WO2017157332A1 - Aromatic amide derivative, preparation method therefor, and pharmaceutical applications thereof - Google Patents

Aromatic amide derivative, preparation method therefor, and pharmaceutical applications thereof Download PDF

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WO2017157332A1
WO2017157332A1 PCT/CN2017/077114 CN2017077114W WO2017157332A1 WO 2017157332 A1 WO2017157332 A1 WO 2017157332A1 CN 2017077114 W CN2017077114 W CN 2017077114W WO 2017157332 A1 WO2017157332 A1 WO 2017157332A1
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alkyl
aryl
cycloalkyl
1h
haloalkyl
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Chinese (zh)
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陆标
苟俊
张民生
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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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
    • A61K31/41841,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/10Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12Radicals substituted by oxygen atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/10Radicals substituted by halogen atoms or nitro radicals
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12Radicals substituted by oxygen atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

An aromatic amide derivative represented by formula (I), a preparation method therefor, a pharmaceutical composition comprising the derivative, uses thereof as an ROR regulator, and users thereof in preventing or treating inflammatory disease, autoimmune diseases, cancers and other diseases. The aromatic amide derivative has an agitation or anti-agitation activity on ROR. The combined medication of the aromatic amide derivative and a PD-1 antibody can be used in treatment of tumors or cancers.

Description

Aromatic amide derivatives, their preparation and their use in medicine FIELD

The present invention belongs to the field of medicine, it relates to aromatic amide derivatives, their preparation and their use in medicine. In particular, the present invention relates to formula (I) derivative in aromatic amides, their preparation, pharmaceutical compositions containing the derivatives, as well as ROR modulators preventing and / or treating autoimmune diseases such as It uses.

Background technique

Retinoic acid-related orphan nuclear receptor (ROR) is a member of the nuclear receptor family, it can regulate a variety of physiological and life processes. ROR family consists of three types RORα, RORβ and RORγ. Three different ROR may be expressed in different tissues and different physiological processes controlled, RORa mainly in the liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus and brain, RORβ small scope, a major role in central nervous system, RORγ can be expressed in many tissues, including liver, animal fat and skeletal muscle. Mammals lack RORγ exhibit reduced blood sugar.

RORγ There are two subtypes: RORγ1 and RORγ2. RORγ1 In many organizations, such as: thymus, muscle, kidney and liver expressed, while RORγ2 only expressed in immune cells, are thought to control the RORγ2 T cell helper T cell differentiation 17 (Th17) is. Th17 cells are a class of helper T cells, which can produce interleukin 17 (IL-17) and other cytokines, has been found been found that human Th17 inflammatory diseases and immune disorders, such as multiple sclerosis, rheumatoid arthritis, psoriasis, asthma and other diseases and disorders cloning a relationship, and now reported in the literature RORγ may be related to the occurrence and development of prostate cancer.

RORγt RORγ specific expression of the isoforms in immune cells, is a major transcription factor human and murine cells Th17, Th17 not only to promote cell differentiation, modulates the expression and secretion can factors specific effector Th17 cells of IL-17, RORγt closely related with a variety of autoimmune diseases, infectious diseases and tumors, and development.

RORy, RORγt particular type, have been identified as an important transcription Th17 cells differentiated regulator. Vanov et al 2006 study found that in mice experiments, RORγt Th17 cell differentiation is an important transcription factor. Their study showed that in mice is difficult to induce the formation of EAE model in the absence of RORγt. In humans Th17 cell differentiation, RORγt soon proved to have an important role similar to the groundbreaking discovery has aroused great attention of RORγt.

Currently, ROR as an inhibitor has been highly valued in the pharmaceutical industry, has become a hot topic, it is now open patent application includes WO2015171610, WO22015171558, WO2015131035, WO2013169864, WO2014179564, WO2015116904 and so on.

The inventors studies ROR modulator process, found in the present invention, compounds of general formula (I) as shown in, change the ring A group ortho to change its regulating effect, when A ring ortho groups are less sterically hindered group (e.g., H and F) a compound of the general formula (I), as inverse agonists, when ring a groups are ortho haloalkyl (e.g. trifluoromethyl), alkyl (e.g. ethyl) and haloalkoxy (e.g. trifluoromethoxy) class hindered when a large group of formula (I) compound represented by ROR agonist, whereby the present invention is to develop a new generation of ROR modulator, and further studies found changes in compounds of different mechanisms may be adjusted.

SUMMARY

Object of the present invention is to provide a compound represented by the general formula (I):

Figure PCTCN2017077114-appb-000001

Or a tautomer thereof, the racemates, racemates, enantiomers, or a non-isomeric forms of a mixture of enantiomers, or a pharmaceutically acceptable salt thereof,

among them:

X, Y are identical or different and Z, and are each independently CR 9 or N;

They are identical or different ring A and ring B, and are each independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

R 1 and R 2 identical or different and are each independently selected from hydrogen atom, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxy, cyano, heterocyclyl , aryl, heteroaryl, -OR 8, -C (O) R 8, -C (O) NHR 8, -C (O) OR 8 and -S (O) m R 8, wherein alkyl, cycloalkyl, alkoxy, haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted aryl group selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl group, one or more cycloalkyl, heterocyclyl, aryl and heteroaryl groups substituted with a substituent;

R 3 and R 4 are the same or different and are each independently selected from hydrogen atom, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxy, cyano, heterocyclyl , aryl, heteroaryl, -OR 8, -C (O) R 8, -C (O) OR 8 and -S (O) m R 8, wherein the alkyl, cycloalkyl, haloalkyl group, heterocyclyl group, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;

Or R 3 and R 4 form an oxo group;

R 5 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkenyl, alkynyl, aryl, heteroaryl, -OR 8, -C (O) R 8, -C (O) OR 8 and -S (O) m R 8, wherein said alkyl, cycloalkyl, haloalkyl, aryl, and heteroaryl are each independently optionally substituted aryl group selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxyl, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups one or more of substituents;

R 6 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxyl, cyano, heterocyclyl, aryl, heteroaryl, -OR 8, -C (O) R 8 , -C (O) OR 8 and -S (O) m R 8, wherein the alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl and heteroaryl each optionally substituted group independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group with one or more substituents;

R 7 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, heterocyclyl, aryl and heteroaryl;

R 8 is selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxyalkyl, hydroxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, amino, cycloalkyl alkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, halo, hydroxy, amino, carboxylic acid ester group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl alkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;

R 9 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkenyl, alkynyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl , haloalkyl, aryl, and heteroaryl are each independently optionally substituted aryl group selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxyl, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl , cycloalkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;

m is 0, 1 or 2;

x is 2, 3 or 4;

y is 2 or 3; and

z is 3 or 4.

In a preferred embodiment of the invention, the compound of formula (I), compound represented by the general formula (II):

Figure PCTCN2017077114-appb-000002

among them:

X is CR 9 or N;

Y is CH or N;

R 9 is a hydrogen atom or alkyl;

Ring A, ring B, R 1 ~ R 7, x, y and z in the general formula (I) as defined above.

In a preferred embodiment of the invention, the compound of formula (I), wherein A and B rings are the same or different and are each independently selected from heterocyclyl, aryl and heteroaryl.

In a preferred embodiment of the invention, the compound of formula (I), in which the compound represented by the general formula (II-A):

Figure PCTCN2017077114-appb-000003

among them:

X is CR 9 or N; R 9 is a hydrogen atom or an alkyl group;

G is CH or N;

R a is selected from alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, bromo, amino, nitro, hydroxyl, cyano, heterocyclyl, aryl, heteroaryl, -OR 8, - C (O) R 8, -C (O) NHR 8, -C (O) OR 8 and -S (O) m R 8, wherein the alkyl, cycloalkyl, alkoxy, haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted aryl group selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl group, heterocyclyl group, aryl and heteroaryl groups with one or more substituents;

p is 2 or 3;

Ring A, R 1 ~ R 8, m, y and z in the general formula (I) as defined above.

In a preferred embodiment of the present invention embodiment, a compound of the general formula (II-A), wherein both

Figure PCTCN2017077114-appb-000004
Selected
Figure PCTCN2017077114-appb-000005
Figure PCTCN2017077114-appb-000006

In a preferred embodiment of the invention, the compound of formula (I) represented by the general formula (III) compound represented by:

Figure PCTCN2017077114-appb-000007

among them:

X is CR 9 or N;

Y is CH or N;

R 9 is a hydrogen atom or alkyl;

Ring A, R 1 ~ R 7, x, y and z in the general formula (I) as defined above.

In a preferred embodiment of the invention, the compound of formula (I), compound represented by the general formula (IV):

Figure PCTCN2017077114-appb-000008

among them:

X is CR 9 or N;

Y is CH or N;

R 9 is a hydrogen atom or an alkyl group;

R 1 ~ R 7, x, y and z in the general formula (I) as defined above.

In a preferred embodiment of the invention, the compound of formula (I) represented by the general formula (IV-A), the general formula (IV-B) or general formula (IV-C) a compound represented by :

Figure PCTCN2017077114-appb-000009

Figure PCTCN2017077114-appb-000010

among them:

X is CR 9 or N;

Y is CH or N;

R 9 is a hydrogen atom or an alkyl group;

R a is selected from alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, nitro, hydroxyl, cyano, heterocyclyl, aryl, heteroaryl, -OR 8, -C ( O) R 8, -C (O ) NHR 8, -C (O) OR 8 and -S (O) m R 8, wherein the alkyl, cycloalkyl, alkoxy, haloalkyl, heterocycle , aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;

R b is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxyl, cyano, heterocyclyl, aryl, heteroaryl, -OR 8, -C (O) R 8 , -C (O) NHR 8, -C (O) OR 8 and -S (O) m R 8, wherein the alkyl, cycloalkyl, alkoxy, haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted aryl group selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl , cycloalkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;

p is 2 or 3;

q is 0, 1 or 2; and

R 1 ~ R 8, m, y and z in the general formula (I) as defined above.

In a preferred embodiment of the present invention embodiment, a compound of the general formula (IV-A) represented by the compound of general formula (IV-A-1) shown below:

Figure PCTCN2017077114-appb-000011

among them:

R 1 ~ R 7, p, y and z of general formula (IV-A) as defined above.

In a preferred embodiment of the invention, the compound of formula (I), in which R 1 is selected from a hydrogen atom, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, halo , cyano, heterocyclyl and -C (O) NHR 8, wherein said alkyl, cycloalkyl, alkoxy and heterocyclyl groups are each independently selected from optionally substituted alkyl, halogen, hydroxy, amino and one or more cyano substituents; preferably, R 1 is selected from alkyl, halo, haloalkyl, alkoxy and haloalkoxy; R 8 is selected from a hydrogen atom or an alkyl group.

In the present invention a preferred embodiment, the compound (I), wherein R 2 of said formula is a halogen; preferably fluoro or chloro.

In a preferred embodiment of the present invention embodiment, a compound represented by the general formula, wherein R is the same or R 3 (I) 4 or different and are each independently selected from hydrogen atom, alkyl, haloalkyl, and hydroxy, together form oxo, or R 3 and R 4.

In a preferred embodiment of the invention, the alkyl group of the formula (I) compound represented by wherein R 5 is selected from alkyl, cycloalkyl, haloalkyl, alkenyl and aryl, wherein said , cycloalkyl and aryl groups are each independently selected from optionally substituted alkyl, substituted with halo, alkenyl group and a hydroxyl group one or more substituents; preferably R 5 is isopropyl or cyclopropyl.

In the present invention a preferred embodiment, the compound (I), wherein R 6 is halogen, the formula; preferably fluorine.

In a preferred embodiment of the present invention embodiment, a compound of the general formula (I), wherein R 7 is optionally selected from halogen, cycloalkyl, and one or more hydroxyl groups substituted with a substituent alkyl group; R 7 is preferably ethyl.

Typical compounds of formula (I), including but not limited to:

Figure PCTCN2017077114-appb-000012

Figure PCTCN2017077114-appb-000013

Figure PCTCN2017077114-appb-000014

Figure PCTCN2017077114-appb-000015

Figure PCTCN2017077114-appb-000016

Figure PCTCN2017077114-appb-000017

Figure PCTCN2017077114-appb-000018

Figure PCTCN2017077114-appb-000019

Figure PCTCN2017077114-appb-000020

Figure PCTCN2017077114-appb-000021

Figure PCTCN2017077114-appb-000022

Figure PCTCN2017077114-appb-000023

Figure PCTCN2017077114-appb-000024

Figure PCTCN2017077114-appb-000025

Figure PCTCN2017077114-appb-000026

Figure PCTCN2017077114-appb-000027

Figure PCTCN2017077114-appb-000028

Or a tautomer thereof, the racemates, racemates, enantiomers, diastereomeric isomers or mixtures thereof, or a pharmaceutically acceptable salt thereof.

The present invention further provides a process for preparing according to formula (I), or a tautomer thereof, the racemates, racemates, diastereomers thereof, or a mixture of enantiomers, or a pharmaceutically acceptable salt intermediates, i.e., compound of the formula (V):

Figure PCTCN2017077114-appb-000029

Or a tautomer thereof, the racemates, racemates, enantiomers, or a non-isomeric forms of a mixture of enantiomers, or a pharmaceutically acceptable salt thereof,

among them:

X, Y are identical or different and Z, and are each independently CR 9 or N;

Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

R 1 is selected hydrogen atom, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxyl, cyano, heterocyclyl, aryl, heteroaryl, -OR 8, -C (O) R 8 , -C (O) NHR 8, -C (O) OR 8 and -S (O) m R 8, wherein the alkyl, cycloalkyl, alkoxy, haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted aryl group selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl , cycloalkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;

R 3 and R 4 are the same or different and are each independently selected from hydrogen atom, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxy, cyano, heterocyclyl , aryl, heteroaryl, -OR 8, -C (O) R 8, -C (O) OR 8 and -S (O) m R 8, wherein the alkyl, cycloalkyl, haloalkyl group, heterocyclyl group, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;

Or R 3 and R 4 form an oxo group;

R 5 is selected from alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkenyl, alkynyl, aryl, heteroaryl, -OR 8, -C (O) R 8, - C (O) OR 8 and -S (O) m R 8, wherein said alkyl, cycloalkyl, haloalkyl, aryl, and heteroaryl are each independently optionally substituted aryl group selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups one or more of substituents;

R 6 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxyl, cyano, heterocyclyl, aryl, heteroaryl, -OR 8, -C (O) R 8 , -C (O) OR 8 and -S (O) m R 8, wherein the alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl and heteroaryl each optionally substituted group independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group with one or more substituents;

R 8 is selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxyalkyl, hydroxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, amino, cycloalkyl alkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, halo, hydroxy, amino, carboxylic acid ester group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl alkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;

R 9 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkenyl, alkynyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl , haloalkyl, aryl, and heteroaryl are each independently optionally substituted aryl group selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxyl, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl , cycloalkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;

m is 0, 1 or 2;

x is 2, 3 or 4;

y is 2 or 3.

The present invention further provides a process for preparing according to formula (II-A) a compound or a tautomer thereof, the racemates, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof intermediates, i.e., formula (II-a-1) compound:

Figure PCTCN2017077114-appb-000030

Or a tautomer thereof, the racemates, racemates, enantiomers, or a non-isomeric forms of a mixture of enantiomers, or a pharmaceutically acceptable salt thereof,

Wherein: ring A, X, R a, R 1, R 3 ~ R 6, p and y are as formula (II-A) as defined above.

The present invention further provides a process for preparing a compound of formula (I) is, the method comprising:

Figure PCTCN2017077114-appb-000031

Formula (V) with a compound of formula (VI) condensation reaction of a compound of general formula (I) compounds;

among them:

Ring A, ring B, X, Y, Z, R 1 ~ R 7, x, y and z in the general formula (I) as defined above.

The present invention further provides a process for preparing the formula (II-A) compounds, the method comprising:

Figure PCTCN2017077114-appb-000032

Formula (II-A-1) a compound of the general formula (II-A-2) a condensation reaction, to give a compound of formula (II-A);

among them:

Ring A, G, X, R a , R 1 ~ R 7, p, y and z are as formula (II-A) as defined above.

Aspect of the invention relates to a pharmaceutical composition of the general formula (I) contains a therapeutically effective dose, (II), (III), (IV), (IV-A), (IV-B), ( IV-C), or a compound or a tautomer thereof, the racemates, racemic bodies shown in (V), to, diastereomers thereof, or a mixture of enantiomers, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carrier, diluent or excipient. The present invention further relates to a process for preparing the above composition which comprises formula (I), (II), (III), (IV), (IV-A), (IV-B), (IV-C ) or (V) compound or a tautomer thereof, the racemates, racemic shown, to, diastereomers thereof, or a mixture of enantiomers, or a pharmaceutically acceptable acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient is mixed.

The present invention further relates to formula (I), or a tautomer thereof, the racemates, racemic shown, for non-isomeric forms of diastereoisomers enantiomers or mixtures thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof as ROR adjusting agent for the prevention and / or treatment of inflammation, autoimmune diseases, tumor or cancer drugs in use.

The present invention further relates to formula (I), or a tautomer thereof, the racemates, racemic shown, for non-isomeric forms of diastereoisomers enantiomers or mixtures thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof as an inverse agonist ROR use and / or prophylaxis of a medicament for the treatment of inflammatory and autoimmune diseases in.

The present invention further relates to formula (I), or a tautomer thereof, the racemates, racemic shown, for non-isomeric forms of diastereoisomers enantiomers or mixtures thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an agonist thereof as ROR use in the prevention and / or medicament for treating a tumor or cancer in.

The present invention further relates to compounds of general formula (IV-A) as shown ROR agonist for the prevention and / or treatment of tumors or the use of cancer.

The present invention further relates to formula (I), or a tautomer thereof, the racemates, racemic shown, for non-isomeric forms of diastereoisomers enantiomers or mixtures thereof, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof for the manufacture of an anti-ROR agonist PD-1 antibody compositions use medicament for treating tumors or cancer.

The present invention further relates to compounds of general formula (IV-A) as shown ROR agonist manufacture of a medicament for the anti-PD 1-antibody in combination with treatment of tumors or cancer.

The present invention further relates to formula (I), or a tautomer thereof, the racemates, racemic shown, for non-isomeric forms of diastereoisomers enantiomers or mixtures thereof, or pharmaceutically acceptable salts, or pharmaceutical compositions comprising the use thereof in the preparation of a medicament for regulating ROR.

The present invention further relates to formula (I), or a tautomer thereof, the racemates, racemic shown, for non-isomeric forms of diastereoisomers enantiomers or mixtures thereof, or pharmaceutically acceptable salt, or a use thereof in the manufacture of a pharmaceutical composition ROR agonist medicament.

The present invention further relates to the general formula (IV-A) use of a compound represented by ROR agonist in the manufacture of a medicament.

The present invention further relates to formula (I), or a tautomer thereof, the racemates, racemic shown, for non-isomeric forms of diastereoisomers enantiomers or mixtures thereof, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in preparation for the prevention and / or treatment of inflammatory and autoimmune diseases.

Herein, the inflammatory and autoimmune diseases selected from psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, inflammatory bowel disease, ankylosing spondylitis, chronic obstructive pulmonary disease , glomerulonephritis, myocarditis, thyroiditis, dry eye, uveitis, Behcet's disease, asthma, atopic dermatitis, acne, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, scleroderma, dermatomyositis bronchitis and allergic rhinitis.

The present invention further relates to formula (I), or a tautomer thereof, the racemates, racemic shown, for non-isomeric forms of diastereoisomers enantiomers or mixtures thereof, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in the preparation for the prevention and / or treatment of tumors or the use of cancer.

Herein, the tumor is selected from cancer and non-Hodgkin's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, synovial sarcoma, breast, cervix, colon, lung, stomach, rectum cancer, pancreas cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, renal cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube cancer, ovarian tumor, peritoneal cancer, IV melanoma, solid tumors, glial stromal tumors, nerve glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck cancer, leukemia, lymphoma, myeloma, and non-small cell lung cancer, especially non-Hodgkin's lymphoma, diffuse large B-cell lymphoma tumor, follicular lymphoma, synovial sarcoma.

The present invention further relates to formula (I) or a compound represented by the tautomer, the racemates, a racemate for use as a medicament, enantiomers, diastereomers or a mixture thereof, or a pharmaceutically acceptable salt thereof.

The present invention further relates to formula (I), or a tautomer thereof, the racemates, racemic bodies shown in, for non diastereoisomers enantiomers or mixtures thereof, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, for the prevention and / or treatment of an inflammatory or autoimmune disease, wherein said inflammatory and autoimmune diseases as defined above.

The present invention further relates to formula (I), or a tautomer thereof, the racemates, racemic bodies shown in, for non diastereoisomers enantiomers or mixtures thereof, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, for the prevention and / or treatment of tumor or cancer, wherein said tumors and cancers as defined above.

The present invention further relates to a compound represented by (IV-A) of the general formula, for the prevention and / or treatment of tumor or cancer, wherein said tumors and cancers as defined above.

The present invention further relates to formula (I), or a tautomer thereof, the racemates, racemic shown, for non-isomeric forms of diastereoisomers enantiomers or mixtures thereof, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof for ROR agonist anti-PD-1 antibody compositions, for the prevention and / or treatment of tumor or cancer, wherein said tumors and cancers as defined above.

The present invention also relates to compounds of general formula (IV-A) as shown with an anti-PD-1 antibody compositions, for the prevention and / or treatment of tumor or cancer, wherein said tumors and cancers as defined above.

The present invention further relates to a method of treating preventing and / or treating or preventing inflammation in autoimmune disease, comprising a compound administering to a patient in need thereof a therapeutically effective dose of the general formula (I), or a tautomer thereof meso form, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Wherein the inflammation and autoimmune diseases as defined above.

The present invention further relates to a method of treating preventing and / or treating or preventing cancer, a tumor, a compound or a tautomer thereof which comprises administering to a patient in need thereof a therapeutically effective amount of a formula (I) shown in the elimination rotary body, racemates, enantiomers, diastereomeric isomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Wherein said tumors and cancers as defined above.

The present invention further relates to a method of treating preventing and / or treating cancer or preventing cancer, comprising a therapeutically effective amount of administering to a patient in need thereof of the general formula (IV-A) as shown compounds. Wherein said tumors and cancers as defined above.

The present invention further relates to a method of treating preventing and / or treating cancer or preventing cancer, comprising a compound administering to a patient in need thereof a therapeutically effective dose of the general formula (IV-A) as shown with an anti-PD-1 antibody composition . Wherein said tumors and cancers as defined above.

The present invention further relates to formula (I), or a tautomer thereof, the racemates, racemic bodies shown in, for non diastereoisomers enantiomers or mixtures thereof, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, for adjusting the ROR.

The present invention also relates to compounds of general formula (IV-A) as shown in, for ROR agonist.

The present invention also relates to the general formula (IV-A) with a compound of anti-PD-1 antibody compositions shown in, for ROR agonist.

The present invention further relates to a method of adjusting ROR, comprising administering to a patient in need thereof a therapeutically effective amount of Formula (I) compound represented by the tautomer thereof, the racemates, a racemate, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir. Oral compositions may be prepared according to any method known in the preparation of a pharmaceutical composition of the present art, such compositions may contain one or more ingredients selected from: sweetening agents, flavoring agents, coloring agents and preservatives, to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient and excipients suitable non-toxic for the manufacture of tablets of pharmaceutically acceptable mixing. These excipients may be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, crosslinked sodium carboxymethyl cellulose, corn starch, or alginic acid; binding agents, for example starch, gelatine, polyvinylpyrrolidone or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. These known techniques tablets may be uncoated or may be masking the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period to pack coating. For example, a water soluble taste masking material such as hydroxypropyl methylcellulose or hydroxypropyl cellulose or prolonged substance such as ethyl cellulose, cellulose acetate butyrate.

It may also be used wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, hard gelatin capsules, wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil soft gelatin capsules to provide an oral formulation.

Aqueous suspensions contain the active materials and excipients suitable for mixing aqueous suspensions prepared. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum acacia; dispersing or wetting agents may be a naturally occurring phospholipids such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene ethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or ethylene oxide derived from fatty acids and hexitol condensation products of partial esters, for example polyoxyethylene sorbitan monooleate, ethylene oxide derived from fatty acids and hexitol anhydrides condensation products of partial esters, for example polyoxyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives such as ethyl paraben or propyl paraben Kim, one or more coloring agents, one or more flavoring agents and one or more sweet flavoring agents, such as sucrose, saccharin or aspartame.

Oil suspensions may arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin formulated by suspending the active ingredient in a vegetable. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. May be added to the sweetening and flavoring agents to provide a palatable preparation. Butylated hydroxyanisole or may α- tocopherol save These compositions, for example, addition of an antioxidant.

By addition of water suitable for preparing aqueous suspension can also Dispersible powders and granules of the active ingredient and provide for mixing of dispersing or wetting agent, suspending agent, or one or more preservatives. Examples of the above-described suitable dispersing or wetting agents and suspending agents may be described. It may also be added to other excipients such as sweetening, flavoring and coloring agents. By the addition of an antioxidant such as ascorbic acid save these compositions.

The pharmaceutical compositions of the invention may also be in the form of oil in water emulsions. The oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifying agents may be naturally occurring phospholipids such as soy lecithin derived from fatty acids and hexitol anhydrides, esters or partial esters such as sorbitan monooleate, and the partial esters and ethylene oxide condensation products, For example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring agents, preservatives and antioxidants. With sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose syrups and elixirs. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.

