CN109963845A - Loop coil carboxamides derivatives, preparation method and its application in medicine - Google Patents

Abstract

Disclose a kind of loop coil carboxamides derivatives, preparation method and its application in medicine.Particularly, disclose loop coil carboxamides derivatives shown in general formula (AI), preparation method, the pharmaceutical composition containing the derivative, its purposes as diseases such as the purposes of ROR regulator and its prevention and or treatment inflammations, autoimmune disease and cancer, each substituent group in formula of (AI) are identical as the definition in specification.

Description

Loop coil carboxamides derivatives, preparation method and its application in medicine Technical field

The invention belongs to field of medicaments, it is related to loop coil carboxamides derivatives, preparation method and its application in medicine.Particularly, the present invention relates to loop coil carboxamides derivatives shown in general formula (AI), preparation method, containing the pharmaceutical composition of the derivative, as the purposes in ROR regulator and its drug for being used for prevention and or treatment inflammation, autoimmune disease, tumour or cancer.

Background technique

Retinoic acid-related orphan nuclear receptor (ROR) is one of the member of nuclear receptor family, it can regulate and control a variety of physiology and life process.ROR family includes three types ROR α, ROR β and ROR γ.Three kinds of different ROR can be expressed in different tissues and be controlled different physiology courses, ROR α is mainly distributed on liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus gland and brain, ROR β sphere of action very little, mainly act on central nervous system, ROR γ can be expressed in many tissues, including liver, animal tallow and skeletal muscle.Mammal lacks ROR γ and shows the phenomenon that blood glucose reduces.

There are two types of hypotypes by ROR γ: ROR γ 1 and ROR γ 2.ROR γ 1 is in many tissues, such as: it is expressed in thymus gland, muscle, kidney and liver, and ROR γ 2 is then only expressed in immunocyte, ROR γ 2 is believed to the differentiation of control T cell T helper cell 17 (Th17).Th17 is the cell of a kind of T helper cell, this cell can produce interleukin-17 (IL-17) and other cell factors, it has been found that Th-17 has been found to and human inflammation's disease and immunologic derangement, such as, multiple sclerosis, rheumatic arthritis, psoriasis, clone's diseases such as disease and asthma have relationship, and document report ROR γ may have relationship with the generation and development of prostate cancer again now.

ROR γ t is the specific expressed hypotype on immunocyte of ROR γ, it is the central transcription factor of people and mouse Th17 cell, it can not only promote Th17 cell differentiation, it is also adjustable the expression and secretion of the specific effector factor IL-17 of Th17 cell, ROR γ t and generation, the development of panimmunity disease, infectious diseases and tumour etc. are closely related.

ROR γ, especially ROR γ t type, it has been determined that be an important transcription regulaton factor of the differentiation of Th17 cell.Vanov's in 2006 et al. the study found that ROR γ t is an important transcription factor of Th17 cell differentiation in mouse experiment.They researches show that mouse to be difficult induced synthesis EAE model when lacking ROR γ t.And in mankind's Th17 cell differentiation procedure, ROR γ t is also proved similar important function quickly, and initiative discovery causes people and pays much attention to ROR γ t.

At present, ROR has obtained the attention of height in the world of medicine as inhibitor, problem is had become a hot topic of research, disclosed patent application includes WO2015171610, WO2015171558, WO2015131035, WO2013169864, WO2014179564, WO2015116904 etc..

Inventor is during studying ROR regulator, it has found in logical formula (I) compound represented of the present invention, the variation of ring A neighboring group can change its regulating effect, leading to formula (I) compound represented when ring A neighboring group is the lesser group of steric hindrance (such as H) is inhibitor, when ring A neighboring group is the biggish group of halogenated alkyl (such as trifluoromethyl) class steric hindrance, logical formula (I) compound represented is ROR agonist, thus the present invention has developed the ROR regulator of a new generation, and further investigation revealed that the adjustable different mechanism of variation on compound structure.

Summary of the invention

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

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

Wherein:

W ¹、W ²And W ³It is identical or different, and it is each independently CH or N；

Ring A and ring B are identical or different, and are each independently selected from naphthenic base, heterocycle, aryl and heteroaryl；

Ring C is naphthenic base or heterocycle；

R ¹It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl, wherein alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

R ²It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl, heteroaryl ,-OR ⁴、-C(O)R ⁴、-C(O)OR ⁴With-S (O) _mR ⁴；

R ³Selected from hydrogen atom, halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl, wherein alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in hydroxyl, halogen, alkyl, halogenated alkyl, cyano, amino, nitro, alkoxy, halogenated alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

R ⁴Selected from hydrogen atom, alkyl, naphthenic base, halogenated alkyl, alkoxy, halogenated alkoxy, heterocycle, aryl and heteroaryl, wherein alkyl, naphthenic base, halogenated alkyl, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in hydroxyl, halogen, alkyl, halogenated alkyl, cyano, amino, nitro, alkoxy, halogenated alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

M is 0,1 or 2；

S is 0,1,2,3 or 4；And

T is 0,1,2,3 or 4.

In a preferred embodiment of the present invention, the general formula (AI) compound represented, middle ring C are C _3-6Naphthenic base or 3 to 6 yuan of heterocycle, wherein the heterocycle contains 1~3 hetero atom for being selected from N, O or S；It is preferably selected from cyclopropyl, cyclobutyl, cyclopenta or THP trtrahydropyranyl.

In a preferred embodiment of the present invention, the general formula (AI) compound represented is logical formula (I) compound represented:

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

Wherein:

N is 1,2 or 3；

Ring A, ring B, R ¹~R ³, s and t be as defined in general formula (AI).

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

Wherein:

Ring A, ring B, R ¹~R ³, s and t be as defined in logical formula (I).

In a preferred embodiment of the present invention, the logical formula (I) compound represented, middle ring A are selected from phenyl, pyridyl group, pyrimidine radicals, cyclohexyl and piperidyl.

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

Wherein:

G ¹And G ²It is identical or different, it is each independently CH or N；

Ring B, R ¹~R ³With t as defined in logical formula (I).

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

Wherein:

R ^bSelected from alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl, wherein alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in halogen, hydroxyl, alkyl, halogenated alkyl, cyano, amino, nitro, alkoxy, halogenated alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

P is 0,1,2 or 3；

Ring B, R ¹~R ³With t as defined in logical formula (I).

In a preferred embodiment of the present invention, the logical formula (I) compound represented, middle ring B are selected from phenyl, pyridyl group, pyrimidine radicals, cyclohexyl and piperidyl.

In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein R ²For-S (O) _mR ⁴；M is 2；And R ⁴For alkyl, preferably ethyl.

In a preferred embodiment of the present invention, the logical formula (III) compound represented is general formula (III-A) compound represented:

Wherein:

R ¹And R ³~R ⁴As defined in logical formula (III).

In a preferred embodiment of the present invention, the logical formula (IV) compound represented is general formula (IV-A) compound represented:

Wherein:

R ^bSelected from alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl, wherein alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in halogen, hydroxyl, alkyl, halogenated alkyl, cyano, amino, nitro, alkoxy, halogenated alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

P is 0,1,2 or 3；

R ¹、R ³And R ⁴As defined in logical formula (IV).

In a preferred embodiment of the present invention, the general formula (III-A) or general formula (IV-A) compound represented, wherein R ⁴For alkyl, preferably ethyl.

In a preferred embodiment of the present invention, the logical formula (IV) or general formula (IV-A) compound represented, wherein R ^bFor halogenated alkyl, preferably trifluoromethyl.

In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein R ¹For halogenated alkyl, preferably trifluoromethyl.

In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein R ³For hydrogen atom, alkyl or hydroxyalkyl.

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

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

On the other hand, the present invention provides compound shown in a kind of general formula (AI-A), for preparation according to general formula (AI) compound or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt intermediate:

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

Wherein:

Ring A, ring C, W ¹、W ²、W ³、R ¹With s as defined in general formula (AI).

One preferred embodiment of another aspect, the present invention provides compound shown in a kind of general formula (I-A), for preparation according to lead to formula (I) compound or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt intermediate:

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

Wherein:

Ring A, R ¹, s and n be as defined in logical formula (I).

The compound of typical general formula (AI-A), including but not limited to:

On the other hand, the present invention provides a kind of method for preparing described general formula (AI) compound, this method comprises:

Condensation reaction occurs for general formula (AI-A) compound and general formula (I-B) compound, obtains general formula (AI) compound；

Wherein:

Ring A, ring B, ring C, W ¹、W ²、W ³、R ¹~R ³, s and t be as defined in general formula (AI).

On the other hand, the present invention provides a kind of method for preparing the logical formula (I) compound, this method comprises:

Condensation reaction occurs for general formula (I-A) compound and general formula (I-B) compound, obtains logical formula (I) compound；

Wherein:

Ring A, ring B, R ¹~R ³, n, s and t be as defined in logical formula (I).

On the other hand, the present invention provides a kind of method for preparing the logical formula (II) compound, this method comprises:

Condensation reaction occurs for general formula (II-A) compound and general formula (I-B) compound, obtains logical formula (II) compound；

Wherein:

Ring A, ring B, R ¹~R ³, s and t be as defined in logical formula (II).

Another aspect of the present invention relates to a kind of pharmaceutical compositions, its logical formula (I) compound represented for containing treatment effective dose or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or pharmaceutical salt and one or more pharmaceutically acceptable carriers, diluent or excipient.The invention further relates to a kind of methods for preparing above-mentioned composition comprising by logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt and pharmaceutically acceptable carrier, diluent or excipient mix.

The invention further relates to or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer forms, or its officinal salt, or the purposes in ROR regulator is being prepared comprising its pharmaceutical composition.

The invention further relates to or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer forms, or its officinal salt, or comprising its pharmaceutical composition preparation for prevention and or treatment inflammation, autoimmune disease, tumour or cancer drug in purposes.

The invention further relates to logical formula (I) compound represented or its tautomers, mesomer, racemic modification, enantiomter, or mixtures thereof diastereoisomer form, or its officinal salt, or comprising its pharmaceutical composition preparation be used for prevention and or treatment inflammation, autoimmune disease, purposes in the drug of tumour or cancer, the inflammation or autoimmune disease is selected from asthma, atopic dermatitis, contact dermatitis, acne, bronchitis, Crohn's disease, regional enteritis, inflammatory enteropathy (IBD), ulcerative colitis, allograft rejection reaction, Xiu Gelian syndrome, uveitis, white Sai Shi disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelities, systemic lupus erythematosus disease (SLE), chorionitis, pancreatitis, silver bits Disease, arthritic psoriasis (PsA), rheumatoid arthritis, arthritis, osteoarthritis, allergic rhinitis, autoimmune diabetes and autoimmune thyroid disease, the tumour or cancer is selected from 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, IV phase melanoma, solid tumor, glioma, spongioblastoma, hepatocellular carcinoma, the renal tumor of mastoid process, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small cell lung cancer.

The invention further relates to logical formula (I) compound represented or its tautomers, mesomer, racemic modification, enantiomter, or mixtures thereof diastereoisomer form, or its officinal salt, or the purposes comprising its pharmaceutical composition as ROR inhibitor in drug of the preparation for prevention and or treatment inflammation and autoimmune disease, the inflammation or autoimmune disease is selected from asthma, atopic dermatitis, contact dermatitis, acne, bronchitis, Crohn's disease, regional enteritis, inflammatory enteropathy (IBD), ulcerative colitis, allograft rejection reaction, Xiu Gelian syndrome, uveitis, white Sai Shi disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelities, systemic lupus erythematosus disease (SLE), chorionitis, pancreatitis, Psoriasis, arthritic psoriasis (PsA), rheumatoid arthritis, arthritis, osteoarthritis, allergic rhinitis, autoimmune diabetes and autoimmune thyroid disease.

