Hydrogenated pyridopyrimidine derivatives, preparation methods thereof and their medical applications

Abstract

The present invention provides hydrogenated pyridopyrimidine derivatives, preparation methods thereof and their use in medicine. Specifically, the present invention provides hydrogenated pyridopyrimidine derivatives represented by general formula (I), preparation methods thereof, pharmaceutical compositions containing the derivatives and their use as therapeutic agents, especially as KRAS inhibitors, wherein the substituents of general formula (I) are the same as those defined in the specification.

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to a hydrogenated pyridopyrimidine derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and the use of the derivative as a therapeutic agent, in particular as a KRAS inhibitor. Background Art

[0002] The RAS (Rat Sarcoma Viral Oncogene Homolog) family belongs to the small GTPase superfamily and is widely expressed in various eukaryotic organisms. There are three RAS genes (HRAS, KARS and NARS) in the human body, which can be expressed as four highly related RAS small GTPases (HRAS, KRAS4A, KARS4B and NRAS). It acts as a binary switch regulated by GDP-GTP. Usually they have two forms of expression: GDP (guanosine diphosphate) binding form in the inactive state and GTP (guanosine triphosphate) binding form in the activated state. RAS proteins regulate multiple downstream pathways including RAF-MEK-ERK, PI3K / Akt / mTOR by switching between two active states, thereby affecting cell growth, proliferation and differentiation (Nat Rev Cancer, 2007, 7, 295-308). The mutation rate of RAS gene is high in pancreatic cancer, colorectal cancer, non-small cell lung cancer and other tumors. The activated mutant RAS protein promotes abnormal signal transduction, leading to the occurrence and development of cancer and resistance to targeted drugs. Among them, KRAS mutation is the gene with the highest mutation rate among human oncogenes, accounting for 20-30% of all tumors.

[0003] In recent years, molecular biology has made significant progress in the study of KRAS protein mutations and signaling pathways, but the development of related targeted drugs is still challenging. In the development of chemical drugs, since the affinity between KRAS and GTP is very high, reaching 60pM, and the intracellular GTP concentration is at the mM level, this type of directly competing molecule requires extremely high affinity for the compound, and there has been no successful case so far. In the development of biological drugs, antibody drugs penetrate the cell membrane to target KRAS protein, and the drug delivery efficiency is relatively low. Therefore, many researchers have tried to find another way, hoping to inhibit the activity of kinases such as RAF, MEK and ERK in the downstream signaling pathway of KRAS to achieve the purpose of inhibiting the KRAS pathway. This type of compound has a certain therapeutic effect, but because the downstream inhibitors cannot completely block the KRAS signal, and the target-related toxic side effects are very large, these compounds have poor efficacy on KRAS mutant tumors. Therefore, the development of KRAS inhibitors with new mechanisms of action has great clinical application value.

[0004] KRAS mutations are mainly point mutations, including mutations at amino acids 12, 13, and 61. The most common mutation is the glycine at position 12 to cysteine ​​(G12C), which is more common in lung cancer, especially non-small cell lung cancer (14%); it is also expressed in some colorectal cancer (4%) and pancreatic cancer (2%) patients. In the American cancer population, the incidence of this gene mutation is even greater than the sum of ALK, RET, and TRK gene mutations.

[0005] Faced with the difficulty of druggability of KRAS protein, Professor Kevan Shokat of the University of California, San Francisco, took the lead in verifying that certain special compounds can bind to KRAS G12C mutant protein through covalent bonds. Through further research, it was found that these covalent compounds can bind to the cysteine ​​at position 12 of KRAS mutant protein and occupy a hydrophobic allosteric regulatory pocket in the switch-II region. The bound KRAS G12C mutant will be irreversibly locked in an inactive state, thereby blocking the signaling pathways and cancer cell viability that depend on the protein (Nature 2013, 503, 548-551). KRASG12C small molecule inhibitor ARS-1620 can effectively inhibit tumor growth in a variety of KRAS G12C mutant tumor models, and even completely regress the tumor. Since KRAS G12C is a mutant protein in tumor cells, and wild-type KRAS does not have this mutation site, it provides a perfect tumor-selective target (Cell, 2018, 572, 578-589). Companies represented by Araxas, Amgen and Mirati have published several patents for KRAS G12C inhibitors (WO2014152588, WO2016164675, WO2017087528, WO2017201161, WO2018119183, etc.). Currently, no KRAS G12C inhibitor drugs have been approved for marketing. The fastest-progressing small molecule KRAS G12C inhibitors from Amgen and Mirati entered Phase I clinical trials in September and December 2018, respectively. Therefore, there are significant unmet medical needs among the relevant patient populations. Summary of the invention

[0006] The object of the present disclosure is to provide a compound represented by general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof,

[0007]

[0008] in:

[0009] Ring A is a cycloalkyl group or a heterocyclic group;

[0010] Ring B is a nitrogen-containing heterocyclic group;

[0011] Y is selected from N or C;

[0012] L1 is selected from -S-(CH2) q -、-O-(CH2) q -、-NH-(CH2) q - or alkylene;

[0013] L2 is a bond or an alkylene group;

[0014] R 1 is selected from cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, -OR 9 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0015] R 2 is selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group, -(CH2) q NR 7 R 8 , aryl and heteroaryl, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, -NR 7 R 8 , aryl and heteroaryl;

[0016] R 3 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl, an alkoxy, a haloalkyl, a hydroxyl, a hydroxyalkyl, a cyano, an amino, and a nitro group, wherein the alkyl, the alkoxy, and the haloalkyl group are optionally further substituted by one or more substituents selected from a halogen, an alkyl, an alkoxy, a haloalkyl, a cyano, an amino, a nitro, a hydroxyl, and a hydroxyalkyl group;

[0017] R 4 Selected from -C(O)R 9 or -S(O)2R 9 ;

[0018] R 5 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl and hydroxyalkyl;

[0019] R 6are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl and hydroxyalkyl;

[0020] R 7 , R 8 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl or hydroxyalkyl; or, R 7 and R 8 Together with the adjacent N atom, it forms a heterocyclic group, wherein the heterocyclic group is optionally further substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl and hydroxyalkyl;

[0021] R 9 is selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, alkynyl, alkenyl, hydroxyl or hydroxyalkyl, wherein the alkyl, alkoxy, haloalkyl, alkynyl and alkenyl are optionally further selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, -(CH2) q NR 10 R 11 , cycloalkyl, heterocyclic, hydroxyl and hydroxyalkyl;

[0022] R 10 , R 11 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl or hydroxyalkyl; or, R 10 and R 11 Together with the adjacent N atom, it forms a heterocyclic group, wherein the heterocyclic group is optionally further substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl and hydroxyalkyl;

[0023] n is 0, 1, 2 or 3;

[0024] m is 0, 1, 2 or 3;

[0025] q is 0, 1, 2, 3, 4, 5 or 6; and

[0026] p is 0, 1, 2, 3 or 4.

[0027] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt, wherein: Ring A is a cycloalkyl group;

[0028] R 2 is selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, -(CH2)q NR 7 R 8 , aryl and heteroaryl, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, -NR 7 R 8 , aryl and heteroaryl;

[0029] R 7 , R 8 , q are as defined in the general formula (I).

[0030] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: ring B is a nitrogen-containing heterocyclic group; preferably, ring B is a 3-8 membered nitrogen-containing heterocyclic group; more preferably, ring B is a piperazinyl group.

[0031] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt is a compound represented by the general formula (II) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt:

[0032]

[0033] in:

[0034] Ring A, L1, L2, R 1 ~R 6 , m, n and p are as defined in the general formula (I).

[0035] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt, wherein: Ring A is a cycloalkyl group; preferably, Ring A is C 3-6 More preferably, ring A is cyclopropyl or cyclobutyl; further preferably, ring A is cyclopropyl.

[0036] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein L1 is selected from -S-, -O-, -O-CH2-, -NH- or -NH-CH2-; preferably, L1 is selected from -S-, -O-, -NH- or -O-CH2-; further preferably, L1 is selected from -S-, -O- or -NH-.

[0037] In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein L2 is a bond or a methylene group; preferably, L2 is a bond.

[0038] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein R 1 Selected from:

[0039]

[0040] in:

[0041] Ring D is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably, ring D is C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; More preferably, ring D is aryl, thienyl or pyrazolyl; Further preferably, ring D is phenyl;

[0042] R a are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclic groups; preferably, R a are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, hydroxyl, C 1-6 Hydroxyalkyl, cyano, amino, nitro, C 3-6 Cycloalkyl and 3-8 membered heterocyclic group;

[0043] R b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclic groups; preferably, R bare the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, hydroxyl, C 1-6 Hydroxyalkyl, cyano, amino, nitro, C 3-6 Cycloalkyl and 3-8 membered heterocyclic group;

[0044] s is 0, 1, 2, 3, or 4; and

[0045] t is 0, 1, 2, 3 or 4.

[0046] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein R 1 Selected from:

[0047]

[0048] in:

[0049] R a are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclic groups; preferably, R a are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, hydroxyl, C 1-6 Hydroxyalkyl, cyano, amino, nitro, C 3-6 Cycloalkyl and 3-8 membered heterocyclic group;

[0050] R b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclic groups; preferably, R b are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, hydroxyl, C 1-6 Hydroxyalkyl, cyano, amino, nitro, C 3-6 Cycloalkyl and 3-8 membered heterocyclic group;

[0051] s is 0, 1, 2, 3, or 4; and

[0052] t is 0, 1, 2, 3 or 4.

[0053] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein R 2 is selected from cycloalkyl, heterocyclyl, heteroaryl or -(CH2) q NR 7 R 8 , the cycloalkyl or heterocyclic group is optionally further substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl and hydroxyalkyl;

[0054] Preferably, R 2 Selected from C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl or -NR 7 R 8 , the C 3-6 Cycloalkyl or 3-8 membered heterocyclic group is optionally further selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, cyano, amino, nitro, hydroxyl and C 1-6 substituted by one or more substituents in the hydroxyalkyl group;

[0055] or preferably, R 2 is a heterocyclic group, which is optionally further substituted by one or more substituents selected from halogen and alkyl; more preferably, R 2 is a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group is optionally further selected from halogen, C 1-6 The alkyl group is substituted by one or more substituents;

[0056] or preferably, R 2 Selected from -NR 7 R 8 , R 7 and R 8 Together with the adjacent N atom, it forms a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, cyano, amino, nitro, hydroxyl and C 1-6 substituted by one or more substituents in the hydroxyalkyl group;

[0057] or preferably, R 2 for R c is halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl or hydroxyalkyl; R dis a hydrogen atom or an alkyl group; w is 0, 1, 2, 3, 4, or 5; and v is 1 or 2.

[0058] R 7 and R 8 As defined in general formula (I).

[0059] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein R 3 is an alkyl group, which is optionally further substituted by one or more cyano groups; preferably -CH2-CN.

[0060] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein R 4 -C(O)R 9 or -S(O)2R 9 ; R 9 is selected from alkyl, alkynyl or alkenyl, wherein the alkyl, alkynyl or alkenyl is optionally further selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, -(CH2) q NR 7 R 8 , heterocyclic group, cycloalkyl group, hydroxyl group and hydroxyalkyl group; preferably, R 9 Selected from C 1-6 Alkyl, C 2-6 Alkynyl or C 2-6 Alkenyl, the C 1-6 Alkyl, C 2-6 Alkynyl, C 2-6 The alkenyl group is optionally further selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, cyano, amino, nitro, -(CH2) q NR 7 R 8 , hydroxyl and C 1-6 is substituted by one or more substituents in the hydroxyalkyl group; further preferably, R 9 For vinyl;

[0061] R 7 , R 8 and q are as defined in formula (I);

[0062] Preferably, R 7 , R 8are the same or different and are each independently selected from hydrogen atom and C 1-6 Alkyl, q is 0, 1, 2, 3, 4, 5 or 6.

[0063] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein R 5 A hydrogen atom.

[0064] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein R 6 A hydrogen atom.

[0065] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt is a compound represented by the general formula (III) or the general formula (IV) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt:

[0066]

[0067] in:

[0068] R e A hydrogen atom or -(CH2) q NR 10 R 11 ;

[0069] R f is a hydrogen atom or a halogen; L1, R 1 , R 2 , R 10 , R 11 and q are as defined in the general formula (I).

[0070] In some preferred embodiments of the present disclosure, the compound represented by the general formula (III) or the general formula (IV) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein:

[0071] R 1 for

[0072] L1 is -O-CH2-,

[0073] R 2 for

[0074] R a are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclic groups; preferably, R a are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, hydroxyl, C 1-6 Hydroxyalkyl, cyano, amino, nitro, C 3-6 Cycloalkyl and 3-8 membered heterocyclic group;

[0075] R b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclic groups; preferably, R b are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, hydroxyl, C 1-6 Hydroxyalkyl, cyano, amino, nitro, C 3-6 Cycloalkyl and 3-8 membered heterocyclic group;

[0076] R c is halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy or hydroxyalkyl;

[0077] s is 0, 1, 2, 3, or 4;

[0078] t is 0, 1, 2, 3, or 4;

[0079] w is 0, 1, 2, 3, 4, 5;

[0080] v is 1 or 2;

[0081] Preferably, R b The same or different, and each independently is C 1-6 Alkyl or halogen, s is 2, t is 0; R 2 for

[0082] Typical compounds of the present disclosure include, but are not limited to:

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097] or its stereoisomers, tautomers, meso racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0098] Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof:

[0099]

[0100] in:

[0101] Ring A is a cycloalkyl group or a heterocyclic group;

[0102] Ring B is a nitrogen-containing heterocyclic group;

[0103] Y is selected from N or C;

[0104] L1 is selected from -S-(CH2) q -、-O-(CH2) q -、-NH-(CH2) q - or alkylene;

[0105] L2 is a bond or an alkylene group;

[0106] R 1is selected from cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, -OR 9 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0107] R 2 is selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group, -(CH2) q NR 7 R 8 , aryl and heteroaryl, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, -NR 7 R 8 , aryl and heteroaryl;

[0108] R 3 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl, an alkoxy, a haloalkyl, a hydroxyl, a hydroxyalkyl, a cyano, an amino, and a nitro group, wherein the alkyl, the alkoxy, and the haloalkyl group are optionally further substituted by one or more substituents selected from a halogen, an alkyl, an alkoxy, a haloalkyl, a cyano, an amino, a nitro, a hydroxyl, and a hydroxyalkyl group;

[0109] R 5 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl and hydroxyalkyl;

[0110] R 6 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl and hydroxyalkyl;

[0111] R 7 , R 8 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl or hydroxyalkyl; or, R 7 and R 8 Together with the adjacent N atom, it forms a heterocyclic group, wherein the heterocyclic group is optionally further substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl and hydroxyalkyl;

[0112] R 9is selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, alkynyl, alkenyl, hydroxyl or hydroxyalkyl, wherein the alkyl, alkoxy, haloalkyl, alkynyl and alkenyl are optionally further selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, -(CH2) q NR 10 R 11 , cycloalkyl, heterocyclic, hydroxyl and hydroxyalkyl;

[0113] R 10 , R 11 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl or hydroxyalkyl; or, R 10 and R 11 Together with the adjacent N atom, it forms a heterocyclic group, wherein the heterocyclic group is optionally further substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl and hydroxyalkyl;

[0114] n is 0, 1, 2 or 3;

[0115] m is 0, 1, 2 or 3;

[0116] q is 0, 1, 2, 3, 4, 5 or 6; and

[0117] p is 0, 1, 2, 3 or 4.

[0118] Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof:

[0119] Wherein: Ring A is a cycloalkyl group;

[0120] R 2 is selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, -(CH2) q NR 7 R 8 , aryl and heteroaryl, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, -NR 7 R 8 , aryl and heteroaryl;

[0121] R 7 , R 8 , q are as defined in the general formula (IA).

[0122] Typical compounds of the general formula (IA) disclosed herein include but are not limited to:

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130] or its stereoisomers, tautomers, meso racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0131] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0132]

[0133] The compound of general formula (IA) is reacted with compound XR under alkaline conditions (with optional addition of a condensing agent) 4 Acylation or sulfonylation reaction occurs to obtain a compound of the general formula (I) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein:

[0134] X is halogen or hydroxyl; XR 4 Acryloyl chloride is preferred;

[0135] Ring A, Ring B, Y, L1, L2, R 1 ~R 6 , m, n and p are as defined in the general formula (I).

[0136] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0137]

[0138] The compound of general formula (IIA) is reacted with compound XR under alkaline conditions (with optional addition of a condensing agent) 4 Acylation or sulfonylation reaction occurs to obtain a compound of general formula (II) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein:

[0139] X is halogen or hydroxyl; XR 4 Acryloyl chloride is preferred;

[0140] Ring A, L1, L2, R 1 ~R 6 , m, n and p are as defined in the general formula (II).

[0141] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0142]

[0143] The compound of general formula (IIIA) is reacted with compound XR under alkaline conditions (condensation agent can be optionally added) 4 Acylation or sulfonylation reaction occurs to obtain a compound of general formula (III) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein:

[0144] X is halogen or hydroxyl; XR 4 Acryloyl chloride is preferred;

[0145] L1, R 1 and R 2 As defined in general formula (III).

[0146] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0147]

[0148] The compound of general formula (IVA) undergoes acylation or sulfonylation reaction with the compound of formula (IVB) under alkaline conditions (optionally with the addition of a condensing agent) to obtain a compound of general formula (IV), wherein:

[0149] X is halogen or hydroxyl;

[0150] L1, R 1 , R 2 , R e and R f As defined in formula (IV).

[0151] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a therapeutically effective amount of a compound represented by the general formula (I) or general formula (II) or general formula (III) of the present disclosure, or its stereoisomers, tautomers, mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0152] The present disclosure further relates to the use of a compound represented by general formula (I) or general formula (II) or general formula (III) or its stereoisomer, tautomer, mesomorph, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same in the preparation of a drug for inhibiting KRAS, preferably in the preparation of a drug for inhibiting KRAS G12C.

