CN112457326B - Aromatic heterocyclic lactam compound, preparation method and application - Google Patents

Abstract

The invention discloses a class of aromatic heterocyclic lactam compounds, a preparation method and application thereof. The invention particularly discloses a class of aromatic heterocyclic lactam compounds shown as a formula (I), or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, solvates, polymorphs or prodrugs thereof, a preparation method thereof and a pharmaceutical application thereof.

Description

Aromatic heterocyclic lactam compound, preparation method and application

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to aromatic heterocyclic lactam compounds, a preparation method and application thereof.

Background

Extracellular signal-regulated kinases (ERKs) are a class of serine/threonine protein kinases found in the 90's of the 20 th century, and are one of the important subfamilies of the mitogen-activated protein kinase MAPKs family. Activated ERK can transmit extracellular signals to the nucleus, promote phosphorylation of cytoplasmic target proteins or regulate the activity of other protein kinases, thereby regulating gene expression. Ras-Raf-MEK-ERK signaling is central to the signaling network involved in regulating cell growth, development and differentiation, and therefore ERK has a variety of biological effects in regulating cell proliferation, differentiation, migration, invasion and apoptosis.

The Ras/Raf/MEK/ERK pathway is a main signal pathway related to the ERK function, is a hot spot for the development of cancer-targeted drugs, and a plurality of drugs developed aiming at node proteins on the signal pathway are successfully marketed in recent years. For example, specific B-Raf inhibitors Vemurafenib and dabrafenib, which are used for treating B-RafV600E mutant non-small cell lung cancer, were marketed in 2011 and 2013, respectively, for the treatment of melanoma, which received FDA-breakthrough drug eligibility. The MEK1/2 inhibitor trametinib was also marketed in 2013 for the treatment of melanoma. However, inhibition of these upstream pathway nodes has its limitations, tumors can rapidly develop resistance to B-Raf and MEK inhibitors, and Ras protein mutations are also found in numerous tumors, such as colorectal, pancreatic, lung, etc. The above mechanisms of drug resistance generation include point mutations, changes in protein multimeric forms, changes in protein peptide chain length, and the like, which are extremely challenging for the development of therapeutic drugs for next generation Ras-Raf-MEK resistance. However, the ERK is used as a downstream key node of the pathway, so that the occurrence of drug-resistant mutation is not discovered at present, and the ERK targeting drug can greatly improve the treatment of patients with drug resistance to upstream target inhibitors, so that the ERK targeting drug is a promising anti-cancer drug research and development field. Although a number of ERK inhibitors have been introduced into clinical studies in the early days, such as GDC0994, SCH772984, etc., these compounds have either been too toxic or poorly druggable to terminate clinical studies. Therefore, the discovery and search of novel ERK inhibitor compounds with high selectivity, high activity and high druggability become a major hot spot at present.

Disclosure of Invention

The invention aims to overcome the defects of single structure, low activity, easy drug resistance and the like of the conventional ERK inhibitor, and provides an aromatic heterocyclic lactam compound, a preparation method and application thereof. The aromatic heterocyclic lactam compound has a novel structure, has good inhibitory activity on ERK kinase, can inhibit the proliferation of tumor cells, and has anti-tumor activity.

The present invention solves the above-described problems by the following means.

The invention provides a compound shown as a formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a solvate, a polymorph or a prodrug thereof,

in the formula (I), the compound is shown in the specification,

R₁independently selected from hydrogen, C₁-C₈Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl; r₂Selected from hydrogen, halogen, cyano, hydroxy, acyl, sulfonyl, sulfone, sulfoxide, sulfinyl, amino, substituted amino, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₁-C₁₀Alkylamino, cycloalkyl or heterocycloalkyl of 3 to 10 members, aryl or heteroaryl of 5 to 10 members;

R_3a、R_3b、R_4a、R_4bindependently selected from hydrogen, halogen, hydroxy, alkoxy, amino, cyclic amino, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl;

or, the above R_3a、R_3b、R_4aAnd R_4bAny two groups in between may form a 3-8 membered saturated or partially unsaturated carbocyclic or heterocyclic ring;

R₅independently selected from hydrogen, halogen, cyano, nitro, C₁-C₆Alkyl, or 3-8 membered cycloalkyl; r₆、R₇、R₈And R₉Independently selected from hydrogen, halogen, hydroxyl, amino, C₁-C₈Alkyl, 3-to 8-membered cycloalkyl or heterocycloalkyl, 5-to 10-membered aryl or heteroaryl;

or, the above R₆、R₇、R₈And R₉Any two groups in between may form a 3-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring;

l is selected from a single bond, O, NR₁、S(O)_pAcyl, sulfonyl, amide,Urea, sulfonylurea, sulfinyl, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl, wherein p is selected from 0-2;

m is selected from N or CR₅；M₁And M₂Independently selected from CH, O, N and S, and M₁And M₂Not being CH at the same time.

m, n and q are independently selected from 0-3;

one or more hydrogen atoms on any of the above groups are substituted with a substituent selected from the group consisting of: deuterium, halogen, C₁-C₈An alkyl group; wherein said heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of: n, O, P and S, said heterocycloalkyl group containing 1 to 3 heteroatoms selected from the group consisting of: n, O, P and S; each ring system is independently a saturated, partially unsaturated or unsaturated monocyclic, fused, bridged or spiro ring.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₁Is C₁-C₈When alkyl, said C₁-C₈Alkyl is preferably C₁-C₄An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably an isopropyl group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₁Is C₁-C₈When alkyl, said C₁-C₈Alkyl is optionally substituted with 1-3 halogens or hydroxy, preferably fluorine.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₁In the case of a 3-to 8-membered heterocycloalkyl group, the 3-to 8-membered heterocycloalkyl group is preferably a 5-to 6-membered heterocycloalkyl group having "one or more hetero atoms selected from N, O and S and a number of hetero atoms of 1 to 3", and more preferably a tetrahydropyranyl group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₁In the case of a 5-to 10-membered heteroaryl group, the 5-to 10-membered heteroaryl group is preferably a 5-to 6-membered heteroaryl group having "one or more hetero atoms selected from N, O and S and a hetero atom number of 1 to 3", more preferably a pyrazolyl group (for example, a pyrazolyl group)

) Or pyridyl (e.g. of

)。

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₁In the case of a 5-10 membered heteroaryl group, said 5-10 membered heteroaryl group is optionally substituted with 1 to 3C₁-C₈Alkyl is substituted, said C₁-C₈Alkyl is preferably C₁-C₄An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably a methyl group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₂In the case of a 3-to 10-membered cycloalkyl group, the 3-to 10-membered cycloalkyl group is preferably a 5-to 6-membered cycloalkyl group, and more preferably a cyclohexyl group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₂In the case of a 5-to 10-membered aryl group, the 5-to 10-membered aryl group is preferably a 6-to 10-membered aryl group or an 8-to 10-membered bicyclic aryl group, the 6-to 10-membered aryl group is preferably a phenyl group, and the 8-to 10-membered bicyclic aryl group is preferably a dihydroindenyl group (for example

)。

In certain preferred embodiments of the present invention, theCertain groups of the compounds of formula (I) are defined below (undefined groups are as described in any of the preceding schemes): when R is₂In the case of a 5-10 membered aryl group, said 5-10 membered aryl group is optionally substituted with 1-3 halogens, preferably fluorine or chlorine.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₂In the case of a 5-10 membered aryl group, said 5-10 membered aryl group is optionally substituted with C₁-C₈Alkyl or R_2-1Substituted C₁-C₈Alkyl substitution, said C₁-C₈Alkyl is preferably C₁-C₄An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably methyl or isopropyl.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₂When 5-10 membered aryl, said 5-10 membered aryl is optionally substituted with R_2-1Substituted C₁-C₈Alkyl substitution, said R_2-1The number of (a) is 1,2 or 3.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₂When 5-10 membered aryl, said 5-10 membered aryl is optionally substituted with R_2-1Substituted C₁-C₈Alkyl substitution, R_2-1Is halogen, preferably fluorine.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₂In the case of a 5-to 10-membered aryl group, the 5-to 10-membered aryl group is substituted with a 5-to 8-membered heteroaryl group, and the 5-to 8-membered heteroaryl group is preferably a 5-to 6-membered heteroaryl group having "one or more hetero atoms selected from N, O and S and 1 to 3 hetero atoms", more preferably an oxazolyl group (for example, oxazolyl group

)。

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₂In the case of a 5-to 10-membered heteroaryl group, the 5-to 10-membered heteroaryl group is preferably an 8-to 9-membered bicyclic heteroaryl group in which "one or more heteroatoms selected from N, O and S and the number of heteroatoms is 1 to 3", or a 5-to 6-membered monocyclic heteroaryl group in which "one or more heteroatoms selected from N, O and S and the number of heteroatoms is 1 to 3", and the 5-to 6-membered monocyclic heteroaryl group is preferably a pyridyl group (for example, a pyridyl group)

) Said 8-9 membered bicyclic heteroaryl is preferably imidazopyridyl (e.g. imidazole-pyridyl)

)。

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₂In the case of a 5-10 membered heteroaryl group, said 5-10 membered heteroaryl group is optionally substituted with C₁-C₈Alkyl substitution, said C₁-C₈Alkyl is preferably C₁-C₄An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably a methyl group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₂In the case of a 5-10 membered heteroaryl group, said 5-10 membered heteroaryl group is optionally substituted with C₁-C₈Alkylamino substitution, said C₁-C₈Alkylamino is preferably C₁-C₄Alkylamino, more preferably alkylamino

In certain preferred embodiments of the invention, the compounds are as describedCertain groups of compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is_3a、R_3b、R_4a、R_4bIndependently is C₁-C₈When alkyl, said C₁-C₈Alkyl is preferably C₁-C₄An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably a methyl group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is_3a、R_3b、R_4a、R_4bIndependently is C₁-C₈When alkyl, said C₁-C₈Alkyl is optionally substituted by 1-3C₁-C₈Alkoxy substitution of said C₁-C₈Alkoxy is preferably C₁-C₄An alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), more preferably a methoxy group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₅When halogen is used, the halogen is preferably fluorine or chlorine.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₅Is C₁-C₆When alkyl, said C₁-C₆Alkyl is preferably C₁-C₄An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably a methyl group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₅Is C₁-C₆When alkyl, said C₁-C₆Alkyl is optionally substituted with 1-3 halogens,the halogen is preferably fluorine.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₆、R₇、R₈And R₉Independently is C₁-C₈When there is an alkyl group, said C₁-C₈Alkyl is preferably C₁-C₄An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably a methyl group or an ethyl group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₆、R₇、R₈And R₉Independently is C₁-C₈When there is an alkyl group, said C₁-C₈Is optionally substituted with 1-3 halogens, preferably fluorine.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₆、R₇、R₈And R₉Independently is C₁-C₈When there is an alkyl group, said C₁-C₈Optionally substituted by 1-3C₁-C₈Alkoxy substitution of said C₁-C₈Alkoxy is preferably C₁-C₄An alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), more preferably a methoxy group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₆、R₇、R₈And R₉Independently is C₁-C₈When there is an alkyl group, said C₁-C₈Optionally substituted by 1-3C₁-C₈Alkylamino substitution, said C₁-C₈Alkylamino is preferably C₁-C₄Alkylamino, more preferably alkylamino

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when L is an amide, said amide is preferably-C (═ O) NH-; wherein, C terminal is connected with

Are connected, N terminal to

Are connected.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₁Is selected from C₁-C₈Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; said C₁-C₈Alkyl is optionally substituted with 1-3 halogens or hydroxy; said 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with 1-3C₁-C₈Alkyl groups are substituted.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₁Is selected from C₁-C₈Alkyl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl; said C₁-C₈Alkyl is optionally substituted with 1-3 halogens or hydroxy; said 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with 1-3C₁-C₈Alkyl groups are substituted.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₁Selected from 5-10 membered heteroaryl; said 5-10 membered heteroaryl group optionally substituted with 1-3C₁-C₈Alkyl radical generationAnd (4) substitution.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₂Selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; said 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with 1-3 halogens, C₁-C₈Alkyl radical, R_2-1Substituted C₁-C₈Alkyl radical, C₁-C₈Alkoxy radical, C₁-C₈Alkylamino, or 5-8 membered heteroaryl; r_2-1Selected from halogen or hydroxyl.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₂Is 6-10 membered aryl or 5-10 membered heteroaryl; said 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted by 1-3 halogen, C₁-C₈Alkyl or C₁-C₈Alkylamino.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₂Is a 6-to 10-membered aryl group; said 6-to 10-membered aryl being optionally substituted by 1-3 halogens, C₁-C₈Alkyl or C₁-C₈Alkylamino.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₂Is a 6-to 10-membered aryl group; said 6-to 10-membered aryl is optionally substituted with 1-3 halogens.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r_3a、R_3b、R_4aAnd R_4bIndependently selected from hydrogen, or C₁-C₈An alkyl group; said C₁-C₈Alkyl is optionally substituted by 1-3C₁-C₈Alkoxy substitution.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r_3a、R_3b、R_4aAnd R_4bIs hydrogen.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₅Independently selected from hydrogen, halogen, cyano, or C₁-C₆An alkyl group; said C₁-C₆Alkyl is optionally substituted with 1-3 halogens.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₆、R₇、R₈And R₉Independently selected from hydrogen, or C₁-C₈Alkyl groups of (a); said C₁-C₈Optionally substituted by 1-3 halogens, hydroxy, C₁-C₈Alkoxy, or C₁-C₈And (4) alkyl amino substitution.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₆、R₇、R₈And R₉Independently selected from hydrogen, or C₁-C₈Alkyl groups of (a); said C₁-C₈Is optionally substituted with 1-3 hydroxyl groups.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₆、R₇、R₈And R₉Independently selected from hydrogen, or C₁-C₈Alkyl groups of (a); said C₁-C₈Is optionally substituted with 1-3 hydroxyl groups; r₆And R₇Is different from R₆And R₇The attached C atom is in the R configuration.

In bookIn certain preferred embodiments of the invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as defined in any of the preceding schemes): r₆And R₇Independently selected from hydrogen, or C₁-C₈Alkyl group of (1).

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₈Is hydrogen, R₉Is C₁-C₈Or R is₈Is C₁-C₈Alkyl of R₉Is hydrogen; said C₁-C₈Is substituted with 1 hydroxyl group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): l is an amide.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m is selected from N or CR₅。

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m is selected from N or CH.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m is CH.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m₁And M₂Independently selected from CH, O, N and S, and M₁And M₂Is not CH at the same time; CH is optionally substituted with halogen.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m₁And M₂Independently selected from CH, O and S, and M₁And M₂Not being CH at the same time.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m₁Is CH; m₂Is O.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m₁Is CH; m₂Is S.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m, n and q are independently selected from 0, 1,2 or 3.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m and n are 1.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): q is selected from 0 or 1.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): q is 0.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₁Is composed of

Preferably,

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₂Is composed of

Preference is given to

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r_3aAnd R_3bIndependently hydrogen or methyl.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r_4aAnd R_4bIndependently is hydrogen, methyl or

Hydrogen is preferred.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₅Is hydrogen, fluorine, chlorine, cyano, methyl or trifluoromethyl.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₆And R₇Independently is hydrogen, methyl, ethyl or-CH₂F, preferably hydrogen or methyl.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₈And R₉Independently hydrogen, methyl, -CH₂OH、

Preferably hydrogen or-CH₂OH。

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): l is-C (═ O) NH-; wherein, C terminal is connected with

Are connected, N terminal to

Are connected.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m is N or CH.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m₁Is CH, CF, N, O or S, preferably CH, CF or N.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m₂Is CH, N, O or S, preferably O or S.

