HK40060604A

HK40060604A - Tricyclic compounds and their use

Info

Publication number: HK40060604A
Application number: HK62022049242.0A
Authority: HK
Inventors: Su Wei-Guo; Zhang Weihan; Li Jinshui
Original assignee: Hutchison Medipharma Limited
Priority date: 2019-06-06
Filing date: 2020-06-05
Publication date: 2022-05-20

Description

Tricyclic compound and use thereof

Technical Field

The present invention relates to tricyclic compounds, pharmaceutical compositions containing them, processes for their preparation and their use in medicine.

Background

The RAS/RAF/MEK/ERK pathway is an evolutionarily conserved signaling cascade that regulates many processes including cell adhesion, cell cycle progression, cell migration, cell survival, differentiation, metabolism and proliferation. It is widely recognized that aberrant activation of this pathway is closely associated with various cancers. In a high proportion of tumors, the ERK signaling pathway is overactivated, mainly due to mutations in the KRAS, NRAS and BRAF genes. About 30% of all human cancers have RAS mutations, with the following mutation ratios in each cancer, respectively: pancreatic cancer 90%, colon cancer 50%, papillary thyroid carcinoma 50%, non-small cell lung cancer (NSCLC) 30%, melanoma 25%. BRAF mutations have been extensively identified in tumors, with a significant proportion (7%) in all human cancers. This mutation is very common in the following cancers: hairy cell leukemia (100%), melanoma (50% -60%), papillary thyroid carcinoma (40% -60%), colon cancer (CRC) (5% -10%), fibrous astrocytoma (10% -15%), non-small cell lung cancer (NSCLC) (3% -5%). MEK mutations occur primarily in melanoma, but also in ovarian cancer cell lines and gliomas. In general, all upstream mutations result in over-activation of the ERK protein, which is responsible for the activity of a range of ERK signaling regulatory substrates and is ultimately associated with various tumors.

Targeting the MAPK/ERK pathway has become a hotspot in cancer treatment. The clinical benefits achieved by BRAF and MEK inhibitors have demonstrated that targeting these downstream RAS effectors is a very promising approach to treat cancers with BRAF mutations. However, there is evidence that inhibition of BRAF or MEK alone is not sufficient to produce clinical benefit of RAS mutated cancers. Both endogenous and acquired resistance to BRAF and MEK inhibitors are often associated with the continued presence of ERK signaling in the presence of the drug, suggesting a need to target ERK. Preliminary efficacy of ERK inhibitors has been observed in clinical trials. In phase I clinical studies with BVD-523, clinical responses were found in patients with BRAF and NRAS mutations, even in patients with prior disease progression using BRAF and/or MEK inhibitors. Methods of use in combination with ERK inhibitors were studied and preclinical data support a combination strategy of inhibitors with other targets, such as CDK4/6 inhibitors, VEGFR2 inhibitors, PARP inhibitors, multi-ERBB inhibitors, and autophagy inhibitors, in KRAS mutant cancer cells. Therefore, ERK inhibitors are likely to benefit more patients clinically.

Thus, there is a need for new compounds and methods for modulating ERK activity and treating related disorders, including cancer. The present invention addresses these needs.

Brief description of the invention

The present invention provides compounds of formula (I):

or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

Z₁and Z₂Each independently is N or C, andis a 5 membered heteroaryl group containing 1,2, 3 or 4 ring heteroatoms selected from N, O or S; said 5-membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting ofThe substituent (b): deuterium, halogen, hydroxy, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂-CN, mercapto, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl, - (C)_1-6Alkyl) -OH and- (C_1-6Alkyl) -O- (C_1-6Alkyl groups); said C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6Haloalkyl is each optionally substituted with one or more deuterium;

l is absent, or L is-NR_cO or S;

R_cis hydrogen or C_1-6An alkyl group;

ar is heteroaryl, optionally substituted with one or more substituents independently selected from: deuterium, halogen, hydroxy, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂-CN, mercapto, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl group), C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl, wherein said C is_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_3-8The cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl are each optionally substituted with one or more deuterium;

R₁selected from hydrogen, C optionally substituted with one or more deuterium_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl), - (C)_1-6Alkyl group) - (C_3-8Cycloalkyl), - (C)_1-6Alkyl) - (3-8 membered heterocyclyl), - (C)_1-6Alkyl-phenyl, - (C)_1-6Alkyl) -heteroaryl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl, wherein said C is_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl each optionally substituted with one or moreSubstituted with one substituent independently selected from: deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-(C_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl group), C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, heteroaryl, C optionally substituted with one or more deuterium_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group;

R₂selected from hydrogen, deuterium, halogen, hydroxy, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂CN, -mercapto, C optionally substituted by one or more deuterium_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl), - (C)_1-6Alkyl group) - (C_3-8Cycloalkyl), - (C)_1-6Alkyl) - (3-8 membered heterocyclyl), - (C)_1-6Alkyl-phenyl, - (C)_1-6Alkyl) -heteroaryl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl, wherein said C is_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8The cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-(C_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl group), C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl and oxo;

R_aand R_bEach independently selected from hydrogen, deuterium, halogen, hydroxy, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-(C_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl), -CN, mercapto, C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group; or, R_a、R_bTogether with the carbon atom to which they are attached form C_3-6Cycloalkyl or 4-6 membered heteroCyclic group wherein said C_3-6The cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from: deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-(C_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl group), C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group;

represents a double or single bond, andwhen represents a double bond, R₃And R₅Is absent;

R₃、R₄、R₅、_R6. r7 and R8 are each independently selected from hydrogen, deuterium, halogen, hydroxy, -CN, mercapto, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-(C_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl group), C_1-6Alkyl, - (C)_1-6Alkyl) -phenyl, C_1-6Alkoxy and C_1-6A haloalkyl group; or, R₃、R₄、R₅、R₆、R₇And R₈Any two of which, together with the carbon atom to which they are attached and ring B, form an 8-13 membered spirocyclic, fused or bridged ring optionally containing 1-3 ring heteroatoms independently selected from N, O or S; said spiro, fused or bridged ring being optionally substituted with one or more substituents independently selected from: deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-(C_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl group), C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group; or, R₃And R₄Together, R₅And R₆Together or R₇And R₈Together are oxo;

n is 0, 1 or 2;

m is 0, 1,2, 3, 4 or 5.

The above-mentioned compounds and the active compounds covered by this range disclosed in the context of the present invention are collectively referred to as "compounds of the present invention".

The invention also provides compounds of the invention for use in inhibiting ERK activity in vivo or in vitro.

The invention also provides a compound of the invention for use as a medicament, in particular for use in the treatment or prevention of a disease responsive to inhibition of ERK.

The invention also provides a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable carrier.

The invention also provides a method of inhibiting ERK activity in vivo or in vitro comprising contacting an effective amount of a compound of the invention with ERK.

The invention also provides a method of treating or preventing a disease responsive to inhibition of ERK comprising administering to a subject in need thereof an effective amount of a compound of the invention.

The invention also provides the use of a compound of the invention in the treatment or prevention of a disease which responds to inhibition of ERK.

The invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of a disease responsive to inhibition of ERK.

Brief description of the drawings

FIG. 1 shows a route to the synthesis of compounds of the invention, wherein X is halogen; z1, Z₂、L、R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R_a、R_bM and n are as defined for the compounds of formula (I) and the compounds of sub-formulae (I-1), (I-2), (I-3) thereof; r₉As defined for the compounds of the formulae (II), (III)。

Detailed Description

Definition of

As used in this application, the following words, phrases and symbols have the meanings as set forth below, unless the context indicates otherwise.

A dash ("-") that is not between two letters or symbols indicates a point of attachment for a substituent. For example, -O (C)_1-6Alkyl) means C attached to the rest of the molecule through an oxygen atom_1-6An alkyl group.

The dashed line intersecting the chemical bond is used to indicate the position of attachment of the group to the rest of the molecule. For example, Ar can beWherein the left and right dotted lines represent and R, respectively₁-NH-linkage and to the A ring.

The term "alkyl" as used herein means containing from 1 to 18 carbon atoms (C)_1-18) Preferably 1 to 10 carbon atoms (C)_1-10) Particularly preferably 1 to 6 carbon atoms (C)_1-6) A straight or branched chain saturated hydrocarbon group of (1). For example, "C_1-6Alkyl "means an alkyl group as described having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

The term "alkenyl" as used herein refers to a group containing 2 to 10 carbon atoms (C ═ C) containing one or more, e.g. 1,2 or 3, carbon-carbon double bonds (C ═ C)_2-10) Preferably 2 to 6 carbon atoms (C)_2-6) More preferably 2 to 4 carbon atoms (C)_2-4) A straight or branched chain unsaturated hydrocarbon group of (1). For example, "C_2-6Alkenyl "means said alkenyl having 2 to 6 carbon atoms, which preferably contains 1 or 2 carbon-carbon double bonds; "C_2-4 alkenyl "means said alkenyl having 2 to 4 carbon atoms, which preferably contains 1 carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, ethenyl, 2-propenyl, and 2-butenyl. The point of attachment of the alkenyl group may or may not be at the double bond.

As used hereinThe term "alkynyl" refers to a compound containing 2 to 10 carbon atoms (C.ident.C) containing one or more, for example 1,2 or 3, carbon-carbon triple bonds (C.ident.C)_2-10) Preferably 2 to 6 carbon atoms (C)_2-6) More preferably 2 to 4 carbon atoms (C)_2-4) A straight or branched chain unsaturated hydrocarbon group of (1). For example, "C_2-6Alkynyl "means said alkynyl having 2 to 6 carbon atoms, which preferably contains 1 or 2 carbon-carbon triple bonds; "C_2-4Alkynyl "means an alkynyl group as described having 2 to 4 carbon atoms, which preferably contains 1 carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. The point of attachment of the alkynyl group may or may not be at the triple bond.

The term "halogen" or "halo" as used herein refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine.

The term "haloalkyl" as used herein refers to an alkyl group as defined herein wherein one or more hydrogen atoms, for example 1,2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same or different from each other. In one embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein wherein two or more hydrogen atoms, for example 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are the same as each other. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein wherein two or more hydrogen atoms, for example 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are different from each other. Examples of haloalkyl include, but are not limited to, -CF3, -CHF2, -CH₂F、-CH₂CF3、-CF₂CF₃、-CF₂CH₃And the like.

The term "alkoxy" as used herein refers to the group-O-alkyl, wherein alkyl is as defined above. Examples of alkoxy groups include, but are not limited to, C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, and hexoxy, including isomers thereof.

The term "cycloalkyl" as used herein means a cyclic hydrocarbon group containing from 3 to 12 ring carbon atoms (C)₃-12), e.g. containing 3 to 8 ring carbon atoms (C)₃-₈)3 to 7 ring carbon atoms (C)₃-₇) Or 3 to 6 ring carbon atoms (C)₃-₆) A saturated or partially unsaturated cyclic hydrocarbon group of (a); it may have 1 or 2 rings. The cyclic hydrocarbon group may include fused rings, bridged rings, or spiro rings. The ring of the cyclic hydrocarbon group may be saturated or may contain one or more, for example one or two, double bonds in the ring (i.e. partially unsaturated), but it is not fully conjugated nor "aryl" as defined in the present invention. In one example, the cycloalkyl group is a monocyclic cycloalkyl group, preferably monocyclic C₃-8 cycloalkyl, more preferably monocyclic C₃-₆A cyclic hydrocarbon group. In another embodiment, the cycloalkyl group is a saturated monocyclic cycloalkyl group, preferably a saturated monocyclic C₃-8 cycloalkyl, more preferably saturated monocyclic C₃-₆A cyclic hydrocarbon group. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl (e.g., 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl), cyclohexenyl (e.g., 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl), cyclohexadienyl. In another example, the cycloalkyl group is a bicyclic cycloalkyl group, preferably bicyclic C₅-C₁2-cycloalkyl, more preferably bicyclic C₇-C₁2 cycloalkyl group. Examples of bicyclic cycloalkyl radicals include, but are not limited to, bicyclo [ 4.1.0%]Heptylalkyl, bicyclo [3.1.1]Heptylalkyl, bicyclo [2.2.1]Heptylalkyl, bicyclo [2.2.2]Octyl, bicyclo [3.2.2]Nonyl, spiro [3.3 ]]Heptylalkyl, spiro [2.2]Pentyl alkyl, spiro [2.3 ]]Hexalkyl, spiro [2.4 ]]Heptylalkyl, spiro [2.5 ]]Octyl, spiro [4.5 ]]Decyl and bicyclo [3.1.1]Hept-2-enyl. Most preferably, the cycloalkyl group is a saturated monocyclic ring C₃-₆Cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term "heterocyclyl" or "heterocycle" as used herein refers to a saturated or partially unsaturated ring having 3 to 12 ring atoms (3-12 members), for example 3 to 8 ring atoms (3-8 members), 5 to 7 ring atoms (5-7 members), 3 to 6 ring atoms (3-6 members) or 4 to 6 ring atoms (4-6 members), of which 1,2 or 3, preferably 1 or 2, are heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon atoms; it may have one or more rings, for example 1,2 or 3, preferably 1 or 2 rings. Where N and S may optionally be oxidized to various oxidation states, the point of attachment of the heterocyclic group may be at the N heteroatom or at a carbon atom. The heterocyclic group may include a fused ring, a bridged ring or a spiro ring. The ring of the heterocyclyl group may be saturated or it may contain one or more, for example one or two, double bonds in the ring (i.e. partially unsaturated), but it is not fully conjugated, nor "heteroaryl" as defined herein. For example, "3-8 membered heterocyclyl" means said heterocyclyl having 3-8 ring atoms containing 1,2 or 3, preferably 1 or 2 ring heteroatoms selected from N, O and S, preferably is a saturated monocyclic 3-8 membered heterocyclyl. As another example, "3-6 membered heterocyclyl" means a heterocyclyl having 3-6 ring atoms as described which contains 1 or 2 ring heteroatoms selected from N, O and S, preferably a saturated monocyclic 3-6 membered heterocyclyl, for example a saturated monocyclic 3, 4,5 or 6 membered heterocyclyl. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, aziridinyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolanyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, and tetrahydropyranyl.

The term "aryl" as used herein means a compound consisting of one or more fused rings and containing from 6 to 14 carbon atoms (C)_6-14) Preferably 6 to 10 carbon atoms (C)_6-10) Wherein at least one ring is an aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, 1,2, 3, 4-tetrahydronaphthyl, phenanthryl, indenyl, indanyl, azulenyl, preferably phenyl and naphthyl.

The term "heteroaryl" as used herein means:

monocyclic heteroaryl, i.e. monocyclic aromatic hydrocarbon having 5,6 or 7 ring atoms (5, 6 or 7 membered) of which one or more, e.g. 1,2 or 3, more preferably 1 or 2 ring heteroatoms independently selected from N, O and S (preferably N), the remaining ring atoms being carbon atoms; preferably a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms (5 or 6 membered) of which 1,2 or 3, more preferably 1 or 2 ring heteroatoms independently selected from N, O and S, more preferably N,

and

bicyclic heteroaryl, i.e. bicyclic aromatic hydrocarbon group having 8 to 12 ring atoms (8 to 12 membered), for example having 8, 9 or 10 ring atoms (8, 9 or 10 membered), of which one or more, for example 1,2, 3 or 4, preferably 2, 3 or 4 ring heteroatoms independently selected from N, O and S (preferably N), the remaining ring atoms being carbon atoms, wherein at least one ring is aromatic. When the total number of S and O atoms in the heteroaryl group exceeds 1, these S and O heteroatoms are not adjacent to each other. For example, bicyclic heteroaryl includes a 5 or 6 membered heteroaryl ring fused to a 5 or 6 membered cycloalkyl ring.

Examples of heteroaryl groups include, but are not limited to: pyridyl, pyridinyloxy, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, and imidazolyl,Azolyl radical, isoAzolyl, 1,2, 5-Oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g. 1, 3, 4-thiadiazolyl), tetrazolyl, triazolyl (e.g. 1,2, 4-triazolyl), triazinyl (e.g. 1, 3, 5-triazinyl), thienyl, furyl, pyranyl, pyrrolyl, pyridazinyl, benzodioxolylAzolyl, benzisoylAzolyl, benzothienyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, triazolopyridinyl, indazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, tetrazolopyridinyl, tetrahydropyrazolopyridinyl, benzofuranyl, benzimidazolinyl, indolyl, 3, 4-dihydro-2H-benzo [ b][1，4]Azinyl, indolinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, 2,4,5, 6-tetrahydrocyclopenta [ c ]]Pyrazolyl and 5,6, 7, 8-tetrahydro [1, 2, 4]]Triazolo [1, 5-a]A pyridyl group.

The terms "fused ring", "fused ring" or "fused ring" as used herein, are used interchangeably to refer to a saturated, partially unsaturated or aromatic ring system formed by two rings sharing a single ring edge. In one example, the "fused ring", "fused ring" or "fused ring" has 8 to 13 ring atoms (8 to 13 members), for example, 9 to 12 ring atoms (9 to 12 members), 8 to 11 ring atoms (8 to 11 members) or 8, 9 or 10 ring atoms (8, 9 or 10 members), among which optionally 1,2 or 3, preferably 1 or 2 ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon atoms.

The term "spirocyclic" as used herein refers to a saturated or partially unsaturated, preferably saturated, ring system wherein two rings share one carbon atom (which is referred to as a "spiro") and wherein optionally 1,2 or 3, preferably 1 or 2 of the ring atoms are ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon atoms. In one example, the "spiro ring" has 8 to 13 ring atoms (8 to 13 members), for example 9 to 12 ring atoms (9 to 12 members), 8 to 11 ring atoms (8 to 11 members) or 8, 9 or 10 ring atoms (8, 9 or 10 members), among which optionally 1,2 or 3, preferably 1 or 2 ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon atoms.

The terms "bridged ring" or "bridged ring" as used herein, are used interchangeably and refer to a saturated or partially unsaturated, preferably saturated, ring system formed by two rings sharing two atoms not directly connected (which are referred to as "bridgehead atoms"), optionally 1,2 or 3, preferably 1 or 2 of the ring atoms being ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon atoms. In one example, the "bridged ring" or "bridged ring" has 8 to 13 ring atoms (8-13 members), for example, 9 to 12 ring atoms (9-12 members), 8 to 11 ring atoms (8-11 members), or 8, 9, or 10 ring atoms (8, 9, or 10 members), among which optionally 1,2, or 3, preferably 1 or 2 ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon atoms.

The term "hydroxy" as used herein refers to an-OH group.

The term "mercapto" as used herein refers to the-SH group.

The term "oxo" or "oxo" as used herein means ═ O.

The term "amino" as used herein refers to-NH₂。

The term "cyano" as used herein refers to-CN.

If a formula herein contains an asterisk, it indicates that the chiral center at the mark of the asterisk in the compound is in a single configuration, either the (R) configuration or the (S) configuration; wherein the single configuration of the label ". mark" is present in an amount of at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100%, or any value between these recited values).

If a certain structural formula herein contains "(RS)", this means that the chiral center at the "(RS)" label in the compound has both (R) and (S) configurations.

The terms "optional," "optional," or "optionally" as used herein mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" includes "unsubstituted alkyl" and "substituted alkyl" as defined herein. It will be understood by those skilled in the art that for any group containing one or more substituents, the group does not include any substitution patterns that are sterically impractical, chemically incorrect, synthetically infeasible and/or inherently unstable.

The term "substituted" or "substituted.. means that one or more hydrogen atoms on a given atom or group are replaced with one or more substituents selected from a given group of substituents, provided that the normal valence of the given atom is not exceeded. When the substituent is oxo (i.e., ═ O), then two hydrogen atoms on a single atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in chemically correct and stable compounds. A chemically correct and stable compound means that the compound is sufficiently stable to be isolated from the reaction mixture.

Unless otherwise indicated, substituents are named into the core structure. For example, it will be understood that when a (cycloalkyl) alkyl group is listed as one possible substituent, it means that the point of attachment of that substituent to the core structure is on the alkyl portion.

The term "substituted with one or more substituents" as used herein means that one or more hydrogen atoms on a given atom or group are independently replaced with one or more substituents selected from the given group. In some embodiments, "substituted with one or more substituents" means that a given atom or group is substituted with 1,2, 3, or 4, preferably with 1,2, or 3, more preferably with 1 or 2 substituents independently selected from the given group.

"leaving group" means an atom or functional group that is displaced during the reaction. Examples of leaving groups include, but are not limited to, halogen, alkoxy, and sulfonyloxy. Examples of sulfonyloxy groups include, but are not limited to, alkylsulfonyloxy groups such as methylsulfonyloxy (also known as mesylate) and trifluoromethylsulfonyloxy (also known as triflate) and arylsulfonyloxy groups such as p-toluenesulfonyloxy (also known as p-toluenesulfonate) and p-nitrobenzenesulfonyloxy (also known as p-nitrobenzenesulfonate).

It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and thus exist as two or more stereoisomers. Racemic mixtures of these isomers, individual isomers and an enantiomerically enriched mixture, as well as diastereomeric and partially enriched mixtures of particular diastereomers when there are two chiral centers, are within the scope of the invention. It will also be understood by those skilled in the art that the present invention includes all individual stereoisomers (e.g. enantiomers), racemic mixtures or partially resolved mixtures of the compounds of formula (I), and where appropriate, individual tautomers thereof.

In other words, in some embodiments, the present invention provides compounds having multiple stereoisomeric purities, i.e., enantiomeric or diastereomeric purities, expressed as different "ee" or "de" values. In some embodiments, a compound of formula (I) or a compound of sub-formula (I-1), (I-2), (I-3) thereof described herein has an enantiomeric purity of at least 60% ee (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% ee, or any number between these recited values). In some embodiments, a compound of formula (I) described herein or a compound of sub-formula (I-1), (I-2), (I-3) thereof has an enantiomeric purity of greater than 99.9% ee. In some embodiments, a compound of formula (I) or a compound of sub-formula (I-1), (I-2), (I-3) thereof described herein has a diastereomeric purity of at least 60% de (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% de, or any number between these recited values). In some embodiments, a compound of formula (I) described herein or a compound of sub-formula (I-1), (I-2), (I-3) thereof has a diastereomeric purity of greater than 99.9% de.

The term "enantiomeric excess" or "ee" refers to the amount of one enantiomer relative to the other. For a mixture of R and S enantiomers, the percentage of enantiomeric excess is defined as | R-S | 100, where R and S are the molar or weight fraction of the respective enantiomer in the mixture, and R + S ═ 1. If the optical rotation of a chiral species is known, the percentage of enantiomeric excess is defined as ([ a ] obs/[ a ] max) × 100, where [ a ] obs is the optical rotation of the mixture of enantiomers and [ a ] max is the optical rotation of the pure enantiomer.

The term "diastereomeric excess" or "de" refers to the amount of one diastereomer relative to the other, and is defined by analogy to an enantiomeric excess. Thus, for a mixture of diastereomers D1 and D2, the percent diastereomeric excess is defined as | D1-D2 |. 100, where D1 and D2 are the molar or weight fractions of the respective diastereomers in the mixture and D1+ D2 is 1.

The determination of diastereomeric and/or enantiomeric excess can be accomplished by a variety of analytical techniques, including nuclear magnetic resonance spectroscopy, chiral column chromatography and/or optical polarimetry, according to conventional protocols familiar to those skilled in the art.

Racemic mixtures can be used as such or can be resolved into their individual isomers. The resolution can result in a stereochemically pure compound or in an enriched mixture of one or more isomers. Methods for separating isomers are well known (see Allinger n.l. and Eliel e.l., "Topics in stereospecificity", volume 6, Wiley Interscience, 1971), including physical methods such as chromatography using chiral adsorbents. The individual isomers can be prepared in chiral form from chiral precursors. Alternatively, individual isomers can be chemically separated from the mixture by: the process comprises forming diastereomeric salts with chiral acids (e.g. individual enantiomers of 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractional crystallization of said salts, and then liberating one or both of the resolved bases, optionally repeating this process, thereby obtaining one or two isomers substantially free of the other isomer, i.e. with an optical purity of > 95%. Alternatively, the racemate may be covalently attached to a chiral compound (the auxiliary) to give diastereomers, which may be separated by chromatography or fractional crystallization, followed by chemical removal of the chiral auxiliary to give the pure enantiomers.