[0153] The present disclosure further relates to the use of a compound represented by general formula (I) or general formula (II) or general formula (III) or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, in the preparation of a medicament for treating or preventing cancer, inflammation, or other proliferative diseases, preferably in the preparation of a medicament for treating or preventing cancer; the cancer is selected from gastric cancer, esophageal cancer, melanoma, liver cancer, kidney cancer, lung cancer (such as non-small cell lung cancer or small cell lung cancer), nasopharyngeal cancer, colorectal cancer, pancreatic cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, leukemia, head and neck squamous cell carcinoma, cervical cancer, thyroid cancer, lymphoma, sarcoma, neuroblastoma, brain tumor, myeloma (such as multiple myeloma), astrocytoma and glioma. Preferably, the cancer is selected from melanoma, liver cancer, kidney cancer, lung cancer (such as non-small cell lung cancer or small cell lung cancer), nasopharyngeal cancer, colorectal cancer, pancreatic cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, leukemia, head and neck squamous cell carcinoma, cervical cancer, thyroid cancer, lymphoma, sarcoma, neuroblastoma, brain tumor, myeloma (such as multiple myeloma), astrocytoma and glioma.

[0154] The present disclosure also relates to a method for inhibiting KRAS, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I) or general formula (II) or general formula (III) or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising the same.

[0155] The present disclosure also relates to a method for treating or preventing a KRAS-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I) or general formula (II) or general formula (III) or its stereoisomers, tautomers, mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0156] The present disclosure also relates to a method for treating or preventing cancer, inflammation, or other proliferative diseases, preferably a method for treating cancer, which comprises administering to a patient in need thereof an effective amount of a compound represented by general formula (I) or general formula (II) or general formula (III) or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising the same; wherein the cancer is selected from gastric cancer, esophageal cancer, melanoma, liver cancer, kidney cancer, lung cancer (such as non-small cell lung cancer or small cell lung cancer), nasopharyngeal cancer, colorectal cancer, pancreatic cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, leukemia, head and neck squamous cell carcinoma, cervical cancer, thyroid cancer, lymphoma, sarcoma, neuroblastoma, brain tumor, myeloma (such as multiple myeloma), astrocytoma and glioma. Preferably, the cancer is selected from melanoma, liver cancer, kidney cancer, lung cancer (such as non-small cell lung cancer or small cell lung cancer), nasopharyngeal cancer, colorectal cancer, pancreatic cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, leukemia, head and neck squamous cell carcinoma, cervical cancer, thyroid cancer, lymphoma, sarcoma, neuroblastoma, brain tumor, myeloma (such as multiple myeloma), astrocytoma and glioma.

[0157] The present disclosure further relates to a compound represented by general formula (I) or general formula (II) or general formula (III) or its stereoisomer, tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which is used as a drug.

[0158] The present disclosure also relates to a compound represented by general formula (I) or general formula (II) or general formula (III) or its stereoisomer, tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, and its use as a KRAS inhibitor, preferably a KRASG12C inhibitor.

[0159] The present disclosure also relates to a compound represented by general formula (I) or general formula (II) or general formula (III) or its stereoisomers, tautomers, mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating or preventing KRAS-mediated diseases, preferably KRAS G12C-mediated diseases.

[0160] The present disclosure also relates to a compound represented by general formula (I) or general formula (II) or general formula (III) or its stereoisomers, tautomers, mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in treating or preventing cancer, inflammation, or other proliferative diseases, preferably cancer; wherein the cancer is selected from gastric cancer, esophageal cancer, melanoma, liver cancer, kidney cancer, lung cancer (such as non-small cell lung cancer or small cell lung cancer), nasopharyngeal cancer, colorectal cancer, pancreatic cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, leukemia, head and neck squamous cell carcinoma, cervical cancer, thyroid cancer, lymphoma, sarcoma, neuroblastoma, brain tumor, myeloma (such as multiple myeloma), astrocytoma and glioma. Preferably, the cancer is selected from melanoma, liver cancer, kidney cancer, lung cancer (such as non-small cell lung cancer or small cell lung cancer), nasopharyngeal cancer, colorectal cancer, pancreatic cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, leukemia, head and neck squamous cell carcinoma, cervical cancer, thyroid cancer, lymphoma, sarcoma, neuroblastoma, brain tumor, myeloma (such as multiple myeloma), astrocytoma and glioma.

[0161] The active compound may be formulated for administration by any appropriate route, preferably in a unit dosage form, or in a form in which a patient can self-administer a single dose. The unit dosage form of the disclosed compound or composition may be tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations.

[0162] The dosage of the compound or composition used in the disclosed treatment methods will generally vary with the severity of the disease, the patient's weight and the relative efficacy of the compound. However, as a general guide, a suitable unit dosage may be 0.1 to 1000 mg.

[0163] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0164] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the following: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing.

[0165] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents and one or more sweetening agents.

[0166] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation.

[0167] Dispersible powders and granules suitable for preparing aqueous suspensions can be provided with the active ingredient and a dispersant or wetting agent, a suspending agent or one or more preservatives for mixing by adding water. Suitable dispersants or wetting agents and suspending agents illustrate the examples above. Other excipients such as sweeteners, flavoring agents and coloring agents may also be added. These compositions may be preserved by adding an antioxidant such as ascorbic acid.

[0168] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions.

[0169] The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Acceptable solvents or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerol and processed to form a microemulsion. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0170] The pharmaceutical composition can be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques using suitable dispersants or wetting agents and suspending agents as described above. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable nontoxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media.

[0171] The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[0172] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound of formula (I) or the type of pharmaceutically acceptable salt can be verified according to traditional treatment plans.

[0173] Detailed description of the invention

[0174] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0175] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably independently selected from one or more substituents selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0176] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above and cycloalkyl is as defined below. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents in H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl.

[0177] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms, and is a straight or branched group containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, and more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like. The alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently selected from one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and oxo.

[0178] The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents of hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0179] The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above. Alkynyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents of hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0180] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused and bridged cycloalkyls.

[0181] The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between the rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0182]

[0183] The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of condensed cycloalkyls include:

[0184]

[0185] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0186]

[0187] The cycloalkyl ring includes a cycloalkyl group as described above (including a monocyclic ring, a spirocyclic ring, a condensed ring and a bridged ring) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc.; preferably phenylcyclopentyl and tetrahydronaphthyl.

[0188] The cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0189] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen or S(O)z (where z is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms, of which 1-3 are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spirocyclic, fused ring and bridged heterocyclyls.

[0190] The term "spiro heterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S(O) z (wherein z is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0191]

[0192] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) z (wherein z is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0193]

[0194]

[0195] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system, and one or more of the ring atoms is selected from nitrogen, oxygen or S(O) z (wherein z is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0196]

[0197] The heterocyclic ring includes a heterocyclic group as described above (including a monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

[0198] wait.

[0199] The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0200] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:

[0201]

[0202]

[0203] The aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0204] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably 5 to 10 yuan, more preferably 5 or 6 yuan, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and its non-limiting examples include:

[0205]

[0206] The heteroaryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0207] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0208] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0209] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0210] The term "hydroxy" refers to an -OH group.

[0211] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0212] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0213] The term "amino" refers to -NH2.

[0214] The term "cyano" refers to -CN.

[0215] The term "nitro" refers to -NO2.

[0216] The term "carbonyl" refers to C=O.

[0217] The term "carboxy" refers to -C(O)OH.

[0218] The term "carboxylate" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0219] The present disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds of formula (I) with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing deuterated forms of compounds of formula (I), or they can be synthesized using deuterated reagents using conventional techniques, and deuterated reagents include but are not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.

[0220] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally further substituted with an alkyl group" means that the alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0221] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0222] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0223] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which are safe and effective when used in mammals and have the desired biological activity.

[0224] The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure of the present disclosure except that hydrogen is replaced by "deuterium" or "tritium", or by 18 F-fluorine labeling ( 18 F isotope) instead of fluorine, or with 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 Compounds in which a carbon atom is replaced by a C-isotope) are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics or receptor studies. Deuterated compounds can generally retain activity comparable to that of undeuterated compounds, and when deuterated at certain specific sites, better metabolic stability can be achieved, thereby obtaining certain therapeutic advantages (such as increased half-life in vivo or reduced dosage requirements).

[0225] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0226] Synthesis method of the disclosed compound

[0227] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0228] Solution 1

[0229] The method for preparing the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, comprises the following steps:

[0230]

[0231] The compound of general formula (IA) is reacted with compound XR under alkaline conditions (with optional addition of a condensing agent) 4 Acylation or sulfonylation reaction occurs to obtain a compound of the general formula (I) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0232] X is halogen or hydroxyl; XR 4 Acryloyl chloride is preferred;

[0233] Ring A, Ring B, Y, L1, L2, R 1 ~R 6 , m, n and p are as defined in the general formula (I).

[0234] Solution 2

[0235] The present invention discloses a method for preparing a compound represented by general formula (II) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0236]

[0237] The compound of general formula (IIA) is reacted with compound XR under alkaline conditions (with optional addition of a condensing agent) 4 Acylation or sulfonylation reaction occurs to obtain a compound of general formula (II) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0238] X is halogen or hydroxyl; XR 4 Acryloyl chloride is preferred;

[0239] Ring A, L1, L2, R 1 ~R 6 , m, n and p are as defined in the general formula (II).

[0240] Option 3

[0241] The present invention discloses a method for preparing a compound represented by general formula (III) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0242]

[0243] The compound of general formula (IIIA) is reacted with compound XR under alkaline conditions (condensation agent can be optionally added) 4Acylation or sulfonylation reaction occurs to obtain a compound of formula (III) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0244] X is halogen or hydroxyl; XR 4 Acryloyl chloride is preferred;

[0245] L1, R 1 , R 2 As defined in general formula (III).

[0246] Option 4

[0247] The present invention discloses a method for preparing a compound represented by general formula (IV) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0248]

[0249] The compound of general formula (IVA) is subjected to acylation or sulfonylation reaction with the compound of formula (IVB) under alkaline conditions (optionally with the addition of a condensing agent) to obtain a compound of general formula (IV) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0250] X is halogen or hydroxyl;

[0251] L1, R 1 , R 2 , R e and R f As defined in general formula (IV). The reagents providing alkaline conditions include organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N, N-diisopropylethylamine, N, N-diethylethylenediamine, n-butyllithium, diisopropyllithium amide, bistrimethylsilylamide lithium, potassium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and sodium n-butoxide, the inorganic bases include but are not limited to sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide; preferably triethylamine.

[0252] The condensing agent includes but is not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N′-dicyclohexylcarbodiimide, N,N′-diisopropylcarbodiimide, O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 2- (7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,NN,N-tetramethyluronium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.

[0253] The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: acetic acid, methanol, ethanol, n-butanol, tert-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof, preferably dichloromethane. DETAILED DESCRIPTION

[0254] The present disclosure is further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present disclosure.

[0255] Example

[0256] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

[0257] MS was measured using Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC / MS (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), Waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), or THERMOUltimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0258] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0259] Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.

[0260] High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0261] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0262] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0263] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0264] Silica gel column chromatography used Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0265] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0266] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0267] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0268] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0269] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.

[0270] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0271] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0272] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0273] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0274] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0275] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0276] Example 1

[0277] 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 1

[0278]

[0279]

[0280] first step

[0281] (S)-2-(1-Hydroxycyclopropyl)pyrrolidine-1-carboxylic acid tert-butyl ester 1b

[0282] Under argon atmosphere, (S)-1-tert-butyl 2-methylpyrrolidine-1,2-dicarboxylate 1a (26 g, 113.4 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) and tetraisopropyl titanate (38.85 g, 136.68 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) were added to 400 mL of tetrahydrofuran, and then ethyl magnesium bromide (1M, 340 mL) was slowly added dropwise. After the addition, the mixture was reacted at room temperature for 3 hours. 50 mL of saturated ammonium chloride solution was added, and the mixture was filtered through diatomaceous earth. The filtrate was separated, and the aqueous phase was extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title compound 1b (8.3 g) was obtained by purification using silica gel column chromatography with eluent system B. The yield was 32.2%.

[0283] Step 2

[0284] (S)-1-(1-Methylpyrrolidin-2-yl)cyclopropyl alcohol 1c

[0285] Compound 1b (7.6 g, 33.43 mmol) was dissolved in 300 mL of tetrahydrofuran, and lithium aluminum hydride (1 M, 100 mL) was added dropwise, and the reaction was stirred at reflux for 17 hours. 50 mL of water was slowly added, and the mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1c (3.9 g), with a yield of 82.6%.

[0286] Step 3

[0287] tert-Butyl 2-(methylthio)-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate 1e

[0288] 4-Hydroxy-2-(methylthio)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tert-butyl ester 1d (10.3 g, 34.64 mmol, prepared by the method disclosed in the patent application "Intermediate 32 in the Example on page 79 of the specification of WO2017 / 201161A1") was dissolved in 200 mL of dichloromethane. N,N-diisopropylethylamine (6.72 g, 52 mmol) and trifluoromethanesulfonic anhydride (11.8 g, 41.82 mmol) were added respectively under ice bath, and stirred at room temperature for 17 hours. Add 50 mL of saturated sodium bicarbonate solution, extract with dichloromethane (300 mL×3), combine the organic phases, wash with saturated sodium chloride solution (100 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify by silica gel column chromatography with eluent system B to give the title compound 1e (9.5 g), yield: 63.9%.

[0289] Step 4

[0290] (S)-tert-butyl 4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylthio)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate 1f

[0291] Compound 1e (9.5 g, 22.12 mmol) was dissolved in 80 mL of acetonitrile, and N, N-diisopropylethylamine (5.72 g, 44.25 mmol) and (2S)-2-(cyanomethyl)piperidine-1-carboxylic acid benzyl ester (6.89 g, 26.57 mmol, prepared by the method disclosed in the patent application "Intermediate 63 in the Example on page 110 of the specification of US2018 / 0072723A1") were added respectively, and refluxed for 17 hours. The reaction solution was concentrated under reduced pressure, 30 mL of saturated sodium bicarbonate solution was added to the residue, and ethyl acetate was extracted (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the title compound 1f (10.3 g), with a yield of 86.4%.

[0292] Step 5

[0293] (S)-4-(4-((Benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylsulfonyl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tert-butyl ester 1 g

[0294] Compound 1f (9.8 g, 18.19 mmol) was dissolved in 200 mL of dichloromethane, and m-chloroperbenzoic acid (6.28 g, 36.38 mmol) was added, and the reaction was stirred at room temperature for 2 hours. 50 mL of saturated sodium bicarbonate solution was added, and dichloromethane was extracted (200 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1 g (10.3 g) of the title product, with a yield of 99.2%.

[0295] MS m / z(ESI):571.2[M+1].

[0296] Step 6

[0297] tert-Butyl 4-((S)-4-((Benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate 1h

[0298] Compound 1c (3.9 g, 27.62 mmol) was dissolved in 100 mL of tetrahydrofuran, cooled to 0°C, sodium bis(trimethylsilyl)amide (2M, 14 mL, Adamas) was added dropwise, stirred for 15 minutes, and compound 1g (10 g, 17.52 mmol) was added, and reacted at room temperature for 1 hour. 20 mL of saturated sodium chloride solution was added, the liquids were separated, the aqueous phase was extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to obtain the title compound 1h (3.2 g), with a yield of 28.9%.

[0299] MS m / z(ESI):632.3[M+1].

[0300] Step 7

[0301] (S)-2-(Cyanomethyl)-4-(2-(1-((S(-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester 1i

[0302] Compound 1h (3.2 g, 5.06 mmol) was dissolved in 20 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and a saturated sodium bicarbonate solution was added to adjust the pH to greater than 8, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1i (2.8 g), which was directly used for the next step without purification.

[0303] MS m / z(ESI):532.3[M+1].

[0304] Step 8

[0305] (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate 1j

[0306] Under argon atmosphere, compound 1i (150 mg, 282.14 umol), 1-bromo-8-chloro-naphthalene (103 mg, 426.48 umol, Shaoyuan Technology (Shanghai) Co., Ltd.), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (71 mg, 84.78 umol, Anaiji Chemical) and cesium carbonate (276 mg, 847.1 umol) were added to 20 mL of toluene and stirred at 95°C for 17 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to obtain the title compound 1j (120 mg) with a yield of 61.4%.

[0307] Step 9

[0308] 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 1k

[0309] Compound 1j (120 mg, 173.34 umol) was dissolved in 10 mL of dichloromethane, and boron tribromide (17% in dichloromethane) (1.0 M, 870 uL) was added at 0°C and stirred for 30 minutes. 10 mL of saturated sodium carbonate solution was added to the reaction solution to adjust the pH to greater than 7, and dichloromethane was extracted (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1k (52 mg), with a yield of 53.7%.

[0310] MS m / z(ESI):558.2[M+1].

[0311] Step 10

[0312] 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 1

[0313] Compound 1k (52 mg, 93.17 umol) was dissolved in 10 mL of dichloromethane, triethylamine (28 mg, 276.70 umol) was added, and acryloyl chloride (17 mg, 187.82 umol) was added dropwise, and stirred at room temperature for 1 hour. Water was added, and the mixture was extracted with dichloromethane (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by thin layer chromatography with developing solvent system A to obtain the title product 1 (5 mg), with a yield of 8.7%.

[0314] MS m / z(ESI):612.2[M+1].

[0315] 1 H NMR (400MHz, CDCl3) δ7.77-7.78 (m, 1H), 7.64-7.66 (m, 1H), 7.55-7.56 (m, 1H), 7.48-7.50 (m, 1H), 7.39-7.40 (m, 1H), 7.29- 7.31(m, 1H), 6.61-6.63(m, 1H), 6.41-6.45(m, 1H), 5.85-5.86(m, 1H), 5.10-5.12(m, 1H), 4.36-4.42(m, 1H), 4.12-4.22(m, 2H), 3.85-3.92(m, 2H), 3.60-3.62(m, 2H), 3.40-3.43(m, 2H), 3.23-3.24(m, 1H), 3.10-3.12(m, 2H), 2.87(s, 3H), 2.72-2.7 4(m, 1H), 2.61-2.64(m, 1H), 2.31-2.34(m, 1H), 2.10-2.15(m, 2H), 2.02-2.04(m, 3H), 1.64-1.66(m, 1H), 0.92-1.03(m, 4H).