In certain preferred embodiments of the invention, the compound having the general formula (1), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, is preferably of the general formula ((I) a), (I) B), (I) C), (I) D), (I) E), (I) F), (I) G) and ((I) H):

wherein R is₁、R₂、R_3a、R_3b、R_4a、R_4b、R₅、R₆、R₇、R₈、R₉M, M, n, q and L are as defined above.

A process for the preparation of a compound of formula (I), said process comprising steps a-c:

a) converting the intermediate compound with the general formula (A) into an intermediate compound with the general formula B1, such as borate, organic tin or organic zinc, through a metal-catalyzed coupling reaction; and

b) carrying out cross-coupling reaction on the intermediate general formula (B1) compound and the intermediate general formula (B2) under the reaction condition of the presence of a transition metal catalyst to obtain a compound shown as a general formula (I) or an intermediate general formula (C);

c) the compound of the general formula (C) and the compound R of the general formula₁NH₂Under the reaction condition of acid catalysis, base catalysis or transition metal catalysis coupling, generating a compound (I) with a general formula;

in the formulas, Mc represents boric acid, boric acid ester, organic tin, organic zinc and other groups, X represents halogen, sulfonic acid ester and other groups, and the definition of other groups is as described above;

preferably, said steps a), b), c) are each carried out in a solvent, and said solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, butanol, ethylene glycol methyl ether, N-methyl pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.

Preferably, the transition 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, palladium trifluoroacetate, triphenylphosphine palladium acetate, [1,1' -bis (diphenylphosphino) acetate) Ferrocene]Palladium dichloride, bis (tri-o-phenylphosphino) palladium dichloride, 1, 2-bis (diphenylphosphino) ethane palladium dichloride, or a combination thereof; the catalyst ligand is selected from the group consisting of: tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-benzylphosphine, tricyclohexylphosphine, tri-o-phenylphosphine, or a combination thereof.

Preferably, the inorganic base is selected from the group consisting of: sodium hydride, potassium hydroxide, sodium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or combinations thereof; 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 hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or a combination thereof.

Preferably, the acid is selected from the group consisting of: hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and the like, or combinations thereof.

In certain preferred embodiments of the present invention, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, wherein the compound of formula (I) may be any one of the following compounds:

the invention also provides a pharmaceutical composition, which comprises the compound shown in the formula (I) or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, solvate, polymorph or prodrug thereof and a pharmaceutically acceptable carrier. The compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof, can be in a therapeutically effective amount.

The pharmaceutical composition is preferably a pharmaceutical composition for preventing and/or treating tumors, and consists of a compound shown as a formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a solvate, a polymorph or a prodrug thereof, and a pharmaceutically acceptable carrier; wherein the tumor includes but is not limited to non-small cell lung cancer, melanoma, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, pancreatic cancer, skin cancer, stomach cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymph cancer or nasopharyngeal cancer.

The pharmaceutical composition is preferably a pharmaceutical composition for preventing and/or treating inflammatory/autoimmune diseases, and consists of a compound shown as a formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a solvate, a polymorph or a prodrug thereof, and a pharmaceutically acceptable carrier; wherein, the inflammatory/autoimmune diseases include but are not limited to arthritis, pancreatitis, erythematodes, inflammatory bowel disease, sepsis, septicemia, etc.

The compound shown in the formula (I) can inhibit various tumor cells, particularly can efficiently kill tumors related to Ras-Raf-MEK-ERK signal channel abnormity, and is a treatment drug with a brand-new action mechanism.

Term(s) for

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the term "comprising" as well as other forms, such as "includes," "including," and "containing," are not limiting.

Definitions for the terms of the standardization sector can be found in the literature references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols.A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, (I) R and UV/V (I) S spectroscopy, and pharmacological methods. Unless a specific definition is set forth, the terms used herein in the pertinent description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the instructions of the kit from the manufacturer, or according to the methods known in the art or the instructions of the present invention. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.

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

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

Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. E.g. C_1-6Alkyl 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 shorthand notation excludes carbons that may be present in a substituent of the group.

In addition to the foregoing, the following terms, when used in the specification and claims of this application, have the meanings indicated below, unless otherwise specifically indicated.

In the present application, the term "halogen" means fluorine, chlorine, bromine or iodine; "hydroxy" means an-OH group; "hydroxyalkyl" refers to an alkyl group as defined below substituted with a hydroxyl (-OH) group; "carbonyl" refers to a-C (═ O) -group; "nitro" means-NO₂(ii) a "cyano" means-CN; "amino" means-NH₂(ii) a "substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., monoalkylamino, dialkylamino, alkylamido, aralkylamino, heteroaralkylamino; "carboxyl" means-COOH.

In the present application, the term "alkyl", as a group or as part of another group (e.g. as used in groups such as halogen-substituted alkyl), means a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing no unsaturated bonds, having, for example, from 1 to 12 (preferably from 1 to 8, more preferably from 1 to 6) carbon atoms and being attached to the rest of the molecule by single bonds. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, and the like.

In the present application, the term "alkenyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms, and being 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, 4-dienyl, and the like.

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

In the present application, the term "cycloalkyl" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon atoms and hydrogen atoms, which may include fused, bridged or spiro ring systems, having 3 to 15 carbon atoms, preferably having 3 to 10 carbon atoms, more preferably having 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the rest of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the specification, carbon atoms in cycloalkyl groups may be optionally oxidized. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2, 3-indanyl, 1,2,3, 4-tetrahydro-naphthyl, 5,6,7, 8-tetrahydro-naphthyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 7-dimethyl-bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [2.2.2] octyl, 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, octahydro-2, 5-methylene-pentalenyl and the like.

In this application, the term "heterocyclyl" as a group or part of another group means a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise specifically indicated in the specification, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or higher ring system, which may include fused ring systems, bridged ring systems or spiro ring systems; wherein the nitrogen, carbon or sulfur atom in the heterocyclic group may be optionally oxidized; the nitrogen atoms may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclic groups containing fused rings, one or more of the 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 spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2, 7-diaza-spiro [3.5] nonan-7-yl, 2-oxa-6-aza-spiro [3.3] heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.

In this application, the term "aryl" as a group or as 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, an aryl group may be a monocyclic, bicyclic, tricyclic or higher polycyclic ring system and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is attached to the remainder of the molecule by a single bond via an atom on the aromatic ring. 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) -one-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 a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or higher ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is attached to the rest of the molecule by a single bond via an atom on the aromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atoms may optionally be 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 a stable 5-to 10-membered aromatic group containing 1 to 4 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, indolizinyl, isoindolyl, indazolyl, isoindolyl, purinyl, quinolyl, isoquinolyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, orthophenanthrolidinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthopyridyl, pyridinyl, and the like, [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-b ] pyridazine, imidazo [1,2-a ] pyrazine and the like.

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

In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.

The terms "moiety," "structural moiety," "chemical moiety," "group," "chemical group" as used herein refer to a specific fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded in or attached to a molecule.

"stereoisomers" refers to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The present invention is intended to cover various stereoisomers and mixtures thereof.

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

"tautomer" refers to an isomer 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 included 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 may therefore give rise to enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting as starting materials or intermediates racemates, diastereomers or enantiomers. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, e.g., crystallization and chiral chromatography.

Conventional techniques for preparing/separating individual isomers include Chiral synthesis from suitable optically pure precursors, or resolution of the racemates (or racemates of salts or derivatives) using, for example, Chiral high performance liquid chromatography, as described, for example, in Gerald Gu (I) tz and Martin G.Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol.243, 2004; m. Stalcup, Chiral Separations, Annu. Rev. anal. chem.3:341-63, 2010; fumiss et al (eds.), VOGEL' S ENCYCOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5. TH ED., Longman Scientific and Technical Ltd., Essex,1991, 809-816; heller, acc, chem, res, 1990,23,128.

In the present application, the term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids which retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formates, acetates, 2-dichloroacetates, trifluoroacetates, propionates, caproates, caprylates, caprates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartates, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbates, salicylates, 4-aminosalicylates, napadisylates, and the like. These salts can be prepared by methods known in the art.

"pharmaceutically acceptable base addition salts" refers to salts with inorganic or organic bases which 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, the following: primary, secondary and tertiary amines, substituted amines including naturally occurring 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, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. 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 different solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present invention may exist in more than one crystalline form and the present invention is intended to include the various crystalline forms and mixtures thereof.

Typically, crystallization will result in solvates of the compounds of the invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of the 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. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrate, hemihydrate, sesquihydrates, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases it is also possible to retain only adventitious water or a mixture of water plus a portion of adventitious solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.

The invention also includes prodrugs of the above compounds. In the present application, the term "prodrug" denotes a compound that can be converted under physiological conditions or by solvolysis to the biologically active compound of the invention. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. Prodrugs may not be active when administered to a subject in need thereof, but are converted in vivo to the active compounds of the invention. Prodrugs are generally rapidly converted in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. Prodrug compounds generally provide solubility, histocompatibility, or sustained release advantages in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups. Specific methods for preparing prodrugs can be found in 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 the present application, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of active ingredients and exert biological activity.

The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.

As used herein, a "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that is approved by the relevant governmental regulatory agency for human or livestock use.

The "tumor" and "diseases related to abnormal cell proliferation" include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, squamous cell lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like.

The terms "preventing," "prevention," and "prevention" as used herein include reducing the likelihood of occurrence or worsening of a disease or disorder 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, particularly when such mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;

(II) inhibiting the disease or disorder, i.e., arresting its development;

(III) alleviating the disease or disorder, i.e., causing regression of the state of the disease or disorder; or

(Iv) alleviating the symptoms caused by the disease or disorder.

The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.

The terms "administering," "administration," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, via the duodenal route, 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, for example, in Goodman and Gilman, The pharmaceutical basic of therapeutics, current ed.; pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

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

It will also be appreciated by those skilled in the art that in the processes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butyloxycarbonyl, benzyloxycarbonyl and the like. Suitable thiol protecting groups include-C (O) -R (where "R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.

Protecting groups may 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 organic Synthesis, (1999),4th Ed., Wiley. The protecting group may also be a polymeric resin.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. The space is not described herein in a repeated fashion.

On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the compound prepared by the invention has a novel structure and better ERK kinase inhibitory activity, and the compound has a specific inhibitory action on ERK kinase, particularly ERK2, at an extremely low concentration (which can be as low as less than or equal to 10nmol/L), has quite excellent cell proliferation inhibitory activity on Ras-Raf-MEK-ERK, and can be used for treating related diseases such as tumors or inflammation or autoimmune diseases caused by Ras-Raf-MEK-ERK kinase mutation or abnormal expression amount.

Detailed Description

The invention will be further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

The first preparation method of the intermediate comprises the following steps: preparation of heteroaromatic hexalactam

Intermediate 1: (R) -tert-butyl 2- (2-bromo-4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionate

The first step is as follows: ethyl 2- (2-hydroxyethyl) furan-3-carboxylate (1.9g, 0.01mol) was dissolved in methanol (10mL), 2M sodium hydroxide (NaOH) (10.3mL) was added, the reaction was allowed to proceed overnight at room temperature, 2M hydrochloric acid solution was added to adjust pH to 2-3, ethyl acetate was extracted 4 times, dried over anhydrous magnesium sulfate, and concentrated to give 2- (2-hydroxyethyl) furan-3-carboxylic acid (1.6g, white solid). LC-MS ESI [ M + H ]]⁺＝155.2。

The second step is that: 2- (2-hydroxyethyl) furan-3-carboxylic acid (1.6g, 10.3mmol) was dissolved in N, N-Dimethylformamide (DMF) (20mL), D-alanine tert-butyl ester (2.8g, 15.4mmol),2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (5.9g, 15.4mmol) and N, N-Diisopropylethylamine (DIEA) (5.3g, 41.2mmol) were added, stirred at room temperature for 5.5h, saturated ammonium chloride (NH) was added₄Cl) solution, ethyl acetate extraction, drying, concentration under reduced pressure, column chromatography purification to give the compound tert-butyl 2- (2-hydroxyethyl) furan-3-carbonyl) -D-alanine (2.5g, white solid). LC-MS ESI [ M + H ]]⁺＝284.2。

The third step: tert-butyl 2- (2-hydroxyethyl) furan-3-carbonyl) -D-alanine (2.5g, 8.8mmol) was dissolved in dichloromethane (20ml), protected with nitrogen, Triethylamine (TEA) (2.7g, 26.4mmol) and methanesulfonyl chloride (Ms-Cl) (1.2g, 10.4mmol) were added, reacted at room temperature for 40 minutes, washed twice with water and dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (20ml), protected with nitrogen, NaH (0.32g,13.2mmol) was added in portions under ice salt bath, reacted overnight at room temperature, saturated NH was added₄Extracting with Cl solution and ethyl acetate, drying, and concentrating under reduced pressureCondensing, purifying by column chromatography to obtain compound (R) -2- (4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid tert-butyl ester (0.64g, white solid). LC-MS ESI [ M + H ]]⁺＝266.2。

The fourth step: mixing (R) -2- (4-oxo-6, 7-dihydrofuran [3, 2-c)]Tert-butyl pyridin-5 (4H) -yl) propionate (2g, 7.5mmol) was dissolved in DMF (20mL), 2mL of acetic acid was added dropwise, N-bromosuccinimide (NBS) (1.3g, 7.5mmol) was added, and the reaction was stirred at room temperature overnight. Adding saturated NH₄Extracting with ethyl acetate, drying, concentrating under reduced pressure, and purifying by column chromatography to obtain compound (R) -2- (2-bromo-4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid tert-butyl ester (0.6g, white solid). LC-MS ESI [ M + H ]]⁺＝344.1。1H-NMR(400MHz,CD₃OD)δ6.64(s,1H),4.92-4.98(q,1H),3.68-3.74(m,2H),2.95-3.06(m,2H),1.45(s,9H),1.43(d,3H)。

With reference to the same synthetic procedures and procedures, the following intermediates 1A-1F were prepared:

and a second intermediate preparation method comprises the following steps: preparation of heteroaromatic pentalactam

Intermediate 2: tert-butyl (R) -2- (2-bromo-4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propionate

