CN109232533A - Nitrogen heterocycles derivative, preparation method and its medical usage - Google Patents

Abstract

The present invention relates to a kind of nitrogen heterocycles derivative, preparation method and its medical usages.Particularly, the present invention relates to nitrogen heterocycles derivative, preparation method shown in logical formula (I), contain the pharmaceutical composition of the derivative, as well as SMO antagonist, especially treating the purposes in disorders such as cancers relevant to Hedgehog signal path.Definition is the same as that in the specification for each group in its formula of (I).

Description

Nitrogen heterocycles derivative, preparation method and its medical usage

Technical field

The present invention relates to a kind of new nitrogen heterocycles derivative, preparation method contains its pharmaceutical composition, Yi Jiqi As the purposes of SMO antagonist, especially the purposes in disorders such as cancers relevant to Hedgehog signal path is being treated.

Background technique

Hedgehog (Hh) signal path is important embryo's access, cell proliferation during embryonic development With important regulating and controlling effect is played in differentiation.There are three types of the homologous Hedgehog albumen that the mankind have identified, and is respectively Sonic hedgehog (Shh), Indian hedgehog (Ihh) and Desert hedgehog (Dhh).Many evidences are shown Shh is also played a very important role on the carcinogenic mechanism of certain cancers including basal cell carcinoma cells etc..Hh signal by with G egg Relevant seven transmembrane protein Smoothened (SMO) conduction of white coupled receptor.In adult body, Hh signal path is typically in Closed state, but the abnormal activation of Hh signal path plays the important and pivotal role in the occurrence and development of tumour.Substrate Mostly variation occurs on PTCH-1 and SMO as the result is shown for the analysis of variance of cancer cell Hh information channel.PTCH-1 is that have The memebrane protein of 12 transmembrane structures, it is the direct action receptor of Shh.In normal circumstances, the intracorporal Hedgehog of people The concentration of albumen is very low, and in this case, PTCH-1 and SMO phase separation inhibit the bioactivity of SMO, make at the channel In closed state.Once Shh in conjunction with PTCH-1, will lead to PTCH-1 and be detached from SMO, so that SMO is made to get rid of suppressed state, The activation of SMO can further induce the activation of the transcription factor Gli (including Gli1, Gli2 and Gli3) in downstream, to regulate and control base The transcription of cause and the growth of cell.Therefore, SMO plays a part of switch to Gli.The excessive of cell will be induced by upsetting its effect Growth and canceration.For example most basal-cell carcinoma is all excessively high as caused by gene mutation or other reasons Hedgehog Information Conduction channel vigor.Therefore the vigor of excessively high Hedgehog Information Conduction access is inhibited to be able to suppress cancer thin The growth of born of the same parents is to reach treatment kinds cancer as caused by the mechanism.

In recent years, the research of Hedgehog access receives scientific circles and more and more payes attention to, and targets Hh access especially It is that the micromolecular inhibitor of novel target spot g protein coupled receptor Smoothened (SMO) has become drugmaker and scientific research institution Research hotspot.Wherein Hedgehog access antagonist Vismodegib (GDC-0449) and Sonidegib (LDE225) difference Ratified to list by Food and Drug Administration (FDA) in 2012 and 2015, for treating adult patients with basal cell carcinomas. These antagonists inhibit the activity of SMO, also may refrain from Hh signal path vigor, to have the function that anticancer.In addition to base Two kinds of cancers of floor cells cancer and pith mother cells cancer, many other cancers is also related with Hh Information Conduction access abnormal activation, packet Include the cancer of the esophagus, gastric cancer, cancer of pancreas, lung cancer etc..Moreover, more and more researches show that the activity of Hh signal path with it is current The acquired resistance problem perplexed in various treatments of cancer is closely related.Such as the increasing of SMO gene extends to the activation of its Hh access It is considered as the main original for enabling Cell Epidermal Growth Factor receptor (EGFR) inhibitor for the treatment of non-small cell lung cancer lose curative effect One of because.Therefore research and development Hedgehog inhibitor is especially treated with other antiradiation drug drug combinations each as anticancer drug Kind cancer prospect is very extensive.

Summary of the invention

For the present inventor by concentrating on studies, design has synthesized a series of nitrogen-containing hetero cyclics, is deeply ground to it Such compound as the result is shown studied carefully antagonism SMO and then can inhibit Hedgehog signal path, and can be developed as control Treat the drug of disease relevant to Hedgehog signal path.

Therefore, the present invention relates to a kind of formula (I) compound represented or its mesomer, racemic modification, enantiomter, Diastereoisomer, or mixtures thereof form or its officinal salt,

Wherein:

A₀、A₁、A₂、A₃It is each independently selected from CR²Or N；

A₄And A₅It is each independently selected from C or N；

Q、V、U₀It is each independently selected from C or N；

R、W、U₁、U₂、U₃、U₄It is each independently selected from CR³Or N；

Ar is selected from aryl or heteroaryl, preferably 5 to 6 yuan of aryl or heteroaryl, more preferable phenyl, pyridyl group, pyrimidine radicals, pyrrole Piperazine base, pyridazinyl；The aryl or heteroaryl are optionally further selected from halogen, amino, hydroxyl, alkyl, alkoxy, naphthenic base One or more groups replace；

Each R¹Independently selected from hydrogen, halogen, oxo base, alkyl, naphthenic base ,-OR^a；

R²Selected from hydrogen, halogen, amino, nitro, cyano, sulfydryl, oxo base, alkyl, naphthenic base, heterocycle, aryl, heteroaryl Base ,-OR^a、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NHC(O)R^a、-NR^aR^b、-S(O)R^a、-S(O)₂R^a、-S (O)NR^aR^b、-S(O)₂NR^aR^b、-NHS(O)R^a、-NHS(O)₂R^a、-P(O)R^aR^b、-B(OH)₂；Wherein the alkyl, naphthenic base, Heterocycle, aryl, heteroaryl optionally further by selected from halogen, amino, nitro, cyano, oxo base, hydroxyl, sulfydryl, carboxyl, One or more groups substitution of alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl, heteroaryl；

R³Selected from hydrogen, halogen, amino, nitro, cyano, sulfydryl, oxo base, alkyl, naphthenic base, heterocycle, aryl, heteroaryl Base ,-OR^a、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NHC(O)R^a、-NR^aR^b、-S(O)R^a、-S(O)₂R^a、-S (O)NR^aR^b、-S(O)₂NR^aR^b、-NHS(O)R^a、-NHS(O)₂R^a、-P(O)R^aR^b、-B(OH)₂；Wherein the alkyl, naphthenic base, Heterocycle, aryl, heteroaryl optionally further by selected from halogen, amino, nitro, cyano, oxo base, hydroxyl, sulfydryl, carboxyl, One or more groups substitution of alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl, heteroaryl；

R^aAnd R^bIt is each independently selected from hydrogen, halogen, hydroxyl, alkyl, naphthenic base, heterocycle, aryl, heteroaryl, wherein institute Alkyl, naphthenic base, heterocycle, aryl and heteroaryl are stated optionally further by selected from halogen, amino, nitro, cyano, hydroxyl, mercapto Base, carboxyl, ester group, oxo base, alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl, one or more of heteroaryl A group replaces；

Or R^aAnd R^bThe nitrogen-atoms connecting with them is formed together nitrogen heterocycle, and the nitrogen heterocycle is optionally into one Step by selected from halogen, amino, nitro, cyano, oxo base, hydroxyl, sulfydryl, carboxyl, ester group, alkyl, alkoxy, alkenyl, alkynyl, One or more groups substitution of naphthenic base, heterocycle, aryl, heteroaryl；

N is integer of 1 to 3；

I is 1 or 2；

J is 1 or 2；

Wherein, leading to each of formula (I) compound H atom can optionally independently be substituted by D atom.

In a preferred embodiment of the present invention, logical formula (I) compound represented according to the present invention or its Mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt, wherein A₄ And A₅It is each independently selected from C.

In another preferred embodiment of the present invention, logical formula (I) compound represented according to the present invention or Its mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt,

Wherein: A₀、A₁、A₂、A₃It is each independently selected from CR²；

R²As defined in logical formula (I).

In another preferred embodiment of the present invention, logical formula (I) compound represented according to the present invention or Its mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt,

Wherein: U₁、U₂、U₃、U₄It is each independently selected from CR³；

R³As defined in logical formula (I).

In another preferred embodiment of the present invention, logical formula (I) compound represented according to the present invention or Its mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt, be It is logical formula (II), (III), (IV) or (V) compound represented or its mesomer, racemic modification, enantiomter, diastereomeric different Structure body, or mixtures thereof form or its officinal salt,

Wherein,

The integer that m is 1 to 4；

The integer that q is 1 to 4；

R^3aAnd R^3bBe each independently selected from hydrogen, halogen, amino, nitro, cyano, sulfydryl, oxo base, alkyl, naphthenic base, Heterocycle, aryl, heteroaryl ,-OR^a、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NHC(O)R^a、-NR^aR^b、-S (O)R^a、-S(O)₂R^a、-S(O)NR^aR^b、-S(O)₂NR^aR^b、-NHS(O)R^a、-NHS(O)₂R^a；The wherein alkyl, naphthenic base, miscellaneous Ring group, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, oxo base, hydroxyl, sulfydryl, carboxyl, alkane One or more groups substitution of base, alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl, heteroaryl；

R^aAnd R^bIt is each independently selected from hydrogen, halogen, hydroxyl, alkyl, naphthenic base, heterocycle, aryl, heteroaryl, wherein institute Alkyl, naphthenic base, heterocycle, aryl and heteroaryl are stated optionally further by selected from halogen, amino, nitro, cyano, hydroxyl, mercapto Base, carboxyl, ester group, oxo base, alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl, one or more of heteroaryl A group replaces；

Or R^aAnd R^bThe nitrogen-atoms connecting with them is formed together nitrogen heterocycle, and the nitrogen heterocycle is optionally into one Step by selected from halogen, amino, nitro, cyano, oxo base, hydroxyl, sulfydryl, carboxyl, ester group, alkyl, alkoxy, alkenyl, alkynyl, One or more groups substitution of naphthenic base, heterocycle, aryl, heteroaryl；

I is 1 and j is 2；Or

I is 2 and j is 1；

Ar、R¹、R², n is as defined in logical formula (I).

In another preferred embodiment of the present invention, logical formula (I) compound represented according to the present invention or Its mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt, be It is logical formula (II), (III), (IV) or (V) compound represented or its mesomer, racemic modification, enantiomter, diastereomeric different Structure body, or mixtures thereof form or its officinal salt, wherein Ar is aryl, preferably phenyl.

In another preferred embodiment of the present invention, logical formula (I) compound represented according to the present invention or Its mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt, be It is logical formula (II), (III), (IV) or (V) compound represented or its mesomer, racemic modification, enantiomter, diastereomeric different Structure body, or mixtures thereof form or its officinal salt, wherein Ar is heteroaryl, preferably pyridyl group.

In another preferred embodiment of the present invention, logical formula (I) compound represented according to the present invention or Its mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt, be It is logical formula (VI), (VII), (VIII) or (IX) compound represented or its mesomer, racemic modification, enantiomter, non-right Reflect isomers, or mixtures thereof form or its officinal salt,

Wherein,

The integer that m is 1 to 4；

The integer that p is 1 to 4；

The integer that q is 1 to 4；

R^3aAnd R^3bIt is each independently selected from hydrogen, halogen, amino, nitro, cyano, sulfydryl, oxo Base, alkyl, naphthenic base, heterocycle, aryl, heteroaryl ,-OR^a、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、- NHC(O)R^a、-NR^aR^b、-S(O)R^a、-S(O)₂R^a、-S(O)NR^aR^b、-S(O)₂NR^aR^b、-NHS(O)R^a、-NHS(O)₂R^a；Wherein The alkyl, naphthenic base, heterocycle, aryl, heteroaryl optionally further by selected from halogen, amino, nitro, cyano, oxo base, Hydroxyl, sulfydryl, carboxyl, alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl, heteroaryl one or more bases Group replaces；

R^aAnd R^bIt is each independently selected from hydrogen, halogen, hydroxyl, alkyl, naphthenic base, heterocycle, aryl, heteroaryl, wherein institute Alkyl, naphthenic base, heterocycle, aryl and heteroaryl are stated optionally further by selected from halogen, amino, nitro, cyano, hydroxyl, mercapto Base, carboxyl, ester group, oxo base, alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl, one or more of heteroaryl A group replaces；

Or R^aAnd R^bThe nitrogen-atoms connecting with them is formed together nitrogen heterocycle, and the nitrogen heterocycle is optionally into one Step by selected from halogen, amino, nitro, cyano, oxo base, hydroxyl, sulfydryl, carboxyl, ester group, alkyl, alkoxy, alkenyl, alkynyl, One or more groups substitution of naphthenic base, heterocycle, aryl, heteroaryl；

R⁴Selected from halogen, amino, hydroxyl, alkyl, alkoxy, naphthenic base；

R¹、R², n is as defined in logical formula (I).

In another preferred embodiment of the present invention, logical formula (I) compound represented according to the present invention or Its mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt, be It is logical formula (VI), (VII), (VIII) or (IX) compound represented or its mesomer, racemic modification, enantiomter, non-right Reflect isomers, or mixtures thereof form or its officinal salt,

Wherein:

R¹Selected from hydrogen, halogen, alkyl, naphthenic base ,-OR^a；

R^aSelected from hydrogen, alkyl, naphthenic base.

In another preferred embodiment of the present invention, logical formula (I) compound represented according to the present invention or Its mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt, be It is logical formula (VI), (VII), (VIII) or (IX) compound represented or its mesomer, racemic modification, enantiomter, non-right Reflect isomers, or mixtures thereof form or its officinal salt,

Wherein, R²Selected from hydrogen, halogen, alkyl, naphthenic base, heterocycle ,-OR^a、-C(O)R^a、-C(O)NR^aR^b、-NHC(O) R^a、-NR^aR^b、-S(O)R^a、-S(O)₂R^a、-P(O)R^aR^b、-B(OH)₂；Wherein the alkyl, naphthenic base, heterocycle are optionally into one Step is replaced by one or more groups selected from halogen, hydroxyl, sulfydryl, cyano, carboxyl, alkyl, alkoxy；

R^aAnd R^bIt is each independently selected from hydrogen, halogen, alkyl, naphthenic base, heterocycle, wherein the alkyl, naphthenic base, miscellaneous Ring group is optionally further replaced by one or more groups selected from halogen, hydroxyl, sulfydryl, carboxyl, ester group, oxo base；

Or R^aAnd R^bThe nitrogen-atoms connecting with them is formed together nitrogen heterocycle, preferably nitrogenous 4~7 member heterocyclic ring containing nitrogen Base, the nitrogen heterocycle optionally further by selected from halogen, hydroxyl, sulfydryl, carboxyl, ester group, alkyl, alkoxy, naphthenic base, One or more groups of heterocycle replace；

Preferably, R²It independently is:

In another preferred embodiment of the present invention, logical formula (I) compound represented according to the present invention or Its mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt, be It is logical formula (VI), (VII), (VIII) or (IX) compound represented or its mesomer, racemic modification, enantiomter, non-right Reflect isomers, or mixtures thereof form or its officinal salt,

Wherein: R^3aAnd R^3bIt is each independently selected from hydrogen, halogen, alkyl, naphthenic base, heterocycle ,-OR^a；It is preferred that R^3aFor hydrogen And R^3bFor alkyl；

R^aSelected from hydrogen, alkyl, naphthenic base.

The typical compound of the present invention includes but is not limited to following compound:

Or its mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its can medicine Use salt.

It is different that another aspect of the present invention provides a kind of logical formula (I) compound represented or its mesomer, racemic modification, mapping Structure body, diastereoisomer, or mixtures thereof form or its officinal salt preparation method, it includes following steps:

Formula (IA) compound and formula (IB) compound in the presence of metal palladium catalyst, are heated under alkaline condition, By Buckwald amination coupling reaction, logical formula (I) compound is obtained；

Wherein, the preferred Pd of the metal palladium catalyst₂(dba)₃/ BINAP or Pd (dppf)₂Cl₂；The alkali is preferred Cs₂CO₃；Preferably 100~120 DEG C of heating temperature；

Wherein,

X is halogen, preferably Br；

Ar、A₀、A₁、A₂、A₃、A₄、A₅、Q、W、V、R、U₀、U₁、U₂、U₃、U₄、R¹, such as logical formula (I) of n, i, j defines.

Another aspect of the present invention provides a kind of logical formula (II), (III), (IV) or (V) compound represented or its meso Body, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt preparation method, It comprises the steps of:

By formula (IA ") compound and formula (IIB), (IIIB), (IVB) or (VB) compound depositing in metal palladium catalyst It under, heats under alkaline condition, by Buckwald amination coupling reaction, obtains logical formula (II), (III), (IV) or (V) Compound；

Wherein, the preferred Pd of the metal palladium catalyst₂(dba)₃/ BINAP or Pd (dppf)₂Cl₂；The alkali is preferred Cs₂CO₃；Preferably 100~120 DEG C of heating temperature；

X is halogen, preferably Br；

Ar、R¹、R²、R^3a、R^3b, m, n, q, i, j be as defined in logical formula (II), (III), (IV) or (V).

