CN116194456A

CN116194456A - Preparation of heterocyclic compounds as KRAS inhibitors and methods of use thereof

Info

Publication number: CN116194456A
Application number: CN202180031448.8A
Authority: CN
Inventors: 田红旗; 黄功超; 高旭光; 施贤; 徐海江; 马卫敏; 王兴凯
Original assignee: KECHOW PHARMA Inc
Current assignee: KECHOW PHARMA Inc
Priority date: 2020-04-30
Filing date: 2021-04-29
Publication date: 2023-05-30
Also published as: TW202144349A; WO2021219072A1

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt, prodrug, tautomer or stereoisomer and solvate thereof, which is useful for the treatment of cancer and inflammation in mammals. Also disclosed are methods of preparing the compounds of formula (I) and pharmaceutical compositions comprising the compounds.

Description

Preparation of heterocyclic compounds as KRAS inhibitors and methods of use thereof

Technical Field

The present invention relates to certain novel heterocyclic compounds or pharmaceutically acceptable salts thereof, which are useful in the treatment or prevention of many different cancers. The invention also relates to pharmaceutical compositions comprising the compounds and salts thereof, intermediates in the preparation of the compounds, and to methods of treating a variety of different cancers using the compounds and salts thereof.

Background

In 1982 Weinberg and Barbacid first isolated a transgene from human bladder cancer cell lines, which resulted in malignant transformation of NIH 3T3 cells, whereas DNA extracted from normal human tissues did not. Subsequently, santos and Parada found that the above-described transformant was not a novel gene, but a human homologous gene to the Harver murine sarcoma virus ras gene, designated H2ras. In the same year, kronitis found a homolog of the Kirsten murine sarcoma virus gene, called K-ras, in human lung cancer cells. Another similar gene is the ras-like gene found when human neuroblastoma DNA infects NIH 3T3 cells, referred to as N2ras, which is independent of the virus.

ras genes are quite conserved in evolution and widely exist in various eukaryotes such as mammals, drosophila, fungi, nematodes and yeast suggesting an important physiological function, the ras gene family of mammals has three members, H-ras, K-ras, N-ras respectively, with A, B variants of the fourth exon of K-ras. The various ras genes have similar structures, each consisting of four exons, distributed over a full length of about 30kb of DNA. The encoded products are proteins with a relative molecular mass of 2.1 ten thousand, and are therefore called P21 proteins. H-ras has been shown to be located on the short arm of chromosome 11 in humans (11p15.1-P15.3), K-ras on the short arm of chromosome 12 (12p1.1-pter), N-ras on the short arm of chromosome 1 (1P 22-P32), and each ras gene encodes P21 with an average distribution of sequences over four exons, with a large variation in introns and sizes, and thus the whole gene is also very different, e.g., human K-ras is 35kb long, and N-ras is 3kb long. Due to the presence of two fourth exons, K-ras can be spliced in two ways, but the mRNA encoding K-ras-B is high. In addition to K-Ras-B containing 188 amino acids, two other Ras proteins contain 189 amino acids.

Ras (P21) protein is located inside the cell membrane and plays an important role in transmitting cell growth differentiation signals. It belongs to a Guanosine Triphosphate (GTP) binding protein, a coupling factor for cellular information transfer, which regulates the transfer of information by the interconversion of GTP with Guanosine Diphosphate (GDP). P21 has a strong affinity for GTP and GDP and a weak GTPase activity. Under normal conditions, the combination of P21 and GDP is in an inactivated state, and when extracellular growth differentiation factors transmit signals to the P21 on the inner side of a cell membrane, the combination activity of the P21 and GTP can be enhanced, so that the combination of the P21 and the GTP is in an activated state, and a signal system is opened. Because of the GTPase activity of P21, GTP can be hydrolyzed into GDP, P21 is deactivated after the combination of P21 and GDP, and the signal system is closed. Normally, the GTPase activity of P21 is weak, and when combined with GTPase Activating Protein (GAP), the hydrolysis rate is increased by 1 ten thousand times to inactivate P21. After P21 and GDP are combined, guanylate releasing protein (GNRP) can be activated, and the GNRP enables P21 to release GDP combined with GTP, so that the P21 can be regulated to turn on and off a signaling system in a controlled manner through the interconversion of GTP and GDP, and the process of transmitting growth differentiation signals into cells is completed.

More than 1/5 of cancer patients are accompanied by mutations in the Ras gene, which occur mostly at residues G12, G13 and Q61, which result in GAP-protein mediated failure, with Ras signals being continuously active; the invention designs and synthesizes a series of chemical molecules with strong ras inhibition biological activity, and provides a method for treating related cancers by inhibiting H-ras, K-ras or N-ras.

Disclosure of Invention

The present invention provides compounds, including stereoisomers, pharmaceutically acceptable salts, tautomers and prodrugs thereof, capable of modulating G12C mutant KRAS, HRAS and/or NRAS proteins. Methods of using such compounds for treating different diseases or conditions, such as cancer, are also provided.

In one aspect of the invention, there is provided a compound having formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or prodrug thereof, wherein the compound of formula (I) is:

wherein:

ring W is a 4 to 12 membered saturated or partially saturated monocyclic ring, bridged ring, or spiro ring, wherein the saturated or partially saturated monocyclic ring is optionally additionally substituted with one or more R ⁴ Instead of the above-mentioned,

wherein the method comprises the steps of

R ⁴ Selected from: oxo (oxo), alkyl, alkenyl, alkyne, cycloalkyl, aryl, heteroaryl, heterocyclyl, cyano, nitro, -C (O) OR ⁵ or-C (O) N (R) ⁵ ) ₂ Wherein alkyl is unsubstituted OR cyano, halo, -OR ⁵ 、-N(R ⁵ ) ₂ Or one or more substitutions in heteroaryl, wherein R ⁵ Each independently is hydrogen or alkyl;

R ¹ is-L ¹ -T，

Wherein the method comprises the steps of

L ¹ is-O-, -S-, -NR ^a -、-C(O)-、-SO ₂ -、-SO-、-C(＝NR ^a )-、-C(O)-O-、-OC(O)-、-C(O)-NR ^a -or-NR ^a C(O)-，

T is-CR ^a ＝CR ^b R ^c 、-C≡CR ^b An alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group, each of which is unsubstituted or oxo, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, CN, nitro or NR ^x R ^y One or more substitutions in (a);

wherein the method comprises the steps of

R ^a Hydrogen, deuterium, cyano, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, aryl, heteroaryl or heterocyclyl;

R ^b and R is ^c Each independently hydrogen, deuterium, cyano, halogen, -C (O) OR ^x An alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group, each of which is unsubstituted or oxo; halogen; a hydroxyl group; an alkyl group; a haloalkyl group; a hydroxyalkyl group; an alkoxy group; a CN; a nitro group; NR (NR) ^x R ^y The method comprises the steps of carrying out a first treatment on the surface of the Aryl unsubstituted or substituted by alkyl, hydroxy, halogen; heteroaryl, unsubstituted or substituted with alkyl, hydroxy, halo; unsubstituted or substituted by one or two of alkyl, hydroxy, halogen,

alternatively, at T is-CR ^a ＝CR ^b R ^c When R is ^a And R is R ^b Or R is ^a And R is R ^c Together with the carbon atoms to which they are attached, form an unsaturated 5-to 8-membered ring, which is unsubstituted or substituted with one or two of oxo, hydroxy, halogen, alkyl, hydroxyalkyl, haloalkyl or alkoxy;

R ^x and R is ^y Each of which is a single pieceIndependently hydrogen or alkyl;

n ¹ 0, 1 or 2;

n ² 0, 1 or 2;

q is N or CR ¹¹ M is N or CR ¹² Provided that at least one of Q and M is N;

Wherein the method comprises the steps of

R ¹¹ And R is ¹² Each independently is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl OR heterocyclyl, -OR ^d 、-C(O)R ^d 、-CO ₂ R ^d 、-CONR ^d R ^e or-NR ^d R ^e Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently oxo, halogen, hydroxy, alkoxy, alkyl, cycloalkyl, nitro, cyano and-NR ^d R ^e Wherein R is one or more substitutions of ^d And R is ^e Each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

alternatively, when Q is CR ¹¹ When R is ¹¹ And R is ⁴ Together with the atoms to which they are attached form a 5-to 8-membered ring containing 0, 1 or 2 members selected from O, S and NR ^d The ring being unsubstituted or substituted by oxo, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, haloalkyl, hydroxyalkyl and-NR ^d R ^e Wherein R is one or more substitutions of ^d And R is ^e Each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

l is a single bond, -O-, -S-, -NR ^a -、-O-CH ₂ -、-S-CH ₂ -、-NR ^a -CH ₂ -、-CH ₂ -O-、-CH ₂ -S-、-CH ₂ -NR ^a -、-C(O)-、-SO ₂ -、-SO-、-C(O)-O-、-OC(O)-、-C(O)-NR ^a -or-NR ^a C(O)-；

R ² Is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl OR heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently unsubstituted OR substituted with halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, oxo, -OR ^d 、-C(O)R ^d 、-CO ₂ R ^d 、-CONR ^d R ^e 、-NR ^d R ^e One or more of cycloalkyl, cycloalkylalkyl, aryl, heteroaryl and heterocyclyl groups, wherein R ^d And R is ^e Each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

R ³ is cycloalkyl, heterocyclyl, aryl or heteroaryl, provided that when M and Q are both N and N ² When 1, R is ³ Is a non-aromatic fused bicyclic group, a non-aromatic fused bicyclic heterocyclic group or a bicyclic heteroaryl group, R ³ Is unsubstituted or substituted with one or more of the following groups: oxo, halogen, cyano, -OR ^d 、-C(O)R ^d 、-CO ₂ R ^d 、-CONR ^d R ^e 、-NR ^d COR ^e 、-NR ^d R ^e 、-S(O) ₂ NR ^d R ^e Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently substituted with halogen, alkyl, cyano, carbamoyl, alkoxy, hydroxy, cycloalkyl and heteroaryl, wherein R ^d And R is ^e Each independently is hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkenyl, or cycloalkyl.

In some embodiments, there is provided a compound having formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or prodrug thereof, wherein the compound of formula (I) is:

Wherein:

wherein the method comprises the steps of

R ¹ is-L ¹ -T，

Wherein the method comprises the steps of

wherein the method comprises the steps of

R ^a Is hydrogen, deuterium, cyano, halogen, hydroxy,Alkyl, haloalkyl, hydroxyalkyl, aryl, heteroaryl or heterocyclyl;

R ^x and R is ^y Each independently is hydrogen or alkyl;

n ¹ 0, 1 or 2;

n ² 0, 1 or 2;

q is N or CR ¹¹ M is N or CR ¹² Provided that at least one of Q and M is N;

wherein the method comprises the steps of

R ¹¹ And R is ¹² Each independently is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl OR heterocyclyl, -OR ^d 、-C(O)R ^d 、-CO ₂ R ^d 、-CONR ^d R ^e or-NR ^d R ^e Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl groups are eachIndependently substituted with oxo, halogen, hydroxy, alkoxy, alkyl, cycloalkyl, nitro, cyano and-NR ^d R ^e Wherein R is one or more substitutions of ^d And R is ^e Each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

R ³ is a non-aromatic condensed bicyclic heterocyclic group, R ³ Is unsubstituted or substituted with one or more of the following groups: oxo, halogen, cyano, -OR ^d 、-C(O)R ^d 、-CO ₂ R ^d 、-CONR ^d R ^e 、-NR ^d COR ^e 、-NR ^d R ^e 、-S(O) ₂ NR ^d R ^e Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently substituted with halogen, alkyl, cyano, carbamoyl, alkoxy, hydroxy, cycloalkyl and heteroaryl, wherein R ^d And R is ^e Each independently is hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkenyl, or cycloalkyl.

In some embodiments, L ¹ is-C (O) -or-SO ₂ -。

In some embodiments, L ¹ is-C (=NR) ^a ) -, wherein R is ^a H, CN or hydroxy.

In some embodiments, T is-CR ^a ＝CR ^b R ^c 、-C≡CR ^b An alkyl group or a heterocyclic group, wherein Ra and Rb are as defined in formula (I).

In some embodiments, T is-CR ^a ＝CR ^b R ^c or-C.ident.CR ^b Wherein R is ^a Is hydrogen, deuterium, cyano, halogen, hydroxy or alkyl, R ^b And R is ^c Each independently hydrogen; halogen; unsubstituted alkyl; by hydroxy, halogen, NR ^x R ^y Or heterocyclyl-substituted alkyl; unsubstituted aryl or heteroaryl; aryl or heteroaryl substituted by alkyl, hydroxy or halogen, wherein R ^x And R is _y Each independently is hydrogen or alkyl. Preferably, in the above-described embodiment,the aryl group being phenyl, which is unsubstituted or substituted by halogen, hydroxy or C _1-3 One or two of the alkyl groups are substituted. Preferably, in the above embodiments, the heteroaryl is thiazolyl, oxazolyl, pyridinyl or pyrimidinyl, which is unsubstituted or substituted by halogen, hydroxy or C _1-3 One or two of the alkyl groups are substituted.

In some embodiments, T is-CR ^a ＝CR ^b R ^c Wherein R is ^a And R is R ^b Or R is ^a And R is R ^c Together with the carbon atoms to which they are attached, form an unsaturated 5-to 8-membered ring, which is unsubstituted or substituted with one or two of hydroxy, halogen, alkyl, hydroxyalkyl, haloalkyl or alkoxy. In some embodiments, T is-CR ^a ＝CR ^b R ^c Wherein R is ^a And R is R ^b Or R is ^a And R is R ^c Together with the carbon atoms to which they are attached, form an unsaturated 5-, 6-, 7-, or to 8-membered carbocyclic ring, which ring is unsubstituted or substituted with one or two of hydroxy, halogen, alkyl, hydroxyalkyl, haloalkyl, or alkoxy. Preferably, the unsaturated 5-, 6-, 7-or to 8-membered carbocycle is a cyclopentene ring, cyclohexene ring, cycloheptene ring or cyclooctene ring.

In some embodiments, T is alkyl, which is unsubstituted or substituted with halogen, hydroxy, NR ^x R ^y Substituted by CN, haloalkyl, hydroxyalkyl, alkoxy or heterocyclyl, where R ^x And R is ^y Each independently is hydrogen or alkyl. Preferably, the heterocyclic group in the above embodiments is a 4-to 8-membered heterocyclic ring containing one or two selected from oxygen, nitrogen and sulfur, such as azetidine, pyrrolidine, piperidinyl, morpholinyl.

In some embodiments, T is heterocyclyl, which is unsubstituted or substituted with halo, hydroxy, NR ^x R ^y Substituted by CN, alkyl, haloalkyl, hydroxyalkyl or alkoxy, where R ^x And R is ^y Each independently is hydrogenOr alkyl. Preferably, T is a 3-to 8-membered heterocyclic ring containing one selected from oxygen, nitrogen and sulfur, such as unsubstituted or methyl substituted propylene oxide.

In some embodiments, L ¹ is-C (O) -or-SO ₂ -, and T is-ch=ch ₂ 。

In some embodiments, L is-O-CH ₂ -or-O-.

In some embodiments, L is-O-CH ₂ -, and R ² Is a heterocyclic group that is unsubstituted or substituted with one or more of halogen and alkyl. Preferably, L is-O-CH ₂ -, and R ² Is a heterocyclic group, wherein the heterocyclic group contains a 4-to 8-membered monocyclic ring of 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, sulfur, the heterocyclic group being unsubstituted or substituted with one or more of halogen and alkyl. More preferably, the heterocyclyl is azetidinyl, pyrrolidinyl or piperidinyl, the ring being unsubstituted or substituted with one or two halogens or alkyl groups. In a further preferred embodiment, L-R ² Is that

In some embodiments, L is-O-, and R ² Is a heterocyclic group that is unsubstituted or substituted with one or more of halogen and alkyl. Preferably, L is-O-, and R ² Is a heterocyclic group, wherein the heterocyclic group is a 7-to 12-membered fused bicyclic heterocyclic group containing 1,2 or 3 heteroatoms selected from oxygen, nitrogen, sulfur, the heterocyclic group being unsubstituted or substituted with one or more of halogen and alkyl. More preferably, the heterocyclyl is a non-aromatic 7-to 12-membered fused bicyclic heterocyclyl containing 1,2 or 3 heteroatoms selected from oxygen, nitrogen, sulfur, said heterocyclyl being unsubstituted or substituted with one or more of halogen and alkyl. In a preferred embodiment, the heterocyclic group is tetrahydropyrrolizine, more preferably tetrahydro-1H-pyrrolazin-7 a-yl

In a further preferred embodiment, L-R2 is 2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yloxy

In some embodiments, R ³ Is aryl, wherein the aryl is phenyl or naphthyl, which phenyl or naphthyl is unsubstituted or substituted with 1,2 or 3 substituents: halogen; cyano group; -OR ^d Wherein R is ^d Is hydrogen, alkyl or haloalkyl; -CONR ^d R ^e Wherein R is ^d And R is ^e Each independently hydrogen, alkyl or cycloalkyl; -NR ^d COR ^e Wherein R is ^d And R is ^e Each independently hydrogen or alkyl; an alkyl group, wherein the alkyl group is unsubstituted or substituted with halogen, cycloalkyl, hydroxy, or alkoxy; cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with alkyl, cyano or carbamoyl; alkynyl; -NR ^d R ^e Wherein R is ^d And R is ^e Each independently hydrogen or alkyl; or heteroaryl.

In some embodiments, R ³ Is a partially hydrogenated naphthyl group, which is unsubstituted or substituted by hydroxy, alkyl, hydroxyalkyl, haloalkyl or halogen. Preferably, R ³ Is 1,2,3, 4-tetrahydronaphthyl, which is unsubstituted or substituted by hydroxy, alkyl, hydroxyalkyl, haloalkyl, halogen, amino, alkylamino or dialkylamino.

In some embodiments, R ³ Is heteroaryl, which is unsubstitutedOr substituted with 1,2 or 3 substituents: oxo, halogen; cyano group; -OR ^d Wherein R is ^d Is hydrogen, alkyl or haloalkyl; -CONR ^d R ^e Wherein R is ^d And R is ^e Each independently hydrogen, alkyl or cycloalkyl; -NR ^d COR ^e Wherein R is ^d And R is ^e Each independently hydrogen, alkyl or alkenyl; an alkyl group, wherein the alkyl group is unsubstituted or substituted with halogen, cycloalkyl, hydroxy, or alkoxy; cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with alkyl, cyano or carbamoyl; alkynyl; or-NR ^d R ^e Wherein R is ^d And R is ^e Each independently is hydrogen or alkyl. Preferably, the heteroaryl is a monocyclic heteroaryl, such as thiophene, thiazole, pyrazole, pyridine or pyrimidine, which is unsubstituted or substituted as described above. Preferably, the heteroaryl is a bicyclic heteroaryl, e.g

Which is unsubstituted or substituted as described above.

In some embodiments, R ³ Is a heterocyclic group, preferably a non-aromatic, fused bicyclic heterocyclic group, which is unsubstituted or substituted with 1, 2 or 3 substituents: oxo, halogen; cyano group; -OR ^d Wherein R is ^d Is hydrogen, alkyl or haloalkyl; -CONR ^d R ^e Wherein R is ^d And R is ^e Each independently hydrogen, alkyl or cycloalkyl; -NR ^d COR ^e Wherein R is ^d And R is ^e Each independently hydrogen, alkyl or alkenyl; an alkyl group, wherein the alkyl group is unsubstituted or substituted with halogen, cycloalkyl, hydroxy, or alkoxy; cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with alkyl, cyano or carbamoyl; alkynyl; or-NR ^d R ^e Wherein R is ^d And R is ^e Each independently is hydrogen or alkyl. In another embodiment, R ³ Is a non-aromatic fused bicyclic heterocyclic group which is unsubstituted or substituted with 1, 2 or 3 substituents of: oxo, halogen; hydroxy, alkoxy, and alkyl; preferably, the substituent is oxo, halogen, hydroxy, methoxy or methyl. In a further embodiment, R ³ Is a non-aromatic condensed bicyclic heterocyclic group which is

Which is unsubstituted or substituted with 1, 2 or 3 substituents: oxo, halogen; hydroxy, alkoxy, and alkyl; preferably, the substituents are oxo, halogen, hydroxy, methoxy or methyl, wherein X, Y and Z are each independently N or CR ⁹ Wherein R is ⁹ Is hydrogen, hydroxy, cyano, alkyl, haloalkyl, halogen, hydroxyalkyl, alkoxyalkyl or alkylsulfonyl.

In some embodiments, the compound of formula (I) is

Wherein:

R ³ is that

Wherein X, Y, Z is selected from N or CR ⁹ The remaining variables are as defined for formula (I).

In some embodiments, the compounds of formula (I) are those of formula (I-3), (I-4), (I-5), (I-6), (I-7) and (I-8):

wherein R is ^a And R is ^b Independently hydrogen, methyl or trifluoromethyl, or R ^a And R is ^b The composition is c=o.

In some embodiments, when Q is CR ¹¹ When R is ¹¹ And R is ⁴ Together with the atoms to which they are attached form a 5-to 8-membered ring containing 0, 1 or 2 members selected from O, S and NR ^d The ring being unsubstituted or substituted by oxo, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, haloalkyl, hydroxyalkyl and-NR ^d R ^e Wherein R is one or more substitutions of ^d And R is ^e Each independently is hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl. Preferably, R ¹¹ And R is ⁴ Together with the atoms to which they are attached form a 6-membered ring containing an additional NAn atom, said ring being unsubstituted or substituted by oxo. More preferably, R ¹¹ And R is ⁴ Together with the atoms to which they are attached, form a 6-membered ring containing an amide bond, i.e., -C (O) -NH-, said ring being unsubstituted or substituted by oxo. Preferably, the compound of formula (I) is wherein R in the compound of formula (I-5) ⁴ And R is R ¹¹ Cyclic compound (I-5-A) of the connection composition:

wherein m is 0, 1 or 2; z is Z ² Is O or NR ² ，R ² Is hydrogen or alkyl; r is R ^a And R is ^b Independently hydrogen or alkyl; or when Z ² Is NR (NR) ² When R is ^a And R is R ^b The composition is c=o.

In some embodiments, R ¹ W is

Wherein the piperazine ring is optionally additionally substituted with one or more R ⁴ Substituted, R ⁴ As defined by formula (I). In some embodiments, R ⁴ Is C _1- C ₃ Alkyl, wherein alkyl is unsubstituted or substituted with cyano.

In some embodiments, R in the compound of formula (I) ¹ W is

In some embodiments, R ¹ Is a group:

in a preferred embodiment, R ¹ W is

In some embodiments, L-R ² Is that

In a preferred embodiment, L-R ² Is that

More preferably

In some embodiments, R ³ Is that

In a preferred embodiment, R ³ Is that

More preferably

In some embodiments, R ¹¹ Is hydrogen, nitro, hydroxy, halogen, cyano, alkyl, haloalkyl, alkoxy or alkoxyalkyl; preferably hydrogen, halogen, cyano, trifluoromethyl or nitro.

In some embodiments, R ¹² Is hydrogen, halogen or C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, heterocyclyl, C ₁ -C ₆ Haloalkyl, aryl or heteroaryl, wherein each of said aryl and heteroaryl is unsubstituted or C-substituted ₁ -C ₃ Alkyl, halogen, C ₁ -C ₃ Haloalkyl and C ₃ -C ₆ One or more substitutions in cycloalkyl.

In some embodiments, R ¹² Is that

In some embodiments, the compound of formula (I) is

Wherein the method comprises the steps of

R ¹ W is

R ³ Is that

Preferably is

and

L-R ² Is that

More preferably

In some embodiments, the compound of formula (I) is

Wherein the method comprises the steps of

R ³ Is that

and

R ² Is that

The remaining variables are as defined for compounds of formula (I).

In some embodiments, the compound of formula (I) is

Wherein the method comprises the steps of

R ³ Is that

Preferably is

L-R ² Is that

Preferably is

The remaining variables are as defined for formula (I).

In some embodiments, the compound of formula (I) is

Another aspect of the invention provides an exemplary method of preparing the compound of formula (I):

The preparation method 1 comprises the following steps:

wherein: r is R ¹ ，R ² ，R ³ L is as defined herein; the alkali used in the first step can be sodium carbonate, potassium carbonate and sodium hydroxide; PG and PG' are amino protecting groups such as tert-butyloxycarbonyl, TEOC, benzyl, benzyloxycarbonyl and the like, and in the case of tert-butyloxycarbonyl, the protecting groups may be removed by trifluoroacetic acid, hydrochloric acid or the like, in the case of TEOC, the protecting groups may be removed by trifluoroacetic acid, cesium fluoride, potassium fluoride or the like, and in the case of the protecting groups being benzyl or benzyloxycarbonyl and the like, the protecting groups may be removed by catalytic hydrogenation; the palladium catalyst used in the Buchwald reaction is Pd ₂ (dba) ₃ The ligand is XPhos, brettPhos, tBuBrettPhos or DavePhos; the copper catalyst used in the Ullmann reaction is cuprous iodide and the ligand may be, but is not limited to, 1, 10-phenanthrene Luo Lintong; the oxidizing agent is, but is not limited to, potassium monopersulfate, m-chloroperoxybenzoic acid; when free amino or alcohol is used for substitution reaction, the alkali can be organic alkali (such as bis (trimethylsilyl amino potassium), triethylamine, diisopropylethylamine, pyridine, potassium tert-butoxide and the like or inorganic alkali (sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate and the like), the acylation reaction can adopt an acid amine condensation method or an acyl chloride method, and the condensation is carried out under a condensing agent (HOBT, EDCI, HATU, TBTU and the like).

The preparation method 2 comprises the following steps:

wherein: r is R ¹ ，R ² ，R ³ L is as defined herein; PG and PG' are amino-protectingProtecting groups such as a common amino protecting group such as t-butyloxycarbonyl, TEOC, benzyl, and benzyloxycarbonyl, and in the case of t-butyloxycarbonyl, the protecting group may be removed by trifluoroacetic acid, hydrochloric acid, or the like, in the case of TEOC, the protecting group may be removed by trifluoroacetic acid, cesium fluoride, potassium fluoride, or the like, and in the case of benzyl or benzyloxycarbonyl, the protecting group may be removed by catalytic hydrogenation; the palladium catalyst used in the Buchwald reaction is Pd ₂ (dba) ₃ The ligand is XPhos, brettPhos, tBuBrettPhos or DavePhos; the copper catalyst used in the Ullmann reaction is cuprous iodide and the ligand may be, but is not limited to, 1, 10-phenanthrene Luo Lintong; the oxidizing agent is, but is not limited to, potassium monopersulfate, m-chloroperoxybenzoic acid; when free amino or alcohol is used for substitution reaction, the alkali can be organic alkali (such as bis (trimethylsilyl amino potassium), triethylamine, diisopropylethylamine, pyridine, potassium tert-butoxide and the like) or inorganic alkali (sodium carbonate, potassium carbonate, sodium bicarbonate and the like); the acylation reaction can adopt an acid amine condensation method or an acyl chloride method; the condensation is performed with a condensing agent (HOBT, EDCI, HATU, TBTU).

The preparation method comprises the following steps:

wherein: r is R ^a ，R ^b ，R ¹ ，R ² ，R ³ L is as defined herein; when free amino or alcohol is used for substitution reaction, the alkali can be organic alkali (such as triethylamine, diisopropylethylamine, pyridine and the like) or inorganic alkali (sodium carbonate, potassium carbonate, sodium bicarbonate and the like); the reducing agent for reductive amination is but not limited to sodium cyanoborohydride, sodium acetate borohydride, sodium borohydride, and the acid used for reductive amination is but not limited to acetic acid, trifluoroacetic acid; the oxidizing agent is, but is not limited to, m-chloroperoxybenzoic acid; PG is an amino protecting group such as t-butyloxycarbonyl, TEOC, benzyl, benzyloxycarbonyl and the like, and in the case of t-butyloxycarbonyl, the protecting group may be removed by trifluoroacetic acid, hydrochloric acid or the like, and in the case of TEOC, the protecting group may be removed byRemoving the protecting group by trifluoroacetic acid, cesium fluoride, potassium fluoride and the like, and when the protecting group is a protecting group such as benzyl or benzyloxycarbonyl, removing the protecting group by catalytic hydrogenation; the acylation reaction can adopt an acid amine condensation method or an acyl chloride method; the condensation is performed with a condensing agent (HOBT, EDCI, HATU, TBTU).

Preparation method 4:

wherein R is ¹ ，R ² ，R ³ L, W are as defined above. PG is a protecting group for amino group, such as Boc-, cbz, etc., X is F, cl, br, I, OTf, etc. The first step is to make substitution reaction under alkaline condition (such as triethylamine, diisopropylethylamine, etc.); secondly, carrying out oxidation reaction under the condition of an oxidant (such as m-chloroperoxybenzoic acid and the like) to obtain an intermediate sulfoxide; the third step is that the intermediate sulfoxide is subjected to substitution reaction under alkaline conditions (triethylamine, sodium hydride, sodium tert-butoxide and the like) to obtain a target intermediate; the fourth step is to selectively remove the protecting group under the condition of hydrogenation (Pd/C, hydrogen and methanol); the fifth step is the Buchwald reaction with R ³ -X euro reaction to give an intermediate; the sixth step is to remove protecting groups (e.g., boc); the seventh step is to react with the corresponding acid or acyl chloride to obtain the target compound.

The preparation method comprises the following steps:

wherein R is ¹ ，R ² ，R ¹¹ ，R ¹² L, W are as defined above. PG is a protecting group for amino group, such as Boc-, cbz, etc., X is F, cl, br, I, OTf, etc. The first step is to carry out substitution reaction with a compound containing exposed amino under alkaline (triethylamine, diisopropylethylamine, etc.) conditions; second part is atPreparing an intermediate under alkaline conditions (triethylamine, sodium hydride, sodium tert-butoxide and the like); the third step is selective deprotection (e.g., hydrogenation-Pd/C); the fourth step is the Buchwald reaction with R ³ -X euro reaction to give an intermediate; the fifth step is to remove the protecting group (e.g. Boc) under acidic conditions to obtain an intermediate; the sixth step is to react with the corresponding acid or acyl chloride to obtain the target compound.

Preparation method 6:

wherein: r is R ¹ ，R ² ，R ³ ，R ¹² L is as defined herein; the base used in the sNAr reaction may be sodium hydride, potassium bis (trimethylsilyl) amide, diisopropylethylamine; the palladium catalyst used in the Buchwald reaction is Pd ₂ (dba) ₃ The ligand is XPhos, brettPhos, tBuBrettPhos or DavePhos; the copper catalyst used in the Ullmann reaction is cuprous iodide and the ligand may be, but is not limited to, 1, 10-phenanthrene Luo Lintong; PG is an amino protecting group, such as a common amino protecting group such as tert-butyloxycarbonyl, benzyloxycarbonyl and the like, wherein when the PG is tert-butyloxycarbonyl, the protecting group can be removed by trifluoroacetic acid, hydrochloric acid and the like, and when the PG is TEOC, the protecting group can be removed by trifluoroacetic acid, cesium fluoride, potassium fluoride and the like, and when the protecting group is a protecting group such as benzyloxycarbonyl and the like, the protecting group can be removed by selective catalytic hydrogenation; the acylation reaction may be carried out by an acid-amine condensation method or an acid chloride method, wherein the acid-amine condensation method is a condensation reaction under a condensing agent (HOBT, EDCI, HATU, TBTU or the like).

Preparation method 7:

wherein: r is R ¹ ，R ² ，R ³ ，R ¹² L is as defined herein;firstly, performing SNAr substitution reaction by using piperazine derivatives, and protecting amino in one step under the condition that the product contains exposed amino; PG is an amino protecting group such as a common amino protecting group such as tert-butyloxycarbonyl, TEOC, benzyl, and benzyloxycarbonyl, and in the case of tert-butyloxycarbonyl, the protecting group may be removed by trifluoroacetic acid, hydrochloric acid, or the like, in the case of TEOC, the protecting group may be removed by trifluoroacetic acid, cesium fluoride, potassium fluoride, or the like, and in the case of the protecting group being a protecting group such as benzyl or benzyloxycarbonyl, the protecting group may be removed by catalytic hydrogenation; when free amino or alcohol is used for substitution reaction, the alkali can be organic alkali (such as triethylamine, diisopropylethylamine, pyridine and the like) or inorganic alkali (sodium hydrogen, sodium carbonate, potassium carbonate, sodium bicarbonate and the like); halogenating agents are, but are not limited to, NCS, NBS, NIS; the palladium catalyst for the Suzik coupling reaction is, but is not limited to, pd (PPh) ₃ ) ₄ ，PdCl ₂ (PPh ₃ ) ₂ ，PdCl ₂ (dppf), etc.; the acylation reaction can adopt an acid amine condensation method or an acyl chloride method; the condensation is performed with a condensing agent (HOBT, EDCI, HATU, TBTU).

Preparation method 8:

wherein: r is R ¹ ，R ² ，R ³ ，R ⁴ ，R ¹³ L is as defined herein; the chlorinating agent is, but is not limited to, phosphorus oxychloride; PG is an amino protecting group, such as a common amino protecting group of tert-butyloxycarbonyl, benzyl, benzyloxycarbonyl and the like, when the PG is tert-butyloxycarbonyl, trifluoroacetic acid, hydrochloric acid and the like can be used for removing the protecting group, and when the PG is a protecting group of benzyl, benzyloxycarbonyl and the like, the protecting group can be removed by catalytic hydrogenation; the reducing agent for reducing nitro is iron powder, and the acidic reagent can be acetic acid or ammonium chloride; when free amino or alcohol is used for substitution reaction, the base can be organic base (such as triethylamine, diisopropylethylamine, pyridine, etc.) or inorganic base (sodium hydrogen, carbonic acid) Sodium, potassium carbonate, sodium bicarbonate, etc.); the acylation reaction can adopt an acid amine condensation method or an acyl chloride method; the condensation is performed with a condensing agent (HOBT, EDCI, HATU, TBTU).

Preparation method 9:

wherein: r is R ¹ ，R ² ，R ³ ，R ⁴ L is as defined herein; when free amino or alcohol is used for substitution reaction, the alkali can be organic alkali (such as triethylamine, diisopropylethylamine, pyridine and the like) or inorganic alkali (sodium hydrogen, sodium carbonate, potassium carbonate and the like); PG, PG' is an amino protecting group such as a common amino protecting group of tert-butyloxycarbonyl, TEOC, benzyl, benzyloxycarbonyl and the like, wherein in the case of tert-butyloxycarbonyl, the protecting group may be removed by trifluoroacetic acid, hydrochloric acid or the like, in the case of TEOC, the protecting group may be removed by trifluoroacetic acid, cesium fluoride, potassium fluoride or the like, and in the case of the protecting group being a protecting group of benzyl, benzyloxycarbonyl or the like, the protecting group may be removed by catalytic hydrogenation; the acylation reaction can adopt an acid amine condensation method or an acyl chloride method; the condensation is performed with a condensing agent (HOBT, EDCI, HATU, TBTU).

The preparation method comprises the following steps:

wherein: r is R ¹ ，R ² ，R ³ As defined herein; the first step of the cyclization reaction is carried out by BF ₃ .Et ₂ O and ethyl diazoacetate react with 1-tert-butyloxycarbonyl-4-piperidone to obtain a target intermediate; the second step is to carry out cyclization under the action of alkali (the alkali can be sodium methoxide, sodium ethoxide, sodium hydride and the like); the third step is to apply OTf under the action of a base (the base may be triethylamine, diisopropylethylamine, etc.); fourth step The nucleophilic substitution reaction is carried out under the action of alkali (the alkali can be triethylamine, diisopropylethylamine, etc.); in the fifth step, oxidizing reaction, wherein the oxidizing agent is preferably an oxidizing agent such as m-CPBA; the sixth step is that nucleophilic substitution reaction is carried out under the action of alkali (sodium tert-butoxide, potassium tert-butoxide, sodium hydride or cesium carbonate, etc.); the seventh step is the selective deamination of the protecting group, such as the deamination of the t-butoxycarbonyl group with trifluoroacetic acid; the eighth step is a coupling reaction such as a Buchwald coupling reaction or a Ullmann coupling reaction; the ninth step is to remove the amino protecting group under hydrogenation or acidic conditions; the tenth step is an acylation reaction, and an acid-amine condensation method or an acid chloride method can be adopted, wherein the acid-amine condensation method is to carry out condensation reaction under a condensing agent (HOBT, EDCI, HATU, TBTU and other condensing agents) to obtain the target compound.

The preparation method 11 comprises the following steps:

the first step is to apply OTf under the action of a base (the base may be triethylamine, diisopropylethylamine, etc.); the second step is nucleophilic substitution reaction under the action of alkali (the alkali can be triethylamine, diisopropylethylamine, etc.); in the third step, oxidizing reaction, wherein the oxidizing agent is preferably an oxidizing agent such as m-CPBA; the fourth step is that nucleophilic substitution reaction is carried out under the action of alkali (sodium tert-butoxide, potassium tert-butoxide, sodium hydride or cesium carbonate, etc.); the fifth step is the selective deamination of the protecting group, such as the deamination of the t-butoxycarbonyl group with trifluoroacetic acid; the sixth step is a coupling reaction such as a Buchwald coupling reaction or a Ullmann coupling reaction; the seventh step is to remove the amino protecting group under hydrogenation or acidic conditions; the eighth step is an acylation reaction, which may be an acid-amine condensation method or an acid chloride method, wherein the acid-amine condensation method is a condensation reaction under a condensing agent (HOBT, EDCI, HATU, TBTU or other condensing agent) to obtain the target compound.

Preparation method 12:

wherein: r is R ¹ ，R ² ，R ³ L is as defined herein; the palladium catalyst used in the first Buchwald reaction was Pd ₂ (dba) ₃ The ligand is XPhos, brettPhos, tBuBrettPhos or DavePhos; the oxidizing agent used in the second step is, but is not limited to, potassium monopersulfate, m-chloroperoxybenzoic acid; the base used in the third step of substitution reaction may be an organic base (e.g., bis (trimethylsilyl aminopotassium), diisopropylethylamine, pyridine, potassium t-butoxide, etc.) or an inorganic base (sodium hydride, cesium carbonate, potassium carbonate, etc.); PG is an amino protecting group such as t-butyloxycarbonyl, TEOC, benzyloxycarbonyl and the like, and in the case of t-butyloxycarbonyl, the protecting group may be removed by trifluoroacetic acid, hydrochloric acid or the like, in the case of TEOC, the protecting group may be removed by trifluoroacetic acid, cesium fluoride, potassium fluoride or the like, and in the case of benzyloxycarbonyl, the protecting group may be removed by catalytic hydrogenation; the fifth step of acylation reaction can be carried out by an acid-amine condensation method or an acid chloride method, wherein the condensation is carried out under a condensing agent (condensing agent such as EDCI/HOBt, HATU, TBTU).

Other general synthetic methods are provided in the examples. It will be apparent to one of ordinary skill in the art that the compounds of formula (I) may be prepared according to one or more methods or in other ways known in the art. It will be apparent that in general, when following the general routes described herein, it is desirable to use differently substituted starting materials and/or protecting groups to obtain the desired compounds. Different substituents may also be added at different points in the synthetic route to prepare the desired compounds.

The present invention relates to pharmaceutical compositions of compounds of formula (I) or pharmaceutically acceptable salts, prodrugs and solvates thereof.

Yet another aspect of the invention provides methods of treating disease conditions, including but not limited to conditions mutated to G12KRAS, HRAS or NRAS (e.g., cancer), using the compounds or pharmaceutical compositions of the invention. The cancer is pancreatic cancer, lung cancer, colorectal cancer, peritoneal cancer, colorectal cancer, small intestine cancer, biliary tract cancer, endometrial cancer, ovarian cancer, genital tract cancer, gastrointestinal cancer, cervical cancer, gastric cancer, urinary tract cancer, hematopoietic and lymphoid tissue cancer, etc. mediated by G12C mutation.

The invention relates to a compound of formula (I) which has better physicochemical properties and safe toxicity parameters and can be used for treating cancers and inflammations of mammals.

In other embodiments, there is also provided a method of inhibiting proliferation of a population of cells, the method comprising contacting the population of cells with any one of the compounds of structure (I).

Other embodiments relate to pharmaceutical compositions. The pharmaceutical composition comprises any one (or more) of the foregoing compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In further embodiments, the pharmaceutical composition comprises a compound disclosed herein and another therapeutic agent (e.g., an anticancer agent). Non-limiting examples of such therapeutic agents are described below.

Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Further, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

Detailed Description

The entire disclosure of the present invention is defined by the following terms, unless otherwise indicated:

as used herein, including the appended claims, singular forms such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

The term "prodrug" refers to any derivative that is converted in the organism to the corresponding active pharmaceutical compound. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

By "pharmaceutically acceptable salt" is meant a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and within the scope of sound medical judgment. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base functionality with a suitable organic acid or by reacting the acidic group with a suitable base.

The term "solvate" refers to a compound molecular compound formed in a solution by attraction of solute molecules or ions to adjacent solvent molecules by intermolecular forces such as coulombic forces, van der waals forces, charge transfer forces, hydrogen bonds, and the like. In one embodiment, the solvent is water, i.e., the compounds of the present invention form hydrates.

The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more centers of step symmetry and thus may give rise to enantiomers, diastereomers and other stereoisomeric forms, which are defined as (R) -or (S) -or as (D) -or (L) -configurations in terms of the absolute stereochemical configuration of the amino acid. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R) -and (S) -or (D) -and (L) -isomers can be obtained by chiral synthesis or chiral preparation, or resolution using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing/separating individual enantiomers include chiral synthesis from suitable optically pure precursors, resolution of the racemate (or of a salt or derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC). The present invention provides pure isomers and isomer mixtures, as well as methods of making and using the same, and compositions comprising the same. For the sake of simplicity, it will be referred to hereinafter as a compound of formula (I), which refers to both the pure optical isomers and, if appropriate, to mixtures of isomers in different proportions.

The compounds of the invention may be present in particular. Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to the fact that at room temperature, different functional group isomers are in dynamic equilibrium and are capable of rapid interconversion. If tautomers are possible (e.g., in solution), chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as proton tautomers) (prototropic tautomer) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence isomers (valencetautomers) include interconversions by recombination of some of the bond-forming electrons.

The term "alkyl" herein refers to a hydrocarbon group selected from the group consisting of straight chain saturated hydrocarbon groups and branched chain saturated hydrocarbon groups, which contain from 1 to 18 (e.g., from 1 to 12, further such as from 1 to 10, still further such as from 1 to 8 or from 1 to 6 or from 1 to 4) carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e. C _1-6 Examples of alkyl) include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1-dimethylethyl or tert-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl and 3, 3-dimethyl-2-butyl.

The term "halogen" herein refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

The term "haloalkyl" herein refers to an alkyl group in which one or more hydrogens are replaced with one or more halogen atoms, such as fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). Examples of haloalkyl groups include halo C _1-8 Alkyl, halogenated C _1-6 Alkyl or halo C _1-4 Alkyl, but not limited to-CF ₃ 、-CH ₂ Cl、-CH ₂ CF ₃ 、-CCl ₂ 、CF ₃ Etc.

The term "herein"Alkenyl "refers to a hydrocarbon group selected from the group consisting of straight chain hydrocarbon groups and branched chain hydrocarbon groups comprising at least one c=c double bond and from 2 to 18 (e.g. from 2 to 8, further such as from 2 to 6) carbon atoms. Examples of alkenyl groups are C _2-6 Alkenyl groups include, but are not limited to, vinyl (ethyl or vinyl), prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-2-enyl, but-3-enyl, but-1, 3-dienyl, 2-methylbut-1, 3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1, 3-dienyl.

The term "alkynyl" herein refers to a hydrocarbyl group selected from the group consisting of straight chain hydrocarbyl and branched chain hydrocarbyl groups containing at least one c≡c triple bond and from 2 to 18 (e.g., from 2 to 8, further such as from 2 to 6) carbon atoms. Examples of alkynyl groups are C _2-6 Alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl.

The term "alkoxy" herein refers to an alkyl group as defined above bonded to oxygen, represented by-O alkyl. Examples of alkoxy groups are C _1-6 Alkoxy or C _1-4 Alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, t-butoxy, pentoxy, hexoxy, and the like.