The pharmaceutical compositions may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable wherein the active ingredient is dissolved in an oil in water microemulsion of the oil phase. The active ingredient is dissolved in a mixture, for example, soybean oil and lecithin. The mixture was then added a solution of the oil in the treated water and glycerol formed a microemulsion. By a large number of local injection, the injectable solution or microemulsion injected into the bloodstream of the patient. Or, preferably, by a compound of the present invention can maintain a constant circulating concentration of administered solution and microemulsion manner. In order to maintain such a constant concentration, using a continuous intravenous delivery device. Examples of such means are Deltec CADD-PLUS.TM.5400 type IV pumps.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. According to the known art, the above suspension was formulated those suitable dispersing or wetting agents and suspending agents. Preparation of sterile injectable solution or suspension, non-toxic diluent or solvent, sterile injectable preparation may also be in a parenterally acceptable, for example a solution in 1,3-butanediol was prepared. In addition, sterile, fixed oils are conveniently used as a solvent or suspending medium. For this purpose, any harmonic fixed oils including synthetic mono- or diglycerides including. In addition, fatty acids such as oleic acid may be the preparation of injectables.

The form of suppositories for rectal administration can be administered a compound of the present invention. These pharmaceutical compositions can be prepared prepared by the suitable mixing the drug with a non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal, therefore will melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of fatty acid esters of polyethylene glycols of various molecular weights and polyethylene glycol.

As those skilled in the art, the dose of the drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound employed, the age, the patient's weight, general health of the patient, the line is, diet, time of administration, route of administration, rate of excretion, drug combination patients; in addition, the best mode of treatment, such as treatment, daily dose compound of formula (I), or a pharmaceutically acceptable salt thereof species can be verified according to a conventional treatment regimen.

Detailed Description of the Invention

Unless otherwise Chen Shu, the terms have the following meanings in the specification and claims use.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is straight-chain or branched-chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbons alkyl atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 , 2-methylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 - methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl pentyl, 3,3-dimethyl-pentyl, 2-pentyl, 3-ethyl-pentyl, n-octyl, 2,3-dimethyl-hexyl, 2,4-dimethyl hexyl group, 2 , 5-dimethyl-hexyl, 2,2-dimethyl-hexyl, 3,3-dimethyl-hexyl, 4,4-dimethyl-hexyl, 2-ethylhexyl, 3-ethylhexyl, 4-b hexyl, 2-methyl-2-pentyl, 2-methyl-3-ethyl-pentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-acetic acid hexyl, 2,2- Diethyl-pentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl group, and various branched chain isomers thereof. More preferred are lower alkyl containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butoxy group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethoxyethane methylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl group, 2,3-dimethylbutyl and the like. Alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment of the substituent is preferably one or more groups, independently selected from alkoxy group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, alkylamino group, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl alkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclyl, alkylthio, oxo, carboxyl or carboxylate groups.

The term "alkylene" refers to a hydrogen atom is further substituted with an alkyl group, for example: "methylene" refers to -CH 2 -, "ethylene" refers to a - (CH 2) 2 -, " propylene" refers to - (CH 2) 3 -, " butylene" refers to - (CH 2) 4 - and the like.

The term "alkenyl" refers to at least two carbon atoms and at least one carbon - carbon double bond as defined above consisting of alkyl groups, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 - butenyl and the like. Alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl group, alkoxy group, alkylthio group, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclyl alkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated, monocyclic or polycyclic cyclic hydrocarbon substituent, cycloalkyl ring containing from 3 to 20 carbon atoms, preferably containing from 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene cycloheptyl, cyclooctyl and the like; polycyclic cycloalkyl groups include spirocyclic, fused and bridged rings.

The term "spiro-cycloalkyl" refers to a shared between 5-20 yuan a monocyclic carbon atoms (referred spiro atom) polycyclic group which may contain one or more double bonds but none of the rings has a completely conjugated the π electron system. Preferably 6 to 14 membered, more preferably from 7 to 10 yuan. The number of atoms in common between the spiro ring and spiro cycloalkyl ring will be divided into single spiro cycloalkyl group, a cycloalkyl group or a bis spiro spiro cycloalkyl group, preferably a monocyclic spiro bis spiro cycloalkyl and cycloalkyl. More preferably 4 yuan / $ 4, 4 yuan / 5-, 4 yuan / 6, 5- / 5-membered or 5/6-membered monocyclic spiro cycloalkyl. Non-limiting examples of spiro groups include:

Figure PCTCN2017077114-appb-000033

The term "fused cycloalkyl" refers to a 5- to $ 20 and the other ring system, each ring in the system shares all-carbon polycyclic group adjacent pair of carbon atoms, wherein one or more rings may contain one or a plurality of double bonds, but none of the rings has a completely conjugated π electron system of. Preferably 6 to 14 membered, more preferably from 7 to 10 yuan. The ring may be divided into the number of component bicyclic, tricyclic, or tetracyclic fused ring group, preferably a bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5 yuan / 6-membered bicyclic groups. Non-limiting examples of fused cycloalkyl groups include:

Figure PCTCN2017077114-appb-000034

The term "bridged cycloalkyl" refers to a 5- to $ 20 of any two rings share all-carbon polycyclic group two carbon atoms are not directly connected, which may contain one or more double bonds but none of the rings has a completely conjugated π electron system. Preferably 6 to 14 membered, more preferably from 7 to 10 yuan. The ring may be divided into the number of component bicyclic, tricyclic, tetracyclic bridged or polycyclic cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

Figure PCTCN2017077114-appb-000035

The cycloalkyl ring may be fused to an aryl group, a heteroaryl or heterocycloalkyl ring, wherein the ring is attached to the parent structure together is cycloalkyl, Nonlimiting examples include indanyl, tetrahydronaphthalene , benzo cycloheptyl and the like. Cycloalkyl may optionally be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocyclic alkylthio, oxo, carboxyl or carboxylate groups.

The term "heterocyclyl" means a saturated or partially unsaturated, monocyclic or polycyclic cyclic hydrocarbon substituent which contains from 3 to 20 ring atoms, wherein one or more ring atoms selected from nitrogen, oxygen, or S (O) m (where m is an integer of 0 to 2) a hetero atom, but does not include -OO -, - OS- or -SS- ring portion, the remaining ring atoms being carbon. Preferably comprising 3 to 12 ring atoms, wherein from 1 to 4 are hetero atoms; most preferably 3 to 8 ring atoms, wherein 1 to 3 are hetero atoms; most preferably 3 to 6 ring atoms, wherein 1 to 2 It is a heteroatom. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydro imidazolyl, dihydro-furyl, dihydro-pyrazolyl, dihydro-pyrrolyl, piperidine yl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like, preferably piperidinyl, piperazinyl or morpholinyl. Polycyclic heterocyclic groups include spiro heterocyclic ring, fused and bridged rings.

The term "spiro-heterocyclyl" refers to a shared between 5-20 yuan a single ring atom (called spiro atom) polycyclic heterocyclic group, in which one or more ring atoms selected from nitrogen, oxygen, or S (O ) m (wherein m is an integer of 0 to 2) heteroatoms, the remaining ring atoms being carbon. It may contain one or more double bonds but none of the rings has a completely conjugated π electron system of. Preferably 6 to 14 membered, more preferably from 7 to 10 yuan. The number of common spiro atom between the rings will be divided into single-spiro heterocyclyl spiro heterocyclic group, a heterocyclic group or spiro-bis spiro heterocyclyl, heterocyclyl is preferably a single-screw and double-spiro heterocyclic group. More preferably 4 yuan / $ 4, 4 yuan / 5-, 4 yuan / 6, 5- / 5-membered or 5/6-membered monocyclic heterocyclic spiro group. Non-limiting examples of spiro-heterocyclyl groups include:

Figure PCTCN2017077114-appb-000036

The term "fused heterocyclic group" refers to a 5- to $ 20 each other ring systems and ring systems in the pair of adjacent atoms shared polycyclic heterocyclic group, one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π electron system, wherein one or more ring atoms selected from nitrogen, oxygen, or S (O) m hetero atoms (wherein m is an integer of 0 to 2), the remaining ring carbon atoms. Preferably 6 to 14 membered, more preferably from 7 to 10 yuan. The ring may be divided into the number of component bicyclic, tricyclic, tetracyclic fused heterocyclic or polycyclic group, preferably a bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5 yuan / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of condensed heterocyclic group comprising:

Figure PCTCN2017077114-appb-000037

The term "bridged heterocyclyl" refers to 5 to 14 yuan, any two atoms common to both rings are not directly linked polycyclic heterocyclic group, which may contain one or more double bonds, but none were complete a ring having π electron conjugated system in which one or more ring atoms selected from nitrogen, oxygen, or S (O) m (wherein m is an integer of 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably from 7 to 10 yuan. The ring may be divided into the number of component bicyclic, tricyclic, tetracyclic bridged heterocyclic or polycyclic group, preferably a bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridging heterocyclic group comprising:

Figure PCTCN2017077114-appb-000038

The heterocyclyl ring may be fused to aryl, heteroaryl or cycloalkyl ring, wherein the ring is attached to the parent structure with a heterocyclic group, non-limiting examples of which include:

Figure PCTCN2017077114-appb-000039
Wait.

Heterocyclyl may optionally be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocyclic alkylthio, oxo, carboxyl or carboxylate groups.

The term "aryl" refers to having a π-electron system conjugated to 6-14 yuan all-carbon monocyclic or fused polycyclic (i.e. shared ring adjacent pairs of carbon atoms) groups, preferably from 6 to 10 yuan, such as benzene and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring is attached to the parent structure together is an aryl ring, non-limiting examples of which include:

Figure PCTCN2017077114-appb-000040

The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl group, alkoxy group, alkylthio group, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclyl alkylthio, carboxyl or carboxylate groups.

The term "heteroaryl" refers to contain 1 to 4 heteroatoms, 5-14 heteroaromatic systems ring atoms, wherein hetero atom selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 million, containing from 1 to 3 hetero atoms; more preferably 5 or 6 membered, containing from 1 to 2 heteroatoms; preferably such as imidazole, furyl, thienyl, thiazolyl, pyrazolyl thiazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazolyl, pyrazinyl and the like, preferably imidazolyl, tetrazolyl, pyridyl, thienyl, pyrazolyl or pyrimidinyl thiazolyl; more selected from pyridyl. The heteroaryl ring may be fused to aryl, heterocyclyl or cycloalkyl ring, wherein the bond to the parent ring structure together heteroaryl ring, non-limiting examples of which include:

Figure PCTCN2017077114-appb-000041

Figure PCTCN2017077114-appb-000042

Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocyclic alkylthio, carboxyl or carboxylate groups.

The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl) wherein alkyl is defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocyclic alkylthio, carboxyl or carboxylate groups.

The term "haloalkyl" refers to a halo substituted with one or more alkyl groups, wherein alkyl is as defined above.

The term "haloalkoxy" refers to a halo substituted with one or more alkoxy, wherein alkoxy is as defined above.

The term "hydroxyalkyl" refers to alkyl substituted by hydroxy, wherein alkyl is as defined above.

The term "hydroxyl" means an -OH group.

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

The term "amino" means -NH 2.

The term "cyano" refers to -CN.

The term "nitro" refers to -NO 2.

The term "oxo" refers to = O.

The term "carbonyl" refers to a C = O.

The term "carboxyl" refers to -C (O) OH.

The term "isocyanato" means -NCO.

The term "oxime group" refers to = N-OH.

The term "carboxylic ester group" refers to a -C (O) O (alkyl), or -C (O) O (cycloalkyl), wherein the alkyl, cycloalkyl as defined above.

The term "acyl halide" refers to a -C (O) - group, a halogen compound.

"X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B, and C", such as different terms are expressed the same sense, that may be represented by X A, B, C, or any one of several.

Events or circumstances "optional" or "optionally" means that the subsequently described may but need not occur, including the description of the event or occasion or may not occur in the environment. For example, "optionally substituted heterocyclic alkyl group" means that the alkyl may but need not be present, the description includes heterocyclic group is an alkyl-substituted heterocyclic group is not the case and the case of the alkyl substituted .

"Substituted" means a group of one or more hydrogen atoms, preferably at most 5, more preferably by the corresponding number of substituents each independently from 1 to 3 hydrogen atoms. Needless to say, only in the substituent group thereof may be chemically position skilled in the art it may or may not be able to determine substitutions (experimentally or theoretically) without paying too much effort. For example, can be unstable when having a free amino or hydroxyl, hydrogen bonded to a carbon atom having an unsaturated (e.g. olefinic) bonds.

"Pharmaceutical composition" means a compound or physiologically / pharmaceutically acceptable salt or prodrug thereof containing one or more carriers described herein with other chemical components of the mixture, as well as other components, such as physiologically / pharmaceutically acceptable and excipients. Purpose of a pharmaceutical composition is to facilitate administration to a living body, and thus conducive to the absorption of the active ingredient to exert biological activity.

"Pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, such salts have safe and effective when used in a mammal, and should have a biological activity.

Synthesis of compounds of the present invention

In order to complete the object of the present invention, the present invention employs the following technical solutions:

Compound or a tautomer thereof, the racemates, the present invention is a racemate of formula (I) shown for the non-form enantiomers or a mixture of enantiomers, or a pharmaceutically salt can be prepared by, comprising the steps of:

Figure PCTCN2017077114-appb-000043

The dissolved compound (IA) compounds of general formula and the general formula (the IB), acetonitrile palladium dichloride-bis-norbornene and the polar solvent, the reaction was heated under basic conditions, to give compounds of formula (IC), preferably the alkaline agent bicarbonate condition, polar solvent, preferably N, N- dimethylacetamide; general formula (IC) reacting a compound obtained with iodomethane under heating and chlorides, alkaline conditions to give pass the compound of formula (ID), the alkaline agent preferably sodium hydride condition; obtained formula (ID) compound under basic conditions, hydrolysis to give the compound of formula (V), the alkaline agent preferably sodium hydroxide condition; the resulting formula (V) with a compound of formula (VI) compounds, 1-hydroxybenzotriazole and N, N- diisopropylethylamine to give compounds of formula (I).

Basic conditions to provide agents include organic bases and inorganic bases, of the organic bases include, but are not limited to triethylamine, N, N- diisopropylethylamine, n-butyllithium, lithium diisopropylamide , potassium acetate, sodium tert-butoxide or potassium tert-butoxide, inorganic bases include, but the are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, potassium carbonate or cesium.

among them:

R x is selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from optionally substituted alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more substituents;

Ring A, ring B, X, Y, Z, R 1 ~ R 7, x, y and z in the general formula (I) as defined above.

Compound or a tautomer thereof, the racemates, a racemate of the present invention of the general formula (II-A) shown on the form of enantiomers or mixtures of diastereomers thereof, or pharmaceutically acceptable salts may be prepared, comprising the steps of:

Figure PCTCN2017077114-appb-000044

Compound (II-1) formula, and the formula (II-2) compound, bis acetonitrile palladium dichloride, and norbornene dissolved in a polar solvent, heating the reaction under basic conditions to give the formula ( II-3) compound, preferably sodium bicarbonate alkaline agent of this condition, a polar solvent, preferably N, N- dimethylacetamide; (II-3) a compound of general formula obtained under heating, basic conditions with iodine chlorinated methane and reacting of general formula (II-4) compound, the alkaline agent preferably sodium hydride condition; formula (II-4) to give compound under basic conditions, hydrolysis of the general formula (II-a -1) compound, preferably sodium hydroxide of the alkaline reagent conditions; compound of the general formula (II-a-2) obtained in the general formula (II-a-1), 1- hydroxybenzotriazole and N, N- diisopropylethylamine to give the compound of formula (II-A).

Basic conditions to provide agents include organic bases and inorganic bases, of the organic bases include, but are not limited to triethylamine, N, N- diisopropylethylamine, n-butyllithium, lithium diisopropylamide , potassium acetate, sodium tert-butoxide or potassium tert-butoxide, inorganic bases include, but the are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, potassium carbonate or cesium.

among them:

R x is selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from optionally substituted alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more substituents;

Ring A, G, X, R a , R 1 ~ R 7, p, y and z are as formula (II-A) as defined above.

BRIEF DESCRIPTION

FIG 30 Effect of Compound 1 embodiment in C57BL / 6 mice to the growth of MC38 colorectal cancer cases.

detailed description

The following examples further describe in conjunction with the present invention, but these examples do not limit the scope of the invention.

Example

Structures of compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts ([delta]) are given in 10 -6 (ppm) units. NMR was measured with Bruker AVANCE-400 NMR instrument, measurement solvent deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD), an internal standard is four tetramethylsilane (TMS).

MS is determined by FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, Model: Finnigan LCQ advantage MAX).

1200DAD Agilent HPLC assay using high pressure liquid chromatography (Sunfire C18 150 × 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatography (Gimini C18 150 × 4.6mm column).

Chiral HPLC analysis using LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.).

TLC on silica gel plates using standard Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, silica gel thin layer chromatography plate (TLC) using employed is 0.15mm ~ 0.2mm, size separation and purification using thin layer chromatography is 0.4mm ~ 0.5mm.

Column chromatography generally used Yantai Huanghai 200-300 mesh silica gel as carrier silica.

Chiral preparative chromatography using Prep Star SD-1 (Varian Instruments Inc.) or SFC-multigram (Berger Instruments Inc.).

The average value of 50 measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

Known starting materials according to the present invention may be employed known in the art or according to the approach to the synthesis, or may be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shao far Chemical Technology (Accela ChemBio Inc), tarry chemicals and other companies.

Example Unless otherwise stated, each reaction can be carried out in an argon atmosphere or nitrogen atmosphere.

Argon or nitrogen atmosphere is argon or nitrogen balloon refers to a reaction flask connected to a volume of about 1L.

Hydrogen atmosphere means a hydrogen balloon connected to the reaction flask volume of approximately 1L.

Pressurizing the hydrogenation reaction-type hydrogenated using Parr 3916EKX meter and clear blue QL-500 type, or hydrogen generator HC2-SS-type hydrogenation apparatus.

The hydrogenation reaction is generally evacuated, filled with hydrogen, repeated three times.

Microwave reactions using CEM Discover-S 908860 microwave reactor.

Example Unless otherwise stated, refers to an aqueous solution.

Example Unless otherwise stated, the reaction temperature was room temperature for 20 ℃ ~ 30 ℃.

Reaction progress was monitored in an embodiment using thin layer chromatography (TLC), developing solvent systems used for the reaction are: A: system dichloromethane and methanol, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone, polar compounds according to the volume of the solvent be adjusted in a different ratio. Developing solvent system, and thin layer chromatography system eluting agent compound was purified by column chromatography include: A: system dichloromethane and methanol, B: n-hexane and ethyl acetate system, C: methylene chloride and acetone system, according to the volume of solvent polar compound different than be adjusted, may be added a small amount of triethylamine and acetic acid and other basic or acidic reagent is adjusted.

Example 1

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2- (2- (trifluoromethoxy) benzyl) lH-indole-5-carboxamide

Figure PCTCN2017077114-appb-000045

first step

2- (2- (trifluoromethoxy) benzyl) lH-indole-5-carboxylic acid methyl ester 1c

The 1H- indole-5-carboxylic acid methyl ester 1a (50mg, 0.28mmol), 1- (bromomethyl) -2-trifluoromethoxybenzene 1b (71mg, 0.28mmol), acetonitrile palladium dichloride bis ( 7mg, 0.03mmol), norbornene (54mg, 0.57mmol), sodium bicarbonate (72mg, 0.86mmol) was dissolved in N, N- dimethylacetamide, the reaction was raised to 70 deg.] C was stirred for 12 hours. The reaction was cooled to room temperature, excess water, extracted with ethyl acetate (20mL × 3), combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by thin layer chromatography method B The residue was purified in a developing solvent system, to give the title product 1c (70mg, yellow solid), yield: 70%.

The second step

1-isopropyl-2- (2- (trifluoromethoxy) benzyl) lH-indole-5-carboxylate 1d

After 1c (60mg, 0.17mmol) was dissolved in N, N- dimethylformamide was added a catalytic amount of potassium iodide, was added sodium hydride (10mg, 0.26mmol, 60% in oil), stirred for 30 minutes the reaction was added 2- bromopropane (103mg, 0.86mmol), raised to 60 deg.] C sealed tube for 12 hours. The reaction was cooled to room temperature, excess water, extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure with a thin B-layer chromatography and the obtained residue was purified by developing solvent system, to give the title product 1d (24mg, yellow oil). yield: 36%.

third step

1-isopropyl-2- (2- (trifluoromethoxy) benzyl) lH-indole-5-carboxylic acid 1e

The 1d (25mg, 0.064mmol) was dissolved in 7mL of methanol and tetrahydrofuran (V: V = 5: 2) mixed solvent was added 4M sodium hydroxide solution 2mL, 60 deg.] C the reaction was stirred for 2 hours. The reaction was cooled to room temperature, was added dropwise concentrated hydrochloric acid to pH 4, extracted with ethyl acetate (20mL × 2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure , by thin layer chromatography and the obtained residue was purified by developing solvent system B to give the title product 1e (20mg, yellow solid), yield: 83%.

the fourth step

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2- (2- (trifluoromethoxy) benzyl) lH-indole-5-carboxamide

The 1e (20mg, 0.053mmol), (4- (ethylsulfonyl) phenyl) methanamine (16mg, 0.08mmol, using patent application "WO2015 / 17335" discloses a process for the preparation derived), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (15mg, 0.08mmol), 1- hydroxybenzotriazole (11mg, 0.08mmol), N, N- diisopropylethylamine (21mg , 0.16 mmol) was dissolved in dichloromethane, stirred for 12 hours. Water was added with dichloromethane and methanol (V: V = 8: 1) mixed solvent (20mL × 3), combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated and purified by thin-layer chromatography to the resulting residue was purified by developing solvent system B to give the title product 1 (20mg, white solid), yield: 65%.

MS m / z (ESI): 559.4 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.06 (s, 1H), 7.87 (d, 2H), 7.64 (d, 1H), 7.53-7.57 (m, 3H), 7.31 (d, 2H), 7.17- 7.21 (m, 1H), 7.03 (d, 1H), 6.64 (t, 1H), 6.34 (s, 1H), 4.79 (d, 2H), 4.41-4.48 (m, 1H), 4.20 (s, 2H) , 3.11 (q, 2H), 1.49 (d, 6H), 1.28 (t, 3H).

Example 2

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2- (2-methoxy-benzyl) lH-indole-5-carboxamide 2

Figure PCTCN2017077114-appb-000046

first step

2- (2-methoxybenzyl) 2b lH-indol-5-carboxylate

The 1a (250mg, 1.43mmol), 1- (bromomethyl) -2-methoxybenzene 2a (301mg, 1.5mmol, using well-known methods "Journal of the American Chemical Society 2013,135 (30), 10934- 10937 "preparation derived), bis acetonitrile palladium dichloride (37mg, 0.14mmol), norbornene (268mg, 2.86mmol) was dissolved in N, N- dimethylacetamide was added sodium bicarbonate (240mg, 2.86 mmol), raised to 70 deg.] C was stirred for 12 hours. The reaction was cooled to room temperature, excess water, extracted with ethyl acetate (20mL × 3), combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, silica gel column chromatography method B in the resulting residue was purified eluent system to give the title product 2b (120mg, white solid), yield: 29%.

The second step

1-isopropyl-2- (2-methoxybenzyl) 2c lH-indol-5-carboxylate

The 2b (110mg, 0.37mmol) was dissolved in N, N- dimethylformamide was added a catalytic amount of potassium iodide, was added sodium hydride (30mg, 0.74mmol, 60% in oil), stirred for 30 minutes after addition of 2- bromopropane (183mg, 1.49mmol), raised to 55 ℃ reaction was stirred for 12 hours. The reaction was cooled to room temperature, excess water, extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by thin layer The resulting purified B to chromatography eluent systems residue to give the title product 2c (25mg, yellow oil). yield: 20%.

third step

1-isopropyl-2- (2-methoxy-benzyl) lH-indole-5-carboxylic acid 2d

The 2c (25mg, 0.085mmol) was dissolved in 6mL of methanol and tetrahydrofuran (V: V = 4: 2) mixed solvent was added 4M sodium hydroxide solution 2mL, stirred for 1 hour 60 ℃. The reaction was cooled to room temperature, was added dropwise concentrated hydrochloric acid to pH 4, extracted with ethyl acetate (20mL × 3), combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure , by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 2d (23mg, yellow solid), yield: 95%.

the fourth step

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2- (2-methoxy-benzyl) lH-indole-5-carboxamide 2

The 2d (23mg, 0.08mmol), (4- (ethylsulfonyl) phenyl) methanamine (24mg, 0.12mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide salt acid (21mg, 0.12mmol), 1- hydroxybenzotriazole (17mg, 0.12mmol), N, N- diisopropylethylamine (53mg, 0.41mmol) was dissolved in dichloromethane, and the reaction stirred for 12 hours . Water was added with dichloromethane and methanol (V: V = 8: 1) mixed solvent (20mL × 3), combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated and purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 2 (21mg, white solid), yield: 50%.

MS m / z (ESI): 505.4 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.03 (s, 1H), 7.87 (d, 2H), 7.62 (d, 1H), 7.53-7.57 (m, 3H), 7.23 (t, 1H), 6.91 ( t, 2H), 6.85 (t, 1H), 6.64 (t, 1H), 6.30 (s, 1H), 4.79 (d, 2H), 4.50-4.56 (m, 1H), 4.12 (s, 2H), 3.88 (s, 3H), 3.11 (q, 2H), 1.51 (d, 6H), 1.27 (t, 3H).