。

The invention further relates to logical formula (I) compound represented or its tautomers, mesomer, racemic modification, enantiomter, or mixtures thereof diastereoisomer form, or its officinal salt, or the purposes in drug for preventing and/or treating tumour or cancer is being prepared as ROR agonist comprising its pharmaceutical composition, the tumour or cancer is selected from 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, IV phase melanoma, solid tumor, glioma, spongioblastoma, hepatocellular carcinoma, mastoid process kidney Property tumor, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small cell lung cancer.

The invention further relates to or mixtures thereof a kind of logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form or its officinal salts, are used as drug.

The invention further relates to or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer forms, or its officinal salt, or the pharmaceutical composition comprising it, make ROR regulator.

The invention further relates to or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer forms, or its officinal salt, or the pharmaceutical composition comprising it, it is used for prevention and or treatment inflammation, autoimmune disease, tumour or cancer.

The invention further relates to logical formula (I) compound represented or its tautomers, mesomer, racemic modification, enantiomter, or mixtures thereof diastereoisomer form, or its officinal salt, or the pharmaceutical composition comprising it, for prevention and or treatment inflammation or autoimmune disease, the inflammation or autoimmune disease is selected from asthma, atopic dermatitis, contact dermatitis, acne, bronchitis, Crohn's disease, regional enteritis, inflammatory enteropathy (IBD), ulcerative colitis, allograft rejection reaction, Xiu Gelian syndrome, uveitis, white Sai Shi disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelities, systemic lupus erythematosus disease (SLE), chorionitis, pancreatitis, psoriasis, arthritic psoriasis (PsA), class Rheumatic arthritis, arthritis, osteoarthritis, allergic rhinitis, autoimmune diabetes and autoimmune thyroid disease.

The invention further relates to logical formula (I) compound represented or its tautomers, mesomer, racemic modification, enantiomter, or mixtures thereof diastereoisomer form, or its officinal salt, or the pharmaceutical composition comprising it, for preventing and/or treating tumour or cancer, the tumour or cancer is selected from 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, IV phase melanoma, solid tumor, glioma, spongioblastoma, hepatocellular carcinoma, the renal tumor of mastoid process, head and neck neoplasm, leukaemia, lymthoma, myeloma And non-small cell lung cancer.

The invention further relates to a kind of prevention and or treatment inflammations, autoimmune disease, the method of tumour or cancer, it includes the logical formula (I) compound represented or its tautomer to the patient's application treatment effective dose for needing it, mesomer, racemic modification, enantiomter, or mixtures thereof diastereoisomer form, or its officinal salt, or the pharmaceutical composition comprising it, the inflammation or autoimmune disease is selected from asthma, atopic dermatitis, contact dermatitis, acne, bronchitis, Crohn's disease, regional enteritis, inflammatory enteropathy (IBD), ulcerative colitis, allograft rejection reaction, Xiu Gelian syndrome, uveitis, white Sai Shi disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelities, systemic lupus erythematosus disease (SLE) , chorionitis, pancreatitis, psoriasis, arthritic psoriasis (PsA), rheumatoid arthritis, arthritis, osteoarthritis, allergic rhinitis, autoimmune diabetes and autoimmune thyroid disease, the tumour or cancer is selected from 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, IV phase melanoma, solid tumor, glioma, spongioblastoma, hepatocellular carcinoma, the renal tumor of mastoid process, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small cell lung cancer.

The invention further relates to a kind of prevention and or treatment inflammation or the methods of autoimmune disease, it include to need its patient apply treatment effective dose as the logical formula (I) compound represented of ROR inhibitor or its tautomer, mesomer, racemic modification, enantiomter, or mixtures thereof diastereoisomer form, or its officinal salt, or the pharmaceutical composition comprising it, the inflammation or autoimmune disease is selected from asthma, atopic dermatitis, contact dermatitis, acne, bronchitis, Crohn's disease, regional enteritis, inflammatory enteropathy (IBD), ulcerative colitis, allograft rejection reaction, Xiu Gelian syndrome, uveitis, white Sai Shi disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelities, systemic lupus erythematosus disease ( SLE), chorionitis, pancreatitis, psoriasis, arthritic psoriasis (PsA), rheumatoid arthritis, arthritis, osteoarthritis, allergic rhinitis, autoimmune diabetes and autoimmune thyroid disease.

The invention further relates to a kind of Prevention and/or the methods for the treatment of tumour or cancer, it include to need its patient apply treatment effective dose as the logical formula (I) compound represented of ROR agonist or its tautomer, mesomer, racemic modification, enantiomter, or mixtures thereof diastereoisomer form, or its officinal salt, or the pharmaceutical composition comprising it, the tumour or cancer is selected from 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, IV phase melanoma, solid tumor, glioma, neuroglia The renal tumor of blastoma, hepatocellular carcinoma, mastoid process, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small cell lung cancer.

The invention further relates to a kind of methods for adjusting ROR, it includes to the logical formula (I) compound represented or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form for needing its patient to apply treatment effective dose, or its officinal salt, or the pharmaceutical composition comprising it.

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.Orally administered composition can be prepared according to any known method for preparing Pharmaceutical composition in this field, such composition can contain one or more ingredients selected from the following: sweetener, corrigent, colorant and preservative, to provide pleasing and palatable pharmaceutical formulation.Tablet contains active constituent and the suitable nontoxic pharmaceutical excipient for preparing tablet for mixing.These excipient can be inert excipient, granulating agent, disintegrating agent, adhesive and lubricant,.These tablets can not be coated or can be by the taste for covering drug or delay disintegration and absorption in the gastrointestinal tract, thus the known technology for providing slow releasing function in a long time is coated.

The Perle offer oral preparation that wherein active constituent is mixed with inert solid diluent or in which active constituent with water-solubility carrier or oily solvent is also provided.

Water slurry contains active material and the suitable excipient for preparing water slurry for mixing.Such excipient is suspending agent, dispersing agent or wetting agent.Aqueous suspension can also contain 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.These compositions can be saved by the way that antioxidant is added.

Pharmaceutical composition of the invention is also possible to the form of oil in water emulsion.Oil mutually can be or mixtures thereof vegetable oil or mineral oil.Suitable emulsifier can be naturally-produced phosphatide, and emulsion can also contain sweetener, corrigent, preservative 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 or solvent that can be used have water, ringer's solution and isotonic sodium chlorrde solution.Aseptic injection preparation can be wherein active constituent be dissolved in the aseptic injection oil-in-water microemulsion of oily phase can be by a large amount of injections in part, will be in the blood flow of injection or micro emulsion injection patient.Alternatively, preferably giving solution and micro emulsion in the way of it can keep the compounds of this invention constant circulating concentration.To keep this constant density, continuous intravenous delivery device can be used.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 form of oil suspension.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.Furthermore, it is convenient to use sterile fixed oil as solvent or suspension media.For this purpose, any reconciliation fixing oil can be used.In addition, fatty acid can also prepare injection.

The compounds of this invention can be given by the suppository form for rectally.Can by by drug be at normal temperatures solid but be in the rectum liquid, thus can dissolve in the rectum and discharge the suitable nonirritant excipient mixing of drug to prepare these pharmaceutical compositions.

As known to those skilled in the art, the dosage of drug depend on many factors, including but be not limited to following factor: the activity of particular compound used, the age of patient, the weight of patient, the health status of patient, the behavior of patient, the diet of patient, administration time, administration mode, the rate of excretion, combination of drug etc.；In addition, optimal therapeutic modality can be verified such as mode, the consumption per day of general formula compound (I) or the type of pharmaceutical salt for the treatment of according to traditional therapeutic scheme.

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 comprises the alkyl of 1 to 12 carbon atom, the alkyl of further preferably 1 to 6 carbon atom.Non-limiting example includes 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 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, n-heptyl, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2, 3- dimethyl amyl group, 2, 4- dimethyl amyl group, 2, 2- bis- Methyl amyl, 3, 3- dimethyl amyl group, 2- ethylpentyl, 3- ethylpentyl, n-octyl, 2, 3- dimethylhexanyl, 2, 4- dimethylhexanyl, 2, 5- dimethylhexanyl, 2, 2- dimethylhexanyl, 3, 3- dimethylhexanyl, 4, 4- dimethylhexanyl, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- methyl -2- ethylpentyl, 2- methyl -3- ethylpentyl, n-nonyl, 2- methyl -2- ethylhexyl, 2- methyl -3- ethylhexyl, 2, 2- diethyl amyl group, positive decyl, 3, 3- diethylhexyl, 2, 2- diethylhexyl, and its various branched isomers etc..Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting embodiment includes 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 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 etc..Alkyl can be substituted or non-substituted, when substituted, substituent group can be substituted on any workable tie point, the 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, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, carboxyl, carboxylate ,-OR ⁴、-C(O)R ⁴、-C(O)OR ⁴With-S (O) _mR ⁴。

Term " alkoxy " refers to-O- (alkyl) and-O- (non-substituted naphthenic base), and wherein alkyl and naphthenic base are as defined above.The non-limiting example of alkoxy includes: methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy.Alkoxy 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, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl, carboxylate ,-OR ⁴、-C(O)R ⁴、-C(O)OR ⁴With-S (O) _mR ⁴。

Term " naphthenic base " refers to that the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, cycloalkyl ring include 3 to 20 carbon atoms, preferably comprises 3 to 12 carbon atoms, more preferably includes 3 to 6 carbon atoms.The non-limiting example of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, 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, 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 spiro cycloalkyl groups or more spiro cycloalkyl groups according to the number for sharing spiro-atom between ring and ring, 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, the full carbon polycyclic moiety of shared a pair of of the carbon atom adjoined of other rings in each ring and system in system, 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.Bicyclic, tricyclic, Fourth Ring or polycyclic fused ring alkyl, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkyl can be divided into according to a group cyclic number.The non-limiting example of cycloalkyl includes:

Term " bridge ring alkyl " refers to 5 to 20 yuan, and any two ring shares the full carbon polycyclic moiety of two carbon atoms being not directly connected, 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, preferably bicyclic, tricyclic or Fourth Ring can be divided into according to a group cyclic number, be more selected as bicyclic or tricyclic.The non-limiting example of bridge ring alkyl includes:

The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to link together with precursor structure is naphthenic base, 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, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, carboxyl, carboxylate ,-OR ⁴、-C(O)R ⁴、-C(O)OR ⁴With-S (O) _mR ⁴。

Term " heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, and it includes 3 to 20 annular atoms, 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 include the loop section of-O-O- ,-O-S- or-S-S-, remaining annular atom is carbon.3 to 12 annular atoms are preferably comprised, wherein 1~4 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-thienyl, glyoxalidine base, dihydrofuryl, pyrazoline base, pyrrolin base, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, high piperazine base, pyranose etc., preferably piperidyl, piperazinyl or morpholinyl.Multiring heterocyclic includes the heterocycle of loop coil, condensed ring and bridged ring.

