WO2020108619A1

WO2020108619A1 - Mnk inhibitor

Info

Publication number: WO2020108619A1
Application number: PCT/CN2019/121976
Authority: WO
Inventors: 杨和平; 高大新
Original assignee: 上海迪诺医药科技有限公司
Priority date: 2018-11-30
Filing date: 2019-11-29
Publication date: 2020-06-04
Also published as: CN111253397A; CN111253397B

Abstract

Disclosed by the present invention is a novel MNK inhibitor having the structure shown in formula I or I'. The MNK inhibitor according to the present invention has a good effect in inhibiting MNK1 and/or MNK2 levels in vivo and in vitro. Furthermore, the MNK inhibitor according to the present invention may also effectively treat MNK1 and/or MNK2-mediated diseases such as a cancer.

Description

MNK inhibitor

This application requires a Chinese patent application CN201811454361.8 with an application date of November 30, 2018, a Chinese patent application CN201910018886.5 with an application date of January 9, 2019, and a Chinese patent application with an application date of January 30, 2019 CN201910089611.0, the application date is the priority of Chinese patent application CN201910270657.2 on April 4, 2019. This application cites the entire text of the aforementioned Chinese patent application.

Technical field

The present invention relates to a novel MNK inhibitor, its pharmaceutical composition and its use as a cancer therapeutic agent.

Background technique

MAP interacting kinases 1 and 2 (MNK1 and MNK2) are a class of serine/threonine protein kinases that can be activated by ERK or p38 and can phosphorylate eukaryotic initiation factor 4E (eIF4E) during protein synthesis and It is essential in the stability of cell function. eIF4E involves cap-dependent translation initiation. The eIF4E protein binds to the 5'cap structure of mRNA, which is necessary for cap-dependent translation initiation. Multiple evidences indicate that eIF4E exhibits a real carcinogenic effect in vivo. eIF4E is overexpressed in many types of human cancer and is related to the poor prognosis of tumor patients (Mamane Y, et al. Oncogene, 2004 23:3172-79; Graff JR, et al., Cancer Res, 2009 69: 3866 -73; Ruggero D, et al. Nat Med, 2004 10:484-6), including colon cancer and breast cancer (Chrestensen, CA, et al., J. Biol. Chem., 2007 282(7): 4243- 52), bladder cancer, lung cancer, prostate cancer (Tomlins, SA, et.al., Nat.Genet., 2007 39(1): 41-51), gastrointestinal cancer, head and neck cancer, Hodgkin's lymphoma, Neuroblastoma, glioma (Bredel, M., et.al, Cancer. Res., 2005 65(10): 4088-96), ovarian cancer (Hendrix, ND, et.al., Cancer Res., 2006 66 ( 3): 1354-62), pancreatic cancer (Lapointe, J., et al., Proc. Natl. Acad. Sci. USA, 2004, 101(3): 811-16), etc. Similarly, transgenic mice overexpressing eIF4E have greatly increased tumor incidence in multiple organs. Clinical results show that not only the overexpression of eIF4E contributes to tumor progression, even the hyperphosphorylation of eIF4E can also contribute to tumor progression. Increased phosphorylation of eIF4E has been observed in a variety of solid tumors and lymphomas and is associated with poor prognosis in patients, especially in non-small cell lung cancer. MNK1 is highly expressed in hematological malignancies (Worch J., et al., Oncogene, 2004 23:9162-72). Both MNK1 and MNK2 are up-regulated in solid tumors such as glioma and ovarian cancer.

The MNK/eIF4E axis is involved in pro-angiogenesis, anti-apoptotic expression, cell cycle and motor proteins, and phosphorylation of eIF4E at the Ser209 site promotes its carcinogenic potential (Topisirovic, I., et al., Cancer Res., 2004 64 (23): 8639-42), and MNK1/2 is the only kinase known to drive this process. Phosphorylation of eIF4E by MNK1/2 can promote the expression of a variety of oncogene proteins, including MCL-1 (Wendel, HG, et al., Genes Dev., 2007 21(24):3232-37), FGF2, c -Myc, VEGF, MMP3, CCL2, BIRC2, cyclin D1 (De Benedetti, A., et.al., Cell Biol., 1999, 31(1): 59-72), cyclin D3 (Graff, JR, et al., Cancer Res., 200868(3):631-34) and ODC. And it is necessary in the transformation process induced by Ras and c-Myc. Plays a key role in multiple intracellular signaling pathways. These include the rapamycin complex 1 (mTORC1) and ERK (classical MAP kinase) pathways. Both signaling pathways are often activated in cancer.

At present, there are several patent publications on MNK1 and/or MNK2 inhibitors, for example: WO2015/200481, WO2017/075394, WO2017/075412, WO2017/087808 disclose a series of isoindol-1-ones and 2,3- Dihydroimidazo[1,5-a]pyridine-1,5-dione compounds; WO2017/085484, WO2017/085483, WO2014/044691, WO2014/048894 disclose a series of thiazolopyrimidine and pyrrolopyrimidine compounds ; WO2015/050505, WO2013/147711 disclose a series of imidazopyridazine compounds.

Although the research on MNKs is continuously deepened, and some small molecular entities have entered the clinical research stage, there is no real MNK inhibitor that has entered the market. With the continuous in-depth study of the structure-activity relationship of MNK inhibitors, the present invention discloses a new type of MNK inhibitor has good MNK1 and MNK2 inhibitory effect.

Summary of the invention

The technical problem to be solved by the present invention is to provide a novel compound represented by formula I or I', its pharmaceutical composition and application. The compound of formula I or I'of the present invention has good MNK1 and/or MNK2 inhibition, and can effectively treat and/or alleviate various related diseases mediated by MNK1 and/or MNK2, such as cancer.

The present invention provides a compound represented by Formula I, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt;

Wherein, W ₁ and W ₂ are independently =O, =S, =NH, =N-OH or =NO (C _1-6 alkyl);

R is -NH-Cy or Cy;

R ₁ is H, -OH, -NH ₂ , R _A , -NH-R _A , -NH-C(O)-R _A or -OR _A ;

R ₂ is H, CN, deuterated C _1-4 alkyl or R _B ;

R ₃ is H, C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl; the R ₃ is unsubstituted or optionally substituted with 1 to 3 R ₉ at any position;

R ₄ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, 5-6 membered heteroaryl, C _3-8 cycloalkyl, 3 -8 membered heterocycloalkyl, C _6-10 aryl C _1-6 alkyl, 5-6 membered heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl C _1-6 alkyl or 3 -8 membered heterocycloalkyl C _1-6 alkyl; said R ₄ is unsubstituted or optionally substituted with 1 to 3 R ₉ at any position;

Each of R ₁ , R ₂ , R ₃ and R ₄ is an independent substituent, or

1) R ₁ and R ₃ are connected to each other to form a 3-10 membered heterocycloalkyl; the 3-10 membered heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 R ₉ at any position;

2) R ₂ and R ₃ are connected to each other to form a 3-10 membered heterocycloalkyl group; the 3-10 membered heterocycloalkyl group is unsubstituted or optionally substituted with 1 to 3 R ₉ at any position;

3) R ₃ and R ₄ together with the carbon atom to which they are connected together form C _3-10 cycloalkyl or 3-10 membered heterocycloalkyl; the C _3-10 cycloalkyl or 3-10 membered heterocycloalkyl Is unsubstituted, or optionally substituted with 1 to 3 R ₉ in any position; or

4) R ₂ and R ₃ are connected to each other to form a double bond with the α bond;

R ₅ and R _5a are independently hydrogen, halogen, cyano, C _1-4 alkyl, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy or C _1-4 alkylamino;

Cy is a 5-10 membered heteroaromatic ring; the Cy is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -CN, -NH ₂ , -NHOH, -OH, -R _C , -OR _C , -NHR _C , -NH-OR _C , -NHC(O)R _C , -C(O)R _C and -C(O)N(R _C ) ₂ substituents are substituted in any position;

Each R _{A is} independently C _1-8 alkyl, C _2-8 alkenyl or C _2-8 alkynyl; the R _A is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -OH , -NH ₂ , oxo, C _1-3 alkoxy and C _1-3 alkylamino substituents are substituted at any position;

Each R _{B is} independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C _3-8 cycloalkyl, 3-8 Member heterocycloalkyl, -(CH ₂ ) _n -phenyl, -(CH ₂ ) _n -(5-6 membered heteroaryl), -(CH ₂ ) _n -C _3-8 cycloalkyl or -( CH ₂ ) _n -(3-8 membered heterocycloalkyl); the R _B is unsubstituted or optionally substituted with 1 to 3 R ₉ at any position;

Each R _{C is} independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C _3-8 cycloalkyl, 3-8 Heterocyclic heterocyclic alkyl, -(CH ₂ ) _n -OC _1-6 alkyl, -(CH ₂ ) _n -phenyl, -(CH ₂ ) _n -(5-6 membered heteroaryl), -(CH ₂ ) _n -C _3-8 cycloalkyl, -(CH ₂ ) _n -(3-8 membered heterocycloalkyl) or -(3-8 membered heterocycloalkyl)-C _1-6 alkyl; Said R _C is unsubstituted, or optionally substituted with 1 to 3 R ₁₀ at any position;

Each R ₉ and each R ₁₀ are independently H, -CN, -NO ₂ , -SH, -NH ₂ , -OH, -C(O)OH, -NHC(O)R ^a , -NHS ( O) ₂ R ^a , -C(O)R ^a , halogen, oxo, ester, amide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{1- 4} alkoxy, C _1-4 alkylamino, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, -(CH ₂ ) _n -NH ₂ , -(CH ₂ ) _n -OH, -(CH ₂ ) _n -(C _1-4 alkylamino) or -(CH ₂ ) _n -(C _1-4 alkoxy);

Each R ^{a is} independently C _1-6 alkyl or C _2-6 alkenyl;

n is 1, 2, 3 or 4.

The present invention provides a compound represented by formula I', its isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts;

Among them, W ₂ is =O, =S, =NH, =N-OH or =NO (C _1-6 alkyl);

A ₁ is N or CR ₅ ;

A ₂ is N or CR _5a ;

A ₃ is N or CR _5b ;

R is -NH-Cy or Cy;

R ₁ is H, -OH, -NH ₂ , R _A , -NH-R _A , -NH-C(O)-R _A or -OR _A ;

R ₂ is H, CN, deuterated C _1-4 alkyl or R _B ;

Each of R ₁ , R ₂ , R ₃ and R ₄ is an independent substituent, or

R ₅ , R _5a and R _5b are independently hydrogen, halogen, cyano, C _1-4 alkyl, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy or C _1-4 alkyl Amino

Each R ^{a is} independently C _1-6 alkyl or C _2-6 alkenyl;

n is 1, 2, 3 or 4.

All embodiments described below in the formula I or I', and combinations of any embodiments are included in the scope of the structural formula of the present invention represented by the formula I or I'.

In some embodiments, the definition of certain groups in the compound of formula I, its isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts may be as follows, without The described group can be as described in any of the above schemes:

Among them, W ₁ is O; W ₂ is O;

R is -NH-Cy;

R ₁ is H, -OH, -NH ₂ , R _A , -NH-R _A , -NH-C(O)-R _A or -OR _A ;

R ₂ and R ₃ are connected to each other to form a 3-10 membered heterocycloalkyl group; the 3-10 membered heterocycloalkyl group is unsubstituted or optionally substituted with 1 to 3 R ₉ at any position;

R ₅ is hydrogen, halogen, cyano or C _1-4 alkyl;

R _5a is hydrogen;

Each R ₉ and each R ₁₀ are independently H, -CN, -NO ₂ , -SH, -NH ₂ , -OH, -C(O)OH, -NHC(O)R ^a , -NHS ( O) ₂ R ^a , -C(O)R ^a , halogen, oxo, ester, amide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{1- 4} alkoxy, C _1-4 alkylamino, halogenated C _1-4 alkyl or halogenated C _1-4 alkoxy;

Each R ^{a is} independently C _1-6 alkyl or C _2-6 alkenyl;

n is 1, 2, 3 or 4.

In some embodiments, each R ₉ and each R ₁₀ are independently H, -CN, -NO ₂ , -SH, -NH ₂ , -OH, -C(O)OH, -NHC(O) R ^a , -NHS(O) ₂ R ^a , halogen, oxo, ester, amide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkyl Oxy, C _1-4 alkylamino, halogenated C _1-4 alkyl or halogenated C _1-4 alkoxy.

In some embodiments, each R ₉ and each R ₁₀ are independently H, -CN, -NO ₂ , -SH, -NH ₂ , -OH, -C(O)OH, -NHC(O) R ^a , -NHS(O) ₂ R ^a , -C(O)R ^a , halogen, oxo, ester, amide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 Alkynyl, C _1-4 alkoxy, C _1-4 alkylamino, halogenated C _1-4 alkyl or halogenated C _1-4 alkoxy.

In some embodiments, the R ₉ is H, -NH ₂ , -OH, F, Cl, =O, -NHC(O)-C _2-6 alkenyl, -C(O)-C _2-6 Alkenyl, -NHS(O) ₂ -C _2-6 alkenyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, halogenated C _1-4 alkyl or halogenated C _1-4 alkoxy.

In some embodiments, R ₉ is H, —NH ₂ , —OH, F, Cl, ═O, —NHC(O)—C _2-6 alkenyl, —NHS(O) ₂ —C _{2- 6} alkenyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, halogenated C _1-4 alkyl or halogenated C _1-4 alkoxy.

In some embodiments, R ₉ is H, F, Cl, =0, -NHC(O)-C _2-6 alkenyl, or C _1-4 alkyl.

In some embodiments, R ₁₀ is H, —CN, —NH ₂ , —OH, F, Cl, ═O, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _1-4 alkoxy, C _1-4 alkylamino, halogenated C _1-4 alkyl or halogenated C _1-4 alkoxy.

In some embodiments, R ₁₀ is H, —NH ₂ or C _1-4 alkylamino.

In some embodiments, R ₁₀ is H.

In some embodiments, R _A is C _1-6 alkyl or C _2-6 alkenyl; the R _A is unsubstituted, or is optionally selected from 1 to 3 selected from F, Cl, -OH, The substituents of -NH ₂ , =O, -OCH ₃ and -N(CH ₃ ) ₂ are substituted at arbitrary positions.

In some embodiments, the R _B is C _1-6 alkyl (eg, methyl, ethyl, n-propyl, isopropyl), C _2-6 alkenyl (eg: allyl), C _3-6 cycloalkyl (for example: cyclopropyl or cyclobutyl), phenyl or 5-6 membered heteroaryl; the R _B is unsubstituted or optionally substituted by 1 to 3 R ₉ in any Position; R _{9 is} as defined above.

In some embodiments, the R _{C is} independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C _3-8 ring Alkyl, 3-8 membered heterocycloalkyl, -(CH ₂ ) _n -OC _1-6 alkyl, -(CH ₂ ) _n -phenyl, -(CH ₂ ) _n -(5-6 membered heteroaryl Group), -(CH ₂ ) _n -C _3-8 cycloalkyl or -(CH ₂ ) _n -(3-8 membered heterocycloalkyl); the R _C is unsubstituted, or optionally 1～ 3 R ₁₀ substitutions at arbitrary positions;

In some embodiments, the R _{C is} independently C _1-6 alkyl, C _2-6 alkenyl, phenyl, 5-6 membered heteroaryl, C _3-6 cycloalkyl, 3-6 membered Heterocycloalkyl, -(CH ₂ ) _n -OC _1-6 alkyl, -(CH ₂ ) _n -phenyl, -(CH ₂ ) _n -(5-6 membered heteroaryl), -(CH ₂ ) _n -C _3-6 cycloalkyl or -(CH ₂ ) _n -(3-6 membered heterocycloalkyl); the R _C is unsubstituted or optionally substituted by 1 to 3 R ₁₀ in any Position; where n is preferably 1, 2, or 3; R ₁₀ is as defined above.

In some embodiments, the R _{C is} independently C _1-6 alkyl or C _3-6 cycloalkyl; the R _C is unsubstituted or optionally substituted with 1 to 3 R ₁₀ at any position ; Where R _{10 is} as defined above.

In some embodiments, the R _{C is} independently C _1-6 alkyl (eg, methyl, ethyl, n-propyl, isopropyl, or tert-butyl) or C _3-6 cycloalkyl (eg : Cyclopropyl).

In some embodiments, the R ₁ is H, -OH, -OCH ₃ , -NH ₂ , -NH(CH ₃ ), -NH(CH ₂ CH ₃ ), or -NH(CH ₂ CH=CH ₂ ) .

In some embodiments, the R ₁ is _{H, -OH, -NH 2, -NH} (CH 3) or -NH (CH ₂ CH _3).

In some embodiments, R ₁ is H.

In some embodiments, R ₂ is H, CD _3, or R _B , wherein R _B is as defined above.

In some embodiments, R ₂ is H or R _B , wherein R _B is as defined above. .

In some embodiments, R ₂ is H, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, phenyl, or 5-6 membered heteroaryl; the R ₂ Is unsubstituted, or is optionally substituted by 1 to 3, 1 to 2 or 1 substituent selected from F, Cl, =O, -NHC(O)-C _2-6 alkenyl and C _1-4 alkyl Replace in any position.

In some embodiments, R ₂ is H, CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, phenyl, or 5-6 membered heteroaryl; Said R ₂ is unsubstituted, or is optionally selected from 1 to 3, 1 to 2 or 1 from F, Cl, =O, -NHC(O)-C _2-6 alkenyl and C _1-4 alkyl Is substituted at any position.

In some embodiments, R ₂ is H, deuterated methyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, —C(O)CH═CH ₂ or

In some embodiments, the R ₃ is H or C _1-6 alkyl; the R ₃ is unsubstituted, or optionally substituted with 1 to 3, 1 to 2, or 1 R ₉ at any position; The definition of R ₉ is as described above.

In some embodiments, R ₃ is H or C _1-6 alkyl.

In some embodiments, R ₃ is H, methyl, or ethyl.

In some embodiments, R ₄ is H, C _1-6 alkyl, phenyl, 5-6 membered heteroaryl, C _3-6 cycloalkyl, or 3-6 membered heterocycloalkyl; R ₄ is unsubstituted or optionally substituted with 1 to 3, 1 to 2 or 1 R ₉ at any position; the definition of R ₉ is as described above.

In some embodiments, the R ₄ is methyl, ethyl, n-propyl, isopropyl, phenyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; the R ₄ It is unsubstituted or optionally substituted with 1 to 3, 1 to 2 or 1 fluorine, chlorine and methyl substituents at any position.

In some embodiments, each of R ₃ and R ₄ is an independent substituent.

In some embodiments, the R ₃ and R ₄ together with the carbon atom to which they are connected together form a C _3-10 cycloalkyl or 3-10 membered heterocycloalkyl; the C _3-10 cycloalkyl or 3- The 10-membered heterocycloalkyl group is unsubstituted, or is optionally substituted with 1 to 3 R ₉ at any position; the definition of R ₉ is as described above.

In some embodiments, the R ₃ and R ₄ together with the carbon atom to which they are connected together form a C _3-10 cycloalkyl group, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,3- Dihydro-1H-indenyl, 2,3-dihydro-1H-indenyl-1-one, spiro[3,2]hexyl or spiro[3.3]heptyl.

In some embodiments, the R ₃ and R ₄ together with the carbon atom to which they are connected together form a 3-10 membered heterocycloalkyl group, more preferably a 3-8 membered heterocycloalkyl group, for example: tetrahydrofuranyl, pyrrolidinyl, Azetidinyl, piperidinyl or thietane 1-oxide.

In some embodiments, the R ₃ and R ₄ together with the carbon atom to which they are connected together form a 3-10 membered heterocycloalkyl group, more preferably a 3-8 membered heterocycloalkyl group, for example: tetrahydrofuranyl, pyrrolidinyl, Azetidinyl, piperidinyl, or 1-oxo-thietanyl.

In some embodiments, each of R ₁ and R ₃ is an independent substituent.

In some embodiments, the R ₁ and R ₃ are connected to each other to form a 3-10 membered heterocycloalkyl; the 3-10 membered heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 R ₉ In any position.

In some embodiments, R ₁ and R ₃ are interconnected to form a 4-8 membered heterocycloalkyl.

In some embodiments, R ₁ and R ₃ are interconnected to form a 5-6 membered heterocycloalkyl.

In some embodiments, R ₂ and R ₃ are each independent substituents.

In some embodiments, the R ₂ and R ₃ are connected to each other to form a 3-10 membered heterocycloalkyl; the 3-10 membered heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 R ₉ In any position.

In some embodiments, the R ₂ and R ₃ are connected to each other to form a 4-8 membered heterocycloalkyl; the 4-8 membered heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 R ₉ In any position.

In some embodiments, the R ₂ and R ₃ are connected to each other to form a 5-6 membered heterocycloalkyl; the 5-6 membered heterocycloalkyl is unsubstituted or optionally substituted by 1=O in any position.

In some embodiments, the R ₂ and R ₃ are interconnected with an α bond (single bond) to form a double bond.

In some embodiments, R ₅ is hydrogen, halogen, cyano, C _1-4 alkoxy, halogenated C _1-4 alkyl, or halogenated C _1-4 alkoxy.

In some embodiments, R ₅ is hydrogen, halogen, or C _1-4 alkyl.

In some embodiments, R ₅ is H, F, Cl, or —CH ₃ .

In some embodiments, R _5a is hydrogen, halogen, cyano, C _1-4 alkoxy, halogenated C _1-4 alkyl, or halogenated C _1-4 alkoxy.

In some embodiments, R _5a is hydrogen.

In some embodiments, R _5b is hydrogen, halogen, cyano, C _1-4 alkoxy, halogenated C _1-4 alkyl, or halogenated C _1-4 alkoxy.

In some embodiments, R _5b is hydrogen, halogen, C _1-4 alkoxy, or C _1-4 alkyl.

In some embodiments, R _5b is H, F, Cl, -CH ₃ or -OCH ₃ .

In some embodiments, A ₁ is CR ₅ , A ₂ is CH, and A ₃ is N or CR _5b .

In some embodiments, R is

Where R ₆ , R ₇ and R ₈ are independently H, halogen, -CN, -NH ₂ , -NHOH, -OH, -R _C , -OR _C , -NHR _C , -NH-OR _C ,- NHC(O)R _C or -NHS(O) ₂ R _C ; R ₆ and R ₇ are independent substituents, or R ₆ and R ₇ are connected to each other to form a heteroaryl or heterocycloalkyl; the heteroaryl Or heterocycloalkyl is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -CN, -NH ₂ , -NHOH, -OH, -R _C , -OR _C , -NHR _C , -NH-OR The substituents of _C , -NHC(O)R _C , -C(O)R _C and -C(O)N(R _C ) ₂ are substituted at any position; the definition of R _C is as described above.

In some embodiments, R is

Where R ₆ , R ₇ and R ₈ are independently H, halogen, -CN, -NH ₂ , -NHOH, -OH, -R _C , -OR _C , -NHR _C , -NH-OR _C ,- NHC(O)R _C or -NHS(O) ₂ R _C ; R ₆ and R ₇ are independent substituents, or R ₆ and R ₇ together with the atoms to which they are attached form a heteroaryl or heterocycloalkyl group; Heteroaryl or heterocycloalkyl is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -CN, -NH ₂ , -NHOH, -OH, -R _C , -OR _C , -NHR _C ,- The substituents of NH-OR _C , -NHC(O)R _C , -C(O)R _C and -C(O)N(R _C ) ₂ are substituted at any position; the definition of R _C is as described above.

