Amide compound as well as preparation method and medical application thereof

Abstract

The invention relates to an amide compound, a preparation method thereof and application of the amide compound in medicine. Specifically, the invention relates to an amide compound shown in a general formula (I), a preparation method of the amide compound, a pharmaceutical composition containing the amide compound and application of the amide compound as a therapeutic agent, especially application of the amide compound as an IL-17 inhibitor and application of the amide compound in preparation of drugs for treating and / or preventing cancers, inflammations or autoimmune diseases. Wherein each group in the general formula (I) is defined in the specification. # imgabs0 #

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to an amide compound, a preparation method thereof and its application in medicine. In particular, the present disclosure relates to an amide compound represented by general formula (I), a preparation method thereof and a pharmaceutical composition containing the amide compound, as well as its use as an IL-17 inhibitor and its use in the preparation of a drug for treating and / or preventing cancer, inflammation or autoimmune diseases. Background Art

[0002] IL-17 is a proinflammatory cytokine mainly produced by Th17 cells. IL-17 can act on epithelial cells, prompting them to secrete antimicrobial peptides, cytokines, and promote damage repair. Therefore, IL-17 plays an important role in the body's defense against foreign pathogens. However, excessive or abnormal IL-17 can induce chronic inflammation, leading to the occurrence of a variety of autoimmune diseases, such as psoriasis, psoriatic arthritis, axial spondyloarthritis, and suppurative hidradenitis. The IL-17 family includes 6 members, namely IL-17A-F, of which IL-17A and IL-17F are Th17-related cytokines. IL-17A and IL-17F can form 3 active dimers, namely IL-17AA, IL-17AF and IL-17FF. Among them, IL-17AA has the strongest proinflammatory activity. Compared with IL-17AA, IL-17AF is 10 times weaker and IL-17FF is 100 times weaker. In addition, IL-17AA is the most important IL-17 cytokine mediating the occurrence of psoriasis, and the IL-17AA content in psoriasis patients is positively correlated with the severity of the disease.

[0003] Currently, the FDA has approved three IL-17 drugs. Novartis' Secukinumab is the first approved IL-17 (IL-17A) drug, with indications including psoriasis, psoriatic arthritis, axial spondyloarthritis and juvenile atopic arthritis. Eli Lilly's Ixekizumab (IL-17A) is approved for the treatment of psoriasis, psoriatic arthritis and axial spondyloarthritis. Valeant's Brodalumab (IL 17RA) is approved for the treatment of psoriasis, but patients taking the drug are at risk of suicide and have been added a black box warning by the FDA. UCB's Bimekizumab (dual inhibition of IL-17A and F) is approved for the treatment of psoriasis in the European Union and Japan, and is awaiting FDA approval in the United States.

[0004] IL-17 biologics have differentiated designs. Secukinumab and Ixekizumab are traditional antibodies that are selective for IL-17A; Bimekizumab is a traditional antibody that dually inhibits IL-17A and F; Sonelokimab is a nanobody that dually inhibits IL-17A and F, with a molecular weight of 40kD and a human albumin-binding domain; Izokibep is an IL-17A-selective Affibody fusion protein with a molecular weight of 18.6kD and a human albumin-binding domain.

[0005] Overall, IL-17 antibodies have a good effect in psoriasis. After 12 weeks of treatment, the PASI75 response rate can reach 75-90%. IL-17A selective Secukinumab and Ixekizumab have similar safety and efficacy. In the head-to-head phase 3 clinical trial of IL17A / F and IL-17A antibodies, IL17A / F antibodies showed better efficacy than IL-17A antibodies, but in terms of the side effect of oral Candida infection, IL17A / F antibodies were significantly higher than IL-17A antibodies. Gene knockout in mice and human genetic studies have also shown that IL-17A and IL-17F both play an important role in the body's resistance to fungal infections such as Candida, and complete inhibition of IL-17A and IL-17F can increase Candida infection. In addition, the characteristics of psoriasis in Asians and Westerners are different. Westerners have larger lesions, while Asians have smaller lesions, but the concentration of IL-17A in Asian lesions is higher. IL-17A antibodies are more effective in treating psoriasis in Asians. Therefore, selective inhibition of IL-17A is the most appropriate choice for psoriasis.

[0006] Hidradenitis suppurativa is an autoimmune disease that is difficult to treat. Currently, only adalimumab has been approved. Hidradenitis suppurativa tissue damage and inflammation occur at deeper sites, requiring therapeutic drugs to have better tissue penetration. In addition, studies have shown that IL-17A and IL-17F are enriched to a certain extent in the lesions of hidradenitis suppurativa, suggesting that IL-17A and IL-17F play a certain role in the occurrence of the disease. In the Phase 3 clinical trial of hidradenitis suppurativa, Secukinumab increased HiSCR50 by 11% compared with placebo, Bimekizumab increased it by 26%, and Sonelokimab increased it by 38%; Izokibep HiSCR50 was 71%, which is currently the most effective IL-17 drug, but there is no placebo control. For hidradenitis suppurativa, Sonelokimab and Izokibep, which have smaller molecular weights and better permeability, have better efficacy.

[0007] The combination of targeting IL-17A and IL-17RA is an effective strategy for treating IL-17A-mediated autoimmune inflammatory diseases. Currently approved IL-17A neutralizing antibodies secukinumab and ixekizulmab can effectively treat IL-17A-mediated autoimmune inflammatory diseases such as psoriasis, psoriatic arthritis, and ankylosing spondylitis.

[0008] Although there are a variety of IL-17A antibodies, given the cost of producing antibodies and the limitations of the route of administration (injection), the development of oral small molecule inhibitors specific for IL-17A has good research and development prospects. Summary of the invention

[0009] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0010]

[0011] in:

[0012] Ring A is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each independently optionally substituted by one or more R A replace;

[0013] Ring C is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each independently optionally substituted by one or more R C replace;

[0014] B is CHR 3 R 4 or ring B;

[0015] Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R B replace;

[0016] R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, a cyano group, an amino group, 10 , cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from oxo, deuterium atom, halogen, alkenyl, alkynyl, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, cyano, amino, nitro, hydroxyl, -OR 10 、-NR11 R 12 、-C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl; or R 1 and R 2 Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclyl group;

[0017] X 1 N or CR 6 ;

[0018] X 2 N or CR 7 ;

[0019] X 3 N or CR 8 ;

[0020] X 4 N or CR 9 ;

[0021] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a hydroxyl group, a cyano group, an amino group, a nitro group, a -(CR x R y ) s OR 10 、-(CR x R y ) s NR 11 R 12 、-C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-OC(O)NR 11 R 12 、-C(O)NR 11 R 12 、-NR 13 C(O)R 10 、-NR 13 C(O)OR 10 、-NR 13 C(O)NR 11 R12 、-SR 10 、-S(O)R 10 、-S(O) 2 R 10 、-S(O) 2 OR 10 、-S(O) 2 NR 11 R 12 and-NR 13 S(O) 2 R 10 wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R 0 replaced by;

[0022] or R 3 and R 4 Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 replace;

[0023] Each R A , R B , R C and R 0 are the same or different and are each independently selected from a deuterium atom, an oxo group, =S, =NR 14 , halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkoxy, haloalkoxy, deuterated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, hydroxyl, cyano, amino, nitro, -(CR x R y ) s OR 10 、-(CR x R y ) s NR 11 R 12 、-C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-OC(O)NR 11 R 12 、-C(O)NR 11 R 12 、-NR 13 C(O)R 10 、-NR 13 C(O)OR 10 、-NR13 C(O)NR 11 R 12 、-SR 10 、-S(O)R 10 、-S(O) 2 R 10 、-S(O) 2 OR 10 、-S(O) 2 NR 11 R 12 and-NR 13 S(O) 2 R 10 wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R t replace;

[0024] Each R t are the same or different and are each independently selected from an oxo group, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, a cyano group, an amino group, a nitro group, -(CR x R y ) s OR 10 、-(CR x R y ) s NR 11 R 12 、-C(O)R 10 、-C(O)OR 10 、-C(O)NR 11 R 12 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0025] R 10 , R 11 , R 12 and R 13 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally replaced by one or more R S replace;

[0026] or R 11 and R 12 Together with the nitrogen atom to which it is attached, it forms a nitrogen-containing heterocyclic group, wherein the nitrogen-containing heterocyclic group is optionally substituted by one or more R S replace;

[0027] R14 is selected from the group consisting of hydrogen, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, hydroxyl, alkoxy, haloalkoxy, deuterated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy and heterocyclyloxy; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy and heterocyclyloxy are each independently optionally replaced by one or more R S replace;

[0028] R 15 and R 16 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 17 、-C(O)R 17 、-C(O)OR 17 and cyano, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R S replace;

[0029] or R 15 and R 16 Together with the carbon atom to which it is attached, it forms a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group and the heterocyclic group are each independently optionally substituted by one or more R S replace;

[0030] Each R S are the same or different and are each independently selected from an oxo group, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cyano group, a nitro group, a hydroxyl group, an amino group, an -NH alkyl group, an -N(alkyl group) 2 , -C(O)alkyl, -C(O)Oalkyl, -C(O)NH 2 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0031] R 17 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0032] R a and R b are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a cycloalkyl group, a cycloalkylalkyl group and a heterocyclic group;

[0033] R x and R yare the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a halogen, an alkenyl group, an alkynyl group, a hydroxyl group, a cyano group, a haloalkyl group, a deuterated alkyl group, an aminoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cycloalkyl group, a cycloalkylalkyl group and a heterocyclic group;

[0034] n is 0 or 1; and

[0035] s is 0, 1, or 2.

[0036] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein B is CHR 3 R 4 ; R 3 and R 4 As defined in formula (I); in some embodiments, B is selected from

[0037] In some embodiments, B is selected from

[0038] In some embodiments, B is selected from In some embodiments, B is selected from In some embodiments, B is

[0039] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 1 and R 2 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R 1 and R 2 are the same or different and are each independently halogen; in some embodiments, R 1 and R 2 For F.

[0040] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 0; in some embodiments, n is 1.

[0041] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R a A hydrogen atom or C 1-6 alkyl; in some embodiments, Ra A hydrogen atom.

[0042] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R b A hydrogen atom or C 1-6 alkyl; in some embodiments, R b A hydrogen atom.

[0043] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R a is a hydrogen atom; R b A hydrogen atom.

[0044] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein X 1 CR 6 ;X 2 CR 7 ;X 3 CR 8 ;X 4 CR 9 ; R 6 , R 7 , R 8 and R 9 As defined in Formula (I); in some embodiments, X 1 N; X 2 CR 7 ;X 3 CR 8 ;X 4 CR 9 ; R 7 , R 8 and R 9 As defined in Formula (I); in some embodiments, X 1 CR 6 ;X 2 N; X 3 CR 8 ;X 4 CR 9 ; R 6 , R 8 and R 9 As defined in Formula (I); in some embodiments, X 1 CR 6 ;X 2 CR 7 ;X 3 N; X 4 CR 9 ; R 6 , R 7 and R9 As defined in Formula (I); in some embodiments, X 1 CR 6 ;X 2 CR 7 ;X 3 CR 8 ;X 4 N; R 6 , R 7 and R 8 As defined in Formula (I); in some embodiments, X 1 CR 6 ;X 2 CH; X 3 CH; X 4 CH; R 6 As defined in Formula (I); in some embodiments, X 1 CR 6 ; R 6 is a hydrogen atom or a halogen; X 2 CH; X 3 CH; X 4 is CH; in some embodiments, X 1 CR 6 ; R 6 is halogen; X 2 CH; X 3 CH; X 4 is CH; in some embodiments, X 1 is CH or CF; X 2 CH; X 3 CH; X 4 is CH; in some embodiments, X 1 CF;X 2 CH; X 3 CH; X 4 For CH.

[0045] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:

[0046]

[0047] in:

[0048] Ring A, Ring C, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9As defined in general formula (I).

[0049] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof:

[0050]

[0051]

[0052] in:

[0053] R 5 is selected from the group consisting of a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a hydroxyl group, a cyano group, an amino group, a nitro group, a -(CR x R y ) s OR 10 、-(CR x R y ) s NR 11 R 12 、-C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-OC(O)NR 11 R 12 、-C(O)NR 11 R 12 、-NR 13 C(O)R 10 、-NR 13 C(O)OR 10 、-NR 13 C(O)NR 11 R 12 、-SR 10 、-S(O)R 10 、-S(O) 2 R 10 、-S(O) 2 OR 10 、-S(O) 2 NR 11 R 12 and-NR 13 S(O) 2 R 10wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R 0 replaced by;

[0054] Ring A, Ring C, R 0 , R 3 , R 4 , R 6 To R 13 , R x , R y and s are as defined in the general formula (II).

[0055] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring C is a 5- to 10-membered heterocyclic group or a 5- to 10-membered heteroaryl group; wherein the 5- to 10-membered heterocyclic group and the 5- to 10-membered heteroaryl group are each independently optionally replaced by one or more R C In some embodiments, ring C is a 5- or 6-membered heterocyclyl or a 5- or 6-membered heteroaryl; wherein the 5- or 6-membered heterocyclyl and the 5- or 6-membered heteroaryl are each independently optionally substituted with one or more R C In some embodiments, ring C is a 5- to 10-membered heterocyclyl; wherein the 5- to 10-membered heterocyclyl is optionally substituted with one or more R C In some embodiments, ring C is a 5- to 8-membered heterocyclyl; wherein the 5- to 8-membered heterocyclyl is optionally substituted with one or more R C In some embodiments, ring C is a 5- or 6-membered heterocyclic group; wherein the 5- or 6-membered heterocyclic group is optionally replaced by one or more R C In some embodiments, ring C is a 5-membered heterocyclic group; wherein the 5-membered heterocyclic group is optionally substituted by one or more R C In some embodiments, ring C is imidazolidinyl, wherein the imidazolidinyl is optionally substituted with one or more R C Replacement; In the above schemes, R C As defined in general formula (I).

[0056] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring C is a 5- to 10-membered heteroaryl group; wherein the 5- to 10-membered heteroaryl group is optionally replaced by one or more R C In some embodiments, ring C is a 5- or 6-membered heteroaryl; wherein the 5- or 6-membered heteroaryl is optionally substituted with one or more R CIn some embodiments, ring C is a 6-membered heteroaryl; wherein the 6-membered heteroaryl is optionally substituted with one or more R C In some embodiments, ring C is pyridone; wherein the pyridone is optionally substituted with one or more R C Replacement; In the above schemes, R C As defined in general formula (I).

[0057] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein each R C are the same or different and are each independently selected from a deuterium atom, an oxo group, a halogen, a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, cyano, hydroxyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl; wherein the C 1-6 alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkylC 1-6 The alkyl groups are each independently optionally selected from cyano, hydroxy, halogen, C 1-6 Alkyl and C 1-6 In some embodiments, each R C are the same or different and are each independently selected from a deuterium atom, a halogen, an oxo group, a C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl; wherein the C 1-6 alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkylC 1-6 The alkyl groups are each independently optionally selected from cyano, halogen, C 1-6 Alkyl and C 1-6 In some embodiments, each R C are the same or different and are each independently selected from oxo, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl; wherein the C 1-6 alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkylC 1-6 The alkyl groups are each independently optionally selected from cyano, halogen, C 1-6 Alkyl and C 1-6In some embodiments, each R C The same or different, and each independently oxo, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6 membered cycloalkyl; wherein the 3 to 6 membered cycloalkyl is optionally substituted with one or more cyano groups; in some embodiments, each R C The same or different, and each independently oxo, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R C are the same or different and are each independently selected from oxo, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R C are the same or different and are each independently oxo or C 1-6 haloalkyl; in some embodiments, each R C are the same or different and are each independently selected from an oxo group, a deuterium atom, F, a methyl group, a difluoromethyl group, a trifluoromethyl group, an isopropyl group, a cyclopropyl group, a -CH 2 CF 3 and In some embodiments, each R C are the same or different and are each independently selected from oxo, methyl and trifluoromethyl; in some embodiments, each R C are the same or different and are each independently oxo or trifluoromethyl.

[0058] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein each R C are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl; in some embodiments, each R C are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R C C 1-6 Alkyl or C 1-6 haloalkyl; in some embodiments, R C C 1-6 haloalkyl; in some embodiments, R C is methyl or trifluoromethyl; in some embodiments, R C It is trifluoromethyl.

[0059] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring C is Each R 1C are the same or different and are each independently selected from deuterium atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl; wherein the C 1-6 alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkylC 1-6 The alkyl groups are each independently optionally selected from cyano, halogen, C 1-6 Alkyl and C 1-6 or two R 1C Together with the carbon atom to which it is attached, it forms a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group are each independently selected from cyano, halogen, C 1-6 Alkyl and C 1-6 is substituted with one or more substituents in haloalkyl; b is 1 or 2; c is 0, 1, 2, 3 or 4; in some embodiments, ring C is R 1C For R C ; or two R 1C Together with the carbon atom to which it is attached, it forms a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group and the heterocyclic group are each independently optionally substituted by one or more R C Replacement; R C As defined in general formula (I); c is 0, 1, 2, 3 or 4;

[0060] In some embodiments, Ring C is Each R 1C are the same or different and are each independently selected from deuterium atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl; wherein the C 1-6 alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkylC 1-6 The alkyl groups are each independently optionally selected from cyano, halogen, C 1-6 Alkyl and C 1-6 or two R 1C Together with the carbon atom to which it is attached, it forms a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group are each independently selected from cyano, halogen, C1-6 Alkyl and C 1-6 The haloalkyl group is substituted by one or more substituents; c is 0, 1, 2, 3 or 4.

[0061] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring C is R 2C is a hydrogen atom or R C ; R C As defined in formula (I); in some embodiments, ring C is R 2C Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6 membered cycloalkyl; wherein the 3 to 6 membered cycloalkyl is optionally substituted with one or more cyano groups.

[0062] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring C is selected from

[0063] In some embodiments, Ring C is selected from

[0064] In some embodiments, Ring C is selected from

[0065] In some embodiments, Ring C is selected from In some embodiments, Ring C is selected from In some embodiments, Ring C is

[0066] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5- to 10-membered heteroaryl or a 6- to 10-membered aryl; wherein the 5- to 10-membered heteroaryl and the 6- to 10-membered aryl are each independently optionally replaced by one or more R A In some embodiments, ring A is phenyl; wherein the phenyl group is optionally substituted with one or more R AIn some embodiments, ring A is a 5- or 6-membered heteroaryl group; wherein the 5- or 6-membered heteroaryl group is optionally substituted with one or more R A In some embodiments, Ring A is a 5-membered heteroaryl; wherein the 5-membered heteroaryl is optionally substituted with one or more R A In some embodiments, ring A is selected from pyridyl, pyrazolyl, pyrrolyl, furanyl, oxadiazolyl, isoxazolyl, tetrazolyl, thienyl, thiazolyl and imidazolyl; wherein each of the rings A is independently optionally substituted with one or more R A In some embodiments, ring A is selected from pyrazolyl, oxadiazolyl and pyrrolyl, and the pyrazolyl, oxadiazolyl and pyrrolyl are each independently optionally substituted with one or more R A In some embodiments, ring A is pyrazolyl; wherein the pyrazolyl is optionally substituted with one or more R A Replacement; In the above schemes, R A As defined in general formula (I).

[0067] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein each R A are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, cyano, nitro, hydroxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, 3- to 6-membered cycloalkyl C 1-6 Alkyl and -NR 11 R 12 wherein the 3 to 6-membered cycloalkyl, 3 to 6-membered heterocyclic group and 3 to 6-membered cycloalkyl C 1-6 The alkyl radicals are each independently optionally selected from halogen and C 1-6 The alkyl group is substituted by one or more substituents; R 11 and R 12 are each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, each R A The same or different, and each independently selected from C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered cycloalkyl C 1-6 Alkyl; wherein the C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered cycloalkyl C 1-6 The alkyl radicals are each independently optionally selected from halogen and C 1-6 In some embodiments, R ASelected from C 1-6 Alkyl, cyano, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl and 3 to 6 membered cycloalkyl C 1-6 alkyl; in some embodiments, R A Selected from C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl and 3 to 6 membered cycloalkyl C 1-6 alkyl; in some embodiments, each R A The same or different, and each independently selected from C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered cycloalkyl C 1-6 alkyl; in some embodiments, each R A The same or different, and each independently selected from C 1-6 alkyl, cyano, and 3- to 6-membered cycloalkyl; in some embodiments, each R A The same or different, and each independently is C 1-6 alkyl or cyano; in some embodiments, each R A The same or different, and each independently is C 1-6 alkyl or 3 to 6 membered cycloalkyl; in some embodiments, each R A The same or different, and each independently is C 1-6 alkyl; in some embodiments, each R A are the same or different and are each independently selected from methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, -CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CF 3 , -CF 2 CH 3 , propyl, isopropyl, -CF(CH 3 ) 2 , cyclopropyl, Cyclopentyl, cyclopropylmethyl, methoxy, hydroxyl and amino; in some embodiments, each R A are the same or different and are each independently selected from methyl, ethyl, isopropyl and cyano; in some embodiments, each R A are the same or different and are each independently selected from methyl, ethyl, isopropyl and cyclopropyl; in some embodiments, each R A are the same or different and are each independently ethyl or isopropyl; in some embodiments, R A It is isopropyl.

