Substituted isoindoline-1,3-diones PDE4 inhibitors and their pharmaceutical applications

Abstract

The present invention relates to a compound represented by formula I, its racemate, stereoisomer, tautomer, isotopically labeled compound, solvate, polymorph, ester, prodrug or pharma- ceutically acceptable salt thereof, and a pharmaceutical composition comprising the same, a method for preparing the same, and a pharmaceutical application thereof. The structure of formula I is as follows: JPEG2024528149000095.jpg7280

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to substituted isoindoline-1,3-diones PDE4 inhibitors, preparation methods, and drug applications.

Background Art

[0002] Cyclic AMP (cAMP) plays a quite important influence and role in biological processes as a second messenger. Upon examination, in diseases such as asthma, chronic obstructive pulmonary disease, and inflammation, the absence or inactivation of cyclic AMP plays a role as one of the causes of these diseases (Lowe and Cheng, Drugs of the Future, 17(9): pp. 799-807, 1992), and an increase in the level of cyclic AMP in inflammatory leukocytes inhibits the release of inflammatory mediators such as TNF-α and NF-κB. At the same time, an increase in the cyclic AMP level leads to a relaxation effect on airway smooth muscle.

[0003] However, the main biological mechanism of cyclic AMP inactivation is that the level of cyclic AMP (Beavo and Reitsnyder, Trends in Pharm., 11: pp. 150-155, 1990) is disrupted by the cyclic nucleotide phosphodiesterase (PDE) family. Eleven family enzymes are known among PDE members, and the PDE4 (PDE IV) inhibitory type has a significant effect on the increase in cyclic AMP and the release of inflammatory mediators (Verghes et al., Journal of Pharmacology and Experimental Therapeutics, 272(3): pp. 1313-1320, 1995). Therefore, selectively inhibiting organic compounds of PDE4 may suppress airway inflammation, promote relaxation of airway smooth muscle, and treat skin inflammation.

[0004] Inhibition of phosphodiesterase 4 can inhibit the activity or production of certain cytokines, including tumor necrosis factor-α (TNF-α). Tumor necrosis factor-α is a cytokine primarily released by mononuclear phage cells in response to immune stimuli. TNF-α can promote most cellular processes, including differentiation, recruitment, proliferation, and protein degradation. At low levels, TNF-α has protective effects against infectious pathogens, tumors, and tissue damage; however, TNF-α also plays a role in inducing and exacerbating many diseases. Administration of TNF-α to mammals or humans can induce or exacerbate inflammation, fever, cardiovascular effects, hemorrhage, and acute responses similar to those seen during acute infection and shock.

[0005] Inflammatory diseases such as arthritis, rheumatoid diseases (e.g., osteoarthritis and rheumatoid arthritis), enteritis (e.g., ileitis and ulcerative colitis), sepsis, psoriasis, atopic dermatitis (AD), contact dermatitis, and chronic obstructive pulmonary disease (COPD), chronic pneumonia, acute respiratory distress syndrome (ARDS), vitiligo, prurigo nodularis, vulvodynia, fibrotic lesions, cachexia, autoimmune diseases, ankylosing spondylitis, osteoporosis, ileitis, ulcerative colitis, enteritis, multiple sclerosis (MS), discoid lupus erythematosus, systemic lupus erythematosus, radiation injury, alveolar damage with high oxygen content (Tracey et al., 1987, Nature, 330: pp. 662-664 and Hinshaw et al., 1990, Circ. Shock, 30: pp. 279-292 (endotoxic shock); Millar et al., 1989, Lancet, 2: pp. 712-714 and Ferrai-Baliviera et al., 1989, Arch. Surg., 124: pp. 1400-1405 (adult respiratory distress syndrome); Bertolini et al., 1986, Nature, 319: pp. 516-518; Pignet et al., 1990, Nature, 344: pp. 245-247, Bissonnette et al., 1989, Inflammation, 13: pp. 329-339 and Baughman et al., 1990, J. Lab. Clin. Med., 115: pp. 36-42 (chronic pneumonia); Elliot et al., 1995, Int. J. Pharmac., 17: pp. 141-145 (rheumatoid arthritis); VonDullemen et al., 1995, Gastroenterology, 109: pp. 129-135 (ileitis)) are common intractable diseases, and tumor necrosis factor-α plays an important role in these inflammatory responses. Inhibition of tumor necrosis factor-α has been shown to be effective in inhibiting chronic and acute inflammatory responses in animal models of inflammatory diseases.

[0006] Many small molecule inhibitors are known to be capable of treating inflammatory diseases involving tumor necrosis factor-α (Lowe, 1998, Exp. Opin. Ther. Patents, Vol. 8, pp. 1309-1332). Such molecules include substituted phenylethyl sulfone compounds described in U.S. Patents US6020358, US6962940, and WO0134606A1, WO0025777, WO2012083153, WO2018157779A1, WO0134604, and WO2012083153. Apremilast is disclosed in U.S. Patent US2003187052, and its corresponding Chinese patents are CN1652772, CN1965823, CN101683334, and CN03811093.8.

[0007] The isoindoline-1,3-dione PDE4 inhibitors in the prior art have relatively general biological activity and are not highly effective, so there is a need to provide an isoindoline-1,3-dione PDE4 inhibitor with good efficacy and a novel structure. Summary of the Invention

[0008] To solve the problems and improve the effects of the prior art, the present invention provides a compound represented by Formula I and its racemates, stereoisomers, tautomers, isotopically labeled compounds, solvates, polymorphs, esters, prodrugs, or pharmaceutically acceptable salts thereof. JPEG0007716147000001.jpg4250

[0009] In the formula, each R is independently H, deuterium, halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, and a C1-C16 hydrocarbon group, a C1-C16 heteroalkyl group, a C3-C12 cycloalkyl group, R'SO2NH-, R'SO2NH-C1-C16 alkyl group-, R'SO2-C1-C16 alkyl group-, R'SO2-, a 3-12 membered heterocyclic group, a C6-C14 aryl group, a 5-14 membered heteroaryl group which is unsubstituted or optionally substituted with one or more Ra; or, independently, a ring may be formed between two Rs at different positions.

[0010] Each Ra is independently selected from deuterium, halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, oxo (=O), and a C1-C16 hydrocarbon group, a C1-C16 heteroalkyl group, a C3-C12 cycloalkyl group, a 3-12 membered heterocyclic group, a C6-C14 aryl group, a 5-14 membered heteroaryl group which is unsubstituted or optionally substituted with one or more Rb,

[0011] Each R' is independently selected from a C1-C16 hydrocarbon group, a C1-C16 heteroalkyl group, a C3-C12 cycloalkyl group, a 3-12 membered heterocyclic group, a C6-C14 aryl group, a 5-14 membered heteroaryl group which is unsubstituted or optionally substituted with one or more Rb,

[0012] Each Rb is selected from deuterium, halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, oxo (=O) and a C1-C16 hydrocarbon group, a C1-C16 heteroalkyl group, a C3-C12 cycloalkyl group, a 3-12 membered heterocyclic group, a C6-C14 aryl group, a 5-14 membered heteroaryl group,

[0013] m is 1, 2, or 3, and n is 0 or 1,

[0014] R 1 is a C1-C16 hydrocarbon group, a C1-C16 heteroalkyl group, a C3-C12 cycloalkyl group which is unsubstituted or optionally substituted with one or more R1a,

[0015] R2 is a C1-C16 hydrocarbon group, a C1-C16 heteroalkyl group, or a C3-C12 cycloalkyl group that is unsubstituted or optionally substituted with one or more R2a,

[0016] alternatively, R1 may form a ring together with R2,

[0017] R 3 is a C1-C16 hydrocarbon group, a C1-C16 heteroalkyl group, or a C3-C12 cycloalkyl group that is unsubstituted or optionally substituted with one or more R3a,

[0018] R 4 is a C1-C16 hydrocarbon group, a C1-C16 heteroalkyl group, or a C3-C12 cycloalkyl group that is unsubstituted or optionally substituted with one or more R4a,

[0019] Each R1a is independently selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O), and a C1-C16 hydrocarbon group, a C1-C16 heteroalkyl group, or a C3-C12 cycloalkyl group that is unsubstituted or optionally substituted with one or more R1b,

[0020] Each R2a is independently selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O), and a C1-C16 hydrocarbon group, a C1-C16 heteroalkyl group, or a C3-C12 cycloalkyl group that is unsubstituted or optionally substituted with one or more R2b,

[0021] Each R3a is independently selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O), and a C1-C16 hydrocarbon group, a C1-C16 heteroalkyl group, or a C3-C12 cycloalkyl group that is unsubstituted or optionally substituted with one or more R3b,

[0022] Each of R4a is independently selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O), and a C1-C16 hydrocarbon group, a C1-C16 heteroalkyl group, a C3-C12 cycloalkyl group which is unsubstituted or optionally substituted by one or more R4b,

[0023] R1b is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O) and a C1-C16 hydrocarbon group, a C1-C16 heteroalkyl group.

[0024] R2b is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O) and a C1-C16 hydrocarbon group, a C1-C16 heteroalkyl group.

[0025] R3b is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O) and a C1-C16 hydrocarbon group, a C1-C16 heteroalkyl group.

[0026] R4b is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O) and a C1-C16 hydrocarbon group, a C1-C16 heteroalkyl group.

[0027] According to some embodiments of the present invention, R1 and R2 may form a 5-, 6- or 7-membered ring.

[0028] According to some embodiments of the present invention, the R may independently be a substituent of 5, 6 or 7.

[0029] According to some embodiments of the present invention, the C1-C16 hydrocarbon group is a C1-C16 alkyl group, a C2-C16 alkenyl group, a C2-C16 alkynyl group.

[0030] According to some embodiments of the present invention, the C1-C16 heteroalkyl group is an alkyl group having one or more heteroatoms selected from N, O, and S. Specifically, the C1-C16 heteroalkyl group is a C1-C16 alkyloxy group, a C1-C8-alkyl group OC1-C8 alkyl group-, a C1-C8-alkyl group -O-C1-C8 alkyl group-NH-, a C1-C16 alkylthio group-, a C1-C8-alkyl group -S-C1-C8 alkyl group-, a C1-C8-alkyl group -S-C1-C8 alkyl group-NH-, a C1-C16 alkyl group-NH-, a C1-C8-alkyl group -NH-C1-C8 alkyl group-, an NH2-C1-C16 alkyl group-, or a -C1-C8-alkyl group -NH-C1-C8 alkyl group-NH2. The number of carbon atoms in the C1-C16 heteroalkyl group is more preferably C1-C12, and even more preferably C5-8.

[0031] According to some embodiments of the present invention, two Rs together with the carbon atoms to which they are attached form a C5-6 membered cycloalkyl group.

[0032] According to some embodiments of the present invention, R is a substituent of 5, 6, or 7, and independently may be H, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and a C1-C12 alkyl group, a C2-C12 alkenyl group, a C2-C12 alkynyl group, a C1-C12 heteroalkyl group, a C3-C8 cycloalkyl group, a 3-10 membered heterocyclic group, a C6-C10 aryl group, or a 5-10 membered heteroaryl group, which is unsubstituted or optionally substituted with one or more Ras.

[0033] According to a preferred embodiment of the present invention, R is a substituent of 5, 6, or 7, and independently may be H, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and a C5-C8 alkyl group, a C5-C8 alkenyl group, a C5-C8 alkynyl group, a C5-C8 heteroalkyl group, a C3-C6 cycloalkyl group, a 3-6 membered heterocyclic group, a C6 aryl group, or a 5-6 membered heteroaryl group, which is unsubstituted or optionally substituted with one or more Ras.

[0034] According to some embodiments of the present invention, each R is independently selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo (=O), and a C1-C12 alkyl group, a C2-C12 alkenyl group, a C2-C12 alkynyl group, a C1-C12 heteroalkyl group, a C3-C8 cycloalkyl group, a 3-12 heterocyclic group, a C6-C14 aryl group, and a 5-10 membered heteroaryl group, each of which is unsubstituted or optionally substituted with one or more Rb.

[0035] According to a preferred embodiment of the present invention, each Ra is independently selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo (=O), and unsubstituted or optionally substituted with one or more Rb C5-C8 alkyl, C5-C8 alkenyl, C5-C8 alkynyl, C5-C8 heteroalkyl, C3-C6 cycloalkyl, 3-6 heterocyclic, C6 aryl, and 5-6 membered heteroaryl.

[0036] According to some embodiments of the present invention, R' is independently selected from a C1-C12 alkyl group, a C2-C12 alkenyl group, a C2-C12 alkynyl group, a C1-C12 heteroalkyl group, a C3-C8 cycloalkyl group, a 3-12 heterocyclic group, a C6-C14 aryl group, and a 5-10 membered heteroaryl group, each of which is unsubstituted or optionally substituted with one or more Rb.

[0037] According to a preferred embodiment of the present invention, R' is independently selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo (=O), and unsubstituted or optionally substituted with one or more Rb C5-C8 alkyl, C5-C8 alkenyl, C5-C8 alkynyl, C5-C8 heteroalkyl, C3-C6 cycloalkyl, 3-6 heterocyclic, C6 aryl, and 5-6 membered heteroaryl.

[0038] According to some embodiments of the present invention, Rb is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O), and C1-C12 alkyl group, C2-C12 alkenyl group, C2-C12 alkynyl group, C1-C12 heteroalkyl group, C3-C8 cycloalkyl group, 3-12 membered heterocyclic group, C6-C14 aryl group, 5-10 membered heteroaryl group.

[0039] According to a preferred embodiment of the present invention, Rb is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O), and C5-C8 alkyl group, C5-C8 alkenyl group, C5-C8 alkynyl group, C5-C8 heteroalkyl group, C3-C6 cycloalkyl group, 3-6 membered heterocyclic group, C6 aryl group, 5-6 membered heteroaryl group.

