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

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 with ERK kinase inhibitory activity, its preparation method and use

technical field

The present invention belongs to the field of medicinal chemistry, specifically, the compound or pharmaceutically acceptable salt thereof, and the pharmaceutical composition containing the compound or salt, which are used as regulator of ERK pathway or as ERK kinase, especially Is an inhibitor of ERK1 and ERK2 kinases.

Background technique

Extracellular signal-regulated kinases (ERKs) are a class of serine/threonine protein kinases discovered in the 1990s and are one of the important subfamilies of the MAPKs family of mitogen-activated protein kinases. Activated ERK can transmit extracellular signals to the nucleus, promote the phosphorylation of cytoplasmic target proteins or regulate the activity of other protein kinases, thereby regulating gene expression. Its signaling is central to signaling networks involved in the regulation of cell growth, development and differentiation. Therefore, ERK participates in various biological effects such as cell proliferation, differentiation, migration, invasion and apoptosis.

The Ras/Raf/MEK/ERK pathway is the main signaling pathway related to ERK function. Since this pathway regulates cell proliferation, differentiation and apoptosis, the node proteins on this pathway have become a hot spot in the development of cancer-targeted drugs in recent years. Specific B-Raf inhibitors Vemurafenib and dabrafenib were launched in 2011 and 2013 respectively for the treatment of melanoma, among which dabrafenib is used for the treatment of B-RafV600E mutant non-small cell lung cancer and has obtained FDA breakthrough drug qualification. The MEK1/2 inhibitor trametinib was also launched in 2013 for the treatment of melanoma. However, inhibiting these upstream pathway nodes has its limitations. Tumors can quickly develop drug resistance to B-Raf and MEK inhibitors. The mechanisms of drug resistance include point mutations, changes in protein polymorphisms, and changes in the length of protein peptide chains. , which is a great obstacle to the next generation of anti-drug-resistant Raf and MEK drugs. ERK is a key node downstream of this pathway, and no drug-resistant mutations have been found so far. ERK-targeted drugs may greatly improve the treatment of patients who are resistant to upstream target inhibitors, and are potential anticancer drugs R & D field.

In summary, there is an urgent need to develop new ERK inhibitor drugs in this field.

Contents of the invention

The object of the present invention is to provide a compound with novel structure, which can effectively inhibit ERK kinase, as well as its preparation method and application.

The first aspect of the present invention provides a compound of formula I, its stereoisomer, racemate, or a pharmaceutically acceptable salt thereof:

In the formula, X ₁ , X ₂ , X ₃ , X ₄ , X ₅ and X ₆ are each independently selected from CR ₅ or N;

Wherein, R is selected from the group consisting of H, substituted or unsubstituted C1 _- C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, -OH, cyano, halogen, amino, substituted or unsubstituted C1 -C8 alkylamino, substituted or unsubstituted C1-C8 alkylcarbonyl, substituted or unsubstituted C1-C8 alkoxycarbonyl, substituted or unsubstituted C1-C8 carboxyl, substituted or unsubstituted C1-C8 ester , substituted or unsubstituted 3-8 membered ring hydrocarbon group, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group;

R is selected from the group consisting of H, substituted or unsubstituted _C1 -C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, halogenated C1-C8 alkyl, Halogenated C2-C8 alkenyl, halogenated C2-C8 alkynyl, substituted or unsubstituted 3-8 membered ring hydrocarbon group, and substituted or unsubstituted aryl;

R ₂ is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3-8 membered ring hydrocarbon groups, and substituted or Unsubstituted 3-8 membered heterocyclic group;

_R is selected from the group consisting of H, substituted or unsubstituted C1-C8 alkyl, -OH, cyano, halogen, C1-C8 alkylene hydroxyl, substituted or unsubstituted 3-8 membered ring hydrocarbon group, substituted or Unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group;

Alternatively, _R3 and _X4 together with adjacent C and N atoms form a substituted or unsubstituted 4-8 membered ring, wherein said ring contains at least 1 N heteroatom and contains a total of 1-3 selected from O , heteroatoms of S and N, and the ring is a saturated or unsaturated ring;

R ₄ is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, -CO(CR ₆ R ₇ ) _m R ₈ , -SO ₂ (CR ₆ R ₇ ) _m R _8. -CONR ₉ (CR ₆ R ₇ ) _m R ₈ , -COO(CR ₆ R ₇ ) _m R ₈ , amino, C1-C8 carboxyl;

m is 0, 1, 2 or 3;

Each R ₆ and R ₇ are each independently selected from the group consisting of H, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylene hydroxyl, substituted or unsubstituted C1-C8 alkoxy, and halogen, Or R ₆ is connected with R ₇ to form a substituted or unsubstituted 3-6 membered ring;

Each R is selected from the group consisting of H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted _3-8 membered ring hydrocarbon group, And a substituted or unsubstituted 3-8 membered heterocyclic group;

Each R ₉ is selected from the group consisting of H, -OH, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylene hydroxy, and substituted or unsubstituted C1-C8 alkoxy.

In another preferred example, the substitution refers to having one or more (such as 1-3) substituents selected from the following group: halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkane Hydroxyl group, -OH, C1-C3 alkoxy group, C1-C3 alkylamino group, 3-8 membered cyclic hydrocarbon group, 3-8 membered heterocyclic group, amino group, nitro group.

In another preferred example, the R ₃ and X ₄ and the connected "=CN-" or "-CN-" jointly form a substituted or unsubstituted 4-8 membered ring.

In another preferred example, the 4-8 membered ring jointly formed by R ₃ and X ₄ and the connected "=CN-" or "-CN-" includes a condensed ring, a spiro ring, or a bridged ring.

In another preferred example, the aryl group includes a C5-C20 aryl group and a C3-C20 heteroaryl group, wherein the heteroaryl group contains 1-3 heteroatoms selected from the group consisting of O, S and N .

In another preferred example, the aryl group is selected from the group consisting of phenyl, pyridyl, pyrazolyl, thiazolyl, imidazolyl, isoxazolyl, and oxazolyl.

In another preferred example, said X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , and X ₆ are each independently selected from CR ₅ or N; and, at least one of X ₁ , X ₂ , and X ₅ is N.

In another preferred example, at least one or two of X ₁ , X ₂ , X ₅ , and X ₆ are N, and the rest are C; and X ₃ , X ₄ are C.

In another preferred embodiment, R ₂ is a substituted or unsubstituted 5-6 membered saturated or unsaturated heterocyclic ring, wherein the substitution refers to having one or more (such as 1-3) selected from the following group Substituents: halogen, C1-C3 alkyl, -OH, amino, cyano, C1-C8 alkoxy, C1-C8 alkylamino.

In another preferred example, R ₂ is a substituted or unsubstituted 5-membered heterocycle.

In another preferred embodiment, R ₂ is a 5-membered heterocyclic ring containing 1-2 N, or a 6-membered heterocyclic ring containing 1 O.

_In another preferred embodiment, R2 is a 5-6 membered heterocyclic ring containing 1-3 substituents selected from the following group: halogen, C1-C3 alkyl, -OH, amino, cyano, C1-C8 alkoxy Base, C1-C8 alkylamino.

In another preferred embodiment, R ₄ is -CO(CR ₆ R ₇ ) _m R ₈ , and R ₈ is a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein said Substitution refers to having one or more (such as 1-3) substituents selected from the following group: halogen, C1-C3 alkyl, -OH, amino, cyano, C1-C8 alkoxy, C1-C8 alkylamino .

In another preferred example, the substitution is 1-3 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 alkoxy.

In another preferred example, R ₈ is substituted or substituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl.

In another preferred example, for the substituted or unsubstituted 4-8-membered ring formed by _R3 and _X4 and the connected "=CN-" or "-CN-", preferably a 5-8-membered ring, More preferred are 5, 6, 7 or 8 membered rings containing 1 or 2 Ns, or 5, 6, 7 and 8 membered rings containing N and O.

In another preferred example, R ₄ is -CO(CR ₆ R ₇ ) _m R ₈ , wherein R ₆ and R ₇ are each independently selected from H or alkyl, substituted or unsubstituted C1-C8 alkylene hydroxyl , and m is 1 or ₂ , R is selected from H, substituted or unsubstituted pyridyl, substituted or unsubstituted phenyl.

