CN109896998A - A kind of 3,4- dihydro-isoquinoline sulfamide compound and its application - Google Patents

Abstract

The invention belongs to pharmaceutical technology field, it is related to 3,4- dihydro-isoquinoline sulfamide compound and its application of a kind of following structural formula (I) or formula (II),

Description

A kind of 3,4- dihydro-isoquinoline sulfamide compound and its application

Technical field

The invention belongs to pharmaceutical technology fields, and in particular to one kind 3,4- dihydro-isoquinoline sulfamide compound and its answer With；The more specifically described compound can be used as ROR γ t agonist for preventing, treating or improving the cell-mediated tumour of Th17 Immune correlated disease.

Background technique

Prior art discloses retinoic acid receptors related orphan receptor (retinoic acid receptor-related Orphan receptor, ROR) belong to ligand-dependent transcription factor nuclear receptor superfamily a member.ROR γ t is the Asia RORs man One of race's Major Members, are distributed mainly on thymus gland, express in the key cells in immune system；ROR γ t is regulation CD4 sun The important transcription factor of property Th17 and CD8 positive Tc17 lymphocyte development and function, and adjust Th17 cell differentiation and generate The key regulator of inflammatory cytokine interleukin-17 (IL-17), research have proven to Thl7 cell infection, inflammation, itself There are crucial pathogenic effects in immunity disease and graft versus host disease(GVH disease).Recently research discovery Thl7 cell also exists in In tumor microenvironment, and there are certain relationship, about 15% tumor infiltrating lymphocyte table with inflammation associated tumour The IL-17 of lymphocytic emiocytosis and the level of other cell factors can be enhanced up to ROR γ t, ROR γ t agonist, to improve The cytotoxicity of lymphocyte；These agonists can also improve the survival rate of Th17 and Tc17 lymphocyte.At the same time, ROR γ t agonist is able to suppress the generation of regulatory T cells, and these cells can inhibit immune hair to answer, therefore agonist can incite somebody to action The balance of immune response pushes the direction of activation to.ROR γ t agonist can also promote such as CD226, CD27 and 4-1BB (CD137) a series of expression of costimulatory molecules (Co-Stimulatory Molecule) such as, and inhibit PD-1, TIGIT, The expression of the Co inhibitors such as TIM3, CD73 and LAG3 (Co-Inhibitory Molecule), to promote t cell activation. In a variety of homology tumor models (Syngeneic Tumor Models), oral ROR γ t agonist can lead to studies have shown that Immune response is crossed to inhibit the growth of tumour and extend the life span of animal.

2011, the Littman professor seminar of New York University and the Burris professor seminar of Scripps research institute were same When delivered that ROR γ t micromolecular inhibitor is related to be studied on Nature magazine: Littman group sieves from compound library Select the inhibitor that cardiotonic digoxin is ROR γ t；Burris group has found that first nonsteroidal small molecule SR1001 can make For ROR α and ROR γ t double inhibitor.Major pharmacy corporation and research institute have started grinding for ROR γ t small-molecule modulators later Study carefully, but is largely focused on the research of ROR γ t micromolecular inhibitor.Lycera company reports ROR γ t small molecule excitement earliest The research and development of agent, 2017, Lycera company announced that the starting clinic 1/2a phase tests the ROR γ t agonist to examine it to research and develop The effect of LYC-55716 treatment carries advanced stage, recurrent or Refractory solid tumor patient.LYC-55716 is to T lymphocyte energy It is enough to generate " double action ", weaken immunosuppression mechanism while activated T lymphocytes function, to make T lymphocyte Anti-cancer function is more powerful.

Currently, ROR γ t agonist has been paid close attention in anti-tumor aspect, see there are numerous studies in the industry, such as hepatocellular carcinoma The cell quantity of expression IL-17A and the survival rate of patient infiltrated in specimens is negatively correlated；Patient with breast cancer's is swollen The Expressions In Lymphocytes IL-17A infiltrated in tumor tissue promotes the proliferation etc. of cancer cell, and the following IL-17 family mentions for oncotherapy For good target spot also it is highly likely that；Therefore, ROR γ t is considered antitumor, anti-inflammatory and autoimmune disease medicine The novel targets of object research and development will can be used as the new way of cancer and autoimmune inflammatory diseases treatment.

Status based on the prior art, present inventor is quasi- to provide one kind 3,4- dihydro-isoquinoline sulfonamides chemical combination Object and its application；Especially the compound is used to prevent, treat or improve cell-mediated swollen of Th17 as ROR γ t agonist Purposes in tumor immune correlated disease.

Summary of the invention

The purpose of the present invention is the statuses based on the prior art, provide one kind 3,4- dihydro-isoquinoline sulfonamides chemical combination Object.

Another object of the present invention is to provide the pharmaceutically acceptable of 3, the 4- dihydro-isoquinoline sulfamide compound Salt, solvate, precursor compound or polymorph.

The further object of the present invention is to provide the preparation method of 3, the 4- dihydro-isoquinoline sulfamide compound.

Fourth object of the present invention provides a kind of pharmaceutical composition.

5th purpose of the invention, provides that 3, the 4- dihydro-isoquinoline sulfamide compound, it can pharmaceutically connect The purposes of salt, solvate, pro-drug or the polymorph received in medicine preparation.

To achieve the above object, the technical solution adopted by the present invention is that:

One kind 3,4- dihydro-isoquinoline sulfonic acid amide derivatives, which is characterized in that the derivant structure general formula are as follows:

Wherein:

X₁、X₂For C or N；

M, n, p are independently optionally from 0,1,2,3 or 4；Preferably, 0 m；N is selected from 0,1,2 or 3；P is selected from 1 or 4；

Substituent R₁Selected from H, (C1-C3) alkyl, halogen (C1-C3) alkyl, aryl, heteroaryl, heterocycle and naphthenic base, Preferably methyl；

Substituent R₂Be not present or at least one position in 2,3,4,5,6, be it is unsubstituted, mono-substituted, It is disubstituted or polysubstituted, substituent R₂Selected from one of following groups, two or more: hydrogen, halogen, nitro, hydroxyl, Carboxyl, trifluoromethyl, cyano, substituted or unsubstituted amino, phenyl, substituted or unsubstituted (C1-C6) alkyl, substitution or not (C1-C6) alkoxy replaced ,-CONH₂、-CONHR₃、-CON(R₃)₂、-COOR₃、-COR₃、-NHCOR₃、-NHCOOR₃Group, Wherein R₃Optionally from H, (C1-C6) alkyl, trifluoromethyl, phenyl；Work as R₂For when double or three replace, substituent group can be identical or not Together；