[0068] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5-membered heteroaryl group; wherein the 5-membered heteroaryl group is optionally replaced by one or more R A Replacement; R A Selected from C 1-6 alkyl, cyano, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group and 3- to 6-membered cycloalkyl C 1-6 alkyl; in some embodiments, ring A is a 5-membered heteroaryl; the 5-membered heteroaryl is optionally substituted by one or more R A Replacement; R A Selected from C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered cycloalkyl C 1-6 In some embodiments, ring A is selected from pyrazolyl, oxadiazolyl and pyrrolyl, and the pyrazolyl, oxadiazolyl and pyrrolyl are each independently optionally substituted with one or more R A Replace; each R A The same or different, and each independently is C 1-6 alkyl or cyano; in some embodiments, ring A is pyrazolyl; the pyrazolyl is optionally substituted by one R A Replacement; R A C 1-6 alkyl.

[0069] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring A is R 1A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl are each independently optionally replaced by one or more R t Substitution; X is N or CR 2A ; R 2A is a hydrogen atom or R A ; a is 0, 1 or 2; R A and R t As defined in general formula (I);

[0070] In some embodiments, Ring A is R 1Ais selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl are each independently optionally replaced by one or more R t Replacement; R t As defined in general formula (I).

[0071] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from

[0072] In some embodiments, Ring A is selected from and In some embodiments, Ring A is selected from

[0073] In some embodiments, Ring A is In some embodiments, Ring A is selected from In some embodiments, Ring A is In some embodiments, Ring A is

[0074] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,

[0075]

[0076] in:

[0077] R 1C For R C ; or two R 1C Together with the carbon atom to which it is attached, it forms a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group and the heterocyclic group are each independently optionally substituted by one or more R C substituted; c is 0, 1, 2, 3 or 4;

[0078] R 1Ais selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl are each independently optionally replaced by one or more R t Substitution; X is N or CR 2A ; R 2A is a hydrogen atom or R A ; a is 0, 1 or 2;

[0079] R 3 To R 9 , R A , R t and R C As defined in general formula (I).

[0080] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof:

[0081]

[0082] in:

[0083] R 5 is selected from the group consisting of a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a hydroxyl group, a cyano group, an amino group, a nitro group, a -(CR x R y ) s OR 10 、-(CR x R y ) s NR 11 R 12 、-C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-OC(O)NR 11 R 12 、-C(O)NR 11 R 12 、-NR 13 C(O)R 10 、-NR 13 C(O)OR 10 、-NR 13C(O)NR 11 R 12 、-SR 10 、-S(O)R 10 、-S(O) 2 R 10 、-S(O) 2 OR 10 、-S(O) 2 NR 11 R 12 and-NR 13 S(O) 2 R 10 wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R 0 replaced by;

[0084] R 0 ,X,R A , R 1A ,a,R 1C ,c,R 3 , R 4 , R 6 To R 13 , R x , R y and s are as defined in the general formula (III).

[0085] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein each R A are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; in some embodiments, each R A are the same or different and are each independently halogen or C 1-6 alkyl.

[0086] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R 2A Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; in some embodiments, R 2A Selected from hydrogen atoms, halogens, C 1-6 alkyl and cyano; in some embodiments, R 2A is cyano; in some embodiments, R 2A Selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 2A A hydrogen atom.

[0087] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein X is N; in some embodiments, X is N or CH; in some embodiments, X is N or C-CN.

[0088] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R 1A Selected from hydrogen atoms, C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered cycloalkyl C 1-6 Alkyl; wherein the C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered cycloalkyl C 1-6 The alkyl radicals are each independently optionally selected from halogen and C 1-6 In some embodiments, R 1A Selected from hydrogen atoms, C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered cycloalkyl C 1-6 alkyl; in some embodiments, R 1A Selected from C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered cycloalkyl C 1-6 alkyl; in some embodiments, R 1A Selected from hydrogen atoms, C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 1A C 1-6 alkyl or 3 to 6 membered cycloalkyl; in some embodiments, R 1A C 1-6alkyl; in some embodiments, R 1A is selected from methyl, ethyl, isopropyl and cyclopropyl; in some embodiments, R 1A is selected from methyl, ethyl and isopropyl; in some embodiments, R 1A is ethyl or isopropyl; in some embodiments, R 1A It is isopropyl.

[0089] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein a is 0.

[0090] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R 1C are the same or different and are each independently selected from deuterium atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl; wherein the C 1-6 alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkylC 1-6 The alkyl groups are each independently optionally selected from cyano, halogen, C 1-6 Alkyl and C 1-6 or two R 1C Together with the carbon atom to which it is attached, it forms a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group are each independently selected from cyano, halogen, C 1-6 Alkyl and C 1-6 In some embodiments, R 1C The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl; or, two adjacent R 1C Together with the carbon atoms to which they are attached, they form a 5-membered cycloalkyl group, which is optionally substituted with one or more halogens; or, two R on the same carbon atom 1C Together with the attached carbon atom, it forms a 3- or 4-membered cycloalkyl group, which is optionally substituted with one or more halogens; in some embodiments, R 1CThe same or different, and each independently selected from C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6 membered cycloalkyl; wherein the 3 to 6 membered cycloalkyl is optionally substituted with one or more cyano groups; in some embodiments, R 1C The same or different, and each independently is C 1-6 Alkyl or C 1-6 haloalkyl; or, two R on the same carbon atom 1C Together with the attached carbon atom, it forms a 3- or 4-membered cycloalkyl group; in some embodiments, R 1C The same or different, and each independently is C 1-6 Alkyl or C 1-6 haloalkyl; or, two R on the same carbon atom 1C Together with the attached carbon atom, it forms a cyclopropyl group; in some embodiments, R 1C The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 1C The same or different, and each independently is C 1-6 Alkyl or C 1-6 haloalkyl; in some embodiments, R 1C The same or different, and each independently is C 1-6 haloalkyl; in some embodiments, R 1C is trifluoromethyl; in some embodiments, two adjacent R 1C Together with the carbon atoms to which they are attached, they form a 5-membered cycloalkyl group, which is optionally substituted with one or more halogens; in some embodiments, two R on the same carbon atom 1C Together with the attached carbon atom, it forms a 3- or 4-membered cycloalkyl group, which is optionally substituted with one or more halogens; in some embodiments, each R 1C are the same or different and are each independently selected from a deuterium atom, F, methyl, difluoromethyl, trifluoromethyl, isopropyl, cyclopropyl, -CH 2 CF 3 and In some embodiments, each R 1C are the same or different and are each independently methyl or trifluoromethyl; or, two R on the same carbon atom 1C Together with the attached carbon atom, form a cyclopropyl group; in some embodiments, each R 1C are the same or different and are each independently methyl or trifluoromethyl; in some embodiments, R 1C It is trifluoromethyl.

[0091] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R 2C Selected from hydrogen atoms, deuterium atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl, the C 1-6 alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkylC 1-6 The alkyl groups are each independently optionally selected from cyano, halogen, C 1-6 Alkyl and C 1-6 In some embodiments, R 2C Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6 membered cycloalkyl; wherein the 3 to 6 membered cycloalkyl is optionally substituted with one or more cyano groups; in some embodiments, R 2C Selected from C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6 membered cycloalkyl; wherein the 3 to 6 membered cycloalkyl is optionally substituted with one or more cyano groups; in some embodiments, R 2C Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 2C Selected from C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 2C Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 2C C 1-6 Alkyl or C 1-6 haloalkyl; in some embodiments, R 2C C 1-6 haloalkyl; in some embodiments, R 2C is selected from hydrogen atom, deuterium atom, F, methyl, difluoromethyl, trifluoromethyl, isopropyl, cyclopropyl, -CH 2 CF 3 and In some embodiments, R 2C is methyl or trifluoromethyl; in some embodiments, R 2C It is trifluoromethyl.

[0092] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or their pharmaceutically acceptable salts, wherein b is 1; in some embodiments, b is 2.

[0093] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein c is 0, 1, 2 or 3; in some embodiments, c is 0, 1 or 2; in some embodiments, c is 1 or 2; in some embodiments, c is 0 or 1; in some embodiments, c is 1; in some embodiments, c is 0.

[0094] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 8 membered cycloalkyl and phenyl, wherein the 3 to 8 membered cycloalkyl and phenyl are each independently optionally selected from halogen and C 1-6 is substituted by one or more substituents in the alkyl group; or, R 3 and R 4 Together with the attached carbon atom, it forms a 3- to 8-membered cycloalkyl group; the 3- to 8-membered cycloalkyl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and is substituted by one or more substituents; R 15 and R 16 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 3 and R 4 are the same or different and are each independently a 3- or 4-membered cycloalkyl group; or, R 3 and R 4 Together with the attached carbon atom, it forms a 3- to 8-membered cycloalkyl group; the 3- to 8-membered cycloalkyl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and is substituted by one or more substituents; R 15 and R16 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 3 and R 4 is cyclopropyl; or, R 3 and R 4 Together with the attached carbon atom, it forms a 5- to 7-membered cycloalkyl group, wherein the 5- to 7-membered cycloalkyl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and is substituted by one or more substituents; R 15 and R 16 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 3 and R 4 are the same or different and are each independently a 3- to 8-membered cycloalkyl group; or, R 3 and R 4 Together with the attached carbon atom, it forms a 3- to 8-membered cycloalkyl group; the 3- to 8-membered cycloalkyl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and is substituted by one or more substituents; R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R 3 and R 4 are the same or different and are each independently a 3- to 6-membered cycloalkyl group; or, R 3 and R 4 Together with the attached carbon atom, it forms a 5- to 7-membered cycloalkyl group; the 5- to 7-membered cycloalkyl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and is substituted by one or more substituents; R 15 and R 16 are the same or different and are each independently a hydrogen atom or F; in some embodiments, R 3 and R 4 are the same or different and are each independently cyclopropyl or cyclobutyl; or, R 3 and R 4 Together with the attached carbon atom, it forms a cyclohexyl or cycloheptyl group; the cyclohexyl or cycloheptyl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and is substituted by one or more substituents; R 15 and R 16are the same or different and are each independently a hydrogen atom or F; in some embodiments, R 3 and R 4 is cyclopropyl; in some embodiments, R 3 and R 4 Together with the attached carbon atom, it forms a cyclohexyl or cycloheptyl group; the cyclohexyl or cycloheptyl group are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and is substituted by one or more substituents; R 15 and R 16 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 3 and R 4 Together with the attached carbon atom, it forms a cyclohexyl group; the cyclohexyl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and is substituted by one or more substituents; R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R 3 and R 4 Together with the attached carbon atom it forms a cycloheptyl group.

[0095] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein Selected from In some embodiments, Selected from and In some embodiments, Selected from In some embodiments, Selected from In some embodiments, for

[0096] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R11 and R 12 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, R 11 and R 12 A hydrogen atom.

[0097] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R 15 and R 16 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R 15 and R 16 are the same or different and are each independently selected from a hydrogen atom, F and a methyl group; in some embodiments, R 15 and R 16 are the same or different and are each independently a hydrogen atom or F; in some embodiments, R 15 and R 16 For F.

[0098] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered cycloalkyl C 1-6 alkyl; in some embodiments, R 5 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 5 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy C1-6 alkyl; in some embodiments, R 5 is selected from methyl, ethyl, propyl, isopropyl, In some embodiments, R 5 C 1-6 alkyl; in some embodiments, R 5 is methyl; in some embodiments, R 5 Selected from methyl, and cyclopropyl; in some embodiments, R 5 Selected from methyl,

[0099] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 1-6 Alkoxy C 1-6 alkyl; in some embodiments, R 6 Selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 6 is a hydrogen atom or a halogen; in some embodiments, R 6 is halogen; in some embodiments, R 6 is a hydrogen atom or F; in some embodiments, R 6 For F.

[0100] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 1-6 Alkoxy C 1-6 alkyl; in some embodiments, R 7 Selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 7 is a hydrogen atom or a halogen; in some embodiments, R7 A hydrogen atom.

[0101] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R 8 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 1-6 Alkoxy C 1-6 alkyl; in some embodiments, R 8 Selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 8 is a hydrogen atom or a halogen; in some embodiments, R 8 A hydrogen atom.

[0102] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R 9 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 1-6 Alkoxy C 1-6 alkyl; in some embodiments, R 9 Selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 9 is a hydrogen atom or a halogen; in some embodiments, R 9 A hydrogen atom.

[0103] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R 6 , R 7 , R 8 and R 9 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 1-6 Alkoxy C 1-6 alkyl; in some embodiments, R 6 , R 7 , R 8 and R 9 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 6 is a hydrogen atom or a halogen; R 7 , R 8 and R 9 is a hydrogen atom; in some embodiments, R 6 is halogen; R 7 , R 8 and R 9 is a hydrogen atom; in some embodiments, R 6 is a hydrogen atom or F; R 7 , R 8 and R 9 is a hydrogen atom; in some embodiments, R 6 F; R 7 , R 8 and R 9 A hydrogen atom.

[0104] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring C is R 1C The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl; or, two adjacent R 1C Together with the carbon atoms to which they are attached, they form a 5-membered cycloalkyl group, which is optionally substituted with one or more halogens; or, two R on the same carbon atom 1C Together with the attached carbon atoms, it forms a 3- or 4-membered cycloalkyl group, wherein the 3- or 4-membered cycloalkyl group is optionally substituted with one or more halogens; c is 0, 1, 2, 3 or 4; Ring A is a 5-membered heteroaryl group; wherein the 5-membered heteroaryl group is optionally substituted with one or more R A Replacement; R A The same or different, and each independently is C 1-6 Alkyl or 3 to 6-membered cycloalkyl; n is 0; R a is a hydrogen atom; R b is a hydrogen atom; X 1 CR 6 ;X 2 CR 7 ;X3 CR 8 ;X 4 CR 9 ; R 5 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy C 1-6 Alkyl; R 6 , R 7 , R 8 and R 9 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; B is CHR 3 R 4 ; R 3 and R 4 are the same or different and are each independently a 3- to 8-membered cycloalkyl group; or, R 3 and R 4 Together with the attached carbon atom, it forms a 3- to 8-membered cycloalkyl group; the 3- to 8-membered cycloalkyl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and is substituted by one or more substituents; R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen.

[0105] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring C is R 1C The same or different, and each independently is C 1-6 Alkyl or C 1-6 haloalkyl; or, two R on the same carbon atom 1C Together with the carbon atom to which it is attached, it forms a 3- or 4-membered cycloalkyl group; b is 1 or 2; c is 0, 1 or 2; R 5 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl and 3 to 6 membered cycloalkyl; X 1 CR 6 ; R 6 is a hydrogen atom or a halogen; X 2 CH; X 3 CH; X 4 CH; R a is a hydrogen atom; R b is a hydrogen atom; B is CHR 3 R 4 ; R 3 and R4 are the same or different and are each independently a 3- or 4-membered cycloalkyl group; or, R 3 and R 4 Together with the attached carbon atom, it forms a 3- to 8-membered cycloalkyl group, wherein the 3- to 8-membered cycloalkyl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and is substituted by one or more substituents; R 15 and R 16 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; n is 0; Ring A is a 5-membered heteroaryl group, the 5-membered heteroaryl group is optionally substituted by one or more R A Replace; each R A The same or different, and each independently is C 1-6 Alkyl or cyano.

[0106] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring C is R 2C Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl; Ring A is R 1A C 1-6 Alkyl or 3 to 6-membered cycloalkyl; R 3 and R 4 are the same or different and are each independently a 3- to 6-membered cycloalkyl group; or, R 3 and R 4 Together with the attached carbon atom, it forms a 5- to 7-membered cycloalkyl group; the 5- to 7-membered cycloalkyl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and is substituted by one or more substituents; R 15 and R 16 are the same or different and are each independently a hydrogen atom or F; R 5 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy C 1-6 Alkyl; R 6 is halogen; R 7 , R 8 and R 9 A hydrogen atom.

[0107] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring C is R 1C The same or different, and each independently is C 1-6 Alkyl or C 1-6 haloalkyl; or, two R on the same carbon atom 1C Together with the carbon atom to which it is attached, it forms a cyclopropyl group; b is 1 or 2; c is 1 or 2; R 5 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl and 3 to 6 membered cycloalkyl; R 6 is a hydrogen atom or a halogen; R 7 , R 8 and R 9 is a hydrogen atom; R 3 and R 4 is cyclopropyl; or, R 3 and R 4 Together with the attached carbon atom, it forms a 5- to 7-membered cycloalkyl group, wherein the 5- to 7-membered cycloalkyl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and is substituted by one or more substituents; R 15 and R 16 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; Ring A is selected from pyrazolyl, oxadiazolyl and pyrrolyl, wherein the pyrazolyl, oxadiazolyl and pyrrolyl are each independently optionally substituted by one or more R A Replace; each R A The same or different, and each independently is C 1-6 Alkyl or cyano.

[0108] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring C is selected from R 5 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl and 3 to 6 membered cycloalkyl; R 6 is a hydrogen atom or a halogen; R 7 , R 8 and R 9 is a hydrogen atom; Selected from Ring A is selected from

[0109] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring C is R 2C C 1-6 Alkyl or C 1-6 Haloalkyl; Ring A is Selected from R 6 is halogen; R 7 , R 8 and R 9 A hydrogen atom.

[0110] In some embodiments of the present disclosure, the compound represented by the general formula (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein X is N or C-CN; R 1A C 1-6 Alkyl; a is 0; Selected from R 5 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl and 3 to 6 membered cycloalkyl; R 6 is a hydrogen atom or a halogen; R 7 , R 8 and R 9 is a hydrogen atom; R 1C C 1-6 Alkyl or C 1-6 Haloalkyl; c is 1.

[0111] In some embodiments of the present disclosure, the compound represented by the general formula (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein X is N or CH; R 1A C 1-6 Alkyl; a is 0; Selected from R 5 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy C 1-6 Alkyl; R 6 is halogen; R 7 , R 8and R 9 is a hydrogen atom; R 1C C 1-6 Alkyl or C 1-6 Haloalkyl; c is 0 or 1.

[0112] In some embodiments of the present disclosure, the compound represented by the general formula (III), (III-1), (III-2), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein X is N; R 1A C 1-6 Alkyl; a is 0; Selected from R 5 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy C 1-6 Alkyl; R 6 is halogen; R 7 , R 8 and R 9 is a hydrogen atom; R 1C C 1-6 Alkyl or C 1-6 Haloalkyl; c is 1.

[0113] Table A Typical compounds of the present disclosure include, but are not limited to:

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135] Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a salt thereof,

[0136]

[0137] in:

[0138] Ring C, B, R a , R b , X 1 , X 2 , X 3 , X 4 and R 5 As defined in general formula (I).

[0139] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or a salt thereof,

[0140]

[0141] in:

[0142] Ring C, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 As defined in general formula (II).

[0143] Another aspect of the present disclosure relates to a compound represented by general formula (II-1A), (II-2A), (II-3A) or (II-4A) or a salt thereof,

[0144]

[0145]

[0146] in:

[0147] Ring C, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 As defined in general formula (II-1), general formula (II-2), general formula (II-3) or general formula (II-4).

[0148] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA) or a salt thereof,

[0149]

[0150] in:

[0151] R 1C , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and c are as defined in the general formula (III).

[0152] Another aspect of the present disclosure relates to a compound represented by general formula (III-1A), (III-2A), (III-3A) or (III-4A) or a salt thereof,

[0153]

[0154] in:

[0155] R 1C , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and c are as defined in the general formula (III-1), (III-2), (III-3) or (III-4).

[0156] Table B Typical intermediate compounds disclosed herein include but are not limited to:

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0173]

[0174] The compound represented by the general formula (IA) or its salt undergoes a condensation reaction with the compound represented by the general formula (IB) or its salt to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt;

[0175] in:

[0176] R w is halogen or hydroxy; in some embodiments, R w is hydroxyl group;

[0177] Ring A, Ring C, B, n, R 1 , R 2 , R a , R b , X 1 , X 2 , X 3 , X 4 and R 5 As defined in general formula (I).

