Aromatic heterocyclic Kv1.3 inhibitors, their manufacturing methods and uses

Abstract

This application provides a novel Kv1.3 channel (or Kv1.3) inhibitor that can be used for the prevention and / or treatment of immune and inflammatory diseases such as multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, type 1 diabetes, psoriasis and asthma, spondylitis, and periodontitis, as well as Kv1.3 channel (or Kv1.3) related diseases including obesity, type 2 diabetes, renal fibrosis, Alzheimer's disease, and ischemic stroke.

Description

Detailed description of the invention

[0001] This application claims priority to a prior application filed with the China National Intellectual Property Administration on October 28, 2022, with application number 202211338806.2 and the title of the invention "Aromatic heterocyclic Kv1.3 inhibitor, method for producing the same and uses therefor," the said prior application is incorporated into this application in its entirety by reference.

[0002] [Technical Field] This application relates to a Kv1.3 inhibitor, a method for producing the same, and its uses. The inhibitor and pharmaceutical compositions containing the same can be used for the prevention and / or treatment of diseases or conditions related to Kv1.3.

[0003] [Background technology] Kv1.3 channels (or Kv1.3) are a type of voltage-gated potassium channel (Kv) that is highly expressed in macrophages, microglia, and effector memory T cells (TEM). Kv1.3 channels indirectly influence calcium signaling in TEM by regulating cell membrane potential. Effector memory T cells mediate various immune and inflammatory diseases, including multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, type 1 diabetes, psoriasis, and asthma.

[0004] Autoimmune diseases are a major group of diseases caused by the autoimmune system attacking normal cells and tissues. Current treatments typically involve anti-inflammatory drugs and immunosuppressants, which only alleviate symptoms and often come with serious toxicity and side effects. Research suggests that effector memory T cells are closely linked to the pathogenesis of autoimmune diseases (Proceedings of the National Academy of Sciences, 103, 46(2006): 17414-17419). By selectively inhibiting the function of effector memory T cells, it may be possible to treat autoimmune diseases while simultaneously avoiding impact on the protective immune response and reducing treatment-related side effects. Effector memory T cells express large amounts of Kv1.3 and rely on it to perform their cellular functions. Therefore, selective Kv1.3 inhibitors are expected to be low-toxicity and highly effective treatments for autoimmune diseases.

[0005] Peptide toxins that inhibit Kv1.3 have been isolated from scorpions and sea anemones, and dalazatide (ShK-186), derived from non-natural amino acids, showed some therapeutic effect in stage Ib clinical trials for psoriasis. However, its low subtype selectivity and the fact that peptide molecules cannot be administered orally limit the application of this type of molecule. Therefore, the development of small molecule Kv1.3 inhibitors with high selectivity that can be administered orally has extremely important social and market value.

[0006] [Summary of the Invention] This application provides a novel Kv1.3 channel (or Kv1.3) inhibitor that can be used for the prevention and / or treatment of diseases related to the Kv1.3 channel (or Kv1.3).

[0007] According to one aspect of the present application, the present application provides a compound represented by formula (I) or a pharmaceutically acceptable salt or deuterated thereof,

[0008] [ka]

[0009] Here, A is selected from 5-member heteroaryl groups containing 1 to 3 cycloheteroatoms independently selected from N, O, and S, Z and T are independently selected from C and N, X and Y are independently selected from CRaRb, NRc, and O, Ra and Rb are independently H, OH, NH2, C 1-4 a linear or branched alkyl group, C 2-4 a linear or branched alkenyl group, C 2-4 a linear or branched alkynyl group, C 1-4 a linear or branched alkyloxy group, or Ra and Rb together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group, or a 3- to 7-member heterocycloalkyl group containing 1 to 3 cycloheteroatoms independently selected from N, O, and S, Rc is H, C 1-4 a linear or branched alkyl group, C 2-4 a linear or branched alkenyl group, C 3-7 selected from cycloalkyl groups, R2, R3, R4, and R5 are independently H, F, Cl, Br, CN, C 1-4 a linear or branched alkyl group, C 2-4 a linear or branched alkenyl group, C 2-4 a linear or branched alkynyl group, C 1-4 a linear or branched alkyloxy group, C 2-4 a linear or branched alkenyloxy group, C 2-4 a linear or branched alkynyloxy group, C 3-7 selected from cycloalkyl groups, R1 is F, Cl, Br, CN, =O, C 1-4 a linear or branched alkyl group, C 2-4 a linear or branched alkenyl group, C 2-4 a linear or branched alkynyl group, C 3-7Cycloalkyl groups, 3-7 membered heterocycloalkyl groups containing 1-3 cycloheteratoms independently selected from N, O, and S and bonded by C or N, aryl groups, 5-11 membered heteroaryl groups containing 1-3 cycloheteratoms independently selected from N, O, and S, C 5-7 A 5-7 member heterocrosslinked cycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member alkane ring; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a benzene ring and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 5-7 member heteroaromatic ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; -C 1-4 Straight-chain or branched-chain alkylenes -R7, -OR7, -OC 1-4 Straight-chain or branched-chain alkylenes -R7, -SR7, -SC 1-4 Straight-chain or branched-chain alkylenes -R7, -N(R6)R7, -N(R6)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -C(O)R7, -C(O)-C 1-4 Straight or branched alkylene -R7, -C(O)R7-OR7, -C(O)R7-N(R6)R7, -S(O)2R7, -N(R6)C(O)R7, -N(R6)C(O)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -C(O)N(R6)R7, -C(O)N(R6)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -N(R6)S(O)2R7, -N(R6)S(O)2-C 1-4 Straight-chain or branched-chain alkylenes -R7, -S(O)2N(R6)R7, -S(O)2N(R6)-C 1-4 From linear or branched alkylene-R7 molecules, they are selected independently of each other, where, The alkylene group may be optionally substituted with an OH group. The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, crosslinked cycloalkyl group, heterocrosslinked cycloalkyl group, the bonding ring is optionally substituted with OH, CN, NH2, =O, F, Cl, Br, or one or more groups independently selected from F, Cl, and Br. 1-4 Linear or branched alkyl groups, and C optionally substituted with one or more groups independently selected from F, Cl, and Br. 2-4 Linear or branched alkenyl groups, optionally substituted with one or more groups independently selected from F, Cl, and Br. 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH, C 1-4 Straight-chain or branched-chain alkylene-NH2,C 2-4 Straight-chain or branched-chain alkenylene-NH2, C 2-4 Straight-chain or branched-chain alkynylene-NH2, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, C(O)OC 2-4 Linear or branched alkenyl group, C(O)OC 2-4 Linear or branched alkynyl groups, -C(O)R7, -S(O)2R7, -N(R6)R7, -N(R6)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -N(R6)C(O)R7, -N(R6)C(O)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -N(R6)S(O)2R7, -N(R6)S(O)2-C 1-4 Straight-chain or branched-chain alkylenes -R7, -S(O)2N(R6)R7, -S(O)2N(R6)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -C(O)N(R6)R7, -C(O)N(R6)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -P(O)(R6)2, substituted or unsubstituted carbon 3-7The group is optionally substituted with one or more groups selected from a cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted 3-7 membered heterocycloalkyl group containing 1-3 cycloheteroatoms independently selected from N, O, and S and bonded by C or N, and a substituted or unsubstituted 5-6 membered heteroaryl group containing 1-3 cycloheteroatoms independently selected from N, O, and S and bonded by C or N, where substituted C 3-7 The substituents of cycloalkyl groups, substituted aryl groups, substituted 3-7 member heterocycloalkyl groups, and substituted 5-6 member heteroaryl groups may be optionally substituted with OH, CN, NH2, =O, F, Cl, Br, or one or more groups independently selected from F, Cl, and Br. 1-4 C optionally substituted with linear or branched alkyl groups, or one or more groups independently selected from F, Cl, and Br. 2-4 Linear or branched alkenyl groups, optionally substituted with one or more groups independently selected from F, Cl, and Br. 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH, C 1-4 Straight-chain or branched-chain alkylene-NH2,C 2-4 Straight-chain or branched-chain alkenylene-NH2, C 2-4 Straight-chain or branched-chain alkynylene-NH2, C 1-4 Selected from linear or branched alkyloxy groups, the two substituents on the same ring carbon atom of the above cycloalkyl, heterocycloalkyl, and heteroaryl groups may optionally be C along with the carbon atom to which they are bonded. 3-6 A cycloalkyl group or a 3-6 membered heterocycloalkyl group containing one cycloheteroatom selected from N and O is formed, and the formed cycloalkyl group or heterocycloalkyl group can independently be OH, CN, NH2, =O, F, Cl, Br, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH, C 1-4 Straight-chain or branched-chain alkylene-NH2,C 2-4 Straight-chain or branched-chain alkenylene-NH2, C 2-4 Straight-chain or branched-chain alkynylene-NH2, C 1-4 Linear or branched alkyloxy group, C 3-6 Optionally substituted with one or more groups independently selected from a cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1 to 3 cycloheteratoons independently selected from N, O, and S, R6 is H, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Selected from linear or branched alkynyl groups, R7 independently contains H, OH, NH2, and C. 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Linear or branched alkyloxy group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 3-7 Selected from a cycloalkyl group, a 3-7 membered heterocycloalkyl group containing 1-3 cycloheteroatoms independently selected from N, O, and S and bonded by C or N, an aryl group, and a 5-11 membered heteroaryl group containing 1-3 cycloheteroatoms independently selected from N, O, and S, wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are independently F, Cl, Br, OH, CN, NH2, =O, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH,-C(O)OC 1-4A linear or branched alkyl group, C(O)OC 2-4 A linear or branched alkenyl group, C(O)OC 2-4 A linear or branched alkynyl group, C(O)NHC 1-4 A linear or branched alkyl group, C(O)NHC 2-4 A linear or branched alkenyl group, C(O)NHC 2-4 Optionally substituted by one or more groups selected from linear or branched alkynyl groups, m is selected from 1 or 2.

[0010] In some preferred embodiments, in the compound of formula I above,

[0011]

Chemical formula

[0012] Here, A is selected from 5-membered heteroaryl groups containing 1 to 3 cycloheteroatoms independently selected from N, O and S, Z and T are independently selected from C and N, X and Y are independently selected from CRaRb, NRc, O, Ra and Rb are independently H, OH, NH2, C 1-4 A linear or branched alkyl group, C 2-4 A linear or branched alkenyl group, C 2-4 A linear or branched alkynyl group, C 1-4 Selected from linear or branched alkyloxy groups, or Ra and Rb together with the carbon atom to which they are attached form a C 3-7 Cycloalkyl group, or a 3- to 7-membered heterocycloalkyl group containing 1 to 3 cycloheteroatoms independently selected from N, O and S, Rc is H, C 1-4 A linear or branched alkyl group, C 2-4 A linear or branched alkenyl group, C 3-7 Selected from cycloalkyl groups, R2, R3, R4, R5 are independently H, F, Cl, Br, CN, C 1-4Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 3-7 Selected from cycloalkyl groups, R1 is F, Cl, Br, CN, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 3-7 Cycloalkyl groups, 3-7 membered heterocycloalkyl groups containing 1-3 cycloheteratoms independently selected from N, O, and S and bonded by C or N, aryl groups, 5-11 membered heteroaryl groups containing 1-3 cycloheteratoms independently selected from N, O, and S, C 5-7 A 5-7 member heterocrosslinked cycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member alkane ring; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a benzene ring and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 5-7 member heteroaromatic ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; -C 1-4 Straight-chain or branched-chain alkylenes -R7, -OR7, -OC 1-4 Straight-chain or branched-chain alkylenes -R7, -SR7, -SC 1-4 Straight-chain or branched-chain alkylenes -R7, -N(R6)R7, -N(R6)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -C(O)R7, -C(O)-C 1-4Straight or branched alkylene -R7, -C(O)R7-OR7, -C(O)R7-N(R6)R7, -S(O)2R7, -N(R6)C(O)R7, -N(R6)C(O)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -C(O)N(R6)R7, -C(O)N(R6)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -N(R6)S(O)2R7, -N(R6)S(O)2-C 1-4 Straight-chain or branched-chain alkylenes -R7, -S(O)2N(R6)R7, -S(O)2N(R6)-C 1-4 From linear or branched alkylene-R7 molecules, they are selected independently of each other, where, The alkylene group may be optionally substituted with an OH group. The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, crosslinked cycloalkyl group, heterocrosslinked cycloalkyl group, the bonding ring is optionally substituted with OH, CN, NH2, =O, F, Cl, Br, or one or more groups independently selected from F, Cl, and Br. 1-4 Linear or branched alkyl groups, and C optionally substituted with one or more groups independently selected from F, Cl, and Br. 2-4 Linear or branched alkenyl groups, optionally substituted with one or more groups independently selected from F, Cl, and Br. 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH, C 1-4 Straight-chain or branched-chain alkylene-NH2,C 2-4 Straight-chain or branched-chain alkenylene-NH2, C 2-4 Straight-chain or branched-chain alkynylene-NH2, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, C(O)OC 2-4 Linear or branched alkenyl group, C(O)OC 2-4 Linear or branched alkynyl groups, -C(O)R7, -S(O)2R7, -N(R6)R7, -N(R6)-C 1-4Straight-chain or branched-chain alkylenes -R7, -N(R6)C(O)R7, -N(R6)C(O)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -N(R6)S(O)2R7, -N(R6)S(O)2-C 1-4 Straight-chain or branched-chain alkylenes -R7, -S(O)2N(R6)R7, -S(O)2N(R6)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -C(O)N(R6)R7, -C(O)N(R6)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -P(O)(R6)2, C 3-7 The cycloalkyl group is optionally substituted with one or more groups independently selected from a 3-7 membered heterocycloalkyl group comprising 1 to 3 cycloheteratoons independently selected from N, O, and S, bonded by C or N, and the two substituents on the same ring carbon atom of the cycloalkyl group, heterocycloalkyl group, or heteroaryl group are optionally bonded to the carbon atom with C 3-6 A cycloalkyl group or a 3-6 membered heterocycloalkyl group containing one cycloheteratom selected from N and O is formed, and the formed cycloalkyl group or heterocycloalkyl group can independently be OH, CN, NH2, =O, F, Cl, Br, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH, C 1-4 Straight-chain or branched-chain alkylene-NH2,C 2-4 Straight-chain or branched-chain alkenylene-NH2, C 2-4 Straight-chain or branched-chain alkynylene-NH2, C 1-4 Linear or branched alkyloxy group, C 3-6 Optionally substituted with one or more groups selected from cycloalkyl groups or 3-6 membered heterocycloalkyl groups containing 1 to 3 cycloheteratoons independently selected from N, O, and S, R6 is H, C 1-4 Linear or branched alkyl groups, C 2-4Linear or branched alkenyl group, C 2-4 Selected from linear or branched alkynyl groups, R7 independently contains H, OH, NH2, and C. 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Linear or branched alkyloxy group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 3-7 Selected from a cycloalkyl group, a 3-7 membered heterocycloalkyl group containing 1-3 cycloheteroatoms independently selected from N, O, and S and bonded by C or N, an aryl group, and a 5-6 membered heteroaryl group containing 1-3 cycloheteroatoms independently selected from N, O, and S, wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are independently F, Cl, Br, OH, CN, NH2, =O, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH,-C(O)OC 1-4 Linear or branched alkyl groups, C(O)OC 2-4 Linear or branched alkenyl group, C(O)OC 2-4 Linear or branched alkynyl group, C(O)NHC 1-4 Linear or branched alkyl groups, C(O)NHC 2-4 Linear or branched alkenyl group, C(O)NHC 2-4 It is optionally substituted with one or more groups selected from linear or branched alkynyl groups. m is selected from 1 or 2.

[0013] In a preferred embodiment,

[0014] [ka]

[0015] is

[0016] [Chem.]

[0017] selected from, and the definitions of X, Y, R1, m, R2, R3, R4, and R5 are as defined for the compound of formula (I) above.

[0018] In a more preferred embodiment, X and Y are CRaRb, and the definitions of R1, m, R2, R3, R4, R5, Ra, and Rb are as defined for the compound of formula (I) above.

[0019] In one preferred embodiment, the present application provides a compound represented by formula (II) or a pharmaceutically acceptable salt or deuteride thereof:

[0020] [Chem.]

[0021] where R1 is C 1-4 a straight-chain or branched-chain alkyl group, C 2-4 a straight-chain or branched-chain alkenyl group, C 2-4 a straight-chain or branched-chain alkynyl group, C 3-6 a cycloalkyl group, a 3- to 6-membered heterocycloalkyl group containing 1 to 3 cycloheteroatoms independently selected from N, O, and S bonded through C or N, a phenyl group, a 5- to 11-membered heteroaryl group containing 1 to 3 cycloheteroatoms independently selected from N, O, and S, C 5-7A 5-7 member heterocrosslinked cycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member alkane ring; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a benzene ring and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 5-7 member heteroaromatic ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; -C 1-4 Straight-chain or branched-chain alkylenes -R7, -OR7, -OC 1-4 Straight-chain or branched-chain alkylenes -R7, -SR7, -SC 1-4 Straight-chain or branched-chain alkylenes -R7, -N(R6)R7, -N(R6)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -C(O)R7, -C(O)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -N(R6)C(O)R7, -N(R6)C(O)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -C(O)N(R6)R7, -C(O)N(R6)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -N(R6)S(O)2R7, -N(R6)S(O)2-C 1-4 Straight-chain or branched-chain alkylenes -R7, -S(O)2N(R6)R7, -S(O)2N(R6)-C 1-4 Selected from linear or branched alkylene-R7, where, The alkylene group may be optionally substituted with an OH group. The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, heteroaryl group, crosslinked cycloalkyl group, heterocrosslinked cycloalkyl group, and the bonding ring are optionally substituted with one or more groups independently selected from OH, CN, NH2, =O, F, Cl, Br, and independently from F, Cl, Br. 1-4 Linear or branched alkyl groups, and C optionally substituted with one or more groups independently selected from F, Cl, and Br. 2-4 Linear or branched alkenyl groups, optionally substituted with one or more groups independently selected from F, Cl, and Br. 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, C(O)OC 2-4 Linear or branched alkenyl group, C(O)OC 2-4 Linear or branched alkynyl group, C(O)NHC 1-4 Linear or branched alkyl groups, C(O)NHC 2-4 Linear or branched alkenyl group, C(O)NHC 2-4 Linear or branched alkynyl group, -C(O)R7, substituted or unsubstituted C 3-7 Optionally substituted with one or more groups selected from cycloalkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted 3-7 membered heterocycloalkyl groups containing 1-3 cycloheteroatoms independently selected from N, O, and S and bonded by C or N, and substituted or unsubstituted 5-6 membered heteroaryl groups containing 1-3 cycloheteroatoms independently selected from N, O, and S and bonded by C or N, where substituted C 3-7 The substituents of cycloalkyl groups, substituted aryl groups, substituted 3-7 member heterocycloalkyl groups, and substituted 5-6 member heteroaryl groups are optionally substituted with OH, CN, NH2, =O, F, Cl, Br, or one or more groups independently selected from F, Cl, and Br. 1-4 Linear or branched alkyl groups, C1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Straight-chain or branched-chain alkylene-NH2,C 2-4 Straight-chain or branched-chain alkenylene-NH2, C 2-4 Straight-chain or branched-chain alkynylene-NH2, C 1-4 Selected from linear or branched alkyloxy groups, R6 is H, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Selected from linear or branched alkynyl groups, R7 is C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 3-6 The alkyl group is selected from a cycloalkyl group, a 3-6 membered heterocycloalkyl group containing 1-3 cycloheteroatoms independently selected from N, O, and S bonded by C or N, a phenyl group, and a 5-11 membered heteroaryl group containing 1-3 cycloheteroatoms independently selected from N, O, and S. The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are independently OH, CN, NH2, =O, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH,-C(O)OC 1-4 Linear or branched alkyl groups, C(O)OC 2-4 Linear or branched alkenyl group, C(O)OC 2-4 Linear or branched alkynyl group, C(O)NHC 1-4 Linear or branched alkyl groups, C(O)NHC 2-4 Linear or branched alkenyl group, C(O)NHC 2-4 It is optionally substituted with one or more groups selected from linear or branched alkynyl groups. R2 and R3 are independently selected from F, Cl, and Br. R4 and R5 are H.

[0022] In some preferred embodiments of the present application, the above formula II compound is

[0023] [ka]

[0024] Here, R1 is C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocycloalkyl groups containing 1-3 cycloheteratoms independently selected from N, O, and S bonded by C or N, phenyl groups, 5-11 membered heteroaryl groups containing 1-3 cycloheteratoms independently selected from N, O, and S, -C 1-4 Straight-chain or branched-chain alkylenes -R7, -OR7, -OC 1-4 Straight-chain or branched-chain alkylenes -R7, -SR7, -SC 1-4 Straight-chain or branched-chain alkylenes -R7, -N(R6)R7, -N(R6)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -C(O)R7, -C(O)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -N(R6)C(O)R7, -N(R6)C(O)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -C(O)N(R6)R7, -C(O)N(R6)-C 1-4 Straight-chain or branched-chain alkylenes -R7, -N(R6)S(O)2R7, -N(R6)S(O)2-C 1-4 Straight-chain or branched-chain alkylenes -R7, -S(O)2N(R6)R7, -S(O)2N(R6)-C 1-4Selected from linear or branched alkylene-R7, the alkylene group is optionally substituted with OH, and the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, heteroaryl group are independently OH, CN, NH2, =O, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH,-C(O)OC 1-4 Linear or branched alkyl groups, C(O)OC 2-4 Linear or branched alkenyl group, C(O)OC 2-4 Linear or branched alkynyl group, C(O)NHC 1-4 Linear or branched alkyl groups, C(O)NHC 2-4 Linear or branched alkenyl group, C(O)NHC 2-4 It is optionally substituted with one or more groups selected from linear or branched alkynyl groups. R6 is H, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Selected from linear or branched alkynyl groups, R7 is C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 3-6 The alkyl group is selected from a cycloalkyl group, a 3-6 membered heterocycloalkyl group containing 1-3 cycloheteroatoms independently selected from N, O, and S bonded by C or N, a phenyl group, and a 5-11 membered heteroaryl group containing 1-3 cycloheteroatoms independently selected from N, O, and S. The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are independently OH, CN, NH2, =O, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C2-4 A linear or branched alkynyl group, C 1-4 A linear or branched alkylene-OH, C 2-4 A linear or branched alkenylene-OH, C 2-4 A linear or branched alkynylene-OH, -C(O)OC 1-4 A linear or branched alkyl group, C(O)OC 2-4 A linear or branched alkenyl group, C(O)OC 2-4 A linear or branched alkynyl group, C(O)NHC 1-4 A linear or branched alkyl group, C(O)NHC 2-4 A linear or branched alkenyl group, C(O)NHC 2-4 Optionally substituted by one or more groups selected from linear or branched alkynyl groups, R2 and R3 are independently selected from F, Cl, Br, R4 and R5 are H.

[0025] In a more preferred embodiment, in formula II, R1 is C 1-4 A linear or branched alkyl group, C 3-6 A cycloalkyl group, a 3-6 member heterocycloalkyl group containing 1-3 cycloheteroatoms independently selected from N, O and S bonded by C or N,

[0026]

Chemical formula

[0027] , pyridine,

[0028]

Chemical formula

[0029] , -C 1-4 A linear or branched alkylene-R7, -OR7, -SR7, -S-C 1-4Linear or branched alkylene selected from -R7, -N(R6)R7, -C(O)R7, -N(R6)C(O)R7, -C(O)N(R6)R7, -N(R6)S(O)2R7, -S(O)2N(R6)R7, wherein the alkylene group is optionally substituted with OH, and the alkyl group, cycloalkyl group, heterocycloalkyl group,

[0030] [ka]

[0031] , pyridine,

[0032] [ka]

[0033] These are independently OH, CN, NH2, =O, and C. 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylenes -OH, -C(O)OC 1-4 Linear or branched alkyl groups, C(O)NHC 1-4 Optionally substituted with one or more groups selected from linear or branched alkyl groups, R6 is H, C 1-4 Selected from linear or branched alkyl groups, R7 is C 1-4 Linear or branched alkyl groups, C 3-6 Cycloalkyl groups, 3-6 membered heterocycloalkyl groups containing 1-3 cycloheteratoms independently selected from N, O, and S bonded by C or N,

[0034] [ka]

[0035] , pyridine,

[0036] [ka]

[0037] Selected from the above alkyl groups, cycloalkyl groups, heterocycloalkyl groups,

[0038] [ka]

[0039] , pyridine,

[0040] [ka]

[0041] These are independently OH, CN, NH2, =O, and C. 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylenes -OH, -C(O)OC 1-4 Linear or branched alkyl groups, C(O)NHC 1-4 Optionally substituted with one or more groups selected from linear or branched alkyl groups, R2 and R3 are independently selected from F, Cl, and Br. R4 and R5 are H.

[0042] In a more preferred embodiment, in formula II, R1 is a carbon atom substituted with one or more OH groups. 1-4 It is a linear or branched alkyl group, R2 and R3 are independently selected from F, Cl, and Br. R4 and R5 are H.

[0043] In a more preferred embodiment, in formula II, R1 is a carbon atom substituted with one OH group. 1-4 It is a linear or branched alkyl group, R2 and R3 are Cl, R4 and R5 are H.

[0044] In some other preferred embodiments of the present application, a compound represented by formula (II)

[0045] [ka]

[0046] In, R1 is C 1-4 Linear or branched alkyl groups, C 3-6 Cycloalkyl groups, 3-6 membered heterocycloalkyl groups containing 1-3 cycloheteratoms independently selected from N, O, and S bonded by C or N, phenyl groups, 5-11 membered heteroaryl groups containing 1-3 cycloheteratoms independently selected from N, O, and S, C 5-7 A 5-7 member heterocrosslinked cycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member alkane ring; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a benzene ring and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 5-7 member heteroaromatic ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; -C 1-4 Straight-chain or branched-chain alkylenes -R7, -OR7, -OC 1-4 Straight-chain or branched-chain alkylenes -R7, -C(O)R7, -C(O)-C 1-4 Selected from linear or branched alkylene-R7, where, The alkylene group may be optionally substituted with an OH group. The alkyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, heteroaryl group, crosslinked cycloalkyl group, heterocrosslinked cycloalkyl group, and the bonding ring are optionally substituted with one or more groups independently selected from OH, CN, NH2, =O, F, Cl, Br, and independently from F, Cl, Br. 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, -C(O)R7, substituted or unsubstituted C 3-7 Optionally substituted by one or more groups selected from substituted or unsubstituted 3-7 membered heterocycloalkyl groups, each containing 1 to 3 cycloheteratoons independently selected from cycloalkyl groups, N, O, and S, bonded by C or N, where substituted C 3-7 The substituents of cycloalkyl groups and substituted 3-7 member heterocycloalkyl groups are optionally substituted with OH, CN, NH2, =O, F, Cl, Br, or one or more groups independently selected from F, Cl, and Br. 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Straight-chain or branched-chain alkylene-NH2,C 1-4 Selected from linear or branched alkyloxy groups, R7 is C 1-4 Linear or branched alkyl groups, C 3-6 The alkyl group is selected from a cycloalkyl group, a 3-6 membered heterocycloalkyl group containing 1-3 cycloheteroatoms independently selected from N, O, and S bonded by C or N, a phenyl group, and a 5-11 membered heteroaryl group containing 1-3 cycloheteroatoms independently selected from N, O, and S, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are independently OH, C 1-4 Linear or branched alkyl groups, C 1-4 Optionally substituted with one or more groups selected from linear or branched alkylene-OH groups, R2 and R3 are independently selected from F, Cl, and Br. R4 and R5 are H.

[0047] In a more preferred embodiment, in formula (II), R1 is C 1-4 Linear or branched alkyl groups, C 3-6 Cycloalkyl groups, 3-6 membered heterocycloalkyl groups containing 1-2 cycloheteratoms independently selected from N and O linked by C or N, phenyl groups,

[0048] [ka]

[0049] , pyridine,

[0050] [ka]

[0051] , a 5-7 member heterobridged cycloalkyl group containing one cycloheteratom O, a bonding ring formed from a 3-7 member heteroalkyl ring containing one cycloheteratom O and a 3-7 member alkane ring, -C 1-4 Selected from linear or branched alkylenes -R7, -OR7, and -C(O)R7, where the alkyl group, cycloalkyl group, heterocycloalkyl group, and phenyl group are listed above.

[0052] [ka]

[0053] , pyridine,

[0054] [ka]

[0055] The heterocrosslinked cycloalkyl groups and their connecting rings are independently OH, CN, NH2, =O, F, Cl, Br, and C. 1-4 Linear or branched alkyl groups, C 1-4Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, -C(O)R7, substituted or unsubstituted C 3-7 Optionally substituted with one or more groups selected from cycloalkyl groups and 3-7 membered heterocycloalkyl groups containing 1-2 cycloheteratoons independently selected from substituted or unsubstituted C or N, where substituted C 3-7 The substituents of the cycloalkyl group and the substituted 3-7 member heterocycloalkyl group are optionally substituted with one or more groups independently selected from F, Cl, and Br. 1-4 Selected from linear or branched alkyl groups, R7 is C 1-4 Linear or branched alkyl groups, C 3-6 The alkyl group is selected from a cycloalkyl group, a 3-6 membered heterocycloalkyl group containing 1-2 cycloheteratoons independently selected from N and O bonded by C or N, and the alkyl group, cycloalkyl group, and heterocycloalkyl group independently contain OH and C 1-4 Optionally substituted with one or more groups selected from linear or branched alkyl groups, R2 and R3 are independently selected from F, Cl, and Br. R4 and R5 are H.

[0056] In a more preferred embodiment, in formula (II), R1 is C 3-6 The cycloalkyl group is selected from a 3-6 member heterocycloalkyl group containing 1-2 cycloheteratoons independently selected from N and O bonded by C or N, where the cycloalkyl group and heterocycloalkyl group are independently OH, CN, NH2, =O, F, Cl, Br, C 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, -C(O)R7, substituted or unsubstituted C 3-6Optionally substituted with one or more groups selected from cycloalkyl groups and 3-6 membered heterocycloalkyl groups containing 1-2 cycloheteratoons independently selected from substituted or unsubstituted C or N bonds, where substituted C 3-6 The substituents of the cycloalkyl group and the substituted 3-6 member heterocycloalkyl group are optionally substituted with one or more groups independently selected from F, Cl, and Br. 1-4 Selected from linear or branched alkyl groups, R7 is C 1-4 Linear or branched alkyl groups, C 3-6 The alkyl group is selected from a cycloalkyl group, a 3-6 membered heterocycloalkyl group containing 1-2 cycloheteratoons independently selected from N and O bonded by C or N, and the alkyl group, cycloalkyl group, and heterocycloalkyl group independently contain OH and C 1-4 Optionally substituted with one or more groups selected from linear or branched alkyl groups, R2 and R3 are independently selected from F, Cl, and Br. R4 and R5 are H.

[0057] In one preferred embodiment of the present application, the present application further provides a compound represented by formula III or a pharmaceutically acceptable salt or deuterated thereof:

[0058] [ka]

[0059] Here, R1 is C 1-4 Linear or branched alkyl groups, C 3-6 Cycloalkyl groups, 3-6 membered heterocycloalkyl groups containing 1-3 cycloheteratoms independently selected from N, O, and S bonded by C or N, C 5-7The alkyl group is selected from a 5-7 membered heterocrosslinked cycloalkyl group containing a crosslinked cycloalkyl group and 1-3 cycloheteroatoms independently selected from N, O, and S, where the alkyl group, cycloalkyl group, heterocycloalkyl group, crosslinked cycloalkyl group, and heterocrosslinked cycloalkyl group are independently OH, CN, NH2, =O, F, Cl, Br, C 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkyloxy groups, substituted or unsubstituted C 3-7 Optionally substituted by one or more groups selected from substituted or unsubstituted 3-7 membered heterocycloalkyl groups, each containing 1 to 3 cycloheteratoons independently selected from cycloalkyl groups, N, O, and S, bonded by C or N, where substituted C 3-7 The substituents of the cycloalkyl group and the substituted 3-7 member heterocycloalkyl group are optionally substituted with one or more groups independently selected from F, Cl, and Br. 1-4 Selected from linear or branched alkyl groups, R2 and R3 are independently selected from F, Cl, and Br. R4 and R5 are H.

[0060] In a more preferred embodiment, in formula III, R1 is C 1-4 Linear or branched alkyl groups, C 3-6 The alkyl group is selected from a cycloalkyl group, a 3-6 membered heterocycloalkyl group containing 1-2 cycloheteratoms independently selected from N and O bonded by C or N, where the alkyl group, cycloalkyl group, and heterocycloalkyl group are independently selected from F, Cl, Br, and C. 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Optionally substituted with one or more groups selected from linear or branched alkyloxy groups, R2 and R3 are independently selected from F, Cl, and Br. R4 and R5 are H.

[0061] In one preferred embodiment of the present application, the present application further provides a compound represented by formula IV or a pharmaceutically acceptable salt or deuterated thereof:

[0062] [ka]

[0063] Here, R1 is C 1-4 Linear or branched alkyl groups, C 3-6 Cycloalkyl groups, 3-6 membered heterocycloalkyl groups containing 1-3 cycloheteratoms independently selected from N, O, and S bonded by C or N, phenyl groups, 5-11 membered heteroaryl groups containing 1-3 cycloheteratoms independently selected from N, O, and S, C 5-7 A 5-7 member heterocrosslinked cycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member alkane ring; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a benzene ring and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 5-7 member heteroaromatic ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; -C 1-4 Straight-chain or branched-chain alkylenes -R7, -OR7, -OC 1-4 Straight-chain or branched-chain alkylenes -R7, -C(O)R7, -C(O)-C 1-4 Selected from linear or branched alkylene-R7, where, The alkylene group may be optionally substituted with an OH group. The alkyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, heteroaryl group, crosslinked cycloalkyl group, heterocrosslinked cycloalkyl group, and bonding ring are independently OH, CN, NH2, =O, F, Cl, Br, C 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, -C(O)R7, substituted or unsubstituted C 3-7 Optionally substituted by one or more groups selected from substituted or unsubstituted 3-7 membered heterocycloalkyl groups, each containing 1 to 3 cycloheteratoons independently selected from cycloalkyl groups, N, O, and S, bonded by C or N, where substituted C 3-7 The substituents of cycloalkyl groups and substituted 3-7 member heterocycloalkyl groups are optionally substituted with OH, CN, NH2, =O, F, Cl, Br, or one or more groups independently selected from F, Cl, and Br. 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Straight-chain or branched-chain alkylene-NH2,C 1-4 Selected from linear or branched alkyloxy groups, R7 is C 1-4 Linear or branched alkyl groups, C 3-6 The alkyl group is selected from a cycloalkyl group, a 3-6 membered heterocycloalkyl group containing 1-3 cycloheteroatoms independently selected from N, O, and S bonded by C or N, a phenyl group, and a 5-11 membered heteroaryl group containing 1-3 cycloheteroatoms independently selected from N, O, and S, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are independently OH, C 1-4 Linear or branched alkyl groups, C 1-4 Optionally substituted with one or more groups selected from linear or branched alkylene-OH groups, R2 and R3 are independently selected from F, Cl, and Br. R4 and R5 are H.

[0064] In a more preferred embodiment, in formula IV, R1 is C 1-4 Linear or branched alkyl groups, C 3-6 Cycloalkyl groups, 3-6 membered heterocycloalkyl groups containing 1-2 cycloheteratoms independently selected from N and O linked by C or N, phenyl groups,

[0065] [ka]

[0066] , pyridine,

[0067] [ka]

[0068] , a 5-7 member heterobridged cycloalkyl group containing one cycloheteratom O, a bonding ring formed from a 3-7 member heteroalkyl ring containing one cycloheteratom O and a 3-7 member alkane ring, -C 1-4 Selected from linear or branched alkylenes -R7, -C(O)R7, and -OR7, where the alkyl group, cycloalkyl group, heterocycloalkyl group, and phenyl group are listed above.

[0069] [ka]

[0070] , pyridine,

[0071] [ka]

[0072] The heterocrosslinked cycloalkyl groups and their connecting rings are independently OH, CN, NH2, =O, F, Cl, Br, and C. 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, -C(O)R7, substituted or unsubstituted C 3-7 Optionally substituted with one or more groups selected from cycloalkyl groups and 3-7 membered heterocycloalkyl groups containing 1-2 cycloheteratoons independently selected from substituted or unsubstituted C or N, where substituted C 3-7 The substituents of the cycloalkyl group and the substituted 3-7 member heterocycloalkyl group are optionally substituted with one or more groups independently selected from F, Cl, and Br. 1-4 Selected from linear or branched alkyl groups, R7 is C 1-4 Linear or branched alkyl groups, C 3-6 The alkyl group is selected from a cycloalkyl group, a 3-6 membered heterocycloalkyl group containing 1-2 cycloheteratoons independently selected from N and O bonded by C or N, and the alkyl group, cycloalkyl group, and heterocycloalkyl group independently contain OH and C 1-4 Optionally substituted with one or more groups selected from linear or branched alkyl groups, R2 and R3 are independently selected from F, Cl, and Br. R4 and R5 are H.

[0073] In a more preferred embodiment, in formula IV, R1 is C 1-4 Linear or branched alkyl groups, C 3-6 Cycloalkyl groups, 3-6 membered heterocycloalkyl groups containing 1-2 cycloheteratoms independently selected from N and O linked by C or N, phenyl groups,

[0074] [ka]

[0075] , -C 1-4 Selected from linear or branched alkylenes -R7, -C(O)R7, and -OR7, where the alkyl group, cycloalkyl group, heterocycloalkyl group, and phenyl group are listed above.

[0076] [ka]

[0077] These are independently OH, CN, NH2, =O, F, Cl, Br, C 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Optionally substituted with one or more groups selected from linear or branched alkyl groups, R7 is C 1-4 Linear or branched alkyl groups, C 3-6 The alkyl group is selected from a cycloalkyl group, a 3-6 membered heterocycloalkyl group containing 1-2 cycloheteratoons independently selected from N and O bonded by C or N, and the alkyl group, cycloalkyl group, and heterocycloalkyl group independently contain OH and C 1-4 Optionally substituted with one or more groups selected from linear or branched alkyl groups, R2 and R3 are independently selected from F, Cl, and Br. R4 and R5 are H.

