CN113999226B

CN113999226B - Heterocyclic compounds as KRAS inhibitors and methods of use thereof

Info

Publication number: CN113999226B
Application number: CN202111225723.8A
Authority: CN
Inventors: 田红旗; 黄功超; 高旭光; 徐海江; 马卫敏; 王兴凯
Original assignee: KECHOW PHARMA Inc
Current assignee: KECHOW PHARMA Inc
Priority date: 2020-12-22
Filing date: 2021-10-21
Publication date: 2023-01-06
Anticipated expiration: 2041-10-21
Also published as: CN113999226A

Abstract

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, prodrugs, tautomers or stereoisomers and solvates thereof, which are useful for treating cancer and inflammation in a mammal. The invention also discloses a preparation method of the compound shown in the formula (I) and a pharmaceutical composition containing the compound.

Description

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 a number of different cancers. The invention also relates to pharmaceutical compositions comprising said compounds and salts thereof, intermediates in the preparation of said compounds, and to methods of using said compounds and salts thereof for the treatment of various cancers.

Background

Weinberg and Barbacid isolated a transforming gene from human bladder cancer cell lines in 1982, which resulted in malignant transformation of NIH 3T3 cells, but not DNA extracted from normal human tissues. Subsequently, santos and Parada found that the above-mentioned transformed gene was not a novel gene, but a human homologous gene of the Harvery murine sarcoma virus ras gene, designated H2ras. In the same year, krontiris found a homolog of the Kirsten murine sarcoma virus gene, called K-ras, in human lung carcinoma cells. Another similar gene is the ras-like gene found when NIH 3T3 cells are infected with human neuroblastoma DNA, designated N2ras, which is not associated with viruses.

The ras gene family of mammals has three members, H-ras, K-ras and N-ras, respectively, wherein the fourth exon of K-ras has two variants A and B. Each ras gene has a similar structure, consisting of four exons, and is distributed over about 30kb of DNA. The encoded products are proteins with relative molecular mass of 2.1 ten thousand, so the protein is called P21 protein. It has been demonstrated that H-ras is located on the short arm of human chromosome 11 (11p15.1-P15.3), K-ras is located on the short arm of chromosome 12 (12p1.1-pter), N-ras is located on the short arm of chromosome 1 (1P 22-P32), and except for the variation of the fourth exon of K-ras, the sequence of P21 encoded by each ras gene is distributed on four exons on average, while the sequence and size of introns vary greatly, so that the whole gene also varies greatly, e.g., human K-ras is 35kb long and N-ras is 3kb long. With two exons four, K-ras can be spliced in two ways, but the mRNA encoding K-ras-B is high. Two other Ras proteins contain 189 amino acids, except that K-Ras-B contains 188 amino acids.

The Ras (P21) protein is located inside the cell membrane and plays an important role in transmitting cell growth and differentiation signals. It belongs to Guanosine Triphosphate (GTP) binding protein, a coupling factor for cellular message transmission, which regulates message transmission by the interconversion of GTP with Guanosine Diphosphate (GDP). P21 has a strong affinity for GTP and GDP and a weak GTPase activity. Normally, the combination of P21 and GDP is in an inactive state, and when the extracellular growth differentiation factor transmits signals to P21 inside the cell membrane, the combination activity of P21 and GTP is enhanced, so that the combination of P21 and GTP is in an activated state, and the signal system is opened. Since P21 has GTPase activity, GTP is hydrolyzed into GDP, P21 is inactivated after P21 and GDP are combined, and the signal system is closed. Normally P21 has a weak GTPase activity and when bound to GTPase Activating Protein (GAP) the rate of hydrolysis is increased by 1 ten thousand fold to inactivate P21. The binding of P21 and GDP can activate guanylate releasing protein (GNRP), and GNRP enables P21 to release GDP to bind GTP, so that the switching on and off of a signal system by P21 can be regulated in a controlled manner through the interconversion of GTP and GDP, and the process of transmitting growth and differentiation signals into cells is completed.

More than 1/5 of cancer patients are accompanied by Ras gene mutations, which occur mostly at residues G12, G13 and Q61, resulting in GAP protein-mediated failure, ras signaling being continuously activated; the invention designs and synthesizes a series of chemical molecules, has strong ras inhibiting 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. Also provided are methods of using such compounds to treat various diseases or conditions, such as cancer.

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 said saturated or partially saturated monocyclic ring is optionally additionally substituted by one or more R ⁴ The substitution is carried out by the following steps,

wherein

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 substituted by cyano, halo, -OR ⁵ 、-N(R ⁵ ) ₂ Or one or more substituents of heteroaryl, wherein R ⁵ Each independently is hydrogen or alkyl;

R ¹ is-L ¹ -T，

Wherein

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 Alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted by oxo, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, CN, nitro or NR ^x R ^y One or more substitutions of (a);

wherein

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

R ^b and R ^c Each independently of the others being hydrogen, deuterium, cyano, halogen, -C (O) OR ^x Alkyl, cycloalkyl, aryl,A 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; CN; a nitro group; NR (nitrogen to noise ratio) ^x R ^y (ii) a Aryl unsubstituted or substituted by alkyl, hydroxy, halogen; heteroaryl unsubstituted or substituted by alkyl, hydroxy, halogen; unsubstituted or substituted by one or two of alkyl, hydroxy, halogen-substituted heterocyclic group,

or, at T, is-CR ^a ＝CR ^b R ^c When R is ^a And R ^b Or R ^a And 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 ^y Each independently hydrogen or alkyl;

Q ¹ 、Q ² and Q ³ Each independently is N or CR ¹¹ ，M ¹ And M ² Each independently is N or CR ¹² Provided that Q is ¹ And M ¹ At least one of which is N;

wherein

R ¹¹ And R ¹² Each independently 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 said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently oxo, halo, hydroxy, alkoxy, alkyl, cycloalkyl, nitro, cyano and-NR ^d R ^e Wherein R is substituted by one or more of ^d And R ^e Each independently of the other is hydrogen, alkyl, C ₃ -C ₆ Cycloalkyl, 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 Cycloalkyl, cycloalkylalkyl, aryl, heteroaryl and heterocyclyl, wherein R is substituted with one or more of ^d And R ^e Each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

R ³ is cycloalkyl, heterocyclyl, aryl or heteroaryl, with the proviso that when M is ¹ And Q ¹ 、Q ² When both are N, R ³ Is a non-aromatic fused bicyclic heterocyclic group, R ³ Is unsubstituted or substituted by 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 is ^d And R ^e Each independently of the other being hydrogen, alkyl, C ₃ -C ₆ Cycloalkyl, 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

R ¹ is-L ¹ -T，

Wherein

wherein

R ^b and R ^c Each independently of the others being hydrogen, deuterium, cyano, halogen, -C (O) OR ^x Alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, said alkyl, cycloalkyl,Each aryl, heteroaryl or heterocyclyl is unsubstituted or oxo; halogen; a hydroxyl group; an alkyl group; a haloalkyl group; a hydroxyalkyl group; an alkoxy group; CN; a nitro group; NR ^x R ^y (ii) a Aryl unsubstituted or substituted by alkyl, hydroxy, halogen; heteroaryl unsubstituted or substituted by alkyl, hydroxy, halogen; unsubstituted or substituted by one or two of alkyl, hydroxy, halogen-substituted heterocyclic groups,

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

wherein

R ¹¹ And R ¹² Each independently 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 said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently oxo, halo, hydroxy, alkoxy, alkyl, cycloalkyl, nitro, cyano and-NR ^d R ^e Wherein R is substituted by one or more of ^d And R ^e Each independently of the other being hydrogen, alkyl, C ₃ -C ₆ Cycloalkyl, hydroxyalkyl, haloalkyl and alkoxyalkyl;

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 、-CH ₂ NR ^d R ^e Cycloalkyl, cycloalkylalkyl, aryl, heteroaryl and heterocyclyl, wherein R is substituted with one or more of R ^d And R ^e Each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

R ³ is a non-aromatic fused bicyclic heterocyclic group, R ³ Is unsubstituted or substituted by 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 is ^d And R ^e Each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkenyl, or cycloalkyl.

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

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

In some embodiments, T is-CR ^a ＝CR ^b R ^c 、-C≡CR ^b Alkyl or heterocyclic radical, wherein R ^a And R ^b 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 ^c Each independently is hydrogen; halogen; an unsubstituted alkyl group; 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 _y Each independently hydrogen or alkyl. Preferably, in the above embodiments, the aryl group is 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, pyridyl or pyrimidinyl, unsubstituted or substituted with 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 ^b Or R ^a And 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 ^b Or R ^a And 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 carbocyclic ring is a cyclopentene, cyclohexene, cycloheptene, or cyclooctene ring.

In some embodiments, T is alkyl, unsubstituted or substituted with halo, hydroxy, NR, or a combination thereof ^x R ^y CN, haloalkyl, hydroxyalkyl, alkoxy or heterocyclyl, wherein R is ^x And R ^y Each independently hydrogen or alkyl. Preferably, heterocyclyl in the above embodiments is a 4-to 8-membered heterocycle containing one or two members selected from oxygen, nitrogen and sulphur, for example azetidine, pyrrolidine, piperidinyl, morpholinyl.

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

In some embodiments, L is 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 heterocyclyl, wherein said heterocyclyl contains a 4-to 8-membered monocyclic ring of 1,2 or 3 heteroatoms selected from oxygen, nitrogen, sulfur, said heterocyclyl is 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 composed of

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

In some embodiments, R ³ Is a partially hydrogenated naphthyl group, which is unsubstituted or substituted with 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 a heteroaryl group, said heteroaryl group being unsubstituted or substituted with 1,2 or 3 of the following substituents: oxo, halo; a cyano group; -OR ^d Wherein R is ^d Is hydrogen, alkyl or haloalkyl; -CONR ^d R ^e Wherein R is ^d And R ^e Each independently is hydrogen, alkyl or cycloalkyl; -NR ^d COR ^e Wherein R is ^d And R ^e Each independently is hydrogen, alkyl or alkenyl; alkyl, wherein the alkyl is unsubstituted or substituted with halo, cycloalkyl, hydroxy or alkoxy; cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with alkyl, cyano or carbamoyl; an alkynyl group; or-NR ^d R ^e Wherein R is ^d And R ^e Each independently hydrogen or alkyl. Preferably, the heteroaryl group is a monocyclic heteroaryl group, 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.

R ^a And R ^b Independently hydrogen, halogen, alkyl, or R ^a And R ^b Independently linked as substituted or unsubstituted C ₃ -C ₆ A cycloalkyl group. 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 of the following substituents: oxo, halo; a cyano group; -OR ^d Wherein R is ^d Is hydrogen, alkyl or haloalkyl; -CONR ^d R ^e Wherein R is ^d And R ^e Each independently hydrogen, alkyl or cycloalkyl; -NR ^d COR ^e Wherein R is ^d And R ^e Each independently hydrogen, alkyl or alkenyl; alkyl, wherein the alkyl is unsubstituted or substituted with halo, cycloalkyl, hydroxy or alkoxy; cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with alkyl, cyano or carbamoyl; an alkynyl group; or-NR ^d R ^e Wherein R is ^d And R ^e Each independently hydrogen or alkyl. In other embodiments, R ³ Is a non-aromatic fused bicyclic heterocyclic group which is unsubstituted or substituted with 1,2 or 3 of the following substituents: oxo, halo; hydroxy, alkoxy, and alkyl; preferably, the substituent is oxo, halogen, hydroxy, methoxy or methyl. In further embodiments, R ³ Is a non-aromatic fused bicyclic heterocyclic group which is

Which is unsubstituted or substituted with 1,2 or 3 of the following substituents: oxo, halo; hydroxy, alkoxy, and alkyl; preferably, the substituent is 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 preferably a

Wherein X, Y and Z are selected from N or CR ⁹ ，R ^a And R ^b Independently hydrogen, halogen, alkyl, or R ^a And R ^b Independently linked as substituted or unsubstituted C ₃ -C ₆ A cycloalkyl group. The remaining variables are as defined for formula (I).

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

Wherein: L-R ² Is composed of

R ³ Preferably, it is,

In some embodiments, the compound of formula (I) is represented by formulas (I-2), (I-3), (I-4), (I-5), and (I-6):

wherein:

R ³ preferably, it is

R ^a And R ^b Independently hydrogen, halogen, alkyl, or R ^a And R ^b Independently linked as substituted or unsubstituted C ₃ -C ₆ A cycloalkyl group.

In some embodiments, R ¹ W is

Wherein the piperazine ring is optionally additionally substituted by one or more R ⁴ Substituted, R ⁴ As defined in 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 the group:

in a preferred embodiment, R ¹ W is

In some embodiments, L-R ² Is composed of

In a preferred embodiment, L-R ² Is composed of

More preferably

In some embodiments, R ³ Is composed of

In a preferred embodiment, R ³ Is composed of

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

In some embodiments, R ¹² Is hydrogen, hydroxy, halogen, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, C ₃ -C ₆ Cycloalkyloxy, heterocyclyl, C ₁ -C ₆ Haloalkyl, aryl or heteroaryl, wherein each of said aryl and heteroaryl is unsubstituted or substituted by C ₁ -C ₃ Alkyl, halogen, C ₁ -C ₃ Haloalkyl and C ₃ -C ₆ One or more substituents in the cycloalkyl group. In a preferred embodiment, R ¹² F and cyclopropyloxy.

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

Wherein

R ¹ W is

R ³ Is composed of

And

L-R ² is composed of

More preferably

R ¹¹ And R ¹² Each independently of the others is hydrogen, hydroxy, alkyl, C ₃ -C ₆ Cycloalkyloxy, or halogen.

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

Another aspect of the present invention provides an exemplary method of preparing the compound of formula (I) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof:

the preparation method comprises the following steps:

wherein R is ¹ ，R ² ，R ³ L and W are as defined above. PG is a protecting group for amino group such as Boc-, cbz, etc., and X is Cl, OTf, etc. The first step is that substitution reaction is carried out under alkaline condition (such as triethylamine, diisopropylethylamine and the like); 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 in alkaline condition (triethylamine sodium hydride,Sodium tert-butoxide, etc.) to obtain a target intermediate; the fourth step is Suzuki Coupling reaction and R ³ -Bpin or R ³ -B(OH) ₂ Carrying out an Oujin reaction to obtain an intermediate; the fifth step is to remove the protecting group (such as Boc); and the sixth step is to react with corresponding acid or acyl chloride to obtain the target compound.

The preparation method 2 comprises the following steps:

wherein R is ¹ ，R ² ，R ³ ，Q ² ，Q ³ ，M ² L and W are as defined above. X is Cl, br, or I. PG is a protective group of amino, such as Boc-, cbz and the like, and the first step is carried out substitution reaction under alkaline conditions (such as triethylamine, diisopropylethylamine and the like); the second step is that substitution reaction is carried out under alkaline conditions (triethylamine, sodium hydride, sodium tert-butoxide and the like) to obtain a target intermediate; the third step is Suzuki Coupling reaction and R ³ -Bpin or R ³ -B(OH) ₂ Carrying out an Oujin reaction to obtain an intermediate; the fourth step is to remove the protecting group (such as Boc); and the fifth step is to react with corresponding acid or acyl chloride to obtain the target compound.

The preparation method 3 comprises the following steps:

wherein R is ¹ ，R ² ，R ³ ，Q ² ，M ² L and W are as defined above. X is Cl, br, or I. PG is a protective group of amino, such as Boc-, cbz and the like, the first step is condensation reaction under a condensing agent (such as EDCI, HOBT, HATU and the like), the second step is cyclization reaction under an alkali condition (such as sodium hydride, sodium methoxide, sodium ethoxide and the like), the third step is chlorination reaction under phosphorus oxychloride condition, and the fourth step is substitution reaction under an alkali condition (such as triethylamine, diisopropylethylamine and the like); the fifth step is the substitution reaction under basic conditions (triethylamine, sodium hydride, sodium tert-butoxide, etc.)Obtaining a target intermediate; the sixth step is the Suzuki Coupling reaction with R ³ -Bpin or R ³ -B(OH) ₂ Coupling reaction to obtain an intermediate; the seventh step is to remove the protecting group (such as Boc); and the eighth step is to react with corresponding acid or acyl chloride to obtain the target compound.

The preparation method 4 comprises the following steps:

wherein R is ¹ ，R ² ，R ³ ，Q ² ，Q ³ ，R ^d L and W are as defined above. X is Cl, br, or I. PG is a protective group of amino, such as Boc-, cbz and the like, and the first step is carried out substitution reaction under alkaline conditions (such as triethylamine, diisopropylethylamine and the like); the second step is that substitution reaction is carried out under alkaline conditions (triethylamine, sodium hydride, sodium tert-butoxide and the like) to obtain a target intermediate; the third step is that substitution reaction is carried out under strong alkaline condition (sodium cyanide, sodium tert-butoxide, potassium tert-butoxide, hexamethyldisilazane and the like); the fourth step is a Suzuki Coupling reaction, the halogenated intermediate and R ³ -Bpin or R ³ -B(OH) ₂ Coupling reaction to obtain an intermediate; the fifth step is to remove the protecting group (such as Boc); and the sixth step is to react with corresponding acid or acyl chloride to obtain the target compound.

Other general synthetic methods are provided in the examples. It will be apparent to those of ordinary skill in the art that 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 route described herein, it will be necessary to use starting materials and/or protecting groups which are differently substituted 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 using the compounds or pharmaceutical compositions of the invention to treat disease conditions, including but not limited to conditions mutated with G12 KRAS, HRAS or NRAS (e.g., cancer). The cancer is pancreatic cancer, lung cancer, colorectal cancer and the like mediated by G12C mutation.

The compound of formula (I) has better physicochemical properties and safe toxicity parameters, and can be used for treating cancer and inflammation of mammals.

In other embodiments, methods of inhibiting proliferation of a cell population are also provided, the methods comprising contacting the cell population 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 aforementioned 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 anti-cancer 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. In addition, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections, to name a few.

Detailed Description

The present invention is defined throughout the disclosure with the following terms, if not otherwise indicated:

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

The term "pharmaceutically acceptable salt", unless otherwise indicated, includes salts of acidic groups (such as, but not limited to, potassium, sodium, magnesium, calcium, and the like) or salts of basic groups (such as, but not limited to, formate, acetate, citrate, tartrate, mesylate, malate, or sulfate, hydrochloride, phosphate, nitrate, carbonate, and the like) that may be present in the compounds of the invention.

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

The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more stereocenters and may therefore 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 racemic and optically pure forms thereof. Optically active (+) and (-), (R) -and (S) -or (D) -and (L) -isomers can be prepared using chiral synthesis or chiral preparation, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation/separation of individual enantiomers include chiral synthesis from suitable optically pure precursors, resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC). The present invention provides pure isomers and isomer mixtures, processes for their preparation and their use, and compositions comprising them. For the sake of simplicity, this is referred to hereinafter as the compound of the formula (I), which refers both to the pure optical isomers and, where appropriate, to mixtures of isomers in different proportions.

The compounds of the invention may be present specifically. Unless otherwise indicated, the term "tautomer" or "tautomeric form" means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be rapidly interconverted. If tautomers are possible (e.g., in solution), then the chemical equilibrium of the tautomers can be reached. For example, proton tautomers (proto tautomers), also known as proton transfer tautomers (prototropic tautomers), include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence isomers (valentetatomers) include interconversion by recombination of some of the bonding electrons.

The alkyl, alkenyl, alkynyl, cycloalkyl moieties may each independently be optionally substituted with one or more groups selected from: hydroxyl, oxo, halogen, cyano, nitro, trifluoromethyl, azido, amino, carboxyl, mercapto.

Saturated or unsaturated hydrocarbon radicals, such as alkyl, alkanediyl or alkenyl, including combinations with heteroatoms, such as alkoxy, can each be straight-chain or branched, respectively.

"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 replaced with a substituent, and may include variations of deuterium and hydrogen, so long as the valency 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 aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemical realizability.

When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly connected, for example, where L represents a single bond in Ar-L-R means that the structure is actually Ar-R. When a substituent is absent, it indicates that the substituent is absent, such as when L is absent in Ar-L-R, ar-L-R indicates that the structure is actually Ar.

Unless otherwise specified, the term "hetero" means a heteroatom or a group of heteroatoms (i.e., a group of atoms containing a heteroatom), including atoms other than carbon (C) and hydrogen (H) and groups of atoms containing such heteroatoms, examples include oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, -C (= O) O-, -C (= O) -, -C (= S) -, -S (= O) 2-, and optionally substituted-C (= O) N (H) -, -C (= NH) -, -S (= O) 2N (H) -or-S (= O) N (H) -.

Unless otherwise specified, "ring" means a substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl group. The ring includes monocyclic ring, and also includes bicyclic or polycyclic ring systems such as spiro ring, fused ring and bridged ring. The number of atoms in the ring is generally defined as the number of ring members, e.g., "5-7 membered ring" means 5-7 atoms arranged around the ring. Unless otherwise specified, the ring optionally contains 1-3 heteroatoms. Thus, "5-7 membered ring" includes, for example, phenyl, pyridyl and piperidinyl; on the other hand, the term "5-7 membered heterocycloalkyl" includes pyridyl and piperidyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.