In another preferred example, the compound of formula I is shown in the following formula Ia:

Wherein, X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ are each independently selected from CR ₅ or N;

_R is selected from the group consisting of H, substituted or unsubstituted C1-C8 alkyl, -OH, cyano, halogen, C1-C8 alkylene hydroxyl, substituted or unsubstituted 3-8 membered ring hydrocarbon group, substituted or Unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted 3-8 membered aryl group, and substituted or unsubstituted 3-8 membered heteroaryl group;

The definitions of R ₂ , R ₄ , and R ₅ are the same as those defined above.

In another preferred example, the compound of formula Ia is represented by the following formula:

Wherein, R ₃ is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, -OH, cyano, halogen, C1-C8 alkylene hydroxyl, substituted or unsubstituted 3-8 membered ring hydrocarbon group, A substituted or unsubstituted 3-8 membered heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

The definitions of R ₂ , R ₄ , and R ₅ are the same as those defined above.

_In another preference, R is selected from the following group:

Wherein, each Ra is independently selected from substituted or unsubstituted C1-C4 alkyl; Rb is selected from the group consisting of halogen, -OH, cyano, amino, substituted or unsubstituted C1-C3 alkyl, C1-C3 haloalkane Group, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl; n is 0, 1, 2 or 3;

R ₃ is selected from H, substituted or unsubstituted C1-C8 alkyl, -OH, cyano, halogen, C1-C8 alkylene hydroxyl, substituted or unsubstituted 3-8 membered ring hydrocarbon group, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

Alternatively, R ₃ and X ₄ and the attached "=CN-" or "-CN-" together form a substituted or unsubstituted 4-8 membered ring, wherein said ring contains at least 1 N heteroatom and contains in total 1-3 heteroatoms selected from the group consisting of O, S and N, and the ring is a saturated or unsaturated ring;

R ₄ is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, -CO(CR ₆ R ₇ ) _m R ₈ , -SO ₂ (CR ₆ R ₇ ) _m R _8. -CONR ₉ (CR ₆ R ₇ ) _m R ₈ , -COO(CR ₆ R ₇ ) _m R ₈ , amino, C1-C8 carboxyl; wherein, m is 0, 1, 2 or 3;

Each R ₆ and R ₇ is independently selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylene hydroxyl, substituted or unsubstituted C1-C8 alkoxy, and halogen, Or R ₆ is connected with R ₇ to form a substituted or unsubstituted 3-6 membered ring;

Each R is selected from the group consisting of H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted _3-8 membered ring hydrocarbon group, And a substituted or unsubstituted 3-8 membered heterocyclic group;

Each R _is selected from the group consisting of H, -OH, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylene hydroxyl, and substituted or unsubstituted C1-C8 alkoxy;

X ₁ , X ₂ , X ₃ , X ₄ , X ₅ and X ₆ are each independently selected from CR ₅ or N;

R is selected from H, substituted or unsubstituted C1 _- C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, -OH, cyano, halogen, amino, substituted or unsubstituted C1-C8 alkylamino, Substituted or unsubstituted C1-C8 alkylcarbonyl, substituted or unsubstituted C1-C8 alkoxycarbonyl, substituted or unsubstituted C1-C8 carboxyl, substituted or unsubstituted C1-C8 ester, substituted or unsubstituted 3-8 membered ring hydrocarbon group, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group.

In another preferred example, R ₅ is selected from H or cyano.

In another preferred example, the compound of formula I is shown in the following formula Ib:

in,

X ₁ , X ₂ , X ₃ , X ₅ , X ₆ are each independently selected from CR ₅ or 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 ^c R ^d , O, S, -NR ^c ; wherein R ^c , R ^d are each independently selected from: H, substituted or unsubstituted C1-C8 alkyl, -OH, Amino, halogen, cyano, substituted or unsubstituted C1-C8 alkylene hydroxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted amino C1-C8 alkyl-, substituted or unsubstituted C1-C8 alkylamino, or -CR ^c R ^d is -C(=O)-;

The definitions of R ₂ , R ₄ , and R ₅ are the same as those defined above.

In another preference, the compound of formula I is:

in,

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 ^c R ^d , O, S, -NR ^c ; wherein R ^c , R ^d are each independently selected from: H, substituted or unsubstituted C1-C8 alkyl, -OH, Amino, halogen, cyano, substituted or unsubstituted C1-C8 alkylene hydroxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted amino C1-C8 alkyl, substituted or unsubstituted C1-C8 alkylamino, or -CR ^c R ^d is -C(=O);

The definitions of R ₂ , R ₄ , and R ₅ are the same as those defined above.

In another preference, in the compound of _formula Ia or Ib, R is selected from the following group:

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

Rb is selected from halogen, -OH, cyano, amino, substituted or unsubstituted C1-C3 alkyl, C1-C3 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 Heterocycloalkyl;

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 ^c R ^d , O, S, -NR ^c ; wherein R ^c , R ^d are each independently selected from: H, substituted or unsubstituted C1-C8 alkyl, -OH, Amino, halogen, cyano, C1-C8 alkylene hydroxy, substituted or unsubstituted C1-C8 alkoxy, amino C1-C8 alkyl, substituted or unsubstituted C1-C8 alkylamino, or -CR ^c R ^d is -C (=O);

R ₄ is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, -CO(CR ₆ R ₇ ) _m R ₈ , -SO ₂ (CR ₆ R ₇ ) _m R _8. -CONR ₉ (CR ₆ R ₇ ) _m R ₈ , -COO(CR ₆ R ₇ ) _m R ₈ , amino, carboxyl; wherein, m is 0, 1, 2 or 3;

Each R ₆ and R ₇ is independently selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylene hydroxyl, substituted or unsubstituted C1-C8 alkoxy, and halogen, Or R ₆ is connected with R ₇ to form a substituted or unsubstituted 3-5 membered ring;

Each R is selected from the group consisting of H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted _3-8 membered ring hydrocarbon group, And a substituted or unsubstituted 3-8 membered heterocyclic group;

Each R ₉ is selected from the group consisting of H, -OH, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylene hydroxy, and substituted or unsubstituted C1-C8 alkoxy.

In another preferred example, in the compound I, R ₁ =H, R ₂ = five-membered heterocyclic ring substituted by methyl, R ₄ =-CO(CR ₆ R ₇ ) _m R ₈ , wherein R ₆ = R ₇ =H, alkyl, alkylhydroxy, and m=1 or 2, R ₈ =substituted or unsubstituted phenyl, pyridyl, or H.

In another preferred embodiment, the compound I is selected from the following group:

The second aspect of the present invention provides a pharmaceutical composition, which comprises a therapeutically effective amount of the compound selected from the first invention of the present invention, its stereoisomer, racemate, or pharmaceutically acceptable salt thereof One or more of them and pharmaceutically acceptable excipients.

The third aspect of the present invention provides a compound as described in the first aspect of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the second aspect of the present invention for use in the preparation of The prevention and treatment of diseases related to ERK kinase and the application of ERK kinase target inhibitor in medicine.

The fourth aspect of the present invention provides a method for preparing the compound as described in the first aspect of the present invention, comprising the steps of:

a) in an inert solvent, under metal catalysis or acid/base catalysis, (1e) reacts with (1f) compound to prepare the compound of formula I;

Wherein, the definitions of each group of X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , R ₁ , R ₂ , and R ₃ are as described in the first aspect of the present invention;

LG ₂ is a leaving group selected from the group consisting of halogen, sulfonate, methylthio, methylsulfone.

In another preferred example, the method further includes: steps (a-1) and (a-2), thereby preparing the compound of formula (1e):

(a-1) In an inert solvent, (1a) and (1b) undergo condensation reaction or reductive amination reaction to obtain compound (1c);

(a-2) In an inert solvent, under a metal catalyst, (1c) and (1d) compound are subjected to a coupling reaction to obtain compound (1e);

In the formula, LG ₁ is a leaving group selected from the group consisting of halogen, sulfonate, boric acid, borate ester, borate, organotin, organozinc;

LG ₂ is a leaving group selected from the group consisting of halogen, sulfonate, methylthio, methylsulfone;

LG ₃ is a leaving group selected from the group consisting of halogen, sulfonate, boronic acid, borate ester, borate;

FG is selected from the group consisting of carboxylic acids, aldehydes, halogens;

The definitions of X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , R ₁ , R ₂ , and R ₃ are as described in the first aspect of the present invention.

In another preferred example, in the (a-1), the reaction is carried out in an inert solvent selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methyl Pyrrolidone, dimethylsulfoxide, tetrahydrofuran, toluene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, di Oxycycline, or a combination thereof.

