WO2017198159A1

WO2017198159A1 - Imidazole derivative containing bridge ring

Info

Publication number: WO2017198159A1
Application number: PCT/CN2017/084604
Authority: WO
Inventors: 张贵民; 王升兰; 孙成宏
Original assignee: 鲁南制药集团股份有限公司
Priority date: 2016-05-16
Filing date: 2017-05-16
Publication date: 2017-11-23

Abstract

Provided are an imidazole derivative containing a bridge ring, and a composition thereof. The imidazole derivative and the composition thereof can be used in the preparation of drugs for treating pathological characteristic diseases that is mediated by indoleamine2,3-dioxygenase and that is related to in the tryptophan metabolism field. Also provided is a method for preparing the derivative and an intermediate thereof.

Description

Imidazole derivative containing bridged ring

Technical field

The invention relates to the field of medicines, in particular to an imidazole derivative containing a bridged ring, a preparation method thereof and use thereof.

Background field

Indoleamine 2,3-dioxygenase, a monomeric enzyme containing heme, catalyzes the epoxidation of L-tryptophan to form kynurenine. The high expression of indoleamine 2,3-dioxygenase results in local cell tryptophan depletion, which induces T cell arrest in the G1 phase, thereby inhibiting T cell proliferation. On the other hand, indoleamine 2,3-dioxygenase-dependent tryptophan degradation leads to an increase in kynurenine levels and also induces oxygen free radical-mediated T cell apoptosis. Third, the up-regulation of dendritic cell guanamine 2,3-dioxygenase expression enhances local regulatory T cell (Treg)-mediated immunosuppression by degrading local tryptophan, promoting the body's tumor-specific antigen Peripheral immune tolerance. Indoleamine 2,3-dioxygenase has become the most important small molecule regulatory target for anti-tumor immunotherapy.

Studies have found that indoleamine 2,3-dioxygenase is associated with many physiological processes in the human body. In 1998, Munn et al. revealed that the fetus was able to survive the pregnancy without being genotyped without being rejected because of placental The somatic trophoblast cells synthesize indoleamine 2,3-dioxygenase, which inhibits the rejection of the fetus by maternal T cells through blood flow. They further implanted pregnant mice with a sustained-release capsule containing the indoleamine 2,3-dioxygenase inhibitor 1-methyltryptophan, and the embryo was repelled and aborted (Munn DH, Zhou M, Attwood) JT, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Scienice, 1998, 281 (5380): 1191-3). In addition, some diseases caused by abnormal immune responses such as transplant rejection and autoimmune diseases are also closely related to indoleamine 2,3-dioxygenase.

Although the treatment of tumors has made great progress in recent years, the clinical efficacy is still unsatisfactory. Immune escape is one of the main biological mechanisms of tumorigenesis and metastasis, and has become an important factor affecting the therapeutic effect of cancer. Indoleamine 2,3-dioxygenase, as an immunomodulatory enzyme, can effectively inhibit T cell function, enhance Treg cell function, and induce NK cell dysfunction. Tumor cells can use these organisms' inherent immune regulation mechanisms. Escape from the identification and killing of the immune system (Jia Yunwei, Wang Yu. Chinese Journal of Cancer Biotherapy, 2004, 21 (6): 693-7). In order to enable tumor patients to get the best benefit from treatment, it is imperative to rationally adjust the treatment strategy for tumor immune escape. The indoleamine 2,3-dioxygenase inhibitor of the invention can effectively regulate the immune system of the patient, block the immune escape of the tumor cells, and has a good therapeutic effect on most spontaneous tumors. Based on the regulation of the immune system, the indoleamine 2,3-dioxygenase inhibitor of the present invention can treat tumors in addition to other diseases related to immunity such as chronic infection and AIDS.

Indoleamine 2,3-dioxygenase is also closely related to neurological diseases. It can lower the level of serotonin and cause mental illness such as depression and anxiety. It can also cause neurotoxic metabolism such as quinolinic acid in the brain. Accumulation of products, which is closely related to the occurrence of neurodegenerative diseases such as Alzheimer's disease. Indoleamine 2,3-dioxygenase affects brain function by at least two mechanisms: 1) by reducing the circulating tryptophan concentration by metabolizing tryptophan in the inflammatory response, thereby lowering serotonin levels , leading to depression; 2) catalyzing the metabolism of tryptophan in the kynurenine pathway to accumulate kynurenine and neurotoxic quinolinic acid. (Kong Linglei, Qu Chunxiang, Yang Qing. Chinese Journal of Pharmaceutical Chemistry, 2009, 19(2): 147-154).

Summary of the invention:

The invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

Where n takes 0 or 1 or 2 or 3;

n ³ takes 0 or 1 or 2;

R _{0 is} selected from the group consisting of OH, C(O)OH, amino, amide, aminoacyl, heteroaryl containing at least one N or O or S, halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano , amino, aryl, heteroaryl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkoxy substituted C1-6 alkoxy or containing at least one N or O or S Heteroaryl, substituted by halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkoxy Carbonyl group, amino group substituted by C1-6 alkyl group, 2-8 membered heteroalkyl group, 3-12 membered heterocycloalkyl group, C1-6 alkoxy group, C3-12 cycloalkenyl group, aryl group, heteroaryl group , amide group, aminoacyl group;

R _{5-8 is a} single bond linked to a benzene ring, and R ₀₀ , R ₁ , R ₂ , R ₃ , R ₄ , R ₉ , and R ₁₀ are each independently selected from H, NH ₂ , halogen, CN, CX _3-s H _s , OH, C(O)OH, C(O)H, alkenyl, alkynyl, sulfinylamino, sulfone, sulfoxide, nitro, alkanoyl, phosphate, ureido, carbonate , C1-6 alkyl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkoxy, C3-12 cycloalkenyl, C2-6 alkenyl, aryl, heteroaryl Base, amide group, aminoacyl group, halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkane a C1-6 alkoxy group, a C3-12 cycloalkenyl substituted C1-6 alkyl group or a C3-12 cycloalkyl group or a C1-6 alkoxy group or an aryl or heteroaryl group, which is halogen, cyano, Amino, aryl, heteroaryl, C1-6 alkyl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkoxy substituted carbonyl, C1-6 alkyl, 2 -8 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkoxy, C3-12 cycloalkenyl, aryl, heteroaryl substituted amino, amido, aminoacyl;

R _5-8 forms a benzo structure with a benzene ring, and takes a C 3-12 cycloalkyl group, a C 3-12 cycloalkenyl group, a 3-12 membered heterocycloalkyl group, a 3-12 membered heterocycloalkenyl group, an aryl group, and a heteroaryl group. Base, by halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkane An oxy, C3-12 cycloalkenyl substituted C3-12 cycloalkyl or C3-12 cycloalkenyl or 3-12 membered heterocycloalkyl or 3-12 membered heterocycloalkenyl or aryl or heteroaryl;

The number n ^{2 of} R _5-8 is 0 or 1 or 2 or 3 or 4;

R ₁₁ is a cycloalkane or a cyclic olefin having a bridged ring structure.

In some aspects the above R _{11 is} selected from

Wherein C ^{1 is} linked to any position where the valence bond on ring r ₁ is reasonable; n ^{0 is} 0 or 1 or 2 or 3; R is a substituent at any position where the valence bond on ring r ₁ is reasonable; R and ring r ₁ is linked in such a way as to share one or more atoms with ring r ₁ ; each R is independently selected from the following substituents: =O, =S(=O) _s , =NR ₂ , =C(R ₂ ) ₂ ,=( Spiro-C3-12 cycloalkyl), or = (spiro-(3-10 membered heterocyclyl)), or

Each R is independently selected from the group consisting of H, NH ₂ , halogen, CN, CF ₃ , OH, C(O)OH, C(O)H, sulfonamido, sulfone, sulfoxide, nitro, Phosphate group, ureido group, carbonate group, C1-6 alkyl group, C3-12 cycloalkyl group, C3-12 cycloalkenyl group, C1-6 heteroalkyl group, C3-12 heterocycloalkyl group, aryl group, hetero Aryl, amide, aminoacyl, C1-6 alkyl or C1-6 substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl Alkoxy or aryl or heteroaryl, carbonyl substituted by halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, C3-12 cycloalkyl, by C1-6 alkyl, C3 -12 cycloalkyl, C 3-12 cycloalkenyl, aryl, heteroaryl substituted amino, amide, aminoacyl;

The number of R is n ¹ , n ¹ is any integer between 0-14 (including the end value); s is 0 or 1 or 2; a is a double bond; the position of a is located on the ring r ₁ Any position that is reasonable; the number of a is 0 or 1 or 2 or 3; when the number of a is 0, the valence bond of its corresponding position is a single bond; x and y are each independently selected from 0 or 1 or 2 or 3.

In some embodiments C ^{1 is} linked to the alpha or beta position on ring r ₁ .

In some aspects, the above R is selected from

Wherein L _{0 is} selected from the group consisting of the following double bond substituents: =O, =S(=O) _s , =C(R ₂ ) ₂ , =(spiro-C3-12 cycloalkyl), =heteroaryl or = (spiro-(3-10 membered heterocyclyl)), wherein = (spiro-C3-12 cycloalkyl), =heteroaryl or =(spiro-(3-10 membered heterocyclyl)) Substituted by one or more R _5-8 ;

or

Selected from the following single bond substituents: H, NH ₂ , halogen, CN, CF ₃ , OH, C(O)OH, C(O)H, heteroalkyl, alkenyl, alkynyl, heterocycloalkyl, sub Sulfonylamino, sulfone, sulfoxide, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, aryl, heteroaryl Alkyl, amide, aminoacyl, C1-6 alkyl or C3-12 ring substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl An alkyl group or a C1-6 alkoxy group or an aryl or heteroaryl group;

In some aspects, the above R is selected from

Wherein, A is selected from N, S, P, O; W is selected from C or S or P; the number of O is s, s is 0 or 1 or 2; and each of R ₁ and R _{3 is} independently selected from hydrogen, Amino, nitro, carbonyl, fluorenyl, halogen, CN, CX _3-s H _s , OH, C(O)OH, C(O)H, sulfonamido, sulfone, sulfoxide, nitro, Alkanoyl, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C2-6 alkenyl, 2-8 membered heteroalkyl, 3- 12-membered heterocycloalkyl, aryl, heteroaryl, amido, aminoacyl, halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl substituted fluorenyl or carbonyl or C1-6 alkyl or C1-6 alkoxy or aryl or heteroaryl or amide or ammonia Acyl or amino or 2-8 membered heteroalkyl or sulfone or sulfoxide.

In some aspects, the above R is selected from

Where x is 0 or 1 or 2, y is 2 or 1 or 0; p is 1 or 2 or 3 or 4 or 5; q is 1 or 2 or 3 or 4; B is C or N or O or S, The number is 0 or 1 or 2, and its position is any one or two of the α, β, γ, δ, and ε positions on the ring; b is a double bond, and its number is 0 or 1 or 2; its position It is a reasonable position of the valence bond on the ring; when the number of b is 0, the valence key of the corresponding position is a single bond.

In some aspects, the above R is selected from

Wherein n ¹ is any integer between 0 and 5 (inclusive); n ² is 0 or 1 or 2 or 3.

In some aspects, the above R _{11 is} selected from

Wherein R is simultaneously bonded to any two atoms of the α, β, γ, and δ positions on the ring r ₁ to form a covalent bond ^; n ^{1 is} 0 or 1 or 2 or 3.

In some aspects, the above ring r _{1 is} selected from

In some embodiments, L _{0 is} selected from the group consisting of the following double bond substituents: =O, =C(R ₂ ) ₂ , =(spiro-C3-12 cycloalkyl), =heteroaryl or =(spiro-( A 3-10 membered heterocyclic group)) wherein the heterocyclic ring in the = (spiro-(3-10 membered heterocyclyl)) contains at least one N or O or S.

In some embodiments, A is selected from the group consisting of N, S, O; wherein N, P are replaced by L ₀₀ and S is substituted by L ₀₀ or one or two = O.

In some embodiments, the heteroaryl is selected from the group consisting of pyridine, pyrimidine, pyrazine, pyridazine, and triazine.

In some embodiments, the C3-12 heterocyclic group is selected from the group consisting of furan, pyrrole, thiophene, pyridine, quinoline, indole, indole, benzimidazole, pyrroline, pyrrolidine, pyran, dioxane, dioxane Ring, pyrazole, imidazole, oxazole, thiazole, triazole, morpholine, piperidine, piperazine.

In some embodiments, R _5-8 are each independently selected from the group consisting of: H, OH, C 1-6 alkyl, halo, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3- 12 cycloalkyl substituted C1-6 alkyl.

In some embodiments, R _{5-8 is} selected from aryl, 3-8 membered heteroaryl containing at least one N or O or S, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-10 membered hetero a cyclic group wherein the aryl group, a 3-8 membered heteroaryl group containing at least one N or O or S, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, and a 3-10 membered heterocyclic group are each one or Multiple R ₁ substitutions.

In some embodiments, R _{5-8 is} selected from aryl, 5- or 6- or 7-membered heteroaryl containing at least one N or O or S, monocyclic C5-8 cycloalkyl, monocyclic C5-8 ring An alkenyl, five- or six-membered monocyclic heterocyclic group, or a (monocyclic C5-8 cycloalkyl) C1-6 alkyl group, wherein each of the above groups is optionally and independently substituted by one or more R ₁ .

In some embodiments, R _{5-8 is} selected from aryl or 5- or 6-membered heteroaryl containing at least one N or O or S, wherein each of the above groups is optionally substituted with one or two R ₁ .

In some embodiments, R _{5-8 is} selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyranyl, furyl, pyrrolyl, thienyl, pyridyl, quinolinyl, cyclopropane And cyclobutane, cyclopentyl, cyclohexane, cycloheptyl and the above groups are each optionally substituted by one or more R ₁ and independently.

In some embodiments, each R, R ₁ -R ₄ , R _5-8 , R ₉ , R ₁₀ are each independently selected from the group consisting of H, NH ₂ , CN, methyl, ethyl, propyl, isopropyl, butyl. , isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2 - dimethylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, pentylmethyl, pentylethyl, pentylpropyl, pentylbutyl, hexylmethyl, Hexylethyl, hexylpropyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, methoxycarbonyl, ethoxy Carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, B _oc , methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, pentyl Sulfone, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl, 2,2-dimethyl Propyl sulfone group, 1,2-dimethylpropyl sulfone group, 1-ethyl propyl sulfone group, hexyl sulfone group, amyl methyl sulfone group, pentyl ethyl sulfone group, pentyl group Sulfhydryl group, amyl butyl sulfone group, hexyl methyl sulfone group, hexylethyl sulfone group, hexyl propyl sulfone group, methylphenyl sulfone group, ethyl phenyl sulfone group, propyl phenyl sulfone group, Cyanophenyl sulfone group, phenyl sulfone group, chlorophenyl sulfone group, fluorophenyl sulfone group, bromophenyl sulfone group, cyclopropyl sulfone group, cyclobutyl sulfone group, cyclopentyl sulfone group , cyclohexylsulfone group, cyclopropylmethylsulfonyl group, cyclopropylethylsulfonyl group, cyclopropylpropylsulfonyl group, cyclobutylmethylsulfonyl group, cyclobutylethylsulfonyl group, cyclobutylpropylsulfonyl group, cyclopentyl group Sulfone, cyclopentylethylsulfonyl, cyclopentylpropylsulfonyl, cyclohexylmethylsulfonyl, cyclohexylethylsulfonyl, cyclohexylpropylsulfonyl, formyl, acetyl, propionyl, butyryl, isobutyryl , valeryl, hexanoyl, cyclopropylformyl, cyclopropylacetyl, cyclobutylformyl, cyclobutylacetyl, cyclopentylformyl, cyclopentylacetyl, cyclohexylformyl, cyclohexylacetyl .

In some embodiments, the above "is C1-6 alkyl, 1-6 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkoxy, C3-12 cycloalkenyl, aryl, heteroaryl The amino-substituted amino, amido, aminoacyl group may be selected from the group consisting of methylamino, ethylamino, propylamino, isopropylamino, 1-butylamino, isobutylamino, tert-butylamino, 1-pentylamino, 1-hexylamino, Ethylene oxide amino, cyclohexylamino, heterocyclic hydrochloride amino (azetidine dihydrochloride 3-amino), 2-cyclopentyloxyphenylamino, 2-(cyclopentyloxy) Amino, morpholin-4-amino, cyclopropenylamino, cyclobutadienyl-2-amino, polybutadienyl azide, cyclopentadienylamino, 2-cyclohexen-1-one -3-amino, DL-aminocaprolactamamino, phenylamino, pyrrol-1-amino, pyrrole-2-amino, pyrrol-3-amino, pyridin-3-amino, pyridin-4-amino, quinoline-2 -amino, quinoline-3-amino, quinoline-4-amino, quinoline-7-amino, quinoline-8-amino, indole-1-amino, indole-4-amino, indole-5- Amino, 吲哚-7-amino, methylamido, ethylamido, propylamido, isopropylamido, butyl amide , isobutyl amide, tert-butyl amide, pentyl amide, hexyl amide, epoxy ethyl amide, propyl propyl amide, epoxy butyl amide, pentyl amide Epoxyhexyl amido, N-morpholine methoxy amide, N-morpholine ethoxy amide, N-morpholinyl propyl amide, methoxy acylamino, ethoxy acylamino, propoxy Aminoamino, isopropoxyamino, butoxyamino, isobutoxyamino, tert-butoxyamino, pentyloxyamido, cyclopropoxyamino, cyclobutoxy Amino, cyclopentyloxyamido, cyclohexyloxyamido, cyclopropylmethoxyamido, cyclopropylethoxyamido, cyclopropylpropionylamino, cyclobutoxyamino, ring Butyoxyamino, cyclobutoxyamino, cyclopentyl methoxyamino, cyclopentyl ethoxyamino, cyclopentyloxyamido, cyclohexyloxyamido, cyclohexyl Oxyamido, cyclohexyloxyamido, cyclopropenylamino, cyclobutadienylamino, cyclopentadienylamino, cyclohexenylamino, cycloheptane Ethynylamido, phenylamido, pyrroleacetamido, 2-pyrrolidinylamino, pyrrole-3-carboxamido, 2-pyridinecarboxamido, 4-pyridinecarboxamido, pyridin-2-acetylamino, Pyridine-3-acetamido, quinoline-8-acetamido, quinoline-2-carboxamido, quinoline-4-carboxamido, quinoline-6-formylamino, quinoline-8-acetylamino, 1-H-indole-5-formylamino, 3-indolylamino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamine Acyl, tert-butylamino, pentylamino, hexylamino, epoxyethylamino, epoxypropylamino, epoxybutylamino, pentylamino, epoxyhexyl , N-morpholine methoxy-aminoacyl, N-morpholine ethoxylated amino group, N-morpholinyloxypropylamino, methoxy-aminoacyl, ethoxylated amino group, propoxyaminoacyl, different Propyloxyacyl, butoxynoyl, isobutoxyamino, tert-butoxycarbonyl, pentyloxyamino, cyclopropoxyl, cyclobutoxyl, cyclopentyloxy Glycosyl group, Hexyloxyamino, cyclopropylmethoxyamino, cyclopropylethoxyl, cyclopropylpropoxyl, cyclobutoxyamino, cyclobutoxyamino, cyclobutane Oxy-aminoacyl, cyclopentylmethoxy-aminoacyl, cyclopentylethoxyaminoacyl, cyclopentyloxyaminoacyl, cyclohexyloxyaminoacyl, cyclohexyloxyaminoacyl, cyclohexyloxy Aminoacyl, cyclopropenylaminoacyl, cyclobutadienylamino, cyclopentadienylamino, cyclohexenylamino, cycloheptenyl, phenylamino, pyrrolyl, pyridine , quinolinyl, prolyl.

In some embodiments, the above carbonyl group is selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl.

In some embodiments, the above acyl group is selected from the group consisting of formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl, cyclopropylformyl, cyclopropylacetyl, cyclopropylpropanoyl, cyclic Butylformyl, cyclobutylacetyl, cyclobutylpropanoyl, cyclopentylformyl, cyclopentylacetyl, cyclopentylpropanoyl, cyclohexylcarbonyl, cyclohexylacetyl, cyclohexylpropanoyl.

In some embodiments, the above alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2- Methyl butyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl , amylmethyl, pentylethyl, pentylpropyl, pentylbutyl, hexylmethyl, hexylethyl, hexylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropane Methyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexane Propyl, N-morpholinylmethyl, N-morpholinylethyl, N-morpholinylpropyl.

In some embodiments, the alkoxy group is selected from the group consisting of N-morpholine methoxy, N-morpholine ethoxy, N-morpholinyloxypropyl, methoxy, ethoxy, propoxy, isopropoxy , butoxy, isobutoxy, tert-butoxy, pentyloxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclopropyl Oxyl, cyclopropylpropoxy, cyclobutylmethoxy, cyclobutylethoxy, cyclobutyloxy, cyclopentyloxy, cyclopentylethoxy, cyclopentyloxy, cyclohexyloxy Base, cyclohexyloxy, cyclohexyloxy.

In some embodiments, the above alkylsulfone group is selected from the group consisting of: methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, Tert-butylsulfonyl, pentylsulfone, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl, 2,2 - dimethyl propyl sulfone group, 1,2-dimethyl propyl sulfone group, 1-ethyl propyl sulfone group, hexyl sulfone group, amyl methyl sulfone group, pentyl ethyl sulfone group, pentyl group Propyl sulfone, pentyl butyl sulfone, hexyl methyl sulfone, hexylethyl sulfone, hexyl propyl sulfone, methyl phenyl sulfone, ethyl phenyl sulfone, propyl phenyl sulfone , aminophenyl sulfone group, nitrophenyl phenyl sulfone group, cyanophenyl sulfone group, phenyl sulfone group, chlorophenyl sulfone group, fluorophenyl sulfone group, bromophenyl sulfone group, ring Propyl sulfone group, cyclobutyl sulfone group, cyclopentyl sulfone group, cyclohexyl sulfone group.

In some embodiments, the alkanoyl group is selected from the group consisting of: formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl, cyclopropylformyl, cyclopropylacetyl, cyclopropylpropionyl , cyclobutylformyl, cyclobutylacetyl, cyclobutylpropionyl, cyclopentylcarbonyl, cyclopentylacetyl, cyclopentylpropanoyl, cyclohexylcarbonyl, cyclohexylacetyl, cyclohexylpropanoyl.

In some embodiments, the compound of formula I above is

Where n takes 0 or 1 or 2 or 3;

C ¹ and r ₁ are linked to the α or β or γ position;

n ¹ is 0 or 1 or 2 or 3;

n ² takes 0 or 1 or 2 or 3;

n ³ takes 0 or 1 or 2;

The number of a is 0 or 1 or 2.

In some embodiments, the above C ¹ and r ₁ rings are linked to the α position, the R and r ₁ rings are linked to the δ position, and R ₀₀ is H, and the compound is

Wherein L _{0 is} selected from the group consisting of the following double bond substituents: =O, =C(R ₂ ) ₂ , =(spiro-C3-8 cycloalkyl), =heteroaryl or =(spiro-(3-8) a heterocyclic group)), wherein = (spiro-C3-8 cycloalkyl), =heteroaryl or =(spiro-(3-8 membered heterocyclyl)) is substituted by one or more R ₂ ;or

Selected from the following single bond substituents: H, NH ₂ , halogen, CN, CF ₃ , OH, C(O)OH, C(O)H, heteroalkyl, alkenyl, alkynyl, heterocycloalkyl, sub Sulfonylamino, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenylaryl, heteroaryl, amide, aminoacyl, C1-6 alkyl or C3-12 cycloalkyl or C1-6 alkoxy substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl Or aryl or heteroaryl;

A is selected from N, S, P, O; wherein N, P are substituted by L ₀₀ and S is substituted by L ₀₀ or one or two = O;

n is selected from an integer of 0-6;

L _{00 is} selected from the group consisting of H, NH ₂ , halogen, CN, CF ₃ , OH, C(O)OH, C(O)H, alkenyl, alkynyl, sulfonamido, nitro, phosphate, ureido , carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl C1-6 heteroalkyl, C3-12 heterocycloalkyl, aryl, heteroaryl, amide, ammonia An acyl group, a C1-6 alkyl group substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl or C3-12 cycloalkyl or C1-6 Alkoxy or aryl or heteroaryl, carbonyl substituted by halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, C3-12 cycloalkyl, by C1-6 alkyl, C3 -12 cycloalkyl, C3-12 cycloalkenyl, aryl, heteroaryl substituted amino, amide, aminoacyl.

In some embodiments, the above C ¹ and r ₁ rings are linked to the alpha position, and the R and r ₁ rings are linked to the delta position, such as structural formula XXXIII.

The present invention provides a compound of the formula Y-I or a pharmaceutically acceptable salt thereof:

Where n takes 0 or 1 or 2 or 3;

r ₁ is a bridged ring; C ¹ and r ₁ are linked to the α or β position;

n ⁰ takes 0 or 1 or 2;

n ³ takes 0 or 1 or 2;

a is a double bond; the position of a is at any position where the valence bond on r ₁ is reasonable; the number of a is 0 or 1 or 2 or 3;

R is a substituent at any position where the valence bond on r ₁ is reasonable; R is n ¹ and n ¹ is an integer between 0-14 (inclusive);

Each R is independently selected from the following double bond substituents: =O, =NR ₂ , =C(R ₂ ) ₂ , =(spiro-C3-12 cycloalkyl), or =(spiro-(3-10) Heterocyclyl)),

or

Each R is independently selected from the group consisting of the following single bond substituents: H, NH ₂ , halogen, CN, CF ₃ , OH, C(O)OH, C(O)H, sulfonamido, sulfone, sulfoxide, nitrate Base, phosphate group, ureido group, carbonate group, C1-6 alkyl group, C3-12 cycloalkyl group, C3-12 cycloalkenyl group, C1-6 heteroalkyl group, C3-12 heterocycloalkyl group, aryl group , heteroaryl, amide, aminoacyl, C1-6 alkyl or C1 substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl -6 alkoxy or aryl or heteroaryl, carbonyl substituted by halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, C3-12 cycloalkyl, C1-6 alkyl , C 3-12 cycloalkyl, C 3-12 cycloalkenyl, aryl, heteroaryl substituted amino, amide, aminoacyl;

Wherein the halogen is selected from the group consisting of F, Cl, Br, I;

R ₁ to R ₁₀ are each independently selected from the group consisting of H, NH ₂ , halogen, CN, CF ₃ , OH, C(O)OH, C(O)H, alkenyl, alkynyl, sulfinylamino, sulfone, sub Sulfone, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C1-6 heteroalkyl, C3-12 heterocycloalkane Base, aryl, heteroaryl, amido, aminoacyl, halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl, C3-12 ring Alkenyl substituted C1-6 alkyl or C3-12 cycloalkyl or C1-6 alkoxy or aryl or heteroaryl, halogen, cyano, amino, aryl, heteroaryl, C1-6 alkane A carbonyl group substituted with a C3-12 cycloalkyl group, an amino group substituted with a C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group or a heteroaryl group, an amide group, or an aminoacyl group.

In some embodiments, n ¹ is 0, and R ₁ to R ₁₀ are each independently selected from the group consisting of H, NH ₂ , halogen, CN, CF ₃ , OH, sulfonamido, C 1-6 alkyl, C 3-12 cycloalkyl. , C3-12 cycloalkenyl, C1-6 heteroalkyl, C3-12 heterocycloalkyl, aryl, heteroaryl, halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, Heteroaryl, C3-12 cycloalkyl, C3-12 cycloalkenyl substituted C1-6 alkyl or C3-12 cycloalkyl or C1-6 alkoxy or aryl or heteroaryl.

In some embodiments, each R in formula YI is independently selected from the group consisting of: =O, =NR ₂ , =C(R ₂ ) ₂ , =(spiro-C3-12 cycloalkyl), or = (spiro-(3-12 membered heterocyclic)),

or

Each R is independently selected from any one or two of the following single bond substituents: H, NH ₂ , halogen, CN, CF ₃ , OH, C(O)OH, C(O)H, sulfene Amino group, sulfone group, sulfoxide group, nitro group, phosphate group, ureido group, carbonate group, C1-6 alkyl group, C3-12 cycloalkyl group, C3-12 cycloalkenyl group, C1-6 heteroalkyl group, C3-12 heterocycloalkyl, aryl, heteroaryl, amido, aminoacyl, halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 naphthenic A substituted C1-6 alkyl or C1-6 alkoxy or aryl or heteroaryl.

In some embodiments, the heteroaryl group of formula Y-I is selected from the group consisting of pyridine, pyrimidine, pyrazine, pyridazine, triazine.

In some embodiments, the C3-12 heterocyclic group of formula YI is selected from the group consisting of furan, pyrrole, thiophene, pyridine, quinoline, indole, indole, benzimidazole, pyrroline, pyrrolidine, pyran, dioxane , dioxane, pyrazole, imidazole, oxazole, thiazole, triazole, morpholine, piperidine, piperazine.

The number of substitutions or substituents not mentioned in the present invention is 0, and the default is the condition that the valence bond is reached by H.

specific,

In the above formula YI, the number of a is 0, and the structural formula is as in the formula Y-II:

In the formula YI, n ¹ is 0, R ₁ to R ₄ and R _{10 are} H, and the structural formula is as in the formula Y-III:

Wherein R ₅ to R ₉ are each independently selected from the group consisting of H, NH ₂ , halogen, CN, CF ₃ , OH, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 1-6 heteroalkyl , C3-12 heterocycloalkyl, aryl, heteroaryl, amido, aminoacyl, halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 a cycloalkyl, C3-12 cycloalkenyl substituted C1-6 alkyl or C3-12 cycloalkyl or C1-6 alkoxy or aryl or heteroaryl, halogen, cyano, amino, aryl, Heteroaryl, C1-6 alkyl, C3-12 cycloalkyl substituted carbonyl, amino substituted by C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, aryl, heteroaryl , amide group, aminoacyl group.

In the above formula YI, the C ¹ and r ₁ rings are linked to the β position, and the structural formula is as in the formula Y-IV:

In the above formula YI, the C ¹ and r ₁ rings are linked to the α-position, and the number of a is taken as 0, and the structural formula is as in the formula YV:

In the above formula I, the C ¹ and r ₁ rings are linked to the β position, and the number of a is taken as 0, and the structural formula is as in the formula VI:

The present invention provides a compound of the formula S-I or a pharmaceutically acceptable salt thereof:

Wherein SR _{1 is} selected from the group consisting of CN, OH, C(O)OH, C(O)H, an amide group, an aminoacyl group, a heteroaryl group containing at least one N or O or S, and a halogen, a hydroxyl group, a carboxyl group, a carbonyl group, Aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl substituted C1-6 alkoxy or heteroaryl containing at least one N or O or S, by hydroxy, carboxy, carbonyl, Aldehyde, cyano, amino substituted C1-6 alkyl or C3-6 cycloalkyl or aryl or heteroaryl, halo, cyano, amino, aryl, heteroaryl, C1-6 alkyl, a C3-12 cycloalkyl-substituted carbonyl group, an amino group substituted with a C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group, an amide group, an aminoacyl group;

L _{0 is} selected from the following double bond substituents: =O, =C(R ₂ ) ₂ , =(spiro-C3-8 cycloalkyl), =heteroaryl or =(spiro-(3-8-membered) a ring group)), wherein = (spiro-C3-8 cycloalkyl), =heteroaryl or =(spiro-(3-8 membered heterocyclyl)) is substituted by one or more R ₂ ;

or

Selected from the following single bond substituents: H, NH ₂ , halogen, CN, CF ₃ , OH, C(O)OH, C(O)H, heteroalkyl, alkenyl, alkynyl, heterocycloalkyl, sub Sulfonylamino, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, aryl, heteroaryl, amide, ammonia An acyl group, a C1-6 alkyl group substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl or C3-12 cycloalkyl or C1-6 Alkoxy or aryl or heteroaryl;

n is selected from an integer of 0-6;

SR ₂ , R ₃ to R ₈ , SR ₉ , SR ₁₀ , SR ₁₁ , L ₀₀ are each independently selected from H, NH ₂ , halogen, CN, CF ₃ , OH, C(O)OH, C(O)H, Alkenyl, alkynyl, sulfonamido, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C1-6 heteroalkane , C3-12 heterocycloalkyl, aryl, heteroaryl, amido, aminoacyl, halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 a cycloalkyl-substituted C1-6 alkyl or C3-12 cycloalkyl or C3-12 cycloalkenyl or C1-6 alkoxy or aryl or heteroaryl, halogen, cyano, amino, aryl, Heteroaryl, C1-6 alkyl, C3-12 cycloalkyl substituted carbonyl, amino substituted by C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, aryl, heteroaryl , amide group, aminoacyl group.

specific:

SR ₂ , SR ₉ , SR ₁₀ , SR ₁₁ are each independently selected from H, NH ₂ , halogen, CN, CF ₃ , OH, C(O)OH, C(O)H, C1-6 alkyl, C3-12 Cycloalkyl, C3-12 cycloalkenyl, C1-6 heteroalkyl, C3-12 heterocycloalkyl, aryl, heteroaryl, amide, aminoacyl, halogen, hydroxy, carboxy, carbonyl, aldehyde , cyano, amino, aryl, heteroaryl, C 3-12 cycloalkyl substituted C 1-6 alkyl or C 3-12 cycloalkyl or C 1-6 alkoxy or aryl or heteroaryl.