[0078] In some other preferred embodiments, the present application further provides compounds represented by formulas V and V' or pharmaceutically acceptable salts and deuterides thereof:

[0079] [ka]

[0080] Here, In equations V and V', R1 may be the same or different, and H and C are independent. 1-4 Linear or branched alkyl groups, C 3-6Cycloalkyl groups, 3-6 membered heterocycloalkyl groups containing 1-3 cycloheteratoms independently selected from N, O, and S bonded by C or N, phenyl groups, 5-11 membered heteroaryl groups containing 1-3 cycloheteratoms independently selected from N, O, and S, C 5-7 A 5-7 member heterocrosslinked cycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member alkane ring; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a benzene ring and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 5-7 member heteroaromatic ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; -C 1-4 Straight-chain or branched-chain alkylenes -R7, -OR7, -OC 1-4 Straight-chain or branched-chain alkylenes -R7, -C(O)R7, -C(O)-C 1-4 Selected from linear or branched alkylene-R7, where, The alkylene group may be optionally substituted with an OH group. The alkyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, heteroaryl group, crosslinked cycloalkyl group, heterocrosslinked cycloalkyl group, and bonding ring are independently OH, CN, NH2, =O, F, Cl, Br, C 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, -C(O)R7, substituted or unsubstituted C 3-7Optionally substituted by one or more groups selected from substituted or unsubstituted 3-7 membered heterocycloalkyl groups, each containing 1 to 3 cycloheteratoons independently selected from cycloalkyl groups, N, O, and S, bonded by C or N, where substituted C 3-7 The substituents of cycloalkyl groups and substituted 3-7 member heterocycloalkyl groups are optionally substituted with OH, CN, NH2, =O, F, Cl, Br, or one or more groups independently selected from F, Cl, and Br. 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Straight-chain or branched-chain alkylene-NH2,C 1-4 Selected from linear or branched alkyloxy groups, R7 is C 1-4 Linear or branched alkyl groups, C 3-6 The alkyl group is selected from a cycloalkyl group, a 3-6 membered heterocycloalkyl group containing 1-3 cycloheteroatoms independently selected from N, O, and S bonded by C or N, a phenyl group, and a 5-11 membered heteroaryl group containing 1-3 cycloheteroatoms independently selected from N, O, and S, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are independently OH, C 1-4 Linear or branched alkyl groups, C 1-4 Optionally substituted with one or more groups selected from linear or branched alkylene-OH groups, R2 and R3 are independently selected from F, Cl, and Br. R4 and R5 are H.

[0081] In a more preferred embodiment, in formulas V and V', R1 can be the same or different, and H and C are independent. 1-4 Linear or branched alkyl groups, C 3-6 The alkyl group is selected from a cycloalkyl group, a 3-6 member heterocycloalkyl group containing 1-2 cycloheteratoms independently selected from N and O bonded by C or N, and a phenyl group, where the alkyl group, cycloalkyl group, heterocycloalkyl group, and phenyl group are independently selected from OH, F, Cl, Br, and C. 1-4Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Optionally substituted with one or more groups selected from linear or branched alkyloxy groups, R2 and R3 are independently selected from F, Cl, and Br. R4 and R5 are H.

[0082] In a more preferred embodiment, in formulas V and V', R1 can be the same or different, and H and C are independent. 1-4 Selected from linear or branched alkyl groups, where the alkyl group is independently OH, F, Cl, Br, C 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Optionally substituted with one or more groups selected from linear or branched alkyloxy groups, R2 and R3 are independently selected from F, Cl, and Br. R4 and R5 are H.

[0083] In preferred embodiments, the compounds of the present application are selected from the following compounds or their pharmaceutically acceptable salts and deuterides:

[0084] [ka]

[0085] [ka]

[0086] [ka]

[0087] In this application, substituents are disclosed as a group or range, but the group or range of groups in this application refers specifically to each specific group included therein. For example, the term “C1-4 alkyl group” refers specifically to the independently disclosed methyl group (i.e., C1 alkyl group), ethyl group (i.e., C2 alkyl group), propyl group (i.e., C3 alkyl group), and butyl group (i.e., C4 alkyl group).

[0088] In this application, "C 3-6 Examples of "cycloalkyl groups" include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0089] In this application, "C 3-7 Examples of "cycloalkyl groups" include the cycloheptyl group in addition to those listed above.

[0090] In this application, examples of "3-6 membered heterocycloalkyl groups containing 1 to 3 cycloheteratoms independently selected from N, O, and S" include, but are not limited to, oxirane, ethylene sulfide, azacyclopropane, oxetane, azetidine, α-lactam ring, β-lactam ring, β-lactone, tetrahydrofuran, thiocyclopentane, pyrrolidine, pyrroline, dioxolane, oxazolidine, oxazoline, isoxazolidine, thiazolidine, isothiazolin, thiazoline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, tetrahydropyran, dihydropyran, pyran, piperidine, 1,4-dioxane, morpholine, piperazine, 1,4-oxazepane, 1,4-thiazepane, etc.

[0091] In this application, "a 3-6 membered heterocycloalkyl group comprising 1 to 3 cycloheteratoms independently selected from N, O, and S bonded by C or N" means that the heterocycloalkyl group is bonded to another group via its ring C or ring N.

[0092] In this application, examples of "3-7 membered heterocycloalkyl groups containing 1 to 3 cycloheteroatoms independently selected from N, O, and S" include, but are not limited to, those listed above, azacycloheptane, epoxyhexane, thiepan, etc.

[0093] In this application, examples of "aryl group" include, but are not limited to, phenyl group, naphthyl group, tetrahydronaphthyl group, phenanthryl group, benzonaphthyl group, and fluorenyl group.

[0094] In this application, examples of a "five-membered heteroaryl group containing one to three cycloheteroatoms independently selected from N, O, and S" include, but are not limited to, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxadiazole, and thiadiazole.

[0095] In this application, examples of a "5-11 membered heteroaryl group containing 1 to 3 cycloheteratoms independently selected from N, O, and S" include, in addition to those listed above, pyridine, pyridine, pyrimidine, pyrimidine, pyridazine, pyridazine, pyridazine, pyrazine, triazine, benzazetidine, benzoβ-lactam ring, benzoβ-lactone, benzodioxol, benzofuran, benzothiophene, indole, indazole, isoindazole, benzimidazole, benzothiazole, benzoisothiazole, benzoxazole, benzisoxazole, benzotriazole, benzoxadiazole, benzothiadiazole, benzodioxane, benzomorpholine, benzopiperidine, benzopyran, benzo This includes, but is not limited to, pyridine, benzopyrimidine, benzotriazine, benzoazacyclohexanone, benzoazacycloheptanone, pyridoazetidinyl, pyrido β-lactam ring, pyrido β-lactone, pyridooxadiene, pyridofuran, pyridothiophene, pyridopyrrole, pyridopyrazole, pyridoimidazole, pyridothiazole, pyridoisothiazole, pyridoxazole, pyridoisoxazole, pyridotriazole, pyridoxadiazole, pyridothiadiazole, pyridodioxane, pyridomorpholine, pyridopiperidine, pyridopyran, pyridopyridine, pyridopyrimidine, pyridotriazine, pyridoazacyclohexanone, phlopyrrole, thiazolopyrimidine, etc.

[0096] In this application, "C 5-7 Examples of "crosslinked cycloalkyl groups" include, but are not limited to, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, and bicyclo[3.1.1]heptane.

[0097] In this application, examples of "5-7 member heterobridged cycloalkyl groups containing 1-3 cycloheteratoms independently selected from N, O, and S" are 2-oxabicyclo[2.2.2]octane, 2-oxabicyclo[2.1.1]hexane, 1-azabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.1]heptane, 7-azabicyclo[2.2.1]heptane, 3,6-diazabicyclo[3.2.2]nonane, 3,6-diazabicyclo[3.1.1]heptane, 3-aza-6-oxabicyclo[ This includes, but is not limited to, [3.1.1]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 3-aza-8-oxabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.2]octane, and 2,5-diazabicyclo[2.2.2]octane.

[0098] In this application, examples of "a bonding ring formed from a 3-7 member heteroalkyl ring containing 1 to 3 cycloheteroatoms independently selected from N, O, and S, and a 3-7 member alkane ring" include, but are not limited to, pyrrolidinocyclopropane, pyrrolidinocyclobutane, pyrrolidinocyclopentane, tetrahydrofuranocypentane, piperidinocyclopropane, piperazinocyclopropane, piperazinocyclobutane, tetrahydropyranocyclopropane, tetrahydropyranocyclohexane, morpholinocyclopropane, and morpholinocyclobutane.

[0099] In this application, examples of "a bonding ring formed from a 3-7 membered heteroalkyl ring containing 1 to 3 cycloheteroatoms independently selected from N, O, and S, and a 3-7 membered heteroalkyl ring containing 1 to 3 cycloheteroatoms independently selected from N, O, and S" include, but are not limited to, pyrrolidinooxetane, pyrrolidinoazetidine, pyrrolidinopyrrolidine, pyrrolidinotetrahydrofuran, tetrahydrofuran, pyrrolidinotetrahydropyran, piperidinooxetane, piperidinoazetidine, piperidinopyrrolidine, piperidinopiperidine, piperazinopiperidine, piperazinopyrrolidine, morpholinoxetane, morpholinoazetidine, morpholinopyrrolidine, etc.

[0100] In this application, examples of "a bonding ring formed from a benzene ring and a 3-7 membered heteroalkyl ring containing 1 to 3 cycloheteratoons independently selected from N, O, and S" include, but are not limited to, benzooxetane, benzotetrahydrofuran, benzopyrrolidine, isatin, 1,3-benzodioxole, 1,4-benzodioxane, benzopiperidine, benzopiperazine, 3,4-dihydro-1H-quinazolin-2-one, 3,4-dihydro-2H-1,4-benzothiazine, 2,3-dihydro-1,4-benzodithiazine, etc.

[0101] In this application, examples of "a bonding ring formed from a 5-7 member heteroaromatic ring containing 1-3 cycloheteroatoms independently selected from N, O, and S, and a 3-7 member heteroalkyl ring containing 1-3 cycloheteroatoms independently selected from N, O, and S" include pyrrolidinothiophene, pyrrolidinofuran, pyrrolidinoimidazole, pyrrolidinopyrazole, pyrrolidinoisoxazole, pyrrolidinothiazole, pyrrolidinotriazole, piperazinoimidazole, piperazinopyrazole, piperazinotriazole, piperazinotetrazole, piperidinooxazole, piperidinothiazole, piperidinoimidazole, piperidinoisoxazole, piperidinopyrazole, piperidinotriazole, pyrazolotetrahydrofuran, pyrazolotetrahydropyran, morphol This includes, but is not limited to, neuridazole, morpholinopyrazole, morpholinothiophene, morpholinothiazole, morpholinoxazole, imidazodihydrothiazine, pyrazolodihydrothiazine, pyridopyrrolidine, pyridopiperidine, pyridopiperazine, pyridodioxane, pyridotetrahydropyran, pyrimidopyrrolidine, pyridotetrahydrofuran, pyrimidopiperazine, pyrimidopiperidine, tetrahydrobenzoazepine, dihydrobenzodioxacycloheptane, tetrahydrobenzoniazepine, tetrahydrobenzoxazepine, tetrahydrobenzothiazepine, tetrahydropyridazepine, pentylenetetrazole, 3,4-propylenedioxythiophene, tetrahydroimidazolide, tetrahydropyrazoloazepine, and others.

[0102] The compounds relating to this application may be asymmetric, for example, having one or more stereocenters. Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are included within the scope of this application. In this application, compounds containing asymmetrically substituted carbon atoms can be isolated in any optically active or racemic form. Various methods for producing optically active forms are known in the art, such as by resolution of racemic mixtures or by stereospecific synthesis.

[0103] This application further includes pharmaceutically acceptable salts of the above compounds. The compounds of this application can be reacted with non-toxic inorganic or organic acids to prepare pharmaceutically acceptable salts. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, hydrogen sulfate, boric acid, hemisulfate, etc. Examples of organic acids include formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, undecanoic acid, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, adipic acid, lactic acid, malic acid, maleic acid, hippuric acid, tartaric acid, citric acid, succinic acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphoric acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, galacturonic acid, dodecyl sulfate, and various amino acids.

[0104] This application further includes hydrates and solvates of the above compound.

[0105] This application further includes all forms in which each atom of the above compound exists in various isotopes. An isotope includes all atoms that have the same atomic number but different mass numbers. For example, the isotopes of hydrogen include deuterium.

[0106] This application further includes a prodrug of the above compound. A "prodrug" refers to a compound that, upon structural modification of the compound of this application, is inactive or has low activity outside the patient's body, but releases the above compound in the body through enzymatic or non-enzymatic transformation, thereby exerting a pharmacokinetic effect.

[0107] Those skilled in the art will understand that the compounds of the present application can be prepared by various methods disclosed in the literature. The compounds of the present application can be prepared by reacting in a suitable solvent, and those skilled in the field of organic synthesis can easily select a suitable solvent that does not react intrinsically with the reactants, intermediates, or products. The reaction can be carried out in one solvent or a mixture of one or more solvents. The compounds of the present application can be prepared by reacting at a suitable temperature, for example, within the range from the freezing point to the boiling point of the solvent. The methods for producing the compounds of the present application involve the protection and deprotection of various chemical groups, and those skilled in the field of organic synthesis can easily determine the need for protection and deprotection of chemical groups and select appropriate protecting groups. The reactions for producing the compounds of the present application can be monitored by any method known in the art, such as nuclear magnetic resonance spectroscopy, infrared spectroscopy, mass spectrometry, and chromatography. The following embodiments 1 to 8 describe the synthetic routes of the compounds of the present application, for example, compounds having the structure of formula I.

[0108] [ka]

[0109] Compounds 1-a, 1-b, and 1-c shown in Embodiment 1 can be produced by any method known in the art and / or purchased commercially. As shown in Embodiment 1, PG refers to a protecting group. Non-limiting examples of protecting groups include methyl, allyl, acetyl, tert-butoxycarbonyl, benzyl, or other protecting groups applicable to OH protecting groups known in the art. Other substituents are defined herein. As shown in Embodiment 1, 1-a can be obtained to 1-c via a two-step reaction of phenol hydroxyl group protection and formylation, 1-c to 1-g via Wittig reaction, nitromethane substitution, nitro group reduction, and intramolecular cyclization, and intermediate 1-h to be obtained by reaction with methyloxonium tetrafluoroborate. Intermediate 1-h is reacted with ethyl carbazate to obtain 1-i, which is then chlorinated with a chlorinating agent (such as phosphorus oxychloride or oxalyl chloride) to obtain 1-j. 1-j can then be converted to 1-k by the Suzuki reaction or Stille reaction, or by substitution with a hydroxyl compound or amino compound to obtain 1-k. Intermediate 1-h can also be cyclized with a substituted acylhydrazine to obtain 1-k, and finally, it is deprotected to obtain 1-i.

[0110] 1-h can be substituted with an amino group to obtain 2-a, which can then react with a bromoacetyl compound, undergo ring closure to obtain 2-b, and finally deprotect to obtain 2-c.

[0111] [ka]

[0112] As shown in Embodiment 2, 1-g reacts with trimethylcyanosilane to produce 3-a, which is hydrolyzed to obtain 3-b, which is then diazotized with nitrite and cyclized with trifluoroacetic anhydride to obtain 3-c, which is then reacted with a substituted alkyne to obtain 3-d, and finally deprotected to obtain 3-e. 3-b can also be reduced to obtain 4-a, which is then reacted with potassium cyanate to obtain 4-c by cyclization and chlorination, 4-c can be obtained by the Suzuki reaction and Stille reaction, or by substitution with a hydroxyl or amino compound to obtain 4-d, and finally deprotected to obtain 4-e.

[0113] [ka]

[0114] Compounds 1-b and 5-a shown in Embodiment 3 can be prepared by any method known in the art and / or purchased commercially. As shown in Embodiment 3, 5-a can be reacted with cyclopentenone to obtain a common intermediate 5-b, 5-b can be reacted with a substituted ester to obtain 5-c, which is then cyclized and deprotected with methylhydrazine to obtain 5-e. 5-c can be cyclized with hydroxylamine hydrochloride to obtain 6-a, which is then deprotected to obtain 6-b. 5-c can also be further reacted with aqueous ammonia to obtain 7-a, which is cyclized with phosphorus pentasulfide / tetrachlorobenzoquinone to obtain 7-b, which is then deprotected to obtain 7-c.

[0115] 5-b can be brominated to obtain 8-a, then cyclized with a substituted amine / formamide to obtain 8-b, and subsequently deprotected to obtain 8-c. 5-b can also be reacted with a suitable silicon reagent to obtain enol silyl ether 9-a, which can then be cyclized with a substituted chloroformaldehyde oxime to obtain 9-b, and subsequently deprotected to obtain 9-c.

[0116] [ka]

[0117] As shown in Embodiment 4, intermediate 1-h can also react with hydrazine to obtain 1-m, then react with a carboxylic acid to obtain 1-n, cyclize to obtain 1-k, and finally deprotect to obtain the final product 1-l.

[0118] [ka]

[0119] As shown in Embodiment 5, 1-h and aminoacetaldehyde dimethyl acetal undergo a two-step reaction of substitution and ring closure to obtain 10-b, which is then brominated to obtain 10-c. 10-c can be converted to 10-d by the Suzuki reaction and Stille reaction, or it can be converted to 10-d by substitution with a hydroxyl or amino-containing compound, or it can be deprotected to obtain the final product 10-e. 1-h can further react with a thioamineacetyl compound to obtain 10-d, which can then be deprotected to obtain the final product 10-e.

[0120] [ka]

[0121] As shown in Embodiment 6, 11-a and the hydroxy compound undergo a Mitsunobu reaction to obtain 11-b, which is then deprotected to obtain intermediate 11-c, 11-c and 1-h undergo a substitution reaction and triphosgene ring closure to obtain 11-f, which is then deprotected to obtain the final product 11-g, and 1-i undergoes a Mitsunobu reaction with the hydroxy compound to obtain 11-f, which is then deprotected to obtain the final product 11-g.

[0122] [ka]

[0123] Compound 12-c shown in Embodiment 7 can be prepared by any method known in the art and / or purchased commercially. As shown in Embodiment 7, 12-a is reacted with triflate to obtain 12-b, 12-d is obtained by the Suzuki reaction with 12-c, 12-e is obtained by reacting with DMFDMA, 12-g is obtained by a two-step reaction of cyclization and reduction with hydrated hydrazine, 12-g and the hydroxy compound are subjected to the Mitsunobu reaction to obtain 12-h, and then deprotected to obtain the final product 12-i. Intermediate 12-f can be cyclized with substituted hydrazine to obtain 12-j, and then reduced and deprotected to obtain the final product 12-l.

[0124] [ka]

[0125] As shown in Embodiment 8, 12-d reacts with propionyl bromide to obtain 13-a, then cyclizes with substituted hydrazine to obtain 13-b and 13-c, and undergoes a two-step reaction of reduction and deprotection to obtain 13-f and 13-g.

[0126] The compounds of the present application can inhibit Kv1.3. According to another aspect of the present application, the present application provides a method for inhibiting Kv1.3 using the compounds of the present application.

[0127] Another aspect of the present application provides a method for preventing and / or treating Kv1.3-related diseases, comprising administering a preventive and / or therapeutically effective amount of the compound of the present application or a pharmaceutical composition containing the compound of the present application to a subject of interest. Kv1.3-related diseases refer to any disease directly and / or indirectly related to the expression and / or activity of Kv1.3, including, for example, diseases that can be prevented and / or treated by inhibiting Kv1.3.

[0128] Kv1.3-related diseases include multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, type 1 diabetes, psoriasis and asthma, immune and inflammatory diseases such as spondylitis and periodontitis, as well as obesity, type 2 diabetes, renal fibrosis, Alzheimer's disease, and ischemic stroke. According to another aspect of the present application, the present application provides an application of the compound of the present application in the manufacture of a Kv1.3 inhibitor.

[0129] According to another aspect of the present application, the present application provides a use for the compound of the present application in the manufacture of a drug for treating and / or preventing Kv1.3-related diseases.

[0130] When using the compound of the present application to treat and / or prevent Kv1.3-related diseases, the compound may be administered in the form of a pharmaceutical composition. Accordingly, according to another aspect of the present application, the present application provides a pharmaceutical composition comprising the compound of the present application and a pharmaceutically acceptable carrier.

[0131] Those skilled in the art will understand that the pharmaceutical compositions of this application can be manufactured by various methods disclosed in the literature. The compounds or pharmaceutical compositions of this application can be administered by various routes depending on the need for local or systemic treatment and the site of treatment. For example, administration may be oral, parenteral (e.g., intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection or infusion), intracranial (e.g., intrathecal or intraventricular), percutaneous, ocular, nasal, vaginal, rectal, or pulmonary (e.g., by inhalation or blowing of powder or aerosol).

[0132] For oral administration, the pharmaceutical compositions of this application are usually provided in the form of tablets, capsules, or solutions. Tablets may contain the compound of this application or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The carrier may include, but is not limited to, diluents, disintegrants, binders, lubricants, colorants, or preservatives. Capsules include hard capsules and soft capsules. For parenteral administration, the pharmaceutical compositions of this application may be administered by intravenous injection, intramuscular injection, or subcutaneous injection. Generally, they are provided as sterile aqueous solutions or suspensions, or as lyophilized powders, and are adjusted to an appropriate pH and isotonicity.

[0133] The effective dose of the compound of this application is determined according to the specific therapeutic use, method of administration, and the condition of the subject requiring the treatment (e.g., the patient). Those skilled in the art will have the ability to appropriately determine the effective dose of the compound of this application. A typical dosage range is, for example, 1 μg / kg / day to 1000 mg / kg / day.

[0134] In the prevention and / or treatment of Kv1.3-related diseases, the compound of the present application may be used in combination with one or more other drugs. Other drugs include prednisone, methylprednisolone, ocrelizumab, natalizumab, alemtuzumab, β-interferon, glatiramer, fingolimod, dimethyl fumarate, diloximel, teriflunomide, siponimod, cladribine, mesalazine, valsalazide, olsalazine, azathioprine, leukerin, methotrexate, infliximab, adalimumab, golimumab, certolizumab, vedolizumab, ustekinumab, methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, abatacept, adalimumab, anakinra, This includes, but is not limited to, becerizumab, etanercept, golimumab, infliximab, rituximab, sarilumab, tocilizumab, baricitinib, tofacitinib, upadacitinib, insulin glulisine, insulin lispro, insulin aspart, insulin glargine, insulin detemir, insulin degludec, fluticasone, budesonide, mometasone furoate, beclomethasone, ciclesonide, montelukast, zafirlukast, ziloteron, salmeterol, omalizumab, mepolizumab, benralizumab, reslizumab, and others.

[0135] [Brief explanation of the drawing] [Figure 1] This is an ellipsoidal diagram of the molecular three-dimensional structure of (S)-4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidine-2-one. [Figure 2] This is an ellipsoidal diagram of the molecular three-dimensional structure of (R)-4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidine-2-one.

[0136] [Modes for carrying out the invention] The present application will be further described below in accordance with specific embodiments. These embodiments are merely illustrative and should be understood not to limit the scope of the present application. Furthermore, after reading the contents of the present application, a person skilled in the art can make various changes and modifications to the present application, and these equivalent forms should be understood to be included within the scope limited by the present application.

[0137] Intermediate 1,3-(6-(allyloxy)-2,3-dichlorophenyl)-5-hydrazine-3,4-dihydro-2H-pyrrole

[0138] [ka]

[0139] Synthesis of 4-(allyloxy)-1,2-dichlorobenzene(2):

[0140] [ka]

[0141] 3,4-Dichlorophenol (120.0 g, 0.74 mol) and potassium carbonate (253.9 g, 1.84 mol) were mixed with N,N-dimethylformamide (1.5 L), and allyl bromide (106.9 g, 0.88 mol) was added in several portions at 0°C. The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with water (1500 mL), extracted twice with ethyl acetate (1500 mL), the organic phases were combined, washed with saturated brine (1500 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain a yellow solid (120.0 g, yield 68%).

[0142] Synthesis of 6-(allyloxy)-2,3-dichlorobenzaldehyde (3):

[0143] [ka]

[0144] 4-(allyloxy)-1,2-dichlorobenzene (120.0 g, 0.59 mol) was dissolved in tetrahydrofuran (1200 mL) at -78°C, and n-butyllithium (260.0 mL, 0.65 mol, in a 2.5 M solution of n-hexane) was added dropwise for at least 30 minutes. N,N-dimethylformamide (86.4 g, 1.18 mol) was added at the same temperature, and the resulting mixture was stirred for a further 3 hours at the same temperature. After the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution (1000 mL), extracted twice with ethyl acetate (3000 mL), the organic phases were combined, washed with saturated brine (1500 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) and eluted to obtain a pale yellow solid (139.5 g, yield 86%). 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.25 (d, J = 9.1 Hz, 1H), 6.13 - 5.96 (m, 1H), 5.46 (m, J = 17.3, 1.7 Hz, 1H), 5.31 (m, J = 10.6, 3.0, 1.4 Hz, 1H), 4.74 (dt, J = 4.9, 1.5 Hz, 2H). Synthesis of (E)-3-(6-(allyloxy)-2,3-dichlorophenyl)ethyl acrylate (4):

[0145] [ka]

[0146] At 0°C, sodium hydride (29.1 g, 0.73 mol, 60% in mineral oil) was added to a solution of 2-(dimethoxyphosphoryl)ethyl acetate (142.6 g, 0.73 mol) in tetrahydrofuran (2000 mL), and the mixture was stirred for 30 minutes. Then, 6-(allyloxy)-2,3-dichlorobenzaldehyde (139.5 g, 0.61 mol) was added, and the mixture was stirred at 0°C for 4 hours. After the reaction was complete, the mixture was diluted with water (2000 mL), extracted with ethyl acetate (4000 mL), washed with saturated brine (2000 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a yellow solid (170.0 g, yield 79%).

[0147] 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 16.2 Hz, 1H), 7.64 (d, J = 9.1 Hz, 1H), 7.17 (d, J = 9.2 Hz, 1H), 6.81 (d, J = 16.2 Hz, 1H), 6.13 - 6.00 (m, 1H), 5.47 - 5.25 (m, 2H), 4.74 (dt, J = 5.2, 1.5 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H). Synthesis of 3-(6-(allyloxy)-2,3-dichlorophenyl)-4-nitrobutyrate ethyl (5):

[0148] [ka]

[0149] At room temperature, ethyl (E)-3-(6-(allyloxy)-2,3-dichlorophenyl)acrylate (170.0 g, 0.56 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (103.1 g, 0.68 mol) were added to a reaction flask containing nitromethane (2000 mL). The reaction mixture was stirred at 60°C for 16 hours. After the reaction was complete, the mixture was diluted with water (1000 mL), extracted with ethyl acetate (3000 mL), washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a pale yellow oily substance (174.0 g, yield 72%).

[0150] 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J = 9.0 Hz, 1H), 7.06 (d, J = 9.1 Hz, 1H), 6.07 (ddd, J = 15.9, 10.6, 5.2 Hz, 1H), 5.41 (d, J = 17.2 Hz, 1H), 5.33 (dd, J = 10.6, 1.1 Hz, 1H), 5.00 (ddd, J = 19.0, 13.0, 7.5 Hz, 2H), 4.69 (d, J = 4.4 Hz, 3H), 4.04 - 3.91 (m, 2H), 2.89 (dq, J = 17.6, 8.7 Hz, 2H), 1.06 (t, J = 7.1 Hz, 3H). Synthesis of 3-(6-(allyloxy)-2,3-dichlorophenyl)-4-aminobutyrate ethyl (6):

[0151] [ka]

[0152] At room temperature, 3-(6-(allyloxy)-2,3-dichlorophenyl)-4-nitrobutyrate ethyl (174.0 g, 0.48 mol) and zinc powder (314.2 g, 4.80 mol) were added to a reaction flask containing glacial acetic acid (2000 mL), and the mixture was stirred at 25°C for 3 hours. After the reaction was complete, the mixture was filtered, the filter cake was washed twice with water and ethyl acetate, and the filtrate was collected and concentrated under reduced pressure to obtain 200.0 g of crude product, which was used directly in the next step without purification. LCMS [M+H] + : 332.1. Synthesis of 4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidine-2-one (7):

[0153] [ka]

[0154] Crude ethyl 3-(6-(allyloxy)-2,3-dichlorophenyl)-4-aminobutyrate (200.0 g, 0.45 mol) and potassium carbonate (311.5 g, 2.26 mol) were added to methanol (2000 mL) and stirred at 50°C for 3 hours. After the reaction was complete, the mixture was diluted with water (1000 mL), extracted three times with ethyl acetate (3000 mL), the organic phases were combined, and the mixture was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a white solid (105.0 g, yield 69%).

[0155] LCMS [M+H] + : 286.0. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 6.01 (ddt, J = 17.2, 10.4, 5.0 Hz, 1H), 5.44 - 5.35 (m, 1H), 5.26 (dd, J = 10.6, 1.5 Hz, 1H), 4.64 (dd, J = 3.6, 1.4 Hz, 2H), 4.33 (dd, J = 18.4, 9.2 Hz, 1H), 3.43 (dt, J = 16.7, 8.9 Hz, 2H), 2.54 (dd, J = 16.7, 9.0 Hz, 1H), 2.36 (dd, J = 16.5, 10.7 Hz, 1H). Synthesis of 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (8):

[0156] [ka]

[0157] 4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidine-2-one (500.0 mg, 1.75 mmol) was dissolved in dichloromethane (5 mL), trimethyloxonium tetrafluoroborate (311.6 mg, 2.11 mmol) was added, and the mixture was stirred at room temperature for 3 hours under nitrogen gas protection. After the reaction was complete, the mixture was directly rotated dry, and the resulting crude product was used directly in the next step without purification.

[0158] Synthesis of 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-hydrazine-3,4-dihydro-2H-pyrrole (9):

[0159] [ka]

[0160] 500 mg, 1.67 mmol of 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole and 267.0 mg, 6.67 mmol, 80% aqueous solution of hydrazine hydrate were stirred in an acetonitrile solution (8.0 mL) at room temperature for 16 hours. After the reaction was complete, the acetonitrile was removed by vacuum distillation. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:20) to obtain a white solid (440.0 mg, yield: 88%).

[0161] LCMS [M+H] + : 299.9. Intermediate 2. (S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole

[0162] [ka]

[0163] Preparation of (S)-4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidine-2-one (2):

[0164] [ka]

[0165] 4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidine-2-one (10 g) was taken and purified by chiral preparative separation (gradient column: CHIRALPAK IC 250 mm × 4.6 mm, 5 μm, flow rate: 3 mL / min, gradient: 40% IPA (NH4OH 0.2%): 60% CO2).

[0166] The first compound obtained by SFC separation was compound 2 (4.5 g, 45% yield), and analysis using the chromatographic conditions for SFC analysis showed a reaction time of 4.51 min.

[0167] LC-MS: [M+H] + : 286.0. The second compound obtained by SFC separation was compound 3 (4.3 g, 43% yield), and analysis using the chromatographic conditions for SFC analysis showed a response time of 6.5 min.

[0168] LC-MS: [M+H] + : 286.0. Single-crystal X-ray diffraction analysis of compound 2 and compound 3 Preparation of single crystals: Single crystals of compound 2 and compound 3 were obtained by solvent diffusion crystallization under ethyl acetate / n-hexane conditions at room temperature for 2 days. Single crystal detection instrument model number: Bruker D8 Venture Instrument parameters: Light source: Cu target X-ray: Cu-Kα (λ=1.54178 Å) Detector: CMOS surface detector Resolution: 0.86 Å Current / voltage: 50 kV, 1.2 mA; Exposure period: 5 s Distance from surface detector to sample: 40 mm; Test temperature: 100°K Structural analysis and refinement process: After integral reduction of the diffraction data using the SAINT program, absorption correction was empirically performed using the SADABS program. The single crystal structure was analyzed using the direct method with SHELXT2014, refined using the least squares method, and the refinement process of hydrogen atoms was determined by isotropic calculations. Hydrogen atoms on CH were added computationally and refined using the Riding model. The Flack constant of compound 2 single crystal is 0.087(13), and C9 has an S configuration. The Flack constant of compound 3 single crystal is 0.073(13), and C3 has an R configuration. Refer to Figures 1 and 2 for the molecular three-dimensional elliptic graphs of compounds 2 and 3. Refer to Table 1 for the crystal structure data of compound 2, and Table 2 for the crystal structure data of compound 3.

[0169] [Table 1]

[0170] [Table 2]

[0171] Synthesis of (S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole(4):

[0172] [ka]

[0173] (S)-4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidine-2-one (1.0 g, 3.5 mmol) was dissolved in dichloromethane (10 mL), trimethyloxonium tetrafluoroborate (623.4 mg, 4.23 mmol) was added, and the mixture was stirred at room temperature for 3 hours under nitrogen gas protection. After the reaction was complete, the mixture was directly rotated dry, and the resulting crude product was used directly in the next step without purification.

[0174] Intermediate 3.1-(2-hydroxyethyl)-1H-pyrazole-4-formohydrazide

[0175] [ka]

[0176] Synthesis of 1-(2-acetoxyethyl)-1H-pyrazole-4-carboxylate methyl(2):

[0177] [ka]

[0178] 1H-Pyrazole-4-carboxylate methyl (600.0 mg, 4.75 mmol) was dissolved in N,N-dimethylformamide (5.0 mL), and sodium hydride (666.6 mg, 16.65 mmol, 60% of the mineral oil) was added in several portions. The reaction mixture was stirred at room temperature for 20 minutes, and then 2-bromoethyl acetate (2.8 g, 16.65 mmol) was added, followed by stirring overnight at 60°C. After the reaction was complete, the mixture was freeze-dried under reduced pressure to remove N,N-dimethylformamide, and the resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (500.0 mg, yield: 49%).

[0179] LC-MS: [M+H] + : 213.1. Synthesis of 1-(2-hydroxyethyl)-1H-pyrazole-4-formohydrazide (3):

[0180] [ka]

[0181] A methanol solution (10.0 mL) of methyl 1-(2-acetoxyethyl)-1H-pyrazole-4-carboxylate (500 mg, 2.35 mmol) and hydrazine hydrate (353.8 g, 8.84 mmol, 80% aqueous solution) was stirred at 60°C for 12 hours. Methanol was removed by vacuum distillation. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (200.0 mg, yield: 40%).

[0182] LC-MS: [M+H] + : 171.1. Examples 1-2 (R)-3,4-dichloro-2-(3-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol and (S)-3,4-dichloro-2-(3-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0183] [ka]

[0184] Synthesis of (2-((3,4-dichlorophenoxy)methoxy)ethyl)trimethylsilyl(2):

[0185] [ka]

[0186] 3,4-Dichlorophenol (44.0 g, 0.27 mol) and potassium carbonate (74.5 g, 0.54 mol) were mixed with N,N-dimethylformamide (1 L), stirred at 0°C, and 2-(trimethylsilylyl)ethoxymethyl chloride (54.0 g, 0.33 mol) was added in several batches. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, it was diluted with water (500 mL), extracted twice with ethyl acetate (500 mL), the organic phases were combined, washed with saturated brine (600 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography. Elution with petroleum ether / ethyl acetate (15 / 1) yielded a colorless oil (65.1 g, yield 82%).

[0187] 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.9 Hz, 1H), 7.16 (d, J = 2.8 Hz, 1H), 6.88 (dd, J = 8.9, 2.8 Hz, 1H), 5.17 (s, 2H), 3.72 (dd, J = 8.9, 7.8 Hz, 2H), 0.94 (dd, J = 8.9, 7.8 Hz, 2H), -0.01 (d, J = 3.3 Hz, 9H). Synthesis of 2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)benzaldehyde (3):

[0188] [ka]

[0189] (2-((3,4-dichlorophenoxy)methoxy)ethyl)trimethylsilyl (10.0 g, 34.10 mmol) was dissolved in tetrahydrofuran (100 mL) at -78°C, and n-butyllithium (15.0 mL, 36.00 mmol, in a 2.4 M solution of n-hexane) was added dropwise for at least 30 minutes. Next, N,N-dimethylformamide (5.0 g, 68.50 mmol) was added at the same temperature, and the mixture was stirred for a further 1 hour. After the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution (100 mL), extracted twice with ethyl acetate (300 mL), the organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (10 / 1) to obtain a pale yellow solid (10.2 g, yield 91%).

[0190] 1H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 7.54 (d, J = 9.1 Hz, 1H), 7.17 (d, J = 9.1 Hz, 1H), 5.30 (s, 2H), 3.76 (dd, J = 11.3, 5.4 Hz, 2H), 0.94 (dd, J = 11.0, 5.7 Hz, 2H), -0.00 (s, 9H). Synthesis of (E)-3-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)ethyl acrylate (4):

[0191] [ka]

[0192] At 0°C, sodium hydride (1.4 g, 35.00 mmol, 60% in mineral oil) was added to a solution of 2-(dimethoxyphosphoryl)ethyl acetate (6.7 g, 34.16 mmol) in tetrahydrofuran (100 mL), and the mixture was stirred for 30 minutes. Then, 2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)benzaldehyde (9.2 g, 28.63 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was complete, the mixture was diluted with water (100 mL), extracted with ethyl acetate (200 mL), the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) and eluted to obtain a white solid (10.0 g, yield 89%).

[0193] 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 16.2 Hz, 1H), 7.34 (d, J = 9.1 Hz, 1H), 7.08 (d, J = 9.1 Hz, 1H), 6.76 (d, J = 16.2 Hz, 1H), 5.26 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.76 - 3.68 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H), 0.95 - 0.88 (m, 2H), -0.02 - -0.04 (m, 9H). Synthesis of 3-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-4-nitrobutyrate ethyl (5):

[0194] [ka]

[0195] At room temperature, (E)-3-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)ethyl acrylate (3.0 g, 7.67 mmol) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (1.4 g, 9.52 mmol) were added to a reaction flask containing nitromethane (50 mL). The reaction mixture was stirred at 60°C for 16 hours. After the reaction was complete, the mixture was diluted with water (50 mL), extracted with ethyl acetate (150 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) and eluted to obtain a pale yellow oily substance (2.5 g, yield 73%).

[0196] 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 9.1 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 5.25 (s, 2H), 4.94 - 4.75 (m, 3H), 4.07 (q, J = 7.1 Hz, 2H), 3.80 - 3.71 (m, 2H), 2.86 (d, J = 3.8 Hz, 2H), 1.16 (dd, J = 7.8, 6.5 Hz, 3H), 0.97 - 0.92 (m, 2H), 0.00 - -0.01 (m, 9H). Synthesis of 3-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-4-aminobutyrate ethyl(6):

[0197] [ka]

[0198] At room temperature, ethyl 3-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-4-nitrobutyrate (5.1 g, 11.27 mmol), iron powder (3.1 g, 56.36 mmol), and ammonium chloride (5.9 g, 0.11 mol) were added to a reaction flask containing ethanol and water (50 mL + 10 mL), and the mixture was stirred at 80°C for 16 hours. After the reaction was complete, the mixture was filtered, the filtrate was diluted with water (50 mL), extracted with ethyl acetate (50 mL), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 4.0 g of crude product, which was used directly in the next step without purification.

