，CDCl₃)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 synthetic route 6.

LCMS:545.1([M+H]⁺).

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

Synthesis of Compound 5-2: compound 5-1(21.19g,109.75mmol,1eq) and compound 11a (30g,109.75mmol,1eq) were dissolved in HOAc (500mL) and stirred at 120 ℃ for 16 h. And (3) carrying out spin drying on the reaction liquid to obtain a crude product, and purifying the crude product by using column chromatography (petroleum ether: ethyl acetate 100/0-1: 1) to obtain a yellow solid compound 5-2(43.3g, yield 89.98%).

¹H-NMR(400MHz,CDCl₃)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 Compounds 5-3: compound 5-2(50.00g,111.15mmol,1eq) was dissolved in EtOAc (400mL), Pd/C (9g, 10%) was added under nitrogen atmosphere, replaced 3 times with hydrogen under vacuum, and stirred at 60 ℃ for 12 hours under hydrogen (50Psi) 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 compound 5-3 as a yellow solid (4g, 85.73% yield).

¹H-NMR(400MHz,CDCl₃)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: dissolving the compound 5-3(47.4g,113.27mmol,1eq) in ethyl acetate (500mL), adding NBS (20.16g,113.27mmol,1eq), stirring at 25 ℃ for 16 hours, and spin-drying the reaction liquid to obtain a crude product, and purifying by column chromatography (petroleum ether: ethyl acetate 100/0-1: 1) to obtain a yellow solid compound 5-4(26.52g, yield 42.07%).

¹H-NMR(400MHz,CDCl₃)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(13.98g,28.11mmol,1eq), Cs₂CO₃(27.47g,84.33mmol,3eq), pentylboronic acid (6.52g,56.22mmol,2eq) was dissolved in dioxane (150mL) and water (30mL) in N₂Adding Pd (dppf) Cl under an atmosphere₂(4.11g,5.62mmol,0.2eq), stirring at 60 ℃ under nitrogen for 18 hours, concentrating the reaction mixture, adding water (50mL) and ethyl acetate (50mL), extracting with ethyl acetate (50 mL. times.3), combining the organic phases, washing with saturated brine, and purifying with Na₂SO₄Drying, filtering, concentrating to obtain crude product, and performing column chromatography (SiO)₂And petroleum ether ethyl acetate 100/0-1: 1) to obtain 5-5(4.78g, yield 34.80%) as a yellow solid.

¹H-NMR(400MHz,CDCl₃)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(4.04g,8.27mmol,1eq) and chlorobutyryl chloride (2.33g,16.54mmol,1.85mL,2eq) were dissolved in DCE (80mL), DIEA (4.27g,33.07mmol,5.76mL,4eq) was added, and the mixture was stirred at 90 ℃ for 3 hours. The reaction solution was spin dried and saturated NaHCO was added₃(20mL) aqueous solution, DCM (20mL), dichloromethane (3X 20mL), combined organic phases and washed with saturated brine, Na₂SO₄Drying, filtering, concentrating to obtain crude product, and performing column chromatography (SiO)₂Ethyl acetate 1/0-1: 1, petroleum ether to give example 5(4.12g, 96.7% ee, 8% yield) as a yellow solid4.01％)。

¹H-NMR(400MHz,CDCl₃)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(200mg, 402.12. mu. mol,1eq), PdCl₂(PPh₃)₂(56.45mg, 80.42. mu. mol,0.2eq), CuI (15.32mg, 80.42. mu. mol,0.2eq), DIEA (155.91mg,1.21mmol, 210.12. mu.L, 3eq) and 1-pentyne (273.91mg,4.02mmol, 394.69. mu.L, 10eq) were dissolved in DMF (2mL) and the reaction solution was N₂Stirring at 60 deg.C for 16 hr, extracting with water (5mL) and ethyl acetate (5mL x 3), mixing organic phases, washing with saturated brine, and adding Na₂SO₄Drying, filtering, concentrating to obtain crude product, and performing column chromatography (SiO)₂Petroleum ether and ethyl acetate 1/0-1: 1) to obtain a yellow solid compound 6-2(S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl]-4-amino-6- [ pent-1-ynyl]Isoindoline-1, 3-dione (98mg, yield 50.29%).