In some embodiments, R is

Where R ₆ , R ₇ and R ₈ are independently H, halogen, -CN, -NH ₂ , -NHOH, -OH, -R _C , -OR _C , -NHR _C , -NH-OR _C ,- NHC(O)R _C or -NHS(O) ₂ R _C ; R _C is as defined above.

In some embodiments, R ₈ is H.

In some embodiments, the R ₆ is H, F, Cl, -CN, -NH ₂ , -CH ₃ , -CF ₃ , -CH ₂ CH ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -OCF _3. -O-n-propyl, -O-isopropyl, cyclopropyl or 1-methyl-1H-pyrazolyl.

In some embodiments, R ₇ is H, —NH ₂ , —NHR _C , —NH—OR _C, or —NHC(O)R _C ; R _C is as defined above.

In some embodiments, R ₇ is H, —NH ₂ , —NHR _C, or —NHC(O)R _C ; R _C is as defined above.

In some embodiments, R ₆ and R ₇ together with the atoms to which they are attached form a 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl; the 5-6 membered heteroaryl or 5-6 membered Heterocycloalkyl is unsubstituted, or is optionally selected from 1-2 or 1 selected from halogen, -CN, -NH ₂ , -NHOH, -OH, -R _C , -OR _C , -NHR _C , -NH- The substituents of OR _C and -NHC(O)R _C are substituted at arbitrary positions; the definition of R _C is as described above.

In some embodiments, the R ₆ and R ₇ together with the atoms to which they are attached form a 5-6 membered heteroaryl or heterocycloalkyl; the 5-6 membered heteroaryl or heterocycloalkyl is unsubstituted, Alternatively, 1-2 or 1 are selected from F, Cl, -CN, -NH ₂ , -CH ₃ , -CF ₃ , -CH ₂ CH ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -OCF ₃ , -O-n-propyl, -O-isopropyl, cyclopropyl, -NHR _C , -NH-OR _C and -NHC(O)R _C substituents are substituted at any position; the definition of R _C As mentioned earlier.

In some embodiments, the R is any of the following structures:

Wherein R ₁₁ and R ₁₂ are independently H, halogen, -CN, -NH ₂ , -NHOH, -OH, -R _C , -OR _C , -NHR _C , -NH-OR _C, or -NHC(O ) R _C ; R _C and R ₈ are as defined above.

In some embodiments, the R ₁₁ is H, F, Cl, -CN, -NH ₂ , -CH ₃ , -CF ₃ , -CH ₂ CH ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -OCF _3. -O-n-propyl, -O-isopropyl, cyclopropyl, -NHR _C , -NH-OR _C or -NHC(O)R _C ; the definition of R _C is as described above.

In some embodiments, R ₁₁ is H.

In some embodiments, the R ₁₂ is H, F, Cl, -CN, -NH 2, -CH 3, -CF 3, -CH 2 CH 3, -OCH 3, -OCH 2 CH 3, -OCF _3. -O-n-propyl, -O-isopropyl, cyclopropyl, -NHR _C , -NH-OR _C or -NHC(O)R _C ; the definition of R _C is as described above.

In some embodiments, R ₁₂ is H.

In some embodiments, W ₁ is O.

In some embodiments, W ₂ is O.

In some embodiments, the compound of formula I, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt is the compound of formula II, its isomer, Prodrug, stable isotope derivative or pharmaceutically acceptable salt:

Where R ₁ is H, -OH, -NH ₂ , R _A , -NH-R _A , -NH-C(O)-R _A or -OR _A ;

R ₂ is H, CN or R _B ;

R ₄ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, 5-6 membered heteroaryl, C _3-8 cycloalkyl, 3 -8 membered heterocycloalkyl; said R ₄ is unsubstituted or optionally substituted with 1 to 3 R ₉ at any position;

The R ₃ and R ₄ are independent substituents, or R ₃ and R ₄ together with the carbon atom to which they are connected together form a C _3-10 cycloalkyl or 3-10 membered heterocycloalkyl; the C _3-10 ring The alkyl group or 3-10 membered heterocycloalkyl group is unsubstituted, or optionally substituted with 1 to 3 R ₉ at any position;

R ₅ is hydrogen, halogen, cyano or C _1-4 alkyl;

R ₆ , R ₇ and R ₈ are independently H, halogen, -CN, -NH ₂ , -NHOH, -OH, -R _C , -OR _C , -NHR _C , -NH-OR _C , -NHC ( O)R _C or -NHS(O) ₂ R _C ;

R ₆ and R ₇ are independent substituents, or R ₆ and R ₇ together with the atoms to which they are attached form a heteroaryl or heterocycloalkyl group; the heteroaryl or heterocycloalkyl group is unsubstituted or is optionally substituted 1 to 3 are selected from halogen, -CN, -NH ₂ , -NHOH, -OH, -R _C , -OR _C , -NHR _C , -NH-OR _C , -NHC(O)R _C , -C( O)R _C and -C(O)N(R _C ) ₂ substituents are substituted at any positions;

Each R _{C is} independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C _3-8 cycloalkyl, 3-8 Heterocyclic heterocyclic alkyl, -(CH ₂ ) _n -OC _1-6 alkyl, -(CH ₂ ) _n -phenyl, -(CH ₂ ) _n -(5-6 membered heteroaryl), -(CH ₂ ) _n -C _3-8 cycloalkyl or -(CH ₂ ) _n -(3-8 membered heterocycloalkyl); the R _C is unsubstituted or optionally substituted by 1 to 3 R ₁₀ in Anywhere

Each R ^{a is} independently C _1-6 alkyl or C _2-6 alkenyl;

n is 1, 2, 3 or 4.

All the embodiments described below in the formula II and combinations of any embodiments described below are included in the scope of the structural formula of the present invention represented by the formula II.

In some embodiments, the definition of certain groups in the compound of formula II, its isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts can be as follows, without The described group can be as described in any of the above schemes:

Among them, R ₂ is H or R _B ;

Each R ₉ and each R ₁₀ are independently H, -CN, -NO ₂ , -SH, -NH ₂ , -OH, -C(O)OH, -NHC(O)R ^a , -NHS ( O) ₂ R ^a , halogen, oxo, ester, amide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _{1- 4} alkylamino, halogenated C _1-4 alkyl or halogenated C _1-4 alkoxy.

In some embodiments, the R _B is C _1-6 alkyl (eg, methyl, ethyl, n-propyl, isopropyl), C _2-6 alkenyl (eg: allyl), C _3-6 cycloalkyl (for example: cyclopropyl), phenyl or 5-6 membered heteroaryl; the R _B is unsubstituted or optionally substituted with 1 to 3 R ₉ at any position; R ₉ The definition is as described above.

In some embodiments, each R ₉ and each R ₁₀ are independently H, -CN, -NO ₂ , -SH, -NH ₂ , -OH, -C(O)OH, -NHC(O) R ^a , -NHS(O) ₂ R ^a , halogen, oxo, ester, amide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkyl Oxygen, C _1-4 alkylamino, halogenated C _1-4 alkyl or halogenated C _1-4 alkoxy;

In some embodiments, R ₁₀ is H.

In some embodiments, R ₁ is H.

In some embodiments, R ₂ is H or R _B.

In some embodiments, R ₂ is H, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, phenyl, or 5-6 membered heteroaryl; the R ₂ Is unsubstituted, or optionally substituted with 1 to 3, 1 to 2 or 1 substituent selected from F, Cl, =O, NHC(O)-C _2-6 alkenyl and C _1-4 alkyl In any position.

In some embodiments, R ₂ is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, —C(O)CH═CH ₂ or

In some embodiments, R ₃ is H or C _1-6 alkyl.

In some embodiments, R ₃ is H, methyl, or ethyl.

In some embodiments, the R ₃ and R ₄ together with the carbon atom to which they are connected together form a C _3-10 cycloalkyl group, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,3 -Dihydro-1H-indenyl, 2,3-dihydro-1H-indenyl-1-one, spiro[3,2]hexyl or spiro[3.3]heptyl.

In some embodiments, the R ₅ is F, Cl, -CN, -CH ₃ or -CH ₂ CH ₃ .

In some embodiments, R ₅ is F.

In some embodiments, the R ₅ is Cl.

In some embodiments, R ₅ is —CH ₃ .

In some embodiments, R ₈ is H.

In some embodiments, the R ₆ and R ₇ together with the atoms to which they are attached form a 5-6 membered heteroaryl or heterocycloalkyl; the 5-6 membered heteroaryl or heterocycloalkyl is unsubstituted, Alternatively, it can be selected from 1-3, 1-2 or 1 selected from halogen, -CN, -NH ₂ , -NHOH, -OH, -R _C , -OR _C , -NHR _C , -NH-OR _C and- The substituent of NHC(O)R _C is substituted at any position; the definition of R _C is as described above.

In some embodiments, the group

For any of the following structures:

In some embodiments, the group

For any of the following structures:

In some embodiments, R ₁₁ is H.

In some embodiments, R ₁₂ is H.

In some embodiments, the compound of formula I, its isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt is the compound of formula III, its isomer, Prodrug, stable isotope derivative or pharmaceutically acceptable salt:

Among them, m is 0, 1, 2 or 3; t is 0, 1, 2 or 3;

X and Y are independently O, NH or CH ₂ ;

The definitions of R ₁ , R ₂ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are as described above.

In some embodiments, the compound of formula I, its isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt is the compound of formula IV, its isomer, Prodrug, stable isotope derivative or pharmaceutically acceptable salt:

Among them, m is 0, 1, 2 or 3; t is 0, 1, 2 or 3;

In some embodiments, the compound of formula I, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt is the compound of formula V, its isomer, Prodrug, stable isotope derivative or pharmaceutically acceptable salt:

Among them, m is 0, 1, 2 or 3; t is 0, 1, 2 or 3;

The definitions of R ₁ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are as described above.

In some embodiments, the compound of formula I, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt is a compound of formula VI, its isomer, Prodrug, stable isotope derivative or pharmaceutically acceptable salt:

Among them, the definitions of R ₁ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are as described above.

In some embodiments, the compound of formula I', its isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt is the compound of formula VII, its isomer , Prodrugs, stable isotope derivatives or pharmaceutically acceptable salts:

Among them, m is 0, 1, 2 or 3; t is 0, 1, 2 or 3;

The definitions of R ₁ , R ₂ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and A ₃ are as described above.

In some embodiments, the compound of formula I′, its isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt is the compound of formula VIII, its isomer , Prodrugs, stable isotope derivatives or pharmaceutically acceptable salts:

Among them, m is 0, 1, 2 or 3; t is 0, 1, 2 or 3;

The definitions of R ₁ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and A ₃ are as described above.

In some embodiments, the compound of Formula I, the isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt is optionally the following compound:

In some embodiments, the compound represented by formula I', the isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt thereof are optionally the following compounds:

In some embodiments, the compound represented by formula I', the isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts thereof are optionally the following compounds:

The present invention also provides a method for preparing a compound represented by Formula I or I', which is any of the following methods:

Method 1: In a solvent, under basic conditions, X or X'and RH are subjected to Buchwald-hartwig coupling or Ullmann coupling reaction to obtain the compound represented by formula I or I';

Among them, L is a halogen or other leaving group, such as -OTf, -OTs or -OMs, L is preferably chlorine, bromine or iodine; R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R _5a , A ₁ , A ₂ , A ₃ , W ₁ and W ₂ are as defined above.

Method 2: In a solvent, under basic conditions, X or X'and RH are subjected to a Buchwald-hartwig coupling reaction to obtain a compound represented by Formula I or I';

Wherein, L is halogen or other leaving group, such as -OTf, -OTs or -OMs, L is preferably chlorine, bromine or iodine; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R _5a , A ₁ , A ₂ , A ₃ , W ₁ , W ₂ and Cy are as defined above.

In the method shown in Reaction Formula 1, when using the Buchwald-hartwig coupling reaction, the R is preferably

In the method shown in method 1 or 2, the conditions and steps of the Buchwald-hartwig coupling reaction may be the conditions and steps of a conventional coupling reaction in the art, and the following reaction conditions are particularly preferred in the present invention: the solvent is preferred 1,4-dioxane or tert-butanol; the amount of the solvent is preferably 5 to 80 mL/mmol compound X, X', XI or XI'; the base used under the alkaline conditions is preferably cesium carbonate or Sodium tert-butoxide; the molar ratio of the base to the compound X, X', XI or XI' is preferably 1.05:1 to 3:1; the coupling reagent is preferably Pd ₂ (dba) ₃ , Xantphos and/or XPhos system Or Pd ₂ (dba) ₃ and Ru-phos system; the temperature of the reaction is preferably 50-120°C; the reaction can be detected by TLC or LCMS, and generally disappears as compound X, X', XI or XI' As the end point of the reaction, it is preferably 1 to 24 hours; after the reaction is completed, the product can be further purified by post-treatment. The organic phase is dried, the organic solvent is removed under reduced pressure, and the residue is purified by conventional purification means, for example, silica gel column chromatography, Flash column chromatography, or prep-HPLC. The purification steps and conditions of silica gel column chromatography, Flash column chromatography or prep-HPLC can be conventional purification steps and conditions in the art.

In the method shown in method 1, when Ullmann coupling reaction is used, the R is preferably

The conditions and steps of the Ullmann coupling reaction can be the conditions and steps of conventional coupling reactions in the art, and the following reaction conditions are particularly preferred in the present invention: the solvent is preferably 1,4-dioxane, and the base Preferably, potassium phosphate and trans-1,2-cyclohexanediamine are reacted in the presence of cuprous iodide to obtain I or I'.

In the method 1 or 2, when -NH ₂ in Cy does not participate in the reaction, the -NH ₂ is preferably protected by a protecting group to avoid any side reactions. If the above amino protecting group is present, it is necessary to go through a subsequent deprotection step to obtain the compound represented by formula I, I', I-1 or I'-1. Any suitable amino protecting group, for example: tert-butoxycarbonyl (Boc) group, acetyl, cyclopropionyl,

Both can be used to protect amino groups. If Boc is used as a protecting group, the subsequent deprotection reaction can be performed under standard conditions, for example, p-toluenesulfonic acid/methanol system, methylene chloride/trifluoroacetic acid system, saturated hydrogen chloride ether solution, or trifluoromethanesulfonic acid trimethylsulfonate Carboxymethyl ester/2,6-lutidine/dichloromethane system; acetyl, cyclopropionyl as protective groups, subsequent deprotection reaction can be under standard conditions, such as potassium hydroxide (sodium)/ethanol /Tetrahydrofuran/water system;

As a protecting group, the subsequent deprotection reaction can be carried out under standard conditions, for example, an ethylenediamine/ethanol system.

In method 1, X (including X, X-1, and X-2) or X'(including X', X'-1, and X'-2) can be synthesized by the methods shown in the following reaction formulas 3 to 4:

Where R _t is H or C _1-6 alkyl; R ₁ is H; R ₂ , R ₃ , R ₄ , R ₅ , R _5a , L, W ₁ and W ₂ are as defined above;

In a solvent (for example: ethanol, 1,4-dioxane), under acidic conditions (for example: concentrated sulfuric acid), the compound XII or XII' is reacted with the corresponding ketone, aldehyde, ketal post-acetal to obtain compound X or X'. The reaction temperature is preferably 70 to 110°C, and the reaction time is preferably 2 to 24 hours.

In Equation 3, when R ₂ is H,

When R ₃ is a substituted C _1-6 alkyl (the substituent includes at least one halogen or ester group), a compound represented by formula X-1 or X′-1 is obtained:

Wherein R ₂ is C _1-6 alkyl or deuterated C _1-4 alkyl (preferably methyl, ethyl or deuterated methyl); R ₁ , R ₃ , R ₄ , R ₅ , R _5a , The definitions of L, W ₁ and W ₂ are as described above; L′ is a halogen or other leaving group, such as -OTf, -OTs or -OMs, and L is preferably bromine or iodine;

In a solvent (for example: DMF), compound X-2 or X'-2 is reacted with R ₂ -L' to obtain compound X or X'. The reaction temperature is preferably 70 to 110°C, and the reaction time is preferably 5 to 48 hours.

The pharmaceutically acceptable salt of the compound represented by formula I or I'can be synthesized by a general chemical method.

In general, the salt can be prepared by reacting a free base or acid with an equivalent stoichiometric amount or an excess of acid (inorganic acid or organic acid) or base (inorganic base or organic base) in a suitable solvent or solvent composition.

The present invention also provides a pharmaceutical composition, which includes an active component and a pharmaceutically acceptable excipient; the active component includes a compound represented by formula I or I', its isomer, prodrug, stable One or more of isotope derivatives and pharmaceutically acceptable salts.

The present invention also provides a pharmaceutical composition, which includes a therapeutically effective amount of an active component and a pharmaceutically acceptable excipient; the active component includes a compound represented by formula I or I', isomers thereof, pro One or more of medicines, stable isotope derivatives and pharmaceutically acceptable salts.

In the pharmaceutical composition, the active component may further include other kinds of therapeutic agents for treating related diseases caused by abnormal levels of MNK1 and/or MNK2; the related diseases caused by abnormal levels of MNK1 and/or MNK2 It is preferably cancer.

In the pharmaceutical composition, the active component may further include other therapeutic agents for cancer.

In the pharmaceutical composition, the pharmaceutically acceptable excipient may include a pharmaceutically acceptable carrier, diluent and/or excipient.

According to the purpose of treatment, the pharmaceutical composition can be made into various types of unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc. , Liquids, suspensions, emulsions, suppositories and injections (solutions and suspensions) are preferred.

To shape the pharmaceutical composition in tablet form, any excipient known and widely used in the art may be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.; binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrants, such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Calcium, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceryl stearate, starch and lactose, etc.; disintegration inhibitors such as white sugar, glycerol tristearate, coconut oil and hydrogenation Oil; Adsorption accelerators, such as quaternary ammonium base and sodium lauryl sulfate, etc.; Wetting agents, such as glycerin, starch, etc.; Adsorbents, such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants, Such as pure talc, stearate, boric acid powder and polyethylene glycol. Ordinary coating materials can also be used to make sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layer film tablets, and multi-layer tablets as needed.

In order to shape the pharmaceutical composition in the form of pills, any known and widely used excipients in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; , Such as gum arabic powder, tragacanth powder, gelatin and ethanol; disintegrants, such as agar and kelp powder.

In order to shape the pharmaceutical composition in the form of suppositories, any excipient known and widely used in the art may be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides .

In order to prepare a pharmaceutical composition in the form of an injection, the solution or suspension can be sterilized (preferably with an appropriate amount of sodium chloride, glucose or glycerin, etc.) to make an injection that is isotonic with blood. When preparing an injection, any carrier commonly used in the art may also be used. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and fatty acid esters of polyethylene sorbitan, etc. In addition, common dissolving agents, buffering agents and analgesics can also be added.

In the present invention, the content of the composition in the pharmaceutical composition is not particularly limited, and can be selected within a wide range, usually 5 to 95% by mass, preferably 30 to 80 by mass %.

In the present invention, the administration method of the pharmaceutical composition is not particularly limited. According to the patient's age, sex and other conditions and symptoms, various formulations can be selected for administration. For example, tablets, pills, solutions, suspensions, emulsions, granules, or capsules are administered orally; injections can be administered alone or mixed with injection delivery fluids (such as glucose solution and amino acid solution) for intravenous injection; suppositories are given Medicine to the rectum.

The present invention also provides the compound of formula I or I', its isomer, prodrug, solvate, hydrate, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition Application in the preparation of MNK1 and/or MNK2 inhibitors. The MNK1 and/or MNK2 inhibitor means that it can inhibit the activity or expression of MNK1 and/or MNK2 (including the abnormal activity or overexpression of MNK1 and/or MNK2).

The present invention also provides the compound of formula I or I', its isomer, prodrug, solvate, hydrate, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition It has the treatment or reduction of tumor cell growth, proliferation and/or survival, uncomfortable cellular immune response and its related disorders, or uncomfortable cell inflammatory response and its related disorders. The tumor cell growth, proliferation and/or survival, uncomfortable cellular immune response and its related disorders, or uncomfortable cell inflammatory response and its related disorders are mediated by MNK1 and/or MNK2.

The present invention also provides the compound of formula I or I', its isomer, prodrug, solvate, hydrate, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition Use in the preparation of a medicament for the treatment, alleviation and/or prevention of related diseases mediated by MNK1 and/or MNK2. The related diseases mediated by MNK1 and/or MNK2 are value-added diseases, preferably cancer.

The present invention also provides the compound of formula I or I', its isomer, prodrug, solvate, hydrate, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition Use in the preparation of therapeutic and/or cancer alleviating drugs.

The present invention also provides the compound of formula I or I', its isomer, prodrug, solvate, hydrate, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition Use in the treatment and/or alleviation of cancer, which includes administering to a mammal a therapeutically effective dose of a compound represented by formula (I), its isomers, prodrugs, solvates, hydrates, stable isotope derivatives or A pharmaceutically acceptable salt, or a pharmaceutical composition containing the same.

The present invention also provides the compound of formula I or I', its isomer, prodrug, solvate, hydrate, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition It is used in combination with one or more other kinds of therapeutic agents and/or treatment methods for the treatment of cancer to treat, alleviate and/or prevent related diseases mediated by MNK1 and/or MNK2. The related diseases mediated by MNK1 and/or MNK2 are proliferative diseases, preferably cancer.

The present invention further provides a combined preparation comprising a compound represented by formula I or I', its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition and other Various kinds of therapeutic agents and/or treatment methods for treating cancer are used in combination.

In the present invention, the other kinds of therapeutic agents for treating cancer may be combined with the above-mentioned compounds of formula I or I'into a single-dose therapeutic dosage form, or separately administered sequentially.

In the present invention, the other kinds of therapeutic agents and/or treatment methods for treating cancer may include but are not limited to: alkylating agents, topozyme I/II inhibitors, antimitotic agents, antimetabolites, hormones and One or more of hormone analogues, antitumor antibiotics, small molecule kinase inhibitors, small molecule immunomodulators, interferons, monoclonal antibodies, and radiotherapy.

In the present invention, the alkylating agent may be selected from but not limited to: cisplatin, carboplatin, oxaliplatin, nedaplatin, nitrogen mustard, N-oxide-nitrogen mustard hydrochloride, chlorambucil, uracil Nitrogen mustard, cyclophosphamide, ifosfamide, thiotepa, carboquinone, triiminoquinone, inprosulfan tosylate, mannosulfan, trioxifan, busulan, nimustine hydrochloride , Dibromomannitol, melphalan, dacarbazine, ramustine, carmustine, lomustine, streptozotocin, temozolomide, procarbazine, ethyleneimine derivatives, methanesulfonate One or more of the class, nitrosourea, triazene.

In the present invention, the topozyme I/II inhibitor may be selected from but not limited to: doxorubicin, daunorubicin, epirubicin, idarubicin, irinotecan, topotecan, lubi One or more of tecan, belotecan, etoposide, teniposide, doxorubicin and dexrazoxane, camptothecin.