Unless otherwise specified, the term "heteroalkyl," by itself or in combination with another term, means a stable straight or branched chain alkyl radical, or combination thereof, consisting of a number 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 heteroatom is optionally quaternized. In other embodiments, the heteroatom groups are 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 the position of attachment of the alkyl group to the remainder of the molecule, but the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used conventionally to refer to those alkyl groups that are attached to the remainder of the molecule through an oxygen atom, an amino group, or a 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 = CHNCCH ₃ )-CH ₃ . Up to two heteroatoms may be consecutive, e.g. -CH ₂ -NH-OCH ₃ 。

Unless otherwise specified, the term "heterocycloalkyl" by itself or in combination with other terms denotes a cyclized "heteroalkyl" group, which includes monocyclic, bicyclic, and tricyclic systems, including spiro, fused, and bridged rings, respectively. Furthermore, with respect to the "heterocycloalkyl group," a heteroatom may occupy the position of the attachment of the heterocycloalkyl group to the rest of the molecule. In some embodiments, the heterocycloalkyl group is a 4-to 6-membered heterocycloalkyl group; in other embodiments, the heterocycloalkyl group is a 5-to 6-membered heterocycloalkyl group. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuryl (including tetrahydrofur-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, or oxepanyl.

"alkoxy" represents the above alkyl group having the specified number of carbon atoms attached through an oxygen bridge, unless otherwise specified, C ₁ -C ₆ Alkoxy includes C ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ And C ₆ Alkoxy group of (2). In some embodiments, the alkoxy is C ₁ -C ₃ An alkoxy group. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and mosquito pentoxy.

Unless otherwise specified, the term "aryl" as used herein denotes a polyunsaturated carbocyclic ring system which may be a monocyclic, bicyclic or polycyclic ring system in which at least one ring is aromatic, each ring in the bicyclic and polycyclic ring systems being fused together. Which may be mono-or poly-substituted, and may be mono-, di-or polyvalent, and in some embodiments the aryl group is C ₆ -C ₁₂ An aryl group; in other embodiments, the aryl is C ₆ -C ₁₀ And (3) an aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, and the like). The substituents of any of the above aryl ring systems are selected from the group of acceptable substituents described herein.

Unless otherwise specified, the term "heteroaryl" as used herein refers to an aryl group containing 1,2,3 or 4 heteroatoms independently selected from B, N, O and S, which may be a monocyclic, bicyclic or tricyclic ring system, wherein the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein), and optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S (O) p, p being 1 or 2). The heteroaryl group may be attached to the rest of the molecule through a heteroatom. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl; in other embodiments, the heteroaryl is a 5-6 membered heteroaryl. Examples of such heteroaryl groups include, but are not limited to, pyrrolyl (including pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, and the like), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, and the like), imidazolyl (including imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, and the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, and the like), triazolyl (1H-1, 2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl, and the like), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, and the like) thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl and the like), furyl (including 2-furyl, 3-furyl and the like), thienyl (including 2-thienyl, 3-thienyl and the like), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl and the like), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl and the like), benzothiazolyl (including 5-benzothiazolyl and the like), purinyl, benzimidazolyl (including 2-benzimidazolyl and the like), indolyl (including 5-indolyl and the like), isoquinolyl (including 1-isoquinolyl, 5-isoquinolyl and the like), and the like, quinoxalinyl (including 2-quinoxalinyl, 5-quinoxalinyl, etc.), quinolyl (including 3-quinolyl, 6-quinolyl, etc.), pyrazinyl, purinyl, phenyloxavaninyl. The substituents of any of the above heteroaryl ring systems are selected from among the acceptable substituents described herein.

Synthesis of

Suitable solvents commonly used in organic reactions can be used in the following steps of the preparation process of the present invention, such as, but not limited to: aliphatic and aromatic, optionally hydrocarbon or halogenated hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, volatile oil, 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 diethylene glycol dimethyl ether, tetrahydrofuran and 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, and N-methylpyrrolidone, etc.), and dimethyl sulfoxide, tetramethylene sulfone and hexamethylphosphoric triamide and N, N-dimethylpropylene urea (DMPU), etc.

The invention employs the following abbreviations: DCM represents dichloromethane; CHCl ₃ Represents trichloromethane; EA represents ethyl acetate; THF represents tetrahydrofuran; meCN represents acetonitrile; meOH represents methanol; etOH represents ethanol; i-PrOH represents isopropanol; PE represents petroleum ether; toulene stands for toluene; DMSO represents dimethyl sulfoxide; DMF represents N, N-dimethylformamide; DMA represents N, N-dimethylacetamide; CDCl ₃ Represents deuterated chloroform; d ₂ O represents heavy water; (CD) ₃ ) ₂ SO represents deuterated DMSO; CD (compact disc) ₃ OD represents deuterated methanol; cuI represents cuprous iodide; DIPEA stands for diisopropylethylamine; TEA stands for triethylamine; k is ₂ CO ₃ Represents potassium carbonate; cs ₂ CO ₃ Represents cesium carbonate; na (Na) ₂ CO ₃ Represents sodium carbonate; naHCO 2 ₃ Represents sodium bicarbonate; naOH represents sodium hydroxide; KOH represents potassium hydroxide; liHMDS represents lithium hexamethyldisilazide; CDI instead of 1,1' -carbonylimidazole; MS represents mass spectrum; NMR stands for nuclear magnetic resonance; TFA represents trifluoroacetic acid; BINAP represents (2r, 3s) -2,2 '-diphenylphosphino-1, 1' -binaphthyl; BOC represents tert-butyloxycarbonyl; cbz represents benzyloxycarbonyl; DBU represents bicyclo-1, 5-diaza-5-undecene; DCC represents 1, 3-dicyclohexylcarbodiimide; DCE represents 1, 2-dichloroethane; DMAP for 4-dimethylaminopyridine; dppf represents bis (diphenylphosphino) ferrocene; liAlH4 represents lithium aluminum hydride; LDA represents lithium diisopropylamide; m-CPBA stands for m-chloroperoxybenzoic acid; MTM represents dimethyl sulfide; NBS represents N-bromosuccinimide; NCS represents N-chlorosuccinimide; NIS represents N-iodosuccinimide; PCC stands for pyridinium dichromate; TBAF stands for tetrabutylammonium fluoride; THP represents tetrahydropyranyl; TMEDA represents tetramethylethylenediamine; TMS represents trimethylsilyl; TMP represents 2, 6-tetramethylpiperidine; ts represents p-toluenesulfonyl; pd (PPh) ₃ ) ₄ Represents palladium tetratriphenylphosphine; pdCl ₂ (dppf) represents 1,1' -bisdiphenylphosphinoferrocene palladium dichloride; pd ₂ (dba) ₃ Represents tris-dibenzylideneacetone dipalladium; HOBT represents 1-hydroxybenzotriazole; HATU for 2- (7-oxo)Benzotriazole)-N,N,N',N'-TetramethylureaHexafluorophosphate ester; TBTU stands for O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate; tf ₂ O represents trifluoroacetic anhydride; pd (OAc) ₂ Represents palladium diacetate; ruPhos stands for 2-dicyclohexylphos-2 ',6' -diisopropoxy-1, 1' -biphenyl; pd (PPh) ₃ ) ₂ Cl ₂ Represents bis triphenylphosphine palladium dichloride; sphos represents 3, 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl; xantPhos stands for 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene; meONa represents sodium methoxide; n-BuLi represents n-butyllithium; t-BuONa represents sodium tert-butoxide; t-BuOK represents potassium tert-butoxide; KSCN for potassium thiocyanide; cuBr stands for cuprous bromide; naNO ₂ Represents sodium nitrite; urea represents Urea; POCl ₃ Represents phosphorus oxychloride; BBr ₃ Represents boron tribromide; NH ₄ Cl represents ammonium chloride; meI represents methyl iodide; NMP stands for N-methylpyrrolidone; k ₃ PO ₄ Represents potassium phosphate; column chromatography represents column chromatography separation; ac represents acetyl; bn represents a benzyl group; fmoc represents fluorenylmethyloxycarbonyl; cy represents cyclohexyl; tf represents trifluoromethanesulfonyl; PDC stands for pyridine dichromate.

Synthesis examples:

preparation of an intermediate:

synthesis of 4, 5-tetramethyl-2- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -1,3, 2-dioxaborane

The compounds 5-bromo-1, 2,3, 4-tetrahydronaphthalene (5.00g, 23.69mmol) and 4,4', 5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborane) (12.03g, 47.37mmol) were dissolved in anhydrous 1, 4-dioxane (50 mL), potassium acetate (6.97g, 71.07mmol) and Pd (d)ppf)Cl ₂ (1.73g, 2.37mmol), the reaction mixture was heated to 100 ℃ with replacement of nitrogen and stirred for 16 hours. After the reaction, the reaction solution is cooled to room temperature, the reaction solution is diluted by water, extracted by ethyl acetate, an organic phase is washed by saturated salt water, dried by anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain a light yellow oily substance. (5.0 g, yield: 82%). ¹ H NMR(400MHz,CDCl ₃ )δ7.58(d,J＝6.9Hz,1H),7.11(s,1H),7.08(d,J＝7.3Hz,1H),3.03(t,J＝5.9Hz,2H),2.77(t,J＝5.8Hz,2H),1.78(dd,J＝7.1,4.3Hz,4H),1.34(s,12H).

Synthesis of intermediate 2- (4-fluoro-5, 6,7, 8-tetrahydronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane:

the compounds 5-bromo-8-fluoro-1, 2,3, 4-tetrahydronaphthalene (2.00g, 8.73mmol) and 4,4', 5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborane) (4.43g, 17.46mmol) were dissolved in anhydrous 1, 4-dioxane (30 mL), and potassium acetate (2.57g, 26.19mmol) and Pd (dppf) Cl were added ₂ (0.64g, 0.87mmol), the reaction mixture was heated to 100 ℃ with nitrogen being replaced, and stirred for 16 hours. After the reaction, the reaction solution is cooled to room temperature, the reaction solution is diluted by water, extracted by ethyl acetate, an organic phase is washed by saturated salt water, dried by anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain a light yellow oily substance. (2.1 g, yield: 87%). ¹ H NMR(600MHz,CDCl ₃ )δ7.63–7.54(m,1H),6.80(t,J＝8.8Hz,1H),3.03(s,2H),2.71(s,2H),1.82–1.72(m,4H),1.33(s,12H).

Step 1: synthesis of 5-chloro-6-fluoro-1, 4-dihydro-1, 4-epoxynaphthalene

Dissolving the compounds 1-bromo-3-chloro-2, 4-difluorobenzene (5.0 g, 21.98mmol) and furan (2.99g, 43.97mmol) in anhydrous toluene (50 mL), cooling the reaction solution to-15 ℃ under nitrogen atmosphere, dropwise adding n-BuLi (10.6 mL, 26.38mmol) into the reaction solution, slowly raising the temperature to room temperature after dropwise adding, stirring for reaction for 12 hours, quenching the reaction with saturated ammonium chloride after the reaction is finished, extracting with methyl tert-butyl ether, washing the organic phase with saturated common salt, drying with anhydrous sodium sulfate, and concentrating to obtain a brown oily substance which is directly used in the next step. (4.3 g, yield: 100%).

Step 2: synthesis of 8-chloro-7-fluoronaphthalen-1-ol

Synthesis of crude Compound 8-chloro-7-fluoronaphthalen-1-ol obtained in the previous step 5-chloro-6-fluoro-1, 4-dihydro-1, 4-epoxynaphthalene (4.3g, 21.98mmol) was dissolved in ethanol (10 mL) and concentrated hydrochloric acid (8 mL), heated to 80 ℃ and stirred for reaction for 4 hours. After the reaction, cooling to room temperature, diluting the reaction solution with water, extracting with ethyl acetate, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, concentrating to obtain brown oily substance, placing the oily substance in a refrigerator for 24 hours, separating out solid, diluting with petroleum ether, filtering, washing with petroleum ether, and drying to obtain off-white solid. 1.3g, yield: 30 percent. ¹ H NMR(400MHz,CDCl ₃ )δ7.91(s,1H),7.75(dd,J＝9.1,5.6Hz,1H),7.44–7.34(m,2H),7.30(d,J＝8.7Hz,1H),7.08(d,J＝7.1Hz,1H).

And step 3: synthesis of trifluoromethanesulfonic acid 8-chloro-7-fluoronaphthalen-1-yl ester

Dissolving the compound 8-chloro-7-fluoronaphthalene-1-ol (1.0g, 5.08mmol) in anhydrous dichloromethane (10 mL), adding DIEA (3.94g, 30.51mmol) and a molecular sieve (1 g), stirring 10 molecules at room temperature, cooling to-40 ℃, dropwise adding trifluoromethanesulfonic anhydride (1.86g, 6.61mmol) into the reaction solution, stirring for 20 minutes, quenching the reaction with water, extracting with dichloromethane, washing the organic phase with saturated common salt water, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain a yellow solid. (1.65 g, yield: 98.8%). ¹ H NMR(400MHz,CDCl ₃ )δ7.90(d,J＝8.1Hz,1H),7.84(dd,J＝9.0,5.4Hz,1H),7.59(d,J＝7.7Hz,1H),7.51(s,1H),7.44(s,1H).

And 4, step 4: synthesis of 2- (8-chloro-7-fluoronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane

The compound trifluoromethanesulfonic acid 8-chloro-7-fluoronaphthalen-1-yl ester (1.65g, 5.02mmol), pinacol boronate (2.53g, 10.04mmol) were dissolved in anhydrous DMF (20 mL), and potassium acetate was added(2.44g, 24.85mmol) and Pd (dppf) Cl ₂ (366 mg, 0.50mmol), the reaction was stirred under nitrogen for 12 hours while replacing nitrogen. After the reaction, cooling to room temperature, diluting the reaction solution with water, extracting with ethyl acetate, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain an off-white solid. 1.25g, yield: 82%). ¹ H NMR(400MHz,CDCl ₃ )δ7.83(t,J＝10.4Hz,1H),7.75(dd,J＝9.0,5.5Hz,1H),7.70(d,J＝6.8Hz,1H),7.50–7.44(m,1H),7.32(t,J＝8.7Hz,1H),1.45(s,12H).

Synthesis of intermediate (tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol:

step 1: synthesis of 2- (3-chloropropyl) pyrrolidine-1, 2-dicarboxylic acid 1-tert-butyl 2-methyl ester: 2-methylpyrrolidine 1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.8g, 25.3mmol) is dissolved in tetrahydrofuran (25 mL), cooled to-78 ℃, liHMDS (1M/L, 37.9 mmol) is added dropwise, 1-bromo-3-chloropropane (19.9g, 126mmol) is added after 30 minutes, the reaction is carried out for 2 hours at room temperature, saturated ammonium chloride aqueous solution is added to quench the reaction, ethyl acetate is extracted, and column chromatography purification is carried out after concentration (petroleum ether/ethyl acetate = 5/1) to obtain transparent oily matter. (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)。

And 2, step: synthesis of methyl 2- (3-chloropropyl) pyrrolidine-2-carboxylate:

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

And 3, step 3: synthesis of tetrahydro-1H-pyrrolizine 7a (5H) -carboxylic acid methyl ester:

dissolving methyl 2- (3-chloropropyl) pyrrolidine-2-carboxylate (670mg, 3.27mmol) in methanol (10 mL), adding potassium carbonate (1.35g, 9.81mmol) and potassium iodide (670mg, 0.327mmol), reacting at room temperature for 2 hr, filtering to obtain solid, concentrating the filtrate, and performing column chromatographyPurification (petroleum ether/ethyl acetate = 5/1) gave a clear 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)。

And 4, step 4: synthesis of (tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol:

tetrahydro-1H-pyrrolizine 7a (5H) -carboxylic acid methyl ester (400mg, 2.37mmol) was dissolved in tetrahydrofuran (10 mL), lithium aluminum hydride (270mg, 7.10 mmol) was added in portions under ice bath, reaction completion was checked by TLC (petroleum ether/ethyl acetate = 10/1) after 1 hour, sodium sulfate decahydrate was added, solid was filtered, and filtrate was concentrated to give a transparent 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)。

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

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

(2S, 3S) -3-hydroxypyrrolidine-2-carboxylic acid (1.31g, 10mmol) was dissolved in tetrahydrofuran (20 mL) and water (10 mL), and sodium hydroxide (0.80g, 20mmol) and Boc anhydride (3.30g, 15mmol) were added thereto, and the mixture was stirred at room temperature for 15 hours, extracted with ethyl acetate, and the aqueous layer was adjusted to pH =2.0 with 1N hydrochloric acid, extracted with ethyl acetate, and concentrated to give a white solid. (1.5 g, yield: 65%). ¹ H NMR(400MHz,CDCl ₃ )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 tert-butyl (2R, 3S) -3-hydroxy-2- (hydroxymethyl) pyrrolidine-1-carboxylate:

(2S, 3S) -1- (tert-Butoxycarbonyl) -3-hydroxypyrrolidine-2-carboxylic acid (1.5g, 6.5mmol) was dissolved in tetrahydrofuran (20 mL), borane dimethylsulfide (2M/L, 14.3 mmol) was added, andheating to reflux for 3 hours, cooling to room temperature, adding methanol dropwise to quench the reaction, concentrating, and purifying by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain a transparent 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)。

And step 3: synthesis of (2R, 3S) tert-butyl 3- (methylsulfonyloxy) -2- ((methylsulfonyloxy) methyl) pyrrolidine-1-carboxylate:

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

And 4, step 4: synthesis of tert-butyl (1R, 5R) -6-benzyl-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 (1.71g, 116mmol) was added, heated to 110 ℃, 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)。

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

(1R, 5R) -6-benzyl-2, 6-diazabicyclo [3.2.0]Tert-butyl heptane-2-carboxylate (145mg, 0.5 mmol) was dissolved in methanol (20 mL), palladium on carbon (10%, 100 mg) was added, reaction was carried out under hydrogen balloon pressure for 20 hours, filtration was carried out, and the filtrate was concentrated to obtain 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)。

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

Step 1: 2-chloro-3-fluoro-5-iodopyridin-4-amine

The compound 2-chloro-3-fluoropyridin-4-amine (4.22g, 28.80mmol) was dissolved in acetonitrile (50 mL), followed by addition of NIS (7.77g, 34.55mmol) and p-toluenesulfonic acid (248mg, 1.44mmol), and the reaction was stirred at 70 ℃ for 16 hours. After the reaction is finished, cooling to room temperature, diluting the reaction solution with water, precipitating a solid, filtering, washing with a saturated sodium thiosulfate aqueous solution, washing with water, and drying in vacuum to obtain the target compound which is directly used in the next step. (7.5 g, yield: 98%). ¹ H NMR(400MHz,CDCl ₃ )δ8.17(s,1H),4.83(s,2H).

Step 2: synthesis of 4-amino-6-chloro-5-fluoronicotinonitrile

The compound 2-chloro-3-fluoro-5-iodopyridin-4-amine (7.7g, 28.26mmol) and Zn (CN) ₂ (4.32g, 36.74mmol) was dissolved in anhydrous DMF (150 mL) and Pd (PPh) was added ₃ ) ₄ (1.63g, 1.41mmol) and 4A molecular sieves (2.5 g), replaced with nitrogen, and heated to 100 ℃ under a nitrogen atmosphere and stirred for reaction for 3 hours. After the reaction, the solid was removed by filtration, the solution was cooled to room temperature, 300mL of water was added to dilute the reaction solution, the solid was precipitated, filtered, washed with water and dried under vacuum to obtain the crude product which was used directly in the next step. (4.85 g, yield: 100%). ¹ H NMR(400MHz,DMSO)δ8.20(s,1H),7.66(s,2H).

And step 3: synthesis of 4-amino-6-chloro-5-fluoronicotinic acid

Dissolving the compound 4-amino-6-chloro-5-fluoronicotinonitrile (4.85g, 28.26mmol) in 50% ₂ SO ₄ (50 mL), the reaction mixture was heated to 120 ℃ and stirred for 6 hours. After the reaction is finished, cooling to room temperature, slowly pouring the reaction liquid into crushed ice, separating out solid, filtering, and washing the solid with water. Dissolving the solid with ethyl acetate, washing with saturated sodium carbonate aqueous solution, and collectingCollecting water phase, adjusting pH of the water phase to 2-3 with 10% hydrochloric acid, precipitating solid, filtering, and vacuum drying to obtain white solid. (4.62 g, yield: 85.8%). ¹ H NMR(400MHz,DMSO)δ8.36(s,1H),7.59(s,2H).

And 4, step 4: synthesis of 7-chloro-8-fluoro-4-hydroxypyrido [4,3-d ] pyrimidine-2 (1H) -thione

Adding the compound 4-amino-6-chloro-5-fluoronicotinic acid into a reaction flask, and then adding POCl ₃ (50 mL), the reaction mixture was heated to 90 ℃ and stirred for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the reaction mixture was concentrated to give an oil which was dissolved in anhydrous tetrahydrofuran (20 mL), and then added dropwise to tetrahydrofuran (80 mL) containing ammonium thiocyanate (3.67g, 48.28mmol), and the reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was washed with water with saturation, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid. Then 10ml of ethyl acetate was added and slurried, filtered to give a pale yellow solid. (4.52 g, yield: 80.8%). ¹ H NMR(400MHz,DMSO)δ13.29(s,1H),12.85(s,1H),8.64(s,1H).