L _{00 is} independently selected from the group consisting of H, NH ₂ , OH, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 1-6 heteroalkyl, C 3-12 heterocycloalkyl, aryl , heteroaryl, amido, aminoacyl, C1-6 alkyl or C3 substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl -12 cycloalkyl or C1-6 alkoxy or aryl or heteroaryl.

In some embodiments, each R in the formula SI is independently selected from the group consisting of: =O, =NR ₂ , =C(R ₂ ) ₂ , =(spiro-C3-8 cycloalkyl), or = (spiro-(3-8 membered heterocyclic)),

or

Each R is independently selected from any one or two of the following single bond substituents: H, NH ₂ , halogen, CN, CF ₃ , OH, C(O)OH, C(O)H, sulfene Amino, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C1-6 heteroalkyl, C3-12 heterocycloalkyl , aryl, heteroaryl, amido, aminoacyl, C1-6 alkane substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl Or a C1-6 alkoxy group or an aryl or heteroaryl group.

In some embodiments, R ₁ in formula SI is selected from the group consisting of OH, C(O)OH, C(O)H, an amide group, a heteroaryl group containing at least one N or O or S, and a hydroxyl group, an amino group, an aryl group, Carboxyl-substituted C1-6 alkyl or C1-6 cycloalkyl or aryl or heteroaryl, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, aryl, heteroaryl Substituted amino, amide, aminoacyl.

In some embodiments, SR ₁ in formula SI is selected from the group consisting of OH, C(O)OH, C(O)H, an amide group, a heteroaryl group containing at least one N or O or S, and a hydroxyl group, an amino group, an aryl group. a carboxy-substituted C1-6 alkyl group or a C1-6 cycloalkyl group or an aryl or heteroaryl group, a C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group A substituted amino group or an amide group.

In some embodiments, SR ₁ in formula SI is selected from the group consisting of OH, C(O)OH, an amino group, a carboxyl group, a heteroaryl group containing at least one N or O or S, and a C1-6 alkane substituted with a hydroxyl group, an amino group, or a carboxyl group. base.

In some aspects, SR ₁ in formula SI is selected from OH.

In some embodiments, L ₀ in formula SI is selected from the group consisting of the following double bond substituents: =O, =C(R ₂ ) ₂ , =(spiro-C3-8 cycloalkyl), =heteroaryl or =( a spiro-(3-8 membered heterocyclyl)) wherein the heterocyclic ring in the = (spiro-(3-8 membered heterocyclyl)) contains at least one N or O or S;

or

Selected from the following single bond substituents: H, OH, C(O)H, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C1-6 heteroalkyl, C3-12 heterocycle Alkyl, aryl, heteroaryl, C1-6 alkyl or C 3 substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl -12 cycloalkyl or aryl or heteroaryl.

In some aspects, A in formula SI is selected from N, S, O; wherein N, P are replaced by L ₀₀ and S is substituted by L ₀₀ or one or two = O.

In some embodiments, the heteroaryl group of formula S-I is selected from the group consisting of pyridine, pyrimidine, pyran, pyridazine, triazine, pyran.

In some embodiments, the C3-12 heterocyclic group in formula SI is selected from the group consisting of furan, pyrrole, thiophene, pyridine, quinoline, indole, indole, benzimidazole, furan, pyrroline, dioxane, dioxane Ring, pyrazole, imidazole, oxazole, thiazole, piperidine, triazole, morpholine, piperidine, piperazine.

specific,

In the above formula SI, A is O, and the structural formula is as in the formula S-II:

Wherein L _{0 is} selected from the group consisting of H, NH ₂ , C1-6 heteroalkyl, C 3-12 heterocycloalkyl, ureido, C 1-10 alkyl, C 3-12 cycloalkyl, aryl, heteroaryl, Halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl substituted C1-6 alkyl or aryl or heteroaryl; hetero atom taken O, N Or S.

In the above formula SI, A is N, and L _{0 is} selected from the following double bond substituents: =C(R ₂ ) ₂ , =(spiro-C3-8 cycloalkyl), =(spiro-(3-8) Heterocyclyl)), =heteroaryl, wherein =(spiro-C3-8 cycloalkyl), =(spiro-(3-8 membered heterocyclyl)), =heteroaryl is one or more SR ₂ substitution;

The structure is as follows:

Wherein, in the formula S-IV, q is 0 or 1 or 2 or 3 or 4 or 5; R _{2 is} independently selected from the group consisting of H, NH ₂ , halogen, CN, CF ₃ , OH, C(O)OH, C ( O) H, sulfonamido, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C1-6 heteroalkyl, C3-12 heterocycloalkyl, aryl, heteroaryl, amido, aminoacyl, halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 naphthenic a substituted C1-6 alkyl group or a C3-12 cycloalkyl group or a C1-6 alkoxy group or an aryl or heteroaryl group, which is halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl a C3-12 cycloalkyl-substituted carbonyl group, an amino group substituted with a C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group, an amide group, an aminoacyl group;

When SR _{2 is} taken with or without a substituted aryl, heteroaryl, C1-6 cycloalkyl group, SR ₂ is a single bond or a side chain linked to the bare ring; the parallel link means two atoms are shared. And a covalent bond between the two atoms;

p is 1 or 2 or 3 or 4 or 5; the hetero atom B is N or O or S, the number of which is 0 or 1 or 2, and its position is any of the α, β, γ, δ and ε positions on the ring. One or two; b is a double bond, the number of which takes 0 or 1 or 2, and its position is any position where the valence bond on the ring is reasonable.

In the above formula SI, A is N, and N is replaced by a L ₀₀ , and the structural formula is as follows:

L ₀ and L ₀₀ are each independently selected from the following single bond substituents: H, OH, C(O)OH, C(O)H, carbonate group, C1-6 alkyl group, C3-12 cycloalkyl group, C3- 12 cycloalkenyl, C1-6 heteroalkyl, C3-12 heterocycloalkyl, aryl, heteroaryl, halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl , C 3-12 cycloalkyl substituted C 1-6 alkyl or C 1-6 alkoxy or aryl or heteroaryl; L _{00 is} selected from H, NH ₂ , halogen, CN, CF ₃ , OH, C (O OH, C(O)H, C1-6 heteroalkyl, C3-12 heterocycloalkyl, C1-6 alkyl, C3-12 cycloalkyl, aryl, heteroaryl, amido, aminoacyl, C1-6 alkyl or C1-6 alkoxy or aryl or heteroaryl substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl base;

In the above formula SV, the formula S-IV, and the formula S-II, R ₁ is a hydroxyl group, R _{2 on the} same carbon atom as R ₁ is hydrogen, and L ₀ in the formula S-II is hydrogen, and the structural formula is respectively S. -VI, formula S-VII, formula S-IX:

Wherein each R is independently selected from the following double bond substituents: =O, =NR ₂ , =C(R ₂ ) ₂ , =(spiro-C3-8 cycloalkyl), or =(spiro-(3- 8-membered heterocyclic group)), wherein each R _{2 is} independently H, NH ₂ , halogen, CN, CF ₃ , OH, C(O)OH, C(O)H, C1-6 alkyl, C1-6 haloalkane a group, a C3-8 cycloalkyl group, or a 3-8 membered heterocyclic group,

or

Each R is independently selected from any one or more of the following single bond substituents: H, NH ₂ , halogen, CN, CF ₃ , OH, C(O)OH, C(O)H, sulfene Amino, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C1-6 heteroalkyl, C3-12 heterocycloalkyl , aryl, heteroaryl, amido, aminoacyl, C1-6 alkane substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl Or a C1-6 alkoxy group or an aryl or heteroaryl group.

In the compound of formula SI, A is N, L ₀ is (R) _y H _x-1 , and the structural formula is formula S-VIII:

x takes 1 or 2, and y takes 1 or 2.

A compound of the formula SI or a pharmaceutically acceptable salt thereof, wherein A is N, L ₀ is R ₁₂ C(L ₁ )(L ₂ ), L ₀₀ is hydrogen, and the formula is SX:

Wherein, L ₁ and L _{2 are} independently selected from the group consisting of H, NH ₂ , halogen, CN, CF ₃ , OH, C(O)OH, C(O)H, C1-6 heteroalkyl, C3-12 heterocycloalkane. Base, sulfonamido, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, aryl, heteroaryl, amide , aminoacyl, C1-6 alkyl or C1-6 alkoxy or aryl substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl Or a heteroaryl group, a carbonyl group substituted by halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, C3-12 cycloalkyl, C1-6 alkyl, C3-12 cycloalkyl , C 3-12 cycloalkenyl, aryl, heteroaryl substituted amino, amide, aminoacyl;

R _{12 is} selected from aryl, heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-10 membered heterocyclic or C3-8 cycloalkyl C1-6 alkyl, wherein aryl, Heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-10 membered heterocyclyl and C3-8 cycloalkyl C1-6 alkyl are each optionally and independently employed by one or more L ₁ Replace

In some embodiments, L ₁ and L ₂ in the formula SX are each independently selected from the group consisting of: H, OH, C 1-6 alkyl, and are halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl. a C3-12 cycloalkyl substituted C1-6 alkyl group; m is 0 or 1 or 2; R ₁₂ is

Where b is a double bond, the position of b is a reasonable position of any valence bond on the ring, and the number of b is 0 or 1 or 2 or 3. When the number of b is 0, the valence bond of the corresponding position is a single bond. Z is selected from N or O or S, the position of Z is a reasonable position of any valence bond on the ring; p is selected from 0 or 1 or 2 or 3; the position of L _{1 is} a reasonable position of any valence bond on the ring; R ₁₂ As a substituent group, the substitution position is on an atom of a reasonable valence bond on the ring.

In some embodiments, R ₁₂ in formula S-VIII is selected from phenyl, C3-8 membered heteroaryl containing at least one N or O or S, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3 a 10-membered heterocyclic group wherein the phenyl group has a C3-8 membered heteroaryl group containing at least one N or O or S, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, and a 3-10 membered heterocyclic group. Each is replaced by one or more L ₁ .

In some embodiments, R ₁₂ in formula SX is phenyl, five- or six- or seven-membered heteroaryl containing at least one N or O or S, monocyclic C5-8 cycloalkyl, monocyclic C5-8 a cycloalkenyl, five- or six-membered monocyclic heterocyclic group, or a (monocyclic C5-8 cycloalkyl) C1-6 alkyl group, wherein each of the above groups is optionally and independently selected by one or more L ₁ Replace.

In some embodiments, R ₁₂ in formula SX is phenyl or a five or six membered heteroaryl group containing at least one N or O or S, wherein each of the above groups is optionally substituted with one or two L ₁ .

In some embodiments, R ₁₂ in formula SX is selected from the group consisting of a benzene ring, a pyridine ring, a pyrimidine ring, a pyran ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, a quinoline ring, a ring. Propane, cyclobutane, cyclopentyl, cyclohexane, cycloheptyl and the above groups are each optionally substituted by one or more L ₁ and independently.

In the formula SX, R ₁₂ is a benzene ring having a substituent such as the formula S-IX:

Wherein, L ₃ to L _{7 are} selected from the group consisting of H, NH ₂ , halogen, CN, CF ₃ , OH, C(O)OH, C(O)H, C1-6 heteroalkyl, C3-12 heterocycloalkyl, Sulfonylamino, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, aryl, heteroaryl, amide, aminoacyl, halogen, hydroxy, Carboxyl, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl substituted C1-6 alkyl or C1-6 alkoxy or aryl or heteroaryl, by halogen, Cyano, amino, aryl, heteroaryl, C1-6 alkyl, C3-12 cycloalkyl substituted carbonyl, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, aromatic A heteroaryl substituted amino group, an amide group, or an aminoacyl group.

In the formula S-XI, SR ₂ , R3 to R8, SR ₉ , SR ₁₀ and R ₁₁ are all hydrogen, as in the formula S-XII:

Wherein C _l is in the R or S configuration; C ₂ is in the R or S configuration. m is selected from 0 or 1 or 2; L ₁ and L ₂ are each independently selected from: H, OH, aryl, heteroaryl, halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, a heteroaryl group, a C3-12 cycloalkyl-substituted aryl group or a heteroaryl group or a cycloalkyl group; L ₃ to L ₇ are each independently selected from the group consisting of: H, OH, C 1-6 alkyl, heteroaryl, by halogen, Hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, C1-6 alkyl, aryl, heteroaryl, C3-12 cycloalkyl substituted aryl or heteroaryl or alkyl.

The present invention provides the above compounds

The synthesis method, wherein each substituent in the formula TM-IX has the same definitions as the formula I and the formula IX, and the specific steps are as follows:

i) M1 is reacted with chloride to obtain M2;

The chloride is at least one selected from the group consisting of phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosgene chloride, thionyl chloride, trimethylchlorosilane, α,α,α-trichlorotoluene;

Ii) M2 reacts with 2a to obtain M3;

Wherein, when L _{0 is} selected from the following double bond substituents: =O, =S(=O) _s , =C(R ₂ ) ₂ , =(spiro-C3-12 cycloalkyl), =heteroaryl or = (spiro-(3-10 membered heterocyclyl)), wherein = (spiro-C3-12 cycloalkyl), =heteroaryl or =(spiro-(3-10 membered heterocyclyl)) When substituted by one or more R ₂ , the reaction is carried out by adding a condensing agent and a base selected from the group consisting of HBTU, DMC, HOBT, HOBT/EDCI, HATU, HATU/DIEPA, DCC, CDI, isopropyl chloroformate; its structural formula is as follows:

The base is an organic base, and in some embodiments is selected as N,N-diisopropylethylamine (DIPEA), diethylamine (DEA) or triethylamine (TEA).

Iv) M3 and 3a are reacted in the presence of a base to obtain M4;

The base is selected from the group consisting of alkyl lithium, cycloalkyl lithium or aryl lithium; further selected from the group consisting of methyl lithium, ethyl lithium, propyl lithium, isopropyl lithium, n-Butyllithium, sec-butyllithium, tert-butyllithium, pentyllithium, hexyllithium, cyclohexyllithium, tert-octyllithium, n-icosyllithium, phenyllithium, methylphenyllithium, butyl Phenyllithium, naphthyllithium, butylcyclohexyllithium; further selected from n-butyllithium, t-butyllithium or hexyllithium; the solvent of the base is at least one selected from the group consisting of hexane, petroleum ether, benzene, toluene or xylene ;

v) M4 is reacted with 4a in the presence of a strong base to obtain M5;

Wherein R _{4 is} H; the strong base is selected from the group consisting of lithium metal alkyl compounds, aromatic alkali metal compounds, aromatic alkyl alkali metal compounds, amine lithium compounds, alkali metal hydrides, alkali metal salts of fatty alcohols; further selected from NaH , Ph ₃ CNa, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium t-butoxide; alkyl butyl lithium, phenyl lithium; lithium diisopropylamide (LDA), lithium hexamethyldisilazide LiHMDS);

Vi) M5 is ringed in the presence of an acid, deprotected to obtain M6;

The acid is selected from the group consisting of alkyd, aromatic acid, enoic acid, saturated fatty acid, phenol; further selected from the group consisting of acetic acid, propionic acid, butyric acid, glycolic acid, lactic acid, benzoic acid, phenylacetic acid, acrylic acid, oleic acid, citric acid, Oxalic acid, malonic acid, succinic acid;

Vii) M6 is reduced with a reducing agent to obtain the target compound XI;

Wherein the reducing agent is preferably at least one of NaBH ₄ , KBH ₄ , NaBH ₄ /LiCl;

The method provided by the present invention is only one way to achieve a synthetic TM-IX compound, wherein the M6, M5, M4, M3, and M2 are independent and are not limited to the method of the present invention.

The present invention provides a method for synthesizing the above compound of formula II, the steps are as follows:

Compound Z-5 is reduced with a reducing agent to obtain the target compound II;

Wherein the reducing agent is selected from the group consisting of NaBH ₄ , KBH ₄ or NaBH ₄ /LiCl.

Among them, the synthesis steps of compound Z-5 are as follows:

Compound Z-4 is cyclized and deprotected in the presence of an acid to give compound Z-5.

Wherein the acid is selected from the group consisting of alkyd, aromatic acid, enoic acid, saturated fatty acid, phenol; further said acid is selected from the group consisting of acetic acid, propionic acid, butyric acid, glycolic acid, lactic acid, benzoic acid, phenylacetic acid, acrylic acid , oleic acid, citric acid, oxalic acid, malonic acid, succinic acid;

Among them, the ring-forming reaction is carried out under heating; preferably, the reaction heating temperature is 50 to 95 °C.

Among them, the number of a is 1, and the position is in the meta position of α.

The present invention provides a method for synthesizing the above compound Z-5. In the compound Z-4, the C ¹ and r ₁ rings are linked to the β position, and the synthesis step of the compound Z-4 is as follows:

Compound Z-2 is reacted with Compound 3 in the presence of an organic base to form compound Z-4.

Wherein, the organic base is selected from the group consisting of lithium metal alkyl compounds, aromatic alkali metal compounds, aromatic alkyl alkali metal compounds, amine lithium compounds, alkali metal hydrides, alkali metal salts of fatty alcohols; further selected from NaH, Ph ₃ CNa, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium t-butoxide, butyl lithium, phenyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS).

The present invention provides a method for synthesizing the above compound of formula I, wherein the C ¹ and r ₁ rings in the compound Z-4 are linked to the α position, and the synthesis step of the compound Z-4 is as follows:

Wherein, the strong base is selected from the group consisting of tC ₄ H ₉ OK, NaH, Ph ₃ CNa, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium t-butoxide; lithium metal alkyl compound, butyl lithium, phenyl Lithium; an amine lithium compound, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS).

The invention provides a method for synthesizing compound Z-3, and the synthetic steps of compound Z-3 are as follows:

The invention provides a method for synthesizing the compound M3, and the synthetic steps of the compound M3 are as follows:

Wherein said X is selected from the group consisting of Cl, Br, and I; said M is selected from the group consisting of Li, Na, and K; and said reducing agent is selected from the group consisting of butyl lithium, t-butyl lithium, tributyltin hydrogen, and zinc/acetic acid.

The invention provides a method for synthesizing the compound M3, and the synthesis steps are as follows:

Wherein the chloride is at least one selected from the group consisting of phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosgene, thionyl chloride, trimethylchlorosilane, and α,α,α-trichlorotoluene. .

The invention provides a method for synthesizing compound Z-2, wherein the synthesis step of compound Z-2 when n ^{3 is} 0 is as follows:

Compound Z-2-x compound 1a is reacted with the compound Z-2-1, said R ^a is selected from H, boric acid, alkenyl boronic acid group or boronate group; said ligand is selected from R ^b PPh ₃ , AsPh ₃ , n-Bu ₃ P, (MeO) ₃ P, Ph ₂ P(CH ₂ ) ₂ PPh ₂ , Ph ₂ P(CH ₂ ) ₃ PPh ₂ ; the X is selected from Cl, Br, I, a triflate group;

The base is selected from the group consisting of potassium carbonate, cesium carbonate, sodium t-butoxide, potassium acetate, potassium phosphate, cesium hydroxide, cesium carbonate;

The reaction temperature is preferably from 70 to 95 °C.

As above, the present invention also provides a method for synthesizing the compound Z-2, wherein the synthesis step of the compound Z-2 when n ^{3 is} 1 or 2 is as follows:

The present invention provides the above compounds

The synthesis method, wherein each substituent of the formula TM-X ⁰ is selected as the formula 1 and the formula X (wherein R _{3 is} selected as Boc-), the specific steps are as follows:

1):

In the compound 1, triethylamine and diphenylphosphoryl azide were sequentially added to obtain a compound 2.

2):

Compound 2 and 3a are reacted in the presence of a base to obtain a compound 3;

The base is selected from the group consisting of alkyl lithium, cycloalkyl lithium or aryl lithium;

Further selected from the group consisting of methyl lithium, ethyl lithium, propyl lithium, isopropyl lithium, n-butyl lithium, sec-butyl lithium, t-butyl lithium, pentyl lithium, hexyl lithium, cyclohexyl lithium, tert-octyl lithium , n-icosyl lithium, phenyl lithium, methyl phenyl lithium, butyl phenyl lithium, naphthyl lithium, butyl cyclohexyl lithium;

Further selected from n-butyllithium, tert-butyllithium or hexyllithium;

The solvent of the base is at least one selected from the group consisting of hexane, petroleum ether, benzene, toluene or xylene;

3): Compound 3 is reacted with 4a in the presence of a strong base to obtain Compound 4;

Wherein, R ₄ take H; strong base selected _{_{tC 4 H 9 OK, NaH,}} KH, Ph 3 CNa, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium t-butoxide, metallic lithium alkyl compound, an amine compound of lithium; Preferably, the lithium metal alkyl compound is butyl lithium or phenyl lithium; preferably the amine lithium compound is diisopropylamino lithium (LDA) or hexamethyldisilazide lithium (LiHMDS);

4): Compound 4 is cyclized in the presence of an acid, deprotected to give Compound 5;

The acid is selected from the group consisting of alkyd, aromatic acid, enoic acid, saturated fatty acid, phenol;

Further selected from the group consisting of acetic acid, propionic acid, butyric acid, glycolic acid, lactic acid, benzoic acid, phenylacetic acid, acrylic acid, oleic acid, citric acid, oxalic acid, malonic acid, succinic acid;

5): Compound 5 is reduced with a reducing agent to obtain the target compound TM-X ⁰ ;

Wherein, the reducing agent is NaBH ₄ , KBH ₄ , NaBH ₄ /LiCl.

The present invention provides the above compounds

a method for synthesizing, wherein each substituent of the formula TM-X ¹ is selected as in Formula 1 and Formula X (R _{3 in the} formula X); the synthesis step is as follows: the compound TM-X ⁰ is reduced with a reducing agent to obtain a target compound TM-X ¹ ;

The acid is preferably at least one selected from the group consisting of hydrochloric acid, hydrobromic acid, and sulfuric acid.

The invention provides a compound

The synthetic method, the steps are as follows:

1): Compound 5 (INT) is hydrolyzed under acidic conditions to obtain compound INT1;

Compound INT is deprotected under acidic conditions to give compound INT1.

2): Reduction of the compound INT1 gives the target compound INT2.

Wherein, the reducing agent is NaBH ₄ , KBH ₄ , NaBH ₄ /LiCl.

The invention provides a compound

The synthesis method, wherein each substituent of the formula TM-XXXIV ⁰ is the same as the formula I and the formula XXXIV, the steps are as follows: 1): the compound INT1 and L ₀ -W(=O)s-Cl or L ₀ -W(=O The s-OH reaction gives the target compound INT3.

2): Compound INT3 is reduced to obtain the target compound TM-XXXIV ⁰

a synthesis

The method wherein each substituent of the formula TM-XXXIII is the same as the formula XXXIII, the steps are as follows:

1):

Compound 1 is reacted with triphosgene (triphosgene) under basic conditions to obtain compound 1; the base is selected from trialkylamine; specifically, at least one selected from the group consisting of trimethylamine, triethylamine, and tripropylamine;

2):

Compound INT1 is reacted with compound 2 to obtain compound 3;

3):

Compound 3 is reduced to give the target compound TM-XXXIII.

Unless otherwise specified, the solvent selected for each step of the above or below of the present invention is a conventional solvent in the art, and the selection principle is to dissolve the reactant but not participate in the reaction, extract the product or separate the corresponding product in the crystal and the impurity. Such as water, halogenated alkanes, alkylamines, aliphatic hydrocarbons, esters, alcohols, aromatic hydrocarbons, ethers, heterocyclic solvents; specifically selected from, but not limited to, these solvents: methanol, ethanol, propanol, isopropanol , a mixture of at least two of diethyl ether, ethyl acetate, acetic acid, cyclohexane, dichloromethane, chloroform, tetrahydrofuran, pyridine, diethylamine, triethylamine, dimethylformamide, toluene, and the like.

The numbers M1 and M11 used in the present invention are numbers for convenience of describing the general formula, and they may be modified into other numbers in the specific embodiment, such as 1, 2, 3, etc., for convenience of description, without affecting the structural formula. The essence of the reaction equation is the expression of the general formula and the general reaction equation. Those skilled in the art will be able to determine that the substituents of each of the intermediates in all of the above synthetic routes are based on the structure of the target compound.

a compound encompassed by the formula of the formula I, II, YI, YII, SI to S-XII, and a specific substance thereof, and a chiral isomer or a cis-trans isomer and an isomer thereof in any ratio The mixture is also encompassed within the scope of the compounds covered by the general formula of the general formula SIS-XII and the specific substances thereof.

Unless otherwise specified, in each of the above or below reactions of the present invention, when there is an excess of the reactants, the termination of the reaction may be carried out by adding a substance which can react with an excess of the reactants. If any of the examples can be quenched with water or with saturated ammonium chloride.

Unless otherwise specified, in each of the above or below reactions of the present invention, the purification of the product in each step of the reaction is selected from the group consisting of extraction, crystallization, solvent removal, column chromatography; the operations are all conventional techniques in the art, and the prior art Personnel can handle it on a case-by-case basis.

The general formula of the present invention and the synthetic method of the general formula can be derived from specific compounds which are not limited to these specific substances, and can be obtained by those skilled in the art without the need of creative labor under the guidance of the general formula and the synthetic method of the general formula of the present invention. All are within the scope of the invention.

In all of the above synthetic methods, it is not limited to the linkage of C ¹ with the α on the ring r ₁ , and other positions where the reaction is feasible, such as β, are also within the scope of the present invention.

While a preferred embodiment of the invention has been shown and described, it will be understood by those skilled in the art Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It is to be understood that various alternatives to the embodiments of the invention described herein may be used to practice the invention. The scope of the invention is intended to be limited by the scope of the appended claims

The present invention provides a pharmaceutical composition comprising the above compound, i.e., I, II, YI, YII, SI to S-XII, and the like, and a compound thereof, and a specific substance thereof, or a pharmaceutically acceptable salt thereof, and One or more pharmaceutically acceptable pharmaceutical excipients.

The application provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical compositions include, but are not limited to, oral dosage forms, parenteral dosage forms, topical dosage forms, and rectal administration dosage forms. The composition may be in the form of a liquid, solid, semi-solid, gel or aerosol. In some embodiments, the pharmaceutical composition may be an oral tablet, a capsule, a pill, a powder, a sustained release preparation, a solution and a suspension, a sterile solution, suspension or emulsion for parenteral injection. A topical ointment or cream, or a suppository for rectal administration. In other embodiments, the pharmaceutical composition is in a unit dosage form suitable for single administration of precise dosages. In other embodiments, the amount of the compound ranges from about 0.001 mg/kg body weight/day to about 1000 mg/kg body weight/day. In other embodiments, the amount of the compound ranges from about 0.5 mg/kg body weight/day to about 50 mg/kg body weight/day. In some embodiments, the amount of the compound is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound is from about 0.002 g/day to about 6 g/day. In other embodiments, the amount of the compound is from about 0.005 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.01 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound is from about 0.1 g/day to about 1 g/day. In other embodiments, a dose level below the lower limit of the above range may already be sufficient. In other embodiments, dose levels above the upper limit of the above range may be required. In some embodiments, the compound is administered in a single dose, once a day. In other embodiments, the compound is administered in multiple doses more than once a day. In some embodiments, the compound is administered twice daily. In other embodiments, the compound is administered three times a day. In other embodiments, the compound is administered four times a day. In other embodiments, the compound is administered more than four times a day. In some embodiments, the individual to which the pharmaceutical composition is administered is a mammal. In other embodiments, the mammal is a human.

The present invention provides the use of all of the above compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof for the preparation of a medicament for treating a tryptophan mediated by indoleamine 2,3-dioxygenase A pathological feature of the acid metabolism pathway. The mediation is, for example, the down-regulation of the expression of the indoleamine 2,3-dioxygenase. The present invention provides the use of all of the above compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof for the preparation of a guanamine 2,3-dioxygenase inhibitor.

The present invention provides all of the above compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, as a guanamine 2,3-dioxygenase inhibitor; or a therapeutic thereof having a guanamine 2,3- A disease characterized by the pathology of a dioxygenase-mediated tryptophan metabolism pathway. The mediation is, for example, the down-regulation of the expression of the indoleamine 2,3-dioxygenase.

The present invention provides a method for inhibiting indoleamine 2,3-dioxygenase by using all of the above compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof. The method includes a method of inhibiting indoleamine 2,3-dioxygenase in vivo and in vitro. Also provided are methods of treating all of the above compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for treating pathological features of the indoleamine 2,3-dioxygenase-mediated tryptophan metabolic pathway.

Pathological features of the indoleamine 2,3-dioxygenase-mediated tryptophan metabolism pathway of the present invention include cancer, infectious diseases, neurodegenerative diseases, depression, anxiety or age-related Cataract

Wherein the cancer is selected from the group consisting of lung cancer, liver cancer, colon cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, renal cancer, head and neck cancer, lymphoma, melanoma or leukemia;

The neurodegenerative disease refers to Alzheimer's syndrome;

The infectious disease refers to an infection caused by bacteria, fungi, viruses or parasites.

The activity test results show that the compound obtained by the present invention has excellent enzyme inhibitory activity. In a particular embodiment, compound S-1 is significantly more active than compound S-20 in comparison to its structurally similar compound S-20.

The results of in vivo experiments show that the compound of the present invention has a high inhibition rate on tumors, and the therapeutic effect on tumors is significantly better than that of chemotherapy drugs, cyclophosphamide and compounds.

The therapeutic effect, in which compound 103 is superior to its structural analog in the treatment of tumors.

(Compound 1505) The therapeutic effect on tumors.

Indoleamine 2,3-dioxygenase inhibitor can significantly reduce the side effects of drugs when used in tumor treatment, and significantly improve the quality of life of mice. It can not only improve the quality of life of patients, but also greatly improve patients. Medication compliance and drug effectiveness. In a specific embodiment, the cyclophosphamide and each compound in the present invention were compared before and after administration, and the results showed that each compound in the present invention can significantly promote the growth of the body weight, the amount and the model of the animal compared with the cyclophosphamide. There was no significant difference in the group comparison. The compound of the invention can significantly improve the learning and memory damage of the animal, improve the learning acquisition ability and the spatial memory ability, and has positive therapeutic significance for neurodegenerative diseases such as Alzheimer's syndrome.

It has been found by the T cell proliferation reaction experiment that the compound of the present invention can promote the action of DC-stimulated T cell proliferation, and can be used for the treatment of tumor diseases, autoimmune diseases, transplant rejection, and infectious diseases.

Absolute bioavailability measurement results show that each compound in the present invention has high bioavailability, and has obvious advantages compared with compound S-21 and compound 1505, and compound 103 is bioavailable compared with its structural analog 1505. The degree is significantly higher than compound 1505.

The indoleamine 2,3-dioxygenase inhibitor of the present invention is used in the preparation of a medicament for treating a pathological characteristic disease having a tryptophan 2,3-dioxygenase-mediated tryptophan metabolic pathway Has the following advantages:

(1) The antitumor effect is remarkable, the compound of the present invention has significant indoleamine 2,3-dioxygenase inhibitory activity, and the in vivo test shows that the compound inhibiting rate of the compound of the present invention is significantly higher than that of the positive control drug cyclophosphorus. Amides and compounds S-21 and 1505.

(2) The side effect is lowered, and the compound of the present invention is a guanamine 2,3-dioxygenase inhibitor, which inhibits the immunity of the body by inhibiting the proliferation inhibition of T cells by inhibiting the activity of the indoleamine 2,3-dioxygenase. Function, thus completing the monitoring and killing effect of the human immune system on tumor cells. Based on this special mechanism of action, this compound does not adversely affect the growth of normal cells of the human body while inhibiting the growth of tumor cells, thus significantly reducing the side effects of the drug. Moreover, it has a significant therapeutic effect on autoimmune diseases, transplant rejection, and infectious diseases associated with T cell proliferation.