The term "pharmaceutically acceptable salts" includes, but is not limited to: acid addition salts of compounds of formula (I) or compounds of sub-formulae (I-1), (I-2), (I-3) thereof with inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, and the like; and acid addition salts of compounds of the formula (I) or of compounds of the sub-formulae (I-1), (I-2), (I-3) thereof with organic acids, for example formates, acetates, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonate, 2-hydroxyethanesulfonates, benzoates, salicylates, stearates and with the formula HOOC- (CH)₂)_nSalts with alkanedicarboxylic acids of-COOH (wherein n is 0 to 4), and the like. "pharmaceutically acceptable salts" also include the base addition salts of the compounds of formula (I) or of the compounds of sub-formulae (I-1), (I-2), (I-3) thereof, which carry an acidic group, with pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium and ammonium.

Furthermore, if the compounds described herein are obtained in the form of an acid addition salt, the free base form thereof can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is in the form of the free base, its acid addition salts, in particular the pharmaceutically acceptable acid addition salts, can be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid, according to the usual procedures for preparing acid addition salts from basic compounds. Those skilled in the art will be able to ascertain without undue experimentation, various synthetic procedures which may be used to prepare non-toxic pharmaceutically acceptable acid or base addition salts.

The term "solvate" means a solvent addition form comprising a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to hold a fixed molar ratio of solvent molecules in the solid state, forming solvates. If it is notWhen the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate. Hydrates are formed by one or more molecules of water with one molecule of the substance, where the water retains its H₂The molecular state of O, such combination being capable of forming one or more hydrates, such as hemihydrate, monohydrate and dihydrate.

The term "deuterated compound" means a compound formed by replacement of one or more, e.g., 1,2, or 3, hydrogen atoms in the compound with deuterium, which is an isotope thereof. Wherein the deuterium element has a deuterium isotope content (deuteration degree) at a substitution position thereof that is at least greater than that of a natural deuterium isotope. In some embodiments, a compound of formula (I) or a deuterated compound of a compound of sub-formula (I-1), (I-2), (I-3) thereof has a deuteration of at least 50% (e.g., 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any number between these recited values). In some embodiments, the compound of formula (I) or a compound of sub-formula (I-1), (I-2), (I-3) thereof has a deuteration of greater than 99.9% to 100%.

As used herein, the terms "group" and "group" are synonymous and are used to refer to a functional group or molecular fragment that can be linked to other molecular fragments.

The terms "treat" or "treating" a disease or disorder refer to administering one or more pharmaceutical substances, particularly a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, to a subject suffering from, or having symptoms of, the disease or disorder to cure, heal, alleviate, alter, treat, ameliorate, improve, or affect the disease or disorder, the symptoms of the disease or disorder. In some embodiments, the disease or disorder is a disease responsive to inhibition of ERK, preferably cancer.

The term "preventing" a disease or disorder refers to administering one or more pharmaceutical substances, in particular a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, to an individual having a predisposition to, or at risk of, said disease or disorder, in order to prevent or slow down the occurrence of said disease or disorder in said individual. In some embodiments, the disease or disorder is a disease responsive to inhibition of ERK, preferably cancer.

The terms "treating", "contacting", and "reacting" when referring to a chemical reaction mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or desired product. It will be appreciated that the reaction that produces the indicated and/or the desired product may not necessarily result directly from the combination of the two reagents that were initially charged, i.e., one or more intermediates that are formed may be present in the mixture that ultimately result in the formation of the indicated and/or the desired product.

The term "effective amount" as used herein refers to an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein that is effective to "treat" or "prevent" a disease or disorder in a subject responsive to inhibition of ERK, as described herein above. An effective amount may cause any one of the visible or detectable changes in the individual as defined above in "treating" or "preventing". For example, in the case of cancer, an effective amount can reduce the number of cancer or tumor cells; reducing the size of the tumor; inhibiting or preventing infiltration of tumor cells into peripheral organs, e.g., tumor spread into soft tissue or bone; inhibiting or preventing metastasis of a tumor; inhibiting or preventing the growth of a tumor; alleviating to some extent one or more symptoms associated with cancer; reducing morbidity and mortality; the quality of life is improved; or a combination of the above effects. An effective amount may be an amount sufficient to reduce the symptoms of a disease responsive to inhibition of ERK. The term "effective amount" also refers to an amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, that is effective to inhibit ERK activity in a subject.

The term "inhibition" refers to a decrease in the baseline activity of a biological activity or process. "inhibiting ERK" refers to a decrease in ERK activity in response, directly or indirectly, to the presence of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein relative to ERK activity in the absence of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The reduction in activity may be caused by a direct interaction of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein with ERK, or by a interaction of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein with one or more other factors which in turn affect ERK activity. For example, the presence of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein may reduce the activity of ERK by binding directly to ERK, by affecting another factor directly or indirectly, or by reducing the amount of ERK present in a cell or body directly or indirectly.

The term "subject" as used herein refers to mammals and non-mammals. Mammal refers to any member of the mammalian family, including but not limited to: a human; non-human primates, such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds and the like. The term "individual" does not limit a particular age or gender.

The term "pharmaceutically acceptable" means that the term later defined material can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and biologically or otherwise free of undesirable properties, particularly for human pharmaceutical use.

The term "about" as used herein means approximately, about, approximately, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the limits above or below the stated values. Generally, the term "about" is used herein to adjust a given value to 20% above or below that value.

Technical and scientific terms used herein that are not specifically defined have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

Detailed Description

Embodiment 1. compounds of formula (I):

Z₁and Z₂Each independently is N or C, andis a 5 membered heteroaryl group containing 1,2, 3 or 4 ring heteroatoms selected from N, O or S; the 5-membered heteroaryl is optionally substituted with one or more substituents independently selected from: deuterium, halogen, hydroxy, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂-CN, mercapto, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl, - (C)_1-6Alkyl) -OH and- (C_1-6Alkyl) -O- (C_1-6Alkyl) of said C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6Haloalkyl is each optionally substituted with one or more deuterium;

l is absent, or L is-NR_cO or S;

R_cis hydrogen or C_1-6An alkyl group;

R₁selected from hydrogen, C optionally substituted by one or more deuterium_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl), - (C)_1-6Alkyl group) - (C_3-8Cycloalkyl), - (C)_1-6Alkyl) - (3-8 membered heterocyclyl), - (C)_1-6Alkyl-phenyl, - (C)_1-6Alkyl) -heteroaryl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl, wherein said C is_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8The cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-(C_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl group), C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, heteroaryl, C optionally substituted with one or more deuterium_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group;

R₂selected from hydrogen, deuterium, halogen, hydroxy, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂CN, -mercapto, C optionally substituted by one or more deuterium_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl), - (C)_1-6Alkyl group) - (C_3-8Cycloalkyl), - (C)_1-6Alkyl) - (3-8 membered heterocyclyl), - (C)_1-6Alkyl-phenyl, - (C)_1-6Alkyl) -heteroaryl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl, wherein said C is_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8The cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: deuterium, halogenElement, -CN, hydroxy, mercapto, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-(C_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl group), C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl and oxo;

R_aand R_bEach independently selected from hydrogen, deuterium, halogen, hydroxy, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-(C_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl), -CN, mercapto, C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group; or, R_a、R_bTogether with the carbon atom to which they are attached form C_3-6Cycloalkyl or 4-6 membered heterocyclyl, said C_3-6The cycloalkyl or 4-6 membered heterocyclyl is each optionally substituted with one or more substituents independently selected from: deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-(C_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl group), C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group;

R₃、R₄、R₅、R₆、R₇and R₈Each independently selected from hydrogen, deuterium, halogen, hydroxy, -CN, mercapto, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-(C_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl group), C_1-6Alkyl, - (C)_1-6Alkyl) -phenyl, C_1-6Alkoxy and C_1-6HalogenatedAn alkyl group; or, R₃、R₄、R₅、R₆、R₇And R₈Any two of which, together with the carbon atom to which they are attached and ring B, form an 8-13 membered spirocyclic, fused or bridged ring optionally containing 1-3 ring heteroatoms independently selected from N, O or S; said spiro, fused or bridged ring being optionally substituted with one or more substituents independently selected from: deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-(C_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl group), C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group; or, R₃And R₄Together, R₅And R₆Together or R₇And R₈Together are oxo;

n is 0, 1 or 2;

m is 0, 1,2, 3, 4 or 5.

Embodiment 2. a compound of formula (I) according to embodiment 1 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, whereinSelected from:

wherein R is₁₀And R₁₁Independently selected from hydrogen, deuterium, halogen, hydroxy, amino, -CN, mercapto, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, - (C)_1-6Alkyl) -OH and- (C_1-6Alkyl) -O- (C_1-6Alkyl) of said C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6The haloalkyl groups are each optionally substituted with one or more deuterium.

Embodiment 3. the formula according to embodiment 1(I) Or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, whereinSelected from:

wherein R is₁₀And R₁₁Independently selected from hydrogen, halogen, -CN, C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group.

Embodiment 4. a compound of formula (I) according to embodiment 3 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, whereinIs thatAnd R is₁₀And R₁₁Independently selected from hydrogen, halogen and C_1-6An alkyl group.

Embodiment 5. a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1-4, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ar is a monocyclic heteroaryl having 5 or 6 ring atoms, of which 1,2 or 3 are ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon atoms; each of which is optionally substituted by oneOr a plurality of substituents independently selected from: deuterium, halogen, hydroxy, -amino, -CN, mercapto, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl group), C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl, wherein said C is_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_3-8The cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl are each optionally substituted with one or more deuterium.

Embodiment 6a compound of formula (I) according to embodiment 5, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ar is selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1, 3, 5-triazinyl, 1,2, 4-triazolyl and thiazolyl (more preferably Ar is selected from the group consisting of pyridinyl, pyrimidinyl and 1, 3, 5-triazinyl), each of which is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -CN, C optionally substituted by one or more deuterium_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group.

Embodiment 7. the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, according to embodiment 6, wherein Ar is:

wherein R is₂₀、R₂₁、R₂₂、R₂₃And R₂₄Each independently selected from hydrogen, halogen, -CN, C optionally substituted with one or more deuterium_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group.

Embodiment 8. A compound of formula (I) according to any one of embodiments 1 to 7 or a pharmaceutically acceptable salt thereofAn acceptable salt, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R₁Is selected from C_1-6Alkyl, - (C)_1-6Alkyl) -OH, saturated monocyclic C_3-8Cycloalkyl, saturated monocyclic 3-8 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, and heteroaryl, wherein said heteroaryl is monocyclic aromatic hydrocarbon having 5 or 6 ring atoms, 1,2 or 3 of said ring atoms are independently selected from N, O and S, the remaining ring atoms are carbon atoms, or is bicyclic aromatic hydrocarbon having 8, 9 or 10 ring atoms, 1,2, 3 or 4 of said ring atoms are independently selected from N, O and S, the remaining ring atoms are carbon atoms, wherein at least one ring is aromatic and when the total number of S and O atoms in the heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other, wherein said C is C and O is C, O, and wherein said C is C, O, and S, or S, or S, or S, or S, or S, or C, S, or S_3-8The cycloalkyl, 3-8 membered heterocyclyl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl), 3-6 membered heterocyclyl, C optionally substituted with one or more deuterium_1-6Alkyl radical, C_1-6Alkoxy or C_1-6A haloalkyl group.

Embodiment 9 a compound of formula (I) according to embodiment 8 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is₁Is a heteroaryl group selected from pyrazolyl, pyridinyl, isoxazolyl, 1,2, 4-triazolyl, 1, 3, 4-thiadiazolyl, 2,4,5, 6-tetrahydrocyclopenta [ c ] s]Pyrazolyl and 5,6, 7, 8-tetrahydro [1, 2, 4]]Triazolo [1, 5-a]A pyridyl group; wherein said heteroaryl is each optionally substituted with one or more substituents independently selected from: c optionally substituted by one or more deuterium_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, halogen, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl) and 3-6 membered heterocyclyl.

Embodiment 10 a compound of formula (I) according to embodiment 9 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is₁Is pyrazolyl optionally substituted with one or more substituents independently selected from: c optionally substituted by one or more deuterium_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, halogen, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl) and oxetanyl.

Embodiment 11. a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described in any one of embodiments 1-10, wherein R is₂Selected from halogen, -CN, C_1-6Alkyl radical, C_1-6Haloalkyl, saturated monocyclic C_3-8Cycloalkyl, phenyl and heteroaryl, said heteroaryl being a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, wherein 1,2 or 3 of said ring atoms are independently selected from N, O and S, the remaining ring atoms being carbon atoms, or a bicyclic aromatic hydrocarbon group having 8, 9 or 10 ring atoms, of which 1,2, 3 or 4 are independently selected from N, O and S, the remaining ring atoms being carbon atoms, wherein at least one ring is an aromatic ring, and when the total number of S and O atoms in the heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other, wherein said C is_3-8The cycloalkyl, phenyl or heteroaryl groups are each optionally substituted with one or more substituents independently selected from: halogen, -CN, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl and oxo.

Embodiment 12. the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, solvate of the compound of formula (I) or a pharmaceutically acceptable salt thereof, according to embodiment 11,An enantiomer, diastereomer or tautomer, wherein R₂Is phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -CN and C_1-6An alkoxy group.

Embodiment 13 a compound of formula (I) according to embodiment 11 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is₂Is a heteroaryl group selected from 1,2, 5-oxadiazolyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, thiazolyl, isothiazolyl, benzo [ d ] d]Isoxazolyl, thienyl, indazolyl, and pyrrolyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of: c_1-6Alkyl, halogen, oxo and-CN.

Embodiment 14 a compound of formula (I) according to embodiment 11 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is₂Is a saturated monocyclic ring C_3-8Cycloalkyl optionally substituted with one or more substituents independently selected from C_1-6Substituted with a haloalkyl.

Embodiment 15 a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1-14, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2.

Embodiment 16. a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1-15, wherein R is_aAnd R_bEach independently selected from hydrogen, halogenElement, hydroxy and C_1-6An alkyl group; or, R_a、R_bTogether with the carbon atom to which they are attached form a saturated monocyclic ring C_3-6Cycloalkyl or form a 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl is a saturated monocyclic ring having 3-6 ring atoms, 1 or 2 of said ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms; wherein said saturated monocyclic ring C_3-6The cycloalkyl or 3-6 membered heterocyclyl is each optionally substituted with one or more substituents selected from halogen.

Embodiment 17. a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described in any one of embodiments 1-16, wherein L is absent, or L is NH, O or S.

Embodiment 18 a compound of formula (I) according to embodiment 1 selected from compounds 1-322, or a pharmaceutically acceptable salt thereof.

Embodiment 19. a compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 0,represents a double bond, R₃And R₅Is absent, R₄And R₆Each independently selected from hydrogen and C_1-6An alkyl group.

Embodiment 20 a compound of formula (I) according to embodiment 19, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-1):

wherein

R₁Is heteroaryl, optionally substituted with one or more substituents independently selected from: c optionally substituted by one or more deuterium_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, halogen, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl) and 3-6 membered heterocyclyl;

ar is heteroaryl, optionally substituted with one or more substituents independently selected from: halogen, -CN, C optionally substituted by one or more deuterium_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group;

R₂selected from halogen, -CN, C_1-6Alkyl radical, C_1-6Haloalkyl, saturated monocyclic C_3-8Cycloalkyl, phenyl and heteroaryl, wherein said monocyclic saturated C_3-8The cycloalkyl, phenyl or heteroaryl groups are each optionally substituted with one or more substituents independently selected from: halogen, -CN, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl and oxo;

R₄and R₆Each independently selected from hydrogen and C_1-6An alkyl group;

R₁₀and R₁₁Independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl and- (C)_1-6Alkyl) -OH;

m is 0, 1 or 2,

R_aand R_bEach independently selected from hydrogen, halogen, hydroxy or C_1-6An alkyl group; or, R_a、R_bTogether with the carbon atom to which they are attached form a saturated monocyclic ring C_3-6Cycloalkyl or form a 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl is a saturated monocyclic ring having 3-6 ring atoms of which 1 or 2 are ring heteroatoms independently selected from N, O and S, the remaining ring atoms are carbon atoms, wherein said saturated monocyclic ring C is_3-6(ii) cycloalkyl or 3-6 membered heterocyclyl are each optionally substituted with one or more substituents selected from halogen;

l is absent, or NH, O or S;

the heteroaryl group is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms of which 1,2 or 3 are independently selected from N, O and S, the remaining ring atoms being carbon atoms, or a bicyclic aromatic hydrocarbon group having 8, 9 or 10 ring atoms of which 1,2, 3 or 4 are independently selected from N, O and S, the remaining ring atoms being carbon atoms, wherein at least one ring is an aromatic ring, and when the total number of S and O atoms in the heteroaryl group exceeds 1, these S and O heteroatoms are not adjacent to each other.

Embodiment 21 a compound of formula (I) according to embodiment 20 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

R₁Is pyrazolyl optionally substituted by one or more substituents independently selected from C_1-6Alkyl substituent substitution;

ar is pyrimidinyl, optionally substituted with one or more substituents independently selected from C optionally substituted with one or more deuterium_1-6Alkyl and halogen;

R₂is selected from C_1-6Haloalkyl or phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from halogen;

R₁₀and R₁₁Is hydrogen;

m is 0 or 1;

R_aand R_bEach independently selected from hydrogen or C_1-6An alkyl group; or, R_a、R_bTogether with the carbon atom to which they are attached form a saturated monocyclic ring C_3-6A cyclic hydrocarbon group; and is

L is absent or NH or O.

Embodiment 22. the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to embodiment 20, wherein the compound of formula (I) is selected from:

embodiment 23. a compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 0,represents a single bond, R₃、R₄、R₅And R₆Each independently selected from hydrogen and C_1-6Alkyl radical, C_1-6Haloalkyl, - (C)_1-6Alkyl) -O- (C_1-6Alkyl) and- (C)_1-6Alkyl) -phenyl; or, R₃And R₄Or R₅And R₆Any pair of (b) together with the carbon atom to which they are attached form a saturated monocyclic ring C_3-6A cyclic hydrocarbyl group or a saturated monocyclic 3-6 membered heterocyclyl group having 1 or 2 ring heteroatoms selected from N, O and S, thereby forming a spiro ring together with the B ring.

Embodiment 24. a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to embodiment 23, wherein the compound of formula (I) is a compound of formula (I-2):

wherein

R₁Is selected from C_1-6Alkyl, - (C)_1-6Alkyl radical) -OH, saturated monocyclic C_3-8Cycloalkyl, saturated 3-8 membered heterocyclyl and heteroaryl containing 1 or 2 ring heteroatoms independently selected from N, O and S, wherein said C is_3-8The cycloalkyl, 3-8 membered heterocyclyl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl), a saturated 3-6 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, C optionally substituted with one or more deuterium_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group;

R₂selected from halogen, -CN, C_1-6Alkyl radical, C_1-6Haloalkyl, saturated monocyclic C_3-8Cycloalkyl, phenyl or heteroaryl, wherein said C_3-8The cycloalkyl, phenyl or heteroaryl groups are each optionally substituted with one or more substituents independently selected from: halogen, -CN, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl and oxo;

Z₃is CR₁₀Or N;

R₃、R₄、R₅and R₆Each independently selected from hydrogen and C_1-6Alkyl radical, C_1-6Haloalkyl, - (C)_1-6Alkyl) -O- (C_1-6Alkyl) and- (C)_1-6Alkyl) -phenyl; or, R₃And R₄Or R₅And R₆Any pair of (b) together with the carbon atom to which they are attached form a saturated monocyclic ring C_3-6A cycloalkyl group or a saturated monocyclic 3-6 membered heterocyclyl group having 1 or 2 ring heteroatoms selected from N, O and S, thereby forming a spirocyclic ring together with ring B;

m is 0, 1 or 2,

l is absent, or NH, O or S;

Embodiment 25 a compound of formula (I) according to embodiment 24 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

R₁Selected from the group consisting of saturated monocyclic 3-8 membered heterocyclic groups and heteroaryl groups containing 1 or 2 ring heteroatoms independently selected from N, O and S, wherein the heteroaryl group is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, 1,2 or 3 of the ring atoms being independently selected from N, O and S, the remaining ring atoms being carbon atoms, or a bicyclic aromatic hydrocarbon group having 8, 9 or 10 ring atoms, 1,2, 3 or 4 of the ring atoms being independently selected from N, O and S, the remaining ring atoms beingAnd (b) is a carbon atom, wherein at least one ring is aromatic, and when the total number of S and O atoms in the heteroaryl group exceeds 1, these S and O heteroatoms are not adjacent to each other, wherein said 3-8 membered heterocyclyl and heteroaryl groups are each optionally substituted with one or more substituents independently selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, halogen, - (C)_1-6Alkyl) -OH, C_1-6Alkoxy, - (C)_1-6Alkyl) -O- (C_1-6Alkyl) and a saturated, monocyclic 3-6 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S;

ar is heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms of which 1,2 or 3 ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon atoms, and when the total number of S and O atoms in the heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other, wherein said heteroaryl is optionally substituted with one or more substituents selected from: c optionally substituted by one or more deuterium_1-6Alkyl and halogen;

R₂selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, phenyl and heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbon radical having 5 or 6 ring atoms of which 1,2 or 3 are independently selected from N, O and S, the remaining ring atoms being carbon atoms, or is a bicyclic aromatic hydrocarbon radical having 8, 9 or 10 ring atoms of which 1,2, 3 or 4 are independently selected from N, O and S, the remaining ring atoms being carbon atoms, wherein at least one ring is an aromatic ring and when the total number of S and O atoms in the heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other, wherein said phenyl and heteroaryl are each optionally substituted with one or more substituents independently selected from: halogen, C_1-6Alkyl radical, C_1-6Alkoxy and oxo;

Z₃is CR₁₀Or N;

R₃、R₄、R₅and R₆Each independently selected from hydrogen and C_1-6Alkyl radical, C_1-6Haloalkyl group、-(C_1-6Alkyl) -O- (C_1-6Alkyl) and- (C)_1-6Alkyl) -phenyl; or, R₃And R₄Or R₅And R₆Any pair of (b) together with the carbon atom to which they are attached form a saturated monocyclic ring C_3-6A cycloalkyl group or a saturated monocyclic 3-6 membered heterocyclyl group having 1 or 2 ring heteroatoms selected from N, O and S, thereby forming a spirocyclic ring together with ring B;

m is a number of 1 or 2,

R_aand R_bEach independently selected from hydrogen and halogen; or, R_a、R_bTogether with the carbon atom to which they are attached form a saturated monocyclic ring C_3-6A cyclic hydrocarbon group;

R₁₀and R₁₁Is hydrogen;

l is absent or L is O.

Embodiment 26 a compound of formula (I) according to embodiment 25 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is₁Selected from the group consisting of morpholinyl, thiomorpholinyl and heteroaryl, wherein said heteroaryl is selected from the group consisting of pyrazolyl, 2,4,5, 6-tetrahydrocyclopenta [ c]Pyrazolyl, 1,2, 4-triazolyl, 5,6, 7, 8-tetrahydro [1, 2, 4] tetrahydro]Triazolo [1, 5-a]Pyridyl, 1, 3, 4-thiadiazolyl and pyridyl, and said heteroaryl is each optionally substituted with one or more groups selected from: c_1-6Alkyl radical, C_1-6Haloalkyl, halogen, - (C)_1-6Alkyl) -OH, C_1-6Alkoxy, - (C)_1-6Alkyl) -O- (C_1-6Alkyl) and oxetanyl.

Embodiment 27. a compound of formula (I) according to embodiment 24 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ar is heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and 1, 3, 5-triazinyl; wherein each of said heteroaryl groups is optionally substituted with one or more substituents selected from the group consisting ofSubstituent group substitution: c optionally substituted by one or more deuterium_1-6Alkyl and halogen.

Embodiment 28. the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, according to embodiment 27, wherein Ar is:

wherein R is₂₀、R₂₁、R₂₂、R_{23 and}R₂₄each independently selected from hydrogen, halogen and C optionally substituted with one or more deuterium_1-6An alkyl group.

