N-containing polycyclic compounds, processes for their preparation and uses thereof

Abstract

The present application provides a preparation method and use of N-containing polycyclic compounds as shown in the following formula (I). The compounds of the present application have lower skin irritation, and are suitable for developing into skin external preparations. Meanwhile, the compounds of the present application can more effectively promote the growth of hair after depilation, and have great clinical value.

Description

Technical Field

[0001] This invention relates to, but is not limited to, the field of pharmaceutical technology. This invention provides a method for preparing pharmaceutically active N-containing polycyclic compounds and their compositions, such derivatives of which can be used to treat or prevent JAK3-mediated diseases. Background Technology

[0002] Janus kinase (JAK) is a non-receptor tyrosine kinase with three main isoforms (JAK1, JAK2, and JAK3). It plays a major role in cytokine signaling and is crucial in various cell differentiation processes. Mutations, overexpression, or abnormal regulation of JAK can lead to overactivation or inactivation of signaling pathways, causing various inflammatory diseases, skin-related diseases, cardiovascular diseases, metabolic diseases, as well as neurodegenerative diseases, immune diseases, and tumor-related diseases. Therefore, JAK, as an important enzyme, has become a target for drug development for therapeutic interventions. When cytokines such as IFN-α, IFN-β, IFN-γ, IL-10, and IL-19 bind to their receptors, JAK is activated. JAK then phosphorylates the cytokine receptors, becoming the molecules involved in signal transduction. Currently, inhibitors developed for different JAKs have shown good efficacy in treating skin diseases, but there is still a need to develop selective JAK inhibitors. Animal studies have shown that selective inhibition of JAK3 activity has significant therapeutic effects on a variety of immune disorders and can prevent JAK2-dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling.

[0003] On December 11, 2020, Pfizer's JAK3 inhibitor, Ritlecitinib, was granted Breakthrough Therapy designation by the CDE (Center for Drug Evaluation) for the treatment of hair loss in patients aged ≥12 years. While its toxicity is lower than that of first-generation JAK inhibitors, its safety profile still requires further evaluation. Therefore, there remains a need to develop drug molecules with better efficacy and fewer side effects. Summary of the Invention

[0004] This invention provides a method for preparing N-containing polycyclic compounds, and the compounds of this invention have relatively low cytotoxicity.

[0005] Another aspect of the present invention provides compounds with lower skin irritation, making them suitable for development into topical skin preparations. Furthermore, the compounds of the present invention can more effectively promote hair growth after hair removal, achieving unexpected beneficial technical effects and possessing significant clinical value.

[0006] This invention first provides an N-containing polycyclic compound or its enantiomers, diastereomers, hydrates, solvates, polymorphs, isotope derivatives, or pharmaceutically acceptable salts represented by the following general formula (I):

[0007]

[0008] In equation (I), X and Y are independently CH or N, respectively;

[0009] When X is N, Y is not N;

[0010] Z is N;

[0011] Q is O or NH;

[0012] n is 0 or 1;

[0013] A can be O, S, or N;

[0014] When A is O or S, R1 does not exist;

[0015] When A is N, R1 is

[0016] Where L and G are independently O or NH;

[0017] m1 is 0 or 1;

[0018] m2 is 0 or 1;

[0019] R a R b Each of the following groups, independently substituted or unsubstituted by one or more groups A, is: C1-C8 alkyl, C3-C10 carbocyclic, C2-C10 heterocyclic, C6-C18 aryl, C3-C12 heteroaryl, or R. a R b Connected to form a ring;

[0020] R c R d Each of the following groups, independently substituted or unsubstituted by one or more groups A, is: C1-C8 alkyl, C3-C10 carbocyclic, C2-C10 heterocyclic, C6-C18 aryl, C3-C12 heteroaryl, or R. a R b Connected to form a ring;

[0021] R e The following groups are either substituted or unsubstituted by one or more groups A: C1-C8 alkyl groups, C3-C10 carbocyclic groups;

[0022] T - For Cl - ,Br- I - OH - CH3COO - CH3CH2COO - BF4 - HSO4 - Citrate, citrate, malate, methanesulfonate, p-toluenesulfonate, tartrate; wherein L and G are independently O or NH;

[0023] R2, R3, R5, and R6 are each independently hydrogen, or are substituted or unsubstituted by one or more of the following groups: C1-C8 alkyl, C1-C8 alkoxy, C3-C10 carbocyclic, C2-C10 heterocyclic, C6-C18 aryl, and C3-C12 heteroaryl.

[0024] R4 is hydrogen, or one or more of the following groups substituted or unsubstituted by group A: C1-C8 alkyl, C1-C8 alkoxy, C3-C10 carbocyclic, C2-C10 heterocyclic, or -(CO)-R9.

[0025] R7 and R8 are each independently hydrogen, a metal ion, or one or more of the following groups substituted or unsubstituted by group A: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino, C2-C8 alkenyl, C2-C8 alkynyl, C3-C10 carbocyclic, C2-C10 heterocyclic, C6-C18 aryl, C3-C12 heteroaryl, or R7 and R8 linked together to form a ring;

[0026] R9 is one of the following groups that is substituted or unsubstituted by one or more groups A: C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C10 carbocyclic, C2-C10 heterocyclic, C6-C18 aryl, and C3-C12 heteroaryl.

[0027] The group A therein is: halogen, amino, hydroxyl, carboxyl, nitro, trifluoromethyl, cyano, methoxy, ethoxy, acetyl, C1-C8 alkyl, C2-C10 heterocyclic, C3-C10 carbocyclic, methyl carbonate, ethyl carbonate, n-propyl carbonate, isopropyl carbonate.

[0028] In embodiments of the present invention, the N-containing polycyclic compound provided by the present invention is as shown in formula (II):

[0029]

[0030] The substituents in formula (II) are defined as defined in formula (I) of claim 1.

[0031] In embodiments of the present invention, the N-containing polycyclic compound provided by the present invention is as shown in formula (III):

[0032]

[0033] The substituents in formula (III) are defined as defined in formula (I) of claim 1.

[0034] In embodiments of the present invention, the N-containing polycyclic compound provided by the present invention is as shown in formula (Ⅳ):

[0035]

[0036] The substituents in formula (Ⅳ) are defined as defined in formula (I) of claim 1.

[0037] In the embodiments of this application, the heteroatoms refer to oxygen (O), nitrogen (N), and sulfur (S).

[0038] In the embodiments of this application, the halogen refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0039] In the embodiments of this application, the salt of formula (I) refers to inorganic acid salts such as hydrochloride, sulfate, phosphate, etc., and organic acid salts such as p-toluenesulfonate, citrate, fumarate, etc.

[0040] In the embodiments of this application, the effective amount refers to a dosage range of 0.01 mg / kg / day to 100 mg / kg / day.

[0041] In the embodiments of this application, the C1-C8 alkyl group refers to a saturated aliphatic hydrocarbon group containing 1 to 8 carbon atoms, including but not limited to: methyl, ethyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, cycloheptyl, etc.

