CN106928216A

CN106928216A - Compound, Preparation Method And The Use with ERK kinase inhibiting activities

Info

Publication number: CN106928216A
Application number: CN201511031186.8A
Authority: CN
Inventors: 曹建华; 耿美玉; 黄敏; 江磊; 李磊; 唐帅; 冯家权; 杨晓彤; 丁健
Original assignee: Shanghai Institute of Materia Medica of CAS; Shanghai Haihe Pharmaceutical Co Ltd
Current assignee: Shanghai Institute of Materia Medica of CAS; Shanghai Haihe Pharmaceutical Co Ltd
Priority date: 2015-12-31
Filing date: 2015-12-31
Publication date: 2017-07-07
Also published as: CN107922405A; WO2017114510A1; CN107922405B

Abstract

The invention provides a kind of compound with ERK kinase inhibiting activities, Preparation Method And The Use, specifically, the invention provides compound of formula I, its stereoisomer, racemic modification or its pharmaceutically acceptable salt, and there is provided its application in the medicine for the prevention and treatment disease related to ERK kinases is prepared.

Description

Compound, Preparation Method And The Use with ERK kinase inhibiting activities

Technical field

The invention belongs to medicinal chemistry art, in particular it relates to compound or its pharmaceutically acceptable salt, And the pharmaceutical composition containing the compound or salt, its conditioning agent for being used as ERK paths or as ERK kinases, particularly The inhibitor of ERK1 and ERK2 kinases.

Background technology

Extracellular signal-regulated kinase (ERK) is the class serine/threonine protein kinase for being found in the nineties in 20th century Enzyme, is one of important subtribe of Mitogen activated protein kinase MAPKs families.The ERK of activation can transmit extracellular signal To nucleus, the phosphorylation for promoting cytoplasm target protein or the activity for adjusting other protein kinases, and then regulatory gene expression. Its signal transduction is to be related to the center of the signal network for adjusting cell growth, development and differentiation.Therefore, ERK participates in the increasing of cell Grow, break up, migrating, attacking and the various biological effect such as apoptosis.

Ras/Raf/MEK/ERK paths are the primary signal pathways related to ERK functions, due to the path regulating cell Propagation, differentiation and apoptosis, therefore the node albumen on the path turns into the focus place of cancer targeting medicament research and development in recent years.It is special The B-Raf inhibitor Vemurafenib and dabrafenib of the opposite sex was listed for melanoma respectively at 2011 and 2013 Treatment, wherein dabrafenib be used for treat B-RafV600E saltant type non-small cell lung cancers, obtain the breakthrough medicine of FDA Goods and materials lattice.The treatment that MEK1/2 inhibitor trametinib was also listed for melanoma in 2013.But suppress on these Trip path node has its limitation, and tumour can quickly develop immunity to drugs to B-Raf and mek inhibitor, the machine that the property of medicine is produced System includes the various ways such as point mutation, albumen Multimeric forms change, protein peptide chain length changes, and this is for overriding resistance of future generation Raf, MEK medicine are greatly to hinder.ERK as the path downstream key node, at present it is not yet found that resistance mutation Occur, the targeted drug of ERK may significantly improve the treatment of the patient that resistance is produced to upstream target spot inhibitor, be great latent The anticarcinogen research and development field of power.

In sum, this area is in the urgent need to developing new ERK inhibitor medicaments.

The content of the invention

It is an object of the invention to provide a structure is novel, compound that is can effectively suppressing ERK kinases, and its preparation method and Using.

First aspect present invention, there is provided a kind of compound of formula I, its stereoisomer, racemic modification or its can pharmaceutically connect The salt received：

In formula, X₁、X₂、X₃、X₄、X₅And X₆It is each independently selected from CR₅Or N；

Wherein, R₅It is selected from the group：H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxyl ,- OH, cyano group, halogen, amino, substituted or unsubstituted C1-C8 alkylaminos, substituted or unsubstituted C1-C8 alkyl-carbonyls, substitution Or unsubstituted C1-C8 alkoxyl carbonyl, substituted or unsubstituted C1-C8 carboxyls, substituted or unsubstituted C1-C8 ester groups, take Generation or unsubstituted 3-8 membered cyclic alkyls, substituted or unsubstituted 3-8 circle heterocycles base, substituted or unsubstituted aryl and substitution or Unsubstituted heteroaryl；

R₁It is selected from the group：H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyls, substitution or not Substituted C2-C8 alkynyls, halo C1-C8 alkyl, halo C2-C8 alkenyls, halo C2-C8 alkynyls, substituted or unsubstituted 3-8 units Cyclic hydrocarbon radical and substituted or unsubstituted aryl；

R₂It is selected from the group：It is substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted Heteroaryl, substituted or unsubstituted 3-8 membered cyclic alkyls and substituted or unsubstituted 3-8 circle heterocycles base；

R₃It is selected from the group：H, substituted or unsubstituted C1-C8 alkyl ,-OH, cyano group, halogen, C1-C8 alkylenehydroxyls, take Generation or unsubstituted 3-8 membered cyclic alkyls, substituted or unsubstituted 3-8 circle heterocycles base, substituted or unsubstituted aryl and substitution or Unsubstituted heteroaryl；

Or, R₃And X₄And adjacent C and N atoms are collectively forming substituted or unsubstituted 4-8 yuan of rings, wherein described Ring contains at least one N hetero atoms and altogether containing the 1-3 hetero atom selected from O, S and N, and the ring is for saturation or not Saturated rings；

R₄Selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxyl ,-CO (CR₆R₇)_mR₈、- SO₂(CR₆R₇)_mR₈、-CONR₉(CR₆R₇)_mR₈、-COO(CR₆R₇)_mR₈, amino, C1-C8 carboxyls；

M is 0,1,2 or 3；

Each R₆And R₇It is each independently selected from the following group：H, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylenehydroxyls, Substituted or unsubstituted C1-C8 alkoxyl and halogen, or R₆With R₇It is connected to form substitution or unsubstituted 3 to 6 yuan of rings；

Each R₈It is selected from the group：H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substitution do not take The heteroaryl in generation, substituted or unsubstituted 3-8 membered cyclic alkyls and substituted or unsubstituted 3-8 circle heterocycles base；

Each R₉It is selected from the group：H ,-OH, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylenehydroxyls and substitution or not Substituted C1-C8 alkoxyl.

In another preference, described substitution refers to the substitution base being selected from the group with one or more (such as 1-3)：Halogen Element, C1-C3 alkyl, C1-C3 haloalkyls, C1-C3 alkyl hydroxies ,-OH, C1-C3 alkoxies, C1-C3 alkylamino radicals, 3-8 yuan of rings Alkyl, 3-8 circle heterocycles base, amino, nitro.

In another preference, described R₃And X₄And connected "=C-N- " or "-C-N- " is collectively forming substitution or not Substituted 4-8 yuan of rings.

In another preference, described R₃And X₄And the 4-8 units that connected "=C-N- " or "-C-N- " is collectively forming Ring includes condensed ring, volution or bridged ring.

In another preference, described aryl includes C5-C20 aryl and C3-C20 heteroaryls, wherein the heteroaryl Contain the 1-3 hetero atom being selected from the group：O, S and N.

In another preference, described aryl is selected from the group：It is phenyl, pyridine radicals, pyrazolyl, thiazolyl, imidazole radicals, different Oxazolyl, is He oxazolyl.

In another preference, the X₁、X₂、X₃、X₄、X₅、X₆It is each independently selected from CR₅Or N；Also, X₁、X₂、X₅In At least one is N.

In another preference, the X₁、X₂、X₅、X₆In at least one or two be N, remaining is C；And X₃、X₄It is C.

In another preference, R₂It is substituted or unsubstituted 5-6 unit's saturations or undersaturated heterocycle, wherein described takes Acute pyogenic infection of finger tip has the substitution base that one or more (such as 1-3) are selected from the group：Halogen, C1-C3 alkyl ,-OH, amino, cyano group, C1- C8 alkoxies, C1-C8 alkylaminos.

In another preference, R₂It is substituted or unsubstituted 5 circle heterocycles.

In another preference, R₂It is 5 circle heterocycles containing 1-2 N or containing 1 hexa-member heterocycle of O.

In another preference, R₂It is to contain the 1-3 5-6 circle heterocycles for being selected from the group substitution base：Halogen, C1-C3 alkane Base ,-OH, amino, cyano group, C1-C8 alkoxyl, C1-C8 alkylaminos.

In another preference, R₄It is-CO (CR₆R₇)_mR₈, and R₈It is substituted or unsubstituted aryl, heteroaryl, cyclic hydrocarbon Base or heterocycle alkyl, wherein described substitution refers to the substitution base being selected from the group with one or more (such as 1-3)：Halogen, C1-C3 alkyl ,-OH, amino, cyano group, C1-C8 alkoxyl, C1-C8 alkylaminos.

In another preference, described is substituted by the 1-3 substitution base being selected from the group：Halogen, C1-C3 alkyl and C1- C3 alkoxies.

In another preference, R₈To replace or replacing the phenyl of base, substituted or unsubstituted pyridine radicals, substitution or do not take The pyrazolyl in generation, substituted or unsubstituted imidazole radicals.

In another preference, for R₃And X₄And the substitutions that are collectively forming of connected "=C-N- " or "-C-N- " or not Substituted 4-8 yuan of rings, preferably 5-8 yuan of rings, more preferably containing 1 or 2 the 5 of N, 6,7 or 8 yuan of rings, or containing N and O 5, 6th, 7 and 8 yuan of rings.

In another preference, R₄It is-CO (CR₆R₇)_mR₈, wherein R₆And R₇Be each independently selected from H or alkyl, substitution or Unsubstituted C1-C8 alkylenehydroxyls, and m is 1 or 2, R₈Selected from H, substituted or unsubstituted pyridine radicals, substituted or unsubstituted Phenyl.

In another preference, the compound of formula I is as shown in following formula I a：

Wherein, X₁、X₂、X₃、X₄、X₅、X₆It is each independently selected from CR₅Or N；

R₃It is selected from the group：H, substituted or unsubstituted C1-C8 alkyl ,-OH, cyano group, halogen, C1-C8 alkylenehydroxyls, take Generation or unsubstituted 3-8 membered cyclic alkyls, substituted or unsubstituted 3-8 circle heterocycles base, substituted or unsubstituted 3-8 unit aryl and Substituted or unsubstituted 3-8 unit's heteroaryls；

R₂、R₄、R₅Definition it is identical with aforementioned definitions.

In another preference, the Formulas I a compounds are shown below：

Wherein, R₃It is selected from the group：H, substituted or unsubstituted C1-C8 alkyl ,-OH, cyano group, halogen, C1-C8 alkylidene hydroxyls Base, substituted or unsubstituted 3-8 membered cyclic alkyls, substituted or unsubstituted 3-8 circle heterocycles base, substituted or unsubstituted aryl and Substituted or unsubstituted heteroaryl；

R₂、R₄、R₅Definition it is identical with aforementioned definitions.

In another preference, R₂It is selected from the group：

Wherein, each Ra is independently selected from substituted or unsubstituted C1-C4 alkyl；Rb is selected from the group：Halogen ,-OH, cyano group, Amino, substituted or unsubstituted C1-C3 alkyl, C1-C3 haloalkyls, substituted or unsubstituted C3-C8 cycloalkyl, substitution or not Substituted C3-C8 Heterocyclylalkyls；N is 0,1,2 or 3；

R₃Selected from H, substituted or unsubstituted C1-C8 alkyl ,-OH, cyano group, halogen, C1-C8 alkylenehydroxyls, substitution or Unsubstituted 3-8 membered cyclic alkyls, substituted or unsubstituted 3-8 circle heterocycles base, substituted or unsubstituted aryl, substitution or unsubstituted Heteroaryl；

Or, R₃And X₄And connected "=C-N- " or "-C-N- " is collectively forming substitution or unsubstituted 4-8 yuan of rings, Wherein described ring contains at least one N hetero atoms and is selected from the group containing 1-3 altogether：The hetero atom of O, S and N, and institute Ring is stated for saturation or unsaturation ring；

R₄Selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxyl ,-CO (CR₆R₇)_mR₈、- SO₂(CR₆R₇)_mR₈、-CONR₉(CR₆R₇)_mR₈、-COO(CR₆R₇)_mR₈, amino, C1-C8 carboxyls；Wherein, m is 0,1,2 or 3；

Each R₆、R₇It is each independently selected from the following group：H, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylenehydroxyls, take Generation or unsubstituted C1-C8 alkoxyl and halogen, or R₆With R₇It is connected to form substitution or unsubstituted 3 to 6 yuan of rings；

Each R₉It is selected from the group：H ,-OH, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylenehydroxyls and substitution or not Substituted C1-C8 alkoxyl；

X₁、X₂、X₃、X₄、X₅And X₆It is each independently selected from CR₅Or N；

R₅Selected from H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxyl ,-OH, cyano group, halogen It is element, amino, substituted or unsubstituted C1-C8 alkylaminos, substituted or unsubstituted C1-C8 alkyl-carbonyls, substituted or unsubstituted C1-C8 alkoxyl carbonyl, substituted or unsubstituted C1-C8 carboxyls, substituted or unsubstituted C1-C8 ester groups, substitution or unsubstituted 3-8 membered cyclic alkyls, substituted or unsubstituted 3-8 circle heterocycles base, substituted or unsubstituted aryl and substituted or unsubstituted miscellaneous Aryl.