Embodiment 29 a compound of formula (I) according to embodiment 24 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is₂Selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, phenyl and heteroaryl, wherein the heteroaryl is selected from isoxazolyl, 1,2, 5-oxadiazolyl, pyrazolyl, oxazolyl, pyridyl, thiazolyl, isothiazolyl, thienyl and benzo [ d]An isoxazolyl group; wherein said phenyl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C_1-6Alkyl radical, C_1-6Alkoxy and oxo.

Embodiment 30 a compound of formula (I) according to embodiment 24, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from:

embodiment 31 a compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 1,represents a single bond, R₃、R₄、R₅R6, R7 and R8 are each independently selected from hydrogen, halogen, hydroxy, C_1-6Alkyl and C_1-6An alkoxy group; wherein said C_1-6Alkyl is optionally substituted with one or more substituents independently selected from: hydroxy and C_1-6An alkoxy group; or, R₃、R₄、R₅、R₆、R₇And R₈In (1)Any two of which, together with the carbon atom to which they are attached and ring B, form a 9-12 membered spirocyclic, bicyclic or bridged ring optionally containing 1-3 ring heteroatoms selected from N, O or S; wherein said spiro, fused or bridged ring is optionally substituted with one or more substituents independently selected from: halogen, hydroxy, amino, C_1-6Alkyl and-CN.

Embodiment 32 a compound of formula (I) according to embodiment 31 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-3):

wherein

R₁Is selected from C_1-6Alkyl, - (C)_1-6Alkyl) -OH, saturated monocyclic C_3-8Cycloalkyl, saturated monocyclic 3-8 membered heterocyclyl and heteroaryl containing 1 or 2 ring heteroatoms independently selected from N, O and S; wherein said C_3-8The cycloalkyl, 3-8 membered heterocyclyl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C optionally substituted by one or more deuterium_1-6Alkyl radical, C_1-6Alkoxy and C₁-₆A haloalkyl group;

R₂selected from halogen, -CN, C_1-6Alkyl radical, C_1-6Haloalkyl, saturated monocyclic C_3-8Cycloalkyl, phenyl or heteroaryl, wherein said monocyclic saturated C_3-8The cycloalkyl, phenyl or heteroaryl groups are each optionally substituted with one or more substituents independently selected from: halogen, -CN, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl and oxo;

R₃、R₄、R₅、R₆、R₇and R₈Each independently selected from hydrogen, halogen, hydroxy, C_1-6Alkyl and C_1-6An alkoxy group; wherein said C_1-6Alkyl is optionally substituted with one or more substituents independently selected from: hydroxy and C_1-6An alkoxy group; or, R₃、R₄、R₅、R₆、R₇And R₈Any two of which, together with the carbon atom to which they are attached and the B ring, formR_dSelected from hydrogen or halogen, t is 0, 1,2 or 3;

m is 0, 1 or 2,

R_aand R_bEach independently selected from hydrogen, halogen, hydroxy or C_1-6An alkyl group; or, R_a、R_bTogether with the carbon atom to which they are attached form saturated C_3-6Cycloalkyl or form a 4-6 membered heterocyclyl, wherein said 4-6 membered heterocyclyl is a saturated monocyclic ring having 4-6 ring atoms, 1 or 2 of said ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms; wherein said saturated C_3-6Cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen;

l is absent, or L is NH, O or S;

Embodiment 33 a compound of formula (I) according to embodiment 32 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

R₁Is selected from C_1-6Alkyl, - (C)_1-6Alkyl) -OH, saturated monocyclic C_3-8Cycloalkyl, saturated monocyclic 3-8 membered heterocyclyl and heteroaryl containing 1 or 2 ring heteroatoms independently selected from N, O and S; wherein said C_3-8The cycloalkyl, 3-8 membered heterocyclyl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C_1-6Alkoxy radical, C_1-6Haloalkyl and C optionally substituted with one or more deuterium₁-₆An alkyl group;

ar is heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms of which 1,2 or 3 ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon atoms, and when the total number of S and O atoms in the heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other, said heteroaryl being optionally substituted with one or more substituents independently selected from: halogen, -CN, C optionally substituted by one or more deuterium_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group;

R₂is selected from-CN, C_1-6Haloalkyl, saturated monocyclic C_3-8Cycloalkyl, phenyl and heteroaryl, wherein said heteroaryl is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms of which 1,2 or 3 ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon atoms, or a bicyclic aromatic hydrocarbon group having 8, 9 or 10 ring atoms, said rings1,2, 3 or 4 of the atoms are ring heteroatoms independently selected from N, O and S, the remaining ring atoms are carbon atoms, wherein at least one ring is aromatic and when the total number of S and O atoms in the heteroaryl group exceeds 1, these S and O heteroatoms are not adjacent to each other, wherein said saturated monocyclic ring C_3-8The cycloalkyl, phenyl or heteroaryl groups are each optionally substituted with one or more substituents independently selected from: halogen, -CN, C_1-6Alkyl and C_1-6A haloalkyl group;

R₃、R₄、R₅、R₆、R₇and R₈Each independently selected from hydrogen, halogen, hydroxy, C_1-6Alkyl and C_1-6An alkoxy group; wherein said C_1-6Alkyl is optionally substituted with one or more substituents independently selected from: hydroxy and C_1-6An alkoxy group; or, R₃、R₄、R₅、R₆、R₇And R₈Any two of which, together with the carbon atom to which they are attached and the B ring, formR_dSelected from hydrogen and halogen, t is 0, 1,2 or 3;

R₁₀and R₁₁Independently selected from hydrogen, halogen and C_1-6An alkyl group;

m is 0, 1 or 2,

R_aand R_bEach independently selected from hydrogen, halogen, hydroxy and C_1-6An alkyl group; or, R_a、R_bTogether with the carbon atom to which they are attached form a saturated monocyclic ring C_3-6Cycloalkyl or form a 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl is a saturated monocyclic ring having 3-6 ring atoms, 1 or 2 of said ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms; wherein said saturated monocyclic ring C_3-6The cycloalkyl or 3-6 membered heterocyclyl is each optionally substituted with one or more substituents selected fromSubstituent substitution of halogen;

l is absent or L is NH or O.

Embodiment 34 a compound of formula (I) according to embodiment 32 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is₁Selected from: (1) c_1-6Alkyl (2) - (C)_1-6Alkyl) -OH, (3) saturated monocyclic C_3-8Cycloalkyl optionally substituted with one or more substituents independently selected from halogen and C_1-6Substituent (S) of alkoxy, (4) a saturated monocyclic 6-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, and (5) a heteroaryl selected from pyrazolyl, pyridinyl, and isoxazolyl, each of which is optionally substituted with one or more substituents independently selected from: c_1-6Alkoxy radical, C_1-6Haloalkyl and C optionally substituted with one or more deuterium_1-6An alkyl group.

Embodiment 35. a compound of formula (I) according to embodiment 32, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ar is heteroaryl, selected from pyridinyl and pyrimidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -CN, C optionally substituted by one or more deuterium_1-6Alkyl radical, C_1-6Alkoxy and C1_{-6 halo}An alkyl substituent.

Embodiment 36. a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to embodiment 35, wherein Ar is:

Embodiment 37 a compound of formula (I) according to embodiment 32 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is₂Selected from: (1) -CN, (2) C_1-6Haloalkyl, (3) saturated monocyclic C_3-8Cycloalkyl optionally substituted by one or more groups selected from C_1-6Haloalkyl substituted, (4) phenyl optionally substituted with one or more substituents independently selected from: halogen and-CN, and (5) heteroaryl selected from 1,2, 5-oxadiazolyl, indolinyl, 1,2, 3, 4-tetrahydroquinolinyl, pyrazolyl, indazolyl, and pyrrolyl, each of said heteroaryl being optionally substituted with one or more substituents independently selected from: halogen, -CN and C_1-6An alkyl group.

Embodiment 38. the compound of formula (I) according to embodiment 32, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from:

embodiment 39 a pharmaceutical composition comprising a compound of any one of embodiments 1-38, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

Embodiment 40 a method of inhibiting ERK activity in vivo or in vitro comprising contacting an effective amount of a compound according to any one of embodiments 1 to 38, or a pharmaceutically acceptable salt thereof, with ERK.

Embodiment 41 the use of a compound of any one of embodiments 1-38, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease that responds to inhibition of ERK.

Embodiment 42 the use of embodiment 41, wherein the medicament is for the treatment of cancer or an autoimmune disease.

Embodiment 43 the use according to embodiment 42, wherein the cancer is a solid tumor or a hematological malignancy, such as leukemia, lymphoma, colorectal cancer, melanoma, glioma, pancreatic cancer, breast cancer, lung cancer (e.g., non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid cancer) or ovarian cancer.

Embodiment 44. a method of treating or preventing a disease responsive to inhibition of ERK, comprising administering to a subject in need thereof an effective amount of a compound according to any one of embodiments 1 to 38, or a pharmaceutically acceptable salt thereof.

Embodiment 45 a compound according to any one of embodiments 1 to 38, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease that responds to inhibition of ERK.

Embodiment 46. a compound according to any one of embodiments 1 to 38, or a pharmaceutically acceptable salt thereof, for use as a medicament.

Embodiment 47. the compound of embodiment 46, or a pharmaceutically acceptable salt thereof, for use as a medicament for treating or preventing a disease responsive to inhibition of ERK.

Embodiment 48 a compound according to embodiment 47, or a pharmaceutically acceptable salt thereof, for use as a medicament in the treatment or prevention of cancer or an autoimmune disease.

Embodiment 49 the compound of embodiment 48, or a pharmaceutically acceptable salt thereof, wherein the cancer is a solid tumor or a hematological malignancy, such as leukemia, lymphoma, colorectal cancer, melanoma, glioma, pancreatic cancer, breast cancer, lung cancer (e.g., non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid cancer), or ovarian cancer.

Embodiment 50 a combination comprising a compound of any one of embodiments 1-38, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

Embodiment 51. the combination product of embodiment 50, wherein the additional therapeutic agent is an anti-tumor therapeutic agent, e.g., a radiotherapeutic agent, a chemotherapeutic agent, an immunotherapy therapeutic agent, a targeted therapeutic agent.

Embodiment 52. compounds of formula (II):

or a racemic mixture or enantiomer thereof, wherein: r₉Is a leaving group; r₁₀And R₁₁Independently selected from hydrogen, halogen and C_1-6An alkyl group; r₃、R₄、R₅、R₆、R₇And R₈Each independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy or C_1-6A haloalkyl group; or, R₃、R₄、R₅、R₆、R₇And R₈Any two of which, together with the carbon atom to which they are attached and the B ring, formR_dSelected from hydrogen and halogen, t is 0, 1,2 or 3; provided that when R is₁₀And R₁₁While being hydrogen, R₃、R₄、R₅、R₆、R₇And R₈Not simultaneously being hydrogen, and when R is₃、R₄、R₅、R₆、R₇And R₈When one of them is methyl, the other groups are not simultaneously hydrogen.

Embodiment 53. a compound of formula (II) according to embodiment 52, selected from:

embodiment 54. compounds of formula (III):

or a racemic mixture or enantiomer thereof, wherein:

R₉is a leaving group; r₁₀、R₁₁Independently selected from hydrogen, halogen and C_1-6An alkyl group;

R₃、R₄、R₅and R₆Each independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl or C optionally substituted by phenyl_1-6An alkyl group; or, R₃And R₄Or R₅And R₆Any pair of (b) together with the carbon atom to which they are attached form a saturated C_3-6A cycloalkyl group or a saturated 3-4 membered heterocyclyl group having 1 or 2 ring heteroatoms selected from N, O and S, thereby forming a spiro ring together with ring B; provided that，R₃、R₄、R₅And R₆Not simultaneously being hydrogen, and when R is₃、R₄、R₅And R₆One or two of them are C_1-6When alkyl, the other groups are not simultaneously hydrogen.

Embodiment 55. a compound of formula (III) according to embodiment 54, selected from:

general synthetic method of compound

The compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein can be synthesized using commercially available starting materials by methods known in the art and disclosed in the present patent application. The synthetic scheme given in fig. 1 illustrates the preparation of some of the compounds disclosed herein, wherein X is halogen; z₁、Z₂、L、R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R_a、R_bM and n are as defined for the compounds of formula (I) and the compounds of sub-formulae (I-1), (I-2), (I-3) thereof; r₉As defined for the compounds of formulae (II), (III).

As shown in fig. 1, there are three main types of key reactions for the synthesis of these compounds: the introduction of an amino substituent on an Ar ring, the bond forming reaction of an Ar ring segment and a tricyclic system, and the construction of a triazole ring in the tricyclic system. Therefore, the synthesis of the target compound can be carried out with different reaction priorities according to actual conditions. As shown in scheme 1, some compounds can be achieved by completing the bond formation reaction before introducing the amino group and finally constructing the triazole sequence as in example 8; as shown in scheme 2, some compounds can be prepared by the sequence of first synthesizing the triazole to obtain the tricyclic fragment, then performing the bond-forming reaction, and finally introducing the amino group, as in examples 13 and 14; as shown in scheme 3, some compounds can be accomplished by the sequence of introduction of the amino group followed by coupling reaction to build the triazole as shown in examples 1 and 7; as shown in scheme 4, a further portion of the compounds may be accomplished by the method of schemes 2 and 3, in which the bond formation reaction is carried out at the end, as in example 12.

The compound obtained in the above-mentioned manner can be further modified at the peripheral position thereof to give a desired compound. Synthetic chemical transformations can be found, for example: larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley and Sons (1999); l.fieser and m.fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L.Patquette, edition, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and its successors.

Prior to use, the compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein may be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable methods.

Pharmaceutical composition and use

Compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein may be administered in various known ways, e.g., orally, parenterally, by inhalation or by implantation. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intraspinal, intralesional and intracranial injection or infusion.

The composition for oral administration may be any orally acceptable dosage form including, but not limited to: tablets, capsules, pills, powders, emulsions and aqueous suspensions, dispersions and solutions. Commonly used tablet carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added to tablets. When administered orally in capsule form, useful diluents include lactose and dried corn starch. When administered orally in the form of an aqueous suspension or emulsion, the active ingredient may be suspended or dissolved in the oily phase by emulsifying or suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Sterile injectable compositions, such as aqueous or oleaginous suspensions, can be formulated according to the techniques known in the art using suitable dispersing or wetting agents (e.g., tween 80) and suspending agents. The sterile injectable composition may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the pharmaceutically acceptable carriers and solvents that may be used are mannitol, water, ringer's solution and physiological saline. In addition, sterile, non-volatile oils, such as synthetic mono-or diglycerides, are conventionally employed as a solvent or suspending medium. Fatty acids such as oleic acid and its glyceride derivatives, as well as natural pharmaceutically acceptable oils such as olive oil or castor oil (especially the polyoxyethylated versions thereof) are commonly used in the preparation of injectable compositions. These oil solutions or suspensions may also contain long chain alcoholic diluents or dispersants or carboxymethyl cellulose or similar dispersants.

Inhalation compositions may be prepared according to techniques well known in the art of pharmaceutical formulation, using benzyl alcohol or other suitable preservatives, using absorption promoters to enhance bioavailability, using fluorocarbons and/or other solubilizing or dispersing agents known in the art, or may be prepared as solutions in saline.

Topical compositions may be formulated in the form of oils, creams, lotions, ointments and the like. Suitable carriers for use in the composition include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (i.e., alcohols having greater than 12 carbon atoms). In some embodiments, a pharmaceutically acceptable carrier is a carrier in which the active ingredient is soluble. If desired, the composition may also contain emulsifiers, stabilizers, humectants and antioxidants, as well as substances which impart color or fragrance thereto. In addition, transdermal penetration enhancers may also be added to the topical formulations. Examples of such accelerators can be found in U.S. patent nos. 3,989,816 and 4,444,762.

Creams may be formulated from a mixture of mineral oil, self-emulsifying beeswax and water, with the active ingredient dissolved in a small amount of oil, such as almond oil, mixed therein. One example of a cream comprises, by weight, about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil. Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, for example almond oil, with warm soft paraffin and cooling the mixture. An example of an ointment comprises about 30% almond oil and about 70% white soft paraffin by weight.

A pharmaceutically acceptable carrier refers to a carrier that is compatible with (in some embodiments, stabilizes) the active ingredient in the composition and is not deleterious to the subject being treated. For example, solubilizing agents such as cyclodextrins (which form specific, more soluble complexes with the compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein) can be used as pharmaceutical excipients to deliver the active ingredient. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D & C Yellow No. 10 (D & C Yellow # 10).

Suitable in vitro assays may be used to preliminarily evaluate the efficacy of the compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein to inhibit ERK activity. For example, compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein may be contacted with ERK kinase or cells and the rate of inhibition of ERK activity determined. The efficacy of the compounds of formula (I) and/or pharmaceutically acceptable salts thereof as described herein for treating or preventing cancer or autoimmune diseases can be further tested by in vivo assays. For example, a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein can be administered to an animal (e.g., a mouse model) having cancer or an autoimmune disease and then its therapeutic effect evaluated. Based on the above results, it is also possible to determine a suitable dosage range and administration route for animals such as humans.

The compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in a subject having cancer.

The term "cancer" as used herein refers to a cellular disorder characterized by uncontrolled or deregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and/or the ability to establish new foci of growth elsewhere. The term "cancer" includes, but is not limited to: solid tumors and hematological tumors. The term "cancer" includes cancers of the skin, tissues, organs, bone, cartilage, blood and blood vessels. The term "cancer" includes both primary and metastatic cancers.

Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; kidney cancers, including, for example, metastatic renal cell carcinoma; hepatocellular carcinoma; lung cancer including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial cancer or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, squamous cell carcinoma of the head and neck; skin cancers including, for example, melanoma; neuroendocrine cancers, including metastatic neuroendocrine tumors; brain tumors, including, for example, gliomas, anaplastic oligodendrogliomas (anaplasic oligodendrogliomas), adult glioblastoma multiforme, and adult anaplastic astrocytomas; bone cancer; soft tissue sarcoma; and thyroid cancer, such as papillary thyroid cancer.

Non-limiting examples of hematological malignancies include Acute Myeloid Leukemia (AML); chronic Myelogenous Leukemia (CML), including accelerated phase CML and CML catastrophe phase (CML-BP); acute Lymphocytic Leukemia (ALL); chronic Lymphocytic Leukemia (CLL); hodgkin lymphoma; non-hodgkin's lymphoma (NHL) including follicular lymphoma and mantle cell lymphoma; b cell lymphoma; t cell lymphoma; multiple Myeloma (MM); waldenstrom's macroglobulinemia (Waldenstrom); myelodysplastic syndromes (MDS) including Refractory Anemia (RA), refractory anemia of cricothyroid granulocytes (RARS), refractory anemia of excess granulocytes (RAEB) and refractory anemia of excess granulocytes with excess processes blast in transformation (RAEB-T); and myeloproliferative syndrome (myeloproliferative syndrome).

The compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein may be used to achieve a beneficial therapeutic or prophylactic effect, for example, in a subject suffering from an autoimmune disease.

The term "autoimmune disease" refers to a disease or condition caused by an immune response to a self-antigen in a body resulting in damage to a self-tissue or organ. Examples of autoimmune diseases include, but are not limited to: chronic Obstructive Pulmonary Disease (COPD), allergic rhinitis, lupus erythematosus, myasthenia gravis, Multiple Sclerosis (MS), Rheumatoid Arthritis (RA), psoriasis, Inflammatory Bowel Disease (IBD), asthma, idiopathic thrombocytopenic purpura (idiopathetic thrombotic purpura), and myeloproliferative diseases such as myelofibrosis (myelofibrosis), polycythemia vera/essential thrombocytosis myelofibrosis (post-PV/ET myelofibrosis).

In addition, compounds of formula (I) described herein (e.g., compounds of sub-formula (I-1), (I-2), or (I-3), as well as compounds 1-321) and/or pharmaceutically acceptable salts thereof can be administered in combination with additional therapeutic agents for the treatment of cancer. The additional therapeutic agent may be administered separately from the compound of formula (I) and/or pharmaceutically acceptable salts thereof described herein, or it may be included in a pharmaceutical composition, such as a fixed dose combination, in accordance with the disclosure of the present application. In some embodiments, the additional therapeutic agent is an agent known or found to be effective for treating a disease modulated by ERK, such as another ERK inhibitor or a compound effective to antagonize another target associated with the particular disease. The combination may be used to improve the therapeutic effect (e.g., by including in the combination a compound that enhances the efficacy or effectiveness of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein), reduce one or more side effects, or reduce the required dosage of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein.

In some embodiments, a compound of formula (I) described herein (e.g., a compound of sub-formula (I-1), (I-2), or (I-3), as well as compounds 1-321), and/or a pharmaceutically acceptable salt thereof, can be administered in combination with an anti-tumor agent. The term "anti-neoplastic agent" as used herein refers to any agent administered to an individual with cancer for the purpose of treating cancer, including, but not limited to, radiotherapeutic agents, chemotherapeutic agents, immunotherapeutic agents, targeted therapeutic agents, and the like.

Non-limiting examples of chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and analogs or metabolites thereof, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, demethoxydaunorubicin, and daunomycin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, nitrosourea mustard, lomustine, methylcyclohexylnitrosourea, streptozotocin, dacarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators and free radical generators such as bleomycin; and nucleoside analogs (e.g., 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidineMercaptopurine, thioguanine, pentostatin, and hydroxyurea); paclitaxel, docetaxel and related analogs; vincristine, vinblastine and related analogs; thalidomide and related analogs (e.g., CC-5013 and CC-4047).

Non-limiting examples of immunotherapeutic or targeted therapeutics include MEK inhibitors, RAF inhibitors, mTOR inhibitors, PAK inhibitors, CDK inhibitors, VEGFR inhibitors, PARP inhibitors, ERBB inhibitors, PI3K inhibitors, AKT inhibitors, autophagy inhibitors, immune checkpoint inhibitors such as PD-1 inhibitors, PD-L1 inhibitors, and the like. For example: trametinib (Trametinib), cabitinib (cobimenib), Vemurafenib (Vemurafenib), Dabrafenib (Dabrafenaib), Rapamycin (Rapamycin), Temsirolimus (Temsirolimus), Everolimus (Everolimus), Peppercillin (Palbociclib), Ribociclib (Ribociclib), Furazolinib (Fruquintinib), Olaparib (Olaparib), Nilaparib (Niraparib), Neratinib (Neratinib), Chloroquine (Chloroquine), Hydroxychloroquine (Hydroxygiroquine), LXH254, Seluminib (Seluminifenib), LGAMLY 4996, Boemaciclib (Abemaciclib), P6 Byfibrutin A-05 (Veibrutinib 14425-05), Abbicinicob (Ab-x), Abelmibritunib (Avibritunib), Ab-Ab (Avibritunib (Avicula-b), Abelmicinib (Avicula-B), Abelmicinib (Ab-Abelib), Ab-Abelizumab (Ab-Abelib), Ab (Abelizumab (Abelib), Abelib (Abelib), Abelib) (Abelib), Abelib) (Abelib), Abelib) (Abelib) and Abelib) (Abelib) and Abelib) (Abelib) and Abelib) (Ab, Tereprinizumab (JS001), Cedilizumab (Sintilimab), Carritizumab (Camrelizumab), and the like.

Examples

The following examples are intended as purely illustrative examples and should not be considered as limiting the invention in any way. Although efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), some experimental errors and deviations should be accounted for.

Unless otherwise indicated, parts are parts by weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. All MS (Mass Spectrometry) data were measured by agilent 6120 and/or agilent 1100.¹The H-NMR spectrum was obtained with a nuclear magnetic resonance instrument at 400 MHz. NMR spectra were obtained using deuterated chloroform as a solution (expressed in ppm) using chloroform as a reference standard (7.26ppm) or tetramethylsilane contained under appropriate conditions as a reference standard (0.00 ppm). Other nuclear magnetic solvents are used as needed. In representing the multiplicity of peaks, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), q (quartet), br (broad), dd (doublet),dt (double triplet). Coupling constants are given in hertz (Hz).

All reagents used in the present invention, except intermediates, are commercially available.

The names of all compounds except reagents were generated by Chemdraw. If both the name and the structural formula of a compound are given, the structure of the compound is taken as the standard unless the context indicates that the structure of the compound is incorrect and the name is correct.

