WO2017198159A1 - Imidazole derivative containing bridge ring - Google Patents

Imidazole derivative containing bridge ring Download PDF

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Publication number
WO2017198159A1
WO2017198159A1 PCT/CN2017/084604 CN2017084604W WO2017198159A1 WO 2017198159 A1 WO2017198159 A1 WO 2017198159A1 CN 2017084604 W CN2017084604 W CN 2017084604W WO 2017198159 A1 WO2017198159 A1 WO 2017198159A1
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group
compound
1h
selected
reaction
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PCT/CN2017/084604
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French (fr)
Chinese (zh)
Inventor
张贵民
王升兰
孙成宏
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鲁南制药集团股份有限公司
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Priority to CN201610326530.4 priority Critical
Priority to CN201610326530.4A priority patent/CN107383012A/en
Priority to CN201610510930.0 priority
Priority to CN201610510930.0A priority patent/CN107556316A/en
Application filed by 鲁南制药集团股份有限公司 filed Critical 鲁南制药集团股份有限公司
Publication of WO2017198159A1 publication Critical patent/WO2017198159A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles
    • A61K31/41881,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems

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 derivatives containing a bridged ring FIELD

The present invention relates to the pharmaceutical field, particularly it relates to imidazole derivatives and their preparation and use containing bridged rings.

BACKGROUND Field

Indoleamine 2,3-dioxygenase, an enzyme-containing monomer is heme, L- tryptophan capable of catalyzing the epoxidation of indole cracking to kynurenine (kynurenine). Indoleamine 2,3-dioxygenase high expression leads to local depletion of tryptophan cells, induce T cell arrest in G1 phase, thus inhibiting the proliferation of T cells. On the other hand, indoleamine 2,3-dioxygenase dependent degradation of tryptophan kynurenine leads to increased levels of oxygen radicals also induce T cell mediated apoptosis. Third, increased dendritic cell expression of indoleamine 2,3-dioxygenase strengthen the immune suppression (of Treg) partially mediated by regulatory T cells localized degradation of tryptophan, so that the body of a tumor-specific antigen the peripheral immune tolerance. Indoleamine 2,3-dioxygenase antitumor immunotherapy has become the most important target for regulation of small molecules.

Found indoleamine 2,3-dioxygenase associated with a number of physiological processes, in 1998, Munn and other studies revealed fetal maternal genotype is able to secure thereto through pregnancy without being excluded because engagement placenta trophoblastic cell body layer of synthetic indoleamine 2,3-dioxygenase, which inhibit the maternal rejection of the fetus T cell response through the bloodstream. They further subcutaneously implanted in pregnant mice containing the indoleamine 2,3-dioxygenase inhibitor 1-methyl-tryptophan release capsules of exclusion embryo abortion (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 abnormal immune response caused by the diseases such as transplant rejection, autoimmune diseases and indoleamine 2,3-dioxygenase closely related.

Although cancer treatment in recent years has made great progress, but clinical efficacy is still unsatisfactory. Immune escape is one of the main biological mechanisms of tumorigenesis and metastasis, it has become an important factor affecting tumor therapeutic effect. Indoleamine 2,3-dioxygenase enzyme as an immunomodulator, can effectively suppress T cell function and enhance Treg cell function and induction of NK cell dysfunction, and tumor cells of the body can use these mechanisms inherent immunomodulatory evade identification and destruction of the immune system (TRANSACTIONS Taki, Wang Yu Chinese Journal of cancer Biotherapy, 2004,21 (6): 693-7). In order for cancer patients can get the best benefit from treatment, escape to a reasonable adjustment for tumor immune therapy strategies is imperative. Indoleamine the present invention is 2,3-dioxygenase inhibitor effective to modulate a patient's immune system to block tumor immune escape, for most of the spontaneous tumors showed good therapeutic effect. Based regulation of the immune system, the present invention indoleamine 2,3-dioxygenase inhibitors may be in addition to the treatment of tumors, also can be treated for other diseases such as chronic immune-related infection and AIDS.

Indoleamine 2,3-dioxygenase and is closely related to diseases of the nervous system, can reduce the level of serotonin and lead to depression, anxiety and other psychiatric disorders can also result in quinolinic acid in the brain and other neurotoxic metabolite the cumulative product, as it is closely related to the neurodegenerative disease is Alzheimer's disease. Indoleamine 2,3-dioxygenase may affect the function of the brain by at least two mechanisms: 1) the inflammatory response by metabolic tryptophan, reducing the concentration of tryptophan circulating, so that serotonin levels are reduced , resulting in depression; 2) the catalytic cycle of tryptophan metabolic pathway of kynurenine and kynurenine cause neurotoxicity quinolinic acid accumulation. (. Ling Lei, Kuangchun Xiang, Yang Qing China Chemical Pharmaceutical Journal, 2009,19 (2): 147-154).

SUMMARY:

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

Figure PCTCN2017084604-appb-000001

Wherein, n 0 or 1 or 2 or 3;

n 3 0 or 1 or 2;

R 0 is selected from OH, C (O) OH, amino, amido, acyl group, containing at least one O or S or N heteroaryl, halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano , amino, aryl, heteroaryl, 2-8 membered heteroalkyl, 3-12-membered heterocycloalkyl, C1-6 alkoxy substituted by 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, substituted C1-6 alkyl, 2-8 membered heteroalkyl, 3-12-membered heterocycloalkyl, C1-6 alkoxy, a C3-12 cycloalkenyl group, an aryl group, heteroaryl group , an amide group, an amino group;

R 5-8 to take a single bond linked with a benzene ring, and R 00, R 1, R 2 , R 3, R 4, R 9, R 10 are each independently selected from H, NH 2, halo, CN, CX 3-s H s, OH, C (O ) OH, C (O) H, alkenyl group, alkynyl group, a sulfonamido group, a sulfone group, a sulfoxide group, a nitro group, an alkoxy group, a phosphate group, a urea group, a carbonate group, C1-6 alkyl, 2-8 membered heteroalkyl, 3-12-membered heterocycloalkyl, C1-6 alkoxy, a C3-12 cycloalkenyl group, a C2-6 alkenyl group, an aryl group, a heteroaryl groups, amido, acyl, halo, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, 2-8 membered heteroalkyl, 3-12-membered heterocycloalkyl yl, C1-6 alkoxy, C3-12 cycloalkenyl or C3-12 alkyl group substituted with a C1-6 cycloalkyl or C1-6 alkoxy or aryl or heteroaryl group, halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, 2-8 membered heteroalkyl, 3-12-membered heterocycloalkyl, C1-6 alkoxy substituted carbonyl group, a C1-6 alkyl group, 2 8-membered heteroalkyl, 3-12-membered heterocycloalkyl, C1-6 alkoxy, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group substituted with an amino, amido, acyl; or

R 5-8 and the phenyl ring to benzene structure, taken C3-12 cycloalkyl, C3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12-membered heterocycloalkenyl, aryl, heteroaryl groups, halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, 2-8 membered heteroalkyl, 3-12-membered heterocycloalkyl, C1-6 alkoxy group, C3-12 cycloalkenyl group substituted by C3-12 cycloalkyl or C3-12 cycloalkenyl group or a 3-12 membered heterocycloalkyl or 3-12 membered heterocycloalkenyl or heteroaryl group or an aryl group;

N 2 number of R 5-8 is 0 or 1 or 2 or 3 or 4;

R 11 is a ring-containing structure or cycloalkene ring bridge.

In some aspects, R 11 is selected from the above-described

Figure PCTCN2017084604-appb-000002
Wherein any position of the link valency on a reasonable C 1 and the ring of r; substituent group at any position of R is a cycloalkyl r valences on a reasonable;; n-0 0 or 1 or 2 or 3 R ring r embodiment 1 is linked with the ring r 1 share one or more atoms; each R is independently selected from the following substituent group: = O, = S (= O) s, = NR 2, = C (R 2) 2, = ( spiro cycloalkyl -C3-12 cycloalkyl), or = (spiro - (3-10 membered heterocyclyl group)), or

Each R is independently selected from the following substituent group: H, NH 2, halo, CN, CF 3, OH, C (O) OH, C (O) H, a sulfonamido group, a sulfone group, a sulfoxide group, a nitro group, phosphate, urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, C1-6 heteroalkyl, a C3-12 heterocycloalkyl, aryl, heteroaryl, an aryl group, an amide group, amino group, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, an aryl group, a heteroaryl group, a C3-12 cycloalkyl or C1-6 alkyl substituted by C1-6 alkoxy or aryl or heteroaryl group, halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, a C3-12 cycloalkyl group substituted with a carbonyl group, a C1-6 alkyl group, C3 -12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group substituted with an amino, amido, acyl;

R is the number of n 1, n 1 is any one between 0-14 (inclusive) an integer; S is 0 or 1, or 2; a is a double bond; ring r a valence bond is located on a any reasonable position; a is 0 or a number 1 or 2 or 3; when a number is 0, the corresponding position valence bond is a single bond; X, Y are each independently selected from 0 or 1 or 2 or 3.

Α or β phase on a link ring r 1 C 1 and in some aspects.

In some embodiments, R is selected from the above-described

Figure PCTCN2017084604-appb-000003
Wherein, L 0 double bond substituents selected from the following group: = O, = S (= O) s, = C (R 2) 2, = ( spiro cycloalkyl -C3-12 cycloalkyl), aryl, or heteroaryl = = (spiro - (3-10 membered heterocyclyl)), where = (spiro cycloalkyl -C3-12 cycloalkyl), aryl, or heteroaryl = = (spiro - (3-10 membered heterocyclyl)) with one or more substituents R 5-8;

or

Substituent group selected from a single bond: H, NH 2, halo, CN, CF 3, OH, C (O) OH, C (O) H, heteroalkyl, alkenyl group, alkynyl group, a heterocyclic group, an alkylene a sulfonamido group, a sulfone group, a sulfoxide group, a nitro group, a phosphate group, a urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group, amide group, amino group, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl or substituted C3-12 cycloalkyl C1-6 alkyl alkyl or C1-6 alkoxy group, or an aryl or heteroaryl group;

In some embodiments, R is selected from the above-described

Figure PCTCN2017084604-appb-000004
Wherein, A is selected from N, S, P, O; W is selected from C or S or P; = O the number of s, s 0 or 1 or 2; each R 1, R 3 is independently selected from hydrogen, an amino group, a nitro group, a carbonyl group, amidino, halo, CN, CX 3-s H s, OH, C (O) OH, C (O) H, a sulfonamido group, a sulfone group, a sulfoxide group, a nitro group, alkanoyl group, a phosphate group, a urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, a C2-6 alkenyl, 2-8 membered heteroalkyl, 3- 12 yuan heterocycloalkyl, aryl, heteroaryl, amido, acyl, halo, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, or substituted amidino group, or C1-6 alkyl carbonyl or C1-6 alkoxy group, or an aryl or heteroaryl group, or an amide or ammonia acyl, or amino or a 2-8-membered heteroalkyl or a sulfone group or sulfoxide group.

In some embodiments, R is selected from the above-described

Figure PCTCN2017084604-appb-000005
Figure PCTCN2017084604-appb-000006
Figure PCTCN2017084604-appb-000007
Wherein, x 0 or 1 or 2, y takes 2 or 1 or 0; P takes 1 or 2 or 3 or 4 or 5; q of 1, or 2 or 3 or 4; B is C or N or O or S, It is the number 0 or 1 or 2, which is any position on the ring a α, β, γ, δ and ε or two bits; B is a double bond, which is the number 0 or 1 or 2; position reasonable valences any position on the ring; when the number of b is 0, its corresponding position valence bond is a single bond. "

In some embodiments, R is selected from the above-described

Figure PCTCN2017084604-appb-000008
Wherein any one of n 1 is an integer of between 0-5 (inclusive); n-2 is 0 or 1 or 2 or 3.

In some embodiments, R 11 is selected from the above-described

Figure PCTCN2017084604-appb-000009
Wherein, α R r 1 while the ring is connected, gamma], any two atoms δ β position, form a covalent bond; n-1 takes 0 or 1 or 2 or 3.

In some embodiments, r 1 is selected from the above-described ring

Figure PCTCN2017084604-appb-000010
Figure PCTCN2017084604-appb-000011
Figure PCTCN2017084604-appb-000012

In some aspects, L 0 double bond substituents selected from the following group: = O, = C (R 2) 2, = ( spiro cycloalkyl -C3-12 cycloalkyl), aryl, or heteroaryl = = (spiro - ( 3-10 membered heterocyclyl)), where = (spiro - (3-10 membered heterocyclyl)) in the heterocyclic ring containing at least one N or O or S.

In some aspects, A is selected from N, S, O; wherein, N, P L 00 are substituted, S L 00 are substituted or one or two = O.

In some embodiments, the heteroaryl group selected from pyridine, pyrimidine, pyrazine, pyridazine, triazine.

In some aspects, a C3-12 heterocyclyl group selected from furan, pyrrole, thiophene, pyridine, quinoline, purine, indole, benzimidazole, pyrrole, pyrrolidine, pyran, dioxolane, dioxane ring, pyrazole, imidazole, oxazole, thiazole, triazole, morpholine, piperidine, piperazine.

In some aspects, R 5-8 are each independently selected from: H, OH, C1-6 alkyl, halo, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3- 12 C1-6 alkyl substituted cycloalkyl.

In some aspects, R 5-8 is selected from an aryl group containing at least one N 3-8 membered heteroaryl or O or S, C3-8 cycloalkyl, a C3-8 cycloalkenyl, 3-10 membered heteroaryl cycloalkyl groups, wherein an aryl group containing at least one N 3-8 membered heteroaryl or O or S, C3-8 cycloalkyl, a C3-8 cycloalkenyl group, a 3-10 membered heterocyclic group each substituted by one or a plurality of R 1.

In some aspects, R 5-8 is selected from aryl, five- or six-or seven-membered heteroaryl containing at least one N or O or S group, monocyclic C5-8 cycloalkyl, C5-8 monocyclic ring alkenyl group, five or six membered monocyclic heterocyclyl, or (C5-8 monocyclic cycloalkyl) a C1-6 alkyl group, wherein each of the above groups substituted with one or plural R 1 s are independently and optionally substituted with .

In some aspects, R 5-8 is selected from aryl or a five or six membered containing at least one O or S or N heteroaryl, wherein each of the above groups substituted with one or two substituents that R 1 may.

In some embodiments, R 5-8 is selected from any position of the following groups: phenyl, pyridyl, pyrimidyl, pyranyl, furyl, pyrrolyl, thienyl, pyridyl, quinolyl, cyclopropane , cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and each of the above groups substituted with one or plural R 1 s optionally and independently substituted.

In some embodiments, each of R, R 1 ~ R 4, R 5-8, R 9, R 10 are each independently selected from H, NH 2, CN, methyl, ethyl, propyl, isopropyl, butyl, , iso-butyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2 - dimethylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl group, pentyl group, a pentyl group, a pentyl propyl, butyl pentyl, hexyl group, hexyl group, a hexyl propyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, methoxycarbonyl, ethoxycarbonyl, carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, iso-butoxycarbonyl, B oc group, methylsulfonyl, ethyl sulfone, propyl sulfone, propyl sulfone, butyl sulfone, isobutyl sulfone group, a tert-butyl sulfone group, pentyl sulfone group, 1-methylbutyl sulfone, 2-methylbutyl sulfone group, a sulfone group 3-methylbutyl, 1,1-dimethylpropyl sulfone, 2,2-dimethyl propyl sulfone group, a 1,2-dimethylpropyl sulfone group, 1-ethylpropyl sulfone, hexyl sulfone, methyl pentyl sulfone, ethyl pentyl sulfone, pentyl Sulfone group, butyl pentyl sulfone, methyl hexyl sulfone, ethyl hexyl sulfone, propyl hexyl sulfone, methyl phenyl sulfone, ethyl phenyl sulfone, propyl phenyl sulfone group, cyanophenyl sulfone group, diphenyl sulfone group, sulfone group chlorophenyl, fluorophenyl sulfone group, bromophenyl sulfone group, a sulfone group cyclopropyl, cyclobutyl sulfone group, cyclopentyl sulfone group , cyclohexyl sulfone group, cyclopropyl methyl sulfone, cyclopropyl ethyl sulfone, propyl sulfone group cyclopropyl, cyclobutyl methyl sulfone group, cyclobutyl ethyl sulfone, propyl sulfone cyclobutyl group, cyclopentyl group A a sulfone group, cyclopentyl ethyl sulfone, cyclopentyl propyl sulfone, cyclohexyl methyl sulfone, cyclohexyl ethyl sulfone, cyclohexyl propyl sulfone group, formyl, acetyl, propionyl, butyryl, isobutyryl , pentanoyl, hexanoyl, cyclopropyl, formyl, acetyl cyclopropyl, cyclobutyl formyl, acetyl cyclobutyl, cyclopentyl, formyl, acetyl cyclopentyl, cyclohexyl, formyl, acetyl cyclohexyl .

In some aspects, the aforementioned "is C1-6 alkyl, 1-6 membered heteroalkyl, 3-12-membered heterocycloalkyl, C1-6 alkoxy, a C3-12 cycloalkenyl, aryl, heteroaryl a substituted amino group, an amide group, amino group "may be selected from methylamino, ethylamino, propylamino, isopropylamino, 1-butylamino, isobutylamino, tert-butylamino, 1-pentylamino, 1-hexylamino, oxirane group, a cyclohexyl group, a heterocyclic amino hydrochloride (azetidin-3-dihydrochloride), 2-cyclopentyloxy-phenylamino, 2- (cyclopentyloxy) acetate amino, morpholin-4-amino, amino cyclopropene, cyclobutadiene -2-amino propionic acid, polybutadiene terminal azido group, cyclopentadienyl group, 2-cyclohexen-1-one -3-amino, acylamino caprolactone DL-amino, phenylamino, 1-amino-pyrrole, pyrrole-2-amino, pyrrolidin-3-amino, 3-amino-pyridine, 4-amino-pyridine, quinolin-2 - amino, 3-amino-quinoline, 4-amino-quinoline, quinolin-7-amino, 8-amino-quinoline, indol-1-amino, 4-amino-indole, indol-5 an amino group, indol-7-amino, methyl amido, ethyl amido, propyl amido, propyl amido, butyl amido , Butylamido isobutyl, t-butyl amide, pentyl amide, hexyl amide groups, amido groups oxiranyl, glycidyl acylamino, amido epoxybutyl, epoxypentyl amido, epoxyhexyl amido, N- amido methoxy-morpholinyl, N- morpholinyl-ethoxy-amido, N- amido morpholine-oxopropyl group, a methoxy group amido, amido ethoxy, propoxy amido, acylamino isopropoxy, butoxy acylamino group, an acylamino group, isobutoxy group, tert-butoxy acylamino group, a pentyl group, an acylamino group, an acylamino group cyclopropyloxy, cyclobutyloxy acid amino, amido cyclopentyloxy, cyclohexyloxy acylamino, amido cyclopropylmethoxy group, an ethoxy cyclopropylmethyl amido, acylamino cyclopropyl propoxy, cyclobutyloxy methoxy amido, ring amido butoxy ethoxy, propoxy, butoxy ring acylamino, amido cyclopentyl methoxy group, an ethoxy amido cyclopentyl, cyclopentyl-propoxy acylamino, amido cyclohexyl methoxy, cyclohexyl acetate acylamino group, an acylamino group propoxy cyclohexyl, cyclopropenyl amido, acylamino cyclobutadienyl, cyclopentadienyl amido, amido cyclohexenyl, cycloheptyl Alkenyl amido, amido phenyl, pyrrole acetamido, 2-pyrrolidin-carboxamido, carboxamido-pyrrole-3-amino-2-pyridyl carboxamido, carboxamido 4-pyridine, pyridine-2-acetylamino, pyridine-3-acetylamino, quinoline-8-acetylamino, quinolin-2-carboxamido, carboxamido quinolin-4, 6-carboxamido-quinoline, quinoline-8-acetylamino, 1-H- indole-5-carboxamido 3-indolyl acetylamino, methylamino group, ethylamino group, propylamino group, isopropyl-amino group, butylamino group, isobutylcarbamoyl acyl, aminoacyl t-butyl, amino pentyl group, hexyl group aminoacyl, aminoacyl oxiranyl, glycidyl amino group, an epoxy-butylamino group, amino group epoxy pentyl, epoxy cyclohexyl alanyl , N- aminoacyl methoxy-morpholinyl, N- aminoacyl morpholinoethoxy, N- morpholine oxopropyl aminoacyl, aminoacyl methoxy, ethoxy aminoacyl, aminoacyl propoxy, iso propoxy aminoacyl, aminoacyl butoxy, isobutoxy aminoacyl, aminoacyl t-butoxy, pentyloxy aminoacyl, aminoacyl cyclopropyloxy, cyclobutyloxy aminoacyl, cyclopentyloxycarbonyl aminoacyl group, Aminoacyl-hexyloxy, cyclopropylmethoxy aminoacyl, aminoacyl cyclopropylmethyl ethoxy, propoxy cyclopropyl amino group, a methoxy group aminoacyl sulfolane, sulfolane aminoacyl ethoxy, propoxy cyclobutyloxy aminoacyl group, cyclopentyl methoxy aminoacyl, aminoacyl cyclopentyl ethoxy, cyclopentyl-propoxy aminoacyl, aminoacyl cyclohexyl methoxy, ethoxy aminoacyl cyclohexyl, cyclohexyl-propoxy aminoacyl, aminoacyl cyclopropenyl, cyclobutadienyl aminoacyl, aminoacyl cyclopentadienyl, cyclohexenyl aminoacyl, aminoacyl cycloheptene, phenylcarbamoyl group, aminoacyl pyrrole, pyridine aminoacyl , quinoline aminoacyl, aminoacyl indole.

In some embodiments, the above-carbonyl group selected from methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, iso-butoxycarbonyl, tert-butoxycarbonyl group.

In some embodiments, the above-described acyl group selected from formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, cyclopropylmethyl group, cyclopropyl acetyl, propionyl cyclopropyl ring butyl formyl, acetyl cyclobutyl, cyclobutyl propionyl group, cyclopentylmethyl group, cyclopentyl acetyl, propionyl cyclopentyl, cyclohexyl, formyl, acetyl cyclohexyl, cyclohexyl propionyl.

In some embodiments, the above-described alkyl group selected from 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 , a pentyl group, pentyl group, a pentyl propyl, butyl pentyl, cyclohexylmethyl, cyclohexylethyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl methyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, ethyl sulfolane, sulfolane cyclopropyl, cyclopentyl-methyl, cyclopentyl ethyl, cyclopentyl propyl, cyclohexyl methyl, cyclohexyl ethyl, cyclohexyl propyl, N- methyl morpholine, N- ethyl morpholine, N- propyl morpholine.

In some embodiments, the alkoxy group is selected from N- morpholino, methoxy, ethoxy N- morpholine, N- morpholino-oxopropyl, methoxy, ethoxy, propoxy, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy, pentyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclopropylmethyl acetate group, cyclopropyl-propoxy, cyclobutyloxy methoxy, cyclobutyloxy ethoxy, propoxy, butoxy ring, cyclopentyl-methoxy, cyclopentyl-ethoxy, cyclopentyl-propoxy, cyclohexyl-methoxy group, cyclohexyl-ethoxy, cyclohexyl-propoxy.

In some embodiments, the alkoxy sulfone group selected from: methyl sulfone, ethyl sulfone, propyl sulfone, propyl sulfone, butyl sulfone, isobutyl sulfone group, a tert-butyl sulfone, pentyl sulfone group, 1-methylbutyl sulfone , 2-methylbutyl sulfone group, a sulfone group 3-methylbutyl, 1,1-dimethylpropyl sulfone, 2,2-dimethylpropyl sulfone, 1,2-dimethyl propyl sulfone group, a sulfone group, 1-ethylpropyl, hexyl sulfone, methyl pentyl sulfone, ethyl pentyl sulfone, propyl pentyl sulfone, butyl pentyl sulfone, methyl hexyl sulfone group, cyclohexylethyl group sulfone, propyl hexyl sulfone, methyl phenyl sulfone, ethyl phenyl sulfone, propyl phenyl sulfone, aminophenyl sulfone group, nitrophenyl phenyl sulfone group, cyanophenyl sulfone group, diphenyl sulfone group, sulfone group chlorophenyl, fluorophenyl sulfone group, bromophenyl sulfone group, a sulfone group cyclopropyl, cyclobutyl sulfone group, cyclopentyl sulfone group cyclohexyl sulfone group.

In some embodiments, the alkoxy group is selected from: formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, cyclopropylmethyl group, cyclopropyl acetyl, propionyl cyclopropyl , formyl cyclobutyl, cyclobutyl acetyl, propionyl cyclobutyl, cyclopentylmethyl group, cyclopentyl acetyl, propionyl cyclopentyl, cyclohexyl, formyl, acetyl cyclohexyl, cyclohexyl propionyl.

In some aspects, the compound of formula I is

Figure PCTCN2017084604-appb-000013
Wherein, n 0 or 1 or 2 or 3;

R 1 and C ring linked to α or β or γ position 1;

n 1 is 0 or 1 or 2 or 3;

n 2 0 or 1 or 2 or 3;

n 3 0 or 1 or 2;

It is 0 or a number 1 or 2.

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

Figure PCTCN2017084604-appb-000014
Wherein, L 0 double bond substituents selected from the following group: = O, = C (R 2) 2, = ( spiro -C3-8 cycloalkyl), aryl, or heteroaryl = = (spiro - (3-8 membered heterocyclic group)), where = (spiro -C3-8 cycloalkyl), aryl, or heteroaryl = = (spiro - (3-8 membered heterocyclyl)) with one or more substituents R 2 ;or

Substituent group selected from a single bond: H, NH 2, halo, CN, CF 3, OH, C (O) OH, C (O) H, heteroalkyl, alkenyl group, alkynyl group, a heterocyclic group, an alkylene sulfonylamino group, a nitro group, a phosphate group, a urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl, aryl, heteroaryl, amide group, amino group, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl or substituted C3-12 cycloalkyl C1-6 alkyl group or a C1-6 alkoxy aryl or heteroaryl group or an aryl group;

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

n is an integer selected from 0-6;

L 00 is selected from H, NH 2, halo, CN, CF 3, OH, C (O) OH, C (O) H, alkenyl group, alkynyl group, a sulfonamido group, a nitro group, a phosphate group, ureido , a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl C1-6 heteroalkyl, a C3-12 heterocycloalkyl, aryl, heteroaryl, amido, acyl, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl or C1-6 alkyl substituted by C1-6 cycloalkyl or C3-12 alkoxy or aryl or heteroaryl group, halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, a C3-12 cycloalkyl group substituted with a carbonyl group, a C1-6 alkyl group, C3 -12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group substituted with an amino, amido, acyl.