Cy¹Selected from H, Ar1, Hetar1 or (C3-C7) naphthenic base；

The above Ar1 indicates the monocyclic aromatic hydrocarbon system with 6-10 carbon atom or bicyclic aromatic hydrocarbon system and ring aromatic hydrocarbon And saturated ring system, the system is unsubstituted or is replaced by one or more identical or different substituent groups selected from the following: (C1-C6) alkyl, (C3-C7) naphthenic base, (C1-C6) alkoxy, carbonyl, carboxyl, amino ,-CONH₂、-COOR₄、-COR₄、- NHCOR₄、-NHCOOR₄、-COH(CF₃)₂、-SONH₂、-SOOR₄、-SOR₄、-NHSOR₄、-NHSOOR₄Group replaces；Wherein R₄Appoint Selected from H, (C1-C6) alkyl；

Above 4,5,6,7,8,9 or 10 yuan of saturation with 1,2 or 3 N and/or O and/or S atom of Hetar1 expression miscellaneous Ring, the heterocycle is unsubstituted or is replaced by one or more identical or different substituent groups selected from the following: (C1-C6) alkyl, (C3-C7) naphthenic base, (C1-C6) alkoxy, carbonyl, carboxyl, amino ,-CONH₂、-COOR₄、-COR₄、-NHCOR₄、- NHCOOR₄、-COH(CF₃)₂、-SONH₂、-SOOR₄、-SOR₄、-NHSOR₄、-NHSOOR₄Group replaces；Wherein R₄Optionally from H, (C1-C6) alkyl.

Preferably, the R₁For methyl.

Preferably, the substituent R₂At least one position in 2,3,4,5,6, is unsubstituted (as R₂For H), mono-substituted, disubstituted or polysubstituted, preferably unsubstituted, monosubstituted or disubstituted, the substituent R₂It is selected from down One of column group, two or more: hydrogen, fluorine, chlorine, trifluoromethyl, cyano, methyl, phenyl, trifluoromethoxy, tert-butyl, Work as R₂When being disubstituted or polysubstituted, substituent group can be identical or different.

Preferably, the X₁Optionally from C or N.

Preferably, the X₂Optionally from C or N.

Preferably, the Cy¹Optionally certainly: 4- acetyl group-piperazine -1- base, 4- (propiono)-piperazine -1- base, 4- cyclopropyl first Acyl-piperazin -1- base, 4- tbutyloxycarbonyl-piperazin -1- base, 4- pivaloyl group-piperazine -1- base, 4- mesyl-piperazine Piperazine -1- base, 4- sulfamoyl-piperazine -1- base, 4- ethanesulfonyl-piperazin -1- base, morpholinyl, piperazinyl, 4- methoxycarbonyl group-benzene Base, 4- carboxyl-phenyl, naphthalene, tetralyl, 3,4- dihydro -1 (2H)-naphthalenone base, piperidyl, 4- Methoxy-piperidin -1- base, 4- Carboxy-piperidin -1- base, 4- (Acetylamino-methyl)-piperidin-1-yl.

It is furthermore preferred that the Cy¹For 4- acetyl group-piperazine -1- base.

Unless otherwise indicated, (C1-C6) alkoxy of the present invention is (C1-C6) straight or branched alkoxyl, is referred to Alkoxy containing 1-6 carbon atom, including but not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, Isobutoxy, sec-butoxy, tert-butoxy, amoxy, hexyloxy, oxygroup in heptan or octyloxy.

Unless otherwise indicated, (C1-C6) alkyl of the present invention is (C1-C6) linear or branched alkyl group, refer to containing The alkyl of 1-6 carbon atom, including but not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, uncle Butyl, amyl, hexyl, heptyl or octyl.

Unless otherwise indicated, (C3-C7) naphthenic base of the present invention refers to the naphthenic base containing 3-7 carbon atom, packet Include but be not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclopropyl and cyclopenta, cyclopropyl and cyclohexyl.

Unless otherwise indicated, term halogen is halogen substituent group, including but not limited to fluorine, chlorine, bromine or iodine.

Wherein, the term " polysubstituted " in the present invention and " a variety of " refer to three kinds or more, and what is appeared below is also phase Same meaning.

As one of optimal embodiment, 3,4- dihydro-isoquinoline sulfonic acid amide derivatives of the present invention are following Particular compound:

- 2 (1H)-Methanesulfomide of 6- (4- Acetylpiperazine -1- base)-N- Benzyl-N-methyl -3,4- dihydro-isoquinoline

- 2 (1H)-Methanesulfomide of 6- (4- Acetylpiperazine -1- base)-N- phenethyl-N- methyl -3,4- dihydro-isoquinoline

- 2 (1H)-Methanesulfomide of 6- (4- Acetylpiperazine -1- base)-N- phenylpropyl-N- methyl -3,4- dihydro-isoquinoline

6- (4- Acetylpiperazine -1- base)-N- (4- romethyl-benzy)-N- methyl -3,4- dihydro-isoquinoline -2 (1H)-Methanesulfomide

6- (4- Acetylpiperazine -1- base)-N- (3- romethyl-benzy)-N- methyl -3,4- dihydro-isoquinoline -2 (1H)-Methanesulfomide

6- (4- Acetylpiperazine -1- base)-N- (2- romethyl-benzy)-N- methyl -3,4- dihydro-isoquinoline -2 (1H)-Methanesulfomide

- 2 (1H)-methylsulphur of 6- (4- Acetylpiperazine -1- base)-N- (the chloro- benzyl of 4-)-N- methyl -3,4- dihydro-isoquinoline Amide

- 2 (1H)-methylsulphur of 6- (4- Acetylpiperazine -1- base)-N- (the chloro- benzyl of 2-)-N- methyl -3,4- dihydro-isoquinoline Amide

- 2 (1H)-methylsulphur of 6- (4- Acetylpiperazine -1- base)-N- (the chloro- benzyl of 3-)-N- methyl -3,4- dihydro-isoquinoline Amide

- 2 (1H)-first of 6- (4- Acetylpiperazine -1- base)-N- (3- Methyl-benzvl)-N- methyl -3,4- dihydro-isoquinoline Sulfonamide

- 2 (1H)-first of 6- (4- Acetylpiperazine -1- base)-N- (4- phenyl-benzyl)-N- methyl -3,4- dihydro-isoquinoline Sulfonamide

6- (4- Acetylpiperazine -1- base)-N- (4- tert-Butyl-benzyI)-N- methyl -3,4- dihydro-isoquinoline -2 (1H) - Methanesulfomide

6- (4- Acetylpiperazine -1- base)-N- (the fluoro- benzyl of the chloro- 6- of 2-)-N- methyl -3,4- dihydro-isoquinoline -2 (1H) - Methanesulfomide