Example 3

1-ethyl -N- (4- (ethanesulfonyl) benzyl) -2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 3

Figure PCTCN2017077114-appb-000047

first step

2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxylic acid methyl ester 3b

The 1a (2.7g, 15.41mmol), 1- (bromomethyl) -2- (trifluoromethyl) benzene 3a (3.87g, 16.18mmol), bis acetonitrile palladium dichloride (399mg, 1.54mmol), drop norbornene (2.9g, 30.82mmol), sodium bicarbonate (2.59g, 30.82mmol) was dissolved in N, N- dimethylacetamide, the reaction was raised to 70 deg.] C was stirred for 12 hours. The reaction was cooled to room temperature, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 3b (4.4g, as a pale yellow solid), yield: 86%.

The second step

1-ethyl-2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxylate 3c

The 3b (4.4g, 13.2mmol) was dissolved in N, N- dimethylformamide was added sodium hydride (1.06g, 26.4mmol, 60% in oil) and iodoethane (10.29g, 66.01mmol), stirred 12 hours. The reaction solution was poured into water, and extracted with ethyl acetate (50mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography to The resulting residue was purified eluent was system B, to give the title product 3c (4.2g, as a pale yellow solid), yield: 88%.

third step

1-ethyl-2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxylic acid 3d

The 3c (1.4g, 3.87mmol) was dissolved in 15mL of methanol was added 2M potassium hydroxide solution 5mL, the reaction was warmed to reflux for 12 hours. The reaction was cooled to room temperature, was added dropwise concentrated hydrochloric acid to pH 4, extracted with ethyl acetate (50mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was and concentrated to give the crude title product 3d (1.1g, as a pale yellow solid), the product was used without purification in the next step.

the fourth step

1-ethyl -N- (4- (ethanesulfonyl) benzyl) -2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 3

The crude 3d (1.1g, 3.17mmol), 4- (ethylsulfonyl) phenyl) methanamine (757.31mg, 3.8mmol), 1- (3- dimethylaminopropyl) -3-ethyl carbodiimide amine hydrochloride (1.21g, 6.33mmol), 1- hydroxybenzotriazole (856g, 6.33mmol), triethylamine (641mg, 6.33mmol) was dissolved in dichloromethane, stirred for 12 hours. 60%: The reaction mixture was concentrated by silica gel column chromatography with eluent systems A resulting residue was purified by HPLC resulting crude title product 3 (1g, light gray white solid), yield of reduced pressure.

MS m / z (ESI): 529.9 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.11 (s, 1H), 7.91 (d, 2H), 7.72-7.77 (m, 2H), 7.61 (d, 2H), 7.37-7.49 (m, 3H), 7.16 (d, 1H), 6.67 (t, 1H), 6.34 (s, 1H), 4.83 (d, 2H), 4.37 (d, 2H), 4.05-4.10 (m, 2H), 3.14 (q, 2H) , 1.25-1.33 (m, 6H).

Example 4

N- (4- (ethanesulfonyl) benzyl) -2- (4-fluoro-2- (trifluoromethyl) benzyl) -1-isopropyl--1H- indole-5-carboxamide 4

Figure PCTCN2017077114-appb-000048

first step

2- (4-fluoro-2- (trifluoromethyl) benzyl) lH-indole-5-carboxylic acid methyl ester 4b

The 1a (200mg, 1.14mmol), 1- (bromomethyl) -4-fluoro-2- (trifluoromethyl) benzene 4a (308.1mg, 1.2mmol), acetonitrile palladium dichloride bis (29.6mg, 0.14 mmol), norbornene (215mg, 2.28mmol), sodium hydrogen carbonate (191.8mg, 2.28mmol) was dissolved in N, N- dimethylacetamide, the reaction was raised to 70 deg.] C was stirred for 12 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 4b (141mg, as a pale yellow solid), yield: 35%.

The second step

2- (4-fluoro-2- (trifluoromethyl) benzyl) -1H- indol-1-isopropyl-5-carboxylate 4c

The 4b (50mg, 0.142mmol) was dissolved in N, N- dimethylformamide was added sodium hydride (12mg, 0.285mmol, 60% in oil), 2- bromopropane (87.53mg, 0.711mmol), 50 ℃ The reaction was stirred for 12 hours. The reaction was cooled to room temperature, poured into water, extracted with ethyl acetate (50mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by silica gel column resulting in a chromatography system, eluent B residue, to give the title product 4c (34mg, pale yellow solid), yield: 61%.

third step

2- (4-fluoro-2- (trifluoromethyl) benzyl) -1-isopropyl-4d -1H- indole-5-carboxylic acid

The 4c ​​(34mg, 0.09mmol) was dissolved in 3mL of methanol was added 2M potassium hydroxide solution 1mL, the reaction was warmed to reflux for 12 hours. The reaction was cooled to room temperature, was added dropwise concentrated hydrochloric acid to pH 4, extracted with ethyl acetate (50mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was and concentrated to give the crude title product 4d (26mg, pale yellow solid), the product was used without purification in the next step.

the fourth step

N- (4- (ethanesulfonyl) benzyl) -2- (4-fluoro-2- (trifluoromethyl) benzyl) -1-isopropyl--1H- indole-5-carboxamide 4

The crude 4d (26mg, 0.068mmol), 4- (ethylsulfonyl) phenyl) methanamine (16.4mg, 0.082mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (26.28mg, 0.137mmol), 1- hydroxybenzotriazole (18.52mg, 0.137mmol), triethylamine (13.87mg, 0.137mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 4 (13mg, yellow solid), yield: 34%.

MS m / z (ESI): 561.3 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.10 (s, 1H), 7.91 (d, 2H), 7.69 (dd, 1H), 7.58-7.61 (m, 3H), 7.48 (dd, 1H), 7.16 ( dt, 1H), 7.08 (d, 1H), 6.67 (t, 1H), 6.34 (s, 1H), 4.83 (d, 2H), 4.40-4.47 (m, 1H), 4.33 (s, 2H), 3.14 (q, 2H), 1.53 (d, 6H), 1.31 (t, 3H).

Example 5

2- (4-chloro-2- (trifluoromethyl) benzyl) -N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-5-carboxamide -1H- indole-5

Figure PCTCN2017077114-appb-000049

first step

2- (4-chloro-2- (trifluoromethyl) benzyl) lH-indole-5-carboxylic acid methyl ester 5b

The 1a (200mg, 1.14mmol), 1- (bromomethyl) -4-chloro-2- (trifluoromethyl) benzene 5a (327.83mg, 1.2mmol), acetonitrile palladium dichloride bis (29.6mg, 0.14 mmol), norbornene (215mg, 2.28mmol), sodium hydrogen carbonate (191.8mg, 2.28mmol) was dissolved in N, N- dimethylacetamide, the reaction was raised to 70 deg.] C was stirred for 12 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems resulting residue was purified B to give the title product 5b (136mg, as a pale yellow solid), yield: 33%.

The second step

2- (4-chloro-2- (trifluoromethyl) benzyl) -1H- indol-1-isopropyl-5-carboxylate 5c

The 5b (50mg, 0.136mmol) was dissolved in N, N- dimethylformamide was added sodium hydride (11mg, 0.272mmol, 60% in oil), 2- bromopropane (84mg, 0.68mmol), stirred for 50 ℃ 12 hours. The reaction was cooled to room temperature, poured into water, extracted with ethyl acetate (50mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by silica gel column resulting in a chromatography system, eluent B residue, to give the title product 5c (38mg, pale yellow solid), yield: 68%.

third step

2- (4-chloro-2- (trifluoromethyl) benzyl) -1-isopropyl-5d -1H- indole-5-carboxylic acid

The 5c (28mg, 0.071mmol) was dissolved in 3mL of methanol was added 2M potassium hydroxide solution 1mL, the reaction was warmed to reflux for 12 hours. The reaction was cooled to room temperature, was added dropwise concentrated hydrochloric acid to pH 4, extracted with ethyl acetate (50mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was and concentrated to give the crude title product 5d (14mg, pale yellow solid), the product was used without purification in the next step.

the fourth step

2- (4-chloro-2- (trifluoromethyl) benzyl) -N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-5-carboxamide -1H- indole-5

The crude 5d (28mg, 0.07mmol), 4- (ethylsulfonyl) phenyl) methanamine (16.92mg, 0.085mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (27.12mg, 0.141mmol), 1- hydroxybenzotriazole (19.12mg, 0.101mmol), triethylamine (14.32mg, 0.141mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 5 (14mg, yellow solid), yield: 34%.

MS m / z (ESI): 577.4 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.08 (s, 1H), 7.81 (d, 2H), 7.65-7.71 (m, 2H), 7.53-7.56 (m, 3H), 7.39 (dd, 1H), 7.00 (d, 1H) ,, 6.78 (t, 1H), 6.30 (s, 1H), 4.78 (d, 2H), 4.35-4.42 (m, 1H), 4.29 (s, 2H), 3.10 (q, 2H ), 1.50 (d, 6H), 1.28 (t, 3H).

Example 6

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 6

Figure PCTCN2017077114-appb-000050

Figure PCTCN2017077114-appb-000051

first step

2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxylate 6a

The 1a (3g, 17.12mmol), 1- (bromomethyl) -2- (trifluoromethyl) benzene 3b (4.3g, 17.98mmol), bis acetonitrile palladium dichloride (444mg, 1.71mmol), norbornyl ene (3.22g, 34.25mmol), sodium bicarbonate (2.88g, 34.25mmol) was dissolved in N, N- dimethylacetamide, the reaction was raised to 70 deg.] C was stirred for 12 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 6a (4.6g, as a pale yellow solid), yield: 81%.

The second step

1-isopropyl-2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxylate 6b

The 6a (4.6g, 13.8mmol) was dissolved in 20mL N, N- dimethylformamide was added sodium hydride (1.1g, 27.6mmol, 60% in oil), 2- bromopropane (84mg, 0.68mmol), 50 ℃ reaction was stirred for 12 hours. The reaction was cooled to room temperature, poured into water, extracted with ethyl acetate (50mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by silica gel column resulting in a chromatography system, eluent B residue, to give the title product 6b (2.9g, as a pale yellow solid), yield: 75%.

third step

1-isopropyl-2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxylic acid 6c

The 6b (1.5g, 4mmol) was dissolved in 15mL of methanol was added 2M potassium hydroxide solution 5mL, warmed to reflux with stirring for 2 hours. The reaction was cooled to room temperature, was added dropwise concentrated hydrochloric acid to pH 4, extracted with ethyl acetate (50mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was and concentrated to give the crude title product 6c (1.33g, pale yellow solid), the product was used without purification in the next step.

the fourth step

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 6

The crude product 6c (1.33g, 3.68mmol), 4- (ethylsulfonyl) phenyl) methanamine (880.11mg, 0.42mmol), 1- (3- dimethylaminopropyl) -3-ethyl carbodiimide amine hydrochloride (1.41g, 7.36mmol), 1- hydroxybenzotriazole (994.66mg, 7.36mmol), triethylamine (744.87mg, 7.36mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was purified by HPLC to give the title product 6 (1.02g, white solid), yield: 51%.

MS m / z (ESI): 544.4 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.11 (s, 1H), 7.89 (d, 2H), 7.76 (d, 1H), 7.69 (dd, 1H), 7.59 (d, 2H), 7.38-7.46 ( m, 2H), 7.10 (d, 1H), 6.74 (t, 1H), 6.35 (s, 1H), 4.83 (d, 2H), 4.42-4.49 (m, 1H), 4.38 (s, 2H), 3.14 (q, 2H), 1.52 (d, 6H), 1.31 (t, 3H).

Example 7

N- (4 - ((cyclopropylmethyl) sulfonyl) benzyl) -1-isopropyl-2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 7

Figure PCTCN2017077114-appb-000052

first step

Sodium 4-cyano-benzene 7b

4-cyano-benzenesulfonyl chloride 7a (1.01g, 5mmol), sodium sulfite (1.26g, 10mmol), sodium bicarbonate (0.84g, 10mmol) was added to 20mL of water, stirred for 5 hours 75 ℃. The reaction was cooled to room temperature, concentrated under reduced pressure to give the crude title product 7b (946mg, white solid), the product was used without purification in the next step.

The second step

4 - ((cyclopropylmethyl) sulfonyl) benzonitrile 7c

The (946mg, 5mmol), (bromomethyl) cyclopropane (2.03g, 15mmol) and a catalytic amount of crude 7b of iodomethane was added to 30mL N, N- dimethylformamide was stirred for 12 hours 75 ℃. The reaction was cooled to room temperature, 100mL of water and extracted with ethyl acetate (50mL × 3), combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, purified by System B eluent by silica gel column chromatography The resulting residue was the title product 7c (670mg, white solid), yield: 61%.

third step

(4 - ((cyclopropylmethyl) sulfonyl) phenyl) methanamine 7d

The 7c (670mg, 3mmol) was dissolved in 30mL of methanol, 5mL was added aqueous ammonia, and then a catalytic amount of Raney nickel, purged with hydrogen three times and stirred for 12 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give the crude title product 7d (0.6g, as a pale yellow oil), the product was used without purification in the next step.

the fourth step

N- (4 - ((cyclopropylmethyl) sulfonyl) benzyl) -1-isopropyl-2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 7

The crude 7d (28.06mg, 0.12mmol), the crude product 6e (30mg, 0.083mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (32mg, 0.166mmol), 1-hydroxybenzotriazole (23mg, 0.166mmol), N, N- diisopropylethylamine (22mg, 0.166mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by thin layer chromatography to the resulting residue was purified by developing solvent system B to give the title product 7 (16mg, pale yellow solid), yield: 34%.

MS m / z (ESI): 569.2 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.13 (s, 1H), 7.89 (d, 2H), 7.76 (d, 1H), 7.71 (d, 1H), 7.57 (t, 3H), 7.38-7.47 ( m, 2H), 7.10 (d, 1H), 6.86 (t, 1H), 6.34 (s, 1H), 4.82 (d, 2H), 4.42-4.49 (m, 1H), 4.37 (s, 2H), 3.03 (d, 2H), 1.52 (d, 6H), 0.99-1.02 (m, 1H), 0.57-0.62 (m, 2H), 0.17-0.21 (m, 2H).

Example 8

N- (4- (ethylsulfonyl) -2-fluoro-benzyl) -1-isopropyl-2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 8

Figure PCTCN2017077114-appb-000053

Figure PCTCN2017077114-appb-000054

first step

4- (ethylsulfonyl) -2-fluoro-benzyl carbamate 8b

4-bromo-2-fluorobenzyl carbamate 8a (400mg, 1.32mmol, using patent application "EP991638" disclosed a process for preparing obtained), ethylimino sodium (229mg, 1.97mmol), carbonate cesium (642.7mg, 1.97mmol) was dissolved in dimethyl sulfoxide, was added a catalytic amount of cuprous iodide and L- proline, stirred for 1 hour was warmed to 120 ℃. The reaction was cooled to room temperature, adding an appropriate amount of ethyl acetate, filtered and the filtrate was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, purified by System B eluent by silica gel column chromatography The resulting residue was the title product 8b (340mg, as a pale yellow oil). yield: 82%.

The second step

(4- (ethylsulfonyl) -2-fluorophenyl) methanamine trifluoroacetate 8c

The 8b (340mg, 1.12mmol) was dissolved in 10mL of dichloromethane was added 2mL of trifluoroacetic acid, the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure to give the crude title product 8c (340mg, light brown solid), the product was used without purification in the next step.

third step

N- (4- (ethylsulfonyl) -2-fluoro-benzyl) -1-isopropyl-2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 8

The crude product 8c (21.64mg, 0.1mmol), 6e (30mg, 0.083mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (31.83mg, 0.166mmol), 1-hydroxybenzotriazole (22.44mg, 0.166mmol), N, N- diisopropylethylamine (21.46mg, 0.166mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 8 (10mg, yellow solid), yield: 21%.

MS m / z (ESI): 561.1 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.10 (s, 1H), 7.95 (s, 1H), 7.75-7.78 (m, 2H), 7.67-7.71 (m, 2H), 7.59 (d, 1H), 7.38-7.48 (m, 2H), 7.10 (d, 1H), 6.89 (t, 1H), 6.35 (s, 1H), 4.85 (d, 2H), 4.42-4.49 (m, 1H), 4.38 (s, 2H), 3.15 (q, 2H), 1.52 (d, 6H), 1.31 (t, 3H).

Example 9

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 9

Figure PCTCN2017077114-appb-000055

first step

1-cyclopropyl-2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxylate 9a

The 6c (100mg, 0.3mmol) was dissolved in 1,2-dichloroethane were added cyclopropyl boronic acid (39mg, 0.45mmol), copper acetate monohydrate (90mg, 0.45mmol), 2,2'- joint pyridine (70mg, 0.45mmol) and sodium carbonate (64mg, 0.6mmol), stirred the reaction temperature was raised to 70 deg.] C for 24 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, water was added to the resulting residue, and extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 9a (65mg, yellow solid), yield: 58%.

The second step

1-cyclopropyl-2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxylic acid 9b

The 9a (65mg, 0.17mmol) was dissolved in 7mL of methanol and tetrahydrofuran (V: V = 5: 2) mixed solvent was added 4M sodium hydroxide solution 2mL, warmed to 60 deg.] C was stirred for 1 hour. The reaction was cooled to room temperature, was added dropwise concentrated hydrochloric acid to pH 4, extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was and concentrated to give the title product 9b (55mg, white solid), the product was used without purification in the next step.

third step

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 9

The crude 9b (55mg, 0.15mmol), 4- (ethylsulfonyl) phenyl) methanamine (40mg, 0.2mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide salt acid (44mg, 0.23mmol), 1- hydroxybenzotriazole (31mg, 0.23mmol), N, N- diisopropylethylamine (59mg, 0.46mmol) was dissolved in dichloromethane, and the reaction stirred for 12 hours . Water was added and a small amount of methanol, dichloromethane and methanol (V: V = 8: 1) mixed solvent (20mL × 2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure and purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 9 (40mg, white solid), yield: 48%.

MS m / z (ESI): 541.4 [M + 1];

1 H NMR (400MHz, DMSO- d 6) δ9.03 (t, 1H), 8.06 (s, 1H), 7.83 (d, 2H), 7.79 (d, 1H), 7.72 (d, 1H), 7.63 ( t, 1H), 7.57 (d, 3H), 7.51 (t, 1H), 7.26 (d, 1H), 6.01 (s, 1H), 4.58 (d, 2H), 4.44 (s, 2H), 3.25 (q , 2H), 3.08-3.13 (m, 1H), 1.10-1.15 (m, 2H), 1.08 (t, 3H), 0.94-0.98 (m, 2H).

Example 10

2- (2- (ethylbenzyl) -N- (4- (ethanesulfonyl) benzyl) -1-isopropyl--1H- indole-5-carboxamide 10

Figure PCTCN2017077114-appb-000056

first step

2- (2- (ethyl-benzyl) lH-indole-5-carboxylic acid methyl ester 10b

The 1a (150mg, 0.856mmol), 1- (bromomethyl) -2-ethylbenzene 10a (179mg, 0.899mmol), palladium bis acetonitrile dichloride (22.2mg, 0.086mmol), norbornene (161.24mg , 1.71 mmol), sodium bicarbonate (143.86mg, 1.71mmol) was dissolved in N, N- dimethylacetamide, the reaction was raised to 70 deg.] C was stirred for 12 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 10b (68mg, pale yellow solid), yield: 27%.

The second step

2- (2- (ethyl-benzyl) -1-isopropyl--1H- indole-5-carboxylic acid methyl ester 10c

The 10b (67mg, 0.23mmol) was dissolved in 5mL N, N- dimethylformamide was added sodium hydride (18.27mg, 0.46mmol, 60% in oil), 2- bromopropane (140.45mg, 1.14mmol), 50 ℃ reaction was stirred for 12 hours. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by silica gel column resulting in a chromatography system, eluent B residue, to give the title product 10c (46mg, pale yellow solid), yield: 60%.

third step

2- (2- (ethyl-benzyl) -1-isopropyl--1H- indole-5-carboxylic acid 10d

The 10c (46mg, 0.137mmol) was dissolved in 5mL of methanol was added 2M potassium hydroxide solution 2mL, warmed to reflux with stirring for 3 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, water was added to the resulting residue, was added dropwise concentrated hydrochloric acid to pH 4-5, and extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride The solution was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 10d (42mg, pale yellow solid), the product was used without purification in the next step.

the fourth step

2- (2- (ethylbenzyl) -N- (4- (ethanesulfonyl) benzyl) -1-isopropyl--1H- indole-5-carboxamide 10

The crude 10d (42mg, 0.13mmol), (4- (ethylsulfonyl) phenyl) methanamine (31.25mg, 0.16mmol), 1- (3- dimethylaminopropyl) -3-ethyl carbodiimide amine hydrochloride (50.01mg, 0.26mmol), 1- hydroxybenzotriazole (35.31mg, 0.26mmol), triethylamine (26.45mg, 0.26mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 10 (16mg, pale yellow solid), yield: 24%.

MS m / z (ESI): 503.5 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.04 (s, 1H), 7.91 (d, 2H), 7.67 (d, 1H), 7.58-7.61 (m, 3H), 7.27-7.31 (m, 2H), 7.16 (t, 1H), 6.99 (d, 1H), 6.62 (t, 1H), 6.18 (s, 1H), 4.83 (d, 2H), 4.54-4.61 (m, 1H), 4.16 (s, 2H) , 3.14 (q, 2H), 2.74 (q, 2H), 1.60 (d, 6H), 1.25-1.31 (m, 6H).

Example 11

N - ((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1-isopropyl-2- (2- (trifluoromethyl) benzyl) lH-indole-5- amide 11

Figure PCTCN2017077114-appb-000057

Figure PCTCN2017077114-appb-000058

The crude 6e (42mg, 0.11mmol), 5- (ethylsulfonyl) pyridin-2-yl) methanamine 11a (26.47mg, 0.13mmol, using patent application "WO201517335" preparation obtained by the method disclosed), 1- ( 3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (42.45mg, 0.22mmol), 1- hydroxybenzotriazole (29.92mg, 0.22mmol), triethylamine (22.41mg, 0.22 mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 11 (16mg, pale yellow solid), yield: 25.8%.

MS m / z (ESI): 544.4 [M + 1].

Example 12

2- (4-chloro-2- (trifluoromethyl) benzyl) -l-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) lH-indole-5-carboxamide 12

Figure PCTCN2017077114-appb-000059

first step

2- (4-chloro-2- (trifluoromethyl) benzyl) -1H- indol-1-cyclopropyl-5-carboxylate 12a

The 5c (150mg, 0.408mmol) was dissolved in 1,2-dichloroethane were added cyclopropyl boronic acid (180mg, 2.04mmol), copper acetate (14.9mg, 0.08mmol), 2,2'- bipyridine (318.5mg, 2.04mmol) and sodium carbonate (86.5mg, 0.816mmol), the reaction temperature was raised to 70 deg.] C for 12 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, the resulting residue was added ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography and the obtained residue was purified B eluent system, to give the title product 12a (21mg, pale yellow oil). yield: 13%.

The second step

2- (4-chloro-2- (trifluoromethyl) benzyl) -1H- indol-1-cyclopropyl-5-carboxylic acid 12b

The 12a (21mg, 0.05mmol) was dissolved in 2mL of methanol, 2mL was added 2M potassium hydroxide solution, the reaction was warmed to reflux with stirring for 3 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, water was added to the resulting residue, was added dropwise concentrated hydrochloric acid to pH 5-6, and extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride The solution was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 12b (16mg, pale yellow oil), the product was used without purification in the next step.

third step

2- (4-chloro-2- (trifluoromethyl) benzyl) -l-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) lH-indole-5-carboxamide 12

The crude 12b (16mg, 0.04mmol), (4- (ethylsulfonyl) phenyl) methanamine (12.2mg, 0.06mmol), 1- (3- dimethylaminopropyl) -3-ethyl carbodiimide amine hydrochloride (15.6mg, 0.08mmol), 1- hydroxybenzotriazole (11mg, 0.08mmol), triethylamine (9mg, 0.08mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 12 (13mg, yellow solid), yield: 56%.

MS m / z (ESI): 575.4 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.02 (s, 1H), 7.87 (d, 2H), 7.68-7.71 (m, 2H), 7.56-7.61 (m, 3H), 7.41 (dd, 1H), 7.02 (d, 1H), 6.62 (t, 1H), 6.20 (s, 1H), 4.79 (d, 2H), 4.42 (s, 2H), 3.10 (q, 2H), 2.96-3.00 (m, 1H) , 1.28 (t, 3H), 1.10-1.14 (m, 2H), 1.97-1.01 (m, 2H).

Example 13

2- (4-fluoro-2- (trifluoromethyl) benzyl) -l-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) lH-indole-5-carboxamide 13

Figure PCTCN2017077114-appb-000060

Figure PCTCN2017077114-appb-000061

first step

2- (4-fluoro-2- (trifluoromethyl) benzyl) -1H- indol-1-cyclopropyl-5-carboxylate 13a

The 4c ​​(100mg, 0.285mmol) was dissolved in 1,2-dichloroethane were added cyclopropyl boronic acid (125.4mg, 1.42mmol), copper acetate (103.4mg, 0.569mmol), 2,2'- joint pyridine (222.3mg, 1.42mmol) and sodium carbonate (60.4mg, 0.569mmol), was heated to 80 deg.] C was stirred for 12 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, ethyl acetate was added to the resulting residue, filtered and the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 13a (71mg, pale yellow oil). yield: 64%.