[0178] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0179]

[0180] The compound represented by the general formula (IIA) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIB) or its salt to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable salt;

[0181] in:

[0182] R w is halogen or hydroxy; in some embodiments, R w is hydroxyl group;

[0183] Ring A, Ring C, R 3 To R 9 As defined in general formula (II).

[0184] Another aspect of the present disclosure relates to a method for preparing a compound represented by the above-mentioned general formula (II-1), general formula (II-2), general formula (II-3) or general formula (II-4) or a pharmaceutically acceptable salt thereof, the method comprising:

[0185]

[0186] The compound represented by the general formula (II-1A) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIB) or its salt to obtain the compound represented by the general formula (II-1) or its pharmaceutically acceptable salt; or

[0187]

[0188] The compound represented by the general formula (II-2A) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIB) or its salt to obtain the compound represented by the general formula (II-2) or its pharmaceutically acceptable salt; or

[0189]

[0190] The compound represented by the general formula (II-3A) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIB) or its salt to obtain the compound represented by the general formula (II-3) or its pharmaceutically acceptable salt; or

[0191]

[0192] The compound represented by the general formula (II-4A) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIB) or its salt to obtain the compound represented by the general formula (II-4) or its pharmaceutically acceptable salt;

[0193] in:

[0194] R wis halogen or hydroxy; in some embodiments, R w is hydroxyl group;

[0195] Ring A, Ring C, R 3 To R 9 As defined in general formula (II-1), general formula (II-2), general formula (II-3) or general formula (II-4).

[0196] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0197]

[0198] The compound represented by the general formula (IIIA) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIIB) or its salt to obtain the compound represented by the general formula (III) or its pharmaceutically acceptable salt;

[0199] in:

[0200] R w is halogen or hydroxy; in some embodiments, R w is hydroxyl group;

[0201] X, R A , R 1A ,a,R 1C , c and R 3 To R 9 As defined in general formula (III).

[0202] Another aspect of the present disclosure relates to a method for preparing a compound represented by the above-mentioned general formula (III-1), general formula (III-2), general formula (III-3) or general formula (III-4) or a pharmaceutically acceptable salt thereof, the method comprising:

[0203]

[0204] The compound represented by the general formula (III-1A) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIIB) or its salt to obtain the compound represented by the general formula (III-1) or its pharmaceutically acceptable salt; or

[0205]

[0206] The compound represented by the general formula (III-2A) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIIB) or its salt to obtain the compound represented by the general formula (III-2) or its pharmaceutically acceptable salt; or

[0207]

[0208] The compound represented by the general formula (III-3A) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIIB) or its salt to obtain the compound represented by the general formula (III-3) or its pharmaceutically acceptable salt; or

[0209]

[0210] The compound represented by the general formula (III-4A) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIIB) or its salt to obtain the compound represented by the general formula (III-4) or its pharmaceutically acceptable salt;

[0211] in:

[0212] R w is halogen or hydroxy; in some embodiments, R w is hydroxyl group;

[0213] X, R A , R 1A ,a,R 1C , c and R 3 To R 9 As defined in general formula (III-1), general formula (III-2), general formula (III-3) or general formula (III-4).

[0214] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0215]

[0216] The compound represented by the general formula (Ia) or its salt undergoes a condensation reaction with the compound represented by the general formula (Ib) or its salt to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt;

[0217] in:

[0218] R w is halogen or hydroxy; in some embodiments, R w is hydroxyl group;

[0219] Ring A, Ring C, B, n, R 1 , R 2 , R a , R b , X 1 , X 2 , X 3 , X 4 and R 5 As defined in general formula (I).

[0220] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0221]

[0222] The compound represented by the general formula (IIa) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIb) or its salt to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable salt;

[0223] in:

[0224] R w is halogen or hydroxy; in some embodiments, R w is hydroxyl group;

[0225] Ring A, Ring C, R 3 To R 9 As defined in general formula (II).

[0226] Another aspect of the present disclosure relates to a method for preparing a compound represented by the above-mentioned general formula (II-1), general formula (II-2), general formula (II-3) or general formula (II-4) or a pharmaceutically acceptable salt thereof, the method comprising:

[0227]

[0228] The compound represented by the general formula (II-1a) or its salt undergoes a condensation reaction with the compound represented by the general formula (II-1b) or its salt to obtain the compound represented by the general formula (II-1) or its pharmaceutically acceptable salt; or

[0229]

[0230] The compound represented by the general formula (II-1a) or its salt undergoes a condensation reaction with the compound represented by the general formula (II-2b) or its salt to obtain the compound represented by the general formula (II-2) or its pharmaceutically acceptable salt; or

[0231]

[0232] The compound represented by the general formula (II-3a) or its salt undergoes a condensation reaction with the compound represented by the general formula (II-1b) or its salt to obtain the compound represented by the general formula (II-3) or its pharmaceutically acceptable salt; or

[0233]

[0234] The compound represented by the general formula (II-3a) or its salt undergoes a condensation reaction with the compound represented by the general formula (II-2b) or its salt to obtain the compound represented by the general formula (II-4) or its pharmaceutically acceptable salt;

[0235] in:

[0236] R w is halogen or hydroxy; in some embodiments, R w is hydroxyl group;

[0237] Ring A, Ring C, R 3 To R 9 As defined in general formula (II-1), general formula (II-2), general formula (II-3) or general formula (II-4).

[0238] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0239]

[0240] The compound represented by the general formula (IIIa) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIIb) or its salt to obtain the compound represented by the general formula (III) or its pharmaceutically acceptable salt;

[0241] in:

[0242] R w is halogen or hydroxy; in some embodiments, R w is hydroxyl group;

[0243] X, R A , R 1A ,a,R 1C , c and R 3 To R 9 As defined in general formula (III).

[0244] Another aspect of the present disclosure relates to a method for preparing a compound represented by the above-mentioned general formula (III-1), general formula (III-2), general formula (III-3) or general formula (III-4) or a pharmaceutically acceptable salt thereof, the method comprising:

[0245]

[0246] The compound represented by the general formula (III-1a) or its salt undergoes a condensation reaction with the compound represented by the general formula (III-1b) or its salt to obtain the compound represented by the general formula (III-1) or its pharmaceutically acceptable salt; or

[0247]

[0248] The compound represented by the general formula (III-1a) or its salt undergoes a condensation reaction with the compound represented by the general formula (III-2b) or its salt to obtain the compound represented by the general formula (III-2) or its pharmaceutically acceptable salt; or

[0249]

[0250] The compound represented by the general formula (III-3a) or its salt undergoes a condensation reaction with the compound represented by the general formula (III-1b) or its salt to obtain the compound represented by the general formula (III-3) or its pharmaceutically acceptable salt; or

[0251]

[0252] The compound represented by the general formula (III-3a) or its salt undergoes a condensation reaction with the compound represented by the general formula (III-2b) or its salt to obtain the compound represented by the general formula (III-4) or its pharmaceutically acceptable salt;

[0253] in:

[0254] R w is halogen or hydroxy; in some embodiments, R w is hydroxyl group;

[0255] X, R A , R 1A ,a,R 1C , c and R 3 To R 9 As defined in general formula (III-1), general formula (III-2), general formula (III-3) or general formula (III-4).

[0256] When R w When it is a halogen, the condensation reaction is carried out under alkaline conditions.

[0257] When R w When it is a hydroxyl group, the condensation reaction is carried out under alkaline conditions and in the presence of a condensation agent;

[0258] In some embodiments, the condensing agent is not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate. Urea hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 2-(7-oxybenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate; in some embodiments, HATU.

[0259] In some embodiments, the reagent providing alkaline conditions includes organic bases and inorganic bases, and the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, N,N-diisopropylethylenediamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrabutylammonium fluoride in tetrahydrofuran or 1,8-diazabicycloundec-7-ene, and the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride and potassium hydroxide; in some embodiments, triethylamine or N,N-diisopropylethylamine.

[0260] In some embodiments, the above reaction is carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof.

[0261] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or shown in Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0262] The present disclosure further relates to the use of a compound of formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing a disease or condition mediated by IL-17; in some embodiments, the IL-17 is IL-17A.

[0263] The present disclosure further relates to the use of a compound of formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing cancer, inflammation or an autoimmune disease; in some embodiments, the inflammation or autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, suppurative hidradenitis, rheumatoid arthritis, juvenile atopic arthritis, spondyloarthritis (e.g., axial spondyloarthritis), glucocorticoid arthritis, spondyloarthritis, leukoderma, leukoderma lucidum, spondyloarthritis ... In some embodiments, the present invention is selected from the group consisting of: pancreatitis (e.g., non-infectious uveitis), bone erosions, intraperitoneal abscesses and adhesions, inflammatory bowel disease (IBD), Crohn's disease, allograft rejection (e.g., kidney), psoriasis, psoriasis, angiogenesis, atherosclerosis, asthma (e.g., bronchial asthma), multiple sclerosis (MS), systemic lupus erythematosus, lupus nephritis, Behcet's disease, ulcerative colitis, Behcet's disease, Wegener's granulomatosis, sarcoidosis, systemic sclerosis, insulin-dependent diabetes mellitus, septic shock syndrome, Alzheimer's disease, inflammatory eye disease, palmoplantar pustulosis (PPP), atopic dermatitis, chronic obstructive pulmonary disease (COPD), and Helicobacter pylori-associated gastritis, in some embodiments selected from the group consisting of psoriasis, rheumatoid arthritis, spondyloarthritis, and multiple sclerosis, in some embodiments psoriasis.

[0264] The present disclosure further relates to a method for inhibiting IL-17, comprising administering to a patient in need thereof a compound of formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; in some embodiments, the IL-17 is IL-17A.

[0265] The present disclosure further relates to a method for treating and / or preventing a disease or condition mediated by IL-17, comprising administering to a patient in need thereof a compound of formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; in some embodiments, the IL-17 is IL-17A.

[0266] The present disclosure further relates to a method for treating and / or preventing cancer, inflammation or autoimmune diseases, comprising administering to a patient in need thereof a compound of formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; in some embodiments, the inflammation or autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, suppurative hidradenitis, rheumatoid arthritis, juvenile atopic arthritis, spondyloarthritis (e.g., axial spondyloarthritis), glucocorticoid arthritis, spondyloarthritis, leukoderma, leukoderma lucidum, leukoderma spondyloarthritis ... In some embodiments, the present invention is selected from the group consisting of: pancreatitis (e.g., non-infectious uveitis), bone erosions, intraperitoneal abscesses and adhesions, inflammatory bowel disease (IBD), Crohn's disease, allograft rejection (e.g., kidney), psoriasis, psoriasis, angiogenesis, atherosclerosis, asthma (e.g., bronchial asthma), multiple sclerosis (MS), systemic lupus erythematosus, lupus nephritis, Behcet's disease, ulcerative colitis, Behcet's disease, Wegener's granulomatosis, sarcoidosis, systemic sclerosis, insulin-dependent diabetes mellitus, septic shock syndrome, Alzheimer's disease, inflammatory eye disease, palmoplantar pustulosis (PPP), atopic dermatitis, chronic obstructive pulmonary disease (COPD), and Helicobacter pylori-associated gastritis, in some embodiments selected from the group consisting of psoriasis, rheumatoid arthritis, spondyloarthritis, and multiple sclerosis, in some embodiments psoriasis.

[0267] The present disclosure further relates to a compound of formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug.

[0268] The present disclosure further relates to a compound of formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as an IL-17 inhibitor; in some embodiments, the IL-17 is IL-17A.

[0269] The present disclosure further relates to a compound of formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used to inhibit IL-17; in some embodiments, the IL-17 is IL-17A.

[0270] The present disclosure further relates to a compound of formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, and its use in a medicament for treating and / or preventing a disease or condition mediated by IL-17; in some embodiments, the IL-17 is IL-17A.

[0271] The present disclosure further relates to a compound of formula (I), (II), (II-1), (II-2), (II-3), (II-4), (III), (III-1), (III-2), (III-3) or (III-4) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing cancer, inflammation or autoimmune diseases; in some embodiments, the inflammation or autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, suppurative hidradenitis, rheumatoid arthritis, juvenile atopic arthritis, spondyloarthritis (e.g., axial spondyloarthritis), uveitis (e.g., non-infectious uveitis), bone erosion, intraperitoneal abscesses and adhesions, inflammatory bowel disease (IBD), Crohn's disease, allogeneic transplant rejection (e.g., kidney), psoriasis, psoriasis, angiogenesis, atherosclerosis, asthma (e.g., bronchial asthma), multiple sclerosis (MS), systemic lupus erythematosus, lupus nephritis, Behcet's disease, ulcerative colitis, Behcet's disease, Wegener's granulomatosis, sarcoidosis, systemic sclerosis, insulin-dependent diabetes mellitus, septic shock syndrome, Alzheimer's disease, inflammatory eye disease, palmoplantar pustulosis (PPP), atopic dermatitis, chronic obstructive pulmonary disease (COPD), and Helicobacter pylori-associated gastritis, in some embodiments selected from psoriasis, rheumatoid arthritis, spondyloarthritis, and multiple sclerosis, in some embodiments psoriasis.

[0272] The IL-17-mediated diseases or conditions described in the present disclosure are selected from cancer, inflammation or autoimmune diseases in some embodiments; inflammation or autoimmune diseases in some embodiments; inflammation in some embodiments; and in some embodiments, the inflammation or autoimmune diseases are selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, juvenile atopic arthritis, spondyloarthritis (e.g., axial spondyloarthritis), uveitis (e.g., non-infectious uveitis), bone erosions, intraperitoneal abscesses and adhesions, inflammatory bowel disease. (IBD), Crohn's disease, allograft rejection (e.g., kidney), psoriasis, psoriasis, angiogenesis, atherosclerosis, asthma (e.g., bronchial asthma), multiple sclerosis (MS), systemic lupus erythematosus, lupus nephritis, Behcet's disease, ulcerative colitis, Behcet's disease, Wegener's granulomatosis, sarcoidosis, systemic sclerosis, insulin-dependent diabetes mellitus, septic shock syndrome, Alzheimer's disease, inflammatory eye disease, palmoplantar pustulosis (PPP), atopic dermatitis, chronic obstructive pulmonary disease (COPD), and Helicobacter pylori-associated gastritis, in some embodiments selected from psoriasis, rheumatoid arthritis, spondyloarthritis, and multiple sclerosis, in some embodiments psoriasis.

[0273] The psoriasis described in the present disclosure is, in some embodiments, selected from plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, and palmoplantar psoriasis.

[0274] The spondyloarthritis described in the present disclosure is, in some embodiments, axial spondyloarthritis.

[0275] The uveitis described in the present disclosure is, in some embodiments, non-infectious uveitis.

[0276] The asthma described in the present disclosure is, in some embodiments, bronchial asthma.

[0277] The IL-17 described in the present disclosure is, in some embodiments, IL-17A or IL-17F; in some embodiments, IL-17A.

[0278] In some embodiments, the cancer described herein is selected from the group consisting of:

[0279] Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;

[0280] Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, mesothelioma;

[0281] Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, viperoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

[0282] Genitourinary tract: Kidney (adenocarcinoma, Wilm's tumor, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma);

[0283] Liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

[0284] Biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer;

[0285] Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondrotic exostosis (osteochronfroma), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor;

[0286] Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningiosarcoma, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors, glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);

[0287] Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovary (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma);

[0288] Hematological: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

[0289] Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, hydatidiform mole, lipoma, hemangioma, dermatofibroma, keloid, psoriasis;

[0290] and adrenal glands: neuroblastoma.

[0291] As a general guide, the active compounds of the present disclosure are in some embodiments in a unit dose form, or in a form that a patient can self-administer in a single dose. The unit dose of the compounds or compositions of the present disclosure can be expressed in tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit doses can be 0.1 to 1000 mg.

[0292] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0293] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0294] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution.

[0295] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.

[0296] The pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic salts or organic salts.

[0297] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

[0298] Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

[0299] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0300] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0301] Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

[0302] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0303] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0304] The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0305] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by the addition of water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0306] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the severity of the disease, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0307] Terminology

[0308] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0309] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 The alkyl group, in some embodiments, has 1 to 12 carbon atoms (i.e., C 1-12 Alkyl), in some embodiments an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6 Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents being selected in some embodiments from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0310] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20The alkylene group, in some embodiments, has an alkylene group of 1 to 12 carbon atoms (i.e., C 1-12 Alkylene), in some embodiments an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 Alkylene). Non-limiting examples include: -CH 2 -、-CH(CH 3 )-、-C(CH 3 ) 2 -、-CH 2 CH 2 -、-CH(CH 2 CH 3 )-、-CH 2 CH(CH 3 )-、-CH 2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 -, etc. Alkylene can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituents are selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl in some embodiments.

[0311] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkenyl group, in some embodiments, has 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, etc. Alkenyl can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituents are selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0312] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C2-12 The alkynyl group, in some embodiments, has 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituents are selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl in some embodiments.

[0313] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy and butoxy, etc. Alkoxy can be substituted or unsubstituted, and when substituted, it can be substituted at any usable point of attachment, and the substituents are selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl in some embodiments.

[0314] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20-membered cycloalkyl). The cycloalkyl group includes, in some embodiments, cycloalkyl groups having 3 to 12 ring atoms (i.e., 3 to 12-membered cycloalkyl) and cycloalkyl groups having 3 to 10 ring atoms (i.e., 3 to 10-membered cycloalkyl), in some embodiments, cycloalkyl groups having 3 to 8 ring atoms (i.e., 3 to 8-membered cycloalkyl), in some embodiments, cycloalkyl groups having 4 to 7 ring atoms (i.e., 4 to 7-membered cycloalkyl), in some embodiments, cycloalkyl groups having 5 or 6 ring atoms (i.e., 5 or 6-membered cycloalkyl), and in some embodiments, cycloalkyl groups having 3 to 6 ring atoms (i.e., 3 to 6-membered cycloalkyl).

[0315] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

[0316] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0317] The term "spirocycloalkyl" refers to a polycyclic system that shares one carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds in the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). The spirocycloalkyl has 6 to 14 ring atoms in some embodiments (i.e., 6 to 14-membered spirocycloalkyl), and has 7 to 10 ring atoms in some embodiments (i.e., 7 to 10-membered spirocycloalkyl). The spirocycloalkyl includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.), in some embodiments, monospirocycloalkyl or bispirocycloalkyl, in some embodiments, 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan monospirocycloalkyl. Non-limiting examples include:

[0318] Its connection point can be at any position;

[0319] wait.

[0320] The term "fused cycloalkyl" refers to a polycyclic system that shares two adjacent carbon atoms between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). The fused cycloalkyl has, in some embodiments, 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and in some embodiments, 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), in some embodiments, bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, in some embodiments, 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused cycloalkyl. Non-limiting examples include:

[0321]

[0322] Its connection point can be at any position;

[0323]

[0324] wait.

[0325] The term "bridged cycloalkyl" refers to a full carbon polycyclic system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl) in some embodiments, and a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl) in some embodiments. The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments is a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl. Non-limiting examples include:

[0326] Its connection point can be at any position.

[0327] The cycloalkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, with the substituents in some embodiments being selected from one or more of a D atom, a halogen, an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, a cycloalkyloxy, a heterocyclyloxy, a hydroxyl, a hydroxyalkyl, an oxo, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl.

[0328] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl), which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-) in the ring, and has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclyl group, in some embodiments, has 3 to 12 ring atoms (i.e., 3 to 12-membered heterocyclyl); further in some embodiments, has 3 to 10 ring atoms (i.e., 3 to 10-membered heterocyclyl) and has 3 to 8 ring atoms (i.e., 3 to 8-membered heterocyclyl); in some embodiments, has 5 to 7 ring atoms (i.e., 5 to 7-membered heterocyclyl); in some embodiments, has 3 to 6 ring atoms (i.e., 3 to 6-membered heterocyclyl); in some embodiments, has 5 or 6 ring atoms (i.e., 5 or 6-membered heterocyclyl) or has 3 to 4 ring atoms (i.e., 3 to 4-membered heterocyclyl).

[0329] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0330] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0331] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl). The spiro heterocyclic radical has a spiro heterocyclic radical (i.e., a 6 to 14-membered spiro heterocyclic radical) of 6 to 14 ring atoms in some embodiments, and a spiro heterocyclic radical (i.e., a 7 to 10-membered spiro heterocyclic radical) of 7 to 10 ring atoms in some embodiments. The spiro heterocyclic radical includes a monospiro heterocyclic radical and a polyspiro heterocyclic radical (such as a bispiro heterocyclic radical, etc.), in some embodiments a monospiro heterocyclic radical or a bispiro heterocyclic radical, in some embodiments 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan monospiro heterocyclic radical. Non-limiting examples include:

[0332] wait.