The term "cycloalkyl" herein refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, which contain monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. For example, cycloalkyl groups can contain 3 to 12 (e.g., 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4) carbon atoms. Even further for example, cycloalkyl groups may be selected from monocyclic groups containing 3 to 12 (e.g., 3 to 10, further e.g., 3 to 8, 3 to 6) carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. In particular, examples of saturated monocyclic cycloalkyl groups are C _3-8 Cycloalkyl groups include, but are not limited to, cyclopropyl,Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In a preferred embodiment, cycloalkyl is a monocyclic ring containing 3 to 6 carbon atoms (abbreviated to C _3-6 Cycloalkyl) including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged to be selected from [4,4 ]]、[4,5]、[5,5]、[5,6]Or [6,6 ]]Bicyclic ring of ring system, or selected from bicyclo [2.2.1 ]]Heptane, bicyclo [2.2.2]Octane and bicyclo [3.2.2]Bridged bicyclic rings of nonane. Other examples of bicyclic cycloalkyl groups include those arranged to be selected from [5,6 ]]And [6,6 ]]Bicyclic cycloalkyl groups of the bicyclic ring system, e.g.

Wherein the wavy line indicates the point of attachment. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but is not fully conjugated and is not aromatic, as aromatic is defined herein.

The term "aryl" used alone or in combination with other terms refers to a group selected from the group consisting of:

a 5 and 6 membered carbocyclic aromatic rings, such as phenyl;

b. bicyclic ring systems, such as 7 to 12 membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, such as naphthyl; and

c. Tricyclic systems, such as 10 to 15 membered tricyclic systems, wherein at least one ring is carbocyclic and aromatic, such as fluorenyl.

The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably in the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C _5-10 Aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalen-1-yl, naphthalen-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalen-1-yl or naphthalen-2-yl) or a benzene ring. In some embodiments, the aromatic hydrocarbon ring is a benzene ring.

The term "heteroaryl" herein refers to a group selected from the group consisting of:

a 5, 6, or 7 membered aromatic monocyclic ring comprising at least one heteroatom, such as 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, in some embodiments 1 to 2 heteroatoms selected from nitrogen (N), sulfur (S), and oxygen (O) (as one or more ring atoms), the remaining ring atoms being carbon;

b.7 to 12 membered bicyclic ring comprising at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms selected from N, O and S (as one or more ring atoms), the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

A 11 to 14 membered tricyclic ring comprising at least one heteroatom, such as 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms selected from N, O and S (as one or more ring atoms), the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

In a preferred embodiment, heteroaryl is a 5 to 6 membered heteroaryl group comprising one nitrogen atom and 0 or 1 additional heteroatoms selected from N, O and S, including but not limited to pyridinyl, isoxazolyl and oxazolyl.

When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is no greater than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is no greater than 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in one or more rings of the heteroaryl group may be oxidized to form an N-oxide.

The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably in the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 ring members, wherein 1, 2, 3, or 4 heteroatom ring members are independently selected from nitrogen (N), sulfur (S), and oxygen (O), the remaining ring members being carbon. In some embodiments, a mono-or bicyclic aromatic heterocycle is a mono-or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a 5-to 6-membered heteroaryl ring that is monocyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is an 8-to 10-membered heteroaryl ring that is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

Examples of heteroaryl or mono-or bicyclic aromatic heterocycles include, but are not limited to (numbering from the attachment position of the indicated priority 1) pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl or 4-pyridinyl), cinnolinyl, pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 2, 4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g. 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl or 1,3, 4-thiadiazolyl), tetrazolyl, thiophenyl (e.g. thiophen-2-yl, thiophen-3-yl), triazinyl, benzothienyl, furanyl (furyl or furyl), benzofuranyl, benzimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (e.g. 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl or 1, 3-oxadiazolyl), triazolo [2, 4-oxadiazolyl, pyrazinyl, 2, 3-triazolo ] 2, 5-oxazolyl, 3-triazolo [2, 4-oxazolyl, 3-pyridinyl ] pyrrolyl, 2, 5-oxazolyl, 3-oxazolyl (e) or 1,3, 4-triazolo [2, 4-oxazolyl ] pyridinyl, 3-pyridinyl, 2, 5-oxazolyl 1-oxa-3, 4-diazolyl, 1-thia-2, 3-diazolyl, 1-thia-2, 4-diazolyl, 1-thia-2, 5-diazolyl, 1-thia-3, 4-diazolyl, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo [ d ] thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7, 8-tetrahydroisoquinoline.

The term "heterocyclic" or "heterocycle" or "heterocyclyl" herein refers to a ring selected from 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered monocyclic, bicyclic and tricyclic saturated and partially unsaturated rings comprising at least one carbon atom and at least one heteroatom, such as 1 to 4 heteroatoms, further such as 1 to 3 heteroatoms or further such as 1 or 2 heteroatoms, selected from nitrogen (N), sulfur (S), oxygen (O), -SO-or-SO ₂ (as one or more ring atoms).

In some embodiments, the heterocyclyl is a 4, 5, 6, 7, or 8 membered monocyclic ring having at least one heteroatom selected from N, O and S. In some preferred embodiments, the heterocyclyl is a 4, 5, 6, 7, or 8 membered saturated monocyclic ring containing one nitrogen heteroatom. Exemplary heterocyclyl groups are azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, and azepanyl. In other embodiments, the heterocyclyl is a 5, 6, 7 or 8 membered saturated monocyclic ring, comprising a nitrogen atom and selected from the group consisting of-NH-O-, -S-, -SO-, or-SO ₂ -1 further heteroatom. Exemplary heterocyclyl groups are morpholino, or piperazinyl rings. In some embodiments, the heterocyclyl is a 7-to 12-membered saturated bicyclic ring, comprising a nitrogen atom and selected from the group consisting of-NH-O-, -S-, -SO-, or-SO ₂ -0 or 1 or 2 further heteroatoms. In some preferred embodiments, the heterocyclyl is a bicyclic bridged ring or a spiro ring.

"heterocycle" herein also refers to a 5 to 7 membered heterocycle comprising at least one heteroatom selected from N, O and S fused to a 5, 6 and/or 7 membered cycloalkyl, carbocyclic aromatic ring or heteroaromatic ring, provided that the entire ring structure is non-aromatic. The heterocycle is not heteroaryl as defined herein. In a preferred embodiment, the heterocyclyl is a 5-to 6-membered heterocyclyl containing one nitrogen atom and 0 or 1 additional heteroatoms selected from N, O and S, including, but not limited to, pyrrolyl, dihydropyridine, morpholino, and tetrahydropyranyl.

Examples of heterocycles include, but are not limited to (numbered from the attachment position designated priority 1) 1-pyrrolidinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2, 5-piperazinyl, pyranyl, morpholinyl, morpholino, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, cyclothiacetyl, azetidinyl, oxetanyl, thietanyl, 1, 2-dithianyl, 1, 3-dithianyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thianyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepinyl thiepinyl, 1, 4-oxathiepinyl, 1, 4-dioxapanyl, 1, 4-oxathiepinyl, 1, 4-dithiepinyl, 1, 4-thiazepinyl and 1, 4-diazacycloheptyl, 1, 4-dithiahexyl (1, 4-dithianyl), 1, 4-azathiepinyl (1, 4-azathianyl), oxazepinyl (oxazepinyl), diazathienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithiolanyl (dithianyl), dithiolanyl (dithiolanyl), pyrazolidinyl, imidazolinyl, pyrimidinonyl, 1-dioxo-thiomorpholinyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl and azabicyclo [2.2.2] hexyl. Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl N-oxide, 1-oxo-1-thiomorpholinyl, and 1, 1-dioxo-1-thiomorpholinyl.

In some embodiments, the heterocyclyl is a non-aromatic, fused bicyclic heterocyclyl, such as the fused bicyclic heterocycles listed above; and non-aromatic, condensed bicyclic heterocyclic groups, e.g. of

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, and may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =o), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on the aromatic group. The term "optionally substituted" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.

When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds. The term "one or more … group substitutions" as disclosed herein includes, for example, 1 to 5 (e.g., 1 to 4, further such as 1, 2, or 3) substituents, provided the valency permits.

Unless otherwise specified, the term "heteroalkyl" by itself or in combination with another term means a moiety defined by a numberA stable linear or branched alkyl radical or a combination thereof, of carbon atoms and at least one heteroatom, or heteroatom group. In some embodiments, the heteroatoms are selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatoms are optionally quaternized. In other embodiments, the heteroatom is selected from-C (=o) O-, -C (=o) -, -C (=s) -, -S (=o) 2-, -C (=o) N (H) -, -C (=nh) -, -S (=o) 2N (H) -, and-S (=o) N (H) -. In some embodiments, the heteroalkyl is C ₁ -C ₆ A heteroalkyl group; in other embodiments, the heteroalkyl is C ₁ -C ₃ A heteroalkyl group. The heteroatom or heteroatom group may be located at any internal position of the heteroalkyl group, including where the alkyl group is attached to the remainder of the molecule, but the terms "alkoxy," "alkylamino" and "alkylthio" (or thioalkoxy) are conventional expressions and refer to those alkyl groups attached to the remainder of the molecule through an oxygen atom, amino group or sulfur atom, respectively. Examples of heteroalkyl groups include, but are not limited to, -OCH ₃ 、-OCH ₂ CH ₃ 、-OCH ₂ CH ₂ CH ₃ 、-OCH ₂ (CH ₃ ) ₂ 、-CH ₂ -CH ₂ -O-CH ₃ 、-NHCH ₃ 、-N(CH ₃ ) ₂ 、-NHCH ₂ CH ₃ 、-N(CH ₃ )(CH ₂ CH ₃ )、-CH ₂ -CH ₂ -NH-CH ₃ 、-CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ 、-SCH ₃ 、-SCH ₂ CH ₃ 、-SCH ₂ CH ₂ CH ₃ 、-SCH ₂ (CH ₃ ) ₂ 、-CH ₂ -SCH ₂ -CH ₃ 、-CH ₂ -CH ₂ 、-S(＝O)-CH ₃ 、-CH ₂ -CH ₂ -S(＝O) ₂ -CH ₃ 、-CH＝CH-O-CH ₃ 、-CH ₂ -CH＝N-OCH ₃ And-ch=chngch ₃ )-CH _3。 At most two heteroatoms may be contiguous, e.g. -CH ₂ -NH-OCH ₃ 。

Unless otherwise indicated, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, etc. moieties described herein may each independently be optionally substituted with one or more groups selected from the group consisting of: hydroxy, oxo, halogen, cyano, nitro, trifluoromethyl, azido, amino, carboxyl, mercapto.

Synthesis

Suitable solvents commonly used in organic reactions may be used in the following steps of the preparation process of the present invention, for example, but not limited to: aliphatic and aromatic, optionally hydrocarbons or halogenated hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, volatile oils, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, and o-dichlorobenzene), aliphatic and aromatic, optionally alcohols (e.g., methanol, ethanol, propanol, isopropanol, t-butanol, ethylene glycol, etc.), ethers (e.g., diethyl ether and dibutyl ether, ethylene glycol dimethyl ether and diglyme, tetrahydrofuran, dioxane, etc.), esters (e.g., methyl acetate or ethyl acetate, etc.), nitriles (e.g., acetonitrile or propionitrile, etc.), ketones (e.g., acetone, butanone, etc.), amides (e.g., dimethylformamide, dimethylacetamide, N-methylpyrrolidone, etc.), and dimethyl sulfoxide, tetramethylene sulfone, hexamethylphosphoric triamide, and N, N-Dimethylpropyleneurea (DMPU), etc.

The invention adopts the following abbreviations: DCM represents dichloromethane; CHCl (CHCl) ₃ Represents chloroform; EA represents ethyl acetate; THF represents tetrahydrofuran; meCN represents acetonitrile; meOH represents methanol; etOH stands for ethanol; i-PrOH represents isopropanol; PE represents petroleum ether; toulene stands for toluene; DMSO represents dimethyl sulfoxide; DMF represents N, N-dimethylformamide; DMA stands for N, N-dimethylacetamide; CDCl ₃ Represents deuterated chloroform; d (D) ₂ O represents heavy water; (CD) ₃ ) ₂ SO represents deuterated DMSO; CD (compact disc) ₃ OD represents deuterated methanol; cuI stands for cuprous iodide; DIPEA stands for diisopropylethylamine; TEA represents triethylamine; k (K) ₂ CO ₃ Represents potassium carbonate; cs (cells) ₂ CO ₃ Represents cesium carbonate; na (Na) ₂ CO ₃ Represents sodium carbonate; naHCO (NaHCO) ₃ Represents sodium bicarbonate; naOH represents sodium hydroxide; KOH represents potassium hydroxide; liHMDS represents lithium hexamethyldisilazide; CDI replaces 1,1' -carbonylimidazole; MS stands for mass spectrum; NMR represents nuclear magnetic resonance; TFA represents trifluoroacetic acid; BINAP stands for (2 r,3 s) -2.2 '-diphenylphosphine-1.1' -binaphthyl; BOC represents tert-butoxycarbonyl; cbz represents a benzyloxycarbonyl group; DBU represents bicyclo-1, 5-diaza-5-undecene; DCC stands for 1, 3-dicyclohexylcarbodiimide; DCE stands for 1, 2-dichloroethane; DMAP represents 4-dimethylaminopyridine; dppf represents bis (diphenylphosphino) ferrocene; liAlH4 represents lithium aluminum hydride; LDA represents lithium diisopropylamide; m-CPBA represents m-chloroperoxybenzoic acid; MTM represents dimethyl sulfide; NBS represents N-bromosuccinimide; NCS represents N-chlorosuccinimide; NIS represents N-iodosuccinimide; PCC represents a pyridine dichromate; TBAF represents tetrabutylammonium fluoride; THP represents tetrahydropyranyl; TMEDA represents tetramethyl ethylenediamine; TMS represents trimethylsilyl; TMP stands for 2, 6-tetramethylpiperidine; ts represents p-toluenesulfonyl; pd (PPh) ₃ ) ₄ Represents tetrakis triphenylphosphine palladium; pdCl ₂ (dppf) represents 1,1' -bis-diphenylphosphino ferrocene palladium dichloride; pd (Pd) ₂ (dba) ₃ Represents dibenzylidene acetone dipalladium; HOBT represents 1-hydroxybenzotriazole; HATU stands for 2- (7-OxidationBenzotriazole)-N,N,N',N'- Tetramethyl ureaHexafluorophosphate esters; TBTU represents O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate; tf (Tf) ₂ O represents trifluoroacetic anhydride; pd (OAc) ₂ Represents palladium diacetate; ruPhos stands for 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl; pd (PPh) ₃ ) ₂ Cl ₂ Represents bis triphenylphosphine palladium dichloride; spos represents 3, 2-bicycloHexyl phosphine-2 ',6' -dimethoxy; xantPhos represents 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene; meONa stands for sodium methoxide; n-BuLi represents n-butyllithium; t-BuONa represents sodium tert-butoxide; t-BuOK represents potassium tert-butoxide; KSCN represents potassium thiocyanate; cuBr stands for cuprous bromide; naNO ₂ Represents sodium nitrite; urea represents Urea; POCl (Point of care testing) ₃ Represents phosphorus oxychloride; BBr (BBr) ₃ Represents boron tribromide; NH (NH) ₄ Cl represents ammonium chloride; meI represents methyl iodide; NMP represents N-methylpyrrolidone; k (K) ₃ PO ₄ Represents potassium phosphate; column chromatography represents column chromatography separation; ac represents acetyl; bn represents benzyl; fmoc represents fluorenylmethoxycarbonyl; cy represents a cyclohexyl group; tf represents trifluoromethanesulfonyl; PDC represents pyridine dichromate.

Synthetic examples:

example 1: synthesis of (S) -1- (4- (6- (8-chloronaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

Step 1: synthesis of tert-butyl 2- (methylthio) -4-oxo-3, 4,5, 7-tetrahydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate

Ethyl N-BOC-4-oxo-3-pyrrolidinecarboxylate (3.5 g,13.6 mmol) was dissolved in water (50 mL), S-methylisothiourea sulfate (7.6 g,27.2 mmol) and sodium carbonate (5.8 g,54.4 mmol) were added, stirred at room temperature for 15 h, TLC detection was complete, ethyl acetate extraction, anhydrous sodium sulfate drying, concentration, column chromatography purification (dichloromethane/methanol=30/1) gave a white solid. (2 g, yield: 52.6%). ¹ H NMR(400MHz,CDCl ₃ )δ4.59-4.46(m,4H),2.59(dd,J＝11.3,1.7Hz,3H),1.58-1.47(m,9H).

Step 2: synthesis of 2- (methylthio) -3,5,6, 7-tetrahydro-4H-pyrrolo [3,4-d ] pyrimidin-4-one

Tert-butyl 2- (methylthio) -4-oxo-3, 4,5, 7-tetrahydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (2 g,7.1 mmol) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (10 mL) was added, stirred at room temperature for 2 hours, TLC detection was complete, concentrated to dryness, aqueous sodium bicarbonate (20 mL) was added, dichloromethane (50 mL) extracted, dried over anhydrous sodium sulfate, and the organic phase concentrated to a pale yellow solid. (850 mg, yield: 65.9%).

Step 3: synthesis of 2- (methylthio) -6- (2, 2-trifluoroacetyl) -3,5,6, 7-tetrahydro-4H-pyrrolo [3,4-d ] pyrimidin-4-one

2- (methylthio) -3,5,6, 7-tetrahydro-4H-pyrrolo [3,4-d ] pyrimidin-4-one (800 mg,4.4 mmol) was dissolved in dichloromethane (50 mL), triethylamine (883 mg,8.8 mmol) was added dropwise, trifluoroacetic anhydride (1.4 g,6.6 mmol) was stirred at room temperature for 2 hours, TLC detection reaction was complete, concentrated to dryness, aqueous sodium bicarbonate solution (20 mL) was added, dichloromethane (50 mL) was used for extraction, anhydrous sodium sulfate was used for drying, and the organic phase was concentrated to a pale yellow solid. (650 mg, yield: 53%).

Step 4: synthesis of 2- (methylthio) -6- (2, 2-trifluoroacetyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl triflate

2- (methylthio) -6- (2, 2-trifluoroacetyl) -3,5,6, 7-tetrahydro-4H-pyrrolo [3,4-d ] pyrimidin-4-one (650 mg,2.3 mmol) was dissolved in dichloromethane (50 mL), DIPEA (601 mg,4.6 mmol) was added dropwise, trifluoromethanesulfonic anhydride (1.3 g,4.6 mmol) was stirred at room temperature for 1 hour, TLC detection reaction was complete, concentrated to dryness and used directly in the next reaction. (945 mg, yield: 100%).

Step 5: synthesis of tert-butyl 4- (2- (methylthio) -6- (2, 2-trifluoroacetyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

2- (methylthio) -6- (2, 2-trifluoroacetyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] triflic acid]Pyrimidine-4-yl ester (900 mg,2.2 mmol) was dissolved in DMF (50 mL), DIPEA (227 mg,4.4 mmol) and Boc piperazine (812 mg,4.4 mmol) were added, heated to 80℃for 5h, TLC detection reaction was complete, ethyl acetate extraction, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane/methanol=30/1) to give a white solid. (850 mg, yield: 86.5%). ¹ H NMR(400MHz,CDCl ₃ )δ5.00(d,J＝46.0Hz,2H),4.75(d,J＝50.8Hz,2H),3.73(dd,J＝7.0,3.6Hz,4H),3.55(td,J＝5.5,5.1,3.1Hz,4H),2.53(d,J＝3.6Hz,3H),1.51(s,9H).

Step 6: synthesis of tert-butyl 4- (2- (methylsulfinyl) -6- (2, 2-trifluoroacetyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

4- (2- (methylthio) -6- (2, 2-trifluoroacetyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (850 mg,1.9 mmol) was dissolved in dichloromethane (50 mL), and mCPBA (410 mg,1.9 mmol) was stirred at room temperature for 1 hour, TLC was checked for completion of the reaction, aqueous sodium bicarbonate (20 mL) was added, dichloromethane (50 mL) was used for extraction, and concentrated to dryness for the next reaction. (880 mg, yield: 100%). ¹ H NMR(400MHz,CDCl ₃ )δ5.10(d,J＝47.3Hz,2H),4.90(d,J＝53.4Hz,2H),3.82(q,J＝4.1Hz,4H),3.59(q,J＝5.6Hz,4H),2.93(d,J＝3.3Hz,2H),1.51(s,9H).

Step 7: synthesis of tert-butyl (S) -4- (2- (((1-methylpyrrolidin-2-yl) methoxy) -6- (2, 2-trifluoroacetyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

Tert-butyl 4- (2- (methylsulfinyl) -6- (2, 2-trifluoroacetyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (480 mg,1.9 mmol) was dissolved in toluene (50 mL), sodium tert-butoxide (365 mg,3.8 mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (4397 mg,3.8 mmol) were added under ice-bath and stirred at room temperature for 1 hour, TLC detection reaction was complete, ethyl acetate extraction, anhydrous sodium sulfate drying, concentration, column chromatography purification (dichloromethane/methanol=20/1) gave a white solid. (600 mg, yield: 61.5%).

Step 8: synthesis of tert-butyl (S) -4- (2- (((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

(S) -4- (2- (((1-methylpyrrolidin-2-yl) methoxy) -6- (2, 2-trifluoroacetyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (600 mg,1.2 mmol) was dissolved in methanol (50 mL), potassium carbonate (497 mg,3.6 mmol) was stirred at room temperature for 10 hours, TLC detection was complete, ethyl acetate extraction, anhydrous sodium sulfate drying, concentration, column chromatography purification (dichloromethane/methanol=30/1) gave a white solid (300 mg, yield: 60%).

Step 9: synthesis of tert-butyl (S) -4- (6- (8-chloronaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

(S) -4- (2- (((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (300 mg,0.72 mmol) was dissolved in toluene (50 mL) and Pd was added ₂ (dba) ₃ (66mg,0.072mmol)，XPhos(68mg,0.144mmol),Cs ₂ CO ₃ (469 mg,1.44 mmol), nitrogen protection, heating to 100deg.C for 15 hours, TLC detection of completion, ethyl acetate extraction, drying over anhydrous sodium sulfate, concentration, column chromatography purification (dichloromethane/methanol=20/1) afforded a white solid. (210 mg, yield: 50.5%).

Step 10: synthesis of (S) -6- (8-chloronaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine

(S) -4- (6- (8-chloronaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (210 mg,0.36 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (5 mL) was added, stirred at room temperature for 2 hours, TLC detected complete reaction, concentrated to dryness, aqueous sodium bicarbonate solution (20 mL) was added, extracted with dichloromethane (50 mL), dried over anhydrous sodium sulfate, and the organic phase concentrated to a pale yellow solid. (150 mg, yield: 86.7%).

Step 11: synthesis of (S) -1- (4- (6- (8-chloronaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

(S) -6- (8-chloronaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d]Pyrimidine (150 mg,0.31 mmol) was dissolved in dichloromethane (10 mL), triethylamine (106 mg,1.04 mmol) was added, acryloyl chloride (28 mg,0.31 mmol) was added under ice bath, TLC was checked for completion of the reaction, aqueous sodium bicarbonate (10 mL) was added, and dichloromethane (50 mL) was used for extractionDried over anhydrous sodium sulfate, concentrated, and prepared as a pale yellow solid purified (dichloromethane/methanol=10/1). (75 mg, yield: 44.9%). ¹ H NMR(400MHz,CDCl ₃ )δ8.34-8.15(m,1H),7.95-7.80(m,1H),7.62(d,J＝8.2Hz,1H),7.54-7.51(m,1H),7.45(t,J＝7.8Hz,1H),7.33-7.28(m,1H),6.58(dd,J＝16.8,10.5Hz,1H),6.35(dd,J＝16.8,1.9Hz,1H),5.77(dd,J＝10.5,2.0Hz,1H),4.94-4.73(m,2H),4.59-4.45(m,2H),3.94-3.36(m,10H),2.89(s,4H),2.38-1.93(m,6H)；MS m/z:533.2[M+H]

Example 2: synthesis of 2- ((S) -1-propenoyl-4- (6- (8-chloronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Ethyl N-BOC-4-oxo-3-pyrrolidinecarboxylate (3.5 g,13.6 mmol) was dissolved in water (50 mL), S-methylisothiourea sulfate (7.6 g,27.2 mmol) and sodium carbonate (5.8 g,54.4 mmol) were added, stirred at room temperature for 15 h, TLC detection was complete, ethyl acetate extraction, anhydrous sodium sulfate drying, concentration, column chromatography purification (dichloromethane/methanol=30/1) gave a white solid. (2 g, yield: 52.6%). ¹ H NMR(400MHz,CDCl3)δ4.59-4.46(m,4H),2.59(dd,J＝11.3,1.7Hz,3H),1.58-1.47(m,9H).

2- (methylthio) -6- (2, 2-trifluoroacetyl) -3,5,6, 7-tetrahydro-4H-pyrrolo [3,4-d ] pyrimidin-4-one (100 mg,0.36 mmol) was dissolved in dichloromethane (5 mL), DIPEA (92 mg,0.71 mmol) was added dropwise, trifluoromethanesulfonic anhydride (151.7 mg,0.53 mmol) was stirred at room temperature for 20 min, TLC detection reaction was complete, concentrated to dryness and used directly in the next reaction.

Step 5: synthesis of (S) -2- (4- (2- (methylthio) -6- (2, 2-trifluoroacetyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

2- (methylthio) -6- (2, 2-trifluoroacetyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl ester (147 mg,0.36 mmol) was dissolved in DMF (10 mL), DIPEA (92 mg,0.71 mmol) and (S) -2- (piperazin-2-yl) acetonitrile hydrochloride (71 mg,0.36 mmol) were added and reacted at room temperature for 5 hours, TLC detection reaction was complete and used directly for the next reaction.

Step 6: synthesis of (S) tert-butyl 2- (cyanomethyl) -4- (2- (methylthio) -6- (2, 2-trifluoroacetyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

Boc2O (314 mg,1.44 mmol), DIPEA (139 mg,0.108 mmol) was added to the reaction mixture in the previous step, and the mixture was reacted at room temperature for 2 hours, and the reaction was completed by TLC, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane/methanol=30/1) to give a white solid. (100 mg, yield: 57.1%) ¹ H NMR(400MHz,CDCl3)δ4.97(d,J＝4.2Hz,2H),4.80(s,2H),3.55-3.12(m,5H),2.78-2.54(m,4H),2.52(d,J＝1.2Hz,3H),1.50(s,9H).

Step 7: synthesis of (S) -2- (cyanomethyl) -4- (2- (methylsulfinyl) -6- (2, 2-trifluoroacetyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

(S) 2- (cyanomethyl) -4- (2- (methylthio) -6- (2, 2-trifluoroacetyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (100 mg,0.20 mmol) was dissolved in dichloromethane (10 mL), mCPBA (46 mg,0.22 mmol), stirred at room temperature for 1 hour, TLC checked for completion, aqueous sodium bicarbonate (10 mL) was added, dichloromethane (20 mL) was extracted, and concentrated to dryness before being used in the next reaction. ¹ H NMR(400MHz,CDCl3)δ5.10(d,J＝6.4Hz,2H),4.98(s,2H),3.64(q,J＝12.4Hz,2H),3.49(t,J＝11.9Hz,3H),2.94(d,J＝4.1Hz,3H),2.79(s,2H),2.63(dd,J＝16.8,5.9Hz,2H),1.53(s,9H).

Step 8: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6- (2, 2-trifluoroacetyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

(S) -2- (cyanomethyl) -4- (2- (methylsulfinyl) -6- (2, 2-trifluoroacetyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (110 mg,0.22 mmol) was dissolved in toluene (10 mL), sodium tert-butoxide (42 mg,0.44 mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (44 mg,0.38 mmol) were added under ice-bath and stirred at room temperature for 1 hour, TLC detection reaction was complete, ethyl acetate extraction, anhydrous sodium sulfate drying, concentration, column chromatography purification (dichloromethane/methanol=20/1) gave a white solid. (60 mg, yield: 49.6%).

Step 9: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

Tert-butyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6- (2, 2-trifluoroacetyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (60 mg,0.11 mmol) was dissolved in methanol (10 mL), potassium carbonate (15 mg,0.22 mmol) was added, stirred at room temperature for 10 hours, TLC detection was complete, ethyl acetate extraction, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane/methanol=10/1) to give a white solid (30 mg, yield: 60%).

Step 10: synthesis of tert-butyl (S) -4- (6- (8-chloronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolidin [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

(S) -2- (cyanomethyl) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (70 mg,0.15 mmol) was dissolved in toluene (20 mL), 1-bromo-8-chloronaphthalene (48 mg,0.20 mmol), pd2 (dba) 3 (28 mg,0.03 mmol), XPhos (22 mg,0.045 mmol) and Cs2CO3 (125 mg,0.38 mmol) were added, nitrogen protection, heated to 100deg.C and reacted for 15 hours, TLC detection reaction completed, ethyl acetate extraction, anhydrous sodium sulfate drying, concentration, column chromatography purification (dichloromethane/methanol=10/1) gave a white solid. (30 mg, yield: 31.7%). ¹ H NMR(400MHz,CDCl3)δ8.31-8.21(m,1H),7.90-7.83(m,1H),7.61(d,J＝8.2Hz,1H),7.55-7.51(m,1H),7.45(t,J＝7.8Hz,1H),7.41-7.34(m,1H),4.78(q,J＝14.1,11.0Hz,2H),4.57(d,J＝7.1Hz,2H),4.03(d,J＝12.6Hz,1H),3.72(d,J＝29.3Hz,1H),3.55-3.02(m,6H),2.92(d,J＝21.8Hz,3H),2.81-2.68(m,2H),2.66-2.51(m,2H),2.38-2.13(m,3H),2.13-1.92(m,3H),1.50(p,J＝5.8,4.6Hz,9H).

Step 11: synthesis of 2- ((S) -4- (6- (8-chloronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolidin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

(S) -4- (6- (8-chloronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolidin [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (30 mg,0.048 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, stirred at room temperature for 2 hours, TLC detection was complete, concentrated to dryness, aqueous sodium bicarbonate solution (10 mL) was added, dichloromethane (20 mL) was used for extraction, anhydrous sodium sulfate was used for drying, and the organic phase was concentrated to give a pale yellow solid (20 mg, yield: 80%).

Step 12: synthesis of 2- ((S) -1-propenoyl-4- (6- (8-chloronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

2- ((S) -4- (6- (8-chloronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolidine [3, 4-d)]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (20 mg,0.039 mmol) was dissolved in dichloromethane (5 mL), triethylamine (5 mg,0.05 mmol) was added, acryloyl chloride (3.84 mg,0.042 mmol) was added under ice-bath, TLC detection reaction was complete, aqueous sodium bicarbonate solution (10 mL) was added, dichloromethane (20 mL) was extracted, dried over anhydrous sodium sulfate, concentrated, and plate-purified (dichloromethane/methanol=10/1) was prepared as a pale yellow solid. (5 mg, yield: 22.7%). ¹ H NMR(400MHz,CDCl3)δ8.33-8.20 (m,1H),7.93-7.83(m,1H),7.85-7.73(m,1H),7.70-7.63(m,1H),7.45(t,J＝7.8Hz,1H),7.37(t,J＝7.7Hz,1H),6.56(s,1H),6.39(d,J＝16.7Hz,1H),5.83(d,J＝10.6Hz,1H),4.87(d,J＝11.9Hz,2H),4.65-4.51(m,2H),4.31-4.10(m,1H),3.94(s,1H),3.61(s,6H),2.88(d,J＝14.8Hz,3H),2.72(s,4H),2.23(d,J＝28.7Hz,3H),2.04(s,3H)；MS m/z:572.2[M+H]

Example 3: synthesis of (S) -1- (4- (6- (5-chloro-6-fluoro-1H-indazol-4-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-1-yl) propyl-2-en-1-one

Ethyl N-BOC-4-oxo-3-pyrrolidinecarboxylate (8.0 g,31.1 mmol) was dissolved in water (150 mL), S-methylisothiourea sulfate (6.49 g,46.6 mmol) and sodium carbonate (13.2 g,124 mmol) were added and stirred at room temperature for 15 hours. TLC detection reaction was complete. Hydrochloric acid (6N) is added under vigorous stirring to a pH of 6 to 7. Dilute hydrochloric acid (1N) was then slowly added to a pH of 3. The solid was collected by suction filtration, washed with water (20 mL. Times.2), and dried under reduced pressure. Pulping with ethyl acetate (15 mL), and vacuum filtering to collect solidSpin-steaming gives a pale yellow solid. (5 g, yield: 57%). ¹ H NMR(400MHz,CDCl3)δ4.59-4.46(m,4H),2.59(dd,J＝11.3,1.7Hz,3H),1.58-1.47(m,9H).

Step 2: synthesis of tert-butyl 2- (methylthio) -4- ((trifluoromethyl) sulfonyl) oxy) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate

Tert-butyl 2- (methylthio) -4-oxo-3, 4,5, 7-tetrahydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (2.83 g,10 mmol) was dissolved in dichloromethane (100 mL) and DIPEA (3.3 mL,20 mmol) was added. Trifluoromethanesulfonic anhydride (2.19 mL,13 mmol) was added dropwise to the ice-water bath. Stirring at room temperature for 1 hour, TLC detection reaction was complete, and concentration gave a dark brown thick material which was used directly in the next reaction.

Step 3: synthesis of tert-butyl 2- (methylthio) -4- (4- ((2- (trimethylsilyl) ethoxy) carbonyl) piperazin-1-yl) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate

The crude 2- (methylthio) -4- ((trifluoromethyl) sulfonyl) oxy) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester obtained in the previous step was dissolved in DMF (35 mL) and DIPEA (3.3 mL,20 mmol) and ethyl 2- (trimethylsilyl) piperazine-1-carboxylate (2.3 g,10 mmol) were added at room temperature. Heated to 80℃and reacted for 16 hours. TLC detection reaction was complete. After cooling to room temperature, ethyl acetate (250 mL) and saturated aqueous ammonium chloride (200 mL) were added. After shaking and separation, the aqueous phase was extracted with ethyl acetate (100 mL). The organic phases were combined, washed with saturated aqueous sodium bicarbonate (50 mL), water (50 mL. Times.2), saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a brown solid (5 g, crude product) which was used directly in the next reaction.

Step 4: synthesis of tert-butyl 2- (methylsulfonyl) -4- (4- ((2- (trimethylsilyl) ethoxy) carbonyl) piperazin-1-yl) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate

To 2- (methylthio) -4- (4- ((2- (trimethylsilyl) ethoxy) carbonyl) piperazin-1-yl) -5, 7-dihydro-6H-pyrrolo [3,4-d ] in an ice water bath ]To a solution of pyrimidine-6-carboxylic acid tert-butyl ester (5 g, crude) in dichloromethane (100 mL) was slowly added a solution of mCPBA (2.23 g,1.9 mmol) in dichloromethane (50 mL). Stirring at room temperature for 1 hour, and TLC detection was complete. Reaction solventWashed with sodium bicarbonate aqueous solution (50 mL), saturated brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The obtained solid was subjected to column chromatography (silica gel, methanol: dichloromethane=1:40) to obtain a pale yellow powder (3.3 g, total yield in 3 steps: 59%). ¹ H NMR(400MHz,CDCl3)δ4.82and 4.80(s,AB,2H),4.62and 4.58(s,AB,2H),4.23(t,J＝8.0Hz,2H),3.78-3.76(m,4H),3.61-3.54(m,4H),2.88(s,3H),1.52(s,9H),1.03(t,J＝8.0Hz,2H),0.05(s,9H).

Step 5: synthesis of tert-butyl (S) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (4- ((2- (trimethylsilyl) ethoxy) carbonyl) piperazin-1-yl) -5, 7-dihydro-6H-pyrrole [3,4-d ] pyrimidine-6-carboxylate

To a solution of (S) - (1-methylpyrrolidin-2-yl) methanol (553 mg,4.8 mmol) in tetrahydrofuran was added dropwise a solution of potassium bis (trimethylsilyl) amide in tetrahydrofuran (4.5 mL,4.5 mmol) in an ice-water bath. The resulting white cloudy solution was stirred in an ice-water bath for 20 minutes and tert-butyl 2- (methylsulfonyl) -4- (4- ((2- (trimethylsilyl) ethoxy) carbonyl) piperazin-1-yl) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (1.54 g,3.0 mmol) was added in one portion. The reaction solution was stirred at room temperature for 15 hours. The reaction mixture was poured into stirred water (100 mL) and extracted with ethyl acetate (100 mL. Times.2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (silica gel, dichloromethane/methanol=10/1) to give a yellow foamy solid (900 mg,1.6mmol, yield: 53%).

Step 6: synthesis of 2- (trimethylsilyl) ethyl ester of (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

A mixture of (S) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (4- ((2- (trimethylsilyl) ethoxy) carbonyl) piperazin-1-yl) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester (500 mg,0.89 mmol) and formic acid (8 mL) was stirred at room temperature for 12 hours. Formic acid was removed by concentration under reduced pressure, and aqueous sodium hydroxide (30 mL) and methylene chloride (50 mL) were added to the residue. After shaking, separation, the aqueous phase was extracted with dichloromethane (50 ml+20 ml). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated. The orange viscous material was purified by column chromatography (silica gel, methylene chloride/methanol=8/1,0.6% ammonia water) to give a pale brown solid (295 mg, yield: 72%).

Step 7: synthesis of 2- (trimethylsilyl) ethyl 4- (6- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

(S) -2- (trimethylsilyl) ethyl 4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-d) ]Pyrimidine-4-yl) piperazine-1-carboxylic acid (80 mg,0.17 mmol) was dissolved in toluene (50 mL) and 4-bromo-5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (75 mg,0.22 mmol), pd was added ₂ (dba) ₃ (32mg,0.034mmol)，XPhos(25mg,0.051mmol),Cs ₂ CO ₃ (140 mg,0.43 mmol), nitrogen protection, heating to 100deg.C for 15 hours, TLC detection of reaction completion, ethyl acetate extraction, drying over anhydrous sodium sulfate, concentration, column chromatography purification (dichloromethane/methanol=10/1) afforded a brown solid. ¹ H NMR (400 mhz, cdcl 3) delta 8.08 (s, 1H), 7.12 (d, j=8.5 hz, 1H), 5.60 (dd, j=9.1, 2.7hz, 1H), 5.06 (t, j=2.5 hz, 2H), 4.91-4.80 (m, 2H), 4.74 (s, 1H), 4.50-4.37 (m, 1H), 4.30-4.12 (m, 2H), 4.08-3.97 (m, 1H), 3.83-3.67 (m, 4H), 3.57 (t, j=5.0 hz, 4H), 3.48 (s, 1H), 2.78 (s, 3H), 2.57-2.45 (m, 1H), 2.31-1.88 (m, 6H), 1.78-1.63 (m, 2H), 1.27 (d, j=7.37 (m, 1H), 3.83-3.67 (m, 4H), 3.57 (t, j=5.0 hz, 4H), 3.48 (s, 1H), 2.78 (s, 3H), 2.57 (t, 2.45 (m, 1H), 1.7.7H).

Step 8: synthesis of (S) -6- (5-chloro-6-fluoro-1H-indazol-4-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine

2- (trimethylsilyl) ethyl 4- (6- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid (50 mg,0.07 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (6 mL) was added, stirred at room temperature for 2 hours, the TLC detection reaction was complete, concentrated to dryness, aqueous sodium bicarbonate solution (10 mL) was added, dichloromethane (20 mL) was extracted, anhydrous sodium sulfate was dried, and the organic phase was concentrated to give a pale yellow solid. (34 mg, yield: 100%).

Step 9: synthesis of (S) -1- (4- (6- (5-chloro-6-fluoro-1H-indazol-4-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-1-yl) propyl-2-en-1-one

(S) -6- (5-chloro-6-fluoro-1H-indazol-4-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d]Pyrimidine (34 mg,0.07 mmol) was dissolved in dichloromethane (5 mL), triethylamine (9.1 mg,0.09 mmol) was added, acryloyl chloride (7 mg,0.077 mmol) was added under ice-bath, TLC detection was complete, aqueous sodium bicarbonate solution (10 mL) was added, dichloromethane (50 mL) was extracted, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow solid which was plate-purified (dichloromethane/methanol=10/1). (6 mg, yield: 15.9%). ¹ H NMR(400MHz,CDCl3)δ8.12(s,1H),6.93(d,J＝8.2Hz,1H),6.61(dd,J＝16.8,10.5Hz,1H),6.38(dd,J＝16.8,1.9Hz,1H),5.79(dd,J＝10.5,1.9Hz,1H),5.14(s,2H),4.85(s,2H),4.66(s,1H),4.34(dd,J＝11.2,4.9Hz,1H),3.76(d,J＝29.3Hz,8H),3.48(d,J＝19.1Hz,1H),3.11(s,1H),2.78(s,3H),2.69-2.48(m,2H),2.14(d,J＝47.6Hz,2H),1.95(s,2H)；MS m/z:541.2[M+H]

Examples 4 to 29 were prepared by the method of example 1

EXAMPLE 30 Synthesis of (S) -1- (4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-2-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

Ethyl N-BOC-4-oxo-3-pyrrolidinecarboxylate (9.7 g,37.7 mmol) was dissolved in water (250 mL), S-methylisothiourea sulfate (7.86 g,56.5 mmol) and sodium carbonate (16.0 g,151 mmol) were added and stirred at room temperature for 15 hours. TLC detection reaction was complete. Hydrochloric acid (170 mL, 1N) was added with vigorous stirring to a pH of 3. The solid was collected by suction filtration, rinsed with water (20 mL ×3) and dried by suction. The mixture was slurried with ethyl acetate/petroleum ether (20 mL, v: v=1:1), the solid collected by suction filtration, rinsed with ethyl acetate/petroleum ether (10 ml×2, v: v=1:1) and rotary distilled to give a pale yellow powder. (6.6 g, yield: 62%). ¹ H NMR(400MHz,CDCl ₃ )δ4.59-4.46(m,4H),2.59(dd,J＝11.3,1.7Hz,3H),1.58-1.47(m,9H).

Tert-butyl 2- (methylthio) -4-oxo-3, 4,5, 7-tetrahydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (1.55 g,5.48 mmol) was dissolved in dichloromethane (55 mL) and DIPEA (1.82 mL,11 mmol) was added. Trifluoromethanesulfonic anhydride (1.20 mL,7.12 mmol) was added dropwise in an ice-water bath. Stirring at room temperature for 1.5 hours, detecting the reaction completion by TLC, and concentrating under reduced pressure to obtain dark brown sticky matter which is directly used for the next reaction.

The crude 2- (methylthio) -4- ((trifluoromethyl) sulfonyl) oxy) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester obtained in the previous step was dissolved in DMF (20 mL) and DIPEA (1.82 mL,11 mmol) and ethyl 2- (trimethylsilyl) piperazine-1-carboxylate (1.39 g,6.03 mmol) were added at room temperature. Heated to 80℃and reacted for 16 hours. TLC detection reaction was complete. After cooling to room temperature, ethyl acetate (100 mL) and saturated aqueous ammonium chloride (100 mL) were added. After shaking and separation, the aqueous phase was extracted with ethyl acetate (100 mL). The organic phases were combined, washed with saturated aqueous sodium bicarbonate (50 mL), water (50 mL. Times.2), saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a brown solid (2.2 g, crude product) which was used directly in the next reaction.

Step 4: synthesis of 2- (trimethylsilyl) ethyl 4- (2- (methylthio) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

The crude 2- (methylthio) -4- (4- ((2- (trimethylsilyl) ethoxy) carbonyl) piperazin-1-yl) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester (2 g) obtained in the previous step was dissolved in ethanol (50 mL), and anhydrous p-toluenesulfonic acid (1.87 g,10.8 mmol) was heated to 80℃for 16 hours.

