Artemisinin compounds, methods of making and using the same

Abstract

The present application relates to artemisinin compounds shown in formula (I), its preparation method and application. The compound structure of the present application is novel, and has significant anti-autoimmune disease effect.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to a class of artemisinin compounds, their preparation methods, pharmaceutical compositions, and their applications in autoimmune diseases. Background Technology

[0002] Multiple sclerosis (MS), rheumatoid arthritis, lupus, and other autoimmune diseases have a serious impact on human health. MS primarily affects young adults aged 20-40 and is one of the most significant contributing factors to non-invasive neurological paralysis and disability in young people, severely impacting their quality of life and posing a serious threat to their physical and mental health (Annu Rev Immunol, 2005, 23:683-747). MS, a common demyelinating disease of the central nervous system, is characterized by multifocal areas of inflammatory infiltration, demyelination, axonal damage, neuronal signal interruption, and immune cell infiltration. The pathogenesis of MS is still unclear, and there are currently no effective treatments. Clinically used drugs are mainly immunosuppressants and interferon. These symptomatic drugs can only control the further deterioration of the disease, and immunosuppressants have significant side effects; long-term use can lead to weakened immunity and infections. Interferon, on the other hand, can cause endocrine disorders, is expensive, requires intramuscular injection, and is cumbersome to administer. Finding new and effective therapeutic targets and drugs has become a hot topic and a challenge in the field of MS (Lancet, 2008, 372(9648):1502-1517).

[0003] Studies have shown that CD4 + T-cell (Th1 and Th17 cells)-mediated autoimmunity is considered a significant cause of MS. Experimental autoimmune encephalomyelitis (EAE) shares many pathological and histological similarities with MS, leading to paralysis, physiological, and neurological problems. Th1 CD4 cells produce interferon-γ (IFN-γ). + T cells and Th17 CD4 cells that secrete interleukin-17 (IL-17A) +T cells play a crucial role in EAE models. T cell polarization, leukocyte migration, and infiltration into the central nervous system are very important steps in the pathogenesis of EAE (J Autoimmun, 2018, 87: 97–108). Increasing evidence suggests that Th17 cells (characterized by IL-17 production) play a role in MS pathogenesis comparable to Th1 cells. For example, mice with low Th17 cell counts are less likely to develop EAE (Exp Med, 2005, 201(2): 233-240), and Th17 cells have been identified in brain lesions of MS patients (Am J Pathol, 2008, 172(1): 146-155). However, there is still no specific treatment for MS. Most of the identified regulatory factors are transcription factors or cytokines (Nat Immunol, 2009, 10(12): 1252-1259). Small molecule anti-MS drugs that can regulate Th17 cell differentiation have not been reported, which provides a potential treatment option for MS.

[0004] Artemisinin is a naturally occurring antimalarial drug found in plants of the genus *Artemisia* in the family Asteraceae. Artemisinin derivatives have also been found to have therapeutic effects on autoimmune diseases such as MS, rheumatoid arthritis, lupus, and ulcerative colitis. Artemisinin derivatives hold great potential in treating autoimmune diseases such as multiple sclerosis (MS), and the development of small-molecule artemisinin candidates with inhibitory effects on Th17 differentiation is of great significance for the treatment of MS. Summary of the Invention

[0005] To address the shortcomings of the prior art, one object of the present invention is to provide a class of artemisinin-like compounds.

[0006] Another object of the present invention is to provide a method for preparing the above-mentioned artemisinin compounds.

[0007] Another object of the present invention is to provide a pharmaceutical composition comprising the above-mentioned artemisinin compounds.

[0008] Another object of the present invention is to provide the use of the above-mentioned artemisinin compounds in the preparation of medicaments for the treatment or prevention of autoimmune diseases.

[0009] In one aspect, this invention provides an artemisinin-like compound represented by the following formula (I), or its stereoisomers, pharmaceutically acceptable salts, or solvates.

[0010]

[0011] in,

[0012] R1 is a halogen, a substituted or unsubstituted C1-C20 straight-chain, branched or cyclic hydrocarbon group, a substituted or unsubstituted C1-C20 straight-chain, branched or cyclic hydrocarbon group, a substituted or unsubstituted C1-C20 straight-chain, branched or cyclic hydrocarbon group, a substituted or unsubstituted 3-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, or a substituted or unsubstituted 3-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur. The substituents are selected from hydroxyl, C1-C20 alkyl, halogen, amino (-NH2), C1-C20 alkylamino, C1-C20 haloalkyl, C1-C20 hydroxyalkyl, and C1-C20 alkyloxy.

[0013] Specifically, R1 is a halogen, a substituted or unsubstituted C1-C10 straight-chain or branched alkyl group, or a cyclic hydrocarbon group, a substituted or unsubstituted C2-C10 straight-chain or branched alkenyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C1-C10 straight-chain or branched alkoxy group, a substituted or unsubstituted C2-C10 straight-chain or branched alkenyloxy group, a substituted or unsubstituted C3-C10 cycloalkyloxy group, a substituted or unsubstituted C1-C10 straight-chain or branched alkylthio group, a substituted or unsubstituted C2-C10 straight-chain or branched alkenylthio group, a substituted or unsubstituted C3-C10 cycloalkylthio group, a substituted or unsubstituted 3-20-membered oxetyloxy group containing 1, 2, 3, or 4 oxygen atoms, or a substituted or unsubstituted 3-20-membered oxetylthio group containing 1, 2, 3, or 4 oxygen atoms. The substituents are selected from hydroxyl, C1-C10 alkyl, halogen, amino (-NH2), C1-C10 alkylamino, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, and C1-C10 alkyloxy.

[0014] More specifically, R1 is a halogen, a substituted or unsubstituted C1-C10 straight-chain or branched alkyl or cyclic hydrocarbon group, a substituted or unsubstituted C2-C10 straight-chain or branched alkenyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C1-C10 straight-chain or branched alkoxy group, a substituted or unsubstituted C2-C10 straight-chain or branched alkenyloxy group, a substituted or unsubstituted C3-C10 cycloalkyloxy group, a substituted or unsubstituted C1-C10 straight-chain or branched alkylthio group, a substituted or unsubstituted C2-C10 straight-chain or branched alkenylthio group, a substituted or unsubstituted C3-C10 cycloalkylthio group, a substituted or unsubstituted 5-7 membered oxecycloalkyloxy group containing 1 or 2 oxygen atoms, or a substituted or unsubstituted 5-7 membered oxecycloalkylthio group containing 1 or 2 oxygen atoms. The substituents are selected from hydroxyl, C1-C6 alkyl, halogen, amino (-NH2), C1-C6 alkylamino, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkyloxy.