Term " spiro heterocyclic radical " refers to that the polycyclic heterocyclic group that an atom (claiming spiro-atom) is shared between 5 to 20 yuan of monocycle, 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 annular atom are 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 spiro heterocyclic radical, double spiro heterocyclic radicals or more spiro heterocyclic radicals according to the number for sharing spiro-atom between ring and ring, preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro heterocyclic radicals.The non-limiting example of spiro heterocyclic radical includes:

Term " condensed hetero ring base " refers to 5 to 20 yuan, the polycyclic heterocyclic group of shared a pair of of the atom adjoined of other rings in each ring and system in system, one or more rings can contain one or more double bonds, but none ring has the pi-electron system of total conjugated, 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 annular atom are carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic condensed hetero ring base, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero ring bases can be divided into according to a group cyclic number.The non-limiting example of condensed hetero ring base includes:

Term " bridge heterocycle " refers to 5 to 14 yuan, any two ring shares the polycyclic heterocyclic group of two atoms being not directly connected, it can contain one or more double bonds, but none ring has the pi-electron system of total conjugated, 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 annular atom are carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge heterocycle, preferably bicyclic, tricyclic or Fourth Ring can be divided into according to a group cyclic number, be more selected as bicyclic or tricyclic.The non-limiting example of bridge heterocycle includes:

The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein the ring to link together with precursor structure is heterocycle, non-limiting example includes:

Deng.

Heterocycle 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, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, carboxyl, carboxylate ,-OR ⁴、-C(O)R ⁴、-C(O)OR ⁴With-S (O) _mR ⁴。

Term " aryl " refers to 6 to the 14 yuan of full carbon monocycles or fused polycycle (rings of namely shared adjacent carbon atoms pair) group, preferably 6 to 10 yuan of the pi-electron system with conjugation, such as phenyl and naphthalene.More preferable phenyl.The aryl rings can be condensed on heteroaryl, heterocycle or cycloalkyl ring, wherein the ring to link together with precursor structure is aryl rings, non-limiting example includes:

Aryl can be substituted 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, 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, and wherein hetero atom is 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, contain 1 to 2 hetero atom；It is preferred that such as imidazole radicals, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrole radicals, tetrazole radical, pyridyl group, pyrimidine radicals, thiadiazoles, pyrazinyl, preferably imidazole radicals, tetrazole radical, pyridyl group, thienyl, pyrazolyl or pyrimidine radicals, thiazolyl；More select pyridyl group.The heteroaryl ring can be condensed on aryl, heterocycle or cycloalkyl ring, wherein the ring to link together with precursor structure is heteroaryl ring, non-limiting example includes:

Heteroaryl 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, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl, carboxylate ,-OR ⁴、-C(O)R ⁴、-C(O)OR ⁴With-S (O) _mR ⁴。

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-NH ₂。

Term " cyano " refers to-CN.

Term " nitro " refers to-NO ₂。

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 defined above.

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

" optional " or " optionally " mean event or environment described later can with but need not occur, which includes the occasion that the event or environment occur or do not occur.For example, mean " optionally by alkyl-substituted heterocyclic group " alkyl can with but necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.

" substituted " refers to that one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom are replaced by the substituent group of respective number independently of one another.Self-evident, substituent group is only in their possible chemistry position, and those skilled in the art can determine in the case where not paying and excessively making great efforts and (pass through experiment or theory) possible or impossible substitution.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key.

" pharmaceutical composition " indicates mixture and other components such as physiology/pharmaceutical carrier and excipient containing one or more compounds described herein or its physiologically/pharmaceutical salt or pro-drug and other chemical constituents.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, has safety and validity when this kind of salt is used in the mammalian body, and have due bioactivity.

R ⁴With m as 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:

The preparation method of or mixtures thereof general formula (AI) compound represented of the present invention or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form or its pharmaceutical salt, comprising the following steps:

The first step, in acid condition, cyclization obtains general formula (AI-2) for general formula (AI-1) compound and paraformaldehyde；

Second step, general formula (AI-2) compound under alkaline condition, in the presence of a catalyst with CO and R ^cOH reacts to obtain general formula (AI-3)；

Third step, general formula (AI-3) compound under alkaline condition, slough trifluoroacetyl group and obtain general formula (AI-4)；

4th step, general formula (AI-4) compound under alkaline condition, in the presence of a catalyst, occur coupling reaction with general formula (I-5) compound and obtain general formula (AI-5) compound；Or general formula (I-4) compound is in acid condition, in the presence of a reducing agent, reduction amination occurs with general formula (I-6) compound and obtains general formula (AI-5) compound；

5th step, under alkaline condition, hydrolysis obtains (AI-A) compound to general formula (AI-5) compound；

6th step, general formula (AI-A) compound and general formula (I-B) compound under alkaline condition, exist in condensing agent

Lower generation condensation reaction obtains general formula (AI) compound；

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

There is provided acid condition reagent include but is not limited to hydrogen chloride, the 1,4- dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, to benzene methanesulfonic acid, Me ₃SiCl and TMSOT _f；

Catalyst includes but is not limited to palladium/carbon, Raney's nickel, tetra-triphenylphosphine palladium, palladium chloride, palladium acetate, 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyl, [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride, 1,1 '-bis- (dibenzyl phosphorus) dichloro diamyl iron palladiums, tris(dibenzylideneacetone) dipalladium or 2- dicyclohexyl phosphine -2', 6'- dimethoxy-biphenyl, preferably [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride or 2- dicyclohexyl phosphine -2', 6'- dimethoxy-biphenyl.

Go back original reagent includes but is not limited to: lithium aluminium hydride reduction, sodium borohydride, DIBAL-H, NaAlH (O-t-Bu) ₃、AlH ₃、NaCNBH ₃、Na(AcO) ₃BH、BH ₃Tetrahydrofuran solution (1N), B ₂H ₅、Li(Et) ₃BH、Pd/C/H ₂With Raney's nickel/H ₂；

Condensing agent includes but is not limited to 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, N, N'- dicyclohexyl carbodiimide, N, N'- diisopropylcarbodiimide, O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester, I-hydroxybenzotriazole, 1- hydroxyl -7- azo benzotriazole, O- benzotriazole-N, N, N', N'- tetramethylurea (TMU) hexafluorophosphoric acid ester, 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, three (dimethylamino) phosphorus hexafluorophosphate of benzotriazole -1- base oxygroup or hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole Alkyl phosphorus, preferably 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester；

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

Wherein:

R ^cFor alkyl, preferably ethyl；

X is halogen, preferably bromine；

Ring A, ring B, ring C, W ¹、W ²、W ³、R ¹~R ³, n, s and t be as defined in logical formula (I).

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

The first step, in acid condition, cyclization obtains general formula (I-2) for general formula (I-1) compound and paraformaldehyde；

Second step, general formula (I-2) compound under alkaline condition, in the presence of a catalyst with CO and R ^cOH reacts to obtain general formula (I-3)；

Third step, general formula (I-3) compound under alkaline condition, slough trifluoroacetyl group and obtain general formula (I-4)；

4th step, general formula (I-4) compound under alkaline condition, in the presence of a catalyst, occur coupling reaction with general formula (I-5) compound and obtain general formula (I-7) compound；Or general formula (I-4) compound is in acid condition, in the presence of a reducing agent, reduction amination occurs with general formula (I-6) compound and obtains general formula (I-7) compound；

5th step, under alkaline condition, hydrolysis obtains (I-A) compound to general formula (I-7) compound；

6th step, general formula (I-A) compound and general formula (I-B) compound under alkaline condition, condensation reaction occur in the presence of condensing agent and obtains logical formula (I) compound；

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

There is provided acid condition reagent include but is not limited to hydrogen chloride, the 1,4- dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, to benzene methanesulfonic acid, Me ₃SiCl and TMSOT _f；

Catalyst includes but is not limited to palladium/carbon, Raney's nickel, tetra-triphenylphosphine palladium, palladium chloride, palladium acetate, 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyl, [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride, 1,1 '-bis- (dibenzyl phosphorus) dichloro diamyl iron palladiums, tris(dibenzylideneacetone) dipalladium or 2- dicyclohexyl phosphine -2', 6'- dimethoxy-biphenyl, preferably [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride or 2- dicyclohexyl phosphine -2', 6'- dimethoxy-biphenyl.

Go back original reagent includes but is not limited to: lithium aluminium hydride reduction, sodium borohydride, DIBAL-H, NaAlH (O-t-Bu) ₃、AlH ₃、NaCNBH ₃、Na(AcO) ₃BH、BH ₃Tetrahydrofuran solution (1N), B ₂H ₅、Li(Et) ₃BH、Pd/C/H ₂With Raney's nickel/H ₂；

Condensing agent includes but is not limited to 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, N, N'- dicyclohexyl carbodiimide, N, N'- diisopropylcarbodiimide, O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester, I-hydroxybenzotriazole, 1- hydroxyl -7- azo benzotriazole, O- benzotriazole-N, N, N', N'- tetramethylurea (TMU) hexafluorophosphoric acid ester, 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, three (dimethylamino) phosphorus hexafluorophosphate of benzotriazole -1- base oxygroup or hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole Alkyl phosphorus, preferably 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester；

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

Wherein:

R ^cFor alkyl, preferably ethyl；

X is halogen, preferably bromine；

Ring A, ring B, R ¹~R ³, n, s and t be as defined in logical formula (I).

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

The first step, in acid condition, cyclization obtains general formula (II-2) for general formula (II-1) compound and paraformaldehyde；

Second step, general formula (II-2) compound under alkaline condition, in the presence of a catalyst with CO and R ^cOH reacts to obtain general formula (II-3)；

Third step, general formula (II-3) compound under alkaline condition, slough trifluoroacetyl group and obtain general formula (II-4)；

4th step, general formula (II-4) compound under alkaline condition, in the presence of a catalyst, occur coupling reaction with general formula (I-5) compound and obtain general formula (II-7) compound；Or general formula (II-4) compound is in acid condition, in the presence of a reducing agent, reduction amination occurs with general formula (I-6) compound and obtains general formula (II-7) compound；

5th step, under alkaline condition, hydrolysis obtains (II-A) compound to general formula (II-7) compound；

6th step, general formula (II-A) compound and general formula (I-B) compound under alkaline condition, condensation reaction occur in the presence of condensing agent and obtains logical formula (II) compound；

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

There is provided acid condition reagent include but is not limited to hydrogen chloride, the 1,4- dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, to benzene methanesulfonic acid, Me ₃SiCl and TMSOT _f；

Catalyst includes but is not limited to palladium/carbon, Raney's nickel, tetra-triphenylphosphine palladium, palladium chloride, palladium acetate, 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyl, [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride, 1,1 '-bis- (dibenzyl phosphorus) dichloro diamyl iron palladiums, tris(dibenzylideneacetone) dipalladium or 2- dicyclohexyl phosphine -2', 6'- dimethoxy-biphenyl, preferably [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride or 2- dicyclohexyl phosphine -2', 6'- dimethoxy-biphenyl；

Go back original reagent includes but is not limited to: lithium aluminium hydride reduction, sodium borohydride, DIBAL-H, NaAlH (O-t-Bu) ₃、AlH ₃、NaCNBH ₃、Na(AcO) ₃BH、BH ₃Tetrahydrofuran solution (1N), B ₂H ₅、Li(Et) ₃BH、Pd/C/H ₂With Raney's nickel/H ₂；

Condensing agent includes but is not limited to 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, N, N'- dicyclohexyl carbodiimide, N, N'- diisopropylcarbodiimide, O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester, I-hydroxybenzotriazole, 1- hydroxyl -7- azo benzotriazole, O- benzotriazole-N, N, N', N'- tetramethylurea (TMU) hexafluorophosphoric acid ester, 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, three (dimethylamino) phosphorus hexafluorophosphate of benzotriazole -1- base oxygroup or hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole Alkyl phosphorus, preferably 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester；

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

Wherein:

R ^cFor alkyl, preferably ethyl；

X is halogen, preferably bromine；

Ring A, ring B, R ¹~R ³, s and t be as defined in logical formula (II).