And 5: synthesis of 7-chloro-8-fluoro-2- (methylthio) pyrido [4,3-d ] pyrimidin-4-ol

Reacting the compound 7-chloro-8-fluoro-4-hydroxypyrido [4,3-d ]]Pyrimidine-2 (1H) -thione (4.52g, 19.51mmol) was dissolved in anhydrous DMF (50 mL), followed by addition of sodium methoxide (1.06g, 19.51mmol), stirring at room temperature for 10 minutes, dropwise addition of methyl iodide (2.77g, 1.21mL, 19.51mmol), and reaction at room temperature for 2 hours with stirring. After the reaction is finished, adding cold water to dilute the reaction solution, separating out a solid, filtering, washing the solid with water, and drying in vacuum to obtain a yellow solid. (3.0 g, yield: 66%). ¹ H NMR(400MHz,DMSO)δ13.24(s,1H),8.81(s,1H),2.62(s,3H).

And 6: synthesis of 4, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4,3-d ] pyrimidine

The compound 7-chloro-8-fluoro-2- (methylthio) pyrido [4,3-d ] pyrimidin-4-ol (420mg, 1.71mmol) was dissolved in phosphorus oxychloride (4 mL), followed by addition of DIEA (442mg, 3.42mmol), and the reaction was heated to 90 ℃ for 3 hours. After the reaction is finished, cooling to room temperature, and concentrating to remove excessive phosphorus oxychloride. Then dissolved in ethyl acetate, washed with saturated brine and water in sequence, the organic phase was dried over anhydrous sodium sulfate and concentrated to give a crude product which was used directly in the next step. (450 mg, yield: 100%).

And 7: synthesis of tert-butyl (S) -4- (7-chloro-8-fluoro-2- (methylthio) pyrido [4,3-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

Reacting the compound 4, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4,3-d ]]Pyrimidine (450mg, 1.71mmol) was dissolved in anhydrous DMF (10 mL), DIEA (1.10g, 8.55mmol) and (S) -2- (piperazin-2-yl) acetonitrile 2 hydrochloride (339mg, 1.71mmol) were added under cooling in an ice-water bath, and after stirring for 10 minutes under cooling in an ice-water bath, di-tert-butyl dicarbonate (747mg, 3.42mmol) was then added, and the reaction was stirred at room temperature for 16 hours. After the reaction, the reaction solution was diluted with 100mL of cold water under stirring, 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 a white-like solid. (710 mg, yield: 91.6%). ¹ H NMR(600MHz,CDCl ₃ )δ8.80(s,1H),4.62(s,1H),4.45(dd,J＝13.9,3.5Hz,1H),4.28(d,J＝12.8Hz,1H),4.08(s,1H),3.84(s,1H),3.66(d,J＝8.6Hz,1H),3.39(s,1H),2.87–2.74(m,1H),2.69(dd,J＝16.8,5.9Hz,1H),2.64(s,3H),1.51(s,9H).

And 8: synthesis of tert-butyl (2S) -4- (7-chloro-8-fluoro-2- (methylsulfinyl) pyrido [4,3-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

The compound (S) -tert-butyl 4- (7-chloro-8-fluoro-2- (methylthio) pyrido [4,3-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (700mg, 1.55mmol) was dissolved in dichloromethane (10 mL), 85% m-chloroperoxybenzoic acid (378mg, 1.86mmol) was added under cooling in an ice-water bath, and the reaction was stirred for 30 minutes under cooling in an ice-water bath. After the reaction, the reaction was quenched with saturated sodium thiosulfate solution, extracted with dichloromethane, the organic phase was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product which was used directly in the next step. (725 mg, yield: 100%).

And step 9: synthesis of (S) -4- (7-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester:

the compound (2S) -tert-butyl 4- (7-chloro-8-fluoro-2- (methylsulfinyl) pyrido [4,3-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (725mg, 1.55mmol) was dissolved in anhydrous toluene (10 mL), followed by addition of (S) - (1-methylpyrrolidin-2-yl) methanol (0.31g, 2.71mmol), addition of sodium tert-butoxide (0.30g, 3.09mmol) with cooling in an ice-water bath, and stirring for 30 minutes with cooling in an ice-water bath. After the reaction, quenching the reaction with cold water, extracting with dichloromethane, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain an off-white solid. (510 mg, yield: 63%).

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

The compound (S) -4- (7-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [4,3-d]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (40mg, 0.08mmol) and 4, 5-tetramethyl-2- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -1,3, 2-dioxaborane (30mg, 0.12mmol) were dissolved in 1, 4-dioxane/water =5/1 (3 mL), cesium carbonate (76mg, 0.23mmol) and Pd (PPh) were added ₃ ) ₄ (45mg, 0.04mmol), nitrogen was replaced, and the reaction mixture was heated to 95 ℃ under nitrogen atmosphere and stirred for 1 hour. After 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, dried over anhydrous sodium sulfate, concentrated, and separated by TLC to give an off-white solid. (20 mg, yield: 42%).

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

The compound (S) -tert-butyl 2- (cyanomethyl) -4- (8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) pyrido [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate (20mg, 0.03mmoL) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added thereto, and the reaction was stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated, then dissolved in dichloromethane, adjusted to PH 8-9 with saturated sodium carbonate solution, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and concentrated to give crude product which was used directly in the next step. (14mg, yield.

Step 12: synthesis of 2- ((S) -1-acryloyl-4- (8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) pyrido [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

The compound 2- ((S) -4- (8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) pyrido [4,3-d]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (14mg, 0.03mmol) was dissolved in methylene chloride (5 mL), DIEA (5mg, 0.03mmol) and acryloyl chloride (3mg, 0.03mmol) were added under cooling in an ice-water bath, and the reaction was stirred for 5 minutes under cooling in an ice-water bath. After the reaction is finished, the reaction is quenched by saturated sodium carbonate, dichloromethane is used for extraction, an organic phase is dried by anhydrous sodium sulfate, concentration and TLC separation and purification are carried out to obtain an off-white solid. (10 mg, yield: 62%%). ¹ H NMR(400MHz,CDCl ₃ )δ9.10(s,1H),7.26-7.21(dd,m,3H),6.62-6.57(m,1H),6.48–6.31(m,1H),5.83(dd,J＝19.7,11.2Hz,1H),5.02(s,2H),4.62-4.58(m,1H),4.49-4.44(m,3H),4.10(d,J＝12.0Hz,1H),3.87-3.83(m,2H),3.65(dd,J＝13.5,6.8Hz,1H),3.57-3.51(m,2H),3.34-3.31(m,1H),3.14–2.95(m,2H),2.87-2.83(m,6H),2.75-2.71(m,1H),2.62(t,J＝5.7Hz,3H),2.30-2.25(m,2H),2.16-2.11(m,2H).MS m/z:570.75[M+H] ⁺

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

Step 1: synthesis of (S) -4- (7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester

Reacting the compound (2S) -4- (7-chloro-8-fluoro-2- (methylsulfinyl) pyrido [4,3-d ]]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (100mg, 0.21mmol) was dissolved in anhydrous toluene (3 mL), and (tetrahydro-1H-pir-ine) was added under cooling in an ice-water bathAlloxazin-7 a (5H) -yl) methanol (46mg, 0.32mmol) and sodium tert-butoxide (31mg, 0.32mmol) were stirred for 3 hours under cooling in an ice-water bath, after the reaction was complete, the reaction was quenched with cold water, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and fractionated by column chromatography to give an off-white solid. (55 mg, yield: 47%). ¹ H NMR(400MHz,CDCl ₃ )δ8.82(s,1H),4.75(dt,J＝23.5,12.9Hz,3H),4.58(s,1H),4.31(d,J＝11.7Hz,1H),4.18–3.88(m,4H),3.82(t,J＝10.1Hz,1H),3.37(s,1H),3.23(dd,J＝16.7,8.9Hz,1H),3.01(s,2H),2.80(dd,J＝16.7,3.9Hz,1H),2.55–2.37(m,2H),2.34–2.21(m,3H),2.15(dt,J＝13.5,6.8Hz,2H),2.02(dd,J＝11.3,6.9Hz,2H),1.49(s,9H).

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

The compound (S) -4- (7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (57mg, 0.10mmol) and 4, 5-tetramethyl-2- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -1,3, 2-dioxaborane (33mg, 0.13mmol) were dissolved in 1, 4-dioxane/water =5/1 (3 mL), and cesium carbonate (102mg, 0.31mmol) and Pd (PPh) were added ₃ ) ₄ (60mg, 0.05mmol), nitrogen was replaced, and the mixture was heated to 95 ℃ under nitrogen atmosphere and stirred for 1 hour. After 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, dried over anhydrous sodium sulfate, concentrated, and separated by TLC to give an off-white solid. (38 mg, yield: 57%). ¹ H NMR(400MHz,CDCl ₃ )δ9.09(s,1H),7.26-7.21(m,3H),4.82(s,2H),4.73–4.57(m,2H),4.41-4.38(m,1H),3.98-3.92(m,4H),3.87-3.82(m,1H),3.47-3.40(m,2H),3.23-3.20(m,1H),3.00(s,2H),2.87(t,J＝6.2Hz,2H),2.63-2.61(m,2H),2.54–2.38(m,2H),2.38–2.20(m,2H),2.14(s,2H),2.03-1.98(m,2H),1.81(d,J＝6.1Hz,2H),1.73-1.71(m,2H),1.50(s,9H).

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

The compound (S) -tert-butyl 2- (cyanomethyl) -4- (8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) pyrido [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate (38mg, 0.06mmol) was dissolved in dichloromethane (3 mL), followed by addition of trifluoroacetic acid (1 mL) and stirring reaction at room temperature for 1 hour. After the reaction, the reaction solution was concentrated, then dissolved in dichloromethane, adjusted to PH 8-9 with saturated sodium carbonate, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and concentrated to give crude product which was used directly in the next step. (32 mg, yield: 100%).

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

The compound (S) -2- (4- (8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) pyrido [4, 3-d)]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (15mg, 0.03mmol) was dissolved in methylene chloride (3 mL), DIEA (5mg, 0.033mmol) and acryloyl chloride (3mg, 0.03mmol) were added under cooling in an ice-water bath, and the reaction was stirred for 5 minutes under cooling in an ice-water bath. After the reaction is finished, saturated sodium carbonate is used for quenching the reaction, dichloromethane is used for extraction, an organic phase is dried by anhydrous sodium sulfate, concentration and TLC separation and purification are carried out to obtain a white-like solid. (8 mg, yield: 49%). ¹ H NMR(400MHz,CDCl ₃ )δ9.13(s,1H),7.21(d,J＝3.8Hz,3H),6.56(s,1H),6.38(d,J＝15.4Hz,1H),5.82(d,J＝9.6Hz,1H),4.82(s,2H),4.62(d,J＝14.6Hz,1H),4.47(d,J＝11.3Hz,1H),4.25-4.22(m,1H),3.93(s,4H),3.66(d,J＝4.6Hz,1H),3.35(dd,J＝16.9,7.6Hz,1H),3.15–2.94(m,4H),2.87(t,J＝6.1Hz,2H),2.63(d,J＝5.9Hz,2H),2.45(ddd,J＝26.5,13.0,6.6Hz,2H),2.28(dd,J＝16.8,8.4Hz,2H),2.18-2.11(m,2H),2.06-1.99(m,2H),1.81(d,J＝6.4Hz,2H),1.73(d,J＝6.2Hz,2H).MS m/z:596.68[M+H] ⁺

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

The compound (S) -2- (4- (8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) pyrido [4, 3-d)]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (15mg, 0.03mmol) and 2-fluoroacrylic acid (4mg, 0.04mmol) were dissolved in dichloromethane (3 mL), HATU (1695g, 0.04mmol) was added, and after cooling to 0 ℃ to 10 ℃ with an ice water bath, DIEA (6mg, 0.04mmol) was added, and the reaction was stirred at 0 ℃ to 10 ℃ for 4 hours. After the reaction, the reaction solution was diluted with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by TLC to obtain an off-white solid. (8 mg, yield: 47%). ¹ H NMR(400MHz,CDCl ₃ )δ9.14(s,1H),7.26-7.22(m,3H),5.60-5.38(m,1H),5.28(dd,J＝16.8Hz,1H),,4.82(s,2H),4.62(d,J＝14.6Hz,1H),4.47(d,J＝11.3Hz,1H),4.25-4.22(m,1H),3.93(s,4H),3.66(d,J＝4.6Hz,1H),3.35(dd,J＝16.9,7.6Hz,1H),3.15–2.94(m,4H),2.87(t,J＝6.1Hz,2H),2.63(d,J＝5.9Hz,2H),2.45(ddd,J＝26.5,13.0,6.6Hz,2H),2.28(dd,J＝16.8,8.4Hz,2H),2.18-2.11(m,2H),2.06-1.99(m,2H),1.81(d,J＝6.4Hz,2H),1.73(d,J＝6.2Hz,2H)MS m/z:614.6[M+H] ⁺

Preparation by application of preparation 1 gives the compounds of examples 4 to 48

Example 49: synthesis of 2- ((S) -1-acryloyl-4- (8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (thiochroman-8-yl) pyridin [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 4, 5-tetramethyl-2- (thiochroman-8-yl) -1,3, 2-dioxolane

To a round bottom flask was added 8-bromo-thiochroman (114mg, 0.5 mmol), bis-pinacol boronate (279mg, 1.1mmol), pd (dppf) Cl ₂ (37mg, 0.05mmol) and potassium acetate (147mg, 1.5mmol). After nitrogen displacement, anhydrous 1, 4-dioxane (5 mL) previously deoxygenated was added. The resulting suspension was stirred at 100 ℃ for 16 hours. After cooling to room temperature, the reaction mixture was extracted with water (20 mL) and methyl tert-butyl ether (20 mL). After separation, the aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with brine (50 mL), dried over sodium sulfate and dried by rotary drying in vacuo. The remaining dark brown oil was purified by column chromatography (silica gel, ethyl acetate: petroleum ether =1 = 40) to give a colorless viscous substance. (42mg, 0.152mmol, yield: 30%)

Step 2: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (8-fluoro-2- (((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (thiocyanic acid-8-yl) pyridinyl [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate

Adding (S) -4- (7-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [4, 3-d) to a round bottom flask]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (52mg, 0.1mmol), 4, 5-tetramethyl-2- (thiochroman 8-yl) -1,3, 2-dioxolane (42mg, 0.15mmol), tetrakisPalladium triphenylphosphine (46mg, 0.4mmol) and cesium carbonate (98mg, 0.3mmol). After nitrogen displacement, previously deoxygenated 1, 4-dioxane (2 mL) and water (0.4 mL) were added. The reaction solution was stirred at 100 ℃ for 3 hours. Ethyl acetate (15 mL) and water (15 mL) were added. After shaking and separation, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate and dried by rotary drying in vacuo. The remaining brown viscous mass was purified by preparative TLC (silica gel, methanol: dichloromethane = 1) to give a light yellow solid. (32mg, 0.05mmol, yield: 50%) MS m/z of 634.7[ 2 ], [ M + H ]] ⁺ 。

And step 3: synthesis of 2- ((S) -4- (8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (thiochroman-8-yl) pyrido [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Trifluoroacetic acid (1 mL) was added dropwise to a solution of (S) -2- (cyanomethyl) -4- (8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (thiocyanic acid-8-yl) pyridinyl [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (32mg, 0.05mmol) in dichloromethane (3 mL) at room temperature, the resulting solution was stirred at room temperature for 1 hour, dichloromethane (7 mL) was added and concentrated in vacuo, the resulting residue was concentrated again with dichloromethane (5 mL) and the process was repeated once a yellow solid was used in the next step.

And 4, step 4: synthesis of 2- ((S) -1-acryloyl-4- (8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (thiochroman-8-yl) pyridin [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To 2- ((S) -4- (8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (thiochroman-8-yl) pyridine [4, 3-d) at room temperature]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile and triethylamine (0.05mL, 0.35mmol) in dichloromethane (2 mL) was slowly added as drops of a solution of acryloyl chloride (0.01mL, 0.122mmol) 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 extracted with dichloromethane (10 mL). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate and rotary evaporated to give a viscous mass. Purification by preparative TLC (methanol: dichloromethane =1 = 8) gave a white solid (17 mg, two-step total yield: 57%). MS m/z 588.6[ m ] +H] ⁺ 。 ¹ H NMR(400MHz,CDCl3)δ9.11(s,1H),7.27(t,J＝7.7Hz,1H),7.16-7.12(m,2H),6.66-6.56(m,1H),6.42(d,J＝16Hz,1H),5.86(d,J＝12Hz,1H),5.10-4.98(m,2H),4.65–4.60(m,1H),4.52-4.40(m,2H),4.10–4.07(m,1H),3.85–3.81(m,1H),3.72–3.25(m,4H),3.06-2.78(m,10H),2.32–1.98(m,3H),1.80-1.55(m,3H).

Example 50: synthesis of 2- ((S) -1-acryloyl-4- (8-fluoro-7- (isochroman-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 2- (isochroman-5-yl) -4, 5-tetramethyl-1, 3, 2-dioxolane

A round-bottomed flask was charged with 5-bromoisochroman (198mg, 0.93mmol), bispinanol borate (709mg, 2.8mmol), pd (dppf) Cl ₂ (102mg, 0.14mmol) and potassium acetate (274mg, 2.8mmol). After nitrogen displacement, anhydrous 1, 4-dioxane (10 mL) previously deoxygenated was added. The resulting suspension was stirred at 100 ℃ for 16 hours. After cooling to room temperature, the reaction mixture was extracted with water (20 mL) and methyl tert-butyl ether (20 mL). After separation, the aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with brine (50 mL), dried over sodium sulfate and dried by rotary drying in vacuo. The remaining dark brown oil was purified by column chromatography (silica gel, ethyl acetate: petroleum ether = 1). (196mg, 0.754mmol, yield: 81%)

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

Adding (S) -4- (7-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [4, 3-d) to a round bottom flask]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (55mg, 0.106mmol), 2- (isochroman-5-yl) -4, 5-tetramethyl-1, 3, 2-dioxolane (52mg, 0.2mmol), palladium tetrakistriphenylphosphine (49mg, 0.0424mmol) and cesium carbonate (104mg, 0.32mmol). After replacement of nitrogen, preliminary deoxidation was added1, 4-dioxane (2 mL) and water (0.4 mL). The reaction mixture was stirred at 100 ℃ for 3 hours. Ethyl acetate (15 mL) and water (15 mL) were added. After shaking and separation, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate and dried by rotary drying in vacuo. The remaining brown viscous mass was purified by preparative TLC (silica gel, methanol: dichloromethane = 1) to give a light yellow powder. (16mg, 0.0259mmol, yield: 24%) MS m/z:618.7[ M + H ])] ⁺ 。

And step 3: synthesis of 2- ((S) -4- (8-fluoro-7- (isochroman-5-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Trifluoroacetic acid (1 mL) was added dropwise to a solution of tert-butyl (S) -2- (cyanomethyl) -4- (8-fluoro-7- (isochroman-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate (1695 mg, 0.0259mmol) in dichloromethane (3 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour. Dichloromethane (7 mL) was added and concentrated in vacuo. To the resulting residue was added dichloromethane (5 mL) and concentrated again and the process repeated once. The resulting yellow solid was used directly in the next step.

And 4, step 4: synthesis of 2- ((S) -1-acryloyl-4- (8-fluoro-7- (isochroman-5-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To 2- ((S) -4- (8-fluoro-7- (isochroman-5-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [4,3-d ] at room temperature]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile and triethylamine (0.06ml, 0.42mmol) in dichloromethane (2 mL) a slow drop of a solution of acryloyl chloride (0.01ml, 0.122mmol) 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 extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and rotary evaporated to give a viscous mass. Purification by preparative TLC (methanol: dichloromethane =1 = 9) gave a white solid (3mg, 0.0052mmol, two-step total yield: 20%). MS m/z is 572.7[ 2 ], [ M ] +H] ⁺ 。 ¹ H NMR(400MHz,CDCl3)δ9.11(s,1H),7.34-7.32(m,2H),7.13(d,J＝4.0Hz,1H),6.66-6.56(m,1H),6.42(d,J＝16Hz,1H),5.86(d,J＝12Hz,1H),5.10-4.98(m,2H),4.89(s,2H),4.56-4.40(m,3H),4.10–4.14(m,1H),3.94(t,J＝8.0Hz,2H),3.85–3.81(m,1H),3.72–3.25(m,2H),3.06-3.00(m,1H),2.80-2.52(m,7H),2.32–1.98(m,3H),1.80-1.55(m,3H).