[0040] According to some embodiments of the present invention,

[0041] R 1 is a C1-C12 alkyl group, C2-C12 alkenyl group, C2-C12 alkynyl group, C1-C12 heteroalkyl group, C3-C8 cycloalkyl group which is unsubstituted or optionally substituted with one or more R1a; each R1a is independently selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O), and a C1-C12 alkyl group, C2-C12 alkenyl group, C2-C12 alkynyl group, C1-C12 heteroalkyl group, C3-C12 cycloalkyl group which is unsubstituted or optionally substituted with one or more R1b; R1b is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O), and

[0042] Preferably, R 1is a C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 heteroalkyl group, C3-C6 cycloalkyl group which is unsubstituted or optionally substituted by one or two or more R1a; each R1a is independently selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo(=O), and a C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 heteroalkyl group, C3-C6 cycloalkyl group which is unsubstituted or optionally substituted by one or two or more R1b; R1b is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo(=O),

[0043] More preferably, R 1 is a C1-C3 alkyl group, C2-C3 alkenyl group, C2-C3 alkynyl group, C1-C3 heteroalkyl group, C3-C6 cycloalkyl group which is unsubstituted or optionally substituted by one or two or more R1a; each R1a is independently selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo(=O), and a C1-C3 alkyl group, C2-C3 alkenyl group, C2-C3 alkynyl group, C1-C3 heteroalkyl group, C3-C6 cycloalkyl group which is unsubstituted or optionally substituted by one or two or more R1b; R1b is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo(=O),

[0044] R 2is a C1-C12 alkyl group, C2-C12 alkenyl group, C2-C12 alkynyl group, C1-C12 heteroalkyl group, C3-C8 cycloalkyl group which is unsubstituted or optionally substituted with one or two or more R2a; each R2a is independently deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O), and a C1-C12 alkyl group, C2-C12 alkenyl group, C2-C12 alkynyl group, C1-C12 heteroalkyl group, C3-C12 cycloalkyl group which is unsubstituted or optionally substituted with one or two or more R2b; R2b is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O),

[0045] Preferably, R 2 is a C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 heteroalkyl group, C3-C6 cycloalkyl group which is unsubstituted or optionally substituted with one or two or more R2a; each R2a is independently deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O), and a C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 heteroalkyl group, C3-C6 cycloalkyl group which is unsubstituted or optionally substituted with one or two or more R2b; R2b is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O),

[0046] More preferably, R 2is a C1-C5 alkyl group, C2-C5 alkenyl group, C2-C5 alkynyl group, C1-C5 heteroalkyl group, C3-C6 cycloalkyl group which is unsubstituted or optionally substituted by one or two or more R2a; each R2a is independently selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O), and a C1-C5 alkyl group, C2-C5 alkenyl group, C2-C5 alkynyl group, C1-C5 heteroalkyl group, C3-C6 cycloalkyl group which is unsubstituted or optionally substituted by one or two or more R2b; R2b is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O),

[0047] R 3 is a C1-C12 alkyl group, C2-C12 alkenyl group, C2-C12 alkynyl group, C1-C12 heteroalkyl group, C3-C8 cycloalkyl group which is unsubstituted or optionally substituted by one or two or more R3a; each R3a is independently selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O), and a C1-C12 alkyl group, C2-C12 alkenyl group, C2-C12 alkynyl group, C1-C12 heteroalkyl group, C3-C12 cycloalkyl group which is unsubstituted or optionally substituted by one or two or more R3b; R3b is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O),

[0048] Preferably, R 3is a C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 heteroalkyl group, C3-C6 cycloalkyl group which is unsubstituted or optionally substituted with one or two or more R3a; each R3a is independently selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O), and a C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 heteroalkyl group, C3-C6 cycloalkyl group which is unsubstituted or optionally substituted with one or two or more R3b; R3b is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O),

[0049] More preferably, R 3 is a C1-C5 alkyl group, C2-C5 alkenyl group, C2-C5 alkynyl group, C1-C5 heteroalkyl group, C3-C6 cycloalkyl group which is unsubstituted or optionally substituted with one or two or more R3a; each R3a is independently selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O), and a C1-C5 alkyl group, C2-C5 alkenyl group, C2-C5 alkynyl group, C1-C5 heteroalkyl group, C3-C6 cycloalkyl group which is unsubstituted or optionally substituted with one or two or more R3b; R3b is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O),

[0050] R 4is a C1-C12 alkyl group, C2-C12 alkenyl group, C2-C12 alkynyl group, C1-C12 heteroalkyl group, C3-C8 cycloalkyl group which is unsubstituted or optionally substituted by one or more R4a; each R4a is independently selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O), and a C1-C12 alkyl group, C2-C12 alkenyl group, C2-C12 alkynyl group, C1-C12 heteroalkyl group, C3-C12 cycloalkyl group which is unsubstituted or optionally substituted by one or more R4b; R4b is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O),

[0051] Preferably, R 4 is a C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 heteroalkyl group, C3-C6 cycloalkyl group which is unsubstituted or optionally substituted by one or more R4a; each R4a is independently selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O), and a C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 heteroalkyl group, C3-C6 cycloalkyl group which is unsubstituted or optionally substituted by one or more R4b; R4b is selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo (=O).

[0052] According to an embodiment of the present invention, the compound represented by the formula I is further selected from the following formula II. JPEG0007716147000002.jpg3943

[0053] In the formula, the said R, R 1 , R 2 , R 3 , R 4 , m are defined in the same manner as above.

[0054] According to an embodiment of the present invention, the compound represented by the formula I is further selected from the following formula III. JPEG0007716147000003.jpg4748

[0055] In the formula, the R, R 4 , and m are defined in the same manner as described above.

[0056] According to an embodiment of the present invention, the formula I is further selected from the following formula IV. JPEG0007716147000004.jpg8282

[0057] In the formula, R, m, and R 4 are defined in the same manner as described above.

[0058] According to an embodiment of the present invention, in the compound represented by the formula I (including formulas II - III) and its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, polymorph, ester, prodrug, or pharmaceutically acceptable salt thereof, exemplary and non-limiting specific examples of the compound represented by the formula I are as follows. JPEG0007716147000005.jpg73149JPEG0007716147000006.jpg73147JPEG0007716147000007.jpg73145JPEG0007716147000008.jpg53150JPEG0007716147000009.jpg49148JPEG0007716147000010.jpg72138JPEG0007716147000011.jpg25148JPEG0007716147000012.jpg78152, JPEG0007716147000013.jpg61156

[0059] The present invention further provides a method for preparing the compound represented by the formula I (including formulas II-III) and its racemates, stereoisomers, tautomers, isotope-labeled compounds, solvates, polymorphs, esters, prodrugs or pharmaceutically acceptable salts thereof, but is not limited to the methods described below. All raw materials are prepared or directly purchased by methods well-known to those skilled in the art of organic chemistry, according to the properties of the target molecule that conform to the general formula rules, by the protocols of these routes. The following methods can be combined with synthetic methods known in the field of organic synthetic chemistry or related modified methods recognized by those skilled in the art to prepare the compounds of the present application. Those skilled in the art know that, according to the specific target structure, they can optionally combine one or more of the following schemes, or combine any steps within one or more schemes, to obtain a synthetic scheme.

[0060] The method for preparing the compound represented by the formula I of the present invention comprises, under suitable conditions, converting I-1 (wherein R' is a halogen, alkane, carboxy group, cyano group, amine group or nitro group, and t is an integer between 1 and 5) as a substituted benzoic acid raw material through synthesis into an anhydride I-2, and further reacting with an amine intermediate I-3 to generate a substituted isoindoline-1,3-dione I-4, and performing protection group attachment, protection group removal, substitution, condensation, and reduction amination or hydrolysis steps under suitable conditions to obtain the compound represented by the formula I. Specifically, it can be synthesized by the following further schemes. JPEG0007716147000014.jpg38134

[0061] (For example, WO2016169533) The preparation of the compounds in the present invention may include one or more steps in the following general steps. Further, the synthetic route of the sulfonylethaneamine I-3 (11) as an intermediate is as follows.

[0062] The starting material, the substituted benzoic acid ester 1, through para-phenol group protection, becomes compound 2, undergoes meta-etherification to become compound 3, and through deprotection of the para-phenol group, compound 4 is obtained. Through similar para-substituted etherification, it becomes compound 5, is reduced to alcohol 6 by ester reduction, and is oxidized to aldehyde 7, which is an intermediate. Further reaction successfully results in methylsulfonylstyrene 8, and further alkylation yields alkylsulfonylstyrene 9, which gives product 10 through an amine reaction. By the method of chiral resolution or separation of benzon, (S)-1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethaneamine 11 is obtained. JPEG0007716147000015.jpg98146

[0063] Also, from benzene cyanide 12, which is the starting material, it may be converted to the benzon intermediate 13 through intermediate 15, reduced to alcohol 15, and methylsulfonylstyrene 8 is also obtained by dehydration. Thus, through further chemical conversion as described above, chiral 1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethaneamine 11 is obtained. JPEG0007716147000016.jpg71128

[0064] Para-alkylated dihydroxy-substituted benzophenone 24 gives compound 17, further alkylation produces dialkoxybenzophenone 18, bromination reaction gives bromobenzophenone 19, thio-etherification gives intermediate 20, and intermediates 11 are synthesized in two routes by compounds 21, 22, and 23. JPEG0007716147000017.jpg109147

[0065] Here, R1, R2, and R3 are as defined in the aforementioned formula I, and X is selected from halogens.

[0066] According to the existing technology in the art, the corresponding chiral compound can be isolated from its racemic compound. Examples include, but are not limited to, the formation of chiral salts, chirality, and the use of high performance liquid chromatography "HPLC", and the formation and crystallization of chiral salts. For example, see Jacques, J. et al., Enantiomers, 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, 268 (edited by E. L. Eliel, University of Notre Dame Press, Notre Dame, IN, 1972).

[0067] As a specific example, the chiral amino acid salts of (S)-2-(3-alkoxy-4-alkoxyphenyl)-1-(alkylsulfonyl)-eth-2-ylamine 11 include, but are not limited to, salts formed from the L-isomers of amino acids or the L-isomers of acylated amino acids.

[0068] According to an embodiment of the present invention, the compounds of the present invention may be synthesized by selecting the following synthetic route (see WO2018157779A1).

[0069] Synthetic Route 1:

[0070] Halogenated O-methylbenzoic acid 24 is subjected to a nitration reaction to produce compound 25, an oxidation reaction is carried out to obtain substituted phthalic acid 26, an acid anhydride reaction is carried out to obtain halogenated 4-nitrobenzoic anhydride 27, and further reacted with 1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethaneamine 11 in acetic acid to obtain halogenated (S)-2-[1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethyl]-4-nitroisoindoline-1,3-dione 28, which is further reduced to nitro to obtain intermediate 29, acylated with compound 30, and substituted with a chain hydrocarbon by a Suzuki reaction or a Sonogashira reaction to obtain (S)-2-[1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethyl]-4-amidoisoindoline-1,3-dione II. JPEG0007716147000018.jpg61130

[0071] Here, the aforementioned R, R 1 , R 2 , R 3 , R 4 , and m are as defined in the aforementioned formula I, and X is selected from halogens (Cl, Br, I).

[0072] Synthetic route 2:

[0073] Halogenated 3-nitrobenzoic anhydride 27 becomes nitro group reduction intermediate 31, becomes 4-acylated benzoic anhydride 32, and is further reacted with 1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethaneamine 11 in acetic acid to obtain halogenated (S)-2-[1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethyl]-4-amidoisoindoline-1,3-dione 30, and further substituted with a chain hydrocarbon by a Suzuki reaction or a Sonogashira reaction to obtain (S)-2-[1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethyl]-4-amidoisoindoline-1,3-dione II. JPEG0007716147000019.jpg67134

[0074] Here, the R and R 1 , R2, R3, R4, m are as defined above in Formula I, and X is selected from halogens (Cl, Br, I).

[0075] Synthetic Route 3:

[0076] The halogenated 4-nitrobenzoic anhydride 33 was further reacted with 1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethanamine 11 in acetic acid to give the halogenated (S)-2-[1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethyl]-4-nitroisoindoline-1,3-dione 34, which was reduced to the intermediate (S)-2-[1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethyl]-4-aminoisoindoline-1,3-dione 35, which was acylated to give (S)-2-[1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethyl]-4-amidoisoindoline-1,3-dione II. JPEG0007716147000020.jpg61128

[0077] Here, the R and R 1 , R 2 , R 3 , R 4 , m are as defined in formula I above.

[0078] Synthetic Route 4:

[0079] Acylation of hydrocarbon-substituted 4-aminobenzoic anhydride 36 gave intermediate 37, which was further reacted with 1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethanamine 11 in acetic acid to give the open-chain hydrocarbon-substituted (S)-2-[1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethyl]-4-amidoisoindoline-1,3-dione II. JPEG0007716147000021.jpg42128

[0080] Among them, the aforementioned R, R 1 , R 2 , R 3 , R 4 , and m are as defined in the aforementioned formula II.

[0081] Synthesis route 5:

[0082] 4-Nitrobenzoic anhydride 27 is subjected to an ammoniation reaction to obtain 38, which is then subjected to a Mitsunobu reaction with alcohol 39 to obtain intermediate 28. After a Suzuki reaction or a Sonogashira reaction, intermediate 34 is obtained, which is further reduced to obtain amino group 35, and then subjected to an acylation reaction to obtain (S)-2-[1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethyl]-4-amidoisoindoline-1,3-dione II substituted with a chain hydrocarbon. JPEG0007716147000022.jpg68128

[0083] Among them, the aforementioned R, R 1 , R 2 , R 3 , R 4 , and m are as defined in the aforementioned formula II.

[0084] Synthesis route 6:

[0085] Halogenated (S)-2-[1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethyl]-4-aminoisoindoline-1,3-dione 35 is subjected to a bromination reaction to obtain 39, which is then subjected to a cyanidation reaction to obtain a cyano group compound 40, which is further reduced to obtain a 4-aminomethyl substituent intermediate 41, and then subjected to an acylation reaction to obtain (S)-2-[1-(3-alkoxy-4-alkoxyphenyl)-2-alkylsulfonylethyl]-4-(amidomethyl)isoindoline-1,3-dione substituted with a chain hydrocarbon. JPEG0007716147000023.jpg65128

[0086] Here, the aforementioned R, R 1 , R 2 , R 3 , R 4 , and m are as defined in the aforementioned formula I.

[0087] The present invention further provides a pharmaceutical composition comprising a compound represented by formula I described in the present invention and its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, polymorph, ester, prodrug, or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the pharmaceutical composition described in the present invention comprises a therapeutically effective amount of a compound represented by formula I described in the present invention and its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, polymorph, metabolite, ester, prodrug, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0089] The carrier in the aforementioned pharmaceutical composition is "acceptable", compatible with (preferably, stabilizing) the active ingredient of the composition, and not harmful to the subject to be treated. One or more solubilizing agents can be used as pharmaceutical excipients for the delivery of the active compound.

[0090] The present invention further provides the use of the compound represented by formula I and its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, polymorph, ester, prodrug, or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a drug for inhibiting phosphodiesterase 4.

[0091] The present invention further provides the use of the compound represented by formula I and its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, polymorph, ester, prodrug, or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a drug for treating a disease by adjusting the intracellular cAMP level.

[0092] The present invention further provides an application of the compound represented by the formula I, and its racemate, stereoisomer, tautomers, isotope-labeled compound, solvate, polymorph, ester, prodrug or pharmaceutically acceptable salt thereof or the said pharmaceutical composition, in the preparation of a drug for inhibiting the production of TNF-α or NF-κB.

[0093] According to an embodiment of the present invention, diseases improved by inhibiting PDE4 for the drug for inhibiting PDE4 include, but are not limited to, dermatitis, psoriasis, atopic dermatitis, seborrheic dermatitis, congestive dermatitis, palmoplantar pustulosis, asthma, inflammation (e.g., inflammation caused by reperfusion), chronic or acute obstructive pulmonary disease, chronic or acute pneumonia, lung diseases caused by viruses such as Covid-19, enteritis, terminal ileitis, psoriasis, psoriatic arthritis, Bechet's disease or colitis.

[0094] In a particular method of the present invention, the compound of the present invention or its pharmaceutically acceptable polymorph, prodrug, salt, solvate, hydrate or gas inclusion compound is administered in combination with at least one other therapeutic agent.

[0095] The unit dosage forms of the present invention are suitable for oral administration, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., subcutaneous, intravenous, single high-dose injection, intramuscular, or arterial) or transdermal, as well as topical or inhaled topical administration. Dosage forms include tablets, pills, capsule-shaped tablets, sustained-release dosage forms, soft elastic gelatin capsules, flat capsules, capsules such as troches, dispersions, suppositories, ointments, pastes (mud coatings), cataplasms, powders, pastes, creams, paste-like agents, solutions, patches, aerosols (e.g., nasal sprays or inhalers), gels, dry powder inhalers, suspensions (e.g., aqueous or non-aqueous suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions, elixirs, and sterile solid dosage forms (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for oral or mucosal administration to patients and liquid dosage forms suitable for parenteral administration to patients, but are not limited thereto. The present invention includes various embodiments of specific dosage forms that are not the same, which will be apparent to those skilled in the art. See, for example, Remington′s Pharmaceutical Sciences, 18th Edition, Mack Publishing, Easton PA (1990).