- 2 (1H)-methylsulphur of 6- (4- Acetylpiperazine -1- base)-N- (the fluoro- benzyl of 2-)-N- methyl -3,4- dihydro-isoquinoline Amide

- 2 (1H)-first of 6- (4- Acetylpiperazine -1- base)-N- (4- Methyl-benzvl)-N- methyl -3,4- dihydro-isoquinoline Sulfonamide

- 2 (1H)-first of 6- (4- Acetylpiperazine -1- base)-N- (2- Methyl-benzvl)-N- methyl -3,4- dihydro-isoquinoline Sulfonamide

6- (4- Acetylpiperazine -1- base)-N- (4- trifluoromethvl-Dvrimidin -2- base)-N- methyl -3,4- dihydro-isoquinoline - 2 (1H)-sulfonamide

- 2 (1H)-methylsulphur of 6- (4- Acetylpiperazine -1- base)-N- (the fluoro- benzyl of 3-)-N- methyl -3,4- dihydro-isoquinoline Amide

- 2 (1H)-methylsulphur of 6- (4- Acetylpiperazine -1- base)-N- (the fluoro- benzyl of 4-)-N- methyl -3,4- dihydro-isoquinoline Amide

6- (4- Acetylpiperazine -1- base)-N- (2,4- diiluoro-benzyl)-N- methyl -3,4- dihydro-isoquinoline -2 (1H) - Methanesulfomide

6- (4- Acetylpiperazine -1- base)-N- (the fluoro- benzyl of 2,3,4,5,6- five)-N- methyl -3,4- dihydro-isoquinoline -2 (1H)-Methanesulfomide

6- (4- Acetylpiperazine -1- base)-N- (2- pyridinyl-methyl)-N- methyl -3,4- dihydro-isoquinoline -2 (1H) - Methanesulfomide

- 2 (1H)-first of 6- (4- Acetylpiperazine -1- base)-N- (Cyclopropyl-methyl)-N- methyl -3,4- dihydro-isoquinoline Sulfonamide

- 2 (1H)-first of 6- (4- Acetylpiperazine -1- base)-N- (4- Cyano-benzyl)-N- methyl -3,4- dihydro-isoquinoline Sulfonamide

- 2 (1H)-first of 6- (4- Acetylpiperazine -1- base)-N- (Cyclohexyl-methyl)-N- methyl -3,4- dihydro-isoquinoline Sulfonamide

6- (4- Acetylpiperazine -1- base)-N- (2- pyrimidine radicals-methyl)-N- methyl -3,4- dihydro-isoquinoline -2 (1H) - Sulfonamide

6- (4- Acetylpiperazine -1- base)-N- (4- trifluoromethoxy-benzyl)-N- methyl -3,4- dihydro-isoquinoline -2 (1H)-sulfonamide

6- (4- Acetylpiperazine -1- base)-N- (4- methoxycarbonyl group-benzyl)-N- methyl -3,4- dihydro-isoquinoline -2 (1H)-sulfonamide

6- (4- Acetylpiperazine -1- base)-N- (2- methyoxy-benzyl)-N- methyl -3,4- dihydro-isoquinoline -2 (1H) - Methanesulfomide

- 2 (1H)-sulphur of 6- (4- Acetylpiperazine -1- base)-N- (4- Carboxy-benzyl)-N- methyl -3,4- dihydro-isoquinoline Amide

To realize above-mentioned second purpose, the technical solution adopted by the present invention is that:

It is the pharmaceutically acceptable salts of the 3,4- dihydro-isoquinoline sulfonic acid amide derivatives, solvate, precursor Close object or polymorph.

Pharmaceutically acceptable salt, solvate, pro-drug or polymorph, which is characterized in that described pharmaceutically The salt of receiving is inorganic salts, organic salt or amino-acid salt；

Wherein inorganic salts are as follows: sodium salt, hydrochloride, trifluoroacetate, sulfate, phosphate, diphosphate, hydrobromate or Nitrate；

Wherein organic salt are as follows: maleate, acetate, fumarate, tartrate, succinate, lactate, to toluene Sulfonate, salicylate or oxalates；

Wherein amino-acid salt are as follows: arginine salt, ornithine salt, lysine salt, leucine salt, isoleucine salt, glycine Salt, cystine salt, cysteine salt, tyrosine salt, alanine salt, phenylalanine salt, histidine salt, serine salt, threonine Salt, methionine salt, tryptophan salt, glutamate, aspartate, valine salt, methionine salt, proline salt or hydroxyl dried meat ammonia Hydrochlorate.

To realize above-mentioned third purpose, the technical solution adopted by the present invention is that:

3, the 4- dihydro-isoquinoline sulfonic acid amide derivatives preparation method, is synthetically prepared, including such as by following below scheme Lower step:

Prepare intermediate b

Raw material a and chlorosulphonyl isocyanate and the tert-butyl alcohol are dissolved in methylene chloride, are stirred at room temperature, is condensed up to intermediate b.

Prepare intermediate c

By intermediate b and R₁X (X Cl, Br or I) is dissolved in n,N-Dimethylformamide, and return stirring is to get centre Body c.

Prepare intermediate d

By intermediate c and Cy¹It carries out coupling reaction or substitution reaction obtains intermediate d.

Prepare intermediate e

Addition trifluoroacetic acid in intermediate d is sloughed to the tertbutyloxycarbonyl of intermediate d.

Prepare compound I or II

By intermediate e and different halides, (halides f) is dissolved in n,N-Dimethylformamide, and K is added₂CO₃Stirring, Up to chemical compounds I or II.

Halides f are as follows:

Or

Wherein, the preparation method of 3,4- dihydro-isoquinoline sulfonic acid amide derivatives pharmaceutically acceptable salt can be according to this Prepared by field conventional method, the compound of the present invention is usually separated as former state, or with its pharmaceutically acceptable salt shape Formula, such as reacted and obtained under normal conditions with inorganic salts, organic salt or amino-acid salt.

To realize above-mentioned 4th purpose, the technical solution adopted by the present invention is that:

A kind of pharmaceutical composition, it includes a) any one of the above 3,4- dihydro-isoquinoline sulfonic acid amide derivatives, and/or Pharmaceutically acceptable salt, solvate, the precursor chemical combination of any one of the above 3,4- dihydro-isoquinoline sulfonic acid amide derivatives Object or polymorph and b) its pharmaceutically acceptable carrier.

Described pharmaceutical composition can be the pharmaceutical preparation of solid form or liquid form, the agent of described pharmaceutical composition Type includes but is not limited to tablet, capsule, powder agent, granule, suspension or injection.

