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

Abstract

The present invention relates to compounds of Formula (I) or pharmaceutically acceptable salts, prodrugs, tautomers or stereoisomers and solvates thereof, which are useful for treating cancer and inflammation in mammals. Methods of making the compounds of Formula (I) and pharmaceutical compositions comprising the compounds are also disclosed.

Description

[0001] This application is a divisional application of Chinese patent application No. 202180085987.X (filed on December 22, 2021, entitled: Preparation and application method of heterocyclic compound as KRAS inhibitor). Technical Field

[0002] This invention relates to certain novel heterocyclic compounds or pharmaceutically acceptable salts thereof, which can be used for the treatment or prevention of many different cancers. The invention also relates to pharmaceutical compositions comprising said compounds and their salts, intermediates in the preparation of said compounds, and methods for treating various cancers using said compounds and their salts. Background Technology

[0003] In 1982, Weinberg and Barbacid first isolated a transforming gene from a human bladder cancer cell line that could induce malignant transformation in NIH 3T3 cells, while DNA extracted from normal human tissue did not have this effect. Subsequently, Santos and Parada discovered that the aforementioned transforming gene was not a novel gene, but a human homologue of the Harvey murine sarcoma virus ras gene, named H2ras. In the same year, Krontiris discovered a homologue of the Kirsten murine sarcoma virus gene in human lung cancer cells, called K-ras. Another similar gene, called N2ras, was discovered when NIH 3T3 cells were infected with human neuroblastoma DNA; this gene is unrelated to the virus.

[0004] The ras gene is highly conserved throughout evolution and is widely found in various eukaryotes such as mammals, fruit flies, fungi, nematodes, and yeast, suggesting an important physiological function. The mammalian ras gene family has three members: H-ras, K-ras, and N-ras, with K-ras having two variants, A and B, in its fourth exon. All ras genes have similar structures, consisting of four exons distributed across approximately 30 kb of DNA. Their encoded product is a protein with a relative molecular mass of 21,000, hence the name P21 protein. It has been shown that H-ras is located on the short arm of human chromosome 11 (11p15.1~p15.3), K-ras is located on the short arm of chromosome 12 (12p1.1~pter), and N-ras is located on the short arm of chromosome 1 (1p22-p32). Except for variations in the fourth exon of K-ras, the sequence encoding P21 in each ras gene is evenly distributed across the four exons. However, the sequences and sizes of introns vary considerably, resulting in significant differences in the overall gene length. For example, human K-ras is 35 kb long, while N-ras is 3 kb long. Because it has two fourth exons, K-ras can be spliced ​​in two ways, but the mRNA encoding K-ras-B is more abundant. Except for K-ras-B, which contains 188 amino acids, the other two Ras proteins each contain 189 amino acids.

[0005] Ras(P21) protein is located on the inner side of the cell membrane and plays an important role in transmitting signals for cell growth and differentiation. It belongs to the guanosine triphosphate (GTP)-binding protein family (a coupling factor in cell signaling), regulating signal transmission through the interconversion of GTP and guanosine diphosphate (GDP). P21 has a strong affinity for both GTP and GDP and exhibits relatively weak GTPase activity. Under normal circumstances, P21 and GDP are in an inactive state. When extracellular growth and differentiation factors transmit signals to P21 on the inner side of the cell membrane, the binding activity of P21 to GTP is enhanced, activating the binding and opening the signaling system. Because P21 possesses GTPase activity, it hydrolyzes GTP to GDP. Upon binding to GDP, P21 becomes inactive, and the signaling system shuts down. While P21's GTPase activity is normally very weak, its hydrolysis rate can increase by 10,000 times when it binds to GTPase activator protein (GAP), thus inactivating P21. After P21 binds to GDP, it can activate guanylate-releasing protein (GNRP). GNRP causes P21 to release GDP and bind GTP. Therefore, through the interconversion of GTP and GDP, the activation and deactivation of the signaling system by P21 can be regulated in a controlled manner, thus completing the process of transmitting growth and differentiation signals into the cell.

[0006] More than one-fifth of cancer patients have Ras gene mutations, most of which occur at G12, G13 and Q61 residues. These mutations cause GAP protein-mediated dysfunction, and Ras signaling remains in an activated state. This invention designs and synthesizes a series of chemical molecules with strong bioactivity in inhibiting Ras, and provides a method for treating related cancers by inhibiting H-ras, K-ras or N-ras. Summary of the Invention

[0007] This invention provides compounds capable of modulating G12C mutant KRAS, HRAS, and / or NRAS proteins, including their stereoisomers, pharmaceutically acceptable salts, tautomers, and prodrugs. It also provides methods for treating various diseases or conditions (such as cancer) using these compounds.

[0008] In one aspect of the invention, a compound having formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or prodrug thereof is provided, wherein the compound of formula (I) is:

[0009]

[0010] in:

[0011] Ring W is a 4- to 12-element saturated or partially saturated monocyclic ring, bridged ring, or helical ring, wherein the saturated or partially saturated monocyclic ring is optionally additionally constituting one or more R... 4 replace,

[0012] in

[0013] R 4 Selected from: oxo, alkyl, alkenyl, alkyne, cycloalkyl, aryl, heteroaryl, heterocyclic, cyano, nitro, -C(O)OR 5 or -C(O)N(R) 5 )2, wherein the alkyl group is unsubstituted or replaced by a cyano, halogen, or -OR group. 5 -N(R) 5 )2 or one or more substitutions in heteroaryl groups, wherein R 5 Each is independently hydrogen or alkyl;

[0014] R 1 -L 1 -T,

[0015] in

[0016] L 1 -O-, -S-, -NR a -, -C(O)-, -SO2-, -SO-, -C(=NR a )-, -C(O)-O-, -OC(O)-, -C(O)-NRa -or-NR a C(O)-,

[0017] T is -CR a =CR b R c -C≡CR b Alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic groups, wherein each of the alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is unsubstituted or oxidized, halogenated, hydroxylated, alkyl, haloalkyl, hydroxyalkyl, alkoxy, CN, nitro, or NR x R y One or more substitutions in;

[0018] in

[0019] R a It can be hydrogen, deuterium, cyano, halogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, aryl, heteroaryl, or heterocyclic.

[0020] R b and R c Each can be independently represented as hydrogen, deuterium, cyano, halogen, or -C(O)OR. x Alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein each of the alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is unsubstituted or oxidized; halogen; hydroxyl; alkyl; haloalkyl; hydroxyalkyl; alkoxy; CN; nitro; NR x R y ; unsubstituted aryl groups or those substituted with alkyl, hydroxyl, or halogen groups; unsubstituted heteroaryl groups or those substituted with alkyl, hydroxyl, or halogen groups; one or both of the unsubstituted or heterocyclic groups substituted with alkyl, hydroxyl, or halogen groups.

[0021] Or, when T is -CR a =CR b R c At that time, R a With R b Or R a With R c Together with the carbon atoms to which they are attached, they form unsaturated 5- to 8-membered rings, which are unsubstituted or substituted by one or two of oxo, hydroxyl, halogen, alkyl, hydroxyalkyl, haloalkyl or alkoxy.

[0022] R x and R y Each is independently hydrogen or alkyl;

[0023] Q 1 Q 2 and Q 3 Each is independently N or CR 11 M1 and M 2 Each is independently N or CR 12 The condition is Q 1 and M 1 At least one of them is N;

[0024] in

[0025] R 11 and R 12 Each can be independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl or heterocyclic, -OR d -C(O)R d -CO2R d -CONR d R e or -NR d R e Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups are each independently converted by oxo, halogen, hydroxyl, alkoxy, alkyl, cycloalkyl, nitro, cyano, and -NR. d R e One or more substitutions in, where R d and R e Each can be independently hydrogen, alkyl, C3-C6 cycloalkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

[0026] L represents a single bond, -O-, -S-, or -NR. a -、-O-CH2-、-S-CH2-、-NR a -CH2-, -CH2-O-, -CH2-S-, -CH2-NR a -, -C(O)-, -SO2-, -SO-, -C(O)-O-, -OC(O)-, -C(O)-NR a -or-NR a C(O)-;

[0027] R 2 It is an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is independently unsubstituted or substituted by halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, oxo, -OR d -C(O)R d -CO2R d -CONR d R e -NR d R e One or more substitutions are made from cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, and heterocyclic groups, wherein Rd and R e Each can be independently classified as hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

[0028] R 3 It is cycloalkyl, heterocyclic, aryl, or heteroaryl, provided that M is... 1 and Q 1 Q 2 When both are N, R 3 It is a non-aromatic fused bicyclic heterocyclic group, R 3 It is either unsubstituted or substituted with one or more of the following groups: oxo, halogen, cyano, -OR d -C(O)R d -CO2R d -CONR d R e -NR d COR e -NR d R e -S(O)2NR d R e Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is independently substituted by a halogen, alkyl, cyano, carbamoyl, alkoxy, hydroxyl, cycloalkyl, and heteroaryl group, wherein R d and R e Each can be independently hydrogen, alkyl, C3-C6 cycloalkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkenyl or cycloalkyl.

[0029] In some embodiments, a compound having formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or prodrug thereof is provided, wherein the compound of formula (I) is:

[0030]

[0031] in:

[0032] Ring W is a 4- to 12-element saturated or partially saturated monocyclic ring, bridged ring, or helical ring, wherein the saturated or partially saturated monocyclic ring is optionally additionally constituting one or more R... 4 replace,

[0033] in

[0034] R 4 Selected from: oxo, alkyl, alkenyl, alkyne, cycloalkyl, aryl, heteroaryl, heterocyclic, cyano, nitro, -C(O)OR 5 or -C(O)N(R) 5)2, wherein the alkyl group is unsubstituted or replaced by a cyano, halogen, or -OR group. 5 -N(R) 5 )2 or one or more substitutions in heteroaryl groups, wherein R 5 Each is independently hydrogen or alkyl;

[0035] R 1 -L 1 -T,

[0036] in

[0037] L 1 -O-, -S-, -NR a -, -C(O)-, -SO2-, -SO-, -C(=NR a )-, -C(O)-O-, -OC(O)-, -C(O)-NR a -or-NR a C(O)-,

[0038] T is -CR a =CR b R c -C≡CR b Alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic groups, wherein each of the alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is unsubstituted or oxidized, halogenated, hydroxylated, alkyl, haloalkyl, hydroxyalkyl, alkoxy, CN, nitro, or NR x R y One or more substitutions in;

[0039] in

[0040] R a It can be hydrogen, deuterium, cyano, halogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, aryl, heteroaryl, or heterocyclic.

[0041] R b and R c Each can be independently represented as hydrogen, deuterium, cyano, halogen, or -C(O)OR. x Alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein each of the alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is unsubstituted or oxidized; halogen; hydroxyl; alkyl; haloalkyl; hydroxyalkyl; alkoxy; CN; nitro; NR x R y ; unsubstituted aryl groups or those substituted with alkyl, hydroxyl, or halogen groups; unsubstituted heteroaryl groups or those substituted with alkyl, hydroxyl, or halogen groups; one or both of the unsubstituted or heterocyclic groups substituted with alkyl, hydroxyl, or halogen groups.

[0042] Or, when T is -CR a =CRb R c At that time, R a With R b Or R a With R c Together with the carbon atoms to which they are attached, they form unsaturated 5- to 8-membered rings, which are unsubstituted or substituted by one or two of oxo, hydroxyl, halogen, alkyl, hydroxyalkyl, haloalkyl or alkoxy.

[0043] R x and R y Each is independently hydrogen or alkyl;

[0044] Q 1 Q 2 and Q 3 Each is independently N or CR 11 M 1 and M 2 Each is independently N or CR 12 The condition is Q 1 and M 1 At least one of them is N;

[0045] in

[0046] R 11 and R 12 Each can be independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl or heterocyclic, -OR d -C(O)R d -CO2R d -CONR d R e or -NR d R e Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups are each independently converted by oxo, halogen, hydroxyl, alkoxy, alkyl, cycloalkyl, nitro, cyano, and -NR. d R e One or more substitutions in, where R d and R e Each can be independently hydrogen, alkyl, C3-C6 cycloalkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

[0047] L represents a single bond, -O-, -S-, or -NR. a -、-O-CH2-、-S-CH2-、-NR a -CH2-, -CH2-O-, -CH2-S-, -CH2-NR a -, -C(O)-, -SO2-, -SO-, -C(O)-O-, -OC(O)-, -C(O)-NRa -or-NR a C(O)-;

[0048] R 2 It is an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is independently unsubstituted or substituted by halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, oxo, -OR d -C(O)R d -CO2R d -CONR d R e -NR d R e -CH2NR d R e One or more substitutions are made from cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, and heterocyclic groups, wherein R d and R e Each can be independently classified as hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

[0049] R 3 It is a non-aromatic fused bicyclic heterocyclic group, R 3 It is either unsubstituted or substituted with one or more of the following groups: oxo, halogen, cyano, -OR d -C(O)R d -CO2R d -CONR d R e -NR d COR e -NR d R e -S(O)2NR d R e Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is independently substituted by a halogen, alkyl, cyano, carbamoyl, alkoxy, hydroxyl, cycloalkyl, and heteroaryl group, wherein R d and R e Each can be independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkenyl, or cycloalkyl.

[0050] In some implementations, L 1 It is -C(O)- or -SO2-.

[0051] In some implementations, L 1 -C(=NR) a )-, where R aIt can be H, CN, or hydroxyl.

[0052] In some implementations, T is -CR a =CR b R c -C≡CR b alkyl or heterocyclic groups, wherein R a and R b As defined in equation (I).

[0053] In some implementations, T is -CR a =CR b R c or -C≡CR b , where R a R is hydrogen, deuterium, cyano, halogen, hydroxyl, or alkyl. b and R c Each is independently hydrogen; halogen; unsubstituted alkyl; with hydroxyl, halogen, NR x R y Alkyl groups substituted with heterocyclic groups; unsubstituted aryl or heteroaryl groups; aryl or heteroaryl groups substituted with alkyl, hydroxyl, or halogen groups, wherein R x and R y Each aryl group is independently hydrogen or alkyl. Preferably, in the above embodiments, the aryl group is phenyl, which is unsubstituted or converted by halogen, hydroxyl, or C. 1-3 One or two of the alkyl groups are substituted. Preferably, in the above embodiments, the heteroaryl group is thiazolyl, oxazolyl, pyridyl, or pyrimidinyl, which is unsubstituted or substituted with halogen, hydroxyl, or C. 1-3 One or two alkyl groups are substituted.

[0054] In some implementations, T is -CR a =CR b R c , where R a With R b Or R a With R c Together with the carbon atoms they are attached to, they form unsaturated 5- to 8-membered rings, which are unsubstituted or substituted with one or two of hydroxyl, halogen, alkyl, hydroxyalkyl, haloalkyl, or alkoxy groups. In some embodiments, T is -CR a =CR b R c , where R a With R b Or R a With R cTogether with the carbon atoms they are attached to, they form unsaturated 5-, 6-, 7-, or up to 8-membered carbon rings, which are unsubstituted or substituted with one or two of a hydroxyl, halogen, alkyl, hydroxyalkyl, haloalkyl, or alkoxy group. Preferably, the unsaturated 5-, 6-, 7-, or up to 8-membered carbon rings are cyclopentene, cyclohexene, cycloheptene, or cyclooctene rings.

[0055] In some embodiments, T is an alkyl group that is unsubstituted or converted to halogen, hydroxyl, or NR. x R y CN, haloalkyl, hydroxyalkyl, alkoxy or heterocyclic substituted, wherein R x and R y Each is independently hydrogen or alkyl. Preferably, the heterocyclic group in the above embodiments is a 4- to 8-membered heterocycle containing one or two selected oxygen, nitrogen and sulfur, such as aza-butane, pyrrolidine, piperidinyl, morpholinyl.

[0056] In some embodiments, T is a heterocyclic group, which is unsubstituted or converted by halogen, hydroxyl, or NR. x R y CN, alkyl, haloalkyl, hydroxyalkyl or alkoxy substitution, wherein R x and R y Each is independently hydrogen or alkyl. Preferably, T is a 3- to 8-membered heterocycle selected from oxygen, nitrogen, and sulfur, such as unsubstituted or methyl-substituted propylene oxide.

[0057] In some implementations, L 1 It is -C(O)- or -SO2-, and T is -CH=CH2.

[0058] In some implementations, L is -O-CH2- or -O-.

[0059] In some implementations, L is -O-CH2-, and R is... 2 The heterocyclic group is either unsubstituted or substituted with one or more of a halogen and an alkyl group. Preferably, L is -O-CH2-, and R is... 2 The heterocyclic group is a heterocyclic group containing one, two, or three 4- to 8-membered monocyclic rings selected from oxygen, nitrogen, and sulfur, wherein the heterocyclic group is unsubstituted or substituted with one or more halogens and alkyl groups. More preferably, the heterocyclic group is an azahexacyclic butyl, pyrrolidinyl, or piperidinyl group, wherein the ring is unsubstituted or substituted with one or two halogens or alkyl groups. In a further preferred embodiment, LR 2 for

[0060] , , , , , .

[0061] In some implementation schemes, R 3 The aryl group is phenyl or naphthyl, wherein the phenyl or naphthyl group is unsubstituted or substituted by 1, 2, or 3 or fewer substituents: halogen; cyano; -OR d , where R d It is hydrogen, alkyl, or haloalkyl; -CONR d R e , where R d and R e Each can be independently hydrogen, alkyl, or cycloalkyl; -NR d COR e , where R d and R e Each is independently hydrogen or alkyl; alkyl, wherein the alkyl group is unsubstituted or substituted with halogen, cycloalkyl, hydroxyl, or alkoxy; cycloalkyl, wherein the cycloalkyl group is unsubstituted or substituted with alkyl, cyano, or carbamoyl; alkynyl; -NR d R e , where R d and R e Each can be an independent hydrogen or alkyl group; or a heteroaryl group.

[0062] In some implementation schemes, R 3 The naphthyl group is partially hydrogenated, and it is either unsubstituted or substituted with a hydroxyl, alkyl, hydroxyalkyl, haloalkyl, or halogen. Preferably, R 3 It is 1,2,3,4-tetrahydronaphthyl, which is unsubstituted or substituted with hydroxyl, alkyl, hydroxyalkyl, haloalkyl, halogen, amino, alkylamino or dialkylamino.

[0063] In some implementation schemes, R 3 The heteroaryl group is unsubstituted or substituted by one, two, or three or fewer substituents: oxo, halogen; cyano; -OR d , where R d It is hydrogen, alkyl, or haloalkyl; -CONR d R e , where R d and R e Each can be independently hydrogen, alkyl, or cycloalkyl; -NR d COR e , where R d and R e Each is independently hydrogen, alkyl, or alkenyl; alkyl, wherein the alkyl group is unsubstituted or substituted with halogen, cycloalkyl, hydroxyl, or alkoxy; cycloalkyl, wherein the cycloalkyl group is unsubstituted or substituted with alkyl, cyano, or carbamoyl; alkynyl; or -NR dR e , where R d and R e Each of the heteroaryl groups is either hydrogen or alkyl. Preferably, the heteroaryl group is a monocyclic heteroaryl group, such as thiophene, thiazole, pyrazole, pyridine, or pyrimidine, which is unsubstituted or substituted as described above. Preferably, the heteroaryl group is a bicyclic heteroaryl group, such as... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or R a and R b Independently hydrogen, halogen, alkyl, or R a With R b The individual linkage is either substituted or unsubstituted C3-C6 cycloalkyl. It is either unsubstituted or substituted as described above.

[0064] In some implementation schemes, R 3 It is a heterocyclic group, preferably a non-aromatic fused bicyclic heterocyclic group, which is unsubstituted or substituted by 1, 2 or 3 or fewer substituents: oxo, halogen; cyano; -OR d , where R d It is hydrogen, alkyl, or haloalkyl; -CONR d R e , where R d and R e Each can be independently hydrogen, alkyl, or cycloalkyl; -NR d COR e , where R d and R eEach is independently hydrogen, alkyl, or alkenyl; alkyl, wherein the alkyl group is unsubstituted or substituted with halogen, cycloalkyl, hydroxyl, or alkoxy; cycloalkyl, wherein the cycloalkyl group is unsubstituted or substituted with alkyl, cyano, or carbamoyl; alkynyl; or -NR d R e , where R d and R e Each is independently hydrogen or alkyl. In other embodiments, R 3 It is a non-aromatic fused bicyclic heterocyclic group, which is unsubstituted or substituted with 1, 2, or 3 or fewer substituents: oxo, halogen; hydroxy, alkoxy, and alkyl; preferably, the substituents are oxo, halogen, hydroxy, methoxy, or methyl. In a further embodiment, R 3 It is a non-aromatic fused bicyclic heterocyclic group, which is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or It is unsubstituted or substituted with 1, 2, or 3 or fewer substituents: oxo, halogen; hydroxy, alkoxy, and alkyl; preferably, the substituents are oxo, halogen, hydroxy, methoxy, or methyl, wherein X, Y, and Z are each independently N or C. 9 , where R 9 It can be hydrogen, hydroxyl, cyano, alkyl, haloalkyl, halogen, hydroxyalkyl, alkoxyalkyl, or alkylsulfonyl.

[0065] In some implementations, the compound of formula (I) is

[0066]

[0067] in:

[0068] R 3 Preferred

[0069] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Where X, Y, and Z are selected from N or CR. 9 R a and R b Independently hydrogen, halogen, alkyl, or R a With R b The individual linkage is either substituted or unsubstituted C3-C6 cycloalkyl. The remaining variables are as defined for formula (I).

[0070] In some implementations, the compound of formula (I) is

[0071]

[0072] Among them: LR 2 for , , , , , , , .

[0073] R 3 Preferred , , , , , , , , , , , .

[0074] In some embodiments, the compound of formula (I) is as shown in formulas (I-2), (I-3), (I-4), (I-5), and (I-6):

[0075] , , , ,

[0076] in:

[0077] R 3 Preferred

[0078] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , R a and R b Independently hydrogen, halogen, alkyl, or R a With R b Individually linked to form substituted or unsubstituted C3-C6 cycloalkyl groups.

[0079] In some implementations, R 1 -W is The piperazine ring is optionally additionally surrounded by one or more R 4 Replace, R 4 As defined in equation (I). In some implementations, R 4 C 1- C3 alkyl, wherein the alkyl group is unsubstituted or substituted with a cyano group.

[0080] In some implementations, R in compound (I) 1 -W is

[0081] , , , , , , .

[0082] In some implementation schemes, R 1 For groups:

[0083] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0084] In the preferred embodiment, R 1 -W is , , or .

[0085] In some implementation schemes, LR 2 for

[0086] , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , .

[0087] In the preferred embodiment, LR 2 for , , , , , , or More preferably , , , , , .

[0088] In some implementation schemes, R 3 for

[0089] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , or .

[0090] In the preferred embodiment, R 3 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0091] In some implementation schemes, R 11It is hydrogen, nitro, hydroxyl, halogen, cyano, alkyl, haloalkyl, alkoxy, or alkoxyalkyl; preferably hydrogen, halogen, cyano, trifluoromethyl, or nitro. In a preferred embodiment, R 11 It is F.

[0092] In some implementation schemes, R 12 The alkyl group is hydrogen, hydroxyl, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, heterocyclic, C1-C6 haloalkyl, aryl, or heteroaryl, wherein the aryl and heteroaryl groups are each unsubstituted or substituted by one or more of C1-C3 alkyl, halogen, C1-C3 haloalkyl, and C3-C6 cycloalkyl. In a preferred embodiment, R 12 It consists of F and cyclopropyloxy groups.

[0093] In some implementations, the compound of formula (I) is ,in

[0094] R 1 -W is , , or ;

[0095] R 3 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;as well as

[0096] LR 2 for , , , , , , , or More preferably , , , , or ;

[0097] R 11 and R 12 Each can be independently hydrogen, hydroxyl, alkyl, C3-C6 cycloalkyloxy, or halogen.