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

The first step, general formula (II-4) compound under alkaline condition, in the presence of a catalyst, occur coupling reaction with general formula (III-1) compound and obtain general formula (III-2) compound；

Second step, under alkaline condition, hydrolysis obtains (III-3) compound to general formula (III-2) compound；

Third step, general formula (III-3) compound and general formula (I-B) compound under alkaline condition, condensation reaction occur in the presence of condensing agent and obtains logical formula (III) compound；

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

Catalyst includes but is not limited to palladium/carbon, Raney's nickel, tetra-triphenylphosphine palladium, palladium chloride, palladium acetate, 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyl, [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride, 1,1 '-bis- (dibenzyl phosphorus) dichloro diamyl iron palladiums, tris(dibenzylideneacetone) dipalladium or 2- dicyclohexyl phosphine -2', 6'- dimethoxy-biphenyl, preferably [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride or 2- dicyclohexyl phosphine -2', 6'- dimethoxy-biphenyl；

Condensing agent includes but is not limited to 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, N, N'- dicyclohexyl carbodiimide, N, N'- diisopropylcarbodiimide, O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester, I-hydroxybenzotriazole, 1- hydroxyl -7- azo benzotriazole, O- benzotriazole-N, N, N', N'- tetramethylurea (TMU) hexafluorophosphoric acid ester, 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, three (dimethylamino) phosphorus hexafluorophosphate of benzotriazole -1- base oxygroup or hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole Alkyl phosphorus, preferably 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester；

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

Wherein:

R ^cFor alkyl, preferably ethyl；

X is halogen, preferably bromine；

Ring B, G ¹、G ²、R ¹~R ³With t as defined in logical formula (III).

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 deuterated dimethyl sulfoxide (DMSO-d ₆), deuterated chloroform (CDCl ₃), deuterated methanol (CD ₃), OD 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).

The measurement of HPLC uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire 150 × 4.6mm of C18 chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini 150 × 4.6mm of C18 chromatographic column).

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

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and the specification that the silica gel plate that thin-layered chromatography (TLC) uses uses is 0.15mm~0.2mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.

Column chromatography is generally carrier using 200~300 mesh silica gel of Yantai Huanghai Sea silica gel.

Chiral preparatory column chromatography uses Prep Star SD-1 (Varian Instruments Inc.) or SFC-multigram (Berger Instruments Inc.).

Kinases average inhibition and IC ₅₀The 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 it is commercially available from ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, splendid remote chemistry scientific and technological (Accela ChemBio Inc) reach the companies such as auspicious chemicals.

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 hydrogenates instrument using Parr 3916EKX type hydrogenation instrument and clear indigo plant QL-500 type hydrogen generator or HC2-SS type.

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), solvent used in reacting, 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/methanol system, B: n-hexane/ethyl acetate system, C: petrol ether/ethyl acetate system, D: acetone, E: methylene chloride/acetone system, F: ethyl acetate/dichloromethane system, G: ethyl acetate/dichloromethane/n-hexane, H: ethyl acetate/dichloromethane/acetone, the volume ratio of solvent is different according to the polarity of compound and 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

N- (4- (ethylsulfonyl) benzyl) -2'- (4- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- formamide 1

The first step

1- (the bromo- 1'H- spiral shell of 7'- [cyclopropane -1,4'- isoquinolin] -2'(3'H)-yl) -2,2,2- trifluoroethanone 1b

By N- ((1- (4- bromophenyl) cyclopropyl) methyl) -2,2,2- trifluoroacetamide 1a (22g, 68.3mmol, it is prepared using method disclosed in PCT Patent Application " WO2011124093 ") it is dissolved in the in the mixed solvent of the prefabricated acetic acid of 150mL and sulfuric acid (V/V=2:3), it is added paraformaldehyde (7.96g, 264.99mmol), is stirred to react 12 hours.Reaction solution pours into 500mL ice water, it is extracted with ethyl acetate (500mL × 2), merge organic phase, water is successively used, saturated sodium bicarbonate solution and saturated sodium chloride solution washing, anhydrous sodium sulfate are dry, filtering, filtrate decompression concentration, obtains crude title compound 1b (4.5g), and product directly carries out next step reaction without further purification.

Second step

2'- (2,2,2- trifluoroacetyl group) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- carboxylic acid, ethyl ester 1c

By crude Compound 1b (4g, 11.97mmol) it is dissolved in the in the mixed solvent of 40mL ethyl alcohol and dimethyl sulfoxide (V/V=1:1), it is added 1, bis- (diphenylphosphine) propane (987.5mg, 2.39mmol) of 3-, triethylamine (1.21g, 11.97mmol) and palladium acetate (537.53mg, 2.39mmol), under carbon monoxide atmosphere, 60 DEG C is warming up to and is stirred to react 12 hours.Reaction solution is cooled to room temperature, it pours into 100mL water, it is extracted with ethyl acetate (100mL × 2), merges organic phase, washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title compound 1c (2.5g, yield: 63.8%).

Third step

2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- carboxylic acid, ethyl ester 1d

1c (2.5g, 7.64mmol) is dissolved in the in the mixed solvent of 100mL second alcohol and water (V/V=1:1), is added potassium carbonate (1.58g, 11.46mmol), reaction 12 hours is stirred at room temperature.Reaction solution pours into 100mL water, it is extracted with ethyl acetate (100mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, it obtains crude title compound 1d (2g), product directly carries out next step reaction without further purification.

4th step

2'- (4- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- carboxylic acid, ethyl ester 1f

By crude Compound 1d (2g, 8.65mmol) and the bromo- 4- of 1- (trifluoromethyl) benzene 1e (2.33g, 10.38mmol, using well known method " Organic Letters; 2014; 16 (16), 4268-4271 " are prepared) be dissolved in 50mL1, in 4- dioxane, cesium carbonate (8.45g is added, 25.94mmol), 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyl (412.22mg, 864.72umol) with tris(dibenzylideneacetone) dipalladium (791.83mg, 864.72umol), it is warming up to 90 DEG C and is stirred to react 3 hours.Reaction solution is cooled to room temperature, it pours into 100mL water, it is extracted with ethyl acetate (100mL × 2), merges organic phase, washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title compound 1f (1.7g, yield: 52.37%).

5th step

2'- (4- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- carboxylic acid 1g

Compound 1f (1.5g, 4mmol) is dissolved in the in the mixed solvent of 60mL second alcohol and water (V/V=5:1), is added sodium hydroxide (799.12mg, 19.98mmol), return stirring is warming up to and reacts 2 hours.Reaction solution is cooled to room temperature, it is concentrated under reduced pressure, 1M hydrochloric acid is added dropwise in gained residue to pH < 2, is extracted with ethyl acetate (50mL × 2), merges organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, it obtains crude title compound 1g (1.5g), product directly carries out next step reaction without further purification.

6th step

N- (4- (ethylsulfonyl) benzyl) -2'- (4- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- formamide 1

By crude Compound 1g (1.4g; 4.03mmol) and (4- (ethylsulfonyl) phenyl) methylamine 1h (1.2g; 6.05mmol; it is prepared using method disclosed in PCT Patent Application " WO2015017335 ") it is dissolved in 30mL N; in dinethylformamide; 2- (7- azo benzotriazole)-N is added; N; N'; N'- tetramethylurea hexafluorophosphoric acid ester (3.06g; 8.06mmol) with triethylamine (1.22g, 12.09mmol), it is stirred to react 12 hours.Reaction solution pours into 100mL water, it is extracted with ethyl acetate (100mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with high performance liquid chromatography purify gained residue, obtain title compound 1 (1.1g, yield: 51.63%).

MS m/z(ESI):529.5[M+1]

¹H NMR (400MHz, DMSO-d ₆)δ9.11(s,1H),7.80-7.85(m,3H),7.69-7.71(m,1H),7.55-7.57(m,2H),7.49-7.50(m,2H),7.11-7.13(m,2H),6.93-6.95(m,1H),4.65(s,2H),4.56-4.57(m,2H),3.54(s,2H),3.23-3.28(m,2H),1.05-1.09(m,7H)。

Embodiment 2

N- (1-4- (ethylsulfonyl) phenyl) -2- ethoxy) -2'- (4- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- formamide 2

By crude Compound 1g (200mg; 575.82umol) and 2- amino -2- (4- (ethylsulfonyl) phenyl) ethyl alcohol 2a (198.05mg; 863.73umol; it is prepared using method disclosed in PCT Patent Application " WO2016061160 ") it is dissolved in 10mL N; in dinethylformamide; 2- (7- azo benzotriazole)-N is added; N; N'; N'- tetramethylurea hexafluorophosphoric acid ester (328.22mg; 863.73umol) with triethylamine (174.8mg, 1.73mmol), it is stirred to react 12 hours.Reaction solution pours into 100mL water, it is extracted with ethyl acetate (100mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with high performance liquid chromatography purify gained residue, obtain title compound 2 (120mg, yield: 37.31%).

MS m/z(ESI):559.1[M+1]

¹H NMR(400MHz,DMSO-d ₆)δ8.75-8.77(m,1H),7.80-7.84(m,3H),7.70-7.72(m,1H),7.64-7.66(m,2H),7.49-7.51(m,2H),7.12-7.14(m,2H),6.92-6.95(m,1H),5.11-5.17(m,1H),4.66(s,2H),4.23(s,1H),3.69-3.75(m,2H),3.54(s,2H),3.24-3.29(m,2H),1.03-1.11(m,7H)。

Embodiment 3,4

(R)-N- (1-4- (ethylsulfonyl) phenyl) -2- ethoxy) -2'- (4- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- formamide 3

(S)-N- (1-4- (ethylsulfonyl) phenyl) -2- ethoxy) -2'- (4- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- formamide 4

2 (120mg, 0.215mmol) progress chirality is prepared into (separation condition: 5 μm of chiral preparatory column Lux Cellulose-1OD 4.6*150mm (band guard column)；Mobile phase: n-hexane: ethyl alcohol: trifluoroacetic acid=50:50:0.01, flow velocity: 1.0mL/min), its respective components is collected, is concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title compound 3 (10mg) and 4 (20mg).

Compound 3:

MS m/z(ESI):559.0[M+1]；

Chiral HPLC: retention time 4.411 minutes, chiral purity: 93% (chromatographic column: Lux Cellulose-1 OD 4.6*150mm 5um (band guard column))；Mobile phase: n-hexane/ethyl alcohol/trifluoroacetic acid=50/50/0.01 (v/v/v)).

¹H NMR(400MHz,DMSO-d ₆)δ8.74-8.76(m,1H),7.79-7.84(m,3H),7.64-7.72(m,3H),7.49-7.51(m,2H),7.12-7.14(m,2H),6.92-6.95(m,1H),5.13-5.15(m,1H),4.66(s,2H),3.70-3.75(s,2H),3.54(s,2H),3.24-3.29(m,2H),0.85-1.11(m,7H)。

Compound 4:

MS m/z(ESI):559.1[M+1]；

Chiral HPLC: retention time 6.9148 minutes, chiral purity: 90%.% (chromatographic column: Superchiral S-AD (Chiralway), 0.46cm I.D.*25cm, 5um；Mobile phase: n-hexane/ethyl alcohol/trifluoroacetic acid=50/50/0.01 (v/v/v)).