In any of the structural formulae herein, if there is a free valence on any atom, the free valence is actually a hydrogen atom not specifically depicted for the sake of simplicity.

In the examples below, the following abbreviations are used:

boc tert-butoxycarbonyl

BPIN bis-pinacol boronate

CDI N-N' -carbonyldiimidazole

DCM chloromethane

DIAD diisopropyl azodicarboxylate

DIBAL-H isobutyl aluminium hydride

DIPEA N, N-diisopropylethylamine

DMF N, N-dimethylformamide

EA acid ethyl ester

EDCI 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride

Et Ethyl group

h hours

HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylureaHexafluorophosphates

HOBT 1-hydroxybenzotriazole

ISCO TELEDYNEISCOCOMOBiFlashRF + chromatographic system

LDA isopropyl amino lithium

min for

MeOH methanol

Ms methanesulfonyl

NBS N-bromosuccinimide

Sodium NaHMDS bis (trimethylsilyl) amide

PE Petroleum Ether

PdCl₂(PPh₃)₂Bis (triphenylphosphine) palladium (II) dichloride

Pd₂(dba)₃Tris (dibenzylideneacetone) dipalladium (0)

Pd(dppf)Cl₂·CH₂Cl₂1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex

Pd(OAc)₂Palladium acetate (II)

Pd(PPh₃)₄Tetrakis (triphenylphosphine) palladium (0)

PMB p-methoxybenzyl

PPh₃Triphenylphosphine

PTLC preparative thin layer chromatography

SEM 2- (trimethylsilyl) ethoxymethyl

THF tetrahydrofuran

TBDPS tert-butyldiphenylsilyl group

TFA trifluoroacetic acid

Ts p-toluenesulfonyl group

Xantphos 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene

Intermediate 1

4-chloro-N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine

(A) 2-chloro-4- ((4-methoxybenzyl) oxy) pyrimidine

To a solution of (4-methoxyphenyl) methanol (40.8g, 295.3mmol) in THF (200mL) was added NaH (16.1g, 402.5mmol, 60% dispersion in liquid paraffin) portionwise at 0 deg.C. The mixture was stirred for a further 30 minutes at 0 ℃ under a nitrogen atmosphere. The mixture was then slowly added to a 0 deg.C solution of 2, 4-dichloropyrimidine (40.0g, 268.5mmol) in THF (200 mL). After addition, the mixture was stirred at room temperature overnight and the reaction was quenched with ice water (200 mL). The mixture was separated, the aqueous layer was extracted with THF (200mL), and the combined organic layers were washed with brine and dried over anhydrous sodium. After filtration, the filtrate was concentrated to give an off-white solid (73.0g) which was used directly in the next step.

(B)4- ((4-methoxybenzyl) oxy) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine

To a solution of 2-chloro-4- ((4-methoxybenzyl) oxy) pyrimidine (73.0g, obtained from the previous step) and 1-methyl-1H-pyrazol-5-amine (56.6g, 582.4mmol) in 1, 4-dioxane (730mL) was added Pd (OAc)₂(3.27g, 14.6mmol)), Xantphos (16.8g, 29.1mmol) and KOAc (85.7g, 873.6 mmol). The mixture was purged with nitrogen and stirred at 90 ℃ overnight under nitrogen atmosphere. After cooling, the mixture was filtered and the filter cake was washed with EA (200 mL). The combined filtrates were washed with brine. After separation, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified using ISCO (elution with water containing 0% to 100% methanol) to give a pale yellow solid (38.5g, yield 42.4%). MS (m/z): 312.1(M + H)⁺

(C) 4-chloro-N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine

To a three-neck round bottom flask was added 4- ((4-methoxybenzyl) oxy) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine (38.5g, 123.7mmol) and TFA (150 mL). The mixture was then stirred at room temperature for 3 hours. The mixture was then concentrated to give a brown solid, which was suspended in POCl₃(150 mL). The mixture was stirred at 100 ℃ for 3 hours, thenAnd then concentrated. The residue was poured into ice water and saturated NaHCO was used₃Adjusting the pH value of the solution to 8-9. The mixture was then extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown solid (23.3g, 89.6% yield). MS (m/z): 210.0(M + H)⁺

The following intermediates were prepared following the procedure for intermediate 1 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Intermediate 3

5-chloro-4-iodo-N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine

To a solution of 1-methyl-1H-pyrazol-5-amine (39.4g, 406mmol) in anhydrous THF (1500mL) was added NaHMDS (406mL, 406mmol, 1mol/LTHF solution) under a nitrogen atmosphere at 0 deg.C, and the solution was stirred for 30 minutes. 5-chloro-2-fluoro-4-iodopyridine (87g, 338mmol) was then added and the resulting mixture was refluxed overnight. The reaction was quenched with methanol/water (40mL, 1: 1) and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA ═ 1: 1) and ISCO (eluted with water containing 0% to 100% methanol) to give a pale yellow solid (39.8g, yield 35%). MS (m/z): 334.9(M + H)⁺

The following intermediates were prepared following the procedure for intermediate 3 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Intermediate 5

5-fluoro-4-iodo-N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine

(A) N- (1-methyl-1H-pyrazol-5-yl) acetamide

To a solution of 1-methyl-1H-pyrazol-5-amine (87g, 90mmol) and acetic anhydride (101g, 99mmol) in EA (1000mL) was added NaOAc (81g, 99mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was then filtered and the filter cake was washed with EA. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (DCM: MeOH ═ 25: 1) to give a pale yellow solid (98g, 78% yield). MS (m/z): 140.1(M + H)⁺

(B) 5-fluoro-4-iodo-N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine

To a solution of N- (1-methyl-1H-pyrazol-5-yl) acetamide (53g, 380mmol) in anhydrous THF/DMF (800mL, 7: 1) at 0 deg.C under nitrogen was added NaHMDS (354mL, 354mmol, 1M solution in THF), and the solution was stirred at room temperature for 30 minutes. 2, 5-difluoro-4-iodopyridine (61g, 253mmol) was then added and the solution was refluxed. The reaction was quenched with methanol/water (200mL, 1: 1) and concentrated in vacuo. The residue was dissolved in methanol/water (200mL, 1: 1). Lithium hydroxide monohydrate (11g, 253mmol) was added, and the resulting solution was stirred at room temperature for 1 hour. The solvent was removed by rotary evaporator and the residue was purified by silica gel chromatography (PE: EA ═ 1: 1) and ISCO (eluted with water containing 0-100% methanol) to give the title compound as a pink solid (30g, 37.5% yield). MS (m/z): 319.0(M + H)⁺

Intermediate 6

4-iodo-N- (1-methyl-1H-pyrazol-5-yl) -5- (trifluoromethyl) pyridin-2-amine

(A) 2-bromo-4-as-5- (trifluoromethyl) pyridine

To a solution of diisopropylamine (3.1g, 30mmol) in dry THF (150mL) under a nitrogen atmosphere at-70 deg.C was added n-butyllithium (12.5mL, 30mmol, 2.4mol/L solution in THF).The solution was stirred at-10 ℃ for 30 minutes. The solution was cooled again to-70 ℃ and 2-bromo-5- (trifluoromethyl) pyridine (5.6g, 25mmol) was added. The resulting dark brown solution was stirred at-70 ℃ for 2 hours. Iodine (6.4g, 25mmol) was added portionwise and the solution stirred for a further 1 h. The reaction was quenched with 10% HOAc (50mL) and saturated sodium thiosulfate solution. The mixture was extracted with EA. The organic layers were combined and dried in vacuo. The residue was purified by silica gel chromatography (PE: EA ═ 50: 1) to give the title compound as a yellow solid (6.1g, yield 69%). MS (m/z): 351.7, 353.7(M + H)⁺

(B) 4-iodo-N- (1-methyl-1H-pyrazol-5-yl) -5- (trifluoromethyl) pyridin-2-amine

To a solution of N- (1-methyl-1H-pyrazol-5-yl) acetamide (1.1g, 4mmol) in anhydrous THF (50mL) at room temperature under a nitrogen atmosphere was added NaH (320mg, 8mmol, 60% dispersion in liquid paraffin) in portions. The mixture was stirred for 30 minutes. 2-bromo-4-iodo-5- (trifluoromethyl) pyridine (556mg, 4mmol) was added, and the mixture was refluxed overnight. The reaction was quenched with methanol. The solvent was removed by rotary evaporator and the residue was purified by ISCO (eluting with water containing 0% to 100% methanol) and silica gel chromatography (DCM: MeOH ═ 25: 1) to give the compound as a brown gum (640mg, 44% yield). MS (m/z): 368.9(M + H)⁺

The following intermediates were prepared following the procedure for intermediate 6 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Intermediate 8

N-cyclopropyl-4-iodo-5- (trifluoromethyl) pyridin-2-amine

(A) N-cyclopropyl-4-iodo-5- (trifluoromethyl) pyridin-2-amine

To a solution of 2-bromo-4-iodo-5- (trifluoromethyl) pyridine (352mg, 1mmol) andto a solution of cyclopropylamine (114mg, 2mmol) in anhydrous THF (10mL) was added DIPEA (390mg, 3 mmol). The solution was refluxed overnight. The solvent was removed on a rotary evaporator and the residue was purified on ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a yellow solid (184mg, 56% yield). MS (m/z): 328.9(M + H)⁺

The following intermediates were prepared following the procedure for intermediate 8 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Intermediate 11

5-Ethyl-4-iodo-N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine

(A) 5-ethyl-2-fluoropyridines

To a solution of 5-bromo-2-fluoropyridine (5.5g, 31.3mmol) and triethylborane (1M) (63mL, 62.6mmol) in DMF (30mL) was added K₂CO₃(12.9g, 94mmol) and Pd (PPh)₃)₄(1.8g, 1.6 mmol). The mixture was degassed and stirred at 80 ℃ overnight under nitrogen, diluted with water, extracted with hexane, washed with water and brine, anhydrous Na₂SO₄Dried, concentrated and purified using ISCO (eluted with PE containing 0% to 100% DCM) to give the title compound as a yellow liquid (3g, yield 77%). MS (m/z): 126.0(M + H)⁺

(B) 5-Ethyl-2-fluoro-3-iodopyridine

LDA (6mL, 12mmol, 2M THF solution) was added dropwise to a solution of 5-ethyl-2-fluoropyridine (1g, 8mmol) in THF (20mL) at-78 deg.C under a nitrogen atmosphere. After stirring for 1 hour at-78 deg.C, iodine (3g, 12mmol) was added. The resulting mixture was stirred at-78 ℃ under nitrogen for 2 hours using HOAc and Na₂SO₃The aqueous solution was quenched and extracted with EA. The organic layer was washed with water and brine, anhydrous Na₂SO₄Dried, concentrated and purified with ISCO (eluted with PE containing 0% to 100% EA) to give the title compound as a yellow oil (1.1g, 55%). MS (m/z): 251.9(M + H)⁺

(C) 5-Ethyl-2-fluoro-4-iodopyridine

LDA (3.3mL, 6.6mmol, 2M in THF) was added dropwise to a solution of 5-ethyl-2-fluoro-3-iodopyridine (1.1g, 4.4mmol) in THF (20mL) at-78 deg.C under a nitrogen atmosphere. The resulting mixture was stirred at-78 ℃ under nitrogen for 2 hours, quenched with saturated aqueous ammonium chloride solution and extracted with EA. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified with ISCO (0% to 100% EA in PE) to give the title compound as a yellow oil (860mg, 78% yield).

(D) 5-Ethyl-4-iodo-N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine

To a solution of 1-methyl-1H-pyrazol-5-amine (648mg, 6.6mmol) in THF (40mL) under a nitrogen atmosphere was added NaHMDS (6.6mL, 6.6mmol, 1M in THF). After stirring at room temperature for 1 hour, 5-ethyl-2-fluoro-4-iodopyridine (830mg, 3.3mmol) was added. The resulting mixture was refluxed overnight, then quenched with water and methanol, concentrated and purified using ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a yellow solid (100mg, 9% yield). MS (m/z): 328.9(M + H)⁺

Intermediate 12

2-bromo-4-iodo-5-methoxypyridine

(A) 2-bromo-5-methoxypyridine

To a solution of 6-bromopyridin-3-ol (1.7g, 10mmol) in anhydrous DMF (20mL) under nitrogen at 0 ℃ was added NaH (600mg, 15mmol, 60% dispersed in liquid paraffin) in portions. The resulting mixture was stirred for 30 minutes. Methyl iodide (2.1g, 15mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride solution. The mixture was extracted with EA. The organic phases were combined, concentrated in vacuo and concentrated. Disabled personThe residue was purified by silica gel chromatography (PE: EA ═ 5: 1) to give the title compound as a yellow solid (1.7g, 91% yield). MS (m/z): 188.0/190.0(M + H)⁺

(B) 2-bromo-4-iodo-5-methoxypyridine

To a solution of 2-bromo-5-methoxypyridine (1.5g, 8mmol) in anhydrous THF (50mL) at-70 deg.C under a nitrogen atmosphere was added LDA (4mL, 8mmol, 2M in THF). The solution was stirred at-70 ℃ for 2 hours. Iodine (2.1g, 8mmol) was added portionwise and the solution stirred for a further 1 h. The reaction was quenched with 10% HOAc and saturated sodium thiosulfate solution. The mixture was extracted with DCM. The organic phases were combined and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA ═ 5: 1) to give the title compound as a pale yellow solid (900mg, yield 39%). MS (m/z): 313.8/315.8(M + H)⁺

Intermediate 13

8-bromo-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-1-ketones

(A) 4-bromo-1- (3- ((tert-butoxycarbonyl) amino) propyl) -1H-pyrrole-2-carboxylic acid methyl ester

To a mixture of methyl 4-bromo-1H-pyrrole-2-carboxylate (100g, 0.49mol) and tert-butyl (3-bromopropyl) carbamate (122g, 0.51mol) in DMF (500mL) was added K₂CO₃(169g, 1.23 mol). The mixture was stirred at room temperature overnight. Then filter out K₂CO₃The filtrate was diluted with water and extracted with EA. The organic layer was washed with brine, over anhydrous Na₂SO₄Drying and concentration gave the title compound as a yellow solid (166g, yield 93.9%). MS (m/z): 261.0/263.0(M + H)⁺

(B)1- (3-aminopropyl) -4-bromo-1H-pyrrole-2-carboxylic acid methyl ester

Reacting 4-bromo-1- (3- ((tert-butoxycarbonyl) amino) propyl)) A mixture of methyl (166g, 0.46mol) of-1H-pyrrole-2-carboxylate in trifluoroacetic acid (200mL) was stirred at 60 ℃ for 3 hours. The mixture was concentrated in saturated NaHCO₃Partitioning between solution and EA. The organic layer was washed with brine, anhydrous Na₂SO₄Drying and concentration gave the title compound as a yellow solid (114.37g, 95.2% yield). MS (m/z): 261.0/263.0(M + H)⁺

(C) 8-bromo-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-1-ketones

To a mixture of methyl 1- (3-aminopropyl) -4-bromo-1H-pyrrole-2-carboxylate (114g, 0.44mol) in MeOH (800mL) was added K₂CO₃(151g, 1.10 mol). The mixture was stirred at 80 ℃ for 3 hours. Then filter out K₂CO₃And the filtrate is concentrated. The residue was diluted with water and extracted with EA. The organic layer was washed with brine, anhydrous Na₂SO₄Drying, concentration and recrystallization afforded the title compound as a white solid (70.0g, 69.9% yield). MS (m/z): 228.9/230.9(M + H)⁺

Intermediate 14

8-bromo-9-chloro-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-1-ketones

(A) 4-bromo-3-chloro-1H-pyrrole-2-carboxylic acid methyl ester

To a solution of methyl 3-chloro-1H-pyrrole-2-carboxylate (10g, 62.7mmol) in DMF (400mL) at room temperature was added dropwise Br₂(3.2mL, 62.7 mmol). The mixture was stirred at room temperature for 8 hours. The mixture was then diluted with water (2.0L) and extracted with EA (3X 1.5L). The organic layer was concentrated and the residue was purified by ISCO (elution with water containing 0% to 100% methanol) to give the title compound asYellow solid (7.0g, yield 46.9%). MS (m/z): 237.8, 239.8(M + H)⁺

(B) 4-bromo-1- (3-bromopropyl) -3-chloro-1H-pyrrole-2-carboxylic acid methyl ester

4-bromo-3-chloro-1H-pyrrole-2-carboxylic acid methyl ester (6g, 25.2mmol), 1, 3-dibromopropane (50.9g, 252mmol) and K₂CO₃(7.0g, 50.4mmol) in CH₃The mixture in CN (150mL) was stirred at 70 ℃ for 3 hours. The reaction mixture was concentrated and partitioned between water (200mL) and EA (200 mL). The aqueous layer was further extracted with EA (2X 200 mL). The combined organic layers were concentrated and purified using ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a white solid (4.2g, 46.3% yield). MS (m/z): 359.8(M + H)⁺

(C) 8-bromo-9-chloro-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-1-ketones

A mixture of 4-bromo-1- (3-bromopropyl) -3-chloro-1H-pyrrole-2-carboxylic acid methyl ester (500mg, 1.39mmol) in ammonium hydroxide (6mL) and MeOH (10mL) was stirred under microwave at 120 ℃ for 3H. The reaction mixture was concentrated and washed with EA (1mL) to give the crude title compound as a white solid (500mg, used directly in the next step). MS (m/z): 262.9, 264.9(M + H)⁺

The following intermediates were prepared following the procedure for intermediate 14 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Intermediate 16

8-bromo-9-fluoro-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-1-ketones

(A)1- (3- (((tert-butoxycarbonyl) amino) propyl) -3-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester

Ethyl 3-fluoro-1H-pyrrole-2-carboxylate (3.14g, 20mmol), (3-bromopropyl) carbamic acid tert-butyl ester (7.14g, 30mmol) and Cs₂CO₃A mixture of (9.75g, 30mmol) in DMF (20mL) was heated at 80 ℃ overnight. After cooling to room temperature, the mixture was extracted with EA, the organic phase was washed with water and brine and purified with ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a yellow solid (6.28 g). MS (m/z): 315.1(M + H)⁺

(B) 4-bromo-1- (3- ((tert-butoxycarbonyl) amino) propyl) -3-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester

To a solution of ethyl 1- (3- (((tert-butoxycarbonyl) amino) propyl) -3-fluoro-1H-pyrrole-2-carboxylate (6.28g, 20mmol) in DMF (15mL) was added NBS (3.56g, 20mmol) portionwise at room temperature, the mixture was stirred for 4H, over Na₂SO₃Quench with aqueous EA, extract with EA, and concentrate to give the crude title compound. MS (m/z): 414.9, 416.9(M +23)⁺

(C) 8-bromo-9-fluoro-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-1-ketones

To a solution of ethyl 4-bromo-1- (3- ((tert-butoxycarbonyl) amino) propyl) -3-fluoro-1H-pyrrole-2-carboxylate (6.1g, 15.5mmol) in methanol (10mL) was added concentrated hydrochloric acid (3mL), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo. The residue was adjusted to pH 8 with aqueous sodium bicarbonate and extracted with DCM. The organic phase was concentrated and the residue dissolved in MeOH (25mL) and K₂CO₃(6.42g, 46.5 mmol). The mixture was stirred at 80 ℃ for 48 hours. Then filter out K₂CO₃And concentrating the filtrate. The residue was purified by ISCO (eluting with PE containing 50% to 100% EA) to give the title compound as a white solid (3g, 78.7% yield). MS (m/z): 247.0, 249.0(M+H)⁺

Intermediate 17

7-bromo-3, 4-dihydropyrrolo [1, 2-a ] pyrazin-1 (2H) -one

(A) 4-bromo-1- (cyanomethyl) -1H-pyrrole-2-carboxylic acid methyl ester

To a solution of 4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (4g, 19.6mmol) in DMF (15mL) was added K₂CO₃(5.4g, 39.2mmol) and 2-bromoacetonitrile (2.4g, 19.6 mmol). The resulting mixture was stirred at 80 ℃ for 3 hours, poured into water and extracted with EA. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as a yellow solid (5.1 g). MS (m/z): 243.0/245.0(M + H)⁺

(B)1- (2-aminoethyl) -4-bromo-1H-pyrrole-2-carboxylic acid methyl ester

To a solution of 4-bromo-1- (cyanomethyl) -1H-pyrrole-2-carboxylic acid methyl ester (5.1g, 19.6mmol) in THF (20mL) at room temperature was added dropwise BH₃.Me₂S (10mL, 19.6mmol, 2M in THF). The resulting mixture was then stirred at 60 ℃ overnight, quenched with cold aqueous sodium bicarbonate at 0 ℃ and extracted with EA. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as a yellow solid (4.5g, yield 93%). MS (m/z): 246.9/248.9(M + H)⁺

(C) 7-bromo-3, 4-dihydropyrrolo [1, 2-a ] pyrazin-1 (2H) -one

To a solution of methyl 1- (2-aminoethyl) -4-bromo-1H-pyrrole-2-carboxylate (4.5g, 18.2mmol) in MeOH (20mL) was added ammonium hydroxide (3 mL). The resulting mixture was stirred at room temperature overnight, concentrated and purified using ISCO (eluted with 0% to 15% MeOH in DCM) to give the title compound as a brown solid (3.2g, 82% yield). MS (m/z): 214.9/216.9(M + H)⁺

Intermediate 18

8 '-bromo-2', 3 '-dihydro-1' H-, 5 'H-spiro [ cyclopropane-1, 4' -pyrrolo [1, 2-a ]][1，4]Diaza derivatives]-1' -ketones

(A) ((1- (hydroxymethyl) cyclopropyl) methyl) carbamic acid tert-butyl ester

To a solution of (1- (aminomethyl) cyclopropyl) methanol (5g, 49.5mmol) in DCM (40mL) was added Boc₂O (10.8g, 49.5mmol) and DIPEA (12.8g, 99 mmol). The mixture was stirred at room temperature for 2 hours, concentrated and purified using ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a yellow solid (9.4g, 94% yield).

(B) 4-bromo-1- ((1- (((tert-butoxycarbonyl) amino) methyl) cyclopropyl) methyl) -1H-pyrrole-2-carboxylic acid methyl ester

To tert-butyl ((1- (hydroxymethyl) cyclopropyl) methyl) carbamate (4.9g, 24.5mmol), methyl 4-bromo-1H-pyrrole-2-carboxylate (5g, 24.5mmol) and PPh at 0 ℃ under a nitrogen atmosphere₃(9.6g, 36.8mmol) in THF (20mL) was added DIAD (7.4g, 36.8mmol) dropwise. The mixture was stirred at room temperature overnight, concentrated and purified with ISCO (eluted with PE containing 0% to 100% EA) to give the title compound as a yellow oil (9.2g, crude).