[0098] In some implementations, the compound of formula (I) is

[0099] , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、

[0100]

[0101]

[0102]

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[0104]

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[0113]

[0114]

[0115]

[0116] 、 、 、 、 、

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[0118]

[0119]

[0120] 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、

[0121] 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、

[0122] 、 、 、 、 、

[0123] 、 、

[0124]

[0125]

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[0128]

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[0199] 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、

[0200]

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[0222] 、 、 、 、 、 、 、 、 、 、 、 、 、

[0223]

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[0240]

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[0250]

[0251]

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[0260]

[0261]

[0262]

[0263]

[0264]

[0265] Another aspect of the present invention provides an exemplary method for preparing the compound of formula (I) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0266] Preparation method 1:

[0267]

[0268] Among them, R 1 R 2 R 3 L and W are as defined above. PG is a protecting group of the amino group, such as Boc-, Cbz, etc., and X is a group such as Cl, OTf, etc. The first step is a substitution reaction under basic conditions (such as triethylamine, diisopropylethylamine, etc.); the second step is an oxidation reaction under oxidizing agent (such as m-chloroperoxybenzoic acid, etc.) to obtain the intermediate sulfoxide; the third step is a substitution reaction of the intermediate sulfoxide under basic conditions (triethylamine, sodium hydride, sodium tert-butoxide, etc.) to obtain the target intermediate; the fourth step is the Suzuki Coupling reaction with R 3-Bpin or R 3 The -B(OH)2 reaction yields the intermediate; the fifth step is the removal of the protecting group (e.g., Boc); the sixth step is the reaction with the corresponding acid or acyl chloride to obtain the target compound.

[0269] Preparation method 2:

[0270]

[0271] Among them, R 1 R 2 R 3 Q 2 Q 3 M 2 L and W are as defined above. X is Cl, Br, or I. PG is a protecting group of the amino group, such as Boc-, Cbz, etc. The first step is a substitution reaction under basic conditions (such as triethylamine, diisopropylethylamine, etc.); the second step is a substitution reaction under basic conditions (triethylamine, sodium hydride, sodium tert-butoxide, etc.) to obtain the target intermediate; the third step is the Suzuki Coupling reaction with R. 3 -Bpin or R 3 The -B(OH)2 reaction yields the intermediate; the fourth step is the removal of the protecting group (e.g., Boc); the fifth step is the reaction with the corresponding acid or acyl chloride to obtain the target compound.

[0272] Preparation method 3:

[0273]

[0274] Among them, R 1 R 2 R 3 Q 2 M 2 L and W are as defined above. X is Cl, Br, or I. PG is a protecting group of the amino group, such as Boc-, Cbz, etc. The first step is a condensation reaction under condensing agent conditions (such as EDCI, HOBT, HATU, etc.), the second step is a cyclization reaction under alkaline conditions (such as sodium hydride, sodium methoxide, sodium ethoxide, etc.), the third step is a chlorination reaction under phosphorus oxychloride conditions, the fourth step is a substitution reaction under alkaline conditions (such as triethylamine, diisopropylethylamine, etc.), the fifth step is a substitution reaction under alkaline conditions (triethylamine, sodium hydride, sodium tert-butoxide, etc.) to obtain the target intermediate, and the sixth step is the Suzuki Coupling reaction with R. 3 -Bpin or R 3 The coupling reaction of -B(OH)2 yields the intermediate; the seventh step is the removal of the protecting group (such as Boc); the eighth step is the reaction with the corresponding acid or acyl chloride to obtain the target compound.

[0275] Preparation method 4:

[0276]

[0277] Among them, R 1 R 2 R 3 Q 2 Q 3 R d L and W are as defined above. X is Cl, Br, or I. PG is a protecting group of the amino group, such as Boc-, Cbz, etc. The first step is a substitution reaction under basic conditions (such as triethylamine, diisopropylethylamine, etc.); the second step is a substitution reaction under basic conditions (triethylamine, sodium hydride, sodium tert-butoxide, etc.) to obtain the target intermediate; the third step is a substitution reaction under strongly basic conditions (sodium cyanide, sodium tert-butoxide, potassium tert-butoxide, potassium hexamethyldisilamide, etc.); the fourth step is the Suzuki Coupling reaction, where the halogenated intermediate reacts with R. 3 -Bpin or R 3 The coupling reaction of -B(OH)2 yields the intermediate; the fifth step is the removal of the protecting group (such as Boc); the sixth step is the reaction with the corresponding acid or acyl chloride to obtain the target compound.

[0278] Other general synthetic methods are provided in the examples. It will be apparent to those skilled in the art that compounds of formula (I) can be prepared by one or more methods or in other ways known in this art. It will be apparent that, in general, when following the general routes described herein, different substituted starting materials and / or protecting groups are required to obtain the desired compounds. Different substituents can also be added at different points in the synthetic route to prepare the desired compounds.

[0279] This invention relates to pharmaceutical compositions of compounds of formula (I) or pharmaceutically acceptable salts, prodrugs and solvates thereof.

[0280] Another aspect of the present invention provides a method for treating disease symptoms using the compounds or pharmaceutical compositions of the present invention, including, but not limited to, symptoms associated with G12 KRAS, HRAS, or NRAS mutations (e.g., cancer). Cancer includes pancreatic cancer, lung cancer, colorectal cancer, etc., mediated by G12C mutations.

[0281] The present invention relates to compounds of formula (I) which have good physicochemical properties and safety and toxicity parameters, and can be used for the treatment of cancer and inflammation in mammals.

[0282] In other embodiments, a method for inhibiting cell population proliferation is also provided, the method comprising contacting the cell population with any one of the compounds of structure (I).

[0283] Other embodiments relate to pharmaceutical compositions. The pharmaceutical composition comprises any one (or more) of the aforementioned compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still other embodiments, the pharmaceutical composition comprises a compound disclosed herein and another therapeutic agent (e.g., an anticancer agent). Non-limiting examples of such therapeutic agents are described below.

[0284] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, non-enteral, ocular, pulmonary, mucosal, percutaneous, vaginal, ear, nasal, and local administration. Additionally, by way of example only, non-enteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracardiac, intraperitoneal, intralymphatic, and intranasal injection. Detailed Implementation

[0285] Unless otherwise specified, all disclosures of this invention are defined using the following terms:

[0286] The term "prodrug" refers to any derivative that can be converted into a corresponding active pharmaceutical compound in vivo. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. Furthermore, prodrugs can be converted into the compounds of the present invention in the in vivo environment by chemical or biochemical methods.

[0287] The term "pharmaceutically acceptable salt" includes, unless otherwise stated, salts of acidic groups (e.g., but not limited to, potassium, sodium, magnesium, calcium, etc.) or salts of basic groups (e.g., but not limited to, formate, acetate, citrate, tartrate, methanesulfonate, malate, sulfate, hydrochloride, phosphate, nitrate, carbonate, etc.) that may be present in the compounds of the present invention.

[0288] The term "solvent" refers to a complex molecular compound formed in solution by solute molecules or ions attracting adjacent solvent molecules through intermolecular forces such as Coulomb forces, van der Waals forces, charge transfer forces, and hydrogen bonds. In one embodiment, the solvent is water, meaning the compound of this invention forms a hydrate.

[0289] The compounds of this invention, or pharmaceutically acceptable salts thereof, may contain one or more step symmetry centers, and thus may produce enantiomers, diastereomers, and other stereoisomers, defined in terms of the absolute stereochemical configuration of the amino acid as (R)- or (S)-, or (D)- or (L)-. This invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be obtained using chiral synthesis or chiral preparation, or by resolution using conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors, and resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). This invention provides pure isomers and mixtures of isomers, methods of their preparation and uses, and compositions comprising them. For simplicity, it will be referred to as compound (I) below, which means both the pure optical isomer and, where appropriate, a mixture of isomers in different proportions.

[0290] The compounds of this invention can exist in specific forms. Unless otherwise stated, the terms "tautomer" or "tautomer form" refer to isomers of different functional groups in dynamic equilibrium at room temperature, capable of rapidly interconverting. If tautomerization is possible (e.g., in solution), a chemical equilibrium of the tautomer can be achieved. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0291] The alkyl, alkenyl, alkynyl, and cycloalkyl moieties may each be independently substituted by one or more groups selected from the following: hydroxyl, oxo, halogen, cyano, nitro, trifluoromethyl, azide, amino, carboxyl, and mercapto.

[0292] Saturated or unsaturated hydrocarbon groups, such as alkyl, alkyldiyl, or alkenyl groups, including those bonded to heteroatoms, such as alkoxy groups, can be either straight-chain or branched.

[0293] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the occurrence of said event or condition and the non-occurrence of said event or condition.

[0294] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on a chemically feasible basis.

[0295] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0296] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly linked. For example, in Ar-LR, when L represents a single bond, it means that the structure is actually Ar-R. When a substituent is vacant, it means that the substituent does not exist. For example, in Ar-LR, when L is vacant, Ar-LR means that the structure is actually Ar.

[0297] Unless otherwise specified, the term “heterogeneous” means heteroatom or heterogroup (i.e., a group of atoms containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups of atoms containing such heteroatoms, such as oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, and optionally substituted -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- or -S(=O)N(H)-.

[0298] Unless otherwise specified, "ring" means a substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloynyl, heterocycloynyl, aryl, or heteroaryl group. The rings include monocyclic rings, as well as bicyclic or polycyclic systems such as spirocyclic, fused, and bridged rings. The number of atoms on a ring is generally defined as the elemental number of the ring; for example, "5-7 membered ring" refers to a ring with 5-7 atoms arranged in a ring. Unless otherwise specified, the ring optionally contains 1-3 heteroatoms. Thus, "5-7 membered ring" includes, for example, phenyl, pyridinyl, and piperidinyl; on the other hand, the term "5-7 membered heterocycloalkyl" includes pyridinyl and piperidinyl, but not phenyl. The term "ring" also includes cyclic systems containing at least one ring, where each "ring" independently meets the above definition.

[0299] Unless otherwise specified, the term "heteroalkyl" on its own or in combination with another term refers to a stable straight-chain or branched alkyl group or a combination thereof consisting of a certain number of carbon atoms and at least one heteroatom, or heterogroup. In some embodiments, the heteroatom is selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heterogroup is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. In some embodiments, the heteroalkyl is a C1-C6 heteroalkyl; In other embodiments, the heteroalkyl group is a C1-C3 heteroalkyl group. Heteroatoms or heterogroups can be located at any internal position of the heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule, but the terms "alkoxy," "alkamino," and "alkathio" (or thioalkoxy) are conventional expressions referring to those alkyl groups that are attached to the rest of the molecule via an oxygen atom, amino atom, or sulfur atom, respectively. Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH 2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-SCH2-CH 3. -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, -CH=CH-O-CH3, -CH2-CH=N-OCH3 and -CH=CHNCCH3)-CH 3。 At most two heteroatoms can be consecutive, for example, -CH2-NH-OCH3.

[0300] Unless otherwise specified, the term "heterocyclic alkyl" on its own or in combination with other terms refers to a cyclic "heteroalkyl" including monocyclic, bicyclic, and tricyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. Furthermore, with respect to the term "heterocyclic alkyl," the heteroatom may occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered heterocyclic alkyl group; in other embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkyl group. Examples of heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl, homopiperidinyl, or oxacycloheptyl.

[0301] "Alkoxy" refers to the aforementioned alkyl group having a specific number of carbon atoms connected by an oxygen bridge. Unless otherwise specified, C1-C6 alkoxy groups include C1, C2, C3, C4, C5, and C6 alkoxy groups. In some embodiments, the alkoxy group is a C1-C3 alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and pentoxy.

[0302] Unless otherwise specified, the term "aryl" in this invention refers to a polyunsaturated carbocyclic system, which can be monocyclic, bicyclic, or polycyclic, wherein at least one ring is aromatic, and the rings in the bicyclic and polycyclic systems are fused together. It can be monosubstituted or polysubstituted, and can be monovalent, divalent, or polyvalent; in some embodiments, the aryl group is C6-C. 12 Aryl; in other embodiments, the aryl group is C6-C. 10 Aryl. Examples of aryl groups include, but are not limited to, phenyl and naphthyl (including 1-naphthyl and 2-naphthyl, etc.). The substituents of any of the above aryl ring systems are selected from the acceptable substituents described in this invention.

[0303] Unless otherwise specified, the term "heteroaryl" in this invention refers to an aryl group containing 1, 2, 3, or 4 independent heteroatoms selected from B, N, O, and S, which can be a monocyclic, bicyclic, or tricyclic system, wherein the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents defined herein) and optionally quaternized, and the nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., NO and S(O)p, where p is 1 or 2). The heteroaryl group can be linked to the rest of the molecule via heteroatoms. In some embodiments, the heteroaryl group is a 5-10 membered heteroaryl group; in other embodiments, the heteroaryl group is a 5-6 membered heteroaryl group. Examples of the heteroaryl groups include, but are not limited to, pyrrole (including pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including imidazole, 2-imidazole, 4-imidazole, and 5-imidazole), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl, and 5-isooxazolyl), and thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl). The substituents in any of the above heteroaryl ring systems are selected from the acceptable substituents described in this invention. These substituents include: furanyl (including 2-furanyl and 3-furanyl), thienyl (including 2-thienyl and 3-thienyl), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl), benzothiazolyl (including 5-benzothiazolyl), purinyl, benzimidazolyl (including 2-benzimidazolyl), indole (including 5-indole), isoquinolinyl (including 1-isoquinolinyl and 5-isoquinolinyl), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl), quinolinyl (including 3-quinolinyl and 6-quinolinyl), pyrazinyl, purinyl, and phenylbenzoxazolyl.

[0304] synthesis

[0305] Suitable solvents commonly used in organic reactions can be used in each step of the preparation method of the present invention, for example, but not limited to: aliphatic and aromatic, optionally hydrocarbons or halogenated hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, volatile oil, benzene, toluene, xylene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene), and aliphatic and aromatic, optionally alcohols (e.g., methanol, ethanol, propanol, isopropanol, tert-butyl...). Alcohols, ethylene glycol, etc.), ethers (e.g., diethyl ether and dibutyl ether, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether, tetrahydrofuran and dioxane, etc.), esters (e.g., methyl acetate or ethyl acetate, etc.), nitriles (e.g., acetonitrile or propionitrile, etc.), ketones (e.g., acetone, butanone, etc.), amides (e.g., dimethylformamide, dimethylacetamide and N-methylpyrrolidone, etc.), as well as dimethyl sulfoxide, tetramethylene sulfone and hexamethylphosphoric triamine and N,N-dimethylpropane urea (DMPU), etc.

[0306] This invention uses the following abbreviations: DCM represents dichloromethane; CHCl3 represents trichloromethane; EA represents ethyl acetate; THF represents tetrahydrofuran; MeCN represents acetonitrile; MeOH represents methanol; EtOH represents ethanol; i-PrOH represents isopropanol; PE represents petroleum ether; Toulene represents toluene; DMSO represents dimethyl sulfoxide; DMF represents N,N-dimethylformamide; DMA represents N,N-dimethylacetamide; CDCl3 represents deuterated chloroform; D2O represents heavy water; (CD3)2SO represents deuterated DMSO; CD3OD represents deuterated methanol; CuI represents cuprous iodide; DIPEA represents diisopropylethylamine; TEA represents triethylamine; K2CO3 represents potassium carbonate; Cs2CO3 represents cesium carbonate; Na2CO3 represents sodium carbonate; NaHCO3 represents sodium bicarbonate; NaOH represents sodium hydroxide; KOH represents potassium hydroxide; LiHMDS represents hexamethyldisilamide lithium; CDI replaces 1,1 ，-Carbonylimidazolium; MS represents mass spectrometry; NMR represents nuclear magnetic resonance; TFA represents trifluoroacetic acid; BINAP represents (2R,3S)-2,2'-diphenylphosphine-1,1'-binaphthyl; BOC represents tert-butyloxycarbonyl; Cbz represents benzyloxycarbonyl; DBU represents bicyclo-1,5-diazol-5-undecene; DCC represents 1,3-dicyclohexylcarbodiimide; DCE represents 1,2-dichloroethane; DMAP represents 4-dimethylaminopyridine; dppf represents bis(diphenylphosphine)ferrocene; LiAlH4 represents lithium aluminum hydride; LDA represents diisopropylaminolithium; m-CPBA represents m-chloroperoxybenzoic acid; MTM The following symbols represent various chemical compounds: dimethyl sulfide; NBS represents N-bromosuccinimide; NCS represents N-chlorosuccinimide; NIS represents N-iodosuccinimide; PCC represents pyridine dichromate; TBAF represents tetrabutylamine fluoride; THP represents tetrahydropyranyl; TMEDA represents tetramethylethylenediamine; TMS represents trimethylsilyl; TMP represents 2,2,6,6-tetramethylpiperidine; Ts represents p-toluenesulfonyl; Pd(PPh3)4 represents tetratetraphenylphosphine palladium; PdCl2(dppf) represents 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride; Pd2(dba)3 represents tridibenzylacetone dipalladium; HOBT represents 1-hydroxybenzotriazole; HATU represents 2-(7-oxo) benzotriazole )-N,N,N',N'- Tetramethylurea Hexafluorophosphate; TBTU represents O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate; Tf2O represents trifluoroacetic anhydride; Pd(OAc)2 represents palladium diacetate; RuPhos represents 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl; Pd(PPh3)2Cl2 represents bis(triphenylphosphine)palladium dichloride; Sphos represents 3,2-bis(cyclohexylphosphine)-2',6'-dimethoxybiphenyl; XantPhos represents 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene; MeONa represents sodium methoxide; n-BuLi represents n-butyllithium; t-BuONa represents sodium tert-butoxide; t-BuOK represents potassium tert-butoxide; KSCN represents potassium thiocyanate; CuBr represents cuprous bromide; NaNO2 represents sodium nitrite; Urea The following symbols represent various chemical groups: urea (POCl3), phosphorus oxychloride (POCl3), boron tribromide (BBr3), ammonium chloride (NH4Cl), iodomethane (MeI), N-methylpyrrolidone (NMP), potassium phosphate (K3PO4), column chromatography (column chromatography), acetyl (Ac), benzyl (Bn), fluorenylmethoxycarbonyl (Fmoc), cyclohexyl (Cy), trifluoromethanesulfonyl (Tf), and pyridine dichromate (PDC).

[0307] Synthesis Example:

[0308] Preparation of intermediates:

[0309] Synthesis of 4,4,5,5-Tetramethyl-2-(5,6,7,8-tetrahydronaphth-1-yl)-1,3,2-dioxaborane

[0310]

[0311] Compounds 5-bromo-1,2,3,4-tetrahydronaphthalene (5.00 g, 23.69 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (12.03 g, 47.37 mmol) were dissolved in anhydrous 1,4-dioxane (50 mL), potassium acetate (6.97 g, 71.07 mmol) and Pd(dppf)Cl2 (1.73 g, 2.37 mmol) were added, nitrogen gas was purged, and the mixture was heated to 100 °C. o The reaction mixture was stirred at C for 16 hours. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a pale yellow oil (5.0 g, yield: 82%). 1 H NMR (400MHz, CDCl3) δ 7.58 (d,J = 6.9Hz, 1H), 7.11 (s, 1H), 7.08 (d,J= 7.3Hz, 1H), 3.03 (t,J = 5.9Hz, 2H), 2.77 (t,J = 5.8Hz, 2H), 1.78 (dd,J =7.1, 4.3Hz, 4H), 1.34 (s, 12H).

[0312] Synthesis of intermediate 2-(4-fluoro-5,6,7,8-tetrahydronaphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane:

[0313]

[0314] Compounds 5-bromo-8-fluoro-1,2,3,4-tetrahydronaphthalene (2.00 g, 8.73 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (4.43 g, 17.46 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL), potassium acetate (2.57 g, 26.19 mmol) and Pd(dppf)Cl2 (0.64 g, 0.87 mmol) were added, nitrogen gas was purged, and the mixture was heated to 100 °C. oThe reaction mixture was stirred at C for 16 hours. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a pale yellow oil (2.1 g, yield: 87%). 1 H NMR (600MHz, CDCl3) δ 7.63 – 7.54 (m, 1H), 6.80 (t,J = 8.8Hz,1H), 3.03 (s, 2H), 2.71 (s, 2H), 1.82 – 1.72 (m, 4H), 1.33 (s, 12H).

[0315]

[0316] Step 1: Synthesis of 5-chloro-6-fluoro-1,4-dihydro-1,4-epoxynaphthalene

[0317] 1-Bromo-3-chloro-2,4-difluorobenzene (5.0 g, 21.98 mmol) and furan (2.99 g, 43.97 mmol) were dissolved in anhydrous toluene (50 mL), and the reaction solution was cooled to -15°C under a nitrogen atmosphere. o After step C, n-BuLi (10.6 mL, 26.38 mmol) was added dropwise to the reaction solution. After the addition was complete, the mixture was slowly brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride, extracted with methyl tert-butyl ether, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a brown oily substance which was directly used in the next step. (4.3 g, yield: 100%)

[0318] Step 2: Synthesis of 8-chloro-7-fluoronaphth-1-ol

[0319] The crude compound 8-chloro-7-fluoronaphth-1-ol obtained in the previous step was synthesized by dissolving 5-chloro-6-fluoro-1,4-dihydro-1,4-epoxynaphthalene (4.3 g, 21.98 mmol) in ethanol (10 mL) and concentrated hydrochloric acid (8 mL), and then heating to 80 °C. o The reaction mixture was stirred at C for 4 hours. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a brown oily substance. The oily substance was placed in a refrigerator for 24 hours, and a solid precipitated. The solid was diluted with petroleum ether, filtered, washed with petroleum ether, and dried to obtain an off-white solid. 1.3 g, yield: 30%. 1H NMR (400MHz, CDCl3) δ 7.91 (s, 1H), 7.75 (dd,J = 9.1, 5.6Hz, 1H), 7.44 – 7.34 (m, 2H), 7.30 (d,J = 8.7Hz, 1H), 7.08 (d,J = 7.1Hz, 1H).

[0320] Step 3: Synthesis of 8-chloro-7-fluoronaphth-1-yl trifluoromethanesulfonic acid ester

[0321] The compound 8-chloro-7-fluoronaphth-1-ol (1.0 g, 5.08 mmol) was dissolved in anhydrous dichloromethane (10 mL), and DIEA (3.94 g, 30.51 mmol) and molecular sieve (1 g) were added. After stirring at room temperature for 10 molecule, the mixture was cooled to -40°C. o C. Trifluoromethanesulfonic anhydride (1.86 g, 6.61 mmol) was added dropwise to the reaction solution. After stirring for 20 minutes, the reaction was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a yellow solid (1.65 g, yield: 98.8%). 1 H NMR (400MHz, CDCl3) δ 7.90 (d,J = 8.1Hz, 1H), 7.84 (dd,J = 9.0,5.4Hz, 1H), 7.59 (d,J = 7.7Hz, 1H), 7.51 (s, 1H), 7.44 (s, 1H).

[0322] Step 4: Synthesis of 2-(8-chloro-7-fluoronaphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

[0323] 8-Chloro-7-fluoronaphth-1-yl trifluoromethanesulfonic acid (1.65 g, 5.02 mmol) and pinacol boronic acid ester (2.53 g, 10.04 mmol) were dissolved in anhydrous DMF (20 mL), and potassium acetate (2.44 g, 24.85 mmol) and Pd(dppf)Cl2 (366 mg, 0.50 mmol) were added. Nitrogen gas was then introduced to displace the solution, and the mixture was stirred under a nitrogen atmosphere for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain an off-white solid (1.25 g, yield: 82%). 1H NMR (400MHz, CDCl3) δ 7.83 (t,J =10.4Hz, 1H), 7.75 (dd,J = 9.0, 5.5Hz, 1H), 7.70 (d,J = 6.8 Hz, 1H), 7.50 –7.44 (m, 1H), 7.32 (t,J = 8.7Hz, 1H), 1.45 (s, 12H).

[0324] Synthesis of intermediate (tetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol:

[0325]

[0326] Step 1: Synthesis of 2-(3-chloropropyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester:

[0327] 2-Methylpyrrolidine 1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.8 g, 25.3 mmol) was dissolved in tetrahydrofuran (25 mL) and cooled to -78°C. o C. LiHMDS (1M / L, 37.9mmol) was added dropwise. After 30 minutes, 1-bromo-3-chloropropane (19.9g, 126mmol) was added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a transparent oil (5.1g, yield: 65.9%). 1 H NMR (400 MHz, CDCl3) δ 3.83 – 3.28 (m, 7H), 2.39 – 1.68 (m, 8H), 1.43 (d, J =13.1 Hz, 9H).