In another preferred example, in the (a-1), the condensation reaction is carried out in the presence of a condensing agent selected from the group consisting of: 2-(7-azobenzotriazole)- N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride , O-benzotriazole-tetramethyluronium hexafluorophosphate, or a combination thereof.

In another preferred example, in (a-1), the reductive amination reaction is carried out in the presence of a catalyst and a reducing agent, and the catalyst is selected from the group consisting of titanium tetraisopropoxide, trifluoroacetic acid, Acetic acid, formic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, or combinations thereof; the reducing agent is selected from the group consisting of sodium borohydride, sodium cyanide borohydride, sodium acetate borohydride, sodium trifluoroacetoxy borohydride, Polymer-supported sodium borohydride reducing agent, sodium trimethoxyborohydride, sodium triethylborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum tetrahydride, or combinations thereof .

In another preferred example, in the (a-2), the metal catalyst is selected from the group consisting of: tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ ), tetrakis(triphenylphosphine ) palladium (Pd(PPh ₃ ) ₄ ), palladium acetate, palladium chloride, dichlorobis(triphenylphosphine) palladium, trifluoroacetate palladium, triphenylphosphine palladium acetate, [1,1'-bis(di Phenylphosphino)ferrocene]palladium dichloride, bis(tri-orthophenylmethylphosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethanepalladium dichloride, or combinations thereof .

In another preferred example, in (a), the reaction is carried out in the presence of a catalyst ligand selected from the group consisting of tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, Tri-n-butylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, tri-o-phenylmethylphosphine, or combinations thereof.

In another preferred example, in (a), the reaction is carried out in the presence of a base, and the base includes inorganic bases and organic bases.

In another preferred example, in the (a), the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, Cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or combinations thereof.

In another preferred example, in (a), the organic base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[ 5.4.0] Undec-7-ene (DBU), lithium hexamethyldisilazyl, sodium hexamethyldisilazyl, lutidine, or a combination thereof.

In another preferred example, in (a), the reaction is carried out in the presence of an acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid , acetic acid, or combinations thereof.

In another preferred example, the temperature of step a) is -78°C-250°C.

In another preferred example, the step a) is carried out at room temperature.

In another preferred example, the step a) is carried out in a dry ice bath or an ice bath.

In another preferred example, the step a) is carried out under heating conditions, and the heating is selected from the group consisting of electric heating, microwave heating, or a combination thereof.

In the fifth aspect of the present invention, there is provided a method for preparing the compound as described in the first aspect of the present invention, comprising the steps of:

b) in an inert solvent, under metal catalysis, (1c) and (1g) compound carry out a coupling reaction to prepare a compound of formula I;

Wherein, the definitions of each group of X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , R ₁ , R ₂ , and R ₃ are as described in the first aspect of the present invention;

LG ₁ is a leaving group selected from the group consisting of halogen, sulfonate, boronic acid, borate ester, borate, organotin, organozinc;

LG ₃ is a leaving group selected from the group consisting of halogen, sulfonate, boronic acid, borate ester, borate.

In another preferred example, the method further includes: steps (b-1) and/or (b-2):

(b-1) (1a) and (1b) are coupled in an inert solvent through condensation or reductive amination reactions to obtain (1c);

(b-2) (1d) is coupled with (1f) in an inert solvent in the presence of a base to obtain (1g);

In the formula, LG ₁ is a leaving group selected from the group consisting of halogen, sulfonate, boric acid, borate ester, borate, organotin, organozinc;

LG ₂ is a leaving group selected from the group consisting of halogen, sulfonate, methylthio, methylsulfone;

LG ₃ is a leaving group selected from the group consisting of halogen, sulfonate, boronic acid, borate ester, borate;

FG is selected from the group consisting of carboxylic acids, aldehydes, halogens;

The definitions of X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , R ₁ , R ₂ , and R ₃ are as described in the first aspect of the present invention.

In another preferred example, the (b-1) is carried out in an inert solvent selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, di Methyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane , or a combination thereof.

In another preferred example, in (b-1), the condensation reaction is carried out in the presence of a condensing agent selected from the group consisting of 2-(7-azobenzotriazole)-N, N,N',N'-tetramethyluronium hexafluorophosphate, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, O - Benzotriazole - Tetramethyluronium hexafluorophosphate, etc., or a combination thereof.

In another preferred example, in the (b-1), the reductive amination reaction is carried out in the presence of a catalyst and a reducing agent, and the catalyst is selected from the group consisting of titanium tetraisopropoxide, trifluoroacetic acid, acetic acid , formic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, or a combination thereof; the reducing agent is selected from the group consisting of sodium borohydride, sodium cyanide borohydride, sodium acetate borohydride, sodium trifluoroacetoxy borohydride, polymer A sodium borohydride reducing agent supported on a substance, sodium trimethoxyborohydride, sodium triethylborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum tetrahydride, or combinations thereof.

In another preferred example, in (b), (1c) and (1g) are coupled in the presence of a metal catalyst selected from the group consisting of: tris(dibenzylideneacetone)dipalladium ( Pd ₂ (dba) ₃ ), tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ), palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, triphenyl phosphine palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bis(tri-orthophenylmethylphosphine)palladium dichloride, 1,2-bis(diphenyl phosphino)ethane palladium dichloride, or a combination thereof.

In another preferred example, in (b), (1c) and (1g) are coupled in the presence of a metal catalyst ligand, and the catalyst ligand is selected from the group consisting of: tri-tert-butylphosphine, tetrafluoro Tri-tert-butylphosphine borate, tri-n-butylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, tri-o-phenylmethylphosphine, or combinations thereof.

In another preferred example, in (b-2), (1d) and (1f) are coupled in the presence of a base, and the base includes inorganic bases and organic bases.

In another preferred example, in (b-2), (1d) and (1f) are coupled in the presence of an inorganic base selected from the group consisting of sodium hydroxide, bistrimethylsilane Lithium trimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, butyllithium, lithium diisopropylamide, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide , sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or combinations thereof.

In another preferred example, (1d) and (1f) in (b-2) are coupled in the presence of an organic base selected from the group consisting of pyridine, triethylamine, N,N- Diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), lithium hexamethyldisilazyl, sodium hexamethyldisilazyl, dimethyl pyridine, or a combination thereof.

In another preferred example, in (b-2), (1d) and (1f) are coupled in the presence of an acid, and the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluene Sulfonic acid, trifluoroacetic acid, formic acid, acetic acid, or combinations thereof.

In another preferred example, the temperature of step b) is -78°C-250°C.

In another preferred example, the step b) is carried out at room temperature.

In another preferred example, the step b) is carried out in a dry ice bath or an ice bath.

In another preferred embodiment, the step b) is performed under heating conditions, and the heating is selected from the group consisting of electric heating, microwave heating, or a combination thereof.

In the sixth aspect of the present invention, there is provided a method for non-therapeutically inhibiting the activity of ERK kinase, comprising the step of: contacting the compound described in the first aspect of the present invention or a pharmaceutically acceptable salt thereof with ERK kinase, thereby inhibiting ERK kinase .

In another preferred embodiment, said contacting is contacting purified ERK kinase or cells expressing ERK kinase.

The seventh aspect of the present invention provides a method for preventing and/or treating diseases related to ERK kinase activity in mammals, comprising administering a therapeutically effective amount of the compound described in the first aspect of the present invention, its steric isomer, or a pharmaceutically acceptable salt thereof, or administer a therapeutically effective amount of the pharmaceutical composition as described in the second aspect of the present invention.

In another preferred example, the ERK kinases include ERK1, ERK2 or a combination thereof.

In another preferred example, the diseases associated with ERK kinase activity refer to diseases associated with high expression or high activity of ERK kinase.

In another preferred example, the disease associated with ERK kinase activity is selected from the group consisting of tumors.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.

detailed description

Through extensive and in-depth research, the present inventor unexpectedly discovered for the first time a compound represented by formula I or a pharmaceutically acceptable salt thereof, which can be used as an ERK kinase inhibitor with high inhibitory activity. The present invention has been accomplished on this basis.

Glossary

As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values between 99 and 101 and in between (eg, 99.1, 99.2, 99.3, 99.4, etc.).

Unless otherwise defined, the following terms used in the specification and claims have the meanings commonly understood by those skilled in the art. All patents, patent applications, and publications cited in their entirety herein are hereby incorporated by reference in their entirety unless otherwise indicated.

It is to be understood that both the foregoing brief description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It must be noted that, unless the context clearly dictates otherwise, as used in the specification and claims, the singular includes the plural of the referents. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the term "comprises" or "includes (comprising)" can be open, semi-closed and closed. In other words, the term also includes "consisting essentially of", or "consisting of".