Step 5: synthesis of 2- (trimethylsilyl) ethyl 4- (2- (methylthio) -6- (naphthalen-2-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

To the reaction flask was added 2- (trimethylsilyl) ethyl 4- (2- (methylsulfanyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (750 mg,1.9 mmol), 2-bromonaphthalene (471 mg,2.28 mmol), tris (dibenzylideneacetone) dipalladium (348 mg,0.38 mmol), 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl (181 mg,0.38 mmol), and cesium carbonate (1.24 g,3.8 mmol). After argon was replaced, pre-deoxygenated anhydrous toluene (20 mL) was added. The reaction solution was heated at 110℃for 16 hours. After cooling to room temperature, the filter cake was washed with ethyl acetate (10 ml×2). The filtrates were combined, concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:4) to give a dark purple solid (620 mg,1.19mmol, yield: 63%). MS m/z 522.2[ M+H ] +.

Step 6: synthesis of 2- (trimethylsilyl) ethyl 4- (2- (methylsulfonyl) -6- (naphthalen-2-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

To a mixture of 2- (trimethylsilyl) ethyl 4- (2- (methylsulfanyl) -6- (naphthalen-2-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (490 mg,0.94 mmol), sodium bicarbonate (331 mg,3.94 mmol), acetone (20 mL), dichloromethane (5 mL), and water (10 mL) was added potassium monopersulfate (750 mg,1.22 mmol). The reaction solution was stirred at room temperature for 16 hours. Ethyl acetate (100 mL) and water (50 mL) were added. After shaking and separation, the mixture was washed with a saturated aqueous sodium carbonate solution (20 mL), a saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give a brown viscous material. Purification by column chromatography (silica gel, methanol/dichloromethane=1/50) afforded a pale brown solid (263 mg,0.3mmol, yield: 32%).

Step 7: synthesis of 2- (trimethylsilyl) ethyl (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-2-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

To a solution of (S) - (1-methylpyrrolidin-2-yl) methanol (56 mg,0.48 mmol) in tetrahydrofuran was added dropwise a solution of potassium bis (trimethylsilyl) amide in tetrahydrofuran (0.45 mL,0.45 mmol) in an ice-water bath. The resulting white cloudy solution was stirred in an ice-water bath for 20 minutes, and 2- (trimethylsilyl) ethyl 4- (2- (methylsulfonyl) -6- (naphthalen-2-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (163 mg,0.30 mmol) was added in portions. The reaction solution was stirred at room temperature for 15 hours. The reaction solution was poured into stirred water (20 mL), and extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give a white foamy solid (120 mg,0.204mmol, yield: 68%) which was purified by preparative TLC plate (dichloromethane/methanol=8/1).

Step 8: synthesis of (S) -6- (3-bromonaphthalen-2-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine

To a solution of (S) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-2-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid 2- (trimethylsilyl) ethyl ester (50 mg,0.085 mmol) in DMF (1.5 mL) was added cesium fluoride (64 mg,0.425 mmol). Stirred at 60℃for 3 hours. After cooling to room temperature, methylene chloride (20 mL) and saturated aqueous sodium carbonate (20 mL) were added. After shaking and separation, the aqueous phase was extracted with dichloromethane (20 mL). The combined organic phases were washed with water (10 mL. Times.3), saturated brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give a light brown viscous material which was used directly in the next reaction.

Step 9: synthesis of (S) -1- (4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -6- (naphthalen-2-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

To (S) -6- (3-bromonaphthalen-2-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -6, 7-dihydro-5H-pyrrole [3,4-d ] in an ice-water bath]A solution of acryloyl chloride (0.01 mL,0.128 mmol) in dichloromethane (1 mL) was slowly dropped in a solution of pyrimidine (crude) and triethylamine (0.036 mL,0.255 mmol) in dichloromethane (2 mL). The ice-water bath was removed, and the reaction solution was stirred at room temperature for 30 minutes. Dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL) were added, shaken, separated and the aqueous phase extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and evaporated to give a viscous material. Purification by preparative TLC (methanol: dichloromethane=1:8) afforded a white solid. (22 mg, two-step total yield: 21%) ¹ H NMR(400MHz,CDCl ₃ )δ7.81(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,2H),7.42(t,J＝8.0Hz,1H),7.25-7.23(m,1H),7.07(d,J＝8.0Hz,1H),6.87(s,1H),6.63(dd,J＝16.8,10.5Hz,1H),6.39(dd,J＝16.8,1.9Hz,1H),5.80(dd,J＝10.5,2.0Hz,1H),4.84-4.80(m,2H),4.59-4.54(m,2H),3.94-3.36(m,10H),2.89(s,4H),2.38-1.93(m,6H)；MS m/z:499.3[M+H]

Examples 31 to 33 were prepared by the method of example 1

EXAMPLE 34 Synthesis of 1- (4- (7- (5-chloro-6-fluoro-1H-indazole-4-carbonyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

Step 1: synthesis of tert-butyl (2- (4, 6-dichloro-2- (methylthio) pyrimidin-5-yl) ethyl) carbamate

The compound 4, 6-dichloro-2- (methylthio) pyrimidine (3.1 g,15.9 mmol) and tert-butyl 1,2, 3-oxathiazolidine-3-carboxylate 2, 2-dioxide (4.2 g,19 mmol) were placed in a 100ml double-necked flask, nitrogen was replaced 3 times with reduced pressure, and ultra-dry THF was added and stirred for dissolution. 1mol/L LiHMDS (47.7 ml,47.7 mmol) was added at-78deg.C and stirred overnight. And adding excessive citric acid solution into the reaction system after the reaction is finished, and continuously stirring for half an hour. The reaction was extracted, separated, and the crude product obtained after drying was separated by column chromatography (silica gel, EA: pet=1:10) to give a pale yellow solid (1.76 g, yield 33%).

Step 2: synthesis of 4-chloro-2- (methylthio) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine

The compound tert-butyl 2- (4, 6-dichloro-2- (methylthio) pyrimidin-5-yl) ethyl) carbamate (1.76 g,5.2 mmol) was dissolved in DCM and CF ₃ In the COOH cosolvent, stirring was carried out at room temperature for 0.5h. After the completion of the reaction, the solvent was removed under reduced pressure. DIEPA (1.73 ml,10.4 mmol) and 20ml acetonitrile were added to the reaction system. The reaction was allowed to react overnight at 50 ℃. After the completion of the reaction, the solvent was removed under reduced pressure to give a pale yellow solid (1.0 g, yield 96%). ¹ H NMR(400MHz,CDCl ₃ )δ6.20(s,1H),3.55(t,2H),3.03(t,2H),2.50(s,2H)。ESI-MS m/z:202.01[M+H] ⁺

Step 3: synthesis of tert-butyl 4- (2- (methylthio) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate

The compound 4-chloro-2- (methylthio) -6, 7-dihydro-5H-pyrrolo [2,3-d]Pyrimidine (1.0 g,5 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.02 g,5.5 mmol) were dissolved in 20ml 1, 4-dioxane and DIEPA (1.7 ml,10 mmol) was added. Reverse-rotationThe reaction system was reacted at 50℃for 3 hours. The solvent in the reaction system was removed under reduced pressure, and the reaction mixture was separated by column chromatography (silica gel, EA: pet=1:10) to give the desired product (1.50 g, yield 85%). ¹ H NMR(400MHz,CDCl ₃ )δ6.20(s,1H),3.73(t,4H),3.55(t,2H),3.32(t,4H),3.01(t,2H),2.50(s,2H),1.42(s,9H)。ESI-MS m/z:352.17[M+H] ⁺

Step 4: synthesis of tert-butyl 4- (7- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-4-carbonyl) -2- (methylsulfanyl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate

The compound 4- (2- (methylthio) -6, 7-dihydro-5H-pyrrolo [2, 3-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (1.50 g,4.25 mmol) and 5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-4-carbonyl chloride (1.6 g,5.1 mmol) were dissolved in 30ml of ultra-dry THF, t-BuOK (1.2 g,10.6 mmol) was added and the reaction stirred overnight at room temperature. After the reaction was completed, the mixture was separated by extraction with ethyl acetate, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure and then separated by column chromatography (silica gel, EA: pet=1; 10) to give the objective product as a pale yellow solid (1.8 g, yield: 67%). ESI-MS m/z 632.21[ M+H ] ] ⁺

Step 5: synthesis of tert-butyl 4- (7- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-4-carbonyl) -2- (methylsulfonyl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate

The compound 4- (7- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-4-carbonyl) -2- (methylsulfanyl) -6, 7-dihydro-5H-pyrrolo [2,3-d]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (1.8 g,2.7 mmol) was dissolved in 40ml DCM and m-CPBA (11.6 g,6.75 mmol) was added and the reaction stirred at room temperature overnight. After the reaction, a proper amount of water is added into the reaction system, and after washing, the organic phase is washed three times with saturated sodium bicarbonate solution. After drying, the organic solvent was removed under reduced pressure to give the desired product (1.4 g, yield 77%). 664.20[ M+H ] ESI-MS m/z] ⁺

Step 6: synthesis of tert-butyl 4- (7- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-4-carbonyl) -2- (((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate

The compound 4- (7- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-4-carbonyl) -2- (methylsulfonyl) -6, 7-dihydro-5H-pyrrolo [2,3-d]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (1.4 g,2.1 mmol) and 2-methyl-5-hydroxy-1, 2,3, 4-tetrahydroisoquinoline (313 mg,3.15 mmol) were dissolved in 30ml of ultra-dry THF, 1mol/L LiHMDS (3.2 ml,3.2 mmol) was added under ice water bath conditions, and after the reaction was allowed to recover to room temperature, the reaction was completed. To the reaction system was added EA, washed three times with an appropriate amount of water, the organic phase was dried and the organic solvent was removed under reduced pressure, and the crude product was separated by column chromatography (silica gel, EA: pet=1:10) to a yellow solid (1.1 g, yield 68%). ESI-MS m/z 747.31[ M+H ] ] ⁺

Step 7: synthesis of (5-chloro-6-fluoro-1H-indazol-4-yl) (2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -4- (piperazin-1-yl) -5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) methanone

The compound tert-butyl 4- (7- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-4-carbonyl) -2- (((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6, 7-dihydro-5H-pyrrolo [2, 3-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid (1.1 g,1.4 mmol) was dissolved in DCM and CF ₃ In a cosolvent of COOH (3:1), stirring was carried out for two hours at room temperature. The organic solvent was removed under reduced pressure to give the desired product as a yellow oily solid (803 mg, yield 100%).

Step 8: synthesis of 1- (4- (7- (5-chloro-6-fluoro-1H-indazole-4-carbonyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

The compound (5-chloro-6-fluoro-1H-indazol-4-yl) (2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -4- (piperazin-1-yl) -5, 6-dihydro-7H-pyrrolo [2, 3-d)]Pyrimidine-7-yl) methanone (800 mg,1.4 mmol) and DIEPA (0.35 ml,2.1 mmol) were dissolved in 20ml DCM, acryloyl chloride (127 mg,1.4 mmol) was added dropwise under ice-water bath, after the reaction was complete, the solvent was removed under reduced pressure and the crude product was isolated by column chromatography (silica gel, EA: PET=1:5) to give the desired product (475 mg, yield 55%). ¹ H NMR(400MHz,CDCl ₃ )δ8.20(s,1H),7.50(d,1H),6.98-6,95(m,3H),6.62(m,1H),6.04(m,1H),5.58(m,1H),3.73-3.70(m,8H),3.32(m,4H),3.08(m,2H),2.96-2.83(m,4H),2.26(s,3H)。ESI-MS m/z:617.21[M+H] ⁺

Examples 35 to 83 were prepared by the method of example 34

Example 84: synthesis of 1- (4- (8- (5-chloro-6-fluoro-1H-indole-4-carbonyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazin-2-en-1-one:

step 1: synthesis of tert-butyl (3- (4, 6-dichloro-2- (methylthio) pyrimidin-5-yl) propyl) carbamate:

the compound 4, 6-dichloro-2- (methylthio) pyrimidine (3.00 g,15.38 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), replaced with nitrogen, liHMDS (1M, 23.07mL,23.07 mmol) was added dropwise under cooling with a dry ice ethanol bath, and after stirring at-78℃for 30 minutes, a solution of tert-butyl 1,2, 3-oxathiazinane-3-carboxylate 2, 2-dioxide (4.01 g,16.92 mmol) in tetrahydrofuran (10 mL) was added dropwise, and after the addition was completed, the reaction was stirred at room temperature for 12 hours. After the completion of the reaction, the reaction was quenched with saturated 1M citric acid, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and separated by column chromatography (petroleum ether/ethyl acetate=10/1) to give an off-white solid. (2.1 g, yield: 39%). ¹ H NMR(400MHz,CDCl ₃ )δ4.62(s,1H),3.22(d,J＝5.8Hz,2H),2.90-2.76(m,2H),2.55(s,3H),1.84-1.72(m,2H),1.45(s,9H).

Step 2: synthesis of 3- (4, 6-dichloro-2- (methylthio) pyrimidin-5-yl) propan-1-amine

The compound (3- (4, 6-dichloro-2- (methylthio) pyrimidin-5-yl) propyl) carbamic acid tert-butyl ester (2.1 g,5.96 mmol) was dissolved in trifluoroacetic acid (15 mL) and reacted at room temperature with stirring for 30 minutes. After the completion of the reaction, the reaction solution was concentrated to give a brown oil which was used directly in the next step.

Step 3: synthesis of 4-chloro-2- (methylthio) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine:

the compound 3- (4, 6-dichloro-2- (methylthio) pyrimidin-5-yl) propan-1-amine (1.5 g,5.95 mmol) was dissolved in anhydrous acetonitrile (15 mL), triethylamine (2.41 g,23.79 mmol) was added, and the mixture was heated to 80℃and reacted under stirring for 30 minutes. After the completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfateConcentration and column chromatography (petroleum ether/ethyl acetate=10/1) gave a white solid. (1.0 g, yield: 78%). ¹ H NMR(400MHz,CDCl ₃ )δ5.47(s,1H),3.40(td,J＝5.8,2.7Hz,2H),2.69(t,J＝6.4Hz,2H),2.47(s,3H),2.00-1.86(m,2H).

Step 4: synthesis of tert-butyl 4- (2- (methylthio) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate:

the compound 4-chloro-2- (methylthio) -5,6,7, 8-tetrahydropyrido [2,3-d]Pyrimidine (1.0 g,4.64 mmol) was dissolved in anhydrous DMF (10 mL), DIEA (0.90 g,6.95 mmol) and tert-butyl piperazine-1-carboxylate (1.04 g,5.56 mmol) were added, heated to 80℃and reacted with stirring for 4 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, diluted with saturated brine, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give an off-white solid. (1.6 g, yield: 94%). ¹ H NMR(400MHz,CDCl ₃ )δ5.40(s,1H),3.46-3.30(m,6H),2.88-2.75(m,4H),2.69(t,J＝6.4Hz,2H),2.47(s,3H),1.98-1.88(m,2H),1.46(s,9H).

Step 5: synthesis of tert-butyl 4- (8- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-4-carbonyl) -2- (methylsulfanyl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate:

the compound 4- (2- (methylsulfanyl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (0.2 g, 0.55 mmol) and 5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-4-carbonyl chloride (209 mg,0.66 mmol) were dissolved in anhydrous THF (10 ml), t-BuOK (148 mg,1.31 mmol) was added and stirred overnight at room temperature. After the completion of the reaction, the mixture was separated by extraction with ethyl acetate, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, followed by separation by column chromatography (dichloromethane/methanol=50/1) to give the objective product as a pale yellow solid (220 mg, yield: 62%).

Step 6:4- (8- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-4-carbonyl) -2- (methylsulfonyl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester was synthesized:

the compound 4- (8- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-4-carbonyl) -2- (methylsulfanyl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (220 mg,0.34 mmol) was dissolved in dichloromethane (10 mL), 85% m-chloroperoxybenzoic acid (83 mg,0.41 mmol) was added with ice water bath cooling and the reaction stirred for 30 min with ice water bath cooling. After the reaction, the reaction was quenched with saturated sodium thiosulfate, extracted with methylene chloride, and the organic phase was washed with saturated sodium bicarbonate and brine in this order, dried over anhydrous sodium sulfate, and concentrated to give an off-white solid which was used directly in the next step. (220 mg, yield: 97%)

Step 7: synthesis of tert-butyl 4- (8- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-4-carbonyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate:

the compound 4- (8- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-4-carbonyl) -2- (methylenesulfonyl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (220 mg,0.33 mol) was dissolved in anhydrous toluene (5 mL), 2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-ol (65 mg,0.40 mmol) was added, sodium t-butoxide (48 mg,0.50 mmol) was added under ice water bath cooling, and the reaction was stirred under ice water bath for 3 hours. After the completion of the reaction, the reaction was quenched with cold water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane/methanol=20/1) to give an off-white solid. (150 mg, yield: 59%).

Step 8: synthesis of (5-chloro-6-fluoro-1H-indazol-4-yl) (2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -4- (piperazin-1-yl) -6, 7-dihydropyrido [2,3-d ] pyrimidin-8 (5H) -yl) methanone:

the compound 4- (8- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-4-carbonyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (150 mg,0.20 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added and the reaction stirred at room temperature for 1 hour. After the completion of the reaction, the reaction solution was concentrated to give a brown oily substance which was used directly in the next step. (113 mg, yield: 100%).

Step 9: synthesis of 1- (4- (8- (5-chloro-6-fluoro-1H-indazole-4-carbonyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazin-2-en-1-one:

the compound (113 mg,0.20 mmol) was dissolved in dichloromethane (5 mL), DIEA (31 mg,0.23 mmol) was added under ice-water bath cooling, then acryloyl chloride (18 mg,0.20 mmol) was added dropwise, and the reaction was stirred under ice-water bath cooling for 30 minutes. After the reaction, the reaction mixture was diluted with water, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and separated by column chromatography (dichloromethane/methanol=10/1) to give an off-white solid. (55 mg, yield: 44.5%). ¹ H NMR(400MHz,CDCl ₃ )δ8.48(s,1H),7.56(d,J＝16.1Hz,1H),6.97(q,J＝5.9Hz,3H),6.12-5.91(m,2H),5.53(dd,J＝26.3,11.6Hz,1H),3.99(t,J＝10.6Hz,4H),3.88(t,J＝10.4Hz,2H),3.70(s,2H),3.32(t,J＝10.6Hz,4H),3.03-2.86(m,4H),2.88-2.72(m,2H),1.76-1.52(m,2H)；MS m/z:631.1[M+H] ⁺ 。

Example 85: synthesis of 1- (4- (8- (1- (5-chloro-6-fluoro-1H-indazol-4-yl) ethyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

Step 1: synthesis of 2- (trimethylsilyl) ethyl 4- (2- (methylthio) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate

To a solution of 4-chloro-2- (methylsulfanyl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine (863 mg,4.00 mmol) in tetrahydrofuran (25 mL) was added nitrogen, nitrogen-diisopropylethylamine (1.03 g,8.00 mmol) and ethyl 2- (trimethylsilyl) piperazine-1-carboxylate (1.11 g,4.8 mmol). The reaction solution was heated to reflux for 6 hours. After cooling to room temperature, the reaction mixture was distilled under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate: petroleum ether=2:1) to give a white solid. (711 mg, yield: 67%) MS m/z 409.6[ M+H ] +.

Step 2: synthesis of 2- (trimethylsilyl) ethyl 4- (8- (1- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) ethyl) -2- (methylsulfanyl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate

To a solution of 2- (trimethylsilyl) ethyl 4- (2- (methylsulfanyl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate (711 mg,2.69 mmol) and 1- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) ethan-1-one (798 mg,2.69 mmol) in dichloromethane (25 mL) was added trifluoroacetic acid (307 mg,2.69 mmol) and sodium borohydride acetate (1.14 g,5.38 mmol). The reaction solution was stirred at room temperature for 16 hours. Saturated aqueous sodium bicarbonate (20 mL) and methylene chloride (15 mL) were added. After shaking and separation, the aqueous phase was extracted with dichloromethane (20 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and spun dry under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate: petroleum ether=1:2) to give a yellowish brown solid. (150 mg, yield: 8.1%) MS m/z 690.4[ M+H ] +.

Step 3: synthesis of 2- (trimethylsilyl) ethyl 4- (8- (1- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) ethyl) -2- (methylsulfanyl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate

To a solution of 2- (trimethylsilyl) ethyl 4- (8- (1- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) ethyl) -2- (methylsulfanyl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate (150 mg,0.21 mmol) in dichloromethane (10 mL) was added m-chloroperoxybenzoic acid (112 mg,0.65 mmol) at room temperature. The reaction solution was stirred for 12 hours. Dichloromethane (10 mL) and saturated aqueous sodium sulfite solution (10 mL) were added, and after shaking and delamination, the organic phase was washed with saturated aqueous sodium carbonate solution (10 mL), saturated aqueous brine and dried over sodium sulfate. Spin-drying under reduced pressure afforded a pale yellow solid and was used directly in the next step. (150 mg, yield: 96%) MS m/z:722.3[ M+H ] +.

Step 4: synthesis of 2- (trimethylsilyl) ethyl 4- (8- (1- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) ethyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate

To a solution of 2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-ol (51 mg,0.312 mmol) in N, N-dimethylformamide (3 mL) was added sodium hydride (13 mg,0.312 mmol) in an ice-water bath. The reaction solution was stirred in an ice-water bath for 30 minutes. 2- (trimethylsilyl) ethyl 4- (8- (1- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) ethyl) -2- (methylsulfanyl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate (150 mg,0.208 mmol) was added, the ice water bath was removed and stirred at room temperature for 16 hours. Ethyl acetate (30 mL) and saturated sodium carbonate (10 mL) were added, and the mixture was shaken and separated. The organic phase was washed with water (5 mL. Times.3) saturated brine (5 mL), dried over sodium sulfate, and spun-dried under reduced pressure. The residue was purified by TLC (methanol: dichloromethane=1:10) to give a white solid. (35 mg, yield: 21%) MS m/z 805.5[ M+H ] +.

Step 5: synthesis of 8- (1- (5-chloro-6-fluoro-1H-indazol-4-yl) ethyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -4- (piperazin-1-yl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine

To a solution of 2- (trimethylsilyl) ethyl 4- (8- (1- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) ethyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate (35 mg,0.0435 mmol) in dichloromethane (3 mL) was slowly added trifluoroacetic acid (1 mL) in an ice-water bath. The reaction solution was stirred at room temperature for 3 hours. Anhydrous dichloromethane (10 mL) was added for dilution and spin-drying under reduced pressure. The resulting pale yellow dope was used directly in the next step. (35 mg, yield: 100%) MS m/z:577.1[ M+H ] +.

Step 6: synthesis of 1- (4- (8- (1- (5-chloro-6-fluoro-1H-indazol-4-yl) ethyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

To 8- (1- (5-chloro-6-fluoro-1H-indazol-4-yl) ethyl) -2- ((2-methyl)1,2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -4- (piperazin-1-yl) -5,6,7, 8-tetrahydropyrido [2,3-d]To a mixed solution of pyrimidine (35 mg, crude) and acrylic acid (4.7 mg,0.0653 mmol) in N, N-dimethylformamide (0.5 mL) and methylene chloride (1.5 mL) were added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (13.4 mg,0.07 mmol), 4-dimethylaminopyridine (0.9 mg, 0.0071 mmol) and triethylamine (19 mg,0.19 mmol). The reaction solution was stirred at room temperature for 12 hours. Dichloromethane (30 mL) was added, washed with saturated aqueous sodium bicarbonate (10 mL), saturated brine (5 mL) and dried over sodium sulfate. The residue obtained was dried by spin-drying under reduced pressure by TLC (methanol: dichloromethane=1:12) to give an off-white solid. (3 mg, yield: 11%) ¹ H NMR(400MHz,DMSO)δ8.21(s,1H),7.22(d,J＝8.0Hz,1H),7.00(t,J＝7.5Hz,1H),6.94-6.91(m,2H),6.78(dd,J＝16.8,10.0Hz,1H),6.08(dd,J＝2.1,16.8Hz,1H),5.68(dd,J＝2.1,10.0Hz,1H),4.91(s,1H),4.45-4.23(m,2H),4.08(q,J＝6.8Hz,1H),3.74-3.68(m,6H),3.22-3.15(m,4H),3.14-3.12(m,2H),3.00-2.74(m,6H),2.36(s,3H),1.85-1.81(m,2H),1.28(d,J＝6.8Hz,3H).MS m/z:631.1[M+H]+。

86-119 Compound prepared by the method of application example 85

Example 120: synthesis of 2- ((S) -1-propenoyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

step 1: synthesis of 4-hydroxy-2- (methylthio) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylic acid tert-butyl ester:

compound 1- (tert-butyl) 4-methyl 3-oxopiperidine-1, 4-carboxylate (20 g,77.73 mmol) was dissolved in dry methanol (160 mL), 30% sodium methoxide solution (42.0 g,233.20 mmol) and thiourea (8.88 g,116.60 mmol) were added and heated to 80℃for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, methyl iodide (13.79 g,6.10mL,97.17 mmol) was added dropwise thereto, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated, the residue was dissolved in water, the pH was adjusted to 6-7 with glacial acetic acid, and a solid was precipitated and filtered to give a white solid. (22 g, yield: 95%). ¹ HNMR(400MHz,CDCl ₃ )δ11.40(s,1H),4.33(s,2H),3.60(t,J＝5.5Hz,2H),2.56(s,5H),1.49(s,9H).

Step 2: synthesis of 2- (methylthio) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-ol:

the compound tert-butyl 4-hydroxy-2- (methylthio) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate (22 g,73.98 mmol) was dissolved in dichloromethane (200 mL), trifluoroacetic acid (50 mL) was added, and the reaction was stirred at room temperature for 3 hours, after the completion of the reaction. Condensing the reaction solution, adding saturated sodium bicarbonate aqueous solution and dichloromethane into the obtained residue, extracting with dichloromethane, washing an organic phase with saturated saline, drying with anhydrous sodium sulfate, and concentrating to obtain a crude product which is directly used in the next step. (14.6 g, yield: 100%)

Step 3: synthesis of benzyl 4-hydroxy-2- (methylthio) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate:

the compound 2- (methylthio) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-ol (14.5 g,73.51 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL), triethylamine (15.37 mL,110.26 mmol) was added under cooling in an ice-water bath, and then benzyloxycarbonyl chloride (13.79 g,80.86 mmol) was slowly added dropwise, and the reaction was stirred under ice-water bath for 1 hour. After the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give the objective compound. (24 g, 98.5%)

Step 4: synthesis of benzyl 2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate:

benzyl 4-hydroxy-2- (methylsulfanyl) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate (24.0 g,72.42 mmol) was dissolved in dichloromethane (300 mL), DIEA (14.04 g,108.63 mmol) was added under ice-water bath cooling, and then trifluoromethanesulfonic anhydride (22.48 g,79.66 mol) was slowly added dropwise, and after the addition, the reaction was continued under stirring under ice-water bath conditions for 1 hour. After the reaction, the reaction solution was concentrated to obtain an oily crude product which was directly used in the next step.

Step 5: synthesis of benzyl (S) -4- (4- (tert-butyloxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate:

the 2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) -5, 8-dihydropyrido [3, 4-d) obtained in the previous step]Pyrimidine-7 (6H) -carboxylic acid benzyl ester (72.42 mmol) was dissolved in anhydrous DMF (300 mL), DIEA (46.80 g,362.07 mmol) and (S) -2- (piperazin-2-yl) acetonitrile.2 hydrochloride (14.35 g,72.42 mmol) were added and the reaction stirred for 1 hour at 80 ℃. After the completion of the reaction, di-tert-butyl dicarbonate (47.42 g,217.26 mmol) was added thereto and the reaction was continued with stirring for 1 hour. After the reaction, the reaction mixture was cooled to room temperature, diluted with saturated brine, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give an off-white solid. (37 g, yield: 95%). ¹ H NMR(400MHz,CDCl ₃ )δ7.37(t,J＝6.3Hz,5H),5.18(s,2H),4.69(d,J＝18.8Hz,1H),4.59(s,1H),4.45(d,J＝19.0Hz,1H),3.94(s,4H),3.43(s,1H),3.25(s,2H),2.97(s,1H),2.81-2.56(m,4H),2.50(s,3H),1.50(s,9H).

Step 6: synthesis of benzyl 4- ((S) -4- (tert-butyloxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate:

the compound benzyl (S) -4- (4- (tert-butyloxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate (37 g,68.69 mmol) was dissolved in dichloromethane (300 mL), 85% of m-chloroperoxybenzoic acid (16.73 g,82.43 mmol) was added under ice water bath cooling and the reaction stirred under ice water bath cooling for 30 minutes. After the reaction, the reaction was quenched by adding a saturated sodium thiosulfate solution, extracted with methylene chloride, the organic phase was washed with saturated sodium bicarbonate and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated to give an off-white solid. (37.5 g, yield: 98%).

Step 7: synthesis of benzyl 4- ((S) -4- (tert-butyloxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate:

the compound 4- ((S) -4- (tert-butyloxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -5, 8-dihydropyrido [3,4-d ]]Pyrimidine-7 (6H) -carboxylic acid benzyl ester (20 g,36.06 mmol) was dissolved in anhydrous toluene (200 mL), and (S) - (1-methylpyrrolidin-2-yl) methanol (7.27 g,63.10 mmol) was added under ice-water bath cooling, sodium t-butoxide (6.93 g,72.12 mmol) was added in portions and the reaction stirred for 20 min under ice-water bath cooling. After the reaction, the reaction mixture was quenched with cold water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give an off-white solid. (13.5 g, yield: 62%). ¹ H NMR(400MHz,CDCl ₃ )δ7.36(d,J＝9.8Hz,5H),5.18(s,2H),4.66(d,J＝18.9Hz,1H),4.57(s,1H),4.44(d,J＝18.9Hz,2H),4.21(s,1H),3.86(d,J＝84.9Hz,4H),3.43(s,1H),3.23(d,J＝13.9Hz,3H),2.95(s,1H),2.84(s,1H),2.79-2.60(m,4H),2.57(s,3H),2.41(s,2H),2.09(d,J＝8.4Hz,1H),1.90(s,1H),1.81(s,2H),1.50(s,9H).

Step 8: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate:

the compound 4- ((S) -4- (tert-butyloxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 8-dihydropyrido [3, 4-d) ]Pyrimidine-7 (6H) -carboxylic acid benzyl ester (13.5 g,22.29 mmol) was dissolved in methanol (150 mL) and methanolic ammonia (6M, 4 mL), 10% wet Pd/C (1.35 g) was added under nitrogen to replace hydrogen and the reaction was stirred at room temperature for 5 hours. After the reaction was completed, it was filtered through celite, and washed with methanol, and the methanol phase was collected and concentrated to give an off-white solid. (10.5 g, yield: 99%). ¹ H NMR(400MHz,CDCl ₃ )δ4.58(s,1H),4.34(dd,J＝10.5,5.0Hz,1H),4.11(dd,J＝10.5,6.9Hz,1H),3.95(d,J＝9.7Hz,3H),3.83(d,J＝12.8Hz,1H),3.20(dd,J＝13.7,3.7Hz,2H),3.09(dd,J＝15.1,9.9Hz,2H),3.02-2.87(m,2H),2.81-2.51(m,5H),2.47(s,3H),2.32-2.21(m,1H),2.05(s,1H),1.86-1.63(m,7H),1.50(s,9H).

Step 9: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate:

the compound (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (100 mg,0.21 mmol) and 5-bromo-1, 2,3, 4-tetrahydronaphthalene (54 mg,0.25 mmol) were dissolved in anhydrous toluene (5 mL), cesium carbonate (173 mg,0.53 mmol), ruPhos (20 mg,0.04 mmol) and Pd were added ₂ (dba) ₃ (39 mg,0.04 mmol), nitrogen was replaced three times, heated to 100℃and stirred for reaction for 12 hours. After the reaction, cooling to room temperature, diluting the reaction solution with ethyl acetate, filtering, concentrating the filtrate, and separating by column chromatography to obtain an off-white solid. (63 mg, yield: 49.4%). ¹ H NMR(400MHz,CDCl ₃ )δ7.12(t,J＝7.7Hz,2H),6.90(t,J＝7.3Hz,2H),4.67-4.52(m,2H),4.20-3.97(m,4H),3.96-3.84(m,2H),3.35- 2.95(m,7H),2.92-2.63(m,10H),2.35-2.10(m,3H),2.10-1.86(m,3H),1.80(dt,J＝12.2,7.1Hz,4H),1.51(s,9H).

Step 10: synthesis of 2- ((S) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

The compound (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (60 mg,0.10 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added and the reaction stirred at room temperature for 1 hour. After the completion of the reaction, the reaction solution was concentrated, and the obtained residue was added with a saturated sodium hydrogencarbonate solution and methylene chloride, followed by extraction with methylene chloride, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product which was directly used in the next step. (50 mg, yield: 100%)

Step 11: synthesis of 2- ((S) -1-propenoyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

The compound 2- ((S) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (50 mg,0.10 mmol) was dissolved in dichloromethane (3 mL), DIEA (16 mg,0.12 mmol) was added under ice-water bath cooling, followed by acryloyl chloride (12 mg,0.13 mmol) and the reaction stirred under ice-water bath for 10 min. After the completion of the reaction, the reaction was quenched with saturated sodium bicarbonate, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane/methanol=15/1) to give an off-white solid. ¹ H NMR(400MHz,CDCl ₃ )δ7.12(t,J＝7.7Hz,2H),6.91(t,J＝7.3Hz,2H),6.66-6.56(m,1H),6.36(d,J＝16.7Hz,1H),5.80(d,J＝10.6Hz,1H),4.67-4.52(m,2H),4.20-3.97(m,4H),3.96-3.84(m,2H),3.35-2.95(m,7H),2.92-2.63(m,10H),2.35-2.10(m,3H),2.10-1.86(m,3H),1.80(dt,J＝12.2,7.1Hz,4H).MS m/z:556.59[M+H] ⁺ 。

Example 121: synthesis of 2- ((S) -1- (2-fluoroacryloyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

The compound was prepared by reacting the compound 2- ((S) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (50 mg,0.10 mmol) was dissolved in dichloromethane (3 mL), and 2-fluoroacrylic acid (14 mg,0.15 mmol), HATU (60 mg,0.15 mmol) and DIEA (20 mg,0.15 mmol) were added and the reaction stirred under ice-water bath cooling for 3 hours. After the reaction, the reaction mixture was diluted with normal water, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane/methanol=20/1) to give an off-white solid. (35 mg, yield: 61.21%). MS m/z 574.59[ M+H ]] ⁺ 。

Examples 122 to 166 were prepared by the methods of examples 120 and 121

Example 198: synthesis of 2- ((S) -1-propenoyl-4- (7- (1, 3-dioxoisoindolin-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

Step 1: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (7- (2- (4-methoxybenzyl) -1, 3-dioxoisoindolin-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

The compound (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (50 mg,0.11 mmol) and the compound 4-bromo-2- (4-methoxybenzyl) isoindoline-1, 3-dione (44 mg,0.13 mmol) were dissolved in anhydrous toluene (5 mL), cesium carbonate (87 mg,0.27 mmol), ruPhos (10 mg,0.02 mmol) and Pd2 (dba) 3 (10 mg,0.01 mmol) were added, nitrogen was replaced, and the reaction was stirred at 100℃for 3 hours. After the reaction was completed, cooled to room temperature and TLC separated to give a yellow solid. (78 mg, yield: 100%). ¹ H NMR(400MHz,CDCl ₃ )δ7.58(d,J＝7.9Hz,1H),7.41(d,J＝7.0Hz,1H),7.37(d,J＝8.7Hz,2H),7.19(d,J＝8.3Hz,1H),6.84(d,J＝8.7Hz,2H),4.77(s,2H),4.62(s,1H),4.34(s,2H),4.18-3.97(m,5H),3.80-3.71(m,4H),3.55-3.44(m,3H),3.31(d,J＝10.9Hz,3H),3.12-3.03(m,3H),2.94-2.90(m,2H),2.82-2.68(m,4H),2.24-2.20(m,1H),2.03-1.99(m,2H),1.52(s,9H).

Step 2: synthesis of 2- ((S) -4- (7- (1, 3-dioxoisoindolin-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

The compound (S) -2- (cyanomethyl) -4- (7- (2- (4-methoxybenzyl) -1, 3-dioxoisoindolin-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] ]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (78 mg,0.11 mmol) was dissolved in dichloromethane (3 mL), then trifluoroacetic acid/trifluoromethanesulfonic acid=2/1 (1.5 mL) and anisole (0.5 mL) were added and the reaction stirred at room temperature for 24 hours. After the reaction was completed, the reaction solution was slowly added dropwise to a cooled saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried over sodium sulfate and concentrated, and TLC separated (dichloromethane/methanol=10/1) to give a yellow solid. (12 mg, yield: 22%). MS m/z 517.53[ M+H ]] ⁺ .

Step 3: synthesis of 2- ((S) -1-propenoyl-4- (7- (1, 3-dioxoisoindolin-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

the compound 2- ((S) -4- (7- (1, 3-dioxoisoindolin-4-yl)) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (12 mg,0.02 mmol) was dissolved in dichloromethane (3 mL), DIEA (4 mg,0.02 mmol) was added under ice-water bath cooling, followed by dropwise addition of a dichloromethane solution (1 mL) of acryloyl chloride, and the reaction was stirred under ice-water bath for 10 minutes. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by TLC ((dichloromethane/methanol=10/1) to give a yellow solid (8 mg, yield: 60%). MS m/z:571.27[ m+h ] ⁺ .

The compounds of examples 199-200 were prepared by the method of example 198

Example 201: synthesis of 2- ((S) -1- (2-fluoroacryloyl) -4- (7- (1-methyl-1, 2,3, 4-tetrahydroquinolin-8-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

step 1: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (7- (1-methyl-1, 2,3, 4-tetrahydroquinolin-8-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate:

the compound (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (100 mg,0.21 mmol) and 8-bromo-1-methyl-1, 2,3, 4-tetrahydroquinoline (72 mg,0.32 mmol) were dissolved in anhydrous toluene (5 mL), cesium carbonate (173 mg,0.53 mmol), xantPhos (20 mg,0.04 mmol) and Pd were added ₂ (dba) ₃ (39 mg,0.04 mmol), nitrogen was replaced three times, heated to 100℃and stirred for reaction for 12 hours. After the reaction is finished, cooling toThe reaction solution was diluted with ethyl acetate at room temperature, filtered, and the filtrate was concentrated and separated by column chromatography (dichloromethane/methanol=30/1) to give an off-white solid. (70 mg, yield: 53.5%)

Step 2: synthesis of 2- ((S) -4- (7- (1-methyl-1, 2,3, 4-tetrahydroquinolin-8-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

the compound (S) -2- (cyanomethyl) -4- (7- (1-methyl-1, 2,3, 4-tetrahydroquinolin-8-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (70 mg,0.11 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added and the reaction stirred at room temperature for 1 hour. After the completion of the reaction, the reaction solution was concentrated, and the obtained residue was added with a saturated sodium hydrogencarbonate solution and methylene chloride, followed by extraction with methylene chloride, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product which was directly used in the next step. (56 mg, yield: 95%)

Step 3: synthesis of 2- ((S) -1- (2-fluoroacryloyl) -4- (7- (1-methyl-1, 2,3, 4-tetrahydroquinolin-8-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

the compound 2- ((S) -4- (7- (1-methyl-1, 2,3, 4-tetrahydroquinolin-8-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d) ]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (56 mg,0.11 mmol) was dissolved in dichloromethane (5 mL), 2-fluoroacrylic acid (15 mg,0.16 mmol), HATU (61 mg,0.16 mmol) and DIEA (21 mg,0.16 mmol) were added and the reaction stirred under ice water bath cooling for 3 h. After the reaction, the reaction mixture was diluted with normal water, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane/methanol=20/1) to give an off-white solid. (25 mg, yield: 39%). ¹ H NMR(400MHz,CDCl ₃ )δ6.45-6.35(m,1H),6.27(dt,J＝14.6,3.4Hz,2H),5.42(d,J＝45.1Hz,1H),5.25(d,J＝16.8Hz,1H),5.02-4.93(m,2H),4.61(s,1H),4.31(p,J＝14.7Hz,1H),4.04-3.87(m,2H),3.81-3.44(m,4H),3.44-3.29(m,4H),3.29-3.19(m,2H),3.15-3.03(m,3H),2.95(dq,J＝17.1,9.2Hz,1H),2.87-2.68(m,6H),2.53-2.29(m,2H),2.26(s,3H),2.07-1.87(m,2H),1.78-1.38(m,4H)；MS m/z:589.34[M+H] ⁺ 。

Examples 202 to 250 were prepared by the method of example 201

Example 251: synthesis of 2- ((S) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile:

step 1: synthesis of 1-tert-butyl 4-ethyl 5-amino-3, 6-dihydro-2H-pyridine-1, 4-dicarboxylic acid:

the compound 1-tert-butyl 4-ethyl 3-oxopiperidine-1, 4-carboxylate (20 g,73.72 mmol) was dissolved in an ethanol solution of ammonia (2M, 80mL,160 mmol), heated to 60℃and stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to give a yellow solid. (19 g, yield 95%). MS (ES+): M/z=271 (M+1).

Step 2: synthesis of 1-tert-butyl 4-ethyl 5- (2-methoxycarbonyl-acetamido) -3, 6-dihydro-2H-pyridine-1, 4-dicarboxylic acid:

The compound 5-amino-3, 6-dihydro-2H-pyridine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (19 g,70.28 mmol) was dissolved in dichloromethane (150 mL), triethylamine (10.78 mL,77.31 mmol) was added, methyl 3-chloro-3-oxopropionate (10.56 g,77.31 mmol) was added dropwise under ice-water bath cooling, and after the addition was completed, the mixture was naturally warmed to room temperature and stirred for 12 hours. After the reaction, the reaction mixture was diluted with water, extracted with methylene chloride, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid which was used directly in the next step. (26 g, yield: 100%). MS (ES-): M/z=369 (M-1).

Step 3: synthesis of 7-tert-butyl 3-methyl 2, 4-dihydroxy-5, 8-dihydro-1, 7-naphthyridine-3, 7 (6H) -dicarboxylate:

the compound 5- (2-methoxycarbonyl-acetamido) -3, 6-dihydro-2H-pyridine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (26 g,70.19 mmol) was dissolved in anhydrous methanol (100 mL), 30% sodium methoxide methanol solution (63.20 g,350.97 mmol) was added, and the mixture was heated under reflux under nitrogen atmosphere for 3 hours. Cooling to room temperature after the reaction is finished, concentrating the reaction solution, and then adding iceDissolving in water, adjusting pH to 5-6 with glacial acetic acid, precipitating solid, filtering, washing the filter cake with water, and vacuum drying to obtain white solid. (13.7 g, 60%). ¹ H NMR(400MHz,DMSO)δ4.26(s,2H),3.81(s,3H),3.52(t,J＝5.56Hz,2H),2.38(t,J＝5.56Hz,2H),1.41(s,9H)

Step 4: synthesis of 5,6,7, 8-tetrahydro-1, 7-naphthyridine-2, 4-diol hydrochloride

The compound 2, 4-dihydroxy-5, 8-dihydro-1, 7-naphthyridine-3, 7 (6H) -dicarboxylic acid 7-tert-butyl 3-methyl ester (5 g,15.42 mmol) was dissolved in concentrated hydrochloric acid (20 mL) and heated to reflux for 12 hours. After the reaction was completed, cooled to room temperature, and concentrated to give an off-white solid which was used directly in the next step. (3.12 g, yield: 100%). ¹ H NMR(400MHz,DMSO)δ12.38(s,1H),9.76(s,2H),6.25(s,1H),4.10(s,2H),3.30(s,2H),2.62(t,J＝5.8Hz,2H).

Step 5: synthesis of benzyl 2, 4-dihydroxy-5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylate:

5,6,7, 8-tetrahydro-1, 7-naphthyridine-2, 4-diol hydrochloride (3.12 g,15.42 mmol) was dissolved in dichloromethane (100 mL), triethylamine (6.44 mL,46.21 mmol) was added, benzyloxycarbonyl chloride (3.94 g,23.11 mmol) was added dropwise under ice water bath cooling, and after the dropwise addition was completed, stirring was carried out at room temperature overnight. After the completion of the reaction, the mixture was concentrated, and the residue was dissolved in methanol (50 mL), followed by addition of potassium carbonate (6.37 g,46.21 mmol) and stirring at room temperature for 2 hours. Concentrating the reaction solution, adding water to dissolve the residue, adding glacial acetic acid to adjust the pH to 5-6, separating out solid, and filtering to obtain white solid. (3.1 g, yield: 67%). ¹ H NMR(400MHz,DMSO)δ12.01(s,2H),7.37(t,J＝9.5Hz,5H),6.12(d,J＝15.4Hz,1H),5.13(s,2H),4.43(s,3H),2.44(s,2H).