The first step is as follows: 2-methylthiophene-3-carboxylic acid (500mg, 3.52mmol) was dissolved in methanol (10mL), thionyl chloride (4mL) was slowly added dropwise, and the mixture was stirred at 80 ℃ for 3 hours. Cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to give methyl 2-methylthiophene-3-carboxylate (500mg, white solid). LC-MS ESI [ M + H ]]⁺＝157.1；¹H NMR(400MHz,DMSO-d6):δ7.33(s,2H),3.78(s,3H),2.68(s,3H)。

The second step is that: methyl 2-methylthiophene-3-carboxylate (500mg, 3.21mmol) was dissolved in carbon tetrachloride (10mL), NBS (685mg, 3.85mmol) and AIBN (105mg, 0.64mmol) were added, and the mixture was stirred at 80 ℃ for 1 hour under nitrogen. Cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to give methyl 2-bromomethylthiophene-3-carboxylate (680mg, white solid). LC-MS ESI [ M + H ]]⁺＝235.2/237.2。

The third step: methyl 2-bromomethylthiophene-3-carboxylate (470mg, 2.0mmol) and D-alanine tert-butyl ester hydrochloride (437mg, 2.4mmol) were dissolved in acetonitrile (10mL), triethylamine (808mg, 8.0mmol) was added dropwise, and the mixture was stirred at 80 ℃ overnight. Cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to give methyl (R) -2- (((1- (tert-butoxy) -1-oxoprop-2-yl) amino) methyl) thiophene-3-carboxylate (465mg, white solid). LC-MS ESI [ M + H ]]⁺＝300.1。

The fourth step: methyl (R) -2- (((1- (tert-butoxy) -1-oxoprop-2-yl) amino) methyl) thiophene-3-carboxylate (600mg, 2.0mmol) was dissolved in methanol (10mL), 1N lithium hydroxide (LiOH) (5mL) was added, and the mixture was stirred at 40 ℃ overnight. Cooling to room temperature, diluting with water, concentrating under reduced pressure, neutralizing the aqueous phase with 1N diluted hydrochloric acid, extracting with dichloromethane, drying the organic phase over anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain (R) -2- (((1- (tert-butoxy) -1-oxoprop-2-yl) amino) methyl) thiophene-3-carboxylic acid (530mg, white solid). LC-MS ESI [ M + H ]]⁺＝286.1。

The fifth step: (R) -2- (((1- (tert-butoxy) -1-oxoprop-2-yl) amino) methyl) thiophene-3-carboxylic acid (300mg, 1.05mmol) was dissolved in DMF (10mL), triethylamine (213mg, 2.10mmol) was added dropwise, HATU (1.6g, 4.2mmol) was added, and the mixture was stirred at room temperature for 2 hours. Concentrating the reaction solution under reduced pressure, and purifying the residue by column chromatography to obtain (R) -2- (4-oxo-4, 6-dihydro-5H-thieno [2, 3-c)]Pyrrol-5-yl) propionic acid tert-butyl ester (252mg, white solid). LC-MS ESI [ M + Na ]]⁺＝290.1。

And a sixth step: reacting (R) -2- (4-oxo-4, 6-dihydro-5H-thieno [2, 3-c)]Pyrrol-5-yl) propionic acid tert-butyl ester (50mg, 0.19mmol) was dissolved in DMF (5mL), and 0.5mL of acetic acid was added dropwise, followed by addition of NBS (37mg, 0.21mmol) and stirring at room temperature overnight. Concentrating under reduced pressure to obtain residue layerPurification by chromatography gave intermediate 2(30mg, white solid). LC-MS ESI [ M + H ]]⁺＝346.1/348.1。¹H-NMR(400MHz,DMSO-d6)δ7.41(s,1H),4.52-4.67(m,3H),1.43(d,J＝7.6Hz,3H)，1.39(s,9H)。

With reference to intermediate 2 and the synthetic route and method of patent WO2017033966a1, the following intermediates 2A-2E were prepared.

And a third intermediate preparation method: synthesis of 2-aminopyridines

Intermediate 3: (4-chloro-5-methylpyridin-2-yl) (1-methyl-1H-pyrazol-5-yl) carbamic acid tert-butyl ester

The first step is as follows: 2, 4-dichloro-5-methylpyridine (50g, 0.31mol) and 1-methyl-1H-pyrazol-5-amine (30g, 0.31mol) were dissolved in DMF (500mL), and cesium carbonate (Cs) was added under nitrogen protection₂CO₃) (202g, 0.62mol), tris (dibenzylideneacetone) dipalladium (Pd₂(dba)₃) (28g, 0.031mol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (xanthphos) (36g, 0.062mol), and the reaction was carried out at 100 ℃ for 2 days. The reaction solution was cooled to room temperature, and saturated NH was added₄The Cl solution was extracted with ethyl acetate, dried, concentrated under reduced pressure, and purified by column chromatography to give 4-chloro-5-methyl-N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine (23.4g, white solid). LC-MS ESI [ M + H ]]⁺＝223.2。

The second step is that: 4-chloro-5-methyl-N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine (23.4g, 0.11mol) was dissolved in Dichloromethane (DCM) (200mL) and di-tert-butyl methyl dicarbonate (Boc) was added₂O) (25.3g, 0.12mol), 4-Dimethylaminopyridine (DMAP) (1.3g, 11mmol) and TEA (16.7g, 0.16mol) were stirred overnight at room temperature and saturated NH was added₄Extracting with Cl solution and dichloromethane, drying, concentrating under reduced pressure, and purifying by column chromatography to obtain (4-chloro-5-methylpyridin-2-yl) (1-methyl)-1H-pyrazol-5-yl) carbamic acid tert-butyl ester (29.6g, white solid). LC-MS ESI [ M + H ]]⁺＝323.4/325.4。¹H-NMR(DMSO-d6,400MHz)δ8.12(s,1H),7.75(s,1H),7.47(d,J＝2Hz,1H),6.08(d,J＝2Hz,1H),3.73(s,3H),2.30(s,3H),1.45(s,9H)。

Referring to intermediate 3 and the synthetic route and method of patent WO2017068412A1, 2-aminopyridine intermediate compounds 3A-3E were prepared.

The general preparation method comprises the following steps: preparation of 2-aminopyrimidine/pyridine lactam compounds

The above substituents are the same as those described above.

The first step is as follows: dissolving the aromatic heterocyclic lactam intermediate (1eq.) in anhydrous dioxane, and sequentially adding pinacol borate (2eq.), anhydrous potassium carbonate powder (2.5eq.) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl₂) (0.1eq.) and reflux with heating under nitrogen for 2 hours. The completion of the reaction was monitored by Thin Layer Chromatography (TLC), cooled to room temperature and used directly in the next reaction.

The second step is that: cooling the reaction solution to room temperature, and rapidly adding 2, 4-dichloropyrimidine intermediate (1.5eq.) or 2-amino-4-clopidogrel compound (1.25eq.) and tetrakis (triphenylphosphine) palladium (Pd (PPh)₃)₄) (0.1eq.) and heating was continued for 2 hours. After the reaction was completed, the mixture was filtered through celite, washed with ethyl acetate, and the filtrate was concentrated. The residue was diluted with dichloromethane, the organic phase was washed successively with water, a saturated sodium bicarbonate solution, and a saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give the objective compound.

The third step: the intermediate 2-chloropyrimidine intermediate compound (1eq.) was dissolved in anhydrous DMF, and the amine compound (1.5eq.) and p-toluenesulfonic acid (0.2eq.) were added in sequence, heated to 100 ℃, and stirred overnight. After the reaction was complete, it was cooled to room temperature and diluted with dichloromethane and saturated sodium bicarbonate solution. Separating out an organic phase, washing with water and saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying by preparative HPLC to obtain a target compound, and confirming the structure by adopting nuclear magnetism and mass spectrometry.

The general preparation method II comprises the following steps: preparation of amides

The above substituents are the same as those described above.

The first step is as follows: the tert-butyl ester raw material (1eq.) is dissolved in dichloromethane, and trifluoroacetic acid (3eq.) and triethylsilane (0.2eq.) are added under ice-bath cooling, and the mixture is stirred for 4 hours until the reaction is finished. The reaction solution was concentrated and dried, and used directly in the next reaction.

The second step is that: the starting acid intermediate (1eq.), amine (1.1eq.), and triethylamine (3eq.) were dissolved in anhydrous DMF, O-benzotriazole-tetramethyluronium Hexafluorophosphate (HBTU) (1.2eq.) was added, and the reaction was stirred at room temperature until completion. Diluting the reaction solution with dichloromethane and saturated ammonium chloride solution, separating out an organic phase, washing with water and saturated saline respectively, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying a crude product by silica gel column chromatography or preparative HPLC to obtain a target compound, and identifying by nuclear magnetism and mass spectrometry respectively.

Examples preparation

The following compounds of examples were prepared and synthesized in sequence from intermediates 1 to 3 and other commercial reagents as starting materials by the general preparative methods of examples one and general preparative methods of examples two, respectively.

Example 1: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propionamide

The first step is as follows: tert-butyl (4-bromopyridin-2-yl) (1-methyl-1H-pyrazol-5-yl) carbamate (150mg, 0.42mmol), pinacol borate (119mg, 0.47mmol), potassium acetate (123mg, 1.26mmol), and 1,1' -bisdiphenylphosphinoferrocene palladium dichloride (Pd (dppf) Cl₂) (61mg, 0.084mmol) was dissolved in dioxane (10mL), bubbled with nitrogen for 10 min, and heated to 80 ℃ under nitrogen for 8 h. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to give tert-butyl (1-methyl-1H-pyrazol-5-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxan-2-yl) pyridin-2-yl) carbamate (yellow oil) which was used as it was in the next reaction. LC-MS ESI [ M + H ]]+＝401.2；¹H-NMR(DMSO-d6,400MHz)δ8.34-8.35(m,1H),7.92(s,1H),7.88(s,1H),7.38(d,J＝2.0Hz,1H),6.14(d,J＝1.6Hz,1H),3.64(s,3H),1.40(s,9H),1.33(s,12H)。

The second step is that: reacting (R) -2- (2-bromo-4-oxo-4, 6-dihydro-5H-thieno [2, 3-c)]Pyrrol-5-yl) propionic acid methyl ester (100mg, 0.33mmol) was dissolved in methanol (5mL) and lithium hydroxide monohydrate (LiOH. H) was added₂O) (21mg, 0.49mmol) of an aqueous solution (1mL) was stirred at room temperature for 2 hours. Concentrating under reduced pressure, adding dichloromethane and water to dissolve, adjusting pH to 3 with 1M hydrochloric acid, shaking, separating organic phase, drying, and concentrating to obtain (R) -2- (2-bromo-4-oxo-4, 6-dihydro-5H-thieno [2, 3-c)]Pyrrol-5-yl) propionic acid (70mg, white solid). LC-MS ESI [ M + H ]]+＝290.1/292.1；¹H-NMR(DMSO-d6,400MHz)δ7.40(s,1H),4.70(q,J＝7.2Hz,1H),4.53(s,2H),1.45(d,J＝7.2Hz,3H)。

The third step: reacting (R) -2- (2-bromo-4-oxo-4, 6-dihydro-5H-thieno [2, 3-c)]Pyrrol-5-yl) propionic acid (70mg, 0.24mmol) was dissolved in N, N-Dimethylformamide (DMF) (10mL), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (184mg, 0.48mmol) and N, N-Diisopropylethylamine (DIEA) (125mg, 0.97mmol) were added, stirred for 5 minutes, (S) -2-amino-2- (3-chlorophenyl) ethyl-1-ol (45mg, 0.26mmol) was added, and the reaction was allowed to proceed at room temperature for 1 hour. Diluting with ethyl acetate, washing with saturated saline water, drying, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain (R) -2- (2-bromo-4-oxo-4, 6-dihydro-5H-thieno [2, 3-c)]Azole compounds-5-yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide (90mg, white solid). LC-MS ESI [ M + H ]]+＝443.1/445.1；¹H-NMR(CDCl3,400MHz)δ7.89(d,J＝7.6Hz,1H),7.33(s,1H),7.11-7.24(m,3H),4.99-5.04(m,2H),4.82(d,J＝18.4Hz,1H),4.46(d,J＝18.4Hz,1H),3.70-3.86(m,3H),1.49(d,J＝7.2Hz,3H)。

The fourth step: reacting (R) -2- (2-bromo-4-oxo-4, 6-dihydro-5H-thieno [2, 3-c)]Pyrrol-5-yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide (40mg, 0.09mmol) and tert-butyl (1-methyl-1H-pyrazol-5-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxan-2-yl) pyridin-2-yl) carbamate (72mg) were dissolved in ethanol (4mL), water (0.1mL), sodium carbonate (19mg, 0.18mmol) and Pd (PPh) were added₃₎₂Cl₂(13mg, 0.018mmol), nitrogen replaced, heated to 80 ℃ for 2 hours and LCMS showed complete reaction. Cooling the reaction solution to room temperature, filtering, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain (4- (5- ((R) -1- (((S) -1- (3-chlorphenyl) -2-hydroxyethyl) amino) -1-oxopropane-2-yl) -4-oxo-5, 6-dihydro-4H-thieno [2, 3-c)]Pyrrol-2-yl) pyridin-2-yl) (1-methyl-1H-pyrazol-5-yl) carbamic acid tert-butyl ester (45mg, yellow solid). LC-MS ESI (M + H) 636.9;¹H-NMR(DMSO-d6,400MHz)δ8.61(d,J＝8.0Hz,1H),8.33(d,J＝5.2Hz,1H),7.99-8.02(m,2H),7.61(d,J＝5.2Hz,1H),7.26-7.40(m,5H),6.19(d,J＝1.6Hz,1H),4.80-4.97(m,4H),4.64-4.68(m,1H),3.68(s,3H),3.55-3.58(m,2H),1.43(s,9H),1.40(d,J＝7.2Hz,3H)。

the fifth step: mixing (4- (5- ((R) -1- (((S) -1- (3-chlorophenyl) -2-hydroxyethyl) amino) -1-oxopropan-2-yl) -4-oxo-5, 6-dihydro-4H-thieno [2, 3-c)]Pyrrol-2-yl) pyridin-2-yl) (1-methyl-1H-pyrazol-5-yl) carbamic acid tert-butyl ester (40mg, 0.063mmol) was dissolved in anhydrous dichloromethane (5mL), trifluoroacetic acid (TFA) (1mL) was added dropwise, the reaction was performed at room temperature for 1 hour, and the reaction solution was concentrated at room temperature to obtain a residue which was preparative purified to give (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-4, 6-dihydro-5H-thiophene [2,3-c ] -3-c]Pyrrol-5-yl) propionamide (21mg, white solid). LC-MS ESI (M + H) 537.1.¹H-NMR(DMSO-d6,400MHz)δ8.89(br s,1H),8.58(d,J＝8.0Hz,1H),8.13(d,J＝5.6Hz,1H),7.79(s,1H),7.26-7.38(m,5H),7.17(dd,J＝1.6,5.2Hz,1H),7.00(d,J＝1.2Hz,1H),6.26(d,J＝2.0Hz,1H),4.61-4.95(m,5H),3.68(s,3H),3.56(t,J＝6.0Hz,2H),1.39(d,J＝7.2Hz,3H)。

