Preparation and application of heterocyclic compounds as KRAS inhibitors

Abstract

Compounds of formula (I) or pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, and solvates thereof are useful for treating cancer and inflammation in mammals. Also disclosed are methods for preparing compounds of formula (I) and pharmaceutical compositions containing the compounds. #imgabs0#

Description

Technical Field

[0001] The present invention relates to certain novel heterocyclic compounds or pharmaceutically acceptable salts thereof, which are useful for treating or preventing a wide variety of cancers. The present invention also relates to pharmaceutical compositions comprising the compounds and their salts, intermediates used in the preparation of the compounds, and methods for treating various cancers using the compounds and their salts. Background Art

[0002] 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, whereas DNA extracted from normal human tissue had no such effect. Subsequently, Santos and Parada discovered that the transforming gene was not a novel gene but rather the human homolog of the ras gene from the Harvey murine sarcoma virus, named H2ras. That same year, Krontiris discovered a homolog of the Kirsten murine sarcoma virus gene in human lung cancer cells, named K-ras. Another similar ras-like gene, N2ras, was discovered when NIH 3T3 cells were infected with human neuroblastoma DNA; this gene is unrelated to viruses.

[0003] The ras gene is highly conserved throughout evolution and is widely present in various eukaryotic organisms, including mammals, fruit flies, fungi, nematodes, and yeast, suggesting its important physiological function. The mammalian ras gene family consists of three members: H-ras, K-ras, and N-ras. K-ras has two variants, A and B, in its fourth exon. All ras genes share a similar structure, consisting of four exons distributed across approximately 30 kb of DNA. They encode proteins with a relative molecular mass of 21,000, hence the name P21 protein. It has been demonstrated that H-ras is located on the short arm of human chromosome 11 (11p15.1-p15.3), K-ras on the short arm of chromosome 12 (12p1.1-pter), and N-ras on the short arm of chromosome 1 (1p22-p32). With the exception of a variation in the fourth exon of K-ras, the sequence encoding P21 is evenly distributed across the four exons of each ras gene. However, the sequence and size of the introns vary significantly, leading to significant variations in the overall gene size. For example, human K-ras is 35 kb long, while N-ras is 3 kb. The presence of two fourth exons allows K-ras to be spliced ​​in two different ways, but the mRNA encoding K-ras-B is highly expressed. With the exception of K-ras-B, which contains 188 amino acids, the other two Ras proteins each contain 189 amino acids.

[0004] The Ras (P21) protein, located on the inner cell membrane, plays a crucial role in transmitting cell growth and differentiation signals. It is a guanosine triphosphate (GTP)-binding protein (a coupling factor in cellular signaling), regulating signaling through the interconversion of GTP and guanosine diphosphate (GDP). P21 has a strong affinity for GTP and GDP and possesses weak GTPase activity. Normally, P21 is inactive when bound to GDP. However, when extracellular growth and differentiation factors transmit signals to P21 on the inner cell membrane, this enhances P21's GTP-binding activity, activating the binding and signaling pathway. Because P21 has GTPase activity, it hydrolyzes GTP to GDP. Once bound to GDP, P21 becomes inactive, shutting down the signaling pathway. While P21's GTPase activity is weak, its hydrolysis rate increases 10,000-fold when bound to GTPase-activating protein (GAP), inactivating P21. The binding of P21 to GDP activates guanylate-releasing protein (GNRP), which causes P21 to release GDP and bind to GTP. Thus, the mutual conversion of GTP and GDP can regulate the opening and closing of the P21 signaling system in a controlled manner, completing the process of transmitting growth and differentiation signals into cells.

[0005] More than one-fifth of cancer patients have Ras gene mutations, most of which occur at residues G12, G13, and Q61. These mutations lead to the failure of GAP protein-mediated signaling, and the Ras signal remains in an activated state. The present invention designs and synthesizes a series of chemical molecules with strong biological activity inhibiting Ras, providing a method for treating related cancers by inhibiting H-ras, K-ras, or N-ras. Summary of the Invention

[0006] The present invention provides compounds capable of modulating G12C mutant KRAS, HRAS and / or NRAS proteins, including stereoisomers, pharmaceutically acceptable salts, tautomers and prodrugs thereof. Methods of using such compounds to treat various diseases or conditions (such as cancer) are also provided.

[0007] In one aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or prodrug thereof, wherein the compound of formula (I) is:

[0008]

[0009] in:

[0010] Ring W is a 4- to 12-membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally additionally substituted with one or more R 4 replace,

[0011] in

[0012] R 4 Selected from: oxo, alkyl, alkenyl, alkyne, cycloalkyl, aryl, heteroaryl, heterocyclyl, cyano, nitro, -C(O)OR 5 or -C(O)N(R 5 )2, wherein the alkyl group is unsubstituted or substituted by cyano, halo, -OR 5 、-N(R 5 )2 or one or more of heteroaryl, wherein R 5 are each independently hydrogen or alkyl;

[0013] R 1 -L 1 -T,

[0014] in

[0015] 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)-,

[0016] T is -CR a =CR b R c 、-C≡CR b , alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is unsubstituted or replaced by oxo, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, CN, nitro or NR x R y One or more substitutions in ;

[0017] in

[0018] R a is hydrogen, deuterium, cyano, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, aryl, heteroaryl or heterocyclic;