¹H NMR(400MHz,DMSO-d ₆)δ8.74-8.75(m,1H),7.79-7.84(m,3H),7.64-7.71(m,3H),7.49-7.51(m,2H),7.12-7.14(m,2H),6.92-6.94(m,1H),5.13-5.15(m,1H),4.66(s,2H),3.67-3.77(m,2H),3.54(s,2H),3.23-3.29(m,2H),0.84-1.11(m,7H)。

Embodiment 5

N- ((5- (ethylsulfonyl) pyridine -2- base) methyl) -2'- (4- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- formamide

By crude Compound 1g (50mg; 0.14mmol) and 5- (ethylsulfonyl) pyridine -2- base) methylamine 5a (43.24mg; 0.22mmol; it is prepared using method disclosed in PCT Patent Application " WO2015017335 ") it is dissolved in 10mL N; in dinethylformamide; 2- (7- azo benzotriazole)-N is added; N; N'; N'- tetramethylurea hexafluorophosphoric acid ester (109.41mg; 0.29mmol) with triethylamine (43.62mg, 0.43mmol), it is stirred to react 12 hours.Reaction solution pours into 30mL water, it is extracted with ethyl acetate (30mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with high performance liquid chromatography purify gained residue, obtain title compound 5 (20mg, yield: 24.92%).

MS m/z(ESI):530.1[M+1]

¹H NMR(400MHz,DMSO-d ₆)δ9.22(s,1H),8.95-8.96(m,1H),8.24-8.26(m,1H),7.83(s,1H),7.74-7.75(m,1H),7.57-7.59(m,1H),7.50-7.52(m,2H),7.13-7.15(m,2H),6.95-6.97(m,1H),4.67(s,4H),3.67-3.70(m,2H),3.37-3.40(m,2H),1.07-1.14(m,7H)。

Embodiment 6

N- ((1- (ethylsulfonyl) piperidin-4-yl) methyl) -2'- (4- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- formamide 6

By crude Compound 1g (100mg; 0.287mmol) and (1- (ethylsulfonyl) piperidin-4-yl) methylamine 6a (89.1mg; 0.432mmol; it is prepared using method disclosed in U.S. Patent application " US20160122318 ") it is dissolved in 20mL N; in dinethylformamide; 2- (7- azo benzotriazole)-N is added; N; N'; N'- tetramethylurea hexafluorophosphoric acid ester (164.11mg; 0.432mmol) with triethylamine (87.4mg, 0.864mmol), it is stirred to react 3 hours.Reaction solution pours into 50mL water, it is extracted with ethyl acetate (50mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with high performance liquid chromatography purify gained residue, obtain title compound 6 (50mg, yield: 34.42%).

MS m/z(ESI):536.5[M+1]

¹H NMR(400MHz,DMSO-d ₆)δ8.46(s,1H),7.74(s,1H),7.63-7.65(m,1H),7.49-7.52(m,2H),7.12-7.14(m,2H),6.90-6.92(m,1H),4.65(s,2H),3.53-3.56(m,3H),3.16-3.19(m,3H),2.99-3.05(m,2H),2.73-2.78(m,2H),1.73-1.76(m,3H),1.02-1.23(m,9H)。

Embodiment 7

N- (4- (ethylsulfonyl) benzyl) -2'- ((1r, 4r) -4- (trifluoromethyl) cyclohexyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- formamide 7

The first step

2'- (4- (trifluoromethyl) cyclohexyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- carboxylic acid, ethyl ester 7b

By crude Compound 1d (300mg, 1, it 3mmol) is dissolved in 10mL methanol, acetic acid (15.58mg, 0.259mmol) and sodium triacetoxy borohydride (549.81mg is added, 2.59mmol), after being stirred to react 2 hours, 4- (trifluoromethyl) hexamethylene -1- ketone 7a (430.99mg, 2.59mmol is added, it is prepared using method disclosed in PCT Patent Application " WO2008007930 "), it is stirred to react 12 hours.Reaction solution pours into 50mL water, it is extracted with ethyl acetate (50mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title compound 7b (100mg, yield: 20.21%).

Second step

2'- (4- (trifluoromethyl) cyclohexyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- carboxylic acid 7c

Compound 7b (100mg, 0.262mmol) is dissolved in the in the mixed solvent of 13mL second alcohol and water (V/V=10:3), is added sodium hydroxide (52.43mg, 1.31mmol), is warming up to 70 DEG C and is stirred to react 2 hours.Reaction solution is cooled to room temperature, it is concentrated under reduced pressure, 1M hydrochloric acid is added dropwise in gained residue to pH < 2, is extracted with ethyl acetate (30mL × 2), merges organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, it obtains crude title compound 7c (92mg), product directly carries out next step reaction without further purification.

Third step

N- (4- (ethylsulfonyl) benzyl) -2'- ((1r, 4r) -4- (trifluoromethyl) cyclohexyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- formamide 7

By crude Compound 7c (50mg, 0.141mmol) and compound 1h (33.83mg, it 0.17mmol) is dissolved in 5mL n,N-Dimethylformamide, 2- (7- azo benzotriazole)-N is added, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (80.65mg, 0.212mmol) and triethylamine (42.95mg, 0.424mmol), it is stirred to react 12 hours.Reaction solution pours into 50mL water, it is extracted with ethyl acetate (50mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with high performance liquid chromatography purify gained residue, obtain title compound 7 (20mg, yield: 26.5%).

MS m/z(ESI):535.2[M+1]

¹H NMR(400MHz,DMSO-d ₆)δ9.03(s,1H),7.83-7.85(m,2H),7.55-7.64(m,4H),6.79-6.81(m,1H),4.55-4.57(m,2H),3.84(s,2H),3.23-3.27(m,2H),2.61(s,2H),1.94(s,3H),1.24-1.36(m,7H),0.90-1.11(m,7H)。

Embodiment 8

N- (4- (ethylsulfonyl) benzyl) -2'- (2- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- formamide 8

The first step

2'- (2- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- carboxylic acid, ethyl ester 8b

By crude Compound 1d (200mg, 0.864mmol) and the bromo- 2- of 1- (trifluoromethyl) benzene 8a (233.48mg, 1.04mmol, using well known method " European Journal, 2013, 19 (52), 17692-17697 " is prepared) it is dissolved in 3mL1, in 4- dioxane, sodium tert-butoxide (249.31mg is added, 2.59mmol), 2- dicyclohexyl phosphorus -2, 4, 6- tri isopropyl biphenyl (82.44mg, 172.94umol) and tris(dibenzylideneacetone) dipalladium (158.37mg, 172.94umol), 105 DEG C are warming up to be stirred to react 18 hours.Reaction solution is cooled to room temperature, it pours into 10mL water, it is extracted with ethyl acetate (20mL × 2), merges organic phase, washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title compound 8b (130mg, yield: 40.05%).

Second step

2'- (2- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- carboxylic acid 8c

Compound 8b (130mg, 0.346mmol) is dissolved in the in the mixed solvent of 12mL second alcohol and water (V/V=5:1), is added sodium hydroxide (138.51mg, 3.46mmol), is warming up to 60 DEG C and is stirred to react 2 hours.Reaction solution is cooled to room temperature, and is concentrated under reduced pressure, and it is 3~4 that 1M hydrochloric acid is added dropwise in gained residue to pH, is concentrated under reduced pressure, is obtained crude title compound 8c (120mg), product directly carries out next step reaction without further purification.

Third step

N- (4- (ethylsulfonyl) benzyl) -2'- (2- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- formamide 8

By crude Compound 8c (100mg, 0.288mmol) it is dissolved in 2mL n,N-Dimethylformamide with compound 1h (114.74mg, 0.576mmol), 2- (7- azo benzotriazole)-N is added, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (218mg, 0.576mmol) and N, N- diisopropylethylamine (111.63mg, 0.864mmol) is stirred to react 1 hour.10mL water is added in reaction solution, it is extracted with ethyl acetate (10mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with high performance liquid chromatography purify gained residue, obtain title compound 8 (40mg, yield: 26.28%).

MS m/z(ESI):529.5[M+1]

¹H NMR(400MHz,CDCl3)δ7.85-7.87(m,2H),7.66-7.68(m,1H),7.59-7.61(m,1H),7.52-7.54(m,4H),7.38-7.40(m,1H),6.80-6.82(m,1H),6.60-6.63(m,1H),4.74-4.75(m,2H),4.29(s,2H),3.08-3.13(m,4H),1.25-1.29(m,3H),1.07-1.10(m,2H),0.95-0.98(m,2H)。

Embodiment 9

N- (4- (ethylsulfonyl) benzyl) -2'- (5- (trifluoromethyl) pyrimidine -2-base) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- formamide 9

The first step

2'- (5- (trifluoromethyl) pyrimidine -2-base) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- carboxylic acid, ethyl ester

9b

By crude Compound 1d (100mg, 0.432mmol) and the chloro- 5- of 2- (trifluoromethyl) pyrimidine 9a (118mg, it 0.646mmol) is dissolved in 2mL DMSO, it is added 1,11 carbon -7- alkene 326mg of 8- diazabicyclo [5.4.0], 1.294mmol), 90 DEG C are warming up to be stirred to react 18 hours.Reaction solution is cooled to room temperature, it pours into 10mL water, it is extracted with ethyl acetate (20mL × 2), merges organic phase, washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title compound 9b (100mg, yield: 61.29%).

Second step

2'- (5- (trifluoromethyl) pyrimidine -2-base) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- carboxylic acid 9c

Compound 9b (50mg, 0.132mmol) is dissolved in the in the mixed solvent of 12mL second alcohol and water (V/V=5:1), is added sodium hydroxide (53mg, 1.32mmol), is warming up to 60 DEG C and is stirred to react 2 hours.Reaction solution is cooled to room temperature, and is concentrated under reduced pressure, and it is 3~4 that 1M hydrochloric acid is added dropwise in gained residue to pH, is concentrated under reduced pressure, is obtained crude title compound 9c (50mg), product directly carries out next step reaction without further purification.

Third step

N- (4- (ethylsulfonyl) benzyl) -2'- (5- (trifluoromethyl) pyrimidine -2-base) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- formamide 9

By crude Compound 9c (50mg, 0.143mmol) it is dissolved in 2mL n,N-Dimethylformamide with compound 1h (28mg, 0.140mmol), 2- (7- azo benzotriazole)-N is added, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (82mg, 0.216mmol) and N, N- diisopropylethylamine (37mg, 0.286mmol) is stirred to react 1 hour.10mL water is added in reaction solution, it is extracted with ethyl acetate (10mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with high performance liquid chromatography purify gained residue, obtain title compound 9 (50mg, yield: 65.84%).

MS m/z(ESI):531.4[M+1]

¹H NMR(400MHz,CDCl ₃)δ8.49-8.51(m,2H),7.65-7.75(m,4H),7.44-7.46(m,2H),7.03-7.06(m,1H),6.85-6.87(m,1H),5.13-5.16(m,2H),4.71-4.73(m,2H),3.96-3.98 (m,2H),3.06-3.11(m,2H),1.24-1.27(m,3H),1.07-1.12(m,4H)。

Embodiment 10

N- (4- (ethylsulfonyl) benzyl) -2'- (4- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclobutane -1,4'- isoquinolin] -7'- formamide 10

The first step

1- (the bromo- 1'H- spiral shell of 7'- [cyclobutane -1,4'- isoquinolin] -2'(3'H)-yl) -2,2,2- trifluoroethanone 10b

By N- ((1- (4- bromophenyl) cyclobutyl) methyl) -2,2,2- trifluoroacetamide 10a (1.2g, 3.57mmol, it is prepared using method disclosed in patent application " WO2011124093 ") it is dissolved in the in the mixed solvent of the prefabricated acetic acid of 27mL and sulfuric acid (V/V=2:3), it is added paraformaldehyde (321mg, 10.69mmol), is stirred to react 12 hours.Reaction solution pours into 100mL ice water, it is extracted with ethyl acetate (50mL × 2), merge organic phase, water is successively used, saturated sodium bicarbonate solution and saturated sodium chloride solution washing, anhydrous sodium sulfate are dry, filtering, filtrate decompression concentration, obtains crude title compound 10b (1g), and product directly carries out next step reaction without further purification.