(C)8 '-bromo-2', 3 '-hydrido-1' H-, 5 'H-spiro [ cyclopropane-1, 4' -pyrrolo [1, 2-a ]][1，4]Diaza derivatives]-1' -ketones

A solution of methyl 4-bromo-1- ((1- (((tert-butoxycarbonyl) amino) methyl) cyclopropyl) methyl) -1H-pyrrole-2-carboxylate (9.2g, 23.8mmol) in TFA (10mL) was stirred at room temperature for 2H. The mixture was concentrated in vacuo. The residue was dissolved in MeOH (30mL) and K2CO was added₃(9.8g, 71.3mmol) and Et₃N (7.2g, 71.3 mmol). The mixture was stirred at room temperature overnight, concentrated and purified using ISCO (eluted with 0% to 100% methanol in water) to give the title compoundAs a yellow solid (4.5g, yield 74%). MS (m/z): 255.0/257.0(M + H)⁺

The following intermediates were prepared following the procedure for intermediate 18 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Intermediate 37

(R) -8-bromo-4-methoxy-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-1-ketones

(A) (R) -8-bromo-4-hydroxy-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-1-ketones

To a solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (60.0g, 0.294mol) and (S) -2- (chloromethyl) oxirane (68.0g, 0.735mol) in EtOH (600mL) at room temperature was added Cs₂CO₃(115g, 0.352 mol). After stirring for 2 hours at 80 ℃, the mixture was diluted with water and extracted with EA. The organic layer was concentrated and the residue was dissolved in EtOH (1000mL) and ammonium hydroxide (100mL, 25-28 wt% aqueous). The mixture was stirred at 80 ℃ for 16 hours. The mixture is concentrated and the residue is recrystallized (EA andEtOH) to give the title compound as a white solid (25g, 34.7% over two steps). MS (m/z): 245.1/247.1(M + H)⁺

(B) (R) -8-bromo-4-methoxy-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-1-ketones

To (R) -8-bromo-4-hydroxy-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivativesTo a solution of (20.0g, 0.082mol) in DCM (300mL) was added CF₃SO₃Me (20g, 0.122 mol). After stirring for 16 hours at 40 ℃, the mixture was concentrated. The residue was dissolved in DMF (250mL) and cooled to 0 ℃. NaH (10.0g, 0.255mol, 60% dispersed in liquid paraffin) was added at 0 ℃ and the mixture was stirred at 0 ℃ for 30 minutes, followed by addition of methyl iodide (24.0g, 0.17 mol). After stirring at room temperature for 3 hours, the mixture was diluted with water and extracted with EA. The organic layer was washed with brine and water, concentrated to give a yellow oil, which was dissolved in MeOH (300 mL). Concentrated hydrochloric acid (60mL) was added and the mixture was stirred at 60 ℃ for 3 hours. The mixture was concentrated and redissolved in MeOH (400 mL). Adding K₂CO₃(40g, 0.289mol), the mixture was stirred at 60 ℃ for 4 hours. The mixture was filtered through celite. The filtrate was concentrated and the residue was purified by ISCO (eluting with water containing 0% to 100% methanol) to give the title compound as a white solid (10.0g, 47.7% total yield over four steps). MS (m/z): 259.0/261.0(M + H)⁺

Intermediate body 38

8 '-bromo-2', 3 '-dihydro-1' H, 5 'H-spiro [ cyclobutane-1, 4' -pyrrolo [1, 2-a ]][1，4]Diaza derivatives]-1' -ketones

(A) Cyclobutane-1, 1-dimethanol

At 0 deg.C under nitrogen atmosphere, to LiAlH₄(2.3g, 60mmol) in THF (30mL) was added dropwise a solution of diethyl cyclobutane-1, 1-dicarboxylate (8g, 40mmol) in THF (40 mL). The mixture was stirred at room temperature overnight, poured into water, adjusted to pH3 with 2N HCl, extracted with EA, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as a yellow oil (2.9g, 63% yield). MS (m/z): 117.1(M + H)⁺

(B)1, 1-bis (4-methylphenylsulfonyloxymethyl) cyclobutane

To a solution of cyclobutane-1, 1-dimethanol (2.9g, 25mmol) in DCM (30mL) at 0 deg.C were added TsCl (10.5g, 55mmol) and Et₃N (7.6g, 75 mmol). The mixture was stirred at room temperature for 3 hours, poured into water, extracted with DCM, washed with water and brine, dried over anhydrous sodium sulfate, concentrated, and purified with ISCO (0% to 100% EA in PE) to give the title compound as a white solid (3.5g, 33% yield). (C)8 '-bromo-2', 3 '-dihydro-1' H, 5 'H-spiro [ cyclobutane-1, 4' -pyrrolo [1, 2-a ]][1，4]Diaza derivatives]-1' -ketones

To a solution of 4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (1.7g, 8.2mmol) in DMF (10mL) was added K2CO₃(3.4g, 24.7mmol) and 1, 1-bis (4-methylphenylsulfonyloxymethyl) cyclobutane (3.5g, 8.2 mmol). The mixture was stirred at 100 ℃ for 5 hours, poured into water and extracted with DCM. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The resulting yellow oil was dissolved in DMF (10mL) and NaN₃(1.1g, 16.4 mmol). The mixture was stirred at 100 ℃ overnight. Poured into water and extracted with EA. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in EA (30mL) and PPh was added₃(2.2g, 8.2 mmol). The mixture was stirred at room temperature for 1 hour and concentrated. The residue was dissolved in MeOH (3mL) and concentrated hydrochloric acid (10mL) was added. The mixture was refluxed for 3 hours, concentrated and redissolvedIn MeOH (10mL), K2CO was added₃(3.4g, 24.7mmol) and Et₃N (4.2g, 41.1 mmol). The mixture was refluxed overnight, concentrated and purified with ISCO (0% to 100% methanol in water) to give the title compound as a yellow solid (1.2g, 54.1% yield). MS (m/z): 269.0/271.0(M + H)⁺

Intermediate 39

(R) -7-bromo-3- (fluoromethyl) -3, 4-dihydropyrrolo [1, 2-a ] pyrazin-1 (2H) -one

(A) N- (tert-Butoxycarbonyl) -O- (tert-butyldiphenylsilyl) -L-serine ethyl ester

To L-serine ethyl ester hydrochloride (8.0g, 47.2mmol) and Et₃N (9.5g, 94.3mmol) in DCM (80mL) was added (Boc)₂O (20.6g, 94.3 mmol). The resulting mixture was stirred at room temperature overnight, then diluted with water (100mL) and extracted with DCM (3X 100 mL). The combined organic layers were concentrated and redissolved in DCM (100 mL). 1H-imidazole (4.7g, 68.6mmol) and TBDPSCl (8.3g, 30.2mmol) were added at 0 ℃. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (100mL) and extracted with DCM (3X 100 mL). The combined organic layers were concentrated and the residue was purified by ISCO (eluting with 0% to 100% methanol in water) to give the title compound as an oil (5.8g, 26.1% yield). MS (m/z): 372.1(M + H-100)⁺

(B) (R) -1- ((tert-butyldiphenylsilyl) oxy) -3-hydroxypropan-2-yl) carbamic acid tert-butyl ester

DIBAL-H (22.9mL, 22.9mmol, 1M in hexanes) was added slowly to a solution of N- (tert-butoxycarbonyl) -O- (tert-butyldiphenylsilyl) -L-serine ethyl ester (5.4g, 11.4mmol) in DCM (40mL) at-78 ℃. The mixture was stirred at-78 ℃ for 30 minutes and then at room temperature overnight. The reaction mixture was cooled to 0 ℃ and quenched with 1mL of water, 1mL of 15% NaOH solution, and 3mL of water. The mixture was stirred at room temperature for 15 min, filtered and the filter cake was washed with DCM (100 mL). The combined filtrates were concentrated using ISCO (at 0%PE elution with 100% EA) to give the title compound as an oil (3.1g, 63.3% yield). MS (m/z): 330.1(M + H-100)⁺

(C) (R) -4-bromo-1- (2- (tert-butoxycarbonyl) amino) -3- ((tert-butyldiphenylsilyl) oxy) propyl-1H-pyrrole-2-carboxylic acid methyl ester

To tert-butyl (R) -1- ((tert-butyldiphenylsilyl) oxy) -3-hydroxypropan-2-yl) carbamate (2.5g, 5.8mmol), methyl 4-bromo-1H-pyrrole-2-carboxylate (1.2g, 5.8mmol) and PPh at 0 deg.C₃(2.3g, 8.7mmol) to a solution in anhydrous THF (100mL) was added DIAD (1.8g, 8.7mmol) slowly. The mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated and partitioned between water (100mL) and DCM (100 mL). The aqueous layer was further extracted with DCM (2X 100 mL). The combined organic layers were concentrated and purified using ISCO (eluted with PE containing 0% to 100% EA) to give the title compound as a white solid (2.0g, 55.8% yield). MS (m/z): 515.1/517.1(M + H-100)⁺

(D) (R) -7-bromo-3- (hydroxymethyl) -3, 4-dihydropyrrolo [1, 2-a ] pyrazin-1 (2H) -one

A solution of (R) -4-bromo-1- (2- (tert-butoxycarbonyl) amino) -3- ((tert-butyldiphenylsilyl) oxy) propyl-1H-pyrrole-2-carboxylic acid methyl ester (2.0g, 3.2mmol) in TFA (40mL) was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure. The residue was redissolved in MeOH (50mL) and Et was added₃N (1.6g, 16.2mmol) and K₂CO₃(2.2g, 16.2 mmol). The resulting mixture was refluxed for 4 hours. The reaction mixture was concentrated and partitioned between water (100mL) and DCM (100 mL). The aqueous layer was further extracted with DCM (2X 100 mL). The combined organic layers were concentrated and purified using ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a white solid (0.35g, 44.2% yield). MS (m/z): 245.0/247.0(M + H)⁺

(E) (R) -7-bromo-3- (fluoromethyl) -3, 4-dihydropyrrolo [1, 2-a ] pyrazin-1 (2H) -one

To (R) -7-bromo-3- (hydroxymethyl) -3, 4-dihydropyrrolo [1, 2-a ] at 0 deg.C]Diethylaminosulfur trifluoride (593mg, 3.68 mm) was added slowly to a solution of pyrazin-1 (2H) -one (450mg, 1.84mmol) in DCM (5mL)ol). The mixture was allowed to warm to room temperature and stirred under nitrogen overnight. The reaction was then quenched with saturated aqueous sodium bicarbonate and extracted with EA. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified using ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a yellow solid (228mg, yield 50.2%). MS (m/z): 246.9/248.9(M + H)⁺

The following intermediates were prepared following the procedure for intermediate 39 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Intermediate 41

7 ' -bromo-4 ' H-spiro [ cyclobutane-1, 3 ' -pyrrolo [1, 2-a ] pyrazine ] -1 ' (2 ' H) -one

(A) (1- (hydroxymethyl) cyclobutyl) carbamic acid tert-butyl ester

To (1-aminocyclobutyl) methanol hydrochloride (2g, 0.015mol) and Et at 0 deg.C₃To a solution of N (6.2mL, 0.044mol) in DCM (40mL) was added (B)_oc)₂O (3.5g, 0.016 mol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was partitioned between DCM (30mL) and saturated aqueous ammonium chloride (30 mL). The organic layer was washed with brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated. Recrystallization from PE/EA gave the title compound as a white solid (2.4g, 87.8% yield).¹H NMR(400MHz，DMSO-d6)δ6.57(s，1H)，4.64(t，J＝5.9Hz，1H)，3.39(d，J＝5.9Hz，2H)，2.17-2.02(m，2H)，1.97-1.85(m，2H)，1.75-1.52(m，2H)，1.35(s，9H).

(B) 4-bromo-1- ((1- ((tert-butoxycarbonyl) amino) cyclobutyl) methyl) -1H-pyrrole-2-carboxylic acid methyl ester

To a solution of tert-butyl (1- (hydroxymethyl) cyclobutyl) carbamate (2.1g, 0.010mol) in DCMEt was added₃N (2.8mL, 0.020mol), then MsCl (0.93mL, 0.012mol) was added dropwise at 0 ℃. The mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between DCM (30mL) and saturated aqueous ammonium chloride (30 mL). The organic layer was washed with brine (30mL), dried over anhydrous sodium sulfate, filtered, concentrated, the residue dissolved in DMF (40mL), and 4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (2g, 0.0096mol) and Cs added₂CO₃(6.3g, 0.0192 mol). The resulting mixture was stirred at 80 ℃ for 8 hours. The reaction mixture was partitioned between EA (200mL) and brine (300mL), and the aqueous layer was extracted with EA (200 mL. times.2). The combined organic layers were concentrated and purified using ISCO (PE/EA) to give the title compound as an oil (1.6g, 41% yield). MS (m/z): 287.0/289.0(M + H-100)⁺

(C)7 ' -bromo-4 ' H-spiro [ cyclobutane-1, 3 ' -pyrrolo [1, 2-a ] pyrazine ] -1 ' (2 ' H) -one

A mixture of 4-bromo-1- ((1- ((tert-butoxycarbonyl) amino) cyclobutyl) methyl) -1H-pyrrole-2-carboxylic acid methyl ester (1.6g, 0.0041mol) in TFA (10mL) was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure. The residue was dissolved in methanol (20mL) and Et was added₃N (3mL) and K₂CO₃(2g, 0.0144 mol). The mixture was refluxed for 6 hours and then concentrated. The residue was purified by ISCO (elution with water containing 0% to 100% methanol) to give the title compound as a white solid (0.7g, 66.8% yield). MS (m/z): 255.9/257.9(M + H)⁺

The following intermediates were prepared following the procedure for intermediate 41 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Intermediate 45: 7 ' -bromo-4 ' H-spiro [ cyclopropane-1, 3 ' -pyrrolo [1, 2-a ] pyrazine ] -1 ' (2 ' H) -one

(A) 4-bromo-1- (cyanomethyl) -1H-pyrrole-2-carboxylic acid methyl ester

4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (10g, 49.0mmol), 2-bromoacetonitrile (6.17g, 51.5mmol) and K₂CO₃(10.1g, 73.5mmol) in CH₃The mixture in CN (100mL) was heated at 80 ℃ for 3.5 hours. The reaction mixture was concentrated and partitioned between water (150mL) and EA (150 mL). The aqueous layer was further extracted with EA (2X 150 mL). The combined organic layers were concentrated to give the title compound as a white solid (11.0g, 92.4% yield). MS (m/z): 242.9/244.9(M + H)⁺

(B)7 ' -bromo-4 ' hydro-spiro [ cyclopropane-1, 3 ' -pyrrolo [1, 2-a ] pyrazine ] -1 ' (2 ' H) -one

To methyl 4-bromo-1- (cyanomethyl) -1H-pyrrole-2-carboxylate (3.0g, 12.3mmol) and Ti (O1Pr) at room temperature₄(5.2g, 18.2mmol) in THF (60mL) was added ethyl magnesium bromide (11mL, 33mmol, 3M in THF) dropwise. After the addition, the mixture was stirred at room temperature for 1 hour. Hydrochloric acid (1N, 50mL) was added. THF was removed under reduced pressure and the aqueous layer was extracted with DCM (3X 50 mL). The combined organic layers were concentrated and the residue was purified using ISCO (PE/EA) to give the title compound as a white solid (0.4g, yield 10.1%). MS (m/z): 241.0/243.0(M + H)⁺。¹H NMR(400MHz，DMSO-d6)δ8.01(brs，1H)，7.11(d，J＝1.8Hz，1H)，6.68(d，J＝1.8Hz，1H)，4.01(s，2H)，0.84-0.79(m，4H)。

The following intermediates were prepared following the procedure for intermediate 45 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Intermediate 47

7-bromo-3-methylpyrrolo [1, 2-a ] pyrazin-1 (2H) -one

(A) 4-bromo-1- (2-oxopropyl) -1H-pyrrole-2-carboxylic acid methyl ester

To a solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (2.0g, 0.01mol) in DMF (10mL) at 0 deg.C was added NaH (0.6g, 0.015mol, 60% in liquid paraffin). The mixture was stirred at 0 ℃ for 30 minutes, then 1-bromopropan-2-one (1.4g, 0.01mol) was added. The mixture was stirred at room temperature for 4 hours, diluted with water and extracted with EA. The organic layer was washed with water and brine, and concentrated to give the title compound as a yellow oil (2.5 g). MS (m/z): 259.9/261.9(M + H)⁺

(B) 7-bromo-3-methylpyrrolo [1, 2-a ] pyrazin-1 (2H) -one

To a solution of 4-bromo-1- (2-oxopropyl) -1H-pyrrole-2-carboxylic acid methyl ester (2.5g, 0.001mol) in methanol (10mL) was added a solution of ammonia in methanol (10mL, 7M). The mixture was sealed in a high pressure closed tank and stirred at 120 ℃ for 16 hours. The mixture was concentrated and the residue was purified by ISCO (elution with water containing 0% to 100% methanol) to give the title compound as a yellow solid (0.5g, 22.0% yield over two steps). MS (m/z): 227.0/229.0(M + H)⁺

Intermediate 48

1- (trifluoromethyl) cyclobutane-1-carbohydrazide

(A)1- (trifluoromethyl) cyclobutane-1-carbohydrazide

To a solution of 1- (trifluoromethyl) cyclobutane-1-carboxylic acid (20g, 119mmol) in methanol (30mL) was added concentrated sulfuric acid (0.75 mL). The mixture was refluxed overnight. Hydrazine hydrate (85%, 30mL) was added. The mixture was refluxed overnight again. The mixture was diluted with EA, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as a yellow solid (19g, yield 68%). MS (m/z): 183.0(M + H)⁺

The following intermediates were prepared following the procedure for intermediate 48 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Intermediate body 54

1- (trifluoromethyl) cyclopropane-1-carbohydrazide

(A)1- (trifluoromethyl) cyclopropane-1-carbohydrazide

To a solution of 1- (trifluoromethyl) cyclopropane-1-carboxylic acid (5.0g, 0.033mol), tert-butyl hydrazinecarboxylate (5.5g, 0.033mol) in DCM (50mL) were added EDCI (6.3g, 0.033mol), HOBT (4.4g, 0.033mol) and Et₃N (6.6g, 0.066 mol). The resulting mixture was stirred at room temperature for 16 hours, then washed with saturated sodium bicarbonate solution and water. The organic layer was concentrated in vacuo. The residue was dissolved in THF (80mL) and concentrated hydrochloric acid (10mL) was added. The resulting mixture was stirred at room temperature overnight. The mixture was then concentrated to give the crude title compound as a yellow solid (5.0 g). MS (m/z): 169.1(M + H)⁺

Intermediate 55

1- (difluoromethyl) -3, 3-difluorocyclobutane-1-carbohydrazide

(A) 1-formyl-3, 3-dimethoxycyclobutane-1-carboxylic acid isopropyl ester

DIBAL-H (35mL, 35.0mmol) was added slowly to a mixture of diisopropyl 3, 3-dimethoxycyclobutane-1, 1-dicarboxylate (5.0g, 17.34mmol) in DCM (50mL) at-78 ℃. The mixture was stirred at-78 ℃ for 0.5 hour under nitrogen atmosphere. The reaction was then quenched with 2N hydrochloric acid and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified using ISCO (eluted with PE containing 0% to 100% EA) to give the title compound as a colorless oil (1.83g, 45.8% yield).¹H NMR(400MHz，CDCl₃)δ9.67(s，1H)，5.11-5.03(m，1H)，3.14(s，3H)，3.11(s，3H)，2.65-2.58(m，4H)，1.24(d，J＝6.3Hz，6H)。

(B) 1-formyl-3-oxocyclobutane-1-carboxylic acid isopropyl ester

A mixture of 1-formyl-3, 3-dimethoxycyclobutane-1-carboxylic acid isopropyl ester (1.83g, 7.95mmol) in 6N HCl (10mL, 60mmol) was stirred at room temperature for 24 hours. The mixture was then extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as a colorless oil (950 mg). MS (m/z): 185.1(M + H)⁺

(C)1- (difluoromethyl) -3, 3-difluorocyclobutane-1-carboxylic acid isopropyl ester

To a mixture of isopropyl 1-formyl-3-oxocyclobutane-1-carboxylate (0.95g) in DCM (5mL) was slowly added diethylaminosulfur trifluoride (4.46g, 27.27mmol) at 0 deg.C. The mixture was stirred at room temperature under nitrogen atmosphere. The reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as a brown oil (1.2 g).¹H NMR(400MHz，CDCl₃)δ6.15(t，J＝56.2Hz，1H)，5.15-5.07(m，1H)，3.01-2.90(m，4H)，1.28(d，J＝6.3Hz，6H)。

(D)1- (difluoromethyl) -3, 3-difluorocyclobutane-1-carbohydrazide

To a mixture of isopropyl 1- (difluoromethyl) -3, 3-difluorocyclobutane-1-carboxylate (1.20g) in MeOH (10mL) was added hydrazine hydrate (85%, 3 mL). The mixture was stirred at 75 ℃ under nitrogen atmosphere overnight. The methanol is then removed and the residue is extracted with EA. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as a yellow oil (1.0 g). MS (m/z): 201.0(M + H)⁺

The following intermediates were prepared following the procedure for intermediate 55 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Example 1: synthesis of Compounds 1-35

Compound 1

4- (3- (2-fluorophenethyl) -6, 7-dihydro-5 ℃ -pyrrolo [1, 2-a ]][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine

(A)8- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-1-ketones

Reacting 8-bromo-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-1-one (6g, 26.19mmol), 4,4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -bis (1, 3, 2-dioxaborolane) (11.97g, 47.15mmol), Pd₂(dba)₃A mixture of (2.4g, 2.62mmol), tricyclohexylphosphine (1.47g, 5.24mmol) and KOAc (7.71g, 78.58mmol) in 1, 4-dioxane (120mL) was stirred at 100 ℃ under nitrogen for 16 hours. The mixture was filtered, the filtrate diluted with EA (200mL), washed with water (100mL) and brine (100 mL). The collected organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by ISCO (eluting with water containing 0% to 100% methanol) to give the title compound as a white solid (3.55g, yield 49.1%). MS (m/z): 277.0(M + H)⁺

(B)8- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a)][1，4]Diaza derivatives-1-ketones

To 8- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives(iii) -1-Ketone (17.76g, 64.32mmol) and 4-chloro-N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine (13.50g, 64.40mmol) in 1, 4-dioxane/water (380mL/70mL) to a mixture of Pd (dppf) Cl₂.CH₂Cl₂(2.63g, 3.22mmol) and cesium carbonate (52.40g, 160.82 mmol). The mixture was then stirred at 90 ℃ for 2 hours under nitrogen. The mixture was filtered and the filtrate was diluted with EA and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by ISCO (eluting with water containing 0% to 100% methanol) to give the title compound as a yellow solid (l6.6g, yield 79.8%). MS (m/z): 324.1(M + H)⁺

(C)4- (1-hydrazino-4, 5-dihydro-3H-pyrrolo [1, 2-a)][1，4]Diaza derivatives-8-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine

Reacting 8- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a)][1，4]Diaza derivatives-1-one (8.00g, 24.74mmol) in POCl₃The suspension in (80mL) was stirred overnight at 100 ℃ under nitrogen. The mixture was concentrated and the residue was poured into cold saturated sodium bicarbonate solution and extracted with EA. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in THF (50mL) and hydrazine hydrate (50mL, 85%) was added. The mixture was then refluxed overnight under nitrogen. The mixture was filtered and the filter cake was washed with THF. Washing the organic layer with water and brine, drying over anhydrous sodium sulfate, and concentrating to obtainTo a brown solid (3.75g, 44.7% yield). MS (m/z): 338.1(M + H)⁺

(D)4- (3- (2-fluorophenethyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine

To 4- (1-hydrazino-4, 5-dihydro-3H-pyrrolo [1, 2-a ]][1，4]Diaza derivativesTo a solution of (8-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine (100mg, 0.30mmol) and 3- (2-fluorophenyl) propionic acid (60mg, 0.35mmol) in 5mL DCM was added HATU (113mg, 0.30mmol) and Et₃N (58mg, 0.58 mmol). The mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the residue was dissolved in 5mL of 1, 4-dioxane and then stirred at 60 ℃ for 1 hour. The mixture was concentrated and purified using ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a white solid (66.6mg, 47.1% yield). MS (m/z): 470.3(M + H)⁺。¹H NMR(400MHz，DMSO-d6)δ9.22(s，1H)，8.31(d，J＝5.2Hz，1H)，7.68(d，J＝2.0Hz，1H)，7.40-7.32(m，3H)，7.28-7.23(m，1H)，7.18-7.09(m，3H)，6.27(d，J＝1.9Hz，1H)，4.37-4.23(m，2H)，4.17-4.00(m，2H)，3.68(s，3H)，3.10-2.98(m，4H)，2.29-2.13(m，2H)。

The following compounds were prepared following the procedure for compound 1 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Example 2: synthesis of Compounds 36-38

Compound 36

N- (1-methyl-1H-pyrazol-5-yl) -4- (3- (phenoxymethyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) pyrimidin-2-amine

(A)4- (3- (chloromethyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine

To 4- (1-hydrazino-4, 5-dihydro-3H-pyrrolo [1, 2-a ] at 0 DEG C][1，4]Diaza derivativesTo a solution of (8-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine (500mg, 1.48mmol) in DCM (50mL) was slowly added DIPEA (287mg, 2.22mmol) and 2-chloroacetyl chloride (201mg, 1.78 mmol). The mixture was then stirred at room temperature overnight and then refluxed for 3 hours. The mixture was diluted with THF (100mL) and water (100 mL). The aqueous layer was extracted with THF. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give a brown oil (587mg), which was used directly in the next step. MS (m/z): 454.2(M + H)⁺

(B) N- (1-methyl-1H-pyrazol-5-yl) -4- (3- (phenoxymethyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) pyrimidin-2-amine

To 4- (3- (chloromethyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivativesTo a solution of (e) -10-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine (73.4mg, 0.19mmol) in DMF (5mL) was added cesium carbonate (151mg, 0.46mmol) and phenol (34.9mg, 0.37 mmol). The resulting mixture was stirred at 60 ℃ for 1 hour. After cooling, the reaction mixture was purified directly with ISCO (eluted with 0% to 100% methanol in water) and PTLC (DCM: MeOH ═ 12: 1) to give the title compound as a pale yellow solid (19.1mg, 22.7% yield). MS (m/z): 396.2(M + H)⁺.¹H NMR(400MHz，DMSO-d6)δ9.26(s，1H)，8.31(s，1H)，7.71(s，1H)，7.42(s，1H)，7.37-7.24(m，3H)，7.15-7.04(m，3H)，7.03-6.92(m，1H)，6.28(s，1H)，5.30(s，2H)，4.45-4.34(m，2H)，4.34-4.24(m，2H)，3.68(s，3H)，2.38-2.27(m，2H).