(3) The treatment of Alzheimer's and other neurodegenerative diseases is effective, which can significantly improve the learning and memory impairment of animals, and significantly improve the ability of learning and spatial memory.

(4) It has high bioavailability and has significant advantages in drug-forming properties.

Certain chemical terms

Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning meaning All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety herein in their entirety herein

The above description and the following detailed description are to be considered as illustrative and not restrictive. In the present application, the use of the singular includes the plural unless otherwise specified. It should also be noted that "or" or "or" is used to mean "and/or" unless otherwise indicated. In addition, the terms "comprises" and "comprising" and "comprising", "include"

The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 ^TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy and pharmacological methods, are employed unless otherwise indicated. Unless specifically defined, the terms used herein in the descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or the reaction can be carried out and purified according to methods well known in the art or as described in the present application. The above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification. In the present specification, the group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, CH ₂ O is equivalent to OCH ₂ .

Unless otherwise indicated, the general chemical terms used, such as but not limited to, "alkyl", "amine", "aryl" are equivalent to the form optionally substituted. For example, "alkyl" as used herein includes an optionally substituted alkyl group.

As used herein, "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes. The compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present application containing asymmetrically substituted carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using a chiral starting material or a chiral reagent. The compounds of the present application also include tautomeric forms. The tautomeric form is derived from the exchange of a single bond with an adjacent double bond and accompanied by a proton transfer. The compounds of the present application also include atoms of all isotopes, whether in the intermediate or the final compound. The atoms of an isotope include the same number of atoms but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium. That is, the compound of the present application includes a compound in which part or all of hydrogen (H) is replaced by hydrazine (T) and/or hydrazine (D); and some or all of ¹² C is replaced by ¹³ C and/or ¹⁴ C Compounds; and alternative compounds between other isotopes (such as N, O, P, S), such as ¹⁴ N and ¹⁵ N; ¹⁸ O and ¹⁷ O; ³¹ P and ³² P; ³⁵ S and ³⁶ S, and the like. The compounds described herein may have one or more stereoisomeric centers, and each isomeric center may exist in the R or S configuration or a combination thereof. Similarly, a compound described herein can have one or more double bonds, and each double bond can exist in an E (trans) or Z (cis) configuration, or a combination thereof. A particular stereoisomer, regioisomer, diastereomer, enantiomer or epimer should be understood to include all possible isomers, such as stereoisomers. Isomers, structural isomers, diastereomers, enantiomers or epimers, and mixtures thereof. Thus, the compounds described herein include all stereoisomers, structural isomers, diastereomers, enantiomers or epimeric forms, and corresponding mixtures thereof, which are different in configuration. Techniques for transforming a particular stereoisomer or retaining a particular stereoisomer, as well as techniques for resolving a mixture of stereoisomers, are well known in the art, and those skilled in the art will be able to select a suitable method for the particular situation. See, for example, Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIAOF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; and Heller, Acc. Chem. Res. 1990 , 23,128.

The term "optional/arbitrary" or "optionally/arbitrarily" means that the subsequently described event or circumstance may or may not occur, the description including the occurrence or non-occurrence of the event or circumstance. For example, according to the definition below, "optionally substituted alkyl" means "unsubstituted alkyl" (alkyl substituted without a substituent) or "substituted alkyl" (alkyl substituted with a substituent) .

(After defining the terms appearing in the claims, making the claims unclear, giving the applicant the necessary explanations, and also providing a basis for possible future modifications; this part needs to be adjusted according to the specific case)

C ₁ -C _n as used herein includes C ₁ -C ₂ , C ₁ -C ₃ , ... C ₁ -C _n . By way of example, the "C ₁ -C ₄ " group means having from 1 to 4 carbon atoms in the moiety, ie the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbons atom. Thus, for example, "C ₁ -C ₄ alkyl" refers to an alkyl group having from 1 to 4 carbon atoms, that is, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and n-butyl Base, isobutyl, sec-butyl and tert-butyl. A numerical range, for example, "1-10" refers to each integer in a given range, for example "1-10 carbon atoms" means that the group may have 1 carbon atom, 2 carbon atoms, 3 Carbon atom, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.

The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched aliphatic hydrocarbon. The "alkyl" herein may preferably have from 1 to about 20 carbon atoms, for example from 1 to about 10 carbon atoms, from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms, or from 1 to about 4. One carbon atom or from 1 to about 3 carbon atoms. Alkyl embodiments herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-1 -butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl 1-yl-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2 - dimethyl-l-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, positive Butyl, isopentyl, neopentyl, tert-amyl and hexyl, as well as longer alkyl groups such as heptyl and octyl. When a group as defined herein, such as "alkyl" appears numerical range, for example, "C ₁ -C ₆ alkyl" or "C ₁ - ₆ alkyl" refers to by a carbon atom, 2 carbon atoms, 3 An alkyl group consisting of a carbon atom, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and the alkyl group herein also contains an unspecified number range.

As used herein, "alkyl" includes alkyl groups bonded to other groups, such as alkyl groups in alkoxy groups, alkyl groups in alkylthio groups, hydroxyalkyl groups, haloalkyl groups, cyanoalkyl groups, alkylamino groups ( Such as "alkyl" in monoalkylamino, dialkylamino) and the like.

The term "alkylamino" as used herein, alone or in combination, means alkylamino (-HN-alkyl (ie, monoalkylamino) or -N-(alkyl) ₂ (ie, dialkylamino). The definition of alkyl is as described above.

The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether group (O-alkyl), non-limiting examples of which include methoxy, ethoxy, n-propoxy, isopropyl Oxyl, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy groups.

The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched monovalent hydrocarbon radical having one or more C=C double bonds. The alkenyl group has, but is not limited to, from 2 to about 18 carbon atoms, for example, from 2 to about 10 carbon atoms, or from 2 to about 8 carbon atoms, from 2 to about 6 carbon atoms, from 2 to about 4 carbon atom. The double bond in these groups may be in the cis or trans conformation and should be understood to encompass both isomers. Examples include, but are not limited to vinyl (CH = CH _2), 1- propenyl _{_{(CH 2 CH = CH 2)}} , isopropenyl _{(C (CH 3) = CH} 2), butenyl and 1,3 Butadienyl and the like. When an alkenyl group as defined herein appears in the numerical range, for example "C ₂ -C ₆ alkenyl" or "C ₂ - ₆ alkenyl" means 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbons An alkenyl group consisting of an atom or 6 carbon atoms, and the alkenyl group herein also covers the case where the numerical range is not specified.

The term "halo" or "halogen-substituted" as used herein, alone or in combination, means that one or more hydrogen atoms of an optionally substituted group (eg, alkyl, alkenyl, and alkynyl) are replaced with fluorine, chlorine. , bromine, iodine atoms or a combination thereof. In some embodiments, two or more hydrogen atoms (eg, difluoromethyl, trifluoromethyl) are replaced with the same halogen atom as each other; in other embodiments, two are replaced with halogen atoms that are not identical to each other. Or a plurality of hydrogen atoms (for example, 1-chloro-1-fluoro-1-iodoethyl). Non-limiting examples of haloalkyl groups are fluoromethyl and bromoethyl. A non-limiting example of a haloalkenyl group is a bromovinyl group. A non-limiting example of a haloalkynyl group is a chloroethynyl group.

The term "aryl/aryl" as used herein, alone or in combination, refers to an optionally substituted aromatic hydrocarbon radical having from 6 to about 20, such as from 6 to 12 or from 6 to 10 ring-forming carbon atoms. It may be a fused aromatic ring or a non-fused aromatic ring. The fused aromatic ring contains 2-4 aromatic ring fused rings, and the other independent rings may be an alicyclic ring, a heterocyclic ring, an aromatic ring, an aromatic heterocyclic ring or any combination thereof. The aryl group herein includes a monocyclic, bicyclic, tricyclic or more cyclic aryl group. Non-limiting examples of monocyclic aryl groups include 6 to about 12, 6 to about 10 or 6 to about 8 monocyclic aryl groups of a ring-forming carbon atom, such as phenyl; fused ring aryl groups include bicyclic rings, A tricyclic or more cyclic aryl group such as a naphthyl group, a phenanthryl group, an anthracenyl group or a fluorenyl group; and a non-fused bisaryl group including a biphenyl group.

The term "heteroaryl" as used herein, alone or in combination, refers to an optionally substituted monovalent heteroaryl group containing from about 5 to about 20, such as from 5 to 12 or from 5 to 10 backbones, wherein one or A plurality of (eg, 1-4, 1-3, 1-2) ring-forming atoms are heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. Atom, but not limited to this. The ring of the group does not contain two adjacent O or S atoms. Heteroaryl groups include monocyclic heteroaryl or polycyclic heteroaryl (eg bicyclic heteroaryl, tricyclic heteroaryl, etc.). In embodiments in which two or more heteroatoms are present in the ring, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other. The term heteroaryl includes an optionally substituted monovalent fused or non-fused heteroaryl having at least one hetero atom. Furthermore, the term heteroaryl also includes fused and non-fused heteroaryl groups containing from 5 to about 12 backbone-forming ring atoms, and fused and non-fused, containing from 5 to about 10 backbone-forming ring atoms. Heteroaryl. It can be bonded to a heteroaryl group through a carbon atom or a hetero atom. Thus, for example, an imidazole can pass through any of its carbon atoms (imidazol-2-yl, imidazol-4-yl or imidazole-5- The base or its nitrogen atom (imidazol-1-yl or imidazol-3-yl) is attached to the parent molecule. Similarly, a heteroaryl group can be further substituted by any or all of its carbon atoms and/or any or all of the heteroatoms. The fused heteroaryl group may contain 2-4 aromatic heterocyclic fused fused rings, and the other independent rings may be an alicyclic ring, a heterocyclic ring, an aromatic ring, an aromatic heterocyclic ring or any combination thereof. Non-limiting examples of monocyclic heteroaryl groups include from 5 to about 12, from 5 to about 10, from 5 to about 7 or 6 monocyclic heteroaryl groups which are backbone-ringed, for example, non-limiting examples thereof Included is pyridyl; fused ring heteroaryl includes benzimidazolyl, quinolinyl, acridinyl, and non-fused biheteroaryl includes bipyridinyl. Other examples of heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, triazine, furan, thiophene, imidazole, triazole, tetrazole, thiazole, isothiazole, 1,2,4-thiadiene Oxazole, pyrrole, pyrazole, oxazole, isoxazole, oxadiazole, benzofuran, benzothiophene, benzothiazole, hydrazine, carbazole, quinoline, isoquinoline, indole, carbazole, benzo Imidazole, pyrrolopyridine, pyrrolopyrimidine, pyrazolopyridine, pyrazolopyrimidine and the like. Acridinyl, phenazinyl, benzoxazolyl, benzothiadiazolyl, benzooxadiazolyl, benzotriazolyl, isoquinolinyl, indolizinyl, isothiazolyl ( Isothiazolyl), isoindolyl, oxadiazolyl, purinyl, phthalazinyl, pteridinyl, quinazolinyl, quinoxaline Quinoxalinyl, triazinyl, thiadiazolyl, etc., and oxides thereof, such as pyridyl-N-oxide.

The term "heterocycle" or "heterocyclyl" as used herein, alone or in combination, refers to a non-aromatic heterocycle, including heterocycloalkyl (saturated heterocyclyl) and heterocycloalkenyl (unsaturated heterocyclyl). One or more (e.g., 1-4, 1-3, 1-2) ring-forming atoms are heteroatoms such as oxygen, nitrogen or sulfur atoms. The heterocyclic group may include a monocyclic heterocyclic group (heterocyclic group having one ring) or a polycyclic heterocyclic group (for example, a bicyclic heterocyclic group (heterocyclic group having two rings), a tricyclic heterocyclic group, or the like). The bicyclic heterocyclic group may be a spiro ring or a bridged ring. Heterocyclyl groups can have from 3 to about 20, such as from 3 to about 10, from 3 to about 8, from 5 to about 8, or from 5 to about 6, ring-forming atoms. Non-limiting examples of heterocyclic groups include azinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl ( Homopiperidinyl), oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3- 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, Dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl (3) -azabicyclo[3.1.0]hexyl), 3-azabicyclo[4.1.0]heptyl (3-azabicyclo[4.1.0]heptyl), 3H-indolyl and quinolizinyl )Wait. The term also encompasses all cyclic forms of saccharides including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Examples include, but are not limited to, aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, isoxazolidine, isothiazolidine, pyrazolidine, morpholine, thio? Porphyrin, piperazine, piperidinyl and the like. Heterocyclyl also includes heterocycles having one or more aromatic rings fused (ie, having a common bond), such as 2,3-dihydrobenzofuran, 1,3-benzodioxolane, benzo -1,4-dioxane, phthalimide, naphthalimide. The heterocyclic group having one or more aromatic condensations may be bonded to other groups through an aromatic ring or a non-aromatic ring moiety. Other groups may be bonded to the heterocycle via a heteroatom or a carbon atom (ie, the heterocycle is attached or further substituted with the parent molecule).

The term "carbocyclyl" as used herein, alone or in combination, refers to a non-aromatic carbocyclic ring, including cycloalkyl and cycloalkenyl. The cycloalkyl group may be a monocyclic cycloalkyl group or a polycyclic cycloalkyl group (for example, having 2, 3 or 4 rings; such as a bicyclic cycloalkyl group), which may be a spiro ring or a bridged ring. The cycloalkyl group may have from 3 to 20 carbon atoms, for example from 3 to about 15 ring-forming carbon atoms or from 3 to about 10 ring-forming carbon atoms or from 3 to 6 ring-forming carbon atoms, and may have 0, 1, 2 Or 3 double keys and / or 0, 1 or 2 triple keys. For example, a cycloalkyl group having 3-8 or 3-6 ring-forming carbon atoms (e.g., a saturated monocyclic cycloalkyl group). The cycloalkyl group also includes a ring having one or more aromatic rings fused (i.e., having a common bond), for example, a benzo derivative substituted pentane, pentene, hexane, or the like. One or more aromatic fused cycloalkyl groups may be attached to the other groups through an aromatic ring or a moiety other than the aromatic ring. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclopentenyl group, a cyclohexadienyl group, a cycloheptatrienyl group, an adamantyl group and the like.

"Halogen" means fluoro, chloro, bromo, iodo. The preferred are fluorine, chlorine and bromine. Cyano refers to "-CN"; hydroxy refers to "-OH"; thiol refers to "-SH"; amino refers to "-NH ₂ "; oxo refers to =0.

The term "substituted" means that one or more hydrogens are replaced by a specified group on a particular atom, if the specified original The normal valence of the subunit is not exceeded in the existing case, and the result is a stable compound after the substitution.

Certain pharmacy terms

Certain pharmacy terms As used herein, the terms "subject," "patient," or "individual" refer to an individual, including a mammal, and a non-mammal, having a disease, disorder, condition, or the like. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domesticated Animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

The term "treatment" and other similar synonyms as used herein includes alleviating, alleviating or ameliorating the symptoms of a disease or condition, inhibiting a disease or condition, such as preventing the progression of a disease or condition, alleviating a disease or condition, improving the disease or condition, and alleviating the disease. Or the symptoms caused by the condition, or the symptoms of the disease or condition, the prevention of other symptoms, the improvement or prevention of the underlying metabolic causes of the symptoms, and the term includes the purpose of prevention. The term also includes obtaining a therapeutic effect and/or a preventive effect. The therapeutic effect refers to curing or ameliorating the underlying disease to be treated. In addition, the healing or amelioration of one or more physiological symptoms associated with a underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, an improvement in the patient's condition is observed. In terms of prophylactic effect, the composition can be administered to a patient at risk of developing a particular disease, or even if a diagnosis of the disease has not been made, the composition is administered to a patient who develops one or more physiological symptoms of the disease.

The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount," as used herein, refers to at least one active substance that is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent after administration ( The amount of the compound as in the present application). The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system. For example, an "effective amount" for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic. An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.

The terms "administering," "administering," "administering," and the like, as used herein, refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. The techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those discussed in Pa.

The term "acceptable" as used herein with respect to a formulation, composition or ingredient means that there is no long-term detrimental effect on the general health of the subject being treated.

The term "pharmaceutically acceptable" as used herein, refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable biological reactions. Or interacting with any of the components contained in the composition in a poor manner.

The term "pharmaceutical composition" as used herein refers to a mixture of a compound of the present application and at least one pharmaceutically acceptable substance. The pharmaceutically acceptable substances include, but are not limited to, carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.

The term "carrier," as used herein, refers to a relatively non-toxic material that facilitates the introduction of a compound of the present application into a cell or tissue.

The term "pharmaceutically acceptable salt" as used herein, refers to a salt which retains the biological effectiveness of the free acid and free base of the specified compound and which has no adverse effects biologically or otherwise. The compounds of the present application also include pharmaceutically acceptable salts. A pharmaceutically acceptable salt refers to a form in which a base group in a parent compound is converted into a salt. Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of base groups such as amine (amino) groups. The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound, i.e., the basic group in the parent compound is reacted with from 1 to 4 equivalents of acid in a solvent system. Suitable salts include the ^{Remingtong's Pharmaceutical Scicences, 17 th ed} ., Mack Publishing Company, Easton, Pa., In 1985, p.1418, and Journal of Pharmaceutical Science, 66,2 (1977 ).

Unless otherwise specified, the salt in the present application refers to an acid salt formed with an organic acid/inorganic acid, and a basic salt formed with an organic base/inorganic base. In addition, when the basic functional group of the compound of the formula is pyridine or imidazole (but not limited to pyridine or imidazole), the acidic functional group is a carboxy group. Zwitterions (internal salts) are formed when the acid is, but not limited to, the carboxylic acid, and the internal salt is also included in the salt of the present application.

detailed description:

Representative of specific compounds of the invention can be synthesized by the synthetic methods of the general formula disclosed herein. The invention is further described below in conjunction with specific embodiments, but the invention is not limited thereto. All other specific compounds which can be obtained by those skilled in the art without any creative work under the guidance of the general formula, the synthetic method of the general formula and the specific embodiments of the present invention are all within the scope of the present invention.

Example 1 Synthesis of XSD1-064

1):

Intermediate 1 (80 mg, 0.23 mmol) was dissolved in dichloromethane (5 mL). After cooling to room temperature, the solvent was evaporated under reduced pressure and the crude material was applied to the next step.

2):

6 mL of anhydrous tetrahydrofuran was added and the compound 2 was dissolved sufficiently. N-methylbenzylamine (180 mg, 0.66 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.32 mmol) were added at 0 ° C and stirred at room temperature. 18h. TLC showed the reaction was complete. The mixture was extracted with EtOAc (EtOAc) (EtOAc)EtOAc. The crude product compound 3 was obtained and used directly in the next reaction.

3):

The crude product of compound 3 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added under ice-cooling, and the reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-064 (25 mg, the total yield of the three-step reaction was 25%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.30 (s, 1H), 7.90 (s, 1H), 7.85-7.88 (m, 2H), 7.72-7.74 (m, 2H), 7.45-7.57 (m, 2H), 7.29-7.35 (m, 2H), 7.23-7.26 (m, 1H), 7.14-7.15 (m, 2H), 5.69-5.72 (m, 1H), 5.20 (brs, 1H), 4.50 (s, 2H), 3.51 (m, 1H), 2.70 ( s, 3H), 1.24-1.99 (m, 16H)

HPLC purity: @214nm 97.56%, @254nm 99.99%

Example 2 Synthesis of XSD1-065

1):

2):

6 mL of anhydrous tetrahydrofuran was added and the compound 2 was dissolved. The aniline (85 mg, 0.88 mmol) and N,N-diisopropylethylamine (0.4 mL, 1.8 mmol). TLC showed the reaction was complete. The mixture was extracted with EtOAc (EtOAc) (EtOAc)EtOAc. The crude product compound 3 was obtained and used directly in the next reaction.

3):

The crude product of compound 3 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added under ice-cooling, and the reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-065 (10 mg, the total yield of the three-step reaction 12%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.30(s,1H), 9.03(s,1H),7.86-7.90(m,2H),8.067(m,1H),7.74-7.76(m,1H),7.52-7.69(m,4H),7.24- 7.28 (m, 2H), 6.99-7.03 (m, 1H), 5.73 (m, 1H), 5.17-5.30 (m, 1H), 3.67-3.69 (m, 1H), 1.24-1.97 (m, 16H)

HPLC purity: @214nm 95.38%, @254nm 98.26%

MS: m/z 442.1 [M+1]

Example 3 Synthesis of XSD1-066

1):

Intermediate 1 (120 mg, 0.33 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (65 mg, 0.50 mmol), O-(7-nitrobenzotriazole)-N, N , N', N'-tetramethylurea hexafluorophosphate (200 mg, 0.50 mmol) and diisopropylethylamine (130 mg, 1.0 mmol), reacted at room temperature under nitrogen overnight, quenched with water, ethyl acetate (30 mL x 5), the combined extracts were washed with brine, dried over anhydrous sodium sulfate The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by Pre-HPLC to give the title compound XSD1-066 (28 mg, 19% yield of the two-step reaction).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.25(s,1H),7.84-7.92(m,3H),7.72-7.74(m,1H),7.49-7.56(m,2H), 7.20-7.24(m,2H),7.09-7.14(m,2H ), 5.69-5.74 (m, 1H), 5.18-5.19 (m, 1H), 4.19-4.20 (m, 2H), 3.50-3.64 (m, 1H), 1.24-2.05 (m, 16H)

HPLC purity: @214nm 97.59%, @254nm 98.56%

MS: m/z 474.2 [M+1]

Example 4 Synthesis of XSD1-067

1):

Intermediate 1 (100 mg, 0.275 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (60 mg, 0.412 mmol), O-(7-nitrobenzotriazole)-N, N , N', N'-tetramethylurea hexafluorophosphate (157.4 mg, 0.412 mmol) and diisopropylethylamine (106.3 mg, 0.824 mmol), reacted at room temperature under nitrogen overnight, quenched with water, acetic acid The ethyl ester (50 mL, EtOAc) was evaporated. The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by Pre-HPLC to give the title compound XSD1-067 (6 mg, 5% yield of the two-step reaction).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.27(s,1H),7.8827-7.93(m,3H),7.73-7.74(m,1H),7.53(s,2H),7.34-7.36(m,2H),7.22(s,2H),5.71( s,1H), 5.18(br s,1H), 4.20(s,2H), 3.39(s,1H),1.24-2.08(m,16H)

HPLC purity: @214nm 99.76%, @254nm 99.94%

MS: m/z 490.1 [M+1]

Example 5 Synthesis of XSD1-068

1):

2):

The crude compound 2 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to yield the title compound XSD 1- 068 (42 mg, mp.

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.31(s,1H), 7.85-7.90(m,3H),7.73-7.74(m,1H), 7.49-7.57(m,2H),7.14-7.28(m,2H),7.01-7.13(m,1H) ), 5.70-5.73 (m, 1H), 4.21-4.22 (m, 2H), 3.48-3.51 (m, 1H), 1.23-2.10 (m, 16H)

HPLC purity: @214nm 98.41%, @254nm 96.59%

MS: m/z 492.2 [M+1]

Example 6 Synthesis of XSD1-069

1):

Intermediate 1 (100 mg, 0.275 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (59 mg, 0.412 mmol), O-(7-nitrobenzotriazole)-N, N , N', N'-tetramethylurea hexafluorophosphate (157.4 mg, 0.412 mmol) and diisopropylethylamine (106.3 mg, 0.824 mmol), reacted at room temperature under nitrogen overnight, quenched with water, acetic acid The ethyl ester (50 mL, EtOAc) was evaporated. The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-069 (50 mg, yield 37%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.31(s,1H), 7.85-7.95(m,3H),7.73-7.74(m,1H),7.52-7.55(m,2H),7.34-7.36(m,1H),7.17-7.22(m,1H ), 7.04 (m, 1H), 5.70-5.73 (m, 1H), 5.07-5.26 (m, 1H), 4.18-4.19 (m, 2H), 3.77-3.50 (m, 1H), 1.97-2.10 (m) , 2H), 1.32-1.81 (m, 14H)

HPLC purity: @214nm 99.20%, @254nm 99.20%

MS: m/z 492.3 [M+1]

Example 7 Synthesis of XSD1-070

1):

2):

The crude compound 2 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the title compound XSD 1-070 (100 mg, y.

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.33(s,1H), 8.65-8.66(m,1H),8.11-8.16(m,2H),7.92-7.94(m,1H),7.86-7.88(m,1H),7.73-7.75(m,1H) ), 7.46-7.59 (m, 4H), 5.72-5.75 (m, 1H), 4.42-4.43 (m, 2H), 3.49-3.52 (m, 1H), 1.32-2.10 (m, 16H)

HPLC purity: @214nm 95.92%, @254nm 92.95%

MS: m/z 457.2 [M+1]

Example 8 Synthesis of XSD1-071

1):

Intermediate 1 (130 mg, 0.36 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and compound 1a (58 mg, 0.54 mmol), 2-(7-benzobenzotriazole)-N,N, N', N'-tetramethylurea hexafluorophosphate (205 mg, 0.54 mmol), N,N-diisopropylethylamine (138 mg, 1.07 mmol). The mixture was stirred at room temperature under reduced pressure. EtOAc (EtOAc m. The crude product was used directly in the next reaction.

2):

The crude compound was dissolved in 5 mL of methanol, and NaBH ₄ (200 mg, 5 mmol) was added to the mixture, and the reaction was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). (30 mL×3), the combined extracts were washed with brine, dried over anhydrous sodium sulfate The crude product was purified by pre-HPLC to give the title compound XSD1-071 (64.68 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 8.41 - 8.42 (m, 2H), 7.93 - 8.03 (m, 2H), 7.57 - 7.64 (m, 3H), 7.41 - 7.78 (m, 3H), 7.15 (s, 1H), 5.36 (s, 1H), 5.99-5.00 (m, 1H), 4.23-4.01 (m, 2H), 3.45-3.32 (m, 1H), 1.98-1.16 (m, 16H).

HPLC purity: @214nm 96.12%, @254nm 98.33%

MS: m/z 457.3 [M+1]

Example 9 Synthesis of XSD1-072

1):

Intermediate 1 (100 mg, 0.275 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 7a (60 mg, 0.412 mmol), O-(7-nitrobenzotriazole)-N, N , N', N'-tetramethylurea hexafluorophosphate (157.4 mg, 0.412 mmol) and diisopropylethylamine (106.3 mg, 0.824 mmol), reacted at room temperature under nitrogen overnight, quenched with water, acetic acid The ethyl ester (50 mL, EtOAc) was evaporated. The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-072 (10 mg, yield 8%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.28(s,1H), 8.45-8.55 (m,3H), 8.07 (m,1H), 7.85-7.89 (m,2H), 7.29-7.74 (m,1H), 7.51-7.57 (m,2H), 5.71 (m, 1H), 5.18-5.20 (m, 1H), 4.35-4.36 (m, 2H), 3.64 - 3.66 (m, 1H), 2.01-2.09 (m, 2H), 1.24-1.82 (m, 14H) )

HPLC purity: @214nm 99.19%, @254nm 99.20%

MS: m/z 458.3 [M+1]

Example 10 Synthesis of XSD1-073

1):

Intermediate 1 (100 mg, 0.275 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (55.8 mg, 0.412 mmol), O-(7-nitrobenzotriazole)-N, N,N',N'-tetramethyluronium hexafluorophosphate (157.4 mg, 0.412 mmol) and diisopropylethylamine (106.3 mg, 0.824 mmol) were reacted overnight at room temperature under nitrogen atmosphere and quenched with water. The mixture was extracted with ethyl acetate (50 mL, EtOAc). The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1- s (60 mg, yield 48%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.30(s,1H), 7.85-7.90(m,2H), 7.72-7.74(m,1H),7.51-7.55(m,2H),7.23-7.26(m,1H),5.71-5.72(m,1H) ), 5.04-5.27 (m, 1H), 3.47-3.49 (m, 1H), 2.91-2.94 (m, 2H), 1.98-2.01 (m, 3H), 1.29-1.82 (m, 20H), 1.06-1.20 (m, 2H)

HPLC purity: @214nm 99.90%, @254nm 99.90%

MS: m/z 448.2 [M+1]

Example 11 Synthesis of XSD1-074

1)

Intermediate 1 (91 mg, 0.25 mmol) was dissolved in 5 mL of N,N'-dimethylformamide, and compound 1a (21.3 mg, 0.3 mmol), O-(7-nitrobenzotriazole)-N, N,N',N'-tetramethyluronium hexafluorophosphate (150 mg, 0.39 mmol) and diisopropylethylamine (52 mg, 0.77 mmol), reacted at room temperature under nitrogen overnight, quenched with water, ethyl acetate The mixture was extracted with EtOAc (EtOAc) (EtOAc) The crude product was used directly in the next reaction.

2)

The crude product of compound 2 was dissolved in 5 mL of methanol, and NaBH ₄ (42 mg, 1.12 mmol) was added under ice-cooling, and the reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-074 (35 mg, yield: 33.5%).

H NMR (DMSO, 400 M): 9.32 (s, 1H), 7.85-7.19 (m, 2H), 7.72 - 7.74 (m, 1H), 7.51 - 7.57 (m, 2H), 7.23 - 7.24 (m, 1H) , 5.70-5.73 (m, 1H), 3.47-3.49 (m, 1H), 2.50-2.52 (s, 4H), 1.29-2.09 (m, 20H)

HPLC purity: @214nm 96.9%, @254nm 99.6%

MS Calcd: 421, MS Found: 422 [M+H] ⁺ .

Example 12 Synthesis of XSD1-076

1):

Intermediate 1 (80 mg, 0.22 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and compound 1a (130 mg, 2.12 mmol), 2-(7-benzotriazole)-N, N , N', N'-tetramethylurea hexafluorophosphate (126 mg, 0.33 mmol), N,N-diisopropylethylamine (567 mg, 0.44 mmol), reacted at room temperature overnight under nitrogen atmosphere, quenched with water, The mixture was extracted with ethyl acetate (50 mL, EtOAc). The crude product was used directly in the next reaction.

2):

The crude product of Compound 2 was dissolved in 5 mL of methanol, and NaBH ₄ (88 mg, 2.2 mmol) was added under ice-cooling, and the reaction was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD 1-076 (20.37 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 9.32 (s, 1H), 7.91-7.89 (m, 2H), 7.74-7.72 (m, 1H), 7.57-7.50 (m, 2H) , 6.92-6.90(m,1H),5.73-5.70(m,1H),3.84-3.79(m,1H),3.41-3.47(m,1H),2.10-1.96(m,17H),1.10(m, 6H).

HPLC purity: @214nm 98.45%, @254nm 99.23%

MS: m/z 408.2 [M+1]

Example 13 Synthesis of XSD1-077

1):

Intermediate 1 (140 mg, 0.38 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and compound 1a (57 mg, 0.77 mmol), 2-(7-benzotriazole)-N,N, N', N'-tetramethylurea hexafluorophosphate (221 mg, 0.58 mmol), N,N-diisopropylethylamine (149 mg, 1.15 mmol). The mixture was stirred at room temperature under reduced pressure. EtOAc (EtOAc m. The crude product was used directly in the next reaction.

2):

The crude product of compound 2 was dissolved in 5 mL of methanol, and NaBH ₄ (154 mg, 3.85 mmol) was added under ice-cooling, and the reaction was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD 1-077 (26.40 mg).

^{1 H-NMR (400MHz, DMSO} -d 6): δ (ppm) 9.32 (s, 1H), 7.91 (s, 1H), 7.85-7.87 (m, 1H), 7.73-7.74 (m, 1H), 7.50 -7.57 (m, 2H), 7.23-7.26 (m, 1H), 5.70-5.73 (m, 1H), 3.47-3.49 (m, 1H), 2.80-2.83 (m, 2H), 1.29-2.10 (m, 17H), 0.78-0.79 (m, 6H).

HPLC purity: @214nm 93.74%, @254nm 87.88%

MS: m/z 422.4 [M+1]

Example 14 Synthesis of XSD1-078

1)

An aqueous solution of cesium hydroxide (1.71 g, 10 mmol) was added to a solution of Compound 1 (4.8 g, 20 mmol) in 40 mL MeOH. After completion of the reaction, the mixture was diluted with EtOAc (EtOAc) (EtOAc m. 81%).