[0316] Example 2

[0317] 2-((S)-1-acryloyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0318]

[0319] first step

[0320] (S)-benzyl 2-(cyanomethyl)-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate 2a

[0321] Under argon atmosphere, compound 1i (150 mg, 282.14 umol), 1-bromo-3-fluoro-2-trifluoromethylbenzene (137 mg, 563.79 umol, Shaoyuan Technology (Shanghai) Co., Ltd.), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (71 mg, 84.79 umol, Anaiji Chemical), cesium carbonate (276 mg, 847.1 umol) were added to 20 mL of toluene and stirred at 95 ° C for 17 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography with developing solvent system A to obtain the title product 2a (120 mg), with a yield of 61.3%.

[0322] MS m / z(ESI):694.0[M+1].

[0323] Step 2

[0324] 2-((S)-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 2b

[0325] Under hydrogen atmosphere, compound 2a (120 mg, 172.98 umol) was added to 10 mL of a mixed solvent of tetrahydrofuran and methanol (V / V=1:1), palladium carbon (37 mg, 17.38 umol, 5% purity) was added, and stirred for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title product 2b (96 mg), with a yield of 99.1%.

[0326] MS m / z(ESI):560.1[M+1].

[0327] Step 3

[0328] 2-((S)-1-acryloyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0329] Compound 2b (96 mg, 171.55 umol) was dissolved in 10 mL of dichloromethane, triethylamine (52 mg, 513.88 umol) was added, and acryloyl chloride (31 mg, 342.51 umol) was added dropwise, and stirred at room temperature for 1 hour. 5 mL of water was added, and the mixture was extracted with dichloromethane (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by thin layer chromatography with developing solvent system A to obtain the title product 2 (52 mg), with a yield of 49.4%.

[0330] MS m / z(ESI):614.1[M+1].

[0331] 1 H NMR (400MHz, CDCl3) δ7.50-7.53 (m, 1H), 7.09-7.11 (m, 1H), 6.96-7.01 (m, 1H), 6.60-6.63 (m, 1H), 6.41-6.44 (m, 1H), 5 .85-5.87(m, 1H), 5.10-5.12(m, 1H), 4.06-4.12(m, 3H), 3.95-3.98(m, 1H), 3.63-3.65(m, 1H), 3.31-3.34(m, 2H), 3.16 -3.18(m, 1H), 3.05-3.07(m, 2H), 2.92-2.94(m, 2H), 2.73-2.75(m, 2H), 2.53(s, 3H), 2.22-2.24(m, 1H), 1.98-2.01(m, 1H), 1.85-1.88(m, 1H), 1.73-1.75(m, 2H), 1.62-1.64(m, 2H), 1.08-1.12(m, 1H), 1.00-1.02(m, 1H), 0.89-0.93(m, 2H).

[0332] Example 3

[0333] 2-((S)-1-acryloyl-4-(7-(5-methyl-1H-indazol-4-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 3

[0334]

[0335]

[0336] first step

[0337] (2S)-2-(cyanomethyl)-4-(7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester 3a

[0338] Under argon atmosphere, compound 1i (200 mg, 376.18 umol), 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole (168 mg, 569.15 umol, prepared by the method disclosed in the patent application "WO2017 / 201161A1, the intermediate 51 in the embodiment on page 95 of the specification"), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (95 mg, 113.45 umol, Anaiji Chemical) and cesium carbonate (368 mg, 1.12 umol) were added to 20 mL of toluene and stirred at 95 ° C for 17 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography with developing agent system A to obtain the title product 3a (150 mg), with a yield of 53.45%.

[0339] MS m / z(ESI):746.2[M+1].

[0340] Step 2

[0341] 2-((2S)-4-(7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 3b

[0342] Under hydrogen atmosphere, compound 3a (150 mg, 201.1 umol) was added to 10 mL of a mixed solvent of tetrahydrofuran and methanol (V / V=1:1), palladium carbon (43 mg, 20.2 umol, 5% purity) was added, and stirred for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title product 3b (120 mg), with a yield of 97.5%.

[0343] MS m / z(ESI):612.2[M+1].

[0344] Step 3

[0345] 2-((2S)-1-acryloyl-4-(7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 3c

[0346] Compound 3b (120 mg, 196.14 umol) was dissolved in 10 mL of dichloromethane, triethylamine (60 mg, 592.94 umol) was added, and acryloyl chloride (36 mg, 397.75 umol) was added dropwise, and stirred at room temperature for 1 hour. 5 mL of water was added, and the mixture was extracted with dichloromethane (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by thin layer chromatography with developing solvent system A to obtain the title product 3c (85 mg), with a yield of 65.08%.

[0347] MS m / z(ESI):666.1[M+1].

[0348] Step 4

[0349] 2-((S)-1-acryloyl-4-(7-(5-methyl-1H-indazol-4-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 3

[0350] Compound 3c (85 mg, 127.66 umol) was dissolved in 10 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, ethyl acetate (20 mL) was added to the residue, and the mixture was washed with saturated sodium carbonate solution (50 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title product 3 (50 mg) was purified by thin layer chromatography using a developing solvent system A, and the yield was 67.33%.

[0351] MS m / z(ESI):582.3[M+1].

[0352] 1H NMR (400MHz, CDCl3) δ10.20-10.23 (m, 1H), 8.11 (s, 1H), 7.28-7.30 (m, 1H), 7.23-7.26 (m, 1H), 6.60-6.64 (m, 1H), 6 .40-6.45(m,1H),5.84-5.87(m,1H),5.10-5.13(m,1H),4.33(s,2H),4.09-4.12(m,1H),3.97-4.00(m,2H),3.56-3 .62(m, 3H), 3.30-3.34(m, 1H), 3.06-3.09(m, 2H), 2.92-2.94(m, 2H), 2.79-2.81(m, 2H), 2.55(s, 3H), 2.45(s, 3H), 2.23-2.26 (m, 1H), 2.00-2.03 (m, 1H), 1.75-1.87 (m, 4H), 1.28-1.31 (m, 1H), 1.11-1.14 (m, 1H), 1.03-1.05 (m, 2H).

[0353] Example 4

[0354] 2-((S)-1-acryloyl-4-(2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0355]

[0356]

[0357] first step

[0358] (S)-benzyl 2-(cyanomethyl)-4-(2-((S)-1-(1-methylpyrrolidin-2-yl)cyclopropyloxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate 4a

[0359] Under argon atmosphere, compound 1i (150 mg, 282.14 umol), 1-bromo-2-trifluoromethylbenzene (96 mg, 426.65 umol, Adamas), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (71 mg, 84.79 umol, Anaiji Chemical) and cesium carbonate (276 mg, 847.1 umol) were added to 20 mL of toluene and stirred at 95 ° C for 17 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography with developing solvent system A to obtain the title product 4a (150 mg) with a yield of 78.7%.

[0360] MS m / z(ESI):676.1[M+1].

[0361] Step 2

[0362] 2-((2S)-4-(2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 4b

[0363] Under hydrogen atmosphere, compound 4a (150 mg, 221.97 umol) was added to 10 mL of a mixed solvent of tetrahydrofuran and methanol (V / V=1:1), palladium carbon (48 mg, 22.55 umol, 5% purity) was added, and stirred for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title product 4b (120 mg), with a yield of 99.8%.

[0364] MS m / z(ESI):542.2[M+1].

[0365] Step 3

[0366] 2-((S)-1-acryloyl-4-(2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0367] Compound 4b (120 mg, 221.56 umol) was dissolved in 10 mL of dichloromethane, triethylamine (67 mg, 662.12 umol) was added, and acryloyl chloride (40 mg, 441.94 umol) was added dropwise, and stirred at room temperature for 1 hour. 5 mL of water was added, and the mixture was extracted with dichloromethane (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by thin layer chromatography with developing solvent system A to obtain the title product 4 (34 mg), with a yield of 25.7%.

[0368] MS m / z(ESI):596.2[M+1].

[0369] 1 H NMR (400MHz, CDCl3) δ7.71-7.72(m, 1H), 7.58-7.62(m, 1H), 7.44-7.46(m, 1H), 7.29-7.35(m, 1H), 6.60-6.63(m, 1H), 6.40-6.45( m, 1H), 5.84-5.88 (m, 1H), 5.10-5.13 (m, 1H), 4.08-4.10 (m, 3H), 3.95-3.98 (m, 1H), 3.62-3.65 (m, 1H), 3.31-3.34 (m, 1H), 3.21-3. 25 (m, 1H), 3.13-3.15 (m, 1H), 3.04-3.06 (m, 1H), 2.93-2.99 (m, 2H), 3.09-3.11 (m, 1H), 2.73-2.77 (m, 2H), 2.53-2.56 (m, 2H), 2.2 2-2.26 (m, 1H), 2.00-2.04 (m, 1H), 1.83-1.86 (m, 1H), 1.73-1.76 (m, 1H), 1.60-1.65 (m, 4H), 0.99-1.09 (m, 2H), 0.87-0.92 (m, 2H).

[0370] Example 5

[0371] 2-((S)-1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 5

[0372]

[0373] first step

[0374] (S)-benzyl 2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate 5a

[0375] Under argon atmosphere, compound 1i (150 mg, 282.14 umol), 1-bromo-8-methylnaphthalene (94 mg, 425.16 umol prepared by a known method Journal of Organic Chemistry, 2016, 81 (22), 10791-10801), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1, 1'-biphenyl) (2-amino-1, 1'-biphenyl-2-yl) palladium (II) (71 mg, 84.umol, Anaiji Chemical) and cesium carbonate (276 mg, 847.09 umol) were added to 20 mL of toluene and stirred at 95 ° C for 17 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography with developing solvent system A to obtain the title product 5a (140 mg) with a yield of 73.8%.

[0376] MS m / z(ESI):672.1[M+1].

[0377] Step 2

[0378] 2-((S)-4-(7-(8-methylnaphthalen-1-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 5b

[0379] Under hydrogen atmosphere, compound 5a (140 mg, 208.38 umol) was added to 10 mL of a mixed solvent of tetrahydrofuran and methanol (V / V=1:1), palladium carbon (44 mg, 20.67 umol, 5% purity) was added, and stirred for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title product 5b (72 mg), with a yield of 64.2%.

[0380] MS m / z(ESI):538.2[M+1].

[0381] Step 3

[0382] 2-((S)-1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 5

[0383] Compound 5b (72 mg, 133.90 umol) was dissolved in 10 mL of dichloromethane, triethylamine (41 mg, 405.18 umol) was added, acryloyl chloride (25 mg, 276.21 umol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. 5 mL of water was added, and the mixture was extracted three times with dichloromethane (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title product 5 (10 mg) was purified by thin layer chromatography using a developing solvent system A, and the yield was 12.6%.

[0384] MS m / z(ESI):592.3[M+1].

[0385] 1 H NMR (400MHz, CDCl3) δ7.68-7.73 (m, 2H), 7.43-7.45 (m, 1H), 7.35-7.37 (m, 1H), 7.24-7.29 (m, 2H), 6.58-6.63 (m, 1H), 6.42-6.46 (m, 1H), 5.85-5.87 (m, 1H), 5.08-5.12 (m, 1H), 4.23-4.27 (m, 1H), 4.11-4.19 (m, 2H), 3.87-3.94 (m, 1H), 3.74-3.80 (m, 1H), 3.52 -3.57(m, 1H), 3.42-3.46(m, 1H), 3.20-3.25(m, 3H), 3.04-3.12(m, 2H), 2.95(s, 3H), 2.85-2.89(m, 1H), 2.76-2.78(m, 1H), 2.66 -2.68 (m, 2H), 2.51-2.54 (m, 2H), 2.23-2.27 (m, 1H), 2.02-2.07 (m, 2H), 1.83-1.86 (m, 3H), 1.03-1.09 (m, 2H), 0.91-0.86 (m, 2H).

[0386] Example 6

[0387] 2-((S)-1-acryloyl-4-(2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-7-(o-tolyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0388]

[0389] first step

[0390] (S)-benzyl 2-(cyanomethyl)-4-(2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-7-(o-tolyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate 6a

[0391] Under argon atmosphere, compound 1i (200 mg, 376.18 umol), 1-bromo-2-methylbenzene (97 mg, 567.13 umol, Shaoyuan Technology (Shanghai) Co., Ltd.), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (95 mg, 113.45 umol, Anaiji Chemical) and cesium carbonate (368 mg, 1.12 umol) were added to 20 mL of toluene and stirred at 95 ° C for 17 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by thin layer chromatography with developing solvent system A to obtain the title product 6a (180 mg), with a yield of 76.9%.

[0392] MS m / z(ESI):622.2[M+1].

[0393] Step 2

[0394] 2-((S)-4-(2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-7-(o-tolyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 6b

[0395] Under hydrogen atmosphere, compound 6a (180 mg, 289.49 umol) was added to 10 mL of a mixed solvent of tetrahydrofuran and methanol (V / V=1:1), palladium carbon (62 mg, 29.12 umol, 5% purity) was added, and stirred for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title product 6b (130 mg), with a yield of 92.1%.

[0396] MS m / z(ESI):488.3[M+1].

[0397] Step 3

[0398] 2-((S)-1-acryloyl-4-(2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-7-(o-tolyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0399] Compound 6b (130 mg, 266.59 umol) was dissolved in 10 mL of dichloromethane, triethylamine (81 mg, 800.48 umol) was added, and acryloyl chloride (48 mg, 530.33 umol) was added dropwise, and stirred at room temperature for 1 hour. 5 mL of water was added, and the mixture was extracted with dichloromethane (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by thin layer chromatography with developing solvent system A to obtain the title product 6 (108 mg), with a yield of 74.7%.

[0400] MS m / z(ESI):542.3[M+1].

[0401] 1 H NMR (400MHz, CDCl3) δ7.23-7.26 (m, 2H), 7.08-7.11 (m, 2H), 6.60-6.63 (m, 1H), 6.38-6.46 (m, 1H), 5.84-5.89 (m, 1 H), 5.08-5.12(m, 1H), 4.18-4.21(m, 1H), 4.08-4.09(m, 2H), 3.99-4.03(m, 1H), 3.82-3.85(m, 1H), 3.60-3.63(m, 2H), 3.27-3.33(m, 2H), 3.12-3.14(m, 2H), 2.90-2.94(m, 5H), 2.73-2.77(m, 3H), 2.38(s, 3H), 2.13-2.16(m, 2H), 2.02-2.05 (m, 2H), 1.81-1.84 (m, 1H), 1.32-1.34 (m, 1H), 1.27-1.29 (m, 1H), 1.12-1.15 (m, 1H), 1.02-1.06 (m, 1H).

[0402] Example 7

[0403] 2-((S)-1-acryloyl-4-(7-(3-hydroxynaphthalen-1-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 7

[0404]

[0405] first step

[0406] (S)-benzyl 2-(cyanomethyl)-4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate 7a

[0407] Under argon atmosphere, compound 1i (150 mg, 282.14 umol), [3-(methoxymethoxy)-1-naphthalene] trifluoromethanesulfonate (142 mg, 422.26 umol, prepared by the method disclosed in the patent application "WO2017 / 201161Al, Example Intermediate 1 on page 59 of the specification), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (71 mg, 84.78 umol, Anaijie Chemical) and cesium carbonate (276 mg, 847.09 umol) were added to 20 mL of toluene and stirred at 95 ° C for 17 hours. The reaction was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the title product 7a (120 mg) was purified by thin layer chromatography with developing solvent system A, with a yield of 59.2%.

[0408] MS m / z(ESI):718.1[M+1].

[0409] Step 2

[0410] 2-((S)-4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 7b

[0411] Under hydrogen atmosphere, compound 7a (120 mg, 167.16 umol) was added to 10 mL of a mixed solvent of tetrahydrofuran and methanol (V / V = 1 / 1), palladium carbon (36 mg, 16.91, 5% purity) was added, and stirred for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 7b (67 mg), with a yield of 68.6%.

[0412] Step 3

[0413] 2-((S)-1-acryloyl-4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 7c

[0414] Compound 7b (67 mg, 114.78 umol) was dissolved in 10 mL of dichloromethane, triethylamine (35 mg, 345.88 umol) was added, and acryloyl chloride (21 mg, 232.02 umol) was added dropwise, and stirred at room temperature for 1 hour. 5 mL of water was added, and the mixture was extracted with dichloromethane (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by thin layer chromatography with developing solvent system A to obtain the title product 7c (45 mg), with a yield of 61.5%.

[0415] Step 4

[0416] 2-((S)-1-acryloyl-4-(7-(3-hydroxynaphthalen-1-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 7

[0417] Compound 7c (45 mg, 70.55 umol) was dissolved in 6 mL of a mixed solvent of tetrahydrofuran and methanol (V / V=1 / 2), 1 mL of hydrochloric acid (6 M) was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was adjusted to a pH greater than 7 with 10 mL of saturated sodium carbonate solution, extracted with dichloromethane (30 mL×3), the organic phases were combined, concentrated under reduced pressure, and purified by thin layer chromatography with a developing solvent system A to obtain the title product 7 (8 mg), with a yield of 19.1%.

[0418] MS m / z(ESI):594.3[M+1].

[0419] 1 H NMR (400MHz, CDCl3) δ7.99-8.01(m, 1H), 7.59-7.61(m, 1H), 7.35-7.39(m, 1H), 7.27-7.29(m, 1H), 6.90-6.92( m, 2H), 6.53-6.58 (m, 1H), 6.37-6.41 (m, 1H), 5.81-5.84 (m, 1H), 5.00-5.04 (m, 1H), 4.50-4.53 (m, 1H), 4.21-4. 25(m, 2H), 4.01-4.04(m, 1H), 3.90-3.92(m, 2H), 3.46-3.49(m, 2H), 3.28-3.31(m, 2H), 3.20-3.23(m, 1H), 3.0 0-3.08 (m, 2H), 2.68-2.83 (m, 7H), 2.48-2.52 (m, 1H), 2.02-2.05 (m, 2H), 1.82-1.87 (m, 2H), 1.03-1.11 (m, 4H).