The second step

2- (4-fluoro-2- (trifluoromethyl) benzyl) -1H- indol-1-cyclopropyl-5-carboxylic acid 13b

The 13a (71mg, 0.174mmol) was dissolved in 3mL of methanol was added 2M potassium hydroxide solution 3mL, warmed to reflux with stirring for 3 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, water was added to the resulting residue, was added dropwise concentrated hydrochloric acid to pH 5-6, and extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride The solution was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 13b (56mg, pale yellow oil), the product was used without purification in the next step.

third step

2- (4-fluoro-2- (trifluoromethyl) benzyl) -l-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) lH-indole-5-carboxamide 13

The crude 13b (56mg, 0.148mmol), (4- (ethylsulfonyl) phenyl) methanamine (44.36mg, 0.222mmol), 1- (3- dimethylaminopropyl) -3-ethyl carbodiimide amine hydrochloride (56.9mg, 0.297mmol), 1- hydroxybenzotriazole (40.11mg, 0.297mmol), triethylamine (30mg, 0.297mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 13 (36mg, white solid), yield: 43%.

MS m / z (ESI): 557.1 [M-1];

1 H NMR (400MHz, CDCl 3 ) δ8.05 (s, 1H), 7.91 (d, 2H), 7.72 (dd, 1H), 7.59-7.65 (m, 3H), 7.48 (dd, 1H), 7.18 ( dt, 1H), 6.64 (t, 1H), 6.21 (s, 1H), 4.82 (d, 2H), 4.45 (s, 2H), 3.14 (q, 2H), 3.00-3.06 (m, 1H), 1.32 (t, 3H), 1.14-1.19 (m, 2H), 1.02-1.05 (m, 2H).

Example 14

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 14

Figure PCTCN2017077114-appb-000062

first step

2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxylic acid methyl ester 14b

The 1a (200mg, 1.14mmol), 1- (bromomethyl) -4-trifluoromethyl) benzene 14a (286mg, 1.97mmol), bis acetonitrile palladium dichloride (16mg, 0.057mmol), norbornene ( 214mg, 2.28mmol), sodium bicarbonate (144mg, 1.71mmol) was dissolved in N, N- dimethylacetamide, the reaction was raised to 70 deg.] C was stirred for 12 hours. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography to B the resulting residue was purified eluent system to give the title product 14b (94mg, pale yellow oil). yield: 25%.

The second step

2- (4- (trifluoromethyl) benzyl) -1-isopropyl--1H- indole-5-carboxylic acid methyl ester 14c

The 14b (94mg, 0.28mmol) was dissolved in 3mL N, N- dimethylformamide was added sodium hydride (27mg, 0.56mmol, 60% in oil), 2- bromopropane (70mg, 0.56mmol), 80 ℃ The reaction was stirred for 12 hours. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title The product 14c (67mg, pale yellow solid), the product was used without purification in the next step.

third step

2- (4- (trifluoromethyl) benzyl) -1-isopropyl--1H- indole-5-carboxylic acid 14d

The crude 14c (67mg, 0.18mmol) was dissolved in 3mL of methanol was added 2M potassium hydroxide solution 1mL, warmed to reflux with stirring for 3 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, water was added to the residue, concentrated hydrochloric acid was added dropwise to pH 5-6, and extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride solution , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 14d (54mg, colorless oil), the product was used without purification in the next step.

the fourth step

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 14

The crude 14d (54mg, 0.15mmol), (4- (ethylsulfonyl) phenyl) methanamine (36mg, 0.18mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (57mg, 0.3mmol), 1- hydroxybenzotriazole (39mg, 0.3mmol), triethylamine (33mg, 0.3mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 14 (23.7mg, white solid), yield: 29%.

MS m / z (ESI): 543.9 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.08 (s, 1H), 7.84 (d, 2H), 7.65 (d, 1H), 7.52-7.58 (m, 5H), 7.30 (d, 2H), 6.74 ( t, 1H), 6.34 (s, 1H), 4.78 (d, 2H), 4.47-4.50 (m, 1H), 4.22 (s, 2H), 3.10 (q, 2H), 1.47 (d, 6H), 1.27 (t, 3H).

Example 15

N- (4- (ethanesulfonyl) benzyl) -2- (2-fluoro-4- (trifluoromethyl) benzyl) -1-isopropyl--1H- indole-5-carboxamide 15

Figure PCTCN2017077114-appb-000063

first step

2- (2-fluoro-4- (trifluoromethyl) benzyl) lH-indole-5-carboxylic acid methyl ester 15b

The 1a (200mg, 1.14mmol), 1- (bromomethyl) -2-fluoro-4-trifluoromethyl) benzene 15a (322.8mg, 1.26mmol), bis acetonitrile palladium dichloride (13mg, 0.057mmol) , norbornene (12mg, 0.114mmol), sodium bicarbonate (144mg, 1.71mmol) was dissolved in N, N- dimethylacetamide, the reaction was raised to 70 deg.] C was stirred for 12 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 15b (104mg, as a pale yellow oil). Yield: 25%.

The second step

2- (2-fluoro-4- (trifluoromethyl) benzyl) -1-isopropyl--1H- indole-5-carboxylic acid methyl ester 15c

The 15b (131mg, 0.37mmol) was dissolved in N, N- dimethylformamide was added sodium hydride (30mg, 0.75mmol, 60% in oil), 2- bromopropane (92mg, 0.75mmol), stirred for 50 ℃ 12 hours. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by silica gel column resulting in a chromatography system, eluent B residue, to give the title product 15c (72mg, colorless oil). yield: 49%.

third step

2- (2-fluoro-4- (trifluoromethyl) benzyl) -1-isopropyl--1H- indole-5-carboxylic acid 15d

The 15c (72mg, 0.183mmol) was dissolved in 3mL of methanol was added 2M potassium hydroxide solution 1mL, stirring the reaction was warmed to 70 ℃ 3 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, water was added to the residue, concentrated hydrochloric acid was added dropwise to pH 5-6, and extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride solution , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 15d (47mg, colorless oil), the product was used without purification in the next step.

the fourth step

N- (4- (ethanesulfonyl) benzyl) -2- (2-fluoro-4- (trifluoromethyl) benzyl) -1-isopropyl--1H- indole-5-carboxamide 15

The crude 15d (47mg, 0.12mmol), (4- (ethylsulfonyl) phenyl) methanamine (30mg, 0.15mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (48mg, 0.25mmol), 1- hydroxybenzotriazole (34mg, 0.25mmol), triethylamine (26mg, 0.25mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, purified by thin layer chromatography to the resulting residue was purified by developing solvent system B to give the title product 15 (3.1mg, white solid). Yield: 5%.

MS m / z (ESI): 561.5 [M + 1];

1 HNMR (400MHz, CDCl 3) δ8.10 (s, 1H), 7.90 (d, 2H), 7.69 (d, 1H), 7.57-7.61 (m, 3H), 7.42 (d, 1H), 7.37 (d , 1H), 7.20 (t, 1H), 6.69 (t, 1H), 6.36 (s, 1H), 4.82 (d, 2H), 4.50-4.57 (m, 1H), 4.25 (s, 2H), 3.14 ( q, 2H), 1.57 (d, 6H), 1.31 (t, 3H).

Example 16

2- (2-chloro-4- (trifluoromethyl) benzyl) -N- (4- (ethanesulfonyl) benzyl) -1-isopropyl--1H- indole-5-carboxamide 16

Figure PCTCN2017077114-appb-000064

first step

2- (2-chloro-4- (trifluoromethyl) benzyl) lH-indole-5-carboxylic acid methyl ester 16b

The 1a (200mg, 1.14mmol), 1- (bromomethyl) -2-chloro-4-trifluoromethyl) benzene 16a (328mg, 1.2mmol), palladium bis acetonitrile dichloride (28mg, 0.11mmol), norbornene (215mg, 2.28mmol), sodium bicarbonate (144mg, 1.71mmol) was dissolved in N, N- dimethylacetamide, the reaction was raised to 70 deg.] C was stirred for 12 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 16b (89mg, pale yellow oil). Yield: 22%.

The second step

2- (2-chloro-4- (trifluoromethyl) benzyl) -1-isopropyl--1H- indole-5-carboxylic acid methyl ester 16c

The 16b (89mg, 0.24mmol) was dissolved in N, N- dimethylformamide was added sodium hydride (20mg, 0.48mmol, 60% in oil), 2- bromopropane (60mg, 0.48mmol), stirred for 50 ℃ 12 hours. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 16c (41mg, colorless oil), the product was used without purification in the next step.

third step

2- (2-chloro-4- (trifluoromethyl) benzyl) -1-isopropyl--1H- indole-5-carboxylic acid 16d

The crude 16c (41mg, 0.1mmol) was dissolved in 3mL of methanol was added 2M potassium hydroxide solution 1mL, stirred for 12 hours 70 ℃. The reaction was cooled to room temperature and concentrated under reduced pressure, water was added to the residue, concentrated hydrochloric acid was added dropwise to pH 5-6, and extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride solution , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 16d (34mg, colorless oil), the product was used without purification in the next step.

the fourth step

2- (2-chloro-4- (trifluoromethyl) benzyl) -N- (4- (ethanesulfonyl) benzyl) -1-isopropyl--1H- indole-5-carboxamide 16

The crude 16d (34mg, 0.086mmol), (4- (ethylsulfonyl) phenyl) methanamine (26mg, 0.13mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (33mg, 0.17mmol), 1- hydroxybenzotriazole (23mg, 0.17mmol), triethylamine (17.4mg, 0.17mmol) was dissolved in dichloromethane, stirred for 12 hours. It was concentrated under reduced pressure and purified by thin layer chromatography and the obtained residue was purified by developing solvent system B to give the title product 16 (6.5mg, white solid), yield: 13%.

MS m / z (ESI): 576.9 [M-1].

Example 17

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2- (3- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 17

Figure PCTCN2017077114-appb-000065

first step

2- (3- (trifluoromethyl) benzyl) lH-indole-5-carboxylic acid methyl ester 17b

The 1a (200mg, 1.13mmol), 1- (bromomethyl) -3-trifluoromethyl) benzene 17a (286mg, 1.2mmol), palladium bis acetonitrile dichloride (16mg, 0.06mmol), norbornene ( 218mg, 2.3mmol), sodium bicarbonate (134mg, 1.71mmol) was dissolved in N, N- dimethylacetamide, the reaction was raised to 70 deg.] C was stirred for 12 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 17b (134mg, as a pale yellow solid), yield: 32%.

The second step

2- (3- (trifluoromethyl) benzyl) -1-isopropyl--1H- indole-5-carboxylic acid 17c

The 17b (134mg, 0.4mmol) was dissolved in N, N- dimethylformamide was added sodium hydride (32mg, 0.8mmol, 60% in oil), 2- bromopropane (99mg, 0.8mmol), stirred for 70 ℃ 12 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 17c (108mg, as a pale yellow solid), yield: 72%.

third step

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2- (3- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 17

The 17c (30mg, 0.08mmol), (4- (ethylsulfonyl) phenyl) methanamine (20mg, 0.1mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide salt acid (33mg, 0.17mmol), 1- hydroxybenzotriazole (23mg, 0.17mmol), triethylamine (17mg, 0.17mmol) was dissolved in dichloromethane, stirred for 12 hours. 24%: by thin layer chromatography was concentrated and the obtained residue was purified by developing solvent system B to give the title product 17 (11mg, white solid), yield of reduced pressure.

MS m / z (ESI): 543.5 [M + 1];

1 HNMR (400MHz, CDCl 3) δ8.08 (s, 1H), 7.85 (d, 2H), 7.65 (d, 1H), 7.50-7.57 (m, 3H), 7.41-7.47 (m, 2H), 7.36 (d, 1H), 6.75 (t, 1H), 6.33 (s, 1H), 4.78 (d, 2H), 4.45-4.53 (m, 1H), 4.22 (s, 2H), 4.10-4.16 (m, 1H ), 3.10 (q, 2H), 1.47 (d, 6H), 1.27 (t, 3H).

Example 18

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2- (4- (trifluoromethoxy) benzyl) lH-indole-5-carboxamide 18

Figure PCTCN2017077114-appb-000066

first step

2- (4- (trifluoromethoxy) benzyl) lH-indole-5-carboxylic acid methyl ester 18b

The 1a (500mg, 2.85mmol), 1- (bromomethyl) -4-trifluoromethyl-methoxybenzene 18a (716mg, 3mmol), bis acetonitrile palladium dichloride (39mg, 0.14mmol), norbornene (534 mg , 5.7 mmol), sodium bicarbonate (360 mg, 4.28mmol) was dissolved in N, N- dimethylacetamide, the reaction was raised to 70 deg.] C was stirred for 12 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 18b (520mg, as a pale yellow solid), yield: 55%.

The second step

1-isopropyl-2- (4- (trifluoromethoxy) benzyl) lH-indole-5-carboxylic acid 18c

The 18b (200mg, 0.573mmol) was dissolved in N, N- dimethylformamide was added sodium hydride (46mg, 0.15mmol, 60% in oil), 2- bromopropane (140.84mg, 1.15mmol), 70 ℃ reaction was stirred for 12 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 18c (92mg, pale yellow oil). Yield: 41%.

third step

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2- (4- (trifluoromethoxy) benzyl) lH-indole-5-carboxamide 18

The 18c (30mg, 0.08mmol), (4- (ethylsulfonyl) phenyl) methanamine (20mg, 0.1mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide salt acid (31mg, 0.16mmol), 1- hydroxybenzotriazole (21mg, 0.16mmol), triethylamine (17mg, 0.16mmol) was dissolved in dichloromethane, stirred for 12 hours. 29%: by thin layer chromatography was concentrated and the obtained residue was purified by developing solvent system B to give the title product 18 (13mg, white solid), yield of reduced pressure.

MS m / z (ESI): 559.5 [M + 1];

1 HNMR (400MHz, CDCl 3) δ8.08 (s, 1H), 7.85 (d, 2H), 7.65 (d, 1H), 7.50-7.57 (m, 3H), 7.41-7.47 (m, 2H), 7.36 (d, 1H), 6.75 (t, 1H), 6.33 (s, 1H), 4.78 (d, 2H), 4.45-4.53 (m, 1H), 4.22 (s, 2H), 4.10-4.16 (m, 1H ), 3.10 (q, 2H), 1.47 (d, 6H), 1.27 (t, 3H).

Example 19

1-ethyl -N- (4- (ethanesulfonyl) benzyl) -2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 19

Figure PCTCN2017077114-appb-000067

Figure PCTCN2017077114-appb-000068

first step

2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxylate 19a

The 1a (1g, 5.71mmol), 14b (1.43g, 5.99mmol), bis acetonitrile palladium dichloride (150mg, 0.571mmol), norbornene (1.1g, 11.42mmol), sodium bicarbonate (0.63g, 7.42 mmol) was dissolved in N, N- dimethylacetamide, the reaction was raised to 70 deg.] C was stirred for 16 h. The reaction was cooled to room temperature, 100mL of water and extracted with ethyl acetate (100mL × 3), combined organic phases were washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure ,, to give crude title product 19a (1.5g, yellow solid), the product was used without purification in the next step.

The second step

1-ethyl-2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxylic acid methyl ester 19b

The crude 19a (0.2g, 0.6mmol) was dissolved in 5mL N, N- dimethylformamide was added sodium hydride (48mg, 1.2mmol, 60% in oil), the reaction stirred for 1 hour at 0 deg.] C, was added ethyl iodide alkyl (0.19g, 1.2mmol), warmed to 50 deg.] C was stirred for 15 hours. The reaction was cooled to room temperature, was added 50mL of water and extracted with ethyl acetate (30mL × 3), combined organic phases were washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, to give The crude title product 19b (63mg, yellow solid), the product was used without purification in the next step.

third step

1-ethyl-2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxylic acid 19c

The crude 19b (63mg, 0.74mmol) was dissolved in 11mL of methanol and water (V: V = 10: 1) mixed solvent, was added sodium hydroxide (35mg, 0.872mmol), 60 deg.] C the reaction stirred for 16 hours. The reaction was cooled to room temperature, 2M hydrochloric acid added dropwise to pH 3-4, and concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent A purification system residues to give 19c (40g, white solid), yield of the title product: 67%.

the fourth step

1-ethyl -N- (4- (ethanesulfonyl) benzyl) -2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 19

The 19c (10mg, 0.029mmol), (4- (ethylsulfonyl) phenyl) methanamine (11.6mg, 0.058mmol), 2- (7- benzotriazole azo) -N, N, N ' , N'- tetramethyluronium hexafluorophosphate (16mg, 0.044mmol), N, N- diisopropylethylamine (18.7mg, 0.044mmol) was dissolved in 5mL N, N- dimethyl formamide, The reaction was stirred for 16 hours. To the reaction solution were added 50mL of water and extracted with dichloromethane (30mL × 3), combined organic phases were washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, by thin layer chromatography method B in the resulting residue was purified by developing solvent system, to give the title product (8mg, white solid), yield 19: 40%.

MS m / z (ESI): 529.5 [M + 1];

1 HNMR (400MHz, CDCl 3) δ8.07 (s, 1H), 7.88 (d, 2H), 7.69 (dd, 1H), 7.56-7.60 (m, 4H), 7.32-7.35 (m, 3H), 6.64 (t, 1H), 6.34 (s, 1H), 4.80 (d, 2H), 4.21 (s, 2H), 4.08 (q, 2H), 3.11 (q, 2H), 1.29 (t, 3H), 1.21 ( t, 3H).

Example 20

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 20

Figure PCTCN2017077114-appb-000069

first step

1-cyclopropyl-2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxylate 20a

The 19c (75mg, 0.22mmol) was dissolved in 1,2-dichloroethane were added cyclopropyl boronic acid (39mg, 0.45mmol), copper acetate monohydrate (45mg, 0.22mmol), 2,2'- joint pyridine (35mg, 0.22mmol) and sodium carbonate (36mg, 0.34mmol), warmed to 70 deg.] C was stirred for 24 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, the resulting residue was added water and extracted with ethyl acetate (30mL × 3), combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate 71%: by thin layer chromatography was concentrated and the obtained residue was purified by developing solvent system B to give the title product 20a (60mg, yellow solid), yield of reduced pressure.

The second step

1-cyclopropyl-2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxylic acid 20b

The 20a (80mg, 0.21mmol) was dissolved in 8mL methanol and tetrahydrofuran (V: V = 1: 1) mixed solvent was added 4M sodium hydroxide solution 2mL, 60 deg.] C the reaction was stirred for 2 hours. The reaction was cooled to room temperature, concentrated hydrochloric acid was added dropwise to pH 5-6, and extracted with ethyl acetate (20mL × 3), combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate reduced pressure and concentrated to give the crude title product 20b (60mg, as a pale yellow solid oil), the product was used without purification in the next step.

third step

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 20

The crude 20b (60mg, 0.17mmol), (4- (ethylsulfonyl) phenyl) methanamine (50mg, 0.25mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (48mg, 0.25mmol), 1- hydroxybenzotriazole (34mg, 0.25mmol), N, N- diisopropylethylamine (65mg, 0.50mmol) was dissolved in dichloromethane, and stirred for 12 hour. Water was added with dichloromethane and methanol (V: V = 8: 1) mixed solvent (20mL × 3), combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated and purified by thin-layer chromatography A purification to the resulting residue was developing solvent system, to give the title product 20 (20mg, white solid), yield: 21%.

MS m / z (ESI): 541.4 [M + 1];

1 H NMR (400MHz, DMSO- d 6) δ9.03 (t, 1H), 8.09 (s, 1H), 7.84 (d, 2H), 7.70 (d, 3H), 7.58 (t, 2.5H), 7.52 (t, 2.5H), 6.24 (s, 1H), 4.58 (d, 2H), 4.37 (s, 2H), 3.25 (q, 2H), 2.94-2.99 (m, 1H), 1.12-1.17 (m, 2H), 1.08 (t, 3H), 0.97-1.01 (m, 2H).

Example 21

N- (4- (ethanesulfonyl) benzyl) -1-methyl-2- (4- (trifluoromethoxy) benzyl) lH-indole-5-carboxamide 21

Figure PCTCN2017077114-appb-000070

first step

2- (4- (trifluoromethoxy) benzyl) -1-methyl -1H- indol-5-carboxylate 21a

The 18c (50mg, 0.14mmol) was dissolved in 5mL of tetrahydrofuran was added sodium hydride (12mg, 0.28 mmol, 60% in oil), the reaction stirred for 5 minutes, iodomethane (30.5mg, 0.21mmol), the reaction was stirred for 30 minutes. The reaction mixture was added water and extracted with ethyl acetate (30mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 21a (28mg, pale yellow oil), the product was used without purification in the next step.

The second step

1-methyl-2- (4- (trifluoromethoxy) benzyl) lH-indole-5-carboxylic acid 21b

The crude 21a (28mg, 0.07mmol) was dissolved in 3mL of methanol was added 2M potassium hydroxide solution 1mL, stirred for 2 hours 70 ℃. The reaction was cooled to room temperature and concentrated under reduced pressure, water was added to the resulting residue, and extracted with ethyl acetate (30mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure to give the crude title product 21b (22mg, pale yellow oil), the product was used without purification in the next step.

third step

N- (4- (ethanesulfonyl) benzyl) -1-methyl-2- (4- (trifluoromethoxy) benzyl) lH-indole-5-carboxamide 21

The crude 21b (22mg, 0.063mmol), (4- (ethylsulfonyl) phenyl) methanamine (25.1mg, 0.126mmol), 1- (3- dimethylaminopropyl) -3-ethyl carbodiimide amine hydrochloride (24mg, 0.126mmol), 1- hydroxybenzotriazole (17mg, 0.126mmol), triethylamine (13mg, 0.126mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 21 (12mg, pale yellow solid), yield: 36%.

MS m / z (ESI): 530.9 [M + 1];

1 HNMR (400MHz, CDCl 3) δ8.07 (s, 1H), 7.85 (d, 2H), 7.69 (d, 1H), 7.55 (d, 2H), 7.30 (d, 1H), 7.16-7.23 (m , 4H), 6.72 (t, 1H), 6.35 (s, 1H), 4.78 (d, 2H), 4.16 (s, 2H), 3.60 (s, 3H), 3.10 (q, 2H), 1.27 (t, 3H).

Example 22

1-ethyl -N- (4- (ethanesulfonyl) benzyl) -2- (2-fluoro-4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 22

Figure PCTCN2017077114-appb-000071

Figure PCTCN2017077114-appb-000072

first step

1-ethyl-2- (2-fluoro-4- (trifluoromethyl) benzyl) lH-indole-5-carboxylate 22a

The 15c (50mg, 0.14mmol) was dissolved in 5mL of tetrahydrofuran was added sodium hydride (12mg, 0.28mmol, 60% in oil), iodoethane (33.3mg, 0.21mmol), stirred for 2 hours 50 ℃. The reaction was cooled to room temperature, concentrated under reduced pressure to give the crude title product 22a (28mg, pale yellow oil), the product was used without purification in the next step.

The second step

1-ethyl-2- (2-fluoro-4- (trifluoromethyl) benzyl) lH-indole-5-carboxylic acid 22b

The crude 22a (28mg, 0.07mmol) was dissolved in 3mL of methanol was added 2M potassium hydroxide solution 1mL, heated to reflux and stirred for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, water was added to the residue, concentrated hydrochloric acid was added dropwise to pH 5-6, and extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride solution , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 22b (24mg, pale yellow oil), the product was used without purification in the next step.

third step

1-ethyl -N- (4- (ethanesulfonyl) benzyl) -2- (2-fluoro-4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 22

The crude 22b (24mg, 0.066mmol), (4- (ethylsulfonyl) phenyl) methanamine (26.2mg, 0.131mmol), 1- (3- dimethylaminopropyl) -3-ethyl carbodiimide amine hydrochloride (26mg, 0.131mmol), 1- hydroxybenzotriazole (18mg, 0.131mmol), triethylamine (13.3mg, 0.131mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 22 (7mg, pale yellow solid), yield: 21%.

MS m / z (ESI): 547.9 [M + 1].

Example 23

1-ethyl -N- (4- (ethanesulfonyl) benzyl) -2- (4- (trifluoromethoxy) benzyl) lH-indole-5-carboxamide 23

Figure PCTCN2017077114-appb-000073

first step

1-ethyl-2- (4- (trifluoromethoxy) benzyl) lH-indole-5-carboxylate 23a

The 18c (50mg, 0.14mmol) was dissolved in 5mL of tetrahydrofuran was added sodium hydride (12mg, 0.28mmol, 60% in oil), iodoethane (33.5mg, 0.21mmol), stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude title product 23a (29mg, pale yellow oil), the product was used without purification in the next step.

The second step

1-ethyl-2- (4- (trifluoromethoxy) benzyl) lH-indole-5-carboxylic acid 23b

The crude 23a (26mg, 0.07mmol) was dissolved in 3mL of methanol was added 2M potassium hydroxide solution 1mL, heated to reflux and stirred for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, water was added to the resulting residue, and extracted with ethyl acetate (30mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure to give the crude title product 23b (21mg, pale yellow oil), the product was used without purification in the next step.

third step

1-ethyl -N- (4- (ethanesulfonyl) benzyl) -2- (4- (trifluoromethoxy) benzyl) lH-indole-5-carboxamide 23

The crude 23b (21mg, 0.057mmol), (4- (ethylsulfonyl) phenyl) methanamine (23mg, 0.115mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (22mg, 0.115mmol), 1- hydroxybenzotriazole (15mg, 0.115mmol), triethylamine (12mg, 0.115mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 23 (8mg, pale yellow solid), yield: 25%.

MS m / z (ESI): 545.9 [M + 1].