The following compounds were prepared following the procedure for compound 36 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Example 3: synthesis of Compounds 39-40

Compound 39

(S) -4- (3- (1- (2-fluorophenoxy) ethyl) pyrrolo [1, 2-a ] [1, 2, 4] triazolo [3, 4-c ] pyrazin-9-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine

(A) 7-bromo-2- ((2- (trimethylsilyl) ethoxy) methyl) pyrrolo [1, 2-a ] pyrazin-1 (2H) -one

To 7-bromopyrrolo [1, 2-a ] at 0 DEG C]To a solution of pyrazin-1 (2H) -one (21.3g, 100mmol) in anhydrous DMF (100mL) was added NaiH (6g, 150mmol, 60% dispersed in liquid paraffin). The mixture was stirred at 0 ℃ for 0.5 h, then 2- (trimethylsilyl) ethoxymethyl chloride (21.6g, 130mmol) was added. The mixture was stirred at room temperature overnight, poured into ice water, extracted with EA, concentrated and purified with ISCO (PE/EA ═ 5: 1) to give the title compound as a yellow solid (16g, yield 47%). MS (m/z): 342.9/344.9(M + H)⁺

(B)7- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- ((2- (trimethylsilyl) ethoxy) methyl) pyrrolo [1, 2-a ] pyrazin-1 (2H) -one

Reacting 7-bromo-2- ((2- (trimethylsilyl) ethoxy) methyl) pyrrolo [1, 2-a]Pyrazin-1 (2H) -one (8.5g, 24.8mmol), BPIN (9.44g, 37.2mmol), Pd₂(dba)₃A mixture of (0.68g, 7.44mmol), KOAc (4.86g, 49.6mmol) and tricyclohexylphosphine (0.417g, 1.488mmol) in 1, 4-dioxane (120mL) was stirred under nitrogen at 100 ℃ for 4 hours. The mixture was diluted with water and extracted with EA. The organic layer was concentrated and purified with ISCO (PE/EA 5: 1) to give the title compound asYellow solid (8.1g, yield 84%). MS (m/z): 391.1(M + H)⁺

(C)7- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2- ((2- (trimethylsilyl) ethoxy) methyl) pyrrolo [1, 2-a ] pyrazin-1 (2H) -one

4-chloro-N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine (627mg, 3mmol), 7- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- ((2- (trimethylsilyl) ethoxy) methyl) pyrrolo [1, 2-a]Pyrazine-1 (2H) -7(1170mg, 3mmol), Pd (dppf) Cl₂.CH₂Cl₂A mixture of (122mg, 0.15mmol) and sodium carbonate (636mg, 3mmol) in 1, 4-dioxane (20mL) and water (2mL) was stirred under nitrogen at 100 ℃ for 3 hours. The mixture was diluted with water and extracted with EA. The organic layer was concentrated and purified with ISCO (DCM: MeOH ═ 20: 1) to give the title compound as a brown solid (800mg, 61% yield). MS (m/z): 438.2(M + H)⁺

(D)7- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) pyrrolo [1, 2-a]Pyrazin-1 (2H) -one reaction of 7- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2- ((2- (trimethylsilyl) ethoxy) methyl) pyrrolo [1, 2-a]A solution of pyrazin-1 (2H) -one (800mg, 1.8mmol) in TFA (3mL) was stirred at room temperature for 0.5H. Volatiles were removed under reduced pressure and ammonium hydroxide was added. Filtration and washing of the filter cake with water and drying gave the title compound as a yellow solid (500 mg). MS (m/z): 380.0(M + H)⁺

(E) (S) -4- (3- (1- (2-fluorophenoxy) ethyl) pyrrolo [1, 2-a ] [1, 2, 4] triazolo [3, 4-c ] pyrazin-9-yl) -N- (1-methyl-1H-pyrazol-5) pyrimidin-2-amine

Reacting 7- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) pyrrolo [1, 2-a]Pyrazin-1 (2H) -one (93mg, 0.3mmol) in POCl₃The mixture in (2mL) was stirred at 100 ℃ for 1 hour. The volatiles were removed under reduced pressure and adjusted to pH 8 with aqueous sodium bicarbonate. The aqueous layer was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in EtOH (5mL) and (S) -2- (2-fluorophenoxy) propyl hydrazide (59mg, 0.3mmol) was added. The resulting mixture was refluxed overnight. Removing volatiles under reduced pressure, and removing by ISCO (using a solution containing 0% -100% of ISCO)Water elution of% methanol) to give the title compound as a yellow solid (85mg, yield 60%). MS (m/z): 470.1(M + H)⁺.¹H NMR(400MHz，CD₃OD)δ8.31(d，J＝5.2Hz，1H)，8.07(s，1H)，7.77(d，J＝6.0Hz，1H)，7.98(d，J＝6.0Hz，1H)，7.60(s，1H)，7.42(d，J＝2.0Hz，1H)，7.20-6.97(m，5H)，6.35(d，J＝2.0Hz，1H)，5.97-5.92(m，1H)，3.75(s，3H)，1.88(d，J＝6.8Hz，3H).

The following compounds were prepared following the procedure for compound 39 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Example 4: synthesis of Compounds 41-43

Compound 41

N- (2-fluorophenyl) -9- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) pyrrolo [1, 2-a ] [1, 2, 4] triazolo [3, 4-c ] pyrazin-3-amine

To 4- (1-chloropyrrolo [1, 2-a ]]To a solution of pyrazin-7-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine (130mg, 0.4mmol) in THF (5mL) was added hydrazine hydrate (2mL, 85%), then the mixture was taken up in 80%The mixture was heated for 4 hours. The mixture was then extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in DCM (5mL), and 1-fluoro-2-isocyanato (isocyanato) benzene (70mg, 0.51mmol) and POCl were added₃(3mL), the resulting mixture was dissolved in water at 60The mixture was heated for 3 hours. Removing volatile under reduced pressure, and adding sodium bicarbonate water solutionThe residue was adjusted to pH 8. The aqueous layer was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by ISCO (eluting with water containing 0% to 100% methanol) to give the title compound as a yellow solid (15mg, yield 10%). MS (m/z): 441.1(M + H)⁺.¹H NMR(400MHz，DMSO-d6)δ9.32(s，1H)，8.41(d，J＝5.2Hz，1H)，8.17(d，J＝1.2Hz，1H)，7.89-7.85(m，1H)，7.84(d，J＝6.4Hz，1H)，7.66(d，J＝6.4Hz，1H)，7.50(s，1H)，7.34(d，J＝2.0Hz，1H)，7.31(d，J＝5.2Hz，1H)，7.21-7.18(m，1H)，7.11-7.07(m，1H)，6.91-6.86(m，1H)，6.30(d，J＝2.0Hz，1H)，3.69(s，3H).

The following compounds were prepared following the procedure of compound 41 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Example 5: synthesis of Compounds 44-52

Compound 44

(S) -4- (3- (1- (2-fluorophenoxy) ethyl) -6, 6-dimethyl-6, 7-dihydroxy-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine

(A)4- (1-chloro-4, 4-dimethyl-4, 5-dihydro-3H-pyrrolo [1, 2-a)][1，4]Diaza derivatives-8-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2) amine

The title compound was prepared following the procedure of example 1 using the corresponding intermediates and reagents.

(B) (S) -4- (3- (1- (2-fluorophenoxy) ethyl) -6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine

4- (1-chloro-4, 4-dimethyl-4, 5-dihydro-3H-pyrrolo [1, 2-a)][1，4]Diaza derivativesA mixture of-8-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine (111mg, 0.3mmol) and (S) -2- (2-fluorophenoxy) propane hydrazide (59mg, 0.3mmol) in ethanol (10mL) was refluxed overnight. The mixture was concentrated and the residue was purified by ISCO (eluting with water containing 0% to 100% methanol) to give the title compound as a yellow solid (40mg, yield 26%). MS (m/z): 514.2(M + H)⁺.¹H NMR(400MHz，CD₃OD)δ8.26(d，J＝5.2Hz，1H)，7.70(d，J＝1.6Hz，1H)，7.42(d，J＝2.0Hz，1H)，7.38(d，J＝1.6Hz，1H)，7.24-7.20(m，1H)，7.17-7.09(m，2H)，7.07-7.00(m，2H)，6.33(d，J＝2.0Hz，1H)，5.81-5.76(m，1H)，4.00(s，2H)，3.92(s，2H)，3.74(s，3H)，1.81(d，J＝6.8Hz，3H)，1.11(s，3H)，1.16(s，3H).

The following compounds were prepared following the procedure for compound 44 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Example 6: synthesis of Compounds 53-54

Compound 53

5-chloro-4- (3- (indolin-1-yl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine

(A) 5-chloro-4- (1-chloro-4, 5-dihydro-3H-pyrrolo [1, 2-a)][1，4]Diaza derivatives-8-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine

(B) Indoline-1-carbohydrazide

At 0Next, to indoline (500mg, 4.2mmol) in DMF (5mL) and DIPEA (0.76mL, 4.6mmol) was added CDI (750mg, 4.6mmol) in portions. The reaction mixture was stirred at room temperature for 2 hours, diluted with water (100mL) and extracted with EA (200 mL. times.2). The combined organic layers were washed with brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in THF (10mL) and hydrazine hydrate (20mL, 85%) was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue partitioned between EA (50mL) and brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (600mg, crude) which was used in the next step without further purification. MS (m/z): 178.1(M + H)⁺

(C) 5-chloro-4- (3- (indolin-1-yl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine

Reacting 5-chloro-4- (1-chloro-4, 5-dihydro-3H-pyrrolo [1, 2-a ]][1，4]Diaza derivativesA mixture of-8-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine (60mg, 0.16mmol) and indoline-1-carbohydrazide (43mg, 0.24mmol) in POCl3(5mL) was stirred at 60 ℃ for 3 hours and then at 90 ℃ for 4 hours. The volatiles were removed under reduced pressure and the residue was adjusted to pH 10 with 2M sodium hydroxide solution and extracted with DCM (30mL × 2). The combined organic layers were washed with brine (30mL), concentrated and purified with PTLC (DCM: MeOH ═ 13: 1) to give the title compound as a yellow solid (12mg, yield 15.0%). MS (m/z): 498.2(M + H)⁺

¹H NMR(400MHz，DMSO-d6)δ8.83(s，1H)，8.13(s，1H)，7.64(d，J＝2.0Hz，1H)，7.32(d，J＝1.9Hz，1H)，7.25-7.21(m，2H)，7.04(t，J＝7.7Hz，1H)，6.99(s，1H)，6.80(t，J＝7.4Hz，1H)，6.68(d，J＝7.9Hz，1H)，6.23(d，J＝1.9Hz，1H)，4.49-4.40(m，2H)，4.14-4.05(m，2H)，3.93(t，J＝8.3Hz，2H)，3.66(s，3H)，3.13(t，J＝8.2Hz，2H)，2.34-2.30(m，2H).

The following compounds were prepared following the procedure for compound 53 using the corresponding intermediates and reagents under conditions deemed appropriate by one skilled in the art.

Example 7: synthesis of Compounds 55-210

Compound 55

5-chloro-N- (1-methyl-1H-pyrazol-5-yl) -4- (3 '- (1- (trifluoromethyl) cyclobutyl) -5' H, 7 'H-spiro [ cyclobutane-1, 6' -pyrrolo [1, 2-a ]][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives]-10' -yl) pyridin-2-amine

(A)8 '- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2', 3 '-dihydro-1' H, 5 'H-spiro [ cyclobutane-1, 4' -pyrrolo [1, 2-a ] s][1，4]Diaza derivatives]-1' -ketones

(B) 5-chloro-N- (1-methyl-1H-pyrazol-5-yl) -4- (3 '- (1- (trifluoromethyl) cyclobutyl) -5' H, 7 'H-spiro [ cyclobutane-1, 6' -pyrrolo [1, 2-a ]][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives]-10' -yl) pyridin-2-amine

Mixing 8 '- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridine-4-yl) -2', 3 '-dihydro-1' H, 5 'H-spiro [ cyclobutane-1, 4' -pyrrolo [1, 2-a ]][1，4]Diaza derivatives]A mixture of-1' -one (55mg, 0.14mmol) and 1- (trifluoromethyl) cyclobutane-1-carbohydrazide (25mg, 0.14mmol) in POCl3(3mL) was stirred at 100 ℃ for 30 min. The volatiles were removed under reduced pressure and the residue was adjusted to pH 8 with sodium bicarbonate solution and extracted with EA. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in ethanol (3mL) and acetic acid (2 drops), and the resulting mixture was stirred under microwave at 100 ℃ for 1.5 hours. The mixture was then concentrated and purified with ISCO (eluted with 0% to 100% methanol in water) and PTLC (DCM/MeOH ═ 15: 1) to give the title compound as a yellow solid (20mg, yield 27%)。MS(m/z)：543.1(M+H)⁺

¹H NMR(400MHz，DMSO-d6)δ8.85(s，1H)，8.12(s，1H)，7.72(d，J＝1.6Hz，1H)，7.31(d，J＝1.6Hz，1H)，7.20(d，J＝2.0Hz，1H)，6.97(s，1H)，6.22(d，J＝1.6Hz，1H)，4.40(s，2H)，4.06(s，2H)，3.64(s，3H)，2.92-2.85(m，2H)，2.80-2.74(m，2H)，2.20-2.13(m，1H)，2.03-1.96(m，2H)，1.89-1.79(m，5H).

The following compounds were prepared following the procedure for compound 55 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Example 8: synthesis of Compound 211-214

Compound 211

5-chloro-4- (3- ((2-fluorophenoxy) methyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine

(A)8- (2, 5-dichloropyrimidin-4-yl) -2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-1-ketones

Reacting 8- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-1-one (2.70g, 9.78mmol), Pd (dppf) Cl₂.CH₂Cl₂A mixture of (799mg, 0.98mmol), 2,4, 5-trichloropyrimidine (1.97g, 10.76mmol) and cesium carbonate (9.56g, 29.33mmol) in 1, 4-dioxane/water (120mL/30mL) was degassed and then stirred at 80 ℃ for 3 hours under a nitrogen atmosphere. The mixture was diluted with DCM, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was suspended in EA, stirred for 30 minutes, then filtered and the filter cake dried under vacuum to give the title compound as a yellow solid (2.85 g). MS (m/z): 296.9(M + H)⁺

(B)8- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a)][1，4]Diaza derivatives-1-ketones

Reacting 8- (2, 5-dichloropyrimidin-4-yl) -2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-1-one (2.80g, 9.46mmol), 1-methyl-1H-pyrazol-5-amine (4.59g, 47.28mmol), Pd₂(dba)₃A mixture of (0.87g, 0.95mmol), Xantphos (1.09g, 1.89mmol) and cesium carbonate (9.24g, 28.36mmol) in 1, 4-dioxane (140mL) was degassed and stirred at 100 ℃ for 6 hours under a nitrogen atmosphere. The mixture was filtered and the filtrate was extracted with EA and water. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by ISCO (elution with a water gradient containing 0% to 100% methanol) to give the title compound as a yellow solid (1.52g, yield 45.0%). MS (m/z): 358.0(M + H)⁺

(C) 5-chloro-4- (3- ((2-fluorophenoxy) methyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine

The title compound was prepared following the procedure of example 1 using the corresponding intermediates and reagents. MS (m/z): 506.2(M + H)⁺

¹H NMR(400MHz，DMSO-d6)δ9.48(s，1H)，8.43(s，1H)，7.97(d，J＝2.0Hz，1H)，7.60(d，J＝2.0Hz，1H)，7.44-7.39(m，1H)，7.36(d，J＝1.9Hz，1H)，7.25-7.20(m，1H)，7.19-7.13(m，1H)，7.04-6.96(m，1H)，6.26(d，J＝1.9Hz，1H)，5.40(s，2H)，4.50-4.41(m，2H)，4.37-4.30(m，2H)，3.68(s，3H)，2.40-2.30(m，2H).

The following compounds were prepared following the procedure for compound 211 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Example 9: synthesis of Compound 215-216

Compound 215

(S) -10- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-6-alcohols

(A) (R) -acetic acid 8-bromo-1-oxo-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-4-yl ester

To (R) -8-bromo-4-hydroxy-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-1-one (1.5g, 6mmol) and Ac₂Et was added to a solution of O (0.7g, 0.006mol) in THF (50mL)₃N (1.3g, 0.012mol) and N, N-dimethylpyridin-amine (40mg, 0.300 mmol). After stirring at 50 ℃ for 1 hour, the mixture was concentrated and the residue was dissolved in DCM. The organic layer was then washed with saturated sodium bicarbonate solution and water and concentrated to give the title compound as a yellow oil (1.5g, 88.2% yield). MS (m/z): 287.0/289.0(M + H)⁺

(B) (R) -acetic acid-1-oxo-8- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-4-yl ester

Under nitrogen atmosphere, (R) -acetic acid 8-bromo-1-oxo-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-4-yl ester (200mg, 0.669mmol), Pd₂(dba)₃A mixture of (32mg, 0.035mmol), tricyclohexylphosphine (10mg, 0.035mmol), BPIN (178mg, 0.669mmol) and KOAc (137mg, 1.398mmol) in 1, 4-dioxane (10mL) was stirred at 100 ℃ for 16 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by ISCO (eluting with water containing 0% to 100% methanol) to give the title compound as a white solid (150mg, yield 64.2%). MS (m/z): 335.1(M + H)⁺

(C) (R) -8- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-hydroxy-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a)][1，4]Diaza derivatives-1-ketones

(R) -acetic acid 1-oxo-8- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ] under a nitrogen atmosphere][1，4]Diaza derivatives-4-yl ester (150mg, 0.449mmol), Pd (dppf) Cl₂.CH₂Cl₂(16mg，0.023mmol)、Na₂CO₃A mixture of (95mg, 0.898mmol) and 5-chloro-4-iodo-N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine (150mg, 0.449mmol) in 1, 4-dioxane (5mL) and water (1mL) was stirred at 80 ℃ for 2 hours. The mixture was diluted with water and extracted with DCM. The organic layer was concentrated and the residue was purified by ISCO (eluting with water containing 0% to 100% methanol) to give the title compound as a white solid (100mg, yield 59.9%). MS (m/z): 373.1(M + H)⁺

(D) (S) -10- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-6-alcohols

Reacting (R) -8- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4-hydroxy-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a)][1，4]Diaza derivatives-1-one (100mg, 0.269mmol), 1- (trifluoromethyl) cyclobutane-1-carbohydrazide (49mg, 0.269mmol) in POCl₃The mixture in (5mL) was stirred at 80 ℃ for 2 hours. The mixture was concentrated and the residue was dissolved in DCM and MeOH. The organic layer was then washed with saturated sodium bicarbonate solution and water, concentrated, and the residue dissolved in NMP (5 mL). One drop of HOAc was added and the mixture was stirred in a microwave at 130 ℃ for 30 minutes. The reaction mixture was then purified directly using ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a pale yellow solid (20mg, 14.4% yield). MS (m/z): 519.0(M + H)⁺¹H NMR(400MHz，DMSO-d6)δ8.85(s，1H)，8.12(s，1H)，7.70(s，1H)，7.31(s，1H)，7.07(s，1H)，6.96(s，1H)，6.21(s，1H)，4.45-4.28(m，2H)，4.14-4.01(m，2H)，3.82-3.7(m，1H)，3.03-2.86(m，2H)，2.73-2.69(m，2H)，2.16-2.12(m，1H)，2.03-2.00(m，1H).

The following compounds were prepared following the procedure for compound 215 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Example 10: synthesis of Compound 217-219

Compound 217

1- ((10- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -6, 6-difluoro-6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-3-yl) methyl) -1H-pyrrole-2-carbonitrile

(A)8- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4, 4-difluoro-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a)][1，4]Diaza derivatives-1-ketones

(B)2- ((4-methoxybenzyl) oxy) acethydrazide

To a solution of ethyl 2-glycolate (3.1g, 30mmol) in anhydrous DMF (50mL) was added NaH (1.5g, 36mmol, 60% dispersion in liquid paraffin) in portions under nitrogen at 5 ℃. The mixture was stirred for 1 hour. 1- (chloromethyl) -4-methoxybenzene (5.6g, 36mmol) was added dropwise and the mixture was stirred at room temperature for 12 hours. The reaction was quenched with saturated ammonium chloride solution and then concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA 4: 1) to give a yellow oil. The oil was dissolved in ethanol (100mL) and hydrazine hydrate (4.5g, 85%) was added. The solution was refluxed for 2 hours. The solvent was removed using a rotary evaporator and the residue was purified using ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a yellow oil (3.7g, 59% yield). MS (m/z): 121.1(M + H)⁺

(C) 5-chloro-4- (3- (chloromethyl) -6, 6-difluoro-6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine

Under a nitrogen atmosphere, 8- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -4, 4-difluoro-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ] is reacted][1，4]Diaza derivatives-1-one (784mg, 2mmol) and 2- ((4-methyl)Oxybenzyl) oxy) acethydrazide (841mg, 4mmol) in POCl₃The mixture in (10mL) was stirred at 100 ℃ for 2 hours. The solvent was removed on a rotary evaporator and the residue was dissolved in DCM and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with DCM. The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The residue was dissolved in acetic acid (2 drops) in n-butanol (20 mL). The solution was stirred at 130 ℃ for 2 hours and then concentrated in vacuo. The residue was purified by ISCO (eluting with water containing 0% to 100% methanol) to give the title compound as a yellow solid (380mg, 41% yield). MS (m/z): 465.1(M + H)⁺

(D)1- ((10- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -6, 6-difluoro-6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-3-yl) methyl) -1H-pyrrole-2-carbonitrile

Under nitrogen atmosphere, 5-chloro-4- (3- (chloromethyl) -6, 6-difluoro-6, 7-dihydro-5H-pyrrolo [1, 2-a ]][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivativesA mixture of-10-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine (80mg, 0.17mmol), 1H-pyrrole-2-carbonitrile (19mg, 0.21mmol), and cesium carbonate (166mg, 0.51mmol) in acetonitrile (10mL) was stirred at room temperature overnight. The reaction was quenched with dilute aqueous hydrochloric acid and neutralized with saturated aqueous sodium bicarbonate to pH 8. The mixture was extracted with DCM/MeOH (10: 1). The organic phases were combined and then concentrated in vacuo. The residue was purified by ISCO (eluting with water containing 0% to 100% methanol) and PTLC (DCM/MeOH ═ 10: 1) to give the title compound as a pale yellow solid (19.1mg, 22% yield). MS (m/z): 521.1(M + H)⁺。

¹H NMR(400MHz，DMSO-d6)δ8.87(s，1H)，8.14(s，1H)，7.87(d，J＝1.9Hz，1H)，7.31(d，J＝1.9Hz，1H)，7.25(dd，J＝2.7，1.6Hz，1H)，7.13(d，J＝1.9Hz，1H)，6.98(dd，J＝4.0，1.6Hz，1H)，6.96(s，1H)，6.23(dd，J＝4.0，2.7Hz，1H)，6.21(d，J＝1.9Hz，1H)，5.60(s，2H)，4.80-4.69(m，4H)，3.64(s，3H).