[0015] R5 is independently selected from substituted or unsubstituted C1-C20 straight-chain or branched alkyl groups, substituted or unsubstituted C3-C20 cyclic alkyl groups, substituted or unsubstituted 3-20 membered heterocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C20 aryl groups, substituted or unsubstituted 5-20 membered heteroaryl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituted or unsubstituted C2-C20 straight-chain or branched alkenyl groups. The substituents are selected from hydroxyl, nitro, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, halogen, amino (-NH2), C1-C20 alkyl groups, and C2-C20 alkyl groups. 10-alkylamino, C1-C10 alkyloxy, R6OC(=O)-, 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterospirocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, unsubstituted or substituted with hydroxyl, nitro, amino (-NH2), halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or two adjacent substituents together with the connected ring atom to form a 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;

[0016] Specifically, R5 is independently selected from substituted or unsubstituted C1-C10 straight-chain or branched alkyl groups, substituted or unsubstituted C3-C10 cyclic alkyl groups, substituted or unsubstituted 3-10 membered heterocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C12 aryl groups, substituted or unsubstituted 5-10 membered heteroaryl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituted or unsubstituted C2-C10 straight-chain or branched alkenyl groups. The substituents are selected from hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogen, amino (-NH2), C1 ~C6 alkylamino, C1~C6 alkyloxy, R6OC(=O)-, 3-7 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-10 membered heterospirocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, unsubstituted or substituted with hydroxyl, nitro, amino (-NH2), halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or two adjacent substituents together with the connected ring atom to form a 5-6 membered monocyclic heterocyclic group containing 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur;

[0017] More specifically, each of R5 is independently selected from substituted or unsubstituted C1-C10 straight-chain or branched alkyl groups, substituted or unsubstituted C3-C10 cyclic alkyl groups, or substituted or unsubstituted 3-10 membered heterocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur (e.g., ), substituted or unsubstituted C6-C12 aryl groups, substituted or unsubstituted 5-10-membered heteroaryl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C2-C10 straight-chain or branched alkenyl groups, wherein the substituents are selected from hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogen, amino (-NH2), C1-C6 alkylamide, C1-C6 alkyloxy, R6OC(=O)-, and 3-7-membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur (e.g., ), containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-10 member heterospirocyclic groups A 5-6 membered monocyclic heterocyclic group consisting of 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, either unsubstituted or substituted with hydroxyl, nitro, amino (-NH2), halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl.

[0018] R6 is a 5-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, selected from C1-C20 straight-chain or branched alkyl groups, unsubstituted or substituted by substituents selected from hydroxyl, nitro, amino (-NH2), halogen, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl.

[0019] Specifically, R6 is selected from C1-C10 straight-chain or branched alkyl groups, unsubstituted or substituted with a group selected from hydroxyl, nitro, amino (-NH2), halogen, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl groups.

[0020] R2 is independently selected from hydrogen, hydroxyl, mercapto, halogen, and trifluoromethyl;

[0021] Or R1 and R2 together form an oxo group (=O);

[0022] R3 and R4 are each independently methyl, hydrogen, hydroxyl, or halogen; preferably, they are not simultaneously hydrogen, hydroxyl, or halogen; or

[0023] R2 and R3 together with the carbon atoms they are attached to form -C=C- double bonds;

[0024] A is either oxygen or does not exist independently.

[0025] In some implementations...

[0026] R1 is selected from halogens and trifluoromethyl; R2 is selected from trifluoromethyl, hydrogen, hydroxyl, mercapto, and halogen, and R1 and R2 are different;

[0027] R3 and R4 are each independently methyl, hydrogen, or halogen, and they cannot both be hydrogen or halogen simultaneously; or

[0028] R2 and R3 together with the carbon atoms they are attached to form -C=C- double bonds;

[0029] A is an oxygen atom or does not exist.

[0030] In some implementations...

[0031] R1 is selected from substituted C1-C20 straight-chain, branched, or cyclic hydrocarbon groups, substituted C1-C20 straight-chain, branched, or cyclic hydrocarbon oxy groups, substituted C1-C20 straight-chain, branched, or cyclic hydrocarbon thio groups, substituted 2-tetrahydrofuranyloxy groups, and substituted 2-tetrahydropyranyloxy groups; the substituted substituents are selected from hydroxyl groups, C1-C20 alkyl groups, halogens, amino groups (-NH2), C1-C20 alkylamide groups, C1-C20 haloalkyl groups, and C1-C20 alkyloxy groups;

[0032] R2 is hydrogen or halogen;

[0033] R3 and R4 are each independently methyl, hydrogen, hydroxyl, or halogen, and they are not simultaneously hydrogen, hydroxyl, or halogen;

[0034] A is an oxygen atom or does not exist.

[0035] In some implementations...

[0036] R1 is selected from

[0037] R5 is independently selected from substituted or unsubstituted C1-C20 straight-chain or branched alkyl groups, substituted or unsubstituted C3-C20 cyclic alkyl groups, substituted or unsubstituted 3-20 membered heterocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C20 aryl groups, substituted or unsubstituted 5-20 membered heteroaryl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituted or unsubstituted C2-C20 straight-chain or branched alkenyl groups. The substituents are selected from hydroxyl, nitro, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, halogen, amino (-NH2), C1-C20 alkyl groups, and C2-C20 alkyl groups. 10-alkylamino, C1-C10 alkyloxy, R6OC(=O)-, 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterospirocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, unsubstituted or substituted C6-C20 aryl group selected from hydroxyl, nitro, amino (-NH2), halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or two adjacent substituents together with the connected ring atom to form a 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;

[0038] Specifically, each of R5 is independently selected from substituted or unsubstituted C1-C10 straight-chain or branched alkyl groups, substituted or unsubstituted C3-C10 cyclic alkyl groups, or substituted or unsubstituted 3-10 membered heterocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur (e.g., ), substituted or unsubstituted C6-C12 aryl groups, substituted or unsubstituted 5-10-membered heteroaryl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C2-C10 straight-chain or branched alkenyl groups, wherein the substituents are selected from hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogen, amino (-NH2), C1-C6 alkylamide, C1-C6 alkyloxy, R6OC(=O)-, and 3-7-membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur (e.g., ), containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-10 member heterospirocyclic groups Unsubstituted or substituted C6-C10 aryl groups selected from hydroxyl, nitro, amino (-NH2), halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or two adjacent substituents together with the connected ring atom to form a 5-6 membered monocyclic heterocyclic group containing 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur.