Example 24

N- (4- (ethanesulfonyl) benzyl) -1- (2-hydroxyethyl) -2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 24

Figure PCTCN2017077114-appb-000074

first step

1- (2 - ((tert-butyldimethylsilyl) oxy) ethyl) -2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxylate 24a

The 14c (60mg, 0.18mmol), cesium carbonate (117mg, 0.36mmol), (2- bromoethoxy) - tert-butyl-dimethylsilane (86mg, 0.36mmol) and a catalytic amount of potassium iodide were dissolved in 3mL N, N- dimethyl formamide, 80 ℃ microwave for 1 hour. The reaction was cooled to room temperature, was added 60mL of ethyl acetate, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, by thin layer chromatography in a developing solvent system, the resulting residue was purified B, to give title product 24a (38mg, viscous substance), yield: 43%.

The second step

1- (2-hydroxyethyl) -2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxylic acid 24b

The 24a (38mg, 0.077mmol) was dissolved in 6mL of methanol was added 1.1 mL of 2M sodium hydroxide solution, stirred for 12 hours 65 ℃. The reaction was cooled to room temperature, concentrated under reduced pressure to remove most of the solvent was added 5mL of tetrahydrofuran was added dropwise to 1M hydrochloric acid at 0 ℃ pH 4, concentrated under reduced pressure to give the crude title product 24b (14mg, pink solid), the product was used without purification the next step reaction.

third step

N- (4- (ethanesulfonyl) benzyl) -1- (2-hydroxyethyl) -2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 24

The crude 24b (14mg, 0.038mmol), (4- (ethylsulfonyl) phenyl) methanamine (10mg, 0.046mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11mg, 0.057mmol), 1- hydroxybenzotriazole (8mg, 0.057mmol), triethylamine (19mg, 0.19mmol) was dissolved in dichloromethane, stirred for 12 hours. Was added 40mL of ethyl acetate, washed with water (20mL), saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by thin layer chromatography using a developing solvent system, the resulting residue was purified B, to give title product 24 (9mg, white solid), yield: 43%.

MS m / z (ESI): 545.5 [M + 1];

1 HNMR (400MHz, CDCl 3) δ8.05 (s, 1H), 7.88-7.83 (m, 2H), 7.65 (d, 1H), 7.50-7.53 (m, 4H), 7.32-7.34 (m, 3H) , 6.74 (brs, 1H), 6.30 (s, 1H), 4.77 (d, 2H), 4.29 (s, 2H), 4.19 (t, 2H), 3.92 (s, 2H), 3.85 (t, 2H), 3.10 (q, 2H), 1.27 (t, 3H).

Example 25

1-ethyl -N- (4- (ethanesulfonyl) benzyl) -2 - ((6- (trifluoromethyl) pyridin-3-yl) methyl) lH-indole-5-carboxamide 25

Figure PCTCN2017077114-appb-000075

first step

2 - ((6- (trifluoromethyl) pyridin-3-yl) methyl) lH-indole-5-carboxylic acid methyl ester 25b

The 1a (300mg, 1.71mmol), 5- (bromomethyl) -2- (trifluoromethyl) pyridine 25a (431.58mg, 1.8mmol), acetonitrile palladium dichloride bis (44.43mg, 0.17mmol), drop norbornene (322.48mg, 3.42mmol), sodium bicarbonate (281.71mg, 3.42mmol) was dissolved in N, N- dimethylacetamide, the reaction was raised to 70 deg.] C was stirred for 12 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 25b (480mg, as a pale yellow solid), yield: 84%.

The second step

1-ethyl-2 - ((6- (trifluoromethyl) pyridin-3-yl) methyl) lH-indole-5-carboxylic acid methyl ester 25c

The 25b (50mg, 2.149mmol) was dissolved in 5mL of acetonitrile was added iodoethane (116.64mg, 0.748mmol) and potassium carbonate (41.34mg, 0.3mmol), 50 ℃ reaction was stirred for 12 hours. The reaction was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems resulting residue was purified B to give the title product 25c (36mg, pale yellow solid), yield: 66%.

third step

1-ethyl-2 - ((6- (trifluoromethyl) pyridin-3-yl) methyl) lH-indole-5-carboxylic acid 25d

The 25c (36mg, 0.1mmol) was dissolved in 3mL of methanol was added 2M sodium hydroxide solution 1mL, 70 deg.] C the reaction was stirred for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, water was added to the resulting residue, was added dropwise concentrated hydrochloric acid to pH 4-5, and extracted with ethyl acetate (30mL × 3), combined organic phases were washed with water, saturated sodium chloride The solution was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 25d (27mg, pale yellow oil), the product was used without purification in the next step.

the fourth step

1-ethyl -N- (4- (ethanesulfonyl) benzyl) -2 - ((6- (trifluoromethyl) pyridin-3-yl) methyl) lH-indole-5-carboxamide 25

The crude 25d (27mg, 0.077mmol), (4- (ethylsulfonyl) phenyl) methanamine (23.17mg, 0.116mmol), 1- (3- dimethylaminopropyl) -3-ethyl carbodiimide amine hydrochloride (29.7mg, 0.155mmol), 1- hydroxybenzotriazole (21mg, 0.155mmol), triethylamine (15.69mg, 0.155mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 25 (22mg, pale yellow solid), yield: 54%.

MS m / z (ESI): 530.3 [M + 1];

1 HNMR (400MHz, CDCl 3) δ8.68 (s, 1H), 8.07 (s, 1H), 7.87 (d, 2H), 7.64-7.72 (m, 3H), 7.57 (d, 2H), 7.35 (d , 1H), 6.64 (t, 1H), 6.29 (s, 1H), 4.79 (d, 2H), 4.23 (s, 2H), 4.11 (q, 2H), 3.11 (q, 2H), 1.26-1.30 ( m, 6H).

Example 26

1-ethyl -N- (4- (ethanesulfonyl) benzyl) -2- (4- (trifluoromethyl) benzoyl) lH-indole-5-carboxamide 26

Figure PCTCN2017077114-appb-000076

Figure PCTCN2017077114-appb-000077

first step

1-ethyl-2- (4- (trifluoromethyl) benzoyl) 26a lH-indol-5-carboxylate

The 19d (180mg, 0.5mmol) was dissolved 20mL1,4- dioxane, was added manganese dioxide (2.18g, 25mmol), stirred 100 deg.] C for 12 hours, additional manganese dioxide (2.18g, 25mmol), 100 deg.] C The reaction was stirred for 36 hours. The reaction was cooled to room temperature, filtered through celite, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure, purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 26a (50mg, white solid), yield: 27%.

The second step

1-ethyl-2- (4- (trifluoromethyl) benzoyl) lH-indole-5-carboxylic acid 26b

The 26a (15mg, 0.04mmol) was dissolved in 5mL of methanol, was added 0.6 mL 1M aqueous sodium hydroxide solution, stirred for 12 hours 60 ℃. The reaction was cooled to room temperature, concentrated under reduced pressure to remove methanol, the resulting residue was added 2mL of tetrahydrofuran was added dropwise 1M hydrochloric acid to pH 4-5, and concentrated under reduced pressure to give the crude title product 26b (14mg, white solid), the product is not purification in the next step directly.

third step

1-ethyl -N- (4- (ethanesulfonyl) benzyl) -2- (4- (trifluoromethyl) benzoyl) lH-indole-5-carboxamide 26

The crude 26b (14mg, 0.04mmol), (4- (ethylsulfonyl) phenyl) methanamine (10mg, 0.048mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (14mg, 0.072mmol), 1- hydroxybenzotriazole (10mg, 0.072mmol), triethylamine (16mg, 0.16mmol) was dissolved in dichloromethane, stirred for 12 hours. Was added 20mL of ethyl acetate, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 26 (16mg, pale yellow solid), yield: 73%.

MS m / z (ESI): 543.3 [M + 1];

1 HNMR (400MHz, CDCl 3) δ8.22 (s, 1H), 8.00 (d, 2H), 7.86-7.91 (m, 3H), 7.79-7.81 (d, 2H), 7.58-7.53 (m, 3H) , 7.07 (s, 1H), 6.67-6.69 (m, 1H), 4.80 (d, 2H), 4.67 (q, 2H), 3.11 (q, 2H), 1.51 (t, 3H), 1.29 (t, 3H ).

Example 27

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2- (2-fluoro-4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 27

Figure PCTCN2017077114-appb-000078

first step

1-cyclopropyl-2- (2-fluoro-4- (trifluoromethyl) benzyl) lH-indole-5-carboxylate 27a

The 15c (150mg, 0.427mmol) was dissolved in 1,2-dichloroethane were added cyclopropyl boronic acid (183.39mg, 2.13mmol), copper acetate monohydrate (15.51mg, 0.085mmol), 2,2 ' - bipyridine (133.38mg, 0.854mmol) and sodium carbonate (90.51mg, 0.853mmol), was heated to 70 deg.] C was stirred for 12 hours. The reaction was cooled to room temperature, methylene chloride, filtered, and the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography with eluant System B resulting residue was purified to give the title product 27a (96mg, colorless oil). Yield: 57%.

The second step

1-cyclopropyl-2- (2-fluoro-4- (trifluoromethyl) benzyl) lH-indole-5-carboxylic acid 27b

The 27a (96mg, 0.254mmol) was dissolved in 4mL of methanol and water (V: V = 1: 1) mixed solvent was added lithium hydroxide (13mg, 0.508mmol), stirred the reaction was warmed to 70 ℃ 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, water was added to the resulting residue, was added dropwise concentrated hydrochloric acid to pH 4-5, and extracted with ethyl acetate (30mL × 3), combined organic phases were washed with water, saturated sodium chloride The solution was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 27b (31mg, pale yellow oil), the product was used without purification in the next step.

third step

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2- (2-fluoro-4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 27

The crude 27b (31mg, 0.082mmol), (4- (ethylsulfonyl) phenyl) methanamine (19.6mg, 0.099mmol), 1- (3- dimethylaminopropyl) -3-ethyl carbodiimide amine hydrochloride (31.5mg, 0.164mmol), 1- hydroxybenzotriazole (22.2mg, 0.164mmol), triethylamine (16.6mg, 0.164mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 27 (13mg, white solid), yield: 28%.

MS m / z (ESI): 559.4 [M + 1];

1 HNMR (400MHz, CDCl 3) δ8.06 (s, 1H), 7.87 (d, 2H), 7.72 (d, 1H), 7.56-7.62 (m, 3H), 7.40 (t, 2H), 7.28 (t , 1H), 6.79 (t, 1H), 6.28 (s, 1H), 4.81 (d, 2H), 4.36 (s, 2H), 3.13 (q, 2H), 3.02-3.07 (m, 1H), 1.30 ( t, 3H), 1.20-1.25 (m, 2H), 1.07-1.11 (m, 2H).

Example 28

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2- (4- (trifluoromethoxy) benzyl) lH-indole-5-carboxamide 28

Figure PCTCN2017077114-appb-000079

first step

1-cyclopropyl-2- (4- (trifluoromethoxy) benzyl) lH-indole-5-carboxylate 28a

The 18c (100mg, 0.286mmol) was dissolved in dichloromethane were added cyclopropyl boronic acid (126.12mg, 1.43mmol), copper acetate (10.4mg, 0.057mmol), 2,2'- bipyridine (223.5mg, 1.43 mmol) and sodium carbonate (60.7mg, 1.572mmol), was heated to 70 deg.] C was stirred for 12 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 28a (71mg, pale yellow oil). Yield: 64%.

The second step

1-cyclopropyl-2- (4- (trifluoromethoxy) benzyl) lH-indole-5-carboxylic acid 28b

The 28a (71mg, 0.182mmol) was dissolved in 3mL of methanol was added 3mL of water, was added potassium hydroxide (35.5mg, 0.91mmol), stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, was added dropwise concentrated hydrochloric acid to pH 5-6, and extracted with ethyl acetate (20mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 28b (56mg, white solid), the product was used without purification in the next step.

third step

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2- (4- (trifluoromethoxy) benzyl) lH-indole-5-carboxamide 28

The crude 28b (56mg, 0.149mmol), (4- (ethylsulfonyl) phenyl) methanamine (44.6mg, 0.223mmol), 1- (3- dimethylaminopropyl) -3-ethyl carbodiimide amine hydrochloride (57.2mg, 0.298mmol), 1- hydroxybenzotriazole (40.3mg, 0.298mmol), triethylamine (30.2mg, 0.298mmol) was dissolved in dichloromethane, stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, purified by thin layer chromatography to B the resulting residue was purified by developing solvent system, to give the title product 28 (36mg, white solid), yield: 43%.

MS m / z (ESI): 557.3 [M + 1];

1 HNMR (400MHz, CDCl 3) δ8.02 (s, 1H), 7.87 (d, 2H), 7.67 (d, 1H), 7.56 (d, 3H), 7.25 (d, 2H), 7.16 (d, 2H ), 6.64 (t, 1H), 6.26 (s, 1H), 4.79 (d, 2H), 4.25 (s, 2H), 3.10 (q, 2H), 2.92-2.96 (m, 1H), 1.28 (t, 3H), 1.13-1.17 (m, 2H), 1.02-1.06 (m, 2H).

Example 29

1-cyclopropyl -N - ((1- (ethanesulfonyl) piperidin-4-yl) methyl) -2- (4- (trifluoromethyl) benzyl) lH-indole-5 carboxamide 29

Figure PCTCN2017077114-appb-000080

first step

4 - ((1-cyclopropyl-2- (4- (trifluoromethyl) benzyl) lH-indol-5-carboxamido) methyl) piperidine-1-carboxylic acid tert-butyl ester 29b

The 20b (23mg, 0.064mmol), 4- (aminomethyl) piperidine-1-carboxylate 29a (21mg, 0.096 mmol, a known method of "Bioorganic & Medicinal Chemistry, 2002,10 (5), 1347-1359 "preparation derived), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (18mg, 0.096mmol), 1- hydroxybenzotriazole (13mg, 0.096mmol) and N, N- diisopropylethylamine (42mg, 0.32mmol) was dissolved in N, N- dimethylformamide, and the reaction stirred for 12 hours. Water was added to the reaction mixture, a mixed solvent with dichloromethane and methanol (V: V = 8: 1) and extracted (20mL × 3), saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated and purified by thin-layer chromatography A purification to the resulting residue was developing solvent system, to give the title product 29b (35.0mg, yield: 98%).

MS m / z (ESI): 554.2 [M-1];

The second step

1-cyclopropyl -N- (piperidin-4-ylmethyl) -2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 29c

The 29b (350mg, 0.063mmol) was dissolved in 5mL of dichloromethane, was added to the reaction mixture 1mL trifluoroacetic acid and stirred for 1 hour, saturated sodium bicarbonate was added to the reaction mixture to neutral, with dichloromethane and a mixed solvent of methanol (V: V = 8: 1) and extracted (20mL × 3), saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title product 29c (25mg), the product without purification in the next reaction.

MS m / z (ESI): 456.3 [M + 1];

third step

1-cyclopropyl -N - ((1- (ethanesulfonyl) piperidin-4-yl) methyl) -2- (4- (trifluoromethyl) benzyl) lH-indole-5 carboxamide 29

The crude sequentially 29c (25mg, 0.055mmol), triethylamine (8.5mg, 0.082mmol) and ethanesulfonyl chloride 29d (8mg, 0.066mmol, using well-known methods "Journal of Organic Chemistry, 2007,72 (15), 5847 -5850 "preparation derived) was dissolved in 5mL of methylene chloride, stirred for 3 hours. Saturated sodium bicarbonate solution was added with dichloromethane and methanol (V: V = 8: 1) mixed solvent (20mL × 3), combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered the filtrate was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product 29 (27mg, yield: 90%).

MS m / z (ESI): 548.5 [M + 1]

1 H NMR (400MHz, DMSO- d 6) δ8.39 (s, 1H), 8.02 (s, 1H), 7.66-7.71 (m, 2H), 7.63-7.64 (d, 1H), 7.48-7.51 (m , 3H), 6.22 (s, 1H), 4.34 (s, 2H), 3.58 (d, 2H), 3.17 (t, 2H), 3.01 (q, 2H), 2.90-2.98 (m, 1H), 2.75 ( t, 2H), 1.73 (m, 3H), 1.12-1.33 (m, 7H), 0.98 (t, 2H).

Example 30

2- (4-chloro-2- (trifluoromethyl) benzyl) -N- (4- (ethanesulfonyl) benzyl) -1- (2-fluoroethyl) lH-indol-5 carboxamide 30

Figure PCTCN2017077114-appb-000081

first step

2- (4-chloro-2- (trifluoromethyl) benzyl) -1- (2-fluoroethyl) 30a lH-indol-5-carboxylate

The 5b (1g, 2.72mmol) was dissolved in 5mL N, N- dimethyl formamide, was added 1-bromo-2-fluoroethane (345.23mg, 2.72mmol) and cesium carbonate (1782.95mg, 5.44mmol) under the conditions of 100 deg.] C, microwave for 1 hour. The reaction was cooled to room temperature, concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems C resulting residue was purified to give the title product 30a (300mg, yield: 23.97%).

MS m / z (ESI): 412.1 [M-1]

The second step

2- (4-chloro-2- (trifluoromethyl) benzyl) -1- (2-fluoroethyl) lH-indole-5-carboxylic acid 30b

The 30a (2g, 4.83mmol) was dissolved in 110mL of mixed solution of ethanol and water (V: V = 3: 8), was added sodium hydroxide (580mg, 14.5mmol), under the conditions of 80 ℃, for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added 30mL, 1M hydrochloric acid was added dropwise to pH 2, extracted with ethyl acetate (2 × 30mL) and the combined organic phases, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 30b (1500mg), was used without purification in the next reaction.

MS m / z (ESI): 400.4 [M-1]

third step

2- (4-chloro-2- (trifluoromethyl) benzyl) -N- (4- (ethanesulfonyl) benzyl) -1- (2-fluoroethyl) lH-indol-5 carboxamide 30

The crude 30b (1.5g, 3.75mmol), (4- (ethylsulfonyl) phenyl) methanamine (44.6mg, 0.223mmol), 2- (7- oxide benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (2138.73mg, 5.63mmol), triethylamine (1136.9mg, 11.26mmol) was dissolved in 30mL N, N- dimethylformamide, and stirred for 12 hours. The reaction mixture was added 50mL of water, extracted with ethyl acetate (50mL × 2), the combined organic phases, the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, by high performance liquid chromatography The resulting residue was purified to give the title product 30 (1100mg, yield: 49.45%).

MS m / z (ESI): 579.1 [M-1]

1 H NMR (400MHz, DMSO- d 6) δ8.98-9.01 (m, 1H), 8.05 (s, 1H), 7.82-7.86 (m, 3H), 7.69-7.73 (m, 2H), 7.53-7.57 (m, 3H), 7.31-7.33 (m, 1H), 5.99 (s, 1H), 4.71-4.72 (m, 1H), 4.57-4.61 (m, 3H), 4.44-4.52 (m, 2H), 4.33 (s, 2H), 3.22-3.27 (m, 2H), 1.05-1.09 (m, 3H).

Example 31

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2 - ((3-methyl-5- (trifluoromethyl) lH-pyrazol-1-yl) methyl) -1H- indole-5-carboxamide 31

Figure PCTCN2017077114-appb-000082

first step

2 - (((tert-butyldimethylsilyl) oxy) methyl) lH-indole-5-carboxylic acid ethyl ester 31c

Under an argon atmosphere, followed by 3-iodo-4- (2,2,2-trifluoroacetamido) benzoate 31b (1.0g, 2.58mmol, using well-known methods "Journal of the Chemical Society, Perkin Transactions 1 : Organic and Bio-Organic Chemistry, 1997 (14), 2059-2063 "preparation derived), tert-butyldimethyl (prop-2-yn-1-yl) silane 31a (660mg, 3.88mmol, using known methods "Journal of the American Chemical Society, 2016,138 (24), 7532-7535" preparation derived), copper iodide (99mg, 0.52mmol), bis triphenylphosphine palladium dichloride (362 mg, 0.52 mmol) and triethylamine (1.3g, 12.9mmol) was dissolved in N, N- dimethylformamide, the addition was completed, the reaction was stirred for 3 hours warming to 60 ℃. The reaction was cooled to room temperature, filtered through celite, the filtrate was added water and extracted with ethyl acetate (50mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate reduced pressure was concentrated, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 31c (460mg, yield: 54%).

MS m / z (ESI): 334.2 [M + 1];

The second step

2 - (((tert-butyldimethylsilyl) oxy) methyl) -1H- indol-1-cyclopropyl-5-carboxylate 31d

The 31c (460mg, 1.4mmol) was dissolved in 1,2-dichloroethane were added cyclopropyl boronic acid (178mg, 2.1mmol), copper acetate monohydrate (393mg, 2.1mmol), 2,2'- joint pyridine (328mg, 2.1mmol) and sodium carbonate (223mg, 2.1mmol), stirred the reaction temperature was raised to 70 deg.] C for 12 hours. Refed with cyclopropyl boronic acid (178mg, 2.1mmol), copper acetate monohydrate (393mg, 2.1mmol), 2,2'- bipyridine (328mg, 2.1mmol) and sodium carbonate (223mg, 2.1mmol), the reaction was stirred 6 hours, the reaction was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure, the residue was added water, extracted with ethyl acetate (50mL × 3), combined organic phases were washed with saturated sodium chloride solution, no over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 31d (329mg, yield: 64%).

third step

1-cyclopropyl-2- (hydroxymethyl) lH-indole-5-carboxylic acid ethyl ester 31f

The 31d (329mg, 0.88mmol) dissolved in tetrahydrofuran was added dropwise 1mL 1M tetrabutylammonium fluoride, and the reaction stirred for 1 hour. Extracted with ethyl acetate (10mL × 3), combined organic phases, the organic phase was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system B and the residue was purified to give the title product 31f (120mg, yield: 52%).

the fourth step

1-cyclopropyl-2 - ((3-methyl-5- (trifluoromethyl) lH-pyrazol-1-yl) methyl) lH-indole-5-carboxylic acid ethyl ester 31g

Under argon atmosphere, 31f (120mg, 0.46mmol), 3- methyl-5- (trifluoromethyl) lH-pyrazol-31e (104mg, 0.69mmol, using well-known methods "Tetrahedron Letters, 2016,57 ( 14), 1555-1559 "preparation derived) and triphenylphosphine (181mg, 0.69mmol) was dissolved in 10mL tetrahydrofuran was added diethyl azodicarboxylate (120mg, 0.69mmol), the addition, the reaction was stirred for 12 hours . The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with eluent systems B obtained was purified residue was then purified by thin layer chromatography to expand the B agent system resulting crude product was purified to give the title product 31g (60mg, yield: 33.1% ).

MS m / z (ESI): 390.1 [M-1];

the fifth step

1-cyclopropyl-2 - ((3-methyl-5- (trifluoromethyl) lH-pyrazol-1-yl) methyl) lH-indole-5-carboxylic acid 31h

The 31g (60mg, 0.15mmol) was dissolved in 6mL of methanol and tetrahydrofuran mixed solution (V: V = 5: 1), was added 2mL of 4M sodium hydroxide solution, under conditions of 60 ℃, for 3 hours. Was added dropwise concentrated hydrochloric acid to pH 3, and extracted with ethyl acetate (30mL × 3), combined organic phases, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 31h (55mg), was used without purification in the next reaction.

MS m / z (ESI): 362.1 [M-1];

Step Six

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2 - ((3-methyl-5- (trifluoromethyl) lH-pyrazol-1-yl) methyl) -1H- indole-5-carboxamide 31

The crude product 31h (30mg, 0.083mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (24mg, 0.12mmol), 1- hydroxybenzotriazole (17mg, 0.12mmol), N, N- diisopropylethylamine (53mg, 0.41mmol) dissolved in dichloromethane was added dropwise 31i (4- (ethylsulfonyl) phenyl) methanamine hydrochloride (44.6 mg, 0.223 mmol, using patent application "US20150291607A1" disclosed a process for preparing obtained), the addition, the reaction was stirred for 12 hours. Water was added to the reaction mixture with dichloromethane and methanol (V: V = 8: 1) mixed solvent (20mL × 3), combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product 31 (30mg, yield: 66%).

MS m / z (ESI): 545.5 [M + 1]

1 H NMR (400MHz, DMSO- d 6) δ9.05 (t, 1H), 8.11 (s, 1H), 7.84 (d, 2H), 7.75 (d, 1H), 7.57-7.61 (t, 3H), 6.79 (s, 1H), 6.16 (s, 1H), 5.72 (s, 2H), 4.59 (d, 2H), 3.27 (q, 2H), 3.20-3.23 (m, 1H), 2.21 (s, 3H) , 1.15-1.21 (m, 2H), 1.09 (t, 3H), 0.98-1.05 (m, 2H).

Example 32

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2 - ((5- (trifluoromethyl) lH-pyrazol-1-yl) methyl) lH-indole 5-carboxamide 32

Figure PCTCN2017077114-appb-000083

Figure PCTCN2017077114-appb-000084

first step

2 - (((tert-butyldimethylsilyl) oxy) methyl) lH-indole-5-carboxylic acid methyl ester 32b

Under an argon atmosphere, followed by 3-iodo-4- (2,2,2-trifluoro-acetylamino) benzoic acid methyl ester 32a (13.0g, 34.85mmol, using well-known methods "Journal of Medicinal Chemistry, 2005,48 ( 5), 1314-1317 "preparation derived), 31a (8.9g, 52.27mmol), copper iodide (1.33g, 6.97mmol), bis triphenylphosphine palladium dichloride (4.89g, 6.97mmol) and triethylamine (17.63g, 174.23mmol) was dissolved in 150mL N, N- dimethylformamide, the addition was completed, the reaction was stirred for 3 hours warming to 60 ℃. The reaction mixture was added water and extracted with ethyl acetate (50mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography to elute The resulting residue was purified by system B was degreasing agent, to give the title product 32b (7.0g, yield: 63%).