Example 51: synthesis of 2- ((S) -1-acryloyl-4- (7- (benzo [ b ] thiophen-7-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 2- (benzothien-7-yl) -4, 5-tetramethyl-1, 3, 2-dioxolane

To a round bottom flask was added 7-bromobenzo [ b ]]Thiophene (150mg, 0.7mmol), biserpinacol Borate (533mg, 2.1mmol), pd (dppf) Cl ₂ (102mg, 0.14mmol) and potassium acetate (206mg, 2.1mmol). After replacement of the nitrogen, dry 1, 4-dioxane (5 mL) previously deoxygenated was added. The resulting suspension was stirred at 100 ℃ for 16 hours. After cooling to room temperature, the reaction mixture was extracted with water (20 mL) and methyl tert-butyl ether (20 mL). After separation, the aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with brine (50 mL), dried over sodium sulfate and dried by spinning in vacuo. The remaining dark brown oil was purified by column chromatography (silica gel, ethyl acetate: petroleum ether =1 = 40) to give a colorless viscous substance. (160mg, 0.615mmol, yield: 99%)

And 2, step: synthesis of (S) -4- (7- (benzothien-7-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [4,3-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester

Adding (S) -4- (7-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [4, 3-d) to a round bottom flask]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (26mg, 0.05mmol), 2- (benzothien-7-yl) -4, 5-tetramethyl-1, 3, 2-dioxolane (26mg, 0.1mmol), palladium tetrakistriphenylphosphine (23mg, 0.02mmol), and cesium carbonate (29mg, 0.15mmol). After nitrogen displacement, previously deoxygenated 1, 4-dioxane (2 mL) and water (0.4 mL) were added. Reaction(s) ofThe solution was stirred at 100 ℃ for 3 hours. Ethyl acetate (15 mL) and water (15 mL) were added. After shaking and separation of the layers, the aqueous layer was extracted with ethyl acetate (10 mL. Times.2). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate and dried by rotary drying in vacuo. The remaining brown viscous mass was purified by preparative TLC (silica gel, methanol: dichloromethane = 1) to give a light yellow solid. (16mg, 0.0259mmol, yield: 52%) MS m/z:618.7[ M + H ])] ⁺ 。

And step 3: synthesis of 2- ((S) -4- (7- (benzo [ b ] thiophen-7-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Trifluoroacetic acid (1 mL) was added dropwise to a solution of (S) -4- (7- (benzothien-7-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [4,3-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (1695g, 0.0259mmol) in dichloromethane (3 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour. Dichloromethane (10 mL) was added and concentrated in vacuo. To the resulting residue was added dichloromethane (5 mL) and concentrated again and the process was repeated once. The resulting yellow solid was used directly in the next step.

And 4, step 4: synthesis of 2- ((S) -1-acryloyl-4- (7- (benzo [ b ] thiophen-7-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To 2- ((S) -4- (7- (benzo [ b ]) at room temperature]Thien-7-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [4,3-d]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile and triethylamine (0.06ml, 0.42mmol) in dichloromethane (2 mL) a slow drop of a solution of acryloyl chloride (0.01ml, 0.122mmol) in dichloromethane (1 mL). The reaction solution was stirred at room temperature for 15 minutes. Methylene chloride (20 mL) and a saturated aqueous solution of sodium carbonate (20 mL) were added, the mixture was shaken and separated, and the aqueous phase was extracted with methylene chloride (10 mL). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate and rotary evaporated to give a viscous mass. Purification by preparative TLC (methanol: dichloromethane =1 = 8) gave a pale yellow powder (10mg, 0.0175mmol, two-step total yield: 67%). MS m/z is 572.6[ 2 ] M + H] ⁺ 。 ¹ H NMR(400MHz,CDCl3)δ9.24(s,1H),8.12(d,J＝8.0Hz,1H),7.97(d,J＝8.0Hz,1H),7.57-7.53(m,2H),7.45(d,J＝4.0Hz,1H),6.66-6.56(m,1H),6.40(d,J＝16Hz,1H),5.86(d,J＝12Hz,1H),5.10-4.98(m,2H),4.67-4.65(m,1H),4.57-4.49(m,2H),4.10–4.14(m,1H),3.89–3.85(m,1H),3.70–3.30(m,2H),2.86(s,3H),2.75-2.65(m,1H),2.32–1.70(m,8H).

Example 52: synthesis of 2- ((2S) -1-acryloyl-4- (8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropan [ a ] inden-2-yl) pyridine [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 4, 5-tetramethyl-2- (1, 1a,6 a-tetrahydrocyclopropan [ a ] inden-2-yl) -1,3, 2-dioxolane

To a round-bottomed flask was added 2-bromo-1,1a, 6,6a-tetrahydrocyclopropane [ a]Indene (180mg, 0.86mmol), biserpinacol borate (655mg, 2.58mmol), pd (dppf) Cl ₂ (126mg, 0.172mmol) and potassium acetate (253mg, 2.58mmol). After replacement of the nitrogen, anhydrous 1, 4-dioxane (6 mL), previously deoxygenated, was added. The resulting suspension was stirred at 100 ℃ for 16 hours. After cooling to room temperature, the reaction mixture was extracted with water (20 mL) and methyl tert-butyl ether (20 mL). After separation, the aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with brine (50 mL), dried over sodium sulfate and dried by spinning in vacuo. The remaining dark brown oil was purified by column chromatography (silica gel, ethyl acetate: petroleum ether =1 = 40) to give a colorless viscous substance. (101mg, 0.395mmol, yield: 46%)

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

Adding (S) -4- (7-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [4, 3-d) to a round bottom flask]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (30mg, 0.058mmol), 4, 5-tetramethyl-2- (1, 1a,6 a-tetrahydrocyclopropane [ a]Inden-2-yl) -1,3, 2-dioxolane (26mg, 0.104mmol), palladium tetrakistriphenylphosphine (27mg, 0.023mmol) and cesium carbonate (57 mg,0.174 mmol). After nitrogen displacement, previously deoxygenated 1, 4-dioxane (2 mL) and water (0.4 mL) were added. The reaction mixture was stirred at 100 ℃ for 3 hours. Ethyl acetate (15 mL) and water (15 mL) were added. After shaking and separation, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate and dried by evaporation in vacuo. The remaining brown viscous mass was purified by preparative TLC (silica gel, methanol: dichloromethane = 1) to give a light yellow solid. (15mg, 0.0244mmol, yield: 42%) MS m/z:614.7[ 2 ], [ M + H ]] ⁺ 。

And step 3: synthesis of 2- ((2S) -4- (8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropane [ a ] inden-2-yl) pyridin [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Trifluoroacetic acid (1 mL) was added dropwise to a solution of (2S) -2- (cyanomethyl) -4- (8-fluoro-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropan [ a ] inden-2-yl) pyridin [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (15mg, 0.0244mmol) in dichloromethane (3 mL) at room temperature, the resulting solution was stirred at room temperature for 1 hour, dichloromethane (10 mL) was added and concentrated in vacuo, dichloromethane (5 mL) was added to the resulting residue and the process was repeated once again.

And 4, step 4: synthesis of 2- ((2S) -1-acryloyl-4- (8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropane [ a ] inden-2-yl) pyridin [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To 2- ((2S) -4- (8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropane [ a ] at room temperature]Inden-2-yl) pyridine [4,3-d]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile and triethylamine (0.03ml, 0.21mmol) in dichloromethane (2 mL) was slowly added dropwise a solution of acryloyl chloride (0.005ml, 0.061mmol) 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 extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and rotary evaporated to give a viscous mass. Purification by preparative TLC (methanol: dichloromethane =1 = 8) gave a light yellow powder (10mg, 0.0176mmol, twoThe total yield of the steps is as follows: 72%). MS m/z 568.6[ M + H ]] ⁺ 。 ¹ H NMR(400MHz,CDCl3)δ9.09(s,1H),7.42(d,J＝8.0Hz,1H),7.37-7.35(m,2H),6.66-6.56(m,1H),6.42(d,J＝16Hz,1H),5.86(d,J＝12Hz,1H),5.04-4.98(m,2H),4.61–4.45(m,3H),4.11–4.07(m,1H),3.81–3.76(m,1H),3.60–3.38(m,1H),3.34-3.24(m,2H),3.06-2.97(m,2H),2.83(s,3H),2.75-2.70(m,1H),2.48-2.44(m,1H),2.32–1.80(m,8H),1.10-1.04(m,1H),0.15-0.11(m,1H).

Preparation of the Compounds of examples 53 to 72 using preparation 1

Example 73: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of tert-butyl (S) -4- (7-bromo-2-chloroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

The compound 7-bromo-2, 4-dichloroquinazoline (200mg, 0.72mmol) was dissolved in DMF (5 mL), followed by addition of DIEA (465mg, 3.60mmol) and (S) -2- (piperazin-2-yl) acetonitrile 2 hydrochloride (142mg, 0.72mmol), and the reaction was stirred at room temperature for 30 minutes. Then di-tert-butyl dicarbonate (472mg, 2.16mmol) was added and the mixture was heatedThe reaction was stirred for 16 hours at 60 ℃. After the reaction, 20mL of cold water was added with stirring to dilute the reaction solution, extraction was performed with ethyl acetate, the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain an off-white solid. (200 mg, yield: 60%). ¹ H NMR(400MHz,CDCl ₃ )δ8.06(d,J＝1.9Hz,1H),7.78(d,J＝8.9Hz,1H),7.60(dd,J＝8.9,1.9Hz,1H),4.68(s,1H),4.37(d,J＝13.3Hz,1H),4.27(d,J＝11.7Hz,1H),4.15(d,J＝7.1Hz,1H),3.71(dd,J＝13.6,3.7Hz,1H),3.59–3.48(m,1H),3.42(s,1H),2.87(s,1H),2.75(s,1H),1.54(s,9H).

Step 2: synthesis of tert-butyl (S) -4- (7-bromo-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

The compound (S) - (1-methylpyrrolidin-2-yl) methanol (149mg, 1.29mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), 60% NaH (52mg, 1.29mmol) was added thereto under cooling in an ice-water bath, and after stirring at room temperature for 20 minutes, t-butyl (S) -4- (7-bromo-2-chloroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (200mg, 0.43mmol) was added and stirred at room temperature for 1 hour. After the reaction is finished, quenching the reaction by cold water, extracting by ethyl acetate, washing an organic phase by saturated water, drying by anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain a white-like solid. (200 mg, yield: 85%)

And step 3: synthesis of tert-butyl (S) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2-cyanomethyl) piperazine-1-carboxylate

The compound (S) -tert-butyl 4- (7-bromo-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (30mg, 0.06mmol) and 2- (8-chloronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (19mg, 0.07) were dissolved in dioxane/water =5/1 (3 mL), followed by cesium carbonate (54mg, 0.17mmol) and Pd (PPh) ₃ ) ₄ (30mg, 0.03mmol), nitrogen was replaced, and the reaction was stirred at 90 ℃ for 1 hour. After the reaction is finished, cooling to room temperature, adding water to dilute the reaction solution, extracting with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, concentrating, and separating and purifying by TLC to obtain an off-white solid. (28 mg, yield: 80%).

¹ H NMR(300MHz,CDCl ₃ )δ7.96(dd,J＝8.2,1.1Hz,1H),7.90(dd,J＝8.1,1.1Hz,1H),7.82(d,J＝8.5Hz,1H),7.75(t,J＝1.7Hz,1H),7.60–7.52(m,2H),7.45(dd,J＝5.6,2.7Hz,1H),7.33(dd,J＝8.5,1.6Hz,1H),7.23(d,J＝7.6Hz,1H),4.86(d,J＝5.8Hz,1H),4.71(s,1H),4.57(d,J＝11.5Hz,1H),4.47–4.25(m,2H),4.15(s,1H),3.64–3.22(m,4H),3.01–2.55(m,6H),2.25(d,J＝6.3Hz,1H),2.18–1.89(m,3H),1.54(s,9H).

And 4, step 4: synthesis of 2- ((S) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazin-2-yl) acetonitrile

The compound (S) -tert-butyl 4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2-cyanomethyl) piperazine-1-carboxylate (28mg, 0.04mmol) was dissolved in dichloromethane (3 mL), followed by addition of trifluoroacetic acid (1 mL) and stirring reaction at room temperature for one hour. After the reaction, the reaction solution is concentrated, then dissolved in dichloromethane, the pH is adjusted to 8-9 by saturated sodium carbonate aqueous solution, the mixture is extracted by dichloromethane, an organic phase is dried by anhydrous sodium sulfate, and the crude product obtained by concentration is directly used in the next step. (23 mg, yield: 100%).

And 5: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazin-2-yl) acetonitrile

The compound 2- ((S) -4- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazin-2-yl) acetonitrile (23mg, 0.04mmol) was dissolved in anhydrous dichloromethane (5 mL), DIEA (8mg, 0.06mmol) and acryloyl chloride (5mg, 0.05mmol) were added with cooling in an ice-water bath, and the reaction was stirred for 5 minutes with cooling in an ice-water bath. After the reaction, the reaction was quenched with saturated aqueous sodium carbonate solution, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by TLC to give an off-white solid. ¹ H NMR(300MHz,CDCl ₃ )δ7.96-7.74(m,4H),7.54(d,J＝7.1Hz,2H),7.43(d,J＝4.9Hz,2H),7.34(d,J＝8.6Hz,1H),6.70-6.61(m,1H),6.49–6.32(m,1H),5.84(d,J＝10.5Hz,1H),5.42-5.34(m,1H),5.13-5.06(m,1H),4.71-4.67(m,1H),4.55–4.31(m,2H),3.89–3.43(m,4H),3.10-2.88(m,6H),2.33(s,2H),2.21-1.96(m,4H).MS m/z:581.58[M+H] ⁺

Example 74: synthesis of 2- ((2S) -1-acryloyl-4- (6-chloro-8-fluoro-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-ylquinazolin-4-ylpiperazin-2-ylacetonitrile

Step 1: synthesis of compound 2-amino-3-fluoro-4-bromobenzamide

The compound 2-amino-3-fluoro-4-bromobenzoic acid (5.0 g, 20mmol) was dissolved in 50ml of DMF, and after dissolution by stirring, TBTU (16.0 g, 50mmol), NH, was added at room temperature in one portion ₄ Cl (27.0 g, 50mmol) and DIEA (14ml, 80mmol), and the reaction was stirred at room temperature for 3 hours. After the reaction, about 300ml of water was added to the reaction system, and a large amount of solid was precipitated. When the solid is not precipitated, the light yellow solid is obtained by suction filtration and is directly used in the next step. (3.7 g, yield: 74%). ¹ H NMR(400MHz,DMSO)δ7.92(s,2H),7.66(s,1H),6.94(s,1H),6.25(s,2H).

Step 2: synthesis of compound 7-bromo-8-fluoroquinazoline-2, 4-diol

The compound 2-amino-4-bromo-5-chlorobenzamide (3.6 g,14.4 mmol) was dissolved in 40ml DMF, and after dissolution by stirring, CDI (9.3 g,57.7 mmol), K, was added at once at room temperature ₂ CO ₃ (8.0 g, 50mmol), the reaction system was heated to 80 ℃ and stirred overnight. After the reaction, about 300ml of water was added to the reaction system, and a large amount of solid was precipitated. When the solid is not precipitated, the light yellow solid is obtained by suction filtration and is directly used in the next step. (3.9 g, yield: 90%). ¹ H NMR(400MHz,DMSO)δ11.34(s,1H),11.40(s,1H),8.12(s,1H),7.93(s,1H).

And step 3: synthesis of compound 7-bromo-2, 4-dichloro-8-fluoroquinazoline

The compound 7-bromo-6-chloroquinazoline-2, 4-diol (3.9g, 14mmol) was dissolved in 50ml of POCl ₃ To the solution was added about 5ml of N, N-diethylaniline at room temperature. The reaction was heated to 110 ℃ and stirred overnight. After the reaction is finished, reducing the reaction systemThe solvent was removed by pressing to obtain a crude product. The crude product was isolated by column chromatography (petroleum ether) to give a yellow solid. (2.62g, 60%). ¹ H NMR(400MHz,CDCl ₃ )δ8.12(s,1H),7.93(s,1H).

And 4, step 4: synthesis of (S) -4- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester

The compounds 7-bromo-2, 4, 6-trichloroquinazoline (312mg, 1mmol) and DIEA (0.6 ml,3.5 mmol) were dissolved in 10ml of DMF and 2-cyanopiperazine (198mg, 1mmol) was added portionwise under ice-water bath conditions. The reaction was stirred and returned to room temperature, after the reaction was monitored by TLC, boc was added ₂ O (0.6ml, 2.5 mmol), and the reaction was stirred at room temperature for 2 hours, and after the reaction was completed, about 70ml of a saturated sodium chloride solution was added to the reaction system, and the separated liquid was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give a pale yellow solid which was used directly in the next reaction. (450 mg, yield 90%). ¹ H NMR(400MHz,CDCl ₃ )δ8.14(s,1H),7.95(s,1H),3.5(m,1H),3.38-3.13(m,4H),3.02-2.98(m,2H),2.73(m,1H),2.48(m,1H),1.42(s,9H).

And 5: synthesis of tert-butyl (S) -4- (7-bromo-8-fluoro-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

(S) - (1-methylpyrrolidin-2-yl) methanol (173mg, 1.5 mmol) was dissolved in super dry THF (15 mL), 60% sodium hydride (36mg, 1.5 mmol) was added under ice water bath conditions, and after stirring for 30min, the compound (S) -tert-butyl 4- (7-bromo-2, 6-dichloroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (250mg, 0.5 mmol) was added and the reaction was stirred at room temperature for one hour. After the reaction was completed, water was added to the reaction system to quench the reaction, and after separating the reaction solution by extraction with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate. Removing the solvent under reduced pressure to obtain a crude product, and separating the crude product by column chromatography to obtain a light yellow solid. (133 mg, yield: 50%).

And 6: synthesis of tert-butyl (S) -4- (6-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid

Reacting the compound tert-butyl (S) -4- (7-bromo-6-chloro-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid salt (64mg, 0.11mmol), 4, 5-tetramethyl-2- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -1,3, 2-dioxaborane (43mg, 0.17mmol), and Cs ₂ CO ₃ (72mg, 0.22mmol) was dissolved in a cosolvent of 1, 4-dioxane and water (4 ml/1 ml), nitrogen was purged and Pd (PPh) was added ₃ ) ₄ Catalyst (13mg, 0.01mmol). The reaction system is stirred for one hour at 90 ℃, after the reaction is finished, the reaction system is extracted by ethyl acetate, separated, dried by organic phase and decompressed to remove the solvent to obtain a crude product. The crude product was subjected to column chromatography to give a pale yellow solid (50 mg, yield: 80%).

And 7: synthesis of 2- ((2S) -1-acryloyl-4- (6-chloro-8-fluoro-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-ylquinazolin-4-ylpiperazin-2-ylacetonitrile

The compound tert-butyl (S) -4- (6-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid (31mg, 0.1mmol) was dissolved in DCM and CF ₃ Stirring for one hour at room temperature in a COOH (3 ml/1 ml) cosolvent, removing the organic solvent in the reaction system under reduced pressure after the reaction is finished, adding dichloromethane to dissolve, spin-drying again, and repeating the same operation once more. The crude product obtained was directly used for the next reaction and dissolved in 3ml of ultra dry dichloromethane, after addition of triethylamine (0.1ml, 0.5mmol) and acryloyl chloride (0.05ml, 0.2mmol), the reaction was stirred at room temperature for one hour. And after the reaction is finished, spin-drying the reaction system, adding ethyl acetate to dissolve the reaction system, neutralizing an organic phase by using a saturated sodium carbonate solution, separating the extracted liquid, drying the organic phase by using anhydrous sodium sulfate, decompressing, removing the solvent to obtain a crude product, and separating the crude product by using a PLC (programmable logic controller) to obtain an off-white solid. (10 mg, yield: 34%) ¹ H NMR(400MHz,CDCl ₃ )δ8.29(s,1H),8.23(s,1H),7.27(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:585.27[M+H] ⁺

Example 75: synthesis of 2- ((S) -1-acryloyl-4- (6-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) quinazolin-4-yl) piperazin-2-yl) acetonitrile:

step 1: synthesis of compound 2-amino-4-bromo-5-chlorobenzamide

The compound 2-amino-4-bromo-5-chlorobenzoic acid (5.0 g, 20mmol) was dissolved in 50ml of DMF, and after dissolving by stirring, TBTU (16.0 g, 50mmol), NH, was added at once at room temperature ₄ Cl (27.0 g, 50mmol) and DIEA (14ml, 80mmol), and the reaction was stirred at room temperature for 3 hours. After the completion of the reaction, about 300ml of water was added to the reaction system, and a large amount of solid was precipitated. When the solid is not precipitated, the light yellow solid is obtained by suction filtration and is directly used for the next step. (3.6 g, yield: 72%). ¹ H NMR(400MHz,DMSO)δ7.90(s,2H),7.68(s,1H),6.96(s,1H),6.27(s,2H).

Step 2: synthesis of compound 7-bromo-6-chloroquinazoline-2, 4-diol

The compound 2-amino-4-bromo-5-chlorobenzamide (3.6 g,14.4 mmol) was dissolved in 40ml of DMF and dissolved by stirring, and CDI (9.3 g,57.7 mmol), K, was added at once at room temperature ₂ CO ₃ (8.0 g, 50mmol), the reaction system was heated to 80 ℃ and stirred overnight. After the reaction, about 300ml of water was added to the reaction system, and a large amount of solid was precipitated. When the solid is not precipitated, the light yellow solid is obtained by suction filtration and is directly used in the next step. (3.9 g, yield: 90%). ¹ H NMR(400MHz,DMSO)δ11.34(s,1H),11.40(s,1H),8.12(s,1H),7.93(s,1H).