[0328] Step 2: Synthesis of methyl 2-(3-chloropropyl)pyrrolidine-2-carboxylic acid ester:

[0329] 1-(tert-butyl)-2-(3-chloropropyl)pyrrolidine-1,2-dicarboxylic acid 2-methyl ester (1 g, 3.27 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, the reaction was carried out at room temperature for 1 hour, concentrated to dryness, and used directly in the next step of the reaction.

[0330] Step 3: Synthesis of tetrahydro-1H-pyrrolazine 7a(5H)-carboxylic acid methyl ester:

[0331] 2-(3-Chloropropyl)pyrrolidine-2-carboxylic acid methyl ester (670 mg, 3.27 mmol) was dissolved in methanol (10 mL), and potassium carbonate (1.35 g, 9.81 mmol) and potassium iodide (670 mg, 0.327 mmol) were added. The mixture was reacted at room temperature for 2 hours. The solid was filtered off, and the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a clear oily substance (400 mg, yield: 72.5%). 1 H NMR(400 MHz, CDCl3) δ 3.72 (s, 3H), 3.21 – 3.11 (m, 2H), 2.64 (d, J = 10.2 Hz,2H), 2.38 – 2.24 (m, 2H), 1.86 – 1.76 (m, 4H), 1.72 – 1.66 (m, 2H).

[0332] Step 4: Synthesis of (tetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol:

[0333] Tetrahydro-1H-pyrrolizine 7a(5H)-carboxylic acid methyl ester (400 mg, 2.37 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (270 mg, 7.10 mmol) was added in portions under ice bath conditions. After 1 hour, the reaction was confirmed to be complete by TLC (petroleum ether / ethyl acetate = 10 / 1). Sodium sulfate decahydrate was added, the solid was filtered off, and the filtrate was concentrated to give a clear oily substance (290 mg, yield: 87%). 1 H NMR(400 MHz, MeOD) δ 3.36 – 3.28 (m, 2H), 2.96 (dt, J = 10.4, 6.1 Hz, 2H), 2.64(ddd, J = 10.5, 7.3, 6.0 Hz, 2H), 1.97 – 1.81 (m, 4H), 1.73 (dt, J = 12.6, 6.8 Hz, 2H), 1.64 – 1.52 (m, 2H).

[0334] Synthesis of intermediate (1R,5R)2,6-diazabicyclo[3.2.0]heptane-2-carboxylic acid tert-butyl ester:

[0335]

[0336] Step 1: Synthesis of (2S,3S)-1-(tert-Butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid:

[0337] (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (1.31 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL) and water (10 mL). Sodium hydroxide (0.80 g, 20 mmol) and Boc anhydride (3.30 g, 15 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The mixture was extracted with ethyl acetate, and the aqueous layer was adjusted to pH 2.0 with 1 N hydrochloric acid. The extract was then extracted with ethyl acetate and concentrated to give a white solid (1.5 g, yield: 65%). 1 H NMR (400 MHz, CDCl3)δ 4.82 (s, 1H), 4.25 (s, 1H), 3.62 (q, J = 9.3 Hz,1H), 3.48 (s, 1H), 2.12 (dd, J = 8.9, 4.5 Hz, 1H), 1.94 (ddd, J = 10.0, 6.7, 3.3 Hz, 1H), 1.51 (s, 9H).

[0338] Step 2: Synthesis of (2R,3S)-3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester:

[0339] (2S,3S)-1-(tert-Butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (1.5 g, 6.5 mmol) was dissolved in tetrahydrofuran (20 mL), and borane dimethyl sulfide (2 M / L, 14.3 mmol) was added. The mixture was heated to reflux for 3 hours, cooled to room temperature, and the reaction was quenched dropwise with methanol. After concentration, the mixture was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a clear oil (1.2 g, yield: 85.7%). 1 H NMR (400 MHz, MeOD) δ 4.42 – 4.21 (m, 1H), 3.66 (d, J = 8.8 Hz,2H), 3.52 – 3.35 (m, 3H), 2.19 – 2.04 (m, 1H), 1.90 – 1.74 (m, 1H), 1.47 (s,9H).

[0340] Step 3: Synthesis of (2R,3S)3-(methylsulfonyloxy)-2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester:

[0341] (2R,3S)-3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.16 g, 5.3 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (2.26 g, 22.4 mmol) and methanesulfonyl chloride (1.83 g, 16 mmol) were added under ice bath conditions. The mixture was reacted at room temperature for 2 hours, then ice water was added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and used directly in the next step of the reaction.

[0342] Step 4: Synthesis of (1R,5R)-6-benzyl-2,6-diazabicyclo[3.2.0]heptane-2-carboxylic acid tert-butyl ester:

[0343] (2R,3S)3-(methanesulfonyloxy)-2-((methanesulfonyloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.0 g, 5.3 mmol) was dissolved in toluene (20 mL), and benzylamine (1.71 g, 16 mmol) was added. The mixture was heated to 110 °C. o C, react for 15 hours, cool to room temperature, filter the solid, concentrate the filtrate and purify by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a light yellow buttery substance (890 mg, yield: 58%). 1 H NMR (400 MHz, MeOD) δ 7.42 – 7.18 (m, 5H), 4.31 – 4.15(m, 1H), 3.99 (d, J = 5.0 Hz, 1H), 3.67 (d, J = 14.7 Hz, 4H), 3.18 (dd, J =6.4, 4.3 Hz, 2H), 1.69 – 1.53 (m, 2H), 1.44 (d, J = 15.2 Hz, 9H).

[0344] Step 5: Synthesis of (1R,5R)2,6-diazabicyclo[3.2.0]heptane-2-carboxylic acid tert-butyl ester:

[0345] (1R,5R)-6-benzyl-2,6-diazabicyclo[3.2.0]heptane-2-carboxylic acid tert-butyl ester (145 mg, 0.5 mmol) was dissolved in methanol (20 mL), and palladium on carbon (10%, 100 mg) was added. The reaction was carried out under hydrogen balloon pressure for 20 hours. The mixture was filtered, and the filtrate was concentrated to give a transparent solid (90 mg, yield: 90.3%). 1H NMR (400 MHz, MeOD) δ 4.11 (dd, J = 10.7, 6.0Hz, 1H), 3.92 (s, 1H), 3.72 (td, J = 10.8, 6.9 Hz, 2H), 3.44 – 3.33 (m, 2H), 2.07 (tt, J = 16.0, 7.9 Hz, 2H), 1.47 (d, J = 4.2 Hz, 12H).

[0346] Example 1: Synthesis of 2-((S)-1-acryloyl-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphth-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0347]

[0348] Step 1: 2-Chloro-3-fluoro-5-iodopyridine-4-amine

[0349] The compound 2-chloro-3-fluoropyridin-4-amine (4.22 g, 28.80 mmol) was dissolved in acetonitrile (50 mL), then NIS (7.77 g, 34.55 mmol) and p-toluenesulfonic acid (248 mg, 1.44 mmol) were added, and the mixture was heated to 70 °C. o The reaction was stirred at C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, the reaction solution was diluted with water, the precipitated solid was filtered, washed with a saturated sodium thiosulfate aqueous solution, washed with water, and dried under vacuum to obtain the target compound, which was directly used in the next step. (7.5 g, yield: 98%) 1 H NMR (400MHz, CDCl3) δ 8.17 (s, 1H), 4.83 (s, 2H).

[0350] Step 2: Synthesis of 4-amino-6-chloro-5-fluoronicotinonitrile

[0351] 2-Chloro-3-fluoro-5-iodopyridin-4-amine (7.7 g, 28.26 mmol) and Zn(CN)₂ (4.32 g, 36.74 mmol) were dissolved in anhydrous DMF (150 mL), then Pd(PPh₃)₄ (1.63 g, 1.41 mmol) and 4A molecular sieve (2.5 g) were added, nitrogen gas was purged, and the mixture was heated to 100 °C under a nitrogen atmosphere. oThe reaction was stirred at C for 3 hours. After the reaction was complete, the solid was removed by filtration. The solution was cooled to room temperature, and 300 mL of water was added to dilute the reaction solution, precipitating a solid. The solid was filtered, washed with water, and dried under vacuum to obtain the crude product, which was directly used in the next step. (4.85 g, yield: 100%) 1 H NMR (400MHz, DMSO) δ 8.20 (s, 1H), 7.66 (s, 2H).

[0352] Step 3: Synthesis of 4-amino-6-chloro-5-fluoronicotinic acid

[0353] The compound 4-amino-6-chloro-5-fluoronicotinonitrile (4.85 g, 28.26 mmol) was dissolved in 50% H2SO4 (50 mL) and heated to 120 °C. o The reaction mixture was stirred for 6 hours. After the reaction was complete, it was cooled to room temperature, and the reaction solution was slowly poured into crushed ice, precipitating a solid. The solid was filtered and washed with water. The solid was dissolved in ethyl acetate, washed with saturated sodium carbonate solution, and the aqueous phase was collected. The pH of the aqueous phase was adjusted to 2-3 with 10% hydrochloric acid, precipitating a solid. The solid was filtered and dried under vacuum to obtain an off-white solid (4.62 g, yield: 85.8%). 1 HNMR (400MHz, DMSO) δ 8.36 (s, 1H), 7.59 (s, 2H).

[0354] Step 4: Synthesis of 7-chloro-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidine-2(1H)-thione

[0355] The compound 4-amino-6-chloro-5-fluoronicotinic acid was added to the reaction flask, followed by the addition of 50 mL of POCl3, and the mixture was heated to 90°C. o The reaction mixture was stirred at C for 4 hours. After the reaction was complete, it was cooled to room temperature, and the reaction solution was concentrated to obtain an oily substance which was dissolved in anhydrous tetrahydrofuran (20 mL). This oil was then added dropwise to a tetrahydrofuran mixture containing ammonium thiocyanate (3.67 g, 48.28 mmol) (80 mL). The mixture was stirred at room temperature for 24 hours. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated water, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid. Then, 10 mL of ethyl acetate was added, the mixture was stirred, filtered, and a pale yellow solid was obtained (4.52 g, yield: 80.8%). 1 H NMR (400MHz, DMSO) δ 13.29 (s, 1H), 12.85 (s, 1H), 8.64 (s, 1H).

[0356] Step 5: Synthesis of 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0357] The compound 7-chloro-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidine-2(1H)-thione (4.52 g, 19.51 mmol) was dissolved in anhydrous DMF (50 mL), followed by the addition of sodium methoxide (1.06 g, 19.51 mmol). After stirring at room temperature for 10 minutes, iodomethane (2.77 g, 1.21 mL, 19.51 mmol) was added dropwise, and the reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with cold water, and a solid precipitated. The solid was filtered, washed with water, and dried under vacuum to obtain a yellow solid (3.0 g, yield: 66%). 1 H NMR (400MHz, DMSO) δ 13.24 (s, 1H), 8.81 (s, 1H), 2.62 (s, 3H).

[0358] Step 6: Synthesis of 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

[0359] The compound 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (420 mg, 1.71 mmol) was dissolved in phosphorus oxychloride (4 mL), and then DIEA (442 mg, 3.42 mmol) was added. The mixture was heated to 90 °C and reacted for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and excess phosphorus oxychloride was removed by concentration. The product was then dissolved in ethyl acetate, washed successively with saturated brine and water, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was used directly in the next step. (450 mg, yield: 100%)

[0360] Step 7: Synthesis of (S)-4-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0361] 4,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (450 mg, 1.71 mmol) was dissolved in anhydrous DMF (10 mL). DIEA (1.10 g, 8.55 mmol) and (S)-2-(piperazin-2-yl)acetonitrile 2-hydrochloride (339 mg, 1.71 mmol) were added under ice-water bath cooling. After stirring for 10 minutes under ice-water bath cooling, di-tert-butyl dicarbonate (747 mg, 3.42 mmol) was added, and the reaction was stirred at room temperature for 16 hours. After the reaction was complete, 100 mL of cold water was added while stirring, the mixture was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain an off-white solid (710 mg, yield: 91.6%). 1H NMR (600MHz, CDCl3) δ 8.80 (s, 1H), 4.62 (s,1H), 4.45 (dd,J = 13.9, 3.5Hz, 1H), 4.28 (d,J = 12.8 Hz, 1H), 4.08 (s, 1H), 3.84 (s, 1H), 3.66 (d,J = 8.6Hz, 1H), 3.39 (s, 1H), 2.87 – 2.74 (m, 1H), 2.69 (dd,J = 16.8, 5.9Hz, 1H), 2.64 (s, 3H), 1.51 (s, 9H).

[0362] Step 8: Synthesis of (2S)-4-(7-chloro-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0363] (S)-4-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (700 mg, 1.55 mmol) was dissolved in dichloromethane (10 mL). 85% m-chloroperoxybenzoic acid (378 mg, 1.86 mmol) was added under ice-water bath cooling, and the mixture was stirred for 30 minutes under ice-water bath cooling. After the reaction was complete, the reaction was quenched with saturated sodium thiosulfate solution, extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate and brine. The mixture was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was used directly in the next step. (725 mg, yield: 100%)

[0364] Step 9: Synthesis of (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester:

[0365] (2S)-4-(7-chloro-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (725 mg, 1.55 mmol) was dissolved in anhydrous toluene (10 mL), followed by the addition of (S)-(1-methylpyrrolidine-2-yl)methanol (0.31 g, 2.71 mmol). Sodium tert-butoxide (0.30 g, 3.09 mmol) was added under ice-water bath cooling, and the mixture was stirred for 30 minutes under ice-water bath cooling. After the reaction was complete, the reaction was quenched with cold water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give an off-white solid (510 mg, yield: 63%).

[0366] Step 10: Synthesis of (S)-2-(cyanomethyl)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0367] Compound (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (40 mg, 0.08 mmol) and 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydronaphthyl)-1,3,2-dioxaborane (30 mg, 0.12 mmol) were dissolved in 1,4-dioxane / water = 5 / 1 (3 mL). Cesium carbonate (76 mg, 0.23 mmol) and Pd(PPh3)4 (45 mg, 0.04 mmol) were added, nitrogen was purged, and the mixture was heated to 95°C under a nitrogen atmosphere. o The reaction mixture was stirred at C for 1 hour. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by TLC to give an off-white solid (20 mg, yield: 42%).

[0368] Step 11: Synthesis of 2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidone-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphth-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0369] Compound (S)-2-(cyanomethyl)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (20 mg, 0.03 mmol / L) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated, then dissolved in dichloromethane, and the pH was adjusted to 8-9 with saturated sodium carbonate solution. The solution was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. The crude product was concentrated and used directly in the next step. (14 mg, yield: 98%)

[0370] Step 12: Synthesis of 2-((S)-1-acryloyl-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphth-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0371] Compound 2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (14 mg, 0.03 mmol) was dissolved in dichloromethane (5 mL). DIEA (5 mg, 0.03 mmol) and acryloyl chloride (3 mg, 0.03 mmol) were added under ice-water bath cooling, and the mixture was stirred for 5 minutes under ice-water bath cooling. After the reaction was complete, the reaction was quenched with saturated sodium carbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to give an off-white solid (10 mg, yield: 62%). 1 H NMR (400MHz, CDCl3) δ 9.10 (s, 1H), 7.26 - 7.21 (dd, m, 3H), 6.62- 6.57 (m, 1H), 6.48– 6.31 (m, 1H), 5.83 (dd, J = 19.7, 11.2 Hz, 1H), 5.02 (s, 2H), 4.62- 4.58(m, 1H), 4.49 - 4.44 (m, 3H), 4.10 (d, J = 12.0 Hz, 1H), 3.87 - 3.83 (m, 2H), 3.65 (dd, J = 13.5, 6.8 Hz, 1H), 3.57 - 3.51 (m, 2H), 3.34- 3.31 (m, 1H), 3.14 – 2.95 (m, 2H), 2.87 – 2.83 (m, 6H), 2.75 – 2.71 (m, 1H), 2.62 (t, J =5.7 Hz, 3H), 2.30 – 2.25 (m, 2H), 2.16 - 2.11 (m, 2H). MS m / z: 570.75 [M+H] +

[0372] Example 2: Synthesis of (S)-2-(1-acryloyl-4-(8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphth-1-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0373]

[0374] Step 1: Synthesis of (S)-4-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0375] (2S)-4-(7-chloro-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.21 mmol) was dissolved in anhydrous toluene (3 mL). (Tetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (46 mg, 0.32 mmol) and sodium tert-butoxide (31 mg, 0.32 mmol) were added under ice-water bath cooling. The mixture was stirred for 3 hours under ice-water bath cooling. After the reaction was complete, the reaction was quenched with cold water, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to give an off-white solid (55 mg, yield: 47%). 1 H NMR (400MHz, CDCl3) δ 8.82 (s, 1H), 4.75 (dt,J = 23.5, 12.9Hz, 3H), 4.58 (s, 1H), 4.31 (d,J = 11.7Hz, 1H), 4.18 – 3.88 (m, 4H), 3.82 (t,J =10.1Hz, 1H), 3.37 (s, 1H), 3.23 (dd,J = 16.7, 8.9Hz, 1H), 3.01 (s, 2H), 2.80(dd,J = 16.7, 3.9Hz, 1H), 2.55 – 2.37 (m, 2H), 2.34 – 2.21 (m, 3H), 2.15 (dt,J = 13.5, 6.8Hz, 2H), 2.02 (dd,J = 11.3, 6.9Hz, 2H), 1.49 (s, 9H).

[0376] Step 2: Synthesis of (S)-2-(cyanomethyl)-4-(8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphth-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0377] Compound (S)-4-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazin-1-carboxylic acid tert-butyl ester (57 mg, 0.10 mmol) and 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydronaphth-1-yl)-1,3,2-dioxaborane (33 mg, 0.13 mmol) were dissolved in 1,4-dioxane / water = 5 / 1 (3 mL), cesium carbonate (102 mg, 0.31 mmol) and Pd(PPh3)4 (60 mg, 0.05 mmol) were added, nitrogen was purged, and the mixture was heated to 95°C under a nitrogen atmosphere. o The reaction mixture was stirred at C for 1 hour. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by TLC to give an off-white solid (38 mg, yield: 57%). 1 H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 7.26 - 7.21 (m, 3H), 4.82 (s, 2H), 4.73 - 4.57 (m, 2H), 4.41 - 4.38 (m, 1H), 3.98 - 3.92 (m, 4H),3.87 -3.82 (m, 1H), 3.47 - 3.40 (m, 2H), 3.23 - 3.20 (m, 1H), 3.00 (s, 2H),2.87 (t, J = 6.2 Hz, 2H), 2.63 - 2.61 (m, 2H), 2.54 – 2.38 (m, 2H), 2.38 –2.20 (m, 2H), 2.14 (s, 2H), 2.03 - 1.98 (m, 2H), 1.81 (d, J = 6.1 Hz, 2H), 1.73 - 1.71 (m, 2H), 1.50 (s, 9H).

[0378] Step 3: Synthesis of (S)-2-(4-(8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphth-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0379] Compound (S)-2-(cyanomethyl)-4-(8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphth-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (38 mg, 0.06 mmol) was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated, dissolved in dichloromethane, and the pH was adjusted to 8-9 with saturated sodium carbonate. The solution was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. The crude product was concentrated and used directly in the next step. (32 mg, yield: 100%)

[0380] Step 4: Synthesis of (S)-2-(1-acryloyl-4-(8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphth-1-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0381] The compound (S)-2-(4-(8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphth-1-yl)pyridino[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (15 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL). DIEA (5 mg, 0.033 mmol) and acryloyl chloride (3 mg, 0.03 mmol) were added under ice-water bath cooling, and the mixture was stirred for 5 minutes under ice-water bath cooling. After the reaction was complete, the reaction was quenched with saturated sodium carbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to give an off-white solid (8 mg, yield: 49%). 1H NMR (400MHz, CDCl3) δ 9.13 (s, 1H), 7.21 (d, J = 3.8 Hz, 3H), 6.56 (s, 1H), 6.38 (d,J = 15.4 Hz, 1H), 5.82 (d, J = 9.6 Hz, 1H), 4.82 (s, 2H), 4.62 (d, J = 14.6Hz, 1H), 4.47 (d, J = 11.3 Hz, 1H), 4.25 - 4.22 (m, 1H), 3.93 (s, 4H), 3.66(d, J = 4.6 Hz, 1H), 3.35 (dd, J = 16.9, 7.6 Hz, 1H), 3.15 – 2.94 (m, 4H), 2.87 (t, J = 6.1 Hz, 2H), 2.63 (d, J = 5.9 Hz, 2H), 2.45 (ddd, J = 26.5,13.0, 6.6 Hz, 2H), 2.28 (dd, J = 16.8, 8.4 Hz, 2H), 2.18 - 2.11 (m, 2H), 2.06- 1.99 (m, 2H), 1.81 (d, J = 6.4 Hz, 2H), 1.73 (d, J = 6.2 Hz, 2H). MS m / z:596.68 [M+H] +

[0382] Example 3: Synthesis of (S)-2-(4-(8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphth-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0383]

[0384] Compound (S)-2-(4-(8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphth-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (15 mg, 0.03 mmol) and 2-fluoroacrylic acid (4 mg, 0.04 mmol) were dissolved in dichloromethane (3 mL), HATU (16 mg, 0.04 mmol) was added, and the mixture was cooled to 0°C in an ice-water bath. o C-10 o After C, add DIEA (6 mg, 0.04 mmol), at 0 oC-10 o The reaction mixture was stirred at C for 4 hours. After the reaction was complete, the reaction solution was diluted with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to obtain an off-white solid (8 mg, yield: 47%). 1 H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 7.26- 7.22 (m, 3H), 5.60 - 5.38(m, 1H), 5.28 (dd, J = 16.8Hz, 1H), , 4.82 (s,2H), 4.62 (d, J = 14.6 Hz, 1H), 4.47 (d, J = 11.3 Hz, 1H), 4.25 - 4.22 (m,1H), 3.93 (s, 4H), 3.66 (d, J = 4.6 Hz, 1H), 3.35 (dd, J = 16.9, 7.6 Hz, 1H),3.15 – 2.94 (m, 4H), 2.87 (t, J = 6.1 Hz, 2H), 2.63 (d, J = 5.9 Hz, 2H), 2.45 (ddd, J = 26.5, 13.0, 6.6 Hz, 2H), 2.28 (dd, J = 16.8, 8.4 Hz, 2H), 2.18 -2.11 (m, 2H), 2.06 - 1.99 (m, 2H), 1.81 (d, J = 6.4 Hz, 2H), 1.73 (d, J = 6.2Hz, 2H)MS m / z: 614.6 [M+H] +

[0385] Compounds in Examples 4-48 were prepared using preparation method 1.

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393] Example 49: Synthesis of 2-((S)-1-acryloyl-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiosom-8-yl)pyridin[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0394]

[0395] Step 1: Synthesis of 4,4,5,5-Tetramethyl-2-(thiochroman-8-yl)-1,3,2-dioxacyclopentane

[0396] Add 8-bromo-thiochromium (114 mg, 0.5 mmol), bis-pinacol boronic acid ester (279 mg, 1.1 mmol), Pd(dppf)Cl2 (37 mg, 0.05 mmol), and potassium acetate (147 mg, 1.5 mmol) to a round-bottom flask. After purging with nitrogen, add 5 mL of pre-deoxygenated anhydrous 1,4-dioxane. Stir the resulting suspension at 100°C for 16 hours. After cooling to room temperature, extract the reaction mixture with water (20 mL) and methyl tert-butyl ether (20 mL). After separation, extract the aqueous phase with methyl tert-butyl ether. Wash the combined organic phases with saturated brine (50 mL), dry to sodium sulfate, and evaporate to dryness under vacuum. The remaining dark brown oily substance was purified by column chromatography (silica gel, ethyl acetate: petroleum ether = 1:40) to give a colorless viscous substance. (42 mg, 0.152 mmol, yield: 30%)

[0397] Step 2: Synthesis of (S)-2-(cyanomethyl)-4-(8-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiocyanate-8-yl)pyridyl[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0398] Add (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (52 mg, 0.1 mmol), 4,4,5,5-tetramethyl-2-(thiochroman-8-yl)-1,3,2-dioxane (42 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium (46 mg, 0.4 mmol), and cesium carbonate (98 mg, 0.3 mmol) to a round-bottom flask. After purging with nitrogen, add pre-deoxygenated 1,4-dioxane (2 mL) and water (0.4 mL). Stir the reaction mixture at 100 °C for 3 hours. Add ethyl acetate (15 mL) and water (15 mL). After shaking and separation, the aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, and evaporated to dryness under vacuum. The remaining brown viscous substance was purified by preparative TLC (silica gel, methanol:dichloromethane = 1:9) to give a pale yellow solid. (32 mg, 0.05 mmol, yield: 50%) MS m / z: 634.7 [M+H) + .