[0042] In the embodiments of this application, the C1-C8 alkoxy group refers to a group in which an oxygen atom is inserted at any reasonable position into a saturated aliphatic hydrocarbon group containing 1 to 8 carbon atoms in the molecule, including but not limited to methoxy, ethoxy, tert-butoxy, butylethoxy, 1-propoxy-2-propyl, etc.

[0043] In the embodiments of this application, the C1-C8 alkylamine group refers to a hydrocarbon group containing 1 to 8 carbon atoms in the molecule with a -NH- or -NH2 group inserted at any reasonable position, including but not limited to methylamino, propylamino, isopropylamino, diethylamino, diisopropylamino, N,N-dimethylbutyl, etc.

[0044] In the embodiments of this application, the C2-C8 alkenyl group refers to a group containing at least one unsaturated carbon-carbon double bond in an aliphatic hydrocarbon group, including straight-chain, substituted branched, or cyclic alkenyl groups, including but not limited to allyl, cis-2-pentenyl, cyclohexenyl, 1,3-cyclohexadienyl, 1-methyl-1-cyclohexenyl, etc.

[0045] In the embodiments of this application, the C2-C8 alkynyl group refers to a group containing at least one unsaturated carbon-carbon triple bond in an aliphatic hydrocarbon group, including straight-chain, substituted branched, or cyclic alkynyl groups, including but not limited to propynyl, 2-octyyn-1-yl, 3-pentyn-2-yl, 3-hexyn-2-yl, etc.

[0046] In the embodiments of this application, the C3-C10 carbocyclic group refers to a cyclic saturated or unsaturated aliphatic hydrocarbon group composed of 3 to 10 carbon atoms, including straight-chain, branched or cyclic hydrocarbon groups, including but not limited to: cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, 3-methyl-1-cyclohexenyl, 4-methyl-1-cyclohexenyl, etc.

[0047] In the embodiments of this application, the C2-C10 heterocyclic group refers to a monovalent saturated or unsaturated cyclic group consisting of 1 to 4 heteroatoms (selected from O, N or S) and 2 to 10 carbon atoms, composed of 1 to 3 rings, including but not limited to ethylene oxide, propylene oxide, acridine, piperidinyl, piperazine, homopiperazine, pyrrolidinyl, morpholinyl, etc.

[0048] In the embodiments of this application, the C6-C18 aryl group refers to a cyclic group consisting of 6 to 18 carbon atoms forming an aromatic carbocyclic system. Such rings can be fused or unfused, and fused rings can be fully saturated, partially unsaturated, or completely unsaturated. The term "fused" indicates that the second ring shares two carbon atoms with the first ring. The C6-C18 aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, α-tetrahydronaphthyl, and 1-hydroxyindenyl.

[0049] In embodiments of this application, the C3-C12 heteroaryl group refers to a group containing one or more fused aromatic ring structures composed of 1 to 4 heteroatoms (i.e., O, N, or S) and 3 to 12 carbon atoms, and the fused ring can be fully saturated, partially unsaturated, or completely unsaturated. The C3-C12 heteroaryl group includes, but is not limited to, pyridinyl, pyrazinyl, pyridazinyl, triazolyl, imidazolyl, furanyl, thiopheneyl, thiazolyl, isothiazolyl, pyrazolyl, triazinyl, purinel, benzoxazolyl, benzofuranyl, benzothiazolyl, indoleyl, etc. Furthermore, the C3-C12 heteroaryl group also includes N-oxides of nitrogen-containing heterocycles.

[0050] In embodiments of this application, the alkylamine group may be a monoalkylamino or a dialkylamino, wherein the alkyl group is as described above.

[0051] In the embodiments of this application, the pharmaceutically acceptable salt includes, but is not limited to, salts that form with metal ions, including but not limited to potassium salts, sodium salts, lithium salts, calcium salts, iron salts, zinc salts, etc. Preferably, it is an alkali metal ion; more preferably, it is a sodium ion or a potassium ion.

[0052] In some embodiments, R1 and R2 are each independently hydrogen, a metal ion, or one or more of the following groups substituted or unsubstituted by one group A: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino, C2-C8 alkenyl, C2-C8 alkynyl, C3-C10 carbocyclic, C2-C10 heterocyclic, C6-C18 aryl, C3-C12 heteroaryl, or R1 and R2 linked together to form a ring.

[0053] In the embodiments of this application, the group A is: halogen, amino, hydroxyl, carboxyl, nitro, trifluoromethyl, cyano, methoxy, ethoxy, acetyl, C1-C8 alkyl, C2-C10 heterocyclic, C3-C10 carbocyclic, methyl carbonate, ethyl carbonate, n-propyl carbonate, isopropyl carbonate.

[0054] In some embodiments, the N-containing polycyclic compounds provided by the present invention are selected from the following compounds:

[0055]

[0056]

[0057] Alternatively, a pharmaceutically acceptable salt of the aforementioned compounds.

[0058] The present invention provides compounds comprising the above-described compounds, their enantiomers, diastereomers, hydrates, solvates, polymorphs, isotope derivatives, pharmaceutically acceptable salts, and pharmaceutically acceptable pharmaceutical compositions thereof.

[0059] Furthermore, the pharmaceutically acceptable salts include their inorganic acid salts, organic acid salts, and metal salts.

[0060] Furthermore, the aforementioned N-containing polycyclic compound or a pharmaceutically acceptable salt thereof is an inhibitor of Janus Kinase 3 (JAK3) in mammals, including humans.

[0061] Furthermore, the pharmaceutical composition or veterinary composition contains an effective amount of the N-containing polycyclic compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier as described in claims 1 to 5.

[0062] Furthermore, the pharmaceutical composition may be used alone or in combination with one or more agents that modulate the mammalian immune system or with anti-inflammatory agents to treat or prevent the following diseases or symptoms in mammals, including humans: organ transplant rejection, rheumatoid arthritis, ulcerative colitis, Crohn's disease, autoimmune thyroid disease, proctitis, eosinophilic gastroenteritis, acute respiratory disease, dry eye syndrome, keratoconjunctivitis, herpetic keratitis, conodontic keratitis, sympathetic ophthalmia, ocular pemphigoid, Molen's ulcer, scleritis, Graves' ophthalmopathy, bullous pemphigoid, endocrine ophthalmopathy, allergic conjunctivitis, pemphigus, bullous pemphigoid, lupus, systemic lupus erythematosus, psoriasis, atopic dermatitis, psoriasis, eczema, dermatitis, pruritus, and alopecia.

[0063] Furthermore, the method for treating or preventing the disease of claim 10 comprises administering an effective amount of the compound of claims 1 to 5 or a pharmaceutically acceptable salt thereof to the desired mammal.

[0064] The present invention provides, in one aspect, a method for preparing the above-mentioned N-containing polycyclic compounds or their enantiomers, diastereomers, hydrates, solvates, polymorphs, isotope derivatives, and pharmaceutically acceptable salts, as well as their use in the prevention and / or treatment of JAK3-mediated related diseases.