In some embodiments, the above C 1 and r 1 ring linked to the α position, R and δ r 1 ring linked to the position, structure of formula XXXIII,

Figure PCTCN2017084604-appb-000015

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

Figure PCTCN2017084604-appb-000016

Wherein, n 0 or 1 or 2 or 3;

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

n 0 or 1 0 or 2;

n 3 0 or 1 or 2;

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

R is a monovalent substituent on reasonable bond r 1 group at any position; R is the number of n 1, n 1 is an integer between 0-14 (inclusive);

Each R is independently selected from a double bond substituent group: = O, = NR 2, = C (R 2) 2, = ( spiro cycloalkyl -C3-12 cycloalkyl), or = (spiro - (3-10 membered heterocyclic group)),

or

Each R is independently selected from a single bond substituent group: H, NH 2, halo, CN, CF 3, OH, C (O) OH, C (O) H, a sulfonamido group, a sulfone group, a sulfoxide group, a nitro group, a phosphate group, a urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, C1-6 heteroalkyl, a C3-12 heterocyclyl group, an aryl group , heteroaryl, amide group, amino group, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, an aryl group, a heteroaryl group, a C3-12 cycloalkyl-substituted C1-6 alkyl group or a C1 -6 alkoxy group or an aryl or heteroaryl group, halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, a C3-12 cycloalkyl group substituted with a carbonyl group, a C1-6 alkyl group , a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group substituted with an amino, amido, acyl;

Wherein said halogen is selected from F, Cl, Br, I;

R 1 ~ R 10 are each independently selected from H, NH 2, halo, CN, CF 3, OH, C (O) OH, C (O) H, alkenyl group, alkynyl group, a sulfonamido group, a sulfone group, an alkylene a sulfone group, a nitro group, a phosphate group, a urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, C1-6 heteroalkyl, a C3-12 heterocycloalkyl group, an aryl group, a heteroaryl group, an amide group, amino group, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, an aryl group, a heteroaryl group, a C3-12 cycloalkyl group, a C3-12 cycloalkyl alkenyl group or a C3-12 alkyl group substituted with a C1-6 cycloalkyl or C1-6 alkoxy or aryl or heteroaryl group, halogen, cyano, amino, aryl, heteroaryl, C1-6 alkoxy group, a C3-12 cycloalkyl group substituted with a carbonyl group, a C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group substituted with an amino, amido, acyl.

In some aspects, n 1 is 0, R 1 ~ R 10 are each independently selected from H, NH 2, halo, CN, CF 3, OH, sulfonamido, C1-6 alkyl, C3-12 cycloalkyl, , a C3-12 cycloalkenyl group, C1-6 heteroalkyl, a C3-12 heterocycloalkyl, aryl, heteroaryl, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, an aryl group, heteroaryl, C3-12 cycloalkyl, C3-12 cycloalkenyl or C3-12 alkyl group substituted with a C1-6 cycloalkyl or C1-6 alkoxy or aryl or heteroaryl.

In some aspects, the formula YI each R is independently selected from a double bond substituent group: = O, = NR 2, = C (R 2) 2, = ( spiro cycloalkyl -C3-12 cycloalkyl), or = (spiro - (3-12 membered heterocyclyl group)),

or

Each R is independently any group selected from a single bond in one or two substituents independently: H, NH 2, halo, CN, CF 3, OH, C (O) OH, C (O) H, sulfinyl an amino group, a sulfone group, a sulfoxide group, a nitro group, a phosphate group, a urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, C1-6 heteroalkyl, C3-12 heterocycloalkyl, aryl, heteroaryl, amide group, amino group, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl substituted C1-6 alkyl or C1-6 alkoxy group, or an aryl or heteroaryl group.

In some aspects, the formula YI heteroaryl group selected from pyridine, pyrimidine, pyrazine, pyridazine, triazine.

In some aspects, the formula YI C3-12 heterocyclyl group selected from furan, pyrrole, thiophene, pyridine, quinoline, purine, indole, benzimidazole, pyrrole, pyrrolidine, pyran, dioxolane , dioxane, pyrazole, imidazole, oxazole, thiazole, triazole, morpholine, piperidine, piperazine.

Substituted or number of substituents is 0, default to achieve a covalent bond with H reasonable conditions of the present invention is not mentioned.

specific,

YI formulas above formula, a is the number 0, the structural formula as Formula Y-II:

Figure PCTCN2017084604-appb-000017

YI type formulas, n 1 is 0, R 1 ~ R 4, R 10 take the H, the structural formula of formula Y-III:

Figure PCTCN2017084604-appb-000018

Wherein, R 5 ~ R 9 are each independently selected from H, NH 2, halo, CN, CF 3, OH, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C1-6 heteroalkyl group, a C3-12 heterocycloalkyl, aryl, heteroaryl, amide group, amino group, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, an aryl group, a heteroaryl group, a C3-12 cycloalkyl, C3-12 cycloalkenyl or C3-12 alkyl group substituted with a C1-6 cycloalkyl or C1-6 alkoxy or aryl or heteroaryl group, halogen, cyano, amino, an aryl group, heteroaryl, C1-6 alkyl, a C3-12 cycloalkyl group substituted with a carbonyl group, a C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group substituted with an amino , an amide group, an aminooxy group.

YI formulas above formulas, C 1 r 1 and the ring linked to the β position, the structural formula of formula Y-IV:

Figure PCTCN2017084604-appb-000019
YI formulas above formulas, C 1 r 1 and the ring linked to the α position, take a number of 0, the structural formula of formula YV:

Figure PCTCN2017084604-appb-000020

Formula I above formulas, C 1 r 1 and the ring linked to the β position, take a number of 0, the structural formula of formula VI:

Figure PCTCN2017084604-appb-000021

Figure PCTCN2017084604-appb-000022

Figure PCTCN2017084604-appb-000023

Figure PCTCN2017084604-appb-000024

Figure PCTCN2017084604-appb-000025

The present invention provides a pharmaceutically acceptable salt thereof, or a compound of formula SI:

Figure PCTCN2017084604-appb-000026

Wherein, SR 1 is selected from CN, OH, C (O) OH, C (O) H, amide group, amino group, containing at least one N or O or S heteroaryl, halogen, hydroxy, carboxy, carbonyl group, aldehyde group, a cyano group, an amino group, an aryl group, a heteroaryl group, a C3-12 cycloalkyl-substituted C1-6 alkoxy group containing at least one N or O or S or heteroaryl, hydroxy, carboxy, carbonyl, aldehyde group, a cyano group, an amino-substituted C1-6 alkyl or C3-6 cycloalkyl or aryl or heteroaryl group, halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl group, C3-12 cycloalkyl substituted carbonyl group, a C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, aryl, heteroaryl, substituted amino, amido, acyl;

L 0 double bond substituents selected from the following group: = O, = C (R 2) 2, = ( spiro -C3-8 cycloalkyl), aryl, or heteroaryl = = (spiro - (3-8 membered heteroaryl cycloalkyl group)), where = (spiro -C3-8 cycloalkyl), aryl, or heteroaryl = = (spiro - (3-8 membered heterocyclyl)) with one or more substituents R 2;

or

Substituent group selected from a single bond: H, NH 2, halo, CN, CF 3, OH, C (O) OH, C (O) H, heteroalkyl, alkenyl group, alkynyl group, a heterocyclic group, an alkylene sulfonylamino group, a nitro group, a phosphate group, a urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl ,, aryl, heteroaryl, amido, acyl, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl or C1-6 alkyl substituted by C1-6 cycloalkyl or C3-12 alkoxy or aryl or heteroaryl;

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

n is an integer selected from 0-6;

SR 2, R 3 ~ R 8 , SR 9, SR 10, SR 11, L 00 are each independently selected from H, NH 2, halo, CN, CF 3, OH, C (O) OH, C (O) H, alkenyl group, an alkynyl group, a sulfonamido group, a nitro group, a phosphate group, a urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, C1-6 heteroalkyl group, a C3-12 heterocycloalkyl, aryl, heteroaryl, amide group, amino group, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, an aryl group, a heteroaryl group, a C3-12 cycloalkyl substituted by C1-6 alkyl or C3-12 cycloalkyl or C3-12 cycloalkenyl group or C1-6 alkoxy group, or an aryl or heteroaryl group, halogen, cyano, amino, an aryl group, heteroaryl, C1-6 alkyl, a C3-12 cycloalkyl group substituted with a carbonyl group, a C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group substituted with an amino , an amide group, an aminooxy group.

specific:

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

L 00 are each independently selected from H, NH 2, OH, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, C1-6 heteroalkyl, a C3-12 heterocyclyl group, an aryl group , heteroaryl, amide group, amino group, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, an aryl group, a heteroaryl group, a C3-12 cycloalkyl group substituted with C1-6 alkyl or C3 -12 cycloalkyl or C1-6 alkoxy or aryl or heteroaryl.

In some embodiments, the SI of the formula each R is independently selected from a double bond substituent group: = O, = NR 2, = C (R 2) 2, = ( spiro -C3-8 cycloalkyl), or = (spiro - (3-8 membered heterocyclyl)),

or

Each R is independently any group selected from a single bond in one or two substituents independently: H, NH 2, halo, CN, CF 3, OH, C (O) OH, C (O) H, sulfinyl amino, nitro, phosphate, urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, C1-6 heteroalkyl, a C3-12 heterocycloalkyl , aryl, heteroaryl, amide group, amino group, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, an aryl group, a heteroaryl group, a C3-12 cycloalkyl-substituted C1-6 alkoxy C1-6 alkoxy group or an aryl group, or an aryl or heteroaryl group.

In some aspects, the formula SI, R 1 is selected from OH, C (O) OH, C (O) H, amide group, containing at least one O or S or N heteroaryl, hydroxy, amino, aryl, carboxy-substituted C1-6 alkyl or C1-6 cycloalkyl or aryl or heteroaryl group, is C1-6 alkyl, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, heteroaryl group a substituted amino group, an amide group, an aminooxy group.

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

In some embodiments, the SI of the formula is selected from SR 1 OH, C (O) OH, amino, carboxy, containing at least one O or S or N heteroaryl, substituted with hydroxy, amino, carboxy, C1-6 alkoxy base.

In some embodiments, the SI of the formula is selected from SR 1 OH.

In some aspects, the formula SI L 0 double bond substituents selected from the following group: = O, = C (R 2) 2, = ( spiro -C3-8 cycloalkyl), aryl, or heteroaryl = = ( spiro - (3-8 membered heterocyclyl)), where = (spiro - (3-8 membered heterocyclyl)) in the heterocyclic ring containing at least one N or O or S;

or

Substituent group selected from a single bond: H, OH, C (O) H, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C1-6 heteroalkyl, C3-12 heterocycle alkyl, aryl, heteroaryl, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, an aryl group, a heteroaryl group, a C3-12 cycloalkyl group substituted with C1-6 alkyl or C 3 -12 cycloalkyl or aryl group or a heteroaryl group.

In some embodiments, A is selected from the formula SI N, S, O; wherein, N, P L 00 are substituted, S L 00 are substituted or one or two = O.

In some aspects, the formula SI heteroaryl group selected from pyridine, pyrimidine, pyran, pyridazine, triazine, pyran.

In some aspects, the formula SI C3-12 heterocyclyl group selected from furan, pyrrole, thiophene, pyridine, quinoline, purine, indole, benzimidazole, furan, pyrroline, dioxolane, dioxane ring, pyrazole, imidazole, oxazole, thiazole, piperidine, triazole, morpholine, piperidine, piperazine.

Substituted or number of substituents is 0, default to achieve a covalent bond with H reasonable conditions of the present invention is not mentioned.

specific,

Formula SI formula wherein A is O, structural formula of formula S-II:

Figure PCTCN2017084604-appb-000027

Where, L 0 is selected from H, NH 2, C1-6 heteroalkyl, a C3-12 heterocyclyl group, a ureido group, a C1-10 alkyl group, a C3-12 cycloalkyl, aryl, heteroaryl, aryl, halogen, hydroxyl, carboxyl, carbonyl, aldehyde, cyano, amino, an aryl group, a heteroaryl group, a C3-12 cycloalkyl group substituted with C1-6 alkyl or aryl or heteroaryl; hetero atom (s) O, N or S.

The above-described structural formula SI wherein A is N, L 0 double bond substituents selected from the following group: = C (R 2) 2 , = ( spiro -C3-8 cycloalkyl), = (spiro - (3-8 membered heterocyclic group)), = heteroaryl, where = (spiro -C3-8 cycloalkyl), = (spiro - (3-8 membered heterocyclyl)), = is a heteroaryl or a SR 2 substituents;

Structural formula:

Figure PCTCN2017084604-appb-000028

Wherein, the formula S-IV, q is 0 or 1 or 2 or 3 or 4 or 5; R 2 is independently selected from H, NH 2, halo, CN, CF 3, OH, C (O) OH, C ( O) H, sulfonamido, nitro, phosphate, urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, C1-6 heteroalkyl, C3-12 heterocycloalkyl, aryl, heteroaryl, amide group, amino group, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl substituted C1-6 alkyl or C3-12 cycloalkyl or C1-6 alkoxy or aryl or heteroaryl group, halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl , a C3-12 cycloalkyl group substituted with a carbonyl group, a C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group substituted with an amino, amido, acyl;

When taken with or without SR 2 substituted aryl, heteroaryl, C1-6 cycloalkyl time, SR 2 with bare ring is a single bond or a link and a link member; and said body link refers to two atoms in common and the covalent bond between two atoms;

p of 1, or 2 or 3 or 4 or 5; any α on the ring, β, γ, δ and ε bits hetero atom and B is N or O or S, in an amount of 0 or 1 or 2, which position one or two; B is a double bond, which is the number 0 or 1 or 2, which is a position on the ring bond reasonable price anywhere.

The above-described structural formula SI wherein A is N, N-substituted L 00 is a structural formula as follows:

Figure PCTCN2017084604-appb-000029

L 0, L 00 are each independently selected from a single bond substituent groups: H, OH, C (O ) OH, C (O) H, a carbonate group, C1-6 alkyl, C3-12 cycloalkyl, C3- 12 cycloalkenyl, C1-6 heteroalkyl, a C3-12 heterocycloalkyl, aryl, heteroaryl, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl , C3-12 cycloalkyl substituted by C1-6 alkyl or C1-6 alkoxy group, or an aryl or heteroaryl group; L 00 is selected from H, NH 2, halo, CN, CF 3, OH, C (O ) OH, C (O) H, C1-6 heteroalkyl, a C3-12 heterocycloalkyl, C1-6 alkyl, a C3-12 cycloalkyl group, an aryl group, a heteroaryl group, an amide group, an amino group, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, an aryl group, a heteroaryl group, a C3-12 cycloalkyl group substituted with C1-6 alkyl or C1-6 alkoxy group, or an aryl or heteroaryl base;

Formula SV, of formula S-IV, of formula S-II wherein R 1 are hydroxyl, and R R on the same carbon atom is hydrogen, the formula S-II in L 0 is a hydrogen, having the formula respectively the formula S -VI, of formula S-VII, of formula S-IX:

Figure PCTCN2017084604-appb-000030

Wherein each R is independently selected from a double bond substituent group: = 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, halo, CN, CF 3, OH, C (O) OH, C (O) H, C1-6 alkyl, C1-6 haloalkyl group, C3-8 cycloalkyl, or 3-8 membered heterocyclyl,

or

Each R is independently any group selected from a single bond in one or several substituents independently: H, NH 2, halo, CN, CF 3, OH, C (O) OH, C (O) H, sulfinyl amino, nitro, phosphate, urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, C1-6 heteroalkyl, a C3-12 heterocycloalkyl , aryl, heteroaryl, amide group, amino group, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, an aryl group, a heteroaryl group, a C3-12 cycloalkyl-substituted C1-6 alkoxy C1-6 alkoxy group or an aryl group, or an aryl or heteroaryl group.

SI compound of formula, A is N, L 0 of (R) y H x-1 , the formula of formula S-VIII:

Figure PCTCN2017084604-appb-000031
Take 1 or x 2, y takes 1 or 2.

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

Figure PCTCN2017084604-appb-000032

Wherein, L 1, L 2 is independently selected from H, NH 2, halo, CN, CF 3, OH, C (O) OH, C (O) H, C1-6 heteroalkyl, C3-12 heterocycloalkyl group, a sulfonamido group, a nitro group, a phosphate group, a urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group, an amide group , aminoacyl, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, an aryl group, a heteroaryl group, a C3-12 cycloalkyl group substituted with C1-6 alkyl or C1-6 alkoxy group or an aryl aryl or heteroaryl group, halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, a C3-12 cycloalkyl group substituted with a carbonyl group, a C1-6 alkyl group, a C3-12 cycloalkyl group , a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group substituted with an amino, amido, acyl;

R 12 is selected from aryl, heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-10 membered heterocyclyl, or C3-8 cycloalkyl C1-6 alkyl group, wherein the aryl group, heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-10 membered heterocyclyl, and C3-8 cycloalkyl C1-6 alkyl group substituted with one or more of each L 1 is independently and optionally replace;

In some aspects, the formula SX L 1, L 2 are each independently selected from: H, OH, C1-6 alkyl, halo, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl group, C3-12 cycloalkyl group substituted with C1-6 alkyl; m 0 or 1 or 2; R 12 is

Figure PCTCN2017084604-appb-000033
Wherein, b is a double bond position, ring b is a valence bond on any appropriate location, the number b is 0 or 1 or 2 or 3, when the number of b is 0, a covalent bond is a single bond corresponding position ; Z is selected from N or O or S, Z position of the key ring for any reasonable price position; p is selected from 0 or 1 or 2 or 3; L 1 is the position of the ring key position on any reasonable price; R 12 as the substituent group, the substituent on the office location to a monovalent ring reasonable bond atoms.

In some aspects, the formula S-VIII R 12 is selected from phenyl, containing at least one N C3-8 membered heteroaryl or O or S, C3-8 cycloalkyl, a C3-8 cycloalkenyl group, 3 5-10 membered heterocyclyl, wherein a phenyl group containing at least one O or S or N C3-8 membered heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-10 membered heterocyclyl each L 1 with one or more substituents.

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

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

In some embodiments, any position in the formula SX R 12 is selected from the following groups: a benzene ring, a pyridine ring, a pyrimidine ring, a pyran ring, a furan ring, pyrrole ring, thiophene ring, pyridine ring, quinoline ring, propane-yl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and each of the above groups substituted with one or more L 1 optionally and independently substituted.

SX in formula, R 12 is a benzene ring substituent group, the formula S-IX:

Figure PCTCN2017084604-appb-000034

Wherein, L 3 ~ L 7 is selected from H, NH 2, halo, CN, CF 3, OH, C (O) OH, C (O) H, C1-6 heteroalkyl, a C3-12 heterocycloalkyl, sulfonamido, nitro, phosphate, urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, an aryl group, a heteroaryl group, an amide group, amino group, halogen, hydroxy, a carboxyl group, a carbonyl group, an aldehyde group, a cyano group, an amino group, an aryl group, a heteroaryl group, a C3-12 cycloalkyl group substituted with C1-6 alkyl or C1-6 alkoxy group, or an aryl or heteroaryl group, halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, a C3-12 cycloalkyl group substituted with a carbonyl group, a C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, an amino substituted heteroaryl group, an amide group, an aminooxy group.

In the formula S-XI, SR 2, R3 ~ R8, SR 9, SR 10, R 11, are hydrogen, the formula S-XII:

Figure PCTCN2017084604-appb-000035

Wherein, C l is R or S configuration; C 2 is R or S configuration. m is selected from 0, 1 or 2; L 1, L 2 are each independently selected from: H, OH, aryl, heteroaryl, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, an aryl group, a heteroaryl group, a C3-12 cycloalkyl group substituted with an aryl or heteroaryl group or a cycloalkyl group; L 3 ~ L 7 are each independently selected from: H, OH, C1-6 alkyl, aryl, heteroaryl, halogen, hydroxyl, carboxyl, carbonyl, aldehyde, cyano, amino, C1-6 alkyl, aryl, heteroaryl, a C3-12 cycloalkyl group or a substituted aryl or heteroaryl group.

The present invention provides the compound

Figure PCTCN2017084604-appb-000036
Synthesis method, wherein, in each formula TM-IX with the definition of the substituents of formula I and formula IX, the following steps:

i) M1 and M2 to obtain the chloride reaction;

Said chloride selected from phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosgene, thionyl chloride, trimethylchlorosilane, α, α, α- trichlorotoluene at least one of;

Figure PCTCN2017084604-appb-000037

ii) M2 reacted with 2a to obtain M3;

Wherein L 0 when the double bond substituents selected from the following: = O, = S (= O) s, = C (R 2) 2, = ( spiro cycloalkyl -C3-12 cycloalkyl), aryl, or heteroaryl = = (spiro - (3-10 membered heterocyclyl)), where = (spiro cycloalkyl -C3-12 cycloalkyl), aryl, or heteroaryl = = (spiro - (3-10 membered heterocyclyl) ) by one or more substituents R 2, this step was added a condensing agent and a base, the reaction proceeds more favorable, the condensing agent is selected HBTU, DMC, HOBT, HOBT / EDCI, HATU, HATU / DIEPA, DCC, CDI, isopropyl chloroformate; structural formula are as follows:

Figure PCTCN2017084604-appb-000038

Figure PCTCN2017084604-appb-000039

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

Figure PCTCN2017084604-appb-000040

iv) M3 and M4 3a obtained reaction conditions in the presence of a base;

Figure PCTCN2017084604-appb-000041

The base is selected from an alkyl lithium, lithium cycloalkyl or lithium-aryl group; further selected from methyl lithium, ethyl lithium, propyl lithium, isopropyl lithium, n-butyllithium, sec-butyllithium, t butyl lithium, pentyl lithium, hexyl lithium, cyclohexyl lithium, tert-octyl lithium, n-eicosyl lithium, phenyl lithium, methylphenyl lithium, butyl phenyl lithium, naphthyl lithium, lithium butylcyclohexyl ; further selected from n-butyllithium, t-butyllithium or hexyllithium; at least one solvent and a base selected from hexane, petroleum ether, benzene, toluene or xylene;

v) M4 4a in the presence of a strong base to obtain a reaction M5;

Figure PCTCN2017084604-appb-000042

Wherein, R 4 take H; alkali metal lithium compound is selected from alkyl, aryl alkali metal compound, an alkali metal alkyl aromatic compound, amine lithium compound, an alkali metal hydride, an alkali metal salt of a fatty alcohol; is 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 group ( LiHMDS);

vi) M5 in the presence of an acid to form a ring, deprotected to obtain M6;

Figure PCTCN2017084604-appb-000043

Said acid is selected from alkyd, aromatic acids, acid, saturated fatty acids, phenol; is further selected from acetic acid, propionic acid, glycolic acid, lactic acid, benzoic acid, phenylacetic acid, acrylic acid, oleic acid, citric acid, oxalic acid, malonic acid, succinic acid;

vii) M6 reducing the target compound XI with a reducing agent;

Figure PCTCN2017084604-appb-000044

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

The method of the present invention provides only one way to achieve the synthesis of compounds of formula TM-IX, wherein the M6, M5, M4, M3, M2 are independent, is not limited to the method of the present invention obtained by the preparation.

The present invention provides a compound of formula II above synthesis method, the following steps:

Figure PCTCN2017084604-appb-000045

Compound Z-5 reduction with a reducing agent to give the title compound II;

Wherein said reducing agent is selected from NaBH 4, KBH 4 or NaBH 4 / LiCl.

Wherein the step of synthesizing the compound Z-5 as follows:

Figure PCTCN2017084604-appb-000046

Compound Z-4 in the presence of an acid to form a ring, deprotected to obtain a compound Z-5.

Wherein said acid is selected from alkyd, aromatic acids, acid, saturated fatty acids, phenols; further the acid is selected from acetic acid, propionic acid, glycolic acid, lactic acid, benzoic acid, phenylacetic acid, acrylic acid , oleic acid, citric acid, oxalic acid, malonic acid, succinic acid;

Wherein the ring-forming reaction is carried out under heat; the reaction is preferably the heating temperature is 50-95 ℃.

The present invention provides a compound of formula II above synthesis method, the following steps:

Figure PCTCN2017084604-appb-000047
Wherein a is the number 1, located between the position α.

The present invention provides the method of synthesizing a compound of Z-5, the compound Z-4 in a C 1 r 1 and the ring linked to the β position, Z-4 Synthesis of Compound of the following steps:

Figure PCTCN2017084604-appb-000048

Compound Z-2 and Compound 3 to yield compound Z-4 in the presence of an organic base in the reaction.

Wherein said organic base selected from alkyl lithium metal compound, alkali metal compound is an aromatic group, an aromatic alkyl alkali metal compound, lithium compound amine, an alkali metal hydride, an alkali metal salt of a fatty alcohol; is 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 group (LiHMDS).

The present invention provides the synthesis of compounds of formula I, in the compound Z-4 with a C 1 α r 1 position linked to the ring, the compound Z-4 synthetic steps are as follows:

Figure PCTCN2017084604-appb-000049
Wherein said strong base is selected from alkali selected tC 4 H 9 OK, NaH, Ph 3 CNa, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium tert-butoxide; alkyl lithium metal compounds, butyl lithium, phenyl lithium; amino lithium compounds, lithium diisopropylamide (LDA), lithium hexamethyldisilazide group (LiHMDS).

The present invention provides a method of synthesis of compounds Z-3, the compound Z-3 synthetic steps as follows:

Figure PCTCN2017084604-appb-000050

The present invention provides a method for the synthesis of compound M3, M3 Compound Synthesis of the following steps:

Figure PCTCN2017084604-appb-000051

Wherein said X is selected from Cl, Br, I; M is selected from the Li, Na, K; said reducing agent is selected from butyl lithium, t-butyl lithium, tributyl tin hydroxide, zinc / acetic acid.

The present invention provides a method for the synthesis of compound M3, the following synthesis steps:

Figure PCTCN2017084604-appb-000052

Wherein said chloride is selected from phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosgene, thionyl chloride, trimethylchlorosilane, α, α, α- least one trichlorotoluene .

The present invention provides a method of synthesizing a compound Z-2, where n 3 0 takes compound Z-2 synthetic steps are as follows:

Figure PCTCN2017084604-appb-000053

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; said X is selected from Cl, Br, I, triflate group;

The base is selected from potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium acetate, potassium phosphate, barium hydroxide, cesium carbonate;

The reaction temperature is preferably 70-95 ℃.

As above, the present invention also provides a method of synthesizing a compound Z-2, wherein n 3 is 1 or 2 taken compound Z-2 Synthesis of the following steps:

Figure PCTCN2017084604-appb-000054

The present invention provides the compound

Figure PCTCN2017084604-appb-000055
Synthesis method, wherein the substituents are selected of formula TM-X 0 in formula 1 and formula X (in the formula X is selected from Boc-R 3), the following steps:

1):

Figure PCTCN2017084604-appb-000056

Compound 1, were added sequentially triethylamine, diphenylphosphoryl azide, the reaction to give compound 2.