[0199] LCMS [M+H]+: 422.0. Synthesis of 4-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)pyrrolidine-2-one (7):

[0200] [ka]

[0201] Ethyl 3-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-4-aminobutyrate (4.0 g, 9.46 mmol) and potassium carbonate (3.2 g, 23.19 mmol) were added to methanol (30 mL) and stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with water (50 mL), extracted three times with ethyl acetate (50 mL), the organic phases were combined, and the mixture was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) and eluted to obtain a pale yellow oily substance (2.4 g, 57% yield in 2 steps).

[0202] LCMS [M+H]+: 398.0. 1 H NMR (400 MHz, CDCl3) δ 7.34 (d, J= 9.0 Hz, 1H), 7.11 (d, J= 9.0 Hz, 1H), 6.61 (s,1H), 5.27 (s, 2H),4.64-4.50 (m, 1H), 3.78-3.71 (m, 2H), 3.63 (dt, J= 29.9, 8.8 Hz, 2H), 2.78 (dd, J= 17.0, 8.3Hz, 1H), 2.61 (dd, J= 17.0, 10.8 Hz, 1H), 0.98-0.92 (m, 2H), 0.02 (s, 9H). Synthesis of 3,4-dichloro-2-(5-methoxy-3,4-dihydro-2H-pyrrole-3-yl)phenol (8):

[0203] [ka]

[0204] 4-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)pyrrolidine-2-one (200.0 mg, 0.53 mmol) and trimethyloxonium tetrafluoroborate (141.9 mg, 0.96 mmol) were dissolved in dichloromethane (6.6 mL), and the mixture was stirred at room temperature for 16 hours. The resulting mixture was directly rotated-dried to obtain 330.0 mg of a colorless oily crude product. This was used directly in the next step without further purification.

[0205] LC-MS: [M+H]+: 260.0. Synthesis of (R)-3,4-dichloro-2-(3-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol and (S)-3,4-dichloro-2-(3-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol:

[0206] [ka]

[0207] Crude 3,4-dichloro-2-(5-methoxy-3,4-dihydro-2H-pyrrole-3-yl)phenol (330.0 mg, approximately 0.53 mmol) and hydroxyacetylhydrazine (143.0 mg, 1.59 mmol) were dissolved in n-butanol (3.0 mL), and the mixture was stirred at 70°C for 3 hours. The mixture was directly transferred to a microwave tube and heated to 160°C and reacted for 2 hours. After the reaction mixture was cooled to room temperature, it was centrifuged and dried, and separated by preparative chromatography to obtain 31.0 mg of a racemic compound, which was a white solid with a yield of 19%. A pair of enantiomers were obtained by separation by SFC.

[0208] SFC Chiral Partitioning Conditions: Equipment: Thar Prep SFC 80 Chiral column: CHIRALPAK® AD-H, 250 mm × 20 mm, 5 μm Fluidity: CO2-EtOH (DEA), Gradient: 0~40% Total flow rate: 40 g / min SFC chiral analysis conditions: Equipment: Thar SFC X-5 Chiral column: CHIRALPAK® AD-H, 250 mm × 4.6 mm, 5 μm Fluidity: CO2-EtOH (DEA), Gradient: 0~40% Total flow rate: 2.5 mL / min The first compound obtained by SFC resolution was numbered Example 1, and analysis under SFC chromatographic conditions showed a retrieval time of 1.69 min.

[0209] LC-MS: [M+H]+: 299.9. 1 H NMR:(400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 5.50 (t, J = 5.0 Hz, 1H), 5.03 - 4.89 (m, 1H), 4.54 (d, J = 4.7 Hz, 2H), 4.26 (t, J = 10.0 Hz, 1H), 4.11 (dd, J = 10.5, 7.9 Hz, 1H), 3.15 - 3.06 (m, 2H). The second compound obtained by SFC separation was numbered as Example 2, and analysis under the chromatographic conditions for SFC analysis showed a retrieval time of 2.16 min.

[0210] LC-MS: [M+H]+: 299.9. 1H NMR:(400 MHz, DMSO-d6) δ 10.65 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 5.50 (s, 1H), 5.01 - 4.91 (m, 1H), 4.54 (s, 2H), 4.26 (t, J = 10.0 Hz, 1H), 4.11 (dd, J = 10.5, 7.9 Hz, 1H), 3.11 (dd, J = 9.0, 4.0 Hz, 2H). Example 3. 3,4-Dichloro-2-(3-(2-hydroxy-2-methylpropyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0211] [ka]

[0212] Synthesis of 3-hydroxy-3-methylbutyrate hydrazide (2):

[0213] [ka]

[0214] Ethyl 3-hydroxy-3-methylbutyrate (2000.0 mg, 13.70 mmol) and hydrazine hydrate (1041.1 mg, 26.03 mmol, 80% aqueous solution) in an ethanol solution (15.0 mL) were stirred at room temperature for 12 hours. After the reaction was complete, dichloromethane (20.0 mL) was added to the resulting mixture to precipitate the product. The solid was filtered to obtain a white solid (620.0 mg, yield: 34%). LCMS [M+H] + : 133.1. Synthesis of N'-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)-3-hydroxy-3-methylbutyrate hydrazide (3):

[0215] [ka]

[0216] A solution of 3-hydroxy-3-methylbutyrate hydrazide (66.2 mg, 0.50 mmol) and 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (50.0 mg, 0.17 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at room temperature for 12 hours. After the reaction was complete, the solution was used directly in the next step without purification.

[0217] LCMS [M+H] + : 400.1. Synthesis of 1-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)-2-methylmethane-2-ol(4):

[0218] [ka]

[0219] A dimethyl sulfoxide solution of N'-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)-3-hydroxy-3-methylbutyrate hydrazide was transferred to a microwave tube and stirred at 150°C for 1.5 hours. After the reaction was complete, the mixture was freeze-dried under reduced pressure to remove the dimethyl sulfoxide. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (30.0 mg, yield: 47%).

[0220] LCMS [M+H] + : 382.0. Synthesis of 3,4-dichloro-2-(3-(2-hydroxy-2-methylpropyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol (5):

[0221] [ka]

[0222] At room temperature, 1-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)-2-methylmethane-2-ol (25.0 mg, 0.07 mmol) was dissolved in tetrahydrofuran (1.0 mL), to which tetrakistriphenylphosphine palladium (7.6 mg, 0.01 mmol) and sodium borohydride (3.7 mg, 0.10 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the organic phase was filtered through a filter membrane, and the filtrate was rotate-dried to purify the crude product, which yielded a white solid (3.0 mg, yield 13%).

[0223] LCMS [M+H] + : 342.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.36 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 4.95 - 4.88 (m, 1H), 4.22 (t, J = 10.0 Hz, 1H), 4.13 - 4.06 (m, 1H), 3.10 (d, J = 9.0 Hz, 2H), 2.73 (s, 2H), 1.23 (s, 3H), 1.14 (d, J = 10.3 Hz, 3H). Example 4. 2-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)-2-methylpropionitrile

[0224] [ka]

[0225] Synthesis of cyanoacetylhydrazine (2):

[0226] [ka]

[0227] A methanol solution (50.0 mL) of methylcyanoacetate (5.0 g, 50.51 mmol) and hydrazine hydrate (4.85 g, 121.25 mmol, 80% aqueous solution) was stirred at room temperature for 12 hours. After the reaction was complete, the resulting mixture was concentrated under reduced pressure, diluted with dichloromethane (20.0 mL), and the product was precipitated. The solid was filtered to obtain a white solid (4.4 g, yield: 88%).

[0228] LCMS [M+H] + : 100.1. Synthesis of N'-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)-2-cyanoacetylhydrazine (3):

[0229] [ka]

[0230] A solution of cyanoacetylhydrazine (297.0 mg, 3.00 mmol) and 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (300.0 mg, 1.00 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at room temperature for 16 hours. After the reaction was complete, a dimethyl sulfoxide solution of the product was obtained and used directly in the next step without purification.

[0231] LCMS [M+H] + : 367.0. Synthesis of 2-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)acetonitrile (4):

[0232] [ka]

[0233] A butanol solution of N'-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)-2-cyanoacetylhydrazine was transferred to a microwave tube and stirred at 150°C for 0.5 hours. After the reaction was complete, the mixture was freeze-dried under reduced pressure to remove dimethyl sulfoxide. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (139.7 mg, yield: 40%).

[0234] LCMS [M+H] + : 349.0. Synthesis of 2-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)-2-isobutyronitrile (5):

[0235] [ka]

[0236] At 0°C, sodium hydride (40 mg, 60% mass fraction, 1.0 mmol) was added to a solution of 2-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)-acetonitrile (70.0 mg, 0.20 mmol) in dimethyl sulfoxide (0.5 mL), and the mixture was stirred at room temperature for 1 hour. Then, the temperature was lowered again to 0°C, and iodomethane (142.0 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate (10 mL), the reaction was quenched with ice water (10 mL), extracted twice with ethyl acetate (10 mL), the organic phases were combined, washed with saturated brine (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (13.6 mg, yield 18%).

[0237] LCMS [M+H] + : 377.0. Synthesis of 2-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)-2-methylpropionitrile (6):

[0238] [ka]

[0239] Compound 2-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)-2-isobutyronitrile (18.0 mg, 0.048 mmol) was dissolved in tetrahydrofuran solution (2.0 mL). Sodium borohydride (2.7 mg, 0.072 mmol) and tetrakistriphenylphosphine palladium (27.6 mg, 0.024 mmol) were added to the reaction mixture, and the mixture was reacted at 25°C for 2 hours. The reaction mixture was filtered, concentrated under reduced pressure, and then purified and separated to obtain a white solid (2.0 mg, yield 12%).

[0240] LCMS [M+H] + : 337.0. 1 H NMR (400 MHz, CD3OD) δ 7.31 (d, J = 8.8 Hz, 1H) , 6.80 (d, J = 8.8 Hz, 1H) , 5.24 (s, 1H) , 4.54 (t, J = 10.1 Hz, 1H) , 4.38 (dd, J = 10.5, 6.8 Hz, 1H), 3.34 (d, J = 10.4 Hz, 1H), 3.20 (d, J = 7.0 Hz, 1H), 1.82 (s, 6H). Example 5. 3,4-Dichloro-2-(3-cyclohexyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0241] [ka]

[0242] The preparation was carried out by referring to the preparation method of Example 3, using methyl cyclohexylcarboxylate instead of ethyl 3-hydroxy-3-methylbutyrate.

[0243] LCMS [M+H] + : 352.0. 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.97 (t, J = 8.4 Hz, 1H), 4.30 (t, J = 9.9 Hz, 1H), 4.08 (dd, J = 10.2, 7.4 Hz, 1H), 3.09 (dt, J = 15.9, 7.0 Hz, 2H), 2.80 - 2.74 (m, 1H), 1.89 (t, J = 12.2 Hz, 2H), 1.75 (s, 2H), 1.66 (d, J = 12.3 Hz, 1H), 1.54 - 1.43 (m, 2H), 1.30 (dt, J = 18.1, 7.9 Hz, 3H). Example 6. 4-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)benzonitrile

[0244] [ka]

[0245] The preparation was carried out using methyl 4-cyanobenzoate instead of ethyl 3-hydroxy-3-methylbutyrate, referring to the preparation method of Example 3.

[0246] LCMS [M+H] + : 371.0. 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 5.08 (ddd, J = 17.2, 9.8, 7.4 Hz, 1H), 4.68 (t, J = 10.0 Hz, 1H), 4.40 (dd, J = 10.3, 7.1 Hz, 1H), 3.32 - 3.25 (m, 1H), 3.15 (dd, J = 16.0, 7.4 Hz, 1H). Example 7. 2-(3-(1H-indazole-5-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenol

[0247] [ka]

[0248] The preparation was carried out by referring to the preparation method of Example 3, using methyl 1H-indazole-5-carboxylate instead of ethyl 3-hydroxy-3-methylbutyrate.

[0249] LCMS [M+H] + : 368.1. 1 H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 11.00 (s, 1H), 8.39 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.96 (dd, J=8.8, 1.4, 1H), 7.65 (d, J=8.8, 1H), 7.38 (d, J=8.8, 1H), 6.87 (d, J=8.8, 1H), 5.12 - 5.05 (m, 1H), 4.65 (t, J=9.9, 1H), 4.41 (dd, J=10.0, 7.5, 1H), 3.24 - 3.14 (m, 2H). Example 8. 3,4-Dichloro-2-(3-isopropyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0250] [ka]

[0251] The preparation was carried out using methyl isobutyrate instead of ethyl 3-hydroxy-3-methylbutyrate, referring to the preparation method of Example 3.

[0252] LCMS [M+H] + : 312.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 5.05 - 4.88 (m, 1H), 4.27 (t, J = 9.9 Hz, 1H), 4.05 (dd, J = 10.1, 7.5 Hz, 1H), 3.15 - 2.98 (m, 3H), 1.24 (t, J = 6.7 Hz, 6H). Example 9. 3-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)benzonitrile

[0253] [ka]

[0254] The preparation was carried out using methyl 3-cyanobenzoate instead of ethyl 3-hydroxy-3-methylbutyrate, referring to the preparation method of Example 3.

[0255] LCMS [M+H] + : 371.5. 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.28 - 8.21 (m, 2H), 7.94 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.64 - 7.54 (m, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 5.12 - 5.03 (m, 1H), 4.69 (t, J = 10.0 Hz, 1H), 4.43 (dd, J = 10.3, 7.3 Hz, 1H), 3.29 - 3.13 (m, 2H). Example 10. Cyclopropyl(4-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)piperidine-1-yl)methanone

[0256] [ka]

[0257] Synthesis of 4-(2-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)hydrazine-1-carbonyl)piperidine-1-carboxylate tert-butyl(2):

[0258] [ka]

[0259] A solution (10.0 mL) of 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (600.0 mg, 2.00 mmol) and 4-(hydrazinecarbonyl)piperidine-1-carboxylate tert-butyl (1.458 g, 6.00 mmol) in n-butanol was stirred at 70°C for 3 hours. After the reaction was complete, the resulting mixture was used directly in the next reaction without any further processing.

[0260] LCMS [M+H] + : 511.0. Synthesis of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole(3):

[0261] [ka]

[0262] A solution of 4-(2-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)hydrazine-1-carbonyl)piperidine-1-carboxylate tert-butyl in n-butanol (1.0 g, 1.96 mmol, in 15 mL of n-butanol solution) was transferred to a microwave tube, and the mixture was stirred at 160°C for 2 hours. After the reaction was complete, n-butanol was removed by vacuum distillation. The resulting crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:1) to obtain a white solid (250.0 mg, yield: 33%).

[0263] LCMS [M+H] + : 392.9. Synthesis of (4-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)piperidine-1-yl)(cyclopropyl)methanone(4):

[0264] [ka]

[0265] To a solution of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole in dichloromethane (125.0 mg, 0.32 mmol, 3 mL solution of dichloromethane), potassium carbonate (88.0 mg, 0.64 mmol) and cyclopropane carbonyl chloride (50.0 mg, 0.48 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with water (20 mL), extracted three times with ethyl acetate (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The resulting crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:1) to obtain the target product (45.0 mg, yield: 31%).

[0266] LCMS [M+H] + : 460.8. Synthesis of cyclopropyl(4-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)piperidine-1-yl)methanone(5):

[0267] [ka]

[0268] At room temperature, sodium borohydride (8.0 mg, 0.20 mmol) and tetrakistriphenylphosphine palladium (5 mg, 0.004 mmol) were added to a solution of (4-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)piperidine-1-yl)(cyclopropyl)methanone (45.0 mg, 0.10 mmol) in tetrahydrofuran (2.0 mL). The gas in the flask was replaced with an argon balloon, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the organic phase was filtered through a filter membrane, and the filtrate was rotate-dried to purify the crude product, which yielded a white solid (5.0 mg, yield 11%).

[0269] LCMS [M+H] + : 420.8. 1 H NMR (400 MHz, CD3OD) δ 7.30 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.16 (dd, J = 16.6, 8.8 Hz, 1H), 4.54 (t, J = 11.7 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H), 4.35 (d, J = 9.8 Hz, 1H), 4.25 (dd, J = 10.3, 7.2 Hz, 1H), 3.37 - 3.30 (m, 1H), 3.22 (dd, J = 8.8, 5.1 Hz, 2H), 3.16 (td, J = 7.8, 3.9 Hz, 1H), 2.84 (t, J = 12.4 Hz, 1H), 2.10 (t, J = 12.7 Hz, 1H), 1.99 (ddd, J = 13.2, 7.9, 3.7 Hz, 2H), 1.83 (dd, J = 25.1, 12.5 Hz, 1H), 1.67 (dd, J = 16.1, 10.7 Hz, 1H), 0.86 (t, J = 3.7 Hz, 2H), 0.82 - 0.78 (m, 2H). Example 11. 3,4-Dichloro-2-(3-(1-cyclopropylpiperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0270] [ka]

[0271] Synthesis of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(1-cyclopropylpiperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole(2):

[0272] [ka]

[0273] To a methanol solution of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (105.0 mg, 0.26 mmol, 3 mL methanol solution), acetic acid (16.0 mg, 0.26 mmol) and (1-ethoxycyclopropoxy)trimethylsilyl (70.0 mg, 0.40 mmol) were added, and the mixture was stirred at room temperature for 0.5 hours. The mixture was cooled to 0°C, and then sodium borohydride (34.0 mg, 0.54 mmol) was added, and the mixture was stirred at room temperature for a further 16 hours. After the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product obtained was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:1) to obtain the target product (65.0 mg, yield: 54%).

[0274] LCMS [M+H] + : 432.8. Synthesis of 3,4-dichloro-2-(3-(1-cyclopropylpiperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol (3):

[0275] [ka]

[0276] At room temperature, 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(1-cyclopropylpiperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (60.0 mg, 0.14 mmol) was added to tetrahydrofuran (2.0 mL) with sodium borohydride (11.0 mg, 0.28 mmol) and tetrakistriphenylphosphine palladium (8.0 mg, 0.007 mmol). The gas in the flask was replaced with an argon balloon, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the organic phase was filtered through a filter membrane, and the filtrate was rotate-dried to purify the crude product, which yielded a white solid (5.5 mg, yield 10%).

[0277] LCMS [M+H] + : 392.9. 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.40 (d, J = 8.7 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 5.00 - 4.91 (m, 1H), 4.28 (t, J = 9.6 Hz, 1H), 4.09 - 4.02 (m, 1H), 3.07 (dt, J = 15.9, 7.0 Hz, 4H), 2.80 (s, 1H), 2.53 (d, J = 8.7 Hz, 1H), 2.47 - 2.35 (m, 1H), 2.09 - 1.80 (m, 3H), 1.69 (s, 2H), 1.18 (s, 1H), 0.48 (s, 3H). Example 12. (6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)(3-hydroxypyrrolidine-1-yl)methanone

[0278] [ka]

[0279] Synthesis of N'-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)-2-hydroxyacetylhydrazine (2):

[0280] [ka]

[0281] A solution of 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (3.0 g, 0.01 mol) and 2-hydroxyacetylhydrazine (1.4 g, 0.02 mol) in dimethyl sulfoxide (30.0 mL) was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was freeze-dried under reduced pressure to remove the solvent. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a colorless oily liquid (3.0 g, yield: 84%).

[0282] LCMS [M+H] + : 358.0. Synthesis of (6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)methanol(3):

[0283] [ka]

[0284] A solution of N'-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)-2-hydroxyacetylhydrazine (3.0 g, 8.40 mmol) in n-butanol (30.0 mL) was stirred for 1 hour under microwave conditions of 160°C. After the reaction was complete, the reaction solution was allowed to cool to room temperature, and the solvent was rotated dry by vacuum concentration. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (1.0 g, yield: 35%).

[0285] LCMS [M+H] + : 340.0. Synthesis of 6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-formaldehyde(4):

[0286] [ka]

[0287] A solution of (6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)methanol (1.0 g, 2.94 mmol) and sodium bicarbonate (2.46 g, 29.29 mmol) in dichloromethane (25.0 mL) was cooled to 0°C, and Dess Martin oxidizing agent (1.87 g, 4.41 mmol) was slowly added to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, saturated sodium thiosulfate aqueous solution was added dropwise to the reaction mixture at 0°C to quench the reaction, and water (40.0 mL) was added to dilute it. Extraction was performed with ethyl acetate (50.0 mL x 2), the organic phase was combined, washed with saline solution (100.0 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and the solvent was rotated dry. The resulting crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:1) to obtain a yellow solid (900.0 mg, yield: 91%).

[0288] LCMS [M+H] + : 338.0. Synthesis of (6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)(3-hydroxypyrrolidine-1-yl)methanone (5):

[0289] [ka]

[0290] At room temperature, tert-butyl hydroperoxide (41.0 mg, 0.46 mmol, 70% aqueous solution) was added to a solution of 6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-formaldehyde (70.0 mg, 0.21 mmol), copper sulfate (3.3 mg, 0.02 mmol), pyrrolidine-3-ol (43.3 mg, 0.50 mmol), and calcium carbonate (45.6 mg, 0.46 mmol) in acetonitrile (5.0 mL), and the mixture was stirred at 50°C for 12 hours. After the reaction was complete, the mixture was diluted with water (8.0 mL), extracted with ethyl acetate (8.0 mL x 2), combined with the organic phase, washed with saline solution (10.0 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to dry the solvent by rotation. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:12.5) to obtain the target product (40.0 mg, yield: 46%).

[0291] LCMS [M+H] + : 423.0. Synthesis of (6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)(3-hydroxypyrroridine-1-yl)methanone (6):

[0292] [ka]

[0293] At room temperature, tetrakistriphenylphosphine palladium (10.9 mg, 0.01 mmol) was added to a solution of (6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)(3-hydroxypyrrolidine-1-yl)methanone (40.0 mg, 0.09 mmol) and sodium borohydride (5.4 mg, 0.14 mmol) in tetrahydrofuran (3.0 mL). The gas in the flask was replaced with an argon balloon, and the mixture was stirred at 25°C for 2 hours. After the reaction was complete, the organic phase was filtered through a filter membrane, and the filtrate was rotate-dried to purify the crude product, which yielded a white solid (4.2 mg, yield 12%).

[0294] 1 H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 5.09 - 4.94 (m, 2H), 4.46 (dd, J = 20.1, 10.2 Hz, 1H), 4.34 (d, J = 25.2 Hz, 1H), 4.24 - 4.18 (m, 1H), 4.13 - 3.86 (m, 2H), 3.62 - 3.44 (m, 2H), 3.29 - 3.21 (m, 1H), 3.11 - 3.02 (m, 1H), 2.01 - 1.80 (m, 2H). Example 13. (6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)(piperazine-1-yl)methanone

[0295] [ka]

[0296] Synthesis of 4-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-carbonyl)piperazine-1-carboxylate tert-butyl(2):

[0297] [ka]

[0298] To an acetonitrile solution of 6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-aldehyde (100.0 mg, 0.30 mmol, 3 mL acetonitrile solution), piperazine 1-formate tert-butyl formate (110.0 mg, 0.60 mmol), calcium carbonate (33.0 mg, 0.33 mmol), and anhydrous copper sulfate (4.0 mg, 0.02 mmol) were added. At room temperature, tert-butyl hydroperoxide (29.0 mg, 0.33 mmol) was added to the mixture, and the mixture was stirred at 50°C for 16 hours under nitrogen gas protection. After the reaction was complete, the mixture was extracted with ethyl acetate (10 mL). The organic phase was washed with saturated saline solution (10 mL), and the extraction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product obtained was purified by silica gel chromatography (methanol:dichloromethane = 20:1) to obtain the target product (50.0 mg, yield: 32%).

[0299] LCMS [M+H] + : 522.1. Synthesis of 4-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-carbonyl)piperazine-1-carboxylate tert-butyl(3):

[0300] [ka]

[0301] At room temperature, 4-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-carbonyl)piperazine-1-carboxylate tert-butyl (50.0 mg, 0.10 mmol) was dissolved in tetrahydrofuran (2.0 mL), to which sodium borohydride (8.0 mg, 0.20 mmol) and tetrakistriphenylphosphine palladium (2.0 mg, 0.0017 mmol) were added, respectively. The gas in the flask was replaced with an argon balloon, and the mixture was stirred at 25°C for 2 hours. After the reaction was complete, the organic phase was filtered through a filter membrane, and the filtrate was rotated dry. The crude product was purified by silica gel chromatography (methanol:dichloromethane = 20:1) to obtain the target product (26.0 mg, yield 54%).

[0302] LCMS [M+H] + : 481.8. Synthesis of (6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)(piperazine-1-yl)methanone (4):

[0303] [ka]

[0304] At room temperature, 4-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-carbonyl)piperazine-1-carboxylate tert-butyl (26.0 mg, 0.05 mmol) was added to a mixed solvent of dichloromethane and trifluoroacetic acid (2.0 mL) in a ratio of 5:1. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was directly rotated dry, and the resulting crude product was purified to obtain a white solid (2.1 mg, yield 11%).

[0305] LCMS [M+H] + : 381.8. 1H NMR (400 MHz, CD3OD) δ 7.33 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.24 - 5.17 (m, 1H), 4.67 (d, J = 20.0 Hz, 2H), 4.59 - 4.53 (m, 1H), 4.44 (dd, J = 11.7, 7.6 Hz, 1H), 3.98 (d, J = 5.2 Hz, 2H), 3.37 (d, J = 19.3 Hz, 6H). Example 14. (6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)(4-isopropylpiperazine-1-yl)methanone

[0306] [ka]

[0307] At room temperature, (6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)(piperazine-1-yl)methanone (15.0 mg, 0.04 mmol) was added to dichloroethane (2.0 mL), acetone (9.0 mg, 0.16 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours, then cooled to 0°C. Sodium triacetoxyborohydride (25.0 mg, 0.12 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (5 mL), and the extraction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The resulting crude product was purified to obtain a white solid (2.6 mg, yield 20%).

[0308] LCMS [M+H] + : 423.8. 1H NMR (400 MHz, CD3OD) δ 7.32 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.86 (s, 1H), 5.24 - 5.16 (m, 1H), 4.86 - 4.72 (m, 1H), 4.56 (t, J = 10.6 Hz, 1H), 4.48 - 4.41 (m, 1H), 3.61 (d, J = 6.6 Hz, 4H), 3.34 (s, 2H), 3.23 (s, 2H), 1.41 (d, J = 6.6 Hz, 6H), 1.31 (d, J = 18.1Hz, 1H). Example 15. 3,4-Dichloro-2-(3-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0309] [ka]

[0310] The preparation was carried out by referring to the preparation method of Example 3, using ethyl 3,3,3-trifluoropropanoate instead of ethyl 3-hydroxy-3-methylbutyrate.

[0311] LCMS [M+H] + : 352.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.40 (d, J = 8.8, 1H), 6.86 (d, J = 8.8, 1H), 4.99 (t, J = 8.7, 1H), 4.30 (t, J = 10.1, 1H), 4.09 (dd, J = 10.4, 7.6, 1H), 4.05 - 3.95 (m, 2H), 3.24 - 3.17 (m, 1H), 3.12 - 3.04 (m, 1H). Example 16. 2-(3-tert-butyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenol

[0312] [ka]

[0313] The preparation was carried out by referring to the preparation method of Example 3, using ethyl pivalate instead of ethyl 3-hydroxy-3-methylbutyrate.

[0314] 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 5.07 - 4.89 (m, 1H), 4.38 (t, J = 9.9 Hz, 1H), 4.14 (dd, J = 10.2, 7.4 Hz, 1H), 3.04 (ddd, J = 23.5, 15.8, 9.0 Hz, 2H), 1.30 (s, 9H). Example 17. 3,4-Dichloro-2-(3-(piperidine-4-ylmethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0315] [ka]

[0316] Synthesis of 4-(2-hydrazine-2-oxoethyl)piperidine-1-carboxylate tert-butyl(2):

[0317] [ka]

[0318] A solution of 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate tert-butyl (2.0 g, 0.01 mol) and hydrazine hydrate (0.7 g, 0.02 mol, 80% aqueous solution) in ethanol (20.0 mL) was stirred at 80°C for 16 hours. After the reaction was complete, the reaction mixture was allowed to cool to room temperature, the solid was filtered, and the solid was washed with dichloromethane to obtain the crude product. The obtained crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (1.6 g, yield: 83%).

[0319] LCMS [M+H-56] + : 202.2. Synthesis of 4-(2-(2-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)hydrazine)-2-oxoethyl)piperidine-1-carboxylate tert-butyl(3):

[0320] [ka]

[0321] A 2.0 mL solution of 3-(6-allyloxy)-2,3-dichlorophenyl-5-methoxy-3,4-dihydro-2H-pyrrole (600.0 mg, 1.99 mmol) and 4-(2-hydrazine-2-oxoethyl)piperidine-1-carboxylate tert-butyl (771.5 mg, 2.99 mmol) in dichloromethane was stirred at 25°C for 16 hours. After the reaction was complete, dichloromethane was removed by vacuum distillation. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:20) to obtain a white solid (1.0 g, yield: 95%).

[0322] LCMS [M+H] + : 525.1. Synthesis of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(piperidine-4-ylmethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole(4):

[0323] [ka]

[0324] A solution of 4-(2-(2-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)hydrazine)-2-oxoethyl)piperidine-1-carboxylate tert-butyl (1.0 g, 1.89 mmol) in n-butanol (10 mL) was stirred for 1 hour under microwave conditions of 160°C. After the reaction was complete, the solvent was rotated dry by vacuum concentration, and the resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:15) to obtain a white solid (400.0 mg, yield: 52%).

[0325] LCMS [M+H] + : 407.1. Synthesis of 3,4-dichloro-2-(3-(piperidine-4-ylmethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol (5):

[0326] [ka]

[0327] At room temperature, tetrakistriphenylphosphine palladium (4.5 mg, 0.004 mmol) was added to a solution of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(piperidine-4-ylmethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (40.0 mg, 0.09 mmol), polymethylhydrogensiloxane (43.7 mg, 0.19 mmol), and zinc chloride (1.2 mg, 0.008 mmol) in tetrahydrofuran (3.0 mL). The gas in the flask was replaced with an argon balloon, and the mixture was stirred at 25°C for 12 hours. After the reaction was complete, the organic phase was filtered through a filter membrane, and the filtrate was rotate-dried to purify the crude product, which yielded a white solid (5.1 mg, yield 13%).

[0328] LCMS [M+H] + : 407.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.04 -5.00 (m, 1H), 4.38 - 4.37 (m, 1H), 4.16-4.15 (m, 1H), 3.44 - 3.09 (m, 5H), 2.93 - 2.73 (m, 4H), 2.06 - 1.97 (m, 1H), 1.81-1.78 (m, 2H), 1.38-1.36 (m, 2H). Example 18. 3,4-Dichloro-2-(3-((1-Isopropylpiperidine-4-yl)methyl)-6,7-Dihydro-5H-Pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0329] [ka]

[0330] Synthesis of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-((1-isopropylpiperidine-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole(2):

[0331] [ka]

[0332] At 0°C, sodium borohydride acetate (234.1 mg, 1.10 mmol) was added in several portions to a solution of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(piperidine-4-ylmethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (150.0 mg, 0.36 mmol) and acetone (64.2 mg, 1.10 mmol) in dichloromethane (2.0 mL), and the mixture was stirred at 40°C for 2 hours. After the reaction was complete, the resulting solution was filtered on a column using a wet method and purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (100.0 mg, yield: 60%).

[0333] LCMS [M+H] + : 449.1. Synthesis of 3,4-dichloro-2-(3-((1-isopropylpiperidine-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol (3):

[0334] [ka]

[0335] At room temperature, tetrakistriphenylphosphine palladium (25.7 mg, 0.02 mmol) was added to a solution of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-((1-isopropylpiperidine-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (100.0 mg, 0.22 mmol) and sodium borohydride (12.6 mg, 0.33 mmol) in tetrahydrofuran (5.0 mL). The gas in the flask was replaced with an argon balloon, and the mixture was stirred at 25°C for 2 hours. After the reaction was complete, the organic phase was filtered through a filter membrane, and the filtrate was rotate-dried to purify the crude product, which was then a white solid (5.8 mg, yield 6.0%).

[0336] 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.99-4.95 (m, 1H), 4.21 (t, J = 9.9 Hz, 1H), 4.01 (dd, J = 10.1, 7.6 Hz, 1H), 3.17 - 2.98 (m, 6H), 2.62 (d, J = 6.3 Hz, 2H), 2.45-2.44 (m, 1H), 1.73 (d, J = 13.5 Hz, 2H), 1.37 - 1.27 (m, 2H), 1.07 (d, J = 6.6 Hz, 6H), 1.00-0.99 (m, 1H). Example 19. 1-((6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)methyl)pyrroridine-3-ol

[0337] [ka]

[0338] Synthesis of 1-((6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)methyl)pyrroridine-3-ol(2):

[0339] [ka]

[0340] Compounds 6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-formaldehyde (192.1 mg, 0.57 mmol) and pyrrolidine-3-ol (45.0 mg, 0.52 mmol) were dissolved in dichloromethane (6 mL). Sodium triacetoxyborohydride (164.2 mg, 0.77 mmol) was added to the mixture at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water (30 mL), extracted three times with dichloromethane (30 mL), and the organic phases were combined and washed twice with saline solution (80 mL). The resulting organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 50:1) to obtain a pale yellow solid (120.0 mg, yield 57%).

[0341] LCMS [M+H] + : 409.0. Synthesis of 1-((6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)methyl)pyrroridine-3-ol(3):

[0342] [ka]

[0343] Compound 1-((6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)methyl)pyrrolidine-3-ol (100.0 mg, 0.24 mmol) was dissolved in tetrahydrofuran solution (10 mL). Sodium borohydride (13.9 mg, 0.37 mmol) and tetrakistriphenylphosphine palladium (56.5 mg, 0.049 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was evaporated, purified, and separated to obtain a white solid (15.6 mg, yield 17%).

[0344] LCMS [M+H] + : 369.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.15 (s, 1H), 7.39 (dd, J = 8.8, 0.8 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 4.95 (dd, J = 17.2, 9.2 Hz, 1H), 4.73 (s, 1H), 4.28 - 4.15 (m, 2H), 4.08 - 4.01 (m, 1H), 3.70 (ddd, J = 17.0, 13.9, 4.7 Hz, 2H), 3.18 - 3.01 (m, 2H), 2.73 - 2.58 (m, 2H), 2.46 - 2.32 (m, 2H), 1.98 (dt, J = 14.2, 7.3 Hz, 1H), 1.54 (dd, J = 8.2, 4.4 Hz, 1H). Example 20. 3,4-Dichloro-2-(3-(morpholinomethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0345] [ka]

[0346] The preparation was carried out using morpholine instead of pyrrolidine-3-ol, referring to the preparation method of Example 19.

[0347] LCMS [M+H] + : 369.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 5.02 - 4.93 (m, 1H), 4.27 (t, J = 10.2 Hz, 1H), 4.08 (dd, J = 10.7, 7.3 Hz, 1H), 3.66 - 3.50 (m, 6H), 3.17 (dd, J = 15.9, 10.2 Hz, 1H), 3.01 (dd, J = 15.9, 7.4 Hz, 1H), 2.36 (d, J = 4.5 Hz, 4H). Example 21. (6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)(morpholinyl)methanone

[0348] [ka]

[0349] The preparation was carried out using morpholine instead of pyrrolidine-3-ol, referring to the preparation method of Example 12.

[0350] LCMS [M+H] + : 383.0. 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 5.05 - 4.95 (m, 1H), 4.45 (dd, J = 11.3, 9.9 Hz, 1H), 4.39 - 4.27 (m, 2H), 4.22 (dd, J = 11.6, 7.1 Hz, 1H), 3.70 - 3.61 (m, 6H), 3.28 - 3.22 (m, 1H), 3.07 (dd, J = 16.2, 7.2 Hz, 1H). Example 22. 3,4-Dichloro-2-(3-(1-(tetrahydro-2H-pyran-4-yl)piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0351] [ka]

[0352] Synthesis of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(1-(tetrahydro-2H-pyran-4-yl)piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole(2):

[0353] [ka]

[0354] At 0°C, 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(piperidine-4-yl)-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazole (150.0 mg, 0.38 mmol) and tetrahydro-4H-pyran-4-one (114.0 mg, 1.14 mmol) were dissolved in dichloromethane (2.0 mL), to which sodium borohydride acetate (242.5 mg, 1.14 mmol) was added, and the mixture was stirred at 25°C for 2 hours. After the reaction was complete, the organic phase was filtered through a filter membrane, and the filtrate was rotate-dried to obtain the crude product, which was purified by silica gel chromatography (methanol:dichloromethane = 1:20) to obtain a white solid (150.0 mg, yield: 82%).

[0355] LCMS [M+H] + : 476.8. Synthesis of 3,4-dichloro-2-(3-(1-(tetrahydro-2H-pyran-4-yl)piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol (3):

[0356] [ka]

[0357] At room temperature, 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(1-(tetrahydro-2H-pyran-4-yl)piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (150.0 mg, 0.31 mmol) and sodium borohydride (17.9 mg, 0.47 mmol) were dissolved in tetrahydrofuran (2.0 mL). Tetrakistriphenylphosphine palladium (60.5 mg, 0.05 mmol) was added, and the gas in the flask was replaced with an argon balloon. The mixture was stirred at 25°C for 2 hours. After the reaction was complete, the organic phase was filtered through a filter membrane, and the filtrate was rotate-dried to purify the crude product, which yielded a white solid (53.0 mg, yield 39%).

[0358] 1 H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 5.04-4.99 (m, 1H), 4.36 (t, J = 9.9 Hz, 1H), 4.13-4.08 (m, 1H), 3.99-3.97 (m, 2H), 3.60 (d, J = 12.4 Hz, 2H), 3.43-3.41 (m, 1H), 3.32 (t, J = 11.3 Hz, 2H), 3.14-3.01 (m, 5H), 2.22 (t, J = 12.9 Hz, 2H), 1.97 (d, J = 12.4 Hz, 4H), 1.73-1.61 (m, 2H). Example 23. 3,4-Dichloro-2-(3-(1-p-toluene)piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0359] [ka]

[0360] At room temperature, a solution of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (200.0 mg, 0.50 mmol) and 1-bromo-4-methylbenzene (86.9 mg, 0.50 mmol) in tetrahydrofuran (5.0 mL) was mixed with tris(dibenzylideneacetone)dipalladium (46.5 mg, 0.05 mmol), 1,1'-bis(diphenylphosphine)ferrocene (28.1 mg, 0.05 mmol), and sodium tert-butoxide (97.7 mg, 1.02 mmol). The mixture was stirred at 80°C for 16 hours under an argon gas atmosphere. After the reaction was complete, the solution was diluted with water (10 mL), extracted three times with ethyl acetate (10 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane:methanol = 10:1 to obtain the crude product, which was then purified to obtain a white solid (1.2 mg, yield 0.53%).