In another preference, R₅Selected from H or cyano group.

In another preference, the compound of formula I is as shown in following formula I b：

Wherein,

X₁、X₂、X₃、X₅、X₆It is each independently selected from CR₅Or N；

P is 0,1,2,3 or 4；

Q is 1,2,3,4 or 5；

And p+q≤5；

Y and Z are each independently selected from-CR^cR^d、O、S、-NR^c；Wherein R^c、R^dIt is each independently selected from：H, substitution do not take It is the C1-C8 alkyl in generation ,-OH, amino, halogen, cyano group, substituted or unsubstituted C1-C8 alkylenehydroxyls, substituted or unsubstituted C1-C8 alkoxyl, substituted or unsubstituted amido C1-C8 alkyl-, substituted or unsubstituted C1-C8 alkylamino radicals, or-CR^cR^d For-C (=O)-；

R₂、R₄、R₅Definition it is identical with aforementioned definitions.

In another preference, the compound of formula I is：

Wherein,

P is 0,1,2,3 or 4；

Q is 1,2,3,4 or 5；

And p+q≤5；

Y and Z are each independently selected from-CR^cR^d、O、S、-NR^c；Wherein R^c、R^dIt is each independently selected from：H, substitution do not take It is the C1-C8 alkyl in generation ,-OH, amino, halogen, cyano group, substituted or unsubstituted C1-C8 alkylenehydroxyls, substituted or unsubstituted C1-C8 alkoxyl, substituted or unsubstituted amido C1-C8 alkyl, substituted or unsubstituted C1-C8 alkylamino radicals, or-CR^cR^d It is-C (=O)；

R₂、R₄、R₅Definition it is identical with aforementioned definitions.

In another preference, in the Formulas I a or Ib compounds, R₂It is selected from the group：

Wherein, each Ra independently selected from：C1-C4 alkyl；

Rb be selected from halogen ,-OH, cyano group, amino, substituted or unsubstituted C1-C3 alkyl, C1-C3 haloalkyls, substitution or Unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 Heterocyclylalkyls；

N is 0,1,2 or 3；

P is 0,1,2,3 or 4；

Q is 1,2,3,4 or 5；

And p+q≤5；

Y and Z are each independently selected from-CR^cR^d、O、S、-NR^c；Wherein R^c、R^dIt is each independently selected from：H, substitution do not take The C1-C8 alkyl in generation ,-OH, amino, halogen, cyano group, C1-C8 alkylenehydroxyls, substituted or unsubstituted C1-C8 alkoxyl, amine Base C1-C8 alkyl, substituted or unsubstituted C1-C8 alkylamino radicals, or-CR^cR^dIt is-C (=O)；

R₄Selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxyl ,-CO (CR₆R₇)_mR₈、- SO₂(CR₆R₇)_mR₈、-CONR₉(CR₆R₇)_mR₈、-COO(CR₆R₇)_mR₈, amino, carboxyl；Wherein, m is 0,1,2 or 3；

Each R₆、R₇It is each independently selected from the following group：H, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylenehydroxyls, take Generation or unsubstituted C1-C8 alkoxyl and halogen, or R₆With R₇It is connected to form substitution or unsubstituted 3 to 5 yuan of rings；

In another preference, in described compound I, R₁=H, R₂=methyl substituted five-ring heterocycles, R₄=-CO (CR₆R₇)_mR₈, wherein R₆=R₇=H, alkyl, alkyl hydroxy, and m=1 or 2, R₈=substituted or unsubstituted phenyl, pyridine radicals, Or H.

In another preference, described compound I is selected from the group：

A kind of second aspect present invention, there is provided pharmaceutical composition, its include therapeutically effective amount selected from such as the present invention first One or more in the described compound of invention, its stereoisomer, racemic modification or its pharmaceutically acceptable salt and Pharmaceutically acceptable excipient.

A kind of third aspect present invention, there is provided compound as described in the first aspect of the invention, its stereoisomer or its Pharmaceutically acceptable salt, or pharmaceutical composition described in second aspect present invention swash with ERK for preventing and treating being prepared Purposes in the medicine of the related disease of enzyme and ERK kinases targeting inhibitor.

Fourth aspect present invention, there is provided a kind of method for preparing compound as described in the first aspect of the invention, including step：

A) in atent solvent, under metal catalytic or acid/base catalysis, (1e) is reacted with (1f) compound, system Obtain compound of formula I；

Wherein, X₁、X₂、X₃、X₄、X₅、X₆、R₁、R₂、R₃The definition of each group is as described in the first aspect of the invention；

LG₂It is the leaving group being selected from the group：Halogen, sulphonic acid ester, methyl mercapto, methyl sulfone.

In another preference, methods described also includes：Step (a-1) and (a-2), so as to formula (1e) compound is obtained：

(a-1) in atent solvent, (1a) by condensation reaction or reductive amination process, obtains compound with (1b) (1c)；

(a-2) in atent solvent, under metallic catalyst, (1c) carries out coupling reaction with (1d) compound, is changed Compound (1e)；

In formula, LG₁It is the leaving group being selected from the group：Halogen, sulphonic acid ester, boric acid, borate, borate, organotin, have Machine zinc；

LG₂It is the leaving group being selected from the group：Halogen, sulphonic acid ester, methyl mercapto, methyl sulfone；

LG₃It is the leaving group being selected from the group：Halogen, sulphonic acid ester, boric acid, borate, borate；

FG is selected from the group：Carboxylic acid, aldehyde, halogen；

X₁、X₂、X₃、X₄、X₅、X₆、R₁、R₂、R₃The definition of each group is as described in the first aspect of the invention.

In another preference, in (a-1), reaction is carried out in atent solvent, and the atent solvent is selected from the group： Water, methyl alcohol, ethanol, isopropanol, ethylene glycol, 1-METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO), tetrahydrofuran, toluene, dichloromethane, Chloroform, 1,2- dichloroethanes, acetonitrile, DMF, DMA, dioxane or its combination.

In another preference, in (a-1), the condensation reaction is carried out in the presence of condensing agent, the condensing agent It is selected from the group：2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, I-hydroxybenzotriazole and 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, O- BTAs-tetramethylurea hexafluorophosphoric acid ester or its group Close.

In another preference, in (a-1), the reductive amination process enters in the presence of catalyst and reducing agent OK, the catalyst is selected from the group：Tetraisopropoxy titanium, trifluoroacetic acid, acetic acid, formic acid, hydrochloric acid, sulfuric acid, p-methyl benzenesulfonic acid or Its combination；The reducing agent is selected from the group：Sodium borohydride, cyaniding sodium borohydride, acetic acid sodium borohydride, trifluoroacetyl epoxide boron hydrogen Change sodium, the sodium borohydride reduction agent of Polymer-supported, sodium trimethoxy borohydride, sodium triethylborohydride, triacetoxy borohydride Sodium hydride, sodium cyanoborohydride, lithium borohydride, Lithium Aluminium Hydride or its combination.

In another preference, in (a-2), the metallic catalyst is selected from the group：Three (dibenzalacetones) two Palladium (Pd₂(dba)₃), tetrakis triphenylphosphine palladium (Pd (PPh₃)₄), palladium, palladium bichloride, dichloro two (triphenylphosphine) palladium, trifluoro Palladium, triphenylphosphine palladium acetate, [double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride, double (three adjacent benzyl phosphines) two Palladium bichloride, (diphenylphosphino) the ethane palladium chlorides of 1,2- bis- or its combination.

In another preference, in (a), the reaction is carried out in the presence of catalyst ligand, and the catalyst is matched somebody with somebody Body is selected from the group：Tri-butyl phosphine, tetrafluoro boric acid tri-butyl phosphine, tri-n-butyl phosphine, triphenylphosphine, three couples of benzyl phosphines, three Cyclohexyl phosphine, tetrafluoro boric acid tricyclohexyl phosphine, three adjacent benzyl phosphines or its combination.

In another preference, in (a), the reaction is carried out in the presence of a base, and the alkali includes inorganic base and has Machine alkali.

In another preference, in (a), the inorganic base is selected from the group：Sodium hydride, potassium hydroxide, sodium acetate, vinegar Sour potassium, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, saleratus, sodium carbonate, sodium acid carbonate, Or its combination.

In another preference, in (a), the organic base is selected from the group：Pyridine, triethylamine, N, N- diisopropyls Ethamine, carbon -7- alkene (DBU) of 1,8- diazabicylos [5.4.0] 11, the silicon substrate lithium of hexamethyl two, the silicon substrate sodium of hexamethyl two, diformazan Yl pyridines or its combination.

In another preference, in (a), the reaction is carried out in presence of an acid, and the acid is selected from the group：Hydrochloric acid, Sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid or its combination.

In another preference, the temperature of the step a) is -78 DEG C -250 DEG C.

In another preference, the step a) is carried out under normal temperature condition.

In another preference, the step a) is carried out under the dry ice bath or condition of ice bath.

In another preference, the step a) is carried out in a heated condition, and the heating is selected from the group：It is electrical heating, micro- Wave heating or its combination.

Fifth aspect present invention, there is provided a kind of method for preparing compound as described in the first aspect of the invention, including step：

B) in atent solvent, under metal catalytic, (1c) carries out coupling reaction with (1g) compound, and Formulas I chemical combination is obtained Thing；

LG₁It is the leaving group being selected from the group：Halogen, sulphonic acid ester, boric acid, borate, borate, organotin, organic zinc；

LG₃It is the leaving group being selected from the group：Halogen, sulphonic acid ester, boric acid, borate, borate.

In another preference, methods described also includes：Step (b-1) and/or (b-2)：

(b-1) (1a) is coupled with (1b) in atent solvent by the reaction such as condensation or reduction amination, is obtained (1c)；

(b-2) (1d) is coupled with (1f) in atent solvent, in the presence of alkali, is obtained (1g)；

FG is selected from the group：Carboxylic acid, aldehyde, halogen；

In another preference, (b-1) is carried out in atent solvent, and the atent solvent is selected from the group：Water, first Alcohol, ethanol, isopropanol, ethylene glycol, 1-METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO), tetrahydrofuran, toluene, dichloromethane, chloroform, 1,2- dichloroethanes, acetonitrile, DMF, DMA, dioxane or its combination.

In another preference, in (b-1), condensation reaction is carried out in the presence of condensing agent, and the condensing agent is selected from The following group：2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, I-hydroxybenzotriazole and 1- (3- Dimethylamino-propyl) -3- ethyl-carbodiimide hydrochlorides, O- BTAs-tetramethylurea hexafluorophosphoric acid ester etc. or its group Close.

In another preference, in (b-1), the reductive amination process enters in the presence of catalyst and reducing agent OK, the catalyst be selected from the group tetraisopropoxy titanium, trifluoroacetic acid, acetic acid, formic acid, hydrochloric acid, sulfuric acid, p-methyl benzenesulfonic acid or Its combination；The reducing agent is selected from the group, sodium borohydride, cyaniding sodium borohydride, acetic acid sodium borohydride, trifluoroacetyl epoxide boron hydrogen Change sodium, the sodium borohydride reduction agent of Polymer-supported, sodium trimethoxy borohydride, sodium triethylborohydride, triacetoxy borohydride Sodium hydride, sodium cyanoborohydride, lithium borohydride, Lithium Aluminium Hydride or its combination.

In another preference, in (b), (1c) is coupled with (1g) in the presence of metallic catalyst, the gold Metal catalyst is selected from the group：Three (dibenzalacetone) two palladium (Pd₂(dba)₃), tetrakis triphenylphosphine palladium (Pd (PPh₃)₄), vinegar Sour palladium, palladium bichloride, dichloro two (triphenylphosphine) palladium, trifluoracetic acid palladium, triphenylphosphine palladium acetate, [1,1'- pairs (diphenylphosphino) Ferrocene] palladium chloride, double (three adjacent benzyl phosphine) palladium chlorides, (diphenylphosphino) the ethane palladium chlorides of 1,2- bis- or its Combination.