Another aspect of the present invention provide a kind of logical formula (VI), (VII), (VIII) or (IX) compound represented or its in disappear Revolve body, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt preparation method, It includes following steps:

By formula (IA ') compound and formula (VIB), (VIIB), (VIIIB) or (IXB) compound in metal palladium catalyst In the presence of, it heats under alkaline condition, by Buckwald amination coupling reaction, obtains logical formula (VI), (VII), (VIII) Or (IX) compound；

Wherein, the preferred Pd of the metal palladium catalyst₂(dba)₃/ BINAP or Pd (dppf)₂Cl₂；The alkali is preferred Cs₂CO₃；Preferably 100~120 DEG C of heating temperature；

X is halogen, preferably Br；

R¹、R²、R^3a、R^3b、R⁴, such as logical formula (VI) of m, n, p, q, (VII), (VIII) or (IX) define.

Another aspect of the present invention provides a kind of pharmaceutical composition, containing shown in logical formula (I) according to the present invention Compound or its mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its is pharmaceutically acceptable Salt and one or more pharmaceutically acceptable carriers, diluent or excipient.Described pharmaceutical composition can also be further Containing another therapeutic activity ingredient, the another kind therapeutic activity ingredient is preferably the drug for the treatment of cancer, and the cancer is excellent Select the carcinoma of the rectum, cancer of pancreas, breast cancer, prostate cancer, cancer of the esophagus, gastric cancer, leukemia, lung cancer, the cancer of the brain, cutaneum carcinoma, head and neck cancer, ovary Cancer, bladder cancer and kidney, more preferable lung cancer, breast cancer, cancer of pancreas and gastric cancer.

The invention further relates to a kind of methods for preparing above-mentioned composition comprising by logical formula (I) compound represented or its Mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form, its prodrug or its officinal salt with Pharmaceutically acceptable carrier, diluent or excipient mix.

Another aspect of the present invention provides logical formula (I) compound represented according to the present invention or its mesomer, outer Raceme, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt, or the pharmaceutical composition comprising it Object is preparing the purposes in SMO antagonist.

Another aspect of the present invention provides logical formula (I) compound represented according to the present invention or its mesomer, outer Raceme, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt, or the pharmaceutical composition comprising it Object, the purposes in the drug that disease relevant to Hedgehog signal path is treated in preparation.It is described logical with Hedgehog signal The relevant disease in road be selected from cancer, the cancer can be the carcinoma of the rectum, cancer of pancreas, breast cancer, prostate cancer, cancer of the esophagus, gastric cancer, Leukemia, lung cancer, the cancer of the brain, cutaneum carcinoma, head and neck cancer, oophoroma, bladder cancer or kidney, preferably leukemia, lung cancer, breast cancer, cancer of pancreas And gastric cancer.

Another aspect of the present invention provides logical formula (I) compound represented according to the present invention or its mesomer, outer Raceme, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt and another therapeutic activity at Divide joint, the purposes in the drug of preparation treating cancer, wherein shown in the another kind therapeutic activity ingredient and logical formula (I) Compound simultaneously, separately or sequentially with；The another kind therapeutic activity ingredient is preferably the drug for the treatment of cancer；The cancer It is preferred that the carcinoma of the rectum, cancer of pancreas, breast cancer, prostate cancer, cancer of the esophagus, gastric cancer, leukemia, lung cancer, the cancer of the brain, cutaneum carcinoma, head and neck cancer, ovum Nest cancer, bladder cancer and kidney, more preferable leukemia, lung cancer, breast cancer, cancer of pancreas and gastric cancer.

According to conventional method of the art, the present invention, which leads to formula (I) compound represented, can generate medicine with acid Acceptable acid addition salt on.The acid includes inorganic acid and organic acid, and acceptable inorganic acid includes hydrochloric acid, hydrogen bromine Acid, sulfuric acid, phosphoric acid etc., acceptable organic acid include methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, naphthalenedisulfonic acid, Acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid etc..

The present invention, which leads to formula (I) compound represented, can generate pharmaceutically acceptable alkali formula addition salts with alkali.The alkali Including inorganic base and organic base, acceptable organic base includes diethanol amine, ethanol amine, N-METHYL-ALPHA-L-GLUCOSAMINE, triethanolamine, ammonia Butantriol etc., acceptable inorganic base include aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide etc..

Pharmaceutical composition of the invention includes that (or its is pharmaceutically acceptable for any one or more compound of the present invention Salt, solvate, hydrate, prodrug or derivative) and optionally include pharmaceutically acceptable carrier.In certain embodiment party In case, these compositions optionally further include one or more other treatment drugs.Optionally, the compound of the present invention can combine One or more other treatment drugs, to the patient's application for having this demand.It will further be understood that certain compounds of the invention can With in a free form, or where appropriate, exist in the form of its officinal salt for treating.

As described above, pharmaceutical composition of the invention further includes pharmaceutically acceptable carrier.Herein, the carrier Including any or all solvent, diluent or other liquid-carriers, dispersion or suspension adjuvant, surfactant, isotonic agent, Thickening or emulsifier, preservative, solid binder, lubricant etc., are adjusted to required given dose form.Remington' S Pharmaceutical Sciences, Sixteenth Edition, E.W.Martin (Mack Publishing Co., Easton, Pa., 1980) disclose the various carriers for compounding pharmaceutical composition, and the known technology for its preparation. Unless any conventional carrier medium is incompatible with the compound of the present invention, for example, by generate any undesirable biological effect or Any other of person and pharmaceutical composition ingredient interact in harmful manner, and otherwise its purposes is estimated belongs to the scope of the invention It is interior.The some examples that can be used as the material of pharmaceutically acceptable carrier include but is not limited to: sugared such as lactose, glucose and Sucrose；Starch such as cornstarch and potato starch；Cellulose and its derivates such as sodium carboxymethylcellulose, ethyl cellulose Element and cellulose acetate；Powdered gum tragacanth；Maltose；Gelatin；Talcum powder；Excipient such as cocoa butter and suppository wax；Oil is for example Peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil；Di-alcohols such as propylene glycol；Ester is for example oily Acetoacetic ester and ethyl laurate；Agar；Buffer such as magnesium hydroxide and aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt Water；Ringer's solution (Ringer ' s solution)；Ethyl alcohol and phosphate buffer solution；And other nontoxic compatible lubrications Agent such as lauryl sodium sulfate and magnesium stearate；And the judgement according to makers-up, colorant also may be present in composition, release Put agent, coating agent, sweetener, flavoring agent and aromatic, preservative and antioxidant.

The compounds of this invention can be applied to patient by various administration routes.These administration routes include but is not limited to: Oral, sublingual administration, subcutaneous injection, intravenous injection, collunarium, surface smearing, skin infiltration, intraperitoneal administration, intramuscular injection, lung Administration etc..

Pharmaceutical composition containing active constituent can be the form of solid, semisolid, liquid and aerosol, for example, tablet, Granule, capsule, powder agent, liquid, suspension, suppository etc..Long-acting injection, infiltration can also for example be passed through in a sustained manner The modes such as pump, pill, patch are administered.

Solid dosage forms for oral administration includes capsule, tablet, pill, powders and granules.In such solid formulation In type, reactive compound and at least one inertia pharmaceutically acceptable excipient or carrier are mixed, such as a) filler or filler, such as Starch, lactose, sucrose, glucose, mannitol and silicic acid, b) adhesive, for example (,) it is carboxymethyl cellulose, alginate/ester, bright Glue, polyvinylpyrrolidone, sucrose and gum arabic, c) moisturizer such as glycerol, d) disintegrating agent, such as agar, calcium carbonate, Potato or tapioca, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents (solution retarding Agent), such as paraffin, f) absorbsion accelerator, such as quarternary ammonium salt compound, g) wetting agent, such as cetanol and monostearate it is sweet Grease, h) absorbent, such as kaolin and bentonite and i) lubricant, such as talcum powder, calcium stearate, magnesium stearate, Gu Body polyethylene glycol, lauryl sodium sulfate and its mixture.In the case where capsule, tablet and pill, the dosage form can also be wrapped Include buffer.

The solid composite of similar type also can be used as filler for filling soft or hard gelatin capsule, and use is for example newborn The excipient of sugar and high molecular weight polyethylene glycol.It can be by tablet, sugar-coat agent (dragee), capsule, pill and granule Solid dosage forms, which is prepared into, has coating and shell (shell) (such as other well known packets of enteric coating and field of pharmaceutical preparations Clothing).It can optionally include opacifier (opacifying agent), can also be only or certain parts preferably in enteron aisle Release, optionally discharges the composition of the active constituent in a delayed fashion.The example of available embedding composition includes height Molecular substance and wax.

Liquid dosage form for oral administration includes but is not limited to pharmaceutical acceptable emulsion, microemulsion, solution, suspension, sugar Starch agent and elixir.In addition to reactive compound, liquid dosage form can also include inert diluent commonly used in the prior art, such as water Or other solvents, solubilizer and emulsifier for example ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Ergol, Propylene glycol, 1,3 butylene glycol, dimethylformamide, oil (especially cottonseed, peanut (peanut), corn, plumule, olive, castor-oil plant With the oil of sesame), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan aliphatic ester and its mixture.In addition to inert diluents Agent, Orally administered composition may also comprise adjuvant (adjuvant), such as wetting agent, emulsification and suspension, sweetener, flavoring agent and virtue Pastil.

Injectable formulation, for example, dispersion appropriate or wetting agent and suspension preparation nothing can be used according to the prior art Bacterium injectable is aqueous or oil-based suspension.The sterile injectable preparation is also possible in the acceptable diluent of nontoxic parenteral Or sterile injectable solution, suspension or lotion in solvent, for example, the solution in 1,3-BDO.Acceptable carrier or Solvent includes water, Ringer's solution and isotonic sodium chlorrde solution.In addition, sterile, fixing oil is conventionally used as solvent or suspension base. For this purpose, any mild fixing oil, monoglyceride or diglyceride including preparation can be used.In addition, fatty acid Such as oleic acid can be used for the preparation of injected material.Injectable formulation can be it is sterile, for example, by bacterium-retaining filter into Row filtering, or fungicide is added in the form of aseptic solid composite by using preceding, sterile water can be dissolved or dispersed in Or in other sterile injectable mediums.

The preferred suppository of composition for rectum or vaginal application, can be by by the compounds of this invention and suitable non-thorn Property excipient or carrier (for example, cocoa butter, polyethylene glycol or suppository wax) mixing are swashed to prepare, and are solid at ambient temperature Body is liquid under body temperature, therefore melts simultaneously release of active compounds in rectum or vaginal canal.

Those skilled in the art are known, and the dosage of drug depends on many factors, including but is not limited to following Factor: the activity of specific compound used, the age of patient, the weight of patient, the health status of patient, the row quilt of patient, disease Diet, administration time, administration mode, the rate of excretion, combination of drug of people etc..In addition, optimal therapeutic modality is as treated Mode, the consumption per day of general formula compound or the type of pharmaceutical salt can be verified according to traditional therapeutic scheme.

It will further be understood that the compound of the present invention or pharmaceutical composition can be prepared, and it is used for combination therapy, i.e. chemical combination Object and pharmaceutical composition can simultaneously, previously or subsequently be prepared with same or various other desired therapies or medical procedure or Application.It will allow for the phase of required therapy and/or program with the specific therapeutic combination (therapy or program) that assembled scheme uses Capacitive and ideal treatment to be achieved effect.

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, excellent Select the alkyl containing 1 to 12 carbon atom, the alkyl of further preferably 1 to 6 carbon atom.Non-limiting example include methyl, Ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- diformazan Base propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl third Base, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethyl butyrate Base, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2,3- dimethylbutyl, n-heptyl, 2- methyl oneself Base, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2,3- dimethyl amyl group, 2,4- dimethyl amyl group, 2,2- dimethyl Amyl, 3,3- dimethyl amyl group, 2- ethylpentyl, 3- ethylpentyl, n-octyl, 2,3- dimethylhexanyl, 2,4- dimethyl oneself Base, 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- ethyl Hexyl, 2- methyl -3- ethylhexyl, 2,2- diethyl amyl group, positive decyl, 3,3- diethylhexyl, 2,2- diethylhexyl, and Its various branched isomer etc..Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting embodiment include first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- Dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- ethyl -2- first Base propyl, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- diformazan Base butyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2,3- dimethylbutyl etc..Alkyl can be with It is substitution or non-substituted, when substituted, substituent group can be substituted on any workable tie point, the substitution Base 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, cycloalkanes Sulfenyl, heterocycle alkylthio group, oxo base, carboxyl or carboxylate.

Term " alkenyl " refers to the alkane as defined above by being at least made of two carbon atoms and at least one carbon-to-carbon double bond Base, such as vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- cyclobutenyl etc..Alkenyl can be it is 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, cycloalkanes oxygen Base, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.

Term " alkynyl " refers to the alkane as defined above by being at least made of two carbon atoms and at least one carbon-carbon triple bond Base, such as acetenyl, propinyl, butynyl etc..Alkynyl can be substituted or non-substituted, and when substituted, substituent group is excellent One or more following groups are selected as, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen Element, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkanes sulphur Base, heterocycle alkylthio group.

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

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

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

Term " bridge ring alkyl " refers to 5 to 20 yuan, and the full carbon that any two ring shares two carbon atoms being not directly connected is more Cyclic group, can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl can be divided into according to a group cyclic number, it is excellent It is selected as bicyclic, tricyclic or Fourth Ring, is 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 being connected to precursor structure Ring together is naphthenic base, and non-limiting example includes indanyl, tetralyl, benzocyclohepta alkyl etc..Naphthenic base can be Optionally replacing or non-substituted, when substituted, substituent group is preferably one or more following groups, independently selected from alkane Base, 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 or carboxylate.

Term " heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, and it includes 3 to 20 rings Atom, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), but do not wrap The loop section of-O-O- ,-O-S- or-S-S- are included, remaining annular atom is carbon.3 to 12 annular atoms are preferably comprised, wherein 1~4 It is hetero atom；3 to 8 annular atoms are most preferably comprised, wherein 1~3 is hetero atom；5 to 7 annular atoms are most preferably comprised, In 1~2 or 1~3 be 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, morpholine Base, thio-morpholinyl, high piperazine base, pyranose etc., preferably 1,2,5- oxadiazoles base, pyranose or morpholinyl.Multiring heterocyclic Heterocycle including loop coil, condensed ring and bridged ring.

Term " spiro heterocyclic radical " refers to the multiring heterocyclic that an atom (claiming spiro-atom) is shared between 5 to 20 yuan of monocycle Group, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom For 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 Member, more preferably 7 to 10 yuan.Spiro heterocyclic radical is divided into single spiro heterocyclic radical, double according to the number for sharing spiro-atom between ring and ring Spiro heterocyclic radical or more spiro heterocyclic radicals, preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 Member/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, each ring in system and the shared a pair adjoined of other rings in system The polycyclic heterocyclic group of atom, one or more rings can be containing one or more double bonds, but none ring is with completely total The pi-electron system of yoke, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_mThe miscellaneous original of (wherein m is integer 0 to 2) Son, remaining annular atom are carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to a group cyclic number can be divided into it is 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 rings Base.The non-limiting example of condensed hetero ring base includes:

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

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

Deng.

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

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

Aryl can be substituted or non-substituted, and when substituted, substituent group is preferably one or more following groups, It is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, ring Alkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl or carboxylic acid Ester group.

Term " heteroaryl " refers to the heteroaromatic system comprising 1 to 4 hetero atom, 5 to 14 annular atoms, and wherein hetero atom selects 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 miscellaneous original Son；It is preferred that such as imidazole radicals, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrole radicals, tetrazole radical, pyridyl group, phonetic Piperidinyl, thiadiazoles, pyrazinyl etc., preferably imidazole radicals, thiazolyl, pyrazolyl or pyrimidine radicals, thiazolyl；More select pyrazolyl or Thiazolyl.The heteroaryl ring can be condensed on aryl, heterocycle or cycloalkyl ring, wherein linking together with precursor structure Ring be heteroaryl ring, non-limiting example includes:

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

Term " alkoxy " refers to-O- (alkyl) and-O- (non-substituted naphthenic base), and wherein alkyl is as defined above. The non-limiting example of alkoxy includes: methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, penta oxygen of ring Base, cyclohexyloxy.Alkoxy can be optionally replacing or non-substituted, and when substituted, substituent group is preferably one or more A following group, 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 alkane sulphur Base, carboxyl or carboxylate.

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

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

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

Term " hydroxyl " refers to-OH group.

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

Term " amino " refers to-NH₂。

Term " cyano " refers to-CN.

Term " nitro " refers to-NO₂。

Term " oxo base " refers to=O.

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

Term " sulfydryl " refers to-SH.

Term " ester group " refers to-C (O) O (alkyl) or-C (O) O (naphthenic base), and wherein alkyl and naphthenic base are as defined above.