2):

Figure PCTCN2017084604-appb-000057

Compound 2 3a the reaction conditions in the presence of a base to obtain compound 3;

The base selected from alkyl lithium, alkyl lithium cycloalkyl or aryl lithium;

It is further selected from methyl lithium, ethyl lithium, propyl lithium, isopropyl lithium, n-butyllithium, sec-butyllithium, tert-butyl lithium, pentyl lithium, hexyl lithium, cyclohexyl lithium, tert-octyl lithium , n-eicosyl lithium, phenyl lithium, methylphenyl lithium, butyl phenyl lithium, naphthyl lithium, cyclohexyl lithium, and butyl;

Still further selected from n-butyllithium, t-butyllithium or hexyllithium;

At least one solvent and a base selected from hexane, petroleum ether, benzene, toluene or xylene;

3): Compound 3 in the presence of a strong base to obtain a compound 4a reaction of 4;

Figure PCTCN2017084604-appb-000058

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; preferred alkyl metal lithium compound is butyl lithium or phenyl lithium; group preferably is a lithium compound of lithium diisopropylamide (LDA) or lithium hexamethyldisilazide group (of LiHMDS);

4): Compound 4 in the presence of an acid to form a ring, deprotected to obtain compound 5;

Figure PCTCN2017084604-appb-000059

Said acid is selected from alkyd, aromatic acids, acid, saturated fatty acids, phenols;

It is further selected from acetic acid, propionic acid, glycolic acid, lactic acid, benzoic acid, phenylacetic acid, acrylic acid, oleic acid, citric acid, oxalic acid, malonic acid, succinic acid;

5): Compound 5 to give the title compound reducing TM-X 0 with a reducing agent;

Figure PCTCN2017084604-appb-000060

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

The present invention provides the compound

Figure PCTCN2017084604-appb-000061
Synthesis method, wherein the formula TM-X 1 each substituent selected with Formula 1 and Formula X (X in the formula R 3 is selected from H); synthesis steps were as follows: Compound TM-X 0 with a reducing agent to give the title compound TM-X 1;

Figure PCTCN2017084604-appb-000062
The acid is preferably selected from hydrochloric acid, hydrobromic acid, at least one of sulfuric acid.

The present invention provides compounds

Figure PCTCN2017084604-appb-000063
Synthesis method, the following steps:

1): Compound 5 (INT) with a compound INT1 hydrolysis under acidic conditions;

Figure PCTCN2017084604-appb-000064

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

2): reducing the compound to give the title compound INT1 INT2.

Figure PCTCN2017084604-appb-000065

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

The present invention provides compounds

Figure PCTCN2017084604-appb-000066
Synthesis method, wherein, in the formula TM-XXXIV 0 substituents in formula I and Formula XXXIV, the following steps: 1): Compound INT1 and L 0 -W (= O) s -Cl , or L 0 -W (= O ) s-OH to afford the title compound INT3.

Figure PCTCN2017084604-appb-000067

2): reducing the compound to give the title compound INT3 TM-XXXIV 0

Figure PCTCN2017084604-appb-000068

A synthetic

Figure PCTCN2017084604-appb-000069
A method wherein the formula TM-XXXIII of each substituent in formula XXXIII, the following steps:

1):

Figure PCTCN2017084604-appb-000070

Compound 1 under basic conditions with Triphosgene (triphosgene) Compound 1; the base is selected from trialkyl ammonia; specifically from trimethylamine, triethylamine, at least one of tripropylene ammonia;

2):

Figure PCTCN2017084604-appb-000071

INT1 compound reacted with Compound 2 Compound 3;

3):

Figure PCTCN2017084604-appb-000072

Reducing Compound 3 to give to give the title compound TM-XXXIII.

Unless otherwise specified, each step of the present invention described above or below the selected reaction solvent art conventional solvent which dissolves the reactants selection principle, but does not participate in the reaction, the product is extracted or the corresponding crystalline product which separated from impurities, water, halogenated alkanes, alkyl amines, aliphatic hydrocarbons, esters, alcohols, aromatic hydrocarbons, ethers, heterocyclic solvent; specifically selected, but not limited to: methanol, ethanol, propanol, isopropanol , diethyl ether, ethyl acetate, cyclohexane, methylene chloride, chloroform, tetrahydrofuran, pyridine, diethylamine, triethylamine, dimethylformamide, toluene, and mixed in at least two.

Used in the present invention and other numbers M1-M11 is convenient to describe the general formula number used, which in particular embodiments may be modified to another number, such as 2, 3, etc., are for convenience of description, it does not affect the structural formula expression of equations belongs to the substance of the reaction equation and the general reaction formula. Those skilled in the art can be determined that all the above synthetic pathway intermediate each substituents are the structure of the target compound may be.

Inter formula I, particularly compounds of the substance represented II, YI, YII, SI ~ S-XII and other target compounds of general formula encompassed chiral isomers or cis isomers and trans isomers thereof in any proportion the mixture is also encompassed within the scope of the representative compounds of particular materials of formula SIS-XII and other target compounds of general formula encompassed.

Unless otherwise specified, each step of the present invention described above or below the selected reaction solvent art conventional solvent which dissolves the reactants selection principle, but does not participate in the reaction, the product is extracted or the corresponding crystalline product which separated from impurities, water, halogenated alkanes, alkyl amines, aliphatic hydrocarbons, esters, alcohols, aromatic hydrocarbons, ethers, heterocyclic solvent; specifically selected, but not limited to: methanol, ethanol, propanol, isopropanol , diethyl ether, ethyl acetate, cyclohexane, methylene chloride, chloroform, tetrahydrofuran, pyridine, diethylamine, triethylamine, dimethylformamide, toluene, and mixed in at least two.

Unless otherwise specified, the present invention is above the or each reaction described below, when the excess reactants, the reaction can be added to terminate the reaction may be quenched with an excess of reactant species is. Examples of water employed was quenched with saturated ammonium chloride or if quenched embodiment.

Unless otherwise specified, all reactions of the present invention described above or below, each step of purification of the reaction product is selected from extraction, crystallization, solvent, column chromatography; its operations are conventional in the art, the skilled art can be treated according to specific circumstances.

Formula and Formula synthesis method of the present invention may be derived not limited to these particular materials, and under the guidance of general formulas and synthetic methods of the present invention of the general formula, those skilled in the art without creative labor to pay particular compound obtained , within the scope of the present invention.

All of the above synthesis method, the α is not limited to C 1 on the ring linked to r 1, the reaction of other possible locations are within the scope of the present invention β.

Although this article has been shown and described preferred embodiments of the present invention, but the skilled person will be apparent that such embodiments are provided by way of example only. Now, it will occur to those skilled in the art without departing from the present invention many variations, changes and substitutions. It should be understood that various alternatives to the embodiments of the present invention, the present invention may be used in the practice of the present invention. It intended to define the scope of the present invention, and thereby covering the methods and structures within the scope of the claims appended claims and their equivalents.

The present invention provides pharmaceutical compositions containing the compounds, pharmaceutically i.e. I, II, YI, YII, SI ~ S-XII and other target compounds of general formula and the specific compounds encompassed by the representative substance, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable pharmaceutical excipients.

The present 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 forms. The composition may be a liquid, solid, semi-solid, gel, or aerosol form. In some embodiments, the pharmaceutical composition may be oral tablets, capsules, pills, powders, sustained release formulations, solution and suspension, for parenteral injection as a sterile solution, suspension or emulsion, with in topical ointment or cream, or suppositories for rectal administration. In other embodiments, the pharmaceutical composition is suitable for single administration of precise dosages unit dosage forms. In other embodiments, the amount of the compound is from about 0.001mg / kg of body weight / day - in the range of about 1000mg / kg body weight / day. In other embodiments, the range of the amount of the compound is from about 0.5mg / kg body weight / day - about 50mg / kg body weight / day. In some embodiments, the amount of the compound is from about 0.001g / day - to about 7g / day. In other embodiments, the amount of the compound is from about 0.002g / day - to about 6g / day. In other embodiments, the amount of the compound is from about 0.005g / day - to about 5g / day. In other embodiments, the amount of the compound is from about 0.01g / day - to about 5g / day. In other embodiments, the amount of the compound is from about 0.02g / day - to about 5g / day. In other embodiments, the amount of the compound is from about 0.05g / day - to about 2.5g / day. In other embodiments, the amount of the compound is from about 0.1g / day - about 1g / day. In other embodiments, the range below the lower limit of the above dosage levels may already be sufficient. In other embodiments, the dosage levels described above may require an upper limit. 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 a day. 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 per day. In some embodiments, the pharmaceutical composition is administered to the individual is a mammal. In other embodiments, the mammal is a human.

The present invention provides the use of all pharmaceutically said compound or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions thereof in the manufacture of a medicament, the medicament for treating a indoleamine 2,3-dioxygenase mediated tryptophanyl pathological features of the disease acid metabolism pathway. For example, the cut-mediated expression of IDO indoleamine 2,3-dioxygenase. The present invention provides a pharmaceutically all the above compound or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions for use in the manufacture of indoleamine 2,3-dioxygenase inhibitors.

The present invention provides a pharmaceutically all the above compound or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions thereof, as indoleamine 2,3-dioxygenase inhibitor; or for treating a indoleamine 2,3 diseases characterized by pathological metabolic pathways of tryptophan dioxygenase mediated. For example, the cut-mediated expression of IDO indoleamine 2,3-dioxygenase.

The present invention provides a process pharmaceutically all the above compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for the inhibition of indoleamine 2,3-dioxygenase. The method comprises in vivo and in vitro methods dioxygenase indoleamine 2,3-bis suppressed. Also provided is a disease characterized by pathological pathway of tryptophan metabolism pharmaceutically all the above compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for treating indoleamine 2,3-dioxygenase mediated.

Said indoleamine 2,3-pathological features of the present invention diseases metabolic pathway of tryptophan dioxygenase mediated, including cancer, infectious diseases, neurodegenerative disease, depression, anxiety, or age-related cataract;

Wherein said cancer is selected from 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;

It refers to the neurodegeneration Alzheimer's syndrome;

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

Activity test results show that the resulting compound of the invention has an excellent enzyme inhibitory activity. In a specific embodiment, the Compound S-1 with the structure similar to the compound compared to S-20, the active compound significantly better than S-20.

Vivo test results show that the compounds of the present invention has a high inhibition rate of tumor, the therapeutic effect on the tumor and significantly better than compound Cyclophoshamide

Figure PCTCN2017084604-appb-000073
Therapeutic effect, the therapeutic effect of Compound 103 on tumor which was significantly better than their structural analogs
Figure PCTCN2017084604-appb-000074
Therapeutic effect (Compound 1505) of the tumor.

Indoleamine 2,3-dioxygenase inhibitors for tumor therapy at significantly reduced drug side effects, significantly improve the quality of life of mice, clinical performance not only can improve the quality of life of patients, and can greatly improve patient medication compliance and effectiveness of the drug. In particular embodiments, before and after the administration of each compound of the present invention and cyclophosphamide were compared, the results show, compared with cyclophosphamide, each compound of the present invention can significantly promote the growth of animal body weight, with the amount of growth model groups showed no significant difference. Compounds of the present invention can significantly improve learning and memory impairment, improve learning ability to obtain and spatial memory capacity, with positive implications for the treatment of neurodegenerative diseases such as Alzheimer's syndrome.

By a T cell proliferative response was found in the compound of the present invention can promote the DC stimulation of T cell proliferation, and thus can be used for neoplastic disease, autoimmune disease, transplant rejection, and response to treatment of infectious diseases.

Absolute bioavailability of measurement results showed that the compounds of the present invention has a high bioavailability, and the compound S-21 compound 1505 has obvious advantages compared to its structural analogs Compound 103 and 1505 compared to bioavailability compound 1505 significantly higher degree.

When the present invention indoleamine 2,3-dioxygenase inhibitors having pharmaceutical tryptophan metabolism indoleamine dioxygenase pathway mediated pathological features of the disease treatment is for the manufacture of 2,3 It has the following advantages:

(1) significant anti-tumor effect, the compounds of the present invention has significant indoleamine 2,3-dioxygenase inhibiting activity, and in vivo tests show inhibitory compounds of the present invention is significantly higher than the positive control drug cyclophosphamide and an amide compound S-21 and 1505.

(2) reduce the side effects, the compounds of the present invention is indoleamine 2,3-dioxygenase inhibitor, by inhibiting the proliferation of indoleamine 2,3-dioxygenase activity of T suppressor cells reverses the body immunomodulatory function, thus completing the monitoring and killing effect of the body's immune system against tumor cells. Based on this particular mechanism of action, such compounds without adverse effects on the growth of human normal cells while inhibiting growth of tumor cells, thus significantly reducing the side effects. And of autoimmune diseases associated with proliferation of T cells, transplant rejection and infectious diseases have a significant therapeutic effect.

(3) when the treatment of neurodegenerative diseases such as Alzheimer significant effect, can significantly improve the learning and memory impairment and significantly improve learning ability to obtain and spatial memory.

(4) have a higher bioavailability, with significant advantages in terms of medicine.

Certain Chemical Terminology

Unless otherwise defined, all technical and scientific terms herein have the same meaning as the right to the same theme skilled in the art commonly understood meaning of the requirements. Unless otherwise stated, all patents herein incorporated by reference, patent applications, published materials are incorporated herein by reference in its entirety.

It should be understood that the above description and the following detailed description are exemplary and only serve to explain, without any of the limitations relating to the present application. In this application, unless specifically stated otherwise, also include the plural use of the singular. It should also be noted that, unless otherwise indicated, used "or", "or" means "and / or." Further, the term "comprising" as well as other forms, such as "comprising", "contains" and "containing" are considered non-limiting description.

Reference may be (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 TH ED." Vols.A (2000) and B (2001), Plenum Press, New York) found in the definitions of standard chemistry terms. Unless otherwise indicated, conventional methods within the skill in the art, such as mass spectrometry, NMR, IR and UV / Vis spectroscopy and pharmacology,. Unless specific definitions proposed otherwise described herein in terms related to the analysis of chemical, pharmaceutical and synthetic organic chemistry and pharmaceutical chemistry are employed known in the art. It may be chemical syntheses, chemical analyzes, pharmaceutical preparation, formulation, and delivery, and using standard techniques for treatment of patients. For example, using the manufacturer's instructions for using the kit, or in accordance with a manner known in the art or described embodiments of the present disclosure to the reaction and purification. Summary and description of a plurality of more specific literature cited and discussed generally in accordance with the present specification, the above-described methods and techniques in a conventional manner known in the art. In the present specification, by one skilled in the art to select groups and substituents thereof to provide stable moieties and compounds.

When the substituent by conventional chemical formulas, written from left to right description, the substituent also include the right to left in chemical equivalent substituents writing structural formula obtained. For example, CH 2 O equal to OCH 2.

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

"Compound" according to the present application is meant to include all stereoisomers, geometric isomers, tautomers and isotopes. This application may be asymmetrical compound, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers thereof. The compounds of the present application contains an asymmetrically substituted carbon atoms may be isolated in pure optically active form or racemic form. Pure optically active form of racemic mixtures can be resolved from the outside, or by use of chiral starting material or chiral reagents synthesis. The present application further compounds include tautomeric forms. Tautomeric forms from a single bond and adjacent double bond exchange and concomitant migration of a proton together. The compounds of the present application also comprises all isotopes of atoms, either in the compounds or intermediates of the final. They include isotopes of other atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. That is, a compound of the present application includes a portion of or all of hydrogen hydrogen (H) tritium (T) and / or deuterium (D) is replaced by compound; further comprising part or all of the 13 C and 12 C / 14 C or alternatively compound; and substitution among other isotopes (e.g., N, O, P, S) compound, 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 stereocenters and each center may exist in the R isomer or S configuration, or a combination of forms. Similarly, the compounds described herein may have one or more double bonds, and each double bond may be present in the E (trans) or Z (cis) configuration, or a combination form. A particular stereoisomers, structural isomers (regioisomers), diastereomers thereof, enantiomers or a difference should be understood to include all possible isomers, stereoisomers such as epimers , structural isomers thereof, diastereomers thereof, enantiomers or epimers and mixtures thereof. Accordingly, the compound includes all configurations of different stereoisomers, structural isomers, diastereomers thereof herein, enantiomer or mixture of the difference and the corresponding isomeric forms thereof. For transforming the specific stereoisomers or a particular stereoisomer maintain the status quo of the technology and the technical resolution of mixtures of stereoisomers are well known in the art, those skilled in the art can select a suitable method of specific cases. See, e.g. 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 "optionally / any" or "optionally / optionally" means that the subsequently described event or circumstance may or may not occur, that the description includes said event or circumstance occurs and the event or circumstance does not occur. For example, the following definition of "optionally substituted alkyl" means "unsubstituted alkyl" (unsubstituted alkyl group substituted) or a "substituted alkyl" (alkyl substituted by a substituent) .

(Around claim defined terms appear in the book, so that the face of the claims is not clear, the need to give an explanation of the applicant, but also to provide a basis for possible future changes; this section need to be adjusted according to specific cases)

As used herein, includes C 1 -C n C 1 -C 2, C 1 -C 3, ...... C 1 -C n. For example, the "C 1 -C 4" group refers to the portion having 1-4 carbon atoms, i.e. the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atom. Thus, for example "C 1 -C 4 alkyl" refers to an alkyl group having 1 to 4 carbon atoms, i.e. the alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl butyl, isobutyl, sec-butyl and tert-butyl. Herein, a numerical range such as "1 to 10" refers to each integer in the given range, e.g., "1 to 10 carbon atoms" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

Alone or in combination herein, the term "alkyl" refers to an optionally substituted straight-chain or optionally substituted branched aliphatic hydrocarbon chain. "Alkyl" herein may preferably have 1 to about 20 carbon atoms, for example 1 to about 10 carbon atoms, having from 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms, or 1 to about 4 carbon atoms, or 1 to about 3 carbon atoms. Example alkyl groups herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl -l- propyl, 2-propyl, 2-methyl- - butyl, 3-methyl -l- butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3- pent-1-yl, 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-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, and 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 carbon atoms, cycloalkylalkyl, of 4 carbon atoms, herein, 5 carbon atoms or 6 carbon atoms are also included without specified numerical range.

"Alkyl" as used herein includes alkyl groups used in combination with other binding groups such as alkoxy, alkylthio the alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, alkylamino ( the monoalkylamino, dialkylamino) "alkyl" and the like.

Alone or in combination herein, the term "alkylamino" means alkylamino (-HN- alkyl (i.e., monoalkylamino) or -N- (alkyl) 2 (i.e., dialkylamino). Wherein, alkyl is defined above.

Alone or in combination, the term "alkoxy" as used herein refers to an alkyl ether group (0- alkyl), non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy group, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy and the like.

Alone or in combination herein, the term "alkenyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain monovalent hydrocarbon radical having one or more C = C double bond. The alkenyl group having, but not limited to, 2 to about 18 carbon atoms, e.g., having 2 to about 10 carbon atoms, or having from 2 to about 8 carbon atoms, 2 to about 6 carbon atoms, 2 to about 4 carbon atom. These groups are bonds may be cis or trans conformation, and should be understood to include the two 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. Alkenyl group as defined herein, a numerical range occurs, for example, "C 2 -C 6 alkenyl" or "C 2 - 6 alkenyl" refers to 2 carbon atoms may, 3 carbon atoms, 4 carbon atoms, 5 carbon alkenyl atoms or 6 carbon atoms, and alkenyl groups are also contemplated herein without the specified numerical range.

Alone or in combination herein, the term "halo" or "halogen-substituted" means optionally substituted with a group (such as alkyl, alkenyl and alkynyl groups) in which one or more hydrogen atoms are replaced by fluorine, chlorine , bromine, iodine atom or a combination thereof. In some embodiments, the same halogen atoms replace one another two or more hydrogen atoms (e.g. difluoromethyl, trifluoromethyl); alternatively use two halogen atoms are not identical to each other in other embodiments or more hydrogen atoms (such as 1-chloro-1-fluoro-1-iodoethyl). Haloalkyl non-limiting examples are fluoromethyl and bromoethyl. Non-limiting examples of haloalkenyl bromovinyl. Non-limiting examples of haloalkynyl are chloroethynyl.

Alone or in combination herein, the term "aryl / aryl" refers to an optionally substituted aromatic hydrocarbon group having 6 to about 20, such as 6-12 or 6-10 ring carbon atoms. Which may be a condensed aromatic ring or fused aromatic ring. Fused aromatic ring containing 2-4 aromatic rings, fused rings, the other ring may independently alicyclic, heterocyclic, aromatic, aromatic heterocyclic, or any combination thereof. Herein, aryl groups include monocyclic, bicyclic, tricyclic or more aryl rings. Non-limiting examples include monocyclic aryl groups having 6 to about 12, about 6 to 10 or 6 to about 8 monocyclic aryl ring carbon atoms, such as phenyl; fused rings comprising a bicyclic aryl group, more or tricyclic aryl ring, such as naphthyl, phenanthrenyl, anthracenyl, azulenyl; non-fused aryl groups include biphenyl bis.

Alone or in combination herein, the term "heteroaryl" refers to an optionally substituted a divalent heteroaryl group, comprising from about 5 to about 20, such as 5 to 12 or 5 to 10 skeletal ring atoms, wherein one or a plurality (e.g., 1-4, 1-3, 1-2) heteroatom ring atoms, said heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin heteroaryl atoms, but is not limited thereto. Ring of said group does not contain two adjacent O or S atoms. Heteroaryl groups include monocyclic heteroaryl or polycyclic heteroaryl group (e.g., bicyclic heteroaryl, tricyclic heteroaryl group). Embodiments there are two or more hetero atoms in the ring mode, the two or more heteroatoms can be the same as each other, or some of the two or more hetero atoms or all different from each other. The term heteroaryl includes a heteroaryl group having at least one hetero atom monovalent fused or non-fused optionally substituted. In addition, the term heteroaryl also includes to fused and non-fused heteroaryl ring atoms containing from 5 to about 12 skeletal, and fused and non-fused containing 5 to about 10 skeletal ring atoms, heteroaryl. It may be bonded via a carbon atom or a heteroatom heteroaryl. Thus, for example, imidazole through which any carbon atoms (imidazol-2-yl, imidazol-4-yl or imidazol-5-yl) or nitrogen atoms (imidazol-1-yl or imidazol-3-yl) attached to the parent molecule. Similarly, any or all of its carbon atoms and / or any or all further heteroatom substituted by a heteroaryl group. Fused heteroaryl groups may contain the heterocyclic 2-4 fused aromatic fused rings, the other ring may independently alicyclic, heterocyclic, aromatic, aromatic heterocyclic, or any combination thereof. Monocyclic heteroaryl, non-limiting examples include 5 to about 12, 5 to about 10, 5 to about 7 or 6 skeletal ring atoms, a monocyclic heteroaryl, such as the non-limiting examples include pyridyl; fused ring heteroaryl groups include benzimidazolyl (benzimidazolyl), quinolyl (quinolinyl), acridinyl (acridinyl), non-fused heteroaryl groups include bis-dipyridyl (bipyridinyl). Other embodiments heteroaryl groups include, but are not limited to: pyridine, pyrimidine, pyrazine, pyridazine, triazine, furan, thiophene, imidazole, triazole, tetrazole, thiazole, isothiazole, 1,2,4-thiadiazole oxazole, pyrrole, pyrazole, oxazole, isoxazole, oxadiazole, benzofuran, benzothiophene, benzothiazole, indole, indazole, quinoline, isoquinoline, purine, carbazole, benzo imidazole, pyrrolopyridine, pyrrolopyrimidine, pyrazolopyridine, pyrazolopyrimidine like. Acridinyl, phenoxazinyl, benzoxazolyl, benzo-thiadiazolyl, benzo-oxadiazolyl, benzotriazolyl, isoquinolyl, indolizinyl (indolizinyl), isothiazolyl ( isothiazolyl), isoindolyl (isoindolyl), oxadiazolyl (oxadiazolyl), purinyl (purinyl), phthalazinyl group (phthalazinyl), pteridinyl (pteridinyl), quinazolinyl (quinazolinyl), quinoxaline morpholinyl (quinoxalinyl), triazinyl (triazinyl) and thiadiazolyl (thiadiazolyl) and the like, and their oxides, e.g. pyridyl-oxide -N- (pyridyl-N-oxide) and the like.

Alone or in combination herein, the term "heterocycle" or "heterocyclyl" means a non-aromatic heterocyclic ring include heterocyclic group (a saturated heterocyclic group), and heterocycloalkenyl group (unsaturated heterocyclic group). Wherein one or more atoms (e.g., 1-4, 1-3, 1-2) of the ring is a heteroatom such as oxygen, nitrogen or sulfur atom. Heterocyclyl group may comprise a monocyclic heterocyclic group (heterocyclic group having a ring) or polycyclic heterocyclic group (e.g., bicyclic heterocyclic group (heterocyclic group having two rings), tricyclic heterocyclic group and the like). Bicyclic heterocyclic group may be a spiro ring, it may be a bridged ring. Heterocyclic group may have 3 to about 20, such as 3 to about 10, 3 to about 8, 5 to about 8, or 5 to about 6 ring atoms. Nonlimiting examples of the heterocyclic group include azine group (azinyl), azetidinyl (azetidinyl), oxetanyl (oxetanyl), thietanyl (thietanyl), homopiperidinyl ( homopiperidinyl), oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl (1,2,3,6-tetrahydropyridinyl), 2- pyrrolinyl (2-pyrrolinyl), 3- pyrrolinyl (3-pyrrolinyl), indolinyl (indolinyl), 2H- pyranyl (2H-pyranyl), 4H- pyranyl (4H-pyranyl), dioxanyl (dioxanyl), 1, 3- dioxolanyl (1,3-dioxolanyl), pyrazolinyl (pyrazolinyl), disulfide cyclohexyl (dithianyl), cyclopentyl disulfide (dithiolanyl), dihydropyranyl (dihydropyranyl), two hydrogen thienyl (dihydrothienyl), dihydrofuranyl (dihydrofuranyl), pyrazolidinyl (pyrazolidinyl), imidazolinyl (imidazolinyl), imidazolidinyl (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 (3H-indolyl) quinolinyl, and (quinolizinyl )Wait. The term also includes all ring forms of the carbohydrates, including but not limited to, monosaccharides, disaccharides and oligosaccharides. Example embodiments also include, but are not limited to, aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, isoxazolidine, isothiazolidine, pyrazolidine, morpholine, thiomorpholine morpholine, piperazine, piperidyl and the like. Heterocyclyl includes heterocyclyl having one or more aromatic rings fused (i.e., having a bond in common with), for example, 2,3-dihydrobenzofuran, 1,3-dioxolane, benzo 1,4-dioxane, phthalimide, naphthalimide. Having one or more fused aromatic heterocyclic group can be attached to other groups through aromatic or non-aromatic ring moiety. Other groups may be via a heteroatom or a carbon atom bound to the heterocycle (i.e. a heterocyclic parent molecule or further substitution).