[0333] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system which shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur within the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more of cycloalkyl, aryl, or heteroaryl, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclyl). The fused heterocyclic radical has a fused heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic radical) in some embodiments, and a fused heterocyclic radical of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic radical) in some embodiments. The fused heterocyclic radical includes bicyclic and polycyclic fused heterocyclic radicals (such as tricyclic fused heterocyclic radicals, tetracyclic fused heterocyclic radicals, etc.), in some embodiments bicyclic fused heterocyclic radicals or tricyclic fused heterocyclic radicals, in some embodiments 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused heterocyclic radicals. Non-limiting examples include:

[0334]

[0335] wait.

[0336] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -OO-, -OS-, or -SS-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups). The bridged heterocyclic group has 6 to 14 ring atoms in some embodiments (i.e., 6 to 14-membered bridged heterocyclic groups), and has 7 to 10 ring atoms in some embodiments (i.e., 7 to 10-membered bridged heterocyclic groups). According to the number of constituent rings, it can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), and in some embodiments, it is a bicyclic bridged heterocyclic group or a tricyclic bridged heterocyclic group. Non-limiting examples include:

[0337] wait.

[0338] The heterocyclyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are, in some embodiments, selected from one or more of a D atom, a halogen, an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, a cycloalkyloxy, a heterocyclyloxy, a hydroxyl, a hydroxyalkyl, an oxo, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl.

[0339] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., 6 to 14-membered aromatic group). The aryl group, in some embodiments, has an aromatic group with 6 to 10 ring atoms (i.e., 6 to 10-membered aromatic group). The monocyclic aromatic group is, for example, phenyl. The polycyclic aromatic group, non-limiting examples include: naphthyl, anthracenyl, phenanthryl, etc. The polycyclic aromatic group also includes phenyl fused with one or more heterocyclic groups or cycloalkyl groups, or naphthyl fused with one or more heterocyclic groups or cycloalkyl groups, wherein the connection point is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:

[0340] wait.

[0341] The aryl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents being selected in some embodiments from one or more of a D atom, a halogen, an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, a cycloalkyloxy, a heterocyclyloxy, a hydroxyl, a hydroxyalkyl, an oxo, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl.

[0342] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -OO-, -OS-, or -SS-), and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl). The heteroaryl has, in some embodiments, 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl), and in some embodiments, 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl).

[0343] The monocyclic heteroaryl group includes, but is not limited to, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

[0344] The polycyclic heteroaryl, non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, etc. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aromatic groups, wherein the connection point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

[0345]

[0346] wait.

[0347] The heteroaryl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, with the substituents in some embodiments being selected from one or more of a D atom, a halogen, an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, a cycloalkyloxy, a heterocyclyloxy, a hydroxyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl.

[0348] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0349] The term "heterocyclylalkyl" refers to an alkyl group substituted by one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

[0350] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein alkoxy and alkyl are as defined above.

[0351] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0352] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0353] The term "aryloxy" refers to an aryl-O- group in which aryl is as defined above.

[0354] The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

[0355] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0356] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0357] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy is as defined above.

[0358] The term "alkoxyalkyl" refers to an alkyl group substituted by one or more alkoxy groups, wherein alkyl and alkoxy are as defined above.

[0359] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0360] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0361] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0362] The term "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxy groups, wherein alkoxy is as defined above.

[0363] The term "methylene" refers to =CH 2 .

[0364] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0365] The term "hydroxy" refers to -OH.

[0366] The term "thiol" refers to -SH.

[0367] The term "amino" refers to -NH 2 .

[0368] The term "cyano" refers to -CN.

[0369] The term "nitro" refers to -NO 2 .

[0370] The term "oxo" or "oxo" refers to "=0".

[0371] The term "carbonyl" refers to C=O.

[0372] The term "acetyl" refers to -C(O)CH 3 .

[0373] The term "amide" refers to -C(O)NH 2 .

[0374] The term "carboxy" refers to -C(O)OH.

[0375] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined above.

[0376] The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). Substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers may be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art to obtain pure isomers. In addition, the separation of enantiomers and diastereoisomers is usually completed by chromatography.

[0377] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or or include both and In the chemical structure of the compounds disclosed in the present invention, the bond The configuration is not specified, that is, it can be Z or E, or both. For all carbon-carbon double bonds, even if only one configuration is named, both Z and E are included; The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations.

[0378] In the chemical structure of the compounds disclosed herein, rac is the abbreviation of racemate (also known as raceme), which refers to an equimolar mixture of a pair of enantiomers. For example, when the compound has only one chiral center, rac refers to an equimolar mixture of (R) configuration and (S) configuration; when the compound has two chiral centers, rac refers to an equimolar mixture of (R,R) configuration and (S,S) configuration; or an equimolar mixture of (R,S) configuration and (S,R) configuration. Specifically, rac-(1R,2R) means that the compound is a racemate, which is an equimolar mixture of (1R,2R) configuration and (1S,2S) configuration.

[0379] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another isomeric form. It includes all possible tautomers, i.e., in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. An example of an enamine-imine equilibrium is shown below:

[0380]

[0381] For example, when referring to pyrazolyl, it is understood to include either or a mixture of two tautomers of the following two structures:

[0382]

[0383] All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

[0384] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example, 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 p. 33 p. 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., and in some embodiments, deuterium.

[0385] Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending drug biological half-life. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

[0386] Compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D", the position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

[0387] "Optionally" or "optionally" means that the event or environment described later can but does not necessarily occur, and includes two situations in which the event or environment occurs or does not occur. For example, "alkyl optionally (optionally) substituted with halogen or cyano" includes the situation in which alkyl is substituted with halogen or cyano and the situation in which alkyl is not substituted with halogen and cyano.

[0388] "Substitution" or "substituted" means that one or more hydrogen atoms, in some embodiments 1 to 6, in some embodiments 1 to 3 hydrogen atoms in a group are replaced independently of each other by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0389] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their pharmaceutically acceptable salts and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients, and thus exert biological activity.

[0390] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and have the desired biological activity. They may be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0391] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0392] As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0393] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and in some embodiments within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation. DETAILED DESCRIPTION

[0394] The following embodiments are used to further describe the present disclosure, but these embodiments are not intended to limit the scope of the present disclosure.

[0395] Example

[0396] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer, and the solvent used was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethylsilane (TMS).

[0397] MS was measured using Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0398] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector)

[0399] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMOQExactive)

[0400] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0401] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0402] High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0403] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0404] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0405] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0406] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0407] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0408] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals and other companies.

[0409] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0410] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0411] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0412] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0413] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0414] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0415] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0416] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0417] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0418] Example 1

[0419] N-((1S)-1-cycloheptyl-2-((2-fluoro-4-(1-(4-methyl-2-oxoimidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 1

[0420]

[0421] first step

[0422] tert-Butyl (4-acetyl-2-fluorophenyl)carbamate 1b

[0423] Dissolve tert-butyl (4-bromo-2-fluorophenyl)carbamate 1a (10.2 g, 35.15 mmol, Shanghai Titan) in tetrahydrofuran (100 mL). Add 2.5 M n-butyllithium in n-hexane (31 mL) dropwise at -78°C under a nitrogen atmosphere. Keep the temperature and stir to react for 1 hour. Add N,N-dimethylacetamide (8.2 mL) dropwise and return to room temperature naturally. React for 2 hours. Add water to the reaction solution, extract with ethyl acetate (30 mL×5), combine the organic phases, dry over anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure. Purify the residue by silica gel column chromatography with eluent system B to obtain the title compound 1b (4.5 g, yield: 50.5%).

[0424] MS m / z(ESI):254.2[M+1].

[0425] Step 2

[0426] tert-Butyl (4-(1-((2-((tert-butoxycarbonyl)amino)propyl)amino)ethyl)-2-fluorophenyl)carbamate 1d

[0427] Compound 1b (530 mg, 2.09 mmol) was dissolved in toluene (10 mL), and tert-butyl (1-aminopropan-2-yl)carbamate 1c (438 mg, 2.51 mmol, Shanghai Leyan) and triethylamine (848 mg, 8.38 mmol) were added. A 1M titanium tetrachloride solution in dichloromethane (1.3 mL) was added dropwise. The mixture was stirred for 16 hours. The reaction solution was filtered, and methanol (5 mL) was added to the filtrate. Sodium borohydride (238 mg, 6.3 mmol) was added under ice bath. The temperature was maintained for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1d (700 mg, yield: 81.2%).

[0428] MS m / z(ESI):412.2[M+1].

[0429] Step 3

[0430] tert-Butyl (2-fluoro-4-(1-(4-methyl-2-oxoimidazolidin-1-yl)ethyl)phenyl)carbamate 1e

[0431] Compound 1d (50 mg, 121.5 μmol) was dissolved in tetrahydrofuran (2 mL), and a 1 M solution of potassium tert-butoxide in tetrahydrofuran (250 μL) was added dropwise. The mixture was stirred at 80° C. for 2 hours. After the reaction solution was cooled to room temperature, water was added and the mixture was extracted with dichloromethane (10 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1e (230 mg, yield: 40%).

[0432] MS m / z(ESI):338.2[M+1].

[0433] Step 4

[0434] 1-(1-(4-amino-3-fluorophenyl)ethyl)-4-methylimidazolidin-2-one 1f

[0435] Compound 1e (230 mg, 681.7 μmol) was dissolved in 4M hydrogen chloride solution in 1,4-dioxane (10 mL), stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 1f (160 mg), which was directly used in the next step without purification.

[0436] MS m / z(ESI):238.2[M+1].

[0437] Step 5: Tert-butyl ((1S)-1-cycloheptyl-2-((2-fluoro-4-(1-(4-methyl-2-oxoimidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)carbamate 1h

[0438] The crude compound 1f (130 mg, 547.9 μmol) was dissolved in N,N-dimethylformamide (10 mL), and (S)-2-((tert-butyloxycarbonyl)amino)-2-cycloheptylacetic acid 1 g (224 mg, 825.5 μmol, Shanghai Leyan), N,N-diisopropylethylamine (354 mg, 2.74 mmol), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (625 mg, 1.64 mmol) were added, and the mixture was stirred at 50°C for 16 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was purified by high performance liquid preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: water (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL / min) to obtain the title compound 1h (45mg, yield: 16.7%).

[0439] MS m / z(ESI):491.2[M+1].

[0440] Step 6 (2S)-2-amino-2-cycloheptyl-N-(2-fluoro-4-(1-(4-methyl-2-oxoimidazolidin-1-yl)ethyl)phenyl)acetamide hydrochloride 1i

[0441] Compound 1h (40 mg, 81.5 μmol) was dissolved in 4M hydrogen chloride solution in 1,4-dioxane (10 mL), stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 1i (31 mg), which was directly used in the next step without purification.

[0442] MS m / z(ESI):391.2[M+1].

[0443] Step 7

[0444] N-((1S)-1-cycloheptyl-2-((2-fluoro-4-(1-(4-methyl-2-oxoimidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 1

[0445] The crude compound 1i (35 mg, 82 μmol) was dissolved in N,N-dimethylformamide, and 1-isopropyl-1H-pyrazole-5-carboxylic acid 1j (13 mg, 84.32 μmol, Shanghai Bidex), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (47 mg, 123.6 μmol) and N,N-diisopropylethylamine (32 mg, 247.6 μmol) were added. The mixture was stirred for 2 hours, the reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-42%, flow rate: 30 mL / min) to obtain the title compound 1 (1 mg, yield: 34.7%).

[0446] MS m / z(ESI):527.3[M+1].

[0447] 1 H-NMR (500 MHz, DMSO-d 6 ): δ9.91(s,1H),8.45-8.43(m,1H),7.76-7.74(m,1H),7.50(s,1H),7.15-7.07(m,2H),6.92(s,1 H),6.52-6.51(m,1H),5.48-5.40(m,1H),4.97-4.96(m,1H),4.63-4.59(m,1H),3.63-3.59(m,1H ),3.47-3.41(m,1H),3.11-3.08(m,2H),2.88-2.85(m,2H),2.48-2.41(m,2H),2.11-2.08(m,1H) ,1.74-1.57(m,3H),1.54-1.51(m,3H),1.38-1.24(m,9H),1.09-1.01(m,2H),0.87-0.85(m,2H).

[0448] Example 2

[0449] N-((S)-1-cycloheptyl-2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 2-1

[0450] or

[0451] N-((S)-1-cycloheptyl-2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 2-2

[0452]

[0453]

[0454] first step

[0455] tert-Butyl (4-(1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)ethyl)-2-fluorophenyl)carbamate 2b

[0456] Compound 1b (2 g, 7.9 mmol) was dissolved in tetrahydrofuran (40 mL), and (S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride 2a (1.9 g, 9.45 mmol, Wuxi Yaoming) and triethylamine (2.4 g, 23.7 mmol) were added. After stirring for 10 minutes, tetraisopropyl titanate (3.37 g, 11.86 mmol) was added. The mixture was stirred at 65°C for 16 hours. The reaction solution was concentrated under reduced pressure, methanol (30 mL) was added, and sodium borohydride (1 g, 26.4 mmol) was added under ice bath. The mixture was naturally restored to room temperature for 2 hours. Saturated ammonium chloride solution was added to the reaction solution, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in sequence. The organic phase was collected, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude title compound 2b (2.88 g). The product was directly used in the next step without purification.

[0457] MS m / z(ESI):366.2[M+1].

[0458] Step 2

[0459] tert-Butyl (2-fluoro-4-(1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)carbamate 2c tert-Butyl (2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)carbamate

[0460] 2c-1

[0461] tert-Butyl (2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)carbamate

[0462] 2c-2

[0463] The crude compound 2b (2.88 g, 7.88 mmol) was dissolved in dichloromethane (80 mL), and N,N-diisopropylethylamine (3.1 g, 24 mmol) and triphosgene (795 mg, 2.68 mmol) were added. The reaction mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 2c (3 g). The crude compound 2c was further purified by HPLC preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to obtain the title compound (1.44 g, yield: 46.6%), (1.1 g, yield: 35.6%).

[0464] Compound 2c: MS m / z (ESI): 392.2 [M+1].

[0465] Single configuration compound (short retention time): (1.44 g, yield: 46.6%)

[0466] MS m / z(ESI):392.2[M+1].

[0467] HPLC analysis: retention time 1.37 minutes, purity: 99% (chromatographic column: ACQUITY BEH, C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%). Single configuration compound (longer retention time): (1.1 g, yield: 35.6%)

[0468] MS m / z(ESI):392.2[M+1].

[0469] HPLC analysis: retention time 1.40 minutes, purity: 99% (chromatographic column: ACQUITY BEH, C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0470] Step 3

[0471] (S)-1-((R)-1-(4-amino-3-fluorophenyl)ethyl)-4-(trifluoromethyl)imidazolidin-2-one 2d-1

[0472] or

[0473] (S)-1-((S)-1-(4-amino-3-fluorophenyl)ethyl)-4-(trifluoromethyl)imidazolidin-2-one 2d-2

[0474] The compound with shorter retention time (243 mg, 650 μmol) of 2c-1 and 2c-2 was dissolved in 4M hydrogen chloride 1,4-dioxane solution (10 mL), stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 2d-1 or 2d-2 (referred to as compound A) (210 mg). The product was used directly in the next step without purification. MS m / z (ESI): 292.1 [M+1].

[0475] Step 4: Tert-butyl ((S)-1-cycloheptyl-2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)carbamate 2e-1

[0476] or tert-butyl ((S)-1-cycloheptyl-2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)carbamate 2e-2

[0477] Compound A (50 mg, 171.6 μmol) was dissolved in N,N-dimethylformamide (10 mL), and compound 1g (56 mg, 206 μmol, Shanghai Leyan), N,N-diisopropylethylamine (88.8 mg, 686.7 μmol), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (195.8 mg, 515 μmol) were added, and the mixture was reacted at 50°C for 16 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was purified by high performance liquid preparative chromatography (Waters-2545, chromatographic column: YMC Triart-ExrsC18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL / min) to obtain the title compound 2e-1 or 2e-2 (14mg, yield: 15%).

[0478] MS m / z(ESI):545.2[M+1].

[0479] Step 5 (S)-2-amino-2-cycloheptyl-N-(2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)acetamide hydrochloride 2f-1

[0480] or (S)-2-amino-2-cycloheptyl-N-(2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)acetamide hydrochloride 2f-2

[0481] The compound 2e-1 or 2e-2 (14 mg, 25.7 μmol) obtained in the fourth step was dissolved in a 4M hydrogen chloride solution in 1,4-dioxane (10 mL), and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude title compound 2f-1 or 2f-2 (12 mg). The product was directly used in the next reaction without purification.

[0482] MS m / z(ESI):445.2[M+1].

[0483] Step 6

[0484] N-((S)-1-cycloheptyl-2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 2-1

[0485] or

[0486] N-((S)-1-cycloheptyl-2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 2-2

[0487] The crude compound 2f-1 or 2f-2 (12 mg, 25 μmol) obtained in the fifth step was dissolved in N,N-dimethylformamide (5 mL), and compound 1j (7.6 mg, 49.5 μmol), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (18.8 mg, 49.5 μmol), and N,N-diisopropylethylamine (17.4 mg, 135 μmol) were added. The mixture was stirred for 2 hours, the reaction solution was filtered, and the filtrate was purified by high performance liquid preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: water (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL / min) to obtain the title compound 2-1 or 2-2 (prepared from the compound with shorter retention time in 2c-1, 2c-2, 5mg, yield: 19.1%).

[0488] MS m / z(ESI):581.2[M+1].

[0489] 1 H-NMR (500 MHz, DMSO-d 6): δ9.91(s,1H),8.43(d,1H),7.75(t,1H),7.54(d,1H),7.49(d,1H),7.13(dd,1H),7.06(d,1H),6.92(d,1H),5.41-5.36(m,1H),4.98(q,1H ),4.60(t,1H),4.41-4.37(m,1H),3.70(t,1H),3.03(dd,1H),2.12-2.07(m,1H),2.02-1.96(m,1H),1.73-1.63(m,3H),1.54-1.34(m,17H).

[0490] Example 2-1 or 2-2

[0491] N-((S)-1-cycloheptyl-2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 2-1

[0492] or

[0493] N-((S)-1-cycloheptyl-2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 2-2

[0494]

[0495] Using the synthetic route of Example 2, the compound with a shorter retention time in the third step 2c-1, 2c-2 is replaced by the compound with a longer retention time in 2c-1, 2c-2 to obtain the title compound 2-1 or 2-2 (prepared from the compound with a longer retention time in 2c-1, 2c-2, 3 mg, yield: 41.6%).

[0496] MS m / z(ESI):581.2[M+1].

[0497] 1 H-NMR (500 MHz, DMSO-d 6): δ9.93(s,1H),8.44(d,1H),7.76(t,1H),7.50(dd,1H),7.20(dd,1H),7.11-7 .09(m,1H),6.92-6.91(m,1H),5.40-5.31(m,1H),4.99(q,1H),4.60(t,1H),4. 36-4.31(m,1H),3.41-3.37(m,4H),3.28-3.23(m,1H),2.12-2.07(m,1H),2.02 -1.96(m,1H),1.74-1.63(m,3H),1.57-1.34(m,9H),1.23(s,4H),0.85(t,1H).

[0498] Example 3

[0499] N-(1,1-dicyclopropyl-3-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 3-1

[0500] or

[0501] N-(1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 3-2

[0502]

[0503] The synthetic route of Example 2 was adopted, and the raw material compound 1g of the fourth step was replaced by 2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropionic acid (Jiangsu Aikon) obtained the title compound 3-1 or 3-2 (prepared from the compound with shorter retention time in 2c-1, 2c-2, 21 mg, yield: 13.1%).

[0504] MS m / z(ESI):579.2[M+1].

[0505] 1 H NMR (500MHz, CD 3OD): δ7.94(t,1H),7.54(d,1H),7.16(d,2H),6.81(d,1H),5.42(p,1H),5.14(q,1H),4.99(d,1H),4.31(ddd,1H),3.80(t,1H),3.21- 3.12(m,1H),1.56(d,3H),1.48(t,6H),0.95-0.86(m,2H),0.82(td,1H),0.58(tt,1H),0.48(dddt,3H),0.38(dq,1H),0.29(ddt,3H).