Term " acyl group " refers to the compound containing-C (O) R group, wherein R be alkyl, it is naphthenic base, heterocycle, aryl, miscellaneous Aryl.

Term " sulfonic group " refers to-S (O)₂OH。

Term " sulfonate group " refers to-S (O)₂O (alkyl) or-S (O)₂O (naphthenic base), wherein alkyl and naphthenic base institute as above Definition.

" 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, meaning that alkyl can be with " optionally by alkyl-substituted heterocyclic group " But necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.

" substituted " refers to one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom Replaced independently of one another by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, this Field technical staff, which can determine in the case where not paying excessive make great efforts and (pass through experiment or theoretical), may or impossible take Generation.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 Fixed.

" pharmaceutical composition " indicate containing one or more compounds described herein or its physiologically/pharmaceutical salt or The mixture and other components such as physiology/pharmaceutical carrier and excipient of pro-drug and other chemical constituents.Medicine The purpose of compositions 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 when this kind of salt is used in the mammalian body and has Effect property, and there is due bioactivity.

The synthetic method of the compounds of this invention

In order to complete the purpose of the present invention, the present invention is adopted the following technical scheme that.

The preparation method of particular compound of the present invention is as follows.

Compound for leading to formula (VI) can be prepared according to the method for following scheme 1:

Scheme 1

Step 1: under alkaline condition by compound VIa and compound VIb, condensation reaction occurs under condensing agent effect, Obtain compound VIc；The reagent for providing alkaline condition can be organic base such as TEA or DIPEA, preferably DIPEA；The condensing agent It can be HATU, HBTU or EDCI/HOBt, preferably HATU；

Step 2: compound VIc being subjected to cyclization under the catalysis of acid, obtains compound VId；The acid can be Various organic acids, preferably acetic acid；

Step 3: in the presence of a catalyst by compound VIe, being restored in acid medium, obtain compound VIf；It is described Catalyst can be Metal Palladium and platinum, preferred platinum dioxide, and the acid medium can be hydrochloric acid, sulfuric acid, formic acid, acetic acid etc., It is preferred that acetic acid；

Step 4: compound VId and compound VIf being subjected to ammonification coupling reaction under the conditions of Buckwald, obtain general formula (VI) compound, the Buckwald condition are Metal Palladium (Pd₂(dba)₃/ BINAP or Pd (dppf)₂Cl₂) it is used as catalyst, Cs₂CO₃As alkali, reaction temperature is 100~120 DEG C.

Compound for leading to formula (VII) can be prepared according to the method for following scheme 2:

Scheme 2

Step 1: using substituted adjacent antifebrin compound VIIa as starting material, being reacted, changed by Sandmeyer Close object VIIb；The Sandmeyer reaction uses t-BuONO as preferred diazo reagent, uses TMSN₃Nucleophilic nitrine is provided Source；Reaction temperature is 0 DEG C to room temperature.

Step 2: compound VIIb and compound VIIc being subjected to condensation reaction under the catalysis of Lewis acid, obtain chemical combination Object VIId；The Lewis acid can be Ti (OiPr)₄、TiCl(OiPr)₃, preferably TiCl₄；

Step 3: compound VIId carries out cyclization in the presence of a catalyst, obtains compound VIIe；The catalysis Agent can be Cu₂O or CuCl, preferably CuI；

Step 4: compound VIIe and compound VIf being subjected to ammonification coupling reaction under the conditions of Buckwald, led to Formula (VI) compound, the Buckwald condition are to use Metal Palladium (Pd₂(dba)₃/ BINAP or Pd (dppf)₂Cl₂) be used as and urge Agent, Cs₂CO₃As alkali, reaction temperature is 100~120 DEG C.

Compound for leading to formula (VIII) can be prepared according to the method for following scheme 3:

Scheme 3

Step 1: using benzaldehyde compound VIIIa as starting material, being condensed with nitro compound, obtain compound VIIIb； Reaction temperature is 80~100 DEG C；

Step 2: compound VIIIb being reacted under reducing agent effect with compound VIIId, obtains compound VIIIc；Institute Stating reducing agent can be FeCl₂、SnCl₂, Cu (OAc), preferably FeCl₂；

Step 3: compound VIIIc and compound VIf being subjected to ammonification coupling reaction under the conditions of Buckwald, led to Formula (VI) compound, the Buckwald condition are that condition is Metal Palladium (Pd₂(dba)₃/ BINAP or Pd (dppf)₂Cl₂) conduct Catalyst, Cs₂CO₃As alkali, reaction temperature is 100~120 DEG C.

Compound for leading to formula (IX) can be prepared according to the method for following scheme 4:

Scheme 4

Step 1: compound VIIIb is stirred at room temperature with compound IXa, and condensation and cyclization reaction occurs by air oxidation, Obtain compound IXb；

Step 2: compound IXb and compound VIf being subjected to ammonification coupling reaction under the conditions of Buckwald, obtain general formula (VI) compound, the Buckwald condition are that condition is Metal Palladium (Pd₂(dba)₃/ BINAP or Pd (dppf)₂Cl₂) be used as and urge Agent, Cs₂CO₃As alkali, reaction temperature is 100~120 DEG C.

Specific embodiment

The compound of the present invention and its preparation are further understood by embodiment, these embodiments illustrate some preparations Or the method using the compound.It is to be appreciated, however, that these embodiments do not limit the present invention.It is currently known or into The variation of the invention of one step exploitation is considered within described herein and scope of the claimed invention.

The compounds of this invention is that preparation is completed using convenient starting material and general preparation step.The present invention gives Typical or tendentious reaction condition, such as reaction temperature, time, solvent, pressure, the molar ratio of reactant are gone out.But Unless specifically indicated, other reaction conditions can also be adopted.Optimal conditions may with the use of specific reactant or solvent and Change, but in general, reacting Optimization Steps and condition can be determined.

In addition, some blocking groups may have been used in the present invention to protect certain functional groups to avoid unnecessary reaction. Be suitable for various functional groups protecting group and their protection or deprotection condition be that those skilled in the art are ripe extensively Know.Such as T.W.Greene and G.M.Wuts " blocking group in organic preparation " (the 3rd edition, Wiley, New York, 1999 With the citation in book) protection or deprotection of a large amount of blocking group is described in detail.

The separation and purifying of compound and intermediate take method and steps appropriate, such as mistake according to specific demand Filter, distillation, crystallization, column chromatography, prepares being used in mixed way for thin layer plate chromatography, preparative high-performance liquid chromatographic or the above method at extraction. Its specifically used method sees the example that the present invention describes.Certainly, other similar separation and means of purification are also that can adopt ?.Conventional method (including physical constant and spectral data) can be used to characterize it.

The structure of compound is by nuclear magnetic resonance (NMR) or/and mass spectrum (MS) come what is determined.NMR is displaced with 10^-6 (ppm) unit provides.The measurement of NMR is to use Brukerdps300 type nuclear magnetic resonance spectrometer, and measurement solvent is deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), deuterated methanol (CD₃OD), inside it is designated as tetramethylsilane (TMS).

The measurement of MS is with ACQUITY H-Class UPLC mass spectrograph (QDa Detector) (manufacturer: Waters).

It prepares liquid phase and uses 2545 high performance liquid chromatograph of Waters (2489 UV/visible of Waters Detector, 2767 Sample MGR, Unitary C18,5 μm 20mm x250mm) (manufacturer: Waters).

Microwave reaction uses Initiator+EU type microwave reactor (manufacturer: Biotage).

Tlc silica gel plate uses Qingdao Haiyang chemical industry GF254 silica gel plate, the silica gel plate that thin-layered chromatography (TLC) uses The specification of use 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 100~200 mesh of Qingdao Haiyang silica gel, 200~300 mesh silica gel.

Known starting material of the invention can be used or be synthesized according to methods known in the art, or can purchase certainly Networking store, Beijing coupling, Sigma, lark prestige, Yi Shiming, Shanghai book Asia, Shanghai Yi Nuokai, the resistance to Jilin Chemical of peace, Shanghai is finished Equal companies.

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.

Reaction dissolvent, organic solvent or atent solvent be respectively expressed as using the solvent under described reaction condition Be not involved in reaction, including, as benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, methylene chloride, Ether, methanol, nitrogen-Jia base Bi Ka Lin ketone (NMP), pyridine etc..Without specified otherwise in embodiment, solution refers to aqueous solution.

Chemical reaction described in the present invention generally carries out under normal pressure.Reaction temperature is between -78 DEG C to 200 DEG C. Reaction time and condition are, for example, between -78 DEG C to 200 DEG C, completing in about 1 to 24 hour under an atmospheric pressure.If Overnight, then the reaction time is generally 16 hours for reaction.Without specified otherwise in embodiment, the temperature of reaction is room temperature, be 20 DEG C~ 30℃。

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

The system of eluant, eluent and the solvent system of thin-layered chromatography for the column chromatography that purifying compound uses include: A: two Chloromethanes and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, the volume ratio root of solvent It is adjusted according to the polarity difference of compound, the alkalinity such as a small amount of triethylamine and acetic acid can also be added or acid reagent carries out It adjusts.

Unless otherwise defined, it anticipates known to all professional and scientific terms as used herein and one skilled in the art Justice is identical.In addition, any method similar to or equal to what is recorded and material can be applied to the method for the present invention.

Abbreviation

μ L=microlitre；

μM=micromole；

NMR=nuclear magnetic resonance；

Boc=tert-butoxycarbonyl

Br=broad peak

D=is bimodal

δ=chemical shift

DEG C=degree Celsius

Dd=double doublet

DMF=N, dinethylformamide

DMSO=dimethyl sulfoxide

DCM=methylene chloride

EA=ethyl acetate

HPLC=efficient liquid phase

Hz=hertz

IC₅₀=inhibit 50% active concentration

J=coupling constant (Hz)

M=multiplet

M+H⁺+ one proton of=parent compound quality

Mg=milligrams

ML=milliliters

Mmol=mMs

MS=mass spectrum

NM=nanomole

PE=petroleum ether

Every million points of ppm=

S=is unimodal

T=triplet

TFA=trifluoroacetic acid

THF=tetrahydrofuran

Prepare the preparation of embodiment 1:2- (the bromo- 2- chlorphenyl of 5-) -3- methyl -2H- indazole (intermediate 1a)

The preparation of step 1:1- (2- azido phenyl) ethane -1- ketone

1- (2- aminophenyl) ethane -1- ketone (2.0g, 14.8mmol) is added in the reaction flask containing acetonitrile (20mL). Reaction solution is cooled to 0 DEG C, azidotrimethylsilane (2.05g, 17.76mmol) and the tertiary fourth of nitrous acid are successively added dropwise under stirring Ester (1.68g, 16.28mmol) finishes and is warmed to room temperature and continues stirring 1 hour.After complete reaction, reaction solution is depressurized dense Contracting.Residue obtains 1- (2- azido phenyl) second by silica gel column chromatography method purifying (eluent PE:EA=10:1) Alkane -1- ketone (2.1g, yellow liquid, yield: 87.5%).

LC-MS (ESI): m/z 162.2 [M+H⁺]。

Step 2:(E) -1- (2- azido phenyl)-N- (the bromo- 2- chlorphenyl of 5-) second -1- imines preparation

Under nitrogen protection, 1- (2- azido phenyl) ethane-is added in the reaction flask containing methylene chloride (20mL) 1- ketone (500mg, 3.1mmol) and the bromo- 2- chloroaniline (578mg, 2.8mmol) of 5-.Reaction mixture is cooled to 0 DEG C, stirring Under triethylamine (858mg, 8.5mmol) and titanium tetrachloride (323mg, 1.7mmol) is successively added dropwise.It finishes, continues to stir in the temperature It mixes 1 hour.After complete reaction, it is quenched with ice water (5mL), reaction solution is extracted with dichloromethane (10mLx3), merges organic phase. By organic phase saturated common salt water washing, anhydrous sodium sulfate is dried, filtered, and is concentrated under reduced pressure, is obtained crude product (E) -1- (2- nitrine Base phenyl)-N- (the bromo- 2- chlorphenyl of 5-) second -1- imines (1.2g, red solid).It is not purified be directly used in it is anti-in next step It answers.

LC-MS (ESI): m/z 349.0/351.0 [M+H⁺]。

The preparation of step 3:2- (the bromo- 2- chlorphenyl of 5-) -3- methyl -2H- indazole

(E) -1- (2- azido phenyl)-N- (bromo- 2- chlorobenzene of 5- is added in the reaction flask containing tetrahydrofuran (15mL) Base) second -1- imines (1.2g, 3.44mmol), cuprous iodide (650mg, 3.44mmol) and triethylamine (444mg, 3.44mmol), It is stirred at room temperature 4 hours.After complete reaction, reaction solution is filtered, and be concentrated under reduced pressure.Residue passes through silica gel column chromatography Method purifies (eluent PE:EA=5:1), and obtaining 2- (the bromo- 2- chlorphenyl of 5-) -3- methyl -2H- indazole, (120mg, white are solid Body, yield: 10.8%).

LC-MS (ESI): m/z 321.0/323.0 [M+H⁺]。

Prepare the preparation of embodiment 2:2- (the bromo- 2- chlorphenyl of 5-) -3- methylimidazole simultaneously [1,2-a] pyridine (intermediate 3a)

Step 1:(E) the chloro- 2- of the bromo- 1- of -4- (2- nitro propyl- 1- alkene -1- base) benzene preparation

Containing nitroethane (25mL) reaction flask in be added the bromo- 2- chlorobenzaldehyde of 5- (Shanghai Su Ya, 3.0g, 13.66mmol) and Ammoniom-Acetate (1.36g, 17.77mmol).Reaction mixture is stirred 2 hours in 85 DEG C, is subsequently cooled to room Ethyl acetate dilution (50mL) is added in temperature.Organic phase saturated common salt water washing, anhydrous sodium sulfate dry, filter, and depressurize dense Contracting.Residue purifies (eluent PE:EA=20:1) by silica gel column chromatography method, obtains the chloro- 2- of the bromo- 1- of (E) -4- (2- nitro propyl- 1- alkene -1- base) benzene (2.9g, yellow solid, yield 69.8%).

The preparation of step 2:2- (the bromo- 2- chlorphenyl of 5-) -3- methylimidazole simultaneously [1,2-a] pyridine

The chloro- 2- of the bromo- 1- of (E) -4- (2- nitro propyl- 1- alkene -1- base) benzene is added in the reaction flask containing DMF (20mL) (1.13g, 4.3mmol), pyridine -2- amine (311mg, 3.3mmol) and four water frerrous chlorides (65.7mg, 0.33mmol).It will be anti- It answers mixture to stir 5 hours in 150 DEG C, after reaction solution is cooled to room temperature, ethyl acetate dilution (50mL) is added.Organic phase is used Saturated common salt water washing, anhydrous sodium sulfate dry, filter, and are concentrated under reduced pressure.Residue (is washed by the purifying of silica gel column chromatography method De- liquid is PE:EA=10:1), obtaining 2- (the bromo- 2- chlorphenyl of 5-) -3- methylimidazole, simultaneously (790mg, yellow are solid for [1,2-a] pyridine Body, yield 74.5%).

LC-MS (ESI): m/z 320.9/322.9 [M+H⁺]。

Prepare the preparation of embodiment 3:2- (the bromo- 2- chlorphenyl of 5-) -3- methylpyrazole simultaneously [1,5-a] pyridine (intermediate 5a)

(Z) -2- (2- nitro propyl- 1- alkene -1- base) -4- is added in the reaction flask containing N-Methyl pyrrolidone (10mL) The bromo- chloro- benzene of 1- (300mg, 1.08mmol) and 1- aminopyridine -1- iodide (200mg, 0.9mmol).It is small to be stirred at room temperature 72 Ethyl acetate (30mL) dilution is added in Shi Hou.Organic phase water and saturated common salt water washing, anhydrous sodium sulfate dry, filter, and subtract Pressure concentration.Residue purifies (eluent PE:EA=3:1) by silica gel column chromatography method, obtains 2- (the bromo- 2- chlorobenzene of 5- Base) -3- methylpyrazole simultaneously [1,5-a] pyridine (90mg, weak yellow liquid, yield: 26%).

LC-MS (ESI): m/z 320.9/322.6 [M+H⁺]。

Prepare embodiment 4:2- (the chloro- 2- fluorophenyl of the bromo- 6- of 3-) -1- methyl-1 H- benzo [d] imidazoles (intermediate 7a) Preparation

The preparation of the chloro- 2- fluobenzoic acid of the bromo- 6- of step 1:3-

Under nitrogen protection, the chloro- 2- fluorobenzene (5.68g, 27.11mmol) of the bromo- 4- of 1- is dissolved in containing anhydrous tetrahydro furan In the reaction flask of (60mL).Reaction solution is cooled to -78 DEG C, LDA is slowly added dropwise under stirring, and (11.44mL, 2M tetrahydrofuran are molten Liquid).It finishes after continuing stirring 1 hour, is passed through dry carbon dioxide gas, and be slowly increased to room temperature.After fully reacting, again It is cooled to 0 DEG C, the NaHCO of saturation is added₃Aqueous solution (100mL) is quenched, and is extracted once with ether (80mL), discards organic phase.Water It after being mutually 2~3 with the salt acid for adjusting pH value of 3N, is extracted with ethyl acetate (100mLx3), the salt of combined organic phase saturation Water washing, anhydrous sodium sulfate dry, filter, and filtrate decompression concentration, obtaining the chloro- 2- fluobenzoic acid of the bromo- 6- of 3-, (3.4g, yellow are solid Body, yield 49.4%).