In another preference, in (b), (1c) is coupled with (1g) in the presence of metal catalyst complex, institute Catalyst ligand is stated to be selected from the group：Tri-butyl phosphine, tetrafluoro boric acid tri-butyl phosphine, tri-n-butyl phosphine, triphenylphosphine, three pairs of benzene Methylphosphine, tricyclohexyl phosphine, tetrafluoro boric acid tricyclohexyl phosphine, three adjacent benzyl phosphines or its combination.

In another preference, in (b-2), (1d) is coupled in the presence of a base with (1f), and the alkali includes nothing Machine alkali and organic base.

In another preference, in (b-2), (1d) is coupled in the presence of an inorganic base with (1f), described inorganic Alkali is selected from the group：NaOH, lithium hexamethyldisilazide, double trimethyl silicon substrate amido sodium, double trimethyl silicon substrate amido potassium, Butyl lithium, lithium diisopropylamine, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, Potassium phosphate, potassium carbonate, saleratus, sodium carbonate, sodium acid carbonate or its combination.

In another preference, (1d) is coupled in the presence of an organic base with (1f) in (b-2), the organic base It is selected from the group：Pyridine, triethylamine, DIPEA, carbon -7- alkene (DBU) of 1,8- diazabicylos [5.4.0] 11, The silicon substrate lithium of hexamethyl two, the silicon substrate sodium of hexamethyl two, lutidines or its combination.

In another preference, in (b-2), (1d) is coupled in presence of an acid with (1f), and the acid is selected from down Group：Hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid or its combination.

In another preference, the temperature of the step b) is -78 DEG C -250 DEG C.

In another preference, the step b) is carried out under normal temperature condition.

In another preference, the step b) is carried out under the dry ice bath or condition of ice bath.

In another preference, the step b) is carried out in a heated condition, and the heating is selected from the group：It is electrical heating, micro- Wave heating or its combination.

Sixth aspect present invention, there is provided a kind of method that non-therapeutic ground suppresses ERK kinase activities, including step：To this Compound or its pharmaceutically acceptable salt described in invention first aspect are contacted with ERK kinases, so as to suppress ERK kinases.

In another preference, described contact is to be connect the cell of the ERK kinases of purifying or expression ERK kinases Touch.

A kind of seventh aspect present invention, there is provided the disease related to ERK kinase activities in prevention and/or treatment mammal Method, including mammal to needing gives compound described in the first aspect present invention of therapeutically effective amount, it is three-dimensional Isomers or its pharmaceutically acceptable salt, or give the medicine as described in invention second aspect of therapeutically effective amount Compositions.

In another preference, the ERK kinases includes ERK1, ERK2 or combination.

In another preference, the described disease related to ERK kinase activities refers to and the expression high of ERK kinases or high activity Related disease.

In another preference, the described disease related to ERK kinase activities is selected from the group：Tumour.

It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) Can be combined with each other between each technical characteristic of body description, so as to constitute new or preferred technical scheme.As space is limited, exist This no longer tires out one by one states.

Specific embodiment

The present inventor's in-depth study by extensive, the compound being surprised to find that first shown in a kind of Formulas I or its medicine Acceptable salt on, it can be high as ERK kinase inhibitors, inhibitory activity.The present invention is completed on this basis.

Term explanation

As used herein, when being used in mentioning the numerical value specifically enumerated, term " about " means that the value can be from enumerating Value changes and is not more than 1%.For example, as used herein, statement " about 100 " including 99 and 101 and between whole values (for example, 99.1st, 99.2,99.3,99.4 etc.).

Unless otherwise defined, the implication that the following terms for otherwise being used in the specification and in the claims have is institute The connotation that category art personnel are generally understood that.Unless otherwise indicated, all patents, patent application, the public affairs for quoting in full herein Material is opened to be integrally incorporated by reference herein.

It should be understood that above-mentioned summary and being specified as hereafter are exemplary and be only used for explaining, without appointing to present subject matter What is limited.Also include plural number when in this application, unless otherwise expressly specified, otherwise using odd number.It has to be noticed that unless in text Separately have and clearly illustrate, singulative otherwise used in the present specification and claims includes the plural shape of referents Formula.It shall yet further be noted that unless otherwise stated, "or" used, "or" represent "and/or".Additionally, term " containing " or " bag Include (include) " can be open, semi-enclosed and enclosed.In other words, the term is also included " substantially by ... structure Into " or " by ... constitute ".

Can be in bibliography (including Carey and Sundberg " ADVANCED ORGANIC CHEMISTRY 4TH ED. " Vols.A (2000) and B (2001), Plenum Press, New York) in find definition to standard chemistry terms. Unless otherwise stated, using the conventional method in the range of art technology, such as mass spectrum, NMR, IR and UV/VIS spectroscopic methodology and Pharmacological method.Unless proposition is specifically defined, otherwise herein in analytical chemistry, Synthetic Organic Chemistry and medicine and pharmaceutical chemistry Relevant description in the term that uses be known in the art.In chemical synthesis, chemical analysis, medicine preparation, preparation and can pass Send, and to using standard technique in the treatment of patient.For example, using manufacturer to the operation instruction of kit, or according to Mode well known in the art or explanation of the invention are implemented to react and are purified.Generally can according in this specification quote and Description in multiple summary and more specific document of discussion, according to conventional method well known in the art implement above-mentioned technology and Method.In this manual, can by those skilled in the art select group and its substitution base with provide stabilization structure division and Compound.

When the conventional chemical formulas by writing from left to right describe substitution base, the substitution base is similarly included from right to left Write substitution base equivalent in chemistry resulting during structural formula.For example ,-CH₂O- is equal to-OCH₂-。

Chapter title used herein is only used for the purpose of organizational, and is not necessarily to be construed as the limit to the theme System.The all documents or literature department point quoted in the application include but is not limited to patent, patent application, article, books, manipulator Volume and paper, are integrally incorporated herein by reference.

Some chemical groups of definition represent carbon atom present in the group previously by symbol is simplified herein Sum.For example, C1-C6 alkyl refers to have 1 to 6 alkyl as defined below of carbon atom altogether.In simplified symbol The total number of carbon atoms does not include the carbon being likely to be present in the substitution base of the group.

In addition to foregoing, when in the description of the present application and claims, unless otherwise specified, otherwise Following term has implication as follows.

In this application, term " halogen " refers to fluorine, chlorine, bromine or iodine.

" hydroxyl " refers to-OH groups.

" hydroxy alkyl " refers to the alkyl as defined below replaced by hydroxyl (- OH).

" carbonyl " refers to-C (=O)-group.

" nitro " refers to-NO₂。

" cyano group " refers to-CN.

" amino " refers to-NH₂。

" substituted amino " refers to by one or two alkyl as defined below, alkyl-carbonyl, aralkyl, heteroaryl alkane The amino of base substitution, for example, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl alkyl amino, heteroarylalkyl amino.

" carboxyl " refers to-COOH.

In this application, (groups such as the alkyl of halogen substitution are used for example in as a part for group or other groups In), term " alkyl " refers to the hydrocarbon chain base of fully saturated straight or branched, is only made up of carbon atom and hydrogen atom, with example Such as 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atom, and be connected with the remainder of molecule by singly-bound, For example include but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, 2- Methyl butyl, 2,2- dimethyl propyls, n-hexyl, heptyl, 2- methylhexyls, 3- methylhexyls, octyl group, nonyl and decyl etc.. For the present invention, term " alkyl " refers to and contains 1 to 6 alkyl of carbon atom.

In this application, as group or a part for other groups, term " alkenyl " means only by carbon atom and hydrogen Atom composition, containing at least one double bond, with such as 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms And the hydrocarbon chain radical of the straight or branched being connected with the remainder of molecule by singly-bound, such as but not limited to vinyl, propylene Base, pi-allyl, but-1-ene base, but-2-ene base, amyl- 1- alkenyls, amyl- 1,4- dialkylenes etc..

In this application, as group or a part for other groups, term " alkynyl " refers to only by carbon atom and hydrogen Atom composition, containing at least one 3 keys, optionally containing at least one double bond, with such as 2 to 14 (preferably 2 to 10, More preferably 2 to 6) hydrocarbon chain radical of carbon atom and the straight or branched being connected with the remainder of molecule by singly-bound, example Such as, but not limited to, acetenyl, propyl- 1- alkynyls, butyl- 1- alkynyls, amyl- 1- alkene -4- alkynyls etc..

In this application, as group or a part for other groups, term " cyclic hydrocarbon radical " mean only by carbon atom and The non-aromatic monocyclic or multi-ring alkyl of the stabilization of hydrogen atom composition, it may include fused ring system, bridged-ring system or volution body System, with 3 to 15 carbon atoms, preferably with 3 to 10 carbon atoms, more preferably with 3 to 8 carbon atoms, and it is saturation Or it is unsaturated and can be connected with the remainder of molecule by singly-bound via any suitable carbon atom.Unless another in this specification Specialize outward, the carbon atom in cyclic hydrocarbon radical can optionally be oxidized.The example of cyclic hydrocarbon radical includes but is not limited to cyclopropyl, ring Butyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cyclooctyl, 1H- indenyls, 2,3- bis- Hydrogenated indenyl, 1,2,3,4- tetrahydro-naphthalenyls, 5,6,7,8- tetrahydro-naphthalenyls, 8,9- dihydro -7H- benzo ring heptene -6- bases, 6,7, 8,9- tetrahydrochysene -5H- benzocycloheptas alkenyl, 5,6,7,8,9,10- hexahydros-benzo ring octenyl, fluorenyl, two rings [2.2.1] heptyl, 7,7- dimethyl-two ring [2.2.1] heptyl, two rings [2.2.1] heptenyl, two rings [2.2.2] octyl group, two rings [3.1.1] heptyl, Two rings [3.2.1] octyl group, two rings [2.2.2] octenyl, two rings [3.2.1] octenyl, adamantyl, octahydro -4,7- methylene - 1H- indenyls and octahydro -2,5- methylene-pentalene base etc..

In this application, as group or a part for other groups, term " heterocyclic radical " means by 2 to 14 carbon originals 3 yuan to 20 yuan non-aromatic cyclic groups of the stabilization that son and 1 to 6 hetero atom selected from nitrogen, phosphorus, oxygen and sulphur are constituted.Remove Specialized in addition in non-this specification, otherwise heterocyclic radical can be the member ring systems of monocyclic, bicyclic, three rings or more ring, and it can Including fused ring system, bridged-ring system or spiro ring system；Nitrogen, carbon or sulphur atom in its heterocyclic radical are optionally oxidized；Nitrogen Atom is optionally quaternized；And heterocyclic radical can be partially or completely saturation.Heterocyclic radical can be via carbon atom or miscellaneous original Son is simultaneously connected by singly-bound with molecule remainder.In the heterocyclic radical comprising condensed ring, one or more rings can be hereafter institute The aryl or heteroaryl of definition, it with the tie point of molecule remainder is non-aromatic annular atom that condition is.With regard to mesh of the invention For, heterocyclic radical is preferably comprising 1 to 34 yuan to 11 yuan nonaro-maticity list selected from the heteroatomic stabilization of nitrogen, oxygen and sulphur Ring, bicyclic, bridged ring or spiro-cyclic groups, more preferably comprising 1 to 34 yuan to 8 of the heteroatomic stabilization for being selected from nitrogen, oxygen and sulphur First non-aromatic monocyclic, bicyclic, bridged ring or spiro-cyclic groups.The example of heterocyclic radical is included but is not limited to：Pyrrolidinyl, morpholinyl, Piperazinyl, homopiperazine base, piperidyl, thio-morpholinyl, 2,7- diaza-spiros [3.5] nonane -7- bases, 2- oxa- -6- azepines - Spiral shell [3.3] heptane -6- bases, 2,5- diazas-bicyclic [2.2.1] heptane -2- bases, azetidinyl, pyranose, oxinane Base, thiapyran base, tetrahydrofuran base, oxazinyls, dioxy cyclopenta, tetrahydro isoquinolyl, Decahydroisoquinolinpreparation base, imidazolinyl, miaow Oxazolidinyl, quinolizine base, thiazolidinyl, isothiazole alkyl, isoxazole alkyl, indolinyl, octahydro indyl, octahydro iso-indoles Base, pyrrolidinyl, pyrazolidinyl, phthaloyl imino etc..