[0039] R6 is selected from C1-C20 straight-chain or branched alkyl groups, unsubstituted or substituted with hydroxyl, nitro, amino (-NH2), halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and 5-20 heterocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur.

[0040] Specifically, R6 is selected from C1-C10 straight-chain or branched alkyl groups, unsubstituted or substituted with a group selected from hydroxyl, nitro, amino (-NH2), halogen, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl groups.

[0041] R2 is selected from hydrogen or halogen;

[0042] R3 and R4 are each independently methyl, hydrogen or halogen, and they are not simultaneously hydrogen or halogen;

[0043] A is selected from oxygen atoms or does not exist.

[0044] In some embodiments, the compound of formula (I) is selected from the compound shown in formula (II):

[0045]

[0046] in,

[0047] A1 is either O or S;

[0048] R7 is selected from H, substituted or unsubstituted C3-C20 cyclic alkyl groups, substituted or unsubstituted 3-20 membered heterocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C20 aryl groups, and substituted or unsubstituted 5-20 membered heteroaryl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur; the substituted substituents are selected from hydroxyl, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, amino (-NH2), C1-C4 alkylamide, and C1-C4 alkyloxy.

[0049] Specifically, R7 is selected from H, 3-10 member monocyclic heterocyclic groups containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 member heterospirocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, and 5-20 member heterocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur.

[0050] More specifically, the R7 is selected from

[0051] In some embodiments, the compound of formula (I) is selected from the compound shown in formula (III):

[0052]

[0053] in,

[0054] A1 is either O or S;

[0055] R8 is selected from R6OC(=O)-, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 cyclic alkyl, substituted or unsubstituted 3-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituted or unsubstituted 5-20 membered heteroaryl group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur; the substituted substituent is selected from hydroxyl, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, amino (-NH2), C1-C4 alkylamide, and C1-C4 alkyloxy.

[0056] In particular, R8 is selected from R6OC(=O)-, unsubstituted or substituted with hydroxyl, nitro, amino (-NH2), halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl;

[0057] R6 is selected from C1-C10 straight-chain or branched alkyl groups, unsubstituted or substituted with hydroxyl, nitro, amino (-NH2), halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and 5-20 member heterocyclic cyclogroups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur (e.g., The definitions of A, R2, R3, and R4 are as described above;

[0058] Specifically, R6 is selected from C1-C4 straight-chain or branched alkyl groups, unsubstituted or substituted with hydroxyl, nitro, amino (-NH2), halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl groups, and 5-20 heterocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur.

[0059] More specifically, R6 is selected from methyl,

[0060] In some embodiments, the compound of formula (I) is selected from the compounds shown in formula (IV):

[0061]

[0062] in,

[0063] A1 is either O or S;

[0064] R9 is selected from substituted or unsubstituted 3-20 membered heterocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the substituted group is selected from hydroxyl, C1-C4 alkyl, halogen, amino (-NH2), C1-C10 alkylamino, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and C1-C10 alkyloxy.

[0065] Specifically, R9 is selected from substituted or unsubstituted 2-tetrahydrofuranyl, substituted or unsubstituted 2-tetrahydropyranyl, substituted or unsubstituted The substituents are selected from hydroxyl, C1-C4 alkyl, halogen, amino (-NH2), C1-C6 alkylamino, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and C1-C6 alkyloxy.

[0066] In some embodiments, the compound of formula (I) is selected from the compounds shown in formula (V):

[0067]

[0068] in,

[0069] R 10 The group is selected from substituted or unsubstituted C1-C20 straight-chain or branched alkyl groups, substituted or unsubstituted C3-C20 cyclic alkyl groups, substituted or unsubstituted 3-20-membered heterocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C20 aryl groups, and substituted or unsubstituted 5-20-membered heteroaryl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur. The substituents are selected from hydroxyl, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, amino (-NH2), C1-C4 alkylamide, C1-C4 alkyloxy, or two adjacent substituents together with the connected ring atom to form a 3-10-membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur.

[0070] In particular, R 10 The group is selected from substituted or unsubstituted C1-C10 straight-chain or branched alkyl groups, substituted or unsubstituted C3-C10 cyclic alkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted naphthyl groups, wherein the substituents are selected from hydroxyl, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, amino (-NH2), C1-C4 alkylamide, C1-C4 alkyloxy, or two adjacent substituents together with the connected ring atom to form a 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur.

[0071] In some embodiments, the compound of formula (I) is selected from the compounds shown in formula (VI):

[0072]

[0073] in,

[0074] R 11 The group is selected from substituted or unsubstituted C3-C20 cyclic alkyl groups, substituted or unsubstituted 3-20 membered heterocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C20 aryl groups, and substituted or unsubstituted 5-20 membered heteroaryl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur. The substituted substituents are selected from hydroxyl, nitro, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, amino (-NH2), C1-C4 alkanoylamino, C1-C4 alkanoyloxy, or two adjacent substituents together with the connected ring atom to form a 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur.

[0075] In particular, R 10 The substituent is selected from substituted or unsubstituted C3-C10 cyclic alkyl groups, substituted or unsubstituted nitrogen-containing 3-10-membered heterocyclic groups, wherein the substituted substituent is selected from hydroxyl, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, amino (-NH2), C1-C4 alkylamide, C1-C4 alkyloxy.

[0076] In this invention,

[0077] Halogens refer to fluorine, chlorine, bromine, or iodine.

[0078] "Straight-chain, branched, or cyclic hydrocarbon groups" include straight-chain or branched alkyl groups, straight-chain or branched alkenyl groups, cycloalkyl groups, and cycloalkenyl groups.

[0079] "alkyl" includes, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.