LC-MS (ESI): m/z 253.0/255.0 [M+H⁺]。

The fluoro- N- of the chloro- 2- of the bromo- 6- of step 2:3- (2- (methylamino) phenyl) benzamide

Containing methylene chloride (20mL) reaction flask in be added the chloro- 2- fluobenzoic acid of the bromo- 6- of 3- (1.05g, 4.14mmol), N-Methyl-O-Phenylenediamine (506mg, 4.14mmol), DIPEA (1.06g, 8.28mmol) and HATU (1.88g, 4.96mmol).Reaction mixture is stirred at room temperature 2 hours, and the sodium bicarbonate aqueous solution that saturation is then added is quenched, and uses dichloromethane Alkane extracts (60mLx3).Combined organic phase saturated common salt water washing, anhydrous sodium sulfate dry, filter, filtrate decompression concentration, Residue obtains the chloro- 2- of the bromo- 6- of 3- fluoro- N- (2- (first by silica gel column chromatography method purifying (eluent PE:EA=1:1) Base amino) phenyl) benzamide (1.06g, yellow solid, yield: 71.6%).

LC-MS (ESI): m/z 357.0/359.1 [M+H⁺]。

The preparation (intermediate 7a) of step 3:2- (the chloro- 2- fluorophenyl of the bromo- 6- of 3-) -1- methyl-1 H- benzo [d] imidazoles

The fluoro- N- of the chloro- 2- of the bromo- 6- of 3- (2- (methylamino) phenyl) benzene first is added in the reaction flask containing acetic acid (15mL) Amide (1.16g, 3.24mmol).Reaction solution is heated to 100 DEG C to stir 1 hour, is concentrated under reduced pressure and removes acetic acid, obtained solid is again The dissolution of 100mL ethyl acetate is added, with saturation NaHCO₃Solution washing is until alkalinity.Organic phase is dry with anhydrous sodium sulfate, mistake Filter, filtrate decompression concentration, residue obtain 2- (2- by silica gel column chromatography method purifying (eluent PE:EA=2:1) Bromo- 5- chloropyridine -4- base) -1- methyl-1 H- benzo [d] imidazoles (652mg, white solid, yield 62.6%).

LC-MS (ESI): m/z 339.1/341.1 [M+H⁺]。

Prepare embodiment 5:2- (the bromo- 5- chloropyridine -4- base of 2-) -1- methyl-1 H- benzo [d] imidazoles (intermediate 9a) Preparation

The preparation of the bromo- 5- chloroisonicotinic acid of step 1:2-

Under nitrogen protection, diisopropylamine (4mL) is added in the reaction flask containing anhydrous THF (45mL), is cooled to -5 DEG C, n-butyllithium solution (12.5mL, 23% hexane solution) is slowly added dropwise.Finish continue stirring 0.5 hour after be cooled to- 78 DEG C, then tetrahydrofuran (45mL) solution of the bromo- 5- chloropyridine (5.0g, 26.00mmol) of 2- is slowly added dropwise.It finishes and continues to stir After 15 minutes, then it is passed through dry carbon dioxide gas, after stirring 30 minutes, reaction solution is warmed to room temperature, is slowly dropped to full In the sodium bicarbonate solution (100mL) of sum, gained mixed liquor extracts (50mL) with ether, discards organic phase, the salt of water phase 1N Acid for adjusting pH filters the white solid of precipitation, drying obtains 2- bromo- 5- chloroisonicotinic acid (4.3g, yield: 73%) to 2~3.

LC-MS (ESI): m/z235.8/237.9 [M+H⁺]。

The preparation of the chloro- N- of the bromo- 5- of step 2:2- (2- (methylamino) phenyl) Pyrazinamide

The bromo- 5- chloroisonicotinic acid (1.9g, 8.18mmol) of 2-, N-1- are added in the reaction flask containing methylene chloride (50mL) Methylbenzene -1,2- diamines (1.0g, 8.18mmol), n,N-diisopropylethylamine (DIPEA) (3.2g, 25.0mmol) and 2- (7- Azo benzotriazole)-tetramethylurea hexafluorophosphoric acid ester (HATU) (4.7g, 12.27mmol).Reaction mixture is stirred in room temperature It mixes 2 hours, is quenched with saturated sodium bicarbonate solution (10mL), ethyl acetate extracts (50mLx3).Combined organic phase saturation Brine It, anhydrous sodium sulfate dry, filter, and filtrate decompression concentration obtains the bromo- 5- of crude product 2- chloro- N- (2- (methyl ammonia Base) phenyl) Pyrazinamide (3.2g, black solid).It is not purified and is directly used in next step.

LC-MS (ESI:m/z 340.1/342.1 [M+H+].

The preparation (intermediate 9a) of step 3:2- (the bromo- 5- chloropyridine -4- base of 2-) -1- methyl-1 H- benzo [d] imidazoles

The chloro- N- of the bromo- 5- of 2- (2- (methylamino) phenyl) Pyrazinamide (3.2g, 9.412mmol) is in acetic acid (100mL) It is heated to reflux 1 hour, is concentrated under reduced pressure and removes acetic acid.Obtained solid is dissolved in 100mL ethyl acetate, then respectively with saturation NaHCO₃ And brine It, anhydrous sodium sulfate dry, filter, filtrate decompression concentration.Residue is purified by silica gel column chromatography method (eluent PE:EA=2:1) obtain 2- (the bromo- 5- chloropyridine -4- base of 2-) -1- methyl-1 H- benzo [d] imidazoles (1.2g, it is white Color solid, yield: 40%).

LC-MS (ESI): m/z 322.0/324.0 [M+H⁺]。

Prepare the preparation of embodiment 6:2- (the bromo- 2- chlorphenyl of 5-) -1- methyl-1 H- benzo [d] imidazoles (intermediate 11a)

The preparation of the chloro- N- of the bromo- 2- of step 1:5- (2- (methylamino) phenyl) benzamide

In room temperature, sequentially added in the reaction flask containing 100mL methylene chloride the bromo- 2- chlorobenzoic acid of 5- (9.6g, 40.80mmol), N- methylbenzene -1,2- diamines (5g, 40.80mmol), HATU (23.34g, 61.38mmol) and DIPEA (21mL, 122.40mmol).After reaction mixture is stirred 2 hours, with saturation NaHCO₃Solution is quenched, methylene chloride extraction (50mL×3).Combined organic phase, with saturated common salt water washing, anhydrous sodium sulfate is dried, filtered, and is concentrated under reduced pressure, is obtained 5- The bromo- chloro- N- of 2- (2- (methylamino) phenyl) benzamide crude product.Its not purified is directly used in is reacted in next step.

LC-MS (ESI): m/z338.9/340.9 [M+H⁺]。

The preparation of step 2:2- (the bromo- 2- chlorphenyl of 5-) -1- methyl-1 H- benzimidazole

The chloro- N- of the bromo- 2- of 5- (2- (methylamino) made from step 1 is added in the reaction flask containing 100mL AcOH Phenyl) benzamide.After 100 DEG C are stirred 1 hour, it is concentrated under reduced pressure and removes AcOH.Obtained solid adds 100mL ethyl acetate Dissolution is saturated NaHCO₃Until alkaline, anhydrous sodium sulfate is dried, filtered for solution washing, is concentrated under reduced pressure.Residue passes through silicagel column Thin layer chromatography method purifies (eluent PE:EA=5:1), obtains 2- (the bromo- 2- chlorphenyl of 5-) -1- methyl-1 H- benzimidazole (10g, white solid, two step yields: 76.6%).

LC-MS (ESI): m/z 320.9/322.9 [M+H⁺]。

Embodiment 1:2- (the chloro- 3- of 4- (3- methyl -2H- indazole -2- base)-phenyl) -6- (methyl sulphonyl) -1,2,3,4- The preparation of tetrahydroisoquinoline (1)

The preparation of step 1:6- (methyl sulphonyl) isoquinolin (1c)

6- bromo-isoquinoline (3.0g, 14.4mmol), methyl Asia are added in the round-bottomed flask containing 50mL dimethyl sulfoxide Sodium sulfonate (2.2g, 30mmol) and cuprous iodide (270mg, 1.4mmol).Under nitrogen protection, it is stirred overnight in 120 DEG C.To After reaction solution is cooled to room temperature, ethyl acetate (100mL) dilution is added, with saturated common salt water washing, anhydrous sodium sulfate is dry, mistake Filter is concentrated under reduced pressure.Residue purifies (eluant, eluent EA:PE=1:4) by silica gel column chromatography method, obtains 6- (methyl sulphur Acyl group) isoquinolin (1.5g, yellow oil, yield 50%).

LC-MS (ESI): m/z 208.0 [M+H⁺]。

The preparation of step 2:6- (methyl sulphonyl) -1,2,3,4- tetrahydroisoquinoline (1d)

6- (methyl sulphonyl) isoquinolin (1.5g, 7.2mmol), PtO are added in the round-bottomed flask containing 20mL methanol₂ (0.1g, 10%) and 10mL acetic acid.Sealing, hydrogen is replaced three times, after reaction solution is stirred at room temperature 4 hours under an atmosphere of hydrogen, mistake Filter.Filtrate decompression concentration, obtains 6- (methyl sulphonyl) -1,2,3,4- tetrahydroisoquinolines (1.1g, yellow oil, yield 72%).

LC-MS (ESI): m/z 212.1 [M+H⁺]。

Step 3:2- (the chloro- 3- of 4- (3- methyl -2H- indazole -2- base)-phenyl) -6- (methyl sulphonyl) -1,2,3,4- four The preparation of hydrogen isoquinoline (1)

In room temperature, 6- (methyl sulphonyl) -1 is added in the round-bottomed flask containing 5mL, 2,3,4- tetrahydroisoquinolines (27mg, 0.13mmol), 2- (the bromo- 2- chlorphenyl of 5-) -3- methyl -2H- indazole (1a) (45mg, 0.14mmol), cesium carbonate (208mg, 0.65mmol), BINAP (16mg, 0.030mmol) and tris(dibenzylideneacetone) dipalladium (23mg, 0.030mmol). Sealing, nitrogen are replaced three times, are heated to 100 DEG C and are stirred 4 hours.It after reaction solution is cooled to room temperature, filters, filtrate decompression is dense Contracting.By preparation HPLC purifying, (acetonitrile/water (0.1% formic acid): C18 20%~100%), obtains 2- (the chloro- 3- of 4- to residue (3- methyl -2H- indazole -2- base)-phenyl) -6- (methyl sulphonyl) -1,2,3,4- tetrahydroisoquinolines (receive by 8mg, white solid Rate: 14%).

LC-MS (ESI): m/z 452.1/454.1 [M+H⁺]。

¹H NMR(400MHz,DMSO-d₆) δ 7.75 (dd, J=14.8,8.1Hz, 3H), 7.57 (dd, J=17.2, 8.9Hz, 2H), 7.48 (d, J=8.1Hz, 1H), 7.34-7.23 (m, 2H), 7.21 (d, J=2.9Hz, 1H), 7.09-7.03 (m, 1H), 4.58 (s, 2H), 3.66 (t, J=5.8Hz, 2H), 3.19 (s, 3H), 3.03 (t, J=5.5Hz, 2H), 2.45 (s, 3H)。

Embodiment 2:2- (2- (the chloro- 3- of 4- (3- methyl -2H- indazole -2- base)-phenyl) -1,2,3,4- tetrahydroisoquinoline -6 Base) -2- propyl alcohol (2) preparation

Step 1:2- (the chloro- 3- of 4- (3- methyl -2H- indazole -2- base)-phenyl) -1,2,3,4- tetrahydroisoquinoline -6- formic acid It is prepared by (2b) of methyl esters

In room temperature, 1,2,3,4- tetrahydroisoquinoline -6- methyl formates are added in the round-bottomed flask containing 5mL (according to special Method disclosed in sharp document WO2016023511 is made) (25mg, 0.13mmol), 2- (the bromo- 2- chlorphenyl of 5-) -3- methyl - 2H- indazole (1a) (45mg, 0.14mmol), cesium carbonate (170mg, 0.42mmol), BINAP (15mg, 0.03mmol) and three (two BENZYLIDENE ACETONE) two palladiums (25mg, 0.03mmol).Sealing, nitrogen are replaced three times, are heated to 100 DEG C and are stirred 4 hours.Reaction solution After being cooled to room temperature, filtering, filtrate decompression concentration.Residue purifies (eluant, eluent EA:PE=by silica gel column chromatography method 1:5), 2- (the chloro- 3- of 4- (3- methyl -2H- indazole -2- base)-phenyl) -1,2,3,4- tetrahydroisoquinoline -6- methyl formates are obtained (40mg, yellow oil, yield 27%).

LC-MS (ESI): m/z 432.4/434.5 [M+H⁺]。

Step 2:2- (2- (the chloro- 3- of 4- (3- methyl -2H- indazole -2- base)-phenyl) -1,2,3,4- tetrahydroisoquinoline -6 Base) -2- propyl alcohol (2) preparation

Under nitrogen protection, by 2- (the chloro- 3- of 4- (3- methyl -2H- indazole -2- base)-phenyl) -1,2,3,4- Tetrahydroisoquinoli-s Quinoline -6- methyl formate (40mg, 0.09mmol) and 2mL anhydrous tetrahydro furan are added in 25mL round-bottomed flask.By reaction mixture After being cooled to 0 DEG C, methyl-magnesium-bromide (0.30mL, 3M diethyl ether solution) is slowly added dropwise under stiring.After being added dropwise, by reaction solution Continue stirring 1 hour in room temperature.Then, add water quenching reaction, be extracted with dichloromethane, organic phase saturated common salt water washing, Anhydrous sodium sulfate dries, filters, filtrate decompression concentration.Residue purifies (C18, acetonitrile/water (0.1% first by preparation HPLC Acid): 40%~100%), obtaining 2-, (2- (the chloro- 3- of 4- (3- methyl -2H- indazole -2- base)-phenyl) -1,2,3,4- tetrahydros are different - 6 base of quinoline) -2- propyl alcohol (9mg, white solid, yield 23%).

LC-MS (ESI): m/z 432.2/434.2 [M+H⁺]。

¹H NMR(400MHz,DMSO-d₆) δ 7.77 (d, J=8.4Hz, 1H), 7.59 (d, J=8.8Hz, 1H), 7.52 (d, J=9.0Hz, 1H), 7.33-7.18 (m, 4H), 7.17-7.10 (m, 2H), 7.09-7.03 (m, 1H), 4.93 (s, 1H), 4.43 (s, 2H), 3.60 (t, J=5.8Hz, 2H), 2.91 (d, J=5.7Hz, 2H), 2.45 (s, 3H), 1.40 (s, 6H).

Embodiment 3:2- (the chloro- 3- of 4- (3- methylimidazole simultaneously [1.2-a] pyridine -2- base)-phenyl) -6- (sulfonyloxy methyl Base) -1,2,3,4- tetrahydroisoquinoline (3) preparation

In room temperature, it is added in the round-bottomed flask containing 25mL toluene by 6- (methyl sulphonyl) -1,2,3,4- tetrahydros are different Quinoline (1d) (30mg, 0.14mmol), 2- (the bromo- 2- chlorphenyl of 5-) -3- methylimidazole simultaneously [1,2-a] pyridine (3a) (50mg, 0.16mmol), cesium carbonate (341mg, 0.7mmol), BINAP (18mg, 0.03mmol) and tris(dibenzylideneacetone) dipalladium (26mg,0.03mmol).Sealing, nitrogen are replaced three times, are heated to 100 DEG C and are stirred 4 hours.After reaction solution is cooled to room temperature, mistake Filter, filtrate concentration.By preparation HPLC purifying, (acetonitrile/water (0.1% formic acid): C18 30%~100%), obtains 2- to residue (the chloro- 3- of 4- (3- methylimidazole simultaneously [1.2-a] pyridine -2- base)-phenyl) -6- (methyl sulphonyl) -1,2,3,4- Tetrahydroisoquinoli- Quinoline (12mg, white solid, yield: 20%).

LC-MS (ESI), m/z 452.1/454.1 [M+H⁺]。

¹H NMR(400MHz,DMSO-d₆) δ 8.32 (d, J=7.0Hz, 1H), 7.73 (dd, J=14.2,6.2Hz, 2H), 7.59 (d, J=9.0Hz, 1H), 7.51 (d, J=8.2Hz, 1H), 7.40 (d, J=8.8Hz, 1H), 7.31-7.25 (m, 1H), 7.11 (dt, J=7.1,3.0Hz, 2H), 6.99 (td, J=6.8,1.1Hz, 1H), 4.53 (s, 2H), 3.62 (t, J=5.9Hz, 2H), 3.18 (s, 3H), 3.03 (t, J=5.7Hz, 2H), 2.39 (s, 3H).