Definitions of standard chemical terms can be found in references, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 THED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectroscopy, NMR, IR and UV/VIS spectroscopy and pharmacological methods are employed. Unless specific definitions are set forth, terms employed herein in the relevant descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are those that are known in the art. Standard techniques can be used in chemical syntheses, chemical analyses, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for the kit, or by methods known in the art or as described herein. The techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.

When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH ₂ O- is equivalent to -OCH ₂ -.

The section headings used herein are for the purpose of organizing the article only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby incorporated by reference in their entirety.

Certain chemical groups defined herein are preceded by abbreviated symbols to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the abbreviated notation does not include carbons that may be present in substituents of the stated group.

In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings shown below unless otherwise specified.

In this application, the term "halogen" means fluorine, chlorine, bromine or iodine.

"Hydroxy" means an -OH group.

"Hydroxyalkyl" means an alkyl group as defined below substituted with a hydroxyl group (-OH).

"Carbonyl" means a -C(=O)- group.

"Nitro" means _-NO2 .

"Cyano" means -CN.

"Amino" refers to _-NH2 .

"Substituted amino" means an amino group substituted by one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., monoalkylamino, dialkylamino, alkyl Amylamino, aralkylamino, heteroaralkylamino.

"Carboxy" means -COOH.

In this application, as a group or a part of other groups (such as used in groups such as halogen-substituted alkyl groups), the term "alkyl" refers to a fully saturated straight-chain or branched hydrocarbon chain group, Consisting solely of carbon and hydrogen atoms, having for example 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and attached to the rest of the molecule by a single bond, for example including but not limited to Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl , n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc. For the purposes of the present invention, the term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms.

In this application, the term "alkenyl", as a group or part of another group, means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10 2, more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group connected to the rest of the molecule by a single bond, such as but not limited to vinyl, propenyl, allyl, but- 1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.

In this application, the term "alkynyl", as a group or part of another group, means consisting only of carbon atoms and hydrogen atoms, containing at least one triple bond, optionally containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by a single bond, straight or branched hydrocarbon chain group, such as but not limited to ethynyl, propane -1-ynyl, but-1-ynyl, pent-1-en-4-ynyl and the like.

In this application, the term "cyclohydrocarbyl", as a group or part of another group, means a stable non-aromatic monocyclic or polycyclic hydrocarbon group composed only of carbon and hydrogen atoms, which may include fused rings system, bridged ring system or spiro ring system, has 3 to 15 carbon atoms, preferably has 3 to 10 carbon atoms, more preferably has 3 to 8 carbon atoms, and it is saturated or unsaturated and can be changed via any suitable The carbon atoms are connected to the rest of the molecule by single bonds. Unless specifically stated otherwise in this specification, carbon atoms in a cycloalkyl group may be optionally oxidized. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indene Base, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzo Cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, Fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl Base, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro -4,7-methylene-1H-indenyl and octahydro-2,5-methylene-pentalenyl, etc.

In this application, the term "heterocyclyl", as a group or part of another group, means a group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Stable 3- to 20-membered non-aromatic cyclic groups. Unless otherwise specified in this specification, the heterocyclic group may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; The nitrogen, carbon, or sulfur atoms of can be optionally oxidized; the nitrogen atoms can be optionally quaternized; and the heterocyclyl can be partially or fully saturated. A heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclyl groups comprising fused rings, one or more rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, heterocyclyl is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur group, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonyl Alkane-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2-yl, aza Cyclobutanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuryl, oxazinyl, dioxolyl, tetrahydroisoquinolyl, decahydroisoquinolyl, imidazolinyl, Imidazolidinyl, Quinazinyl, Thiazolidinyl, Isothiazolidinyl, Isoxazolidinyl, Indolinyl, Octahydroindolyl, Octahydroisoindolyl, Pyrrolidinyl, Pyrazolidinyl , Phthalimide, etc.

In the present application, the term "aryl", as a group or part of another group, means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present invention, aryl can be a monocyclic, bicyclic, tricyclic or multicyclic ring system and can also be fused to a cycloalkyl or heterocyclyl as defined above, provided that the aryl is via The atoms on the aromatic ring are connected to the rest of the molecule by single bonds. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-Benzoxazin-3(4H)-on-7-yl and the like.

In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.

In this application, the term "heteroaryl", as a group or part of another group, means having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 carbon atoms selected from the group consisting of nitrogen A 5- to 16-membered conjugated ring system group of heteroatoms of oxygen and sulfur. Unless specifically stated otherwise in this specification, heteroaryl may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, and may be fused to a cycloalkyl or heterocyclyl as defined above, provided that hetero An aryl group is connected to the rest of the molecule by a single bond through an atom on the aromatic ring. A nitrogen, carbon or sulfur atom in a heteroaryl can be optionally oxidized; the nitrogen atom can be optionally quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 to 4 heteroatoms selected from A stable 5- to 10-membered aromatic group of heteroatoms selected from nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolyl, isoindolyl, indazolyl, isoindazolyl , Purinyl, quinolinyl, isoquinolinyl, diazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridine Base, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizyl, o-phenanthrenyl, Isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4 ,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1, 2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine Wait.

In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted by a heteroaryl group as defined above.

In this application, "optionally" or "optionally" means that the subsequently described event or situation may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted aryl" means that the aryl is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl. The "optional" substituents described in the claims and description of the present invention are selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl.

As used herein, the terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" refer to a specific segment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities embedded or attached to molecules.

"Stereoisomer" refers to compounds composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures. The present invention will encompass each stereoisomer and mixtures thereof.

When olefinic double bonds are contained in the compounds of the present invention, unless otherwise stated, the compounds of the present invention are intended to include both E- and Z-geometric isomers.

"Tautomer" refers to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be within the scope of the invention.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereoisomers and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as their racemates and optically pure forms. The preparation of the compounds of the present invention can select racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

Conventional techniques for the preparation/isolation of individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography. ), see, for example, Gerald 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 OFPRACTICAL 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, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include but not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but not limited to formate, acetate, 2,2-dichloroacetate , Trifluoroacetate, Propionate, Caproate, Caprylate, Caprate, Undecylenate, Glycolate, Gluconate, Lactate, Sebacate, Hexanoate glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-amino salicylate, naphthalene disulfonate, etc. These salts can be prepared by methods known in the art.

"Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, those of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, Lysine, Arginine, Histidine, Caffeine, Procaine, Choline, Betaine, Ethylenediamine, Glucosamine, Methylglucamine, Theobromine, Purine, Piperazine, Piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

"Polymorph" refers to the different solid crystalline phases of certain compounds of the present invention due to the existence of two or more different molecular arrangements in the solid state. Certain compounds of the present invention may exist in more than one crystalline form, and the present invention is intended to include each crystalline form and mixtures thereof.

Often, crystallization will result in solvates of the compounds of the invention. The term "solvate" as used in the present invention refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Accordingly, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the present invention may form true solvates, but in some cases may also retain adventitious water only or a mixture of water plus part of the adventitious solvent. The compounds of the present invention can be reacted in solvents or precipitated or crystallized from solvents. Solvates of the compounds of the present invention are also included within the scope of the present invention.

The present invention also includes prodrugs of the above compounds. In the present application, the term "prodrug" means a compound that can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis. Accordingly, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the present invention. Prodrugs may be inactive when administered to an individual in need thereof, but are converted in vivo to the active compound of the invention. Prodrugs are generally transformed rapidly in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. Prodrug compounds typically provide solubility, tissue compatibility or sustained release advantages in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups. For specific prodrug preparation methods, please 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, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.

The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively nontoxic, i.e., the substance can be administered to an individual without causing adverse biological effects. React or interact in an undesirable manner with any component contained in the composition.

In this application, "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, glidants, enhancers, Sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizing agents, isotonic agents, solvents or emulsifying agents.

The "tumor" and "diseases related to abnormal cell proliferation" in the present invention include but are not limited to leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.

As used herein, the terms "prophylactic", "prevention" and "prevention" include reducing the likelihood of a disease or condition occurring or worsening in a patient.

As used herein, the term "treatment" and other similar synonyms include the following meanings:

(i) preventing the occurrence of a disease or condition in a mammal, especially when such mammal is susceptible to the disease or condition but has not been diagnosed as having the disease or condition;

(ii) inhibiting a disease or condition, i.e. arresting its development;

(iii) ameliorating a disease or condition, i.e., causing regression of the state of the disease or condition; or

(iv) Alleviating the symptoms caused by the disease or condition.