The second step

2 - (((tert-butyldimethylsilyl) oxy) methyl) -1H- indol-1-cyclopropyl-5-carboxylate 32c

The 32b (956mg, 2.99mmol), cyclopropyl boronic acid (1.3g, 14.96mmol), copper acetate (1.14g, 6.28mmol), 2,2'- bipyridine (1.03g, 6.58mmol) and sodium carbonate (698 mg the reaction, 6.58 mmol) was dissolved in 1,2-dichloroethane was heated to 70 deg.] C for 12 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 32c (500mg, yield: 46%).

third step

1-cyclopropyl-2- (hydroxymethyl) lH-indole-5-carboxylate 32d

The 32c (500mg, 1.39mmol) was dissolved in 5mL of tetrahydrofuran, cooled to 0 deg.] C, was added dropwise ammonium 2.8mL1M tetrabutylammonium fluoride tetrahydrofuran solution, dropwise addition, stirred for 0.5 hours. Water was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (50mL × 3), combined organic phases, the organic phase washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give crude title product 32d (300mg). Products without purification, direct investment in the next step.

the fourth step

1-cyclopropyl-2 - ((5- (trifluoromethyl) lH-pyrazol-1-yl) methyl) lH-indole-5-carboxylate 32f

Under an argon atmosphere, the crude product 32d (120mg, 0.53mmol), 3- methyl -1H- pyrazol-32e (104mg, 0.69mmol) and triphenylphosphine (208mg, 0.795mmol) was dissolved in 3mL of tetrahydrofuran, was added azobis dicarboxylic acid diethyl ester (138mg, 0.795mmol), the addition, the reaction was stirred for 12 hours. (: 26% 51mg, yield) The reaction mixture was concentrated by silica gel column chromatography with eluent systems B resulting residue under reduced pressure to give the title product 32f.

the fifth step

1-cyclopropyl-2 - ((5- (trifluoromethyl) lH-pyrazol-1-yl) methyl) lH-indole-5-carboxylic acid 32g

The 32f (51mg, 0.14mmol) was dissolved in 2mL of methanol was added 1.4mL of 2M potassium hydroxide solution, under conditions of 70 ℃, 3 hours. The reaction was cooled to room temperature, 1M hydrochloric acid was added dropwise to pH 1-2, and extracted with dichloromethane (30mL × 3), wash the combined organic phases, the organic phase washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered the filtrate was concentrated under reduced pressure to give crude title product 32g (45mg), was used without purification in the next reaction.

Step Six

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2 - ((5- (trifluoromethyl) lH-pyrazol-1-yl) methyl) lH-indole 5-carboxamide 32

The crude product 32g (20mg, 0.057mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (22mg, 0.115mmol), 1- hydroxybenzotriazole (16mg, 0.118 mmol), triethylamine (23mg, 0.227mmol) was dissolved in dichloromethane, was added (4- (ethylsulfonyl) phenyl) methanamine (23mg, 0.115mmol), the addition, the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was purified by HPLC to give the title product 32 (15mg, yield: 50%).

MS m / z (ESI): 531.2 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.04 (s, 1H), 7.88-7.86 (d, 2H), 7.75-7.72 (d, 1H), 7.65-7.61 (m, 2H), 7.57-7.55 (d , 2H), 6.81-6.78 (m, 1H), 6.75 (s, 1H), 6.31 (s, 1H), 5.76 (s, 2H), 4.81-4.79 (d, 2H), 3.29-3.24 (m, 1H ), 3.16-3.10 (q, 2H), 1.32-1.28 (t, 3H) 1.27-1.24 (m, 2H), 1.12.40-1.08 (m, 2H).

Example 33

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2 - ((4- (trifluoromethyl) piperidin-1-yl) methyl) lH-indol-5 carboxamide 33

Figure PCTCN2017077114-appb-000085

Figure PCTCN2017077114-appb-000086

first step

2 - ((4- (trifluoromethyl) piperidin-1-yl) methyl) lH-indole-5-carboxylic acid ethyl ester 33b

Under argon atmosphere, 1- (prop-2-yn-1-yl) -4- (trifluoromethyl) piperidine 33a (950mg, 6.2mmol, the method disclosed in the patent "WO2003093253" preparation derived), 31b (1.2g, 3.1mmol), cuprous iodide (118mg, 0.62mmol), bis triphenylphosphine palladium dichloride (217mg, 0.31mmol) and triethylamine (1.57g, 15.5mmol) was dissolved in N, N - dimethylformamide, the addition was completed, the reaction temperature was raised to 60 deg.] C for 5 hours. The reaction was cooled to room temperature, the reaction mixture was added water and extracted with ethyl acetate (50mL × 3), combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography system, eluent B resulting residue was crude title product 33b (920mg), the product was used without purification in the next reaction.

The second step

1-isopropyl-2 - ((4- (trifluoromethyl) piperidin-1-yl) methyl) lH-indole-5-carboxylic acid ethyl ester 33c

The crude 33b (140mg, 0.40mmol) was dissolved in 5mL N, N- dimethylformamide was added sodium hydride (24mg, 0.60mmol, 60% in oil), the reaction was stirred for 5 min, 2-iodopropane (67 mg of , 0.40 mmol), under sealed tube conditions of 60 deg.] C, the reaction was stirred for 12 hours. The reaction was cooled to room temperature, water was added and extracted with ethyl acetate (30mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by thin layer chromatography in method B developing solvent system resulting residue was purified to give the title product 33c (105mg, yield: 67%).

third step

1-isopropyl-2 - ((4- (trifluoromethyl) piperidin-1-yl) methyl) lH-indole-5-carboxylic acid 33d

The 33c (105mg, 0.26mmol) was dissolved in 10mL of ethanol, 3mL 4M sodium hydroxide solution were added, under 60 ℃, stirred for 12 hours. The reaction was cooled to room temperature, was added dropwise concentrated hydrochloric acid to a pH of 4, a mixed solution of dichloromethane and methanol (V: V = 1: 1) and extracted (20mL × 3), combined organic phase was concentrated under reduced pressure to give the crude title The product 33d (95mg), the product was used without purification in the next step.

MS m / z (ESI): 367.2 [M-1];

the fourth step

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2 - ((4- (trifluoromethyl) piperidin-1-yl) methyl) lH-indol-5 carboxamide 33

The crude 33d (55mg, 0.15mmol), (4- (ethylsulfonyl) phenyl) methanamine (45mg, 0.22mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (43mg, 0.22mmol), N, N- diisopropylethylamine (97mg, 0.75mmol) was dissolved in N, N- dimethylformamide, and the reaction stirred for 12 hours. Water was added with dichloromethane and methanol (V: V = 8: 1) mixed solvent (20mL × 3), combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate reduced pressure concentrated and the resulting residue was purified by HPLC to give the title product 33 (40mg, yield: 50%).

MS m / z (ESI): 550.4 [M + 1]

1 H NMR (400MHz, DMSO- d 6) δ9.02 (t, 1H), 8.12 (s, 1H), 7.85-7.95 (m, 2H), 7.66 (s, 2H), 7.56-7.59 (m, 2H ), 6.42 (s, 1H), 4.91-4.95 (m, 1H), 4.59 (d, 2H), 6.65 (s, 2H), 3.25 (q, 2H), 2.88 (d, 2H), 2.26 (brs, 1H), 1.97 (t, 2H), 1.79 (d, 2H), 1.56 (d, 6H), 1.36-1.39 (m, 2H), 1.08 (t, 3H).

Example 34

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2 - ((4- (trifluoromethyl) piperidin-1-yl) methyl) lH-indol-5 carboxamide 34

Figure PCTCN2017077114-appb-000087

first step

1-cyclopropyl-2 - ((4- (trifluoromethyl) piperidin-1-yl) methyl) lH-indole-5-carboxylic acid ethyl ester 34a

The crude 33b (220mg, 0.62mmol) was dissolved in 1,2-dichloroethane were added copper acetate monohydrate (178mg, 0.93mmol), 2,2'- bipyridine (145mg, 0.93mmol), sodium carbonate (99mg, 0.93mmol) and cyclopropyl boronic acid (39mg, 0.45mmol), warmed to 70 ℃, stirred for 12 hours. Was added cyclopropyl boronic acid (39mg, 0.45mmol), copper acetate monohydrate (178mg, 0.93mmol) and 2,2'-bipyridyl (145mg, 0.93mmol), 12 hours. The reaction was cooled to room temperature, filtered through celite, washed with ethyl acetate and concentrated filtrate under reduced pressure, water was added to the resulting residue, and extracted with ethyl acetate (30mL × 3), combined organic phases were washed with saturated sodium chloride solution , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product 34a (175mg, yield: 71%).

MS m / z (ESI): 395.2 [M + 1];

The second step

1-cyclopropyl-2 - ((4- (trifluoromethyl) piperidin-1-yl) methyl) lH-indole-5-carboxylic acid 34b

The 34a (175mg, 0.44mmol) was dissolved in 15mL of methanol and tetrahydrofuran (V: V = 2: 1) mixed solvent was added 4mL 4M sodium hydroxide solution, stirred for 12 hours 60 ℃. The reaction was cooled to room temperature, concentrated hydrochloric acid was added dropwise to a pH 4 solution was mixed with dichloromethane and methanol (V: V = 1: 1) were washed, and the combined organic phase was concentrated under reduced pressure to give the crude title product 34b (170mg) product without purification in the next step.

MS m / z (ESI): 367.0 [M + 1];

third step

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2 - ((4- (trifluoromethyl) piperidin-1-yl) methyl) lH-indol-5 carboxamide 34

The crude 34b (80mg, 0.22mmol), (4- (ethylsulfonyl) phenyl) methanamine (65mg, 0.32mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61mg, 0.32mmol), N, N- diisopropylethylamine (142mg, 1.1mmol) was dissolved in N, N- dimethylformamide, and the reaction stirred for 12 hours. Water was added with dichloromethane and methanol (V: V = 8: 1) mixed solvent (20mL × 3), combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated and purified by thin-layer chromatography A purification to the resulting residue was developing solvent system, to give the title product 34 (55mg, yield: 46%).

MS m / z (ESI): 548.5 [M + 1]

1 H NMR (400MHz, DMSO- d 6) δ9.03 (t, 1H), 8.11 (s, 1H), 7.83-7.85 (m, 2H), 7.54-7.59 (m, 4H), 6.45 (s, 1H ), 4.59 (d, 2H), 3.71 (d, 2H), 3.25 (q, 2H), 3.01 (m, 1H), 2.28 (brs, 1H), 2.06 (t, 2H), 1.78 (d, 2H) , 1.45 (q, 2H), 1.15 (t, 2H), 1.05-1.10 (m, 7H).

Example 35

2 - ((2-ethyl-4,4-difluoro-piperidin- 1-yl) methyl) -N- (4- (ethanesulfonyl) benzyl) -1-isopropyl--1H- indole 5-carboxamide 35

Figure PCTCN2017077114-appb-000088

From oxopiperidine-1-carboxylate ethyl -4- 35a starting using synthetic routes similar to Example 33, the title product 35 (4mg).

MS m / z (ESI): 545.5 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ9.07 (s, 1H), 8.16-8.18 (m, 1H), 8.09 (s, 1H), 7.71-7.73 (m, 1H), 7.58-7.62 (m, 2H ), 7.34-7.37 (m, 1H), 6.49 (s, 1H), 4.91-4.92 (m, 2H), 4.22-4.25 (m, 1H), 3.58-3.62 (m, 1H), 3.25-3.28 (m , 1H), 3.14-3.20 (m, 2H), 2.87-2.93 (m, 1H), 2.61-2.63 (m, 1H), 2.40-2.43 (m, 1H), 2.08-2.12 (m, 1H), 1.84 -1.93 (m, 3H), 0.89-1.35 (m, 12H).

Example 36

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2- (4-fluoro-2- (trifluoromethoxy) benzyl) lH-indole-5-carboxamide 36

Figure PCTCN2017077114-appb-000089

From 1- (bromomethyl) -4-fluoro-2- (trifluoromethoxy) benzene starting Example 1 using the synthetic route similar embodiments, the title product 36 (35mg).

MS m / z (ESI): 575.3 [M + 1].1 H NMR (400MHz, DMSO- d 6) δ9.00 (t, 1H), 7.99 (s, 1H), 7.82 (d, 2H), 7.70 (d, 1H), 7.52-7.5 8 (m, 4H) , 7.33-7.39 (m, 2H), 5.78 (s, 1H), 4.56 (d, 2H), 4.31 (s, 2H), 3.22-3.30 (m, 3H), 1.26 (q, 2H), 1.05-1.09 (m, 5H).

Example 37

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2- (1- (4- (trifluoromethyl) phenyl) ethyl) lH-indole-5-carboxamide 37

Figure PCTCN2017077114-appb-000090

From 1- (1-bromoethyl) -4- (trifluoromethyl) benzene starting Example 1 using the synthetic route similar embodiments, the title product 37 (12mg). MS m / z (ESI): 555.3 [M + 1]

1 H NMR (400MHz, CDCl 3 ) δ7.85-7.81 (m, 3H), 7.57-7.55 (m, 1H), 7.52-7.48 (m, 5H), 7.37 (d, 2H), 7.02 (s, 1H ), 6.62 (t, 1H), 4.72 (d, 2H), 4.42 (q, 1H), 3.37-3.35 (m, 1H), 3.09 (q, 2H), 1.68 (d, 3H), 1.26 (t, 3H), 1.11-1.09 (m, 2H), 1.04-1.03 (m, 2H).

Example 38 and 39

(R) -1- cyclopropyl -N - ((5- (ethylsulfonyl) pyridin-2-yl) methyl) -2 - ((2- (trifluoromethyl) piperidin-1-yl) methyl) lH-indole-5-carboxamide 38

(S) -1- cyclopropyl -N - ((5- (ethylsulfonyl) pyridin-2-yl) methyl) -2 - ((2- (trifluoromethyl) piperidin-1-yl) methyl) lH-indole-5-carboxamide 39

Figure PCTCN2017077114-appb-000091

first step

(5-bromo--1H- indol-2-yl) (2- (trifluoromethyl) piperidin-1-yl) methanone 38c

5-Bromo -1H- indole-2-carboxylic acid 38b (600mg, 2.5mmol, using well-known methods "Journal of Medicinal Chemistry, 2009,52 (23), 7512-7527" preparation derived) was dissolved in 15mL of tetrahydrofuran was added 2- (trifluoromethyl) piperidine 38a (382.8mg, 2.5mmol, using well-known methods "Tetrahedron, 2011,67 (1), 69-74" preparation derived), 2- (7-oxidation of benzene and triazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (1424.7mg, 3.75mmol) and N, N- diisopropylethylamine (967.3mg, 7.5mmol), After complete addition, the reaction stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with eluent systems A resulting residue to give the title product 38c (400mg, yield: 42.66%).

MS m / z (ESI): 375.3 [M + 1];

The second step

5-bromo-2 - ((2- (trifluoromethyl) piperidin-1-yl) methyl) lH-indole 38d

The 38c (400mg, 1.07mmol) was dissolved in N, N- dimethylformamide was added lithium aluminum hydride (121.38mg, 3.2mmol), the addition, the reaction was stirred for 18 hours. The reaction solution was concentrated under reduced pressure to give the crude title product 38d (120mg), the product was used without purification in the next step.

MS m / z (ESI): 361.4 [M + 1];

third step

Bromo-1-cyclopropyl-2 - ((2- (trifluoromethyl) piperidin-1-yl) methyl) lH-indole 38e

The crude 38d (120mg, 0.33mmol) was dissolved in 1,2-dichloroethane 5 mL was added cyclopropyl boronic acid (42.81mg, 0.50mmol), 2,2'- bipyridine (77.83mg, 0.50mmol), copper acetate (99.17mg, 0.50mmol) and sodium carbonate (52.82mg, 0.50mmol), the addition, under 70 ℃, stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with eluent systems C resulting residue was purified to give the title product 38e (300mg, yield: 22.5%).

the fourth step

1-cyclopropyl-2 - ((2- (trifluoromethyl) piperidin-1-yl) methyl) lH-indole-5-carboxylic acid ethyl ester 38f

The 38e (100mg, 0.25mmol) was dissolved in 2mL of ethanol and dimethylsulfoxide (V: V = 1: 1) mixed solvent, palladium acetate (11.23mg, 0.05mmol), 1,3- bis (diphenylphosphino phosphine) propane (25.7mg, 0.06mmol) and triethylamine (25.17mg, 0.25mmol), the addition, under a carbon monoxide atmosphere under 80 ℃, stirred for 16 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems C resulting residue was purified to give the title product 38f (80mg, yield: 81.39%).

the fifth step

1-cyclopropyl-2 - ((2- (trifluoromethyl) piperidin-1-yl) methyl) lH-indole-5-carboxylic acid 38g

The 38f (30mg, 0.08mmol) was dissolved in 2.1mL of methanol and tetrahydrofuran (V: V = 20: 1) mixed solvent, was added sodium hydroxide (30.42mg, 0.76mmol), the addition was completed, the condition 45 deg.] C, the reaction was stirred 3 hours. pH of the reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid was added dropwise to the reaction solution 3 is concentrated under reduced pressure to give the crude title product 38g (27mg), the product was used without purification in the next step.

MS m / z (ESI): 365.4 [M-1];

Step Six

(R) -1- cyclopropyl -N - ((5- (ethylsulfonyl) pyridin-2-yl) methyl) -2 - ((2- (trifluoromethyl) piperidin-1-yl) methyl) lH-indole-5-carboxamide 38

(S) -1- cyclopropyl -N - ((5- (ethylsulfonyl) pyridin-2-yl) methyl) -2 - ((2- (trifluoromethyl) piperidin-1-yl) methyl) lH-indole-5-carboxamide 39

The crude product 38g (30mg, 0.08mmol) was dissolved in 1.5mL N, N- dimethylformamide was added 11a (32.8mg, 0.16mmol), 2- (7- oxide benzotriazole) -N, N The reaction, N ', N'- tetramethyluronium hexafluorophosphate (62.23mg, 0.16mmol) and N, N- diisopropylethylamine (31.69mg, 0.25mmol), the addition, stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with eluent systems C resulting residue was purified to give the title product 38 (12mg, yield: 36.7%) and 39 (12mg, yield: 36.7%).

Compound 38:

MS m / z (ESI): 549.1 [M + 1];

Chiral HPLC analysis: retention time 16.910 minutes, chiral purity: 98% (Column: Lux Amylose-3 (AD), 4.6 * 150cm Length, 5um; mobile phase: ethanol / n-hexane = 60/40 (v / v )).

1 H NMR (400MHz, CDCl 3 ) δ9.06 (s, 1H), 8.15-8.17 (m, 1H), 8.09 (s, 1H), 7.71-7.73 (m, 1H), 7.57-7.62 (m, 2H ), 7.35-7.39 (m, 1H), 6.47 (s, 1H), 4.91-4.92 (m, 2H), 4.07-4.15 (m, 2H), 3.28-3.30 (m, 2H), 3.14-3.19 (m , 2H), 2.86-2.92 (m, 1H), 2.63-2.66 (m, 1H), 1.90-1.93 (m, 1H), 1.75-1.79 (m, 1H), 1.56-1.64 (m, 3H), 1.31 -1.35 (m, 4H), 1.15-1.17 (m, 2H), 1.08-1.10 (m, 2H).

Compound 39:

MS m / z (ESI): 549.1 [M + 1];

Chiral HPLC analysis: retention time 11.940 minutes, chiral purity: 98% (Column: Lux Amylose-3 (AD), 4.6 * 150cm Length, 5um; mobile phase: ethanol / n-hexane = 60/40 (v / v )).

1 H NMR (400MHz, CDCl 3 ) δ9.06 (s, 1H), 8.15-8.18 (m, 1H), 8.09 (s, 1H), 7.71-7.74 (m, 1H), 7.58-7.62 (m, 2H ), 7.34-7.37 (m, 1H), 6.47 (s, 1H), 4.91-4.92 (m, 2H), 4.08-4.15 (m, 2H), 3.27-3.33 (m, 2H), 3.14-3.19 (m , 2H), 2.86-2.92 (m, 1H), 2.63-2.66 (m, 1H), 1.90-1.94 (m, 1H), 1.75-1.79 (m, 1H), 1.56-1.61 (m, 3H), 1.31 -1.35 (m, 4H), 1.15-1.18 (m, 2H), 1.08-1.10 (m, 2H).

Example 40

2 - ((2-ethyl-piperidin-1-yl) methyl) -N- (4- (ethanesulfonyl) benzyl) -1-isopropyl--1H- indole-5-carboxamide 40

Figure PCTCN2017077114-appb-000092

From 2-ethylpiperidine 40a starting using synthetic routes similar to Example 33, the title product 40 (70mg).

MS m / z (ESI): 510.5 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.08 (s, 1H), 7.90 (d, 2H), 7.65-7.66 (m, 1H), 7.59 (s, 2H), 6.67 (s, 1H), 6.40 ( s, 1H), 5.14-5.16 (m, 1H), 4.82 (s, 2H), 4.09 (d, 1H), 3.42 (d, 1H), 3.14 (q, 2H), 2.61-2.63 (m, 1H) , 2.27-2.29 (m, 1H), 2.09-2.11 (m, 1H), 1.62-1.71 (m, 10H), 1.39-1.49 (m, 4H), 1.31 (t, 3H), 0.94-0.96 (m, 3H).

Example 41

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2 - ((2- (trifluoromethyl) pyridin-3-yl) methyl) lH-indole-5- amide 41

Figure PCTCN2017077114-appb-000093

Example 2 Scheme embodiment employed, the raw material 2a in the first step with 3- (bromomethyl) -2- (trifluoromethyl) pyridine, to give the title product 41 (10mg).

MS m / z (ESI): 544.3 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.62-8.61 (m, 1H), 8.07 (s, 1H), 7.87 (d, 2H), 7.68-7.66 (m, 1H), 7.57-7.55 (m, 3H ), 7.46-7.42 (m, 2H), 6.65 (t, 1H), 6.30 (s, 1H), 4.79 (d, 2H), 4.43-4.40 (m, 1H), 4.37 (s, 2H), 3.10 ( q, 2H), 1.51 (d, 6H), 1.28 (t, 3H).

Example 42

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2- (2- (trifluoromethyl) benzyl) - lH-benzo [d] imidazole-5-carboxamide 42

Figure PCTCN2017077114-appb-000094

From 2- (2- (trifluoromethyl) phenyl) acetic acid 42a (using the method disclosed in "Tetrahedron, 2002,58 (50), 9925-9932" preparation derived) and 3-amino-4- (isopropyl ylamino) starting Example 1 using the synthetic route similar embodiments, the title product 42 (15mg).

MS m / z (ESI): 544.4 [M + 1]; 1 H NMR (400MHz, DMSO-d 6) δ9.13 (t, 1H), 8.17 (s, 1H), 7.77-7.85 (m, 5H) , 7.59-7.62 (m, 3H), 7.51-7.57 (m, 1H), 7.22 (d, 1H), 4.68-4.72 (m, 1H), 4.59 (d, 2H), 4.49 (s, 2H), 3.25 (q, 2H), 1.51 (d, 6H), 1.09 (t, 3H).

Example 43

6-Chloro-1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2- (4-fluoro-2- (trifluoromethyl) benzyl) lH-indole-5 carboxamide 43

Figure PCTCN2017077114-appb-000095

From -1H- indole-6-chloro-5-carboxylate (the method disclosed in patent application "WO2004022712A2" preparation derived) starting, using a similar synthetic route described in Example 4, to give product 43 (2.8mg).

MS m / z (ESI): 593.2 [M + 1]

Example 44

N- (2- chloro-4- (ethylsulfonyl) phenyl) -1-cyclopropyl-2 - ((4- (trifluoromethyl) piperidin-1-yl) methyl) lH-indazol indole-5-carboxamide 44

Figure PCTCN2017077114-appb-000096

Starting, using a similar synthetic route described in Example 8 from 2-chlorobenzyl-amino-4-bromo-tert-butyl ( "WO2005082859A1" obtained by using the method of preparation disclosed in patent application), to give product 44 (10mg).

MS m / z (ESI): 582.2 [M + 1];

1 H NMR (400MHz, CD 3 OD) δ8.11 (s, 1H), 7.95 (s, 1H), 7.83-7.81 (m, 1H), 7.74-7.72 (m, 1H), 7.67-7.63 (m, 2H), 6.48 (s, 1H), 4.75 (s, 2H), 3.80 (s, 2H), 3.29-3.21 (m, 3H), 3.12-3.09 (m, 2H), 2.19-2.09 (m, 3H) , 1.88-1.85 (m, 2H), 1.64-1.54 (m, 2H), 1.24-1.20 (m, 5H), 1.12-1.08 (m, 2H).

Example 45

1-isopropyl -N- (4- (methylsulfonyl) benzyl) -2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 45

Figure PCTCN2017077114-appb-000097

Example embodiments using Scheme 14, the starting material of the fourth step (4- (ethylsulfonyl) phenyl) methanamine to replace (4- (methylsulfonyl) phenyl) methanamine (employed Patent Application "US20160122318A1" disclosed in The method of preparation derived), to give the title product 45 (17.1mg).