And 3, step 3: synthesis of compound 7-bromo-2, 4, 6-trichloroquinazoline

The compound 7-bromo-6-chloroquinazoline-2, 4-diol (3.9g, 14mmol) was dissolved in 50ml of POCl ₃ To the solution was added about 5ml of N, N-diethylaniline at room temperature. The reaction was heated to 110 ℃ and stirred overnight. After the reaction is finished, decompressing the reaction system and removing the solvent to obtain a crude product. The crude product was isolated by column chromatography (petroleum ether) to give a yellow solid. (2.62g, 60%). ¹ H NMR(400MHz,CDCl ₃ )δ8.12(s,1H),7.93(s,1H).

And 4, step 4: synthesis of Compound (S) -4- (7-bromo-2, 6-dichloroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester

The compound 7-bromo-2, 4, 6-trichloroquinazoline (312mg, 1mmol) and DIEA (0.6 ml,3.5 mmol) were dissolved in 10ml of DMF and 2-cyanopiperazine (198mg, 1mmol) was added portionwise under ice-water bath conditions. The reaction was stirred to return to room temperature, and after TLC monitoring of the reaction, boc was added ₂ O (0.6 ml,2.5 mmol), and the reaction was stirred at room temperature for 2 hours, and after completion of the reaction, about 70ml of a saturated sodium chloride solution was added to the reaction system, and the separated liquid was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give a pale yellow solid which was used directly in the next reaction. (450 mg, yield 90%). ¹ H NMR(400MHz,CDCl ₃ )δ8.14(s,1H),7.95(s,1H),3.5(m,1H),3.38-3.13(m,4H),3.02-2.98(m,2H),2.73(m,1H),2.48(m,1H),1.42(s,9H).

And 5: synthesis of tert-butyl (S) -4- (7-bromo-6-chloro-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

(S) - (1-methylpyrrolidin-2-yl) methanol (173mg, 1.5 mmol) was dissolved in super dry THF (15 mL), 60% sodium hydride (36mg, 1.5 mmol) was added under ice water bath conditions, and after stirring for 30min, the compound (S) -tert-butyl 4- (7-bromo-2, 6-dichloroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (250mg, 0.5 mmol) was added and the reaction was stirred at room temperature for one hour. After the reaction, water was added to the reaction system to quench the reaction, and after separating the liquid by extraction with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate. Removing the solvent under reduced pressure to obtain a crude product, and separating the crude product by column chromatography to obtain a light yellow solid. (150 mg, yield: 52%).

Step 6: synthesis of tert-butyl (S) -4- (6-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid

The compound tert-butyl (S) -4- (7-bromo-6-chloro-2- (((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (64mg, 0.11mmol), 4, 5-tetra-n-butyl-4- (7-bromo-6-chloro-2- (((((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (64mg, 0.111mmol), 4, 5-tetra-n-butyl-ethyl acetate was preparedMethyl-2- (5, 6,7, 8-Tetrahydronaphthalen-1-yl) -1,3, 2-dioxaborane (43mg, 0.17mmol) and Cs ₂ CO ₃ (72mg, 0.22mmol) was dissolved in a cosolvent of 1, 4-dioxane and water (4 ml/1 ml), nitrogen was purged and Pd (PPh) was added ₃ ) ₄ Catalyst (13mg, 0.01mmol). The reaction system is stirred for one hour at 90 ℃, after the reaction is finished, the reaction system is extracted by ethyl acetate, separated, dried by organic phase and decompressed to remove the solvent to obtain a crude product. The crude product was subjected to column chromatography to give a pale yellow solid (62 mg, yield: 89%).

And 7: synthesis of 2- ((S) -1-acryloyl-4- (6-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) quinazolin-4-yl) piperazin-2-yl) acetonitrile

The compound tert-butyl (S) -4- (6-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid (62mg, 0.1mmol) was dissolved in DCM and CF ₃ Stirring for one hour at room temperature in a COOH (3 ml/1 ml) cosolvent, removing the organic solvent in the reaction system under reduced pressure after the reaction is finished, adding dichloromethane to dissolve, spin-drying again, and repeating the same operation once more. The crude product obtained was directly used in the next reaction and dissolved in 3ml of ultra-dry dichloromethane, after addition of triethylamine (0.1ml, 0.5mmol) and acryloyl chloride (0.05ml, 0.2mmol), the reaction was stirred at room temperature for one hour. And after the reaction is finished, spin-drying the reaction system, adding ethyl acetate to dissolve the reaction system, neutralizing an organic phase by using a saturated sodium carbonate solution, separating the extracted liquid, drying the organic phase by using anhydrous sodium sulfate, decompressing, removing the solvent to obtain a crude product, and separating the crude product by using a PLC (programmable logic controller) to obtain an off-white solid. (20 mg, yield: 34%) ¹ H NMR(400MHz,CDCl ₃ )δ8.29(s,1H),8.23(s,1H),7.27(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:585.27[M+H] ⁺

Example 76: synthesis of 1- (4- (6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one

Step 1: synthesis of 4- (6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) quinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

The compound (S) -tert-butyl 4- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (56mg, 0.11mmol), 4, 5-tetramethyl-2- (5, 6,7, 8-tetrahydronaphthalen-1-yl) -1,3, 2-dioxaborane (43mg, 0.17mmol) and Cs2CO3 (72mg, 0.22mmol) were dissolved in a cosolvent of 1, 4-dioxane and water (4 ml/1 ml), and after purging nitrogen, pd (PPh 3) 4 catalyst (13mg, 0.01mmol) was added. The reaction system is stirred for one hour at 90 ℃, after the reaction is finished, the reaction system is extracted by ethyl acetate, liquid separation is carried out, and the solvent is removed under reduced pressure after an organic phase is dried to obtain a crude product. The crude product was subjected to column chromatography to give a pale yellow solid (33 mg, yield: 50%).

And 2, step: synthesis of 1- (4- (6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one

The compound, tert-butyl 4- (6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) quinazolin-4-yl) piperazine-1-carboxylate (33mg, 0.05mmol), was dissolved in a co-solvent of DCM and CF3COOH (3 ml/1 ml), stirred at room temperature for one hour, after the reaction was completed, the organic solvent in the reaction system was removed under reduced pressure, dissolved by adding dichloromethane, and then spin-dried again, and the same operation was repeated once more. The crude product obtained was directly used in the next reaction and dissolved in 3ml of ultra-dry dichloromethane, after addition of triethylamine (0.1ml, 0.5mmol) and acryloyl chloride (0.05ml, 0.2mmol), the reaction was stirred at room temperature for one hour. And after the reaction is finished, spin-drying the reaction system, adding ethyl acetate to dissolve the reaction system, neutralizing an organic phase by using a saturated sodium carbonate solution, separating the extracted liquid, drying the organic phase by using anhydrous sodium sulfate, decompressing, removing the solvent to obtain a crude product, and separating the crude product by using a PLC (programmable logic controller) to obtain an off-white solid. (8 mg, yield: 28%) ¹ H NMR(400MHz,CDCl ₃ )δ8.00(s,1H),7.27(m,1H),7.11(m,1H),7.02(m,1H),6.62(m,1H),6.04(m,1H),5.58(m,1H),3.65-3.40(m,2H),3.38-3.13(m,4H),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:585.27[M+H]+

Example 77: synthesis of 2- ((S) -1-acryloyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) pyrido [2,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of tert-butyl (S) -2- (cyanomethyl) -4- (2, 7-dichloropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate

Reacting the compound 2,4, 7-trichloropyrido [2,3-d]Pyrimidine (200mg, 0.85mmol) was dissolved in anhydrous DMF (5 mL), DIEA (552mg, 4.27mmol) and (S) -2- (piperazin-2-yl) acetonitrile 2 hydrochloride (19mg, 0.85mmol) were added under cooling in an ice-water bath, and the reaction was stirred for 10 minutes under cooling in an ice-water bath, followed by di-tert-butyl dicarbonate (372g, 1.70mmol), heating to 40 ℃ and stirring for 3 hours. After the reaction, cooling to room temperature, adding saturated saline solution to dilute the reaction solution, extracting with ethyl acetate, washing the organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain a light yellow solid. (335 mg, yield: 93%). ¹ H NMR(400MHz,CDCl ₃ )δ8.18(d,J＝8.6Hz,1H),7.34(d,J＝8.6Hz,1H),4.65(s,1H),4.47(dd,J＝13.9,3.0Hz,1H),4.30(d,J＝12.0Hz,1H),4.12(d,J＝7.1Hz,1H),3.82(d,J＝12.2Hz,1H),3.69(s,1H),3.54(s,1H),3.02–2.87(m,1H),2.80(d,J＝13.8Hz,1H),1.52(s,9H).

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

The compound (S) -2- (cyanomethyl) -4- (2, 7-dichloropyrido [2, 3-d)]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (100mg, 0.24mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (82mg, 0.71mmol) were dissolved in anhydrous 1, 4-dioxane (5 mL), DIEA (92mg, 0.71mmol) was added, and heat was appliedThe reaction was stirred to 80 ℃ for 16 hours. After the reaction, the reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by TLC separation to give an off-white solid. (70 mg, yield: 59%). ¹ H NMR(400MHz,CDCl ₃ )δ8.14(d,J＝8.6Hz,1H),7.26(d,J＝8.6Hz,1H),5.04(s,1H),4.82(s,1H),4.61(s,1H),4.45(d,J＝13.9Hz,1H),4.21(d,J＝12.6Hz,1H),4.07(s,1H),3.73(d,J＝10.6Hz,2H),3.64–3.47(m,2H),3.45–3.25(m,2H),2.95(s,3H),2.86–2.61(m,3H),2.28(s,2H),2.10(d,J＝21.3Hz,2H),1.51(s,9H).

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

The compound (S) -4- (7-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [2,3-d]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (30mg, 0.06mmol) and 4,4,5,5-tetramethyl-2- (5,6,7,8-tetrahydronaphthalen-1-yl) -1,3, 2-dioxaborane (19mg, 0.07mmol) were dissolved in 1,4-dioxane/water =5/1 (3 mL), cesium carbonate (59mg, 0.18mmol) and Pd (PPh) were added ₃ ) ₄ (35mg, 0.03mmol), the nitrogen gas was replaced, and the mixture was heated to 95 ℃ under a nitrogen atmosphere and stirred for reaction for 1 hour. After 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, dried over anhydrous sodium sulfate, concentrated, and separated by TLC to give an off-white solid. (27 mg, yield: 75%). MS m/z 598.84[ M ] +H] ⁺ .

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

The compound (S) -tert-butyl 2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) pyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate (27mg, 0.04mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated, a saturated aqueous sodium carbonate solution and dichloromethane were added, extraction was performed with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and the crude product obtained by concentration was used directly in the next step.

And 5:2- ((S) -1-acryloyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) pyrido [2,3-d]Synthesis of 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) pyrido [2,3-d]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (22mg, 0.04mmol) was dissolved in dichloromethane (5 mL), DIEA (8mg, 0.06mmol) and acryloyl chloride (5mg, 0.05mmol) were added under cooling in an ice-water bath, and the reaction was stirred for 5 minutes under cooling in an ice-water bath. After the reaction is finished, adding saturated sodium carbonate to quench the reaction, extracting by dichloromethane, drying an organic phase by anhydrous sodium sulfate, concentrating, and separating and purifying by TLC to obtain an off-white solid. (18 mg, yield: 74%). ¹ H NMR(400MHz,CDCl ₃ )δ8.24(d,J＝8.4Hz,1H),7.39(d,J＝8.4Hz,1H),7.22-7.16(m,3H),6.59(s,1H),6.41(d,J＝16.3Hz,1H),5.84(d,J＝11.7Hz,1H),5.02(s,2H),4.84(d,J＝11.2Hz,1H),4.47(d,J＝14.0Hz,1H),4.37-4.34(m,1H),3.84(d,J＝10.3Hz,1H),3.77-3.49(m,4H),3.08(ddd,J＝16.9,11.4,7.7Hz,2H),2.97(s,3H),2.89-2.73(m,6H),2.42–2.17(m,4H),2.09-2.03(m,4H).MS m/z:552.64[M+H] ⁺ .

Preparation by application of preparation Process 2 gives the Compounds of examples 78 to 614

Example 615: synthesis of (S) -1- (4- (6-chloro-8-fluoro-7- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one

Step 1: synthesis of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid

2-amino-4-bromo-3-fluorobenzoic acid (2.30g, 10mmol) and NCS (1.60g, 12mmol) were dissolved in 30ml of DMF, and the reaction was stirred at 70 ℃ overnight. After the reaction, 300ml of water was added to the reaction system, and a large amount of solid was precipitated. Suction filtering, drying and weighing to obtain a light yellow solid. (1.34 g, yield: 50%). ¹ H NMR(400MHz,DMSO)δ13.11(s,1H),7.63(s,1H),6.62(s,2H)。

Step 2: synthesis of 7-bromo-6-chloro-8-fluoroquinazoline-2, 4-diol

Putting 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (1.34g, 5 mmol) and urea (1.5 g, 25mmol) into a 50ml single-neck bottle, heating a reaction system to 180 ℃ under the protection of nitrogen, reacting for three hours, adding 30ml 1N/mol NaOH solution into the reaction system, stirring, separating out a large amount of insoluble solids, and performing suction filtration to obtain a light yellow solid. (514mg, 35%). ¹ H NMR(400MHz,DMSO)δ11.40(s,1H),11.34(s,1H),7.70(s,1H)。

And 3, step 3: synthesis of 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline

The compound 7-bromo-6-chloro-8-fluoroquinazoline-2, 4-diol (500mg, 1.73mmol) was dissolved in 10ml of phosphorus oxychloride, 1ml of DMF was added, and the reaction was heated to 110 ℃ and stirred overnight. After the reaction is finished, removing the phosphorus oxychloride under reduced pressure to obtain black pasty liquid. Under the condition of ice-water bathIce water was added thereto and stirred, and a large amount of solid was precipitated, which was dried by suction filtration to give a yellow solid (300mg, 54%). ¹ H NMR(400MHz,DMSO)δ7.70(s,1H)。

And 4, step 4: synthesis of tert-butyl 4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) piperazine-1-carboxylate

The compounds 7-bromo-2, 4, 6-trichloro-8-fluoroquinolizine (300mg, 0.9 mmol) and tert-butyl piperazine-1-carboxylate (167.4 mg,0.9 mmol) were dissolved in 4ml of 1, 4-dioxane, and after DIEA (0.5 ml, 2.25mmol) was added, the reaction was heated at 55 ℃ for three hours. After the reaction is finished, the solvent is removed under reduced pressure to obtain a crude product, the crude product is dissolved by DCM, an organic phase is washed three times by 0.5mol/L HCl, after extraction and liquid separation, the organic phase is dried and then is removed under reduced pressure to obtain a yellow solid. (414 mg, yield: 96%). ¹ H NMR(400MHz,CDCl ₃ )δ7.70(s,1H),3.73(m,4H),3.32(m,4H),1.44(s,9H)。

And 5: synthesis of tert-butyl (S) -4- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate

The compound tert-butyl 4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) piperazine-1-carboxylate (414mg, 0.86mmol) and K were added ₂ CO ₃ (240mg, 1.72mmol) was dissolved in 30ml of ultra-dry acetonitrile, and (S) - (1-methylpyrrolidin-2-yl) methanol (96mg, 0.86mmol) was added. The reaction system is heated to 90 ℃ under the protection of nitrogen and stirred for 6 hours. After the reaction was completed, the solvent was removed under reduced pressure to give a crude product, which was isolated by column chromatography (DCM: meOH = 10) to give a brown solid. (170mg, 35%)

Step 6: synthesis of tert-butyl (S) -4- (6-chloro-8-fluoro-7- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) -2- (((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylic acid

Tert-butyl 4- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (38mg, 0.05mmol), 6-fluoro-1, 2,3, 4-tetrahydroquinoline (26mg, 0.18mmol), t-BuONa (34mg, 0.34mmol), ruPhos (38mg, 0.08mmol) were dissolved in 6ml toluene, and after purging the nitrogen, pd2 (dba) 3 (38mg, 0.04mmol) was added, and after further purging the nitrogen, the reaction was allowed to react overnight at 100 ℃. After the reaction was completed, the solvent was removed under reduced pressure to obtain a crude product. The crude product is separated by column chromatography to obtain a light yellow target product. (70mg, 65%).

And 7: synthesis of (S) -6-chloro-8-fluoro-7- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) quinazoline

The compound tert-butyl (S) -4- (6-chloro-8-fluoro-7- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) -2- (((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylic acid (62mg, 0.1mmol) was dissolved in a co-solvent of DCM and CF3COOH (3 ml/1 ml), stirred at room temperature for one hour, after the reaction was completed, the organic solvent in the reaction system was removed under reduced pressure, dichloromethane was added to dissolve the organic solvent, the reaction was again spun dry, and the same operation was repeated once more, and the crude product obtained was directly used in the next reaction (53 mg, yield: 100%)

And 8: synthesis of (S) -1- (4- (6-chloro-8-fluoro-7- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one

The compound (S) -6-chloro-8-fluoro-7- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) quinazoline (53mg, 0.1mmol) was dissolved in dichloromethane (3 mL), DIEA (80mg, 0.60mmol) was added under cooling in an ice-water bath, acryloyl chloride (18mg, 0.13mmol) was then added, and the reaction was stirred for 10 minutes under cooling in an ice-water bath. 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 PLC separated (dichloromethane/methanol = 15/1) to give an off-white solid. (30 mg, yield: 50%). ¹ H NMR(400MHz,CDCl ₃ )δ7.47(d,J＝9.1Hz,1H),7.31–7.23(m,1H),6.93–6.80(m,1H),6.71(s,1H),6.54(dd,J＝16.7,10.5Hz,1H),6.30(d,J＝16.7Hz,1H),5.71(d,J＝11.9Hz,1H),5.12(s,1H),4.67(d,J＝10.9Hz,1H),4.10(t,J＝8.1Hz,2H),3.80(s,7H),3.13(t,J＝8.2Hz,2H),2.95(s,3H),2.77(s,1H),2.37–1.86(m,5H),1.61(s,4H).MS m/z:583.23[M+H]+

The procedure of example 615 was used to prepare the compounds of examples 616-619

Example 620: synthesis of (S) -4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (8-chloro-7-fluoronaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinoline-3-carbonitrile

Step 1: synthesis of methyl 4-bromo-2- (2-cyanoacetamido) benzoate

The compound methyl 2-amino-4-bromobenzoate (10g, 43.47mmol) and cyanoacetic acid (4.44g, 52.16mmol) were dissolved in dichloromethane (100 mL), EDCI (12.5g, 65.10mmol) was added under cooling in an ice-water bath, and the reaction was stirred for 1 hour under cooling in an ice-water bath. After the reaction, the reaction solution was diluted with water, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the objective compound. (12.9 g, yield: 100%). ¹ H NMR(400MHz,CDCl ₃ )δ11.73(s,1H),8.88(d,J＝1.5Hz,1H),7.92(d,J＝8.6Hz,1H),7.32(dd,J＝8.6,1.8Hz,1H),3.97(s,3H),3.61(s,2H).

Step 2: 7-bromo-2, 4-dihydroxyquinoline-3-carbonitrile

Dissolving a compound, namely 4-bromo-2- (2-cyanoacetamido) methyl benzoate (12.9 g, 43.42mmol), in absolute methanol (100 mL), dropwise adding a 30% sodium methoxide solution (11.73g, 65.13mmol) under cooling in an ice-water bath, stirring and reacting for 30 minutes under cooling in the ice-water bath, adjusting the pH to 2-3 by using a 10% hydrochloric acid aqueous solution after the reaction is finished, adding 100mL of water to dilute the reaction solution, precipitating a solid, filtering, and drying in vacuum to obtain an off-white solid. (11.18 g, yield: 97%). ¹ H NMR(400MHz,DMSO)δ11.62(s,1H),7.90(d,J＝8.6Hz,1H),7.45(d,J＝1.8Hz,1H),7.37(dd,J＝8.6,1.8Hz,1H).

And step 3: synthesis of 7-bromo-2, 4-dichloroquinoline-3-carbonitrile

The compound 7-bromo-2, 4-dihydroxyquinoline-3-carbonitrile (11.0 g, 41.50mmol) was dissolved in acetonitrile (10 mL) and POCl ₃ (40 mL), the mixture was heated to 90 ℃ and stirred for 16 hours. After the reaction was complete, it was cooled to room temperature and concentrated to give a pale yellow solid which was used directly in the next step. (12.53 g, yield: 100%).

And 4, step 4: synthesis of (S) -4- (7-bromo-2-chloro-3-cyanoquinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester

The compound 7-bromo-2, 4-dichloroquinoline-3-carbonitrile (5.00g, 16.56mmol) was dissolved in anhydrous DMF (50 mL), DIEA (12.84g, 16.42mL, 99.36mmol) was added under cooling in an ice-water bath, followed by (S) -2- (piperazin-2-yl) acetonitrile 2 hydrochloride (3.6 g, 18.22mmol) and stirring for reaction for 10 minutes under cooling in an ice-water bath, followed by di-tert-butyl dicarbonate (7.25g, 33.12mmol) and stirring for reaction for 16 hours at room temperature. After the reaction is finished, adding 100mL of cold water to dilute the reaction solution under stirring, separating out a solid, filtering, washing the solid with water, and drying in vacuum to obtain a light yellow solid which is directly used in the next step. (7.2 g, yield: 88.59%). ¹ H NMR(400MHz,CDCl ₃ )δ8.20(d,J＝1.8Hz,1H),7.84(d,J＝9.0Hz,1H),7.71(dd,J＝9.0,1.8Hz,1H),4.76(s,1H),4.20(s,1H),4.07(dd,J＝12.5,3.5Hz,1H),3.76(d,J＝13.0Hz,1H),3.67(d,J＝11.7Hz,1H),3.56(s,1H),3.44(s,1H),2.83(s,2H).