[0065] On the other hand, the N-containing polycyclic compounds of the present invention can be formulated into pharmaceutical compositions and administered to patients via a variety of suitable routes of administration, including systemic administration such as oral or topical application, intravenous injection, intramuscular injection, transdermal or subcutaneous administration, etc. Detailed Implementation

[0066] To make the objectives and technical solutions of this application clearer, the embodiments of the present invention will be described in detail below, but this does not limit the present invention in any way.

[0067] The following examples will enable those skilled in the art to more fully understand the present invention. The structures of all compounds have been analyzed by MS or... 1 H NMR confirmed.

[0068] Compounds 1, 2, and 3 used in this invention were prepared according to the synthetic method reported in the literature (Org. Process Res.Dev.23,2019.1872-1880), and their structures are as follows:

[0069]

[0070] Example 1: Synthesis of compound DSC5101

[0071]

[0072] 1.54 g (10.0 mmol) of 4-chlorofuran[2,3-d]pyrimidine was added to 30 mL of tert-butanol, followed by compound 5 (2.40 g, 12.0 mmol) and triethylamine (2.02 g, 20.0 mmol). After the addition was complete, the mixture was heated to 50 °C and reacted for 3.0 h. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a solid. The solid was then added to 20 mL of hydrochloric acid-methanol under ice bath conditions and stirred at room temperature for 1.0 h. After the reaction was complete, the mixture was concentrated, and 20 mL of tetrahydrofuran and 2.0 mL of triethylamine were added for neutralization. The mixture was then concentrated again, and 1.50 g of the purified DSC5101 product was obtained by liquid chromatography. Yield: 69%. Purity: 98.4%. [M+H] + =219.12. 1 H NMR(300MHz, CDCl3)δ:8.40(s,1H),8.10(d,J=6.2Hz,1H),7.41(d,J=6.2Hz,1H) ,2.82-2.79(m,3H),2.71-2.69(m,1H),1.85-1.82(m,2H),1.07(d,J=7.2Hz,3H).

[0073] Example 2: Synthesis of compound DSC5102

[0074]

[0075] 1.54 g (10.0 mmol) of 4-chlorofuran[2,3-d]pyrimidine was added to 30 mL of tert-butanol, followed by compound 3 (2.98 g, 12.0 mmol) and triethylamine (3.03 g, 30.0 mmol). After the addition was complete, the mixture was heated to 50 °C and reacted for 3.0 h. The reaction was then cooled to room temperature and concentrated under reduced pressure to obtain a solid. 20 mL of water was added, and the mixture was stirred for 1.0 h. The solid was then filtered, and 50 mL of methanol and 0.20 g of catalyst Pd / C were added to the filter cake. The mixture was refluxed under a hydrogen atmosphere and stirred for 2.0 h. The catalyst was removed by filtration, and the mixture was concentrated. The solid was recrystallized from THF / H₂O to obtain 1.16 g of purified DSC5102. Yield: 50%. Purity: 98.8%. [M+H] + =233.34. 1 H NMR (300MHz, CDCl3) δ: 8.41 (s, 1H), 8.12 (d, J = 6.3Hz, 1H), 7.43 (d, J = 6.3Hz, 1H) ,2.84-2.81(m,3H),2.65-2.63(m,1H),1.55-1.52(m,4H),1.08(d,J=7.1Hz,3H).

[0076] Example 3: Synthesis of compound DSC5103

[0077]

[0078] Synthesis of intermediate 7:

[0079] Compound 2 (2.14 g, 10.0 mmol) and compound 6 (1.42 g, 10.0 mmol) were added to 30 mL of tetrahydrofuran under nitrogen protection. Triethylamine (2.02 g, 20.0 mmol) was added, and the mixture was stirred at room temperature for 2.0 h. The mixture was then concentrated to dryness under reduced pressure. 20 mL of methanol hydrochloric acid was added, and the mixture was stirred at room temperature for 1.0 h. The mixture was then concentrated under reduced pressure. 20 mL of tetrahydrofuran and 2.0 mL of triethylamine were added, and the mixture was concentrated again. Recrystallization from THF / H₂O yielded 1.53 g of purified intermediate 7. Yield: 70%. Purity: 97.1%. [M+H] + =220.14.

[0080] Synthesis of compound DSC5103:

[0081] 1.54 g (10.0 mmol) of 4-chlorofuran[2,3-d]pyrimidine was added to 30 mL of tert-butanol, followed by intermediate 7 (2.63 g, 12.0 mmol) and triethylamine (2.02 g, 20.0 mmol). After the addition was complete, the mixture was heated to 50 °C and reacted for 3.0 h. The reaction was then cooled to room temperature and concentrated under reduced pressure to obtain a solid. Liquid chromatography was performed to obtain 1.89 g of purified DSC5103. Yield: 56%. Purity: 98.6%. [M+H] + =338.20. 1 H NMR (300MHz, CDCl3) δ: 8.78 (s, 1H), 8.69-8.67 (m, 1H), 8.40 (s, 1H), 8.19-8.17 (m, 1H), 8.10 (d, J = 6.4Hz, 1H), 7.59- 7.57(m,1H),7.41(d,J=6.4Hz,1H),2.83-2.80(m,3H),2.63-2.60(m,1H),1.52-1.50(m,4H),1.05(d,J=7.1Hz,3H).

[0082] Example 4: Synthesis of compound DSC5104

[0083]

[0084] Compound 8 (1.54 g, 10.0 mmol) was added to 30 mL of tert-butanol, followed by compound 5 (2.40 g, 12.0 mmol) and triethylamine (2.02 g, 20.0 mmol). After the addition was complete, the mixture was heated to 50 °C and reacted for 3.0 h. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a solid. The solid was then added to 20 mL of methanol hydrochloric acid in an ice bath and stirred at room temperature for 1.0 h. After the reaction was complete, the mixture was concentrated, and then neutralized with 20 mL of tetrahydrofuran and 2.0 mL of triethylamine. The solution was then concentrated and purified by liquid chromatography to obtain 1.58 g of the purified DSC5104 product. Yield: 73%. Purity: 98.5%. [M+H] + =218.13. 1 H NMR(300MHz, CDCl3)δ:8.13(d,J=6.4Hz,1H),7.92(d,J=6.5Hz,1H),7.41(d,J=6.4Hz,1H),6.90( d,J=6.5Hz,1H),2.81-2.79(m,3H),2.70-2.67(m,1H),1.84-1.81(m,2H),1.06(d,J=7.1Hz,3H).