In this application, as group or a part for other groups, term " aryl " means there is 6 to 18 carbon originals The conjugated hydrocarbon member ring systems group of sub (preferably with 6 to 10 carbon atoms).For purposes of the invention, aryl can be single The member ring systems of ring, bicyclic, three rings or more ring, can also condense with cycloalkyl defined above or heterocyclic radical, and condition is virtue Base is connected by singly-bound via the atom on aromatic rings with the remainder of molecule.The example of aryl include but is not limited to phenyl, Naphthyl, anthryl, phenanthryl, fluorenyl, 2,3- dihydro -1H- isoindolyls, 2- benzoxazolinones, 2H-1,4- benzoxazines -3 (4H) -one -7- bases etc..

In this application, term " aryl alkyl " refers to the alkane defined above replaced by aryl defined above Base.

In this application, as group or a part for other groups, term " heteroaryl " means there is 1 to 15 in ring Individual carbon atom (preferably with 1 to 10 carbon atom) and 1 to 6 heteroatomic 5 yuan to 16 yuan conjugate ring selected from nitrogen, oxygen and sulphur It is group.Unless specialized in addition in this specification, otherwise heteroaryl can be the ring body of monocyclic, bicyclic, three rings or more ring System, can also condense with cycloalkyl defined above or heterocyclic radical, and condition is that heteroaryl passes through via the atom on aromatic rings Singly-bound is connected with the remainder of molecule.Nitrogen, carbon or sulphur atom in heteroaryl are optionally oxidized；Nitrogen-atoms is optionally It is quaternized.For purposes of the invention, heteroaryl is preferably the heteroatomic stabilization selected from nitrogen, oxygen and sulphur comprising 1 to 5 5 yuan to 12 yuan aromatic radicals, more preferably comprising 1 to 45 yuan to 10 of heteroatomic stabilization selected from nitrogen, oxygen and sulphur First aromatic radical or comprising 1 to 3 heteroatomic 5 yuan to 6 yuan aromatic radical selected from nitrogen, oxygen and sulphur.Heteroaryl Example include but is not limited to thienyl, imidazole radicals, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyls, pyridine radicals, Pyrimidine radicals, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazoles base, indyl, furyl, pyrrole radicals, triazolyl, tetrazolium Base, triazine radical, indolizine base, isoindolyl, indazolyl, iso indazolyl, purine radicals, quinolyl, isoquinolyl, phenodiazine naphthyl, naphthalene Piperidinyl, quinoxalinyls, pteridyl, carbazyl, carboline base, phenanthridinyl, phenanthroline, acridinyl, phenazinyl, isothiazolyl, benzene It is benzothiazolyl, benzothienyl, oxatriazoles base, cinnolines base, quinazolyl, thiophenyl, indolizine base, phenanthrolene base, different Oxazolyl, phenoxazine groups, phenothiazinyl, 4,5,6,7- tetrahydro benzos [b] thienyl, naphtho- pyridine radicals, [1,2,4] triazol [4,3-b] pyridazine, [1,2,4] triazol [4,3-a] pyrazine, [1,2,4] triazol [4,3-c] pyrimidine, [1,2,4] triazol [4,3-a] pyridine, imidazo [1,2-a] pyridine, imidazo [1,2-b] pyridazine, imidazo [1,2-a] pyrazine etc..

In this application, term " heteroaryl alkyl " refer to by heteroaryl defined above replaced it is defined above Alkyl.

In this application, " optionally " or " optionally " represent then description event or situation may be likely to not Occur, and the description includes the situation that the event or situation occur and do not occur simultaneously.For example, " aryl being optionally substituted " Represent that aryl substituted or unsubstituted, and the description includes substituted aryl and unsubstituted aryl simultaneously.The present invention The substitution base of " optionally " described in claims and specification part be selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, Haloalkenyl group, halo alkynyl, cyano group, nitro, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cyclic hydrocarbon radical, Optionally substituted heterocycle alkyl.

During terms used herein " part ", " structure division ", " chemical part ", " group ", " chemical group " refer to molecule Specific fragment or functional group.Chemical part is typically considered the chemical entities being embedded or attached on molecule.

" stereoisomer " refers to be made up of same atoms, is bonded by identical key, but with different three-dimensional structures Compound.The present invention will cover various stereoisomers and its mixture.

When alkene double bond is contained in compound of the invention, unless otherwise stated, compound of the invention is intended to bag Containing E- and Z- geometric isomers.

" dynamic isomer " refers to that proton is formed from an atom transfer of molecule to another atom of identical molecule Isomers.All tautomeric forms of compound of the invention also will be contained in the scope of the present invention.

Compound of the invention or its pharmaceutically acceptable salt may contain one or more asymmetric carbon atoms, and therefore Enantiomter, diastereoisomer and other stereoisomeric forms in any ratio can be produced.Each asymmetric carbon atom can be based on three-dimensional Learn and be defined as (R)-or (S)-.It is contemplated that including all possible isomers, and its racemic modification and optical voidness Form.The preparation of compound of the invention racemic modification, diastereoisomer or enantiomter can be selected as raw material or Intermediate.Optically active isomers can be prepared using chiral synthon or chiral reagent, or be entered using routine techniques Row splits, for example with methods such as crystallization and chiral chromatograms.

The routine techniques of preparation/separation individual isomeric includes being synthesized by the chirality of suitable optical voidness precursor, or makes With such as chiral hplc resolution of racemic body (or racemic modification of salt or derivative), Gerald is see, for example, Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols, Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations, Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128.

In this application, term " pharmaceutically acceptable salt " includes pharmaceutically acceptable acid-addition salts and pharmaceutically may be used The base addition salts of receiving.

" pharmaceutically acceptable acid-addition salts " be refer to retain free alkali biological effectiveness and without other side effects , the salt formed with inorganic acid or organic acid.Inorganic acid salt includes but is not limited to hydrochloride, hydrobromate, sulfate, nitric acid Salt, phosphate etc.；Acylate includes but is not limited to formates, acetate, 2,2- DCAs, trifluoroacetate, propionic acid Salt, caproate, caprylate, caprate, undecylenate, glycollate, gluconate, lactate, sebacate, adipic acid Salt, glutarate, malonate, oxalates, maleate, succinate, fumarate, tartrate, citrate, palm Hydrochlorate, stearate, oleate, cinnamate, laruate, malate, glutamate, pyroglutamate, aspartic acid Salt, benzoate, mesylate, benzene sulfonate, tosilate, alginate, ascorbate, salicylate, 4- ammonia Base salicylate, napadisilate etc..These salt can be prepared by method known in the art.

" pharmaceutically acceptable base addition salts " be refer to keep free acid biological effectiveness and without other side effects And salt that inorganic base or organic base are formed.Salt derived from inorganic base includes but is not limited to sodium salt, sylvite, lithium salts, ammonium Salt, calcium salt, magnesium salts, molysite, zinc salt, mantoquita, manganese salt, aluminium salt etc..Preferred inorganic salts are ammonium salt, sodium salt, sylvite, calcium salt and magnesium Salt.Salt derived from organic base includes but is not limited to following salt：Primary amine class, secondary amine class and tertiary amines, substituted amine, bag Include natural substituted amine, cyclic amine and deacidite, such as ammonia, isopropylamine, trimethylamine, diethylamine, three Ethamine, tripropyl amine (TPA), monoethanolamine, diethanol amine, triethanolamine, dimethylethanolamine, DMAE, 2- lignocaine second Alcohol, dicyclohexyl amine, lysine, arginine, histidine, caffeine, procaine, choline, glycine betaine, ethylenediamine, gucosamine, Methyl glucose osamine, theobromine, purine, piperazine, piperidines, N-ethylpiperidine, polyamino resin etc..Preferred organic base includes isopropyl Amine, diethylamine, monoethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.These salt can be by method known in the art Prepare.

" polymorph " refers to some compounds of the invention in the solid state due to there is two or more not The different solid crystal phases produced with molecules align.Some compounds of the invention there may be more than one crystal formation, this hair It is bright to be intended to include various crystal formations and its mixture.

Generally, crystallization effect can produce the solvate of the compounds of this invention.Term " the solvation used in the present invention Thing " refers to the aggregation comprising one or more the compounds of this invention molecules Yu one or more solvent molecules.Solvent can be Water, solvate in this case is hydrate.Or, solvent can be organic solvent.Therefore, compound of the invention can be with Exist with hydrate, including monohydrate, dihydrate, semihydrate, times semihydrate, trihydrate, tetrahydrate etc., with And corresponding solvation form.The compounds of this invention can form real solvate, but in some cases, it is also possible to only protect Indefinite water or water are stayed plus the mixture of the indefinite solvent in part.Compound of the invention can react in a solvent or from Precipitation or crystallized out in solvent.The solvate of the compounds of this invention is also contained within the scope of the present invention.

Present invention additionally comprises the prodrug of above-claimed cpd.In this application, term " prodrug " expression can be in physiological conditions Compound lower or that bioactive compound of the invention is converted to by solvolysis.Therefore, term " prodrug " refers to The pharmaceutically acceptable metabolic precursor thereof of compound of the invention.When being given in need individual, prodrug can not have Activity, but reactive compound of the invention is converted in vivo.Prodrug generally rapid conversion in vivo, and produce of the invention Parent compound, for example, realized by hydrolyzing in blood.Prodrug compound generally provides molten in mammalian organism The advantage of Xie Du, histocompatbility or sustained release.Prodrug includes known amino protecting group and carboxyl-protecting group.Specific prodrug system Preparation Method can refer to Saulnier, M.G., et al., Bioorg.Med.Chem.Lett.1994,4,1985-1990； Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。

In this application, " pharmaceutical composition " refers to the generally receiving of the compounds of this invention and this area for biology to be lived Property compound is delivered to the preparation of the medium of mammal (such as people).The medium includes pharmaceutically acceptable carrier.Medicine The purpose of composition is to promote the administration of organism, absorption beneficial to active component and then plays bioactivity.

Terms used herein " pharmaceutically acceptable " refers to the bioactivity or property for not influenceing the compounds of this invention Material (such as carrier or diluent), and relative nontoxic, the i.e. material can be applied to individuality without causing bad biological respinse Or interacted with any component included in bad mode and composition.

In this application, " pharmaceutically acceptable excipient " includes but is not limited to any by related government administration section Permit adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, the dye to be subjected to being used for the mankind or domestic animal Material/colouring agent, flavouring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifying agent.

" tumour " of the present invention, " cell proliferative disorder relevant disease " etc. include but is not limited to leukaemia, gastro-intestinal stromal Knurl, histiocytic lymphoma, non-small cell lung cancer, ED-SCLC, cancer of pancreas, lung squamous cancer, adenocarcinoma of lung, breast cancer, prostatitis Gland cancer, liver cancer, cutaneum carcinoma, cell carcinoma, cervical carcinoma, oophoroma, intestinal cancer, nasopharyngeal carcinoma, the cancer of the brain, osteocarcinoma, cancer of the esophagus, melanin The diseases such as knurl, kidney, carcinoma of mouth.

Terms used herein " prevention ", " prevention " and " preventing " includes sufferer is reduced disease or illness generation or evil The possibility of change.

Term " treatment " the used herein synonym similar with other includes following meanings：

I () prevention disease or illness occur in mammal, particularly when this kind of mammal be susceptible to the disease or Illness, but when being not yet diagnosed as having suffered from the disease or illness；

(ii) suppress disease or illness, that is, contain that it develops；

(iii) disease or illness are alleviated, i.e. the state of the disease or illness is disappeared；Or

(iv) disease or the symptom caused by illness are mitigated.

Term " effective dose ", " therapeutically effective amount " or " pharmacy effective dose " used herein refers to take metapedes with certain At least one medicament or the amount of compound of one or more symptoms of the treated disease of alleviation or illness in degree.Its result Can be sign, symptom or the cause of disease abatement and/or alleviation, or biosystem it is any other needed for change.For example, for controlling " effective dose " treated is the composition comprising compound disclosed herein needed for clinically providing significant remission effect Amount.The technology of such as dose escalation trial can be used to determine the effective dose being suitable in any individual case.

Terms used herein " taking ", " administration ", " administration " etc. are to refer to be delivered to compound or composition carry out The method in the required site of biological agent.These methods include but is not limited to oral route, through intraduodenal routes, parenteral note Penetrate (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), local administration and per rectum administration.This area Can be used for the application technique of Compounds and methods for described herein known to technical staff, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, discuss in Pa Those.In preferred embodiments, the compound and composition being discussed herein are by Orally administered.