Step 5 Synthesis of (S) -4- (7-bromo-3-cyano-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester:

the compound (tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (44mg, 0.31mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), and NaH (13mg, 0.31mmol) was added to the solution at 60% under cooling in an ice-water bath, and after stirring and reacting for 20 minutes under cooling in an ice-water bath, (S) -tert-butyl 4- (7-bromo-2-chloro-3-cyanoquinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (100mg, 0.20mmol) was added to the reaction solution, and the reaction was stirred at room temperature for 4 hours. After the reaction is finished, quenching the reaction by cold water, extracting by ethyl acetate, washing an organic phase by saturated salt water, drying by anhydrous sodium sulfate, concentrating, and separating and purifying by TLC to obtain a beige solid. (100 mg, yield: 82.7%). ¹ H NMR(400MHz,CDCl ₃ )δ8.05–7.99(m,1H),7.77–7.68(m,1H),7.57–7.48(m,1H),4.81–4.62(m,3H),4.18(s,1H),4.00(dd,J＝12.4,3.5Hz,1H),3.82(d,J＝42.0Hz,2H),3.66(dd,J＝29.7,12.2Hz,2H),3.49(s,1H),3.35(t,J＝11.2Hz,1H),3.06–2.72(m,4H),2.29(d,J＝20.6Hz,4H),2.11(d,J＝5.8Hz,2H),1.98(s,2H),1.53(s,9H).

Step 6: synthesis of (S) -4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -3-cyano-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester

The compound (S) -tert-butyl 4- (7-bromo-3-cyano-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (35mg, 0.06mmol) and 2- (8-chloro-7-fluoronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (22mg, 0.07mmol) were dissolved in dioxane/water =5/1 (3 mL), followed by addition of cesium carbonate (58mg, 0.18mmol) and Pd (PPh) ₃ ) ₄ (34mg, 0.03mmol), nitrogen was replaced, and the reaction was stirred at 90 ℃ for 1 hour. After the reaction is finished, cooling to room temperature, adding water to dilute the reaction solution, extracting with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, concentrating, and separating and purifying by TLC to obtain a beige solid. (22 mg, yield: 53%). ¹ H NMR(400MHz,CDCl ₃ )δ7.93(d,J＝8.2Hz,1H),7.87(dd,J＝9.4,3.7Hz,1H),7.83(s,1H),7.57–7.50(m,2H),7.48–7.36(m,4H),4.93(dd,J＝20.0,11.4Hz,1H),4.84–4.65(m,2H),4.20(s,1H),4.11–3.97(m,3H),3.91–3.65(m,2H),3.46(d,J＝39.4Hz,3H),3.00(s,3H),2.93–2.70(m,1H),2.58–2.28(m,4H),2.22–1.95(m,4H),1.54(s,9H).

And 7: synthesis of (S) -7- (8-chloro-7-fluoronaphthalen-1-yl) -4- (3- (cyanomethyl) piperazin-1-yl) -2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinoline-3-carbonitrile

The compound (S) -tert-butyl 4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -3-cyano-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (22mg, 0.03mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added and the reaction was stirred at room temperature for one hour. After the reaction, the reaction solution was concentrated to remove excess trifluoroacetic acid, and then dissolved in dichloromethane, washed with saturated aqueous sodium carbonate solution, extracted with dichloromethane, the organic phase washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain an off-white solid which was directly used in the next step. (19 mg, yield: 100%).

And 8: synthesis of (S) -4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (8-chloro-7-fluoronaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinoline-3-carbonitrile

The compound (S) -7- (8-chloro-7-fluoronaphthalen-1-yl) -4- (3- (cyanomethyl) piperazin-1-yl) -2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinoline-3-carbonitrile (18mg, 0.03mmol) was dissolved in anhydrous dichloromethane (5 mL), DIEA (7 mg, 0.05mmol) and acryloyl chloride (3.2mg, 0.04mmol) were added with cooling in an ice-water bath, and the reaction was stirred in an ice-water bath for 10 minutes. After the reaction is finished, quenching the reaction by saturated sodium carbonate aqueous solution, extracting by dichloromethane, drying an organic phase by anhydrous sodium sulfate, concentrating, and separating and purifying by TLC to obtain an off-white solid. (18 mg, yield: 91.7%). ¹ H NMR(400MHz,CDCl ₃ )δ7.94-7.84(m,4H),7.55–7.38(m,4H),6.67-6.64(m,1H),6.42(d,J＝16.7Hz,1H),5.85(d,J＝10.3Hz,1H),4.92(dd,J＝20.6,11.8Hz,1H),4.71(d,J＝11.6Hz,1H),4.16–3.75(m,6H),3.49(s,1H),3.01(s,4H),2.58–2.25(m,4H),2.15-2.12(m,2H),2.09–1.94(m,2H).MS m/z:649.67[M+H] ⁺

Example 621: synthesis of (S) -4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (8-chloro-7-fluoronaphthalen-1-yl) -6-fluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinoline-3-carbonitrile

Step 1: synthesis of methyl 4-bromo-2- (2-cyanoacetamido) -5-fluorobenzoate

The compound methyl 2-amino-4-bromo-5-fluorobenzoate (1.2g, 4.84mmol) and cyanoacetic acid (0.49g, 5.81mmol) were dissolved in dichloromethane (15 mL), EDCI (1.39g, 7.26mmol) was added under cooling in an ice-water bath, and the reaction was stirred for 1 hour under cooling in an ice-water bath. After the reaction, the reaction solution was diluted with water, extracted with dichloromethane, and the organic phase was washed with saturated brine and anhydrous sulfurDrying sodium salt, and concentrating to obtain the target compound. (1.5 g, yield: 98%). ¹ H NMR(400MHz,CDCl ₃ )δ11.58(s,1H),8.97(d,J＝6.4Hz,1H),7.80(d,J＝8.8Hz,1H),3.99(s,3H),3.60(s,2H).

Step 2: synthesis of 7-bromo-6-fluoro-2, 4-dihydroxyquinoline-3-carbonitrile

Dissolving a compound 4-bromo-2- (2-cyanoacetamido) -5-fluorobenzoic acid methyl ester (1.5g, 4.76mmol) in absolute methanol (10 mL), dropwise adding a 30% sodium methoxide solution (1.29g, 7.14mmol) under cooling in an ice water bath, stirring and reacting for 30 minutes under cooling in an ice water bath, after the reaction is finished, adjusting the pH to 2-3 by using a 10% hydrochloric acid aqueous solution, adding 50mL of water to dilute the reaction solution, precipitating a solid, filtering, and drying in vacuum to obtain an off-white solid. (1.35 g, yield: 100%). ¹ H NMR(400MHz,DMSO)δ11.47(s,1H),7.82(d,J＝9.3Hz,1H),7.53(d,J＝5.9Hz,1H).

And step 3: synthesis of 7-bromo-2, 4-dichloro-6-fluoroquinoline-3-carbonitrile

The compound 7-bromo-6-fluoro-2, 4-dihydroxyquinoline-3-carbonitrile (0.24g, 0.85mmol) was dissolved in acetonitrile (1 mL) and POCl ₃ (4 mL), the reaction mixture was heated to 90 ℃ and stirred for 16 hours. After the reaction was complete, it was cooled to room temperature and concentrated to give a pale yellow solid which was used directly in the next step. (271 mg, yield: 100%). ¹ H NMR(400MHz,CDCl ₃ )δ8.38(d,J＝6.3Hz,1H),7.94(d,J＝8.3Hz,1H).

And 4, step 4: synthesis of tert-butyl (S) -4- (7-bromo-2-chloro-3-cyano-6-fluoroquinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

The compound 7-bromo-2, 4-dichloro-6-fluoroquinoline-3-carbonitrile (271mg, 0.85mmol) was dissolved in anhydrous DMF (5 mL), DIEA (659mg, 5.09mmol) was added under cooling in an ice-water bath, then (S) -2- (piperazin-2-yl) acetonitrile 2 hydrochloride (185mg, 0.93mmol) was added, and the reaction was stirred for 10 minutes under cooling in an ice-water bath, then di-tert-butyl dicarbonate (372mg, 1.70mmol) was added, and the reaction was stirred at room temperature for 16 hours. After the reaction is finished, adding 30mL of cold water to dilute the reaction solution under stirring, separating out a solid, filtering, washing the solid with water, and drying in vacuum to obtain a light yellow solid which is directly used in the next step. (400 mg, yield: 93%). ¹ H NMR(400MHz,CDCl ₃ )δ8.31(d,J＝6.6Hz,1H),7.64(d,J＝9.0Hz,1H),4.76(s,1H),4.21(s,1H),4.08(dd,J＝12.4,3.6Hz,1H),3.78–3.33(m,4H),2.83(qd,J＝16.9,7.6Hz,2H),1.53(s,9H).

And 5: synthesis of (S) -4- (7-bromo-3-cyano-6-fluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester

The compound (tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (44mg, 0.31mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), 60% NaH (13mg, 0.31mmol) was added under cooling in an ice-water bath, and after stirring and reacting for 20 minutes under cooling in an ice-water bath, (S) -4- (7-bromo-2-chloro-3-cyano-6-fluoroquinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (100mg, 0.20mmol) was added to the reaction solution, and the reaction was stirred and reacted for 2 hours under heating to 60 ℃. After the reaction is finished, cooling to room temperature, quenching the reaction by cold water, extracting by ethyl acetate, washing an organic phase by saturated salt water, drying by anhydrous sodium sulfate, concentrating, and separating and purifying by TLC to obtain a white-like solid. (100 mg, yield: 83%). ¹ H NMR(400MHz,CDCl ₃ )δ8.10(d,J＝6.6Hz,1H),7.53(d,J＝9.1Hz,1H),4.75(s,3H),4.19(s,1H),4.01(dd,J＝12.4,3.5Hz,1H),3.82(d,J＝42.0Hz,2H),3.66(dd,J＝29.7,12.2Hz,2H),3.49(s,1H),3.35(t,J＝11.2Hz,1H),3.06–2.72(m,4H),2.29(d,J＝20.6Hz,4H),2.11(d,J＝5.8Hz,2H),1.98(s,2H),1.53(s,9H).

Step 6: synthesis of (S) -4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -3-cyano-6-fluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester

The compound (S) -tert-butyl 4- (7-bromo-3-cyano-6-fluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (30mg, 0.05mmol) and 2- (8-chloro-7-fluoronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (22mg, 0.07mmol) were dissolved in dioxane/water =5/1 (3 mL), followed by addition of cesium carbonate (58mg, 0.18mmol) and Pd (PPh) ₃ ) ₄ (34mg, 0.03mmol), nitrogen was replaced, and the reaction was stirred at 90 ℃ for 1 hour. After the reaction is finished, cooling to room temperature, adding water to dilute the reaction solution, extracting with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, concentrating, and performing TLC separation and purification to obtain a beige solid. (20 mg, yieldRate: 57%). MS m/z 714[ m ] +H] ⁺

And 7: synthesis of (S) -7- (8-chloro-7-fluoronaphthalen-1-yl) -4- (3- (cyanomethyl) piperazin-1-yl) -6-fluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinoline-3-carbonitrile

The compound (S) -tert-butyl 4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -3-cyano-6-fluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (20mg, 0.03mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added to stir the reaction at room temperature for one hour. After the reaction, the reaction solution was concentrated to remove excess trifluoroacetic acid, and then dissolved in dichloromethane, washed with saturated aqueous sodium carbonate solution, extracted with dichloromethane, the organic phase washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain an off-white solid which was directly used in the next step. (17 mg, yield: 100%).

And step 8: synthesis of (S) -4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (8-chloro-7-fluoronaphthalen-1-yl) -6-fluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinoline-3-carbonitrile

The compound (S) -7- (8-chloro-7-fluoronaphthalen-1-yl) -4- (3- (cyanomethyl) piperazin-1-yl) -6-fluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinoline-3-carbonitrile (17mg, 0.03mmol) was dissolved in anhydrous dichloromethane (5 mL), DIEA (7 mg, 0.05mmol) and acryloyl chloride (3.2mg, 0.04mmol) were added with cooling in an ice-water bath, and the reaction was stirred under an ice-water bath for 10 minutes. After the reaction is finished, quenching the reaction by using saturated sodium carbonate aqueous solution, extracting by using dichloromethane, drying an organic phase by using anhydrous sodium sulfate, concentrating, and separating and purifying by TLC to obtain a white-like solid. (10 mg, yield: 54%). ¹ H NMR(400MHz,CDCl ₃ )δ7.93-7.84(m,4H),7.55–7.38(m,3H),6.67-6.63(m,1H),6.41(d,J＝16.7Hz,1H),5.84(d,J＝10.3Hz,1H),4.93(dd,J＝20.6,11.8Hz,1H),4.72(d,J＝11.6Hz,1H),4.17–3.75(m,6H),3.49(s,1H),3.01(s,4H),2.58–2.25(m,4H),2.15-2.12(m,2H),2.09–1.94(m,2H).MS m/z:667.6[M+H] ⁺

Example 622: synthesis of 4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6-chloro-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) quinoline-3-carbonitrile

Step 1: synthesis of methyl 4-bromo-5-chloro-2- (2-cyanoacetamido) benzoate

The compound methyl 2-amino-4-bromo-5-chlorobenzoate (1.0g, 3.78mmol) and cyanoacetic acid (0.39g, 4.53mmol) were dissolved in methylene chloride (15 mL), EDCI (1.08g, 5.67mmol) was added thereto under cooling in an ice-water bath, and the reaction was stirred for 1 hour under cooling in an ice-water bath. After the reaction, the reaction solution was diluted with water, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the objective compound. (1.19 g, yield: 95%). ¹ H NMR(400MHz,CDCl ₃ )δ11.63(s,1H),9.03(s,1H),8.13(s,1H),3.99(s,3H),3.61(s,2H).

Step 2: synthesis of 7-bromo-6-chloro-2, 4-dihydroxyquinoline-3-carbonitrile

Dissolving a compound 4-bromo-2- (2-cyanoacetamido) -5-chlorobenzoic acid methyl ester (1.19g, 3.59mmol) in absolute methanol (10 mL), dropwise adding a 30% sodium methoxide solution (0.97g, 5.39mmol) under cooling of an ice-water bath, stirring and reacting for 30 minutes under cooling of the ice-water bath, adjusting the pH to 2-3 by using a 10% hydrochloric acid aqueous solution after the reaction is finished, adding 50mL of water to dilute the reaction solution, precipitating a solid, filtering, and drying in vacuum to obtain an off-white solid. (1.07 g, yield: 100%). ¹ H NMR(400MHz,DMSO)δ11.40(s,1H),8.06(s,1H),7.57(s,1H).

And 3, step 3: synthesis of 7-bromo-2, 4, 6-trichloroquinoline-3-carbonitrile

The compound 7-bromo-6-chloro-2, 4-dihydroxyquinoline-3-carbonitrile (0.20g, 0.67mmol) was dissolved in acetonitrile (1 mL) and POCl ₃ (4 mL), the reaction mixture was heated to 90 ℃ and stirred for 16 hours. After the reaction was complete, it was cooled to room temperature and concentrated to give a pale yellow solid which was used directly in the next step. (225 mg, yield: 100%).

And 4, step 4: synthesis of (S) -4- (7-bromo-2, 6-dichloro-3-cyanoquinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester

The compound 7-bromo-2, 4, 6-trichloroquinoline-3-carbonitrile (225 m)g,0.67 mmol) was dissolved in anhydrous DMF (5 mL), DIEA (518mg, 4.01mmol) was added under cooling in an ice-water bath, followed by (S) -2- (piperazin-2-yl) acetonitrile 2 hydrochloride (146mg, 0.74mmol), and the reaction was stirred for 10 minutes under cooling in an ice-water bath, followed by di-tert-butyl dicarbonate (2922mg, 1.34mmol) and stirred at room temperature for 4 hours. After the reaction is finished, adding 30mL of cold water to dilute the reaction solution under stirring, separating out a solid, filtering, washing the solid with water, and drying in vacuum to obtain a light yellow solid which is directly used in the next step. (230 mg, yield: 89%). ¹ H NMR(300MHz,CDCl ₃ )δ8.35(s,1H),8.05(s,1H),4.78(s,1H),4.51(s,1H),4.26(d,J＝22.4Hz,1H),3.82–3.39(m,4H),3.10(d,J＝13.7Hz,1H),2.83(qd,J＝16.9,7.6Hz,2H),1.55(s,9H).

And 5: synthesis of tert-butyl (S) -4- (7-bromo-6-chloro-3-cyano-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

The compound (S) - (1-methylpyrrolidin-2-yl) methanol (40mg, 0.34mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), 60% NaH (14mg, 0.34mmol) was added under cooling in an ice-water bath, and after stirring and reacting for 20 minutes under cooling in an ice-water bath, S) -4- (7-bromo-2, 6-dichloro-3-cyanoquinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (60mg, 0.11mmol) was added to the reaction solution, and heating was carried out to 60 ℃ for stirring and reacting for 2 hours. After the reaction is finished, cooling to room temperature, quenching the reaction with cold water, extracting with ethyl acetate, washing an organic phase with saturated salt water, drying with anhydrous sodium sulfate, concentrating, and separating and purifying by TLC to obtain an off-white solid. (50 mg, yield: 83%). ¹ H NMR(400MHz,CDCl ₃ )δ8.13(s,1H),7.92(s,1H),4.75(s,1H),4.60(s,1H),4.19(s,1H),4.02(dd,J＝12.4,3.6Hz,1H),3.71–3.31(m,6H),2.84(s,3H),2.72(s,3H),2.52(s,1H),2.18(s,1H),2.03(s,1H),1.91(s,3H),1.53(s,9H).

Step 6: synthesis of (S) -4- (6-chloro-3-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) quinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester

The compound (S) -4- (7-bromo-6-chloro-3-cyano-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) quinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (25mg, 0.04mmol)And 4,4,5,5-tetramethyl-2- (5,6,7,8-tetrahydronaphthalen-1-yl) -1,3, 2-dioxaborane (13mg, 0.05mmol) was dissolved in dioxane/water =5/1 (3 mL), followed by addition of cesium carbonate (40mg, 0.12mmol) and Pd (PPh) ₃ ) ₄ (24mg, 0.02mmol), the nitrogen gas was replaced, and the reaction mixture was heated to 90 ℃ and stirred for 1 hour. After the reaction is finished, cooling to room temperature, adding water to dilute the reaction solution, extracting with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, concentrating, and separating and purifying by TLC to obtain a beige solid. (27 mg, yield: 100%). MS m/z 655.7[ m ] +H] ⁺

And 7: synthesis of 6-chloro-4- ((S) -3- (cyanomethyl) piperazin-1-yl) -2- (((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) quinoline-3-carbonitrile

The compound (S) -4- (6-chloro-3-cyano-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) quinolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (27mg, 0.04mmol) was dissolved in dichloromethane (3 mL), then trifluoroacetic acid (1 mL) was added and the reaction was stirred at room temperature for one hour. After the reaction, the reaction solution was concentrated to remove excess trifluoroacetic acid, and then dissolved in dichloromethane, washed with saturated aqueous sodium carbonate solution, extracted with dichloromethane, the organic phase washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain an off-white solid which was directly used in the next step. (23 mg, yield: 100%).

And 8: synthesis of 4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6-chloro-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) quinoline-3-carbonitrile

The compound 6-chloro-4- ((S) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (5, 6,7, 8-tetrahydronaphthalen-1-yl) quinoline-3-carbonitrile (23mg, 0.04mmol) was dissolved in anhydrous dichloromethane (5 mL), DIEA (7mg, 0.05mmol) and acryloyl chloride (5mg, 0.05mmol) were added under cooling in an ice-water bath, and stirred for 10 minutes under cooling in an ice-water bath, after completion of the reaction, the reaction was quenched with a saturated aqueous sodium carbonate solution, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by TLC separation to give an off-white solid (8 mg, yield: 32%). ¹ H NMR(400MHz,CDCl ₃ )δ7.94(d,J＝2.5Hz,1H),7.73(t,J＝10.6Hz,1H),7.19(t,J＝5.1Hz,2H),6.96(dd,J＝10.4,6.6Hz,1H),6.61(d,J＝10.6Hz,1H),6.43(d,J＝15.8Hz,1H),5.87(d,J＝10.9Hz,1H),4.69(s,1H),4.07(d,J＝12.9Hz,1H),3.93–3.69(m,3H),3.48(s,2H),3.01(d,J＝8.4Hz,2H),2.87-2.55(m,6H),2.54–2.14(m,4H),1.88-1.74(m,10H).MS m/z:609.67[M+H] ⁺ .

Preparation 3 was used to prepare the compounds of examples 623-839.