[0361] LCMS [M+H] + : 443.2. 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 7.40 (d, J=8.8, 1H), 7.02 (d, J=8.2, 2H), 6.86 (d, J=8.6, 2H), 5.00 - 4.95 (m, 1H), 4.31 (s, 1H), 4.09 (s, 1H), 3.65 (s, 2H), 3.14 (d, J=5.5, 1H), 3.05 (d, J=7.4, 1H), 2.92 (s, 1H), 2.74 (t, J=11.1, 2H), 2.19 (s, 3H), 2.02 - 1.96 (m, 2H), 1.84 - 1.78 (m, 2H). Example 24. 3,4-Dichloro-2-(3-(1-(4-trifluoromethylphenyl)piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0362] [ka]

[0363] The preparation was carried out using 1-bromo-4-trifluoromethylbenzene instead of 1-bromo-4-methylbenzene, referring to the preparation method of Example 23.

[0364] LCMS [M+H] + : 497.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 2H), 7.47 (d, J=8.8, 2H), 7.31 (d, J=8.7, 1H), 7.07 (d, J=8.7, 2H), 6.80 (d, J=8.8, 1H), 5.19 (s, 1H), 4.39 (t, J=9.9, 1H), 4.27 (dd, J=10.3, 7.2, 1H), 4.01 - 3.91 (m, 2H), 3.23 (dd, J=8.8, 4.2, 2H), 3.21 - 2.99 (m, 2H), 2.20 - 1.94 (m, 5H). Example 25. 3,4-Dichloro-2-(3-(difluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0365] [ka]

[0366] The preparation was carried out by referring to the preparation method of Example 3, using 2,2-difluoroacetate instead of ethyl 3-hydroxy-3-methylbutyrate.

[0367] LCMS [M+H] + : 320.1. 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H) , 7.46 - 7.20 (m, 2H) , 6.85 (d, J = 8.8 Hz, 1H) , 5.09 - 5.03 (m, 1H) , 4.43 (t, J = 10.2 Hz, 1H), 4.15 (dd, J = 10.7, 6.8 Hz, 1H), 3.30 - 3.25 (m, 1H), 3.07 - 3.01 (m, 1H). Example 26. 3,4-Dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-methoxyphenol

[0368] [ka]

[0369] Synthesis of 4,5-dichlorobenzene-1,2-diol(2):

[0370] [ka]

[0371] The compound catechol (19.5 g, 177.1 mmol) was dissolved in ethyl ether solution (80.0 mL), and the compound sulfonyl chloride (21.9 g, 162.3 mmol) was slowly added to the mixture at 0°C. The mixture was stirred at room temperature for 1 hour under nitrogen gas protection. The reaction mixture was concentrated under vacuum, the concentrate was slurryed with petroleum ether, filtered, and a gray solid (23.0 g, yield 73%) was obtained.

[0372] LCMS [M+H] + : 176.9. Synthesis of 4,5-dichloro-2-methoxyphenol (3):

[0373] [ka]

[0374] Compound 4,5-dichlorobenzene-1,2-diol (100 mg, 0.56 mmol) and potassium carbonate (77.22 mg, 0.56 mmol) were dissolved in N,N-dimethylformamide solution (2.0 mL). Iodomethane (21.9 mg, 0.15 mmol) was added to the mixture at 0°C, and the mixture was stirred at 50°C for 2 hours. The reaction solution was diluted with ethyl acetate and washed twice with saline solution. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 3:2) to obtain a pale yellow solid (60.0 mg, yield 56%).

[0375] LCMS [M+H] + : 190.9. Synthesis of 4,5-dichloro-2-methoxyphenyldiethylcarbamate (4):

[0376] [ka]

[0377] Compound 4,5-dichloro-2-methoxyphenol (4.8 g, 24.87 mmol) was dissolved in pyridine (24.0 mL), and compound diethylaminocarbonyl chloride (6.75 g, 49.78 mmol) was added to the mixture at room temperature. The mixture was stirred at 40°C for 16 hours. The reaction mixture was concentrated under vacuum to remove the pyridine, the residue was diluted with ethyl acetate, washed twice with saline solution, the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under vacuum, and the resulting crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1) to obtain a pale yellow solid (5.4 g, yield 74%).

[0378] LCMS [M+H] + : 291.9. Synthesis of 3,4-dichloro-2-formyl-6-methoxyphenyldiethylcarbamate (5):

[0379] [ka]

[0380] Compound 4,5-dichloro-2-methoxyphenyldiethylcarbamate (5.40 g, 18.50 mmol) was dissolved in tetrahydrofuran (108.0 mL), and n-butyllithium (1.42 g, 22.20 mmol) was added to the mixture at -65°C. The mixture was stirred at -65°C for 30 minutes under nitrogen gas protection. N,N-dimethylformamide solution (2.03 g, 27.75 mmol) was added to the mixture at -65°C, and the mixture was stirred for a further 1 hour at -65°C under nitrogen gas protection. The reaction mixture was quenched with saturated ammonium chloride solution, the mixture was extracted three times with ethyl acetate, washed twice with saline solution, the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under vacuum, and the resulting crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 4:1) to obtain a pale yellow solid (2.2 g, yield 37%). LCMS [M+H] + : 319.8. Synthesis of (E)-3-(2,3-dichloro-6-((diethylaminoformyl)oxy)-5-methoxyphenyl)ethyl acrylate (6):

[0381] [ka]

[0382] Compound 2-(dimethoxyphosphoryl)ethyl acetate (2.03 g, 10.35 mmol) was dissolved in tetrahydrofuran (44.0 mL), and sodium hydride (0.25 g, 6.25 mmol, 60% in mineral oil) was added to the mixture at 0°C, and the mixture was stirred at 0°C for 30 minutes. Compound 3,4-dichloro-2-formyl-6-methoxyphenyldiethylcarbamate (2.2 g, 6.90 mmol) was added to the mixture at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution, the mixture was extracted three times with ethyl acetate, washed twice with saline solution, the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under vacuum, and the resulting crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 4:1) to obtain a white solid (2.2 g, yield 81%).

[0383] LCMS [M+H] + : 389.9. Synthesis of 3-(2,3-dichloro-6-((diethylaminoformyl)oxy)-5-methoxyphenyl)-4-ethyl nitrobutyrate (7):

[0384] [ka]

[0385] Compound (E)-3-(2,3-dichloro-6-((diethylaminoformyl)oxy)-5-methoxyphenyl)ethyl acrylate (1.7 g, 4.40 mmol) was dissolved in nitromethane (17.0 mL), and compound tetramethylguanidine (100.0 mg, 0.88 mmol) was added to the mixture at room temperature. The mixture was stirred at 50°C for 3 hours. The reaction solution was diluted with ethyl acetate and washed twice with saline solution. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a pale yellow solid (0.8 g, yield 41%).

[0386] LCMS [M+H] + : 450.8. Synthesis of 4-amino-3-(2,3-dichloro-6-((diethylaminoformyl)oxy)-5-methoxyphenyl)ethyl butyrate (8):

[0387] [ka]

[0388] Compound 3-(2,3-dichloro-6-((diethylaminoformyl)oxy)-5-methoxyphenyl)-4-ethyl nitrobutyrate (240.0 mg, 0.53 mmol) was dissolved in glacial acetic acid (5.0 mL), and zinc powder (347.9 mg, 5.32 mmol) was added to the mixture at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filter cake was washed with methanol. The resulting filtrate was concentrated under vacuum and adjusted to pH 8 with saturated sodium carbonate aqueous solution. The mixture was extracted three times with ethyl acetate and washed twice with saline solution. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain a colorless oily liquid (200.0 mg, yield 89%).

[0389] LCMS [M+H] + : 421.1. Synthesis of 3,4-dichloro-6-methoxy-2-(5-oxopyrrolidine-3-yl)phenyldiethylcarbamate (9):

[0390] [ka]

[0391] Compound 4-amino-3-(2,3-dichloro-6-((diethylaminoformyl)oxy)-5-methoxyphenyl)ethyl butyrate (600 mg, 1.42 mmol) was dissolved in methanol (12.0 mL), and potassium carbonate (590.5 mg, 4.27 mmol) was added to the mixture at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate and washed twice with saline solution. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain a white solid (450.0 mg, yield 84%).

[0392] LCMS [M+H] + : 375.0. Synthesis of 3,4-dichloro-6-methoxy-2-(5-methoxy-3,4-dihydro-2H-pyrrole-3-yl)phenyldiethylcarbamate (10):

[0393] [ka]

[0394] Compound 3,4-dichloro-6-methoxy-2-(5-oxopyrrolidine-3-yl)phenyldiethylcarbamate (600.0 mg, 1.60 mmol) was dissolved in dichloromethane (12.0 mL), and compound trimethyloxonium tetrafluoroborate (283.8 mg, 1.92 mmol) was added to the mixture at room temperature. The mixture was stirred at 30°C for 3 hours. The reaction solution was concentrated under vacuum to obtain a white solid (600.0 mg, yield 96%).

[0395] LCMS [M+H] + : 389.0. Synthesis of 3,4-dichloro-6-methoxy-2-(5-(2-propionylhydrazine)-3,4-dihydro-2H-pyrrole-3-yl)phenyldiethylcarbamate (11):

[0396] [ka]

[0397] Compound 3,4-dichloro-6-methoxy-2-(5-methoxy-3,4-dihydro-2H-pyrrole-3-yl)phenyldiethylcarbamate (600.0 mg, 1.54 mmol) was dissolved in a dichloromethane solution (12.0 mL). Propionyl hydrazide (407.4 mg, 4.62 mmol) was added to the mixture at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum, and the resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain a colorless oily liquid (650.0 mg, yield 95%).

[0398] LCMS [M+H] + : 444.9. Synthesis of 3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-methoxyphenyldiethylcarbamate (12):

[0399] [ka]

[0400] Compound 3,4-dichloro-6-methoxy-2-(5-(2-propionylhydrazine)-3,4-dihydro-2H-pyrrole-3-yl)phenyldiethylcarbamate (650.0 mg, 1.46 mmol) was dissolved in n-butanol solution (13.0 mL), and the mixture was stirred at 150°C under microwave irradiation for 1.5 hours. The reaction mixture was concentrated under vacuum, and the resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 5:1) to obtain a white solid (460.0 mg, yield 74%).

[0401] LCMS [M+H] + : 427.0. Synthesis of 3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-methoxyphenol (13):

[0402] [ka]

[0403] Compound 3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-methoxyphenyldiethylcarbamate (25.0 mg, 0.059 mmol) was dissolved in dimethyl sulfoxide solution (2.5 mL), potassium hydroxide (16.4 mg, 0.29 mmol) was added to the reaction mixture, and the mixture was reacted at 100°C for 4 hours. The reaction mixture was diluted with ethyl acetate, washed twice with saline solution, and the resulting organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified and separated to obtain a white solid (4.1 mg, yield 21%).

[0404] LCMS [M+H] + : 328.0. 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H) , 7.22 (s, 1H) , 4.97 - 4.90 (m, 1H) , 4.21 (t, J = 9.8 Hz, 1H) , 4.05 - 3.99 (m, 1H) , 3.82 (s, 3H) , 3.12 - 3.05 (m, 2H) , 2.67 (d, J = 7.6 Hz, 2H) , 1.20 (t, J = 7.6 Hz, 3H). Example 27. 3,4-Dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-methylphenol

[0405] [ka]

[0406] Synthesis of 3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-hydroxyphenyldiethylcarbamate (2):

[0407] [ka]

[0408] Compound 3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-methoxyphenyldiethylcarbamate (480.0 mg, 1.12 mmol) was dissolved in a dichloroethane solution (10.0 mL), and boron tribromide (562.8 mg, 2.25 mmol) was added to the mixture at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with ice water, and the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with ethyl acetate and washed twice with saline solution. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 7:1) to obtain a gray solid (300.0 mg, yield 65%).

[0409] LCMS [M+H] + : 413.0. Synthesis of 4,5-dichloro-2-((diethylaminoformyl)oxy)-3-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenyl triflate (3):

[0410] [ka]

[0411] Compounds 3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-hydroxyphenyldiethylcarbamate (100.0 mg, 0.24 mmol) and 4-dimethylaminopyridine (14.8 mg, 0.12 mmol) were dissolved in dichloromethane (5.0 mL). At 0°C, N-phenylbis(trifluoromethanesulfonyl)imide (172.9 mg, 0.48 mmol) and triethylamine (10.1 mg, 0.1 mmol) were added to the mixture, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate and washed twice with saline solution. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 7:1) to obtain a colorless oily liquid (60.0 mg, yield 45%).

[0412] LCMS [M+H] + : 544.7. Synthesis of 3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-methylphenyldiethylcarbamate (4):

[0413] [ka]

[0414] Compounds 4,5-dichloro-2-((diethylaminoformyl)oxy)-3-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenyltriflate (50.0 mg, 0.092 mmol) and trimethylboroxine (13.8 mg, 0.11 mmol) were dissolved in dioxane (5.0 mL). At room temperature, tetrakistriphenylphosphinepalladium (5.30 mg, 0.0046 mmol) and potassium phosphate (29.2 mg, 0.14 mmol) were added to the mixture, and the mixture was stirred at 100°C for 16 hours under nitrogen gas protection. The reaction solution was diluted with ethyl acetate and washed twice with saline solution. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 14:1) to obtain a pale yellow solid (30.0 mg, yield 80%).

[0415] LCMS [M+H] + : 410.9. Synthesis of 3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-methylphenol (5):

[0416] [ka]

[0417] Compound 3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-methylphenyldiethylcarbamate (30.0 mg, 0.073 mmol) was dissolved in dimethyl sulfoxide solution (3.0 mL), potassium hydroxide (20.5 mg, 0.37 mmol) was added to the reaction mixture, and the mixture was reacted at 100°C for 6 hours. The reaction mixture was diluted with ethyl acetate, washed twice with saline solution, and the resulting organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified and separated to obtain a white solid (0.9 mg, yield 4%).

[0418] LCMS [M+H] + : 312.0. 1 H NMR (400 MHz, DMSO-d6) δ 7.35 (s, 1H) , 5.03 - 4.94 (m, 1H) , 4.23 (t, J = 9.9 Hz, 1H) , 4.00 (dd, J = 10.1, 7.4 Hz, 1H) , 3.08 (dt, J = 15.8, 6.9 Hz, 2H), 2.67 (d, J = 7.5 Hz, 2H), 2.16 (s, 3H), 1.21 (t, J = 7.6 Hz, 3H). Example 28. 3,4-Dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-isopropylphenol

[0419] [ka]

[0420] Synthesis of 3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-(prop-1-en-2-yl)phenyldiethylcarbamate (2):

[0421] [ka]

[0422] Compounds 4,5-dichloro-2-((diethylaminoformyl)oxy)-3-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenyltriflate (80.0 mg, 0.15 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (123.3 mg, 0.73 mmol) were dissolved in dioxane (8.0 mL). Compounds tetrakistriphenylphosphinepalladium (33.9 mg, 0.029 mmol) and potassium phosphate (155.7 mg, 0.73 mmol) were added to the mixture at room temperature, and the mixture was heated in a microwave reactor at 100°C for 30 minutes under nitrogen gas protection and stirred. The reaction solution was diluted with water, extracted three times with ethyl acetate, and washed twice with saline solution. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under vacuum, and the crude product was purified by silica gel chromatography (dichloromethane:methanol = 14:1) to obtain a yellow oily substance (40.0 mg, yield 62%).

[0423] LCMS [M+H] + : 436.8. Synthesis of 3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-isopropylphenyldiethylcarbamate (3):

[0424] [ka]

[0425] Compound 3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-(prop-1-en-2-yl)phenyldiethylcarbamate (30.0 mg, 0.073 mmol) was dissolved in a dichloromethane solution (6.0 mL), platinum dioxide (20.5 mg, 0.37 mmol) was added to the reaction mixture, and the mixture was stirred at 25°C for 6 hours. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with methanol, the filtrate was collected and concentrated under vacuum to obtain a yellow oily substance (25.0 mg, yield 83%).

[0426] LCMS [M+H] + : 438.9. Synthesis of 3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-isopropylphenol (4):

[0427] [ka]

[0428] Compound 3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-isopropylphenyldiethylcarbamate (25.0 mg, 0.057 mmol) was dissolved in dimethyl sulfoxide solution (2.5 mL), potassium hydroxide (16.0 mg, 0.28 mmol) was added to the reaction mixture, and the mixture was reacted at 100°C for 1 hour. The reaction mixture was diluted with water, extracted three times with ethyl acetate, and washed twice with saline solution. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under vacuum, and the resulting crude product was purified and separated to obtain a white solid (4.0 mg, yield 4%).

[0429] LCMS [M+H] + : 339.8. 1H NMR (400 MHz, DMSO-d6) δ 7.28 (s, 1H), 5.02 - 4.92 (m, 1H), 4.19 (t, J = 10.0 Hz, 1H), 3.98 (dd, J = 10.0, 7.4 Hz, 1H), 3.20 (dd, J = 13.7, 6.8 Hz, 1H), 3.13 - 2.97 (m, 2H), 2.63 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H), 1.08 (d, J = 6.7 Hz, 6H). Examples 29 / 30. (S)-3,4,6-trichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol and (R)-3,4,6-trichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0430] [ka]

[0431] Synthesis of 1-(allyloxy)-2,4,5-trichlorobenzene(2):

[0432] [ka]

[0433] 2,4,5-Trichlorophenol (10.0 g, 50.65 mmol) and potassium carbonate (14.1 g, 102.02 mmol) were mixed with N,N-dimethylformamide (150.0 mL), and allyl bromide (7.4 g, 61.16 mmol) was added in several portions at 0°C. The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with water (150.0 mL), extracted twice with ethyl acetate (150.0 mL), the organic phases were combined, washed with saturated brine (150.0 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain a yellow solid (10.0 g, yield 83%).

[0434] Synthesis of 2-(allyloxy)-3,5,6-trichlorobenzaldehyde (3):

[0435] [ka]

[0436] 1-(allyloxy)-2,4,5-trichlorobenzene (500.0 mg, 2.12 mmol) was dissolved in tetrahydrofuran (10.0 mL) at -78°C, and n-butyllithium (1.0 mL, 2.54 mmol, in a 2.5 M solution of n-hexane) was added dropwise for at least 30 minutes. After the addition was complete, the mixture was stirred for 30 minutes, and then N,N-dimethylformamide (198.0 mg, 2.54 mmol) was added at the same temperature. The resulting mixture was then stirred at the same temperature for 2 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution (10.0 mL), extracted twice with ethyl acetate (30.0 mL), the organic phases were combined, washed with saturated brine (15.0 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) and eluted to obtain the target product (370.0 mg, yield 47%).

[0437] Synthesis of (E)-3-(2-(allyloxy)-3,5,6-trichlorophenyl)ethyl acrylate (4):

[0438] [ka]

[0439] At 0°C, sodium hydride (112.0 mg, 2.80 mmol, 60% in mineral oil) was added to a solution of 2-(dimethoxyphosphoryl)ethyl acetate (412.0 mg, 2.10 mmol) in tetrahydrofuran (10.0 mL), and the mixture was stirred at 0°C for 30 minutes. Then, 2-(allyloxy)-3,5,6-trichlorobenzenealdehyde (370 mg, 1.40 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was diluted with water (10.0 mL), extracted with ethyl acetate (20.0 mL), washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a yellow solid (370.0 mg, yield 79%).

[0440] Synthesis of 3-(2-(allyloxy)-3,5,6-trichlorophenyl)-4-ethyl nitrobutyrate (5):

[0441] [ka]

[0442] At room temperature, ethyl (E)-3-(2-(allyloxy)-3,5,6-trichlorophenyl)acrylate (370.0 mg, 1.11 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (201.0 mg, 1.33 mmol) were added to a reaction flask containing nitromethane (5.0 mL). The reaction mixture was stirred at 60°C for 16 hours. After the reaction was complete, the mixture was diluted with water (10.0 mL), extracted with ethyl acetate (20.0 mL), washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a pale yellow oily substance (270.0 mg, yield 62%).

[0443] Synthesis of 3-(2-(allyloxy)-3,5,6-trichlorophenyl)-4-aminobutyrate ethyl (6):

[0444] [ka]

[0445] At room temperature, ethyl 3-(2-(allyloxy)-3,5,6-trichlorophenyl)-4-nitrobutyrate (270.0 mg, 0.68 mmol) and zinc powder (445.0 mg, 6.80 mmol) were added to a reaction flask containing glacial acetic acid (5.0 mL), and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was filtered, the filter cake was washed twice with ethyl acetate, the filtrate was collected, and concentrated under reduced pressure to obtain 300 mg of crude product, which was used directly in the next step without purification. LCMS [M+H] + : 365.9. Synthesis of 4-(2-(allyloxy)-3,5,6-trichlorophenyl)pyrrolidine-2-one (7):

[0446] [ka]

[0447] Crude ethyl 3-(2-(allyloxy)-3,5,6-trichlorophenyl)-4-aminobutyrate (300.0 mg, 0.82 mmol) and potassium carbonate (565.0 mg, 4.09 mmol) were added to methanol (7.0 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with water (10 mL), extracted three times with ethyl acetate (20 mL), the organic phases were combined, and the mixture was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) and eluted to obtain a white solid (150.0 mg, yield 86%).

[0448] LCMS [M+H] + : 320.0. Synthesis of 3-(2-(allyloxy)-3,5,6-trichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (8):

[0449] [ka]

[0450] 4-(2-(allyloxy)-3,5,6-trichlorophenyl)pyrrolidine-2-one (150.0 mg, 0.47 mmol) and trimethyloxonium tetrafluoroborate (84.0 mg, 0.56 mmol) were added to dichloromethane (3.0 mL) and stirred at 30°C under nitrogen gas protection for 3 hours. After the reaction was complete, the mixture was filtered and directly concentrated under reduced pressure to obtain 170 mg of crude product, which was used directly in the next step without purification.

[0451] LCMS [M+H] + : 333.8. Synthesis of N'-(3-(2-(allyloxy)-3,5,6-trichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)propionylhydrazide (9):

[0452] [ka]

[0453] 3-(2-(allyloxy)-3,5,6-trichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (170.0 mg, 0.51 mmol) and propionyl hydrazide (135.0 mg, 1.53 mmol) were added to dichloromethane (3.0 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated under direct reduced pressure. It was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain a white solid (150.0 mg, yield 90%).

[0454] LCMS [M+H] + : 389.8. Synthesis of 6-(2-(allyloxy)-3,5,6-trichlorophenyl)-3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole(10):

[0455] [ka]

[0456] Compound N'-(3-(2-(allyloxy)-3,5,6-trichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)propionylhydrazide (150.0 mg, 0.40 mmol) was dissolved in n-butanol (3.0 mL), and the mixture was directly placed in a microwave tube and reacted at 150°C for 20 minutes. After the reaction was complete, the mixture was cooled to room temperature. The crude product was rotated dry and purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain a white solid (80.0 mg, yield 95%).

[0457] LCMS [M+H] + : 286.0. Synthesis of (S)-3,4,6-trichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol and (R)-3,4,6-trichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol (11 / 12):

[0458] [ka]

[0459] At room temperature, 6-(2-(allyloxy)-3,5,6-trichlorophenyl)-3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (80.0 mg, 0.21 mmol) was added to tetrahydrofuran (2.0 mL) with sodium borohydride (16.0 mg, 0.43 mmol) and tetrakistriphenylphosphine palladium (12.0 mg, 0.01 mmol). The gas in the flask was replaced with an argon balloon, and the mixture was stirred at 25°C for 2 hours. After the reaction was complete, the organic phase was filtered through a filter membrane, and the filtrate was rotary-dried to purify the crude product, which yielded a white solid (20.0 mg, yield 23%). The product was separated by SFC (column: CHIRALPAK AD-H 250 mm × 20 mm, 5 μm; mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to obtain a pair of enantiomers.

[0460] The first compound obtained by SFC separation was numbered as Example 29, and analysis under SFC chromatographic conditions showed a retrieval time of 2.19 min.

[0461] LC-MS: [M+H] + : 331.9. 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H) , 7.17 (s, 1H) , 5.35 - 5.28 (m, 1H) , 4.34 (t, J = 10.4 Hz, 1H) , 4.08 (dd, J = 10.8, 7.3 Hz, 1H), 3.25 (s, 1H), 3.07 (dd, J = 16.3, 7.5 Hz, 1H), 2.68 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). The second compound obtained by SFC separation was numbered as Example 30, and analysis under the chromatographic conditions for SFC analysis showed a retrieval time of 2.9 minutes.

[0462] LC-MS: [M+H] + : 331.9. 1 H NMR (400 MHz, DMSO-d6) δ 7.16 (s, 1H) , 5.34 - 5.28 (m, 1H) , 4.34 (t, J = 10.5 Hz, 1H) , 4.08 (dd, J = 10.8, 7.3 Hz, 1H) , 3.23 (s, 1H), 3.08 (d, J = 8.8 Hz, 1H), 2.68 (d, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 31. 3,4-Dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-fluorophenol

[0463] [ka]

[0464] Synthesis of 2-(4,5-dichloro-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2):

[0465] [ka]

[0466] A solution of 1-bromo-4,5-dichloro-2-fluorobenzene (200.0 mg, 0.82 mmol) in tetrahydrofuran (5 mL) was stirred at -10°C for 5 minutes. Then, isopropyl magnesium chloride (0.5 mL, 2 M tetrahydrofuran solution) was added dropwise to the mixture, and the mixture was stirred at -10°C for 1 hour. Subsequently, a solution of isopropanolboronic acid pinacol ester (181.1 mg, 0.98 mmol) in tetrahydrofuran (3 mL) was added dropwise. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 1 hour. After the reaction was complete, the mixture was diluted with water (20.0 mL), extracted twice with ethyl acetate (30.0 mL), the organic phases were combined, washed with saturated brine (50.0 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain a white solid (100.0 mg, yield 41%).

[0467] 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 5.6 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 1.36 (s, 12H). Synthesis of 4,5-dichloro-2-fluorophenol (3):

[0468] [ka]

[0469] An aqueous solution of 1 M sodium hydroxide (0.4 g, 10.20 mmol) was added to a solution of 2-(4,5-dichloro-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 3.40 mmol) in tetrahydrofuran (10 mL). The mixture was cooled to 0°C, and then hydrogen peroxide (0.3 g, 10.20 mmol) was added to the mixture. The mixture was stirred at 25°C for 4 hours. After the reaction was complete, the mixture was quenched with sodium bisulfite (10.0 mL), extracted twice with ethyl acetate (50.0 mL), the organic phases were combined, washed with saturated brine (50.0 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was used directly in the next step without purification.

[0470] LC-MS: [M+H] + : 179.0. Synthesis of 1-(allyloxy)-4,5-dichloro-2-fluorobenzene (4):

[0471] [ka]

[0472] 4,5-Dichloro-2-fluorophenol (1.0 g, 5.50 mmol) and potassium carbonate (1.9 g, 13.75 mmol) were mixed with N,N-dimethylformamide (10.0 mL), and allyl bromide (1.0 g, 8.25 mmol) was added in several portions at 0°C. The mixture was stirred at 25°C for 16 hours. After the reaction was complete, the mixture was diluted with water (20.0 mL), extracted twice with ethyl acetate (100.0 mL), the organic phases were combined, washed with saturated brine (100.0 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain a yellow solid (0.8 g, yield 65%).

[0473] 1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 10.9 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 6.04 (ddd, J = 22.5, 10.6, 5.4 Hz, 1H), 5.42 (dd, J = 17.3, 1.6 Hz, 1H), 5.31 (dd, J = 10.5, 1.3 Hz, 1H), 4.70 (d, J = 5.4 Hz, 2H). Synthesis of 2-(allyloxy)-5,6-dichloro-3-fluorobenzaldehyde (5):

[0474] [ka]

[0475] 1-(allyloxy)-4,5-dichloro-2-fluorobenzene (550.0 mg, 2.49 mmol) was dissolved in tetrahydrofuran (10.0 mL) at -78°C, and n-butyllithium (1.0 mL, 2.61 mmol, in a 2.5 M solution of n-hexane) was added dropwise for at least 3 minutes. After the addition was complete, the mixture was stirred for 30 minutes, and then N,N-dimethylformamide (363.7 mg, 4.98 mmol) was added at the same temperature. The resulting mixture was then stirred at the same temperature for 2 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution (10.0 mL), extracted twice with ethyl acetate (30.0 mL), the organic phases were combined, washed with saturated brine (15.0 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether:ethyl acetate (15:1) to obtain the target product (500.0 mg, yield 80%).

[0476] 1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 6.18 - 5.96 (m, 1H), 5.43 (dd, J = 17.3, 1.6 Hz, 1H), 5.33 (dd, J = 10.5, 1.3 Hz, 1H), 4.76 (d, J = 5.3 Hz, 2H). Synthesis of (E)-3-(2-(allyloxy)-5,6-dichloro-3-fluorophenyl)ethyl acrylate (6):

[0477] [ka]

[0478] At 0°C, sodium hydride (82.9 mg, 2.07 mmol, 60% in mineral oil) was added to a solution of 2-(dimethoxyphosphoryl)ethyl acetate (406.4 mg, 2.07 mmol) in tetrahydrofuran (10.0 mL), and the mixture was stirred at 0°C for 30 minutes. Then, 2-(allyloxy)-5,6-dichloro-3-fluorobenzaldehyde (430.0 mg, 1.73 mmol) was added, and the mixture was stirred for another 3 hours. After the reaction was complete, the mixture was diluted with water (30.0 mL), extracted twice with ethyl acetate (30.0 mL), the organic phases were combined, washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) and eluted to obtain a yellow solid (550.0 mg, yield 94%).

[0479] 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 16.3 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 6.53 (dd, J = 16.4, 0.7 Hz, 1H), 6.07 - 5.94 (m, 1H), 5.39 (dd, J = 17.3, 1.6 Hz, 1H), 5.32 - 5.24 (m, 1H), 4.68 (dd, J = 4.1, 1.2 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H). Synthesis of 3-(2-(allyloxy)-5,6-dichloro-3-fluorophenyl)-4-nitrobutyrate ethyl (7):

[0480] [ka]

[0481] At room temperature, ethyl (E)-3-(2-(allyloxy)-5,6-dichloro-3-fluorophenyl)acrylate (550.0 mg, 1.72 mmol) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (314.8 mg, 2.07 mmol) were added to a reaction flask containing nitromethane (10.0 mL). The reaction mixture was stirred at 60°C for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting crude product was diluted with water (10.0 mL), extracted with ethyl acetate (20.0 mL), washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) and eluted to obtain a pale yellow oily substance (500.0 mg, yield 64%).

[0482] LC-MS: [M+Na] + : 401.8. Synthesis of 3-(2-(allyloxy)-5,6-dichloro-3-fluorophenyl)-4-aminobutyrate ethyl (8):

[0483] [ka]

[0484] At room temperature, 3-(2-(allyloxy)-5,6-dichloro-3-fluorophenyl)-4-nitrobutyrate ethyl (250.0 mg, 0.66 mmol) and zinc powder (430.1 mg, 6.58 mmol) were added to a reaction flask containing glacial acetic acid (5.0 mL), and the mixture was stirred at 25°C for 16 hours. After the reaction was complete, the mixture was filtered, the filter cake was washed twice with ethyl acetate (10 mL), the filtrate was collected, and concentrated under reduced pressure to obtain 200 mg of crude product, which was used directly in the next step without purification. LC-MS: [M+H] + : 350.0. Synthesis of 4-(2-(allyloxy)-5,6-dichloro-3-fluorophenyl)pyrrolidine-2-one (9):

[0485] [ka]

[0486] Crude ethyl 3-(2-(allyloxy)-5,6-dichloro-3-fluorophenyl)-4-aminobutyrate (400.0 mg, 1.14 mmol) and potassium carbonate (472.9 mg, 3.43 mmol) were added to methanol (10.0 mL) and stirred at 25°C for 3 hours. After the reaction was complete, the mixture was diluted with water (10 mL), extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) and eluted to obtain a yellow solid (260.0 mg, yield 63%).

[0487] LC-MS: [M+H] + : 304.0. Synthesis of 3-(2-(allyloxy)-5,6-dichloro-3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole(10):

[0488] [ka]

[0489] 4-(2-(allyloxy)-5,6-dichloro-3-fluorophenyl)pyrrolidine-2-one (260.0 mg, 0.85 mmol) and trimethyloxonium tetrafluoroborate (139.1 mg, 0.94 mmol) were added to dichloromethane (3.0 mL) and stirred at 30°C under nitrogen gas protection for 3 hours. After the reaction was complete, the mixture was filtered and directly concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without purification.

[0490] LC-MS: [M+H] + : 318.0. Synthesis of N'-(3-(2-(allyloxy)-5,6-dichloro-3-fluorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)propionylhydrazide (11):

[0491] [ka]

[0492] 3-(2-(allyloxy)-5,6-dichloro-3-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (260.0 mg, 0.82 mmol) and propionyl hydrazide (216.0 mg, 2.45 mmol) were added to dichloromethane (3.0 mL) and stirred at 25°C for 16 hours. After the reaction was complete, the mixture was concentrated under direct reduced pressure. The solution was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) and eluted to obtain a white solid (140.0 mg, yield 38%).

[0493] LC-MS: [M+H] + : 374.0. Synthesis of 6-(2-(allyloxy)-5,6-dichloro-3-fluorophenyl)-3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole(12):

[0494] [ka]

[0495] Compound N'-(3-(2-(allyloxy)-5,6-dichloro-3-fluorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)propionylhydrazide (120.0 mg) was dissolved in n-butanol (3.0 mL), and the mixture was directly placed in a microwave tube and reacted at 150°C for 30 minutes. After the reaction was complete, it was cooled to room temperature. The crude product was rotated dry and purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain a white solid (80.0 mg, yield 70%).

[0496] LC-MS: [M+H] + : 356.1. Synthesis of 3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-6-fluorophenol (13):

[0497] [ka]

[0498] At room temperature, 6-(2-(allyloxy)-5,6-dichloro-3-fluorophenyl)-3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (80.0 mg, 0.22 mmol) was added to tetrahydrofuran (2.0 mL) with sodium borohydride (12.7 mg, 0.34 mmol) and tetrakistriphenylphosphine palladium (25.9 mg, 0.02 mmol). The gas in the flask was replaced with an argon balloon, and the mixture was stirred at 25°C for 2 hours. After the reaction was complete, the organic phase was filtered through a filter membrane, and the filtrate was rotate-dried to purify the crude product, which yielded a white solid (5.1 mg, yield 7%).

[0499] LC-MS: [M+H] + : 316.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.21 (d, J = 8.5 Hz, 1H), 4.91 (dd, J = 12.2, 4.7 Hz, 1H), 4.37 (t, J = 10.1 Hz, 1H), 4.00 (dd, J = 10.8, 7.0 Hz, 1H) , 3.30 (d, J = 11.2 Hz, 1H) , 2.95 (dd, J = 16.5, 7.4 Hz, 1H) , 2.69 (q, J = 7.5 Hz, 2H) , 1.21 (t, J = 7.6 Hz, 3H). Example 32. (S)-3,4-dichloro-2-(3-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0500] [ka]

[0501] Synthesis of 3-hydroxypropionylhydrazide (2):

[0502] [ka]

[0503] A methanol solution (50.0 mL) of methyl 3-hydroxypropionate (5.0 g, 0.048 mol) and hydrazine hydrate (6.0 g, 0.14 mol, 80% aqueous solution) was stirred at 60°C for 12 hours. After the reaction was complete, dichloromethane (20.0 mL) was added to the resulting mixture to precipitate the product. The solid was filtered to obtain a white solid (2.5 g, yield: 50%).

[0504] LC-MS: [M+H] + : 105.2. Synthesis of (S)-N'-3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)-3-hydroxypropionylhydrazide (3):

[0505] [ka]

[0506] A solution of 3-hydroxypropionyl hydrazide (208.0 mg, 1.99 mmol) and (S)-3-(6-allyloxy)-2,3-dichlorophenyl-5-methoxy-3,4-dihydro-2H-pyrrole (200.0 mg, 0.66 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was freeze-dried under reduced pressure to remove the dimethyl sulfoxide. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (150.0 mg, yield: 60%).

[0507] LC-MS: [M+H] + : 372.1. Synthesis of (S)-2-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)ethane-1-ol (4):

[0508] [ka]

[0509] (S)-N'-3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)-3-hydroxypropionyl hydrazide (150.0 mg, 0.41 mmol) was transferred to a microwave tube, and n-butanol solution (3.0 mL) was added. The mixture was stirred at 150°C for 1 hour. After the reaction was complete, n-butanol was removed by vacuum distillation. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (80.0 mg, yield: 56%).

[0510] LC-MS: [M+H] + : 354.2. Synthesis of (S)-3,4-dichloro-2-(3-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol (5):

[0511] [ka]

[0512] At room temperature, (S)-2-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)ethane-1-ol (80.0 mg, 0.22 mmol) was dissolved in tetrahydrofuran (1.0 mL), to which tetrakistriphenylphosphine palladium (130.4 mg, 0.11 mmol) and sodium borohydride (13.8 mg, 0.36 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the organic phase was filtered through a filter membrane, and the filtrate was rotate-dried to purify the crude product, which yielded a white solid (10.5 mg, yield 14%).

[0513] LC-MS: [M+H] + : 314.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.40 (d, J=8.8, 1H), 6.87 (d, J=8.8, 1H), 4.98 - 4.88 (m, 1H), 4.83 (t, J=5.3, 1H), 4.23 (t, J=9.9, 1H), 4.08 (dd, J=10.2, 8.0, 1H), 3.68 (dd, J=11.9, 6.4, 2H), 3.10 (d, J=9.0, 2H), 2.81 (t, J=6.6, 2H). Example 33. (S)-3,4-dichloro-2-(3-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0514] [ka]

[0515] The preparation was carried out using tetrahydro-2H-pyran-4-formohydrazide instead of 3-hydroxypropionylhydrazide, referring to the preparation method of Example 32.

[0516] LCMS [M+H] + : 354.0. 1 H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 5.02 - 4.90 (m, 1H), 4.28 (t, J = 9.8 Hz, 1H), 4.06 (dd, J = 10.1, 7.5 Hz, 1H), 3.91 (dd, J = 8.3, 3.6 Hz, 2H), 3.45 - 3.39 (m, 2H), 3.12 (dd, J = 15.8, 10.0 Hz, 1H), 3.06 - 2.98 (m, 2H), 1.87 - 1.67 (m, 4H). Example 34. (S)-3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0517] [ka]

[0518] The preparation was carried out using propionyl hydrazide instead of 3-hydroxypropionyl hydrazide, referring to the preparation method of Example 32.