2)

Mercury oxide (2.16 g, 10 mmol), iodine (7.74 g, 30 mmol) was added to a solution of compound 2 (2.12 g, 10 mmol) and chloroform (100 mL) at 0 ° C, then the reaction temperature was slowly raised to 90 ° C Continue reaction for 18h, TLC (ethyl acetate: petroleum Ether = 2:1) The reaction was monitored. After the reaction was completed, the solvent was evaporated under reduced pressure, and then ethyl acetate (100 mL*3) was added and the organic phase was extracted and dried over anhydrous sodium sulfate. Compound 3, (1.8 g, yield 61.2%).

3)

Compound 3 (1.2 g, 4.08 mmol) was dissolved in tetrahydrofuran (30 mL), EtOAc (EtOAc) EtOAc. After stirring for 2 h, then slowly warming to room temperature and stirring for 18 h, the reaction mixture was cooled to 0 ° C, and saturated aqueous ammonium chloride (20 mL) was added to quench the reaction, and the organic phase was extracted with ethyl acetate (80 mL*3) and washed with water. The mixture was washed with brine, dried over anhydrous sodium sulfate

4)

Compound 3a (1.02m g, 4.07mmol) was dissolved in 30mL anhydrous tetrahydrofuran, cooled to -70 ° C in a dry ice acetone bath, slowly added dropwise butyl lithium (8mL, 4.07mmol) and kept at an internal temperature of -60 ° C, quickly A solution of compound 4 (500 mg, 3.26 mmol) in anhydrous tetrahydrofuran (10 mL) was added to the reaction flask and maintained at an internal temperature of -60 °C. The reaction mixture was stirred at -70 ° C for 2 hours, quenched with saturated aqueous ammonium chloride and warmed to room temperature. The extract was extracted with dichloromethane (100 mL EtOAc). The crude product was subjected to column chromatography to give the product compound 5 (200 m, yield: 63.2%).

5)

Compound 5 (200 mg, 0.51 mmol) was dissolved in 10 mL of anhydrous THF, and sodium hydrogen sulfate (51 mg, 1.27 mmol) was added, and the mixture was stirred at room temperature for 1 hour. A solution of Compound 4a (211 mg, 0.51 mmol) in 5 mL of anhydrous tetrahydrofuran was added to the reaction flask under ice bath. The reaction mixture was stirred at rt. EtOAc EtOAc. The crude product was subjected to column chromatography to give the product compound 6 (120 mg, yield: 34.6%).

6)

Compound 6 (120 mg, 0.18 mmol) was dissolved in 10 mL of methanol, 1 mL of glacial acetic acid was added, and the mixture was stirred at 90 ° C, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, and 100 mL of saturated sodium hydrogen carbonate was added and extracted with dichloromethane (50 mL*3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate The crude product of compound 7 (150 mg) was obtained and used directly in the next reaction.

7)

Compound 7 (150mg, 0.1mmol) was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (19mg, 0.5mmol), the reaction stirred for 1 hour, the reaction solution (30mL) and quenched with saturated ammonium chloride solution and rotary evaporated to remove most of The mixture was extracted with EtOAc (3 mL, EtOAc). Pre-HPLC gave compound XSD 1-078 (17 mg).

¹ H-NMR (400 MHz, DMSO-d6): δ (ppm) 9.23 (s, 1H), 7.41 - 7.91 (m, 6H), 6.91 (s, 1H), 5.7 (s, 1H), 4.96 (s, 1H), 3.62-3.64 (m, 1H) 2.05-2.13 (m, 2H), 1.23-1.43 (m, 15H),

HPLC purity: @214nm 99.9%, @254nm 99.99%

MS: m/z 323.2 [M+1]

Example 15 Synthesis of XSD1-079

1):

Sodium hydrogen (20 g, 0.5 mol) was dissolved in 400 mL of ethylene glycol dimethyl ether in an ice bath. Compound 1 (50 g, 0.22 mol) was added portionwise, and refluxed at 105 ° C for 12 h. The system gradually changed from white to pink and purple. The system was spun dry, 60 mL of ethylene glycol dimethyl ether was added, 1,3-dibromopropane was added, and the mixture was refluxed at 105 ° C for 48 h, and the system gradually changed from purple to white suspension. The system was filtered while hot, washed with dichloromethane, and the filtrate was evaporated to dryness.

1H-NMR (400MHz, CDCl3): d (ppm)

3.78(s,6H),3.3518-3.40(m,2H),2.74-2.78(m,2H),2.47-2.51(m,2H),1.94-1.98(m,2H),1.78-1.81(m,2H )

2):

Compound 2 (23 g, 0.086 mol) was dissolved in 230 mL of anhydrous toluene, followed by the addition of 1,2-ethanedithiol (58 mL, 0.69 mol), p-toluenesulfonic acid (0.73 g, 3.8 mmol). Under reflux with nitrogen at 130 ° C overnight. After quenching with water, ethyl acetate (200 mL×3) was evaporated and evaporated. Column chromatography gave 10 g of a yellow solid, yield 24%.

1H-NMR (400MHz, CDCl3): d (ppm) 3.65 (s, 6H), 3.55-3.59 (m, 2H), 3.35-3.42 (m, 4H), 3.24-3.29 (m, 4H), 2.94-2.98 (m, 2H), 2.55-2.58 (m, 2H), 1.87-1.90 (m, 4H)

3):

Compound 3 (1.0 g, 2.4 mmol) was dissolved in 60 mL of ethanol, and Raney nickel (20 g) was added, and the mixture was stirred at 100 ° C for 72 h. It was filtered while hot, washed with 1 liter of hot ethanol, and the filtrate was evaporated to give a product. 450 mg, yield 79%.

4):

The compound 4 (240 mg, 1.0 mmol) was dissolved in a mixture of 2.2 mL of methanol and 0.5 mL of water, and hydrazine hydroxide octahydrate (160 mg, 0.5 mmol) was added, and the mixture was reacted overnight at room temperature under nitrogen atmosphere. The aqueous phase was adjusted to pH 2 with EtOAc (EtOAc) (EtOAc) The crude product was used directly in the next reaction.

5):

Compound 5 (120 mg, crude) was dissolved in 3 mL of N,N'-dimethylformamide, followed by benzylamine (91 mg, 0.85 mmol), O-(7-nitrobenzotriazole)-N,N,N ', N'-Tetramethylurea hexafluorophosphate (330 mg, 0.85 mmol) and diisopropylethylamine (210 mg, 1.6 mmol), reacted at room temperature under N2 overnight, quenched with water, ethyl acetate (50 mL) The mixture was extracted with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. Column chromatography separated to give the product 160 mg.

6):

Compound 6 (160 mg, 0.51 mmol) was dissolved in 6 mL of anhydrous tetrahydrofuran, the system was cooled to -78 ° C, n-butyl lithium (1.3 mL, 3.1 mmol) was added dropwise, and the temperature was controlled at -70 ° C to -55 ° C. A solution of the compound 6 in anhydrous tetrahydrofuran was added rapidly, and the addition was continued, and stirring was continued at -70 ° C to -55 ° C for 2 h. The mixture was extracted with EtOAc (EtOAc m.) Column chromatography gave the product 140 mg (yield: 68%).

7):

The compound 7 (140 mg, 0.35 mmol) was dissolved in 6 mL of anhydrous tetrahydrofuran, and then cooled to 0 ° C, then sodium hydrogen was added, and the mixture was stirred at room temperature for 30 min, and the solution of compound 7a in anhydrous tetrahydrofuran was added and the mixture was stirred at room temperature for 18 h. After quenching with saturated aqueous ammonium chloride, ethyl acetate (50 mL, EtOAc) was evaporated.

8):

Compound 8 (130 mg, 0.19 mmol) was dissolved in 10 mL of methanol, and 1 mL of acetic acid was added and reacted at 90 ° C overnight under nitrogen atmosphere. After adding a saturated sodium hydrogencarbonate solution, the mixture was adjusted to pH 8 and ethyl acetate (50 mL EtOAc) was evaporated.

9):

The crude product of compound 9 was dissolved in 3 mL of anhydrous methanol, and sodium borohydride (90 mg, 2.25 mmol) was added in an ice bath, and the mixture was stirred at room temperature overnight under nitrogen atmosphere, quenched with saturated ammonium chloride, solvent was evaporated, ethyl acetate (30mL The combined extracts were washed with brine, dried over anhydrous sodium sulfate The crude product was purified by pre-HPLC to yield compound XSD 1-079, 20 mg.

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers) 9.31 (s, 1H), 7.86-7.91 (m, 3H), 7.73-7.74 (m, 1H), 7.50-7.57 (m) , 2H), 7.27-7.31 (m, 2H), 7.18-7.21 (m, 3H), 5.71-5.74 (m, 1H), 4.22-4.23 (m, 2H), 1.23-2.07 (m, 16H)

HPLC purity: @214nm 98.40%, @254nm 97.16%

MS: m/z 456.1 [M+1]

Example 16 Synthesis of XSD1-080

1):

Intermediate 1 (100mg, 0.27mmol) was dissolved in 3mL of methanol was added NaBH ₄ under ice (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was treated with saturated ammonium chloride solution (30mL) was quenched, and rotary evaporated to remove large Part of the methanol was extracted with chloroform: isopropyl alcohol = 3:1 (30 mL). The crude product was purified by pre-HPLC to yield the object compound XSD1-080 (5 mg, yield 6%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

11.72 (brs, 1H), 8.99 (s, 1H), 7.79-7.81 (m, 1H), 7.68-7.70 (m, 2H), 7.46-7.53 (m, 2H), 5.62-5.64 (m, 1H), 5.16-5.17(m,1H), 3.61-3.62(m,1H), 1.28-2.08(m,16H)

HPLC purity: @214nm 96.41%, @254nm 98.21%

MS: m/z 367.3 [M+1]

Example 17 Synthesis of XSD1-084

1):

Intermediate 1 (100 mg, 0.275 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (230 mg, 1.12 mmol), O-(7-nitrobenzotriazole)-N, N , N', N'-tetramethylurea hexafluorophosphate (157.4mg, 0.412mmol) and diisopropylethylamine (300mg, 2.24mmol), reacted at room temperature overnight under nitrogen, quenched with water, acetic acid The mixture was extracted with EtOAc (EtOAc) (EtOAc) The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of dichloromethane, and trifluoroacetic acid (0.6 mL) was added under ice-cooling, and the reaction was stirred for 18 hours. The reaction mixture was adjusted to basic with saturated sodium hydrogen carbonate solution (10 mL), chloroform: isopropyl alcohol The extract was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The crude product was used directly in the next reaction.

3):

The crude product of compound 3 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added under ice-cooling, and the reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the title compound XSD1-084 (16 mg, 13% of the three-step reaction). Preparation of the two diastereomers P1 (10 mg), P2 (6.0 mg). XSD1-084-P1

1H-NMR (400MHz, DMSO-d6): d (ppm)

7.94(s,1H), 7.55-7.61(m,2H), 7.36-7.40(m,1H), 7.25-7.29(m,1H),7.11(s,1H),6.93-6.95(m,1H), 5.31-5.33 (m, 1H), 5.00 (s, 1H), 3.36-3.51 (m, 3H), 2.87-2.90 (m, 2H), 2.39-2.45 (m, 2H), 1.98-2.00 (m, 1H) ), 1.24-1.77 (m, 19H)

HPLC purity: @214nm 95.71%, @254nm 96.09%

MS: m/z 449.3 [M+1]

XSD1-084-P2

1H-NMR (400MHz, DMSO-d6): d (ppm)

7.94(s,1H), 7.55-7.61(m,2H), 7.36-7.40(m,1H), 7.25-7.29(m,1H),7.11(s,1H),6.93-6.95(m,1H), 5.31-5.33 (m, 1H), 4.99 (s, 1H), 3.36-3.52 (m, 3H), 2.87-2.90 (m, 2H), 2.39-2.44 (m, 2H), 1.98-1.99 (m, 1H) ), 1.24-1.77 (m, 19H)

HPLC purity: @214nm 97.59%, @254nm 98.18%

MS: m/z 449.3 [M+1]

Example 18 Synthesis of XSD1-085

1):

Intermediate 1 (100 mg, 0.275 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (220 mg, 1.12 mmol), O-(7-nitrobenzotriazole)-N, N , N', N'-tetramethylurea hexafluorophosphate (157.4mg, 0.412mmol) and diisopropylethylamine (300mg, 2.3mmol), reacted at room temperature overnight under nitrogen, quenched with water, acetic acid The mixture was extracted with EtOAc (EtOAc) (EtOAc) The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the title compound XSD1-085 (15 mg, 12% yield of the two-step reaction).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.94 (s, 1H), 7.55-7.60 (m, 2H), 7.36-7.40 (m, 1H), 7.25-7.29 (m, 1H), 7.11 (s, 1H), 7.00-7.02 (m, 1H), 5.31-5.34 (m, 1H), 4.99-5.00 (m, 1H), 3.86-3.88 (m, 2H), 3.68-3.69 (m, 1H), 3.48-3.50 (m , 1H), 2.735 (s, 2H), 1.97-2.00 (m, 1H), 1.23-1.78 (m, 28H)

HPLC purity: @214nm 99.53%, @254nm 99.81%

MS: m/z 549.3 [M+1]

Example 19 Synthesis of XSD1-086

1):

Intermediate 1 (100 mg, 0.27 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and compound 1a (115 mg, 1.10 mmol), 2-(7-benzotriazole)-N,N, N', N'-tetramethylurea hexafluorophosphate (160 mg, 0.41 mmol), N,N-diisopropylethylamine (290 mg, 2.20 mmol), reacted at room temperature under nitrogen overnight, quenched with water, acetic acid The ethyl ester (50 mL, EtOAc) was evaporated. The crude product was used directly in the next reaction.

2):

The crude product of compound 2 was dissolved in 5 mL of methanol, and NaBH ₄ (110 mg, 2.75 mmol) was added under ice-cooling, and the reaction was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the title compound XSD1.

^{1 H-NMR (400MHz, DMSO} -d6): δ (ppm) 7.93 (s, 1H), 7.55-7.60 (m, 2H), 7.36-7.40 (m, 1H), 7.25-7.28 (m, 1H), 7.10(s,1H), 7.01-7.21(m,1H),5.31-5.34(m,1H),4.96-4.98(m,1H),3.79-3.82(m,2H),3.69-3.72(m,1H) ), 3.39-3.43 (m, 1H), 3.26-3.28 (m, 2H), 1.26-2.00 (m, 20H).

HPLC purity: @214nm 98.12%, @254nm 99.93%

MS: m/z 450.5 [M+1]

Example 20 Synthesis of XSD1-087

1):

Compound 7 (100mg, 0.275mmol) was dissolved in 3mL of methanol was added, the ice bath NaBH ₄ (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction solution (30mL) and quenched with saturated ammonium chloride solution and rotary evaporated to remove most of Methanol, chloroform: isopropyl alcohol = 3:1 (30 mL×3), and the combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (180 mg, 1.2 mmol), O-(7-nitrobenzotriazole)-N,N,N',N' Tetramethyluronium hexafluorophosphate (171 mg, 0.45 mmol) and diisopropylethylamine (400 mg, 3.0 mmol) were reacted overnight at room temperature under nitrogen atmosphere, quenched with water, ethyl acetate (50mL×5) The combined extracts were washed with brine, dried over anhydrous sodium sulfate The crude product was purified by pre-HPLC to give the title compound XSD 1- 087 (16 mg, 14% yield of the two-step reaction).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.95 (s, 1H), 7.56-7.61 (m, 2H), 7.36-7.40 (m, 1H), 7.25-7.29 (m, 1H), 7.07-7.11 (m, 2H), 5.31-5.33 (m, 1H) ), 4.99-5.00 (m, 1H), 4.02-4.04 (m, 1H), 3.48-3.49 (m, 1H), 2.39-2.45 (m, 2H), 2.19-2.22 (m, 2H), 1.24-2.03 (m, 20H)

HPLC purity: @214nm 97.81%, @254nm 98.67%

MS: m/z 462.2 [M+1]

Example 21 Synthesis of XSD1-088

1):

Intermediate 1 (100 mg, 0.275 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (172 mg, 1.0 mmol), O-(7-nitrobenzotriazole)-N, N , N', N'-tetramethylurea hexafluorophosphate (200 mg, 0.50 mmol) and diisopropylethyl The amine (450 mg, 3.3 mmol), EtOAc (EtOAc m. The crude product was used directly in the next reaction.

2):

The crude compound was dissolved in 3 mL of methanol, and NaBH4 (55 mg, 1.375 mmol) was added, and the mixture was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). (30 mL×3), the combined extracts were washed with brine, dried over anhydrous sodium sulfate The crude product was purified by pre-HPLC to give the title compound XSD1 - 8-8 (21 mg, 17% yield of the two-step reaction).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.96 (s, 1H), 7.55-7.95 (m, 2H), 7.36-7.39 (m, 1H), 7.25-7.28 (m, 1H), 7.10-7.13 (m, 1H), 7.02-7.04 (m, 1H) ), 5.31-5.39 (m, 1H), 4.96-5.03 (m, 1H), 3.68-3.70 (m, 1H), 3.31-3.43 (m, 1H), 1.32-2.09 (m, 24H)

HPLC purity: @214nm 99.17%, @254nm 99.85%

MS: m/z 484.2 [M+1]

Example 22 Synthesis of XSD1-089

1):

Intermediate 1 (100 mg, 0.275 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and then compound 1a (180 mg, 1.2 mmol), O-(7-nitrobenzotriazole)-N, N , N', N'-tetramethyluron hexafluorophosphate (171 mg, 0.45 mmol) and diisopropylethylamine (400 mg, 3.0 mmol), reacted at room temperature under nitrogen overnight, quenched with water, ethyl acetate (50 mL x 5), the combined extracts were washed with brine, dried over anhydrous sodium sulfate The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the title compound XSD1-089 (24 mg, 20% yield of the two-step reaction).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.94 (s, 1H), 7.55-7.61 (m, 2H), 7.36-7.40 (m, 1H), 7.25-7.29 (m, 1H), 7.11 (s, 1H), 6.85-6.87 (m, 2H), 5.32-5.34 (m, 1H), 4.97-4.98 (m, 1H), 4.50-4.51 (m, 1H), 3.45-3.49 (m, 2H), 3.16-3.19 (m, 1H), 1.98-2.00 (m , 1H) 1.14-1.76 (m, 23H)

HPLC purity: @214nm 99.53%, @254nm 99.21%

MS: m/z 464.1 [M+1]

Example 23 Synthesis of XSD1-090

1):

Intermediate 1 (100 mg, 0.275 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (91.5 mg, 0.412 mmol), O-(7-nitrobenzotriazole)-N, N,N',N'-tetramethyluronium hexafluorophosphate (157.4 mg, 0.412 mmol) and diisopropylethylamine (106.3 mg, 0.824 mmol) were reacted overnight at room temperature under nitrogen atmosphere and quenched with water. The mixture was extracted with ethyl acetate (50 mL, EtOAc). The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-090 (60 mg, yield 40.8%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.94-7.98 (m, 2H), 7.73-7.75 (m, 2H), 7.56-7.60 (m, 2H), 7.34-7.36 (m, 3H), 7.28 (m, 3H), 7.11 (m, 1H), 5.32 (m, 1H), 4.78-4.99 (m, 1H), 4.25-4.27 (m, 2H), 3.42 (m, 1H), 1.99-2.01 (m, 2H), 1.24-1.79 (m, 14H)

HPLC purity: @214nm 99.08%, @254nm 98.40%

MS: m/z 535.1 [M+1]

Example 24 Synthesis of XSD1-091

1):

Intermediate 1 (100 mg, 0.275 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (97.3 mg, 0.412 mmol), O-(7-nitrobenzotriazole)-N, N,N',N'-tetramethyluronium hexafluorophosphate (157.4 mg, 0.412 mmol) and diisopropylethylamine (106.3 mg, 0.824 mmol) were reacted overnight at room temperature under nitrogen atmosphere and quenched with water. The mixture was extracted with ethyl acetate (50 mL, EtOAc). The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-091 (15 mg, yield 10%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.60 (m, 1H), 7.93 (m, 1H), 7.83 (m, 1H), 7.55-7.60 (m, 2H), 7.36-7.39 (m, 1H), 7.25-7.28 (m, 1H), 7.10- 7.13(m,5H), 5.32(m,1H), 4.96-4.97(m,1H), 4.16-4.17(m,2H), 3.42(m,1H), 2.95(m,3H), 2.00(m, 2H), 1.24-1.78 (m, 14H)

HPLC purity: @214nm 99.41%, @254nm 99.15%

MS: m/z 549.3 [M+1]

Example 25 Synthesis of XSD1-092

1):

Intermediate 1 (100 mg, 0.275 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (66 mg, 0.412 mmol), O-(7-nitrobenzotriazole)-N, N , N', N'-tetramethylurea hexafluorophosphate (157.4 mg, 0.412 mmol) and diisopropylethylamine (106.3 mg, 0.824 mmol), reacted at room temperature under nitrogen overnight, quenched with water, acetic acid The ethyl ester (50 mL, EtOAc) was evaporated. The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-092 (10 mg, yield 10%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.93 (m, 1H), 7.55-7.60 (m, 2H), 7.36-7.42 (m, 2H), 7.26-7.28 (m, 1H), 7.10 (m, 1H), 6.85 (m, 2H), 5.32 ( m, 1H), 4.96-4.98 (m, 1H), 3.37-3.42 (m, 3H), 3.03-3.07 (m, 2H), 1.78 (m, 2H), 1.24-1.75 (m, 14H)

HPLC purity: @214nm 99.08%, @254nm 98.40%

MS: m/z 473.0 [M+1]

Example 26 Synthesis of XSD1-093

1):

Compound 2 (100 mg, 0.625 mmol) was dissolved in dichloromethane (2 mL), triethylamine (126.3 mg, 1.25 mmol). MsCl (85.5 mg, 0.75 mmol) was dissolved in 1 ml of dichloromethane, added dropwise to the reaction system, and reacted at room temperature for 1 h. After quenching with water, dichloromethane (50 mL EtOAc) was evaporated. The crude product was used directly in the next reaction.

2):

The crude compound 3 was dissolved in 1 mL of 1,4-dioxane, and a solution of HCl in 1,4-dioxane (2 mL, 4 mol/L) was added under ice-cooling, and stirred at room temperature for 2 h. The crude product was used directly in the next reaction.

3):

Intermediate 1 (100 mg, 0.275 mmol) was dissolved in 3 mL of N,N'-dimethylformamide and compound 4 (71.7 mg, 0.412 mmol), O-(7-nitrobenzotriazole)-N, N,N',N'-tetramethyluronium hexafluorophosphate (157.4 mg, 0.412 mmol) and diisopropylethylamine (106.3 mg, 0.824 mmol) were reacted overnight at room temperature under nitrogen atmosphere and quenched with water. The mixture was extracted with ethyl acetate (50 mL, EtOAc). The crude product was used directly in the next reaction.

4):

The crude product of compound 5 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added under ice-cooling, and the reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-093 (13 mg, yield 10%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.93 (m, 1H), 7.51-7.60 (m, 2H), 7.26-7.40 (m, 3H), 7.10 (m, 1H), 7.00-7.02 (m, 1H), 5.32 (m, 1H), 4.96- 4.98 (m, 1H), 3.40-3.43 (m, 1H), 3.09-3.13 (m, 2H), 2.90-2.96 (m, 2H), 2.87 (m, 3H), 1.93-2.17 (m, 2H), 1.28-1.76(m,14H)

HPLC purity: @214nm 93.30%, @254nm 90.40%

MS: m/z 487.0 [M+1]

Example 27 Synthesis of XSD1-094

1):

Intermediate 1 (90 mg, 0.257 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (85.6 mg, 0.386 mmol), O-(7-nitrobenzotriazole)-N, N,N',N'-tetramethyluronium hexafluorophosphate (147.3 mg, 0.386 mmol) and diisopropylethylamine (99.5 mg, 0.771 mmol) were reacted overnight at room temperature under nitrogen atmosphere and quenched with water. The mixture was extracted with ethyl acetate (50 mL, EtOAc). The crude product was used directly in the next reaction.

2):

The crude compound was dissolved in 3 mL of methanol, and NaBH ₄ (51.4 mg, 1.286 mmol) was added under ice-cooling, and the reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The mixture was extracted with chloroform (30 mL×3). The crude product was purified by pre-HPLC to give the title compound XSD1-094 (60 mg, yield 40.8%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.94-8.02 (m, 2H), 7.72-7.74 (m, 2H), 7.55-7.60 (m, 2H), 7.27-7.40 (m, 4H), 7.10-7.13 (m, 2H), 5.34 (m, 1H) ), 5.32 (m, 1H), 4.26-4.27 (m, 2H), 3.48-3.51 (m, 1H), 3.14 - 3.18 (m, 1H), 1.99-2.01 (m, 2H), 1.30-1.67 (m , 12H)

HPLC purity: @214nm 98.22%, @254nm 98.62%

MS: m/z 521.2 [M+1]

Example 28 Synthesis of XSD1-095

1):

Intermediate 1 (100 mg, 0.275 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (50.3 mg, 0.412 mmol), O-(7-nitrobenzotriazole)-N, N,N',N'-tetramethylurea hexafluorophosphate (157.4 mg, 0.412 mmol) and diisopropyl B The amide (106.3 mg, 0.824 mmol) was evaporated. The crude product was used directly in the next reaction.

2):

Compound 2 (387.4 mg, 2.75 mmol) was dissolved in 3 mL of dichloromethane and then cooled to zero with ice water. t-BuOH (203.3 mg, 2.75 mmol) was dissolved in 2 mL of dichloromethane and added dropwise to the reaction. The reaction was kept at zero temperature for 30 min and used directly for the next reaction.

3):

The crude compound 4 was dissolved in 3 mL of dichloromethane, triethylamine (305.2 mg, 3.02 mmol) was then weighed and cooled to zero. The crude compound 3 was added dropwise to the reaction system. The reaction was carried out at room temperature overnight. The reaction solution was dried under reduced pressure and the crude material was applied to the next step.

4):

The crude compound 5 was dissolved in 2 mL of 1,4-dioxane, stirred in an ice water bath to zero temperature, and a solution of HCl in 1,4-dioxane (10 mL, 4 mol/L) was added. The reaction was carried out at room temperature overnight. The reaction mixture was evaporated to dryness crystall

5):

Compound 6 was dissolved in 1 mL of methanol, and NaBH ₄ (20 mg, 0.5 mmol) was added and the mixture was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). (30 mL×3), the combined extracts were washed with brine, dried over anhydrous sodium sulfate

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.35 (m, 1H), 8.22 (m, 1H), 7.81-7.81 (m, 1H), 7.64-7.65 (m, 2H), 7.41-7.42 (m, 1H), 7.27-7.31 (m, 2H), 7.17-7.21 (m, 4H), 7.02-7.08 (m, 2H), 5.41 (m, 1H), 5.03 (m, 1H), 4.14 (m, 2H), 3.41-3.42 (m, 1H), 1.97- 2.03 (m, 2H), 1.19-1.79 (m, 14H)

HPLC purity: @214nm 95.13%, @254nm 97.34%

MS: m/z 550.2 [M+1]

Example 29 Synthesis of XSD1-096

1):

Intermediate 1 (100 mg, 0.275 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (50.3 mg, 0.412 mmol), O-(7-nitrobenzotriazole)-N, N,N',N'-tetramethyluronium hexafluorophosphate (157.4 mg, 0.412 mmol) and diisopropylethylamine (106.3 mg, 0.824 mmol) were reacted overnight at room temperature under nitrogen atmosphere and quenched with water. The mixture was extracted with ethyl acetate (50 mL, EtOAc). The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD 1- s (20 mg, yield 15.4%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.93 (m, 1H), 7.55-7.62 (m, 3H), 7.36-7.39 (m, 1H), 7.26-7.28 (m, 1H), 7.10 (m, 1H), 6.83-6.85 (m, 2H), 6.46-6.48 (m, 2H), 5.32 (m, 1H), 4.95-4.96 (m, 1H), 4.86 (m, 2H), 4.02-4.04 (m, 2H) 3.41 (m, 1H), 1.99 (m) , 2H), 1.28-1.79 (m, 14H)

HPLC purity: @214nm 94.35%, @254nm 92.97%

MS: m/z 471.1 [M+1]

Example 30 Synthesis of XSD1-097

1):

Intermediate 1 (100 mg, 0.275 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (77.5 mg, 0.412 mmol), O-(7-nitrobenzotriazole)-N, N,N',N'-tetramethyluronium hexafluorophosphate (157.4 mg, 0.412 mmol) and diisopropylethylamine (106.3 mg, 0.824 mmol) were reacted overnight at room temperature under nitrogen atmosphere and quenched with water. The mixture was extracted with ethyl acetate (50 mL, EtOAc). The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-097 (30 mg, yield: 21.8%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

8.16-8.18(m,2H), 8.06(m,1H), 7.94(m,1H), 7.56-7.60(m,2H),7.44-7.46(m,2H),7.38(m,1H),7.27- 7.29 (m, 1H), 7.02 (m, 1H), 5.33 (m, 1H), 4.99-5.00 (m, 1H), 4.31-4.33 (m, 2H), 3.42 (m, 1H), 1.97-2.00 ( m, 2H), 1.40-1.80 (m, 14H)

HPLC purity: @214nm 95.09%, @254nm 95.45%

MS: m/z 501.4 [M+1]

Example 31 Synthesis of XSD1-098

1):

Intermediate 1 (300 mg, 0.824 mmol) was dissolved in 5 mL of tert-butanol, followed by triethylamine (91.5 mg, 0.91 mmol), diphenyl azide (272.0 mg, 0.989 mmol), 75 ° under nitrogen. After overnight, the reaction mixture was dried under reduced pressure and purified by chromatography to give Compound 2.

2):

Compound 2 (60 mg, 0.138 mmol) was dissolved in 1 mL of 1,4-dioxane, and THF (1 mL, 4 mol/L) was added to EtOAc. The reaction solution was dried under reduced pressure to give Compound 3.

3):

The crude product of compound 3 was dissolved in 2 mL of methanol, and NaBH ₄ (27.6 mg, 0.690 mmol) was added under ice-cooling, and the reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The mixture was extracted with chloroform (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-098 (15 mg, yield 5%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.91-7.92 (m, 1H), 7.47-7.60 (m, 2H), 7.35-7.39 (m, 1H), 7.24-7.28 (m, 1H), 7.10-7.13 (m, 1H), 5.31 (m, 1H) ), 4.94.-4.95 (m, 1H), 3.38-3.40 (m, 1H), 2.54 (m, 2H), 1.95-2.01 (m, 2H), 1.23-1.77 (m, 14H)

HPLC purity: @214nm 98.60%, @254nm 98.27%

MS: m/z 338.3 [M+1]

Example 32 Synthesis of XSD1-117

1):

Compound 7 (100 mg, 1.75 mmol) was dissolved in dichloromethane (3 mL), triethylamine (531 g, 5.26 mmol). Add triphosgene (173 mg, 0.585 mmol), and react under nitrogen for 3 h at room temperature. After confirming the completion of the reaction of the raw materials, the reaction solution was directly used for the next reaction.

2):

Compound 6 (80 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL). A one-step reaction solution was added dropwise, and the reaction was allowed to proceed overnight at room temperature under a nitrogen atmosphere. After quenching with water, dichloromethane (50 mL EtOAc) was evaporated. The crude product was used directly in the next reaction.

3):

The crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-117 (24 mg, yield 26.4%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.94 (m, 1H), 7.55-7.60 (m, 2H), 7.36-7.40 (m, 1H), 7.26-7.28 (m, 1H), 7.11 (m, 1H), 5.82-5.83 (m, 1H), 5.34(m,1H), 5.27(m,1H),4.83-4.84(m,1H), 3.45-3.46(m,1H),2.33-2.36(m,1H), 2.00(m,1H),1.69- 1.71 (m, 7H), 1.38-1.47 (m, 6H), 0.48-0.51 (m, 2H), 0.22-0.25 (m, 2H)

HPLC purity: @214nm 99.10%, @254nm 99.48%

MS: m/z 407.3 [M+1]

Example 33 Synthesis of XSD1-124

1):

Compound 6 (80.0 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL). A solution of the compound 6a (36.8 mg, 0.269 mmol) in dichloromethane (2 mL), EtOAc (EtOAc m. Dry with sodium sulfate and spin dry under reduced pressure. The crude product was used directly in the next reaction.