Term " drug regimen " used herein, " drug combination ", " drug combination ", " apply other treatment ", " apply it Its therapeutic agent " etc. refers to the drug therapy obtained by mixing or combining more than one active component, and it includes active component Fixation and non-fixed Combination.Term " fixed Combination " refers to be administered simultaneously to patient in the form of single entity or single formulation At least one compound as herein described and at least one collaboration medicament.Term " not fixed Combination " refers to the shape of corpus separatum Formula is administered simultaneously to patient, share or at least one compound as herein described is sequentially applied with variable interval time and at least One kind collaboration preparation.These are also applied in HAART, such as using three or more active component.

It should also be appreciated by one skilled in the art that in method discussed below, midbody compound functional group may need To be protected by appropriate protection group.Such functional group includes hydroxyl, amino, sulfydryl and carboxylic acid.Suitable hydroxyl protecting group bag Include trialkylsilkl or diarylalkyl-silyl (such as t-butyldimethylsilyl, tert-butyl diphenyl first Silylation or trimethyl silyl), THP trtrahydropyranyl, benzyl etc..The protection group of suitable amino, amidino groups and guanidine radicals includes uncle Butoxy carbonyl, benzyloxycarbonyl group etc..Suitable sulfhydryl protected base includes-C (O)-R " (wherein R " be alkyl, aryl or aralkyl), To methoxy-benzyl, trityl etc..Suitable carboxyl-protecting group includes alkyl, aryl or aralkyl esters.

Protection group can be introduced and removed according to standard technique well known by persons skilled in the art and as described herein.Protect The use for protecting base is specified in Greene, T.W. and P.G.M.Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., in Wiley.Protection group can also be fluoropolymer resin.

The preparation of compound of formula I

Following reaction scheme it is exemplary illustrate prepare compound of formula I, its stereoisomer or its mixture or its medicine The method of acceptable salt on：

Wherein,

X₁、X₂、X₃、X₄、X₅、X₆、R₁、R₂、R₃、R₄As described in the embodiment part of compound of formula I above.Should Understand in following reaction scheme, the combination of base and/or variable is replaced in the formula only causes stabilization in this kind of combination It is only during compound admissible.It will also be understood that other formulas, such as formula (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia- 4), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), and other compound of formula I specifically disclosed herein can be by organic Chemical technician skilled in the art is by method disclosed herein (by the appropriate parent material for replacing of application and using this area skill Method known to art personnel changes synthetic parameters as needed) or known method be prepared.

Technical staff can understand that in some cases parent material and intermediate can be wrapped in the preparation of the compounds of this invention Being contained in building-up process needs functional group to be protected.The certainty of any protection group used will be depending on protected functional group Characteristic, this is apparent to those skilled in the art.Select suitable protection group and it is connected and is removed The guidance of synthesis strategy may refer to for example, Green＆Wuts, Green'sProtective Groups in Organic Synthesis,(《Protection group in organic synthesis》)3d Edition,Jon Wiley&Sons,Inc.,New York(1999) And the document quoted in the book.

Therefore, protection group refers to when being connected with the active function groups in molecule, shelters, lowers or prevent the anti-of the functional group The atomic group of answering property.Usual protection group can as needed and optionally be removed in building-up process.

Reaction scheme 1：

In various, X₁、X₂、X₃、X₄、X₅、X₆、R₁、R₂、R₃、R₄、LG₁And LG₂The equal such as embodiment party of compound of formula I above Described in case part.

Reaction scheme 2：

X₁、X₂、X₃、X₄、X₅、X₆、R₁、R₂、R₃、R₄、LG₁、LG₂And LG₃The equal such as embodiment portions of compound of formula I above Described in point.

Main advantages of the present invention are：

1. a kind of compound shown in formula I is provided.

2. a kind of novel ERK kinase inhibitors of structure, its preparation method and application, described inhibitor pair are provided ERK kinases has inhibitory activity higher.

3. the pharmaceutical composition of class treatment and ERK kinase activity related diseases is provided.

With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention Rather than limitation the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to conventional strip Part, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number are percentage by weight and weight Number.

Experiment material used and reagent can be obtained from commercially available channel unless otherwise instructed in following examples.

Embodiment 1

The synthesis of 1- (5- bromine indoline -1- bases) -2- Phenyl ethyl ketones

Sequentially added in dry 50mL there-necked flasks compound 1 (1.10g, 5.55mmol), phenyllacetyl chloride (858mg, 5.55mmol), triethylamine (1.68g, 16.66mmol), is dissolved in dichloromethane (20mL).LCMS is detected after completion of the reaction, directly It is concentrated under reduced pressure, with silicagel column (ethyl acetate：Petroleum ether=1：10) product 2 (1.2g, white solid), yield, are obtained：68%.

LCMS:m/z 318.1(M+H)；RT=1.40min (2min)

2- phenyl -1- (5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) indoline -1- bases) The synthesis of ethyl ketone

Addition compound 2 (1.4g, 4.42mmol), connection boric acid pinacol ester are sequentially added in dry 50mL there-necked flasks (2.25g, 8.84mmol), [1,1'- double (diphenylphosphino) ferrocene] palladium chloride (322mg, 0.44mmol), potassium acetate (866mg, 8.84mmol), Isosorbide-5-Nitrae-dioxane (20mL).100 degrees Celsius of 3 hours of reaction are heated under nitrogen protection.Reaction After finishing, pour into 30mL water, extracted with ethyl acetate (30mL × 2), merge organic phase.Organic phase uses saturated aqueous common salt successively (50mL) is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silicagel column (ethyl acetate：Petroleum ether=1：20), Obtain product 3 (1.3g, yellow solid), yield：94%.

LCMS:m/z 364.4(M+H)；RT=1.53min (2min)

The synthesis of 1- (5- (2- chlorine pyrimidine-4-yl) indoline -1- bases) -2- Phenyl ethyl ketones

Compound 3 (700mg, 1.92mmol), 2,4- dichloro pyrimidines are sequentially added in dry 50mL there-necked flasks (286mg, 1.92mmol), [1,1'- double (diphenylphosphino) ferrocene] palladium chloride (139mg, 0.19mmol), potassium carbonate (400mg, 2.89mmol), Isosorbide-5-Nitrae-dioxane (8mL) and water (2mL).100 degrees Celsius are heated under nitrogen protection, 3 are reacted Hour.After completion of the reaction, pour into 30mL water, extracted with ethyl acetate (30mL × 2), merge organic phase.Organic phase is used successively Saturated aqueous common salt (50mL × 1) is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, and plate (ethyl acetate is prepared with thickness： Petroleum ether=1：5) product 5 (250mg, yellow solid), yield, are obtained：37%.

LCMS:m/z 350.1(M+H)；RT=1.48min (2min)

1- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) indoline -1- bases) -2- phenyl second The synthesis of ketone

Compound 4 (200mg, 0.57mmol), 1- methyl -5- amino-pyrazols are sequentially added in dry 50mL there-necked flasks (55mg, 0.57mmol), three (dibenzalacetone) two palladium (55mg, 0.06mmol), 4,5- double diphenylphosphine -9,9- dimethyl Xanthene (35mg, 0.06mmol), cesium carbonate (279mg, 0.86mmol) Isosorbide-5-Nitrae-dioxane (10mL).The lower heating of nitrogen protection To 100 degrees Celsius, 4 hours are reacted.After completion of the reaction, pour into 30mL water, extracted with ethyl acetate (30mL × 2), merge Organic phase.Organic phase is washed with saturated aqueous common salt (50mL × 1) successively, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, With reversely post is prepared, product HE153 (16mg, yellow solid), yield are obtained：7%.

LCMS:m/z 411.4(M+H)；RT=1.27min (2min)

1H-NMR(MeOD 400MHz):8.38-8.39(m,1H),8.19-8.21(m,1H),7.96-7.98(m,2H), 7.56(s,1H),7.26-7.38(m,7H),4.19-4.23(m,2H),3.89(s,2H),3.79(s,3H),3.20-3.23(m, 2H).

Embodiment 2

The synthesis of 1- (bromo- 2,3- dihydros -1H- pyrrolo-es [2,3-b] pyridine -1- bases of 5-) -2- Phenyl ethyl ketones

Sequentially add compound 5 (398mg, 2.0mmol) in the single port bottle of dry 50mL, phenylacetic acid (272mg, 2.0mmol), HATU (1.1g, 3.0mmol) and DMF (10mL), after DIPEA (517mg, 4.0mmol) is added dropwise, Room temperature reaction is overnight.After completion of the reaction, 15 milliliters of water are added, is extracted with ethyl acetate (20 milliliters × 2), merge organic phase.Have Machine is mutually washed, anhydrous sodium sulfate drying with saturated aqueous common salt (15 milliliters × 3), is concentrated under reduced pressure, crude product silica gel column chromatography (stone Oily ether:Ethyl acetate=6:1) purifying obtains yellow solid compound 6 (539mg, yield：85%).

LCMS:m/z 318.8(M+H)⁺；RT=1.652min (254nm).

The synthesis of 1- (2- phenyl acetyls) -2,3- dihydro -1H- pyrrolo- [2,3-b] pyridine -5- ylboronic acids

Compound 7 (317mg, 1.0mmol) is added in dry 50mL there-necked flasks, Isosorbide-5-Nitrae-dioxane (8mL) is double Join any borate (381mg, 1.5mmol) frequently, potassium acetate (194mg, 2.0mmol) and [1,1'- double (diphenylphosphinos) two cyclopentadienyl Iron] palladium chloride (73mg, 0.1mmol).Vacuumize and taken a breath 3 times with nitrogen, under nitrogen protection, 90 DEG C of stirring reactions 6h, TLC The detection complete reaction solutions of reaction are cooled to room temperature, and crude product silica gel column chromatographies concentrated under reduced pressure purify (dichloromethane:Methyl alcohol= 5:1) yellow solid compound 8 (169mg, yield are obtained：60%).

LCMS:m/z 282.9(M+H)⁺。

1- (5- (2- chlorine pyrimidine-4-yl) -2,3- dihydro -1H- pyrrolo- [2,3-b] pyridine -1- bases) -2- Phenyl ethyl ketones Synthesis

Addition compound 9 (169mg, 0.6mmol) in dry 50mL there-necked flasks, 2,4- dichloro pyrimidines (134mg, 0.9mmol), [1,1'- double (diphenylphosphino) ferrocene] palladium chloride (44mg, 0.06mmol), cesium carbonate (391mg, 1.2mmol), Isosorbide-5-Nitrae-dioxane (8mL) and water (0.5mL).Vacuumize and taken a breath 3 times with nitrogen, under nitrogen protection, 90 DEG C are stirred Reaction 6h is mixed, reaction solution is cooled to room temperature, crude product silica gel column chromatographies concentrated under reduced pressure purify (petroleum ether:Ethyl acetate=2: 1) yellow solid compound 10 (105mg, yield are obtained：50%).

LCMS:m/z 350.9(M+H)⁺。

1- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) -2,3- dihydro -1H- pyrrolo-es [2,3- B] pyridine -1- bases) -2- diphenylphosphino ethane -1- ketone synthesis

Compound 10 (70mg, 0.2mmol), 1- methyl -5- amino-pyrazols are sequentially added in dry 50mL there-necked flasks (29mg, 0.3mmol), three (dibenzalacetone) two palladium (18mg, 0.02mmol), 4,5- double diphenylphosphine -9,9- dimethyl Xanthene (10mg, 0.02mmol), cesium carbonate (130mg, 0.4mmol) and Isosorbide-5-Nitrae-dioxane (6mL).The lower heating of nitrogen protection To 105 degrees Celsius, reaction is overnight.After completion of the reaction, ethyl acetate (15mL) dilution is added, saturated aqueous common salt (10mL × 3) is washed Wash, anhydrous sodium sulfate drying, crude product silica gel column chromatography concentrated under reduced pressure purifies (petroleum ether:Ethyl acetate=1:2) Huang is obtained Color solid chemical compound A2 (5mg, yield：6%).

¹HNMR(400MHz,CDCl₃- d) δ 8.81 (s, 1H), 8.46 (d, 1H, J=5.2Hz), 8.09 (s, 1H), 7.51 (d, 1H, J=2.0Hz), 7.39 (d, 2H, J=7.2Hz), 7.32-7.17 (m, 4H), 6.89 (s, 1H), 6.35 (d, 1H, J= 2.0Hz), 4.61 (s, 2H), 4.18 (t, 2H, J=8.8Hz), 3.82 (s, 3H), 3.12 (t, 2H, J=8.4Hz).