[0080] "Alkoxy" refers to the group formed by attaching an oxygen atom to the end of the alkyl group, such as methoxy, ethoxy, n-propoxy, sec-butoxy, tert-butyl, n-hexoxy, etc.

[0081] "Halogenated alkyl" refers to a group obtained by replacing one or more hydrogen atoms on the aforementioned alkyl group with a halogen, such as trifluoromethyl.

[0082] "Hydroxyalkyl" refers to a group in which one or more hydrogen atoms on the alkyl group are replaced by hydroxyl groups, such as hydroxymethyl.

[0083] "Cycloalkyl" refers to a monocyclic or polycyclic saturated alkyl group containing only carbon on the ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, etc.

[0084] "Amino" refers to -NH2.

[0085] "Alkylamino" refers to the RC(=O)-N group, where R is the alkyl group mentioned above.

[0086] "Alkyloxy" refers to the RC(=O)-O group, where R is the alkyl group mentioned above.

[0087] "Aryl" refers to a monocyclic or polycyclic aromatic group containing only carbon on the ring, including, without limitation, phenyl, naphthyl, etc.

[0088] "Heterocyclic group" refers to a non-aromatic monocyclic or polycyclic group containing a heteroatom selected from oxygen, nitrogen, or sulfur on its ring, whether saturated or unsaturated. It includes, without limitation, aziridine, aziridine butyl, aziridine heptyl, piperidinyl, oxadicyclopropyl, oxadicyclobutyl, tetrahydrofuranyl, pyranyl, dihydropyranyl, tetrahydropyranyl, dioxadicyclopentyl, dioxadicyclohexyl, piperazine, morpholinyl, benzodioxadicyclopentyl, etc. And so on, but not limited to these.

[0089] "Heterocyclic groups" include heterospirocyclic groups, heterocyclic groups, and monocyclic heterocyclic groups.

[0090] "Heterospirocyclic group" refers to a saturated or unsaturated spirocyclic group containing heteroatoms selected from oxygen, nitrogen, and sulfur, for example...

[0091] "Hypocyclic rings" refer to saturated or unsaturated fused rings containing heteroatoms selected from oxygen, nitrogen, and sulfur, for example...

[0092] "Heteroaryl" refers to a monocyclic or polycyclic aromatic group containing heteroatoms selected from oxygen, nitrogen, and sulfur. It includes, but is not limited to, furanyl, pyridinyl, thienyl, thiazolyl, thiaranyl, benzofuranyl, benzothiazolyl, etc.

[0093] "Pharmaceutically acceptable salts" include salts formed with acids or bases; said acids include inorganic acids and organic acids; preferably, said inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; preferably, said organic acids include formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glutamic acid, and dihydroxynaphthyl acid; said bases include hydroxides, carbonates, and bicarbonates of sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0094] The compounds and their pharmaceutically acceptable salts involved in this application may have isomers or racemates, such as optical isomers (including diastereomers and enantiomers), transisomers, geometric isomers (cis-trans isomers), conformational isomers, tautomers, and mixtures thereof, but are not limited thereto. These isomers are also included within the scope defined by the claims of this invention.

[0095] In this document, all features or conditions defined in the form of numerical ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible sub-ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "3 to 20" should be considered as specifically disclosing all sub-ranges such as 3 to 15, 4 to 20, 4 to 15, 4 to 10, 5 to 20, 5 to 15, etc., particularly sub-ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0096] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, whether or not such ranges are disclosed separately.

[0097] The above embodiments are merely exemplary embodiments of the present invention and are not intended to limit the present invention. The scope of protection of the present invention is defined by the claims. Those skilled in the art can make various modifications or equivalent substitutions to the present invention within its substance and scope of protection, and such modifications or equivalent substitutions should also be considered to fall within the scope of protection of the present invention.

[0098] In some embodiments, the compound is selected from compounds with the following structures:

[0099]

[0100] In another aspect, the present invention provides a method for preparing a compound of general formula I, wherein the method is one of the following methods.

[0101] Method 1:

[0102]

[0103] Using a1 as a starting material, fluorinated product I-1 was obtained in the presence of a fluorinating reagent.

[0104] A, R3, and R4 are as defined above.

[0105] The fluorinated reagent may be selected from: diethylaminosulfur trifluoride, tetrabutylammonium fluoride, 1-chloromethyl-4-fluoro-1,4-diazidobiscyclo[2.2.2]octane bis(tetrafluoroborate), N-fluorobis(benzenesulfonamide), but is not limited to these.

[0106] Method 2:

[0107]

[0108] Using a2 as a raw material, a condensation reaction is carried out with acid R5C(=O)OH to obtain condensation product I-2.

[0109] A, R3, R4, and R5 are as defined above.

[0110] The acid is preferably, for example, biotin, lipoic acid, monomethyl fumarate, maleic acid, ferulic acid, but is not limited thereto.

[0111] The condensation reaction can be carried out in the presence of a condensing agent. The condensing agent may be selected from one or a combination of several of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), and 1-hydroxybenzotriazole (HOBT), or a condensing agent with a similar mechanism in the art may be used.

[0112] Method 3:

[0113]

[0114] Using a3 as a raw material, a condensation reaction is carried out with substituted isocyanate R5NCO or substituted isothiocyanate R5NCS to obtain carbamate product or aminothiocarbamate product I-3.

[0115] Among them, A, R3, R4 and R5 are as defined above, and A1 and A2 are each independently selected from oxygen or sulfur.

[0116] The substituted isocyanate or substituted isothiocyanate is preferably, for example, n-butyl isocyanate, cyclopropyl isocyanate, p-trifluoromethoxyphenyl isocyanate, p-trifluoromethoxyphenyl isothiocyanate, 1-adamantane isocyanate, 1-naphthyl isocyanate, 3,4-(methylenedioxy)phenyl isocyanate, but is not limited thereto.

[0117] The condensation reaction can be carried out in the presence of a base. Commonly used bases can be triethylamine, ammonia, 4-dimethylaminopyridine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N,N-dimethylaminopyridine, or a combination of one or more of these bases, or reagents with similar mechanisms.

[0118] Method 4:

[0119]

[0120] Using a3 as a starting material, condensation with R9A1H yields ether product I-4.

[0121] Among them, A, R3, R4, and R9 are as defined above.

[0122] A1 is selected from oxygen or sulfur.