Step 6: synthesis of benzyl 2, 4-bis (((trifluoromethyl) sulfonyl) oxy) -5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylate:

benzyl 2, 4-dihydroxy-5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylate (1.0 g,3.33 mmol) was dissolved in anhydrous dichloromethane (15 mL), triethylamine (0.74 g,7.33 mmol) was added under cooling in an ice-water bath, and then trifluoromethanesulfonic anhydride (1.97 g,6.99 mmol) was added dropwise, and the reaction was stirred under cooling in an ice-water bath for 30 minutes. After the reaction was completed, the reaction mixture was diluted with methylene chloride, and the organic phase was washed with 1M hydrochloric acid and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated to give a brown oil which was used directly in the next step. (1.88 g, yield: 100%)

Step 7: synthesis of benzyl (S) -4- (4- (tert-butyloxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((trifluoromethyl) sulfonyl) oxy) -5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylate:

benzyl 2, 4-bis (((trifluoromethyl) sulfonyl) oxy) -5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylate (1.88 g,3.33 mmol) was dissolved in anhydrous acetonitrile (20 mL), triethylamine (405 mg,4.00 mmol) was added with cooling in an ice water bath, and tert-butyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (751 mg,3.33 mmol) was then added and the reaction stirred at room temperature for 12 hours. After the reaction, ethyl acetate was added to dilute the reaction solution, the mixture was washed with water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give an off-white solid. (1.05 g, 49%)

Step 8: synthesis of benzyl 4- ((S) -4- (tert-butyloxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylate:

the compound (S) -4- (4- (tert-butyloxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((trifluoromethyl) sulfonyl) oxy) -5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylic acid benzyl ester (1.05 g,1.64 mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (284 mg,2.46 mmol) were dissolved in dry toluene (15 mL), sodium tert-butoxide (284 mg,4.10 mmol), BINAP (103 mg,0.16 mmol) and palladium acetate (37 mg,0.16 mmol) were added, nitrogen was replaced, and the reaction was heated to 80 ℃ under nitrogen atmosphere with stirring for 8 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane/methanol=10/1) to give an off-white solid. (850 mg, yield: 86%).

Step 9: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) piperazine-1-carboxylate:

the compound 4- ((S) -4- (tert-butyloxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylic acid benzyl ester (850 mg,1.41 mmol) was dissolved in methanol (50 mL) and methanolic ammonia solution (2 m,1 mL), 10% wet Pd/C (100 mg) was added under nitrogen atmosphere to displace hydrogen, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, pd/C was removed by filtration, washed with methanol, and the organic phase was concentrated to give an off-white solid. (650 mg, yield: 98%).

Step 10: synthesis of tert-butyl (S) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate:

the compound (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (100 mg,0.21 mmol) and 1-bromo-8-chloronaphthalene (77 mg,0.32 mmol) were dissolved in anhydrous toluene (3 mL), cesium carbonate (173 mg,0.53 mmol), ruPhos (20 mg,0.04 mmol) and Pd were added ₂ (dba) ₃ (37 mg,0.04 mmol), nitrogen was replaced 3 times, and the reaction was stirred under nitrogen atmosphere at 100℃for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, the insoluble matter was removed by filtration, and the organic phase was concentrated and separated by column chromatography (dichloromethane/methanol=20/1) to give a brown solid. (50 mg, yield: 37%)

Step 11: synthesis of 2- ((S) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) piperazin-2-yl) acetonitrile:

the compound (S) -tert-butyl 4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (50 mg,0.08 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added and the reaction stirred at room temperature for 1 hour. After the reaction, the reaction mixture was concentrated, the residue was dissolved in methylene chloride, washed with saturated sodium hydrogencarbonate and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated to give a crude product which was used directly in the next step. (40 mg, yield: 95%)

Step 12: synthesis of 2- ((S) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile

Compound 2- ((S) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) piperazin-2-yl) acetonitrile (40 mg,0.07 mmol) and 2-fluoroacrylic acid (10 mg,0.11 mmol) were dissolved in dichloromethane, HATU (42 mg,0.11 mmol) and DIEA (15 mg,0.11 mmol) were added and the reaction stirred at room temperature for 3 hours. After the completion of the reaction, the reaction was quenched with water, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane/methanol=10/1) to give an off-white solid. (21 mg, yield: 46%). ¹ H NMR(400MHz,CDCl ₃ )δ7.66(dt,J＝14.9,3.0Hz,1H),7.60-7.38(m,4H),7.31(t,J＝14.9Hz,1H),5.90(s,1H),5.23(d,J＝30.6Hz,1H),5.06(dd,J＝13.4,4.2Hz,1H),5.00-4.97(m,1H),4.19-3.96(m,2H),3.89(dd,J＝24.7,14.9Hz,1H),3.73-3.32(m,7H),3.29-3.19(m,2H),3.09(t,J＝11.2Hz,2H),3.02-2.88(m,1H),2.86-2.69(m,1H),2.58(dd,J＝24.8,6.5Hz,1H),2.39(dt,J＝24.6,14.1Hz,1H),2.26(s,3H),1.79-1.32(m,4H)；MS m/z:603.2[M+H] ⁺ 。

Examples 252 to 301 were prepared by the method of example 251

Example 302: synthesis of 7- (8-chloronaphthalen-1-yl) -4- ((S) -3- (cyanomethyl) -4- (2-fluoroacryloyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-1, 7-naphthyridine-3-methyl)

Step 1: synthesis of 1-tert-butyl 4-ethyl 5- (2-cyanoacetamido) -3, 6-dihydropyridine-1, 4 (2H) -dicarboxylate:

the compound 5-amino-3, 6-dihydro-2H-pyridine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (15 g,55.49 mmol) was dissolved in dichloromethane (150 mL), triethylamine (8.51 mL,61.04 mmol) was added, 2-cyanoacetyl chloride (6.32 g,61.04 mmol) was added dropwise under ice-water bath cooling, and after the addition was completed, the reaction was allowed to spontaneously warm to room temperature and stirred for 12 hours. After the reaction, the reaction mixture was diluted with water, extracted with methylene chloride, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid which was used directly in the next step. (18.72 g, yield: 100%). ¹ HNMR(400MHz,CDCl ₃ )δ12.14(s,1H),4.74(s,2H),4.25(q,J＝7.1Hz,2H),3.59-3.41(m,4H),2.45(s,2H),1.47(s,9H),1.31(t,J＝7.1Hz,3H).

Step 2: synthesis of 3-cyano-2, 4-hydroxy-5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylic acid tert-butyl ester:

the compound 5- (2-cyanoacetamido) -3, 6-dihydropyridine-1, 4 (2H) -dicarboxylic acid 1-tert-butyl 4-ethyl ester (3.0 g,8.89 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), 60% NaH (1.42 g,35.57 mmol) was added in portions with ice-water bath cooling, and then heated to 70℃for 6 hours. After the reaction was completed, saturated ammonium chloride was added under cooling in an ice-water bath to quench the reaction, extraction was performed with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane/methanol=50/1) to obtain a yellow solid. (1.7 g, yield: 66%). ¹ HNMR(400MHz,DMSO)δ12.18(s,1H),11.72(s,1H),4.26(s,2H),3.49(s,3H),2.37(s,2H),1.41(s,9H).

Step 3: synthesis of 2, 4-hydroxy-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-3-carbonitrile:

the compound 3-cyano-2, 4-hydroxy-5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylic acid tert-butyl ester (1.7 g,5.84 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (6 mL) was added and the reaction stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated to give a brown oil which was used directly in the next step. (1.12 g, yield: 100%)

Step 4: synthesis of benzyl 3-cyano-2, 4-hydroxy-5, 8-hydrogen-1, 7-naphthyridine-7 (6H) -carboxylate:

the compound 2, 4-hydroxy-5, 6,7, 8-tetrahydro-1, 7-naphthyridine-3-carbonitrile (1.12 g,5.84 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), triethylamine (1.78 g,17.57 mmol) was added, benzyloxycarbonyl chloride (1.10 g,6.44 mmol) was added dropwise under cooling in an ice water bath, and the reaction was stirred at room temperature for 12 hours. After the completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography (dichloromethane/methanol=50/1) to give an off-white solid. (1.53 g, yield: 80%)

Step 5: synthesis of benzyl 3-cyano-2, 4-bis (((trifluoromethyl) sulfonyl) oxy) -5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylate:

benzyl 3-cyano-2, 4-hydroxy-5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylate (1.53 g,4.70 mmol) was dissolved in dichloromethane (20 mL), triethylamine (514 mg,7.05 mmol) and trifluoromethanesulfonic anhydride (1.46 g,5.17 mmol) were added under ice-water bath cooling, and the reaction was stirred under ice-water bath for 30 minutes. After the reaction, the reaction solution was concentrated and used directly in the next step. (2.77 g, yield: 100%)

Step 6: (S) -4- (4- (tert-Butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -3-cyano-2- (((trifluoromethyl) sulfonyl) oxy) -5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylic acid benzyl ester was synthesized:

the compound 3-cyano-2, 4-bis (((trifluoromethyl) sulfonyl) oxy) -5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylic acid benzyl ester (2.77 g,4.70 mmol) was dissolved in anhydrous acetonitrile (30 mL), triethylamine (571 mg,6.64 mmol) was added with ice water bath cooling, and then tert-butyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (1.06 mg,4.70 mmol) was added and the reaction stirred for 12 hours at room temperature. After the reaction, ethyl acetate was added to dilute the reaction solution, the mixture was washed with water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give an off-white solid (dichloromethane/methanol=50/1). (1.32 g, 42%)

Step 7:4- ((S) -4- (tert-butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -3-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylic acid benzyl ester was synthesized:

the compound (S) -4- (4- (tert-butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -3-cyano-2- (((trifluoromethyl) sulfonyl) oxy) -5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylic acid benzyl ester (1.32 g,1.99 mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (349 mg,2.98 mmol) were dissolved in dry toluene (15 mL), sodium tert-butoxide (477 mg,4.96 mmol), BINAP (125 mg,0.20 mmol) and palladium acetate (45 mg,0.20 mmol) were added, nitrogen was replaced, and the reaction was heated to 80 ℃ under nitrogen atmosphere with stirring for 8 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane/methanol=20/1) to give an off-white solid. (1.1 g, yield: 87%).

Step 8: synthesis of tert-butyl (S) -4- (3-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate:

the compound 4- ((S) -4- (tert-butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -3-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylic acid benzyl ester (1.1 g,1.75 mmol) was dissolved in methanol (50 mL) and methanolic ammonia solution (2 m,2 mL), 10% wet Pd/C (110 mg) was added under nitrogen atmosphere to displace hydrogen, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, pd/C was removed by filtration, washed with methanol, and the organic phase was concentrated to give an off-white solid. (850 mg, yield: 98%).

Step 9: synthesis of tert-butyl (S) -4- (7- (8-chloronaphthalen-1-yl) -3-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate:

the compound (S) -4- (3-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (100 mg,0.20 mmol) and 1-bromo-8-chloronaphthalene (73 mg,0.30 mmol) were dissolved in anhydrous toluene (5 mL), cesium carbonate (165 mg,0.50 mmol), ruPhos (20 mg,0.04 mmol) and Pd were added ₂ (dba) ₃ (37 mg,0.04 mmol), nitrogen was replaced 3 times, and the reaction was stirred under nitrogen atmosphere at 100℃for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, the insoluble matter was removed by filtration, and the organic phase was concentrated and separated by column chromatography (dichloromethane/methanol=20/1) to give a brown solid. (60 mg, yield: 45%)

Step 10: synthesis of 7- (8-chloronaphthalen-1-yl) -4- ((S) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-1, 7-naphthyridine-3-carbonitrile:

the compound (S) -tert-butyl 4- (7- (8-chloronaphthalen-1-yl) -3-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (60 mg,0.09 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added and the reaction stirred at room temperature for 1 hour. After the reaction, the reaction mixture was concentrated, the residue was dissolved in methylene chloride, washed with saturated sodium hydrogencarbonate and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated to give a crude product which was used directly in the next step. (46 mg, yield: 90%)

Step 11: synthesis of 7- (8-chloronaphthalen-1-yl) -4- ((S) -3- (cyanomethyl) -4- (2-fluoroacryloyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-1, 7-naphthyridine-3-methyl)

The compound 7- (8-chloronaphthalen-1-yl) -4- ((S) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-1, 7-naphthyridine-3-carbonitrile (46 mg,0.08 mmol) and 2-fluoroacrylic acid (11 mg,0.12 mmol) were dissolved in dichloromethane, HATU (43 mg,0.12 mmol) and DIEA (16 mg,0.12 mmol) were added and the reaction was stirred at room temperature for 3 hours. After the completion of the reaction, the reaction was quenched with water, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane/methanol=10/1) to give an off-white solid. (21 mg, yield: 46%). ¹ H NMR(400MHz,CDCl ₃ )δ7.66(dt,J＝14.8,3.0Hz,1H),7.61-7.51(m,1H),7.51-7.39(m,3H),7.31(t,J＝14.9Hz,1H),5.30-5.17(m,2H),5.11-4.97(m,2H),4.39(p,J＝14.2Hz,1H),4.09-3.94(m,2H),3.84-3.32(m,6H),3.30-2.89(m,6H),2.79(dt,J＝24.9,13.1Hz,1H),2.52-2.30(m,2H),2.26(s,3H),1.82-1.64(m,1H),1.61-1.35(m,3H)；MS m/z:628.2[M+H] ⁺ 。

Application of the preparation method of example 302 to prepare examples 303 to 375

Example 376: synthesis of 2- ((S) -1-propenoyl-4- (3- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6) - (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydro-2, 6-naphthyridin-1-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of benzyl (S) -7-chloro-5- (3- (cyanomethyl) piperazin-1-yl) -3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylate

To a solution of (S) -2- (piperazin-2-yl) acetonitrile (557 mg,4.45 mmol) in N, N-dimethylformamide (25 mL) was added sodium hydride (178 mg,4.45 mmol) in an ice-water bath. The reaction was stirred in an ice-water bath for 30 minutes, and benzyl 5, 7-dichloro-3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylate (1.5 g,4.45 mmol) was added. The reaction solution was stirred at 60℃for 12 hours. After cooling to room temperature, the reaction solution was used directly in the next step. MS m/z 426.2[ M+H ] +.

Step 2: synthesis of benzyl (S) -5- (4- (tert-butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -7-chloro-3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylate

To a crude solution of benzyl (S) -7-chloro-5- (3- (cyanomethyl) piperazin-1-yl) -3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylate was added di-tert-butyl dicarbonate (970 mg,4.45 mmol) at room temperature. The reaction solution was stirred at room temperature for 1 hour. Ethyl acetate (150 mL) and saturated aqueous ammonium chloride (50 mL) were added and stirred vigorously for 20 minutes. The mixture was separated, and the organic phase was washed with water (30 mL. Times.3), saturated brine (30 mL) and dried over sodium sulfate. After spin-drying under reduced pressure, the residue was purified by column chromatography (silica gel, ethyl acetate: petroleum ether=1:5) to give a light brown viscous material. (880 mg, overall yield in two steps: 38%) MS m/z:526.2[ M+H ] +.

Step 3: synthesis of benzyl 5- ((S) -4- (tert-butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -7- ((S) -1-methylpyrrolidin-2-yl) methoxy) -3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylate

To the reaction flask were added benzyl (S) -5- (4- (tert-butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -7-chloro-3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylate (880 mg,1.67 mmol), (S) - (1-methylpyrrolidin-2-yl) methanol (385 mg,3.34 mmol), tris (dibenzylideneacetone) dipalladium (15 mg,0.0167 mmol), 2-di-tert-butylphosphine-2 ',4',6 '-triisopropyl-3, 6-dimethoxy-1, 1' -biphenyl (16 mg,0.0334 mmol) and sodium tert-butoxide (321 mg,3.34 mmol). After argon was replaced, pre-deoxygenated anhydrous toluene (15 mL) was added. The reaction solution was heated at 110℃for 16 hours. After cooling to room temperature, ethyl acetate (50 mL) and water (50 mL) were added, shaken and separated. The organic phase was washed with saturated brine (10 mL), dried over sodium sulfate, and spun dry under reduced pressure. The residue was purified by column chromatography (silica gel, methanol: dichloromethane=1:12) to give a pale brown viscous material. (330 mg, yield: 33%) MS m/z 605.3[ M+H ] +.

Step 4: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (3- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-2, 6-naphthyridin-1-yl) piperazine-1-carboxylate

A suspension of benzyl 5- ((S) -4- (tert-butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -7- ((S) -1-methylpyrrolidin-2-yl) methoxy) -3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylate (171 mg,0.282 mmol) and palladium on carbon (300 mg,0.0282 mmol) in ethyl acetate (3 mL) and tetrahydrofuran (3 mL) was stirred under an atmosphere of hydrogen (balloon) for 6 hours. The solids were filtered off and the filter cake was rinsed with ethyl acetate. The filtrates were combined and evaporated under reduced pressure to give a grey dope. (108 mg, yield: 81%) MS m/z:471.3[ M+H ] +.

Step 5: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (3- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydro-2, 6-naphthyridin-1-yl) piperazine-1-carboxylate

To the reaction flask was added (S) -2- (cyanomethyl) -4- (3- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-2, 6-naphthyridin-1-yl) piperazine-1-carboxylic acid tert-butyl ester (108 mg,0.228 mmol), 5-bromo-1, 2,3, 4-tetrahydronaphthalene (72 mg, 0.348 mmol), tris (dibenzylideneacetone) dipalladium (23 mg,0.025 mmol), 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl (24 mg,0.05 mmol) and cesium carbonate (147 mg,0.45 mmol). After argon was replaced, pre-deoxygenated anhydrous toluene (4 mL) was added. The reaction solution was heated at 110℃for 16 hours. After cooling to room temperature, ethyl acetate (30 mL) and water (15 mL) were added, shaken and separated. The organic phase was washed with saturated brine (10 mL), dried over sodium sulfate, and spun dry under reduced pressure. The residue was purified by column chromatography (silica gel, methanol: dichloromethane=1:10) to give a pale brown viscous material. (80 mg, yield: 58%) MS m/z:601.4[ M+H ] +.

Step 6: synthesis of 2- ((S) -4- (3- ((S) -1-methylpyrrolidin-2-yl) methoxy) -6- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydro-2, 6-naphthyridin-1-yl) piperazin-2-yl) acetonitrile

To a solution of tert-butyl (S) -2- (cyanomethyl) -4- (3- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydro-2, 6-naphthyridin-1-yl) piperazine-1-carboxylate (80 mg,0.133 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) in an ice-water bath. The resulting solution was stirred at room temperature for 3 hours. The reaction solution was dried under reduced pressure to give a white viscous material which was used directly in the next reaction. MS m/z 501.3[ M+H ] +.

Step 7: synthesis of 2- ((S) -1-propenoyl-4- (3- ((S) -1-methylpyrrolidin-2-yl) methoxy) -6- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydro-2, 6-naphthyridin-1-yl) piperazin-2-yl) acetonitrile

To a solution of- ((S) -4- (3- ((S) -1-methylpyrrolidin-2-yl) methoxy) -6- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydro-2, 6-naphthyridin-1-yl) piperazin-2-yl) acetonitrile (crude) and triethylamine (119 mg,1.18 mmol) in dichloromethane (10 mL) was slowly dropped a solution of acryloyl chloride (33 mg,0.36 mmol) in dichloromethane (1 mL) in an ice-water bath. The ice-water bath was removed, and the reaction solution was stirred at room temperature for 15 minutes. The residue was purified by preparative TLC (methanol: dichloromethane=1:10) under reduced pressure to give a pale yellow solid. (15 mg, two-step total yield: 20%) ¹ H NMR(400MHz,CDCl3)δ7.12(t,J＝7.7Hz,2H),6.91(t,J＝7.3Hz,2H),6.66-6.56(m,1H),6.45(s,1H),6.36(d,J＝16.7Hz,1H),5.80(d,J＝10.6Hz,1H),4.67-4.52(m,2H),4.20-3.97(m,4H),3.96-3.84(m,2H),3.35-2.95(m,7H),2.92-2.63(m,10H),2.35-2.10(m,3H),2.10-1.86(m,3H),1.80(dt,J＝12.2,7.1Hz,4H).MS m/z:555.34[M+H]+。

The compounds of examples 377-428 were prepared by the method of example 376

Example 429: synthesis of 2- ((2S) -4- (4- (2, 4-dimethylpyridin-3-yl) -6- (1-methyl-1, 2,3, 4-tetrahydroquinolin-8-yl) -3- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-2, 6-naphthyridin-1-yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile

Step 1: synthesis of benzyl 5- ((S) -4- (tert-butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -8-iodo-7- ((S) -1-methylpyrrolidin-2-yl) methoxy) -3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylate

To a solution of benzyl 5- ((S) -4- (tert-butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -7- ((S) -1-methylpyrrolidin-2-yl) methoxy) -3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylate (330 mg, 0.540 mmol) in N, N-dimethylformamide (5 mL) was added nitrogen-iodosuccinimide (149 mg,0.66 mmol) at room temperature. The reaction solution was stirred at room temperature for 12 hours. Ethyl acetate (50 mL) and saturated aqueous sodium carbonate (20 mL) were added. After shaking and delamination, the organic phase was washed with saturated aqueous sodium sulfite (10 mL), water (10 mL. Times.2), saturated brine (10 mL), dried over sodium sulfate and spun-dried under reduced pressure to give a yellow dope, which was used directly in the next step. (280 mg, yield: 70%) MS m/z 730.7[ M+H ] +.

Step 2: synthesis of benzyl 5- ((S) -4- (tert-butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -8- (2, 4-dimethylpyridin-3-yl) -7- ((S) -1-methylpyrrolidin-2-yl) methoxy) -3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylate

To the reaction flask was added benzyl 5- ((S) -4- (tert-butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -8-iodo-7- ((S) -1-methylpyrrolidin-2-yl) methoxy) -3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylate (280 mg,0.383 mmol), (2, 4-dimethylpyridin-3-yl) boronic acid (116 mg,0.766 mmol), 1-bis (diphenylphosphino) ferrocene palladium dichloride (28 mg,0.038 mmol) and potassium phosphate (163 mg,0.766 mmol). After nitrogen substitution, pre-deoxygenated 1, 4-dioxane (8 mL) and water (2 mL) were added. The reaction solution was stirred at 80℃for 4 hours. Ethyl acetate (50 mL) and water (20 mL) were added. After shaking and delamination, the organic phase was washed with saturated aqueous sodium carbonate (10 mL), saturated aqueous sodium chloride (10 mL), dried over sodium sulfate, and spun-dried under reduced pressure. The residue was purified by column chromatography (silica gel, methanol: dichloromethane=1:10) to give a white solid. (200 mg, yield: 74%) MS m/z:709.9[ M+H ] +.

Step 3: synthesis of tert-butyl (2S) -2- (cyanomethyl) -4- (4- (2, 4-dimethylpyridin-3-yl) -3- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-2, 6-naphthyridin-1-yl) piperazine-1-carboxylate

A suspension of benzyl 5- ((S) -4- (tert-butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -8- (2, 4-dimethylpyridin-3-yl) -7- ((S) -1-methylpyrrolidin-2-yl) methoxy) -3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylate (200 mg,0.282 mmol) and palladium on carbon (300 mg,0.0282 mmol) in ethyl acetate (4 mL) and tetrahydrofuran (4 mL) was stirred under an atmosphere of hydrogen (balloon) for 3 hours. The solids were filtered off and the filter cake was rinsed with ethyl acetate. The filtrates were combined and dried under reduced pressure to give a gray dope. (131 mg, yield: 81%) MS m/z:575.7[ M+H ] +.

Step 4: synthesis of tert-butyl (2S) -2- (cyanomethyl) -4- (4- (2, 4-dimethylpyridin-3-yl) -6- (1-methyl-1, 2,3, 4-tetrahydroquinolin-8-yl) -3- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-2, 6-naphthyridin-1-yl) piperazine-1-carboxylate

To the reaction flask was added (2S) -2- (cyanomethyl) -4- (4- (2, 4-dimethylpyridin-3-yl) -3- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-2, 6-naphthyridin-1-yl) piperazine-1-carboxylic acid tert-butyl ester (131 mg,0.228 mmol), 8-bromo-1-methyl-1, 2,3, 4-tetrahydroquinoline (77 mg, 0.348 mmol), tris (dibenzylideneacetone) dipalladium (23 mg,0.025 mmol), 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl (24 mg,0.05 mmol) and cesium carbonate (147 mg,0.45 mmol). After argon was replaced, pre-deoxygenated anhydrous toluene (4 mL) was added. The reaction solution was heated at 110℃for 16 hours. After cooling to room temperature, ethyl acetate (30 mL) and water (15 mL) were added, shaken and separated. The organic phase was washed with saturated brine (10 mL), dried over sodium sulfate, and spun dry under reduced pressure. The residue was purified by column chromatography (silica gel, methanol: dichloromethane=1:10) to give a pale brown viscous material. (28 mg, yield: 17%) MS m/z:721.0[ M+H ] +.

Step 5: synthesis of 2- ((2S) -4- (4- (2, 4-dimethylpyridin-3-yl) -6- (1-methyl-1, 2,3, 4-tetrahydroquinolin-8-yl) -3- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-2, 6-naphthyridin-1-yl) piperazin-2-yl) acetonitrile

To a solution of tert-butyl (2S) -2- (cyanomethyl) -4- (4- (2, 4-dimethylpyridin-3-yl) -6- (1-methyl-1, 2,3, 4-tetrahydroquinolin-8-yl) -3- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-2, 6-naphthyridin-1-yl) piperazine-1-carboxylate (28 mg,0.0388 mmol) in dichloromethane (3 mL) was slowly added trifluoroacetic acid (1 mL). The reaction solution was stirred at room temperature for 3 hours. Anhydrous dichloromethane (15 mL) was added for dilution and spin-drying under reduced pressure. The resulting pale yellow dope was used directly in the next step. (44 mg, yield: 100%) MS m/z:620.8[ M+H ] +.

Step 6: synthesis of 2- ((2S) -4- (4- (2, 4-dimethylpyridin-3-yl) -6- (1-methyl-1, 2,3, 4-tetrahydroquinolin-8-yl) -3- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-2, 6-naphthyridin-1-yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile

To a solution of 2- ((2S) -4- (4- (2, 4-dimethylpyridin-3-yl) -6- (1-methyl-1, 2,3, 4-tetrahydroquinolin-8-yl) -3- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydro-2, 6-naphthyridin-1-yl) piperazin-2-yl) acetonitrile (44 mg, crude) and 2-fluoroacrylic acid (7 mg,0.0776 mmol) in dichloromethane (5 mL) was added 2- (7-azabenzotriazol) -N, N' -tetramethylurea hexafluorophosphate (29 mg,0.075 mmol) and nitrogen, nitrogen-diisopropylethylamine (20 mg,0.155 mmol). The reaction solution was stirred at room temperature for 12 hours. Adding two Methyl chloride (30 mL), washed with saturated aqueous sodium bicarbonate (10 mL), saturated brine (10 mL), and dried over sodium sulfate. The residue obtained was dried by spin-drying under reduced pressure by TLC (methanol: dichloromethane=1:10) to give a yellow solid. (2 mg, yield: 7.4%) ¹ H NMR(400MHz,DMSO)δ8.49(d,J＝5.6Hz,1H),7.48(d,J＝5.6Hz,1H),6.40(t,J＝7.5Hz,1H),6.29-6.26(m,2H),5.44-5.26(m,2H),5.26(s,2H),5.18(d,J＝3.6,16.8Hz,1H),3.68-3.50(m,5H),3.37-3.32(m,3H),3.24-3.01(m,8H),3.03(s,3H),2.79-2.73(m,3H),2.75(s,3H),2.68(s,3H),2.46-2.32(m,3H),2.36(s,3H),1.94-1.91(m,2H),1.68-1.51(m,4H).MS m/z:692.9[M+H]+。

Examples 430 to 443 were prepared by the method of example 429

Example 444: synthesis of (8 aR, 11R) -10-acryloyl-3- (8-chloronaphthalen-1-yl) -7, 11-dimethyl-6- ((S) -1-methylpyrrolidin-2-yl) methoxy) -2,3,4,7,9,10,11,12-octahydro-1H-pyrazin [1',2:4,5] pyrazin [2,3-c ] [1,7] naphthyridin-8 (8 aH) -one

Step 1: synthesis of 4-hydroxy-5, 6,7, 8-tetrahydro-1, 7-naphthyridin-2 (1H) -one

7- (tert-butyl) ester 3-methyl 4-hydroxy-2-oxo-2, 5,6, 8-tetrahydro-1, 7-naphthyridine-3, 7 (1H) -dicarboxylate (3.0 g,9.26 mmol) with saltThe mixture of acids (2N, 60 mL) was heated at reflux for 24 hours. After cooling to room temperature, the reaction solution was used directly in the next step. MS m/z 166.1[ M+H ]] ⁺ 。

Step 2: synthesis of benzyl 4-hydroxy-2-oxo-2, 5,6, 8-tetrahydro-1, 7-naphthyridine-7 (1H) -carboxylate

Sodium hydroxide was added to a crude solution of 4-hydroxy-5, 6,7, 8-tetrahydro-1, 7-naphthyridin-2 (1H) -one in an ice-water bath to a pH of 11. Tetrahydrofuran (50 mL) was added. Benzyl chloroformate (1.57 g,9.26 mmol) was slowly dropped. The reaction solution was stirred at room temperature for 12 hours. Methanol (5 mL) was added and stirred for 30 min. Most of the tetrahydrofuran was removed by rotary evaporation. Hydrochloric acid (6N) was added to a pH of 2. The solid is collected by filtration, washed with water and dried to obtain pale yellow solid. (900 mg, yield: 32%) MS m/z:300.1[ M+H ] ] ⁺ 。

Step 3: synthesis of benzyl 4-hydroxy-3-nitro-2-oxo-2, 5,6, 8-tetrahydro-1, 7-naphthyridine-7 (1H) -carboxylate

A mixture of benzyl 4-hydroxy-2-oxo-2, 5,6, 8-tetrahydro-1, 7-naphthyridine-7 (1H) -carboxylate (900 mg,3 mmol) and concentrated sulfuric acid (5 mL) was vigorously stirred. Concentrated nitric acid (1 mL) was slowly added dropwise. After stirring for 5 hours, the reaction solution was slowly poured into ice water (200 mL). The solid was collected by filtration, washed with water (5 mL. Times.2), and dried to give an orange solid. (600 mg, yield: 58%) MS m/z:345.1[ M+H ]] ⁺ 。

Step 4: synthesis of benzyl 2, 4-dichloro-3-nitro-5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylate

A mixture of benzyl 4-hydroxy-3-nitro-2-oxo-2, 5,6, 8-tetrahydro-1, 7-naphthyridine-7 (1H) -carboxylate (600 mg,1.74 mmol) and phosphorus oxychloride (6 mL) was heated at 100℃for 6 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. Anhydrous toluene (10 mL) was added and the process was repeated twice. The yellow dope obtained was used directly in the next step. (600 mg, crude) MS m/z 381.0[ M+H ]] ⁺ 。

Step 5: synthesis of 1- (tert-butyl) 3-methyl (3R, 6R) -4- (7- ((phenoxy) carbonyl) -2-chloro-3-nitro-5, 6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) -6-methylpiperazine-1, 3-dicarboxylate

To benzyl 2, 4-dichloro-3-nitro-5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylate (600 mg, crude product) ) To a solution of tetrahydrofuran (20 mL) was added nitrogen, diisopropylethylamine (774 mg,6.0 mmol) and (3R, 6R) -6-methylpiperazine-1, 3-dicarboxylic acid 1- (tert-butyl) ester 3-methyl ester (539 mg,2.09 mmol). The reaction solution was heated at 65℃for 2 hours. After cooling to room temperature, ethyl acetate (100 mL) and saturated aqueous ammonium chloride (50 mL) were added. After shaking, delamination, the organic phase was washed with saturated brine (50 mL), dried over sodium sulfate and spun dry under reduced pressure to a yellow viscous mass and used directly in the next step. (300 mg, overall yield of two steps: 29%) MS m/z 602.3[ M+H ]] ⁺ 。

Step 6: synthesis of 3R, 6R) -4- (7- ((phenoxy) carbonyl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -3-nitro-5, 6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) -6-methylpiperazine-1, 3-dicarboxylic acid 1- (tert-butyl) ester 3-methyl (ester

To a solution of (3R, 6R) -4- (7- ((phenoxy) carbonyl) -2-chloro-3-nitro-5, 6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) -6-methylpiperazine-1, 3-dicarboxylic acid 1- (tert-butyl) ester 3-methyl ester (300 mg,0.5 mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (58 mg,0.5 mmol) in N, N-dimethylformamide (4 mL) was added nitrogen, nitrogen-diisopropylethylamine (129 mg,1.0 mmol). The reaction solution was heated at 80℃for 12 hours. Ethyl acetate (50 mL) and saturated aqueous sodium carbonate (30 mL) were added. After shaking and delamination, the organic phase was washed with water (10 mL. Times.3), saturated brine (10 mL), dried over sodium sulfate, and spun dry under reduced pressure. The residue was purified by column chromatography (silica gel, methanol: dichloromethane=1:10) to give a yellow solid. (290 mg, yield: 85%) MS m/z 682.3[ M+H ] ] ⁺ 。

Step 7: synthesis of 3-benzyl 10- (tert-butyl) ester of 3-benzyl (8 aR, 11R) -11-methyl-6- ((S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo-1, 4,7, 8a,9,11, 12-octahydro-3H-pyrazine [1',2:4,5] pyrazine [2,3-c ] [1,7] naphthyridine-3, 10 (2H) -dicarboxylate

To a solution of (3R, 6R) -4- (7- ((phenoxy) carbonyl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -3-nitro-5, 6,7, 8-tetrahydro-1, 7-naphthyridin-4-yl) -6-methylpiperazine-1, 3-dicarboxylic acid 1- (tert-butyl) ester 3-methyl ester (290 mg,0.425 mmol) in ethanol (15 mL) was added ammonium chloride (228 mg,4.3 mmol) and iron powder (123 mg,2.2 mmol). The reaction solution was heated to reflux for 8 hours. Cooling to room temperature, filtering, and washing with ethanolWashing the solid. The filtrate was concentrated under reduced pressure to give a dark brown solid and used directly in the next step. (165 mg, yield: 63%) MS m/z:620.3[ M+H ]] ⁺ 。

Step 8: synthesis of 3-benzyl 10- (tert-butyl) ester of (8 aR, 11R) -7, 11-dimethyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo-1, 4,7, 8a,9,11, 12-octahydro-3H-pyrazin [1',2:4,5] pyrazin [2,3-c ] [1,7] naphthyridine-3, 10 (2H) -dicarboxylic acid

To (8 aR, 11R) -11-methyl-6- ((S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo-1, 4,7, 8a,9,11, 12-octahydro-3H-pyrazine [1',2:4,5]]Pyrazine [2,3-c ] ][1,7]To a solution of naphthyridine-3, 10 (2H) -dicarboxylic acid 3-benzyl ester 10- (tert-butyl) ester (165 mg,0.266 mmol) in N, N-dimethylformamide (4 mL) was added potassium carbonate (73 mg,0.53 mmol) and methyl iodide (121 mg,0.85 mmol). The reaction solution was stirred at 40℃for 12 hours. After cooling to room temperature, ethyl acetate (50 mL) and water (30 mL) were added. After shaking, delamination, the organic phase was washed with water (10 ml×2), saturated brine (10 mL), dried over sodium sulfate and spun dry under reduced pressure to brown solid which was directly used in the next step. (99 mg, yield: 59%) MS m/z 634.4[ M+H ]] ⁺ 。

Step 9: synthesis of tert-butyl (8 aR, 11R) -7, 11-dimethyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo-1, 2,3,4,7, 8a,9,11, 12-decahydro-10H-pyrazin [1',2:4,5] pyrazin [2,3-c ] [1,7] naphthyridine-10-carboxylate

(8 aR, 11R) -7, 11-dimethyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo-1, 4,7, 8a,9,11, 12-octahydro-3H-pyrazine [1',2:4, 5) under hydrogen (balloon) atmosphere]Pyrazine [2,3-c ]][1,7]A suspension of naphthyridine-3, 10 (2H) -dicarboxylic acid 3-benzyl ester 10- (tert-butyl) ester (99 mg,0.156 mmol) and palladium on carbon (170 mg,0.016 mmol) in ethyl acetate (2 mL) and tetrahydrofuran (2 mL) was stirred for 3 hours. The solids were filtered off and the filter cake was rinsed with ethyl acetate. The filtrates were combined and dried under reduced pressure. The residue was purified by TLC (methanol: ethyl acetate=1:1) to give a yellow solid. (65 mg, yield: 83%) MS m/z:500.3[ M+H ] ] ⁺ 。

Step 10: synthesis of tert-butyl (8 aR, 11R) -3- (8-chloronaphthalen-1-yl) -7, 11-dimethyl-6- ((S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo-1, 2,3,4,7, 8a,9,11, 12-decahydro-10H-pyrazine [1',2':4,5] pyrazine [2,3-c ] [1,7] naphthyridine-10-carboxylate

To the reaction flask was added (8 aR, 11R) -7, 11-dimethyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo-1, 2,3,4,7, 8a,9,11, 12-decahydro-10H-pyrazine [1',2:4, 5)]Pyrazine [2,3-c ]][1,7]Naphthyridine-10-carboxylic acid tert-butyl ester (65 mg,0.13 mmol), 1-bromo-8-chloronaphthalene (48 mg,0.20 mmol), tris (dibenzylideneacetone) dipalladium (12 mg,0.013 mmol), 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl (12 mg,0.026 mmol) and cesium carbonate (85 mg,0.26 mmol). After argon was replaced, pre-deoxygenated anhydrous toluene (3 mL) was added. The reaction solution was heated at 110℃for 16 hours. After cooling to room temperature, ethyl acetate (30 mL) and water (30 mL) were added, shaken and separated. The organic phase was washed with saturated brine (10 mL), dried over sodium sulfate, and spun dry under reduced pressure. The residue was purified by TLC (methanol: dichloromethane=1:10) to give a light brown thick material. (22 mg, yield: 23%) MS m/z 660.3[ M+H ]] ⁺ 。

Step 11: synthesis of (8 aR, 11R) -3- (8-chloronaphthalen-1-yl) -7, 11-dimethyl-6- ((S) -1-methylpyrrolidin-2-yl) methoxy) -2,3,4,7,9,10,11,12-octahydro-1H-pyrazin [1',2:4,5] pyrazin [2,3-c ] [1,7] naphthyridin-8 (8 aH) -one

To (8 aR, 11R) -3- (8-chloronaphthalen-1-yl) -7, 11-dimethyl-6- ((S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo-1, 2,3,4,7, 8a,9,11, 12-decahydro-10H-pyrazine [1',2':4, 5]]Pyrazine [2,3-c ]][1,7]To a solution of tert-butyl naphthyridine-10-carboxylate (22 mg,0.030 mmol) in dichloromethane (3 mL) was slowly added trifluoroacetic acid (1 mL). The reaction solution was stirred at room temperature for 3 hours. Anhydrous dichloromethane (10 mL) was added for dilution and spin-drying under reduced pressure. The resulting pale yellow dope was used directly in the next step. MS m/z 560.3[ M+H ]] ⁺ 。

Step 12: synthesis of (8 aR, 11R) -10-acryloyl-3- (8-chloronaphthalen-1-yl) -7, 11-dimethyl-6- ((S) -1-methylpyrrolidin-2-yl) methoxy) -2,3,4,7,9,10,11,12-octahydro-1H-pyrazin [1',2:4,5] pyrazin [2,3-c ] [1,7] naphthyridin-8 (8 aH) -one

To (8 aR, 11R) -3- (8-chloronaphthalen-1-yl) -7, 11-dimethyl-6- ((S) -1-methylpyrrolidin-2-yl) methoxy) -2,3,4,7,9,10,11,12-octahydro-1H-pyrazine [1 ]',2:4,5]Pyrazine [2,3-c ]][1,7]Naphthyridin-8 (8 aH) -one and nitrogen, N-diisopropylethylamine (39 mg,0.3 mmol) in dichloromethane (3 mL) was slowly dropped in a solution of acryloyl chloride (2.7 mg,0.03 mmol) in dichloromethane (1 mL). The ice-water bath was removed, and the reaction solution was stirred at room temperature for 15 minutes. The residue was purified by TLC (methanol: dichloromethane=1:10) under reduced pressure to give a pale yellow solid. (3 mg, two-step total yield: 16%) ¹ H NMR(400MHz,DMSO)δ7.72-7.64(m,1H),7.53(t,J＝7.2Hz,1H),7.48(t,J＝7.2Hz,1H),7.35(td,J＝7.8,13.2Hz,1H),7.28-7.20(m,2H),6.92-6.78(m,1H),6.20(brd,J＝16.2Hz,1H),5.79-5.72(m,1H),4.35-4.31(m,1H),3.68-3.50(m,6H),3.42(s,3H),3.37-3.32(m,1H),3.24-3.01(m,7H),2.46-2.32(m,2H),2.36(s,3H),1.68-1.51(m,4H),1.31(s,3H).MS m/z:614.3[M+H] ⁺ 。

Examples 445 to 487 were prepared by the method of example 444

Example 488: synthesis of 1- ((8 aR, 11R) -3- (8-chloronaphthalen-1-yl) -11-methyl-6- ((S) -1-methylpyrrolidin-2-yl) methoxy) -1,2,3,4,8a,9,11, 12-Xin Qingbi oxazino [1',2:4,5] [1,4] oxazino [2,3-c ] [1,7] naphthyridin-10 (8H) -yl) prop-2-en-one

Step 1: synthesis of benzyl 4- ((2R, 5R) -4- (tert-butoxycarbonyl) -2- (hydroxymethyl) -5-methylpiperazin-1-yl) -2-chloro-3-nitro-5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylate

A solution of 2, 4-dichloro-3-nitro-5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylate (535 mg,1.40 mmol), tert-butyl (2R, 5R) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylic acid benzyl ester (345 mg,1.5 mmol) and nitrogen, diisopropylethylamine (258 mg,2 mmol) in DMF (15 mL) was stirred at 75deg.C for 4 hours. After cooling to room temperature, ethyl acetate (150 mL) and saturated aqueous ammonium chloride (100 mL) were added. After shaking and separation, the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phases were washed with water (40 mL. Times.3), saturated brine (40 mL), dried over sodium sulfate and spun-dried under reduced pressure to give a brown viscous material. Column chromatography (silica gel, ethyl acetate/petroleum ether=1/1) gave a viscous material (400 mg,0.69mmol, yield: 49%).

Step 2: synthesis of benzyl 4- ((2R, 5R) -4- (tert-butoxycarbonyl) -2- (hydroxymethyl) -5-methylpiperazin-1-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -3-nitro-5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylate

To a solution of 4- ((2R, 5R) -4- (tert-butoxycarbonyl) -2- (hydroxymethyl) -5-methylpiperazin-1-yl) -2-chloro-3-nitro-5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylic acid benzyl ester (311 mg,0.54 mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (67 mg,0.58 mmol) in N, N-dimethylformamide (5 mL) was added potassium carbonate (129 mg,1.0 mmol). The reaction solution was heated at 60℃for 12 hours. After cooling to room temperature, ethyl acetate (50 mL) and saturated aqueous sodium carbonate (30 mL) were added. After shaking and delamination, the organic phase was washed with water (10 mL. Times.3), saturated brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give a dark brown solid which was used directly in the next reaction.