2):

The crude compound 7 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-124 (11 mg, yield 10.4%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.26 (m, 1H), 7.90-7.94 (m, 1H), 7.55-7.60 (m, 2H), 7.36-7.40 (m, 1H), 7.25-7.33 (m, 3H), 7.11-7.13 (m, 1H) ), 6.99-7.04 (m, 2H), 5.78 (m, 1H), 5.32-5.36 (m, 1H), 4.85-4.87 (m, 1H), 3.46-3.50 (m, 1H), 2.02-1.95 (m , 7H), 1.74-1.78 (m, 7H), 1.31-1.54 (m, 2H)

HPLC purity: @214nm 96.13%, @254nm 98.2%

MS: m/z 457.4 [M+1]

Example 34 Synthesis of XSD1-125

1):

Compound 6 (80.0 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL). Stir at room temperature for 15 min. A solution of the compound 6a (41.1 mg, 0.269 mmol) in dichloromethane (2 mL), EtOAc (EtOAc m. Dry with sodium sulfate and spin dry under reduced pressure. The crude product was used directly in the next reaction.

2):

The crude compound 7 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-125 (11 mg, yield: 14.8%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

8.40 (m, 1H), 7.94 (m, 1H), 7.55-7.60 (m, 2H), 7.33-7.40 (m, 3H), 7.21-7.29 (m, 3H), 7.11 (m, 1H), 5.96 ( m,1H), 5.34 (m, 1H), 5.01 (m, 1H), 3.47-3.48 (m, 1H), 1.98 (m, 2H), 1.74-1.78 (m, 6H), 1.39-1.54 (m, 8H)

HPLC purity: @214nm 93.59%, @254nm 96.70%

MS: m/z 491.1 [M+1]

Example 35 Synthesis of XSD1-126

1):

Compound 1 (80.0 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL). A solution of the compound 1a (33.6 mg, 0.269 mmol) in dichloromethane (2 mL), EtOAc (EtOAc m. Dry with sodium sulfate and spin dry under reduced pressure. The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-126 (4.1 mg, yield: 8.9%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.35 (m, 1H), 7.90-7.54 (m, 3H), 7.38-7.11 (m, 7H), 6.15 (m, 1H), 5.94 (m, 1H), 5.21-4.99 (m, 2H), 3.32 ( m,1H), 1.99-1.96 (m, 2H), 1.87-1.49 (m, 14H)

HPLC purity: @214nm 97.45%, @254nm 99.27%

MS: m/z 475.3 [M+1]

Example 36 Synthesis of XSD1-133

1):

2):

The crude compound 2 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD 1-133 (20 mg, yield 19.9%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.92 (m, 1H), 7.59-7.54 (m, 2H), 7.36-7.10 (m, 3H), 6.15 (m, 1H), 5.51-5.49 (m, 1H), 5.46-5.40 (m, 2H), 4.99(m,1H), 3.47-3.32(m,1H), 3.29(m,1H),1.87-1.70(m,2H),1.67-1.50(m,14H),1.27-0.98(m,10H)

HPLC purity: @214nm 94.91%, @254nm 98.87%

MS: m/z 463.4 [M+1]

Example 37 Synthesis of XSD1-141

1):

Compound 7 (100 mg, 0.741 mmol) was dissolved in dichloromethane (3 mL) and triethylamine (224 mg, 2.22 <RTIgt; Triphosgene (73.3 mg, 0.247 mmol) was added and the mixture was reacted under nitrogen for 3 h at room temperature. After confirming the completion of the reaction of the raw materials, the reaction solution was directly used for the next reaction.

2):

3):

The crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD 1-141 (20.5 mg, yield 15.1%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.92 (m, 1H), 7.53-7.59 (m, 2H), 7.35-7.39 (m, 1H), 7.24-7.31 (m, 5H), 7.10-7.16 (m, 2H), 6.06 (m, 1H), 5.48 (m, 1H), 5.32-5.34 (m, 1H), 4.82-4.83 (m, 1H), 3.45 (m, 1H), 2.02 (m, 1H), 1.62-1.69 (m, 7H), 1. 1.47 (m, 12H)

HPLC purity: @214nm 99.18%, @254nm 99.09%

MS: m/z 485.4 [M+1]

Example 38 Synthesis of XSD1-142

1):

Compound 7 (100 mg, 0.935 mmol) was dissolved in dichloromethane (3 mL), triethylamine (283 mg, 2. Add triphosgene (92.5 mg, 0.312 mmol), and react under nitrogen for 3 h at room temperature. After confirming the completion of the reaction of the raw materials, the reaction solution was directly used for the next reaction.

2):

2):

The crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-142 (10 mg, yield 9.8%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

8.11 (m, 1H), 7.94 (m, 1H), 7.55-7.60 (m, 2H), 7.36-7.40 (m, 1H), 7.27-7.29 (m, 1H), 7.18-7.20 (m, 2H), 7.11-7.14(m,1H), 6.97-6.99(m,2H), 5.77(m,1H),5.32-5.34(m,1H),4.82-4.83(m,1H), 3.47(m,1H), 2.19 (m, 3H), 2.02 (m, 1H), 1.71-1.77 (m, 7H), 1.42-1.51 (m, 6H)

HPLC purity: @214nm 99.25%, @254nm 98.70%

MS: m/z 457.4 [M+1]

Example 39 Synthesis of XSD1-143

1):

Compound 7 (100 mg, 0.286 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 7a (46.3 mg, 0.343 mmol), O-(7-nitrobenzotriazole)-N, N , N', N'-tetramethylurea hexafluorophosphate (131 mg, 0.343 mmol) and diisopropylethylamine (86.6 mg, 0.857 mmol), reacted at room temperature under nitrogen overnight, quenched with water, ethyl acetate The mixture was extracted with EtOAc (EtOAc) (EtOAc) The crude product was used directly in the next reaction.

2):

The crude product of compound 8 was dissolved in 3 mL of methanol, and NaBH ₄ (55 mg, 1.375 mmol) was added under ice-cooling, and the reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD 1-43 (18.3 mg, yield: 13.7%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.99 (m, 1H), 7.56-7.61 (m, 2H), 7.37-7.40 (m, 1H), 7.21-7.30 (m, 5H), 7.11-7.16 (m, 3H), 5.36 (m, 1H), 4.87-4.89 (m, 1H), 3.49 (m, 1H), 2.08 (m, 1H), 1.70 (m, 1H), 1.62-1.66 (m, 6H), 1.50 (m, 6H), 1.32-1.47 ( m,6H)

HPLC purity: @214nm 97.97%, @254nm 98.14%

MS: m/z 470.3 [M+1]

Example 40 Synthesis of XSD1-144

1):

Compound 7 (100 mg, 0.752 mmol) was dissolved in dichloromethane (3 mL) and triethylamine (228 mg, 2.26 <RTIgt; Triphosgene (74.4 mg, 0.251 mmol) was added and the reaction was carried out for 3 h at room temperature under nitrogen. After confirming the completion of the reaction of the raw materials, the reaction solution was directly used for the next reaction.

2):

3):

The crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD 1-144 (10 mg, yield 9.3%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.93 (m, 1H), 7.54-7.60 (m, 2H), 7.35-7.39 (m, 1H), 7.23-7.28 (m, 3H), 7.08-7.13 (m, 4H), 6.51 (m, 1H), 5.31-5.34(m,2H),4.84-4.86(m,1H),3.44-3.47(m,1H), 2.00(m,1H),1.63-1.70(m,7H),1.39-1.45(m,6H) ), 1.05-1.07 (m, 4H)

HPLC purity: @214nm 99.42%, @254nm 97.20%

MS: m/z 483.3 [M+1]

Example 41 Synthesis of XSD1-145

1):

Compound 7 (100 mg, 0.725 mmol) was dissolved in dichloromethane (3 mL) and triethylamine (220 mg, 2.17 mmol). Triphosgene (71.7 mg, 0.242 mmol) was added and the mixture was reacted under nitrogen for 3 h at room temperature. After confirming the completion of the reaction of the raw materials, the reaction solution was directly used for the next reaction.

2):

3):

The crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD 1- s (4 mg, yield: 2.9%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

8.95 (m, 1H), 8.01-8.04 (m, 2H), 7.86 (m, 1H), 7.45-7.53 (m, 4H), 7.28-7.30 (m, 1H), 7.19-7.21 (m, 1H), 7.03(m,1H),6.06(m,1H),5.32-5.34(m,1H),4.81-4.82(m,1H), 3.46-3.51(m,1H),1.91-1.94(m,1H), 1.64-1.72 (m, 7H), 1.38-1.48 (m, 6H)

HPLC purity: @214nm 98.93%, @254nm 98.17%

MS: m/z 488.3 [M+1]

Example 42 Synthesis of XSD1-146

1):

Compound 7 (100 mg, 0.813 mmol) was dissolved in dichloromethane (3 mL) and triethylamine (246 mg, 2.44 mmol). Triphosgene (80.5 mg, 0.271 mmol) was added, and the mixture was reacted under nitrogen for 3 h at room temperature. Check the board to confirm the raw material After completion, the reaction solution was used directly for the next reaction.

2):

3):

The crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-146 (8 mg, yield 7.6%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

8.01 (m, 1H), 7.94 (m, 1H), 7.55-7.61 (m, 2H), 7.36-7.40 (m, 1H), 7.20-7.29 (m, 3H), 7.11 (m, 1H), 6.76- 6.79 (m, 2H), 5.70 (m, 1H), 5.32-5.36 (m, 1H), 4.87-4.89 (m, 1H), 3.67 (m, 3H), 3.47-3.48 (m, 1H), 2.03 ( m, 1H), 1.73-1.77 (m, 7H), 1.39-1.50 (m, 6H)

HPLC purity: @214nm 97.95%, @254nm 99.31%

MS: m/z 473.4 [M+1]

Example 43 Synthesis of XSD1-147

1):

Compound 7 (100 mg, 0.775 mmol) was dissolved in dichloromethane (3 mL), triethylamine (235 mg, 2.33 mmol). Triphosgene (76.7 mg, 0.259 mmol) was added and the mixture was reacted under nitrogen for 3 h at room temperature. After confirming the completion of the reaction of the raw materials, the reaction solution was directly used for the next reaction.

2):

3):

The crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD 1-147 (10 mg, yield 9.3%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

8.0. 6.94 (m, 1H), 6.34 (m, 1H), 5.34 (m, 1H), 4.88-4.90 (m, 1H), 3.47-3.48 (m, 1H), 2.03 (m, 1H), 1.74-1.78 ( m,7H), 1.39-1.51 (m, 6H)

HPLC purity: @214nm 99.72%, @254nm 99.55%

MS: m/z 479.3 [M+1]

Example 44 Synthesis of XSD1-148

1):

Compound 1 (100 mg, 0.621 mmol) was dissolved in dichloromethane (3 mL), triethylamine (188 mg, 1.86 mmol). Add triphosgene (61.5 mg, 0.207 mmol), and react under nitrogen for 3 h at room temperature. After confirming the completion of the reaction of the raw materials, the reaction solution was directly used for the next reaction.

2):

Compound 2' (80 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL). A one-step reaction solution was added dropwise, and the reaction was allowed to proceed overnight at room temperature under a nitrogen atmosphere. After quenching with water, dichloromethane (50 mL EtOAc) was evaporated. The crude product was used directly in the next reaction.

3):

The crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD 1-148 (20 mg, yield: 17.5%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.26 (m, 1H), 8.66 (m, 1H), 7.49-7.60 (m, 2H), 7.36-7.40 (m, 1H), 7.27-7.14 (m, 6H), 5.98 (m, 1H), 5.34 ( m, 1H), 4.87-4.88 (m, 1H), 3.48 (m, 1H), 2.00 (m, 2H), 1.75-1.79 (m, 6H), 1.43-1.52 (m, 8H)

HPLC purity: @214nm 97.41%, @254nm 95.07%

MS: m/z 525.3 [M+1]

Example 45 Synthesis of XSD1-149

1):

2):

3):

The crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD 1-149 (10 mg, yield 9.8%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.93 (m, 1H), 7.55-7.60 (m, 2H), 7.36-7.40 (m, 1H), 7.25-7.32 (m, 3H), 7.20-7.21 (m, 3H), 7.10 (m, 1H), 6.05-6.06(m,1H),5.57(m,1H),5.33(m,1H),4.85-4.86(m,1H),4.12-4.13(m,2H), 3.46(m,1H),2.05( m, 1H), 1.69-1.73 (m, 7H), 1.40-1.51 (m, 6H)

HPLC purity: @214nm 99.76%, @254nm 99.73%

MS: m/z 457.4 [M+1]

Example 46 Synthesis of XSD1-150

1):

Intermediate 1 (40 mg, 0.109 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (72 mg, 1.0 mmol), O-(7-nitrobenzotriazole)-N, N , N', N'-tetramethylurea hexafluorophosphate (100 mg, 0.50 mmol) and diisopropylethyl The amine (250 mg, 3.3 mmol), EtOAc (EtOAc m. The crude product was used directly in the next reaction.

2):

The crude compound was dissolved in 3 mL of methanol, and NaBH4 (55 mg, 1.375 mmol) was added, and the mixture was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). (30 mL×3), the combined extracts were washed with brine, dried over anhydrous sodium sulfate The crude product was purified by pre-HPLC to give the object compound XSD 1-150 (4 mg, 16% yield of the two-step reaction).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

8.06-7.9 (m, 2H), 7.87-7.84 (m, 2H), 7.74-7.50 (m, 2H), 7.27-7.29 (m, 3H), 7.11-7.14 (m, 3H), 5.09 (m, 2H) ), 4.24 (m, 1H), 1.89-1.88 (m, 2H) 1.75-1.79 (m, 8H), 1.43-1.52 (m, 6H), 1.23-1.05 (m, 4H)

HPLC purity: @214nm 98.22%, @254nm 98.42%

MS: m/z 482.4 [M+1]

Example 47 Synthesis of XSD1-151

1):

2):

3):

The crude compound 3 was dissolved in 10 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD 1-151 (2.6 mg, yield 7.2%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.27 (m, 1H), 8.16 (m, 2H), 7.87-7.84 (m, 2H), 7.74-7.50 (m, 3H), 7.27-7.29 (m, 2H), 7.11-7.14 (m, 1H), 5.91 (m, 1H), 5.69 (m, 1H), 4.87-4.88 (m, 1H), 3.67 (m, 3H) 3.48 (m, 1H), 1.89-1.88 (m, 2H) 1.75-1.79 (m, 8H), 1.43-1.52 (m, 6H) HPLC purity: @214nm 98.22%, @254nm 98.42%

MS: m/z 487.4 [M+1]

Example 48 Synthesis of XSD1-152

1):

2):

3):

The crude compound 3 was dissolved in 10 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-153 (3.7mg, yield 8.2%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.27(m,1H), 8.16(m,2H), 7.87-7.84(m,2H), 7.74-7.50(m,2H), 7.27-7.29(m,2H),7.11-7.14(m,1H), 5.91 (m, 1H), 5.69 (m, 1H), 4.87-4.88 (m, 1H), 3.48 (m, 1H), 1.89-1.88 (m, 2H) 1.75-1.79 (m, 8H), 1.43-1.52 (m, 6H)

HPLC purity: @214nm 99.01%, @254nm 99.12%

MS: m/z 493.3 [M+1]

Example 49 Synthesis of XSD1-153

1):

2):

3):

The crude compound 3 was dissolved in 10 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-153 (2.9mg, yield 7.5%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

9.27(m,1H),8.16(m,1H),7.87-7.84(m,6H),7.74-7.50(m,1H), 7.27-7.29(m,1H),7.11-7.14(m,1H), 5.91 (m, 1H), 5.69 (m, 1H), 4.87-4.88 (m, 1H), 3.48 (m, 1H), 2.00 (m, 3H), 1.89-1.88 (m, 2H) 1.75-1.79 (m , 8H), 1.43-1.52 (m, 6H)

HPLC purity: @214nm 99.01%, @254nm 99.58%

MS: m/z 471.3 [M+1]

Example 50 Synthesis of XSD1-075

1):

Intermediate 1 (91 mg, 0.25 mmol) was dissolved in 5 mL of N,N'-dimethylformamide, and compound 1a (25.5 mg, 0.3 mmol), O-(7-nitrobenzotriazole)-N, N,N',N'-tetramethyluronium hexafluorophosphate (150 mg, 0.39 mmol) and diisopropylethylamine (52 mg, 0.77 mmol), reacted at room temperature under nitrogen overnight, quenched with water, ethyl acetate The mixture was extracted with EtOAc (EtOAc) (EtOAc) The crude product was used directly in the next reaction.

2):

The crude product of compound 2 was dissolved in 5 mL of methanol, and NaBH ₄ (42 mg, 1.12 mmol) was added under ice-cooling, and the reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-075 (36 mg, yield: 33.4%).

H NMR XSD 1-075 (DMSO, 400 M): 9.33 (s, 1H), 7.85-7.91 (m, 2H), 7.66-7.77 (m, 1H), 7.49-7.66 (m, 2H), 6.96-7.00 (m) , 1H), 5.71-5.80 (m, 1H), 3.92-3.98 (m, 1H), 3.47-3.49 (m, 1H), 2.50-3.13 (m, 1H) 1.30-2.10 (m, 24H)

HPLC purity: @214nm 96.9%, @254nm 99.6%

MS Calcd: 433, MS Found: 434.3 [M+H] ⁺ .

Example 51 Synthesis of XSD1-081

The method of synthesizing XSD1-081 with XSD1-074

1):

Intermediate 1 (91 mg, 0.25 mmol) was dissolved in 5 mL of N,N'-dimethylformamide, and compound 1a (16.0 mg, 0.3 mmol), O-(7-nitrobenzotriazole)-N, N,N',N'-tetramethyluronium hexafluorophosphate (150 mg, 0.39 mmol) and diisopropylethylamine (52 mg, 0.77 mmol), reacted at room temperature under nitrogen overnight, quenched with water, ethyl acetate Ester (50mL x5) extraction, combined The extract was washed with brine, dried over anhydrous sodium sulfate The crude product was used directly in the next reaction.

2):

The crude product of compound 2 was dissolved in 5 mL of methanol, and NaBH ₄ (42 mg, 1.12 mmol) was added under ice-cooling, and the reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-081 (30 mg, yield: 33.0%).

</ RTI> <RTIgt; ), 6.58 (S, 1H), 5.69-5.72 (m, 1H), 5.16 (s, 1H), 3.46-3.68 (m, 1H), 1.29-2.12 (m, 16H)

HPLC purity: @214nm 97.0%, @254nm 94.0%

MS Calcd: 365, MS Found: 366.3 [M+H] ⁺ .

Example 52 Synthesis of XSD1-082

The method of synthesizing XSD1-082 with the method of XSD1-074

1):

Intermediate 1 (91 mg, 0.25 mmol) was dissolved in 5 mL of N,N'-dimethylformamide, and compound 1a (20.3 mg, 0.3 mmol), O-(7-nitrobenzotriazole)-N, N,N',N'-tetramethyluronium hexafluorophosphate (150 mg, 0.39 mmol) and diisopropylethylamine (52 mg, 0.77 mmol), reacted at room temperature under nitrogen overnight, quenched with water, ethyl acetate The mixture was extracted with EtOAc (EtOAc) (EtOAc) The crude product was used directly in the next reaction.

2):

The crude product of compound 2 was dissolved in 5 mL of methanol, and NaBH ₄ (42 mg, 1.12 mmol) was added under ice-cooling, and the reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-074 (32 mg, yield: 33.9%).

H NMR XSD 1-082 (DMSO, 400 M): 9.29 (s, 1 H), 7.51-7.57 (m, 2H), 7.72-7.74 (m, 1H), 7.84-7.89 (m, 2H), 5.69-75.72 (m) , 1H), 5.17 (m, 1H), 3.40-3.49 (m, 1H), 1.33-2.08 (m, 19H)

HPLC purity: @214nm 99.2%, @254nm 99.7%

MS Calcd: 379, MS Found: 380.3 [M+H] ⁺ .

Example 53 Synthesis of XSD1-083

The method of synthesizing XSD1-083 with the method of XSD1-074

1):

Intermediate 1 (91 mg, 0.25 mmol) was dissolved in 5 mL of N,N'-dimethylformamide, and compound 1a (24.5 mg, 0.3 mmol), O-(7-nitrobenzotriazole)-N, N,N',N'-tetramethyluronium hexafluorophosphate (150 mg, 0.39 mmol) and diisopropylethylamine (52 mg, 0.77 mmol), reacted at room temperature under nitrogen overnight, quenched with water, ethyl acetate The mixture was extracted with EtOAc (EtOAc) (EtOAc) The crude product was used directly in the next reaction.

2):

The crude product of compound 2 was dissolved in 5 mL of methanol, and NaBH ₄ (42 mg, 1.12 mmol) was added under ice-cooling, and the reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD 1- s (33 mg, yield 33.7%).

H NMR XSD 1-083 (DMSO, 400 M): 9.31 (s, 1H), 7.85-7.90 (m, 2H), 7.72-7.74 (m, 1H), 7.51-7.55 (m, 2H), 5.69-5.73 (m) , 1H), 5.17 (m, 1H), 3.47-3.49 (m, 1H), 2.87 (s, 6H), 1.34 - 2.87 (m, 16H)

HPLC purity: @214nm 99.8%, @254nm 99.8%

MS Calcd: 393, MS Found: 394.3 [M+H] ⁺ .

Example 54 Synthesis of XSD1-031

1):

Compound 1 (170 mg, 0.4 mmol), compound 2 (73 mg, 0.4 mmol) and sodium ethoxide (55 mg, 0.8 mmol) were dissolved in THF / EOH = 3 mL / 1 ml and stirred at room temperature overnight. The mixture was extracted with EtOAc (EtOAc)EtOAc. The crude product was beaten with PE/EA = (5/1), filtered, and dried to give product compound 3 (140 mg, yield 61%).

MS: m/z 575.4 [M+1]

2):

Compound 3 (140 mg, 0.24 mmol) was dissolved in methanol (5 mL), EtOAc (EtOAc) The reaction mixture was dried with EtOAc (EtOAc)EtOAc. The crude product was 120 mg and used directly in the next reaction.

MS: m/z 333.4 [M+1]

LC-MS:

3):

The crude compound (60 mg, 0.12 mmol) was dissolved in methanol (10 mL), and NaBH ₄ (14 mg, 0.36 mmol) was added, and the reaction was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL). Most of the methanol was removed, washed with dichloromethane (20 mL×2), brine (EtOAc) The crude product was purified by pre-HPLC to give the object compound XSD 1-031 (15 mg, yield: 25%).

^{1 H-NMR (400MHz, DMSO} -d6): δppm 7.95 (m, 1H), 7.61-7.56 (m, 2H), 7.40-7.25 (m, 2H), 7.10 (m, 1H), 5.35 (m, 1H ), 4.95-4.85 (m, 1H), 2.00-1.20 (m, 12H).

HPLC purity: @214nm 90.33%, @254nm 97.55%

MS: m/z 335.4 [M+1]

Example 55 Synthesis of XSD1-100

1):

Compound INT1 (45.7 mg, 0.336 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, followed by O-(7-nitrobenzotriazole)-N,N,N',N'-tetra Base urea hexafluorophosphate (128 mg, 0.336 mmol), compound Ia (80.0 mg, 0.336 mmol) and diisopropylethylamine (116 mg, 0.896 mmol), reacted at room temperature under nitrogen overnight, quenched with water, ethyl acetate The mixture was extracted with EtOAc (EtOAc) (EtOAc) The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-100 (20 mg, yield: 20.2%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.92 (m, 1H), 7.51-7.60 (m, 3H), 7.35-7.37 (m, 1H), 7.19-7.29 (m, 6H), 7.10 (m, 1H), 5.33 (m, 1H), 4.84 4.86 (m, 1H), 3.46 (m, 1H), 3.37 (m, 2H), 2.09 (m, 1H), 1.72-1.76 (m, 7H), 1.38-1.47 (m, 6H)

HPLC purity: @214nm 96.18%, @254nm 95.48%

MS: m/z 442.3 [M+1]

Example 56 Synthesis of XSD1-101

1):

The crude compound INT (7 g) was dissolved in 10 mL of 1,4-dioxane, and HCl/dioxane (20 mL, 4 mol/L) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 2 h, and the reaction solution was directly dried to give a crude compound INT1. (6g).

2):

The crude compound INT1 (80.0 mg) was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). Most of the methanol was removed and extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-101 (20 mg, yield: 27.6%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.68-7.86(m,6H),7.44-7.53(m,2H),5.63-5.66(m,1H), 5.15-5.16(m,1H),3.54-3.57(m,1H),2.07-2.08(m , 1H), 1.90- 1.93 (m, 1H), 1.59-1.66 (m, 6H), 1.49-1.56 (m, 6H)

HPLC purity: @214nm 96.18%, @254nm 95.48%

MS: m/z 324.4 [M+1]

Example 57 Synthesis of XSD1-102

1):

Compound 1 (10.0 g, 0.0472 mol) was dissolved in 50.0 mL of tert-butanol, and then triethylamine (5.24 g, 0.0519 mol), diphenyl azide (15.6 g, 0.0567 mol) was added, and heated under nitrogen atmosphere. 75 ° C overnight. Direct decompression and spin drying, column chromatography. Compound 2 (5.00 g, 37.5%) was obtained.

2):

Compound 2a (13.2 g, 0.106 mol) was dissolved in 50.0 mL of tetrahydrofuran, and the mixture was cooled to -78 ° C with a dry ice acetone bath, and n-butyllithium (66.3 mL, 0.106 mol) was slowly added dropwise. Compound 2 (5.00 g, 0.0117 mol) was dissolved in 30.0 mL of tetrahydrofuran, and was quickly added to the previous reaction mixture, and the reaction was stirred at -78 ° C for 2 h. The reaction mixture was quenched with EtOAc EtOAc EtOAc (EtOAc) Column chromatography gave compound 3 (5.4 g, 81.5%).

3):

Compound 3 (5.40 g, 0.0144 mol) was dissolved in 30.0 mL of tetrahydrofuran and sodium hydrogen (0.864 g, 0.036 mol) was added under nitrogen. Compound 3a (5.96 g, 0.0144 mol) was dissolved in 10.0 mL of tetrahydrofuran and added dropwise to the previous reaction mixture at room temperature overnight. The reaction mixture was quenched with EtOAc EtOAc EtOAc (EtOAc) Crude compound 4 (9.0 g) was obtained.

4):

The crude compound 4 (9.0 g) was dissolved in 60.0 mL of methanol, and 30 mL of acetic acid was added. The reaction was carried out at 90 ° C for 2 h. The reaction mixture was dried with EtOAc (EtOAc m.). Crude compound 5 (7.0 g) was obtained.

5):

The crude compound 5 (80.0 mg) was dissolved in 3 mL of methanol, and sodium borohydride (76.0 mg, 1.90 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). Most of the methanol was removed and extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-102 (20 mg, yield: 24.4%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.93 (m, 1H), 7.54-7.60 (m, 2H), 7.37 (m, 1H), 7.26-7.28 (m, 1H), 7.10 (m, 1H), 6.30 (m, 1H), 5.33 (m, 1H), 4.83-4.85 (m, 1H), 3.44-3.48 (m, 1H), 2.02 (m, 1H), 1.65-1.69 (m, 7H), 1.34-1.44 (m, 6H), 1.31 (m, 9H)

HPLC purity: @214nm 96.18%, @254nm 95.48%

MS: m/z 424.4 [M+1]

Example 58 Synthesis of XSD1-103

1):

Compound 1a (41.0 mg, 0.336 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, followed by O-(7-nitrobenzotriazole)-N,N,N',N'-tetra Base urea hexafluorophosphate (128 mg, 0.336 mmol), compound INT1 (80.0 mg, 0.224 mmol) and diisopropylethylamine (144 mg, 1.12 mmol), reacted at room temperature under nitrogen overnight, quenched with water, ethyl acetate The mixture was extracted with EtOAc (EtOAc) (EtOAc) The crude product was used directly in the next reaction.

2):

The crude compound 1 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-103 (20 mg, yield: 20.9%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.94 (m, 1H), 7.74-7.76 (m, 2H), 7.56-7.61 (m, 3H), 7.36-7.47 (m, 4H), 7.27-7.29 (m, 1H), 7.11 (m, 1H), 5.35 (m, 1H), 4.86-4.88 (m, 1H), 3.47-3.49 (m, 1H), 2.03-2.04 (m, 1H), 7.88-1.92 (m, 6H), 1.75 (m, 1H), 1.46-1.53 (m, 6H)

HPLC purity: @214nm 99.15%, @254nm 99.58%

MS: m/z 428.3 [M+1]

Example 59 Synthesis of XSD1-104

1):

Compound 1a (43.0 mg, 0.336 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, followed by O-(7-nitrobenzotriazole)-N,N,N',N'-tetra Base urea hexafluorophosphate (128 mg, 0.336 mmol), compound INT1 (80.0 mg, 0.224 mmol) and diisopropylethylamine (144 mg, 1.12 mmol), reacted at room temperature under nitrogen overnight, quenched with water, ethyl acetate The mixture was extracted with EtOAc (EtOAc) (EtOAc) The crude product was used directly in the next reaction.

2):

The crude compound 1 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-104 (20 mg, yield: 20.6%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.93 (m, 1H), 7.54-7.60 (m, 2H), 7.37 (m, 1H), 7.26-7.28 (m, 1H), 7.04-7.10 (m, 2H), 5.33 (m, 1H), 4.83 4.84 (m, 1H), 3.43 (m, 1H), 1.99-2.02 (m, 2H), 1.65-1.73 (m, 9H), 1.56-1.59 (m, 4H), 1.37-1.46 (m, 6H), 1.12-1.26 (m, 4H)

HPLC purity: @214nm 98.22%, @254nm 98.61%

MS: m/z 434.4 [M+1]

Example 60 Synthesis of XSD1-105

1):

Compound 1a (20.2 mg, 0.336 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, followed by O-(7-nitrobenzotriazine) Azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (128 mg, 0.336 mmol), compound INT1 (80.0 mg, 0.224 mmol) and diisopropylethylamine (144 mg, 1.12 mmol) The mixture was reacted with EtOAc (EtOAc) (EtOAc) The crude product was used directly in the next reaction.

2):

The crude compound 1 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD 1- s (20 mg, yield: 24.5%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.93 (m, 1H), 7.54-7.60 (m, 2H), 7.35-7.39 (m, 1H), 7.26-7.28 (m, 2H), 7.10 (m, 1H), 5.33-5.34 (m, 1H), 4.83-4.84(m,1H),3.43-3.46(m,1H), 2.02(m,1H),1.71-1.75(m,10H),1.40-1.45(m,6H)

HPLC purity: @214nm 98.22%, @254nm 98.61%

MS: m/z 366.3 [M+1]

Example 61 Synthesis of XSD1-106

1):

Compound INT1 (80.0 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL). A solution of the compound 1a (32.0 mg, 0.269 mmol) in dichloromethane (2 mL) was evaporated, evaporated, m. m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m Dry with sodium sulfate and spin dry under reduced pressure. The crude product was used directly in the next reaction.

2):

The crude compound 1 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-106 (20 mg, yield: 20.2%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

8.21 (m, 1H), 8.06 (m, 1H), 7.57-7.63 (m, 2H), 7.38-7.41 (m, 1H), 7.27-7.31 (m, 3H), 7.16-7.20 (m, 3H), 6.85-6.87 (m, 1H), 5.82 (m, 1H), 5.37 (m, 1H), 4.89-4.90 (m, 1H), 3.48 (m, 1H), 2.08 (m, 1H), 1.75-1.78 ( m, 7H), 1.42-1.51 (m, 6H)

HPLC purity: @214nm 98.88%, @254nm 98.89%

MS: m/z 443.3 [M+1]

Example 62 Synthesis of XSD1-107

1):

Compound 1a (47.7 mg, 0.336 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, followed by O-(7-nitrobenzotriazole)-N,N,N',N'-tetra Base urea hexafluorophosphate (128 mg, 0.336 mmol), compound INT1 (80.0 mg, 0.224 mmol) and diisopropylethylamine (116 mg, 0.896 mmol), reacted at room temperature overnight under nitrogen atmosphere, quenched with water, ethyl acetate The mixture was extracted with EtOAc (EtOAc) (EtOAc) The crude product was used directly in the next reaction.