¹H-NMR(400MHz CDCl₃)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 Compounds 6-3:

compound 6-2(98mg, 202.24. mu. mol,1eq) was dissolved in EtOAc (10mL), Pd/C (100mg, 10%) was added under nitrogen atmosphere, replaced 3 times with hydrogen under vacuum, and stirred at 60 ℃ for 16 hours under hydrogen (50Psi) 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 compound 6-3 as a yellow solid (60mg, 60.72% yield).

¹H-NMR(400MHz CDCl₃)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(12.5mg, 25.58. mu. mol,1eq.) and cyclopropylchloride (13.37mg, 127.92. mu. mol, 11.63. mu.L, 5eq) were dissolved in DCE (1mL) and DIEA (26.45mg, 204.67. mu. mol, 35.65. mu.L, 8eq) was added and stirred at 90 ℃ for 2 hours. The reaction was spun dry and purified by prep-HPLC (formic acid system) to give example 6(5mg, 35.11% yield) as a white solid.

¹H-NMR(400MHz，CDCl₃)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) yl isoindoline-1, 3-dione

Synthesis of example 7:

dissolve Compound 6-2(180mg, 371.47. mu. mol,1.0eq.) in Ac₂In O (1mL), the reaction was stirred for 3 h, spun dry and purified by prep-HPLC (formic acid system) to afford example 7 as a white solid (119mg, 60.8% yield).

¹H-NMR(400MHz DMSO-δ₆)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-decanamide-7-pentene (-1) -yl isoindoline-1, 3-dione

Synthesis via synthetic route 3

¹H-NMR(400MHz，CDCl₃)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 via synthetic route 3

¹H-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-butanamide-7-pentylisoindoline-1, 3-dione

Synthesis via synthetic route 3

¹H-NMR(400MHz,CDCl₃)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

¹H-NMR(400MHz,CDCl₃)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

¹H-NMR(400MHz,CDCl₃)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

¹H-NMR(400MHz,CDCl₃)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

¹H-NMR(400MHz,CDCl₃)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

¹H-NMR(400MHz,CDCl₃)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-butanamide-7-nonylisoindoline-1, 3-dione

¹H-NMR(400MHz,CDCl₃)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

¹H-NMR(400MHz,CDCl₃)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

¹H-NMR(400MHz,CDCl₃)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

¹H-NMR(400MHz,CDCl₃)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. -chlorobutanamide) -7-hexylisoindoline-1, 3-dione

¹H-NMR(400MHz,CDCl₃)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. -chlorobutanamide) -7-heptylisoindoline-1, 3-dione

¹H-NMR(400MHz,CDCl₃)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-chlorobutanamide) -7-octylisoindoline-1, 3-dione

¹H-NMR(400MHz,CDCl₃)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

¹H-NMR(400MHz,CDCl₃)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-chlorobutanamide) -7-pentylisoindoline-1, 3-dione

¹H-NMR(400MHz,CDCl₃)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

¹H-NMR(400MHz,CDCl₃)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

¹H-NMR(400MHz,CDCl₃)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. -chlorobutanamide) -7-butylisoindoline-1, 3-dione

¹H-NMR(400MHz,CDCl₃)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

¹H-NMR(400MHz,CDCl₃)＝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

¹H-NMR(400MHz,CDCl₃)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(200mg,0.409mmol,1.0eq) was dissolved in DCM (7mL) and DIEA (158mg,1.228mmol,3.0eq) and compound 30-1(111.77mg,0.818mmol,2.0eq) were added and stirred at room temperature for 1 hour. The reaction was quenched with water, water (10mL) was added, extraction was performed with ethyl acetate (20 x 2mL), the organic phases were combined, washed with saturated brine, and washed with Na₂SO₄Drying, filtering, concentrating to obtain crude product, and performing column chromatography (SiO)₂And petroleum ether ethyl acetate 1/0-1: 1) to obtain compound 30-2(150mg, yield 62.5%).

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(150mg,0.255mmol,1.0eq) was dissolved in THF (5mL) and H₂To O (2.5mL) was added NaOH (2.5g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with water (20mL) and ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated brine, and washed with Na₂SO₄Drying, filtering, concentrating to obtain crude product, and performing prep-TLC (SiO)₂Dichloromethane methanol 10: 1) purification yielded example 30(43.86mg, yield 31.49%).