Example 2: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propanamide

The first step is as follows: reacting (R) -2- (4-oxo-4, 6-dihydro-5H-thieno [2, 3-c)]Pyrrol-5-yl) propionic acid tert-butyl ester (1.0g,3.8mmol), Diphanolanyl borate (B)₂pin₂) (531mg,2.1mmol), 4, 4-di-tert-butylbipyridine (dtbpy) (20mg,0.076mmol) and 1, 5-cyclooctadienemethoxyiridium [ Ir (cod) OMe]2(25mg,0.038mmol) was dissolved in Tetrahydrofuran (THF) (20mL), purged with nitrogen for 10 min and heated to 80 ℃ under nitrogen overnight. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to give (R) -2- (4-oxo-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxan-2-yl) -4, 6-dihydro-5H-thieno [2,3-c ]]Pyrrol-5-yl) propionic acid tert-butyl ester (1.4g, red oil) was used directly in the next reaction. LC-MS ESI [ M + H ]]⁺＝394.2。

The second step is that: mixing (R) -2- (4-oxo-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxan-2-yl) -4, 6-dihydro-5H-thieno [2,3-c ]]Pyrrol-5-yl) propionic acid tert-butyl ester (800mg, crude) and 2, 4-dichloro-5-methylpyrimidine (470mg,2.9mmol) were dissolved in 1, 4-dioxane (10mL), water (1mL), sodium carbonate (Na)₂CO₃) (604mg, 5.7mmol) and Tetratriphenylphosphine Palladium (Pd (PPh)₃)₄) (110mg,0.1mmol), nitrogen displacement, heating to 90 ℃ for 4 hours, LCMS detection shows reaction completion. Cooling the reaction solution to room temperature, filtering, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain (R) -2- (2- (2-chloro-5-methylpyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2, 3-c)]Pyrrol-5-yl) propionic acid tert-butyl ester (230mg, white solid). LC-MS ESI [ M + H ]]⁺＝394.1。

The third step: mixing (R) -2- (2- (2-chloro-5-methylpyrimidine)Pyridin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c]Pyrrol-5-yl) propionic acid tert-butyl ester (204mg,0.52mmol), 1-methyl-1H-pyrazol-5-amine (55mg,0.57mmol), cesium Carbonate (CS)₂CO₃) (254mg,0.78mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos) (60mg,0.1mmol) and dipalladium tris (dibenzylideneacetone) (Pd)₂(dba)₃) (48mg,0.05mmol) was dissolved in 1, 4-dioxane (6mL) and heated to 100 ℃ under nitrogen for overnight reaction. Cooling the reaction solution to room temperature, filtering, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain (R) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidine-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2, 3-c)]Pyrrol-5-yl) propionic acid tert-butyl ester (90mg, red oil). LC-MS: ESI (M + H) 455.2.

The fourth step: dissolving tert-butyl (R) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propionate (90mg,0.2mmol) in anhydrous dichloromethane (2mL), adding TFA (1mL) dropwise, reacting at room temperature for 1 hour, concentrating under reduced pressure to obtain (R) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propionic acid (yellow solid) was used directly in the next reaction. LC-MS: ESI (M + H) 399.2.

The fifth step: (R) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propionic acid (110mg, crude) was dissolved in DMF (2mL), HATU (160mg,0.42mmol) and Triethylamine (TEA) (85mg,0.84mmol) were added, and after stirring for 5 minutes, (S) -2-amino-2- (3-chlorophenyl) ethyl-1-ol (44mg,0.25mmol) was added, and the reaction was carried out at room temperature for 1 hour. Concentration under reduced pressure and preparative purification of the residue yielded (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propionamide (23mg, white solid). LC-MS: ESI (M + H) 552.3.

Example 3: (2R) -N- (2-hydroxy-1- (m-toluene) ethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propanamide

Example 3, LC-MS: ESI (M + H)530.5, was synthesized by the same procedure as in example 1.

Example 4: (2R) -N- (1- (3, 4-difluorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propionamide

Example 4, LC-MS: ESI (M + H)553.2, was synthesized by the same procedure as in example 1.

Example 5: (2R) -N- (1- (3, 4-difluorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propanamide

Example 5, LC-MS: ESI (M + H)554.2, was synthesized by the same procedure as in example 2.

Example 6: (2R) -N- (2-hydroxy-1- (6-methylpyridin-2-yl) ethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propionamide

Example 6, LC-MS: ESI (M + H)532.1, was synthesized in the same manner as in example 1.

Example 7: (R) -N- ((S) -2-hydroxy-1- (6-methylpyridin-2-yl) ethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propanamide

Example 7, LC-MS: ESI (M + H)532.2, was synthesized by the same procedure as in example 1.

Example 8: (2R) -2- (2- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) -N- (1- (3, 4-difluorophenyl) -2-hydroxyethyl) propionamide

Example 8, LC-MS: ESI (M + H)574.1, was synthesized by the same procedure as in example 2.

Example 9: (2R) -2- (2- (5-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) -N- (2-hydroxy-1- (m-toluene) ethyl) propanamide

Synthesis of example 9, LC-MS: ESI (M + H)535.2, was carried out in the same manner as in example 1.

Example 10: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide

The first step is as follows: tert-butyl (2- ((tert-butoxycarbonyl) (1-methyl-1H-pyrazol-5-yl) amino) -5-methylpyridin-4-yl) borate (580mg, 1.75mmol), (R) -2- (2-bromo-4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionate (600mg, 1.75mmol) was dissolved in dioxane/water (20mL/4mL), Pd (PPh3)4(92.4mg, 0.08mmol) and Cs2CO3(1.15g, 3.5mmol) were added, and the mixture was heated to 90 degrees and reacted for 18 hours. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give tert-butyl (R) -2- (2- (2- ((tert-butoxycarbonyl) (1-methyl-1H-pyrazol-5-yl) amino) -5-methylpyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionate (530mg, white solid). LC-MS: ESI [ M + H ] + ═ 552.3.

The second step is that: tert-butyl (R) -2- (2- (2- ((tert-butoxycarbonyl) (1-methyl-1H-pyrazol-5-yl) amino) -5-methylpyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionate (530mg, 0.96mmol) was dissolved in dichloromethane (40mL), and trifluoroacetic acid (10mL) was added to react at room temperature for 18H. Concentrating under reduced pressure, and purifying the residue by column chromatography to obtain (R) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridine-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridine-5 (4H) -yl) propionic acid (white solid). LC-MS: ESI [ M + H ] + -396.2.

The third step: mixing (R) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridine-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid (50mg, 0.12mmol) and (S) -2-amino-2- (3-chlorophenyl) ethyl-1-ol (23mg, 0.13mmol) were dissolved in DMF (20mL), HATU (136.8mg, 0.36mmol) and DIEA (31mg, 0.24mmol) were added and reacted at room temperature for 18H. Concentrating under reduced pressure, and purifying the residue by column chromatography to obtain (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridine-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionamide (5.2mg, white solid). LC-MS: ESI (M + H) 549.5.¹H-NMR(CD₃OD,400MHz)δ7.85(s,1H),7.33(d,J＝2.0Hz,1H),7.29(s,1H),7.14-7.23(m,3H),7.00(s,1H),6.92(s,1H),6.11(d,J＝2.0Hz,1H),5.17-5.23(m,1H),4.86-4.89(m,1H),3.61-3.70(m,7H),3.06-3.12(m,1H),2.91-2.97(m,1H),2.26(s,1H),1.32(d,J＝7.2Hz,3H)。

Example 11: (2R) -N- (1- (3, 4-difluorophenyl) -2-hydroxyethyl) -2- (2- (2- (isopropylamino) -5-methylpyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propanamide

Example 11, LC-MS: ESI (M + H)516.2, was synthesized by the same procedure as example 2.

Example 12: (2R) -N- (1- (3, 4-difluorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propanamide

Example 12, LC-MS: ESI (M + H)558.2, was synthesized using the same procedure as example 2.

Example 13: (2R) -N- (2-hydroxy-1- (m-toluene) ethyl) -2- (2- (5-methyl-2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propanamide

Example 13, LC-MS: ESI (M + H)536.4, was synthesized by the same procedure as in example 2.

Example 14: (2R) -N- (1- (3, 4-difluorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((2-methylpyridin-4-yl) amino) pyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propionamide

Example 14, LC-MS: ESI (M + H)565.3, was synthesized by the same procedure as in example 2.

Example 15: (2R) -2- (2- (2- ((1-fluoropropan-2-yl) amino) -5-methylpyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) -N- (2-hydroxy-1- (6-methylpyridin-2-yl) ethyl) propanamide

Example 15, LC-MS: ESI (M + H)513.2, was synthesized using the same procedure as example 2.

Example 16: (2R) -N- (1- (4-chloro-3-fluorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propanamide

Example 16, LC-MS: ESI (M + H)574.2, was synthesized by the same procedure as in example 2.

Example 17: (R) -N- ((S) -1- (3, 4-difluorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propanamide

Example 17, LC-MS: ESI (M + H)558.2, was synthesized by the same procedure as in example 2.

Example 18: (2R) -N- (1- (3, 4-difluorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-pyrrolo [3,4-d ] thiazol-5-yl) propanamide

Example 18, LC-MS: ESI (M + H)559.2, was synthesized by the same procedure as in example 2.

Example 19: (2R) -N- (2-hydroxy-1- (m-toluene) ethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propanamide

Example 19, LC-MS: ESI (M + H)532.2, was synthesized using the same procedure as example 2.

Example 20: (R) -N- ((R) -1- (3-3-chlorophenyl) ethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propionamide

Synthesized by the same method as in example 1, LC-MS: ESI (M + H) 521.3.¹H-NMR(CD₃OD,400MHz)δ8.00(d,J＝6.4Hz,1H),7.96(s,1H),7.69(s,1H),7.50(d,J＝6.8Hz,1H),7.40(s,1H),7.16-7.29(m,4H),6.52(d,J＝2.0Hz,1H),4.73-4.98(m,4H),3.85(s,3H),1.58(d,J＝7.6Hz,3H),1.46(d,J＝7.2Hz,3H)。

Example 21: n- ((6- (dimethylamino) pyridin-2-yl) methyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propionamide

Synthesized by the same method as in example 1, LC-MS: ESI (M + H) 517.4.¹H-NMR(CD₃OD,400MHz)δ8.04(d,J＝6.4Hz,1H),7.89-7.93(m,2H),7.63(d,J＝1.6Hz,1H),7.42(dd,J＝1.6,6.8Hz,1H),7.28(s,1H),7.13(d,J＝9.2Hz,1H),6.83(d,J＝6.8Hz,1H),6.45(d,J＝2.0Hz,1H),4.78-4.90(m,2H),4.45-4.60(m,2H),3.82(s,3H),3.71-3.74(m,1H),3.28(s,6H),1.64(d,J＝7.2Hz,3H)。

Example 22: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propanamide

Synthesized by the same method as in example 1, LC-MS: ESI (M + H) 551.4.¹H-NMR(CD₃OD,400MHz)δ8.23(s,1H),7.77(s,1H),7.63(d,J＝2.4Hz,1H),7.25-7.38(m,4H),6.83(s,1H),6.41(d,J＝2.0Hz,1H),4.70-5.00(m,4H),3.78(s,3H),3.71-3.75(m,2H),2.43(s,3H),1.54(d,J＝7.2Hz,3H)。

Example 23: (R) -N- ((6- (dimethylamino) pyridin-2-yl) methyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide

Synthesized by the same method as in example 10, LC-MS: ESI (M + H) 515.5.¹H-NMR(DMSO-d6,400MHz)δ9.52(br s,1H),8.63(t,J＝5.6Hz,1H),8.12(d,J＝6.0Hz,1H),7.82(t,J＝8.0Hz,1H),7.61(s,1H),7.47(d,J＝2.0Hz,1H),7.29(d,J＝5.6Hz,1H),7.13(s,1H),6.98(d,J＝8.4Hz,1H),6.67(d,J＝7.2Hz,1H),6.34(d,J＝2.0Hz,1H),5.07-5.09(m,1H),4.38-4.40(m,2H),3.68-3.71(m,5H),3.18(s,6H),3.12(t,J＝7.2Hz,2H),1.38(d,J＝7.2Hz,3H)。

Example 24: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide

Synthesized by the same method as in example 10, LC-MS: ESI (M + H) 535.5.¹H-NMR(CD₃OD,400MHz)δ8.06-8.09(m,1H),7.46(s,1H),7.24-7.37(m,5H),7.10(d,J＝6.8Hz,1H),6.99(s,1H),6.24(d,J＝1.6Hz,1H),5.26-5.28(m,1H),4.92-4.97(m,1H),3.69-3.80(m,7H),3.04-3.21(m,2H),1.43(d,J＝7.2Hz,3H)。

Example 25: (2R) -N- (1- (3, 4-difluorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide

Example 10, LC-MS: ESI (M + H)551.1, was synthesized in the same manner as in example 10.