[0085] Example 5: Synthesis of compound DSC5107

[0086]

[0087] Compound 9 (1.54 g, 10.0 mmol) was added to 30 mL of tert-butanol, followed by compound 5 (2.40 g, 12.0 mmol) and triethylamine (2.02 g, 20.0 mmol). After the addition was complete, the mixture was heated to 50 °C and reacted for 3.0 h. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a solid. The solid was then added to 20 mL of methanol hydrochloric acid in an ice bath and stirred at room temperature for 1.0 h. After the reaction was complete, the mixture was concentrated, and then neutralized with 20 mL of tetrahydrofuran and 2.0 mL of triethylamine. The solution was then concentrated again, and liquid chromatography was performed to obtain 1.42 g of purified DSC5107. Yield: 65%. Purity: 98.2%. [M+H] + =219.29. 1 H NMR (300MHz, CDCl3) δ: 8.45 (s, 1H), 8.11 (d, J = 6.4Hz, 1H), 7.42 (d, J = 6.4Hz, 1H) ,2.81-2.79(m,3H),2.71-2.68(m,1H),1.86-1.83(m,2H),1.07(d,J=7.0Hz,3H).

[0088] Example 6: Synthesis of compound DSC5110

[0089]

[0090] Compound 10 (2.01 g, 10.0 mmol) was added to 30 mL of tetrahydrofuran under nitrogen protection, followed by the addition of NaH (0.80 g, 20.0 mmol). The mixture was stirred at room temperature for 2.0 h. Compound 4 (1.54 g, 10.0 mmol) was then added, and the mixture was stirred at room temperature for 12.0 h. The reaction was stopped, and 2.0 mL of water was added. The mixture was concentrated under reduced pressure. The resulting solid was added to 20 mL of water, extracted with DCM (30 mL × 2), washed with saturated brine (30 mL × 1), and concentrated. The resulting solid was then added to 20 mL of hydrochloric acid-methanol mixture under ice bath conditions. The mixture was stirred at room temperature for 1.0 h. After the reaction was complete, the mixture was concentrated, and 20 mL of tetrahydrofuran was added. After neutralization with 2.0 mL of triethylamine, the mixture was concentrated again. Liquid chromatography was used to obtain 0.55 g of purified DSC5110. Yield: 25%. Purity: 98.1%. [M+H] + =220.39. 1 H NMR(300MHz, CDCl3)δ:8.47(s,1H),8.14(d,J=6.2Hz,1H),7.44(d,J=6.2Hz,1H) ,2.84-2.81(m,3H),2.72-2.69(m,1H),1.86-1.82(m,2H),1.09(d,J=7.4Hz,3H).

[0091] Example 7: Synthesis of compounds DSC5125, DSC5126, and DSC5127

[0092]

[0093] Synthesis of compound 11:

[0094] Compound 1 (28.54 g, 0.10 mol) was added to 500 mL of tetrahydrofuran, followed by 10 mL of water. Boc₂O (26.19 g, 0.12 mol) was then slowly added. After the addition was complete, the mixture was heated to 60 °C and reacted for 5.0 h. The reaction was then cooled to room temperature, and the mixture was concentrated under reduced pressure to obtain a solid. Recrystallization from THF / H₂O yielded 23.50 g of purified compound 11. Yield: 61%. [M+H] + =386.27.

[0095] Synthesis of compound 13:

[0096] Compound 11 (19.27 g, 0.05 mol) was added to 300 mL of THF under nitrogen protection and cooled to 0 °C. NaH (4.00 g, 0.10 mol) was slowly added. After the addition was complete, the mixture was stirred at room temperature for 1.0 h and then cooled to 0 °C. Compound 12 (12.15 g, 0.06 mol) was added, and the internal temperature was controlled to ≤5.0 °C. After the addition was complete, the mixture was reacted at room temperature for 3.0 h and then cooled to 0 °C. 20 mL of ice water was slowly added to quench the reaction. The mixture was concentrated under reduced pressure to obtain a brown solid. 60 mL of water was added and the mixture was stirred for 1.0 h. The mixture was filtered, and the solid was recrystallized from THF / H₂O to obtain 15.44 g of purified compound 13. Yield: 56%. [M+H] + =552.25.

[0097] Synthesis of compound DSC5125:

[0098] Compound 13 (11.03 g, 0.02 mol) was added to 50 mL of methanol under nitrogen protection. The mixture was cooled to 0 °C, and 50 mL of methanol hydrochloric acid was slowly added. The mixture was heated to 50 °C and reacted for 2.0 h. After cooling, the mixture was concentrated to dryness under reduced pressure. 50 mL of ethyl acetate and 5 mL of triethylamine were added, and the mixture was stirred to neutralize the solution. The solution was then concentrated to dryness again. Liquid chromatography yielded 4.6 g of purified DSC5125. Yield: 52%. Purity: 98.5%. [M+H] + =452.20. 1 H NMR (300MHz, CDCl3) δ: 8.38 (s, 1H), 7.44-7.42 (m, 1H), 6.92 (d, J = 1.8Hz, 1H), 6.8 3-6.81(m,1H),6.12-6.10(m,1H),5.83-5.80(m,2H),5.68-5.66(m,1H),4.85-4. 82(m,1H),4.44-4.41(m,1H),4.11-4.09(m,1H),4.07-4.05(m,4H),4.00-3.97(m ,1H),3.15-3.13(m,1H),1.90-1.86(m,4H),1.29-1.26(m,6H),1.22-1.19(m,3H).

[0099] Synthesis of compound DSC5126:

[0100] Under nitrogen protection, compound DSC5125 (4.51 g, 10.0 mmol) was dissolved in 60 mL of acetonitrile. The mixture was cooled to 0 °C, and 3.68 g (24.0 mmol) of trimethylbromosilane (TMSBr) was added. The reaction was carried out at room temperature for 3.0 h. Excess trimethylbromosilane was removed by concentration, and the mixture was quenched with 15 mL of water. The resulting solid was filtered, purified by recrystallization from acetonitrile / water, and dried at 45 °C for 12.0 h to obtain 1.74 g of product DSC5126. Yield: 44%. Purity: 98.2%. [M+H] + =396.36. 1 H NMR (300MHz, CDCl3) δ: 8.37 (s, 1H), 7.42-7.40 (m, 1H), 6.91 (d, J = 1.9Hz, 1H), 6.82-6.79 (m, 1H), 6.10-6.07 (m, 1H), 5.66-5.63 (m, 1H), 5.25-5. 21(m,2H),4.81-4.77(m,1H),4.43-4.41(m,1H),4.09-4.05(m,1H),4.0 0-3.97(m,1H),3.13-3.10(m,1H),1.89-1.86(m,4H),1.22-1.19(m,3H).