Alone or in combination herein, the term "carbocyclic group" refers to a non-aromatic carbon ring, including cycloalkyl and cycloalkenyl. Cycloalkyl group can be monocyclic or polycyclic cycloalkyl group (e.g., 2, 3 or 4 ring there; such bicyclic cycloalkyl), which may be a spiro ring or a bridged ring. Cycloalkyl group can have 3 to 20 carbon atoms, for example 3 to about 15 ring carbon atoms, or 3 to about 10 ring carbon atoms, or 3-6 ring-forming carbon atoms, and may have 0,1,2 or 3 double bonds and / or 0, 1 or 2 triple bonds. E.g. having 3-8 or 3-6 ring carbon atoms, a cycloalkyl group (e.g., saturated monocyclic cycloalkyl). Further comprises cycloalkyl ring having one or more aromatic rings fused (i.e., having a bond in common with), e.g., benzo-substituted derivatives of pentane, pentene, hexane and the like. One or more aromatic fused cycloalkyl may be connected to other groups by partial aromatic or non-aromatic ring. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, adamantyl and the like.

"Halogen" refers to fluoro, chloro, bromo, iodo. Preferred are fluoro, chloro and bromo. It means cyano "-CN"; refers to a hydroxyl group "-OH"; mercapto refers to "-SH"; amino means a "-NH 2"; oxo means = O.

The term "substituted" means one or more hydrogens replaced by a group designated in a particular atom, if the normal valency of the designated atom is not exceeded in the conventional case, then the result is a substituted stable compound.

Certain pharmaceutically term

Some of the terms used herein, the term pharmaceutically acceptable "subject", "patient" or "individual" refers to an individual suffering from other diseases, disorder or condition, including mammals and non-mammals. Example of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs and cats; laboratory animals including rodents, such as rats, mice and guinea pigs. Example nonhuman mammals include, but are not limited to, birds, and fish. In a related embodiment the methods and compositions of the embodiments provided herein, the mammal is a human.

As used herein, the term "treating" and other similar Synonyms include alleviating, abating or ameliorating a disease or condition symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition of the disease or condition improves, alleviate the disease or symptoms of a disorder caused by, or stopping the symptoms of the disease or disorder, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, in addition, the term encompasses prevention purposes. The term also includes the therapeutic effect and / or prophylactic effect. The therapeutic effect refers to the potential cure of the disease being treated or improved. In addition, cure or improvement is the therapeutic effect of one or more of the physiological symptoms associated with the underlying disease, for example, even though the patient may still be affected by the underlying disease, but observed that the patient's condition improved. For prophylactic effect, the composition may be administered to a patient suffering from a particular disease risk patient is administered the composition, or even yet to make diagnosis, but a plurality of the disease or physiological symptoms to appear.

As used herein, the term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" means an amount sufficient at least one active substance in the treatment of a disease or relieve to some extent one or more symptoms of the disorder after taking ( the amount of the compound of the present application) a. The result can be a sign of symptoms or causes of a reduction and / or mitigation, or any other desired changes in biological systems. For example, for the treatment of an "effective amount" is to provide a significant amount of disease-modifying composition comprising a compound disclosed herein the desired clinical results. Determination of an effective amount may be adapted to any individual case using techniques such as a dose escalation trial.

As used herein, the term "administration", "administering", "administration" refers to a method capable of other compounds or compositions for delivery to a desired site of biological action. These methods include, but are not limited to, oral routes, by intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical, and rectal administration. Those skilled in the art may be used for administration techniques are well known compounds and methods described herein, 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, Pa those discussed.

Paper formulation, composition or ingredient, the term "acceptable" means that no long-term harmful effects on the general health of the subject being treated.

As used herein, the term "pharmaceutically acceptable" refers to substances of the present application does not affect the biological activity or properties of the compound (e.g., a carrier or diluent), and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological reactions or interact in any way defective components included in the composition.

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

As used herein, the term "vector" refers to the relatively non-toxic substance, which facilitates the application of the present compound into cells or tissues.

The term "pharmaceutically acceptable salts" refers to retain the biological effectiveness of the free acids and bases of the specified compound used, and no adverse effect on the biologically or otherwise salts. The present application further compounds include pharmaceutically acceptable salts thereof. It refers to pharmaceutically acceptable salts of the parent compound to convert the group into an alkali salt form. Pharmaceutically acceptable salts include, but are not limited to, groups such as an inorganic base or an organic amine salt (amino) group. Pharmaceutically acceptable salts of the present application can be synthesized from the parent compound, i.e., the parent compound basic group with 1-4 equivalents of an 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 indicated, refers to salts of the present application, acid salts formed with organic / inorganic acids, as well as basic salts formed with an organic base / inorganic bases. Further, when a basic functional group of the general formula is a pyridine or imidazole compounds (but not limited to a pyridine or imidazole), an acidic functional group is a carboxylic acid (but not limited to a carboxylic acid) can form zwitterions (inner salts), the inner salt salts are also included within the present application.

detailed description:

Synthesis of specific compounds of formula representative of the present invention are disclosed by the present invention can be synthesized. Below in connection with specific embodiments of the present invention will be further described, but the present invention is not limited thereto. And under the guidance of the present invention of the general formula, the formula and the synthesis methods of the specific embodiments, those skilled in the art without paying creative work to other specific compounds obtained are within the scope of the present invention.

Synthesis Example 1 XSD1-064 embodiment

1):

Figure PCTCN2017084604-appb-000075

Intermediate 1 (80mg, 0.23mmol) was dissolved in 5mL of dichloromethane, was slowly added thionyl chloride (0.5 mL), the reaction mixture was warmed to 75 deg.] C for 2 hours. Cooled to room temperature, the solvent was distilled off under reduced pressure, the crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000076

6mL anhydrous tetrahydrofuran was added and sufficiently dissolved the compound 2, was added N- methyl-benzylamine (180mg, 0.66mmol) and N, N- diisopropylethyl amine (0.25mL, 1.32mmol) at 0 deg.] C, stirred at room temperature 18h. TLC showed the reaction was complete. Quenched with 20mL of water was added, extracted with ethyl acetate (10mL x5), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. Compound 3 obtained crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000077

The crude compound 3 was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (20 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-064 (25mg, three-step total yield 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%

Synthesis Example 2 XSD1-065 embodiment

1):

Figure PCTCN2017084604-appb-000078

Intermediate 1 (80mg, 0.23mmol) was dissolved in 5mL of dichloromethane, was slowly added thionyl chloride (0.5 mL), the reaction mixture was warmed to 75 deg.] C for 2 hours. Cooled to room temperature, the solvent was distilled off under reduced pressure, the crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000079

6mL anhydrous tetrahydrofuran was added and sufficiently dissolved the compound 2, was added aniline (85mg, 0.88mmol) and N at 0 ℃, N- diisopropylethyl amine (0.4mL, 1.8mmol), stirred at rt for 18h. TLC showed the reaction was complete. Quenched with 20mL of water was added, extracted with ethyl acetate (10mL x5), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. Compound 3 obtained crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000080

The crude compound 3 was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (20 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-065 (10mg, 12% overall yield in three steps).

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]

Synthesis Example 3 XSD1-066 embodiment

1):

Figure PCTCN2017084604-appb-000081

Intermediate 1 (120mg, 0.33mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (65mg, 0.50mmol), O- (7- nitrogen Benzotriazole) -N, N , N ', N'- tetramethyluronium hexafluorophosphate (200mg, 0.50mmol) and diisopropylethyl amine (130mg, 1.0mmol), under nitrogen at room temperature overnight, quenched with water, ethyl acetate (30mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000082

The crude Compound 2 product was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by Pre-HPLC, to give the title compound XSD1-066 (28mg, 19% overall yield in two steps).

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]

Synthesis Example 4 XSD1-067 embodiment

1):

Figure PCTCN2017084604-appb-000083

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (60mg, 0.412mmol), O- (7- nitrogen Benzotriazole) -N, N , N ', N'- tetramethyluronium hexafluorophosphate (157.4mg, 0.412mmol) and diisopropyl ethyl amine (106.3mg, 0.824mmol), under nitrogen at rt overnight, quenched with water, acetic acid ethyl ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000084

The crude Compound 2 product was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by Pre-HPLC, to give the title compound XSD1-067 (6mg, 5% of total yield in two steps).

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]

Synthesis Example 5 XSD1-068 embodiment

1):

Figure PCTCN2017084604-appb-000085

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (60mg, 0.412mmol), O- (7- nitrogen Benzotriazole) -N, N , N ', N'- tetramethyluronium hexafluorophosphate (157.4mg, 0.412mmol) and diisopropyl ethyl amine (106.3mg, 0.824mmol), under nitrogen at rt overnight, quenched with water, acetic acid ethyl ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000086

The crude Compound 2 product was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give XSD1-068 (42mg, two steps total yield 32%) of the title compound.

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]

Synthesis Example 6 XSD1-069 embodiment

1):

Figure PCTCN2017084604-appb-000087

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (59mg, 0.412mmol), O- (7- nitrogen Benzotriazole) -N, N , N ', N'- tetramethyluronium hexafluorophosphate (157.4mg, 0.412mmol) and diisopropyl ethyl amine (106.3mg, 0.824mmol), under nitrogen at rt overnight, quenched with water, acetic acid ethyl ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000088

The crude Compound 2 product was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-069 (50mg, 37% yield).

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]

Synthesis Example 7 XSD1-070 embodiment

1):

Figure PCTCN2017084604-appb-000089

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (60mg, 0.412mmol), O- (7- nitrogen Benzotriazole) -N, N , N ', N'- tetramethyluronium hexafluorophosphate (157.4mg, 0.412mmol) and diisopropyl ethyl amine (106.3mg, 0.824mmol), under nitrogen at rt overnight, quenched with water, acetic acid ethyl ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000090

The crude Compound 2 product was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-070 (100mg, 80% overall yield in two steps).

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]

Synthesis Example 8 XSD1-071 embodiment

1):

Figure PCTCN2017084604-appb-000091

Intermediate 1 (130mg, 0.36mmol) was dissolved in 5mL N, N- dimethylformamide, were added the compound 1a (58mg, 0.54mmol), 2- (7- oxide benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (205mg, 0.54mmol), N, N- diisopropylethylamine (138mg, 1.07mmol). The reaction overnight at room temperature under nitrogen, water was added, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000092

The crude Compound 2 was dissolved in 5mL of methanol, under an ice bath was added NaBH 4 (200mg, 5mmol), reaction was stirred for 1 hour, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-071 (64.68mg).

1 H-NMR (400MHz, 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]

Synthesis Example 9 XSD1-072 embodiment

1):

Figure PCTCN2017084604-appb-000093

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added compound 7a (60mg, 0.412mmol), O- (7- nitrogen Benzotriazole) -N, N , N ', N'- tetramethyluronium hexafluorophosphate (157.4mg, 0.412mmol) and diisopropyl ethyl amine (106.3mg, 0.824mmol), under nitrogen at rt overnight, quenched with water, acetic acid ethyl ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000094

The crude Compound 2 product was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-072 (10mg, 8% yield).

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]

Synthesis Example 10 XSD1-073 embodiment

1):

Figure PCTCN2017084604-appb-000095

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (55.8mg, 0.412mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (157.4mg, 0.412mmol) and diisopropyl ethyl amine (106.3mg, 0.824mmol), under nitrogen at rt overnight, quenched with water, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000096

The crude Compound 2 product was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-073 (60mg, 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]

Synthesis Example 11 XSD1-074 embodiment

1)

Figure PCTCN2017084604-appb-000097

Intermediate 1 (91mg, 0.25mmol) was dissolved in 5mL N, N'- dimethylformamide, were added the compound 1a (21.3mg, 0.3mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (150mg, 0.39mmol) and diisopropylethyl amine (52mg, 0.77mmol), the reaction at room temperature under nitrogen overnight, quenched with water, ethyl acetate ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2)

Figure PCTCN2017084604-appb-000098

The crude Compound 2 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, and rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-074 (35mg, yield 33.5%).

H NMR (DMSO, 400M): 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] +.

Synthesis Example 12 XSD1-076 embodiment

1):

Figure PCTCN2017084604-appb-000099

Intermediate 1 (80mg, 0.22mmol) was dissolved in 5mL N, N- dimethylformamide, were added the compound 1a (130mg, 2.12mmol), 2- (7- oxide benzotriazole) -N, N , N ', N'- tetramethyluronium hexafluorophosphate (126mg, 0.33mmol), N, N- diisopropylethylamine (567mg, 0.44mmol), the reaction at room temperature under nitrogen overnight, quenched with water, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000100

The crude Compound 2 was dissolved in 5mL of methanol was added under ice bath NaBH 4 (88mg, 2.2mmol), the reaction stirred for 1 hour, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-076 (20.37mg).

1 H-NMR (400MHz, 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]

Synthesis of Example 13 XSD1-077

1):

Figure PCTCN2017084604-appb-000101

Intermediate 1 (140mg, 0.38mmol) was dissolved in 5mL N, N- dimethylformamide, were added the compound 1a (57mg, 0.77mmol), 2- (7- oxide benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (221mg, 0.58mmol), N, N- diisopropylethylamine (149mg, 1.15mmol). The reaction overnight at room temperature under nitrogen, water was added, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000102

The crude Compound 2 was dissolved was added NaBH 4 (154mg, 3.85mmol) 5mL of methanol under ice bath, the reaction was stirred for 1 hour, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-077 (26.40mg).

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]

Synthesis Example 14 XSD1-078 embodiment

1)

Figure PCTCN2017084604-appb-000103

The aqueous solution of barium hydroxide (1.71g, 10mmol) was added compound 1 (4.8g, 20mmol) in 40mL methanol, and the reaction was stirred overnight at rt. After the reaction was neutralized with 1N HCl, extracted with ethyl acetate (50mL * 2), the organic phase was dried over anhydrous sodium sulfate and concentrated, Column chromatography afforded the product as a white solid 2 (2.16g, Yield: 81%).

2)

Figure PCTCN2017084604-appb-000104

At 0 deg.] C, the mercuric oxide (2.16g, 10mmol), iodine (7.74g, 30mmol) was added to compound 2 (2.12g, 10mmol), and chloroform (100 mL) solution, and then the reaction temperature was slowly raised to 90 deg.] C the reaction was continued for 18 h, the reaction TLC (ethyl acetate:: petroleum ether = 21) monitoring, after the completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, was added 100mL of water, (100mL * 3) organic phase was extracted with ethyl acetate, dried over anhydrous over sodium sulfate, and purified by column chromatography and concentrated to give compound 3, (1.8g, yield 61.2%).

3)

Figure PCTCN2017084604-appb-000105

Compound 3 (1.2g, 4.08mmol) was dissolved in tetrahydrofuran (30mL) in a dry ice acetone bath to -65 ℃, was slowly added dropwise tert-butyllithium (6mL, 8.16mmol) in tetrahydrofuran was added and the reaction was maintained -65 ℃ stirred 2h, then slowly warmed to room temperature and stirring was continued for 18 h, the reaction solution was reduced to 0 deg.] C, was added a saturated aqueous ammonium chloride solution (20mL) to quench the reaction, extracted with ethyl acetate (80mL * 3) organic phase was extracted, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure, purified by column chromatography to give compound 4 (500mg, 71.4% yield).

4)

Figure PCTCN2017084604-appb-000106

Compound 3a (1.02mg, 4.07mmol) was dissolved in 30mL anhydrous tetrahydrofuran, a dry ice acetone bath to -70 deg.] C, slowly butyllithium (8mL, 4.07mmol) and maintained internal temperature of -60 deg.] C, quickly compound anhydrous 4 (500mg, 3.26mmol) solution in tetrahydrofuran (10 mL) was added and the reaction flask kept internal temperature of -60 ℃. At -70 deg.] C, the reaction was continued stirring for 2 hours, quenched with saturated ammonium chloride, warmed to room temperature. With dichloromethane (100mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product by column chromatography to obtain the product compound 5 (200m g, yield 63.2%).

5)

Figure PCTCN2017084604-appb-000107

Compound 5 (200mg, 0.51mmol) was dissolved in 10mL anhydrous tetrahydrofuran, was added sodium hydride (51mg, 1.27mmol), warmed to room temperature with stirring under ice-cooling for 1 hour. Under ice Compound 4a (211mg, 0.51mmol) was dissolved in 5mL of anhydrous tetrahydrofuran was added to the reaction flask. The reaction was stirred overnight and warm to room temperature, quenched with saturated ammonium chloride and extracted with dichloromethane (50mL * 3), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product by column chromatography to obtain the product compound 6 (120mg, 34.6% yield).

6)

Figure PCTCN2017084604-appb-000108

Compound 6 (120mg, 0.18mmol) was dissolved in 10mL of methanol was added 1mL of glacial acetic acid, raised to 90 deg.] C the reaction was stirred overnight, the solvent was distilled off under reduced pressure, was added 100mL of saturated sodium bicarbonate and extracted with dichloromethane (50mL * 3), The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. Compound 7 to give a crude product (150 mg of) and used directly in the next reaction.

7)

Figure PCTCN2017084604-appb-000109

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 methanol, (30mL * 3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Pre-HPLC to give Compound XSD1-078 (17mg).

1 H-NMR (400MHz, 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]

Synthesis Example 15 XSD1-079 embodiment

1):

Figure PCTCN2017084604-appb-000110

Sodium bicarbonate (20g, 0.5mol) dissolved in 400mL of ethylene glycol dimethyl ether, an ice bath, was added compound 1 (50g, 0.22mol), 105 ℃ reflux for 12h, the system gradually from white to pink, purple. The system rotary evaporation, was added 60mL of ethylene glycol dimethyl ether, 1,3-dibromo-propane was added, refluxed for 48h 105 ℃, the system is gradually changed from purple to white suspension. System was filtered hot, washed with dichloromethane, the filtrate by rotary evaporation, recrystallized from ethanol to give the product 22g, 42% yield.

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):

Figure PCTCN2017084604-appb-000111

Compound 2 (23g, 0.086mol) was dissolved in 230mL of anhydrous toluene, were added 1,2-ethanedithiol (58mL, 0.69mol), p-toluenesulfonic acid (0.73g, 3.8mmol), trap operation , 130 ℃ refluxed under nitrogen overnight. Quenched with water, ethyl acetate (200mL x3), the combined extracts were washed with 2N sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. Column chromatography to give a yellow solid 10g, 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):

Figure PCTCN2017084604-appb-000112

Compound 3 (1.0g, 2.4mmol) was dissolved in 60mL of ethanol was added Raney nickel (20g), 100 ℃, stirred for 72h. Filtered while hot, washed with 1 l of hot ethanol, the filtrate by rotary evaporation, column chromatography, to give the product 450mg, 79% yield.

4):

Figure PCTCN2017084604-appb-000113

Compound 4 (240mg, 1.0mmol) was dissolved in 2.2mL methanol and 0.5mL water mixture was added barium hydroxide octahydrate (160mg, 0.5mmol), under nitrogen at room temperature overnight, quenched with water, washed with n-hexane, The aqueous phase was adjusted to PH 2, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate with 2N HCl, rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

5):

Figure PCTCN2017084604-appb-000114

Compound 5 (120mg, crude) was dissolved in 3mL N, N'- dimethylformamide, were added benzylamine (91mg, 0.85mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (330mg, 0.85mmol) and diisopropylethyl amine (210mg, 1.6mmol), the reaction at room temperature under nitrogen overnight, quenched with water, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. Column chromatography to give the product 160mg.

6):

Figure PCTCN2017084604-appb-000115

Compound 6 (160mg, 0.51mmol) was dissolved in 6mL of dry tetrahydrofuran, cooled to -78 deg.] C the system, n-butyllithium (1.3mL, 3.1mmol), temperature at -70 ℃ ~ -55 ℃, dropwise addition , dry tetrahydrofuran was added rapidly a solution of compound 6, completion of the addition, stirring was continued for 2h at -70 ℃ ~ -55 ℃. Quenched with saturated ammonium chloride, methylene chloride (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. Column chromatography to give 140 mg of product, 68% yield.

7):

Figure PCTCN2017084604-appb-000116

Compound 7 (140mg, 0.35mmol) was dissolved in 6mL of dry tetrahydrofuran, cooled to 0 deg.] C, was added sodium bisulfite, stirred at rt for 30min, the ice bath was added a solution of compound 7a in dry tetrahydrofuran at room temperature for 18h. Quenched with saturated ammonium chloride, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to give the product 130mg, 56% yield.

8):

Figure PCTCN2017084604-appb-000117

Compound 8 (130mg, 0.19mmol) was dissolved in 10mL of methanol was added 1mL of acetic acid, 90 deg.] C under nitrogen overnight. Saturated sodium bicarbonate solution was adjusted to PH 8, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, crude 130mg, was used directly in the next reaction.

9):

Figure PCTCN2017084604-appb-000118

The crude compound 9 was dissolved in 3mL dry methanol, ice bath was added sodium borohydride (90mg, 2.25mmol), the reaction at room temperature under nitrogen overnight, quenched with saturated ammonium chloride, rotary evaporation, ethyl acetate (30mL x5) and extracted The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford compound XSD1-079,20mg, 25% yield.

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]

Synthesis Example 16 XSD1-080 embodiment

1):

Figure PCTCN2017084604-appb-000119

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 portions of methanol, chloroform: isopropyl alcohol = 3: 1 (30mLx3), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-080 (5mg, 6% yield).

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]

Synthesis Example 17 XSD1-084 embodiment

1):

Figure PCTCN2017084604-appb-000120

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (230mg, 1.12mmol), O- (7- nitrogen Benzotriazole) -N, N , N ', N'- tetramethyluronium hexafluorophosphate (157.4mg, 0.412mmol) and diisopropyl ethylamine (300mg, 2.24mmol), the reaction at room temperature under nitrogen overnight, quenched with water, ethyl acetate ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000121

The crude Compound 2 product was dissolved in 3mL of dichloromethane was added trifluoroacetic acid (0.6 mL) under ice-cooling, and the reaction stirred for 18 hours, the reaction solution (10 mL) was made basic with saturated sodium bicarbonate solution and chloroform: isopropanol = 3: 1 (30mLx5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000122

The crude compound 3 was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-084 (16mg, 13% overall yield in three steps). Preparing two separated diastereomers thereof P1 (10mg), P2 (6.0mg). 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]

Synthesis Example 18 XSD1-085 embodiment

1):

Figure PCTCN2017084604-appb-000123

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (220mg, 1.12mmol), O- (7- nitrogen Benzotriazole) -N, N , N ', N'- tetramethyluronium hexafluorophosphate (157.4mg, 0.412mmol) and diisopropyl ethylamine (300mg, 2.3mmol), the reaction at room temperature under nitrogen overnight, quenched with water, ethyl acetate ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000124

The crude Compound 2 product was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-085 (15mg, 12% overall yield in two steps).

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]

Synthesis of Example 19 XSD1-086

1):

Figure PCTCN2017084604-appb-000125

Intermediate 1 (100mg, 0.27mmol) was dissolved in 5mL N, N- dimethylformamide, were added the compound 1a (115mg, 1.10mmol), 2- (7- oxide benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (160mg, 0.41mmol), N, N- diisopropylethylamine (290mg, 2.20mmol), the reaction at room temperature under nitrogen overnight, quenched with water, acetic acid ethyl ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000126

The crude Compound 2 was dissolved in 5mL of methanol was added under ice bath NaBH 4 (110mg, 2.75mmol), the reaction stirred for 1 hour, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-086 (28.12mg).

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]

Synthesis Example 20 XSD1-087 embodiment

1):

Figure PCTCN2017084604-appb-000127

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 (30mLx3), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000128

The crude Compound 2 product was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (180mg, 1.2mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N' - tetramethyluronium hexafluorophosphate (171mg, 0.45mmol) and diisopropylethyl amine (400mg, 3.0mmol), the reaction at room temperature under nitrogen overnight, quenched with water, ethyl acetate (50mL x5) extracted, The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-087 (16mg, overall yield of two steps 14%).

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]

Synthesis of Example 21 XSD1-088

1):

Figure PCTCN2017084604-appb-000129

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (172mg, 1.0mmol), O- (7- nitrogen Benzotriazole) -N, N , N ', N'- tetramethyluronium hexafluorophosphate (200mg, 0.50mmol) and diisopropylethyl amine (450mg, 3.3mmol), under nitrogen at room temperature overnight, quenched with water, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000130

Compound 2 was added 3mL crude product was dissolved in methanol, under ice bath NaBH4 (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford XSD1-088 (21mg, two steps total yield 17%) of the title compound.

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]

Synthesis of Example 22 XSD1-089

1):

Figure PCTCN2017084604-appb-000131

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (180mg, 1.2mmol), O- (7- nitrogen Benzotriazole) -N, N , N ', N'- tetramethyluronium hexafluorophosphate (171mg, 0.45mmol) and diisopropylethyl amine (400mg, 3.0mmol), under nitrogen at room temperature overnight, quenched with water, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000132

The crude Compound 2 product was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-089 (24mg, two steps total yield 20%).

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]

Synthesis Example 23 XSD1-090 embodiment

1):

Figure PCTCN2017084604-appb-000133

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (91.5mg, 0.412mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (157.4mg, 0.412mmol) and diisopropyl ethyl amine (106.3mg, 0.824mmol), under nitrogen at rt overnight, quenched with water, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000134

The crude Compound 2 product was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-090 (60mg, 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]

Synthesis Example 24 XSD1-091 embodiment

1):

Figure PCTCN2017084604-appb-000135

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (97.3mg, 0.412mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (157.4mg, 0.412mmol) and diisopropyl ethyl amine (106.3mg, 0.824mmol), under nitrogen at rt overnight, quenched with water, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000136

The crude Compound 2 product was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-091 (15mg, 10% yield).

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]

Synthesis Example 25 XSD1-092 embodiment

1):

Figure PCTCN2017084604-appb-000137

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (66mg, 0.412mmol), O- (7- nitrogen Benzotriazole) -N, N , N ', N'- tetramethyluronium hexafluorophosphate (157.4mg, 0.412mmol) and diisopropyl ethyl amine (106.3mg, 0.824mmol), under nitrogen at rt overnight, quenched with water, acetic acid ethyl ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000138

The crude Compound 2 product was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-092 (10mg, 10% yield).

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]

Synthesis of Example 26 XSD1-093

1):

Figure PCTCN2017084604-appb-000139

Compound 2 (100mg, 0.625mmol) was dissolved in 2mL of dichloromethane was added triethylamine (126.3mg, 1.25mmol), cooled to zero degrees ice-water bath, stirred for 10 minutes. The MsCl (85.5mg, 0.75mmol) was dissolved in 1ml of methylene chloride, the reaction system was added dropwise at rt 1h. Quenched with water, (50mL x3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000140

The crude compound 3 was dissolved in 1 mL 1,4-dioxane was added under ice-HCl in 1,4-dioxane (2mL, 4mol / L), stirred at room temperature 2h, the reaction solution by rotary evaporation under reduced pressure, The crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000141

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added compound 4 (71.7mg, 0.412mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (157.4mg, 0.412mmol) and diisopropyl ethyl amine (106.3mg, 0.824mmol), under nitrogen at rt overnight, quenched with water, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

4):

Figure PCTCN2017084604-appb-000142

The crude compound 5 was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-093 (13mg, 10% yield).