[0506] Example 3-1-1, 3-1-2 or 3-2-1, 3-2-2

[0507] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 3-1-1

[0508] N-((R)-1,1-dicyclopropyl-3-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)

[0509] phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 3-1-2

[0510] or

[0511] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 3-2-1

[0512] N-((R)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 3-2-2

[0513]

[0514]

[0515] Compound 3-1 or 3-2 (prepared from the compound with shorter retention time in 2c-1, 2c-2, 20 mg) was separated by chiral column (Gilson 281, chromatographic column: Columntek AD, 250*20 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (+0.1% 7.0 M ammonia methanol solution), gradient ratio: A:B is 70:30, flow rate: 60 mL / min) to obtain the title compound (8 mg, 40%), (5 mg, 25%).

[0516] Chiral HPLC analysis of compound 3-1 or 3-2 (prepared from the compound with shorter retention time in 2c-1, 2c-2): retention time 6.443 minutes, 12.102 minutes (chromatographic column: CHIRALPAK AD-H, 250*4.6mm, 5μm; mobile phase A: ethanol (+0.1% diethylamine), mobile phase B: n-hexane, gradient ratio: A:B is 50.2:49.8, flow rate: 1mL / min).

[0517] Single configuration compound (short retention time): (8 mg, 40%, 6.443 minutes).

[0518] MS m / z(ESI):579.2[M+1].

[0519] 1 H NMR (500MHz, CD 3 OD): δ7.94(t,1H),7.54(d,1H),7.16(d,2H),6.81(d,1H),5.42(p,1H),5.14(q,1H),4.99(d,1H),4.31(ddt,1H),3.80(t,1H),3.17(d d,1H),1.56(d,3H),1.48(t,6H),0.95-0.85(m,2H),0.82(td,1H),0.58(dq,1H),0.54-0.41(m,3H),0.38(dq,1H),0.34-0.23(m,3H).

[0520] Single configuration compound (longer retention time): (5 mg, 25%, 12.102 minutes).

[0521] MS m / z(ESI):579.2[M+1].

[0522] 1 H NMR (500MHz, CD 3OD): δ7.94(t,1H),7.54(d,1H),7.19-7.12(m,2H),6.81(d,1H),5.42(p,1H),5.14(q,1H),4.99(d,1H),4.31(ddt,1H),3.80(t,1H),3. 17(dd,1H),1.56(d,3H),1.48(t,6H),0.95-0.85(m,2H),0.82(td,1H),0.58(dt,1H),0.55-0.41(m,3H),0.38(dq,1H),0.29(ddt,3H).

[0523] Example 4

[0524] N-(1,1-dicyclopropyl-3-((2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)

[0525] (ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 4-1

[0526] or

[0527] N-(1,1-dicyclopropyl-3-((2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)

[0528] ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 4-2

[0529]

[0530]

[0531] first step

[0532] tert-Butyl (2-fluoro-4-(2-methoxyacetyl)phenyl)carbamate 4b

[0533] Dissolve tert-butyl (4-bromo-2-fluorophenyl)carbamate 1a (7.5 g, 25.85 mmol, Shanghai Titan) in tetrahydrofuran (100 mL), replace with nitrogen, add dropwise 2.5 M n-hexyllithium n-hexane solution (26.1 mL) at -78°C, keep stirring and react for 1 hour, add dropwise N,2-dimethoxy-N-methylacetamide (4.2 g, 31.54 mmol, Jiangsu Aikang), return to room temperature naturally and stir and react for 2 hours, the reaction is completed, add saturated ammonium chloride solution to the reaction solution, extract with ethyl acetate (30×3 mL), wash with water and saturated sodium chloride solution in turn, dry over anhydrous sodium sulfate, filter to remove the desiccant and concentrate under reduced pressure, the residue is purified by silica gel column chromatography with eluent system B to obtain the title compound 4b (3.5 g, yield: 47.8%)

[0534] MS m / z(ESI):284.3[M+1].

[0535] Step 2: tert-Butyl (2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)carbamate 4c-1

[0536] Tert-butyl (2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)carbamate 4c-2

[0537] The first step to the second step of the synthetic route of Example 2 was adopted, and the first step raw material compound 1b was replaced by compound 4b to obtain the title compound (230 mg, yield: 24.5%), (190 mg, yield: 20.2%). Single configuration compound (short retention time) (230 mg, yield: 24.5%)

[0538] MS m / z(ESI):422.2[M+1].

[0539] HPLC analysis: retention time 1.35 minutes, purity: 99% (chromatographic column: ACQUITY BEH, C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%). Single configuration compound (longer retention time) (190 mg, yield: 20.2%)

[0540] MS m / z(ESI):422.2[M+1].

[0541] HPLC analysis: retention time 1.38 minutes, purity: 99% (chromatographic column: ACQUITY BEH, C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0542] Step 3

[0543] (S)-1-((S)-1-(4-amino-3-fluorophenyl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one 4d-1

[0544] or

[0545] (S)-1-((R)-1-(4-amino-3-fluorophenyl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one 4d-2

[0546] The compound with a shorter retention time in 4c-1, 4c-2 (230 mg, 545.8 μmol) was dissolved in dichloromethane (10 mL), and a 4M solution of hydrogen chloride in 1,4-dioxane (5 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain a crude title compound 4d-1 or 4d-2 (200 mg). The product was used directly in the next step without purification.

[0547] MS m / z(ESI):322.1[M+1].

[0548] Step 4: Tert-butyl (1,1-dicyclopropyl-3-((2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropan-2-yl)carbamate 4e-1

[0549] or tert-butyl (1,1-dicyclopropyl-3-((2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropan-2-yl)carbamate 4e-2

[0550] The crude compound 4d-1 or 4d-2 (120 mg, 372.5 μmol) obtained in the third step was dissolved in pyridine (5 mL), and 2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropionic acid (108 mg, 401 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (193 mg, 1 mmol) were added. The reaction was carried out at 50° C. for 16 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system C to give the title compound 4e-1 or 4e-2 (120 mg, yield: 62.4%).

[0551] MS m / z(ESI):573.2[M+1].

[0552] Step 5

[0553] 2-amino-3,3-dicyclopropyl-N-(2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidine-1-

[0554] (4-(2-( ...

[0555] or

[0556] 2-amino-3,3-dicyclopropyl-N-(2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidine-1-

[0557] (4-(2-( ...

[0558] The compound 4e-1 or 4e-2 (120 mg, 209.6 μmol) obtained in the fourth step was dissolved in a 4M hydrogen chloride solution in 1,4-dioxane (10 mL), and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude title compound 4f-1 or 4f-2 (100 mg). The product was directly used in the next step without purification.

[0559] MS m / z(ESI):73.24[M+1].

[0560] Step 6

[0561] N-(1,1-dicyclopropyl-3-((2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)

[0562] (ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 4-1

[0563] or

[0564] N-(1,1-dicyclopropyl-3-((2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)

[0565] ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 4-2

[0566] The crude compound 4f-1 or 4f-2 (50 mg, 98.2 μmol) obtained in the fifth step was dissolved in N,N-dimethylformamide (3 mL), and compound 1j (16 mg, 103.7 μmol), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (56 mg, 147.2 μmol), and N,N-diisopropylethylamine (39 mg, 301.7 μmol) were added. The mixture was stirred for 2 hours, the reaction solution was filtered, and the filtrate was purified by high performance liquid preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: water (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30mL / min) to obtain the title compound 4-1 or 4-2 (12mg, yield: 20%) (prepared from the compound with shorter retention time in 4c-1, 4c-2). MS m / z (ESI): 609.2 [M+1].

[0567] 1 H-NMR (500 MHz, DMSO-d 6 ): δ9.98(s,1H),8.43(d,1H),7.86(t,1H),7.51(d,2H),7.23(d,1H),7.12(d, 1H),6.91(d,1H),5.40(p,1H),5.03-4.91(m,2H),4.39(s,1H),3.80(d,1H),3 .73(d,1H),3.54-3.44(m,2H),3.29(s,3H),1.37(d,6H),0.92(d,2H),0.85(q ,1H),0.81(q,1H),0.75(q,1H),0.47(d,1H),0.32(s,1H),0.26-0.12(m,3H).

[0568] Example 4-1 or 4-2

[0569] N-(1,1-dicyclopropyl-3-((2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)

[0570] (ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 4-1

[0571] or

[0572] N-(1,1-dicyclopropyl-3-((2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)

[0573] ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 4-2

[0574]

[0575] Using the synthetic route of Example 4, the compound with a shorter retention time in the third step 4c-1, 4c-2 was replaced by the compound with a longer retention time in 4c-1, 4c-2 to obtain the title compound (15 mg, yield: 12.5%) (prepared from the compound with a longer retention time in 4c-1, 4c-2).

[0576] MS m / z(ESI):609.2[M+1].

[0577] 1 H-NMR (500 MHz, DMSO-d 6 ): δ9.98(s,1H),8.43(d,1H),7.86(t,1H),7.51(dd,2H),7.23(dt,1H),7.12 (d,1H),6.91(d,1H),5.40(p,1H),5.03-4.91(m,2H),4.39(s,1H),3.80(dd, 1H),3.73(dd,1H),3.54-3.44(m,2H),3.29(s,3H),1.37(dd,6H),0.92(dq,2 H),0.85(q,1H),0.75(q,1H),0.47(dd,1H),0.32(s,1H),0.26-0.12(m,3H).

[0578] Example 4-1-1, 4-1-2 or 4-2-1, 4-2-2

[0579] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 4-1-1

[0580] N-((R)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 4-1-2

[0581] or

[0582] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 4-2-1

[0583] N-((R)-1,1-dicyclopropyl-3-((2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 4-2-2

[0584]

[0585] Compound 4-1 or 4-2 (5 mg, prepared from the compound with shorter retention time in 4c-1, 4c-2) was separated by chiral column (Gilson 281, chromatographic column: Lux Amylose-2, 250*20 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol, gradient ratio: A: B is 70:30, flow rate: 20 mL / min) to obtain the title compound (2 mg, yield: 40%, 14.3 minutes), (2 mg, yield: 40%, 21.2 minutes). .

[0586] MS m / z(ESI):609.2[M+1].

[0587] Single configuration compound (short retention time): (2 mg, yield: 40%, 14.3 minutes).

[0588] MS m / z(ESI):609.2[M+1].

[0589] HPLC analysis: retention time 1.47 minutes, purity: 99% (chromatographic column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0590] 1 H-NMR (500 MHz, DMSO-d 6): δ9.98(s,1H),8.43(d,1H),7.86(t,1H),7.51(d,2H),7.23(d,1H),7.12(d, 1H),6.91(d,1H),5.40(p,1H),5.03-4.91(m,2H),4.39(s,1H),3.80(d,1H),3 .73(d,1H),3.54-3.44(m,2H),3.29(s,3H),1.37(d,6H),0.92(d,2H),0.85(q ,1H),0.81(q,1H),0.75(q,1H),0.47(d,1H),0.32(s,1H),0.26-0.12(m,3H). Single configuration compound (longer retention time): (2 mg, yield: 40%, 21.2 minutes).

[0591] MS m / z(ESI):609.2[M+1].

[0592] HPLC analysis: retention time 1.47 minutes, purity: 99% (chromatographic column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0593] 1 H-NMR (500 MHz, DMSO-d 6 ): δ9.98(s,1H),8.43(d,1H),7.86(t,1H),7.51(d,2H),7.23(d,1H),7.12(d, 1H),6.91(d,1H),5.40(p,1H),5.03-4.91(m,2H),4.39(s,1H),3.80(d,1H),3 .73(d,1H),3.54-3.44(m,2H),3.29(s,3H),1.37(d,6H),0.92(d,2H),0.85(q ,1H),0.81(q,1H),0.75(q,1H),0.47(d,1H),0.32(s,1H),0.26-0.12(m,3H).

[0594] Example 5-1 or 5-2

[0595] N-(1,1-dicyclopropyl-3-((4-((R)-3,3-difluoro-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propane

[0596] (2-(2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 5-1

[0597] or

[0598] N-(1,1-dicyclopropyl-3-((4-((S)-3,3-difluoro-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propane

[0599] 5-(2-(2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0600]

[0601] MS m / z(ESI):629.2[M+1].

[0602] Example 5-1-1, 5-1-2 or 5-2-1, 5-2-2

[0603] N-((S)-1,1-dicyclopropyl-3-((4-((R)-3,3-difluoro-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)-2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 5-1-1

[0604] N-((R)-1,1-dicyclopropyl-3-((4-((R)-3,3-difluoro-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)-2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 5-1-2

[0605] or

[0606] N-((S)-1,1-dicyclopropyl-3-((4-((S)-3,3-difluoro-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)-2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 5-2-1

[0607] N-((R)-1,1-dicyclopropyl-3-((4-((S)-3,3-difluoro-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)-2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide 5-2-2

[0608]

[0609] Compound 5-1 or 5-2 is separated by chiral column to obtain the title compound.

[0610] MS m / z(ESI):629.2[M+1].

[0611] Example 6-1 or 6-2

[0612] N-(1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 6-1

[0613] or

[0614] N-(1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 6-2

[0615]

[0616]

[0617] first step

[0618] 2-(1-Isopropyl-1H-pyrazole-5-carboxamide)-2-(1,4-dioxaspiro[4.5]dec-8-yl)acetate 6b

[0619] 2-Amino-2-(1,4-dioxaspiro[4.5]dec-8-yl)acetic acid methyl ester 6a (300 mg, 1.3 mmol, prepared by a known method Bioorganic and Medicinal Chemistry Letters, 2009, vol.19, #3, p.976-980) was dissolved in N,N-dimethylformamide (2 mL), and compound 1j (201 mg, 1.3 mmol), N,N-diisopropylethylamine (422 mg, 3.27 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (597 mg, 1.57 mmol) were added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system C to obtain the title compound 6b (200 mg, yield: 41.8%). MS m / z(ESI):366.2[M+1].

[0620] Step 2

[0621] 2-(1-isopropyl-1H-pyrazole-5-carboxamide)-2-(4-oxocyclohexyl)acetic acid methyl ester 6c

[0622] Compound 6b (200 mg, 547.3 μmol) was dissolved in tetrahydrofuran (5 mL), and a 4M hydrogen chloride solution in 1,4-dioxane (1.5 mL) was added. The mixture was stirred for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to >7. Water was added and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the filtrate was concentrated under reduced pressure to obtain the crude title compound 6c (169 mg). The product was used directly in the next step without purification.

[0623] MS m / z(ESI):322.2[M+1].

[0624] Step 3

[0625] Methyl 2-(4-(difluoromethylene)cyclohexyl)-2-(1-isopropyl-1H-pyrazole-5-carboxamide)acetate 6d

[0626] Compound 6c (48 mg, 149.3 μmol) was dissolved in N,N-dimethylformamide (2 mL), and 2-((difluoromethyl)sulfonyl)pyridine (28.8 mg, 149.3 μmol) and 1M potassium tert-butoxide tetrahydrofuran solution (224 μL) were added at -40°C. The temperature was maintained and stirred for 2 hours. Saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography with developing solvent system C to obtain the title compound 6d (28 mg, yield: 52.7%).

[0627] MS m / z(ESI):356.2[M+1].

[0628] Step 4

[0629] 2-(4-(Difluoromethylene)cyclohexyl)-2-(1-isopropyl-1H-pyrazole-5-carboxamide)acetic acid 6e

[0630] Compound 6d (28 mg, 78.4 μmol) was dissolved in methanol (1 mL), water (1 mL) and tetrahydrofuran (2 mL), and lithium hydroxide monohydrate (5.3 mg, 126.1 μmol) was added. The reaction mixture was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 6 with 1M hydrochloric acid. The mixture was extracted with dichloromethane (5 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 6e (26 mg). The product was directly used in the next step without purification.

[0631] MS m / z(ESI):340.1[M-1].

[0632] Step 5

[0633] N-(-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 6-1

[0634] or

[0635] N-(-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 6-2

[0636] The crude compound A (52.5 mg, 180.2 μmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 6e (26 mg, 76.1 μmol), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (34.7 mg, 91.4 μmol), and N,N-diisopropylethylamine (29.5 mg, 228.5 μmol) were added. The mixture was stirred at 50°C for 16 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: water (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL / min) to obtain the title compound 6-1 or 6-2 (prepared from compound A, 19.3mg, yield: 41.2%).

[0637] MS m / z(ESI):615.2[M+1].

[0638] 1 H NMR (500MHz, CD 3 OD): δ7.86(t,1H),7.51(d,1H),7.21-7.08(m,2H),6.80(d,1H),5.38(p,1H),5.12(q,1H),4.60(d,1H),4.34-4.23(m,1H ),3.77(t,1H),3.15(m,1H),2.53(m,2H),2.09-1.98(m,2H),1.91(d,3H),1.54(d,3H),1.45(dd,6H),1.36-1.16(m,4H).

[0639] Example 6-1-1, 6-1-2 or 6-2-1, 6-2-2

[0640] N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 6-1-1

[0641] N-((R)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 6-1-2

[0642] or

[0643] N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 6-2-1

[0644] N-((R)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 6-2-2

[0645]

[0646] Compound 6-1 or 6-2 (19 mg, prepared from compound A) was separated by chiral column (Gilson 281, chromatographic column: ChiralPak IG, 250*20 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (1% 7M ammonia methanol solution), gradient ratio: A: B is 70:30, flow rate: 20 mL / min) to obtain the title compound (7.26 mg, yield: 39.2%), (7.03 mg, yield: 37%).

[0647] MS m / z(ESI):615.2[M+1].

[0648] Chiral HPLC analysis of isomer compound 6-1 or 6-2 (prepared from compound A): retention time 3.878 minutes (49.8%), 7.242 minutes (50.1%), (chromatographic column: CHIRALPAK IG, 250*4.6mm, 5μm; mobile phase A: ethanol (+0.1% diethylamine), mobile phase B: n-hexane, gradient ratio: A:B is 30:70, flow rate: 1mL / min).

[0649] Single configuration compound (short retention time): (7.26 mg, 39.2%, 3.878 minutes).

[0650] MS m / z(ESI):615.2[M+1].

[0651] HPLC analysis: retention time 1.47 minutes, purity: 99% (chromatographic column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0652] 1 H NMR (500MHz, CD 3 OD): δ7.86(t,1H),7.51(d,1H),7.22-7.10(m,2H),6.80(d,1H),5.38(dt,1H),5.13(q,1H),4.60(d,1H),4.30(ddq,1H),3.77(t,1 H),3.15(dt,1H),2.53(dd,2H),2.11-1.98(m,2H),1.97-1.78(m,3H),1.54(d,3H),1.45(dd,5H),1.30-1.16(m,2H),0.90(t,1H).

[0653] Single configuration compound (longer retention time): (7.03 mg, 37%, 7.242 minutes).

[0654] MS m / z(ESI):615.2[M+1].

[0655] HPLC analysis: retention time 1.47 minutes, purity: 99% (chromatographic column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0656] 1 H NMR (500MHz, CD 3OD): δ7.86(t,1H),7.51(d,1H),7.20-7.08(m,2H),6.80(d,1H),5.38(dt,1H),5.12(q,1H),4.60(d,1H),4.30(ddd,1H),3.77(t,1 H),3.18-3.08(m,1H),2.60-2.49(m,2H),2.11-1.96(m,2H),1.89(ddt,3H),1.54(d,3H),1.45(t,5H),1.23(qd,2H),0.90(t,1H).

[0657] Example 7

[0658] N-((S)-1-cycloheptyl-2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 7-1

[0659] or

[0660] N-((S)-1-cycloheptyl-2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 7-2

[0661]

[0662] Using the synthetic route of Example 2, the sixth step compound 1j was replaced by 1-ethyl-1H-pyrazole-5-carboxylic acid (Shanghai Bidex) to obtain the title compound 7-1 or 7-2 (prepared from the compound with shorter retention time in 2c-1, 2c-2, 18 mg, yield: 16.4%).

[0663] MS m / z(ESI):567.5[M+1].

[0664] 1 H NMR (500MHz, CD 3 OD): δ7.86(t,1H),7.51(d,1H),7.24-7.06(m,2H),6.87(d,1H),5.14(q,1H),4.65(d,1H),4.55(q,2H),4.39-4 .26(m,1H),3.79(t,1H),3.16(dd,1H),2.25-2.16(m,1H),1.94-1.74(m,4H),1.74-1.42(m,11H),1.39(t,3H).

[0665] Example 8

[0666] N-((S)-1-cycloheptyl-2-((2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 8-1

[0667] or

[0668] N-((S)-1-cycloheptyl-2-((2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)

[0669] ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 8-2

[0670]

[0671] Using the synthetic route of Example 4, the 2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropionic acid in the fourth step was replaced by compound 1g, and the compound 1j in the sixth step was replaced by 1-ethyl-1H-pyrazole-5-carboxylic acid (Shanghai Bidex) to obtain the title compound 8-1 or 8-2 (prepared from the compound with shorter retention time in 4c-1, 4c-2, 7.8 mg, yield: 15.3%).