[0096] Explanation of terms:

[0097] Unless otherwise specified, the term definitions in the specification and claims of this application, such as the definitions of groups, exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the examples, can be arbitrarily combined or joined with each other. After such combination or joining, the definitions of the groups and the compound structures should be within the scope described in this specification.

[0098] The term "halogen" refers to F, Cl, Br, and I. In other words, F, Cl, Br, and I may be referred to as "halogen" in this specification.

[0099] In this text, when it is optionally substituted with a substituent, it may be unsubstituted or substituted with one or more substituents. For example, "optionally substituted with one or two or more Rs" means not substituted with R (unsubstituted) or substituted with one or two or more Rs.

[0100] The term "hydrocarbon group" includes saturated or unsaturated, linear or branched chain or cyclic hydrocarbon groups, and the hydrocarbon group may be selected from an alkyl group, an alkenyl group, an alkynyl group, etc. The number of carbon atoms of the hydrocarbon group (alkyl group, alkenyl group, alkynyl group) is preferably 1-16, and more preferably in the ranges of 1-12, 1-8, 5-8, 1-5, 1-3, etc. Specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isoamyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 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, ethylcyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl can be mentioned, but are not limited thereto. The hydrocarbon group (including alkyl group, alkenyl group, alkynyl group) part in other terms also conforms to this definition.

[0101] The term "heteroalkyl group" by itself or in combination with another term refers to a stable straight-chain or branched alkyl group atom group or its composition consisting of a specific number of carbon atoms and at least one heteroatom. The number of carbon atoms may be 1 - 16, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16. The heteroalkyl group may optionally have one or more heteroatoms selected from N, O, S (or may be interpreted as optionally inserting a heteroatom into an alkyl group having any C-C bond and C-H bond). The heteroatoms O, N, and S may be located anywhere inside the heteroalkyl group or may be attached to the location where the alkyl group is bonded to the rest of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms can be consecutive, for example -CH2-NH-OCH3.

[0102] The term "cycloalkyl group" 3-12 includes "C 3-8 cycloalkyl group", preferably C 3-6 cycloalkyl group, and more preferably C 3-8 cycloalkyl group, and should be understood to mean a saturated or unsaturated monovalent monocyclic or bicyclic having 3 - 12 carbon atoms. For example, C 3-12 cycloalkyl group should be understood to mean a saturated or unsaturated monovalent monocyclic or bicyclic having 3, 4, 5, 6, 7, or 8 carbon atoms. The C

[0103] The term "3- to 12-membered heterocyclic group" should be understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 1 to 5 heteroatoms independently selected from N, O and S and a total ring number of 3 to 12 (for example, the number of atoms is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12), for example, a "3- to 10-membered heterocyclic group". The term "3- to 10-membered heterocyclic group" should be understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S, for example, 1, 2, 3 heteroatoms independently selected from N, O and S. The heterocyclic group is bonded to any one of the carbon atoms, or the nitrogen atom (if present) can be bonded to the rest of the molecule. In particular, examples of the heterocyclic group include a 4-membered ring such as an azacyclobutane group and an oxacyclobutane group, a 5-membered ring such as a tetrahydrofuranyl group, a dioxacyclopentenyl group, a pyrrolidyl group, an imidazolidinyl group, a pyrazolidinyl group, a pyrroline group, or a 6-membered ring such as a trahydropyranyl group, a piperidinyl group, a morpholino group, a dithialkyl group, a thiomorpholine group, a piperazinyl group, or a trithialkyl group, or a 7-membered ring such as a diazacycloheptyl group, but are not limited thereto. Optionally, the heterocyclic group may be condensed with a benzene ring. The heterocyclic group may be bicyclic, for example, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The nitrogen atom-containing ring may be partially unsaturated, that is, those containing one or more double bonds such as a 2,5-dihydro-1H-pyrrole group, a 4H-[1,3,4]thiadiazine group, a 4,5-dihydrooxazole group, or a 4H-[1,4]thiazide group, but are not limited thereto, and may be condensed with a benzene ring such as a dihydroisoquinoline group. According to the present invention, the heterocyclic group may be non-aromatic.When the 3- to 12-membered heterocyclic group is combined with other groups to form the compound of the present invention, the carbon atoms on the 3- to 12-membered heterocyclic group can be combined with other groups, and the heteroatoms on the ring of the 3- to 12-membered heterocyclic group can also be combined with other groups. For example, if the 3- to 12-membered heterocyclic group is selected from piperazine groups, the nitrogen atoms on the piperazine group can be combined with other groups. Or if the 3- to 12-membered heterocyclic group is selected from piperidinyl groups, the nitrogen atom on the ring of the piperidinyl group can be combined with the carbon atom at its para position.

[0104] "C 6-14 The term "aryl group" means, for example, a monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, which is monovalent aromatic or partially aromatic, in particular a phenyl group or a C6 aryl group such as a biphenyl group, or a C9 aryl group such as an indane group or an indanyl group, or a C10 aryl group such as a tetrahydronaphthalene group, a dihydronaphthalene group or a naphthalene group, 10 aryl group", or a C13 aryl group such as a fluorenyl group, 13 aryl group", or a C14 aryl group such as an anthracene group, 14 aryl group", etc., and should be understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 14 carbon atoms. When the C 6-20 aryl group is substituted, it can be mono-substituted or multi-substituted. Also, there is no restriction on the substitution site, and it can be, for example, ortho-substituted, para-substituted, or meta-substituted.

[0105] The term "5- to 14-membered heteroaryl group" or "becoming a 5- to 14-membered heteroaryl group" should be understood as a monocyclic, bicyclic or tricyclic aromatic ring system such as aromatic or partially aromatic, having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S. For example, it can have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, particularly 5 or 6 or 9 or 10 carbon atoms, including 1-5, preferably 1-3 heteroatoms independently selected from N, O and S, and in any case, it is fused to a benzene ring. In particular, the heteroaryl group includes a thiophenyl group, a furanyl group, a pyrrole group, an oxazole group, a thiazole group, an imidazole group, a pyrazole group, an isoxazole group, an isothiazole group, an oxadiazole group, a triazole group, a thio-4H-pyrazole group, etc. and their benzo derivatives, for example, a benzofuran group, a benzothiophene group, a benzoxazole group, a benzoisoxazole group, a benzimidazole group, a benzotriazole group, an inazolyl group, an indole group, an isoindolyl group, etc.; or a pyridyl group, a pyridazine group, a pyrimidinyl group, a pyrazine group, a triazine group, etc. and their benzo derivatives, for example, a quinoline group, a quinazoline group, an isoquinolino group, etc., or an acasin group, an indide group, a purine group, etc. and their benzo derivatives, or an oxolino group, a phthalazine group, a quinazoline group, a quinoxaline group, a naphthyridine group, a pteridine group, a carbazole group, an acridinyl group, a phenothiazine group, a phenoxazine group, etc. When the 5- to 14-membered heteroaryl group is combined with other groups to form the compound of the present invention, a carbon atom on the ring of the 5- to 14-membered heteroaryl group can be combined with other groups, and a heteroatom on the ring of the 5- to 14-membered heteroaryl group can be combined with other groups. When the 5- to 14-membered heteroaryl group is substituted, it can be mono-substituted or multi-substituted. Also, there is no restriction on the substitution site. For example, a hydrogen atom bonded to a carbon atom on the ring of the heteroaryl group may be substituted, or a hydrogen atom bonded to a heteroatom on the ring of the heteroaryl group may be substituted.

[0106] Unless otherwise specified, heterocyclic, heteroaryl or heteroarylene groups include all possible isomeric forms thereof, including their positional isomers. Thus, some illustrative non-limiting examples include pyridin-2-yl, pyridylene-2-yl, pyridin-3-yl, pyridylene-3-yl, pyridin-4-yl and pyridylene-4-yl; thiophene or thiophenyl groups such as thiophen-2-yl, thiophenyl-2-yl, thiophen-3-yl and thiophenyl-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, etc., substituted or bonded to other groups at one or more of their positions, such as at the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions (if present), etc.

[0107] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein that is sufficient to achieve its intended use (including, but not limited to, the treatment of diseases as defined below). A therapeutically effective amount may vary depending on factors such as the intended application (in vitro or in vivo), or the subject being treated, and the disease state being treated, e.g., the subject's weight and age, the severity of the condition, and the mode of administration, which can be readily determined by one of ordinary skill in the art. The specific dose may vary depending on factors such as the particular compound selected, the administration regimen undertaken, whether it is administered in combination with other compounds, the timing of administration, the tissue to which the drug is administered, and the physical delivery system that carries it.

[0108] The term "solvate" refers to a form of the compound of the present invention that forms a complex by coordination with solvent molecules in a solid or liquid state. A hydrate is a specific form of solvate in which the coordination is with water. In the present invention, the preferred solvate is a hydrate. Further, the pharmaceutically acceptable solvate (hydrate) of the compound represented by the general formula I of the present invention refers to a eutectic and an inclusion complex formed with the compound I and one or more stoichiometric molecules of water or other solvents. Solvents used for solvates include, but are not limited to, water, methanol, ethanol, ethylene glycol, and acetic acid.

[0109] The term "prodrug" is also called "drug precursor" and represents a compound represented by the aforementioned general formula or a specific compound that is converted in the body. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion to the parent structure by an enzyme in the blood or tissue. The prodrug described in the present invention may be an ester. In the present invention, esters that can be used as prodrugs include phenyl esters, aliphatic esters, acyloxymethyl esters, carbonates, carbamate esters, and amino acid esters. For example, one compound in the present invention contains a hydroxyl group / carboxyl group, that is, a compound that can be acylated to form a prodrug. Other forms of prodrugs include, for example, phosphate esters obtained by phosphorylation of a parent hydroxyl group.

Advantages of the Invention

[0110] The isatin-1,3-dione compound in the present invention has a prominent inhibitory effect on the biological reaction of phosphodiesterase 4, and further improves the cAMP level or inhibits factors such as TNF-α, effectively treating psoriasis, psoriatic arthritis, scalp psoriasis, Bechet's disease, atopic dermatitis (AD), vitiligo vulgaris, seborrheic dermatitis, congestive dermatitis, palmoplantar pustulosis, chronic obstructive pulmonary disease (COPD), acute pneumonia (ARDS), viral lung diseases and respiratory inflammatory diseases. The compound in the present invention has a prominent inhibitory activity on the biological enzyme PDE4 of the isatin-1,3-dione series compound, and has the beneficial effect of higher efficacy.

Embodiments for Carrying out the Invention

[0111] Hereinafter, the technical solution of the present invention will be described in more detail by specific examples. It should be understood that the following examples are only illustrative and are only for explaining or interpreting the present invention, and should not be construed as limiting the protection scope of the present invention. All technical solutions realized based on the above content of the present invention are included within the scope to be protected by the present invention.

[0112] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available and are prepared by known methods.

[0113] (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-(γ-chlorobutanamido)-5-hexylisatin-1,3-dione JPEG0007716147000024.jpg90141JPEG0007716147000025.jpg33128

[0114] Synthesis of Compound 1-2: Compound 1-1 (5 g, 23.25 mmol, 1 eq) was added batchwise to fuming nitric acid (1.47 g, 23.25 mmol, 16 mL, 1 eq) at 0 °C, and then stirred at 0 °C for 1 hour 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), dried over Na2SO4, and concentrated in vacuo. The yellow solid Compound 1-2 (5.3 g, crude product) was obtained.

[0115] Synthesis of Compound 1-3: Compound 1-2 (5.3 g, 6.73 mmol, 1 eq) was dissolved in H2O (60 mL), NaOH (2.42 g, 60.53 mmol, 9 eq) was added, the temperature was raised to 80 °C, and KMnO4 (25.51 g, 161.42 mmol, 24 eq) was added batchwise within 3 hours. Then stirring was continued for 30 minutes, followed by suction filtration. The solid was washed with hot water (30 mL * 3). The aqueous phase was cooled with ice water, adjusted to pH = 2 with 2M HCl, extracted with ethyl acetate (100 mL * 2), the organic phases were combined, washed with saturated brine, dried over Na2SO4, filtered, and concentrated to obtain the yellow solid Compound 1-3 (1.9 g, crude product).

[0116] Synthesis of Compound 1-4: Compound 1-3 (1.9 g, 3.93 mmol, 1 eq) was dissolved in Ac2O (21.80 g, 213.54 mmol, 20 mL, 54.33 eq), stirred at 140 °C for 16 hours, and concentrated to obtain the light brown solid Compound 1-4 (1.6 g, crude product).

[0117] Synthesis of Compound 1-5: Compound 1-4 (1.6 g, 3.53 mmol, 1 eq) and Compound 11a (1.54 g, 5.65 mmol, 1.6 eq) were dissolved in AcOH (20 mL), 120 oIt was stirred at 18 °C for 18 hours. The crude product obtained by concentrating the reaction solution was purified by column chromatography (petroleum ether:ethyl acetate 10 / 1 to 1 / 1) to obtain a yellow solid compound 1-5 (1.2 g, crude product).

[0118] Synthesis of compound 1-6: Compound 1-5 (1.2 g, 1.50 mmol, 1 eq), PdCl2(PPh3)2 (210.83 mg, 300.37 μmol, 0.2 eq), CuI (57.21 mg, 300.37 μmol, 0.2 eq), DIEA (582.31 mg, 4.51 mmol, 784.78 μL, 3 eq) and 1-hexyne (370.11 mg, 4.51 mmol, 506.99 μL, 3 eq) were dissolved in DMF (12 mL), and the reaction solution was stirred at 60 o °C for 18 hours. Water (15 mL) and ethyl acetate (20 mL) were added to the reaction system, and it was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and the crude product obtained by concentration was purified by column chromatography (SiO2, PE:EtOAc = 10:1 to 1:1) to obtain a yellow solid compound 1-6 (376 mg, yield 47.36%).

[0119] Of compound 1-6 1H-NMR (400 MHz, CDCl3) δ = 7.87 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.11 - 7.06 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H), 5.86 (dd, J = 4.4, 10.4 Hz, 1H), 4.50 (dd, J = 10.4, 14.0 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.87 - 3.84 (m, 3H), 3.70 (dd, J = 4.4, 14.4 Hz, 1H), 2.89 - 2.84 (m, 3H), 2.44 (t, J = 7.2 Hz, 2H), 1.62 - 1.56 (m, 2H), 1.49 - 1.41 (m, 5H), 0.97 - 0.91 (m, 3H).

[0120] Synthesis of Compound 1-7: Compound 1-6 (370.00 mg, 700.00 μmol, 1 eq) was dissolved in methanol (10 mL), d / C (100 mg, 10% purity) was added under a nitrogen gas atmosphere, and the mixture was evacuated and replaced with hydrogen gas three times. Then, it was stirred at 60 o °C for 16 h under a hydrogen gas (50 Psi) atmosphere. The reaction mixture was filtered through diatomaceous earth to remove solids, the filter cake was washed with EtOAc, concentrated, and purified by prep-HPLC (formic acid system) to obtain Compound 1-7 (128 mg, yield 36.38%) and Compound 1-7A (25 mg, yield 7.13%).