The term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" as used herein refers to at least one agent or compound which, when administered, is sufficient to relieve to some extent one or more symptoms of the disease or condition being treated amount. The result may be a reduction and/or alleviation of a sign, symptom or cause, or any other desired change in a biological system. For example, a therapeutically "effective amount" is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant disease-modifying effect. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation assays.

As used herein, the terms "administering", "administering", "administering" and the like refer to methods capable of delivering a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art, as described, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton , those discussed in Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

As used herein, the terms "pharmaceutical combination", "drug combination", "combination", "administration of other treatments", "administration of other therapeutic agents" and the like refer to drug treatments obtained by mixing or combining more than one active ingredient, It includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration to a patient of at least one compound described herein and at least one co-agent in the form of a single entity or single dosage form. The term "variable combination" refers to simultaneous, concomitant or sequential administration at variable intervals of at least one compound described herein and at least one synergistic agent as separate entities to a patient. These also apply to cocktail therapy, eg the administration of three or more active ingredients.

Those skilled in the art will also understand that in the methods described below, the functional groups of intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.

Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in OrganiSynthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymeric resin.

The preparation of formula I compound

The following reaction schemes exemplify the preparation of compounds of formula I, their stereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof:

in,

X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , R ₁ , R ₂ , R ₃ , R ₄ are all as described above in the embodiments section for compounds of formula I. It is to be understood that in the following reaction schemes, combinations of substituents and/or variables within the general formulae are permissible only if such combinations result in stable compounds. It should also be understood that other general formulas, such as general formula (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ib), (Ib-1), ( Ib-2), (Ib-3), (Ib-4), and other compounds of formula I specifically disclosed herein can be obtained by those skilled in the art of organic chemistry by the methods disclosed herein (by using appropriately substituted starting materials and using The methods known to those skilled in the art can be prepared by modifying the synthesis parameters as necessary) or known methods.

The skilled artisan will appreciate that in some cases the starting materials and intermediates in the preparation of the compounds of the invention may contain functional groups which require protection during the synthetic process. The exact nature of any protecting group used will depend on the identity of the functional group being protected, as will be apparent to those skilled in the art. Guidance on selecting suitable protecting groups and synthetic strategies for their attachment and removal can be found, for example, in Green & Wuts, Green's Protective Groups in Organic Synthesis, 3d Edition, Jon Wiley & Sons, Inc., New York (1999) and references cited therein.

Thus, a protecting group refers to an atomic group that, when attached to a reactive functional group in a molecule, masks, reduces or prevents the reactivity of that functional group. In general, protecting groups can be selectively removed as needed during the synthesis.

Reaction scheme 1:

In each formula, X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , R ₁ , R ₂ , R ₃ , R ₄ , LG ₁ and LG ₂ are all as in the embodiment of the compound of formula I above described in the section.

Reaction scheme 2:

X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , R ₁ , R ₂ , R ₃ , R ₄ , LG ₁ , LG ₂ and LG ₃ are all as in the embodiments section for compounds of formula I above described in .

The main advantages of the present invention are:

1. A compound as shown in formula I is provided.

2. Provide an ERK kinase inhibitor with a novel structure, its preparation method and application, and the said inhibitor has relatively high inhibitory activity on ERK kinase.

3. A pharmaceutical composition for treating diseases related to ERK kinase activity is provided.

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.

The experimental materials and reagents used in the following examples can be obtained from commercially available channels unless otherwise specified.

Example 1

Synthesis of 1-(5-bromoindolin-1-yl)-2-phenylethanone

Add compound 1 (1.10g, 5.55mmol), phenylacetyl chloride (858mg, 5.55mmol), triethylamine (1.68g, 16.66mmol) sequentially into a dry 50mL three-necked flask, and dissolve in dichloromethane (20mL). After the reaction was detected by LCMS, it was directly concentrated under reduced pressure and used a silica gel column (ethyl acetate:petroleum ether=1:10) to obtain product 2 (1.2g, white solid), yield: 68%.

LCMS: m/z 318.1 (M+H); RT = 1.40min (2min).

2-Phenyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl) Synthesis of ethyl ketone

Add compound 2 (1.4g, 4.42mmol), biboronic acid pinacol ester (2.25g, 8.84mmol), [1,1'-bis(diphenylphosphino)dicene) to a dry 50mL three-necked flask successively. Iron] Palladium dichloride (322 mg, 0.44 mmol), potassium acetate (866 mg, 8.84 mmol), 1,4-dioxane (20 mL). Heated to 100° C. for 3 hours under nitrogen protection. After the reaction was completed, it was poured into 30 mL of water, extracted with ethyl acetate (30 mL×2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the product 3 (1.3 g, yellow solid ), yield: 94%.

LCMS: m/z 364.4 (M+H); RT = 1.53min (2min).

Synthesis of 1-(5-(2-chloropyrimidin-4-yl)indolin-1-yl)-2-phenylethanone

Add compound 3 (700mg, 1.92mmol), 2,4-dichloropyrimidine (286mg, 1.92mmol), [1,1'-bis(diphenylphosphino)ferrocene] in sequence in a dry 50mL three-necked flask Palladium dichloride (139 mg, 0.19 mmol), potassium carbonate (400 mg, 2.89 mmol), 1,4-dioxane (8 mL) and water (2 mL). Heated to 100° C. under nitrogen protection, and reacted for 3 hours. After the reaction was completed, it was poured into 30 mL of water, extracted with ethyl acetate (30 mL×2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the product 5 (250mg, Yellow solid), yield: 37%.

LCMS: m/z 350.1 (M+H); RT = 1.48min (2min).

Synthesis of 1-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)indolin-1-yl)-2-phenylethanone

Add compound 4 (200mg, 0.57mmol), 1-methyl-5-aminopyrazole (55mg, 0.57mmol), tris(dibenzylideneacetone) dipalladium (55mg, 0.06mmol) into a dry 50mL three-necked flask successively ), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (35 mg, 0.06 mmol), cesium carbonate (279 mg, 0.86 mmol) 1,4-dioxane (10 mL). Heated to 100° C. under nitrogen protection, and reacted for 4 hours. After the reaction was completed, it was poured into 30 mL of water, extracted with ethyl acetate (30 mL×2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the product HE153 (16 mg, yellow solid) was obtained with a reverse preparative column, yield: 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).

Example 2

Synthesis of 1-(5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-phenylethanone

Add compound 5 (398mg, 2.0mmol), phenylacetic acid (272mg, 2.0mmol), HATU (1.1g, 3.0mmol) and DMF (10mL) sequentially into a dry 50mL single-necked bottle, and add N,N-diiso Propylethylamine (517mg, 4.0mmol) was reacted overnight at room temperature. After the reaction was completed, 15 ml of water was added, extracted with ethyl acetate (20 ml×2), and the organic phases were combined. The organic phase was washed with saturated brine (15 ml×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=6:1) to obtain yellow solid compound 6 ( 539 mg, yield: 85%).

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

Synthesis of 1-(2-phenylacetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-ylboronic acid

Add compound 7 (317mg, 1.0mmol), 1,4-dioxane (8mL), double pinaborate (381mg, 1.5mmol), potassium acetate (194mg, 2.0mmol) into a dry 50mL three-necked flask ) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol). Vacuumize and ventilate 3 times with nitrogen, under the protection of nitrogen, stir and react at 90°C for 6h, TLC detects that the reaction is complete. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (dichloromethane:methanol = 5:1) to obtain yellow solid compound 8 (169 mg, yield: 60%).

LCMS: m/z 282.9 (M+H) ⁺ .

Synthesis of 1-(5-(2-chloropyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-phenylethanone

Add compound 9 (169mg, 0.6mmol), 2,4-dichloropyrimidine (134mg, 0.9mmol), [1,1'-bis(diphenylphosphino)ferrocene] di Palladium chloride (44 mg, 0.06 mmol), cesium carbonate (391 mg, 1.2 mmol), 1,4-dioxane (8 mL) and water (0.5 mL). Vacuumize and ventilate with nitrogen for 3 times, under the protection of nitrogen, stir and react at 90°C for 6h, cool the reaction liquid to room temperature, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) Compound 10 (105 mg, yield: 50%) was obtained as a yellow solid.

LCMS: m/z 350.9 (M+H) ⁺ .