To realize above-mentioned 5th purpose, the technical solution adopted by the present invention is that:

3, the 4- dihydro-isoquinoline sulfonic acid amide derivatives, pharmaceutically acceptable salt, solvate, precursor medicine The purposes of object, polymorph or pharmaceutical composition in medicine preparation applies in general to exciting ROR γ t.Therefore, in some realities Apply in example, the present invention provides a kind of excited retinoic acid relevant orphan receptor γ (ROR γ), and prevention or treating cancer, from Body immunological diseases, metabolism, inflammation and Other diseases or illness, it includes the compound or compositions that administering provides.More precisely It says, compounds and compositions described herein serve as the regulator of ROR γ.

The disease and the patient's condition that can be treated according to the method for the present invention include but is not limited to solid tumor and cancer, such as, multiple Property myeloma, pernicious myeloma, colon cancer, oophoroma, prostate cancer, breast cancer, cervix cancer, bladder cancer, gland cancer, adrenal gland Cortical carcinoma, B cell lymphoma, lung cancer, chronic lymphocytic leukemia, chronic granulocytic leukemia, Hodgkin's disease or Gastric cancer；Inflammation, metabolism, autoimmune disease, such as: psoriasis, rheumatoid arthritis, multiple sclerosis, ulcerative colitis, Asthma, lupus erythematosus, oneself immunity hepatitis or I type and II type glycosuria, diabetic complication, nephrosis, diabetes Property retinopathy, diabetic retinitis, diabetic microangiopathy, ophthalmology disease, uveitis, atherosclerosis, Psoriasis arthropathica, atopic dermatitis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, ephritis, organ are of the same race Allograft rejection, fibroid lung, cystic fibrosis, renal insufficiency, pulmonary tuberculosis, Chronic Obstructive Pulmonary Disease, meat sample It is inflammation, allergic rhinitis, allergic conjunctivitis after tumor disease, invasive staphyloderma, cataract operation, chronic Nettle rash, systemic loupus erythematosus, asthma, allergic asthma, steroid resistant asthma, neutrophilic asthma, periodontal Disease, periodontitis, gingivitis, gum disease, diastolic cardiomyopathies, myocardial infarction, myocarditis, chronic heart failure.

Further, the present invention also provides 3, the 4- dihydro-isoquinoline sulfonic acid amide derivatives or its is pharmaceutically acceptable Salt, solvate, precursor compound or polymorph preparation treatment inflammation disease drug in application.

Further, the present invention also provides 3, the 4- dihydro-isoquinoline sulfonic acid amide derivatives or its is pharmaceutically acceptable Salt, solvate, precursor compound or polymorph preparation treatment autoimmune disease drug in application.

Further, the present invention also provides 3, the 4- dihydro-isoquinoline sulfonic acid amide derivatives or its is pharmaceutically acceptable Salt, solvate, precursor compound or polymorph preparation treatment metabolism related diseases drug in application.

Optimal, the present invention also provides 3, the 4- dihydro-isoquinoline sulfonic acid amide derivatives or its is pharmaceutically acceptable Salt, solvate, precursor compound or polymorph treat Huppert's disease, pernicious myeloma, colon cancer, ovary in preparation Cancer, prostate cancer, breast cancer, cervix cancer, bladder cancer, gland cancer, adrenocortical carcinoma, B cell lymphoma, lung cancer, chronic leaching Bar cell leukemia, chronic granulocytic leukemia, Hodgkin's disease or gastric cancer drug in application.

Specific embodiment

The present invention is explained further below in conjunction with specific embodiment, but embodiment does not do any type of limit to the present invention It is fixed.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition, or suggest according to manufacturer Condition.

In chemicals of the present invention, as any variable (such as R₁、R₂Deng) occur more than in any component it is primary, then Its definition occurred every time is independently of other definition occurred every time.Equally, the combination for allowing substituent group and variable, as long as this Combination stablizes compound.The line for being divided into loop system from substituent group indicates that signified key may be connected to any annular atom that can replace On.If loop system be it is polycyclic, it means that this key is connected only on any carbon atom appropriate of adjacent loops.It is appreciated that this Field those of ordinary skill may be selected the compounds of this invention substituent group and substitution pattern and provide chemically stable and can lead to The compound that the method for crossing art technology and following proposition is readily synthesized from readily available raw material.If substituent group is certainly Body is exceeded a group and replaces, it should be understood that these groups can be in identical carbon atoms or on different carbon atoms, as long as making structure Stablize.Phrase " being optionally substituted by one or more substituents " is considered " optionally being replaced " phase by least one substituent group with phrase When and preferred embodiment will have 0-3 substituent group in the case.

Terms used herein " alkyl " and " alkylidene " mean include have particular carbon atom number branch and straight chain Saturated fat alkyl.For example, in " C1-C6 alkyl " definition of " C1-C6 " include with linear chain or branched chain arrangement have 1,2, 3, the group of 4,5 or 6 carbon atoms.For example, " C1-6 alkyl " specifically include methyl, ethyl, n-propyl, isopropyl, normal-butyl, Tert-butyl, isobutyl group, amyl, sec-butyl, tert-butyl, hexyl.Term " naphthenic base " refers to the monocycle with particular carbon atom number Saturated fat alkyl.Such as " naphthenic base " includes cyclopropyl, methyl-cyclopropyl, 2,2- dimethyl-cyclobutyl, 2- ethyl-ring penta Base, cyclohexyl etc..

Terms used herein " aryl " refers to containing 6 to 10 carbon atoms and with all carbon monocycles of conjugated pi electron system Or condensed ring polycyclic aromatic group, such as phenyl or naphthyl.

Terms used herein " heteroaryl " represents in ring in the stable monocycle or each ring of up to 6 atoms up to 6 Atom bicyclic carbocyclic, wherein at least one ring are aromatic rings, and the hetero atom of O, N and S are selected from containing 1-4.This range of definition Interior heteroaryl includes but is not limited to: imidazole radicals, triazolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrrole Piperazine base, pyridazinyl, pyridyl group, pyrimidine radicals, pyrrole radicals.Definition for following heteroaryl, " heteroaryl " also are understood as including appointing The N- oxide derivative of what heteroaryl containing nitrogen.It is bicyclic in heteroaryl substituent and is nonaro-maticity containing a ring Or without containing in heteroatomic example, it should be understood that respectively through aromatic rings or through being connected containing heteroatomic ring.