[0123] The condensation reaction can be carried out in the presence of a condensing agent. Commonly used condensing agents are boron trifluoride diethyl ether or reagents with similar mechanisms.

[0124] Method 5:

[0125]

[0126] Cycloamine compounds Reaction with triphosgene yields Then, it undergoes a condensation reaction with a3 to give compound I-5.

[0127] Among them, A, R3 and R4 are as defined above, and A1 is selected from oxygen or sulfur.

[0128] Cycloamine The cyclic amine can be a substituted or unsubstituted 3-20 nucleotide, preferably 3-10 nucleotide monocyclic or polycyclic cyclic amine compound, such as a monocyclic alkylamine, a fused cyclic amine, or a spirocyclic amine, except that it contains at least one ring nitrogen atom. Optionally, it may also contain 1-5 heteroatoms selected from oxygen, nitrogen, and sulfur. The substituents are selected from hydroxyl, nitro, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, halogen, amino (-NH2), C1-C10 alkylamide, C1-C10 alkyloxy, R6OC(=O)-, 3-10 membered monocyclic heterocyclic groups containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterospirocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, and 5-20 membered heterocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur. The substituents are unsubstituted or selected from hydroxyl, nitro, amino (-NH2), halogen, C1- C6-C20 aryl groups substituted with C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl, or two adjacent substituents together with the connected ring atom to form a 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur; preferably, the substituents are selected from hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogen, amino (-NH2), C1-C6 alkylamide, C1-C6 alkyloxy, R6OC(=O)-, or 3-7 membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur (e.g., ), containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-10 member heterospirocyclic groups C6-C10 aryl groups that are unsubstituted or substituted with hydroxyl, nitro, amino (-NH2), halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl;

[0129] R6 is defined above.

[0130] The condensation reaction can be carried out in the presence of a base. Commonly used bases include triethylamine or reagents with similar mechanisms.

[0131] The starting materials used in this invention are commercially available or prepared according to known synthetic methods for similar compounds.

[0132] Another aspect of the present invention provides a pharmaceutical composition comprising an effective amount of one or more selected from the compounds, stereoisomers thereof, pharmaceutically acceptable salts and solvates according to the present invention, and optionally, one or more pharmaceutical excipients.

[0133] Another aspect of the present invention provides the use of the said compound, its stereoisomers, pharmaceutically acceptable salts or solvates in the preparation of medicaments for the treatment or prevention of autoimmune diseases.

[0134] Another aspect of the present invention provides a method for treating or preventing autoimmune diseases, the method comprising administering to a subject in need an effective amount of one or more selected from the compounds, stereoisomers thereof, pharmaceutically acceptable salts and solvates thereof, or the pharmaceutical compositions thereof.

[0135] The autoimmune disease may be selected from at least one of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, ankylosing spondylitis, dermatomyositis, scleroderma, pemphigus, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, and ulcerative colitis.

[0136] Beneficial effects

[0137] The compounds of this invention have the following beneficial effects: novel structure and significant anti-autoimmune disease activity. Detailed Implementation

[0138] To further understand the present invention, the following description, in conjunction with embodiments, illustrates the invention in detail. These embodiments are merely for illustrating the features of the invention in detail and are not intended to limit the scope of the invention or the scope of the claims. Simple substitutions or improvements made to the invention by those skilled in the art are all within the scope of the technical solutions protected by this invention.

[0139] Example 1: Synthesis of Compound I1

[0140]

[0141] 200 mg of trifluoromethyl-substituted artemisinin and 5 mL of dichloromethane were added to a 25 mL three-necked flask. 184 mg of diethylaminosulfur trifluoride (DAST) was added to the reaction solution at 0 °C, and the mixture was heated to 25 °C and reacted for 10 h. 2 mL of water was added to separate the reaction phases. 2 mL of saturated brine was added to the organic phase to separate the phases again, and the organic phase was dried over anhydrous sodium sulfate. The concentrated organic phase was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 50:1-10:1) to give 130 mg of a white solid product I1, with a yield of 67.3%. 1H NMR (400MHz, DMSO-d6): δ5.83(d,J=2.7Hz,1H),2.75(ddt,J=32.7,13.3,6.0Hz,1H),2.23(ddd,J=14.7,12.9,4.0Hz,1H),2.06(ddd, J=14.7,4.8,2.9Hz,1H),1.87(ddt,J=13.1,6.3,3.4Hz,1H),1.33(s,3H),1.02(dd,J=7.3,1.7Hz,3H),0.91(d,J=6.4Hz,3H).ESI-MS m / z 355.2(M+H) + .

[0142] Example 2: Synthesis of compound I2

[0143]

[0144] 200 mg of dihydroartemisinin, 172 mg of biotin, 270 mg of EDCI, 43 mg of 4-dimethylaminopyridine (DMAP), and 3 mL of dimethylformamide (DMF) were added to a 10 mL three-necked flask and reacted at 25 °C for 10 h. After adding 3 mL of water and 10 mL of dichloromethane, the mixture separated into layers. Then, 3 mL of water was added to the organic phase to separate the layers again, followed by 3 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate. The concentrated organic phase was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1-2:1) to give 255 mg of a white solid product I2, with a yield of 71.0%. 1 H NMR (400MHz, CDCl3): δ5.81(d,J=9.8Hz,1H),5.45(s,1H),5.32(s,1H),4.55( s,1H),4.35(s,1H),3.18(s,1H),2.99–2.90(m,1H),2.82(d,J=12.8Hz,1H),2 .62–2.32(m,4H),2.05(ddd,J=14.7,4.9,3.0Hz,1H),1.91(ddt,J=13.4,6.5, 3.6Hz,1H),1.45(s,3H),0.98(d,J=5.9Hz,3H),0.86(d,J=7.1Hz,3H).ESI-MS m / z 533.2(M+Na) + .

[0145] Example 3: Synthesis of Compound I3

[0146]

[0147] Following the same method as in Example 2, except that lipoic acid was used instead of biotin, the yield was 47.0%. 1 HNMR (400MHz, CDCl3): δ5.81(d,J=9.9Hz,1H),5.45(s,1H),3.58(dq,J=8.3,6.4Hz,1H),3.24-3.08(m,2H),2.58(dqd,J=9.8,7.1,4.5Hz,1H) ,2.52-2.33(m,5H),2.05(ddd,J=14.6,4.9,3.0Hz,1H),1.97-1.88(m,2H),1.45(s,3H),0.98(d,J=6.0Hz,3H),0.86(d,J=7.1Hz,3H).ESI-MS m / z 495.2(M+Na) + .