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]

Synthesis Example 27 XSD1-094 embodiment

1):

Figure PCTCN2017084604-appb-000143

Intermediate 1 (90mg, 0.257mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (85.6mg, 0.386mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (147.3mg, 0.386mmol) and diisopropyl ethyl amine (99.5mg, 0.771mmol), under nitrogen at rt overnight, quenched with water, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000144

The crude Compound 2 product was dissolved in 3mL of methanol was added NaBH 4 under ice bath (51.4mg, 1.286mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, diethyl dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-094 (60mg, 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]

Synthesis Example 28 XSD1-095 embodiment

1):

Figure PCTCN2017084604-appb-000145

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (50.3mg, 0.412mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (157.4mg, 0.412mmol) and diisopropyl ethyl amine (106.3mg, 0.824mmol), under nitrogen at rt overnight, quenched with water, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000146

Compound 2 (387.4mg, 2.75mmol) was dissolved in 3mL of methylene chloride, cooled to ice bath zero. The t-BuOH (203.3mg, 2.75mmol) was dissolved in 2mL of dichloromethane, was added dropwise the reaction system. The reaction kept zero 30min, was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000147

The crude Compound 4 was dissolved in 3mL of dichloromethane was added triethylamine (305.2mg, 3.02mmol), ice-water bath was cooled to zero degrees. Compound 3 was added dropwise the crude reaction system. Rt overnight. The reaction solution by rotary evaporation under reduced pressure, the crude product was used directly in the next step.

4):

Figure PCTCN2017084604-appb-000148

The crude product was dissolved in 5 Compound 2 mL 1,4-dioxane was stirred in an ice-water bath was cooled to zero degrees, was added HCl in 1,4-dioxane (10mL, 4mol / L). Rt overnight. The reaction solution by rotary evaporation under reduced pressure, the crude product was purified by pre-HPLC to give Compound 6 (45mg).

5):

Figure PCTCN2017084604-appb-000149

Compound 6 was dissolved in 1mL of methanol were added, the ice bath was NaBH 4 (20mg, 0.5mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to give the title compound XSD1-095 (18mg, yield 11.9%).

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]

Synthesis Example 29 XSD1-096 embodiment

1):

Figure PCTCN2017084604-appb-000150

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (50.3mg, 0.412mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (157.4mg, 0.412mmol) and diisopropyl ethyl amine (106.3mg, 0.824mmol), under nitrogen at rt overnight, quenched with water, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000151

The crude Compound 2 product was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-096 (20mg, 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]

Synthesis Example 30 XSD1-097 embodiment

1):

Figure PCTCN2017084604-appb-000152

Intermediate 1 (100mg, 0.275mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (77.5mg, 0.412mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (157.4mg, 0.412mmol) and diisopropyl ethyl amine (106.3mg, 0.824mmol), under nitrogen at rt overnight, quenched with water, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000153

The crude Compound 2 product was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-097 (30mg, 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]

Synthesis of Example 31 XSD1-098

1):

Figure PCTCN2017084604-appb-000154

Intermediate 1 (300mg, 0.824mmol) was dissolved in 5mL t-butanol, were added triethylamine (91.5mg, 0.91mmol), diphenylphosphoryl azide (272.0mg, 0.989mmol), under nitrogen, the reaction of 75 overnight, the reaction solution by rotary evaporation under reduced pressure, purification by column chromatography to give compound 2.

2):

Figure PCTCN2017084604-appb-000155

Compound 2 (60mg, 0.138mmol) was dissolved in 1 mL 1,4-dioxane was stirred in an ice bath was added HCl in 1,4-dioxane (10mL, 4mol / L), stirred at rt for 2h. The reaction solution by rotary evaporation under reduced pressure to give compound 3.

3):

Figure PCTCN2017084604-appb-000156

The crude compound 3 was dissolved in 2mL of methanol was added, the ice bath was NaBH 4 (27.6mg, 0.690mmol), the reaction stirred for 18 hours, the reaction solution (30mL) and quenched with saturated ammonium chloride solution, and rotary evaporated to remove most of the methanol, diethyl dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-098 (15mg, 5% yield).

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]

Synthesis Example 32 XSD1-117 embodiment

1):

Figure PCTCN2017084604-appb-000157

Compound 7 (100mg, 1.75mmol) was dissolved in 3mL of dichloromethane was added triethylamine (531mg, 5.26mmol), ice-water bath lowered to 0 ℃. Was added triphosgene (173mg, 0.585mmol), under nitrogen at rt 3h. After completion confirmation gusset material of the reaction, the reaction solution was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000158

Compound 6 (80mg, 0.224mmol) was dissolved in 2mL of dichloromethane was added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. The reaction solution was dropwise adding step, at room temperature under nitrogen overnight. Quenched with water, (50mL x3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000159

The crude compound 9 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-117 (24mg, 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]

Synthesis of Example 33 XSD1-124

1):

Figure PCTCN2017084604-appb-000160

Compound 6 (80.0mg, 0.224mmol) was dissolved in 2mL of dichloromethane were added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. Solution of compound 6a (36.8mg, 0.269mmol) in dichloromethane (2mL) at room temperature the reaction solution under nitrogen atmosphere overnight, (50mL x5) quenched with water and extracted with dichloromethane, combined extracts were washed with saturated brine, no over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000161

The crude compound 7 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-124 (11mg, 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]

Synthesis Example 34 XSD1-125 embodiment

1):

Figure PCTCN2017084604-appb-000162

Compound 6 (80.0mg, 0.224mmol) was dissolved in 2mL of dichloromethane were added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. Solution of compound 6a (41.1mg, 0.269mmol) in dichloromethane (2mL) at room temperature the reaction solution under nitrogen atmosphere overnight, (50mL x5) quenched with water and extracted with dichloromethane, combined extracts were washed with saturated brine, no over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000163

The crude compound 7 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-125 (11mg, 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]

Synthesis of Example 35 XSD1-126

1):

Figure PCTCN2017084604-appb-000164

Compound 1 (80.0mg, 0.224mmol) was dissolved in 2mL of dichloromethane were added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. Solution of compound 1a (33.6mg, 0.269mmol) in dichloromethane (2mL) at room temperature the reaction solution under nitrogen atmosphere overnight, (50mL x5) quenched with water and extracted with dichloromethane, combined extracts were washed with saturated brine, no over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000165

The crude Compound 2 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-126 (4.1mg, 8.9% yield).

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]

Synthesis Example 36 XSD1-133 embodiment

1):

Figure PCTCN2017084604-appb-000166

Compound 1 (80.0mg, 0.224mmol) was dissolved in 2mL of dichloromethane were added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. Solution of compound 1a (33.6mg, 0.269mmol) in dichloromethane (2mL) at room temperature the reaction solution under nitrogen atmosphere overnight, (50mL x5) quenched with water and extracted with dichloromethane, combined extracts were washed with saturated brine, no over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000167

The crude Compound 2 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-133 (20mg, 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]

Synthesis Example 37 XSD1-141 embodiment

1):

Figure PCTCN2017084604-appb-000168

Compound 7 (100mg, 0.741mmol) was dissolved in 3mL of dichloromethane was added triethylamine (224mg, 2.22mmol), ice-water bath lowered to 0 ℃. Was added triphosgene (73.3mg, 0.247mmol), under nitrogen at rt 3h. After completion confirmation gusset material of the reaction, the reaction solution was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000169

Compound 6 (80mg, 0.224mmol) was dissolved in 2mL of dichloromethane was added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. The reaction solution was dropwise adding step, at room temperature under nitrogen overnight. Quenched with water, (50mL x3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000170

The crude compound 9 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-141 (20.5mg, 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), 1.32- 1.47 (m, 12H)

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

MS: m / z 485.4 [M + 1]

Synthesis Example 38 XSD1-142 embodiment

1):

Figure PCTCN2017084604-appb-000171

Compound 7 (100mg, 0.935mmol) was dissolved in 3mL of dichloromethane was added triethylamine (283mg, 2.80mmol), ice-water bath lowered to 0 ℃. Was added triphosgene (92.5mg, 0.312mmol), under nitrogen at rt 3h. After completion confirmation gusset material of the reaction, the reaction solution was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000172

Compound 6 (80mg, 0.224mmol) was dissolved in 2mL of dichloromethane was added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. The reaction solution was dropwise adding step, at room temperature under nitrogen overnight. Quenched with water, (50mL x3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000173

The crude compound 9 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-142 (10mg, 9.8% yield).

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]

Synthesis Example 39 XSD1-143 embodiment

1):

Figure PCTCN2017084604-appb-000174

Compound 7 (100mg, 0.286mmol) was dissolved in 3mL N, N'- dimethylformamide, were added compound 7a (46.3mg, 0.343mmol), O- (7- nitrogen Benzotriazole) -N, N , N ', N'- tetramethyluronium hexafluorophosphate (131mg, 0.343mmol) and diisopropyl ethyl amine (86.6mg, 0.857mmol), under nitrogen at rt overnight, quenched with water, ethyl acetate ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000175

The crude compound 8 was dissolved in 3mL of methanol was added NaBH 4 under ice bath (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-143 (18.3mg, 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]

Synthesis Example 40 XSD1-144 embodiment

1):

Figure PCTCN2017084604-appb-000176

Compound 7 (100mg, 0.752mmol) was dissolved in 3mL of dichloromethane was added triethylamine (228mg, 2.26mmol), ice-water bath lowered to 0 ℃. Was added triphosgene (74.4mg, 0.251mmol), under nitrogen at rt 3h. After completion confirmation gusset material of the reaction, the reaction solution was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000177

Compound 6 (80mg, 0.224mmol) was dissolved in 2mL of dichloromethane was added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. The reaction solution was dropwise adding step, at room temperature under nitrogen overnight. Quenched with water, (50mL x3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000178

The crude compound 9 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-144 (10mg, 9.3% yield).

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]

Synthesis Example 41 XSD1-145 embodiment

1):

Figure PCTCN2017084604-appb-000179

Compound 7 (100mg, 0.725mmol) was dissolved in 3mL of dichloromethane was added triethylamine (220mg, 2.17mmol), ice-water bath lowered to 0 ℃. Was added triphosgene (71.7mg, 0.242mmol), under nitrogen at rt 3h. After completion confirmation gusset material of the reaction, the reaction solution was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000180

Compound 6 (80mg, 0.224mmol) was dissolved in 2mL of dichloromethane was added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. The reaction solution was dropwise adding step, at room temperature under nitrogen overnight. Quenched with water, (50mL x3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000181

The crude compound 9 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-145 (4mg, 2.9% yield).

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]

Synthesis Example 42 XSD1-146 embodiment

1):

Figure PCTCN2017084604-appb-000182

Compound 7 (100mg, 0.813mmol) was dissolved in 3mL of dichloromethane was added triethylamine (246mg, 2.44mmol), ice-water bath lowered to 0 ℃. Was added triphosgene (80.5mg, 0.271mmol), under nitrogen at rt 3h. Gusset material confirmed completion of the reaction, the reaction solution was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000183

Compound 6 (80mg, 0.224mmol) was dissolved in 2mL of dichloromethane was added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. The reaction solution was dropwise adding step, at room temperature under nitrogen overnight. Quenched with water, (50mL x3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000184

The crude compound 9 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-146 (8mg, 7.6% yield).

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]

Synthesis Example 43 XSD1-147 embodiment

1):

Figure PCTCN2017084604-appb-000185

Compound 7 (100mg, 0.775mmol) was dissolved in 3mL of dichloromethane was added triethylamine (235mg, 2.33mmol), ice-water bath lowered to 0 ℃. Was added triphosgene (76.7mg, 0.259mmol), under nitrogen at rt 3h. After completion confirmation gusset material of the reaction, the reaction solution was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000186

Compound 6 (80mg, 0.224mmol) was dissolved in 2mL of dichloromethane was added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. The reaction solution was dropwise adding step, at room temperature under nitrogen overnight. Quenched with water, (50mL x3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000187

The crude compound 9 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-147 (10mg, 9.3% yield).

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

8.04-8.07 (m, 2H), 7.94 (m, 1H), 7.56-7.61 (m, 2H), 7.36-7.40 (m, 1H), 7.20-7.29 (m, 2H), 7.11 (m, 1H), 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]

Synthesis Example 44 XSD1-148 embodiment

1):

Figure PCTCN2017084604-appb-000188

Compound 1 (100mg, 0.621mmol) was dissolved in 3mL of dichloromethane was added triethylamine (188mg, 1.86mmol), ice-water bath lowered to 0 ℃. Was added triphosgene (61.5mg, 0.207mmol), under nitrogen at rt 3h. After completion confirmation gusset material of the reaction, the reaction solution was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000189

Compound 2 '(80mg, 0.224mmol) was dissolved in 2mL of dichloromethane was added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. The reaction solution was dropwise adding step, at room temperature under nitrogen overnight. Quenched with water, (50mL x3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000190

The crude compound 9 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-148 (20mg, 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]

Synthesis Example 45 XSD1-149 embodiment

1):

Figure PCTCN2017084604-appb-000191

Compound 7 (100mg, 0.935mmol) was dissolved in 3mL of dichloromethane was added triethylamine (283mg, 2.80mmol), ice-water bath lowered to 0 ℃. Was added triphosgene (92.5mg, 0.312mmol), under nitrogen at rt 3h. After completion confirmation gusset material of the reaction, the reaction solution was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000192

Compound 6 (80mg, 0.224mmol) was dissolved in 2mL of dichloromethane was added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. The reaction solution was dropwise adding step, at room temperature under nitrogen overnight. Quenched with water, (50mL x3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000193

The crude compound 9 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-149 (10mg, 9.8% yield).

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]

Synthesis Example 46 XSD1-150 embodiment

1):

Figure PCTCN2017084604-appb-000194

Intermediate 1 (40mg, 0.109mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (72mg, 1.0mmol), O- (7- nitrogen Benzotriazole) -N, N , N ', N'- tetramethyluronium hexafluorophosphate (100mg, 0.50mmol) and diisopropylethyl amine (250mg, 3.3mmol), under nitrogen at room temperature overnight, quenched with water, ethyl acetate (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000195

Compound 2 was added 3mL crude product was dissolved in methanol, under ice bath NaBH4 (55mg, 1.375mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-150 (4mg, 16% overall yield in two steps).

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]

Synthesis Example 47 XSD1-151 embodiment

1):

Figure PCTCN2017084604-appb-000196

Compound 1 (100mg, 0.621mmol) was dissolved in 3mL of dichloromethane was added triethylamine (188mg, 1.86mmol), ice-water bath lowered to 0 ℃. Was added triphosgene (61.5mg, 0.207mmol), under nitrogen at rt 3h. After completion confirmation gusset material of the reaction, the reaction solution was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000197

Compound 2 '(80mg, 0.224mmol) was dissolved in 2mL of dichloromethane was added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. The reaction solution was dropwise adding step, at room temperature under nitrogen overnight. Quenched with water, (50mL x3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000198

The crude compound 3 was dissolved in 10mL of sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-151 (2.6mg, 7.2% yield).

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]

Synthesis Example 48 XSD1-152 embodiment

1):

Figure PCTCN2017084604-appb-000199

Compound 1 (100mg, 0.621mmol) was dissolved in 3mL of dichloromethane was added triethylamine (188mg, 1.86mmol), ice-water bath lowered to 0 ℃. Was added triphosgene (61.5mg, 0.207mmol), under nitrogen at rt 3h. After completion confirmation gusset material of the reaction, the reaction solution was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000200

Compound 2 '(80mg, 0.224mmol) was dissolved in 2mL of dichloromethane was added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. The reaction solution was dropwise adding step, at room temperature under nitrogen overnight. Quenched with water, (50mL x3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000201

The crude compound 3 was dissolved in 10mL of sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-153 (3.7mg, 8.2% yield).

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]

Synthesis Example 49 XSD1-153 embodiment

1):

Figure PCTCN2017084604-appb-000202

Compound 1 (100mg, 0.621mmol) was dissolved in 3mL of dichloromethane was added triethylamine (188mg, 1.86mmol), ice-water bath lowered to 0 ℃. Was added triphosgene (61.5mg, 0.207mmol), under nitrogen at rt 3h. After completion confirmation gusset material of the reaction, the reaction solution was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000203

Compound 2 '(80mg, 0.224mmol) was dissolved in 2mL of dichloromethane was added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. The reaction solution was dropwise adding step, at room temperature under nitrogen overnight. Quenched with water, (50mL x3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000204

The crude compound 3 was dissolved in 10mL of sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-153 (2.9mg, 7.5% yield).

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]

Synthesis Example 50 XSD1-075 embodiment

1):

Figure PCTCN2017084604-appb-000205

Intermediate 1 (91mg, 0.25mmol) was dissolved in 5mL N, N'- dimethylformamide, were added the compound 1a (25.5mg, 0.3mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (150mg, 0.39mmol) and diisopropylethyl amine (52mg, 0.77mmol), the reaction at room temperature under nitrogen overnight, quenched with water, ethyl acetate ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000206

The crude Compound 2 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, and rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-075 (36mg, yield 33.4%).

H NMR XSD1-075 (DMSO, 400M): 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] +.

Synthesis Example 51 XSD1-081 embodiment

The method of XSD1-081 synthesized with XSD1-074

1):

Figure PCTCN2017084604-appb-000207

Intermediate 1 (91mg, 0.25mmol) was dissolved in 5mL N, N'- dimethylformamide, were added the compound 1a (16.0mg, 0.3mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (150mg, 0.39mmol) and diisopropylethyl amine (52mg, 0.77mmol), the reaction at room temperature under nitrogen overnight, quenched with water, ethyl acetate ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000208

The crude Compound 2 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, and rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-081 (30mg, yield 33.0%).

H NMR 1-081 (DMSO, 400M): 9.29 (s, 1H), 7.85-7.89 (m, 2H), 7.72-7.74 (m, 1H), 7.49-7.57 (m, 2H), 6.84 (S, 1H ), 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] +.

Synthesis Example 52 XSD1-082 embodiment

A method of synthesizing the same XSD1-074 of XSD1-082

1):

Figure PCTCN2017084604-appb-000209

Intermediate 1 (91mg, 0.25mmol) was dissolved in 5mL N, N'- dimethylformamide, were added the compound 1a (20.3mg, 0.3mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (150mg, 0.39mmol) and diisopropylethyl amine (52mg, 0.77mmol), the reaction at room temperature under nitrogen overnight, quenched with water, ethyl acetate ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000210

The crude Compound 2 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, and rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-074 (32mg, yield 33.9%).

H NMR XSD1-082 (DMSO, 400M): 9.29 (s, 1H), 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] +.

Synthesis Example 53 XSD1-083 embodiment

XSD1-074 the same synthetic method XSD1-083

1):

Figure PCTCN2017084604-appb-000211

Intermediate 1 (91mg, 0.25mmol) was dissolved in 5mL N, N'- dimethylformamide, were added the compound 1a (24.5mg, 0.3mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (150mg, 0.39mmol) and diisopropylethyl amine (52mg, 0.77mmol), the reaction at room temperature under nitrogen overnight, quenched with water, ethyl acetate ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

Figure PCTCN2017084604-appb-000212

2):

The crude Compound 2 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, and rotary evaporated to remove most of the methanol, treated with dichlorobis methane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-083 (33mg, yield 33.7%).

H NMR XSD1-083 (DMSO, 400M): 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] +.

Synthesis Example 54 XSD1-031 embodiment

1):

Figure PCTCN2017084604-appb-000213

Compound 1 (170mg, 0.4mmol), Compound 2 (73mg, 0.4mmol) and sodium ethoxide (55mg, 0.8mmol) was dissolved in THF / EOH = 3mL / 1ml, stirred at room temperature overnight, the reaction was treated with saturated ammonium chloride solution ( 25 mL) quenched, extracted with ethyl acetate (25mL x2), saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and rotary evaporation under reduced pressure. The crude product was PE / EA = (5/1) mixture was filtered, and dried to give the product compound 3 (140mg, 61% yield).

MS: m / z 575.4 [M + 1]

2):

Figure PCTCN2017084604-appb-000214

Compound 3 (140mg, 0.24mmol) was dissolved in methanol (5mL), was added glacial acetic acid (1mL), and stirred overnight The reaction was 90 ℃. The reaction solution by rotary evaporation, dissolved in dichloromethane (10 mL), neutralized with saturated sodium bicarbonate, separated, then the organic phase with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure to give The crude product 120mg, was used directly in the next reaction.

MS: m / z 333.4 [M + 1]

LC-MS:

3):

Figure PCTCN2017084604-appb-000215

The crude compound 4 (60mg, 0.12mmol) was dissolved in methanol (10 mL), under ice-cooling was added NaBH 4 (14mg, 0.36mmol), the reaction stirred for 1 hour, the reaction was quenched with saturated ammonium chloride solution (10 mL), rotary evaporated most of the methanol was removed, (20 mLx2) and extracted with methylene chloride, saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-031 (15mg, 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]

Synthesis Example 55 XSD1-100 embodiment

1):

Figure PCTCN2017084604-appb-000216

Compound INT1 (45.7mg, 0.336mmol) was dissolved in 3mL N, N'- dimethylformamide, were added O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyl yl hexafluorophosphate (128mg, 0.336mmol), compound Ia (80.0mg, 0.336mmol) and diisopropyl ethyl amine (116mg, 0.896mmol), under nitrogen at room temperature overnight, quenched with water, ethyl acetate ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000217

The crude Compound 2 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-100 (20mg, 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]

Synthesis of Example 56 XSD1-101

1):

Figure PCTCN2017084604-appb-000218

The crude compound INT (7g) was dissolved in 10 mL 1,4-dioxane was added HCl / dioxane (20mL, 4mol / L) under ice-cooling, reaction was warmed to room temperature stirred for 2h, the reaction liquid was directly spin dryness to give crude compound INT1 (6g).

2):

Figure PCTCN2017084604-appb-000219

The crude compound INT1 (80.0mg) was dissolved in sodium borohydride (89.6mg, 2.24mmol) 3mL of methanol was added at an ice bath, the reaction warmed to room temperature stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated most of the methanol was removed and extracted with dichloromethane (30 mL x 3), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-101 (20mg, 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]

Synthesis Example 57 XSD1-102 embodiment

1):

Figure PCTCN2017084604-appb-000220

Compound 1 (10.0g, 0.0472mol) was dissolved in 50.0mL tert-butanol, were added triethylamine (5.24g, 0.0519mol) was heated, under nitrogen diphenylphosphoryl azide (15.6g, 0.0567mol) to 75 ℃ overnight. Direct rotary evaporation under reduced pressure, column chromatography. Compound 2 (5.00g, 37.5%).

2):

Figure PCTCN2017084604-appb-000221

Compound 2a (13.2g, 0.106mol) was dissolved in 50.0mL of tetrahydrofuran, under nitrogen, a dry ice acetone bath cooled to -78 deg.] C, was slowly added dropwise n-butyllithium (66.3mL, 0.106mol). Compound 2 (5.00g, 0.0117mol) was dissolved in tetrahydrofuran, 30.0mL, before quickly added to the reaction mixture, the reaction was stirred for 2h -78 ℃. The reaction was washed with saturated ammonium chloride solution (100 mL) quenched by rotary evaporation to remove most of the tetrahydrofuran, and extracted with dichloromethane (80mLx3), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure, column chromatography to give compound 3 (5.4g, 81.5%).

3):

Figure PCTCN2017084604-appb-000222

Compound 3 (5.40g, 0.0144mol) was dissolved in 30.0mL of tetrahydrofuran, under nitrogen, was added sodium hydroxide (0.864g, 0.036mol). Compound 3a (5.96g, 0.0144mol) was dissolved in 10.0mL of tetrahydrofuran, prior to the reaction solution was added dropwise at room temperature overnight. The reaction was washed with saturated ammonium chloride solution (50mL) was quenched, and rotary evaporated to remove most of the tetrahydrofuran, and extracted with dichloromethane (80mLx3), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure, to give crude compound 4 (9.0g).

4):

Figure PCTCN2017084604-appb-000223

The crude compound 4 (9.0g) was dissolved in 60.0mL of methanol, 30mL acetic acid was added. 90 ℃ reaction 2h. The reaction liquid was directly spin-dried, the pH adjusted to 7 with saturated sodium bicarbonate solution and extracted with dichloromethane (80mLx3), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. To give crude Compound 5 (7.0g).