[0399] Step 3: Synthesis of 2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiosom-8-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0400] At room temperature, trifluoroacetic acid (1 mL) was added dropwise to a solution of (S)-2-(cyanomethyl)-4-(8-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiocyanate-8-yl)pyridyl[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (32 mg, 0.05 mmol) in dichloromethane (3 mL). The resulting solution was stirred at room temperature for 1 hour. Dichloromethane (7 mL) was added and the solution was concentrated under vacuum. The residue was then concentrated again with dichloromethane (5 mL) and this process was repeated once. The resulting yellow solid was used directly in the next step.

[0401] Step 4: Synthesis of 2-((S)-1-acryloyl-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiosom-8-yl)pyridin[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0402] At room temperature, a solution of acryloyl chloride (0.01 mL, 0.122 mmol) in dichloromethane (1 mL) was slowly added dropwise to a solution of 2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiosom-8-yl)pyridin[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile and triethylamine (0.05 mL, 0.35 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 15 minutes. Then, 20 mL of dichloromethane and 20 mL of saturated sodium carbonate aqueous solution were added, and the mixture was shaken, separated, and the aqueous phase was extracted with 10 mL of dichloromethane. The combined organic phases were washed with 10 mL of saturated brine, dried over sodium sulfate, and rotary evaporated to obtain a viscous substance. Purification by preparative TLC (methanol:dichloromethane = 1:8) yielded a white solid (17 mg, overall yield of two steps: 57%). MS m / z: 588.6 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.27 (t, J = 7.7 Hz,1H), 7.16-7.12 (m, 2H), 6.66-6.56 (m, 1H), 6.42 (d, J = 16 Hz, 1H), 5.86 (d,J = 12 Hz, 1H), 5.10-4.98 (m, 2H), 4.65 – 4.60 (m, 1H), 4.52-4.40 (m, 2H), 4.10 – 4.07 (m, 1H), 3.85 – 3.81 (m, 1H), 3.72 – 3.25 (m, 4H), 3.06-2.78 (m,10H), 2.32 – 1.98 (m, 3H), 1.80-1.55 (m, 3H).

[0403] Example 50: Synthesis of 2-((S)-1-acryloyl-4-(8-fluoro-7-(isochrome-5-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0404]

[0405] Step 1: Synthesis of 2-(isochroman-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane

[0406] 5-Bromoisocyanate (198 mg, 0.93 mmol), bis-pinacolborate (709 mg, 2.8 mmol), Pd(dppf)Cl2 (102 mg, 0.14 mmol), and potassium acetate (274 mg, 2.8 mmol) were added to a round-bottom flask. After purging with nitrogen, 10 mL of pre-deoxygenated anhydrous 1,4-dioxane was added. The resulting suspension was stirred at 100°C for 16 hours. After cooling to room temperature, the reaction mixture was extracted with water (20 mL) and methyl tert-butyl ether (20 mL). After separation, the aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, and evaporated to dryness under vacuum. The remaining dark brown oil was purified by column chromatography (silica gel, ethyl acetate: petroleum ether = 1:30) to give a colorless oil (196 mg, 0.754 mmol, yield: 81%).

[0407] Step 2: Synthesis of (S)-2-(cyanomethyl)-4-(8-fluoro-7-(isochroman-5-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0408] Add (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (55 mg, 0.106 mmol), 2-(isochroman-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (52 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (49 mg, 0.0424 mmol), and cesium carbonate (104 mg, 0.32 mmol) to a round-bottom flask. After purging with nitrogen, add pre-deoxygenated 1,4-dioxane (2 mL) and water (0.4 mL). Stir the reaction mixture at 100 °C for 3 hours. Add ethyl acetate (15 mL) and water (15 mL). After shaking and separation, the aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, and evaporated to dryness under vacuum. The remaining brown viscous substance was purified by preparative TLC (silica gel, methanol:dichloromethane = 1:9) to obtain a pale yellow powder. (16 mg, 0.0259 mmol, yield: 24%) MS m / z: 618.7 [M+H] + .

[0409] Step 3: Synthesis of 2-((S)-4-(8-fluoro-7-(isotryptamine-5-yl)-2-((S)-1-methylpyrrolidine-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0410] At room temperature, trifluoroacetic acid (1 mL) was added dropwise to a solution of (S)-2-(cyanomethyl)-4-(8-fluoro-7-(isochroman-5-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (16 mg, 0.0259 mmol) in dichloromethane (3 mL). The resulting solution was stirred at room temperature for 1 hour. Dichloromethane (7 mL) was added and the solution was concentrated under vacuum. The residue was then concentrated again with dichloromethane (5 mL) and this process was repeated once. The resulting yellow solid was used directly in the next step.

[0411] Step 4: Synthesis of 2-((S)-1-acryloyl-4-(8-fluoro-7-(isochrome-5-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0412] At room temperature, a solution of acryloyl chloride (0.01 mL, 0.122 mmol) in dichloromethane (1 mL) was slowly added dropwise to a solution of 2-((S)-4-(8-fluoro-7-(isotryptamine-5-yl)-2-((S)-1-methylpyrrolidine-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile and triethylamine (0.06 mL, 0.42 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 15 minutes. Dichloromethane (20 mL) and a saturated aqueous sodium carbonate solution (20 mL) were added, and the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, and rotary evaporated to obtain a viscous substance. Purification by preparative TLC (methanol:dichloromethane = 1:9) yielded a white solid (3 mg, 0.0052 mmol, overall yield: 20%). MS m / z: 572.7 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.34-7.32 (m,2H), 7.13 (d, J = 4.0 Hz, 1H), 6.66-6.56 (m, 1H), 6.42 (d, J = 16 Hz, 1H), 5.86 (d, J = 12 Hz, 1H), 5.10-4.98 (m, 2H), 4.89 (s, 2H), 4.56-4.40 (m, 3H), 4.10 – 4.14 (m, 1H), 3.94 (t, J = 8.0 Hz, 2 H), 3.85 – 3.81 (m, 1H), 3.72 –3.25 (m, 2H), 3.06-3.00 (m, 1H), 2.80-2.52 (m, 7H), 2.32 – 1.98 (m, 3H), 1.80-1.55 (m, 3H).

[0413] Example 51: Synthesis of 2-((S)-1-acryloyl-4-(7-(benzo[b]thiophene-7-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0414]

[0415] Step 1: Synthesis of 2-(benzothiophene-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane

[0416] 7-Bromobenzo[b]thiophene (150 mg, 0.7 mmol), bis-pinacolborate (533 mg, 2.1 mmol), Pd(dppf)Cl2 (102 mg, 0.14 mmol), and potassium acetate (206 mg, 2.1 mmol) were added to a round-bottom flask. After purging with nitrogen, 5 mL of pre-deoxygenated anhydrous 1,4-dioxane was added. The resulting suspension was stirred at 100°C for 16 hours. After cooling to room temperature, the reaction mixture was extracted with water (20 mL) and methyl tert-butyl ether (20 mL). After separation, the aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, and evaporated to dryness under vacuum. The remaining dark brown oily substance was purified by column chromatography (silica gel, ethyl acetate: petroleum ether = 1:40) to obtain a colorless viscous substance. (160 mg, 0.615 mmol, yield: 99%)

[0417] Step 2: Synthesis of (S)-4-(7-(benzothiophene-7-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0418] Add (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (26 mg, 0.05 mmol), 2-(benzothiophene-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (26 mg, 0.1 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), and cesium carbonate (29 mg, 0.15 mmol) to a round-bottom flask. After purging with nitrogen, add pre-deoxygenated 1,4-dioxane (2 mL) and water (0.4 mL). Stir the reaction mixture at 100 °C for 3 hours. Add ethyl acetate (15 mL) and water (15 mL). After shaking and separation, the aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, and evaporated to dryness under vacuum. The remaining brown viscous substance was purified by preparative TLC (silica gel, methanol:dichloromethane = 1:9) to give a pale yellow solid. (16 mg, 0.0259 mmol, yield: 52%) MS m / z: 618.7 [M+H) + .

[0419] Step 3: Synthesis of 2-((S)-4-(7-(benzo[b]thiophene-7-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0420] At room temperature, trifluoroacetic acid (1 mL) was added dropwise to a solution of (S)-4-(7-(benzothiophene-7-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (16 mg, 0.0259 mmol) in dichloromethane (3 mL). The resulting solution was stirred at room temperature for 1 hour. Dichloromethane (10 mL) was added and the solution was concentrated under vacuum. The residue was then concentrated again with dichloromethane (5 mL) and this process was repeated once. The resulting yellow solid was used directly in the next step.

[0421] Step 4: Synthesis of 2-((S)-1-acryloyl-4-(7-(benzo[b]thiophene-7-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0422] At room temperature, a solution of acryloyl chloride (0.01 mL, 0.122 mmol) in dichloromethane (1 mL) was slowly added dropwise to a solution of 2-((S)-4-(7-(benzo[b]thiophene-7-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile and triethylamine (0.06 mL, 0.42 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 15 minutes. Dichloromethane (20 mL) and a saturated aqueous sodium carbonate solution (20 mL) were added, and the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, and rotary evaporated to obtain a viscous substance. The solution was purified by preparative TLC (methanol:dichloromethane = 1:8) to obtain a pale yellow powder (10 mg, 0.0175 mmol, overall yield of both steps: 67%). MS m / z: 572.6 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.57-7.53 (m, 2H), 7.45 (d, J = 4.0 Hz, 1H), 6.66 -6.56 (m, 1H), 6.40 (d, J = 16 Hz, 1H), 5.86 (d, J= 12 Hz, 1H), 5.10-4.98 (m, 2H), 4.67-4.65 (m, 1H), 4.57-4.49 (m, 2H), 4.10 –4.14 (m, 1H), 3.89 – 3.85 (m, 1H), 3.70 – 3.30 (m, 2H), 2.86 (s, 3H), 2.75-2.65 (m, 1H), 2.32 – 1.70 (m, 8H).

[0423] Example 52: Synthesis of 2-((2S)-1-acryloyl-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-2-yl)pyridin[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0424]

[0425] Step 1: Synthesis of 4,4,5,5-Tetramethyl-2-(1,1a,6,6a-tetrahydrocyclopropane[a]inden-2-yl)-1,3,2-dioxane

[0426] Add 2-bromo-1,1a,6,6a-tetrahydrocyclopropane[a]indene (180 mg, 0.86 mmol), bis-pinacolborate (655 mg, 2.58 mmol), Pd(dppf)Cl2 (126 mg, 0.172 mmol), and potassium acetate (253 mg, 2.58 mmol) to a round-bottom flask. After purging with nitrogen, add 6 mL of pre-deoxygenated anhydrous 1,4-dioxane. Stir the resulting suspension at 100°C for 16 hours. After cooling to room temperature, extract the reaction mixture with water (20 mL) and methyl tert-butyl ether (20 mL). After separation, extract the aqueous phase with methyl tert-butyl ether. Wash the combined organic phases with saturated brine (50 mL), dry to sodium sulfate, and evaporate to dryness under vacuum. The remaining dark brown oily substance was purified by column chromatography (silica gel, ethyl acetate: petroleum ether = 1:40) to obtain a colorless viscous substance. (101 mg, 0.395 mmol, yield: 46%)

[0427] Step 2: Synthesis of (2S)-2-(cyanomethyl)-4-(8-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-2-yl)pyridin[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0428] Add (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (30 mg, 0.058 mmol), 4,4,5,5-tetramethyl-2-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-2-yl)-1,3,2-dioxane (26 mg, 0.104 mmol), tetrakis(triphenylphosphine)palladium (27 mg, 0.023 mmol), and cesium carbonate (57 mg, 0.174 mmol) to a round-bottom flask. After purging with nitrogen, add pre-deoxygenated 1,4-dioxane (2 mL) and water (0.4 mL). Stir the reaction mixture at 100 °C for 3 hours. Add ethyl acetate (15 mL) and water (15 mL). After shaking and separation, the aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, and evaporated to dryness under vacuum. The remaining brown viscous substance was purified by preparative TLC (silica gel, methanol:dichloromethane = 1:9) to give a pale yellow solid. (15 mg, 0.0244 mmol, yield: 42%) MS m / z: 614.7 [M+H] + .

[0429] Step 3: Synthesis of 2-((2S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidone-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-2-yl)pyridin[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0430] At room temperature, trifluoroacetic acid (1 mL) was added dropwise to a solution of (2S)-2-(cyanomethyl)-4-(8-fluoro-2-((((S)-1-methylpyrrolidine-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-2-yl)pyridin[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (15 mg, 0.0244 mmol) in dichloromethane (3 mL). The resulting solution was stirred at room temperature for 1 hour. Dichloromethane (10 mL) was added and the solution was concentrated under vacuum. The residue was then concentrated again with dichloromethane (5 mL) and this process was repeated once. The resulting yellow solid was used directly in the next step.

[0431] Step 4: Synthesis of 2-((2S)-1-acryloyl-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-2-yl)pyridin[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0432] At room temperature, a solution of acryloyl chloride (0.005 mL, 0.061 mmol) in dichloromethane (1 mL) was slowly added dropwise to a solution of 2-((2S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-2-yl)pyridin[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile and triethylamine (0.03 mL, 0.21 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 15 minutes. Dichloromethane (20 mL) and a saturated aqueous sodium carbonate solution (20 mL) were added, and the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, and rotary evaporated to obtain a viscous substance. The solution was purified by preparative TLC (methanol:dichloromethane = 1:8) to obtain a pale yellow powder (10 mg, 0.0176 mmol, overall yield of both steps: 72%). MS m / z: 568.6 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 9.09(s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.37-7.35 (m, 2H), 6.66 -6.56 (m, 1H), 6.42 (d, J = 16 Hz, 1H), 5.86 (d, J = 12 Hz, 1H), 5.04-4.98 (m, 2H), 4.61 –4.45 (m, 3H), 4.11 – 4.07 (m, 1H), 3.81 – 3.76 (m, 1H), 3.60 – 3.38 (m, 1H),3.34-3.24 (m, 2 H), 3.06-2.97 (m, 2H), 2.83 (s, 3H), 2.75-2.70 (m, 1H), 2.48-2.44 (m, 1H), 2.32 – 1.80 (m, 8H), 1.10-1.04 (m, 1H), 0.15-0.11 (m, 1H).

[0433] Compounds from Examples 53-72 were prepared using preparation method 1.

[0434]

[0435]

[0436]

[0437]

[0438] Example 73: Synthesis of 2-((S)-1-acryloyl-4-(7-(8-chloronaphthyl-1-yl)-2-(((S)-1-methylpyrrolidone-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0439]

[0440] Step 1: Synthesis of (S)-4-(7-bromo-2-chloroquinazoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0441] The compound 7-bromo-2,4-dichloroquinazoline (200 mg, 0.72 mmol) was dissolved in DMF (5 mL), followed by the addition of DIEA (465 mg, 3.60 mmol) and (S)-2-(piperazin-2-yl)acetonitrile 2-hydrochloride (142 mg, 0.72 mmol). The mixture was stirred at room temperature for 30 minutes. Then, di-tert-butyl dicarbonate (472 mg, 2.16 mmol) was added, and the mixture was heated to 60°C. o The reaction mixture at step C was stirred for 16 hours. After the reaction was complete, 20 mL of cold water was added with stirring to dilute the reaction solution. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain an off-white solid (200 mg, yield: 60%). 1 H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 1.9 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.60 (dd, J = 8.9, 1.9 Hz, 1H), 4.68 (s, 1H), 4.37 (d, J = 13.3 Hz, 1H), 4.27 (d,J = 11.7 Hz, 1H), 4.15 (d, J = 7.1 Hz, 1H), 3.71 (dd, J = 13.6, 3.7 Hz, 1H), 3.59 – 3.48 (m, 1H), 3.42 (s, 1H), 2.87 (s, 1H), 2.75 (s, 1H), 1.54 (s, 9H).

[0442] Step 2: Synthesis of (S)-4-(7-bromo-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0443] (S)-(1-methylpyrrolidone-2-yl)methanol (149 mg, 1.29 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL). 60% NaH (52 mg, 1.29 mmol) was added under ice-water bath cooling. After stirring at room temperature for 20 minutes, (S)-4-(7-bromo-2-chloroquinazoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.43 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with cold water, extracted with ethyl acetate, washed with saturated water, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give an off-white solid (200 mg, yield: 85%).

[0444] Step 3: Synthesis of (S)-4-(7-(8-chloronaphthyl-1-yl)-2-(((S)-1-methylpyrrolidone-2-yl)methoxy)quinazolin-4-yl)-2-cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0445] Compounds (S)-4-(7-bromo-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (30 mg, 0.06 mmol) and 2-(8-chloronaphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (19 mg, 0.07 mmol) were dissolved in dioxane / water = 5 / 1 (3 mL), then cesium carbonate (54 mg, 0.17 mmol) and Pd(PPh3)4 (30 mg, 0.03 mmol) were added, nitrogen gas was purged, and the mixture was heated to 90°C. o The reaction mixture was stirred at C for 1 hour. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to obtain an off-white solid (28 mg, yield: 80%).

[0446] 1H NMR (300MHz, CDCl3) δ 7.96 (dd,J = 8.2, 1.1Hz, 1H), 7.90 (dd,J =8.1, 1.1Hz, 1H), 7.82 (d,J = 8.5Hz, 1H), 7.75 (t,J = 1.7Hz, 1H), 7.60 – 7.52(m, 2H), 7.45 (dd,J = 5.6, 2.7Hz, 1H), 7.33 (dd,J = 8.5, 1.6Hz, 1H), 7.23 (d,J = 7.6Hz, 1H), 4.86 (d,J = 5.8Hz, 1H), 4.71 (s, 1H), 4.57 (d,J = 11.5Hz,1H), 4.47 – 4.25 (m, 2H), 4.15 (s, 1H), 3.64 – 3.22 (m, 4H), 3.01 – 2.55 (m,6H), 2.25 (d,J = 6.3Hz, 1H), 2.18 – 1.89 (m, 3H), 1.54 (s, 9H).

[0447] Step 4: Synthesis of 2-((S)-4-(7-(8-chloronaphthyl-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0448] Compound (S)-4-(7-(8-chloronaphthyl-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-2-cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (28 mg, 0.04 mmol) was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for one hour. After the reaction was complete, the reaction solution was concentrated, then dissolved in dichloromethane, and the pH was adjusted to 8-9 with saturated sodium carbonate aqueous solution. The solution was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. The crude product was concentrated and used directly in the next step. (23 mg, yield: 100%)

[0449] Step 5: Synthesis of 2-((S)-1-acryloyl-4-(7-(8-chloronaphthyl-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0450] Compound 2-((S)-4-(7-(8-chloronaphthyl-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile (23 mg, 0.04 mmol) was dissolved in anhydrous dichloromethane (5 mL). DIEA (8 mg, 0.06 mmol) and acryloyl chloride (5 mg, 0.05 mmol) were added under ice-water bath cooling, and the mixture was stirred for 5 minutes under ice-water bath cooling. After the reaction was complete, the reaction was quenched with saturated sodium carbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and separated by TLC to obtain an off-white solid. 1 H NMR (300 MHz, CDCl3) δ 7.96 - 7.74 (m, 4H),7.54 (d, J = 7.1 Hz, 2H), 7.43 (d, J = 4.9 Hz, 2H), 7.34 (d, J = 8.6 Hz, 1H),6.70 - 6.61 (m, 1H), 6.49 – 6.32 (m, 1H), 5.84 (d, J = 10.5 Hz, 1H), 5.42-5.34 (m, 1H), 5.13 – 5.06 (m, 1H), 4.71 – 4.67 (m, 1H), 4.55 – 4.31 (m, 2H),3.89 – 3.43 (m, 4H), 3.10 -2.88 (m, 6H), 2.33 (s, 2H), 2.21 - 1.96 (m, 4H).MS m / z: 581.58 [M+H] +

[0451] Example 74: Synthesis of 2-((2S)-1-acryloyl-4-(6-chloro-8-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-ylquinazoline-4-ylpiperazin-2-ylacetonitrile)

[0452]

[0453] Step 1: Synthesis of compound 2-amino-3-fluoro-4-bromobenzamide

[0454] 2-Amino-3-fluoro-4-bromobenzoic acid (5.0 g, 20 mmol) was dissolved in 50 mL of DMF. After stirring and dissolving, TBTU (16.0 g, 50 mmol), NH4Cl (27.0 g, 50 mmol), and DIEA (14 mL, 80 mmol) were added in one step at room temperature. The reaction system was stirred at room temperature for 3 hours. After the reaction was complete, about 300 mL of water was added to the reaction system, and a large amount of solid precipitated. When the solid stopped precipitating, it was filtered to obtain a pale yellow solid, which was directly used in the next step. (3.7 g, yield: 74%) 1 H NMR (400MHz, DMSO) δ 7.92 (s, 2H), 7.66 (s, 1H), 6.94 (s, 1H), 6.25 (s, 2H).

[0455] Step 2: Synthesis of compound 7-bromo-8-fluoroquinazoline-2,4-diol

[0456] 2-Amino-4-bromo-5-chlorobenzamide (3.6 g, 14.4 mmol) was dissolved in 40 ml of DMF. After stirring to dissolve, CDI (9.3 g, 57.7 mmol) and K2CO3 (8.0 g, 50 mmol) were added in one step at room temperature. The reaction system was heated to 80°C. o Stir overnight at C. After the reaction is complete, add about 300 ml of water to the reaction system, and a large amount of solid precipitates. When the solid stops precipitating, filter to obtain a pale yellow solid, which can be used directly in the next step. (3.9 g, yield: 90%) 1 H NMR(400MHz, DMSO) δ 11.34 (s,1H), 11.40 (s, 1H), 8.12 (s, 1H), 7.93 (s, 1H).

[0457] Step 3: Synthesis of compound 7-bromo-2,4-dichloro-8-fluoroquinazoline

[0458] 7-Bromo-6-chloroquinazoline-2,4-diol (3.9 g, 14 mmol) was dissolved in 50 mL of POCl3, and approximately 5 mL of N,N-diethylaniline was added at room temperature. The reaction mixture was heated to 110 °C and stirred overnight. After the reaction was complete, the solvent was removed from the reaction mixture under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether) to give a yellow solid (2.62 g, 60%). 1 H NMR (400MHz, CDCl3) δ 8.12 (s, 1H), 7.93 (s, 1H).

[0459] Step 4: Synthesis of (S)-4-(7-bromo-2-chloro-8-fluoroquinazoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0460] Compound 7-bromo-2,4,6-trichloroquinazoline (312 mg, 1 mmol) and DIEA (0.6 ml, 3.5 mmol) were dissolved in 10 ml of DMF. 2-cyanoperpiperazine (198 mg, 1 mmol) was added in portions under ice-water bath conditions. The reaction mixture was stirred until it reached room temperature. After the reaction was complete as monitored by TLC, Boc₂O (0.6 ml, 2.5 mmol) was added, and the reaction was continued to be stirred at room temperature for 2 hours. After the reaction was complete, approximately 70 ml of saturated sodium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a pale yellow solid, which was directly used in the next reaction step (450 mg, 90% yield). 1 H NMR (400MHz, CDCl3) δ 8.14 (s, 1H), 7.95 (s, 1H), 3.5 (m, 1H), 3.38-3.13 (m, 4H), 3.02-2.98 (m, 2H), 2.73 (m, 1H), 2.48 (m, 1H), 1.42 (s,9H).