[0148] Example 4: Synthesis of Compound I4

[0149]

[0150] Following the same method as in Example 2, except that monomethyl fumarate was used instead of biotin, the yield was 75.2%. 1 H NMR (400MHz, CDCl3): δ6.89 (dd, J=23.5, 7.7Hz, 2H), 5.85 (d, J=9.8Hz, 1H), 5.47 (s, 1H), 3.82 (d, J=4. 6Hz,3H),2.63(ddt,J=14.4,11.3,5.6Hz,1H),2.38(td,J=14.0,4.0Hz,1H),2.09-2.01(m,1H),1.90(d dt,J=13.7,6.7,3.5Hz,1H),1.76(ddt,J=20.1,13.3,3.5Hz,2H),1.65(dt,J=13.6,4.4Hz,1H),1.58-1 .45(m,1H),1.45-1.23(m,6H),1.10-0.99(m,1H),0.97(d,J=5.8Hz,3H),0.86(d,J=7.1Hz,3H).ESI-MS m / z 419.4(M+Na) + .

[0151] Example 5: Synthesis of Compound I5

[0152]

[0153] 900 mg of dihydroartemisinin, 150 mg of maleic acid, 512 mg of EDCI, 740 mg of HOBT, 80 mg of DMAP, and 20 mL of dichloromethane were added to a 100 mL three-necked flask and reacted at 25 °C for 10 h. 5 mL of 1N hydrochloric acid was added to separate the layers. Then, 5 mL of water was added to the organic phase to separate the layers again, followed by 5 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate. The concentrated organic phase was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1–3:1) to give 140 mg of a white solid product I5, with a yield of 17.1%. 1 HNMR (400MHz, DMSO-) d 6): δ6.96(s,2H),5.79(d,J=9.8Hz,2H),5.64(s,2H),2.52(p,J=1.9Hz,2H),2.41(ddd,J=9.7,7.2,4.3Hz,2H),2.21(td,J=14.0,3 .9Hz,2H),2.08-1.99(m,2H),1.84(ddt,J=13.7,6.7,3.4Hz,2H),1.30(s,6H),0.91(d,J=6.4Hz,6H),0.84(d,J=7.1Hz,6H).ESI-MS m / z 671.3(M+Na) + .

[0154] Example 6: Synthesis of Compound I8

[0155]

[0156] 200 mg of dihydroartemisinin and 2 mL of acetonitrile were added to a 10 mL three-necked flask. Then, 110 mg of triethylamine and 77 mg of n-butyl isocyanate were added to the reaction solution, and the reaction was carried out at 25 °C for 10 h. 2 mL of 1N hydrochloric acid and 5 mL of ethyl acetate were added to separate the layers. 2 mL of water was added to the organic phase for further separation, followed by 2 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate. The concentrated organic phase was purified by column chromatography (SiO2, petroleum ether:acetone = 10:1-4:1) to give 150 mg of oily product I8, with a yield of 53.6%. 1H NMR (400MHz, CDCl3): δ5.71(d,J=9.8Hz,1H),5.45(s,1H),4.92(t,J=5.8Hz,1H), 3.19(qd,J=6.9,2.8Hz,2H),2.59–2.48(m,1H),2.38(ddd,J=14.6,13.4,4.0Hz,1 H),2.03(ddd,J=14.6,4.9,3.0Hz,1H),1.89(ddt,J=13.6,6.8,3.6Hz,1H),1.44( s,3H),0.97(d,J=6.1Hz,3H),0.93(t,J=7.3Hz,3H),0.88(d,J=7.1Hz,3H).ESI-MS m / z 406.2(M+Na) + .

[0157] Example 7: Synthesis of Compound I9

[0158]

[0159] Following the same method as in Example 6, except that cyclohexyl isocyanate was used instead of n-butyl isocyanate, with a yield of 48.4%. 1 H NMR (400MHz, CDCl3): δ5.71(d,J=9.8Hz,1H),5.46(s,1H),4.79(d,J=7.8Hz ,1H),3.51(td,J=14.1,6.9Hz,2H),2.53(ddd,J=10.8,7.1,4.5Hz,1H),2.39 (ddd,J=14.6,13.4,4.0Hz,1H),2.04(ddd,J=14.6,4.9,3.0Hz,1H),2.00-1. 86(m,3H),1.45(s,3H),0.98(d,J=6.1Hz,3H),0.89(d,J=7.1Hz,3H).ESI-MS m / z 432.3(M+Na) + .

[0160] Example 8: Synthesis of Compound I10

[0161]

[0162] 200 mg piperidine and 5 mL dichloromethane were added to a 25 mL three-necked flask. 231 mg triphosgene was added to the reaction solution at 0 °C, and the reaction was carried out at 25 °C for 10 h. The reaction solution was then concentrated to dryness. 670 mg dihydroartemisinin, 730 mg triethylamine, and 20 mL dichloromethane were added to the above reaction flask, and the reaction was carried out at 25 °C for 10 h. Then, 3 mL of 1 N hydrochloric acid was added to the reaction solution, and the mixture was allowed to stand for phase separation. 5 mL of saturated sodium chloride was added to the organic phase, and the mixture was allowed to stand for phase separation. After drying the organic phase with anhydrous sodium sulfate, the concentrated organic phase was purified by column chromatography (SiO2, petroleum ether:acetone = 30:1-4:1) to obtain 350 mg of white solid product I10, with a yield of 38.3%. 1 H NMR(400MHz,Chloroform-d)δ5.69(d,J=9.8Hz,1H),5.44(s,1H),3.54-3.43(m,4H),2.66-2.51(m,1H),2.36(ddd,J=14.6,13.4,4.0Hz,1H),2.09-2.0 0(m,1H),1.88(ddt,J=13.5,6.7,3.7Hz,1H),1.81-1.45(m,12H),1.43(s,3 H),1.39-1.19(m,2H),0.95(d,J=6.1Hz,3H),0.86(d,J=7.1Hz,3H).ESI-MS m / z 418.2(M+Na) + .