[0121] of Compound 1-7 1H-NMR (400 MHz, CDCl3) δ = 7.25 (broad singlet, 1H), 7.15 - 7.07 (multiplet, 3H), 6.82 (doublet, J = 8.0 Hz, 1H), 5.83 (doublet of doublets, J = 5.2, 9.6 Hz, 1H), 5.28 (singlet, 2H), 4.52 (doublet of doublets, J = 9.2, 14.4 Hz, 1H), 4.10 (quartet, J = 7.2 Hz, 2H), 3.84 (singlet, 3H), 3.79 (doublet of doublets, J = 5.2, 14.4 Hz, 1H), 2.80 (singlet, 3H), 2.51 (triplet, J = 8.0 Hz, 2H), 1.64 - 1.58 (multiplet, 2H), 1.46 (triplet, J = 7.2 Hz, 3H), 1.35 - 1.29 (multiplet, 6H), 0.90 - 0.87 (multiplet, 3H).

[0122] Of Compound 1-7A 1 H-NMR (400 MHz, CDCl3) δ = 7.43 (doublet, J = 7.2 Hz, 1H), 7.16 - 7.10 (multiplet, 3H), 6.84 (doublet, J = 8.4 Hz, 1H), 6.36 - 6.30 (multiplet, 1H), 6.26 - 6.18 (multiplet, 1H), 5.85 (doublet of doublets, J = 5.2, 9.6 Hz, 1H), 5.36 (singlet, 2H), 4.52 (doublet of doublets, J = 9.6, 14.4 Hz, 1H), 4.12 (quartet, J = 7.2 Hz, 2H), 3.85 (singlet, 3H), 3.80 (doublet of doublets, J = 4.8, 14.4 Hz, 1H), 2.81 (singlet, 3H), 2.30 - 2.23 (multiplet, 2H), 1.51 - 1.447 (multiplet, 5H), 1.43 - 1.35 (multiplet, 2H), 0.97 - 0.92 (multiplet, 3H).

[0123] Synthesis of Example 1:

[0124] Compound 1-7 (40 mg, 79.58 μmol, 1 eq) and chlorobutyryl chloride (11.22 mg, 79.58 μmol, 8.91 μL, 1 eq) were dissolved in DCE (2 mL), DIEA (10.29 mg, 79.58 μmol, 13.86 μL, 1 eq) was added to the reaction solution, and the mixture was stirred at 50 o °C for 3 h. The reaction solution was rotary evaporated and purified by prep-HPLC (formic acid system) to obtain Example 1 as a white solid (14.04 mg, yield 29.06%).

[0125] 1 1H-NMR (400 MHz, CDCl3) δ = 7.94 (br s, 1H), 7.65 - 7.57 (m, 2H), 7.07 (d, J = 2.0 Hz, 1H), 7.09 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 5.85 (dd, J = 4.4, 10.0 Hz, 1H), 4.51 (dd, J = 10.4, 14.4 Hz, 1H), 4.10 (q, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.74 (dd, J = 4.4, 14.4 Hz, 1H), 3.69 (t, J = 6.4 Hz, 2H), 2.84 (s, 3H), 2.74 - 2.60 (m, 4H), 2.24 (quin, J = 6.8 Hz, 2H), 1.63 - 1.56 (m, 2H), 1.46 (t, J = 7.2 Hz, 3H), 1.28 (br s, 6H), 0.92 - 0.82 (m, 3H).

[0126] LCMS: 607.0 ([M+H] + ).

[0127] Example 2. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-(γ-chlorobutanamido)-5-hexen(-1)yl-isoindoline-1,3-dione JPEG0007716147000026.jpg34128

[0128] Compound 1-7A (20.00 mg, 39.95 μmol, 1 eq) and chlorobutyryl chloride (6.20 mg, 43.95 μmol, 4.92 μL, 1.1 eq) were dissolved in DCE (2 mL), and DIEA (5.16 mg, 39.95 μmol, 6.96 μL, 1 eq) was added to the reaction solution. The mixture was stirred at 50 °C for 16 h. The reaction solution was rotary evaporated and purified by prep-HPLC (formic acid system) to obtain Example 2 as a white solid (5.13 mg, yield 21.22%).

[0129] 1 1H-NMR (400 MHz, CDCl3) δ = 8.03 (br s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.11 - 7.06 (m, 2H), 6.83 (d, J = 8.8 Hz, 1H), 6.42 - 6.28 (m, 2H), 5.85 (dd, J = 4.4, 10.4 Hz, 1H), 4.51 (br dd, J = 10.4, 14.4 Hz, 1H), 4.10 (q, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.77 - 3.62 (m, 3H), 2.83 (s, 3H), 2.69 (br s, 2H), 2.23 (quin, J = 7.2 Hz, 4H), 1.50 - 1.43 (m, 5H), 1.40 - 1.33 (m, 2H), 0.96 - 0.87 (m, 3H).

[0130] LCMS: 605.1([M+H] + ).

[0131] Example 3. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-cyclopropanamide-5-octylisoindoline-1,3-dione JPEG0007716147000027.jpg59146

[0132] Synthesis of Compound 3-2: 5-Bromo-2-methyl-3-nitrobenzoic acid (20 g, 76.91 mmol, 1 eq.), which is Compound 3-1, was dissolved in H2O (20 mL), and NaOH (9.23 g, 230.73 mmol, 3 eq) was added. The temperature was raised to 80 o °C, and KMnO4 (97.24 g, 615.29 mmol, 8 eq.) was added in batches over 3 hours. After the addition, the mixture was stirred at 80 o °C for 30 min, then suction filtered, and the filter cake was washed with hot water (300 mL * 3). The aqueous phase was cooled with ice water, adjusted to pH = 1 with 2M HCl, extracted with EtOAc (400 mL * 3), the combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated to obtain Compound 3-2 as a yellow solid (5 g, yield 22.42%).

[0133] 1 1H-NMR (400 MHz, DMSO-d6) δ = 13.98 (br s, 2H), 8.52 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H).

[0134] Synthesis of Compound 3-3: Compound 3-2 (5 g, 17.24 mmol, 1 eq.) was dissolved in Ac2O (20 mL) and stirred at 140 o °C for 16 hours. The crude product obtained by rotary drying the reaction solution was purified by column chromatography (petroleum ether:ethyl acetate 100 / 0 to 1 / 1) to obtain Compound 3-3 as a yellow solid (4.5 g, crude product).

[0135] Synthesis of Compound 3-4: Compound 3-3 (4 g, 14.71 mmol, 1 eq) and Compound 11a (4.02 g, 14.71 mmol, 1 eq.) were dissolved in AcOH (80 mL) and stirred at 120 °C for 16 hours. The crude product obtained by rotary drying the reaction solution was purified by column chromatography (petroleum ether:ethyl acetate 100 / 0 ~ 1 / 1) to obtain Compound 3-4 as a yellow solid (2.9 g, yield 37.40%).

[0136] 1 H-NMR (400 MHz, CDCl3) δ = 8.24 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.13 - 7.06 (m, 2H), 6.84 (d, J = 7.6 Hz, 1H), 5.91 (dd, J = 11.2, 4.4 Hz, 1H), 4.57 (dd, J = 14.4, 11.2 Hz, 1H), 4.14 - 4.07 (m, 2H), 3.85 (s, 3H), 3.66 (dd, J = 14.4, 4.0 Hz, 1H), 2.91 (s, 3H), 1.47 (t, J = 7.2 Hz, 3H).

[0137] Synthesis of Compounds 3-5: Compound 3-4 (400.00 mg, 758.52 μmol, 1 eq), PdCl2(PPh3)2 (106.48 mg, 151.70 μmol, 0.2 eq), CuI (28.89 mg, 151.70 μmol, 0.2 eq), DIEA (294.09 mg, 2.28 mmol, 396.35 μL, 3 eq) and 1-octyne (417.93 mg, 3.79 mmol, 5 eq) were dissolved in DMF (4 mL), and the reaction mixture was stirred at 60 o °C for 16 h under a nitrogen atmosphere. Water (10 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, concentrated, and the resulting crude product was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 100:1 to 1:1) to obtain yellow solid Compound 3-5 (130 mg, yield 30.79%).

[0138] 11H-NMR (400 MHz, CDCl3) δ = 7.13 - 7.07 (m, 3H), 6.85 - 6.80 (m, 2H), 5.82 (dd, J = 9.6, 5.2 Hz, 1H), 5.15 (s, 2H), 4.49 (dd, J = 14.4, 9.6 Hz, 1H), 4.10 (d, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.78 (dd, J = 14.4, 5.2 Hz, 1H), 2.80 (s, 3H), 2.39 (t, J = 7.2 Hz, 2H), 1.63 - 1.56 (m, 2H), 1.46 (t, J = 7.2 Hz, 3H), 1.32 - 1.30 (m, 3H), 0.88 - 0.87 (m, 4H).

[0139] Synthesis of Compound 3-6: Compound 3-5 (130 mg, 233.55 μmol, 1 eq) was dissolved in EtOAc (15 mL), and Pd / C (140 mg, 10%) was added under a nitrogen gas atmosphere. The mixture was evacuated and replaced with hydrogen gas three times, and then stirred at 60 o °C for 16 h under a hydrogen gas (50 Psi) atmosphere. The reaction mixture was filtered through diatomaceous earth to remove solids, the filter cake was washed with EtOAc, and the filtrate was rotary evaporated to obtain a yellow solid of Compound 3-6 (100 mg, yield 80.68%).

[0140] 1H-NMR (400 MHz, CDCl3) δ = 7.14 - 7.08 (m, 2H), 7.00 - 6.96 (m, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.62 (s, 1H), 5.82 (dd, J = 5.2, 9.6 Hz, 1H), 5.30 (s, 1H), 5.12 (s, 2H), 4.51 (dd, J = 14.8, 9.6 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.79 (dd, J = 14.8, 5.2 Hz, 1H), 2.80 (s, 3H), 2.57 (t, J = 7.6 Hz, 2H), 2.05 - 1.98 (m, 1H), 1.57 (br s, 2H), 1.46 (t, J = 7.2 Hz, 3H), 1.26 (br d, J = 6.8 Hz, 8H), 0.89 - 0.86 (m, 3H).

[0141] Synthesis of Example 3:

[0142] Compound 3-6 (10 mg, 18.84 μmol, 1 eq) and cyclopropanecarbonyl chloride (9.85 mg, 94.22 μmol, 8.56 μL, 5 eq.) were dissolved in DCE (1 mL), and DIEA (19.48 mg, 150.75 μmol, 26.26 μL, 8 eq) was added to the reaction solution, followed by stirring at 90 °C for 2 hours. The reaction solution was rotary dried and purified by prep-HPLC (formic acid system) to obtain Example 3 as a white solid (8.2 mg, yield 72.68%).

[0143] 1H-NMR (400 MHz, 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, 4.4 Hz, 1H), 4.55 (dd, J = 14.4, 10.4 Hz, 1H), 4.11 (q, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.74 (dd, J = 14.4, 4.4 Hz, 1H), 2.86 (s, 3H), 2.69 - 2.64 (m, 2H), 1.67 - 1.58 (m, 3H), 1.47 (t, J = 7.2 Hz, 3H), 1.26 (br d, J = 12.4 Hz, 10H), 1.12 (quin, J = 3.6 Hz, 2H), 0.97 - 0.91 (m, 2H), 0.89 - 0.84 (m, 3H)

[0144] LCMS: 599.1 [M+H] + .

[0145] Example 4. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-acetamidomethyl-7-penty lisoindoline-1,3-dione JPEG0007716147000028.jpg30162

[0146] Example 4 was synthesized according to Synthetic Route 6.

[0147] LCMS: 545.1 ([M+H] + ).

[0148] Example 5. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-(γ-chlorobutanamide)-7-penty lisoindoline-1,3-dione JPEG0007716147000029.jpg64140

[0149] Synthesis of Compound 5-2: Compound 5-1 (21.19 g, 109.75 mmol, 1 eq) and Compound 11a (30 g, 109.75 mmol, 1 eq) were dissolved in HOAc (500 mL) and stirred at 120 °C for 16 h. The crude product obtained by rotary evaporation of the reaction solution was purified by column chromatography (petroleum ether: ethyl acetate 100 / 0 - 1:1) to obtain yellow solid Compound 5-2 (43.3 g, yield 89.98%).

[0150] 1 H-NMR (400 MHz, CDCl3) δ = 8.13 - 8.07 (m, 2H), 7.92 - 7.86 (m, 1H), 7.15 - 7.09 (m, 2H), 6.84 (d, J = 8.0 Hz, 1H), 5.93 (dd, J = 4.0, 10.8 Hz, 1H), 4.58 (dd, J = 10.8, 14.4 Hz, 1H), 4.15 - 4.07 (m, 2H), 3.85 (s, 3H), 3.70 (dd, J = 4.4, 14.4 Hz, 1H), 2.90 (s, 3H), 1.47 (t, J = 7.2 Hz, 3H).

[0151] Synthesis of Compound 5-3: Compound 5-2 (50.00 g, 111.15 mmol, 1 eq) was dissolved in EtOAc (400 mL), Pd / C (9 g, 10%) was added under a nitrogen gas atmosphere, and the mixture was evacuated and replaced with hydrogen gas three times. Then, it was stirred at 60 °C for 12 h under a hydrogen gas (50 Psi) atmosphere. The reaction solution was filtered through diatomaceous earth to remove the solid, the filter cake was washed with EtOAc, and the filtrate was rotary evaporated to obtain yellow solid Compound 5-3 (4 g, yield 85.73%).

[0152] 11H-NMR (400 MHz, CDCl3) δ = 7.37 (dd, J = 7.2, 8.4 Hz, 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, 9.8 Hz, 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, 14.8 Hz, 1H), 2.79 (s, 3H), 1.47 - 1.42 (m, 3H).

[0153] Synthesis of Compound 5-4: Compound 5-3 (47.4 g, 113.27 mmol, 1 eq) was dissolved in ethyl acetate (500 mL), NBS (20.16 g, 113.27 mmol, 1 eq) was added, and the mixture was stirred at 25 o °C for 16 h. The crude product obtained by rotary evaporation of the reaction solution was purified by column chromatography (petroleum ether:ethyl acetate 100 / 0 ~ 1:1) to give yellow solid Compound 5-4 (26.52 g, yield 42.07%).

[0154] 1 1H-NMR (400 MHz, CDCl3) δ = 7.44 (d, J = 8.4 Hz, 1H), 7.16 - 7.08 (m, 2H), 6.84 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 5.86 (dd, J = 4.4, 10.4 Hz, 1H), 5.55 - 5.15 (m, 2H), 4.55 (dd, J = 10.4, 14.4 Hz, 1H), 4.15 - 4.02 (m, 2H), 3.86 (s, 3H), 3.77 (dd, J = 4.8, 1'4.4 Hz, 1H), 2.85 (s, 3H), 1.47 (t, J = 7.2 Hz, 3H).