[0672] MS m / z(ESI):597.6[M+1].

[0673] 1 H NMR (500MHz, CD 3 OD): δ7.86(t,1H),7.51(d,1H),7.21-7.09(m,2H),6.87(d,1H),5.14(dd,1H),4.65(d,1H),4.55(q,2H),4.34(ddd,1H),3. 97-3.81(m,3H),3.43(s,3H),3.39(dd,1H),2.20(td,1H),1.87(td,2H),1.82-1.73(m,2H),1.70-1.43(m,8H),1.39(t,3H).

[0674] Example 9

[0675] 1-Ethyl-N-((S)-2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide 9-1

[0676] or

[0677] 1-ethyl-N-((S)-2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide 9-2

[0678]

[0679] The synthetic route of Example 2 was adopted, and the fourth step compound 1g was replaced by (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (WuXi AppTec), and the sixth step compound 1j was replaced by 1-ethyl-1H-pyrazole-5-carboxylic acid (Shanghai BiDe) to obtain the title compound 9-1 or 9-2 (prepared from the compound with shorter retention time in 2c-1, 2c-2, 18 mg, yield: 13.3%).

[0680] MS m / z(ESI):567.3[M+1].

[0681] 1 H NMR (500MHz, CD 3 OD): δ7.87(t,1H),7.51(d,1H),7.22-7.10(m,2H),6.88(d,1H),5.14(q,1H),4.59-4.51(m,3H),4.36-4.26(m,1H),3.79(t,1H), 3.16(dd,1H),1.98-1.87(m,2H),1.82(td,3H),1.56(d,3H),1.39(t,3H),1.30(dd,2H),1.21(qd,1H),1.01(qd,2H),0.93(d,3H).

[0682] Example 10

[0683] N-(1,1-dicyclopropyl-3-oxo-3-((4-(1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)propan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide 10

[0684] N-(1,1-dicyclopropyl-3-oxo-3-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)propan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide 10-1

[0685] N-(1,1-dicyclopropyl-3-oxo-3-((4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)propan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide 10-2

[0686]

[0687] first step

[0688] (2S)-3,3,3-Trifluoro-N 1 -(1-(4-nitrophenyl)ethyl)propane-1,2-diamine 10b

[0689] p-Nitroacetophenone 10a (1 g, 6.05 mmol, Shanghai Shaoyuan) was dissolved in isopropanol (40 mL) and methanol (40 mL), and compound 2a (1.22 g, 6.07 mmol) and triethylamine (1.23 g, 12.1 mmol) were added. The mixture was stirred at 75°C for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in methanol (40 mL), and sodium cyanoborohydride (1.34 g, 22.4 mmol) was added. After stirring for 5 minutes, acetic acid (1.71 g, 28.4 mmol) was added. After reacting at 40°C for 0.5 hours, the reaction solution was cooled to room temperature and concentrated under reduced pressure. Dichloromethane was added to the residue to dissolve it, and the mixture was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 10b (2.57 g). The product was directly used in the next step without purification. MS m / z(ESI):278.4[M+1].

[0690] Step 2

[0691] (4S)-1-(1-(4-nitrophenyl)ethyl)-4-(trifluoromethyl)imidazolidin-2-one 10c

[0692] The crude compound 10b (1.57 g, 5.66 mmol) was dissolved in dichloromethane (20 mL), N,N-diisopropylethylamine (2.19 g, 16.94 mmol) was added, triphosgene (554.55 mg, 1.86 mmol) was added under ice bath, and the mixture was stirred and reacted at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution to quench, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system to obtain the title compound 10c (1.7 g, yield: 99%). MS m / z (ESI): 304.0 [M+1].

[0693] Step 3

[0694] (4S)-1-(1-(4-aminophenyl)ethyl)-4-(trifluoromethyl)imidazolidin-2-one 10d

[0695] Compound 10c (1.7 g, 5.6 mmol) was dissolved in ethanol (10 mL), and 10% palladium carbon hydrogenation catalyst (119 mg) was added. The mixture was replaced with hydrogen and stirred for 16 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound 10d (1.5 g), which was used directly in the next step without purification.

[0696] MS m / z(ESI):274.1[M+1].

[0697] Step 4: tert-butyl (1,1-dicyclopropyl-3-oxo-3-((4-(1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)propan-2-yl)carbamate 10e

[0698] The crude compound 10d (405.82 mg, 1.48 mmol) and 2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropionic acid (400 mg, 1.48 mmol) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (480 mg, 3.72 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (903.5 mg, 2.37 mmol) were added under ice bath. The mixture was naturally restored to room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 10e (621 mg, yield: 79.7%).

[0699] MS m / z(ESI):525.4[M+1].

[0700] Step 5

[0701] 2-Amino-3,3-dicyclopropyl-N-(4-(1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)propanamide hydrochloride 10f

[0702] Compound 10e (523 mg, 997 μmol) was dissolved in dichloromethane (5 mL), and a 4M solution of hydrogen chloride in 1,4-dioxane (2 mL) was added. The mixture was stirred for 3 hours, and the reaction solution was concentrated under reduced pressure to obtain a crude title compound 10f (433 mg). The product was used directly in the next step without purification.

[0703] MS m / z(ESI):425.4[M+1].

[0704] Step 6

[0705] N-(1,1-dicyclopropyl-3-oxo-3-((4-(1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)

[0706] (amino) propan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide 10

[0707] N-(1,1-dicyclopropyl-3-oxo-3-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)propan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide 10-1

[0708] N-(1,1-dicyclopropyl-3-oxo-3-((4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)propan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide 10-2

[0709] Compound 10f (180 mg, 390.5 μmol) was dissolved in N,N-dimethylformamide (5 mL), and 1-ethyl-1H-pyrazole-5-carboxylic acid (65.6 mg, 468.6 μmol), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (193 mg, 507.6 μmol), and N,N-diisopropylethylamine (136.2 mg, 1.05 mmol) were added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 10 (200 mg), which was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL / min) to obtain the title compound (22mg, yield: 11%), (16mg, yield: 8%).

[0710] Single configuration compound (short retention time): (22 mg, yield: 11%).

[0711] MS m / z(ESI):547.4[M+1].

[0712] HPLC analysis: retention time 1.32 minutes, purity: 99% (chromatographic column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0713] 1 H NMR (500MHz, CD 3 OD): δ7.62(d,2H),7.52(d,1H),7.31(d,2H),6.88(s,1H),5.15(q,1H),4.56(q,2H),4.29(dt,1H),3.77(t,1H),3.11( dd,1H),2.21(t,1H),2.05(d,1H),1.56(d,3H),1.40(t,3H),0.95-0.88(m,1H),0.84-0.75(m,1H),0.61-0.16(m,8H).

[0714] Single configuration compound (longer retention time): (16 mg, yield: 8%).

[0715] MS m / z(ESI):547.4[M+1].

[0716] HPLC analysis: retention time 1.36 minutes, purity: 99% (chromatographic column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0717] 1 H NMR (500MHz, CD 3 OD): δ7.63(d,2H),7.51(d,1H),7.33(d,2H),6.90(d,1H),5.16(t,1H),4.91(d,1H),4.60-4.48(m,2H),4.24(ddd,1 H),3.51(dd,1H),3.37(d,1H),1.55(d,3H),1.39(t,3H),1.31(d,1H),0.91(dq,1H),0.82(q,1H),0.61-0.19(m,8H).

[0718] Embodiment 11

[0719] N-(1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidine-1-

[0720] (2-( ...

[0721] or

[0722] N-(1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidine-1-

[0723] (2-( ...

[0724]

[0725] Using the synthetic route of Example 6, the first step compound 1j was replaced by 1-ethyl-1H-pyrazole-5-carboxylic acid to obtain the title compound 11-1 or 11-2 (prepared from compound A, 4.36 mg, yield: 7%).

[0726] MS m / z(ESI):601.1[M+1].

[0727] 1 H NMR (500MHz, CD 3OD): δ7.86(t,1H),7.49(d,1H),7.14(dd,2H),6.87(d,1H),5.12(q,1H),4.61(d,1H),4.53(q,2H),4.36-4.25(m,1H),3.77 (t,1H),3.18-3.12(m,1H),2.53(d,2H),2.10-1.99(m,2H),1.93-1.81(m,3H),1.54(d,3H),1.37(t,3H),1.30-1.18(m,2H).

[0728] Example 11-1-1, 11-1-2 or 11-2-1, 11-2-2

[0729] N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidine

[0730] -1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 11-1-1

[0731] N-((R)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidine

[0732] -1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 11-1-2

[0733] or

[0734] N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidine

[0735] -1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 11-2-1

[0736] N-((R)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidine

[0737] -1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 11-2-2

[0738]

[0739] Compound 11-1 or 11-2 (prepared from compound A, 15 mg) was separated by chiral column (Shimadzu LC-20AP, chromatographic column: ChiralPak IE, 250*20 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol, gradient ratio: A:B is 70:30, flow rate: 20 mL / min) to obtain the title compound (4.69 mg, yield: 31.2%), (5.17 mg, yield: 34.4%).

[0740] Chiral HPLC analysis of isomer compound 11-1 or 11-2: retention time 5.985 minutes (49.9%), 7.270 minutes (50%), (chromatographic column: CHIRALPAK IE, 250*4.6mm, 5μm; mobile phase A: ethanol (+0.1% diethylamine), mobile phase B: n-hexane, gradient ratio: A:B is 30:70, flow rate: 1mL / min).

[0741] Single configuration compound (short retention time): (4.69 mg, yield: 31.2%, 5.985 minutes).

[0742] MS m / z(ESI):601.1[M+1].

[0743] HPLC analysis: retention time 1.35 minutes, purity: 99% (chromatographic column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0744] 1 H NMR (500MHz, CD 3 OD): δ7.86(t,1H),7.49(t,1H),7.14(dd,2H),6.87(t,1H),5.12(q,1H),4.69-4.46(m,3H),4.29(dt,1H),3.77(dd,1H ),3.14(dd,1H),2.53(d,2H),2.10-1.95(m,2H),1.93-1.81(m,3H),1.54(d,3H),1.42-1.33(m,3H),1.31-1.17(m,2H).

[0745] Single configuration compound (longer retention time): (5.17 mg, yield: 34.4%, 7.270 minutes).

[0746] MS m / z(ESI):601.1[M+1].

[0747] HPLC analysis: retention time 1.35 minutes, purity: 99% (chromatographic column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0748] 1 H NMR (500MHz, CD 3 OD): δ7.86(t,1H),7.49(d,1H),7.19-7.11(m,2H),6.87(d,1H),5.12(q,1H),4.61(d,1H),4.53(q,2H),4.29(dtd,1H),3.77 (t,1H),3.14(dd,1H),2.57-2.47(m,2H),2.09-1.96(m,2H),1.92-1.80(m,3H),1.54(d,3H),1.37(t,3H),1.31-1.17(m,2H).

[0749] Example 12

[0750] N-((1S)-1-cycloheptyl-2-((4-(cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-2-fluorophenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 12

[0751] N-((S)-1-cycloheptyl-2-((4-((R)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-2-fluorophenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 12-p1

[0752] N-((S)-1-cycloheptyl-2-((4-((S)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-2-fluorophenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 12-p2

[0753]

[0754] first step

[0755] tert-Butyl (4-(cyclopropanecarbonyl)-2-fluorophenyl)carbamate 12c

[0756] Tert-butyl (4-bromo-2-fluorophenyl)carbamate 12a (2 g, 6.89 mmol, Sinopharm) was dissolved in tetrahydrofuran (6 mL), replaced with nitrogen, and 2.5 M n-hexyllithium n-hexane solution (6.9 mL) was added dropwise at -78°C, and the temperature was maintained for reaction for 1 hour. N-methoxy-N-methylcyclopropanecarboxamide 12b (1.16 g, 8.98 mmol, Shanghai Titan) was added dropwise, and the reaction was naturally restored to room temperature for 2 hours. Saturated ammonium chloride solution was added to the reaction solution for quenching, and ethyl acetate was extracted (30 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound 12c (1.03 g, yield: 53.5%).

[0757] MS m / z(ESI):280.3[M+1].

[0758] Step 2 Tert-butyl (4-((((S)-2-amino-3,3,3-trifluoropropyl)amino)(cyclopropyl)methyl)-2-fluorophenyl)carbamate 12d

[0759] Compound 12c (500 mg, 1.79 mmol) was dissolved in tetrahydrofuran (4 mL), and compound 2a (359.85 mg, 1.79 mmol) and triethylamine (543.44 mg, 5.37 mmol) were added. After stirring for 10 minutes, tetraisopropyl titanate (763.18 mg, 2.68 mmol) was added. The mixture was stirred at 75°C for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in methanol (5 mL). Sodium borohydride (135.45 mg, 3.58 mmol) was added under ice bath. The mixture was naturally restored to room temperature for 2 hours. Saturated ammonium chloride solution was added to the reaction solution, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in sequence. The organic phase was collected, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude title compound 12d (201 mg). The product was used directly in the next step without purification.

[0760] MS m / z(ESI):392.3[M+1].

[0761] Step 3 Tert-butyl (4-(cyclopropyl-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-2-fluorophenyl)carbamate 12e

[0762] The crude compound 12d (201 mg, 513.53 μmol) was dissolved in dichloromethane (6 mL), and N,N-diisopropylethylamine (305.31 mg, 2.36 mmol) was added. Triphosgene (50.3 mg, 169.47 μmol) was added under ice bath. The mixture was naturally stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give the title compound 12e (196 mg, yield: 91.4%).

[0763] MS m / z(ESI):418.3[M+1].

[0764] Step 4 (4S)-1-((4-amino-3-fluorophenyl)(cyclopropyl)methyl)-4-(trifluoromethyl)imidazolidin-2-one 2,2,2-trifluoroacetate 12f

[0765] Compound 12e (196 mg, 469.5 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude title compound 12f (202 mg), which was used directly in the next step without purification.

[0766] MS m / z(ESI):318.2[M+1].

[0767] Step 5

[0768] N-((1S)-1-cycloheptyl-2-((4-(cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-2-fluorophenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 12

[0769] N-((S)-1-cycloheptyl-2-((4-((R)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-2-fluorophenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 12-p1

[0770] N-((S)-1-cycloheptyl-2-((4-((S)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-2-fluorophenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 12-p2

[0771] The synthetic route of Example 10 was adopted, and the compound 10d in the fourth step was replaced by compound 12f to obtain the crude title compound 12 (117 mg), which was purified by preparative HPLC (Gilson-GX-281, chromatographic column: Boston phlex prepc18, 30×150 mm; 5 um; mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 25-60%, flow rate: 30 mL / min) to obtain the title compound (4.81 mg, yield: 4.1%), (4.21 mg, yield: 3.6%).

[0772] Single configuration compound (short retention time): (4.81 mg, yield: 4.1%).

[0773] MS m / z(ESI):593.5[M+1].

[0774] HPLC analysis: retention time 1.52 minutes, purity: 96% (chromatographic column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0775] 1 H NMR (500MHz, CD 3 OD): δ7.83(t,1H),7.49(d,1H),7.23(d,2H),6.85(d,1H),4.64(d,1H),4.53(q,2H),4.35(ddd,1H),4.12(d,1H),3.94(t,1H),2.22- 2.15(m,1H),1.86(dq,2H),1.79-1.72(m,2H),1.67-1.45(m,8H),1.38(t,3H),1.33(q,2H),0.87(dd,1H),0.66(t,1H),0.46(dq,2H).

[0776] Single configuration compound (longer retention time): (4.21 mg, yield: 3.6%).

[0777] MS m / z(ESI):593.5[M+1].

[0778] HPLC analysis: retention time 1.56 minutes, purity: 98% (chromatographic column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0779] 1 H NMR (500MHz, CD3 OD): δ7.84(t,1H),7.49(d,1H),7.30-7.22(m,2H),6.85(d,1H),4.63(d,1 H),4.53(q,2H),4.34-4.26(m,1H),4.12(d,1H),3.68(dd,1H),3.54(t,1H) ,2.22-2.14(m,1H),1.90-1.81(m,2H),1.79-1.70(m,2H),1.68-1.42(m,8 H),1.38(t,3H),1.34(s,1H),0.92-0.83(m,1H),0.66(t,1H),0.43(p,2H).

[0780] Embodiment 13

[0781] 1-Ethyl-N-((S)-2-((2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide 13-1

[0782] or

[0783] 1-Ethyl-N-((S)-2-((2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide 13-2

[0784]

[0785] The synthetic route of Example 4 was used, and the fourth step compound 2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropionic acid was replaced by (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid, and the sixth step compound 1j was replaced by 1-ethyl-1H-pyrazole-5-carboxylic acid to obtain the title compound 13-1 or 13-2 (prepared from the compound with shorter retention time in 4c-1, 4c-2, 5 mg, yield: 5.1%).

[0786] MS m / z(ESI):597.5[M+1].

[0787] 1 H-NMR (500 MHz, DMSO-d 6): δ9.93(d,1H),8.48-8.46(m,1H),7.78-7.74(m,1H),7.58(s,1H),7.47(s,1H),7.20-6.99(m,3H),5.01-4.98(m,1H),4.54-4.44 (m,4H),3.84-3.79(m,1H),3.75-3.70(m,2H),2.20-1.99(m,2H),1.81(t,2H),1.71-1.63(m,2H),1.39-1.23(m,8H),0.86(d,6H).

[0788] Embodiment 14

[0789] 5-cyano-N-(1,1-dicyclopropyl-3-oxo-3-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)

[0790] ethyl)phenyl)amino)propan-2-yl)-1-methyl-1H-pyrrole-2-carboxamide 14-p1

[0791] 5-cyano-N-(1,1-dicyclopropyl-3-oxo-3-((4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)

[0792] ethyl)phenyl)amino)propan-2-yl)-1-methyl-1H-pyrrole-2-carboxamide 14-p2

[0793]

[0794] The synthetic route of Example 10 was used to replace the sixth step compound 1-ethyl-1H-pyrazole-5-carboxylic acid with 5-cyano-1-methyl-1H-pyrrole-2-carboxylic acid (prepared by the method disclosed in the document Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, #11, p. 3219-3223) to obtain the title compound (13.9 mg, yield: 6.7%), (11.5 mg, yield: 5.6%).

[0795] Single configuration compound (short retention time): (13.9 mg, yield: 6.7%).

[0796] MS m / z(ESI):557.4[M+1].

[0797] HPLC analysis: retention time 1.41 minutes, purity: 99% (chromatographic column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0798] 1 H NMR (500MHz, CD 3 OD: δ7.62(d,2H),7.31(d,2H),6.96-6.83(m,2H),5.15(q,1H),4.29(ddd,1H),4.02(s,3H), 3.77(t,1H),3.11(dd,1H),1.56(d,3H),1.35(s,1H),0.95-0.75(m,3H),0.63-0.18(m,8H).

[0799] Single configuration compound (longer retention time): (11.5 mg, yield: 5.6%).

[0800] MS m / z(ESI):557.4[M+1].

[0801] HPLC analysis: retention time 1.45 minutes, purity: 99% (chromatographic column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0802] 1 H NMR (500MHz, CD 3 OD): δ7.62(d,2H),7.34(d,2H),6.93-6.84(m,2H),5.16(q,1H),4.23(ddd,1H),4.02(s,3H) ,3.52(dd,1H),3.37(d,1H),1.55(d,3H),1.35(s,1H),0.92-0.75(m,3H),0.61-0.20(m,8H).

[0803] Embodiment 15

[0804] N-((1S)-1-cycloheptyl-2-((2-fluoro-4-(1-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 15

[0805]

[0806] first step

[0807] tert-Butyl (4-(1-(((1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)methyl)amino)ethyl)-2-fluorophenyl)carbamate 15b

[0808] Compound 1b (300 mg, 1.18 mmol) and tert-butyl ((1-(aminomethyl)cyclopropyl)methyl)carbamate 15a (260 mg, 1.3 mmol, Shanghai Leyan) were dissolved in tetrahydrofuran (40 mL), tetraisopropyl titanate (680 mg, 2.39 mmol) was added, and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in methanol (30 mL). Sodium borohydride (90 mg, 2.37 mmol) was added under ice bath, and the reaction was stirred for 2 hours. Saturated ammonium chloride solution was added to the reaction solution, and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 15b (425 mg, yield: 82%).

[0809] MS m / z(ESI):438.5[M+1].