2):

The crude compound 1 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) Extracted with dichloromethane (30 mL x 3), The combined extracts were washed with brine, dried over anhydrous sodium sulfate The crude product was purified by pre-HPLC to give the object compound XSD1-107 (20 mg, yield 19.9%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.98 (m, 1H), 7.54-7.60 (m, 2H), 7.37 (m, 1H), 7.26-7.28 (m, 1H), 7.10-7.16 (m, 2H), 5.33 (m, 1H), 4.84 4.85 (m, 1H), 3.43 (m, 1H), 2.05 (m, 1H), 1.84-1.85 (m, 2H), 1.71-1.75 (m, 7H), 1.58-1.63 (m, 6H), 1.40- 1.45 (m, 6H), 1.12-1.18 (m, 3H), 0.84-0.86 (m, 2H)

HPLC purity: @214nm 97.39%, @254nm 95.58%

MS: m/z 448.3 [M+1]

Example 63 Synthesis of XSD1-108

1):

Compound INT1 (80.0 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL). A solution of the compound 1a (30.7 mg, 0.269 mmol) in dichloromethane (2 mL) was evaporated, evaporated, m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m Dry with sodium sulfate and spin dry under reduced pressure. The crude product was used directly in the next reaction.

2):

The crude compound 1 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-108 (20 mg, yield: 22.3%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.93 (m, 1H), 7.54-7.60 (m, 2H), 7.36-7.39 (m, 1H), 7.24-7.28 (m, 1H), 7.10 (m, 1H), 6.75 (m, 1H), 5.31 5.34 (m, 1H), 4.87-4.88 (m, 1H), 3.44-3.46 (m, 1H), 2.89 (m, 3H), 2.00 (m, 1H), 1.71-1.74 (m, 7H), 1.39- 1.49 (m, 6H)

HPLC purity: @214nm 98.88%, @254nm 98.89%

MS: m/z 402.2 [M+1]

Example 64 Synthesis of XSD1-109

1):

Compound INT1 (80.0 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL). A solution of the compound 1a (47.3 mg, 0.269 mmol) in dichloromethane (2 mL) was evaporated. Dry with sodium sulfate and spin dry under reduced pressure. The crude product was used directly in the next reaction.

2):

The crude compound 1 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-109 (20 mg, yield: 19.3%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.79-7.89(m,3H), 7.48-7.60(m,6H),7.34-7.37(m,1H),7.21-7.25(m,1H),7.08-7.11(m,1H),5.27-5.30(m , 1H), 4.81-4.82 (m, 1H), 3.36-3.40 (m, 1H), 1.94 (m, 1H), 1.62-1.67 (m, 1H), 1.52-1.56 (m, 6H), 1.23-1.38 (m, 6H)

HPLC purity: @214nm 97.75%, @254nm 97.16%

MS: m/z 464.3 [M+1]

Example 65 Synthesis of XSD1-110

1):

Compound INT1 (80.0 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL). A solution of the compound 1a (41.1 mg, 0.269 mmol) in dichloromethane (2 mL) was evaporated. EtOAc m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m Dry with sodium sulfate and spin dry under reduced pressure. The crude product was used directly in the next reaction.

2):

The crude compound 1 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-110 (20 mg, yield 18.8%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

8.36 (m, 1H), 7.94 (m, 1H), 7.55-7.60 (m, 2H), 7.33-7.40 (m, 3H), 7.21-7.29 (m, 3H), 7.11 (m, 1H), 5.85 ( m, 1H), 5.34 (m, 1H), 4.86-4.88 (m, 1H), 3.47-3.48 (m, 1H), 2.05 (m, 1H), 1.74-1.78 (m, 7H), 1.39-1.54 ( m,6H)

HPLC purity: @214nm 92.22%, @254nm 98.48%

MS: m/z 477.3 [M+1]

Example 66 Synthesis of XSD1-111

1):

Compound INT1 (80.0 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL). A solution of the compound 1a (36.8 mg, 0.269 mmol) in dichloromethane (2 mL), EtOAc (EtOAc m. Dry with sodium sulfate and spin dry under reduced pressure. The crude product was used directly in the next reaction.

2):

The crude compound 1 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-111 (20 mg, yield 19.4%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

8.24 (m, 1H), 7.90-7.94 (m, 1H), 7.55-7.60 (m, 2H), 7.36-7.40 (m, 1H), 7.25-7.33 (m, 3H), 7.11-7.13 (m, 1H) ), 6.99-7.04 (m, 2H), 5.78 (m, 1H), 5.32-5.36 (m, 1H), 4.85-4.87 (m, 1H), 3.46-3.50 (m, 1H), 2.02 (m, 1H) ), 1.74-1.78 (m, 7H), 1.42-1.54 (m, 6H)

HPLC purity: @214nm 99.32%, @254nm 99.26%

MS: m/z 461.4 [M+1]

Example 67 Synthesis of XSD1-112

1):

Compound INT1 (80.0 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL). A solution of the compound 1a (38.7 mg, 0.269 mmol) in dichloromethane (2 mL) was evaporated, evaporated, m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m Dry with sodium sulfate and spin dry under reduced pressure. The crude product was used directly in the next reaction.

2):

The crude compound 1 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to obtain the target compound XSD1-112 (20 mg, yield 19.1%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

8.82 (m, 1H), 8.24 (m, 1H), 7.59-7.66 (m, 4H), 7.48-7.50 (m, 2H), 7.42 (m, 1H), 7.28-7.34 (m, 2H), 6.10 ( m, 1H), 5.45 (m, 1H), 4.92-4.93 (m, 1H), 3.60 (m, 1H), 2.09 (m, 1H), 1.75-1.79 (m, 7H), 1.43-1.52 (m, 6H)

HPLC purity: @214nm 94.96%, @254nm 93.57%

MS: m/z 468.3 [M+1]

Example 68 Synthesis of XSD1-113

1):

Compound INT1 (80.0 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL). A solution of the compound 1a (33.6 mg, 0.269 mmol) in dichloromethane (2 mL), EtOAc (EtOAc m. Dry with sodium sulfate and spin dry under reduced pressure. The crude product was used directly in the next reaction.

2):

The crude compound 1 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-113 (20 mg, yield 19.9%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.89-7.93 (m, 1H), 7.55-7.60 (m, 2H), 7.36-7.40 (m, 1H), 7.25-7.28 (m, 1H), 7.11-7.13 (m, 1H), 6.15 (m, 1H) ), 5.51-5.59 (m, 1H), 5.32-5.34 (m, 2H), 4.80 (m, 1H), 3.44-3.47 (m, 1H), 2.01 (m, 1H), 1.58-1.74 (m, 13H) ), 1.38-1.47 (m, 6H), 1.15 - 1.28 (m, 4H)

HPLC purity: @214nm 91.38%, @254nm 96.39%

MS: m/z 449.4 [M+1]

Example 69 Synthesis of XSD1-116

1):

Compound INT1 (80.0 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL). A solution of compound 1a (19.1 mg, 0.269 mmol) in dichloromethane (2 mL) was evaporated. Dry with sodium sulfate and spin dry under reduced pressure. The crude product was used directly in the next reaction.

2):

The crude compound 1 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-116 (20 mg, yield: 22.7%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.89-7.93 (m, 1H), 7.54-7.60 (m, 2H), 7.35-7.39 (m, 1H), 7.24-7.28 (m, 1H), 7.11-7.13 (m, 1H), 5.51-5.54 (m , 1H), 5.31-5.38 (m, 2H), 4.83-4.84 (m, 1H), 3.44 - 3.47 (m, 1H), 2.88-2.95 (m, 2H), 2.00 (m, 1H), 1.66-1.74 (m, 7H), 1.37-1.46 (m, 6H), 0.91-0.95 (m, 3H)

HPLC purity: @214nm 98.37%, @254nm 98.09%

MS: m/z 395.3 [M+1]

Example 70 Synthesis of XSD1-119

1):

Compound INT1 (80.0 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL). A solution of compound 1a (26.6 mg, 0.269 mmol) in dichloromethane (2 mL) The reaction was stirred overnight, EtOAc (EtOAc)EtOAc. The crude product is directly used in the next reaction

2):

The crude compound 1 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-119 (20 mg, yield: 21.1%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.93 (m, 1H), 7.54-7.60 (m, 2H), 7.36-7.39 (m, 1H), 7.26-7.28 (m, 1H), 7.10-7.13 (m, 1H), 5.53 (m, 1H), 5.2. 1.16(m,9H)

HPLC purity: @214nm 99.58%, @254nm 99.99%

MS: m/z 423.4 [M+1]

Example 71 Synthesis of XSD1-123

1):

Compound 1 (100 mg, 0.885 mmol) was dissolved in dichloromethane (3 mL), triethylamine (268 mg, 2. Triphosgene (87.6 mg, 0.295 mmol) was added, heated to 50 ° C under nitrogen, and refluxed for 6 h. After confirming the completion of the reaction of the raw materials, the reaction solution was directly used for the next reaction.

2):

Compound INT1 (80 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL). A one-step reaction solution was added dropwise, and the reaction was allowed to proceed overnight at room temperature under a nitrogen atmosphere. After quenching with water, dichloromethane (50 mL EtOAc) was evaporated. The crude product was used directly in the next reaction.

3):

The crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-123 (20 mg, yield: 19.3%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

HPLC purity: @214nm 98.37%, @254nm 98.09%

MS: m/z 395.3 [M+1]

Example 72 Synthesis of XSD1-138

1):

Compound INT1 (80.0 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL). A solution of Compound 1a (22.9 mg, 0.269 mmol) in dichloromethane (2 mL) was evaporated. Dry with sodium sulfate and spin dry under reduced pressure. The crude product was used directly in the next reaction.

2):

The crude compound 7 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to yield the title compound XSD 1- </RTI> (20 mg, yield: 21.9%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

7.89-7.93 (m, 1H), 7.54-7.60 (m, 2H), 7.36-7.39 (m, 1H), 7.24-7.28 (m, 1H), 7.10-7.13 (m, 1H), 5.42-5.44 (m , 1H), 5. 30-5.34 (m, 2H), 4.83-4.84 (m, 1H), 3.56-3.57 (m, 1H), 3.44 (m, 1H), 2.00 (m, 1H), 1.66-1.70 (m, 7H), 1.37-1.46 (m, 6H), 0.96-0.97 (m, 6H)

HPLC purity: @214nm 99.41%, @254nm 99.39%

MS: m/z 409.4 [M+1]

Example 73 Synthesis of XSD1-140

1):

2):

3):

The crude compound 3 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD1-140 (20 mg, yield: 17.5%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

8.66 (m, 1H), 7.94 (m, 1H), 7.49-7.60 (m, 6H), 7.36-7.40 (m, 1H), 7.27-7.29 (m, 1H), 7.11-7.14 (m, 1H), 5.98 (m, 1H), 5.34 (m, 1H), 4.87-4.88 (m, 1H), 3.48 (m, 1H), 2.00 (m, 1H), 1.75-1.79 (m, 7H), 1.43-1.52 ( m,6H)

HPLC purity: @214nm 98.71%, @254nm 98.21%

MS: m/z 511.3 [M+1]

Example 74 Synthesis of XSD1-040

1)

Compound 1 (1.08 g, 6 mmol), carbon tetrabromide (CBr ₄ , 3.6 g, 6 mmol), triphenylphosphine (3.0 g, 12 mmol) was dissolved in dichloromethane (30 mL). After stirring at room temperature for 12 h, the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. mjjjjjjj

2)

The compound 2 (1.02 g, 4.8 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, and the mixture was dried in acetone, and the temperature was dropped to -60 ° C. Then, t-butyl lithium (6.4 mL, 9.6 mmol) was slowly added dropwise. The reaction solution was further stirred at -60 ° C for 1 h, then methanol (4 mL) was slowly added dropwise to the mixture and stirring was continued for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL), and the mixture was evaporated to ethyl acetate (50mL*3). The organic phase was washed with water (20*2), brine (30*2) White solid (708 mg, yield 83%).

3)

Compound 3 (708 mg, 4.2 mmol) was dissolved in 2N HCl / dioxane (5 mL). After the completion of the reaction, the saturated sodium carbonate solution was washed to neutral, and ethyl acetate (50 mL*2) was evaporated.

4)

Compound 4 (508 mg, 4.04 mmol) was dissolved in dimethyl ether / ethanol (16 mL / 0.6 mL), then TosMIC (780 mg, 4.04 mmol) and potassium t-butoxide (448 mg, 8.04 mmol) The reaction solution was stirred at 0 ° C for half an hour, then warmed to 50 ° C and stirred for 2 h. After filtration, the filtrate was concentrated and purified by column chromatography (jjjjjjjjjjjj

NMR: mc10899-005

5)

Methyl lithium/pentane (1.28 mL, 2.4 mmol) was slowly added dropwise to a solution of compound 5 (154 mg, 1.2 mmol) in diethyl ether (5 mL), and stirred at 0 ° C for 1 h then acetone / hydrochloric acid (3mL / 3mL) Stir at room temperature overnight. The reaction mixture was extracted with ethyl acetate (50 mL*2)

6)

Compound 6 (100 mg, 0.67 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and sodium hydride (51 m, 1.27 mmol) was added, and the mixture was stirred at room temperature for 1 hour. A solution of Compound 6a (211 mg, 0.51 mmol) dissolved in 5 mL of anhydrous tetrahydrofuran was added to the reaction flask under ice bath. The mixture was stirred at room temperature, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated The crude product was subjected to column chromatography to give the product compound 5 (102 mg, yield: 34.6%).

7)

Compound 7 (102 mg, 0.18 mmol) was dissolved in 10 mL of methanol, 1 mL of glacial acetic acid was added, and the mixture was stirred at 90 ° C, and the reaction was stirred overnight. The solvent was evaporated under reduced pressure, and 100 mL of saturated sodium hydrogen carbonate was added and extracted with dichloromethane (20 mL×3). The extract was washed with brine, dried over anhydrous sodium sulfate Compound 8 (42 mg) was obtained and used directly in the next step.

8)

Compound 8 (42mg, 0.14mmol) was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (15mg, 0.4mmol), the reaction stirred for 1 hour, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of The mixture was extracted with EtOAc (3 mL EtOAc). The crude product was purified by pre-HPLC to give the object compound XSD 1-040 (8 mg, yield 12%).

¹ H-NMR (400 MHz, DMSO-d6): δ (ppm) 9.28 (s, 1H), 7.69-7.38 (m, 6H), 6.91 (s, 1H), 5.56 (s, 1H), 4.92 (s, 1H), 2.26-2.01 (m, 2H), 1.49-1.30 (m, 13H),

HPLC purity: @214nm 95.6%, @254nm 96.1%

MS: m/z 309.2 [M+1]

Example 75 Synthesis of XSD1-61

1):

Compound 1 (508 mg, 4.04 mmol) was dissolved in dimethyl ether / ethanol (16 mL / 0.6 mL), then TosMIC (780 mg, 4.04 mmol) and potassium t-butoxide (448 mg, 8.04 mmol) The reaction solution was stirred at 0 ° C for half an hour, then warmed to 50 ° C and stirred for 2 h. After filtration, the filtrate was concentrated and purified by column chromatography (jjjjjjjjjjjj

2)

Methyl lithium/pentane (1.28 mL, 2.4 mmol) was slowly added dropwise to a solution of compound 2 (154 mg, 1.2 mmol) in diethyl ether (5 mL), and stirred at 0 ° C for 1 h then acetone / hydrochloric acid (3mL / 3mL) Stir at room temperature overnight. The reaction mixture was extracted with ethyl acetate (50 mL*2)

3)

Compound 3 (100 mg, 0.67 mmol) was dissolved in 10 mL of anhydrous THF, and sodium hydrogen sulfate (51 m, 1.27 mmol) was added, and the mixture was stirred at room temperature for 1 hour. A solution of Compound 6a (211 mg, 0.51 mmol) dissolved in 5 mL of anhydrous tetrahydrofuran was added to the reaction flask under ice bath. The mixture was stirred at room temperature, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated The crude product was subjected to column chromatography to give the product compound 4 (102 mg, yield: 34.6%).

4)

Compound 4 (102 mg, 0.18 mmol) was dissolved in 10 mL of methanol, 1 mL of glacial acetic acid was added, and the mixture was stirred at 90 ° C, and the reaction was stirred overnight. The solvent was evaporated under reduced pressure, and 100 mL of saturated sodium hydrogen carbonate was added and extracted with dichloromethane (20 mL×3). The extract was washed with brine, dried over anhydrous sodium sulfate Compound 5 (42 mg) was obtained and used directly in the next step.

5)

Compound 5 (42 mg, 0.14 mmol) was dissolved in 5 mL of methanol. NaHH ₄ (15 mg, 0.4 mmol) was added and the mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The mixture was extracted with EtOAc (3 mL EtOAc). The crude product was purified by pre-HPLC to give the object compound XSD1-061 (8 mg, yield 12%).

Example 76 Synthesis of XSD1-139

1):

Compound 1 (100 mg, 0.286 mmol) was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (57.0 mg, 0.429 mmol), O-(7-nitrobenzotriazole)-N,N , N', N'-tetramethylurea hexafluorophosphate (163.7 mg, 0.429 mmol) and diisopropylethylamine (184.3 mg, 1.429 mmol), reacted at room temperature under nitrogen overnight, quenched with water, acetic acid The ethyl ester (50 mL, EtOAc) was evaporated. The crude product was used directly in the next reaction.

2):

The crude compound 2 was dissolved in 3 mL of methanol, and NaBH ₄ (114.3 mg, 2.86 mmol) was added under ice-cooling, and the reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The mixture was extracted with chloroform (30 mL×3). The crude product was purified by pre-HPLC to give the object compound XSD 1-139 (20 mg, yield 15.1%).

1H-NMR (400MHz, DMSO-d6): d (ppm) (mixture of diastereomers)

8.06 (m, 1H), 7.91-7.95 (m, 1H), 7.56-7.61 (m, 2H), 7.36-7.40 (m, 1H), 7.21-7.29 (m, 3H), 7.09-7.14 (m, 2H) ), 7.03-7.05 (m, 2H), 5.33-5.37 (m, 1H), 4.89 (m, 1H), 3.48-3.51 (m, 1H), 2.03-2.04 (m, 1H), 1.63-1.74 (m , 7H), 1.35-1.44 (m, 6H), 1.12-1.15 (m, 2H), 1.04-1.08 (m, 2H)

HPLC purity: @214nm 97.38%, @254nm 99.30%

MS: m/z 468.3 [M + 1].

Example 77 Synthesis of S-1

Reaction 1:

Compound 1 (1.7 g, 8.0 mmol) was dissolved in 30 mL of dichloromethane, then thionyl chloride (2.86 g, 24.0 mmol) was slowly added, and the reaction mixture was warmed to 70 ° C for 2 hours. The solvent was evaporated to room temperature, and the solvent was evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, TLC showed the reaction was complete. The mixture was extracted with EtOAc (3 mL). The crude product was subjected to column chromatography to give the product compound 3 (2.0 g, yield 66%). For the detection of compound 3: MS: m/z 302.0 [M+1]; ¹ H-NMR (400 MHz, DMSO-d6): δ ppm 8.02 (brs, 1H), 7.30-7.28 (m, 2H), 7.22-7.19 (m, 3H), 4.27 (d, J = 4.4 Hz, 2H), 3.58 (s, 3H), 1.78-1.70 (m, 12H).

Reaction 2:

Compound 3a (2.42 g, 19.53 mmol) was dissolved in 30 mL of anhydrous tetrahydrofuran, cooled to -78 ° C in dry ice acetone bath, and a solution of 1.5 M butyl lithium n-hexane (13 mL, 19.53 mmol) was slowly added dropwise and kept at -60 ° C. the following. Thereafter, a solution of Compound 3 (980 mg, 3.26 mmol) dissolved in 10 mL of anhydrous tetrahydrofuran was added to the reaction flask and kept at an internal temperature of -60 ° C or lower. The reaction was stirred at -78 °C for 2 hours, quenched with saturated aqueous ammonium chloride and warmed to room temperature. After adding 200 mL of water and extracting with dichloromethane (100 mL × 5), the combined extracts were washed with brine, dried over anhydrous sodium sulfate The crude product was subjected to column chromatography to give the product compound 4 (1.25 g, yield 97.6%). For the detection of compound 4: MS: m/z 394.2 [M+1]; ¹ H-NMR (400 MHz, DMSO-d6): δ ppm 8.00 (brs, 1H), 7.32-7.28 (m, 2H), 7.22-7.18 (m, 3H), 4.25 (d, J = 4.8 Hz, 2H), 3.65 (s, 3H), 3.62 (s, 3H), 3.38-3.34 (m, 2H), 1.74-1.68 (m, 12H).

Reaction 3:

Compound 4 (200 mg, 0.51 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and 30.5 mg of sodium hydride was added under ice bath, and the mixture was stirred at room temperature for 1 hour. A solution of Compound 4a (211 mg, 0.51 mmol) in 5 mL of anhydrous tetrahydrofuran was added to the reaction flask under ice bath. The mixture was stirred at room temperature, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated The crude product was subjected to column chromatography to give the product compound 5 (120 mg, yield: 34.6%). MS of compound 5: m/z 682.3 [M + 1]; ¹ H-NMR (400 MHz, DMSO-d6): δ ppm 8.03-7.96 (m, 2H), 7.79-7.05 (m, 26H), 6.95 (s) , 1H), 4.26 (d, J = 6.0 Hz, 2H), 1.74-1.56 (m, 12H).

Reaction 4:

Compound 5 (120 mg, 0.18 mmol) was dissolved in 10 mL of methanol, 1 mL of glacial acetic acid was added, and the mixture was stirred at 90 ^{° C, and the} reaction was stirred overnight. The solvent was evaporated under reduced pressure, and 100 mL of saturated sodium hydrogencarbonate was added and extracted three times with dichloromethane (50 mL×3) The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate The crude product of compound 6 (150 mg) was obtained and used directly in the next reaction. MS: m/z 440.1 [M + 1]; ¹ H-NMR (400 MHz, DMSO-d6): δ ppm 8.00 (brs, 1H), 7.60-7.12 (m, 11H), 5.76-5.58 (m, 1H), 4.24 (d, J = 4.8 Hz, 2H), 3.44 - 3.34 (m, 1H), 3.13 - 3.06 (m, 1H), 1.74-1.58 (m, 12H).

Reaction 5:

Compound 6 (70mg, 0.1mmol) was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (15mg, 0.4mmol), the reaction stirred for 1 hour, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of The mixture was extracted with EtOAc (3 mL, EtOAc). The crude product was purified by pre-HPLC to give the title compound s-1 (8 mg, yield: 18%).

¹ H-NMR (400 MHz, DMSO-d6): δ ppm 7.95 (s, 2H), 7.61-7.56 (m, 2H), 7.38-7.36 (m, 1H), 7.29-7.11 (m, 7H), 5.35 (s) , 1H), 4.91 (brs, 1H), 4.24 - 4.23 (d, J = 3.6 Hz, 2H), 3.51-3.48 (d, 1H), 2.88-2.86 (m, 1H), 2.08-1.99 (m, 1H) ), 1.75-1.65 (m, 6H), 1.44-1.37 (d, 6H).

HPLC purity: @214nm 99.20%, @254nm 99.36%

MS: m/z 442.3 [M + 1].

Example 78 Synthesis of S-2

Reaction 1:

Compound 6 (220 mg, 0.5 mmol) was dissolved in 30 mL of hydrobromic acid solution (48% aqueous solution), stirred at 125 ° C overnight in a humidified tank, and extracted with a mixture of chloroform and isopropanol (3:1) (50 mL×5). The organic phase was combined, washed with brine, dried over anhydrous sodium sulfate Column chromatography gave Compound 7 (170 mg, yield 97%).

MS: m/z 351.2 [M + 1].

Reaction 2:

Compound 7 (35mg, 0.1mmol) was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (15mg, 0.4mmol), the reaction stirred for 1 hour, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The crude product was purified by pre-HPLC to yield the title compound s-2 (6 mg, yield 17%).

^{1 H-NMR (400MHz, DMSO} -d6) :( a mixture of diastereomers) δ (ppm) 11.98 (s, 1H), 9.26 (s, 1H), 7.93-7.80 (m, 2H), 7.79-7.60 (m , 1H), 7.60-7.44 (m, 2H), 5.79-5.66 (m, 1H), 5.11 (s, 1H), 3.61-3.49 (m, 1H), 2.16-2.02 (m, 1H), 2.02-1.87 (m, 1H), 1.69-1.57 (m, 6H), 1.49-1.33 (m, 6H).

HPLC purity: @214nm 99.41%, @254nm 98.89%

MS: m/z 353.3 [M + 1].

Example 79 Synthesis of S-3

Reaction 1:

Compound 7 (80 mg, 0.23 mmol) was dissolved in dichloromethane (5 mL), chlorosulfone (65 mg, 0.55 mmol) was slowly added, and the reaction mixture was warmed to 85 ° C for 2 hours. The solvent was evaporated to room temperature, and the solvent was evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, TLC showed the reaction was complete. The mixture was extracted with EtOAc (EtOAc) (EtOAc)EtOAc. The crude product compound 10 (60 mg, yield 70%) was obtained.

MS: m/z 426.3 [M + 1].

Reaction 2:

The crude Compound 10 was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (30mg, 0.79mmol), stirred for 18 hours at room temperature, the reaction solution (30mL) and quenched with saturated ammonium chloride solution, most of the methanol removed by rotary evaporation, treated with dichlorobis The extract was extracted with methylene chloride (30 mL × 3). The crude product was purified by pre-HPLC to give the title compound s-3 (15.2 mg, yield 15%).

^{1 H-NMR (400MHz, DMSO} -d6): δppm 9.29 (s, 1H), 9.07 (s, 1H), 7.91-7.84 (m, 2H), 7.74-7.52 (m, 6H), 7.26 (t, J = 7.2 Hz, 2H), 7.03-7.00 (m, 1H), 5.74 (m, 1H), 5.06 (m, 1H), 3.65-3.58 (m, 1H), 2.02-1.95 (m, 2H), 1.79- 1.70 (m, 6H), 1.49-1.38 (d, 6H)

HPLC purity: @214nm 98.74%, @254nm 98.99%

MS: m/z 428.5 [M + 1].

Example 80 Synthesis of S-4

Reaction 1:

Compound 7 (70 mg, 0.20 mmol) was dissolved in 5 mL of DMF, then compound 7a (43 mg, 0.30 mmol), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (HATU 165mg, 0.43mmol) and diisopropylethylamine (77mg, 0.60mmol), reacted at room temperature overnight under nitrogen atmosphere, quenched with water, extracted with ethyl acetate (50mL × 5), combined with extraction The solution was washed with brine, dried over anhydrous sodium sulfate

MS: m/z 458.1 [M + 1].

Reaction 2:

The crude Compound 11 was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (80mg, 2.0mmol), stirred for 18 h at rt, saturated ammonium chloride solution (30mL) quenched with methanol removed by rotary evaporation, dichloromethane (30mL × 3) The extract was combined and washed with brine, dried over anhydrous sodium sulfate The crude product was purified by pre-HPLC to yield the title compound s-4 (20.0 mg, yield: 21.1%).

^{1 H-NMR (400MHz, DMSO} -d6): δppm 9.26 (s, 1H), 7.95-7.82 (m, 3H), 7.74-7.71 (m, 1H), 7.57-7.48 (m, 2H), 7.22-7.09 (m, 4H), 5.74-5.70 (m, 1H), 5.32-5.05 (m, 1H), 4.21-4.19 (d, J = 5.6 Hz, 2H), 3.51-3.48 (m, 1H), 2.12-1.95 (m, 2H), 1.72-1.62 (m, 6H), 1.49-1.37 (m, 6H)

HPLC purity: @214nm 96.10%, @254nm 94.01%

MS: m/z 460.3 [M + 1].

Example 81 Synthesis of S-5

Reaction 1:

Compound 7 (60 mg, 0.17 mmol) was dissolved in 5 mL DMF and compound 7a (40 mg, 0.26 mmol), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (150 mg, 0.39 mmol) and diisopropylethylamine (70 mg, 0.51 mmol) were reacted overnight at room temperature under nitrogen atmosphere, quenched with water, and extracted with ethyl acetate (50mL×5) The solution was washed with brine, dried over anhydrous sodium sulfate

MS: m/z 474.2 [M + 1].

Reaction 2:

The crude Compound 11 was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (70mg, 1.7mmol), stirred at room temperature for 18 hours the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol removed by rotary evaporation, treated with dichlorobis The extract was extracted with methylene chloride (30 mL × 3). The crude product was purified by pre-HPLC to give the title compound s-5 (15.2 mg, yield of 19% in two steps).

¹ H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.01 - 7.95 (m, 2H), 7.60 - 7.58 (m, 2H), 7.40 - 7.11 (m, 7H), 5.35 (m, 1H), 4.89 (m, 1H), 4.20 (d, J = 4.8 Hz, 2H), 3.51-3.47 (m, 1H), 2.12-1.98 (m, 1H), 1.76-1.64 (m, 7H), 1.45-1.37 ( m,6H)

HPLC purity: @214nm 98.13%, @254nm 97.82%

MS: m/z 476.2 [M + 1].

Example 82 Synthesis of S-6

Reaction 1:

Compound 7 (60 mg, 0.17 mmol) was dissolved in 5 mL of DMF and compound 7a (49 mg, 0.34 mmol), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (99 mg, 0.26 mmol) and N-ethyldiisopropylamine (65 mg, 0.50 mmol) were reacted overnight at room temperature under nitrogen atmosphere, quenched with water and extracted with ethyl acetate (50mL×3) The solution was washed with brine, dried over anhydrous sodium sulfate

MS: m/z 476.2 [M + 1].

Reaction 2:

Compound 11 (90mg, 0.17mmol) was dissolved in 5mL of methanol was added NaBH ₄ under ice bath (65mg, 1.7mmol), the reaction was stirred for 2 hours, the reaction solution (30mL) and quenched with saturated ammonium chloride solution, rotary evaporation to remove most of The mixture was extracted with EtOAc (MeOH) (EtOAc (EtOAc:EtOAc) The crude product was purified by pre-HPLC to give the title compound s-6 (25 mg, yield 23%).

^{1 H-NMR (400MHz, DMSO} -d6): δppm 9.31 (s, 1H), 7.95-7.91 (m, 3H), 7.75-7.72 (m, 1H), 7.57-7.49 (m, 2H), 7.26-7.02 (m, 3H), 5.75-5.72 (m, 1H), 5.09 (brs, 1H), 4.21 (m, 2H), 3.57-3.53 (m, 1H), 2.16-1.93 (m, 2H), 1.65-1.59 (m, 6H), 1.46-1.34 (m, 6H)

HPLC purity: @214nm 98.68%, @254nm 97.94%

MS: m/z 478.1 [M + 1].

Example 83 Synthesis of S-7

Reaction 1:

Compound 7 (70 mg, 0.20 mmol) was dissolved in 5 mL of DMF, then compound 7a (43 mg, 0.30 mmol), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (165 mg, 0.43 mmol) and diisopropylethylamine (77 mg, 0.60 mmol) were reacted overnight at room temperature under nitrogen atmosphere, quenched with water, ethyl acetate (50 mL×5) The organic layer was washed with brine, dried over anhydrous sodium sulfate

MS: m/z 476.1 [M + 1].

Reaction 2:

The crude Compound 11 was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (80mg, 2.0mmol), stirred for 18 h at rt, saturated ammonium chloride solution (30mL) quenched with methanol removed by rotary evaporation, dichloromethane (30mL × 3) The extract was combined and washed with brine, dried over anhydrous sodium sulfate The crude product was purified by pre-HPLC to give the title compound s-7 (28.4 mg, yield 30%).

^{1 H-NMR (400MHz, DMSO} -d6): δppm 9.15 (s, 1H), 7.99 (m, 1H), 7.84-7.80 (m, 2H), 7.73-7.70 (m, 1H), 7.55-7.47 (m , 2H), 7.38-7.34 (m, 1H), 7.22-7.17 (m, 1H), 7.02 (m, 1H), 5.69-5.66 (m, 1H), 5.06 (brs, 1H), 4.20 (d, J) = 5.6 Hz, 2H), 3.56-3.47 (m, 1H), 2.12-1.90 (m, 2H), 1.65-1.59 (m, 6H), 1.46-1.32 (m, 6H).

HPLC purity: @214nm 99.10%, @254nm 99.33%

MS: m/z 478.3 [M + 1].

Example 84 Synthesis of S-8

Reaction 1:

The compound 7 (35 mg, 0.1 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran, oxalyl chloride (51 mg, 0.4 mmol) and one drop of dimethylformamide were added and allowed to react overnight at room temperature. The crude product of compound 9 (50 mg) was obtained and used directly in the next reaction.

Reaction 2:

Compound 9 (50 mg, 0.1 mmol) was dissolved in EtOAc EtOAc (EtOAc) The crude product of compound 10 (100 mg) was obtained and used directly in the next reaction.

MS: m/z 350.0 [M + 1].