[0101] Synthesis of compound DSC5127:

[0102] Compound DSC5126 (0.79 g, 2.0 mmol) was dissolved in 10 mL of a 1:1 mixture of acetone and water (v / v). Sodium hydroxide (0.32 g, 8.0 mmol) was added, and the mixture was heated to 60 °C for 2.0 h. After cooling to 4 °C, a solid precipitated. The precipitate was filtered, and the filter cake was washed with a 1.0 mL / 3 acetone / water mixture. The resulting solid was recrystallized from acetone and water to give 0.19 g of product DSC5127. Yield: 22%. Purity: 98.1%. [M+Na] + =462.31. 1 H NMR (300MHz, CDCl3) δ: 8.37 (s, 1H), 7.42-7.40 (m, 1H), 6.91 (d, J = 1.9Hz, 1H), 6.82-6.79 (m, 1H), 6.10-6.07 (m, 1H), 5.66-5.63 (m, 1H), 5.25-5. 21(m,2H),4.81-4.77(m,1H),4.43-4.41(m,1H),4.09-4.05(m,1H),4.0 0-3.97(m,1H),3.13-3.10(m,1H),1.89-1.86(m,4H),1.22-1.19(m,3H).

[0103] Example 8: Synthesis of compounds DSC5128 and DSC5132

[0104]

[0105] Synthesis of compound 14:

[0106] Compound 13 (5.51 g, 10.0 mol) was dissolved in 60 mL of acetonitrile under nitrogen protection. The mixture was cooled to 0 °C, and 3.68 g (24.0 mmol) of trimethylbromosilane (TMSBr) was added. The reaction was carried out at room temperature for 3.0 h. Excess trimethylbromosilane was removed by concentration, and the mixture was quenched with 15 mL of water. The resulting solid was filtered, purified by recrystallization from acetonitrile / water, and dried at 45 °C for 12.0 h to give 1.98 g of compound 14. Yield: 40%. Purity: 98.1%. [M+H] + =496.40.

[0107] Synthesis of DSC5128:

[0108] Under nitrogen protection, compound 14 (0.99 g, 2.0 mmol) was dissolved in 30 mL of acetonitrile. The mixture was cooled to 0 °C, and thionyl chloride (0.57 g, 4.8 mmol) was added. The reaction was carried out at room temperature for 1.0 h, then cooled to 0 °C. Isopropanol (0.36 g, 6.0 mmol) and triethylamine (1.01 g, 10.0 mmol) were slowly added. The mixture was heated to 60 °C and reacted for 2.0 h. After cooling and concentration, 15 mL of hydrochloric acid-methanol solution was added, and the mixture was heated to 60 °C and reacted for 2.0 h. After cooling and concentration, 10 mL of sodium bicarbonate solution (0.5 M) was added and stirred for 1.0 h. The mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, concentrated, and purified by preparative liquid chromatography to give 0.29 g of product DSC5128. Yield: 30%. Purity: 98.5%. [M+H] + =480.04. 1 HNMR (300MHz, CDCl3) δ: 8.39 (s, 1H), 7.43-7.40 (m, 1H), 6.93 (d, J = 1.7Hz, 1H), 6. 84-6.80(m,1H),6.11-6.09(m,1H),5.87-5.84(m,2H),5.67-5.64(m,1H),4.83-4. 79(m,1H),4.62-4.59(m,2H),4.45-4.42(m,1H),4.10-4.08(m,1H),4.01-3.97(m, 1H),3.15-3.11(m,1H),1.90-1.86(m,4H),1.29-1.27(m,12H),1.24-1.21(m,3H).

[0109] Synthesis of DSC5132:

[0110] Under nitrogen protection, compound 14 (0.99 g, 2.0 mmol) was dissolved in 30 mL of acetonitrile, cooled to 0 °C, and thionyl chloride (0.57 g, 4.8 mmol) was added to the system. The reaction was carried out at room temperature for 1.0 h, cooled to 0 °C, and isopropanol (0.14 g, 2.4 mmol) and triethylamine (1.01 g, 10.0 mmol) were slowly added. The reaction was heated to 60 °C and carried out for 2.0 h, cooled to 0 °C, and menthol was slowly added. 0.38 g (2.4 mmol) was heated to 60 °C for 2.0 h, cooled, concentrated, and 15 mL of hydrochloric acid-methanol solution was added. The mixture was heated to 60 °C for 2.0 h, cooled, concentrated, and then 10 mL of sodium bicarbonate solution (0.5 M) was added and stirred for 1.0 h. The mixture was extracted with ethyl acetate (30 mL × 2), and the combined organic phases were washed with saturated brine (30 mL × 1). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by preparative liquid chromatography to obtain 0.37 g of product DSC5132. Yield: 32%. Purity: 98.7%. [M+H] + =576.07. 1 H NMR (300MHz, CDCl3) δ: 8.38 (s, 1H), 7.42-7.40 (m, 1H), 6.91 (d, J = 1.8Hz, 1H), 6.83-6.80 (m, 1H), 6.10-6. 08(m,1H),5.84-5.81(m,2H),5.66-5.64(m,1H),4.81-4.78(m,1H),4.44-4.42(m,1H),4.09-4.06(m,1H) ,4.01-3.97(m,1H),3.45-3.41(m,1H),3.14-3.11(m,1H),1.90-1.86(m,4H),1.62-1.59(m,5H),1.57-1. 53(m,2H),1.42-1.40(m,1H),1.29-1.27(m,6H),1.28-1.26(m,1H),1.24-1.21(m,3H),0.89-0.88(m,9H).

[0111] Example 9: Synthesis of compound DSC5133

[0112]

[0113] Under nitrogen protection, compound 14 (0.99 g, 2.0 mmol) was dissolved in 30 mL of acetonitrile, cooled to 0 °C, and thionyl chloride (0.57 g, 4.8 mmol) was added to the system. The reaction was carried out at room temperature for 1.0 h, cooled to 0 °C, and isopropanol (0.14 g, 2.4 mmol) and triethylamine (1.01 g, 10.0 mmol) were slowly added. The reaction was heated to 60 °C and carried out for 2.0 h, cooled to 0 °C, and isopropylamine (…) was slowly added… 0.14 g (2.4 mmol) was heated to 60 °C for 2.0 h, cooled, concentrated, and 15 mL of hydrochloric acid-methanol solution was added. The mixture was heated to 60 °C for 2.0 h, cooled, concentrated, and then 10 mL of sodium bicarbonate solution (0.5 M) was added and stirred for 1.0 h. The mixture was extracted with ethyl acetate (30 mL × 2), and the combined organic phases were washed with saturated brine (30 mL × 1). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by preparative liquid chromatography to obtain 0.20 g of product DSC5133. Yield: 21%. Purity: 98.3%. [M+H] + =479.25. 1 H NMR (300MHz, CDCl3) δ: 8.37 (s, 1H), 7.41-7.38 (m, 1H), 6.90 (d, J = 1.9Hz, 1H), 6.83-6.79 (m ,1H),6.11-6.09(m,1H),5.68-5.64(m,1H),5.23-5.19(m,2H),4.80-4.77(m,1H),4.42-4. 39(m,1H),4.15-4.11(m,1H),4.07-4.05(m,1H),4.00-3.97(m,1H),3.11-3.09(m,1H),2.8 1-2.79(m,1H),1.87-1.84(m,4H),1.25-1.22(m,3H),1.21-1.18(m,3H),1.06-1.02(m,6H).