Second step

2'- (2,2,2- trifluoroacetyl group) -2', 3'- dihydro -1'H- spiral shell [cyclobutane -1,4'- isoquinolin] -7'- carboxylic acid, ethyl ester 10c

By crude Compound 10b (1g, 2.87mmol) it is dissolved in the in the mixed solvent of 20mL ethyl alcohol and dimethyl sulfoxide (V/V=1:1), it is added 1, bis- (diphenylphosphine) propane (118mg, 0.28mmol) of 3-, triethylamine (290mg, 2.86mmol) and palladium acetate (64mg, 0.28mmol), under carbon monoxide atmosphere, 60 DEG C is warming up to and is stirred to react 12 hours.Reaction solution is cooled to room temperature, it pours into 100mL water, it is extracted with ethyl acetate (100mL × 2), merges organic phase, washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title compound 10c (400mg, yield: 40.8%).

Third step

2', 3'- dihydro -1'H- spiral shell [cyclobutane -1,4'- isoquinolin] -7'- carboxylic acid, ethyl ester 10d

10c (400mg, 1.17mmol) is dissolved in the in the mixed solvent of 50mL second alcohol and water (V/V=1:1), is added potassium carbonate (485mg, 3.51mmol), reaction 12 hours is stirred at room temperature.Reaction solution pours into 100mL water, it is extracted with ethyl acetate (50mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, it obtains crude title compound 10d (350mg), product directly carries out next step reaction without further purification.

4th step

2'- (4- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclobutane -1, 4'- isoquinolin] -7'- carboxylic acid, ethyl ester 10f is by crude Compound 10d (350mg, 1.42mmol) and the bromo- 4- of 1- (trifluoromethyl) benzene 10e (481mg, 2.13mmol, using well known method " Organic Letters, 2014, 16 (16), 4268-4271 " is prepared) it is dissolved in 30mL1, in 4- dioxane, cesium carbonate (1.4g is added, 4.29mmol), 2- dicyclohexyl phosphorus -2, 4, 6- tri isopropyl biphenyl (68mg, 142.64 μm of ol) and tris(dibenzylideneacetone) dipalladium (130mg , 141.96 μm of ol), it is warming up under 90 DEG C of helium protections and is stirred to react 3 hours.Reaction solution is cooled to room temperature, it pours into 50mL water, it is extracted with ethyl acetate (50mL × 2), merges organic phase, washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title compound 10f (400mg, yield: 71.99%).

5th step

2'- (4- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclobutane -1,4'- isoquinolin] -7'- carboxylic acid 10g

Compound 10f (400mg, 1.03mmol) is dissolved in the in the mixed solvent of 30mL second alcohol and water (V/V=5:1), is added sodium hydroxide (164mg, 4.10mmol), return stirring is warming up to and reacts 2 hours.Reaction solution is cooled to room temperature, it is concentrated under reduced pressure, 1M hydrochloric acid is added dropwise in gained residue to pH < 2, is extracted with ethyl acetate (50mL × 2), merges organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, it obtains crude title compound 10g (300mg), product directly carries out next step reaction without further purification.

6th step

N- (4- (ethylsulfonyl) benzyl) -2'- (4- (trifluoromethyl) phenyl) -2', 3'- dihydro -1'H- spiral shell [cyclobutane -1,4'- isoquinolin] -7'- formamide 10

By crude Compound 10g (300mg; 0.83mmol) and (4- (ethylsulfonyl) phenyl) methylamine 10h (198mg; 0.99mmol; it is prepared using method disclosed in patent application " WO2015017335 ") it is dissolved in 10mL N; in dinethylformamide; 2- (7- azo benzotriazole)-N is added; N; N'; N'- tetramethylurea hexafluorophosphoric acid ester (630mg; 1.66mmol) with triethylamine (252mg, 2.49mmol), it is stirred to react 12 hours.Reaction solution pours into 50mL water, it is extracted with ethyl acetate (50mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with high performance liquid chromatography purify gained residue, obtain title compound 10 (200mg, yield: 44.39%).

MS m/z(ESI):543.2[M+1]

¹H NMR (400MHz, DMSO-d ₆)δ9.13-9.15(m,1H),7.83-7.85(m,3H),7.74-7.79(m,2H),7.53-7.58(m,4H),7.16-7.18(m,2H),4.58-4.59(m,2H),4.49(s,2H),3.67(s,2H),3.23-3.28(m,2H),2.22-2.35(m,3H),2.01-2.10(m,3H),1.06-1.09(m,3H)。

Embodiment 11

N- (4- (ethylsulfonyl) benzyl) -2- (4- (trifluoromethyl) phenyl) -2,2 ', 3,3 ', 5 ', 6 '-hexahydro -1H- spiral shell [isoquinolin -4,4 '-pyrans] -7- formamide 11

The first step

4- (4- bromophenyl) tetrahydro -2H- pyrans -4- formonitrile HCN 11b

By 2- (4- bromophenyl) acetonitrile 11a (2.5g, 12.75mmol), it is dissolved in 30mL dimethyl sulfoxide, it is cooled to 0 DEG C, is slowly added to sodium hydrogen (1.02g, 25.50mmol), stirring 30 minutes, the bromo- 2- of 1- (2- bromine oxethyl) ethane (3.22g, 14.03mmol) is added, is stirred at room temperature 12 hours.Reaction solution pours into 100mL ice water, it is extracted with ethyl acetate (50mL × 2), merge organic phase, successively uses water, saturated sodium chloride solution washing, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title compound 11b (2.5g, yield: 73.75%).

Second step

(4- (4- bromophenyl) tetrahydro -2H- pyrans -4- base) methylamine 11c

By crude Compound 11b (2.5g, it 9.39mmol) is dissolved in 100mL tetrahydrofuran, 1M borine tetrahydrofuran solution (28.18ml is added, 28.18mmol), return stirring is warming up to react 12 hours, reaction solution is cooled to room temperature, pH<2 are adjusted to 1M hydrochloric acid, it is warming up to reflux 1 hour, it is cooled to room temperature, reaction solution is concentrated under reduced pressure, residue pours into 200ml water, PH>9 are adjusted to 1M sodium hydroxide solution, it is extracted with ethyl acetate (200mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, obtain title compound 11c (2g, yield: 78.81%).

Third step N- ((4- (4- bromophenyl) tetrahydro -2H- pyrans -4- base) methyl) -2,2,2- trifluoroacetamide 11d

11c (2g, 7.40mmol) is dissolved in 100ml methylene chloride, is cooled to 0 DEG C, it is added triethylamine (2.25g, 22.21mmol), trifluoroacetic anhydride (2.02g is slowly added dropwise, 9.02mmol), it is warmed to room temperature and is stirred to react 12 hours.Reaction solution pours into 100mL water, layering, organic phase uses saturated sodium bicarbonate respectively, sodium chloride solution washing, anhydrous sodium sulfate dry, filter, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title compound 11d (2g, yield: 73.78%).

4th step

1- (7- bromo- 2', 3', 5', 6'- tetrahydro -1H- spiral shell [isoquinolin -4,4'- pyrans] -2 (3H)-yls) -2,2,2- trifluoroethanone 11e

By 11d (2g, 5.46mmol), it is dissolved in the in the mixed solvent of the prefabricated acetic acid of 50mL and sulfuric acid (V/V=2:3), is added paraformaldehyde (492mg, 16.39mmol), is stirred to react 12 hours.Reaction solution pours into 300mL ice water, it is extracted with ethyl acetate (100mL × 2), merge organic phase, successively uses water, saturated sodium bicarbonate solution and saturated sodium chloride solution washing, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title compound 11e (600mg, yield: 29.05%).

5th step

2- (2,2,2- trifluoroacetyl group) -2,2', 3,3', 5', 6'- hexahydro -1H- spiral shell [isoquinolin -4,4'- pyrans] -7- carboxylic acid, ethyl ester 11f

By compound 11e (600mg, 1.59mmol) it is dissolved in the in the mixed solvent of 20mL ethyl alcohol and dimethyl sulfoxide (V/V=1:1), it is added 1, bis- (diphenylphosphine) propane of 3- (130mg, 317.31 μm of ol), triethylamine (481mg, 4.76mmol) and palladium acetate (71mg, 317.71 μm of ol), under carbon monoxide atmosphere, it is warming up to 60 DEG C and is stirred to react 12 hours.Reaction solution is cooled to room temperature, it pours into 100mL water, it is extracted with ethyl acetate (100mL × 2), merges organic phase, washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title compound 11f (100mg, yield: 16.97%).

6th step

2,2', 3,3', 5', 6'- hexahydro -1H- spiral shell [isoquinolin -4,4'- pyrans] -7- carboxylic acid, ethyl ester 11g

11f (100mg, 269.29 μm of ol) is dissolved in the in the mixed solvent of 50mL second alcohol and water (V/V=1:1), is added potassium carbonate (111mg, 807.86 μm of ol), reaction 12 hours is stirred at room temperature.Reaction solution pours into 30mL water, it is extracted with ethyl acetate (50mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, it obtains crude title compound 11g (70mg), product directly carries out next step reaction without further purification.

7th step

2- (4- (trifluoromethyl) phenyl) -2,2', 3,3', 5', 6'- hexahydro -1H- spiral shell [isoquinolin -4,4'- pyrans] -7- carboxylic acid, ethyl ester 11h

By crude Compound 11g (50mg, 181.59 μm of ol) and 1- bromo- 4- (trifluoromethyl) benzene 1e (61mg, 272 μm of ol, using well known method " Organic Letters, 2014, 16 (16), 4268-4271 " is prepared) it is dissolved in 30mL 1, in 4- dioxane, cesium carbonate (177mg is added, 544.78 μm ol), 2- dicyclohexyl phosphorus -2, 4, 6- tri isopropyl biphenyl (8mg, 18.16 μm ol) and tris(dibenzylideneacetone) dipalladium (16mg, 18.16 μm ol), it is warming up under 90 DEG C of helium protections and is stirred to react 3 hours.Reaction solution is cooled to room temperature, it pours into 50mL water, it is extracted with ethyl acetate (50mL × 2), merges organic phase, washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title compound 11h (30mg, yield: 39.39%).

8th step

2- (4- (trifluoromethyl) phenyl) -2,2', 3,3', 5', 6'- hexahydro -1H- spiral shell [isoquinolin -4,4'- pyrans] -7- carboxylic acid 11i

Compound 11h (30mg, 71.52 μm of ol) is dissolved in the in the mixed solvent of 30mL second alcohol and water (V/V=5:1), is added sodium hydroxide (14mg, 357.62 μm of ol), return stirring is warming up to and reacts 2 hours.Reaction solution is cooled to room temperature, it is concentrated under reduced pressure, 1M hydrochloric acid is added dropwise in gained residue to pH < 2, is extracted with ethyl acetate (50mL × 2), merges organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, it obtains crude title compound 11i (30mg), product directly carries out next step reaction without further purification.

9th step

N- (4- (ethylsulfonyl) benzyl) -2- (4- (trifluoromethyl) phenyl) -2,2', 3,3', 5', 6'- hexahydro -1H- spiral shell [isoquinolin -4,4'- pyrans] -7- formamide 11

By crude Compound 11i (30mg; 76.65 μm of ol) and (4- (ethylsulfonyl) phenyl) methylamine 1h (18mg; 91.98 μm ol; it is prepared using method disclosed in patent application " WO2015017335 ") it is dissolved in 10mL N; in dinethylformamide; 2- (7- azo benzotriazole)-N is added; N; N'; N'- tetramethylurea hexafluorophosphoric acid ester (43mg; 114.98 μm of ol) and triethylamine (23mg, 229.95 μm of ol), it is stirred to react 12 hours.Reaction solution pours into 50mL water, it is extracted with ethyl acetate (50mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with high performance liquid chromatography purify gained residue, obtain title compound 11 (15mg, yield: 34.17%).