MS m / z (ESI): 529.5 [M + 1]

Example 46

N- (4- (ethanesulfonyl) benzyl) -2- (4-fluorobenzyl) -1H- indol-1-isopropyl-5-carboxamide 46

Figure PCTCN2017077114-appb-000098

Synthetic route of Example 14, the raw material 14a in the first step is replaced with 1-bromomethyl-4-fluorobenzene to give product 46 (26mg).

MS m / z (ESI): 493.5 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.11 (s, 1H), 7.85 (d, 2H), 7.67 (d, 1H), 7.53-7.57 (m, 3H), 7.15-7.19 (m, 2H), 7.01-7.05 (m, 2H), 6.87 (t, 1H), 6.3 6 (s, 1H), 4.80 (d, 2H), 4.51-4.58 (m, 1H), 4.16 (s, 2H), 3.11 (q , 2H), 1.49 (d, 6H), 1.30 (t, 3H).

Example 47

N- (4- (ethanesulfonyl) benzyl) -1-methyl-2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 47

Figure PCTCN2017077114-appb-000099

Example 14 Scheme employs embodiment, the second step of the raw material 2-bromopropane replacing iodomethane, to give the title product 47 (26mg).

MS m / z (ESI): 515.5 [M + 1];

1 H NMR (400MHz, CD 3 OD) δ8.10 (s, 1H), 7.88 (d, 2H), 7.71-7.61 (m, 5H), 7.44-7.39 (m, 3H), 6.35 (s, 1H) , 4.70 (s, 2H), 4.31 (s, 2H), 3.63 (s, 3H), 3.19 (q, 2H), 0.90 (t, 3H).

Example 48

2- (4-bromobenzyl) -N- (4- (ethanesulfonyl) benzyl) -1-isopropyl--1H- indole-5-carboxamide 48

Figure PCTCN2017077114-appb-000100

Example 2 Scheme embodiment employs, in the first step the raw material 2a is replaced with 1-bromo-4- (bromomethyl) benzene, to give the title product 48 (58mg).

MS m / z (ESI): 552.9 [M + 1]

Example 49

2- (4-cyanobenzyl) -N- (4- (ethanesulfonyl) benzyl) -1-isopropyl--1H- indole-5-carboxamide 49

Figure PCTCN2017077114-appb-000101

The 48 (50mg, 0.09mmol), cuprous cyanide (17mg, 0.18mmol), and copper iodide (17.1mg, 0.09mmol) dissolved in 1mL N, N- dimethylacetamide at, 200 ℃ conditions, microwave 30 minutes. The reaction was cooled to room temperature, concentrated under reduced pressure, purified by thin layer chromatography in a developing solvent system, the resulting residue was purified by C to give the title product 49 (39mg, yield: 86.7%).

MS m / z (ESI): 500.5 [M + 1]

Example 50

2- (4-carbamoyl-benzyl) -N- (4- (ethanesulfonyl) benzyl) -1-isopropyl--1H- indole-5-carboxamide 50

Figure PCTCN2017077114-appb-000102

The 49 (20mg, 0.04mmol) was dissolved in methanol, was added 0.1mL 0.1mL 2M potassium hydroxide solution and hydrogen peroxide addition was completed, the reaction for 15 minutes. The reaction solution was poured into water, extracted with ethyl acetate (20mL × 3), combined organic phases, the organic phase washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title product 50 (16mg).

MS m / z (ESI): 518.2 [M + 1]

Example 51

N - ((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1-isopropyl-2- (4- (trifluoromethyl) benzyl) lH-indole-5- amide 51

Figure PCTCN2017077114-appb-000103

Example 14 Scheme embodiment employed, the fourth step starting material (4- (ethylsulfonyl) phenyl) methanamine replaced 11a, to give the title product 51 (11mg).

MS m / z (ESI): 544.5 [M + 1]

Example 52

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-3-methyl-2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 52

Figure PCTCN2017077114-appb-000104

Example 14 using the synthetic route, in the first step the raw material 1a is replaced with 3-methyl -1H- indol-5-carboxylate (using well-known methods "RSC Advances, 2015,5 (86), 70329-70332" preparation derived), to give the title product 52 (9mg).

MS m / z (ESI): 557.5 [M + 1]

Example 53

L-Cyclopentyl--N- (4- (ethanesulfonyl) benzyl) -2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 53

Figure PCTCN2017077114-appb-000105

Example 14 Scheme employed embodiment, the second step of replacing 2-bromopropane as starting material bromocyclopentane to give the title product 53 (23mg).

MS m / z (ESI): 569.5 [M + 1]

Example 54

N- (4- (ethylsulfonyl) -2-fluoro-benzyl) -1-isopropyl-2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 54

Figure PCTCN2017077114-appb-000106

Example 14 Scheme embodiment employed, the fourth step starting material (4- (ethylsulfonyl) phenyl) methanamine replaced 8C, to give the title product 54 (11mg).

MS m / z (ESI): 561.5 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.10 (d, 1H), 7.59-7.70 (m, 7H), 7.31-7.35 (m, 2H), 6.82 (t, 1H), 6.38 (s, 1H), 4.83 (d, 2H), 4.50-4.53 (m, 1H), 4.25 (s, 1H), 3.15 (q, 2H), 1.49 (d, 6H), 1.32 (t, 3H).

Example 55

N- (4- (ethanesulfonyl) benzyl) -1-phenyl-2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 55

Figure PCTCN2017077114-appb-000107

Example 20 using the synthetic route, the starting material in Example 20 Step cyclopropyl acid with phenylboronic acid gave the title product 55 (2.7mg)

MS m / z (ESI): 577.1 [M + 1]

1 H NMR (400MHz, CDCl 3 ) δ8.76-8.74 (dd, 1H), 8.44-8.41 (dd, 1H), 8.12 (s, 1H), 7.89-7.87 (d, 2H), 7.61-7.53 (m , 3H), 7.49-7.43 (m, 4H), 7.19-7.17 (m, 2H), 7.11-7.06 (m, 2H), 6.64-6.61 (t, 1H), 6.62 (s, 1H), 6.48 (s , 1H), 4.80-4.78 (d, 2H), 2.25-2.18 (m, 2H), 0.91-0.87 (t, 3H).

Example 56

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2- (3- (trifluoromethyl) benzyl) - lH-benzo [d] imidazole-5-carboxamide 56

Figure PCTCN2017077114-appb-000108

Synthetic route of Example 42, the raw material 42a in the first step is replaced with 2- (3- (trifluoromethyl) phenyl) acetic acid (a known method of "Angewandte Chemie, International Edition, 2010,49 (27), 4665-4668, S4665 / 1-S4665 / 60 "preparation derived), to give the title product 56 (4.6mg)

MS m / z (ESI): 544.5 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.18 (s, 1H), 7.89-7.87 (dd, 1H), 7.83-7.81 (dd, 1H), 7.58-7.39 (m, 7H), 6.72 (s, 1H ), 4.81-4.79 (d, 2H), 4.62-4.55 (m, 1H), 4.42 (s, 2H), 3.14-3.08 (m, 2H), 1.47-1.45 (d, 6H), 1.30-1.262 (t , 3H).

Example 57

N- (4- (ethanesulfonyl) benzyl) -2- (2-fluoro-4- (trifluoromethyl) benzyl) -1-isopropyl--1H- benzo [d] imidazole-5 carboxamide 57

Figure PCTCN2017077114-appb-000109

Example 42 Scheme embodiment employed, the raw material 42a in the first step is replaced with 2- (2-fluoro-4- (trifluoromethyl) phenyl) acetic acid (Admas), to give the title product 57 (4.6mg).

MS m / z (ESI): 562.5 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.18 (s, 1H), 7.84-7.81 (m, 3H), 7.59-7.52 (m, 3H), 7.39-7.27 (m, 3H), 6.87-6.85 (t , 1H), 4.78-4.76 (d, 2H), 4.66-4.59 (m, 1H), 4.39 (s, 2H), 3.12-3.06 (m, 2H), 1.55-1.53 ​​(d, 6H), 2.28-1.24 (t, 3H).

Example 58

N- (4- (ethanesulfonyl) benzyl) -2- (4-fluorobenzyl) -1-isopropyl--1H- benzo [d] imidazole-5-carboxamide 58

Figure PCTCN2017077114-appb-000110

Example 42 Scheme embodiment employed, the raw material 42a in the first step is replaced with 4-fluoro-phenylacetic acid (using well-known methods "RSC Advances, 2016,6 (8), 6719-6723" preparation derived), to give the title product 58 ( 4.6mg).

MS m / z (ESI): 494.5 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.18-8.09 (d, 2H), 7.80-7.75 (dd, 3H), 7.54 (s, 2H), 7.24 (s, 2H), 7.07-7.06 (d, 2H ), 4.80-4.73 (d, 3H), 4.61 (s, 2H), 3.11-3.06 (m, 2H), 1.55-1.53 ​​(d, 6H), 1.31-1.23 (t, 3H).

Example 59

N- (2- chloro-4- (ethylsulfonyl) benzyl) -1-isopropyl-2- (4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 59

Figure PCTCN2017077114-appb-000111

Example 8 Scheme embodiment uses, in the first step is replaced with the raw material 8a-2-chlorobenzyl 4-bromo tert-butyl, the second step is replaced with the raw material 6e 14d, the title product 59 (16mg).

MS m / z (ESI): 577.5 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.08 (s, 1H), 7.52-7.74 (m, 7H), 7.29-7.31 (m, 2H), 6.93 (t, 1H), 6.34 (s, 1H), 4.81 (d, 2H), 4.22 (s, 2H), 3.48 (m, 1H), 3.11 (q, 2H), 1.47 (d, 6H), 1.26 (t, 3H).

Example 60

N- (4- (ethanesulfonyl) benzyl) -1-isopropyl-2- (4- (trifluoromethoxy) benzyl) - lH-benzo [d] imidazole-5-carboxamide 60

Figure PCTCN2017077114-appb-000112

Example 42 using the synthetic route, in the first step the raw material 42a is replaced 4-trifluoromethoxy-phenylacetic acid, the title product 60 (15mg).

MS m / z (ESI): 559.9 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.52 (s, 2H), 8.20-8.18 (d, 1H), 8.00 (s, 1H), 7.83-7.76 (m, 3H), 7.57-7.55 (d, 2H ), 7.35-7.33 (d, 2H), 7.26-7.24 (d, 2H), 4.84-4.81 (m, 2H), 4.68 (s, 2H), 3.16-3.09 (m, 2H), 1.58-1.57 (d , 6H), 1.30-1.26 (t, 3H).

Example 61

N- (4- (ethanesulfonyl) benzyl) -2- (2-fluoro-4- (trifluoromethyl) benzyl) -1-methyl -1H- indol-5-carboxamide 61

Figure PCTCN2017077114-appb-000113

Example 15 using the synthetic route embodiment, the second step of the raw material 2-bromopropane replacing iodomethane, to give the title product 61 (15mg).

MS m / z (ESI): 532.9 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.10 (s, 1H), 7.87 (m, 2H), 7.74 (d, 1H), 7.57 (m, 2H), 7.30-7.37 (m, 3H), 7.21 ( t, 1H), 6.83 (t, 1H), 6.38 (s, 1H), 4.80 (d, 2H), 4.25 (s, 2H), 3.68 (s, 3H), 3.12 (q, 2H), 1.32 (t , 3H).

Example 62

1-ethyl -N- (4- (ethanesulfonyl) benzyl) -2- (4- (trifluoromethyl) benzyl) - lH-benzo [d] imidazole-5-carboxamide 62

Figure PCTCN2017077114-appb-000114

Example 42 using the synthetic route, in the first step the raw material is replaced 42a acid 4-trifluoromethyl, 42b is replaced with 3-amino-4- (ethylamino) benzoate (using well-known methods "Bioorganic & Medicinal Chemistry , 2005,13 (5), 1587-1597 "preparation derived), to give the title product 62 (15mg).

MS m / z (ESI): 530.4 [M + 1]

1 H NMR (400MHz, DMSO- d 6) δ9.16 (t, 1H), 9.21 (s, 1H), 7.83-7.85 (m, 3H), 7.71 (d, 2H), 7.55-7.62 (m, 5H ), 4.60 (d, 2H), 4.47 (s, 2H), 4.27 (t, 2H), 3.26 (q, 2H), 1.23 (t, 3H), 1.09 (t, 3H).

Example 63

1-cyclopropyl -N - ((1- (cyclopropylsulfonyl) piperidin-4-yl) methyl) -2- (4- (trifluoromethyl) benzyl) lH-indole - 5-carboxamide 63

Figure PCTCN2017077114-appb-000115

From (piperidin-4-ylmethyl) carbamate ( "WO2001096303A1" obtained by using the method of preparation disclosed in patent application) starting using synthetic routes similar to Example 19, the title product 63 (15mg).

MS m / z (ESI): 560.5 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ7.95 (m, 1H), 7..63-7.53 (m, 4H), 7.35-7.33 (m, 2H), 6.32-6.27 (m, 2H), 4.31 ( s, 2H), 3.85-3.82 (m, 3H), 3.42-3.39 (t, 2H), 3.10-3.07 (t, 1H), 2.93-2.90 (m, 1H), 2.85-2.78 (m, 3H), 2.29-2.23 (m, 1H), 1.28-1.25 (m, 2H), 1.18-1.16 (m, 4H), 1.06-1.00 (m, 2H), 0.98-0.96 (m, 2H).

Example 64

1-allyl -N- (4- (ethanesulfonyl) benzyl) -2- (2-fluoro-4- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 64

Figure PCTCN2017077114-appb-000116

Example 15 using the synthetic route embodiment, the second step is replaced with the raw material 2-bromopropane, allyl bromide, to give the fourth step the product 64 (13mg).

MS m / z (ESI): 559.4 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.11 (s, 1H), 7.89-7.91 (m, 2H), 7.58-7.63 (m, 3H), 7.37-7.41 (m, 2H), 7.30-7.34 (m , 2H), 6.70 (t, 1H), 5.99 (m, 1H), 5.01 (dd, 2H), 4.81 (d, 2H), 4.21 (s, 3H), 3.61 (d, 2H), 3.14 (q, 2H), 1.31 (t, 3H).

Example 65

1-cyclopropyl -N - ((5- (ethylsulfonyl) pyridin-2-yl) methyl) -2 - ((4- (trifluoromethyl) piperidin-1-yl) methyl) - 1H- indole-5-carboxamide 65

Figure PCTCN2017077114-appb-000117

Example 20 Scheme employed, the first step in Example 20 starting material 19c alternative embodiment of the 33b, the third step of replacing the raw material methylamine (4- (ethylsulfonyl) phenyl) as 11a, to give the title product 65 (38mg ).

MS m / z (ESI): 549.5 [M + 1];

1 H NMR (400MHz, DMSO- d 6) δ9.13 (brs, 1H), 8.97 (s, 1H), 8.27 (d, 1H), 8.15 (s, 1H), 7.75 (d, 1H), 7.59 ( d, 2H), 6.46 (s, 1H), 4.69 (d, 2H), 3.73 (s, 2H), 3.38 (q, 2H), 3.27 (brs, 1H), 3.01 (d, 2H), 2.28 (brs , 1H), 2.07 (t, 2H), 1.78 (d, 2H), 1.47 (q, 2H), 1.06-1.17 (m, 7H).

Example 66

1-ethyl -N- (4- (ethanesulfonyl) benzyl) -2- (piperidin-1-methyl) lH-indole-5-carboxamide 66

Figure PCTCN2017077114-appb-000118
From (prop-2-yn-1-yloxy) tetrahydro -2H- pyran (using well-known methods "ChemCatChem, 2016,8 (18), 2912-2915" preparation derived) starting Example 33 using similar synthetic route, to give the title product 66 (21mg).

MS m / z (ESI): 468.4 [M + 1];

1 H NMR (400MHz, DMSO- d 6) δ9.06 (brs, 1H), 8.13 (s, 1H), 7.83 (d, 2H), 7.73 (brs, 1H), 7.58 (d, 2H), 7.49 ( brs, 1H), 6.41 (s, 1H), 4.58 (d, 2H), 4.27 (brs, 2H), 3.58 (brs, 2H), 3.25 (q, 2H), 2.36 (brs, 3H), 1.79 (brs , 2H), 1.48 (brs, 2H), 1.39 (brs, 2H), 1.31 (brs, 2H), 1.23 (brs, 2H), 1.08 (t, 3H).

Example 67

1-ethyl -N- (4- (ethanesulfonyl) benzyl) -2- (morpholinomethyl) lH-indole-5-carboxamide 67

Figure PCTCN2017077114-appb-000119

Example 66 Scheme embodiment employed, the piperidine starting material replacing the third step of morpholine, gave the title product 67 (21mg).

MS m / z (ESI): 470.4 [M + 1];

1 H NMR (400MHz, DMSO- d 6) δ9.06 (brs, 1H), 8.16 (brs, 1H), 7.83 (d, 2H), 7.73 (brs, 1H), 7.58 (d, 2H), 7.50 ( brs, 1H), 6.47 (brs, 1H), 4.59 (d, 2H), 4.32 (brs, 2H), 3.57-3.64 (m, 4H), 3.36 (brs, 4H), 3.27 (q, 2H), 2.41 (brs, 2H), 1.30 (brs, 3H), 1.08 (t, 3H).

Example 68

1-ethyl -N- (4- (ethanesulfonyl) benzyl) -2 - ((4-methyl-piperazin-1-yl) methyl) lH-indole-5-carboxamide 68

Figure PCTCN2017077114-appb-000120

(Using well-known methods "Chemical Communications (Cambridge, United Kingdom), 2013,49 (61), 6867-6869" preparation derived) from piperazine-1-carboxylate 68a, similar to Synthetic Example 33 using route, the title product 68 (11mg).

MS m / z (ESI): 483.4 [M + 1];

1 H NMR (400MHz, DMSO- d 6) δ9.06 (brs, 1H), 8.15 (s, 1H), 7.83-7.85 (m, 2H), 7.72 (d, 1H), 7.58 (d, 2H), 7.49 (d, 1H), 6.49 (s, 1H), 4.589 (d, 2H), 4.28 (q, 2H), 3.7 (s, 2H), 3.42 (brs, 4H), 3.23 (q, 2H), 2.85 (brs, 4H), 2.60 (s, 3H), 1.31 (t, 3H), 1.09 (t, 3H)

Example 69

N- (4- (ethanesulfonyl) benzyl) -1-methyl-2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 69

Figure PCTCN2017077114-appb-000121

Example embodiments using Scheme 3, the second step is replaced with iodoethane material iodomethane, to give the title product 69 (8mg).

MS m / z (ESI): 515.4 [M + 1];

Example 70

2- (2-bromobenzyl) -N- (4- (ethanesulfonyl) benzyl) -1-isopropyl--1H- indole-5-carboxamide 70

Figure PCTCN2017077114-appb-000122

Synthetic route of Example 1, in the first step the raw material is replaced with 1-bromo-1b-2- (bromomethyl) benzene, the title product 70 (21mg).

MS m / z (ESI): 553.3 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.03 (s, 1H), 7.85 (d, 2H), 7.60-7.64 (m, 2H), 7.53-7.56 (m, 3H), 7.18-7.20 (m, 1H ), 7.12-7.14 (m, 1H), 6.97-6.99 (m, 1H), 6.65 (t, 1H), 6.25 (s, 1H), 4.77 (d, 2H), 4.44-4.49 (m, 1H), 4.23 (s, 2H), 3.09 (q, 2H), 1.53 (d, 6H), 1.28 (t, 3H).

Example 71

2- (2-cyanobenzyl) -N- (4- (ethanesulfonyl) benzyl) -1-isopropyl--1H- indole-5-carboxamide 71

Figure PCTCN2017077114-appb-000123

Example embodiments using Scheme 1, the starting material 1b is a first step to replace 2- (bromomethyl) benzonitrile, the title product 71 (15mg).

MS m / z (ESI): 500.2 [M + 1]

Example 72

2- (2-cyclopropyl-benzyl) -N- (4- (ethanesulfonyl) benzyl) -1-isopropyl--1H- indole-5-carboxamide 72

Figure PCTCN2017077114-appb-000124

From 1-bromo-2- (bromomethyl) benzene starting a similar synthetic route of Example 1, gave the title product 72 (9mg).

MS m / z (ESI): 515.3 [M + 1];

Example 73

N- (4- (ethylsulfonyl) -2-chloro-benzyl) -1-isopropyl-2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 73

Figure PCTCN2017077114-appb-000125

Example 8 Scheme embodiment adopts, in the first step the raw material is replaced 8a chlorobenzyl tert-butyl bromo-2, gave the title product 73 (11mg).

MS m / z (ESI): 577.1 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.07 (d, 1H), 7.88 (d, 1H), 7.53-7.73 (m, 6H), 7.35-7.44 (m, 2H), 7.06 (d, 1H), 6.31 (s, 1H), 4.79 (d, 2H), 4.38-4.45 (m, 1H), 4.34 (s, 2H), 3.11 (q, 2H), 1.48 (d, 6H), 1.27 (t, 3H)

Example 74

1-cyclopropyl-2 - ((4,4-difluoro-1-yl) methyl) -N - ((5- (ethylsulfonyl) pyridin-2-yl) methyl) lH- indole-5-carboxamide 74

Figure PCTCN2017077114-appb-000126

first step

1-cyclopropyl-2 - ((4,4-difluoro-1-yl) methyl) lH-indole-5-carbonitrile 74b

Starting from 4,4-difluoropiperidine, using synthetic routes similar to Example 38, the title product 74 (10mg). MS m / z (ESI): 517.5 [M + 1];

Example 75

6-Chloro-1-cyclopropyl -N - ((1- (ethanesulfonyl) piperidin-4-yl) methyl) -2- (4- (trifluoromethyl) benzyl) lH-indazol indole-5-carboxamide 75

Figure PCTCN2017077114-appb-000127

From -1H- indole-6-chloro-5-carboxylate, using the synthetic routes similar to Example 19, the title product 75 (5mg).

MS m / z (ESI): 582.2 [M + 1]

Example 76

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2- (4- (trifluoromethyl) benzoyl) lH-indole-5-carboxamide 76

Figure PCTCN2017077114-appb-000128

Starting from 20a, using the synthetic route similar to Example 1, to give the title product 76 (35mg).

MS m / z (ESI): 555.3 [M + 1];

1 H NMR (400MHz, DMSO- d 6) δ9.21 (t, 1H), 8.33 (s, 1H), 8.11 (d, 2H), 7.96-7.98 (m, 3H), 7.84 (d, 2H), 7.74 (d, 1H), 7.59 (d, 2H), 7.13 (s, 1H), 4.60 (d, 2H), 3.62-3.67 (m, 1H), 3.25 (q, 2H), 1.15 (brs, 2H) , 1.08 (t, 3H), 0.80-0.84 (m, 2H)

Example 77

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2- (hydroxy (4- (trifluoromethyl) phenyl) methyl) lH-indole-5-carboxamide 77

Figure PCTCN2017077114-appb-000129

The 76 (10mg, 0.018mmol) was dissolved in 4mL of methanol and a mixed solvent of tetrahydrofuran (V: V = 3: 1), sodium borohydride (1.5mg, 0.036mmol), stirred for 2 hours. (: 96% 9.7mg, yield) by thin layer chromatography the reaction was concentrated and the obtained residue A purification system was developing solvent, to give the title product 77 under reduced pressure.

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

1 H NMR (400MHz, DMSO- d 6) δ9.06 (brs, 1H), 8.11 (s, 1H), 7.83 (d, 2H), 7.73-7.75 (m, 3H), 7.67 (d, 2H), 7.56-7.58 (m, 3H), 6.27 (d, 1H), 6.24 (d, 1H), 6.18 (s, 1H), 4.57 (d, 2H), 3.25 (q, 2H), 3.02-3.07 (m, 1H), 1.15 (brs, 2H), 1.07 (t, 3H), 0.84 (m, 2H).

Example 78

(S) -1- cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2 - ((2- (trifluoromethyl) piperidin-1-yl) methyl) lH-indazol indole-5-carboxamide 78

Figure PCTCN2017077114-appb-000130

Synthetic route of Example 39, the sixth step is replaced with a raw material 11a 4- (ethylsulfonyl) phenyl) methanamine, the title product 78 (20mg).

MS m / z (ESI): 548.6 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.07 (s, 1H), 7.85-7.87 (m, 2H), 7.70-7.73 (m, 1H), 7.62-7.64 (m, 1H), 7.4-7.56 (m , 2H), 6.82-6.85 (m, 1H), 6.63 (s, 1H), 4.79-4.80 (m, 2H), 4.40-4.54 (m, 2H), 3.83-3.86 (m, 1H), 3.33-3.40 (m, 3H), 3.08-3.14 (m, 2H), 2.85-2.89 (m, 1H), 2.01-2.04 (m, 2H), 1.63-1.80 (m, 5H), 1.42-1.43 (m, 1H) , 1.03-1.08 (m, 2H), 0.87-0.90 (m, 2H).

Example 79

N- (4- (ethanesulfonyl) benzyl) -6-fluoro-1-isopropyl-2- (2- (trifluoromethyl) benzyl) lH-indole-5-carboxamide 79

Figure PCTCN2017077114-appb-000131

From 6-fluoro-l- (triisopropylsilyl) lH-indole-5-carboxylate 79a (using well-known methods "European Journal of Organic Chemistry, 2006, (13), 2956-2969" prepared derived) starting using synthetic routes similar to Example 6, the title product 79 (6mg).