[0155] Synthesis of Compound 5-5: Compound 5-4 (13.98 g, 28.11 mmol, 1 eq), Cs2CO3 (27.47 g, 84.33 mmol, 3 eq), pentylboronic acid (6.52 g, 56.22 mmol, 2 eq) were dissolved in dioxane (150 mL) and water (30 mL). Under a nitrogen atmosphere, Pd(dppf)Cl2 (4.11 g, 5.62 mmol, 0.2 eq) was added, and the mixture was stirred at 60 o °C under a nitrogen gas atmosphere for 18 hours. The reaction solution was concentrated, water (50 mL) and ethyl acetate (50 mL) were added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and the concentrated crude product was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 100 / 0 to 1:1) to obtain yellow solid Compound 5-5 (4.78 g, yield 34.80%).

[0156] 1 1H-NMR (400 MHz, CDCl3) δ = 7.18 (d, J = 8.4 Hz, 1H), 7.16 - 7.10 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.83 (dd, J = 5.2, 9.6 Hz, 1H), 5.14 (s, 2H), 4.50 (dd, J = 9.6, 14.4 Hz, 1H), 4.16 - 4.09 (m, 2H), 3.85 (s, 3H), 3.83 - 3.78 (m, 1H), 3.64 (t, J = 6.8 Hz, 1H), 2.96 - 2.86 (m, 2H), 2.83 - 2.76 (m, 3H), 1.62 - 1.57 (m, 2H), 1.46 (t, J = 7.2 Hz, 3H), 1.38 - 1.27 (m, 4H), 0.94 - 0.85 (m, 3H)

[0157] Synthesis of Example 5

[0158] Compound 5-5 (4.04 g, 8.27 mmol, 1 eq) and chlorobutyryl chloride (2.33 g, 16.54 mmol, 1.85 mL, 2 eq) were dissolved in DCE (80 mL), and DIEA (4.27 g, 33.07 mmol, 5.76 mL, 4 eq) was added. The mixture was stirred at 90 o °C for 3 h. The reaction solution was rotary evaporated, saturated aqueous NaHCO3 (20 mL) and DCM (20 mL) were added, and the mixture was extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, concentrated, and the resulting crude product was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 1 / 0 - 1:1) to obtain Example 5 as a yellow solid (4.12 g, ee value 96.7%, yield 84.01%).

[0159] 1 1H-NMR (400 MHz, CDCl3) δ = 9.58 (s, 1H), 8.63 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.13 - 7.08 (m, 2H), 6.88 - 6.82 (m, 1H), 5.86 (dd, J = 4.8, 10.0 Hz, 1H), 4.53 (dd, J = 10.4, 14.4 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.75 (dd, J = 4.8, 14.4 Hz, 1H), 3.66 (t, J = 6.4 Hz, 2H), 3.03 - 2.94 (m, 2H), 2.85 (s, 3H), 2.66 (t, J = 7.2 Hz, 2H), 2.22 (quin, J = 6.8 Hz, 2H), 1.65 - 1.57 (m, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.36 - 1.30 (m, 4H), 0.91 - 0.86 (m, 3H).

[0160] LCMS: 593.1([M+H] + ).

[0161] Example 6. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-cyclopropamido-7-pentylisoindoline-1,3-dione JPEG0007716147000030.jpg28157

[0162] Synthesis of Compound 6-2:

[0163] Compound 5-4 (200 mg, 402.12 μmol, 1 eq), PdCl2(PPh3)2 (56.45 mg, 80.42 μmol, 0.2 eq), CuI (15.32 mg, 80.42 μmol, 0.2 eq), DIEA (155.91 mg, 1.21 mmol, 210.12 μL, 3 eq) and 1-pentyne (273.91 mg, 4.02 mmol, 394.69 μL, 10 eq) were dissolved in DMF (2 mL), and the reaction solution was stirred at 60 o °C for 16 hours. Water (5 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 1 / 0 to 1:1) to obtain 98 mg (yield 50.29%) of yellow solid Compound 6-2 (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-aminogroup-6-[pent-1-yl]isoindoline-1,3-dione.

[0164] 1H-NMR (400 MHz, CDCl3) δ = 7.36 (d, J = 8.4 Hz, 1H), 7.15 - 7.10 (m, 2H), 6.82 (d, J = 8.8 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 5.84 (dd, J = 9.6, 5.2 Hz, 1H), 5.32 (d, J = 13.2 Hz, 2H), 4.48 (dd, J = 14.4, 9.2 Hz, 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 = 7.2 Hz, 2H), 1.67 (sxt, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H), 1.08 (t, J = 7.2 Hz, 3H).

[0165] Synthesis of Compound 6-3:

[0166] Compound 6-2 (98 mg, 202.24 μmol, 1 eq) was dissolved in EtOAc (10 mL), and Pd / C (100 mg, 10%) was added under a nitrogen gas atmosphere. The mixture was evacuated and replaced with hydrogen gas three times, and then stirred at 60 o °C for 16 h under a hydrogen gas (50 Psi) atmosphere. The reaction mixture was filtered through diatomaceous earth to remove solids, and the filter cake was washed with EtOAc. The filtrate was rotary evaporated to obtain a yellow solid of Compound 6-3 (60 mg, yield 60.72%).

[0167] 1H-NMR (400 MHz, CDCl3) δ = 7.20 - 7.10 (m, 3H), 6.83 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.84 (dd, J = 9.2, 5.2 Hz, 1H), 5.14 (s, 2H), 4.50 (dd, J = 14.8, 9.6 Hz, 1H), 4.11 (q, J = 6.8 Hz, 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 = 7.2 Hz, 3H), 1.35 - 1.28 (m, 4H), 0.91 - 0.85 (m, 3H).

[0168] Synthesis of Example 6:

[0169] Compound 6-3 (12.5 mg, 25.58 μmol, 1 eq.) and cyclopropanecarbonyl chloride (13.37 mg, 127.92 μmol, 11.63 μL, 5 eq) were dissolved in DCE (1 mL), and DIEA (26.45 mg, 204.67 μmol, 35.65 μL, 8 eq) was added, and the mixture was stirred at 90 o °C for 2 hours. The reaction solution was rotary evaporated and purified by prep-HPLC (formic acid system) to obtain Example 6 as a white solid (5 mg, yield 35.11%).

[0170] 11H-NMR (400 MHz, CDCl3) δ = 9.76 (s, 1H), 8.63 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.14 - 7.08 (m, 2H), 6.88 - 6.81 (m, 1H), 5.87 (dd, J = 10.0, 4.8 Hz, 1H), 4.53 (dd, J = 14.4, 10.0 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.76 (dd, J = 14.4, 4.4 Hz, 1H), 3.01 - 2.94 (m, 2H), 2.84 (s, 3H), 1.67 - 1.58 (m, 3H), 1.47 (t, J = 7.2 Hz, 3H), 1.37 - 1.27 (m, 4H), 1.15 - 1.07 (m, 2H), 0.96 - 0.84 (m, 5H).

[0171] LCMS: 557.1 ([M+H] + ).

[0172] Example 7. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-acetamido-7-pent(-1)enyl-isoindoline-1,3-dione JPEG0007716147000031.jpg44128

[0173] Synthesis of Example 7:

[0174] Compound 6-2 (180 mg, 371.47 μmol, 1.0 eq.) was dissolved in Ac2O (1 mL), and the reaction mixture was stirred for 3 hours. The reaction mixture was rotary evaporated and purified by prep-HPLC (formic acid system) to obtain Example 7 as a white solid (119 mg, yield 60.8%).

[0175] 11H-NMR (400 MHz, DMSO-δ6) δ = 9.77 (s, 1H), 8.46 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 1.9 Hz, 1H), 7.03 - 6.93 (m, 2H), 5.79 (dd, J = 10.4, 4.3 Hz, 1H), 4.35 (dd, J = 14.3, 10.5 Hz, 1H), 4.17 (dd, J = 14.3, 4.4 Hz, 1H), 4.04 (d, J = 7.0 Hz, 2H), 3.75 (s, 3H), 3.04 (s, 3H), 2.49 (d, J = 6.9 Hz, 2H), 2.22 (s, 3H), 1.62 (p, J = 7.2 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H), 1.06 (t, J = 7.4 Hz, 3H).

[0176] LCMS: 527.2 ([M+H] + ).

[0177] Example 8. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-decanamido-7-penten(-1)yl-isoindoline-1,3-dione JPEG0007716147000032.jpg2552

[0178] Synthesis by Synthetic Route 3

[0179] 11H-NMR (400 MHz, CDCl3) δ = 9.47 (s, 1H), 8.79 (d, J = 8.4 Hz, 1H), 7.74 - 7.59 (m, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.11 (dd, J = 5.9, 2.1 Hz, 2H), 6.84 (d, J = 8.9 Hz, 1H), 5.87 (dd, J = 10.4 Hz, 4.4 Hz, 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 = 7.5 Hz, 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).

[0180] LCMS: 573.6 ([M+H] + ).

[0181] Example 9. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-acetamido-7-pentylisoindoline-1,3-dione JPEG0007716147000033.jpg3539

[0182] Synthesis by Synthetic Route 3

[0183] 11H-NMR (400 MHz, DMSO-δ6) δ = 9.70 (s, 1H), 8.35 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 1.8 Hz, 1H), 7.03 - 6.92 (m, 2H), 5.78 (dd, J = 10.4, 4.3 Hz, 1H), 4.37 (dd, J = 14.3 Hz, 10.5 Hz, 1H), 4.15 (dd, J = 14.3 Hz, 4.4 Hz, 1H), 4.03 (q, J = 7.0 Hz, 2H), 3.75 (s, 3H), 3.02 (s, 3H), 2.99 - 2.92 (m, 2H), 2.19 (s, 3H), 1.57 (p, J = 7.3 Hz, 2H), 1.38 - 1.25 (m, 7H), 0.87 (t, J = 6.9 Hz, 3H).

[0184] LCMS: 531.2 ([M+H] + ).

[0185] Example 10. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-butylamido-7-pentylisoindoline-1,3-dione JPEG0007716147000034.jpg3545

[0186] Synthesis by Synthetic Route 3

[0187] 11H-NMR (400 MHz, CDCl3) δ = 9.54 (s, 1H), 8.66 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.15 - 7.06 (m, 2H), 6.84 (d, J = 8.8 Hz, 1H), 5.85 (dd, J = 4.4, 10.0 Hz, 1H), 4.52 (dd, J = 10.4, 14.4 Hz, 1H), 4.11 (q, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.76 (dd, J = 4.4, 14.4 Hz, 1H), 3.03 - 2.94 (m, 2H), 2.84 (s, 3H), 2.42 (t, J = 7.6 Hz, 2H), 1.78 (qd, J = 7.2, 14.8 Hz, 2H), 1.62 - 1.57 (m, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.37 - 1.28 (m, 4H), 1.02 (t, J = 7.2 Hz, 3H), 0.94 - 0.82 (m, 3H).

[0188] LCMS: 559.1([M+H] + ).

[0189] Example 11. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-isovaleramido-7-butylisoindoline-1,3-dione JPEG0007716147000035.jpg3646

[0190] 11H-NMR (400 MHz, CDCl3) δ = 9.52 (s, 1H), 8.67 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.14 - 7.08 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 5.85 (dd, J = 4.8, 10.0 Hz, 1H), 4.52 (dd, J = 10.0, 14.4 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.77 (dd, J = 4.8, 14.4 Hz, 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 = 7.2 Hz, 3H), 1.37 - 1.29 (m, 4H), 1.03 (d, J = 6.4 Hz, 6H), 0.92 - 0.85 (m, 3H).

[0191] LCMS: 573.1 ([M+H] + ).

[0192] Example 12. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-hexamido-7-butylisoindoline-1,3-dione JPEG0007716147000036.jpg3348

[0193] 11H-NMR (400 MHz, CDCl3) δ = 9.54 (broad singlet, 1H), 8.66 (broad doublet, J = 8.4 Hz, 1H), 7.42 (broad doublet, J = 8.8 Hz, 1H), 7.19 - 7.03 (multiplet, 2H), 6.84 (broad doublet, J = 8.4 Hz, 1H), 5.85 (broad doublet of doublets, J = 4.0, 9.2 Hz, 1H), 4.58 - 4.44 (multiplet, 1H), 4.18 - 4.04 (multiplet, 2H), 3.85 (singlet, 3H), 3.76 (broad doublet of doublets, J = 4.0, 14.4 Hz, 1H), 2.98 (broad triplet, J = 7.2 Hz, 2H), 2.84 (singlet, 3H), 2.44 (broad triplet, J = 7.2 Hz, 2H), 1.75 (broad singlet, 2H), 1.60 (broad singlet, 2H), 1.47 (broad triplet, J = 6.8 Hz, 3H), 1.35 (broad doublet, J = 16.4 Hz, 8H), 0.95 - 0.85 (multiplet, 6H).

[0194] LCMS: 587.1 ([M+H] + ).

[0195] Example 13. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-propionamido-7-pentylisoindoline-1,3-dione JPEG0007716147000037.jpg3644

[0196] 11H-NMR (400 MHz, CDCl3) δ = 9.56 (s, 1H), 8.66 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.15 - 7.06 (m, 2H), 6.84 (d, J = 8.8 Hz, 1H), 5.85 (dd, J = 4.8, 10.0 Hz, 1H), 4.52 (dd, J = 10.0, 14.4 Hz, 1H), 4.15 - 4.08 (m, 2H), 3.85 (s, 3H), 3.76 (dd, J = 4.8, 14.4 Hz, 1H), 3.02 - 2.94 (m, 2H), 2.84 (s, 3H), 2.48 (q, J = 7.6 Hz, 2H), 1.63 - 1.58 (m, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.33 - 1.25 (m, 7H), 0.89 - 0.86 (m, 3H).

[0197] LCMS: 545.1 ([M+H] + ).

[0198] Example 14. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-acetamido-7-tridecylindoline-1,3-dione JPEG0007716147000038.jpg4338

[0199] 11H-NMR (400 MHz, CDCl3) δ = 9.53 (s, 1H), 8.64 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.15 - 7.06 (m, 2H), 6.85 (d, J = 8.8 Hz, 1H), 5.86 (dd, J = 4.4, 10.0 Hz, 1H), 4.53 (dd, J = 10.4, 14.4 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.75 (dd, J = 4.8, 14.4 Hz, 1H), 2.98 (dd, J = 6.4, 8.8 Hz, 2H), 2.85 (s, 3H), 2.25 (s, 3H), 1.63 - 1.57 (m, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.33 - 1.18 (m, 20H), 0.91 - 0.85 (m, 3H).

[0200] LCMS: 643.3 ([M+H] + ).

[0201] Example 15. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-cyclopropylamide-7-tridecylisoindoline-1,3-dione JPEG0007716147000039.jpg4339

[0202] 11H-NMR (400 MHz, CDCl3) δ = 9.76 (s, 1H), 8.63 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.15 - 7.08 (m, 2H), 6.85 (d, J = 8.8 Hz, 1H), 5.87 (dd, J = 4.4, 10.0 Hz, 1H), 4.53 (dd, J = 10.4, 14.4 Hz, 1H), 4.12 (q, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.76 (dd, J = 4.8, 14.4 Hz, 1H), 2.97 (br t, J = 7.6 Hz, 2H), 2.84 (s, 3H), 1.68 - 1.57 (m, 3H), 1.47 (t, J = 7.2 Hz, 3H), 1.36 - 1.23 (m, 20H), 1.13 - 1.09 (m, 2H), 0.92 (br dd, J = 3.2, 7.6 Hz, 2H), 0.88 (br t, J = 6.8 Hz, 3H).

[0203] LCMS: 669.2 ([M+H] + ).