[0163] Example 9: Synthesis of Compound I11

[0164]

[0165] Following the same method as in Example 8, except that 8-azaspiro[4.5]decane was used instead of piperidine, yield 26.2%. 1H NMR(400MHz,Chloroform-d)δ5.69(d,J=9.8Hz,1H),5.44(s,1H),3.55-3.35(m,4H),2.56(dqd, J=14.3,7.1,4.4Hz,1H),2.43-2.31(m,1H),2.02(ddd,J=14.7,4.9,3.0Hz,1H),1.87(ddt,J=13. 5,6.6,3.6Hz,1H),1.73(ddq,J=22.1,16.5,3.4Hz,2H),1.61(dq,J=7.2,3.8Hz,5H),1.54-1.19( m,15H),1.01(td,J=13.6,13.1,3.5Hz,1H),0.95(d,J=6.1Hz,3H),0.85(d,J=7.1Hz,3H).ESI-MS m / z 450.22(M+H) + .

[0166] Example 10: Synthesis of compound I12

[0167]

[0168] Following the same method as in Example 6, except that 1-adamantane isocyanate was used instead of n-butyl isocyanate, with a yield of 16.3%. 1 H NMR(400MHz,Chloroform-d)δ5.65(d,J=9.8Hz,1H),5.41(s,1H),4.76(s,1H),2.49(ddd,J=10.3,7. 2,4.4Hz,1H),2.43-2.30(m,1H),2.06(dt,J=5.7,2.9Hz,3H),2.04-1.98(m,1H),1.93(d,J=2.9Hz,6 H),1.87(ddd,J=13.5,6.5,3.4Hz,1H),1.80-1.68(m,1H),1.67-1.63(m,6H),1.63-1.45(m,2H),1.4 3(s,3H),1.35-1.20(m,4H),1.06-0.97(m,1H),0.95(d,J=6.0Hz,3H),0.86(d,J=7.2Hz,3H).ESI-MS m / z 484.1(M+Na) + .

[0169] Example 11: Synthesis of compound I14

[0170]

[0171] Following the same method as in Example 6, except that 3,4-(methylenedioxy)phenyl isocyanate was used instead of n-butyl isocyanate, with a yield of 37.9%. 1 H NMR(400MHz,Chloroform-d)δ7.19(s,1H),7.09(s,1H),6.70(t,J=7.7Hz,2H),5.91 (s,2H),5.75(d,J=9.8Hz,1H),5.49(s,1H),2.69-2.54(m,1H),2.37(td,J=14.0,3. 9Hz,1H),2.02(d,J=14.7Hz,2H),1.96-1.85(m,1H),1.85-1.56(m,3H),1.57-1.17( m,6H),1.05(d,J=14.5Hz,1H),0.96(d,J=5.9Hz,3H),0.93(d,J=7.2Hz,3H).ESI-MS m / z 470.0(M+Na) +

[0172] Example 12: Synthesis of Compound I15

[0173]

[0174] Step 1: Add 1000 mg of dihydroartemisinin, 100 mg of 10% palladium on carbon, and 20 mL of dichloromethane to a 50 mL three-necked flask. Replace with hydrogen three times and react at 40 °C for 10 h. Filter the palladium on carbon using diatomaceous earth, concentrate the organic phase, and purify by column chromatography (SiO2, petroleum ether:ethyl acetate = 50:1-10:1) to obtain 450 mg of intermediate 1, yield 48.5%.

[0175] Step 2: The same method as in Example 6 was followed, except that cyclohexyl isocyanate was used instead of n-butyl isocyanate, with a yield of 38.3%. 1 H NMR (400MHz, DMSO-d6) δ7.15(d,J=7.9Hz,1H),5.49(d,J=8.0Hz,1H),5.33(s,1H),3.31-3.14(m,1H),2.32(td,J=7.4,4.2Hz,1H),1.73(dddd,J=32.1 ,16.0,7.7,3.7Hz,7H),1.62-1.44(m,2H),1.41(s,3H),1.16(ddt,J=21.6 ,15.9,12.5Hz,6H),1.02-0.87(m,1H),0.84(dd,J=6.9,3.2Hz,6H).ESI-MS m / z 415.8(M+Na) + .

[0176] Example 13: Synthesis of Compound I17

[0177]

[0178] 100 mg of dimethyldihydroartemisinin and 3 mL of dichloromethane were added to a 10 mL three-necked flask. 0.1 mL of boron trifluoride diethyl ether solution was slowly added dropwise to the reaction mixture at -25 °C, and the reaction was carried out at -25 °C for 10 h. 1 mL of saturated sodium bicarbonate solution was added to separate the layers. 1 mL of saturated brine was added to the organic phase to further separate the layers, and the organic phase was dried over anhydrous sodium sulfate. The concentrated organic phase was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 500:1-100:1) to obtain 50 mg of a white solid product I17, with a yield of 52.2%. 1 H NMR (400MHz, CDCl3) δ5.89(s,1H),5.76(s,1H),5.37(d,J=12.3Hz,1H),4.80(s,1H),4.68(s,1H),2.36(tdd,J=13.6,6.6,3.9Hz,2H),2.02(d t,J=13.4,3.5Hz,3H),1.95-1.71(m,4H),1.55(s,3H),1.45(s,3H),1.43(d,J=5.1Hz,3H),1.39(d,J=3.1Hz,3H),1.02-0.85(m,12H).ESI-MS m / z 596.4(M+NH4) + .

[0179] Example 14: Synthesis of Compound I18

[0180]

[0181] 200 mg of mercaptodihydroartemisinin, 194 mg of ferulic acid, 176 mg of EDCI, 40 mg of DMAP, and 5 mL of DMF were added to a 25 mL three-necked flask and reacted at 25 °C for 3 h. 10 mL of ethyl acetate and 2 mL of 1N hydrochloric acid were added to separate the layers. 5 mL of water was added to the organic phase for further separation, followed by 5 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate. The concentrated organic phase was purified by column chromatography (SiO2, petroleum ether:acetone = 10:1-2:1) to give 125 mg of a white solid product I18, with a yield of 39.3%. 1HNMR (400MHz, CDCl3): δ7.55(d,J=15.7Hz,1H), 7.09(dd,J=8.3,1.9Hz,1H), 7.02(d,J=1.9Hz,1H), 6.92(d,J=8.2Hz,1H),6.56(d,J=15.8Hz,1H),5.53(d,J=11.4Hz,1H),5.43(s,1H),3.94(s,3H),2.7 3(ddd,J=11.2,7.3,4.0Hz,1H),2.37(td,J=13.9,4.0Hz,1H),2.02(dd,J=14.7,4.5Hz,1H),1.96-1 .84(m,1H),1.76(t,J=7.0Hz,1H),1.42(s,3H),0.97(d,J=6.2Hz,3H),0.92(d,J=7.2Hz,3H).ESI-MS m / z 499.2(M+Na)+.