[0519] LCMS [M+H] + : 298.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.97 (dd, J = 17.5, 8.5 Hz, 1H), 4.21 (t, J = 9.8 Hz, 1H), 4.03 (dd, J = 10.1, 7.8 Hz, 1H), 3.14 - 3.03 (m, 2H), 2.67 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 35. (S)-3,4-dichloro-2-(3-(piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0520] [ka]

[0521] Synthesis of (S)-4-(2-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)hydrazine-1-carbonyl)piperidine-1-carboxylate tert-butyl(2):

[0522] [ka]

[0523] (S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (125.0 mg, 0.42 mmol) and 4-(hydrazinecarbonyl)piperidine-1-carboxylate tert-butyl (305.2 mg, 1.25 mmol) were mixed in an n-butanol solution (2.0 mL) and stirred at 70°C for 3 hours. After the reaction was complete, an n-butanol solution of the target product (approximately 200 mg, yield: 94%) was obtained and used directly in the next reaction.

[0524] LC-MS: [M+H] + : 511.1. Synthesis of (S)-4-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)piperidine-1-carboxylate tert-butyl(3):

[0525] [ka]

[0526] A solution of (S)-4-(2-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)hydrazine-1-carbonyl)piperidine-1-carboxylate tert-butyl in n-butanol (200.0 mg, 0.39 mmol, in 2.0 mL of n-butanol solution) was transferred to a microwave tube, and the mixture was stirred at 160°C for 2 hours. After the reaction was complete, n-butanol was removed by vacuum distillation. The resulting crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:1) to obtain a white solid (140 mg, yield: 73%).

[0527] LC-MS: [M-Boc +H] + : 393.1. Synthesis of (S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole(4):

[0528] [ka]

[0529] (S)-4-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)piperidine-1-carboxylate tert-butyl (120.0 mg, 0.24 mmol) was mixed with trifluoroacetic acid (1.0 mL) and dichloromethane (2.0 mL) and stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by vacuum distillation. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (30.0 mg, yield: 31%).

[0530] LC-MS: [M+H] + : 393.1. Synthesis of (S)-3,4-dichloro-2-(3-(piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol (5):

[0531] [ka]

[0532] At room temperature, tetrakistriphenylphosphine palladium (2.8 mg, 0.002 mmol) was added to a solution of (S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (24.0 mg, 0.06 mmol), polymethylhydrogensiloxane (27.1 mg, 0.12 mmol), and zinc chloride (0.8 mg, 0.005 mmol) in tetrahydrofuran (2.0 mL). The gas in the flask was replaced with an argon balloon, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the organic phase was filtered through a filter membrane, and the filtrate was rotate-dried to purify the crude product, which yielded a white solid (2.1 mg, yield 10%).

[0533] LC-MS: [M+H] + : 353.1. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.00 - 4.92 (m, 1H), 4.26 (t, J = 9.8 Hz, 1H), 4.07 (dd, J = 9.9, 7.7 Hz, 1H), 3.19 (d, J = 9.4 Hz, 2H), 3.12 - 3.04 (m, 2H), 3.01 (d, J = 4.4 Hz, 1H), 2.81 (t, J = 11.1 Hz, 2H), 1.95 (t, J = 12.1 Hz, 2H), 1.82 - 1.71 (m, 2H). Example 36. (S)-3,4-dichloro-2-(3-(1-isopropylpiperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0534] [ka]

[0535] At room temperature, triethylamine (6.0 mg, 0.06 mmol) was added to a methanol and dichloromethane mixture (volume ratio 1:1, 3.0 mL) containing (S)-3,4-dichloro-2-(3-(piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol (21.2 mg, 0.06 mmol) and stirred for 5 minutes. Then acetone (7.0 mg, 0.12 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After cooling to 0°C, sodium triacetoxyborohydride (39.0 mg, 0.18 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After monitoring the completion of the reaction by liquid chromatography-mass spectrometry, the mixture was extracted with ethyl acetate (10 mL). The organic phase was washed with saturated saline solution (10 mL), extracted three times, dried over anhydrous sodium sulfate, and the resulting residue was concentrated under reduced pressure and further purified to obtain a white solid (6.9 mg, yield: 29%).

[0536] LC-MS: [M+H] + : 395.1. 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.97 (t, J = 8.6 Hz, 1H), 4.27 (t, J = 9.8 Hz, 1H), 4.07 (dd, J = 10.0, 7.6 Hz, 1H), 3.13 - 2.96 (m, 5H), 2.89 - 2.81 (m, 1H), 2.54 (d, J = 3.7 Hz, 1H), 2.48 (s, 1H), 1.98 (t, J = 12.5Hz, 2H), 1.85 - 1.74 (m, 2H), 1.07 (d, J = 6.6 Hz, 6H). Example 37. (S)-1-(4-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)piperidine-1-yl)ethane-1-one

[0537] [ka]

[0538] Synthesis of (S)-2-(3-(1-acetylpiperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenylacetate (2):

[0539] [ka]

[0540] At room temperature, acetic anhydride (12.0 mg, 0.12 mmol) was added to a 3.0 mL dichloromethane solution (21.2 mg, 0.06 mmol) of (S)-3,4-dichloro-2-(3-(piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol, stirred at room temperature for 10 minutes, then cooled to 0°C. Sodium acetate (15 mg, 0.18 mmol) was added, and the mixture was reacted at 0°C for 1 hour. After monitoring the completion of the reaction by liquid chromatography-mass spectrometry, the mixture was directly rotated-dried to obtain a white solid, which was used directly in the next step.

[0541] LC-MS: [M+H] + : 436.1. Synthesis of (S)-1-(4-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)piperidine-1-yl)ethane-1-one (3):

[0542] [ka]

[0543] At room temperature, lithium hydroxide (6.0 mg, 0.24 mmol) was added to a mixed solution (5:1, 3.0 mL) of crude (S)-2-(3-(1-acetylpiperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenyl acetate (25.0 mg, 0.06 mmol) with tetrahydrofuran and water. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by liquid chromatography-mass spectrometry. The solution was then directly rotated-dried and preparatively purified to obtain a white solid (1.7 mg, yield: 7%).

[0544] LC-MS: [M+H] + : 395.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 5.01 - 4.92 (m, 1H), 4.30 (dd, J = 20.4, 10.9 Hz, 2H), 4.07 (s, 1H), 3.85 (d, J = 10.3 Hz, 1H), 3.08 (ddd, J = 23.3, 21.4, 9.9 Hz, 4H), 2.72 (t, J = 11.4 Hz, 1H), 2.01 (s, 3H), 1.95 - 1.83 (m, 2H), 1.72 - 1.62 (m, 1H), 1.54 - 1.45 (m, 1H). Example 38. (S)-5-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)-1-methylpyridine-2(1H)-one

[0545] [ka]

[0546] The preparation can be carried out by referring to the preparation method of Example 32, and replacing 3-hydroxypropionyl hydrazide with 1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide.

[0547] LCMS [M+H] + : 377.0. 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.01 (d, J = 9.3 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 9.5 Hz, 1H), 5.26 (dd, J = 16.2, 8.0 Hz, 1H), 4.62 (t, J = 9.6 Hz, 1H), 4.53 - 4.47 (m, 1H), 3.64 (s, 3H), 3.36 (d, J = 8.9 Hz, 2H). Example 39. (S)-4-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)-1-methylpyridine-2(1H)-one

[0548] [ka]

[0549] The preparation can be carried out by referring to the preparation method of Example 32, and replacing methyl 3-hydroxypropionate with methyl 1-methyl-2-oxo-1,2-dihydropyridine-4-formate.

[0550] LCMS [M+H] + : 377.0. 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 0H) , 7.81 (d, J = 7.1 Hz, 1H) , 7.38 (d, J = 8.8 Hz, 1H) , 6.83 (d, J = 8.7 Hz, 1H) , 6.75 (dd, J = 7.1, 2.0 Hz, 1H), 6.71 (d, J = 1.8 Hz, 1H), 5.10 - 5.00 (m, 1H), 4.63 (t, J = 10.0 Hz, 1H), 4.33 (dd, J = 10.3, 7.0 Hz, 1H), 3.45 (s, 3H), 3.25 (d, J = 10.2 Hz, 1H) , 3.11 (dd, J = 16.2, 7.3 Hz, 1H). Example 40. (S)-3,4-dichloro-2-(3-(1-methyl-1H-pyrazole-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0551] [ka]

[0552] The preparation can be carried out by referring to the preparation method of Example 32, and replacing 3-hydroxypropionyl hydrazide with 1-methylpyrazole-4-formohydrazide.

[0553] LCMS [M+H] + : 350.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.26 (s, 1H), 7.87 (s, 1H), 7.38 (d, J=8.8, 1H), 6.85 (d, J=8.8, 1H), 5.10 - 5.01 (m, 1H), 4.43 (t, J=9.9, 1H), 4.19 (dd, J=10.1, 7.4, 1H), 3.88 (s, 3H), 3.14 (dt, J=15.8, 6.9, 2H). Example 41. (S)-2-(3-(1H-indazole-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenol

[0554] [ka]

[0555] The preparation can be carried out by referring to the preparation method of Example 32, and replacing methyl 3-hydroxypropionate with methyl 1H-indazole-4-carboxylate. LCMS [M+H] + : 386.0. 1 H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 10.76 (s, 1H), 8.63 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 6.9 Hz, 1H), 7.41 (dd, J = 15.9, 8.4 Hz, 2H), 6.85 (d, J = 8.8 Hz, 1H), 5.12 (t, J = 8.7 Hz, 1H), 4.68 (t, J = 9.9 Hz, 1H), 4.41 (dd, J = 10.2, 7.0 Hz, 1H), 3.28 (d, J = 10.2 Hz, 1H), 3.18 (d, J = 7.4 Hz, 1H). Example 42. (S)-2-(3-(6-aminopyridine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenol

[0556] [ka]

[0557] The preparation can be carried out by referring to the preparation method of Example 32, with the 3-hydroxypropionyl hydrazide replaced by 6-aminonicotinyl hydrazide.

[0558] LCMS [M+H] + : 362.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.41 (s, 1H), 8.22 (s, 1H), 7.94 (s, 2H), 7.43 (d, J = 8.8 Hz, 1H), 6.90 (t, J = 9.5 Hz, 2H), 5.12 - 5.03 (m, 1H), 4.66 (t, J = 10.0 Hz, 1H), 4.44 - 4.32 (m, 1H), 3.35 (dd, J = 16.1, 10.0 Hz, 1H), 3.23 (dd, J = 16.3, 7.4 Hz, 1H). Example 43. (S)-2-(3-(2-aminopyridine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenol

[0559] [ka]

[0560] The preparation can be carried out by referring to the preparation method of Example 32, but replacing 3-hydroxypropionyl hydrazide with 2-aminoisonicotinyl hydrazide.

[0561] LCMS [M+H] + : 362.0. 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.13 (s, 1H), 7.99 (d, J = 5.3 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.95 (dd, J = 7.6, 2.2 Hz, 2H), 6.87 (d, J = 8.8 Hz, 1H), 6.19 (s, 2H), 5.13 - 5.04 (m, 1H), 4.59 (t, J = 10.0 Hz, 1H), 4.30 (dd, J = 10.2, 7.0 Hz, 1H), 3.26 (dd, J = 16.0, 10.2Hz, 1H), 3.12 (dd, J = 16.0, 7.4 Hz, 1H). Example 44. (S)-3,4-dichloro-2-(3-(1-(2-hydroxyethyl)-1H-pyrazole-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0562] [ka]

[0563] The preparation can be carried out by referring to the preparation method of Example 32, and replacing 3-hydroxypropionyl hydrazide with 1-(2-hydroxyethyl)-1H-pyrazole-4-formohydrazide.

[0564] LCMS [M+H] + : 380.1. 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.24 (s, 1H), 7.89 (d, J=0.4, 1H), 7.41 (d, J=8.8, 1H), 6.87 (d, J=8.8, 1H), 5.06 (s, 1H), 4.93 (t, J=5.3, 1H), 4.45 (t, J=10.0, 1H), 4.21 - 4.14 (m, 3H), 3.76 (q, J=5.5, 2H), 3.24 - 3.16 (m, 1H), 3.10 (d, J=7.6, 1H). Example 45. (S)-2-(3-(azetidine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenol

[0565] [ka]

[0566] Synthesis of 3-(hydrazinecarbonyl)azetidine-1-carboxylate tert-butyl(2):

[0567] [ka]

[0568] A methanol solution (30.0 mL) of 1-(tert-butyl)-3-methylazetidine-1,3-dicarboxylic acid ester (3.0 g, 0.014 mol) and hydrazine hydrate (2.5 g, 0.062 mol, 80% aqueous solution) was stirred at 50°C for 16 hours. Methanol was removed by vacuum distillation. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (2 g, yield: 67%).

[0569] Synthesis of (S)-3-(2-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)hydrazine-1-carbonyl)azetidine-1-carboxylate tert-butyl (3):

[0570] [ka]

[0571] A solution of tert-butyl 3-(hydrazinecarbonyl)azetidine-1-carboxylate (648.3 mg, 2.99 mmol) and (S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (300.0 mg, 0.99 mmol) in dimethyl sulfoxide (10.0 mL) was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was freeze-dried under reduced pressure to remove the dimethyl sulfoxide. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (250.0 mg, yield: 51%). LC-MS: [M+H] + : 483.1. Synthesis of (S)-3-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)azetidine-1-carboxylate tert-butyl(4):

[0572] [ka]

[0573] (S)-3-(2-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)hydrazine-1-carbonyl)azetidine-1-carboxylate tert-butyl (250.0 mg, 0.51 mmol) was transferred to a microwave tube, and n-butanol solution (3.0 mL) was added. The mixture was stirred at 150°C for 30 minutes. After the reaction was complete, n-butanol was removed by vacuum distillation. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (100.0 mg, yield: 41%). LC-MS: [M+H] + : 365.2. Synthesis of (S)-3-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)azetidine-1-carboxylate tert-butyl(5):

[0574] [ka]

[0575] At room temperature, (S)-3-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)azetidine-1-carboxylate tert-butyl (100.0 mg, 0.20 mmol) was dissolved in tetrahydrofuran (3.0 mL), to which tetrakistriphenylphosphine palladium (123.8 mg, 0.10 mmol) and sodium borohydride (12.1 mg, 0.32 mmol) were added, and the mixture was stirred at 25°C for 2 hours. After the reaction was complete, the solvent was removed by vacuum distillation. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:5) to obtain the target product (80.0 mg, yield 87%).

[0576] LC-MS: [M+H] + : 425.2. Synthesis of (S)-2-(3-(azetidine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenol(6):

[0577] [ka]

[0578] At room temperature, (S)-3-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)azetidine-1-carboxylate tert-butyl (60.0 mg, 0.14 mmol) was dissolved in a mixed solvent of dichloromethane / trifluoroacetic acid = 3:1 (3.0 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the organic phase was filtered through a filter membrane, the filtrate was rotated dry, and the crude product was purified to obtain a white solid (5.0 mg, yield 10%).

[0579] LC-MS: [M+H] + : 325.1. 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 0.33H), 7.39 (d, J=8.8, 1H), 6.87 (d, J=8.9, 1H), 5.00 - 4.94 (m, 1H), 4.26 (q, J=9.8, 1H), 4.03 (dd, J=15.8, 8.1, 2H), 3.91 - 3.77 (m, 4H), 3.10 (t, J=8.9, 3H). Example 46. (S)-2-(3-(1H-pyrazole-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenol

[0580] [ka]

[0581] The preparation can be carried out by referring to the preparation method of Example 32, and replacing methyl 3-hydroxypropionate with methyl 1H-pyrazole-4-carboxylate.

[0582] LCMS [M+H] + : 336.1. 1 H NMR (400 MHz, DMSO-d6) δ 13.26 (s, 1H), 10.82 - 10.40 (m, 1H), 8.17 (ddd, J=103.5, 75.2, 55.7, 2H), 7.35 (d, J=8.8, 1H), 6.81 (d, J=8.7, 1H), 5.01 (s, 1H), 4.42 (t, J=10.0, 1H), 4.16 (dd, J=10.1, 7.4, 1H), 3.11 (dd, J=24.1, 8.9, 2H). Examples 47-48. 3,4-Dichloro-2-((S)-3-((S)-pyrroridine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol and 3,4-Dichloro-2-((S)-3-((R)-pyrroridine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0583] [ka]

[0584] Synthesis of 3-(2-((S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate tert-butyl(2):

[0585] [ka]

[0586] Compound (S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (600.0 mg, 2.00 mmol) and 3-(hydrazinecarbonyl)pyrrolidine-1-carboxylate tert-butyl (920.6 mg, 4.00 mmol) were dissolved in dimethyl sulfoxide solution (6 mL) and reacted at 25°C for 16 hours. After the reaction was complete, the reaction mixture was freeze-dried under vacuum, and the resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain a white solid (800.0 mg, yield 80%).

[0587] LC-MS: [M+H] + : 497.0. Synthesis of 3-((S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrrolidine-1-carboxylate tert-butyl(3) and (S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(pyrrolidine-3-yl)-6,7-dihydro-5H-pyrrololo[2,1-c][1,2,4]triazole(3'):

[0588] [ka]

[0589] Compound 3-(2-((S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate tert-butyl (600.0 mg, 1.20 mmol) was dissolved in n-butanol (6 mL), and the mixture was stirred at 150°C under microwave for 30 minutes. After the reaction was complete, the reaction solution was concentrated under vacuum, and the resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain the target product (3) (200.0 mg, yield 35%), which was a white solid. LC-MS: [M+H] + : 479.0. Furthermore, the target product (3') (300.0 mg, 66% yield), a white solid, was simultaneously obtained during the column chromatography process. LC-MS: [M+H] + : 379.0. Synthesis of 3-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrroridine-1-carboxylate tert-butyl(4):

[0590] [ka]

[0591] Compound 3-((S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrrolidine-1-carboxylate tert-butyl (200.0 mg, 0.42 mmol) was dissolved in tetrahydrofuran solution (20 mL). Sodium borohydride (23.6 mg, 0.62 mmol) and tetrakistriphenylphosphine palladium (96.2 mg, 0.083 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum, and the resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain a white solid (120.0 mg, yield 65%).

[0592] LC-MS: [M+H] + : 439.0. Synthesis of 3,4-dichloro-2-((6S)-3-(pyrroridine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol (5):

[0593] [ka]

[0594] Compound 3-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrrolidine-1-carboxylate tert-butyl (100.0 mg, 0.23 mmol) was dissolved in a mixed solution of trifluoroacetic acid and dichloromethane (3:1, 4 mL) and reacted at room temperature for 2 hours. After the reaction was complete, the reaction mixture was evaporated, purified, and separated to obtain a white solid (50.0 mg, yield 65%).

[0595] LC-MS: [M+H] + : 339.0. Preparation of 3,4-dichloro-2-((6S)-3-((S)-pyrrolidine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol and 3,4-dichloro-2-((6S)-3-((R)-pyrrolidine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol:

[0596] [ka]

[0597] 3,4-Dichloro-2-((6S)-3-(pyrroridine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol (50.0 mg, 0.15 mmol) was purified by chiral preparative separation (column: CHIRALPAK IC 250 mm 20 mm, 5 μm, mobile phase: 40% IPA (NH4OH 0.2%)) to obtain a pair of enantiomers.

[0598] The first compound obtained by SFC resolution was numbered as Example 47 (10.1 mg, 20% yield), and analysis under SFC chromatographic conditions showed a retrieval time of 6.75 min.

[0599] 1H NMR (400 MHz, DMSO-d6) δ 7.32 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.99 - 4.90 (m, 1H), 4.22 (t, J = 9.8 Hz, 1H), 4.11 - 4.03 (m, 1H), 3.67 - 3.37 (m, 1H), 3.34 - 3.25 (m, 1H), 3.20 - 3.12 (m, 1H), 3.08 (d, J = 8.9 Hz, 2H), 2.93 - 2.85 (m, 2H), 2.08 (dt, J = 13.8, 8.2Hz, 1H), 1.93 (dt, J = 19.8, 7.2 Hz, 1H). The second compound obtained by SFC separation was numbered as Example 48 (11.9 mg, 24% yield), and analysis under SFC chromatographic conditions showed an RT of 9.0 min.

[0600] 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 4.95 (dd, J = 17.3, 8.9 Hz, 1H), 4.27 (t, J = 9.9 Hz, 1H), 4.07 (dd, J = 10.0, 7.7 Hz, 1H), 3.55 - 3.48 (m, 1H), 3.44 - 3.37 (m, 1H), 3.23 (dd, J = 11.1, 7.2 Hz, 1H), 3.11 (dtt, J = 15.7, 10.5, 5.2 Hz, 4H), 2.23 (td, J = 13.3, 7.7 Hz, 1H), 1.97 (td, J = 15.0, 7.5 Hz, 1H). Example 49. 3,4-Dichloro-2-((6S)-3-(1-methylpyrrolidine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0601] [ka]

[0602] At room temperature, a solution of 3,4-dichloro-2-((6S)-3-(pyrroridine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol (15.0 mg, 0.04 mmol) in dichloromethane (2.0 mL) was mixed with paraformaldehyde (12.0 mg, 0.40 mmol), and the mixture was stirred at room temperature for 0.5 hours. After cooling to 0°C, sodium triacetoxyborohydride (28.0 mg, 0.13 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was directly rotated dry, and the crude product was preparatively purified to obtain a white solid (3.0 mg, yield: 20%).

[0603] LC-MS: [M+H] + : 353.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.9 Hz, 1H), 5.00 (dd, J = 15.6, 7.6 Hz, 1H), 4.32 (t, J = 9.9 Hz, 1H), 4.16 - 4.09 (m, 1H), 3.93 (d, J = 7.1 Hz, 1H), 3.70 (d, J = 29.7 Hz, 1H), 3.48 - 3.36 (m, 1H), 3.18 (t, J = 8.8 Hz, 2H), 2.91 (d, J = 17.5 Hz, 3H), 2.51 (s, 1H), 2.35 (dd, J = 27.3, 9.3 Hz, 2H). Examples 50-51. (S)-3-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrrolidine-1-carboxylate methyl and (R)-3-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrrolidine-1-carboxylate methyl

[0604] [ka]

[0605] Synthesis of 3-((S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrrolidine-1-carboxylate methyl (2):

[0606] [ka]

[0607] Compound (6S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(pyrroridine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (380.0 mg, 1.00 mmol) and potassium carbonate (415.4 mg, 3.00 mmol) were dissolved in dichloromethane (15 mL). Methyl chloroformate (303.0 mg, 3.21 mmol) was slowly added dropwise to the mixture under an ice bath, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water (50 mL), extracted three times with dichloromethane (50 mL), the organic phases were combined, washed with saline solution (100 mL), the resulting organic phases were dried over anhydrous sodium sulfate, concentrated under vacuum, and the resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 50:1) to obtain a pale yellow solid (200.0 mg, yield 46%).

[0608] LC-MS: [M+H]+ : 437.0. Synthesis of 3-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrroridine-1-carboxylate methyl (3):

[0609] [ka]

[0610] Compound 3-((S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrrolidine-1-carboxylate methyl (200.0 mg, 0.46 mmol) was dissolved in tetrahydrofuran solution (10 mL). Sodium borohydride (26.0 mg, 0.69 mmol) and tetrakistriphenylphosphine palladium (105.7 mg, 0.091 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was evaporated, purified, and separated to obtain a white solid (30.0 mg, yield 17%).

[0611] LC-MS: [M+H] + : 397.0. Preparation of (S)-3-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrrolidine-1-carboxylate methyl and (R)-3-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrrolidine-1-carboxylate methyl:

[0612] [ka]

[0613] 3-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrrolidine-1-carboxylate methyl (30.0 mg, 0.076 mmol) was purified by chiral preparative separation (column: CHIRALPAK IC 250 mm 20 mm, 5 μm, mobile phase: 40% EtOH (NH4OH 0.2%)) to obtain a pair of enantiomers.

[0614] The first compound obtained by SFC resolution was numbered as Example 50 (11.7 mg, 39% yield), and analysis under SFC chromatographic conditions showed a retrieval time of 6.24 min.

[0615] 1 H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.99 (dd, J = 17.4, 7.9 Hz, 1H), 4.27 (t, J = 9.9 Hz, 1H), 4.06 (t, J = 8.5 Hz, 1H), 3.69 (dd, J = 13.0, 8.6 Hz, 1H), 3.59 (s, 3H), 3.57 - 3.42 (m, 3H), 3.37 (d, J = 8.4 Hz, 1H), 3.17 - 3.01 (m, 2H), 2.25 (s, 1H), 2.16 - 2.07 (m, 1H). The second compound obtained by SFC resolution was numbered as Example 51 (11.4 mg, 38% yield), and analysis under SFC chromatographic conditions showed a retrieval time of 8.08 min.

[0616] 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 5.02 - 4.93 (m, 1H), 4.27 (t, J = 9.9 Hz, 1H), 4.06 (dd, J = 10.1, 7.5 Hz, 1H), 3.70 (d, J = 6.1 Hz, 1H), 3.59 (s, 3H), 3.50 (td, J = 13.8, 6.0 Hz, 3H), 3.40 - 3.35 (m, 1H), 3.09 (dt, J = 15.7, 6.9 Hz, 2H), 2.25 (d, J = 5.5 Hz, 1H), 2.11 - 2.01 (m, 1H). Examples 52-53. (R)-4-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrroridine-2-one and (S)-4-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrroridine-2-one

[0617] [ka]

[0618] Synthesis of 5-oxopyrrolidine-3-formohydrazide (2):

[0619] [ka]

[0620] A 10.0 mL ethanol solution of methyl 5-oxopyrrolidine-3-carboxylate (1.0 g, 7.00 mmol) and hydrazine hydrate (1.05 g, 41.02 mmol, 80% aqueous solution) was stirred at 80°C for 12 hours. Ethanol was removed by vacuum distillation. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (500.0 mg, yield: 50%).

[0621] LC-MS: [M+H] + : 144.2. Synthesis of N'-((S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)-5-oxopyrrolidine-3-formohydrazide (3):

[0622] [ka]

[0623] A solution of 5-oxopyrrolidine-3-formohydrazide (178.8 mg, 1.24 mmol) and (S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (125.0 mg, 0.41 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was lyophilized under reduced pressure to remove the dimethyl sulfoxide. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (80.0 mg, yield: 46%).

[0624] LC-MS: [M+H] + : 411.1. Synthesis of 4-((S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrroridine-2-one (4):

[0625] [ka]

[0626] N'-((S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)-5-oxopyrrolidine-3-formohydrazide (80.0 mg, 0.19 mmol) was placed in a microwave tube, n-butanol (3.0 mL) was added, and the mixture was stirred at 150°C for 1 hour. After the reaction was complete, n-butanol was removed by vacuum distillation. The resulting crude product was purified by silica gel chromatography to obtain a white solid (50.0 mg, yield: 65%).

[0627] LC-MS: [M+H] + : 393.1. Synthesis of 4-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrroridine-2-one (5):

[0628] [ka]

[0629] At room temperature, tetrakistriphenylphosphine palladium (73.4 mg, 0.06 mmol) and sodium borohydride (7.2 mg, 0.19 mmol) were added to a solution of 4-((S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrrolidine-2-one (50.0 mg, 0.12 mmol) in tetrahydrofuran (1.0 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the organic phase was filtered through a filter membrane, the filtrate was rotated dry, and the crude product was purified to obtain a white solid (10.5 mg, yield 12%).

[0630] LC-MS: [M+H] + : 353.1. Preparation of (R)-4-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyrroridine-2-one and (S)-4-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyrroridine-2-one:

[0631] [ka]

[0632] 4-(S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrroridine-2-one (45.0 mg, 0.12 mmol) was purified by chiral preparative separation (column: CHIRALPAK IC 250 mm 20 mm, 5 μm, mobile phase: CO2-MeOH (NH4OH 0.2%)) to obtain a pair of enantiomers.

[0633] The first compound obtained by SFC resolution was numbered as Example 52 (10.5 mg, 23% yield), and analysis under SFC chromatographic conditions showed a retrieval time of 2.22 min.

[0634] LC-MS: [M+H] + : 353.1. 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.77 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.97 (m, 1H), 4.24 (t, J = 9.9 Hz, 1H), 4.04 (dd, J = 10.1, 7.5 Hz, 1H), 3.77 (dd, J = 15.6, 7.9 Hz, 1H), 3.63 (t, J = 8.9 Hz, 1H), 3.43 (dd, J = 9.5, 6.5 Hz, 1H), 3.10 (m, 2H), 2.56 (dd, J = 16.4, 9.2 Hz, 1H), 2.44 (dd, J = 16.4, 7.7 Hz, 1H). The second compound obtained by SFC resolution was numbered as Example 53 (10.2 mg, 23% yield), and analysis under SFC chromatographic conditions showed a response time of 3.08 min.

[0635] LC-MS: [M+H] + : 353.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.77 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.98 (t, J = 8.6 Hz, 1H), 4.24 (d, J = 9.9 Hz, 1H), 4.03 (dd, J = 10.1, 7.5 Hz, 1H), 3.78 (m, 1H), 3.61 (d, J = 8.6 Hz, 1H), 3.42 (dd, J = 9.5, 6.6 Hz, 1H), 3.07 (m, 2H), 2.56 (m, 1H), 2.45 (m, 1H). Examples 54-55. 3,4-Dichloro-2-((S)-3-((S)-tetrahydrofuran-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol and 3,4-Dichloro-2-((S)-3-((R)-tetrahydrofuran-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0636] [ka]

[0637] The preparation can be carried out by referring to the preparation methods of Examples 52-53, and replacing methyl 5-oxopyrrolidine-3-carboxylate with methyl tetrahydrofuran-3-carboxylate.

[0638] The first compound obtained by SFC resolution was numbered as Example 54, and analysis under SFC chromatographic conditions showed a retrieval time of 2.89 min.

[0639] LC-MS: [M+H] + : 340.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.97 (m, 1H), 4.26 (m, 1H), 4.06 - 3.98 (m, 2H), 3.86 (m, 1H), 3.80 - 3.73 (m, 2H), 3.57 - 3.50 (m, 1H), 3.09 (m, 2H), 2.30 - 2.22 (m, 1H), 2.17 - 2.09 (m, 1H). The second compound obtained by SFC separation was numbered as Example 55, and analysis under SFC chromatographic conditions showed a retrieval time of 3.70 min.

[0640] LC-MS: [M+H]+ : 340.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.96 (m, 1H), 4.25 (m, 1H), 4.07 - 3.98 (m, 2H), 3.87 (m, 1H), 3.77 (m, 2H), 3.53 (m, 1H), 3.16 - 3.01 (m, 2H), 2.31 - 2.22 (m, 1H), 2.10 (m, 1H). Examples 56-57. (R)-4-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)piperidine-2-one and (S)-4-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)piperidine-2-one

[0641] [ka]

[0642] The preparation can be carried out by referring to the preparation methods of Examples 52-53, and replacing methyl 5-oxopyrrolidine-3-carboxylate with methyl 2-oxopiperidine-4-formate.

[0643] The first compound obtained by SFC separation was numbered as Example 56, and analysis under SFC chromatographic conditions showed a retrieval time of 2.40 min.

[0644] LC-MS: [M+H] + : 407.0. 1H NMR (400 MHz, CD3OD) δ 7.21 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 5.12 - 5.03 (m, 1H), 4.23 (t, J = 10.0 Hz, 1H), 4.14 (dd, J = 10.4, 7.5 Hz, 1H), 3.26 - 3.22 (m, 2H), 3.15 (d, J = 9.3 Hz, 2H), 3.08 (d, J = 10.2 Hz, 1H), 2.83 - 2.74 (m, 2H), 2.30 - 2.20 (m, 1H), 1.88 - 1.78 (m, 1H). The second compound obtained by SFC separation was numbered as Example 57, and analysis under SFC chromatographic conditions showed a retrieval time of 3.01 min.

[0645] LC-MS: [M+H] + : 407.0. 1 H NMR (400 MHz, CD3OD) δ 7.33 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.19 (dd, J = 9.1, 7.5 Hz, 1H), 4.38 (t, J = 10.0 Hz, 1H), 4.25 (dd, J = 10.4, 7.3 Hz, 1H), 3.38 - 3.34 (m, 2H), 3.28 (t, J = 8.4 Hz, 2H), 3.20 (d, J = 10.7 Hz, 1H), 2.95 - 2.84 (m, 2H), 2.41 - 2.30 (m, 1H), 2.06 - 1.94 (m, 1H). Examples 58-59. 3,4-Dichloro-2-((S)-3-((S)-piperidine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol and 3,4-Dichloro-2-((S)-3-((R)-piperidine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0646] [ka]

[0647] The preparation can be carried out by referring to the preparation methods of Examples 47-48, and replacing 3-(hydrazinecarbonyl)pyrrolidine-1-carboxylate tert-butyl with 3-(hydrazinecarbonyl)piperidine-1-carboxylate tert-butyl.

[0648] The first compound obtained by SFC resolution was numbered Example 58, and analysis under SFC chromatographic conditions showed a retrieval time of 3.95 min.

[0649] LC-MS: [M+H] + : 353.0. 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 4.97 (s, 1H), 4.29 (s, 1H), 4.14 - 4.03 (m, 1H), 3.28 (s, 1H), 3.08 (s, 4H), 2.91 (s, 1H), 2.77 - 2.61 (m, 1H), 1.98 (s, 1H), 1.65 (d, J = 9.7 Hz, 2H), 1.54 (s, 1H). The second compound obtained by SFC separation was numbered as Example 59, and analysis under SFC chromatographic conditions showed a retrieval time of 3.99 min.

[0650] LC-MS: [M+H] + : 353.0. 1H NMR (400 MHz, DMSO-d6) δ 7.36 (d, J = 8.7 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.94 (dd, J = 16.9, 8.9 Hz, 1H), 4.26 (t, J = 9.8 Hz, 1H), 4.11 - 4.02 (m, 1H), 3.30 (s, 1H), 3.06 (dt, J = 15.6, 11.4 Hz, 3H), 2.93 - 2.78 (m, 2H), 2.67 (t, J = 11.0 Hz, 1H), 1.95 (d, J = 8.4 Hz, 1H), 1.62 (d, J = 10.7 Hz, 2H), 1.43 (d, J = 11.3 Hz, 1H). Examples 60-61. 2-((S)-3-((1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenol and 2-((S)-3-((1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenol

[0651] [ka]

[0652] The preparation can be carried out by referring to the preparation methods of Examples 52-53, and replacing methyl 5-oxopyrrolidine-3-carboxylate with methyl endo-7-oxabicyclo[2.2.1]heptane-2-formate. The first compound obtained by SFC separation was numbered as Example 60, and analysis under SFC chromatographic conditions showed a retrieval time of 2.38 min.

[0653] LC-MS: [M+H] + : 366.1. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H) , 7.39 (d, J = 8.8 Hz, 1H) , 6.86 (d, J = 8.8 Hz, 1H) , 4.94 (t, J = 8.6 Hz, 1H) , 4.65 (t, J = 4.0 Hz, 1H), 4.57 (s, 1H), 4.28 (t, J = 10.0 Hz, 1H), 4.03 (dd, J = 10.4, 7.4 Hz, 1H), 3.17 (dd, J = 8.8, 5.1 Hz, 1H), 3.13 - 3.00 (m, 2H), 1.97 (dd, J = 11.2, 5.7 Hz, 1H) , 1.90 (dd, J = 11.9, 9.0 Hz, 1H) , 1.64 - 1.49 (m, 4H). The second compound obtained by SFC separation was numbered as Example 61, and analysis under SFC chromatographic conditions showed a retrieval time of 2.92 min.

[0654] LC-MS: [M+H] + : 353.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H) , 7.39 (d, J = 8.8 Hz, 1H) , 6.86 (d, J = 8.8 Hz, 1H) , 5.01 - 4.89 (m, 1H) , 4.64 (dd, J = 12.9, 8.9 Hz, 2H), 4.24 (t, J = 10.0 Hz, 1H), 4.05 (dd, J = 10.4, 7.5 Hz, 1H), 3.19 - 3.14 (m, 1H), 3.13 - 2.98 (m, 2H), 2.06 - 1.97 (m, 1H), 1.89 (dd, J = 11.9, 9.1 Hz, 1H), 1.64 - 1.48 (m, 4H). Examples 62-63. 2-((S)-3-((1R,2R,4S)-7-oxabicyclo[2.2.1]heptan-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenol and 2-((S)-3-((1S,2S,4R)-7-oxabicyclo[2.2.1]heptan-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenol

[0655] [ka]

[0656] The preparation can be carried out by referring to the preparation methods of Examples 52-53, and replacing methyl 5-oxopyrrolidine-3-carboxylate with methyl exo-7-oxabicyclo[2.2.1]heptane-2-formate. The first compound obtained by SFC resolution was numbered as Example 62, and analysis under SFC chromatographic conditions showed a retrieval time of 3.073 min.

[0657] LC-MS: [M+H] + : 366.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.94 (t, J = 8.6 Hz, 1H), 4.65 (t, J = 4.0 Hz, 1H), 4.57 (s, 1H), 4.27 (t, J = 10.0 Hz, 1H), 4.03 (dd, J = 10.4, 7.4 Hz, 1H), 3.17 (dd, J = 8.8, 5.1 Hz, 1H), 3.12 - 3.00 (m, 2H), 1.93 (ddd, J = 20.9, 12.0, 7.8 Hz, 2H), 1.63 - 1.48 (m, 4H). The second compound obtained by SFC separation was numbered as Example 63, and analysis under SFC chromatographic conditions showed a retrieval time of 3.074 min.

[0658] LC-MS: [M+H] + : 353.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 5.02 - 4.88 (m, 1H), 4.64 (dd, J = 13.0, 9.0 Hz, 2H), 4.24 (t, J = 10.0 Hz, 1H), 4.05 (dd, J = 10.4, 7.6 Hz, 1H), 3.19 - 3.14 (m, 1H), 3.13 - 2.98 (m, 2H), 2.04 - 1.97 (m, 1H), 1.89 (dd, J = 11.9, 9.1 Hz, 1H), 1.64 - 1.47 (m, 4H). Examples 64-65. 3,4-Dichloro-2-((S)-3-((S)-3-methyltetrahydrofuran-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol and 3,4-Dichloro-2-((S)-3-((R)-3-methyltetrahydrofuran-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0659] [ka]

[0660] The preparation can be carried out by referring to the preparation methods of Examples 52-53, and replacing methyl 5-oxopyrrolidine-3-carboxylate with methyl 3-methyltetrahydrofuran-3-formate.

[0661] The first compound obtained by SFC resolution was numbered as Example 64, and analysis under SFC chromatographic conditions showed a retrieval time of 3.28 min.

[0662] LC-MS: [M+H] + : 354.0. 1 H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.19 (s, 1H), 4.43 (d, J = 9.9 Hz, 1H), 4.34 - 4.24 (m, 1H), 4.13 (d, J = 8.7 Hz, 1H), 3.98 (t, J = 7.2 Hz, 2H), 3.76 (d, J = 8.7 Hz, 1H), 3.25 (d, J = 10.3 Hz, 1H), 3.17 (d, J = 7.1 Hz, 1H), 2.50 (d, J = 12.5 Hz, 1H), 2.14 - 2.06 (m, 1H), 1.49 (s, 3H). The second compound obtained by SFC separation was numbered as Example 65, and analysis under SFC chromatographic conditions showed a retrieval time of 4.11 min.