Example 840:2- ((S) -1-acryloyl-4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [3,2-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 7-bromo-2, 4-dichloropyrido [3,2-d ] pyrimidine

To a mixture of 7-bromopyrido [3,2-d ] pyrimidine-2, 4-diol (1.04g, 4.3 mmol) and phosphorus oxychloride (10 mL) was added nitrogen, nitrogen-diethylaniline (1.41g, 9.45mmol) at room temperature. The resulting pale yellow suspension was stirred for 5 minutes and then heated and stirred in an oil bath at 110 ℃ for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was mixed with toluene (20 mL. Times.2) and concentrated under reduced pressure. A light brown solid was obtained and used directly in the next reaction.

And 2, step: synthesis of (S) -2- (4- (7-bromo-2-chloropyrido [3,2-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To a mixture of 7-bromo-2, 4-dichloropyrido [3,2-d ] pyrimidine and tetrahydrofuran (30 mL) was added nitrogen, N-diisopropylethylamine (4.27mL, 25.8mmol) in one portion in an ice-water bath. After stirring for 2 minutes, (S) -2- (piperazin-2-yl) acetonitrile hydrochloride (0.85g, 4.3mmol) was added. The reaction solution was gradually warmed to room temperature and stirred for 5 hours. The reaction solution was used in the next reaction without further treatment.

And step 3: synthesis of tert-butyl (S) -4- (7-bromo-2-chloropyrido [3,2-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

Triethylamine (0.6mL, 4.3mmol) and di-tert-butyl dicarbonate (1.31g, 6mmol) were added to the reaction solution in the upper step at room temperature. The reaction solution was stirred at room temperature for 17 hours. Ethyl acetate (100 mL) and water (100 mL) were added and the mixture was extracted and separated. The aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a dark brown viscous substance. Column chromatography (silica gel, ethyl acetate: petroleum ether =1 to ethyl acetate: petroleum ether = 1). (210mg, 0.449mmol, total yield in three steps: 10%). MS m/z of 467.4[ mu ] M + H ], [ beta ] C] ⁺ 。

Step 4 Synthesis of tert-butyl (S) -4- (7-bromo-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [3,2-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate:

dissolved in (S) - (1-methylpyrrolidin-2-yl) methanol (77mg, 0.67mmol) and tetrahydrofuran (2 mL) were added with sodium hydride (1695g, 0.67mmol) at 0 ℃ and reacted at room temperature for 0.5h. Then, the compound (S) -4- (7-bromo-2-chloropyrido [3,2-d ] was added]A solution of tert-butyl pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (100mg, 0.22mmol) in tetrahydrofuran (2 mL) was allowed to react at room temperature for an additional 1h. Concentrating the reaction mixture under reduced pressure, and purifying with PLC to obtain compound (S) -4- (7-bromo-2- ((((S) -1-methylpyrrolidine-2-yl) methoxyl) pyrido [3,2-d]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (82mg, 67%). MS M/z [ M + H ]] ⁺ ＝546.6。

Step 5 Synthesis of tert-butyl (S) -4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [3,2-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate:

reacting the compound (S) -4- (7-bromo-2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [3, 2-d)]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (50mg, 0.091mmol) and 2- (8-chloro-7-fluoronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (56.1mg, 0.18mmol) were dissolved in 1, 4-dioxane (2.0 mL). Under nitrogen atmosphere, pd (PPh) is added in sequence ₃ ) ₄ (31.7mg, 0.027mmol), caesium carbonate (89.4mg, 0.27mmol) and water (0.1 mL) and then heated to 100 ℃ and the reaction stirred at this temperature for 5h. Concentrating the reaction mixture under reduced pressure, and purifying with PLC to obtain compound (S) -4- (7- (8-chloro-7-fluoronaphthalene-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxyl) pyrido [3,2-d]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (35.5mg, 60%). MS M/z [ M + H ]] ⁺ ＝646.7。

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

the compound (S) -4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [3,2-d]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (34mg, 0.053mmol) 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, separated, CH ₂ Cl ₂ Extraction, washing with saturated brine and drying (Na) ₂ SO ₄ ) Filtering, and concentrating under reduced pressure to obtain compound 2- ((S) -4- (7- (8-chloro-7-fluoronaphthalene-1-yl) -2- (((S) -1-methylpyrrolidine-2-yl) methoxyl) pyridyl [3,2-d]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (24.3mg, 84%). MS M/z [ M + H ]] ⁺ ＝546.6。

Step 7 synthesis of 2- ((S) -1-acryloyl-4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [3,2-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile:

the compound 2- ((S) -4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridineAnd [3,2-d]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (23mg, 0.042mmol) and triethylamine (13mg, 0.13mmol) were dissolved in CH ₂ Cl ₂ (1.0 mL), acryloyl chloride (7.6 mg, 0.08mmol) was then added dropwise to the solution, stirring at room temperature for 1h. Concentrating the reaction solution under pressure, and purifying with PLC to obtain compound 2- ((S) -1-acryloyl-4- (7- (8-chloro-7-fluoronaphthalene-1-yl) -2- (((S) -1-methylpyrrolidine-2-yl) methoxyl) pyrido [3,2-d]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (24mg, 94%). ¹ H NMR(400MHz,CDCl ₃ )δ8.59(s,1H),7.98(d,J＝8.0Hz,1H),7.91(dd,J＝8.9,5.5Hz,2H),7.56(dd,J＝15.5,7.4Hz,1H),7.50–7.38(m,2H),7.05–6.81(m,1H),6.45–6.30(m,1H),5.81(dd,J＝21.5,10.7Hz,1H),4.76–4.68(m,1H),4.43(s,1H),4.25–3.28(m,5H),3.05–2.91(m,4H),2.49–1.87(m,10H).MS m/z:[M+H] ⁺ ＝600.6

The compounds of examples 841-853 were prepared by applying the procedure of example 840

Example 854: synthesis of (S) -2- (1-acryloyl-4- (7- (8-chloronaphthalen-1-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methanol

Compound (1- (aminomethyl) cyclopropyl) methanol (500mg, 4.94mmol) and 1, 4-dibromobutane (1.12g, 5.19mmol) were dissolved in acetonitrile (20 mL), followed by addition of potassium carbonate (1.78g, 12.85mmol), and the reaction was stirred at room temperature for 12 hours. After the reaction was complete, the solid was removed by filtration. Concentrating the organic phase and separating by column chromatography (DCM/7M NH3 in MeO)H = 100/1) gave a colorless oil. (390 mg, yield: 50.8%). ¹ H NMR(400MHz,CDCl ₃ )δ3.55(s,2H),2.70–2.53(m,6H),1.83–1.69(m,4H),0.49(q,J＝4.6Hz,2H),0.36(t,J＝5.2Hz,2H).

Step 2: synthesis of tert-butyl (S) -4- (7-chloro-8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

The compound (2S) -4- (7-chloro-8-fluoro-2- (methylsulfinyl) pyrido [4,3-d]T-butyl pyrimidin-4-yl-2- (cyanomethyl) piperazine-1-carboxylate (100mg, 0.21mmol) and (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methanol (37mg, 0.23mmol) were dissolved in anhydrous toluene (3 mL), and sodium t-butoxide (25mg, 0.25mmol) was added under cooling in an ice-water bath, followed by stirring for 30 minutes. Quenching the reaction solution with cold water after the reaction solution is finished, extracting with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, concentrating, and separating and purifying by preparative TLC to obtain a white-like solid. (50 mg, yield: 42%). ¹ H NMR(400MHz,CDCl ₃ )δ8.78(s,1H),4.62(s,1H),4.42(q,J＝10.9Hz,3H),4.29(d,J＝12.8Hz,1H),4.08(s,1H),3.88(s,1H),3.66(s,1H),3.46(s,1H),2.87–2.77(m,1H),2.73(d,J＝5.7Hz,1H),2.53(s,6H),1.74(s,4H),1.51(s,9H),0.68(s,2H),0.51(s,2H).

And step 3: synthesis of tert-butyl (S) -4- (7- (8-chloronaphthalen-1-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

The compound (S) -4- (7-chloro-8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrido [4,3-d]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (50mg, 0.09mmol), 2- (8-chloronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (34mg, 0.12mmol), and cesium carbonate (87mg, 0.27mmol) were dissolved in 1, 4-dioxane/water =5/1 (3 mL), followed by addition of Pd (PPh) ₃ ) ₄ (52mg, 0.04mmol), the nitrogen gas was replaced by 3 times, and the reaction mixture was heated to 100 ℃ and stirred for 2 hours. After the reaction, cooling to room temperature, diluting the reaction solution with water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, concentrating, and separating and purifying by preparative TLC to obtain an off-white solid. (20 mg, yield: 33%).

And 4, step 4: synthesis of (S) -2- (4- (7- (8-chloronaphthalen-1-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

The compound (S) -tert-butyl 4- (7- (8-chloronaphthalen-1-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (20mg, 0.03mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added to stir the reaction at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated to obtain a crude product which was used directly in the next step.

And 5: synthesis of (S) -2- (1-acryloyl-4- (7- (8-chloronaphthalen-1-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

The compound (S) -2- (4- (7- (8-chloronaphthalen-1-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrido [4,3-d]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (17mg, 0.03mmol) was dissolved in dichloromethane (3 mL), DIEA (5mg, 0.03mmol) and acryloyl chloride (3mg, 0.03mmol) were added under cooling in an ice-water bath, and the reaction was stirred for 5 minutes under cooling in an ice-water bath. After the reaction is finished, quenching the reaction by using saturated sodium bicarbonate aqueous solution, extracting by using dichloromethane, drying an organic phase by using anhydrous sodium sulfate, concentrating, and separating and purifying by preparative TLC to obtain an off-white solid. (10 mg, yield: 50%). ¹ H NMR(400MHz,CDCl ₃ )δ9.05(s,1H),8.01(dd,J＝7.9,1.5Hz,1H),7.88(d,J＝8.1Hz,1H),7.66–7.50(m,3H),7.42(td,J＝7.8,2.4Hz,1H),6.59(s,1H),6.42(d,J＝16.8Hz,1H),5.85(d,J＝10.8Hz,1H),5.08(s,1H),4.46(d,J＝10.5Hz,4H),3.90(d,J＝103.6Hz,5H),3.06(s,1H),2.82(d,J＝17.1Hz,2H),2.55(s,4H),1.78(s,4H),0.73(s,2H),0.57(s,2H).MS m/z:[M+H] ⁺ ＝640.59

Example 855: synthesis of (S) -2- (1-acryloyl-4- (7- (8-chloronaphthalen-1-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) quinazolin-4-yl) piperazin-2-yl) acetonitrile

Step 1: synthesis of tert-butyl (S) -4- (7-bromo-8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) quinazolin-4-yl-2- (cyanomethyl) piperazine-1-carboxylate

The compound (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methanol (84mg, 0.54mmol) was dissolved in anhydrous THF (5 mL), and NaH (2 0mg, 0.50mmol) was added to the solution under cooling in an ice-water bath in an amount of 60% and the reaction was stirred for 20 minutes under cooling in an ice-water bath, and then the compound (S) -4- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (200mg, 0.41mmol) was added thereto and the reaction was stirred at room temperature for 8 hours. After the reaction is finished, quenching the reaction by cold water, extracting by ethyl acetate, drying an organic phase by anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain a light yellow solid. (150 mg, yield: 61%). ¹ H NMR(400MHz,CDCl ₃ )δ7.46(d,J＝9.1Hz,1H),7.38(dd,J＝9.0,6.0Hz,1H),4.65(s,1H),4.42(s,2H),4.24(d,J＝12.2Hz,1H),4.16(d,J＝10.8Hz,2H),3.54(dd,J＝13.8,3.6Hz,1H),3.32(d,J＝10.4Hz,2H),2.87–2.69(m,2H),2.50(s,6H),1.71(s,4H),1.52(s,11H),0.67(s,2H),0.48(s,2H).

Step 2: synthesis of (S) -4- (7- (8-chloronaphthalene) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester

The compound (S) -tert-butyl 4- (7-bromo-8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) quinazolin-4-yl-2- (cyanomethyl) piperazine-1-carboxylate (130mg, 0.22mmol), 2- (8-chloronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (93mg, 0.0.32mmol) and potassium carbonate (60mg, 0.43mmol) were dissolved in 1, 4-dioxane/water =5/1 (3 mL), followed by addition of Pd (dppf) Cl ₂ (31mg, 0.04mmol), the nitrogen gas was replaced by 3 times, and the reaction mixture was heated to 100 ℃ and stirred for 2 hours. After the reaction, the reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and subjected to preparative TLC separation and purification to obtain an off-white solid. (80 mg, yield: 54.3%). ¹ H NMR(400MHz,CDCl ₃ )δ7.97(d,J＝8.1Hz,1H),7.88(d,J＝7.4Hz,1H),7.54(dd,J＝14.2,4.9Hz,3H),7.45–7.38(m,2H),7.23(d,J＝6.6Hz,1H),4.70(s,1H),4.36(dd,J＝30.7,19.9Hz,4H),4.14(s,1H),3.55(d,J＝11.7Hz,1H),3.36(s,2H),2.87(s,2H),2.51(s,4H),1.71(s,4H),1.53(s,9H),0.67(s,2H),0.47(s,2H).

And step 3: synthesis of (S) -2- (4- (7- (8-chloronaphthalen-1-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) quinazolin-4-yl) piperazin-2-yl) acetonitrile

The compound tert-butyl (S) -4- (7- (8-chloronaphthalene) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (80mg, 0.12mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated to obtain a crude product which was used in the next step.

And 4, step 4: synthesis of (S) -2- (1-acryloyl-4- (7- (8-chloronaphthalen-1-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) quinazolin-4-yl) piperazin-2-yl) acetonitrile

The compound (S) -2- (4- (7- (8-chloronaphthalen-1-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) quinazolin-4-yl) piperazin-2-yl) acetonitrile (68mg, 0.12mmol) was dissolved in dichloromethane (10 mL), DIEA (18mg, 0.14mmol) and acryloyl chloride (12mg, 0.13mmol) were added under cooling in an ice-water bath, and the reaction was stirred for 5 minutes under cooling in an ice-water bath. After the reaction is finished, quenching the reaction by using saturated sodium bicarbonate aqueous solution, extracting by using dichloromethane, drying an organic phase by using anhydrous sodium sulfate, concentrating, and separating and purifying by preparative TLC to obtain an off-white solid. (42 mg, yield: 56%). ¹ H NMR(400MHz,CDCl ₃ )δ7.97(d,J＝7.3Hz,1H),7.88(d,J＝7.4Hz,1H),7.68–7.60(m,1H),7.55(dd,J＝9.7,8.0Hz,2H),7.43(dd,J＝7.8,2.3Hz,2H),7.26(m,1H),6.61(s,1H),6.42(d,J＝16.8Hz,1H),5.84(d,J＝10.5Hz,1H),5.16(s,1H),4.54–4.26(m,4H),4.02(s,1H),3.53(d,J＝89.6Hz,4H),3.01(s,1H),2.89(d,J＝34.6Hz,1H),2.51(s,6H),1.72(s,4H),0.69(s,2H),0.48(s,2H).MS m/z:[M+H] ⁺ ＝639.61.

The compounds of example 856-871 were prepared by applying the preparation processes of examples 854 and 855

Example 872: synthesis of 2- ((2S) -4- (8-fluoro-2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropane [ a ] inden-5-yl) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile

Step 1: synthesis of 5-bromo-1,1a, 6,6a-tetrahydrocyclopropane [ a ] indene

A solution of diethylzinc/n-hexane (1M, 423mL) in anhydrous dichloromethane (200 mL) was cooled in an ice-water bath. A solution of trifluoroacetic acid (31mL, 423mmol) in dry dichloromethane (200 mL) was added dropwise. After stirring at this temperature for 20 minutes, a solution of diiodomethane (34.3 mL, 423mmol) in dry dichloromethane (100 mL) was added. After stirring for an additional 20 minutes, a solution of 7-bromo-1H-indene (22g, 113mmol) in dry dichloromethane (100 mL) was slowly added dropwise. The ice-water bath was removed and stirred for 16 hours to give a white suspension. Dilute hydrochloric acid (0.1M, 500mL) was added slowly with stirring. The resulting mixture was extracted with petroleum ether (500mL + 200mL). The combined organic phases were washed with saturated sodium bicarbonate solution (300 mL), saturated brine (300 mL), dried over sodium sulfate and concentrated in vacuo to give a yellow oil. Column chromatography (silica gel, petroleum ether) to obtain 5-bromo-1, 1a,6 a-tetrahydrocyclopropane [ a]The indene product was a pale yellow oil (22g, 105mmol, 93% yield). ¹ H NMR(400MHz,CDCl ₃ )δ7.24-7.20(m,2H),7.00-6.96(m,1H),3.13(dd,J＝17.6,6.7Hz,1H),2.97(d,J＝17.6Hz,1H),2.46-2.41(m,1H),1.91-1.85(m,1H),1.12-1.06(m,1H),0.13-0.10(m,1H)

Step 2: synthesis of 4, 5-tetramethyl-2- (1, 1a,6 a-tetrahydrocyclopropane [ a ] inden-5-yl) -1,3, 2-dioxolane

To a round-bottomed flask was added 5-bromo-1, 1a,6 a-tetrahydrocyclopropane [ a]Indene (30g, 144mmol), biserpinacol borate (72.9g, 287mmol), pd (dppf) Cl ₂ (21g, 28.7 mmol) and potassium acetate (42g, 431mmol). After replacement of the nitrogen, dry, previously deoxygenated 1, 4-dioxane (400 mL) was added. The resulting suspension was stirred at 100 ℃ for 16 hours. After cooling to room temperature, the reaction mixture was extracted with water (500 mL) and methyl tert-butyl ether (500 mL). After separation, the aqueous phase was extracted with methyl tert-butyl ether (300 mL). The combined organic phases were washed with brine (300 mL), dried over sodium sulfate and dried by rotary drying in vacuo. The remaining dark brown oil was purified by column chromatography (silica gel, ethyl acetate: petroleum ether =1 = 40) to give a colorless oil which slowly became a pale yellow solid upon standing (26g, 101mmol, yield: 70%). ¹ H NMR(400MHz,CDCl ₃ )δ7.54(dd,J＝8.0,2.0Hz,1H),7.38(dd,J＝8.0,0.2Hz,1H),7.11(t,J＝8.0Hz,1H),3.29(dd,J＝17.6,6.7Hz,1H),3.20(d,J＝17.6Hz,1H),2.36-2.31(m,1H),1.88-1.81(m,1H),1.55(s,12H),1.05-1.00(m,1H),0.06-0.01(m,1H)

And step 3: synthesis of tert-butyl (2S) -2- (cyanomethyl) -4- (8-fluoro-2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropan [ a ] inden-5-yl) quinazolin-4-yl) piperazine-1-carboxylate

To a round bottom flask was added (S) -4- (7-bromo-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (300mg, 0.53mmol), 4, 5-tetramethyl-2- (1, 1a,6 a-tetrahydrocyclopropane [ a ] a]Inden-2-yl) -1,3, 2-dioxolane (244mg, 0.954mmol), pd (dppf) Cl ₂ (78mg, 0.106mmol) and potassium carbonate (146mg, 1.06mmol). After the nitrogen gas had been replaced, previously deoxygenated 1, 4-dioxane (5 mL) and water (1 mL) were added. The reaction mixture was stirred at 100 ℃ for 4 hours. Ethyl acetate (30 mL) and water (20 mL) were added. After shaking and separating the layers, the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate and dried by rotary drying in vacuo. Brown color remainedThe thick mass was purified by preparative TLC (silica gel, methanol: dichloromethane = 1. (140mg, 0.228mmol, yield: 43%) MS m/z of 613.4[ 2 ], [ M + H ]] ⁺ 。

And 4, step 4: synthesis of 2- ((2S) -4- (8-fluoro-2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropane [ a ] inden-5-yl) quinazolin-4-yl) piperazin-2-yl) acetonitrile

Trifluoroacetic acid (0.8 mL) was added dropwise to a solution of tert-butyl (2S) -2- (cyanomethyl) -4- (8-fluoro-2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropan [ a ] inden-5-yl) quinazolin-4-yl) piperazine-1-carboxylate (29mg, 0.047 mmol) in dichloromethane (4 mL) at room temperature. The resulting solution was stirred at room temperature for 4 hours. Dichloromethane (10 mL) was added and concentrated in vacuo. To the resulting residue was added dichloromethane (5 mL) and concentrated again and the process was repeated once. The resulting yellow solid was used directly in the next step.