1-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b Synthesis of ]pyridin-1-yl)-2-phenylethan-1-one

Add compound 10 (70mg, 0.2mmol), 1-methyl-5-aminopyrazole (29mg, 0.3mmol), tris(dibenzylideneacetone) dipalladium (18mg, 0.02mmol) into a dry 50mL three-necked flask successively ), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (10 mg, 0.02 mmol), cesium carbonate (130 mg, 0.4 mmol) and 1,4-dioxane (6 mL). Heated to 105°C under the protection of nitrogen, and reacted overnight. After the reaction was completed, ethyl acetate (15 mL) was added to dilute, washed with saturated brine (10 mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 2) A yellow solid compound A2 (5 mg, yield: 6%) was obtained.

¹ HNMR (400MHz, CDCl ₃ -d) δ8.81(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).

Example 3

Synthesis of N-(5-bromopyridin-2-yl)-2-phenylacetamide

Add compound 11 (2.00g, 14.71mmol), 2-amino-5-bromopyridine (2.54g, 14.71mmol), HATU (5.59g, 14.71mmol) in DMF (20mL) into a dry 50mL single-necked bottle successively , after adding N,N-diisopropylethylamine (1.91 g, 14.71 mmol) dropwise, react at room temperature for 4 hours. After the LCMS detection is completed, add water to the reaction solution, then extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate and pass through a silica gel column (developing agent is ethyl acetate:petroleum ether) =1:10) to obtain compound 2 (2.8g, white solid), yield: 67%.

LCMS: m/z 291.1 (M+H); RT = 1.33min (2.0min).

Synthesis of (6-(2-phenylacetylamino)pyridin-3-yl)boronic acid

Add compound 12 (1.4g, 4.81mmol), biboronic acid pinacol ester (2.44g, 9.62mmol), [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (351 mg, 0.48 mmol), potassium acetate (942 mg, 9.62 mmol), 1,4-dioxane (20 mL). Heated to 100° C. for 3 hours under nitrogen protection. After the reaction was completed, it was poured into 30 mL of water, extracted with ethyl acetate (30 mL×2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the product 13 (1.0g, yellow solid), yield: 81%.

LCMS: m/z 257.1 (M+H); RT = 0.39min (2min).

Synthesis of N-(5-(2-chloropyrimidin-4-yl)pyridin-2-yl)-2-phenylacetamide

In a dry 50mL three-necked flask, add compound 13 (1.0g, 3.91mmol), 2,4-dichloropyrimidine (582mg, 3.91mmol), [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (293 mg, 0.40 mmol), potassium carbonate (810 mg, 5.87 mmol), 1,4-dioxane (20 mL) and water (5 mL). Heated to 100° C. under nitrogen protection, and reacted for 3 hours. After the reaction was completed, it was poured into 30 mL of water, extracted with ethyl acetate (30 mL×2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and used to prepare plates (ethyl acetate:petroleum ether=1:3) to obtain product 14 (500mg, Yellow solid), yield: 40%.

LCMS: m/z 325.2 (M+H); RT = 1.28min (2min).

Synthesis of N-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2-yl)-2-phenylacetamide

Add compound 14 (50mg, 0.15mmol), 1-methyl-5-aminopyrazole (15mg, 0.15mmol), tris(dibenzylideneacetone) dipalladium (18mg, 0.02mmol) into a dry 50mL three-necked flask successively ), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (12 mg, 0.02 mmol), cesium carbonate (49 mg, 0.15 mmol) 1,4-dioxane (10 mL). Heated to 100° C. under nitrogen protection, and reacted for 2 hours. After the reaction was completed, it was poured into 30 mL of water, extracted with ethyl acetate (30 mL×2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the product A3 (16 mg, yellow solid) was obtained with a reverse preparative column, yield: 28%.

LCMS: m/z 386.2 (M+H); RT = 1.26min (2min).

¹ H-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).

Example 4

Synthesis of 2-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

Add compound 15 (500mg, 2.28mmol), phenylacetic acid (310mg, 2.28mmol), HATU (1.30g, 3.42mmol) in DMF (10mL) in a dry 50mL single-necked bottle, and drop triethylamine (461mg , 4.56mmol), react at room temperature for 3 hours. After the LCMS detection is completed, add water to the reaction solution, then extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate and pass through a silica gel column (developing agent is ethyl acetate:petroleum ether) =1:20) to obtain compound 16 (520mg, white solid), yield: 68%.

LCMS: m/z 338.2 (M+H); RT = 1.09min (2.0min).

Synthesis of N-(5-(2-chloropyrimidin-4-yl)pyridin-2-yl)-2-phenylethyl

Add compound 16 (520mg, 1.54mmol), 2,4-dichloropyrimidine (275mg, 1.85mmol), [1,1'-bis(diphenylphosphino)ferrocene] to a dry 50mL three-necked flask Palladium dichloride (110 mg, 0.15 mmol), potassium carbonate (319 mg, 2.31 mmol), 1,4-dioxane (8 mL) and water (2 mL). Heated to 100° C. under nitrogen protection, and reacted for 3 hours. After the reaction was completed, it was poured into 30 mL of water, extracted with ethyl acetate (30 mL×2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and used to prepare a plate (ethyl acetate:petroleum ether=1:5) to obtain product 17 (480mg, Yellow solid), yield: 96%.

LCMS: m/z 324.3 (M+H); RT=1.10min (2min).

Synthesis of N-(4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)phenyl)-2-phenylacetamide

Add compound 17 (200mg, 0.62mmol), 1-methyl-5-aminopyrazole (60mg, 0.62mmol), tris(dibenzylideneacetone) dipalladium (155mg, 0.06mmol) into a dry 50mL three-necked flask successively ), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (35 mg, 0.06 mmol), cesium carbonate (302 mg, 0.93 mmol) 1,4-dioxane (10 mL). Heated to 100° C. under nitrogen protection, and reacted for 2 hours. After the reaction was completed, it was poured into 30 mL of water, extracted with ethyl acetate (30 mL×2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and a reverse preparative column was used to obtain product A4 (50mg, yellow solid), yield: 21%.

LCMS: m/z 385.4 (M+H); RT = 1.13min (2min).

¹ H-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).

Example 5

Synthesis of 4-bromo-2-fluoroaniline

Add 4-bromo-2-fluoro-1-nitrobenzene (2.2g, 10mmol), iron powder (2.8g, 50mmol) and tetrahydrofuran (20mL) into a 100mL round bottom flask, add hydrochloric acid (30mL, 2N), stirred at room temperature for 2 h, added anhydrous sodium carbonate (2 g) and anhydrous sodium sulfate, filtered, washed with ethyl acetate, concentrated under reduced pressure to obtain yellow solid compound 19 (1.65 g, yield: 87%).

LCMS: m/z 191.1 (M+H) ⁺ ; RT = 1.405 min.

N-(4-Bromo-2-fluorophenyl)-2-phenylacetamide

Add compound 19 (950mg, 5mmol), phenylacetic acid (680mg, 5mmol), HATU (3.42g, 9mmol), DMF (15mL) and N,N-diisopropylethylamine ( 1.29 g, 10 mmol). Stir at room temperature for 6 h, add ethyl acetate (20 mL) to dilute, wash with saturated brine (10 mL×3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 8 : 1) Purification to obtain yellow solid compound 20 (1.07g, yield: 70%).

LCMS: m/z 309.8 (M+H) ⁺ ; RT = 1.457 min.

N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-phenylacetamide Synthesis

Add compound 20 (1.01g, 3.3mmol), 1,4-dioxane (10mL), double pinaborate (4.2g, 16.7mmol), potassium acetate (648mg, 6.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (220 mg, 0.3 mmol). Vacuumize and ventilate 3 times with nitrogen, under the protection of nitrogen, stir and react at 90°C for 6h, TLC detects that the reaction is complete. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate =5:1) to obtain yellow solid compound 21 (703 mg, yield: 60%).

LCMS: m/z 355.8 (M+H) ⁺ ; RT = 1.699 min.

Synthesis of N-(4-(2-chloropyrimidin-4-yl)-2-fluorophenyl)-2-phenylacetamide

In a dry 10mL round bottom flask, add 21 (355mg, 1.0mmol), 2,4-dichloropyrimidine (222mg, 1.5mmol), [1,1'-bis(diphenylphosphino)dicene Fe]palladium dichloride (73 mg, 0.1 mmol), cesium carbonate (652 mg, 2.0 mmol), 1,4-dioxane (6 mL) and water (1 mL). Vacuumize and ventilate 3 times with nitrogen, under the protection of nitrogen, stir and react at 90°C for 6h, TLC detects that the reaction is complete. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate =3:1) to obtain yellow solid compound 22 (174 mg, yield: 51%).