[0663] LC-MS: [M+H] + : 354.0. 1H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.17 (d, J = 9.8 Hz, 1H), 4.42 (t, J = 10.0 Hz, 1H), 4.30 (dd, J = 10.4, 7.0 Hz, 1H), 4.13 (d, J = 8.6 Hz, 1H), 3.98 (dd, J = 7.6, 6.7 Hz, 2H), 3.76 (d, J = 8.6 Hz, 1H), 3.28 - 3.22 (m, 1H), 3.16 (dd, J = 16.2, 7.4 Hz, 1H), 2.56 - 2.45 (m, 1H), 2.09 (dt, J = 12.9, 6.6 Hz, 1H), 1.49 (s, 3H). Example 66. (S)-2-(3-(2-oxabicyclo[2.1.1]hexane-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenol

[0664] [ka]

[0665] The preparation can be carried out by referring to the preparation method of Example 32, with methyl 3-hydroxypropionate replaced by methyl 2-oxabicyclo[2.1.1]hexane-4-carboxylate. LCMS [M+H] + : 352.1. 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H) , 7.39 (d, J=8.8, 1H) , 6.86 (d, J=8.8, 1H) , 5.04 - 4.97 (m, 1H) , 4.58 (s, 1H) , 4.36 (t, J=10.0, 1H) , 4.13 - 4.08 (m, 1H) , 3.88 (dd, J=11.8, 5.7, 2H) , 3.16 - 3.06 (m, 2H) , 2.24 (dd, J=12.9, 5.1, 2H) , 1.77 (dd, J=9.4, 6.6, 2H). Example 67. (S)-3,4-dichloro-2-(3-cyclopentyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0666] [ka]

[0667] The preparation can be carried out by referring to the preparation method of Example 32, with methyl 3-hydroxypropionate replaced by cyclopentane carboxylate.

[0668] LCMS [M+H] + : 338.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.97 (t, J = 8.6 Hz, 1H), 4.23 (t, J = 9.9 Hz, 1H), 4.02 (dd, J = 10.1, 7.4 Hz, 1H), 3.12 (ddd, J = 15.8, 8.9, 3.5 Hz, 2H), 3.01 (dd, J = 15.7, 7.8 Hz, 1H), 2.02 - 1.93 (m, 2H), 1.80 - 1.56 (m, 6H). Examples 68-69. 3,4-Dichloro-2-((S)-3-((S)-tetrahydro-2H-pyran-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol and 3,4-Dichloro-2-((S)-3-((R)-tetrahydro-2H-pyran-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0669] [ka]

[0670] The preparation can be carried out by referring to the preparation methods of Examples 52-53, and replacing 5-oxopyrrolidine-3-formohydrazide with tetrahydro-2H-pyran-3-carbohydrazide.

[0671] The first compound obtained by SFC separation was numbered Example 68, and analysis under SFC chromatographic conditions showed a retrieval time of 2.69 min.

[0672] LC-MS: [M+H] + : 354.0. 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.95 (t, J = 8.6 Hz, 1H), 4.29 (t, J = 9.9 Hz, 1H), 4.09 (dd, J = 10.1, 7.6 Hz, 1H), 3.93 (dd, J = 11.0, 2.8 Hz, 1H), 3.83 (d, J = 11.3 Hz, 1H), 3.46 (t, J = 10.7 Hz, 1H), 3.38 (dd, J = 11.1, 8.3 Hz, 1H), 3.14 - 3.03 (m, 2H), 3.01 - 2.95 (m, 1H), 2.02 (d, J = 13.1 Hz, 1H), 1.82 - 1.74 (m, 1H), 1.68 - 1.56 (m, 2H). The second compound obtained by SFC separation was numbered as Example 69, and analysis under SFC chromatographic conditions showed a retrieval time of 3.54 min.

[0673] LC-MS: [M+H] + : 354.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 4.95 (t, J = 8.7 Hz, 1H), 4.30 (t, J = 9.9 Hz, 1H), 4.07 (dd, J = 10.2, 7.5 Hz, 1H), 4.00 (dd, J = 11.2, 2.7 Hz, 1H), 3.84 (d, J = 11.1 Hz, 1H), 3.45 (t, J = 10.8 Hz, 1H), 3.39 (dd, J = 11.0, 3.2Hz, 1H), 3.14 - 3.02 (m, 2H), 2.98 (dd, J = 7.9, 3.9 Hz, 1H), 2.01 (s, 1H), 1.80 - 1.72 (m, 1H), 1.68 - 1.58 (m, 2H). Examples 70-71. 3,4-Dichloro-2-((S)-3-((1s,3R)-3-hydroxycyclobutyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol and 3,4-Dichloro-2-((S)-3-((1r,3S)-3-hydroxycyclobutyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0674] [ka]

[0675] The preparation can be carried out by referring to the preparation methods of Examples 52-53, and replacing methyl 5-oxopyrrolidine-3-carboxylate with methyl 3-hydroxycyclobutane-1-formate. The first compound obtained by SFC resolution was numbered Example 70, and analysis under SFC chromatographic conditions showed a retrieval time of 4.31 min.

[0676] LC-MS: [M+H] + : 340.0. 1 H NMR (400 MHz, CD3OD) δ 7.30 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.17 (t, J = 8.4 Hz, 1H), 4.35 (d, J = 10.5 Hz, 1H), 4.29 - 4.19 (m, 2H), 3.26 - 3.06 (m, 3H), 2.73 (ddd, J = 11.4, 7.0, 3.7 Hz, 2H), 2.32 - 2.12 (m, 2H). The second compound obtained by SFC separation was numbered as Example 71, and analysis under SFC chromatographic conditions showed a retrieval time of 4.56 min.

[0677] LC-MS: [M+H] + : 340.0. Examples 72-73. 2-((6S)-3-((1S)-3-oxabicyclo[3.1.0]hexane-1-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenol and 2-((6S)-3-((1R)-3-oxabicyclo[3.1.0]hexane-1-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)-3,4-dichlorophenol

[0678] [ka]

[0679] The preparation can be carried out by referring to the preparation methods of Examples 52-53, and replacing methyl 5-oxopyrrolidine-3-carboxylate with methyl 3-oxabicyclo[3.1.0]hexane-1-formate.

[0680] The first compound obtained by SFC separation was numbered Example 72, and analysis under SFC chromatographic conditions showed a retrieval time of 4.35 min.

[0681] LC-MS: [M+H] + : 351.9. 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.96 (dd, J = 13.3, 5.5 Hz, 1H), 4.26 (t, J = 9.8 Hz, 1H), 4.06 (dd, J = 10.0, 7.5 Hz, 1H), 4.00 (d, J = 8.2 Hz, 1H), 3.87 (d, J = 8.2 Hz, 1H), 3.78 (dt, J = 8.5, 5.5 Hz, 2H), 3.08 (dt, J = 15.8, 6.9 Hz, 2H), 2.18 (ddd, J = 7.8, 4.8, 2.6 Hz, 1H), 1.25 (d, J = 4.8 Hz, 1H), 0.91 (t, J = 4.8 Hz, 1H). The second compound obtained by SFC separation was numbered as Example 73, and analysis under SFC chromatographic conditions showed a retrieval time of 5.04 min.

[0682] LC-MS: [M+H] + : 351.9. 1 H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.95 (td, J = 9.5, 4.7 Hz, 1H), 4.27 (t, J = 9.8 Hz, 1H), 4.05 (dd, J = 10.0, 7.5 Hz, 1H), 3.99 (d, J = 8.2 Hz, 1H), 3.92 (d, J = 8.3 Hz, 1H), 3.81 (d, J = 8.4 Hz, 1H), 3.76 (dd, J = 8.5, 2.7 Hz, 1H), 3.08 (dt, J = 15.8, 6.9 Hz, 2H), 2.19 (ddd, J = 7.9, 4.9, 2.7 Hz, 1H), 1.22 - 1.19 (m, 1H), 0.91 (t, J = 4.9 Hz, 1H). Examples 74-75. (S)-3,4-dichloro-2-(3-(4-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol and (R)-3,4-dichloro-2-(3-(4-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0683] [ka]

[0684] The preparation can be carried out by referring to the preparation methods of Examples 52-53, replacing 5-oxopyrrolidine-3-formohydrazide with 4-methoxybenzoylhydrazine and (S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole with 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole. The first compound obtained by SFC resolution was numbered Example 74, and analysis under SFC chromatographic conditions showed a retrieval time of 2.49 min.

[0685] LC-MS: [M+H] + : 375.8. 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 1H), 5.09 - 5.03 (m, 1H), 4.58 (t, J = 9.8 Hz, 1H), 4.30 (dd, J = 9.9, 7.4 Hz, 1H), 3.81 (s, 3H), 3.26 - 3.19 (m, 1H), 3.10 (dd, J = 15.9, 7.8 Hz, 1H). The second compound obtained by SFC separation was numbered as Example 75, and analysis under SFC chromatographic conditions showed a retrieval time of 4.62 min.

[0686] LC-MS: [M+H] + : 375.8. 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 8.9 Hz, 2H), 7.36 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 8.8 Hz, 1H), 5.09 - 5.03 (m, 1H), 4.56 (t, J = 9.8 Hz, 1H), 4.31 (dd, J = 10.1, 7.3 Hz, 1H), 3.81 (s, 3H), 3.23 - 3.18 (m, 1H), 3.14 - 3.08 (m, 1H). Examples 76-77. (S)-3,4-dichloro-2-(3-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol and (R)-3,4-dichloro-2-(3-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0687] [ka]

[0688] The preparation can be carried out by referring to the preparation methods of Examples 52-53, replacing 5-oxopyrrolidine-3-formohydrazide with 3-methoxybenzoylhydrazine and (S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole with 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole. The first compound obtained by SFC resolution was numbered Example 76, and analysis under SFC chromatographic conditions showed a retrieval time of 2.67 min.

[0689] LC-MS: [M+H] + : 375.8. 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.45 - 7.38 (m, 3H), 7.33 (d, J = 8.7 Hz, 1H), 7.03 (dt, J = 7.1, 2.2 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 5.10 - 5.01 (m, 1H), 4.62 (t, J = 9.9 Hz, 1H), 4.33 (dd, J = 10.1, 7.1 Hz, 1H), 3.82 (s, 3H), 3.24 (dd, J = 15.9, 10.2 Hz, 1H), 3.12 (dd, J = 15.9, 7.5 Hz, 1H). The second compound obtained by SFC separation was numbered as Example 77, and analysis under SFC chromatographic conditions showed a retrieval time of 3.47 min.

[0690] LC-MS: [M+H] + : 375.8. 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 7.40 (dd, J = 12.1, 5.2 Hz, 4H), 7.03 (dt, J = 7.1, 2.2 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 5.15 - 4.92 (m, 1H), 4.64 (t, J = 9.9 Hz, 1H), 4.33 (dd, J = 10.2, 7.2 Hz, 1H), 3.82 (s, 3H), 3.18 (ddd, J = 23.4, 15.9, 8.9 Hz, 2H). Examples 78-79. (S)-3,4-dichloro-2-(3-(1-cyclohexylpiperidine-4-yl)-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazole-6-yl)phenol and (R)-3,4-dichloro-2-(3-(1-cyclohexylpiperidine-4-yl)-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazole-6-yl)phenol

[0691] [ka]

[0692] Synthesis of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(1-cyclohexylpiperidine-4-yl)-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazole(2):

[0693] [ka]

[0694] At 0°C, 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(piperidine-4-yl)-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazole (150.0 mg, 0.38 mmol) and cyclohexanone (112.5 mg, 1.14 mmol) were dissolved in dichloromethane (2.0 mL), to which sodium borohydride acetate (242.5 mg, 1.14 mmol) was added, and the mixture was stirred at 25°C for 2 hours. After the reaction was complete, the organic phase was filtered through a filter membrane, and the filtrate was rotated dry to obtain the crude product, which was purified by silica gel chromatography (methanol:dichloromethane = 1:20) to obtain a white solid (150.0 mg, yield: 83%).

[0695] LC-MS: [M+H] + : 475.2. Synthesis of 3,4-dichloro-2-(3-(1-cyclohexylpiperidine-4-yl)-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazole-6-yl)phenol (3):

[0696] [ka]

[0697] At room temperature, tetrakistriphenylphosphine palladium (60.5 mg, 0.05 mmol) was added to a solution of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(1-cyclohexylpiperidine-4-yl)-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazole (150.0 mg, 0.32 mmol) and sodium borohydride (18.2 mg, 0.48 mmol) in tetrahydrofuran (2.0 mL). The gas in the flask was replaced with an argon balloon, and the mixture was stirred at 25°C for 2 hours. After the reaction was complete, the organic phase was filtered through a filter membrane, the filtrate was rotated dry, and the crude product was purified to obtain a white solid (56.0 mg, yield 41%).

[0698] LC-MS: [M+H] + : 435.1. Preparation of (S)-3,4-dichloro-2-(3-(1-cyclohexylpiperidine-4-yl)-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazole-6-yl)phenol and (R)-3,4-dichloro-2-(3-(1-cyclohexylpiperidine-4-yl)-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazole-6-yl)phenol:

[0699] [ka]

[0700] 3,4-Dichloro-2-(3-(1-cyclohexylpiperidine-4-yl)-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazole-6-yl)phenol (30.0 mg, 0.07 mmol) was purified by chiral preparative separation (column: CHIRALPAK IC 250 mm 20 mm, 5 μm, mobile phase: 40% EtOH (NH4OH 0.2%)) to obtain a pair of enantiomers.

[0701] The first compound obtained by SFC resolution was numbered as Example 78 (2.3 mg, 7.6% yield), and analysis under SFC chromatographic conditions showed a retrieval time of 2.69 min.

[0702] LC-MS: [M+H] + : 435.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.95-4.92 (m, 1H), 4.27 (t, J = 9.8 Hz, 1H), 4.05 (dd, J = 10.0, 7.6 Hz, 1H), 3.16-3.00 (m, 5H), 2.55-2.52 (m, 3H), 1.99-1.93 (m, 2H), 1.86-1.72 (m, 6H), 1.58 (d, J = 12.5 Hz, 1H), 1.33-1.24 (m, 4H), 1.07-1.05 (m, 1H). The second compound obtained by SFC resolution was numbered as Example 79 (7.3 mg, 14% yield), and analysis under SFC chromatographic conditions showed a response time of 3.22 min.

[0703] LC-MS: [M+H] + : 435.1. 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.99-4.95 (m, 1H), 4.28-4.26 (m, 1H), 4.07 (dd, J = 10.1, 7.4 Hz, 1H), 3.49-3.45 (m, 3H), 3.19-3.07 (m, 5H), 2.17-2.10 (m, 2H), 2.00-1.99 (m, 4H), 1.83 (d, J = 13.0 Hz, 2H), 1.62 (d, J = 12.7 Hz, 1H), 1.47-1.27 (m, 4H), 1.16-1.09 (m, 1H). Example 80. 3,4-Dichloro-2-((S)-3-((R)-1-isopropylpyrrolidine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0704] [ka]

[0705] Synthesis of (R)-3-(hydrazinecarbonyl)pyrrolidine-1-carboxylate tert-butyl(2):

[0706] [ka]

[0707] (R)-1-(tert-butyl)-3-methylpyrrolidine-1,3-dicarboxylic acid ester (5.0 g, 0.02 mol) and hydrazine hydrate (3.2 g, 0.08 mol, 80% aqueous solution) were mixed in an ethanol solution (100.0 mL) and stirred at 80°C for 3 hours. Ethanol was removed by vacuum distillation. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (2.2 g, yield: 44%).

[0708] LC-MS: [M+H] + : 174.2. Synthesis of (R)-3-(2-((S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate tert-butyl (3):

[0709] [ka]

[0710] Compound (S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (800.0 mg, 2.66 mmol) and (R)-3-(hydrazinecarbonyl)pyrrolidine-1-carboxylate tert-butyl (1841.4 mg, 7.99 mmol) were dissolved in dimethyl sulfoxide solution (10 mL) and reacted at 25°C for 16 hours. After the reaction was complete, the reaction mixture was freeze-dried under vacuum, and the resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain a white solid (1200.0 mg, yield 90%).

[0711] LC-MS: [M+H] + : 497.2. Synthesis of (S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-3-((R)-pyrrolidine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole(4):

[0712] [ka]

[0713] Compound (R)-3-(2-((S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate tert-butyl (600.0 mg, 1.20 mmol) was dissolved in n-butanol (6 mL), and the mixture was stirred at 150°C under microwave for 30 minutes. After the reaction was complete, the reaction solution was concentrated under vacuum, and the resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain a white solid (370.0 mg, yield 40%).

[0714] LC-MS: [M+H] + : 379.2. Synthesis of (S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-3-((R)-1-isopropylpyrrolidine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole(5):

[0715] [ka]

[0716] Compound (S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-3-((R)-pyrrolidine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (400.0 mg, 1.05 mmol) was dissolved in dichloromethane solution (5 mL), and acetone (1.2 g, 20.66 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 2 hours. The reaction mixture was then cooled to 0°C, and sodium triacetoxyborohydride (447.0 mg, 2.1 mmol) was added in several batches. The resulting mixture was stirred at room temperature overnight. After the reaction was complete, the reaction mixture was concentrated under vacuum, and the resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain a white solid (300.0 mg, yield 67%).

[0717] LC-MS: [M+H] + : 421.2. Synthesis of 3,4-dichloro-2-((S)-3-((R)-1-isopropylpyrrolidine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol(6):

[0718] [ka]

[0719] Compound (S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-3-((R)-1-isopropylpyrrolidine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (140.0 mg, 0.33 mmol) was dissolved in tetrahydrofuran solution (20 mL). Polymethylhydrogensiloxane (147.8 mg, 0.66 mmol), zinc chloride (4.1 mg, 0.029 mmol), and tetrakistriphenylphosphine palladium (15.3 mg, 0.013 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum, and the resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain a white solid (19.5 mg, yield 15%).

[0720] LC-MS: [M+H] + : 381.2. 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.17 (s, 1H), 7.40 (d, J=8.8, 1H), 6.87 (d, J=8.8, 1H), 4.97 (t, J=8.0, 1H), 4.27 (dd, J=12.2, 7.7, 1H), 4.05 (dd, J=10.1, 7.7, 1H), 3.52 - 3.46 (m, 0H), 3.16 - 3.06 (m, 1H), 2.81 (dd, J=17.4, 9.8, 0H), 2.65 (dd, J=12.0, 5.8, 1H), 2.24 - 2.17 (m, 1H), 2.04 (dd, J=13.1, 7.1, 1H), 1.08 (dd, J=6.2, 2.7, 6H). Example 81. 1-((R)-3-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrroridine-1-yl)ethane-1-one

[0721] [ka]

[0722] Synthesis of 1-((R)-3-((S)-6-(6-allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrroridine-1-yl)ethane-1-one (2):

[0723] [ka]

[0724] Compound (S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-3-((R)-pyrrolidine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (150.0 mg, 0.39 mmol) and triethylamine (80.0 mg, 0.79 mmol) were dissolved in dichloromethane solution (2 mL). The reaction mixture was cooled to 0°C, and acetic anhydride (60.5 mg, 0.59 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with water (10 mL), extracted three times with dichloromethane (10 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain a white solid (100.0 mg, yield 60%).

[0725] LC-MS: [M+H] + : 421.2. Synthesis of 1-((R)-3-((S)-6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrroridine-1-yl)ethane-1-one (3):

[0726] [ka]

[0727] Compound 1-((R)-3-((S)-6-(6-allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)pyrroridine-1-yl)ethane-1-one (100.0 mg, 0.23 mmol) was dissolved in tetrahydrofuran solution (3 mL). Polymethylhydrogensiloxane (105.6 mg, 0.47 mmol), zinc chloride (2.9 mg, 0.021 mmol), and tetrakistriphenylphosphine palladium (10.9 mg, 0.0094 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum, and the crude product was purified to obtain a white solid (15.0 mg, yield 16%).

[0728] LC-MS: [M+H] + : 381.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.42 (d, J=8.8, 1H), 6.89 (d, J=8.8, 1H), 5.10 - 5.00 (m, 1H), 4.52 - 4.44 (m, 1H), 4.30 - 4.22 (m, 1H), 3.95 - 3.69 (m, 2H), 3.67 - 3.60 (m, 1H), 3.56 - 3.42 (m, 2H), 3.39 - 3.32 (m, 1H), 3.28 - 3.19 (m, 1H), 2.43 - 2.29 (m, 1H), 2.23 - 2.06 (m, 1H), 1.96 (s, 3H). Example 82. 3,4-Dichloro-2-((S)-3-((R)-1-(1-isopropylpiperidine-4-yl)pyrrolidine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0729] [ka]

[0730] The solution can be prepared by referring to the preparation method of Example 80, but replacing acetone with 1-isopropylpiperidine-4-one.

[0731] LCMS [M+H] + : 463.9. 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 5.04 - 4.98 (m, 1H), 4.66 (s, 2H), 4.32 (t, J = 9.6 Hz, 1H), 4.17 - 4.11 (m, 1H), 3.80 (s, 3H), 3.52 (t, J = 12.5 Hz, 4H), 3.31 (s, 1H), 3.18 (d, J = 7.8 Hz, 2H), 3.00 (d, J = 8.2 Hz, 2H), 2.36 (d, J = 12.2 Hz, 2H), 2.21 (s, 1H), 1.93 (d, J = 12.4 Hz, 2H), 1.25 (d, J = 6.6 Hz, 6H). Example 83. 3,4-Dichloro-2-((S)-3-((R)-1-(tetrahydro-2H-pyran-4-yl)pyrroridine-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0732] [ka]

[0733] The preparation can be carried out by referring to the preparation method of Example 80, with acetone replaced by tetrahydro-4H-pyran-4-one.

[0734] LCMS [M+H] + : 423.2. 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H) , 7.39 (d, J = 8.8 Hz, 1H) , 6.85 (d, J = 8.8 Hz, 1H) , 5.02 - 4.92 (m, 1H) , 4.30 - 4.22 (m, 1H) , 4.10 - 4.00 (m, 1H) , 3.82 (d, J = 11.5 Hz, 2H) , 3.46 - 3.40 (m, 1H) , 3.27 (d, J = 11.5 Hz, 2H) , 3.15 - 2.96 (m, 3H) , 2.69 - 2.65 (m, 1H) , 2.63 - 2.55 (m, 2H) , 2.21 (ddd, J = 22.8, 11.2, 4.6 Hz, 2H) , 2.04 - 1.97 (m, 1H) , 1.75 (d, J = 11.8 Hz, 2H) , 1.37 (d, J = 12.7 Hz, 2H). Example 84. (S)-3,4-dichloro-2-(3-(2-methylpyridine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0735] [ka]

[0736] The preparation can be carried out by referring to the preparation method of Example 32, with methyl 3-hydroxypropionate replaced by methyl 2-methylisonicotinate.

[0737] LCMS [M+H] + : 361.1. 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H) , 8.55 (d, J=5.2, 1H) , 7.70 - 7.65 (m, 2H) , 7.39 (d, J=8.8, 1H) , 6.85 (d, J=8.8, 1H) , 5.09 (s, 1H), 4.69 (t, J=10.0, 1H), 4.46 - 4.40 (m, 1H), 3.28 (d, J=5.9, 1H), 3.18 (d, J=7.5, 1H), 2.53 (s, 3H). Example 85. (S)-3,4-dichloro-2-(3-(1,1-difluoroethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0738] [ka]

[0739] The preparation can be carried out by referring to the preparation method of Example 32, and replacing methyl 3-hydroxypropionate with 2,2-difluoropropionate.

[0740] LCMS [M+H] + : 333.8. 1 H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H) , 7.39 (d, J = 8.8 Hz, 1H) , 6.83 (d, J = 8.8 Hz, 1H) , 5.14 - 4.99 (m, 1H) , 4.42 (t, J = 10.2 Hz, 1H), 4.16 (dd, J = 10.7, 6.9 Hz, 1H), 3.29 - 3.21 (m, 1H), 3.04 (dd, J = 16.1, 7.0 Hz, 1H), 2.12 (t, J = 19.2 Hz, 3H). Example 86. (S)-3,4-dichloro-2-(3-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0741] [ka]

[0742] The preparation can be carried out by referring to the preparation method of Example 32, but replacing 3-hydroxypropionyl hydrazide with 2,2,2-trifluoroacetohydrazide.

[0743] LCMS [M+H] + : 338.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 5.09 (tt, J = 10.0, 6.6 Hz, 1H), 4.51 (t, J = 10.3 Hz, 1H), 4.20 (dd, J = 10.8, 6.5 Hz, 1H), 3.38 (d, J = 10.4 Hz, 1H), 3.08 (dd, J = 16.4, 6.6 Hz, 1H). Example 87. (S)-3,4-dichloro-2-(3-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0744] [ka]

[0745] The preparation can be carried out by referring to the preparation method of Example 32, and replacing methyl 3-hydroxypropionate with ethyl 3,3,3-trifluoropropionate.

[0746] LCMS [M+H] + : 352.1. 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.41 (d, J=8.8, 1H), 6.86 (d, J=8.8, 1H), 4.99 (t, J=8.7, 1H), 4.30 (t, J=10.0, 1H), 4.09 (dd, J=10.5, 7.5, 1H), 4.01 (dd, J=11.1, 3.5, 2H), 3.25 - 3.18 (m, 1H), 3.09 (dd, J=15.9, 7.7, 1H). Example 88. 3,4-Dichloro-2-(3-(2,2,6,6-tetramethylpiperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0747] [ka]

[0748] The preparation can be carried out by referring to the preparation method of Example 3, and replacing ethyl 3-hydroxy-3-methylbutyrate with ethyl 2,2,6,6-tetramethylpiperidine-4-formate.

[0749] LCMS [M+H] + : 408.9. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.02 - 4.90 (m, 1H), 4.31 (t, J = 9.8 Hz, 1H), 4.16 - 4.05 (m, 1H), 3.36 (t, J = 12.6 Hz, 1H), 3.11 (d, J = 9.1 Hz, 2H), 1.89 (dd, J = 23.0, 13.1 Hz, 2H), 1.53 (t, J = 13.1 Hz, 2H), 1.32 (s, 6H), 1.24 (s, 6H). Example 89. 3,4-Dichloro-2-(3-(2,2-dimethylpiperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0750] [ka]

[0751] Synthesis of (Z)-4-(methoxymethylene)-2,2-dimethylpiperidine-1-carboxylate tert-butyl(2):

[0752] [ka]

[0753] A solution of (methoxymethyl)triphenylphosphonium chloride (5.6 g, 16.50 mmol) in tetrahydrofuran (50 mL) was cooled to 0°C, and sodium hydride (5.8 g, 145 mmol, 60% in mineral oil) was added in several portions, and the mixture was stirred at 0°C for 1 hour. A solution of 2,2-dimethyl-4-oxopiperidine-1-carboxylate tert-butyl (2.5 g, 11.00 mmol) in tetrahydrofuran (10 mL) was slowly added, and the resulting reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water (100 mL), extracted three times with ethyl acetate (100 mL), the organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether:ethyl acetate = 10:1), and eluted to obtain a colorless oily product (1 g, yield: 35%).

[0754] Synthesis of 4-formyl-2,2-dimethylpiperidine-1-carboxylate tert-butyl(3):

[0755] [ka]

[0756] A solution of (Z)-4-(methoxymethylene)-2,2-dimethylpiperidine-1-carboxylate tert-butyl (1.2 g, 4.90 mmol) in acetonitrile (115 mL) was cooled to 0°C, 1 M aqueous HCl (5.75 mL) was added, and the mixture was stirred at 0°C for 5 hours to allow the reaction to proceed. After the reaction was complete, the solution was diluted with saturated aqueous sodium bicarbonate (20 mL), extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the target product (0.5 g, yield: 42%).

[0757] Synthesis of 1-(tert-butoxycarbonyl)-2,2-dimethylpiperidine-4-carboxylic acid (4):

[0758] [ka]

[0759] 4-Formyl-2,2-dimethylpiperidine-1-carboxylate tert-butyl (900.0 mg, 3.71 mmol) was dissolved in tert-butanol (5.4 mL) and 2-methyl-2-butene (10.8 mL), the mixture was cooled to 0°C, and an aqueous solution (6 mL) of sodium chlorite (3.3 g, 37.1 mmol) and sodium dihydrogen phosphate (3.6 g, 30 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was diluted with water (20 mL), extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a white solid product (500.0 mg, yield: 52%).

[0760] Synthesis of 4-(2-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)hydrazine-1-carbonyl)-2,2-dimethylpiperidine-1-carboxylate tert-butyl(5):

[0761] [ka]

[0762] 1-(tert-butoxycarbonyl)-2,2-dimethylpiperidine-4-carboxylic acid (146.2 mg, 0.56 mmol), 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-hydrazine-3,4-dihydro-2H-pyrrole (170.0 mg, 0.56 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (151.9 mg, 0.79 mmol), and 4-dimethylaminopyridine (6.92 mg, 0.056 mmol) were dissolved in N,N-dimethylformamide (3.0 mL), and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was diluted with water (10 mL), extracted three times with ethyl acetate (10 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a white solid product (30.0 mg, yield: 9%).

[0763] LC-MS: [M+H] + : 539.3. Synthesis of 4-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)-2,2-dimethylpiperidine-1-carboxylate tert-butyl(6):

[0764] [ka]

[0765] 4-(2-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)hydrazine-1-carbonyl)-2,2-dimethylpiperidine-1-carboxylate tert-butyl (90.0 mg, 0.16 mmol) was transferred to a microwave tube, n-butanol (3.0 mL) was added, and the mixture was stirred at 160°C for 3 hours. After the reaction was complete, n-butanol was removed by vacuum distillation. The resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:20) to obtain a white solid (30.0 mg, yield: 34%).

[0766] LC-MS: [M+H] + : 521.3. Synthesis of 4-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)-2,2-dimethylpiperidine-1-carboxylate tert-butyl (7):

[0767] [ka]

[0768] Compound 4-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)-2,2-dimethylpiperidine-1-carboxylate tert-butyl (30.0 mg, 0.057 mmol) was dissolved in tetrahydrofuran solution (2 mL). Polymethylhydrogensiloxane (25.5 mg, 0.11 mmol), zinc chloride (0.7 mg, 0.0051 mmol), and tetrakistriphenylphosphine palladium (2.6 mg, 0.0023 mmol) were added to the reaction mixture, and the mixture was reacted at 25°C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum, and the resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain a white solid (10.0 mg, yield 36%).

[0769] LC-MS: [M+H] + : 481.3. Synthesis of 3,4-dichloro-2-(3-(2,2-dimethylpiperidine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol (8):

[0770] [ka]

[0771] A solution of compound 4-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)-2,2-dimethylpiperidine-1-carboxylate tert-butyl (10.0 mg, 0.02 mmol) in dichloromethane / trifluoroacetic acid (3 mL / 1 mL) was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum, and the crude product was purified to obtain a white solid (3.9 mg, yield 49%).

[0772] LC-MS: [M+H] + : 381.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.40 (d, J=8.8, 1H), 6.88 (d, J=9.0, 1H), 5.01 - 4.88 (m, 1H), 4.29 (q, J=9.6, 1H), 4.07 (dd, J=17.9, 8.2, 1H), 3.25 - 3.16 (m, 2H), 3.14 - 3.03 (m, 3H), 2.00 (dd, J=30.6, 15.0, 2H), 1.72 (dd, J=24.5, 12.5, 2H), 1.31 (d, J=8.1, 6H), 1.23 (s, 1H). Examples 90-91. (S)-3,4-dichloro-2-(3-cyclopentyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol and (R)-3,4-dichloro-2-(3-cyclopentyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol

[0773] [ka]

[0774] Synthesis of 3-(6-(allyloxy)-2,3-dichlorophenyl)-N-(2,2-dimethoxyethyl)-3,4-dihydro-2H-pyrrole-5-amine(2):

[0775] [ka]

[0776] At room temperature, 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (10.0 g, 33.33 mmol) and 2,2-dimethoxyethyl-1-amine (4.2 g, 39.92 mmol) were added to methanol (100.0 mL), and the resulting solution was stirred at 70°C for 4 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was used directly in the next step without purification.

[0777] LC-MS: [M+H] + : 373.0. Synthesis of 6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (3):

[0778] [ka]

[0779] At room temperature, the crude product obtained in the previous step was dissolved in formic acid (100 mL), and the resulting mixture was stirred at 130°C for 4 hours. After the reaction was complete, the formic acid was removed by vacuum concentration, and the resulting residue was diluted with saturated sodium bicarbonate aqueous solution (200.0 mL), extracted three times with ethyl acetate (500.0 mL), combined the organic phases, washed with saturated sodium chloride (200.0 mL), dried over anhydrous sodium sulfate, and then concentrated under vacuum to separate the residue by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain the target product (8.1 g, 66%).

[0780] LC-MS: [M+H] + : 308.9. Synthesis of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (4):

[0781] [ka]

[0782] 6.5 g, 0.021 mol of 6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (6.5 g, 0.021 mol) was dissolved in acetonitrile (65 mL) at -10°C, and N-bromosuccinimide (3.4 g, 0.019 mol) was added in several portions. The mixture was then stirred for 30 minutes while maintaining the temperature. After the reaction was complete, the mixture was quenched with sodium thiosulfate solution (100 mL), extracted twice with ethyl acetate (200 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) and eluted to obtain a pale yellow solid (2.4 g, yield 25%).

[0783] LC-MS: [M+H] + : 386.7. Synthesis of 3,4-dichloro-2-(3-(cyclopenta-1-en-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol (5):

[0784] [ka]

[0785] At room temperature, 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (500.0 mg, 1.29 mmol), cyclopentene-1-ylboronic acid (360.1 mg, 3.22 mmol), sodium carbonate (273.1 mg, 2.58 mmol), and tetrakistriphenylphosphine palladium (297.7 mg, 0.26 mol) were added to a reaction flask containing dioxane and water (5 mL, 1 mL), and the mixture was stirred at 110°C for 16 hours. After the reaction was complete, the mixture was diluted with water (50 mL), extracted twice with ethyl acetate (50 mL), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1), and eluted to obtain an off-white solid (150 mg, yield 33%).

[0786] LC-MS: [M+H] + : 335.0. Synthesis of 3,4-dichloro-2-(3-cyclopentyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol (6):

[0787] [ka]

[0788] 3,4-Dichloro-2-(3-(cyclopenta-1-en-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol (150.0 mg, 0.45 mol) and platinum dioxide (75.0 mg) were added to methanol (10 mL) and stirred at 25°C for 1 hour under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (50 mg, 98% yield).

[0789] LC-MS: [M+H] + : 336.9. Preparation of (S)-3,4-dichloro-2-(3-cyclopentyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol and (R)-3,4-dichloro-2-(3-cyclopentyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol:

[0790] [ka]

[0791] 3,4-Dichloro-2-(3-cyclopentyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol (50.0 mg, 0.14 mmol) was purified by chiral preparative separation (column: CHIRALPAK IC 250 mm 20 mm, 5 μm; mobile phase: 40% EtOH (NH4OH 0.2%)) to obtain a pair of enantiomers.

[0792] The first compound obtained by SFC resolution was numbered as Example 90 (10.7 mg, yield 21.4%), and analysis under SFC chromatographic conditions showed a retrieval time of 3.26 min.

[0793] LC-MS: [M+H] + : 336.9. 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.68 (s, 1H), 4.87 - 4.78 (m, 1H), 4.21 (t, J = 9.8 Hz, 1H), 4.08 - 4.02 (m, 1H), 3.03 (d, J = 8.7 Hz, 2H), 2.99 - 2.94 (m, 1H), 1.95 (s, 2H), 1.69 (s, 2H), 1.58 (dd, J = 11.5, 6.8 Hz, 2H), 1.51 (d, J = 10.8 Hz, 2H). The second compound obtained by SFC separation was numbered as Example 91 (11.6 mg, yield 23.2%), and analysis under SFC chromatographic conditions showed an RT of 6.36 min.

[0794] LC-MS: [M+H] + : 336.9. 1 H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.58 (s, 1H), 4.85 - 4.75 (m, 1H), 4.16 (t, J = 9.6 Hz, 1H), 4.08 - 3.99 (m, 1H), 2.96 (dd, J = 15.2, 7.6 Hz, 3H), 1.95 (d, J = 7.4 Hz, 2H), 1.58 (ddd, J = 34.9, 30.8, 17.5 Hz, 6H). Examples 92-93. (S)-3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol and (R)-3,4-dichloro-2-(3-ethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol

[0795] [ka]

[0796] The preparation can be carried out by referring to the preparation methods of Examples 90-91, and replacing cyclopentene-1-ylboronic acid with 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane. The first compound obtained by SFC separation was numbered as Example 92, and analysis under SFC chromatographic conditions showed a retrieval time of 2.92 min.

[0797] LC-MS: [M+H] + : 296.8. 1 H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.57 (s, 1H), 4.79 (p, J = 8.8 Hz, 1H), 4.13 (t, J = 9.6 Hz, 1H), 4.06 - 3.98 (m, 1H), 3.07 - 2.91 (m, 2H), 2.53 (d, J = 7.6 Hz, 2H), 1.14 (t, J = 7.5 Hz, 3H). The second compound obtained by SFC separation was numbered as Example 93, and analysis under SFC chromatographic conditions showed a retrieval time of 4.07 min.

[0798] LC-MS: [M+H] + : 296.8. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (dd, J = 51.5, 28.6 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.57 (s, 1H), 4.79 (t, J = 9.0 Hz, 1H) , 4.12 (t, J = 9.6 Hz, 1H) , 4.06 - 4.00 (m, 1H) , 3.00 (ddd, J = 25.1, 15.3, 9.1 Hz, 2H) , 2.52 (s, 2H) , 1.14 (t, J = 7.5 Hz, 3H). Examples 94-95. (S)-3,4-dichloro-2-(3-(1-isopropylpiperidine-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol and (R)-3,4-dichloro-2-(3-(1-isopropylpiperidine-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol

[0799] [ka]

[0800] Synthesis of 4-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl(2):

[0801] [ka]

[0802] At room temperature, 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (500.0 mg, 1.29 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-tert-butyl formate (799.4 mg, 2.58 mmol), sodium carbonate (409.7 mg, 3.87 mmol), and tetrakistriphenylphosphine palladium (297.7 mg, 0.26 mol) were added to a reaction flask containing dioxane and water (5 mL, 1 mL), and the mixture was stirred at 110°C for 16 hours. After the reaction was complete, the solution was diluted with water (50 mL), extracted twice with ethyl acetate (50 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain a white solid (210 mg, yield 28%).