5):

Figure PCTCN2017084604-appb-000224

The crude Compound 5 (80.0mg) was dissolved in sodium borohydride (76.0mg, 1.90mmol) 3mL of methanol was added at an ice bath, the reaction warmed to room temperature stirred for 2h, the reaction solution (30mL) and quenched with saturated ammonium chloride solution, and rotary evaporated most of the methanol was removed and extracted with dichloromethane (30 mL x 3), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-102 (20mg, 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]

Synthesis of Example 58 XSD1-103

1):

Figure PCTCN2017084604-appb-000225

Compound 1a (41.0mg, 0.336mmol) was dissolved in 3mL N, N'- dimethylformamide, were added O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyl yl hexafluorophosphate (128mg, 0.336mmol), compound INT1 (80.0mg, 0.224mmol) and diisopropyl ethylamine (144mg, 1.12mmol), under nitrogen at room temperature overnight, quenched with water, ethyl acetate ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000226

The crude compound was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-103 (20mg, 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]

Synthesis Example 59 XSD1-104 embodiment

1):

Figure PCTCN2017084604-appb-000227

Compound 1a (43.0mg, 0.336mmol) was dissolved in 3mL N, N'- dimethylformamide, were added O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyl yl hexafluorophosphate (128mg, 0.336mmol), compound INT1 (80.0mg, 0.224mmol) and diisopropyl ethylamine (144mg, 1.12mmol), under nitrogen at room temperature overnight, quenched with water, ethyl acetate ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000228

The crude compound was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-104 (20mg, 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]

Synthesis of Example 60 XSD1-105

1):

Figure PCTCN2017084604-appb-000229

Compound 1a (20.2mg, 0.336mmol) was dissolved in 3mL N, N'- dimethylformamide, were added O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyl yl hexafluorophosphate (128mg, 0.336mmol), compound INT1 (80.0mg, 0.224mmol) and diisopropyl ethylamine (144mg, 1.12mmol), under nitrogen at room temperature overnight, quenched with water, ethyl acetate ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000230

The crude compound was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-105 (20mg, 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]

Synthesis Example 61 XSD1-106 embodiment

1):

Figure PCTCN2017084604-appb-000231

Compound INT1 (80.0mg, 0.224mmol) was dissolved in 2mL of dichloromethane were added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. Solution of compound 1a (32.0mg, 0.269mmol) in dichloromethane (2mL) at room temperature the reaction solution under nitrogen atmosphere overnight, (50mL x5) quenched with water and extracted with dichloromethane, combined extracts were washed with saturated brine, no over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000232

The crude compound was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-106 (20mg, 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]

Synthesis Example 62 XSD1-107 embodiment

1):

Figure PCTCN2017084604-appb-000233

Compound 1a (47.7mg, 0.336mmol) was dissolved in 3mL N, N'- dimethylformamide, were added O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyl yl hexafluorophosphate (128mg, 0.336mmol), compound INT1 (80.0mg, 0.224mmol) and diisopropyl ethyl amine (116mg, 0.896mmol), under nitrogen at room temperature overnight, quenched with water, ethyl acetate ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000234

The crude compound was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-107 (20mg, 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]

Synthesis of Example 63 XSD1-108

1):

Figure PCTCN2017084604-appb-000235

Compound INT1 (80.0mg, 0.224mmol) was dissolved in 2mL of dichloromethane were added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. Solution of compound 1a (30.7mg, 0.269mmol) in dichloromethane (2mL) at room temperature the reaction solution under nitrogen atmosphere overnight, (50mL x5) quenched with water and extracted with dichloromethane, combined extracts were washed with saturated brine, no over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000236

The crude compound was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-108 (20mg, 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]

Synthesis Example 64 XSD1-109 embodiment

1):

Figure PCTCN2017084604-appb-000237

Compound INT1 (80.0mg, 0.224mmol) was dissolved in 2mL of dichloromethane were added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. Solution of compound 1a (47.3mg, 0.269mmol) in dichloromethane (2mL) at room temperature the reaction solution under nitrogen atmosphere overnight, (50mL x5) quenched with water and extracted with dichloromethane, combined extracts were washed with saturated brine, no over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000238

The crude compound was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-109 (20mg, 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]

Synthesis Example 65 XSD1-110 embodiment

1):

Figure PCTCN2017084604-appb-000239

Compound INT1 (80.0mg, 0.224mmol) was dissolved in 2mL of dichloromethane were added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. Solution of compound 1a (41.1mg, 0.269mmol) in dichloromethane (2mL) at room temperature the reaction solution under nitrogen atmosphere overnight, (50mL x5) quenched with water and extracted with dichloromethane, combined extracts were washed with saturated brine, no over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000240

The crude compound was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-110 (20mg, 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]

Synthesis of Example 66 XSD1-111

1):

Figure PCTCN2017084604-appb-000241

Compound INT1 (80.0mg, 0.224mmol) was dissolved in 2mL of dichloromethane were added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. Solution of compound 1a (36.8mg, 0.269mmol) in dichloromethane (2mL) at room temperature the reaction solution under nitrogen atmosphere overnight, (50mL x5) quenched with water and extracted with dichloromethane, combined extracts were washed with saturated brine, no over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000242

The crude compound was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-111 (20mg, 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]

Synthesis Example 67 XSD1-112 embodiment

1):

Figure PCTCN2017084604-appb-000243

Compound INT1 (80.0mg, 0.224mmol) was dissolved in 2mL of dichloromethane were added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. Solution of compound 1a (38.7mg, 0.269mmol) in dichloromethane (2mL) at room temperature the reaction solution under nitrogen atmosphere overnight, (50mL x5) quenched with water and extracted with dichloromethane, combined extracts were washed with saturated brine, no over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000244

The crude compound was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-112 (20mg, 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]

Synthesis of Example 68 XSD1-113

1):

Figure PCTCN2017084604-appb-000245

Compound INT1 (80.0mg, 0.224mmol) was dissolved in 2mL of dichloromethane were added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. Solution of compound 1a (33.6mg, 0.269mmol) in dichloromethane (2mL) at room temperature the reaction solution under nitrogen atmosphere overnight, (50mL x5) quenched with water and extracted with dichloromethane, combined extracts were washed with saturated brine, no over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000246

The crude compound was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-113 (20mg, 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]

Synthesis Example 69 XSD1-116 embodiment

1):

Figure PCTCN2017084604-appb-000247

Compound INT1 (80.0mg, 0.224mmol) was dissolved in 2mL of dichloromethane were added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. Solution of compound 1a (19.1mg, 0.269mmol) in dichloromethane (2mL) at room temperature the reaction solution under nitrogen atmosphere overnight, (50mL x3) quenched with water and extracted with dichloromethane, combined extracts were washed with saturated brine, no over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000248

The crude compound was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-116 (20mg, 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]

Synthesis Example 70 XSD1-119 embodiment

1):

Figure PCTCN2017084604-appb-000249

Compound INT1 (80.0mg, 0.224mmol) was dissolved in 2mL of dichloromethane were added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. Solution of compound 1a (26.6mg, 0.269mmol) in dichloromethane (2mL) at room temperature the reaction solution under nitrogen atmosphere overnight, (50mL x3) quenched with water and extracted with dichloromethane, combined extracts were washed with saturated brine, no over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction

2):

Figure PCTCN2017084604-appb-000250

The crude compound was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-119 (20mg, 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), 5.28-5.32 (m, 2H), 4.83-4.84 (m, 1H), 3.46 (m, 1H), 2.00 (m, 1H), 1.65-1.69 (m, 7H), 1.36-1.46 (m, 6H), 1.16 (m, 9H)

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

MS: m / z 423.4 [M + 1]

Synthesis Example 71 XSD1-123 embodiment

1):

Figure PCTCN2017084604-appb-000251

Compound 1 (100mg, 0.885mmol) was dissolved in 3mL of dichloromethane was added triethylamine (268mg, 2.66mmol), ice-water bath lowered to 0 ℃. Was added triphosgene (87.6mg, 0.295mmol), under nitrogen, was heated to 50 ℃, the reaction was refluxed for 6h. After completion confirmation gusset material of the reaction, the reaction solution was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000252

Compound INT1 (80mg, 0.224mmol) was dissolved in 2mL of dichloromethane was added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. The reaction solution was dropwise adding step, at room temperature under nitrogen overnight. Quenched with water, (50mL x3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000253

The crude compound 9 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-123 (20mg, yield 19.3%).

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]

Synthesis Example 72 XSD1-138 embodiment

1):

Figure PCTCN2017084604-appb-000254

Compound INT1 (80.0mg, 0.224mmol) was dissolved in 2mL of dichloromethane were added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. Solution of compound 1a (22.9mg, 0.269mmol) in dichloromethane (2mL) at room temperature the reaction solution under nitrogen atmosphere overnight, (50mL x3) quenched with water and extracted with dichloromethane, combined extracts were washed with saturated brine, no over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000255

The crude compound 7 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound XSD1-138 (20mg, 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]

Synthesis Example 73 XSD1-140 embodiment

1):

Figure PCTCN2017084604-appb-000256

Compound 1 (100mg, 0.621mmol) was dissolved in 3mL of dichloromethane was added triethylamine (188mg, 1.86mmol), ice-water bath lowered to 0 ℃. Was added triphosgene (61.5mg, 0.207mmol), under nitrogen at rt 3h. After completion confirmation gusset material of the reaction, the reaction solution was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000257

Compound INT1 (80mg, 0.224mmol) was dissolved in 2mL of dichloromethane was added triethylamine (113mg, 1.12mmol), stirred at rt for 15min. The reaction solution was dropwise adding step, at room temperature under nitrogen overnight. Quenched with water, (50mL x3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

3):

Figure PCTCN2017084604-appb-000258

The crude compound 3 was dissolved in 3mL sodium borohydride (89.6mg, 2.24mmol) of methanol was added, the ice bath warmed to room temperature the reaction stirred for 2h, the reaction was quenched with saturated ammonium chloride solution (30 mL), most of the methanol was removed by rotary evaporation with dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-140 (20mg, 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]

Synthesis of Example 74 XSD1-040

1)

Figure PCTCN2017084604-appb-000259

Compound 1 (1.08g, 6mmol), carbon tetrabromide (CBr 4, 3.6g, 6mmol) , triphenylphosphine (3.0g, 12mmol) was dissolved in dichloromethane (30mL), under nitrogen and the reaction was stirred at room temperature for 12h, TLC monitored the reaction. After completion of the reaction, the reaction mixture by rotary evaporation, column chromatography (petroleum ether → petroleum ether: ethyl acetate = 1 → 8: 1) to give the desired product 1.0g, 89% yield.

2)

Figure PCTCN2017084604-appb-000260

Compound 2 (1.02g, 4.8mmol) was dissolved in 20mL of dry tetrahydrofuran, dry ice acetone bath, the temperature was lowered to -60 deg.] C, was slowly added dropwise tert-butyllithium (6.4mL, 9.6mmol), after the completion of the dropwise addition, the reaction was continued stirring at -60 ℃ 1h, and methanol (4mL) was slowly added dropwise to the reaction mixture, stirring was continued for 1h. With saturated ammonium chloride solution (10 mL) quenched the reaction, ethyl acetate (50mL * 3) The reaction solution was extracted and the organic phase washed with water (20 * 2), saturated brine (2 * 30), after which it was concentrated to give the title compound as a white solid (708mg, 83% yield).

3)

Figure PCTCN2017084604-appb-000261

Compound 3 (708mg, 4.2mmol) was dissolved in 2N HCl / dioxane (5mL) solution, stirred at room temperature overnight. After completion of the reaction, saturated sodium carbonate solution and washed to neutral, extracted with ethyl acetate (50mL * 2), the organic phase was washed with brine, dried and concentrated to give 508 mg of the title compound as a pale yellow oil, used directly.

4)

Figure PCTCN2017084604-appb-000262

Compound 4 (508mg, 4.04mmol) was dissolved in dimethyl ether / ethanol (16mL / 0.6mL) then added TosMIC (780mg, 4.04mmol) and potassium t-butoxide (448mg, 8.04mmol) at 0 deg.] C, the the reaction was stirred at 0 ℃ for half an hour, then warmed to 50 deg.] C continued stirred for 2h. The filtrate was concentrated by column chromatography (Al2O3 column, n-hexane → n-hexane: dichloromethane = 1 → 5: 1) to give the title compound (154mg, yield 51%).

NMR: mc10899-005

5)

Figure PCTCN2017084604-appb-000263

Methyl lithium / pentane (1.28mL, 2.4mmol) was slowly added dropwise Compound 5 (154mg, 1.2mmol) in diethyl ether (5mL) and stirred at 0 ℃ 1h, followed by addition of acetone / hydrochloric acid (3mL / 3mL) It was stirred overnight at room temperature. The reaction mixture with ethyl acetate (50mL * 2) and extracted, washed with water and dried to give the title compound 6 (100mg, 75%).

6)

Figure PCTCN2017084604-appb-000264

Compound 6 (100mg, 0.67mmol) was dissolved in 10mL of anhydrous tetrahydrofuran was added under ice-cooling sodium hydride (51m, 1.27mmol), warmed to room temperature stirred for 1 hour. Under ice Compound 6a (211mg, 0.51mmol) was dissolved in 5mL of anhydrous tetrahydrofuran was added to the reaction flask. The reaction was stirred overnight and warm to room temperature, quenched with saturated ammonium chloride, was added 100mL of water and extracted with dichloromethane (50mL × 3), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product by column chromatography to obtain the product compound 5 (102mg, 34.6% yield).

7)

Figure PCTCN2017084604-appb-000265

Compound 7 (102mg, 0.18mmol) was dissolved in 10mL of methanol was added 1mL of glacial acetic acid, raised to 90 deg.] C the reaction was stirred overnight, the solvent was distilled off under reduced pressure, was added 100mL of saturated sodium bicarbonate and extracted with dichloromethane (20mL x3), combined The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. To give Compound 8 (42mg) and used directly in the next reaction.

8)

Figure PCTCN2017084604-appb-000266

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 methanol, and extracted with dichloromethane (30 mL x 3), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-040 (8mg, 12% yield).

1 H-NMR (400MHz, 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]

Synthesis of Example 75 XSD1-61

1):

Figure PCTCN2017084604-appb-000267

Compound 1 (508mg, 4.04mmol) was dissolved in dimethyl ether / ethanol (16mL / 0.6mL) then added TosMIC (780mg, 4.04mmol) and potassium t-butoxide (448mg, 8.04mmol) at 0 deg.] C, the the reaction was stirred at 0 ℃ for half an hour, then warmed to 50 deg.] C continued stirred for 2h. The filtrate was concentrated by column chromatography (Al2O3 column, n-hexane → n-hexane: dichloromethane = 1 → 5: 1) to give the title compound 2 (154mg, yield 51%).

2)

Figure PCTCN2017084604-appb-000268

Methyl lithium / pentane (1.28mL, 2.4mmol) was slowly added dropwise compound 2 (154mg, 1.2mmol) in diethyl ether (5mL) and stirred at 0 ℃ 1h, followed by addition of acetone / hydrochloric acid (3mL / 3mL) It was stirred overnight at room temperature. The reaction mixture with ethyl acetate (50mL * 2) and extracted, washed with water and dried to give a white solid (100mg, 75%).

3)

Figure PCTCN2017084604-appb-000269

Compound 3 (100mg, 0.67mmol) was dissolved in 10mL of anhydrous tetrahydrofuran was added under ice-cooling sodium hydride (51m, 1.27mmol), warmed to room temperature stirred for 1 hour. Under ice Compound 6a (211mg, 0.51mmol) was dissolved in 5mL of anhydrous tetrahydrofuran was added to the reaction flask. The reaction was stirred overnight and warm to room temperature, quenched with saturated ammonium chloride, was added 100mL of water and extracted with dichloromethane (50mL × 3), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product by column chromatography to give the product Compound 4 (102mg, 34.6% yield).

4)

Figure PCTCN2017084604-appb-000270

Compound 4 (102mg, 0.18mmol) was dissolved in 10mL of methanol was added 1mL of glacial acetic acid, raised to 90 deg.] C the reaction was stirred overnight, the solvent was distilled off under reduced pressure, was added 100mL of saturated sodium bicarbonate and extracted with dichloromethane (20mL x3), combined The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. To give Compound 5 (42mg) and used directly in the next reaction.

5)

Figure PCTCN2017084604-appb-000271

Compound 5 (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 solution (30mL) and quenched with saturated ammonium chloride solution and rotary evaporated to remove most of methanol, and extracted with dichloromethane (30 mL x 3), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-061 (8mg, 12% yield).

Synthesis of Example 76 XSD1-139

1):

Figure PCTCN2017084604-appb-000272

Compound 1 (100mg, 0.286mmol) was dissolved in 3mL N, N'- dimethylformamide, were added the compound 1a (57.0mg, 0.429mmol), O- (7- nitrogen Benzotriazole) -N, N , N ', N'- tetramethyluronium hexafluorophosphate (163.7mg, 0.429mmol) and diisopropyl ethyl amine (184.3mg, 1.429mmol), under nitrogen at rt overnight, quenched with water, acetic acid ethyl ester (50mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was used directly in the next reaction.

2):

Figure PCTCN2017084604-appb-000273

The crude Compound 2 was dissolved in 3mL of methanol was added under ice bath NaBH 4 (114.3mg, 2.86mmol), the reaction stirred for 18 hours, the reaction was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of the methanol, diethyl dichloromethane (30 mL x 3) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-139 (20mg, 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].

Synthesis Example 77 S-1 embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000274

Compound 1 (1.7g, 8.0mmol) was dissolved in 30mL of dichloromethane, was slowly added thionyl chloride (2.86g, 24.0mmol), the reaction mixture was warmed to 70 deg.] C for 2 hours. Cooled to room temperature, the solvent was distilled off under reduced pressure, 30mL of anhydrous tetrahydrofuran was added and sufficiently dissolved, was added benzylamine at 0 ℃ (1.3g, 12.0mmol) and triethylamine (1.62g, 16.0mmol), stirred at room temperature overnight. TLC showed the reaction was complete. Quenched with 300mL of water was added and extracted with dichloromethane (100mL × 5), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product by column chromatography to obtain the product compound 3 (2.0g, 66% yield). Inspection of Compound 3: MS: m / z 302.0 [ M + 1]; 1 H-NMR (400MHz, DMSO-d6): δppm 8.02 (brs, 1H), 7.30-7.28 (m, 2H), 7.22-7.19 (m, 3H), 4.27 (d, J = 4.4Hz, 2H), 3.58 (s, 3H), 1.78-1.70 (m, 12H).

Reaction 2:

Figure PCTCN2017084604-appb-000275

Compound 3a (2.42g, 19.53mmol) was dissolved in 30mL anhydrous tetrahydrofuran, cooled to dry ice-acetone bath at -78 deg.] C, was slowly added dropwise 1.5M butyllithium in hexane (13mL, 19.53mmol) maintaining the internal temperature of -60 ℃ the following. After Compound 3 (980mg, 3.26mmol) was dissolved in 10mL of anhydrous tetrahydrofuran was added to the reaction flask and maintained internal temperature of -60 ℃. When the reaction was stirred for 2 hours at -78 deg.] C, quenched with saturated ammonium chloride, warmed to room temperature. 200mL of water was added and extracted with dichloromethane (100mL × 5), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product by column chromatography to obtain the product compound 4 (1.25g, yield 97.6%). Inspection of Compound 4: MS: m / z 394.2 [ M + 1]; 1 H-NMR (400MHz, DMSO-d6): δppm 8.00 (brs, 1H), 7.32-7.28 (m, 2H), 7.22-7.18 (m, 3H), 4.25 (d, J = 4.8Hz, 2H), 3.65 (s, 3H), 3.62 (s, 3H), 3.38-3.34 (m, 2H), 1.74-1.68 (m, 12H).

Reaction 3:

Figure PCTCN2017084604-appb-000276

Compound 4 (200mg, 0.51mmol) was dissolved in 10mL anhydrous tetrahydrofuran, 30.5 mg of sodium hydride was added under ice-cooling, warmed to room temperature with stirring for 1 hour. Under ice Compound 4a (211mg, 0.51mmol) was dissolved in 5mL of anhydrous tetrahydrofuran was added to the reaction flask. The reaction was stirred overnight and warm to room temperature, quenched with saturated ammonium chloride, was added 100mL of water and extracted with dichloromethane (50mL × 3), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product by column chromatography to obtain the product compound 5 (120mg, 34.6% yield). Compound of MS 5: m / z 682.3 [M + 1]; 1 H-NMR (400MHz, DMSO-d6): δppm8.03-7.96 (m, 2H), 7.79-7.05 (m, 26H), 6.95 (s , 1H), 4.26 (d, J = 6.0Hz, 2H), 1.74-1.56 (m, 12H).

Reaction 4:

Figure PCTCN2017084604-appb-000277
Compound 5 (120mg, 0.18mmol) was dissolved in 10mL of methanol was added 1mL of glacial acetic acid, raised to 90 deg.] C the reaction was stirred overnight, the solvent was distilled off under reduced pressure, was added 100mL of saturated sodium bicarbonate, extracted three times with dichloromethane (50mL × 3) The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. Compound 6 to give a crude product (150 mg of) and used directly in the next reaction. MS 6 of compound: m / z 440.1 [M + 1]; 1 H-NMR (400MHz, DMSO-d6): δppm 8.00 (brs, 1H), 7.60-7.12 (m, 11H), 5.76-5.58 (m, 1H), 4.24 (d, J = 4.8Hz, 2H), 3.44-3.34 (m, 1H), 3.13-3.06 (m, 1H), 1.74-1.58 (m, 12H).

Reaction 5:

Figure PCTCN2017084604-appb-000278

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 methanol, (30mL × 3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound s-1 (8mg, yield 18%).

1 H-NMR (400MHz, DMSO -d6): δppm 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 = 3.6Hz, 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].

Synthesis Example 78 S-2 of the embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000279

Compound 6 (220mg, 0.5mmol) was dissolved in 30mL solution of hydrobromic acid (48% aqueous solution), and stirred overnight in a closed pot 125 ℃, (3: 1) of chloroform and isopropyl alcohol mixture solution (50mL × 5) and extracted The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. Column chromatography to give compound 7 (170mg, yield 97%).

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

Reaction 2:

Figure PCTCN2017084604-appb-000280

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 methanol, treated with dichloromethane (30mL × 3), washed with saturated brine the organic phase were combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound s-2 (6mg, 17% yield).

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].

Synthesis Example 79 S-3 embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000281

Compound 7 (80mg, 0.23mmol) was dissolved in 5mL of dichloromethane, was slowly added thionyl chloride (65mg, 0.55mmol), the reaction mixture was warmed to 85 ℃ 2 hours. Cooled to room temperature, the solvent was distilled off under reduced pressure, and added to 5mL of anhydrous tetrahydrofuran was sufficiently dissolved, aniline was added at 0 ℃ (50mg, 0.53mmol) and triethylamine (101mg, 1.0mmol), at room temperature stirred for 2h. TLC showed the reaction was complete. Quenched with 20mL of water was added, extracted with ethyl acetate (10mL × 5), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. To give the crude product compound 10 (60mg, 70% yield).

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

Reaction 2:

Figure PCTCN2017084604-appb-000282

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 methane (30mL × 3). The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound s-3 (15.2mg, 15% yield).

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 = 7.2Hz, 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].

Synthesis Example 80 S-4 of the embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000283

Compound 7 (70mg, 0.20mmol) was dissolved in 5mL DMF, were added compound 7a (43mg, 0.30mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyl- hexafluorophosphate (HATU 165mg, 0.43mmol) and diisopropylethyl amine (77mg, 0.60mmol), the reaction at room temperature under nitrogen overnight, quenched with water, ethyl acetate (50mL × 5), and the combined extracts was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary done under reduced pressure the crude compound 11, it was used directly in the next reaction.

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

Reaction 2:

Figure PCTCN2017084604-appb-000284

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) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound s-4 (20.0mg, 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 = 5.6Hz, 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].

Synthesis Example 81 S-5 embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000285

Compound 7 (60mg, 0.17mmol) was dissolved in 5mL DMF, were added compound 7a (40mg, 0.26mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyl- hexafluorophosphate (150mg, 0.39mmol) and diisopropylethyl amine (70mg, 0.51mmol), the reaction at room temperature under nitrogen overnight, quenched with water, extracted with ethyl acetate (50mL × 5), combined extracts was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary done under reduced pressure the crude compound 11, it was used directly in the next reaction.

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

Reaction 2:

Figure PCTCN2017084604-appb-000286

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 methane (30mL × 3). The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound s-5 (15.2mg, 19% yield two steps).

1 H-NMR (400MHz, 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 = 4.8Hz, 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].

Synthesis Example 82 S-6 embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000287

Compound 7 (60mg, 0.17mmol) was dissolved in 5mL DMF, were added compound 7a (49mg, 0.34mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyl- hexafluorophosphate (99mg, 0.26mmol) and N- ethyldiisopropylamine (65mg, 0.50mmol), the reaction at room temperature under nitrogen overnight, quenched with water, extracted with ethyl acetate (50mL × 3), combined extracts It was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure to give crude compound 11 and 90mg was used directly in the next reaction.

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

Reaction 2:

Figure PCTCN2017084604-appb-000288

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 methanol, with dichloromethane methanol (10: 1,30mL × 3). The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound s-6 (25mg, 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].

Synthesis Example 83 S-7 embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000289

Compound 7 (70mg, 0.20mmol) was dissolved in 5mL DMF, were added compound 7a (43mg, 0.30mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyl- hexafluorophosphate (165mg, 0.43mmol) and diisopropylethyl amine (77mg, 0.60mmol), the reaction at room temperature under nitrogen overnight, quenched with water, ethyl acetate (50mL × 5). the combined extracts were was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary done under reduced pressure the crude compound 11, it was used directly in the next reaction.

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

Reaction 2:

Figure PCTCN2017084604-appb-000290

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) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound s-7 (28.4mg ,, 30% yield).

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 = 5.6Hz, 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].

Synthesis Example 84 S-8 embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000291

Compound 7 (35mg, 0.1mmol) was dissolved in 5mL of anhydrous tetrahydrofuran, was added oxalyl chloride (51mg, 0.4mmol) and one drop of dimethylformamide at room temperature overnight, the reaction solution under reduced pressure after the reaction was completed spin dry. To give a crude product Compound 9 (50mg) and used directly in the next reaction.

Reaction 2:

Figure PCTCN2017084604-appb-000292

Compound 9 (50mg, 0.1mmol) was dissolved in a solution of ammonia in tetrahydrofuran (5mL, 7M), overnight at room temperature, rotary evaporation under reduced pressure. To give a crude product Compound 10 (100mg) and was used directly in the next reaction.

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

Reaction 3:

Figure PCTCN2017084604-appb-000293

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 methanol, treated with dichloromethane (30mL × 3), washed with saturated brine the organic phase were combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound s-8 (7mg, 20% yield).

1 H-NMR (400MHz, DMSO -d6): δ (ppm) 9.28 (s, 1H), 9.26 (s, 1H), 7.94-7.80 (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].

Synthesis Example 85 S-9 embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000294

Compound 7 (40mg, 0.11mmol) was dissolved in 5mL DMF, were added methylamine hydrochloride (15mg, 0.23mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (HATU 65mg, 0.17mmol) and N- ethyldiisopropylamine (74mg, 0.57mmol), the reaction at room temperature under nitrogen overnight, quenched with water, extracted with ethyl acetate (50mL × 5) The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product was purified by preparative plate thickness of the compound 11 (25mg, 63% yield).

1 H-NMR (400MHz, 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 = 4.0Hz, 3H), 1.82-1.60 (m, 12H).

Reaction 2:

Figure PCTCN2017084604-appb-000295

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 methanol, treated with dichloromethane (30mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound s-9 (6.3mg, 21% yield).

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), 5.08and 4.63 (two s, 1H), 3.55and3.15 (two d, J = 10.0Hz and 9.6Hz , 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].

Synthesis Example 86 S-10 in the embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000296

Compound 7 (40mg, 0.11mmol) was dissolved in 5mL DMF, were added successively dimethylamine hydrochloride (19mg, 0.23mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N' - tetramethyluronium hexafluorophosphate (65mg, 0.17mmol) and N- ethyldiisopropylamine (74mg, 0.57mmol), the reaction at room temperature under nitrogen overnight, quenched with water, extracted with ethyl acetate (50mL × 5) The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure by rotary evaporation under reduced pressure. To give crude Compound 11 (30mg, 71%) was purified by preparative plate thickness.

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

Reaction 2:

Figure PCTCN2017084604-appb-000297

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 methanol, treated with dichloromethane (30mL × 3), washed with saturated brine the organic phase were combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound s-10 (6.6mg, 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].

Synthesis Example 87 S-11 in the embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000298

Compound 7 (40mg, 0.11mmol) was dissolved in 10mL dichloromethane was added 1mL thionyl chloride, refluxed for 2 hours at 65 ℃, rotary evaporation under reduced pressure. Compound 8 to give a crude product (80 mg of) and used directly in the next reaction.

Reaction 2:

Figure PCTCN2017084604-appb-000299

Compound 8 (80mg, 0.11mmol) was dissolved in 5mL of tetrahydrofuran, was added Compound 8a (28mg, 0.23mmol) and N- ethyldiisopropylamine (28mg, 0.23mmol) under ice-water bath, at room temperature overnight, the reaction was washed with saturated chloride sodium solution (30mL) was quenched with ethyl acetate (30mL × 3). The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product under reduced pressure by rotary evaporation. To give a crude product Compound 9 (120mg, together with small trial) and used directly in the next reaction.

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

Reaction 3:

Figure PCTCN2017084604-appb-000300

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, (30mL × 3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound s-11 (20mg, yield 19%).