The following compounds were prepared following the procedure for compound 217 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Example 11: synthesis of Compound 220-228

Compound 220

(R) -4- (3- ((2-chlorophenyl) difluoromethyl) -5- (methoxymethyl) -5, 6-dihydroimidazo [1, 2-a ] [1, 2, 4] triazolo [3, 4-c ] pyrazin-9-yl) -5-methyl-N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine

(A)1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole-2-carboxylic acid methyl ester

To 1H-imidazole-2-carboxylic acid methyl ester (10g, 79.3mmol) and K₂CO₃To a solution in acetone (300mL) was added (2- (chloromethoxy) ethyl) trimethylsilane (14.3g, 85.6 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (PE: EA ═ 2: 1) to give the title compound as a yellow oil (11.9g, 58.5% yield). MS (m/z): 257.0(M + H)⁺。

(B)4- (2-chloro-5-methylpyrimidin-4-yl) -1H-imidazole-2-carboxylic acid methyl ester

To a mixture of methyl 1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole-2-carboxylate (16.6g, 64.7mmol), BPIN (32.8g, 129.2mmol), (1, 5-cyclooctadiene) (methoxy) iridium (I) dimer (2.2g, 3.3mmol), and 3, 4,7, 8-tetramethyl-1, 10-phenanthroline (1.5g, 6.5mmol) was added anhydrous THF (110mL), and the resulting mixture was purged with nitrogen 3 times. The mixture was then refluxed over liquid under nitrogen atmosphere. For treatingThe mixture was filtered and the filtrate was concentrated. The residue was dissolved in DMF (400mL) and Pd (PPh3) was added₄(3.8g，3.3mmol)、CuI(1.3g，6.5mmol)、Cs₂CO₃(15.8g, 97.0mmol) and 2, 4-dichloro-5-methylpyrimidine (15.8g, 97.0 mmol). The resulting mixture was purged with nitrogen 3 times. The mixture was then stirred at 90 ℃ overnight under nitrogen. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in TFA (100mL) and refluxed for 2 hours. The volatiles were removed and the residue was neutralized with saturated sodium bicarbonate solution and extracted with DCM/MeOH (10: 1). The combined organic layers were concentrated and the residue was purified by silica gel chromatography (DCM: MeOH ═ 10: 1) to give the title compound as an off-white solid (15.2g, yield 92.9%). MS (m/z): 253.0(M + H)⁺。

(C) (R) -1- (2- ((tert-butoxycarbonyl) amino) -3-methoxypropyl) -4- (2-chloro-5-methylpyrimidin-4-yl) -1H-imidazole-2-carboxylic acid methyl ester

To methyl 4- (2-chloro-5-methylpyrimidin-4-yl) -1H-imidazole-2-carboxylate (2.5g, 9.9mmol), (R) - (1-hydroxy-3-methoxypropan-2-yl) carbamic acid tert-butyl ester (2.3g, 12.0mmol) and PPh at 0 deg.C₃(5.3g, 20.0mmol) DIAD (4.6g, 20.0mmol) was added dropwise to a solution in dry THF (100 mL). The resulting solution was stirred at room temperature overnight under nitrogen. The mixture was concentrated and the residue was purified by silica gel chromatography (PE: EA ═ 2: 1) to give the title compound as a yellow gum (2.5g, yield 57.4%). MS (m/z): 440.0(M + H)⁺。

(D) (R) -2- (2-chloro-5-methylpyrimidin-4-yl) -6- (methoxymethyl) -6, 7-dihydroimidazo [1, 2-a ] pyrazin-8 (5H) -one

A mixture of (R) -methyl 1- (2- ((tert-butoxycarbonyl) amino) -3-methoxypropyl) -4- (2-chloro-5-methylpyrimidin-4-yl) -1H-imidazole-2-carboxylate (2.5g, 5.7mmol) and TFA (15mL) in DCM (20mL) was stirred at room temperature for 3H. The mixture was concentrated and the residue dissolved in MeOH (10mL) and a solution of ammonia in methanol (30mL, 7M) was added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was purified by silica gel chromatography (DCM: MeOH ═ 20: 1) to give the title compound as a yellow compound (1.21g, yield 69.2%). MS (m/z): 308.0(M + H)⁺。

(E) (R) -6- (methoxymethyl) -2- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -6, 7-dihydroimidazo [1, 2-a ] pyrazin-8 (5H) -one

To a solution of 1-methyl-1H-pyrazol-5-amine (0.12g, 1.24mmol) in THF (10mL) at room temperature was added NaHMDS (0.5mL, 1.0mmol, 2M in THF), and the resulting mixture was stirred under nitrogen for another 20 minutes. Adding (R) -2- (2-chloro-5-methylpyrimidin-4-yl) -6- (methoxymethyl) -6, 7-dihydroimidazo [1, 2-a)]Pyrazin-8 (5H) -one (0.12g, 0.39mmol), and the mixture was refluxed overnight. The reaction was quenched with 4N HCl. The volatiles were removed and the residue was neutralized with saturated sodium bicarbonate solution. The solvent was removed and the residue was purified by silica gel chromatography (DCM: MeOH ═ 10: 1) to give the title compound as a yellow solid (0.118g, yield 82.1%). MS (m/z): 369.2(M + H)⁺。

(F) (R) -4- (3- ((2-chlorophenyl) difluoromethyl) -5- (methoxymethyl) -5, 6-dihydroimidazo [1, 2-a ] [1, 2, 4] triazolo [3, 4-c ] pyrazin-9-yl) -5-methyl-N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine

The title compound was prepared following the procedure of example 7 using the corresponding intermediates and reagents. MS (m/z): 553.0(M + H)⁺。

¹H NMR(400MHz，DMSO-d6)δ9.22(s，1H)，8.32(s，1H)，8.12(s，1H)，7.89(d，J＝7.5Hz，1H)，7.70-7.64(m，2H)，7.62-7.54(m，1H)，7.32(d，J＝1.8Hz，1H)，6.30(d，J＝1.8Hz，1H)，5.38-5.32(m，1H)，4.87(d，J＝14.0Hz，1H)，4.69(dd，J＝14.0，5.1Hz，1H)，3.69(s，3H)，3.62-3.51(m，2H)，3.13(s，3H)，2.52(s，3H).

The following compounds were prepared following the procedure for compound 220 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Example 12: synthesis of Compounds 229-274, 322

Compound 229

(S) -2- ((5-chloro-4- (3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) pyridin-2-yl) amino) propan-1-ol

(A)10- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3- (1- (trifluoromethyl) cyclobutyl) -6, 7-Hhydro-5H-pyrrolo [1, 2-a ]][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives

The title compound was prepared following the procedure of example 1 using the corresponding intermediates and reagents. MS (m/z): 423.1(M + H)⁺.

(B) (S) -2- ((5-chloro-4- (3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) pyridin-2-yl) amino) propan-1-ol

Reacting 10- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a ]][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives(85mg, 0.2mmol), (S) -2- ((5-chloro-4-iodopyridin-2-yl) amino) propan-1-ol (94mg, 0.3mmol), Pd (PPh)₃)₄(23mg，0.02mmol) and Na₂CO₃A mixture of (63mg, 0.6mmol) in 1, 4-dioxane/water (10mL, 4: 1) was stirred at 80 ℃ for 2 hours under nitrogen atmosphere. The solvent was removed on a rotary evaporator and the residue was purified using ISCO (eluted with 0% to 100% methanol in water) and PTLC (DCM: MeOH ═ 10: 1) to give the title compound as a pale yellow solid (39mg, yield 41%). MS (m/z): 481.1(M + H)⁺.

¹H NMR(400MHz，DMSO-d6)δ7.95(s，1H)，7.61(d，J＝2.0Hz，1H)，7.18(d，J＝2.0Hz，1H)，6.71(s，1H)，6.32(d，J＝7.8Hz，1H)，4.69(t，J＝5.5Hz，1H)，4.32(t，J＝6.0Hz，2H)，4.05(t，J＝6.0Hz，2H)，3.92-3.86(m，1H)，3.49-3.43(m，1H)，3.30-3.24(m，1H)，2.95-2.87(m，2H)，2.79-2.68(m，2H)，2.35-2.26(m，2H)，2.23-2.10(m，1H)，2.05-1.96(m，1H)，1.11(d，J＝6.6Hz，3H).

The following compounds were prepared following the procedure of compound 229 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Example 13: synthesis of the Compound 275-280

Compound 275

(S) -2- ((5-methyl-4- (3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) pyrimidin-2-yl) amino) propan-1-ol

(A)10- (2-chloro-5-methylpyrimidin-4-yl) -3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives

Reacting 10- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a ]][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives(2.0g, 4.7mmol), 2, 4-dichloro-5-methylpyrimidine (620mg, 3.8mmol), Pd (dppf) Cl₂·CH₂Cl₂A mixture of (300mg, 0.40mmol) and sodium carbonate (1.0g, 9.4mmol) in 1, 4-dioxane (40mL) and water (8mL) was stirred at 90 ℃ for 4 hours. The resulting mixture was concentrated and purified using ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a white solid (500mg, yield 25.0%). MS (m/z): 423.0(M + H)⁺

(B) (S) -2- ((5-methyl-4- (3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) pyrimidin-2-yl) amino) propan-1-ol

Reacting 10- (2-chloro-5-methylpyrimidin-4-yl) -3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a ]][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivativesA mixture of (50mg, 0.12mmol), (S) -2-aminopropan-1-ol (44mg, 0.59mmol) and DIPEA (76mg, 0.59mmol) in NMP (2mL) was stirred under microwave at 180 ℃ for 2.5 h. The resulting mixture was purified directly with ISCO (eluted with 0% to 100% methanol in water) and PTLC (DCM: MeOH ═ 15: 1) to give the title compound as a white solid (8.0mg, 14.7% yield). MS (m/z): 462.1(M + H)⁺

¹H NMR(400MHz，DMSO-d6)δ8.03(s，1H)，7.62(d，J＝1.7Hz，1H)，7.40(d，J＝1.7Hz，1H)，6.15(d，J＝8.1Hz，1H)，4.58(s，1H)，4-37-4.29(m，2H)，4.09-3.95(m，3H)，3.53-3.45(m，1H)，3.40-3.32(m，2H)，2.97-2.86(m，2H)，2.74-2.71(m，2H)，2-35-2.28(m，2H)，2.25(s，3H)，2.21-2.11(m，1H)，2.04-1.94(m，1H)，1.14(d，J＝6.6Hz，3H).

The following compounds were prepared following the procedure for compound 275 using the corresponding intermediates and reagents under conditions deemed appropriate by one skilled in the art.

Example 14: synthesis of 281-298

Compound 281

5-methyl-N- (2-methylpyridin-4-yl) -4- (3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a ]][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) pyrimidin-2-amine

Reacting 10- (2-chloro-5-methylpyrimidin-4-yl) -3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a ]][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives(30mg, 0.07mmol), 2-methylpyridin-4-amine (15mg, 0.14mmol), Pd₂(dba)₃(16mg, 0.007mmol), Xantphos (4.1mg, 0.007mmol) and Cs₂CO₃(69mg, 0.21mmol) in 1, 4-dioxane (2mL) was stirred under microwave at 50 ℃ for 30 min. The mixture was concentrated and partitioned between water (10mL) and DCM (10 mL). The aqueous layer was extracted with DCM (10 mL. times.2). The combined organic layers were concentrated and purified with PTLC (DCM: MeOH ═ 15: 1) to give the title compound as a white solidA colored solid (8.5mg, yield 24.2%). MS (m/z): 495.1(M + H)⁺

¹H NMR(400MHz，DMSO-d6)δ9.63(s，1H)，8.34(s，1H)，8.19(d，J＝5.7Hz，1H)，7.73(d，J＝6.0Hz，2H)，7.59-7.54(m，1H)，7.55-7.52(m，1H)，4.42-4.35(m，2H)，4.11-4.05(m，2H)，2.98-2.89(m，2H)，2.76-2.72(m，2H)，2.41(s，3H)，2.38(s，3H)，2.34-2.30(m，2H)，2.23-2.12(m，1H)，2.05-1.95(m，1H).

The following compounds were prepared following the procedure for compound 281 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Example 15: synthesis of Compound 299

Compound 299

(10- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-6-yl) methanol

(A) 8-bromo-1-oxo-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ]][1，4]Diaza derivatives-4-carboxylic acid

To a solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (5.0g, 24.5mmol) in DMF (100mL) at 0 deg.C was slowly added NaH (3.43g, 85.7mmol, 60% in liquid paraffin). The reaction mixture was stirred for 0.5 hour, then 3-bromo-2- (bromomethyl) propionic acid was added. The reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction was then quenched with saturated ammonium chloride solution, adjusted to pH < 4 with dilute HCl and extracted with EA. The organic layer was washed with brine, dried and concentrated. Ammonium hydroxide (50mL) was added to the residue and the resulting mixture was stirred at 100 ℃ overnight. The mixture was concentrated and purified using ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a yellow solid (1.30g, 16.1% yield). MS (m/z): 273.0/275.0(M + H)⁺

(B) 8-bromo-4- (hydroxymethyl) -2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a][1，4]Diaza derivatives-1-ketones

To 8-bromo-1-oxo-2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ] at 0 deg.C][1，4]Diaza derivatives-4-Carboxylic acid (800mg, 2.93mmol) in THF (10mL) was added BH₃·Me₂S (4.5mL, 9.0 mmol). The reaction was stirred at 50 ℃ for 3 hours under nitrogen. The reaction was then quenched with methanol, concentrated, and purified using ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a yellow solid (250mg, yield 32.8%). MS (m/z): 259.0/261.0(M + H)⁺

(C) Acetic acid (10-bromo-3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-6-yl) methyl ester

To 8-bromo-4- (hydroxymethyl) -2, 3, 4, 5-tetrahydro-1H-pyrrolo [1, 2-a ] at 0 deg.C][1，4]Diaza derivativesEt was added to a mixture of (1-one) (250mg, 0.96mmol) in DCM (10mL)₃N(194.3mg，1.92mmol)、AC₂O (148mg, 1.44mmol) and N, N-lutidin-4-amine (12mg, 0.096 mmol). The reaction was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was then quenched with water and extracted with DCM. The organic layer was washed with brine, dried and concentrated. The residue was combined with 1- (trifluoromethyl) cyclobutane-1-carbohydrazide (210mg, 1.15mmol) and POCl3(5 mL). The resulting mixture was stirred at 70 ℃ for 2 hours. Volatiles were removed and the residue was dissolved in DCM and MeOH. The organic layer was then washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in NMP (5mL) and two drops of HOAc. The resulting mixture was stirred under microwave conditions at 130 ℃ for 0.5 hour. The reaction mixture was then purified directly using ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a yellow solid (220mg, 51.0% yield). MS (m/z): 447.0/449.0(M + H)⁺

(D) Acetic acid (10- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-6-yl) methyl ester

Acetic acid (10-bromo-3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a) under nitrogen atmosphere][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-6-yl) methyl ester (80mg, 0.18mmol) and BPIN (91mg, 0.36mmol), Pd₂(dba)₃(116mg, 0.018mmol), tricyclohexylA mixture of phosphine (10mg, 0.036mmol) and potassium acetate (53mg, 0.54mmol) in 1, 4-dioxane (8mL) was stirred at 100 ℃ for 5 hours. The reaction was diluted with water and extracted with DCM. The organic layer was dried, concentrated in vacuo, and purified using ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a white solid (10mg, yield 11.1%). MS (m/z): 495.1(M + H)⁺

(E) (10- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-6-yl) methanol

Acetic acid (10- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a ] under a nitrogen atmosphere][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-6-yl) methyl ester (10mg, 0.02mmol), 5-chloro-4-iodo-N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine (9mg, 0.024mmol), Pd (dppf) Cl₂·CH₂Cl₂A mixture of (2mg, 0.002mmol) and sodium carbonate (6.4mg, 0.06mmol) in 1, 4-dioxane (8mL) and water (2mL) was degassed and stirred at 80 ℃ for 1 hour. The mixture was then concentrated and the residue was purified using ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a pale yellow solid (3.0mg, 28.0% yield). MS (m/z): 533.0(M + H)⁺

¹H NMR(400MHz，DMSO-d6)δ8.86(s，1H)，8.14(s，1H)，7.70(s，1H)，7.33(s，1H)，7.14(s，1H)，6.98(s，1H)，6.24(s，1H)，5.06(t，J＝5.0Hz，1H)，4.32-4.17(m，2H)，4.14-4.09(m，1H)，3.75-3.69(m，1H)，3.67(s，3H)，3.50-3.36(m，3H)，2.97-2.89(m，2H)，2.77-2.72(m，2H)，2.19-2.14(m，1H)，2.08-1.94(m，1H).

Example 16: synthesis of Compound 300-303

Compound 300

5-chloro-4- (6- (methoxymethyl) -3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine

(A) 10-bromo-6- (methoxymethyl) -3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives

Acetic acid (10-bromo-3- (1- (trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivativesA mixture of-6-yl) methyl ester (140mg, 0.31mmol) and sodium carbonate (99mg, 0.93mmol) in THF (3mL) and water (3mL) was stirred at room temperature for 0.5 h. The mixture was then diluted with water and extracted with DCM. The organic layer was washed with brine, dried and concentrated. The residue was dissolved in THF (10mL) and cooled to 0 ℃. NaH (20mg, 0.50mmol, 60% dispersion in liquid paraffin) was added and the mixture was stirred for a further 20 minutes. Methyl iodide was added and the reaction was stirred at room temperature for 0.5 hour. The reaction was quenched with saturated ammonium chloride solution and extracted with DCM. The organic layer was concentrated and purified using ISCO (eluted with 0% to 100% methanol in water) to give the title compound as a white solid (110mg, yield 83.8%). MS (m/z): 419.0/421.0(M + H)⁺

(B) 5-chloro-4- (6- (methoxymethyl) -3- (1-trifluoromethyl) cyclobutyl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives-10-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine

The title compound was prepared following the procedure of example 15 using the corresponding intermediates and reagents. MS (m/z): 547.1(M + H)⁺

¹H NMR(400MHz，DMSO-d6)δ8.83(s，1H)，8.12(s，1H)，7.67(s，1H)，7.31(s，1H)，7.12(s，1H)，6.96(s，1H)，6.21(s，1H)，4.23(d，J＝4.3Hz，2H)，4.08-4.05(m，1H)，3.82-3.72(m，1H)，3.64(s，3H)，3.36-3.30(m，2H)，3.24(s，3H)，2.93-2.85(m，2H)，2.75-2.68(m，3H)，2.18-2.13(m，1H)，2.03-1.97(m，1H).

The following compounds were prepared following the procedure for compound 300 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.

Example 17: synthesis of Compound 304-321

Compound 304

5-chloro-N- (1-methyl-1H-pyrazol-5-yl) -4- (3 '- (1, 1,2, 2-tetrafluoroethyl) -5' H, 7 'H-spiro [ oxetane-3, 6' -pyrrolo [1, 2-a ]][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives]-10' -yl) pyridin-2-amine

(A)10 ' -bromo-3 ' - (1, 1,2, 2-tetrafluoroethyl) -5 ' H, 7 ' H-spiro [ oxetane-3, 6 ' -pyrrolo [1, 2-a ]][1，2，4]A triazolo [3 ] group,4-c][1，4]diaza derivatives]

To 8 '-bromo-2', 3 '-dihydro-1' H, 5 'H-spiro [ oxetane-3, 4' -pyrrolo [1, 2-a ]][1，4]Diaza derivatives](ii) -1' -Ketone (400mg, 1.48mmol) in DCM (30mL) was added CF₃SO₃Me (291mg, 1.77mmol), the mixture was then stirred at reflux temperature under nitrogen overnight. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in isoalk-2-ol (20mL) and 2, 2, 3, 3-tetrafluoropropanehydrazide (283mg, 1.77mmol) and HOAc (2 drops) were added. The mixture was then purged with nitrogen and stirred at 70 ℃ for 3 hours and then at 90 ℃ for 3 hours. The mixture was concentrated and the residue was purified by ISCO (eluting with water containing 0% to 100% methanol) to give an off-white solid (203mg, 34.7% yield). MS (m/z): 394.9/396.9(M + H)⁺

(B) 5-chloro-N- (1-methyl-1H-pyrazol-5-yl) -4- (3 '- (1, 1,2, 2-tetrafluoroethyl) -5' H, 7 'H-spiro [ oxetane-3, 6' -pyrrolo [1, 2-a ]][1，2，4]Triazolo [3, 4-c][1，4]Diaza derivatives]-10' -yl) pyridin-2-amine

The title compound was prepared following the procedure of example 15 using the corresponding intermediates and reagents. MS (m/z): 523.0(M + H)⁺

¹H NMR(400MHz，DMSO-d6)δ8.83(s，1H)，8.15(s，1H)，7.89(s，1H)，7.62-7.14(m，3H)，6.98(s，1H)，6.23(s，1H)，4.73(s，2H)，4.66(s，2H)，4.51-4.42(m，2H)，4.41-4.31(m，2H)，3.64(s，3H).

The following compounds were prepared following the procedure for compound 304 using the corresponding intermediates and reagents under conditions deemed appropriate by one skilled in the art.

The following compounds were prepared according to the procedures of the above examples using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art:

example 18: z-lyte kinase assay for ERK2

1. Materials and reagents:

2. the reaction steps are as follows:

orifice plate arrangement pattern

3. Preparation of solutions

1)1.33 Xkinase buffer: by ddH₂O dilute 5X kinase buffer to 1.33X.

2)4X dilution of test compound: test compounds were serially diluted to 4-fold the desired concentration and DMSO concentration was maintained at 8%. Final concentrations were 1, 0.33, 0.11, 0.037, 0.012, 0.004, 0.0014, 0.00046 μ M, with a final DMSO concentration of 2%.

3) Kinase/peptide mixture (P/K solution): by dissolving kinase and Z-LYTE in 1.33 Xkinase buffer^TMThe kinase/peptide mixture was prepared by diluting the Ser/Thr3 peptide to 0.6. mu.g/mL and 4. mu.M, respectively. Mix gently with pipetting.

4) Phospho-peptide solution (PP solution): mixing 0.4 μ l Z-LYTE^TMSer/Thr3 phospho-peptide was added to 99.6. mu.l of 1.33 Xkinase buffer.

5) ATP solution: an ATP solution was prepared by diluting 10mM ATP to 100. mu.M with 1.33 Xkinase buffer.

6) Developing solution: the developing reagent A was diluted with a developing buffer at a ratio of 1: 1024.

4. Reaction of

1) Kinase reaction (10. mu.l volume)

a. In 384 plates, 2.5 μ l of 4 × test compound was added to each well, except Cl, C2, C3 wells. Add 2.5. mu.l of 8% DMSO into Cl, C2, C3 wells

b. Place the plate on ice

c. Add 5. mu. L P/K mix to each test compound well and to C1, C2 wells

d. Add 5. mu.l PP solution to C3 well

e. Add 2.5. mu.l 1.33 Xkinase buffer to C1 and C3 wells

f. To each test compound well and C2 well was added 2.5 μ l of 4X ATP solution, respectively. The plate was shaken for 30 seconds and centrifuged (1500rpm, 1 minute)

g. The plates were sealed in the dark and incubated at room temperature (25-30 ℃) for 1 hour

2) Development reaction

a. Add 5. mu.l of developing solution to all wells

b. The plate was shaken for 30 seconds and centrifuged (1500rpm, 1 minute)

c. The plates were sealed in the dark and incubated at room temperature (25-30 ℃) for 1 hour

3) Terminate and read board

a. Add 5. mu.l of stop reagent to all wells

b. The plate was shaken for 30 seconds and centrifuged (1500rpm, 1 minute)

c. Coumarin values (excitation wavelength 400nm, emission wavelength 445nm) and fluorescein values (excitation wavelength 400nm, emission wavelength 520nm) were measured, respectively.