And 5: synthesis of 2- ((2S) -4- (8-fluoro-2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropane [ a ] inden-5-yl) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile

A solution of 2-fluoroacrylic acid (8.5mg, 0.095mmol) and HATU (27mg, 0.071mmol) in dichloromethane (3 mL) was cooled in an ice-water bath. Triethylamine (0.026mL, 0.189mmol) was added dropwise. The ice water bath was removed and stirred for 20 minutes. Adding 2- ((2S) -4- (8-fluoro-2- ((S) -1-methylpyrrolidine-2-yl) methoxyl) -7- (1, 1a,6 a-tetrahydrocyclopropane [ a ] in one time]Inden-5-yl) quinazolin-4-yl) piperazin-2-yl) acetonitrile in dichloromethane (2 mL). Stirred at room temperature for 6 hours. Dichloromethane (17 mL), water (15 mL) and saturated sodium carbonate solution (5 mL) were added, shaken, separated and the aqueous phase extracted with dichloromethane (20 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and rotary evaporated under reduced pressure to give a yellow solid. Purification by preparative TLC (methanol: dichloromethane =1 = 8) gave 2- ((2S) -4- (8-fluoro-2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (1, 1a,6 a-tetrahydrocyclopropane [ a]Inden-5-yl) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (60mg, 0.103mmol, total yield over two steps: 63%). ¹ H NMR(400MHz,CDCl ₃ )δ7.64(d,J＝7.8Hz,1H),7.39(d,J＝7.8Hz,1H),7.26–7.21(m,2H),7.09(d,J＝7.8Hz,1H),5.46(d,J＝16Hz,1H),5.27(dd,J＝16.4,4.0Hz,1H),4.99–4.94(m,1H),4.64(dd,J＝8.0,4.0Hz,1H),4.44(d,J＝16Hz,1H),4.34(d,J＝16Hz,1H),3.73–3.40(m,6H),3.16–3.05(m,2H),2.86(s,3H),2.77-2.73(m,1H),2.45-2.41(m,1H),2.30-2.25(m,1H),2.30-2.25(m,1H),2.16-2.00(m,3H),1.88-1.83(m,1H),1.11-1.06(m,1H),0.14-0.12(m,1H).MS m/z:[M+H] ⁺ ＝585.4.

The preparation of the compounds of examples 873-902 was carried out using the method of preparation of example 872

Example 915: synthesis of 2- ((2S) -4- (6-chloro-7- (8-chloro-7-fluoronaphthalen-1-yl) -8-cyclopropoxy-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -ylmethoxy) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile

Step 1: synthesis of tert-butyl (S) -4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

To a mixture of 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline (2.5g, 7.58mmol) and N, N-dimethylformamide (30 mL) was added nitrogen, nitrogen-diisopropylethylamine (4.27ml, 25.8 mmol) in one portion in an ice-water bath. After stirring for 2 min, (S) -2- (piperazin-2-yl) acetonitrile hydrochloride (1.50g, 7.60mmol) was added. The reaction was stirred in an ice-water bath at room temperature for 1 hour.

Nitrogen, N-diisopropylethylamine (1.42mL, 8.6 mmol) and di-tert-butyl dicarbonate (1.96g, 9mmol) were added to the above reaction solution at room temperature. The reaction solution was stirred at room temperature for 4 hours. Ethyl acetate (200 mL) and water (200 mL) were added, and the mixture was extracted and separated. The aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with water (50 mL x 3), saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to a dark brown viscous mass. Column chromatography (silica gel, ethyl acetate: petroleum ether =1 to ethyl acetate: petroleum ether = 1) gave a yellow solid. (3.8g, 7.32mmol, yield: 96%). MS m/z 518.2[ m ] +H] ⁺ 。

Step 2 Synthesis of t-butyl (S) -4- (7-bromo-6-chloro-8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

A solution of ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (1.4g, 8.78mmol) in tetrahydrofuran (30 mL) was cooled in an ice-water bath. Sodium hydride (0.32g, 8.05mmol) was added and the reaction was carried out at room temperature for 0.5h. Adding tert-butylA solution of the group (S) -4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (3.8g, 7.32mmol) in tetrahydrofuran (15 mL) was allowed to react at room temperature for 1h. Ethyl acetate (100 mL) and dilute aqueous sodium carbonate solution (100 mL) were added and the aqueous phase extracted with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a beige solid. Purification by column chromatography (silica gel, methanol: dichloromethane =1 40) gave tert-butyl (S) -4- (7-bromo-6-chloro-8-fluoro-2- ((2r, 7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (2.1g, 3.21mmol, yield: 44%). MS M/z [ M + H] ⁺ ＝641.3。

Step 3 Synthesis of tert-butyl (S) -4- (7-bromo-6-chloro-8-cyclopropoxy-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

Tert-butyl (S) -4- (7-bromo-6-chloro-8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (1.9g, 2.96mmol) and cyclopropanol (0.34g, 6.0 mmol) were dissolved in tetrahydrofuran (20 mL). Sodium hydrogen (0.14g, 3.5mmol) was added under a nitrogen atmosphere, and the mixture was heated to 60 ℃ to react for 2 hours. Ethyl acetate (100 mL) and water (100 mL) were added and extracted. The organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The remaining dope was purified by column chromatography (silica gel, methanol: dichloromethane =1 = 40) to give tert-butyl (S) -4- (7-bromo-6-chloro-8-cyclopropoxy-2- ((2r, 7as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (0.8g, 1.18mmol, yield: 40%). MS M/z [ M + H] ⁺ ＝679.4。

Step 4 Synthesis of tert-butyl (2S) -4- (6-chloro-7- (8-chloro-7-fluoronaphthalen-1-yl) -8-cyclopropoxy-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

Tert-butyl (S) -4- (7-bromo-6-chloro-8-cyclopropoxy-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (200mg, 0.294mmol), 2- (8-chloro-7-fluoropropoxy)Naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (144mg, 0.47mmol), pd (dppf) Cl ₂ (22mg, 0.0294mmol) and potassium carbonate (81mg, 0.59mmol) were put in an eggplant type flask. The nitrogen was replaced three times. A pre-deoxygenated mixture of 1, 4-dioxane (10 mL) and water (2 mL) was added. The nitrogen was replaced three times. Then the reaction was stirred for 4h while heating to 100 ℃. After cooling to room temperature, ethyl acetate (50 mL) and dilute aqueous sodium carbonate (50 mL) were added and extracted. The organic phase was washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting brown viscous substance was subjected to column chromatography (silica gel, triethylamine: methanol: dichloromethane =0.04: 1). MS M/z [ M + H ]] ⁺ ＝779.5。

Step 5 Synthesis of 2- ((2S) -4- (6-chloro-7- (8-chloro-7-fluoronaphthalen-1-yl) -8-cyclopropoxy-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylmethoxy) quinazolin-4-yl) piperazin-2-yl) acetonitrile

The compound tert-butyl (2S) -4- (6-chloro-7- (8-chloro-7-fluoronaphthalen-1-yl) -8-cyclopropoxy-2- (((2r, 7as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (40mg, 0.0513mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added dropwise. The reaction was stirred at room temperature for 4h. Dichloromethane (30 mL) and saturated aqueous sodium carbonate (20 mL) were added and extracted. The aqueous phase was extracted with dichloromethane (10 ml x 2). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give 2- ((2S) -4- (6-chloro-7- (8-chloro-7-fluoronaphthalen-1-yl) -8-cyclopropoxy-2- ((2r, 7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylmethoxy) quinazolin-4-yl) piperazin-2-yl) acetonitrile. The product was used in the next reaction without further purification. MS M/z [ M + H ] + =679.4.

Step 6 Synthesis of 2- ((2S) -4- (6-chloro-7- (8-chloro-7-fluoronaphthalen-1-yl) -8-cyclopropoxy-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylmethoxy) quinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile

A solution of 2-fluoroacrylic acid (8.5mg, 0.095mmol) and HATU (27mg, 0.071mmol) in dichloromethane (3 mL) was cooled in an ice-water bath. Triethylamine (0.026mL, 0.189mmol) was added dropwise. The ice-water bath was removed and stirred for 20 minutes. A solution of 2- ((2S) -4- (6-chloro-7- (8-chloro-7-fluoronaphthalen-1-yl) -8-cyclopropoxy-2- ((2r, 7as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylmethoxy) quinazolin-4-yl) piperazin-2-yl) acetonitrile in dichloromethane (2 mL) was added in one portion. Stirred at room temperature for 6 hours. Dichloromethane (17 mL), water (15 mL) and saturated sodium carbonate solution (5 mL) were added, shaken, separated and the aqueous phase extracted with dichloromethane (20 mL). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate and rotary evaporated under reduced pressure to give a yellow solid. Purification by preparative TLC (methanol: dichloromethane =1 10) gave 2- ((2S) -4- (6-chloro-7- (8-chloro-7-fluoronaphthalen-1-yl) -8-cyclopropoxy-2- ((2r, 7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylmethoxy) quinazolin-4-yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile (19mg, 0.0253mmol, total yield in two steps: 48%). ¹ H NMR(400MHz,CDCl ₃ )δ7.96(d,J＝7.8Hz,1H),7.88-7.86(m,1H),7.65-7.63(m,1H),7.55(t,J＝7.8Hz,1H),7.33(s,1H),7.27–7.24(m,1H),5.45(d,J＝48Hz,1H),5.46(d,J＝16Hz,1H),5.27(dd,J＝16.4,4.0Hz,1H),4.89(brs,1H),4.45–4.24(m,4H),3.67-3.64(m,2H),3.48-3.44(m,2H),3.33-3.31(m,3H),3.24-3.19(m,2H),3.10-2.88(m,3H),2.29-2.16(m,2H),1.96-1.92(m,3H),0.30-0.10(m,4H).MS m/z:[M+H] ⁺ ＝751.4

The preparation of the compound of example 916-938 was carried out using the preparation of example 915

Example 939: synthesis of 2- ((2S) -4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylmethoxy) -6-hydroxyquinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile

Step 1: synthesis of tert-butyl (S) -4- (7-bromo-2-chloro-8-fluoro-6-methoxyquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

To a solution of 7-bromo-2, 4-dichloro-8-fluoro-6-methoxyquinazoline (4.0g, 12.3 mmol) in N, N-dimethylformamide (40 mL) was added nitrogen, N-diisopropylethylamine (6.6 mL, 40mmol) in one portion in an ice-water bath. After stirring for 1 minute, (S) -2- (piperazin-2-yl) acetonitrile hydrochloride (2.55g, 12.9mmol) was added. The reaction was stirred in an ice-water bath at room temperature for 1 hour.

To the above reaction mixture were added nitrogen, nitrogen-diisopropylethylamine (2.2 mL,13.3 mmol) and di-tert-butyl dicarbonate (3.27g, 15mmol) at room temperature. The reaction solution was stirred at room temperature for 4 hours. Ethyl acetate (200 mL) and water (200 mL) were added and the mixture was extracted and separated. The aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with water (60 mL x 3), saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a dark brown viscous substance. Column chromatography (silica gel, ethyl acetate: petroleum ether =1 to ethyl acetate: petroleum ether = 1) gave a yellow solid. (5.4g, 10.5mmol, yield: 85%). MS m/z:514.2[ 2 ], [ M ] +H ] +.

Step 2 Synthesis of t-butyl (S) -4- (7-bromo-8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylmethoxy) -6-methoxyquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

A solution of ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (1.9g, 12mmol) in tetrahydrofuran (40 mL) was cooled in an ice-water bath. Sodium hydride (0.44g, 11mmol) was added and reacted at room temperature for 0.5h. Adding tert-butyl (S) -4- (7-bromo-2) in one step-chloro-8-fluoro-6-methoxyquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (5.4 g, 10.5mmol) and the reaction was continued at room temperature for 1h. Ethyl acetate (100 mL) and dilute aqueous sodium carbonate solution (100 mL) were added and the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a beige solid. Purification by column chromatography (silica gel, methanol: dichloromethane =1 40) gave tert-butyl (S) -4- (7-bromo-6-chloro-8-fluoro-2- ((2r, 7as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (4.0g, 6.27mmol, yield: 60%). MS M/z [ M + H] ⁺ ＝637.4。

Step 3 Synthesis of tert-butyl (2S) -4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -6-methoxyquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

Tert-butyl (S) -4- (7-bromo-8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylmethoxy) -6-methoxyquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (300mg, 0.47mmol), 2- (8-chloro-7-fluoronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (230mg, 0.75mmol), pd (dppf) Cl ₂ (34mg, 0.047mmol) and potassium carbonate (127mg, 0.94mmol) were put in a round flask. The nitrogen was replaced three times. A pre-deoxygenated mixture of 1, 4-dioxane (10 mL) and water (2 mL) was added. The nitrogen was replaced three times. The reaction was then stirred for 4h while heating to 100 ℃. After cooling to room temperature, ethyl acetate (50 mL) and dilute aqueous sodium carbonate (50 mL) were added and extracted. The organic phase was washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting brown dope was subjected to column chromatography (silica gel, triethylamine: methanol: dichloromethane =0.04: 1) to give the compound tert-butyl (2S) -4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((2r, 7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -6-methoxyquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (71mg, 0.096mmol, yield: 20%). MS M/z [ M + H ]] ⁺ ＝737.5。

Step 4 Synthesis of 2- ((2S) -4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylmethoxy) -6-hydroxyquinazolin-4-yl) piperazin-2-yl) acetonitrile

The compound tert-butyl (2S) -4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((2r, 7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -6-methoxyquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (70mg, 0.096 mmol) was dissolved in dichloromethane (6 mL), cooled in an ice-water bath, and a solution of boron tribromide (0.057 mL, 0.77mmol) in dichloromethane (3 mL) was added dropwise. The reaction was stirred in an ice-water bath for 1h. Dichloromethane (30 mL) was added and methanol (10 mL) was slowly added. The mixture was rotary-evaporated under reduced pressure, and the residue was extracted by adding methylene chloride (20 mL) and a saturated aqueous sodium carbonate solution (20 mL). The aqueous phase was extracted with dichloromethane (10 ml x 2). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give a yellow viscous mass. Purification by preparative TLC (methanol: dichloromethane =1 = 7) yielded 2- ((2S) -4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((2r, 7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylmethoxy) -6-hydroxyquinazolin-4-yl) piperazin-2-yl) acetonitrile (15mg, 0.024mmol, yield: 25%). MS M/z [ M + H ] + =623.4.

Step 5 Synthesis of 2- ((2S) -4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylmethoxy) -6-hydroxyquinazolin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile

A solution of 2-fluoroacrylic acid (4.3mg, 0.048mmol) and HATU (11mg, 0.03mmol) in dichloromethane (3 mL) was cooled in an ice-water bath. Triethylamine (0.014mL, 0.1mmol) was added dropwise. The ice water bath was removed and stirred for 20 minutes. A solution of 2- ((2S) -4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((2r, 7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylmethoxy) -6-hydroxyquinazolin-4-yl) piperazin-2-yl) acetonitrile (15mg, 0.024mmol) in dichloromethane (2 mL) was added in one portion. Stirred at room temperature for 2 hours. Dichloromethane (17 mL), water (15 mL) and saturated sodium carbonate solution (5 mL) were added, shaken, separated and the aqueous phase extracted with dichloromethane (20 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate and rotary evaporated under reduced pressure to give a yellow solid. Purification by preparative TLC (methanol: dichloromethane =1 10) gave 2- ((2S) -4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((2r, 7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -ylmethoxy) -6-hydroxyquinazolin-4-yl) -1- (2-fluoroacryloyl) piperazine-2-yl) acetonitrile (5mg, 0.0072mmol, yield: 30%). ¹ H NMR(400MHz,CDCl ₃ )δ7.88(d,J＝7.8Hz,1H),7.88-7.86(m,1H),7.65-7.63(m,1H),7.55(t,J＝7.8Hz,1H),7.27–7.24(m,1H),7.01(s,1H),5.45(d,J＝48Hz,1H),5.46(d,J＝16Hz,1H),5.27(dd,J＝16.4,4.0Hz,1H),4.90(brs,1H),4.45–4.29(m,4H),3.68-3.64(m,2H),3.46-3.44(m,2H),3.33-3.31(m,2H),3.24-3.19(m,2H),3.10-2.88(m,3H),2.29-2.16(m,2H),1.96-1.92(m,3H).MS m/z:[M+H] ⁺ ＝695.4

The preparation of the compound of example 940-945 was carried out using the preparation of example 939

The embodiment is as follows: cell viability assay

1. Cell: h358 was purchased from Shanghai enzyme research Biotech, inc.

2. Reagent: RPMI1640 medium, tryple, MTT (5 mg/mL), DMSO, DPBS.

3. The instrument comprises: 37 ℃,5% CO2 incubator, UTAO microplate reader, biosafety cabinet, cell counting plate, ott optical microscope.

4. Experiment consumables: stock number of 96-well plate: 3599 And a 96-hole round bottom dispensing plate.

Activity testing of H358 cells experimental procedure:

1. plate paving: cells in the logarithmic growth phase were digested with Tryple, terminated with fresh medium, counted, adjusted to 55555/mL with fresh medium, 90 μ L per well, and the other edges filled with sterile DPBS.

2. Incubate at 37 ℃ for 24 hours in a 5% CO2 incubator to allow cells to fill the bottom of the wells by about 50%.

3. The experimental group dosage is as follows: the drug is dissolved in DMSO to prepare 20mmol/L stock solution, then diluted with DMSO to prepare 2mmol/L, diluted 3 times and 8 concentration gradients are sequentially obtained to obtain 200 Xcompound gradient solution, 10. Mu.L gradient compound solution is added into 190. Mu.L RPMI1640 culture medium to obtain 10 Xgradient compound solution, 10. Mu.L 10 Xcompound solution is added into 90. Mu.L 96-well cell culture plate, each gradient is repeated three times, the concentration gradient of the compound in 96-well cell culture plate is 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 DMSO concentration is 0.5%.

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

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

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

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

7. And (3) zeroing a hole, adding 150 mu L of dimethyl sulfoxide (DMSO) into each hole of the experimental group and the control group, oscillating at a medium speed of a microplate reader for 10s, fully dissolving a crystal, and measuring the light absorption value at the wavelength of 492 nm.

IC of partial compound ₅₀ The values are shown in table 1:

KRAS G12C-GDP exchange test:

1. 4-fold gradiently diluted compounds (10 concentration points in total) were premixed with KRAS G12C-GDP (ICE, kras 20191018) in reaction wells for 1 hour, respectively, in reaction buffer (25mM Hepes PH7.4, 125mM NaCl,5mM MgCl2,0.01% Tween20,0.1% BSA);

2. a mixture of 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) was added to perform a catalytic reaction for 2 hours.

3. The fluorescence signals of the emitted light at 615nm and 665nm under 320nm excitation were read with a Biotek microplate reader (Synergy 4).

4. The IC50 (half maximal inhibitory concentration) of the compound was obtained using the following non-linear fit equation: y = Bottom + (Top-Bottom)/(1 +10^ ((Logicc 50-X) × Hill Slope)), data analysis was performed with Graphpad 6.0 software.

Example Compound numbering	IC ₅₀ ((nM)	Number of example Compounds	IC ₅₀ ((nM)
				1	20.31	840	4.52
2	10.59	854	0.59
				3	13.85	873	0.79
10	8.0	877	0.71
				17	1.65	879	0.59
73	1.34	881	0.71
				254	8.90	883	0.49
286	9.91	887	1.02
				358	2.40	895	1.29
394	1.44	903	0.89
				395	1.32	904	0.93
465	2.23

Pharmacokinetic experiments in SD rats:

1.SPF male rats are randomly grouped, and the compounds to be tested are respectively administrated by intravenous injection and oral gavage, wherein each administration mode of each compound to be tested comprises 3 animals. The administration of the solvent as 5% DMSO +10% by volume of Solutol +85% normal saline or 85% PBS, the test substances are dissolved in the solvent to obtain clear solution. Dosing concentration and volume: 1) 0.6mg/mL of the compound to be detected is injected into a single vein, the administration volume is 5mL/kg, and the administration dose is 3mg/kg; 2) The single oral gavage is carried out on 1mg/mL of the compound to be tested, the administration volume is 10mL/kg, and the administration dosage is 10mg/kg. Fasting was overnight (10-14 hours) before dosing and fed 4 hours after dosing.

2. Blood is collected via jugular vein or other suitable method at 200 μ L/time point, anticoagulated with K2-EDTA, collected, placed on ice and centrifuged to separate plasma within 1 hour (centrifugation conditions: 6800g,6 min, 2-8 ℃). The blood sampling points of the animals in the intravenous injection group are respectively as follows: before administration, 5, 15, 30min after administration, 1,2,4,8, 24h; the blood sampling points of the animals in the oral administration group are respectively 15 hours, 30min,1,2,4,6,8 and 24 hours before and after administration.

3. And (3) detecting the blood concentration, and calculating a pharmacokinetic parameter AUC (0-t) by using Phoenix WinNonlin according to the blood concentration data of different time points. To take medicine substitutionIn parameter calculation, the BLQ (including "No peak") before Cmax is calculated as 0; BLQ (including "No peak") appearing after Cmax does not participate in the calculation uniformly. Oral bioavailability calculation formula: f% = AUC0-t _{Is administered orally} /AUC0-t _Vein *(10/3)*100％

Example Compound numbering	Oral bioavailability F%
		358	2.35％
367	11.57％
		879	16.9％
887	25.85％
		903	28.6％
904	30.28％
		914	28.49％
WO2020/146613A1 example 229	22.69％

Claims

1. A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, which compound is

Wherein: r ¹ W is

R ¹ Is composed of

Wherein

R ¹¹ Is hydrogen and R ¹² Is halogen;

L-R ² is composed of

R ³ Is composed of

2. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R ¹ Is composed of

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R ³ Is composed of

4. A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the compound is:

。

5. a pharmaceutical composition comprising a compound of any one of claims 1-4, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

6. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and a pharmaceutical composition according to claim 5, in the manufacture of a medicament for the treatment of a cancer mediated by KRAS G12C, HRAS G12C or NRAS G12 mutations.