Embodiment 4:2- (2- (the chloro- 3- of 4- (3- methylimidazole simultaneously [1.2-a] pyridine -2- base)-phenyl) -1,2,3,4- four - 6 base of hydrogen isoquinoline) -2- propyl alcohol (4) preparation

Step 1:2- (the chloro- 3- of 4- (3- methylimidazole simultaneously [1.2-a] pyridine -2- base)-phenyl) -1,2,3,4- Tetrahydroisoquinoli- The preparation of quinoline -6- methyl formate (4a)

In room temperature, 1,2,3,4- tetrahydroisoquinoline -6- methyl formates (2a) are added in the round-bottomed flask containing 5mL toluene (50mg, 0.26mmol), 2- (the bromo- 2- chlorphenyl of 5-) -3- methylimidazole simultaneously [1.2-a] pyridine (3a) (93mg, 0.29mmol), Cesium carbonate (341mg, 1.04mmol), BINAP (30mg, 0.05mmol) and tris(dibenzylideneacetone) dipalladium (50mg, 0.05mmol).Sealing, nitrogen are replaced three times, are heated to 100 DEG C and are stirred 4 hours.After reaction solution is cooled to room temperature, filtering, filtrate It is concentrated under reduced pressure.Residue purifies (eluant, eluent EA:PE=1:5) by silica gel column chromatography method, obtains the 2- (chloro- 3- (3- of 4- Methylimidazole simultaneously [1.2-a] pyridine -2- base)-phenyl) -1,2,3,4- tetrahydroisoquinoline -6- methyl formate (30mg, yellow oilies Object, yield: 27%).

LC-MS (ESI): m/z 432.4/434.4 [M+H⁺]。

Step 2:2- (2- (the chloro- 3- of 4- (3- methylimidazole simultaneously [1.2-a] pyridine -2- base)-phenyl) -1,2,3,4- tetrahydro - 6 base of isoquinolin) -2- propyl alcohol (4) preparation

Under nitrogen protection, by 2- (the chloro- 3- of 4- (3- methylimidazole simultaneously [1.2-a] pyridine -2- base)-phenyl) -1,2,3, 4- tetrahydroisoquinoline -6- methyl formate (30mg, 0.07mmol) and 2mL anhydrous tetrahydro furan are added in 25mL round-bottomed flask, in 0 DEG C methyl-magnesium-bromide (0.35mL, 3M diethyl ether solution) is slowly added dropwise.After being added dropwise, continue stirring 2 hours in room temperature.Then, Add water quenching reaction, be extracted with dichloromethane, organic phase saturated common salt water washing, anhydrous sodium sulfate dries, filters, and filtrate subtracts Pressure concentration.By preparation HPLC purifying, (acetonitrile/water (0.1% formic acid): C18 20%~100%), obtains 2- (2- to residue (the chloro- 3- of 4- (3- methylimidazole simultaneously [1.2-a] pyridine -2- base)-phenyl) -6 base of -1,2,3,4- tetrahydroisoquinoline) -2- propyl alcohol (18mg, white solid, yield 60%).

LC-MS (ESI): m/z 432.2/434.2 [M+H⁺]。

¹H NMR(400MHz,CDCl₃) δ 7.85 (d, J=6.8Hz, 1H), 7.60 (d, J=9.0Hz, 1H), 7.29 (d, J =8.8Hz, 1H), 7.22 (d, J=5.3Hz, 2H), 7.16-7.11 (m, 1H), 7.06 (dd, J=10.3,5.8Hz, 2H), 6.88 (dd, J=8.9,3.1Hz, 1H), 6.82 (t, J=6.2Hz, 1H), 4.35 (s, 2H), 3.51 (t, J=5.9Hz, 2H), 2.92 (t, J=5.7Hz, 2H), 2.38 (s, 3H), 1.51 (s, 6H).

Embodiment 5:2- (the chloro- 3- of 4- (3- methylpyrazole simultaneously [1,5-a] pyridine -2- base)-phenyl) -6- (sulfonyloxy methyl Base) -1,2,3,4- tetrahydroisoquinoline (5) preparation

In room temperature, 6- (methyl sulphonyl) -1 is added in the round-bottomed flask containing 5mL toluene, 2,3,4- tetrahydroisoquinolines (1d) (50mg, 0.24mmol), 2- (the bromo- 2- chlorphenyl of 5-) -3- methylpyrazole simultaneously [1,5-a] pyridine (5a) (60mg, 0.24mmol), cesium carbonate (310mg, 1.2mmol), BINAP (18mg, 0.050mmol) and tris(dibenzylideneacetone) dipalladium (26mg,0.050mmol).Sealing, nitrogen are replaced three times, are heated to 100 DEG C and are stirred 4 hours.After reaction solution is cooled to room temperature, mistake Filter, filtrate decompression concentration.By preparation HPLC purifying, (acetonitrile/water (0.1% formic acid): C18 30%~100%), is obtained residue To 2- (the chloro- 3- of 4- (3- methylpyrazole simultaneously [1,5-a] pyridine -2- base)-phenyl) -6- (methyl sulphonyl) -1,2,3,4- tetrahydro Isoquinolin (15mg, white solid, yield 14%).

LC-MS (ESI): m/z 452.1/454.1 [M+H⁺]。

¹H NMR(400MHz,DMSO-d₆) δ 8.63 (d, J=7.0Hz, 1H), 7.76 (s, 1H), 7.74-7.70 (m, 1H), 7.66 (d, J=8.8Hz, 1H), 7.50 (d, J=8.2Hz, 1H), 7.42 (d, J=8.9Hz, 1H), 7.24-7.18 (m, 1H), 7.14 (dd, J=9.0,3.1Hz, 1H), 7.05 (d, J=3.1Hz, 1H), 6.88 (td, J=6.9,1.3Hz, 1H), 4.53 (s, 2H), 3.62 (t, J=5.9Hz, 2H), 3.18 (s, 3H), 3.02 (t, J=5.8Hz, 2H), 2.16 (s, 3H).

Embodiment 6:2- (2- (the chloro- 3- of 4- (3- methylpyrazole simultaneously [1,5-a] pyridine -2- base)-phenyl) -1,2,3,4- tetra- - 6 base of hydrogen isoquinoline) -2- propyl alcohol (6) preparation

Step 1:2- (the chloro- 3- of 4- (3- methylpyrazole simultaneously [1,5-a] pyridine -2- base)-phenyl) -1,2,3,4- Tetrahydroisoquinoli- The preparation of quinoline -6- methyl formate (6a)

At room temperature, 1,2,3,4- tetrahydroisoquinoline -6- methyl formates are added in the round-bottomed flask containing 5mL toluene (6a) (21mg, 0.11mmol), 2- (the bromo- 2- chlorphenyl of 5-) -3- methylpyrazole simultaneously [1,5-a] pyridine (5a) (35mg, 0.12mmol), cesium carbonate (142mg, 0.44mmol), BINAP (14mg, 0.02mmol) and tris(dibenzylideneacetone) dipalladium (20mg,0.02mmol).Sealing, nitrogen are replaced three times, are heated to 100 DEG C and are stirred 4 hours.After reaction solution is cooled to room temperature, mistake Filter, filtrate decompression concentration.Residue purifies (eluant, eluent EA:PE=1:5) by silica gel column chromatography method, obtains 2- (4- Chloro- 3- (3- methylpyrazole simultaneously [1,5-a] pyridine -2- base)-phenyl) -1,2,3,4- tetrahydroisoquinoline -6- methyl formates (20mg, Yellow oil, yield 42%).

LC-MS (ESI): m/z 432.4/434.4 [M+H⁺]。

Step 2:2- (2- (the chloro- 3- of 4- (3- methylpyrazole simultaneously [1,5-a] pyridine -2- base)-phenyl) -1,2,3,4- tetrahydros - 6 base of isoquinolin) -2- propyl alcohol (6) preparation

Under nitrogen protection, by 2- (the chloro- 3- of 4- (3- methylpyrazole simultaneously [1,5-a] pyridine -2- base)-phenyl) -1,2,3, 4- tetrahydroisoquinoline -6- methyl formate (20mg, 0.05mmol) and 2mL anhydrous tetrahydro furan are added in 25mL round-bottomed flask.In 0 DEG C methyl-magnesium-bromide (0.30mL, 3M diethyl ether solution) is slowly added dropwise.After being added dropwise, continue stirring 2 hours in room temperature.Then, Add water quenching reaction, be extracted with dichloromethane, organic phase saturated common salt water washing, anhydrous sodium sulfate dries, filters, and filtrate subtracts Pressure concentration.By preparation HPLC purifying, (acetonitrile/water (0.1% formic acid): C18 30%~100%), obtains 2- (2- to residue (the chloro- 3- of 4- (3- methylpyrazole simultaneously [1,5-a] pyridine -2- base)-phenyl) -6 base of -1,2,3,4- tetrahydroisoquinoline) -2- propyl alcohol (4mg, white solid, yield 18%).

LC-MS (ESI): m/z 432.2/434.2 [M+H⁺]。

¹HNMR(400MHz,CDCl₃) δ 8.37 (d, J=7.1Hz, 1H), 7.39 (d, J=8.9Hz, 1H), 7.30 (d, J= 8.8Hz, 1H), 7.23 (s, 2H), 7.07-6.99 (m, 2H), 6.96 (d, J=3.1Hz, 1H), 6.89 (dd, J=8.9, 3.1Hz, 1H), 6.67 (d, J=6.8Hz, 1H), 4.34 (s, 2H), 3.50 (d, J=5.9Hz, 2H), 2.92 (s, 2H), 2.17 (s, 3H), 1.51~1.48 (m, 6H).

Embodiment 7:2- (the fluoro- 3- of the chloro- 2- of 4- (1- methyl-1 H- benzo [d] imidazoles -2- base) phenyl) -6- ((3S, 5R) - 3,5- dimethyl -1- base) -1,2,3,4- tetrahydroisoquinoline (7) preparation

The preparation of bromo- -2 (the 1H)-carboxylic acid tert-butyl ester (7c) of 3,4- dihydro-isoquinoline of step 1:6-

The addition 6- bromo- 1 in the reaction flask containing methylene chloride (20mL), 2,3,4- tetrahydroisoquinolines (1.4g, 6.60mmol) and di-tert-butyl dicarbonic acid ester (2.16g, 9.90mmol).It is stirred at room temperature 30 minutes, then depressurizes reaction solution Concentration.Residue purifies (eluent PE:EA/10:1) by silica gel column chromatography method, obtains bromo- 3, the 4- dihydro isoquinoline of 6- Quinoline -2 (1H)-carboxylic acid tert-butyl ester (2.0g, colourless grease, yield: 97%).

LC-MS (ESI): m/z 312.1/314.3 [M+H⁺]。

Step 2:6-((3S, 5R)-3,5- lupetazin-1- base)-3,4- dihydro-isoquinoline-2 (1H)-carboxylic acid tert-butyl ester The preparation of (7d)

In room temperature, by bromo- -2 (the 1H)-carboxylic acid tert-butyl ester (300mg, 0.96mmol) of 3,4- dihydro-isoquinoline of 6-, (2S, 6R) -2,6-dimethyl-piperizine (131mg, 1.15mmol), BINAP (119mg, 0.19mmol), sodium tert-butoxide (276mg, 2.88mmol)、Pd₂(dba)₃(87.9mg, 0.10mmol) and toluene (6mL) are added in reaction flask.Sealing, nitrogen displacement 3 It is secondary, it is heated to 100 DEG C and reacts 4 hours.After reaction solution is cooled to room temperature, ethyl acetate dilution (50mL) is added, organic phase is used Saturated common salt water washing, anhydrous sodium sulfate dry, filter, filtrate decompression concentration.Residue is pure by silica gel column chromatography method Change (eluent DCM:MeOH/10:1), obtains 6- ((3S, 5R) -3,5- lupetazin -1- base) -3,4- dihydro-isoquinoline - 2 (1H)-carboxylic acid tert-butyl ester (330mg, yellow solid, yields: 99.69%).

LC-MS (ESI): m/z 346.2 [M+H⁺]。

The preparation of step 3:6-((3S, 5R)-3,5- lupetazin-1- base)-1,2,3,4- four hydrogen isoquinoline hydrochloric acid salt

6- ((3S, 5R) -3,5- lupetazin -1- base) -3,4- is added in the reaction flask containing methylene chloride (5mL) Dihydro-isoquinoline -2 (1H)-carboxylic acid tert-butyl ester (330mg, 0.95mmol) and hydrochloric acid dioxane (0.5mL, 4M).It is stirred at room temperature After 30 minutes, reaction solution is concentrated under reduced pressure, obtains 6- ((3S, 5R) -3,5- lupetazin -1- base) -1,2,3,4- tetrahydros are different Quinoline hydrochloride (213mg, white solid, yield: 91%).

LC-MS (ESI): m/z 246.2 [M+H⁺]。

Step 4:2- (the fluoro- 3- of the chloro- 2- of 4- (1- methyl-1 H- benzo [d] imidazoles-2- base) phenyl)-6-((3S, 5R)-3, 5- dimethyl -1- base) -1,2,3,4- tetrahydroisoquinoline preparation

In room temperature, by 2- (the chloro- 2- fluorophenyl of the bromo- 6- of 3-) -1- methyl-1 H- benzo [d] imidazoles (7a) (50mg, 0.15mmol), 6- ((3S, 5R) -3,5- lupetazin -1- base) -1,2,3,4- tetrahydroisoquinolines (50.5mg, 0.20mmol), BINAP (18.3mg, 0.03mmol), cesium carbonate (143mg, 0.44mmol), Pd₂(dba)₃(13.4mg, 0.01mmol) it is added in reaction flask with toluene (4mL).Sealing, nitrogen are replaced 3 times, are heated to 100 DEG C and are stirred 4 hours.Reaction After liquid is cooled to room temperature, filtering, filtrate decompression concentration.Residue purifies (C18, acetonitrile/water (0.1% first by preparation HPLC Acid), 10%~100%), obtain 2- (the fluoro- 3- of the chloro- 2- of 4- (1- methyl-1 H- benzo [d] imidazoles-2- base) phenyl)-6-((3S, 5R) -3,5- dimethyl -1- base) -1,2,3,4- tetrahydroisoquinolines (23.7mg, white solid, yield: 31.9%).

LC-MS (ESI): m/z 504.3/506.4 [M+H⁺]。

¹H NMR(400MHz,DMSO-d₆) δ 7.70 (dd, J=21.0,8.0Hz, 2H), 7.46 (d, J=8.9Hz, 1H), 7.40-7.24 (m, 3H), 7.02 (d, J=8.5Hz, 1H), 6.81 (dd, J=8.4,2.4Hz, 1H), 6.71 (d, J=2.4Hz, 1H), 4.24 (q, J=15.1Hz, 2H), 3.66 (s, 3H), 3.53 (dd, J=11.6,2.7Hz, 2H), 3.42 (t, J= 5.9Hz, 2H), 3.09-2.72 (m, 3H), 2.16 (t, J=11.0Hz, 2H), 1.06 (d, J=6.2Hz, 6H).

Embodiment 8:(2S, 6R) -4- (2- (the fluoro- 3- of the chloro- 2- of 4- (1- methyl-1 H- benzo [d] imidazoles -2- base) phenyl) - 1,2,3,4- tetrahydroisoquinoline -6- base) -2,6- thebaine (8) preparation

Step 1:6- ((2S, 6R) -2,6- thebaine generation) -3,4- dihydro-isoquinoline -2 (1H)-carboxylic acid tert-butyl ester The preparation of (8a)

In room temperature, by bromo- -2 (the 1H)-carboxylic acid tert-butyl ester (7c) (200mg, 0.64mmol) of 3,4- dihydro-isoquinoline of 6-, (2S, 6R) -2,6- thebaine (88.5mg, 0.77mmol), BINAP (79.7mg, 0.13mmol), Pd₂(dba)₃ (58.6mg, 0.06mmol), sodium tert-butoxide (184mg, 1.92mmol) and toluene (4mL) are added in reaction flask.Sealing, nitrogen Displacement 3 times is heated with stirring to 100 DEG C and reacts 4 hours.After reaction solution is cooled to room temperature, ethyl acetate dilution (50mL) is added, Organic phase saturated common salt water washing, anhydrous sodium sulfate dry, filter, filtrate decompression concentration.Residue passes through silica gel column chromatography It purifies (eluent PE:EA/5:1), obtains 6- ((2S, 6R) -2,6- thebaine generation) -3,4- dihydro-isoquinoline -2 (1H)-carboxylic acid tert-butyl ester (190mg, the grease of yellow, yield: 90.4%).