In the present invention, the anti-mitotic agents include but are not limited to: paclitaxel, docetaxel, polyglutamic acid paclitaxel, isovinblastine, vincristine, vinblastine, vindesine, vinpodine, etoposide, and One or more of nipatoside, ixabepilone, raloxatose, ortataxel, tesetaxel, tocosal, and ispins.

In the present invention, the antimetabolite drugs may be selected from but not limited to: folic acid antagonists, pyrimidine analogs, purine analogs, adenosine deaminase inhibitors, such as: methotrexate, 5-fluorouracil, fluorourea One or more of glycosides, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin and gemcitabine.

In the present invention, the hormone therapeutic agent may be selected from, but not limited to: phosphoestrol, diethylstilbestrol, chlorostilbestrol, medroxyprogesterone acetate, megestrol acetate, chlorgesterone acetate, cyproterone acetate , Danazol, dienogest, allyl estradiol, gestrinone, nomegestrol, tonazepam, mepatricin, raloxifene, omemexifen, zomeloxifen, an Lumit, testosterone, anti-estrogen, LH-RH derivatives, aromatase inhibitors, anti-androgens, adrenocortical hormones, androgen synthesis inhibitors, retinoic acid and drugs that delay retinoic acid metabolism One or more.

In the present invention, the anti-tumor antibiotics include but are not limited to: actinomycin D, doxorubicin, daunorubicin, bleomycin, pelopromycin, mitomycin C, arubicin , One or more of pirarubicin, epirubicin, netastatin, idarubicin, sirolimus and penrorubicin.

In the present invention, the small molecule kinase inhibitors include but are not limited to: erlotinib, imatinib, apatinib, nilotinib, crizotinib, dasatinib, pazopanib , Regefenib, rusolitinib, sorafenib, sunitinib, vandetanib, verofenib, bosutinib, gefitinib, afatinib, axitinib Nigra, dalapini, dacomitinib, nidanib, lovastinib, marcetinib, middoturin, lenatinib, panatinib, redotinib, trametinib , Alanine brinibub, sildenibu, carbotinib malate, ibrutinib, icotinib, cipatinib, cobinitin, and ideralide Or more.

In the present invention, the monoclonal antibodies include but are not limited to: alemtuzumab, bentuximab, cetuximab, rituximab, denosumab, epilimumab, ofatumumab MAb, panitumumab, tositumomab, trastuzumab, bevacizumab, pertuzumab, catumaxomab, elotuzumab, epalizumab, One of the resistance to rituximab, nimotuzumab, tocilizumab, matuzumab, zalutumumab, atuzumab, ramucirumab, and nivolumab Or more.

In the present invention, the small molecule immunomodulators include but are not limited to: TLR7 agonists, TLR8 agonists, TLR9 agonists, IDO inhibitors, CD73 inhibitors, STING inhibitors, A2AR antagonists, PD-L1 inhibitors One or more.

In the present invention, the interferon used for cancer treatment includes but is not limited to: interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a or interferon gamma-n1, etc. .

In the present invention, the radiotherapy is well known in the art and includes X-ray therapy, such as gamma radiation, radiopharmaceutical therapy, and the like.

In the present invention, the cancer includes metastatic and non-metastatic cancers, and also includes family inherited and sporadic cancers, and may also include solid tumors and non-solid tumors.

In the present invention, specific examples of the solid tumor may include but are not limited to: eye cancer, bone cancer, lung cancer, gastric cancer, pancreatic cancer, islet cell cancer, breast cancer, triple negative breast cancer, prostate cancer, trend-resistant prostate cancer , Brain cancer (including malignant glioma, medulloblastoma), CNS cancer, glioblastoma, ovarian cancer, bladder cancer, urothelial cancer, cervical cancer, testicular cancer, kidney cancer (including glands Cancer and Wilms Cancer), oral cancer (including squamous cell carcinoma), tongue cancer, laryngeal cancer, nasopharyngeal cancer, head and neck cancer, colon cancer, small intestine cancer, rectal cancer, colorectal cancer, parathyroid cancer, thyroid Cancer, esophageal cancer, gallbladder cancer, cholangiocarcinoma, cervical cancer, liver cancer, hepatocellular carcinoma, lung cancer, non-small cell lung cancer, sarcoma, leiomyosarcoma, myoblastoma, fibroids, rhabdomyosarcoma, gangliomas, neuroepithelial tumors , One or more of neuroblastoma, skin cancer, melanoma, malignant carcinoid syndrome, carcinoid heart disease.

In the present invention, specific examples of the non-solid tumors (including hematological tumors) may include, but are not limited to: B-cell lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, Hodgkin lymphoma, non-Hodgkin Chikin lymphoma, Burkitt lymphoma, myelodysplastic syndrome, lymphocytic leukemia (including lymphoblastic leukemia, lymphoma, myeloma, multiple myeloma, chronic lymphocytic leukemia (T cell chronic lymphocytic leukemia, One or more of B-cell chronic lymphocytic leukemia) and myeloid-related leukemia (including acute myeloid leukemia, chronic myelogenous leukemia).

In the present invention, the therapeutically effective dose of the compound represented by formula I or I′ or a pharmaceutically acceptable salt is given, and the therapeutically effective dose varies according to various factors, including, for example, the activity of the specific compound used, the Factors such as the metabolic stability and duration of action of the compound, the patient's age, weight, health status, gender, mode and time of administration, absorption metabolic properties, severity of specific diseases or conditions, and other factors. "Therapeutically effective amount" refers to an amount sufficient to provide an effective treatment for a MNK1 and/or MNK2 related disorder or disease in the mammal when administered to the mammal. The amount of the compound of the present invention constituting a therapeutically effective amount needs to vary according to the compound, the condition and its severity, the mode of administration, and the age of the mammal to be treated, but it can be determined by those skilled in the art based on the knowledge and the present invention The content is determined routinely.

In the present invention, the mammal is preferably a human.

In the present invention, unless otherwise stated, the term "substituted by 1 to 3 groups at any position" refers to any 1, 2 or 3 of the 1, 2, or 3 atoms specified on the group The hydrogen atom is substituted with the specified group, provided that the normal valence of the specified atom is not exceeded, and the substitutions are all reasonable substitutions common in the art.

In the present invention, when the bond to the substituent is shown to intersect with the bond connecting the two atoms in the ring, then such a substituent may be bonded to any bondable ring atom on the ring.

Unless otherwise stated, the following terms appearing in the description and claims of the present invention have the following meanings:

The term "alkyl" refers to a saturated linear or branched hydrocarbon group containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8, 1-6, 1-4, 1-3 carbons Representative examples of atoms, alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl , Octyl, nonyl, decyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and their various isomers Wait.

The term "deuterated alkyl" refers to an alkyl group optionally substituted with a deuterium atom. The deuterated alkyl group described in the present invention is preferably an alkyl group completely substituted with a deuterium atom, for example, -CD ₃ , -C ₂ D ₅ .

The term "cycloalkyl" refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) monocyclic or polycyclic group containing 3-20 carbon atoms. "Cycloalkyl" is preferably C _3-10 cycloalkyl, more preferably C _3-8 monocycloalkyl, C _3-6 monocycloalkyl, and representative examples of the "monocycloalkyl" include but are not limited to : Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl. "Polycyclic cycloalkyl" includes "bridged cycloalkyl", "fused cycloalkyl" and "spirocycloalkyl". Representative examples of "bridged cycloalkyl" include but are not limited to: norbornyl, bicyclic [2.2. 1] Heptenyl, bicyclic [3.1.1] heptyl, bicyclic [2.2.1] heptyl, bicyclic [2.2.2] octyl, bicyclic [3.2.2] nonyl, bicyclic [3.3. 1] Nonyl, bicyclo[4.2.1] nonyl, adamantyl, etc. "Fused cycloalkyl" includes cycloalkyl rings fused to phenyl, cycloalkyl or heteroaryl groups. Condensed cycloalkyl groups include but are not limited to: benzocyclobutenyl, 2,3-di Hydrogen-1H-indenyl, 5,6-dihydro-4H-cyclopentyl[B]thienyl, decahydronaphthyl, etc. "Spirocycloalkyl" refers to a bicyclic group formed by two monocyclic cycloalkyls sharing one carbon atom. Spirocycloalkyl includes but is not limited to: spiro[3,3]heptyl, spiro[3,2]hexyl , Spiro[2,5]octyl, spiro[2,4]heptyl, spiro[4,5]decyl, etc. "C _3-10 cycloalkyl" refers to a cycloalkyl group containing 3-10 carbon atoms; "C _3-8 cycloalkyl" refers to a cycloalkyl group containing 3-8 carbon atoms. "C _3-6 cycloalkyl" refers to a cycloalkyl group containing 3 to 6 carbon atoms. The monocyclic cycloalkyl or polycyclic cycloalkyl can be linked to the parent molecule through any one or two carbon atoms in the ring.

The term "heterocycloalkyl" refers to a saturated or partially unsaturated (including 1 or 2 double bonds) non-aromatic cyclic group composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, or sulfur. The group may be a monocyclic or polycyclic group. In the present invention, the number of hetero atoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl group may be optionally Oxidized. The nitrogen atom may optionally be further substituted with other groups to form a tertiary amine or quaternary ammonium salt. The "monocyclic heterocycloalkyl group" is preferably a 3-10 membered monocyclic heterocycloalkyl group, and more preferably a 3-8 membered monocyclic heterocycloalkyl group. For example: aziridinyl, tetrahydrofuranyl, morpholin-4-yl, thiomorpholinyl, thiomorpholinyl-S-oxide-4-yl, piperidinyl, pyrrolidinyl, piperazinyl, sulfur Heterocyclobutane 1-oxide, 1-oxo-thioheterobutyl, etc. "Polycyclic heterocycloalkyl" includes "fused heterocycloalkyl", "spiro heterocyclyl" and "bridged heterocycloalkyl". "Fused heterocycloalkyl" includes monocyclic heterocycloalkyl rings fused to phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl. Condensed heterocycloalkyl includes, but is not limited to: 2,3 -Dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, dihydroindolyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzopiperanyl, 1, 2,3,4-tetrahydroquinolinyl, 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidinyl, etc. "Spiroheterocyclyl" refers to a bicyclic group formed by two heterocycloalkyl groups or a cycloalkyl group and a heterocycloalkyl group sharing a carbon atom. Spiroheterocyclic groups include, but are not limited to: 5-aza[2.5 ] Octyl, 4-aza[2.5]octyl, 4-aza[2.4]heptyl, etc. The 9-10 membered heterocycloalkyl group is preferably a 9-10 membered fused heterocycloalkyl group. Monocyclic heterocycloalkyl and polycyclic heterocycloalkyl can be linked to the parent molecule through any one or two ring atoms on the ring. The above ring atoms specifically refer to carbon atoms and/or nitrogen atoms constituting the ring skeleton.

The term "cycloalkylalkyl" refers to the connection between the cycloalkyl group and the parent core structure through an alkyl group. Thus, "cycloalkylalkyl" includes the above definitions of alkyl and cycloalkyl.

The term "heterocycloalkylalkyl" refers to the connection between the heterocycloalkyl group and the parent core structure through an alkyl group. Thus, "heterocycloalkylalkyl" includes the above definitions of alkyl and heterocycloalkyl.

The term "alkoxy" refers to a cyclic or acyclic alkyl group having the number of carbon atoms connected through an oxygen bridge, and includes alkyloxy, cycloalkyloxy, and heterocycloalkyloxy groups. Thus, "alkoxy" includes the above definitions of alkyl, heterocycloalkyl, and cycloalkyl.

The term "alkenyl" refers to a linear, branched or cyclic non-aromatic hydrocarbon group containing at least one carbon-carbon double bond. There may be 1-3 carbon-carbon double bonds, preferably one carbon-carbon double bond. The term "C _2-4 alkenyl" refers to an alkenyl group having 2-4 carbon atoms, and the term "C _2-6 alkenyl" refers to an alkenyl group having 2-6 carbon atoms, including vinyl, propenyl , Butenyl, 2-methylbutenyl and cyclohexenyl.

The term "alkynyl" refers to a linear, branched, or cyclic hydrocarbon group containing at least one carbon-carbon triple bond. There may be 1-3 carbon-carbon triple bonds, preferably one carbon-carbon triple bond. The term "C _2-6 alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms, including ethynyl, propynyl, butynyl, and 3-methylbutynyl.

The term "aryl" refers to any stable 6-20 membered monocyclic or polycyclic aromatic group, such as: phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl, etc. .

The term "heteroaryl" refers to an aromatic ring group formed by replacing at least one ring carbon atom with a heteroatom selected from nitrogen, oxygen, or sulfur, which may be a 5-7 membered monocyclic heteroaryl or 7 -20 fused heteroaryl. At least one ring in the "fused heteroaryl group" is a heteroaromatic ring, and the "heteroaryl ring" is preferably a 5-6 membered monocyclic heteroaryl group and a 9-12 or 9-10 membered fused heteroaryl group . In the present invention, the number of hetero atoms is preferably 1, 2, or 3, 5-6 membered heteroaryl groups include but are not limited to: pyridyl, pyrimidinyl, piperazinyl, pyridazin-3(2H)-keto , Furanyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl , 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, etc.; Examples of 9-10 membered fused heteroaryl groups include, but are not limited to: indazolyl, isoindazolyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzene Oxazolyl, quinolinyl, isoquinolinyl, isoquinolinone, quinazolinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, 1H-pyrazolo[3,4-d ]Pyrimidine, thiazolo[5,4-d]pyrimidine, 9H-purine, thiazolo[4,5-d]pyrimidine-2(3H)-keto, 3H-[1,2,3]triazolo [4,5-d]pyrimidinyl, 5,6,7,8-tetrahydrobenzo[4,5]thiazolo[2,3-d]pyrimidinyl, 6,7-dihydro-5H-cyclopentane Alk[4,5]thiazolo[2,3-d]pyrimidinyl and the like.

The term "arylalkyl" refers to the connection between the aryl group and the parent core structure through an alkyl group. Thus, "arylalkyl" includes the above definitions of alkyl and aryl.

The term "heteroarylalkyl" refers to the connection between the heterocycloalkyl group and the parent core structure through an alkyl group. Thus, "heteroarylalkyl" includes the above definitions of alkyl and heteroaryl. The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "haloalkyl" refers to an alkyl group optionally substituted with halogen. Thus, "haloalkyl" includes the above definitions of halogen and alkyl.

The term "haloalkoxy" refers to an alkoxy group optionally substituted with halogen. Thus, "haloalkoxy" includes the above definitions of halogen and alkoxy.

The term "ester group" means -C(O)OR', and R'is C _1-6 alkyl.

The term "amido" means -C(O)N(R") ₂ , R" is hydrogen, C _1-6 alkyl or C _2-6 alkenyl.

The term "carboxy" refers to -C(O)OH.

The term "acyl" refers to -C(O)R"', R"' is C _1-6 alkyl, C _2-6 alkenyl or C _3-8 cycloalkyl.

The term "nitro" refers to -NO ₂ .

The term "oxo" refers to =O.

The term "cyano" refers to -CN.

The term "hydroxyl" refers to -OH.

The term "mercapto" refers to -SH.

The term "amino" refers to -NH _2.

The term "alkylamino" means that at least one hydrogen atom on the amino group is replaced by an alkyl group, including but not limited to: -NHCH ₃ , -N(CH ₃ ) ₂ , -N(CH ₃ )(CH ₂ CH ₃ ),- N(CH ₂ CH ₃ ) ₂ . Thus, "alkylamino" includes the above definitions of alkyl and amino.

The symbol "=" indicates a double bond;

The "room temperature" in the present invention refers to 15-30°C.

The stable isotope derivatives include: isotope substituted derivatives obtained by replacing any hydrogen atom in formula I with 1-5 deuterium atoms (for example: R ₂ is CD ₃ ), and any carbon atom in formula I is replaced by 1 -Isotope substituted derivatives obtained by substitution of 3 carbon 14 atoms or isotope substituted derivatives obtained by substitution of any oxygen atom in formula I or I'with 1-3 oxygen 18 atoms.

The "prodrug" refers to the conversion of the compound into the original active compound after metabolism in the body. Typically, the prodrug is an inactive substance, or less active than the active parent compound, but can provide convenient handling, administration, or improved metabolic properties.

The "pharmaceutically acceptable salts" of the present invention are discussed in Berge, et al., "Pharmaceutically Acceptable Salts", J. Pharm. Sci., 66, 1-19 (1977), It is obvious that the salts are essentially non-toxic and can provide the required pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. The compound of the present invention may have an acidic group, a basic group or an amphoteric group. Typical pharmaceutically acceptable salts include salts prepared by reacting the compound of the present invention with an acid, for example: hydrochloride, hydrobromic acid Salt, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, Propionate, caprate, caprylate, formate, acrylate, isobutyrate, caproate, enanthate, oxalate, malonate, succinate, suberate, Benzoate, methylbenzoate, phthalate, maleate, mesylate, p-toluenesulfonate, (D,L)-tartrate, citrate, male Acid salt, (D,L)-malate, fumarate, lactate, triflate, naphthalene-1-sulfonate, mandelate, pyruvate, stearate, Ascorbate, salicylate. When the compound of the present invention contains an acidic group, its pharmaceutically acceptable salts may also include: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic alkali salts, such as ammonia and alkyl Salts formed by base aminos, hydroxyalkyl aminos, amino acids (lysine, arginine), N-methylglucamine, etc.

The "isomer" in the present invention means that the compound of formula I or I'of the present invention may have an asymmetric center and a racemate, a racemic mixture and a single diastereomer, all of these isomers, The stereoisomers, geometric isomers, atropisomers, and tautomers are included in the present invention. In the present invention, when the compound of formula I or I'or its salt exists in stereoisomeric form (for example, it contains one or more asymmetric carbon atoms), the individual stereoisomer (enantiomer and Diastereomers) and mixtures thereof are included within the scope of the present invention. The present invention also includes individual isomers of compounds or salts represented by formula I or I', and mixtures of isomers in which one or more chiral centers are inverted. The scope of the present invention includes mixtures of stereoisomers, as well as purified enantiomers or enantiomer/diastereomer-enriched mixtures. The present invention includes all enantiomers and mixtures of stereoisomers of all possible different combinations of diastereomers. The present invention includes all combinations and subsets of the stereoisomers of all specific groups defined above. The invention also includes geometric isomers of compounds of formula I or I'or salts thereof, said geometric isomers including cis-trans isomers. The present invention also includes tautomers of compounds of formula I or I'or salts thereof, where tautomers refer to the migration of protons from one atom of a molecule to another atom of the same molecule. For example, when W ₁ is =0 and R ₁ is H, the present invention provides tautomers of the compound represented by formula I or I′, as shown below:

On the basis of not violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred examples of the present invention.

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

detailed description

The present invention is further described by way of examples below, but does not limit the present invention to the scope of the described examples. The experimental methods without specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.

The structures of all compounds of the present invention can be identified by nuclear magnetic resonance ( ¹ H NMR) and/or mass spectrometry (MS).

^{The 1} H NMR chemical shift (δ) is reported in ppm (10 ^-6 ). NMR was performed by Bruker AVANCE-400 spectrometer. Suitable solvents are deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), deuterated dimethyl sulfoxide (DMSO-d ₆ ), and tetramethylsilane as an internal standard (TMS).

Low-resolution mass spectrometry (MS) was measured by Utimate 3000 HPLC-MSQ Plus MS mass spectrometer, using Kinetex 2.6u C18 100A (50×4.6mm) LCMS-02-001, ESI source, gradient elution conditions: 95% solvent A and 5% Solvent B (less than 1.5 minutes or greater than 3 minutes), then 5% Solvent A and 95% Solvent B (1.5 minutes to 3 minutes), the percentage is the volume percentage of a certain solvent in the total solvent volume. Solvent A: 10 mM ammonium bicarbonate aqueous solution; solvent B: acetonitrile.

The purification of the compounds and intermediates of the present invention can use conventional preparation of silica gel plates or the use of rapid separators for separation and purification. The elution system can be ethyl acetate/petroleum ether system or dichloromethane/methanol system. Preparative HPLC can also be used for separation.

High-performance liquid chromatograph (prep-HPLC) uses GilsonGX-281 to prepare liquid chromatography. The column is xtimate C18, 10um, 21.2×250mm. Separation conditions 1: Elution gradient, mobile phase B from 10% to 25%, elution time 5 minutes, mobile phase B from 25% to 45%, elution time 15 minutes, mobile phase A: 10 mM ammonium bicarbonate aqueous solution, Mobile phase B: Acetonitrile; Separation conditions 2: Elution gradient, mobile phase B from 15% to 30%, elution time 5 minutes, mobile phase B from 30% to 50%, elution time 15 minutes, mobile phase A: 0.05% aqueous hydrochloric acid, mobile phase B: acetonitrile; separation conditions 3: mobile phase B from 15% to 20%, elution time 5 minutes, mobile phase B from 20% to 40%, elution time 15 minutes, mobile phase A: 0.05% aqueous hydrochloric acid, mobile phase B: acetonitrile; separation conditions 4: mobile phase B from 10% to 20%, elution time 5 minutes, mobile phase B from 20% to 45%, elution time 15 minutes, Mobile phase A: 0.05% aqueous hydrochloric acid, mobile phase B: acetonitrile; separation conditions 5: mobile phase B from 5% to 10%, elution time 5 minutes, mobile phase B from 10% to 30%, elution time 15 Minutes, mobile phase A: 0.05% aqueous hydrochloric acid, mobile phase B: acetonitrile; separation conditions 6: mobile phase B from 10% to 10%, elution time 5 minutes, mobile phase B from 10% to 35%, elution At 15 minutes, mobile phase A: 0.05% aqueous hydrochloric acid, mobile phase B: acetonitrile. Detection wavelength: 214nm, 254nm and/or 262nm; flow rate: 15.0mL/min.

The thin-layer silicone board (prep-TLC) is Yantai Huanghai HSGF254 or Qingdao GF254 silicone board.

The rapid separation machine (Flash column chromatography) (Flash system/Cheetah ^TM ) uses Agela Technologies MP200, and the supporting separation column is Flashcolumm Silica-CS (80g), Cat No. CS140080-0.

All compounds of the present invention can be analyzed by an ultra-high performance liquid chromatograph (UPLC) using the Waters ACQUITY Hclass platform, the chromatography column is: Waters ACQUITY UPLC BEH Shield RP18 2.1mm*100mm, 1.7μm, mobile phase A: acetonitrile, mobile phase B: 5mm potassium dihydrogen phosphate aqueous solution (adjust pH to 2.5 with phosphoric acid). Gradient elution time 15 minutes, flow rate: 0.4mL/min, detection wavelength: 214nm &254nm; column temperature: 40°C; injection volume 1μL; gradient elution conditions are as follows in Table 1:

Table 1

时间(分钟)Time (minutes)	流速相A(％)Flow rate phase A (%)	流速相B(％)Flow rate phase B (%)
0.000.00	1010	9090
5.005.00	4040	6060
7.007.00	9090	1010
13.0013.00	9090	1010
13.1013.10	1010	9090
15.0015.00	1010	9090

The chiral compounds or intermediates involved in the present invention can be separated and analyzed by supercritical fluid chromatography (SFC).