[0420] Example 8

[0421] (S)-2-(1-acryloyl-4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 8

[0422]

[0423]

[0424] first step

[0425] 1-(Pyrrolidine-1-carbonyl)cyclopropane-1-carboxylic acid methyl ester 8b

[0426] Under ice-water bath, 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid 8a (3 g, 20.81 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was dissolved in 80 mL of dichloromethane, oxalyl chloride (10.5 g, 83.26 mmol) and 3 drops of N,N-dimethylformamide were added at 0°C, and stirred for 10 minutes. The reaction was heated to 35°C and continued to stir for 3 hours, and then concentrated under reduced pressure. 60 mL of anhydrous dichloromethane was added, cooled to 0°C, triethylamine (10 g, 104.15 mmol) and pyrrolidine (1.77 g, 24.90 mmol) were added, and the reaction was continued for 3 hours, and then concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 8b (3.2 g), with a yield of 77.9%.

[0427] MS m / z(ESI):198.1[M+1].

[0428] Step 2

[0429] (1-(Pyrrolidin-1-ylmethyl)cyclopropyl)methanol 8c

[0430] Compound 8b (1.5 g, 7.60 mmol) was dissolved in 20 mL of tetrahydrofuran, cooled to -78 °C, and 16.7 mL (1 M) of lithium aluminum tetrahydride was added, and stirred at room temperature for 2 hours. The reaction solution was cooled to -60 °C, 30 mL of ethyl acetate was slowly added, and then 10 mL of water and 20 mL of 2M sodium hydroxide solution were added, stirred at room temperature for 1 hour, and filtered. The filter cake was washed with dichloromethane (100 mL × 3), the organic phase in the filtrate was concentrated under reduced pressure, the aqueous phase was extracted with dichloromethane (100 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title product 8c (300 mg), yield: 25.4%.

[0431] MS m / z(ESI):156.1[M+1].

[0432] Step 3

[0433] (S)-benzyl 2-(cyanomethyl)-4-(2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate 8e

[0434] (S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazine-1-yl)-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester 8d (3 g, 5.57 mmol, prepared by the method disclosed in the patent application "US2019 / 144444, 2019, A1, Example Intermediate 68 on page 157 of the specification") was dissolved in 20 mL of dichloromethane and 5 mL of trifluoroacetic acid, stirred for 1 hour, and concentrated under reduced pressure. 30 mL of saturated sodium bicarbonate aqueous solution was added to the residue, stirred for 10 minutes, extracted with dichloromethane (100 mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 8e (1.77 g), yield: 72.5%.

[0435] MS m / z(ESI):439.1[M+1].

[0436] Step 4

[0437] (S)-2-(Cyanomethyl)-4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester 8f

[0438] Under argon atmosphere, compound 8e (1 g, 2.28 mmol), 7-fluoro-8-methylnaphthalene-1-yl trifluoromethanesulfonate (702 mg, 2.28 mmol, prepared by the method disclosed in the intermediate 77 in the embodiment on page 76 of the specification of the patent application "US2019 / 0270743A1"), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (347 mg, 0.46 mmol, Anaiji Chemical) and cesium carbonate (1.86 g, 5.71 mmol) were added to 60 mL of toluene and stirred at 95 ° C for 17 hours. The reaction was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 8f (0.57 g) with a yield of 41.9%.

[0439] MS m / z(ESI):597.2[M+1].

[0440] Step 5

[0441] 8 g of (2S)-2-(cyanomethyl)-4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester

[0442] Compound 8f (0.57 g, 0.95 mmol) and 3-chloroperoxybenzoic acid (180 mg, 1.05 mmol) were dissolved in 20 mL of dichloromethane and stirred for 2 hours. 10 mL of saturated sodium bicarbonate solution was added to the reaction solution and stirred for 10 minutes. The layers were separated and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 8g (0.41 g) with a yield of 70%.

[0443] MS m / z(ESI):613.2[M+1].

[0444] Step 6

[0445] (S)-2-(Cyanomethyl)-4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester 8h

[0446] Compound 8c (0.2 g, 1.28 mmol) was dissolved in 10 mL of tetrahydrofuran, cooled to 0°C, sodium bis(trimethylsilyl)amide (2 M, 0.64 mL, Adamas) was added dropwise, stirred for 15 minutes, and compound 8g (0.39 g, 0.64 mmol) was added, and the mixture was reacted at room temperature for 1 hour. 20 mL of saturated sodium chloride solution was added, the liquids were separated, the aqueous phase was extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 8h (0.24 g), with a yield of 52.9%.

[0447] MS m / z(ESI):704.3[M+1].

[0448] Step 7

[0449] (S)-2-(4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 8i

[0450] Compound 8h (240 mg, 340.98 umol) was added to 10 mL of tetrahydrofuran, palladium carbon (100 mg, 5% purity) was added, hydrogen was replaced three times, stirred for 2 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 8i (180 mg), with a yield of 92.6%.

[0451] MS m / z(ESI):570.3[M+1].

[0452] Step 8

[0453] (S)-2-(1-acryloyl-4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 8

[0454] Compound 8i (70 mg, 122.87 umol) was dissolved in 10 mL of dichloromethane, N,N-diethylethylenediamine (32 mg, 245.81 umol) was added, and acryloyl chloride (12 mg, 35.23 umol) was added dropwise, and the mixture was stirred for 1 hour. Water was added, and the mixture was extracted with dichloromethane (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography using a developing solvent system A to obtain the title product 8 (25 mg), with a yield of 32.6%.

[0455] MS m / z(ESI):624.2[M+1].

[0456] 1 H NMR (400MHz, DMSO-d6) δ7.84 (t, 1H), 7.71 (t, 1H), 7.47-7.36 (m, 3H), 6.85 (br, s, 1H), 6.18 (d, 1H), 5.78 (d, 1H), 4.96-4.41 (m, 4H), 4.10-3.98(m, 5H), 3.71-3.41(m, 6H), 3.08-3.06(m, 6H), 2.88(s, 3H), 2.86-2.78(m, 3H), 1.67(s, 3H), 0.57-0.41(m, 4H).

[0457] Example 9

[0458] (S)-2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 9

[0459]

[0460] The synthetic route of Example 8 was used to prepare the title compound 9 (12 mg), by replacing the first step raw material pyrrolidine with dimethylamine and the fourth step raw material 7-fluoro-8-methylnaphthalen-1-yl trifluoromethanesulfonate with 1-bromo-8-chloronaphthalene.

[0461] MS m / z(ESI):602.0[M+1].

[0462] 1 H NMR (400MHz, DMSO-d6) δ7.45 (d, 1H), 7.61 (t, 1H), 7.51 (d, 1H), 7.43-7.45 (m, 1H), 7. 33(t, 1H), 7.23-7.26(m, 1H), 6.58(br, s, 1H), 6.38(d, 1H), 5.80(d, 1H), 4.50-4.53(m , 1H), 4.26-4.44(m, 3H), 4.02-4.12(m, 1H), 3.80-3.90(m, 2H), 3.49-3.56(m, 2H), 3.1 0-3.26(m, 6H), 2.62-3.01(m, 9H), 2.47-2.61(m, 1H), 0.98(s, 2H), 0.85-0.88(m, 2H).

[0463] Example 10

[0464] (S)-2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 10

[0465]

[0466] first step

[0467] 1-(Chlorocarbonyl)cyclopropane-1-carboxylic acid methyl ester 10-1

[0468] Compound 8a (1.4 g, 9.71 mmol) was dissolved in 20 mL of dichloromethane, 0.2 mL of N,N-dimethylformamide was added, oxalyl chloride (1.26 g, 9.92 mmol, Titanium) was added dropwise at 0°C, and the reaction was stirred at 0°C for 1 hour. The resulting mixture was concentrated to obtain the title product crude product 10-1 (1.58 g), which was directly used for the next step without purification.

[0469] Step 2

[0470] 1-(Pyrrolidine-1-carbonyl)cyclopropane-1-carboxylic acid methyl ester 10-2

[0471] Compound 10-1 (1.58 g, 9.71 mmol) was dissolved in 500 mL of tetrahydrofuran, and pyrrolidine (3.45 g, 48.48 mmol, Anaiji) was added at 0°C. The reaction solution was stirred at room temperature for 16 hours, and the reaction was stopped. 50 mL of water was added, and ethyl acetate (50 mL × 3) was used for extraction, drying, filtering, and concentrating under reduced pressure to obtain the title product 10-2 (1.64 g), which was directly used for the next step without purification.

[0472] 1 H NMR (400MHz, CDCl3) δ3.72 (s, 3H), 3.50 (t, 2H), 3.44 (t, 2H), 1.94-1.87 (m, 4H), 1.48-1.45 (m, 2H), 1.36-1.33 (m, 2H).

[0473] Step 3

[0474] (1-(Pyrrolidin-1-ylmethyl)cyclopropyl)methanol 10-3

[0475] Under argon atmosphere, compound 10-2 (1.0 g, 5.07 mmol) was dissolved in 100 mL of tetrahydrofuran, and lithium aluminum tetrahydride tetrahydrofuran solution (1M, 10 mL, 10 mmol, Anaiji) was added at 0°C, and the reaction solution was stirred at 0°C for 4 hours. 3.2 g of sodium sulfate decahydrate was added to quench the reaction. Drying, filtering, and concentrating the filtrate under reduced pressure gave the title product 10-3 (624 mg) with a yield of 79%.

[0476] 1 H NMR (400MHz, CDCl3) δ3.55 (s, 2H), 2.61-2.57 (m, 6H), 1.77-1.73 (m, 4H), 0.49-0.47 (m, 2H), 0.37-0.35 (m, 2H).

[0477] Step 4

[0478] (S)-2-(1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 10

[0479] The synthetic route of Example 1 was adopted, and the raw material compound 1c in the sixth step was replaced by compound 10-3 to obtain the title product 10 (10 mg). Yield: 11.4%.

[0480] MS m / z(ESI):626.0[M+1].

[0481] 1 H NMR (400MHz, CDCl3) δ7.73-7.75 (m, 1H), 7.59-7.61 (m, 1H), 7.50-7.52 (m, 1H), 7.36-7.46 (m, 1H), 7.30-7.34 (m, 1H), 7.19-7.26 (m, 1H), 6.58 (br, 1H), 6.36-6.41 (m, 1H), 5.80-5.83 (m, 1H), 4.40-4.45 (m, 1H), 4.22-4.3 7(m, 2H), 4.0-4.18(m, 1H), 3.78-3.93(m, 2H), 3.56-3.72(m, 1H), 3.28-3.50(m, 1H), 3.02-3.25(m, 4H), 2.65 -2.95(m, 8H), 2.40-2.65(m, 2H), 1.68-1.93(m, 4H), 1.28-1.38(m, 1H), 0.65-0.78(m, 2H), 0.48-0.62(m, 2H).

[0482] Embodiment 11

[0483] (S)-2-(1-acryloyl-4-(7-(8-chloronaphth-1-yl)-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 11

[0484]

[0485] first step

[0486] 1-(Piperidine-1-carbonyl)cyclopropyl-1-carboxylic acid methyl ester 11-1

[0487] Compound 8a (5.0 g, 34.69 mmol), piperidine (2.95 g, 34.69 mmol, Bidex Pharmaceuticals), 1-hydroxybenzotriazole (5.63 g, 41.03 mmol, Titan), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.98 g, 41.03 mmol, Titan) and N, N-diisopropylethylamine (13.45 g, 104.08 mmol) were dissolved in 50 mL of dichloromethane and stirred for 3 hours. 20 mL of water was added and extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title compound 11-1 (4.8 g).

[0488] Step 2

[0489] (1-(Piperidin-1-ylmethyl)cyclopropyl)methanol 11-2

[0490] Under argon atmosphere, compound 11-1 (4.8 g, 22.72 mmol) was dissolved in 50 mL of dry tetrahydrofuran, and lithium aluminum hydride tetrahydrofuran solution (1 M, 68 mL, 68 mmol, Chinese medicine) was added at 0°C, and the reaction solution was stirred at 0°C for 1 hour. Sodium sulfate decahydrate (70 g) was added, stirred for 30 minutes and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title product 11-2 (1.81 g), with a yield of 47%.

[0491] 1 H NMR (400MHz, CDCl3) δ6.13 (brs, 1H), 3.54 (s, 2H), 2.52 (brs, 4H), 2.44 (s, 2H), 1.61-1.56 (m, 4H), 1.44 (s, 2H), 0.51-0.48 (m, 2H), 0.36-0.33 (m, 2H).

[0492] Step 3

[0493] (S)-2-(1-acryloyl-4-(7-(8-chloronaphth-1-yl)-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 11

[0494] The synthetic route of Example 1 was adopted, and the raw material compound 1c in the sixth step was replaced by compound 11-2 to obtain the title product 11 (10 mg). Yield: 15.6%.

[0495] MS m / z(ESI):640.1[M+1].

[0496] 1H NMR (400MHz, CDCl3) δ7.73-7.75 (m, 1H), 7.60-7.62 (m, 1H), 7.50-7.52 (m, 1H), 7.38-7.48 (m, 1H), 7.30-7.34 (m, 1H), 7.23-7 .26(m, 1H), 6.50-6.75(br, 1H), 6.36-6.40(m, 1H), 5.80-5.82(m, 1H), 4.38-4.45(m, 1H), 4.12-4.32(m, 2H), 3.98-4.13(m, 1H ), 3.75-3.95(m, 2H), 3.51-3.76(m, 1H), 3.32-3.51(m, 1H), 2.92-3.29(m, 4H), 2.65-2.91(m, 2H), 2.28-2.65(m, 6H), 2.09-2. 26 (m, 1H), 1.81-2.08 (m, 1H), 1.45-1.75 (m, 4H), 1.33-1.43 (m, 2H), 1.25-1.32 (m, 1H), 0.55-0.75 (m, 2H), 0.28-0.55 (m, 2H).

[0497] Example 12

[0498] 2-((S)-1-acryloyl-4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 12

[0499]

[0500]

[0501] first step

[0502] (R)-1-(3-fluoropyrrolidine-1-carbonyl)cyclopropane-1-carboxylic acid methyl ester 12-1

[0503] At 0°C, 3-(R)-fluoropyrrolidine hydrochloride (0.6 g, 4.78 mmol, Jingshi Pharmaceuticals), compound 8a (0.8 g, 5.55 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.2 g, 6.26 mmol, Bidex) and 1-hydroxybenzotriazole (0.83 g, 6.14 mmol, Bidex) were dissolved in 20 mL of dichloromethane, N,N-diisopropylethylamine (4.0 g, 30.95 mmol) was added, and the mixture was stirred for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 12-1 (0.6 g), with a yield of 50%.

[0504] Step 2

[0505] (R)-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol 12-2

[0506] Under argon atmosphere, compound 12-1 (0.6 g, 2.79 mmol) was added to 20 mL of tetrahydrofuran, and lithium aluminum hydride (1 M tetrahydrofuran solution, 5.6 mL, 5.6 mmol) was added at 0°C. The reaction solution was stirred at 0°C for 4 hours. Sodium sulfate decahydrate (3.2 g) was added to quench the reaction, filtered, and concentrated under reduced pressure to obtain a crude product 12-2 (0.4 g), which was directly used for the next step without purification.

[0507] Step 3

[0508] 2-((S)-1-acryloyl-4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 12

[0509] The synthetic route of Example 8 was adopted, and the compound 8c in the sixth step was replaced by compound 12-2 to obtain the title product 12 (16 mg) with a yield of 21%.

[0510] MS m / z(ESI):642.1[M+1].

[0511] 1H NMR (400MHz, DMSO-d6) δ.85 (t, 1H), 7.72 (t, 1H), 7.45-7.34 (m, 3H), 6.84 (brs, 1H), 6. 19(d,1H),5.78(d,1H),5.16(d,1H),4.99-4.73(m,1H),4.44-3.60(m,7H),3.50-3.41( m, 2H), 3.24-3.03 (m, 4H), 2.94-2.72 (m, 6H), 2.68-2.50 (m, 2H), 2.46-2.42 (m, 2H), 2. 34-2.25 (m, 2H), 2.08-2.01 (m, 1H), 1.87-1.78 (m, 1H), 0.56-0.54 (m, 2H), 0.40 (s, 2H).

[0512] Example 13

[0513] 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 13

[0514]

[0515] The synthetic route of Example 1 was adopted, and the raw material compound 1c in the sixth step was replaced by compound 12-2 to obtain the title product 13 (10 mg) with a yield of 15.5%.

[0516] MS m / z(ESI):644.1[M+1].

[0517] 1H NMR (400MHz, CDCl3) δ7.66-7.82(m, 1H), 7.55-7.66(m, 1H), 7.48-7.55(m, 1H), 7.36-7.48(m, 1H), 7.29-7.36(m, 1H), 7.15-7.25( m, 1H), 6.50-6.75 (br, 1H), 6.30-6.48 (m, 1H), 5.72-5.92 (m, 1H), 4.35-4.78 (m, 1H), 4.28-4.34 (m, 1H), 4.13-4.23 (m, 1H), 4.00-4 .12(m,1H),3.86-3.98(m,1H),3.75-3.89(m,1H),3.52-3.75(m,2H),3.33-3.50(m,1H),2.96-3.30(m,5H),2.78-2.98(m,3H),2.6 3-2.77 (m, 2H), 2.53-2.63 (m, 1H), 2.32-2.50 (m, 1H), 1.91-2.15 (m, 2H), 1.70-1.92 (m, 1H), 1.25-1.42 (m, 2H), 0.31-0.83 (m, 4H).

[0518] Embodiment 14

[0519] (S)-2-(1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 14

[0520]

[0521] The synthetic route of Example 1 was used to replace the sixth step raw material compound 1c with compound 11-2, and the eighth step raw material compound 1-bromo-8-chloro-naphthalene with compound 1-bromo-8-methylnaphthalene to obtain the title product 14 (5 mg) in a yield of 13%.

[0522] MS m / z(ESI):620.2[M+1].