LCMS:m/z 412.1(M+H)⁺；RT=1.179min (254nm).

Embodiment 3

The synthesis of N- (5- bromopyridine -2- bases) -2- phenyl acetamides

Compound 11 (2.00g, 14.71mmol), 2- amino -5- bromine pyrroles are sequentially added in the single port bottle of dry 50mL Pyridine (2.54g, 14.71mmol), HATU (5.59g, 14.71mmol) is dissolved in DMF (20mL), and DIPEA is added dropwise After (1.91g, 14.71mmol), room temperature reaction 4 hours.After LCMS detections are finished, water is added to reaction solution, then use ethyl acetate Extraction, organic phase uses saturated common salt water washing, anhydrous sodium sulfate drying to filter again, and by silicagel column, (solvent is second after concentration Acetoacetic ester：Petroleum ether=1：10) compound 2 (2.8g, white solid), yield are obtained：67%.

LCMS:m/z291.1(M+H)；RT=1.33min (2.0min)

The synthesis of (6- (2- phenylacetamidos) pyridin-3-yl) boric acid

Compound 12 (1.4g, 4.81mmol), connection boric acid pinacol ester are sequentially added in dry 50mL there-necked flasks (2.44g, 9.62mmol), [1,1'- double (diphenylphosphino) ferrocene] palladium chloride (351mg, 0.48mmol), potassium acetate (942mg, 9.62mmol), Isosorbide-5-Nitrae-dioxane (20mL).100 degrees Celsius of 3 hours of reaction are heated under nitrogen protection.Reaction After finishing, pour into 30mL water, extracted with ethyl acetate (30mL × 2), merge organic phase.Organic phase uses saturated aqueous common salt successively (50mL × 1) washs, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silicagel column (ethyl acetate：Petroleum ether=1： 3) product 13 (1.0g, yellow solid), yield, are obtained：81%.

LCMS:m/z257.1(M+H)；RT=0.39min (2min)

The synthesis of N- (5- (2- chlorine pyrimidine-4-yl) pyridine -2- bases) -2- phenyl acetamides

Compound 13 (1.0g, 3.91mmol), 2,4- dichloro pyrimidines are sequentially added in dry 50mL there-necked flasks (582mg, 3.91mmol), [1,1'- double (diphenylphosphino) ferrocene] palladium chloride (293mg, 0.40mmol), potassium carbonate (810mg, 5.87mmol), Isosorbide-5-Nitrae-dioxane (20mL) and water (5mL).100 degrees Celsius, reaction 3 are heated under nitrogen protection Individual hour.After completion of the reaction, pour into 30mL water, extracted with ethyl acetate (30mL × 2), merge organic phase.Organic phase is successively Washed with saturated aqueous common salt (50mL × 1), anhydrous sodium sulfate drying, filtered, filtrate decompression concentration prepares plate (acetic acid second after Ester：Petroleum ether=1：3) product 14 (500mg, yellow solid), yield, are obtained：40%.

LCMS:m/z325.2(M+H)；RT=1.28min (2min)

N- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) pyridine -2- bases) -2- phenyl-acetamides Synthesis

Compound 14 (50mg, 0.15mmol), 1- methyl -5- amino-pyrazols are sequentially added in dry 50mL there-necked flasks (15mg, 0.15mmol), three (dibenzalacetone) two palladium (18mg, 0.02mmol), 4,5- double diphenylphosphine -9,9- dimethyl Xanthene (12mg, 0.02mmol), cesium carbonate (49mg, 0.15mmol) Isosorbide-5-Nitrae-dioxane (10mL).The lower heating of nitrogen protection To 100 degrees Celsius, 2 hours are reacted.After completion of the reaction, pour into 30mL water, extracted with ethyl acetate (30mL × 2), merge Organic phase.Organic phase is washed with saturated aqueous common salt (50mL) successively, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with anti- To post is prepared, product A3 (16mg, yellow solid), yield are obtained：28%.

LCMS:m/z386.2(M+H)；RT=1.26min (2min)

¹H-NMR(MeOD 400MHz):9.01-9.02(m,1H),8.46-8.47(m,2H),8.15-8.16(m,1H), 7.52-7.53(m,1H),7.33-7.40(m,6H),6.42-6.43(m,1H),3.78-3.79(m,5H).

Embodiment 4

The conjunction of 2- phenyl-N- (4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) phenyl) acetamide Into

Sequentially add compound 15 (500mg, 2.28mmol) in the single port bottle of dry 50mL, phenylacetic acid (310mg, 2.28mmol), HATU (1.30g, 3.42mmol) is dissolved in DMF (10mL), after triethylamine (461mg, 4.56mmol) is added dropwise, room temperature Reaction 3 hours.After LCMS detections are finished, water is added to reaction solution, then be extracted with ethyl acetate, organic phase uses saturated aqueous common salt again Washing, anhydrous sodium sulfate drying, filtering, by silicagel column, (solvent is ethyl acetate after concentration：Petroleum ether=1：20) obtain Compound 16 (520mg, white solid), yield：68%.

LCMS:m/z338.2(M+H)；RT=1.09min (2.0min)

The synthesis of N- (5- (2- chlorine pyrimidine-4-yl) pyridine -2- bases) -2- phenethyls

Compound 16 (520mg, 1.54mmol), 2,4- dichloro pyrimidines are sequentially added in dry 50mL there-necked flasks (275mg, 1.85mmol), [1,1'- double (diphenylphosphino) ferrocene] palladium chloride (110mg, 0.15mmol), potassium carbonate (319mg, 2.31mmol), Isosorbide-5-Nitrae-dioxane (8mL) and water (2mL).100 degrees Celsius are heated under nitrogen protection, 3 are reacted Hour.After completion of the reaction, pour into 30mL water, extracted with ethyl acetate (30mL × 2), merge organic phase.Organic phase is used successively Saturated aqueous common salt (50mL × 1) is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, and plate (ethyl acetate is prepared after： Petroleum ether=1：5) product 17 (480mg, yellow solid), yield, are obtained：96%.

LCMS:m/z324.3(M+H)；RT=1.10min (2min)

The synthesis of N- (4- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) phenyl) -2- phenyl-acetamides

Compound 17 (200mg, 0.62mmol), 1- methyl -5- amino pyrroles are sequentially added in dry 50mL there-necked flasks Azoles (60mg, 0.62mmol), three (dibenzalacetone) two palladium (155mg, 0.06mmol), 4,5- double diphenylphosphine -9,9- bis- Methyl xanthene (35mg, 0.06mmol), cesium carbonate (302mg, 0.93mmol) Isosorbide-5-Nitrae-dioxane (10mL).Under nitrogen protection 100 degrees Celsius are heated to, 2 hours are reacted.After completion of the reaction, pour into 30mL water, extracted with ethyl acetate (30mL × 2), Merge organic phase.Organic phase is washed with saturated aqueous common salt (50mL × 1) successively, anhydrous sodium sulfate drying, and filtering, filtrate decompression is dense Contracting, with reversely post is prepared, obtains product A4 (50mg, yellow solid), yield：21%.

LCMS:m/z385.4(M+H)；RT=1.13min (2min)

¹H-NMR(CDCl3,400MHz):8.22-8.24 (m, 1H), 8.00 (d, j=8.4,2H), 7.62 (d, j=8.4, 2H),7.50-7.54(m,2H),7.34-7.44(m,6H),6.47(s,1H),3.79-3.88(m,5H).

Embodiment 5

The synthesis of the bromo- 2- fluoroanilines of 4-

The addition 4- fluoro- 1- nitrobenzene (2.2g, 10mmol) of bromo- 2- in 100mL round-bottomed flasks, iron powder (2.8g, 50mmol) with tetrahydrofuran (20mL), lower dropwise addition hydrochloric acid (30mL, 2N) is stirred at room temperature, 2h is stirred at room temperature, add Carbon Dioxide Sodium (2g) and anhydrous sodium sulfate, filtering, ethyl acetate washing are concentrated under reduced pressure to give yellow solid compound 19 (1.65g, yield： 87%).

LCMS:m/z 191.1(M+H)⁺；RT=1.405min.

N- (the bromo- 2- fluorophenyls of 4-) -2- phenyl-acetamides

Sequentially add compound 19 (950mg, 5mmol) in the single port bottle of dry 50mL, phenylacetic acid (680mg, 5mmol), HATU (3.42g, 9mmol), DMF (15mL) and DIPEA (1.29g, 10mmol).Stir at room temperature 6h, plus ethyl acetate (20mL) dilution, saturated aqueous common salt (10mL × 3) washing, anhydrous sodium sulfate drying is concentrated under reduced pressure, thick to produce Product silica gel column chromatography (petroleum ether:Ethyl acetate=8:1) purifying obtains yellow solid compound 20 (1.07g, yield： 70%).

LCMS:m/z 309.8(M+H)⁺；RT=1.457min.

N- (the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) phenyl) -2- phenylacetyls The synthesis of amine

Addition compound 20 (1.01g, 3.3mmol) in dry 50mL there-necked flasks, Isosorbide-5-Nitrae-dioxane (10mL), Duplex frequency any borate (4.2g, 16.7mmol), potassium acetate (648mg, 6.6mmol) and [1,1'- double (diphenylphosphinos) two is luxuriant Iron] palladium chloride (220mg, 0.3mmol).Vacuumize and taken a breath 3 times with nitrogen, under nitrogen protection, 90 DEG C of stirring reaction 6h, The TLC detection complete reaction solutions of reaction are cooled to room temperature, and crude product silica gel column chromatographies concentrated under reduced pressure purify (petroleum ether:Acetic acid Ethyl ester=5:1) yellow solid compound 21 (703mg, yield are obtained：60%).

LCMS:m/z 355.8(M+H)⁺；RT=1.699min.

The synthesis of N- (4- (2- chlorine pyrimidine-4-yl) -2- fluorophenyls) -2- phenyl-acetamides

Sequentially add 21 (355mg, 1.0mmol), 2,4- dichloro pyrimidines at room temperature in dry 10mL round-bottomed flasks (222mg, 1.5mmol), [1,1'- double (diphenylphosphino) ferrocene] palladium chloride (73mg, 0.1mmol), cesium carbonate (652mg, 2.0mmol), Isosorbide-5-Nitrae-dioxane (6mL) and water (1mL).Vacuumize and taken a breath 3 times with nitrogen, under nitrogen protection, 90 DEG C of stirring reaction 6h, TLC detection complete reaction solutions of reaction are cooled to room temperature, and the crude products that are concentrated under reduced pressure are pure with silica gel column chromatography Change (petroleum ether:Ethyl acetate=3:1) yellow solid compound 22 (174mg, yield are obtained：51%).

LCMS:m/z 341.9(M+H)⁺；RT=1.677min.

N- (the fluoro- 4- of 2- (2- (1- methyl isophthalic acid H- pyrazoles -5- bases amino) pyrimidine-4-yl) phenyl) -2- phenyl-acetamides Synthesis

Compound 22 (68mg, 0.2mmol), 1- methyl -5- amino-pyrazols are sequentially added in dry 25mL there-necked flasks (29mg, 0.3mmol), three (dibenzalacetone) two palladium (18mg, 0.02mmol), 4,5- double diphenylphosphine -9,9- dimethyl Xanthene (12mg, 0.02mmol), cesium carbonate (130mg, 0.4mmol) and Isosorbide-5-Nitrae-dioxane (3mL).The lower microwave of nitrogen protection 100 degrees Celsius are heated to, 2 hours are reacted.After completion of the reaction, ethyl acetate (20mL) dilution, saturated aqueous common salt (10mL are added × 3) wash, anhydrous sodium sulfate drying, it is concentrated under reduced pressure, crude product acidity prep-HPLC purifying obtains yellow solid compound A5 (6mg, yield：7%).

¹HNMR(400MHz,CDCl₃- d) δ 8.49 (t, 1H, J=8.4Hz), 8.41 (d, 1H, J=5.2Hz), 7.78 (s, 1H), 7.76 (d, 1H, J=4.8Hz), 7.50-7.35 (m, 7H), 7.16 (d, 1H, J=5.6Hz), 6.35 (d, 1H, J= 1.6Hz), 3.81 (s, 5H).

LCMS:m/z 402.9(M+H)⁺；RT=1.385min.