For chiral resolution, a supercritical fluid chromatograph SFC-80 (Thar, Waters) was used with a flow rate of 80 g/min and a column temperature of 35°C. The detection wavelength is 214 and/or 254 nM. Chiral resolution conditions: Chiral column IC 20×250mm, 10um (Daicel), mobile phase carbon dioxide/methanol (containing 0.2% ammonia methanol solution)=50/50, sample concentration: 5mg/mL (methanol) Sample volume: 4mL.

The chiral analysis of the compound of the present invention uses a supercritical fluid chromatography analyzer SFC Method Station (Thar, Waters) with a flow rate of 4 mL/min, a column temperature of 40° C. and a detection wavelength of 214 and/or 254 nM. Chiral analysis conditions: Chiral column Cellulose-SC 4.6×100mm, 5um (YMC), mobile phase is carbon dioxide/methanol (containing 0.2% ammonia methanol solution) = 65/35.

The use of the microwave reaction described in the embodiments of the present invention

Initiator+Microwave System EU (356006) type microwave reactor. Unless otherwise specified in the present invention, all the reactions in the examples are carried out under the protection of nitrogen or argon.

The meanings of the abbreviations used in the embodiments of the present invention are as follows:

NaBH ₄ : sodium borohydride, TFA: trifluoroacetic acid, Cs ₂ CO ₃ : cesium carbonate, Boc ₂ O: di-tert-butyl dicarbonate, DMAP: 4-dimethylaminopyridine, Xantphos: 4,5-bisdi Phenylphosphine-9,9-dimethylxanthene, Ruphos: 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, XPhos: 2-bicyclo Hexylphospho-2,4,6-triisopropylbiphenyl, Pd ₂ (dba) ₃ : tris(dibenzylideneacetone) dipalladium, THF: tetrahydrofuran, PE: petroleum ether, EtOAc: ethyl acetate, DCM : Dichloromethane, DMF: N,N-dimethylformamide, MeOH: methanol, EtOH: ethanol, MTBE: methyl tert-butyl ether, DMSO: dimethyl sulfoxide, HOBT: 1-hydroxybenzotriazole , EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

Synthesis of intermediates:

Synthesis of Intermediate 1.1

Step 1: To a solution of 5-bromo-3-methylpyridine-2-carboxylic acid (50 g, 231 mmol) in ethanol (250 mL), concentrated sulfuric acid (12.5 mL) was added dropwise. The reaction solution was stirred at 95°C overnight and concentrated under reduced pressure. The residue was dissolved with DCM (500 mL), and the pH was adjusted to 7 with saturated aqueous sodium carbonate solution. The organic phase was separated and the aqueous phase was extracted with DCM. The organic phases were combined and washed with water and saturated saline, respectively. It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain ethyl 5-bromo-3-methylpyridine-2-carboxylate (55.1 g) as a pale yellow oil. m/z: [M+H] ⁺ 276.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.61 (s, 1H), 8.12 (s, 1H), 4.33 (q, J=7.2 Hz, 2H ), 2.44 (s, 3H), 1.31 (t, J = 7.2Hz, 3H).

Step 2: Under ice bath conditions, to the DCM (280 mL) solution of the product obtained in Step 1 (55 g, 225 mmol) was added urea peroxide (37.1 g, 394 mmol) in portions, and then trifluoroacetic anhydride (55.6 mL, 394mmol). After the addition, the reaction system was raised to room temperature and stirred for 5 hours. The reaction solution was poured into ice water, and extracted with DCM (2×200 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 5-bromo-2-(ethoxycarbonyl)-3-methylpyridine 1-oxide (58g) as a tan Oily matter. m/z:[M+H] ⁺ 260.0,262.0.

Step 3: To the DMF (200 mL) solution of the product (58 g, 223 mmol) obtained in step 2, trifluoroacetic anhydride (55 mL, 390 mmol) was slowly added dropwise. After the addition, the reaction system was heated to 40°C and stirred for 1 hour. The reaction solution was poured into ice water, a large amount of white solid was generated, and filtered. The filter cake was washed sequentially with water and MTBE. The filter cake was dried in vacuo to give ethyl 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate (25 g) as a white solid. m/z:[M+H] ⁺ 260.0,262.0.

Step 4: Stir the product obtained in Step 3 (5.6g, 21.5mmol) and Cs ₂ CO ₃ (28.1g, 86.1mmol) in DMF (50mL) for 15 minutes, then add O-(diphenylphosphine oxide Base) hydroxylamine (10 g, 43.1 mmol). After the addition, the reaction system was stirred at room temperature for 2 hours. Water (150 mL) was added to the reaction solution, and extracted with EtOAc (50 mL×4). The combined organic phases were washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1-amino-5- Bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid ethyl ester (6g, crude product) is a yellow oily liquid. m/z:[M+H] ⁺ 275.0.

Step 5: The product obtained in Step 4 (500 mg, crude product) and ammonia methanol solution (7 mol/L, 10 mL) were added to a sealed tube, heated to 85° C., and stirred for 2 days. Then, the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain 1-amino-5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (500 mg, crude product) as yellow. solid. m/z: [M+H] ⁺ 246.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.96 (s, 1H), 7.91 (s, 1H), 7.86 (s, 1H), 5.85 (s , 2H), 2.02 (s, 3H).

Step 6: The product obtained in Step 5 (400 mg, crude product) and cyclohexanone (1.6 g, 16.3 mmol) were added to 1,4-dioxane (10 mL), and the reaction solution was stirred at 95° C. for 2 hours, slowly After cooling to room temperature, concentrated sulfuric acid (0.1 mL) was added thereto with vigorous stirring, and stirring was continued for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was prepared with prep-TLC (DCM/MeOH=20 /1) Purification to obtain 7'-bromo-5'-methylspiro[cyclohexane-1,2'-pyrido[2,1-f][1,2,4]triazine-4',8'(1'H,3'H)-Diketone (intermediate 1.1, 400 mg) is an off-white solid. m/z: [M+H] ⁺ 326.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.17 (s, 1H), 7.92 (s, 1H), 3.57 (s, 1H), 2.38 (s ,3H),1.70-1.40(m,10H).

Synthesis of Intermediates 1.2-1.6

Using the synthetic method of Intermediate 1.1, replace 5-bromo-3-methylpyridine-2-carboxylic acid in Step 1 with the corresponding substituted 3,5-dibromopyridine-2-carboxylic acid and the ring in Step 6. Replacement of hexanone with the corresponding ketone gives intermediate 1.2-1.6:

Table 2

Synthesis of Intermediate 1.8

Step 1: Combine ethyl 1-amino-5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate (300 mg, 1.09 mmol) in acetone (5 mL) and 1,4 -Dioxane (10 mL) solution was added to the sealed tube, and the reaction system was stirred at 110°C for 2 days. After cooling, the reaction solution was directly concentrated to obtain ethyl 5-bromo-3-methyl-6-oxo-1-(prop-2-ylideneamino)-1,6-dihydropyridine-2-carboxylate (370 mg) It is a yellow liquid. m/z:[M+H] ⁺ 315.0,317.0.

Step 2: Sodium borohydride (126 mg, 3.33 mmol) was added to the MeOH (10 mL) solution of the product (350 mg, crude) obtained in Step 1. The reaction system was stirred at room temperature for 3 days. The reaction solution was poured into water and extracted with ethyl acetate (3×30 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 5-bromo-1-(isopropylamino)-3-methyl Ethyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid ethyl ester (70 mg) is a yellow liquid. m/z:[M+H] ⁺ 317.0,319.0.

Step 3: Lithium hydroxide monohydrate (26 mg, 0.63 mmol) was added to the mixed solution of the product (50 mg, 0.16 mmol) obtained in Step 2 in MeOH/THF/water (5 mL/5 mL/5 mL). The reaction system was heated to 50°C and stirred for 16 hours. The reaction solution was concentrated, poured into water, and adjusted to pH=5 with 1N HCl. The aqueous phase was extracted with ethyl acetate (3×30 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 5-bromo- 1-(isopropylamino)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (45 mg) is a yellow solid. m/z:[M+H] ⁺ 289.0,291.0.

Step 4: The product obtained in Step 3 (45 mg, 0.16 mmol) was added to sulfoxide chloride (5 mL) and DCM (5 mL). The reaction system was heated to 50° C. and stirred for 8 hours. The reaction solution was concentrated and ammonia methanol (5 mL) was added. , 7M), the reaction system was stirred at room temperature for 2 hours and concentrated to give 5-bromo-1-(isopropylamino)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (40mg) is a brown solid. m/z:[M+H] ⁺ 288.0,290.0.

Step 5: Add concentrated sulfuric acid (2 drops) to a solution of the product obtained in Step 4 (40 mg, crude) and cyclohexanone (136 mg, 1.39 mmol) in 1,4-dioxane (10 mL). The reaction solution was heated to 95°C and stirred for 16 hours. After cooling, the reaction solution was concentrated, and water and petroleum ether were added to the residue for beating, filtration and vacuum drying of the filter cake to obtain 7'-bromo-1'-isopropyl-5'-methylspiro[cyclohexane-1, 2'-pyrido[2,1-f][1,2,4]triazine-4',8'(1'H,3'H)-dione (intermediate 1.8, 50 mg) is a brown solid. m/z:[M+H] ⁺ 368.0,370.0.

Synthesis of Intermediate 1.9

Step 1: Add copper acetate (1.98g, 10.9mmol) and pyridine (1.15g, 15.5mmol) to 1-amino-5-bromo-3-methyl-6-oxo-1,6-dihydropyridine- In a solution of ethyl 2-formate (2.0 g, 7.27 mmol) and 3-nitrophenylboronic acid (2.43 g, 14.5 mmol) in DCM (10 mL), the reaction system was stirred at 45° C. for 16 hours. The reaction system was cooled to room temperature and poured into water. The aqueous phase was extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to Flash column chromatography (PE/ EtOAc = 1/1) purification to obtain 5-bromo-3-methyl-1-((3-nitrophenyl)amino)-6-oxo-1,6-dihydropyridine-2-carboxylic acid ethyl ester ( 700 mg) is a yellow solid. m/z:[M+H] ⁺ 395.8.

Step 2: Lithium hydroxide monohydrate (297mg, 7.07mmol) was added to the MeOH/THF/water (3mL/3mL/3mL) mixed solution of the product (700mg, 1.77mmol) obtained in Step 1, and the reaction system was stirred at room temperature 4 hour. The reaction solution was concentrated, poured into water, and adjusted to pH=3 with 1N hydrochloric acid. The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 5-bromo- 3-Methyl-1-((3-nitrophenyl)amino)-6-oxo-1,6-dihydropyridine-2-carboxylic acid (650 mg) is a yellow solid. m/z:[M+H] ⁺ 367.8.

Step 3: The product obtained in Step 2 (650 mg, 1.77 mmol) was added to sulfoxide chloride (5 mL) and DCM (5 mL), and the reaction system was stirred at 50°C for 4 hours. After the reaction solution was concentrated, an ammonia methanol solution (7M, 5 mL) was added, the reaction system was stirred at room temperature for 1 hour, and concentrated under reduced pressure to obtain 5-bromo-3-methyl-1-((3-nitrophenyl)amino )-6-oxo-1,6-dihydropyridine-2-carboxamide (800 mg) is a yellow solid. m/z:[M+H] ⁺ 366.8.

Step 4: Add concentrated sulfuric acid (0.1 mL) dropwise to the 1,4-dioxane (10 mL) solution of the product (400 mg, 1.09 mmol) and cyclobutanone (611 mg, 8.72 mmol) obtained in step 3, the reaction system Stir at 50°C for 4 hours. After cooling, the reaction solution was concentrated, added to water and filtered to obtain a solid, which was then pulped with ethanol (5 mL), filtered, and the filter cake was vacuum dried to obtain 7'-bromo-5'-methyl-1'-(3-nitrophenyl) Spiro[cyclobutane-1,2'-pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione (middle Body 1.9, 294 mg) is a yellow solid. m/z:[M+H] ⁺ 418.8.

Synthesis of Intermediate 1.10

1-Amino-5-bromo-3-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (200 mg, 0.75 mmol) and 3,3-dimethylcyclobutanone (295 mg, 3.0 mmol) was added to absolute ethanol (5 mL), the reaction system was heated to 90°C, and concentrated sulfuric acid (6 drops) was slowly added dropwise. The mixed solution was heated and stirred for 4 hours, and a white solid precipitated. Concentrate under reduced pressure, disperse the solid into saturated aqueous sodium bicarbonate, and filter. The filter cake was washed with water and petroleum ether respectively. The filter cake was vacuum dried to obtain 7'-bromo-5'-chloro-3,3-dimethylspiro[cyclobutane-1,2'-pyrido[2,1-f][1,2,4] Azine]-4',8'(1'H,3'H)-dione (intermediate 1.10, 240mg) is a light yellow solid. m/z: [M+H] ⁺ 346.0, 348.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.76 (s, 1H), 8.15 (s, 1H), 7.33 (s, 1H), 2.12 -1.94(m,4H), 1.22(s,3H), 1.14(s,3H).

Synthesis of Intermediate 1.11-1.14

Using the synthetic method of intermediate 1.10, 3,3-dimethylcyclobutanone was replaced with the corresponding ketone to obtain intermediate 1.11-1.14:

table 3

Synthesis of Intermediate 2.1

Step 1: Compound 1.4 (200 mg, 0.6 mmol), methyl iodide (445 mg, 3 mmol) and DMF (2 mL) were added to a sealed tube, and the reaction system was stirred at 105°C for 16 hours. Then the reaction solution was concentrated under reduced pressure, and the residue was purified by prep-TLC (EtOAc) to obtain 7'-bromo-5'-chloro-1'-methylspiro[cyclobutane-1,2'-pyrido[2, 1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione (200mg) is a yellow solid. m/z:[M+H] ⁺ 331.9.

Step 2: Under nitrogen protection, the product obtained in Step 1 (60mg, 0.18mmol), tert-butyl carbamate (42mg, 0.36mmol), Pd ₂ (dba) ₃ (3mg), Xantphos (3mg), XPhos (3mg) , A mixture of Cs ₂ CO ₃ (118 mg, 0.36 mmol) and tert-butanol (1.6 mL) was stirred at 85° C. for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-TLC (PE/EtOAc = 1/1) to obtain (5'-chloro-1'-methyl-4', 8'-dioxo-1', 3 ',4',8'-tetrahydrospiro[cyclobutane-1,2'-pyrido[2,1-f][1,2,4]triazine]-7'-yl)carbamic acid tert-butyl The ester (40 mg) was a white solid. m/z:[M+H] ⁺ 368.9.

Step 3: Under ice bath conditions, TFA (0.3 mL) was added dropwise to a solution of the product (40 mg, 0.11 mmol) obtained in Step 2 in DCM (0.3 mL). After the addition, the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with DCM, solid sodium bicarbonate was added to adjust pH=7, stirred for about 20 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain 7′-amino-5′-chloro-1′-methyl Spiro[cyclobutane-1,2'-pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione (middle Body 2.1, 40 mg) is a yellow solid. m/z:[M+H] ⁺ 269.0.

Synthesis of intermediates 3.1 and 3.2

1-Amino-5-bromo-3-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (100 mg, 0.4 mmol), 5-chloro-2-pentanone (113 mg, 0.9 mmol ) And concentrated sulfuric acid (1 drop) were added to ethanol (1 mL) and stirred at 80°C for 8 hours. Slowly cool to room temperature, filter, and dry the filter cake in vacuo to give 7-bromo-5-chloro-2-(3-chloropropyl)-2-methyl-2,3-dihydro-1H-pyrido[2,1 -f][1,2,4]triazine-4,8-dione (intermediate 3.1) and 8-bromo-6-chloro-3a-methyl-2,3,3a,4-tetrahydro-1H -A mixture of pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazine-5,9-dione (intermediate 3.2) (85 mg, 3.1/3.2=1 /2.7) is a white solid. m/z:[M+H] ⁺ 368.0,332.0.

Synthesis of Intermediate 3.3

Combine 1-amino-5-bromo-3-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (150 mg, 0.56 mmol) and 6-chloro-2-hexanone (227 mg, 1.69 mmol) ) In an ethanol (6 mL) solution was stirred in a sealed tube at 110°C for 16 hours. The reaction solution was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate. The organic phase was washed with water. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 9-bromo-7-chloro-4a-methyl -1,2,3,4,4a,5-hexahydrodipyrido[1,2-b:2',1'-f][1,2,4]triazine-6,10-dione ( Intermediate 3.3, 150 mg) brown solid. m/z:[M+H] ⁺ 345.8.

Synthesis of Intermediate 3.4-3.6

Using the synthetic method of Intermediate 3.3, 1-Amino-5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide and the corresponding chloroketone were reacted to obtain Intermediate 3.4 -3.6:

Table 4

Synthesis of Intermediate 4.1

1-Amino-5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (100 mg, 0.4 mmol), methyl levulinate (264 mg, 2 mmol) and concentrated Sulfuric acid (1 drop) was added to 1,4-dioxane (1 mL) and stirred at 95°C for 4 hours. Slowly cool to room temperature, filter, and the filtrate is concentrated under reduced pressure to give 8-bromo-3a,6-dimethyl-2,3,3a,4-tetrahydro-1H-pyrido[2,1-f]pyrrolo[1 ,2-b][1,2,4]triazine-1,5,9-trione (intermediate 4.1, 80 mg) is a yellow oil. m/z:[M+H] ⁺ 326.0.

Synthesis of Intermediate 5.1

Combine 1-amino-5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (60mg, 0.2mmol), antimony trichloride (6mg) and triethyl orthoacetate The ester (0.6 mL) was placed in a microwave tube and reacted at 100°C for 10 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was slurried with absolute ethanol (2 mL), filtered, and the filter cake was dried in vacuo to obtain 7-bromo-5-chloro-2-methyl-3H-pyrido[2,1 -f][1,2,4]triazine-4,8-dione (intermediate 5.1, 50 mg) is a white solid. m/z:[M+H] ⁺ 289.8.

Synthesis of Intermediate 6.1

Step 1: Under ice bath, add a solution of 2-methyl-3-nitro-5-bromoaniline (5g, 21.6mmol) in acetonitrile (40mL) dropwise to cuprous chloride (3.3g, 33.5mmol) and In a suspension of tert-butyl nitrite (3.5 g, 33.5 mmol) in acetonitrile (40 mL), the reaction system was stirred at 30° C. overnight. The reaction solution was poured into hydrochloric acid (0.5N) and extracted with EtOAc (3×150 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to Flash column chromatography (PE/EtOAc) = 1/1) Purification gave 5-bromo-1-chloro-2-methyl-3-nitrobenzene (3.23g) as a yellow-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.15 (d, J = 8.8 Hz, 2H), 2.37 (s, 3H).

Step 2: At 80°C, add potassium permanganate (15.8g, 100mmol) in batches to the mixed solution of the product (5g, 20mmol) obtained in step 1 in pyridine (75mL) and water (50mL) within 6 hours. Stir at 80°C overnight. Ethanol (100 mL) was added to the reaction solution, and after refluxing for 30 minutes, it was filtered while hot, and the filter cake was washed with THF (3×50 mL). The combined filtrate was concentrated, 10% aqueous sodium hydroxide solution was added to the residue, and the impurities were extracted with EtOAc (3×80 mL). The aqueous phase was adjusted to pH=2 with 1N hydrochloric acid and extracted with DCM/MeOH=10/1 (3×80 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 4-bromo-2-chloro- 6-Nitrobenzoic acid (1.56g) is an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 14.55 (br.s, 1H), 8.39 (d, J=5.6 Hz, 2H).

Step 3: To the product obtained in Step 2 (1.96g, 7mmol), aqueous sodium hydroxide solution (0.88N, 9.8mL), ferric chloride (0.12g, 0.77mmol) and isopropanol (1.0mL) were added successively. The reaction system was heated to 75°C, and 80% hydrazine hydrate (2.2 g, 35.2 mmol) was slowly added dropwise thereto with stirring, and the reaction system was stirred at 75°C for 2 hours. After cooling to room temperature and filtering, the filtrate was concentrated and poured into water (10 mL), adjusted to pH=2 with 1N hydrochloric acid, filtered and the filter cake dried in vacuo to obtain 2-amino-4-bromo-6-chlorobenzoic acid (Intermediate 6.1 , 1.5g) is an off-white solid. m/z:[M+H] ⁺ 249.8.

Synthesis of Intermediate 6.2

Step 1: To a mixture of trichloroacetaldehyde (9g, 61mmol), anhydrous sodium sulfate (35g, 243mmol) and water (165mL) was added 3-bromo-5-chloro-2-methoxyaniline (7.2g, 30.4 mmol) of DMF (75 mL) followed by concentrated hydrochloric acid (3.8 mL) and the reaction system was stirred at 90°C for 25 minutes. Hydroxylamine hydrochloride (12.7 g, 182 mmol) was added to the above reaction system and stirred at 90°C for 5 hours. The reaction mixture was cooled to room temperature, added water (1L) and stirred vigorously, filtered, and the filter cake was dried in vacuum to obtain N-(3-bromo-5-chloro-2-methoxyphenyl)-2-(oximino)acetamide (7.56g) is a yellow-white solid. m/z: [M+H] ⁺ 307.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.52 (s, 1H), 9.54 (s, 1H), 8.23 (s, 1H), 7.81 (s , 1H), 7.54 (s, 1H), 3.78 (s, 3H).

Step 2: Preheat concentrated sulfuric acid (60 mL) to 30°C, add the product obtained in step 1 (7.4g, 23.9mmol) in batches with stirring and keep the internal temperature at 30-50°C, after addition, the reaction system is at 70°C Stir for 15 minutes. The reaction mixture was slowly poured into vigorously stirred crushed ice (160 g) and ice water (320 mL). The precipitated solid was collected by filtration, washed with ice water at pH=7, and dried in vacuo. After drying, the solid was slurried with ethanol (20 mL), filtered, and the filter cake was dried in vacuum to obtain 6-bromo-4-chloro-7-methoxyindole Porphyrin-2,3-dione (5.59g) is an orange solid. m/z: [M+H] ⁺ 289.8; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.63 (s, 1H), 7.43 (s, 1H), 3.75 (s, 3H).

Step 3: Under ice bath conditions, to the 1,4-dioxane solution (84 mL) of the product (5.6 g, 19.2 mmol) obtained in Step 2 was added 30% hydrogen peroxide (9.8 mL), and then aqueous sodium hydroxide solution was added dropwise (0.67N, 360 mL), the resulting mixture was slowly warmed to room temperature and stirred for 3 hours. Extract with ethyl acetate (3×80 mL) to remove impurities. After adjusting pH=2 with 1N hydrochloric acid, extract with ethyl acetate (3×80 mL). Combine the organic phases and dry with anhydrous sodium sulfate. Concentrate under pressure to obtain 2-amino-4-bromo-6-chloro-3-methoxybenzoic acid (Intermediate 6.2, 4.58 g) as a yellow solid. m/z:[M+H] ⁺ 279.8.

Synthesis of Intermediate 6.3

Using the synthesis method of Intermediate 6.2, using 3-bromo-5-chloro-2-fluoroaniline (synthesis method refers to US20110052578A1) to obtain 2-amino-4-bromo-6-chloro-3-fluorobenzoic acid (Intermediate 6.3 ). m/z:[M+H] ⁺ 267.8.