[0523] 1H NMR (400MHz, DMSO-d6) δ7.77-7.71(m, 2H), 7.48-7.44(m, 1H), 7.35-7.27(m, 3H), 6.86(br, 1 H), 6.19 (d, 1H), 5.78 (d, 1H), 4.99-4.76 (m, 1H), 4.40-3.90 (m, 5H), 3.75-3.60 (m, 2H), 3.43 -3.36(m, 3H), 3.27-3.12(m, 4H), 3.09-2.98(m, 1H), 2.86(s, 3H), 2.80-2.55(m, 1H), 2.32(b rs, 4H), 2.21 (s, 2H), 1.44-1.42 (m, 4H), 1.34 (s, 2H), 0.56-0.54 (s, 2H), 0.36-0.33 (s, 2H).

[0524] Embodiment 15

[0525] (S)-2-(1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 15

[0526]

[0527] The synthetic route of Example 1 was used to replace the sixth step raw material compound 1c with compound 10-3, and the eighth step raw material compound 1-bromo-8-chloro-naphthalene with compound 1-bromo-8-methylnaphthalene to obtain the title product 15 (13 mg) with a yield of 20%.

[0528] MS m / z(ESI):606.4[M+1].

[0529] 1 H NMR (400MHz, DMSO-d6) δ7.76-7.68(m, 2H), 7.48-7.26(m, 4H), 6.86(brs, 1H), 6.19(d, 1H), 5.78(d, 1H), 4.97-4.79(m, 1H), 4.15-3.94(m, 6H), 3.76-3.62(m, 1H), 3.12-3.04(m, 6H), 2.86(s, 3H), 2.73-2.68(m, 1H), 2.42-2.36(m, 6H), 1.64(s, 4H), 1.23(m, 2H), 0.53(d, 2H), 0.38(s, 2H).

[0530] Example 16

[0531] 2-((S)-1-acryloyl-4-(2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-7-(8-methylnaphth-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 16

[0532]

[0533] The synthetic route of Example 1 was used to replace the sixth step raw material compound 1c with compound 12-2, and the eighth step raw material compound 1-bromo-8-chloro-naphthalene with compound 1-bromo-8-methylnaphthalene to obtain the title compound 16 (12 mg) with a yield of 9.1%.

[0534] MS m / z(ESI):624.6[M+1].

[0535] 1 H NMR (400MHz, DMSO-d6) δ7.76-7.68 (m, 2H), 7.46-7.26 (m, 4H), 6.86 (brs, 1H), 6.21-6.05 (m, 1H), 5 .78(d,1H),5.23-5.09(m,1H),4.97-4.77(m,1H),4.15-3.94(m,6H),3.70-3.66(m,1H),3.42-3.3 9(m, 1H), 3.12-3.10(m, 5H), 2.92-2.90(m, 1H), 2.86(s, 3H), 2.82-2.76(m, 3H), 2.71-2.60(m, 1H) , 2.62-2.43(m, 2H), 2.33-2.28(m, 2H), 2.10(m, 1H), 1.88-1.80(m, 1H), 0.54(d, 2H), 0.40(s, 2H).

[0536] Embodiment 17

[0537] (S)-2-(1-acryloyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 17

[0538]

[0539] The synthetic route of Example 1 was used, and the raw material compound 1c in the sixth step was replaced by compound 10-1, and the raw material compound 1-bromo-8-chloro-naphthalene in the eighth step was replaced by compound 1-bromo-3-fluoro-2-(trifluoromethyl)benzene (Bis) to obtain the title product 17 (23 mg), with a yield of 40.4%.

[0540] MS m / z(ESI):628.2[M+1].

[0541] 1 H NMR (400MHz, CDCl3) δ7.43-7.54(m, 1H), 7.04-7.06(m, 1H), 6.90-7.00(m, 1H), 6.51-6.63(m, 1H ), 6.34-6.45(m, 1H), 5.80-5.83(m, 1H), 4.16-4.29(m, 2H), 4.05-4.16(m, 3H), 3.85-4.02(m, 2H) , 3.48-3.71(m, 1H), 3.20-3.36(m, 2H), 3.12-3.19(m, 1H), 3.00-3.11(m, 1H), 2.76-2.98(m, 3H) , 2.65-2.76(m, 2H), 2.33-2.63(m, 6H), 1.65-1.82(m, 4H), 0.55-0.68(m, 2H), 0.32-0.54(m, 2H).

[0542] Embodiment 18

[0543] (S)-2-(4-(7-(8-chloronaphthalen-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile 18

[0544]

[0545]

[0546] Compound 18-1 (55 mg, 101 ummol, prepared by using the synthetic route of Example 8, replacing the first step raw material pyrrolidine with dimethylamine, and replacing the fourth step raw material 7-fluoro-8-methylnaphthalene-1-yl trifluoromethanesulfonate with 1-bromo-8-chloronaphthalene), 2-fluoroacrylic acid (18 mg, 200 umol), benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate (90 mg, 203 umol, Adamas), N, N-diethylethylenediamine (40 mg, 309 umol) were added to 20 mL of dichloromethane and stirred at room temperature for 16 hours. 60 mL of water was added to the reaction solution, extracted with dichloromethane (30 mL × 3), the organic phases were combined, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by TLC using developing solvent system A to give the title product 18 (15 mg). Yield: 24.1%.

[0547] MS m / z(ESI):619.0[M+1].

[0548] 1 H NMR (400MHz, DMSO-d6) δ7.74 (d, 1H), 7.60 (t, 1H), 7.51 (d, 1H), 7.42-7.45 (m, 1H), 7.32 (t, 1H), 6.99-7.22(m, 1H), 5.22-5.46(m, 2H), 4.38-4.45(m, 1H), 4.16-4.21(m, 2H), 4.02-4.0 6(m, 1H), 3.79-3.91(m, 3H), 3.57-3.58(m, 1H), 3.29-3.31(m, 1H), 3.09-3.21(m, 4H), 2.84 -2.86(m, 2H), 2.55(t, 1H), 2.26-2.35(m, 8H), 1.26-1.39(m, 1H), 0.64(s, 2H), 0.45(s, 2H).

[0549] Embodiment 19

[0550] (S)-2-(1-acryloyl-4-(7-(2,3-(dimethylphenyl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 19

[0551]

[0552] The synthetic route of Example 1 was used to replace the sixth step raw material compound 1c with compound 10-1, and the eighth step raw material compound 1-bromo-8-chloro-naphthalene with compound 1-bromo-2,3-dimethylbenzene (adamas) to obtain the title product 19 (25 mg) with a yield of 43.8%.

[0553] MS m / z(ESI):570.3[M+1].

[0554] 1 H NMR (400MHz, CDCl3) δ7.05-7.15(m, 1H), 6.91-6.98(m, 2H), 6.51-6.65(m, 1H), 6.33-6.43(m, 1H), 5.78-5.86(m, 1H), 4.16-4.30(m, 2H), 4.08-4.15(m, 1H), 4.00-4.05(m, 2H), 3.86-4.00( m, 2H), 3.42-3.71 (m, 1H), 3.23-3.35 (m, 1H), 3.01-3.21 (m, 3H), 2.67-2.98 (m, 5H), 2.35-2.6 6(m, 6H), 2.29(s, 3H), 2.26(s, 3H), 1.71-1.86(m, 4H), 0.55-0.68(m, 2H), 0.38-0.54(m, 2H).

[0555] Embodiment 20

[0556] (S)-2-(1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclobutyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 20

[0557]

[0558] first step

[0559] 1-(Pyrrolidine-1-carbonyl)cyclobutane-1-carboxylic acid ethyl ester 20-1

[0560] At 0°C, 1-(ethoxycarbonyl)cyclobutyric acid 20-0 (4.5 g, 26.16 mmol, Leyan), pyrrolidine (1.86 g, 26.16 mmol), 1-hydroxybenzotriazole (4.24 g, 31.39 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.12 g, 31.39 mmol), N,N-diisopropylethylamine (10.1 g, 78.48 mmol) were dissolved in 100 mL of dichloromethane and stirred for 5 hours. 20 mL of water was added to the resulting mixture, and dichloromethane (20 mL×3) was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent B to obtain the title product 20-1 (4.0 g), with a yield of 67%.

[0561] Step 2

[0562] (1-(Pyrrolidin-1-ylmethyl)cyclobutyl)methanol 20-2

[0563] Under argon atmosphere, compound 20-1 (4.0 g, 17.76 mmol) was dissolved in 50 mL of dry tetrahydrofuran, and lithium aluminum hydride tetrahydrofuran solution (1 M, 53 mL, 53 mmol) was added at 0°C and stirred for 1 hour. After quenching with ethyl acetate, sodium sulfate decahydrate (50 g) was added and stirred for 30 minutes, filtered, and concentrated under reduced pressure to obtain a crude product. The title product 20-2 (800 mg) was purified by CombiFlash rapid preparation instrument with eluent A, and the yield was 26%.

[0564] Step 3

[0565] (S)-2-(1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclobutyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 20

[0566] The synthetic route of Example 1 was used to replace the sixth step raw material compound 1c with compound 20-2, and the eighth step raw material compound 1-bromo-8-chloro-naphthalene with compound 1-bromo-8-methylnaphthalene to obtain the title product 20 (22 mg) in a yield of 19%.

[0567] MS m / z(ESI):620.5[M+1].

[0568] 1H NMR (400MHz, DMSO-d6) δ7.77-7.68 (m, 2H), 7.47-7.42 (m, 1H), 7.39-7.26 (m, 3H), 6.8 5(br,1H),6.19(d,1H),5.79-5.76(d,1H),4.98-4.77(m,1H),4.27-4.25(m,2H),4.0 6-3.96(m, 4H), 3.72-3.67(m, 2H), 3.43-3.39(m, 1H), 3.29-3.00(m, 6H), 2.92(s, 3H) , 2.88-2.84(m, 1H), 2.56(s, 2H), 2.41(s, 4H), 1.95-1.80(m, 6H), 1.62-1.61(m, 4H).

[0569] Embodiment 21

[0570] (S)-2-(4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile 21

[0571]

[0572] first step

[0573] ((S)-2-(4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile 21

[0574] Compound 8i (150 mg, 263.29 mmol), 2-fluoroacrylic acid (47 mg, 526.68 mmol), benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (233 mg, 526.58 mmol, Adamas), N,N-diethylethylenediamine (136 mg, 1.05 mmol) were added to 20 mL of dichloromethane and stirred at room temperature for 16 hours. 60 mL of water was added to the reaction solution, extracted with dichloromethane (30 mL×3), the organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography with developing solvent system A to obtain the title product 21 (43 mg), with a yield of 25.4%.

[0575] MS m / z(ESI):642.2[M+1].

[0576] 1 H NMR (400MHz, DMSO-d6) δ7.85 (t, 1H), 7.72 (t, 1H), 7.44-7.32 (m, 3H), 5.42-5.21 (m, 3H), 4.09-3.98 (m, 6H), 3.73 (t, 2H), 3.43-3.40 (m, 3H) ), 3.3. (s, 2H), 3.08 (d, 1H), 2.96 (d, 3H), 2.80 (t, 1H), 2.78 (s, 3H), 2.67-2.43 (m, 2H), 2.33 (brs, s, 3H), 1.66 (s, 3H), 0.55-0.41 (d, 4H).

[0577] Embodiment 22

[0578] (S)-2-(4-(7-(8-chloronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile 22

[0579]

[0580] Compound 22-1 (100 mg, 174 umol, prepared by the synthetic route of Example 10) was dissolved in 20 mL of dichloromethane, 2-fluoroacrylic acid (32 mg, 355 umol), benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (154 mg, 348 umol) were added, and N, N-diisopropylethylamine (67 mg, 519 umol) was added dropwise, and stirred for 3 hours. Water was added, extracted with dichloromethane (10 mL×3), washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography with developing solvent system A to obtain the title product 22 (28 mg), with a yield of 24.8%.

[0581] MS m / z(ESI):644.2[M+1].

[0582] 1H NMR (400MHz, CDCl3) δ7.73-7.75(m, 1H), 7.60-7.68(m, 1H), 7.50-7.55(m, 1H), 7.38-7.46(m, 1H), 7. 30-7.36(m, 1H), 7.15-7.25(m, 1H), 5.34-5.46(m, 1H), 5.21-5.26(m, 1H), 4.37-4.45(m, 1H), 4.16-4. 26(m, 2H), 3.95-4.15(m, 2H), 3.75-3.95(m, 2H), 3.52-3.66(m, 1H), 3.32-3.48(m, 1H), 2.95-3.29(m , 4H), 2.75-2.96 (m, 2H), 2.27-2.75 (m, 7H), 1.65-1.98 (m, 5H), 0.55-0.72 (m, 2H), 0.38-0.54 (m, 2H).

[0583] Embodiment 23

[0584] (S)-2-(1-acryloyl-4-(2-(1-((dimethylamino)methyl)cyclopropyloxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 23

[0585]

[0586] first step

[0587] 1-Hydroxy-N,N-dimethylcyclopropane-1-carboxamide 23-1

[0588] Compound 23-0 (1 g, 9.80 mmol, Bid) was added to a mixed solvent of N, N-dimethylformamide and dichloromethane (21 mL, V / V = 1 / 20), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.82 g, 14.71 mmol), 1-hydroxybenzotriazole (1.46 g, 10.80 mmol), N-methylmorpholine (2.20 g, 21.75 mmol) and 1M dimethylamine (10 mL) were added. The reaction was stirred at 0°C for 1 hour. 20 mL of water was added to the reaction solution, and dichloromethane was extracted (40 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent B to obtain the title product 23-1 (770 mg), with a yield of 60%.

[0589] Step 2

[0590] 1-((Dimethylamino)methyl)cyclopropane-1-ol 23-2

[0591] Under argon atmosphere, compound 23-1 (0.25 g, 1.94 mmol) was added to 10 mL of tetrahydrofuran, and 1 M borane tetrahydrofuran solution (7.8 mL, Anaiji) was added at 0°C. The reaction solution was stirred at 0°C for 0.5 hours, then heated to 35°C and stirred for 1 hour. 20 mL of methanol was added at 0°C to quench, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 23-2 (0.2 g), which was directly used for the next step without purification.

[0592] 1 H NMR (400MHz, DMSO-d6) δ5.51 (s, 1H), 2.88 (s, 2H), 2.69 (s, 6H), 0.68-0.59 (m, 4H).

[0593] Step 3

[0594] (S)-2-(1-acryloyl-4-(2-(1-((dimethylamino)methyl)cyclopropyloxy)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 23

[0595] The synthetic route of Example 1 was used to replace the sixth step raw material compound 1c with compound 23-2, and the eighth step raw material compound 1-bromo-8-chloro-naphthalene with compound 1-bromo-8-methylnaphthalene to obtain the title product 23 (16 mg) with a yield of 20%.

[0596] MS m / z(ESI):566.3[M+1].

[0597] 1 H NMR (400MHz, DMSO-d6) δ7.77-7.68(m, 2H), 7.49-7.45(m, 1H), 7.39-7.26(m, 3H), 6.87-6.83(m, 1H), 6.21-6.17(m, 1H), 5.78(d, 1H), 4.9 7-4.77 (m, 1H), 4.08-3.87 (m, 4H), 3.85-3.56 (m, 3H), 3.20-2.98 (m, 6H), 2.87 (s, 3H), 2.72-2.67 (m, 3H), 2.20 (s, 6H), 0.88-0.76 (m, 4H).

[0598] Embodiment 24

[0599] (S)-2-(1-acryloyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 24

[0600]

[0601] first step

[0602] 1-(Pyrrolidine-1-carbonyl)cyclopropylcarbonitrile 24-1

[0603] Compound 1-cyano-1-cyclopropanecarboxylic acid 24-0 (2 g, 18 mmol, Bid) was dissolved in 20 mL of dichloromethane, pyrrolidine (1.28 g, 18 mmol, 1.5 mL, Anaiji), N, N-diisopropylethylamine (4.65 g, 36 mmol, 5.9 mL), benzotriazole-N, N, N', N'-tetramethyluronium hexafluorophosphate (8.19 g, 21.6 mmol, Adamas) were added, and stirred at room temperature for 17 hours. Water was added, and the aqueous phase was extracted with dichloromethane (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 24-1 (2.5 g), with a yield of 84.5%.

[0604] Step 2

[0605] (1-(Pyrrolidin-1-ylmethyl)cyclopropyl)methanamine 24-2

[0606] Compound 24-1 (2.5 g, 15.24 mmol) was dissolved in 20 mL of tetrahydrofuran, and lithium aluminum hydride (1 M, 18.2 mL) was added dropwise at 0°C, and the reaction was refluxed and stirred for 17 hours. The mixture was cooled to 0°C, and water was slowly added dropwise to quench the mixture, and then 1 mL of 20% sodium hydroxide solution was added dropwise, filtered, and the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound 24-2 (820 mg), which was directly used for the next step without purification.

[0607] Step 3

[0608] (S)-tert-butyl 4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate 24-3

[0609] Compound 1g (2g, 3.5mmol) was dissolved in 30mL tetrahydrofuran, compound 24-2 (811mg, 5.25mmol) and sodium tert-butoxide (337mg, 3.5mmol) were added, and the reaction was stirred at room temperature for 3 hours. Water was added, and the mixture was extracted with ethyl acetate (30mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 24-3 (600mg), with a yield of 26.5%.

[0610] Step 4

[0611] (S)-2-(1-acryloyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 24

[0612] The synthetic route of Example 1 was used, and the compound 24-3 was used to replace 1h in the seventh step, and 1-bromo-8-chloro-naphthalene in the eighth step was replaced by 1-bromo-3-fluoro-2-(trifluoromethyl)benzene to obtain the title product 24 (35 mg). Yield: 53.3%. MS m / z (ESI): 627.3 [M+1].

[0613] 1 H NMR (400MHz, CDCl3) δ7.39-7.49 (m, 1H), 7.03-7.10 (m, 1H), 6.87-6.97 (m, 1H), 6.50-6.66 (m, 1H), 6. 33-6.43 (m, 1H), 5.77-5.86 (m, 1H), 3.99-4.05 (m, 2H), 3.89-3.95 (m, 1H), 3.77-3.86 (m, 1H), 3.46-3. 52(m, 3H), 3.35-3.43(m, 2H), 3.11-3.28(m, 3H), 2.93-2.99(m, 1H), 2.83-2.90(m, 1H), 2.70-2.80(m , 2H), 2.59-2.68(m, 2H), 2.49-2.58(m, 3H), 2.37-2.48(m, 2H), 1.72-1.87(m, 4H), 1.54-1.71(m, 4H).