1 H-NMR (400MHz, DMSO -d6): δppm 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 = 10.4Hz, 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].

Synthesis Example 88 S-12 in the embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000301

Compound 7 (70mg, 0.20mmol) was dissolved in 5mL DMF, were added compound 7a (35mg, 0.30mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyl- hexafluorophosphate (165mg, 0.30mmol) and diisopropylethyl amine (78mg, 0.60mmol), the reaction at room temperature under nitrogen overnight, quenched with water, extracted with ethyl acetate (50mL × 5), combined extracts was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary done under reduced pressure the crude compound 11, it was used directly in the next reaction.

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

Reaction 2:

Figure PCTCN2017084604-appb-000302

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 × 3). The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound s-12 (20.0mg, 23% yield 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 = 5.6Hz, 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].

Synthesis Example 89 S-13 in the embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000303

Compound 7 (60mg, 0.17mmol) was dissolved in 5mL DMF, were added compound 7a (37mg, 0.34mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyl- hexafluorophosphate (99mg, 0.26mmol) and N- ethyldiisopropylamine (68mg, 0.51mmol), the reaction at room temperature under nitrogen overnight, quenched with water, extracted with ethyl acetate (50mL × 5), combined extracts It was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary done under reduced pressure the crude compound 11 was used directly in the next reaction and 100mg.

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

Reaction 2:

Figure PCTCN2017084604-appb-000304

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 methanol, with dichloromethane methanol (10: 1,30mL × 5). The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound s-13 (10mg, 13% yield).

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 = 4.8Hz, 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].

Synthesis Example 90 S-14 in the embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000305

Compound 7a (52mg, 0.39mmol) was dissolved in 5mL DMF, were added sodium hydroxide (288mg, 7.2mmol), anhydrous sodium sulfate (120mg, 0.85mmol), stirred at rt for 7h. The system was filtered, the filtrate was successively added Compound 7 (80mg, 0.23mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (200mg , 0.53 mmol) and diisopropylethyl amine (300mg, 2.3mmol), under nitrogen at room temperature overnight, quenched with water, ethyl acetate (50mL × 5). the combined extracts were washed with saturated brine, no over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product 8 was used directly in the next reaction.

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

Reaction 2:

Figure PCTCN2017084604-appb-000306

The crude compound 8 was dissolved was added NaBH 4 (130mg, 3.2mmol) 5mL of methanol under ice bath, the reaction stirred 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 methane (30mL × 3). The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound s-14 (5.0mg, 6.0% yield, two steps).

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 = 5.6Hz, 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].

Synthesis Example 91 S-15 in the embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000307

Compound 7 (40mg, 0.11mmol) was dissolved in 5mL DMF, were added compound 7a (20mg, 0.20mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyl- hexafluorophosphate (65mg, 0.17mmol) and diisopropylethyl amine (77mg, 0.60mmol), the reaction at room temperature under nitrogen overnight, quenched with water, ethyl acetate (50mL × 5). the combined extracts were It was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product 8 was used directly in the next reaction.

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

Reaction 2:

Figure PCTCN2017084604-appb-000308

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) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound s-15 (15.0mg, 30% yield two steps).

1 H-NMR (400MHz, 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 = 6.0Hz, 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].

Synthesis Example 92 S-16 in the embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000309

Compound 7 (100mg, 0.43mmol) was dissolved in 5mL DMF, were added compound 7a (55mg, 0.64mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyl- hexafluorophosphate (243mg, 0.64mmol) and N- ethyldiisopropylamine (111mg, 0.86mmol), the reaction at room temperature under nitrogen overnight, quenched with water, extracted with ethyl acetate (50mL × 5), combined extracts It was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure by rotary evaporation under reduced pressure. To give crude Compound 8 (116mg, 65%) was purified by preparative plate thickness.

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

Reaction 2:

Figure PCTCN2017084604-appb-000310

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 methanol, (30 mL × 3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound s-16 (43mg, 43% yield).

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 = 10.8Hz, 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].

Synthesis Example 93 S-17 in the embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000311

Compound 7 (100mg, 0.43mmol) was dissolved in 5mL DMF, were added compound 7a (59mg, 0.64mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyl- hexafluorophosphate (243mg, 0.64mmol) and N- ethyldiisopropylamine (111mg, 0.86mmol), the reaction at room temperature under nitrogen overnight, quenched with water, extracted with ethyl acetate (50mL × 5), combined extracts It was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure by rotary evaporation under reduced pressure. To give crude Compound 8 (104mg, 62%) was purified by preparative plate thickness.

Reaction 2:

Figure PCTCN2017084604-appb-000312

Compound 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 (30mL) and quenched with saturated ammonium chloride solution, rotary evaporation to remove most of methanol, (30mL × 3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound s-17 (25mg, 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 = 10.4Hz, 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].

Synthesis Example 94 S-18 in the embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000313

Compound 7 (70mg, 0.20mmol) was dissolved in 5mL DMF, were added compound 7a (30mg, 0.41mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyl- hexafluorophosphate (165mg, 0.43mmol) and diisopropylethyl amine (77mg, 0.60mmol), the reaction at room temperature under nitrogen overnight, quenched with water, ethyl acetate (50mL × 5). the combined extracts were It was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product 8 was used directly in the next reaction.

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

Reaction 2:

Figure PCTCN2017084604-appb-000314

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) and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound s-18 (30.0mg, 37% yield 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].

Synthesis Example 95 S-19 in the embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000315

Compound 7 (90mg, 0.26mmol) was dissolved in 5mL DMF, were added compound 7a (28mg, 0.39mmol), O- (7- nitrogen Benzotriazole) -N, N, N ', N'- tetramethyl- hexafluorophosphate (150mg, 0.39mmol) and diisopropylethyl amine (52mg, 0.77 mmol), the reaction at room temperature under nitrogen overnight, quenched with water, ethyl acetate (50mL × 5). the combined extracts were It was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product 8 was used directly in the next reaction.

Reaction 2:

Figure PCTCN2017084604-appb-000316

The crude compound 8 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, most of the methanol removed by rotary evaporation, treated with dichlorobis methane (30mL × 3). The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound s-19 (6.6mg, 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].

Synthesis Example 96 S-20 in the embodiment

Reaction 1:

Figure PCTCN2017084604-appb-000317

Compound 1 (1.5g, 8.0mmol) was dissolved in 30mL of dichloromethane, was slowly added thionyl chloride (2.86g, 24.0mmol), the reaction mixture was warmed to 70 deg.] C for 2 hours. Cooled to room temperature, the solvent was distilled off under reduced pressure, 30mL of anhydrous tetrahydrofuran was added and sufficiently dissolved, was added benzylamine at 0 ℃ (1.3g, 12.0mmol) and triethylamine (1.62g, 16.0mmol), stirred at room temperature overnight. TLC showed the reaction was complete. Quenched with 300mL of water was added and extracted with dichloromethane (100mL × 5), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product by column chromatography to obtain the product compound 3 (1.3g, 60% yield). MS: m / z 275.3 [M + 1].

Reaction 2:

Figure PCTCN2017084604-appb-000318

Compound 3a (2.42g, 19.53mmol) was dissolved in 30mL anhydrous tetrahydrofuran, cooled to dry ice-acetone bath at -78 deg.] C, was slowly added dropwise 1.5M butyllithium in hexane (13mL, 19.53mmol) maintaining the internal temperature of -60 ℃ the following. After Compound 3 (896mg, 3.26mmol) was dissolved in 10mL of anhydrous tetrahydrofuran was added to the reaction flask and kept the internal temperature at -60 ℃. The reaction was stirred for 2 hours at -78 deg.] C, quenched with saturated ammonium chloride, warmed to room temperature. 200mL of water was added and extracted with dichloromethane (100mL × 5), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product by column chromatography to obtain the product compound 4 (1.07g, yield 90.6%). Inspection of Compound 4: MS: m / z 367.4 [M + 1].

Reaction 3:

Figure PCTCN2017084604-appb-000319

Compound 4 (188mg, 0.51mmol) was dissolved in 10mL anhydrous tetrahydrofuran, 30.5 mg of sodium hydride was added under ice-cooling, warmed to room temperature with stirring for 1 hour. Under ice Compound 4a (211mg, 0.51mmol) was dissolved in 5mL of anhydrous tetrahydrofuran was added to the reaction flask. The reaction was stirred overnight and warm to room temperature, quenched with saturated ammonium chloride, was added 100mL of water and extracted with dichloromethane (50mL × 3), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product by column chromatography to obtain the product compound 5 (134mg, 40.1% yield). Compound of MS 5: m / z 656.0 [M + 1].

Reaction 4:

Figure PCTCN2017084604-appb-000320

Compound 5 (118mg, 0.18mmol) was dissolved in 10mL of methanol was added 1mL of glacial acetic acid, raised to 90 deg.] C the reaction was stirred overnight, the solvent was distilled off under reduced pressure, was added 100mL of saturated sodium bicarbonate, extracted three times with dichloromethane (50mL × 3) The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. Compound 6 to give a crude product (156 mg of) and used directly in the next reaction.

Reaction 5:

Figure PCTCN2017084604-appb-000321

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, (30mL × 3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC to afford the title compound s-20 (18mg, yield 36%).

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

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

1 H-NMR (400MHz, DMSO -d6): δppm 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).

Synthesis Example 97 XSD1-029 embodiment

Reaction 1

Figure PCTCN2017084604-appb-000322

Compound D1 (2.2g, 5.0mmol), o-aldehyde boronic acid (1.2g, 7.5mmol), K 3 PO 4 (3.2g, 15mmol), Pd (PPh 3) 4 (0.6g, 1.0mmol) was dissolved in DMF / H in 2 O (30mL / 6mL). System was replaced with nitrogen, heated to 90 ℃, the reaction was stirred overnight. The reaction was diluted with ethyl acetate (50 mL), washed with saturated brine (25mL × 3), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (PE: EA = 5: 1), to give a brown solid compound 1 (810mg, 39%).

Compound 1 H-NMR (400MHz, CDCl3 ) 1 is: δ (ppm) 10.47 (s , 1H), 7.77 (d, J = 8.0Hz, 1H), 6.90 (d, J = 7.6Hz, 1H), 7.62- 7.57 (m, 2H), 7.48-7.38 (m, 11H), 7.21-7.18 (m, 6H).

Reaction 2:

Figure PCTCN2017084604-appb-000323

Compound 1 (360mg, 0.87mmol), compound 2 (117mg, 0.87mmol) and sodium ethoxide (88mg, 1.3mmol) was dissolved in THF / EOH (volume ratio 6mL / 3ml), stirred at room temperature overnight, the reaction was washed with saturated chloride ammonium hydroxide solution (25mL) quenched, extracted with ethyl acetate (25mL x2), saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and rotary evaporation under reduced pressure. The crude product was PE / EA mixture (volume ratio 5: 1) mixture was filtered, and dried to give the product compound 3 (300mg, yield 65%).

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

Reaction 3:

Figure PCTCN2017084604-appb-000324

Compound 3 (210mg, 0.39mmol) was dissolved in methanol (10mL), was added glacial acetic acid (1mL), and stirred overnight The reaction was 90 ℃. The reaction solution by rotary evaporation, dissolved in dichloromethane (20 mL), neutralized with saturated sodium bicarbonate, separated, the organic phase with saturated saline water (10mL), dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, to give the crude compound 140mg 4, it was used directly in the next reaction.

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

Reaction 4:

Figure PCTCN2017084604-appb-000325

Compound 4 (80mg, 0.27mmol) was dissolved in methanol (10 mL), under ice-cooling was added NaBH 4 (32mg, 0.83mmol), the reaction stirred for 1 hour, the reaction was quenched with saturated ammonium chloride solution (20 mL), was removed by rotary evaporation most of the methanol, (20 mLx2) and extracted with methylene chloride, saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by pre-HPLC, to give the title compound XSD1-029 (63mg, 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].

Synthesis of Example 98 XSD1-039

Reaction 1:

Figure PCTCN2017084604-appb-000326

At 0 deg.] C, the mercuric oxide (2.16g, 10mmol), iodine (7.74g, 30mmol) was added 1 (2.12g, 10mmol) and dichloromethane (100mL) solution of the compound, then the reaction temperature was slowly raised to 90 deg.] C reaction was continued for 18 h, the reaction TLC (ethyl acetate V:: V = 2 1 petroleum ether) to monitor, after the completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, water was added 100mL ethyl acetate (100mL * 3) extraction with an organic phase was dried over anhydrous sodium sulfate, and purified by column chromatography and concentrated to give 1.8g of compound 2 (yield 61.2%).

Compound 1 H-NMR (400MHz, CDCl3 ) 2 is: δ (ppm) 3.63 (s , 3H), 2.49-2.44 (m, 6H), 1.95-1.91 (m, 6H).

Reaction 2:

Figure PCTCN2017084604-appb-000327

Compound 2 (1.2g, 4.08mmol) was dissolved in tetrahydrofuran (30mL) in a dry ice acetone bath to -65 ℃, was slowly added dropwise tert-butyllithium (6mL, 8.16mmol) in tetrahydrofuran was added and the reaction was maintained -65 ℃ stirred 2h, then slowly warmed to room temperature and stirring was continued for 18 h, the reaction solution was reduced to 0 deg.] C, was added a saturated aqueous ammonium chloride solution (20mL) to quench the reaction, extracted with ethyl acetate (80mL * 3) organic phase was extracted, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure, purified by column chromatography to give compound 3 (490mg, 71.4% yield).

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

Reaction 3:

Figure PCTCN2017084604-appb-000328

Compound 3a (504mg, 4.07mmol) was dissolved in 30mL anhydrous tetrahydrofuran, a dry ice acetone bath to -70 deg.] C, slowly butyllithium (8mL, 4.07mmol) and maintained internal temperature of -60 deg.] C, fast Compound 3 (548mg, 3.26mmol) in dry tetrahydrofuran (10 mL) was added and the reaction flask kept internal temperature of -60 ℃. At -70 deg.] C, the reaction was continued stirring for 2 hours, quenched with saturated ammonium chloride, warmed to room temperature. With dichloromethane (100mL x5), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product by column chromatography to obtain the product compound 4 (284m g, yield 33.6%).

Compound 1 H-NMR (400MHz, CDCl3 ) 4 is: 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:

Figure PCTCN2017084604-appb-000329

Compound 4 (132mg, 0.51mmol) was dissolved in 10mL anhydrous tetrahydrofuran, was added sodium hydride (51mg, 1.27mmol), warmed to room temperature with stirring under ice-cooling for 1 hour. Under ice Compound 4a (211mg, 0.51mmol) was dissolved in 5mL of anhydrous tetrahydrofuran was added to the reaction flask. The reaction was stirred overnight and warm to room temperature, quenched with saturated ammonium chloride and extracted with dichloromethane (50mL * 3), combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. The crude product by column chromatography to obtain the product compound 5 (97mg, yield 34.6%).

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

Reaction 5:

Figure PCTCN2017084604-appb-000330

Compound 5 (99mg, 0.18mmol) was dissolved in 10mL of methanol was added 1mL of glacial acetic acid, raised to 90 deg.] C the reaction was stirred overnight, the solvent was distilled off under reduced pressure, was added 100mL of saturated sodium bicarbonate and extracted with dichloromethane (50mL * 3), The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure. Compound 6 to give a crude product (150 mg of) and used directly in the next reaction.

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

Reaction 6:

Figure PCTCN2017084604-appb-000331

Compound 6 (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 was quenched with saturated ammonium chloride solution (30 mL), rotary evaporated to remove most of methanol, (30mL * 3) and extracted with dichloromethane, combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Pre-HPLC to give Compound XSD1-039 (18mg, 59% yield).

1 H-NMR (400MHz, 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].

Determination of 2,3-dioxygenase Example 99 Amine-indol-inhibitory activity IC 50 and the detection of

Construction of a plasmid containing human indoleamine 2,3-dioxygenase gene expression in E. coli, are by extraction and purification methods reported Littlejohn like (Takikawa O, Kuroiwa T, Yamazaki F, et al. J.Biol.Chem.1988,263,2041-2048). 96 well plates in 50mM potassium phosphate buffer (pH 6.5), 20mM ascorbate, methylene blue and 20 uM purified human indoleamine 2,3-dioxygenase IDO protein mixture was added to the mixture and tryptophan 200μML- inhibitors. The reaction is carried out at 37 ℃ 60 min by addition of 30% trichloroacetic acid to stop the reaction, and incubated at 65 deg.] C for 15 minutes to N- formyl-kynurenine hydrolysis of kynurenine, centrifuged at 4000rpm at 5min remove precipitated protein, the supernatant is transferred into a new 96-well plate, was added 2% (w / v) of - dimethylaminobenzaldehyde solution in acetic acid, the reaction was incubated at 25 deg.] C for 10 min and at 480nm readings 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 IC 50 1 each compound

Compound No. IC 50 (nM)
S-1 9
S-2 twenty two
S-3 12
S-4 10
S-5 9
S-6 12
S-7 11
S-8 28
S-9 twenty three
S-10 twenty four
S-11 11
S-12 10
S-13 twenty one
S-14 19
S-15 10
S-16 10
S-17 twenty one
S-18 twenty two
S-19 twenty three
S-20 1023

IC was measured for each compound shown in Table 50 below according to the embodiments Detection:

Table IC 50 2 for each compound

Figure PCTCN2017084604-appb-000332

Figure PCTCN2017084604-appb-000333

The IC of each compound of the above embodiment of the detector 50 measured as shown in the following table:

Table IC 50 3 individual compound

Figure PCTCN2017084604-appb-000334

Figure PCTCN2017084604-appb-000335

Vivo 2,3 dioxygenase inhibitor Example 100 indoleamine embodiment Antitumor Activity Test

1. Animal grouping and test method

LLC cells taking the logarithmic growth phase, cell viability by trypan blue staining, viable cell concentration adjusted to 1 × 10 7 / ml, and press 0.2ml / only, homologous injected subcutaneously into C57BL6 mice. Once the tumor is established, the mice were tumor weight and body weight were randomly divided into model group, cyclophosphamide (CTX) group, the compound S-21 group, the compound group S-1, S-4 compound groups, the compound S-5 group, compound S-8 groups of 10 each, the CTX group were 150mg · kg -1 intraperitoneal injection, the compound S-21 group, the compound S-8 intragastric administration group, model group at the same time given the same volume of physiological saline, The frequency of each group were administered once a day. 21 days after the end of the test administration.

24h after the last administration, the animals were weighed sacrificed, the tumors and weighed to calculate the average inhibitory rate (inhibition rate, I), the following formula: I = (1- mean tumor weight of treatment group / average tumor weight of untreated group) × 100 %

2. Data processing and statistical methods

The data was spss16.0, one-way ANOVA one way ANOV analysis, statistically significant p <0.05 for the difference.

3. Test results and discussion

Results Table 4 Compound inhibition of LLC tumors in mice

Figure PCTCN2017084604-appb-000336

Compared with model group, ## P <0.01;

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

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

As can be seen from Table 4, in each treatment group tumor weight compared with model group had significant difference (P <0.01); S-21 compound and the groups of each compound group and cyclophosphamide group having a significant difference compared ( P <0.01); each compound group with a compound of the present invention is S-21 group have significant difference (P <0.05) as compared. This result indicates that each of the compounds of the present invention, the therapeutic effect on the tumor significantly better therapeutic effect of chemotherapeutic agents cyclophosphamide and the compound S-21.

TABLE 5 Effect of compounds on body weight of mice

Figure PCTCN2017084604-appb-000337

Compared with cyclophosphamide group, ## p <0.01.

As can be seen from Table 5, each compound group and model group was no significant difference compared to the body weight of mice, there was a significant difference in comparison with the CTX group, these results indicate that the compounds of the present invention can be increased while the control mice were tumor growth weight, reduced drug side effects, significantly improve the quality of life in mice. Can improve the quality of life of patients with clinically and significantly improve the effectiveness of drugs and medication compliance of patients.

Determination of inhibitory effect of the compounds of the present invention, a tumor in the same manner as in Example above embodiment, the results shown in the following table:

The results in Table 6 Compound inhibition of LLC tumors in mice

Figure PCTCN2017084604-appb-000338

Compared with model group, ## P <0.01;

1505 and compared with the CTX group group, P <0.05.

As can be seen from Table 6, in each treatment group tumor weight compared with model group had significant difference (P <0.01); cyclophosphamide group group of each compound and compared to 1505 groups significantly different (P <0.05 ). This result indicates that the treatment effect of the compound of the present invention is significantly better than for tumor treatment and the compound prior Cyclophoshamide 1505 pairs of tumors.

Table 7 Effect of compounds on body weight of mice

Figure PCTCN2017084604-appb-000339

Compared with cyclophosphamide group, ## p <0.01.

As can be seen from Table 7, each of the compound group and model group was no significant difference compared to the body weight of mice, there was a significant difference in comparison with the CTX group, these results indicate that the compounds of the present invention, no weight loss while the control mice were tumor growth the phenomenon, reduce drug side effects, significantly improve the quality of life of mice. Can improve the quality of life of patients with clinically and significantly improve the effectiveness of drugs and medication compliance of patients. Determination of inhibitory effect of the compounds of the present invention, a tumor in the same manner as in Example above embodiment, the results shown in the following table:

The results in Table 8 Compound to inhibit the LLC tumors in mice

Figure PCTCN2017084604-appb-000340

Compared with model group, ## P <0.01;

Compared with the CTX group, ※ P <0.05, ※※ P <0.01;

Compared with S 21-group, $ P <0.05.

As it is seen from Table 8, in each treatment group tumor weight compared with model group had significant difference (P <0.01); each compound group compared to cyclophosphamide group were significantly different (P <0.05, P <0.01); the group of compounds of the present invention with the compound S-21 group have significant difference (P <0.05) as compared. This result indicates that the compounds of the present invention for treatment of tumors was significantly superior therapeutic effect of chemotherapeutic agents cyclophosphamide and the compound S-21.

TABLE 9 Effect of compounds on body weight of mice

Figure PCTCN2017084604-appb-000341

Compared with cyclophosphamide group, # p <0.05.

As can be seen from Table 9, the compounds of the present invention with the model group was no significant difference in body weight compared to mice, there was a significant difference in comparison with the CTX group, these results indicate that the compounds of the present invention, while the control mice no tumor growth weight loss phenomenon, reduce drug side effects, significantly improve the quality of life of mice. Can improve the quality of life of patients with clinically and significantly improve the effectiveness of drugs and medication compliance of patients.

In addition, we also used from Colon26 mouse colon carcinoma, mouse hepatoma Hepa 1-6, 4T1 mouse breast cancer cell lines tested, etc., the results show the compounds of the present invention showed significant inhibitory effect on these tumors.

Behavior Example 101 Morris water maze detected changes of Alzheimer mice

1. Animal grouping and test method

9 month-old mice of the present invention is selected Richardson et rat model of AD produced bilateral hippocampal CA3 region of a single injection of Aβ1-42 aggregation method, which was then divided into model group, the compound S-1 group, the compound S- group 4, group and compound S-5 compound S-8 group, n = 10, male and female. Analysis (Netherlands Noldus company Ethovision XT monitoring and analysis software, Morris water maze system) using the Morris water maze behavior of mice. Water maze test process into a continuous 5d and find the hidden platform on day to obtain a test probe test space 6 in two parts, according to the test group and each test before dosing design. Training 4 times a day, each time in a different region of the mice water, press water maze is divided into four cardinal points 1,2,3,4 region, i.e., the fifth region the platform is located within the fourth region. Every time swimming 60s, each training interval of about 1h, the mice did not find the latency computing platform by 60s. Hidden platform test for detection of mouse get to learn the ability to obtain; space exploration test to detect spatial memory in mice.

2. Data processing and statistical methods

The use of statistical analysis software SPSS16.0, hidden escape platform to obtain an incubation period of trial use of multiple measures analysis of variance test the effectiveness of learning; analysis swim time for each quadrant of the search space through trials and the number of targets using one-way ANOVA. Data mean ± standard deviation, the difference is set to two-sided significance level P = 0.05.

3. Test results and discussion

Table search platform latency test in each group of 10 animals hidden platform (s)

Figure PCTCN2017084604-appb-000342

Compared with model group, # P <0.05, ## P <0.01 ;;

And S 21-group, ※ P <0.05, ※※ P <0.01.

Table 11 animals in each group platform area residence time and frequency

Figure PCTCN2017084604-appb-000343

Figure PCTCN2017084604-appb-000344

Compared with model group, # P <0.05;

And S-21 group, P <0.05.

As can be seen from Table 10 and Table 11, the compounds of the present invention can significantly improve the learning and memory impairment, significantly improve the ability of learning and spatial memory capacity is obtained, and it is obviously better than the compound S-21 group. These results indicate that the compounds of the present invention has great value in the treatment of the development of Alzheimer's syndrome.

Determine the effect of compounds of this invention on mouse behavior changes of Alzheimer same manner as in the above embodiment examples, the results shown in the following table:

Table 12 animals in each group to search for the hidden platform test platform incubation period (s)

Figure PCTCN2017084604-appb-000345

Compared with model group, # P <0.05, ## P <0.01;

Group and 1505, ※ P <0.05, ※※ P <0.01.

Table area residence time and the number of 13 animals in each group platform

Figure PCTCN2017084604-appb-000346

Compared with model group, ## P <0.01;

Group and 1505, ※ P <0.05, ※※ P <0.01.

As can be seen from Table 13 and Table 12, each of the compounds can significantly improve the learning and memory impairment, significantly improve the ability of learning and spatial memory capacity is obtained and superior to compound 1505, the results show that the compounds of the present invention to al the treatment of Alzheimer syndrome has great development value.

Determine the effect of compounds of this invention on mouse behavior changes of Alzheimer same manner as in the above embodiment examples, the results shown in the following table:

Table 14 animals in each group to search for the hidden platform test platform incubation period (s)

Figure PCTCN2017084604-appb-000347

Figure PCTCN2017084604-appb-000348

Compared with model group, # P <0.05;

And S-21 group, P <0.05.

Table 15 animals in each group platform area residence time and frequency

Figure PCTCN2017084604-appb-000349

Compared with model group, # P <0.05;

And S-21 group, P <0.05.

As can be seen from Table 15 and Table 14, the compounds of the present invention can significantly improve the learning and memory impairment, and enhance the ability to obtain spatial learning and memory, and it is significantly better than compound S-21 group. These results indicate that the compounds of the present invention has great value in the treatment of the development of Alzheimer's syndrome.

Embodiment Example 102 T cells after stimulation of the proliferation of drug-treated reactions DC

Dendritic cells (Dendritic cell, DC) are the most potent antigen presenting cells (the APC), effective to activate naive T cells (naive T cell) proliferate, DC is the main difference with the other APC. DC is to start the immune response, because of its CD4 +, CD8 + T cell immune response in the key role played by the response, DC has become one of the immunology research focus, mainly focused on DC in tumor diseases, autoimmune diseases, transplant rejection and the fight against infection in.