[0461] Step 5: Synthesis of tert-butyl(S)-4-(7-bromo-8-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0462] (S)-(1-methylpyrrolidin-2-yl)methanol (173 mg, 1.5 mmol) was dissolved in ultradry THF (15 mL). Under ice-water bath conditions, 60% sodium hydride (36 mg, 1.5 mmol) was added, and the mixture was stirred for 30 min. Then, (S)-4-(7-bromo-2,6-dichloroquinazoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.5 mmol) was added, and the reaction mixture was stirred at room temperature for one hour. After the reaction was complete, water was added to quench the reaction mixture. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The crude product was obtained after removing the solvent under reduced pressure. The crude product was separated by column chromatography to obtain a pale yellow solid (133 mg, yield: 50%).

[0463] Step 6: Synthesis of tert-butyl(S)-4-(6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid The compounds tert-butyl(S)-4-(7-bromo-6-chloro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (64 mg, 0.11 mmol), 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydronaphthyl-1-yl)-1,3,2-dioxaborane (43 mg, 0.17 mmol), and Cs₂CO₃ (72 mg, 0.22 mmol) were dissolved in a co-solvent of 1,4-dioxane and water (4 ml / 1 ml). After purging with nitrogen, a Pd(PPh₃)₄ catalyst (13 mg, 0.01 mmol) was added. The reaction system was kept at 90 °C. o The mixture was stirred at C for one hour. After the reaction was complete, the reaction system was extracted with ethyl acetate, separated, and the organic phase was dried and the solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by column chromatography to obtain a pale yellow solid (50 mg, yield: 80%).

[0464] Step 7: Synthesis of 2-((2S)-1-acryloyl-4-(6-chloro-8-fluoro-2-((((S)-1-methylpyrrolidone-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-ylquinazoline-4-ylpiperazin-2-ylacetonitrile)

[0465] The compound tert-butyl(S)-4-(6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)quinazolin-4-yl)-2-(cyanomethyl)piperazin-1-carboxylic acid (31 mg, 0.1 mmol) was dissolved in a co-solvent of DCM and CF3COOH (3 ml / 1 ml). The mixture was stirred at room temperature for one hour. After the reaction was complete, the organic solvent in the reaction system was removed under reduced pressure, and the mixture was dissolved in dichloromethane and then evaporated to dryness again. This process was repeated once more. The crude product was directly used in the next step of the reaction. It was dissolved in 3 ml of ultra-dry dichloromethane, and triethylamine (0.1 ml, 0.5 mmol) and acryloyl chloride (0.05 ml, 0.2 mmol) were added. The reaction system was stirred at room temperature for one hour. After the reaction was complete, the reaction system was evaporated to dryness, dissolved in ethyl acetate, and the organic phase was neutralized with saturated sodium carbonate solution. After extraction and separation, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was then separated by PLC to obtain an off-white solid. (10 mg, yield: 34%) 1H NMR (400MHz, CDCl3) δ 8.29 (s, 1H), 8.23 ​​(s, 1H), 7.27 (m,1H), 7.21 (m,1H), 7.02 (m, 1H), 6.62 (m, 1H), 6.04 (m, 1H), 5.58 (m, 1H), 3.65-3.40 (m, 3H), 3.38-3.13 (m, 4H), 3.02-2.98 (m, 2H), 2.85 (m, 1H), 2.75-2.70 (m, 5H), 2.50-2.30 (m, 3H), 2.26 (s, 3H), 1.74-1.41 (m, 8H). MS m / z: 585.27 [M+H] +

[0466] Example 75: Synthesis of 2-((S)-1-acryloyl-4-(6-chloro-2-(((S)-1-methylpyrrolidone-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile:

[0467]

[0468] Step 1: Synthesis of compound 2-amino-4-bromo-5-chlorobenzamide

[0469] 2-Amino-4-bromo-5-chlorobenzoic acid (5.0 g, 20 mmol) was dissolved in 50 ml of DMF. After stirring to dissolve, TBTU (16.0 g, 50 mmol), NH4Cl (27.0 g, 50 mmol), and DIEA (14 ml, 80 mmol) were added in one step at room temperature. The reaction system was stirred at room temperature for 3 hours. After the reaction was complete, about 300 ml of water was added to the reaction system, and a large amount of solid precipitated. When the solid stopped precipitating, it was filtered to obtain a pale yellow solid, which was directly used in the next step. (3.6 g, yield: 72%) 1 H NMR (400MHz, DMSO) δ 7.90 (s, 2H), 7.68 (s, 1H), 6.96 (s, 1H), 6.27(s, 2H).

[0470] Step 2: Synthesis of compound 7-bromo-6-chloroquinazoline-2,4-diol

[0471] 2-Amino-4-bromo-5-chlorobenzamide (3.6 g, 14.4 mmol) was dissolved in 40 ml of DMF. After stirring to dissolve, CDI (9.3 g, 57.7 mmol) and K2CO3 (8.0 g, 50 mmol) were added in one step at room temperature. The reaction system was heated to 80°C. o Stir overnight at C. After the reaction is complete, add about 300 ml of water to the reaction system, and a large amount of solid precipitates. When the solid stops precipitating, filter to obtain a pale yellow solid, which can be used directly in the next step. (3.9 g, yield: 90%) 1 H NMR(400MHz, DMSO) δ 11.34 (s,1H), 11.40 (s, 1H), 8.12 (s, 1H), 7.93 (s, 1H).

[0472] Step 3: Synthesis of compound 7-bromo-2,4,6-trichloroquinazoline

[0473] 7-Bromo-6-chloroquinazoline-2,4-diol (3.9 g, 14 mmol) was dissolved in 50 mL of POCl3, and approximately 5 mL of N,N-diethylaniline was added at room temperature. The reaction mixture was heated to 110 °C and stirred overnight. After the reaction was complete, the solvent was removed from the reaction mixture under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether) to give a yellow solid (2.62 g, 60%). 1 H NMR (400MHz, CDCl3) δ 8.12 (s, 1H), 7.93 (s, 1H).

[0474] Step 4: Synthesis of tert-butyl (S)-4-(7-bromo-2,6-dichloroquinazoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0475] Compound 7-bromo-2,4,6-trichloroquinazoline (312 mg, 1 mmol) and DIEA (0.6 ml, 3.5 mmol) were dissolved in 10 ml of DMF. 2-cyanoperpiperazine (198 mg, 1 mmol) was added in portions under ice-water bath conditions. The reaction mixture was stirred until it reached room temperature. After the reaction was complete as monitored by TLC, Boc₂O (0.6 ml, 2.5 mmol) was added, and the reaction was continued to be stirred at room temperature for 2 hours. After the reaction was complete, approximately 70 ml of saturated sodium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a pale yellow solid, which was directly used in the next reaction step (450 mg, 90% yield). 1H NMR (400MHz, CDCl3) δ 8.14 (s, 1H), 7.95 (s, 1H), 3.5 (m, 1H), 3.38-3.13 (m, 4H), 3.02-2.98 (m, 2H), 2.73 (m, 1H), 2.48 (m, 1H), 1.42 (s,9H).

[0476] Step 5: Synthesis of tert-butyl(S)-4-(7-bromo-6-chloro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0477] (S)-(1-methylpyrrolidone-2-yl)methanol (173 mg, 1.5 mmol) was dissolved in ultra-dry THF (15 mL). Under ice-water bath conditions, 60% sodium hydride (36 mg, 1.5 mmol) was added, and the mixture was stirred for 30 min. Then, (S)-4-(7-bromo-2,6-dichloroquinazoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.5 mmol) was added, and the reaction mixture was stirred at room temperature for one hour. After the reaction was complete, water was added to quench the reaction mixture. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The crude product was obtained after removing the solvent under reduced pressure. The crude product was separated by column chromatography to obtain a pale yellow solid (150 mg, yield: 52%).

[0478] Step 6: Synthesis of tert-butyl(S)-4-(6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid The compounds tert-butyl(S)-4-(7-bromo-6-chloro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (64 mg, 0.11 mmol), 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydronaphthyl-1-yl)-1,3,2-dioxaborane (43 mg, 0.17 mmol), and Cs₂CO₃ (72 mg, 0.22 mmol) were dissolved in a co-solvent of 1,4-dioxane and water (4 ml / 1 ml). After purging with nitrogen, a Pd(PPh₃)₄ catalyst (13 mg, 0.01 mmol) was added. The reaction system was kept at 90 °C. oThe mixture was stirred at C for one hour. After the reaction was complete, the reaction system was extracted with ethyl acetate, separated, and the organic phase was dried and the solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by column chromatography to obtain a pale yellow solid (62 mg, yield: 89%).

[0479] Step 7: Synthesis of 2-((S)-1-acryloyl-4-(6-chloro-2-(((S)-1-methylpyrrolidone-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0480] The compound tert-butyl(S)-4-(6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)quinazolin-4-yl)-2-(cyanomethyl)piperazin-1-carboxylic acid (62 mg, 0.1 mmol) was dissolved in a co-solvent of DCM and CF3COOH (3 ml / 1 ml). The mixture was stirred at room temperature for one hour. After the reaction was complete, the organic solvent in the reaction system was removed under reduced pressure, and the mixture was dissolved in dichloromethane and then evaporated to dryness again. This process was repeated once more. The crude product was directly used in the next step of the reaction. It was dissolved in 3 ml of ultra-dry dichloromethane, and triethylamine (0.1 ml, 0.5 mmol) and acryloyl chloride (0.05 ml, 0.2 mmol) were added. The reaction system was stirred at room temperature for one hour. After the reaction was complete, the reaction system was evaporated to dryness, dissolved in ethyl acetate, and the organic phase was neutralized with saturated sodium carbonate solution. After extraction and separation, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by PLC to obtain an off-white solid. (20 mg, yield: 34%) 1 H NMR (400MHz, CDCl3) δ 8.29 (s, 1H), 8.23 ​​(s, 1H), 7.27 (m,1H), 7.21 (m,1H), 7.02 (m, 1H), 6.62 (m, 1H), 6.04 (m, 1H), 5.58 (m, 1H), 3.65-3.40 (m, 3H), 3.38-3.13 (m, 4H), 3.02-2.98 (m, 2H), 2.85 (m, 1H), 2.75-2.70 (m, 5H), 2.50-2.30 (m, 3H), 2.26 (s, 3H), 1.74-1.41 (m, 8H). MS m / z: 585.27 [M+H] +

[0481] Example 76: Synthesis of 1-(4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0482]

[0483] Step 1: Synthesis of tert-butyl 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidone-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)quinazolin-4-yl)piperazine-1-carboxylic acid Compounds (S)-4-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (56 mg, 0.11 mmol), 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydronaphthyl-1-yl)-1,3,2-dioxaborane (43 mg, 0.17 mmol), and Cs₂CO₃ (72 mg, 0.22 mmol) were dissolved in a co-solvent of 1,4-dioxane and water (4 ml / 1 ml). After purging with nitrogen, Pd(PPh₃)₄ catalyst (13 mg, 0.01 mmol) was added. The reaction system was stirred at 90 °C for one hour. After the reaction was completed, the reaction system was extracted with ethyl acetate, separated, and the organic phase was dried and the solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by column chromatography to obtain a pale yellow solid (33 mg, yield: 50%).

[0484] Step 2: Synthesis of 1-(4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0485] Compound 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)quinazolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (33 mg, 0.05 mmol) was dissolved in a co-solvent of DCM and CF3COOH (3 ml / 1 ml). The mixture was stirred at room temperature for one hour. After the reaction was complete, the organic solvent in the reaction system was removed under reduced pressure, and the mixture was dissolved in dichloromethane and then evaporated to dryness again. This process was repeated once more. The crude product was directly used in the next step of the reaction. It was dissolved in 3 ml of ultra-dry dichloromethane, and triethylamine (0.1 ml, 0.5 mmol) and acryloyl chloride (0.05 ml, 0.2 mmol) were added. The reaction system was stirred at room temperature for one hour. After the reaction was complete, the reaction system was evaporated to dryness, dissolved in ethyl acetate, and the organic phase was neutralized with saturated sodium carbonate solution. After extraction and separation, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by PLC to obtain an off-white solid. (8 mg, yield: 28%) 1 H NMR (400MHz, CDCl3) δ 8.00 (s, 1H), 7.27 (m,1H), 7.11 (m,1H), 7.02 (m, 1H), 6.62 (m, 1H), 6.04 (m, 1H), 5.58 (m, 1H), 3.65-3.40 (m, 2H),3.38-3.13 (m, 4H), 2.85 (m,1H), 2.75-2.70 (m, 5H), 2.50-2.30 (m, 3H), 2.26 (s, 3H), 1.74-1.41 (m, 8H).MS m / z: 585.27 [M+H]+

[0486] Example 77: Synthesis of 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphth-1-yl)pyrido[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0487]

[0488] Step 1: Synthesis of (S)-2-(cyanomethyl)-4-(2,7-dichloropyridino[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0489] Compound 2,4,7-trichloropyrido[2,3-d]pyrimidine (200 mg, 0.85 mmol) was dissolved in anhydrous DMF (5 mL). DIEA (552 mg, 4.27 mmol) and (S)-2-(piperazin-2-yl)acetonitrile 2-hydrochloride (169 mg, 0.85 mmol) were added under ice-water bath cooling. The mixture was stirred for 10 minutes under ice-water bath cooling, then di-tert-butyl dicarbonate (372 g, 1.70 mmol) was added, and the mixture was heated to 40°C. o The reaction mixture was stirred at C for 3 hours. After the reaction was complete, it was cooled to room temperature, diluted with saturated brine, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give a pale yellow solid (335 mg, yield: 93%). 1 H NMR (400MHz, CDCl3) δ 8.18 (d,J = 8.6Hz, 1H), 7.34 (d,J = 8.6Hz, 1H), 4.65 (s, 1H), 4.47 (dd,J = 13.9, 3.0Hz, 1H), 4.30 (d,J = 12.0Hz, 1H), 4.12 (d,J = 7.1Hz, 1H), 3.82 (d,J = 12.2Hz, 1H), 3.69 (s,1H), 3.54 (s, 1H), 3.02 – 2.87 (m, 1H), 2.80 (d,J = 13.8Hz, 1H), 1.52 (s,9H).

[0490] Step 2: Synthesis of (S)-4-(7-chloro-2-(((S)-1-methylpyrrolidone-2-yl)methoxy)pyrido[2,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0491] Compound (S)-2-(cyanomethyl)-4-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.24 mmol) and (S)-(1-methylpyrrolidone-2-yl)methanol (82 mg, 0.71 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL), and DIEA (92 mg, 0.71 mmol) was added. The mixture was heated to 80 °C. o The reaction mixture was stirred at C for 16 hours. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to give an off-white solid (70 mg, yield: 59%). 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.6 Hz, 1H), 7.26 (d,J = 8.6Hz, 1H), 5.04 (s, 1H), 4.82(s, 1H), 4.61 (s, 1H), 4.45 (d, J = 13.9 Hz, 1H), 4.21 (d, J = 12.6 Hz, 1H), 4.07 (s, 1H), 3.73 (d, J = 10.6 Hz, 2H), 3.64 – 3.47 (m, 2H), 3.45 – 3.25 (m,2H), 2.95 (s, 3H), 2.86 – 2.61 (m, 3H), 2.28 (s, 2H), 2.10 (d, J = 21.3 Hz,2H), 1.51 (s, 9H).

[0492] Step 3: Synthesis of (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)pyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0493] Compound (S)-4-(7-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[2,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (30 mg, 0.06 mmol) and 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydronaphth-1-yl)-1,3,2-dioxaborane (19 mg, 0.07 mmol) were dissolved in 1,4-dioxane / water = 5 / 1 (3 mL). Cesium carbonate (59 mg, 0.18 mmol) and Pd(PPh3)4 (35 mg, 0.03 mmol) were added, nitrogen was purged, and the mixture was heated to 95°C under a nitrogen atmosphere. o The reaction mixture was stirred at C for 1 hour. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by TLC to give an off-white solid (27 mg, yield: 75%). MS m / z: 598.84 [M+H] + .

[0494] Step 4: Synthesis of 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphth-1-yl)pyrido[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0495] The compound (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)pyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (27 mg, 0.04 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated, and saturated sodium carbonate aqueous solution and dichloromethane were added. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. The crude product was concentrated and used directly in the next step.

[0496] Step 5: Synthesis of 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphth-1-yl)pyrido[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0497] Compound 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)pyrido[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (22 mg, 0.04 mmol) was dissolved in dichloromethane (5 mL). DIEA (8 mg, 0.06 mmol) and acryloyl chloride (5 mg, 0.05 mmol) were added under ice-water bath cooling, and the mixture was stirred for 5 minutes under ice-water bath cooling. After the reaction was complete, saturated sodium carbonate was added to quench the reaction. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to give an off-white solid (18 mg, yield: 74%). 1H NMR (400MHz, CDCl3) δ 8.24 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.22- 7.16(m, 3H), 6.59 (s, 1H), 6.41 (d, J = 16.3 Hz, 1H), 5.84 (d, J = 11.7 Hz, 1H), 5.02 (s, 2H), 4.84 (d, J = 11.2 Hz, 1H), 4.47 (d, J = 14.0 Hz, 1H), 4.37 -4.34 (m, 1H), 3.84 (d, J = 10.3 Hz, 1H), 3.77 - 3.49 (m, 4H), 3.08 (ddd, J =16.9, 11.4, 7.7 Hz, 2H), 2.97 (s, 3H), 2.89 - 2.73 (m, 6H), 2.42 - 2.17 (m,4H), 2.09 - 2.03 (m, 4H).MS m / z: 552.64 [M+H] + .

[0498] Compounds 78-614 were prepared using preparation method 2.

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

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[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

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[0559]

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[0566]

[0567]

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[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575] Example 615: Synthesis of (S)-1-(4-(6-chloro-8-fluoro-7-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0576]

[0577] Step 1: Synthesis of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid

[0578] 2-Amino-4-bromo-3-fluorobenzoic acid (2.30 g, 10 mmol) and NCS (1.60 g, 12 mmol) were dissolved in 30 mL of DMF, and the reaction system was heated to 70 °C. o The mixture was stirred overnight at temperature C. After the reaction was complete, 300 ml of water was added to the reaction system, and a large amount of solid precipitated out. The solid was filtered, dried, and weighed to obtain a pale yellow solid (1.34 g, yield: 50%). 1 H NMR (400MHz, DMSO) δ 13.11 (s, 1H), 7.63 (s, 1H), 6.62 (s, 2H).

[0579] Step 2: Synthesis of 7-bromo-6-chloro-8-fluoroquinazoline-2,4-diol

[0580] 2-Amino-4-bromo-5-chloro-3-fluorobenzoic acid (1.34 g, 5 mmol) and urea (1.5 g, 25 mmol) were placed in a 50 ml single-necked flask, and the reaction mixture was heated to 180°C under nitrogen protection. o C. After reacting for three hours, 30 ml of 1 N / mol NaOH solution was added to the reaction system and stirred. A large amount of insoluble solid precipitated out, and the solid was filtered to obtain a pale yellow solid (514 mg, 35%). 1 H NMR (400MHz, DMSO) δ 11.40 (s, 1H), 11.34 (s, 1H), 7.70 (s, 1H).

[0581] Step 3: Synthesis of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline

[0582] The compound 7-bromo-6-chloro-8-fluoroquinazoline-2,4-diol (500 mg, 1.73 mmol) was dissolved in 10 ml of phosphorus oxychloride, and 1 ml of DMF was added. The reaction system was heated to 110°C. o C. Stir overnight. After the reaction is complete, phosphorus oxychloride is removed under reduced pressure to obtain a black paste-like liquid. Ice water is added and stirred under ice-water bath conditions, and a large amount of solid precipitates out. After filtration and drying, a yellow solid is obtained (300 mg, 54%). 1 H NMR (400MHz, DMSO) δ 7.70 (s, 1H).

[0583] Step 4: Synthesis of tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazoline-4-yl)piperazine-1-carboxylic acid

[0584] Compound 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (300 mg, 0.9 mmol) and piperazine-1-carboxylic acid tert-butyl ester (167.4 mg, 0.9 mmol) were dissolved in 4 ml of 1,4-dioxane. After adding DIEA (0.5 ml, 2.25 mmol), the reaction system was heated to 55 °C. o Heating was performed at C for three hours. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product. The crude product was dissolved in DCM, and the organic phase was washed three times with 0.5 mol / L HCl. After extraction and separation, the organic phase was dried and removed under reduced pressure to obtain a yellow solid (414 mg, yield: 96%). 1 H NMR (400MHz, CDCl3) δ 7.70 (s, 1H), 3.73 (m, 4H), 3.32 (m, 4H), 1.44 (s, 9H).

[0585] Step 5: Synthesis of (S)-4-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0586] Compound 4-(7-bromo-2,6-dichloro-8-fluoroquinazoline-4-yl)piperazine-1-carboxylic acid tert-butyl ester (414 mg, 0.86 mmol) and K₂CO₃ (240 mg, 1.72 mmol) were dissolved in 30 mL of ultra-dry acetonitrile, and (S)-(1-methylpyrrolidone-2-yl)methanol (96 mg, 0.86 mmol) was added. The reaction system was heated to 90°C under nitrogen protection. o C. Stir for 6 hours. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product. The crude product is then separated by column chromatography (DCM:MeOH=10:1) to give a brown solid. (170 mg, 35%)

[0587] Step 6: Synthesis of tert-butyl(S)-4-(6-chloro-8-fluoro-7-(6-fluoro-3,4-dihydroquinoline-1(2H)-yl)-2-(((1-methylpyrrolidone-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylic acid

[0588] Compounds (S)-4-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (38 mg, 0.05 mmol), 6-fluoro-1,2,3,4-tetrahydroquinoline (26 mg, 0.18 mmol), t-BuONa (34 mg, 0.34 mmol), and RuPhos (38 mg, 0.08 mmol) were dissolved in 6 ml of toluene. After purging with nitrogen, Pd2(dba)3 (38 mg, 0.04 mmol) was added. After further purging with nitrogen, the reaction was carried out at 100 °C. o The reaction was carried out overnight at C. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by column chromatography to obtain the pale yellow target product (70 mg, 65%).

[0589] Step 7: Synthesis of (S)-6-chloro-8-fluoro-7-(6-fluoro-3,4-dihydroquinoline-1(2H)-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)-4-(piperazin-1-yl)quinazoline

[0590] The compound tert-butyl(S)-4-(6-chloro-8-fluoro-7-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-(((1-methylpyrrolidone-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylic acid (62 mg, 0.1 mmol) was dissolved in a co-solvent of DCM and CF3COOH (3 ml / 1 ml). The mixture was stirred at room temperature for one hour. After the reaction was complete, the organic solvent in the reaction system was removed under reduced pressure, and the mixture was dissolved in dichloromethane and then evaporated to dryness. This process was repeated once more. The crude product was used directly in the next step of the reaction. (53 mg, yield: 100%)

[0591] Step 8: Synthesis of (S)-1-(4-(6-chloro-8-fluoro-7-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0592] The compound (S)-6-chloro-8-fluoro-7-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)-4-(piperazin-1-yl)quinazoline (53 mg, 0.1 mmol) was dissolved in dichloromethane (3 mL). DIEA (80 mg, 0.60 mmol) was added under ice-water bath cooling, followed by acryloyl chloride (18 mg, 0.13 mmol). The reaction was stirred for 10 minutes under ice-water bath. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and separated by PLC (dichloromethane / methanol = 15 / 1) to give an off-white solid (30 mg, yield: 50%). 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 9.1 Hz, 1H), 7.31 – 7.23 (m, 1H), 6.93 – 6.80 (m, 1H), 6.71 (s, 1H), 6.54 (dd, J = 16.7, 10.5 Hz, 1H), 6.30 (d,J = 16.7 Hz, 1H), 5.71 (d, J = 11.9 Hz, 1H), 5.12 (s, 1H), 4.67 (d, J = 10.9Hz, 1H), 4.10 (t, J = 8.1 Hz, 2H), 3.80 (s, 7H), 3.13 (t, J = 8.2 Hz, 2H),2.95 (s, 3H), 2.77 (s, 1H), 2.37 – 1.86 (m, 5H), 1.61 (s, 4H). MS m / z: 583.23[M+H]+

[0593] Compounds of Examples 616-619 were prepared using the method of Example 615.