Example 26: (R) -N- ((6- (dimethylamino) pyridin-2-yl) methyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide

Synthesized by the same method as in example 10, LC-MS: ESI (M + H) 529.4.¹H-NMR(DMSO-d6,400MHz)δ8.76(s,1H),8.33-8.37(m,1H),8.04(s,1H),7.44(t,J＝7.6Hz,1H),7.31(d,J＝5.6Hz,1H),7.13(s,1H),7.07(s,1H),6.46(t,J＝8.4Hz,2H),6.24(s,1H),5.14-5.19(m,1H),4.21(d,J＝6.0Hz,2H),3.63-3.70(m,5H),3.00-3.10(m,2H),2.98(s,6H),2.38(s,3H),1.37(d,J＝7.2Hz,3H)。

Example 27: (S) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide

Synthesized by the same method as in example 10, LC-MS: ESI (M + H) 535.5.¹H-NMR(CD₃OD,400MHz)δ8.06-8.09(m,1H),7.42-7.46(m,1H),7.22-7.33(m,5H),7.10(d,J＝7.2Hz,1H),6.99(s,1H),6.24(d,J＝2.0Hz,1H),5.26-5.31(m,1H),4.92-4.97(m,1H),3.58-3.79(m,7H),2.94-3.13(m,2H),1.45(d,J＝7.2Hz,3H)。

Example 28: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (4-oxo-2- (2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanamide

The first step is as follows: mixing (R) -2- (2-bromo-4-oxo-6, 7-dihydrofuro [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid tert-butyl ester (1.0g, 3.3mmol) and tributyl (1-ethoxyvinyl) stannane (1.4g, 4.0mmol) were dissolved in DMF (20mL) and Pd (PPh) was added₃)₂Cl₂(230mg, 0.3mmol), nitrogen substitution, heating to 115 ℃ for reaction for 4 hours, cooling to room temperature, pouring into an aqueous solution of potassium fluoride, extracting with ethyl acetate, concentrating under reduced pressure, dissolving the residue in tetrahydrofuran, adding 2M dilute hydrochloric acid, and stirring at room temperature for 1 hour. Concentrating under reduced pressure, and purifying the residue by column chromatography to obtain compound (R) -2- (2-acetyl-4-oxo-6, 7-dihydrofuro [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid (0.59g, white solid). LC-MS ESI [ M + H ]]⁺＝252.1。

The second step is that: mixing (R) -2- (2-acetyl-4-oxo-6, 7-dihydrofuro [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid (0.59g, 2.4mmol) was dissolved in DMF (5mL) and HATU (1.8g, 4.8mmol) and DIEA (0) were added93g, 7.2mmol), stirred at room temperature for 5 minutes, and then (S) -2-amino-2- (3-chlorophenyl) ethyl-1-ol (0.48g, 2.8mmol) was added and reacted at room temperature for 1 hour. Diluting with ethyl acetate, washing with saturated saline, drying, concentrating, and purifying by column chromatography to obtain compound (R) -2- (2-acetyl-4-oxo-6, 7-dihydrofuro [3, 2-c)]Pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide (0.85g, white solid). LC-MS ESI [ M + H ]]⁺＝405.1。

The third step: mixing (R) -2- (2-acetyl-4-oxo-6, 7-dihydrofuro [3, 2-c)]Pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide (670mg, 1.7mmol) was dissolved in N, N-dimethylformamide dimethyl acetal (5mL), heated to 100 ℃ for 2 hours, concentrated under reduced pressure, and the residue was purified by column chromatography to give the compound (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (3- (dimethylamino) acryloyl) -4-oxo-6, 7-dihydrofuro [3,2-c ]]Pyridin-5 (4H) -yl) propionamide (380mg, yellow solid). LC-MS ESI [ M + H ]]⁺＝460.3。

The fourth step: mixing (R) -N- ((S) -1- (3-chlorphenyl) -2-hydroxyethyl) -2- (2- (3- (dimethylamino) acryloyl) -4-oxo-6, 7-dihydrofuro [3, 2-c)]Pyridin-5 (4H) -yl) propionamide (30mg, 0.07mmol) and 1- (tetrahydro-2H-pyran-4-yl) guanidine (11.2mg, 0.08mmol) were dissolved in DMF (3mL) and K was added₂CO₃(18mg, 0.13mmol), nitrogen substitution, heating to 90 ℃ for reaction overnight, cooling to room temperature, filtering, concentrating under reduced pressure, and column chromatography purification of the residue to give the compound (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (4-oxo-2- (2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -6, 7-dihydrofuran [3,2-c]Pyridin-5 (4H) -yl) propionamide (5mg, yellow solid). LC-MS: ESI (M + H) 540.5.¹H-NMR(CDCl₃,400MHz)δ8.28(d,J＝5.2Hz,1H),7.42(br s,1H),7.19-7.31(m,5H),6.81(d,J＝5.2Hz,1H),5.29-5.34(m,1H),5.02-5.07(m,1H),4.00-4.10(m,3H),3.72-3.90(m,4H),3.54-3.60(m,2H),3.03-3.18(m,2H),2.02-2.07(m,2H),1.57-1.72(m,2H),1.44(d,J＝7.2Hz,3H)。

Example 29: (R) -2- (2- (5-chloro-2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide

The procedure is as in example 28, LC-MS: ESI (M + H) 574.4.¹H-NMR(CD₃OD,400MHz)δ8.29(s,1H),7.74(s,1H),7.35-7.38(m,4H),5.27-5.32(m,1H),4.95-4.98(m,1H),3.96-4.06(m,3H),3.70-3.81(m,4H),3.52-3.57(m,2H),3.07-3.30(m,2H),1.98-2.01(m,2H),1.55-1.68(m,2H),1.43(d,J＝7.2Hz,3H)。

Example 30: (S) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide

Synthesized by the same method as in example 1, LC-MS: ESI (M + H) 549.3.¹H-NMR(CD₃OD,400MHz)δ7.95(s,1H),7.44(d,J＝2.0Hz,1H),7.23-7.32(m,4H),7.14(s,1H),7.07(s,1H),6.21(d,J＝1.6Hz,1H),5.29-5.32(m,1H),4.94-4.99(m,1H),3.58-3.80(m,8H),2.98-3.04(m,1H),2.39(s,3H),1.45(d,J＝6.8Hz,3H)。

Example 31: (R) -2- (2- (5-chloro-2- (isopropylamino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide

The operation is as in example 28, LC-MS: ESI (M + H) 532.4.¹H-NMR(CD₃OD,400MHz)δ8.27(s,1H),7.74(s,1H),7.25-7.38(m,4H),5.27-5.32(m,1H),4.88-4.98(m,1H),4.11-4.14(m,1H),3.70-3.81(m,4H),3.07-3.26(m,2H),1.43(d,J＝7.2Hz,3H),1.23(d,J＝6.4Hz,6H)。

Example 32: (R) -2- (2- (5-chloro-2- ((1, 3-dihydroxypropyl-2-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide

In operation as in example 28, LC-MS ESI (M + H) 564.4;¹H-NMR(CD₃OD,400MHz)δ：8.30(s,1H),7.75(s,1H),7.24-7.39(m,4H),5.27-5.34(m,1H),4.96-4.99(m,1H),4.09-4.14(m,1H),3.71-3.81(m,8H),3.05-3.31(m,2H),1.42(d,J＝7.2Hz,3H)。

example 33: (R) -N- ((S) -2-hydroxy-1- (m-tolyl) ethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide

Synthesized by the same method as in example 1, LC-MS: ESI (M + H) 529.4;¹H-NMR(CD₃OD,400MHz)δ：8.76(s,1H),8.30(d,J＝8.0Hz,1H),8.05(s,1H),7.33(s,1H),7.03-7.21(m,6H),6.25(s,1H),5.17-5.19(m,1H),4.82-4.85(m,2H),3.55-3.72(m,7H),3.05-3.18(m,2H),2.35(s,3H),2.29(s,3H),1.29(d,J＝6.8Hz,3H)。

example 34: (R) -N- ((S) -1- (3-chloro-4-fluorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide

Synthesized by the same method as in example 1, LC-MS: ESI (M + H) 567.4;¹H-NMR(CD₃OD,400MHz)δ：7.98(s,1H),7.43-7.49(m,2H),7.23-7.26(m,1H),7.20(t,J＝8.8Hz,1H),7.13(s,1H),7.07(s,1H),6.21(d,J＝1.6Hz,1H),5.22-5.28(m,1H),4.92-4.97(m,1H),3.72-3.78(m,7H),3.02-3.22(m,2H),2.40(s,3H),1.43(d,J＝7.2Hz,3H)。

example 35: (2R) -2- (2- (5-chloro-2- ((1-hydroxypropyl-2-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide

In operation as in example 28, LC-MS ESI (M + H) 548.4;¹H-NMR(CD₃OD,400MHz)δ：8.25(s,1H),7.70(d,J＝2.8Hz,1H),7.40(s,1H),7.24-7.33(m,3H),5.28-5.34(m,1H),4.96-5.00(m,1H),4.09-4.11(m,1H),3.72-3.80(m,4H),3.55-3.64(m,2H),3.03-3.31(m,2H),1.41(d,J＝7.2Hz,3H),1.24(d,J＝6.8Hz,3H)。

example 36: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanamide

The first step is as follows: tert-butyl (R) -2- (4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionate (1g,3.8mmol), B2pin2(531mg,2.1mmol), dtbpy (20mg,0.076mmol) and [ Ir (cod) OMe ]2(25mg,0.038mmol) were dissolved in THF (20mL), replaced with nitrogen for 10 min and heated to 80 ℃ under nitrogen for overnight reaction. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to give tert-butyl (R) -2- (4-oxo-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxan-2-yl) -6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionate (1.5g, red oil) which was used as it was in the next reaction. LC-MS: ESI [ M + H ] + ═ 392.2.

The second step is that: tert-butyl (R) -2- (4-oxo-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxan-2-yl) -6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanoate (750mg, crude) and 2, 4-dichloropyrimidine (425mg,2.9mmol) were dissolved in 1, 4-dioxane (10mL), water (1mL), sodium carbonate (604mg, 5.7mmol) and Pd (PPh3)4(110mg,0.1mmol) were added, the reaction was allowed to react for 4 hours under nitrogen displacement and heating to 90 degrees, and LCMS showed completion of the reaction. The reaction mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give tert-butyl (R) -2- (2- (2-chloropyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionate (225mg, white solid). LC-MS: ESI [ M + H ] + ═ 378.4.

The third step: tert-butyl (R) -2- (2- (2-chloropyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanoate (195mg,0.52mmol), 1-methyl-1H-pyrazol-5-amine (55mg,0.57mmol), CS2CO3(254mg,0.78mmol), Xantphos (60mg,0.1mmol) and Pd2(dba)3(48mg,0.05mmol) were dissolved in 1, 4-dioxane (6mL), displaced with nitrogen for 10 minutes and heated to 100 ℃ under nitrogen atmosphere for overnight reaction. The reaction was cooled to room temperature, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give tert-butyl (R) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionate (93mg, red oil). LC-MS: ESI (M + H) 439.0.

The fourth step: tert-butyl (R) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanoate (93mg,0.21mmol) was dissolved in anhydrous dichloromethane (2mL), TFA (1mL) was added dropwise, reaction was carried out at room temperature for 1 hour, and concentration under reduced pressure was carried out to give (R) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanoic acid (yellow solid), directly used for the next reaction. LC-MS ESI (M + H) 383.0.

The fifth step: reacting (R) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionic acid (105mg, crude) was dissolved in DMF (1mL), HATU (160mg,0.42mmol) and TEA (85mg,0.84mmol) were added, stirred at room temperature for 5 minutes, and (S) -2-amino-2- (3-chlorophenyl) ethyl-1-ol (44mg,0.25mmol) was added and reacted at room temperature for 1 hour. Concentrating under reduced pressure, and purifying the residue to obtain (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3, 2-c)]Pyridin-5 (4H) -yl) propionamide (29.7mg, white solid). LC-MS ESI (M + H) 536.3;¹H-NMR(CD₃OD,400MHz)δ：8.42(d,J＝5.2Hz,1H),7.43-7.44(m,2H),7.38(s,1H),7.25-7.34(m,3H),7.13(d,J＝5.6Hz,1H),6.35(d,J＝2.0Hz,1H),5.26-5.32(m,1H),4.95-4.99(m,1H),3.70-3.81(m,7H),3.03-3.26(m,2H),1.42(d,J＝7.2Hz,3H)。

example 37: (R) -2- (2- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide

Synthesized by the same method as in example 36, LC-MS: ESI (M + H) 569.9;¹H-NMR(CD₃OD,400MHz)δ：8.38(s,1H),7.75(m,1H),7.54(d,J＝2.4Hz,1H),7.43(s,1H),7.25-7.32(m,3H),6.58(d,J＝2.0Hz,1H),5.32-5.35(m,1H),4.95-5.01(m,1H),3.74-3.82(m,7H),3.30-3.36(m,1H),3.02-3.07(m,1H),1.40(d,J＝7.2Hz,3H)。

example 38: (R) -2- (2- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) -N- ((S) -2-hydroxy-1- (m-methylphenyl) ethyl) propionamide

Synthesized by the same method as in example 36, LC-MS: ESI (M + H) 550.4.

Example 39: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanamide

Synthesized by the same method as in example 36, LC-MS: ESI (M + H) 550.4;¹H-NMR(CD₃OD,400MHz)δ：8.34(s,1H),7.77(s,1H),7.48(s,1H),7.39(s,1H),7.25-7.34(m,3H),6.78(s,1H),5.28-5.33(m,1H),4.86-5.00(m,1H),3.88(s,3H),3.72-3.83(m,4H),3.21-3.31(m,1H),3.07-3.12(m,1H),2.44(s,3H),1.43(d,J＝7.2Hz,3H)。

example 40: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (5-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanamide

The same procedure as in example 36 was adoptedSynthesis, LC-MS: ESI (M + H) 554.0;¹H-NMR(CD₃OD,400MHz)δ：8.42(d,J＝3.2Hz,1H),7.58(d,J＝2.4Hz,1H),7.49(d,J＝2.4Hz,1H),7.40(s,1H),7.25-7.32(m,3H),6.59(d,J＝2.4Hz,1H),5.30-5.32(m,1H),4.96-5.00(m,1H),3.72-3.83(m,7H),3.06-3.31(m,2H),1.42(d,J＝7.2Hz,3H)。

example 41: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (5-cyano-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanamide

Synthesized by the same method as in example 36, LC-MS: ESI (M + H) 561.2.

Example 42: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide

Synthesized by the same method as in example 36, LC-MS: ESI (M + H) 604.2.

Example 43: (R) -2- (2- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -7, 7-dimethyl-4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) propionamide

Synthesized by the same method as in example 36, LC-MS: ESI (M + H) 598.4.

Example 44: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (3-fluoro-2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanamide

Synthesized by the same method as in example 36, LC-MS: ESI (M + H) 554.4.

Example 45: (R) -2- (2- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) -N- ((S) -1- (3-chloro-4-fluorophenyl) -2-hydroxyethyl) propionamide

Synthesized by the same method as in example 36, LC-MS: ESI (M + H) 588.3.

Example 46: (R) -N- ((S) -1- (3-chloro-4-fluorophenyl) -2-hydroxyethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanamide

Synthesized by the same method as in example 36, LC-MS: ESI (M + H) 554.2.

Example 47: (R) -N- ((S) -2-hydroxy-1- (m-toluene) ethyl) -2- (2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanamide

Synthesized by the same method as in example 36, LC-MS: ESI (M + H) 516.2.

Example 48: (R) -N- ((S) -2-hydroxy-1- (m-toluene) ethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanamide

Synthesized by the same method as in example 36, LC-MS: ESI (M + H) 530.2.

Example 49: (R) -N- ((S) -1- (3-chloro-4-fluorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide

Synthesized by the same method as in example 36, LC-MS: ESI (M + H) 568.1.

Example 50: (R) -N- ((S) -1- (3, 5-difluorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide

Synthesized by the same method as in example 36, LC-MS: ESI (M + H) 552.2.

Example 51: (R) -N- ((S) -1- (3-chloro-4-fluorophenyl) -2-hydroxyethyl) -2- (2- (5-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propionamide

Synthesized by the same method as in example 36, LC-MS: ESI (M + H) 572.2.¹H-NMR(CD₃OD,400MHz)δ：8.42(d,J＝3.2Hz,1H),7.58(d,J＝2.4Hz,1H),7.49(d,J＝2.4Hz,1H),7.43(d,J＝2.0Hz,1H),7.18-7.32(m,2H),6.59(d,J＝2.4Hz,1H),5.30-5.32(m,1H),4.96-5.00(m,1H),3.72-3.83(m,7H),3.06-3.31(m,2H),1.42(d,J＝7.2Hz,3H)。

Example 52: (R) -2- (2- (5-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) -N- ((S) -2-hydroxy-1- (m-methylphenyl) ethyl) propionamide

Synthesized by the same method as in example 36, LC-MS: ESI (M + H) 534.2.¹H-NMR(CD₃OD,400MHz)δ：8.42(d,J＝3.2Hz,1H),7.58(d,J＝2.4Hz,1H),7.49(d,J＝2.4Hz,1H),7.03-7.21(m,4H),6.59(d,J＝2.4Hz,1H),5.30-5.32(m,1H),4.96-5.00(m,1H),3.72-3.83(m,7H),3.06-3.31(m,2H),2.31(s,3H),1.42(d,J＝7.2Hz,3H)。

Example 53: (R) -N- ((S) -1- (3, 5-difluorophenyl) -2-hydroxyethyl) -2- (2- (5-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -4-oxo-6, 7-dihydrofuran [3,2-c ] pyridin-5 (4H) -yl) propanamide

Synthesized by the same method as in example 36, LC-MS: ESI (M + H) 556.2.¹H-NMR(CD₃OD,400MHz)δ：8.42(d,J＝3.2Hz,1H),7.58(d,J＝2.4Hz,1H),7.49(d,J＝2.4Hz,1H),6.65-6.74(m,3H),6.59(d,J＝2.4Hz,1H),5.30-5.32(m,1H),4.96-5.00(m,1H),3.72-3.83(m,7H),3.06-3.31(m,2H),1.42(d,J＝7.2Hz,3H)。

Example 54: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (2- ((1-m-ethyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -6-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propionamide

The first step is as follows: tert-butyl (R) -2- (2-bromo-6-oxo-4, 6-dihydro-5H-thieno [2, 3-c)]Pyrrol-5-yl) propionate (214mg) was dissolved in dichloromethane (5mL), followed by addition of TFA (0.5mL), stirring for 3h, concentration, and removal of TFA to give a white solid (166 mg). LC-MS [ M + H ]]⁺:m/z 290.0/292.0。

The second step is that: the above intermediate (166mg,0.572mmol) and amino alcohol starting material (117.5mg,0.687mmol) were dissolved in DMF (7mL) and HATU (434.7mg,1.14mmol) and DIEA (297.2mg,2.29mmol) were added and stirred for 16 h. After the reaction was completed, it was poured into 20mL of water and extracted with ethyl acetate (50mL × 3), washed with saturated brine, dried, and concentrated by column chromatography to give a gray solid (240 mg). LC-MS [ M + H ]]⁺:m/z 445.0；¹H NMR(400MHz,DMSO-d6)δ8.59(d,1H),7.47(s,1H),7.37-7.25(m,4H),4.95(t,1H),4.89-4.76(m,2H),4.62(d,1H),4.45(d,1H),3.55(t,2H),1.37(d,3H)。

The third step: the above grey solid (100mg,0.226mmol) and tert-butyl (1-methyl-1H-pyrazol-5-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) carbamate (153.5mg,0.384mmol) were dissolved in dioxane/water (4mL/0.4mL), protected with nitrogen, and Pd (PPh) was added₃)Cl₂(7.93mg,0.0113mmol) and Na₂CO₃(71.87mg,0.678mmol), 90 ℃ overnight, poured into 100mL water and extracted with ethyl acetate (50mL x 3), washed with saturated brine and dried to give the crude product as a yellow solid (199 mg). LC-MS [ M + H ]]⁺:m/z 637.1。

The fourth step: the yellow solid (199mg) was dissolved in dichloromethane (5mL), TFA (1mL) was added, the mixture was stirred at room temperature for 3h, concentrated, and TFA was removed, and the resulting mixture was purified by preparative chromatography to give example 53 (yellow solid, 18.9 mg). LC-MS [ M + H ]]⁺:m/z 537.1。¹H NMR(400MHz,MeOD-d₄)δ8.12(d,1H),7.65(s,1H),7.45(d,1H),7.40-7.23(m,4H),7.13(dd,1H),7.02(s,1H),6.27(d,1H),4.98-4.92(m,2H),4.73(d,1H),4.56(d,1H),3.73-3.24(m,5H),1.54(d,3H)。

Example 55: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -6-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propionamide

The title compound, example 54, was synthesized in the same manner as in example 54. LC-MS [ M + H ]]⁺:m/z 551.1.¹H NMR(400MHz,MeOD-d₄)δ8.64(d,1H),8.01(s,1H),7.60(d,1H),7.53(s,1H),7.39-7.25(m,4H),7.13(s,1H),6.44(d,1H),5.05-4.91(m,2H),4.77(d,1H),4.60(d,1H),3.80(s,3H),3.77-3.71(m,2H),2.42(s,3H),1.56(d,3H)。

Examples 56-1 and 56-2: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (4, 4-dimethyl-2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -6-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propionamide and (S) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (4, 4-dimethyl-2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -6-oxo- 4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propanamide

The objective compounds, examples 56-1 and 56-2, were synthesized in the same manner as in example 54.

Yellow solid, LC-MS [ M + H ]]⁺:m/z 565.0.¹H NMR(400MHz,MeOD-d₄):δ8.06(d,1H),7.88(s,1H),7.63(s,1H),7.41(d,1H),7.36-7.17(m,5H),6.47(d,1H),5.09(q,1H),5.00(d,1H),3.85-3.73(m,5H),1.71(d,6H),1.64(d,3H)。

Yellow solid, LC-MS [ M + H ]]⁺:m/z 565.1.¹H NMR(400MHz,MeOD-d₄):δ8.07(d,1H),7.95-7.79(m,2H),7.61(s,1H),7.45-7.35(m,2H),7.35-7.25(m,4H),6.44(d,1H),5.15-5.04(m,1H),4.97(d,1H),3.86-3.66(m,5H),1.72(s,6H),1.67(d,3H)

Examples 57-1 and 57-2: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (4, 4-dimethyl-2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -6-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propionamide and (S) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (4, 4-dimethyl-2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridine- 4-yl) -6-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) propanamide

LC-MS[M+H]⁺:m/z 579.1.¹H NMR(400MHz,MeOD-d₄):δ8.02(s,1H),7.88(d,1H),7.62(s,1H),7.54(d,1H),7.36(s,1H),7.28(d,2H),7.23(d,1H),7.13(d,1H),6.45(d,1H),5.09(q,1H),5.01(d,1H),3.85-3.71(m,5H),1.72(d,6H),1.64(d,3H)

LC-MS[M+H]⁺:m/z 579.2.¹H NMR(400MHz,MeOD-d₄):δ8.02(s,1H),7.89(d,1H),7.61(s,1H),7.54(s,1H),7.42(s,1H),7.35-7.29(m,2H),7.25(d,1H),7.13(s,1H),6.45(d,1H),5.10(q,1H),5.02-4.93(m,1H),3.86-3.69(m,5H),1.72(d,6H),1.66(d,3H)

Example 58-example 62 were synthesized using the same procedure as example 1:

example 63: (S) -N- (1- (3-chlorophenyl) -2-hydroxyethyl) -2- (6, 6-dimethyl-2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) acetamide

The first step is as follows: 2-bromo-6, 6-dimethyl-5, 6-dihydro-4H-thieno [2, 3-c)]Pyrrol-4-one (900mg, 3.7mmol) was dissolved in THF (15mL), NaH 60% (191mg, 4.8mmol) was added under ice bath, stirred for 30 minutes under ice bath, t-butyl bromoacetate (936mg, 4.8mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. Ethyl acetate (50mL) was diluted, washed once with water, dried, concentrated and column chromatographed (EA/PE ═ 1/7) to give (white solid, 1.12 g). LC-MS [ M + H ]]⁺:m/z 360.3

The second step is that: the above white solid (1.05g, 3.5mmol) was dissolved in anhydrous dichloromethane (10mL), TFA (5mL) was added dropwise, reacted at room temperature for 2 hours, and concentrated to give (white solid, 1.0 g). LC-MS [ M + H ]]⁺:m/z 304.2

The third step: the above white solid compound (400mg, 1.3mmol) was dissolved in DMF (5mL), HATU (988mg, 1.6mmol) and DIEA (671mg, 5.2mmol) were added, stirred at room temperature for 5 minutes, and the amino alcohol starting material (274mg, 1.6mmol) was added and reacted at room temperature for 1 hourThen (c) is performed. Dilution with ethyl acetate, washing with saturated brine, drying, concentration, and column chromatography gave (white solid, 252 mg). LC-MS M/z 457.2[ M-H ]]^-。

The fourth step: mixing the above white solid compound (100mg,0.22 mmol), boric acid starting material (136mg, 0.33mmol), and Na₂CO₃(70mg，0.66mmol)，Pd(PPh₃)₂Cl₂(7.7mg, 0.01mmol) was dissolved in dioxane (4mL) and water (0.4mL), bubbled with nitrogen for 10 min, and heated to 90 ℃ under nitrogen blanket for overnight reaction. Filtration and concentration gave a crude red oil (360 mg). LC-MS [ M + H ]]+:m/z 665.6。

The fifth step: the crude compound (360mg, 0.22mmol) was dissolved in anhydrous dichloromethane (4mL), TFA (1mL) was added dropwise, and the reaction was carried out at room temperature for 1 hour to obtain example compound 62 (yellow solid, 61.3mg) after concentration at room temperature. LC-MS [ M + H ]]+:m/z 565.2；¹H NMR(400MHz,CD₃OD):δ7.99(s,1H),7.57-7.62(m,2H),7.40(s,1H),7.25-7.32(m,3H),7.15(s,1H),6.44(d,1H),4.98(t,1H),4.26(s,2H),3.72-3.82(m,5H),2.44(s,3H),1.61(s,3H),1.58(s,3H)。

EXAMPLE 64 (S) -N- (1- (3-chlorophenyl) -2-hydroxyethyl) -2- (6, 6-dimethyl-2- (2- ((1-methylethyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) acetamide

The title compound, example 64, was synthesized in the same manner as in example 63. LC-MS [ M + H ]]⁺:m/z 551.1.¹H NMR(400MHz,CD₃OD):δ8.03(d,1H),7.85(s,1H),7.60(s,1H),7.23-7.40(m,6H),6.42(d,1H),4.97(t,1H),4.25(s,2H),3.72-3.80(m,5H),1.61(s,3H),1.57(s,3H)。

Example 65: 6, 6-dimethyl-2- (2- ((1-m-ethyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -5- (1- (3- (trifluoromethyl) phenyl) ethyl) -5, 6-dihydro-4H-thieno [2,3-c ] pyrrol-4-one

The first step is as follows: dissolving 4-bromo-2- (trifluoromethyl) pyridine (5.0g,22.1mmol) in THF (50mL), cooling to 0 deg.C with ice bath, slowly adding isopropyl magnesium chloride tetrahydrofuran solution (18.7mL,24.3mmol,1.3mol/L), reacting at about 10 deg.C for 1.5 hr, cooling to 0 deg.C, adding acetaldehyde tetrahydrofuran solution (6.7mL,33.2mmol,5mol/L), reacting at room temperature for 1 hr, quenching with saturated ammonium chloride aqueous solution, extracting aqueous phase with ethyl acetate for 3 times, and MgSO (MgSO) extracting organic phase with MgSO₄Drying, filtration, spin-drying and column chromatography (PE/EA ═ 3:1) gave a colourless oil (4.11 g). LC-MS [ M + H ]]⁺:m/z 192.1。

The second step is that: the oil from the previous step (500mg,2.62mmol) was dissolved in DCM (10mL), cooled to 5 ℃ with an ice bath, TEA (397mg,3.93mmol) and methanesulfonyl chloride (360mg,3.14mmol) were added, reacted at room temperature for 1 hour, spun dry, the residue was dissolved in ethyl acetate, followed by saturated NaHCO₃Washing the aqueous solution with saturated brine, and washing the organic phase with MgSO₄Dried, filtered and spun-dried to give a dark red oil (570mg) which was used directly in the next reaction. LC-MS [ M + H ]]⁺:m/z 270.4。

The third step: dissolving the red oil (250mg,1.02mmol) in THF (5mL), cooling to 0-5 deg.C with ice bath, adding NaH (53mg,1.32mmol, 60% in oil), stirring at room temperature for 30min, cooling to 0-5 deg.C with ice bath, adding 2-bromo-6, 6-dimethyl-5, 6-dihydro-4H-thiophene [2,3-c ] -2]Pyrrol-4-one (355mg,1.32mmol) was then heated under reflux for 2 days, cooled, quenched with saturated aqueous ammonium chloride, extracted 3 times with ethyl acetate and the organic phase with MgSO 4₄Drying, filtration, spin-drying and column chromatography (PE/EA ═ 1:1) gave a white solid (320 mg). LC-MS [ M + H ]]⁺:m/z 421.3。¹H NMR(400MHz,CDCl₃):δ8.67(d,1H),7.72(s,1H),7.58(d,1H),7.19(s,1H),4.60-4.65(m,1H),1.94(d,3H),1.74(s,3H),1.52(s,3H)。

The fourth step: the white solid from the above step (80mg,0.19mmol) was dissolved in 1, 4-dioxane/water (H)₂O) (3ml/0.3ml), was added a borate compound (114mg,0.29mmol), Na₂CO₃(61mg,0.57mmol) under nitrogen protectionGas 3 times, then add Pd (PPh)₃)₂Cl₂(7mg,0.01mmol) and 3 air exchanges. Reacting at 90 ℃ overnight, cooling, filtering, washing a filter cake by EA, washing with water, separating liquid, drying an organic phase by anhydrous sodium sulfate, and concentrating to obtain a crude yellow solid (116mg), wherein the crude yellow solid is directly used for the next reaction. LC-MS [ M + H ]]⁺:m/z 612.8。

The fifth step: the crude product from the previous step (116mg,10.2mmol) was dissolved in DCM (4.5mL), TFA (1mL) was added, and the mixture was reacted at room temperature for 1.5h under nitrogen, concentrated and dried to afford the title compound (white solid, 25 mg). LC-MS [ M + H ]]⁺:m/z 513.1。¹H NMR(400MHz,MeOD-d₄):δ8.65(d,1H),8.11(d,1H),7.90(s,1H),7.73(d,1H),7.61(s,1H),7.45(d,1H),7.10(dd,1H),6.98(s,1H),6.26(d,1H),5.02(dd,1H),3.74(s,3H),1.93(d,3H),1.76(s,3H),1.62(s,3H)。

Example 66: 6, 6-dimethyl-2- (5-m-ethyl-2- ((1-m-ethyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -5- (1- (3- (trifluoromethyl) phenyl) ethyl) -5, 6-dihydro-4H-thieno [2,3-c ] pyrrol-4-one

The first step is as follows: 2-bromo-6, 6-dimethyl-5- (1- (3- (trifluoromethyl) phenyl) ethyl) -5, 6-dihydro-4H-thiophene [2, 3-c)]Pyrrol-4-one (80mg,0.19mmol) dissolved in dioxane/H₂To O (3ml/0.3ml), a borate compound (120mg,0.29mmol), Na were added₂CO₃(61mg,0.57mmol) was purged 3 times with nitrogen, followed by addition of Pd (PPh)₃)₂Cl₂(7mg,0.01mmol) and 3 air exchanges. Reacting at 90 ℃ overnight, cooling, filtering, washing a filter cake by ethyl acetate, washing by adding water, separating liquid, drying an organic phase by anhydrous sodium sulfate, and concentrating to obtain a yellow oily crude product (125mg), wherein the yellow oily crude product is directly used for the next reaction. LC-MS [ M + H ]]⁺:m/z 626.8。

The second step is that: the crude product from the previous step (118.7mg,0.19mmol) was dissolved in DCM (4.5mL), TFA (1.0mL) was added, the reaction was carried out at room temperature for 1.5h under nitrogen, concentrated and dried to afford the title compound (white solid, 50 mmol)mg)。LC-MS[M+H]⁺:m/z 527.2。¹HNMR(400MHz,MeOD-d₄):δ8.65(d,1H),8.03(s,1H),7.91(s,1H),7.74(d,1H),7.43(d,1H),7.34(s,1H),6.82(s,1H),6.22(d,1H),5.03(dd,1H),5.02(dd,1H),3.73(s,3H),2.36(s,3H),1.93(d,3H),1.76(s,3H),1.63(s,3H)。

Example 67: 2- (5-fluoro-2- ((1-m-ethyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -6, 6-dimethyl-5- (1- (3- (trifluoromethyl) phenyl) ethyl) -5, 6-dihydro-4H-thieno [2,3-c ] pyrrol-4-one

The first step is as follows: 2-bromo-6, 6-dimethyl-5- (1- (3- (trifluoromethyl) phenyl) ethyl) -5, 6-dihydro-4H-thiophene [2, 3-c)]Pyrrol-4-one (181mg,0.43mmol) dissolved in dioxane/H₂To O (7ml/0.7ml), a boric acid compound (190mg,1.1mmol) and Na were added₂CO₃(137mg,1.3mmol) under nitrogen, 3 gassings, then Pd (PPh) is added₃)₂Cl₂(60mg,0.09mmol) and 3 air exchanges. The reaction was allowed to proceed at 90 ℃ overnight, cooled, filtered, the filter cake washed with EA and column chromatographed (PE/EA: 3/1) to give a pale yellow solid (86.4 mg). LC-MS [ M + H ]]⁺:m/z 470.4.¹H NMR(400MHz,CDCl₃):δ8.69(d,1H),8.34(d,1H),7.74(s,1H),7.74(s,2H),7.61(d,1H),7.53(d,1H),4.66(d,1H),1.99(d,3H),1.78(s,3H),1.60(s,3H)。

The second step is that: dissolving the yellowish solid (75mg,0.16mmol) in dioxane (3mL), adding aminopyrazole (31mg,0.32mmol), Cs₂CO₃(157mg,0.48mmol)，Xantphos(10mg,0.02mmol)，Pd₂(dba)₃(15mg,0.02mmol), reaction at 140 ℃ for 2h with microwave, filtration, washing of the filter cake with EA, and concentration to give the title compound (white solid, 4.9 mg). LC-MS [ M + H ]]⁺:m/z 531.5。¹HNMR(400MHz,MeOD-d₄):δ8.65(d,1H),8.11(d,1H),7.91(s,1H),7.74(d,1H),7.69(s,1H),7.42(d,1H),7.07(d,1H),6.27(d,1H),5.04(dd,1H),3.74(s,3H),1.93(d,3H),1.77(s,3H),1.64(s,3H)。

Example 68: (S) -N- (1- (3-chlorophenyl) -2-hydroxyethyl) -2- (4, 4-dimethyl-2- (2- ((1-m-ethyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -6-oxo-4, 6-dihydro-5H-thieno [2,3-c ] pyrrol-5-yl) acetamido

The first step is as follows: 3-bromothiophene-2-carboxylic acid (5g,67.5mmol) was dissolved in THF (100mL), cooled to below-65 deg.C, n-BuLi (1.6M, 36.23mL,57.96mmol) was added dropwise, stirred for 1h after addition was complete, then anhydrous acetone (2.31mL,31.4mmol) was added dropwise at below-65 deg.C, stirred for 30min, allowed to rise to 0 deg.C naturally, stirred for 2h, 1M HCl was added dropwise to pH 2-3, then water (50mL) and ethyl acetate (100mL) were added, the layers were separated, extracted, dried, and spun dry to give a crude pale red oil (5.1 g). LC-MS [ M-H ]]^-:m/z 185.1。

The second step is that: the above oil (510mg) was dissolved in toluene (6mL), and water (0.4mL) and p-toluenesulfonamide (PTSA) (183mg,0.96mmol) were added, followed by heating to 100 ℃ for reaction for 16h, followed by addition of water (30mL) and ethyl acetate (50mL), layer separation, washing of the organic layer with saturated sodium bicarbonate (50mL) three times, liquid separation, drying, and spin-drying to give a yellow oil (270 mg). LC-MS [ M + H ]]⁺:m/z 169.4。¹HNMR(400MHz,DMSO-d₆):δ8.23(d,1H),7.34(d,1H),1.63(s,6H).

The third step: the above oil (2.68g,16.0mmol) was dissolved in NMP (9mL) and p-methoxybenzylamine (PMB-NH) was added₂) (4.4g,31.9mmol), heated to 120 ℃ to react for 36h, then added with water (100mL) and ethyl acetate (50mL), separated, dried, spun-dried, and column chromatographed (PE/EA ═ 5: 1) a red oil (3.7g) was obtained. LC-MS [ M + H ]]⁺:m/z 306.1。¹H NMR(400MHz,DMSO-d₆):δ10.04(t,1H),7.58(d,1H),7.25(d,2H),7.09(d,1H),6.90(d,2H),6.52(s,1H),4.39(d,2H),3.74(s,3H),1.50(s,6H).

The fourth step: the above oil (2.86g) was dissolved in trifluoroacetic acid (30mL), stirred at room temperature for 5h, then spin-dried, dichloromethane (50mL) was added, and the organic layer was washed three times with saturated sodium bicarbonate (50mL), separated, dried, and spin-driedColumn chromatography (PE/EA ═ 10: 1) afforded a brick-red oil (2.2 g). LC-MS [ M + H ]]⁺:m/z 288.4。¹H-NMR(400MHz,DMSO-d₆):δ7.87(d,1H),7.25(d,2H),7.18(d,1H),6.87(d,2H),4.44(s,2H),3.73(s,3H),1.60(s,6H)。

The fifth step: the above oil (2g) was dissolved in trifluoroacetic acid/dichloromethane (20mL/20mL), trifluoromethanesulfonic acid (10mL) was added dropwise with stirring at room temperature, the addition was completed, refluxed overnight, trifluoroacetic acid and dichloromethane were spun off, added dropwise to ice water, filtered, the filtrate was added dropwise to saturated sodium bicarbonate (1L) and extracted with ethyl acetate, separated, dried, spun dry, and slurried with petroleum ether to give a white solid (341 mg). LC-MS [ M + H ]]⁺:m/z 168.1。¹H-NMR(400MHz,DMSO-d₆):δ7.89(d,1H),7.41(d,1H),1.71(s,6H)。

Example 68 (white solid, 12mg) was prepared according to the synthetic procedure of example 63, using the white solid obtained in the previous step as a starting material. LC-MS [ M + H ]]+:m/z 551.1/553.2。¹HNMR(400MHz,CD₃OD):δ8.02(s,1H),7.88(d,1H),7.62(s,1H),7.54(d,1H),7.36(s,1H),7.28(d,2H),7.23(d,1H),7.13(d,1H),6.45(d,1H),5.07(t,1H),4.28(s,2H),3.72-3.85(m,5H),2.44(s,3H),1.61(s,3H),1.58(s,3H)。

Comparative compound 1: (R) -N- ((S) -1- (3-chlorophenyl) -2-hydroxyethyl) -2- (6- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -1-oxoisoindolin-2-yl) propionamide

The title compound was prepared by reference to the procedures and reaction conditions of the examples of WO2017068412A1, LC-MS: ESI (M + H) 531.3.¹H-NMR(CD₃OD,400MHz)8.16(d,J＝8.0Hz,1H),8.06(d,J＝1.2Hz,1H),7.93(dd,J＝1.6,8.0Hz,1H),7.71(d,J＝8.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.26-7.39(m,4H),7.14(dd,J＝1.6,5.6Hz,1H),7.02(d,J＝1.2Hz,1H),6.27(d,J＝2.0Hz,1H),5.07-5.09(m,1H),4.95(t,J＝6.4Hz,1H),4.81(d,J＝17.6Hz,1H),4.66(d,J＝17.6Hz,1H),3.72-3.75(m,5H),1.58(d,J＝7.6Hz,3H)。

Test example 1 determination of the inhibitory Activity of the Compounds of the present invention against ERK2 kinase

(1) Preparing 1 XKinase buffer; (2) preparation of compound concentration gradient: test compounds were tested at 10uM starting concentration, 3-fold diluted 10 concentrations, duplicate wells tested, and serially diluted in 96-well plates to 100-fold final concentration of 10 different concentration solutions. Then further diluting each concentration of compound with 1 x Kinase buffer to an intermediate diluted solution of 5 times the final concentration; (3) respectively adding 5 mu L of the prepared compound solution into compound holes of a 384-hole plate, and testing each concentration single hole; adding 5 mu L of 5% DMSO into the negative control well and the positive control well respectively; (4) preparing a Kinase solution with 2.5 times of final concentration by using 1 XKinase buffer; (5) add 10. mu.L of 2.5 fold final concentration kinase solution to the compound well and positive control well, respectively; add 10. mu.L of 1 XKinase buffer to the negative control wells; (6) centrifuging at 1000rpm for 30 s, shaking, mixing uniformly, and incubating at room temperature for 10 min; (7) preparing a mixed solution of ATP and Kinase substrate22 at a final concentration of 2.5 times with 1 XKinase buffer; (8) adding 10 μ L of a mixed solution of ATP and substrate at 2.5 times final concentration to initiate reaction; (9) centrifuging a 384-well plate at 1000rpm for 30 seconds, shaking and uniformly mixing, and then respectively incubating at 28 ℃ for corresponding time; (10) adding 30 mu L of termination detection solution to stop kinase reaction, centrifuging at 1000rpm for 30 seconds, and uniformly mixing by oscillation; (11) reading the conversion rate by using a Caliper EZ Reader II, taking a log value of the concentration as an X axis and a percent inhibition rate as a Y axis, and fitting a dose-effect curve by adopting log (inhibitor) vs. response-Variable slope of GraphPad Prism 5 analysis software, thereby obtaining IC (integrated Circuit) of each compound on enzyme activity₅₀The value is obtained.

2. As a result, the present invention provides examples 1 to 68, which have IC of inhibitory activity against ERK2₅₀All values are less than 500nM, and the inhibitory activity IC of most of the examples₅₀Less than 100nM, even less than 2nM, as in examples 3,4, 7, 9,10, 22, 24, 33, 34, 40, 63, 64, 65, 68, show stronger enzyme inhibitory activity. The specific data are shown in table one.

Table one: example Compounds Activity against ERK2 kinase inhibition

Test example 2: test of Effect of Compounds of the present invention on Ras-Raf-MEK-ERK-mediated proliferation Capacity of tumor cells

1. The test method comprises the following steps: colo-205 cells (ATCC) in logarithmic growth phase were inoculated into 96-well culture plates at an appropriate density, 90. mu.L per well, incubated overnight, and then a solvent control group (negative control) was set by adding compounds at different concentrations for 72 hr. After the compound acts on cells for 72 hours, the influence of the compound on cell proliferation is detected by a CCK-8 cell counting kit (Dojindo), 10 mu L of CCK-8 reagent is added into each hole, the hole is placed in a 370C incubator for 2 to 4 hours, a SpectraMax 190 reading is carried out by a full-wavelength microplate reader, and the measurement wavelength is 450 nm. The inhibition rate (%) of the compound on the growth of tumor cells was calculated by the following formula (OD negative control well-OD administration well)/OD negative control well × 100%. IC (integrated circuit)₅₀The values were determined by regression with a four parameter method using a microplate reader random plus software.

2. As a result, the present invention provides proliferation inhibitory activity, IC, of Colo-205 cells against most of the compounds of examples 1-68₅₀Values were all less than 500nM, IC for inhibitory activity of some of the example compounds₅₀Values even less than 50nM, as in examples 30, 33, 65, show strong cell proliferation inhibitory activity. The specific data are shown in table two.

Table two: the compounds of the examples have inhibitory activity on Colo-205 cell proliferation.

Meanwhile, as shown in table three, compared with the comparative compound and the positive compound, the compound of some examples of the invention has the advantages that the 1-oxoisoindoline mother nucleus in the comparative compound and the pyrrole mother nucleus, the pyridone mother nucleus and the 5, 6-dihydro-4H-thiophene [2,3-c ] pyrrole-4-ketone mother nucleus in the positive compound are replaced by the 4-oxo-6, 7-dihydrofuran [3,2-c ] pyridine mother nucleus structure, so that the compound of the invention has obvious advantages on the proliferation inhibition activity of ERK2 kinase and Colo-205 cells, and indicates that the compound of the invention has unique action mechanism, obvious in vitro cell proliferation inhibition activity and obvious medicament advantages.

TABLE III, some examples and comparative compounds inhibit the activity of ERK2 kinase and Colo-205 cell proliferation

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (19)

1. A compound as shown in formula (I), or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer and tautomer thereof,

in the formula (I), the compound is shown in the specification,

R₁is selected from C₁-C₈Alkyl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl; said C₁-C₈Alkyl is optionally substituted with 1-3 halogens or hydroxy; said 3-8 membered heterocycloalkyl or 5-10 membered heteroaryl being optionally substituted by 1-3C₁-C₈Alkyl substituted; said heteroaryl group comprising 1 to 3 heteroatoms selected from the group consisting of: n, O, P and S, said heterocycloalkyl group containing 1 to 3 heteroatoms selected from the group consisting of: n, O, P and S;

R₂selected from 6-10 membered aryl or 5-10 membered heteroaryl; said 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted by 1-3 halogen, C₁-C₈Alkyl radical, C₁-C₈Alkylamino, or R_2-1Substituted C₁-C₈Alkyl substituted; r_2-1Selected from halogen or hydroxy; said heteroaryl group comprising 1 to 3 heteroatoms selected from the group consisting of: n, O, P and S;

R_3a、R_3b、R_4aand R_4bIndependently selected from hydrogen;

R₆、R₇、R₈and R₉Independently selected from hydrogen, or C₁-C₈Alkyl groups of (a); said C₁-C₈Is optionally substituted with 1-3 halogens, hydroxy;

l is an amide group; the amido is-C (═ O) NH-; wherein, C terminal is connected with

Are connected, N terminal to

Connecting;

m is selected from N or CR₅；R₅Independently selected from hydrogen, halogen, cyano, or C₁-C₆An alkyl group; said C is₁-C₆One or more hydrogen atoms on the alkyl group may be substituted, the substituent being halogen;

m1 is CH; m2 is O, N and S;

m, n are independently selected from 0, 1,2 or 3; q is 0 or 1.