The present invention can be obtained following compound using method like above：

Embodiment 6

The tert-butyl group -5- (2- (1- methyl isophthalic acid H- pyrazoles -5- bases amino) pyrimidine-4-yl) indoline -1- carboxylic acid tert-butyl esters Synthesis

¹HNMR(400MHz,CDCl₃- d) δ 8.38 (d, 1H, J=5.2Hz), 7.85 (s, 2H), 7.49 (d, 1H, J= 1.6Hz), 7.15 (d, 1H, J=5.2Hz), 6.87 (s, 1H), 6.35 (d, 1H, J=1.2Hz), 4.03 (t, 2H, J= 8.8Hz), 3.80 (s, 3H), 3.15 (t, 2H, J=8.8Hz), 1.58 (s, 9H).

LCMS:m/z 393.3(M+H)⁺；RT=1.461min (254nm).

Embodiment 7

1- (5- (2- (1- methyl isophthalic acid H- pyrazoles -5- bases amino) pyrimidine-4-yl) indoline -1- bases) -3- phenyl propyl-s 1- The synthesis of ketone

¹HNMR(400MHz,CDCl₃- d) δ 8.40 (d, 1H, J=5.2Hz), 8.32 (d, 1H, J=8.4Hz), 7.88- 7.86 (m, 2H), 7.49 (d, 1H, J=1.6Hz), 7.32-7.16 (m, 6H), 6.95 (s, 1H), 6.35 (d, 1H, J= 1.6Hz), 4.03 (t, 2H, J=8.4Hz), 3.80 (s, 3H), 3.21 (t, 2H, J=8.4Hz), 3.08 (t, 2H, J= 7.6Hz), 2.76 (t, 2H, J=7.6Hz).

LCMS:m/z 425.0(M+H)⁺；RT=1.339min (254nm).

Embodiment 8

The synthesis of 4- (indoline -5- bases)-N- (1- methyl isophthalic acid H- pyrazoles -5- bases) pyrimidine -2- amine

¹HNMR(400MHz,DMSO-d₆) δ 8.38 (d, 1H, J=5.6Hz), 7.93-7.91 (m, 3H), 7.47 (d, 1H, J =1.6Hz), 7.40 (d, 1H, J=5.6Hz), 6.82 (d, 1H, J=8.0Hz), 6.36 (d, 1H, J=1.6Hz), 5.74 (d, 1H, J=2.8Hz), 3.73 (s, 3H), 3.64 (t, 2H, J=8.4Hz), 3.09 (t, 2H, J=8.4Hz).

LCMS:m/z 293.2(M+H)⁺；RT=0.958min (254nm).

Embodiment 9

2- (2- chlorphenyls) -1- (5- (2- (1- methyl isophthalic acid H- pyrazoles -5- bases amino) pyrimidine-4-yl) indoline -1- Base) ethyl ketone synthesis

¹HNMR(400MHz,CDCl₃- d) δ 8.41 (d, 1H, J=5.2Hz), 8.31 (d, 1H, J=8.8Hz), 7.91 (s, 1H), 7.86 (d, 1H, J=8.4Hz), 7.49 (d, 1H, J=1.6Hz), 7.43 (d, 1H, J=2.0Hz), 7.42-7.24 (m, 3H), 7.17 (d, 1H, J=5.2Hz), 6.80 (s, 1H), 6.35 (d, 1H, J=2.0Hz), 4.23 (t, 2H, J=8.8Hz), 3.95 (s, 2H), 3.81 (s, 3H), 3.30 (t, 2H, J=8.4Hz).

LCMS:m/z 445.4(M+H)⁺；RT=1.36min (254nm).

Embodiment 10

2- (3- chlorphenyls) -1- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) indoline -1- Base) ethyl ketone synthesis

¹H-NMR(CDCl₃,400MHz)：(m, 2H), 8..30-8.35 7.88-7.91 (m, 2H), 7.51-7.52 (d, J= 1.2Hz, 1H), 7.29-7.32 (m, 3H), 7.20-7.25 (m, 2H), 6.41 (d, J=1.2Hz, 1H), 4.15-4.19 (m, 2H),3.85(s,3H),3.82(s,2H),3.25-3.29(m,2H).

LCMS:m/z444.9(M+H)；RT=1.475min (2.50min)

Embodiment 11

2- (4- chlorphenyls) -1- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) indoline -1- Base) ethyl ketone synthesis

LCMS:m/z445.4(M+H)；RT=1.39min (2.0min)

¹H-NMR(CDCl₃,400MHz):8.28-8.34(m,2H),7.88-7.91(m,2H),7.52(s,1H),7.33- 7.35 (m, 2H), 7.24-7.26 (m, 4H), 6.42 (s, 1H), 4.17 (t, j=8.0,2H), 3.85 (s, 3H), 3.81 (s, 2H), 3.26 (t, j=8.0,2H)

Embodiment 12

3- hydroxyls -1- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) indoline -1- bases) -2- The synthesis of phenyl propyl- 1- ketone

LCMS:m/z441.3(M+H)；RT=1.15min (2.0min)

¹H-NMR(CDCl₃,400MHz):7.95-7.97(m,1H),7.83-7.85(m,1H),7.69(s,1H),7.52 (s, 1H), 7.31-7.39 (m, 5H), 7.09-7.10 (m, 1H), 6.43-6.54 (m, 2H), 4.00-4.11 (m, 2H), 3.85 (s,3H),3.47-3.67(m,2H),3.43-3.61(m,1H),3.02-3.07(m,2H).

Embodiment 13

1- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) indoline -1- bases) -2- phenyl propyl-s The synthesis of 1- ketone

¹H-NMR(CDCl₃,400MHz)：(d, J=7.6Hz, 1H), 8..43-8.45 7.19-8.20 (d, J=7.6Hz, 1H), 7.91-7.93 (d, J=8.4Hz, 1H), 7.81 (s, 1H), 7.54-7.55 (d, J=2.0Hz, 1H), 7.27-7.37 (m, 6H), 6.45-6.46 (d, J=2.0Hz, 1H), 4.17-4.22 (m, 1H), 3.86-3.91 (m, 5H), 3.04-3.12 (m, 2H), 1.54-1.55 (d, J=6.8Hz, 3H)

LCMS:m/z425.3(M+H)；RT=1.462min (2.50min)

Embodiment 14

2- (2- chlorphenyls)-N- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) pyridine -2- bases) Acetamide

¹H-NMR(CDCl₃,400MHz)：8.92 (d, J=2.0Hz, 1H), 7.99-8.01 (d, J=9.2Hz, 1H), 8.49-8.52 (m, 1H), 8.44-8.46 (d, J=6.0Hz, 1H), 7.61-7.62 (d, J=3.6Hz, 1H), 7.7.43-7.46 (dd,J₁=3.6Hz, J₂=7.2Hz, 1H), 7.37-7.39 (dd, J₁=3.6Hz, J₂=7.2Hz, 1H), 7.28-7.32 (m, 3H), (s, the 3H) of 6.50-6.51 (d, J=2.4Hz, 1H), 4.01 (s, 2H), 3.92

LCMS:m/z419.9(M+H)；RT=1.375min (2.50min)

Embodiment 15

The synthesis of 3N- (5- (2- (1- methyl isophthalic acid H- pyrazoles -5- bases amino) pyrimidine-4-yl) pyridine -2- bases) acetamide

¹HNMR(400MHz,CDCl₃- d) δ 10.77 (s, 1H), 9.49 (s, 1H), 9.04 (s, 1H), 8.52 (d, 1H, J= 4.8Hz), 8.44 (d, 1H, J=8.4Hz), 8.21 (d, 1H, J=8.8Hz), 7.47 (d, 1H, J=4.8Hz), 7.36 (s, 1H), 6.28 (s, 1H), 3.70 (s, 3H), 2.13 (s, 3H).

LCMS:m/z 310.0(M+H)⁺；RT=0.771min.

Embodiment 17

The synthesis of N- (1- methyl isophthalic acid H- pyrazoles -5- bases) -4- (6- (PhenethyIamino) pyridin-3-yl) pyrimidine -2- amine

Compound A-13 (20mg, 0.05mmol) is added in the single port bottle of dry 50mL, tetrahydrofuran (5mL) is dissolved in, After being slowly added to Lithium Aluminium Hydride (5mg, 0.13mmol), room temperature reaction is overnight.After LCMS detections are finished, water is added to reaction solution, It is extracted with ethyl acetate again, organic phase uses saturated common salt water washing, anhydrous sodium sulfate drying, filtering, by anti-phase after concentration again Prepare post and obtain compound A17 (5mg, white solid), yield：27%.

¹H-NMR(CDCl₃,400MHz):8.74 (s, 1H), 8.35 (d, j=5.6,1H), 8.06-8.08 (m, 1H), 7.47-7.48(m,1H),7.30-7.34(m,2H),7.22-7.24(m,2H),6.95-7.09(m,2H),6.34-6.43(m, 2H),4.93(s,1H),3.80(s,3H),3.62-3.66(m,2H),2.93-2.97(m,2H).

LCMS:m/z372.2(M+H)；RT=1.08min (2.0min)

Embodiment 18

4N- (the chloro- 4- of 2- (2- (1- methyl isophthalic acid H- pyrazoles -5- bases amino) pyrimidine-4-yl) phenyl) -2- phenyl-acetamides Synthesis

¹HNMR(400MHz,CDCl₃- d) δ 8.44 (d, 1H, J=8.8Hz), 8.32 (d, 1H, J=5.2Hz), 7.92 (d, 1H, J=2.0Hz), 7.78 (dd, 1H, J=2.0Hz, 8.8Hz), 7.72 (s, 1H), 7.39-7.27 (m, 6H), 7.03 (d, 1H, J=6.0Hz), 6.86 (s, 1H), 6.24 (d, 1H, J=2.4Hz), 3.73 (s, 2H), 3.70 (s, 3H).

LCMS:m/z 418.9(M+H)⁺；RT=1.504min.

Embodiment 19

N- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) pyridine -2- bases) -1- phenyl methanesulfonamide acyls The synthesis of amine

¹H-NMR(CDCl3 400MHz):8.47-8.57(m,2H),8.18-8.21(m,1H),7.52-7.53(m,1H), 7.30-7.33(m,1H),7.25-7.26(m,1H),7.00-7.23(m,5H),6.36(s,1H),4.46(s,2H),3.83(m, 3H).

LCMS:m/z421.9(M+H)；RT=1.14min (2.5min)

Embodiment 20

2- (2,6- dichlorophenyls) -1- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) dihydro Yin Diindyl -1- bases) ethyl ketone synthesis

¹H-NMR(CDCl₃,400MHz):8.41 (d, j=5.2,1H), 8.26 (d, j=8.8,1H), 7.94 (s, 1H), 7.84 (d, j=8.4,1H), 7.49-7.50 (m, 1H), 7.36-7.38 (m, 2H), 7.16-7.22 (m, 2H), 6.81 (m, 1H), 6.35-6.36 (m, 1H), 4.34 (t, j=8.4,2H), 4.16 (s, 2H), 3.81 (s, 3H), 3.37 (t, j=8.4,2H), 2.80(s,1H).

LCMS:m/z479.3(M+H)；RT=1.43min (2.0min)

Embodiment 21

2- (2- chlorphenyls) -1- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) -2,3- dihydros - 1H- pyrrolo-es [2,3-b] pyridine -1- bases) ethyl ketone synthesis

¹H-NMR(CDCl3 400MHz):8.90(s,1H),8.44-8.45(m,1H),8.29(s,1H),7.26-7.49 (m,7H),6.39(s,1H),4.65-4.66(m,2H),4.18-4.19(m,2H),3.77(s,3H),3.21-3.23(m,2H).