Reaction 3:

Compound 10 (100mg, 0.1mmol) was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (19mg, 0.5mmol), the reaction stirred for 1 hour, the reaction solution (30mL) and quenched with saturated ammonium chloride solution, rotary evaporation to remove most of The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The crude product was purified by pre-HPLC to give the title compound s-8 (7 mg, yield 20%).

¹ H-NMR (400 MHz, DMSO-d6): δ (ppm) 9.28 (s, 1H), 9.26 (s, 1H), 7.94-7.8 (m, 2H), 7.79-7.61 (m, 1H), 7.62 7.44 (m, 2H), 6.91 (s, 1H), 6.69 (s, 1H), 5.82-5.65 (m, 1H), 5.08 (s, 1H), 3.61-3.46 (m, 1H), 2.17-2.03 ( m, 1H), 2.02-1.87 (m, 1H), 1.65-1.53 (m, 6H), 1.47-1.19 (m, 6H).

HPLC purity: @214nm 99.01%, @254nm 99.04%

MS: m/z 352.3 [M + 1].

Example 85 Synthesis of S-9

Reaction 1:

Compound 7 (40 mg, 0.11 mmol) was dissolved in 5 mL of DMF, followed by methylamine hydrochloride (15 mg, 0.23 mmol), O-(7-nitrobenzotriazole)-N,N,N',N'- Tetramethylurea hexafluorophosphate (HATU 65 mg, 0.17 mmol) and N-ethyldiisopropylamine (74 mg, 0.57 mmol) were reacted overnight at room temperature under nitrogen atmosphere, quenched with water and ethyl acetate (50mL×5) The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate The crude product was purified using a thick preparative plate to afford compound 11 (25 mg, yield 63%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.71 (s, 1H), 7.58-7.21 (m, 5H), 5.78-5.62 (m, 2H), 3.23 - 3.15 (m, 1H), 3.00 - 2.90 (m, 1H), 2.78 (d, J = 4.0 Hz, 3H), 1.82-1.60 (m, 12H).

Reaction 2:

Compound 11 (25mg, 0.07mmol) was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (37mg, 0.97mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of The mixture was extracted with EtOAc (EtOAc)EtOAc. The crude product was purified by pre-HPLC to give the title compound s-9 (6.3 mg, yield 21%).

^{1 H-NMR (400MHz, DMSO} -d6): δ (ppm) 14.64 (s, 1H), 9.30 (s, 1H), 9.28,7.96-7.81 (m, 2H), 7.79-7.61 (m, 1H), 7.58-7.39 (m, 2H), 7.28 (s, 1H), 5.85-5.68 (m, 1H), 5.08 and 4.63 (two s, 1H), 3.55 and 3.15 (two d, J = 10.0 Hz and 9.6 Hz) , 1H), 2.51 (s, 3H), 2.38-2.07 (m, 1H), 1.96 (m, 1H), 1.65-1.53 (m, 6H), 1.48-1.31 (m, 6H).

HPLC purity: @214nm 98.16%, @254nm 99.86%

MS: m/z 366.2 [M + 1].

Example 86 Synthesis of S-10

Reaction 1:

Compound 7 (40 mg, 0.11 mmol) was dissolved in 5 mL DMF, followed by dimethylamine hydrochloride (19 mg, 0.23 mmol), O-(7-nitrobenzotriazole)-N,N,N',N' Tetramethylurea hexafluorophosphate (65 mg, 0.17 mmol) and N-ethyldiisopropylamine (74 mg, 0.57 mmol), mp. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate The crude product was purified using EtOAc (EtOAc):

MS: m/z 378.4 [M + 1].

Reaction 2:

Compound 11 (30mg, 0.07mmol) was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (42mg, 1.12mmol), the reaction stirred for 18 hours, the reaction solution (30mL) and quenched with saturated ammonium chloride solution, rotary evaporation to remove most of The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The crude product was purified by pre-HPLC to give the title compound s-10 (6.6 mg, yield 22%).

^{1 H-NMR (400MHz, DMSO} -d6): δ (ppm) 14.48 (s, 1H), 9.30 (s, 1H), 7.96-7.80 (m, 2H), 7.79-7.61 (m, 1H), 7.61- 7.45 (m, 2H), 5.86-5.67 (m, 1H), 5.06 (s, 1H), 3.65-3.49 (m, 1H), 2.92 (s, 6H), 2.38-2.02 (m, 1H), 2.02- 1.89 (m, 1H), 1.80-1.68 (m, 6H), 1.49-1.29 (m, 6H).

HPLC purity: @214nm 99.47%, @254nm 98.87%

MS: m/z 380.3 [M + 1].

Example 87 Synthesis of S-11

Reaction 1:

Compound 7 (40 mg, 0.11 mmol) was dissolved in 10 mL of dichloromethane, then 1 mL of chlorosulfoxide was added and refluxed at 65 ° C for 2 hr. The crude product of compound 8 (80 mg) was obtained and used directly in the next step.

Reaction 2:

Compound 8 (80 mg, 0.11 mmol) was dissolved in 5 mL of tetrahydrofuran. Compound 8a (28 mg, 0.23 mmol) and N-ethyldiisopropylamine (28 mg, 0.23 mmol) were added to the mixture. The sodium solution (30 mL) was evaporated and evaporated. The crude product was dried under reduced pressure. The crude product of compound 9 (120 mg, combined with a small test) was obtained and used directly in the next reaction.

MS: m/z 454.2 [M + 1].

Reaction 3:

Compound 9 (100mg, 0.22mmol) was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (84mg, 2.2mmol), the reaction was stirred for 2 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of Methanol, and the mixture was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the title compound s-11 (20 mg, yield 19%).

¹ H-NMR (400 MHz, DMSO-d6): δ ppm 9.32 (s, 1H), 7.91-7.72 (m, 3H), 7.57-7.49 (m, 2H), 7.35-7.12 (m, 5H), 5.74 (m) , 1H), 5.09 (brs, 1H), 4.57 (s, 2H), 3.55 (d, J = 10.4 Hz, 1H), 2.90 (s, 3H), 2.12-1.92 (m, 2H), 1.81-1.78 ( m, 6H), 1.46-1.38 (m, 6H)

HPLC purity: @214nm 97.92%, @254nm 96.61%

MS: m/z 456.2 [M + 1].

Example 88 Synthesis of S-12

Reaction 1:

Compound 7 (70 mg, 0.20 mmol) was dissolved in 5 mL DMF and compound 7a (35 mg, 0.30 mmol), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (165 mg, 0.30 mmol) and diisopropylethylamine (78 mg, 0.60 mmol) were reacted overnight at room temperature under nitrogen atmosphere, quenched with water, and extracted with ethyl acetate (50mL×5) The solution was washed with brine, dried over anhydrous sodium sulfate

MS: m/z 441.2 [M + 1].

Reaction 2:

The crude Compound 11 was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (80mg, 2.0mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), methanol was removed by rotary evaporation, dichloromethane (30 mL The extract was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated evaporated. The crude product was purified by pre-HPLC to yield the title compound s-12 (20.0 mg, yield of 23% in two steps).

^{1 H-NMR (400MHz, DMSO} -d6): δ (ppm) 8.47 (s, 1H), 8.16-7.92 (m, 2H), 7.75-7.56 (m, 3H), 7.40-7.12 (m, 5H), 5.38-5.34 (m, 1H), 4.90 (brs, 1H), 4.32 (d, J = 5.6 Hz, 2H), 3.60-3.52 (m, 1H), 2.08-1.99 (m, 1H), 1.77-1.67 ( m, 7H), 1.46-1.24 (m, 6H)

HPLC purity: @214nm 99.62%, @254nm 99.19%

MS: m/z 443.2 [M + 1].

Example 89 Synthesis of S-13

Reaction 1:

Compound 7 (60 mg, 0.17 mmol) was dissolved in 5 mL DMF and compound 7a (37 mg, 0.34 mmol), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (99 mg, 0.26 mmol) and N-ethyldiisopropylamine (68 mg, 0.51 mmol) were reacted overnight at room temperature under nitrogen atmosphere, quenched with water, and extracted with ethyl acetate (50mL×5) The solution was washed with saturated brine and dried over anhydrous sodium sulfate.

MS: m/z 441.1 [M + 1].

Reaction 2:

Compound 11 (100mg, 0.17mmol) was dissolved in 5mL of methanol was added NaBH ₄ under ice bath (65mg, 1.7mmol), the reaction was stirred for 2 hours, the reaction solution (30mL) and quenched with saturated ammonium chloride solution, rotary evaporation to remove most of The mixture was extracted with methylene chloride (10:1, 30 mL, 5). The crude product was purified by pre-HPLC to give the title compound s-13 (10 mg, yield 13%).

^{1 H-NMR (400MHz, DMSO} -d6): δppm 8.41 (m, 2H), 8.03-7.98 (m, 2H), 7.62-7.56 (m, 3H), 7.33-7.25 (m, 3H), 7.13 (m , 1H), 5.36 (s, 1H), 4.91 (m, 1H), 4.24 (d, J = 4.8 Hz, 1H), 3.51-3.49 (m, 1H), 2.05-2.00 (m, 1H), 1.75- 1.62 (m, 7H), 1.43-1.37 (m, 6H)

HPLC purity: @214nm 97.87%, @254nm 96.60%

MS: m/z 222.1 [M/2+1].

Example 90 Synthesis of S-14

Reaction 1:

Compound 7a (52 mg, 0.39 mmol) was dissolved in EtOAc (EtOAc m. The system was filtered, and the compound 7 (80 mg, 0.23 mmol), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (200 mg) was sequentially added to the filtrate. , 0.53 mmol) and diisopropylethylamine (300 mg, 2.3 mmol), reacted at room temperature overnight under nitrogen atmosphere, quenched with water, ethyl acetate (50 mL×5), and the extracts were washed with saturated brine. Dry with sodium sulfate and spin dry under reduced pressure. The crude product 8 was used directly for the next reaction.

MS: m/z 442.2 [M + 1].

Reaction 2:

The crude product of compound 8 was dissolved in 5 mL of methanol, and NaBH ₄ (130 mg, 3.2 mmol) was added under ice-cooling, and the reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL × 3). The crude product was purified by pre-HPLC to give the title compound s-14 (5.0 mg, yield:

^{1 H-NMR (400MHz, DMSO} -d6): δppm 8.55-8.44 (m, 3H), 8.11-7.91 (m, 2H), 7.61-7.11 (m, 5H), 5.38-5.34 (m, 1H), 4.91 (brs, 1H), 4.37 (d, J = 5.6 Hz, 2H), 3.52-3.48 (m, 1H), 2.08-2.00 (m, 1H), 1.76-1.61 (m, 7H), 1.45-1.21 (m , 6H)

HPLC purity: @214nm 90.71%, @254nm 96.58%

MS: m/z 444.3 [M + 1].

Example 91 Synthesis of S-15

Reaction 1:

Compound 7 (40 mg, 0.11 mmol) was dissolved in 5 mL of DMF, then compound 7a (20 mg, 0.20 mmol), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (65 mg, 0.17 mmol) and diisopropylethylamine (77 mg, 0.60 mmol) were reacted at room temperature under nitrogen overnight, quenched with water, ethyl acetate (50 mL×5) The extract was washed with brine, dried over anhydrous sodium sulfate The crude product 8 was used directly for the next reaction.

MS: m/z 432.4 [M + 1].

Reaction 2:

The crude compound 8 was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (80mg, 2.0mmol), stirred for 18 h at rt, saturated ammonium chloride solution (30mL) quenched with methanol removed by rotary evaporation, dichloromethane (30mL × 3) The extract was combined and washed with brine, dried over anhydrous sodium sulfate The crude product was purified by pre-HPLC to give the title compound s-15 (15.0 mg, yield of 30% in two steps).

¹ H-NMR (400 MHz, DMSO-d6): δ (ppm) 9.23 (s, 1H), 7.86-7.83 (m, 2H), 7.73-7.71 (m, 1H), 5.56-7.50 (m, 2H), 7.29-7.26 (m, 1H), 5.76-5.69 (m, 1H), 5.04-5.01 (m, 1H), 3, 54-3.50 (m, 1H), 2.91 (d, J = 6.0 Hz, 2H), 2.11-1.92 (m, 3H), 1.62-1.16 (m, 20H)

HPLC purity: @214nm 99.13%, @254nm 98.81%

MS: m/z 434.5 [M + 1].

Example 92 Synthesis of S-16

Reaction 1:

Compound 7 (100 mg, 0.43 mmol) was dissolved in 5 mL DMF and compound 7a (55 mg, 0.64 mmol), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (243 mg, 0.64 mmol) and N-ethyldiisopropylamine (111 mg, 0.86 mmol) were reacted at room temperature overnight under nitrogen atmosphere, quenched with water, extracted with ethyl acetate (50 mL×5) The solution was washed with brine, dried over anhydrous sodium sulfate The crude product was purified using a thick preparative plate to afford compound 8 (116 mg, 65%).

MS: m/z 418.3 [M + 1].

Reaction 2:

Compound 8 (100mg, 0.24mmol) was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (27mg, 0.72mmol), the reaction stirred for 18 hours, the reaction solution (30mL) and quenched with saturated ammonium chloride solution, rotary evaporation to remove most of The mixture was extracted with methylene chloride (30 mL × 3). The crude product was purified by pre-HPLC to yield the title compound s-16 (43 mg, yield 43%).

^{1 H-NMR (400MHz, DMSO} -d6): δ (ppm) 7.94 (s, 1H), 7.60-7.55 (m, 2H), 7.40-7.00 (m, 4H), 5.35 (m, 1H), 4.88 ( Brs, 1H), 4.24 - 3.93 (m, 1H), 3.48 (d, J = 10.8 Hz, 1H), 2.06-1.98 (m, 1H), 1.74-1.26 (m, 21H).

HPLC purity: @214nm 99.69%, @254nm 98.85%

MS: m/z 420.3 [M + 1].

Example 93 Synthesis of S-17

Reaction 1:

Compound 7 (100 mg, 0.43 mmol) was dissolved in 5 mL DMF and compound 7a (59 mg, 0.64 mmol), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (243 mg, 0.64 mmol) and N-ethyldiisopropylamine (111 mg, 0.86 mmol) were reacted at room temperature overnight under nitrogen atmosphere, quenched with water, extracted with ethyl acetate (50 mL×5) The solution was washed with brine, dried over anhydrous sodium sulfate The crude product was purified using EtOAc (EtOAc:EtOAc)

Reaction 2:

Hua Hewu 8 (100mg, 0.26mmol) was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (27mg, 0.72mmol), the reaction stirred for 18 hours, the reaction solution (30 mL) quenched with saturated ammonium chloride solution, rotary evaporation to remove most of Methanol, and the mixture was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the title compound s-17 (25 mg, yield 25%).

^{1 H-NMR (400MHz, DMSO} -d6): δ (ppm) 7.94 (s, 1H), 7.60-7.54 (m, 2H), 7.39-7.25 (m, 2H), 7.14-7.10 (m, 1H), 6.96-6.93 (m, 1H), 5.34 (m, 1H), 4.89 (brs, 1H), 3.86-3.80 (m, 1H), 3.49 (d, J = 10.4 Hz, 1H), 2.06-1.98 (m, 1H), 1.74-1.68 (m, 7H), 1.42-1.34 (m, 6H), 1.00 (m, 6H)

HPLC purity: @214nm 99.54%, @254nm 99.48%

MS: m/z 394.3 [M + 1].

Example 94 Synthesis of S-18

Reaction 1:

Compound 7 (70 mg, 0.20 mmol) was dissolved in 5 mL of DMF, then compound 7a (30 mg, 0.41 mmol), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (165 mg, 0.43 mmol) and diisopropylethylamine (77 mg, 0.60 mmol) were reacted overnight at room temperature under nitrogen atmosphere, quenched with water, ethyl acetate (50 mL×5) The extract was washed with brine, dried over anhydrous sodium sulfate The crude product 8 was used directly for the next reaction.

MS: m/z 406.4 [M + 1].

Reaction 2:

The crude compound 8 was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (80mg, 2.0mmol), stirred for 18 h at rt, saturated ammonium chloride solution (30mL) quenched with methanol removed by rotary evaporation, dichloromethane (30mL × 3) The extract was combined and washed with brine, dried over anhydrous sodium sulfate The crude product was purified by pre-HPLC to give the title compound s-18 (30.0 mg, yield of 37% in two steps).

1H-NMR (400MHz, DMSO-d6): δ (ppm) 9.26 (s, 1H), 7.88-7.84 (m, 2H), 7.74-7.72 (m, 1H), 7.56-7.48 (m, 2H), 7.28 -7.13(m,1H), 5.72(m,1H),5.05(brs,1H),3.62-3.54(m,1H),2.82(t,J=5.8Hz,2H),2.13-2.08(m,1H ), 1.96-1.91 (m, 1H), 1.71-1.23 (m, 13H), 0.77 (m, 6H)

HPLC purity: @214nm 97.04%, @254nm 97.84%

MS: m/z 408.4 [M + 1].

Example 95 Synthesis of S-19

Reaction 1:

Compound 7 (90 mg, 0.26 mmol) was dissolved in 5 mL of DMF, and then compound 7a (28 mg, 0.39 mmol), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (150 mg, 0.39 mmol) and diisopropylethylamine (52 mg, 0.77) The mixture was stirred at room temperature under reduced pressure. EtOAc (EtOAc m. The crude product 8 was used directly for the next reaction.

Reaction 2:

The crude compound was dissolved in 5 mL of methanol, and NaBH ₄ (42 mg, 1.12 mmol) was added, and the mixture was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL × 3). The crude product was purified by pre-HPLC to yield the title compound s-19 (6.6 mg, yield 22%).

^{1 H-NMR (400MHz, DMSO} -d6): δ (ppm) 9.32 (s, 1H), 7.91-7.50 (m, 5H), 5.74 (m, 1H), 4.18-3.88 (m, 4H), 4.05 ( Brs,1H),3.56-3.50(m,1H),2.12-2.08(m,1H),1.97-1.94(m,1H),1.81-1.43(m,10H),1.50-1.32(m,6H)

HPLC purity: @214nm 99.61%, @254nm 99.80%

MS: m/z 406.3 [M + 1].

Example 96 Synthesis of S-20

Reaction 1:

Compound 1 (1.5 g, 8.0 mmol) was dissolved in 30 mL of dichloromethane, then thionyl chloride (2.86 g, 24.0 mmol) was slowly added, and the reaction mixture was warmed to 70 ° C for 2 hours. The solvent was evaporated to room temperature, and the solvent was evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, TLC showed the reaction was complete. The mixture was extracted with EtOAc (3 mL). The crude product was subjected to column chromatography to give the product Compound 3 (1.3 g, yield 60%). MS: m/z 275.3 [M + 1].

Reaction 2:

Compound 3a (2.42g, 19.53mmol) was dissolved in 30mL of anhydrous tetrahydrofuran, cooled to -78 ° C in dry ice acetone bath, slowly added dropwise 1.5 M butyl lithium n-hexane solution (13 mL, 19.53 mmol) and maintained at an internal temperature of -60 ° C or less. Thereafter, a solution of Compound 3 (896 mg, 3.26 mmol) dissolved in 10 mL of anhydrous tetrahydrofuran was added to the reaction flask and kept at an internal temperature of -60 ° C or lower. The reaction was stirred at -78 °C for 2 h, quenched with saturated EtOAc then EtOAc. After adding 200 mL of water and extracting with dichloromethane (100 mL × 5), the combined extracts were washed with brine, dried over anhydrous sodium sulfate The crude product was subjected to column chromatography to give the product compound 4 (1.07 g, yield: 90.6%). Detection of Compound 4: MS: m/z 367.4 [M + 1].

Reaction 3:

Compound 4 (188 mg, 0.51 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and 30.5 mg of sodium hydride was added under ice bath, and the mixture was stirred at room temperature for 1 hour. A solution of Compound 4a (211 mg, 0.51 mmol) in 5 mL of anhydrous tetrahydrofuran was added to the reaction flask under ice bath. The mixture was stirred at room temperature, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated The crude product was subjected to column chromatography to give the product compound 5 (134 mg, yield 40.1%). MS of Compound 5: m/z 656.0 [M + 1].

Reaction 4:

Compound 5 (118 mg, 0.18 mmol) was dissolved in 10 mL of methanol, 1 mL of glacial acetic acid was added, and the mixture was stirred at 90 ° C, and the reaction was stirred overnight. The solvent was evaporated under reduced pressure, and 100 mL of saturated sodium hydrogencarbonate was added and extracted three times with dichloromethane (50 mL×3) The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate The crude product of compound 6 (156 mg) was obtained and used directly in the next reaction.

Reaction 5:

Compound 6 (100mg, 0.12mmol) was dissolved in 5mL of methanol was added under ice bath NaBH ₄ (15mg, 0.4mmol), the reaction stirred for 1 hour, the reaction solution (30mL) and quenched with saturated ammonium chloride solution, rotary evaporation to remove most of Methanol, and the mixture was extracted with dichloromethane (30 mL×3). The crude product was purified by pre-HPLC to give the title compound s-20 (18 mg, yield 36%).

HPLC purity: @214nm 98.30%, @254nm 98.56%

MS of S-20: m/z 415.2 [M + 1].

¹ H-NMR (400 MHz, DMSO-d6): δ ppm 7.80-7.76 (s, 2H), 7.63-7.59 (s, 1H), 7.50-7.20 (m, 9H), 5.95-5.91 (s, 1H), 5.21. -5.15(d,1H),4.32-4.28(d,2H),3.51-3.56(m,1H),3.03-2.95(m,1H),2.69-2.60(m,1H),2.33-2.24(d, 1H), 2.16-2.06 (d, 1H), 1.80-1.72 (m, 4H), 1.45-1.32 (m, 4H).

Example 97 Synthesis of XSD1-029

Reaction 1

Compound D1 (2.2 g, 5.0 mmol), o-aldehyde phenylboronic acid (1.2 g, 7.5 mmol), K ₃ PO ₄ (3.2 g, 15 mmol), Pd(PPh ₃ ) ₄ (0.6 g, 1.0 mmol) DMF/H ₂ O (30 mL / 6 mL). The system was replaced with nitrogen, warmed to 90 ° C and stirred overnight. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. Purification by column chromatography (EtOAc: EtOAc = EtOAc)

¹ H-NMR (400 MHz, CDCl 3 ) of Compound 1 : δ (ppm) 10.47 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 7.62 7.57 (m, 2H), 7.48-7.38 (m, 11H), 7.21-7.18 (m, 6H).

Reaction 2:

Compound 1 (360 mg, 0.87 mmol), Compound 2 (117 mg, 0.87 mmol) and sodium ethoxide (88 mg, 1.3 mmol) were dissolved in THF / EOH (volume ratio 6 mL / 3 ml) and stirred at room temperature overnight with saturated The solution was diluted with EtOAc (EtOAc) (EtOAc) The crude product was beaten with a PE/EA mixture (volume ratio of 5:1), filtered, and dried to give the product compound 3 (300 mg, yield 65%).

MS of Compound 3: m/z 533.4 [M + 1].

Reaction 3:

Compound 3 (210 mg, 0.39 mmol) was dissolved in methanol (10 mL), EtOAc (EtOAc) The reaction mixture was dried with EtOAc EtOAc EtOAc m. The crude product of Compound 4, 140 mg, was used directly in the next reaction.

MS of Compound 4: m/z 291.2 [M+1].

Reaction 4:

The compound 4 (80 mg, 0.27 mmol) was dissolved in methanol (10 mL), and NaHH ₄ (32 mg, 0.83 mmol) was added, and the mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) and evaporated. The mixture was extracted with EtOAc (EtOAc) (EtOAc) The crude product was purified by pre-HPLC to give the object compound XSD1-029 (63 mg, yield: 79%).

^{1 H-NMR (400MHz, DMSO} -d6): δ (ppm) (a mixture of diastereomers) 9.34-9.30 (m, 1H), 7.92-7.86 (m, 2H), 7.75-7.63 (m, 1H), 7.53 (m, 2H), 6.15-6.07 (m, 2H), 5.80-5.74 (m, 1H), 3.80-3.67 (m, 1H), 3.20-3.02 (m, 1H), 2.38-1.59 (m, 5H) , 1.37-1.10 (m, 1H), 1.01-0.81 (m, 4H).

HPLC purity: @214nm 98.29%, @254nm 99.88%.

MS: m/z 293.3 [M + 1].

Example 98 Synthesis of XSD1-039

Reaction 1:

Mercury oxide (2.16 g, 10 mmol), iodine (7.74 g, 30 mmol) was added to compound 1 (2.12 g, 10 mmol) at 0 °C. And the solution of dichloromethane (100 mL), then the reaction temperature was slowly raised to 90 ° C to continue the reaction for 18 h, TLC (V ethyl acetate: V petroleum ether = 2:1) to monitor the reaction, after the reaction was completed, steam distillation under reduced pressure The solvent was removed, and the organic phase was extracted with ethyl acetate (100 mL*3), dried over anhydrous sodium sulfate, and concentrated, and then purified by column chromatography to afford 1.8 g of compound 2 (yield 61.2%).

¹ H-NMR (400 MHz, CDCl 3 ) of Compound 2: δ (ppm) 3.63 (s, 3H), 2.49 - 2.44 (m, 6H), 1.95-1.91 (m, 6H).

Reaction 2:

Compound 2 (1.2 g, 4.08 mmol) was dissolved in tetrahydrofuran (30 mL), EtOAc (EtOAc) EtOAc. After stirring for 2 h, then slowly warming to room temperature and stirring for 18 h, the reaction mixture was cooled to 0 ° C, and saturated aqueous ammonium chloride (20 mL) was added to quench the reaction, and the organic phase was extracted with ethyl acetate (80 mL*3) and washed with water. The mixture was washed with brine, dried over anhydrous sodium sulfate

<^1> H-NMR (400 MHz, CDCl3) of Compound 3: δ (ppm) 3.63 (s, 3H), 1.85-1.71 (m, 6H), 1.64-1.56 (m, 7H).

Reaction 3:

Compound 3a (504 mg, 4.07 mmol) was dissolved in 30 mL of anhydrous tetrahydrofuran, cooled to -70 ° C in dry ice acetone bath, and butyl lithium (8 mL, 4.07 mmol) was slowly added dropwise and kept at an internal temperature of -60 ° C or less. A solution (10 mL) of (548 mg, 3.26 mmol) in anhydrous tetrahydrofuran was added to the reaction flask and maintained at an internal temperature of -60 °C. The reaction mixture was stirred at -70 ° C for 2 hours, quenched with saturated aqueous ammonium chloride and warmed to room temperature. The extract was extracted with dichloromethane (100 mL EtOAc). The crude product was subjected to column chromatography to give the product compound 4 (284 m g, yield: 33.6%).

¹ H-NMR (400 MHz, CDCl 3 ) of Compound 4: δ (ppm) 3.76 (s, 3H), 3.73 (s, 3H), 3.15 (s, 1H), 3.09 (s, 1H), 1.86-1.61 (m) , 13H).

Reaction 4:

Compound 4 (132 mg, 0.51 mmol) was dissolved in 10 mL of anhydrous THF, and sodium hydrogen sulfate (51 mg, 1.27 mmol) was added, and the mixture was stirred at room temperature for 1 hour. A solution of Compound 4a (211 mg, 0.51 mmol) in 5 mL of anhydrous tetrahydrofuran was added to the reaction flask under ice bath. The reaction mixture was stirred at rt. EtOAc EtOAc. The crude product was subjected to column chromatography to give the product compound 5 (97 mg, yield: 34.6%).

MS of Compound 5: m/z 549.2 [M+1].

Reaction 5:

Compound 5 (99 mg, 0.18 mmol) was dissolved in 10 mL of methanol, 1 mL of glacial acetic acid was added, and the mixture was stirred at 90 ° C, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure and ethyl acetate (100 mL) The combined extracts were washed with brine, dried over anhydrous sodium sulfate The crude product of compound 6 (150 mg) was obtained and used directly in the next reaction.

MS of Compound 6 m/z 307.1 [M + 1].

Reaction 6:

Compound 6 (150 mg, 0.1 mmol) was dissolved in 5 mL of methanol. NaHH ₄ (19 mg, 0.5 mmol) was added and the mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The mixture was extracted with EtOAc (3 mL, EtOAc). Pre-HPLC gave Compound XSD 1-039 (18 mg, yield 59%).

¹ H-NMR (400 MHz, DMSO-d6): δ (ppm) 9.27 (s, 1H), 7.60-7.39 (m, 6H), 6.91 (s, 1H), 5.56 (s, 1H), 3.71 (s, 1H), 2.24-2.03 (m, 2H), 1.50-1.33 (m, 13H),

HPLC purity: @214nm 99.9%, @254nm 99.99%,

MS: m/z 309.2 [M + 1].

Example 99 Detection of indoleamine 2,3-dioxygenase inhibitory activity and determination of IC ₅₀

The construction of the plasmid containing the human indoleamine 2,3-dioxygenase gene, expression, extraction and purification in E. coli were carried out according to the method reported by Littlejohn et al. (Takikawa O, Kuroiwa T, Yamazaki F, et al. J. Biol. Chem. 1988, 263, 2041-2048). 50 mM potassium phosphate buffer (pH 6.5), 20 mM ascorbate, 20 μM methylene blue and purified human guanamine 2,3-dioxygenase protein were mixed in a 96-well plate, and 200 μML-tryptophan was added to the mixture. Inhibitor. The reaction was carried out at 37 ° C for 60 minutes, the reaction was stopped by adding 30% trichloroacetic acid, and incubated at 65 ° C for 15 minutes to hydrolyze N-formyl kynurenine to kynurenine, and centrifuged at 4000 rpm for 5 min. The precipitated protein was removed, and the supernatant was transferred to a new 96-well plate, reacted with 2% (w/v) p-dimethylaminobenzaldehyde in acetic acid, and the reaction was incubated at 25 ° C for 10 minutes. Read at 480 nm on a spectrophotometer. No indoleamine 2,3-dioxygenase inhibitors without or indoleamine 2,3-dioxygenase as control wells for the measurement parameter IC ₅₀ of each compound necessary to nonlinear regression. ₅₀ measured values and non-linear regression using GraphPad PRism 4 IC software. Compound IC ₅₀ of less than 10μM is considered to be effective inhibitors of the assay.

Table 1 IC _{50 of} each compound

化合物编号Compound number	IC₅₀(nM)IC ₅₀ (nM)
S-1S-1	99
S-2S-2	22twenty two
S-3S-3	1212
S-4S-4	1010
S-5S-5	99
S-6S-6	1212
S-7S-7	1111
S-8S-8	2828
S-9S-9	23twenty three
S-10S-10	24twenty four
S-11S-11	1111
S-12S-12	1010
S-13S-13	21twenty one
S-14S-14	1919
S-15S-15	1010
S-16S-16	1010
S-17S-17	21twenty one
S-18S-18	22twenty two
S-19S-19	23twenty three
S-20S-20	10231023

The IC ₅₀ of each compound measured according to the detection method of the above examples is shown in the following table:

Table 2 IC _{50 of} each compound

Table 3 IC _{50 of} individual compounds

Example 100 In vivo antitumor activity test of indoleamine 2,3-dioxygenase inhibitor

1. Animal grouping and test methods

The LLC cells in the logarithmic growth phase were detected by trypan blue staining, and the viable cell concentration was adjusted to 1×10 ⁷ cells/ml, and 0.2 ml/mouse was injected subcutaneously into homologous C57BL6 mice. Once the tumor was established, the mice were randomly divided into model group, cyclophosphamide (CTX) group, compound S-21 group, compound S-1 group, compound S-4 group, compound S-5 group, compound according to tumor weight and body weight. In the S-8 group, 10 in each group, the CTX group was administered intraperitoneally at 150 mg·kg ^-1 , and the compound S-21 group and the compound S-8 group were intragastrically administered. The model group was given the same volume of physiological saline at the same time. The frequency of administration in each group was once a day. The test was terminated 21 days after administration.

After 24 hours of the last administration, the animals were weighed and weighed, and the tumor was weighed. The average inhibition rate (I) was calculated as follows: I = (1 - mean tumor weight of the drug-administered group / mean tumor weight of the model group) × 100 %

2. Data statistics and processing methods

The experimental data were analyzed by spss16.0, one-way variance one way ANOV analysis, p<0.05 was considered statistically significant.

3. Test results and discussion

Table 4 Results of inhibition of compound tumors on mouse tumors in mice

Compared with the model group, ^## P<0.01;

Compared with the CTX group, ^※※ P<0.01;

Compared with the S-21 group, ^$ P<0.01.