MS m/z(ESI):573.6[M+1]

¹H NMR (400MHz, DMSO-d ₆)δ9.11(s,1H),7.78-7.80(m,4H),7.53-7.62(m,5H),7.15-7.16(m,2H),4.53(s,4H),3.73-7.75(m,6H),2.04(m,2H),1.49-1.52(m,2H),1.20(m,2H),1.05(m,3H)。

Embodiment 12

N- (4- (ethylsulfonyl) benzyl) -2'- (5- (trifluoromethyl) pyridine -2- base) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- formamide 12

The first step

2'- (5- (trifluoromethyl) pyridine -2- base) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- carboxylic acid, ethyl ester 12b

By crude Compound 1d (500mg; 2.16mmol) and the chloro- 5- of 2- (trifluoromethyl) pyridine 12a (732mg; 3.24mmol) it is dissolved in 50mL1; in 4- dioxane; cesium carbonate (2.11g is added; 6.49mmol); 2- dicyclohexyl phosphorus -2; 4; 6- tri isopropyl biphenyl (103mg; 216.82 μm of ol) and tris(dibenzylideneacetone) dipalladium (197mg, 216.18 μm of ol), it is warming up under 90 DEG C of helium protections and is stirred to react 3 hours.Reaction solution is cooled to room temperature, it pours into 100mL water, it is extracted with ethyl acetate (100mL × 2), merges organic phase, washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title compound 12b (450mg, yield: 55.31%).

Second step

2'- (5- (trifluoromethyl) pyridine -2- base) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- carboxylic acid 12c

Compound 12b (1.5g, 3.99mmol) is dissolved in the in the mixed solvent of 60mL second alcohol and water (V/V=5:1), is added sodium hydroxide (797.12mg, 19.93mmol), return stirring is warming up to and reacts 2 hours.Reaction solution is cooled to room temperature, it is concentrated under reduced pressure, 1M hydrochloric acid is added dropwise in gained residue to pH < 2, is extracted with ethyl acetate (50mL × 2), merges organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, it obtains crude title compound 12c (1.3g), product directly carries out next step reaction without further purification.

Third step

N- (4- (ethylsulfonyl) benzyl) -2'- (5- (trifluoromethyl) pyridine -2- base) -2', 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- formamide 12

By crude Compound 12c (1g; 2.87mmol) and (4- (ethylsulfonyl) phenyl) methylamine 1h (858mg; 4.31 mmol; it is prepared using method disclosed in patent application " WO2015017335 ") it is dissolved in 30mL N; in dinethylformamide; 2- (7- azo benzotriazole)-N is added; N; N'; N'- tetramethylurea hexafluorophosphoric acid ester (1.64g; 4.31mmol) with triethylamine (871mg, 8.61mmol), it is stirred to react 12 hours.Reaction solution pours into 100mL water, it is extracted with ethyl acetate (100mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with high performance liquid chromatography purify gained residue, obtain title compound 12 (1g, yield: 65.77%).

MS m/z(ESI):530.4[M+1]

¹H NMR (400MHz, DMSO-d ₆) δ 9.12-9.15 (m, 1H), 8.43 (s, 1H), 7.81-7.86 (m, 4H), 7.71-7.73 (m, 1H), 7.57-7.59 (m, 2H), 7.07-7.09 (m, 1H), 6.97-6.99 (m, 1H), 4.99 (s, 2H), 4.58-4.59 (m, 2H), 3.83 (s, 2H), 3.24-3.30 (m, 2H), 1.07-1.11 (m, 7H).

Embodiment 13

(R)-N- (1- (5- (ethylsulfonyl) pyridine -2- base) -2- ethoxy) -2'- (4- (trifluoromethyl) phenyl) -2'; 3'- dihydro -1'H- spiral shell [cyclopropane -1,4'- isoquinolin] -7'- formamide 13

By crude Compound 1g (50mg; 143.96 μm of ol) and (R) -2- amino -2- (5- (ethylsulfonyl) pyridine -2- base) ethyl alcohol 13a (39mg; 172.75 μm of ol; it is prepared using method disclosed in patent application " WO2016061160 ") it is dissolved in 10mL N; in dinethylformamide; 2- (7- azo benzotriazole)-N is added; N; N'; N'- tetramethylurea hexafluorophosphoric acid ester (82mg; 215.93 μm of ol) and triethylamine (43mg, 431.87 μm of ol), it is stirred to react 12 hours.Reaction solution pours into 30mL water, it is extracted with ethyl acetate (30mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with high performance liquid chromatography purify gained residue, obtain title compound 13 (20mg, yield: 24.83%).

MS m/z(ESI):560.6[M+1]

¹H NMR (400MHz, DMSO-d ₆) δ 8.98 (s, 1H), 8.43 (s, 1H), 8.73-8.75 (m, 1H), 8.23-8.24 (m, 1H), 7.83 (s, 1H), 7.67-7.72 (m, 2H), 7.50-7.51 (m, 2H), 7.13-7.14 (m, 1H), 6.94-6.96 (m, 1H), 5.21 (s, 1H), 4.67 (s, 2H), 3.85-3.87 (m, 3H), 3.55 (s, 2H), 3.39-3.40 (m, 2H), 1.05-1.13 (m, 7H).

Embodiment 14

N- (4- (ethylsulfonyl) benzyl) -6'- (4- (trifluoromethyl) phenyl) -6', 7'- dihydro -5'H- spiral shell [cyclopropane -1,8'- [1,6] naphthyridines] -3'- formamide 14

The first step

3'- nitro -5'H- spiral shell [cyclopropane -1,8'- [1,6] naphthyridines] -6'(7'H)-carboxylic acid tert-butyl ester 14b

By compound 14a (600mg, 2.66mmol is prepared using method disclosed in patent application " WO2010114957 "), it is dissolved in 30ml 7M methanolic ammonia solution, compound 14b (530mg is added, 60 DEG C 2.66mmol) are warming up to, reaction is stirred overnight.Reaction solution be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title compound 14c (300mg, yield: 36.89%).

Second step

3'- amino -5'H- spiral shell [cyclopropane -1,8'- [1,6] naphthyridines] -6'(7'H)-t-butyl formate 14d

By compound 14c (300mg, 982.54 μm of ol) it is dissolved in the in the mixed solvent of 50ml second alcohol and water (V/V=2:1), iron powder (274mg is added, 4.90mmol), ammonium chloride (106mg, 1.96mmol), it is warming up to return stirring to react 3 hours, reaction solution is cooled to room temperature, reaction solution pours into 50ml water, it is extracted with methylene chloride (100mL × 2), merges organic phase, washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, obtains crude title compound 14d (270mg).

Third step

The bromo- 5'H- spiral shell of 3'- [cyclopropane -1,8'- [1,6] naphthyridines] -6'(7'H)-carboxylic acid tert-butyl ester 14e

14d (250mg, 907.95 μm of ol) is dissolved in 30ml acetonitrile, 0 DEG C is cooled to, isoamyl nitrite (212mg, 1.81mmol) is slowly added dropwise, finishes stirring 30 minutes, cuprous bromide is added, is warmed to room temperature and is stirred to react 12 hours.Reaction solution pours into 50mL water, it is extracted with ethyl acetate (50mL × 2), merge organic phase, successively uses water, saturated sodium bicarbonate solution and saturated sodium chloride solution washing, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title compound 14e (100mg, yield: 32.46%).

4th step

6'- (tert-butyl) 3'- ethyl 5'H- spiral shell [cyclopropane -1,8'- [1,6] naphthyridines] -3', 6'(7'H)-dicarboxylic ester 14f

By compound 14e (100mg, 294.78 μm of ol) it is dissolved in the in the mixed solvent of 20mL ethyl alcohol and dimethyl sulfoxide (V/V=1:1), it is added 1, bis- (diphenylphosphine) propane of 3- (25mg, 57.25 μm of ol), potassium carbonate (61mg, 442.03 μm of ol) and palladium acetate (6mg, 26.72 μm of ol), under carbon monoxide atmosphere, it is warming up to 60 DEG C and is stirred to react 12 hours.Reaction solution is cooled to room temperature, it pours into 30mL water, it is extracted with ethyl acetate (30mL × 2), merges organic phase, washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title compound 14f (80mg, yield: 81.64%).

5th step

6', 7'- dihydro -5'H- spiral shell [cyclopropane -1,8'- [1,6] naphthyridines] -3'- carboxylic acid, ethyl ester 14g

14f (80mg, 240.68 μm of ol) is dissolved in the in the mixed solvent of 20mL second alcohol and water (V/V=1:1), 4M methanol hydrochloride solution 5ml is added, reaction 12 hours is stirred at room temperature.Reaction solution liquid is concentrated under reduced pressure, residue is adjusted to PH > 8 with 1N NaOH solution, it is extracted with ethyl acetate (30mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression is concentrated to get crude title compound 14g (70mg), and product directly carries out next step reaction without further purification.

6th step

6'- (4- (trifluoromethyl) phenyl) -6', 7'- dihydro -5'H- spiral shell [cyclopropane -1,8'- [1,6] naphthyridines] -3'- carboxylic acid, ethyl ester 14h

By crude Compound 14g (70mg, 301.36 μm of ol) and 1- bromo- 4- (trifluoromethyl) benzene 1e (101mg, 448.87 μm of ol, using well known method " Organic Letters, 2014, 16 (16), 4268-4271 " is prepared) it is dissolved in 20mL 1, in 4- dioxane, cesium carbonate (294mg is added, 902.34 μm ol), 2- dicyclohexyl phosphorus -2, 4, 6- tri isopropyl biphenyl (14mg, 29.37 μm ol) and tris(dibenzylideneacetone) dipalladium (27mg, 29.48 μm ol), it is warming up under 90 DEG C of helium protections and is stirred to react 3 hours.Reaction solution is cooled to room temperature, it pours into 30mL water, it is extracted with ethyl acetate (30mL × 2), merges organic phase, washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title compound 14h (100mg, yield: 88.16%).

7th step

6'- (4- (trifluoromethyl) phenyl) -6', 7'- dihydro -5'H- spiral shell [cyclopropane -1,8'- [1,6] naphthyridines] -3'- carboxylic acid 14i

Compound 14h (100mg, 265.69 μm of ol) is dissolved in the in the mixed solvent of 20mL second alcohol and water (V/V=5:1), is added sodium hydroxide (53mg, 1.32mmol), return stirring is warming up to and reacts 2 hours.Reaction solution is cooled to room temperature, it is concentrated under reduced pressure, 1M hydrochloric acid is added dropwise in gained residue to pH < 2, is extracted with ethyl acetate (50mL × 2), merges organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, it obtains crude title compound 14i (80mg), product directly carries out next step reaction without further purification.

8th step

N- (4- (ethylsulfonyl) benzyl) -6'- (4- (trifluoromethyl) phenyl) -6', 7'- dihydro -5'H- spiral shell [cyclopropane -1,8'- [1,6] naphthyridines] -3'- formamide 14

By crude Compound 14i (80mg; 229.67 μm of ol) and (4- (ethylsulfonyl) phenyl) methylamine 1h (68mg; 341.24 μm of ol; it is prepared using method disclosed in patent application " WO2015017335 ") it is dissolved in 10mL N; in dinethylformamide; 2- (7- azo benzotriazole)-N is added; N; N'; N'- tetramethylurea hexafluorophosphoric acid ester (130mg; 342.10 μm of ol) and triethylamine (69mg, 681.88 μm of ol), it is stirred to react 12 hours.Reaction solution pours into 30mL water, it is extracted with ethyl acetate (30mL × 2), merge organic phase, it is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with high performance liquid chromatography purify gained residue, obtain title compound 14 (30mg, yield: 24.66%).