[0114] Example 10: Synthesis of compound DSC5136

[0115]

[0116] Under nitrogen protection, compound 14 (0.99 g, 2.0 mmol) was dissolved in 30 mL of acetonitrile. The mixture was cooled to 0 °C, and thionyl chloride (0.57 g, 4.8 mmol) was added. The reaction was carried out at room temperature for 1.0 h, then cooled to 0 °C. Isopropylamine (0.35 g, 6.0 mmol) and triethylamine (1.01 g, 10.0 mmol) were slowly added. The mixture was heated to 60 °C and reacted for 2.0 h. After cooling and concentration, 15 mL of hydrochloric acid-methanol solution was added, and the mixture was heated to 60 °C and reacted for 2.0 h. After cooling and concentration, 10 mL of sodium bicarbonate solution (0.5 M) was added and stirred for 1.0 h. The mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, concentrated, and purified by preparative liquid chromatography to give 0.19 g of product DSC5136. Yield: 20%. Purity: 98.1%. [M+H] + =478.09. 1 HNMR (300MHz, CDCl3) δ: 8.38 (s, 1H), 7.41-7.38 (m, 1H), 6.91 (d, J = 1.9Hz, 1H), 6. 82-6.80(m,1H),6.10-6.07(m,1H),5.87-5.84(m,2H),5.66-5.64(m,1H),4.82-4. 78(m,1H),4.43-4.41(m,1H),4.10-4.08(m,1H),4.00-3.97(m,1H),3.14-3.11(m, 1H),2.80-2.75(m,2H),1.91-1.88(m,4H),1.23-1.21(m,3H),1.09-1.06(m,12H).

[0117] Example 11: Synthesis of compound DSC5138

[0118]

[0119] Synthesis of compound 16:

[0120] Compound 11 (7.71 g, 0.02 mol) was added to 150 mL of dichloromethane under nitrogen protection and cooled to 0 °C. NaH (1.20 g, 0.03 mol) was slowly added to the mixture, and the mixture was stirred for 30 min. Then, methyl chloroacetate (3.25 g, 0.03 mol) was slowly added to the mixture, keeping the internal temperature ≤ 5.0 °C. After the addition was complete, the mixture was reacted at room temperature for 3.0 h. The mixture was washed with water (100 mL × 1) and saturated brine (100 mL × 1). After drying with anhydrous sodium sulfate, the mixture was concentrated to obtain 8.81 g of crude compound 16, which was directly used in the next reaction.

[0121] Synthesis of compound 17:

[0122] 8.60 g of crude compound 16 was added to 100 mL of methanol, followed by 0.2 g (5.0 mmol) of sodium hydroxide. The mixture was heated to 60 °C and reacted for 2.0 h. The reaction was stopped after TLC monitoring showed completion, and the product was concentrated to obtain a brown solid. The solid was extracted with 100 mL of water and then extracted with dichloromethane (100 mL × 2). The solid was washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, and concentrated to obtain a solid. The solid was purified by recrystallization from acetonitrile / water and dried under blast furnace at 45 °C for 12.0 h to obtain 4.32 g of purified compound 17. Yield: 52%. Purity: 98.0%. [M+H] + =416.48.

[0123] Synthesis of compound DSC5138:

[0124] Under nitrogen protection, freshly distilled phosphorus oxychloride (1.53 g, 10.0 mmol) was added dropwise to a solution of 1,3-propanediol (0.76 g, 10.0 mmol) and anhydrous Et3N (2.43 g, 24.0 mmol) in 30 mL of cold anhydrous Et2O. The mixture was heated to reflux for 2.0 h, cooled to room temperature, and stirred for 12.0 h. The precipitated solid was filtered, washed with Et2O (5 mL × 2), and the resulting white solid was directly dissolved in 50 mL of dichloromethane. Under nitrogen protection, compound 17 (4.15 g, ...) was slowly added. 10.0 mmol) and Et3N (2.02 g, 20.0 mmol) were added, and the mixture was heated to 40 °C for 2.0 h. After cooling, the mixture was washed with water (30 mL × 1) and saturated brine (30 mL × 1). The mixture was concentrated, and 20 mL of hydrochloric acid-methanol solution was added. The mixture was heated to 50 °C for 2.0 h. After cooling, 50 mL of dichloromethane and 20 mL of sodium bicarbonate solution (0.5 M) were added, and the mixture was stirred for 1.0 h. The organic phase was washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, concentrated, and purified by preparative liquid chromatography to obtain 0.87 g of product DSC5138. Yield: 20%. Purity: 98.2%. [M+H] + =436.40. 1H NMR (300MHz, CDCl3) δ: 8.39 (s, 1H), 7.43-7.41 (m, 1H), 6.93 (d, J = 1.7Hz, 1H) ,6.85-6.81(m,1H),6.11-6.07(m,1H),5.85-5.83(m,2H),5.67-5.65(m,1H) ,4.82-4.79(m,1H),4.45-4.42(m,1H),4.09-4.06(m,1H),4.02-3.98(m,5H) ,3.16-3.13(m,1H),2.05-2.02(m,2H),1.89-1.86(m,4H),1.23-1.20(m,3H).

[0125] Example 12: Synthesis of compound DSC5139

[0126]

[0127] Under nitrogen protection, freshly distilled phosphorus oxychloride (1.53 g, 10.0 mmol) was added dropwise to a solution of 3-amino-1-propanol (0.75 g, 10.0 mmol) and anhydrous Et3N (2.43 g, 24.0 mmol) in 30 mL of cold anhydrous Et2O. The mixture was heated to reflux for 2.0 h, cooled to room temperature, and stirred for 12.0 h. The precipitated solid was filtered, washed with Et2O (5 mL × 2), and the resulting white solid was directly dissolved in 50 mL of dichloromethane. Compound 17 (4.15 g) was slowly added under nitrogen protection. 10.0 mmol) and Et3N (2.02 g, 20.0 mmol) were added, and the mixture was heated to 40 °C for 2.0 h. After cooling, the mixture was washed with water (30 mL × 1) and saturated brine (30 mL × 1). The mixture was concentrated, and 20 mL of hydrochloric acid-methanol solution was added. The mixture was heated to 50 °C for 2.0 h. After cooling, 50 mL of dichloromethane and 20 mL of sodium bicarbonate solution (0.5 M) were added, and the mixture was stirred for 1.0 h. The organic phase was washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, concentrated, and separated by preparative liquid chromatography to obtain 0.65 g of product DSC5139. Yield: 15%. Purity: 98.1%. [M+H] + =435.18. 1H NMR (300MHz, CDCl3) δ: 8.37 (s, 1H), 7.41-7.38 (m, 1H), 6.91 (d, J = 1.8Hz, 1H), 6.8 4-6.81(m,1H),6.10-6.06(m,1H),5.83-5.80(m,2H),5.64-5.61(m,1H),4.81-4. 78(m,1H),4.43-4.41(m,1H),4.08-4.06(m,1H),4.01-3.97(m,3H),3.15-3.13(m ,1H),2.62-2.58(m,2H),1.97-1.94(m,2H),1.87-1.84(m,4H),1.22-1.19(m,3H).