[0810] Step 2

[0811] Tert-butyl (2-fluoro-4-(1-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)ethyl)phenyl)carbamate 15c

[0812] Compound 15b (100 mg, 228.54 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL), sodium tert-butoxide (110 mg, 1.14 mmol) was added, and the mixture was sealed at 65°C for 40 minutes. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 15c (77 mg, yield: 92.7%).

[0813] MS m / z(ESI):364.4[M+1].

[0814] Step 3

[0815] N-((1S)-1-cycloheptyl-2-((2-fluoro-4-(1-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 15

[0816] The synthetic route of Example 12 was adopted, and the raw material compound 12e in the fourth step was replaced by compound 15c to obtain the title compound 15 (16 mg, yield: 14.4%).

[0817] MS m / z(ESI):539.5[M+1].

[0818] 1 H NMR (500MHz, CD 3 OD): δ7.83(t,1H),7.51(d,1H),7.16(dd,2H),6.87(d,1H),5.74(q,1H),4.65(d,1H),4.55(q,2H),3.20(d,1H),3.13(d,1H),2.89(d ,1H),2.47(d,1H),2.24-2.16(m,1H),2.14-1.67(m,5H),1.66-1.43(m,8H),1.42-1.14(m,5H),0.72-0.41(m,3H),0.36-0.24(m,1H).

[0819] Example 16

[0820] N-(1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide 16-1

[0821] or

[0822] N-(1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide 16-2

[0823]

[0824] Using the synthetic route of Example 6, the first step compound 1j was replaced by 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (Shanghai Bidex), and the fifth step compound A was replaced by compound 4d-1 or 4d-2 (prepared from the compound with a shorter retention time in 4c-1 or 4c-2) to obtain the title compound 16-1 or 16-2 (5 mg, yield: 13.1%). MS m / z (ESI): 619.1 [M+1].

[0825] 1 H NMR (500MHz, CD 3OD): δ7.88(t,1H),7.68-7.37(m,1H),7.26-7.08(m,2H),6.56(d,1H),6.43(t,1H),5.14(dd,1H),4.71(d,1H),4.32-4.36(m,1H),3.99-3 .79(m,3H),3.43(s,3H),3.42-3.36(m,1H),2.56(s,3H),2.53(s,1H) ,2.15-1.97(m,2H),1.90(dtd,3H),1.43-1.29(m,2H),1.24(qd,1H).

[0826] Embodiment 17

[0827] N-(1,1-dicyclopropyl-3-((2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)

[0828] (ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide 17-1

[0829] or

[0830] N-(1,1-dicyclopropyl-3-((2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)

[0831] ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide 17-2 (

[0832]

[0833] Using the synthetic route of Example 4, the sixth step compound 1j was replaced by 1-ethyl-1H-pyrazole-5-carboxylic acid (Shanghai Bidex) to obtain the title compound 17-1 or 17-2 (prepared from the compound with shorter retention time in 4c-1, 4c-2, 10 mg, yield: 15.9%).

[0834] MS m / z(ESI):595.6[M+1].

[0835] 1 H-NMR (500 MHz, DMSO-d 6): δ9.98(s,1H),8.43(d,1H),7.84(t,1H),7.58(d,1H),7.49(d,1H),7.17 (m,1H),7.08(m,1H),7.00(d,1H),5.04-4.93(m,2H),4.49(m,2H),4.45(s, 2H),3.83(dd,1H),3.78-3.70(m,2H),3.31(s,3H),1.29(t,3H),0.92(tq, 1H),0.85(m,1H),0.84-0.71(m,1H),0.50-0.46(m,1H),0.42-0.12(m,5H).

[0836] Example 17-1-1, 17-1-2 or 17-2-1, 17-2-2

[0837] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide 17-1-1

[0838] N-((R)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide 17-1-2

[0839] or

[0840] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide 17-2-1

[0841] N-((R)-1,1-dicyclopropyl-3-((2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide 17-2-2

[0842]

[0843] Compound 17-1 or 17-2 (prepared from the compound with shorter retention time in 4c-1, 4c-2, 10 mg) was separated by chiral column (Gilson 281, chromatographic column: ChiralPak IF, 250*20 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol, gradient ratio: A:B is 80:20, flow rate: 20 mL / min) to obtain the title compound (3 mg, yield: 30%, 16.9 minutes), (5 mg, yield: 50%, 26.5 minutes).

[0844] Single configuration compound (short retention time): (3 mg, yield: 30%, 16.9 minutes).

[0845] HPLC analysis: retention time 1.33 minutes, purity: 98% (chromatographic column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0846] MS m / z(ESI):595.6[M+1].

[0847] 1 H-NMR (500 MHz, DMSO-d 6 ): δ9.98(s,1H),8.43(d,1H),7.84(t,1H),7.58(d,1H),7.49(d,1H),7.17 (m,1H),7.08(m,1H),7.00(d,1H),5.04-4.93(m,2H),4.49(m,2H),4.45(s, 2H),3.83(dd,1H),3.78-3.70(m,2H),3.31(s,3H),1.29(t,3H),0.92(tq, 1H),0.85(m,1H),0.84-0.71(m,1H),0.50-0.46(m,1H),0.42-0.12(m,5H).

[0848] Single configuration compound (longer retention time): (5 mg, yield: 50%, 26.5 minutes).

[0849] HPLC analysis: retention time 1.33 minutes, purity: 98% (chromatographic column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0850] MS m / z(ESI):595.6[M+1].

[0851] 1H-NMR (500 MHz, DMSO-d 6 ):9.98(s,1H),8.43(d,1H),7.84(t,1H),7.58(d,1H),7.49(d,1H),7.17( m,1H),7.08(m,1H),7.00(d,1H),5.04-4.93(m,2H),4.49(m,2H),4.45(s, 2H),3.83(dd,1H),3.78-3.70(m,2H),3.31(s,3H),1.29(t,3H),0.92(tq, 1H),0.85(m,1H),0.84-0.71(m,1H),0.50-0.46(m,1H),0.42-0.12(m,5H).

[0852] Embodiment 18

[0853] 1-ethyl-N-(2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino

[0854] 1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide 18-1

[0855] or

[0856] 1-ethyl-N-(2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino

[0857] 1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide 18-2

[0858]

[0859]

[0860] first step

[0861] 2-(((Benzyloxy)carbonyl)amino)-2-(1,4-dioxaspiro[4.5]dec-8-ylidene)acetic acid methyl ester 18b

[0862] Benzyloxycarbonyl-α-phosphonoglycine trimethyl ester (21.2 g, 64.00 mmol, Shanghai Shaoyuan) was dissolved in dichloromethane (100 mL), and bicyclo[5.4.0]-1,8-diaza-7-nonene (DBU) (9.70 g, 63.72 mmol) was added dropwise at room temperature. The mixture was reacted at room temperature for 30 minutes. A dichloromethane solution (20 mL) of 1,4-dioxaspiro[4.5]decan-8-one 18a (10 g, 64.03 mmol, Shanghai Shaoyuan) was added. The mixture was stirred at room temperature for 16 hours under nitrogen protection. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (60 mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 18b (10.5 g, yield: 45.4%).

[0863] MS m / z(ESI):362.3[M+1].

[0864] Step 2

[0865] 2-Amino-2-(1,4-dioxaspiro[4.5]dec-8-yl)acetic acid methyl ester 18c

[0866] Compound 18b (10.5 g, 29.05 mmol) was dissolved in methanol (40 mL), and 10% palladium carbon (containing 55% water) (927 mg, 8.71 mmol) was added. The gas was replaced with a hydrogen balloon and the reaction was stirred at room temperature for 16 hours. The reaction solution was filtered through diatomaceous earth and the organic phase was concentrated under reduced pressure to obtain the crude title compound 18c (6 g, yield: 90.1%), which was directly used in the next step without purification.

[0867] MS m / z(ESI):230.4[M+1].

[0868] Step 3

[0869] 2-(((Benzyloxy)carbonyl)amino)-2-(1,4-dioxaspiro[4.5]dec-8-yl)acetic acid methyl ester 18d

[0870] Compound 18c (6 g, 26.17 mmol) was dissolved in tetrahydrofuran (60 mL) and saturated sodium bicarbonate solution (60 mL), and benzyl chloroformate (6 g, 35.17 mmol, Shanghai Shaoyuan) was added dropwise under ice bath, and stirred at room temperature for 16 hours. The reaction solution was extracted with ethyl acetate (60 mL×3), the organic phases were combined, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 18d (6.5 g, yield: 68.3%). MS m / z (ESI): 364.1 [M+1].

[0871] Step 4

[0872] 2-(((Benzyloxy)carbonyl)amino)-2-(1,4-dioxaspiro[4.5]dec-8-yl)acetic acid 18e

[0873] Compound 18d (485 mg, 1.33 mmol) was dissolved in tetrahydrofuran (6 mL) and water (6 mL), lithium hydroxide monohydrate (112 mg, 2.67 mmol) was added, and the reaction was stirred at room temperature for 16 hours. 1N hydrochloric acid was added to adjust the pH to about 5, and the reaction solution was extracted with ethyl acetate (20 mL×3). The organic phases were combined and concentrated under reduced pressure to give the crude title compound 18e (390 mg, yield: 83.6%), which was directly used in the next step without purification.

[0874] MS m / z(ESI):350.3[M+1].

[0875] Step 5

[0876] (2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxy

[0877] -1-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl)benzyl carbamate 18f-1

[0878] or

[0879] (2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxy

[0880] -1-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl)benzyl carbamate 18f-2

[0881] Compound A (100 mg, 343.3 μmol) was dissolved in pyridine (5 mL), and compound 18e (119 mg, 340.6 μmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (133 mg, 766.3 μmol) were added. The mixture was reacted at 50°C for 16 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 18f-1 or 18f-2 (197 mg, yield: 92.1%).

[0882] MS m / z(ESI):623.5[M+1].

[0883] Step 6

[0884] 2-Amino-N-(2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)-2-(1,4-dioxaspiro[4.5]dec-8-yl)acetamide 18g-1

[0885] or

[0886] 2-Amino-N-(2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)-2-(1,4-dioxaspiro[4.5]dec-8-yl)acetamide 18g-2

[0887] Compound 18f-1 or 18f-2 (197 mg, 316.4 μmol) was dissolved in tetrahydrofuran (3 mL) and ethanol (3 mL), 10% palladium carbon (135 mg) was added, and hydrogen was replaced. The reaction was stirred for 16 hours. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude title compound 18g-1 or 18g-2 (150 mg), which was directly used in the next reaction without purification.

[0888] MS m / z(ESI):489.4[M+1].

[0889] Step 7

[0890] 1-Ethyl-N-(2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxo-1-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl)-1H-pyrazole-5-carboxamide 18h-1

[0891] or

[0892] 1-Ethyl-N-(2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxo-1-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl)-1H-pyrazole-5-carboxamide 18h-2

[0893] Compound 18g-1 or 18g-2 (150 mg, 307 μmol) was dissolved in N,N-dimethylformamide (5 mL), and 1-ethyl-1H-pyrazole-5-carboxylic acid (52 mg, 371 μmol), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (175 mg, 460.2 μmol), and N,N-diisopropylethylamine (119 mg, 920.7 μmol) were added. The reaction was stirred for 2 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 18h-1 or 18h-2 (180 mg, yield: 96%).

[0894] MS m / z(ESI):611.5[M+1].

[0895] Step 8

[0896] 1-ethyl-N-(2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino

[0897] (4-(2-(4-oxocyclohexyl)ethyl)-1H-pyrazole-5-carboxamide 18i-1

[0898] or

[0899] 1-ethyl-N-(2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino

[0900] (4-(2-(4-oxocyclohexyl)ethyl)-1H-pyrazole-5-carboxamide 18i-2

[0901] Compound 18h-1 or 18h-2 (180 mg, 194.8 μmol) was dissolved in tetrahydrofuran (5 mL), 1 M hydrochloric acid (3 mL) was added, and the reaction was stirred for 3 hours. Saturated sodium bicarbonate solution was added to the reaction solution for neutralization, and the solution was extracted with ethyl acetate (10 mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 18i-1 or 18i-2 (138 mg, yield: 82.6%).

[0902] MS m / z(ESI):567.0[M+1].

[0903] Step 9

[0904] 1-ethyl-N-(2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino

[0905] 1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide 18-1

[0906] or

[0907] 1-ethyl-N-(2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino

[0908] 1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide 18-2

[0909] (Fluoromethyl) triphenylphosphine tetrafluoroborate (81 mg, 212 μmol, Shanghai Bis(R)) was dissolved in tetrahydrofuran (2 mL), 1 M lithium bis(trimethylsilyl)amide tetrahydrofuran solution (424 μL) was added at -78°C, the temperature was maintained and stirred for 1 hour, compound 18i-1 or 18i-2 (40 mg, 70.6 μmol) was added, the temperature was naturally restored to room temperature and stirred for 16 hours, water was added to the reaction solution to quench, and the solution was extracted with ethyl acetate (5 mL×3), the organic phases were combined, and concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: water (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30mL / min) to obtain the title compound 18-1 or 18-2 (prepared from compound A, 18mg, yield: 43.7%).

[0910] MS m / z(ESI):583.4[M+1].

[0911] 1 H NMR (500 MHz, CDCl 3): δ8.27(d,1H),8.19(dt,1H),7.48(q,1H),7.12-7.00(m,2H),6.69(d,1H),6. 61(t,1H),6.49(s,1H),5.40-5.31(m,1H),5.26(s,1H),5.22(dd,1H),4.71-4. 54(m,3H),4.11(s,1H),3.63(q,1H),3.16(ddd,1H),2.88(d,1H),2.22(t,1H), 1.95(s,3H),1.74(d,1H),1.64(t,1H),1.53(d,3H),1.43(td,3H),0.88(t,1H).

[0912] Embodiment 19

[0913] 1-ethyl-N-(2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino

[0914] 1-(4-(propan-2-ylidene)cyclohexyl)ethyl)-1H-pyrazole-5-carboxamide 19-1

[0915] or

[0916] 1-ethyl-N-(2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino

[0917] 1-(4-(propan-2-ylidene)cyclohexyl)ethyl)-1H-pyrazole-5-carboxamide 19-2

[0918]

[0919]

[0920] first step

[0921] 4-(Propan-2-ylidene)cyclohexyl 4-methylbenzenesulfonate 19b

[0922] 4-(Propan-2-ylidene)cyclohexane-1-ol 19a (1.81 g, 12.9 mmol, prepared by the method disclosed in the document "Journal of Organic Chemistry, 1996, vol.61, #6, p.1940-1945") and p-toluenesulfonyl chloride (4.92 g, 25.8 mmol) were dissolved in dichloromethane (40 mL), and pyridine (4.1 g, 51.8 mmol) and 4-dimethylaminopyridine (1.59 g, 12.9 mmol) were added. The reaction was stirred for 3 days, and the reaction solution was purified by silica gel column chromatography with eluent system B to obtain the title compound 19b (2.26 g, yield: 59.4%).

[0923] MS m / z(ESI):293.2[M-1].

[0924] Step 2

[0925] 2-((Diphenylmethylene)amino)-2-(4-(propan-2-ylidene)cyclohexyl)acetic acid methyl ester 19c

[0926] Compound 2-(diphenylmethylene)amino)ethyl acetate (2.05 g, 7.67 mmol, Shanghai Titan) and compound 19b (2.26 g, 7.67 mmol) were dissolved in toluene (25 mL), and 1 M lithium bistrimethylsilylamide in tetrahydrofuran solution (9.6 mL) was added dropwise. The tube was sealed and reacted at 100°C for 16 hours. The reaction solution was cooled to room temperature and quenched with water. It was extracted with ethyl acetate (50 mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 19c (1.65 g, yield: 55.2%).

[0927] MS m / z(ESI):390.5[M+1].

[0928] Step 3

[0929] 2-((Diphenylmethylene)amino)-2-(4-(propan-2-ylidene)cyclohexyl)acetic acid 19d

[0930] Compound 19c (176 mg, 451.83 μmol) was dissolved in a mixture of tetrahydrofuran (2 mL), methanol (2 mL) and water (1 mL), and sodium hydroxide (91 mg, 2.27 mmol) was added. The mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the pH was slowly adjusted to 6-7 with 1N hydrochloric acid solution. The mixture was extracted with dichloromethane (10 mL×3), and the organic phases were combined and concentrated under reduced pressure to obtain the crude title compound 19d (475 mg), which was directly used in the next step without purification. MS m / z (ESI): 362.2 [M+1].

[0931] Step 4

[0932] 2-Amino-2-(4-(propan-2-ylidene)cyclohexyl)acetic acid 19e

[0933] Compound 19d (160 mg, 410.75 μmol) was dissolved in tetrahydrofuran (3 mL), 2M hydrochloric acid (1.8 mL) was added, and the mixture was stirred at room temperature for 1 hour. After monitoring the completion of the reaction, the mixture was concentrated under reduced pressure, sodium bicarbonate solution was added, pH was adjusted to 8-9, and the mixture was extracted with ethyl acetate (3 mL×3), the organic phases were combined, and the mixture was concentrated under reduced pressure to obtain the crude title compound 19e (92 mg), which was directly used in the next step without purification.

[0934] MS m / z(ESI):226.3[M+1].

[0935] Step 5

[0936] 2-((tert-Butoxycarbonyl)amino)-2-(4-(propan-2-ylidene)cyclohexyl)acetic acid 19f

[0937] The crude compound 19e (115 mg, 510.3 μmol) was dissolved in 1,4-dioxane (2 mL), and N,N-diisopropylethylamine (270 mg, 2.08 mmol) was added. A solution of di-tert-butyl dicarbonate (335 mg, 1.53 mmol) in 1,4-dioxane (2 mL) was added under ice bath. The reaction was stirred for 16 hours, and a saturated sodium bicarbonate solution was added to the reaction solution. The mixture was extracted with ethyl acetate (10 mL×2). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 19f (100 mg, yield: 60.2%).

[0938] Step 6

[0939] 2-((tert-Butoxycarbonyl)amino)-2-(4-(prop-2-ylidene)cyclohexyl)acetic acid 19 g

[0940] Compound 19f (108 mg, 331.85 μmol) was dissolved in ethanol (1 mL), and 2M aqueous sodium hydroxide solution (0.35 mL) was added. The mixture was stirred for 6 hours, and the pH of the reaction solution was adjusted to about 6 with 2M hydrochloric acid solution. The reaction solution was extracted with ethyl acetate (10 mL×3), and the organic phases were combined and concentrated under reduced pressure to give the crude title compound 19g (98 mg), which was used directly in the next step without purification.

[0941] MS m / z(ESI):296.2[M-1].

[0942] Step 7

[0943] 1-ethyl-N-(2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino

[0944] 1-(4-(propan-2-ylidene)cyclohexyl)ethyl)-1H-pyrazole-5-carboxamide 19-1

[0945] or

[0946] 1-ethyl-N-(2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino

[0947] 1-(4-(propan-2-ylidene)cyclohexyl)ethyl)-1H-pyrazole-5-carboxamide 19-2

[0948] Using the synthetic route of Example 2, the fourth step compound 1g was replaced by compound 19g, and the sixth step compound 1j was replaced by 1-ethyl-1H-pyrazole-5-carboxylic acid (Shanghai Bidex) to obtain the title compound 19-1 or 19-2 (prepared from the compound with shorter retention time in 2c-1, 2c-2, 3 mg, yield: 3.7%).

[0949] MS m / z(ESI):593.5[M+1].

[0950] 1 H NMR (500MHz, CD 3 OD): δ7.88(t,1H),7.51(d,1H),7.22-7.09(m,2H),6.89(d,1H),5.36(t,1H),5.14(q,1H),4.70(d,1H),4.59-4.53( m,2H),4.33-4.27(m,1H),3.79(t,1H),2.07-2.00(m,2H),1.94-1.87(m,2H),1.67-1.58(m,2H),1.43-1.23(m,15H).

[0951] Embodiment 20

[0952] N-((S)-1-(4,4-difluorocyclohexyl)-2-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)

[0953] (ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 20-1

[0954] or

[0955] N-((S)-1-(4,4-difluorocyclohexyl)-2-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)

[0956] ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 20-2

[0957]

[0958] The synthetic route of Example 2 was adopted, and the fourth step compound 1g was replaced by (S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid (WuXi AppTec), and the sixth step compound 1j was replaced by 1-ethyl-1H-pyrazole-5-carboxylic acid (Shanghai BiDe) to obtain the title compound 20-1 or 20-2 (prepared from the compound with shorter retention time in 2c-1, 2c-2, 3 mg, yield: 3.7%).

[0959] MS m / z(ESI):589.5[M+1].