MS m/z(ESI):530.2[M+1]

¹H NMR (400MHz, DMSO-d ₆) δ 9.27-9.29 (m, 1H), 8.81-8.82 (m, 1H), 8.09-8.10 (m, 1H), 7.84-7.86 (m, 2H), 7.58-7.60 (m, 2H), 7.51-7.53 (m, 2H), 7.18-7.21 (m, 2H), 4.73 (s, 2H) 4.60-4.61 (m, 2H), 3.74 (s, 2H), 3.25-3.30 (m, 2H), 1.26-1.28 (m, 2H), 1.07-1.09 (m, 5H).

Biological assessment

The explanation present invention is further described below in conjunction with test case, but these embodiments are in no way meant to be limiting for the scope of the invention.

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

Adjusting using LanthaScreen TR-FRET (time-resolved fluorescence resonance energy transfer) ROR γ co-activation System For Screening the compound of the present invention to ROR gamma activity.

Preparing complete buffer D (complete TR-FRET Coregulator) (Life Technologies) first includes final concentration 5mM DTT.DMSO final concentration of 2%.By untested compound, serial dilution is 2x final concentration, maximum dose level be 60 μm in the complete buffer D containing 2%DMSO.The test hole (PerkinElmer) of 384 orifice plates is added in 10 holes μ l/.2 parallel control holes are arranged in each detection compound under same concentrations.Prepare 4X ROR γ LBD (AB Vector).It the use of complete 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 the complete buffer D of 5 μ L, no ROR γ LBD.Anti-GST antibody (4X) (Life Technologies) mixed liquor marked containing 0.6 μM of fluorescein-D22 (4X) and 8nM terbium (Tb) is prepared using liquid D is completely buffered, 5 μ L mixed liquors are added in 384 orifice plates.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.

The IC of untested compound is calculated by the ratio of 6.0 Software on Drawing launch wavelength 520nm/495nm of GraphPad Prism and the logarithmic curve of compound concentration using Tecan Infinite M1000 detection fluorescence reading ₅₀/EC ₅₀Value.

The compounds of this invention is measured ROR γ external activity by above test, the IC measured ₅₀/EC ₅₀Value is shown in Table 1.

IC of 1 the compounds of this invention of table to ROR γ external activity ₅₀/EC ₅₀Value

A: if it is inhibitor, numerical marker IC ₅₀；If it is agonist, numerical marker EC ₅₀。

Conclusion: the compounds of this invention has apparent adjustment effect to ROR γ external activity, the change that A ring substituents in logical formula (I) compound represented are shown in experimental result shows different mechanism to the adjusting of ROR γ external activity, when there is lesser substituent group (such as: hydrogen atom) at the ortho position of ring A, show the effect inhibited (see Examples 1 to 7 and embodiment 9~14 etc.), when there is biggish substituent group (such as: trifluoromethyl) at the ortho position of ring A, show the effect of excitement (see embodiment 8).

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.CO ₂Incubator (Fisher Scientific)

7. centrifuge (Fisher Scientific)

8.96 porocyte culture plates (Fisher Scientific)

9. microplate reader (Tecan)

Two, experimental procedure

By the human peripheral blood mononuclear cell frozen (PBMC), rapid fluid resuscitation, centrifugation 1000rpm, 10min remove cells and supernatant, cell are gently suspended in TexMACS culture medium, count cell in the lymphocytes culture medium of preheating.T cell activation reagent cytostim (10 μ l/ml) is proportionally added into cell suspension, then with 1 × 105 peripheral blood mononuclear cells/hole density by cell seeding in 96 porocyte culture plates.It using TexMACS culture medium gradient dilution untested compound, is separately added into 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 collects cell culture supernatant after 3 days, oil removal is removed in centrifugation.Then IL-17A in supernatant is quantified using IL-17A enzyme linked immunological kit.The IC of untested compound is calculated using GraphPad Prism 6.0 ₅₀/EC ₅₀Value.

The compounds of this invention is measured the quantitative analysis of IL-17A enzyme linked immunological by above test, the IC measured ₅₀Value is shown in Table 2.

IC of 2 the compounds of this invention of table to IL-17A enzyme linked immunological quantitative analysis ₅₀Value

Embodiment number	IC 50(nM)
1	22
2	28
3	18
4	291
5	297
9	289
10	59
12	45
13	134

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

Claims (25)

1. A kind of general formula (AI) compound represented:

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

   Wherein:

   W ¹、W ²And W ³It is identical or different, and it is each independently CH or N；

   Ring A and ring B are identical or different, and are each independently selected from naphthenic base, heterocycle, aryl and heteroaryl；

   Ring C is naphthenic base or heterocycle；

   R ¹It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl, wherein alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

   R ²It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl, heteroaryl ,-OR ⁴、-C(O)R ⁴、-C(O)OR ⁴With-S (O) _mR ⁴；

   R ³Selected from hydrogen atom, halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl, wherein alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in hydroxyl, halogen, alkyl, halogenated alkyl, cyano, amino, nitro, alkoxy, halogenated alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

   R ⁴Selected from hydrogen atom, alkyl, naphthenic base, halogenated alkyl, alkoxy, halogenated alkoxy, heterocycle, aryl and heteroaryl, wherein alkyl, naphthenic base, halogenated alkyl, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in hydroxyl, halogen, alkyl, halogenated alkyl, cyano, amino, nitro, alkoxy, halogenated alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

   M is 0,1 or 2；

   S is 0,1,2,3 or 4；And

   T is 0,1,2,3 or 4.
2. General formula (AI) compound represented according to claim 1, middle ring C are C _3-6Naphthenic base or 3 to 6 yuan of heterocycle, wherein the heterocycle contains 1~3 hetero atom for being selected from N, O or S；It is preferably selected from cyclopropyl, cyclobutyl, cyclopenta or THP trtrahydropyranyl.
3. General formula (AI) compound represented according to claim 1, to lead to formula (I) compound represented:

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

   Wherein:

   N is 1,2 or 3；

   Ring A, ring B, R ¹~R ³, s and t it is as defined in claim 1.
4. Logical formula (I) compound represented according to claim 3, to lead to formula (II) compound represented:

   Wherein:

   Ring A, ring B, R ¹~R ³, s and t it is as defined in claim 3.
5. Compound according to any one of claims 1 to 4, middle ring A are selected from phenyl, pyridyl group, pyrimidine radicals, cyclohexyl and piperidyl.
6. Logical formula (I) compound represented according to claim 3 or 4, to lead to formula (III) compound represented:

   Wherein:

   G ¹And G ²It is identical or different, and it is each independently CH or N；

   Ring B, R ¹~R ³It is as defined in claim 3 with t.
7. Logical formula (I) compound represented according to claim 3 or 4, to lead to formula (IV) compound represented:

   Wherein:

   R ^bSelected from alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl, wherein alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in halogen, hydroxyl, alkyl, halogenated alkyl, cyano, amino, nitro, alkoxy, halogenated alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

   P is 0,1,2 or 3；

   Ring B, R ¹~R ³It is as defined in claim 3 with t.
8. Compound according to any one of claims 1 to 7, middle ring B are selected from phenyl, pyridyl group, pyrimidine radicals, cyclohexyl and piperidyl.
9. Compound described according to claim 1~any one of 8, wherein R ²For-S (O) _mR ⁴；M is 2；And R ⁴For alkyl.
10. Logical formula (III) compound represented according to claim 6 is general formula (III-A) compound represented:

    Wherein:

    R ⁴For alkyl；

    R ¹And R ³As defined in claim 6.
11. Logical formula (IV) compound represented according to claim 7 is general formula (IV-A) compound represented:

    Wherein:

    R ^bSelected from alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl, wherein alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in halogen, hydroxyl, alkyl, halogenated alkyl, cyano, amino, nitro, alkoxy, halogenated alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

    R ⁴For alkyl；

    P is 0,1,2 or 3；

    R ¹And R ³As defined in claim 1.
12. The logical formula (I) compound represented according to any one of claim 7 or 11, wherein R ^bFor halogenated alkyl.
13. General formula described according to claim 1~any one of 12 (AI) compound represented, wherein R ¹For halogenated alkyl.
14. General formula described according to claim 1~any one of 13 (AI) compound represented, wherein R ³For hydrogen atom, alkyl or hydroxyalkyl.
15. According to claim 1, compound described in~any one of 14, be selected from:
16. Compound shown in a kind of general formula (AI-A):

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

    Wherein:

    Ring A, ring C, W ¹、W ²、W ³、R ¹It is as defined in claim 1 with s.
17. General formula (AI-A) compound represented according to claim 16 is compound shown in general formula (I-A):

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

    Wherein:

    Ring A, R ¹, s and n it is as defined in claim 16.
18. General formula (AI-A) compound represented according to claim 16 or 17, is selected from
19. A method of general formula according to claim 1 (AI) compound is prepared, this method comprises:

    Condensation reaction occurs for general formula (AI-A) compound and general formula (I-B) compound, obtains general formula (AI) compound；

    Wherein:

    Ring A, ring B, ring C, W ¹、W ²、W ³、R ¹~R ³, s and t it is as defined in claim 1.
20. A method of logical formula (I) compound according to claim 3 is prepared, this method comprises:

    Condensation reaction occurs for general formula (I-A) compound and general formula (I-B) compound, obtains logical formula (I) compound；

    Wherein:

    Ring A, ring B, R ¹~R ³, n, s and t it is as defined in claim 1.
21. A kind of pharmaceutical composition, containing therapeutically effective amount according to claim 1~any one of 15 described in logical formula (I) compound represented and one or more pharmaceutically acceptable carriers, diluent or excipient.
22. According to claim 1, logical formula (I) compound represented or pharmaceutical composition according to claim 21 described in~any one of 15 preparing the purposes in ROR regulator.
23. Purposes of the logical formula (I) compound represented or pharmaceutical composition according to claim 21 described according to claim 1~any one of 15 in drug of the preparation for prevention and or treatment inflammation, autoimmune disease, tumour or cancer.
24. According to claim 1, logical formula (I) compound represented or pharmaceutical composition according to claim 21 described in~any one of 15 as ROR inhibitor in preparation for the purposes in the drug of prevention and or treatment inflammation or autoimmune disease, the inflammation or autoimmune disease is selected from asthma, atopic dermatitis, contact dermatitis, acne, bronchitis, Crohn's disease, regional enteritis, inflammatory enteropathy (IBD), ulcerative colitis, allograft rejection reaction, Xiu Gelian syndrome, uveitis, white Sai Shi disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelities, systemic lupus erythematosus disease (SLE), chorionitis, pancreatitis, psoriasis, arthritic psoriasis (PsA), rheumatoid arthritis, arthritis, Osteoarthritis, allergic rhinitis, autoimmune diabetes and autoimmune thyroid disease.
25. According to claim 1, logical formula (I) compound represented or pharmaceutical composition according to claim 21 described in~any one of 15 preparing the purposes in the drug for preventing and/or treating tumour or cancer as ROR agonist, the tumour or cancer is selected from 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, IV phase melanoma, solid tumor, glioma, spongioblastoma, hepatocellular carcinoma, the renal tumor of mastoid process, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small cell lung cancer.