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(1.0g,11.1mmol,1.0eq) was dissolved in DCM (15mL) and added (COCl) at 0 deg.C₂(1.8g,14.4mmol,1.3eq), followed by addition of a catalytic amount of DMF (0.1mL) and stirring at room temperature for 18 h. The reaction solution was used directly in the next step.

Synthesis of example 31:

compound 5-5(100mg,0.20mmol,1.0eq) was dissolved in DCM (5mL) and DIEA (400mg,3.05mmol,5.0eq) and compound 31-2(1.0mL) were added and stirred at room temperature for 2 hours. Water (10mL) and ethyl acetate were added to the reaction mixtureThe ester (20 mL. times.2) was extracted, the organic phases combined and washed with saturated brine, over Na₂SO₄After drying, filtration and concentration the crude product was purified by prep-HPLC (formic acid system) to give example 31(15.28mg, 10% yield).

¹H-NMR(400MHz,CDCl₃)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

Synthesis of Compound 32-1:

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

Synthesis of Compound 32-3:

compound 32-2(8.05g,69.30mmol,1.0eq) was dissolved in THF (100mL) and LiAlD was added at 0 deg.C₄(3.2g,41.98mmol,1.1eq), the mixture was gradually warmed to room temperature and stirred for 5 hours. The reaction was quenched with ethyl acetate (4mL), concentrated, the solid suspended in ethyl acetate (100mL) at 0 ℃, cold water (80mL) was added in small amounts, the pH of the solution was adjusted to 1 with 2M HCl, and extracted with ethyl acetate (60mL × 2). The combined organic phases were washed with brine and Na₂SO₄After drying and filtration, Compound 32-3(5.13g,56.89mmol, 82.11% yield) was concentrated.

Synthesis of Compound 32-4:

HBr (14.62g, 40% purity,72.26mmol,1.27eq) was dissolved in H₂SO₄(3.64mL) plusThe compound (32-3) (5.13g,56.89mmol,1eq) was added and stirred at 120 ℃ for 2 hours. The reaction solution was quenched with water (500mL), extracted with ethyl acetate 100mL x 3), the organic phases were combined and washed with saturated brine, washed with Na₂SO₄After drying, filtration and concentration gave compound 32-4(1.79g,11.69mmol, 20.56% yield).

Synthesis of Compounds 32-5:

b is to be₂Pin₂(3.199g,12.64mmol,1.5eq)、CuI(160mg,0.84mmol,0.1eq)、LiO^tBu (1.349g,16.86mmol,2eq) was dissolved in tetrahydrofuran (10mL) and compound 32-4(1.29g,8.42mmol,1eq) was added under nitrogen and stirred at room temperature for 16 h. The reaction was filtered and concentrated to give a crude product which was purified by column chromatography (silica, hexane: ethyl acetate: 100: 1-50: 1) to give compound 32-5(1.28g,6.39mmol, 75.96% yield).

Synthesis of Compounds 32-6:

dissolve compound 32-5(400mg,1.99mmol,1.0eq) in methanol (5mL) and add KHF₂(4.5mL,19.99mmol,4.5M,10eq), stir at room temperature for 16 h. The reaction was concentrated to give crude product which was dissolved in hot acetone (10mL) and filtered, the combined filtrates were concentrated to 4mL, ether (10mL) was added and the white solid precipitated was filtered and the filter cake was dried to give compound 32-6(260mg,1.44mmol, 72.36% yield).

Synthesis of Compounds 32-7:

compound 32-6(260mg,1.44mmol,1.0eq) was dissolved in acetonitrile/water (2mL/1mL) and trimethoxychlorosilane (468mg,4.31mmol,3eq) was added and stirred at room temperature for 16 hours. The reaction solution was diluted with saturated sodium bicarbonate solution (10mL), extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with saturated brine, and washed with Na₂SO₄After drying, filtration and concentration gave compound 32-7(30mg,0.25mmol, 17.66% yield).