Step 3: synthesis of 3-benzyl 10-tert-butyl (8 aR, 11R) -11-methyl-6- ((S) -1-methylpyrrolidin-2-yl) methoxy) -1,4,8a,9,11, 12-hexahydropyrazine [1',2:4,5] [1,4] oxazine [2,3-c ] [1,7] naphthyridine-3, 10 (2H, 8H) -dicarboxylate

Sodium hydride (24 mg,0.60 mmol) was added to a solution of 4- ((2 r,5 r) -4- (tert-butoxycarbonyl) -2- (hydroxymethyl) -5-methylpiperazin-1-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -3-nitro-5, 8-dihydro-1, 7-naphthyridine-7 (6H) -carboxylic acid benzyl ester in N, N-dimethylformamide (5 mL) in an ice-water bath. The reaction was stirred in an ice-water bath for 15 minutes, heated to 120℃and stirred for 24 hours. After cooling to room temperature, ethyl acetate (50 mL) and water (30 mL) were added. After shaking and delamination, the organic phase was washed with water (10 mL. Times.2), saturated brine (10 mL), dried over sodium sulfate and spun-dried under reduced pressure to a brown solid. Column chromatography (silica gel, methanol/dichloromethane=1/10) gave a yellow solid (195 mg,0.32mmol, two-step yield: 59%). MS m/z 608.3[ M+H ] ] ⁺ 。

Step 4: synthesis of tert-butyl 8aR, 11R) -11-methyl-6- ((S) -1-methylpyrrolidin-2-yl) methoxy) -1,2,3,4,8a,9,11, 12-Xin Qingbi oxazine [1',2:4,5] [1,4] oxazine [2,3-c ] [1,7] naphthyridine-10 (8H) -carboxylate

Stirring (8 aR, 11R) -11-methyl-6- ((S) -1-methylpyrrolidin-2-yl) methoxy) -1,4,8a,9,11, 12-hexahydropyrazine [1',2:4,5] under hydrogen (balloon) atmosphere][1,4]Oxazines [2,3-c][1,7]Naphthyridine-3, 10 (2H, 8H) -dicarboxylic acid 3-benzyl ester 10-tert-butyl ester(178 mg,0.293 mmol) and palladium on carbon (319 mg,0.03 mmol) in ethyl acetate (8 mL) and tetrahydrofuran (8 mL) for 3 hours. The solid was filtered off and the filter cake was rinsed with ethyl acetate (10 ml×2). The filtrates were combined and dried under reduced pressure. The residue was purified by preparative TLC (methanol: ethyl acetate=1:1) to give a yellow solid (125 mg,0.26mmol, yield: 90%). MS m/z 474.3[ M+H ]] ⁺ 。

Step 5: synthesis of tert-butyl (8 aR, 11R) -3- (8-chloronaphthalen-1-yl) -11-methyl-6- ((S) -1-methylpyrrolidin-2-yl) methoxy) -1,2,3,4,8a,9,11, 12-octahydropyrazine [1',2:4,5] [1,4] oxazine [2,3-c ] [1,7] naphthyridine-10 (8H) -carboxylate

To the reaction flask was added (8 aR, 11R) -11-methyl-6- ((S) -1-methylpyrrolidin-2-yl) methoxy) -1,2,3,4,8a,9,11, 12-Xin Qingbi oxazine [1',2:4,5] ][1,4]Oxazines [2,3-c][1,7]Naphthyridine-10 (8H) -carboxylic acid tert-butyl ester (119 mg,0.25 mmol), 1-bromo-8-chloronaphthalene (72 mg,0.3 mmol), tris (dibenzylideneacetone) dipalladium (28 mg,0.03 mmol), 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl (14 mg,0.03 mmol) and cesium carbonate (163 mg,0.5 mmol). After argon was replaced, pre-deoxygenated anhydrous toluene (5 mL) was added. The reaction solution was heated at 110℃for 16 hours. After cooling to room temperature, the filter cake was washed with ethyl acetate (10 ml×2). The filtrates were combined and dried under reduced pressure. The residue was purified by preparative TLC (methanol: dichloromethane=1:10) to give a light brown thick material (35 mg,0.055mmol, yield: 22%). MS m/z 634.3[ M+H ]] ⁺ 。

Step 6: synthesis of (8 aR, 11R) -3- (8-chloronaphthalen-1-yl) -11-methyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) -1,2,3,4,8a,9, 10,11, 12-decahydropyrazine [1',2:4,5] [1,4] oxazine [2,3-c ] [1,7] naphthyridine

To a solution of (8 aR, 11R) -3- (8-chloronaphthalen-1-yl) -11-methyl-6- ((S) -1-methylpyrrolidin-2-yl) methoxy) -1,2,3,4,8a,9,11, 12-octahydropyrazine [1',2:4,5] [1,4] oxazine [2,3-c ] [1,7] naphthyridine-10 (8H) -carboxylic acid tert-butyl ester (28 mg,0.063 mmol) in dichloromethane (3 mL) was slowly added trifluoroacetic acid (1 mL). The reaction solution was stirred at room temperature for 2 hours. Anhydrous dichloromethane (10 mL) was added for dilution and spin-drying under reduced pressure. The resulting pale yellow dope was used directly in the next step.

Step 7: synthesis of 1- ((8 aR, 11R) -3- (8-chloronaphthalen-1-yl) -11-methyl-6- ((S) -1-methylpyrrolidin-2-yl) methoxy) -1,2,3,4,8a,9,11, 12-Xin Qingbi oxazino [1',2:4,5] [1,4] oxazino [2,3-c ] [1,7] naphthyridin-10 (8H) -yl) prop-2-en-one

To ((8 aR, 11R) -3- (8-chloronaphthalen-1-yl) -11-methyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) -1,2,3,4,8a,9, 10,11, 12-decahydropyrazine [1',2:4, 5) in an ice-water bath][1,4]Oxazines [2,3-c][1,7]A solution of naphthyridine and triethylamine (39 mg,0.3 mmol) in dichloromethane (3 mL) was slowly dropped in a solution of acryloyl chloride (8.1 mg,0.09 mmol) in dichloromethane (1 mL). The ice-water bath was removed, and the reaction solution was stirred at room temperature for 15 minutes. The residue was purified by preparative TLC (methanol: dichloromethane=1:10) under reduced pressure to give a pale yellow solid (4 mg,0.0068mmol, total yield in two steps: 11%). ¹ H NMR(400MHz,DMSO)δ7.72-7.64(m,1H),7.53(t,J＝7.2Hz,1H),7.48(t,J＝7.2Hz,1H),7.35(td,J＝7.8,13.2Hz,1H),7.28-7.20(m,2H),6.92-6.78(m,1H),6.20(brd,J＝16.2Hz,1H),5.79-5.72(m,1H),3.68-3.50(m,6H),3.37-3.32(m,3H),3.24-3.01(m,8H),2.46-2.32(m,2H),2.36(s,3H),1.68-1.51(m,4H),1.31(s,3H).MS m/z:614.3[M+H] ⁺ 。

Examples 489-525 were prepared by the method of example 488

Example 526: synthesis of (S) -1- (4- (7- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazin-1-yl) prop-2-en-1-one:

step 1: synthesis of 1-tert-butyl 4-ethyl 5-oxaheptane-1, 4-dicarboxylic acid

The compound 1-tert-butyloxycarbonyl-4-piperidone (10 g,50.19 mmol) was dissolved in diethyl ether (100 mL) and BF was added under ice-water bath cooling ₃ .Et ₂ O (7 mL,55.21 mmol) and then ethyl azoacetate (6.85 mL,55.21 mmol) were added dropwise slowly and after the addition was complete, stirring was continued for 1 hour. After the completion of the reaction, the reaction was quenched with 30% aqueous sodium carbonate and water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane/methanol=50/1) to give an oil. (14 g, yield: 97%) ¹ H NMR(400MHz,CDCl ₃ ):4.25-2.03(m,11H),1.47-1.45(d,J＝7.8Hz,9H),1.31-1.24(m,3H).

Step 2: synthesis of 4-hydroxy-2- (methylthio) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepan-7-tert-butyl ester

The compound 1-tert-butyl 4-ethyl 5-oxaheptane-1, 4-dicarboxylic acid (14 g,49.06 mmol) was dissolved in dry methanol (80 mL), 30% sodium methoxide solution (26.5 g,147.18 mmol) and thiourea (5.60 g,73.60 mmol) were added and heated to 80℃to react for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, methyl iodide (8.7 g,3.82mL,61.33 mmol) was added dropwise thereto, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated, the residue was dissolved in water, the pH was adjusted to 6-7 with glacial acetic acid, and a solid was precipitated and filtered to give a white solid. (13.1 g, yield: 85%) ¹ HNMR(400MHz,CDCl ₃ )δ10.98(s,1H),3.56(d,J＝30.3Hz,4H),2.88(d,J＝32.7Hz,4H),2.56(s,3H),1.48(s,9H).

Step 3:

the compound tert-butyl 4-hydroxy-2- (methylsulfanyl) -5,6,8, 9-tetrahydro-7H-pyrimidine [4,5-d ] azepane-7-carboxylate (5.0 g,16.06 mmol) was dissolved in anhydrous dichloromethane (50 mL), DIEA (3.11 g,24.08 mmol) and trifluoromethanesulfonic anhydride (5.44 g,19.27 mmol) were added under ice-water bath cooling, and the reaction was stirred for 30 minutes under ice-water bath cooling, after the reaction was completed, the reaction mixture was concentrated until the crude product was directly used in the next step. (7.12 g, yield: 100%)

Step 4; synthesis of tert-butyl 4- (4- (benzyloxy) carbonyl) piperazin-1-yl) -2- (methylthio) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepan-7-carboxylate

The crude product from the previous step (3.0 g,6.77 mmol) was dissolved in anhydrous DMF (30 mL) and DIEA (1.31 g,10.15 mmol) and benzyl piperazine-1-carboxylate (1.79 g,8.12 mmol) were added and the reaction heated to 80℃with stirring for one hour. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was dried over saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane/methanol=50/1) to give an off-white solid. (2.62 g, yield: 75%). ¹ HNMR(400MHz,CDCl ₃ )δ7.39-7.30(m,5H),5.16(s,2H),3.61(d,J＝4.9Hz,6H),3.51(s,2H),3.24(s,4H),2.97(s,2H),2.74(s,2H),2.50(s,3H),1.48(s,9H).

Step 5: synthesis of tert-butyl 4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- (methylsulfinyl) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepane-7-carboxylate:

the compound tert-butyl 4- (4- (benzyloxy) carbonyl) -piperazin-1-yl) -2- (methylsulfanyl) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepane-7-carboxylate (1.0 g,1.95 mmol) was dissolved in dichloromethane (20 mL) and 85% m-chloroperoxybenzoic acid (0.41 g,2.34 mmol) was added with cooling in an ice water bath and the reaction stirred for 30 min. After the reaction, the mixture was quenched with saturated sodium thiosulfate, extracted with methylene chloride, and the organic phase was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give an off-white solid. (1.0 g, yield: 97%)

Step 6: synthesis of tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepan-7-carboxylate

The compound tert-butyl 4- (4- ((benzyloxy) carbonyl) -piperazin-1-yl) -2- (methylsulfinyl) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepan-7-carboxylate (1.0 g,1.89 mmol) was dissolved in anhydrous toluene (10 mL), added (S) - (1-methylpyrrolidin-2-yl) methanol (380 mg,3.30 mmol) and sodium tert-butoxide (363 mg,3.78 mmol) with cooling in an ice water bath and reacted for 4 hours with stirring. After the reaction, the reaction was quenched with cold water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane/methanol=30/1) to give an off-white solid. (0.85 g, yield: 77%)

Step 7: synthesis of benzyl (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazine-1-carboxylate:

the compound (S) -4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepane-7-carboxylic acid tert-butyl ester (0.85 g,1.45 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was added and the reaction stirred at room temperature for 3 hours. After the reaction, the reaction mixture was concentrated, dissolved in methylene chloride, washed with saturated sodium hydrogencarbonate, extracted with methylene chloride, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give an off-white solid. (700 mg, yield: 99.5%)

Step 8: synthesis of benzyl (S) -4- (7- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazine-1-carboxylate:

the compound (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4, 5-d)]Azepan-4-yl) piperazine-1-carboxylic acid benzyl ester (100 mg,0.21 mmol) and 1-bromo-8-methylnaphthalene (92 mg,0.42 mmol) were added to the reaction flask, cesium carbonate (172 mg,0.53 mmol), X-phos (20 mg,0.04 mmol) and Pd were added ₂ (dba) ₃ (37 mg, m0.04 mol) was added with anhydrous toluene (5 mL), nitrogen was replaced 3 times, and the reaction was stirred under nitrogen atmosphere at 100℃for 12 hours. The reaction was cooled to room temperature, concentrated, and separated by TLC (dichloromethane/methanol=20/1) to give a pale yellow solid. (40 mg, yield: 31%)

Step 9: synthesis of (S) -7- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepane:

benzyl (S) -4- (7- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazine-1-carboxylate (40 mg,0.06 mmol) was dissolved in methanol (10 mL), 10% wet Pd/C (10 mg) was added under nitrogen atmosphere, hydrogen was replaced, and the reaction was stirred under hydrogen atmosphere for 3 hours. After the reaction was completed, pd/C was removed by filtration, and the organic phase was concentrated to give an off-white solid. (30 mg, yield: 96%)

Step 10: synthesis of (S) -1- (4- (7- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazin-1-yl) prop-2-en-1-one:

the compound (S) -7- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d]Azepane (mg, mmol) was dissolved in dichloromethane (5 mL), DIEA (mg, mmol) was added under ice-water bath cooling, then acryloyl chloride (mg, mmol) was added dropwise, and stirring was carried out under ice-water bath for 10 minutes. After the reaction is finished, adding a fullAnd aqueous sodium bicarbonate, extracted with dichloromethane, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and TLC separated (dichloromethane/methanol=10/1) to give an off-white solid. ¹ H NMR(400MHz,CDCl ₃ )δ7.61(dt,J＝15.0,2.9Hz,1H),7.55-7.41(m,2H),7.37-7.24(m,2H),6.87(dd,J＝ 14.9,3.0Hz,1H),6.14(dd,J＝33.0,20.0Hz,1H),6.00(dd,J＝20.0,4.9Hz,1H),5.53(dd,J＝33.0,4.9Hz,1H),4.12(td,J＝9.7,8.0Hz,2H),3.99(t,J＝10.4Hz,4H),3.65(dd,J＝24.8,10.2Hz,1H),3.47-3.24(m,9H),3.15(t,J＝9.8Hz,2H),3.03-2.90(m,4H),2.79(dt,J＝24.9,14.0Hz,1H),2.40(dt,J＝24.8,14.1Hz,1H),2.26(s,3H),1.81-1.32(m,4H)；MS m/z:541.3[M+H] ⁺ 。

Example 527: synthesis of (S) -1- (4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazin-1-yl) prop-2-en-1-one:

step 1: synthesis of benzyl (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazine-1-carboxylate:

The compound (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4, 5-d)]Azepan-4-yl) piperazine-1-carboxylic acid benzyl ester (100 mg,0.21 mmol) and 1-bromonaphthalene (92 mg,0.42 mmol) were added to the reaction flask, cesium carbonate (172 mg,0.53 mmol), X-phos (20 mg,0.04 mmol) and Pd were added ₂ (dba) ₃ (37 mg, m0.04 mol) was added with anhydrous toluene (5 mL), nitrogen was replaced 3 times, and the reaction was stirred under nitrogen atmosphere at 100℃for 12 hours. The reaction was cooled to room temperature, concentrated, and separated by TLC (dichloromethane/methanol=20/1) to give a pale yellow solid. (40 mg, yield: 31%)

Step 2: (S) -2- ((1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -4- (piperazin-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan

Benzyl (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazine-1-carboxylate (40 mg,0.06 mmol) was dissolved in methanol (10 mL), 10% wet Pd/C (10 mg) was added under nitrogen to displace hydrogen, and the reaction stirred under hydrogen for 3 hours. After the reaction was completed, pd/C was removed by filtration, and the organic phase was concentrated to give an off-white solid. (30 mg, yield: 96%)

Step 3: (S) -1- (4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazin-1-yl) prop-2-en-1-one

The compound (S) -2- ((1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -4- (piperazin-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d]Azepane (mg, mmol) was dissolved in dichloromethane (5 mL), DIEA (mg, mmol) was added under ice-water bath cooling, then acryloyl chloride (mg, mmol) was added dropwise, and stirring was carried out under ice-water bath for 10 minutes. After the reaction was completed, the reaction was quenched by addition of saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by TLC (dichloromethane/methanol=10/1) to give an off-white solid. ¹ HNMR(400MHz,CDCl ₃ )δ8.32(d,J＝7.8Hz,1H),7.85(d,J＝7.3Hz,1H),7.61-7.45(m,3H),7.39(t,J＝7.7Hz,1H),7.08(d,J＝7.1Hz,1H),6.60(dd,J＝16.6,10.4Hz,1H),6.32(d,J＝16.8Hz,1H),5.74(d,J＝11.7Hz,1H),5.12(s,1H),4.60(d,J＝11.4Hz,1H),3.96(s,1H),3.69(d,J＝35.6Hz,6H),3.28(d,J＝15.0Hz,9H),3.04(s,5H),2.95-2.82(m,1H),2.34(s,2H),2.20(s,2H)；MS m/z:527.3[M+H] ⁺ 。

Example 528: synthesis of 2- ((S) -1-propenoyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazin-2-yl) acetonitrile:

step 1: synthesis of tert-butyl (S) -4- (3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepan-7-carboxylate:

the compound 2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepine-7-carboxylic acid tert-butyl ester (2 g,4.51 mmol) was dissolved in anhydrous DMF (10 mL), DIEA (2.04 g,15.80 mmol) and (S) -2- (piperazin-2-yl) acetonitrile. 2 hydrochloride (480 mg,4.96 mmol) were added and the reaction stirred for 2 hours at 60 ℃. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product which was used directly in the next step. (1.9 g, yield: 100%)

Step 2: synthesis of tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepane-7-carboxylate:

the crude product from the previous step (1.89 g,4.51 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), DIEA (874 mg,6.77 mmol) and Cbz-Cl (846 mg,4.96 mmol) were added and the reaction stirred at room temperature for 2 hours. After the completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane/methanol=50/1) to give an off-white solid. (1.84 g, yield: 74%)

Step 3: synthesis of tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepane-7-carboxylate:

the compound (S) -tert-butyl 4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfanyl) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepane-7-carboxylate (1.84 g,3.33 mmol) was dissolved in dichloromethane (20 mL), 85% m-CPBA (0.74 g,3.66 mmol) was added with ice water cooling and the reaction stirred for 30 minutes with ice water cooling. After the reaction, the reaction was quenched with saturated sodium thiosulfate solution, extracted with methylene chloride, the organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give an off-white solid. (1.89 g, yield: 100%)

Step 4: synthesis of tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepane-7-carboxylate:

the compound 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepan-7-carboxylic acid tert-butyl ester (1.89 g,3.32 mmol) was dissolved in anhydrous toluene (20 mL), (S) - (1-methylpyrrolidin-2-yl) methanol (67 mg,5.83 mmol) was added, sodium tert-butoxide (328 mg,6.64 mmol) was added with ice water bath cooling and the reaction stirred for 4 hours with ice water bath cooling. After the completion of the reaction, the reaction was quenched with cold water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane/methanol=30/1) to give an off-white solid. (1.8 g, yield: 87%)

Step 5: synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazine-1-carboxylate

The compound 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepane-7-carboxylic acid tert-butyl ester (1.8 g,2.90 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (5 mL) was added and the reaction stirred at room temperature for 12 hours. After the reaction, the reaction mixture was concentrated to give a residue, which was then added with saturated sodium hydrogencarbonate, extracted with methylene chloride, and the organic phase was dried over anhydrous sodium sulfate with water to obtain an off-white solid. (1.5 g, yield: 99%)

Step 6: synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazine-1-carboxylate:

the compound (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4, 5-d)]Azepan-4-yl) piperazine-1-carboxylic acid benzyl ester (200 mg,0.38 mmol) and 1-bromonaphthalene (160 mg,0.77 mmol) were added to the reactionIn a bottle, cesium carbonate (372 mg,1.14 mmol), X-Phos (36 mg,0.08 mmol) and Pd were added ₂ (dba) ₃ (70 mg,0.08 mmol), nitrogen was substituted, and the reaction was heated to 100℃with stirring for 12 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered, and the organic phase was concentrated and separated by column chromatography (dichloromethane/methanol=20/1) to give a pale yellow solid. (70 mg, yield: 28%)

Step 7: synthesis of 2- ((S) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazin-2-yl) acetonitrile:

benzyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazine-1-carboxylate (70 mg,0.11 mmol) was dissolved in methanol (10 mL), 10% wet Pd/C (20 mg) was added under nitrogen atmosphere, hydrogen was replaced, and the reaction was stirred under hydrogen atmosphere for 3 hours. After the reaction was completed, the mixture was filtered through celite, and the filtrate was concentrated to give an off-white solid. (50 mg, yield: 90%)

Step 8: synthesis of 2- ((S) -1-propenoyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazin-2-yl) acetonitrile:

the compound 2- ((S) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimido [4, 5-d)]Azepan-4-yl) piperazin-2-yl) acetonitrile (50 mg,0.10 mmol) was dissolved in dichloromethane (5 mL), DIEA (20 mg,0.15 mmol) and acryloyl chloride (10 mg,0.11 mmol) were added with ice-water bath cooling and the reaction stirred for 10 min with ice-water bath cooling. After the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate, extracted with dichloromethane, and the organic phase was washed with water and separated by column chromatography (dichloromethane/methanol=10/1) to give an off-white solid. (25 mg, yield: 45%) ¹ H NMR(400MHz,CDCl ₃ )δ8.50(dd,J＝11.1,6.9Hz,1H),7.78(ddd,J＝11.0,6.9,2.8Hz,1H),7.60-7.28(m,5H),6.26(dd,J＝33.3,20.0Hz,1H),6.00(dd,J＝20.0,4.4Hz,1H),5.53(dd,J＝33.4,4.5Hz,1H),4.22-4.10(m,2H),4.01(ddd,J＝43.2,22.5,12.1Hz,2H),3.71-3.51(m,4H),3.48-3.19(m,8H),3.11(t,J＝9.8Hz,2H),3.02-2.89(m,1H),2.79(dt,J＝24.8,14.1Hz,1H),2.41(dt,J＝24.8,14.1Hz,1H),2.29-2.14(m,4H),1.80-1.31(m,4H)；MS m/z:566.8[M+H] ⁺ 。

Example 529: synthesis of 2- ((S) -1-propenoyl-4- (7- (8-naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazin-2-yl) acetonitrile:

further prepared by substituting 1-bromo-8-methylnaphthalene for 1-bromonaphthalene in step 6 of example 528. MS m/z 580.8[ M+H ]] ⁺ 。

Example 530: synthesis of 2- ((S) -1-propenoyl-4- (7- (8-fluoronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazin-2-yl) acetonitrile:

Further prepared by substituting 1-bromo-8-fluoronaphthalene for 1-bromonaphthalene in step 6 of example 528. MS m/z 584.7[ M+H ]] ⁺ 。

Example 531: synthesis of 2- ((S) -1-propenoyl-4- (7- (4-fluoronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazin-2-yl) acetonitrile:

further prepared by substituting 1-bromo-4-fluoronaphthalene for 1-bromonaphthalene in step 6 of example 528. MS m/z 584.8[ M+H ]] ⁺ 。

Example 532: synthesis of 2- ((S) -1-propenoyl-4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazin-2-yl) acetonitrile:

step 1: synthesis of 2- (methylthio) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-ol

The compound tert-butyl 4-hydroxy-2- (methylthio) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepane-7-carboxylate (5.0 g,16.06 mmol) was dissolved in dichloromethane (30 mL), trifluoroacetic acid (10 mL) was added and the reaction stirred at room temperature for 3 hours. After the completion of the reaction, the reaction solution was concentrated to give a brown oily crude product which was used directly in the next step.

Step 2: synthesis of benzyl 4-hydroxy-2- (methylthio) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepane-7-carboxylate:

The oily substance (16.06 mmol) obtained in the previous step was dissolved in anhydrous tetrahydrofuran (30 mL), triethylamine (4.88 g,48.18 mmol) was added, and then benzyloxycarbonyl chloride (3.0 g,17.67 mmol) was added under cooling in an ice-water bath, and the reaction was stirred for 30 minutes. After the reaction, water quenching reaction is added, ethyl acetate is used for extraction, the organic phase is washed by 1M hydrochloric acid water solution, saturated saline water is used for washing, anhydrous sodium sulfate is used for drying, and the white solid (semi-oil semi-solid) is obtained after concentration. (4.6 g, yield: 83%)

Step 3: synthesis of benzyl 2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepane-7-carboxylate:

the compound 4-hydroxy-2- (methylthio) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepane-7-carboxylic acid benzyl ester (4.6 g,13.32 mmol) was dissolved in anhydrous dichloromethane (50 mL), DIEA (2.58 g,19.98 mmol) was added, triflic anhydride (4.13 g,14.65 mmol) was added with ice water bath cooling, stirred for 30 min with ice water bath cooling, concentrated, and separated by column chromatography (dichloromethane/methanol=80/1) to give an oil. (4.8 g, yield: 75%)

Step 4: synthesis of benzyl (S) -4- (4- (tert-butyloxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepane-7-carboxylate

The compound 2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepan-7-carboxylic acid benzyl ester (4.8 g,10.05 mmol) was dissolved in anhydrous DMF (30 mL), DIEA (1.95 g,15.08 mmol) and (S) -2- (piperazin-2-yl) acetonitrile.2 hydrochloride (1.99 g,10.05 mmol) were added and the reaction stirred at 80℃for 1 hour. After the reaction was completed, DIEA (1.95 g,15.08 mmol) and di-tert-butyl dicarbonate (6.58 g,30.15 mmol) were added and the reaction was continued with stirring for 1 hour. After the completion of the reaction, the reaction mixture was cooled to room temperature, diluted with saturated brine, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated, and separated by column chromatography (dichloromethane/methanol=50/1) to give an off-white solid. (4.5 g, yield: 81%)

Step 5: synthesis of benzyl (S) -4- (4- (tert-butyloxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylenesulfonyl) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepane-7-carboxylate:

the compound (S) -benzyl 4- (4- (tert-butyloxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepane-7-carboxylate (4.5 g,8.14 mmol) was dissolved in dichloromethane (50 mL) and 85% m-chloroperoxybenzoic acid (1.82 g,8.95 mmol) was added with ice water cooling and stirred for 30 min. After the reaction, the reaction was quenched with saturated sodium thiosulfate solution, extracted with methylene chloride, the organic phase was washed with saturated sodium bicarbonate and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated to give an off-white solid. (4.6 g, yield: 99%)

Step 6: synthesis of benzyl 4- ((S) -4- (tert-butyloxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepan-7-carboxylate:

the compound (S) -benzyl 4- (4- (tert-butyloxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylenesulfonyl) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepan-7-carboxylate (4.6 g,8.09 mmol) was dissolved in anhydrous toluene (30 mL), (S) - (1-methylpyrrolidin-2-yl) methanol (1.63 g,14.16 mmol) was added, sodium tert-butoxide (1.55 g,16.18 mmol) was added under ice water bath cooling and the reaction stirred under ice water bath cooling for 4 hours. After the completion of the reaction, the reaction was quenched with cold water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane/methanol=30/1) to give an off-white solid. (4.1 g, yield: 82%)

Step 7: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazine-1-carboxylate:

benzyl compound 4- ((S) -4- (tert-butyloxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,8, 9-tetrahydro-7H-pyrimido [4,5-d ] azepan-7-carboxylate (4.1 g,6.62 mmol) was dissolved in methanol (50 mL), 10% wet Pd/C (410 mg) was added under nitrogen atmosphere, hydrogen was replaced, and the reaction was stirred under hydrogen atmosphere for 6 hours. After the reaction was completed, the mixture was filtered through celite, and the filtrate was concentrated to give an off-white solid. (3.05 g, yield: 95%)

Step 8: synthesis of tert-butyl (S) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate:

the compound (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4, 5-d)]Azepan-4-yl) piperazine-1-carboxylic acid tert-butyl ester (100 mg,0.21 mmol) and 1-bromonaphthalene (75 mg,0.31 mmol) were added to the reaction flask, cesium carbonate (168 mg,0.52 mmol), ruPhos (10 mg,0.02 mmol) and Pd were added ₂ (dba) ₃ (19 mg,0.02 mmol), nitrogen was replaced, and the reaction was heated to 100℃with stirring for 12 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered, and the organic phase was concentrated and separated by column chromatography (dichloromethane/methanol=20/1) to give a pale yellow solid. (45 mg, yield: 34%)

Step 9: synthesis of 2- ((S) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazin-2-yl) acetonitrile:

the compound (S) -tert-butyl 4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (45 mg,0.07 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added and the reaction stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated to obtain a crude product which was directly used in the next step. (38 mg, yield: 100%)

Step 10: synthesis of 2- ((S) -1-propenoyl-4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-d ] azepan-4-yl) piperazin-2-yl) acetonitrile:

the compound 2- ((S) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4, 5-d)]Azepan-4-yl) piperazin-2-yl) acetonitrile (38 mg,0.07 mmol) was dissolved in dichloromethane (5 mL), DIEA (23 mg,0.18 mmol) was added with ice-water bath cooling, then acryloyl chloride (7 mg,0.07 mmol) was added and the reaction stirred for 20 min with ice-water bath cooling. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate, extracted with dichloromethane, the organic phase was dried over saturated brine, anhydrous sodium sulfate, concentrated, and purified by TLC separation (dichloromethane/methanol=10/1) to give an off-white solid. (20 mg, yield: 48%). ¹ H NMR(400MHz,CDCl ₃ )δ7.66(dt,J＝14.8,3.0Hz,1H),7.60-7.52(m,1H),7.51-7.39(m,3H),7.31(t,J＝14.9Hz,1H),6.25(dd,J＝33.4,20.1Hz,1H),6.00(dd,J＝20.1,4.5Hz,1H),5.53(dd,J＝33.4,4.5Hz,1H),4.17-4.05(m,3H),4.03-3.90(m,1H),3.70-3.46(m,4H),3.46-3.20(m,8H),3.15(t,J＝9.8Hz,2H),2.96(tt,J＝16.7,9.9Hz,1H),2.80(dt,J＝24.8,14.2Hz,1H),2.41(dt,J＝24.8,14.1Hz,1H),2.30-2.13(m,4H),1.79-1.33(m,4H)；MS m/z:600.8[M+H] ⁺ 。

Application of the preparation method of example 532 to prepare examples 533-576

Example 577: synthesis of 1- (4- (8- (5-chloro-6-fluoro-1H-indazol-4-yl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepan-4-yl) piperazin-1-yl) prop-2-en-1-one:

step 1: synthesis of 2- (methylthio) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepan-4-ol

The compound tert-butyl 4-hydroxy-2- (methylthio) -5,6,7, 9-tetrahydro-8H-pyrimido [4,5-c ] azepine-8-carboxylate (2 g,6.42 mmol) was dissolved in dichloromethane (30 mL), trifluoroacetic acid (10 mL) was added and the reaction stirred at room temperature for 3 hours. After the completion of the reaction, the reaction solution was concentrated to give a brown oil which was used directly in the next step.

Step 2: synthesis of benzyl 4-hydroxy-2- (methylthio) -5,6,7, 9-tetrahydro-8H-pyrimido [4,5-c ] azepine-8-carboxylate:

the compound 2- (methylthio) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepan-4-ol (1.36 g,6.42 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), triethylamine (1.62 g,16.05 mmol) and benzyloxycarbonyl chloride (1.21 g,7.08 mmol) were added under ice-water bath cooling, and the reaction was stirred under ice-water bath cooling for 30 minutes. After the reaction, the reaction mixture was diluted with water, extracted with dichloromethane, the organic phase was washed with 1M hydrochloric acid, saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product which was used directly in the next step. (2.22 g, yield: 100%)

Step 3: synthesis of benzyl 2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) -5,6,7, 9-tetrahydro-8H-pyrimido [4,5-c ] azepine-8-carboxylate:

the compound 4-hydroxy-2- (methylthio) -5,6,7, 9-tetrahydro-8H-pyrimido [4,5-c ] azepine-8-carboxylic acid benzyl ester (2.22 g,6.42 mmol) was dissolved in methylene chloride (30 mL), DIEA (1.24 g,9.63 mmol) and trifluoromethanesulfonic anhydride (1.99 g,7.07 mmol) were added under ice-water bath cooling, and the reaction mixture was stirred under ice-water bath cooling for 30 minutes, after the reaction, the reaction mixture was concentrated to obtain a brown oil which was used directly in the next step. (3.07 g, yield: 100%)

Step 4: synthesis of benzyl 4- (4- (tert-butyloxycarbonyl) piperazin-1-yl) -2- (methylthio) -5,6,7, 9-tetrahydro-8H-pyrimido [4,5-c ] azepine-8-carboxylate:

the compound 2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) -5,6,7, 9-tetrahydro-8H-pyrimido [4,5-c ] azepine-8-carboxylic acid benzyl ester (3.07 g,6.42 mmol) was dissolved in anhydrous DMF (20 mL), DIEA (1.66 g,12,86 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.44 g,7.72 mmol) were added and the reaction stirred at 80℃for 2 hours. After the completion of the reaction, the reaction mixture was cooled, diluted with saturated brine, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated, and separated by column chromatography (dichloromethane/methanol=30/1) to give an off-white solid. (2.1 g, yield: 63%)

Step 5: synthesis of benzyl 4- (4- (tert-butyloxycarbonyl) piperazin-1-yl) -2- (methylsulfinyl) -5,6,7, 9-tetrahydro-8H-pyrimido [4,5-c ] azepine-8-carboxylate:

the compound benzyl 4- (4- (tert-butyloxycarbonyl) piperazin-1-yl) -2- (methylthio) -5,6,7, 9-tetrahydro-8H-pyrimido [4,5-c ] azepine-8-carboxylate (2.1 g,4.09 mmol) was dissolved in dichloromethane (30 mL), and m-chloroperoxybenzoic acid (996 mg,4.91 mmol) was added with cooling in an ice water bath and the reaction stirred for 30 min with cooling in an ice water bath. After the reaction, the reaction was quenched with saturated sodium thiosulfate, extracted with methylene chloride, the organic phase was washed with saturated sodium bicarbonate and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated to give the crude product which was used directly in the next step. (2.05 g, yield: 95%)

Step 6: synthesis of benzyl 4- (4- (tert-butyloxycarbonyl) piperazin-1-yl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -5,6,7, 9-tetrahydro-8H-pyrimido [4,5-c ] azepine-8-carboxylate:

the compound benzyl 4- (4- (tert-butyloxycarbonyl) piperazin-1-yl) -2- (methylenesulfonyl) -5,6,7, 9-tetrahydro-8H-pyrimido [4,5-c ] azepine-8-carboxylate (2.05 g,3.87 mmol) was dissolved in anhydrous toluene (20 mL), and 5-hydroxy-2-methyl-1, 2,3, 4-tetrahydroisoquinoline (695 mg,4.26 mmol) and sodium tert-butoxide (268 mg,5.81 mmol) were added with cooling in an ice water bath and the reaction stirred at room temperature for 8 hours. After the reaction, the reaction mixture was quenched with cold water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane/methanol=30/1) to give an off-white solid. (2.1 g, yield: 86%)

Step 7: synthesis of tert-butyl 4- (2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepan-4-yl) piperazine-1-carboxylate:

benzyl 4- (4- (tert-butyloxycarbonyl) piperazin-1-yl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -5,6,7, 9-tetrahydro-8H-pyrimido [4,5-C ] azepan-8-carboxylate (2.1 g,3.34 mmol) was dissolved in methanol (50 mL), 10% wet Pd/C (210 mg) was added under nitrogen atmosphere, hydrogen was replaced, and the reaction was stirred under a hydrogen balloon for 3 hours. After the reaction was completed, it was filtered through celite and washed with methanol, and concentrated to give an off-white solid. (1.6 g, yield: 97%)

Step 8: synthesis of tert-butyl 4- (8- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepan-4-yl) piperazine-1-carboxylate:

the compound 4- (2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepan-4-yl) piperazine-1-carboxylic acid tert-butyl ester (100 mg,0.16 mmol) and 4-bromo-5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (64 mg,0.19 mmol) were dissolved in anhydrous toluene (5 mL), ruPhos (15 mg,0.03 mmol), cesium carbonate (130 mg,0.40 mmol) and Pd2 (dba) 3 (28 mg,0.03 mmol) were added, nitrogen was replaced 3 times, and the reaction was stirred under nitrogen atmosphere heated to 110 ℃ for 12 hours. After the reaction was completed, the reaction solution was cooled, diluted with ethyl acetate, filtered, concentrated, and separated by column chromatography (dichloromethane/methanol=20/1) to give a pale yellow solid. (40 mg, yield: 34%)

Step 9: synthesis of 8- (5-chloro-6-fluoro-1H-indazol-4-yl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -4- (piperazin-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepine:

the compound 4- (8- (5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepan-4-yl) piperazine-1-carboxylic acid tert-butyl ester (40 mg, mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added and the reaction stirred at room temperature for 2 hours. After the reaction is finished, the reaction solution is concentrated to obtain a crude product which is directly used for the next step. (30 mg, yield: 99%)

Step 10: synthesis of 1- (4- (8- (5-chloro-6-fluoro-1H-indazol-4-yl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepan-4-yl) piperazin-1-yl) prop-2-en-1-one:

the compound 8- (5-chloro-6-fluoro-1H-indazol-4-yl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -4- (piperazin-1-yl) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-c]Azepane (30 mg,0.05 mmol) was dissolved in dichloromethane (5 mL), DIEA (8 mg,0.06 mmol) was added with cooling in an ice-water bath, then a solution of acryloyl chloride (5 mg,0.05 mmol) in dichloromethane (2 mL) was added dropwise and the reaction stirred for 30 min with ice-water bath. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by TLC (dichloromethane/methanol=10/1) to give an off-white solid. (15 mg, yield: 45%). ¹ H NMR(400MHz,CDCl ₃ )δ8.40(s,1H),7.03-6.84(m,4H),6.13-5.90(m,2H),5.51(dd,J＝31.1,6.8Hz,1H),5.23(s,1H),5.05(s,1H),3.97(q,J＝10.2Hz,6H),3.69(s,2H),3.31(t,J＝10.1Hz,4H),3.00-2.86(m,4H),2.87-2.74(m,2H),2.25(s,3H),1.99(p,J＝10.5Hz,2H)；MS m/z:617.67[M+H] ⁺ 。

Application of the method of example 577 to preparation of examples 578-612

Example 613: synthesis of 2- ((S) -1-acryloyl-4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (thiochroman-8-yl) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 3- ((2-bromophenyl) thio) propanoic acid

Acrylic acid (2.04 mL,30 mmol) was added dropwise to a solution of 2-bromophenylthiophenol (5.67 g,30 mmol) and triethylamine (4.4 mL,31.5 mmol) in anhydrous tetrahydrofuran (15 mL) in an ice water bath. The reaction solution was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was dried under reduced pressure to give a colorless oil. Aqueous sodium hydroxide (2.0 g/70 mL) was added and stirred. The aqueous solution was extracted with ethyl acetate/petroleum ether mixture (V: v=1:1, 50ml×2). The remaining aqueous phase was cooled in an ice-water bath and hydrochloric acid (6M) was added dropwise with stirring to a pH of 1. The resulting milky white suspension was extracted with ethyl acetate (100 mL). After separation, the organic phase was washed with saturated brine (20 mL), dried over sodium sulfate, and spun-dried under reduced pressure. The resulting solid was redissolved in dichloromethane (50 mL) and dried again under reduced pressure to give a white solid after high vacuum treatment. (7.6 g,29.1mmol, yield: 97%) MS m/z:261.1[ M+H ]] ⁺ 。

Step 2: synthesis of 8-bromothiochroman-4-one

3- ((2-bromophenyl) thio) propanoic acid (7.6 g,29.1 mmol) was added in portions to concentrated sulfuric acid in an ice-water bath. The resulting dark red solution was stirred at room temperature overnight. The resulting mucus was slowly poured into ice water (200 mL) with rapid stirring. The resulting pink suspension was extracted twice with ethyl acetate (200 ml+100 ml). The organic phases were combined and washed with water (50 mL), saturated aqueous sodium bicarbonate (50 mL) and saturated brine (50 mL). After drying over sodium sulfate and spin-drying under vacuum, the residue was treated under high vacuum to give a colorless oil which was used directly in the next step. (4.2 g,17.3mmol, yield: 60%)

Step 3: synthesis of 8-bromothiochroman

To 8-bromothiochroman-4-one (3.0 g,12.3 mmol) in dichloromethane (120 mL) was slowly added boron trifluoride diethyl ether (15.5 mL,123 mmol) at room temperature. Triethylsilane (15.5 mL,97.5 mmol) was added dropwise to the bright yellow solution. The reaction solution was stirred at room temperature for 16 hours. Cooled in an ice-water bath, water (100 mL) was slowly added and stirred for 20 minutes. After separation, the aqueous phase was extracted with dichloromethane (100 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate (50 mL), saturated brine (50 mL), dried over sodium sulfate and concentrated in vacuo (water bath temperature 38-45 ℃ C.) to give a pale yellow oil. (1.9 g, crude yield: 100%)

Step 4: synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (thiochroman-8-yl) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

In a 10mL single vial was added (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid benzyl ester (51 mg,0.1 mmol), 8-bromothiochroman (46 mg,0.2 mmol), tris (dibenzylideneacetone) dipalladium (28 mg,0.03 mmol), 2-di-tert-butylphosphine-2 ',4',6 '-triisopropyl-3, 6-dimethoxy-1, 1' -biphenyl (19 mg,0.04 mmol) and sodium tert-butoxide (16 mg,0.17 mmol). After nitrogen substitution, pre-deoxygenated anhydrous toluene (1 mL) was added. The reaction solution was heated at 100℃for 16 hours. After cooling to room temperature, ethyl acetate (2 mL) and dichloromethane (2 mL) were added, filtered and the filter cake rinsed with ethyl acetate/dichloromethane (4 mL, v: v=1:1). The combined filtrates were dried by vacuum spin-drying. The residue was purified by preparative TLC (silica gel, methanol: dichloromethane=1:6) to give a yellowish brown solid. (26 mg,0.04mmol, yield: 40%) MS m/z 654.7[ M+H ] ] ⁺ 。

Step 5: synthesis of 2- ((S) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (thiochroman-8-yl) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To (S) -2- (cyanomethyl) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy)Yl) -7- (thiochroman-8-yl) -5,6,7, 8-tetrahydropyridine [3,4-d]To a solution of benzyl pyrimidin-4-yl-piperazine-1-carboxylate (36 mg,0.04 mmol) in methanol (2 mL) was added ammonia in methanol (7M, 2 mL) and wet palladium on carbon (70 mg, 5%). After replacing the hydrogen with a hydrogen balloon, stirring was carried out at room temperature for 18 hours. The solid was filtered off and rinsed with methanol (4 mL). The combined organic phases were dried. The residue was mixed with dichloromethane (10 mL) and dried by spinning. The residue was taken up with ethyl acetate (10 mL) and dried by spin to give an off-white powder. The powder was used directly in the next reaction. MS m/z 520.6[ M+H ]] ⁺ 。

Step 6: synthesis of 2- ((S) -1-acryloyl-4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (thiochroman-8-yl) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To 2- ((S) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (thiochroman-8-yl) -5,6,7, 8-tetrahydropyridine [3, 4-d) at room temperature]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile and triethylamine (31. Mu.L, 0.22 mmol) in dichloromethane (2 mL) was slowly dropped a solution of acryloyl chloride (9. Mu.L, 0.11 mmol) in dichloromethane (1 mL). The reaction solution was stirred at room temperature for 15 minutes. Dichloromethane (20 mL) and saturated aqueous sodium carbonate (20 mL) were added, the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and evaporated to give a viscous material. Purification by preparative TLC (methanol: dichloromethane=1:7) afforded an off-white solid (7 mg, overall yield in two steps: 22%). MS m/z 574.7[ M+H ] ] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.00(d,J＝8.0Hz,1H),6.94(d,J＝8.0Hz,1H),6.87-6.85(m,1H),6.66-6.56(m,1H),6.37(d,J＝16.7Hz,1H),5.81(d,J＝10.6Hz,1H),5.20-5.16(m 1H),4.96-4.74(AB,J＝68,20Hz,2H),4.58-4.55(m,1H),4.25-4.22(m,1H),4.13(s,2H),4.01-3.77(m,1H),3.55-3.05(m,6H),3.00-2.68(m,8H),2.35-2.26(m,3H),2.16-2.08(m,2H),1.98-1.92(m,6H).