[0803] LC-MS: [M+H] + : 449.8. Synthesis of 4-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)piperidine-1-formate tert-butyl(3):

[0804] [ka]

[0805] 4-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (300.0 mg, 0.66 mmol) and platinum dioxide (75.0 mg) were added to methanol (10 mL) and stirred at 25°C for 2 hours under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid (230 mg, yield 64%).

[0806] LC-MS: [M+H] + : 451.9. Synthesis of 3,4-dichloro-2-(3-(piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol (4):

[0807] [ka]

[0808] Compound 4-(6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)piperidine-1-formate tert-butyl (260.0 mg, 0.57 mmol) was dissolved in a 3:1 solution of dichloromethane and trifluoroacetic acid (4.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to obtain a white solid (230.0 mg, 95% yield).

[0809] LC-MS: [M+H] + : 351.9. Synthesis of 3,4-dichloro-2-(3-(1-isopropylpiperidine-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol (5):

[0810] [ka]

[0811] Compound 3,4-dichloro-2-(3-(piperidine-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol 3 (230.0 mg, 0.65 mmol) and acetone (379.2 mg, 6.53 mmol) were dissolved in methanol (10.0 mL), and the mixture was stirred at 0°C for 30 minutes. Then, sodium triacetoxyborohydride (123.1 mg, 0.58 mmol) was added to the mixture at 0°C, and the mixture was stirred at 50°C for 2 hours. The reaction mixture was extracted three times with dichloromethane and washed twice with saline solution. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 3:2) to obtain a white solid (80.0 mg, yield 29%).

[0812] LC-MS: [M+H] + : 394.0. Preparation of (S)-3,4-dichloro-2-(3-(1-isopropylpiperidine-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol and (R)-3,4-dichloro-2-(3-(1-isopropylpiperidine-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol:

[0813] [ka]

[0814] 3,4-Dichloro-2-(3-(1-isopropylpiperidine-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol (80.0 mg, 0.20 mmol) was purified by chiral preparative fractionation (column: CHIRALPAK AD-H 250 mm × 20 mm, 5 μm; mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to obtain a pair of enantiomers.

[0815] The first compound obtained by SFC resolution was numbered as Example 94 (13.1 mg, 16% yield), and analysis under SFC chromatographic conditions showed a retrieval time of 2.51 min.

[0816] LC-MS: [M+H] + : 394.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.56 (s, 1H), 4.75 (d, J = 8.8 Hz, 1H), 4.11 (dd, J = 21.2, 8.8 Hz, 2H), 3.02 (d, J = 8.4 Hz, 1H), 2.94 (d, J = 9.8 Hz, 1H), 2.79 (dd, J = 11.2, 6.8 Hz, 2H), 2.72 - 2.64 (m, 1H), 2.45 (s, 1H), 2.15 (dd, J = 11.6, 9.4 Hz, 2H), 1.82 (d, J = 14.8 Hz, 2H), 1.47 (td, J = 12.1, 3.7 Hz, 2H), 0.95 (d, J = 6.6 Hz, 6H). The second compound obtained by SFC resolution was numbered as Example 95 (11.3 mg, 14% yield), and analysis under SFC chromatographic conditions showed a response time of 3.27 min.

[0817] LC-MS: [M+H] + : 394.0. 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 7.44 - 7.38 (m, 1H), 7.05 (s, 1H), 6.88 (d, J = 8.8 Hz, 1H), 5.00 - 4.83 (m, 1H), 4.39 (t, J = 9.9 Hz, 1H), 4.14 (dd, J = 10.1, 7.2 Hz, 1H), 3.47 (dd, J = 23.1, 16.7 Hz, 3H), 3.28 - 3.21 (m, 1H), 3.14 (dd, J = 16.1, 7.1 Hz, 1H), 3.01 (dd, J = 26.8, 14.6 Hz, 3H), 2.13 (t, J = 13.3 Hz, 2H), 1.82 (dd, J = 25.1, 12.9 Hz, 2H), 1.25 (d, J = 6.6 Hz, 6H). Example 96. 3,4-Dichloro-2-(3-(4-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol

[0818] [ka]

[0819] At room temperature, a 3.0 mL mixture of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (35.0 mg, 0.09 mmol) dioxane and water (volume ratio 10:1) was prepared. (4-methoxyphenyl)boronic acid (16.0 mg, 0.11 mmol) was added, and sodium carbonate (29.0 mg, 0.27 mmol) and bis(triphenylphosphine)dichloride palladium (13 mg, 0.02 mmol) were added. The mixture was stirred in a 150°C microwave reactor for 10 minutes. After the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (30 mL), and the resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified to obtain a white solid (4.8 mg, yield: 15%).

[0820] LC-MS: [M+H] + : 375.0. 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 1H), 5.23 (tt, J = 10.2, 6.4 Hz, 1H), 4.75 (t, J = 10.2 Hz, 1H), 4.49 (dd, J = 10.9, 6.4 Hz, 1H), 3.82 (s, 3H), 3.60 (dd, J = 17.1, 10.2 Hz, 1H), 3.42 (dd, J = 17.3, 6.2 Hz, 1H). Example 97. 3,4-Dichloro-2-(3-(1-methyl-1H-pyrazole-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol

[0821] [ka]

[0822] The preparation can be carried out by referring to the preparation method of Example 96, and replacing (4-methoxyphenyl)boronic acid with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

[0823] LC-MS: [M+H] + : 349.0. 1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.84 (s, 1H), 7.61 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 5.32 - 5.21 (m, 1H), 4.72 (t, J = 9.9 Hz, 1H), 4.48 (dd, J = 10.5, 6.4 Hz, 1H), 3.94 (s, 3H), 3.58 (d, J = 10.4 Hz, 1H), 3.46 (d, J = 6.7 Hz, 1H). Example 98. 2-(3-(1-(tert-butyl)-1H-pyrazole-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)-3,4-dichlorophenol

[0824] [ka]

[0825] Synthesis of 1-(tert-butyl)-4-(tributylstannyl)-1H-pyrazole (2):

[0826] [ka]

[0827] 4-bromo-1-tert-butylpyrazole (3.0 g, 0.015 mol) was added to a three-necked reaction flask containing tetrahydrofuran (30 mL). Under nitrogen gas protection at -78°C, n-butyllithium (6.5 mL, 2.5 M n-hexane solution) was slowly added dropwise, and the mixture was stirred at -78°C for 30 minutes. Then, tributyltin chloride (5.3 g, 0.016 mol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was quenched with aqueous ammonium chloride (20 mL), extracted twice with ethyl acetate (100 mL), the organic phases were combined, washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) and eluted to obtain a colorless oily substance (2.8 g, yield 39%).

[0828] Synthesis of 2-(3-(1-(tert-butyl)-1H-pyrazole-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)-3,4-dichlorophenol (5):

[0829] [ka]

[0830] 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (120.0 mg, 0.31 mmol), 1-(tert-butyl)-4-(tributylstannyl)-1H-pyrazole (255.5 mg, 0.62 mmol), and tetrakistriphenylphosphine palladium (71.2 mg, 0.06 mmol) were mixed with 1,4-dioxane and water (5 mL / 0.5 mL), and the mixture was microwaved at 150°C for 1.5 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with water (10 mL), extracted twice with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol = 5:1). The crude product was then eluted and further purified to obtain a white solid (5.2 mg, yield 4%).

[0831] LC-MS: [M+H] + : 390.8. 1 H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.69 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.07 (s, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.88 (d, J = 8.7 Hz, 1H), 4.44 (t, J = 9.8 Hz, 1H), 4.20 (dd, J = 9.7, 7.9 Hz, 1H), 3.09 (d, J = 8.9 Hz, 2H), 1.52 (s, 9H). Example 99. 2-(3-(1H-pyrazole-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)-3,4-dichlorophenol

[0832] [ka]

[0833] 10.0 mg of 2-(3-(1-(tert-butyl)-1H-pyrazole-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)-3,4-dichlorophenol was added to a 100 mL reaction flask, concentrated hydrochloric acid (10 mL) was added, and the resulting solution was stirred at 100°C for 48 hours. After the reaction was complete, the solution was concentrated under reduced pressure, and the residue was preparatively purified to obtain a white solid (3.0 mg, yield 37%).

[0834] LC-MS: [M+H] + : 335.0. 1 H NMR (400 MHz, CD3OD) δ 12.97 (s, 1H), 11.17 - 10.52 (m, 1H), 7.86 (s, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.02 (s, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.87 (p, J = 8.8 Hz, 1H), 4.38 (t, J = 9.7 Hz, 1H), 4.19 (dd, J = 9.6, 8.0 Hz, 1H), 3.11 - 3.00 (m, 2H). Example 100. 3,4-Dichloro-2-(3-(4-isopropylpiperazin-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol

[0835] [ka]

[0836] Synthesis of (2-(4-isopropylpiperazin-1-yl)-2-thioethyl)tert-butylcarbamate (2):

[0837] [ka]

[0838] At 0°C, Lawson's reagent (1.9 g, 4.68 mmol) was added to 15.0 mL of toluene solution of (2-(4-isopropylpiperazin-1-yl)-2-oxoethyl)tert-butylcarbamate (1.1 g, 3.90 mmol), and the mixture was stirred at 70°C for 16 hours under nitrogen gas protection. After the reaction was complete, the reaction solution was diluted with water (50 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined and washed with saturated brine (100 mL), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain the target product (1.0 g, yield: 86%).

[0839] LC-MS: [M+H] + : 302.0. Synthesis of 2-amino-1-(4-isopropylpiperazine-1-yl)ethane-1-thion (3):

[0840] [ka]

[0841] At room temperature, (2-(4-isopropylpiperazin-1-yl)-2-thioethyl)tert-butylcarbamate (700.0 mg, 2.32 mmol) was added to a solution of trifluoroacetic acid and dichloromethane (1:5, 6.0 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was directly rotated to obtain a yellow oil (700.0 mg, crude product, yield 80%).

[0842] LC-MS: [M+H] + : 202.0. Synthesis of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(4-isopropylpiperazin-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (4):

[0843] [ka]

[0844] At room temperature, 2-amino-1-(4-isopropylpiperazin-1-yl)ethane-1-thion (450.0 mg, 2.24 mmol) was added to a solution of 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (200.0 mg, 0.67 mmol) in dichloromethane (5.0 mL), and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was directly rotated dry, and the resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 20:1) to obtain the target product (80.0 mg, yield: 28%).

[0845] LC-MS: [M+H] + : 434.9. Synthesis of 3,4-dichloro-2-(3-(4-isopropylpiperazin-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-6-yl)phenol (5):

[0846] [ka]

[0847] At room temperature, tetrakistriphenylphosphine palladium (21.0 mg, 0.02 mmol) was added to a solution of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(4-isopropylpiperazin-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (80.0 mg, 0.18 mmol) and sodium borohydride (14.0 mg, 0.35 mmol) in tetrahydrofuran (3.0 mL). The gas in the flask was replaced with an argon balloon, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the organic phase was filtered through a filter membrane, the filtrate was rotated dry, and the crude product was purified to obtain a white solid (15.5 mg, yield 22%).

[0848] LC-MS: [M+H] + : 394.9. 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.20 (s, 1H), 6.91 (d, J = 8.3 Hz, 1H), 5.01 (s, 1H), 4.55 (t, J = 10.1 Hz, 1H), 4.18 (dd, J = 10.2, 6.1 Hz, 1H), 3.78 (d, J = 7.0 Hz, 6H), 3.29 - 3.00 (m, 5H), 1.26 (t, J = 9.6 Hz, 6H). Example 101. 3,4-Dichloro-2-(3-Molfolino-6,7-Dihydro-5H-Pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0849] [ka]

[0850] Synthesis of 2-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)hydrazine-1-carboxylate ethyl(2):

[0851] [ka]

[0852] Compound 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (5.0 g, 0.02 mol) and a solution of ethyl hydrazinecarboxylate (2.6 g, 0.03 mol) in dimethyl sulfoxide (50.0 mL) were stirred at 25°C for 16 hours. After the reaction was complete, the solvent was freeze-dried under reduced pressure, and the resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:12) to obtain a yellow oily substance (6.0 g, yield 97%).

[0853] LC-MS: [M+H] + : 371.8. Synthesis of 6-(6-(allyloxy)-2,3-dichlorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one(3):

[0854] [ka]

[0855] 2-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)hydrazine-1-carboxylate ethyl (6.0 g, 0.02 mol) was dissolved in ethanol (60.0 mL), to which sodium ethanol (11.0 g, 0.16 mmol, 20% wt ethanol solution) was added, and the mixture was stirred at 80°C for 2 days. After the reaction was complete, the reaction solution was allowed to cool to room temperature, then diluted with water (200.0 mL), extracted three times with ethyl acetate (300.0 mL), the organic phases were combined, washed twice with saturated brine (500.0 mL), concentrated under vacuum, and the organic phase was dried. Dichloromethane (20.0 mL) was added to the obtained crude product to dissolve it, and the solution was slowly stirred. Petroleum ether (100.0 mL) was added, causing a large amount of solid to precipitate. The solid was filtered, the filter cake was washed with petroleum ether, and the filter cake was dried to obtain a brown solid (3.4 g, yield 65%).

[0856] LC-MS: [M+H] + : 325.8. 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 5.81 (ddd, J = 22.5, 10.6, 5.3 Hz, 1H), 5.26 - 5.14 (m, 2H), 4.85 (tt, J = 10.0, 6.9 Hz, 1H), 4.57 (d, J = 4.6 Hz, 2H), 3.92 (t, J = 9.9 Hz, 1H), 3.61 (dd, J = 10.0, 6.6 Hz, 1H), 3.07 (dd, J = 16.4, 10.5 Hz, 1H), 2.83 (dd, J = 16.4, 7.1 Hz, 1H). Synthesis of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-chloro-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole(4):

[0857] [ka]

[0858] Compound 6-(6-(allyloxy)-2,3-dichlorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one (1.0 g, 3.1 mmol) was dissolved in phosphorus oxychloride (5 mL), and the mixture was stirred at 130°C for 16 hours. The reaction solution was quenched in ice water, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with ethyl acetate and washed twice with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:4) to obtain a brown solid (70.0 mg, yield 6%).

[0859] LC-MS: [M+H] + : 344.0. Synthesis of 4-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)morpholine (5):

[0860] [ka]

[0861] Compound 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-chloro-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (70.0 mg, 0.20 mmol) was dissolved in N-methylpyrrolidone (2 mL), morpholine (176.9 mg, 2.03 mmol) was added to the mixture, and the mixture was stirred at 150°C for 16 hours. The reaction solution was diluted with water, extracted three times with ethyl acetate, washed twice with saturated brine, concentrated under vacuum, and dried. The resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain a white solid (30.0 mg, yield 37%).

[0862] LC-MS: [M+H] + : 395.0. Synthesis of 3,4-dichloro-2-(3-morpholino-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol (6):

[0863] [ka]

[0864] Compound 4-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)morpholine (30.0 mg, 0.076 mmol) was dissolved in tetrahydrofuran solution (5 mL). Sodium borohydride (4.3 mg, 0.11 mmol) and tetrakistriphenylphosphine palladium (17.5 mg, 0.015 mmol) were added to the reaction mixture, and the mixture was reacted at 25°C for 2 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated and dried to purify and separate the solution, yielding a white solid (2.0 mg, yield 7%).

[0865] LC-MS: [M+H] + : 355.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.91 (dd, J = 17.2, 9.1 Hz, 1H), 4.23 (t, J = 9.6 Hz, 1H), 4.01 (dd, J = 9.6, 7.6 Hz, 1H), 3.73 - 3.62 (m, 4H), 3.20 - 3.13 (m, 4H), 3.00 (dd, J = 9.0, 3.6 Hz, 2H). Example 102. 3,4-Dichloro-2-(3-((1-Isopropylpiperidine-4-yl)oxo)-6,7-Dihydro-5H-Pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0866] [ka]

[0867] Synthesis of 4-((6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)oxo)piperidine-1-carboxylate tert-butyl(2):

[0868] [ka]

[0869] Compound 4-hydroxypiperidine-1-formate tert-butyl (87.5 mg, 0.44 mmol) was dissolved in tetrahydrofuran (20.0 mL), and sodium hydride (17.3 mg, 0.44 mmol, 60% in mineral oil) was added to the mixture at 0°C, and the mixture was stirred at 0°C for 30 minutes. Then, 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-chloro-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (100 mg, 0.29 mmol) was added to the mixture at 0°C, and the mixture was stirred at 65°C for 24 hours. The reaction mixture was extracted three times with dichloromethane and washed twice with saline solution. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was used directly in the next step without purification.

[0870] LC-MS: [M+H] + : 508.8. Synthesis of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(piperidine-4-oxy)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole(3):

[0871] [ka]

[0872] Compound 4-((6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-3-yl)oxo)piperidine-1-carboxylate tert-butyl (200 mg, 0.39 mmol) was dissolved in a 3:1 solution of dichloromethane and trifluoroacetic acid (4.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated, purified, and separated to obtain a white solid (90.0 mg, yield 56%).

[0873] LC-MS: [M+H] + : 409.1. Synthesis of 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-((1-isopropylpiperidine-4-yl)oxo)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole(4):

[0874] [ka]

[0875] Compound 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-(piperidine-4-oxy)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (90 mg, 0.22 mmol) and acetone (25.5 mg, 0.44 mmol) were dissolved in dichloromethane (9.0 mL). Triethylamine (44.5 mg, 0.44 mmol) was added to the mixture at 0°C, and the mixture was stirred at 0°C for 30 minutes. Then, sodium triacetoxyborohydride (93.2 mg, 0.44 mmol) was added to the mixture at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted three times with dichloromethane and washed twice with saline solution. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 3:2) to obtain a yellow oily liquid (50.0 mg, yield 50%).

[0876] LC-MS: [M+H] + : 450.9. Synthesis of 3,4-dichloro-2-(3-((1-isopropylpiperidine-4-yl)oxo)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol (5):

[0877] [ka]

[0878] Compound 6-(6-(allyloxy)-2,3-dichlorophenyl)-3-((1-isopropylpiperidine-4-yl)oxo)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (50.0 mg, 0.11 mmol) was dissolved in tetrahydrofuran solution (9.0 mL). Sodium borohydride (6.3 mg, 0.17 mmol) and tetrakistriphenylphosphine palladium (25.6 mg, 0.022 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was filtered through a filter membrane, and the resulting filtrate was evaporated and dried to purify and separate the solution, yielding a white solid (18.9 mg, yield 41%).

[0879] LC-MS: [M+H] + : 411.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 8.8, 3.5 Hz, 1H), 6.89 (dd, J = 8.8, 5.6 Hz, 1H), 5.12 - 4.93 (m, 2H), 4.19 (t, J = 18.6 Hz, 1H), 3.99 (dd, J = 16.8, 9.6 Hz, 1H), 3.56 - 3.44 (m, 2H), 3.35 (d, J = 6.1 Hz, 1H), 3.29 - 3.05 (m, 4H), 2.43 (d, J = 11.4 Hz, 1H), 2.27 (s, 1H), 2.17 - 2.05 (m, 1H), 1.90 (s, 1H), 1.26 (dd, J = 6.6, 3.4 Hz, 6H). Examples 103-104. (S)-6-(2,3-dichloro-6-hydroxyphenyl)-2-(1-isopropylpiperidine-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one and (R)-6-(2,3-dichloro-6-hydroxyphenyl)-2-(1-isopropylpiperidine-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[0880] [ka]

[0881] Synthesis of 4-(6-(6-(allyloxy)-2,3-dichlorophenyl)-3-carbonyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)piperidine-1-carboxylate tert-butyl(2):

[0882] [ka]

[0883] Compound 6-(6-(allyloxy)-2,3-dichlorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one (600.0 mg, 1.84 mmol) and 4-hydroxypiperidine-1-carboxylate tert-butyl (1.17 g, 5.81 mmol) were dissolved in tetrahydrofuran solution (10.0 mL). Cyanomethylenetri-n-butylphosphine (1.33 g, 5.52 mmol) was added to the mixture at room temperature, and the mixture was heated under microwave at 150°C for 40 minutes under nitrogen gas protection, with stirring. The reaction mixture was extracted three times with ethyl acetate and washed twice with saline solution. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a pale yellow solid (650.0 mg, yield 69%).

[0884] LC-MS: [M+H] + : 508.8. Synthesis of 6-(6-(allyloxy)-2,3-dichlorophenyl)-2-(piperidine-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one(3):

[0885] [ka]

[0886] 4-(6-(6-(allyloxy)-2,3-dichlorophenyl)-3-carbonyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazole-2(5H)-yl)piperidine-1-carboxylate tert-butyl (650.0 mg, 1.28 mmol) was dissolved in a 3:1 mixture of dichloromethane and trifluoroacetic acid (12.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated, purified, and separated to obtain a white solid (300.0 mg, yield 57%).

[0887] LC-MS: [M+H] + : 409.0. Synthesis of 6-(6-(allyloxy)-2,3-dichlorophenyl)-2-(1-isopropylpiperidine-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one(4):

[0888] [ka]

[0889] Compound 6-(6-(allyloxy)-2,3-dichlorophenyl)-2-(piperidine-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one (300.0 mg, 0.73 mmol) and acetone (127.7 mg, 2.20 mmol) were dissolved in dichloromethane (12.0 mL). Triethylamine (148.3 mg, 1.47 mmol) was added to the mixture at 0°C, and the mixture was stirred at 0°C for 30 minutes. Then, sodium triacetoxyborohydride (466.0 mg, 2.20 mmol) was added to the mixture at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted three times with dichloromethane and washed twice with saline solution. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 5:1) to obtain a yellow oily liquid (200.0 mg, yield 60%).

[0890] LC-MS: [M+H] + : 450.9. Synthesis of 6-(2,3-dichloro-6-hydroxyphenyl)-2-(1-isopropylpiperidine-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one (5):

[0891] [ka]

[0892] Compound 6-(6-(allyloxy)-2,3-dichlorophenyl)-2-(1-isopropylpiperidine-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one (150.0 mg, 0.33 mmol) was dissolved in tetrahydrofuran solution (15.0 mL). Sodium borohydride (18.9 mg, 0.50 mmol) and tetrakistriphenylphosphine palladium (76.8 mg, 0.066 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was filtered through a filter membrane, and the resulting filtrate was evaporated and dried to purify and separate it, yielding a pale red solid (34.3 mg, yield 25%).

[0893] LC-MS: [M+H] + : 410.9. 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.20 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.77 (t, J = 8.6 Hz, 1H), 3.96 - 3.87 (m, 2H), 3.72 (dd, J = 9.8, 7.2 Hz, 1H), 3.10 - 3.03 (m, 1H), 2.95 (dd, J = 16.2, 7.7 Hz, 3H), 2.90 - 2.83 (m, 1H), 2.39 (t, J = 11.1Hz, 2H), 1.96 - 1.83 (m, 2H), 1.77 (s, 2H), 1.02 (d, J = 6.6 Hz, 6H). Preparation of (S)-6-(2,3-dichloro-6-hydroxyphenyl)-2-(1-isopropylpiperidine-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one and (R)-6-(2,3-dichloro-6-hydroxyphenyl)-2-(1-isopropylpiperidine-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one:

[0894] [ka]

[0895] 6-(2,3-dichloro-6-hydroxyphenyl)-2-(1-isopropylpiperidine-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one (34.3 mg, 0.084 mmol) was purified by chiral preparative fractionation (column: CHIRALPAK AD-H 250 mm × 20 mm, 5 μm; mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to obtain a pair of enantiomers. The first compound obtained by SFC resolution was numbered as Example 103 (9.6 mg, 28% yield), and analysis under SFC chromatographic conditions showed a retrieval time of 4.412 min.

[0896] LC-MS: [M+H] + : 410.9. 1 H NMR (400 MHz, DMSO-d6) δ 7.38 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.81 - 4.72 (m, 1H), 3.93 (t, J = 9.7 Hz, 1H), 3.87 - 3.78 (m, 1H), 3.72 (dd, J = 9.8, 7.1 Hz, 1H), 3.06 (dd, J = 16.3, 10.1 Hz, 1H), 2.98 - 2.84 (m, 3H), 2.75 (dt, J = 13.2, 6.5 Hz, 1H), 2.25 (t, J = 11.5 Hz, 2H), 1.87 - 1.69 (m, 4H), 0.98 (d, J = 6.6 Hz, 6H). The second compound obtained by SFC resolution was numbered as Example 104 (10.6 mg, 31% yield), and analysis under SFC chromatographic conditions showed a retrieval time of 4.403 min.

[0897] LC-MS: [M+H]+ : 410.9. 1 H NMR (400 MHz, DMSO-d6) δ 7.38 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.82 - 4.71 (m, 1H), 3.93 (t, J = 9.7 Hz, 1H), 3.89 - 3.80 (m, 1H), 3.72 (dd, J = 9.9, 7.1 Hz, 1H), 3.06 (dd, J = 16.3, 10.1 Hz, 1H), 2.98 - 2.86 (m, 3H), 2.77 (dt, J = 13.0, 6.5 Hz, 1H), 2.28 (t, J = 11.4 Hz, 2H), 1.81 (ddd, J = 29.4, 19.0, 3.1 Hz, 4H), 0.99 (d, J = 6.6 Hz, 6H). Example 105. 6-(2,3-dichloro-6-hydroxyphenyl)-2-(piperidine-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[0898] [ka]

[0899] Compound 6-(6-(allyloxy)-2,3-dichlorophenyl)-2-(piperidine-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one (100.0 mg, 0.24 mmol) was dissolved in tetrahydrofuran solution (10.0 mL). Sodium borohydride (13.9 mg, 0.37 mmol) and tetrakistriphenylphosphine palladium (56.5 mg, 0.049 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was filtered through a filter membrane, and the resulting filtrate was evaporated and dried to purify and separate the solution, yielding a white solid (9.3 mg, yield 10%).

[0900] LC-MS: [M+H] +: 369.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.14 - 9.13 (m, 1H), 8.35 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.81 - 4.70 (m, 1H), 4.20 - 4.09 (m, 1H), 3.93 (t, J = 9.7 Hz, 1H), 3.74 (dd, J = 9.8, 7.3 Hz, 1H), 3.25 (d, J = 11.2 Hz, 2H), 3.10 - 2.96 (m, 2H), 2.91 (dd, J = 20.9, 8.7 Hz, 2H), 1.89 (dt, J = 23.8, 10.9 Hz, 4H). Example 106. (S)-6-(2,3-dichloro-6-hydroxyphenyl)-2-ethyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[0901] [ka]

[0902] Synthesis of (1,3-dihydroisoindole-2-yl)(ethyl)tert-butylcarbamate (2):

[0903] [ka]

[0904] At room temperature, triphenylphosphine (4.5 g, 17.10 mmol) and ethanol (0.79 g, 17.10 mmol) were added to a solution of (1,3-dihydroisoindole-2-yl)tert-butylcarbamate (3.0 g, 11.40 mmol) in tetrahydrofuran (50 mL). The mixture was cooled to 0°C, and then diisopropyl azodicarboxylic acid (3.5 g, 17.10 mmol) was added. The mixture was stirred at 50°C for 3 hours. After the reaction was complete, water (50.0 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (50.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was rotated dry by vacuum concentration, and the resulting crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:5) to obtain a pale yellow solid (4.0 g, yield: 80%).

[0905] LC-MS: [M+H-Boc] + : 191.0. Synthesis of 1-ethylhydrazine-1-formate tert-butyl(3):

[0906] [ka]

[0907] A solution of (1,3-dihydroisoindole-2-yl)(ethyl)tert-butylcarbamate (3.5 g, 12.00 mmol) and hydrazine hydrate (1.15 g, 28.75 mmol, 80% aqueous solution) in methanol (40.0 mL) was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (dichloromethane:methanol = 20:1) to obtain a white solid (1.4 g, yield 74%). LC-MS: [M+H-56] + : 105.0. Synthesis of (S)-2-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)-1-ethylhydrazine-1-formate tert-butyl (4):

[0908] [ka]

[0909] (S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (350.0 mg, 1.17 mmol) was dissolved in dichloromethane (8.0 mL), to which 1-ethylhydrazine-1-formate tert-butyl (1878.0 mg, 11.70 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was rotated dry by vacuum concentration, and the resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (350.0 mg, yield: 82%).

[0910] LC-MS: [M+H] + : 428.0. Synthesis of (S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-(2-ethylhydrazino)-3,4-dihydro-2H-pyrrole(5):

[0911] [ka]

[0912] (S)-2-(3-(6-(allyloxy)-2,3-dichlorophenyl)-3,4-dihydro-2H-pyrrole-5-yl)-1-ethylhydrazine-1-formate tert-butyl (350.0 mg, 0.81 mmol) was added to a mixed solvent of dichloromethane and trifluoroacetic acid (5:1, 6.0 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was rotated dry by vacuum concentration, and the resulting crude product (350.0 mg, yield: 80%) was used directly in the next step.

[0913] LC-MS: [M+H] + : 328.0. Synthesis of (S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-2-ethyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one(6):

[0914] [ka]

[0915] A solution of (S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-(2-ethylhydrazino)-3,4-dihydro-2H-pyrrole (200.0 mg, 0.61 mmol) and triethylamine (308.0 mg, 3.01 mmol) in tetrahydrofuran (5.0 mL) was cooled to 0°C in an ice bath. Next, triphosgene (163.0 mg, 0.55 mmol) was slowly added to the above mixture. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (20.0 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (20.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was rotated dry by vacuum concentration, and the resulting crude product was purified by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain a white solid (80.0 mg, yield: 47%).

[0916] LC-MS: [M+H] + : 353.9. Synthesis of (S)-6-(2,3-dichloro-6-hydroxyphenyl)-2-ethyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one (7):

[0917] [ka]

[0918] At room temperature, tetrakistriphenylphosphine palladium (13 mg, 0.01 mmol) was added to a solution of (S)-6-(6-(allyloxy)-2,3-dichlorophenyl)-2-ethyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one (80.0 mg, 0.23 mmol) and sodium borohydride (17.0 mg, 0.45 mmol) in tetrahydrofuran (3.0 mL). The gas in the flask was replaced with an argon balloon, and the mixture was stirred at 25°C for 2 hours. After the reaction was complete, the organic phase was filtered through a filter membrane, and the filtrate was rotate-dried to purify the crude product, which yielded a white solid (20.0 mg, yield 29%).

[0919] LC-MS: [M+H] + : 314.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.77 (t, J = 7.6 Hz, 1H), 3.93 (t, J = 9.7 Hz, 1H), 3.74 - 3.69 (m, 1H), 3.67 - 3.62 (m, 2H), 3.09 - 3.02 (m, 1H), 2.94 (dd, J = 16.3, 7.6 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H). Example 107. (S)-6-(2,3-dichloro-6-hydroxyphenyl)-2-(2,2-difluoroethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[0920] [ka]

[0921] The preparation can be carried out by referring to the preparation method of Example 106, but replacing ethanol with 2,2-difluoroethane-1-ol.

[0922] LC-MS: [M+H] + : 349.8. 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.25 (tt, J = 55.0, 3.7 Hz, 1H), 4.83 - 4.76 (m, 1H), 4.07 (dd, J = 15.0, 11.4 Hz, 2H), 3.98 (t, J = 9.8 Hz, 1H), 3.73 (dd, J = 9.9, 7.0 Hz, 1H), 3.10 (dd, J = 16.5, 10.2 Hz, 1H), 2.95 (dd, J = 16.5, 7.5 Hz, 1H). Example 108. (S)-6-(2,3-dichloro-6-hydroxyphenyl)-2-(tetrahydro-2H-pyran-4-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[0923] [ka]

[0924] The preparation can be carried out by referring to the preparation method of Example 106, and replacing ethanol with tetrahydro-2H-pyran-4-ol.

[0925] LC-MS: [M+H] + : 370.1. 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H) , 7.38 (d, J = 8.8 Hz, 1H) , 6.85 (d, J = 8.8 Hz, 1H) , 4.77 (dt, J = 17.2, 8.7 Hz, 1H) , 4.12 (td, J = 11.3, 5.6 Hz, 1H), 3.93 (dd, J = 17.1, 7.4 Hz, 3H), 3.73 (dd, J = 9.7, 7.2 Hz, 1H), 3.42 (t, J = 11.9 Hz, 2H), 3.01 (ddd, J = 24.1, 16.3, 9.0 Hz, 2H), 1.92 - 1.77 (m, 2H), 1.69 (s, 2H). Examples 109-110. (S)-6-(2,3-dichloro-6-hydroxyphenyl)-2-((S)-tetrahydrofuran-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one and (S)-6-(2,3-dichloro-6-hydroxyphenyl)-2-((R)-tetrahydrofuran-3-yl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-3-one

[0926] [ka]

[0927] The mixture was prepared according to the preparation method of Example 106, with ethanol replaced by 3-hydroxytetrahydrofuran. The resulting racemic mixture was purified by chiral preparative separation (column: CHIRALPAK AD-H 250 mm × 20 mm, 5 μm mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to obtain a pair of enantiomers.

[0928] The first compound obtained by SFC resolution was numbered Example 109, and analysis under SFC chromatographic conditions showed a retrieval time of 3.26 min.

[0929] LC-MS: [M+H] + : 355.8. 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.83 - 4.70 (m, 2H), 3.98 - 3.85 (m, 3H), 3.82 - 3.68 (m, 3H), 3.01 (dt, J = 16.4, 7.5 Hz, 2H), 2.22 - 2.05 (m, 2H). The second compound obtained by SFC separation was numbered as Example 110, and analysis under SFC chromatographic conditions showed a retrieval time of 4.23 minutes.

[0930] LC-MS: [M+H] + : 355.8. 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.82 - 4.69 (m, 2H), 3.97 - 3.86 (m, 3H), 3.81 - 3.65 (m, 3H), 3.11 - 2.92 (m, 2H), 2.23 - 2.08 (m, 2H). Example 111. (S)-3,4-dichloro-2-(3-(2-(trifluoromethyl)pyridine-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0931] [ka]

[0932] The preparation can be carried out by referring to the preparation method of Example 32, with the substitution of methyl 3-hydroxypropionate with methyl 2-(trifluoromethyl)isonicotinate.

[0933] LCMS [M+H] + : 414.9. 1 H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.89 (d, J = 5.1 Hz, 1H), 8.24 (s, 1H), 8.15 (d, J = 5.1 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H) , 5.14 - 5.06 (m, 1H) , 4.78 (t, J = 10.0 Hz, 1H) , 4.48 (dd, J = 10.3, 7.2 Hz, 1H) , 3.20 (dd, J = 16.1, 7.5 Hz, 2H). Example 112. 3,4-Dichloro-2-(2-ethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-yl)phenol

[0934] [ka]

[0935] Synthesis of 3-oxocyclopenta-1-en-1-yltrifluoromethanesulfonate (2):

[0936] [ka]

[0937] At 0°C, triethylamine (20.5 g, 0.20 mol) was added to a solution of 1,3-cyclopentanedione (10.0 g, 0.10 mol) in tetrahydrofuran (150.0 mL). After stirring for 10 minutes, trifluoromethanesulfonic anhydride (34.5 g, 0.12 mol) was slowly added dropwise to the mixture, maintaining the temperature at 0°C. After the addition was complete, the mixture was raised to room temperature and stirred for 3 hours. The reaction was detected to be complete by TLC, the solvent of the mixture was concentrated under reduced pressure at 30°C, and the residue was wet-cell-laden with the sample and eluted with an eluent (petroleum ether:ethyl acetate = 20:1). The resulting product was concentrated under reduced pressure at 30°C, and most of the solvent was used directly in the next step.

[0938] Synthesis of 3-(2,3-dichloro-6-methoxyphenyl)cyclopenta-2-en-1-one (3):

[0939] [ka]

[0940] To a mixed solution of (2,3-dichloro-6-methoxyphenyl)boronic acid (10.0 g, 0.04 mol) (dioxane:water = 5:1, 300 mL), 3-oxocyclopenta-1-en-1-yltrifluoromethanesulfonate (20.0 g, 0.09 mol), potassium carbonate (16.2 g, 0.12 mol), and tetrakistriphenylphosphine palladium (5.2 g, 0.004 mol) were added. The mixture was stirred at 80°C for 16 hours under nitrogen gas protection. After the reaction was complete, the solution was diluted with water (100.0 mL), extracted twice with ethyl acetate (100.0 mL), the organic phases were combined, washed with saturated brine (200.0 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) and eluted to obtain the target product (4.0 g, yield 34%).

[0941] LC-MS: [M+H] + : 257.0. Synthesis of (E)-3-(2,3-dichloro-6-methoxyphenyl)-5-((dimethylamino)methylene)cyclopenta-2-en-1-one (4):

[0942] [ka]

[0943] At room temperature, 3-(2,3-dichloro-6-methoxyphenyl)cyclopenta-2-en-1-one (1.2 g, 4.67 mmol) was added to a solution of N,N-dimethylformamide dimethyl acetal (16.0 mL), and the mixture was stirred at 110°C for 3 hours. After the reaction was complete, the mixture was directly rotated dry to obtain the crude product, which was used directly in the next step.

[0944] LC-MS: [M+H] + : 312.0. Synthesis of 5-(2,3-dichloro-6-methoxyphenyl)-2,4-dihydrocyclopenta[c]pyrazole (5):

[0945] [ka]

[0946] (E)-3-(2,3-dichloro-6-methoxyphenyl)-5-((dimethylamino)methylene)cyclopenta-2-en-1-one (1.0 g, 3.22 mmol) and hydrazine hydrochloride (0.9 g, 13.13 mmol) were dissolved in ethanol (20.0 mL) and triethylamine was added until the pH reached 8. The mixture was stirred at 80°C for 1 hour. After the reaction was complete, the filtrate was rotated dry by vacuum concentration, and the resulting crude product was purified by silica gel c...