[0614] Embodiment 25

[0615] (S)-2-(1-acryloyl-4-(2-((1-(methylamino)cyclopropyl)methoxy)-7-(8-methylnaphth-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 25

[0616]

[0617]

[0618] first step

[0619] (S)-2-(Cyanomethyl)-4-(2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester 25-1

[0620] Compound 1f (6.5 g, 12.07 mmol) was dissolved in 5 mL of dichloromethane, 10 mL of trifluoroacetic acid was added dropwise, and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure to obtain the title product 25-1 (5.2 g), which was used directly in the next step without purification.

[0621] Step 2

[0622] (S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester 25-2

[0623] Under argon atmosphere, compound 25-1 (5.2 g, 11.86 mmol), 1-bromo-8-methylnaphthalene (2.62 g, 11.86 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2′, 6′-diisopropoxy-1,1′-biphenyl) (2-amino-1,1′-biphenyl-2-yl) (II) (992 mg, 1.19 mmol, Aibo Chemical), cesium carbonate (11.59 g, 35.57 mmol) were added to 10 mL of toluene, and the reaction was stirred at 90° C. for 16 hours. The crude product was concentrated under reduced pressure and purified by CombiFlash rapid preparation instrument with eluent A system to obtain the title product 25-2 (2.6 g), with a yield of 37%.

[0624] Step 3

[0625] (2S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester 25-3

[0626] At 0°C, compound 25-2 (2.6 g, 4.49 mmol) and m-chloroperbenzoic acid (866 mg, 5.03 mmol, Jinan Jiabin, 85%) were dissolved in 10 mL of dichloromethane, and the reaction solution was stirred at 0°C for 30 minutes to stop the reaction. The resulting mixture was concentrated at low temperature to obtain a crude product, which was purified by CombiFlash rapid preparation instrument with eluent B system to obtain the title product 25-3 (2.2 g), with a yield of 82%.

[0627] Step 4

[0628] (S)-4-(2-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methoxy)-7-(8-methylnaphth-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester 25-4

[0629] Under argon atmosphere, compound 25-3 (600 mg, 1.01 mmol), tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (283 mg, 1.51 mmol, Shaoyuan), sodium tert-butoxide (193 mg, 2.02 mmol, Titan) were dissolved in 8 mL of toluene and stirred at 0°C for 30 minutes. The resulting mixture was quenched with 20 mL of water, extracted with dichloromethane (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by CombiFlash rapid preparation instrument with eluent B system to obtain the title product 25-4 (500 mg), with a yield of 69%.

[0630] Step 5

[0631] (S)-4-(2-((1-((tert-butyloxycarbonyl)(methyl)amino)cyclopropyl)methoxy)-7-(8-methylnaphth-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester 25-5

[0632] Compound 25-4 (250 mg, 0.348 mmol) was dissolved in 10 mL of tetrahydrofuran, and sodium hydride (16.7 mg, 0.696 mmol, Titan) was added at 0°C, and stirred for 1 hour. Methyl iodide (98.86 mg, 0.696 mmol, Chinese medicine) was added, and the reaction was continued at room temperature for 2 hours. 20 mL of water was added, and dichloromethane (20 mL × 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by CombiFlash rapid preparation instrument with eluent B system to obtain the title product 25-5 (200 mg), with a yield of 78%.

[0633] Step 6

[0634] (S)-tert-butyl (1-(((4-(3-(cyanomethyl)piperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)(methyl)carbamate 25-6

[0635] Compound 25-5 (200 mg, 0.273 mmol) was dissolved in 5 mL of methanol, palladium carbon (40 mg, 5% purity, Quanzhong Chemical) was added, hydrogen was replaced three times, and stirred for 1 hour. The resulting mixture was filtered and concentrated to obtain the title product 25-6 (105 mg), which was used directly in the next step without purification.

[0636] Step 7

[0637] (S)-tert-butyl (1-(((4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)(methyl)carbamate 25-7

[0638] Compound 25-6 (105 mg, 0.175 mmol) was dissolved in 5 mL of dichloromethane, and acryloyl chloride (15.9 mg, 0.175 mmol, Bid) was added dropwise at 0°C, followed by triethylamine (53.3 mg, 0.526 mmol). The reaction was stirred at 0°C for 1 hour. The resulting mixture was quenched with aqueous sodium bicarbonate solution (20 mL), extracted with dichloromethane (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by CombiFlash rapid preparation instrument with eluent A system to obtain the title product 25-7 (90 mg), with a yield of 78%.

[0639] Step 8

[0640] (S)-2-(1-acryloyl-4-(2-((1-(methylamino)cyclopropyl)methoxy)-7-(8-methylnaphth-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 25

[0641] Compound 25-7 (90 mg, 0.138 mmol) was dissolved in 5 mL of dichloromethane, trifluoroacetic acid (5 mL) was added dropwise to the reaction solution, and the reaction was stirred at room temperature for 1 hour. The resulting mixture was quenched with sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The title product 25 (14 mg) was obtained by high-performance liquid preparative separation (formic acid), with a yield of 18%.

[0642] MS m / z(ESI):552.3[M+1].

[0643] 1 H NMR (400MHz, DMSO-d6) δ7.76-7.68(m, 2H), 7.48-7.26(m, 4H), 6.85-6.85(brs, 1H), 6.20-6.16(d, 1H), 5.79-5.76(d, 1H), 4.95-4.78(m, 1 H), 4.22-4.21(m, 2H), 4.03-3.65(m, 5H), 3.34-3.31(m, 3H), 3.18-2.92(m, 5H), 2.86(s, 3H), 2.72-2.54(m, 1H), 2.33(d, 3H), 0.62(m, 4H).

[0644] Embodiment 26

[0645] 2-((S)-1-acryloyl-4-(7-(2-chloro-4-fluorophenyl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 26

[0646]

[0647] The synthetic route of Example 1 was adopted, and the raw material in the eighth step, 1-bromo-8-chloro-naphthalene, was replaced by 1-bromo-2-chloro-4-fluorobenzene to obtain the title product 26 (3 mg) with a yield of 9.1%.

[0648] MS m / z(ESI):580.3[M+1].

[0649] 1 H NMR (400MHz, CDCl3) δ7.19-7.16 (m, 1H), 7.02-6.98 (m, 1H), 6.73 (brs, s, 1H), 6.20 (d, 1H), 5.75 (d, 1H), 4.49 (t, 2H), 40.14-3.94 (m, 3H), 3.62 (brs, s, 1H), 3.37-3.29 (m, 3H), 3.06 (s, 3H), 2.88-2.73 (m, 5H), 2.16- 2.10 (m, 1H), 1.94 (d, 2H), 1.84 (s, 3H), 1.70 (s, 1H), 1.24-0.81 (m, 6H).

[0650] Embodiment 27

[0651] (S)-2-(4-(7-(8-chloronaphth-1-yl)-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile 27

[0652]

[0653] Compound 27-1 (80 mg, 136 umol, prepared by the synthetic route of Example 11) was dissolved in 20 mL of dichloromethane, 2-fluoroacrylic acid (25 mg, 277 umol), benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (121 mg, 273 umol) were added, and N, N-diisopropylethylamine (53 mg, 410 umol) was added dropwise, and stirred for 3 hours. Water was added, extracted with dichloromethane (10 mL×3), washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography with developing solvent system A to obtain the title product 27 (8 mg), with a yield of 8.9%.

[0654] MS m / z(ESI):658.1[M+1].

[0655] 1 H NMR (400MHz, CDCl3) δ7.73-7.75(m, 1H), 7.55-7.68(m, 1H), 7.50-7.55(m, 1H), 7.38-7.48(m, 1H), 7.30-7.38(m, 1H), 7.15-7. 25(m, 1H), 5.31-5.51(m, 1H), 5.15-5.30(m, 1H), 4.35-4.48(m, 1H), 4.16-4.31(m, 2H), 4.08-4.18(m, 1H), 3.97-4.08(m, 1H), 3.72-3.95(m, 2H), 3.52-3.63(m, 1H), 3.35-3.48(m, 1H), 2.96-3.30(m, 4H), 2.73-2.95(m, 2H), 2.26-2.70(m, 5H), 2.12-2.25 (m, 1H), 1.95-2.08 (m, 1H), 1.70-1.93 (m, 3H), 1.50-1.70 (m, 3H), 1.38-1.48 (m, 1H), 0.60-1.80 (m, 2H), 0.25-0.6-58 (m, 2H).

[0656] Embodiment 28

[0657] (S)-2-(1-acryloyl-4-(2-((1-(dimethylamino)cyclopropyl)methoxy)-7-(8-methylnaphth-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 28

[0658]

[0659] first step

[0660] (1-Aminocyclopropyl)methanol hydrochloride 28-1

[0661] Compound 1-(tert-butyloxycarbonylamino)cyclopropylmethanol 28-0 (1.0 g, 5.31 mmol, Shaoyuan) was dissolved in 10 mL 1,4-dioxane, 4 M hydrogen chloride 1,4-dioxane solution (4 mL, Chemart) was added, and stirred for 1 hour. The resulting mixture was concentrated to obtain the title product crude 28-1 (465 mg), which was used directly in the next step without purification.

[0662] Step 2

[0663] (1-(Dimethylamino)cyclopropyl)methanol 28-2

[0664] Compound 28-1 (232 mg, 2.66 mmol) was dissolved in 20 mL of 1,2-dichloroethane, and aqueous formaldehyde solution (1.2 g, 30%, Sinopharm) and sodium triacetoxyborohydride (3.4 g, 16.04 mmol, Shaoyuan) were added and stirred for 16 hours. The resulting mixture was quenched with 50 mL of water, extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The title product 28-2 (100 mg) was purified by CombiFlash rapid preparation instrument with eluent A system, with a yield of 33%.

[0665] 1 H NMR (400MHz, DMSO-d6) δ4.33 (t, 1H), 3.47 (d, 2H), 2.34 (s, 6H), 0.49-0.46 (m, 2H), 0.41-0.38 (m, 2H).

[0666] Step 3

[0667] (S)-2-(1-acryloyl-4-(2-((1-(dimethylamino)cyclopropyl)methoxy)-7-(8-methylnaphth-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 28

[0668] The synthetic route of Example 1 was used to replace the sixth step raw material compound 1c with compound 28-2, and the eighth step raw material compound 1-bromo-8-chloronaphthalene with compound 1-bromo-8-methylnaphthalene to obtain the title product 28 (32 mg) in a yield of 33%.

[0669] MS m / z(ESI):566.2[M+1].

[0670] 1 H NMR (400MHz, DMSO-d6) δ7.77-7.68(m, 2H), 7.49-7.26(m, 4H), 6.87-6.83( m, 1H), 6.19 (d, 1H), 5.78 (d, 1H), 5.01-4.72 (m, 1H), 4.28 (d, 2H), 4.06-3.9 4(m, 3H), 3.77-3.66(m, 1H), 3.42-3.39(m, 2H), 3.29-3.24(m, 1H), 3.21-2. 86 (m, 5H), 2.82 (s, 3H), 2.74-2.56 (m, 2H), 2.35 (s, 6H), 0.64-0.56 (m, 4H).

[0671] Embodiment 29

[0672] 2-((S)-4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)-piperazin-2-yl)-acetonitrile 29

[0673]

[0674] The synthetic route of Example 18 was adopted, and the raw material compound 18-1 was replaced by compound 2-((S)-4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (prepared using the synthetic route of Example 12) to obtain the title product 29 (10 mg) with a yield of 8.9%.

[0675] MS m / z(ESI):660.1[M+1].

[0676] 1H NMR (400MHz, DMSO-d6) δ7.85 (t, 1H), 7.72 (t, 1H), 7.46-7.34 (m, 3H), 5.42-5.09 (m, 3H), 4.15-4.05 (m 6H), 3.74(t, 2H), 3.30(s, 3H), 3.21(d, 2H), 3.09.(d, 4H), 2.95-2.91( m, 2H), 2.80 (s, 6H), 2.46-2.33 (m, 3H), 2.29-1.80 (m, 3H), 0.48 (d, 4H).

[0677] Embodiment 30

[0678] 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile 30

[0679]

[0680] Compound 30-1 (50 mg, 84 umol, prepared by the synthetic route of Example 13) was dissolved in 20 mL of dichloromethane, 2-fluoroacrylic acid (16 mg, 177 umol), benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (75 mg, 169 umol) were added, and N, N-diisopropylethylamine (33 mg, 255 umol) was added dropwise, and stirred for 3 hours. Water was added, extracted with dichloromethane (10 mL×3), washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography with developing solvent system A to obtain the title product 30 (10 mg), with a yield of 17.5%.

[0681] MS m / z(ESI):662.2[M+1].

[0682] 1H NMR (400MHz, CDCl3) δ7.74-7.76 (m, 1H), 7.60-7.68 (m, 1H), 7.49-7.55 (m, 1H), 7.38-7 .48(m, 1H), 7.30-7.38(m, 1H), 7.16-7.26(m, 1H), 5.32-5.50(m, 1H), 5.18-5.28(m, 1H) , 3.75-4.50(m, 8H), 3.51-3.64(m, 1H), 2.95-3.50(m, 7H), 2.75-2.95(m, 3H), 2.25-2. 70(m, 4H), 1.85-2.20(m, 1H), 1.25-1.40(m, 2H), 0.71-1.03(m, 2H), 0.35-0.70(m, 2H).

[0683] Embodiment 31

[0684] (S)-2-(1-(2-fluoroacryloyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 31

[0685]

[0686] The synthetic route of Example 18 was used to replace the raw material compound 18-1 with compound (S)-2-(4-(7-(8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (prepared using the synthetic route of Example 15) to obtain the title product 31 (20 mg) with a yield of 25.3%.

[0687] MS m / z(ESI):624.2[M+1].

[0688] 1 H NMR (400MHz, CDCl3) δ7.69-7.62(m, 2H), 7.39-7.19(m, 4H), 5.34-5.14(m, 2H), 4.36-4.95(m, 1H), 4.00-3.81(m, 6H), 3.63(t , 2H), 3.15(d, 2H), 3.02(m, 4H), 2.87(m, 1H), 2.79(s, 3H), 2.65(d, 1H), 2.38(d, 6H), 1.58(s, 4H), 0.47(s, 2H), 0.33(s, 2H).

[0689] Embodiment 32

[0690] 2-((S)-1-acryloyl-4-(7-(8-fluoronaphthalen-1-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 32

[0691]

[0692] The synthetic route of Example 1 was adopted, and the raw material compound 1-bromo-8-chloro-naphthalene in the eighth step was replaced by the compound 1-bromo-8-fluoronaphthalene (prepared by the known method "Tetrahedron Letters, 2007, vol.48, #31, p.5539-5541") to obtain the title product 32 (5 mg) in a yield of 9.1%.

[0693] MS m / z(ESI):596.1[M+1].

[0694] 1 H NMR (400MHz, CDCl3) δ7.57-7.59(m, 1H), 7.50-7.57(m, 1H), 7.28-7.43(m, 2H), 7.02-7.13(m, 2H), 6.45-6 .57(m, 1H), 6.28-6.40(m, 1H), 5.72-82(m, 1H), 4.12-4.35(m, 2H), 4.00-4.11(m, 2H), 3.76-3.98(m, 2H), 3.50-3.75(m, 2H), 3.23-3.40(m, 1H), 3.08-3.20(m, 1H), 3.00-3.07(m, 1H), 2.90-3.00(m, 3H), 2.65-2.8 8(m, 3H), 2.40-2.63(m, 1H), 2.06-2.36(m, 2H), 1.75-2.05(m, 2H), 1.32-1.45(m, 3H), 0.85-1.10(m, 4H).

[0695] Embodiment 33

[0696] 2-((S)-1-acryloyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 33

[0697]

[0698] The synthetic route of Example 1 was adopted, and the raw material compound 1-bromo-8-chloro-naphthalene in the eighth step was replaced by the compound 1-bromo-3-chloro-2-(trifluoromethyl)benzene (adamas) to obtain the title product 33 (8 mg) with a yield of 9.5%.

[0699] MS m / z(ESI):630.2[M+1].

[0700] 1 H NMR (400MHz, CDCl3) δ7.43-7.48 (m, 1H), 7.30-7.33 (m, 1H), 7.24-7.26 (m, 1H), 6.55-6.68 (m, 1H), 6.38-6 .48(m, 1H), 5.81-5.92(m, 1H), 4.97-5.20(m, 1H), 4.15-4.26(m, 1H), 4.06-4.14(m, 2H), 3.91-4.05(m, 2H) , 3.52-3.77(m, 2H), 3.26-3.42(m, 2H), 3.08-3.21(m, 2H), 2.83-3.03(m, 4H), 2.60-2.80(m, 3H), 2.19-2. 30 (m, 1H), 2.08-2.18 (m, 1H), 1.95-2.06 (m, 2H), 1.76-1.88 (m, 2H), 0.96-1.15 (m, 2H), 0.76-0.91 (m, 2H).

[0701] Embodiment 34

[0702] 2-((S)-1-acryloyl-4-(7-(2,3-dimethylphenyl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 34

[0703]

[0704] The synthetic route of Example 1 was adopted, and the raw material compound 1-bromo-8-chloro-naphthalene in the eighth step was replaced by the compound 1-bromo-2,3-dimethylbenzene (adamas) to obtain the title product 34 (8 mg) with a yield of 16.0%.

[0705] MS m / z(ESI):556.2[M+1].

[0706] 1H NMR (400MHz, CDCl3) δ7.08-7.16 (m, 1H), 6.90-7.02 (m, 2H), 6.51-6.66 (m, 1H), 6.33-6.44 (m, 1H), 5.76-5.8 7(m, 1H), 4.86-5.22(m, 1H), 4.32-4.48(m, 1H), 4.18-4.28(m, 1H), 4.06-4.14(m, 1H), 3.97-4.05(m, 3H), 3. 86-3.96(m, 1H), 3.28-3.38(m, 1H), 3.18-3.27(m, 1H), 2.87-3.16(m, 7H), 2.64-2.85(m, 3H), 2.34(s, 3H), 2 .30(s, 3H), 2.17-2.25(m, 2H), 1.98-2.08(m, 2H), 1.58-1.66(m, 1H), 1.11-1.20(m, 2H), 0.93-1.08(m, 2H).