Examples 614 to 624 were prepared by the method of example 613

Example 625: synthesis of 2- ((S) -1-propenoyl-4- (7- (isothiochroman-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 2- ((2-bromophenyl) thio) acetyl chloride

Thionyl chloride (0.29 mL,4 mmol) was mixed with 2- ((2-bromophenyl) thio) acetic acid (550 mg,2 mmol) to give a pale yellow solution. Heated in an oil bath at 82℃for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the mixture was subjected to high vacuum to give a pale yellow oil which was used directly in the next reaction.

Step 2: synthesis of 5-bromoisothiochroman

A suspension of aluminum trichloride (560 mg,4.2 mmol) in dry dichloromethane (1 mL) was cooled in an ice-water bath, a solution of 2- ((2-bromophenyl) thio) acetyl chloride in dry dichloromethane (2 mL) was slowly added dropwise, the reaction was slowly warmed to room temperature and stirred for 2 hours, the reaction was poured into ice cubes (20 g) and vigorously stirred for 5 minutes, the more yellow suspension was extracted with methyl tert-butyl ether (20 mL. Times.2), the organic phases were combined, washed with saturated aqueous sodium carbonate (10 mL), saturated brine (10 mL), dried over sodium sulfate and spun dry under reduced pressure to give a yellow oil, column chromatography (silica gel, petroleum ether) was purified to give a white solid (211 mg,0.92mmol, yield: 46%)

Step 3: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (7- (isothioroman-5-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

In a 10mL single vial was added (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (66 mg,0.14 mmol), 5-bromoisothiochroman (64 mg,0.28 mmol), tris (dibenzylideneacetone) dipalladium (38 mg,0.042 mmol), 2-di-tert-butylphosphine-2 ',4',6 '-triisopropyl-3, 6-dimethoxy-1, 1' -biphenyl (26 mg,0.056 mmol) and sodium tert-butoxide (23 mg,0.238 mmol). After nitrogen substitution, pre-deoxygenated anhydrous toluene (2 mL) was added. The reaction solution was heated at 100℃for 16 hours. After cooling to room temperature, ethyl acetate (2 mL) and dichloromethane (2 mL) were added, filtered and the filter cake rinsed with ethyl acetate/dichloromethane (4 mL, v: v=1:1). The combined filtrates were dried by vacuum spin-drying. The residue was purified by preparative TLC (silica gel, methanol: dichloromethane=1:8) to give a pale yellow solid. (56 mg, 0.09mmol, yield: 65%) MS m/z:620.7[ M+H ]] ⁺ 。

Step 4: synthesis of 2- ((S) -4- (7- (isothioroman-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To a solution of tert-butyl (S) -2- (cyanomethyl) -4- (7- (isotherm-5-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (20 mg,0.032 mmol) in dichloromethane (3 mL) was added dropwise trifluoroacetic acid (1 mL) at room temperature the resulting solution was stirred at room temperature for 1 hour, dichloromethane (7 mL) was added and concentrated in vacuo.

Step 5: synthesis of 2- ((S) -1-propenoyl-4- (7- (isothiochroman-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To 2- ((S) -4- (7- (isotherm-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3, 4-d) at room temperature]PyrimidineA solution of acryloyl chloride (0.0053 mL,0.064 mmol) in dichloromethane (1 mL) was slowly dropped in a solution of 4-yl-piperazin-2-yl) acetonitrile and triethylamine (0.027 mL,0.19 mmol) in dichloromethane (2 mL). The reaction solution was stirred at room temperature for 15 minutes. Dichloromethane (20 mL) and saturated aqueous sodium carbonate (20 mL) were added, the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and evaporated to give a viscous material. Purification by preparative TLC (methanol: dichloromethane=1:8) afforded a white solid (9.4 mg, overall yield in two steps: 51%). MS m/z 574.7[ M+H ] ] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.22-7.18(m,1H),7.03(d,J＝8.0Hz,1H),6.97(d,J＝8.0Hz,1H),6.66-6.56(m,1H),6.40(d,J＝16.7Hz,1H),5.83(d,J＝10.6Hz,1H),5.10-5.00(m,1H),4.47-4.45(m,1H),4.22-4.19(m,1H),4.06-4.04(m,1H),4.03(s,2H),3.76(s,2H),3.65-3.35(m,2H),3.24-3.04(m,5H),3.00-2.68(m,10H),2.35-2.15(m,4H),2.10-1.98(m,4H).

Example 626 Synthesis of 2- ((S) -1-propenoyl-4- (7- (isochroman-8-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy)) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

step 1 (S) -Synthesis of tert-butyl 2- (cyanomethyl) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate:

the compound (S) -2- (cyanomethyl) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (50 mg,0.11 mmol) and 8-bromochroman (33.9 mg,0.16 mmol) were dissolved in toluene. Pd is added in turn under the nitrogen atmosphere ₂ (dba) ₃ (38.8 mg,0.042 mmol), ruPhos (24.7 mg,0.053 mmol) and t-Buona (25.0 mg,0.27 mmol) were then heated to 100℃and stirred at this temperature overnight. Concentrating the reaction mixture under reduced pressure, and purifying by PLC to obtain the compound (S) -2- (cyanomethyl) -4- (7- (iso)Chroman-8-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (22 mg, 34%). MS M/z [ M+H ]] ⁺ ＝604.3。

Step 2 Synthesis of 2- ((S) -4- (7- (isochroman-8-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

The compound (S) -2- (cyanomethyl) -4- (7- (isochroman-8-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (22 mg,0.036 mmol) was dissolved in CH ₂ Cl ₂ (2.4 mL) and TFA (0.8 mL) was added dropwise. The reaction solution was stirred at room temperature until the reaction was completed. Then, the reaction solution was adjusted to ph=10 with 10% naoh aqueous solution, and the solution was separated, CH ₂ Cl ₂ Extraction, washing with saturated saline, drying (Na ₂ SO ₄ ) Filtering, concentrating under reduced pressure to obtain compound 2- ((S) -4- (7- (isochroman-8-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (18 mg, 100%). MS M/z [ M+H ]] ⁺ ＝504.7。

Step 3 Synthesis of 2- ((S) -1-propenoyl-4- (7- (isochroman-8-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy)) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

the compound 2- ((S) -4- (7- (isochroman-8-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (18 mg,0.036 mmol) and triethylamine (10.8 mg,0.11 mmol) were dissolved in CH ₂ Cl ₂ (1.0 mL) and then acryloyl chloride (6.4 mg,0.072 mmol) was added dropwise to the solution and stirred at room temperature for 1h. Concentrating the reaction solution under the condition of pressurization, and purifying by using a PLC to obtain the compound 2- ((S) -1-acryloyl-4- (7- (isochroman-8-yl) -2- ((((S) -1-methylpyrrolidine-2-yl) methoxy)) -5,6,7, 8-tetrahydropyrido [3, 4-d) ]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (11.5 mg, 58%). MS M/z [ M+H ]] ⁺ ＝558.8。 ¹ H NMR(400MHz,CDCl ₃ )δ7.20(t,J＝7.7Hz,1H),6.96(dd,J＝19.1,10.3Hz,2H),6.58(m,1H),6.38(d,J＝16.6Hz,1H),5.82(d,J＝10.1Hz,1H),4.82(m,2H),4.73-4.43(m,1H),4.33-4.17(m,1H),4.16-3.84(m,4H),3.36-2.97(m,7H),2.91-2.62(m,10H),2.35-2.10(m,3H),2.10-1.86(m,3H),1.80(dt,J＝12.2,7.1Hz,4H).

Example 627: synthesis of 2- ((S) -1-acryloyl-4- (7- (isochroman-5-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (7- (isochroman-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

In a 10mL single vial was added (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (66 mg,0.14 mmol), 5-bromochroman (60 mg,0.28 mmol), tris (dibenzylideneacetone) dipalladium (38 mg,0.042 mmol), 2-di-tert-butylphosphine-2 ',4',6 '-triisopropyl-3, 6-dimethoxy-1, 1' -biphenyl (26 mg,0.056 mmol) and sodium tert-butoxide (23 mg,0.238 mmol). After nitrogen substitution, pre-deoxygenated anhydrous toluene (2.5 mL) was added. The reaction solution was heated at 100℃for 16 hours. After cooling to room temperature, ethyl acetate (2 mL) and dichloromethane (2 mL) were added, filtered and the filter cake rinsed with ethyl acetate/dichloromethane (4 mL, v: v=1:1). The combined filtrates were dried by vacuum spin-drying. The residue was purified by preparative TLC (silica gel, methanol: dichloromethane=1:8) to give a pale yellow solid. (37 mg, 0.062mmol, yield: 44%) MS m/z 604.7[ M+H ] ] ⁺ 。

Step 2: synthesis of 2- ((S) -4- (7- (isochroman-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To a solution of tert-butyl (S) -2- (cyanomethyl) -4- (7- (isochroman-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (18 mg,0.03 mmol) in dichloromethane (3 mL) was added dropwise trifluoroacetic acid (1 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour. Dichloromethane (7 mL) was added and concentrated in vacuo. Dichloromethane (5 mL) was added to the resulting residue to concentrate again and the process was repeated once. The yellow solid obtained was used directly in the next step.

Step 3: synthesis of 2- ((S) -1-acryloyl-4- (7- (isochroman-5-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To 2- ((S) -4- (7- (isochroman-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3, 4-d) at room temperature]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile and triethylamine (0.026 mL,0.18 mmol) in dichloromethane (2 mL) was slowly dropped a solution of acryloyl chloride (0.005 mL,0.062 mmol) in dichloromethane (1 mL). The reaction solution was stirred at room temperature for 15 minutes. Dichloromethane (20 mL) and saturated aqueous sodium carbonate (20 mL) were added, the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and evaporated to give a viscous material. Purification by preparative TLC (methanol: dichloromethane=11:80) afforded a white solid (10 mg, total yield in two steps: 60%). MS m/z 558.7[ M+H ] ] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.27-7.18(m,1H),6.95(d,J＝8.0Hz,1H),6.79(d,J＝8.0Hz,1H),6.66-6.56(m,1H),6.40(d,J＝16.7Hz,1H),5.83(d,J＝10.6Hz,1H),5.20-5.02(m,2H),4.82(s,2H),4.56-4.53(m,1H),4.25-4.12(m,1H),4.08-3.90(m,5H),3.65-3.35(m,2H),3.20-3.04(m,2H),3.00-2.68(m,10H),2.35-2.15(m,4H),2.10-1.98(m,4H).

Examples 628 to 651 were prepared by the method of example 627

Example 652:2- ((S) -1-propenoyl-4- (2- ((((1 r, 2S) -2- (dimethylamino) cyclopentyl) oxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate

The compound tert-butyl 4- (4- (((benzyloxy) carbonyl) piperazin-1-yl) -2- (methylthio) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate (538 mg,1 mmol) was dissolved in 10ml of dichloromethane, 85% m-chloroperoxybenzoic acid (m-CPBA) (244 mg,1.2 mmol) was added under ice-water bath conditions, the reaction system was stirred under ice-water bath conditions for 30min, after the reaction was completed, saturated sodium thiosulfate solution was added to quench the reaction, extraction was performed with dichloromethane, the organic phase was washed with saturated sodium bicarbonate and saturated salt in this order, dried over anhydrous sodium sulfate, and concentrated to give an off-white solid (550 mg, yield: 100%). No treatment was used for the next reaction.

Step 2: synthesis of tert-butyl 4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- (((((1R, 2S) -2- (dimethylamino) cyclopentyl) oxy) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate

The compound tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate and (1S, 2S) -2- (dimethylamino) cyclopentan-1-ol (550 mg,1 mmol) were dissolved in 10ml of dry toluene, sodium tert-butoxide (), added in portions under ice water bath conditions for one hour, stirring was continued, after the reaction was completed, the reaction was quenched with cold water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give an off-white solid. (150 mg, yield: 35%).

Step 3: synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- ((((1R, 2S) -2- (dimethylamino) cyclopentyl) oxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

The compound tert-butyl 4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- ((((((1R, 2S) -2- (dimethylamino) cyclopentyl) oxy) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate (150 mg,0.3 mmol) was dissolved in a cosolvent of TFA and DCM (DCM/TFA: 3ml/1 ml), stirred at room temperature for one hour after completion of the reaction, the reaction was condensed, the resulting residue was added to saturated aqueous sodium bicarbonate and dichloromethane, extracted, the separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product which was used directly in the next step (130 mg, yield: 95%)

Step 4: synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- ((((1R, 2S) -2- (dimethylamino) cyclopentyl) oxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid

The compound (S) -2- (cyanomethyl) -4- (2- ((((1R, 2S) -2- (dimethylamino) cyclopentyl) oxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid benzyl ester (52 mg,0.1 mmol) and 5-bromo-1, 2,3, 4-tetrahydronaphthalene (27 mg,0.12 mmol) were dissolved in anhydrous toluene (5 mL), cesium carbonate (81 mg,0.25 mmol), ruPhos (8.3 mg,0.02 mmol) and Pd were added ₂ (dba) ₃ (9.1 mg,0.01 mmol), nitrogen was replaced three times, heated to 100℃and stirred for reaction for 12 hours. After the reaction, cooling to room temperature, diluting the reaction solution with ethyl acetate, filtering, concentrating the filtrate, and separating by column chromatography to obtain an off-white solid. (65 mg, yield: 49.4%).

Step 5: synthesis of 2- ((S) -4- (2- (((((1R, 2S) -2- (dimethylamino) cyclopentyl) oxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

The compound benzyl (S) -2- (cyanomethyl) -4- (2- ((((1R, 2S) -2- (dimethylamino) cyclopentyl) oxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid (52 mg,0.10 mmol) was dissolved in 5ml of anhydrous methanol, about 0.5ml of 7M/L ammonia methanol solution and 10% Pd/C were added, and after the reaction was completed, the reaction system was filtered through celite to give an off-white solid, (25 mg, yield: 80%) which was directly used for the next reaction without any treatment.

Step 6 Synthesis of 2- ((S) -1-propenoyl-4- (2- ((((1R, 2S) -2- (dimethylamino) cyclopentyl) oxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Compound 2- ((S) -4- (2- (((((1 r, 2S) -2- (dimethylamino) cyclopentyl) oxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (25 mg,0.10 mmol) was dissolved in dichloromethane (3 mL), DIEA (80 mg,0.60 mmol) was added under ice-water bath cooling, followed by acryloyl chloride (18 mg,0.13 mmol) and the reaction stirred under ice-water bath for 10 min. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and PLC separated (dichloromethane/methanol=15/1) to give an off-white solid. (8.8 mg, yield: 45%). ¹ HNMR(400MHz,CDCl ₃ )δ7.27(m,1H),7.21(m,1H),7.02(m,1H),6.62(m,1H),6.04(m,1H),5.58(m,1H),3.65-3.40(m,3H),3.38-3.13(m,4H),3.02-2.98(m,2H),2.85(m,1H),2.75-2.70(m,5H),2.50-2.30(m,3H),2.26(s,3H),1.74-1.41(m,8H).MS m/z:570.35[M+H] ⁺

Example 653: synthesis of (S) -2- (1-propenoyl-4- (2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 2-methyl 1- (tert-butyl) 2- (3-chloropropyl) pyrrolidine-1, 2-dicarboxylic acid:

pyrrolidine 1, 2-dicarboxylic acid 1- (tert-butyl) 2-methyl ester (5.8 g,25.3 mmol) was dissolved in tetrahydrofuran (25 mL), cooled to-78 ℃, liHMDS (1M/L, 37.9 mmol) was added dropwise, after 30 minutes, 1-bromo-3-chloropropane (19.9 g,126 mmol) was added, reacted at room temperature for 2 hours, quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, concentrated and purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give a transparent oil. (5.1 g, yield: 65.9%). ¹ H NMR(400MHz,CDCl ₃ )δ3.83-3.28(m,7H),2.39-1.68(m,8H),1.43(d,J＝13.1Hz,9H)。

Step 2: synthesis of methyl 2- (3-chloropropyl) pyrrolidine-2-carboxylate:

2-methyl 1- (tert-butyl) 2- (3-chloropropyl) pyrrolidine-1, 2-dicarboxylic acid (1 g,3.27 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, and the mixture was reacted at room temperature for 1 hour, and concentrated to dryness, and was directly used in the next reaction.

Step 3: synthesis of methyl tetrahydro-1H-pyrrolizine 7a (5H) -carboxylate:

methyl 2- (3-chloropropyl) pyrrolidine-2-carboxylate (640 mg,3.27 mmol) was dissolved in methanol (10 mL), potassium carbonate (1.35 g,9.81 mmol) was added, potassium iodide (640 mg,0.327 mmol) was reacted at room temperature for 2 hours, the solid was filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give a transparent oil. (400 mg, yield: 72.5%). ¹ H NMR(400MHz,CDCl ₃ )δ3.72(s,3H),3.21-3.11(m,2H),2.64(d,J＝10.2Hz,2H),2.38-2.24(m,2H),1.86-1.76(m,4H),1.72-1.66(m,2H)。

Step 4: synthesis of (tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol:

tetrahydro-1H-pyrrolizine 7a (5H) -carboxylic acid methyl ester (400 mg,2.37 mmol) was dissolved in tetrahydrofuran (10 mL), lithium aluminum hydride (270 mg,7.10 mmol) was added in portions under ice bath, after 1 hour TLC (Petroleum ether/ethyl acetate=10/1) was used to detect completion of the reaction, sodium sulfate decahydrate was added, and filtration was performedThe solid, filtrate was concentrated to a clear oil. (290 mg, yield: 87%). ¹ H NMR(400MHz,MeOD)δ3.36-3.28(m,2H),2.96(dt,J＝10.4,6.1Hz,2H),2.64(ddd,J＝10.5,7.3,6.0Hz,2H),1.97-1.81(m,4H),1.73(dt,J＝12.6,6.8Hz,2H),1.64-1.52(m,2H)。

Step 5: synthesis of benzyl (S) -4- (4- (tert-butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate:

4- ((S) -4- (tert-Butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -5, 8-dihydropyrido [3,4-d ]]Pyrimidine-7 (6H) -carboxylic acid benzyl ester (100 mg,0.18 mmol) and tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (38 mg,0.27 mmol) were dissolved in toluene (10 mL), sodium tert-butoxide (34.6 mg,0.36 mmol) was added under ice-bath, reacted for 1 hour, extracted with dichloromethane, concentrated and purified by column chromatography (dichloromethane/methanol=10/1) to give a pale yellow oil. (100 mg, yield: 88.5%). MS m/z 632.6[ M+H ]] ⁺ 。

Step 6: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (2- (((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate:

(S) -4- (4- (tert-Butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5, 8-dihydropyrido [3,4-d ]]Pyrimidine-7 (6H) -carboxylic acid benzyl ester (100 mg,0.16 mmol) was dissolved in methanol (10 mL), palladium on carbon (10%, 100 mg) was added, reacted under hydrogen balloon pressure for 6 hours, filtered, and the filtrate was concentrated to give a transparent solid. (70 mg, yield: 89.7%). MS m/z 498.5[ M+H ]] ⁺ 。

Step 7: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate:

(S) -2- (cyanomethyl) -4- (2- (((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (74 mg,0.15 mmol) was dissolved in toluene (5 mL) and 5-bromo-1, 2,3, 4-tetrahydronaphthalene (41 mg,0.19 mmol), pd was added ₂ (dba) ₃ (13.6 mg,0.015 mmol), ruPhos (13.8 mg,0.030 mmol), cesium carbonate (121 mg,0.37 mmol), nitrogen-protected, heated to 100 ℃, reacted overnight, TLC monitored completion of the reaction, concentrated solvent, and plate purified (dichloromethane/methanol=10/1) to give an off-white solid (20 mg, yield: 19.3%). MS m/z 628.7[ M+H ]] ⁺ 。

Step 8: synthesis of (S) -2- (4- (2- (((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -7] - (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

(S) -2- (cyanomethyl) -4- (2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (20 mg,0.032 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, reacted at room temperature for 1 hour, concentrated to dryness, aqueous sodium bicarbonate solution was added, dichloromethane extraction, concentrated to light yellow solid, and used directly in the next reaction.

Step 9: synthesis of (S) -2- (1-propenoyl-4- (2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

(S) -2- (4- (2- (((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7)]- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-4-yl) piperazin-2-yl acetonitrile (16.8 mg,0.032 mmol) was dissolved in dichloromethane (5 mL), DIPEA (8.8 mg,0.068 mmol) was added, acryloyl chloride (3 mg,0.033 mmol) was added under ice-bath, the reaction was complete after ten minutes, aqueous sodium bicarbonate solution was added, dichloromethane extraction was performed, and plate purification (dichloromethane/methanol=10/1) was prepared after concentration to give a white solid. (6 mg, yield: 32.4%). ¹ H NMR(400MHz,CDCl ₃ )δ7.09(q,J＝4.4,3.9Hz,2H), 6.77-6.56(m,2H),6.18(dd,J＝13.7,10.1Hz,1H),5.67(dd,J＝16.8,13.8Hz,1H),5.30(dd,J＝17.2,2.7Hz,1H),4.93-4.78(m,1H),4.36-4.23(m,2H),4.02(td,J＝12.1,2.3Hz,1H),3.92(s,2H),3.89-3.62(m,3H),3.38-3.07(m,6H),3.01(dtd,J＝9.6,7.0,4.4Hz,2H),2.97-2.72(m,4H),2.53-2.25(m,3H),2.19-1.88(m,4H),1.88-1.58(m,6H),1.55-1.32(m,2H)；MS m/z:582.3[M+H] ⁺ 。

Examples 654 to 673 were prepared by the method of example 653

EXAMPLE 674 Synthesis of 2- ((S (-1-propenoyl-4- (7- (3-methyl-2, 3-dihydro-1H-indan-4-yl) -2- (((S) -1-methylpyrrolidin-2- (yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

step 1 (S) -Synthesis of tert-butyl 2- (cyanomethyl) -4- (7- (3-methyl-2, 3-dihydro-1H-indan-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate:

The compound (S) -2- (cyanomethyl) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (83.8 mg,0.18 mmol) and 7-bromo-1-methyl-2, 3-dihydro-1H-indene (40 mg,0.21 mmol) were dissolved in toluene (2.5 mL). Pd is added in turn under the nitrogen atmosphere ₂ (dba) ₃ (65.1 mg,0.071 mmol), ruPhos (41.4 mg,0.089 mmol) and t-Buona (42.7 mg,0.27 mmol) were then heated to 100℃and stirred at this temperature overnight. Concentrating the reaction mixture under reduced pressure, and purifying by PLC to obtain the compound(S) -2- (cyanomethyl) -4- (7- (3-methyl-2, 3-dihydro-1H-indan-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (48.1 mg, 45%). MS M/z [ M+H ]] ⁺ ＝602.4。

Step 2 Synthesis of 2- ((S) -4- (7- (3-methyl-2, 3-dihydro-1H-indan-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

the compound (S) -2- (cyanomethyl) -4- (7- (3-methyl-2, 3-dihydro-1H-indan-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (48 mg,0.080 mmol) dissolved in CH ₂ Cl ₂ (1.5 mL) and TFA (0.5 mL) was added dropwise. The reaction solution was stirred at room temperature until the reaction was completed. Then, the reaction solution was adjusted to ph=10 with 10% naoh aqueous solution, and the solution was separated, CH ₂ Cl ₂ Extraction, washing with saturated saline, drying (Na ₂ SO ₄ ) Filtering, concentrating under reduced pressure to obtain compound 2- ((S) -4- (7- (3-methyl-2, 3-dihydro-1H-indan-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (38.5 mg, 96%). MS M/z [ M+H ]] ⁺ ＝502.3。

Step 3 Synthesis of 2- ((S (-1-acryloyl-4- (7- (3-methyl-2, 3-dihydro-1H-indan-4-yl) -2- (((S) -1-methylpyrrolidin-2- (yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

the compound 2- ((S) -4- (7- (3-methyl-2, 3-dihydro-1H-indan-4-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (38 mg,0.076 mmol) and triethylamine (23 mg,0.23 mmol) were dissolved in CH ₂ Cl ₂ (1.0 mL) and then acryloyl chloride (13.7 mg,0.15 mmol) was added dropwise to the solution and stirred at room temperature for 1h. Concentrating the reaction solution under the condition of pressurization, and purifying by a PLC to obtain a compound 2- ((S (-1-acryloyl-4- (7- (3-methyl-2, 3-dihydro-1H-indan-4-yl) -2- ((((S) -1-methylpyrrolidine-2- (yl) methoxy) -5,6,7, 8-tetrahydropyridine) And [3,4-d ]]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (11.3 mg, 27%). MS M/z [ M+H ]] ⁺ ＝556.3。 ¹ H NMR(400MHz,CDCl ₃ )δ7.20-7.09(m,1H),7.02-6.91(m,1H),6.88-6.81(m,1H),6.35(d,J＝16.5Hz,1H),6.20-6.09(m,1H),5.78(d,J＝10.1Hz,1H),4.62-4.43(m,2H),4.41-3.84(m,4H),3.78-2.91(m,8H),2.90-2.44(m,10H),2.42-2.05(m,3H),2.07-1.84(m,4H),1.82(dt,J＝12.1,7.0Hz,4H).

Example 675: synthesis of 2- ((S) -1-acryloyl-4- (7- (2, 2-dimethyl-2, 3-dihydro-1H-inden-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 4-bromo-2, 2-dimethyl-2, 3-dihydro-1H-inden-1-one

To a suspension of sodium hydrogen (268 mg,9.2 mmol) in tetrahydrofuran (10 mL) was added dropwise a solution of 4-bromo-2, 3-dihydro-1H-inden-1-one (844 mg,4.0 mmol) in tetrahydrofuran (5 mL) in an ice-water bath. The resulting brown suspension was slowly warmed to room temperature and stirred for 45 minutes. Methyl iodide (1.0 mL,16 mmol) was added dropwise. The resulting dark brown solution was stirred at room temperature for 1.5 hours. The reaction was quenched by slow addition of water (2 mL). Methyl tert-butyl ether (50 mL) and water (30 mL) were added. After shaking and separation, the aqueous phase was extracted with methyl tert-butyl ether (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over sodium sulfate and concentrated in vacuo to a brown oil (970 mg, crude) which was used directly in the next reaction.

Step 2: synthesis of 4-bromo-2, 2-dimethyl-2, 3-dihydro-1H-indene

To 4-bromo-2, 2-dimethyl-2, 3-dihydro-1H-inden-1-one (359 mg, crude) in dichloromethane (15 mL) was slowly added boron trifluoride diethyl ether (1.88 mL,15 mmol) at room temperature. Triethylsilane (1.9 ml,12 mmol) was added dropwise to the bright yellow solution. The reaction solution was stirred at room temperature for 16 hours. Cooled in an ice-water bath, water (20 mL) was slowly added and stirred for 20 minutes. After separation, the aqueous phase was extracted with dichloromethane (20 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate (10 mL), saturated brine (10 mL), dried over sodium sulfate and concentrated in vacuo (water bath temperature 38-45 ℃ C.) to give a pale yellow oil. (152 mg, overall yield in two steps: 46%)

Step 3: synthesis of benzyl (S) -2- (cyanomethyl) -4- (7- (2, 2-dimethyl-2, 3-dihydro-1H-inden-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

In a 10mL single vial was added (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid benzyl ester (51 mg,0.1 mmol), 4-bromo-2, 2-dimethyl-2, 3-dihydro-1H-indene (30 mg,0.13 mmol), tris (dibenzylideneacetone) dipalladium (27 mg,0.03 mmol), 2-di-tert-butylphosphine-2 ',4',6 '-triisopropyl-3, 6-dimethoxy-1, 1' -biphenyl (19 mg,0.04 mmol), and sodium tert-butoxide (16 mg,0.17 mmol). After nitrogen substitution, pre-deoxygenated anhydrous toluene (1.0 mL) was added. The reaction solution was heated at 100℃for 16 hours. After cooling to room temperature, ethyl acetate (2 mL) and dichloromethane (2 mL) were added, filtered and the filter cake rinsed with ethyl acetate/dichloromethane (4 mL, v: v=1:1). The combined filtrates were dried by vacuum spin-drying. The residue was purified by preparative TLC (silica gel, methanol: dichloromethane=1:8) to give a pale yellow solid. (16 mg, 0.0246mmol, yield: 25%) MS m/z 604.7[ M+H ]] ⁺ 。

Step 4: synthesis of 2- ((S) -4- (7- (2, 2-dimethyl-2, 3-dihydro-1H-inden-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To a solution of benzyl (S) -2- (cyanomethyl) -4- (7- (2, 2-dimethyl-2, 3-dihydro-1H-inden-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (15 mg,0.023 mmol) in methanol (1.5 mL) was added ammonia in methanol (7M, 1.5 mL) and wet palladium on carbon (33 mg, 5%). After replacing the hydrogen with a hydrogen balloon, stirring was carried out at room temperature for 4 hours. The solid was filtered off and rinsed with methanol (5 mL). The combined organic phases were dried. The residue was mixed with dichloromethane (10 mL) and dried by spinning. The residue was taken up with ethyl acetate (10 mL) and dried by spin to give an off-white powder. The powder was used directly in the next reaction.

Step 5: synthesis of 2- ((S) -1-acryloyl-4- (7- (2, 2-dimethyl-2, 3-dihydro-1H-inden-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To 2- ((S) -4- (7- (2, 2-dimethyl-2, 3-dihydro-1H-inden-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3,4-d ] at room temperature]To a solution of pyrimidin-4-yl-piperazin-2-yl) acetonitrile and triethylamine (0.040 mL,0.28 mmol) in dichloromethane (2 mL) was added dropwise acryloyl chloride (0.01 mL). The reaction solution was stirred at room temperature for 15 minutes. Dichloromethane (20 mL) and saturated aqueous sodium carbonate (20 mL) were added, the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and evaporated to give a viscous material. Purification by preparative TLC (methanol: dichloromethane=1:8) gave a pale yellow solid (7 mg,0.123mmol, overall yield in two steps: 53%). MS m/z 570.7[ M+H ] ] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.15-7.11(m,1H),6.90(d,J＝8.0Hz,1H),6.76(d,J＝8.0Hz,1H),6.66-6.56(m,1H),6.40(d,J＝16.7Hz,1H),5.83(d,J＝10.6Hz,1H),5.20-5.02(m,2H),4.56-4.53(m,1H),4.26-3.78(m,6H),3.65-3.49(m,2H),3.32-2.80(m,6H),2.78-2.58(m,6H),2.35-2.15(m,4H),2.10-1.98(m,4H),1.16(s,6H).

Example 676: synthesis of 2- ((2S) -1-acryloyl-4- (7- (2-methyl-2, 3-dihydro-1H-inden-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 4-bromo-2-methyl-2, 3-dihydro-1H-inden-1-one

Lithium bis- (trimethylsilyl) amide (1M, 6 mL) in tetrahydrofuran (10 mL) was cooled to-70 ℃. A solution of 4-bromo-2, 3-dihydro-1H-inden-1-one (1.27 g,6 mmol) in tetrahydrofuran (5 mL) was added dropwise. The reaction solution was stirred at this temperature for 30 minutes. Methyl iodide (0.37 mL,6 mmol) was added. The reaction solution was gradually warmed to room temperature and stirred for 16 hours. The reaction was quenched by slow addition of saturated aqueous ammonium chloride (15 mL). Methyl tert-butyl ether (50 mL) and water (15 mL) were added. After shaking and separation, the aqueous phase was extracted with methyl tert-butyl ether (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over sodium sulfate, concentrated in vacuo to a brown oil, which was purified by column chromatography (silica gel, ethyl acetate: petroleum ether=1:40) to give a colorless oil. (125 mg, yield: 9.3%)

Step 2: synthesis of 4-bromo-2-methyl-2, 3-dihydro-1H-indene

To 4-bromo-2-methyl-2, 3-dihydro-1H-inden-1-one (62 mg,0.275 mmol) in dichloromethane (3 mL) was slowly added boron trifluoride diethyl ether (0.35 mL,2.75 mmol) at room temperature. Triethylsilane (0.35 ml,2.18 mmol) was added dropwise to the bright yellow solution. The reaction solution was stirred at room temperature for 16 hours. Cooled in an ice water bath, water (20 mL) and dichloromethane (17 mL) were slowly added and stirred for 20 minutes. After separation, the aqueous phase was extracted with dichloromethane (20 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate (10 mL), saturated brine (10 mL), dried over sodium sulfate, concentrated in vacuo and worked up in high vacuum to give a colorless oil. (47 mg,0.223mmol, yield: 81%)

Step 3: synthesis of benzyl (2S) -2- (cyanomethyl) -4- (7- (2-methyl-2, 3-dihydro-1H-inden-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

In a 10mL single vial was added (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid benzyl ester (60 mg,0.119 mmol), 4-bromo-2-methyl-2, 3-dihydro-1H-indene (47 mg,0.223 mmol), tris (dibenzylideneacetone) dipalladium (33 mg,0.036 mmol), 2-di-tert-butylphosphine-2 ',4',6 '-triisopropyl-3, 6-dimethoxy-1, 1' -biphenyl (28 mg,0.06 mmol), and sodium t-butoxide (19 mg,0.2 mmol). After nitrogen substitution, pre-deoxygenated anhydrous toluene (1.5 mL) was added. The reaction solution was heated at 100℃for 16 hours. After cooling to room temperature, ethyl acetate (2 mL) and dichloromethane (2 mL) were added, filtered and the filter cake was flushed with ethyl acetate/dichloromethane (4 mL, v: v=1:1)And (5) washing. The combined filtrates were dried by vacuum spin-drying. The residue was purified by preparative TLC (silica gel, methanol: dichloromethane=1:8) to give a pale yellow solid. (13 mg, 0.0204mmol, yield: 17%) MS m/z 604.7[ M+H ]] ⁺ 。

Step 4: synthesis of 2- ((2S) -4- (7- (2-methyl-2, 3-dihydro-1H-inden-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To a solution of benzyl (2S) -2- (cyanomethyl) -4- (7- (2-methyl-2, 3-dihydro-1H-inden-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (13 mg,0.0204 mmol) in methanol (1.5 mL) was added ammonia in methanol (7 m,1.5 mL) and wet palladium on carbon (33 mg, 5%). After replacing the hydrogen with a hydrogen balloon, stirring was carried out at room temperature for 4 hours. The solid was filtered off and rinsed with methanol (5 mL). The combined organic phases were dried. The residue was mixed with dichloromethane (10 mL) and dried by spinning. The residue was taken up with ethyl acetate (10 mL) and dried by spin to give an off-white powder. The powder was used directly in the next reaction.

Step 5: synthesis of 2- ((2S) -1-acryloyl-4- (7- (2-methyl-2, 3-dihydro-1H-inden-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To 2- ((S) -4- (7- (5-methyl-5, 6,7, 8-tetrahydropyridine [3, 2-d) at room temperature]Pyrimidin-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3,4-d]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile and triethylamine (0.04 mL,0.28 mmol) in dichloromethane (2 mL) was slowly dropped a solution of acryloyl chloride (0.005 mL,0.062 mmol) in dichloromethane (1 mL). The reaction solution was stirred at room temperature for 15 minutes. Dichloromethane (20 mL) and saturated aqueous sodium carbonate (20 mL) were added, the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and evaporated to give a viscous material. Purification by preparative TLC (MeOH: dichloromethane=1:5) gave a white solid (7 mg,0.0126mmol, overall yield in two steps: 63%). MS m/z 556.7[ M+H ] ] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.15-7.11(m,1H),6.93(d,J＝8.0Hz,1H),6.77(d,J＝8.0Hz,1H),6.66-6.56(m,1H),6.40(d,J＝16.7Hz,1H),5.83(d,J＝10.6Hz,1H),5.10-4.80(m,2H),4.46-4.40(m,1H),4.26-3.88(m,6H),3.65-3.49(m,2H),3.32-2.78(m,4H),2.76-2.54(m,6H),2.52-2.49(m,3H),2.35-2.15(m,4H),2.10-1.98(m,4H),1.17(s,3H).

Examples 677-683 were prepared using the method of example 676

Example 684: synthesis of 2- ((2S) -1-acryloyl-4- (7- (1-methyl-2, 3-dihydro-1H-inden-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 4-bromo-1-methylene-2, 3-dihydro-1H-indene

To a solution of potassium tert-butoxide (1M, 2 mL) in anhydrous tetrahydrofuran (5 mL) was added methyltriphenyl phosphorus iodide (178 mg,2.0 mmol) at room temperature. The resulting yellow suspension was stirred at room temperature for 40 minutes. 4-bromo-2, 3-dihydro-1H-inden-1-one (211 mg,1.0 mmol) was added in one portion. The resulting cyan reaction solution was stirred at room temperature for 13 hours. The reaction solution was poured into water (30 mL) and methyl tert-butyl ether (30 mL). After shaking and separation, the aqueous phase was extracted with methyl tert-butyl ether (15 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and spun-dried in vacuo. The remaining purplish red oil was purified by column chromatography (silica gel, petroleum ether) to give a colorless oil. (150 mg, yield: 72%)

Step 2: synthesis of benzyl (S) -2- (cyanomethyl) -4- (7- (1-methylene-2, 3-dihydro-1H-inden-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

In a 10mL single vial was added (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid benzyl ester (51 mg,0.1 mmol), 4-bromo-1-methylene-2, 3-dihydro-1H-indene (42 mg,0.2 mmol), tris (dibenzylideneacetone) dipalladium (28 mg,0.03 mmol), 2-di-tert-butylphosphine-2 ',4',6 '-triisopropyl-3, 6-dimethoxy-1, 1' -biphenyl (19 mg,0.04 mmol), and sodium t-butoxide (16 mg,0.17 mmol). After nitrogen substitution, pre-deoxygenated anhydrous toluene (1.5 mL) was added. The reaction solution was heated at 100℃for 16 hours. After cooling to room temperature, ethyl acetate (2 mL) and dichloromethane (2 mL) were added, filtered and the filter cake rinsed with ethyl acetate/dichloromethane (4 mL, v: v=1:1). The combined filtrates were dried by vacuum spin-drying. The residue was purified by preparative TLC (silica gel, methanol: dichloromethane=1:8) to give a pale yellow solid. (13 mg,0.02mmol, yield: 20%) MS m/z:634.7[ M+H ]] ⁺ 。

Step 3: synthesis of 2- ((2S) -4- (7- (1-methyl-2, 3-dihydro-1H-inden-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To a solution of benzyl (S) -2- (cyanomethyl) -4- (7- (1-methylene-2, 3-dihydro-1H-inden-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (13 mg,0.02 mmol) in methanol (2 mL) was added ammonia in methanol (7M, 2 mL) and wet palladium on carbon (29 mg, 5%). After replacing the hydrogen with a hydrogen balloon, stirring was carried out at room temperature for 3 hours. The solid was filtered off and rinsed with methanol (5 mL). The combined organic phases were dried. The residue was mixed with dichloromethane (10 mL) and dried by spinning. The residue was taken up with ethyl acetate (10 mL) and dried by spin to give an off-white powder. The powder was used directly in the next reaction.

Step 4: synthesis of 2- ((2S) -1-acryloyl-4- (7- (1-methyl-2, 3-dihydro-1H-inden-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To 2- ((2S) -4- (7- (1-methyl-2, 3-dihydro-1H-inden-4-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3,4-d ] at room temperature]A solution of acryloyl chloride (0.01 mL,0.122 mmol) in dichloromethane (1 mL) was slowly dropped in a solution of pyrimidin-4-yl) piperazin-2-yl) acetonitrile and triethylamine (0.04 mL,0.287 mmol) in dichloromethane (2 mL). The reaction solution was stirred at room temperature for 15 minutes. Dichloromethane (20 mL) and saturated aqueous sodium carbonate (20 mL) were added, the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and evaporated to give a viscous material. Purification by preparative TLC (methanol: dichloromethane=1:8) gave a white powder (6 mg, overall yield in two steps: 30%). MS m/z 556.7[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.21-7.17(m,1H),6.93(d,J＝8.0Hz,1H),6.80(d,J＝8.0Hz,1H),6.66-6.56(m,1H),6.40(d,J＝16.7Hz,1H),5.83(d,J＝10.6Hz,1H),5.10-5.00(m,1H),4.80-4.75(m,1H),4.46-4.40(m,1H),4.26-3.88(m,6H),3.65-3.49(m,2H),3.32-2.78(m,4H),2.76-2.54(m,6H),2.52-2.49(m,3H),2.35-2.15(m,4H),2.10-1.98(m,4H),1.25(s,3H).

Example 685: synthesis of 2- ((2S) -1-acryloyl-4- (2- (((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (4-methylthiochroman-8-yl) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 8-bromo-4-methylenethiochroman

To a solution of potassium tert-butoxide (1M, 2 mL) in anhydrous tetrahydrofuran (5 mL) was added methyltriphenyl phosphorus iodide (178 mg,2.0 mmol) at room temperature. The resulting yellow suspension was stirred at room temperature for 30 minutes. 8-bromo-thiochroman-4-one (243 mg,1.0 mmol) was added in one portion. The resulting orange reaction solution was stirred at room temperature for 16 hours. The reaction solution was poured into water (30 mL) and methyl tert-butyl ether (30 mL). After shaking and separation, the aqueous phase was extracted with methyl tert-butyl ether (15 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and spun-dried in vacuo. The remaining purplish red oil was purified by column chromatography (silica gel, petroleum ether) to give a colorless oil. (31 mg,0.129mmol, yield: 13%)

Step 2: synthesis of benzyl (S) -2- (cyanomethyl) -4- (7- (4-methylenethiochroman-8-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

In a 10mL single vial was added (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid benzyl ester (66 mg,0.13 mmol), 8-bromo-4-methylenethiochroman (42 mg,0.174 mmol), tris (dibenzylideneacetone) dipalladium (36 mg,0.039 mmol), 2-di-tert-butylphosphine-2 ',4',6 '-triisopropyl-3, 6-dimethoxy-1, 1' -biphenyl (30 mg,0.065 mmol), and sodium t-butoxide (21 mg,0.221 mmol). After nitrogen substitution, pre-deoxygenated anhydrous toluene (1.5 mL) was added. The reaction solution was heated at 100℃for 16 hours. After cooling to room temperature, ethyl acetate (2 mL) and dichloromethane (2 mL) were added, filtered and the filter cake rinsed with ethyl acetate/dichloromethane (4 mL, v: v=1:1). The combined filtrates were dried by vacuum spin-drying. The residue was purified by preparative TLC (silica gel, methanol: dichloromethane=1:8) to give a pale yellow solid. (17 mg, 0.0255mmol, yield: 20%) MS m/z:666.7[ M+H ] ] ⁺ 。

Step 3: synthesis of 2- ((2S) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (4-methylthiochroman-8-yl) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To a solution of benzyl (S) -2- (cyanomethyl) -4- (7- (4-methylenethiochroman-8-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (17 mg,0.0255 mmol) in methanol (2 mL) was added a solution of ammonia in methanol (7 m,2 mL) and wet palladium on carbon (29 mg, 5%). After replacing the hydrogen with a hydrogen balloon, stirring was carried out at room temperature for 3 hours. The solid was filtered off and rinsed with methanol (5 mL). The combined organic phases were dried. The residue was mixed with dichloromethane (10 mL) and dried by spinning. The residue was taken up with ethyl acetate (10 mL) and dried by spin to give an off-white powder. The powder was used directly in the next reaction.