[0594]

[0595] Example 620: Synthesis of (S)-4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-chloro-7-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-3-carboxylonitrile

[0596]

[0597] Step 1: Synthesis of methyl 4-bromo-2-(2-cyanoacetamido)benzoate

[0598] 10 g (43.47 mmol) of methyl 2-amino-4-bromobenzoate and cyanoacetic acid (4.44 g, 52.16 mmol) were dissolved in 100 mL of dichloromethane. EDCI (12.5 g, 65.10 mmol) was added under ice-water bath cooling, and the mixture was stirred for 1 hour under ice-water bath cooling. After the reaction was complete, the reaction solution was diluted with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the target compound (12.9 g, yield: 100%). 1H NMR(400MHz, CDCl3) δ 11.73 (s, 1H), 8.88 (d,J = 1.5Hz, 1H), 7.92 (d,J = 8.6Hz,1H), 7.32 (dd,J = 8.6, 1.8Hz, 1H), 3.97 (s, 3H), 3.61 (s, 2H).

[0599] Step 2: 7-Bromo-2,4-Dihydroxyquinoline-3-carboxynitrile

[0600] Methyl 4-bromo-2-(2-cyanoacetamido)benzoate (12.9 g, 43.42 mmol) was dissolved in anhydrous methanol (100 mL). A 30% sodium methoxide solution (11.73 g, 65.13 mmol) was added dropwise under ice-water bath cooling. The mixture was stirred for 30 minutes under ice-water bath cooling. After the reaction was complete, the pH was adjusted to 2-3 with 10% hydrochloric acid aqueous solution. The reaction solution was diluted with 100 mL of water, and a solid precipitated. The solid was filtered and dried under vacuum to obtain an off-white solid (11.18 g, yield: 97%). 1 H NMR (400MHz, DMSO) δ11.62 (s, 1H), 7.90 (d,J = 8.6Hz, 1H), 7.45 (d,J = 1.8Hz, 1H), 7.37 (dd, J =8.6, 1.8Hz, 1H).

[0601] Step 3: Synthesis of 7-bromo-2,4-dichloroquinoline-3-carboxynitrile

[0602] The compound 7-bromo-2,4-dihydroxyquinoline-3-carboxynitrile (11.0 g, 41.50 mmol) was dissolved in acetonitrile (10 mL) and POCl3 (40 mL), and heated to 90 °C. o The reaction was stirred for 16 hours. After the reaction was complete, it was cooled to room temperature and concentrated to obtain a pale yellow solid, which was used directly in the next step. (12.53 g, yield: 100%)

[0603] Step 4: Synthesis of (S)-4-(7-bromo-2-chloro-3-cyanoquinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0604] 7-Bromo-2,4-dichloroquinoline-3-carboxynitrile (5.00 g, 16.56 mmol) was dissolved in anhydrous DMF (50 mL). DIEA (12.84 g, 16.42 mL, 99.36 mmol) was added under ice-water bath cooling, followed by (S)-2-(piperazin-2-yl)acetonitrile 2-hydrochloride (3.6 g, 18.22 mmol). The mixture was stirred for 10 minutes under ice-water bath cooling, then di-tert-butyl dicarbonate (7.25 g, 33.12 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, 100 mL of cold water was added while stirring to dilute the reaction solution, precipitating a solid. The solid was filtered, washed with water, and dried under vacuum to obtain a pale yellow solid for the next step (7.2 g, yield: 88.59%). 1 H NMR (400MHz, CDCl3) δ 8.20 (d,J = 1.8Hz, 1H), 7.84 (d,J= 9.0Hz, 1H), 7.71 (dd,J = 9.0, 1.8Hz, 1H), 4.76 (s, 1H), 4.20 (s, 1H), 4.07(dd,J = 12.5, 3.5Hz, 1H), 3.76 (d,J = 13.0Hz, 1H), 3.67 (d,J = 11.7 Hz, 1H), 3.56 (s, 1H), 3.44 (s, 1H), 2.83 (s, 2H).

[0605] Step 5: Synthesis of (S)-4-(7-bromo-3-cyano-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester:

[0606] The compound (tetrahydro-1H-pyrrolazin-7a(5H)-yl) was dissolved in methanol (44 mg, 0.31 mmol) in anhydrous tetrahydrofuran (3 mL). 60% NaH (13 mg, 0.31 mmol) was added under ice-water bath cooling. After stirring for 20 minutes under ice-water bath cooling, (S)-4-(7-bromo-2-chloro-3-cyanoquinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.20 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction was quenched with cold water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to obtain a pale yellow solid (100 mg, yield: 82.7%). 1H NMR (400 MHz, CDCl3) δ 8.05 – 7.99 (m, 1H), 7.77 –7.68 (m, 1H), 7.57 – 7.48 (m, 1H), 4.81 – 4.62 (m, 3H), 4.18 (s, 1H), 4.00(dd, J = 12.4, 3.5 Hz, 1H), 3.82 (d, J = 42.0 Hz, 2H), 3.66 (dd, J = 29.7,12.2 Hz, 2H), 3.49 (s, 1H), 3.35 (t, J = 11.2 Hz, 1H), 3.06 – 2.72 (m, 4H),2.29 (d, J = 20.6 Hz, 4H), 2.11 (d, J = 5.8 Hz, 2H), 1.98 (s, 2H), 1.53 (s,9H).

[0607] Step 6: Synthesis of (S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-3-cyano-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0608] Compound (S)-4-(7-bromo-3-cyano-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-4-yl)-2-(cyanomethyl)piperazin-1-carboxylic acid tert-butyl ester (35 mg, 0.06 mmol) and 2-(8-chloro-7-fluoronaphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (22 mg, 0.07 mmol) were dissolved in dioxane / water = 5 / 1 (3 mL), then cesium carbonate (58 mg, 0.18 mmol) and Pd(PPh3)4 (34 mg, 0.03 mmol) were added, nitrogen gas was purged, and the mixture was heated to 90°C. o The reaction mixture was stirred at C for 1 hour. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to obtain a pale yellow solid (22 mg, yield: 53%). 1H NMR (400MHz, CDCl3) δ7.93 (d,J = 8.2Hz, 1H), 7.87 (dd,J = 9.4, 3.7Hz, 1H), 7.83 (s, 1H), 7.57 –7.50 (m, 2H), 7.48 – 7.36 (m, 4H), 4.93 (dd,J = 20.0, 11.4Hz, 1H), 4.84 –4.65 (m, 2H), 4.20 (s, 1H), 4.11 – 3.97 (m, 3H), 3.91 – 3.65 (m, 2H), 3.46(d,J = 39.4Hz, 3H), 3.00 (s, 3H), 2.93 – 2.70 (m, 1H), 2.58 – 2.28 (m, 4H), 2.22 – 1.95 (m, 4H), 1.54 (s, 9H).

[0609] Step 7: Synthesis of (S)-7-(8-chloro-7-fluoronaphth-1-yl)-4-(3-(cyanomethyl)piperazin-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-3-carboxylonitrile

[0610] Compound (S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-3-cyano-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (22 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for one hour. After the reaction was complete, the reaction solution was concentrated to remove excess trifluoroacetic acid, and then dissolved in dichloromethane. The solution was washed with saturated sodium carbonate aqueous solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain an off-white solid for direct use in the next step. (19 mg, yield: 100%)

[0611] Step 8: Synthesis of (S)-4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-chloro-7-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-3-carboxylonitrile

[0612] Compound (S)-7-(8-chloro-7-fluoronaphthyl-1-yl)-4-(3-(cyanomethyl)piperazin-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-3-carboxynitrile (18 mg, 0.03 mmol) was dissolved in anhydrous dichloromethane (5 mL). DIEA (7 mg, 0.05 mmol) and acryloyl chloride (3.2 mg, 0.04 mmol) were added under ice-water bath cooling, and the mixture was stirred for 10 minutes under ice-water bath. After the reaction was complete, the reaction was quenched with saturated sodium carbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to give an off-white solid (18 mg, yield: 91.7%). 1 H NMR (400MHz, CDCl3) δ 7.94- 7.84 (m, 4H), 7.55 – 7.38 (m, 4H), 6.67 – 6.64 (m, 1H), 6.42 (d, J = 16.7 Hz, 1H), 5.85 (d, J = 10.3 Hz, 1H), 4.92 (dd, J = 20.6,11.8 Hz, 1H), 4.71 (d, J = 11.6 Hz, 1H), 4.16 – 3.75 (m, 6H), 3.49 (s, 1H), 3.01 (s, 4H), 2.58 – 2.25 (m, 4H), 2.15 - 2.12(m, 2H), 2.09 – 1.94 (m, 2H).MS m / z: 649.67 [M+H] +

[0613] Example 621: Synthesis of (S)-4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-chloro-7-fluoronaphth-1-yl)-6-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-3-carboxylonitrile

[0614]

[0615] Step 1: Synthesis of methyl 4-bromo-2-(2-cyanoacetamido)-5-fluorobenzoate

[0616] Methyl 2-amino-4-bromo-5-fluorobenzoate (1.2 g, 4.84 mmol) and cyanoacetic acid (0.49 g, 5.81 mmol) were dissolved in dichloromethane (15 mL). EDCI (1.39 g, 7.26 mmol) was added under ice-water bath cooling, and the mixture was stirred for 1 hour under ice-water bath cooling. After the reaction was complete, the reaction solution was diluted with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the target compound (1.5 g, yield: 98%). 1 H NMR (400MHz, CDCl3) δ 11.58 (s, 1H), 8.97 (d,J = 6.4Hz, 1H), 7.80 (d,J = 8.8Hz, 1H), 3.99 (s, 3H), 3.60 (s, 2H).

[0617] Step 2: Synthesis of 7-bromo-6-fluoro-2,4-dihydroxyquinoline-3-carboxynitrile

[0618] Methyl 4-bromo-2-(2-cyanoacetamido)-5-fluorobenzoate (1.5 g, 4.76 mmol) was dissolved in anhydrous methanol (10 mL). A 30% sodium methoxide solution (1.29 g, 7.14 mmol) was added dropwise under ice-water bath cooling. The mixture was stirred for 30 minutes under ice-water bath cooling. After the reaction was complete, the pH was adjusted to 2-3 with 10% hydrochloric acid aqueous solution. The reaction solution was diluted with 50 mL of water, and a solid precipitated. The solid was filtered and dried under vacuum to obtain a white solid (1.35 g, yield: 100%). 1 H NMR (400MHz, DMSO)δ 11.47 (s, 1H), 7.82 (d,J = 9.3Hz, 1H), 7.53 (d,J = 5.9Hz, 1H).

[0619] Step 3: Synthesis of 7-bromo-2,4-dichloro-6-fluoroquinoline-3-carboxynitrile

[0620] The compound 7-bromo-6-fluoro-2,4-dihydroxyquinoline-3-carboxynitrile (0.24 g, 0.85 mmol) was dissolved in acetonitrile (1 mL) and POCl3 (4 mL), and heated to 90 °C. o The reaction was stirred at C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated to obtain a pale yellow solid, which was used directly in the next step. (271 mg, yield: 100%) 1 H NMR (400MHz, CDCl3) δ 8.38 (d,J =6.3Hz, 1H), 7.94 (d,J = 8.3Hz, 1H).

[0621] Step 4: Synthesis of (S)-4-(7-bromo-2-chloro-3-cyano-6-fluoroquinoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0622] 7-Bromo-2,4-dichloro-6-fluoroquinoline-3-carboxynitrile (271 mg, 0.85 mmol) was dissolved in anhydrous DMF (5 mL). DIEA (659 mg, 5.09 mmol) was added under ice-water bath cooling, followed by (S)-2-(piperazin-2-yl)acetonitrile 2-hydrochloride (185 mg, 0.93 mmol). The mixture was stirred for 10 minutes under ice-water bath cooling, then di-tert-butyl dicarbonate (372 mg, 1.70 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, 30 mL of cold water was added while stirring to dilute the reaction solution, precipitating a solid. The solid was filtered, washed with water, and dried under vacuum to obtain a pale yellow solid, which was directly used in the next step. (400 mg, yield: 93%) 1 H NMR (400MHz, CDCl3) δ 8.31 (d,J = 6.6Hz, 1H), 7.64 (d,J = 9.0Hz,1H), 4.76 (s, 1H), 4.21 (s, 1H), 4.08 (dd,J = 12.4, 3.6Hz, 1H), 3.78 – 3.33(m, 4H), 2.83 (qd,J = 16.9, 7.6Hz, 2H), 1.53 (s, 9H).

[0623] Step 5: Synthesis of (S)-4-(7-bromo-3-cyano-6-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0624] The compound (tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (44 mg, 0.31 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL). 60% NaH (13 mg, 0.31 mmol) was added under ice-water bath cooling. After stirring for 20 minutes under ice-water bath cooling, (S)-4-(7-bromo-2-chloro-3-cyano-6-fluoroquinoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.20 mmol) was added to the reaction solution, and the mixture was heated to 60°C. o The reaction was stirred at C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with cold water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to give an off-white solid (100 mg, yield: 83%). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J= 6.6 Hz, 1H), 7.53 (d, J = 9.1 Hz, 1H), 4.75 (s, 3H), 4.19 (s, 1H), 4.01(dd, J = 12.4, 3.5 Hz, 1H), 3.82 (d, J = 42.0 Hz, 2H), 3.66 (dd, J = 29.7,12.2 Hz, 2H), 3.49 (s, 1H), 3.35 (t, J = 11.2 Hz, 1H), 3.06 – 2.72 (m, 4H),2.29 (d, J = 20.6 Hz, 4H), 2.11 (d, J = 5.8 Hz, 2H), 1.98 (s, 2H), 1.53 (s,9H).

[0625] Step 6: Synthesis of (S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-3-cyano-6-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0626] Compound (S)-4-(7-bromo-3-cyano-6-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-4-yl)-2-(cyanomethyl)piperazin-1-carboxylic acid tert-butyl ester (30 mg, 0.05 mmol) and 2-(8-chloro-7-fluoronaphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (22 mg, 0.07 mmol) were dissolved in dioxane / water = 5 / 1 (3 mL), then cesium carbonate (58 mg, 0.18 mmol) and Pd(PPh3)4 (34 mg, 0.03 mmol) were added, nitrogen gas was purged, and the mixture was heated to 90°C. o The reaction mixture was stirred at C for 1 hour. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to obtain a pale yellow solid. (20 mg, yield: 57%). MS m / z: 714 [M+H] +

[0627] Step 7: Synthesis of (S)-7-(8-chloro-7-fluoronaphth-1-yl)-4-(3-(cyanomethyl)piperazin-1-yl)-6-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-3-carboxylonitrile

[0628] Compound (S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-3-cyano-6-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (20 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for one hour. After the reaction was complete, the reaction solution was concentrated to remove excess trifluoroacetic acid, and then dissolved in dichloromethane. The solution was washed with saturated sodium carbonate aqueous solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain an off-white solid for direct use in the next step. (17 mg, yield: 100%)

[0629] Step 8: Synthesis of (S)-4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-chloro-7-fluoronaphth-1-yl)-6-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-3-carboxylonitrile

[0630] The compound (S)-7-(8-chloro-7-fluoronaphth-1-yl)-4-(3-(cyanomethyl)piperazin-1-yl)-6-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-3-carboxynitrile (17 mg, 0.03 mmol) was dissolved in anhydrous dichloromethane (5 mL). DIEA (7 mg, 0.05 mmol) and acryloyl chloride (3.2 mg, 0.04 mmol) were added under ice-water bath cooling, and the reaction was stirred for 10 minutes under ice-water bath. After the reaction was complete, the reaction was quenched with saturated sodium carbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to give an off-white solid (10 mg, yield: 54%). 1 H NMR(400 MHz, CDCl3) δ 7.93 - 7.84 (m, 4H), 7.55 - 7.38 (m, 3H), 6.67 - 6.63 (m,1H), 6.41 (d, J = 16.7 Hz, 1H), 5.84 (d, J = 10.3 Hz, 1H), 4.93 (dd, J =20.6, 11.8 Hz, 1H), 4.72 (d, J = 11.6 Hz, 1H), 4.17 – 3.75 (m, 6H), 3.49 (s,1H), 3.01 (s, 4H), 2.58 – 2.25 (m, 4H), 2.15 - 2.12(m, 2H), 2.09 – 1.94 (m,2H). MS m / z: 667.6[M+H] +

[0631] Example 622: Synthesis of 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-chloro-2-((((S)-1-methylpyrrolidone-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)quinoline-3-nitrile

[0632]

[0633] Step 1: Synthesis of methyl 4-bromo-5-chloro-2-(2-cyanoacetamido)benzoate

[0634] Methyl 2-amino-4-bromo-5-chlorobenzoate (1.0 g, 3.78 mmol) and cyanoacetic acid (0.39 g, 4.53 mmol) were dissolved in dichloromethane (15 mL). EDCI (1.08 g, 5.67 mmol) was added under ice-water bath cooling, and the mixture was stirred for 1 hour under ice-water bath cooling. After the reaction was complete, the reaction solution was diluted with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the target compound (1.19 g, yield: 95%). 1 H NMR (400MHz, CDCl3) δ 11.63 (s, 1H), 9.03 (s, 1H), 8.13 (s, 1H), 3.99 (s, 3H), 3.61 (s, 2H).

[0635] Step 2: Synthesis of 7-bromo-6-chloro-2,4-dihydroxyquinoline-3-carboxynitrile

[0636] Methyl 4-bromo-2-(2-cyanoacetamido)-5-chlorobenzoate (1.19 g, 3.59 mmol) was dissolved in anhydrous methanol (10 mL). A 30% sodium methoxide solution (0.97 g, 5.39 mmol) was added dropwise under ice-water bath cooling. The mixture was stirred for 30 minutes under ice-water bath cooling. After the reaction was complete, the pH was adjusted to 2-3 with 10% hydrochloric acid aqueous solution. 50 mL of water was added to dilute the reaction solution, and a solid precipitated. The solid was filtered and dried under vacuum to obtain an off-white solid (1.07 g, yield: 100%). 1 H NMR (400MHz, DMSO)δ 11.40 (s, 1H), 8.06 (s, 1H), 7.57 (s, 1H).

[0637] Step 3: Synthesis of 7-bromo-2,4,6-trichloroquinoline-3-carboxylon

[0638] The compound 7-bromo-6-chloro-2,4-dihydroxyquinoline-3-carboxynitrile (0.20 g, 0.67 mmol) was dissolved in acetonitrile (1 mL) and POCl3 (4 mL), and heated to 90°C. o The reaction was stirred for 16 hours. After the reaction was complete, it was cooled to room temperature and concentrated to obtain a pale yellow solid, which was used directly in the next step. (225 mg, yield: 100%)

[0639] Step 4: Synthesis of tert-butyl (S)-4-(7-bromo-2,6-dichloro-3-cyanoquinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0640] 7-Bromo-2,4,6-trichloroquinoline-3-carboxynitrile (225 mg, 0.67 mmol) was dissolved in anhydrous DMF (5 mL). DIEA (518 mg, 4.01 mmol) was added under ice-water bath cooling, followed by (S)-2-(piperazin-2-yl)acetonitrile 2-hydrochloride (146 mg, 0.74 mmol). The mixture was stirred for 10 minutes under ice-water bath cooling, then di-tert-butyl dicarbonate (2922 mg, 1.34 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, 30 mL of cold water was added while stirring to dilute the reaction solution, precipitating a solid. The solid was filtered, washed with water, and dried under vacuum to obtain a pale yellow solid, which was directly used in the next step. (230 mg, yield: 89%) 1 H NMR (300MHz, CDCl3) δ 8.35 (s, 1H), 8.05 (s, 1H), 4.78 (s, 1H), 4.51 (s, 1H), 4.26 (d,J = 22.4Hz, 1H), 3.82 – 3.39 (m, 4H), 3.10 (d,J =13.7Hz, 1H), 2.83 (qd,J = 16.9, 7.6Hz, 2H), 1.55 (s, 9H).

[0641] Step 5: Synthesis of (S)-4-(7-bromo-6-chloro-3-cyano-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0642] Compound (S)-(1-methylpyrrolidone-2-yl)methanol (40 mg, 0.34 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL). 60% NaH (14 mg, 0.34 mmol) was added under ice-water bath cooling. After stirring for 20 minutes under ice-water bath cooling, tert-butyl (S)-4-(7-bromo-2,6-dichloro-3-cyanoquinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (60 mg, 0.11 mmol) was added to the reaction solution, and the mixture was heated to 60°C. o The reaction was stirred at C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with cold water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to give an off-white solid (50 mg, yield: 83%). 1 H NMR (400MHz, CDCl3) δ 8.13 (s, 1H), 7.92 (s,1H), 4.75 (s, 1H), 4.60 (s, 1H), 4.19 (s, 1H), 4.02 (dd, J = 12.4, 3.6Hz,1H), 3.71 – 3.31 (m, 6H), 2.84 (s, 3H), 2.72 (s, 3H), 2.52 (s, 1H), 2.18 (s,1H), 2.03 (s, 1H), 1.91 (s, 3H), 1.53 (s, 9H).

[0643] Step 6: Synthesis of (S)-4-(6-chloro-3-cyano-2-(((S)-1-methylpyrrolidone-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)quinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0644] Compound (S)-4-(7-bromo-6-chloro-3-cyano-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (25 mg, 0.04 mmol) and 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydronaphthyl)-1,3,2-dioxaborane (13 mg, 0.05 mmol) were dissolved in dioxane / water = 5 / 1 (3 mL), then cesium carbonate (40 mg, 0.12 mmol) and Pd(PPh3)4 (24 mg, 0.02 mmol) were added, nitrogen gas was purged, and the mixture was heated to 90°C. oThe reaction mixture was stirred at C for 1 hour. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to obtain a pale yellow solid (27 mg, yield: 100%). MS m / z: 655.7 [M+H] +

[0645] Step 7: Synthesis of 6-chloro-4-((S)-3-(cyanomethyl)piperazin-1-yl)-2-((((S)-1-methylpyrrolidone-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)quinoline-3-carboxylonitrile

[0646] Compound (S)-4-(6-chloro-3-cyano-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)quinolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (27 mg, 0.04 mmol) was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for one hour. After the reaction was complete, the reaction solution was concentrated to remove excess trifluoroacetic acid, then dissolved in dichloromethane, washed with saturated sodium carbonate aqueous solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain an off-white solid for direct use in the next step. (23 mg, yield: 100%)

[0647] Step 8: Synthesis of 4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-chloro-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)quinoline-3-nitrile

[0648] 6-Chloro-4-((S)-3-(cyanomethyl)piperazin-1-yl)-2-((((S)-1-methylpyrrolidone-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthyl-1-yl)quinoline-3-carboxynitrile (23 mg, 0.04 mmol) was dissolved in anhydrous dichloromethane (5 mL). DIEA (7 mg, 0.05 mmol) and acryloyl chloride (5 mg, 0.05 mmol) were added under ice-water bath cooling, and the mixture was stirred for 10 minutes under ice-water bath. After the reaction was complete, the reaction was quenched with saturated sodium carbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to give an off-white solid (8 mg, yield: 32%). 1H NMR (400MHz, CDCl3) δ 7.94 (d, J = 2.5 Hz, 1H), 7.73 (t, J = 10.6 Hz, 1H), 7.19 (t, J= 5.1 Hz, 2H), 6.96 (dd, J = 10.4, 6.6 Hz, 1H), 6.61 (d, J = 10.6 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 5.87 (d, J = 10.9 Hz, 1H), 4.69 (s, 1H), 4.07 (d,J = 12.9 Hz, 1H), 3.93 – 3.69 (m, 3H), 3.48 (s, 2H), 3.01 (d, J = 8.4 Hz, 2H), 2.87 - 2.55 (m, 6H), 2.54 - 2.14 (m, 4H), 1.88 - 1.74 (m, 10H). MS m / z:609.67 [M+H] + .

[0649] The compounds of Examples 623-839 were prepared using preparation method 3.

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677] Example 840: 2-((S)-1-acryloyl-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-2-(((S)-1-methylpyrrolidinyl-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0678]

[0679]

[0680] Step 1: Synthesis of 7-bromo-2,4-dichloropyrido[3,2-d]pyrimidine

[0681] At room temperature, nitrogen-2,4-diethylaniline (1.41 g, 9.45 mmol) was added to a mixture of 7-bromopyrido[3,2-d]pyrimidine-2,4-diol (1.04 g, 4.3 mmol) and phosphorus oxychloride (10 mL). The resulting pale yellow suspension was stirred for 5 minutes and then heated and stirred in an oil bath at 110°C for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was mixed with toluene (20 mL × 2) and concentrated under reduced pressure. The resulting light brown solid was used directly in the next reaction.