2. As claimed in claim 1, of the formula (I)A compound, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer thereof, wherein when R is₁Is C₁-C₈When alkyl, said C₁-C₈Alkyl is C₁-C₄An alkyl group;

or, when R is₁Is C₁-C₈Alkyl radical, said C₁-C₈When alkyl is optionally substituted with 1-3 halogens or hydroxy, said halogen is fluorine;

or, when R is₁When the heterocyclic group is a 3-8 membered heterocyclic group, the 3-8 membered heterocyclic group is a 5-6 membered heterocyclic group in which "one or more heteroatoms selected from N, O and S, and the number of the heteroatoms is 1-3";

or, when R is₁When the aryl group is a 5-10-membered heteroaryl group, the 5-10-membered heteroaryl group is a 5-6-membered heteroaryl group in which "one or more heteroatoms selected from N, O and S are contained, and the number of the heteroatoms is 1-3";

or, when R is₁Is a 5-10 membered heteroaryl group, said 5-10 membered heteroaryl group optionally substituted with 1-3C₁-C₈When alkyl is substituted, said C₁-C₈Alkyl is C₁-C₄An alkyl group;

or, when R is₂Is 6-10 membered aryl, and the 6-10 membered aryl is phenyl;

or, when R is₂Is 6-10 membered aryl, said 6-10 membered aryl, when optionally substituted with 1-3 halogens, said halogen is fluoro or chloro;

or, when R is₂Is a 6-10 membered aryl group, said 6-10 membered aryl group being optionally substituted by C₁-C₈Alkyl or R_2-1Substituted C₁-C₈When substituted by alkyl, said C₁-C₈Alkyl is C₁-C₄An alkyl group;

or, when R is₂Is 6-10 membered aryl, said 6-10 membered aryl being optionally substituted by R_2-1Substituted C₁-C₈When substituted by alkyl, R_2-1Is halogen;

or, when R is₂Is 5-10 membered heteroaryl, said 5-10 membered heteroaryl5-6 membered monocyclic heteroaryl group wherein "heteroatom (S) is (are) selected from N, O and S, and the number of heteroatoms is 1-3";

or, when R is₂Is a 5-10 membered heteroaryl, said 5-10 membered heteroaryl optionally substituted with C₁-C₈Alkyl substitution, said C₁-C₈Alkyl is C₁-C₄An alkyl group;

or, when R is₂Is a 5-10 membered heteroaryl, said 5-10 membered heteroaryl optionally substituted with C₁-C₈Alkylamino substitution, said C₁-C₈Alkylamino is C₁-C₄An alkylamino group;

or, when R is₅When the halogen is fluorine or chlorine;

or, when R is₅Is C₁-C₆Alkyl radical, said C₁-C₆Alkyl is C₁-C₄An alkyl group;

or, when R is₅Is C₁-C₆Alkyl radical, said C₁-C₆Alkyl is optionally substituted with 1-3 halogens, said halogens being fluorine;

or, when R is₆、R₇、R₈And R₉Independently is C₁-C₈When there is an alkyl group, said C₁-C₈Alkyl is C₁-C₄An alkyl group;

or, when R is₆、R₇、R₈And R₉Independently is C₁-C₈Alkyl of (a), said C₁-C₈When the alkyl group of (a) is optionally substituted with 1 to 3 halogens, said halogens are fluorine.

3. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer thereof, as claimed in claim 1, wherein when R is₁Is C₁-C₈When alkyl, said C₁-C₈Alkyl is isopropyl;

or, when R is₁When it is a 3-to 8-membered heterocycloalkyl group, theThe 3-to 8-membered heterocycloalkyl group of (a) is tetrahydropyranyl;

or, when R is₁In the case of a 5-10 membered heteroaryl group, said 5-10 membered heteroaryl group is pyrazolyl or pyridyl;

or, when R is₁Is a 5-10 membered heteroaryl group, said 5-10 membered heteroaryl group optionally substituted with 1-3C₁-C₈When alkyl is substituted, said C₁-C₈Alkyl is methyl;

or, when R is₂Is a 6-10 membered aryl group, said 6-10 membered aryl group being optionally substituted by C₁-C₈Alkyl or R_2-1Substituted C₁-C₈When substituted by alkyl, said C₁-C₈Alkyl is methyl or isopropyl; r_2-1Is fluorine;

or, when R is₂Is a 5-10 membered heteroaryl, said 5-10 membered heteroaryl optionally substituted with C₁-C₈When substituted by alkyl, said C₁-C₈Alkyl is methyl;

or, when R is₂Is a 5-10 membered heteroaryl, said 5-10 membered heteroaryl optionally substituted with C₁-C₈When alkylamino is substituted, said C₁-C₈Alkylamino is

Or, when R is₅Is C₁-C₆Alkyl radical, said C₁-C₆Alkyl is methyl;

or, when R is₆、R₇、R₈And R₉Independently is C₁-C₈When there is an alkyl group, said C₁-C₈Alkyl is methyl or ethyl.

4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer thereof, as claimed in claim 1,

R₂is 6-10 membered aryl or 5-10 membered heteroaryl; said 6-to 10-membered aryl or 5-to 10-membered heteroarylOptionally substituted by 1-3 halogens, C₁-C₈Alkyl or C₁-C₈Alkyl amino substituted;

or, R₆、R₇、R₈And R₉Independently selected from hydrogen, or C₁-C₈Alkyl groups of (a); said C₁-C₈Is optionally substituted with 1-3 hydroxyl groups;

alternatively, M is selected from N or CH;

alternatively, m and n are 1.

5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer thereof, as claimed in claim 1, wherein R is₁Selected from 5-10 membered heteroaryl; said 5-10 membered heteroaryl group optionally substituted with 1-3C₁-C₈Alkyl substituted;

or, R₂Is a 6-to 10-membered aryl group; said 6-to 10-membered aryl being optionally substituted by 1-3 halogens, C₁-C₈Alkyl or C₁-C₈Alkyl amino substituted;

or, R₆、R₇、R₈And R₉Independently selected from hydrogen, or C₁-C₈Alkyl groups of (a); said C₁-C₈Is optionally substituted with 1-3 hydroxyl groups; r₆And R₇Is different from R₆And R₇The attached C atom is in the R configuration;

or, R₆And R₇Independently selected from hydrogen, or C₁-C₈Alkyl groups of (a); r₈Is hydrogen, R₉Is C₁-C₈Or R is₈Is C₁-C₈Alkyl of R₉Is hydrogen; said C₁-C₈Is substituted with 1 hydroxyl group;

or, M is CH;

or, M₁Is CH, M₂Is O, or, M₁Is CH, M₂Is S;

alternatively, q is 0.

6. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer thereof, as claimed in claim 1, wherein R is₁Is composed of

Or, R₂Is composed of

Or, R₅Is hydrogen, fluoro, chloro, cyano, methyl or trifluoromethyl;

or, R₆And R₇Independently is hydrogen, methyl, ethyl or-CH₂F；

Or, R₈And R₉Independently hydrogen, methyl, -CH₂OH or

Or, M is N or CH;

or, M₁Is CH;

or, M₂Is O or S.

7. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer thereof, as claimed in claim 1,

R₁independently selected from:

wherein R is_a，R_bEach independently selected from hydrogen, unsubstituted C1-C8 alkyl;

R₂independently selected from a substituted or unsubstituted benzene ring, a substituted or unsubstituted pyridine ring; the substituents are independently selected from halogen and C₁-C₈Alkyl radical, C₁-C₈Alkylamino, or R_2-1Substituted C₁-C₈An alkyl group; r_2-1Selected from halogen or hydroxy; the number of the substituent groups is 1-3;

R_3a、R_3b、R_4a、R_4bindependently selected from hydrogen;

R₅independently selected from hydrogen, halogen, cyano, C₁-C₆An alkyl group;

R₆，R₇，R₈，R₉independently selected from hydrogen, C₁-C₈Alkyl groups of (a);

l is selected from-CONH-; wherein, C terminal is connected with

Are connected, N terminal to

Connecting;

m is independently selected from N or CH;

m and n are respectively selected from 1 or 2; q is selected from 0 or 1.

8. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer thereof, as claimed in claim 1,

R₁is selected from C₁-C₈Alkyl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl; said C₁-C₈Alkyl is optionally substituted with 1-3 halogens or hydroxy; said 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with 1-3C₁-C₈Alkyl substituted;

R₂is 6-10 membered aryl or 5-10 membered heteroaryl; 6-1 as described0-membered aryl or 5-10-membered heteroaryl optionally substituted by 1-3 halogens or C₁-C₈Alkyl or C₁-C₈Alkyl amino substituted;

R_3a、R_3b、R_4aand R_4bIndependently selected from hydrogen;

R₅independently selected from hydrogen, halogen, cyano, or C₁-C₆An alkyl group; said C₁-C₆Alkyl is optionally substituted with 1-3 halogens;

R₆、R₇、R₈and R₉Independently selected from hydrogen, or C₁-C₈Alkyl groups of (a); said C₁-C₈Is optionally substituted with 1-3 hydroxyl groups;

l is-C (═ O) NH-; wherein, C terminal is connected with

Are connected, N terminal to

Connecting;

m is selected from N or CH;

M₁is CH; m₂Independently selected from O, N and S;

m and n are 1;

q is selected from 0 or 1.

9. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer thereof, as claimed in claim 1,

R₁is selected from C₁-C₈Alkyl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl; said C₁-C₈Alkyl is optionally substituted with 1-3 hydroxyl groups; said 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with 1-3C₁-C₈Alkyl substituted;

R₂is 6-10 membered aryl or 5-10 membered heteroaryl; said 6-to 10-membered aryl or 5-to 10-membered heteroaryl being optionally substituted by 1 to 3Halogen, C₁-C₈Alkyl or C₁-C₈Alkyl amino substituted;

R_3a、R_3b、R_4aand R_4bIndependently is hydrogen;

R₅independently selected from hydrogen, halogen, or C₁-C₆An alkyl group;

R₆、R₇、R₈and R₉Independently selected from hydrogen, or C₁-C₈Alkyl groups of (a); said C₁-C₈Is optionally substituted with 1-3 hydroxyl groups;

l is-C (═ O) NH-; wherein, C terminal is connected with

Are connected, N terminal to

Connecting;

m is selected from N or CH;

M₁is CH; m₂Independently selected from O and S;

m and n are 1;

q is selected from 0 or 1.

10. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer thereof, as claimed in claim 1,

R₁is selected from C₁-C₈Alkyl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl; said C₁-C₈Alkyl is optionally substituted with 1-3 halogens or 1 hydroxyl; said 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with 1-3C₁-C₈Alkyl substituted;

R₂is a 6-to 10-membered aryl group; said 6-to 10-membered aryl group being optionally substituted by 1-3 halogens or C₁-C₈Alkyl substituted;

R_3a、R_3b、R_4aand R_4bIs hydrogen;

R₅independently selected from hydrogen, halogen, cyano, or C₁-C₆An alkyl group; said C₁-C₆Alkyl is optionally substituted with 1-3 halogens;

R₆、R₇、R₈and R₉Independently selected from hydrogen, or C₁-C₈Alkyl groups of (a); said C₁-C₈Is optionally substituted with 1-3 hydroxyl groups; r₆And R₇Is different from R₆And R₇The attached C atom is in the R configuration;

l is-C (═ O) NH-; wherein, C terminal is connected with

Are connected, N terminal to

Connecting;

m is selected from N or CH;

M₁is CH; m₂Is O;

m and n are 1;

q is selected from 0 or 1.

11. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer thereof, as claimed in claim 1,

R₁selected from 5-10 membered heteroaryl; said 5-10 membered heteroaryl group optionally substituted with 1-3C₁-C₈Alkyl substituted;

R₂is a 6-to 10-membered aryl group; said 6-10 membered aryl is optionally substituted with 1-3 halogens;

R_3a、R_3b、R_4aand R_4bIs hydrogen;

R₅is hydrogen;

R₆and R₇Independently selected from hydrogen, or C₁-C₈Alkyl groups of (a);

R₈is hydrogen, R₉Is C₁-C₈Or R is₈Is C₁-C₈Alkyl of R₉Is hydrogen; said C₁-C₈Is substituted with 1 hydroxyl group;

l is-C (═ O) NH-; wherein, C terminal is connected with

Are connected, N terminal to

Connecting;

m is CH;

M₁is CH; m₂Is S;

m and n are 1;

q is selected from 0.

12. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer thereof, as claimed in claim 1,

R₁selected from 5-10 membered heteroaryl; said 5-10 membered heteroaryl group optionally substituted with 1-3C₁-C₈Alkyl substituted;

R₂is a 6-to 10-membered aryl group; said 6-to 10-membered aryl group being optionally substituted by 1-3 halogens or C₁-C₈Alkyl or C₁-C₈Alkyl amino substituted;

R_3a、R_3b、R_4aand R_4bIndependently selected from hydrogen;

R₅independently selected from hydrogen, halogen, cyano, or C₁-C₆An alkyl group; said C₁-C₆Alkyl is optionally substituted with 1-3 halogens;

R₆、R₇、R₈and R₉Independently selected from hydrogen, or C₁-C₈Alkyl groups of (a); said C₁-C₈Is optionally substituted with 1-3 hydroxyl groups; r₆And R₇Is different from R₆And R₇To C atoms ofIs in the R configuration;

l is-C (═ O) NH-; wherein, C terminal is connected with

Are connected, N terminal to

Connecting;

m is selected from N or CH;

M₁is CH; m₂Is O;

m and n are 1;

q is selected from 0 or 1.

13. The compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer thereof, according to any one of claims 1 to 12, wherein the compound of formula (1) is selected from the following general formulae ((I) a), (I) C):

wherein R is₁、R₂、R_3a、R_3b、R_4a、R_4b、R₅、R₆、R₇、R₈、R₉M, M, n, q and L are as defined in any one of claims 1 to 12.

14. A kind of aromatic heterocyclic lactam compound or its pharmaceutically acceptable salt, or its enantiomer, diastereoisomer, tautomer, it is any one of the following compounds:

15. a pharmaceutical composition comprising a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. Use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the prophylaxis and/or treatment of tumours; the tumor is selected from non-small cell lung cancer, melanoma, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostatic cancer, liver cancer, pancreatic cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymph cancer or nasopharyngeal carcinoma.

17. Use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, in the manufacture of a medicament for use in association with an ERK kinase inhibitor.

18. The use according to claim 17 wherein the ERK kinase is selected from ERK1 and ERK 2.

19. The use according to claim 17, wherein the ERK kinase is ERK 2.