[0204] Example 16. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-butylamido-7-nonylisoindoline-1,3-dione JPEG0007716147000040.jpg4746

[0205] 11H-NMR (400 MHz, CDCl3) δ = 9.55 (s, 1H), 8.67 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.14 - 7.08 (m, 2H), 6.85 (d, J = 8.8 Hz, 1H), 5.85 (dd, J = 4.8, 10.0 Hz, 1H), 4.52 (dd, J = 10.0, 14.4 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.76 (dd, J = 4.8, 14.4 Hz, 1H), 2.98 (dd, J = 6.8, 8.8 Hz, 2H), 2.84 (s, 3H), 2.43 (t, J = 7.6 Hz, 2H), 1.79 (sxt, J = 7.6 Hz, 2H), 1.64 - 1.57 (m, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.32 - 1.18 (m, 12H), 1.03 (t, J = 7.6 Hz, 3H), 0.89 - 0.86 (m, 3H).

[0206] LCMS: 615.2 ([M+H] + ).

[0207] Example 17. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-cyclopropylamide-7-nonylisoindoline-1,3-dione JPEG0007716147000041.jpg4241

[0208] 11H-NMR (400 MHz, CDCl3) δ = 9.76 (s, 1H), 8.62 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.15 - 7.08 (m, 2H), 6.85 (d, J = 8.8 Hz, 1H), 5.87 (dd, J = 4.8, 10.0 Hz, 1H), 4.53 (dd, J = 10.0, 14.4 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.77 (dd, J = 4.8, 14.4 Hz, 1H), 3.03 - 2.92 (m, 2H), 2.84 (s, 3H), 1.67 - 1.57 (m, 3H), 1.47 (t, J = 7.2 Hz, 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).

[0209] LCMS: 613.1 ([M+H] + ).

[0210] Example 18. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-propionamido-7-nonylisoindoline-1,3-dione JPEG0007716147000042.jpg4443

[0211] 11H-NMR (400 MHz, CDCl3) δ = 9.56 (s, 1H), 8.66 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.14 - 7.07 (m, 2H), 6.84 (d, J = 8.8 Hz, 1H), 5.85 (dd, J = 4.8, 10.0 Hz, 1H), 4.52 (dd, J = 10.0, 14.4 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.76 (dd, J = 4.8, 14.4 Hz, 1H), 2.98 (dd, J = 6.8, 8.4 Hz, 2H), 2.84 (s, 3H), 2.48 (q, J = 7.6 Hz, 2H), 1.61 - 1.56 (m, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.34 - 1.21 (m, 15H), 0.87 (t, J = 6.8 Hz, 3H)

[0212] LCMS: 601.2 ([M+H] + ).

[0213] Example 19. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-propionamido-7-tridecylisoindoline-1,3-dione JPEG0007716147000043.jpg5045

[0214] 11H-NMR (400 MHz, CDCl3) δ = 9.56 (s, 1H), 8.66 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.16 - 7.06 (m, 2H), 6.84 (d, J = 8.8 Hz, 1H), 5.85 (dd, J = 4.4, 10.0 Hz, 1H), 4.52 (dd, J = 10.0, 14.4 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.76 (dd, J = 4.8, 14.4 Hz, 1H), 2.98 (dd, J = 6.8, 8.8 Hz, 2H), 2.84 (s, 3H), 2.48 (q, J = 7.6 Hz, 2H), 1.62 (br s, 2H), 1.47 (t, J = 7.2 Hz, 2H), 1.49 - 1.43 (m, 3H), 1.37 - 1.23 (m, 23H), 0.90 - 0.84 (m, 3H)

[0215] LCMS: 657.3 ([M+H] + ).

[0216] Example 20. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-(γ-chlorobutanamido)-7-hexylisoindoline-1,3-dione JPEG0007716147000044.jpg4156

[0217] 11H-NMR (400 MHz, CDCl3) δ = 9.58 (s, 1H), 8.63 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.11 (br d, J = 4.4 Hz, 2H), 6.85 (br d, J = 8.8 Hz, 1H), 5.86 (br dd, J = 4.4, 10.0 Hz, 1H), 4.53 (br dd, J = 10.4, 14.4 Hz, 1H), 4.12 (q, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.75 (br dd, J = 4.4, 14.4 Hz, 1H), 3.66 (t, J = 6.4 Hz, 2H), 2.99 (br t, J = 7.6 Hz, 2H), 2.85 (s, 3H), 2.66 (br t, J = 7.2 Hz, 2H), 2.22 (quin, J = 6.6 Hz, 2H), 1.64 - 1.57 (m, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.34 - 1.25 (m, 6H), 0.90 - 0.84 (m, 3H)

[0218] LCMS: 607.1 ([M+H] + ).

[0219] Example 21. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-(γ-chlorobutanamido)-7-heptylisoindoline-1,3-dione JPEG0007716147000045.jpg4455

[0220] 11H-NMR (400 MHz, CDCl3) δ = 9.58 (s, 1H), 8.63 (br d, J = 8.4 Hz, 1H), 7.42 (br d, J = 8.8 Hz, 1H), 7.11 (br s, 2H), 6.85 (br d, J = 8.8 Hz, 1H), 5.86 (br dd, J = 4.4, 10.0 Hz, 1H), 4.53 (br dd, J = 10.4, 14.0 Hz, 1H), 4.12 (q, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.75 (br dd, J = 4.4, 14.4 Hz, 1H), 3.66 (br t, J = 6.0 Hz, 2H), 3.07 - 2.91 (m, 2H), 2.85 (s, 3H), 2.65 (br t, J = 7.2 Hz, 2H), 2.22 (quin, J = 6.5 Hz, 2H), 1.58 (br d, J = 6.4 Hz, 2H), 1.47 (br t, J = 6.8 Hz, 3H), 1.34 - 1.23 (m, 8H), 0.87 (br t, J = 6.4 Hz, 3H).

[0221] LCMS: 621.1 ([M+H] + ).

[0222] Example 22. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-(γ-chlorobutanamido)-7-octylisoindoline-1,3-dione JPEG0007716147000046.jpg4553

[0223] 11H-NMR (400 MHz, CDCl3) δ = 9.58 (s, 1H), 8.63 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.11 (dd, J = 2.4, 4.4 Hz, 2H), 6.88 - 6.82 (m, 1H), 5.86 (dd, J = 4.4, 10.0 Hz, 1H), 4.53 (dd, J = 10.4, 14.4 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.75 (dd, J = 4.8, 14.4 Hz, 1H), 3.66 (t, J = 6.4 Hz, 2H), 3.03 - 2.91 (m, 2H), 2.85 (s, 3H), 2.66 (t, J = 7.2 Hz, 2H), 2.22 (quin, J = 6.8 Hz, 2H), 1.64 - 1.56 (m, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.35 - 1.23 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H).

[0224] LCMS: 635.1 ([M+H] + ).

[0225] Example 23. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-propionamido-6-hexylisoindoline-1,3-dione JPEG0007716147000047.jpg3361

[0226] 11H-NMR (400 MHz, CDCl3) δ = 8.00 (broad singlet, 1H), 7.60 (quartet, J = 7.6 Hz, 2H), 7.11 - 7.05 (multiplet, 2H), 6.83 (doublet, J = 7.6 Hz, 1H), 5.85 (doublet of doublets, J = 4.8, 10.0 Hz, 1H), 4.51 (doublet of doublets, J = 9.6, 14.4 Hz, 1H), 4.10 (quartet, J = 7.2 Hz, 2H), 3.85 (singlet, 3H), 3.75 (doublet of doublets, J = 4.4, 14.4 Hz, 1H), 2.83 (singlet, 3H), 2.71 - 2.63 (multiplet, 2H), 2.51 (quartet, J = 7.2 Hz, 2H), 1.60 - 1.56 (multiplet, 2H), 1.46 (triplet, J = 7.2 Hz, 3H), 1.32 - 1.25 (multiplet, 9H), 0.90 - 0.84 (multiplet, 3H).

[0227] LCMS: 559 ([M+H] + ).

[0228] Example 24. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-(γ-chlorobutanamido)-7-pentylisoindoline-1,3-dione JPEG0007716147000048.jpg3547

[0229] 11H-NMR (400 MHz, CDCl3) δ = 9.63 (s, 1H), 8.65 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.15 - 7.07 (m, 2H), 6.85 (d, J = 8.8 Hz, 1H), 5.86 (dd, J = 4.4, 10.4 Hz, 1H), 4.53 (dd, J = 10.4, 14.4 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.88 (t, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.75 (dd, J = 4.4, 14.4 Hz, 1H), 3.03 - 2.95 (m, 2H), 2.91 (t, J = 6.4 Hz, 2H), 2.85 (s, 3H), 1.64 - 1.56 (m, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.37 - 1.29 (m, 4H), 0.93 - 0.85 (m, 3H).

[0230] LCMS: 579 ([M+H] + ).

[0231] Example 25. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-(chloroacetamido)-7-penty lisoindoline-1,3-dione JPEG0007716147000049.jpg3544

[0232] 11H-NMR (400 MHz, CDCl3) δ = 10.57 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.17 - 7.09 (m, 2H), 6.85 (d, J = 8.0 Hz, 1H), 5.87 (dd, J = 4.8, 10.0 Hz, 1H), 4.53 (dd, J = 10.4, 14.4 Hz, 1H), 4.21 (s, 2H), 4.16 - 4.09 (m, 2H), 3.85 (s, 3H), 3.77 (dd, J = 4.8, 14.4 Hz, 1H), 3.04 - 2.98 (m, 2H), 2.84 (s, 3H), 1.63 - 1.59 (m, 2H), 1.47 (t, J = 6.8 Hz, 3H), 1.36 - 1.31 (m, 4H), 0.91 - 0.87 (m, 3H)

[0233] LCMS: 587 ([M+Na] + ).

[0234] Example 26. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-chloroacetamido-7-butylisoindoline-1,3-dione JPEG0007716147000050.jpg3245

[0235] 11H-NMR (400 MHz, CDCl3) δ = 10.57 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.17 - 7.10 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 5.87 (dd, J = 4.8, 10.0 Hz, 1H), 4.53 (dd, J = 9.6, 14.4 Hz, 1H), 4.21 (s, 2H), 4.17 - 4.08 (m, 2H), 3.85 (s, 3H), 3.77 (dd, J = 4.8, 14.4 Hz, 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 = 7.2 Hz, 3H)

[0236] LCMS: 551 ([M+H] + ).

[0237] Example 27. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-(γ-chlorobutanamide)-7-butylisoindoline-1,3-dione JPEG0007716147000051.jpg3557

[0238] 11H-NMR (400 MHz, CDCl3) δ = 9.59 (s, 1H), 8.63 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.15 - 7.07 (m, 2H), 6.85 (d, J = 8.8 Hz, 1H), 5.86 (dd, J = 4.4, 10.0 Hz, 1H), 4.53 (dd, J = 10.0, 14.4 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.75 (dd, J = 4.8, 14.4 Hz, 1H), 3.67 (t, J = 6.4 Hz, 2H), 3.04 - 2.96 (m, 2H), 2.85 (s, 3H), 2.66 (t, J = 7.2 Hz, 2H), 2.22 (quin, J = 6.8 Hz, 2H), 1.63 - 1.56 (m, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.43 - 1.34 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H).

[0239] LCMS: 579 ([M+H] + ).

[0240] Example 28. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-fluoroacetamido-7-pentylisoindoline-1,3-dione JPEG0007716147000052.jpg3745

[0241] 11H-NMR (400 MHz, CDCl3) δ = 10.34 (broad d, J = 4.4 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.16 - 7.10 (m, 2H), 6.84 (d, J = 8.8 Hz, 1H), 5.86 (dd, J = 4.4, 10.0 Hz, 1H), 5.04 - 4.86 (m, 2H), 4.54 (dd, J = 10.0, 14.4 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.75 (dd, J = 4.4, 14.4 Hz, 1H), 3.01 (dd, J = 6.8, 8.8 Hz, 2H), 2.85 (s, 3H), 1.67 - 1.59 (m, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.39 - 1.32 (m, 4H), 0.93 - 0.87 (m, 3H).

[0242] LCMS: 571 ([M+Na] + ).

[0243] Example 29. (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-alkylsulfonylethyl]-4-acrylamido-7-pentylisoindoline-1,3-dione JPEG0007716147000053.jpg3441

[0244] 11H-NMR (400 MHz, CDCl3) δ = 9.73 (s, 1H), 8.73 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.11 (qd, J = 2.0, 4.4 Hz, 2H), 6.85 (d, J = 8.8 Hz, 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, 14.4 Hz, 1H), 4.12 (q, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.76 (dd, J = 4.4, 14.4 Hz, 1H), 3.03 - 2.96 (m, 2H), 2.85 (s, 3H), 1.66 - 1.57 (m, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.38 - 1.31 (m, 4H), 0.92 - 0.85 (m, 3H)

[0245] LCMS: 543 ([M+H] + ).

[0246] Example 30: JPEG0007716147000054.jpg40154

[0247] Synthesis of Compound 30-2:

[0248] Compound 5-5 (200 mg, 0.409 mmol, 1.0 eq) was dissolved in DCM (7 mL), added to DIEA (158 mg, 1.228 mmol, 3.0 eq) and Compound 30-1 (111.77 mg, 0.818 mmol, 2.0 eq), and stirred at room temperature for 1 hour. The reaction solution was quenched with water, water (10 mL) was added, extracted with ethyl acetate (20 * 2 mL), the organic phases were combined, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 1 / 0 to 1:1) to obtain Compound 30-2 (150 mg, yield 62.5%).

[0249] 1H-NMR (400 MHz, DMSO) δ 10.10 (s, 1H), 8.42 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 1.8 Hz, 1H), 6.97 (dt, J = 16.7, 5.1 Hz, 2H), 5.77 (dd, J = 10.1, 4.6 Hz, 1H), 4.76 (s, 2H), 4.34 (dd, J = 14.3, 10.2 Hz, 1H), 4.16 (dd, J = 14.4, 4.7 Hz, 1H), 4.03 (d, J = 7.1 Hz, 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 = 6.9 Hz, 3H), 1.30 - 1.22 (m, 4H), 0.85 (t, J = 6.8 Hz, 3H).

[0250] Synthesis of Example 30:

[0251] Compound 30-2 (150 mg, 0.255 mmol, 1.0 eq) was dissolved in THF (5 mL) and H2O (2.5 mL), NaOH (2.5 g) was added, and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by prep-TLC (SiO2, dichloromethane:methanol = 10:1) to obtain Example 30 (43.86 mg, yield 31.49 %).

[0252] 1H NMR (400 MHz, DMSO) δ 10.66 (s, 1H), 8.65 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 1.9 Hz, 1H), 6.98 (dt, J = 19.0, 5.2 Hz, 2H), 6.32 (t, J = 5.6 Hz, 1H), 5.77 (dd, J = 10.3, 4.4 Hz, 1H), 4.35 (dd, J = 14.3, 10.5 Hz, 1H), 4.15 (dd, J = 14.3, 4.5 Hz, 1H), 4.09 - 3.98 (m, 4H), 3.74 (s, 3H), 3.02 (d, J = 5.9 Hz, 3H), 2.99 - 2.88 (m, 2H), 1.66 - 1.41 (m, 2H), 1.35 - 1.23 (m, 7H), 0.85 (t, J = 6.9 Hz, 3H).

[0253] LCMS: (M+H) + : 547.