Step 4: synthesis of 2- ((2S) -1-acryloyl-4- (2- (((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (4-methylthiochroman-8-yl) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To 2- ((2S) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (4-methylthiochroman-8-yl) -5,6,7, 8-tetrahydropyridine [3, 4-d) at room temperature ]A solution of acryloyl chloride (0.01 mL,0.122 mmol) in dichloromethane (1 mL) was slowly dropped in a solution of pyrimidin-4-yl) piperazin-2-yl) acetonitrile and triethylamine (0.04 mL,0.287 mmol) in dichloromethane (2 mL). The reaction solution was stirred at room temperature for 16 hours. Dichloromethane (20 mL) and saturated aqueous sodium carbonate (20 mL) were added, the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and evaporated to give a viscous material. Purification by preparative TLC (methanol: dichloromethane=11:96) gave a pale yellow powder (10 mg,0.017mmol, overall yield in two steps: 67%). MS m/z 588.7[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.06-7.01(m,1H),6.98-6.94(m,2H),6.66-6.56(m,1H),6.40(d,J＝16.7Hz,1H),5.83(d,J＝10.6Hz,1H),5.10-5.00(m,1H),4.80-4.75(m,1H),4.46-4.40(m,1H),4.26-3.88(m,6H),3.65-3.49(m,2H),3.32-2.98(m,4H),2.96-2.54(m,7H),2.23-1.98(m,10H),1.29(s,3H).

Example 686 Synthesis of 2- (((2S) -1-propenoyl-4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy)) -7- (1 a,2,3,7 b-tetrahydro-1H-cyclopropa [ a ] naphthalen-7-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

step 1, synthesis of 5-bromo-1, 2-dihydronaphthalene:

the compound 8-bromo-1, 2,3, 4-tetrahydronaphthalen-1-ol (500mg,2.20 mmol) and triethylamine (267 mg,2.64 mmol) were dissolved in dichloromethane (10 mL). A solution of trifluoromethanesulfonic anhydride (745 mg,2.64 mmol) in methylene chloride (6 mL) was added dropwise at-10℃and then reacted at 0℃for 2h. At 0 ℃, saturated NaHCO is added ₃ The reaction was continued for 1h. Dichloromethane was added to dilute, the solution was separated, and the organic phase was washed with saturated brine and dried (Na ₂ SO ₄ ) Filtering, concentrating under reduced pressure to obtain crude product, and column chromatography to obtain compound 5-bromo-1, 2-dihydronaphthalene (450 mg, 97%). ¹ H NMR(400MHz,CDCl ₃ )δ7.38(d,J＝7.9Hz,1H),7.02(t,J＝10.0Hz,1H),6.95(t,J＝7.7Hz,1H),6.84(d,J＝9.8Hz,1H),6.24-6.10(m,1H),2.79(t,J＝8.2Hz,2H),2.36-2.23(m,2H).

Step 2 synthesis of 7-bromo-1 a,2,3,7 b-tetrahydro-1H-cyclopropa [ a ] naphthalene:

the compound 5-bromo-1, 2-dihydronaphthalene (440 mg,2.10 mmol) and diethyl zinc (16.8 mL,16.83mmol,1.0M in toluene) were dissolved in toluene (5 mL). Diiodomethane (2.71 mL,9.02g,33.67 mmol) was added dropwise to the above solution at room temperature, and the reaction was stirred at room temperature for 24h. The reaction solvent was removed under pressure and the crude product was dissolved in dichloromethane (5.2 mL) and saturated NaHCO was added ₃ Solution (5.2 mL). m-CPBA (726 mg,4.21 mmol) was added at 0deg.C and the reaction was stirred at room temperature overnight. The mixture was separated, extracted with dichloromethane, and the organic phase was washed with saturated brine and dried (Na ₂ SO ₄ ) Filtering, concentrating under reduced pressure to obtain crude product, and purifying by PLC to obtain compound 7-bromo-1 a,2,3,7 b-tetrahydro-1H-cyclopropane [ a ]]Naphthalene (83.4 mg, 18%). ¹ H NMR(400MHz,CDCl ₃ )δ7.39(d,J＝7.8Hz,1H),7.01-6.86(m,2H),2.60(dd,J＝16.0,3.1Hz,1H),2.52-2.39(m,1H),2.39-2.29(m,1H),2.14-2.01(m,1H),1.82-1.68(m,1H),1.65-1.58(m,2H),1.03-0.92(m,1H).

Step 3 (S) -Synthesis of benzyl 2- (cyanomethyl) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1 a,2,3,7 b-tetrahydro-1H-cyclopropa [ a ] naphthalen-7-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate:

The compound (S) -2- (cyanomethyl) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine)And [3,4-d ]]Pyrimidine-4-yl) piperazine-1-carboxylic acid benzyl ester (75.7 mg,0.15 mmol) and 7-bromo-1 a,2,3,7 b-tetrahydro-1H-cyclopropa [ a ]]Naphthalene (40 mg,0.18 mmol) was dissolved in toluene (2.1 mL). Pd is added in turn under the nitrogen atmosphere ₂ (dba) ₃ (54.7 mg,0.060 mmol), ruPhos (34.9 mg,0.075 mmol) and t-Buona (35.9 mg,0.37 mmol) were then heated to 100deg.C and stirred at this temperature overnight. Concentrating the reaction mixture under reduced pressure, and purifying by PLC to obtain the compound (S) -2- (cyanomethyl) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1 a,2,3,7 b-tetrahydro-1H-cyclopropane [ a ])]Naphthalen-7-yl) -5,6,7, 8-tetrahydropyrido [3,4-d]Pyrimidine-4-yl) piperazine-1-carboxylic acid benzyl ester (56.6 mg, 58%). MS M/z [ M+H ]] ⁺ ＝648.9。

Step 4 Synthesis of 2- ((S) -4- (2- (((((S) -1-methylpyrrolidin-2-yl) methoxy ] ] -7- (1 a,2,3,7 b-tetrahydro-1H-cyclopropa [ a ] naphthalen-7-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

the compound (S) -2- (cyanomethyl) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1 a,2,3,7 b-tetrahydro-1H-cyclopropa [ a ])]Naphthalen-7-yl) -5,6,7, 8-tetrahydropyrido [3,4-d]Pyrimidine-4-yl) piperazine-1-carboxylic acid benzyl ester (22 mg,0.034 mmol) was dissolved in methanol (1 mL) and methanolic ammonia (0.2 mL, 7M) and 10% wet Pd/C (20 mg) was added under nitrogen atmosphere to replace hydrogen and the reaction was stirred at room temperature for 5 hours. After completion of the reaction, the mixture was filtered through celite and washed with methanol, the methanol phase was collected and concentrated to give 2- ((S) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) group) ]]-7- (1 a,2,3,7 b-tetrahydro-1H-cyclopropa [ a)]Naphthalen-7-yl) -5,6,7, 8-tetrahydropyrido [3,4-d]Pyrimidin-4-yl) piperazin-2-yl-acetonitrile (17 mg, yield: 97%). MS M/z [ M+H ]] ⁺ ＝514.3。

Step 5 Synthesis of 2- (((S) -1-propenoyl-4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy)) -7- (1 a,2,3,7 b-tetrahydro-1H-cyclopropa [ a ] naphthalen-7-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

compound 2- ((S) -4- (2- (((((S) -1-methylpyrrolidin-2-yl) methoxy) group)]]-7- (1 a,2,3,7 b-tetrahydro-1H-cyclopropa [ a)]Naphthalen-7-yl) -5,6,7, 8-tetrahydropyrido [3,4-d]Pyrimidin-4-yl) piperazin-2-yl acetonitrile (10 mg,0.025 mmol) and triethylamine (4.5)mg,0.05 mmol) in CH ₂ Cl ₂ (1.0 mL) and then acryloyl chloride (7.6 mg,0.075 mmol) was added dropwise to the solution and stirred at room temperature for 1h. Concentrating the reaction solution under the condition of pressurization, and purifying by using a PLC (programmable logic controller) to obtain the compound 2- (((S) -1-acryloyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy)) -7- (1 a,2,3,7 b-tetrahydro-1H-cyclopropane [ a)]Naphthalen-7-yl) -5,6,7, 8-tetrahydropyrido [3,4-d]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (7.3 mg, 52%). MSm/z [ M+H ]] ⁺ ＝568.3。 ¹ H NMR(400MHz,CDCl ₃ )δ7.04(m,1H),6.94-6.85(m,1H),6.77(m,1H),6.48-6.26(m,1H),6.15(dd,J＝17.1,10.1Hz,1H),5.78(dd,J＝10.1Hz,1H),4.82-3.51(m,8H),3.44-3.21(m,1H),3.19-2.94(m,5H),2.89-2.76(m,6H),2.73-2.56(m,4H),2.51-2.37(m,1H),2.33-2.22(m,1H),2.12(m,1H),1.97(m,1H),1.66(s,3H),1.53(s,1H),1.08-0.91(m,1H),0.90-0.74(m,2H).

Example 687: synthesis of 2- ((2S) -1-propenoyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropan [ a ] inden-2-yl) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 4-bromo-2, 3-dihydro-1H-inden-1-ol

To a suspension of 4-bromo-2, 3-dihydro-1H-inden-1-one (3.17 g,15 mmol) and ethanol (40 mL) was added sodium borohydride (0.74 g,19.5 mmol) in portions at room temperature. The reaction solution was stirred at room temperature for 18 hours. The ethanol was removed by rotary evaporation under reduced pressure. Hydrochloric acid (10% wt,30 mL) and methyl tert-butyl ether (30 mL) were added to the remaining white solid and stirred vigorously for 10 minutes. After separation, the aqueous phase was extracted with methyl tert-butyl ether (30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and spun-dried in vacuo. The remaining oil was treated with high vacuum to give a pale yellow solid. (3.4 g, crude yield: 100%). ¹ H NMR(400MHz,CDCl ₃ )δ7.44(d,J＝7.8Hz,1H),7.36(d,J＝7.8Hz,1H),7.14(t,J＝Hz,1H),5.32(t,J＝8.0Hz,1H),3.13-3.05(m,1H),2.88-2.80(m,1H),2.57-2.50(m,1H),2.02-1.95(m,1H)

Step 2: synthesis of 4-bromo-1H-indene

Concentrated sulfuric acid (5 mL) was mixed with water (25 mL). 4-bromo-2, 3-dihydro-1H-inden-1-ol (3.1 g,14.6 mmol) was added. The reaction mixture was stirred at reflux for 12 hours. After cooling to room temperature, water (100 mL) and methyl tert-butyl ether (150 mL) were added. After shaking and delamination, the organic phase was washed with saturated aqueous sodium bicarbonate (50 mL), saturated brine (50 mL), dried over sodium sulfate and spun-dried under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether) to give a colorless oil. (1.57 g, yield: 55%). ¹ H NMR(400MHz,CDCl ₃ )δ7.36-7.33(m,2H),7.17(t,J＝8Hz,1H),6.94-6.91(m,1H),6.64-6.62(m,1H),3.41(s,2H)

Step 3: synthesis of crude 2-bromo-1, 1a,6 a-tetrahydrocyclopropane [ a ] indene

A solution of diethyl zinc/toluene (2M, 40 mL) in anhydrous dichloromethane (40 mL) was cooled in an ice water bath. A solution of trifluoroacetic acid (2.97 mL,40 mmol) in anhydrous dichloromethane (20 mL) was added dropwise. After stirring at this temperature for 20 minutes, a solution of diiodomethane (3.23 mL,40 mmol) in anhydrous dichloromethane (20 mL) was added. After stirring for a further 20 minutes, a solution of 4-bromo-1H-indene (1.27 g,6.5 mmol) in dry dichloromethane (20 mL) was slowly added dropwise. The ice-water bath was removed and stirred for 24 hours to give a white suspension. Dilute hydrochloric acid (1 n,150 ml) was slowly added with stirring. The resulting mixture was extracted with petroleum ether (200 mL. Times.2). The combined organic phases were washed with saturated brine (100 mL), dried over sodium sulfate and concentrated in vacuo to a yellow oil. Column chromatography (silica gel, petroleum ether) afforded the products of 2-bromo-1, 1a,6 a-tetrahydrocyclopropane [ a ] indene and 4-bromo-1H-indene as colorless oils. (2.12 g)

Step 4: synthesis of 2-bromo-1, 1a,6 a-tetrahydrocyclopropane [ a ] indene

To 2-bromo-1, 1a,6 a-tetrahydrocyclopropane [ a ]]A mixture of indene and 4-bromo-1H-indene (418 mg) was added to dichloromethane (8 mL) and saturated aqueous sodium bicarbonate (8 mL) and cooled with an ice-water bath. M-chloroperoxybenzoic acid (594 mg,85% purity, 2.9 mmol) was added. The resulting white suspension was warmed to room temperature and stirred for 24 hours. Dichloromethane (10 mL) and saturated aqueous sodium sulfite solution (10 mL) were added and Stirring for 20 minutes. After separation, the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate (10 mL), brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give a pale yellow oil. Purification by column chromatography (silica gel, petroleum ether) gave a colorless oil (160 mg,0.766mmol, total yield over two steps: 38%). ¹ H NMR(400MHz,CDCl ₃ )δ7.27-7.21(m,2H),6.98(t,J＝8Hz,1H),3.14(AB,J＝16,4Hz,1H),2.97(AB,J＝16Hz,1H),2.45-2.41(m,1H),1.91-1.85(m,1H),1.12-1.07(m,1H),0.13(m,1H)

Step 5: synthesis of tert-butyl (2S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropan [ a ] inden-2-yl) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

In a 10mL single vial was added (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3, 4-d)]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (50 mg,0.106 mmol), 2-bromo-1, 1a,6 a-tetrahydrocyclopropane [ a ]]Indene (44 mg,0.212 mmol), tris (dibenzylideneacetone) dipalladium (29 mg,0.0318 mmol), 2-di-tert-butylphosphine-2 ',4',6 '-triisopropyl-3, 6-dimethoxy-1, 1' -biphenyl (20 mg,0.0424 mmol) and sodium tert-butoxide (18 mg,0.191 mmol). After nitrogen substitution, pre-deoxygenated anhydrous toluene (1.0 mL) was added. The reaction solution was heated at 100℃for 16 hours. After cooling to room temperature, ethyl acetate (2 mL) and dichloromethane (2 mL) were added, filtered and the filter cake rinsed with ethyl acetate/dichloromethane (4 mL, v: v=1:1). The combined filtrates were dried by vacuum spin-drying. The residue was purified by preparative TLC (silica gel, methanol: dichloromethane=1:8) to give a pale yellow solid. (23 mg, 0.0383mmol, yield: 36%) MS m/z 600.7[ M+H ] ] ⁺ 。

Step 6: synthesis of 2- ((2S) -4- (2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropan [ a ] indol-2-yl) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To a solution of tert-butyl (2S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropa [ a ] inden-2-yl) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (23 mg,0.038 mmol) in dichloromethane (3 mL) was added dropwise trifluoroacetic acid (1 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour. Dichloromethane (7 mL) was added and concentrated in vacuo. Dichloromethane (5 mL) was added to the resulting residue to concentrate again and the process was repeated once. The yellow solid obtained was used directly in the next step.

Step 7: synthesis of 2- ((2S) -1-propenoyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropan [ a ] inden-2-yl) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To 2- ((2S) -4- (2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropane [ a) at room temperature]Indol-2-yl) -5,6,7, 8-tetrahydropyridine [3,4-d]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile and triethylamine (0.06 mL,0.42 mmol) in dichloromethane (2 mL) was slowly dropped a solution of acryloyl chloride (0.01 mL,0.122 mmol) in dichloromethane (1 mL). The reaction solution was stirred at room temperature for 15 minutes. Dichloromethane (20 mL) and saturated aqueous sodium carbonate (20 mL) were added, the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and evaporated to give a viscous material. Purification by preparative TLC (MeOH: dichloromethane=1:8) gave a white solid (10 mg,0.018mmol, overall yield over two steps: 47%). MS m/z 554.7[ M+H ] ] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.12(t,J＝8.0Hz,1H),7.05(d,J＝8.0Hz,1H),6.76(d,J＝8.0Hz,1H),6.66-6.56(m,1H),6.40(d,J＝16.7Hz,1H),5.83(d,J＝10.6Hz,1H),5.10-5.00(m,1H),4.80-4.75(m,1H),4.46-4.40(m,1H),4.17-4.13(m,1H),4.12(s,2H),4.02-3.88(m,2H),3.65-3.49(m,2H),3.32-2.98(m,4H), 2.96-2.54(m,8H),2.33-2.31(m,1H),2.26-1.98(m,8H),1.08-1.03(m,1H),0.09-0.06(m,1H).

Examples 688-708 were prepared using the method of example 687.

Example 709: synthesis of 2- ((2S) -1-propenoyl-4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7] - (1, 2,3, 4-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of tert-butyl (2S) -2- (cyanomethyl) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 2,3, 4-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid

The compound tert-butyl (S) -2- (cyanomethyl) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid (50 mg,0.11 mmol), 1-chloro-1, 2,3, 4-tetrahydronaphthalene (57 mg,0.33 mmol), potassium carbonate (40 mg,0.29 mmol) and sodium iodide (33 mg,0.22 mmol) were mixed in DMF (1.5 ml), heated to 150℃and stirred for 2 hours, the solvent was removed under reduced pressure, the resulting residue was taken up in water and dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated, and preparative TLC (dichloromethane/7N methanolic 20/1) was separated to give a yellow solid (16.5 mg, yield 25%). MS m/z 602.80 M+H ] + [ H ].

Step 2: synthesis of 2- ((2S) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 2,3, 4-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

The compound tert-butyl (2S) -2- (cyanomethyl) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 2,3, 4-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid (16.5 mg,0.027 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the reaction was stirred at room temperature for 1 hour.

Step 3: synthesis of 2- ((2S) -1-propenoyl-4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7] - (1, 2,3, 4-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

2- ((2S) -4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 2,3, 4-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (0.027 mmol) was dissolved in dichloromethane (2 mL), DIEA (7 mg,0.05 mmol) was added under ice-water bath cooling, then acryloyl chloride (4 mg,0.04 mmol) was added, and the reaction was stirred under ice-water bath for 10 minutes. After the reaction was quenched with saturated sodium bicarbonate, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated, and preparative TLC (dichloromethane/7N methanolic ammonia 30/1) separated to give a yellow solid (9 mg, 60% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ7.24-7.21(m,1H),7.01-7.13(m,2H),6.94(m,1H),6.71(dd,J＝17.0,10.9Hz,1H),6.21(dd,J＝17.0,1.5Hz,1H),5.87(dd,J＝10.9,1.5Hz,1H),4.21(d,J＝4.9Hz,1H),4.19(d,J＝4.9Hz,1H),4.01-3.51(m,9H),3.48-3.20(m,2H),3.15-3.06(m,3H),3.02-2.98(m,1H),2.85-2.54(m,5H),2.51-2.35(m,1H),2.43(s,3H),2.06-1.56(m,8H)。MS m/z 556.73[M+H] ⁺ 。

Example 710: synthesis of 2- ((2S) -1-propenoyl-4- (7- (decahydronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

step 1: synthesis of tert-butyl (2S) -2- (cyanomethyl) -4- (7- (decahydronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid:

the compound 1-decalin (20 mg,0.13 mmol), tert-butyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid (50 mg,0.11 mmol), magnesium sulfate (67 mg,0.56 mmol) and acetic acid (20 mg,0.33 mmol) were mixed in methanol (2 ml), reacted for 2 hours at 40℃with stirring, sodium cyanoborohydride (21 mg,0.33 mmol) was added and the reaction mixture was stirred at 40℃overnight, the resulting residue was concentrated to give a saturated sodium bicarbonate solution and dichloromethane, the organic phase was then extracted with anhydrous sodium sulfate, dried, concentrated, and the prepared TLC (dichloromethane/7N methanolic 30/1) was separated to give a yellow solid (9 mg, yield 13%). MS m/z 608.82[ M+H ] +.

Step 2: synthesis of 2- ((2S) -4- (7- (decalin-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3],4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

The compound tert-butyl (2S) -2- (cyanomethyl) -4- (7- (decahydronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid (20 mg,0.033 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, the reaction was stirred at room temperature for 1 hour, after the reaction was completed, the reaction solution was concentrated, the obtained residue was added with a saturated sodium hydrogencarbonate solution and dichloromethane, then extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, and concentrated to give the crude product which was used directly in the next step (17 mg, yield 100%).

Step 3: synthesis of 2- ((2S) -1-propenoyl-4- (7- (decahydronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

2- ((2S) -4- (7- (decalin-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [ 3)]，4-d]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (0.033 mmol) was dissolved in dichloromethane (2 mL), DIEA (9 mg,0.07 mmol) was added under ice-water bath cooling, then acryloyl chloride (5 mg,0.055 mmol) was added, and the reaction was stirred under ice-water bath for 10 minutes. After the reaction was quenched with saturated sodium bicarbonate, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated, and preparative TLC (dichloromethane/7N methanolic ammonia 30/1) separated to give a yellow solid (9 mg, yield 49%). ¹ H NMR(400MHz,CDCl3):δ6.71(dd,J＝17.0,10.9Hz,1H)，6.21(dd,J＝17.0,1.5Hz,1H),5.87(dd,J＝10.9,1.5Hz,1H),4.20(d,J＝4.9Hz,1H),4.18(d,J＝4.9Hz,1H),3.98-3.90(m,1H),3.85(d,J＝18.0Hz,1H),3.75(d,J＝18.0Hz,1H),3.68-3.54(m,5H),3.43-3.35(m,1H),3.27(dd,J＝15.1,10.2Hz,1H),3.15-3.06(m,3H),3.03-2.97(m,1H),2.84-2.66(m,3H),2.63-2.57(m,1H),2.51-2.35(m,1H),2.43(s,3H),2.06-1.53(m,8H),1.56(m,1H),1.51-1.11(m,11H)。MS m/z 562.79[M+H]+。

Example 711: synthesis of 2- ((S) -4- (7- (H-imidazo [1,2-a ] pyridin-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -1-propenoylpiperazin-2-yl) acetonitrile

Step 1: synthesis of tert-butyl (S) 4- (7- (H-imidazo [1,2-a ] pyridin-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate:

(S) 4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy)) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidine-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (30 mg,0.064 mmol) was dissolved in toluene (5 mL) and 5-bromoH-imidazo [1,2-a was added]Pyridine (16 mg,0.083 mm)ol)，Pd ₂ (dba) ₃ (5.9 mg,0.064 mmol), ruPhos (6 mg,0.128 mmol), cesium carbonate (51.8 mg, 0.1599 mmol), nitrogen protection, heating to 100 ℃, reaction overnight, TLC monitoring reaction completion, concentrating solvent, preparing plate purification (dichloromethane/methanol=10/1) to give pale yellow solid. (20 mg, yield: 54%). MS m/z 588.3[ M+H ]] ⁺ 。

Step 2: synthesis of 2- ((S) -4- (7- (H-imidazo [1,2-a ] pyridin-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

(S) 4- (7- (H-imidazo [1,2-a ] pyridinyl-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (20 mg,0.034 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, reacted at room temperature for 1 hour, concentrated to dryness, aqueous sodium bicarbonate solution was added, extracted with dichloromethane, and concentrated to obtain a pale yellow solid, which was directly used in the next reaction.

Step 3: synthesis of 2- ((S) -4- (7- (H-imidazo [1,2-a ] pyridin-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -1-propenoylpiperazin-2-yl) acetonitrile:

2- ((S) -4- (7- (H-imidazo [1, 2-a)]Pyridin-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-4-yl) piperazin-2-yl acetonitrile (16 mg,0.034 mmol) was dissolved in dichloromethane (5 mL), DIPEA (8.8 mg,0.068 mmol) was added, acryloyl chloride (3 mg,0.033 mmol) was added under ice bath, the reaction was complete after ten minutes, aqueous sodium bicarbonate solution was added, dichloromethane extraction was performed, and plate purification (dichloromethane/methanol=10/1) was prepared after concentration to give a pale yellow solid. (7 mg, yield: 39.3%). ¹ H NMR(400MHz,CDCl ₃ )δ7.76(d,J＝7.5Hz,1H),7.45-7.29(m,2H),6.90(dd,J＝7.5,1.5Hz,1H),6.62(dd,J＝16.8,10.0Hz,1H),6.31(dd,J＝7.4,1.6Hz,1H),6.11(dd,J＝13.8,10.0Hz,1H),5.64(dd,J＝16.9,13.7Hz,1H),5.32(ddd,J＝17.9,2.6,1.0Hz,1H),4.73(t,J＝7.1Hz,1H),4.39-4.20(m,3H),4.11(td,J＝12.1,4.1Hz,1H),3.96(dd,J＝12.4,7.1Hz,1H),3.86(dd,J＝12.5,7.0Hz,1H),3.78-3.59(m,3H),3.42-3.20(m,2H),3.22-3.11(m,2H),3.06(dd,J＝12.4,7.0Hz,1H),2.95(ddd,J＝12.6,4.0,1.8Hz,1H),2.62(t,J＝6.8Hz,1H),2.46(dd,J＝12.4,7.1Hz,1H),2.35(s,3H),2.19-2.12(m,1H),1.92-1.66(m,4H)；MS m/z:542.3[M+H] ⁺ 。

Example 712: synthesis of 2- ((S) -1-propenoyl-4- (7- (2, 3-dihydro-1H-cyclopenta [ a ] naphthalen-9-yl) -2- ((((S) -1-methylpyrrolidin-2- (yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 8-bromo-1-naphthaldehyde:

1, 8-Dibromonaphthalene (500 mg,1.75 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to-78deg.C, n-BuLi (2.5M/L, 2.62 mmol) was added dropwise, DMF (242 mg,3.32 mmol) was added after 30 min, water quench reaction was added after one hour, dichloromethane extraction, and column chromatography purification (petroleum ether/ethyl acetate=100/1) gave a white solid. (150 mg, yield: 36.6%). ¹ H NMR(400MHz,CDCl ₃ )δ11.44(s,1H),8.01(dd,J＝8.3,1.2Hz,1H),7.97-7.85(m,3H),7.57(t,J＝7.7Hz,1H),7.41(s,1H)。

Step 2: synthesis of 3- (8-bromonaphthalen-1-yl) propionic acid:

formic acid (587 mg,12.7 mmol) was added dropwise to DMF (10 mL) under ice bath, triethylamine (587 mg,12.7 mmol) was added successively, 2-dimethyl-1, 3-dioxane-4, 6-dione (322 mg,2.33 mmol), 8-bromo-1-naphthalene aldehyde (500 mg,2.12 mmol) was heated to 100deg.C and reacted for 15 hours, poured into ice water, 2N hydrochloric acid was adjusted to pH=2.0, extracted with ethyl acetate, and column chromatography purified (petroleum ether/ethyl acetate=5/1) after concentration to give a pale yellow solid. (300 mg, yield: 50.6%). ¹ H NMR(400MHz,DMSO-d ₆ )δ12.11(s,1H),7.98(dd,J＝8.1,1.3Hz,1H),7.91(ddd,J＝7.0,5.1,1.6Hz,2H),7.55-7.44(m,2H),7.36(t,J＝7.8Hz,1H),3.72(t,J＝7.9Hz,2H),2.63(dd,J＝8.6,7.1Hz,2H)。

Step 3: synthesis of 9-bromo-1, 2-dihydro-3H-cyclopenta [ a ] naphthalen-3-one:

3- (8-bromonaphthalen-1-yl) propionic acid (300 mg,1.07 mmol) was dissolved in polyphosphoric acid (1 mL), heated to 120 ℃ and reacted for 2 hours, poured into ice water, extracted with ethyl acetate, and concentrated and purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give a pale yellow solid. (140 mg, yield: 50.0%). ¹ H NMR(400MHz,CDCl ₃ )δ7.90(dd,J＝7.8,5.1Hz,2H),7.84-7.75(m,2H),7.42(t,J＝7.9Hz,1H),4.13-4.00(m,2H),2.87-2.72(m,2H)。

Step 4: synthesis of 9-bromo-2, 3-dihydro-1H-cyclopenta [ a ] naphthalene:

9-bromo-1, 2-dihydro-3H-cyclopenta [ a ]]Naphthalene-3-one (140 mg, 0.534 mmol) was dissolved in dichloromethane (3 mL), boron trifluoride diethyl etherate (1.2 mL), triethylsilane (1.2 mL) was added, reacted at room temperature for 15 hours, poured into ice water, extracted with dichloromethane, concentrated and purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give a transparent oil. (100 mg, yield: 75.7%). ¹ H NMR(400MHz,CDCl ₃ )δ7.75(dd,J＝7.7,4.5Hz,2H),7.65(d,J＝8.2Hz,1H),7.40(d,J＝ 8.2Hz,1H),7.15(t,J＝7.8Hz,1H),3.87(t,J＝7.5Hz,2H),3.04(t,J＝7.7Hz,2H),2.26-2.08(m,2H)。

Step 5: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (7- (2, 3-dihydro-1H-cyclopenta [ a ] naphthalen-9-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate:

(S) 4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy)) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidine-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (30 mg,0.064 mmol) was dissolved in toluene (5 mL) and 9-bromo-2, 3-dihydro-1H-cyclopenta [ a ] was added]Naphthalene (20 mg,0.083 mmol), pd ₂ (dba) ₃ (5.9 mg,0.064 mmol), ruPhos (6 mg,0.128 mmol), cesium carbonate (51.8 mg, 0.1599 mmol), nitrogen protection, heating to 100 ℃, reaction overnight, TLC monitoring reaction completion, concentrating solvent, preparation plate purification (dichloromethane/methanol=10/1) to give pale yellow solid, (15 mg, yield: 37%). MS m/z 638.3[ M+H ]] ⁺ 。

Step 6: synthesis of 2- ((S) -4- (7- (2, 3-dihydro-1H-cyclopenta [ a ] naphthalen-9-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

(S) -2- (cyanomethyl) -4- (7- (2, 3-dihydro-1H-cyclopenta [ a ] naphthalen-9-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (15 mg,0.023 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, reacted for 1 hour at room temperature, concentrated to dryness, aqueous sodium bicarbonate solution was added, dichloromethane extraction was performed, and concentrated to a pale yellow solid, which was used directly in the next reaction.

Step 7: synthesis of 2- ((S) -1-propenoyl-4- (7- (2, 3-dihydro-1H-cyclopenta [ a ] naphthalen-9-yl) -2- ((((S) -1-methylpyrrolidin-2- (yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

2- ((S) -4- (7- (2, 3-dihydro-1H-cyclopenta [ a ])]Naphthalen-9-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-4-yl) piperazin-2-yl acetonitrile (12.6 mg,0.023 mmol) was dissolved in dichloromethane (5 mL), DIPEA (8.8 mg,0.068 mmol) was added, acryloyl chloride (3 mg,0.033 mmol) was added under ice-bath, the reaction was complete after ten minutes, aqueous sodium bicarbonate solution was added, dichloromethane extraction was performed, and plate purification (dichloromethane/methanol=10/1) was prepared after concentration to give a pale yellow solid. (7 mg, yield: 50.3%). ¹ H NMR(400MHz,CDCl ₃ )δ7.61(dd,J＝7.5,5.3Hz,2H),7.50-7.35(m,2H),7.23(d,J＝7.5Hz,1H),6.62(dd,J＝16.8,10.0Hz,1H),6.15(dd,J＝13.9,10.1Hz,1H),5.67(dd,J＝16.9,13.7Hz,1H),5.45(dd,J＝17.6,2.7Hz,1H),4.75(p,J＝7.1Hz,1H),4.57-4.40(m,2H),4.35-4.16(m,2H),4.07(dd,J＝12.5,7.0Hz,1H),3.91(dd,J＝12.4,7.0Hz,1H),3.74(dd,J＝12.6,7.1Hz,1H),3.70-3.56(m,2H),3.50-3.26(m,4H),3.22-2.80(m,6H),2.64(ddd,J＝13.9,8.6,6.9Hz,2H),2.38(s,3H),2.35-2.07(m,3H),1.91-1.64(m,3H),1.54-1.33(m,1H)；MS m/z:592.3[M+H] ⁺ 。

Example 713: synthesis of 2- ((S) -1-propenoyl-4- (7- (8-methyl-5, 6-dihydronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 8-bromo-1-methyl-1, 2,3, 4-tetrahydronaphthalen-1-ol:

8-bromo-3, 4-dihydronaphthalen-1 (2H) -one (100 mg,0.44 mmol) was dissolved in tetrahydrofuran (5 mL), methylmagnesium bromide (3M/L, 1.33 mmol) was added dropwise under ice-bath, reacted at room temperature for 15 hours, poured into ice-water, extracted with ethyl acetate, concentrated and purified by column chromatography (petroleum ether/ethyl acetate=20/1) to give a transparent oil. (80 mg, yield: 75.7%). ¹ H NMR(600MHz,CDCl ₃ )δ7.41(d,J＝7.8Hz,1H),7.08-7.03(m,1H),6.97(t,J＝7.7Hz,1H),3.70(s,1H),2.87(ddt,J＝11.1,5.5,1.1Hz,1H),2.84-2.78(m,1H),2.03-1.97(m,2H),1.92-1.87(m,1H),1.75(s,4H)。

Step 2: synthesis of 5-bromo-4-methyl-1, 2-dihydronaphthalene:

8-bromo-1-methyl-1, 2,3, 4-tetrahydronaphthalen-1-ol (80 mg,0.33 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (76 mg,0.66 mmol), triethylsilane (77 mg,0.66 mmol) was added, reacted at room temperature for 15 hours, poured into ice water, extracted with dichloromethane, concentrated and purified by column chromatography (petroleum ether=1) to give a transparent oil. (50 mg, yield: 67.5%).

Step 3: synthesis of (S) tert-butyl 2- (cyanomethyl) -4- (7- (8-methyl-5, 6-dihydronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate:

(S) 4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy)) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidine-4-yl) -2- (cyanomethyl) -piperazine-1-carboxylic acid tert-butyl ester (57 mg,0.12 mmol) was dissolved in toluene (5 mL) and 5-bromo-4-methyl-1, 2-dihydronaphthalene (41 mg,0.182 mmol), pd was added ₂ (dba) ₃ (22 mg,0.024 mmol), xantPhos (28 mg,0.048 mmol), cesium carbonate (118 mg, 0.803 mmol), nitrogen protection, heating to 100 ℃, reaction overnight, TLC monitoring reaction completion, concentrating solvent, preparation plate purification (dichloromethane/methanol=10/1) to give pale yellow solid (10 mg, yield: 13.5%). MS (MS)m/z:614.3[M+H] ⁺ 。

Step 4: synthesis of 2- ((S) -4- (7- (8-methyl-5, 6-dihydro-naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

(S) tert-butyl 2- (cyanomethyl) -4- (7- (8-methyl-5, 6-dihydronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (10 mg,0.016 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, reacted at room temperature for 1 hour, concentrated to dryness, aqueous sodium bicarbonate solution was added, dichloromethane extraction was performed, and concentrated to give a pale yellow solid, which was directly used in the next reaction.

Step 5: synthesis of 2- ((S) -1-propenoyl-4- (7- (8-methyl-5, 6-dihydronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

2- ((S) -4- (7- (8-methyl-5, 6-dihydronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidin-4-yl) piperazin-2-yl acetonitrile (8.4 mg,0.016 mmol) was dissolved in dichloromethane (5 mL), DIPEA (8.8 mg,0.068 mmol) was added, acryloyl chloride (3 mg,0.033 mmol) was added under ice-bath, the reaction was complete after ten minutes, aqueous sodium bicarbonate solution was added, dichloromethane extraction was performed, and plate purification (dichloromethane/methanol=10/1) was prepared after concentration to give a pale yellow solid. (3 mg, yield: 32.6%). ¹ H NMR(400MHz,CDCl ₃ )δ7.11(t,J＝7.5Hz,1H),6.93(dd,J＝7.5,2.0Hz,1H),6.81(dt,J＝7.5,1.6Hz,1H),6.62(dd,J＝16.7,10.0Hz,1H),6.11(dd,J＝13.8,10.0Hz,1H),5.64(dd,J＝16.7,13.8Hz,1H),5.56-5.50(m,1H),5.38(ddd,J＝17.6,2.5,1.0Hz,1H),4.79-4.66(m,1H),4.39-4.23(m,3H),4.10(td,J＝12.2,4.1Hz,1H),3.96(dd,J＝12.4,7.0Hz,1H),3.84(dd,J＝12.5,7.0Hz,1H),3.72-3.60(m,2H),3.44-3.10(m,6H),3.06(dd,J＝12.4,7.0Hz,1H),2.97-2.83(m,2H),2.69-2.56(m,1H),2.55-2.37(m,3H),2.34(s,3H),2.20-2.02(m,4H),1.94-1.66(m,4H)；MS m/z:568.3[M+H] ⁺ 。

Example 714: synthesis of 2- ((S) -1-propenoyl-4- (7- (6-methyl-5, 6,7, 8-tetrahydronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2- (yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of methyl 5-bromo-1-oxo 1,2,3, 4-tetrahydronaphthalene-2-carboxylate:

sodium hydride (120 mg,3 mmol) was dissolved in dimethyl carbonate (5 mL), 5-bromo-3, 4-dihydronaphthalen-1 (2H) -one (225 mg,1 mmol) was added and heated to 91 ℃ and reacted for 15 hours, ice water was added, extraction with ethyl acetate, concentration and column chromatography purification (petroleum ether/ethyl acetate=20/1) gave a clear oil. (180 mg, yield: 63.6%).

Step 2: synthesis of methyl 5-bromo-2-methyl-1-oxo 1,2,3, 4-tetrahydronaphthalene-2-carboxylate:

methyl 5-bromo-1-oxo 1,2,3, 4-tetrahydronaphthalene-2-carboxylate (180 mg,0.64 mmol) was dissolved in tetrahydrofuran (5 mL), sodium hydride (38 mg,0.95 mmol) was added under ice-bath, methyl iodide (180 mg,1.27 mmol) was added after 15 minutes, reacted for 3 hours, ice water was added, extraction with ethyl acetate, and column chromatography purification (petroleum ether/ethyl acetate=20/1) was performed after concentration to give a transparent oil. (120 mg, yield: 63.5%). ¹ H NMR(600MHz,CDCl ₃ )δ8.04(dd,J＝7.9,1.3Hz,1H),7.75(dd,J＝7.8,1.3Hz,1H),7.25-7.18(m,1H),3.68(s,3H),3.08-3.00(m,1H),2.97(dt,J＝8.3,4.1Hz,1H),2.64(dt,J＝13.9,5.0Hz,1H),2.05(ddd,J＝14.1,9.9,5.2Hz,1H),1.50(s,3H)。

Step 3: synthesis of 5-bromo-2-methyl-3, 4-dihydronaphthalen-1 (2H) -one:

methyl 5-bromo-2-methyl-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate (180 mg,0.64 mmol) was dissolved in concentrated hydrochloric acid (5 mL), heated to 100 ℃ and reacted for 2 hours, cooled to room temperature, and extracted with ethyl acetate to give a clear oil. (80 mg, yield: 82.9%). ¹ H NMR(600MHz,CDCl ₃ )δ8.04(dd,J＝7.8,1.3Hz,1H),7.75(dd,J＝7.8,1.3Hz,1H),7.21(t,J＝7.8Hz,1H),3.18(dt,J＝17.7,4.3Hz,1H),2.94(ddd,J＝17.1,11.3,4.9Hz,1H),2.61(ddd,J＝12.4,6.7,4.6Hz,1H),2.26(dq,J＝13.5,4.5Hz,1H),1.90(dddd,J＝13.5,12.3,11.3,4.7Hz,1H),1.29(d,J＝6.7Hz,4H)。

Step 4: synthesis of 5-bromo-2-methyl-1, 2,3, 4-tetrahydronaphthalene:

5-bromo-2-methyl-3, 4-dihydronaphthalen-1 (2H) -one (80 mg,0.33 mmol) was dissolved in dichloromethane (3 mL), boron trifluoride diethyl ether (1.5 mL), triethylsilane (1.5 mL) was added, reacted at room temperature for 15 hours, poured into ice water, extracted with dichloromethane, concentrated, and purified by column chromatography (petroleum ether=1) to give a transparent oil. (40 mg, yield: 53.3%). ¹ H NMR(400MHz,CDCl ₃ )δ7.37(s,1H),7.03-6.93(m,2H),2.92(q,J＝8.4Hz,2H),2.80(ddd,J＝16.4,5.2,1.8Hz,1H),2.64(ddd,J＝17.6,11.1,6.5Hz,1H),2.41(dd,J＝16.5,10.6Hz,1H),2.27(t,J＝8.4Hz,1H),1.81(dtd,J＝10.8,3.9,2.2Hz,1H),1.06(d,J＝6.6Hz,3H)。

Step 5: synthesis of tert-butyl (S) 2- (cyanomethyl) -4- (7- (6-methyl-5, 6,7, 8-tetrahydronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate:

(S) 4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy)) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidine-4-yl) -2- (cyanomethyl) -piperazine-1-carboxylic acid tert-butyl ester (48 mg,0.102 mmol) was dissolved in toluene (5 mL) and 5-bromo-2-methyl-1, 2,3, 4-tetrahydronaphthalene (30 mg,0.133 mmol), pd was added ₂ (dba) ₃ (9.3 mg,0.102 mmol), ruPhos (9.5 mg,0.0204 mmol), cesium carbonate (83 mg,0.255 mmol), nitrogen protection, heating to 100 ℃, reaction overnight, TLC monitoring reaction completion, concentrating solvent, preparative plate purification (dichloromethane/methanol=10/1) to give pale yellow solid (10 mg, yield: 16%). MS m/z 616.4[ M+H ] ] ⁺ 。

Step 6: synthesis of 2- ((S) -4- (7- (6-methyl-5, 6,7, 8-tetrahydronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

(S) tert-butyl 2- (cyanomethyl) -4- (7- (6-methyl-5, 6,7, 8-tetrahydronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (10 mg,0.016 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, reacted at room temperature for 1 hour, concentrated to dryness, aqueous sodium bicarbonate solution was added, dichloromethane extraction was performed, and the mixture was concentrated to obtain a pale yellow solid, which was directly used in the next reaction.

Step 7: synthesis of 2- ((S) -1-propenoyl-4- (7- (6-methyl-5, 6,7, 8-tetrahydronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2- (yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

2- ((S) -4- (7- (6-methyl-5, 6,7, 8-tetrahydronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidin-4-yl) piperazin-2-yl acetonitrile (8.4 mg,0.016 mmol) was dissolved in dichloromethane (5 mL), DIPEA (8.8 mg,0.068 mmol) was added, acryloyl chloride (3 mg,0.033 mmol) was added under ice-bath, the reaction was complete after ten minutes, aqueous sodium bicarbonate solution was added, dichloromethane extraction was performed, and plate purification (dichloromethane/methanol=10/1) was prepared after concentration to give a pale yellow solid. (5 mg, yield: 54.3%). ¹ H NMR(400MHz,CDCl ₃ ) ¹ H NMR(500MHz,Chloroform-d)δ7.15-7.05(m,2H),6.75-6.58(m,2H),6.11(dd,J＝13.8,10.0Hz,1H),5.64(dd,J＝16.7,13.8Hz,1H),5.30(ddd,J＝17.5,2.6,1.1Hz,1H),4.74-4.64(m,1H),4.34-4.23(m,3H),4.12(td,J＝12.2,4.0Hz,1H),3.96(dd,J＝12.4,6.9Hz,1H),3.83(dd,J＝12.4,6.9Hz,1H),3.71-3.56(m,2H),3.35(dtd,J＝12.2,3.2,2.8,1.3Hz,2H),3.30-2.88(m,7H),2.88-2.72(m,1H),2.66-2.54(m,2H),2.46(dd,J＝12.4,6.9Hz,1H),2.33(s,3H),2.14(dt,J＝9.6,6.6Hz,1H),1.94-1.63(m,6H),1.53-1.35(m,1H),1.00(d,J＝6.4Hz,3H)；MS m/z:570.3[M+H] ⁺ 。

Example 715: synthesis of 2- ((S) -1-propenoyl-4- (7- (6, 6-dimethyl-5, 6,7, 8-tetrahydronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 5-bromo-2, 2-dimethyl-3, 4-dihydronaphthalen-1 (2H) -one:

5-bromo-3, 4-dihydronaphthalen-1 (2H) -one (225 mg,1 mmol) was dissolved in tetrahydrofuran (5 mL), sodium hydride (120 mg,3 mmol) was added under ice-bath, methyl iodide (710 mg,5 mmol) was added after 15 minutes, the reaction was performed for 2 hours, ice water was added, extraction was performed with ethyl acetate, and column chromatography purification (petroleum ether/ethyl acetate=20/1) was performed after concentration to give a transparent oil. (130 mg, yield: 51.3%). ¹ H NMR(600MHz,CDCl ₃ )δ8.02(dd,J＝7.7,1.3Hz,1H),7.73(dd,J＝7.8,1.3Hz,1H),7.23-7.16(m,1H),2.99(t,J＝6.4Hz,2H),2.00(t,J＝6.4Hz,2H),1.21(s,6H)。

Step 2: synthesis of 5-bromo-2, 2-dimethyl-1, 2,3, 4-tetrahydronaphthalene:

5-bromo-2, 2-dimethyl-3, 4-dihydro-naphthalen-1 (2H) -one (130 mg,0.51 mmol) was dissolved in dichloromethane (3 mL), boron trifluoride diethyl ether (1.5 mL), triethylsilane (1.5 mL) was added, reacted at room temperature for 15 hours, poured into ice water, extracted with dichloromethane, concentrated, and purified by column chromatography (petroleum ether=1) to give a transparent oil. (100 mg, yield: 82%). ¹ H NMR(600MHz,CDCl ₃ )δ7.43-7.32(m,1H),7.05-6.90(m,2H),2.75(t,J＝6.8Hz,2H),2.54(s,2H),1.59(s,2H),0.97(s,6H)。

Step 3: synthesis of (S) tert-butyl 2- (cyanomethyl) -4- (7- (6, 6-dimethyl-5, 6,7, 8-tetrahydronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate:

(S) 4- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy)) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidine-4-yl) -2- (cyanomethyl) -piperazine-1-carboxylic acid tert-butyl ester (50 mg,0.106 mmol) was dissolved in toluene (5 mL) and 5-bromo-2, 2-dimethyl-1, 2,3, 4-tetrahydronaphthalene (33 mg,0.137 mmol), pd was added ₂ (dba) ₃ (9.7 mg,0.0106 mmol), ruPhos (9.9 mg,0.0212 mmol), cesium carbonate (86 mg,0.265 mmol), nitrogen protection, heating to 100 ℃, reaction overnight, TLC monitoring reaction completion, concentrating solvent, preparative plate purification (dichloromethane/methanol=10/1) to give pale yellow solid, (15 mg, yield: 22.5%). MS m/z 630.4[ M+H ]] ⁺ 。

Step 4: synthesis of 2- ((S) -4- (7- (6, 6-dimethyl-5, 6,7, 8-tetrahydronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

(S) tert-butyl 2- (cyanomethyl) -4- (7- (6, 6-dimethyl-5, 6,7, 8-tetrahydronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (15 mg,0.024 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, reacted for 1 hour at room temperature, concentrated to dryness, aqueous sodium bicarbonate solution was added, dichloromethane extracted, concentrated to a pale yellow solid, which was used directly in the next reaction.