[0707] Embodiment 35

[0708] 2-((S)-1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-(1-((R)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 35

[0709]

[0710] first step

[0711] (R)-2-(1-Hydroxycyclopropyl)pyrrolidine-1-carboxylic acid tert-butyl ester 35-1

[0712] Under argon atmosphere, compound N-tert-butyloxycarbonyl-D-proline methyl ester 35-0 (10 g, 43.61 mmol, Bid) was dissolved in 300 mL of tetrahydrofuran, tetraisopropyl titanate (14.87 g, 52.31 mmol, 15.5 mL) was added, and then ethyl magnesium bromide (2M, 65.4 mL) was slowly added dropwise, and the reaction was carried out at room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to quench, and the mixture was filtered through diatomaceous earth. The filtrate was separated, and the aqueous phase was extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 35-1 (7.8 g) with a yield of 78.6%.

[0713] Step 2

[0714] (R)-1-(1-methylpyrrolidin-2-yl)cyclopropyl alcohol 35-2

[0715] Compound 35-1 (7.8 g, 34.31 mmol) was dissolved in 200 mL of tetrahydrofuran, and lithium aluminum hydride (1 M, 102.8 mL) was added dropwise, and the reaction solution was refluxed and stirred for 17 hours. The mixture was cooled to 0°C, 50 mL of water was slowly added, and the mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 35-2 (4.5 g), which was directly used for the next step without purification.

[0716] Step 3

[0717] 2-((S)-1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-(1-((R)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 35

[0718] The synthetic route of Example 1 was used to replace the sixth step raw material compound 1c with compound 35-2, and the eighth step raw material compound 1-bromo-8-chloronaphthalene with compound 1-bromo-8-methylnaphthalene to obtain the title product 35 (8 mg) in a yield of 14.5%.

[0719] MS m / z(ESI):592.4[M+1].

[0720] 1 H NMR (400MHz, CDCl3) δ7.59-7.75(m, 2H), 7.31-7.55(m, 3H), 7.16-7.23(m, 1H), 6.50-6.67( m, 1H), 6.33-6.45 (m, 1H), 5.76-5.87 (m, 1H), 4.91-5.17 (m, 1H), 4.45-4.72 (m, 1H), 4.02-4. 32(m, 4H), 3.83-3.95(m, 1H), 3.68-3.81(m, 1H), 3.47-3.59(m, 2H), 3.29-3.43(m, 2H), 3.0 8-3.28(m, 4H), 2.86-3.05(m, 6H), 2.70-2.85(m, 4H), 2.50-2.68(m, 2H), 0.92-1.18(m, 4H).

[0721] Embodiment 36

[0722] (S)-2-(1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-(((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 36

[0723]

[0724] Using the synthetic route of Example 1, replacing 1h in the seventh step with compound 24-3, and replacing 1-bromo-8-chloro-naphthalene in the eighth step with 1-bromo-8-methyl-naphthalene, the title product 36 (8 mg) was prepared in a yield of 11.2%.

[0725] MS m / z(ESI):605.3[M+1].

[0726] 1 H NMR (400MHz, CDCl3) δ7.58-7.65 (m, 1H), 7.52-7.55 (m, 1H), 7.23-7.35 (m, 3H), 7.11-7.13 (m, 1H), 6.45-6 .61(m, 1H), 6.26-6.36(m, 1H), 5.68-5.76(m, 1H), 3.98-4.02(m, 1H), 3.77-3.95(m, 2H), 3.62-3.75(m, 1H) , 3.51-3.62(m, 1H), 3.37-3.47(m, 1H), 3.27-3.35(m, 2H), 3.14-3.26(m, 1H), 2.91-3.13(m, 4H), 2.83-2. 88 (m, 4H), 2.71-2.79 (m, 1H), 2.38-2.56 (m, 4H), 1.88-2.00 (m, 1H), 1.70-1.85 (m, 4H), 1.46-1.69 (m, 8H).

[0727] Embodiment 37

[0728] 2-((S)-1-acryloyl-4-(7-(4-fluoro-2-(trifluoromethyl)phenyl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 37

[0729]

[0730] The synthetic route of Example 1 was adopted, and the raw material compound 1-bromo-8-chloro-naphthalene in the eighth step was replaced by the compound 1-bromo-4-fluoro-2-(trifluoromethyl)benzene (Shaoyuan) to obtain the title product 37 (10 mg) with a yield of 15.2%.

[0731] MS m / z(ESI):614.1[M+1].

[0732] 1H NMR (400MHz, CDCl3) δ7.36-7.50 (m, 1H), 7.28-7.35 (m, 1H), 7.02-7.19 (m, 1H), 6.51-6.67 (m, 1H), 6.35-6 .47(m, 1H), 5.81-5.91(m, 1H), 5.02-5.16(m, 1H), 4.13-4.25(m, 1H), 3.85-4.10(m, 4H), 3.52-3.73(m, 2H) , 3.26-3.41(m, 1H), 3.14-3.24(m, 1H), 3.03-3.13(m, 2H), 2.84-3.02(m, 4H), 2.62-2.83(m, 3H), 2.19-2. 27 (m, 1H), 2.08-2.18 (m, 1H), 1.95-2.06 (m, 2H), 1.72-1.90 (m, 2H), 0.96-1.15 (m, 2H), 0.77-0.95 (m, 2H).

[0733] Embodiment 38

[0734] 2-((S)-1-acryloyl-4-(7-(benzo[b]thiophen-4-yl)-2-(1-((S)-1-methylpyrrolidin-2-yl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 38

[0735]

[0736] The synthetic route of Example 1 was adopted, and the raw material compound 1-bromo-8-chloro-naphthalene in the eighth step was replaced by the compound 4-bromo-benzo[b]thiophene (Bidder) to obtain the title product 38 (5 mg) with a yield of 15.1%.

[0737] MS m / z(ESI):584.2[M+1].

[0738] 1H NMR (400MHz, CDCl3) δ7.58-7.65(m, 1H), 7.42-7.47(m, 2H), 7.28-7.34(m, 2H), 6.91-7.01(m, 1H ), 6.51-6.67(m, 1H), 6.34-6.46(m, 1H), 5.78-5.88(m, 1H), 4.19-4.37(m, 3H), 3.94-4.08(m, 3H) , 3.59-3.69(m, 1H), 3.26-3.39(m, 2H), 3.08-3.18(m, 2H), 2.99-3.06(m, 4H), 2.87-2.98(m, 2H) , 2.65-2.84(m, 3H), 2.12-2.31(m, 2H), 1.86-2.11(m, 2H), 1.42-1.49(m, 2H), 0.96-1.09(m, 2H).

[0739] Embodiment 39

[0740] (S)-2-(1-acryloyl-4-(2-((1-((3,3-difluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-7-(8-methylnaphth-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 39

[0741]

[0742]

[0743] first step

[0744] 1-(3,3-difluoropyrrolidine-1-carbonyl)cyclopropane-1-carboxylic acid methyl ester 39-1

[0745] Compound 1,1-cyclopropyldicarboxylic acid monomethyl ester 39-0 (700 mg, 4.86 mmol, Dingdang Chemical), 3,3-difluoropyrrolidine (697 mg, 4.86 mmol, Bid), 1-hydroxybenzotriazole (787 mg, 5.83 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride triethylamine (1.12 g, 5.83 mmol), N,N-diisopropylethylamine (1.88 g, 14.57 mmol) were dissolved in 15 mL of dichloromethane at 0°C and stirred for 16 hours. 20 mL of water was added, and dichloromethane (20 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by CombiFlash rapid preparation instrument with eluent B system to obtain the title product 39-1 (800 mg) with a yield of 70%.

[0746] Step 2

[0747] (1-((3,3-difluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol 39-2

[0748] Compound 39-1 (600 mg, 2.57 mmol) was dissolved in 10 mL of tetrahydrofuran, 1 M lithium aluminum hydride (7.7 mL, 7.7 mmol) was added, and the reaction was stirred at 0°C for 1 hour. The resulting mixture was quenched with ethyl acetate, and then sodium sulfate decahydrate (8 g) was added and stirred for 30 minutes, filtered and concentrated to obtain a crude product. The title product 39-2 (220 mg) was purified by CombiFlash rapid preparation instrument with eluent B system, and the yield was 44%.

[0749] Step 3

[0750] (S)-2-(1-acryloyl-4-(2-((1-((3,3-difluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-7-(8-methylnaphth-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 39

[0751] The synthetic route of Example 1 was used to replace the sixth step raw material compound 1c with compound 39-2, and the eighth step raw material compound 1-bromo-8-chloronaphthalene with compound 1-bromo-8-methylnaphthalene to obtain the title product 39 (55 mg) in a yield of 28%.

[0752] MS m / z(ESI):642.5[M+1].

[0753] 1 H NMR (400MHz, DMSO-d6) δ7.76-7.74(m, 1H), 7.70-7.67(m, 1H), 7.46-7.44(m, 1H), 7.38-7. 25(m, 3H), 6.82-6.82(brs, 1H), 6.20-6.16(d, 1H), 5.79-5.76(d, 1H), 4.96-4.78(m, 1H), 4.09-3.93(m, 5H), 3.70-3.65(m, 2H), 3.42-3.38(m, 2H), 3.24-3.04(m, 5H), 2.90-2.84(m , 6H), 2.68-2.68(m, 3H), 2.40-2.40(s, 2H), 2.22-2.15(m, 2H), 0.55(s, 2H), 0.40(s, 2H).

[0754] Embodiment 40

[0755] (S)-2-(1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-(1-(pyrrolidin-1-ylmethyl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 40

[0756]

[0757] first step

[0758] (1-Hydroxycyclopropyl)(pyrrolidin-1-yl)methanone 40-1

[0759] Compound 1-hydroxycyclopropanecarboxylic acid 40-0 (1.0 g, 9.80 mmol, Bidex Pharmaceuticals), pyrrolidine (1.04 g, 14.69 mmol, Titan), O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.72 g, 9.80 mmol) and triethylamine (2.97 g, 29.39 mmol) were dissolved in 10 mL N,N-dimethylformamide and stirred for 16 hours. 20 mL of water was added, and the mixture was extracted with dichloromethane (20 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The title product 40-1 (600 mg) was purified by CombiFlash rapid preparation instrument with eluent A system, and the yield was 39%.

[0760] Step 2

[0761] 1-(Pyrrolidin-1-ylmethyl)cyclopropane-1-ol 40-2

[0762] Compound 40-1 (400 mg, 2.58 mmol) was dissolved in 10 mL of tetrahydrofuran, and borane tetrahydrofuran solution (1.11 g, 12.89 mmol, Titanium) was added, stirred at 0°C for 1 hour, heated to 40°C, and reacted for 4 hours. Methanol was added to quench, and the title product 40-2 (200 mg) was obtained by concentration, which was used directly in the next step without purification.

[0763] Step 3

[0764] (S)-2-(1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-(1-(pyrrolidin-1-ylmethyl)cyclopropyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 40

[0765] The synthetic route of Example 1 was used to replace the sixth step raw material compound 1c with compound 40-2, and the eighth step raw material compound 1-bromo-8-chloronaphthalene with compound 1-bromo-8-methylnaphthalene to obtain the title product 40 (4 mg) in a yield of 5.7%.

[0766] MS m / z(ESI):592.3[M+1].

[0767] 1 H NMR (400MHz, DMSO-d6) δ7.76-7.68(m, 2H), 7.48-7.26(m, 4H), 6.89-6.83(brs, 1 H), 6.21-6.16(d, 1H), 5.79-5.76(d, 1H), 4.96-4.77(m, 1H), 4.41(m, 1H), 4.01- 3.91(m, 4H), 3.71-3.42(m, 5H), 3.13-3.08(m, 2H), 3.04-2.90(m, 5H), 2.86-2.8 0 (m, 2H), 2.78-2.75 (m, 3H), 2.72-2.62 (m, 1H), 1.64 (s, 4H), 0.86-0.76 (m, 4H).

[0768] Embodiment 41

[0769] (S)-2-(1-acryloyl-4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 41

[0770]

[0771] The synthetic route of Example 8 was adopted, and the raw material pyrrolidine in the first step was replaced by piperidine to obtain the title product 41 (6 mg) with a yield of 10.9%.

[0772] MS m / z(ESI):638.2[M+1].

[0773] 1 H NMR (400MHz, CD3OD) δ7.76-7.65 (m, 2H), 7.43-7.24 (m, 3H), 6.85-6.79 (m, 1H), 6.31 (d, 1H), 5.85 (d, 1H), 5.08 (t, 1H), 4.63 (d, 2H), 4 .36-4.07(m, 5H), 3.78-3.50(m, 4H), 3.25-3.10(m, 4H), 2.98-2.67(m, 5H), 2.48-2.37(m, 5H), 1.62-1.30(m, 6H), 0.67-0.48(m, 4H).

[0774] Embodiment 42

[0775] (S)-2-(1-acryloyl-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(7-fluoro-8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 42

[0776]

[0777] The synthetic route of Example 8 was adopted, and the first step raw material pyrrolidine was replaced by dimethylamine (2M tetrahydrofuran solution, Alfa) to obtain the title product 42 (18 mg) with a yield of 23.4%.

[0778] MS m / z(ESI):598.1[M+1].

[0779] 1H NMR (400MHz, CDCl3) δ7.70-7.60 (m, 1H), 7.40-7.34 (m, 1H), 7.25-7.20 (m, 3H), 6.60 (s, 1H), 6.42 (d, 1H), 5.84 (d, 1H), 5.10 (s, 1H) , 4.31-3.77(m, 8H), 3.54(t, 2H), 3.23-2.98(m, 4H), 2.86(s, 4H), 2.64(t, 1H), 2.29(s, 6H), 1.34-1.27(m, 2H), 0.67-0.47(m, 4H).

[0780] Embodiment 43

[0781] (S)-2-(1-acryloyl-4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 43

[0782]

[0783] first step

[0784] 1-(Morpholine-4-carbonyl)cyclopropanecarboxylic acid methyl ester 43a

[0785] Compound 8a (3 g, 20.81 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was dissolved in 80 mL of dichloromethane, and oxalyl chloride (10.5 g, 83.26 mmol) and 3 drops of DMF were added dropwise under an ice-water bath, stirred for 10 minutes, and the temperature was raised to 35°C to continue the reaction for 3 hours. The mixture was concentrated under reduced pressure, 60 mL of anhydrous dichloromethane was added, cooled to 0°C, triethylamine (10 g, 104 mmol) and morpholine (2.18 g, 25.02 mmol) were added, and the reaction was continued for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 43a (2 g) with a yield of 45.06%.

[0786] MS m / z(ESI):214.1[M+1].

[0787] Step 2

[0788] (1-(Morpholinomethyl)cyclopropyl)methanol 43b

[0789] Compound 43a (1.0 g, 4.69 mmol) was dissolved in 20 mL of tetrahydrofuran, cooled to -78°C, 9.38 mL of lithium aluminum hydroxide (1 M) was added, and then stirred at room temperature for 2 hours. The reaction solution was cooled to -60°C, 30 mL of ethyl acetate was slowly added, and then 10 mL of water and 20 mL of 2M sodium hydroxide solution were added, stirred at room temperature for 1 hour, filtered, the filter cake was washed with dichloromethane (100 mL×3), the filtrate was concentrated under reduced pressure, the aqueous phase was extracted with dichloromethane (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title product 43b (760 mg), yield: 94.6%.

[0790] MS m / z(ESI):172.1[M+1].

[0791] Step 3

[0792] (S)-Benzyl 2-(cyanomethyl)-4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid 43c

[0793] Compound 8g (0.3 g, 0.49 mmol) and compound 43b (0.13 g, 0.74 mmol) were dissolved in 10 mL of tetrahydrofuran, cooled to 0°C, and lithium bis(trimethylsilyl)amide (1 M, 1.47 mL, Adamas) was added dropwise, and stirred for 35 minutes. 20 mL of saturated sodium chloride solution was added, and the liquids were separated. The aqueous phase was extracted with ethyl acetate (100 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 43c (0.11 g) with a yield of 31.2%.

[0794] MS m / z(ESI):720.2[M+1].

[0795] Step 4

[0796] (S)-2-(4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 43d

[0797] Compound 43c (110 mg, 152.81 umol) was added to 10 mL of methanol, palladium carbon (100 mg, 5% purity) was added, hydrogen was replaced three times, and stirred for 16 hours. The filtrate was filtered and concentrated under reduced pressure to obtain the title product 43d (70 mg), with a yield of 78.2%.

[0798] MS m / z(ESI):586.1[M+1].

[0799] Step 5

[0800] (S)-2-(1-acryloyl-4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 43

[0801] Compound 43d (70 mg, 119.51 umol) was dissolved in 10 mL of dichloromethane, triethylamine (36 mg, 358.53 umol) was added, and acryloyl chloride (12 mg, 131.46 umol) was added dropwise, and stirred at room temperature for 1 hour. Water was added, and the mixture was extracted with dichloromethane (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography using a developing solvent system A to obtain the title product 43 (11.2 mg), with a yield of 14.6%.

[0802] MS m / z(ESI):640.1[M+1].

[0803] 1 H NMR (400MHz, CD3OD) δ7.77-7.65 (m, 1H), 7.23-7.64 (m, 3H), 6.82 (s, 1H), 6.31 (d, 1H), 5.85 (d, 1H), 5.08 (s, 1H), 4.60 (s, 1H), 4 .34-4.10(m, 6H), 3.76-3.52(m, 7H), 3.25-3.10(m, 4H), 2.93-2.67(m, 5H), 2.49-2.38(m, 6H), 1.31(t, 1H), 0.67-0.47(m, 4H).