[0682] Step 2: Synthesis of (S)-2-(4-(7-bromo-2-chloropyridino[3,2-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0683] Nitrogen-diisopropylethylamine (4.27 mL, 25.8 mmol) was added in a single batch to a mixture of 7-bromo-2,4-dichloropyridino[3,2-d]pyrimidine and tetrahydrofuran (30 mL). After stirring for 2 minutes, (S)-2-(piperazin-2-yl)acetonitrile hydrochloride (0.85 g, 4.3 mmol) was added. The reaction mixture was gradually brought to room temperature and stirred for 5 hours. This reaction mixture was used directly for the next reaction without further treatment.

[0684] Step 3: Synthesis of (S)-4-(7-bromo-2-chloropyridino[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0685] At room temperature, triethylamine (0.6 mL, 4.3 mmol) and di-tert-butyl dicarbonate (1.31 g, 6 mmol) were added to the reaction solution from the previous step. The reaction solution was stirred at room temperature for 17 hours. Ethyl acetate (100 mL) and water (100 mL) were added for extraction and separation. The aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain a dark brown viscous substance. The solution was purified by column chromatography (silica gel, ethyl acetate:petroleum ether = 1:20 to ethyl acetate:petroleum ether = 1:5) to give a yellow solid. (210 mg, 0.449 mmol, total yield of three steps: 10%). MS m / z: 467.4 [M+H] + .

[0686] Step 4: Synthesis of (S)-4-(7-bromo-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester:

[0687] Dissolve 2 mL of (S)-(1-methylpyrrolidone-2-yl)methanol (77 mg, 0.67 mmol) in tetrahydrofuran. oSodium hydride (16 mg, 0.67 mmol) was added at C, and the reaction was carried out at room temperature for 0.5 h. Then, a tetrahydrofuran (2 mL) solution of (S)-4-(7-bromo-2-chloropyridino[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.22 mmol) was added, and the reaction was continued at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and purified by PLC to give (S)-4-(7-bromo-2-((((S)-1-methylpyrrolidine-2-yl)methoxy)pyridino[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (82 mg, 67%). MS m / z: [M+H] + =546.6.

[0688] Step 5: Synthesis of (S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-2-((((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester:

[0689] Compound (S)-4-(7-bromo-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.091 mmol) and 2-(8-chloro-7-fluoronaphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (56.1 mg, 0.18 mmol) were dissolved in 1,4-dioxane (2.0 mL). Under a nitrogen atmosphere, Pd(PPh3)4 (31.7 mg, 0.027 mmol), cesium carbonate (89.4 mg, 0.27 mmol), and water (0.1 mL) were added sequentially, and then the mixture was heated to 100 °C. o The mixture was stirred at temperature C for 5 hours. The reaction mixture was concentrated under reduced pressure and purified by PLC to obtain compound (S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-2-((((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (35.5 mg, 60%). MS m / z: [M+H] + =646.7.

[0690] Step 6: Synthesis of 2-((S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyridyl[3,2-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0691] Compound (S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-2-((((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (34 mg, 0.053 mmol) was dissolved in CH2Cl2 (1.5 mL), and TFA (0.5 mL) was added dropwise. The reaction solution was stirred at room temperature until the reaction was complete. Then, the pH of the reaction solution was adjusted to 10% NaOH aqueous solution. 10. Separate the liquid and extract with CH2Cl2, wash with saturated brine, dry (Na2SO4), filter, and concentrate under reduced pressure to give compound 2-((S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyridyl[3,2-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (24.3 mg, 84%). MS m / z: [M+H] + =546.6.

[0692] Step 7: Synthesis of 2-((S)-1-acryloyl-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-2-(((S)-1-methylpyrrolidinyl-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0693] Compound 2-((S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (23 mg, 0.042 mmol) and triethylamine (13 mg, 0.13 mmol) were dissolved in CH2Cl2 (1.0 mL), and then acryloyl chloride (7.6 mg, 0.08 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under pressure and purified by PLC to obtain compound 2-((S)-1-acryloyl-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-2-(((S)-1-methylpyrrolidinyl-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (24 mg, 94%). 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.98 (d, J = 8.0Hz, 1H), 7.91 (dd, J = 8.9, 5.5 Hz, 2H), 7.56 (dd, J = 15.5, 7.4 Hz, 1H),7.50 – 7.38 (m, 2H), 7.05 – 6.81 (m, 1H), 6.45 – 6.30 (m, 1H), 5.81 (dd, J =21.5, 10.7 Hz, 1H), 4.76 – 4.68 (m, 1H), 4.43 (s, 1H), 4.25 – 3.28 (m, 5H),3.05 – 2.91 (m, 4H), 2.49 – 1.87 (m, 10H). MS m / z: [M+H] + =600.6

[0694] Compounds of Examples 841-853 were prepared using the preparation method of Example 840.

[0695]

[0696]

[0697] Example 854: Synthesis of (S)-2-(1-acryloyl-4-(7-(8-chloronaphth-1-yl)-8-fluoro-2-((1-(pyrrolidine-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0698]

[0699] Step 1: Synthesis of (1-(pyrrolidone-1-ylmethyl)cyclopropyl)methanol

[0700] The compound (1-(aminomethyl)cyclopropyl)methanol (500 mg, 4.94 mmol) and 1,4-dibromobutane (1.12 g, 5.19 mmol) were dissolved in acetonitrile (20 mL), and then potassium carbonate (1.78 g, 12.85 mmol) was added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete, the solid was removed by filtration. The organic phase was concentrated and separated by column chromatography (DCM / 7M NH3 in MeOH = 100 / 1) to give a colorless oil (390 mg, yield: 50.8%). 1H NMR (400 MHz, CDCl3) δ 3.55 (s,2H), 2.70 – 2.53 (m, 6H), 1.83 – 1.69 (m, 4H), 0.49 (q, J = 4.6 Hz, 2H), 0.36(t, J = 5.2 Hz, 2H).

[0701] Step 2: Synthesis of (S)-4-(7-chloro-8-fluoro-2-((1-(pyrrolidone-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0702] Compound (2S)-4-(7-chloro-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.21 mmol) and (1-(pyrrolidine-1-ylmethyl)cyclopropyl)methanol (37 mg, 0.23 mmol) were dissolved in anhydrous toluene (3 mL). Sodium tert-butoxide (25 mg, 0.25 mmol) was added under ice-water bath cooling, and the reaction was stirred for 30 minutes. After the reaction was complete, the reaction was quenched with cold water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by preparative TLC to obtain an off-white solid (50 mg, yield: 42%). 1 H NMR(400 MHz, CDCl3) δ 8.78 (s, 1H), 4.62 (s, 1H), 4.42 (q, J = 10.9 Hz, 3H), 4.29 (d, J = 12.8 Hz, 1H), 4.08 (s, 1H), 3.88 (s, 1H), 3.66 (s, 1H), 3.46 (s,1H), 2.87 – 2.77 (m, 1H), 2.73 (d, J = 5.7 Hz, 1H), 2.53 (s, 6H), 1.74 (s,4H), 1.51 (s, 9H), 0.68 (s, 2H), 0.51 (s, 2H).

[0703] Step 3: Synthesis of (S)-4-(7-(8-chloronaphth-1-yl)-8-fluoro-2-((1-(pyrrolidine-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0704] Compounds (S)-4-(7-chloro-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.09 mmol), 2-(8-chloronaphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (34 mg, 0.12 mmol), and cesium carbonate (87 mg, 0.27 mmol) were dissolved in 1,4-dioxane / water = 5 / 1 (3 mL), then Pd(PPh3)4 (52 mg, 0.04 mmol) was added, nitrogen was purged three times, and the mixture was heated to 100 °C. o The reaction mixture was stirred at C for 2 hours. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to obtain an off-white solid (20 mg, yield: 33%).

[0705] Step 4: Synthesis of (S)-2-(4-(7-(8-chloronaphth-1-yl)-8-fluoro-2-((1-(pyrrolidine-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0706] The compound (S)-4-(7-(8-chloronaphthyl-1-yl)-8-fluoro-2-((1-(pyrrolidine-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (20 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction solution was concentrated to obtain the crude product, which was directly used in the next step.

[0707] Step 5: Synthesis of (S)-2-(1-acryloyl-4-(7-(8-chloronaphth-1-yl)-8-fluoro-2-((1-(pyrrolidine-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0708] Compound (S)-2-(4-(7-(8-chloronaphthyl-1-yl)-8-fluoro-2-((1-(pyrrolidine-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (17 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL). DIEA (5 mg, 0.03 mmol) and acryloyl chloride (3 mg, 0.03 mmol) were added under ice-water bath cooling, and the mixture was stirred for 5 minutes under ice-water bath cooling. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to obtain an off-white solid (10 mg, yield: 50%). 1 H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.01 (dd, J = 7.9, 1.5 Hz, 1H), 7.88 (d, J =8.1 Hz, 1H), 7.66 – 7.50 (m, 3H), 7.42 (td, J = 7.8, 2.4 Hz, 1H), 6.59 (s,1H), 6.42 (d, J = 16.8 Hz, 1H), 5.85 (d, J = 10.8 Hz, 1H), 5.08 (s, 1H), 4.46(d, J = 10.5 Hz, 4H), 3.90 (d, J = 103.6 Hz, 5H), 3.06 (s, 1H), 2.82 (d, J =17.1 Hz, 2H), 2.55 (s, 4H), 1.78 (s, 4H), 0.73 (s, 2H), 0.57 (s, 2H). MS m / z:[M+H] + =640.59

[0709] Example 855: Synthesis of (S)-2-(1-acryloyl-4-(7-(8-chloronaphth-1-yl)-8-fluoro-2-((1-(pyrrolidone-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0710]

[0711] Step 1: Synthesis of (S)-4-(7-bromo-8-fluoro-2-((1-(pyrrolidone-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0712] The compound (1-(pyrrolidone-1-ylmethyl)cyclopropyl)methanol (84 mg, 0.54 mmol) was dissolved in anhydrous THF (5 mL). 60% NaH (20 mg, 0.50 mmol) was added under ice-water bath cooling. After stirring for 20 minutes under ice-water bath cooling, the compound (S)-4-(7-bromo-2-chloro-8-fluoroquinazoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.41 mmol) was added, and the reaction was stirred at room temperature for 8 hours. After the reaction was complete, the reaction was quenched with cold water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give a pale yellow solid (150 mg, yield: 61%). 1 H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 9.1 Hz, 1H), 7.38 (dd, J = 9.0, 6.0 Hz, 1H), 4.65 (s, 1H), 4.42 (s, 2H), 4.24 (d, J = 12.2 Hz, 1H), 4.16 (d, J = 10.8Hz, 2H), 3.54 (dd, J = 13.8, 3.6 Hz, 1H), 3.32 (d, J = 10.4 Hz, 2H), 2.87 –2.69 (m, 2H), 2.50 (s, 6H), 1.71 (s, 4H), 1.52 (s, 11H), 0.67 (s, 2H), 0.48 (s, 2H).

[0713] Step 2: Synthesis of (S)-4-(7-(8-chloronaphthalene)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

[0714] Compounds (S)-4-(7-bromo-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (130 mg, 0.22 mmol), 2-(8-chloronaphthyl-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (93 mg, 0.32 mmol), and potassium carbonate (60 mg, 0.43 mmol) were dissolved in 1,4-dioxane / water = 5 / 1 (3 mL). Then, Pd(dppf)Cl2 (31 mg, 0.04 mmol) was added, nitrogen gas was purged three times, and the mixture was heated to 100 °C. oThe reaction mixture was stirred at C for 2 hours. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to obtain an off-white solid (80 mg, yield: 54.3%). 1 H NMR(400 MHz, CDCl3) δ 7.97 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.54(dd, J = 14.2, 4.9 Hz, 3H), 7.45 – 7.38 (m, 2H), 7.23 (d, J = 6.6 Hz, 1H), 4.70 (s, 1H), 4.36 (dd, J = 30.7, 19.9 Hz, 4H), 4.14 (s, 1H), 3.55 (d, J =11.7 Hz, 1H), 3.36 (s, 2H), 2.87 (s, 2H), 2.51 (s, 4H), 1.71 (s, 4H), 1.53 (s, 9H), 0.67 (s, 2H), 0.47 (s, 2H).

[0715] Step 3: Synthesis of (S)-2-(4-(7-(8-chloronaphthyl-1-yl)-8-fluoro-2-((1-(pyrrolidine-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0716] Compound (S)-4-(7-(8-chloronaphthalene)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (80 mg, 0.12 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated to obtain the crude product, which was used directly in the next step.

[0717] Step 4: Synthesis of (S)-2-(1-Acryloyl-4-(7-(8-chloronaphth-1-yl)-8-fluoro-2-((1-(pyrrolidone-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0718] Compound (S)-2-(4-(7-(8-chloronaphthyl-1-yl)-8-fluoro-2-((1-(pyrrolidine-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile (68 mg, 0.12 mmol) was dissolved in dichloromethane (10 mL). DIEA (18 mg, 0.14 mmol) and acryloyl chloride (12 mg, 0.13 mmol) were added under ice-water bath cooling, and the mixture was stirred for 5 minutes under ice-water bath cooling. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by TLC to obtain an off-white solid (42 mg, yield: 56%). 1 H NMR (400MHz, CDCl3) δ 7.97 (d, J = 7.3 Hz, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.68 – 7.60(m, 1H), 7.55 (dd, J = 9.7, 8.0 Hz, 2H), 7.43 (dd, J = 7.8, 2.3 Hz, 2H), 7.26(m, 1H), 6.61 (s, 1H), 6.42 (d, J = 16.8 Hz, 1H), 5.84 (d, J = 10.5 Hz, 1H), 5.16 (s, 1H), 4.54 – 4.26 (m, 4H), 4.02 (s, 1H), 3.53 (d, J = MS m / z: [M+H] + =639.61.

[0719] Compounds of Examples 856-871 were prepared using the preparation methods of Examples 854 and 855.

[0720]

[0721]

[0722] Example 872: Synthesis of 2-((2S)-4-(8-fluoro-2-((S)-1-methylpyrrolidone-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0723]

[0724]

[0725] Step 1: Synthesis of 5-bromo-1,1a,6,6a-tetrahydrocyclopropane[a]indene

[0726] A solution of diethylzinc / n-hexane (1 M, 423 mL) in anhydrous dichloromethane (200 mL) was cooled in an ice-water bath. A solution of trifluoroacetic acid (31 mL, 423 mmol) in anhydrous dichloromethane (200 mL) was added dropwise. After stirring at this temperature for 20 minutes, a solution of diiodomethane (34.3 mL, 423 mmol) in anhydrous dichloromethane (100 mL) was added dropwise. After continuing stirring for another 20 minutes, a solution of 7-bromo-1H-indene (22 g, 113 mmol) in anhydrous dichloromethane (100 mL) was slowly added dropwise. The ice-water bath was removed, and the mixture was stirred for 16 hours to obtain a white suspension. Dilute hydrochloric acid (0.1 M, 500 mL) was slowly added with stirring. The resulting mixture was extracted with petroleum ether (500 mL + 200 mL). The combined organic phases were washed with saturated sodium bicarbonate solution (300 mL), then with saturated brine (300 mL), dried over sodium sulfate, and concentrated under vacuum to give a yellow oil. Column chromatography (silica gel, petroleum ether) yielded 5-bromo-1,1a,6,6a-tetrahydrocyclopropane[a]indene as a pale yellow oil (22 g, 105 mmol, yield 93%). 1 H NMR (400 MHz, CDCl3) δ7.24-7.20 (m, 2H), 7.00-6.96 (m, 1H), 3.13 (dd, J = 17.6, 6.7 Hz, 1H), 2.97(d, J = 17.6 Hz, 1H), 2.46-2.41 (m, 1H), 1.91-1.85 (m, 1H), 1.12-1.06 (m,1H), 0.13-0.10 (m, 1H)

[0727] Step 2: Synthesis of 4,4,5,5-Tetramethyl-2-(1,1a,6,6a-tetrahydrocyclopropane[a]inden-5-yl)-1,3,2-dioxane

[0728] Add 5-bromo-1,1a,6,6a-tetrahydrocyclopropane[a]indene (30 g, 144 mmol), bis-pinacolborate (72.9 g, 287 mmol), Pd(dppf)Cl2 (21 g, 28.7 mmol), and potassium acetate (42 g, 431 mmol) to a round-bottom flask. After purging with nitrogen, add pre-deoxygenated anhydrous 1,4-dioxane (400 mL). Stir the resulting suspension at 100°C for 16 hours. After cooling to room temperature, extract the reaction mixture with water (500 mL) and methyl tert-butyl ether (500 mL). After separation, extract the aqueous phase with methyl tert-butyl ether (300 mL). Wash the combined organic phases with saturated brine (300 mL), dry to sodium sulfate, and evaporate to dryness under vacuum. The remaining dark brown oily substance was purified by column chromatography (silica gel, ethyl acetate: petroleum ether = 1:40) to obtain a colorless oily substance, which slowly turned into a light yellow solid upon standing (26 g, 101 mmol, yield: 70%). 1 H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 8.0, 2.0 Hz, 1H), 7.38 (dd, J = 8.0, 0.2 Hz, 1H), 7.11(t, J = 8.0 Hz, 1H), 3.29 (dd, J = 17.6, 6.7 Hz, 1H), 3.20 (d, J = 17.6 Hz,1H), 2.36-2.31 (m, 1H), 1.88-1.81 (m, 1H), 1.55 (s, 12H), 1.05-1.00 (m, 1H),0.06-0.01 (m, 1H)

[0729] Step 3: Synthesis of tert-butyl(2S)-2-(cyanomethyl)-4-(8-fluoro-2-((S)-1-methylpyrrolidone-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl)quinazolin-4-yl)piperazine-1-carboxylic acid ester

[0730] Add (S)-4-(7-bromo-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazin-1-carboxylic acid tert-butyl ester (300 mg, 0.53 mmol), 4,4,5,5-tetramethyl-2-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-2-yl)-1,3,2-dioxane (244 mg, 0.954 mmol), Pd(dppf)Cl2 (78 mg, 0.106 mmol), and potassium carbonate (146 mg, 1.06 mmol) to a round-bottom flask. After purging with nitrogen, add pre-deoxygenated 1,4-dioxane (5 mL) and water (1 mL). Stir the reaction mixture at 100 °C for 4 hours. Add ethyl acetate (30 mL) and water (20 mL). After shaking and separation, the aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over sodium sulfate, and evaporated to dryness under vacuum. The remaining brown viscous substance was purified by preparative TLC (silica gel, methanol:dichloromethane = 1:9) to give a pale yellow solid. (140 mg, 0.228 mmol, yield: 43%) MS m / z: 613.4 [M+H] + .

[0731] Step 4: Synthesis of 2-((2S)-4-(8-fluoro-2-((S)-1-methylpyrrolidone-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0732] At room temperature, 0.8 mL of trifluoroacetic acid was added dropwise to a solution of tert-butyl(2S)-2-(cyanomethyl)-4-(8-fluoro-2-((S)-1-methylpyrrolidine-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl)quinazolin-4-yl)piperazine-1-carboxylic acid ester (29 mg, 0.047 mmol) in dichloromethane (4 mL). The resulting solution was stirred at room temperature for 4 hours. 10 mL of dichloromethane was added and the solution was concentrated under vacuum. 5 mL of dichloromethane was added to the residue, and the concentration was repeated once. The resulting yellow solid was used directly in the next step.

[0733] Step 5: Synthesis of 2-((2S)-4-(8-fluoro-2-((S)-1-methylpyrrolidone-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0734] Cool a solution of 2-fluoroacrylic acid (8.5 mg, 0.095 mmol) and HATU (27 mg, 0.071 mmol) in dichloromethane (3 mL) in an ice-water bath. Add triethylamine (0.026 mL, 0.189 mmol) dropwise. Remove from the ice-water bath and stir for 20 minutes. Add a solution of 2-((2S)-4-(8-fluoro-2-((S)-1-methylpyrrolidine-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile in dichloromethane (2 mL) all at once. Stir at room temperature for 6 hours. Add dichloromethane (17 mL), water (15 mL), and saturated sodium carbonate solution (5 mL), shake, separate, and extract the aqueous phase with dichloromethane (20 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over sodium sulfate, and evaporated under reduced pressure to give a yellow solid. The solid was purified by preparative TLC (methanol:dichloromethane = 1:8) to give 2-((2S)-4-(8-fluoro-2-((S)-1-methylpyrrolidine-2-yl)methoxy)-7-(1,1a,6,6a-tetrahydrocyclopropane[a]indene-5-yl)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (60 mg, 0.103 mmol, total yield: 63%). 1 H NMR (400 MHz, CDCl3) δ 7.64(d, J = 7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.26 – 7.21 (m, 2H), 7.09 (d,J = 7.8 Hz, 1H), 5.46 (d, J = 16 Hz, 1H), 5.27 (dd, J = 16.4, 4.0 Hz, 1H), 4.99 – 4.94 (m, 1H), 4.64 (dd, J = 8.0, 4.0 Hz, 1H), 4.44 (d, J = 16 Hz, 1H), 4.34 (d, J = 16 Hz, 1H), 3.73 – 3.40 (m, 6H), 3.16 – 3.05 (m, 2H), 2.86 (s,3H), 2.77-2.73 (m, 1H), 2.45-2.41 (m, 1H), 2.30-2.25 (m, 1H), 2.30-2.25 (m,1H), 2.16-2.00 (m, 3H), 1.88-1.83 (m, 1H), 1.11-1.06 (m, 1H), 0.14-0.12 (m,1H). MS m / z: [M+H] + =585.4.

[0735] Compounds of Examples 873-902 were prepared using the preparation method of Example 872.

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745] Example 915: Synthesis of 2-((2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthyl-1-yl)-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrololin-7a(5H)-ylmethoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0746]

[0747] Step 1: Synthesis of tert-butyl(S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester

[0748] In an ice-water bath, nitrogen-N,N-diisopropylethylamine (4.27 mL, 25.8 mmol) was added in a single addition to a mixture of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (2.5 g, 7.58 mmol) and N,N-dimethylformamide (30 mL). After stirring for 2 minutes, (S)-2-(piperazin-2-yl)acetonitrile hydrochloride (1.50 g, 7.60 mmol) was added. The reaction was carried out at room temperature in an ice-water bath with stirring for 1 hour.

[0749] Nitrogen, N-diisopropylethylamine (1.42 mL, 8.6 mmol), and di-tert-butyl dicarbonate (1.96 g, 9 mmol) were added to the above reaction solution at room temperature. The reaction solution was stirred at room temperature for 4 hours. Ethyl acetate (200 mL) and water (200 mL) were added for extraction and separation. The aqueous phase was extracted with ethyl acetate (100 mL). The organic phases were combined, washed with water (50 mL x 3), washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain a dark brown viscous substance. The substance was purified by column chromatography (silica gel, ethyl acetate:petroleum ether = 1:10 to ethyl acetate:petroleum ether = 1:5) to give a yellow solid (3.8 g, 7.32 mmol, yield: 96%). MS m / z: 518.2 [M+H] + .

[0750] Step 2: Synthesis of tert-butyl(S)-4-(7-bromo-6-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester

[0751] A solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (1.4 g, 8.78 mmol) in tetrahydrofuran (30 mL) was cooled in an ice-water bath. Sodium hydride (0.32 g, 8.05 mmol) was added, and the reaction was allowed to proceed at room temperature for 0.5 h. A solution of tert-butyl(S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester (3.8 g, 7.32 mmol) in tetrahydrofuran (15 mL) was added, and the reaction was allowed to continue at room temperature for 1 h. The mixture was extracted with ethyl acetate (100 mL) and diluted sodium carbonate aqueous solution (100 mL), and the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a light brown solid. The product was purified by column chromatography (silica gel, methanol:dichloromethane = 1:40) to give tert-butyl(S)-4-(7-bromo-6-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester (2.1 g, 3.21 mmol, yield: 44%). MS m / z: [M+H] + =641.3.