[0254] Example 31: JPEG0007716147000055.jpg46147

[0255] Synthesis of Compound 31-2:

[0256] Compound 31-1 (1.0 g, 11.1 mmol, 1.0 eq) was dissolved in DCM (15 mL), and at 0 o °C, (COCl)2 (1.8 g, 14.4 mmol, 1.3 eq) was added, followed by a catalytic amount of DMF (0.1 mL), and the mixture was stirred at room temperature for 18 hours. The reaction solution was used directly in the next step.

[0257] Synthesis of Example 31:

[0258] Compound 5-5 (100 mg, 0.20 mmol, 1.0 eq) was dissolved in DCM (5 mL), DIEA (400 mg, 3.05 mmol, 5.0 eq) and Compound 31-2 (1.0 mL) were added, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, concentrated, and the resulting crude product was purified by prep-HPLC (formic acid system) to obtain Example 31 (15.28 mg, yield 10%).

[0259] 1 1H-NMR (400 MHz, CDCl3) δ 10.47 (s, 1 H), 8.70 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1 H), 7.14 - 7.12 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 5.88 (q, J = 4.8 Hz, 1 H), 4.52 - 4.47 (m, 1 H), 4.13 - 4.12 (m, 2 H), 4.06 (d, J = 1.0 Hz, 2H), 3.85 (s, 3 H), 3.81 (dd, J = 5.2 Hz, 14.4 Hz, 1H), 3.58 (s, 3H), 2.99 (t, J = 8.0 Hz, 2H), 2.82 (s, 3 H), 1.48 (t, J = 10.2 Hz, 4H), 1.35 - 1.32 (m, 5H), 1.26 (s, 1H), 0.92 - 0.87 (m, 3H).

[0260] LCMS: (M+H)+ :561.

[0261] Example 32 JPEG0007716147000056.jpg74159

[0262] Synthesis of Compound 32-1:

[0263] Compound 5-4 (2 g, 4.12 mmol, 1.0 eq) was added to acetic anhydride (9 mL), and the mixture was stirred at 110 °C for 2 hours. The reaction solution was concentrated to obtain a residue, and the residue was pulped with methyl tert-butyl ether / ethyl acetate (20 mL / 10 mL), filtered, and the filter cake was washed with methyl tert-butyl ether to obtain Compound 32-1 (1.8 g, 3.34 mmol, yield 80.99%).

[0264] Synthesis of Compound 32-3:

[0265] Compound 32-2 (8.05 g, 69.30 mmol, 1.0 eq) was dissolved in THF (100 mL), and LiAlD4 (3.2 g, 41.98 mmol, 1.1 eq) was added at 0 o °C, and the temperature was gradually raised to room temperature and stirred for 5 hours. The reaction solution was quenched with ethyl acetate (4 mL) and concentrated to obtain a solid, which was suspended in ethyl acetate (100 mL) at 0 o °C, a small amount of cold water (80 mL) was added, the pH of the solution was adjusted to 1 with 2M HCl, and the mixture was extracted with ethyl acetate (60 mL * 2). After combining the organic phases, the mixture was washed with saturated brine, dried over Na2SO4, filtered, and concentrated to obtain Compound 32-3 (5.13 g, 56.89 mmol, yield 82.11%).

[0266] Synthesis of Compound 32-4:

[0267] HBr (14.62 g, 40% purity, 72.26 mmol, 1.27 eq) was dissolved in H2SO4 (3.64 mL), and Compound 32-3 (5.13 g, 56.89 mmol, 1 eq) was added, and the mixture was heated at 120 oIt was stirred at 2 °C for 2 hours. The reaction solution was quenched with water (500 mL), extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with saturated brine, dried over Na2SO4, filtered, and concentrated to obtain compound 32-4 (1.79 g, 11.69 mmol, yield 20.56%).

[0268] Synthesis of compound 32-5:

[0269] B2Pin2 (3.199 g, 12.64 mmol, 1.5 eq), CuI (160 mg, 0.84 mmol, 0.1 eq), LiO t Bu (1.349 g, 16.86 mmol, 2 eq) were dissolved in tetrahydrofuran (10 mL), compound 32-4 (1.29 g, 8.42 mmol, 1 eq) was added, and the mixture was stirred at room temperature for 16 hours under a nitrogen gas atmosphere. The reaction solution was filtered, and the obtained crude product was purified by column chromatography (silicon dioxide, hexane:ethyl acetate = 100:1:501) to obtain compound 32-5 (1.28 g, 6.39 mmol, yield 75.96%).

[0270] Synthesis of compound 32-6:

[0271] Compound 32-5 (400 mg, 1.99 mmol, 1.0 eq) was dissolved in methanol (5 mL), KHF2 (4.5 mL, 19.99 mmol, 4.5 M, 10 eq) was added, and the mixture was stirred at room temperature for 16 hours. The obtained crude product was concentrated, the product was dissolved in hot acetone (10 mL) and filtered, the combined filtrates were concentrated to 4 mL, ethyl ether (10 mL) was added, the precipitated white solid was filtered, and the filter cake was dried to obtain compound 32-6 (260 mg, 1.44 mmol, yield 72.36%).

[0272] Synthesis of compound 32-7:

[0273] Compound 32-6 (260 mg, 1.44 mmol, 1.0 eq) was dissolved in acetonitrile / water (2 mL / 1 mL), trimethoxychlorosilane (468 mg, 4.31 mmol, 3 eq) was added, and the mixture was stirred at room temperature for 16 h. The reaction solution was diluted with saturated sodium hydrogen carbonate solution (10 mL), extracted with ethyl acetate (10 mL × 2), the combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, concentrated to obtain Compound 32-7 (30 mg, 0.25 mmol, yield 17.66%).

[0274] Synthesis of Example 32:

[0275] Compound 32-7 (30 mg, 0.25 mmol, 2 eq) was dissolved in dioxane (0.5 mL), Compound 32-1 (68.5 mg, 0.127 mmol, 1 eq), K2CO3 (52.6 mg, 0.381 mmol, 3 eq) and Pd(dppf)Cl2 (4.6 mg, 6.35 μmol, 0.05 eq) were added, and the mixture was stirred at 100 o °C for 4 h under a nitrogen gas atmosphere. Water (10 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (3 mL × 2), the combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and the obtained crude product was purified by prep-HPLC (formic acid system) to obtain Example 32 (24.87 mg, 0.047 mmol, yield 36.81%).

[0276] 11H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 8.64 (d, J = 8 Hz, 1H), 7.42 (d, J = 8 Hz, 1H), 7.10 (s, 2H), 6.85 (d, J = 8 Hz, 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 = 4 Hz, 2H), 0.88 (t, 3H).

[0277] LCMS: (M+H) + :533.3

[0278] Example 33: JPEG0007716147000057.jpg108142

[0279] Synthesis of Compound 33-2: Compound 33-1 (1 g, 5.88 mmol, 1eq) was dissolved in H2SO4 (3.75 mL), and HNO3 (1.48 g, 23.51 mmol, 1.06 mL, 4eq) was added. The reaction mixture was stirred at 100 o °C for 3 hours. The reaction mixture was slowly poured into ice water (50 mL), extracted with ethyl acetate (50 mL * 3), the organic phases were combined, washed with saturated brine, dried over Na2SO4, filtered, and the crude product obtained by concentration was purified by column chromatography to give Compound 33-2 (970 mg, 4.08 mmol, yield 69.37%).

[0280] LCMS (ESI+): m / z 258.9 (M+1+46) +

[0281] Synthesis of Compound 33-3: Compound 33-2 (970 mg, 4.53 mmol, 1 eq) was dissolved in acetic anhydride (15 mL) and stirred at 120 °C for 2 hours. The crude product obtained by concentrating the reaction solution, Compound 33-3 (888 mg, 4.53 mmol, yield 99.96%), was used directly in the next step.

[0282] Synthesis of Compound 33-4: Compound 11a (1.36 g, 4.98 mmol, 1.1 eq) and Compound 33-3 (888 mg, 4.53 mmol, 1 eq) were dissolved in AcOH (15 mL) and stirred at 120 o °C for 16 hours. The crude product obtained by concentrating the reaction solution was purified by column chromatography (petroleum ether:ethyl acetate 10 / 1 - 4 / 1) to obtain Compound 33-4 (680 mg, 1.51 mmol, yield 33.27%).

[0283] LCMS (ESI+): m / z 451.5 (M+1) + :

[0284] Synthesis of Compound 33-5: Compound 33-4 (580 mg, 1.28 mmol, 1 eq) was dissolved in ethyl acetate (5 mL), Pd / C (100 mg, 7.71 mmol, purity 10%) was added under a hydrogen gas atmosphere, and the mixture was stirred at 50 o °C for 3 hours under a hydrogen gas (15 psi) atmosphere. The reaction solution was filtered and concentrated to obtain Compound 33-5 (520 mg, 1.23 mmol, yield 96.03%).

[0285] LCMS (ESI+): m / z 451.5 (M+1) +

[0286] Synthesis of Compound 33-6: Compound 33-5 (520 mg, 1.23 mmol, 1 eq) was dissolved in ethyl acetate (10 mL), NBS (219.59 mg, 1.23 mmol, 1 eq) was added, and the mixture was stirred at 25 oStirred at C for 4 h, extracted with water (30 mL) and ethyl acetate (3 * 30 mL), combined the organic phases, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The obtained crude product was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 100 / 0 - 1:1) to obtain compound 33-6 (534 mg, 1.07 mmol, yield 86.67%).

[0287] LCMS (ESI+): m / z 499.6 (M+1) +

[0288] Synthesis of compound 33-7: Dissolve compound 33-6 (534 mg, 1.07 mmol, 1eq) in acetic anhydride (190.33 mg, 1.86 mmol, 174.61 uL, 1.74eq), stir the reaction solution at 120 o C for 3 h, concentrate the reaction solution to obtain the crude product, compound 33-7 (450 mg, 831.17 umol, yield 77.73%).

[0289] Synthesis of compound 33-8: Dissolve compound 33-7 (100 mg, 184.70 umol, 1eq), CuI (7.04 mg, 36.94 umol, 0.2eq), Pd(PPh3)2Cl2 (25.93 mg, 36.94 umol, 0.2eq), DIEA (71.61 mg, 554.11 umol, 96.52 uL, 3eq) and 1-pentyne (125.81 mg, 1.85 mmol, 181.29 uL, 10eq) in DMF (4 mL), stir the reaction solution at 60 o C under N2 atmosphere for 16 h, add water (5 mL) to the reaction system, extract with ethyl acetate (5 mL * 3), combine the organic phases, wash with saturated brine, dry over Na2SO4, filter, and concentrate. The obtained crude product was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 1 / 0 - 1:1) to obtain compound 33-8 (75 mg, 141.88 umol, yield 76.82%).

[0290] LCMS (ESI+): m / z 529.4 (M+1) +

[0291] Synthesis of Example 33: Compound 33-8 (75 mg, 141.88 μmol, 1 eq) was dissolved in EtOAc (5 mL), and Pd / C (160 mg, 141.88 μmol, 10% purity) was added under a nitrogen gas atmosphere. The mixture was evacuated and replaced with hydrogen gas three times, and then stirred at 50 o °C for 16 hours under a hydrogen gas (15 Psi) atmosphere. The reaction solution was filtered through diatomaceous earth to remove solids, the filter cake was washed with EtOAc, and the filtrate was rotary evaporated. The resulting crude product was purified by prep-HPLC (formic acid system) to obtain Example 33 (19 mg, 35.67 μmol, yield 25.14%).

[0292] 1 H NMR (400 MHz, DMSO-d6) δ 0.85 (s, 3 H), 1.22 - 1.36 (m, 7 H), 1.44 - 1.66 (m, 2 H), 2.17 (s, 3 H), 2.95 (t, J = 7.15 Hz, 2 H), 3.01 (s, 3 H) 3.73 (s, 3 H), 4.01 (d, J = 6.85 Hz, 2 H), 4.08 - 4.19 (m, 1 H), 4.28 - 4.41 (m, 1 H), 5.76 (d, J = 5.99 Hz, 1 H), 6.89 - 7.01 (m, 2 H), 7.07 (s, 1 H) 9.68 (s, 1 H).

[0293] LCMS (ESI+): m / z 533.1 (M+1) +

[0294] Example 55 JPEG0007716147000058.jpg78140JPEG0007716147000059.jpg42137

[0295] Synthesis of Compound 55-2: Compound 32-1 (5 g, 9.27 mmol) was dissolved in dioxane (60 mL) and water (15 mL). Pd(dppf)Cl2 (900 mg, 1.23 mmol), 55-1A (3.18 g, 23.8 mmol), and potassium phosphate (6.89 g, 32.4 mmol) were added to the reaction solution under a nitrogen gas atmosphere. The reaction system was purged with nitrogen gas and then stirred at 95 °C for 16 h under a nitrogen gas atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL × 2), and then washed with saturated brine (200 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and separated and purified by column chromatography to obtain yellow solid Compound 55-2 (4.2 g, 7.77 mmol, yield 83.8%).

[0296] LCMS (ESI+): m / z 478.0 (M+1) + :

[0297] Synthesis of Compound 55-3: Compound 55-2 (4.2 g, 8.63 mmol, 1 eq) was dissolved in acetone (400 mL), dichloromethane (150 mL), and water (150 mL). K2O S O4 (1.26 g, 3.42 mmol, 0.4 eq) was added to the reaction solution, and the mixture was stirred at 0 °C for 5 min. Then, NaIO4 (7.39 g, 34.6 mmol, 1.92 mL, 4 eq) was added to the reaction solution, and the mixture was stirred at 20 °C for 6 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (1000 mL), and then washed with saturated brine (300 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and separated and purified by column chromatography to obtain yellow solid Compound 55-3 (3.5 g, 6.45 mmol, yield 74.7%).

[0298] LCMS (ESI+): m / z 489.3 (M+1) + : 1.34 min.

[0299] Synthesis of Example 55: Compound 55-3 (3.5 g, 7.16 mmol, 1 eq) was dissolved in THF (10 mL). The reaction solution was cooled to -78 °C, and n-BuLi (1.6 M, 13.5 mL, 3 eq) was added dropwise. The mixture was stirred at -78 °C for 1 h, then quenched with saturated NH4Cl solution (20 mL), diluted with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and separated and purified by pre-HPLC (FA) to obtain Example 55 (289.80.74 mg, 0.53 mmol, 7.4% yield), which is a pair of diastereoisomeric compounds. Example 55 was subjected to chiral resolution to obtain Example 55 A (107.1 mg, purity 99%) and Example 55 B (117.5 mg, purity 99%).

[0300] Of Example 55 1 1H NMR (400 MHz, CDCl3) δ ppm 0.79 - 0.84 (m, 3 H), 1.19 - 1.32 (m, 4 H), 1.41 (s, 3 H), 1.69 - 1.80 (m, 1 H), 1.70 - 1.76 (m, 1 H), 2.19 (s, 3 H), 2.80 (s, 3 H), 3.67 (dt, J = 14.4, 5.1 Hz, 1 H), 3.79 (s, 3 H), 4.04 (q, J = 7.0 Hz, 2 H), 4.41 - 4.50 (m, 1 H), 4.96 (br d, J = 5.4 Hz, 1 H), 5.77 - 5.84 (m, 1 H), 6.76 - 6.81 (m, 1 H), 6.99 - 7.05 (m, 2 H), 7.19 (s, 7 H), 7.54 (d, J = 8.8 Hz, 1 H), 8.64 (d, J = 8.3 Hz, 1 H), 9.48 (s, 1 H).