As can be seen from Table 4, the tumor weight of each drug-administered group was significantly different from that of the model group (P<0.01); the compound S-21 group and each compound group were significantly different from the cyclophosphamide group ( P < 0.01); each compound group in the present invention was significantly different from the compound S-21 group (P < 0.05). This result indicates that the therapeutic effect of each compound in the present invention on tumors is significantly better than that of the chemotherapy drugs cyclophosphamide and compound S-21.

Table 5 Effect of compounds on body weight of mice

Compared with the cyclophosphamide group, ^## p<0.01.

As can be seen from Table 5, there was no significant difference in body weight between the respective compound groups and the model group, and there was a significant difference compared with the CTX group. This result indicates that the compound of the present invention can increase the mouse while controlling tumor growth. Weight, reduced side effects of the drug, significantly improved the quality of life of the mice. Clinically, it can improve the quality of life of patients and greatly improve the patient's medication compliance and drug effectiveness.

The inhibitory effect of the compound of the present invention on tumor was measured in the same manner as in the above examples, and the results are shown in the following table:

Table 6 Results of inhibition of compound tumors on mouse tumors in mice

Compared with the model group, ^## P<0.01;

Compared with CTX group and 1505 group, ^※ P<0.05.

It can be seen from Table 6 that the tumor weight of each drug-administered group was significantly different from that of the model group (P<0.01); there was a significant difference between each compound group and the cyclophosphamide group and the 1505 group (P<0.05). ). This result indicates that the therapeutic effect of the compound of the present invention on tumors is significantly better than that of the existing chemotherapeutic agents cyclophosphamide and compound 1505.

Table 7 Effect of Compounds on Body Weight of Mice

Compared with the cyclophosphamide group, ^## p<0.01.

As can be seen from Table 7, there was no significant difference in body weight between the respective compound groups and the model group, and there was a significant difference from the CTX group. This result indicates that the compound of the present invention has no tumor weight loss while controlling tumor growth. The phenomenon of reducing drug side effects significantly improves the quality of life of mice. Clinically, it can improve the quality of life of patients and greatly improve the patient's medication compliance and drug effectiveness. The inhibitory effect of the compound of the present invention on tumor was measured in the same manner as in the above examples, and the results are shown in the following table:

Table 8 Results of inhibition of compound tumors on mouse tumors in mice

Compared with the model group, ^## P<0.01;

Compared with the CTX group, ^※ P<0.05, ^※※ P<0.01;

Compared with the S-21 group, ^$ P<0.05.

It can be seen from Table 8 that the tumor weight of each drug-administered group was significantly different from that of the model group (P<0.01); there was a significant difference between each compound group and the cyclophosphamide group (P<0.05, P). <0.01); The compound group in the present invention was significantly different from the compound S-21 group (P<0.05). This result indicates that the therapeutic effect of the compound of the present invention on tumor is significantly better than that of the chemotherapy drug cyclophosphamide and compound S-21.

Table 9 Effect of compounds on body weight of mice

Compared with cyclophosphamide group, ^# p <0.05.

As can be seen from Table 9, the compound group of the present invention showed no significant difference in body weight compared with the model group, and there was a significant difference from the CTX group. This result indicates that the compound of the present invention has no mouse while controlling tumor growth. The phenomenon of weight loss reduces the side effects of drugs and significantly improves the quality of life of mice. Clinically, it can improve the quality of life of patients and greatly improve the patient's medication compliance and drug effectiveness.

In addition, we have also tested cell lines such as mouse colon cancer Colon26, mouse liver cancer Hepa 1-6, and mouse breast cancer 4T1, and the results show that the compounds of the present invention have a significant inhibitory effect on these tumors.

Example 101 Morris water maze detection of behavioral changes in Alzheimer's mice

1. Animal grouping and test methods

In the present invention, a 9-month-old mouse is selected according to Richardson et al., and a single injection of aggregated Aβ1-42 in the bilateral hippocampal CA3 region of rats is used to prepare an AD model, which is then divided into a model group, a compound S-1 group, a compound S- Group 4, compound S-5 group and compound S-8 group, each group of 10, male and female. Mouse behavioral analysis was performed using the Morris water maze (Ethovision XT monitoring analysis software from the Netherlands Noldus, Morris water maze system). The water maze test process was divided into two parts: the continuous 5d hidden platform acquisition test and the 6th day space exploration test. Each test was administered according to the test group and the design dose. Training 4 times a day, each time the mice are launched in different areas, the water maze is divided into 1, 2, 3, 4 areas according to the southeast and northwest, the platform is the 5th area, located in the 4th area. Each swimming time was 60s, and each training interval was about 1h. The mice did not find the platform to calculate the incubation period by 60s. The hidden platform was tested to test the ability of mice to learn; the spatial exploration test was used to detect the spatial memory ability of mice.

2. Data statistics and processing methods

Using the statistical analysis of SPSS16.0 software, the escape latency of the hidden platform acquisition experiment is tested by the multivariate analysis of variance. The test is effective. The swimming time and the number of crossing targets in each quadrant in the space search experiment are analyzed by one-way ANOVA. Data were average ± standard deviation, and the significant difference was set to two sides P = 0.05.

3. Test results and discussion

Table 10 Search platform latency (s) in each group of animals hidden platform test

Compared with the model group, ^# P<0.05, ^## P<0.01;

Compared with the S-21 group, ^※ P<0.05, ^※※ P<0.01.

Table 11 Time and number of stays in each group of animal platforms

Compared with the model group, ^# P<0.05;

Compared with the S-21 group, ^* P<0.05.

As can be seen from Tables 10 and 11, the compounds of the present invention can significantly improve learning and memory impairment in animals, significantly improve learning ability and spatial memory ability, and the effect is significantly better than the compound S-21 group. This result indicates that the compound of the present invention has great development value in the treatment of Alzheimer's syndrome.

The effects of the compounds of the present invention on behavioral changes in Alzheimer's mice were determined in the same manner as in the above examples, and the results are shown in the following table:

Table 12 Search platform latency (s) in each group of animals hidden platform test

Compared with the model group, ^# P<0.05, ^## P<0.01;

Compared with the 1505 group, ^※ P<0.05, ^※※ P<0.01.

Table 13 Residence time and frequency of each group of animal platforms

Compared with the model group, ^## P<0.01;

Compared with the 1505 group, ^※ P<0.05, ^※※ P<0.01.

As can be seen from Tables 12 and 13, each compound can significantly improve the learning and memory impairment of the animal, significantly improve the learning acquisition ability and spatial memory ability, and the effect is superior to the compound 1505, and the results indicate that the compound of the present invention is in the pair of Al The treatment of syndrome is of great developmental value.

Table 14 Search platform latency (s) in each group of animals hidden platform test

Compared with the model group, ^# P<0.05;

Compared with the S-21 group, ^* P<0.05.

Table 15 Residence time and frequency of each group of animal platforms

Compared with the model group, ^# P<0.05;

Compared with the S-21 group, ^* P<0.05.

As can be seen from Tables 14 and 15, the compounds of the present invention can significantly improve learning and memory impairment, improve learning acquisition ability and spatial memory ability, and the effect is significantly better than that of the compound S-21 group. This result indicates that the compound of the present invention has great development value in the treatment of Alzheimer's syndrome.

Example 102 DC-stimulated T cell proliferative response after drug treatment

Dendritic cells (DCs) are the most powerful antigen-presenting cells (APCs), which can effectively activate naive T cells for proliferation, which is the most important difference between DC and other APCs. DC is the initiator of immune response. DC has become one of the hotspots in immunology research because of its key role in CD4 ⁺ and CD8 ⁺ T cell immune response. At present, DC is mainly focused on tumor disease and autoimmunity. Sexual diseases, transplant rejection and prevention and treatment in anti-infection.

1. Isolation and culture of human peripheral blood dendritic cells

The peripheral blood leukocyte layer was taken and diluted with 0.01 mol/L PBS. PBMC was routinely isolated with lymphocyte stratification solution, adjusted to a cell concentration of 3×10 ⁶ ml ^-1 in complete RPMI1640 medium, added to a 6-well plate, 3 ml P-well, 5% CO 2, and cultured in a 37 ° C incubator for 2 hours. The non-adherent cells were washed away with PBS for 3 times, and culture medium containing IL-4 (100 U/ml), GM-CSF (150 ng/ml) and TNF-α (500 U/ml) was routinely cultured, and the solution was changed every other day. After 8 days of culture, it was used for identification and experiment.

2. Preparation of T cells

The human PBMC layer was separated by the method in the step 1, and the macrophage was removed by the adherence method, and the B cells were removed by the nylon hair column method, and the obtained T cells were adjusted to a cell concentration of 1 × 10 ⁶ /ml.

3. Preparation of DC

The mature DC with a purity of 99% was centrifuged, and RPMI1640 was added to adjust the cell concentration to 1 × 10 ⁵ , 4 × 10 ⁴ , 2 × 10 ⁴ / ml, and added to a 96-well plate, and each well was set to eight wells, 100 μl / well. . Compound 1505, compound XSD1-033, compound XSD1-065, compound XSD1-067, compound XSD1-068, compound XSD1-103, compound XSD1-110, and compound XSD1-126 were separately added and cultured for 2 days.

4. T cell proliferation assay (MLR)

T cells were added to each of the above-mentioned drug-added groups DC, 100 μl/well. 5% CO2, cultured in a 37 ° C incubator for 72 hours, gently aspirate 100 μl of the culture solution per well 6 hours before the end of the culture, add 10 μl of MTT (5 mg / ml), and put it in the incubator for 6 hours, then add 0.01 mol. /L HCl-10% SDS 100 μl, placed at 37 ° C overnight, the A570nm value measured by a microplate reader showed T cell proliferation level.

5. Experimental results and analysis

Table 16 Effect of each compound on the proliferation of DC-stimulated T cells

Compared with the control ^{^{group, # P <0.05, ## P}} <0.01;

Compared with the 1505 group, ^* P < 0.05.

As can be seen from Table 16, compared with the control group, the group of compounds of the present invention and the 1505 number of T cells increased, with significant difference ^{^{(# P <0.05, ## P}} <0.01), and the present invention, each Compared with the compound 1505 group, the compound group had a more significant effect on the proliferation of T cells, and there was a significant difference ( ^※ P < 0.05). This indicates that the compound of the present invention has a remarkable effect of promoting DC-stimulated T cell proliferation, and the effect is remarkably superior to that of the compound 1505, and is further useful for the treatment of tumor diseases and infectious diseases.

Example 103 Determination of Bioavailability of Each Compound

1. Animal grouping and administration

Twenty Wistar rats (270±30) g, male and female, were provided by Shandong New Times Pharmaceutical Co., Ltd. Experimental Animal Center, production license number: SCXK (Lu) 20060019. Breeding at a temperature of 20 to 22 ° C, relative humidity of 45% to 65%, light / dark 12h / 12h, free diet, drinking water. The experiment was freely divided into 2 groups of 10 each:

Compound 1505 and XSD1-103 intragastric administration group: 10 healthy Wistar rats, which had been fasted for 12 hours and were free to drink, were administered orally and administered in a single dose at a dose of 10 mg/kg. Fasting 12 hours before dosing, free drinking water. The blood was taken from the posterior venous plexus of about 300 μL before administration (0h), 0.083, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24h after administration. Heparin anticoagulation, 4°C After centrifugation at 4000 rpm for 5 min, the plasma was separated and stored in a -20 ° C low temperature freezer. Drink freely during the experiment and eat 2 hours after gavage.

Compound 1505 and Compound XSD1-103 intravenous administration group: 10 healthy Wistar rats, which had been fasted for 12 hours and were free to drink, were administered to the compound NLG919 and Compound 1-033 by tail vein injection. It is 2 mg/kg. Before the administration (0h), 0.033, 0.083, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24h after the administration, blood was taken from the orbital venous plexus for about 300 μL, and heparin was anticoagulated. After centrifugation at 4000 rpm for 4 min at 4 ° C, the plasma was separated and stored in a -20 ° C low temperature freezer. Free to eat and drink during the experiment.

2. Determination of plasma samples

All processed plasma samples were subjected to UPLC-MS/MS quantitative analysis to determine plasma drug concentration

3. Calculation of bioavailability

The measured plasma concentration-time data was calculated using DAS software (Drug and Statistics, Chinese Academy of Mathematical Pharmacology, Sun Ruiyuan, etc.) to calculate pharmacokinetic parameters. The absolute bioavailability of each compound was calculated according to the formula, and t is the sampling time of the last measurable drug concentration.

The bioavailability of the compounds S-21, XSD1-033, XSD1-065, XSD1-110 and XSD1-126 can be determined by the same method as in the above examples.

4. Absolute bioavailability of each compound

Table 17 Bioavailability of each compound

As can be seen from the above table, the bioavailability of the compound XSD1-103 in the present invention is significantly higher than the bioavailability of the structural analog 1505, and the bioavailability of each compound in the present invention is significantly higher than that of the compound 1505 and S-21, which indicates that the compounds of the present invention have significant advantages in terms of drug-forming properties.

Claims

a compound of formula I or a pharmaceutically acceptable salt thereof:

Where n takes 0 or 1 or 2 or 3;

n 3 takes 0 or 1 or 2;

R 0 is selected from the group consisting of OH, C(O)OH, amino, amide, aminoacyl, heteroaryl containing at least one N or O or S, halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano , amino, aryl, heteroaryl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkoxy substituted C1-6 alkoxy or containing at least one N or O or S Heteroaryl, substituted by halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkoxy Carbonyl group, amino group substituted by C1-6 alkyl group, 2-8 membered heteroalkyl group, 3-12 membered heterocycloalkyl group, C1-6 alkoxy group, C3-12 cycloalkenyl group, aryl group, heteroaryl group , amide group, aminoacyl group;

R 5-8 is linked to the benzene ring by a single bond, and is independently selected from H 00 , R 1 , R 2 , R 3 , R 4 , R 9 , and R 10 independently from H, NH 2 , halogen, CN, CX 3- s H s , OH, C(O)OH, C(O)H, alkenyl, alkynyl, fluorenyl, sulfonamido, sulfone, sulfoxide, nitro, alkanoyl, phosphate, urea Base, carbonate group, C1-6 alkyl group, 2-8 membered heteroalkyl group, 3-12 membered heterocycloalkyl group, C1-6 alkoxy group, C3-12 cycloalkenyl group, C2-6 alkenyl group, aromatic Base, heteroaryl, amido, aminoacyl, halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, 2-8 membered heteroalkyl, 3-12 a heterocycloalkyl group, a C1-6 alkoxy group, a C3-12 cycloalkenyl substituted C1-6 alkyl group or a C3-12 cycloalkyl group or a C1-6 alkoxy group or an aryl or heteroaryl group, which is halogen , cyano, amino, aryl, heteroaryl, C1-6 alkyl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkoxy substituted carbonyl, C1-6 Alkyl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkoxy, C3-12 cycloalkenyl, aryl, heteroaryl substituted amino, amido, aminoacyl; or

R 5-8 forms a benzo structure with a benzene ring, and takes a C 3-12 cycloalkyl group, a C 3-12 cycloalkenyl group, a 3-12 membered heterocycloalkyl group, a 3-12 membered heterocycloalkenyl group, an aryl group, and a heteroaryl group. Base, by halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkane An oxy, C3-12 cycloalkenyl substituted C3-12 cycloalkyl or C3-12 cycloalkenyl or 3-12 membered heterocycloalkyl or 3-12 membered heterocycloalkenyl or aryl or heteroaryl;

The number n 2 of R 5-8 is 0 or 1 or 2 or 3 or 4;

R 11 is a cycloalkane or a cyclic olefin having a bridged ring structure.
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein n = 1, n 3 = 0, R 0 is selected from OH, R 00 , R 1 , R 2 , R 3 , R 4 , R 5-8 and R 10 are each independently selected from H.
The compound of formula 1 or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 11 is selected from
Wherein C 1 in formula I is linked to any position where the valence bond on ring r 1 is reasonable; n 0 is 0 or 1 or 2 or 3; R is a substituent at any position where the valence bond on ring r 1 is reasonable; R r of the ring linked to the ring mode 1 r 1 share one or more atoms; each R is independently selected from the following substituent group: = O, = S, = NR 2, = C (R 2) 2, = ( spiro Ring-C3-12 cycloalkyl), or = (spiro-(3-10 membered heterocyclyl)), or

Each R is independently selected from the group consisting of H, NH 2 , halogen, CN, CF 3 , OH, C(O)OH, C(O)H, sulfonamido, sulfone, sulfoxide, nitro, Phosphate group, ureido group, carbonate group, C1-6 alkyl group, C3-12 cycloalkyl group, C3-12 cycloalkenyl group, C1-6 heteroalkyl group, C3-12 heterocycloalkyl group, aryl group, hetero Aryl, amide, aminoacyl, C1-6 alkyl or C1-6 substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl Alkoxy or aryl or heteroaryl, carbonyl substituted by halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, C3-12 cycloalkyl, by C1-6 alkyl, C3 -12 cycloalkyl, C 3-12 cycloalkenyl, aryl, heteroaryl substituted amino, amide, aminoacyl;

The number of R is n 1 , n 1 is any integer between 0-14 (including the end value) (for example, n 1 is 1); s is 0 or 1 or 2; a is a double bond; the position of a is located Any position where the valence bond on ring r 1 is reasonable; the number of a is 0 or 1 or 2 or 3. When the number of a is 0, a does not represent a double bond, but represents a single bond; x and y are independent It is selected from 0 or 1 or 2 or 3, but not both.
The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein s is 1; n 0 is 1; x and y are each one of 1 and 0, or both are 1; =0.
A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein said R is selected from the group consisting of

Wherein L 0 is selected from the group consisting of the following double bond substituents: =O, =S(=O) s , =C(R 2 ) 2 , =(spiro-C3-12 cycloalkyl), =heteroaryl or = (spiro-(3-10 membered heterocyclyl)), wherein = (spiro-C3-12 cycloalkyl), =heteroaryl or =(spiro-(3-10 membered heterocyclyl)) Substituted by one or more R 2 ;

or

Selected from the following single bond substituents: H, NH 2 , halogen, CN, CF 3 , OH, C(O)OH, C(O)H, heteroalkyl, alkenyl, alkynyl, heterocycloalkyl, sub Sulfonylamino, sulfone, sulfoxide, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, aryl, heteroaryl Alkyl, amide, aminoacyl, C1-6 alkyl or C3-12 ring substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl Alkyl or C1-6 alkoxy or aryl or heteroaryl.
A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein said R is selected from the group consisting of
Wherein A is selected from N, S, P, O; W is selected from C or S or P; = O is s, s is 0 or 1 or 2; R 1 is selected from hydrogen, amino, nitro, carbonyl , fluorenyl, halogen, CN, CX 3-s H s , OH, C(O)OH, C(O)H, sulfinylamino, sulfone, sulfoxide, nitro, alkanoyl, phosphate , ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C2-6 alkenyl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl , aryl, heteroaryl, amido, aminoacyl, halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C1-6 alkyl, 3-12 a cycloalkyl group, a 3-12 membered heterocycloalkyl substituted fluorenyl or carbonyl group or a C1-6 alkyl group or a C1-6 alkoxy group or an aryl group or a heteroaryl group or an amide group or an aminoacyl group or an amino group or a 2- 8-membered heteroalkyl or sulfone group or sulfoxide group.
A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein said R is selected from the group consisting of

Wherein A is selected from N, S, P, O; wherein, N, P are substituted by R 1 , S is substituted by R 1 or one or two = O; n is selected from an integer of 0 to 6; Each of R 1 , L 00 and R 3 of N or S is independently selected from the group consisting of amino, sulfone, nitro, carbonyl, decyl, halogen, CN, CX 3-s H s , OH, C(O)OH, C (O)H, sulfonamido, sulfone, sulfoxide, nitro, alkanoyl, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 Cycloalkenyl, C2-6 alkenyl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, aryl, heteroaryl, amido, aminoacyl, halogen, amino, oxo, hydroxy, Carboxyl, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl substituted fluorenyl or carbonyl or C1- 6 alkyl or C1-6 alkoxy or amido or aminoacyl or aryl or heteroaryl or amido or aminoacyl or amino or 2-8 membered heteroalkyl or sulfone or sulfoxide; x is taken as 0 Or 1 or 2, y takes 2 or 1 or 0; p takes 1 or 2 or 3 or 4 or 5; q takes 1 or 2 or 3 or 4; B is C or N or O or S, the number of which is 0 or 1 or 2, the position is α, β on the ring Any one or two of the γ, δ, and ε positions; b is a double bond, the number of which is 0 or 1 or 2, and its position is any position where the valence bond on the ring is reasonable.
A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R is selected from

Wherein R 1 is selected from H or C 1-6 alkyl, and R 3 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 5-10 aryl, C 3-6 cycloalkyl , C 1-6 alkyl C 5-10 aryl, C 1-6 alkyl C 3-6 cycloalkyl, C 5-10 heteroaryl, C 3-6 heterocyclyl, C 1-6 alkyl a C 5-10 heteroaryl group, a C 1-6 alkyl C 3-6 heterocyclic group, the hetero atom is selected from 1 to 3 N, O or S, and the above group is optionally a halogen, a nitro group or an amino group. , cyano, hydroxy, -S(O) 2 NH 2 , -S(O) 2 NH 2 , -NC 1-6 alkyl S(O) 2 , -NHS(O) 2 , -NHS(O) 2 NH 2 , -NC 1-6 alkyl S(O) 2 NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 5-10 aryl, C 3-6 cycloalkyl, C 5 -10 heteroaryl, C 3-6 heterocyclyl substituted, or cycloalkyl optionally oxo;

L 0 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, C 5-10 aryl, C 3-6 cycloalkyl, -S(O) 2 C 1-6 alkyl, - S(O) 2 C 5-10 aryl, C 1-6 alkyl C 5-10 aryl, C 1-6 alkyl C 3-6 cycloalkyl, C 5-10 heteroaryl, C 3- a 6 heterocyclic group, a C 1-6 alkyl C 5-10 heteroaryl group, a C 1-6 alkyl C 3-6 heterocyclic group, the hetero atom being selected from 1 to 3 N, O or S, The group is optionally halogen, nitro, amino, cyano, hydroxy, -S(O) 2 NH 2 , -S(O) 2 NH 2 , -NC 1-6 alkyl S(O) 2 , -NHS (O) 2 , -NHS(O) 2 NH 2 , -NC 1-6 alkyl S(O) 2 NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 5-10 aryl , C 3-6 cycloalkyl, C 5-10 heteroaryl, C 3-6 heterocyclyl, or cycloalkyl, optionally oxo.
A compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein said R is selected from the group consisting of
Wherein n 1 is any integer between 0 and 5 (inclusive); n 2 is 0 or 1 or 2 or 3.
A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein said R 11 is selected from the group consisting of
Wherein R is simultaneously bonded to any two atoms of the α, β, γ, and δ positions on the ring r 1 to form a covalent bond n 1 of 0 or 1 or 2 or 3.
The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the ring r 1 is selected from
A compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein said R 00 is H, and said compound of formula I is

Where n takes 0 or 1 or 2 or 3;

C 1 and r 1 are linked to the α or β or γ position;

n 1 is 0 or 1 or 2 or 3;

n 2 takes 0 or 1 or 2 or 3;

n 3 takes 0 or 1 or 2;

The number of a is 0 or 1 or 2.
The compound according to any one of claims 1 to 12, wherein the C 1 and r 1 rings are linked to the α position, and the R and r 1 rings are linked to the δ position, R 00 Is H, the compound is

Each group in the above structure is as defined in the preceding claims.
A compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, wherein said C 1 and r 1 rings are linked to the alpha position, and the R and r 1 rings are linked to δ. Bit, as in the formula XXXIII,
Each group in the above structure is as defined in the preceding claims.
A compound of formula I, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is selected from the group consisting of:
A process for the preparation of the compound of claim 1, which is represented by the formula TM-IX, which comprises the steps of: reducing the M6 with a reducing agent to obtain the target compound TM-XI;

The reducing agent is preferably at least one of NaBH 4 , KBH 4 , and NaBH 4 /LiCl.
The method according to claim 16, wherein said M6 is obtained by ring-forming and deprotecting M5 in the presence of an acid;

The acid is selected from the group consisting of alkyds, aromatic acids, eno acids, saturated fatty acids, and phenols.
The method according to claim 17, wherein said M5 is obtained by reacting M4 with 4a in the presence of a strong base;

Wherein R 4 is H; the strong base is selected from the group consisting of an alkyl metal lithium compound, an aromatic alkali metal compound, an aromatic alkyl alkali metal compound, an amine lithium compound, an alkali metal hydride, and a fatty alcohol alkali metal salt.
The method according to claim 18, wherein said M4 is obtained by reacting M3 with 3a in the presence of a base;

The base is selected from the group consisting of alkyl lithium, cycloalkyl lithium or aryl lithium.
The method of claim 19 wherein said M3 is obtained by reacting M2 with 2a:

Wherein, when L 0 is selected from the following double bond substituents: =O, =S(=O) s , =C(R 2 ) 2 , =(spiro-C3-12 cycloalkyl), =heteroaryl or = (spiro-(3-10 membered heterocyclyl)).
The method according to claim 20, wherein said L 0 is selected from the group consisting of a substituent of the following double bond: = (spiro-C3-12 cycloalkyl), = heteroaryl or = (spiro-(3) -10 membered heterocyclic group)) is substituted by one or more R 2 , and a condensing agent and a base are added to the reaction, and the condensing agent is selected from the group consisting of HBTU, DMC, HOBT, HOBT/EDCI, HATU, HATU/DIEPA, DCC, CDI , isopropyl chloroformate.
The method of claim 20 wherein said M2 is obtained by reacting M1 with chloride:
The chloride is at least one selected from the group consisting of phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosgene, thionyl chloride, trimethylchlorosilane, and α,α,α-trichlorotoluene.
A process for the preparation of a compound of claim 1 which is represented by the formula Z-II and which comprises the steps of:

Among them, the number of a is 1.
A process for the preparation of a compound of claim 1 which is represented by Formula II and which comprises the steps of:

Compound Z-5 is reduced with a reducing agent to give the target compound II; wherein the reducing agent is selected from the group consisting of NaBH 4 , KBH 4 or NaBH 4 /LiCl.
The method according to claim 24, wherein the synthesizing step of the C 1 and r 1 ring in the compound Z-5 linked to the α-position of the compound Z-5 is as follows:
Compound Z-4 is cyclized and deprotected in the presence of an acid to give compound Z-5; wherein the acid is selected from the group consisting of alkyds, aromatic acids, eno acids, saturated fatty acids, phenols.
The method according to claim 25, wherein in the method for synthesizing the compound Z-5, the C 1 and r 1 rings in the compound Z-4 are linked to the β-position, and the synthesis of the compound Z-4 is as follows:

Compound Z-2 is reacted with compound 3 in the presence of an organic base to form compound Z-4, wherein the organic base is selected from the group consisting of lithium metal alkyl compounds, aromatic alkali metal compounds, aromatic alkyl alkali metal compounds, and amine groups. A lithium compound, an alkali metal hydride, an alkali metal salt of a fatty alcohol.
The method according to claim 26, wherein the C 1 and r 1 rings in the compound Z-4 are linked to the α position, and the synthesis of the compound Z-4 is as follows:
Wherein, the strong base is selected from the group consisting of tC 4 H 9 OK, NaH, Ph 3 CNa, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium t-butoxide; lithium metal alkyl compound, butyl lithium, phenyl Lithium; an amine lithium compound, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS).
The method according to claim 27, wherein the synthesis of the compound Z-3, the synthesis of the compound Z-3 is as follows:
The method of claim 28, wherein the step of synthesizing the compound M3 is as follows:

Wherein, said X is selected from the group consisting of Cl, Br, and I; said M is selected from the group consisting of Li, Na, and K; and said reducing agent is selected from the group consisting of butyl lithium, t-butyl lithium, tributyltin hydrogen, zinc/acetic acid; The chloride is at least one selected from the group consisting of phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosgene, thionyl chloride, trimethylchlorosilane, and α,α,α-trichlorotoluene.
The method according to claim 29, wherein the synthesis method of the compound Z-2, wherein n 3 is 0 or 1 or 2; the synthesis step of the compound Z-2 is as follows:

Compound Z-2-x is reacted with compound 1a to obtain compound Z-2-1; wherein said R a is selected from H, a boronic acid group, an alkenyl boronic acid group or a boronic acid ester group; said ligand R b It is selected from the group consisting of PPh 3 , AsPh 3 , n-Bu 3 P, (MeO) 3 P, Ph 2 P(CH 2 ) 2 PPh 2 , Ph 2 P(CH 2 ) 3 PPh 2 ; Cl, Br, I, trifluoromethanesulfonate group; the base is selected from the group consisting of potassium carbonate, cesium carbonate, sodium t-butoxide, potassium acetate, potassium phosphate, cesium hydroxide, cesium carbonate.
A process for the preparation of a compound according to claim 1, which is represented by the formula TM-X 0 , the process comprising the steps of: compound 5 is reduced to give the target compound TM-X 0 ;

Wherein, the reducing agent is NaBH4, KBH4, NaBH4/LiCl.
The method according to claim 31, wherein said compound 5 is obtained by ring-forming, deprotecting compound 4 in the presence of an acid;
The acid is selected from the group consisting of alkyds, aromatic acids, eno acids, saturated fatty acids, and phenols.
The method according to claim 32, wherein the compound 4 is synthesized by reacting compound 3 with 4a in the presence of a strong base to obtain compound 4;

Wherein R4 is H; the strong base is selected from the group consisting of t-C4H9OK, NaH, KH, Ph3CNa, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium t-butoxide, lithium metal alkyl compounds, and lithium amine compounds.
The method according to claim 33, wherein said compound 3 is obtained by reacting Compound 2 with 3a in the presence of a base;
The base is selected from the group consisting of alkyl lithium, cycloalkyl lithium or aryl lithium.
The method according to claim 34, wherein the compound 2 is obtained by the following steps: in the compound 1, sequentially adding triethylamine, diphenyl azide, and reacting to obtain the compound 2
A process for the preparation of a compound according to claim 1, which is represented by the formula TM-X 1 , the process comprising the steps of: reducing the compound TM-X0 with a reducing agent to obtain the target compound TM-X1;

The acid is selected from at least one of hydrochloric acid, hydrobromic acid, and sulfuric acid.
A process for the preparation of a compound according to claim 1, which is represented by the formula INT2, which comprises the step of reducing the compound INT1 to give the target compound INT2:

Among them, the reducing agent is NaBH4, KBH4, NaBH4/LiCl.
The method according to claim 37, wherein the compound INT1 is obtained by the following steps: compound 5 (INT) is hydrolyzed under acidic conditions to obtain compound INT1;

Compound 5 (INT) is deprotected under acidic conditions to give compound INT1.
A process for the preparation of a compound according to claim 1, which is represented by the formula TM-XXXIV 0 , which comprises the step of reducing the compound INT3 to give the target compound TM-XXXIV 0
The method according to claim 39, wherein said compound INT3 is obtained by the following steps: compound INT1 and L 0 -W(=O)s-Cl or L 0 -W(=O)s-OH Reaction to obtain the target compound INT3:
A process for the preparation of a compound according to claim 1, which is represented by the formula TM-XXXIII, which comprises the process of the following steps, the steps being as follows:

Compound 3 is reduced to give the target compound TM-XXXIII.
The method of claim 41 wherein said compound 3 is obtained by the following steps:

Compound INT1 is reacted with Compound 2 to give Compound 3.
The method of claim 42 wherein said compound 2 is obtained by the following steps:

Compound 1 is reacted with triphosgene (triphosgene) under basic conditions to obtain compound 2; the base is selected from trialkylamine; specifically, at least one selected from the group consisting of trimethylamine, triethylamine, and tripropylamine.
The use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of guanamine 2,3-dioxygen A pathology characterized by an enzyme-mediated pathology of the tryptophan metabolism pathway.
The use of a compound according to claim 44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the preparation of a medicament for the treatment of cancer, infectious diseases, neurodegenerative diseases, depression, anxiety Or age-related cataracts.
The use of a compound according to claim 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament, wherein the cancer is selected from the group consisting of lung cancer, liver cancer, colon cancer, pancreatic cancer, breast cancer, prostate cancer, brain Cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head and neck cancer, lymphoma, melanoma or leukemia.
The use of a compound according to claim 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament, wherein said neurodegenerative disease refers to Alzheimer's disease.
The use of a compound according to claim 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament, wherein the infectious disease refers to an infection caused by bacteria, fungi, viruses or parasites.