[0960] 1 H NMR (500MHz, CD 3 OD): δ7.88(t,1H),7.51(d,1H),7.20-7.11(m,2H),6.89(d,1H),5.14(q,1H),4.68(d,1H),4.55(q,2H),4.31(ddt,1H) ,3.79(t,1H),3.15(dd,1H),2.17-2.04(m,3H),2.03-1.95(m,1H),1.93-1.75(m,3H),1.62-1.48(m,5H),1.39(t,3H).

[0961] Embodiment 21

[0962] N-(1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)

[0963] Imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 21-1

[0964] or

[0965] N-(1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)

[0966] Imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 21-2

[0967]

[0968] first step

[0969] 1-ethyl-N-(2-((2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxo-1-(4-oxocyclohexyl)ethyl)-1H-pyrazole-5-carboxamide 21a-1

[0970] or

[0971] 1-ethyl-N-(2-((2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxo-1-(4-oxocyclohexyl)ethyl)-1H-pyrazole-5-carboxamide 21a-2

[0972] Using the synthetic route of Example 18, the fifth step compound A was replaced by compound 4d-1 or 4d-2 (prepared from the compound with a shorter retention time in 4c-1 or 4c-2) to obtain the title compound 21a-1 or 21a-2 (13 mg, yield: 66%).

[0973] MS m / z(ESI):597.5[M+1].

[0974] Step 2

[0975] N-(1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)

[0976] Imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 21-1

[0977] or

[0978] N-(1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)

[0979] Imidazolidin-1-yl)ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 21-2

[0980] Compound 21a-1 or 21a-2 (13 mg, 21.8 μmol) and 2-((difluoromethyl)sulfonyl)pyridine (5.1 mg, 26.2 μmol) were dissolved in N,N-dimethylformamide (3 mL), and a 1 M solution of potassium tert-butoxide in tetrahydrofuran (76.3 μL) was added at -40°C. The reaction mixture was stirred at -40°C for 4 hours, and glacial acetic acid was added to the reaction solution for quenching. The mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate (5 mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 21-1 or 21-2 (prepared from the compound with a shorter retention time in 4c-1 or 4c-2, 0.83 mg, yield: 6%).

[0981] MS m / z(ESI):631.5[M+1].

[0982] 1 H NMR (500MHz, CD 3 OD): δ7.86(t,1H),7.49(d,1H),7.23-7.06(m,2H),6.87(d,1H),5.34(t,1H),5.12(dd,1H),4.66-4.50(m,3H),4.32(ddd,1H),3.95-3.80(m, 2H),3.45-3.34(m,4H),2.53(d,1H),2.19(t,1H),2.09-1.98(m,2H),1 .94-1.84(m,2H),1.61(s,1H),1.38(t,3H),1.22(dd,1H),0.90(t,1H).

[0983] Biological evaluation

[0984] Test Example 1. Inhibitory activity of the disclosed compounds on the binding of human IL-17A:IL-17RA (IL-17AAcompetition assay)

[0985] 1. Experimental Materials and Instruments

[0986] 1. IL-17A protein, Human (HEK293, His) (MCE, HY-P70527)

[0987] 2.IL-17RA,Fc fusion,Biotin-labeled(Human)Recombinant(BPS Bioscience,91013-2)

[0988] 3.Streptavidin-d2(cisbio,610SADLF)

[0989] 4.MAb Anti-6HIS Tb cryptate Gold(cisbio,61HI2TLA)

[0990] 5.1M HEPES (Sangon Biotech, E607018-0100)

[0991] 6.Tween-20 (Sangon Biotech, A100777-0500)

[0992] 7.DMSO (Sigma, D2650)

[0993] 8.BSA(Sangon Biotech,A500023-0100)

[0994] 9.5M NaCl solution (Sangon Biotech, B548121-0100)

[0995] 10.UltraPure Distilled Water(Invitrogen,10977-015)

[0996] 11.96-well plate (Sangon Biotech, F610960-0010)

[0997] 12.384-well white plate (Perkin Elmer, 6007290)

[0998] 13. PHERAstar FS microplate reader (BMG Labtech)

[0999] 2. Experimental Principle

[1000] IL17A can bind to its receptor IL17RA / IL17RC heterodimer in the form of a dimer (IL-17AA) and exert biological effects. It is reported that the binding mode of IL-17AA and IL17RA / IL17RC heterodimer is that IL-17AA preferentially binds to IL-17RA and then further binds to IL-17RC. This experiment uses the homogeneous time-resolved fluorescence (HTRF) method to detect the inhibitory effect of the compound on the binding between IL-17A and IL-17RA, thereby evaluating the activity of the compound.

[1001] 3. Experimental steps

[1002] Reaction buffer (1×): 10 mM HEPES, 150 mM NaCl, 0.02% BSA, 0.01% Tween-20;

[1003] Compound preparation: 20mM test compound dissolved in 100% DMSO was diluted to 0.333mM with 100% DMSO as the highest drug concentration. This concentration of compound was serially diluted 3-fold with 100% DMSO in a 96-well plate to 10 concentration points, and the blank well was 100% DMSO. The above serially diluted compounds and 100% DMSO were diluted 20-fold with reaction buffer as 10× concentration compounds, and fully mixed for later use;

[1004] Prepare 4× Streptavidin-d2 dilution: dilute the Streptavidin-d2 stock solution 50 times with reaction buffer and place on ice for later use;

[1005] Prepare 4×MAb Anti-6HIS Tb cryptate Gold dilution: dilute Streptavidin-d2 (3 μM) stock solution to 6 nM with reaction buffer and place on ice for later use;

[1006] Dilute the IL-17A protein with reaction buffer to a final concentration of 5nM (i.e., 5×IL-17A protein solution), add 4μL of 5nM IL-17A protein solution to each well of the 384-well plate, and 4μL of reaction buffer to the negative control well. Add 2μL of 10× concentration compound to each well, and add 2μL of 5% DMSO to the negative control well (no IL-17A or compound) and the positive control well (no compound). Seal the well plate and centrifuge, shake and mix for 2min, and place at room temperature for 10min;

[1007] The IL-17RA protein was diluted with reaction buffer to a final concentration of 12.5 nM (i.e., 5× IL-17RA protein solution), and 4 μL of 12.5 nM IL-17RA protein solution was added to each well of the 384-well plate. The plate was sealed and centrifuged, shaken and mixed for 2 min, and placed at room temperature for 60 min.

[1008] Mix 4×Streptavidin-d2 dilution and 4×MAb Anti-6HIS Tb cryptate Gold dilution in a volume ratio of 1:1, add 10 μL of Streptavidin-d2:MAb Anti-6HIS Tb cryptate Gold mixture to each well, centrifuge, shake for 2 minutes, centrifuge again, stand at room temperature for 2 hours, then read the plate and detect the 665 / 620Ratio value.

[1009] The inhibition curve was drawn based on the concentrations of the compounds and the corresponding inhibition rates using Graphpad Prism software, and the concentration of the compound when the inhibition rate reached 50%, i.e., IC 50 value.

[1010] Table 1 Inhibitory activity IC of the disclosed compounds on the binding of human IL-17A:IL-17RA 50 value

[1011]

[1012]

[1013] Conclusion: The disclosed compounds have good inhibitory activity on the binding of human IL-17A:IL-17RA. Test Example 2. Inhibitory activity of the disclosed compounds on the secretion of chemokine CXCL1 induced by human IL-17A on HaCaT cells (HaCaT IL-17A neutralization assay)

[1014] 1. Experimental Materials and Instruments

[1015] 1.IL-17A,His,Human(GenScript,Z03228)

[1016] 2. DMEM / high glucose version, containing L-glutamine and sodium pyruvate (Mei Lun, PWL003)

[1017] 3.Fetal Bovine Serum(Gibco,10091-148)

[1018] 4.Pen strep (Gibco, 15140-122)

[1019] 5. PBS (1x) (Mei Lun, PWL050-Aug-05I)

[1020] 6.0.25% Typsin-EDTA(1x)(Gibco, 25200-072)

[1021] 7.Human CXCL1 / GRO alpha DuoSet ELISA (R&D System, DY275)

[1022] 8.DMSO (Sigma, D2650)

[1023] 9.BSA (Sangon Biotech,A500023-0100)

[1024] 10.Tween-20(Sangon Biotech,A100777-0500)

[1025] 11.25cm 2 Filter cap cell culture flask (JET / JET, TCF012050)

[1026] 12.96Well Black Polystyrene Microplate(Xinyou Biotechnology,060096)

[1027] 13. Disposable cell culture plate 96-well U-bottom sterilized, surface untreated (JET / JET, TCP002096)

[1028] 14.TMB (high sensitivity) substrate (Xinbosheng, TMH.100)

[1029] 15. TMB color stop solution (450nm, without sulfuric acid) (Xinbosheng, P0215-100ml)

[1030] 16. ELISA plate (Corning, 3590)

[1031] 17. PHERAstar FS microplate reader (BMG Labtech)

[1032] 18.Automated cell counter(Countstar)

[1033] 19.Hood(Thermo)

[1034] 20.Thermo Incubator (Thermo)

[1035] 21.Centrifuge (Beckman coulter)

[1036] 2. Experimental Principle

[1037] HaCaT is a human epidermal cell, which is a target cell of IL-17 and highly expresses IL-17 receptors. IL-17A binds to the IL-17 receptors on HaCaT cells and can induce the activation of downstream signaling pathways, thereby expressing and secreting chemokine CXCL1. This experiment uses enzyme-linked immunosorbent assay (ELISA) to detect the inhibitory effect of compound treatment on cell secretion of CXCL1, thereby evaluating the activity of the compound.

[1038] 3. Experimental steps

[1039] Cell growth and test medium: DMEM / high glucose version (containing L-glutamine, sodium pyruvate), 10% FBS, 1% Pen strep;

[1040] ELISA sample diluent: 1×PBS, 1% BSA;

[1041] ELISA washing buffer: 1× PBS, 0.1% Tween-20;

[1042] Cell plating and drug addition:

[1043] a. Discard the culture medium, rinse the cells once with 1× PBS, add 0.25% trypsin, 5% CO 2 , digest in a 37°C incubator for 6-8 minutes;

[1044] b. Add an equal volume of culture medium as pancreatin to terminate digestion and centrifuge at 300g for 3 minutes;

[1045] c. Discard the supernatant, re-add appropriate culture medium to mix the cells by pipetting, and then resuspend the cells in 1 ml of culture medium for counting and viability detection;

[1046] d. According to the counting results, dilute the cells to 2×10 5 cells / mL, then 50μL / well (10,000

[1047] cell / well) for plating;

[1048] e. Place the cells in 5% CO 2 , in a 37°C incubator.

[1049] Compound preparation:

[1050] a. A 20 mM test compound dissolved in 100% DMSO was diluted to 5 mM with 100% DMSO as the highest drug concentration. This concentration of the compound was serially diluted 3-fold with 100% DMSO in a 96-well plate to 10 concentration points, and the negative wells and positive wells were blank with 100% DMSO;

[1051] b. Dilute the IL-17A protein stock solution to 10 ng / mL of 2×IL-17A protein dilution using growth and test medium;

[1052] c. Dilute the compound 250 times with 2×IL-17A protein diluent, and dilute the negative control well with growth and test medium without IL-17A protein, mix well and set aside;

[1053] Dosing:

[1054] a. Take the plate out of the incubator, add 50 μL / well of compound or DMSO dilution into the corresponding wells, and tap the plate to mix;

[1055] b. Place the plate in 5% CO 2 , and continue culturing in a 37°C incubator for 24 h.

[1056] Sample collection and ELISA testing:

[1057] The cell culture supernatant was collected into a 96-well plate, and CXCL1 in the cell culture supernatant was quantified using the ELISA kit of R&D System.

[1058] a. Capture antibody coating: dilute the capture antibody 120 times with 1×PBS and dispense into the ELISA plate, 100 μL / well, and place in a 37°C incubator for 3 hours;

[1059] b. Blocking: Wash the coated plate 5 times with a plate washer, add 100 μL of sample diluent to each well, place at room temperature for 1 hour or at 4°C overnight, wash the plate 5 times with a plate washer, and set aside;

[1060] c. Sample incubation: dilute the sample 10 times with ELISA sample diluent and dispense into the ELISA plate, 100 μL / well, and incubate at room temperature for 2 hours;

[1061] d. Add detection antibody: Wash the plate 5 times with a plate washer, dilute the detection antibody 60 times with sample diluent and dispense into the ELISA plate, 100 μL / well, and incubate at room temperature for 2 hours;

[1062] e. Add HRP-conjugated anti-antibody: Wash the plate 5 times with a plate washer, dilute the HRP-conjugated anti-antibody 40 times with sample diluent and dispense into the ELISA plate, 100 μL / well, and incubate at room temperature in the dark for 20 minutes;

[1063] f. Color development: Wash the plate 5 times with a plate washer, add 100 μL TMB substrate to each well, and incubate at room temperature in the dark for 20 min;

[1064] g. Stop reaction and read plate: Add 50 μL TMB colorimetric stop reaction solution to each well and detect 450 within 10 minutes.

[1065] Absorbance value at nm wavelength.

[1066] The inhibition curve was drawn based on the concentrations of the compounds and the corresponding inhibition rates using Graphpad Prism software, and the concentration of the compound when the inhibition rate reached 50%, i.e., IC 50 value.

[1067] Table 2 IC inhibitory activity of the disclosed compounds on the secretion of CXCL1 induced by human IL-17A on HaCaT cells 50 value

[1068]

[1069] Conclusion: The disclosed compounds have inhibitory activity on the secretion of chemokine CXCL1 induced by human IL-17A on HaCaT cells.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each independently optionally substituted by one or more R A replace; Ring C is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each independently optionally substituted by one or more R C replace; B is CHR 3 R 4 or ring B; Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R B replace; R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, a cyano group, an amino group, 10 , cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from oxo, deuterium atom, halogen, alkenyl, alkynyl, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, cyano, amino, nitro, hydroxyl, -OR 10 、-NR 11 R 12 、-C(O)R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl; or R 1 and R 2 Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclyl group; X 1 N or CR 6 ; X 2 N or CR 7 ; X 3 N or CR 8 ; X 4 N or CR 9 ; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a hydroxyl group, a cyano group, an amino group, a nitro group, a -(CR x R y ) s OR 10 、-(CR x R y ) s NR 11 R 12 、-C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-OC(O)NR 11 R 12 、-C(O)NR 11 R 12 、-NR 13 C(O)R 10 、-NR 13 C(O)OR 10 、-NR 13 C(O)NR 11 R 12 、-SR 10 、-S(O)R 10 、-S(O)2R 10 、-S(O)2OR 10 、-S(O)2NR 11 R 12 and-NR 13 S(O)2R 10 wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R 0 replaced by; or R 3 and R 4 Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 replace; Each R A , R B , R C and R 0 are the same or different and are each independently selected from a deuterium atom, an oxo group, =S, =NR 14 , halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkoxy, haloalkoxy, deuterated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, hydroxyl, cyano, amino, nitro, -(CR x R y ) s OR 10 、-(CR x R y ) s NR 11 R 12 、-C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-OC(O)NR 11 R 12 、-C(O)NR 11 R 12 、-NR 13 C(O)R 10 、-NR 13 C(O)OR 10 、-NR 13 C(O)NR 11 R 12 、-SR 10 、-S(O)R 10 、-S(O)2R 10 、-S(O)2OR 10 、-S(O)2NR 11 R 12 and-NR 13 S(O)2R 10 wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R t replace; Each R t are the same or different and are each independently selected from an oxo group, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, a cyano group, an amino group, a nitro group, -(CR x R y ) s OR 10 、-(CR x R y ) s NR 11 R 12 、-C(O)R 10 、-C(O)OR 10 、-C(O)NR 11 R 12 , cycloalkyl, heterocyclyl, aryl and heteroaryl; R 10 , R 11 , R 12 and R 13 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally replaced by one or more R S replace; or R 11 and R 12 Together with the nitrogen atom to which it is attached, it forms a nitrogen-containing heterocyclic group, which is optionally substituted by one or more R S replace; R 14 is selected from the group consisting of hydrogen, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, hydroxyl, alkoxy, haloalkoxy, deuterated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy and heterocyclyloxy; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy and heterocyclyloxy are each independently optionally replaced by one or more R S replace; R 15 and R 16 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 17 、-C(O)R 17 、-C(O)OR 17 and cyano, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R S replace; or R 15 and R 16 Together with the carbon atom to which it is attached, it forms a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group and the heterocyclic group are each independently optionally substituted by one or more R S replace; Each R S are the same or different and are each independently selected from the group consisting of an oxo group, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cyano group, a nitro group, a hydroxyl group, an amino group, a -NH alkyl group, a -N(alkyl)2 group, a -C(O)alkyl group, a -C(O)Oalkyl group, a -C(O)NH2 group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 17 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; R a and R b are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a cycloalkyl group, a cycloalkylalkyl group and a heterocyclic group; R x and R y are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a halogen, an alkenyl group, an alkynyl group, a hydroxyl group, a cyano group, a haloalkyl group, a deuterated alkyl group, an aminoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cycloalkyl group, a cycloalkylalkyl group and a heterocyclic group; n is 0 or 1; and s is 0, 1, or 2.

2. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of general formula (II) or a pharmaceutically acceptable salt thereof: in: Ring A, Ring C, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 As defined in claim 1.

3. The compound represented by the general formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring C is Each R 1C are the same or different and are each independently selected from deuterium atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl; wherein the C 1-6 alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkylC 1-6 The alkyl groups are each independently optionally selected from cyano, halogen, C 1-6 Alkyl and C 1-6 or two R 1C Together with the carbon atom to which it is attached, it forms a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group are each independently selected from cyano, halogen, C 1-6 Alkyl and C 1-6 is substituted by one or more substituents in a haloalkyl group; b is 1 or 2; c is 0, 1, 2, 3 or 4; preferably, ring C is R 2C Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6 membered cycloalkyl; wherein the 3 to 6 membered cycloalkyl is optionally substituted with one or more cyano groups.

4. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein ring C is selected from Preferably selected from More preferably 5. The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl group; wherein the 5-membered heteroaryl group is optionally replaced by one or more R A Replacement; R A Selected from C 1-6 alkyl, cyano, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group and 3- to 6-membered cycloalkyl C 1-6 Alkyl; preferably, ring A is pyrazolyl; wherein the pyrazolyl is optionally replaced by one R A Replacement; R A C 1-6 alkyl.

6. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein ring A is selected from Preferably selected from 7. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are the same or different and are each independently a 3- or 4-membered cycloalkyl group; or, R 3 and R 4 Together with the attached carbon atom, it forms a 3- to 8-membered cycloalkyl group; the 3- to 8-membered cycloalkyl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and is substituted by one or more substituents; R 15 and R 16 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl.

8. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein Selected from Preferably, Selected from 9. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 5 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 alkyl and 3 to 6-membered cycloalkyl; preferably, R 5 Selected from methyl, and cyclopropyl.

10. The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R 6 , R 7 , R 8 and R 9 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, R 6 is a hydrogen atom or a halogen; R 7 , R 8 and R 9 A hydrogen atom.

11. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, which is selected from any one of the following compounds:

12. A compound represented by general formula (IIA) or a salt thereof: in: Ring C, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 As defined in claim 2.

13. A compound or a salt thereof selected from the following compounds:

14. A method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising: The compound represented by the general formula (IIA) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIB) or its salt to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable salt; in: R w is halogen or hydroxyl; preferably hydroxyl; Ring A, Ring C, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 As defined in claim 2.

15. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

16. Use of a compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 15 in the preparation of a medicament for treating and / or preventing a disease or condition mediated by IL-17; preferably, the IL-17 is IL-17A.

17. Use of the compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating and / or preventing cancer, inflammation or autoimmune diseases; preferably, the inflammation or autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, suppurative hidradenitis, rheumatoid arthritis, juvenile atopic arthritis, spondyloarthritis, uveitis, bone erosion, intraperitoneal abscesses and adhesions, inflammatory bowel disease (IBD ), Crohn's disease, allogeneic transplant rejection, psoriasis, psoriasis, angiogenesis, atherosclerosis, asthma, multiple sclerosis (MS), systemic lupus erythematosus, lupus nephritis, Behcet's disease, ulcerative colitis, Behcet's disease, Wegener's granulomatosis, sarcoidosis, systemic sclerosis, insulin-dependent diabetes mellitus, septic shock syndrome, Alzheimer's disease, inflammatory eye disease, palmoplantar pustulosis (PPP), atopic dermatitis, chronic obstructive pulmonary disease (COPD) and Helicobacter pylori-associated gastritis, preferably selected from psoriasis, rheumatoid arthritis, spondyloarthritis and multiple sclerosis, more preferably psoriasis.

Images