[0128] Example 13: Synthesis of compound DSC5140

[0129]

[0130] Under nitrogen protection, freshly distilled phosphorus oxychloride (1.53 g, 10.0 mmol) was added dropwise to a solution of 1,3-propanediamine (0.74 g, 10.0 mmol) and anhydrous Et3N (2.43 g, 24.0 mmol) in 30 mL of cold anhydrous Et2O. The mixture was heated to reflux for 2.0 h, cooled to room temperature, and stirred for 12.0 h. The precipitated solid was filtered, washed with Et2O (5 mL × 2), and the resulting white solid was directly dissolved in 50 mL of dichloromethane. Compound 17 (4.15 g, ...) was slowly added under nitrogen protection. 10.0 mmol) of Et3N (2.02 g, 20.0 mmol) was added, and the mixture was heated to 40 °C for 2.0 h. After cooling, the mixture was washed with water (30 mL × 1) and saturated brine (30 mL × 1). The mixture was concentrated, and 20 mL of hydrochloric acid-methanol solution was added. The mixture was heated to 50 °C for 2.0 h. After cooling, 50 mL of dichloromethane and 20 mL of sodium bicarbonate solution (0.5 M) were added, and the mixture was stirred for 1.0 h. The organic phase was washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, concentrated, and purified by preparative liquid chromatography to obtain 0.61 g of product DSC5140. Yield: 14%. Purity: 98.0%. [M+H] + =434.20. 1H NMR (300MHz, CDCl3) δ: 8.37 (s, 1H), 7.40-7.37 (m, 1H), 6.90 (d, J = 1.9Hz, 1H), 6.8 3-6.81(m,1H),6.10-6.07(m,1H),5.82-5.80(m,2H),5.62-5.59(m,1H),4.80-4. 77(m,1H),4.42-4.39(m,1H),4.07-4.05(m,1H),4.00-3.97(m,1H),3.13-3.10(m ,1H),2.60-2.56(m,4H),1.94-1.92(m,2H),1.86-1.84(m,4H),1.20-1.17(m,3H).

[0131] Example 14: Synthesis of compound DSC5145

[0132]

[0133] Compound 18 (0.18 g, 1.0 mmol) was added to anhydrous THF (20 mL) under nitrogen protection. Thionyl chloride (0.12 g, 1.0 mmol) was slowly added in an ice bath, and stirring continued for 1 hour. Compound 7 (0.41 g, 1.0 mmol) was then added, followed by anhydrous Et3N (0.30 g, 3.0 mmol) slowly added in an ice bath. After the addition was complete, the mixture was stirred at room temperature for 6 hours. The mixture was filtered, concentrated, and the residue was pre-selected by liquid chromatography to give 0.09 g of product DSC5145. Yield: 20%. Purity: 97.1%. [M+H] + =443.14. 1 H NMR (300MHz, CDCl3) δ: 8.41 (s, 1H), 7.44-7.43 (m, 1H), 6.95 (d, J = 2.7Hz, 1H), 6.86-6.84 (m, 1H), 6.17-6.15 (m, 1H), 5.69-5.67 (m, 1H), 4.84-4. 82(m,1H),4.47-4.43(m,1H),4.11-4.07(m,1H),4.03-3.92(m,3H),2.6 6-2.60(m,2H),3.16-3.08(m,5H),1.92-1.87(m,4H),1.25-1.17(m,9H).

[0134] Example 15: Synthesis of compound DSC5149

[0135]

[0136] Compound DSC5145 (0.44 g, 1.0 mmol) was added to anhydrous acetone (20 mL) under nitrogen protection. Ethyl chloride (0.06 g, 1.0 mmol) was slowly added in an ice bath. After the addition was complete, the mixture was stirred at room temperature for 60 hours. The mixture was filtered, the filtrate was concentrated, and the resulting solid was recrystallized from water / acetonitrile to give 0.12 g of product DSC5149. Yield: 24%. Purity: 96.1%. [M+H] + =507.21. 1 HNMR (300MHz, CDCl3) δ: 8.36 (s, 1H), 7.41-7.40 (m, 1H), 6.91 (d, J = 2.4Hz, 1H), 6.83-6.82 (m, 1H), 6.14-6.12 (m, 1H), 5.65-5.63 (m, 1H), 4.80-4. 79(m,1H),4.44-4.42(m,1H),4.06-4.02(m,1H),4.02-3.96(m,3H),2.67 -2.62(m,4H),3.13-3.07(m,5H),1.90-1.86(m,4H),1.22-1.11(m,12H).

[0137] The compounds of the following examples were synthesized using the same method as in the above embodiments, either commercially available compounds or intermediate compounds appropriately synthesized from commercially available compounds.

[0138]

[0139]

[0140]

[0141]

[0142] Example 16: MTT assay for the cytotoxicity of N-containing polycyclic compounds

[0143] On a 96-well plate at 1×10 4 Human normal hepatocytes (HHL-5 cells) were seeded at high density, with 200 μL of PBS added to each well. After the cells adhered evenly, they were incubated at 37°C for 24 hours until the cell concentration reached 1 × 10⁻⁶ cells / well. 5Add 50 μL of a pre-prepared solution containing N polycyclic aromatic hydrocarbons or Compound 1 (in medium containing 0.2% DMSO), maintaining a final drug concentration of 10 μM. Repeat the process three times per group. After drug addition, incubate at 37°C for 24 h. Prepare MTT to 5.0 mg / mL with PBS, adding 20 μL to each well. Incubate for another 4.0 h, remove the medium, add 200 μL of DMSO to each well, shake well, and measure the absorbance at 490 nm. Use the absorbance of the untreated wells as 100% cell viability. Calculate cell viability using Graphpad Prism 7.0 software. Data are expressed as percentages. See Table 1 below for the data:

[0144] Table 1: Cell viability determination by MTT assay

[0145]

[0146]

[0147] Experimental results showed that, compared with the control, normal cells treated with the synthesized N-containing polycyclic compound had a higher survival rate, indicating that the synthesized N-containing polycyclic compound had significantly reduced toxicity to normal cells.

[0148] Example 17: Determination of skin irritation caused by N-containing polycyclic compounds

[0149] Twenty-four healthy rabbits, weighing 2.50 ± 0.25 kg (half male and half female), were randomly divided into six groups (DSC5125 group, DSC5126 group, DSC5130 group, DSC5138 group, DSC5149 group, and compound group 1), with four rabbits in each group. Hair was removed from both sides of the spine of each rat, taking care to avoid skin damage. The hair-removed area on both sides of the spine was 3.0 cm × 3.0 cm. The next day, a 10.0 mg / mL solution of the corresponding compound was prepared and applied to the skin on one side of the corresponding rat after hair removal. The application volume was 0.2 mL, and the application area was 1.5 cm × 1.5 cm. After application, the skin was covered with a non-irritating membrane and fixed. The other side of the skin was left untreated as a control. The drug was administered once daily for 14 consecutive days (to ensure experimental accuracy, the hair needed to be shaved again if necessary). Local skin reactions were observed 1.0 h after daily drug removal (washing with purified water at 40℃) and 1 h, 24 h, 48 h, and 72 h after the last drug removal. Irritation was scored according to Table 2 below:

[0150] Table 2: Skin Irritation Response Scoring Criteria

[0151]

[0152]

[0153] The primary stimulation index of each animal to the compound was calculated by dividing the total score of erythema and edema on the skin at 1 h, 24 h, 48 h, and 72 h by the total number of animals observed. The average primary stimulation score was calculated by dividing the primary stimulation index of the experimental animal by the total number of animals tested. The experimental results are shown in Table 3.