5. Data analysis

Emission Ratio (ER) ═ coumarin emission reading (445 nm)/fluorescein emission reading (520nm)

% phosphorylation ═ 1- [ ER x C3_520nm-C3_445nm]/[(C1_445nm-C3_445nm)+ER x(C3_520nm-C1_520nm)]

Inhibition Rate (IR) ═ 1-% phosphorylation_{Test compounds}/% phosphorylation_C2

6.IC₅₀The value: software XL-Fit attached to Microsoft Excel by ID Business Solutions (Guildford, UK)^TM(version 2.0) determination of IC₅₀

Example 19: P-RSK (Thr359) Acumen assay in colo205

1. Cell lines

colo205(SIBS)

2. Materials and reagents

Phospho-p90RSK (Thr359) (D1E9) rabbit mab: cell signal, #8753

·Alexa488 donkey anti-rabbit IgG: invitrogen, # A-21206

Propidium iodide: sigma, # p4170

4% paraformaldehyde: SCRC, # DF021

·10％Triton X-100：PIERCE，#28314

96-well plates (black, transparent bottom): BD, #354640

·eX3(A Multilaser Microplate Cytometer For Enhanced High Content Screening)：TTP LabTech

Acumen assay protocol

Cells were seeded at 4000 cells/well in 100 μ l 10% FBS in 96-well plates at 37 ℃ with 5% CO₂Incubate overnight.

Compounds were diluted to 3, 1, 0.33, 0.11, 0.037, 0.012, 0.004, 0.001 μ M, maintaining DMSO concentration at 5%. mu.L of diluted compound was added to each well at 37 ℃ with 5% CO₂Incubate for 1 hour.

Add 100 μ L of 4% pre-warmed paraformaldehyde (final concentration of 2%) and incubate at room temperature for 45 min.

Removing the paraformaldehyde solution. Cells were fixed for 30 min at room temperature by adding 100 μ L of ice-cold 0.1% Triton.

Wash twice with 150 μ L PBS and incubate with 100 μ L blocking solution (1% BSA in PBS) for 2-3 hours at room temperature, seal plate.

Wash once with 150. mu.L PBS and incubate overnight at 4 ℃ with 35. mu. L p-RSK (Thr359) (1: 1000 dilution) with a plate of the plate.

Washed twice with PBS and 35. mu.l of Alexa diluted 1: 1000 in antibody dilution buffer (1% BSA in PBS)488 donkey anti-rabbit IgG were incubated together at room temperature for 1.5 hours. The plate was covered with tinfoil paper to protect from light.

Wash twice with 150. mu.L PBS. To each well was added 35 μ l of 1.5 μ M propidium iodide stock to determine cell number, and plates were sealed.

Incubate at room temperature for 30 minutes. The plate was placed in Acumen Explorer and scanned with the appropriate instrument settings.

4. Data analysis

Wherein:

percent positive for cells treated with compound indicated by percent of percent positive

Percentage minimum well indicates the Percentage of positive cells treated with 3. mu.M GDC0994

·Percentage_{Largest hole}Indicates the percent positivity of cells not treated with the compound

5.IC₅₀The value: software XL-Fit attached to Microsoft Excel by ID Business Solutions (Guildford, UK)^TM(version 2.0) determination of IC₅₀

As a result:

remarking: a is less than or equal to 5; b is more than 5 and less than or equal to 10; c is more than 10; d is less than or equal to 100; e is more than 100.

Claims

1. A compound of formula (I):

Z₁and Z₂Each independently is N or C, andis composed of 1_、2_、A 5 membered heteroaryl of 3 or 4 ring heteroatoms selected from N, O or S; the 5-membered heteroaryl is optionally substituted with one or more substituents independently selected from: deuterium, halogen, hydroxy, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂-CN, mercapto, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl, - (C)_1-6Alkyl) -OH and- (C_1-6Alkyl) -O- (C_1-6Alkyl) of said C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6Haloalkyl is each optionally substituted with one or more deuterium;

l is absent, or L is-NR_cO or S;

R_cis hydrogen or C_1-6An alkyl group;

R₁selected from hydrogen, C optionally substituted by one or more deuterium_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl), - (C)_1-6Alkyl group) - (C_3-8Cycloalkyl), - (C)_1-6Alkyl) - (3-8 membered heterocyclyl), - (C)_1-6Alkyl-phenyl, - (C)_1-6Alkyl) -heteroaryl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroarylWherein said C is_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8The cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-(C_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl group), C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, heteroaryl, C optionally substituted with one or more deuterium_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group;

R₃、R₄、R₅、R₆、R₇and R₈Each independently selected from hydrogen, deuterium, halogen, hydroxy, -CN, mercapto, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-(C_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl group), C_1-6Alkyl, - (C)_1-6Alkyl) -phenyl, C_1-6Alkoxy and C_1-6A haloalkyl group; or, R₃、R₄、R₅、R₆、R₇And R₈Any two of which, together with the carbon atom to which they are attached and ring B, form an 8-13 membered spirocyclic, fused or bridged ring optionally containing 1-3 ring heteroatoms independently selected from N, O or S; said spiro, fused or bridged ring being optionally substituted with one or more substituents independently selected from: deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、-(C_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl group), C_1-6Alkyl radical、C_1-6Alkoxy and C_1-6A haloalkyl group; or, R₃And R₄Together, R₅And R₆Together or R₇And R₈Together are oxo;

n is 0, 1 or 2;

m is 0, 1,2, 3, 4 or 5.

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1, whereinSelected from:

3.A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1, whereinSelected from:

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 3, whereinIs thatAnd R is₁₀And R₁₁Independently selected from hydrogen, halogen and C_1-6An alkyl group.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to any one of claims 1-4, wherein Ar is a monocyclic heteroaryl group having 5 or 6 ring atoms, of which 1,2 or 3 are ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon atoms; each of which is optionally substituted with one or more substituents independently selected from: deuterium, halogen, hydroxy, -amino, -CN, mercapto, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl group), C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl, wherein said C is_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_3-8The cycloalkyl, 3-8 membered heterocyclyl, phenyl and heteroaryl are each optionally substituted with one or more deuterium.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 5, wherein Ar is selected from pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1, 3, 5-triazinyl, 1,2, 4-triazolyl and thiazolyl (more preferably Ar is selected from pyridinyl, pyrimidinyl and 1, 3, 5-triazinyl), each of which is optionally substituted with one or more substituents independently selected from: halogen, -CN, C optionally substituted by one or more deuterium_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 6, wherein Ar is:

8. The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein R₁Is selected from C_1-6Alkyl, - (C)_1-6Alkyl) -OH, saturated monocyclic C_3-8Cycloalkyl, saturated monocyclic 3-8 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, and heteroaryl, wherein said heteroaryl is having 5 or 6 ringsA monocyclic aromatic hydrocarbon group of atoms, of which 1,2 or 3 are independently selected from N, O and S, the remaining ring atoms being carbon atoms, or a bicyclic aromatic hydrocarbon group of 8, 9 or 10 ring atoms, of which 1,2, 3 or 4 are independently selected from N, O and S, the remaining ring atoms being carbon atoms, wherein at least one ring is an aromatic ring, and when the total number of S and O atoms in the heteroaryl group exceeds 1, these S and O heteroatoms are not adjacent to each other, wherein said C is_3-8The cycloalkyl, 3-8 membered heterocyclyl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl), 3-6 membered heterocyclyl, C optionally substituted with one or more deuterium_1-6Alkyl radical, C_1-6Alkoxy or C_1-6A haloalkyl group.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 8, wherein R is₁Is a heteroaryl group selected from pyrazolyl, pyridinyl, isoxazolyl, 1,2, 4-triazolyl, 1, 3, 4-thiadiazolyl, 2,4,5, 6-tetrahydrocyclopenta [ c ] s]Pyrazolyl and 5,6, 7, 8-tetrahydro [1, 2, 4]]Triazolo [1, 5-a]A pyridyl group; wherein said heteroaryl is each optionally substituted with one or more substituents independently selected from: c optionally substituted by one or more deuterium_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, halogen, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl) and 3-6 membered heterocyclyl.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 9, wherein R is₁Is pyrazolyl, which is optionally mono-or disubstituted bySubstituted with one or more substituents independently selected from: c optionally substituted by one or more deuterium_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, halogen, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl) and oxetanyl.

11. The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-10, wherein R is₂Selected from halogen, -CN, C_1-6Alkyl radical, C_1-6Haloalkyl, saturated monocyclic C_3-8Cycloalkyl, phenyl and heteroaryl, said heteroaryl being a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, wherein 1,2 or 3 of said ring atoms are independently selected from N, O and S, the remaining ring atoms being carbon atoms, or a bicyclic aromatic hydrocarbon group having 8, 9 or 10 ring atoms, of which 1,2, 3 or 4 are independently selected from N, O and S, the remaining ring atoms being carbon atoms, wherein at least one ring is an aromatic ring, and when the total number of S and O atoms in the heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other, wherein said C is_3-8The cycloalkyl, phenyl or heteroaryl groups are each optionally substituted with one or more substituents independently selected from: halogen, -CN, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl and oxo.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 11, wherein R is₂Is phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -CN and C_1-6An alkoxy group.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 11, wherein R is₂Is a heteroaryl group selected from 1,2, 5-oxadiazolyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, thiazolyl, isothiazolyl, benzo [ d ] d]Isoxazolyl, thienyl, indazolyl, and pyrrolyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of: c_1-6Alkyl, halogen, oxo and-CN.

14. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 11, wherein R is₂Is a saturated monocyclic ring C_3-8Cycloalkyl optionally substituted with one or more substituents independently selected from C_1-6Substituted with a haloalkyl.

15. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-14, wherein m is 0, 1 or 2.

16. The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-15, wherein R is_aAnd R_bEach independently selected from hydrogen, halogen, hydroxy and C_1-6An alkyl group; or, R_a、R_bTogether with the carbon atom to which they are attached form a saturated monocyclic ring C_3-6Cycloalkyl or form a 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl is a saturated monocyclic ring having 3-6 ring atoms, 1 or 2 of said ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms; wherein said saturated monocyclic ring C_3-6The cycloalkyl or 3-6 membered heterocyclyl is each optionally substituted with one or more substituents selected from halogen.

17. The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-16, wherein L is absent, or L is NH, O or S.

18. A compound of formula (I) according to claim 1 selected from compounds 1-322, or a pharmaceutically acceptable salt thereof.

19. The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein n is 0,represents a double bond, R₃And R₅Is absent, R₄And R₆Each independently selected from hydrogen and C_1-6An alkyl group.

20. The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer of the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 19, wherein the compound of formula (I) is a compound of formula (I-1):

wherein

R₄and R₆Each independently selected from hydrogen and C_1-6An alkyl group;

m is 0, 1 or 2,

R_aand R_bEach independently selected from hydrogen, halogen, hydroxy or C_1-6An alkyl group; or, R_a、R_bTogether with the carbon atom to which they are attached form a saturated monocyclic ring C_3-6Cycloalkyl or form a 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl is a saturated monocyclic ring having 3-6 ring atoms, 1 or 2 of said ring atoms are ring heteroatoms independently selected from N, O and S, the remaining ring atoms are carbon atoms, wherein saidSaturated monocyclic ring of (2)_3-6(ii) cycloalkyl or 3-6 membered heterocyclyl are each optionally substituted with one or more substituents selected from halogen;

l is absent, or NH, O or S;

21. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 20, wherein

R₁₀and R₁₁Is hydrogen;

m is 0 or 1;

L is absent or NH or O.

22. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 20, wherein the compound of formula (I) is selected from:

23. the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein n is 0,represents a single bond, R₃、R₄、R₅And R₆Each independently selected from hydrogen and C_1-6Alkyl radical, C_1-6Haloalkyl, - (C)_1-6Alkyl) -O- (C_1-6Alkyl) and- (C)_1-6Alkyl) -phenyl; or, R₃And R₄Or R₅And R₆Any pair of (b) together with the carbon atom to which they are attached form a saturated monocyclic ring C_3-6A cyclic hydrocarbyl group or a saturated monocyclic 3-6 membered heterocyclyl group having 1 or 2 ring heteroatoms selected from N, O and S, thereby forming a spiro ring together with the B ring.

24. The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer of the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 23, wherein the compound of formula (I) is a compound of formula (I-2):

wherein

R₁Is selected from C_1-6Alkyl, - (C)_1-6Alkyl) -OH, saturated monocyclic C_3-8Cycloalkyl, saturated 3-8 membered heterocyclyl and heteroaryl containing 1 or 2 ring heteroatoms independently selected from N, O and S, wherein said C is_3-8The cycloalkyl, 3-8 membered heterocyclyl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, - (C)_1-6Alkyl) -OH, - (C)_1-6Alkyl) -O- (C_1-6Alkyl), a saturated 3-6 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, C optionally substituted with one or more deuterium_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group;

Z₃is CR₁₀Or N;

R₃、R₄、R₅and R₆Each independently selected from hydrogen and C_1-6Alkyl radical, C_1-6Haloalkyl, - (C)_1-6Alkyl) -O- (C_1-6Alkyl) and- (C)_1-6Alkyl) -phenyl; or, R₃And R₄Or R₅And R₆Any pair of (b) together with the carbon atom to which they are attached form a saturated monocyclic ring C_3-6Cycloalkyl or saturated with 1 or 2 ring hetero atoms selected from N, O and SAnd monocyclic 3-6 membered heterocyclyl, thereby forming a spiro ring together with ring B;

m is 0, 1 or 2,

l is absent, or NH, O or S;

25. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 24, wherein

R₁Selected from the group consisting of saturated monocyclic 3-8 membered heterocyclyl and heteroaryl containing 1 or 2 ring heteroatoms independently selected from N, O and S, wherein said heteroaryl is monocyclic aromatic hydrocarbon having 5 or 6 ring atoms, said1,2 or 3 ring heteroatoms independently selected from N, O and S among the ring atoms, the remaining ring atoms being carbon atoms, or a bicyclic aromatic hydrocarbon group having 8, 9 or 10 ring atoms, 1,2, 3 or 4 ring heteroatoms independently selected from N, O and S among the ring atoms, the remaining ring atoms being carbon atoms, wherein at least one ring is an aromatic ring, and when the total number of S and O atoms in the heteroaryl group exceeds 1, these S and O heteroatoms are not adjacent to each other, wherein each of said 3-8 membered heterocyclyl and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, halogen, - (C)_1-6Alkyl) -OH, C_1-6Alkoxy, - (C)_1-6Alkyl) -O- (C_1-6Alkyl) and a saturated, monocyclic 3-6 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S;

Z₃is CR₁₀Or N;

m is a number of 1 or 2,

R₁₀and R₁₁Is hydrogen;

l is absent or L is O.

26. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 25, wherein R is₁Selected from the group consisting of morpholinyl, thiomorpholinyl and heteroaryl, wherein said heteroaryl is selected from the group consisting of pyrazolyl, 2,4,5, 6-tetrahydrocyclopenta [ c]Pyrazolyl, 1,2, 4-triazolyl, 5,6, 7, 8-tetrahydro [1, 2, 4] tetrahydro]Triazolo [1, 5-a]Pyridyl, 1, 3, 4-thiadiazolyl and pyridyl, and said heteroaryl is each optionally substituted with one or more groups selected from: c_1-6Alkyl radical, C_1-6Haloalkyl, halogen, - (C)_1-6Alkyl) -OH, C_1-6Alkoxy, - (C)_1-6Alkyl) -O- (C_1-6Alkyl) and oxetanyl.

27. A compound of formula (I) according to claim 24 or a pharmaceutically acceptable salt thereofA salt of the compound of formula (I) or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a pharmaceutically acceptable salt thereof, wherein Ar is heteroaryl selected from pyridinyl, pyrimidinyl and 1, 3, 5-triazinyl; wherein each of said heteroaryl groups is optionally substituted with one or more substituents selected from: c optionally substituted by one or more deuterium_1-6Alkyl and halogen.

28. The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer of the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 27, wherein Ar is:

wherein R is₂₀、R₂₁、R₂₂、R₂₃And R₂₄Each independently selected from hydrogen, halogen and C optionally substituted with one or more deuterium_1-6An alkyl group.

29. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 24, wherein R is₂Selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, phenyl and heteroaryl, wherein the heteroaryl is selected from isoxazolyl, 1,2, 5-oxadiazolyl, pyrazolyl, oxazolyl, pyridyl, thiazolyl, isothiazolyl, thienyl and benzo [ d]An isoxazolyl group; wherein said phenyl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C_1-6Alkyl radical, C_1-6Alkoxy and oxo.

30. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 24, wherein the compound of formula (I) is selected from:

31. the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein n is 1,represents a single bond, R₃、R₄、R₅、R₆、R₇And R₈Each independently selected from hydrogen, halogen, hydroxy, C_1-6Alkyl and C_1-6An alkoxy group; wherein said C_1-6Alkyl is optionally substituted with one or more substituents independently selected from: hydroxy and C_1-6An alkoxy group; or, R₃、R₄、R₅、R₆、R₇And R₈Any two of which, together with the carbon atom to which they are attached and ring B, form a 9-12 membered spirocyclic, fused or bridged ring optionally containing 1-3 ring heteroatoms selected from N, O or S; wherein said spiro, fused or bridged ring is optionally substituted with one or more substituents independently selected from: halogen, hydroxy, amino, C_1-6Alkyl and-CN.

32. The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer of the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 31, wherein the compound of formula (I) is a compound of formula (I-3):

wherein

R₁Is selected from C_1-6Alkyl, - (C)_1-6Alkyl) -OH, saturated monocyclic C_3-8Cycloalkyl, saturated monocyclic 3-8 membered heterocyclyl and heteroaryl containing 1 or 2 ring heteroatoms independently selected from N, O and S; wherein said C_3-8The cycloalkyl, 3-8 membered heterocyclyl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C optionally substituted by one or more deuterium_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group;

R₃、R₄、R₅、R₆、R₇and R₈Each independently selected from hydrogen, halogen, hydroxy, C_1-6Alkyl and C_1-6An alkoxy group; said C_1-6Alkyl is optionally substituted with one or more substituents independently selected from: hydroxy and C_1-6An alkoxy group; or, R₃、R₄、R₅、R₆、R₇And R₈Any two of which, together with the carbon atom to which they are attached and the B ring, formR_dSelected from hydrogen or halogen, t is 0, 1,2 or 3;

m is 0, 1 or 2,

l is absent, or L is NH, O or S;

33. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 32, wherein

R₁Is selected from C_1-6Alkyl, - (C)_1-6Alkyl) -OH, saturated monocyclic C_3-8Cycloalkyl, saturated monocyclic 3-8 membered heterocyclyl and heteroaryl containing 1 or 2 ring heteroatoms independently selected from N, O and S; wherein said C_3-8The cycloalkyl, 3-8 membered heterocyclyl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C_1-6Alkoxy radical, C_1-6Haloalkyl and C optionally substituted with one or more deuterium_1-6An alkyl group;

R₂is selected from-CN, C_1-6Haloalkyl, saturated monocyclic C_3-8Cycloalkyl, phenyl and heteroaryl, wherein said heteroaryl is monocyclic aromatic hydrocarbon having 5 or 6 ring atoms of which 1,2 or 3 are independently selected from N, O and S, the remaining ring atoms being carbon atoms, or is bicyclic aromatic hydrocarbon having 8, 9 or 10 ring atoms of which 1,2, 3 or 4 are independently selected from N, O and S, the remaining ring atoms being carbon atoms, wherein at least one ring is aromatic and when the total number of S and O atoms in the heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other, wherein said saturated monocyclic C is_3-8The cycloalkyl, phenyl or heteroaryl groups are each optionally substituted with one or more substituents independently selected from: halogen, -CN, C_1-6Alkyl and C_1-6A haloalkyl group;

m is 0, 1 or 2,

R_aand R_bEach independently selected from hydrogen, halogen, hydroxy and C_1-6An alkyl group; or, R_a、R_bTogether with the carbon atom to which they are attached form a saturated monocyclic ring C_3-6Cycloalkyl or form a 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl is a saturated monocyclic ring having 3-6 ring atoms, 1 or 2 of said ring atoms are ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms; wherein said saturated monocyclic ring C_3-6(ii) cycloalkyl or 3-6 membered heterocyclyl are each optionally substituted with one or more substituents selected from halogen;

l is absent or L is NH or O.

34. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 32, wherein R is₁Selected from: (1) c_1-6Alkyl (2) - (C)_1-6Alkyl) -OH, (3) saturated monocyclic C_3-8Cycloalkyl optionally substituted with one or more substituents independently selected from halogen and C_1-6Substituent (S) of alkoxy, (4) a saturated monocyclic 6-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from N, O and S, and (5) a heteroaryl selected from pyrazolyl, pyridinyl, and isoxazolyl, each of which is optionally substituted with one or more substituents independently selected from: c_1-6Alkoxy radical, C_1-6Haloalkyl and C optionally substituted with one or more deuterium_1-6An alkyl group.

35. According to claim 32A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ar is heteroaryl, selected from pyridinyl and pyrimidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -CN, C optionally substituted by one or more deuterium_1-6Alkyl radical, C_1-6Alkoxy and C_1-6A haloalkyl group.

36. The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer of the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 35, wherein Ar is:

37. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 32, wherein R is₂Selected from: (1) -CN, (2) C_1-6Haloalkyl, (3) saturated monocyclic C_3-8Cycloalkyl optionally substituted by one or more groups selected from C_1-6Haloalkyl substituted, (4) phenyl optionally substituted with one or more substituents independently selected from: halogen and-CN, and (5) heteroaryl selected from 1,2, 5-oxadiazolyl, indolinyl, 1,2, 3, 4-tetrahydroquinolinyl, pyrazolyl, indazolyl, and pyrrolyl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, and-CN, and (5) heteroarylSubstituted with one substituent independently selected from: halogen, -CN and C_1-6An alkyl group.

38. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 32, wherein the compound of formula (I) is selected from:

39. a pharmaceutical composition comprising a compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

40. A method of inhibiting ERK activity in vivo or in vitro comprising contacting an effective amount of a compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, with ERK.

41. Use of a compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease that responds to inhibition of ERK.

42. The use of claim 41, wherein the medicament is for treating cancer or an autoimmune disease.

43. The use of claim 42, wherein the cancer is a solid tumor or a hematological malignancy, such as leukemia, lymphoma, colorectal cancer, melanoma, glioma, pancreatic cancer, breast cancer, lung cancer (e.g., non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid cancer) or ovarian cancer.

44. A method of treating or preventing a disease responsive to inhibition of ERK, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof.

45. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease which responds to inhibition of ERK.

46. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, for use as a medicament.

47. A compound according to claim 46, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment or prevention of a disease responsive to inhibition of ERK.

48. A compound according to claim 47, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment or prevention of cancer or an autoimmune disease.

49. A compound or pharmaceutically acceptable salt thereof according to claim 48, wherein the cancer is a solid tumor or a hematological malignancy, such as leukemia, lymphoma, colorectal cancer, melanoma, glioma, pancreatic cancer, breast cancer, lung cancer (e.g. non-small cell lung cancer), thyroid cancer (e.g. papillary thyroid cancer) or ovarian cancer.

50. A combination comprising a compound of any one of embodiments 1-38, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

51. A combination product according to claim 50, wherein the additional therapeutic agent is an anti-tumour therapeutic agent, such as a radiotherapeutic agent, a chemotherapeutic agent, an immunotherapeutic therapeutic agent, a targeted therapeutic agent.

52. A compound of formula (II):

53. A compound of formula (II) according to claim 52, selected from:

54. a compound of formula (III):

or a racemic mixture or enantiomer thereof, wherein:

R₃、R₄、R₅and R₆Each independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl or C optionally substituted by phenyl_1-6An alkyl group; or, R₃And R₄Or R₅And R₆Any pair of (b) together with the carbon atom to which they are attached form a saturated C_3-6Cycloalkyl or a saturated 3-to 4-membered heterocyclic ring having 1 or 2 ring heteroatoms selected from N, O and SA group, thereby forming a spiro ring together with the B ring; provided that R is₃、R₄、R₅And R₆Not simultaneously being hydrogen, and when R is₃、R₄、R₅And R₆One or two of them are C_1-6When alkyl, the other groups are not simultaneously hydrogen.

55. A compound of formula (III) according to claim 54, selected from: