HK40060604B - Tricyclic compounds and their use - Google Patents

Description

Tricyclic compounds and their uses

Technical Field

This invention relates to tricyclic compounds, pharmaceutical compositions comprising them, methods for their preparation, and pharmaceutical uses.

Background Technology

The RAS/RAF/MEK/ERK pathway is an evolutionarily conserved signaling cascade that regulates numerous 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, primarily due to mutations in the KRAS, NRAS, and BRAF genes. RAS mutations are present in approximately 30% of all human cancers, with the following mutation rates across various cancers: pancreatic cancer 90%, colon cancer 50%, papillary thyroid carcinoma 50%, non-small cell lung cancer (NSCLC) 30%, and melanoma 25%. BRAF mutations have been extensively identified in tumors, present in a significant proportion (7%) of all human cancers. This mutation is highly prevalent in the following cancers: hairy cell leukemia (100%), melanoma (50%-60%), papillary thyroid carcinoma (40%-60%), colorectal cancer (CRC) (5%-10%), fibrous astrocytoma (10%-15%), and non-small cell lung cancer (NSCLC) (3%-5%). MEK mutations primarily occur in melanoma, but also in ovarian cancer cell lines and gliomas. Generally, all upstream mutations lead to overactivation of the ERK protein, which is responsible for the activity of a range of ERK signaling substrates and is ultimately associated with various tumors.

Targeting the MAPK/ERK pathway has become a hot topic in cancer therapy. The clinical benefits achieved by BRAF and MEK inhibitors have demonstrated that targeting these downstream RAS effectors is a very promising approach for treating cancers with BRAF mutations. However, current evidence suggests that inhibiting BRAF or MEK alone is insufficient to generate clinical benefits in RAS-mutant cancers. Both intrinsic and acquired resistance to BRAF and MEK inhibitors are often associated with the persistence of ERK signaling in the presence of the drugs, implying the need for ERK targeting. Preliminary efficacy of ERK inhibitors has been observed in clinical trials. In the Phase I clinical trial of BVD-523, clinical responses were observed in patients with BRAF and NRAS mutations, and even in patients whose disease had progressed with prior use of BRAF and/or MEK inhibitors. Combination therapy with ERK inhibitors has been investigated, and preclinical data support a strategy of combining inhibitors with other targets in KRAS-mutant cancer cells, such as CDK4/6 inhibitors, VEGFR2 inhibitors, PARP inhibitors, multi-ERBB inhibitors, and autophagy inhibitors. Therefore, ERK inhibitors have the potential to benefit more patients in clinical practice.

Therefore, there is a need for novel compounds and methods for modulating ERK activity and treating related disorders, including cancer. This invention addresses these needs.

Invention Summary

This 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:

_Z1 and _Z2 are each independently N or C, and are 5-membered heteroaryl groups containing 1, 2, 3, or 4 cyclic heteroatoms selected from N, O, or S; said 5-membered heteroaryl group is optionally substituted by one or more substituents independently selected from: deuterium, halogen, hydroxyl, amino, -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -CN, mercapto, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkoxy, _C1-6 haloalkyl, -( _C1-6 alkyl)-OH, and -( _C1-6 alkyl)-O-( _{C1-6 alkyl} ); said _C1-6 alkyl, _C1-6 alkoxy, and _C1-6 haloalkyl are each optionally substituted by one or more deuterium groups;

L does not exist, or L is -NR _c , O, or S;

_Rc is hydrogen or _C1-6 alkyl;

Ar is a heteroaryl group, which is optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, hydroxyl, amino, -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -CN, mercapto, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkoxy, _C1-6 haloalkyl, -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _{C1-6 alkyl} ), C3-8 cyclic hydrocarbon, _3-8 membered heterocyclic, phenyl, and heteroaryl, wherein the _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, _C3-8 cyclic hydrocarbon, 3-8 membered heterocyclic, phenyl, and heteroaryl are each optionally substituted by one or more deuterium groups;

_R1 is selected from hydrogen, _C1-6 alkyl, C2-6 alkenyl, _C2-6 ynyl, _C1-6 haloalkyl, -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl), -( _C1-6 alkyl)-(C3-8 cycloalkyl), -( _C1-6 alkyl)-( _3-8 heterocyclic), -( _C1-6 alkyl)-phenyl, -( _C1-6 alkyl)-heteroaryl, _{C3-8 cycloalkyl, 3-8 heterocyclic} , phenyl, and heteroaryl, wherein the _C2-6 alkenyl, _C2-6 ynyl, C3-8 cycloalkyl, _3-8 heterocyclic, phenyl, and heteroaryl are each optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, hydroxyl, mercapto, amino, -NH(C _C1-6 alkyl), -N( _C1-6 alkyl) ₂ , -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl), _C3-8 cyclic hydrocarbon, 3-8 membered heterocyclic group, phenyl, heteroaryl, _C1-6 alkyl optionally substituted with one or more deuterium, _C1-6 alkoxy and _C1-6 haloalkyl;

_R2 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -CN, mercapto, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, _C1-6 haloalkyl, -(C1-6 alkyl)-OH, -( _{C1-6 alkyl)-O-(C1-6} alkyl), -( _C1-6 alkyl)-( _C3-8 cycloalkyl), -( _C1-6 alkyl)-( _3-8 membered heterocyclic), -( _C1-6 alkyl)-phenyl, -( _C1-6 alkyl)-heteroaryl, C3-8 cycloalkyl, 3-8 membered heterocyclic, phenyl, and heteroaryl, wherein the _C2-6 alkenyl, _C2-6 ynyl, C3-6 alkyl, C2-6 alkyl, _C3-8 cycloalkyl, _C3-8 membered heterocyclic, phenyl, and heteroaryl are selected from these groups. _{The 3-8} cyclic hydrocarbon group, the 3-8 membered heterocyclic group, the phenyl group, and the heteroaryl group are each optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, -CN, hydroxyl, mercapto, amino, -NH (C _1-6 alkyl), -N (C _1-6 alkyl) ₂ , -(C _1-6 alkyl)-OH, -(C _1-6 alkyl)-O-(C _1-6 alkyl), C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, and oxo group;

_Ra and _Rb are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl), -CN, mercapto, _C1-6 alkyl, _C1-6 alkoxy, and _C1-6 haloalkyl; or, _Ra and _Rb together with the carbon atoms attached to them form a _C3-6 cyclic hydrocarbon or a 4-6 membered heterocyclic group, wherein the _C3-6 cyclic hydrocarbon or 4-6 membered heterocyclic group is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, hydroxyl, mercapto, amino, -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl), C _1-6 alkyl, _C1-6 alkoxy, and _C1-6 haloalkyl;

It represents a double bond or a single bond, and when it represents a double bond, _R3 and _R5 do not exist;

_R3 , _R4 , _R5 , _R6 , R7, and R8 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, -CN, mercapto, amino, -NH ( _C1-6 alkyl), -N (C1-6 alkyl) ₂ , -( _C1-6 alkyl)-OH, -(C1-6 alkyl)-O-(C1-6 alkyl), _C1-6 alkyl, -( _C1-6 alkyl)-phenyl, _C1-6 alkoxy, and C1-6 haloalkyl; or, R3, R4, _R5 , R6, R7, and _R8 are each selected from hydrogen, deuterium, halogen, hydroxyl, -CN, mercapto, amino, -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl)2, -( _C1-6 alkyl)-OH, -(C1-6 alkyl)-O-(C1-6 alkyl), _C1-6 alkyl, -( _C1-6 alkyl) _-phenyl , C1-6 alkoxy, and _C1-6 haloalkyl; Any two carbon atoms in ₈ , together with ring B, form an 8-13 membered spirocyclic, fused, or bridged ring optionally containing 1-3 independently selected cyclic heteroatoms chosen from N, O, or S; said spirocyclic, fused, or bridged ring is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, hydroxyl, mercapto, amino, -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl), _C1-6 alkyl, _C1-6 alkoxy, and _C1-6 haloalkyl; or, _R3 together with _R4 , _R5 together with _R6 , or _R7 together with _R8 are oxo groups;

n is 0, 1, or 2;

m can be 0, 1, 2, 3, 4, or 5.

The compounds described above, as well as the active compounds covered by this invention as disclosed in the context, are collectively referred to as "the compounds of this invention".

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

The present invention also provides compounds of the present invention for use as medicines, and in particular compounds of the present invention for treating or preventing diseases that respond to inhibition of ERK.

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

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

The present invention also provides a method for treating or preventing diseases that respond to inhibition of ERK, comprising administering an effective amount of the compound of the present invention to an individual in need of it.

The present invention also provides the use of the compounds of the present invention in the treatment or prevention of diseases that respond to inhibition of ERK.

The present invention also provides the use of the compounds of the present invention in the preparation of medicaments for the treatment or prevention of diseases that respond to inhibition of ERK.

Brief description of the attached figures

Figure 1 shows the route for synthesizing the compounds of the present invention, wherein X is a halogen; Z1, _Z2 , L, _R1 , _R2 , _R3 , _R4 , _R5 , _R6 , _R7 , _R8 , _Ra , _Rb , m and n are as defined for compounds of formula (I) and compounds of sub-formulas (I-1), (I-2), and (I-3); _R9 is as defined for compounds of formulas (II) and (III).

Invention Details

definition

The following words, phrases and symbols used in this application have the meanings described below, unless otherwise stated in the context.

A hyphen ("-") not between two letters or symbols indicates the connection point of a substituent. For example, -O ( _C1-6 alkyl) refers to a _C1-6 alkyl group connected to the rest of the molecule via an oxygen atom.

The dashed lines intersecting with chemical bonds are used to indicate the positions where the group connects to the rest of the molecule. For example, Ar could be represented by two dashed lines indicating connection to _R1 -NH- and connection to the A ring, respectively.

As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group containing 1-18 carbon atoms ( _C1-18 ), preferably 1-10 carbon atoms ( _C1-10 ), and particularly preferably 1-6 carbon atoms ( _C1-6 ). For example, " _C1-6 alkyl" refers to the alkyl group having 1-6 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.

As used herein, the term "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing one or more, for example, 1, 2, or 3 carbon-carbon double bonds (C=C), and containing 2-10 carbon atoms (C _2-10 ), preferably 2-6 carbon atoms (C _2-6 ), and more preferably 2-4 carbon atoms (C _2-4 ). For example, "C _2-6 alkenyl" refers to an alkenyl group having 2-6 carbon atoms, preferably containing 1 or 2 carbon-carbon double bonds; "C _2-4 alkenyl" refers to an alkenyl group having 2-4 carbon atoms, preferably containing 1 carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl. The linkage of the alkenyl group may or may not be on a double bond.

As used herein, the term "alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing one or more, for example, 1, 2, or 3 carbon-carbon triple bonds (C≡C), and containing 2-10 carbon atoms (C _2-10 ), preferably 2-6 carbon atoms (C _2-6 ), and more preferably 2-4 carbon atoms (C _2-4 ). For example, "C _2-6 alkynyl" indicates an alkynyl group having 2-6 carbon atoms, preferably containing 1 or 2 carbon-carbon triple bonds; "C _2-4 alkynyl" indicates an alkynyl group having 2-4 carbon atoms, preferably containing 1 carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. The alkynyl group may or may not be attached to a triple bond.

As used herein, the term "halogen" or "halogenated" refers to fluorine, chlorine, bromine, and iodine, preferably fluorine, chlorine, and bromine, and more preferably fluorine and chlorine.

As used herein, the term "haloalkyl" refers to an alkyl group as defined herein, in which one or more hydrogen atoms, such as 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 as or different from each other. In one embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein, in which two or more hydrogen atoms, such as 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, in which two or more hydrogen atoms, such as 2, 3, 4, or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are different from each other. Examples of haloalkyl groups include, but are not limited to _, -CF3, -CHF2, _-CH2F , _-CH2CF3 , _-CF2CF3 , _-CF2CH3 , _etc.

As used herein, the term "alkoxy" refers to the -O-alkyl group, where the alkyl group 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 their isomers.

As used herein, the term "cyclic hydrocarbon group" refers to _a saturated or partially _unsaturated cyclic hydrocarbon group containing 3-12 ring carbon atoms ( _C3-12 ), for example, 3-8 ring carbon atoms ( _C3-8 ), 3-7 ring carbon atoms ( _C3-7 ), or _{3-6 ring carbon atoms (C3-6 )} ; it may have one or two rings. Cyclic hydrocarbon groups may include fused rings, bridged rings, or spirocyclic rings. The rings of the cyclic hydrocarbon group may be saturated, or may contain one or more double bonds, such as one or two double bonds (i.e., partially unsaturated), but it is not fully conjugated and is not an "aryl" group as defined herein. In one example, the cyclic hydrocarbon group is a monocyclic cyclic hydrocarbon group, preferably a monocyclic _C3-8 cyclic hydrocarbon group, more preferably a monocyclic _{C3-6 cyclic} hydrocarbon group. In another embodiment, the cyclic hydrocarbon group is a saturated monocyclic hydrocarbon group, preferably a saturated monocyclic _C3-8 cyclic hydrocarbon group, more preferably a saturated monocyclic _{C3-6 cyclic} hydrocarbon group. Examples of monocyclic hydrocarbon 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), and cyclohexadienyl. In another example, the cyclic hydrocarbon group is a bicyclic hydrocarbon group, preferably a bicyclic _C5 - _C12 cyclic hydrocarbon group, more preferably a bicyclic _C7 - _C12 cyclic hydrocarbon group. Examples of bicyclic cycloalkyl groups include, but are not limited to, bicyclic [4.1.0]heptyl, bicyclic [3.1.1]heptyl, bicyclic [2.2.1]heptyl, bicyclic [2.2.2]octyl, bicyclic [3.2.2]nonyl, spiro[3.3]heptyl, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[4.5]decyl, and bicyclic [3.1.1]hept- ₂ -enyl. Most preferably, the cycloalkyl group is a saturated monocyclic _C3-6 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, the term "heterocyclic group" or "heterocycle" refers to a saturated or partially unsaturated ring having 3-12 ring atoms (3-12 members), such as 3-8 ring atoms (3-8 members), 5-7 ring atoms (5-7 members), 3-6 ring atoms (3-6 members), or 4-6 ring atoms (4-6 members), wherein one, two, or three, preferably one or two, of the ring atoms are heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms; it may have one or more rings, such as one, two, or three, preferably one or two rings. N and S may optionally be oxidized to various oxidation states, and the linkage of the heterocyclic group may be on the N heteroatom or on the carbon atom. Heterocyclic groups may include fused rings, bridged rings, or spirocyclic rings. The rings of a heterocyclic group may be saturated, or may contain one or more, such as one or two, double bonds (i.e., partially unsaturated), but it is not fully conjugated and is not a "heteroaryl" as defined in this invention. For example, "3-8 membered heterocyclic group" refers to a heterocyclic group having 3-8 ring atoms, comprising 1, 2, or 3, preferably 1 or 2, cyclic heteroatoms selected from N, O, and S, and preferably a saturated monocyclic 3-8 membered heterocyclic group. As another example, "3-6 membered heterocyclic group" refers to a heterocyclic group having 3-6 ring atoms, comprising 1 or 2 cyclic heteroatoms selected from N, O, and S, and preferably a saturated monocyclic 3-6 membered heterocyclic group, such as a saturated monocyclic 3, 4, 5, or 6 membered heterocyclic group. Examples of heterocyclic groups include, but are not limited to: ethylene oxide, aziridinyl, oxetyl, aziridine, pyrrolyl, tetrahydrofuranyl, dioxopentyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazine, and tetrahydropyranyl.

As used herein, the term "aryl" refers to a carbocyclic hydrocarbon group consisting of one or more fused rings containing 6-14 carbon atoms (C _6-14 ), preferably 6-10 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, indenyl, azulel, with phenyl and naphthyl being preferred.

The term "heteroaryl" as used in this article refers to:

A monocyclic heteroaryl group, i.e., a monocyclic aromatic hydrocarbon group having 5, 6, or 7 ring atoms (5, 6, or 7-membered), wherein one or more, for example 1, 2, or 3, more preferably 1 or 2, cyclic heteroatoms independently selected from N, O, and S (preferably N), and the remaining ring atoms are carbon atoms; preferably, a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms (5 or 6-membered), wherein one, 2, or 3, more preferably 1 or 2, cyclic heteroatoms independently selected from N, O, and S (preferably N),

and

A bicyclic heteroaryl group is a bicyclic aromatic hydrocarbon group having 8-12 ring atoms (8-12 members), for example, having 8, 9, or 10 ring atoms (8, 9, or 10 members), wherein one or more, for example 1, 2, 3, or 4, preferably 2, 3, or 4, independently selected from N, O, and S (preferably N), and the remaining ring atoms are carbon atoms, wherein at least one ring is an aromatic ring. 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, a bicyclic heteroaryl group includes a 5- or 6-membered heteroaryl ring fused to a 5- or 6-membered alkyl ring.

Examples of heteroaryl groups include, but are not limited to: pyridyl, N-pyridyl oxide, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, azole, isozolyl, 1,2,5-diazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,3,4-thiadiazolyl), tetrazolyl, triazolyl (e.g., 1,2,4-triazolyl), triazinyl (e.g., 1,3,5-triazinyl), thiophene, furanyl, pyranyl, pyrroloyl, pyridazinyl, benzo[m]dioxacyclopentenyl, benzo[azolyl], benzo[azolyl]isoazolyl, benzo[azolyl]thienyl, benzo[azolyl]thiazolyl, benzo[azolyl]isoazolyl, benzo[azolyl]thiophene, benzo[azolyl]thiazolyl, benzo[azolyl]isoazolyl Azolyl, imidazopyridyl, triazolylpyridyl, indazole, pyrrolopyridyl, pyrrolopyrimidyl, pyrazolylpyridyl, pyrazolylpyrimidyl, tetraazolylpyridyl, tetrahydropyrazolylpyridyl, benzofuranyl, benzimidazolinyl, indolyl, 3,4-dihydro-2H-benzo[b][1,4]azinyl, dihydroindolyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, 2,4,5,6-tetrahydrocyclopentadien[c]pyrazolyl and 5,6,7,8-tetrahydro[1,2,4]triazol[1,5-a]pyridyl.

The terms “fused ring,” “dense ring,” or “fused ring” as used herein are interchangeable and 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,” “dense ring,” or “fused ring” has 8-13 ring atoms (8-13-membered), for example, 9-12 ring atoms (9-12-membered), 8-11 ring atoms (8-11-membered), or 8, 9, or 10 ring atoms (8, 9, or 10-membered), wherein optionally 1, 2, or 3, preferably 1 or 2, cyclic heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms.

As used herein, the term "spirocyclic ring" refers to a saturated or partially unsaturated, preferably saturated, ring system in which two rings share a single carbon atom (referred to as a "spiral junction"), wherein optionally one, two, or three, preferably one or two, of the ring atoms are cyclic heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms. In one example, the "spirocyclic ring" has 8-13 ring atoms (8-13-membered), for example, 9-12 ring atoms (9-12-membered), 8-11 ring atoms (8-11-membered), or 8, 9, or 10 ring atoms (8, 9, or 10-membered), wherein optionally one, two, or three, preferably one or two, of the ring atoms are cyclic heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms.

The terms "bridged ring" or "bridged ring" as used herein are interchangeable and refer to a saturated or partially unsaturated, preferably saturated ring system formed by two rings sharing two non-directly connected atoms (referred to as "bridgehead atoms"). Optionally, one, two, or three, preferably one or two, of the ring atoms are cyclic heteroatoms independently selected from N, O, and S, while the remaining ring atoms are carbon atoms. In one example, the "bridged ring" or "bridged ring" has 8-13 ring atoms (8-13-membered), for example, 9-12 ring atoms (9-12-membered), 8-11 ring atoms (8-11-membered), or 8, 9, or 10 ring atoms (8, 9, or 10-membered), of which optional one, two, or three, preferably one or two, cyclic heteroatoms independently selected from N, O, and S, while the remaining ring atoms are carbon atoms.

The term "hydroxyl group" as used in this article refers to the -OH group.

The term "thiol" as used in this article refers to the -SH group.

The term “oxo” or “oxo” as used in this article refers to =O.

The term "amino" as used in this article refers to _-NH₂ .

The term "cyano" as used in this article refers to -CN.

If a structural formula in this document contains an asterisk “*”, it indicates that the chiral center at the “*” mark in the compound is a single configuration of (R) or (S) configuration; wherein the content of the single configuration marked “*” is 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 listed values).

If a structural formula in this paper contains "(RS)", it means that the chiral center at the "(RS)" mark in the compound contains both "(R)" and "(S)" configurations.

As used herein, the terms “optional,” “optional,” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both scenarios in which the event or situation occurs and scenarios in which the event or situation does not occur. For example, “optionally substituted alkyl” includes both “unsubstituted alkyl” and “substituted alkyl” as defined herein. Those skilled in the art will understand that, for any group containing one or more substituents, the group does not include any substitution pattern that is spatially impractical, chemically incorrect, synthetically infeasible, and/or inherently unstable.

As used herein, the terms "substituted" or "replaced by" mean that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from a given group of substituents, provided that the substitution does not exceed the normal valence of the given atom. When the substituent is an oxo group (i.e., =O), two hydrogen atoms on a single atom are replaced. Such combinations are permitted only if the combination of substituents and/or variables results in a chemically correct and stable compound. A chemically correct and stable compound means that the compound is stable enough to be isolated from the reaction mixture.

Unless otherwise stated, substituents are named within the core structure. For example, it should be understood that when a (cycloalkyl)alkyl group is listed as a possible substituent, it indicates that the substituent is attached to the core structure at the alkyl moiety.

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

A "leaving group" refers to an atom or functional group that is replaced during a reaction. Examples of leaving groups include, but are not limited to, halogens, alkoxy groups, and sulfonyloxy groups. Examples of sulfonyloxy groups include, but are not limited to, alkylsulfonyloxy groups (e.g., methylsulfonyloxy (also known as methanesulfonate group) and trifluoromethylsulfonyloxy (also known as trifluoromethanesulfonate group)) and arylsulfonyloxy groups (e.g., p-toluenesulfonyloxy (also known as p-toluenesulfonate group) and p-nitrobenzenesulfonyloxy (also known as p-nitrobenzenesulfonate group)).

Those skilled in the art will understand that some compounds of formula (I) may contain one or more chiral centers, and thus have two or more stereoisomers. Racemic mixtures of these isomers, mixtures of single isomers and enantiomer-enriched mixtures, and mixtures of diastereomers and specific diastereomer-enriched mixtures when there are two chiral centers are all within the scope of this invention. Those skilled in the art will also understand that this invention includes all single stereoisomers (e.g., enantiomers), racemic mixtures, or partially separated mixtures of compounds of formula (I), and, where appropriate, single tautomers thereof.

In other words, in some embodiments, the present invention provides compounds containing multiple stereoisomer purities, i.e., enantiomeric or diastereomeric purities expressed in different "ee" or "de" values. In some embodiments, the compounds of formula (I) described herein or their sub-formulas (I-1), (I-2), and (I-3) have 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 value between these listed values). In some embodiments, the compounds of formula (I) described herein or their sub-formulas (I-1), (I-2), and (I-3) have an enantiomeric purity greater than 99.9% ee. In some embodiments, the compounds of formula (I) described herein or their sub-formulas (I-1), (I-2), and (I-3) have 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 value between these listed values). In some embodiments, the compounds of formula (I) described herein or their sub-formulas (I-1), (I-2), and (I-3) have a diastereomeric purity greater than 99.9% de.

The term "enantiomer excess" or "ee" indicates the amount of one enantiomer relative to another. For a mixture of R and S enantiomers, the percentage of enantiomer excess is defined as |R-S|*100, where R and S are the molar or weight fractions of their respective enantiomers in the mixture, and R+S＝1. If the optical rotation of a chiral substance is known, the percentage of enantiomer excess is defined as ([a]obs/[a]max)*100, where [a]obs is the optical rotation of the enantiomer mixture, and [a]max is the optical rotation of the pure enantiomer.

The term "diasteresome excess" or "de" indicates the amount of one diastereomer relative to another, and is defined by analogy based on enantiomer excess. Therefore, for a mixture of diastereomers D1 and D2, the percentage of diastereomer excess is defined as |D1-D2|*100, where D1 and D2 are the molar or weight fractions of their respective diastereomers in the mixture, and D1+D2＝1.

The determination of diastereomers and/or enantiomer excesses can be performed using a variety of analytical techniques, including nuclear magnetic resonance spectroscopy, chiral column chromatography, and/or optical rotation determination, according to conventional procedures familiar to those skilled in the art.

Racemic mixtures can be used in their original form or can be resolved into their individual isomers. Resolution yields stereochemically pure compounds or mixtures enriched with one or more isomers. Methods for isomer separation are well-known (see Allinger N.L. and Eliel E.L., "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), including physical methods such as chromatography using chiral adsorbents. Individual isomers in chiral forms can be prepared from chiral precursors. Alternatively, a single isomer can be obtained by chemically separating the mixture using the following method: forming a diastereomeric salt with a chiral acid (e.g., a single enantiomer of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salt, and then freeing one or both of the resolved bases. This process can optionally be repeated to obtain one or two isomers that substantially do not contain the other isomer, i.e., isomers with an optical purity >95%. Alternatively, a racemic compound can be covalently attached to a chiral compound (auxiliary compound) to obtain a diastereomeric isomer, which can be separated by chromatography or fractional crystallization, followed by chemical removal of the chiral auxiliary compound to obtain a pure enantiomer.

The term "pharmaceutically acceptable salt" includes, but is not limited to: acid addition salts formed by compounds of formula (I) or their sub-formulas (I-1), (I-2), and (I-3) with inorganic acids, such as hydrochlorides, hydrobromates, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, etc.; and acid addition salts formed by compounds of formula (I) or their sub-formulas (I-1), (I-2), and (I-3) with organic acids, such as formates, acetates, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethanesulfonates, benzoates, salicylates, stearates, and salts formed with alkyl dicarboxylic acids of formula HOOC-( _CH2 ) _n -COOH (where n is 0-4), etc. "Pharmaceutical acceptable salts" also include base addition salts formed by compounds of formula (I) with an acidic group or compounds of its sub-formulas (I-1), (I-2), (I-3) with pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium and ammonium.

Furthermore, if the compound described herein is obtained as an acid addition salt, its free base form can be obtained by alkalizing the solution of the acid addition salt. Conversely, if the product is in the form of a free base, its acid addition salt, particularly a pharmaceutically acceptable acid addition salt, can be obtained by following the conventional procedure for preparing acid addition salts from basic compounds, by dissolving the free base in a suitable solvent and treating the solution with acid. Those skilled in the art can determine various synthetic methods for preparing non-toxic, pharmaceutically acceptable acid or base addition salts without extensive experimentation.

The term "solvate" refers to a solvation form containing stoichiometric or non-stoichiometric solvents. Some compounds have a tendency to engulf solvent molecules in a fixed molar ratio in the solid state, thus forming solvates. If the solvent is water, the formed solvate is a hydrate; when the solvent is ethanol, the formed solvate is an ethanolate. Hydrates are formed by one or more molecules of water with one molecule of the substance in which the water retains its _H₂O molecular state; such combinations can form one or more hydrates, such as hemihydrates, monohydrates, and dihydrates.

The term "deuterated compound" refers to a compound formed by replacing one or more, for example, 1, 2, or 3 hydrogen atoms with the isotope deuterium. The degree of deuteration is at least greater than that of naturally occurring deuterium isotopes at the substitution sites. In some embodiments, the deuterated compound in the compound of formula (I) or its sub-formulas (I-1), (I-2), (I-3) has a degree of 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 value between these listed values). In some embodiments, the compound of formula (I) or the compounds of its sub-formulas (I-1), (I-2), and (I-3) have a deuteration degree greater than 99.9% and reaching 100%.

The terms “group” and “base” used in this article are synonyms and are used to refer to functional groups or molecular segments that can be linked to other molecular segments.

The term "treatment" or "treatment" of a disease or disorder refers to the administration of one or more pharmaceutical substances, particularly compounds of formula (I) or pharmaceutically acceptable salts thereof, to an individual suffering from or exhibiting symptoms of said disease or disorder, in order to cure, heal, alleviate, reduce, alter, treat, improve, improve, or influence said disease or disorder or its symptoms. In some embodiments, said disease or disorder is a disease that responds to inhibition of ERK, preferably cancer.

The term "prevention" of a disease or disorder refers to the administration of one or more pharmaceutical substances, particularly compounds of formula (I) or pharmaceutically acceptable salts thereof, to an individual who is susceptible to or at risk of developing the disease or disorder, to prevent or slow the onset of the disease or disorder in that individual. In some embodiments, the disease or disorder is a disease that responds to inhibition of ERK, preferably cancer.

When referring to chemical reactions, the terms “treatment,” “contact,” and “reaction” mean the addition or mixing of two or more reagents under appropriate conditions to produce the shown and/or desired product. It should be understood that the reaction producing the shown and/or desired product may not necessarily originate directly from the combination of the two initially added reagents; that is, one or more intermediates may be present in the mixture that ultimately lead to the formation of the shown and/or desired product.

As used herein, the term "effective amount" refers to the amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, that is effective as described above in "treating" or "preventing" a disease or disorder in an individual who responds to inhibition of ERK. An effective amount may cause any visible or detectable change in the individual described in the preceding "treatment" or "prevention." For example, in the case of cancer, an effective amount may reduce the number of cancer or tumor cells; shrink the size of the tumor; inhibit or prevent the invasion of tumor cells into surrounding organs, such as the spread of the tumor into soft tissue or bone; inhibit or prevent tumor metastasis; inhibit or prevent tumor growth; alleviate one or more cancer-related symptoms to some extent; reduce morbidity and mortality; improve quality of life; or a combination of the above effects. An effective amount may be sufficient to reduce the symptoms of a disease in which inhibition of ERK is responsive. The term "effective amount" also refers to the amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, that is effective in inhibiting the ERK activity of an individual.

The term “inhibition” refers to a reduction in the baseline activity of a biological activity or process. “ERK inhibition” refers to a reduction in ERK activity resulting from a direct or indirect response to the presence of a compound of formula (I) or its pharmaceutically acceptable salt, relative to the absence of the compound of formula (I) or its pharmaceutically acceptable salt. The reduction in activity may be caused by a direct interaction between the compound of formula (I) or its pharmaceutically acceptable salt and ERK, or by the interaction of the compound of formula (I) or its pharmaceutically acceptable salt with one or more other factors, thereby affecting ERK activity. For example, the presence of the compound of formula (I) or its pharmaceutically acceptable salt may reduce ERK activity by directly binding to ERK, by directly or indirectly affecting another factor, or by directly or indirectly reducing the amount of ERK present in cells or the body.

As used herein, the term "individual" refers to both mammals and non-mammals. Mammals include any member of the mammalian class, including but not limited to: humans; non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; etc. Examples of non-mammals include, but are not limited to, birds. The term "individual" is not limited to a specific age or sex.

The term "pharmaceutical acceptable" means that the substance specified after the term can be used to prepare a pharmaceutical composition, which is generally safe, non-toxic, and has no undesirable properties in a biological or other sense, especially for human medicinal use.

As used herein, the term "approximately" means approximately, around, roughly, or about. When the term "approximately" is used with a numerical range, it adjusts the range by extending the boundary to be higher or lower than the given value. Generally, the term "approximately" is used herein to adjust a given value to be 20% higher or lower than that value.

Undefined technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

Detailed Implementation

Implementation Scheme 1. 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:

_Z1 and _Z2 are each independently N or C, and are 5-membered heteroaryl groups containing 1, 2, 3 or 4 cyclic heteroatoms selected from N, O or S; said 5-membered heteroaryl group is optionally substituted by one or more substituents independently selected from: deuterium, halogen, hydroxyl, amino, -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -CN, mercapto, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkoxy, _C1-6 haloalkyl, -( _C1-6 alkyl)-OH and - _{( C1-6} alkyl)-O-( _C1-6 alkyl), wherein said _C1-6 alkyl, _C1-6 alkoxy and _C1-6 haloalkyl are each optionally substituted by one or more deuterium groups;

L does not exist, or L is -NR _c , O, or S;

_Rc is hydrogen or _C1-6 alkyl;

Ar is a heteroaryl group, which is optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, hydroxyl, amino, -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -CN, mercapto, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkoxy, _C1-6 haloalkyl, -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _{C1-6 alkyl} ), C3-8 cyclic hydrocarbon, _3-8 membered heterocyclic, phenyl, and heteroaryl, wherein the _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, _C3-8 cyclic hydrocarbon, 3-8 membered heterocyclic, phenyl, and heteroaryl are each optionally substituted by one or more deuterium groups;

_R1 is selected from hydrogen, _C1-6 alkyl, _C2-6 alkenyl, C2-6 ynyl, _C1-6 haloalkyl, -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl), -(C1-6 alkyl)-( _C3-8 cycloalkyl), -( _C1-6 alkyl)-( _3-8 heterocyclic), -( _C1-6 alkyl)-phenyl, -( _C1-6 alkyl)-heteroaryl, _C3-8 cycloalkyl, _3-8 heterocyclic, phenyl, and heteroaryl, wherein the _C2-6 alkenyl, _C2-6 ynyl, C3-8 cycloalkyl, _3-8 heterocyclic, phenyl, and heteroaryl are each optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, hydroxyl, mercapto, amino, -NH(C _C1-6 alkyl), -N( _C1-6 alkyl) ₂ , -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl), _C3-8 cyclic hydrocarbon, 3-8 membered heterocyclic group, phenyl, heteroaryl, _C1-6 alkyl optionally substituted with one or more deuterium, _C1-6 alkoxy and _C1-6 haloalkyl;

_R2 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -CN, mercapto, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, _C1-6 haloalkyl, -(C1-6 alkyl)-OH, -(C1-6 alkyl)-O-( _C1-6 alkyl), -( _C1-6 alkyl)-( _C3-8 cycloalkyl), -( _C1-6 alkyl)-( _3-8 membered heterocyclic), -(C1-6 alkyl)-phenyl, -( _C1-6 alkyl)-heteroaryl, C3-8 cycloalkyl, 3-8 membered heterocyclic, phenyl, and heteroaryl, wherein the _C2-6 alkenyl, _C2-6 ynyl, _C3-6 alkyl, C2-6 alkyl, C3-8 cycloalkyl, _C3-8 membered heterocyclic, phenyl, _and heteroaryl are selected from these groups. _{The 3-8} cyclic hydrocarbon group, the 3-8 membered heterocyclic group, the phenyl group, and the heteroaryl group are each optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, -CN, hydroxyl, mercapto, amino, -NH (C _1-6 alkyl), -N (C _1-6 alkyl) ₂ , -(C _1-6 alkyl)-OH, -(C _1-6 alkyl)-O-(C _1-6 alkyl), C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, and oxo group;

_Ra and _Rb are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl), -CN, mercapto, _C1-6 alkyl, _C1-6 alkoxy, and _C1-6 haloalkyl; or, _Ra and _Rb together with the carbon atoms attached to them form a _C3-6 cyclic hydrocarbon group or a 4-6 membered heterocyclic group, wherein each of the _C3-6 cyclic hydrocarbon group or the 4-6 membered heterocyclic group is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, hydroxyl, mercapto, amino, -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl), C _1-6 alkyl, _C1-6 alkoxy, and _C1-6 haloalkyl;

It represents a double bond or a single bond, and when it represents a double bond, _R3 and _R5 do not exist;

_R3 , _R4 , _R5 , _R6 , _R7 , and _R8 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, -CN, mercapto, amino, -NH ( _C1-6 alkyl), -N (C1-6 alkyl) ₂ , -( _C1-6 alkyl)-OH, -(C1-6 alkyl)-O-(C1-6 alkyl), _C1-6 alkyl, -( _C1-6 alkyl)-phenyl, C1-6 alkoxy, and _C1-6 haloalkyl; or, R3, R4, R5, R6, R7, and R8 are each selected from hydrogen, deuterium, halogen, hydroxyl, -CN, mercapto, amino, -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -(C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-(C1-6 alkyl), _C1-6 alkyl, -( _C1-6 alkyl) _-phenyl , _C1-6 alkoxy, and _C1-6 haloalkyl; Any two carbon atoms in ₈ , together with ring B, form an 8-13 membered spirocyclic, fused, or bridged ring optionally containing 1-3 independently selected cyclic heteroatoms chosen from N, O, or S; said spirocyclic, fused, or bridged ring is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, hydroxyl, mercapto, amino, -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl), _C1-6 alkyl, _C1-6 alkoxy, and _C1-6 haloalkyl; or, _R3 together with _R4 , _R5 together with _R6 , or _R7 together with _R8 are oxo groups;

n is 0, 1, or 2;

m can be 0, 1, 2, 3, 4, or 5.

Implementation Scheme 2. A compound of formula (I) according to Implementation Scheme 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 the compound is selected from:

_R10 and _R11 are independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, -CN, mercapto, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, -( _C1-6 alkyl)-OH and -( _C1-6 alkyl)-O-( _C1-6 alkyl), wherein the _C1-6 alkyl, _C1-6 alkoxy and _C1-6 haloalkyl are each optionally substituted with one or more deuterium.

Implementation Scheme 3. A compound of formula (I) according to Implementation Scheme 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 the compound is selected from:

_R10 and _R11 are independently selected from hydrogen, halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy and _C1-6 haloalkyl.

Implementation Scheme 4. A compound of formula (I) according to Implementation Scheme 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, wherein _R10 and _R11 are independently selected from hydrogen, halogen and _C1-6 alkyl.

Implementation Scheme 5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 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 group having 5 or 6 ring atoms, wherein 1, 2, or 3 of the ring atoms are independently selected from N, O, and S, and the remaining ring atoms are carbon atoms; each of which is optionally substituted by one or more substituents independently selected from: deuterium, halogen, hydroxyl, amino, -CN, mercapto, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl), _C3-8 cyclic hydrocarbon, 3-8 membered heterocyclic group, phenyl, and heteroaryl, wherein the _C1-6 alkyl, _C1-6 alkoxy, C3-8 membered heterocyclic group, C3-8 membered heterocyclic group, phenyl, and heteroaryl group are... _{The 1-6} haloalkyl, _C3-8 cyclic hydrocarbon, 3-8 membered heterocyclic, phenyl and heteroaryl groups are each optionally substituted with one or more deuterium groups.

Implementation Scheme 6. A compound of formula (I) according to Implementation Scheme 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 pyridinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazolyl, and thiazolyl (more preferably, Ar is selected from pyridinyl, pyrimidinyl, and 1,3,5-triazinyl), each optionally substituted by one or more substituents independently selected from: halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy, and _C1-6 haloalkyl optionally substituted with one or more deuterium groups.

Implementation Scheme 7. A compound of formula (I) according to Implementation Scheme 6, 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:

_R20 , _R21 , _R22 , _R23 and _R24 are each independently selected from hydrogen, halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy and _C1-6 haloalkyl optionally substituted with one or more deuterium.

Implementation Scheme 8. A compound of formula (I) according to any one of Implementation Schemes 1-7, 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 _R1 is selected from _C1-6 alkyl, -( _C1-6 alkyl)-OH, saturated monocyclic C _{A 3-8} cyclic hydrocarbon group, a saturated monocyclic 3-8-membered heterocyclic group and a heteroaryl group containing one or two cyclic heteroatoms independently selected from N, O and S, wherein the heteroaryl group is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, wherein the ring atoms have 1, 2 or 3 cyclic heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms; or a bicyclic aromatic hydrocarbon group having 8, 9 or 10 ring atoms, wherein the ring atoms have 1, 2, 3 or 4 cyclic heteroatoms independently selected from N, O and S, and the remaining ring atoms are 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 the C _3-8 cyclic hydrocarbon group, the 3-8-membered heterocyclic group and the heteroaryl group are each optionally substituted by one or more substituents independently selected from: halogen, -(C _1-6 alkyl)-OH, -(C _1-6 alkyl)-O-(C _C1-6 alkyl, C1-6 heterocyclic, _C1-6 alkyl, _C1-6 alkoxy or _C1-6 haloalkyl optionally substituted with one or more deuterium groups.

Implementation Scheme 9. A compound of formula (I) according to Implementation Scheme 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 _R1 is a heteroaryl group selected from pyrazolyl, pyridinyl, isoxazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 2,4,5,6-tetrahydrocyclopentadien[c]pyrazolyl, and 5,6,7,8-tetrahydro[1,2,4]triazol[1,5-a]pyridinyl; wherein each of the heteroaryl groups is optionally substituted by one or more substituents independently selected from: _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, halogen, -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-(C _1-6 alkyl groups and 3-6 heterocyclic groups.

Implementation Scheme 10. A compound of formula (I) according to Implementation Scheme 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 _R1 is a pyrazolyl group, optionally substituted by one or more substituents independently selected from: _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, halogen, -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl) and oxetane.

Implementation Scheme 11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1-10, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from halogens, -CN, _C1-6 alkyl, _C1-6 haloalkyl, saturated monocyclic C _{The 3-8} cyclic hydrocarbon group, phenyl group, and heteroaryl group are monocyclic aromatic hydrocarbon groups having 5 or 6 ring atoms, wherein 1, 2, or 3 of the ring atoms are independently selected from N, O, and S, and the remaining ring atoms are carbon atoms; or they are bicyclic aromatic hydrocarbon groups having 8, 9, or 10 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are independently selected from N, O, and S, and the remaining ring atoms are 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 the _C3-8 cyclic hydrocarbon group, phenyl group, or heteroaryl group is optionally substituted by one or more substituents independently selected from: halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, and oxo.

Implementation Scheme 12. A compound of formula (I) according to implementation scheme 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 _R2 is a phenyl group, wherein the phenyl group is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN and _C1-6 alkoxy.

Implementation Scheme 13. A compound of formula (I) according to implementation scheme 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 _R2 is a heteroaryl group selected from 1,2,5-oxadiazolyl, indolyl, dihydroindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, thiazolyl, isothiazolyl, benzo[d]isooxazolyl, thiophenyl, indazole and pyrroleyl, each optionally substituted by one or more substituents independently selected from: _C1-6 alkyl, halogen, oxo, and -CN.

Implementation Scheme 14. A compound of formula (I) according to Implementation Scheme 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 _R2 is a saturated monocyclic _C3-8 cyclic hydrocarbon group, optionally substituted by one or more substituents independently selected from _C1-6 haloalkyl groups.

Implementation Scheme 15. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 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.

Implementation Scheme 16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1-15, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein _Ra and _Rb are independently selected from hydrogen, halogen, hydroxyl, and _C1-6 alkyl, respectively; or, _Ra , _Rb together with the carbon atoms to which they are attached form a saturated monocyclic _C3-6 cyclic hydrocarbon group or a 3-6 membered heterocyclic group, wherein the 3-6 membered heterocyclic group is a saturated monocycle having 3-6 ring atoms, one or two of which are cyclic heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms; wherein the saturated monocyclic _C3-6 cyclic hydrocarbon group or the 3-6 membered heterocyclic group is optionally substituted by one or more substituents selected from halogens.

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

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

Implementation Scheme 19. A compound of formula (I) according to Implementation Scheme 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, representing a double bond, _R3 and _R5 are absent, and _R4 and _R6 are each independently selected from hydrogen and _C1-6 alkyl groups.

Implementation Scheme 20. A compound of formula (I) according to Implementation Scheme 19, 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):

in

_R1 is a heteroaryl group, which is optionally substituted by one or more substituents independently selected from the following: _C1-6 alkyl, _{C1-6 haloalkyl, C1-6} alkoxy, halogen, -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _{C1-6 alkyl} ) and 3-6 membered heterocyclic groups optionally substituted with one or more deuterium groups;

Ar is a heteroaryl group, which is optionally substituted by one or more substituents independently selected from the following: halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy and _C1-6 haloalkyl, optionally substituted by one or more deuterium groups;

_R2 is selected from halogen, -CN, _C1-6 alkyl, _C1-6 haloalkyl, saturated monocyclic _C3-8 cyclic hydrocarbon, phenyl, and heteroaryl, wherein the saturated monocyclic _C3-8 cyclic hydrocarbon, phenyl, or heteroaryl is optionally substituted by one or more substituents independently selected from: halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, and oxo;

_R4 and _R6 are each independently selected from hydrogen and _C1-6 alkyl groups;

_R10 and _R11 are independently selected from hydrogen, halogen, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl and -( _C1-6 alkyl)-OH;

m is 0, 1, or 2.

_Ra and _Rb are each independently selected from hydrogen, halogen, hydroxyl, or _C1-6 alkyl; or _Ra and _Rb together with the carbon atoms attached to them form a saturated monocyclic _C3-6 cyclic hydrocarbon group or a 3-6 membered heterocyclic group, wherein the 3-6 membered heterocyclic group is a saturated monocycle having 3-6 ring atoms, one or two of which are cyclic heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms, wherein the saturated monocyclic _C3-6 cyclic hydrocarbon group or the 3-6 membered heterocyclic group is optionally substituted by one or more substituents selected from halogens;

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

The heteroaryl group is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are independently selected from N, O and S, and the remaining ring atoms are carbon atoms; or a bicyclic aromatic hydrocarbon group having 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are independently selected from N, O and S, and the remaining ring atoms are 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.

Implementation Scheme 21. A compound of formula (I) according to Implementation Scheme 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...

_R1 is a pyrazolyl group, which is optionally substituted by one or more substituents independently selected from _C1-6 alkyl groups;

Ar is a pyrimidinyl group, which is optionally substituted by one or more substituents independently selected from _C1-6 alkyl groups and halogens optionally substituted by one or more deuterium groups;

_R2 is selected from _C1-6 haloalkyl or phenyl, wherein the phenyl is optionally substituted by one or more substituents independently selected from halogens;

_R10 and _R11 are hydrogen;

m is 0 or 1;

_Ra and _Rb are each independently selected from hydrogen or _C1-6 alkyl groups; or, _Ra and _Rb together with the carbon atoms they are attached to form a saturated monocyclic _C3-6 cyclic hydrocarbon group; and

L is absent, or it is either NH or O.

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

Implementation Scheme 23. A compound of formula (I) according to Implementation Scheme 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, representing a single bond, and _R3 , _R4 , _R5 , and _R6 are independently selected from hydrogen, _C1-6 alkyl, _C1-6 haloalkyl, -( _C1-6 alkyl)-O-( _C1-6 alkyl), and -( _C1-6 alkyl)-phenyl, respectively; or, any pair of _R3 and _R4 or _R5 and _R6 together with the carbon atoms attached to them form a saturated monocyclic _C3-6 cyclic hydrocarbon group or a saturated monocyclic 3-6 membered heterocyclic group having one or two cyclic heteroatoms selected from N, O, and S, thereby forming a spirocycle together with the B ring.

Implementation Scheme 24. A compound of formula (I) according to implementation scheme 23, 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-2):

in

_R1 is selected from _C1-6 alkyl, -( _C1-6 alkyl)-OH, saturated monocyclic _C3-8 cyclic hydrocarbon, saturated 3-8 membered heterocyclic group and heteroaryl group containing one or two cyclic heteroatoms independently selected from N, O and S, wherein the _C3-8 cyclic hydrocarbon, 3-8 membered heterocyclic group and heteroaryl group are each optionally substituted by one or more substituents independently selected from: halogen, -( _C1-6 alkyl)-OH, -( _C1-6 alkyl)-O-( _C1-6 alkyl), saturated 3-6 membered heterocyclic group containing one or two cyclic heteroatoms independently selected from N, O and S, _C1-6 alkyl, _C1-6 alkoxy and _C1-6 haloalkyl optionally substituted with one or more deuterium;

Ar is a heteroaryl group, which is optionally substituted by one or more substituents independently selected from the following: halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy and _C1-6 haloalkyl, optionally substituted with one or more deuterium groups;

R ₂ is selected from halogen, -CN, _C1-6 alkyl, _C1-6 haloalkyl, saturated monocyclic _C3-8 cyclic hydrocarbon, phenyl or heteroaryl, wherein each of the _C3-8 cyclic hydrocarbon, phenyl or heteroaryl is optionally substituted by one or more substituents independently selected from: halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl and oxo;

Z ₃ is CR ₁₀ or N;

_R3 , _R4 , _R5 , and _R6 are each independently selected from hydrogen, _C1-6 alkyl, _C1-6 haloalkyl, -( _C1-6 alkyl)-O-( _C1-6 alkyl), and -( _C1-6 alkyl)-phenyl; or, any pair of _R3 and _R4 or _R5 and _R6 together with the carbon atoms attached to them form a saturated monocyclic _C3-6 cyclic hydrocarbon group or a saturated monocyclic 3-6 membered heterocyclic group having one or two cyclic heteroatoms selected from N, O, and S, thereby forming a spirocycle together with the B ring;

_R10 and _R11 are independently selected from hydrogen, halogen, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl and -( _C1-6 alkyl)-OH;

m is 0, 1, or 2.

_Ra and _Rb are each independently selected from hydrogen, halogen, hydroxyl, or _C1-6 alkyl; or _Ra and _Rb together with the carbon atoms attached to them form a saturated monocyclic _C3-6 cyclic hydrocarbon group or a 3-6 membered heterocyclic group, wherein the 3-6 membered heterocyclic group is a saturated monocycle having 3-6 ring atoms, one or two of which are cyclic heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms, wherein the saturated monocyclic _C3-6 cyclic hydrocarbon group or the 3-6 membered heterocyclic group is optionally substituted by one or more substituents selected from halogens;

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

The heteroaryl group is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are independently selected from N, O and S, and the remaining ring atoms are carbon atoms; or a bicyclic aromatic hydrocarbon group having 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are independently selected from N, O and S, and the remaining ring atoms are 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.

Implementation Scheme 25. A compound of formula (I) according to Implementation Scheme 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...

_R1 is selected from saturated monocyclic 3-8-membered heterocyclic groups and heteroaryl groups containing one or two cyclic heteroatoms independently selected from N, O, and S, wherein the heteroaryl group is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, wherein one, two, or three cyclic heteroatoms are independently selected from N, O, and S, and the remaining ring atoms are carbon atoms; or a bicyclic aromatic hydrocarbon group having 8, 9, or 10 ring atoms, wherein one, two, three, or four cyclic heteroatoms are independently selected from N, O, and S, and the remaining ring atoms are 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 the 3-8-membered heterocyclic group and heteroaryl group are each optionally substituted by one or more substituents independently selected from: _C1-6 alkyl, _C1-6 haloalkyl, halogen, -( _C1-6 alkyl)-OH, _C1-6 alkoxy, -(C1-6 alkyl)-OH ... _1-6 alkyl)-O-(C _1-6 alkyl) and saturated monocyclic 3-6 membered heterocyclic groups containing one or two cyclic heteroatoms independently selected from N, O and S;

Ar is a heteroaryl group, wherein the heteroaryl group is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, wherein there are 1, 2 or 3 ring heteroatoms independently selected from N, O and S, the remaining ring atoms are carbon atoms, 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 the heteroaryl group is optionally substituted by one or more substituents selected from the following: _C1-6 alkyl groups optionally substituted with one or more deuterium groups and halogens;

_R2 is selected from halogens, _C1-6 alkyl groups, _C1-6 haloalkyl groups, phenyl groups, and heteroaryl groups, wherein the heteroaryl group is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, wherein 1, 2, or 3 ring heteroatoms are independently selected from N, O, and S, and the remaining ring atoms are carbon atoms; or a bicyclic aromatic hydrocarbon group having 8, 9, or 10 ring atoms, wherein 1, 2, 3, or 4 ring heteroatoms are independently selected from N, O, and S, and the remaining ring atoms are 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 the phenyl and heteroaryl groups are each optionally substituted by one or more substituents independently selected from: halogens, _C1-6 alkyl groups, _C1-6 alkoxy groups, and oxo groups;

Z ₃ is CR ₁₀ or N;

_R3 , _R4 , _R5 , and _R6 are each independently selected from hydrogen, _C1-6 alkyl, _C1-6 haloalkyl, -( _C1-6 alkyl)-O-( _C1-6 alkyl), and -( _C1-6 alkyl)-phenyl; or, any pair of _R3 and _R4 or _R5 and _R6 together with the carbon atoms attached to them form a saturated monocyclic _C3-6 cyclic hydrocarbon group or a saturated monocyclic 3-6 membered heterocyclic group having one or two cyclic heteroatoms selected from N, O, and S, thereby forming a spirocycle together with the B ring;

m is 1 or 2

_Ra and _Rb are independently selected from hydrogen and halogen, respectively; or, _Ra and _Rb together with the carbon atoms they are attached to form a saturated monocyclic _C3-6 cyclic hydrocarbon group;

_R10 and _R11 are hydrogen;

L does not exist, or L is O.

Implementation Scheme 26. A compound of formula (I) according to Implementation Scheme 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 _R1 is selected from morpholino, thiomorpholino, and heteroaryl, wherein the heteroaryl is selected from pyrazolyl, 2,4,5,6-tetrahydrocyclopentadien[c]pyrazolyl, 1,2,4-triazolyl, 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridyl, 1,3,4-thiadiazolyl, and pyridyl, and each of the heteroaryl groups is optionally substituted by one or more groups selected from: _C1-6 alkyl, _C1-6 haloalkyl, halogen, -( _C1-6 alkyl)-OH, _C1-6 alkoxy, -( _C1-6 alkyl)-O-(C _1-6 alkyl) and oxocyclic butyl.

Implementation Scheme 27. A compound of formula (I) according to implementation scheme 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 a heteroaryl group selected from pyridinyl, pyrimidinyl and 1,3,5-triazinyl; wherein each of the heteroaryl groups is optionally substituted by one or more substituents selected from: _C1-6 alkyl groups optionally substituted with one or more deuterium groups and halogens.

Implementation Scheme 28. A compound of formula (I) according to Implementation Scheme 27, 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:

_R20 , _R21 , _R22 , R23 _{and R24} are each independently selected from hydrogen, halogens and _C1-6 alkyl groups optionally substituted with one or more deuterium atoms.

Implementation Scheme 29. A compound of formula (I) according to implementation scheme 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 _R2 is selected from halogen, _C1-6 alkyl, _C1-6 haloalkyl, phenyl and heteroaryl, wherein the heteroaryl is selected from isoxazolyl, 1,2,5-oxadiazolyl, pyrazolyl, oxazolyl, pyridinyl, thiazolyl, isothiazolyl, thiophene, and benzo[d]isooxazolyl; wherein the phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from: halogen, _C1-6 alkyl, _C1-6 alkoxy and oxo.

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

Implementation Scheme 31. A compound of formula (I) according to Implementation Scheme 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, representing a single bond, and _R3 , R4, _R5 , R6, _R7 , and R8 are each independently selected from hydrogen, halogen, hydroxyl, _C1-6 alkyl, and _C1-6 alkoxy; wherein the _C1-6 alkyl is optionally substituted by one or more substituents independently selected from: hydroxyl and C1-6 alkoxy; or, _R3 , _R4 , _R5 , _R6 , _R7 , and R8 are each independently selected from: hydroxyl and _C1-6 alkoxy. Any two of the carbon atoms in ₈ , together with the B ring, form a 9-12 member spirocyclic, fused, or bridged ring optionally containing 1-3 cyclic heteroatoms selected from N, O, or S; wherein the spirocyclic, fused, or bridged ring is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, _C1-6 alkyl, and -CN.

Implementation Scheme 32. A compound of formula (I) according to implementation scheme 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):

in

_R1 is selected from _C1-6 alkyl, -( _C1-6 alkyl)-OH, saturated monocyclic _C3-8 cyclic hydrocarbon, saturated monocyclic 3-8-membered heterocyclic group and heteroaryl containing one or two cyclic heteroatoms independently selected from N, O and S; wherein the _C3-8 cyclic hydrocarbon, 3-8-membered heterocyclic group and heteroaryl group are each optionally substituted by one or more substituents independently selected from: halogen, _C1-6 alkyl, _C1-6 alkoxy and _C1-6 haloalkyl, optionally substituted with one or _more deuterium.

Ar is a heteroaryl group, which is optionally substituted by one or more substituents independently selected from the following: halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy and _C1-6 haloalkyl, optionally substituted with one or more deuterium groups;

_R2 is selected from halogen, -CN, _C1-6 alkyl, _C1-6 haloalkyl, saturated monocyclic _C3-8 cyclic hydrocarbon, phenyl or heteroaryl, wherein the saturated monocyclic _C3-8 cyclic hydrocarbon, phenyl or heteroaryl is optionally substituted by one or more substituents independently selected from: halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl and oxo;

_R3 , _R4 , _R5 , _R6 , _R7 and _R8 are each independently selected from hydrogen, halogen, hydroxyl, _C1-6 alkyl and _C1-6 alkoxy; wherein the _C1-6 alkyl is optionally substituted by one or more substituents independently selected from hydroxyl and _C1-6 alkoxy; or, any two of _R3 , _R4 , _R5 , _R6 , _R7 and _R8 together with the carbon atom attached to them and the B ring form _Rd selected from hydrogen or halogen, and t is 0, 1, 2 or 3;

_R10 and _R11 are independently selected from hydrogen, halogen, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl and -( _C1-6 alkyl)-OH;

m is 0, 1, or 2.

_Ra and _Rb are each independently selected from hydrogen, halogen, hydroxyl, or _C1-6 alkyl; or, _Ra and _Rb together with the carbon atoms attached to them form a saturated _C3-6 cyclic hydrocarbon group or a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is a saturated monocycle having 4-6 ring atoms, wherein one or two of the ring atoms are cyclic heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms; wherein the saturated _C3-6 cyclic hydrocarbon group or the 4-6 membered heterocyclic group is optionally substituted by one or more substituents selected from halogens;

L does not exist, or L is NH, O or S;

The heteroaryl group is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are independently selected from N, O and S, and the remaining ring atoms are carbon atoms; or a bicyclic aromatic hydrocarbon group having 8, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are independently selected from N, O and S, and the remaining ring atoms are 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.

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

_R1 is selected from _C1-6 alkyl, -( _C1-6 alkyl)-OH, saturated monocyclic _C3-8 cyclic hydrocarbon, saturated monocyclic 3-8-membered heterocyclic group and heteroaryl containing one or two cyclic heteroatoms independently selected from N, O and S; wherein the _C3-8 cyclic hydrocarbon, 3-8-membered heterocyclic group and heteroaryl group are each optionally substituted by one or more substituents independently selected from: halogen, _C1-6 alkoxy, _{C1-6 haloalkyl and C1-6 alkyl} optionally substituted with one or more deuterium;

Ar is a heteroaryl group, wherein the heteroaryl group is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, wherein 1, 2 or 3 ring heteroatoms are independently selected from N, O and S, and the remaining ring atoms are carbon atoms, 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 the heteroaryl group is optionally substituted by one or more substituents independently selected from: halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy and _C1-6 haloalkyl optionally substituted with one or more deuterium groups;

_R2 is selected from -CN, _C1-6 haloalkyl, saturated monocyclic _C3-8 cyclic hydrocarbon, phenyl, and heteroaryl, wherein the heteroaryl is a monocyclic aromatic hydrocarbon having 5 or 6 ring atoms, wherein 1, 2, or 3 of the ring atoms are independently selected from N, O, and S, and the remaining ring atoms are carbon atoms; or a bicyclic aromatic hydrocarbon having 8, 9, or 10 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are independently selected from N, O, and S, and the remaining ring atoms are carbon atoms, wherein at least one ring is an aromatic ring, and when the total number of S and O atoms in the heteroaryl is greater than 1, these S and O heteroatoms are not adjacent to each other, wherein the saturated monocyclic _C3-8 cyclic hydrocarbon, phenyl, or heteroaryl is each optionally substituted by one or more substituents independently selected from: halogen, -CN, _C1-6 alkyl, and _C1-6 haloalkyl;

_R3 , _R4 , _R5 , _R6 , _R7 , and _R8 are each independently selected from hydrogen, halogen, hydroxyl, _C1-6 alkyl, and _C1-6 alkoxy; wherein the _C1-6 alkyl is optionally substituted by one or more substituents independently selected from hydroxyl and _C1-6 alkoxy; or, any two of _R3 , _R4 , R5, _R6 , _R7 , _{and R8} together with the carbon atom attached to them and the B ring form _Rd selected from hydrogen and halogen, and t is 0, 1, 2, or 3;

_R10 and _R11 are independently selected from hydrogen, halogens, and _C1-6 alkyl groups;

m is 0, 1, or 2.

_Ra and _Rb are each independently selected from hydrogen, halogen, hydroxyl, and _C1-6 alkyl; or, _Ra and _Rb together with the carbon atoms attached to them form a saturated monocyclic _C3-6 cyclic hydrocarbon group or a 3-6 membered heterocyclic group, wherein the 3-6 membered heterocyclic group is a saturated monocycle having 3-6 ring atoms, one or two of which are cyclic heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms; wherein the saturated monocyclic _C3-6 cyclic hydrocarbon group or the 3-6 membered heterocyclic group is optionally substituted by one or more substituents selected from halogens.

L does not exist, or L is NH or O.

Implementation Scheme 34. A compound of formula (I) according to implementation scheme 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 _R1 is selected from: (1) _C1-6 alkyl, (2) -( _C1-6 alkyl)-OH, (3) a saturated monocyclic _C3-8 cyclic hydrocarbon group, optionally substituted with one or more substituents independently selected from halogens and _C1-6 alkoxy groups, (4) a saturated monocyclic 6-membered heterocyclic group containing one or two cyclic heteroatoms independently selected from N, O and S, and (5) a heteroaryl group selected from pyrazolyl, pyridyl and isoxazolyl groups, each of which is optionally substituted with one or more substituents independently selected from: _C1-6 alkoxy, _C1-6 haloalkyl and _C1-6 alkyl optionally substituted with one or more deuterium groups.

Implementation Scheme 35. A compound of formula (I) according to implementation scheme 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 a heteroaryl group selected from pyridinyl and pyrimidinyl, each of which is optionally substituted by one or more substituents independently selected from: halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy and _C1-6 haloalkyl optionally substituted with one or more deuterium groups.

Implementation Scheme 36. A compound of formula (I) according to implementation scheme 35, 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:

_R20 , _R21 , _R22 , _R23 and _R24 are each independently selected from hydrogen, halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy and _C1-6 haloalkyl optionally substituted with one or more deuterium.

Implementation Scheme 37. A compound of formula (I) according to implementation scheme 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 _R2 is selected from: (1) -CN, (2) _C1-6 haloalkyl, (3) a saturated monocyclic _C3-8 cyclic hydrocarbon group, optionally substituted with one or more substituents selected from _C1-6 haloalkyl, (4) a phenyl group, optionally substituted with one or more substituents independently selected from: halogen and -CN, and (5) a heteroaryl group, selected from 1,2,5-oxadiazolyl, dihydroindolyl, 1,2,3,4-tetrahydroquinolinyl, pyrazolyl, indazoleyl and pyrroleyl, wherein each heteroaryl group is optionally substituted with one or more substituents independently selected from: halogen, -CN and _C1-6 alkyl.

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

Implementation Scheme 39. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof described in any one of Implementation Schemes 1-38, and optionally comprising a pharmaceutically acceptable carrier.

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

Implementation Scheme 41. Use of any compound or pharmaceutically acceptable salt thereof from any of Implementation Schemes 1-38 in the preparation of a medicament for the treatment or prevention of a disease that responds to inhibition of ERK.

Implementation Scheme 42. The use according to Implementation Scheme 41, wherein the drug is used to treat cancer or autoimmune diseases.

Implementation Scheme 43. The use according to Implementation Scheme 42, wherein the cancer is a solid tumor or hematologic 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 carcinoma) or ovarian cancer.

Implementation Scheme 44. A method for treating or preventing a disease that responds to inhibition of ERK, comprising administering to an individual in need an effective amount of the compound described in any one of Implementation Schemes 1-38 or a pharmaceutically acceptable salt thereof.

Implementation Scheme 45. The compound or a pharmaceutically acceptable salt thereof described in any one of Implementation Schemes 1-38, for the treatment or prevention of diseases that respond to inhibition of ERK.

Implementation Scheme 46. The compound or a pharmaceutically acceptable salt thereof described in any one of Implementation Schemes 1-38, used as a medicine.

Implementation Scheme 47. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme 46, used as a medicament for treating or preventing diseases that respond to inhibition of ERK.

Implementation Scheme 48. The compound or a pharmaceutically acceptable salt thereof described in Implementation Scheme 47, used as a medicine for treating or preventing cancer or autoimmune diseases.

Implementation Scheme 49. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 48, wherein the cancer is a solid tumor or hematologic 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 carcinoma) or ovarian cancer.

Implementation Scheme 50. A combination product comprising the compound or a pharmaceutically acceptable salt thereof described in any one of Implementation Schemes 1-38, and at least one additional therapeutic agent.

Implementation Scheme 51. The combination product according to Implementation Scheme 50, wherein the additional therapeutic agent is an anti-tumor therapeutic agent, such as a radiotherapy agent, a chemotherapy agent, an immunotherapy agent, or a targeted therapy agent.

Implementation scheme 52. Compound of formula (II):

Or its racemic mixture or enantiomers, wherein: _R9 is a leaving group; _R10 and _R11 are independently selected from hydrogen, halogens, and _C1-6 alkyl groups; _R3 , _R4 , _R5 , _R6 , _R7 , and _R8 are independently selected from hydrogen, halogens, _C1-6 alkyl groups, _C1-6 alkoxy groups, or _C1-6 haloalkyl groups, respectively; or, any two of _R3 , _R4 , _R5 , _R6 , _R7 , and _R8 together with their attached carbon atoms and the B ring form _Rd , which is selected from hydrogen and halogens, and t is 0, 1, 2, or 3; provided that when _R10 and _R11 are both hydrogen, _R3 , _R4 , _R5 , _R6 , _R7 , and _R8 are not both hydrogen, and when _R3 , _R4 , _R5 , _R6 , _R7 , and R8 are both hydrogen, Rd is selected from hydrogen and halogens, and ... When one of the groups in group ₈ is a methyl group, the other groups are not all hydrogen groups.

Implementation Scheme 53. The compound of formula (II) according to Implementation Scheme 52, which is selected from:

Implementation scheme 54. Compound of formula (III):

Or its racemic mixtures or enantiomers, wherein:

_R9 is a leaving group; _R10 and _R11 are independently selected from hydrogen, halogens, and _C1-6 alkyl groups;

_R3 , _R4 , _R5 , and _R6 are each independently selected from hydrogen, halogen, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, or optionally phenyl-substituted _C1-6 alkyl; or, any pair of _R3 and _R4 or _R5 and _R6 together with the carbon atoms attached to them form a saturated _C3-6 cyclic hydrocarbon group or a saturated 3-4 membered heterocyclic group having one or two cyclic heteroatoms selected from N, O, and S, thereby forming a spirocycle together with the B ring; provided that _R3 , _R4 , _R5 , and _R6 are not simultaneously hydrogen, and when one or two of _R3 , _R4 , _R5 , and _R6 are _C1-6 alkyl, the other groups are not simultaneously hydrogen.

Implementation Scheme 55. The compound of formula (III) according to Implementation Scheme 54, which is selected from:

General synthetic methods for compounds

The compounds of formula (I) and/or their pharmaceutically acceptable salts described herein can be synthesized from commercially available starting materials using methods known in the art and disclosed in this patent application. The synthetic routes given in Figure 1 illustrate some of the methods for preparing the compounds disclosed herein, wherein X is a halogen; _Z1 , _Z2 , L, _R1 , _R2 , _R3 , _R4 , _R5 , _R6 , R7, _R8 , _Ra , _Rb , _m and n are as defined for compounds of formula (I) and their sub-formulas (I-1), (I-2), and (I-3); _R9 is as defined for compounds of formulas (II) and (III).

As shown in Figure 1, the synthesis of these compounds mainly involves three types of key reactions: the introduction of amino substituents on the Ar ring, the bonding reaction between the Ar ring fragment and the tricyclic system, and the construction of the triazole ring in the tricyclic system. Therefore, the synthesis of the target compound can be carried out with different reaction priorities according to the actual situation. As shown in Route 1, some compounds can be synthesized by first completing the bonding reaction, then introducing the amino group, and finally constructing the triazole, as in Example 8; as shown in Route 2, some compounds can be synthesized by first synthesizing the triazole to obtain the tricyclic fragment, then carrying out the bonding reaction, and finally introducing the amino group, as in Examples 13 and 14; as shown in Route 3, some compounds can be synthesized by first introducing the amino group, then carrying out the coupling reaction, and finally constructing the triazole, as in Examples 1 and 7; as shown in Route 4, some compounds can also be synthesized by combining the methods of Route 2 and 3, in which the bonding reaction is carried out last, as in Example 12.

The compounds obtained by the above method can be further modified at their peripheral positions to obtain the desired compounds. For synthetic chemical transformations, see, for example: R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd ed., 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. Paquette (ed.), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

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

Pharmaceutical Compositions and Uses

Compositions comprising a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof may be administered in a variety of known manners, such as oral, parenteral, inhalation, or implantation. The term “parenteral” as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intravertebral, intralesional, and intracranial injection or infusion.

Orally administered compositions can be in any orally acceptable dosage form, including but not limited to: tablets, capsules, pills, powders, emulsions, and aqueous suspensions, dispersants, and solutions. Common tablet carriers include lactose and corn starch. Lubricants such as magnesium stearate are also frequently added to tablets. When administered orally in capsule form, useful diluents include lactose and dried corn starch. When administered orally in aqueous suspension or emulsion form, emulsifiers or suspending agents can be used to suspend or dissolve the active ingredient in the oil phase. If necessary, certain sweeteners, flavoring agents, or colorings may be added.

Sterile injectable compositions (such as aqueous or oily suspensions) can be formulated using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. Sterile injectable compositions can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Pharmaceutically acceptable carriers and solvents, in particular mannitol, water, Ringer's solution, and physiological saline, are commonly used. Furthermore, sterile, non-volatile oils, such as synthetic mono- or di-glycerides, are often used as solvents or suspension media. 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 in their polyoxyethylated forms), are commonly used in the preparation of injectable compositions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethyl cellulose or similar dispersants.

Inhalation compositions can be prepared using benzyl alcohol or other suitable preservatives, absorption enhancers that improve bioavailability, fluorocarbons and/or other solubilizers or dispersants known in the art, according to techniques well known in the pharmaceutical formulation field, or they can be prepared as solutions in saline.

Topical compositions can be formulated as oils, creams, lotions, ointments, etc. Suitable carriers for the compositions include vegetable or mineral oils, white petrolatum (white paraffin), branched-chain fatty acids or oils, animal fats, and high molecular weight alcohols (i.e., alcohols with more than 12 carbon atoms). In some embodiments, pharmaceutically acceptable carriers are those in which the active ingredient can dissolve. If desired, the composition may also contain emulsifiers, stabilizers, wetting agents, and antioxidants, as well as substances that impart color or fragrance. Furthermore, transdermal penetration enhancers may be added to the topical formulation. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.

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

A pharmaceutically acceptable carrier is one that is compatible with (and in some embodiments, stabilizes) the active ingredient in the composition and is harmless to the individual being treated. For example, solubilizers such as cyclodextrins (which can form specific, more soluble complexes with compounds of formula (I) described herein and/or their pharmaceutically acceptable salts) can be used as pharmaceutical excipients to deliver the active ingredient. Other examples of carriers include colloidal silica, magnesium stearate, cellulose, sodium dodecyl sulfate, and pigments such as D&C Yellow #10.

Suitable in vitro experiments can be used to preliminarily evaluate the efficacy of compounds of formula (I) and/or their pharmaceutically acceptable salts in inhibiting ERK activity. For example, compounds of formula (I) and/or their pharmaceutically acceptable salts can be contacted with ERK kinases or cells to determine their inhibition rate of ERK activity. The efficacy of compounds of formula (I) and/or their pharmaceutically acceptable salts in treating or preventing cancer or autoimmune diseases can be further investigated through in vivo experiments. For example, compounds of formula (I) and/or their pharmaceutically acceptable salts can be administered to animals (e.g., mouse models) with cancer or autoimmune diseases, and their therapeutic effects can then be evaluated. Based on the above results, suitable dosage ranges and routes of administration for animals, such as humans, can also be determined.

The compounds of formula (I) described herein and/or their pharmaceutically acceptable salts may be used to achieve beneficial therapeutic or preventive effects, for example, in individuals with cancer.

As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or disordered cell proliferation, reduced cell differentiation, inappropriate invasion of surrounding tissues, and/or the ability to establish new growth sites in other locations. The term "cancer" includes, but is not limited to, solid tumors and hematologic malignancies. The term "cancer" includes cancers of the skin, tissues, organs, bones, 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 cancer, 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 carcinoma or primary peritoneal carcinoma; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, squamous cell carcinoma of the head and neck; skin cancer, including, for example, melanoma; neuroendocrine carcinoma, including metastatic neuroendocrine tumors; brain tumors, including, for example, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; soft tissue sarcoma; and thyroid cancer, such as papillary thyroid carcinoma.

Non-limiting examples of hematologic malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and CML blast crisis (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's 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; and myelodysplastic syndrome (MDS). These include refractory anemia (RA), refractoryanemia with ringed siderblast (RARS), refractory anemia with excess blast (RAEB), and refractory anemia with excess blast in transformation (RAEB-T); as well as myeloproliferative syndrome.

The compounds of formula (I) described herein and/or their pharmaceutically acceptable salts may be used to achieve beneficial therapeutic or preventive effects, for example, in individuals with autoimmune diseases.

The term "autoimmune disease" refers to a disease or condition caused by damage to one's own tissues or organs due to an immune response to self-antigens. 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, and myeloproliferative diseases, such as myelofibrosis, post-polycythemia vera/essential thrombocytosis myelofibrosis (post-PV/ET myelofibrosis).

Furthermore, compounds of formula (I) described herein (e.g., compounds of sub-formulas (I-1), (I-2), or (I-3), and compounds 1-321) and/or their pharmaceutically acceptable salts may be used in combination with additional therapeutic agents for the treatment of cancer. The additional therapeutic agent may be administered separately from the compounds of formula (I) described herein and/or their pharmaceutically acceptable salts, or may be included in a pharmaceutical composition, such as a fixed-dose combination drug, as disclosed in this application. In some embodiments, the additional therapeutic agent is an ingredient known or found to be effective in treating ERK-regulated diseases, such as another ERK inhibitor or a compound that effectively antagonizes another target associated with that particular disease. Combination therapy may be used to improve efficacy (e.g., by including a compound that enhances the potency or effectiveness of the compounds of formula (I) described herein and/or their pharmaceutically acceptable salts in the combination therapy), reduce one or more side effects, or reduce the required dose of the compounds of formula (I) described herein and/or their pharmaceutically acceptable salts.

In some embodiments, compounds of formula (I) described herein (e.g., compounds of sub-formulas (I-1), (I-2), or (I-3), and compounds 1-321) and/or their pharmaceutically acceptable salts may be used in combination with antitumor agents. As used herein, the term "antitumor agent" refers to any agent administered to an individual with cancer for the purpose of treating cancer, including but not limited to radiotherapy agents, chemotherapy agents, immunotherapy agents, targeted therapy agents, etc.

Non-limiting examples of chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and its analogues or metabolites, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, demethoxydaunorubicin, and donomycin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, nitrosourea mustard, cyclohexanenitrosourea, methylcyclohexanenitrosourea, streptozotocin, aminoimide, methotrexate, mitomycin C, and cyclohexanenitrosourea). Phosphoramides; DNA intercalating agents (e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalating agents and free radical generating agents such as bleomycin; and nucleoside analogs (e.g., 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine mercaptopurine, thioguanine, pentostatin, and hydroxyurea); paclitaxel, taxanes, and related analogs; vincristine, vinblastine, and related analogs; thalidomide and related analogs (e.g., CC-5013 and CC-4047).

Non-limiting examples of immunotherapy agents or targeted therapies include MEK inhibitors, RAF inhibitors, mTOR inhibitors, PAK inhibitors, CDK inhibitors, VEGFR inhibitors, PARP inhibitors, ERBB inhibitors, PI3K inhibitors, AKT inhibitors, autophagy inhibitors, and immune checkpoint inhibitors such as PD-1 inhibitors and PD-L1 inhibitors. For example: Trametinib, Cobimetinib, Vemurafenib, Dabrafenib, Rapamycin, Temsirolimus, Everolimus, Palbociclib, Ribociclib, Fruquintinib, Olaparib, Niraparib, Neratinib, Chloroquine, Hydroxychloroquine, LXH254, Selumetinib, LY3214996, Abemaciclib, P1446A-05 (vorucicli b) LGX818 (encorafenib), ARRY-162 (binimetinib), cetuximab, gefitinib, panitumumab, BYL719 (Alpelisib), bevacizumab, pembrolizumab, atezolizumab, PDR001 (Spartalizumab), durvalumab, nivolumab, avelumab, Libtayo (Cemiplimab), tislelizumab, toripalimab (JS001), sintilimab, camrelizumab, etc.

Example

The following examples are intended as purely illustrative and should not be construed as limiting the invention in any way. While efforts have been made to ensure the accuracy of the numerical values used (e.g., quantities, temperatures, etc.), some experimental errors and biases should be taken into account.

Unless otherwise specified, parts are by weight, temperatures are in degrees Celsius, and pressures are at or near atmospheric pressure. All MS (mass spectrometry) data were obtained using an Agilent 6120 and/or Agilent 1100. ^¹H -NMR spectra were obtained using a 400 MHz NMR instrument. NMR spectra were obtained with deuterated chloroform as a solution (in ppm), using chloroform as a reference standard (7.26 ppm), or, under appropriate conditions, with the included tetramethylsilane as a reference standard (0.00 ppm). Other NMR solvents were used as needed. The following abbreviations are used to represent peak multiplicity: s (singleton), d (doublet), t (triplet), m (multiplet), q (quartet), br (broad peak), dd (doublet), dt (doubletuplet). Coupling constants are given in Hertz (Hz).

All reagents used in this invention, except for intermediates, are commercially available.

All compound names, except for reagents, are generated by Chemdraw. If a compound is given both its name and structural formula, and they are inconsistent, the structural formula shall prevail, unless the context indicates that the structure is incorrect while the name is correct.

In any structural formula of this application, if there is a vacant valence on any atom, the vacant valence is actually a hydrogen atom that is not specifically described for simplicity.

In the following embodiments, the following abbreviations are used:

Boc tert-Butoxycarbonyl

BPIN (Biopinol Borate)

CDI N-N'-Carbonyldiimidazole

DCM Chloromethane

DIAD (Diisopropyl Azodicarbonate)

DIBAL-H Isobutylaluminum hydride

DIPEA (N,N-diisopropylethylamine)

DMF (N,N-dimethylformamide)

EA ethyl acetate

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

Et Ethyl

h hours

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

HOBT (1-hydroxybenzotriazole)

ISCO TELEDYNEISCO CombiFlashRF+ Chromatography System

LDA (Lithium Isopropylamine)

min

MeOH Methanol

Ms. Methanesulfonyl

NBS N-bromosuccinimide

NaHMDS Sodium bis(trimethylsilyl)amino

PE (petroleum ether)

_PdCl₂ ( _PPh₃ ) _₂bis (triphenylphosphine)palladium(II) chloride

_Pd₂ (dba) _₃tris (dibenzylacetone)dipalladium(0)

Pd(dppf) _Cl₂ · _CH₂Cl₂ 1,1′- _bis (diphenylphosphine)ferrocene palladium(II) dichloromethane complex

Pd(OAc) _₂palladium (II) acetate

Pd(PPh ₃ ) ₄ tetrakis(triphenylphosphine)palladium(0)

PMB (p-methoxybenzyl)

PPh ₃ triphenylphosphine

PTLC (Preparative Thin-Layer Chromatography)

SEM 2-(trimethylsilyl)ethoxymethyl

THF (Tetrahydrofuran)

TBDPS tert-butyldiphenylsilyl

TFA (Trifluoroacetic acid)

Ts p-Toluenesulfonyl group

Xantphos 4,5-Bisdiphenylphosphine-9,9-Dimethylxanthanium

Intermediate 1

4-Chloro-N-(1-Methyl-1H-pyrazol-5-yl)pyrimidin-2-amine

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

NaH (16.1 g, 402.5 mmol, 60% dispersed in liquid paraffin) was added in portions to a solution of (4-methoxyphenyl)methanol (40.8 g, 295.3 mmol) in THF (200 mL) at 0 °C. The mixture was stirred at 0 °C for 30 minutes under a nitrogen atmosphere. Then, the mixture was slowly added to a solution of 2,4-dichloropyrimidine (40.0 g, 268.5 mmol) in THF (200 mL) at 0 °C. After addition, the mixture was stirred overnight at room temperature, and the reaction was quenched with ice water (200 mL). The mixture was separated, the aqueous layer was extracted with THF (200 mL), the combined organic layers were washed with brine, and dried over anhydrous sodium. After filtration, the filtrate was concentrated to give a grayish-white solid (73.0 g), 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 (73.0 g, obtained from the previous step) and 1-methyl-1H-pyrazole-5-amine (56.6 g, 582.4 mmol) in 1,4-dioxane (730 mL), Pd(OAc) _₂ (3.27 g, 14.6 mmol), Xantphos (16.8 g, 29.1 mmol), and KOAc (85.7 g, 873.6 mmol) were added. The mixture was purged with nitrogen and stirred overnight at 90 °C under a 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 (eluting with water containing 0%–100% methanol) to give a pale yellow solid (38.5 g, 42.4% yield). MS(m/z): 312.1(M+H) ⁺

(C)4-Chloro-N-(1-Methyl-1H-pyrazol-5-yl)pyrimidin-2-amine

4-((4-methoxybenzyl)oxy)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (38.5 g, 123.7 mmol) and TFA (150 mL) were added to a three-necked round-bottom flask. 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 °C for 3 hours and then concentrated. The residue was poured into ice water and adjusted to pH 8–9 with saturated _NaHCO3 solution. 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 (23.3 g, yield 89.6%). MS (m/z): 210.0 (M+H) ⁺

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

Intermediate 3

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

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

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

Intermediate 5

5-Fluoro-4-iodo-N-(1-methyl-1H-pyrazol-5-yl)pyridine-2-amine

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

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

(B) 5-Fluoro-4-iodo-N-(1-methyl-1H-pyrazol-5-yl)pyridine-2-amine

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

Intermediate 6

4-Iodo-N-(1-Methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyridine-2-amine

(A) 2-Bromo-4-Fan-5-(trifluoromethyl)pyridine

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

(B) 4-Iodo-N-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyridine-2-amine

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

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

Intermediate 8

N-Cyclopropyl-4-iodo-5-(trifluoromethyl)pyridine-2-amine

(A) N-Cyclopropyl-4-iodo-5-(trifluoromethyl)pyridine-2-amine

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

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

Intermediate 11

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

(A) 5-Ethyl-2-fluoropyridine

To a solution of 5-bromo-2-fluoropyridine (5.5 g, 31.3 mmol) and triethylborane (1 M) (63 mL, 62.6 mmol) in DMF (30 mL), _K₂CO₃ (12.9 _g , 94 mmol) and Pd( _PPh₃ ) _₄ (1.8 g, 1.6 mmol) were added. The mixture was degassed and stirred overnight at 80 °C under a nitrogen atmosphere, diluted with water, extracted with hexane, washed with water and brine, dried over anhydrous _{Na₂SO₄ ,} concentrated, and purified by ISCO (eluting with PE containing 0%–100% DCM) to give the title compound as a yellow liquid (3 g, 77% yield). MS (m/z): 126.0 (M+H) ^⁺

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

LDA (6 mL, 12 mmol, 2 M THF solution) was added dropwise to a THF (20 mL) solution of 5-ethyl-2-fluoropyridine (1 g, 8 mmol) at -78 °C under a nitrogen atmosphere. After stirring at -78 °C for 1 hour, iodine (3 g, 12 mmol) was added. The resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 2 hours, quenched with HOAc and _{aqueous Na₂SO₃} solution, and extracted with EA. _The organic layer was washed with water and brine, dried over anhydrous _Na₂SO₄ , concentrated, and purified with ISCO (eluting with PE containing 0%–100% EA) to give the title compound as a yellow oil (1.1 g, 55%). MS (m/z): 251.9 (M+H) ^⁺

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

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

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

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

Intermediate 12

2-Bromo-4-iodo-5-methoxypyridine

(A) 2-Bromo-5-methoxypyridine

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

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

Under a nitrogen atmosphere, at -70°C, LDA (4 mL, 8 mmol, 2 M THF solution) was added to a solution of 2-bromo-5-methoxypyridine (1.5 g, 8 mmol) in anhydrous THF (50 mL). The solution was stirred at -70°C for 2 hours. Iodine (2.1 g, 8 mmol) was added in portions, and the solution was stirred for another hour. 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 under vacuum. The residue was purified by silica gel chromatography (PE:EA = 5:1) to give the title compound as a pale yellow solid (900 mg, 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-1-one

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

_K₂CO₃ ( ₁₆₉ g, 1.23 mol) was added to a mixture of methyl 4-bromo-1H-pyrrole-2-carboxylate (100 g, 0.49 mol) and tert-butyl (3-bromopropyl)carbamate (122 g, 0.51 mol) in DMF (500 mL). The mixture was stirred overnight at room temperature. _{The K₂CO₃} was then filtered off, the filtrate was diluted with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous _{Na₂SO₄ ,} and concentrated to give the title compound as a yellow solid (166 g, 93.9% yield). MS (m/z): 261.0/263.0 (M+H) ^⁺

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

A mixture of methyl 4-bromo-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrrole-2-carboxylate (166 g, 0.46 mol) in trifluoroacetic acid (200 mL) was stirred at 60 °C for 3 h. The mixture was concentrated and partitioned between a saturated _NaHCO₃ solution and EA. The organic layer was washed with brine, dried over anhydrous _{Na₂SO₄ ,} and concentrated to give the title compound as a yellow solid (114.37 g, 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-1-one

_K₂CO₃ ( ₁₅₁ g, 1.10 mol) was added to a mixture of methyl 1-(3-aminopropyl)-4-bromo-1H-pyrrole-2-carboxylate (114 g, 0.44 mol) in MeOH (800 mL). The mixture was stirred at 80 °C for 3 hours. _{The K₂CO₃} was then filtered off, and the filtrate was concentrated. The residue was diluted with water and extracted with EA. The organic layer was washed with brine, dried over _{anhydrous Na₂SO₄} , concentrated, and recrystallized to give the title compound as a white solid (70.0 g, 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-1-one

(A) Methyl 4-bromo-3-chloro-1H-pyrrole-2-carboxylate

_Br₂ (3.2 mL, 62.7 mmol) was added dropwise to a DMF (400 mL) solution of methyl 3-chloro-1H-pyrrole-2-carboxylate (10 g, 62.7 mmol). The mixture was stirred at room temperature for 8 hours. The mixture was then diluted with water (2.0 L) and extracted with EA (3 × 1.5 L). The organic layer was concentrated, and the residue was purified with ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a yellow solid (7.0 g, yield 46.9%). MS (m/z): 237.8, 239.8 (M+H) ^⁺

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

A mixture of methyl 4-bromo-3-chloro-1H-pyrrole-2-carboxylate (6 g, 25.2 mmol), 1,3- _{dibromopropane} (50.9 g, 252 mmol), and _K₂CO₃ (7.0 g, 50.4 mmol) in _CH₃CN (150 mL) was stirred at 70 °C for 3 h. The reaction mixture was concentrated and partitioned between water (200 mL) and EA (200 mL). The aqueous layer was further extracted with EA (2 × 200 mL). The combined organic layers were concentrated and purified with ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a white solid (4.2 g, yield 46.3%). 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-1-one

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

The following intermediates were prepared using the appropriate intermediates and reagents in accordance with the procedure for intermediate 14, under conditions deemed suitable 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-1-one

(A) Ethyl 1-(3-(((tert-butoxycarbonyl)amino)propyl)-3-fluoro-1H-pyrrole-2-carboxylate

A mixture of ethyl 3-fluoro-1H-pyrrole-2-carboxylate (3.14 g, 20 mmol), tert-butyl ( ₃ -bromopropyl)carbamate (7.14 g, 30 mmol), and _Cs₂CO₃ (9.75 g, 30 mmol) in DMF (20 mL) was heated overnight at 80 °C. After cooling to room temperature, the mixture was extracted with EA, the organic phase was washed with water and brine, and purified with ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a yellow solid (6.28 g). MS (m/z): 315.1 (M+H) ^⁺

(B) Ethyl 4-bromo-1-(3-((tert-butoxycarbonyl)amino)propyl)-3-fluoro-1H-pyrrole-2-carboxylate

NBS (3.56 g, 20 mmol) was added fractionally to a solution of ethyl 1-(3-(((tert-butoxycarbonyl)amino)propyl)-3-fluoro-1H-pyrrole-2-carboxylate (6.28 g, 20 mmol) in DMF (15 mL) at room temperature. The mixture was stirred for 4 hours, quenched with _{aqueous Na₂SO₃} solution, extracted with EA, and concentrated 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-1-one

To a solution of ethyl 4-bromo-1-(3-((tert-butoxycarbonyl)amino)propyl)-3-fluoro-1H-pyrrole-2-carboxylate (6.1 g, 15.5 mmol) in methanol (10 mL), concentrated hydrochloric acid (3 mL) was added, and the resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum. The residue was adjusted to pH 8 with an aqueous sodium bicarbonate solution and extracted with DCM. The organic phase was concentrated, and the residue was dissolved in MeOH (25 mL) and _K₂CO₃ (6.42 g, 46.5 mmol). The mixture was stirred at 80 ° _C for 48 hours. _{The K₂CO₃} was then filtered off, and the filtrate was concentrated. The residue was purified by ISCO (eluting with PE containing 50%–100% EA) to give the title compound as a white solid (3 g, 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) Methyl 4-bromo-1-(cyanomethyl)-1H-pyrrole-2-carboxylate

To a DMF (15 mL) solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (4 g, _19.6 mmol), _K₂CO₃ (5.4 g, 39.2 mmol) and 2-bromoacetonitrile (2.4 g, 19.6 mmol) were added. The resulting mixture was stirred at 80 °C 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) Methyl 1-(2-aminoethyl)-4-bromo-1H-pyrrole-2-carboxylate

At room temperature, _BH₃ · _Me₂S (10 mL, 19.6 mmol, 2 M THF solution) was added dropwise to a THF solution of methyl 4-bromo-1-(cyanomethyl)-1H-pyrrole-2-carboxylate (5.1 g, 19.6 mmol). The resulting mixture was then stirred overnight at 60 °C, quenched with cold aqueous sodium bicarbonate solution at 0 °C, 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 (4.5 g, 93% yield). MS (m/z): 246.9/248.9 (M+H) ^⁺

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

Ammonium hydroxide (3 mL) was added to a solution of methyl 1-(2-aminoethyl)-4-bromo-1H-pyrrole-2-carboxylate (4.5 g, 18.2 mmol) in MeOH (20 mL). The resulting mixture was stirred overnight at room temperature, concentrated, and purified by ISCO (eluting with DCM containing 0%–15% MeOH) to give the title compound as a brown solid (3.2 g, 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]-1′-one

(A)((1-(hydroxymethyl)cyclopropyl)methyl)tert-butyl carbamate

_Boc₂O (10.8 g, 49.5 mmol) and DIPEA (12.8 g, 99 mmol) were added to a solution of (1-(aminomethyl)cyclopropyl)methanol (5 g, 49.5 mmol) in DCM (40 mL). The mixture was stirred at room temperature for 2 hours, concentrated, and purified by ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a yellow solid (9.4 g, 94% yield).

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

At 0 °C under a nitrogen atmosphere, DIAD (7.4 g, 36.8 mmol) was added dropwise to a THF (20 mL) solution of ((1-(hydroxymethyl)cyclopropyl)methyl)carbamate (4.9 g, 24.5 mmol), methyl 4-bromo-1H-pyrrole-2-carboxylate (5 g, 24.5 mmol), and PPh ₃ (9.6 g, 36.8 mmol). The mixture was stirred overnight at room temperature, concentrated, and purified by ISCO (eluting with PE containing 0%–100% EA) to give the title compound as a yellow oil (9.2 g, crude).

(C)8′-bromo-2′,3′-hydrogen-1′H-,5′H-spiro[cyclopropane-1,4′-pyrrolo[1,2-a][1,4]diaza]-1′-one

A solution of methyl 4-bromo-1-((1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)methyl)-1H-pyrrole-2-carboxylate (9.2 g, 23.8 mmol) in TFA (10 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum. The residue was dissolved in MeOH (30 mL) and _K₂CO₃ (9.8 g, 71.3 mmol) and _Et₃N (7.2 g, 71.3 mmol) were added. The mixture was stirred overnight at room temperature, concentrated, and purified by ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a yellow solid (4.5 g, 74% yield). MS (m/z): 255.0/257.0 (M+H) ^⁺

The following intermediates were prepared using the appropriate intermediates and reagents in accordance with the procedure for intermediate 18, under conditions deemed suitable 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-1-one

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

At room temperature, _Cs₂CO₃ (115 g, 0.352 mol) was added to a solution of methyl 4-bromo-1H-pyrrole-2 _- carboxylate (60.0 g, 0.294 mol) and (S)-2-(chloromethyl)ethylene oxide (68.0 g, 0.735 mol) in EtOH (600 mL). After stirring at 80 °C for 2 hours, the mixture was diluted with water and extracted with EA. The organic layer was concentrated, and the residue was dissolved in EtOH (1000 mL) and ammonium hydroxide (100 mL, 25–28 wt% aqueous solution). The mixture was stirred at 80 °C for 16 hours. The mixture was concentrated, and the residue was recrystallized (EA and EtOH) to give the title compound as a white solid (25 g, two-step yield 34.7%). 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-1-one

To a solution of (R)-8-bromo-4-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diaza-1-one (20.0 g, 0.082 mol) in DCM (300 mL), _CF₃SO₃Me ( ₂₀ g, 0.122 mol) was added. After stirring at 40 °C for 16 hours, the mixture was concentrated. The residue was dissolved in DMF (250 mL) and cooled to 0 °C. NaH (10.0 g, 0.255 mol, 60% dispersed in liquid paraffin) was added at 0 °C, and the mixture was stirred at 0 °C for 30 minutes, followed by the addition of iodomethane (24.0 g, 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, and the resulting yellow oil was dissolved in MeOH (300 mL). Add concentrated hydrochloric acid (60 mL) and stir the mixture at 60 °C for 3 hours. Concentrate the mixture and redissolve it in _MeOH (400 mL). Add _K₂CO₃ (40 g, 0.289 mol) and stir the mixture at 60 °C for 4 hours. Filter the mixture through diatomaceous earth. Concentrate the filtrate and purify the residue with ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a white solid (10.0 g, overall yield of 47.7% in four steps). MS (m/z): 259.0/261.0 (M+H) ^⁺

Intermediate 38

8′-Bromo-2′,3′-Dihydro-1′H,5′H-spiro[cyclobutane-1,4′-pyrrolo[1,2-a][1,4]diaza]-1′-one

(A) Cyclobutane-1,1-diethanol

Under a nitrogen atmosphere, a solution of diethyl cyclobutane-1,1-dicarboxylate (8 g, 40 mmol) in 40 mL of THF was added dropwise to a suspension of _LiAlH₄ (2.3 g, 60 mmol) in 30 mL of THF. The mixture was stirred overnight at room temperature, poured into water, and the pH was adjusted to 3 with 2N HCl. Extraction was performed with EA, followed by washing with water and brine, drying over anhydrous sodium sulfate, and concentration to give the title compound as a yellow oil (2.9 g, 63% yield). MS (m/z): 117.1 (M+H) ^⁺

(B) 1,1-Di(4-methylbenzenesulfonyloxymethyl)cyclobutane

At 0 °C, TsCl (10.5 g, 55 mmol) and _Et3N (7.6 g, 75 mmol) were added to a DCM (30 mL) solution of cyclobutane-1,1-diethanol (2.9 g, 25 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 (eluting with PE containing 0%–100% EA) to give the title compound as a white solid (3.5 g, 33% yield). (C)8′-bromo-2′,3′-dihydro-1′H,5′H-spiro[cyclobutane-1,4′-pyrrolo[1,2-a][1,4]diaza]-1′-one

To a DMF (10 mL) solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (1.7 g, 8.2 mmol), _K₂CO₃ (3.4 g, 24.7 mmol) and 1,1-bis(4-methylbenzenesulfonyloxymethyl)cyclobutane (3.5 g, 8.2 mmol) were added. The mixture was stirred at 100 °C 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 (10 mL) and _NaN₃ (1.1 g, 16.4 mmol). The mixture was stirred at 100 °C overnight. It was 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 (30 mL) and _PPh₃ (2.2 g, 8.2 mmol) was added. The mixture was stirred at room temperature for 1 hour and concentrated. The residue was dissolved in MeOH (3 mL) and concentrated hydrochloric acid (10 mL) was added. The mixture was refluxed for 3 hours, concentrated, and then dissolved again in MeOH (10 mL) with _K₂CO₃ (3.4 g, 24.7 mmol) and _Et₃N (4.2 g, 41.1 mmol). The mixture was refluxed overnight, concentrated, and purified by ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a yellow solid (1.2 g, yield 54.1%). 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

Add (Boc) _₂O (20.6 g, 94.3 mmol) to a solution of L-serine ethyl ester hydrochloride (8.0 g, 47.2 mmol) and _Et₃N (9.5 g, 94.3 mmol) in DCM (80 mL). Stir the resulting mixture overnight at room temperature, then dilute with water (100 mL) and extract with DCM (3 × 100 mL). Concentrate the combined organic layers and dissolve again in DCM (100 mL). At 0 °C, add 1H-imidazole (4.7 g, 68.6 mmol) and TBDPSCl (8.3 g, 30.2 mmol). Stir the mixture overnight at room temperature. Dilute the reaction mixture with water (100 mL) and extract with DCM (3 × 100 mL). Concentrate the combined organic layers and purify the residue with ISCO (eluting with water containing 0%–100% methanol) to give the title compound as an oil (5.8 g, 26.1% yield). MS (m/z): 372.1 (M+H-100) ⁺

(B)(R)-1-((tert-butyldiphenylsilyl)oxy)-3-hydroxypropane-2-yl)tert-butyl carbamate

At -78 °C, DIBAL-H (22.9 mL, 22.9 mmol, 1 M hexane solution) was slowly added to a DCM (40 mL) solution of N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-L-serine ethyl ester (5.4 g, 11.4 mmol). The mixture was stirred at -78 °C for 30 min, then stirred overnight at room temperature. The reaction mixture was cooled to 0 °C and quenched with 1 mL water, 1 mL 15% NaOH solution, and 3 mL 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 and purified with ISCO (eluting with PE containing 0%-100% EA) to give the title compound as an oil (3.1 g, yield 63.3%). MS (m/z): 330.1 (M+H-100) ⁺

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

At 0 °C, DIAD (1.8 g, 8.7 mmol) was slowly added to a solution of (R)-1-((tert-butyldiphenylsilyl)oxy)-3-hydroxypropane-2-yl)carbamate (2.5 g, 5.8 mmol), methyl 4-bromo-1H-pyrrole-2-carboxylate (1.2 g, 5.8 mmol), and PPh ₃ (2.3 g, 8.7 mmol) in anhydrous THF (100 mL). The mixture was then heated to room temperature and stirred overnight. The reaction mixture was concentrated and partitioned between water (100 mL) and DCM (100 mL). The aqueous layer was further extracted with DCM (2 × 100 mL). The combined organic layers were concentrated and purified with ISCO (eluting with PE containing 0%–100% EA) to give the title compound as a white solid (2.0 g, 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 methyl (R)-4-bromo-1-(2-(tert-butoxycarbonyl)amino)-3-((tert-butyldiphenylsilyl)oxy)propyl-1H-pyrrole-2-carboxylate (2.0 g, 3.2 mmol) in TFA (40 mL) was stirred at room temperature for 2 hours. Volatile substances were removed under reduced pressure. The residue was redissolved in MeOH (50 mL), and _Et3N (1.6 g, 16.2 mmol) and _K2CO3 (2.2 g, 16.2 mmol) were added. The resulting mixture was refluxed for 4 hours. The reaction mixture was concentrated and partitioned between water (100 _mL ) and DCM (100 mL). The aqueous layer was further extracted with DCM (2 × 100 mL). The combined organic layers were concentrated and purified with ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a white solid (0.35 g, 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

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

The following intermediates were prepared using the appropriate intermediates and reagents in accordance with the procedure for intermediate 39, under conditions deemed suitable 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)carbamate tert-butyl ester

At 0 °C, ( _Boc ) _₂O (3.5 g, 0.016 mol) was added to a solution of (1-aminocyclobutyl)methanol hydrochloride (2 g, 0.015 mol) and _Et₃N (6.2 mL, 0.044 mol) in DCM (40 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between DCM (30 mL) and a saturated aqueous solution of ammonium chloride (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Recrystallization with PE/EA gave the title compound as a white solid (2.4 g, 87.8% yield). ¹ H 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) Methyl 4-bromo-1-((1-((tert-butoxycarbonyl)amino)cyclobutyl)methyl)-1H-pyrrole-2-carboxylate

Add _Et3N (2.8 mL, 0.020 mol) to a DCM solution of tert-butyl (1-(hydroxymethyl)cyclobutyl)carbamate (2.1 g, 0.010 mol), and then add MsCl (0.93 mL, 0.012 mol) dropwise at 0 °C. Stir the mixture at room temperature for 2 hours. Partition the reaction mixture between DCM (30 mL) and a saturated aqueous solution of ammonium chloride (30 mL). Wash the organic layer with brine (30 mL), dry to anhydrous sodium sulfate, filter, concentrate, dissolve the residue in DMF (40 mL), and add methyl 4-bromo-1H-pyrrole-2-carboxylate (2 g, 0.0096 mol) and _Cs2CO3 ( _6.3 g, 0.0192 mol). Stir the resulting mixture at 80 °C for 8 hours. Partition the reaction mixture between EA (200 mL) and brine (300 mL), and extract the aqueous layer again with EA (200 mL × 2). The combined organic layers were concentrated and purified by ISCO (PE/EA) to give the title compound as an oil (1.6 g, 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 methyl 4-bromo-1-((1-((tert-butoxycarbonyl)amino)cyclobutyl)methyl)-1H-pyrrole-2-carboxylate (1.6 g, 0.0041 mol) in TFA (10 mL) was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure. The residue was dissolved in methanol (20 mL), and _Et3N (3 mL) and _K2CO3 (2 g, 0.0144 mol) were added. The mixture was refluxed for 6 hours and then concentrated. The residue was purified by ISCO (eluting with water containing 0 _% –100% methanol) to give the title compound as a white solid (0.7 g, 66.8% yield). MS (m/z): 255.9/257.9 (M+H) ⁺

The following intermediates were prepared using the appropriate intermediates and reagents in accordance with the procedure for intermediate 41, under conditions deemed suitable 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) Methyl 4-bromo-1-(cyanomethyl)-1H-pyrrole-2-carboxylate

A mixture of methyl 4-bromo-1H-pyrrole-2-carboxylate (10 g, 49.0 mmol), 2- _{bromoacetonitrile} (6.17 g, 51.5 mmol), and _K₂CO₃ (10.1 g, 73.5 mmol) in _CH₃CN (100 mL) was heated at 80 °C for 3.5 h. The reaction mixture was concentrated and partitioned between water (150 mL) and EA (150 mL). The aqueous layer was further extracted with EA (2 × 150 mL). The combined organic layers were concentrated to give the title compound as a white solid (11.0 g, 92.4% yield). MS (m/z): 242.9/244.9 (M+H) ^⁺

(B)7′-Bromo-4′H-spiro[cyclopropane-1,3′-pyrrolo[1,2-a]pyrazine]-1′(2′H)-one

At room temperature, ethyl magnesium bromide (11 mL, 33 mmol, 3 M THF solution) was added dropwise to a mixture of methyl 4-bromo-1-(cyanomethyl)-1H-pyrrole-2-carboxylate (3.0 g, 12.3 mmol) and Ti(O1Pr) ₄ (5.2 g, 18.2 mmol) in THF (60 mL). After addition, the mixture was stirred at room temperature for 1 hour. Hydrochloric acid (1 N, 50 mL) was added. THF was removed under reduced pressure, and the aqueous layer was extracted with DCM (3 × 50 mL). The combined organic layers were concentrated, and the residue was purified by ISCO (PE/EA) to give the title compound as a white solid (0.4 g, 10.1% yield). MS (m/z): 241.0/243.0 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ 8.01 (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 using the appropriate intermediates and reagents according to the procedure for intermediate 45, under conditions deemed suitable by those skilled in the art.

Intermediate 47

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

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

At 0 °C, NaH (0.6 g, 0.015 mol, 60% dispersed in liquid paraffin) was added to a DMF (10 mL) solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (2.0 g, 0.01 mol). The mixture was stirred at 0 °C for 30 min, and then 1-bromopropane-2-one (1.4 g, 0.01 mol) was added. The mixture was stirred at room temperature for 4 h, diluted with water, and extracted with EA. The organic layer was washed with water and brine, concentrated, and the title compound was given 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

A methanol solution of ammonia (10 mL, 7 M) was added to a methanol solution of methyl 4-bromo-1-(2-oxopropyl)-1H-pyrrole-2-carboxylate (2.5 g, 0.001 mol). The mixture was sealed in an autoclave and stirred at 120 °C for 16 hours. The mixture was concentrated, and the residue was purified by ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a yellow solid (0.5 g, two-step yield 22.0%). MS (m/z): 227.0/229.0 (M+H) ⁺

Intermediate 48

1-(trifluoromethyl)cyclobutane-1-carbonylhydrazine

(A) 1-(trifluoromethyl)cyclobutane-1-carbazide

Concentrated sulfuric acid (0.75 mL) was added to a methanol (30 mL) solution of 1-(trifluoromethyl)cyclobutane-1-carboxylic acid (20 g, 119 mmol). The mixture was refluxed overnight. Hydrazine hydrate (85%, 30 mL) was added. The mixture was refluxed again overnight. 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 (19 g, 68% yield). MS (m/z): 183.0 (M+H) ⁺

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

Intermediate 54

1-(trifluoromethyl)cyclopropane-1-carbonylhydrazine

(A) 1-(trifluoromethyl)cyclopropane-1-carbazide

To a solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (5.0 g, 0.033 mol), tert-butyl hydrazide (5.5 g, 0.033 mol), and DCM (50 mL), EDCI (6.3 g, 0.033 mol), HOBT (4.4 g, 0.033 mol), and _Et3N (6.6 g, 0.066 mol) were added. The resulting mixture was stirred at room temperature for 16 hours and then washed with saturated sodium bicarbonate solution and water. The organic layer was concentrated under vacuum. The residue was dissolved in THF (80 mL) and concentrated hydrochloric acid (10 mL) was added. The resulting mixture was stirred at room temperature overnight. The mixture was then concentrated to give the title compound as a crude yellow solid (5.0 g). MS (m/z): 169.1 (M+H) ⁺

Intermediate 55

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

(A) Isopropyl 1-formyl-3,3-dimethoxycyclobutane-1-carboxylic acid

At -78 °C, DIBAL-H (35 mL, 35.0 mmol) was slowly added to a mixture of 3,3-dimethoxycyclobutane-1,1-dicarboxylic acid diisopropyl ester (5.0 g, 17.34 mmol) in DCM (50 mL). The mixture was stirred at -78 °C under a nitrogen atmosphere for 0.5 h. 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 with ISCO (eluting with PE containing 0%–100% EA) to give the title compound as a colorless oil (1.83 g, yield 45.8%). ¹ H NMR (400MHz, CDCl ₃ ) δ 9.67 (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) Isopropyl 1-formyl-3-oxocyclobutane-1-carboxylic acid

A mixture of 1-formyl-3,3-dimethoxycyclobutane-1-carboxylic acid isopropyl ester (1.83 g, 7.95 mmol) in 6N HCl (10 mL, 60 mmol) 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) Isopropyl 1-(difluoromethyl)-3,3-difluorocyclobutane-1-carboxylate

At 0 °C, diethylaminosulfur trifluoride (4.46 g, 27.27 mmol) was slowly added to a mixture of 0.95 g of 1-formyl-3-oxocyclobutane-1-carboxylic acid isopropyl ester in DCM (5 mL). The mixture was stirred at room temperature under a 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 (400 MHz, _CDCl₃ ) δ 6.15 (t, J = 56.2 Hz, 1H), 5.15–5.07 (m, 1H), 3.01–2.90 (m, 4H), 1.28 (d, J = 6.3 Hz, 6H).

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

Hydrazine hydrate (85%, 3 mL) was added to a mixture of 1-(difluoromethyl)-3,3-difluorocyclobutane-1-carboxylic acid isopropyl ester (1.20 g) in MeOH (10 mL). The mixture was stirred overnight at 75 °C under a nitrogen atmosphere. Methanol was then removed, and the residue was 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 using the appropriate intermediates and reagents according to the procedure for intermediate 55, under conditions deemed suitable by those skilled in the art.

Example 1: Synthesis of Compounds 1-35

Compound 1

4-(3-(2-fluorophenylethyl)-6,7-dihydro-5℃-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diaza-10-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine

(A)8-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diaza-1-one

A mixture of 8-bromo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diaza-1-one (6 g, 26.19 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborhexacyclopentane) (11.97 g, 47.15 mmol), _Pd₂ (dba) _₃ (2.4 g, 2.62 mmol), tricyclohexylphosphine (1.47 g, 5.24 mmol), and KOAc (7.71 g, 78.58 mmol) in 1,4-dioxane (120 mL) was stirred at 100 °C under a nitrogen atmosphere for 16 hours. The mixture was filtered, the filtrate was diluted with EA (200 mL), and washed with water (100 mL) and brine (100 mL). The collected organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a white solid (3.55 g, 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-1-one

To a mixture of 8-(4,4,5,5-tetramethyl-1,3,2-dioxabortiacyclopentan-2-yl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diaza-1-one (17.76 g, 64.32 mmol) and 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (13.50 g, 64.40 mmol) in 1,4-dioxane/water (380 mL/70 mL), Pd(dppf) _{Cl₂.CH₂Cl₂} (2.63 g, 3.22 _mmol ) and cesium _carbonate (52.40 g, 160.82 mmol) were added. The mixture was then stirred at 90 °C for 2 hours under a nitrogen atmosphere. The mixture was filtered, 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%–100% methanol) to give the title compound as a yellow solid (16.6 g, 79.8% yield). MS (m/z): 324.1 (M+H) ⁺

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

A suspension of 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-1-one (8.00 g, 24.74 mmol) in _POCl3 (80 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was concentrated, and the residue was poured into a 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 (50 mL) and hydrazine hydrate (50 mL, 85%) was added. The mixture was then refluxed overnight under a nitrogen atmosphere. The mixture was filtered, and the filter cake was washed with THF. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give a brown solid (3.75 g, 44.7% yield). MS(m/z): 338.1(M+H) ⁺

(D)4-(3-(2-fluorophenylethyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diaza-10-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine

To a solution of 4-(1-hydrazino-4,5-dihydro-3H-pyrrolo[1,2-a][1,4]diaza-8-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (100 mg, 0.30 mmol) and 3-(2-fluorophenyl)propionic acid (60 mg, 0.35 mmol) in 5 mL of LCM, HATU (113 mg, 0.30 mmol) and Et ₃ N (58 mg, 0.58 mmol) were added. The mixture was stirred at room temperature for 1 hour. Volatiles were removed under reduced pressure, and the residue was dissolved in 5 mL of 1,4-dioxane and stirred at 60 °C for 1 hour. The mixture was concentrated and purified by ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a white solid (66.6 mg, 47.1% yield). MS (m/z): 470.3 (M+H) ⁺ . ¹ H 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 using the appropriate intermediates and reagents in accordance with the procedure for compound 1, under conditions deemed suitable 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-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-10-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine

At 0 °C, DIPEA (287 mg, 2.22 mmol) and 2-chloroacetyl chloride (201 mg, 1.78 mmol) were slowly added to a solution of 4-(1-hydrazino-4,5-dihydro-3H-pyrrolo[1,2-a][1,4]diaza-8-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (500 mg, 1.48 mmol) in DCM (50 mL). The mixture was then stirred overnight at room temperature and refluxed for 3 hours. The mixture was diluted with THF (100 mL) 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 (587 mg), which was used directly for 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-10-yl)pyrimidin-2-amine

Cesium carbonate (151 mg, 0.46 mmol) and phenol (34.9 mg, 0.37 mmol) were added to a solution of 4-(3-(chloromethyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diaza-10-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (73.4 mg, 0.19 mmol) in DMF (5 mL). The resulting mixture was stirred at 60 °C for 1 hour. After cooling, the reaction mixture was purified directly by ISCO (eluting with water containing 0%–100% methanol) and PTLC (DCM:MeOH = 12:1) to give the title compound as a pale yellow solid (19.1 mg, yield 22.7%). MS(m/z)：396.2(M+H) ⁺ . ¹ H 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 using the appropriate intermediates and reagents in accordance with the procedure for compound 36, under conditions deemed suitable 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

At 0 °C, NaiH (6 g, 150 mmol, 60% dispersed in liquid paraffin) was added to a solution of 7-bromopyrrolo[1,2-a]pyrazin-1(2H)-one (21.3 g, 100 mmol) in anhydrous DMF (100 mL). The mixture was stirred at 0 °C for 0.5 h, and then 2-(trimethylsilyl)ethoxymethyl chloride (21.6 g, 130 mmol) was added. The mixture was stirred overnight at room temperature, 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 (16 g, 47% yield). MS (m/z): 342.9/344.9 (M+H) ⁺

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

A mixture of 7-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[1,2-a]pyrazin-1(2H)-one (8.5 g, 24.8 mmol), BPIN (9.44 g, 37.2 mmol), _Pd2 (dba) ₃ (0.68 g, 7.44 mmol), KOAc (4.86 g, 49.6 mmol), and tricyclohexylphosphine (0.417 g, 1.488 mmol) in 1,4-dioxane (120 mL) was stirred at 100 °C for 4 hours under nitrogen atmosphere. 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 as a yellow solid (8.1 g, 84% yield). 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

A mixture of 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (627 mg, 3 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[1,2-a]pyrazine-1(2H)-7 (1170 mg, 3 mmol), Pd(dppf) _{Cl₂.CH₂Cl₂} ( ₁₂₂ mg, 0.15 mmol) _, and sodium carbonate (636 mg, 3 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was stirred at 100 °C for 3 hours under a nitrogen atmosphere. 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 (800 mg, 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 A solution of 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 (800 mg, 1.8 mmol) in TFA (3 mL) was stirred at room temperature for 0.5 h. Volatiles were removed under reduced pressure, and ammonium hydroxide was added. The mixture was filtered, the filter cake was washed with water, and dried to give 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

A mixture of 7-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one (93 mg, 0.3 mmol) in _POCl3 (2 mL) was stirred at 100 °C for 1 hour. Volatiles were removed under reduced pressure, and the pH was adjusted to 8 with aqueous sodium bicarbonate solution. The aqueous layer was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in EtOH (5 mL), and (S)-2-(2-fluorophenoxy)propylhydrazine (59 mg, 0.3 mmol) was added. The resulting mixture was refluxed overnight. Volatiles were removed under reduced pressure, and the residue was purified with ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a yellow solid (85 mg, 60% yield). MS(m/z): 470.1(M+H) ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ 8.31 (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 using the appropriate intermediates and reagents in accordance with the procedure for compound 39, under conditions deemed suitable 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

Hydrazine hydrate (2 mL, 85%) was added to a solution of 4-(1-chloropyrrolo[1,2-a]pyrazin-7-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (130 mg, 0.4 mmol) in THF (5 mL), and the mixture was heated at 80°C 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 (5 mL), and 1-fluoro-2-isocyanatobenzene (70 mg, 0.51 mmol) and _POCl3 (3 mL) were added. The resulting mixture was heated at 60°C for 3 hours. Volatiles were removed under reduced pressure, and the residue was adjusted to pH 8 with an aqueous sodium bicarbonate solution. 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%–100% methanol) to give the title compound as a yellow solid (15 mg, 10% yield). MS (m/z): 441.1 (M+H) ⁺ . ¹ H 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 using the appropriate intermediates and reagents in accordance with the procedure for compound 41, under conditions deemed suitable 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-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-8-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2)amine

The title compound was prepared using the appropriate intermediates and reagents according to the procedure in Example 1.

(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-10-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine

A mixture of 4-(1-chloro-4,4-dimethyl-4,5-dihydro-3H-pyrrolo[1,2-a][1,4]diaza-8-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (111 mg, 0.3 mmol) and (S)-2-(2-fluorophenoxy)propanehydrazine (59 mg, 0.3 mmol) in ethanol (10 mL) was refluxed overnight. The mixture was concentrated, and the residue was purified by ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a yellow solid (40 mg, 26% yield). MS (m/z): 514.2 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃₎ OD) 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), 3.9 2(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 using the appropriate intermediates and reagents in accordance with the procedure for compound 44, under conditions deemed suitable by those skilled in the art.

Example 6: Synthesis of compounds 53-54

Compound 53

5-Chloro-4-(3-(dihydroindol-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diaza-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-8-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine

The title compound was prepared using the appropriate intermediates and reagents according to the procedure in Example 1.

(B) Dihydroindole-1-carbazide

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

(C)5-Chloro-4-(3-(dihydroindol-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diaza-10-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine

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

¹ H 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 using the appropriate intermediates and reagents in accordance with the procedure for compound 53, under conditions deemed suitable by those skilled in the art.

Example 7: Synthesis of Compound 55-210

Compound 55

5-Chloro-N-(1-Methyl-1H-pyrazole-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]-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][1,4]diaza]-1′-one

The title compound was prepared using the appropriate intermediates and reagents according to the procedure in Example 1.

(B) 5-Chloro-N-(1-Methyl-1H-pyrazole-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]-10′-yl)pyridin-2-amine

A mixture of 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][1,4]diaza]-1′-one (55 mg, 0.14 mmol) and 1-(trifluoromethyl)cyclobutane-1-carbazide (25 mg, 0.14 mmol) in POCl3 (3 mL) was stirred at 100 °C for 30 min. 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 (3 mL) and acetic acid (2 drops), and the resulting mixture was stirred in a microwave at 100 °C for 1.5 h. The mixture was then concentrated and purified by ISCO (eluting with water containing 0%–100% methanol) and PTLC (DCM/MeOH = 15:1) to give the title compound as a yellow solid (20 mg, yield 27%). MS (m/z): 543.1 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6) δ 8.85 (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), 2.8 0-2.74(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 using the appropriate intermediates and reagents in accordance with the procedure for compound 55, under conditions deemed suitable by those skilled in the art.

Example 8: Synthesis of compounds 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-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-1-one

A mixture of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2,3,4,5 _- tetrahydro-1H-pyrrolo[1,2-a][1,4]diaza-1-one (2.70 g, 9.78 mmol), Pd(dppf) _{Cl₂.CH₂Cl₂} (799 _mg , 0.98 mmol), 2,4,5-trichloropyrimidine (1.97 g, 10.76 mmol), and cesium carbonate (9.56 g, 29.33 mmol) in 1,4-dioxane/water (120 mL/30 mL) was degassed and then stirred at 80 °C for 3 hours under a nitrogen atmosphere. The mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was suspended in EA and stirred for 30 minutes, then filtered. The filter cake was 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-1-one

A mixture of 8-(2,5-dichloropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diaza-1-one (2.80 g, 9.46 mmol), 1-methyl-1H-pyrazole-5-amine (4.59 g, 47.28 mmol), _Pd₂ (dba) _₃ (0.87 g, 0.95 mmol), Xantphos (1.09 g, 1.89 mmol), and cesium carbonate (9.24 g, 28.36 mmol) in 1,4-dioxane (140 mL) was degassed and stirred at 100 °C 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 (eluting with a gradient of water containing 0%–100% methanol) to give the title compound as a yellow solid (1.52 g, 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-10-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine

The title compound was prepared using the appropriate intermediates and reagents according to the procedure in Example 1. MS (m/z): 506.2 (M+H) ⁺

¹ H 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 using the appropriate intermediates and reagents in accordance with the procedure for compound 211, under conditions deemed suitable by those skilled in the art.

Example 9: Synthesis of compounds 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-6-ol

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

To a solution of (R)-8-bromo-4-hydroxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diaza-1-one (1.5 g, 6 mmol) and _Ac₂O (0.7 g, 0.006 mol) in THF (50 mL), _Et₃N (1.3 g, 0.012 mol) and N,N-dimethylpyridinium-amine (40 mg, 0.300 mmol) were added. After stirring at 50 °C 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 (1.5 g, yield 88.2%). MS (m/z): 287.0/289.0 (M+H) ⁺

(B)(R)-Acetate-1-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diaza-4-yl ester

Under a nitrogen atmosphere, a mixture of (R)-acetic acid 8-bromo-1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diaza-4-yl ester (200 mg, 0.669 mmol), _Pd₂ (dba) _₃ (32 mg, 0.035 mmol), tricyclohexylphosphine (10 mg, 0.035 mmol), BPIN (178 mg, 0.669 mmol), and KOAc (137 mg, 1.398 mmol) in 1,4-dioxane (10 mL) was stirred at 100 °C for 16 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a white solid (150 mg, 64.2% yield). 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-1-one

Under a nitrogen atmosphere, a mixture of (R)-acetic acid 1-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxabortiacyclopentan-2-yl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diaza-4-yl ester (150 _mg , 0.449 mmol), Pd(dppf) _{Cl₂.CH₂Cl₂} ( ₁₆ mg, 0.023 mmol), _Na₂CO₃ (95 mg, 0.898 mmol), and 5-chloro- ₄ -iodo-N-(1-methyl-1H-pyrazol-5-yl)pyridine-2-amine (150 mg, 0.449 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 80 °C 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%–100% methanol) to give the title compound as a white solid (100 mg, 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-6-ol

A mixture of (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-1-one (100 mg, 0.269 mmol) and 1-(trifluoromethyl)cyclobutane-1-carbazide (49 mg, 0.269 mmol) in _POCl3 (5 mL) was stirred at 80 °C for 2 h. 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 was dissolved in NMP (5 mL). One drop of HOAc was added, and the mixture was stirred in a microwave at 130 °C for 30 min. The reaction mixture was then purified directly with ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a pale yellow solid (20 mg, yield 14.4%). MS(m/z)：519.0(M+H) ⁺¹ H 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 using the appropriate intermediates and reagents in accordance with the procedure for compound 215, under conditions deemed suitable by those skilled in the art.

Example 10: Synthesis of compounds 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-3-yl)methyl)-1H-pyrrolo-2-carboxynitrile

(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-1-one

The title compound was prepared using the appropriate intermediates and reagents according to the procedure in Example 1.

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

Under a nitrogen atmosphere at 5 °C, NaH (1.5 g, 36 mmol, 60% dispersed in liquid paraffin) was added dropwise to a solution of ethyl 2-hydroxyacetate (3.1 g, 30 mmol) in anhydrous DMF (50 mL). The mixture was stirred for 1 hour. 1-(chloromethyl)-4-methoxybenzene (5.6 g, 36 mmol) was added dropwise, and the mixture was stirred at room temperature for 12 hours. The reaction was quenched with saturated ammonium chloride solution, followed by vacuum concentration. The residue was purified by silica gel chromatography (PE:EA = 4:1) to give a yellow oil. This oil was dissolved in ethanol (100 mL), and hydrazine hydrate (4.5 g, 85%) was added. The solution was refluxed for 2 hours. The solvent was removed by rotary evaporation, and the residue was purified by ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a yellow oil (3.7 g, 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-10-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine

Under a nitrogen atmosphere, a mixture of 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-1-one (784 mg, 2 mmol) and 2-((4-methoxybenzyl)oxy)acetylhydrazine (841 mg, 4 mmol) in _POCl3 (10 mL) was stirred at 100 °C for 2 hours. The solvent was removed by rotary evaporation, and the residue was dissolved in DCM and washed with a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with DCM. The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under vacuum. The residue was dissolved in a solution of acetic acid (2 drops) in n-butanol (20 mL). The solution was stirred at 130 °C for 2 hours and then concentrated under vacuum. The residue was purified by ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a yellow solid (380 mg, 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-3-yl)methyl)-1H-pyrrolo-2-carboxynitrile

Under a nitrogen atmosphere, a mixture of 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-10-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (80 mg, 0.17 mmol), 1H-pyrrolo-2-carboxynitrile (19 mg, 0.21 mmol), and cesium carbonate (166 mg, 0.51 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature. The reaction was quenched with dilute aqueous hydrochloric acid and then neutralized to pH 8 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with DCM/MeOH (10:1). The organic phases were combined and then concentrated under vacuum. The residue was purified by ISCO (eluting with water containing 0%–100% methanol) and PTLC (DCM/MeOH = 10:1) to give the title compound as a pale yellow solid (19.1 mg, 22% yield). MS (m/z): 521.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d6) δ 8.87 (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 using the appropriate intermediates and reagents in accordance with the procedure for compound 217, under conditions deemed suitable by those skilled in the art.

Example 11: Synthesis of compounds 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) Methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-carboxylate

To a solution of methyl 1H _- imidazolium-2-carboxylate (10 g, 79.3 mmol) and _K₂CO₃ in acetone (300 mL), (2-(chloromethoxy)ethyl)trimethylsilane (14.3 g, 85.6 mmol) was added. 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 (11.9 g, yield 58.5%). MS (m/z): 257.0 (M+H) ^⁺ .

(B) Methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazol-2-carboxylate

Anhydrous THF (110 mL) was added to a mixture of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-carboxylate (16.6 g, 64.7 mmol), BPIN (32.8 g, 129.2 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (2.2 g, 3.3 mmol), and 3,4,7,8-tetramethyl-1,10-phenanthroline (1.5 g, 6.5 mmol). The resulting mixture was purged with nitrogen three times. The mixture was then refluxed under a nitrogen atmosphere. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in DMF (400 mL), and Pd(PPh3) ₄ (3.8 _g , 3.3 mmol), CuI (1.3 g, 6.5 mmol), _Cs2CO3 (15.8 g, 97.0 mmol), and 2,4-dichloro-5-methylpyrimidine (15.8 g, 97.0 mmol) were added. The resulting mixture was purged with nitrogen three times. The mixture was then stirred overnight at 90 °C under a nitrogen atmosphere. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in TFA (100 mL) and refluxed for 2 hours. To remove volatiles, the residue was neutralized with saturated sodium bicarbonate solution and then 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 a grayish-white solid (15.2 g, 92.9% yield). MS(m/z): 253.0(M+H) ⁺ .

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

At 0 °C, DIAD (4.6 g, 20.0 mmol) was added dropwise to a solution of methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazolium-2-carboxylate (2.5 g, 9.9 mmol), (R)-(1-hydroxy-3-methoxypropane-2-yl)carbamate tert-butyl ester (2.3 g, 12.0 mmol), and PPh ₃ (5.3 g, 20.0 mmol) in anhydrous THF (100 mL). The resulting solution was stirred overnight at room temperature under a nitrogen atmosphere. 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 gel (2.5 g, 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)-1-(2-((tert-butoxycarbonyl)amino)-3-methoxypropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazolium-2-carboxylate (2.5 g, 5.7 mmol) and TFA (15 mL) in DCM (20 mL) was stirred at room temperature for 3 hours. The mixture was concentrated, and the residue was dissolved in MeOH (10 mL) and a methanol solution of ammonia (30 mL, 7 M) 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 (1.21 g, 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

At room temperature, 0.12 g of 1-methyl-1H-pyrazol-5-amine (1.24 mmol) in 10 mL of THF was added to NaHMDS (0.5 mL, 1.0 mmol, 2 M THF solution), and the resulting mixture was stirred for 20 min under a nitrogen atmosphere. (R)-2-(2-chloro-5-methylpyrimidin-4-yl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one (0.12 g, 0.39 mmol) was added, 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 (0.118 g, 82.1% yield). 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 using the appropriate intermediates and reagents according to the procedure in Example 7. MS (m/z): 553.0 (M+H) ⁺ .

¹ H 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), 6.3 0 (d, J=1.8Hz, 1H), 5.38-5.32 (m, 1H), 4.87 (d, J=14.0Hz, 1H), 4.69 (dd, J=1 4.0, 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 using the appropriate intermediates and reagents in accordance with the procedure for compound 220, under conditions deemed suitable by those skilled in the art.

Example 12: Synthesis of compounds 229-274 and 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-10-yl)pyridin-2-yl)amino)propane-1-ol

(A)10-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-H-hydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diaza

The title compound was prepared using the appropriate intermediates and reagents according to the procedure in Example 1. 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-10-yl)pyridin-2-yl)amino)propane-1-ol

A mixture of 10-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diaza (85 mg, 0.2 mmol), (S)-2-((5-chloro-4-iodopyridin-2-yl)amino)propane-1-ol (94 mg, 0.3 mmol), Pd( _PPh3 ) ₄ (23 mg, 0.02 mmol) and _Na2CO3 ( ₆₃ mg, 0.6 mmol) in 1,4-dioxane/water (10 mL, 4:1) was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The solvent was removed by rotary evaporation, and the residue was purified by ISCO (eluting with water containing 0%–100% methanol) and PTLC (DCM:MeOH = 10:1) to give the title compound as a pale yellow solid (39 mg, yield 41%). MS (m/z): 481.1 (M+H) ⁺ .

¹ H 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 using the appropriate intermediates and reagents in accordance with the procedure for compound 229, under conditions deemed suitable by those skilled in the art.

Example 13: Synthesis of compounds 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-10-yl)pyrimidin-2-yl)amino)propane-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

A mixture of 10-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diaza (2.0 g, 4.7 mmol), 2,4-dichloro-5-methylpyrimidine (620 _mg , 3.8 mmol), Pd(dppf) _Cl₂ · _CH₂Cl₂ (300 mg, 0.40 mmol), and sodium carbonate (1.0 g, 9.4 mmol) in 1,4-dioxane (40 mL) and water (8 mL) was stirred at 90 °C for 4 hours. The concentrated mixture was purified by ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a white solid (500 mg, 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-10-yl)pyrimidin-2-yl)amino)propane-1-ol

A mixture of 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 (50 mg, 0.12 mmol), (S)-2-aminopropane-1-ol (44 mg, 0.59 mmol), and DIPEA (76 mg, 0.59 mmol) in NMP (2 mL) was stirred in a microwave oven at 180 °C for 2.5 h. The resulting mixture was purified directly by ISCO (eluting with water containing 0%–100% methanol) and PTLC (DCM:MeOH = 15:1) to give the title compound as a white solid (8.0 mg, yield 14.7%). MS (m/z): 462.1 (M+H) ⁺

¹ H 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 using the appropriate intermediates and reagents in accordance with the procedure for compound 275, under conditions deemed suitable by those skilled in the art.

Example 14: Synthesis of compounds 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-10-yl)pyrimidin-2-amine

A mixture of 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 (30 mg, 0.07 mmol), 2-methylpyridin-4-amine (15 mg, 0.14 mmol), _Pd₂ (dba) _₃ (16 mg, 0.007 mmol), Xantphos (4.1 mg, 0.007 mmol), and _Cs₂CO₃ (69 _mg , 0.21 mmol) in 1,4-dioxane (2 mL) was microwaved at 50 °C for 30 min. The mixture was concentrated and partitioned between water (10 mL) and DCM (10 mL). The aqueous layer was extracted with DCM (10 mL × 2). The combined organic layers were concentrated and purified by PTLC (DCM:MeOH = 15:1) to give the title compound as a white solid (8.5 mg, yield 24.2%). MS (m/z): 495.1 (M+H) ⁺

¹ H 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, 3 H), 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 using the appropriate intermediates and reagents in accordance with the procedure for compound 281, under conditions deemed suitable 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-6-yl)methanol

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

At 0 °C, NaH (3.43 g, 85.7 mmol, 60% dispersed in liquid paraffin) was slowly added to a DMF (100 mL) solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (5.0 g, 24.5 mmol). The reaction mixture was stirred for 0.5 h, and then 3-bromo-2-(bromomethyl)propionic acid was added. The reaction was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was then quenched with saturated ammonium chloride solution, and the pH was adjusted to <4 with dilute HCl. The mixture was extracted with EA. The organic layer was washed with brine, dried, and concentrated. Ammonium hydroxide (50 mL) was added to the residue, and the resulting mixture was stirred overnight at 100 °C. The mixture was concentrated and purified by ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a yellow solid (1.30 g, 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-1-one

At 0 °C, _BH₃ · _Me₂S (4.5 mL, 9.0 mmol) was added to a mixture of 8-bromo-1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diaza-4-carboxylic acid (800 mg, 2.93 mmol) in THF (10 mL). The reaction was stirred at 50 °C under a nitrogen atmosphere for 3 hours. The reaction was then quenched with methanol, concentrated, and purified with ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a yellow solid (250 mg, 32.8% yield). 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-6-yl)methyl ester

At 0 °C, Et _3N (194.3 mg, 1.92 mmol), AC 2O (148 mg, 1.44 mmol), and N,N-dimethylpyridin-4-amine (12 mg, 0.096 mmol) were added to a mixture of 8-bromo-4-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diaza- ₁ -one (250 mg, 0.96 mmol) in DCM (10 mL). The reaction was stirred at room temperature under a 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 mixed with 1-(trifluoromethyl)cyclobutane-1-carbonylhydrazine (210 mg, 1.15 mmol) and POCl 3 (5 mL). The resulting mixture was stirred at 70 °C for 2 hours. After removing volatiles, 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 (5 mL) and two drops of HOAc. The resulting mixture was stirred in a microwave at 130 °C for 0.5 h. The reaction mixture was then purified directly with ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a yellow solid (220 mg, yield 51.0%). MS (m/z): 447.0/449.0 (M+H) ⁺

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

Under a nitrogen atmosphere, a mixture of 10-bromo-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diaza-6-yl)methyl ester (80 mg, 0.18 mmol) and BPIN (91 mg, 0.36 mmol), _Pd₂ (dba) _₃ (116 mg, 0.018 mmol), tricyclohexylphosphine (10 mg, 0.036 mmol), and potassium acetate (53 mg, 0.54 mmol) in 1,4-dioxane (8 mL) was stirred at 100 °C for 5 hours. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried, concentrated under vacuum, and purified with ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a white solid (10 mg, 11.1% yield). 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-6-yl)methanol

Under a nitrogen atmosphere, a mixture of acetic acid (10-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diaza-6-yl) methyl ester (10 mg, 0.02 mmol), 5-chloro-4-iodo-N-(1-methyl-1H-pyrazol-5-yl)pyridine-2-amine (9 mg, 0.024 mmol), Pd(dppf) _Cl₂ · _CH₂Cl₂ (2 mg, 0.002 mmol), and sodium carbonate (6.4 _mg , 0.06 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was degassed and stirred at 80 °C for 1 hour. The mixture was then concentrated, and the residue was purified by ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a pale yellow solid (3.0 mg, yield 28.0%). MS (m/z): 533.0 (M+H) ⁺

¹ H 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 Compounds 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-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

A mixture of 140 mg (0.31 mmol) of 10-bromo-3-(1-(trifluoromethyl)cyclobutyl)-6,7-dihydro-5H-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diaza-6-yl)methyl ester of acetic acid and sodium carbonate (99 mg, 0.93 mmol) in THF (3 mL) and water (3 mL) 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 (10 mL) and cooled to 0 °C. NaH (20 mg, 0.50 mmol, 60% dispersed in liquid paraffin) was added, and the mixture was stirred for another 20 min. Iodomethane was added, and the reaction was stirred at room temperature for 0.5 h. The reaction was quenched with saturated ammonium chloride solution and extracted with DCM. The concentrated organic layer was purified by ISCO (eluting with water containing 0%–100% methanol) to give the title compound as a white solid (110 mg, 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-10-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine

The title compound was prepared using the appropriate intermediates and reagents according to the procedure in Example 15. MS (m/z): 547.1 (M+H) ⁺

¹ H 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 using the appropriate intermediates and reagents in accordance with the procedure for compound 300, under conditions deemed suitable by those skilled in the art.

Example 17: Synthesis of compounds 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[oxacyclobutane-3,6′-pyrrolo[1,2-a][1,2,4]triazolo[3,4-c][1,4]diaza]-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]triazolo[3,4-c][1,4]diaza]

To a solution of 8′-bromo-2′,3′-dihydro-1′H,5′H-spiro[oxacyclobutane-3,4′-pyrrolo[1,2-a][1,4]diaza]-1′-one (400 mg, 1.48 mmol) in DCM (30 mL), _CF₃SO₃Me ( ₂₉₁ mg, 1.77 mmol) was added, and the mixture was stirred overnight at reflux under a nitrogen atmosphere. 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 isoalkyl-2-ol (20 mL), and 2,2,3,3-tetrafluoropropionylhydrazine (283 mg, 1.77 mmol) and HOAc (2 drops) were added. The mixture was then purged with nitrogen and stirred at 70 °C for 3 hours, followed by stirring at 90 °C for 3 hours. The mixture was concentrated, and the residue was purified by ISCO (eluting with water containing 0%–100% methanol) to give a grayish-white solid (203 mg, yield 34.7%). MS (m/z): 394.9/396.9 (M+H) ⁺

(B) 5-Chloro-N-(1-methyl-1H-pyrazole-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]-10′-yl)pyridin-2-amine

The title compound was prepared using the appropriate intermediates and reagents according to the procedure in Example 15. MS (m/z): 523.0 (M+H) ⁺

¹ H 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 using the appropriate intermediates and reagents in accordance with the procedure for compound 304, under conditions deemed suitable by those skilled in the art.

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

Example 18: Z-lyte kinase assay for ERK2

1. Materials and reagents:

2. Reaction steps:

Orifice plate layout diagram

3. Solution preparation

1) 1.33X Kinase Buffer: Dilute 5X kinase buffer to 1.33X with _ddH2O .

2) 4X Dilution of Test Compounds: Dilute the test compound series to 4 times the required concentration while maintaining the DMSO concentration at 8%. The final concentrations are 1, 0.33, 0.11, 0.037, 0.012, 0.004, 0.0014, and 0.00046 μM, with a final DMSO concentration of 2%.

3) Kinase/peptide mixture (P/K solution): The kinase/peptide mixture was prepared by diluting the kinase and Z-LYTE ^™ Ser/Thr3 peptide to 0.6 μg/mL and 4 μM, respectively, in 1.33X kinase buffer. The mixture was then gently mixed by pipetting.

4) Phosphopeptide solution (PP solution): Add 0.4 μl of Z-LYTE ^™ Ser/Thr3 phosphopeptide to 99.6 μl of 1.33X kinase buffer.

5) ATP solution: ATP solution is prepared by diluting 10 mM ATP to 100 μM with 1.33X kinase buffer.

6) Developer solution: Dilute developer A with developer buffer at a ratio of 1:1024.

4. Reaction

1) Kinase reaction (10 μl volume)

a. In a 384 plate, add 2.5 μl of the test compound (4X) to each well except for wells C1, C2, and C3. Add 2.5 μl of 8% DMSO to wells C1, C2, and C3.

b. Place the board on the ice.

c. Add 5 μL of P/K mixture to each well of the test compound and wells C1 and C2.

d. Add 5 μl of PP solution to well C3.

e. Add 2.5 μl of 1.33X kinase buffer to wells C1 and C3.

f. Add 2.5 μl of 4X ATP solution to each well of the tested compound and to well C2. Shake the plate for 30 seconds and centrifuge (1500 rpm, 1 minute).

g. Seal the plate in a dark place and incubate it at room temperature (25-30℃) for 1 hour.

2) Development reaction

a. Add 5 μl of developing solution to all wells.

b. Shake the plate for 30 seconds and centrifuge (1500 rpm, 1 minute).

c. Seal the plate in a dark place and incubate it at room temperature (25-30℃) for 1 hour.

3) Termination and plate reading

a. Add 5 μl of stop reagent to all wells.

b. Shake the plate for 30 seconds and centrifuge (1500 rpm, 1 minute).

c. Measure the coumarin value (excitation wavelength 400 nm, emission wavelength 445 nm) and the fluorescein value (excitation wavelength 400 nm, emission wavelength 520 nm) respectively.

5. Data Analysis

Emittance ratio (ER) = Coumarin emission reading (445nm) / 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 - % phosphorylated _{test compound} / % phosphorylated _C2

6. IC ₅₀ Value: Determine the IC ₅₀ using XL-Fit ^™ (version 2.0), the software bundled with Microsoft Excel from ID Business Solutions (Guildford, UK).

Example 19: p-RSK(Thr359) Acumen assay in COLO205

1. Cell lines

colo205 (SIBS)

2. Materials and Reagents

Phospho-p90RSK(Thr359)(D1E9) rabbit monoclonal antibody: 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 plate (black, clear back): BD, #354640

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

3. Acumen assay protocol

Cells were seeded in 100 μl of 10% FBS at a density of 4000 cells/well in 96-well plates and incubated overnight at 37°C and 5% _CO2 .

• Dilute the compound to 3, 1, 0.33, 0.11, 0.037, 0.012, 0.004, and 0.001 μM, maintaining the DMSO concentration at 5%. Add 10 μL of the diluted compound to each _well and incubate at 37°C and 5% CO2 for 1 hour.

Add 100 μL of 4% preheated paraformaldehyde (final concentration 2%) and incubate at room temperature for 45 minutes.

Remove the paraformaldehyde solution. Add 100 μL of ice-cold 0.1% Triton to fix the cells at room temperature for 30 minutes.

Wash twice with 150 μL PBS, incubate with 100 μL blocking buffer (1% BSA in PBS) at room temperature for 2-3 hours, and then seal the plate.

Wash once with 150 μL PBS, incubate overnight at 4°C with 35 μL p-RSK(Thr359) (1:1000 dilution), and seal the plate.

• Wash twice with PBS, then incubate with 35 μl of Alexa488 donkey anti-rabbit IgG diluted 1:1000 in antibody dilution buffer (PBS solution of 1% BSA) at room temperature for 1.5 hours. Cover the plate with aluminum foil to protect it from light.

• Wash twice with 150 μL PBS. Add 35 μL of 1.5 μM propidium iodide stock solution to each well to determine the cell count, and then seal the plate.

Incubate at room temperature for 30 minutes. Place the plate in Acumen Explorer and scan using the appropriate instrument settings.

4. Data Analysis

in:

.Percentage (compound well) indicates the percentage of positive cells treated with the compound.

The percentage (minimum well) represents the percentage of positive cells treated with 3 μM GDC0994.

• Percentage _{(maximum well)} represents the percentage of positive cells not treated with the compound.

5. IC ₅₀ Value: Determine the IC ₅₀ using XL-Fit ^™ (version 2.0), the software bundled with Microsoft Excel from ID Business Solutions (Guildford, UK).

result:

Note: A≤5; 5＜B≤10; C＞10; D≤100; E＞100.

Claims (27)

1. Compounds of formula (I-3): Or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer or diastereomer of a compound of formula (I-3) or a pharmaceutically acceptable salt thereof, wherein _R1 is selected from: (1) _C1-6 alkyl, (2) -( _C1-6 alkyl)-OH, (3) saturated monocyclic _C3-8 cyclic hydrocarbon group, which is optionally substituted by one or more substituents independently selected from halogen and _C1-6 alkoxy, (4) saturated monocyclic 6-membered heterocyclic group containing one or two cyclic heteroatoms independently selected from N, O and S, and (5) heteroaryl group, which is selected from pyrazolyl, pyridinyl and isoxazolyl, each of which is optionally substituted by one or more substituents independently selected from: _C1-6 alkoxy, _C1-6 haloalkyl and _C1-6 alkyl group optionally substituted by one or more deuterium; Ar is a heteroaryl group selected from pyridinyl and pyrimidinyl, each of which is optionally substituted by one or more substituents independently selected from: halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy and _C1-6 haloalkyl optionally substituted by one or more deuterium groups; _R2 is selected from: (1)-CN, (2) _C1-6 haloalkyl, (3) saturated monocyclic _C3-8 cyclic hydrocarbon group, which is optionally substituted with one or more substituents selected from _C1-6 haloalkyl, (4) phenyl, which is optionally substituted with one or more substituents independently selected from the following: halogen and -CN, and (5) heteroaryl, which is selected from 1,2,5-oxadiazolyl, dihydroindolyl, 1,2,3,4-tetrahydroquinolinyl, pyrazolyl, indazolyl and pyrroliyl, each of which is optionally substituted with one or more substituents independently selected from the following: halogen, -CN and _C1-6 alkyl; _R3 , _R4 , _R5 , _R6 , _R7 , and _R8 are each independently selected from hydrogen, halogen, hydroxyl, _C1-6 alkyl, and _C1-6 alkoxy; wherein the _C1-6 alkyl is optionally substituted by one or more substituents independently selected from hydroxyl and _C1-6 alkoxy; or, any two of _R3 , _R4 , R5, _R6 , _R7 , _{and R8} together with the carbon atom attached to them and the B ring form _Rd selected from hydrogen and halogen, and t is 0, 1, 2, or 3; _R10 and _R11 are independently selected from hydrogen, halogens, and _C1-6 alkyl groups; m is 0, 1, or 2. _Ra and _Rb are each independently selected from hydrogen, halogen, hydroxyl, and _C1-6 alkyl; or, _Ra and _Rb together with the carbon atoms attached to them form a saturated monocyclic _C3-6 cyclic hydrocarbon group or a 3-6 membered heterocyclic group, wherein the 3-6 membered heterocyclic group is a saturated monocycle having 3-6 ring atoms, one or two of which are cyclic heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms; wherein the saturated monocyclic _C3-6 cyclic hydrocarbon group or the 3-6 membered heterocyclic group is optionally substituted by one or more substituents selected from halogens. L does not exist, or L is NH, O, or S. 2. A compound of formula (I-3) according to claim 1, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, or diastereomer of a compound of formula (I-3) or a pharmaceutically acceptable salt thereof, wherein _R1 is a heteroaryl group selected from pyrazolyl, pyridyl, and isoxazolyl, each of which is optionally substituted by one or more substituents independently selected from: _C1-6 alkoxy, _C1-6 haloalkyl, and _C1-6 alkyl optionally substituted with one or more deuterium groups. 3. The compound of formula (I-3) according to claim 2 or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer or diastereomer of the compound of formula (I-3) or a pharmaceutically acceptable salt thereof, wherein _R1 is a pyrazolyl group, which is optionally substituted by one or more substituents independently selected from: _C1-6 alkyl groups optionally substituted by one or more deuterium groups. 4. A compound of formula (I-3) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, or diastereomer of a compound of formula (I-3) or a pharmaceutically acceptable salt thereof, wherein Ar is: _R20 , _R21 , _R22 , _R23 and _R24 are each independently selected from hydrogen, halogen, -CN, _C1-6 alkyl, _C1-6 alkoxy and _C1-6 haloalkyl optionally substituted with one or more deuterium. 5. A compound of formula (I-3) according to claim 4, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, or diastereomer of a compound of formula (I-3) or a pharmaceutically acceptable salt thereof, wherein Ar is: _R20 , _R21 and _R22 are each independently selected from hydrogen, halogens and _C1-6 alkyl groups optionally substituted with one or more deuterium atoms. 6. A compound of formula (I-3) according to claim 4, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, or diastereomer of a compound of formula (I-3) or a pharmaceutically acceptable salt thereof, wherein Ar is: _R23 and _R24 are each independently selected from hydrogen, halogens, and _C1-6 alkyl groups optionally substituted with one or more deuterium atoms. 7. A compound of formula (I-3) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, or a racemic mixture, enantiomer or diastereomer of a compound of formula (I-3) or a pharmaceutically acceptable salt thereof, wherein _R2 is a _C1-6 haloalkyl group. 8. The compound of formula (I-3) according to claim 4 or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer or diastereomer of the compound of formula (I-3) or a pharmaceutically acceptable salt thereof, wherein _R2 is a _C1-6 haloalkyl group. 9. A compound of formula (I-3) according to claim 5 or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer or diastereomer of a compound of formula (I-3) or a pharmaceutically acceptable salt thereof, wherein _R2 is a _C1-6 haloalkyl group. 10. A compound of formula (I-3) according to claim 6 or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer or diastereomer of a compound of formula (I-3) or a pharmaceutically acceptable salt thereof, wherein _R2 is a _C1-6 haloalkyl group. 11. A compound of formula (I-3) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, or a racemic mixture, enantiomer or diastereomer of a compound of formula (I-3) or a pharmaceutically acceptable salt thereof, wherein _R3 , _R4 , _R5 , _R6 , _R7 and _R8 are each independently selected from hydrogen and halogen. 12. A compound of formula (I-3) according to any one of claims 1 to 3, or a racemic mixture, enantiomer or diastereomer of a compound of formula (I-3) or a pharmaceutically acceptable salt thereof, wherein m is 1. 13. A compound of formula (I-3) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, or a racemic mixture, enantiomer or diastereomer of a compound of formula (I-3) or a pharmaceutically acceptable salt thereof, wherein _Ra and _Rb are independently selected from hydrogen and halogen, respectively. 14. A compound of formula (I-3) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, or a racemic mixture, enantiomer or diastereomer of a compound of formula (I-3) or a pharmaceutically acceptable salt thereof, wherein _Ra , _Rb together with the carbon atoms to which they are attached form a saturated monocyclic _C3-6 cyclic hydrocarbon group or form an oxacyclobutane; wherein the saturated monocyclic _C3-6 cyclic hydrocarbon group is optionally substituted by one or more substituents selected from halogens. 15. A compound of formula (I-3) according to any one of claims 1 to 3, or a racemic mixture, enantiomer or diastereomer of a compound of formula (I-3) or a pharmaceutically acceptable salt thereof, wherein L is absent. 16. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 17. A pharmaceutical composition comprising a compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable carrier. 18. A method for in vitro inhibition of ERK activity for non-diagnostic and therapeutic purposes, comprising contacting an effective amount of the compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof with ERK. 19. Use of the compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of a disease that responds to inhibition of ERK. 20. The use according to claim 19, wherein the drug is used to treat cancer or an autoimmune disease. 21. The use according to claim 20, wherein the cancer is a solid tumor or a hematologic malignancy. 22. The use according to claim 21, wherein the cancer is selected from leukemia, lymphoma, colorectal cancer, melanoma, glioma, pancreatic cancer, breast cancer, lung cancer, thyroid cancer, or ovarian cancer. 23. The use according to claim 22, wherein the lung cancer is non-small cell lung cancer. 24. The use according to claim 22, wherein the thyroid cancer is papillary thyroid carcinoma. 25. A combination product comprising a compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent. 26. The combination product of claim 25, wherein the additional therapeutic agent is an antitumor therapeutic agent. 27. The combination product of claim 26, wherein the antitumor therapeutic agent is selected from radiotherapy agents, chemotherapy agents, immunotherapy agents, and targeted therapy agents.