LCMS: m/z 341.9 (M+H) ⁺ ; RT = 1.677min.

Synthesis of N-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-5-ylamino)pyrimidin-4-yl)phenyl)-2-phenylacetamide

Add compound 22 (68mg, 0.2mmol), 1-methyl-5-aminopyrazole (29mg, 0.3mmol), tris(dibenzylideneacetone) dipalladium (18mg, 0.02mmol) into a dry 25mL three-necked flask successively ), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (12 mg, 0.02 mmol), cesium carbonate (130 mg, 0.4 mmol) and 1,4-dioxane (3 mL). Under the protection of nitrogen, microwave heating to 100 degrees Celsius, and react for 2 hours. After the reaction was completed, ethyl acetate (20 mL) was added to dilute, washed with saturated brine (10 mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by acidic prep-HPLC to obtain yellow solid compound A5 (6 mg, yield rate: 7%).

¹ HNMR (400MHz, CDCl ₃ -d) δ8.49 (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 = 1.385 min.

The present invention uses above similar method to make following compound:

Example 6

Synthesis of tert-butyl-5-(2-(1-methyl-1H-pyrazol-5-ylamino)pyrimidin-4-yl)indoline-1-carboxylic acid tert-butyl ester

¹ H NMR (400MHz, CDCl ₃ -d) δ8.38 (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 = 1.461 min (254 nm).

Example 7

1-(5-(2-(1-methyl-1H-pyrazol-5-ylamino)pyrimidin-4-yl)indolin-1-yl)-3-phenylpropan-1-one synthesis

¹ HNMR (400MHz, CDCl ₃ -d) δ8.40 (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).

Example 8

Synthesis of 4-(indolin-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.38 (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).

Example 9

2-(2-chlorophenyl)-1-(5-(2-(1-methyl-1H-pyrazol-5-ylamino)pyrimidin-4-yl)indolin-1-yl)ethyl Ketone synthesis

¹ HNMR (400MHz, CDCl ₃ -d) δ8.41 (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).

Example 10

2-(3-chlorophenyl)-1-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)indolin-1-yl ) Synthesis of ethyl ketone

¹ H-NMR (CDCl ₃ , 400MHz): 8..30-8.35 (m, 2H), 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/z 444.9 (M+H); RT = 1.475min (2.50min).

Example 11

2-(4-chlorophenyl)-1-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)indolin-1-yl ) Synthesis of ethyl ketone

LCMS: m/z 445.4 (M+H); RT = 1.39min (2.0min).

¹ H-NMR(CDCl ₃ ,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).

Example 12

3-Hydroxy-1-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)indolin-1-yl)-2-phenyl Synthesis of propan-1-one

LCMS: m/z 441.3 (M+H); RT = 1.15min (2.0min).

¹ H-NMR(CDCl ₃ ,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).

Example 13

1-(5-(2-((1-Methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)indolin-1-yl)-2-phenylpropan-1- Ketone synthesis

¹ H-NMR (CDCl ₃ , 400MHz): 8..43-8.45 (d, J=7.6Hz, 1H), 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/z 425.3 (M+H); RT = 1.462min (2.50min).

Example 14

2-(2-Chlorophenyl)-N-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2-yl)acetamide

¹ H-NMR (CDCl ₃ , 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, J ₁ = 3.6Hz, J ₂ = 7.2Hz, 1H), 7.37-7.39 (dd, J ₁ =3.6Hz, J ₂ =7.2Hz, 1H), 7.28-7.32(m, 3H), 6.50-6.51(d, J=2.4Hz, 1H), 4.01(s, 2H), 3.92( s,3H).

LCMS: m/z 419.9 (M+H); RT = 1.375min (2.50min).

Example 15

Synthesis of 3N-(5-(2-(1-methyl-1H-pyrazol-5-ylamino)pyrimidin-4-yl)pyridin-2-yl)acetamide

¹ HNMR (400MHz, CDCl ₃ -d) δ10.77(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 = 0.771 min.

Example 17

Synthesis of N-(1-methyl-1H-pyrazol-5-yl)-4-(6-(phenethylamino)pyridin-3-yl)pyrimidin-2-amine

Compound A3 (20mg, 0.05mmol) was added to a dry 50mL single-necked bottle, dissolved in tetrahydrofuran (5mL), and lithium aluminum hydride (5mg, 0.13mmol) was added slowly, and reacted overnight at room temperature. After the LCMS detection was completed, water was added to the reaction solution, and then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and passed through a reverse-phase preparative column to obtain compound A17 (5 mg, white solid ), yield: 27%.

¹ H-NMR(CDCl ₃ ,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/z 372.2 (M+H); RT = 1.08min (2.0min).

Example 18

Synthesis of 4N-(2-chloro-4-(2-(1-methyl-1H-pyrazol-5-ylamino)pyrimidin-4-yl)phenyl)-2-phenylacetamide

¹ HNMR (400MHz, CDCl ₃ -d) δ8.44 (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.

Example 19

Synthesis of N-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2-yl)-1-phenylmethanesulfonamide

¹ H-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/z 421.9 (M+H); RT = 1.14min (2.5min).

Example 20

2-(2,6-Dichlorophenyl)-1-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)indoline- Synthesis of 1-yl)ethanone

¹ H-NMR (CDCl ₃ , 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/z 479.3 (M+H); RT = 1.43min (2.0min).

Example 21

2-(2-chlorophenyl)-1-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-2,3-dihydro- Synthesis of 1H-pyrrolo[2,3-b]pyridin-1-yl)ethanone

¹ H-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/z 446.2 (M+H); RT = 1.30min (2min).

Example 22

2-(2,6-Dichlorophenyl)-1-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-2,3- Synthesis of Dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethanone

¹ H-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/z 480.2 (M+H); RT = 1.41min (2min).

Example 23

N-methyl N-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2-yl)-2-phenylacetamide synthesis

Example 24

Synthesis of 3-methyl-N-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2-yl)butanamide

Example 25

2-(3-chlorophenyl)-N-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2-yl)acetamide Synthesis

Example 26

Synthesis of 1-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2-yl)-3-phenylurea

Example 27

Synthesis of N-(2-cyano-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)phenyl)-2-phenylacetamide

Example 28

2-(2-fluorophenyl)-1-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-2,3-dihydro- Synthesis of 1H-pyrrolo[2,3-b]pyridin-1-yl)ethan-1-one

Example 29

2-(3-fluorophenyl)-1-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-2,3-dihydro- Synthesis of 1H-pyrrolo[2,3-b]pyridin-1-yl)ethan-1-one

Synthesis of Comparative Example C1 4-(6-aminopyridin-3-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine

In a 25 mL round bottom flask were added A15 (180 mg, 0.58 mmol), sodium hydroxide (116 mg, 2.91 mmol), methanol (5 mL) and water (2 mL) sequentially. The reaction was stirred at 80°C for 6 h, and the reaction was complete as detected by TLC. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=5:1) to obtain yellow solid compound C1 (124 mg, yield : 80%).

¹ HNMR (400MHz, CDCl ₃ -d) δ8.75 (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

Preparation of 4-(6-aminopyridin-3-yl)pyrimidin-2-amine:

Add compound C2-1 (200mg, 1.45mmol), C2-2 (188mg, 1.45mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloro to a dry 50mL three-necked flask successively Palladium chloride (110 mg, 0.15 mmol), potassium carbonate (300 mg, 2.17 mmol), 1,4-dioxane (8 mL) and water (2 mL). Heated to 100° C. under nitrogen protection, and reacted for 3 hours. After the reaction was completed, it was poured into 30 mL of water, extracted with ethyl acetate (30 mL×2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by Flash (dichloromethane:methanol=30:1～10:1) to obtain the product C2( 120mg, pale yellow solid), yield: 30%.

¹ HNMR (400MHz, MeOD-d ₄ ) δ8.76 (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/z 188.1 (M+H); RT = 0.29min (2min).

Test example 1 The compound of the present invention is to the mensuration of ERK kinase activity

Materials and Instruments

ERK2enzyme (PV3595, Invitrogen)

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

Synergy 2 Microplate Reader (BioTec)

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

experiment method:

Z'-LYTE ^TM Ser/Thr 3 Peptide Substrate, Phospho-peptide, 5X Kinase Buffer, ATP, Development Reagent A, Development Buffer, Stop Reagent All reagents were equilibrated to room temperature and ready to be added.

The screening concentration for detecting the effect of the compound on the ERK kinase activity was serially diluted 3 times starting from 1 μM (0.2 μM), and 8 concentrations were taken. Multiple wells were taken for each concentration, and 4% DMSO was used as a co-solvent. After the reaction was completed, 5 μl of Development Reagent A diluted with Development Buffer was added to all the reaction wells, and after 1 hour of reaction at room temperature, 5 μl of Stop Reagent was added to all the reaction wells to terminate the reaction, and the fluorescence signal was detected with Synergy 2 Microplate Reader (the wavelength of the excitation light was 400 nm , the emitted light wavelength is 460nm, 528nm).

The inhibition rate of each well was calculated from the total active wells and the background signal wells. Experiments were repeated twice in parallel. The IC50 value can be calculated by the inhibitory value of the test compound on the kinase at a series of different concentrations.

Table 1 The compound of the present invention is to the inhibitory rate of different kinase activity

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (10)

1. A compound of formula I, its stereoisomer, racemate, or a pharmaceutically acceptable salt thereof: In the formula, X ₁ , X ₂ , X ₃ , X ₄ , X ₅ and X ₆ are each independently selected from CR ₅ or N; Wherein, R is selected from the group consisting of H, substituted or unsubstituted C1 _- C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, -OH, cyano, halogen, amino, substituted or unsubstituted C1 -C8 alkylamino, substituted or unsubstituted C1-C8 alkylcarbonyl, substituted or unsubstituted C1-C8 alkoxycarbonyl, substituted or unsubstituted C1-C8 carboxyl, substituted or unsubstituted C1-C8 ester , substituted or unsubstituted 3-8 membered ring hydrocarbon group, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group; R is selected from the group consisting of H, substituted or unsubstituted _C1 -C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, halogenated C1-C8 alkyl, Halogenated C2-C8 alkenyl, halogenated C2-C8 alkynyl, substituted or unsubstituted 3-8 membered ring hydrocarbon group, and substituted or unsubstituted aryl; R ₂ is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3-8 membered ring hydrocarbon groups, and substituted or Unsubstituted 3-8 membered heterocyclic group; _R is selected from the group consisting of H, substituted or unsubstituted C1-C8 alkyl, -OH, cyano, halogen, C1-C8 alkylene hydroxyl, substituted or unsubstituted 3-8 membered ring hydrocarbon group, substituted or Unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group; Alternatively, _R3 and _X4 together with adjacent C and N atoms form a substituted or unsubstituted 4-8 membered ring, wherein said ring contains at least 1 N heteroatom and contains a total of 1-3 selected from O , heteroatoms of S and N, and the ring is a saturated or unsaturated ring; R ₄ is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, -CO(CR ₆ R ₇ ) _m R ₈ , -SO ₂ (CR ₆ R ₇ ) _m R _8. -CONR ₉ (CR ₆ R ₇ ) _m R ₈ , -COO(CR ₆ R ₇ ) _m R ₈ , amino, C1-C8 carboxyl; m is 0, 1, 2 or 3; Each R ₆ and R ₇ are each independently selected from the group consisting of H, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylene hydroxyl, substituted or unsubstituted C1-C8 alkoxy, and halogen, Or R ₆ is connected with R ₇ to form a substituted or unsubstituted 3-6 membered ring; Each R is selected from the group consisting of H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted _3-8 membered ring hydrocarbon group, And a substituted or unsubstituted 3-8 membered heterocyclic group; Each R ₉ is selected from the group consisting of H, -OH, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylene hydroxy, and substituted or unsubstituted C1-C8 alkoxy. 2. The compound as claimed in claim 1, its stereoisomer, racemate, or pharmaceutically acceptable salt thereof, is characterized in that, the substitution means having one or more (such as 1-3 A) a substituent selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkylhydroxy, -OH, C1-C3 alkoxy, C1-C3 alkylamino, 3- 8-membered cyclic hydrocarbon group, 3-8-membered heterocyclic group, amino group, nitro group. 3. the compound as claimed in claim 1, its stereoisomer, racemate or its pharmaceutically acceptable salt, it is characterized in that, described formula I compound is shown in following formula Ia: Wherein, X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ are each independently selected from CR ₅ or N; _R is selected from the group consisting of H, substituted or unsubstituted C1-C8 alkyl, -OH, cyano, halogen, C1-C8 alkylene hydroxyl, substituted or unsubstituted 3-8 membered ring hydrocarbon group, substituted or Unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted 3-8 membered aryl group, and substituted or unsubstituted 3-8 membered heteroaryl group; The definitions of R ₂ , R ₄ , and R ₅ are the same as those in claim 1. 4. the compound as claimed in claim 1, its stereoisomer, racemate or its pharmaceutically acceptable salt, is characterized in that, described formula I compound is shown in following formula Ib: in, X ₁ , X ₂ , X ₃ , X ₅ , X ₆ are each independently selected from CR ₅ or 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 ^c R ^d , O, S, -NR ^c ; wherein R ^c , R ^d are each independently selected from: H, substituted or unsubstituted C1-C8 alkyl, -OH, Amino, halogen, cyano, substituted or unsubstituted C1-C8 alkylene hydroxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted amino C1-C8 alkyl-, substituted or unsubstituted C1-C8 alkylamino, or -CR ^c R ^d is -C(=O)-; The definitions of R ₂ , R ₄ , and R ₅ are the same as those in claim 1. 5. The compound according to claim 1, its stereoisomer, racemate, or a pharmaceutically acceptable salt thereof, wherein, in the compound of _formula Ia or Ib, R is selected from the following Group: Wherein, each Ra is independently selected from: C1-C4 alkyl; Rb is selected from halogen, -OH, cyano, amino, substituted or unsubstituted C1-C3 alkyl, C1-C3 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 Heterocycloalkyl; 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 ^c R ^d , O, S, -NR ^c ; wherein R ^c , R ^d are each independently selected from: H, substituted or unsubstituted C1-C8 alkyl, -OH, Amino, halogen, cyano, C1-C8 alkylene hydroxy, substituted or unsubstituted C1-C8 alkoxy, amino C1-C8 alkyl, substituted or unsubstituted C1-C8 alkylamino, or -CR ^c R ^d is -C (=O); R ₄ is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, -CO(CR ₆ R ₇ ) _m R ₈ , -SO ₂ (CR ₆ R ₇ ) _m R _8. -CONR ₉ (CR ₆ R ₇ ) _m R ₈ , -COO(CR ₆ R ₇ ) _m R ₈ , amino, carboxyl; wherein, m is 0, 1, 2 or 3; Each R ₆ and R ₇ is independently selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylene hydroxyl, substituted or unsubstituted C1-C8 alkoxy, and halogen, Or R ₆ is connected with R ₇ to form a substituted or unsubstituted 3-5 membered ring; Each R is selected from the group consisting of H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted _3-8 membered ring hydrocarbon group, And a substituted or unsubstituted 3-8 membered heterocyclic group; Each R ₉ is selected from the group consisting of H, -OH, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkylene hydroxy, and substituted or unsubstituted C1-C8 alkoxy. 6. A pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the compound as claimed in claim 1, its stereoisomer, racemate, or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients. 7. The compound as claimed in claim 1, its stereoisomer or its pharmaceutically acceptable salt, or the pharmaceutical composition as claimed in claim 6 is used for preventing and treating diseases related to ERK kinase and ERK Use of a kinase targeting inhibitor in a medicament. 8. A method for preparing the compound as claimed in claim 1, comprising the steps of: a) in an inert solvent, under metal catalysis or acid/base catalysis, (1e) reacts with (1f) compound to prepare the compound of formula I; Wherein, the definitions of each group of X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , R ₁ , R ₂ , and R ₃ are as described in claim 1; LG ₂ is a leaving group selected from the group consisting of halogen, sulfonate, methylthio, methylsulfone. 9. A method for preparing a compound as claimed in claim 1, comprising the steps of: b) in an inert solvent, under metal catalysis, (1c) and (1g) compound carry out a coupling reaction to prepare a compound of formula I; Wherein, the definitions of each group of X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , R ₁ , R ₂ , and R ₃ are as described in claim 1; LG ₁ is a leaving group selected from the group consisting of halogen, sulfonate, boronic acid, borate ester, borate, organotin, organozinc; LG ₃ is a leaving group selected from the group consisting of halogen, sulfonate, boronic acid, borate ester, borate. 10. A method for non-therapeutically inhibiting the activity of ERK kinase, characterized by comprising the step of: contacting the compound of claim 1 or a pharmaceutically acceptable salt thereof with ERK kinase, thereby inhibiting ERK kinase.