[0154] Table 3: Results of skin irritation response of the compounds to rabbits

[0155]

[0156] The above irritation test data indicate that the compounds synthesized in this invention have lower scores and lower skin irritation compared to compound 1. It is anticipated that compounds DSC5125, DSC5126, DSC5130, DSC5138, and DSC5149 of this invention can be developed into topical skin formulations.

[0157] Example 18: Effect of the compound on the length of new hair growth in the bald area of ​​rats

[0158] One hundred SD rats were randomly divided into five groups of 20 each: normal control group, model control group, minoxidil group, DSC5126 group, and DSC5149 group. In the normal control group, a 2.5cm × 2.5cm square area was cut into the back of each rat using scissors. In the model control group, minoxidil group, DSC5126 group, and DSC5149 group, a 2.5cm × 2.5cm square area was created on the back of each rat using a rosin / wax mixture. Minoxidil, DSC5126, and DSC5149 were each prepared into 0.1 mM solutions and evenly applied to the hair-removed areas of the corresponding groups of rats. 0.2 mL was applied each time, while the normal control group and the model control group were only applied with 0.2 mL of water. After 15 minutes of even application, the rats were rinsed with water. This application procedure was performed once a day for 30 consecutive days. The hair growth in the hair-removed areas was observed, and the hair length was measured with calipers. The weighted average of the degree of new hair growth in each group was used as the final hair length. The data processing is shown in Table 4.

[0159] Table 4: Effects of compounds on the length of new hair growth in the bald areas of rats

[0160] Group Number of animals (individuals) Dosage concentration (mM) Dosage (mL) New hair growth length (mm) normal control group 20 --- 0.2 10.7±0.9 Model control group 20 --- 0.2 3.1±1.1 Minoxidil group 20 0.1 0.2 4.8±0.7 DSC5126 group 20 0.1 0.2 7.0±1.0 DSC5149 group 20 0.1 0.2 7.3±0.8

[0161] Data showed that the hair growth rate in the model group rats was significantly reduced, indicating successful model establishment. The hair growth rate in the drug-treated group rats was significantly higher than that in the model control group rats. Compared with the hair growth rate in the minoxidil group rats, the hair growth rate in the DSC5126 and DSC5149 groups was significantly higher than that in the minoxidil group rats, achieving unexpected and beneficial technical results.

[0162] This application describes several embodiments, but these descriptions are exemplary and not restrictive, and it will be apparent to those skilled in the art that there are many more embodiments and implementations within the scope of the embodiments described herein.

Claims

1. An N-containing polycyclic compound or a pharmaceutically acceptable salt thereof, represented by the general formula (I): In equation (I), X and Y are independently CH or N, respectively; When X is N, Y is not N; Z is N; Q is O or NH; n is 1; A can be O, S, or N; When A is O or S, R1 does not exist; When A is N, R1 is in, L and G are independently O or NH; m1 is 0 or 1; m2 is 0 or 1; R a R b Each of the following groups, individually substituted or unsubstituted by one or more groups A: C1-C8 alkyl groups, or R a R b Connected to form a ring; R c R d Each is an alkyl group that is independently C1-C8; R e It is a C1-C8 alkyl group; T - For Cl - ,Br - I - OH - CH3COO - CH3CH2COO - BF4 - HSO4 - Citrate, citrate, malate, methanesulfonate, p-toluenesulfonate, tartrate; R2, R3, R5, and R6 are, independently, hydrogen and C1-C8 alkyl groups, respectively; R4 is -(CO)-R9; R7 and R8 are each independently hydrogen, a metal ion, or one or more of the following groups substituted or unsubstituted by group A: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino, C3-C10 carbocyclic, C6-C18 aryl, or R7 and R8 linked together to form a ring. R9 is an alkenyl group or an alkynyl group of C2-C8 that is substituted or unsubstituted with one or more groups A; The group A mentioned therein is: amino, hydroxyl, carboxyl, methyl carbonate, ethyl carbonate, n-propyl carbonate, or isopropyl carbonate.

2. The N-containing polycyclic compound or a pharmaceutically acceptable salt thereof as described in claim 1, as shown in formula (II): The substituents in formula (II) are defined as defined in formula (I) of claim 1.

3. The N-containing polycyclic compound or a pharmaceutically acceptable salt thereof as described in claim 1, as shown in formula (III): The substituents in formula (III) are defined as defined in formula (I) of claim 1.

4. The N-containing polycyclic compound or a pharmaceutically acceptable salt thereof as described in claim 1, as shown in formula (Ⅳ): The substituents in formula (Ⅳ) are defined as defined in formula (I) of claim 1.

5. The N-containing polycyclic compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 4, selected from the following structures:

6. The N-containing polycyclic compound or its pharmaceutically acceptable salt according to claim 1, characterized in that, The pharmaceutically acceptable salts include their inorganic acid salts, organic acid salts, and metal salts.

7. A pharmaceutical composition comprising the N-containing polycyclic compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

8. Use of the N-containing polycyclic compound or its pharmaceutically acceptable salt as described in any one of claims 1 to 5, or the pharmaceutical composition as described in claim 7, in the preparation of a Janus Kinase 3 (JAK3) inhibitor medicament for mammals, including humans.

9. Use of the pharmaceutical composition of claim 7 in combination with one or more agents or anti-inflammatory agents that modulate the mammalian immune system in the preparation of a medicament for the treatment or prevention of immune system diseases or inflammation in mammals, including humans.

10. The use according to claim 9, characterized in that, The immune system diseases or inflammations mentioned include: organ transplant rejection, rheumatoid arthritis, ulcerative colitis, Crohn's disease, autoimmune thyroid disease, proctitis, eosinophilic gastroenteritis, acute respiratory disease, dry eye syndrome, keratoconjunctivitis, herpetic keratitis, conodontitis, sympathetic ophthalmia, ocular pemphigoid, Molen's ulcer, scleritis, Graves' ophthalmopathy, bullous pemphigoid, endocrine ophthalmopathy, allergic conjunctivitis, pemphigus, bullous pemphigoid, lupus, systemic lupus erythematosus, psoriasis, atopic dermatitis, psoriasis, eczema, dermatitis, pruritus, and alopecia.

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