Synthesis of example 32:

dissolving compound 32-7(30mg,0.25mmol,2eq) in dioxane (0.5mL) and adding compound 32-1(68.5mg,0.127mmol,1eq), K₂CO₃(52.6mg,0.381mmol,3 eq.) and Pd (dppf) Cl₂(4.6mg, 6.35. mu. mol,0.05 eq.) was stirred at 100 ℃ for 4 hours under a nitrogen atmosphere. Water (10mL) and ethyl acetate were added to the reaction mixtureThe ester (3mL x 2) was extracted, the organic phases were combined and washed with saturated brine, over Na₂SO₄After drying, filtration and concentration the crude product was purified by prep-HPLC (formic acid system) to give example 32(24.87mg,0.047mmol, 36.81% yield).

¹H NMR(400MHz,CDCl₃)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: dissolve compound 33-1(1g,5.88mmol,1eq) in H₂SO₄(3.75mL) HNO was added₃(1.48g,23.51mmol,1.06mL,4 eq). The reaction solution was stirred at 100 ℃ for 3 hours. Slowly adding the reaction solution into ice water (50mL), extracting with ethyl acetate (50mL x 3), mixing the organic phases, washing with saturated brine, and adding Na₂SO₄After drying, filtration and concentration, the crude product was purified by column chromatography to give compound 33-2(970mg,4.08mmol, 69.37% yield).

LCMS(ESI+):m/z 258.9(M+1+46)⁺

Synthesis of Compound 33-3: compound 33-2(970mg,4.53mmol,1eq) was dissolved in acetic anhydride (15mL) and stirred at 120 ℃ for 2 hours. The reaction was concentrated to give crude compound 33-3(888mg,4.53mmol, 99.96% yield) which was used directly in the next step.

Synthesis of Compound 33-4: compound 11a (1.36g,4.98mmol,1.1eq) and compound 33-3(888mg,4.53mmol,1eq) were dissolved in AcOH (15mL) and stirred at 120 ℃ for 16 h. The reaction solution was concentrated to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate 10/1-4: 1) to give compound 33-4(680mg,1.51mmol, 33.27% yield).

LCMS(ESI+):m/z 451.5(M+1)⁺:

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

LCMS(ESI+):m/z 451.5(M+1)⁺

Synthesis of Compounds 33-6: dissolving compound 33-5(520mg,1.23mmol,1eq) in ethyl acetate (10mL), adding NBS (219.59mg,1.23mmol,1eq), stirring at 25 deg.C for 4 hours, adding water (30mL) and ethyl acetate (3X 30mL) for extraction, combining the organic phases, washing with saturated brine, and washing with Na₂SO₄Drying, filtering, concentrating to obtain crude product, and performing column chromatography (SiO)₂Ethyl acetate 100/0-1: 1) to give compound 33-6(534mg,1.07mmol, 86.67% yield).

LCMS(ESI+):m/z 499.6(M+1)⁺

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

Synthesis of Compounds 33-8: compounds 33-7(100mg,184.70umol,1eq), CuI (7.04mg,36.94umol,0.2eq), Pd (PPh)₃)₂Cl₂(25.93mg,36.94umol,0.2eq), DIEA (71.61mg,554.11umol,96.52uL,3eq) and 1-pentyne (125.81mg,1.85mmol,181.29uL,10eq) were dissolved in DMF (4mL) and the reaction solution was stirred in N₂Stirring at 60 deg.C for 16 hr, extracting with water (5mL) and ethyl acetate (5mL x 3), mixing organic phases, washing with saturated brine, and adding Na₂SO₄Drying, filtering, concentrating to obtain crude product, and performing column chromatography (SiO)₂And petroleum ether ethyl acetate 1/0-1: 1) to obtain a compound 33-8(75mg,141.88umol, 76.82% yield).

LCMS(ESI+):m/z 529.4(M+1)⁺

Synthesis of example 33: compound 33-8(75mg,141.88umol,1eq) was dissolved in EtOAc (5mL), Pd/C (160mg,141.88umol, 10% purity) was added under nitrogen atmosphere, replaced 3 times with hydrogen under vacuum, and stirred at 50 ℃ for 16 hours under hydrogen (15Psi) 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 the crude product which was purified by prep-HPLC (formic acid system) to afford example 33(19mg,35.67umol, 25.14% yield).

¹H 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

Examples of the biological Activity of the Compounds

cLogP value calculation:

compound cLogP is one of the methods to assess the lipophilicity of a compound. A high cLogP value indicates that the compound is more lipophilic and tends to be more passively (by diffusion of the concentration of the compound) permeable to the lipid layers of the human body. Compound CLogP values are given in the table below:

compound numbering	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: all of the examples 0 referred to in the present invention represent the control drug apremilast.

Inhibition assay of the PDE4D3 enzyme:

materials and instruments:

PDE4D3 TR-FRET assay kit (BPS, cat.60701):
	PDE4D3 recombinase
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

The measurement conditions were as follows:

preparation of reagents:

FAM substrate: stock solutions of 20 μ M FAM substrate were diluted to 200nM with PDE assay buffer. Each reaction well was charged with 12.5. mu.L of diluted substrate.

A compound: test compounds were first dissolved in DMSO to 10mM stock. mu.L of compound stock was added to 45. mu.L of DMSO to make a 1mM dilution. Then 5. mu.L of 1mM dilution was added to 45. mu.L of PDE assay buffer to prepare a gradient dilution initiation point. Then, 5. mu.L of the solution of the previous concentration was added to 15. mu.L of PDE assay buffer, and the solution was diluted 9 times in a gradient to prepare 10 concentrations of compound working solutions. Add to the well of the compound at 2.5. mu.L/well.

PDE4D 3: mu.L of PDE4D3 recombinase stock was added to 1500. mu.L PDE buffer and added to all compound wells and positive control wells at 10. mu.L/well. 10 μ L of PDE assay buffer was added to the substrate control wells.

Binding liquid: take 3750. mu.L of binding buffer A and 3750. mu.L of binding buffer B, mix well. Then 150. mu.L of binder was added and mixed well. Then 7.5. mu.L of Tb donor was added and mixed well. Add to all wells at 50. mu.L/well.

Data processing:

FRET＝(S₅₂₀-(Tb₅₂₀×S₄₉₀/Tb₄₉₀))×1000/S₄₉₀

S₅₂₀520nm reading for sample

S₄₉₀490nm reading for sample

Tb₅₂₀Tb only 520nm reading

Tb₄₉₀Tb only 490nm reading.

％Inhibition rate＝(FRET_P-FRET_S)/(FRET_P-FRET_Sub)×100％

FRET_SSample FRET

FRET_PPositive control FRET

FRET_SubSubstrate control FRET.

Inhibition assay of the PDE4a1 enzyme:

materials and instruments:

PDE4A1 kit (BPS, Cat.60340)
	PDE4A1 recombinase
FAM-Cyclic-3′,5′-AMP
	PDE buffers
Adhesive agent
	Binding buffer
Binder diluent (cAMP)
	Black plate
Envision 2104 Multi-tag reader (PerkinElmer)

The measurement conditions were as follows:

preparation of reagents:

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

A compound: test compounds were first dissolved in DMSO to 10mM stock. mu.L of compound stock was added to 45. mu.L of DMSO to make a 1mM dilution. Then 5. mu.L of 1mM dilution was added to 45. mu.L of PDE assay buffer to prepare a gradient dilution initiation point. Then, 5. mu.L of the solution of the previous concentration was added to 15. mu.L of PDE assay buffer, and the solution was diluted 9 times in a gradient to prepare 10 concentrations of compound working solutions. Add to the wells of the compound at 5. mu.L/well.

PDE4a 1: PDE4A1 stock was first diluted 100-fold to a concentration of 4.9 ng/. mu.L, and then 1.8. mu.L of the dilution was added to 2200. mu.L of PDE test buffer and added to all compound wells and positive control wells at 20. mu.L/well. Substrate control wells were loaded with 20. mu.L of PDE assay buffer.

Binding liquid: add 95. mu.L of binding buffer to 9.5mL of binder diluent and mix well. Add to all wells at 100. mu.L/well.

Data processing:

Inhibition rate＝(FP_P-FP_S)/(FP_P-FP_Sub)×100％

FP_Ssample FP

FP_PPositive control FP

FP_SubSubstrate control FP.

Inhibition assay of the PDE4B2 enzyme:

materials and instruments:

PDE4B2 kit (BPS, Cat.60343)
	PDE4B2 recombinase
FAM-Cyclic-3′,5′-AMP
	PDE buffers
Adhesive agent
	Binding buffer
Binder diluent (cAMP)
	Black plate
Envision 2104 Multi-tag reader (PerkinElmer)

The measurement conditions were as follows:

preparation of reagents:

PDE4B 2: PDE4B2 stock was first diluted 100-fold to a concentration of 5.2 ng/. mu.L, and then 3.2. mu.L of the dilution was added to 2200. mu.L of PDE test buffer and added to all compound wells and positive control wells at 20. mu.L/well. Substrate control wells were loaded with 20. mu.L of PDE assay buffer.

Binding liquid: add 95. mu.L of binder to 9.5mL of binder diluent and mix well. Add to all wells at 100. mu.L/well.

Data processing:

％Inhibition rate＝(FP_P-FP_S)/(FP_P-FP_Sub)×100％

FP_Ssample FP

FP_PPositive control FP

FP_SubSubstrate control FP.

Inhibition assay of the PDE4C1 enzyme:

materials and instruments:

PDE4C1 kit (BPS, Cat.60384)
	PDE4C1 recombinase
FAM-Cyclic-3′,5′-AMP
	PDE buffers
Adhesive agent
	Binding buffer
Binder diluent (cAMP)
	Black plate
Envision 2104 Multi-tag reader (PerkinElmer)

The measurement conditions were as follows:

preparation of reagents:

FAM substrate: mu.L of FAM substrate stock was added to 1250. mu.L of PDE test buffer. Each reaction well was charged with 12.5. mu.L of diluted substrate.

PDE4C 1: PDE4C1 stock was first diluted 100-fold to a concentration of 3.2 ng/. mu.L, and 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. The substrate control wells were loaded with 10. mu. LPDE assay buffer.

Binding liquid: 50 μ L of the binder was added to 5mL of the binder diluent and mixed well. Add to all wells at 50. mu.L/well.

Data processing:

％Inhibition rate＝(FP_P-FP_S)/(FP_P-FP_Sub)×100％

FP_Ssample FP

FP_PPositive control FP

FP_SubSubstrate control FP.

6. The experimental results show that the compounds of the examples of the present invention have inhibitory effect on PDE4, wherein representative compounds are exemplified as follows:

IC of PDE4D3₅₀Table:

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

IC of PDE4A1₅₀Table:

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

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

IC of PDE4B2₅₀Table:

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

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

IC of PDE4C1₅₀Table:

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

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

The selective specificity of a compound for PDE4 was assessed by assaying a single concentration of the compound. Such as the PDE1a enzyme, the PDE1c enzyme, the PDE2a enzyme, the PDE3a enzyme, the PDE3b enzyme, the PDE5a1 enzyme, the PDE7a enzyme, the PDE7b enzyme, the PDE10a1 enzyme and the PDE11a4 enzyme. The selective inhibition of the enzymatic activity of PDE1C, PDE2A, PDE3B, PDE5A1, PDE7A, PDE10A1 by different compounds at concentrations of 10. mu.M and 1. mu.M, respectively, is given in the following table:

inhibition ratio (%) of PDE1C

Compound (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 ratio (%) of PDE2A

Compound (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 ratio (%) of PDE3B

Compound (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 ratio (%) of PDE5A1

Compound (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 ratio (%) of PDE7A

Compound (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 ratio (%) of PDE10A1

Compound (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

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

Human peripheral blood mononuclear cell LPS/SEB-induced TNF-alpha, IL-2, INF-gamma determination:

1. the purchased PBMC frozen cells were thawed at 37 ℃ and transferred to RMPI1640 medium at 37 ℃ with 5% CO₂The culture was carried out overnight in an incubator.

2. The next day, press 2X 10⁵cells/well were plated at 100. mu.L per well.

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

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

5. 7℃，5％CO₂The culture was carried out overnight in an incubator.

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

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 herein below:

the compound provided by the invention has the advantage that the activity of inhibiting the expression of inflammation-related factors is obviously improved.

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, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A compound of 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, and can be independently C1-C16 hydrocarbyl (including alkyl, alkenyl, alkynyl), C3-C7 cycloalkyl, or H, halogen, cyano, wherein alkyl, alkenyl, alkynyl can be optionally substituted or unsubstituted chain or cyclic groups, and wherein the substituent can be independently selected from halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 alkylthio, etc.;

r at independently different positions may form a cyclic group;

m is 1, 2, or 3;

n is 0 or 1;

R¹is C1-C3 alkyl or C1-C3 haloalkylOr alternatively C3-C6 cycloalkyl;

R²is C1-C5 alkyl or C1-C5 haloalkyl, or is C3-C6 cycloalkyl;

independently R1 and R2 may form a 5, 6, 7 ring cyclic;

R³is C1-C5 alkyl or C1-C5 haloalkyl, or is C3-C6 cycloalkyl;

R⁴is C1-C12 alkyl or C3-C6 cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, or C1-C3 alkylthio, etc.

2. The compound of formula I as claimed in claim 1, wherein the compound of formula I is further selected from formula II as follows:

wherein R is a 5, 6, or 7 substituent, and can be independently C3-C10 hydrocarbyl (including alkyl, alkenyl, alkynyl), C3-C7 cycloalkyl, or H, halogen, cyano, wherein alkyl, alkenyl, alkynyl can be optionally substituted or unsubstituted chain or cyclic groups, and wherein the substituent can be independently selected from halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 alkylthio, etc.;

r at independently different positions may form a cyclic group;

m is 1, 2, or 3;

R¹is C1-C3 alkyl or C1-C3 haloalkyl, or is C3-C6 cycloalkyl;

R²is C1-C5 alkyl or C1-C5 haloalkyl, or is C3-C6 cycloalkyl;

independently R1 and R2 may form a 5, 6, 7 ring cyclic;

R³is C1-C5 alkylOr C1-C5 haloalkyl, or also C3-C6 cycloalkyl;

3. The compound of formula I as claimed in claim 1 or 2, wherein the compound of formula I is further selected from formula III below, and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, prodrugs or pharmaceutically acceptable salts thereof:

wherein R is a 5, 6, or 7 substituent, and can be independently C5-C8 hydrocarbyl (including alkyl, alkenyl, alkynyl), C3-C7 cycloalkyl, or H, halogen, cyano, wherein alkyl, alkenyl, alkynyl can be optionally substituted or unsubstituted chain or cyclic groups, and wherein the substituent can be independently selected from halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 alkylthio, etc.;

m is 1, 2, or 3;

4. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1to 3 and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, prodrugs or pharmaceutically acceptable salts thereof;

preferably, it comprises a therapeutically effective amount of the compound of formula I and racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs thereof or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

5. Use of a compound of formula I according to any one of claims 1to 3, and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, prodrugs or pharmaceutically acceptable salts thereof or said pharmaceutical composition thereof in the manufacture of a medicament for inhibiting the PDE4 enzyme;

preferably, the condition ameliorated by the agent that inhibits PDE4 by inhibiting PDE4 includes, but is not limited to, asthma, inflammation (e.g., due to reperfusion), chronic or acute obstructive pulmonary disease, chronic or acute pneumonia, inflammatory bowel disease, crohn's disease, psoriasis, Bechet's disease, or colitis.

6. Use of a compound of formula I according to any one of claims 1to 3, and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, prodrugs or pharmaceutically acceptable salts thereof or the pharmaceutical composition thereof for the manufacture of a medicament for the treatment of diseases related to the modulation of intracellular cAMP levels.

7. Use of a compound of formula I according to any one of claims 1to 3, and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, prodrugs or pharmaceutically acceptable salts thereof or said pharmaceutical composition thereof for the manufacture of a medicament for inhibiting the production of TNF- α or NF- κ B.

8. Use of a compound of formula I according to any one of claims 1to 3, and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, prodrugs or pharmaceutically acceptable salts thereof, or the pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of diseases and conditions selected from the group consisting of: depression, asthma, inflammation (e.g., contact dermatitis, atopic dermatitis, psoriasis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, inflammatory skin diseases, inflammation due to reperfusion), chronic or acute obstructive pulmonary disease, chronic or acute pneumonia, pneumonia caused by viruses such as Covid-19, enteritis, crohn's disease, behcet's disease, or colitis.

9. A method of controlling intracellular cAMP levels, the method comprising the steps of: contacting a cell with an effective amount of a compound of any one of claims 1-3, or a pharmaceutically acceptable prodrug, polymorph, salt, solvate, hydrate, or clathrate thereof.