Synthesis of Intermediate 6.4

Step 1: 2,3-Dimethyl-5-bromonitrobenzene (31.2 g, 132 mmol) was dissolved in DMF (150 mL), and the solution was heated to 100° C. and stirred overnight. After cooling to room temperature, the reaction solution was quickly added to a previously cooled sodium periodate (113.2 g, 529 mmol) solution (DMF/water=1/1,300 mL). The reaction solution was stirred at room temperature for 5 hours and filtered. The filter cake was washed with PE/EtOAc (10/1) until there was no product, and the filtrate was extracted with PE/EtOAc (10/1). The organic phases were combined and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue was purified by Flash column chromatography (PE/EtOAc=10/1) to obtain 4-bromo-2-methyl-6-nitrobenzaldehyde (5.8 g) as a light brown solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.28 (s, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 2.50 (s, 3H).

Step 2: The ethanol/water (3/1,200mL) solution of the product (4.8g, 19.7mmol) and ammonium chloride (10.5g, 196.7mmol) obtained in Step 1 was heated to 60°C, and then iron powder (11g) was added in portions , 197mmol), the resulting mixture was stirred for 2 hours. After filtration, the filter cake was washed with EtOAc until no product remained, and the filtrate was extracted with EtOAc. The organic phases were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-amino-4-bromo-6-methylbenzaldehyde (4.1 g) as a light brown solid. m/z: [M+H] ⁺ 216.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.24 (s, 1H), 7.58 (br.s, 2H), 6.91 (s, 1H), 6.61 (s,1H), 2.54(s,3H).

Step 3: Sodium chlorite (5.2g, 57.46mmol) and sodium dihydrogen phosphate (6.89g, 57.5mmol) were dissolved in water (50mL), and then the solution was added dropwise to the product obtained in step 2 (4.1g, 19.2 mmol) and 2-methyl-2-butene (6.72 g, 95.8 mmol) in tert-butanol/THF (1/1,100 mL) solution, stirred at room temperature overnight. The reaction was quenched with aqueous sodium hydroxide (0.5M) and extracted with EtOAc. The aqueous phase was adjusted to pH=6 with dilute hydrochloric acid (1N) and extracted with DCM. The DCM phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with DCM/PE (1/100), filtered, and the filter cake was dried in vacuo to give 2-amino-4-bromo-6-methylbenzoic acid (compound 6.4, 2.15 g) as a light brown solid. m/z:[M+H] ⁺ 230.0.

Synthesis of Intermediate 7.1

To a mixture of 2,6-dichloro-4-methylnicotinamide (2.6 g, 12.7 mmol) and 1,4-dioxane (25 mL) was added ammonia water (10 mL). The reaction system was sealed, heated to 135°C and stirred for 24 hours. It was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (DCM/MeOH=50/1～20/1) to give 2-amino-6-chloro-4-methylnicotinic acid amide (intermediate 7.1, 660 mg) as pale yellow. solid. m/z: [M+H] ⁺ 186.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.80 (s, 1H), 7.64 (s, 1H), 6.50 (s, 1H), 6.17 (s , 2H), 2.20 (s, 3H).

Synthesis of Intermediate 8.1

Step 1: 2-amino-4-bromo-3-methoxy-6-methylbenzoic acid (synthesis method refers to US2009143353A1) (2.6g, 10mmol), HOBT (1.6g, 12mmol) and EDCI (2.1g, 11mmol) ) Dissolved in DMF (25mL), stirred at room temperature for 15 minutes, cooled to 0°C, 30% ammonia water (25mL) was added dropwise, and stirred at room temperature for 16 hours. It was extracted with ethyl acetate (50 mL×3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with EtOAc/PE (9/1) solution, filtered, and filtered The cake was dried in vacuo to give 2-amino-4-bromo-3-methoxy-6-methylbenzamide (1.2 g) as a light yellow solid. m/z: [M+H] ⁺ 259.0, ¹ H NMR (400MHz, DMSO-d ₆ ): δ 7.75 (s, 1H), 7.59 (s, 1H), 6.66 (s, 1H), 4.99 (br .s, 2H), 3.66 (s, 3H), 2.17 (s, 3H).

Step 2: The product obtained in Step 1 (200 mg, 0.77 mmol) and cyclopentanone (324 mg, 3.86 mmol) were suspended in ethanol (5 mL), concentrated sulfuric acid (75 mg, 0.77 mmol) was added, and the reaction solution was refluxed at 95°C for 3 hours , Cooled to room temperature, filtered to obtain 7'-bromo-8'-methoxy-5'-methyl-1'H-spiro[cyclopentane-1,2'-quinazoline]-4'(3' H)-one (intermediate 8.0, 250 mg) is a gray solid. m/z:[M+H] ⁺ 259.0.

Step 3: DMF (3mL) solution of Intermediate 8.0 (150mg, 0.46mmol) and methyl iodide (0.5mL) was stirred at 105°C in a sealed tube overnight, the reaction solution was cooled to room temperature, diluted with ethyl acetate, and the organic phase was used The aqueous solution of sodium thiosulfate was washed, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (PE/EtOAc=3/1) to obtain 7'-bromo-8'- Methoxy-1',5'-dimethyl-1'H-spiro[cyclopentane-1,2'-quinazoline]-4'(3'H)-one (intermediate 8.1, 75mg) It is a white solid. m/z:[M+H] ⁺ 339.0.

Synthesis of Intermediate 8.2-8.16

Using the synthetic method of intermediate 8.0, the corresponding substituted benzoic acid or benzamide and the corresponding cycloalkyl ketone or heterocycloalkyl ketone are reacted to obtain intermediate 8.2-8.14:

Using the synthetic method of intermediate 8.1, the corresponding substituted benzoic acid or benzamide and cyclobutanone are reacted to obtain intermediate 8.15-8.16:

table 5

Synthesis of Intermediate 9.1

Step 1: Add Xantphos (18 mg, 30.2 μmol) and Pd ₂ (dba) ₃ (14 mg, 15.2 mmol) to N,N-dimethyl-3-(piperazin-1-yl)propan-1-amine in this order (100 mg, 0.302 mmol), N,N-di-Boc-2-amino-6-chloropyrimidine (156 mg, 0.30 mmol) and cesium carbonate (494 mg, 1.52 mmol) in 1,4-dioxane (10 mL) In the solution, the reaction system was replaced with nitrogen three times and stirred at 95°C for 3 hours. After cooling, the reaction was quenched by adding water (15 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic phases were concentrated under reduced pressure and the residue Purified by prep-TLC (PE/EtOAc=1/1) to obtain N,N-di-Boc-2-amino-6-(4-(3-(dimethylamino)propyl)piperazin-1-yl ) Pyrimidine (80mg) is a light brown liquid. m/z:[M+H] ⁺ 465.2.

Step 2: TFA (2mL) was added to the DCM (5mL) solution of the product (80mg, 0.172mmol) obtained in Step 1, the reaction system was stirred at room temperature for 4 hours, and the reaction solution was concentrated to obtain 6-(4-(3-(two Methylamino)propyl)piperazin-1-yl)pyrimidine-4-amine (Intermediate 9.1, 80 mg) is a yellow oil. m/z:[M+H] ⁺ 264.0.

Synthesis of compounds:

Example 1: 7'-((6-aminopyrimidin-4-yl)amino)-5'-methylspiro[cyclohexane-1,2'-pyrido[2,1-f][1,2 ,4]Triazine]-4',8'(1'H,3'H)-Dione Hydrochloride (Compound 1-1)

Step 1: Intermediate 1.1 (100 mg, 0.3 mmol), tert-butyl 6-aminopyrimidine-4-carbamate (77.3 mg, 0.37 mmol), Pd ₂ (dba) ₃ (15 mg), Xantphos (15 mg), Cs A mixture of ₂ CO ₃ (200 mg, 0.61 mmol) and 1,4-dioxane (2.5 mL) was replaced with nitrogen three times, and then the reaction system was heated to 85° C. and stirred for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was slurried with ethanol (2.5 mL) and filtered. The filter cake was rinsed with a small amount of cold ethanol. The filter cake was dried in vacuum to give (6-((5'-methyl-4',8'-Dicarbonyl-1',3',4',8'-tetrahydrospiro[cyclohexane-1,2'-pyridine[2,1-f][1,2,4]triazine]-7' -Yl)amino)pyrimidin-4-yl)carbamic acid tert-butyl ester (200 mg, crude) is a yellow solid. m/z:[M+H] ⁺ 456.0.

Step 2: Under ice bath conditions, TFA (1.8 mL) was added dropwise to the DCM (1.5 mL) solution of the product (200 mg, crude product) obtained in Step 1, after the addition, the reaction system was slowly raised to room temperature and stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate aqueous solution was added to the residue to adjust pH=7, bubbles were generated and a gray solid was precipitated, filtered, the solid was collected and purified by prep-HPLC (separation condition 2) to obtain compound 1-1 27.5 mg, two-step yield: 26%) is a light yellow solid. m/z: [M+H] ⁺ 356.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.81 (s, 1H), 8.98 (s, 1H), 8.47 (s, 1H), 7.98 (br .s, 3H), 6.42 (s, 1H), 2.43 (s, 3H), 1.73-1.20 (m, 10H).

Example 2: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-methylspiro[cyclohexane-1,2'-pyrido[2, 1-f][1,2,4]Triazine]-4',8'(1'H,3'H)-Dione Hydrochloride (Compound 1-2)

Intermediate 1.1 (50 mg, 0.15 mmol), 7H-pyrrolo[2,3-d]pyrimidin-4-amine (25 mg, 0.18 mmol), Pd ₂ (dba) ₃ (10 mg), Xantphos (10 mg), Cs A mixture of ₂ CO ₃ (100 mg, 0.3 mmol) and 1,4-dioxane (1.2 mL) was replaced with nitrogen three times, and then the reaction system was heated to 95° C. and stirred for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 2) to obtain compound 1-2 (20 mg, yield: 34%) as a yellow solid. m/z: [M+H] ⁺ 380.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.42 (s, 1H), 9.75 (br.s, 1H), 9.03 (s, 1H), 8.45 (s, 1H), 8.21 (s, 1H), 7.46 (s, 1H), 6.89 (s, 1H), 2.49 (s, 3H), 1.75-1.25 (m, 10H).

Example 3: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chlorospiro[cyclohexane-1,2'-pyrido[2,1 -f][1,2,4]Triazine]-4',8'(1'H,3'H)-Dione Hydrochloride (Compound 1-3)

Using the synthetic method of compound 1-2, intermediate 1.1 was replaced with 1.2 to obtain compound 1-3 as a white solid. m/z: [M+H] ⁺ 400.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.27 (s, 1H), 9.25 (br.s, 1H), 9.12 (s, 1H), 8.64 (s,1H), 8.51 (s, 1H), 7.44 (s, 1H), 6.89 (s, 1H), 1.84-1.16 (m, 10H).

Example 4: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1',5'-dimethylspiro[cyclohexane-1,2'-pyridine Of [2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-4)

Step 1: Intermediate 1.1 (50 mg, 0.15 mmol) and iodomethane (44 mg, 0.31 mmol) were added to DMF (5 mL), and the reaction system was heated to 70° C. in a sealed tube and stirred for 2 days. The reaction solution was poured into EtOAc, washed with water and saturated brine, the organic phase was separated and dried over anhydrous sodium sulfate, and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-TLC (DCM/MeOH=20/1) 7'-Bromo-1',5'-dimethylspiro[cyclohexane-1,2'-pyrido[2,1-f][1,2,4]triazine]-4',8 '(1'H,3'H)-dione (30 mg, yield: 58%) is a yellow liquid. m/z:[M+H] ⁺ 340.0,342.0.

Step 2: Add XPhos (4mg, 8.82μmol), Xantphos (5mg, 8.82μmol) and Pd ₂ (dba) ₃ (4mg, 4.41μmol) to the product obtained in Step 1 (30mg, 88.2μmol), 7H-pyrrolo [2,3-d]pyrimidine-4-amine (13 mg, 97.0 μmol) and Cs ₂ CO ₃ (37 mg, 0.12 mmol) in 1,4-dioxane (4 mL) solution, the reaction system was replaced with nitrogen three times Then, microwave reaction was carried out at 110°C for 3 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (separation condition 2) to obtain compound 1-4 (11.3 mg, yield: 33%) as a pale yellow solid. m/z: [M+H] ⁺ 394.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.16 (br.s, 1H), 8.74 (s, 1H), 8.46 (s, 2H), 7.42 (s,1H), 6.79 (s, 1H), 2.58 (s, 3H), 2.50 (3H, overlapping with solvent), 2.20-1.23 (m, 10H).

Example 5: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1'-acryloyl-5'-methylspiro[cyclohexane-1,2' -Synthesis of pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-5)

Step 1: Acryloyl chloride (1.2 mL, 14.8 mmol) was added dropwise to a solution of intermediate 1.1 (0.30 g, 0.9 mmol) in DMF (9 mL), and the reaction system was stirred at 85°C for 20 minutes. Under an ice bath, the reaction solution was poured into saturated aqueous sodium bicarbonate solution (30 mL) to quench the reaction. The aqueous phase was extracted with EtOAc (3×15 mL). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-TLC (PE/EtOAc = 1/2) to obtain 1'-acryloyl-7'-bromo-5'-methylspiro[cyclohexane-1,2'-Pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione (250mg, yield: 71%) is light yellow solid. m/z:[M+H] ⁺ 380.0.

Step 2: Add Ru-phos (6 mg, 13.2 μmol) and Pd ₂ (dba) ₃ (6.0 mg, 6.6 mmol) to the product obtained in Step 1 (50 mg, 0.13 mmol), 7H-pyrrolo[2,3- d) A solution of pyrimidine-4-amine (27 mg, 0.20 mmol) and sodium tert-butoxide (16 mg, 0.17 mmol) in toluene (3 mL). The reaction system was replaced with nitrogen three times, and stirred at 105° C. for 3 hours. After cooling, water was added (15 mL) The reaction was quenched, the aqueous phase was extracted with ethyl acetate (3×10 mL), the combined organic phase was concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 2) to obtain compound 1-5 (0.65 mg, yield) : 1%) is a light yellow solid. m/z: [M+H] ⁺ 434.1; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.06 (br.s, 1H), 9.31 (s, 1H), 8.77 (s, 1H), 8.73 (s,1H), 8.49 (s, 1H), 7.39 (s, 1H), 6.86 (s, 1H), 6.29-6.21 (m, 1H), 6.10-6.01 (m, 1H), 5.79-5.73 (m , 1H), 3.03-2.97 (m, 1H), 2.50 (overlapping with solvent, 3H), 1.89-1.27 (m, 9H).

Example 6: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chloro-1'-methylspiro[cyclohexane-1,2'- Synthesis of pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-6)

Using the synthetic method of compound 1-4, intermediate 1.1 was replaced with 1.2 to obtain compound 1-6 as a pale yellow solid. m/z: [M+H] ⁺ 414.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.18 (s, 1H), 9.02 (s, 1H), 8.93 (s, 1H), 8.72 (s , 1H), 8.51(s, 1H), 7.43(s, 1H), 6.85(s, 1H), 2.61(s, 3H), 1.65-1.27(m, 10H).

Example 7: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chlorospiro[cyclopentane-1,2'-pyrido[2,1 -f][1,2,4]Triazine]-4',8'(1'H,3'H)-Dione Hydrochloride (Compound 1-7)

Using the synthetic method of compound 1-2, intermediate 1.1 was replaced with 1.3 to obtain compound 1-7 as a pale yellow solid. m/z: [M+H] ⁺ 386.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.24 (s, 1H), 9.30 (s, 1H), 9.20 (br.s, 1H), 8.66 (s,1H), 8.51 (s, 1H), 7.43 (s, 1H), 6.88 (s, 1H), 1.84-1.70 (m, 8H).

Example 8: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1'-ethyl-5'-methylspiro[cyclohexane-1,2' -Synthesis of pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-8)

Using the synthesis method of compound 1-4, methyl iodide was replaced with ethyl iodide to obtain compound 1-8 as a pale yellow solid. m/z: [M+H] ⁺ 408.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.49 (br.s, 1H), 9.83 (br.s, 1H), 8.81 (s, 1H) , 8.47 (s, 1H), 8.23 (br.s, 1H), 7.47 (s, 1H), 6.91 (s, 1H), 3.31-3.17 (m, 1H), 2.90-2.78 (m, 1H), 2.48 (s, 3H), 2.00-1.89(m, 1H), 1.79-1.44(m, 6H), 1.38-1.20(m, 3H), 0.97(t, J=7.2Hz, 3H).

Example 9: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chlorospiro[cyclobutane-1,2'-pyrido[2,1 -f][1,2,4]Triazine]-4',8'(1'H,3'H)-Dione Hydrochloride (Compound 1-9)

Using the synthetic method of compound 1-2, intermediate 1.1 was replaced with 1.4 to obtain compound 1-9 as a pale yellow solid. m/z: [M+H] ⁺ 372.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.28 (s, 1H), 9.58 (s, 1H), 9.31 (br.s, 1H), 8.62 (s,1H), 8.51(s,1H), 7.45(s,1H), 6.90(s,1H), 2.24-2.16(m,4H),1.90-1.75(m,2H).

Example 10: 7-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-chloro-2,2-dimethyl-2,3-dihydro-1H-pyridine Synthesis of [2,1-f][1,2,4]triazine-4,8-dione hydrochloride (Compound 1-10)

Using the synthetic method of compound 1-2, intermediate 1.1 was replaced with 1.5 to obtain compound 1-10 as a white solid. m/z: [M+H] ⁺ 360.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.29 (br.s, 1H), 9.40 (br.s, 1H), 9.17 (s, 1H) , 8.64 (s, 1H), 8.51 (s, 1H), 7.44 (s, 1H), 6.90 (s, 1H), 1.36 (s, 6H).

Example 11: 7'-((6-amino-5-fluoropyrimidin-4-yl)amino)-5'-chlorospiro[cyclobutane-1,2'-pyrido[2,1-f][ Synthesis of 1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-11)

Using the synthesis method of compound 1-1, intermediate 1.4 was reacted with tert-butyl (6-amino-5-fluoropyrimidin-4-yl)carbamate to obtain compound 1-11 as a pale yellow solid. m/z: [M+H] ⁺ 366.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.51 (s, 1H), 8.42 (s, 1H), 8.20 (s, 1H), 8.09 (s , 1H), 7.35-7.05 (m, 3H), 2.25-2.10 (m, 3H), 2.05-1.95 (m, 1H), 1.88-1.70 (m, 2H).

Example 12: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chloro-1'-methylspiro[cyclopentane-1,2'- Synthesis of pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-12)

Using the synthetic method of compound 1-4, intermediate 1.1 was replaced with 1.3 to obtain compound 1-12 as a pale yellow solid. m/z: [M+H] ⁺ 400.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.37 (br.s, 1H), 9.58 (br.s, 1H), 9.25 (s, 1H) , 8.64-8.45 (m, 2H), 7.46 (s, 1H), 6.92 (s, 1H), 2.66 (s, 3H), 2.01-1.55 (m, 8H).

Example 13: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1'-isopropyl-5'-methylspiro[cyclohexane-1,2 Synthesis of'-pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-13)

XPhos (6 mg, 13.6 μmol), Xantphos (8 mg, 13.6 μmol) and Pd ₂ (dba) ₃ (6 mg, 6.80 μmol) were added to intermediate 1.8 (50 mg, 136 μmol), 7H-pyrrolo[2,3- d) In pyrimidine-4-amine (22 mg, 163 μmol) and Cs ₂ CO ₃ (66 mg, 0.20 mmol) in 1,4-dioxane (10 mL), the reaction system was replaced with nitrogen three times, and then at 95° C. After stirring for 16 hours, filtering, the filtrate was concentrated and purified by prep-HPLC (separation condition 2) to obtain compound 1-13 (19.8 mg, yield: 29%) as a pale yellow solid. m/z: [M+H] ⁺ 422.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.42 (br.s, 1H), 9.45 (br.s, 1H), 8.80 (s, 1H) , 8.47(s, 1H), 8.45(s, 1H), 7.44(t, J=2.8Hz, 1H), 6.88(t, J=2.4Hz, 1H), 2.47(overlapping with solvent, 3H), 2.05- 1.85 (m, 1H), 1.60-1.84 (m, 4H), 1.45-1.55 (m, 2H), 1.44-1.20 (m, 4H), 1.18 (d, J=6.4Hz, 3H), 0.90 (d, J = 6.4 Hz, 3H).

Example 14: N-(5-chloro-6-((5'-chloro-4',8'-dioxo-1',3',4',8'-tetrahydrospiro[cyclopentane- 1,2'-pyrido[2,1-f][1,2,4]triazine]-7'-yl)amino)pyrimidin-4-yl)cyclopropanamide hydrochloride (Compound 1-14) Synthesis

Using the synthetic method of compound 1-2, intermediate 1.3 was reacted with N-(6-amino-5-chloropyrimidin-4-yl)cyclopropanamide to obtain compound 1-14 as a pale yellow solid. m/z: [M+H] ⁺ 464.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.77 (s, 1H), 9.33 (s, 1H), 8.90 (s, 1H), 8.69 (s , 1H), 8.58 (s, 1H), 7.06 (br.s, 1H), 2.05-1.85 (m, 1H), 1.84-1.60 (m, 8H), 0.90-0.80 (m, 4H).

Example 15: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-methylspiro[cyclobutane-1,2'-pyrido[2, 1-f][1,2,4]Triazine]-4',8'(1'H,3'H)-Dione Hydrochloride (Compound 1-15)

Using the synthetic method of compound 1-2, intermediate 1.1 was replaced with 1.6 to obtain compound 1-15 as a yellow solid. m/z: [M+H] ⁺ 352.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.75 (br.s, 1H), 10.87 (br.s, 1H), 9.60 (s, 1H) , 8.44 (s, 1H), 7.90 (br.s, 1H), 7.52 (s, 1H), 7.05 (s, 1H), 2.44 (s, 3H), 2.30-2.18 (m, 4H), 1.85-1.74 (m,2H).

Example 16: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chloro-1'-methylspiro[cyclobutane-1,2'- Synthesis of pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-16)

Using the synthetic method of compound 1-4, intermediate 1.1 was replaced with 1.4 to obtain compound 1-16 as a yellow solid. m/z: [M+H] ⁺ 386.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.27 (s, 1H), 9.46 (s, 1H), 9.32 (s, 1H), 8.64 (s , 1H), 8.51(s, 1H), 7.45(s, 1H), 6.90(s, 1H), 2.60(s, 3H), 2.32(dd, J=15.0, 7.6Hz, 2H), 2.05-1.92( m, 2H), 1.81 (dd, J=15.2, 7.6Hz, 2H).

Example 17: 7'-((6-amino-5-chloropyrimidin-4-yl)amino)-5'-chlorospiro[cyclopentane-1,2'-pyrido[2,1-f][ Synthesis of 1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-17)

Potassium hydroxide (145 mg, 2.58 mmol) was added to a mixed solution of compound 1-14 (120 mg, 0.26 mmol) in ethanol (5 mL), THF (5 mL) and water (5 mL), and the reaction system was heated to 50°C and stirred 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was slurried with water and filtered to obtain a solid, which was purified by prep-HPLC (separation condition 2) to obtain compound 1-17 (7.8 mg, yield: 8%) as a pale yellow solid. m/z: [M+H] ⁺ 396.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.26 (s, 1H), 8.54 (s, 2H), 8.23 (s, 1H), 7.25 (br .s, 2H), 1.81-1.23(m, 6H).

