CN109485595A

CN109485595A - Indole carboxamides analog derivative, preparation method and its application in medicine that hydrophilic radical replaces

Info

Publication number: CN109485595A
Application number: CN201811055424.2A
Authority: CN
Inventors: 陆标; 刘�东; 沈晓冬; 陈磊; 刘苏星; 张儒民; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Shandong Shengdi Pharmaceutical Co ltd; Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2017-09-12
Filing date: 2018-09-11
Publication date: 2019-03-19
Anticipated expiration: 2038-09-11
Also published as: CN109485595B

Abstract

Indole carboxamides analog derivative, preparation method and its application in medicine replaced the present invention relates to hydrophilic radical.Particularly, the present invention relates to the indole carboxamides analog derivative of the substitution of hydrophilic radical shown in logical formula (I), preparation method and contain the pharmaceutical composition of the derivative, the invention further relates to it as the purposes of ROR agonist and its purposes for being used to prevent and/or treat tumour or cancer, and each substituent group in formula of (I) is identical as the definition in specification.

Description

Hydrophilic radical replace indole carboxamides analog derivative, preparation method and its Application pharmaceutically

Technical field

The invention belongs to field of medicaments, are related to indole carboxamides analog derivative, the preparation method of hydrophilic radical substitution And its application in medicine.Particularly, the present invention relates to the indole carboxamides that hydrophilic radical shown in logical formula (I) replaces Analog derivative, preparation method and the pharmaceutical composition containing the derivative, the invention further relates to its as ROR agonist with And its purposes in the drug for preventing and/or treating tumour or cancer.

Background technique

Retinoic acid-related orphan nuclear receptor (Retinoid-related orphan receptors, ROR) is nuclear receptor man One of member of race, and the transcription factor of a kind of ligand-dependent, it can regulate and control a variety of physiology and biochemical process, including life Grow (the Mech Dev.1998Jan, 70 (1-2:147-53 such as development, metabolism, immune system； EMBO J.1998Jul 15,17(14):3867-77).ROR family includes three types ROR α, ROR β and ROR γ (Curr Drug Targets Inflamm Allergy.2004Dec, 3 (4): 395-412), wherein ROR γ can be expressed in many tissues, including chest Gland, liver, kidney, fat and skeletal muscle etc. (Immunity.1998Dec, 9 (6): 797-806.).

There are two types of hypotypes by ROR γ: ROR γ 1 and ROR γ t (ROR γ 2), wherein ROR γ 1 is expressed in many tissues, Such as: it is expressed in thymus gland, muscle, kidney and liver, and ROR γ t then only expresses (Eur J in immunocyte Immunol.1999Dec,29(12):4072-80).It has been reported that ROR γ t can be adjusted in immune cell differentiation The survival of T cell in the process, and can activate and promote the cell differentiation of CD4+, CD8+ at T helper cell 17 (Th17) and cell Cytotoxic T cell (Tc17) (J Immunol.2014Mar 15,192 (6): 2564-75), wherein TH17 and Tc17 cell is one Class effector cell promotes inflammatory reaction, enhancing to obtain by secretion interleukin-17 (IL-17) and other inflammatory factors (such as IL-21) Obtain property immune response and autoimmune response.In addition, existing, there are some researches prove by being transplanted to lotus knurl for Th17 and Tc17 cell In mouse, it can obviously inhibit the growth (J Immunol.2010Apr 15,184 (8): 4215-27) of transplantable tumor.Th17 is also Cytotoxicity CD8+T cell can be recruited and natural killer cells enters tumor microenvironment, to kill tumour cell, reached Antitumor purpose (Blood.2009Aug 6,114 (6): 1141-9；Clin Cancer Res.2008Jun 1,14(11): 3254-61).Therefore, ROR γ t is activated, it is possible to as new antitumor therapy.

Currently, existing pharmaceuticals develops the agonist of ROR γ t, such as small point of the exploitation of Lycera Corp. company Sub- drug LYC-54143.Preclinical study shows that LYC-54143 can inhibit tumour growth, table by two different accesses Reveal superior anticancer activity.Firstly, it is thin to adjust Th17 and Tc17 by classical pathway after LYC-54143 activation ROR γ t The differentiation of born of the same parents promotes the expression of other cell factors such as IL-17, improves T cell activity.In addition, the ROR γ t of activation can be adjusted The several genes expression in immune system is saved, the expression of cytoscopy receptor PD-1 is inhibited, to reduce immunosupress, is improved Anticancer activity (Oncoimmunology.2016Nov 4,5 (12): e1254854；ACS Chem Biol.2016 Apr 15, 11(4):1012-8).Although the small molecule excitement comes into clinical II phase, the medicine in relation to the target spot agonist at present Object is still considerably less, and without marketed drug occur, it has been disclosed that patent just like WO2015171558, WO2008152260, WO2007068580, WO2007068579, WO2005056516, WO2005056510, WO2005066116, WO00228810, There is still a need for the more efficient new ROR γ t agonists of continual exploitation, to provide new effective anticancer drug for patient.

The present inventor, which designs, has the indole carboxamides class compound for leading to structure shown in formula (I), on indoles theheterocyclic nitrogen atom Substituent group is hydrophilic radical, have preferable solvent degree, while the ortho position of ring A have biggish substituent group (such as: trifluoro Methyl), show the effect of significant excitement ROR.

Summary of the invention

The purpose of the present invention is to provide a kind of logical formula (I) compounds represented:

Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer shape Formula or its pharmaceutical salt,

Wherein:

For double bond or singly-bound；

G¹、G²And G³It is identical or different, and it is each independently selected from C, CH, CH₂And N；

Ring A is selected from aryl, heteroaryl, naphthenic base and heterocycle；

Ring B is aryl or heteroaryl；

L¹For alkylidene；

R¹It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, halogenated alkyl, alkoxy, alkyl halide Oxygroup, cyano, amino, nitro, hydroxyl and hydroxyalkyl；

R²For halogenated alkyl；

R³Selected from hydrogen atom, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, halogen, cyano, amino, Nitro, hydroxyl, naphthenic base, heterocycle, aryl and heteroaryl, wherein the alkyl, halogenated alkyl, naphthenic base, heterocycle, Aryl and heteroaryl are optionally taken by one or more substituent groups in hydroxyl, halogen, alkyl and amino each independently Generation；

R⁴It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, halogenated alkyl, alkoxy, alkyl halide Oxygroup, cyano, amino, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

R⁵Selected from hydrogen atom, alkyl, halogenated alkyl, amino, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl Base；

R⁶It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, halogenated alkyl, alkoxy, alkyl halide Oxygroup, cyano, amino, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

R⁷Selected from hydroxyl, amino, cyano, alkoxy, halogenated alkoxy ,-OR¹⁰、-NR¹¹R¹²With-C (O) NR¹¹R¹²；

R⁸And R⁹It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, halogenated alkyl, alkoxy, cyanogen Base, amino, nitro, hydroxyl and hydroxyalkyl；

R¹⁰Selected from hydrogen atom, alkyl, halogenated alkyl, hydroxyalkyl, naphthenic base and heterocycle；

R¹¹And R¹²It is identical or different, and it is each independently selected from hydrogen atom, alkyl, halogenated alkyl, hydroxyl and hydroxyalkyl；

N is 0,1,2,3 or 4；

S is 0,1,2 or 3；And

T is 0,1,2 or 3.

In a preferred embodiment of the present invention, the logical formula (I) compound represented, middle ring A are selected from benzene Base, pyridyl group, imidazole radicals, pyrazolyl, piperidyl and morpholinyl；And ring B is phenyl or pyridyl group.

In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein It is selected from:

In a preferred embodiment of the present invention, the logical formula (I) compound represented is shown in logical formula (II) Compound:

Wherein:

W and G are identical or different, and independent is CH or N；

R¹、R³、R⁵~R⁷、L¹, n and t be as defined in logical formula (I).

In a preferred embodiment of the present invention, the logical formula (I) compound represented is logical formula (III) institute The compound shown:

Wherein:

W and G are identical or different, and independent is CH or N；

The integer that p is 1 to 6；

R¹、R³、R⁵、R⁶、R¹⁰, n and t be as defined in logical formula (I).

In a preferred embodiment of the present invention, the logical formula (I) compound represented is shown in logical formula (IV) Compound:

Wherein:

The integer that p is 1 to 6；

R¹、R³、R⁵、R⁶、R¹⁰, n and t be as defined in logical formula (I).

In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein R¹For hydrogen original Son, halogen and alkyl.

In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein R³For hydrogen original Son, alkyl or hydroxyalkyl.

In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein R⁵For alkyl, Preferably ethyl.

In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein R⁶For hydrogen original Son or halogen.

The compound of typical logical formula (I), including but not limited to:

Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer shape Formula or its officinal salt.

Another aspect of the present invention relates to compounds shown in a kind of logical formula (V), to prepare in logical formula (I) compound Mesosome,

Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer shape Formula or its officinal salt,

Wherein:

For double bond or singly-bound；

Ring A is selected from aryl, heteroaryl, naphthenic base and heterocycle；

L¹For alkylidene；

R²For halogenated alkyl；

N is 0,1,2,3 or 4；And

T is 0,1,2 or 3.

The compound of typical logical formula (V), including but not limited to:

Another aspect of the present invention relates to a kind of methods for preparing logical formula (I) compound, this method comprises:

Condensation reaction occurs for logical formula (V) compound and logical formula (VI) compound, obtains logical formula (I) compound；

Wherein:

Ring A, ring B, G¹~G³、R¹~R⁹、L¹, n, s and t be as defined in logical formula (I).

Another aspect of the present invention relates to a kind of pharmaceutical compositions, shown in the logical formula (I) containing treatment effective dose Compound or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof shape Formula or pharmaceutical salt and one or more pharmaceutically acceptable carriers, diluent or excipient.The invention further relates to A method of preparing described pharmaceutical composition comprising by logical formula (I) compound represented or its tautomer, interior disappear Revolve body, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt with pharmaceutically Acceptable carrier, diluent or excipient mix.

The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, Or mixtures thereof enantiomter, diastereoisomer form or its officinal salt, or made comprising its pharmaceutical composition Purposes in standby ROR agonist.

The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, Or mixtures thereof enantiomter, diastereoisomer form or its officinal salt, or made comprising its pharmaceutical composition The purposes being ready for use in the drug of prevention and/or treatment tumour or cancer, especially as ROR agonist in preparation for pre- Purposes in the drug of anti-and/or treatment tumour or cancer.

The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, Or mixtures thereof enantiomter, diastereoisomer form or its officinal salt, or comprising its pharmaceutical composition, use Make drug.

The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, mappings Or mixtures thereof isomers, diastereoisomer form or its officinal salt, or include its pharmaceutical composition, conduct ROR agonist.

The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, mappings Or mixtures thereof isomers, diastereoisomer form or its officinal salt, or comprising its pharmaceutical composition, be used for pre- Anti- and/or treatment tumour or cancer, especially as ROR agonist for preventing and/or treating tumour or cancer.

Tumour or cancer of the present invention are solid tumor and blood tumor, are preferably selected from non-Hodgkin lymphoma, diffuse greatly B cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical carcinoma, colon cancer, lung cancer, gastric cancer, the carcinoma of the rectum, pancreas Cancer, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, bladder cancer, liver cancer, fallopian tube cneoplasms, ovary Tumor, peritoneal tumor, IV phase melanoma, glioma, spongioblastoma, hepatocellular carcinoma, the renal tumor of mastoid process, neck Portion's tumour, leukaemia, lymthoma, myeloma and non-small cell lung cancer.

The invention further relates to a kind of Prevention and/or the methods for the treatment of tumour or cancer comprising to needing its trouble The logical formula (I) compound represented or its tautomer, meso as ROR agonist of person's application treatment effective dose Or mixtures thereof body, racemic modification, enantiomter, diastereoisomer form or its officinal salt, or the medicine comprising it Compositions.

Pharmaceutical composition containing active constituent, which can be, is suitable for oral form, such as tablet, dragee, pastille, water Or oil suspension, dispersible powder or particle, lotion, hard or soft capsule or syrup or elixir.It can be any according to this field The known method for preparing Pharmaceutical composition prepares Orally administered composition, and such composition can contain one or more selected from the following Ingredient: sweetener, corrigent, colorant and preservative, to provide pleasing and palatable pharmaceutical formulation.Tablet containing it is active at Point and for mixing the suitable nontoxic pharmaceutical excipient for preparing tablet.These excipient can be inert excipient, Granulating agent, disintegrating agent, adhesive and lubricant,.These tablets can not be coated or can by cover drug taste or Delay disintegration and absorption in gastrointestinal tract, thus the known technology for providing slow releasing function in a long time is coated.

Also wherein active constituent and inert solid diluent or in which active constituent and water-solubility carrier or oily solvent can be used Mixed Perle provides oral preparation.

Water slurry contains active material and the suitable excipient for preparing water slurry for mixing.Such excipient It is suspending agent, dispersing agent or wetting agent.Aqueous suspension can also containing one or more preservatives, one or more colorants, One or more corrigents and one or more sweeteners.

Oil suspension can active constituent be suspended in vegetable oil or mineral oil is formulated by making.Oil suspension can contain Thickener.Above-mentioned sweetener and corrigent can be added, to provide palatable preparation.This can be saved by the way that antioxidant is added A little compositions.

Pharmaceutical composition of the invention is also possible to the form of oil in water emulsion.Oil mutually can be vegetable oil or mineral oil Or mixtures thereof.Suitable emulsifier can be naturally-produced phosphatide, and emulsion can also contain sweetener, corrigent, anti-corrosion Agent and antioxidant.Such preparation can also contain moderator, preservative, colorant and antioxidant.

Pharmaceutical composition of the invention can be sterile injectable aqueous form.The acceptable solvent that can be used or Solvent has water, ringer's solution and isotonic sodium chlorrde solution.Aseptic injection preparation can be the nothing that wherein active constituent is dissolved in oily phase Bacterium injects oil-in-water microemulsion can be by a large amount of injections in part, will be in injection or the blood flow of micro emulsion injection patient.Alternatively, best Solution and micro emulsion are given in the way of it can keep the compounds of this invention constant circulating concentration.To keep this constant density, can make With continuous intravenous delivery device.The example of this device is Deltec CADD-PLUS.TM.5400 type Iv pump.

Pharmaceutical composition of the invention can be for intramuscular and the aseptic injection water of subcutaneous administration or the shape of oil suspension Formula.Can be by known technology, the dispersing agent or wetting agent and suspending agent for being suitable for those described above prepare the suspension.Aseptic injection Preparation is also possible to the aseptic injectable solution or suspension prepared in the acceptable non-toxic diluent of parenteral or solvent.This Outside, it is convenient to use sterile fixed oil as solvent or suspension media.For this purpose, any reconciliation fixing oil can be used.This Outside, fatty acid can also prepare injection.

The compounds of this invention can be given by the suppository form for rectally.It can be by by drug and in ordinary temp Down it is solid but is in the rectum liquid, thus can dissolves and discharge in the rectum the suitable nonirritant excipient of drug Mixing is to prepare these pharmaceutical compositions.

As it is well known to the skilled in the art, the dosage of drug depends on many factors, including but and non-limiting In following factor: the activity of particular compound used, the age of patient, the weight of patient, the health status of patient, patient Behavior, the diet of patient, administration time, administration mode, the rate of excretion, combination of drug etc.；In addition, optimal treatment side Formula can be according to traditional therapeutic scheme such as the type of the mode for the treatment of, the consumption per day of general formula compound (I) or pharmaceutical salt To verify.

Detailed description of the invention

Unless stated to the contrary, the term used in the specification and in the claims has following meanings.

Term " alkyl " refers to saturated aliphatic hydrocarbons group, is the linear chain or branched chain group comprising 1 to 20 carbon atom, Preferably comprise the alkyl of 1 to 12 carbon atom, the alkyl of further preferably 1 to 6 carbon atom.Non-limiting example includes first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- Dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- ethyl -2- Methyl-propyl, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- Dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2,3- dimethylbutyl, positive heptan Base, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2,3- dimethyl amyl group, 2,4- dimethyl-penten Base, 2,2- dimethyl amyl group, 3,3- dimethyl amyl group, 2- ethylpentyl, 3- ethylpentyl, n-octyl, 2,3- dimethyl oneself Base, 2,4- dimethylhexanyl, 2,5- dimethylhexanyl, 2,2- dimethylhexanyl, 3,3- dimethylhexanyl, 4,4- dimethyl oneself Base, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- methyl -2- ethylpentyl, 2- methyl -3- ethylpentyl, positive nonyl Base, 2- methyl -2- ethylhexyl, 2- methyl -3- ethylhexyl, 2,2- diethyl amyl group, positive decyl, 3,3- diethylhexyl, 2,2- diethylhexyls and its various branched isomers etc..Low alkyl group more preferably containing 1 to 6 carbon atom, it is non- Restricted embodiment include methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl fourth Base, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2, 3- dimethylbutyl etc..Alkyl can be it is substituted or non-substituted, when substituted, substituent group can it is any can be used Tie point on be substituted, the substituent group is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynes It is base, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, miscellaneous Aryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, carboxyl and carboxylate.

Term " alkylidene " refers to the linear chain or branched chain aliphatic alkyl of saturation, and the same carbon with 2 from parent alkane is former Residue derived from two hydrogen atoms is removed on son or two different carbon atoms, is the straight chain comprising 1 to 20 carbon atom Or branched group, preferably comprise 1 to 12 carbon atom, the alkylidene of further preferably 1 to 6 carbon atom.The non-limit of alkylidene Property example processed includes but is not limited to methylene (- CH₂), 1,1- ethylidene (- CH (CH₃) -), 1,2- ethylidene (- CH₂CH₂)-、 1,1- propylidene (- CH (CH₂CH₃) -), 1,2- propylidene (- CH₂CH(CH₃) -), 1,3- propylidene (- CH₂CH₂CH₂-)、1,4- Butylidene (- CH₂CH₂CH₂CH₂) and 1,5- butylidene (- CH₂CH₂CH₂CH₂CH₂) etc..Alkylidene can be substituted or non- Replace, when substituted, substituent group can be substituted on any workable tie point, preferably one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitre Base, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, Oxo base, carboxyl and carboxylate.

Term " alkoxy " refers to-O- (alkyl) and-O- (non-substituted naphthenic base), the wherein definition of alkyl and naphthenic base As described above.The non-limiting example of alkoxy includes: methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, ring fourth Oxygroup, cyclopentyloxy, cyclohexyloxy.Alkoxy can be optionally replacing or non-substituted, and when substituted, substituent group is excellent One or more following groups are selected as, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen Element, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkanes Sulfenyl, heterocycle alkylthio group, carboxyl and carboxylate.

Term " naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, cycloalkyl ring include 3 to 20 carbon atoms, preferably comprise 3 to 12 carbon atoms, more preferably include 3 to 6 carbon atoms.Monocyclic cycloalkyl it is non-limiting Example includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptyl Trialkenyl, cyclooctyl etc.；Polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring.

Term " spiro cycloalkyl group " refers to the polycyclic moiety that a carbon atom (claiming spiro-atom) is shared between 5 to 20 yuan of monocycle, It can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, More preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, double spiral shells according to the number for sharing spiro-atom between ring and ring Naphthenic base or more spiro cycloalkyl groups, preferably single spiro cycloalkyl group and double spiro cycloalkyl groups.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/ 6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl groups.The non-limiting example of spiro cycloalkyl group includes:

Term " cycloalkyl " refers to 5 to 20 yuan, each ring in system and the shared a pair adjoined of other rings in system The full carbon polycyclic moiety of carbon atom, wherein one or more rings can be containing one or more double bonds, but none ring has The pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.It can be divided into according to a group cyclic number double Ring, tricyclic, Fourth Ring or polycyclic fused ring alkyl, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkane Base.The non-limiting example of cycloalkyl includes:

Term " bridge ring alkyl " refers to 5 to 20 yuan, and the full carbon that any two ring shares two carbon atoms being not directly connected is more Cyclic group, can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Preferably 6 To 14 yuan, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl can be divided into according to a group cyclic number, Bicyclic or tricyclic is more selected as at preferably bicyclic, tricyclic or Fourth Ring.The non-limiting example of bridge ring alkyl includes:

The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein being connected to precursor structure Ring together is naphthenic base, and non-limiting example includes indanyl, tetralyl, benzocyclohepta alkyl etc..Naphthenic base can be Optionally replacing or non-substituted, when substituted, substituent group is preferably one or more following groups, independently selected from Alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, heterocycle alkane Base, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, carboxyl and carboxylate Base.

Term " heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, and it includes 3 to 20 rings Atom, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), but do not wrap The loop section of-O-O- ,-O-S- or-S-S- are included, remaining annular atom is carbon.3 to 12 annular atoms are preferably comprised, wherein 1~4 It is hetero atom；3 to 8 annular atoms are most preferably comprised, wherein 1~3 is hetero atom；3 to 6 annular atoms are most preferably comprised, wherein 1~2 is hetero atom.The non-limiting example of monocyclic heterocycles base includes pyrrolidinyl, imidazolidinyl, tetrahydrofuran base, tetrahydro thiophene It is pheno base, glyoxalidine base, dihydrofuryl, pyrazoline base, pyrrolin base, piperidyl, piperazinyl, morpholinyl, thio Quinoline base, high piperazine base, pyranose etc., preferably piperidyl, piperazinyl or morpholinyl.Multiring heterocyclic include loop coil, condensed ring and The heterocycle of bridged ring.

Term " spiro heterocyclic radical " refers to the multiring heterocyclic that an atom (claiming spiro-atom) is shared between 5 to 20 yuan of monocycle Group, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), remaining ring are former Son is carbon.It can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Preferably 6 To 14 yuan, more preferably 7 to 10 yuan.Spiro heterocyclic radical is divided into single spiroheterocyclic according to the number for sharing spiro-atom between ring and ring Base, double spiro heterocyclic radicals or more spiro heterocyclic radicals, preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 3 yuan/6 yuan, 4 yuan/4 The single spiro heterocyclic radical of member, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan.The non-limiting example of spiro heterocyclic radical includes:

Term " condensed hetero ring base " refers to 5 to 20 yuan, each ring in system and the shared a pair adjoined of other rings in system The polycyclic heterocyclic group of atom, one or more rings can be containing one or more double bonds, but none ring is with completely total The pi-electron system of yoke, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_mThe miscellaneous original of (wherein m is integer 0 to 2) Son, remaining annular atom are carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.It can be divided into according to a group cyclic number double Ring, tricyclic, Fourth Ring or polycyclic condensed hetero ring base, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclics it is thick miscellaneous Ring group.The non-limiting example of condensed hetero ring base includes:

Term " bridge heterocycle " refers to 5 to 14 yuan, and any two ring shares the polycyclic heterocycle of two atoms being not directly connected Group, can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated, one of them or Multiple annular atoms are selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom are carbon.Preferably 6 To 14 yuan, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge heterocycle can be divided into according to a group cyclic number, Bicyclic or tricyclic is more selected as at preferably bicyclic, tricyclic or Fourth Ring.The non-limiting example of bridge heterocycle includes:

The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein being connected to one with precursor structure The ring risen is heterocycle, and non-limiting example includes:

Deng.

Heterocycle can be it is optionally replacing or non-substituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitre Base, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, Oxo base, carboxyl and carboxylate.

Term " aryl " refers to that 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle are (namely total Enjoy the ring of adjacent carbon atoms pair) group, preferably 6 to 10 yuan, such as phenyl and naphthalene.More preferable phenyl.The aryl rings can To condense on heteroaryl, heterocycle or cycloalkyl ring, wherein be aryl rings with the ring that precursor structure links together, it is non- Limitative examples include:

Aryl can be substituted or non-substituted, and when substituted, substituent group is preferably one or more following bases Group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyanogen Base, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl Or carboxylate.

Term " heteroaryl " refers to the heteroaromatic system comprising 1 to 4 hetero atom, 5 to 14 annular atoms, wherein hetero atom Selected from oxygen, sulphur and nitrogen.Heteroaryl is preferably 5 to 10 yuan, contains 1 to 3 hetero atom；It is more preferably 5- or 6-membered, it is miscellaneous containing 1 to 2 Atom；It is preferred that for example imidazole radicals, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrole radicals, tetrazole radical, pyridyl group, Pyrimidine radicals, thiadiazoles, pyrazinyl etc., preferably imidazole radicals, tetrazole radical, pyridyl group, thienyl, pyrazolyl or pyrimidine radicals, thiazole Base；More select pyridyl group.The heteroaryl ring can be condensed on aryl, heterocycle or cycloalkyl ring, wherein with precursor structure The ring to link together is heteroaryl ring, and non-limiting example includes:

Heteroaryl can be it is optionally replacing or non-substituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitre Base, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, Carboxyl and carboxylate.

Term " halogenated alkyl " refers to the alkyl replaced by one or more halogens, and wherein alkyl is as defined above.

Term " halogenated alkoxy " refers to the alkoxy replaced by one or more halogens, and wherein alkoxy is as defined above.

Term " hydroxyalkyl " refers to the alkyl being optionally substituted by a hydroxyl group, and wherein alkyl is as defined above.

Term " hydroxyl " refers to-OH group.

Term " halogen " refers to fluorine, chlorine, bromine or iodine.

Term " amino " refers to-NH₂。

Term " cyano " refers to-CN.

Term " nitro " refers to-NO₂。

Term " oxo base " refers to=O.

Term " carbonyl " refers to C=O.

Term " carboxyl " refers to-C (O) OH.

Term " carboxylate " refers to-C (O) O (alkyl) or-C (O) O (naphthenic base), and wherein alkyl, naphthenic base are as above determined Justice.

Term " carboxylic acid halides " refers to the compound containing-C (O)-halogen group.

Term " hydrophilic radical " refers to the group that can be dissolved or ionize in water, preferably hydroxyl (- OH), alkoxy, Halogenated alkoxy, cyano, carboxyl (- COOH), amide groups, amino (- NH₂)、-OR¹⁰、-NR¹¹R¹²With-C (O) NR¹¹R¹²。

" optional " or " optionally " mean event or environment described later can with but need not occur, this illustrates to wrap Include the occasion that the event or environment occur or do not occur.For example, meaning that alkyl can " optionally by alkyl-substituted heterocyclic group " With but necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted feelings Shape.

" substituted " refers to one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen original Son is replaced by the substituent group of respective number independently of one another.Self-evident, substituent group is only in their possible chemical potential It sets, those skilled in the art can determine in the case where not paying excessive make great efforts may or can not (by experiment or theory) The substitution of energy.For example, may when amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key It is unstable.

" pharmaceutical composition " is indicated containing one or more compounds described herein or its physiologically/pharmaceutical salt Or the mixture and other components such as physiology/pharmaceutical carrier and figuration of pro-drug and other chemical constituents Agent.The purpose of pharmaceutical composition is the administration promoted to organism, plays bioactivity in turn conducive to the absorption of active constituent.

" officinal salt " refers to the salt of the compounds of this invention, this kind of salt in the mammalian body when have safety and Validity, and there is due bioactivity.

Wherein R¹⁰~R¹²As defined in logical formula (I).

The synthetic method of the compounds of this invention

In order to complete the purpose of the present invention, the present invention adopts the following technical scheme:

Method one

The present invention leads to formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomerism The preparation method of or mixtures thereof body, diastereoisomer form or its pharmaceutical salt, comprising the following steps:

The first step, general formula (I-A) compound, general formula (I-B) compound and bicyclic [2.2.1] -2- heptene, in catalyst In the presence of, under alkaline condition, coupling reaction occurs, obtains general formula (I-C) compound；

Under alkaline condition, nucleophilic displacement of fluorine occurs for the compound of second step, general formula (I-C) compound and general formula (I-E) anti- It should obtain general formula (I-D) compound；

Third step, general formula (I-D) compound under alkaline condition, occur hydrolysis and obtain the compound of logical formula (V)；

4th step leads to formula (V) compound and logical formula (VI) compound under alkaline condition, in the presence of condensing agent, occurs Condensation reaction obtains the compound of logical formula (I),

Wherein:

X is halogen；

R^xFor alkyl；Preferably methyl or ethyl；

The reagent for providing alkaline condition includes organic base and inorganic base, and the organic bases include but is not limited to three Ethamine, n,N-diisopropylethylamine, n-BuLi, lithium diisopropylamine, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, it is described Inorganic base include but is not limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate.

Catalyst include but is not limited to two (acetonitrile) palladium chlorides, tetra-triphenylphosphine palladium, palladium chloride, palladium acetate, [1, Bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride, 1,1 '-bis- (dibenzyl phosphorus) dichloro diamyl iron palladiums or three (dibenzylidenes Acetone) two palladiums, preferably two (acetonitrile) palladium chlorides.

Condensing agent includes but is not limited to 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, N, bis- ring of N'- Hexyl carbodiimides, N, N'- diisopropylcarbodiimide, O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boron Acid esters, I-hydroxybenzotriazole, 1- hydroxyl -7- azo benzotriazole, O- benzotriazole-N, N, N', N'- tetramethylurea (TMU) six Fluorophosphoric acid ester, 2- (7- azo benzotriazole)-N, N, N', (7- aoxidizes three nitrogen of benzo by N'- tetramethylurea hexafluorophosphoric acid ester, 2- Azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, three (dimethylamino) phosphorus hexafluoro phosphorus of benzotriazole -1- base oxygroup Hydrochlorate or hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus, preferably 1- (3- dimethylamino-propyl) -3- ethyl Carbodiimide hydrochloride.

Above-mentioned reaction preferably carries out in a solvent, and solvent for use includes but is not limited to: acetic acid, methanol, ethyl alcohol, toluene, four Hydrogen furans, methylene chloride, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4- dioxane, water, N, N- dimethyl Formamide and its mixture.

Method two

The present invention leads to formula (II) compound represented or its tautomer, mesomer, racemic modification, enantiomerism The preparation method of or mixtures thereof body, diastereoisomer form or its pharmaceutical salt, comprising the following steps:

The first step, general formula (I-A) compound, general formula (II-1) compound and bicyclic [2.2.1] -2- heptene, in catalyst In the presence of, under alkaline condition, coupling reaction occurs, obtains general formula (II-2) compound；

Under alkaline condition, nucleophilic displacement of fluorine occurs for the compound of second step, general formula (II-2) compound and general formula (I-E) Reaction obtains general formula (II-3) compound；

Third step, general formula (II-3) compound under alkaline condition, occur hydrolysis and obtain the chemical combination of general formula (II-4) Object；

4th step, general formula (II-4) compound and general formula (II-5) compound under alkaline condition, exist in condensing agent Under, condensation reaction occurs and obtains the compound of logical formula (II),

Wherein:

X is halogen；

R^xFor alkyl；Preferably methyl or ethyl；

G、W、R¹、R³、R⁵~R⁷、L¹, n and t be as defined in logical formula (II).

Method three

The present invention leads to formula (III) compound represented or its tautomer, mesomer, racemic modification, enantiomerism The preparation method of or mixtures thereof body, diastereoisomer form or its pharmaceutical salt, comprising the following steps:

The compound of second step, general formula (II-2) compound and general formula (III-1) under alkaline condition, occurs nucleophilic and takes Generation reaction obtains general formula (III-2) compound；

Third step, general formula (III-2) compound under alkaline condition, occur hydrolysis and obtain the change of general formula (III-3) Close object；

4th step, general formula (III-3) compound and general formula (II-5) compound under alkaline condition, exist in condensing agent Under, condensation reaction occurs and obtains the compound of logical formula (III),

Wherein:

X is halogen；

R^xFor alkyl；Preferably methyl or ethyl；

G、W、R¹、R³、R⁵、R⁶、R¹⁰, p, n and t be as defined in logical formula (III).

Method four

The present invention leads to formula (IV) compound represented or its tautomer, mesomer, racemic modification, enantiomerism The preparation method of or mixtures thereof body, diastereoisomer form or its pharmaceutical salt, comprising the following steps:

The first step, general formula (I-A) compound, general formula (IV-1) compound and bicyclic [2.2.1] -2- heptene, in catalyst In the presence of, under alkaline condition, coupling reaction occurs, obtains general formula (IV-2) compound；

The compound of second step, general formula (IV-2) compound and general formula (III-1) under alkaline condition, occurs nucleophilic and takes Generation reaction obtains general formula (IV-3) compound；

Third step, general formula (IV-3) compound under alkaline condition, occur hydrolysis and obtain the chemical combination of general formula (IV-4) Object；

4th step, general formula (IV-4) compound and general formula (IV-5) compound under alkaline condition, exist in condensing agent Under, condensation reaction occurs and obtains the compound of logical formula (IV),

Wherein:

X is halogen；

R^xFor alkyl；Preferably methyl or ethyl；

R¹、R³、R⁵、R⁶、R¹⁰, p, n and t be as defined in logical formula (IV).

Specific embodiment

The present invention is further described with reference to embodiments, but these embodiments not limit the scope of the present invention.

Embodiment

The structure of compound is by nuclear magnetic resonance (NMR) or/and mass spectrum (MS) come what is determined.NMR is displaced (δ) with 10^-6 (ppm) unit provides.The measurement of NMR is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometer, and measurement solvent is that deuterated dimethyl is sub- Sulfone (DMSO-d₆), deuterated chloroform (CDCl₃), deuterated methanol (CD₃OD), inside it is designated as tetramethylsilane (TMS).

The measurement of MS is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: Finnigan LCQ advantage MAX)。

High performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD With Waters HPLC e2695-2489 high pressure liquid chromatograph.

Chiral HPLC measurement uses Agilent 1260DAD high performance liquid chromatograph.

Efficient liquid phase preparation uses Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP With Gilson-281 preparative scale chromatography instrument.

Chirality preparation uses Shimadzu LC-20AP preparative scale chromatography instrument.

The quick preparing instrument of CombiFlash uses Combiflash Rf200 (TELEDYNE ISCO).

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and thin-layered chromatography (TLC) makes The specification that silica gel plate uses is 0.15mm~0.2mm, thin-layer chromatography isolate and purify product use specification be 0.4mm~ 0.5mm。

It is carrier that silica gel column chromatography, which generally uses 200~300 mesh silica gel of Yantai Huanghai Sea silica gel,.

Kinases average inhibition and IC₅₀The measurement of value is with NovoStar microplate reader (German BMG company).

Known starting material of the invention can be used or be synthesized according to methods known in the art, or commercially available From ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, splendid remote chemistry science and technology (Accela ChemBio Inc), the companies such as auspicious chemicals are reached.

Without specified otherwise in embodiment, reaction can be carried out under argon atmospher or nitrogen atmosphere.

Argon atmospher or nitrogen atmosphere refer to that reaction flask connects the argon gas or nitrogen balloon of an about 1L volume.

Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.

Pressure hydration reaction uses Parr 3916EKX type hydrogenation instrument and clear indigo plant QL-500 type hydrogen generator or HC2-SS Type hydrogenates instrument.

Hydrogenation usually vacuumizes, and is filled with hydrogen, operates 3 times repeatedly.

Microwave reaction uses 908860 type microwave reactor of CEM Discover-S.

Without specified otherwise in embodiment, solution refers to aqueous solution.

Without specified otherwise in embodiment, it is 20 DEG C~30 DEG C that the temperature of reaction, which is room temperature,.

The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), reacts the system of used solvent Have: A: methylene chloride and methanol system, B: n-hexane and ethyl acetate system, the volume ratio of solvent is according to the polarity of compound It is different and be adjusted.

The system of eluant, eluent and the solvent system of thin-layered chromatography for the column chromatography that purifying compound uses include: A: Methylene chloride and methanol system, B: n-hexane and ethyl acetate system, the volume ratio of solvent it is different according to the polarity of compound and It is adjusted, the alkalinity such as a small amount of triethylamine and acetic acid can also be added or acid reagent is adjusted.

Embodiment 1

2- (4- chloro- 2- (trifluoromethyl) benzyl)-N- (4- (ethylsulfonyl) benzyl) -1- (2- ethoxy) -1H- indoles - 5- formamide 1

The first step

(4- chloro- 2- (trifluoromethyl) phenyl) methanol 1b

By 4- chloro- 2- (trifluoromethyl) benzaldehyde 1a (10g, 48mmol, using patent application " WO2011021492 " public affairs The method opened is prepared) it is dissolved in 100mL ethyl alcohol, sodium borohydride (1.83g, 48mmol) is added portionwise, it is small to be stirred to react 2 When.Reaction solution is concentrated under reduced pressure, and water is added in gained residue, is extracted with ethyl acetate, organic phase is washed with saturated sodium chloride solution It washs, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, and gained residue silica gel column chromatography is pure with eluant, eluent system B Change, obtains title compound 1b (9.5g, yield: 95%).

Second step

1- (bromomethyl) -4- chloro- 2- (trifluoromethyl) benzene 1c

Compound 1b (9.5g, 45.2mmol) is dissolved in 100mL methylene chloride, be added dropwise to phosphorus tribromide (24.5 g, 90.5mmol), it is stirred to react 2 hours.Water is added in reaction solution, separates organic phase, water phase is extracted with dichloromethane, is associated with Machine phase is successively washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, and anhydrous sodium sulfate dries, filters, filtrate It is concentrated under reduced pressure, obtains crude title compound 1c (10.5g), product directly carries out next step reaction without further purification.

Third step

2- (4- chloro- 2- (trifluoromethyl) benzyl) -1H- indole -5-carboxylic acid methyl esters 1e

By 1H- indole -5-carboxylic acid methyl esters 1d (4.4g, 25.8mmol, using well known method " Huaxue Shiji, 2015,37 (7), 585-589,594 " are prepared) it is dissolved in 40mL n,N-dimethylacetamide, two (acetonitrile) dichloros are added Change palladium (1.34g, 5.16mmol), bicyclic [2.2.1] -2- heptene (4.85g, 51.6mmol) and sodium bicarbonate (4.25 g, 51mmol), crude Compound 1c (7.4g, 27mmol) is added, 70 DEG C is warming up to and is stirred to react 12 hours.Reaction solution is cooling To room temperature, 200mL water is added, is extracted with ethyl acetate three times, merges organic phase, successively washed with water, saturated sodium chloride solution It washs, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, and gained residue silica gel column chromatography is pure with eluant, eluent system B Change, obtains title compound 1e (8.1g, yield: 87%).

MS m/z(ESI):368.1[M+1]。

4th step

1- (2- ((t-Butyldimethylsilyl) oxygroup) ethyl) -2- (4- chloro- 2- (trifluoromethyl) benzyl) -1H- indoles - 5- methyl formate 1g

By compound 1e (3g, 1.36mmol), (2- bromine oxethyl) (tert-butyl) dimethyl-silicon 1f (1.3g, 5.4 mmol, Be prepared using method disclosed in patent application " WO2011053821 ") and cesium carbonate (886mg, 2.72 mmol) be added to In 5mL n,N-Dimethylformamide, it is warming up to 100 DEG C of microwaves and is stirred to react 1 hour.Reaction solution is cooled to room temperature, and water is added, It is extracted with ethyl acetate three times, merges organic phase, washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate It is concentrated under reduced pressure, gained residue silica gel column chromatography is with eluant, eluent system B purifying, and obtaining title compound 1g, (4.4g is produced Rate: 100%).

MS m/z(ESI):526.1[M+1]。

5th step

2- (4- chloro- 2- (trifluoromethyl) benzyl) -1- (2- ethoxy) -1H- indole -5-carboxylic acid methyl esters 1h

Compound 1g (4.4g, 8.4mmol) is dissolved in 40mL tetrahydrofuran, the tetrabutyl ammonium fluoride of 1M is added dropwise to Tetrahydrofuran solution (9.2mL, 9.2mmol) is stirred to react 1 hour.Water is added in reaction solution, is extracted with ethyl acetate three times, Merge organic phase, washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, gained residue Purified with silica gel column chromatography with eluant, eluent system B, obtains title compound 1h (2.3g, yield: 67%).

6th step

2- (4- chloro- 2- (trifluoromethyl) benzyl) -1- (2- ethoxy) -1H- indole -5-carboxylic acid 1i

Compound 1h (2g, 4.85mmol) is dissolved in the in the mixed solvent of 14mL methanol and tetrahydrofuran (V/V=5:2), The sodium hydroxide solution of 5mL 4M is added, is warming up to 60 DEG C and is stirred to react 1 hour.Reaction solution is cooled to room temperature, and is concentrated under reduced pressure, Water is added in gained residue, it is 4 that concentrated hydrochloric acid, which is added dropwise, to pH, is extracted with ethyl acetate three times, merges organic phase, with saturation chlorine Change sodium solution washing, anhydrous sodium sulfate dries, filters, and filtrate decompression concentration is obtained crude title compound 1i (1.8g), produced Product directly carry out next step reaction without further purification.

MS m/z(ESI):398.0[M+1]。

7th step

By crude Compound 1i (1.8g, 4.5mmol) and (4- (ethylsulfonyl) phenyl) methylamine 1j (1.35g, 6.8 Mmol is prepared using method disclosed in patent application " WO2015017335 ") it is dissolved in 10mL n,N-Dimethylformamide In, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (1.3g, 6.8mmol), I-hydroxybenzotriazole is added (920mg, 6.8mmol) and n,N-diisopropylethylamine (2.9g, 22.6mmol), is stirred to react 12 hours.Reaction solution pours into water In, three times with the extraction of the mixed solvent (V/V=10:1) of methylene chloride and methanol, merge organic phase, successively with water and saturation chlorine Change sodium solution washing, anhydrous sodium sulfate dries, filters, and filtrate decompression concentration, gained residue silica gel column chromatography is to elute Agent system A purifying, obtains title compound 1 (2.2g, yield: 84%).

MS m/z(ESI):579.8[M+1]。

¹H NMR(400MHz,DMSO-d₆)δ8.98(t,1H),8.06(s,1H),7.86-7.83(m,3H), 7.68- 7.67(m,2H),7.58-7.56(d,2H),7.51-7.49(d,1H),7.27-7.29(d,1H),5.99(s,1H), 4.95 (t,1H),4.58(d,2H),4.39(s,2H),4.18(t,2H),3.63(q,2H),3.25(q,2H),1.08(t, 3H)。

Embodiment 2

2- (4- chloro- 2- (trifluoromethyl) benzyl)-N- (4- (ethylsulfonyl) benzyl) the fluoro- 1- of -6- (2- ethoxy) -1H- Indoles -5- formamide 2

The first step

The fluoro- 1H- indole -5-carboxylic acid methyl esters 2b of 6-

By 6- fluoro- 1- (triisopropylsilyl) -1H- indole -5-carboxylic acid 2a (300mg, 0.89mmol, using well known side Method " European Journal of Organic Chemistry, 2006, (13), 2956-2969 " is prepared) it is dissolved in In 10mL methanol, it is added dropwise to the 0.5mL concentrated sulfuric acid, 60 DEG C is warming up to and is stirred to react 12 hours.Reaction solution is cooled to room temperature, decompression It is concentrated, water is added in gained residue, be extracted with ethyl acetate three times, merge organic phase, successively use saturated sodium bicarbonate solution It is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, gained residue silica gel column chromatography Method obtains title compound 2b (170mg, yield: 98.5%) with eluant, eluent system B purifying

MS m/z(ESI):194.1[M+1]。

Second step

2- (4- chloro- 2- (trifluoromethyl) benzyl) fluoro- 1H- indole -5-carboxylic acid methyl esters 2c of -6-

Compound 2b (70mg, 0.37mmol) is dissolved in 5mL n,N-dimethylacetamide, two (acetonitrile) dichloros are added Change palladium (19mg, 0.072mmol), bicyclic [2.2.1] -2- heptene (68mg, 0.72mmol) and sodium bicarbonate (61mg, 0.73mmol), crude Compound 1c (100mg, 0.37mmol) is added, 70 DEG C is warming up to and is stirred to react 12 hours.Reaction solution It being cooled to room temperature, water is added, be extracted with ethyl acetate three times, merge organic phase, successively use water, saturated sodium chloride solution is washed, Anhydrous sodium sulfate dries, filters, and filtrate decompression concentration, gained residue thin-layered chromatography is obtained with solvent system B purifying To title compound 2c (80mg, yield: 56%).

MS m/z(ESI):386.0[M+1]。

Third step

1- (2- ((t-Butyldimethylsilyl) oxygroup) ethyl) -2- (4- chloro- 2- (trifluoromethyl) benzyl) fluoro- 1H- of -6- Indole -5-carboxylic acid methyl esters 2d

By compound 2c (80mg, 0.22mmol), compound 1f (208mg, 0.87mmol), cesium carbonate (142 mg, 0.44mmol) and potassium iodide (10mg, 0.06mmol) be added in 1.5mL n,N-Dimethylformamide, be warming up to 100 DEG C it is micro- Wave is stirred to react 1 hour.Reaction solution is cooled to room temperature, and water is added, and is extracted with ethyl acetate three times, is merged organic phase, with saturation Sodium chloride solution washing, anhydrous sodium sulfate dry, filter, and filtrate decompression concentration, gained residue thin-layered chromatography is to be unfolded Agent system B purifying, obtains title compound 2d (110mg, yield: 91.9%).

4th step

2- (4- chloro- 2- (trifluoromethyl) benzyl) the fluoro- 1- of -6- (2- ethoxy) -1H- indole -5-carboxylic acid methyl esters 2e

Compound 2d (110mg, 0.2mmol) is dissolved in 5mL tetrahydrofuran, the tetrabutyl ammonium fluoride of 1M is added dropwise to Tetrahydrofuran solution (0.4mL, 0.4mmol) is stirred to react 1 hour.Water is added in reaction solution, is extracted with ethyl acetate three times, Merge organic phase, washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, gained residue Purified with thin-layered chromatography with solvent system B, obtains title compound 2e (80mg, yield: 93%).

MS m/z(ESI):430.0[M+1]。

5th step

2- (4- chloro- 2- (trifluoromethyl) benzyl) the fluoro- 1- of -6- (2- ethoxy) -1H- indole -5-carboxylic acid 2f

Compound 2e (80mg, 0.19mmol) is dissolved in the mixed solvent of 6mL methanol and tetrahydrofuran (V/V=5:1) In, the sodium hydroxide solution of 2mL 4M is added, is warming up to 60 DEG C and is stirred to react 1 hour.Reaction solution is cooled to room temperature, and is depressurized dense It contracts, water is added in gained residue, it is 4 that concentrated hydrochloric acid, which is added dropwise, to pH, is extracted with ethyl acetate three times, merges organic phase, with saturation Sodium chloride solution washing, anhydrous sodium sulfate dry, filter, and filtrate decompression concentration obtains crude title compound 2f (60mg), Product directly carries out next step reaction without further purification.

6th step

Crude Compound 2f (60mg, 0.14mmol) and compound 1j (44mg, 0.22mmol) are dissolved in 10 mL N, N- In dimethylformamide, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (42 mg, 0.22mmol), 1- is added Hydroxybenzotriazole (30mg, 0.22mmol) and n,N-diisopropylethylamine (93mg, 0.72mmol), are stirred to react 12 hours. Reaction solution is poured into water, and three times with the extraction of the mixed solvent (V/V=10:1) of methylene chloride and methanol, merges organic phase, successively It is washed with water and saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, gained residue thin layer color Spectrometry obtains title compound 2 (44mg, yield: 51%) with solvent system A purifying.

MS m/z(ESI):597.1[M+1]。

¹H NMR(400MHz,DMSO-d₆)δ8.74(t,1H),7.86-7.84(m,3H),7.80(d,1H),7.76(d, 1H),7.59(d,2H),7.41(d,1H),7.30(d,1H),5.95(s,1H),4.95(t,1H),4.58(d,2H), 4.37 (brs,2H),4.16(t,2H),3.64(q,2H),3.27(q,2H),1.09(t,3H)。

Embodiment 3

2- (4- chloro- 2- (trifluoromethyl) benzyl)-N- (4- (ethylsulfonyl) benzyl) -1- (2- methoxy ethyl) -1H- Yin Diindyl -5- formamide 3

Using the synthetic route of embodiment 1, raw material compound 1f is replaced with into the bromo- 2- Ethyl Methyl Ether of 1- (using patent Method disclosed in application " CN101671238 " is prepared) title compound 3 (47mg) is made.

MS m/z(ESI):593.4[M+1]。

¹H NMR(400MHz,DMSO-d₆)δ8.98(t,1H),8.04(d,1H),7.85(d,1H),7.83(d,2H), 7.73(dd,1H),7.68(dd,1H),7.57(d,2H),7.52(d,1H),7.29(d,1H),5.96(d,1H),4.57 (d, 2H),4.37(s,2H),4.30(t,2H),3.56(t,2H),3.25(q,2H),3.15(s,3H),1.07(t,3H)。

Embodiment 4

N- (4- (ethylsulfonyl) benzyl) fluoro- 2- of -6- (4- fluoro- 2- (trifluoromethyl) benzyl) -1- (2- ethoxy) -1H- Indoles -5- formamide 4

Using the synthetic route of embodiment 1, raw material compound 1c is replaced with into the fluoro- 2- (fluoroform of 1- (bromomethyl) -4- Base) benzene (Adamas), raw material compound 1d replaces with compound 2b, and title compound 4 (38mg) is made.

MS m/z(ESI):581.4[M+1]。

¹H NMR(400MHz,DMSO-d₆)δ8.73(brs,1H),7.85(d,2H),7.79(d,1H),7.69(d, 1H), 7.61(d,2H),7.59-7.58(m,1H),7.44(d,1H),7.41-7.35(m,1H),5.91(s,1H),4.96 (t,1H), 4.58(d,2H),4.35(brs,2H),4.18(t,2H),3.64(q,2H),3.27(q,2H),1.09(t,3H)

Embodiment 5

2- (4- chloro- 2- (trifluoromethyl) benzyl) -1- (2- (difluoro-methoxy) ethyl)-N- (4- (ethylsulfonyl) benzyl Base) -1H- indoles -5- formamide 5

The first step

2- (4- chloro- 2- (trifluoromethyl) benzyl) -1- (2- (difluoro-methoxy) ethyl) -1H- indole -5-carboxylic acid methyl esters 5a

Compound 1h (0.1g, 242.84 μm of ol) and cuprous iodide (23.12mg, 121.42 μm of ol) are dissolved in 10 mL second In nitrile, 50 DEG C are warming up to, is added 2- fluorosulfonyl difluoroacetic acid (86.49mg, 485.67 μm of ol), is stirred to react 1 hour.Instead It answers liquid to be cooled to room temperature, is concentrated under reduced pressure, gained residue silica gel column chromatography is obtained titled with eluant, eluent system B purifying Close object 5a (20mg, yield: 17.83%).

MS m/z(ESI):462.1[M+1]。

Second step

2- (4- chloro- 2- (trifluoromethyl) benzyl) -1- (2- (difluoro-methoxy) ethyl) -1H- indole -5-carboxylic acid 5b

Compound 5a (0.02g, 43.31 μm of ol) is dissolved in 2mL methanol, addition 1mL sodium hydroxide (159.99 mg, 4.00mmol) solution is warming up to 60 DEG C and is stirred to react 1 hour.Reaction solution is cooled to room temperature, and dropwise addition 2M hydrochloric acid to pH is 3~4, It is concentrated under reduced pressure, obtains crude title compound 5b (19mg), product directly carries out next step reaction without further purification.

MS m/z(ESI):448.1[M+1]。

Third step

By crude Compound 5b (0.019g, 42.43 μm of ol) and (4- (ethylsulfonyl) phenyl) methylamine hydrochloride 5c (20.00mg, 84.86 μm of ol are prepared using method disclosed in patent application " WO2015035032 ") is dissolved in 2mL N, N- In dimethylformamide, O- (7- azepine benzo triazol-1-yl)-N, N, N, N '-tetramethylurea hexafluorophosphoric acid ester is added (19.97mg, 84.86 μm of ol) and n,N-diisopropylethylamine (16.45mg, 127.29 μm of ol), is stirred to react 1 hour.Reaction Liquid pours into 20mL water, is extracted with ethyl acetate (20mL × 2), merges organic phase, is washed with saturated sodium chloride solution, anhydrous Sodium sulphate dries, filters, and filtrate decompression concentration, gained residue silica gel column chromatography is obtained with eluant, eluent system A purifying Title compound 5 (5mg, yield: 18.73%).

MS m/z(ESI):629.5[M+1]。

Embodiment 6

2- (4- chloro- 2- (trifluoromethyl) benzyl) -1- (2- (difluoro-methoxy) ethyl)-N- (4- (ethylsulfonyl) benzyl Base) the fluoro- 1H- indoles -5- formamide 6 of -6-

Using the synthetic route of embodiment 5, raw material compound 1h is replaced with into 2e, title compound 6 (8 mg) is made.

MS m/z(ESI):647.5[M+1]。

Embodiment 7

(R) -2- (4- chloro- 2- (trifluoromethyl) benzyl)-N- (1- (4- (ethylsulfonyl) phenyl) -2- ethoxy) -6- is fluoro- 1- (2- ethoxy) -1H- indoles -5- formamide 7

By crude Compound 2f (20mg, 48.1 μm of ol) and (R) -2- amino -2- (4- (ethylsulfonyl) phenyl) ethyl alcohol 7a (11.03mg, 48.1 μm of ol are prepared using method disclosed in patent application " US9481674 ") is dissolved in 5mL N, N- diformazan In base formamide, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (18.38mg, 96.21 μm of ol), 1- are added Hydroxybenzotriazole (14.64mg, 96.21 μm of ol) and n,N-diisopropylethylamine (18.65 mg, 144.31 μm of ol), stirring are anti- It answers 12 hours.Reaction solution is poured into water, and is extracted with ethyl acetate, and is merged organic phase, is successively washed with water and saturated sodium chloride solution It washs, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, and gained residue silica gel column chromatography is pure with eluant, eluent system B Change, obtains title compound 7 (10mg, yield: 33.15%).

MS m/z(ESI):627.5[M+1]。

¹H NMR(400MHz,DMSO-d₆)δ8.44(m,1H),7.84(d,3H),7.77-7.73(m,2H),7.65 (d, 2H),7.43(d,1H),7.30(d,1H),5.94(s,1H),5.15-5.12(m,1H),5.06(t,1H),4.94(t, 1H), 4.36(s,2H),4.16(t,2H),3.71(t,2H),3.62(t,2H),3.30-3.24(m,2H),1.09(t, 3H)。

Embodiment 8

(R)-N- (1- (4- (ethylsulfonyl) phenyl) -2- ethoxy) -2- (4- fluoro- 2- (trifluoromethyl) benzyl) -1- (2- Ethoxy) -1H- indoles -5- formamide 8

Using the synthetic route of embodiment 1, raw material compound 1c is replaced with into the fluoro- 2- (fluoroform of 1- (bromomethyl) -4- Base) benzene (Adamas), raw material compound 1j replaces with compound 7a, and title compound 8 (10.1mg) is made.

MS m/z(ESI):593.6[M+1]。

¹H NMR(400MHz,CDCl₃)δ8.68-8.66(d,1H),8.10(s,1H),7.91-7.89(d,2H), 7.73- 7.71(d,2H),7.57-7.56(d,1H),7.50-7.48(d,1H),7.36-7.28(m,2H),6.11(s,1H), 5.33- 5.28(m,1H),4.3(s,2H),4.26-4.23(t,2H),3.94-3.93(d,2H),3.82-3.79(t,2H), 3.23- 3.18(q,2H),1.24-1.21(t,3H)。

Embodiment 9

(R)-N- (1- (4- (ethylsulfonyl) phenyl) -2- ethoxy) the fluoro- 2- of -6- (4- fluoro- 2- (trifluoromethyl) benzyl) - 1- (2- methoxy ethyl) -1H- indoles -5- formamide 9

Using the synthetic route of embodiment 2, raw material compound 1c is replaced with into the fluoro- 2- (fluoroform of 1- (bromomethyl) -4- Base) benzene (Adamas), raw material compound 1f replaces with the bromo- 2- Ethyl Methyl Ether of 1-, and raw material compound 1j replaces with compound Title compound 9 (6.5mg) is made in 7a.

MS m/z(ESI):625.5[M+1]。

¹H NMR(400MHz,CDCl₃)δ8.24(d,1H),7.90(d,2H),7.65-7.61(m,3H),7.43(d, 1H),7.16-7.06(m,3H),6.17(s,1H),5.40(s,1H),4.30(s,3H),4.12-3.99(m,3H),3.56 (d, 1H),3.24(s,3H),3.13-3.07(m,2H),1.27(t,3H)。

Embodiment 10

(R)-N- (1- (4- (ethylsulfonyl) phenyl) -2- ethoxy) the fluoro- 2- of -6- (4- fluoro- 2- (trifluoromethyl) benzyl) - 1- (2- ethoxy) -1H- indoles -5- formamide 10

Using the synthetic route of embodiment 2, raw material compound 1c is replaced with into the fluoro- 2- (fluoroform of 1- (bromomethyl) -4- Base) benzene (Adamas), raw material compound 1j replaces with compound 7a, and title compound 10 (5mg) is made.

MS m/z(ESI):611.5[M+1]。

¹H NMR(400MHz,DMSO-d₆)δ8.44(m,1H),7.84(d,2H),7.75(d,1H),7.69-7.64 (m, 3H),7.52(t,1H),7.42(d,1H),7.33(t,1H),5.90(s,1H),5.14-5.11(m,1H),5.05(t, 1H), 4.94(t,1H),4.34(s,2H),4.17(t,2H),3.70(t,2H),3.61(t,2H),3.29-3.24(m,2H), 1.09 (t,3H)。

Embodiment 11

2- (4- chloro- 2- (trifluoromethyl) benzyl) -1- (2- (dimethylamino) ethyl)-N- (4- (ethylsulfonyl) benzyl Base) -1H- indoles -5- formamide 11

The first step

2- (4- chloro- 2- (trifluoromethyl) benzyl) -1- (2- (dimethylamino) -2- oxoethyl) -1H- indoles -5- first Sour methyl esters 11b

By the chloro- n,N-dimethylacetamide 11a of compound 1e (100mg, 0.272mmol), 2- (67mg, 0.55 mmol, Be prepared using method disclosed in patent application " CN1721392 ") and cesium carbonate (177mg, 0.55 mmol) be dissolved in 10mL second In nitrile, 100 DEG C are warming up to, microwave is stirred to react 1 hour.Reaction solution is cooled to room temperature, filtering, and filtrate decompression concentration obtains crude product Title compound 11b (133mg), product directly carry out next step reaction without further purification.

Second step

2- (4- chloro- 2- (trifluoromethyl) benzyl) -1- (2- (dimethylamino) ethyl) -1H- indole -5-carboxylic acid methyl esters 11c

Crude Compound 11b (133mg, 0.296mmol) is dissolved in 10mL tetrahydrofuran, the borine diformazan of 2M is added The tetrahydrofuran solution (0.5mL, 1mmol) of thioether is warming up to 60 DEG C and is stirred to react 12 hours.1mL 3M is added in reaction solution Hydrochloric acid, 60 DEG C are stirred to react 15 minutes, are cooled to room temperature, be added dropwise to saturated sodium bicarbonate solution to pH be greater than 7, use acetic acid Ethyl ester extracts three times, merges organic phase, is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, gained residue silica gel Column chromatography obtains title compound 11c (55mg, yield: 43%) with eluant, eluent system B purifying

MS m/z(ESI):439.1[M+1]。

Third step

2- (4- chloro- 2- (trifluoromethyl) benzyl) -1- (2- (dimethylamino) ethyl) -1H- indole -5-carboxylic acid 11d

Compound 11c (55mg, 0.125mmol) is dissolved in 19mL methanol, tetrahydrofuran and water (V/V/V=10:3:6) In the mixed solvent, be added sodium hydroxide (100mg, 2.5mmol), be warming up to 50 DEG C and be stirred to react 3 hours.Reaction solution is cooling It to room temperature, is concentrated under reduced pressure, water is added in gained residue, 1M hydrochloric acid is added dropwise to pH less than 7, is concentrated under reduced pressure, obtains crude title Compound 11d (53mg), product directly carry out next step reaction without further purification.

4th step

Crude Compound 11d (53mg, 0.125mmol) and compound 1j (36mg, 0.188mmol) are dissolved in 5mL N, In dinethylformamide, addition 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (37 mg, 0.188mmol), I-hydroxybenzotriazole (25mg, 0.188mmol) and triethylamine (0.1mL, 0.72 mmol), are stirred to react 12 Hour.Reaction solution is concentrated under reduced pressure, and gained residue silica gel column chromatography obtains title compound with eluant, eluent system A purifying 11 (22mg, yields: 29.1%).

MS m/z(ESI):606.5[M+1]。

¹H NMR(400MHz,DMSO-d₆)δ8.08(s,1H),7.87(d,2H),7.73-7.69(m,2H), 7.58- 7.52(m,3H),7.44-7.42(m,1H),7.06(d,1H),6.65(t,1H),6.30(s,1H),4.80(d, 2H),4.36- 4.31(m,4H),3.11(q,2H),2.69(s,2H),2.41(s,6H),1.28(t,3H)。

Embodiment 12

N- ((5- (ethylsulfonyl) pyridine -2- base) methyl) -1- (2- methoxy ethyl) -2- ((2- (trifluoromethyl) piperazine Pyridine -1- base) methyl) -1H- indoles -5- formamide 12

The first step

2- (((t-Butyldimethylsilyl) oxygroup) methyl) -1H- indole -5-carboxylic acid's ethyl ester 12c

By 3- iodo -4- (2,2,2- trifluoroacetamido) ethyl benzoate 12a (2g, 5.17mmol, splendid remote), tertiary fourth Base dimethyl (propyl- 2- alkynes -1- base oxygroup) silane 12b (1.32g, 7.75mmol, Sigma), dichloro two (triphenylphosphine) palladium (181mg, 0.258mmol), triethylamine (2.61g, 25.83mmol) and cuprous iodide (98.4mg, 0.517mmol) are added to In 50mL n,N-Dimethylformamide, it is warming up to 100 DEG C and is stirred to react 12 hours.Reaction solution is cooled to room temperature, and is poured into water, It is extracted with ethyl acetate, merges organic phase, dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, gained residue silicon Rubber column gel column chromatography obtains title compound 12c (800mg, yield: 46.43%) with eluant, eluent system B purifying.

MS m/z(ESI):334.2[M+1]。

Second step

2- (methylol) -1H- indole -5-carboxylic acid's ethyl ester 12d

Compound 12c (300mg, 899.56 μm of ol) is dissolved in 5mL tetrahydrofuran, under ice bath is cooling, is added dropwise to 1M's The tetrahydrofuran solution (202.56mg, 899.56umol) of tetrabutyl ammonium fluoride, is stirred to react 2 hours.Reaction solution pours into water In, it is extracted with ethyl acetate, merges organic phase, dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration obtains crude title Compound 12d (190mg), product directly carry out next step reaction without further purification.

MS m/z(ESI):220.2[M+1]。

Third step

2- formoxyl -1H- indole -5-carboxylic acid's ethyl ester 12e

Crude Compound 12d (200mg, 912.26 μm of ol) and manganese dioxide (79.31mg, 912.26 μm of ol) are added Into 5mL tetrahydrofuran, it is stirred to react 12 hours.Reaction solution filtering, filtrate decompression concentration, gained residue silicagel column color Spectrometry obtains title compound 12e (160mg, yield: 80.74%) with eluant, eluent system B purifying.

MS m/z(ESI):218.1[M+1]。

4th step

2- ((2- (trifluoromethyl) piperidin-1-yl) methyl) -1H- indole -5-carboxylic acid's ethyl ester 12g

By compound 12e (100mg, 460.36 μm of ol) and 2- (trifluoromethyl) piperidinyl-1 2f (84.6mg, 552.43 μ Mol, splendid remote) be added in 5mL tetrahydrofuran, 3 drop acetic acid are added dropwise to, after reaction being stirred at room temperature 3 hours, three second are added portionwise Reaction 12 hours is stirred at room temperature in acyl group sodium borohydride (292.71mg, 1.38mmol).Reaction solution is poured into water, and uses ethyl acetate Extraction merges organic phase, is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, gained residue silica gel column chromatography With eluant, eluent system B purifying, title compound 12g (100mg, yield: 61.3%) are obtained.

MS m/z(ESI):355.2[M+1]。

5th step

1- (2- methoxy ethyl) -2- ((2- (trifluoromethyl) piperidin-1-yl) methyl) -1H- indole -5-carboxylic acid's ethyl ester 12h

Compound 12g (100mg, 282.19 μm of ol) is dissolved in tetrahydrofuran, addition sodium hydride (22.57mg, 564.39 μm of ol), after being stirred to react 15 minutes, it is added the bromo- 2- Ethyl Methyl Ether of 1- (58.83mg, 423.29 μm of ol), microwave 80 DEG C are stirred to react 1 hour.Reaction solution is cooled to room temperature, and is poured into water, and is extracted with ethyl acetate, and organic phase is merged, and use is anhydrous Sodium sulphate dries, filters, and filtrate decompression concentration obtains crude title compound 12h (116.39mg), product is straight without further purification Row is tapped into react in next step.

6th step

1- (2- methoxy ethyl) -2- ((2- (trifluoromethyl) piperidin-1-yl) methyl) -1H- indole -5-carboxylic acid 12i

Crude Compound 12h (80mg, 193.97 μm of ol) and sodium hydroxide (38.79mg, 969.83 μm of ol) are added to In 5mL methanol, it is added 2 and drips, be warming up to 100 DEG C and be stirred to react 2 hours.Reaction solution is cooled to room temperature, and is concentrated under reduced pressure, gained It is 3 that 1M dilute hydrochloric acid, which is added dropwise, to pH in residue, is extracted with ethyl acetate, merges organic phase, dried, filtered with anhydrous sodium sulfate, filters Liquid is concentrated under reduced pressure, and obtains crude title compound 12i (60mg), and product directly carries out next step reaction without further purification.

MS m/z(ESI):383.1[M+1]。

7th step

By crude Compound 12i (20mg, 52.03 μm of ol) and (5- (ethylsulfonyl) pyridine -2- base) methylamine 12j (12.50mg, 62.44 μm of ol, splendid remote) is dissolved in 3mL n,N-Dimethylformamide, and 1- (3- dimethylamino-propyl) -3- is added Ethyl-carbodiimide hydrochloride (19.98mg, 104.06 μm of ol), I-hydroxybenzotriazole (15.83mg, 104.06 μm of ol) and N,N-diisopropylethylamine (20.17mg, 156.09 μm of ol), is stirred to react 12 hours.Reaction solution is poured into water, with acetic acid second Ester extraction, merges organic phase, is successively washed with water and saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression Concentration, gained residue silica gel column chromatography with eluant, eluent system B purifying, obtain title compound 12 (12mg, yield: 41.4%).

MS m/z(ESI):567.5[M+1]。

1H NMR(400MHz,CDCl₃)δ9.06(s,1H),8.17(d,1H),8.11(s,1H),7.72(d,1H), 7.58(d,1H),7.41(d,1H),7.35(t,1H),6.48(s,1H),4.91(d,2H),4.45(d,2H),4.12(d, 1H),4.02(d,1H),3.69(t,2H),3.29(s,3H),3.21-3.13(m,3H),2.89(bar,1H),2.55(bar, 1H),1.85(bar,2H),1.54(bar,3H),1.32(t,3H)。

Embodiment 13

1- (2- amino -2- oxoethyl) -2- (4- chloro- 2- (trifluoromethyl) benzyl)-N- (4- (ethylsulfonyl) benzyl) - 1H- indoles -5- formamide 13

The first step

1- (2- (tert-butoxy) -2- oxoethyl) -2- (4- chloro- 2- (trifluoromethyl) benzyl) -1H- indole -5-carboxylic acid Methyl esters 13b

By compound 1e (21.6 mg, 0.059 mmol), 2- bromo-acetic acid tert-butyl 13a (43.4 μ L, 0.294 mmol, Using well known method " Tetrahedron, 2007,63 (2), 337-346 " are prepared) and cesium carbonate (95.7 mg, 0.294 mmol) it is added in 1 mL n,N-Dimethylformamide, it is warming up to 110 DEG C of microwaves and is stirred to react 1.5 hours.Reaction After title compound 13b reaction solution, do not deal with directly carry out next step reaction.

Second step

2- (2- (4- chloro- 2- (trifluoromethyl) benzyl) -5- (methoxycarbonyl group) -1H- indoles -1- base) acetic acid 13c

1 mL methanol is added into the reaction solution of above compound 13b, the potassium hydroxide solution of 1 mL 2M, stirring is added Reaction 16 hours.Reaction solution, less than 3, is extracted with ethyl acetate three times with 6M salt acid for adjusting pH, merges organic phase, with saturation chlorine Change sodium solution washing, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, purify gained remnants with high performance liquid chromatography Object obtains title compound 13c (10 mg, yield: 40%).

MS m/z(ESI):426[M+1]。

Third step

1- (2- amino -2- oxoethyl) -2- (4- chloro- 2- (trifluoromethyl) benzyl) -1H- indole -5-carboxylic acid methyl esters 13d

Compound 13c (10 mg, 0.0235 mmol) is dissolved in 1mL n,N-Dimethylformamide, ((1H- benzene is added And [d] [1,2,3] triazol-1-yl) oxygroup) three (pyrrolidin-1-yl) Phosphonium hexafluorophosphate (V) (18.3 mg, 0.0352 Mmol), triethylamine (20 μ L, 0.141 mmol) and ammonium chloride (12.56 mg, 0.235 mmol), are stirred to react 16 hours.Instead Answer liquid to be concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title compound 13d (4 mg, yield: 40%)

MS m/z(ESI):425[M+1]。

4th step

1- (2- amino -2- oxoethyl) -2- (4- chloro- 2- (trifluoromethyl) benzyl) -1H- indole -5-carboxylic acid 13e

Compound 13d (4 mg, 9 μm of ol) is dissolved in the mixed of 2 mL methanol and n,N-Dimethylformamide (V/V=1:1) In bonding solvent, the potassium hydroxide solution of 1 mL 2M is added, reaction 3 hours is stirred at room temperature, the potassium hydroxide for adding 1 mL 2M is molten Liquid is stirred at room temperature reaction 16 hours, is warming up to 50 DEG C and is stirred to react 24 hours, adds the potassium hydroxide solution of 1 mL 2M, and 50 DEG C It is stirred to react 48 hours.Reaction solution is cooled to room temperature, and 6M hydrochloric acid is added dropwise to pH less than 2, is concentrated under reduced pressure, uses high performance liquid chromatography Method purifying gained residue, obtains title compound 13e (2.5 mg, yield: 60%).

MS m/z(ESI):411[M+1]。

5th step

Compound 13e (2.5 mg, 6.09 μm of ol) and compound 1j (2.4 mg, 12.2 μm of ol) are dissolved in 1 mL dichloro In methane, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (2.3 mg, 12.2 μm of ol), 1- hydroxy benzenes are added And triazole (1.65 mg, 12.2 μm of ol) and triethylamine (4.3 μ L, 30.4 μm of ol), it is stirred to react 16 hours.Reaction solution decompression is dense Contracting, with high performance liquid chromatography purify obtained by residue, obtain title compound 13 (1.5 mg, yield: 42%).

MS m/z(ESI):592[M+1]。

Embodiment 14

(R)-N- (1- (4- (ethylsulfonyl) phenyl) -2- ethoxy) -1- (2- ethoxy) -2- ((2- (trifluoromethyl) pyrrole Pyridine -3- base) methyl) -1H- indoles -5- formamide 14

Using the synthetic route of embodiment 1, raw material compound 1c is replaced with into 3- (bromomethyl) -2- (trifluoromethyl) pyrrole Pyridine (is prepared) using method disclosed in patent application " WO2016168633 ", and raw material compound 1j replaces with compound 7a, Title compound 14 (2.3 mg) is made.

MS m/z(ESI):576[M+1]。

Embodiment 15

(R) -2- (4- chloro- 2- (trifluoromethyl) benzyl)-N- (1- (4- (ethylsulfonyl) phenyl) -2- methoxyethyl) - 1- (2- ethoxy) -1H- indoles -5- formamide 15

The first step

1- (2- ((t-Butyldimethylsilyl) oxygen) ethyl) -2- (4- chloro- 2- (trifluoromethyl) benzyl) -1H- indoles -5- Methyl formate 1j

Compound 1e (110 mg, 0.3 mmol) is dissolved in the n,N-Dimethylformamide of 4 mL, 2- tert-butyl is added Dimethyl oxygen bromide ethane (215 mg, 0.9 mmol) and cesium carbonate (195 mg, 0.6 mmol), microwave heating to 100 DEG C it is anti- It answers 2 hours.Cooling reaction, is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title Compound 1j (200 mg).

Second step

2- (4- chloro- 2- (trifluoromethyl) benzyl) -1- (2- hydroxyethyl) -1H- indole -5-carboxylic acid 1i

It is dissolved in compound 1j (120 mg, 0.23 mmol) in 2 mL methanol, 2N sodium hydrate aqueous solution (1.2 is added ML, 23.0 mmol), it is heated to 70 DEG C and is stirred to react 1 hour.Cooling reaction solution, is acidified to PH=3~4 with 1N dilute hydrochloric acid, It is spin-dried for obtaining crude Compound 1i (90 mg).

Third step

By crude Compound 1i (40.05 mg, 0.10 mmol), crude Compound 15a (49.02 mg, 0.20 mmol) It is dissolved in 5 mL n,N-Dimethylformamide, sequentially adds 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea Hexafluorophosphoric acid ester (76.00 mg, 0.21 mmol) and n,N-diisopropylethylamine (38.00 mg, 0.30 mmol), room temperature is stirred Mix reaction 1 hour.Reaction solution be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, marked Inscribe compound 15 (10 mg, yield: 16%).

MS m/z(ESI):623[M+1]。

Biological assessment

The explanation present invention is further described below in conjunction with test case, but these embodiments are not meant as the limitation present invention Range.

The measurement of test case 1, the compounds of this invention to ROR γ external activity

One, experimental material and instrument

1.TR-FRET ROR γ co-activation system (Life Technologies)

2.RORγLBD(AB Vector)

3.DMSO(SigmaAldrich)

4. microplate reader (Tecan)

Two, experimental procedure

It is sieved using LanthaScreen TR-FRET (time-resolved fluorescence resonance energy transfer) ROR γ co-activation system Select adjusting of the compound of the present invention to ROR gamma activity.

Complete buffer D (complete TR-FRET Coregulator) (Life Technologies) is prepared first Include final concentration 5mM DTT.DMSO final concentration of 2%.Untested compound is connected in the complete buffer D containing 2%DMSO It is continuous to be diluted to 2x final concentration, maximum dose level be 60 μm.The test hole (PerkinElmer) of 384 orifice plates is added in 10 holes μ l/.Often 2 parallel control holes are arranged in a detection compound under same concentrations.Prepare 4X ROR γ LBD (AB Vector).It has used Whole buffer D dilution ROR γ LBD concentration is 1ng/ μ L.The test hole of 384 hole assay plates is added in 5 holes μ l/.Negative control hole is 5 μ L complete buffer D, no ROR γ LBD.Contain 0.6 μM of fluorescein-D22 (4X) and 8nM terbium using completely buffering liquid D and preparing (Tb) 5 μ L mixed liquors are added to 384 orifice plates by anti-GST antibody (4X) (Life Technologies) mixed liquor marked In.Overall reaction system is 20 μ L.384 orifice plate is mixed gently on the oscillator and is protected from light incubation 2-4 hours at room temperature.

Fluorescence reading is detected using Tecan Infinite M1000, is sent out by 6.0 Software on Drawing of GraphPad Prism The ratio of the long 520nm/495nm of ejected wave and the logarithmic curve of compound concentration, calculate the EC of untested compound₅₀Value.

The compounds of this invention is measured ROR γ external activity by above test, the EC measured₅₀Value is shown in Table 1.

EC of 1 the compounds of this invention of table to ROR γ external activity₅₀Value

Embodiment number	EC₅₀(nM)	Emax (%)
			1	2	112%
7	49	95%
			8	16	101%
9	24	104%
			10	49	107%

Conclusion: the compounds of this invention has apparent agonism to ROR γ external activity.

Test case 2, the compounds of this invention are to IL-17A enzyme linked immunological quantitative analysis determination of activity

One, experimental material and instrument

1. human peripheral blood mononuclear cell (PBMC) (Zenbio)

2. lymphocytes culture medium (Zenbio)

3.TexMACS(Miltenyi Biotec)

4. people Cytostim (Miltenyi Biotec)

5. human il-17 enzyme linked immunological kit (R&D system)

6.CO₂Incubator (Fisher Scientific)

7. centrifuge (Fisher Scientific)

8. 96 porocyte culture plates (Fisher Scientific)

9. microplate reader (Tecan)

Two, experimental procedure

Rapid fluid resuscitation, centrifugation in the lymphocytes culture medium of preheating by the human peripheral blood mononuclear cell frozen (PBMC) 1000rpm, 10min remove cells and supernatant, cell are gently suspended in TexMACS culture medium, count cell.Thin T cell activation reagent cytostim (10 μ l/ml) is proportionally added into born of the same parents' suspension, then with 1 × 10⁵Peripheral blood mononuclear cells/ The density in hole is by cell seeding in 96 porocyte culture plates.Using TexMACS culture medium gradient dilution untested compound, divide It is not added in each experimental port, every group of 2-3 parallel hole.Prepare the negative control hole that cytostim is free of containing only cell, to obtain Background reading.Tissue culture plate is placed in 5% carbon dioxide, 37 DEG C of incubators to be incubated for 3 days.Drug-treated is collected carefully after 3 days Oil removal is removed in born of the same parents' culture supernatant, centrifugation.Then IL-17A in supernatant is quantified using IL-17A enzyme linked immunological kit. The EC of untested compound is calculated using GraphPad Prism 6.0₅₀Value.

The compounds of this invention is measured the quantitative analysis of IL-17A enzyme linked immunological by above test, the EC measured₅₀ Value is shown in Table 2.

EC of 2 the compounds of this invention of table to IL-17A enzyme linked immunological quantitative analysis₅₀Value

Embodiment number	EC₅₀(nM)	Emax (%)
			1	3	80%
2	105	129%
			3	27	80%
7	49	95%
			8	66	110%
9	26	96%
			10	74	97%

Conclusion: the compounds of this invention has apparent adjustment effect to IL-17A enzyme linked immunological quantitative analysis activity.

Claims

1. a kind of logical formula (I) compound represented:

Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form, or Its pharmaceutical salt,

Wherein:

For double bond or singly-bound；

Ring A is selected from aryl, heteroaryl, naphthenic base and heterocycle；

Ring B is aryl or heteroaryl；

L¹For alkylidene；

R¹It is identical or different, and be each independently selected from hydrogen atom, halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, Cyano, amino, nitro, hydroxyl and hydroxyalkyl；

R²For halogenated alkyl；

R³Selected from hydrogen atom, halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl Base, naphthenic base, heterocycle, aryl and heteroaryl, wherein the alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and miscellaneous Aryl is each independently optionally replaced one or more substituent groups in hydroxyl, halogen, alkyl and amino；

R⁴It is identical or different, and be each independently selected from hydrogen atom, halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, Cyano, amino, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

R⁵Selected from hydrogen atom, alkyl, halogenated alkyl, amino, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

R⁶It is identical or different, and be each independently selected from hydrogen atom, halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, Cyano, amino, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

R⁸And R⁹It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, halogenated alkyl, alkoxy, cyano, ammonia Base, nitro, hydroxyl and hydroxyalkyl；

N is 0,1,2,3 or 4；

S is 0,1,2 or 3；And

T is 0,1,2 or 3.

2. logical formula (I) compound represented according to claim 1, middle ring A is selected from phenyl, pyridyl group, imidazole radicals, pyrrole Oxazolyl, piperidyl and morpholinyl；And ring B is phenyl or pyridyl group.

3. logical formula (I) compound represented according to claim 1 or 2, to lead to formula (II) compound represented:

Wherein:

W and G are identical or different, and independent is CH or N；

R¹、R³、R⁵~R⁷、L¹, n and t it is as defined in claim 1.

4. logical formula (I) compound represented described in any one of claim 1 to 3, to change shown in logical formula (III) Close object:

Wherein:

W and G are identical or different, and independent is CH or N；

The integer that p is 1 to 6；

R¹、R³、R⁵、R⁶、R¹⁰, n and t it is as defined in claim 1.

5. logical formula (I) compound represented according to any one of claims 1 to 4, to change shown in logical formula (IV) Close object:

Wherein:

The integer that p is 1 to 6；

R¹、R³、R⁵、R⁶、R¹⁰, n and t it is as defined in claim 1.

6. logical formula (I) compound represented according to any one of claims 1 to 5, wherein R¹Selected from hydrogen atom, halogen And alkyl.

7. logical formula (I) compound represented described according to claim 1~any one of 6, wherein R³Selected from hydrogen atom, alkyl And hydroxyalkyl.

8. logical formula (I) compound represented according to any one of claims 1 to 7, wherein R⁵For alkyl.

9. logical formula (I) compound represented described according to claim 1~any one of 8, wherein R⁶For hydrogen atom or halogen.

10. logical formula (I) compound represented described according to claim 1~any one of 9, is selected from:

11. compound shown in a kind of logical formula (V):

Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form, or Its officinal salt,

Wherein:

For double bond or singly-bound；

Ring A is selected from aryl, heteroaryl, naphthenic base and heterocycle；

L¹For alkylidene；

R²For halogenated alkyl；

N is 0,1,2,3 or 4；And

T is 0,1,2 or 3.

12. logical formula (V) compound represented according to claim 11, is selected from:

13. a kind of method for preparing logical formula (I) compound according to claim 1, this method comprises:

Wherein:

Ring A, ring B, G¹~G³、R¹~R⁹、L¹, n, s and t it is as defined in claim 1.

14. a kind of pharmaceutical composition, containing therapeutically effective amount according to claim 1~any one of 10 described in general formula (I) compound represented and one or more pharmaceutically acceptable carriers, diluent or excipient.

15. logical formula (I) compound represented described according to claim 1~any one of 10 or according to claim 1 described in 4 Pharmaceutical composition preparing the purposes in ROR agonist.

16. logical formula (I) compound represented described according to claim 1~any one of 10 or according to claim 1 described in 4 Pharmaceutical composition preparing the purposes in drug for preventing and/or treating tumour or cancer.

17. purposes according to claim 16 is preferably selected from wherein the tumour or cancer is solid tumor and blood tumor Non-Hodgkin lymphoma, Diffuse Large B-Cell Lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical carcinoma, colon cancer, Lung cancer, gastric cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, bladder cancer, Liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, melanoma, glioma, spongioblastoma, hepatocellular carcinoma, The renal tumor of mastoid process, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small cell lung cancer.