MS m / z (ESI): 561.4 [M + 1];

1 H NMR (400MHz, CDCl 3 ) δ8.38 (d, 1H), 7.91 (d, 2H), 7.76 (d, 1H), 7.61 (d, 2H), 7.47 (t, 1H), 7.42 (s, 1H), 7.30-7.35 (m, 1H), 7.24 (d, 1H), 7.10 (d, 1H), 6.35 (s, 1H), 4.85 (d, 2H), 4.39-4.42 (m, 1H), 4.34 (s, 2H), 1.34 (q, 2H), 1.49 (d, 6H), 1.32 (t, 3H).

Example 80

1-cyclopropyl -N - ((5- (ethylsulfonyl) pyridin-2-yl) methyl) -2- (4 - (- (trifluoromethyl) benzyl) lH-indol-5 - carboxamide 80

Figure PCTCN2017077114-appb-000132

Example 20 using the synthetic route, a third step the raw material (4- (ethylsulfonyl) phenyl) methanamine replaced 11a, to give the title product 80 (60mg).

MS m / z (ESI): 542.4 [M + 1];

1 H NMR (400MHz, DMSO- d 6) δ9.09 (t, 1H), 8.95 (d, 1H), 8.25 (dd, 1H), 8.11 (d, 1H), 7.70-7.73 (m, 3H), 7.57 (t, 2H), 7.51 (d, 2H), 6.25 (s, 1H), 4.68 (d, 2H), 4.38 (s, 2H), 3.39 (q, 2H), 2.97-2.99 (m, 1H) , 1.11-1.16 (m, 5H), 1.00-1.02 (m, 2H).

Example 81

2- (4-chloro-2- (trifluoromethyl) benzyl) -N- (4- (ethanesulfonyl) benzyl) -6-fluoro-1- (2-fluoroethyl) lH-indazol indole-5-carboxamide 81

Figure PCTCN2017077114-appb-000133

Example 5 using the synthetic route embodiment, the first step is replaced with the raw material 79B 5a, the second step is replaced with the raw material 2-bromopropane 1-bromo-2-fluoroethane, to give the title product 81 (55mg).

MS m / z (ESI): 599.4 [M + 1];

1 H NMR (400MHz, DMSO- d 6) δ8.76 (brs, 1H), 7.84-7.86 (m, 3H), 7.79 (d, 1H), 7.76 (d, 1H), 7.58-7.60 (m, 2H ), 7.48 (d, 1H), 7.34 (d, 1H), 5.94 (s, 1H), 4.73 (brs, 1H), 4.57-4.61 (m, 3H), 4.51 (brs, 1H), 4.44 (brs, 1H), 4.31 (s, 2H), 3.26 (q, 2H), 1.09 (t, 3H).

Example 82

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2 - ((6- (trifluoromethyl) pyridin-3-yl) methyl) lH-indole-5- amide 82

Figure PCTCN2017077114-appb-000134

5- (bromomethyl) -2- (trifluoromethyl) pyridine starting in Example 1 using the synthetic route similar embodiments, the title product 82 (55mg) from.

MS m / z (ESI): 542.2 [M + 1];

1 H NMR (400MHz, DMSO- d 6) δ9.03 (t, 1H), 8.77 (s, 1H), 8.08 (s, 1H), 7.94 (d, 1H), 7.83-7.89 (m, 3H), 7.71 (d, 1H), 7.54-7.59 (m, 3H), 6.18 (s, 1H), 4.58 (d, 2H), 4.42 (s, 2H), 3.25 (q, 2H), 3.02-3.06 (m, 1H), 1.10-1.12 (m, 2H), 1.08 (t, 3H), 1.02-1.03 (m, 2H).

Example 83

1-cyclopropyl -N- (4- (ethanesulfonyl) benzyl) -2 - ((5- (trifluoromethyl) pyridin-2-yl) methyl) lH-indole-5- amide 83

Figure PCTCN2017077114-appb-000135

Starting from 2- (bromomethyl) -5- (trifluoromethyl) pyridine (patent application uses "WO2009103478A1" disclosed a process for preparing obtained), using synthetic routes similar to Example 1, the title product 83 (12mg) .

MS m / z (ESI): 542.2 [M + 1]

Example 84

1-cyclopropyl -N - ((5- (ethylsulfonyl) pyridin-2-yl) methyl) -6-fluoro-2 - ((4- (trifluoromethyl) piperidin-1-yl) methyl) lH-indole-5-carboxamide 84

Figure PCTCN2017077114-appb-000136

From amino-2-fluorobenzoate using synthetic routes similar to Example 33 to give the title product 84 (27mg).

MS m / z (ESI): 566.5 [M + 1]

Example 85

1-cyclopropyl -N - ((5- (ethylsulfonyl) pyridin-2-yl) methyl) -2 - ((3-methyl-5- (trifluoromethyl) lH-pyrazole - 1- yl) methyl) lH-indole-5-carboxamide 85

Figure PCTCN2017077114-appb-000137

Example 31 Scheme embodiment employed, the sixth step is replaced 31i material 11a, the title product 85 (30mg).

MS m / z (ESI): 546.5 [M + 1];

1 H NMR (400MHz, DMSO- d 6) δ9.12 (brs, 1H), 8.95 (s, 1H), 8.23-8.25 (m, 1H), 8.13 (s, 1H), 7.78 (d, 1H), 7.57-7.62 (m, 2H), 6.79 (s, 1H), 6.17 (s, 1H), 5.72 (s, 2H), 4.67 (s, 2H), 3.39 (d, 2H), 3.21 (brs, 1H) , 2.20 (s, 3H), 1.11-1.16 (m, 5H), 1.01 (brs, 2H).

Biological Evaluation

Test further described below in conjunction with embodiments of the present invention is explained, but these examples are not meant to limit the scope of the present invention.

Test Example 1, an assay in vitro activity of the compounds RORγ embodiment of the present invention

First, experimental materials and equipment

1.

Figure PCTCN2017077114-appb-000138
TR-FRET RORγ coactivator System (Life Technologies)

2.RORγLBD (AB Vector)

3.DMSO (SigmaAldrich)

4.384-well cell culture plates (Perkin Elmer)

5. microplate reader (a Tecan)

Second, the experimental procedures

Using LanthaScreen TR-FRET (time-resolved fluorescence resonance energy transfer) system RORy coactivator screening modulating compounds of the present invention RORy activity.

First, the complete formulation buffer D (complete TR-FRET Coregulator) (Life Technologies) containing a final concentration of 5mM DTT. Final DMSO concentration of 2%. Test compounds were serially diluted 2x final concentration in the full buffer D containing 2% DMSO, the highest dose of 60μm. 10μl / well of 384 well plate assay wells (PerkinElmer). Each test compound is provided with two parallel control wells at the same concentration. Ready 4X RORγLBD (AB Vector). Full Buffer D using diluted RORγLBD concentration 1ng / μL. 5μl / well of assay wells 384 well assay plate. Negative control wells was 5μL complete buffer D, no RORγLBD. Buffer D using a fully formulated containing 0.6μM fluorescein -D22 (4X) 8nM and terbium (Tb) labeled anti-GST antibody (4X) (Life Technologies) mixture, the mixture was added to 5μL 384-well plate. The total reaction system was 20μL. Mix gently on a shaker in the dark for 384-well plates and 2-4 hours at room temperature.

Using Tecan Infinite M1000 detecting fluorescence readings by GraphPad Prism 6.0 software emission logarithmic curve plotted compound concentration ratio of wavelength 520nm / 495nm was calculated 50 / EC 50 value of the test compound IC.

RORγ compounds of the invention in vitro activity was measured by the above test, the measured IC 50 / EC 50 values are shown in Table 1.

Table 1 Compound IC50 values of the present invention in vitro activity IC RORγ 50 / EC

Figure PCTCN2017077114-appb-000139

Figure PCTCN2017077114-appb-000140

Figure PCTCN2017077114-appb-000141
a: If the inverse agonist is, the value denoted IC 50; if it is an agonist, the value denoted EC 50.

Conclusion: The compounds of the present invention has a significant effect on the regulation RORγ activity in vitro experimental results shown in the general formula (I) are shown in changing the A ring substituents different mechanisms regulating RORγ display in vitro activity, the A ortho larger ring substituents: when (e.g. trifluoromethyl, methoxy, ethyl, trifluoromethoxy), exhibit agonistic effects (see Examples 1,2,4,6 and 10, etc.), the a ring at the ortho position with a smaller substituent group (e.g.: a hydrogen atom, fluorine), exhibited inhibition effect (see Examples 15, 17 and 18, etc.).

Test Example 2, the activity of enzyme-linked immunosorbent assay for the quantitative analysis of IL-17A Example Compound of the invention

First, experimental materials and equipment

1. Human peripheral blood mononuclear cells (PBMC) (Zenbio)

2. Lymphocyte medium (ZenBio)

3.TexMACS (Miltenyi Biotec)

4. Human Cytostim (Miltenyi Biotec)

The human IL-17 ELISA kits (R & D Systems)

6.CO 2 incubator (Fisher Scientific)

7. Centrifuge (Fisher Scientific)

8.96-well cell culture plate (Fisher Scientific)

9. microplate reader (a Tecan)

Second, the experimental procedures

Of frozen human peripheral blood mononuclear cells (PBMC) rapid recovery of lymphocytes preheated medium, centrifuged at 1000rpm, 10min, cell culture supernatant was removed, the cells were gently resuspended in TexMACS medium, cells were counted. Proportionally cell suspension was added to T cell activation agent cytostim (10μl / ml), and then at a density of 1 × 105 peripheral blood mononuclear cells / well Cells were seeded in 96-well cell culture plate. Use TexMACS medium dilutions of the test compound were added to each test well, 2-3 parallel wells each. Preparation containing only negative control wells containing no cells cytostim to obtain a background reading. The cell culture plate was placed in a 5% carbon dioxide incubator at 37 [deg.] C incubated for 3 days. 3 days after the drug treatment cells were harvested culture supernatant was centrifuged to remove suspended solids. Then IL-17A IL-17A quantitative ELISA kits supernatant. Calculated using GraphPad Prism 6.0 50 / EC 50 value of the test compound IC.

Compounds of the invention analyzed by the above tests was measured quantitative enzyme-linked immunosorbent IL-17A, the measured IC 50 / EC 50 values are shown in Table 2.

TABLE 2 Compound IC 50 value of the invention enzyme-linked immunosorbent quantitative analysis of IL-17A 50 / EC

Figure PCTCN2017077114-appb-000142

Figure PCTCN2017077114-appb-000143

a: If the inverse agonist is, the value denoted IC 50; if it is an agonist, the value denoted EC 50.

Conclusion: The compounds of the invention enzyme-linked immunosorbent quantitative analysis of IL-17A activity has a significant regulatory role.

Vivo efficacy studies Example Compound Test Example 3, embodiments of the present invention

First, experimental materials and equipment

1. -PD-1 anti-mouse antibody (BioXCell)

2. mouse IgG2a (BioXcell)

Second, the experimental procedures

By detecting MC38 mouse colon tumor growth in syngeneic C57BL / 6 mice to evaluate anti-tumor activity alone or in vivo Example 30 Example 30 with anti-mouse antibody combination -PD-1 embodiment embodiment.

The MC38 cells (5 × 10 5) subcutaneously implanted in the right side of the abdomen of each mouse to be 5 days, when the tumor grew to 40-80mm 3, mice were randomized into 4 groups, each administration. Grouped as follows:

① The first group: control group, the control antibody is administered in combination with CMC-Na formulation with the solvent IgG2a isotype. Wherein the dosing regimen solvent formulations CMC-Na with the first group of drugs ② alone group, IgG2a isotype control antibody dosing regimen with the first group ③ antibody alone group.

The first group ②: a drug alone group, administered daily (Example 30,12.5mg / kg) 2 times for consecutive 21 days.

③ The first group: antibody alone group, i.e. in FIG. 1, "an anti-PD-1 antibody" group, 5,8,1 1, 14 days after the first tumor bearing mice species, carried by peritoneal tumor MC38 (ip) injections anti-mouse PD-1 (CD279) antibody (BioXcell) (5mg / only).

④ The first group: Example 30 Compound antibody combination group, i.e., FIG. 1, "an anti-PD-1 antibody + Example 30." Wherein the antibody administration group with the first antibody alone ③ dosing regimen, compound of Example 30 with the administration of the drug alone group ② regimen embodiment.

Tumor volumes were measured with calipers in three dimensions, and then calculated according to the formula:

Tumor volume (mm 3) = l × w × h × 0.5236, where 1 denotes the length of tumor, W represents the width of the tumor, h represents a height of the tumor in mm.

As shown in FIG 1, when administered alone in Example 30 12.5mg / kg embodiment, 34% TGI. When injected alone anti-mouse PD-1 (CD279) antibody (5mg / only), TGI of 25%. When the combination Example 30 (12.5mg / kg) and anti-mouse PD-1 monoclonal antibody (5mg / only) embodiment, showed strong synergistic effects (TGI 68%).

TGI% = 100x (TV control -TV -TV initial tumor) / (initial -TV TV control), where TGI = Tumor growth inhibition rate; TV control = tumor volume of control group; Tumor Volume TV = tumor treatment group; TV initial tumor volume = 5 days.

These data indicate that in the MC38 colon tumor model, administration of Example 30 alone showed antitumor activity embodiment, simultaneously with the 30 combination cases of PD-1 antibody showed strong synergism, which also shows embodiment 30 embodiment has RORγ activation (instead of suppression) consistent with biological activity, in order to improve the efficacy of immunotherapy has opened up new avenues.

Claims (29)

  1. : Compound (I) of formula
    Figure PCTCN2017077114-appb-100001
    Or a tautomer thereof, the racemates, racemates, enantiomers, or a non-isomeric forms of a mixture of enantiomers, or a pharmaceutically acceptable salt thereof,
    among them:
    X, Y are identical or different and Z, and are each independently CR 9 or N;
    They are identical or different ring A and ring B, and are each independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
    R 1 and R 2 identical or different and are each independently selected from hydrogen atom, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxy, cyano, heterocyclyl , aryl, heteroaryl, -OR 8, -C (O) R 8, -C (O) NHR 8, -C (O) OR 8 and -S (O) m R 8, wherein alkyl, cycloalkyl, alkoxy, haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted aryl group selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl group, one or more cycloalkyl, heterocyclyl, aryl and heteroaryl groups substituted with a substituent;
    R 3 and R 4 are the same or different and are each independently selected from hydrogen atom, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxy, cyano, heterocyclyl , aryl, heteroaryl, -OR 8, -C (O) R 8, -C (O) OR 8 and -S (O) m R 8, wherein the alkyl, cycloalkyl, haloalkyl group, heterocyclyl group, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;
    Or R 3 and R 4 form an oxo group;
    R 5 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkenyl, alkynyl, aryl, heteroaryl, -OR 8, -C (O) R 8, -C (O) OR 8 and -S (O) m R 8, wherein said alkyl, cycloalkyl, haloalkyl, aryl, and heteroaryl are each independently optionally substituted aryl group selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxyl, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups one or more of substituents;
    R 6 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxyl, cyano, heterocyclyl, aryl, heteroaryl, -OR 8, -C (O) R 8 , -C (O) OR 8 and -S (O) m R 8, wherein the alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl and heteroaryl each optionally substituted group independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group with one or more substituents;
    R 7 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, heterocyclyl, aryl and heteroaryl;
    R 8 is selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxyalkyl, hydroxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, amino, cycloalkyl alkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, halo, hydroxy, amino, carboxylic acid ester group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl alkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;
    R 9 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkenyl, alkynyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl , haloalkyl, aryl, and heteroaryl are each independently optionally substituted aryl group selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxyl, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl , cycloalkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;
    m is 0, 1 or 2;
    x is 2, 3 or 4;
    y is 2 or 3; and
    z is 3 or 4.
  2. A compound represented by formula (I) according to claim 1, which is a compound of formula (II) shown below:
    Figure PCTCN2017077114-appb-100002
    among them:
    X is CR 9 or N;
    Y is CH or N;
    R 9 is a hydrogen atom or alkyl;
    Ring A, ring B, R 1 ~ R 7, x, y and z are as defined in claim 1 and claim.
  3. The compounds of general formula (I), wherein A and B rings are the same or different and are each independently selected from heterocyclyl, aryl and heteroaryl claim 1 or claim 2.
  4. A compound of the formula (I), as claimed in any of claims 1 to 3, which is a compound of formula (II-A) shown below:
    Figure PCTCN2017077114-appb-100003
    among them:
    X is CR 9 or N; R 9 is a hydrogen atom or an alkyl group;
    G is CH or N;
    R a is selected from alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, bromo, amino, nitro, hydroxyl, cyano, heterocyclyl, aryl, heteroaryl, -OR 8, - C (O) R 8, -C (O) NHR 8, -C (O) OR 8 and -S (O) m R 8, wherein the alkyl, cycloalkyl, alkoxy, haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted aryl group selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl group, heterocyclyl group, aryl and heteroaryl groups with one or more substituents;
    p is 2 or 3;
    Ring A, R 1 ~ R 8, m, y and z are as defined in claim 1 and claim.
  5. Compounds of general formula 4 in the (II-A) according to claim shown, wherein
    Figure PCTCN2017077114-appb-100004
    Selected
    Figure PCTCN2017077114-appb-100005
  6. A compound of the formula (I), as claimed in any of claims 1 to 3, which is a compound of formula (III) shown below:
    Figure PCTCN2017077114-appb-100006
    among them:
    X is CR 9 or N;
    Y is CH or N;
    R 9 is a hydrogen atom or alkyl;
    Ring A, R 1 ~ R 7, x, y and z are as defined in claim 1.
  7. One of the Formula (I), a compound according to claim 1 to 3 and 6, any one which is a compound of formula (IV) shown below:
    Figure PCTCN2017077114-appb-100007
    among them
    X is CR 9 or N;
    Y is CH or N;
    R 9 is a hydrogen atom or alkyl;
    R 1 ~ R 7, x, y and z are as defined in claim 1.
  8. A compound of the formula (I), according to claims 1 to 3 and 6 to 7, which is a compound of formula (IV-A) shown below:
    Figure PCTCN2017077114-appb-100008
    among them:
    X is CR 9 or N;
    Y is CH or N;
    R 9 is a hydrogen atom or an alkyl group;
    R a is selected from alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, nitro, hydroxyl, cyano, heterocyclyl, aryl, heteroaryl, -OR 8, -C ( O) R 8, -C (O ) NHR 8, -C (O) OR 8 and -S (O) m R 8, wherein the alkyl, cycloalkyl, alkoxy, haloalkyl, heterocycle , aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;
    p is 1, 2 or 3; and
    R 1 ~ R 8, m, y and z are as defined in claim 1 and claim.
  9. Compound represented by Formula (IV-A) according to claim 8, which is a compound of formula (IV-A-1) shown below:
    Figure PCTCN2017077114-appb-100009
    among them:
    R 1 ~ R 7, p, y and z are as defined in claim 8.
  10. 1 to 9 compounds of general formula according to any one of (I), according to claim, wherein R 1 is selected hydrogen atom, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, halo , cyano, heterocyclyl and -C (O) NHR 8, wherein said alkyl, cycloalkyl, alkoxy and heterocyclyl groups are each independently selected from optionally substituted alkyl, halogen, hydroxy, amino and one or more cyano substituents; preferably, R 1 is selected from alkyl, halo, haloalkyl, alkoxy and haloalkoxy; R 8 is selected from a hydrogen atom or an alkyl group.
  11. The compounds of general formula (I), wherein R 2 is halogen, 1 to 10 in any one of claim 1; preferably fluoro or chloro.
  12. The compounds of general formula (I), wherein R 3 are identical or different and R 4, and are each independently selected from hydrogen atom, alkyl, haloalkyl and hydroxy 1 to 11 according to any one of the claims, together form oxo, or R 3 and R 4.
  13. 1 to 12 according to formula according to any one of (I) a compound of the claims, wherein R 5 is selected from alkyl, cycloalkyl, haloalkyl, alkenyl and aryl, wherein the alkyl group , cycloalkyl and aryl groups are each independently selected from optionally substituted alkyl, substituted with halo, alkenyl group and a hydroxyl group one or more substituents; preferably R 5 is isopropyl or cyclopropyl.
  14. The compounds of general formula (I), wherein R 7 is selected from halogen, optionally 1 to 13 according to any one of the claims, one or more cycloalkyl and hydroxy group substituted with a substituent alkyl group; R 7 is preferably ethyl.
  15. A compound according to any of claims 1 to 14, selected from:
    Figure PCTCN2017077114-appb-100010
    Figure PCTCN2017077114-appb-100011
    Figure PCTCN2017077114-appb-100012
  16. The general formula (V) compound shown:
    Figure PCTCN2017077114-appb-100013
    Or a tautomer thereof, the racemates, racemates, enantiomers, or a non-isomeric forms of a mixture of enantiomers, or a pharmaceutically acceptable salt thereof,
    among them:
    X, Y are identical or different and Z, and are each independently CR 9 or N;
    Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
    R 1 is selected hydrogen atom, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxyl, cyano, heterocyclyl, aryl, heteroaryl, -OR 8, -C (O) R 8 , -C (O) NHR 8, -C (O) OR 8 and -S (O) m R 8, wherein the alkyl, cycloalkyl, alkoxy, haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted aryl group selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl , cycloalkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;
    R 3 and R 4 are the same or different and are each independently selected from hydrogen atom, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxy, cyano, heterocyclyl , aryl, heteroaryl, -OR 8, -C (O) R 8, -C (O) OR 8 and -S (O) m R 8, wherein the alkyl, cycloalkyl, haloalkyl group, heterocyclyl group, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;
    Or R 3 and R 4 form an oxo group;
    R 5 is selected from alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkenyl, alkynyl, aryl, heteroaryl, -OR 8, -C (O) R 8, - C (O) OR 8 and -S (O) m R 8, wherein said alkyl, cycloalkyl, haloalkyl, aryl, and heteroaryl are each independently optionally substituted aryl group selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups one or more of substituents;
    R 6 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxyl, cyano, heterocyclyl, aryl, heteroaryl, -OR 8, -C (O) R 8 , -C (O) OR 8 and -S (O) m R 8, wherein the alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl and heteroaryl each optionally substituted group independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group with one or more substituents;
    R 8 is selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxyalkyl, hydroxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, amino, cycloalkyl alkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, halo, hydroxy, amino, carboxylic acid ester group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl alkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;
    R 9 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkenyl, alkynyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl , haloalkyl, aryl, and heteroaryl are each independently optionally substituted aryl group selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxyl, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl , cycloalkyl, heterocyclyl, aryl and heteroaryl groups with one or more substituents;
    m is 0, 1 or 2;
    x is 2, 3 or 4;
    y is 2 or 3.
  17. A process for preparing the formula according to claim 1 of a compound (I), the method comprising:
    Figure PCTCN2017077114-appb-100014
    Formula (V) with a compound of formula (VI) condensation reaction of a compound of general formula (I) compounds;
    among them:
    Ring A, ring B, X, Y, Z, R 1 ~ R 7, x, y and z are as defined in claim 1 and claim.
  18. A pharmaceutical composition which comprises a therapeutically effective amount of the claim formula (I) compounds represented, and one or more pharmaceutically acceptable carriers 1 to 15 according to any preceding claim, diluent or excipients.
  19. 1 to 15 according to formula according to any one of claims (I) or a compound represented by the pharmaceutical composition according to claim 18 as ROR adjusting agent for the prevention and / or treatment of inflammation, autoimmune disease, tumor or cancer drugs in use.
  20. 1 to 15 according to formula according to any one of claims (I) or a compound represented by the pharmaceutical composition according to claim 18 in the manufacture of a ROR inverse agonists for the prevention and / or treatment of inflammation or itself Drug use in autoimmune diseases.
  21. According to formula (I) or a compound represented by the pharmaceutical composition according to claim 18 as ROR agonist for the prevention and / or treatment of tumor or cancer 1 to 15 in any one of claims drug use.
  22. A compound of formula 8-9 according to any one of (IV-A) as shown in claim ROR agonist for the prevention and / or treatment of tumors or the use of cancer.
  23. The compound represented by Formula (I) or a pharmaceutical composition according to claim 18 for the preparation of agonist anti-ROR 1 to 15 in any one of claims PD-1 antibody compositions for treating tumors or cancer drugs in use.
  24. Compounds of general formula (IV-A) shown in FIG. 8 to 9 according to claim ROR as an agonist for the manufacture of a medicament an anti-PD 1-antibody in combination with treatment of tumors or cancer.
  25. 1 to 15 according to formula according to any one of claims (I) or a compound represented by ROR adjustment in the preparation of a medicament in the pharmaceutical composition according to claim 18.
  26. Compound of formula (I) 1 ~ 15 in any one of the claims or an agonist for the manufacture of a medicament ROR pharmaceutical composition according to claim 18;
  27. Use of a compound represented by the agonist in the manufacture of a medicament ROR formula (IV-A) according to claim 8 to 9.
  28. The use according to claim 20, wherein the inflammatory or autoimmune disease is selected from psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, inflammatory bowel disease, ankylosing spondylitis inflammation, chronic obstructive pulmonary disease, glomerulonephritis, myocarditis, thyroiditis, dry eye, uveitis, Behcet's disease, asthma, atopic dermatitis, acne, Crohn's disease, ulcerative colitis, systemic lupus erythematosus lupus, scleroderma, dermatomyositis bronchitis and allergic rhinitis.
  29. 21 ~ 24 The use according to any one of claims, wherein the tumor or cancer is selected from non-Hodgkin's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer , cervix, colon, lung, stomach, colorectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, renal cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube cancer, ovarian tumor, peritoneum tumor, IV melanoma, a solid tumor, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck cancer, leukemia, lymphoma, myeloma, and non-small cell lung cancer.
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