[0182] Example 15: Synthesis of Compound I19

[0183]

[0184] 200 mg of mercaptodihydroartemisinin, 220 mg of monomethyl fumarate, 412 mg of DCC, 80 mg of DMAP, and 5 mL of LDCM were added to a 25 mL three-necked flask and reacted at 25 °C for 10 h. 2 mL of 1 N hydrochloric acid was added to separate the layers. 2 mL of water was added to the organic phase to separate the layers, followed by 2 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate. The concentrated organic phase was purified by column chromatography (SiO2, petroleum ether:acetone = 10:1–4:1) to give 148 mg of a white solid product I19, with a yield of 53.8%. 1 H NMR (400MHz, CDCl3): δ7.07 (d, J = 15.7Hz, 1H), 6.78 (d, J = 15.7Hz, 1H), 5.51 (d, J = 11 .5Hz,1H),5.42(s,1H),3.84(s,3H),2.74(ddd,J=11.4,7.3,4.2Hz,1H),2.38(td,J= 14.0,4.0Hz,1H),2.19(s,1H),2.04(ddd,J=14.6,4.9,2.9Hz,1H),1.91(ddd,J=13.9 ,6.8,3.5Hz,1H),1.43(s,3H),,0.99(d,J=6.3Hz,3H),0.91(d,J=7.2Hz,3H).ESI-MS m / z 435.2(M+Na) + .

[0185] Example 16: Synthesis of Compound I20

[0186]

[0187] 200 mg of mercaptodihydroartemisinin, 280 mg of lipoic acid, 220 mg of EDCI, 40 mg of DMAP, and 5 mL of DMF were added to a 25 mL three-necked flask and reacted at 25 °C for 10 h. 10 mL of ethyl acetate and 2 mL of 1N hydrochloric acid were added to separate the layers. 5 mL of water was added to the organic phase for further separation, followed by 5 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate. The concentrated organic phase was purified by column chromatography (SiO2, petroleum ether:acetone = 10:1-5:1) to give 180 mg of oily product I20, with a yield of 55.2%. 1 H NMR (400MHz, CDCl3): δ5.41(s,1H),5.39(s,1H),3.58(p,J=6.5Hz,1H),3.30-3.11(m,3H),2.52-2.33(m,2H),2.19(s,2H), 2.14-1.99(m,1H),1.99-1.86(m,2H),1.84-1.66(m,4H),1.43(s,3H),0.98(d,J=6.3Hz,3H),0.89(d,J=7.2Hz,3H).ESI-MS m / z 511.2(M+Na) + .

[0188] Pharmacological experiments

[0189] 1. Experimental Objective

[0190] This study first uses CD4 + T cell in vitro differentiation system detection of compounds on CD4 + Inhibitory activity of T cells in differentiating towards Th17.

[0191] 2. Experimental Methods

[0192] 2.1 CD4 + T cell isolation and in vitro differentiation

[0193] Magnetic beads (Invitrogen; 11415D) were used to isolate CD4 from the spleen of 7-8 week old C57BL / 6 mice. + T cells, 6 × 10 5Cells were seeded into 96-well plates and cultured in 200 μL of 1640 complete medium containing 10% FBS, 2 mM L-glutamine, and 50 μM β-mercaptoethanol. Cells were activated with anti-CD3 (2 μg / ml; BD Pharmingen) and anti-CD28 (2 μg / ml; BD Pharmingen) antibodies. For Th17 cell differentiation, in addition to anti-IL-4 (10 μg / ml) and anti-IFN-γ (10 μg / ml, BD Bioscience, 551216) antibodies, a Th17 cytokine mixture was added, including IL-6 (30 ng / ml), TGF-β1 (3 ng / ml), IL-23 (10 ng / ml), TNF-α (10 ng / ml), and IL-1β (10 ng / ml). Different concentrations of the compounds were added along with the cytokines. After 3 days of culture, the culture supernatant and cells were collected to assess their effects on the differentiation of various T cell subtypes.

[0194] 2.2 Cell staining and flow cytometry analysis

[0195] In vitro CD4 + T cell differentiation experiments were performed by stimulating cells with PMA (50 ng / ml; Sigma-Aldrich), ionomycin (750 ng / ml; Sigma-Aldrich), and brefeldin A (5 μg / ml; Sigma-Aldrich) at 37°C for 5 hours. Cells were resuspended in fixative and fixed in the dark for 30 min, followed by centrifugation to remove the fixative. Resuspended cells were then stained with intracellular IL-17A (BioLegend, 506904, 1:100). Flow cytometry analysis was performed using the BD FACS Verse system and analyzed with FlowJo V10 software. The results are shown in Table 1.

[0196] Table 1. Inhibitory activity of artemisinin-like compounds against Th17.

[0197]

[0198] As can be seen from the data in Table 1 above, except for I15 and I17, the content of IL-17A in the compounds of this application embodiment decreased significantly with the increase of compound concentration, showing strong Th17 inhibitory activity and having the potential to be developed into an anti-multiple sclerosis drug.

Claims

1. Compounds selected from the following structures, or their stereoisomers, or pharmaceutically acceptable salts: 、 、 、 、 、 。 2. A pharmaceutical composition comprising an effective amount of one or more selected from the compounds, stereoisomers thereof, and pharmaceutically acceptable salts according to claim 1, and optionally, one or more pharmaceutical excipients.

3. The use of the compound, its stereoisomer, or pharmaceutically acceptable salt according to claim 1 in the preparation of a medicament for the treatment or prevention of autoimmune diseases.

4. The application according to claim 3, wherein, The autoimmune disease is selected from at least one of the following: multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, ankylosing spondylitis, dermatomyositis, scleroderma, pemphigus, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, and ulcerative colitis.

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