[0804] Embodiment 44

[0805] (S)-2-(1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 44

[0806]

[0807] first step

[0808] 5-Chloro-6-fluoro-1,4-dihydro-1,4-epoxynaphthalene 44-1

[0809] Under argon atmosphere, compound 1-bromo-3-chloro-2,4-difluorobenzene 44-0 (10.0 g, 43.97 mol, Shaoyuan) and furan (3.59 g, 52.76 mol, Shaoyuan) were dissolved in dry 100 mL toluene, the reaction solution was cooled to -15 ° C, n-butyl lithium (1.6 M n-hexane solution, 2.82 g, 43.97 mmol, Hualun Chemical) was added dropwise, and stirred at room temperature for 3 hours. Water (20 mL) was added to the reaction solution, and ethyl acetate (100 mL × 3) was used for extraction. The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 44-1 (8.4 g), which was directly used for the next step without purification.

[0810] Step 2

[0811] 8-Chloro-7-fluoronaphthalene-1-ol 44-2

[0812] Compound 44-1 (8.4 g, 42.85 mmol) was dissolved in 40 mL of anhydrous ethanol at room temperature, and 16 mL of concentrated hydrochloric acid was added. The reaction solution was heated to 78°C and stirred for 2 hours. The mixture was cooled and concentrated under reduced pressure. 20 mL of water was added to the residue, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title compound 44-2 (3.2 g) with a yield of 38%.

[0813] Step 3

[0814] 8-Chloro-7-fluoronaphthalen-1-yl trifluoromethanesulfonate 44-3

[0815] Under argon atmosphere, compound 44-2 (3.2 g, 16.32 mmol) and N,N-diisopropylethylamine (10.5 g, 81.6 mmol) were dissolved in 200 mL of dichloromethane, cooled to -78 ° C, trifluoromethanesulfonic anhydride (5.5 g, 19.59 mmol) was added, and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 44-3 (3.4 g) with a yield of 63%.

[0816] Step 4

[0817] (S)-2-(1-acryloyl-4-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 44

[0818] The synthetic route of Example 1 was used to replace the sixth step raw material compound 1c with compound 10-3, and the eighth step raw material compound 1-bromo-8-chloro-naphthalene with compound 44-3 to obtain the title compound 44 (95 mg) with a yield of 54.4%.

[0819] MS m / z(ESI):644.1[M+1].

[0820] 1H NMR (400MHz, CD3OD-d4) δ7.77-7.81 (m, 1H), 7.60-7.62 (m, 1H), 7.38-7.40 (m, 1H), 7.28-7.3 3(m, 2H), 6.61-6.76(m, 1H), 6.17-6.21(m, 1H), 5.72-5.75(m, 1H), 4.90-4.98(m, 1H), 4.81- 4.89(m, 1H), 3.98-4.20(m, 5H), 3.51-3.66(m, 1H), 3.39-3.49(m, 2H), 3.25-3.34(m, 2H), 3. 11-3.13 (m, 3H), 2.60-3.03 (m, 7H), 2.56-2.66 (m, 1H), 1.80-1.89 (m, 4H), 0.60-0.70 (m, 4H).

[0821] Embodiment 45

[0822] 2-((S)-1-Acryloyl-4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(((S)-2-methylpyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 45

[0823]

[0824] The synthetic route of Example 1 was adopted, and the raw material compound 1c in the sixth step was replaced by the compound (S)-(1-((2-methylpyrrolidin-1-yl)methyl)cyclopropyl)methanol (prepared by adopting the synthetic route of Example 11, and replacing the raw material compound pyrrolidine in the first step with S-2-methylpyrrolidine), and the raw material compound 1-bromo-8-chloro-naphthalene in the eighth step was replaced by the compound 7-fluoro-8-methylnaphthalene-1-yltrifluoromethanesulfonic acid to obtain the title compound 45 (4 mg) with a yield of 5.0%.

[0825] MS m / z(ESI):638.1[M+1].

[0826] 1H NMR (400MHz, DMSO-d6) δ7.84-7.82 (m, 1H), 7.73-7.70 (m, 1H), 7.42-7.36 (m, 3H), 6.8-6.83 (brs, 1H), 6.20-6.16 (d, 1H), 5.79-5.76(m, 1H), 4.95-4.78(m, 1H), 4.4-4.42(m, 1H), 4.06-3.97(m, 4H), 3.74-3.72(m, 2H), 3.42-3.40(m, 2H), 3.23-3 .12(m, 2H), 3.10-3.03(m, 6H), 2.80-2.78(m, 3H), 2.75-2.67(m, 1H), 2.23-2.21(m, 1H), 2.02-1.99(m, 1H), 1.81-1.80(m , 1H), 1.60-1.58(m, 2H), 1.50-1.47(m, 1H), 1.21-1.20(m, 1H), 0.93-0.91(m, 3H), 0.51-0.49(m, 3H), 0.44-0.44(m, 1H).

[0827] Embodiment 46

[0828] (S,E)-2-(4-(7-(8-chloronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(4-(dimethylamino)but-2-enoyl)piperazin-2-yl)acetonitrile 46

[0829]

[0830] (E)-4-(Dimethylamino)but-2-enoic acid (44 mg, 0.263 mmol, Bid) was dissolved in 2.0 mL N, N-dimethylformamide, and O-(7-azabenzotriazole-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (66 mg, 0.173 mmol, Bid) and N, N-diisopropylethylamine (74 mg, 0.577 mmol, Danyu Biotechnology) were added under ice-water bath. The reaction solution was stirred for 15 minutes under argon protection, and then compound 22-1 (33 mg, 0.058 mmol, prepared using Example 10) was added to the reaction solution and stirred at room temperature for 1 hour. LC-MS detected that the reaction was complete. The reaction solution was poured into ice water and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL×5), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title product 46 (4.44 mg). Yield: 11%.

[0831] MS m / z(ESI):683.6[M+1].

[0832] 1 H NMR (400MHz, DMSO-d6) δ7.92 (d, 1H), 7.80-7.69 (m, 1H), 7.56 (dd, 2H), 7.45 (t, 1H), 7.39-7.28 (m, 1H), 6.68 (s, 2H), 4.84 (m, 1H), 4.40 (s, 1H), 4.2 5-3.93(m, 6H), 3.71(d, 2H), 3.46(m, 6H), 3.08(m, 5H), 2.37(s, 2H), 2.16 (s, 5H), 1.99 (s, 1H), 1.66 (s, 4H), 1.19 (m, 2H), 0.55 (s, 2H), 0.40 (s, 2H).

[0833] Embodiment 47

[0834] (S)-2-(4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile 47

[0835]

[0836] The synthetic route of Example 30 was adopted, and the raw material compound 30-1 was replaced by 43d to prepare the title compound 47 (18 mg) with a yield of 40%.

[0837] MS m / z(ESI):658.5[M+1].

[0838] 1 H NMR (400MHz, CDCl3) δ7.70-7.64 (m, 1H), 7.62-7.58 (m, 1H), 7.40-7.31 (m, 1H), 7.25-7.1 7(m, 2H), 5.35-5.48(d, 1H), 5.23-5.27(d, 1H), 5.10-4.43(d, 2H), 4.29-4.22(m, 3H), 4. 20-3.89(m, 2H), 3.89-3.75(m, 2H), 3.66(s, 3H), 3.60-3.35(m, 2H), 3.32-2.94(m, 5H), 2 .84-2.83(m, 5H), 2.68-2.56(m, 1H), 2.43(d, 4H), 2.0(s, 1H), 0.63(s, 2H), 0.43(s, 2H).

[0839] Embodiment 48

[0840] (S,E)-2-(1-(4-(dimethylamino)but-2-enoyl)-4-(7-(7-fluoro-8-methylnaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 48

[0841]

[0842] The synthetic route of Example 46 was adopted to replace the raw material compound 22-1 with 8i to prepare the title compound 48 (39 mg) with a yield of 27%.

[0843] MS m / z(ESI):681.3[M+1].

[0844] 1 H NMR (400MHz, DMSO-d6) δ7.89-7.79 (m, 1H), 7.73 (d, 1H), 7.49-7.41 (m, 1H), 7.37 (t, 2H), 7.05-6 .80(m, 1H), 6.70-6.53(m, 1H), 5.05-4.65(m, 1H), 4.55-4.37(m, 1H), 4.27(d, 4H), 4.14-3.97(m , 2H), 3.81-3.71(m, 1H), 3.70-3.52(m, 3H), 3.50-3.35(m, 2H), 3.33-3.14(m, 4H), 3.14-2.94(m , 5H), 2.93-2.82(m, 1H), 2.77(s, 9H), 2.72-2.55(m, 1H), 2.00(s, 2H), 1.87(s, 2H), 0.80(s, 4H).

[0845] Biological evaluation

[0846] Test Example 1: Biological evaluation of the inhibition of ERK phosphorylation in H358 cells by the compounds of the present invention

[0847] 1. Test Purpose

[0848] This experiment detects the inhibitory effect of compounds on cell ERK phosphorylation. 50 The inhibitory effect of the disclosed compounds on the KRAS target (containing the G12C mutation) was evaluated.

[0849] 2. Experimental Methods

[0850] H358 cells (ATCC, CRL-5807) were cultured with RPMI1640 (Hyclone, SH30809.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, H358 cells were seeded in a 96-well plate at a density of 25,000 cells / well using complete medium, with 190 μL of cell suspension per well, and placed in a 37°C, 5% CO2 cell culture incubator overnight. On the second day, 10 μL of the compound to be tested prepared with complete medium was added to each well, and the final concentration of the compound was 9 concentration points of 6-fold gradient dilution starting from 10 μM, and a blank control containing 0.5% DMSO was set, and the well plate was placed in a 37°C, 5% CO2 cell culture incubator for 3 hours. After 3 hours, the 96-well cell culture plate was removed, the medium was aspirated, and 200 μL PBS (Shanghai Yuanpei Biotechnology Co., Ltd., B320) was added to each well to wash once. PBS was removed, and 50 μL of lysis buffer (Cisbio, 64KL1FDF) containing blocking reagent (Cisbio, 64KB1AAC) was added to each well. The well plate was placed on a shaker for 30 minutes at room temperature for lysis. After lysis, the well was mixed by pipetting, and 16 μL of lysis solution was transferred to each well into two HTRF 96-well detection plates (Cisbio, 66PL96100), and then 4 μL of premixed phospho-ERK1 / 2 antibody solution (Cisbio, 64AERPEG) or 4 μL of premixed total-ERK1 / 2 antibody solution (Cisbio, 64NRKPEG) was added to the two plates. The microplate was sealed with a sealing film, centrifuged in a microplate centrifuge for 1 minute, and incubated overnight at room temperature in the dark. On the third day, the fluorescence values ​​were read using a PHERAstar multifunctional microplate reader (BMG Labtech, S / N 471-0361) with an excitation wavelength of 337 nm and an emission wavelength of 665 nm and 620 nm.

[0851] 3. Data Analysis

[0852] Graphpad Prism software was used to calculate the IC of the inhibitory activity of the compound based on the compound concentration and the ratio of pERK / total ERK. 50 The results are shown in Table 1 below.

[0853] Table 1 Inhibitory activity data of the compounds of the present invention on ERK phosphorylation in H358 cells

[0854]

[0855]

[0856] Conclusion: The disclosed compounds have a good inhibitory effect on ERK phosphorylation in H358 cells.

[0857] Test Example 2: Biological evaluation of the inhibitory effect of the compounds of the present invention on H358 cell proliferation

[0858] 1. Test Purpose

[0859] The inhibitory effect of the disclosed compounds on the KRAS target (containing the G12C mutation) was evaluated by testing the inhibitory effect of the disclosed compounds on the proliferation of H358 cells.

[0860] 2. Experimental Methods

[0861] H358 cells (ATCC, CRL-5807) were cultured with complete culture medium, i.e., RPMI1640 culture medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, H358 cells were seeded in a 96-well plate at a density of 1500 cells / well using complete culture medium, with 100 μL of cell suspension in each well, and cultured overnight in a 37°C, 5% CO2 cell culture incubator. On the second day, 10 μL of the compound to be tested prepared with complete culture medium was added to each well. The final concentration of the compound was 9 concentration points of 5-fold gradient dilution starting from 10 μM. A blank control containing 0.5% DMSO was set up, and the well plate was placed in a 37°C, 5% CO2 cell culture incubator for 120 hours. On the seventh day, the 96-well cell culture plate was removed, and 50 μL of the compound to be tested was added to each well. Luminescent Cell Viability Assay (Promega, G7573) was placed at room temperature for 10 minutes, and then the luminescent signal value was read using a multi-function microplate reader (PerkinElmer, VICTOR 3).

[0862] 3. Data Analysis

[0863] The IC of the inhibitory activity of the compounds was calculated using Graphpad Prism software 5o The results are shown in Table 2 below.

[0864] Table 2 Inhibitory activity data of the compounds of the present invention on H358 cell proliferation

[0865]

[0866]

[0867] Conclusion: The disclosed compounds have a good inhibitory effect on H358 cell proliferation.

[0868] Test Example 3: Blocking effect of the compounds of the present invention on hERG potassium current

[0869] 1. Purpose of the experiment

[0870] The blocking effect of the disclosed compounds on hERG potassium current was tested using fully automated patch clamp on a stable cell line transfected with hERG potassium channel.

[0871] 2. Experimental methods

[0872] 2.1 Experimental Materials and Instruments

[0873] 2.1.1 Experimental materials:

[0874]

[0875] 2.1.2 Experimental instruments:

[0876]

[0877]

[0878] 2.2 Fully automated patch clamp experimental steps

[0879] HEK293-hERG stable cell line (constructed internally by Shanghai Hengrui Medicine Co., Ltd.: refer to the method in Zhou, Z., et al. (1998) Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. Biophysical Journal; 74: 230-241, according to 3000 transfection reagent instructions: herg-pcDNA3.1 plasmid was transferred into HEK293 cells. After transfection for 48 hours, G418 was added to screen positive cells. Monoclonal cell lines expressing herg were selected by Western blot. The cells were subcultured in MEM / EBSS medium (10% FBS, 400μg / ml G418, 1% MEM non-essential amino acid solution (100×), 1% sodium pyruvate solution) at a density of 1:4. The fully automated patch clamp experiment was performed within 48-72 hours of culture. On the day of the experiment, the cells were digested with 0.25% trypsin (invitrogen, 25200-072#), collected by centrifugation, and resuspended in extracellular solution (140mMNaCl, 4mM KCl, 1mM MgCl2, 2mM CaCl2, 5mMDexodeoxyglucose, 10mM Hepes, pH7.4, 298mOsmol) to prepare a cell suspension. The cell suspension is placed on the cell bank of the Patchliner instrument. The Patchliner instrument uses a negative pressure controller to add cells to the chip (NPC-16). The negative pressure attracts single cells to the small holes of the chip. When the whole cell mode is formed, the instrument will obtain the hERG current according to the set hERG current voltage program, and then the instrument automatically perfuses the compound from low concentration to high concentration. The current at each concentration of the compound and the blank control current are analyzed by the data analysis software provided by HEAK Patchmaster (Nanion), HEAK EPC10 patch clamp amplifier (Nanion), Pathliner software, and Pathcontrol HT software.

[0880] 2.3 Test Results

[0881] The blocking effect of the disclosed compounds on hERG potassium current was determined by the above test, and the measured IC 50 See Table 3 for values.

[0882] Example No. <![CDATA[IC 50 (μM)]]> 1 8.7 3 18 7 13 12 5.8 43 7.4 45 5.6

[0883] Conclusion: The disclosed compounds have weak inhibitory effects on hERG and can reduce the side effects caused by the hERG pathway.

Claims

1. A compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, in: Ring A is cyclopropyl; Ring B is piperazinyl; Y is selected from N; L1 is -O-(CH2) q ; L2 is a bond or a methylene group; R 1 for Ring D is phenyl or a 5-membered heteroaryl group; R a are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl and hydroxyl groups; R b are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl and hydroxyl groups; s is 0, 1, or 2; t is 0, 1, or 2; R 2 is selected from 5 or 6 membered heterocyclic groups, wherein the 5 or 6 membered heterocyclic groups are optionally further selected from halogen, C 1-6 The alkyl group is substituted by one or more substituents; R 3 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with one or more cyano groups; R 4 Selected from -C(O)R 9 ; R 9 is vinyl, which is optionally further substituted with halogen; n is 0; m is 0; q is 0 or 1; and p is 1.

2. The compound according to claim 1, or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring D is phenyl.

3. The compound of claim 1 or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: in: R a , R b ,s,t as defined in claim 1.

4. The compound according to claim 1 or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, wherein: R 3 It is -CH2-CN.

5. The compound of the general formula (I) according to claim 1, or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, which is the compound of the general formula (III) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt: in: L1, R 1 and R 2 As defined in claim 1.

6. A compound or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, which is selected from any of the following compounds:

7. A compound represented by the general formula (IA) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, in: Ring A, Ring B, Y, L1, L2, R 1 , R 2 , R 3 , n, m, p as defined in claim 1.

8. A compound or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, selected from:

9. A method for preparing a compound of the general formula (I) according to claim 1 or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising the following steps: The compound of general formula (IA) reacts with compound XR under alkaline conditions 4 Acylation or sulfonylation reaction occurs to obtain a compound represented by general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: X is halogen or hydroxyl; Ring A, Ring B, Y, L1, L2, R 1 ~R 4 , m, n and p are as defined in claim 1.

10. The method according to claim 9, wherein X is Cl.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the general formula (I) according to any one of claims 1 to 6 or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

12. Use of a compound of formula (I) according to any one of claims 1 to 6 or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11 in the preparation of a medicament for inhibiting KRAS.

13. The use according to claim 12, which is use in preparing a medicament for inhibiting KRAS G12C.

14. Use of a compound of the general formula (I) according to any one of claims 1 to 6 or its stereoisomer, tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11 in the preparation of a medicament for treating or preventing cancer, inflammation, or other proliferative diseases.

15. The use according to claim 14, which is for use in preparing a medicament for treating or preventing cancer; the cancer is selected from gastric cancer, esophageal cancer, melanoma, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, colorectal cancer, pancreatic cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, leukemia, head and neck squamous cell carcinoma, cervical cancer, thyroid cancer, lymphoma, sarcoma, neuroblastoma, brain tumor, myeloma, astrocytoma and glioma.

Images