Term " heterocycle " used herein or " heterocycle " refer to heteroatomic 5 yuan or 6 selected from O, N and S containing 1-4 First armaticity or non-aromatic heterocyclic rings, and including bicyclic radicals." heterocycle " includes therefore above mentioned heteroaryl, also includes Its dihydro and tetrahydro analog." heterocycle " further example includes but is not limited to: imidazole radicals, indazolyl, isothiazole Base, isoxazolyl, oxadiazoles base, oxazolyl, oxetanyl, pyranose, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl group, Pyrimidine radicals, pyrrole radicals, quinoxaline base, tetrazole radical, thiadiazolyl group, thiazolyl, thienyl, triazolyl, l, 4- dioxanes base, pyrroles Alkyl, glyoxalidine base, dihydro-isoxazole base, dihydro isothiazolyl, dihydro oxadiazoles base, dihydro-oxazole base, dihydro pyrazine base, Pyrazoline base, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, dihydro tetrazole radical, thiodiazoline base, thiazoline Base, dihydrothiophene, dihydro triazolyl, dihydro azetidinyl, tetrahydrofuran base and tetrahydro-thienyl and its N- oxidation Object.The connection of heterocyclic substituent can be realized by carbon atom or by hetero atom.

As will be appreciated by a person skilled in the art, " halogen " used herein means to include chlorine, fluorine, bromine and iodine.

Unless otherwise defined, alkyl, naphthenic base, aryl, heteroaryl and heterocyclyl substituent can be considered it is unsubstituted or Replace.For example, (C1-C4) alkyl can be selected from OH, halogen, alkoxy, dialkyl amido or heterocycle by one, two or three The substituent group of base, such as morpholinyl, piperidyl etc. replaces.

The present invention includes the free form of type I compound, also includes its pharmaceutically acceptable salt and stereoisomer.This Some specific exemplary compounds are the protonated salt of aminated compounds in text.Term " free form " refers to non-salt shape The aminated compounds of formula.The pharmaceutically acceptable salt being included not only includes the exemplary of specific compound described herein Salt also includes the typical pharmaceutically acceptable salt of all type I compound free forms.Techniques known in the art point can be used Free form from the compound specific salts.For example, can be by with alkali dilute aqueous solution appropriate such as NaOH dilute aqueous solution, carbon Sour potassium dilute aqueous solution, weak aqua ammonia and sodium bicarbonate dilute aqueous solution, which handle the salt, regenerates free form.Free form is in certain objects Rationality matter for example in polar solvent respectively more or less distinguish solubility with its by salifie form, but the purpose for invention is this Respectively free form is suitable with its in terms of other pharmacy for hydrochlorate and alkali salt.

It can be synthesized by conventional chemical processes from the compounds of this invention containing alkaline part or acidic moiety of the invention Pharmaceutically acceptable salt.In general, by ion-exchange chromatography or passing through free alkali and stoichiometric amount or excessive required salt The reaction in the combination of appropriate solvent or multi-solvents of the inorganic or organic acid of form prepares the salt of alkali compounds.Similar, The salt of acid compound is formed by reacting with appropriate inorganic or organic base.

Therefore, the pharmaceutically acceptable salt of the compounds of this invention includes by alkaline the compounds of this invention and inorganic or have Machine acid reacts the conventional non-toxic salts for the compounds of this invention to be formed.For example, conventional nontoxic salts include deriving from inorganic acid such as salt The salt of acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid etc. also includes from organic acid such as acetic acid, propionic acid, succinic acid, second Alkyd, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, flutter acid, maleic acid, hydroxymaleic acid, phenylacetic acid, Glutamic acid, benzoic acid, salicylic acid, p-aminobenzene sulfonic acid, 2- acetoxy-benzoic, fumaric acid, toluenesulfonic acid, methanesulfonic acid, second The salt of the preparations such as alkane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid.

If the compounds of this invention be it is acid, " pharmaceutically acceptable salt " appropriate refers to by pharmaceutically acceptable Nontoxic alkali include inorganic base and organic base preparation salt derive from inorganic base salt include aluminium salt, ammonium salt, calcium salt, mantoquita, iron Salt, ferrous salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt etc..Particularly preferred ammonium salt, calcium salt, magnesium salts, sylvite And sodium salt.Salt derived from pharmaceutically acceptable organic nontoxic alkali, the alkali include the salt of primary amine, secondary amine and tertiary amine, are replaced Amine include naturally occurring substitution amine, cyclic amine and deacidite such as arginine, glycine betaine, caffeine, gallbladder Alkali, N, N'- dibenzyl-ethylenediamin, diethylamine, 2- DEAE diethylaminoethanol, 2-dimethylaminoethanol, ethylaminoethanol, ethyl alcohol Amine, N-ethylmorpholine, N-ethylpiperidine, gucosamine, Glucosamine, histidine, hydroxycobalamin, isopropylamine, relies ethylenediamine Propylhomoserin, methyl glucose osamine, morpholine, piperazine, piperidines, croak smack one's lips, polyamines resin, procaine, purine, theobromine, triethylamine, three Methylamine, tripropyl amine (TPA), tromethamine etc..

Since the acidic moiety such as carboxyl of deprotonation in compound in physiological conditions can be anion, and it is this The charge having then can be by the internal protonated or alkylated alkaline part such as quaternary nitrogen atom with cation Balance is offset, it is noted that the compounds of this invention is potential inner salt or amphoteric ion.

Pharmaceutical composition of the present invention can be liquid, semiliquid or solid form, according to be suitable for it is used to The mode of medicine approach is prepared.Pharmaceutical composition of the present invention can be administered according to following administration mode: oral, parenteral, The modes such as peritonaeum is interior, intravenous, transdermal, sublingual, intramuscular, rectum, oral cavity, intranasal, liposome.

Combination of oral medication can be solid, gel or liquid.The example of solid pharmaceutical preparation includes but is not limited to tablet, glue Wafer, granule and bulk powder.These preparations contain adhesive, diluent, disintegrating agent, lubricant, help stream in which can choose Agent, sweetener and corrigent etc..The example of adhesive include but is not limited to microcrystalline cellulose, glucose solution, mucialga of arabic gummy, Gelatin solution, sucrose and gelatinized corn starch；The example of lubricant includes but is not limited to talcum, starch, magnesium stearate, calcium stearate, hard Resin acid；The example of diluent includes but is not limited to lactose, sucrose, starch, mannitol, Dicalcium Phosphate；The example packet of glidant It includes but is not limited to silica；The example of disintegrating agent includes but is not limited to croscarmellose sodium, primojel, algae Acid, cornstarch, potato starch, methylcellulose, agar and carboxymethyl cellulose.