Claims

1. The compound shown in formula (I) or its pharmaceutically acceptable salts or deuterated compounds. 【Chemistry 1】 (Here, A is selected from a 5-membered heteroaryl group containing 1 to 3 cycloheteratoons independently selected from N, O, and S. Z and T are independently selected from C and N. X and Y are independently selected from CRaRb, NRc, and O. Ra and Rb independently form H, OH, and NH. 2 , C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Selected from linear or branched alkyloxy groups, or Ra and Rb together with the carbon atom to which they are bonded, C 3-7 A cycloalkyl group, or a 3-7 membered heterocycloalkyl group comprising 1 to 3 cycloheteratoons independently selected from N, O, and S, is formed. Rc is H, C 1-4 a linear or branched alkyl group, C 2-4 a linear or branched alkenyl group, C 3-7 selected from cycloalkyl groups, R 2 , R 3 , R 4 , R 5 These are independently H, F, Cl, Br, CN, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Linear or branched alkyloxy group, C 2-4 Linear or branched alkenyloxy group, C 2-4 Linear or branched alkynyloxy group, C 3-7 Selected from cycloalkyl groups, R 1 is F, Cl, Br, CN, =O, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 3-7 Cycloalkyl groups, 3-7 membered heterocycloalkyl groups containing 1-3 cycloheteratoms independently selected from N, O, and S and bonded by C or N, aryl groups, 5-11 membered heteroaryl groups containing 1-3 cycloheteratoms independently selected from N, O, and S, C 5-7 A 5-7 member heterocrosslinked cycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member alkane ring; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a benzene ring and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 5-7 member heteroaromatic ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; -C 1-4 Straight-chain or branched-chain alkylene-R 7 , -OR 7 ,-OC 1-4 Straight-chain or branched-chain alkylene-R 7 , -SR 7 , -SC 1-4 Straight-chain or branched-chain alkylene-R 7 , -N(R 6 )R 7 , -N(R 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 , -C(O)R 7 , -C(O)-C 1-4 Straight-chain or branched-chain alkylene-R 7 , -C(O)R 7 -OR 7 , -C(O)R 7 -N(R 6 )R 7 , -S(O) 2 R 7 , -N(R 6 ) C(O)R 7 , -N(R 6 )C(O)-C 1-4 Straight-chain or branched-chain alkylene-R 7 ,-C(O)N(R 6 )R 7 ,-C(O)N(R 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 , -N(R 6 )S(O) 2 R 7 , -N(R 6 )S(O) 2 -C 1-4 Straight-chain or branched-chain alkylene-R 7 , -S(O) 2 N(R) 6 )R 7 -S(O) 2 N(R) 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 They were chosen independently of each other, and here, The alkylene group may be optionally substituted with an OH group. When the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, bridged cycloalkyl group, heterobridged cycloalkyl group, linked ring is OH, CN, NH 2 、=O, F, Cl, Br, independently optionally substituted by one or more groups selected from F, Cl, Br C 1-4 a straight-chain or branched alkyl group, independently optionally substituted by one or more groups selected from F, Cl, Br C 2-4 a straight-chain or branched alkenyl group, independently optionally substituted by one or more groups selected from F, Cl, Br C 2-4 a straight-chain or branched alkynyl group, C 1-4 a straight-chain or branched alkylene-OH, C 2-4 a straight-chain or branched alkenylene-OH, C 2-4 a straight-chain or branched alkynylene-OH, C 1-4 a straight-chain or branched alkylene-NH 2 、C 2-4 a straight-chain or branched alkenylene-NH 2 、C 2-4 a straight-chain or branched alkynylene-NH 2 、C 1-4 a straight-chain or branched alkyloxy group, -C(O)OC 1-4 a straight-chain or branched alkyl group, C(O)OC 2-4 a straight-chain or branched alkenyl group, C(O)OC 2-4 a straight-chain or branched alkynyl group, -C(O)R 7 、-S(O) 2 R 7 、-N(R 6 )R 7 、-N(R 6 )-C 1-4 a straight-chain or branched alkylene-R 7 、-N(R 6 )C(O)R 7 、-N(R 6 )C(O)-C 1-4 a straight-chain or branched alkylene-R 7 、-N(R 6 )S(O) 2 R 7 、-N(R 6 )S(O) 2 -C 1-4 Straight-chain or branched-chain alkylene-R 7 -S(O) 2 N(R) 6 )R 7 -S(O) 2 N(R) 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 ,-C(O)N(R 6 )R 7 ,-C(O)N(R 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 , -P(O)(R 6 ) 2 , substitution or non-substitution of C 3-7 It is optionally substituted with one or more groups independently selected from a cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted 3-7 membered heterocycloalkyl group containing 1-3 cycloheteroatoms independently selected from N, O, and S and bonded by C or N, and a substituted or unsubstituted 5-6 membered heteroaryl group containing 1-3 cycloheteroatoms independently selected from N, O, and S and bonded by C or N, where, substitution C 3-7 The substituents for cycloalkyl groups, substituted aryl groups, substituted 3-7 member heterocycloalkyl groups, and substituted 5-6 member heteroaryl groups are OH, CN, and NH. 2 , =O, F, Cl, Br, C which can be optionally substituted by one or more groups independently selected from F, Cl, Br. 1-4 Linear or branched alkyl groups, and C optionally substituted with one or more groups independently selected from F, Cl, and Br. 2-4 Linear or branched alkenyl groups, optionally substituted with one or more groups independently selected from F, Cl, and Br. 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH, C 1-4 Linear or branched alkylene-NH 2 , C 2-4 Linear or branched alkenylene-NH 2 , C 2-4 Straight-chain or branched-chain alkynylene-NH 2 , C 1-4 Selected from linear or branched alkyloxy groups, The two substituents on the same ring carbon atom of the cycloalkyl, heterocycloalkyl, or heteroaryl group may optionally be C along with the carbon atom to which they are bonded. 3-6 A cycloalkyl group or a 3-6 membered heterocycloalkyl group containing one cycloheteratom selected from N and O is formed, and the formed cycloalkyl group or heterocycloalkyl group is OH, CN, NH 2 ,=O,F,Cl,Br,C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH, C 1-4 Linear or branched alkylene-NH 2 , C 2-4 Linear or branched alkenylene-NH 2 , C 2-4 Straight-chain or branched-chain alkynylene-NH 2 , C 1-4 Linear or branched alkyloxy group, C 3-6 Optionally substituted with one or more groups independently selected from a cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1 to 3 cycloheteratoons independently selected from N, O, and S, R 6 H, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Selected from linear or branched alkynyl groups, R 7 These are independently H, OH, and NH. 2 , C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Linear or branched alkyloxy group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 3-7 From a cycloalkyl group, a 3-7 membered heterocycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S and bonded by C or N, an aryl group, and a 5-11 membered heteroaryl group containing 1-3 cycloheteratoms independently selected from N, O, and S, The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are F, Cl, Br, OH, CN, and NH. 2 ,=O,C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH,-C(O)OC 1-4 Linear or branched alkyl groups, C(O)OC 2-4 Linear or branched alkenyl group, C(O)OC 2-4 Linear or branched alkynyl group, C(O)NHC 1-4 Linear or branched alkyl groups, C(O)NHC 2-4 Linear or branched alkenyl group, C(O)NHC 2-4 The linear or branched alkynyl groups are optionally substituted with one or more groups independently selected from the linear or branched alkynyl groups. m is selected from 1 or 2.

2. A compound represented by formula (I) as described in claim 1, or a pharmaceutically acceptable salt or deuterated thereof. 【Chemistry 2】 (Here, A is selected from a 5-membered heteroaryl group containing 1 to 3 cycloheteratoons independently selected from N, O, and S. Z and T are independently selected from C and N. X and Y are independently selected from CRaRb, NRc, and O. Ra and Rb independently form H, OH, and NH. 2 , C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Selected from linear or branched alkyloxy groups, or Ra and Rb together with the carbon atom to which they are bonded, C 3-7 A cycloalkyl group, or a 3-7 membered heterocycloalkyl group comprising 1 to 3 cycloheteratoons independently selected from N, O, and S, is formed. Rc is H, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 3-7 Selected from cycloalkyl groups, R 2 , R 3 , R 4 , R 5 These are independently H, F, Cl, Br, CN, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 3-7 Selected from cycloalkyl groups, R 1 F, Cl, Br, CN, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 3-7 Cycloalkyl groups, 3-7 member heterocycloalkyl groups containing 1-3 cycloheteratoms independently selected from N, O, and S and bonded by C or N, aryl groups, 5-11 member heteroaryl groups containing 1-3 cycloheteratoms independently selected from N, O, and S, C 5-7 A crosslinked cycloalkyl group, a 5-7 member heterocrosslinked cycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S, a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member alkane ring, a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S, a bonding ring formed from a benzene ring and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S, a bonding ring formed from a 5-7 member heteroaromatic ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S, -C 1-4 Straight-chain or branched-chain alkylene-R 7 , -OR 7 ,-OC 1-4 Straight-chain or branched-chain alkylene-R 7 , -SR 7 , -SC 1-4 Straight-chain or branched-chain alkylene-R 7 , -N(R 6 )R 7 , -N(R 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 , -C(O)R 7 , -C(O)-C 1-4 Straight-chain or branched-chain alkylene-R 7 , -C(O)R 7 -OR 7 , -C(O)R 7 -N(R 6 )R 7 -S(O) 2 R 7 , -N(R 6 ) C(O)R 7 , -N(R 6 )C(O)-C 1-4 Straight-chain or branched-chain alkylene-R 7 ,-C(O)N(R 6 )R 7 ,-C(O)N(R 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 , -N(R 6 )S(O) 2 R 7 , -N(R 6 )S(O) 2 -C 1-4 Straight-chain or branched-chain alkylene-R 7 -S(O) 2 N(R) 6 )R 7 -S(O) 2 N(R) 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 They were chosen independently of each other, and here, The alkylene group may be optionally substituted with an OH group. The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, crosslinked cycloalkyl group, heterocrosslinked cycloalkyl group, and the bonding ring are OH, CN, NH 2 , =O, F, Cl, Br, C which can be optionally substituted by one or more groups independently selected from F, Cl, Br. 1-4 Linear or branched alkyl groups, and C optionally substituted with one or more groups independently selected from F, Cl, and Br. 2-4 Linear or branched alkenyl groups, optionally substituted with one or more groups independently selected from F, Cl, and Br. 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH, C 1-4 Linear or branched alkylene-NH 2 , C 2-4 Linear or branched alkenylene-NH 2 , C 2-4 Straight-chain or branched-chain alkynylene-NH 2 , C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, C(O)OC 2-4 Linear or branched alkenyl group, C(O)OC 2-4 Linear or branched alkynyl group, -C(O)R 7 -S(O) 2 R 7 , -N(R 6 )R 7 , -N(R 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 , -N(R 6 ) C(O)R 7 , -N(R 6 )C(O)-C 1-4 Straight-chain or branched-chain alkylene-R 7 , -N(R 6 )S(O) 2 R 7 , -N(R 6 )S(O) 2 -C 1-4 Straight-chain or branched-chain alkylene-R 7 -S(O) 2 N(R) 6 )R 7 -S(O) 2 N(R) 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 ,-C(O)N(R 6 )R 7 ,-C(O)N(R 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 , -P(O)(R 6 ) 2 , C 3-7 Optionally substituted with one or more groups independently selected from a cycloalkyl group, a 3-7 membered heterocycloalkyl group containing 1 to 3 cycloheteratoons independently selected from N, O, and S, and bonded by C or N, The two substituents on the same ring carbon atom of the cycloalkyl, heterocycloalkyl, or heteroaryl group may optionally be C along with the carbon atom to which they are bonded. 3-6 A cycloalkyl group or a 3-6 membered heterocycloalkyl group containing one cycloheteratom selected from N and O is formed, and the formed cycloalkyl group or heterocycloalkyl group is OH, CN, NH 2 ,=O,F,Cl,Br,C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH, C 1-4 Linear or branched alkylene-NH 2 , C 2-4 Linear or branched alkenylene-NH 2 , C 2-4 Straight-chain or branched-chain alkynylene-NH 2 , C 1-4 Linear or branched alkyloxy group, C 3-6 Optionally substituted with one or more groups independently selected from a cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1 to 3 cycloheteratoons independently selected from N, O, and S, R 6 H, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Selected from linear or branched alkynyl groups, R 7 These are independently H, OH, and NH. 2 , C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Linear or branched alkyloxy group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 3-7 From a cycloalkyl group, a 3-7 membered heterocycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S and bonded by C or N, an aryl group, and a 5-6 membered heteroaryl group containing 1-3 cycloheteratoms independently selected from N, O, and S, The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are F, Cl, Br, OH, CN, and NH. 2 ,=O,C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH,-C(O)OC 1-4 Linear or branched alkyl groups, C(O)OC 2-4 Linear or branched alkenyl group, C(O)OC 2-4 Linear or branched alkynyl group, C(O)NHC 1-4 Linear or branched alkyl groups, C(O)NHC 2-4 Linear or branched alkenyl group, C(O)NHC 2-4 The linear or branched alkynyl groups are optionally substituted with one or more groups independently selected from the linear or branched alkynyl groups. m is selected from 1 or 2. 【Request Item 3】 【Chemistry 3】 teeth 【Chemistry 4】 A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or deuterated thereof, characterized by being selected from the above.

4. The compound according to claim 3 or a pharmaceutically acceptable salt or deuterated thereof, characterized in that X and Y are CRaRb.

5. The compound is characterized by having the structure shown in formula (II), as described in claim 1, or a pharmaceutically acceptable salt or deuterated thereof. 【Transformation 5】 (Here, R 1 C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 3-6 A cycloalkyl group, a 3-6 member heterocycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S and bonded by C or N, a phenyl group, a 5-11 member heteroaryl group containing 1-3 cycloheteratoms independently selected from N, O, and S, C 5-7 A 5-7 member heterocrosslinked cycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member alkane ring; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a benzene ring and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 5-7 member heteroaromatic ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; -C 1-4 Straight-chain or branched-chain alkylene-R 7 , -OR 7 ,-OC 1-4 Straight-chain or branched-chain alkylene-R 7 , -SR 7 , -SC 1-4 Straight-chain or branched-chain alkylene-R 7 , -N(R 6 )R 7 , -N(R 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 , -C(O)R 7 , -C(O)-C 1-4 Straight-chain or branched-chain alkylene-R 7 , -N(R 6 ) C(O)R 7 , -N(R 6 )C(O)-C 1-4 Straight-chain or branched-chain alkylene-R 7 ,-C(O)N(R 6 )R 7 ,-C(O)N(R 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 , -N(R 6 )S(O) 2 R 7 , -N(R 6 )S(O) 2 -C 1-4 Straight-chain or branched-chain alkylene-R 7 -S(O) 2 N(R) 6 )R 7 -S(O) 2 N(R) 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 From, he was chosen, and here, The alkylene group may be optionally substituted with an OH group. The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, heteroaryl group, crosslinked cycloalkyl group, heterocrosslinked cycloalkyl group, and the bonding ring are OH, CN, NH 2 , =O, F, Cl, Br, C which can be optionally substituted by one or more groups independently selected from F, Cl, Br. 1-4 Linear or branched alkyl groups, and C optionally substituted with one or more groups independently selected from F, Cl, and Br. 2-4 Linear or branched alkenyl groups, optionally substituted with one or more groups independently selected from F, Cl, and Br. 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, C(O)OC 2-4 Linear or branched alkenyl group, C(O)OC 2-4 Linear or branched alkynyl group, C(O)NHC 1-4 Linear or branched alkyl groups, C(O)NHC 2-4 Linear or branched alkenyl group, C(O)NHC 2-4 Linear or branched alkynyl group, -C(O)R 7 , substitution or non-substitution of C 3-7 It is optionally substituted with one or more groups independently selected from a cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted 3-7 membered heterocycloalkyl group containing 1-3 cycloheteroatoms independently selected from N, O, and S and bonded by C or N, and a substituted or unsubstituted 5-6 membered heteroaryl group containing 1-3 cycloheteroatoms independently selected from N, O, and S and bonded by C or N, where, substitution C 3-7 The substituents for cycloalkyl groups, substituted aryl groups, substituted 3-7 member heterocycloalkyl groups, and substituted 5-6 member heteroaryl groups are OH, CN, and NH. 2 , =O, F, Cl, Br, C which can be optionally substituted by one or more groups independently selected from F, Cl, Br. 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkylene-NH 2 , C 2-4 Linear or branched alkenylene-NH 2 , C 2-4 Straight-chain or branched-chain alkynylene-NH 2 , C 1-4 Selected from linear or branched alkyloxy groups, R 6 H, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Selected from linear or branched alkynyl groups, R 7 C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 3-6 From a cycloalkyl group, a 3-6 membered heterocycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S and bonded by C or N, and a phenyl group, a 5-11 membered heteroaryl group containing 1-3 cycloheteratoms independently selected from N, O, and S, The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are OH, CN, and NH. 2 ,=O,C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH,-C(O)OC 1-4 Linear or branched alkyl groups, C(O)OC 2-4 Linear or branched alkenyl group, C(O)OC 2-4 Linear or branched alkynyl group, C(O)NHC 1-4 Linear or branched alkyl groups, C(O)NHC 2-4 Linear or branched alkenyl group, C(O)NHC 2-4 The linear or branched alkynyl groups are optionally substituted with one or more groups independently selected from the linear or branched alkynyl groups. R 2 and R 3 They are independently selected from F, Cl, and Br. R 4 and R 5 (This is H.)

6. The compound according to claim 5, or a pharmaceutically acceptable salt or deuterated thereof. (In Equation II, R 1 C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 3-6 A cycloalkyl group, a 3-6 member heterocycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S and bonded by C or N, a phenyl group, a 5-11 member heteroaryl group containing 1-3 cycloheteratoms independently selected from N, O, and S, -C 1-4 Straight-chain or branched-chain alkylene-R 7 , -OR 7 ,-OC 1-4 Straight-chain or branched-chain alkylene-R 7 , -SR 7 , -SC 1-4 Straight-chain or branched-chain alkylene-R 7 , -N(R 6 )R 7 , -N(R 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 , -C(O)R 7 , -C(O)-C 1-4 Straight-chain or branched-chain alkylene-R 7 , -N(R 6 ) C(O)R 7 , -N(R 6 )C(O)-C 1-4 Straight-chain or branched-chain alkylene-R 7 ,-C(O)N(R 6 )R 7 ,-C(O)N(R 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 , -N(R 6 )S(O) 2 R 7 , -N(R 6 )S(O) 2 -C 1-4 Straight-chain or branched-chain alkylene-R 7 -S(O) 2 N(R) 6 )R 7 -S(O) 2 N(R) 6 )-C 1-4 Straight-chain or branched-chain alkylene-R 7 From, The alkylene group may be optionally substituted with an OH group. The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are OH, CN, and NH. 2 ,=O,C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH,-C(O)OC 1-4 Linear or branched alkyl groups, C(O)OC 2-4 Linear or branched alkenyl group, C(O)OC 2-4 Linear or branched alkynyl group, C(O)NHC 1-4 Linear or branched alkyl groups, C(O)NHC 2-4 Linear or branched alkenyl group, C(O)NHC 2-4 The linear or branched alkynyl groups are optionally substituted with one or more groups independently selected from the linear or branched alkynyl groups. R 6 H, C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Selected from linear or branched alkynyl groups, R 7 C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 3-6 From a cycloalkyl group, a 3-6 membered heterocycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S and bonded by C or N, and a phenyl group, a 5-11 membered heteroaryl group containing 1-3 cycloheteratoms independently selected from N, O, and S, The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are OH, CN, and NH. 2 ,=O,C 1-4 Linear or branched alkyl groups, C 2-4 Linear or branched alkenyl group, C 2-4 Linear or branched alkynyl group, C 1-4 Straight-chain or branched-chain alkylene-OH, C 2-4 Straight-chain or branched-chain alkenylene-OH, C 2-4 Straight-chain or branched-chain alkynylene-OH,-C(O)OC 1-4 Linear or branched alkyl groups, C(O)OC 2-4 Linear or branched alkenyl group, C(O)OC 2-4 Linear or branched alkynyl group, C(O)NHC 1-4 Linear or branched alkyl groups, C(O)NHC 2-4 Linear or branched alkenyl group, C(O)NHC 2-4 The linear or branched alkynyl groups are optionally substituted with one or more groups independently selected from the linear or branched alkynyl groups. R 2 and R 3 They are independently selected from F, Cl, and Br. R 4 and R 5 H is, Preferably, in formula II, R 1 C 1-4 Linear or branched alkyl groups, C 3-6 A cycloalkyl group, a 3-6 member heterocycloalkyl group comprising 1 to 3 cycloheteratoons independently selected from N, O, and S, bonded by C or N, 【Transformation 6】 , pyridine, 【Transformation 7】 , -C 1-4 Straight-chain or branched-chain alkylene-R 7 , -OR 7 , -SR 7 , -SC 1-4 Straight-chain or branched-chain alkylene-R 7 , -N(R 6 )R 7 , -C(O)R 7 , -N(R 6 ) C(O)R 7 ,-C(O)N(R 6 )R 7 , -N(R 6 )S(O) 2 R 7 -S(O) 2 N(R) 6 ) R 7 From, The alkylene group may be optionally substituted with an OH group. The alkyl group, cycloalkyl group, heterocycloalkyl group, 【Transformation 8】 , pyridine, 【Chemistry 9】 OH, CN, NH 2 ,=O,C 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene -OH, -C(O)OC 1-4 Linear or branched alkyl groups, C(O)NHC 1-4 Optionally substituted with one or more groups independently selected from linear or branched alkyl groups, R 6 H, C 1-4 Selected from linear or branched alkyl groups, R 7 C 1-4 Linear or branched alkyl groups, C 3-6 A cycloalkyl group, a 3-6 member heterocycloalkyl group comprising 1 to 3 cycloheteratoons independently selected from N, O, and S, bonded by C or N, 【Chemistry 10】 , pyridine, 【Chemistry 11】 Selected from, The alkyl group, cycloalkyl group, heterocycloalkyl group, 【Chemistry 12】 , pyridine, 【Chemistry 13】 OH, CN, NH 2 ,=O,C 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene -OH, -C(O)OC 1-4 Linear or branched alkyl groups, C(O)NHC 1-4 Optionally substituted with one or more groups independently selected from linear or branched alkyl groups, R 2 and R 3 They are independently selected from F, Cl, and Br. R 4 and R 5 H is, More preferably, in formula II, R 1 C is substituted with one or more OH groups. 1-4 It is a linear or branched alkyl group, R 2 and R 3 They are independently selected from F, Cl, and Br. R 4 and R 5 H is, More preferably, in formula II, R 1 C is substituted with one OH group. 1-4 It is a linear or branched alkyl group, R 2 and R 3 It is Cl, R 4 and R 5 It is characterized by being H.

7. The compound is characterized by having the structure shown in formula (II), as described in claim 1, or a pharmaceutically acceptable salt or deuterated thereof. 【Chemistry 14】 (Here, R 1 C 1-4 Linear or branched alkyl groups, C 3-6 A cycloalkyl group, a 3-6 member heterocycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S and bonded by C or N, a phenyl group, a 5-11 member heteroaryl group containing 1-3 cycloheteratoms independently selected from N, O, and S, C 5-7 A 5-7 member heterocrosslinked cycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member alkane ring; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a benzene ring and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 5-7 member heteroaromatic ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; -C 1-4 Straight-chain or branched-chain alkylene-R 7 , -OR 7 ,-OC 1-4 Straight-chain or branched-chain alkylene-R 7 , -C(O)R 7 , -C(O)-C 1-4 Straight-chain or branched-chain alkylene-R 7 From, he was chosen, and here, The alkylene group may be optionally substituted with an OH group. The alkyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, heteroaryl group, crosslinked cycloalkyl group, heterocrosslinked cycloalkyl group, and the bonding ring are OH, CN, NH 2 , =O, F, Cl, Br, C which can be optionally substituted by one or more groups independently selected from F, Cl, Br. 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, -C(O)R 7 , substitution or non-substitution of C 3-7 Optionally substituted with one or more groups independently selected from substituted or unsubstituted 3-7 member heterocycloalkyl groups, which contain 1 to 3 cycloheteratoons independently selected from cycloalkyl groups, N, O, and S, and bonded by C or N, where, substitution C 3-7 The substituents of cycloalkyl groups and substituted 3-7 member heterocycloalkyl groups are OH, CN, and NH. 2 , =O, F, Cl, Br, C which can be optionally substituted by one or more groups independently selected from F, Cl, Br. 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkylene-NH 2 , C 1-4 Selected from linear or branched alkyloxy groups, R 7 C 1-4 Linear or branched alkyl groups, C 3-6 From a cycloalkyl group, a 3-6 membered heterocycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S and bonded by C or N, and a phenyl group, a 5-11 membered heteroaryl group containing 1-3 cycloheteratoms independently selected from N, O, and S, The alkyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are OH, C 1-4 Linear or branched alkyl groups, C 1-4 The linear or branched alkylene-OH group is optionally substituted with one or more groups independently selected, R 2 and R 3 They are independently selected from F, Cl, and Br. R 4 and R 5 H is, Preferably, in formula (II), R 1 C 1-4 Linear or branched alkyl groups, C 3-6 A cycloalkyl group, a 3-6 member heterocycloalkyl group containing 1-2 cycloheteratoms independently selected from N and O, bonded by C or N, a phenyl group, 【Chemistry 15】 , pyridine, 【Chemistry 16】 , a 5-7 member heterobridged cycloalkyl group containing one cycloheteratom O, a bonding ring formed from a 3-7 member heteroalkyl ring containing one cycloheteratom O and a 3-7 member alkane ring, -C 1-4 Straight-chain or branched-chain alkylene-R 7 , -OR 7 , -C(O)R 7 From, he was chosen, and here, The alkyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, 【Chemistry 17】 , pyridine, [Chemistry 18] Heterocrosslinked cycloalkyl groups, the connecting rings are OH, CN, NH 2 ,=O,F,Cl,Br,C 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, -C(O)R 7 , substitution or non-substitution of C 3-7 It is optionally substituted with one or more groups independently selected from substituted or unsubstituted 3-7 member heterocycloalkyl groups, which contain one or two cycloheteratoons independently selected from cycloalkyl groups, N, and O, and are bonded by C or N, where, substitution C 3-7 The substituents of cycloalkyl groups and substituted 3-7 member heterocycloalkyl groups may be optionally substituted with one or more groups independently selected from F, Cl, and Br. 1-4 Selected from linear or branched alkyl groups, R 7 C 1-4 Linear or branched alkyl groups, C 3-6 From a 3-6 member heterocycloalkyl group containing 1-2 cycloheteratoms independently selected from cycloalkyl groups, N, and O, and bonded by C or N, The alkyl group, cycloalkyl group, and heterocycloalkyl group in question are OH, C 1-4 Optionally substituted with one or more groups independently selected from linear or branched alkyl groups, R 2 and R 3 They are independently selected from F, Cl, and Br. R 4 and R 5 H is, More preferably, in formula (II), R 1 C 3-6 A cycloalkyl group is selected from a 3-6 member heterocycloalkyl group containing one or two cycloheteratoms independently selected from N and O, bonded by C or N, where, The cycloalkyl groups and heterocycloalkyl groups are OH, CN, and NH. 2 ,=O,F,Cl,Br,C 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, -C(O)R 7 , substitution or non-substitution of C 3-6 It is optionally substituted with one or more groups independently selected from substituted or unsubstituted 3-6 member heterocycloalkyl groups, which contain one or two cycloheteratoons independently selected from cycloalkyl groups, N, and O, and are bonded by C or N, where, substitution C 3-6 The substituents of cycloalkyl groups and substituted 3-6 member heterocycloalkyl groups may be optionally substituted with one or more groups independently selected from F, Cl, and Br. 1-4 Selected from linear or branched alkyl groups, R 7 C 1-4 Linear or branched alkyl groups, C 3-6 From a 3-6 member heterocycloalkyl group containing 1-2 cycloheteratoms independently selected from cycloalkyl groups, N, and O, and bonded by C or N, The alkyl group, cycloalkyl group, and heterocycloalkyl group in question are OH, C 1-4 Optionally substituted with one or more groups independently selected from linear or branched alkyl groups, R 2 and R 3 They are independently selected from F, Cl, and Br. R 4 and R 5 (This is H.)

8. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated thereof, characterized in that the compound has the structure shown in formula III. 【Chemistry 19】 (Here, R 1 C 1-4 Linear or branched alkyl groups, C 3-6 A cycloalkyl group, a 3-6 membered heterocycloalkyl group comprising 1 to 3 cycloheteratoons independently selected from N, O, and S, bonded by C or N, C 5-7 A crosslinked cycloalkyl group is selected from a 5-7 membered heterocrosslinked cycloalkyl group containing 1 to 3 cycloheteratoons independently selected from N, O, and S, where, The alkyl group, cycloalkyl group, heterocycloalkyl group, crosslinked cycloalkyl group, and heterocrosslinked cycloalkyl group are OH, CN, and NH. 2 ,=O,F,Cl,Br,C 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkyloxy groups, substituted or unsubstituted C 3-7 Optionally substituted with one or more groups independently selected from substituted or unsubstituted 3-7 member heterocycloalkyl groups, which contain 1 to 3 cycloheteratoons independently selected from cycloalkyl groups, N, O, and S, and bonded by C or N, where, substitution C 3-7 The substituents of cycloalkyl groups and substituted 3-7 member heterocycloalkyl groups may be optionally substituted with one or more groups independently selected from F, Cl, and Br. 1-4 Selected from linear or branched alkyl groups, R 2 and R 3 They are independently selected from F, Cl, and Br. R 4 and R 5 H is, Preferably, in formula III, R 1 C 1-4 Linear or branched alkyl groups, C 3-6 A cycloalkyl group is selected from a 3-6 member heterocycloalkyl group containing one or two cycloheteratoms independently selected from N and O, bonded by C or N, where, The alkyl groups, cycloalkyl groups, and heterocycloalkyl groups are F, Cl, Br, and C. 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Optionally substituted with one or more groups independently selected from linear or branched alkyloxy groups, R 2 and R 3 They are independently selected from F, Cl, and Br. R 4 and R 5 (This is H.)

9. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated thereof, characterized in that the compound has the structure shown in formula IV. 【Chemistry 20】 (Here, R 1 C 1-4 Linear or branched alkyl groups, C 3-6 A cycloalkyl group, a 3-6 member heterocycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S and bonded by C or N, a phenyl group, a 5-11 member heteroaryl group containing 1-3 cycloheteratoms independently selected from N, O, and S, C 5-7 A 5-7 member heterocrosslinked cycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member alkane ring; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a benzene ring and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 5-7 member heteroaromatic ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; -C 1-4 Straight-chain or branched-chain alkylene-R 7 , -OR 7 ,-OC 1-4 Straight-chain or branched-chain alkylene-R 7 , -C(O)R 7 , -C(O)-C 1-4 Straight-chain or branched-chain alkylene-R 7 From, he was chosen, and here, The alkylene group may be optionally substituted with an OH group. The alkyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, heteroaryl group, crosslinked cycloalkyl group, heterocrosslinked cycloalkyl group, and the bonding ring are OH, CN, NH 2 ,=O,F,Cl,Br,C 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, -C(O)R 7 , substitution or non-substitution of C 3-7 Optionally substituted with one or more groups independently selected from substituted or unsubstituted 3-7 member heterocycloalkyl groups, which contain 1 to 3 cycloheteratoons independently selected from cycloalkyl groups, N, O, and S, and bonded by C or N, where, substitution C 3-7 The substituents of cycloalkyl groups and substituted 3-7 member heterocycloalkyl groups are OH, CN, and NH. 2 , =O, F, Cl, Br, C which can be optionally substituted by one or more groups independently selected from F, Cl, Br. 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkylene-NH 2 , C 1-4 Selected from linear or branched alkyloxy groups, R 7 C 1-4 Linear or branched alkyl groups, C 3-6 From a cycloalkyl group, a 3-6 membered heterocycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S and bonded by C or N, and a phenyl group, a 5-11 membered heteroaryl group containing 1-3 cycloheteratoms independently selected from N, O, and S, The alkyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are OH, C 1-4 Linear or branched alkyl groups, C 1-4 Optionally substituted with one or more groups independently selected from a linear or branched alkylene-OH group, R 2 and R 3 They are independently selected from F, Cl, and Br. R 4 and R 5 H is, Preferably, in formula IV, R 1 C 1-4 Linear or branched alkyl groups, C 3-6 A cycloalkyl group, a 3-6 member heterocycloalkyl group containing 1-2 cycloheteratoms independently selected from N and O, bonded by C or N, a phenyl group, 【Chemistry 21】 , pyridine, 【Chemistry 22】 , a 5-7 member heterobridged cycloalkyl group containing one cycloheteratom O, a bonding ring formed from a 3-7 member heteroalkyl ring containing one cycloheteratom O and a 3-7 member alkane ring, -C 1-4 Straight-chain or branched-chain alkylene-R 7 , -C(O)R 7 , -OR 7 From, he was chosen, and here, The alkyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, 【Chemistry 23】 , pyridine, 【Chemistry 24】 Heterocrosslinked cycloalkyl groups, the connecting rings are OH, CN, NH 2 ,=O,F,Cl,Br,C 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, -C(O)R 7 , substitution or non-substitution of C 3-7 It is optionally substituted with one or more groups independently selected from substituted or unsubstituted 3-7 member heterocycloalkyl groups, which contain one or two cycloheteratoons independently selected from cycloalkyl groups, N, and O, and are bonded by C or N, where, substitution C 3-7 The substituents of cycloalkyl groups and substituted 3-7 member heterocycloalkyl groups may be optionally substituted with one or more groups independently selected from F, Cl, and Br. 1-4 Selected from linear or branched alkyl groups, R 7 C 1-4 Linear or branched alkyl groups, C 3-6 From a 3-6 member heterocycloalkyl group containing 1-2 cycloheteratoms independently selected from cycloalkyl groups, N, and O, and bonded by C or N, The alkyl group, cycloalkyl group, and heterocycloalkyl group in question are OH, C 1-4 Optionally substituted with one or more groups independently selected from linear or branched alkyl groups, R 2 and R 3 They are independently selected from F, Cl, and Br. R 4 and R 5 H is, More preferably, in formula IV, R 1 C 1-4 Linear or branched alkyl groups, C 3-6 A cycloalkyl group, a 3-6 member heterocycloalkyl group containing 1-2 cycloheteratoms independently selected from N and O, bonded by C or N, a phenyl group, 【Chemistry 25】 , -C 1-4 Straight-chain or branched-chain alkylene-R 7 , -C(O)R 7 , -OR 7 From, he was chosen, and here, The alkyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, 【Chemistry 26】 OH, CN, NH 2 ,=O,F,Cl,Br,C 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Optionally substituted with one or more groups independently selected from linear or branched alkyl groups, R 7 C 1-4 Linear or branched alkyl groups, C 3-6 From a 3-6 member heterocycloalkyl group containing 1-2 cycloheteratoms independently selected from cycloalkyl groups, N, and O, and bonded by C or N, The alkyl group, cycloalkyl group, and heterocycloalkyl group in question are OH, C 1-4 Optionally substituted with one or more groups independently selected from linear or branched alkyl groups, R 2 and R 3 They are independently selected from F, Cl, and Br. R 4 and R 5 (This is H.)

10. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated thereof, characterized in that the compound has a structure represented by formula V or formula V'. 【Chemistry 27】 (In equation V or equation V', R 1 They may be the same or different, H, C 1-4 Linear or branched alkyl groups, C 3-6 A cycloalkyl group, a 3-6 member heterocycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S and bonded by C or N, a phenyl group, a 5-11 member heteroaryl group containing 1-3 cycloheteratoms independently selected from N, O, and S, C 5-7 A 5-7 member heterocrosslinked cycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member alkane ring; a bonding ring formed from a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a benzene ring and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; a bonding ring formed from a 5-7 member heteroaromatic ring containing 1-3 cycloheteratoms independently selected from N, O, and S and a 3-7 member heteroalkyl ring containing 1-3 cycloheteratoms independently selected from N, O, and S; -C 1-4 Straight-chain or branched-chain alkylene-R 7 , -OR 7 ,-OC 1-4 Straight-chain or branched-chain alkylene-R 7 , -C(O)R 7 , -C(O)-C 1-4 Straight-chain or branched-chain alkylene-R 7 From, independently selected, Here, The alkylene group may be optionally substituted with an OH group. The alkyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, heteroaryl group, crosslinked cycloalkyl group, heterocrosslinked cycloalkyl group, and the bonding ring are OH, CN, NH 2 ,=O,F,Cl,Br,C 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkyloxy group, -C(O)OC 1-4 Linear or branched alkyl groups, -C(O)R 7 , substitution or non-substitution of C 3-7 Optionally substituted with one or more groups independently selected from substituted or unsubstituted 3-7 member heterocycloalkyl groups, which contain 1 to 3 cycloheteratoons independently selected from cycloalkyl groups, N, O, and S, and bonded by C or N, where, substitution C 3-7 The substituents of cycloalkyl groups and substituted 3-7 member heterocycloalkyl groups are OH, CN, and NH. 2 , =O, F, Cl, Br, C which can be optionally substituted by one or more groups independently selected from F, Cl, Br. 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Linear or branched alkylene-NH 2 , C 1-4 Selected from linear or branched alkyloxy groups, R 7 C 1-4 Linear or branched alkyl groups, C 3-6 From a cycloalkyl group, a 3-6 membered heterocycloalkyl group containing 1-3 cycloheteratoms independently selected from N, O, and S and bonded by C or N, and a phenyl group, a 5-11 membered heteroaryl group containing 1-3 cycloheteratoms independently selected from N, O, and S, The alkyl group, cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are OH, C 1-4 Linear or branched alkyl groups, C 1-4 Optionally substituted with one or more groups independently selected from a linear or branched alkylene-OH group, R 2 and R 3 They are independently selected from F, Cl, and Br. R 4 and R 5 H is, Preferably, in formula V or formula V', R 1 They may be the same or different, H, C 1-4 Linear or branched alkyl groups, C 3-6 A cycloalkyl group, a 3-6 membered heterocycloalkyl group containing 1-2 cycloheteratoms independently selected from N and O, bonded by C or N, and a phenyl group, where, The alkyl group, cycloalkyl group, heterocycloalkyl group, and phenyl group are OH, F, Cl, Br, and C. 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Optionally substituted with one or more groups independently selected from linear or branched alkyloxy groups, R 2 and R 3 They are independently selected from F, Cl, and Br. R 4 and R 5 H is, More preferably, in formula V or formula V', R 1 They may be the same or different, and H and C are independent of each other. 1-4 Selected from linear or branched alkyl groups, Here, The alkyl group in question is OH, F, Cl, Br, C 1-4 Linear or branched alkyl groups, C 1-4 Straight-chain or branched-chain alkylene-OH, C 1-4 Optionally substituted with one or more groups independently selected from linear or branched alkyloxy groups, R 2 and R 3 They are independently selected from F, Cl, and Br. R 4 and R 5 (This is H.)

11. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated thereof, characterized by being selected from the following compounds. （ 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 。）

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt or deuterated thereof, and a pharmaceutically acceptable carrier.

13. A method for the prevention and / or treatment of a Kv1.3-related disease, comprising administering to a subject in an amount effective for prevention and / or treatment to the subject in question a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt or deuterated thereof, or a pharmaceutical composition according to claim 12. Preferably, the disease includes immune and inflammatory diseases such as multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, type 1 diabetes, psoriasis and asthma, spondylitis, and periodontitis, as well as obesity, type 2 diabetes, renal fibrosis, Alzheimer's disease, and ischemic stroke, and is a method for preventing and / or treating Kv1.3-related diseases.

14. Uses of the compound described in any one of claims 1 to 11 or a pharmaceutically acceptable salt or deuterated thereof in the manufacture of a drug for the prevention and / or treatment of Kv1.3-related disease, Preferably, the diseases include immune and inflammatory diseases such as multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, type 1 diabetes, psoriasis and asthma, spondylitis, and periodontitis, as well as obesity, type 2 diabetes, renal fibrosis, Alzheimer's disease, and ischemic stroke.

Images