Step 5: synthesis of 2- ((S) -1-propenoyl-4- (7- (6, 6-dimethyl-5, 6,7, 8-tetrahydronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

2- ((S) -4- (7- (6, 6-dimethyl-5, 6,7, 8-tetrahydronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidin-4-yl) piperazin-2-yl acetonitrile (12.6 mg,0.024 mmol) was dissolved in dichloromethane (5 mL), DIPEA (8.8 mg,0.068 mmol) was added, acryloyl chloride (3 mg,0.033 mmol) was added under ice-bath, the reaction was complete after ten minutes, aqueous sodium bicarbonate solution was added, dichloromethane extraction was performed, and plate purification (dichloromethane/methanol=10/1) was prepared after concentration to give a pale yellow solid. (5 mg, yield: 36%). ¹ H NMR(400MHz,CDCl ₃ )δ7.16-7.05(m,2H),6.77-6.54(m,2H),6.16(dd,J＝13.9,10.1Hz,1H),5.66(dd,J＝16.8,13.8Hz,1H),5.30(ddd,J＝17.4,2.6,1.0Hz,1H),4.82(t,J＝7.0Hz,1H),4.42-4.20(m,3H),4.11-3.92(m,2H),3.90-3.59(m,3H),3.37-2.85(m,9H),2.75-2.54(m,3H),2.49-2.30(m,4H),2.14(dt,J＝9.4,6.9Hz,1H),1.93-1.53(m,6H),1.02(d,J＝20.9Hz,6H)；MS m/z: 584.3[M+H] ⁺ 。

Example 716: synthesis of 1- ((1R, 5R) -6- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7) - (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -2, 6-diazabicyclo [3.2.0] hept-2-yl) prop-2-en-1-one

Step 1: synthesis of (2S, 3S) -1- (tert-butoxycarbonyl) -3-hydroxypyrrolidine-2-carboxylic acid:

(2S, 3S) -3-hydroxypyrrolidine-2-carboxylic acid (1.31 g,10 mmol) was dissolved in tetrahydrofuran (20 mL) and water (10 mL), sodium hydroxide (0.80 g,20 mmol) and Boc anhydride (3.30 g,15 mmol) were added, stirred at room temperature for 15 hours, extracted with ethyl acetate, the aqueous layer was adjusted pH with 1N hydrochloric acid=2.0, extracted with ethyl acetate, and concentrated to give a white solid. (1.5 g, yield: 65%). ¹ H NMR(400MHz,CDCl3)δ4.82(s,1H),4.25(s,1H),3.62(q,J＝9.3Hz,1H),3.48(s,1H),2.12(dd,J＝8.9,4.5Hz,1H),1.94(ddd,J＝10.0,6.7,3.3Hz,1H),1.51(s,9H)。

Step 2: synthesis of (2R, 3S) 3-hydroxy-2- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester:

(2S, 3S) -1- (tert-Butoxycarbonyl) -3-hydroxypyrrolidine-2-carboxylic acid (1.5 g,6.5 mmol) was dissolved in tetrahydrofuran (20 mL), borane dimethyl sulfide (2M/L, 14.3 mmol) was added, heated to reflux for 3 hours, cooled to room temperature, quenched with methanol dropwise, concentrated and purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give a clear oil. (1.2 g, yield: 85.7%). ¹ H NMR(400MHz,MeOD)δ4.42-4.21(m,1H),3.66(d,J＝8.8Hz,2H),3.52-3.35(m,3H),2.19-2.04(m,1H),1.90-1.74(m,1H),1.47(s,9H)。

Step 3: synthesis of (2R, 3S) 3- (methylsulfonyloxy) -2- ((methylsulfonyloxy) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester:

(2R, 3S) 3-hydroxy-2- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.16 g,5.3 mmol) was dissolved in dichloromethane (20 mL), triethylamine (2.26 g,22.4 mmol) was added under ice bath, methanesulfonyl chloride (1.83 g,16 mmol) was reacted at room temperature for 2 hours, ice water was added, dichloromethane extraction was performed, anhydrous sodium sulfate was dried, filtered, concentrated and used directly for the next reaction.

Step 4: synthesis of tert-butyl 6-benzyl (1R, 5R) -2, 6-diazabicyclo [3.2.0] heptane-2-carboxylate:

(2R, 3S) 3- (methylsulfonyloxy) -2- ((methylsulfonyloxy) methyl)) Pyrrolidine-1-carboxylic acid tert-butyl ester (2.0 g,5.3 mmol) was dissolved in toluene (20 mL), benzylamine (1.71 g,16 mmol) was added, heated to 110 ℃ and reacted for 15 hours, cooled to room temperature, the solid was filtered, the filtrate was concentrated and purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give a pale yellow oil. (890 mg, yield: 58%). ¹ H NMR(400MHz,MeOD)δ7.42-7.18(m,5H),4.31-4.15(m,1H),3.99(d,J＝5.0Hz,1H),3.67(d,J＝14.7Hz,4H),3.18(dd,J＝6.4,4.3Hz,2H),1.69-1.53(m,2H),1.44(d,J＝15.2Hz,9H)。

Step 5: synthesis of tert-butyl (1R, 5R) 2, 6-diazabicyclo [3.2.0] heptane-2-carboxylate:

(1R, 5R) -2, 6-diazabicyclo [3.2.0]Heptane-2-carboxylic acid tert-butyl ester 6-benzyl ester (145 mg,0.5 mmol) was dissolved in methanol (20 mL), palladium on carbon (10%, 100 mg) was added, reacted under hydrogen balloon pressure for 20 hours, filtered, and the filtrate was concentrated to give a transparent solid. (90 mg, yield: 90.3%). ¹ H NMR(400MHz,MeOD)δ4.11(dd,J＝10.7,6.0Hz,1H),3.92(s,1H),3.72(td,J＝10.8,6.9Hz,2H),3.44-3.33(m,2H),2.07(tt,J＝16.0,7.9Hz,2H),1.47(d,J＝4.2Hz,12H)。

Step 6: synthesis of benzyl 2- (methylthio) -4- (trifluoromethylsulfonyloxy) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylate:

benzyl 2- (methylthio) -4-oxo-3, 4,5, 6-tetrahydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylate (150 mg,0.45 mmol) was dissolved in dichloromethane (10 mL), diisopropylethylamine (117 mg,0.91 mmol) was added, trifluoromethanesulfonic anhydride (154 mg,0.54 mmol) was added under ice-bath, and the mixture was concentrated and used directly in the next reaction.

Step 7: synthesis of benzyl 4- ((1R, 5R) -2- (tert-butoxycarbonyl) -2, 6-diazabicyclo [3.2.0] hept-6-yl) -2- (methylsulfanyl) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylate:

2- (methylthio) -4- (trifluoromethylsulfonyloxy) -5, 6-dihydropyrido [3,4-d ]]Pyrimidine-7 (8H) -carboxylic acid benzyl ester (208 mg,0.45 mmol) was dissolved in DMF (10 mL) and diisopropylethylamine (284 mg,2.27 mmol) and (1R, 5R) 2, 6-diazabicyclo [3.2.0 were added under ice-bath ]Heptane-2-carboxylic acid tert-butyl ester (90 mg,0.45 mmol), reacted at room temperature for 3 hours, extracted with ethyl acetate, concentrated and purified by column chromatography (petroleum ether/ethyl acetate=)1/1) to give a pale yellow oil. (110 mg, yield: 47.4%). ¹ H NMR(400MHz,CDCl3)δ7.46-7.27(m,5H),5.18(d,J＝5.7Hz,2H),4.61(dd,J＝45.7,18.1Hz,2H),4.48-4.18(m,3H),4.17-3.81(m,3H),3.58(s,1H),3.27(d,J＝11.1Hz,1H),2.67(s,1H),2.47(s,3H),2.23(dd,J＝13.8,6.4Hz,1H),1.94(s,1H),1.52(d,J＝35.4Hz,10H)。

Step 8: synthesis of benzyl 4- ((1R, 5R) -2- (tert-butoxycarbonyl) -2, 6-diazabicyclo [3.2.0] hept-6-yl) -2- (methylsulfinyl) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylate:

benzyl 4- ((1R, 5R) -2- (tert-Butoxycarbonyl) -2, 6-diazabicyclo [3.2.0] hept-6-yl) -2- (methylsulfanyl) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylate (110 mg,0.21 mmol) was dissolved in dichloromethane (10 mL), m-chloroperoxybenzoic acid (53 mg,0.26 mmol) was added under ice-bath for 10 min, aqueous sodium thiosulfate was added, dichloromethane extraction was performed, and concentrated and used directly in the next reaction.

Step 9: synthesis of benzyl 4- ((1R, 5R) -2- (tert-butoxycarbonyl) -2, 6-diazabicyclo [3.2.0] hept-6-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylate:

benzyl 4- ((1 r,5 r) -2- (tert-butoxycarbonyl) -2, 6-diazabicyclo [3.2.0] hept-6-yl) -2- (methylsulfinyl) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylate (113 mg,0.21 mmol) was dissolved in toluene (10 mL) with N-methyl prolinol (43.5 mg,0.37 mmol), sodium tert-butoxide (41 mg,0.43 mmol) was added under ice-bath, reacted for 2 hours, ice-water was added, dichloromethane extraction, post-concentration column chromatography purification (dichloromethane/methanol=10/1) gave a pale yellow oil. (100 mg, yield: 80.6%).

Step 10: synthesis of tert-butyl (1R, 5R) 6- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -2, 6-diazabicyclo [3.2.0] heptane-2-carboxylate:

benzyl 4- ((1R, 5R) -2- (tert-Butoxycarbonyl) -2, 6-diazabicyclo [3.2.0] hept-6-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylate (100 mg,0.17 mmol) was dissolved in methanol (20 mL), palladium on carbon (10%, 100 mg) was added and reacted under hydrogen balloon pressure for 20 hours, filtered and the filtrate concentrated to give a clear solid (70 mg, yield: 90.9%).

Step 11: synthesis of tert-butyl (1R, 5R) 6- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -2, 6-diazabicyclo [3.2.0] heptane-2-carboxylate:

(1R, 5R) 6- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -2, 6-diazabicyclo [3.2.0] heptane-2-carboxylic acid tert-butyl ester (70 mg,0.16 mmol) was dissolved in toluene (5 mL), 5-bromo 1,2,3, 4-tetrahydronaphthalene (41 mg,0.19 mmol), pd2 (dba) 3 (13.6 mg,0.015 mmol), ruPhos (13.8 mg, 0.030 mmol), cesium carbonate (121 mg,0.37 mmol), nitrogen protection, heating to 100 ℃, reaction, TLC monitoring reaction completion, concentrating solvent, preparation plate purification (dichloromethane/methanol=10/1) gave an off-white solid (15 mg, yield: 16.7%). MS m/z:575.4[ M+H ] + ].

Step 12: synthesis of 4- (((1R, 5R) -2, 6-azabicyclo [3.2.0] heptan-6-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine):

(1R, 5R) 6- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -2, 6-diazabicyclo [3.2.0] heptane-2-carboxylic acid tert-butyl ester (15 mg,0.026 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, the reaction was carried out at room temperature for 1 hour, concentrated to dryness, aqueous sodium bicarbonate solution was added, dichloromethane extraction was carried out, and the mixture was concentrated to give a pale yellow solid, which was directly used in the next reaction.

Step 13: synthesis of 1- ((1R, 5R) -6- (2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7) - (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -2, 6-diazabicyclo [3.2.0] hept-2-yl) prop-2-en-1-one:

((1R, 5R) -2, 6-azabicyclo [ 3.2.0)]Heptane-6-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidine (12.4 mg,0.026 mmol) was dissolved in dichloromethane (5 mL) and DIPEA (8.8 mg,0.068 mmol) was added, ice-bathAcryloyl chloride (3 mg,0.033 mmol) was added under the reaction, after ten minutes the reaction was complete, aqueous sodium bicarbonate solution was added, extracted with dichloromethane, and after concentration the plate was purified (dichloromethane/methanol=10/1) to give a white solid. (5 mg, yield: 36.2%). ¹ H NMR(400MHz,CDCl3)δ7.19-7.00(m,2H),6.77-6.55(m,2H),6.29(dd,J＝13.8,10.0Hz,1H),5.67(dd,J＝16.8,13.8Hz,1H),5.20(dd,J＝14.2,2.5Hz,1H),4.54-4.35(m,2H),4.32-4.16(m,2H),4.14-4.04(m,2H),3.92(ddd,J＝26.7,11.8,7.0Hz,2H),3.69-3.40(m,3H),3.22-2.93(m,4H),2.93-2.71(m,3H),2.64(t,J＝6.9Hz,1H),2.36(s,4H),2.12(dt,J＝9.4,6.9Hz,1H),2.07-1.91(m,3H),1.91-1.62(m,5H),1.53-1.40(m,1H)；MS m/z:529.3[M+H]+。

Examples 717-737 were prepared using the preparation method of example 716

Example 738: synthesis of 1- (4- (8- ((5-chloro-6-fluoro-1H-indazol-4-yl) methyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

Step 1: synthesis of tert-butyl 4- (2- (methylthio) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate

To a solution of 4-chloro-2- (methylsulfanyl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine (863 mg,4.00 mmol) in tetrahydrofuran (25 mL) was added nitrogen, nitrogen-diisopropylethylamine (1.03 g,8.00 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.11 g,4.8 mmol). The reaction solution was heated to reflux for 16 hours. After cooling to room temperature, the reaction mixture was distilled under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate: petroleum ether=1:4) to give a white solid. (490 mg, yield: 34%) MS m/z 366.6[ M+H ] +.

Step 2: synthesis of tert-butyl 4- ((4- (4- (tert-butoxycarbonyl) piperazin-1-yl) -2- (methylthio) -6, 7-dihydropyrido [2,3-d ] pyrimidin-8 (5H) -yl) methyl) -5-chloro-6-fluoro-1H-indazole-1-carboxylate

To a solution of tert-butyl 4- (2- (methylsulfanyl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate (490 mg,1.34 mmol) and tert-butyl 5-chloro-6-fluoro-4-formyl-1H-indazole-1-carboxylate (400 mg,1.34 mmol) in dichloromethane (25 mL) was added trifluoroacetic acid (153 mg,1.34 mmol) and sodium borohydride acetate (0.57 g,2.7 mmol). The reaction solution was stirred at room temperature for 16 hours. Saturated aqueous sodium bicarbonate (20 mL) and methylene chloride (15 mL) were added. After shaking and separation, the aqueous phase was extracted with dichloromethane (20 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and spun dry under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate: petroleum ether=1:2) to give a yellowish brown solid. (122 mg, yield: 14%) MS m/z:648.6[ M+H ] +.

Step 3: synthesis of tert-butyl 4- ((4- (4- (tert-butoxycarbonyl) piperazin-1-yl) -2- (methylsulfonyl) -6, 7-dihydropyrido [2,3-d ] pyrimidin-8 (5H) -yl) methyl) -5-chloro-6-fluoro-1H-indazole-1-carboxylate

To a solution of 4- ((4- (4- (tert-butoxycarbonyl) piperazin-1-yl) -2- (methylthio) -6, 7-dihydropyrido [2,3-d ] pyrimidin-8 (5H) -yl) methyl) -5-chloro-6-fluoro-1H-indazole-1-carboxylic acid tert-butyl ester (120 mg,0.185 mmol) in dichloromethane (10 mL) was added m-chloroperoxybenzoic acid (95 mg,0.55 mmol) at room temperature. The reaction solution was stirred for 12 hours. Dichloromethane (10 mL) and saturated aqueous sodium sulfite solution (10 mL) were added, and after shaking and delamination, the organic phase was washed with saturated aqueous sodium carbonate solution (10 mL), saturated aqueous brine and dried over sodium sulfate. Spin-drying under reduced pressure afforded a pale yellow solid and was used directly in the next step. (100 mg, yield: 79%) MS m/z 680.6[ M+H ] +.

Step 4: synthesis of tert-butyl 4- ((4- (4- (tert-butoxycarbonyl) piperazin-1-yl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6, 7-dihydropyrido [2,3-d ] pyrimidin-8 (5H) -yl) methyl) -5-chloro-6-fluoro-1H-indazole-1-carboxylate

To a solution of 2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-ol (51 mg,0.312 mmol) in N, N-dimethylformamide (3 mL) was added sodium hydride (13 mg,0.312 mmol) in an ice-water bath. The reaction solution was stirred in an ice-water bath for 30 minutes. 4- ((4- (4- (tert-Butoxycarbonyl) piperazin-1-yl) -2- (methylsulfonyl) -6, 7-dihydropyrido [2,3-d ] pyrimidin-8 (5H) -yl) methyl) -5-chloro-6-fluoro-1H-indazole-1-carboxylic acid tert-butyl ester (100 mg,0.147 mmol) was added, the ice water bath was removed and stirring was performed at room temperature for 16 hours. Ethyl acetate (30 mL) and saturated sodium carbonate (10 mL) were added, and the mixture was shaken and separated. The organic phase was washed with water (5 mL. Times.3) saturated brine (5 mL), dried over sodium sulfate, and spun-dried under reduced pressure. The residue was purified by TLC (methanol: dichloromethane=1:10) to give a white solid. (51 mg, yield: 45%) MS m/z 763.7[ M+H ] +.

Step 5: synthesis of 8- ((5-chloro-6-fluoro-1H-indazol-4-yl) methyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -4- (piperazin-1-yl) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidine

To a solution of 4- ((4- (4- (tert-butoxycarbonyl) piperazin-1-yl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6, 7-dihydropyridin [2,3-d ] pyrimidin-8 (5H) -yl) methyl) -5-chloro-6-fluoro-1H-indazole-1-carboxylic acid tert-butyl ester (51 mg,0.067 mmol) in dichloromethane (3 mL) was slowly added trifluoroacetic acid (1 mL) in an ice-water bath. The reaction solution was stirred at room temperature for 1 hour. Anhydrous dichloromethane (10 mL) was added for dilution and spin-drying under reduced pressure. The resulting pale yellow dope was used directly in the next step. MS m/z 563.6[ M+H ] +.

Step 6: synthesis of 1- (4- (8- ((5-chloro-6-fluoro-1H-indazol-4-yl) methyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -5,6,7, 8-tetrahydropyrido [2,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

To 8- ((5-chloro-6-fluoro-1H-indazol-4-yl) methyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -4- (piperazin-1-yl) -5,6,7, 8-tetrahydropyrido [2,3-d ]]To a mixed solution of crude pyrimidine and acrylic acid (5.8 mg,0.08 mmol) in N, N-dimethylformamide (0.5 mL) and methylene chloride (1.5 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (19 mg,0.1 mmol), 4-dimethylaminopyridine (0.9 mg, 0.0070 mmol) and triethylamine (19 mg,0.19 mmol). The reaction solution was stirred at room temperature for 12 hours. Dichloromethane (30 mL) was added, washed with saturated aqueous sodium bicarbonate (10 mL), saturated brine (5 mL) and dried over sodium sulfate. The residue obtained was dried by spin-drying under reduced pressure by TLC (methanol: dichloromethane=1:6) to give an off-white solid. (14 mg, yield: 34%) MS m/z:617.6[ M+H ] ]+。 ¹ H NMR(400MHz,DMSO)δ8.21(s,1H),7.22(d,J＝8.0Hz,1H),7.00(t,J＝7.5Hz,1H),6.94-6.91(m,2H),6.78(dd,J＝16.8,10.0Hz,1H),6.08(dd,J＝2.1,16.8Hz,1H),5.68(dd,J＝2.1,10.0Hz,1H),4.68-4.64(m,2H),4.45-4.23(m,2H),4.08(q,J＝6.8Hz,1H),3.74-3.68(m,6H),3.22-3.15(m,4H),3.14-3.12(m,2H),3.00-2.74(m,6H),2.36(s,3H),1.85-1.81(m,2H).

Examples 739 to 765 were prepared using the method of example 738

Example 766:

step 1: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (2- (methylthio) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

To a mixed solution of (S) -tert-butyl 4- (7-benzyl-2- (methylthio) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (12 g,24.3 mmol) and N, N-diisopropylethylamine (9.3 g,72.5 mmol) in 1, 2-dichloroethane was added 1-chloroethyl chloroformate (8.5 g,60.1 mmol) at 0 ℃. The reaction was stirred at this temperature for one hour. Next, distillation under reduced pressure was performed to remove the solvent. Methanol (150 mL) was added to the remaining mixture and stirred at reflux for 2 hours. After completion of the reaction, most of the methanol was removed under reduced pressure distillation, followed by washing the crude product with petroleum ether (5X 30 mL). Next, the solvent was distilled off under reduced pressure. The crude product was further dissolved in ethyl acetate (50 mL) and water (20 mL), after which the pH was adjusted to 8 with saturated sodium bicarbonate solution. Ethyl acetate (2 x 100 mL) was used to extract the organic phase. The concentrated organic phase was then dried over sodium sulfate. The crude product was finally subjected to silica gel column chromatography to give a pale brown solid target product (8.1 g, yield: 85%).

Step 2: synthesis of (S) -4- (7- (8-chloronaphthalen-1-yl) -2- (methylthio) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester

Under argon, to (S) -2- (cyanomethyl) -4- (2- (methylthio) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (450 mg,1.1 mmol), cesium carbonate (530 mg,2.2 mmol),

to a mixture of molecular sieve (400 mg) and anhydrous toluene (5 mL) was added sequentially 1-bromo-8-chloronaphthalene (530 mg,2.2 mmol), xantPhos (635 mg,1.1 mmol) and Pd ₂ (dba) ₃ (458 mg,0.5 mmol) the reaction was stirred at 100deg.C for 16 hours. Wait for the reaction to cool to room temperature and filter. The filter cake was washed with ethyl acetate (3X 100 mL) and then the solvent was removed from the filtrate under reduced pressure to give a crude product. The final column chromatography method (petroleum ether/ethyl acetate, 10:1 to 3:1) gave the product as a yellow solid (210 mg, yield: 33%).

Step 3: synthesis of tert-butyl ((2S) -4- (7- (8-chloronaphthalen-1-yl) -2- (methylsulfinyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

To a mixed solution of (S) -tert-butyl 4- (7- (8-chloronaphthalen-1-yl) -2- (methylthio) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (70 mg,0.12 mmol) and dichloromethane (3 mL) at 0deg.C was added m-chloroperoxybenzoic acid (34 mg,80% purity, 0.16 mmol). The reaction was stirred at this temperature for 2 hours. After the reaction was completed, a saturated sodium bicarbonate solution (3×2 mL) was used to wash the reaction solution. All aqueous phases were then brought together and extracted with ethyl acetate (3 mL). Then, all the organic phase was washed with saturated brine and dried over sodium sulfate, and the final product was obtained under reduced pressure distillation (48 mg, yield: 67%).

Step 4: synthesis of tert-butyl (2S) -4- (7- (8-chloronaphthalen-1-yl) -2- ((2-methylhexahydrocyclopenta [ c ] pyrrol-3 a (1H) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

Sodium hydrogen (0.95 mg, 60% pure, 0.023 mmol) was added to (2-methyl hexahydrocyclopenta [ c ] pyrrol-3 a (1H) -yl) methanol (6 mg,0.038 mmol) and anhydrous tetrahydrofuran (0.5 mL) under argon protection in ice bath. The reaction was kept at this temperature and stirred for 6 hours. After the completion of the re-reaction, the product was separated by column chromatography to give a yellow solid final product (5 mg, yield 44%).

Step 5: synthesis of 2- ((2S) -1-propenoyl-4- (7- (8-chloronaphthalen-1-yl) -2- ((2-methylhexahydrocyclopenta [ c ] pyrrol-3 a (1H) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To (2S) -4- (7- (8-chloronaphthalen-1-yl) -2- ((2-methylhexahydrocyclopenta [ c ] pyrrol-3 a (1H) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (11 mg,0.016 mmol) and dichloromethane (0.2 mL) was added trifluoroacetic acid (0.1 mL) under argon. The reaction was stirred at ambient temperature for 1 hour, after which time the solvent and trifluoroacetic acid were removed under reduced pressure to give the crude product free of Boc and carried directly to the next step.

To the crude product and dichloromethane (0.5 mL) was added triethylamine (2.6 mg,0.026 mmol) and acryloyl chloride (1.5 mg,0.016 mmol) successively. The reaction was stirred under ice-bath conditions for 1 hour. After the reaction was completed, the solvent and the acryloyl chloride were removed under reduced pressure, and the product was obtained as a yellow solid by the pre-TLC method (5 mg, comprehensive yield: 50%). MS m/z 626.57[ M+H ] +.

Examples 767-810 were prepared by the method of example 766

Examples: cell Activity assay

1. And (3) cells: h358, MIA-PACA-2 were purchased from Shanghai Biotechnology Inc.

2. Reagent: RPMI 1640 medium, tryple, MTT (5 mg/mL), DMSO, DPBS.

3. Instrument: 37 ℃,5% CO2 incubator, UTRAO enzyme labelling instrument, biosafety cabinet, cell counting plate, ort optical microscope.

4. Experiment consumable: 96 well plate number: 3599 96-well round bottom dispensing plate.

Activity test of H358 cells experimental procedure:

1. and (3) paving: cells in the logarithmic growth phase were digested with Tryple, fresh medium was stopped, cells were counted, cell concentration was adjusted to 55555/mL with fresh medium, 90 μl was added to each well, and the other edges were filled with sterile DPBS.

2. The cells were allowed to confluent at about 50% of the bottom of the wells by incubation for 24 hours at 37℃in a 5% CO2 incubator.

3. Experimental group prescription: dissolving the drug in DMSO to prepare 20mmol/L stock solution, diluting the stock solution with DMSO to prepare 2mmol/L solution, sequentially diluting the stock solution by 3 times, and carrying out 8 concentration gradients to obtain 200 Xcompound gradient solution, adding 10 mu L gradient compound solution into 190 mu L RPMI1640 medium to obtain 10 Xgradient compound solution, adding 10 mu L10 Xcompound solution into 90 mu L96-well cell culture plates, wherein the concentration gradients of the compound in the 96-well cell culture plates are 0.05080526nM, 1.524158nM, 4.572474nM, 13.717420nM, 41.152260nM, 123.456800nM, 370.370400nM, 1111.111000nM, 3333.333000nM, 10000.000000nM, and 100 mu L of each well is 0.5% of final concentration of DMSO.

The control group, containing the same volume of solvent as the experimental group, was diluted with complete medium, 100 μl per well.

4. Incubate in a 5% CO2 incubator at 37℃for 5 days.

After 5.5 days, 10. Mu.L MTT solution (5 mg/mL) was added to each well and the incubation was continued for 4h.

6. The culture was terminated and the culture solution in the wells was carefully aspirated.

7. Zeroing holes, adding 150 mu L of dimethyl sulfoxide (DMSO) into each hole of an experimental group and a control group, vibrating at a speed of an enzyme-labeled instrument for 10s, and measuring the absorbance at 492nm wavelength of the crystals after the crystals are fully dissolved.

IC of partial Compound ₅₀ The values are shown in table 1.

MIA-PACA-2 cells Activity test Experimental procedure:

1. and (3) paving: cells in the logarithmic growth phase were digested with Tryple, fresh medium was stopped, cells were counted, cell concentration was adjusted to 22222 cells/mL with fresh medium, 90 μl was added to each well, and the other edges were filled with sterile DPBS.

2. At 37 ℃,5% CO ₂ Incubate in incubator for 24 hours, let cells to confluence at about 50% of the bottom of the well.

3. Experimental group prescription: the drug was dissolved in DMSO to prepare a 20mmol/L stock solution, which was then diluted with DMSO to prepare a 2mmol/L solution, which was diluted 3-fold, followed by 8 concentration gradients to provide a 200 XCompound gradient solution, 10. Mu.L of the gradient compound solution was added to 190. Mu.L of RPMI1640 medium to provide a 10 Xgradient compound solution, 10. Mu.L of the 10 Xcompound solution was added to 90. Mu.L of 96 well cell culture plates, three replicates of each gradient, and the concentration gradients of the compound in the 96 well cell culture plates were 0.05080526nM, 1.524158nM, 4.572474nM, 13.717420nM, 41.152260nM, 123.456800nM, 370.370400nM, 1111.111000nM, 3333.333000nM, 10000.000000nM, 100. Mu.L per well, and the final concentration of DMSO was 0.5%.

4. Incubate in a 5% CO2 incubator at 37℃for 5 days.

After 5.5 days, 10. Mu. LMTT solution (5 mg/mL) was added to each well and the incubation was continued for 4h.

KRAS G12C-GDP exchange test:

1. pre-mixing 4-fold gradient diluted compounds (10 concentration points total) with KRAS G12C-GDP (ICE, KRAS 20191018) in reaction buffer (25mM Hepes PH7.4, 125mM NaCl,5mM MgCl2,0.01%Tween20,0.1%BSA) in reaction wells for 1 hour, respectively;

2. SOS (Pharmaron, ZZY-20190823), cRAF (Pharmaron, ZZY-20190823), GTP (Sigma, A6885-100 MG), MAb Anti 6HIS-d2/MAb Anti GST-Eu (Cisbio, 61HISDLB/61 GSTKLB) were added and the catalytic reaction was carried out for 2 hours.

3. Fluorescence signals of the emitted light at 615nm and 665nm under 320nm excitation light were read with a Biotek microplate reader (Synergy 4).

4. The IC50 (median inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula: y=bottom+ (Top-Bottom)/(1+10.

Examples compound numbering	IC ₅₀ ((nM)
1	301.1
2	1201
3	1750
30	505
120	23.3
121	88.8
122	980
123	988.2
124	14.3
128	9
130	>10000
132	80.3
134	8
136	44.2
142	4771
146	>10000
149	3499
151	322.2
156	>10000
157	>10000
158	441.2
159	>10000
172	126.7
217	>10000
241	>10000
528	465

536	>10000
613	20.1
615	24.6
617	24.8
624	1041
625	88.7
626	108.7
627	63.4
628	9.2
630	8.5
632	12.7
633	11.7
637	>10000
638	>10000
639	314.1
640	88.7
641	8511
653	34.3
654	>10000
674	25.8
675	6678
676	137.2
684	90
685	838.2
686	699.9
687	16.3
709	2900
710	>10000
711	>10000
712	49.9
713	>10000
714	>10000
715	>10000

Claims

A compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein the compound is:

wherein:

ring W is 4 toA 12 membered saturated or partially saturated monocyclic ring, bridged ring, or spiro ring, wherein the saturated or partially saturated monocyclic ring is optionally additionally substituted with one or more R ⁴ Instead of the above-mentioned,

wherein the method comprises the steps of

R ⁴ Selected from: oxo (oxo), alkyl, alkenyl, alkyne, cycloalkyl, aryl, heteroaryl, heterocyclyl, cyano, nitro, -C (O) OR ⁵ or-C (O) N (R) ⁵ ) ₂ Wherein alkyl is unsubstituted OR cyano, halo, -OR ⁵ 、-N(R ⁵ ) ₂ Or one or more substitutions in heteroaryl, wherein R ⁵ Each independently is hydrogen or alkyl;

R ¹ is-L ¹ -T，

Wherein the method comprises the steps of

L ¹ is-O-, -S-, -NR ^a -、-C(O)-、-SO ₂ -、-SO-、-C(＝NR ^a )-、-C(O)-O-、-OC(O)-、-C(O)-NR ^a -or-NR ^a C(O)-，

T is-CR ^a ＝CR ^b R ^c 、-C≡CR ^b An alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group, each of which is unsubstituted or oxo, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, CN, nitro or NR ^x R ^y One or more substitutions in (a);

wherein the method comprises the steps of

R ^a Hydrogen, deuterium, cyano, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, aryl, heteroaryl or heterocyclyl;

R ^b And R is ^c Each independently hydrogen, deuterium, cyano, halogen, -C (O) OR ^x An alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group, each of which is unsubstituted or oxygenatedSubstitution; halogen; a hydroxyl group; an alkyl group; a haloalkyl group; a hydroxyalkyl group; an alkoxy group; a CN; a nitro group; NR (NR) ^x R ^y The method comprises the steps of carrying out a first treatment on the surface of the Aryl unsubstituted or substituted by alkyl, hydroxy, halogen; heteroaryl, unsubstituted or substituted with alkyl, hydroxy, halo; unsubstituted or substituted by one or two of alkyl, hydroxy, halogen,

alternatively, at T is-CR ^a ＝CR ^b R ^c When R is ^a And R is R ^b Or R is ^a And R is R ^c Together with the carbon atoms to which they are attached, form an unsaturated 5-to 8-membered ring, which is unsubstituted or substituted with one or two of oxo, hydroxy, halogen, alkyl, hydroxyalkyl, haloalkyl or alkoxy;

R ^x and R is ^y Each independently is hydrogen or alkyl;

n ¹ 0, 1 or 2;

n ² 0, 1 or 2;

q is N or CR ¹¹ M is N or CR ¹² Provided that at least one of Q and M is N;

wherein the method comprises the steps of

R ¹¹ And R is ¹² Each independently is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl OR heterocyclyl, -OR ^d 、-C(O)R ^d 、-CO ² R ^d 、-CONR ^d R ^e or-NR ^d R ^e Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently oxo, halogen, hydroxy, alkoxy, alkyl, cycloalkyl, nitro, cyano and-NR ^d R ^e Wherein R is one or more substitutions of ^d And R is ^e Each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

alternatively, when Q is CR ¹¹ When R is ¹¹ And R is ⁴ Together with the atoms to which they are attached form a 5-to 8-membered ring containing 0, 1 or 2 members selected from O, S and NR ^d The ring being unsubstituted or substituted by oxo, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, haloalkyl, hydroxyalkyl and-NR ^d R ^e Wherein R is one or more substitutions of ^d And R is ^e Each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

l is a single bond, -O-, -S-, -NR ^a -、-O-CH ₂ -、-S-CH ₂ -、-NR ^a -CH ₂ -、-CH ₂ -O-、-CH ₂ -S-、-CH ₂ -NR ^a -、-C(O)-、-SO ₂ -、-SO-、-C(O)-O-、-OC(O)-、-C(O)-NR ^a -or-NR ^a C(O)-；

R ² Is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl OR heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently unsubstituted OR substituted with halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, oxo, -OR ^d 、-C(O)R ^d 、-CO ₂ R ^d 、-CONR ^d R ^e 、-NR ^d R ^e One or more of cycloalkyl, cycloalkylalkyl, aryl, heteroaryl and heterocyclyl groups, wherein R ^d And R is ^e Each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

R ³ is cycloalkyl, heterocyclyl, aryl or heteroaryl, provided that when M and Q are both N and N ² When 1, R is ³ Is a non-aromatic condensed bicyclic group, non-aromaticCondensed bicyclic heterocyclyl or bicyclic heteroaryl, R ³ Is unsubstituted or substituted with one or more of the following groups: oxo, halogen, cyano, -OR ^d 、-C(O)R ^d 、-CO ₂ R ^d 、-CONR ^d R ^e 、-NR ^d COR ^e 、-NR ^d R ^e 、-S(O) ₂ NR ^d R ^e Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently substituted with halogen, alkyl, cyano, carbamoyl, alkoxy, hydroxy, cycloalkyl and heteroaryl, wherein R ^d And R is ^e Each independently is hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkenyl, or cycloalkyl.
The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein L ¹ is-C (O) -or-SO ₂ -, and T is-CR ^a ＝CR ^b R ^c or-C.ident.CR ^b Wherein R is ^a Is hydrogen, deuterium, cyano, halogen, hydroxy or alkyl, R ^b And R is ^c Each independently hydrogen; halogen; unsubstituted alkyl; by hydroxy, halogen, NR ^x R ^y Or heterocyclyl-substituted alkyl; unsubstituted aryl or heteroaryl; aryl or heteroaryl substituted by alkyl, hydroxy or halogen, wherein R ^x And R is _y Each independently is hydrogen or alkyl.
The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein L is-O-CH ₂ -or-O-.
Claim and claim3 or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein R ² Is a heterocyclic group that is unsubstituted or substituted with one or more of halogen and alkyl.
The compound of claim 3 or 4, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein L-R ² Is that
The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R ³ Is aryl, wherein the aryl is phenyl or naphthyl, which phenyl or naphthyl is unsubstituted or substituted with 1, 2 or 3 substituents: halogen; cyano group; -OR ^d Wherein R is ^d Is hydrogen, alkyl or haloalkyl; -CONR ^d R ^e Wherein R is ^d And R is ^e Each independently hydrogen, alkyl or cycloalkyl; -NR ^d COR ^e Wherein R is ^d And R is ^e Each independently hydrogen or alkyl; an alkyl group, wherein the alkyl group is unsubstituted or substituted with halogen, cycloalkyl, hydroxy, or alkoxy; cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with alkyl, cyano or carbamoyl; alkynyl; -NR ^d R ^e Wherein R is ^d And R is ^e Each independently hydrogen or alkyl; or heteroaryl.
A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable thereofAcceptable salts, tautomers, prodrugs or stereoisomers, wherein R ³ Is a partially hydrogenated naphthyl group, which is unsubstituted or substituted by hydroxy, alkyl, hydroxyalkyl, haloalkyl or halogen.
The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R ³ Is heteroaryl, which heteroaryl is unsubstituted or substituted with 1, 2 or 3 substituents: oxo, halogen; cyano group; -OR ^d Wherein R is ^d Is hydrogen, alkyl or haloalkyl; -CONR ^d R ^e Wherein R is ^d And R is ^e Each independently hydrogen, alkyl or cycloalkyl; -NR ^d COR ^e Wherein R is ^d And R is ^e Each independently hydrogen, alkyl or alkenyl; an alkyl group, wherein the alkyl group is unsubstituted or substituted with halogen, cycloalkyl, hydroxy, or alkoxy; cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with alkyl, cyano or carbamoyl; alkynyl; or-NR ^d R ^e Wherein R is ^d And R is ^e Each independently is hydrogen or alkyl.
The compound of claim 8, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein the heteroaryl is a monocyclic heteroaryl selected from thiophene, thiazole, pyrazole, pyridine, or pyrimidine; or bicyclic heteroaryl selected from

Which is unsubstituted or substituted as described above.
The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R ³ Is a non-aromatic fused bicyclic heterocyclic group which is unsubstituted or substituted with 1, 2 or 3 substituents of: oxo, halogen; cyano group; -OR ^d Wherein R is ^d Is hydrogen, alkyl or haloalkyl; -CONR ^d R ^e Wherein R is ^d And R is ^e Each independently hydrogen, alkyl or cycloalkyl; -NR ^d COR ^e Wherein R is ^d And R is ^e Each independently hydrogen, alkyl or alkenyl; an alkyl group, wherein the alkyl group is unsubstituted or substituted with halogen, cycloalkyl, hydroxy, or alkoxy; cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with alkyl, cyano or carbamoyl; alkynyl; or-NR ^d R ^e Wherein R is ^d And R is ^e Each independently is hydrogen or alkyl.
The compound of claim 10, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R ³ Is that

Which is unsubstituted or substituted with 1, 2 or 3 substituents: oxo, halogen; hydroxy, alkoxy, and alkyl; preferably, the substituents are oxo, halogen, hydroxy, methoxy or methyl, wherein X, Y and Z are each independently N or CR ⁹ Wherein R is ⁹ Is hydrogen, hydroxy, cyano, alkyl, haloalkyl, halogen, hydroxyalkyl, alkoxyalkyl or alkylsulfonyl.
The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, which is

Wherein:

R ³ is that

Wherein X, Y, Z is selected from N or CR ⁹ The remaining variables are as defined for formula (I).
The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, which is

Wherein R is ^a And R is ^b Independently hydrogen, methyl or trifluoromethyl, or R ^a And R is ^b The composition is c=o.
The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, which is

Wherein m is 0, 1 or 2; z is Z ² Is O or NR ² ，R ² Is hydrogen or alkyl; r is R ^a And R is ^b Independently hydrogen or alkyl; or when Z ² Is NR (NR) ² When R is ^a And R is R ^b The composition is c=o.
The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R ¹ -W is
Wherein the piperazine ring is optionally additionally substituted with one or more R ⁴ And (3) substitution.
The compound of claim 15, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R ¹ Is that
The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R ³ The method comprises the following steps:
the compound of claim 1, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R ¹¹ Is hydrogen, nitro, hydroxy, halogen, cyano, alkyl, haloalkyl, alkoxy or alkoxyalkyl.
The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R ¹² Is hydrogen, halogen or C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, heterocyclyl, C ₁ -C ₆ Haloalkyl, aryl or heteroaryl, wherein each of said aryl and heteroaryl is unsubstituted or C-substituted ₁ -C ₃ Alkyl, halogen, C ₁ -C ₃ Haloalkyl and C ₃ -C ₆ One or more substitutions in cycloalkyl.
The compound of claim 19, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R ¹² Is that
The compound of claim 12, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R ² Is that
R is as follows ³ Is that

Which is unsubstituted or substituted with 1, 2 or 3 substituents: oxo, halogen; hydroxy, alkoxy, and alkyl; preferably, the substituents are oxo, halogen, hydroxy, methoxy or methyl, wherein X, Y and Z are each independently N or CR ⁹ Wherein R is ⁹ Is hydrogen, hydroxy, cyano, alkyl, haloalkyl, halogen, hydroxyalkyl, alkoxyalkyl or alkylsulfonyl.
The compound of claim 12, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R ² Is that
R is as follows ³ Is that
The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein the compound is
A pharmaceutical composition comprising a compound of any one of claims 1-23, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof.
Use of a compound according to any one of claims 1-23, or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, and a pharmaceutical composition according to claim 22, for the manufacture of a medicament for the treatment of cancer mediated by KRAS G12C, HRAS G12C or NRAS G12 mutations.
The use of claim 25, wherein the cancer is lung cancer, colorectal cancer or pancreatic cancer.