Pharmaceutical composition of the present invention is given with parenteral, generally based on injection, including subcutaneous, intramuscular or intravenous note It penetrates.Injection can be made into any conventionally form, and such as liquid solution or suspension is suitable for being dissolved or suspended in front of injection Solid form or emulsion in liquid.The example that can be used for the pharmaceutically acceptable carrier of injection of the present invention includes but not Be limited to aqueous carrier, non-aqueous carrier, antimicrobial, isotonic agent, buffer, antioxidant, suspension and dispersing agent, emulsifier, Chelating agent and other pharmaceutically acceptable substances.The example of aqueous carrier include sodium chloride injection, woods format injection, etc. Seep glucose injection, Sterile Water Injection, glucose and Lactated ringer's injection；The example of non-aqueous carrier includes planting Fixing oil, cottonseed oil, corn oil, sesame oil and the peanut oil in object source；The example of antimicrobial include metacresol, benzylalcohol, Methaform, benzalkonium chloride etc.；The example of isotonic agent includes sodium chloride and glucose；Buffer includes phosphate and citrate.

Pharmaceutical composition of the present invention can also be prepared into sterile freeze drying powder injection, and it is molten that compound is dissolved in sodium phosphate buffer Liquid, wherein containing glucose or other suitable excipient, it then will be molten under standard conditions well known by persons skilled in the art Liquid is sterile filtered, and is followed by freeze-drying, obtains required preparation.

Except known in the literature or in addition to the standard method of illustration, can be used as shown in following scheme in experimental arrangement Reaction prepare the compounds of this invention.Therefore, following illustrative approach is purpose to illustrate without being limited to listed chemical combination Object or any specific substituent group.The substituent group number shown in scheme not necessarily meets number used in claim, And for clarity, show that monosubstituted base is connected to the compound under the definition of hereinbefore Formulas I or II allowed to have multi-substituent On.

The present invention will be further described for following embodiment, but the embodiment is not intended to limit protection model of the invention It encloses.

- 2 (1H)-Methanesulfomide of embodiment 16- (4- Acetylpiperazine)-N- Benzyl-N-methyl -3,4- dihydro-isoquinoline The preparation of (compound 1)

Step 1: preparing tert-butyl ((the bromo- 3,4- dihydroquinoline -2 (1H) of 6-) sulfonyl) carbamate (intermediate (b))

Chlorosulfonic acid isocyanate (0.75g, 5mmol), the tert-butyl alcohol (0.37g, 5mmol) are dissolved in methylene chloride (15ml), ice Bath stirring 0.5hr.Be added again into reaction solution the bromo- 3,4- dihydro-isoquinoline (1.05g, 5mmol) of 6- and triethylamine (1.5g, 15mmol), 6hr is stirred at room temperature.To the end of reacting, add 15ml water, extracted with methylene chloride (10ml × 3), merges organic phase, nothing Aqueous sodium persulfate is evaporated under reduced pressure concentration after drying, filtering, and column chromatography for separation (PE:EtOAc=20:1) obtains white solid 1.6g, receives Rate 81%.Obtain intermediate (b)；

Step 2: preparation N- tert-butyl-n-methyl-((the bromo- 3,4- dihydroquinoline -2 (1H) of 6-) sulfonyl) carbamate (intermediate (c))

Intermediate (b) (0.76g, 1.84mmol) and potassium carbonate (0.51g, 3.7mmol) are dissolved in DMF (15ml), are added dropwise Iodomethane (0.18mL, 2.8mmol), 110 DEG C of reflux.TLC detection reaction.It lets cool after reaction, adds 35ml water, with acetic acid second Ester (30ml × 3) extraction merges organic phase, and anhydrous sodium sulfate is evaporated under reduced pressure after drying, filtering and is concentrated, column chromatography for separation (PE: EtOAc=20:1), white solid 0.55g, yield 70% are obtained.Obtain intermediate (c)；

Step 3: preparation 6- (4- Acetylpiperazine)-N- tertbutyloxycarbonyl-N- methyl -3,4- dihydro-isoquinoline -2 (1H) - Methanesulfomide (intermediate (d))

Intermediate (c) (1.82g, 4.8mmol), palladium acetate (52mg, 0.24mmol), 2- dicyclohexyl phosphine -2 ', 6 '-two Methoxyl biphenyl (240mg, 0.48mmol), cesium carbonate (2.32g, 7.2mmol) are dissolved in dioxane (25ml), add 1- second Acyl piperazine (0.92g, 7.2mmol), nitrogen protection, 100 DEG C of return stirring 6hr, TLC detection reactions.Wait react, it is down to room 15ml water is added in temperature, is extracted with ethyl acetate (10ml × 3), merges organic phase, and anhydrous sodium sulfate depressurizes after drying, filtering to be steamed Concentration is evaporated, column chromatography for separation (PE:EtOAc=1:1) obtains white solid 1.5g, yield 75%.Intermediate (d) is obtained,¹HNMR (400MHz, cdcl3) δ 6.99 (d, J=8.4Hz, 1H), 6.81 (s, 1H), 6.67 (s, 1H), 4.44 (s, 2H), 3.76 (s, 2H), 3.60 (t, J=5.8Hz, 4H), 3.28 (s, 3H), 3.21-2.98 (m, 4H), 2.87 (t, J=5.6Hz, 2H), 2.11 (d, J=11.8Hz, 3H), 1.44 (s, 9H).

Step 4: preparation -2 (1H)-Methanesulfomide of 6- (4- Acetylpiperazine)-N- methyl -3,4- dihydro-isoquinoline is (intermediate Body (e))

Intermediate (d) (1.5g, 3.3mmol) is dissolved in methylene chloride, is added trifluoroacetic acid (3mL, 33mmol), is stirred at room temperature 2hr is slowly added into reaction solution in trash ice (40g), and saturated solution of sodium bicarbonate, stirring, until PH=8, uses ethyl acetate is added dropwise (30ml × 3) extraction merges organic phase, and anhydrous sodium sulfate is evaporated under reduced pressure after drying, filtering and is concentrated, column chromatography for separation (PE: EtOAc=1:2), yellow solid 0.7g, yield 60% are obtained.Intermediate (e) is obtained,¹H NMR(400MHz,dmso)δ7.22(q, J=4.7Hz, 1H), 7.00 (t, J=11.7Hz, 1H), 6.81 (t, J=9.1Hz, 1H), 6.73 (s, 1H), 4.18 (s, 2H), 3.55 (d, J=4.6Hz, 4H), 3.35 (dd, J=11.1,5.3Hz, 2H), 3.11 (d, J=4.5Hz, 2H), 3.07-2.99 (m, 2H), 2.82 (t, J=5.5Hz, 2H), 2.50 (s, 2H), 2.49 (s, 1H), 2.03 (s, 3H)；

Step 5: preparation -2 (1H)-methylsulfonyl of 6- (4- Acetylpiperazine)-N- Benzyl-N-methyl -3,4- dihydro-isoquinoline Amine

Intermediate (e) (0.1g, 0.28mmol) and potassium carbonate (0.07g, 0.56mmol) are dissolved in DMF (5ml), benzyl is added dropwise Bromine (0.145mg, 0.85mmol) is stirred at room temperature.TLC detection reaction.It lets cool after reaction, adds 15ml water, use ethyl acetate (10ml × 3) extraction merges organic phase, and anhydrous sodium sulfate is evaporated under reduced pressure after drying, filtering and is concentrated, column chromatography for separation (PE: EtOAc=1:1), white solid 0.09g, yield 72% are obtained.Obtain final product (compound 1).