Example 18: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1',5'-dimethylspiro[cyclobutane-1,2'-pyridine Of [2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-18)

Using the synthetic method of compound 1-4, intermediate 1.1 was replaced with 1.6 to obtain compound 1-18 as a yellow solid. m/z: [M+H] ⁺ 366.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.59 (s, 1H), 10.32 (s, 1H), 9.37 (s, 1H), 8.44 (s , 1H), 8.08 (s, 1H), 7.49 (s, 1H), 6.98 (s, 1H), 2.57 (s, 3H), 2.45 (s, 3H), 2.38-2.29 (m, 2H), 2.02- 1.91(m, 2H), 1.82-1.75(m, 2H).

Example 19: N-(3-(7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-methyl-4',8'-dioxo -3',4'-dihydrospiro[cyclobutane-1,2'-pyrido[2,1-f][1,2,4]triazine]-1'(8'H)-yl) Synthesis of phenyl)acrylamide hydrochloride (Compound 1-19)

Step 1: Add iron powder (75 mg, 1.33 mmol) to compound Z-1 (using the synthetic method of compound 2 and replace intermediate 1.1 with 1.9 to obtain compound Z-1) (90 mg, 0.19 mmol) in acetic acid solution (5 mL ), the reaction system was stirred at 50°C for 16 hours. After cooling, filtering, the filtrate was concentrated, poured into water, adjusted to pH=7 with saturated aqueous sodium bicarbonate solution, filtered and the filter cake was dried in vacuo to obtain compound Z-2 (80 mg, yield: 95%) as a yellow solid. m/z:[M+H] ⁺ 443.0.

Step 2: Acryloyl chloride (15 mg, 170 μmol) was added dropwise to a solution of compound Z-2 (50 mg, 113 μmol) in DMF (2 mL) at 0° C. The reaction system was stirred at room temperature for 20 minutes. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (15 mL) at 0°C to quench the reaction. The aqueous phase was extracted with ethyl acetate (3×15 mL), the organic phases were combined and concentrated under reduced pressure, and the residue was subjected to prep-HPLC ( Isolation condition 2) Purification gave compound 1-19 (0.62 mg, yield: 1%) as a light yellow solid. m/z: [M+H] ⁺ 497.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.15 (br.s, 1H), 10.24 (s, 1H), 9.53 (s, 1H), 9.02 (br.s, 1H), 8.59(s, 1H), 8.47(s, 1H), 7.50-7.44(m, 1H), 7.39(s, 2H), 7.29-7.21(m, 1H), 6.80(s ,1H),6.64-6.56(m,1H),6.45-6.34(m,1H),6.28-6.18(m,1H),5.77-5.68(m,1H),2.89-2.79(m,1H),2.54 (s, 3H), 2.39-2.14 (m, 2H), 2.05-1.85 (m, 3H).

Example 20: 5'-chloro-1'-methyl-7'-(thieno[2,3-d]pyrimidin-4-ylamino)spiro[cyclobutane-1,2'-pyrido[2 ,1-f][1,2,4]Triazine]-4',8'(1'H,3'H)-Dione Hydrochloride (Compound 1-20)

Using the synthetic method of compound 1-4, intermediate 1.4 was reacted with thieno[2,3-d]pyrimidin-4-amine to obtain compound 1-20 as a yellow solid. m/z: [M+H] ⁺ 403.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.47 (s, 1H), 9.27 (s, 1H), 8.76 (s, 1H), 8.72 (s , 1H), 7.90-7.82 (m, 2H), 2.61 (s, 3H), 2.50-2.33 (m, 2H), 2.00-1.95 (m, 2H), 1.85-1.75 (m, 2H).

Example 21: 5'-chloro-7'-(thieno[2,3-d]pyrimidin-4-ylamino)spiro[cyclopentane-1,2'-pyrido[2,1-f][ Synthesis of 1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-21)

Using the synthetic method of compound 1-2, intermediate 1.3 was reacted with thieno[2,3-d]pyrimidin-4-amine to obtain compound 1-21 as a pale yellow solid. m/z: [M+H] ⁺ 403.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.32 (s, 1H), 9.24 (s, 1H), 8.76 (s, 1H), 8.70 (s , 1H), 7.90-7.83 (m, 2H), 7.55-7.33 (m, 1H), 1.90-1.79 (m, 2H), 1.78-1.64 (m, 6H).

Example 22: 7'-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-5'-chloro-1'-methylspiro[cyclobutane-1,2' -Synthesis of pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-22)

Using the synthesis method of compound 1-4, intermediate 1.4 was reacted with 1H-pyrazolo[3,4-d]pyrimidin-4-amine to obtain compound 1-22 as a pale yellow solid. m/z: [M+H] ⁺ 387.2; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 13.83 (br.s, 1H), 9.77 (s, 1H), 9.46 (s, 1H), 8.83 (s,1H),8.63(s,1H),8.62(s,1H),2.61(s,3H),2.45-2.23(m,2H),2.03-1.92(m,2H),1.86-1.75(m , 2H).

Example 23: 7'-((6-aminopyrimidin-4-yl)amino)-5'-chloro-1'-methylspiro[cyclobutane-1,2'-pyrido[2,1-f ][1,2,4]Triazine]-4',8'(1'H,3'H)-Dione Hydrochloride (Compound 1-23) Synthesis

Step 1: Under nitrogen protection, the intermediate 2.1 (40mg, 0.15mmol), N,N-di-Boc-2-amino-6-chloropyrimidine (59mg, 0.18mmol), Pd ₂ (dba) ₃ (5mg) , Xantphos (5 mg), XPhos (5 mg), a mixture of Cs ₂ CO ₃ (73 mg, 0.22 mmol) and tert-butanol (1.5 mL) was stirred at 85° C. for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-TLC (PE/EtOAc=1/1) to obtain compound X-1 (60 mg, yield: 73%) as a pale yellow solid. m/z:[M+H] ⁺ 562.0.

Step 2: Under ice bath conditions, TFA (0.4 mL) was added dropwise to a solution of Compound X-1 (60 mg, 0.11 mmol) in DCM (0.4 mL). After the addition, the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with DCM, solid sodium bicarbonate was added to adjust pH=7, stirred for about 20 minutes, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 2) to obtain compound 1 -23 (1.67 mg, yield: 4%) is a yellow solid. m/z: [M+H] ⁺ 362.2; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.97 (s, 1H), 9.45 (s, 1H), 8.53 (s, 1H), 8.32 (s , 1H), 7.98 (s, 2H), 6.56 (s, 1H), 2.56 (s, 3H), 2.40-2.27 (m, 2H), 2.00-1.90 (m, 2H), 1.84-1.76 (m, 2H ).

Example 24: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chloro-3,3-dimethylspiro[cyclobutane-1,2 Synthesis of'-pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-24)

Using the synthetic method of compound 1-2, replacing intermediate 1.1 with 1.10 gave compound 1-24 as a pale yellow solid. m/z: [M+H] ⁺ 400.2; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.18 (s, 1H), 9.48 (s, 1H), 9.08 (br.s, 1H), 8.73 (s,1H), 8.51 (s, 1H), 7.42 (s, 1H), 6.92 (s, 1H), 2.04 (s, 4H), 1.28 (s, 3H), 1.15 (s, 3H).

Example 25: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chloro-1',3,3-trimethylspiro[cyclobutane- 1,2'-pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-25 )Synthesis

Using the synthetic method of compound 1-4, replacing intermediate 1.1 with 1.10 gave compound 1-25 as a light yellow solid. m/z: [M+H] ⁺ 414.2; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.24 (s, 1H), 9.39 (s, 1H), 9.23 (br.s, 1H), 8.69 (s,1H),8.51(s,1H),7.44(s,1H),6.92(s,1H),2.59(s,3H),2.26-2.13(m,2H),1.91-1.76(m,2H ), 1.22(s, 3H), 1.15(s, 3H).

Example 26: 7-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-chloro-2-(3-fluorophenyl)-2-methyl-2,3 -Dihydro-1H-pyrido[2,1-f][1,2,4]triazine]-4,8-dione hydrochloride (Compound 1-26)

Using the synthetic method of compound 1-2, replacing intermediate 1.1 with 1.11 gave compound 1-26 as a light yellow solid. m/z: [M+H] ⁺ 440.2; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.28 (s, 1H), 9.95 (s, 1H), 9.32 (br.s, 1H), 8.55 -8.40(m, 2H), 7.81(br.s, 1H), 7.45-7.30(m, 4H), 7.09(t, J=8.4Hz, 1H), 6.92(s, 1H), 1.65(s, 3H ).

Example 27: 7'-((6-amino-5-fluoropyrimidin-4-yl)amino)-5'-chlorospiro[cyclobutane-1,2'-pyrido[2,1-f][ Synthesis of 1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-27)

Using the synthesis method of compound 1-1, compound 1.4 was reacted with tert-butyl (6-amino-5-chloropyrimidin-4-yl)carbamate to obtain compound 1-27 as a pale yellow solid. m/z: [M+H] ⁺ 382.1; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.54 (s, 1H), 8.56 (s, 1H), 8.53 (s, 1H), 8.25 (s , 1H), 7.36 (br.s, 2H), 2.17 (t, J=8.0Hz, 4H), 1.86-1.72 (m, 2H).

Example 28: 8-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-chloro-3a-methyl-2,3,3a,4-tetrahydro-1H- Synthesis and Example 29 of pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazine-5,9-dione hydrochloride (Compound 1-28): 7-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-9-chloro-3a-methyl-2,3,3a,4-tetrahydro-1H-pyrido[2 Of 1,1-f]pyrrolo[2,1-c][1,2,4]triazine-6,10-dione hydrochloride (Compound 1-29)

By using the synthetic method of compound 1-2, intermediate 1.1 was replaced with a mixture of 3.1 and 3.2 to obtain both compounds 1-28 and 1-29 as light yellow solids (prep-HPLC separation conditions: 3). Compound 1-28, UPLC RT = 4.508 min, m/z: [M+H] ⁺ 386.2; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.24 (s, 1H), 9.20 (br.s, 1H), 8.95(s, 1H), 8.68(s, 1H), 8.51(s, 1H), 7.44(s, 1H), 6.88(s, 1H), 3.71-3.62(m, 2H), 2.00-1.86 (m, 4H), 1.31 (s, 3H); compound 1-29, UPLC RT = 4.550 min, m/z: [M+H] ⁺ 386.2; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12. 20(s, 1H), 9.09(br.s, 1H), 8.72(s, 1H), 8.51(s, 1H), 7.42(s, 1H), 6.89(s, 1H), 3.63-3.53(m, 2H), 2.09-1.90 (m, 4H), 1.26 (s, 3H).

Example 30: 8-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3a,6-dimethyl-2,3,3a,4-tetrahydro-1H-pyridine Synthesis of [2,1-f]pyrrolo[1,2-b][1,2,4]triazine-1,5,9-trione (Compound 1-30)

Using the synthetic method of compound 1-2, replacing intermediate 1.1 with 4.1 gave compound 1-30 as a pale yellow solid (prep-HPLC separation conditions: 1). m/z: [M+H] ⁺ 380.1; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.05 (s, 1H), 9.11 (s, 1H), 8.78 (s, 1H), 8.66 (s , 1H), 8.48 (s, 1H), 7.38 (s, 1H), 6.85 (s, 1H), 2.78-2.64 (m, 2H), 2.50 (overlapping, 3H), 2.40-2.26 (m, 2H), 1.49(s,3H).

Example 31: 7'-((6-amino-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5'-chlorospiro[cyclobutane-1 ,2'-pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-31) Synthesis

Using the synthetic method of compound 1-1, intermediate 1.4 was reacted with (6-amino-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)carbamic acid tert-butyl ester to obtain compound 1-31 is a light yellow solid. m/z: [M+H] ⁺ 428.2; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.09 (s, 1H), 9.58 (s, 1H), 8.61 (s, 1H), 8.44 (d , J = 8.0Hz, 2H), 8.01 (s, 1H), 7.64 (br.s, 3H), 3.96 (s, 3H), 2.22-2.00 (m, 4H), 1.87-1.67 (m, 2H).

Example 32: 7'-((6-amino-5-methoxypyrimidin-4-yl)amino)-5'-chlorospiro[cyclobutane-1,2'-pyrido[2,1-f ][1,2,4]Triazine]-4',8'(1'H,3'H)-Dione Hydrochloride (Compound 1-32)

Using the synthetic method of compound 1-1, intermediate 1.4 was reacted with tert-butyl (6-amino-5-methoxypyrimidin-4-yl)carbamate to obtain compound 1-32 as a pale yellow solid. m/z: [M+H] ⁺ 378.2; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.56 (s, 1H), 8.57 (s, 1H), 8.37 (s, 1H), 8.29 (s , 1H), 7.70 (br.s, 2H), 3.75 (s, 3H), 2.54 (s, 1H), 2.25-2.08 (m, 4H), 1.92-1.63 (m, 2H).

Example 33: 5'-chloro-1'-( ² H ₃ )methyl-7'-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1'H,3 'H-spiro[cyclobutane-1,2'-pyrido[2,1-f][1,2,4]triazine]-4',8'-dione hydrochloride (Compound 1-33 )Synthesis

Using the synthesis method of compound 1-4, using intermediate 1.4 and deuterated methyl iodide as starting materials to obtain compound 1-33 as a yellow solid. m/z: [M+H] ⁺ 389.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.29 (s, 1H), 9.61-9.13 (m, 2H), 8.64 (s, 1H), 8.51 (s, 1H), 7.45 (s, 1H), 6.91 (s, 1H), 2.41-2.26 (m, 2H), 2.09-1.91 (m, 2H), 1.87-1.72 (m, 2H).

Example 34: 5″-chloro-7″-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1″H,3″H-dispiro[cyclobutane-1 ,1'-cyclobutane-3',2″-pyrido[2,1-f][1,2,4]triazine]-4″,8″-dione hydrochloride (Compound 1-34 )Synthesis

Using the synthetic method of compound 1-2, replacing intermediate 1.1 with 1.13 gave compound 1-34 as a pale yellow solid. m/z: [M+H] ⁺ 412.2; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.15 (s, 1H), 9.44 (s, 1H), 8.99 (br.s, 1H), 8.76 (s, 1H), 8.51 (s, 1H), 7.42 (s, 1H), 6.90 (s, 1H), 2.27 (d, J = 12 Hz, 2H), 2.20 (d, J = 12.4 Hz, 2H), 2.12 (t, J = 7.2 Hz, 2H), 1.98 (t, J = 7.2 Hz, 2H), 1.82-1.72 (m, 2H).

Example 35: 5″-chloro-1″-methyl-7″-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1″H,3″H-dispiro [Cyclobutane-1,1'-cyclobutane-3',2″-pyrido[2,1-f][1,2,4]triazine]-4″,8″-dione hydrochloride Synthesis of Salt (Compound 1-35)

Using the synthetic method of compound 1-4, intermediate 1.1 was replaced with 1.13 to obtain compound 1-35 as a pale yellow solid. m/z: [M+H] ⁺ 426.2; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.38 (s, 1H), 9.61 (br.s, 1H), 9.41 (s, 1H), 8.55 (s,1H),8.52(s,1H),7.46(s,1H),6.95(s,1H),2.57(s,3H),2.44-2.30(m,2H),2.15-1.90(m,6H ), 1.82-1.70 (m, 2H).

Example 36: 7'-((9H-purin-6-yl)amino)-5'-chlorospiro[cyclobutane-1,2'-pyrido[2,1-f][1,2,4 ]Triazine]-4',8'(1'H,3'H)-Dione Hydrochloride (Compound 1-36)

Using the synthetic method of compound 1-2, intermediate 1.4 and 9H-purin-6-amine were reacted to obtain compound 1-36 as a light yellow solid. m/z: [M+H] ⁺ 373.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.59 (s, 1H), 9.14 (s, 1H), 8.78 (s, 1H), 8.69 (s , 1H), 8.56 (s, 1H), 2.32-2.09 (m, 4H), 1.93-1.66 (m, 2H).

Example 37: 5'-chloro-1'-( ² H ₃ )methyl-7'-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1'H,3 'H-spiro[cyclopentane-1,2'-pyrido[2,1-f][1,2,4]triazine]-4',8'-dione hydrochloride (Compound 1-37 )Synthesis

Using the synthetic method of compound 1-4, using intermediate 1.3 and deuterated methyl iodide as starting materials to obtain compound 1-37 as a yellow solid. m/z: [M+H] ⁺ 403.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.41 (br.s, 1H), 9.70 (br.s, 1H), 9.26 (s, 1H) , 8.61-8.41 (m, 2H), 7.46 (s, 1H), 6.93 (s, 1H), 2.03-1.52 (m, 8H).

Example 38: 9-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-7-chloro-4a-methyl-1,2,3,4,4a,5-hexa Synthesis of hydrodipyrido[1,2-b:2',1'-f][1,2,4]triazine-6,10-dione hydrochloride (compound 1-38)

Using the synthetic method of compound 1-2, intermediate 1.1 was replaced with 3.3 to obtain compound 1-38 as a yellow solid. m/z: [M+H] ⁺ 400.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.18 (s, 1H), 9.11-8.87 (m, 2H), 8.75 (s, 1H), 8.52 (s, 1H), 7.43 (t, J = 2.8Hz, 1H), 6.83 (t, J = 2.8Hz, 1H), 3.05 (d, J = 10.4Hz, 1H) 2.73-2.61 (m, 1H), 1.94 (d, J = 13.6 Hz, 1H), 1.80-1.46 (m, 5H), 1.22 (s, 3H).

Example 39: 5'-chloro-7'-(pyrimidin-4-ylamino)spiro[cyclobutane-1,2'-pyrido[2,1-f][1,2,4]triazine] -Synthesis of -4',8'(1'H,3'H)-diketone hydrochloride (Compound 1-39)

Using the synthesis method of compound 1-2, intermediate 1.4 was reacted with pyrimidine-4-amine to obtain compound 1-39 as a yellow solid. m/z: [M+H] ⁺ 333.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.40 (brs, 1H), 9.63 (s, 1H), 9.04 (s, 1H), 8.64 (s , 1H), 8.53 (d, J = 6.4Hz, 1H), 7.58 (d, J = 6.4Hz, 1H), 2.19 (t, J = 8.0Hz, 3H), 2.06-1.92 (m, 1H), 1.90 -1.72(m,2H).

Example 40: 5'-chloro-7'-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)spiro[cyclobutane-1,2'-pyrido[2,1-f] Synthesis of [1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-40)

Using the synthetic method of compound 1-2, intermediate 1.4 was reacted with 7H-pyrrolo[2,3-d]pyrimidine to obtain compound 1-40 as a yellow solid. m/z: [M+H] ⁺ 357.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.95 (s, 1H), 9.44 (s, 1H), 9.19 (s, 1H), 8.28-8.18 (m, 2H), 7.10 (d, J = 3.6 Hz, 1H), 2.26 (t, J = 8.0 Hz, 4H), 1.91-1.67 (m, 2H).

Example 41: 8-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3a,6-dimethyl-2,3,3a,4-tetrahydro-1H-pyridine Synthesis of [2,1-f]pyrrolo[1,2-b][1,2,4]triazine-5,9-dione hydrochloride (Compound 1-41)

Using the synthetic method of compound 1-2, intermediate 1.1 was replaced with 3.4 to obtain compound 1-41 as a pale yellow solid. m/z: [M+H] ⁺ 366.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.54 (s, 1H), 10.12 (br.s, 1H), 8.85 (s, 1H), 8.45 (s,1H),8.14(s,1H),7.48(s,1H),6.94(s,1H),3.64(overlapping with the solvent,1H),2.80-2.70(m,1H),2.50(overlapping with the solvent,3H),2.26-2.11(m,1H),1.93(br.s,3H),1.29(s,3H).

Example 42: 7-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-chloro-2-cyclobutyl-2-methyl-2,3-dihydro- Synthesis of 1H-pyrido[2,1-f][1,2,4]triazine]-4,8-dione hydrochloride (Compound 1-42)

Using the synthetic method of compound 1-2, intermediate 1.1 was replaced with 1.12 to obtain compound 1-42 as a pale yellow solid. m/z: [M+H] ⁺ 400.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.12 (s, 1H), 9.12 (s, 1H), 8.85 (s, 1H), 8.75 (s , 1H), 8.50 (s, 1H), 7.40 (s, 2H), 6.85 (s, 1H), 2.54 (s, 3H), 1.88-1.54 (m, 8H).

Example 43: 7-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-chloro-2-methyl-3H-pyrido[2,1-f][1 Of 2,2,4]triazine]-4,8-dione hydrochloride (Compound 1-43)

Using the synthetic method of compound 1-2, intermediate 1.1 was replaced with 5.1 to obtain compound 1-43 as a pale yellow solid. m/z: [M+H] ⁺ 344.0; ¹ H NMR (400MHz, DMSO-d ₆ +CD ₃ OD): δ 8.97 (s, 1H), 8.50 (s, 1H), 7.39 (s, 1H) , 6.80 (s, 1H), 2.17 (s, 3H).

Example 44: 7'-((4-amino-1,3,5-triazin-2-yl)amino)-5'-chlorospiro[cyclobutane-1,2'-pyrido[2,1 -f][1,2,4]Triazine]-4',8'(1'H,3'H)-Dione Hydrochloride (Compound 1-44)

Using the synthetic method of compound 1-2, intermediate 1.4 was reacted with 2,4-diamino-1,3,5-triazine to obtain compound 1-44 as a light yellow solid. m/z: [M+H] ⁺ 349.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.57 (br.s, 1H), 8.68-8.47 (m, 2H), 8.44 (s, 1H) , 8.39 (s, 1H), 8.07 (br.s, 1H), 7.95 (br.s, 1H), 7.84 (s, 1H), 2.18 (t, J=8.4Hz, 4H), 1.89-1.69 (m , 2H).

Example 45: 9-((6-aminopyrimidin-4-yl)amino)-7-chloro-4a-methyl-1,2,3,4,4a,5-hexahydrodipyrido[1,2 -b: Synthesis of 2',1'-f][1,2,4]triazine-6,10-dione hydrochloride (Compound 1-45)

Using the synthetic method of compound 1-1, intermediate 1.1 was replaced with 3.3 to obtain compound 1-45 as a yellow solid. m/z: [M+H] ⁺ 376.0, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.98 (s, 1H), 9.06 (s, 1H), 8.56 (s, 1H), 8.32 (s, 2H), 8.09 (br.s, 2H), 6.58 (s, 1H), 3.01 (d, J = 10.0 Hz, 1H), 2.64 (t, J = 11.2 Hz, 1H), 1.93 (d, J = 14.0 Hz, 1H), 1.77-1.44 (m, 5H), 1.19 (s, 3H).

Example 46: 5″-chloro-7″-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1″H,3″H-dispiro[cyclopropane-1, 1'-cyclobutane-3',2″-pyrido[2,1-f][1,2,4]triazine]-4″,8″-dione hydrochloride (Compound 1-46) Synthesis

Using the synthetic method of compound 1-2, replacing intermediate 1.1 with 1.14 gave compound 1-46 as a light yellow solid. m/z: [M+H] ⁺ 398.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.14 (s, 1H), 9.67 (s, 1H), 8.97 (s, 1H), 8.78 (s , 1H), 8.50 (s, 1H), 7.42 (s, 1H), 6.89 (s, 1H), 2.47-2.23 (m, 4H), 0.58-0.44 (m, 4H).