LCMS:m/z446.2(M+H)；RT=1.30min (2min)

Embodiment 22

2- (2,6- dichlorophenyls) -1- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) -2,3- two Hydrogen -1H- pyrrolo-es simultaneously [2,3-b] pyridine -1- bases) ethyl ketone synthesis

¹H-NMR(CDCl3 400MHz):8.81(s,1H),8.45(s,1H),8.13(s,1H),7.51(s,1H), 7.33-7.35 (m, 2H), 7.17-7.19 (m, 2H), 6.96 (s, 1H), 6.35 (s, 1H), 4.88 (s, 2H), 4.23 (t, j= 8.4,2H), 3.82 (s, 3H), 3.18 (t, j=8.4,2H)

LCMS:m/z480.2(M+H)；RT=1.41min (2min)

Embodiment 23

N- methyl Ns-(5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) pyridine -2- bases) -2- phenyl The synthesis of acetamide

Embodiment 24

3- methyl-N- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) pyridine -2- bases) butyramide Synthesis

Embodiment 25

2- (3- chlorphenyls)-N- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) pyridine -2- bases) The synthesis of acetamide

Embodiment 26

The conjunction of 1- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) pyridine -2- bases) -3- phenylureas Into

Embodiment 27

N- (2- cyano group -4- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) phenyl) -2- phenylacetyls The synthesis of amine

Embodiment 28

2- (2- fluorophenyls) -1- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) -2,3- dihydros - 1H- pyrrolo-es [2,3-b] pyridine -1- bases) second -1- ketone synthesis

Embodiment 29

2- (3- fluorophenyls) -1- (5- (2- ((1- methyl isophthalic acid H- pyrazoles -5- bases) amino) pyrimidine-4-yl) -2,3- dihydros - 1H- pyrrolo-es [2,3-b] pyridine -1- bases) second -1- ketone synthesis

The synthesis of comparative example C1 4- (6- aminopyridine -3- bases)-N- (1- methyl isophthalic acid H- pyrazoles -5- bases) pyrimidine -2- amine

Sequentially add A15 (180mg, 0.58mmol) in 25mL round-bottomed flasks, NaOH (116mg, 2.91mmol), Methyl alcohol (5mL) and water (2mL).80 DEG C of stirring reaction 6h, TLC detection complete reaction solutions of reaction are cooled to room temperature, and be concentrated under reduced pressure Crude product silica gel column chromatography purifies (dichloromethane:Methyl alcohol=5:1) yellow solid compound C1 (124mg, yield are obtained： 80%).

¹HNMR(400MHz,CDCl₃- d) δ 8.75 (d, 1H, J=1.6Hz), 8.38 (d, 1H, J=5.2Hz), 8.10 (dd, 1H, J=2.4Hz, 8.8Hz), 7.49 (d, 1H, J=2.0Hz), 7.10 (d, 1H, J=5.6Hz), 6.83 (s, 1H), 6.56 (d, 1H, J=8.8Hz), 6.34 (d, 1H, J=1.6Hz), 4.81 (s, 2H), 3.80 (s, 3H).

LCMS:m/z 268.2(M+H)⁺；RT=0.648min.

Comparative example C2

The preparation of 4- (6- aminopyridine -3- bases) pyrimidine -2- amine：

Sequentially add compound C2-1 (200mg, 1.45mmol) in dry 50mL there-necked flasks, C2-2 (188mg, 1.45mmol), [1,1'- double (diphenylphosphino) ferrocene] palladium chloride (110mg, 0.15mmol), potassium carbonate (300mg, 2.17mmol), Isosorbide-5-Nitrae-dioxane (8mL) and water (2mL).100 degrees Celsius are heated under nitrogen protection, 3 hours are reacted.Instead After should finishing, pour into 30mL water, extracted with ethyl acetate (30mL × 2), merge organic phase.Organic phase uses saturated common salt successively Water (50mL × 1) is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, and (dichloromethane is purified with Flash：Methyl alcohol= 30：1~10:1) product C2 (120mg, faint yellow solid), yield, are obtained：30%.

¹HNMR(400MHz,MeOD-d₄) δ 8.76 (d, 1H, J=1.6Hz), 8.59 (dd, 1H, J=2.0Hz, 9.2Hz), 8.31 (d, 1H, J=6.4Hz), 7.36 (d, 1H, J=6.4Hz), 7.09 (d, 1H, J=9.2Hz).

LCMS:m/z188.1(M+H)；RT=0.29min (2min)

Measure of the compounds of this invention of test case 1 to ERK kinase activities

Material and instrument

ERK2enzyme(PV3595,Invitrogen)

Kinase Assay Kit-Ser/Thr 3Peptide(PV3176)

Synergy 2Microplate Reader(BioTec)

ProxiPlate-384Plus F,Black 384-shallow well Microplate(Cat.6008269, PerkinElmer)

Test method：

Z′-LYTE^TMSer/Thr 3Peptide Substrate, Phospho-peptide, 5X Kinase Buffer, ATP, Development Reagent A, Development Buffer, the Stop all reagents of Reagent balance accurate to room temperature Standby sample-adding.

Detection compound 3 times of gradient dilutions since 1 μM (0.2 μM) on the screening concentration of ERK kinases work influence, 8 dense Degree, each concentration takes multiple holes, using 4% DMSO as cosolvent.After the completion of reaction, passed through to 5 μ l are added in all reacting holes The Development Reagent A of Development Buffe dilutions, after room temperature reaction 1h, to adding 5 in all reacting holes μ l Stop Reagent terminating reactions, (excitation light wave is a length of to detect fluorescence signal with Synergy 2Microplate Reader 400nm, wavelength of transmitted light is 460nm, 528nm).

The inhibiting rate in each hole is calculated by full activity hole and background signal hole.Experiment is parallel to be repeated twice.IC50 values Can be by the way that under a series of various concentrations, test-compound be calculated for the suppression numerical value of kinases.

Inhibiting rate of the compounds of this invention of table 1 to different kinase activities

The all documents referred in the present invention are all incorporated as reference in this application, independent just as each document It is incorporated as with reference to such.In addition, it is to be understood that after above-mentioned instruction content of the invention has been read, those skilled in the art can Made various changes or modifications with to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited Enclose.

Claims

1. a kind of compound of formula I, its stereoisomer, racemic modification or its pharmaceutically acceptable salt：

Wherein, R₅It is selected from the group：H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxyl ,-OH, cyanogen Base, halogen, amino, substituted or unsubstituted C1-C8 alkylaminos, substituted or unsubstituted C1-C8 alkyl-carbonyls, substitution do not take The C1-C8 alkoxyl carbonyl in generation, substituted or unsubstituted C1-C8 carboxyls, substituted or unsubstituted C1-C8 ester groups, substitution or not Substituted 3-8 membered cyclic alkyls, substituted or unsubstituted 3-8 circle heterocycles base, substituted or unsubstituted aryl and substitution or unsubstituted Heteroaryl；

R₁It is selected from the group：H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyls, substitution or unsubstituted C2-C8 alkynyls, halo C1-C8 alkyl, halo C2-C8 alkenyls, halo C2-C8 alkynyls, substituted or unsubstituted 3-8 unit cyclic hydrocarbon Base and substituted or unsubstituted aryl；

R₂It is selected from the group：Substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl Base, substituted or unsubstituted 3-8 membered cyclic alkyls and substituted or unsubstituted 3-8 circle heterocycles base；

R₃It is selected from the group：H, substituted or unsubstituted C1-C8 alkyl ,-OH, cyano group, halogen, C1-C8 alkylenehydroxyls, substitution or Unsubstituted 3-8 membered cyclic alkyls, substituted or unsubstituted 3-8 circle heterocycles base, substituted or unsubstituted aryl and substitution do not take The heteroaryl in generation；

Or, R₃And X₄And adjacent C and N atoms are collectively forming substituted or unsubstituted 4-8 yuan of rings, wherein described ring contains There are at least one N hetero atoms and altogether containing the 1-3 hetero atom selected from O, S and N, and the ring is saturation or unsaturation Ring；

R₄Selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxyl ,-CO (CR₆R₇)_mR₈、-SO₂ (CR₆R₇)_mR₈、-CONR₉(CR₆R₇)_mR₈、-COO(CR₆R₇)_mR₈, amino, C1-C8 carboxyls；

M is 0,1,2 or 3；

Each R₆And R₇It is each independently selected from the following group：H, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylenehydroxyls, substitution Or unsubstituted C1-C8 alkoxyl and halogen, or R₆With R₇It is connected to form substitution or unsubstituted 3 to 6 yuan of rings；

Each R₈It is selected from the group：It is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted miscellaneous Aryl, substituted or unsubstituted 3-8 membered cyclic alkyls and substituted or unsubstituted 3-8 circle heterocycles base；

Each R₉It is selected from the group：H ,-OH, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylenehydroxyls and substitution or unsubstituted C1-C8 alkoxyl.

2. compound as claimed in claim 1, its stereoisomer, racemic modification or its pharmaceutically acceptable salt, it is special Levy and be, described substitution refers to the substitution base being selected from the group with one or more (such as 1-3)：Halogen, C1-C3 alkyl, C1- C3 haloalkyls, C1-C3 alkyl hydroxies ,-OH, C1-C3 alkoxies, C1-C3 alkylamino radicals, 3-8 membered cyclic alkyls, 3-8 circle heterocycles base, Amino, nitro.

3. compound as claimed in claim 1, its stereoisomer, racemic modification or its pharmaceutically acceptable salt, it is special Levy and be, the compound of formula I is as shown in following formula I a：

R₃It is selected from the group：H, substituted or unsubstituted C1-C8 alkyl ,-OH, cyano group, halogen, C1-C8 alkylenehydroxyls, substitution or Unsubstituted 3-8 membered cyclic alkyls, substituted or unsubstituted 3-8 circle heterocycles base, substituted or unsubstituted 3-8 unit's aryl and substitution Or unsubstituted 3-8 unit's heteroaryls；

R₂、R₄、R₅Definition it is identical with claim 1.

4. compound as claimed in claim 1, its stereoisomer, racemic modification or its pharmaceutically acceptable salt, it is special Levy and be, the compound of formula I is as shown in following formula I b：

Wherein,

P is 0,1,2,3 or 4；

Q is 1,2,3,4 or 5；

And p+q≤5；

Y and Z are each independently selected from-CR^cR^d、O、S、-NR^c；Wherein R^c、R^dIt is each independently selected from：It is H, substituted or unsubstituted C1-C8 alkyl ,-OH, amino, halogen, cyano group, substituted or unsubstituted C1-C8 alkylenehydroxyls, substituted or unsubstituted C1- C8 alkoxies, substituted or unsubstituted amido C1-C8 alkyl-, substituted or unsubstituted C1-C8 alkylamino radicals, or-CR^cR^dFor-C (=O)-；

R₂、R₄、R₅Definition it is identical with claim 1.

5. compound as claimed in claim 1, its stereoisomer, racemic modification or its pharmaceutically acceptable salt, it is special Levy and be, in the Formulas I a or Ib compounds, R₂It is selected from the group：

Wherein, each Ra independently selected from：C1-C4 alkyl；

Rb is selected from halogen ,-OH, cyano group, amino, substituted or unsubstituted C1-C3 alkyl, C1-C3 haloalkyls, substitution or does not take The C3-C8 cycloalkyl in generation, substituted or unsubstituted C3-C8 Heterocyclylalkyls；

N is 0,1,2 or 3；

P is 0,1,2,3 or 4；

Q is 1,2,3,4 or 5；

And p+q≤5；

Y and Z are each independently selected from-CR^cR^d、O、S、-NR^c；Wherein R^c、R^dIt is each independently selected from：It is H, substituted or unsubstituted C1-C8 alkyl ,-OH, amino, halogen, cyano group, C1-C8 alkylenehydroxyls, substituted or unsubstituted C1-C8 alkoxyl, amido C1-C8 alkyl, substituted or unsubstituted C1-C8 alkylamino radicals, or-CR^cR^dIt is-C (=O)；

R₄Selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxyl ,-CO (CR₆R₇)_mR₈、-SO₂ (CR₆R₇)_mR₈、-CONR₉(CR₆R₇)_mR₈、-COO(CR₆R₇)_mR₈, amino, carboxyl；Wherein, m is 0,1,2 or 3；

Each R₆、R₇It is each independently selected from the following group：H, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylenehydroxyls, substitution or Unsubstituted C1-C8 alkoxyl and halogen, or R₆With R₇It is connected to form substitution or unsubstituted 3 to 5 yuan of rings；

6. a kind of pharmaceutical composition, its include therapeutically effective amount selected from compound as claimed in claim 1, its alloisomerism One or more in body, racemic modification or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.

7. compound as claimed in claim 1, its stereoisomer or its pharmaceutically acceptable salt, or claim 6 institute The pharmaceutical composition stated targets the medicine of inhibitor preparing for the prevention and treatment disease related to ERK kinases and ERK kinases Purposes in thing.

8. a kind of method for preparing compound as claimed in claim 1, it is characterised in that including step：

A) in atent solvent, under metal catalytic or acid/base catalysis, (1e) is reacted with (1f) compound, and Formulas I is obtained Compound；

Wherein, X₁、X₂、X₃、X₄、X₅、X₆、R₁、R₂、R₃The definition of each group is as claimed in claim 1；

9. a kind of method for preparing compound as claimed in claim 1, it is characterised in that including step：

B) in atent solvent, under metal catalytic, (1c) carries out coupling reaction with (1g) compound, and compound of formula I is obtained；

10. a kind of method that non-therapeutic ground suppresses ERK kinase activities, it is characterised in that including step：By claim 1 institute The compound stated or its pharmaceutically acceptable salt are contacted with ERK kinases, so as to suppress ERK kinases.