1. Isolation and culture of human peripheral blood dendritic cells

Human peripheral blood mononuclear layer was taken, diluted with 0.01mol / L PBS like fold. Conventional PBMCs isolated by Ficoll solution, RPMI1640 medium to completely adjust the cell concentration to 3 × 10 6 ml -1, was added 6-well plate, 3mlP hole, incubated for 2 hours in a 5% CO2,37 ℃ incubator to non-adherent cells were washed PBS, three times, added containing IL-4 (100U / ml), GM-CSF (150ng / ml) and TNF-α (500U / ml) in a conventional culture medium, the medium was changed every other day half the amount , 8 days in culture for identification and experiment.

Cells prepared 2.T

The method of step 1 in human PBMC layer was isolated, adherent macrophages addition, removing B cells, T cells obtained by nylon wool column method to adjust the cell concentration to 1 × 10 6 cells / ml.

Preparation of 3.DC

Mature DC was centrifuged purity of 99%, RPMI1640 was added to adjust the cell concentration 1 × 10 5, 4 × 10 4, 2 × 10 4 / ml, and added to 96 well plate, eight holes provided each concentration, 100μl / hole . Were added compound 1505, compound XSD1-033, compound XSD1-065, compound XSD1-067, compound XSD1-068, compound XSD1-103, compound XSD1-110, compound XSD1-126, co-cultured for 2 days.

4.T cell proliferation assay (MLR)

T cells were added, 100μl / holes in each dosing group in DC. After culturing 5% CO2,37 ℃ incubator for 72 hours, incubated for 6 hours before the end of each hole was gently aspirated and 100μl culture, added MTT (5mg / ml) 10μl, placed in the incubator and cultured for 6 hours was added 0.01mol / L HCl-10% SDS 100μl, 37 [deg.] C overnight and put the value of the level of T cell proliferation is shown as measured with a microplate reader A570nm.

5. Results and Discussion

Table 16 Effects of various compounds on the DC to stimulate T cell proliferation

Figure PCTCN2017084604-appb-000350

Figure PCTCN2017084604-appb-000351

Compared with the control group, # P <0.05, ## P <0.01;

Group and 1505, 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 compound 1505 compound group compared with the group of more significant effect on the proliferation of T cells, with significant difference (※ P <0.05). This indicates that the compounds of the present invention has a significant role in promoting DC stimulation of T cell proliferation, and better than compound 1505, and further useful for the treatment of neoplastic diseases and infectious diseases.

Determination of bioavailability embodiment each compound in Example 103

1. Animal Grouping and administration

20 Wistar rats (270 ± 30) g, male and female, from Shandong New Time Pharmaceutical Co., Ltd. Experimental Animal Center, the production license number: SCXK (Lu) 20060019. At a temperature of 20 ~ 22 ℃, relative humidity of 45% to 65%, keeping the light / dark 12h / 12h conditions, free food and water. Experiment consisting of divided into two groups of 10 each:

Compound 1505 and XSD1-103 intragastric administration group: 12 hours of fasting will have free access to water of 10 healthy Wistar rats, male and female, a single oral administration, a dose of 10mg / kg. 12h fasted before administration, free access to water. Were taken before administration (0h), 0.083,0.25,0.5,1,1.5,2,3,4,6,8,12, and 24h after administration of about retroorbital venous plexus blood 300μL, heparin, 4 ℃ centrifuged at 4000rpm 5min, plasma was separated and stored at -20 ℃ deep freezer. Free access to water during the experiment, 2h feeding after administration.

Compound 1505 and Compound XSD1-103 intravenous administration group: The Wistar rats were fasted 12 hours healthy drinking water 10 free, male and female, were injected intravenously administered Compound 1-033, and Compound NLG919 injection dose of 2mg / kg. Were taken before administration (0h), 0.033,0.083,0.25,0.5,1,1.5,2,3,4,6,8,12, and 24h after administration retroorbital venous plexus of about 300 L of blood, heparin, centrifuged 5min at 4 ℃ 4000rpm conditions, plasma was separated and stored at -20 ℃ deep freezer. Free access to food and water during the experiment.

2. Determination of plasma samples

All the treated plasma samples, UPLC-MS / MS quantitative analysis, determination of plasma drug concentration

3. The bioavailability calculated

The measured plasma concentration - time data pharmacokinetic parameters calculated by DAS software (Drug and Statistics, China Mathematics Pharmacological Society, Jui-yuan, and preparation). The formula for calculating the respective absolute bioavailability of the compound, t is the final drug concentration can be measured sampling time.

Figure PCTCN2017084604-appb-000352

In the same manner as in Example S-21, XSD1-033, XSD1-065, XSD1-110 XSD1-126 and bioavailability of the compounds can be determined using the above-described embodiment, respectively.

4. The absolute bioavailability of each compound

Table bioavailability of each compound 17

Figure PCTCN2017084604-appb-000353

Figure PCTCN2017084604-appb-000354

From the above table it can be seen, the bioavailability of the compounds of the present invention XSD1-103 significantly higher bioavailability structural analogs of 1505, and the bioavailability of the compounds of the present invention, the respective compounds were significantly higher than 1505, and S-21, indicating that the compound in medicine aspect of the present invention has obvious advantages.

Claims (48)

  1. A compound of formula or a pharmaceutically acceptable salt thereof represented by I:
    Figure PCTCN2017084604-appb-100001
    Wherein, n 0 or 1 or 2 or 3;
    n 3 0 or 1 or 2;
    R 0 is selected from OH, C (O) OH, amino, amido, acyl group, containing at least one O or S or N heteroaryl, halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano , amino, aryl, heteroaryl, 2-8 membered heteroalkyl, 3-12-membered heterocycloalkyl, C1-6 alkoxy substituted by 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, substituted C1-6 alkyl, 2-8 membered heteroalkyl, 3-12-membered heterocycloalkyl, C1-6 alkoxy, a C3-12 cycloalkenyl group, an aryl group, heteroaryl group , an amide group, an amino group;
    R 5-8 linked by a single bond to the phenyl ring, and with R 00, R 1, R 2 , R 3, R 4, R 9, R 10 are each independently selected from H, NH 2, halo, CN, CX 3- s H s, OH, C ( O) OH, C (O) H, alkenyl group, alkynyl group, amidino group, a sulfonamido group, a sulfone group, a sulfoxide group, a nitro group, an alkoxy group, a phosphate group, a urea group, a carbonate group, C1-6 alkyl, 2-8 membered heteroalkyl, 3-12-membered heterocycloalkyl, C1-6 alkoxy, a C3-12 cycloalkenyl group, a C2-6 alkenyl group, an aryl group, a heteroaryl group, an amide group, amino group, halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkoxy, C3-12 cycloalkenyl or C3-12 alkyl substituted C1-6 cycloalkyl group or a C1-6 alkoxy group, or an aryl or heteroaryl group, halogen , cyano, amino, aryl, heteroaryl, C1-6 alkyl, 2-8 membered heteroalkyl, 3-12-membered heterocycloalkyl, C1-6 alkoxy substituted carbonyl group, a C1-6 alkyl, 2-8 membered heteroalkyl, 3-12-membered heterocycloalkyl, C1-6 alkoxy, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group substituted with an amino, amido, acyl; or
    R 5-8 and the phenyl ring to benzene structure, taken C3-12 cycloalkyl, C3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12-membered heterocycloalkenyl, aryl, heteroaryl groups, halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, 2-8 membered heteroalkyl, 3-12-membered heterocycloalkyl, C1-6 alkoxy group, C3-12 cycloalkenyl group substituted by C3-12 cycloalkyl or C3-12 cycloalkenyl group or a 3-12 membered heterocycloalkyl or 3-12 membered heterocycloalkenyl or heteroaryl group or an aryl group;
    N 2 number of R 5-8 is 0 or 1 or 2 or 3 or 4;
    R 11 is a ring-containing structure or cycloalkene ring bridge.
  2. The compound of claim 1 or a pharmaceutically acceptable salt thereof as claimed in claim, wherein said n = 1, n 3 = 0 , R 0 is selected from OH, R 00, R 1, R 2, R 3, R 4, R 5-8, R 10 are each independently selected from H.
  3. 1 or 2 of the compound of Formula 1 or a pharmaceutically acceptable salt thereof as claimed in claim, wherein said R 11 is selected from
    Figure PCTCN2017084604-appb-100002
    Wherein Formula I is a C 1 to any position of the link ring r value on a key sound; substituted cycloalkyl r value on a key reasonable anywhere R is; n-0 0 or 1 or 2 or 3; 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 cycloalkyl -C3-12 cycloalkyl), or = (spiro - (3-10 membered heterocyclyl group)), or
    Each R is independently selected from the following substituent group: H, NH 2, halo, CN, CF 3, OH, C (O) OH, C (O) H, a sulfonamido group, a sulfone group, a sulfoxide group, a nitro group, phosphate, urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, C1-6 heteroalkyl, a C3-12 heterocycloalkyl, aryl, heteroaryl, an aryl group, an amide group, amino group, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, an aryl group, a heteroaryl group, a C3-12 cycloalkyl or C1-6 alkyl substituted by C1-6 alkoxy or aryl or heteroaryl group, halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, a C3-12 cycloalkyl group substituted with a carbonyl group, a C1-6 alkyl group, C3 -12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group substituted with an amino, amido, acyl;
    R is the number of n 1, any integer between n 1 is 0-14 (inclusive) (e.g., n 1 is 1); S is 0 or 1, or 2; a is a double bond; A is located in the valency at any position on the ring r is reasonable 1; a is 0 or a number 1, 2 or 3, when a is a number of 0, does not represent a double bond, and represents a single bond; X, Y are each independently is selected from 0 or 1 or 2 or 3, but not both zero.
  4. The compound of claim 3 or a pharmaceutically acceptable salt thereof as claimed in claim wherein, s is 1; n-1 is 0; X and y are 0 and 1 one, or both is 1; A = 0.
  5. The compound or a pharmaceutically acceptable salt thereof as the one claimed in any one of claims 1-4, wherein said R is selected from
    Figure PCTCN2017084604-appb-100003
    Figure PCTCN2017084604-appb-100004
    Wherein, L 0 double bond substituents selected from the following group: = O, = S (= O) s, = C (R 2) 2, = ( spiro cycloalkyl -C3-12 cycloalkyl), aryl, or heteroaryl = = (spiro - (3-10 membered heterocyclyl)), where = (spiro cycloalkyl -C3-12 cycloalkyl), aryl, or heteroaryl = = (spiro - (3-10 membered heterocyclyl)) with one or more substituents R 2;
    or
    Substituent group selected from a single bond: H, NH 2, halo, CN, CF 3, OH, C (O) OH, C (O) H, heteroalkyl, alkenyl group, alkynyl group, a heterocyclic group, an alkylene a sulfonamido group, a sulfone group, a sulfoxide group, a nitro group, a phosphate group, a urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group, amide group, amino group, halogen, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl or substituted C3-12 cycloalkyl C1-6 alkyl alkyl or C1-6 alkoxy group, or an aryl or heteroaryl group.
  6. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of the claims 1-5, wherein said R is selected from
    Figure PCTCN2017084604-appb-100005
    Wherein, A is selected from N, S, P, O; W is selected from C or S or P; = O the number of s, s 0 or 1 or 2; R 1 is selected from hydrogen, an amino group, a nitro group, a carbonyl group , amidino, halo, CN, CX 3-s H s, OH, C (O) OH, C (O) H, a sulfonamido group, a sulfone group, a sulfoxide group, a nitro group, an alkoxy group, a phosphate group , a urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, a C2-6 alkenyl, 2-8 membered heteroalkyl, 3-12-membered heterocycloalkyl , aryl, heteroaryl, amido, acyl, halo, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, or substituted amidino group, or C1-6 alkyl carbonyl or C1-6 alkoxy group, or an aryl or heteroaryl group or an amide or amino acyl, or amino or 2- 8 yuan heteroalkyl or a sulfone group or sulfoxide group.
  7. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of the claims 1-6, wherein said R is selected from
    Figure PCTCN2017084604-appb-100006
    Figure PCTCN2017084604-appb-100007
    Wherein, A is selected from N, S, P, O; wherein, N, P is substituted with 1 R, S substituted with R 1 or one or two = O; n is an integer selected from 0-6; hetero atom (s) O, N or S, each of R 1, L 00, R 3 is independently selected from an amino group, a sulfone group, a nitro group, a carbonyl group, amidino, halo, CN, CX 3-s H s, OH, C (O) OH, C (O) H, a sulfonamido group, a sulfone group, a sulfoxide group, a nitro group, an alkoxy group, a phosphate group, a urea group, a carbonate group, C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, a C2-6 alkenyl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, aryl, heteroaryl, amide group, amino group, halogen, amino, oxo, hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl or alkyl-substituted amidino group or a carbonyl C1- 6 alkyl or C1-6 alkoxy group or amino group or an amide group, or an aryl or heteroaryl group or an amide or amino group or an amino group or a 2-8-membered heteroalkyl or a sulfoxide group or a sulfone group; X takes 0 or 1 or 2, y takes 2 or 1 or 0; P takes 1 or 2 or 3 or 4 or 5; q of 1, or 2 or 3 or 4; B is C or N or O or S, the number 0 or 1 or 2, which is a position on a ring α, beta] , Γ, δ and ε arbitrary one or two bits; B is a double bond, which is the number 0 or 1 or 2, which is a position on the ring bond reasonable price anywhere.
  8. Acceptable compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof as claimed in claim wherein, R is selected from
    Figure PCTCN2017084604-appb-100008
    Wherein, R 1 is selected from H or C 1-6 alkyl, 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 C 5-10 heteroaryl, C 1-6 alkyl C 3-6 heterocyclyl group, said heteroatoms selected from 1 to 3 N, O or S, which is optionally substituted by halogen, nitro, amino, , cyano, hydroxyl, -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 substituted heterocyclyl, or cycloalkyl group optionally substituted by oxo;
    L 0 is selected from 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- 6 heterocyclyl, C 1-6 alkyl C 5-10 heteroaryl, C 1-6 alkyl C 3-6 heterocyclyl group, said heteroatoms selected from 1 to 3 N, O or S, the above-described group optionally substituted with 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 substituted heterocyclyl, or cycloalkyl group is optionally oxo.
  9. The compound or a pharmaceutically acceptable salt thereof according to any one of the claims 1-8, wherein said R is selected from
    Figure PCTCN2017084604-appb-100009
    Wherein any one of n 1 is an integer of between 0-5 (inclusive); n-2 is 0 or 1 or 2 or 3.
  10. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of the claims 1-9, wherein said R 11 is selected from
    Figure PCTCN2017084604-appb-100010
    Wherein, α R r 1 while the ring is connected, gamma], any two atoms δ β position, forms a covalent bond n 1 0 or 1 or 2 or 3.
  11. The compound or a pharmaceutically acceptable salt thereof according to any one of the claims 1 to 10, wherein said ring r 1 is selected from
    Figure PCTCN2017084604-appb-100011
    Figure PCTCN2017084604-appb-100012
    Figure PCTCN2017084604-appb-100013
  12. 11 The compound or a pharmaceutically acceptable salt thereof as claimed in claim wherein the R 00 is H, the compound of formula I is
    Figure PCTCN2017084604-appb-100014
    Wherein, n 0 or 1 or 2 or 3;
    R 1 and C ring linked to α or β or γ position 1;
    n 1 is 0 or 1 or 2 or 3;
    n 2 0 or 1 or 2 or 3;
    n 3 0 or 1 or 2;
    It is 0 or a number 1 or 2.
  13. The compound or a pharmaceutically acceptable salt thereof according to any one of the claims 1 to 12, wherein said r 1 C 1 and the ring linked to the α position, R r 1 and the ring linked to the δ position, R 00 is H, the compound is
    Figure PCTCN2017084604-appb-100015
    Definition of each group of the above structure as claimed in the preceding claims.
  14. 1-12 a pharmaceutically said compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any claim, wherein said r 1 C 1 and the ring linked to the α position, R and δ r 1 ring linked to bit structure of formula XXXIII,
    Figure PCTCN2017084604-appb-100016
    Definition of each group of the above structure as claimed in the preceding claims.
  15. Pharmaceutically compound of claim 1 of formula I or a pharmaceutically acceptable salt thereof as claimed in claim, wherein said compound is selected from:
    Figure PCTCN2017084604-appb-100017
    Figure PCTCN2017084604-appb-100018
    Figure PCTCN2017084604-appb-100019
    Figure PCTCN2017084604-appb-100020
    Figure PCTCN2017084604-appb-100021
  16. The method of preparing the compound of claim 1, the compound of formula The structure of TM-IX shown, comprising the steps of: M6 with a reducing agent to give the title compound TM-XI;
    Figure PCTCN2017084604-appb-100022
    Wherein said reducing agent is preferably NaBH 4, KBH 4, at least one of NaBH 4 / LiCl in.
  17. The method according to claim 16, wherein, in said M5 M6 is cyclized in the presence of an acid, to give deprotected;
    Figure PCTCN2017084604-appb-100023
    Said acid is selected from alkyd, aromatic acids, acid, saturated fatty acids, phenols.
  18. The method according to claim 17, wherein said M4 M5 in the presence of a strong base and reacting to give 4a;
    Figure PCTCN2017084604-appb-100024
    Wherein, R 4 take H; alkali metal lithium compound is selected from alkyl, aryl alkali metal compound, an alkali metal alkyl aromatic compound, amine lithium compound, an alkali metal hydride, an alkali metal salt of a fatty alcohol.
  19. The method according to claim 18, wherein said M3 and M4 3a obtained by the reaction in the presence of a base;
    Figure PCTCN2017084604-appb-100025
    The lithium base selected from alkyl, cycloalkyl, aryl lithium or lithium.
  20. The method according to claim 19, wherein said M2 and M3 are obtained by the reaction of 2a:
    Figure PCTCN2017084604-appb-100026
    Wherein L 0 when the double bond substituents selected from the following: = O, = S (= O) s, = C (R 2) 2, = ( spiro cycloalkyl -C3-12 cycloalkyl), aryl, or heteroaryl = = (spiro - (3-10 membered heterocyclyl group)).
  21. The method according to claim 20, wherein L 0 is selected from the substituted double bond group: = (-C3-12 spiro cycloalkyl), aryl, or heteroaryl = = (spiro - (3 10-membered heterocyclic group)) with one or more substituents R 2, the reaction was added a condensing agent and a base, a condensing agent selected HBTU, DMC, HOBT, HOBT / EDCI, HATU, HATU / DIEPA, DCC, CDI , isopropyl chloroformate.
  22. The method according to claim 20, wherein said M1 and M2 is obtained by the reaction with chloride:
    Figure PCTCN2017084604-appb-100027
    Said chloride selected from phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosgene, thionyl chloride, trimethylchlorosilane, α, α, α- at least one of benzotrichloride.
  23. The method of preparing the compound of claim 1, wherein the compound represented by the formula Z-II, comprising the steps of:
    Figure PCTCN2017084604-appb-100028
    Wherein a is the number 1.
  24. The method of preparing the compound of claim 1, wherein the compound is represented by formulas II, comprising the steps of:
    Figure PCTCN2017084604-appb-100029
    Compound Z-5 reduction with a reducing agent to give the title compound II; wherein said reducing agent is selected from NaBH 4, KBH 4 or NaBH 4 / LiCl.
  25. The method according to claim 24, wherein, in the compound Z-5 with a C 1 r 1 ring linked to the α position of the compound synthesis step Z-5 as follows:
    Figure PCTCN2017084604-appb-100030
    Compound Z-4 in the presence of an acid to form a ring, deprotected to obtain a compound Z-5; wherein said acid is selected from alkyd, aromatic acids, acid, saturated fatty acids, phenols.
  26. The method according to claim 25, wherein said compound synthesis of Z-5, the compound Z-4 in a C 1 r 1 and the ring linked to the β position, Z-4 Synthesis of Compound of the following steps:
    Figure PCTCN2017084604-appb-100031
    Figure PCTCN2017084604-appb-100032
    Z-2 and Compound 3 Compound generating compound in the presence of an organic base Z-4, wherein said organic base selected from alkyl lithium metal compound, alkali metal compound is an aromatic group, an aromatic alkyl alkali metal compound, amine a lithium compound, an alkali metal hydride, an alkali metal salt of a fatty alcohol.
  27. The method according to claim 26, wherein, in the compound Z-4 with a C 1 α r 1 position linked to the ring, the compound Z-4 synthetic steps are as follows:
    Figure PCTCN2017084604-appb-100033
    Wherein said strong base is selected from alkali selected tC 4 H 9 OK, NaH, Ph 3 CNa, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium tert-butoxide; alkyl lithium metal compounds, butyl lithium, phenyl lithium; amino lithium compounds, lithium diisopropylamide (LDA), lithium hexamethyldisilazide group (LiHMDS).
  28. The method according to claim 27, wherein the method for synthesizing Compound Z-3, the compound Z-3 synthetic steps as follows:
    Figure PCTCN2017084604-appb-100034
  29. The method according to claim 28, wherein said step of synthesizing a compound M3 as follows:
    Figure PCTCN2017084604-appb-100035
    Figure PCTCN2017084604-appb-100036
    Wherein said X is selected from Cl, Br, I; M is selected from the Li, Na, K; said reducing agent is selected from butyl lithium, t-butyl lithium, tributyl tin hydroxide, zinc / acetic acid; said chloride selected from phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosgene, thionyl chloride, trimethylchlorosilane, α, α, α- at least one of benzotrichloride.
  30. The method according to claim 29, wherein the synthetic compound Z-2, wherein n 3 0 or 1 or 2; Z-2 Synthesis of compound of the following steps:
    Figure PCTCN2017084604-appb-100037
    Figure PCTCN2017084604-appb-100038
    Compound Z-2-x compound obtained is reacted with a compound Z-2-1. 1A; wherein said R a is selected from H, boric acid, alkenyl boronic acid group or boronate group; R b is the ligand is selected from 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; X is selected from the substituent group cl, Br, I, triflate group; said base is selected from potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium acetate, potassium phosphate, barium hydroxide, cesium carbonate.
  31. The method of preparing the compound of claim 1, which compound is represented by the formula TM-X 0, said method comprising the steps of: a compound 5 is reduced to give the title compound TM-X 0;
    Figure PCTCN2017084604-appb-100039
    Wherein said reducing agent is NaBH4, KBH4, NaBH4 / LiCl.
  32. The method according to claim 31, wherein the compound 5 from compound 4 is cyclized in the presence of an acid, to give deprotected;
    Figure PCTCN2017084604-appb-100040
    Said acid is selected from alkyd, aromatic acids, acid, saturated fatty acids, phenols.
  33. The method according to claim 32, wherein said step of synthesizing the compound is 4: 3 and the compound to obtain a compound 4a reactor 4 in the presence of a strong base;
    Figure PCTCN2017084604-appb-100041
    Wherein, R4 take H; strong base is selected from t-C4H9OK, NaH, KH, Ph3CNa, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium t-butoxide, lithium metal alkyl compound, a lithium amine compound.
  34. The method according to claim 33, wherein said compound 3 is reacted with compound 3a obtained in the presence of a base;
    Figure PCTCN2017084604-appb-100042
    Said base is selected from lithium alkyl, cycloalkyl or aryl lithium lithium.
  35. Compound 2 Compound 1, were added sequentially triethylamine, diphenylphosphoryl azide, a reaction: The method according to claim 34, wherein the compound 2 is obtained by the following steps
    Figure PCTCN2017084604-appb-100043
  36. The method of preparing the compound of claim 1 of the compound of the formula TM-X 1, said method comprising the steps of: reducing a compound of TM-X0 TM-X1 to give the title compound with a reducing agent;
    Figure PCTCN2017084604-appb-100044
    The acid is selected from hydrochloric acid, hydrobromic acid, at least one of sulfuric acid.
  37. The method of preparing a compound as claimed in claim 1, wherein the compound is represented by the formula INT2, comprising the steps of: reducing a compound of INT1 INT2 to give the title compound:
    Figure PCTCN2017084604-appb-100045
    Wherein said reducing agent is NaBH4, KBH4, NaBH4 / LiCl.
  38. The method according to claim 37, wherein said compound INT1 being obtained by the steps of: Compound 5 (INT) by hydrolysis under acidic conditions to obtain compound INT1;
    Figure PCTCN2017084604-appb-100046
    Compound 5 (INT) is deprotected under acidic conditions to give a compound of INT1.
  39. The compound according to claim 1 for preparing a compound represented by the formula TM-XXXIV 0 indicates, comprising the steps of: reducing a compound of INT3 to give the title compound TM-XXXIV 0
    Figure PCTCN2017084604-appb-100047
  40. The method according to claim 39, wherein said compound INT3 being obtained by the steps of: a compound of INT1 and L 0 -W (= O) s -Cl , or L 0 -W (= O) s -OH to afford the title compound INT3:
    Figure PCTCN2017084604-appb-100048
  41. The compound according to claim 1 for preparing the compound represented by the formula TM-XXXIII, comprising the steps of a method, the steps of:
    Figure PCTCN2017084604-appb-100049
    Reducing Compound 3 to give to give the title compound TM-XXXIII.
  42. The method according to claim 41, wherein said compound 3 is obtained by the following steps:
    Figure PCTCN2017084604-appb-100050
    Reaction of compound 2 with compound INT1 Compound 3.
  43. The method according to claim 42, wherein said compound is obtained by the following 2 steps:
    Figure PCTCN2017084604-appb-100051
    Compound 1 under basic conditions with Triphosgene (triphosgene) to give compound 2; the base is selected from trialkyl ammonia; specifically from trimethylamine, triethylamine, at least one of tripropylene ammonia.
  44. As claimed in any of claims 1-15 the compound or a pharmaceutically acceptable salt or pharmaceutical composition thereof for the manufacture of a medicament dioxygenase, wherein the medicament for treating a indoleamine 2,3 disease pathology mediated tryptophan metabolic pathway characterized by conducting an enzyme.
  45. The pharmaceutically claimed in claim 44 weight compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for the manufacture of a medicament, the medicament for the treatment of cancer, infectious disease, neurodegenerative disease, depression, anxiety or age-related cataracts.
  46. A compound or a pharmaceutically acceptable salt or a pharmaceutical composition thereof for the preparation of a medicament as claimed in claim 45, wherein said cancer is selected from lung, liver, colon, pancreas, breast, prostate, brain cancer, ovarian cancer, cervical cancer, testicular cancer, renal cancer, head and neck cancer, lymphoma, melanoma or leukemia.
  47. A compound or a pharmaceutically acceptable salt or a pharmaceutical composition thereof for the preparation of a medicament as claimed in claim 45, wherein said neurodegenerative disease is Alzheimer's disease means.
  48. A compound or a pharmaceutically acceptable salt or a pharmaceutical composition thereof for the preparation of a medicament as claimed in claim 45, wherein said infectious disease refers to an infection caused by bacteria, fungi, viruses or parasites.
PCT/CN2017/084604 2016-05-16 2017-05-16 Imidazole derivative containing bridge ring WO2017198159A1 (en)

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