Example 47: 8-((6-aminopyrimidin-4-yl)amino)-6-chloro-3a-methyl-2,3,3a,4-tetrahydro-1H-pyrido[2,1-f Synthesis of pyrrolidine [1,2-b][1,2,4]triazine-5,9-dione hydrochloride (Compound 1-47)

Using the synthetic method of compound 1-1, intermediate 1.1 was replaced with 3.2 to obtain compound 1-47 as a yellow solid. m/z: [M+H] ⁺ 362.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.00 (s, 1H), 8.96 (s, 1H), 8.55 (s, 1H), 8.33 (s , 1H), 8.03 (s, 2H), 6.58 (s, 1H), 1.93 (s, 4H), 1.28 (s, 2H).

Example 48: 8-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-methyl-3a-phenyl-2,3,3a,4-tetrahydro-1H -Synthesis of pyrido[2,1-f]pyrrolidine[1,2-b][1,2,4]triazine-5,9-dione hydrochloride (Compound 1-48)

Using the synthetic method of compound 1-2, replacing intermediate 1.1 with 3.6 gave compound 1-48 as a pale yellow solid. m/z: [M+H] ⁺ 428.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.51 (br.s, 1H), 9.99 (s, 1H), 9.68 (s, 1H), 8.41 (s, 1H), 8.05 (br.s, 1H), 7.49 (t, J = 8.0Hz, 3H), 7.32 (t, J = 7.6Hz, 2H), 7.24 (t, J = 7.2Hz, 1H) , 6.93 (s, 1H), 3.89 (d, J = 7.6Hz, 1H), 2.99 (q, J = 8.4Hz, 1H), 2.37 (s, 4H), 2.15-2.04 (m, 2H), 2.02- 1.90(m,1H).

Example 49: 9-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4a,7-dimethyl-1,2,3,4,4a,5-hexahydro Synthesis of dipyrido[1,2-b:2',1'-f][1,2,4]triazine-6,10-dione hydrochloride (Compound 1-49)

Using the synthetic method of compound 1-2, replacing intermediate 1.1 with 3.5 gave compound 1-49 as a pale yellow solid. m/z: [M+H] ⁺ 380.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.61 (br.s, 1H), 10.31 (br.s, 1H), 8.96 (s, 1H) , 8.44 (d, J = 1.6 Hz, 1H), 8.07 (s, 1H), 7.50 (q, J = 2.4 Hz, 1H), 6.95 (s, 1H), 3.08 (d, J = 10.8 Hz, 1H) , 2.64 (t, J = 10.8 Hz, 1H), 2.49 (s, 3H), 1.94 (d, J = 13.6 Hz, 1H), 1.77-1.50 (m, 5H), 1.19 (s, 3H).

Example 50: 7'-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5'-chloro-1'-methylspiro[cyclobutane-1,2' -Synthesis of pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-50)

Synthesis of N,N-dimethyl-N'-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)formamidine: To 4-amino-7H-pyrrole[2,3-d]pyrimidine To a solution of (1 g, 7.45 mmol) in DMF (10 mL) was added N,N-dimethylformamide dimethyl acetal (1.07 g, 8.95 mmol), and the reaction system was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, DCM (30 mL) was added, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with isopropyl ether, filtered, and the filter cake was dried to give the product (0.57 g) as a yellow solid. m/z: [M+H] ⁺ 190.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.64 (br.s, 1H), 8.79 (s, 1H), 8.29 (s, 1H), 7.22 (d, J = 1.6 Hz, 1H), 6.45 (d, J = 1.6 Hz, 1H), 3.16 (s, 3H), 3.10 (s, 3H).

Step 1: Under nitrogen protection, to 7'-bromo-5'-chloro-1'-methyl spiro[cyclobutane-1,2'-pyrido[2,1-f][1,2,4] Triazine]-4',8'(1'H,3'H)-dione (100mg, 301μmol) and N,N-dimethyl-N'-(7H-pyrrolo[2,3-d] To a solution of pyrimidin-4-yl)formamidine (74mg, 391μmol) in 1,4-dioxane (5mL) was added trans-1,2-cyclohexanediamine (17mg, 150μmol) and cuprous iodide successively (27 mg, 150 μmol) and potassium phosphate (192 mg, 902 μmol), the reaction system was replaced with nitrogen three times and stirred at 90° C. overnight. After the reaction was cooled, the reaction solution was concentrated under reduced pressure, water (15 mL) was added, and extracted with ethyl acetate (3×15 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound Y- 1 (125 mg, 98% yield) is a yellow solid. m/z:[M+H] ⁺ 441.0.

Step 2: To a solution of compound Y-1 (125 mg, 284 μmol) in ethanol (3 mL) was added ethylenediamine (34 mg, 567 μmol), and the reaction system was stirred at 80° C. overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 5) to obtain compound 1-50 (49.2 mg, yield: 45%) as a pale yellow solid. m/z: [M+H] ⁺ 386.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.77 (s, 1H), 9.25 (br.s, 1H), 8.55 (br.s, 1H) , 8.42 (s, 1H), 8.08 (s, 1H), 7.80-7.74 (m, 1H), 7.10-7.04 (m, 1H), 2.60 (s, 3H), 2.40-2.27 (m, 2H), 2.11 -1.96(m, 2H), 1.88-1.74(m, 2H).

Example 51: 5'-chloro-7'-((6-(4-(3-(dimethylamino)propyl)piperazin-1-yl)pyrimidin-4-yl)amino)-1'- Methylspiro[cyclobutane-1,2'-pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione Synthesis of Hydrochloride (Compound 1-51)

Using the synthesis method of compound 1-4, replace intermediate 1.1 in step 1 with 1.4, and replace 7H-pyrrolo[2,3-d]pyrimidin-4-amine with intermediate 9.1 in step 2 to obtain compound 1 -51 is a yellow solid. m/z: [M+H] ⁺ 516.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.59 (br.s, 1H), 10.76 (br.s, 1H), 9.39 (s, 1H) , 9.18 (s, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 6.89 (s, 1H), 4.37 (d, J = 13.6 Hz, 2H), 3.61 (d, J = 13.6 Hz, 2H), 3.49 (t, J = 13.2 Hz, 2H), 3.28-3.14 (m, 4H), 3.08 (d, J = 10.8 Hz, 2H), 2.76 (d, J = 4.8 Hz, 6H), 2.56 ( s, 3H), 2.40-2.28(m, 2H), 2.25-2.13(m, 2H), 2.02-1.88(m, 2H), 1.86-1.72(m, 2H).

Example 52: Preparation of Compounds 1-28A and 1-28B

Chiral resolution of 1 g of compound 1-28 by SFC gave compound 1-28A (430 mg, chiral analysis RT=1.9 minutes, ee%=99.1%) and compound 1-28B (444 mg, chiral analysis RT=2.5 minutes , Ee%=98.2%), all are yellow solids.

Compound 1-28A (430 mg) was added to a mixture solution of DCM (50 mL) and MeOH (5 mL), then hydrochloric acid methanol solution (4N, 0.3 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour and then directly concentrated under reduced pressure to obtain 1-28A hydrochloride (428 mg) is a yellow solid. m/z: [M+H] ⁺ 428.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.24 (s, 1H), 9.20 (br.s, 1H), 8.95 (s, 1H), 8.68 (s,1H),8.51(s,1H),7.44(s,1H),6.88(s,1H),3.71-3.62(m,2H),2.00-1.86(m,4H),1.31(s,3H ).

Using the method of preparing 1-28A hydrochloride, 1-28B was used to obtain 1-28B hydrochloride. m/z: [M+H] ⁺ 428.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.24 (s, 1H), 9.20 (br.s, 1H), 8.95 (s, 1H), 8.68 (s,1H),8.51(s,1H),7.44(s,1H),6.88(s,1H),3.71-3.62(m,2H),2.00-1.86(m,4H),1.31(s,3H ).

Example 53: Preparation of Compounds 1-38A and 1-38B

SFC chiral resolution of 640 mg of compound 1-38 gave compound 1-38A (245 mg, chiral analysis RT=1.96 minutes, ee%=100%) and compound 1-38B (244 mg, chiral analysis RT=2.92 minutes , Ee%=99.3%), all are yellow solids.

Using 1-28A hydrochloride preparation method, 1-38A is used to prepare 1-38A hydrochloride. m/z: [M+H] ⁺ 400.0, ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.18 (s, 1H), 9.11-8.87 (m, 2H), 8.75 (s, 1H), 8.52 (s, 1H), 7.43 (t, J = 2.8Hz, 1H), 6.83 (t, J = 2.8Hz, 1H), 3.05 (d, J = 10.4Hz, 1H) 2.73-2.61 (m, 1H), 1.94 (d, J = 13.6 Hz, 1H), 1.80-1.46 (m, 5H), 1.22 (s, 3H).

Using 1-28A hydrochloride preparation method, 1-38B was used to prepare 1-38B hydrochloride. m/z: [M+H] ⁺ 400.0, ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.18 (s, 1H), 9.11-8.87 (m, 2H), 8.75 (s, 1H), 8.52 (s, 1H), 7.43 (t, J = 2.8Hz, 1H), 6.83 (t, J = 2.8Hz, 1H), 3.05 (d, J = 10.4Hz, 1H) 2.73-2.61 (m, 1H), 1.94 (d, J = 13.6 Hz, 1H), 1.80-1.46 (m, 5H), 1.22 (s, 3H).

Example 54: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8'-methoxy-5'-methyl-1'H-spiro[cyclopentane Synthesis of alkane-1,2'-quinazoline]-4'(3'H)-one hydrochloride (Compound 2-1)

The intermediate 8.7 (80 mg, 0.25 mmol), 7H-pyrrolo[2,3-d]pyrimidin-4-amine (41 mg, 0.30 mmol), Pd ₂ (dba) ₃ (20 mg), Pd(OAc) ₃ ( 10 mg), a mixture of Xantphos (20 mg), Xphos (20 mg), Cs ₂ CO ₃ (165 mg, 0.51 mmol) and 1,4-dioxane (3 mL) was placed in a microwave reaction tube, and nitrogen was blown for 5 minutes, then Stir at 120°C for 8 hours under microwave conditions. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 4) to obtain compound 2-1 (7 mg, yield: 8%) as a yellow solid. m/z: [M+H] ⁺ 380.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.42 (s, 1H), 9.75 (br.s, 1H), 9.03 (s, 1H), 8.45 (s, 1H), 8.21 (s, 1H), 7.46 (s, 1H), 6.89 (s, 1H), 2.49 (s, 3H), 1.75-1.25 (m, 10H).

Example 55: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chloro-1'H-spiro[cyclobutane-1,2'-quino Of oxazoline]-4'(3'H)-one hydrochloride (Compound 2-2)

Using the synthetic method of compound 2-1, intermediate 8.7 was replaced with 8.8 to obtain compound 2-2 as a yellow solid. m/z: [M+H] ⁺ 355.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.08 (br.s, 1H), 9.72 (br.s, 1H), 8.53-8.36 (m, 2H), 7.64-7.30 (m, 3H), 7.17 (s, 1H), 6.92-6.85 (m, 1H), 2.32-2.16 (m, 4H), 1.81-1.69 (m, 2H).

Example 56: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chloro-1'H-spiro[cyclohexane-1,2'-quino Of oxazoline]-4'(3'H)-one hydrochloride (compound 2-3)

Using the synthetic method of compound 2-1, intermediate 8.7 was replaced with 8.9 to obtain compound 2-3 as a pale yellow solid. m/z: [M+H] ⁺ 383.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.10 (br.s, 1H), 9.76 (br.s, 1H), 8.39 (s, 1H) , 7.88 (s, 1H), 7.51 (s, 1H), 7.35 (s, 1H), 7.12 (s, 1H), 7.01 (s, 1H), 6.87 (s, 1H), 1.77-1.49 (m, 8H ), 1.43-1.25 (m, 2H).

Example 57: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1'H-spiro[cyclobutane-1,2'-pyrido[2,3 -d]Pyrimidine]-4'(3'H)-one hydrochloride (Compound 2-4)

Using the synthetic method of compound 2-1, intermediate 8.7 was replaced with 8.10 to obtain compound 2-4 as a pale yellow solid. m/z:[M+H] ⁺ 322.0.

Example 58: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1'H-spiro[cyclobutane-1,2'-pyrido[2,3 -d]Pyrimidine]-4'(3'H)-one hydrochloride (Compound 2-5)

Using the synthetic method of compound 2-1, intermediate 8.7 was replaced with 8.11 to obtain compound 2-5 as a pale yellow solid. m/z: [M+H] ⁺ 385.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.20 (br.s, 1H), 9.97 (br.s, 1H), 8.41 (s, 1H) , 8.16 (s, 1H), 7.51 (s, 1H), 7.37 (s, 1H), 7.24 (s, 1H), 7.15 (s, 1H), 6.90 (s, 1H), 3.70 (overlapping with solvent, 4H ), 1.91-1.66 (m, 4H).

Example 59: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8'-methoxy-1',5'-dimethyl-1'H- Synthesis of spiro[cyclopentane-1,2'-quinazoline]-4'(3'H)-one hydrochloride (Compound 2-6)

Intermediate 8.1 (75 mg, 0.22 mmol), 7H-pyrrolo[2,3-d]pyrimidin-4-amine (44 mg, 0.33 mmol), Pd ₂ (dba) ₃ (20 mg), Xantphos (20 mg), Xphos A mixture of (20 mg), Cs ₂ CO ₃ (86 mg, 0.26 mmol) and 1,4-dioxane (3 mL) was placed in a microwave reaction tube, nitrogen gas was blown for 5 minutes, and then the reaction was conducted at 120° C. for 8 hours under microwave. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 3) to obtain compound 2-6 (15 mg, yield: 17%) as an off-white solid. m/z: [M+H] ⁺ 393.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.97 (s, 1H), 11.63 (br.s, 1H), 8.37 (s, 1H), 8.32 (s,1H), 7.50 (s, 1H), 7.09 (s, 1H), 6.96 (br.s, 1H), 3.69 (s, 3H), 2.66 (s, 3H), 2.57 (s, 3H), 2.00-1.60(m, 8H).

Example 60: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8'-methoxy-1',5'-dimethyl-1'H- Synthesis of spiro[cyclobutane-1,2'-quinazoline]-4'(3'H)-one hydrochloride (Compound 2-7)

Using the synthetic method of compound 2-6, intermediate 8.0 was replaced with 8.2 to obtain compound 2-7 as a brown solid. m/z: [M+H] ⁺ 379.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.97 (s, 1H), 11.66 (s, 1H), 8.70 (s, 1H), 8.33 (s ,1H),7.51(s,1H),7.11(s,1H),6.98(s,1H),3.75(s,3H),2.61(s,3H),2.57(s,3H),2.29-2.21( m, 2H), 2.14-2.05 (m, 2H), 1.88-1.65 (m, 2H).

Example 61: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8'-methoxy-1',5'-dimethyl-1'H- Synthesis of spiro[cyclohexane-1,2'-quinazoline]-4'(3'H)-one hydrochloride (Compound 2-8)

Using the synthetic method of compound 2-6, intermediate 8.0 was replaced with 8.3 to obtain compound 2-8 as a brown solid. m/z: [M+H] ⁺ 407.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.92 (s, 1H), 11.45 (s, 1H), 8.32 (s, 1H), 8.11 (s ,1H),7.51(s,1H),7.10(s,1H),6.92(s,1H),3.73(s,3H),2.64(s,3H),2.58(s,3H),1.83(s, 2H), 1.65-1.30 (m, 8H).

Example 62: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chloro-8'-methoxy-1'-methyl-1'H Of -spiro[cyclobutane-1,2'-quinazoline]-4'(3'H)-one hydrochloride (compound 2-9)

Using the synthetic method of compound 2-6, intermediate 8.0 was replaced with 8.5 to obtain compound 2-9 as an off-white solid. m/z: [M+H] ⁺ 399.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.62 (br.s, 1H), 10.67 (br.s, 1H), 8.84 (s, 1H) , 8.38 (s, 1H), 7.75 (br.s, 1H), 7.48 (s, 1H), 6.96 (s, 1H), 3.81 (s, 3H), 2.63 (s, 3H), 2.30-2.20 (m , 2H), 2.16-2.04 (m, 2H), 1.90-1.69 (m, 2H).

Example 63: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chloro-1'-methyl-1'H-spiro[cyclopentane- Synthesis of 1,2'-quinazoline]-4'(3'H)-one hydrochloride (Compound 2-10)

Using the synthetic method of compound 2-6, intermediate 8.0 was replaced with 8.7 to obtain compound 2-10 as a pale yellow solid. m/z: [M+H] ⁺ 383.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.20 (br.s, 1H), 10.03 (br.s, 1H), 8.41 (s, 1H) , 8.32(s, 1H), 7.59(s, 1H), 7.41-7.31(m, 2H), 6.90(s, 1H), 2.81(s, 3H), 2.00-1.90(m, 2H), 1.88-1.77 (m, 2H), 1.76-1.55 (m, 4H).

Example 64: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chloro-1'-methyl-1'H-spiro[cyclobutane- Synthesis of 1,2'-quinazoline]-4'(3'H)-one hydrochloride (Compound 2-11)

Using the synthetic method of compound 2-6, intermediate 8.0 was replaced with 8.8 to obtain compound 2-11 as a yellow solid. m/z: [M+H] ⁺ 369.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.15 (br.s, 1H), 9.91 (br.s, 1H), 8.79 (s, 1H) , 8.42 (s, 1H), 7.65 (s, 1H), 7.47-7.32 (m, 2H), 6.88 (s, 1H), 2.94 (s, 3H), 2.48-2.43 (m, 2H), 2.21-2.10 (m, 2H), 1.85-1.60 (m, 2H).

Example 65: 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1',5'-dimethyl-1'H-spiro[cyclobutane-1 Of 2,2'-pyridine[2,3-d]pyrimidine]-4'(3'H)-one hydrochloride (Compound 2-12)

Using the synthetic method of compound 2-6, intermediate 8.0 was replaced with 8.12 to obtain compound 2-12 as a yellow solid. m/z:[M+H] ⁺ 350.0.

Example 66: 2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6a-methyl-6a,7,8,9-tetrahydropyrido[3,2- e] Synthesis and Example 67 of pyrrolo[1,2-a]pyrimidin-5(6H)-one hydrochloride (Compound 2-13): 2-(4-amino-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)-6a-methyl-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrimidin-5(6H)- Synthesis of Ketone Hydrochloride (Compound 2-14)

Step 1: Heat an absolute ethanol solution (5mL) of 2-amino-6-chloronicotinamide (70mg, 0.4mmol) and 5-chloro-2-pentanone (150mg, 1.22mmol) to 95°C, then slowly drop Add concentrated sulfuric acid (3 drops). After the addition, the reaction system was stirred at 95°C overnight. The reaction solution was poured into ice water, and a solid precipitated, stirred for 5 minutes, and filtered. The filter cake was washed with petroleum ether and dried in vacuo to give 2-chloro-6a-methyl-6a, 7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrimidine- 5(6H)-one (60 mg, yield: 62%) is a light yellow solid. m/z: [M+H] ⁺ 238.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.66 (s, 1H), 7.89 (d, J=8.0 Hz, 1H), 6.71 (d, J = 8.0Hz, 1H), 3.61-3.50 (m, 2H), 2.15-1.92 (m, 4H), 1.32 (s, 3H).

Step 2: Combine the product obtained in Step 1 (60 mg, 0.25 mmol), 7H-pyrrolo[2,3-d]pyrimidin-4-amine (37 mg, 0.28 mmol), Cs ₂ CO ₃ (99 mg, 0.3 mmol), Pd A mixture of ₂ (dba) ₃ (23 mg, 0.025 mmol), XPhos (12 mg, 0.025 mmol), XantPhos (15 mg, 0.025 mmol) and 1,4-dioxane (3 mL) was purged with nitrogen and microwaved at 100°C React for 2 hours. After cooling to room temperature, filtering, the filter cake was washed with DCM/MeOH (10/1). The organic phases were combined and concentrated under reduced pressure. The residue was purified by prep-HPLC (separation condition 6) to obtain compounds 2-13 (12.8 mg, yield: 15%) and 2-14 (5.8 mg, yield: 7%), both of which were pale yellow solids. Compound 2-13: UPLCRT = 2.970 min; m/z: [M+H] ⁺ 336.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 13.10 (s, 1H), 12.39 (br.s, 1H ), 8.84(s, 1H), 8.61(s, 1H), 8.08(d, J=8.0Hz, 1H), 7.68(s, 1H), 7.39(s, 1H), 6.91(s, 1H), 3.97 -3.87(m,1H), 3.87-3.75(m,1H),2.23-2.02(m,4H),1.39(s,3H). Compound 2-14: UPLCRT=3.501min; m/z: [M+ H] ⁺ 336.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.37 (br.s, 2H), 8.65 (s, 1H), 8.52 (s, 1H), 8.25 (s, 1H), 8.15 (d, J = 8.0Hz, 1H), 7.84 (d, J = 8.0Hz, 1H), 7.16 (s, 1H), 3.73-3.64 (m, 2H), 2.20-1.96 (m, 4H), 1.37 ( s,3H).

Example 68: 8-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-chloro-3a-methyl-2,3,3a,4-tetrahydropyrrolo[ Synthesis of 1,2-a]quinazoline-5(1H)-one hydrochloride (Compound 2-15)

Using the synthetic method of compound 2-13, 2-amino-6-chloronicotinamide was replaced with 2-amino-4-bromo-6-chlorobenzamide to obtain compound 2-15 as a yellow solid. m/z: [M+H] ⁺ 369.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.08 (br.s, 1H), 9.77 (br.s, 1H), 8.39 (s, 1H) , 8.29 (s, 1H), 7.42 (s, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 6.87 (s, 1H), 3.46-3.41 (m, 2H), 2.14-1.95 (m , 4H), 1.27 (s, 3H).

Example 69: 9-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-7-chloro-4a-methyl-3,4,4a,5-tetrahydro-1H- Synthesis of pyrido[1,2-a]quinazoline-6(2H)-one hydrochloride (Compound 2-16)

Using the synthesis method of compound 2-13, 2-amino-4-bromo-6-chlorobenzamide and 6-chloro-2-hexanone were reacted to obtain compound 2-16 as a yellow solid. m/z: [M+H] ⁺ 383.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.10 (br.s, 1H), 9.82 (br.s, 1H), 8.40 (s, 1H) , 8.23 (s, 1H), 7.66 (s, 1H), 7.41-7.32 (m, 2H), 6.86 (s, 1H), 2.77-2.69 (m, 1H), 2.57-2.53 (m, 1H), 1.91 -1.79(m, 2H), 1.76-1.44(m, 4H), 1.24(s, 3H).