LC-MS (ESI): m/z 347.2 [M+H⁺]。

Step 2:(2S, 6R) -2,6- dimethyl -4- (1,2,3,4- tetrahydroisoquinoline -6- base) morpholine (8b) preparation

6- ((2S, 6R) -2,6- thebaine generation) -3,4- two is added in the reaction flask containing methylene chloride (4mL) Hydrogen isoquinoline -2 (1H)-carboxylic acid tert-butyl ester (190mg, 0.55mmol) and hydrochloric acid dioxane (0.5mL, 4M).It is stirred at room temperature 30 It after minute, is concentrated under reduced pressure, and is suspended with ethyl acetate (30mL), with saturation NaHCO₃Solution and saturated common salt water washing, it is anhydrous Sodium sulphate dries, filters, filtrate decompression concentration.Residue by silica gel column chromatography method purify (eluent PE:EA/1: 1), obtaining (2S, 6R) -2,6- dimethyl -4- (1,2,3,4- tetrahydroisoquinoline -6- base) morpholine, (130mg, yellow solid are received Rate: 96.2%).

LC-MS (ESI): m/z 247.2 [M+H⁺]。

Step 3:(2S, 6R) -4- (2- (the fluoro- 3- of the chloro- 2- of 4- (1- methyl-1 H- benzo [d] imidazoles -2- base) phenyl) -1, 2,3,4- tetrahydroisoquinoline -6- base) -2,6- thebaine (8) preparation

In room temperature, by 2- (the chloro- 2- fluorophenyl of the bromo- 6- of 3-) -1- methyl-1 H- benzo [d] imidazoles (7a) (30mg, 0.08mmol), (2S, 6R) -2,6- dimethyl -4- (1,2,3,4- tetrahydroisoquinoline -6- base) morpholine (30mg, 0.12mmol), BINAP (10mg, 0.02mmol) and cesium carbonate (78mg, 0.24mmol), Pd₂(dba)₃(7.3mg, 0.008mmol) and toluene (2mL) is added in reaction flask.Sealing after being replaced 3 times with nitrogen, is heated to 100 DEG C and stirs 4 hours.It is cooled to reaction solution After room temperature, filtering, filtrate decompression concentration.Residue by preparation HPLC purifying (C18, acetonitrile/water (0.1% formic acid), 10%~ 100%), obtain (2S, 6R) -4- (2- (the fluoro- 3- of the chloro- 2- of 4- (1- methyl-1 H- benzo [d] imidazoles -2- base) phenyl) -1,2,3, 4- tetrahydroisoquinoline -6- base) -2,6- thebaine (6.8mg, yellow solid, yield: 11%).

LC-MS (ESI): m/z 505.4/507.3 [M+H⁺]。

¹H NMR(400MHz,DMSO-d₆) δ 7.70 (dd, J=20.6,8.0Hz, 2H), 7.46 (d, J=8.8Hz, 1H), 7.41-7.24 (m, 3H), 7.04 (d, J=8.5Hz, 1H), 6.82 (dd, J=8.4,2.5Hz, 1H), 6.72 (d, J=2.4Hz, 1H), 4.30-4.16 (m, 2H), 3.66 (s, 3H), 3.60-3.49 (m, 2H), 3.42 (t, J=5.9Hz, 2H), 3.33 (s, 2H), 2.87 (t, J=6.0Hz, 2H), 2.20 (t, J=11.1Hz, 2H), 1.15 (d, J=6.2Hz, 6H).

Embodiment 9:2- (the chloro- 4- of 5- (1- methyl-1 H- benzo [d] imidazoles -2- base) pyridine -2- base) -6- ((3S, 5R) - 3,5- dimethyl -1- base) -1,2,3,4- tetrahydroisoquinoline (9) preparation

2- (the bromo- 5- chloropyridine -4- base of 2-) -1- methyl-1 H- benzo [d] is added in the reaction flask of (4mL) containing toluene Imidazoles (9a) (77mg, 0.24mmol), 6- ((3S, 5R) -3,5- lupetazin -1- base) -1,2,3,4- tetrahydroisoquinolines (7e) (50mg, 0.20mmol), BINAP (25mg, 0.04mmol), cesium carbonate (195mg, 0.60mmol) and Pd₂(dba)₃ (37mg, 0.04mmol).Sealing, nitrogen replace 3 times, are heated to 100 DEG C and are stirred overnight.It is cooled to room temperature to reaction mixture Afterwards, it filters, filtrate decompression concentration.Residue by preparation HPLC purifying (C18, acetonitrile/water (0.1% formic acid), 1%~ 100%) 2- (the chloro- 4- of 5- (1- methyl-1 H- benzo [d] imidazoles -2- base) pyridine -2- base) -6- ((3S, 5R) -3,5- bis-, is obtained Methyl-1-yl)-1,2,3,4- tetrahydroisoquinolines (26mg, white solid, yield: 27%).

LC-MS (ESI): m/z 488.2/490.2 [M+H⁺]。

¹H NMR(400MHz,CHCl₃- d) δ 8.23 (s, 1H), 7.79 (d, J=7.0Hz, 1H), 7.37 (d, J=7.2Hz, 1H), 7.34-7.24 (m, 2H), 7.00 (d, J=8.4Hz, 1H), 6.79 (s, 1H), 6.73 (d, J=8.3Hz, 1H), 6.66 (s, 1H), 4.57 (s, 2H), 3.78 (t, J=5.9Hz, 2H), 3.66 (s, 3H), 3.46 (d, J=10.3Hz, 2H), 3.16 (s, 2H), 2.63-2.54 (m, 2H), 1.23 (d, J=6.5Hz, 6H).

Embodiment 10:(2S, 6R) -4- (2- (the chloro- 4- of 5- (1- methyl-1 H- benzo [d] imidazoles -2- base) pyridine -2- base) - 1,2,3,4- tetrahydroisoquinoline -6- base) -2,6- thebaine (10) preparation

2- (the bromo- 5- chloropyridine -4- base of 2-) -1- methyl-1 H- benzo [d] is added in the reaction flask of (4mL) containing toluene Imidazoles (9a) (65mg, 0.20mmol), (2S, 6R) -2,6- dimethyl -4- (1,2,3,4- tetrahydroisoquinoline -6- base) morpholine (8b) (50mg, 0.20mmol), BINAP (25mg, 0.04mmol), cesium carbonate (195mg, 0.60mmol) and Pd₂(dba)₃ (37mg, 0.04mmol).Sealing, nitrogen replace 3 times, are heated to 100 DEG C and are stirred overnight.It is cooled to room temperature to reaction mixture Afterwards, it filters, filtrate decompression concentration.Residue by preparation HPLC purifying (C18, acetonitrile/water (0.1% formic acid), 10%~ 100%), obtain (2S, 6R) -4- (2- (the chloro- 4- of 5- (1- methyl-1 H- benzo [d] imidazoles -2- base) pyridine -2- base) -1,2,3, 4- tetrahydroisoquinoline -6- base) -2,6- thebaine (4mg, white solid, yield: 5%).

LC-MS (ESI): m/z 487.2/489.2 [M+H⁺]。

¹H NMR(400MHz,CHCl₃-d)δ8.23(s,1H),7.78(s,1H),7.29(s,2H),6.99(s,1H), 6.79(s,1H),6.65(s,1H),4.56(s,2H),3.78(s,2H),3.66(s,3H),3.35(s,2H),2.86(s,2H), 2.33 (s, 2H), 1.19 (d, J=6.2Hz, 6H).

Embodiment 11:2- (2- (the chloro- 3- of 4- (1- methyl-1 H- benzo [d] imidazoles -2- base) phenyl) -1,2,3,4- tetrahydro Isoquinolin -6- base) propan-2-ol (11) preparation

Step 1: the preparation of isoquinolin -6- formonitrile HCN (11c)

In room temperature, by 6- bromo-isoquinoline (2g, 9.61mmol), zinc cyanide (2.25g, 19.22mmol), Pd (PPh₃)₄ (1.2g, 1.44mmol) and DMF (30mL) are added in 100mL reaction flask.Sealing, nitrogen replace three times, are heated to 100 DEG C and stir It mixes 1 hour.After reaction solution is cooled to room temperature, 100 (mL) ethyl acetate are added and dilute, organic phase saturated common salt water washing, Anhydrous sodium sulfate dries, filters, filtrate decompression concentration.Residue by silica gel column chromatography method purify (eluent PE: EA/5:1 isoquinolin -6- formonitrile HCN (1.0g, yellow solid, yield: 67.1%)) are obtained.

LC-MS (ESI): m/z 155.2 [M+H⁺]。

Step 2: the preparation of isoquinolin -6- carboxylic acid (11d)

Isoquinolin -6- formonitrile HCN (1g, 6.49mmol) is heated to reflux 4 hours in 10mL concentrated hydrochloric acid, it is cooling to reaction solution To room temperature, with saturation NaHCO₃Solution adjusts pH value to~6, and the white precipitate of generation is collected by filtration, dry, obtains isoquinoline Quinoline -6- carboxylic acid (1.2g, white solid).

LC-MS(ESI),m/z 174.1[M+H⁺]。

Step 3: the preparation of methylisoquinolinium -6- carboxylate (11e)

In the reaction flask containing 10mL methanol, isoquinolin -6- carboxylic acid (1.2g, 6.92mmol) and the concentrated sulfuric acid is added (5mL).Reaction solution is refluxed overnight, after being cooled to room temperature, with the NaHCO of saturation₃Aqueous solution neutralizes, methylene chloride extraction (50mL x3) merges organic phase, saturated common salt water washing, and anhydrous sodium sulfate dries, filters, and filtrate decompression concentration obtains methyl Isoquinolin -6- carboxylate (900mg, yellow solid, yield 69.4%).

LC-MS(ESI),m/z 188.2[M+H⁺]。

Step 4: the preparation of methyl 1,2,3,4- tetrahydroisoquinoline -6- carboxylic acid, ethyl ester (11f)

Methylisoquinolinium -6- carboxylate (900mg, 4.8mmol), acetic acid are added in the round-bottomed flask containing 20mL methanol (1mL) and platinum dioxide (200mg, 0.86mmol).Reaction system is replaced 3 times with hydrogen, and it is small to be then heated to 40 DEG C of reactions 4 When.It is filtered after reaction solution is cooled to room temperature, filtrate decompression concentration.100mL ethyl acetate is added in residue, then uses respectively Saturated sodium bicarbonate aqueous solution and saturated common salt water washing, anhydrous sodium sulfate dry, filter, filtrate decompression concentration.Residue is logical Silica gel column chromatography method purifying (eluent DCM:MeOH/10:1) is crossed, 1,2,3,4- tetrahydroisoquinoline -6- carboxylic of methyl is obtained Acetoacetic ester (800mg, yellow solid, yield: 78.4%).

LC-MS(ESI),m/z 192.3[M+H⁺]。

Step 5:2- (the chloro- 3- of 4- (1- methyl-1 H- benzo [d] imidazoles -2- base) phenyl) -1,2,3,4- tetrahydroisoquinoline - The preparation of 6- carboxylate methyl ester (11g)

In room temperature, 2- (the bromo- 2- chlorphenyl of 5-) -1- methyl-1 H- benzo [d] imidazoles is added into 20mL round-bottomed flask 1,2,3,4- tetrahydroisoquinoline -6- carboxylic acid, ethyl ester (101mg, 0.53mmol) of (11a) (170mg, 0.53mmol), methyl, BINAP (65.8mg, 0.11mmol), cesium carbonate (516mg, 1.58mmol), Pd₂(dba)₃(48.3mg, 0.05mmol) and toluene (5mL).Sealing, reaction suspension are replaced 3 times with nitrogen, are heated to 100 DEG C and are stirred overnight.After reaction solution is cooled to room temperature, Filtering, filtrate decompression concentration.Residue purifies (eluent PE:EA/1:1) by silica gel column chromatography method, obtains 2- (4- Chloro- 3- (1- methyl-1 H- benzo [d] imidazoles -2- base) phenyl) and -1,2,3,4- tetrahydroisoquinoline -6- carboxylate methyl ester (140mg, it is white Color solid, yield 74.4%).

LC-MS(ESI),(m/z)432.2[M+1]。

Step 6:2- (2- (the chloro- 3- of 4- (1- methyl-1 H- benzo [d] imidazoles -2- base) phenyl) -1,2,3,4- Tetrahydroisoquinoli- Quinoline -6- base) propan-2-ol preparation

Under nitrogen protection, 2- (the chloro- 3- of 4- (1- methyl-1 H- benzo [d] imidazoles -2- is added into 20mL round-bottomed flask Base) phenyl) -1,2,3,4- tetrahydroisoquinoline -6- carboxylate methyl esters (45mg, 0.10mmol) and anhydrous THF (2mL).To reaction solution After being cooled to 0 DEG C, methyl-magnesium-bromide (0.17mL, 3M diethyl ether solution) is slowly added dropwise.After being added dropwise, reaction solution is risen into room Temperature, continue stirring 30 minutes after, be quenched with the aqueous ammonium chloride solution of saturation, ethyl acetate extract (10mLx3), merging it is organic The brine It of saturation is mutually used, anhydrous sodium sulfate dries, filters, filtrate decompression concentration.Residue passes through preparation HPLC purifying (C18, acetonitrile/water (0.1% formic acid), 10%~100%) obtains 2- (2- (the chloro- 3- of 4- (1- methyl-1 H- benzo [d] imidazoles- 2- yl) phenyl) -1,2,3,4- tetrahydroisoquinoline -6- bases) propyl- 2- base alcohol (15mg, white solid, yield 33.3%).

LC-MS (ESI): m/z 432.2/434.2 [M+H⁺]。

¹H NMR (400MHz, DMSO-d6) δ 7.70 (d, J=7.8Hz, 1H), 7.63 (d, J=7.9Hz, 1H), 7.48 (d, J=9.0Hz, 1H), 7.36-7.23 (m, 4H), 7.21 (dd, J=9.0,3.1Hz, 1H), 7.16-7.10 (m, 2H), 4.96 (s, 1H), 4.43 (s, 2H), 3.63 (d, J=17.2Hz, 5H), 2.92 (t, J=5.9Hz, 2H), 1.41 (s, 6H).

Embodiment 12:2- (the chloro- 3- of 4- (1- methyl-1 H- benzo [d] imidazoles -2- base) phenyl) -6- (cyclopentyloxy) -1, The preparation of 2,3,4- tetrahydroisoquinoline (12)

The preparation of -2 (1H)-carboxylic acid tert-butyl ester (12b) of step 1:6- hydroxyl -3,4- dihydro-isoquinoline

Containing methanol (3mL) reaction flask in be added 1,2,3,4- tetrahydroisoquinoline -6- alcohol (200mg, 1.34mmol), Triethylamine (339mg, 3.35mmol) and Boc acid anhydrides (467mg, 2.14mmol) are stirred at room temperature overnight.After completion of the reaction, will Reaction solution is concentrated under reduced pressure, and residue purifies (eluent PE:EA=5:1) by silica gel column chromatography method, and it is solid to obtain white Body 6- hydroxyl -3,4- dihydro-isoquinoline -2 (1H)-carboxylic acid tert-butyl ester (220mg, white solid, yield: 66%).

250.7 [M+H of LC-MS (ESI), m/z⁺]。

The preparation of -2 (1H)-carboxylic acid tert-butyl ester (12c) of step 2:6- (cyclopentyloxy) -3,4- dihydro-isoquinoline

- 2 (1H)-carboxylic acid tert-butyl ester of 6- hydroxyl -3,4- dihydro-isoquinoline is added in the reaction flask containing DMF (15mL) (220mg, 0.88mmol), bromocyclopentane (145mg, 0.97mmol) and potassium carbonate (120mg, 0.88mmol).Reaction is mixed Object is closed to stir 100 hours in 100 DEG C.After reaction mixture is cooled to room temperature, ethyl acetate (10mL) dilution is added, with water and Saturated common salt water washing, anhydrous sodium sulfate dry, filter, filtrate decompression concentration.Residue is pure by silica gel column chromatography method Change (eluent PE:EA=5:1), obtains white solid 6- (cyclopentyloxy) -3,4- dihydro-isoquinoline -2 (1H)-tertiary fourth of carboxylic acid Ester (60mg, white solid, yield: 21%).

318.6 [M+H of LC-MS (ESI), m/z⁺]。

The preparation of step 3:6- (cyclopentyloxy) -1,2,3,4- four hydrogen isoquinoline hydrochloric acid salt (12d)

- 2 (1H)-carboxylic of 6- (cyclopentyloxy) -3,4- dihydro-isoquinoline is added in the reaction flask containing methylene chloride (2mL) Tert-butyl acrylate (60mg, 0.188mmol) is added dropwise hydrochloric acid dioxane solution (2mL, 4M), is stirred at room temperature 0.5 hour.Then, Reaction solution is concentrated under reduced pressure, is obtained crude product 6- (cyclopentyloxy) -1,2,3,4- four hydrogen isoquinoline hydrochloric acid salts are not purified And it is directly used in and reacts in next step.

218.6 [M+H of LC-MS (ESI), m/z⁺]。

Step 4:2- (the chloro- 3- of 4- (1- methyl-1 H- benzo [d] imidazoles -2- base) phenyl) -6- (cyclopentyloxy) -1,2,3, The preparation of 4- tetrahydroisoquinoline (12)

6- (cyclopentyloxy) -1,2,3,4- four hydrogen isoquinoline hydrochloric acid salt is added in the reaction flask of (6mL) containing toluene (60mg, 0.28mmol), 2- (the bromo- 2- chlorphenyl of 5-) -1- methyl-1 H- benzo [d] imidazoles (11a) (74mg, 0.23mmol), BINAP (29mg, 0.046mmol), cesium carbonate (224mg, 0.69mmol) and Pd₂(dba)₃(42mg, 0.046mmol).Sealing, Nitrogen is replaced 3 times, is heated to 100 DEG C and is stirred overnight.After reaction mixture is cooled to room temperature, filtering, filtrate decompression concentration.It is residual Excess obtains 2- (4- chloro- 3- (1- first by preparation HPLC purifying (C18, acetonitrile/water (0.1% formic acid), 20%~100%) Base -1H- benzo [d] imidazoles -2- base) phenyl) -6- (cyclopentyloxy) -1,2,3,4- tetrahydroisoquinolines (receive by 8mg, white solid Rate: 7.4%).

LC-MS (ESI): m/z 458.3/460.3 [M+H⁺]。

¹H NMR(400MHz,CHCl₃- d) δ 7.88 (d, J=7.3Hz, 1H), 7.40 (dd, J=18.8,9.7Hz, 5H), 7.12 (s, 1H), 7.05 (d, J=7.9Hz, 2H), 6.76 (s, 1H), 6.70 (s, 1H), 4.76 (s, 1H), 4.39 (s, 2H), 3.73 (s, 3H), 3.58 (t, J=5.8Hz, 2H), 2.96 (s, 2H), 1.89-1.51 (m, 8H).

Embodiment 13:N- (5- (4- (the chloro- 3- of 4- (1- methyl-1 H- benzo [d] imidazoles -2- base) phenyl) piperazine -1- base) Pyrimidine -2-base) pivaloyl amine (13) preparation

Step 1:(Z) -3- ((dimethylamino) methylene) -4- oxo-piperidine -1- carboxylic acid tert-butyl ester (13b) preparation

4- t-butoxycarbonylpiperidin is added in the reaction flask containing N,N-dimethylformamide dimethylacetal (40mL) Ketone (4.0g, 20.0mmol) is heated to 90 DEG C and is stirred overnight.After reaction mixture is cooled to room temperature, ethyl acetate is added (50mL) dilution, is washed twice with water and saturated salt solution, and anhydrous sodium sulfate dries, filters, and filtrate decompression concentration is slightly produced Product (Z) -3- ((dimethylamino) methylene) -4- oxo-piperidine -1- carboxylic acid tert-butyl ester (6.1g, yellow solid).

255.8 [M+H of LC-MS (ESI), m/z⁺]。

The preparation of step 2:2- amino -7,8- dihydro pyrido [4,3-d] pyrimidine -6 (5H)-carboxylic acid tert-butyl ester (13c)

In room temperature, guanidine hydrochloride (1.92g, 20.1mmol), sodium ethoxide are added in the reaction flask containing ethyl alcohol (20mL) (1.37g, 20.1mmol).After being stirred at room temperature 0.5 hour, (Z) -3- ((dimethylamino) methylene) -4- oxo piperazine is added Pyridine -1- carboxylic acid tert-butyl ester (3.1g, 12.2mmol), finishes and is heated to being refluxed overnight.It is cooled to room temperature to reaction solution, acetic acid is added Ethyl ester (50mL) dilution, with water and saturated common salt water washing, anhydrous sodium sulfate is dried, filtered, filtrate decompression concentration.Residue is logical Silica gel column chromatography method purifying (eluent PE:EA=1:2) is crossed, it is phonetic to obtain 2- amino -7,8- dihydro pyrido [4,3-d] Pyridine -6 (5H)-carboxylic acid tert-butyl ester (750mg, orange liquid, yield: 25%).

251.4 [M+H of LC-MS (ESI), m/z⁺]。

Step 3:2- pivaloyl amino -7,8- dihydro pyrido [4,3-d] pyrimidine -6 (5H)-carboxylic acid tert-butyl ester (13d) Preparation

2- amino -7,8- dihydro pyrido [4,3-d] pyrimidine -6 is added in the reaction flask containing methylene chloride (4mL) (5H)-carboxylic acid tert-butyl ester (200mg, 0.80mmol) and triethylamine (162mg, 0.96mmol), are cooled to 0 DEG C, are slowly added dropwise new Valeric chloride (116mg, 0.96mmol).It finishes and is warmed to room temperature, continue to be stirred overnight.After complete reaction, reaction solution is depressurized dense Contracting.Residue purifies (eluent PE:EA=2:1) by silica gel column chromatography method, obtains 2- pivaloyl amino -7,8- bis- Pyridinium hydroxide simultaneously [4,3-d] pyrimidine -6 (5H)-carboxylic acid tert-butyl ester (200mg, colourless liquid, yield: 75%).

335.6 [M+H of LC-MS (ESI), m/z⁺]。

The preparation of step 4:N- (5,6,7,8- tetrahydropyridine simultaneously [4,3-d] pyrimidine -2-base) pivaloyl amine hydrochloride (13e)

It is phonetic that 2- pivaloyl amino -7,8- dihydro pyrido [4,3-d] is added in the reaction flask containing methylene chloride (2mL) Pyridine -6 (5H)-carboxylic acid tert-butyl ester (200mg, 0.595mmol) is added dropwise hydrochloric acid dioxane solution (2mL), is stirred at room temperature 0.5 After hour, reaction solution is concentrated under reduced pressure, obtains crude product N- (5,6,7,8- tetrahydropyridines simultaneously [4,3-d] pyrimidine -2-base) new penta Amide hydrochloride (200mg, white solid).Its not purified is directly used in is reacted in next step.

LC-MS (ESI): m/z 235.9 [M+H⁺]。

(5- (4- (the chloro- 3- of 4- (1- methyl-1 H- benzo [d] imidazoles -2- base) phenyl) piperazine -1- base) is phonetic by step 5:N- Pyridine -2- base) pivaloyl amine (13) preparation

It is new that N- (5,6,7,8- tetrahydropyridine simultaneously [4,3-d] pyrimidine -2-base) is added in the reaction flask of (4mL) containing toluene Pentanamide (50mg, 0.213mmol), 2- (the bromo- 2- chlorphenyl of 5-) -1- methyl-1 H- benzo [d] imidazoles (11a) (54mg, 0.178mmol), BINAP (22mg, 0.036mmol), cesium carbonate (174mg, 0.534mmol) and Pd₂(dba)₃(33mg, 0.036mmol).Sealing, nitrogen replace 3 times, are heated to 100 DEG C and are stirred overnight.After reaction mixture is cooled to room temperature, mistake Filter, filtrate decompression concentration.Residue is obtained by preparation HPLC purifying (C18, acetonitrile/water (0.1% formic acid), 20%~100%) To N- (5- (4- (the chloro- 3- of 4- (1- methyl-1 H- benzo [d] imidazoles -2- base) phenyl) piperazine -1- base) pyrimidine -2-base) pivaloyl Amine (8mg, white solid, yield: 10%).

LC-MS (ESI): m/z 475.2/477.3 [M+H⁺]。

¹H NMR(400MHz,CHCl₃- d) δ 8.34 (s, 1H), 7.99 (s, 1H), 7.78 (s, 1H), 7.35 (d, J= 8.8Hz, 2H), 7.29 (s, 2H), 7.11 (s, 1H), 7.02 (s, 1H), 4.32 (s, 2H), 3.62 (d, J=18.1Hz, 5H), 3.00(s,2H),1.26(s,9H)。

Biological assessment

Test case 1 the compounds of this invention cell in vitro Hedgehog signal path (SMO) inhibitory activity test experiments

Use transcription factor Gli bioluminescence element enzyme Reporter System (luciferase report assay System the transcriptional control of Gli gene and expression after) detection SMO is suppressed, turn Gli gene to detect, assess compound Record the excitement or inhibiting effect of regulation.This experiment is with the IC of compound₅₀Value is that metrics evaluation compound is logical to Hedgehog signal Road (SMO) inhibiting effect.

1.1 test materials and instrument

1.2 cell strain

Shh-LIGHT2 (Shanghai Hui Yuan biology), fibroblast strain Shh-LIGHT2 is based on l cell NIH 3T3 differentiation transformation is formed.By stablizing building Gli correlation firefly luciferase (GLI- on NIH 3T3 cell Dependent Firefly Luciferase) and internal reference renilla luciferase (Renilla Luciferase), Shh- LIGHT2 cell strain possesses twin object luciferase reporter gene system, is ideal drug screening cell platform.

1.3 test reagent

1.4 cell culture fluid

Grown cultures liquid:

DMEM:Invitrogen, Cat#31053036

10%FBS:Invitrogen, Cat#10099-141

1%PenStrep:Invitrogen, Cat#15140-122

1% Sodium Pyruvate: Invitrogen, Cat#11360070

1%GlutaMax:Invitrogen, Cat#35050061

Complete culture solution

DMEM:Invitrogen, Cat#31053036

10%FBS:Invitrogen, Cat#10099-141

1%PenStrep:Invitrogen, Cat#15140-122

1% Sodium Pyruvate: Invitrogen, Cat#11360070

1%GlutaMax:Invitrogen, Cat#35050061

0.4mg/ml G418:GIBCO, Cat#10131-027

0.15mg/ml antimycin: Invitrogen, Cat#R25005

1.5 cell culture protocol

A) cell recovery

1) by Shh-LIGHT2 cell cryopreservation tube from being removed and placed in 37 DEG C of water-baths in liquid nitrogen container, lasting shaking is thin Born of the same parents' cryopreservation tube until cell thaws, complete in 30 seconds to 1 minute by the Row control that entirely thaws；

2) prepare a 15ml centrifuge tube, be added 10ml preheating grown cultures liquid in (without screening antibiotic G418 and Antimycin), by cell from being transferred in cryopreservation tube in the centrifuge tube, then with 1000rpm centrifugation 5 minutes；

3) supernatant is removed, the grown cultures liquid of 10ml preheating is added in centrifuge tube, is transferred to cell after mixing In 10cm culture dish, it is placed in 37 DEG C and 5%CO₂Incubator in cultivate；

4) 24 hours culture after, remove grown cultures liquid, be added 10ml complete culture solution (containing screening antibiotic G418 and Antimycin), it is placed in 37 DEG C and 5%CO₂Incubator in cultivate.

B) cell passes on

1) cell is observed daily, after the area of 10cm culture dish 85% covers with cell, carries out cell passage；

2) culture solution is removed, cell surface is cleaned using PBS, removes PBS；Use 0.25% trypsase-EDTA of 1ml After vitellophag 1-3 minutes, 2ml culture solution is added and terminates digestion；Cell is softly blown and beaten using liquid-transfering gun until cell is from culture Ware surface falls off；

3) 1ml cell suspension is transferred in new culture dish according to the ratio of 1:3,9ml complete culture solution is added, mixed Culture dish is placed in 37 DEG C and 5%CO₂Incubator in cultivate.

C) cell cryopreservation

1) extra Tissue Culture Dish can carry out cell cryopreservation for future use；Vitellophag simultaneously carries out cell count, will be thin Born of the same parents collect in 15ml centrifuge tube, and with 1000rpm centrifugation 5 minutes, centrifugation simultaneously, prepared cells frozen storing liquid (90%FBS+10% DMSO)；

2) supernatant is removed, cells frozen storing liquid is added, cell concentration is made to maintain 2 × 10⁶Cell/ml is resuspended cell, takes 1ml cell liquid is placed in cell cryopreservation tube out；

3) cell cryopreservation tube is placed in cell cryopreservation box, is placed in -80 DEG C of refrigerator overnights, be transferred to liquid nitrogen container within second day In (- 196 DEG C) for a long time store.

1.6 luciferase reporter gene systems detect activity Step

Step 1: preparing tissue culture plate

A) cell culture fluid is prepared

Grown cultures liquid:

DMEM:Invitrogen, Cat#31053036

10%FBS:Invitrogen, Cat#10099-141

1%PenStrep:Invitrogen, Cat#15140-122

1% Sodium Pyruvate: Invitrogen, Cat#11360070

1%GlutaMax:Invitrogen, Cat#35050061

Detect culture solution:

DMEM:Invitrogen, Cat#31053036

2%FBS:Invitrogen, Cat#10099-141

1%PenStrep:Invitrogen, Cat#15140-122

1% Sodium Pyruvate: Invitrogen, Cat#11360070

1%GlutaMax:Invitrogen, Cat#35050061

B) repopulating cell

1) vitellophag and cell count is carried out；

2) cell density is adjusted to 3.2*10 using grown cultures liquid⁵Cell/mL trains cell seeding to 384 hole cells It supports plate (Corning#3570), every hole: 8k cell/25 μ L；

3) tissue culture plate is placed in 37 DEG C and 5%CO₂Incubator in cultivate, until 80% density.

Step 2: preparing untested compound, carry out the detection of Agonist Mode and inhibitor mode respectively

A) Agonist Mode preparation of samples

1) untested compound and 2,6,9- ternary substituted purin are dissolved in analysis and research in DMSO and being stored in -20 DEG C；

2) untested compound and 2 is taken out, 6,9- ternary substituted purins thaw completely；

3) prepare untested compound concentration (100 μM of initial concentration, according to 3 times ratio diluted concentration 9 times, altogether 10 to Survey concentration)；

4) prepare 2,6,9- ternary substituted purins as positive control drug (10 μM of initial concentration, it is dense according to 3 times of dilution proportions Degree 9 times, altogether 10 concentration to be measured)；

5) the full positive reference group (HPE) of test preparation and the full negative reference group (ZPE) of test；The preparation method of HPE: 4 μM 2,6,9- ternary substituted purin；The preparation method of ZPE: 0.5% analysis and research DMSO.

6) all untested compounds, 2,6,9- ternary substituted purins, HPE, ZPE are prepared by every 35 μ l of hole, are laid on 384 orifice plates On (drug plate) (Corning#3656).

B) it is added on sample to tissue culture plate under Agonist Mode

1) tissue culture plate is taken out from incubator；

2) cell liquid in thin culture plate is got rid of manually, movement is soft；

3) tissue culture plate is inverted in centrifuge low speed (200rpm) centrifugation and completely removes culture solution in 30 seconds；

4) 25 μ l samples are accurately shifted from drug plate into tissue culture plate using Bravo instrument；

5) tissue culture plate is placed in 37 DEG C and 5%CO₂Incubator in cultivate 28 hours, wait luciferase reporting Genetic test.

C) inhibitor mode preparation of samples

1) untested compound, GDC-0449, GANT61 and 2,6,9- ternary substituted purin analysis and research are dissolved in use In DMSO and it is stored in -20 DEG C；

2) untested compound, GDC-0449, GANT61,2 are taken out, 6,9- ternary substituted purins sufficiently thaw；

3) prepare untested compound concentration (1 μM of initial concentration, according to 3 times ratio diluted concentration 9 times, altogether 10 it is to be measured Concentration)；

4) prepare GDC-0449, GANT61 as positive control drug (1 μM of GDC-0449 initial concentration, it is dilute according to 3 times of ratios Release concentration 9 times, altogether 10 concentration to be measured；100 μM of GANT61 initial concentration, according to 3 times ratio diluted concentration 9 times, altogether 10 A concentration to be measured)；

5) the full positive reference group (HPE) of test preparation and the full negative reference group (ZPE) of test；The preparation method of HPE: 100 μ M GANT61；The preparation method of ZPE: 0.5% analysis and research DMSO.

6) all untested compounds, GDC-0449, GANT61, HPE, ZPE are prepared by every 35 μ l of hole, are layered on (the suppression of 384 orifice plates Preparation medicine plate) on (Corning#3656)；

7) prepare 2,6,9- ternary substituted purin as agonist (9 μM of concentration)；

8) 2,6,9- ternary substituted purins are prepared by every 20 μ l of hole, are layered on 384 orifice plates (anti-depressant medications plate) (Corning#3656)。

D) it is added on sample to tissue culture plate under inhibitor mode

1) tissue culture plate is taken out from incubator；

2) cell liquid in thin culture plate is got rid of manually, movement is soft；

3) tissue culture plate is inverted in centrifuge low speed (200rpm) centrifugation and completely removes culture solution in 30 seconds；

4) using Bravo instrument accurately shifted from inhibitor medicaments plate 25 μ l untested compounds, GDC-0449, GANT61, HPE, ZPE are into tissue culture plate；

5) tissue culture plate is placed in 37 DEG C and 5%CO₂Incubator in cultivate 30 minutes；

6) tissue culture plate is taken out from incubator, accurately shifts 5 μ l from anti-depressant medications plate using Bravo instrument 2,6,9- ternary substituted purin (1.5 μM of 2,6,9- ternary substituted purin final concentration at this time) into tissue culture plate；

7) tissue culture plate is placed in 37 DEG C and 5%CO₂Incubator in cultivate 28 hours, wait luciferase reporting base Because of test.