[0752] Step 3: Synthesis of tert-butyl(S)-4-(7-bromo-6-chloro-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester

[0753] 1.9 g (2.96 mmol) of tert-butyl(S)-4-(7-bromo-6-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester and cyclopropanol (0.34 g, 6.0 mmol) were dissolved in tetrahydrofuran (20 mL). Sodium hydroxide (0.14 g, 3.5 mmol) was added under a nitrogen atmosphere, and the mixture was heated to 60 °C. o The reaction was carried out at C for 2 h. Extraction was performed with ethyl acetate (100 mL) and water (100 mL). The organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The remaining viscous residue was purified by column chromatography (silica gel, methanol:dichloromethane = 1:40) to give tert-butyl(S)-4-(7-bromo-6-chloro-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester (0.8 g, 1.18 mmol, yield: 40%). MS m / z: [M+H] + =679.4.

[0754] Step 4: Synthesis of tert-butyl(2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthyl-1-yl)-8-cyclopropoxy-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester

[0755] Add tert-butyl(S)-4-(7-bromo-6-chloro-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester (200 mg, 0.294 mmol), 2-(8-chloro-7-fluoronaphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (144 mg, 0.47 mmol), Pd(dppf)Cl2 (22 mg, 0.0294 mmol), and potassium carbonate (81 mg, 0.59 mmol) to a round-bottom flask. Purge with nitrogen three times. Add a pre-deoxygenated mixture of 1,4-dioxane (10 mL) and water (2 mL). Purge with nitrogen three times. Then heat to 100 o The reaction mixture was stirred at C for 4 h. After cooling to room temperature, ethyl acetate (50 mL) and diluted sodium carbonate aqueous solution (50 mL) were added for extraction. The organic phase was washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting brown viscous substance was subjected to column chromatography (silica gel, triethylamine:methanol:dichloromethane = 0.04:1:40) to give tert-butyl(2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthyl-1-yl)-8-cyclopropoxy-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester (41 mg, 0.0525 mmol, yield: 18%). MS m / z: [M+H] + =779.5.

[0756] Step 5: Synthesis of 2-((2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthyl-1-yl)-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0757] The compound tert-butyl(2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthyl-1-yl)-8-cyclopropoxy-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester (40 mg, 0.0513 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 4 h. Extraction was performed by adding dichloromethane (30 mL) and saturated sodium carbonate aqueous solution (20 mL). The aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 2-((2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthyl-1-yl)-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile. This product was used directly in the next reaction without further purification. MS m / z: [M+H]+ = 679.4.

[0758] Step 6: Synthesis of 2-((2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthyl-1-yl)-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0759] Cool a solution of 2-fluoroacrylic acid (8.5 mg, 0.095 mmol) and HATU (27 mg, 0.071 mmol) in dichloromethane (3 mL) in an ice-water bath. Add triethylamine (0.026 mL, 0.189 mmol) dropwise. Remove from the ice-water bath and stir for 20 minutes. Add a solution of 2-((2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthyl-1-yl)-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile in dichloromethane (2 mL) all at once. Stir at room temperature for 6 hours. Add dichloromethane (17 mL), water (15 mL), and saturated sodium carbonate solution (5 mL), shake, separate, and extract the aqueous phase with dichloromethane (20 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over sodium sulfate, and evaporated under reduced pressure to give a yellow solid. The solid was purified by preparative TLC (methanol: dichloromethane = 1:10) to give 2-((2S)-4-(6-chloro-7-(8-chloro-7-fluoronaphthyl-1-yl)-8-cyclopropoxy-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (19 mg, 0.0253 mmol, total yield: 48%). 1 HNMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.8 Hz, 1H), 7.88-7.86 (m, 1H), 7.65-7.63(m, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.33 (s, 1H), 7.27 – 7.24 (m, 1H), 5.45(d, J = 48 Hz, 1H), 5.46 (d, J = 16 Hz, 1H), 5.27 (dd, J = 16.4, 4.0 Hz, 1H), 4.89 (brs, 1H), 4.45 – 4.24 (m, 4H), 3.67-3.64 (m, 2H), 3.48-3.44 MS m / z: [M+H] + =751.4

[0760] Compounds of Examples 916-938 were prepared using the preparation method of Example 915.

[0761]

[0762]

[0763]

[0764]

[0765] Example 939: Synthesis of 2-((2S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy)-6-hydroxyquinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0766]

[0767]

[0768] Step 1: Synthesis of tert-butyl(S)-4-(7-bromo-2-chloro-8-fluoro-6-methoxyquinazoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester

[0769] In an ice-water bath, nitrogen, N-diisopropylethylamine (6.6 mL, 40 mmol) was added in a single addition to a solution of 7-bromo-2,4-dichloro-8-fluoro-6-methoxyquinazoline (4.0 g, 12.3 mmol) in N,N-dimethylformamide (40 mL). After stirring for 1 minute, (S)-2-(piperazin-2-yl)acetonitrile hydrochloride (2.55 g, 12.9 mmol) was added. The reaction was carried out at room temperature in an ice-water bath with stirring for 1 hour.

[0770] Nitrogen, N-diisopropylethylamine (2.2 mL, 13.3 mmol), and di-tert-butyl dicarbonate (3.27 g, 15 mmol) were added to the above reaction solution at room temperature. The reaction solution was stirred at room temperature for 4 hours. Ethyl acetate (200 mL) and water (200 mL) were added for extraction and separation. The aqueous phase was extracted with ethyl acetate (100 mL). The organic phases were combined, washed with water (60 mL x 3), washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain a dark brown viscous substance. The solution was purified by column chromatography (silica gel, ethyl acetate:petroleum ether = 1:10 to ethyl acetate:petroleum ether = 1:5) to give a yellow solid (5.4 g, 10.5 mmol, yield: 85%). MS m / z: 514.2 [M+H]+.

[0771] Step 2: Synthesis of tert-butyl(S)-4-(7-bromo-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy)-6-methoxyquinazoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester

[0772] A solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (1.9 g, 12 mmol) in tetrahydrofuran (40 mL) was cooled in an ice-water bath. Sodium hydride (0.44 g, 11 mmol) was added, and the reaction was allowed to proceed for 0.5 h at room temperature. Tert-butyl(S)-4-(7-bromo-2-chloro-8-fluoro-6-methoxyquinazoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester (5.4 g, 10.5 mmol) was added in a single batch, and the reaction was allowed to continue for 1 h at room temperature. The mixture was extracted with ethyl acetate (100 mL) and diluted sodium carbonate aqueous solution (100 mL), and the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a light brown solid. The product was purified by column chromatography (silica gel, methanol:dichloromethane = 1:40) to give tert-butyl(S)-4-(7-bromo-6-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester (4.0 g, 6.27 mmol, yield: 60%). MS m / z: [M+H] + =637.4.

[0773] Step 3: Synthesis of tert-butyl(2S)-4-(7-(8-chloro-7-fluoronaphth-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-methoxyquinazoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester

[0774] Add tert-butyl(S)-4-(7-bromo-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy)-6-methoxyquinazoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester (300 mg, 0.47 mmol), 2-(8-chloro-7-fluoronaphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (230 mg, 0.75 mmol), Pd(dppf)Cl2 (34 mg, 0.047 mmol), and potassium carbonate (127 mg, 0.94 mmol) to a round-bottom flask. Purge with nitrogen three times. Add a pre-deoxygenated mixture of 1,4-dioxane (10 mL) and water (2 mL). Purge with nitrogen three times. Then heat to 100°C. o The reaction mixture was stirred at C for 4 h. After cooling to room temperature, ethyl acetate (50 mL) and diluted sodium carbonate aqueous solution (50 mL) were added for extraction. The organic phase was washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting brown viscous substance was subjected to column chromatography (silica gel, triethylamine:methanol:dichloromethane = 0.04:1:50) to give tert-butyl(2S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-methoxyquinazoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester (71 mg, 0.096 mmol, yield: 20%). MS m / z: [M+H + =737.5.

[0775] Step 4: Synthesis of 2-((2S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy)-6-hydroxyquinazoline-4-yl)piperazin-2-yl)acetonitrile

[0776] The compound tert-butyl(2S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-methoxyquinazoline-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid ester (70 mg, 0.096 mmol) was dissolved in dichloromethane (6 mL), cooled in an ice-water bath, and a solution of boron tribromide (0.057 mL, 0.77 mmol) in dichloromethane (3 mL) was added dropwise. The reaction was stirred in an ice-water bath for 1 h. Dichloromethane (30 mL) and low-valent methanol (10 mL) were added slowly. The mixture was rotary evaporated under reduced pressure, and the residue was extracted with dichloromethane (20 mL) and a saturated sodium carbonate aqueous solution (20 mL). The aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a yellow viscous substance. The solution was purified by preparative TLC (methanol:dichloromethane = 1:7) to give 2-((2S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy)-6-hydroxyquinazoline-4-yl)piperazin-2-yl)acetonitrile (15 mg, 0.024 mmol, yield: 25%). MS m / z: [M+H]+ = 623.4.

[0777] Step 5: Synthesis of 2-((2S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-methoxy)-6-hydroxyquinazoline-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0778] Cool a solution of 2-fluoroacrylic acid (4.3 mg, 0.048 mmol) and HATU (11 mg, 0.03 mmol) in dichloromethane (3 mL) in an ice-water bath. Add triethylamine (0.014 mL, 0.1 mmol) dropwise. Remove from the ice-water bath and stir for 20 minutes. Add a single solution of 2-((2S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy)-6-hydroxyquinazoline-4-yl)piperazin-2-yl)acetonitrile (15 mg, 0.024 mmol) in dichloromethane (2 mL). Stir at room temperature for 2 hours. Add dichloromethane (17 mL), water (15 mL), and saturated sodium carbonate solution (5 mL), shake, separate, and extract the aqueous phase with dichloromethane (20 mL). Combine the organic phases, wash with saturated brine (10 mL), dry to sodium sulfate, and rotary evaporate under reduced pressure to give a yellow solid. Purify by preparative TLC (methanol:dichloromethane = 1:10) to give 2-((2S)-4-(7-(8-chloro-7-fluoronaphthyl-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy)-6-hydroxyquinazoline-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (5 mg, 0.0072 mmol, yield: 30%). 1 HNMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.8 Hz, 1H), 7.88-7.86 (m, 1H), 7.65-7.63(m, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.27 – 7.24 (m, 1H), 7.01 (s, 1H), 5.45 (d, J = 48 Hz, 1H), 5.46 (d, J = 16 Hz, 1H), 5.27 (dd, J = 16.4, 4.0 Hz, 1H), 4.90 (brs, 1H), 4.45 – 4.29 (m, 4H), 3.68-3.64 (m, 2H), 3.46-3.44 (m, 2H),3.33-3.31 (m, 2H), 3.24-3.19 (m, 2H), 3.10-2.88 (m, 3H), 2.29-2.16 (m, 2H),1.96-1.92 (m, 3H). MS m / z: [M+H] + =695.4

[0779] Compounds of Examples 940-945 were prepared using the preparation method of Example 939.

[0780]

[0781] Example: Cell viability assay

[0782] 1. Cells: H358 were purchased from Shanghai Enzyme Research Biotechnology Co., Ltd.

[0783] 2. Reagents: RPMI 1640 medium, Tryple, MTT (5 mg / mL), DMSO, DPBS.

[0784] 3. Instruments: 37℃, 5% CO2 incubator, UTRAO microplate reader, biosafety cabinet, cell counting chamber, and Austen optical microscope.

[0785] 4. Experimental consumables: 96-well plate, part number: 3599, 96-well round bottom preparation plate.

[0786] H358 cell viability assay procedure:

[0787] 1. Plating: Digest cells in the logarithmic growth phase with Tryple, stop with fresh medium, count the cells, adjust the cell concentration to 55,555 cells / mL with fresh medium, add 90 μL to each well, and fill the other edges with sterile DPBS.

[0788] 2. Incubate at 37℃ in a 5% CO2 incubator for 24 hours, allowing the cells to cover approximately 50% of the bottom of the well.

[0789] 3. Experimental drug preparation: Dissolve the drug in DMSO to prepare a 20 mmol / L stock solution, then dilute it with DMSO to prepare a 2 mmol / L solution. Repeat this 3-fold dilution to obtain 8 concentration gradients, resulting in a 200× compound gradient solution. Add 10 μL of each gradient compound solution to 190 μL of RPMI 1640 medium to obtain a 10× compound gradient solution. Add 10 μL of each 10× compound solution to 90 μL of a 96-well cell culture plate. Perform three replicates for each gradient. The concentration gradients of the compound in the 96-well cell culture plate were 0.05080526 nM, 1.524158 nM, and 4.572474 nM. nM, 13.717420nM, 41.152260nM, 123.456800nM, 370.370400nM, 1111.111000nM, 3333.333000nM, 10000.000000nM, 100 μL per well, final DMSO concentration 0.5%.

[0790] The control group contained the same volume of solvent as the experimental group, diluted with complete culture medium, 100 μL per well.

[0791] 4. Incubate at 37°C in a 5% CO2 incubator for 5 days.

[0792] 5. After 5 days, add 10 μL of MTT solution (5 mg / mL) to each well and continue culturing for 4 hours.

[0793] 6. Terminate the culture and carefully aspirate the culture medium from the wells.

[0794] 7. Zeroing wells: Add 150 μL of dimethyl sulfoxide (DMSO) to each well of the experimental group and control group. Shake at medium speed for 10 s in an ELISA reader until the crystals are fully dissolved. Measure the absorbance at 492 nm.

[0795] IC50 of some compounds 50 The values ​​are shown in Table 1:

[0796]

[0797]

[0798]

[0799]

[0800] KRAS G12C-GDP Exchange Test:

[0801] 1. In reaction buffer (25 mM Hepes pH 7.4, 125 mM NaCl, 5 mM MgCl2, 0.01% Tween 20, 0.1% BSA), the compound was serially diluted 4 times (10 concentration points in total) and premixed with KRAS G12C-GDP (ICE, Kras 20191018) in the reaction wells for 1 hour.

[0802] 2. Add a mixture of SOS (Pharmaron, ZZY-20190823), cRAF (Pharmaron, ZZY-20190823), GTP (Sigma, A6885-100MG), and MAb Anti 6HIS-d2 / MAb Anti GST-Eu (Cisbio, 61HISDLB / 61GSTKLB) and carry out a catalytic reaction for 2 hours.

[0803] 3. Use a Biotek microplate reader (Synergy4) to read the fluorescence signals of the emitted light at 615nm and 665nm under 320nm excitation light.

[0804] 4. The IC50 (half-maximal inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * Hill Slope)). Data analysis was performed using Graphpad 6.0 software.

[0805]

[0806] Pharmacokinetics experiment in SD rats:

[0807] 1. SPF-grade male rats were randomly assigned to groups. Test compounds were administered via intravenous injection or oral gavage, with three animals per test compound and three animals per administration route. The administration solvents were 5% DMSO + 10% Solutol + 85% physiological saline or 85% PBS, ensuring clear solutions of the test compounds in both solutions. Dosage concentrations and volumes: 1) Single intravenous injection of 0.6 mg / mL test compound, administration volume 5 mL / kg, dose 3 mg / kg; 2) Single oral gavage of 1 mg / mL test compound, administration volume 10 mL / kg, dose 10 mg / kg. Rats were fasted overnight (10-14 hours) before administration and fed 4 hours after administration.

[0808] 2. Blood was collected at 200 μL per time point via the jugular vein or other suitable method, anticoagulated with K2-EDTA, and placed on ice after collection. Plasma was separated by centrifugation within 1 hour (centrifugation conditions: 6800g, 6 minutes, 2-8ºC). Blood collection points for animals in the intravenous injection group were: before administration, and 5, 15, 30 min, 1, 2, 4, 8, and 24 h after administration; blood collection points for animals in the oral administration group were: before administration, and 15, 30 min, 1, 2, 4, 6, 8, and 24 h after administration.

[0809] 3. Measure blood drug concentrations and calculate the pharmacokinetic parameter AUC(0-t) using blood drug concentration data at different time points using Phoenix WinNonlin. When calculating pharmacokinetic parameters, BLQ values ​​before Cmax (including "No peak") are calculated as 0; BLQ values ​​after Cmax (including "No peak") are not included in the calculation. Oral bioavailability calculation formula: F% = AUC0 - t 口服 / AUC0-t 静脉 *(10 / 3)*100%

[0810]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein the compound of formula (I) is: in: Ring W is a 4- to 12-element saturated or partially saturated monocyclic ring, bridged ring, or helical ring, wherein the saturated or partially saturated monocyclic ring is optionally additionally constituting one or more R... 4 replace, in R 4 Selected from: oxo, alkyl, alkenyl, alkyne, cycloalkyl, aryl, heteroaryl, heterocyclic, cyano, nitro, -C(O)OR 5 or -C(O)N(R) 5 )2, wherein the alkyl group is unsubstituted or replaced by a cyano, halogen, or -OR group. 5 -N(R) 5 )2 or one or more substitutions in heteroaryl groups, wherein R 5 Each is independently hydrogen or alkyl; R 1 -L 1 -T, in L 1 is -O-, -S-, -NR a -, -C(O)-, -SO2-, -SO-, -C(=NR a )-, -C(O)-O-, -OC(O)-, -C(O)-NR a - or -NR a C(O)-, T is -CR a =CR b R c -C≡CR b Alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic groups, wherein each of the alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is unsubstituted or oxidized, halogenated, hydroxylated, alkyl, haloalkyl, hydroxyalkyl, alkoxy, CN, nitro, or NR x R y One or more substitutions in; in R a It can be hydrogen, deuterium, cyano, halogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, aryl, heteroaryl, or heterocyclic. R b and R c Each can be independently represented as hydrogen, deuterium, cyano, halogen, or -C(O)OR. x Alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein each of the alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is unsubstituted or oxidized; halogen; hydroxyl; alkyl; haloalkyl; hydroxyalkyl; alkoxy; CN; nitro; NR x R y ; unsubstituted aryl groups or those substituted with alkyl, hydroxyl, or halogen groups; unsubstituted heteroaryl groups or those substituted with alkyl, hydroxyl, or halogen groups; one or both of the unsubstituted or heterocyclic groups substituted with alkyl, hydroxyl, or halogen groups. Or, when T is -CR a =CR b R c At that time, R a With R b Or R a With R c Together with the carbon atoms to which they are attached, they form unsaturated 5- to 8-membered rings, which are unsubstituted or substituted by one or two of oxo, hydroxyl, halogen, alkyl, hydroxyalkyl, haloalkyl or alkoxy. R x and R y Each is independently hydrogen or alkyl; Q 1 Q 2 and Q 3 Each is independently N or CR 11 M 1 and M 2 Each is independently N or CR 12 The condition is Q 1 and M 1 At least one of them is N; in R 11 and R 12 Each can be independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl or heterocyclic, -OR d -C(O)R d -CO2R d -CONR d R e or -NR d R e Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups are each independently converted by oxo, halogen, hydroxyl, alkoxy, alkyl, cycloalkyl, nitro, cyano, and -NR. d R e One or more substitutions in, where R d and R e Each can be independently hydrogen, alkyl, C3-C6 cycloalkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl; L represents a single bond, -O-, -S-, or -NR. a -、-O-CH2-、-S-CH2-、-NR a -CH2-, -CH2-O-, -CH2-S-, -CH2-NR a -, -C(O)-, -SO2-, -SO-, -C(O)-O-, -OC(O)-, -C(O)-NR a -or-NR a C(O)-; R 2 It is an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is independently unsubstituted or substituted by halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, oxo, -OR d -C(O)R d -CO2R d -CONR d R e -NR d R e -CH2NR d R e One or more substitutions are made from cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, and heterocyclic groups, wherein R d and R e Each can be independently classified as hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl; R 3 It is cycloalkyl, heterocyclic, aryl, or heteroaryl, provided that M is... 1 and Q 1 Q 2 When both are N, R 3 R is a non-aromatic fused bicyclic group, a non-aromatic fused bicyclic heterocyclic group, or a bicyclic heteroaryl group. 3 It is either unsubstituted or substituted with one or more of the following groups: oxo, halogen, cyano, -OR d -C(O)R d -CO2R d -CONR d R e -NR d COR e -NR d R e -S(O)2NR d R e Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is independently substituted by a halogen, alkyl, cyano, carbamoyl, alkoxy, hydroxyl, cycloalkyl, and heteroaryl group, wherein R d and R e Each can be independently hydrogen, alkyl, C3-C6 cycloalkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkenyl or cycloalkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein L 1 For -C(O)- or -SO2-, and for T, -CR a =CR b R c or -C≡CR b , where R a R is hydrogen, deuterium, cyano, halogen, hydroxyl, or alkyl. b and R c Each is independently hydrogen; halogen; unsubstituted alkyl; with hydroxyl, halogen, NR x R y Alkyl groups substituted with heterocyclic groups; unsubstituted aryl or heteroaryl groups; aryl or heteroaryl groups substituted with alkyl, hydroxyl, or halogen groups, wherein R x and R y Each can be either hydrogen or alkyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein L is -O-CH2- or -O-.

4. The compound of claim 3 or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R 2 The heterocyclic group is either unsubstituted or substituted with one or more of a halogen and an alkyl group.

5. The compound of claim 4 or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein LR 2 for , , , , or .

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R 3 The aryl group is phenyl or naphthyl, wherein the phenyl or naphthyl group is unsubstituted or substituted by 1, 2, or 3 or fewer substituents: halogen; cyano; -OR d , where R d It is hydrogen, alkyl, or haloalkyl; -CONR d R e , where R d and R e Each can be independently hydrogen, alkyl, or cycloalkyl; -NR d COR e , where R d and R e Each is independently hydrogen or alkyl; alkyl, wherein the alkyl group is unsubstituted or substituted with halogen, cycloalkyl, hydroxyl, or alkoxy; cycloalkyl, wherein the cycloalkyl group is unsubstituted or substituted with alkyl, cyano, or carbamoyl; alkynyl; -NR d R e , where R d and R e Each can be an independent hydrogen or alkyl group; or a heteroaryl group.

7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R 3 It is a partially hydrogenated naphthyl group, which is unsubstituted or substituted with hydroxyl, alkyl, hydroxyalkyl, haloalkyl or halogen.

8. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R 3 The heteroaryl group is unsubstituted or substituted by one, two, or three or fewer substituents: oxo, halogen; cyano; -OR d , where R d It is hydrogen, alkyl, or haloalkyl; -CONR d R e , where R d and R e Each can be independently hydrogen, alkyl, or cycloalkyl; -NR d COR e , where R d and R e Each is independently hydrogen, alkyl, or alkenyl; alkyl, wherein the alkyl group is unsubstituted or substituted with halogen, cycloalkyl, hydroxyl, or alkoxy; cycloalkyl, wherein the cycloalkyl group is unsubstituted or substituted with alkyl, cyano, or carbamoyl; alkynyl; or -NR d R e , where R d and R e Each can be either hydrogen or alkyl.

9. The compound of claim 8 or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein the heteroaryl group is a monocyclic heteroaryl group selected from thiophene, thiazole, pyrazole, pyridine, or pyrimidine; or a bicyclic heteroaryl group selected from... R a and R b Independently hydrogen, halogen, alkyl, or R a With R b The individual linkage is either substituted or unsubstituted C3-C6 cycloalkyl. It is either unsubstituted or substituted as described above.

10. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, tautomer, prodrug, or stereoisomer thereof, wherein R 3 It is a non-aromatic fused bicyclic heterocyclic group, which is unsubstituted or substituted with 1, 2, or 3 or fewer substituents: oxo, halogen; cyano; -OR d , where R d It is hydrogen, alkyl, or haloalkyl; -CONR d R e , where R d and R e Each can be independently hydrogen, alkyl, or cycloalkyl; -NR d COR e , where R d and R e Each is independently hydrogen, alkyl, or alkenyl; alkyl, wherein the alkyl group is unsubstituted or substituted with halogen, cycloalkyl, hydroxyl, or alkoxy; cycloalkyl, wherein the cycloalkyl group is unsubstituted or substituted with alkyl, cyano, or carbamoyl; alkynyl; or -NR d R e , where R d and R e Each can be either hydrogen or alkyl.

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