[0301] LCMS (ESI+): m / z 569.3 (M+Na) +

[0302] Synthesis of Example 56: JPEG0007716147000060.jpg42128

[0303] Synthesis of Example 56: Compound 55 (60 mg, 0.11 mmol, 1 eq) was dissolved in DCM (1 mL), DMP (120 mg, 0.28 mmol, 2.6 eq) was added, and the mixture was stirred at room temperature for 1 h. Then, DCM (30 mL) was added to the reaction solution, and it was diluted with saturated NaHCO3 solution (3 mL) and saturated NH4Cl (3 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and separated and purified by pre-HPLC (FA) to obtain Compound Example 56 (43.1 mg, 0.08 mmol, yield 72.1%).

[0304] 1 H NMR (400 MHz, CDCl3) δ ppm 0.86 (t, J = 7.3 Hz, 3 H), 1.27 - 1.36 (m, 2 H), 1.41 (s, 3 H), 1.57 - 1.66 (m, 2 H), 2.15 - 2.30 (m, 3 H), 2.78 - 2.88 (m, 3 H), 2.98 (t, J = 7.4 Hz, 2 H), 3.63 (dd, J = 14.3, 4.3 Hz, 1 H), 3.79 (s, 3 H), 4.04 (q, J = 7.0 Hz, 2 H), 4.48 (dd, J = 14.3, 10.8 Hz, 1 H), 5.81 (dd, J = 10.7, 4.2 Hz, 1 H), 6.78 (d, J = 8.2 Hz, 1 H), 6.96 - 7.07 (m, 2 H), 7.61 (d, J = 8.7 Hz, 1 H), 8.73 (d, J = 8.7 Hz, 1 H), 9.66 (s, 1 H).

[0305] LCMS (ESI+): m / z 545.3 (M+H) +

[0306] Examples 34 - 54 JPEG0007716147000061.jpg 245168 JPEG0007716147000062.jpg 224168

[0307] Compound Examples 57 - 82 were synthesized with reference to Example 9, 55 or 56 JPEG0007716147000063.jpg 229136 JPEG0007716147000064.jpg 248136 JPEG0007716147000065.jpg 246136

[0308] Examples of the Biological Activity of the Compounds

[0309] 1. Calculation of cLogP value:

[0310] Compound cLogP is one of the methods to evaluate the lipophilicity of a compound. A high cLogP value indicates that the compound has strong lipophilicity and is likely to passively cross the body's lipid layer (by the principle of diffusion of compound concentration). The compound CLogP values are as shown in the following table: JPEG0007716147000066.jpg 4253

[0311] Note: All Examples 0 involved in the present invention represent the control drug apremilast.

[0312] 2. Measurement of Inhibition of PDE4D3 Enzyme:

[0313] Materials and Equipment: JPEG0007716147000067.jpg 60152

[0314] Measurement Conditions: JPEG0007716147000068.jpg 35134

[0315] Reagent Preparation:

[0316] FAM Substrate: The stock solution of 20 μM FAM substrate in PDE test buffer was diluted to 200 nM. 12.5 μL of the diluted substrate was added to each well.

[0317] Compound: First, the compound to be measured was dissolved in DMSO to form a 10 mM stock solution. 5 μL of the compound stock solution was added to 45 μL of DMSO to prepare a 1 mM dilution. Further, 5 μL of the 1 mM dilution was added to 45 μL of PDE test buffer to prepare the starting point of serial dilution. Next, serial dilution was performed 9 times by adding 5 μL of the previous concentration solution to 15 μL of PDE test buffer to prepare working solutions of the compound at 10 concentrations. 2.5 μL / well was added to the wells of the compound.

[0318] PDE4D3: 0.054 μL of the PDE4D3 recombinase stock solution was added to 1500 μL of PDE buffer and added to all the wells of the compound and the positive control at 10 μL / well. 10 μL of PDE test buffer was added to the substrate control wells.

[0319] Binding Solution: 3750 μL of Binding Buffer A and 3750 μL of Binding Buffer B were taken and mixed uniformly. Next, 150 μL of the adhesive was added and mixed uniformly. Again, 7.5 μL of the Tb donor was added and mixed uniformly. 50 μL / well was added to all the wells. JPEG0007716147000069.jpg54156

[0320] Data Processing: FRET=(S 520 -(S 520 ×S 490 / S 490 ))×1000 / S 490 S 520 = Sample 520 nm reading S 490 = Sample 490 nm reading Tb 520 = Tb only 520 nm reading Tb 490= Tb only 490 nm reading value %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.

[0321] 3. Measurement of PDE4A1 enzyme inhibition:

[0322] Materials and equipment: JPEG0007716147000070.jpg46154

[0323] Measurement conditions: JPEG0007716147000071.jpg31149

[0324] Reagent preparation:

[0325] FAM substrate: 25 μL of FAM substrate stock solution was added to 2500 μL of PDE test buffer. 25 μL of the diluted substrate was added to each well.

[0326] Compound: First, the compound to be measured was dissolved in DMSO to make a 10 mM stock solution. 5 μL of the compound stock solution was added to 45 μL of DMSO to prepare a 1 mM dilution. Further, 5 μL of the 1 mM dilution was added to 45 μL of PDE test buffer to prepare the starting point of serial dilution. Next, serial dilution was performed 9 times by adding 5 μL of the previous concentration solution to 15 μL of PDE test buffer to prepare working solutions of the compound at 10 concentrations. 5 μL / well was added to the compound wells.

[0327] PDE4A1: First, the PDE4A1 stock solution was diluted 100-fold to a concentration of 4.9 ng / μL. Then, 1.8 μL of the diluted solution was added to 2200 μL of the PDE test buffer and added to all compound wells and positive control wells at 20 μL / well. 20 μL of the PDE test buffer was added to the substrate control wells.

[0328] Binding solution: 95 μL of the binding buffer was added to 9.5 mL of the adhesive diluent and mixed uniformly. It was added to all wells at 100 μL / well. JPEG0007716147000072.jpg60141

[0329] 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.

[0330] 4. Measurement of the inhibition of PDE4B2 enzyme:

[0331] Materials and equipment: JPEG0007716147000073.jpg7073

[0332] Measurement conditions: JPEG0007716147000074.jpg46128

[0333] Reagent preparation:

[0334] FAM substrate: 25 μL of the FAM substrate stock solution was added to 2500 μL of the PDE test buffer. 25 μL of the diluted substrate was added to each well.

[0335] Compound: First, the compound to be measured was dissolved in DMSO to prepare a 10 mM stock solution. 5 μL of the compound stock solution was added to 45 μL of DMSO to prepare a 1 mM dilution. Further, 5 μL of the 1 mM dilution was added to 45 μL of the PDE test buffer to prepare the starting point for serial dilution. Next, serial dilution was performed 9 times by adding 5 μL of the solution at the previous concentration to 15 μL of the PDE test buffer to prepare working solutions of the compound at 10 concentrations. It was added to the compound wells at 5 μL / well.

[0336] PDE4B2: First, the PDE4B2 stock solution was diluted 100-fold to a concentration of 5.2 ng / μL, and then 3.2 μL of the dilution was added to 2200 μL of the PDE test buffer and added to all the compound wells and the positive control wells at 20 μL / well. 20 μL of the PDE test buffer was added to the substrate control wells.

[0337] Binding solution: 95 μL of the adhesive was added to 9.5 mL of the adhesive diluent and mixed uniformly. It was added to all the wells at 100 μL / well. JPEG0007716147000075.jpg55158

[0338] 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.

[0339] 5. Measurement of inhibition of PDE4C1 enzyme:

[0340] Materials and equipment: JPEG0007716147000076.jpg49153

[0341] Measurement conditions: JPEG0007716147000077.jpg32149

[0342] Reagent preparation:

[0343] FAM substrate: 12.5 μL of FAM substrate stock solution was added to 1250 μL of PDE test buffer. 12.5 μL of the diluted substrate was added to each well.

[0344] Compound: First, the compound to be measured was dissolved in DMSO to form a 10 mM stock solution. 5 μL of the compound stock solution was added to 45 μL of DMSO to prepare a 1 mM dilution. Further, 5 μL of the 1 mM dilution was added to 45 μL of PDE test buffer to prepare the starting point of serial dilution. Next, serial dilution was performed 9 times by adding 5 μL of the previous concentration solution to 15 μL of PDE test buffer to prepare working solutions of the compound at 10 concentrations. 2.5 μL / well was added to the wells of the compound.

[0345] PDE4C1: First, the PDE4C1 stock solution was diluted 100-fold to a concentration of 3.2 ng / μL, and then 13.75 μL of the dilution was added to 1100 μL of PDE test buffer and added to all compound wells and positive control wells at 10 μL / well. 10 μL of PDE assay buffer was added to the substrate control wells.

[0346] Binding solution: 50 μL of the adhesive was added to 5 mL of the adhesive diluent and mixed uniformly. 50 μL / well was added to all wells. JPEG0007716147000078.jpg32168

[0347] 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.

[0348] 6. The experimental results show that the example compounds of the present invention have an inhibitory effect on PDE4, and examples of representative compounds are as follows:

[0349] IC of PDE4D3 50 Table: JPEG0007716147000079.jpg21945

[0350] The above biological activities are: A + <5 nM; A is 5 - 10 nM; B is 10 - 50 nM; C is 50 - 200 nM; D is greater than 200 nM. Although the embodiments of the present invention have been described, the present invention is not limited to the above embodiments. Modifications, equivalent substitutions, improvements, etc. made within the spirit and principle scope of the present invention shall be included in the protection scope of the present invention.

[0351] Note: All examples 0 involved in the present invention represent the control drug apremilast.

[0352] IC of PDE4A1 50 Table: JPEG0007716147000080.jpg5645

[0353] The above biological activities are: A <100 nM, B is 100 - 200 nM. Although the embodiments of the present invention have been described, the present invention is not limited to the above embodiments. Modifications, equivalent substitutions, improvements, etc. made within the spirit and principle scope of the present invention shall be included in the protection scope of the present invention.

[0354] Note: All examples 0 involved in the present invention represent the control drug apremilast.

[0355] IC of PDE4B2 50 Table: JPEG0007716147000081.jpg5645

[0356] The above biological activity is such that A < 100 nM and B is 100 - 200 nM. Although the embodiments of the present invention have been described, the present invention is not limited to the above embodiments. Modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

[0357] Note: All of Example 0 involved in the present invention represents the control drug apremilast.

[0358] IC of PDE4C1 50 Table: JPEG0007716147000082.jpg5645

[0359] The above biological activity is such that A < 200 nM and B is 200 - 500 nM. Although the embodiments of the present invention have been described, the present invention is not limited to the above embodiments. Modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

[0360] Note: All of Example 0 involved in the present invention represents the control drug apremilast.

[0361] 7. Measurement of the Selective Inhibitory Activity of PDE1, 2, 3, 5, 7, 10, and 11 Enzymes

[0362] The selective specificity of the compound for PDE4 was evaluated by measuring a single concentration of the compound. For example, tests were performed on PDE1a enzyme, PDE1c enzyme, PDE2a enzyme, PDE3a enzyme, PDE3b enzyme, PDE5a1 enzyme, PDE7a enzyme, PDE7b enzyme, PDE10a1 enzyme, and PDE11a4 enzyme. The selective inhibitory effects of different compounds at concentrations of 10 μM and 1 μM respectively on the PDE1C, PDE2A, PDE3B, PDE5A1, PDE7A, and PDE10A1 enzyme activities are shown in the following table: Inhibition Rate of PDE1C (%) JPEG0007716147000083.jpg Inhibition rate (%) of 7182 PDE2A JPEG0007716147000084.jpg Inhibition rate (%) of 7180 PDE3B JPEG0007716147000085.jpg Inhibition rate (%) of 7185 PDE5A1 JPEG0007716147000086.jpg Inhibition rate (%) of 7182 PDE7A JPEG0007716147000087.jpg Inhibition rate (%) of 7185 PDE10A1 JPEG0007716147000088.jpg 7182

[0363] Note: All of Example 0 involved in the present invention represent the control drug apremilast.

[0364] 8. Measurement of inhibition of inflammatory factors TNF-α, IL-2, and INF-γ

[0365] Measurement of induction of TNF-α, IL-2, and INF-γ by LPS / SEB- in human peripheral blood mononuclear cells:

[0366] 1. After thawing the purchased PBMC frozen cells at 37°C, transfer them to RPMI1640 medium and incubate overnight in a 37°C, 5% CO2 incubator.

[0367] 2. The next day, plate at 2×10 5 cells / well, with 100 μL in each well.

[0368] 3. Dilute the compound to be tested in a 3-fold stepwise manner. The final drug concentrations are 3000, 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46 nM.

[0369] 4. Add LPS to each well and stimulate at a final concentration of 10 ng / ml.

[0370] 5. Incubated overnight in a 5% CO2 incubator at 37°C.

[0371] 6. On the third day, the cell culture supernatant was collected and cytokine measurement was performed using the MSD method.

[0372] The experimental results show that the example compounds of the present invention have the effect of inhibiting inflammatory factors such as TNF-α, IL-2, and IFN-γ. Examples of representative compounds are as follows: JPEG0007716147000089.jpg44131

[0373] The compounds of the present invention significantly improve the activity of inhibiting the expression of inflammation-related factors.

[0374] Note: Example 0 involved in the present invention all represents the control drug apremilast.

[0375] As described above, the embodiments of the present invention have been described. However, the present invention is not limited to the above embodiments. Modifications, equivalent substitutions, improvements, etc. made within the spirit and principle scope of the present invention shall be included in the protection scope of the present invention. In particular, the optical mirror image isomers, diastereoisomers, stereoisomers, and mixtures thereof of the compounds of the present invention are all within the protection scope of this application.

Claims

1. A compound represented by formula IV, and its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, polymorph, or a pharmaceutically acceptable salt thereof. In the formula, R is pentyl which is unsubstituted or optionally substituted with one or more Ra, and each Ra is independently selected from deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group. R ４ is methyl.

2. A pharmaceutical composition comprising the compound represented by formula IV according to Claim 1, and its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, polymorph, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. A drug for inhibiting PDE4, wherein the diseases improved by inhibiting PDE4 include asthma, inflammation, chronic or acute obstructive pulmonary disease, chronic or acute pneumonia, enteritis, ileitis, psoriasis, seborrheic dermatitis, congestive dermatitis, palmoplantar pustulosis, psoriatic arthritis, Behçet's disease or colitis. A drug comprising the compound represented by formula IV according to Claim 1, and its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, polymorph, or a pharmaceutically acceptable salt thereof.

4. A drug for adjusting intracellular cAMP level, comprising the compound represented by formula IV according to Claim 1, and its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, polymorph, or a pharmaceutically acceptable salt thereof.

5. A drug for inhibiting the production of TNF-α or NF-κB, comprising the compound represented by formula IV according to Claim 1, and its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, polymorph, or a pharmaceutically acceptable salt thereof.

6. A therapeutic agent for depression, asthma, contact dermatitis, atopic dermatitis, seborrheic dermatitis, congestive dermatitis, palmoplantar pustulosis, psoriasis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, inflammatory skin diseases, or inflammation including inflammation due to reperfusion, chronic or acute obstructive pulmonary disease, chronic or acute pneumonia, viral lung diseases, enteritis, ileitis, Behçet's disease or colitis, comprising the compound represented by formula IV according to Claim 1, and its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, polymorph, or a pharmaceutically acceptable salt thereof.

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