Step 3: luciferase reporter gene test

1) Dual-Glo luciferase reagent (Promega) is prepared in thaw at RT and to specifications；

2) it takes out tissue culture plate and is placed in room temperature 30 minutes；

3) 25 μ l Dual-Glo luciferase reagents are added in tissue culture plate using multidrop combi instrument, Low-speed centrifugal (1000rpm) 1 minute；The liquid in every hole on cell plates is mixed using Bravo instrument；

4) 30 minutes are stood at room temperature, detects firefly luciferase numerical value using ViewLux；

5) Dual-Glo Stop&Glo reagent (Promega) is prepared at room temperature, uses multidrop combi instrument 25 μ l Dual-Glo Stop&Glo reagents are added in tissue culture plate, low-speed centrifugal (1000rpm) 1 minute；Use Bravo Instrument mixes the liquid in every hole on tissue culture plate；

6) 30 minutes are stood at room temperature, detects sea pansy fluorescein plum numerical value using ViewLux；

7) operation and analysis are carried out to detection numerical result using Matlab4, obtains the IC of the compounds of this invention₅₀(nM) Value.

As a result as shown in table 1 below.

1 the compounds of this invention cell in vitro Hedgehog signal path (SMO) inhibitory activity IC of table₅₀Value

Embodiment	IC50(nM)
		Embodiment 1	14.1
Embodiment 2	23.8
		Embodiment 3	5.5
Embodiment 4	6.0
		Embodiment 5	26.2
Embodiment 6	27.2
		Embodiment 7	26.6
Embodiment 8	14.2
		Embodiment 9	31.7
Embodiment 10	41.7
		Embodiment 11	5.0
Embodiment 12	10.3
		Embodiment 13	6.1
GDC-0449	54.7
		GANT61	4160.0

By upper table 1 it is found that the compounds of this invention can effectively inhibit transcription factor in cell Hedgehog signal path The regulation and expression of Gli.Compared with positive control medicine GDC-0449, GANT61, stronger rejection ability is shown.

Claims (21)

1. a kind of logical formula (I) compound represented or its mesomer, racemic modification, enantiomter, diastereoisomer or Its form of mixtures or its officinal salt,

Wherein:

A₀、A₁、A₂、A₃It is each independently selected from CR²Or N；

A₄And A₅It is each independently selected from C or N；

Q、V、U₀It is each independently selected from C or N；

R、W、U₁、U₂、U₃、U₄It is each independently selected from CR³Or N；

Ar is selected from aryl or heteroaryl, preferably 5 to 6 yuan of aryl or heteroaryl, more preferable phenyl, pyridyl group, pyrimidine radicals, pyrazine Base, pyridazinyl；The aryl or heteroaryl are optionally further by selected from halogen, amino, hydroxyl, alkyl, alkoxy, naphthenic base One or more groups replace；

Each R¹Independently selected from hydrogen, halogen, oxo base, alkyl, naphthenic base ,-OR^a；

R²Selected from hydrogen, halogen, amino, nitro, cyano, sulfydryl, oxo base, alkyl, naphthenic base, heterocycle, aryl, heteroaryl ,- OR^a、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NHC(O)R^a、-NR^aR^b、-S(O)R^a、-S(O)₂R^a、-S(O) NR^aR^b、-S(O)₂NR^aR^b、-NHS(O)R^a、-NHS(O)₂R^a、-P(O)R^aR^b、-B(OH)₂；The wherein alkyl, naphthenic base, heterocycle Base, aryl, heteroaryl optionally further by selected from halogen, amino, nitro, cyano, oxo base, hydroxyl, sulfydryl, carboxyl, alkyl, One or more groups substitution of alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl, heteroaryl；

R³Selected from hydrogen, halogen, amino, nitro, cyano, sulfydryl, oxo base, alkyl, naphthenic base, heterocycle, aryl, heteroaryl ,- OR^a、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NHC(O)R^a、-NR^aR^b、-S(O)R^a、-S(O)₂R^a、-S(O) NR^aR^b、-S(O)₂NR^aR^b、-NHS(O)R^a、-NHS(O)₂R^a、-P(O)R^aR^b、-B(OH)₂；The wherein alkyl, naphthenic base, heterocycle Base, aryl, heteroaryl optionally further by selected from halogen, amino, nitro, cyano, oxo base, hydroxyl, sulfydryl, carboxyl, alkyl, One or more groups substitution of alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl, heteroaryl；

R^aAnd R^bIt is each independently selected from hydrogen, halogen, hydroxyl, alkyl, naphthenic base, heterocycle, aryl, heteroaryl, wherein the alkane Base, naphthenic base, heterocycle, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, sulfydryl, carboxylic Base, ester group, oxo base, alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl, heteroaryl one or more bases Group replaces；

Or R^aAnd R^bThe nitrogen-atoms connecting with them is formed together nitrogen heterocycle, the nitrogen heterocycle optionally further by Selected from halogen, amino, nitro, cyano, oxo base, hydroxyl, sulfydryl, carboxyl, ester group, alkyl, alkoxy, alkenyl, alkynyl, cycloalkanes One or more groups substitution of base, heterocycle, aryl, heteroaryl；

N is integer of 1 to 3；

I is 1 or 2；

J is 1 or 2；

Wherein, leading to each of formula (I) compound H atom can optionally independently be substituted by D atom.

2. logical formula (I) compound represented according to claim 1 or its mesomer, racemic modification, enantiomter, Diastereoisomer, or mixtures thereof form or its officinal salt,

Wherein: A₄And A₅It is each independently selected from C.

3. logical formula (I) compound represented according to claim 1 or 2 or its mesomer, racemic modification, enantiomerism Body, diastereoisomer, or mixtures thereof form or its officinal salt,

Wherein: A₀、A₁、A₂、A₃It is each independently selected from CR²；

R²As defined in claim 1.

4. logical formula (I) compound represented according to any one of claim 1 to 3 or its mesomer, racemic modification, Enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt,

Wherein: U₁、U₂、U₃、U₄It is each independently selected from CR³；

R³As defined in claim 1.

5. logical formula (I) compound represented according to any one of claim 1 to 4 or its mesomer, racemic modification, Enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt, for logical formula (II), (III), (IV) or (V) compound represented or its mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form, Or its officinal salt,

Wherein,

The integer that m is 1 to 4；

The integer that q is 1 to 4；

R^3aAnd R^3bIt is each independently selected from hydrogen, halogen, amino, nitro, cyano, sulfydryl, oxo base, alkyl, naphthenic base, heterocycle Base, aryl, heteroaryl ,-OR^a、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NHC(O)R^a、-NR^aR^b、-S(O) R^a、-S(O)₂R^a、-S(O)NR^aR^b、-S(O)₂NR^aR^b、-NHS(O)R^a、-NHS(O)₂R^a；The wherein alkyl, naphthenic base, heterocycle Base, aryl, heteroaryl optionally further by selected from halogen, amino, nitro, cyano, oxo base, hydroxyl, sulfydryl, carboxyl, alkyl, One or more groups substitution of alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl, heteroaryl；

R^aAnd R^bIt is each independently selected from hydrogen, halogen, hydroxyl, alkyl, naphthenic base, heterocycle, aryl, heteroaryl, wherein the alkane Base, naphthenic base, heterocycle, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, sulfydryl, carboxylic Base, ester group, oxo base, alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl, heteroaryl one or more bases Group replaces；

Or R^aAnd R^bThe nitrogen-atoms connecting with them is formed together nitrogen heterocycle, the nitrogen heterocycle optionally further by Selected from halogen, amino, nitro, cyano, oxo base, hydroxyl, sulfydryl, carboxyl, ester group, alkyl, alkoxy, alkenyl, alkynyl, cycloalkanes One or more groups substitution of base, heterocycle, aryl, heteroaryl；

I is 1 and j is 2；Or

I is 2 and j is 1；

Ar、R¹、R², n it is as defined in claim 1.

6. logical formula (I) compound represented according to any one of claim 1 to 5 or its mesomer, racemic modification, Enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt, wherein Ar is aryl, preferably phenyl.

7. logical formula (I) compound represented according to any one of claim 1 to 5 or its mesomer, racemic modification, Enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt, wherein Ar is heteroaryl, preferably pyridine Base.

8. logical formula (I) compound represented according to any one of claim 1 to 7 or its mesomer, racemic modification, Enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt, for logical formula (VI), (VII), (VIII) Or (IX) compound represented or its mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof shape Formula or its officinal salt,

Wherein,

The integer that m is 1 to 4；

The integer that p is 1 to 4；

The integer that q is 1 to 4；

R^3aAnd R^3bIt is each independently selected from hydrogen, halogen, amino, nitro, cyano, sulfydryl, oxo base, alkane Base, naphthenic base, heterocycle, aryl, heteroaryl ,-OR^a、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NHC(O) R^a、-NR^aR^b、-S(O)R^a、-S(O)₂R^a、-S(O)NR^aR^b、-S(O)₂NR^aR^b、-NHS(O)R^a、-NHS(O)₂R^a；The wherein alkane Base, naphthenic base, heterocycle, aryl, heteroaryl optionally further by selected from halogen, amino, nitro, cyano, oxo base, hydroxyl, Sulfydryl, carboxyl, alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl, heteroaryl one or more groups take Generation；

R^aAnd R^bIt is each independently selected from hydrogen, halogen, hydroxyl, alkyl, naphthenic base, heterocycle, aryl, heteroaryl, wherein the alkane Base, naphthenic base, heterocycle, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, sulfydryl, carboxylic Base, ester group, oxo base, alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl, heteroaryl one or more bases Group replaces；

Or R^aAnd R^bThe nitrogen-atoms connecting with them is formed together nitrogen heterocycle, the nitrogen heterocycle optionally further by Selected from halogen, amino, nitro, cyano, oxo base, hydroxyl, sulfydryl, carboxyl, ester group, alkyl, alkoxy, alkenyl, alkynyl, cycloalkanes One or more groups substitution of base, heterocycle, aryl, heteroaryl；

R⁴Selected from halogen, amino, hydroxyl, alkyl, alkoxy, naphthenic base；

R¹、R², n it is as defined in claim 1.

9. logical formula (I) compound represented according to any one of claim 1 to 8 or its mesomer, racemic modification, Enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt,

Wherein:

R¹Selected from hydrogen, halogen, alkyl, naphthenic base ,-OR^a；

R^aSelected from hydrogen, alkyl, naphthenic base.

10. logical formula (I) compound represented according to any one of claim 1 to 9 or its mesomer, racemic Body, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt,

Wherein, R²Selected from hydrogen, halogen, alkyl, naphthenic base, heterocycle ,-OR^a、-C(O)R^a、-C(O)NR^aR^b、-NHC(O)R^a、- NR^aR^b、-S(O)R^a、-S(O)₂R^a、-P(O)R^aR^b、-B(OH)₂；Wherein the alkyl, naphthenic base, heterocycle optionally further by One or more groups selected from halogen, hydroxyl, sulfydryl, cyano, carboxyl, alkyl, alkoxy replace；

R^aAnd R^bIt is each independently selected from hydrogen, halogen, alkyl, naphthenic base, heterocycle, wherein the alkyl, naphthenic base, heterocycle Optionally further replaced by one or more groups selected from halogen, hydroxyl, sulfydryl, carboxyl, ester group, oxo base；

Or R^aAnd R^bThe nitrogen-atoms connecting with them is formed together nitrogen heterocycle, preferably nitrogenous 4~7 member heterocyclic ring containing nitrogen base, institute Nitrogen heterocycle is stated optionally further by selected from halogen, hydroxyl, sulfydryl, carboxyl, ester group, alkyl, alkoxy, naphthenic base, heterocycle One or more groups of base replace.

11. logical formula (I) compound represented or its mesomer, racemic according to any one of claim 5 to 10 Body, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt,

Wherein:

R^3aAnd R^3bIt is each independently selected from hydrogen, halogen, alkyl, naphthenic base, heterocycle ,-OR^a；

It is preferred that R^3aFor hydrogen and R^3bFor alkyl；

R^aSelected from hydrogen, alkyl, naphthenic base.

12. logical formula (I) compound represented according to any one of claim 1 to 11 or its mesomer, racemic Body, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt, wherein the compound is selected from:

13. logical formula (I) compound represented according to any one of claim 1 to 12 or its mesomer, racemic Body, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt preparation method, it includes following steps It is rapid:

Formula (IA) compound and formula (IB) compound in the presence of metal palladium catalyst, are heated under alkaline condition, passed through Buckwald amination coupling reaction obtains logical formula (I) compound；

Wherein, the preferred Pd of the metal palladium catalyst₂(dba)₃/ BINAP or Pd (dppf)₂Cl₂；The preferred Cs of alkali₂CO₃；Add Preferably 100~120 DEG C of hot temperature；

Wherein,

X is halogen, preferably Br；

Ar、A₀、A₁、A₂、A₃、A₄、A₅、Q、W、V、R、U₀、U₁、U₂、U₃、U₄、R¹, n, i, j it is as defined in claim 1.

14. logical formula (I) compound represented according to claim 5 or its mesomer, racemic modification, enantiomerism Body, diastereoisomer, or mixtures thereof form or its officinal salt preparation method, for logical formula (II), (III), (IV) Or (V) compound represented or its mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof shape The preparation method of formula or its officinal salt, it includes following steps:

By formula (IA ") compound and formula (IIB), (IIIB), (IVB) or (VB) compound in the presence of metal palladium catalyst, It heats under alkaline condition, by Buckwald amination coupling reaction, obtains logical formula (II), (III), (IV) or (V) chemical combination Object；

Wherein, the preferred Pd of the metal palladium catalyst₂(dba)₃/ BINAP or Pd (dppf)₂Cl₂；The preferred Cs of alkali₂CO₃；Add Preferably 100~120 DEG C of hot temperature；

Wherein,

X is halogen, preferably Br；

Ar、R¹、R²、R^3a、R^3b, m, n, q, i, j it is as defined in claim 5.

15. logical formula (I) compound represented according to claim 8 or its mesomer, racemic modification, enantiomerism Body, diastereoisomer, or mixtures thereof form or its officinal salt preparation method, for logical formula (VI), (VII), (VIII) or (IX) compound represented or its mesomer, racemic modification, enantiomter, diastereoisomer or it is mixed The preparation method of solvate form or its officinal salt, it includes following steps:

By formula (IA ') compound and formula (VIB), (VIIB), (VIIIB) or (IXB) compound metal palladium catalyst presence Under, heat under alkaline condition, by Buckwald amination coupling reaction, obtain logical formula (VI), (VII), (VIII) or (IX) compound；

Wherein, the preferred Pd of the metal palladium catalyst₂(dba)₃/ BINAP or Pd (dppf)₂Cl₂；The preferred Cs of alkali₂CO₃；Add Preferably 100~120 DEG C of hot temperature；

Wherein,

X is halogen, preferably Br；

R¹、R²、R^3a、R^3b、R⁴, m, n, p, q it is as defined in claim 8.

16. a kind of pharmaceutical composition contains chemical combination shown in logical formula (I) according to any one of claim 1 to 12 Object or its mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt, And one or more pharmaceutically acceptable carriers, diluent or excipient.

17. pharmaceutical composition according to claim 16 further contains another therapeutic activity ingredient, described another Kind of therapeutic activity ingredient is preferably the drug for the treatment of cancer, the preferred carcinoma of the rectum of the cancer, cancer of pancreas, breast cancer, prostate cancer, Cancer of the esophagus, gastric cancer, leukemia, lung cancer, the cancer of the brain, cutaneum carcinoma, head and neck cancer, oophoroma, bladder cancer and kidney, more preferable lung cancer, mammary gland Cancer, cancer of pancreas and gastric cancer.

18. logical formula (I) compound represented according to any one of claim 1 to 12 or its mesomer, racemic Body, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt or 6 or 17 institute according to claim 1 The pharmaceutical composition stated is preparing the purposes in SMO antagonist.

19. logical formula (I) compound represented according to any one of claim 1 to 12 or its mesomer, racemic Body, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt or 6 or 17 institute according to claim 1 Purposes of the pharmaceutical composition stated in the drug that disease relevant to Hedgehog signal path is treated in preparation.

20. purposes according to claim 19, wherein the disease relevant to Hedgehog signal path is cancer, it is excellent Select the carcinoma of the rectum, cancer of pancreas, breast cancer, prostate cancer, cancer of the esophagus, gastric cancer, leukemia, lung cancer, the cancer of the brain, cutaneum carcinoma, head and neck cancer, ovary Cancer, bladder cancer and kidney, more preferable leukemia, lung cancer, breast cancer, cancer of pancreas and gastric cancer.

21. logical formula (I) compound represented according to any one of claim 1 to 12 or its mesomer, racemic Body, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt and another therapeutic activity ingredient join It closes, the purposes in the drug of preparation treating cancer, wherein chemical combination shown in the another kind therapeutic activity ingredient and logical formula (I) Object simultaneously, separately or sequentially with；The another kind therapeutic activity ingredient is preferably the drug for the treatment of cancer；The cancer is preferred The carcinoma of the rectum, cancer of pancreas, breast cancer, prostate cancer, cancer of the esophagus, gastric cancer, leukemia, lung cancer, the cancer of the brain, cutaneum carcinoma, head and neck cancer, ovary Cancer, bladder cancer and kidney, more preferable leukemia, lung cancer, breast cancer, cancer of pancreas and gastric cancer.