Example 70: 8-((7H-pyrrole[2,3-d]pyrimidin-4-yl)amino)-9-methoxy-3a,6-dimethyl-2,3,3a,4-tetra Synthesis of Hydropyrrolo[1,2-a]quinazoline-5(1H)-one hydrochloride (Compound 2-17)

Using the synthetic method of compound 2-13, 2-amino-6-chloronicotinamide was replaced with 2-amino-4-bromo-3-methoxy-6-methylbenzamide to obtain compound 2-17 as a yellow solid . m/z: [M+H] ⁺ 379.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.91 (s, 1H), 11.50 (br.s, 1H), 8.30 (s, 1H), 8.12 (s,1H),7.51(s,1H),6.97(s,1H),6.88(s,1H),3.73-3.68(m,1H),3.50(overlapping with the solvent,3H),3.36-3.29( m,1H), 2.59 (s, 3H), 2.29-2.18 (m, 1H), 2.03-1.84 (m, 3H), 1.37 (s, 3H).

Example 71: 9-((7H-pyrrole[2,3-d]pyrimidin-4-yl)amino)-10-methoxy-4a,7-dimethyl-3,4,4a,5-tetra Synthesis of Hydrogen-1H-pyrido[1,2-a]quinazoline-6(2H)-one hydrochloride (Compound 2-18)

Using the synthesis method of compound 2-13, 2-amino-4-bromo-3-methoxy-6-methylbenzamide and 6-chloro-2-hexanone were reacted to obtain compound 2-18 as a yellow solid. m/z: [M+H] ⁺ 393.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.91 (s, 1H), 11.33 (s, 1H), 8.33 (s, 1H), 8.23 (s ,1H),7.51(s,1H),7.19(s,1H),6.85(s,1H),3.76(s,3H),3.70-3.65(m,1H),3.15-3.05(m,1H), 2.60 (s, 3H), 2.02-1.91 (m, 1H), 1.74-1.45 (m, 5H), 1.25 (s, 3H).

Example 72: 7'-((6-aminopyrimidin-4-yl)amino)-5'-chloro-1'-methyl-1'H-spiro[cyclobutane-1,2'-quinazoline ]-4'(3'H)-ketohydrochloride (Compound 2-19) Synthesis

Using the synthetic method of compound 1-1, intermediate 1.1 was replaced with 8.15 to obtain compound 2-19 as a yellow solid. m/z: [M+H] ⁺ 345.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.69 (s, 1H), 8.82 (s, 1H), 8.50 (s, 1H), 8.12 (br .s,2H),7.22(s,1H),7.02(s,1H),6.24(s,1H),2.91(s,3H),2.46(overlapping with the solvent,2H),2.22-2.04(m, 2H), 1.84-1.61(m, 2H).

Example 73: 7'-((7H-pyrrole[2,3-d]pyrimidin-4-yl)amino)-1',5'-dimethyl-1'H-spiro[cyclobutane-1, Synthesis of 2'-quinazoline]-4'(3'H)-one hydrochloride (Compound 2-20)

Using the synthetic method of compound 2-6, intermediate 8.0 was replaced with 8.13 to obtain compound 2-20 as a light yellow solid. m/z: [M+H] ⁺ 349.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.79 (s, 1H), 11.20 (br.s, 1H), 8.72 (s, 1H), 8.38 (s,1H),7.49(s,1H),7.06(s,1H),7.01(s,1H),6.92(s,1H),3.93-3.83(m,1H),2.90(s,3H), 2.81 (d, J = 8.0 Hz, 1H), 2.60 (s, 3H), 2.23-2.10 (br.s, 2H), 1.86-1.73 (m, 1H), 1.74-1.61 (m, 1H).

Example 74: 7'-((7H-pyrrole[2,3-d]pyrimidin-4-yl)amino)-5'-chloro-8'-fluoro-1'-methyl-1'H-spiro[ Synthesis of cyclobutane-1,2'-quinazoline]-4'(3'H)-one hydrochloride (Compound 2-21)

Using the synthetic method of compound 2-6, intermediate 8.0 was replaced with 8.14 to obtain compound 2-21 as a yellow solid. m/z: [M+H] ⁺ 387.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.30 (br.s, 1H), 10.16 (br.s, 1H), 8.91 (s, 1H) , 8.37(s, 1H), 7.86(d, J=5.6Hz, 1H), 7.41(s, 1H), 6.89(s, 1H), 2.63(s, 3H), 2.29-2.17(m, 2H), 2.15-2.04(m, 2H), 1.91-1.68(m, 2H).

Example 75: 7'-((6-aminopyrimidin-4-yl)amino)-5'-chloro-8'-fluoro-1'-methyl-1'H-spiro[cyclobutane-1,2 Synthesis of'-quinazoline]-4'(3'H)-one hydrochloride (Compound 2-22)

Using the synthetic method of compound 1-1, intermediate 1.1 was replaced with 8.16 to obtain compound 2-22 as a yellow solid. m/z: [M+H] ⁺ 362.8; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.07 (br.s, 1H), 8.85 (s, 1H), 8.38 (s, 1H), 8.07 -7.35(m,3H),6.08(s,1H),2.61(s,3H),2.26-2.16(m,2H),2.12-2.02(m,2H),1.90-1.67(m,2H).

Biological example

Example 1: MNK1 and MNK2 in vitro enzyme inhibition level test

In this experiment, the ADP-Glo ^™ Max Assay Kit (Promega, V9101) was used to detect the amount of ADP produced to calculate the inhibition rate of the compound on the enzyme. The components of the buffer used in the experiment were: 15 mM HEPES, 10 mM MgCl ₂ , 20 mM NaCl, 1 mM EGTA, 0.1 mg/ml bovine serum protein, 0.02% Tween-20. MNK1 reaction system includes 20nM MNK1 (Thermo, PR9138A), 100uM polypeptide (Gill Biochemical, sequence: Ac-TATKSGSTTKNR-NH2), 200uM ATP and different concentrations of the test compound, the final concentration of DMSO is 0.33%, the reaction system is at room temperature Incubate for 60 minutes. The MNK2 reaction system includes 5nM MNK2 (Thermo, PR8046A), 100uM polypeptide (Gill Biochemical, sequence: Ac-TATKSGSTTKNR-NH2), 100uM ATP and different concentrations of the test compound. The final concentration of DMSO is 0.33%. The reaction system was incubated at room temperature for 45 minutes. After the incubation, the ADP-Glo ^™ Max Assay Kit was used to detect the generated ADP and TECAN M1000-pro. The experimental data was analyzed and processed by GraphPad Prism 5 software to obtain the IC ₅₀ value. Table 6

编号Numbering	MNK1IC ₅₀(nM) MNK1IC ₅₀ (nM)	MNK2IC ₅₀(nM) MNK2IC ₅₀ (nM)	编号Numbering	MNK1IC ₅₀(nM) MNK1IC ₅₀ (nM)	MNK2IC ₅₀(nM) MNK2IC ₅₀ (nM)
1-11-1	5.7505.750	6.2056.205	1-371-37	2.0332.033	1.1551.155
1-21-2	3.3493.349	3.1623.162	1-381-38	2.1472.147	1.3461.346
1-31-3	1.8701.870	1.3061.306	1-391-39	8.5058.505	6.6236.623
1-41-4	1.3681.368	1.1941.194	1-401-40	192.6192.6	462.5462.5
1-51-5	150.3150.3	21.0321.03	1-411-41	3.1273.127	2.3072.307
1-61-6	2.4762.476	1.1121.112	1-421-42	8.3538.353	7.6727.672
1-71-7	1.7591.759	1.0351.035	1-431-43	10.5610.56	20.1020.10
1-81-8	2.1792.179	1.5821.582	1-441-44	8.0968.096	9.2889.288
1-91-9	1.8031.803	0.8970.897	1-451-45	4.7664.766	2.2092.209
1-101-10	3.8173.817	2.1752.175	1-461-46	2.9302.930	3.2523.252
1-111-11	2.3992.399	2.8602.860	1-471-47	3.3733.373	1.7881.788
1-121-12	1.8181.818	1.1291.129	1-481-48	5.7135.713	4.7644.764
1-131-13	7.8327.832	3.8363.836	1-491-49	2.8342.834	1.6141.614
1-141-14	19.5819.58	25.9525.95	1-501-50	21.2421.24	26.8226.82
1-151-15	2.8002.800	1.3931.393	1-511-51	462.3462.3	88.3088.30
1-161-16	1.5481.548	0.7020.702	2-12-1	3.9963.996	2.0482.048
1-171-17	2.2662.266	1.8521.852	2-22-2	2.2122.212	0.9680.968
1-181-18	2.1462.146	1.8131.813	2-32-3	2.1062.106	0.8090.809
1-191-19	48.1848.18	19.6319.63	2-42-4	3.8733.873	4.2464.246
1-201-20	1.7051.705	2.3722.372	2-52-5	1.8611.861	1.0701.070
1-211-21	2.8632.863	4.1264.126	2-62-6	3.8173.817	1.6111.611
1-221-22	2.4352.435	1.4241.424	2-72-7	2.7062.706	1.5011.501
1-231-23	2.6492.649	1.6491.649	2-82-8	1.2931.293	0.9410.941
1-241-24	3.3233.323	1.7181.718	2-92-9	1.9341.934	0.7330.733
1-251-25	2.2012.201	1.1301.130	2-102-10	2.5562.556	1.0101.010
1-261-26	4.2374.237	6.1386.138	2-112-11	3.2133.213	1.1101.110
1-271-27	2.2232.223	1.8181.818	2-132-13	5.2715.271	3.1523.152
1-281-28	2.9262.926	1.6201.620	2-142-14	4.9814.981	2.8722.872
1-291-29	13.9213.92	14.1414.14	2-152-15	3.5093.509	1.3361.336

1-301-30	6.1876.187	4.3114.311	2-162-16	2.8112.811	1.5901.590
1-311-31	4.1094.109	8.4308.430	2-172-17	2.8032.803	1.9001.900
1-321-32	2.6292.629	1.6261.626	2-182-18	8.7328.732	4.0264.026
1-331-33	2.4572.457	0.9660.966	2-192-19	1.5861.586	0.6530.653
1-341-34	2.9522.952	2.7212.721	2-202-20	1.5231.523	0.8900.890
1-351-35	2.8852.885	1.6151.615	2-212-21	0.9490.949	0.3840.384
1-361-36	4.3824.382	6.0876.087	2-222-22	2.7752.775	1.0581.058

Example 2: pEIF4E cell level detection

By phosphorylating eukaryotic initiation factor eIF4E and other key effector proteins, kinases MNK1 and MNK2 integrate several oncogenic factors and immune signaling pathways, thereby selectively regulating cellular mRNA stability and transcription.

Phospho-EIF4E (Ser209) cellular kit (Cisibo) was used to determine the endogenous phosphorylation level of EIF4E in OCI-LY7B cell non-Hodgkin's lymphoma cells. The experiment was conducted according to the manufacturer's experimental protocol. In short, OCI-LY7 cells were plated on a 96-well cell culture plate with 50 uL of 2×106 cells/ml of serum-free IMDM medium and incubated at 37°C overnight. The next day, the concentration range of the test compound was created by diluting 100% DMSO and then further diluting it with serum-free medium. Cells were added with diluted compounds and incubated at 37°C for 3h. Then add 4X cell lysate to the cells and shake at room temperature for 30 minutes. Transfer 16uL of the lysate to a 384 white shallow well plate, then add 4uL of pre-formulated antibody mixed solution, and centrifuge at 1000rpm for 30s. Seal the plate with a sealing plate and incubate overnight at room temperature. Then use the HTRF setting to test on the TECAN M1000 Pro reader. The results are shown in Table 7 below:

Table 7

Numbering	IC ₅₀ (nM)	Numbering	IC ₅₀ (nM)
1-3	5.132	1-38B	1.250
1-4	3.610	2-2	2.321
1-6	2.179	2-9	1.600
1-9	2.600	2-11	0.479
1-12	1.556	2-15	0.731
1-16	1.588	2-19	3.195
1-28	1.574	2-20	4.822
1-28B	0.690	2-21	0.682
1-38	1.410	2-22	0.934

.

Claims

A compound represented by formula I or I', its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt;

Wherein, W 1 and W 2 are independently =O, =S, =NH, =N-OH or =NO (C 1-6 alkyl);

A 1 is N or CR 5 ;

A 2 is N or CR 5a ;

A 3 is N or CR 5b ;

R is -NH-Cy or Cy;

R 1 is H, -OH, -NH 2 , R A , -NH-R A , -NH-C(O)-R A or -OR A ;

R 2 is H, CN, deuterated C 1-4 alkyl or R B ;

R 3 is H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; the R 3 is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;

R 4 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3 -8 membered heterocycloalkyl, C 6-10 aryl C 1-6 alkyl, 5-6 membered heteroaryl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl or 3 -8 membered heterocycloalkyl C 1-6 alkyl; said R 4 is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;

Each of R 1 , R 2 , R 3 and R 4 is an independent substituent, or

1) R 1 and R 3 are connected to each other to form a 3-10 membered heterocycloalkyl; the 3-10 membered heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;

2) R 2 and R 3 are connected to each other to form a 3-10 membered heterocycloalkyl group; the 3-10 membered heterocycloalkyl group is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;

3) R 3 and R 4 together with the carbon atom to which they are connected together form C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl; the C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl Is unsubstituted, or optionally substituted with 1 to 3 R 9 in any position; or

4) R 2 and R 3 are connected to each other to form a double bond with the α bond;

R 5 , R 5a and R 5b are independently hydrogen, halogen, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy or C 1-4 alkyl Amino

Cy is a 5-10 membered heteroaromatic ring; the Cy is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C , -NHC(O)R C , -C(O)R C and -C(O)N(R C ) 2 substituents are substituted in any position;

Each R A is independently C 1-8 alkyl, C 2-8 alkenyl or C 2-8 alkynyl; the R A is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -OH , -NH 2 , oxo, C 1-3 alkoxy and C 1-3 alkylamino substituents are substituted at any position;

Each R B is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3-8 Member heterocycloalkyl, -(CH 2 ) n -phenyl, -(CH 2 ) n -(5-6 membered heteroaryl), -(CH 2 ) n -C 3-8 cycloalkyl or -( CH 2 ) n -(3-8 membered heterocycloalkyl); the R B is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;

Each R C is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3-8 Heterocyclic heterocyclic alkyl, -(CH 2 ) n -OC 1-6 alkyl, -(CH 2 ) n -phenyl, -(CH 2 ) n -(5-6 membered heteroaryl), -(CH 2 ) n -C 3-8 cycloalkyl, -(CH 2 ) n -(3-8 membered heterocycloalkyl) or -(3-8 membered heterocycloalkyl)-C 1-6 alkyl; Said R C is unsubstituted, or optionally substituted with 1 to 3 R 10 at any position;

Each R 9 and each R 10 are independently H, -CN, -NO 2 , -SH, -NH 2 , -OH, -C(O)OH, -NHC(O)R a , -NHS ( O) 2 R a , -C(O)R a , halogen, oxo, ester, amide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1- 4 alkoxy, C 1-4 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, -(CH 2 ) n -NH 2 , -(CH 2 ) n -OH, -(CH 2 ) n -(C 1-4 alkylamino) or -(CH 2 ) n -(C 1-4 alkoxy);

Each R a is independently C 1-6 alkyl or C 2-6 alkenyl;

n is 1, 2, 3 or 4.
The compound of formula I or I'according to claim 1, wherein the isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt is characterized in that R is

Where R 6 , R 7 and R 8 are independently H, halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C ,- NHC(O)R C or -NHS(O) 2 R C ; R 6 and R 7 are independent substituents, or R 6 and R 7 are connected to each other to form a heteroaryl or heterocycloalkyl; the heteroaryl Or heterocycloalkyl is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR The substituents of C , -NHC(O)R C , -C(O)R C and -C(O)N(R C ) 2 are substituted at arbitrary positions.
The compound of formula I or I'according to claim 2, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt, characterized in that R 6 is H, F, Cl, -CN, -NH 2 , -CH 3 , -CF 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -O-n-propyl, -O-isopropyl , Cyclopropyl or 1-methyl-1H-pyrazolyl;

And/or, R 7 is H, -NH 2 , -NHR C , -NH-OR C, or -NHC(O)R C ;

And/or, R 8 is H.
The compound of formula I or I'according to claim 2, wherein the isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt is characterized in that R is

Wherein R 11 and R 12 are independently H, halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C, or -NHC(O ) R C.
The compound of formula I or I'according to claim 4, wherein its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt, wherein R 8 is H;

And/or, R 11 is H;

And/or, R 12 is H.
The compound of formula I or I'according to claim 1, wherein its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt, wherein R 9 is H, -NH 2 , -OH, F, Cl, =O, -NHC(O)-C 2-6 alkenyl, -C(O)-C 2-6 alkenyl, -NHS(O) 2 -C 2-6 alkenes Group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy.
The compound of formula I or I'according to claim 1, wherein the isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt is characterized in that W 1 is O; W 2 Is O;

And/or, R 1 is H, -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), -NH(CH 2 CH 3 ), or -NH(CH 2 CH=CH 2 );

And/or, R 2 is H, CD 3 , C 1-6 alkyl, C 2-6 alkenyl, phenyl, or 5-6 membered heteroaryl; the R 2 is unsubstituted, or optionally substituted 1 to 3 substituents selected from F, Cl, -OH, -NH 2 , =O, -OCH 3 , -N(CH 3 ) 2 and -NHC(O)CH=CH 2 are substituted at arbitrary positions;

And/or, R 3 is H, methyl or ethyl;

And/or, R 4 is methyl, ethyl, n-propyl, isopropyl, phenyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; said R 4 is unsubstituted, Or optionally substituted by 1 to 2 or 1 substituent selected from fluorine, chlorine, methyl and trifluoromethyl at any position;

And/or, R 5 is hydrogen, halogen or C 1-4 alkyl;

And/or R 5a is H;

And/or, R 5b is hydrogen, halogen, C 1-4 alkoxy or C 1-4 alkyl.
The compound of formula I or I'according to claim 1, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt, characterized in that R 3 and R 4 are in common with The connected carbon atoms together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1H-indenyl, 2,3-dihydro-1H-indenyl-1-one, spiro [3,2]hexyl, spiro[3.3]heptyl, tetrahydrofuranyl, pyrrolidinyl, azetidinyl, piperidinyl or 1-oxo-thioheterobutyl;

Or, R 2 and R 3 are connected to each other to form a 5-6 membered heterocycloalkyl group; the 5-6 membered heterocycloalkyl group is unsubstituted or optionally substituted with 1=O at any position.
The compound of formula I or I'according to claim 1, its isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt, wherein the compound of formula I or I The compound represented by'is a compound represented by formula II, its isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts,

Where R 1 is H, -OH, -NH 2 , R A , -NH-R A , -NH-C(O)-R A or -OR A ;

R 2 is H, CN or R B ;

R 3 is H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; the R 3 is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;

R 4 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl or 3 -8 membered heterocycloalkyl; said R 4 is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;

The R 3 and R 4 are independent substituents, or R 3 and R 4 together with the carbon atom to which they are connected together form a C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl; the C 3-10 ring The alkyl group or 3-10 membered heterocycloalkyl group is unsubstituted, or optionally substituted with 1 to 3 R 9 at any position;

R 5 is hydrogen, halogen, cyano or C 1-4 alkyl;

R 6 , R 7 and R 8 are independently H, halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C , -NHC ( O)R C or -NHS(O) 2 R C ;

R 6 and R 7 are independent substituents, or R 6 and R 7 together with the atoms to which they are attached form a heteroaryl or heterocycloalkyl group; the heteroaryl or heterocycloalkyl group is unsubstituted or is optionally substituted 1 to 3 are selected from halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C , -NHC(O)R C , -C( O)R C and -C(O)N(R C ) 2 substituents are substituted at any positions;

Each R A is independently C 1-8 alkyl, C 2-8 alkenyl or C 2-8 alkynyl; the R A is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -OH , -NH 2 , oxo, C 1-3 alkoxy and C 1-3 alkylamino substituents are substituted at any position;

Each R B is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3-8 Member heterocycloalkyl, -(CH 2 ) n -phenyl, -(CH 2 ) n -(5-6 membered heteroaryl), -(CH 2 ) n -C 3-8 cycloalkyl or -( CH 2 ) n -(3-8 membered heterocycloalkyl); the R B is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;

Each R C is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3-8 Heterocyclic heterocyclic alkyl, -(CH 2 ) n -OC 1-6 alkyl, -(CH 2 ) n -phenyl, -(CH 2 ) n -(5-6 membered heteroaryl), -(CH 2 ) n -C 3-8 cycloalkyl, -(CH 2 ) n -(3-8 membered heterocycloalkyl) or -(3-8 membered heterocycloalkyl)-C 1-6 alkyl; Said R C is unsubstituted, or optionally substituted with 1 to 3 R 10 at any position;

Each R 9 and each R 10 are independently H, -CN, -NO 2 , -SH, -NH 2 , -OH, -C(O)OH, -NHC(O)R a , -NHS ( O) 2 R a , -C(O)R a , halogen, oxo, ester, amide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1- 4 alkoxy, C 1-4 alkylamino, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy;

Each R a is independently C 1-6 alkyl or C 2-6 alkenyl;

n is 1, 2, 3 or 4.
The compound of formula I or I'according to any one of claims 1 to 6, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt, characterized in that The compound represented by formula I or I'is a compound represented by formula IV, V, VI, VII or VIII, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt,

The compound represented by general formula IV, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt:

Among them, m is 0, 1, 2 or 3; t is 0, 1, 2 or 3;

R 1 , R 2 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined in any one of claims 1 to 6;

The compound represented by the general formula V, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt:

Among them, m is 0, 1, 2 or 3; t is 0, 1, 2 or 3;

The definitions of R 1 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined in any one of claims 1 to 6;

Compound represented by general formula VI, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt:

Wherein, R 1 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in any one of claims 1 to 6;

The compound represented by the general formula VII, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt:

Among them, m is 0, 1, 2 or 3; t is 0, 1, 2 or 3;

The definitions of R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 and A 3 are as defined in any one of claims 1 to 6;

The compound represented by the general formula VIII, its isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt:

Among them, m is 0, 1, 2 or 3; t is 0, 1, 2 or 3;

The definitions of R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and A 3 are as defined in any one of claims 1 to 6.
The compound of formula I or I'according to claim 1, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt is any of the following compounds:
A pharmaceutical composition comprising an active component and a pharmaceutically acceptable excipient; the active component comprises the compound of formula I or I'according to any one of claims 1 to 11, and its isomerism Body, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts.
The pharmaceutical composition according to claim 12, further comprising other kinds of therapeutic agents for treating related diseases caused by abnormal levels of MNK1 and/or MNK2.
The pharmaceutical composition according to claim 13, wherein the related disease caused by abnormal levels of MNK1 and/or MNK2 is cancer.
A compound according to any one of claims 1 to 11, a compound represented by formula I or I', an isomer thereof, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable salt, or claim 12 The use of the pharmaceutical composition in the preparation of MNK1 and/or MNK2 inhibitor drugs.
A compound according to any one of claims 1 to 11, a compound represented by formula I or I', an isomer thereof, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable salt, or claim 12 Use of the pharmaceutical composition described in and 13 in the preparation of a medicament for treating and/or alleviating the related diseases caused by abnormal levels of MNK1 and/or MNK2.
The use according to claim 16, wherein the related disease caused by abnormal levels of MNK1 and/or MNK2 is cancer.