Embodiment 2-29

Embodiment 1 is repeated, difference is: using different raw materials, so that compound 2-29 be made.It is specific as follows:

By beta- bromo vinylbenzene, the bromo- 3- phenylpropyl alcohol alkane of 1-, 4- trifluoromethyl bromobenzyl, 3- trifluoromethyl bromobenzyl, 2- trifluoro Methyl bromobenzyl, 4- chlorine bromobenzyl, 2- chlorine bromobenzyl, 3- chlorine bromobenzyl, 3- methyl bromobenzyl, 4- bromomethylbiphenyl, 4- tert-butyl bromobenzyl, 2- Chloro- 6- fluoro benzyl bromide, 2- fluorine bromobenzyl, 4- methyl bromobenzyl, 2- methyl bromobenzyl, 2- chloro- 4- (trifluoromethyl) pyrimidine, 3- fluorine bromobenzyl, 4- fluorine bromobenzyl, 2,4- difluorobenzyl bromide, 2,3,4,5,6- five fluorine bromobenzyls, 2- bromo methyl cycloheptapyridine, bromomethyl cyclopropane, 4- cyano bromine Benzyl, bromomethylcyclohexane, 2- (chloromethyl) pyrimidine, 4- trifluoromethoxy bromobenzyl, 4- methoxycarbonyl group bromide benzyl, 2- methoxyl group bromobenzyl Respectively in above-described embodiment intermediate (e) and potassium carbonate be prepared, respectively correspond compound 2,3,4,5,6,7,8,9, 10、11、12、13、14、15、16、17、18、19、20、21、22、21、22、23、24、25、26、27、28、29。

30 6- of embodiment (4- Acetylpiperazine)-N- (4- Carboxy-benzyl)-N- methyl -3,4- dihydro-isoquinoline -2 The preparation of (1H)-sulphonyl amine amide (compound 30)

Embodiment 28 is repeated, difference is: compound 28 is hydrolyzed, so that compound 30 be made.It is specific as follows:

Compound 28 (0.5g) is dissolved in first alcohol and water (50:50,10mL), is added NaOH (0.2g), flow back 2h, final to make Obtain compound 30.

The chemical structure for the target product that the present invention has synthesized is shown in Table 1.Nucleus magnetic hydrogen spectrum, mass spectrometer system characterize target product Chemical structure, data are shown in Table 2.

The chemical structure of 1. target product of table

The nucleus magnetic hydrogen spectrum of 2. target compound of table, mass spectrometric data

Embodiment 33:

Pharmacological activity:

Activity test in vitro: the present invention is using double fluorescence resonance energy transfer (fluorescenceresonance Energy transfer, FRET) method validation the compounds of this invention exciting ROR γ t protein active ability.

Test compound is dissolved in dimethyl sulfoxide (DMSO) to prepare 10.0mM stock solution and be diluted to required dense Degree.DMSO ultimate density in reaction is no more than 1% (v/v).By in the compound presence or absence of required concentration In the case where by GST label ROR γ ligand binding domains (LBD) be mixed in containing 25mMHEPES, 100mMNaCl, 5mMDTT In the buffer of 0.01%BSA, incubated 1 hour at 25 DEG C.By Steroid Receptor Coactivator-1 (SRC- 1), (676-700), biotin labeled and MAb AntiGST-Tb and Streptavidin-d2 are added to reaction mixture It shakes again after five minutes, reactant is incubated 1 hour at room temperature and at 4 DEG C again in SpectraMax Paradigm enzyme mark The signal that 620,665 are read on instrument, the albumen agonist activity of test compound is calculated according to 620/665 TR-FRET ratio. By using the nonlinear regression analysis of GraphPad Prism software, IC is calculated according to compound concentration excitement curve₅₀Value.

Prepared compound is tested using said determination program and acquired results are provided in table 3.It measures described Compound has the IC less than 5 μM₅₀, preferably IC₅₀Compound, more preferable IC less than 1 μM₅₀Compound less than 0.1 μM.

IC₅₀Value is set forth in table 3, and " NA ", which refers to, not to be detected.

The FRET activity data of 3. compound of table

Compound	IC50(μM)	Compound	IC50(μM)
				1	0.514	16	0.220
2	2.170	17	6.108
				3	0.529	18	0.544
4	1.914	19	0.950
				5	0.352	20	0.130
6	0.094	21	NA
				7	NA	22	12.040
8	0.098	23	NA
				9	0.136	24	NA
10	0.212	25	NA
				11	NA	26	NA
12	NA	27	NA
				13	0.02	28	NA
14	0.344	29	0.388
				15	0.385	30	NA

As known from Table 3, the compound of the present invention has agonist activity to ROR γ t, this efficient for exploitation, novel, specificity The tumour that strong ROR γ t is mediated is with inflammation and autoimmune disease such as Huppert's disease, pernicious myeloma, colon cancer, ovum It is nest cancer, prostate cancer, breast cancer, cervix cancer, bladder cancer, gland cancer, adrenocortical carcinoma, B cell lymphoma, lung cancer, chronic Lymphocytic leukemia, chronic granulocytic leukemia, Hodgkin's disease or gastric cancer, psoriasis, rheumatoid arthritis, The drug of the diseases such as multiple sclerosis is laid a good foundation, and has good Development volue.

The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art Member, under the premise of not departing from the present invention, can also make several improvement and supplement, these are improved and supplement also should be regarded as this hair Bright protection scope.

Claims (10)

1. one kind 3,4- dihydro-isoquinoline sulfonic acid amide derivatives, which is characterized in that the derivant structure general formula is Formulas I or formula II compound:

Wherein:

X₁For C or N；

X₂For C or N；

M, n, p are independently optionally from 0,1,2,3 or 4；

Substituent R₁Selected from H, (C1-C3) alkyl, halogen (C1-C3) alkyl, aryl, heteroaryl, heterocycle and naphthenic base；

Substituent R₂It is not present or at least one position in 2,3,4,5,6, is unsubstituted, mono-substituted, disubstituted Or polysubstituted, substituent R₂Selected from one of following groups, two or more: hydrogen, halogen, nitro, hydroxyl, carboxyl, It is trifluoromethyl, cyano, substituted or unsubstituted amino, phenyl, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C1-C6) alkoxy ,-CONH₂、-CONHR₃、-CON(R₃)₂、-COOR₃、-COR₃、-NHCOR₃、-NHCOOR₃Group, wherein R₃Optionally from H, (C1-C6) alkyl, trifluoromethyl, phenyl；When R2 is double or three replace, substituent group can be identical or different；

Cy¹Selected from H, Ar1, Hetar1 or (C3-C7) naphthenic base

The above Ar1 indicates the monocyclic aromatic hydrocarbon system with 6-10 carbon atom or bicyclic aromatic hydrocarbon system and aromatic hydrocarbon saturation simultaneously Ring system, the system is unsubstituted or is replaced by one or more identical or different substituent groups selected from the following: (C1-C6) alkane Base, (C1-C6) alkoxy, (C3-C7) naphthenic base, carbonyl, carboxyl, amino ,-CONH₂、-COOR₄、-COR₄、-NHCOR₄、- NHCOOR₄、-COH(CF₃)₂、-SONH₂、-SOOR₄、-SOR₄、-NHSOR₄、-NHSOOR₄Group replaces；Wherein R₄Optionally from H, (C1-C6) alkyl；

The above Hetar1 indicates the saturation 4,5,6,7,8,9 or 10 circle heterocyclic rings with 1,2 or 3 N and/or O and/or S atom, should Heterocycle is unsubstituted or is replaced by one or more identical or different substituent groups selected from the following: (C1-C6) alkyl, (C1- C6) alkoxy, (C3-C7) naphthenic base, carbonyl, carboxyl, amino ,-CONH₂、-COOR₄、-COR₄、-NHCOR₄、-NHCOOR₄、- COH(CF₃)₂、-SONH₂、-SOOR₄、-SOR₄、-NHSOR₄、-NHSOOR₄Group replaces；Wherein R₄Optionally from H, (C1-C6) alkane Base.

2. 3,4- dihydro-isoquinoline sulfonic acid amide derivatives according to claim 1, which is characterized in that the substituent R₁ It is methyl.

3. 3,4- dihydro-isoquinoline sulfonic acid amide derivatives according to claim 1 or 2, which is characterized in that the substitution Base R₂At least one position in 2,3,4,5,6, be it is unsubstituted, mono-substituted, disubstituted or polysubstituted, it is excellent It is selected as unsubstituted, monosubstituted or disubstituted, the substituent R₂Selected from one of following groups, two or more: hydrogen, fluorine, Chlorine, trifluoromethyl, cyano, methyl, methoxyl group, phenyl, trifluoromethoxy, tert-butyl, methoxycarbonyl, carboxyl, work as R₂It is double When replacing or is polysubstituted, each substituent group can be identical or different.

4. 3,4- dihydro-isoquinoline sulfonic acid amide derivatives according to any one of claim 1 to 3, which is characterized in that The n is optionally from 0,1,2 or 3；M is 0；P is optionally from 1 or 4.

5. according to claim 1 to 3,4- dihydro-isoquinoline sulfonic acid amide derivatives described described in any one of 4, feature exists In the Cy¹Optionally certainly: 4- acetyl group-piperazine -1- base, 4- (propiono)-piperazine -1- base, 4- cyclopropane carbonyl-piperazine -1- Base, 4- tbutyloxycarbonyl-piperazin -1- base, 4- methanesulphonyl-piperazine -1- base, 4- sulfamoyl-piperazine -1- base, 4- second sulphonyl Base-piperazine -1- base, morpholinyl, piperazinyl, 4- methoxycarbonyl-phenyl, 4- carboxyl-phenyl, naphthalene, tetralyl, 3,4- bis- Hydrogen -1 (2H)-naphthalenone base, piperidyl, 4- Methoxy-piperidin -1- base, 4- Carboxy-piperidin -1- base, 4- (Acetylamino-methyl) - Piperidin-1-yl.

6. 3,4- dihydro-isoquinoline sulfonic acid amide derivatives according to claim 5, which is characterized in that Cy¹For 4- acetyl Base-piperazine -1- base.

7. the pharmaceutically acceptable salt of any 3,4- dihydro-isoquinoline sulfonic acid amide derivatives of claim 1-6, molten Agent compound, precursor compound or polymorph.

8. pharmaceutically acceptable salt according to claim 7, solvate, precursor compound or polymorph, special Sign is that the pharmaceutically acceptable salt is inorganic salts, organic salt or amino-acid salt；

Wherein inorganic salts are as follows: hydrochloride, sulfate, phosphate, diphosphate, hydrobromate or nitrate；

Wherein organic salt are as follows: acetate, maleate, fumarate, tartrate, succinate, lactate, p-methyl benzenesulfonic acid Salt, salicylate or oxalates；

Wherein amino-acid salt are as follows: arginine salt, ornithine salt, lysine salt, leucine salt, isoleucine salt, glycinate, Guang Propylhomoserin salt, cysteine salt, tyrosine salt, alanine salt, phenylalanine salt, histidine salt, serine salt, threonine salt, egg Propylhomoserin salt, tryptophan salt, glutamate, aspartate, valine salt, methionine salt, proline salt or hydroxyproline salt.

9. a kind of pharmaceutical composition, which is characterized in that it includes a) any 3, the 4- dihydro-isoquinoline sulphonyl of claim 1-6 The pharmaceutically acceptable salt of 3,4- dihydro-isoquinoline sulfonic acid amide derivatives described in amine derivant, claim 7 or 8, One or more of solvate, precursor compound and polymorph and b) its pharmaceutically acceptable carrier.

10. any 3, the 4- dihydro-isoquinoline sulfonic acid amide derivatives of claim 1-6,3 described in claim 7 or 8, Pharmaceutically acceptable salt, its solvate, pro-drug or the polymorph of 4- dihydro-isoquinoline sulfonic acid amide derivatives, or The purposes of pharmaceutical composition as claimed in claim 9 in medicine preparation, which is characterized in that the drug is used for: cancer or At least one of inflammation, autoimmune disease, metabolism related diseases disease；The preferably disease are as follows: multiple marrow Tumor, pernicious myeloma, colon cancer, oophoroma, prostate cancer, breast cancer, cervix cancer, bladder cancer, gland cancer, adrenal cortex Cancer, B cell lymphoma, lung cancer, chronic lymphocytic leukemia, chronic granulocytic leukemia, Hodgkin's disease or gastric cancer At least one of.