[0019] R b and R c Each is independently hydrogen, deuterium, cyano, halogen, -C(O)OR x , alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic, each of which is unsubstituted or substituted with oxo; halogen; hydroxy; alkyl; haloalkyl; hydroxyalkyl; alkoxy; CN; nitro; NR x Ry ; aryl which is unsubstituted or substituted by alkyl, hydroxyl or halogen; heteroaryl which is unsubstituted or substituted by alkyl, hydroxyl or halogen; one or two of heterocyclic groups which are unsubstituted or substituted by alkyl, hydroxyl or halogen,

[0020] Or, in T-CR a =CR b R c When R a With R b or R a With R c , together with the carbon atoms to which they are attached, form an unsaturated 5- to 8-membered ring, said ring being unsubstituted or substituted with one or two of oxo, hydroxy, halogen, alkyl, hydroxyalkyl, haloalkyl, or alkoxy;

[0021] R x and R y are each independently hydrogen or alkyl;

[0022] n 1 is 0, 1, or 2;

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

[0024] Q is N or CR 11 , M is N or CR 12 , provided that at least one of Q and M is N;

[0025] in

[0026] R 11 and R 12 are each independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, -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 heterocyclyl are each independently replaced by oxo, halogen, hydroxy, alkoxy, alkyl, cycloalkyl, nitro, cyano and -NR d R e One or more substitutions, wherein R d and R e each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

[0027] Or, when Q is CR 11 When R 11 and R4 Together with the atoms to which they are attached, they form a 5- to 8-membered ring containing 0, 1 or 2 atoms selected from O, S and NR d heteroatoms, the ring is unsubstituted or replaced by oxo, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, haloalkyl, hydroxyalkyl and -NR d R e One or more substitutions, wherein R d and R e each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

[0028] L is 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)-;

[0029] R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently unsubstituted or substituted with halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, oxo, -OR d 、-C(O)R d 、-CO2R d 、-CONR d R e 、-NR d R e , cycloalkyl, cycloalkylalkyl, aryl, heteroaryl and heterocyclic groups, wherein R d and R e each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

[0030] R 3 is a cycloalkyl, heterocyclyl, aryl or heteroaryl group, provided that when M and Q are both N and n 2 When R is 1, 3 is a non-aromatic fused bicyclic group, a non-aromatic fused bicyclic heterocyclic group or a bicyclic heteroaryl group, R 3 is unsubstituted or substituted by one or more of the following groups: oxo, halogen, cyano, -OR d 、-C(O)R d 、-CO2Rd 、-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 heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently substituted with halogen, alkyl, cyano, carbamoyl, alkoxy, hydroxy, cycloalkyl and heteroaryl, wherein R d and R e Each is independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkenyl or cycloalkyl.

[0031] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or prodrug thereof is provided, wherein the compound of formula (I) is:

[0032]

[0033] in:

[0034] Ring W is a 4- to 12-membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally additionally substituted with one or more R 4 replace,

[0035] in

[0036] R 4 Selected from: oxo, alkyl, alkenyl, alkyne, cycloalkyl, aryl, heteroaryl, heterocyclyl, cyano, nitro, -C(O)OR 5 or -C(O)N(R 5 )2, wherein the alkyl group is unsubstituted or substituted by cyano, halo, -OR 5 、-N(R 5 )2 or one or more of heteroaryl, wherein R 5 are each independently hydrogen or alkyl;

[0037] R 1 -L 1 -T,

[0038] in

[0039] 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)-,

[0040] T is -CR a =CR b R c 、-C≡CR b , alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is unsubstituted or replaced by oxo, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, CN, nitro or NR x R y One or more substitutions in ;

[0041] in

[0042] R a is hydrogen, deuterium, cyano, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, aryl, heteroaryl or heterocyclic;

[0043] R b and R c Each is independently hydrogen, deuterium, cyano, halogen, -C(O)OR x , alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein each of the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with oxo; halogen; hydroxy; alkyl; haloalkyl; hydroxyalkyl; alkoxy; CN;

[0044] Nitro; NR x R y ; aryl which is unsubstituted or substituted by alkyl, hydroxyl or halogen; heteroaryl which is unsubstituted or substituted by alkyl, hydroxyl or halogen; one or two of heterocyclic groups which are unsubstituted or substituted by alkyl, hydroxyl or halogen,

[0045] Or, in T-CR a =CR b R c When R a With R b or R a With R c , together with the carbon atoms to which they are attached, form an unsaturated 5- to 8-membered ring, said ring being unsubstituted or substituted with one or two of oxo, hydroxy, halogen, alkyl, hydroxyalkyl, haloalkyl, or alkoxy;

[0046] R x and R y are each independently hydrogen or alkyl;

[0047] n 1is 0, 1, or 2;

[0048] n 2 is 0, 1, or 2;

[0049] Q is N or CR 11 , M is N or CR 12 , provided that at least one of Q and M is N;

[0050] in

[0051] R 11 and R 12 are each independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, -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 heterocyclyl are each independently replaced by oxo, halogen, hydroxy, alkoxy, alkyl, cycloalkyl, nitro, cyano and -NR d R e One or more substitutions, wherein R d and R e each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

[0052] Or, when Q is CR 11 When R 11 and R 4 Together with the atoms to which they are attached, they form a 5- to 8-membered ring containing 0, 1 or 2 atoms selected from O, S and NR d heteroatoms, the ring is unsubstituted or replaced by oxo, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, haloalkyl, hydroxyalkyl and -NR d R e One or more substitutions, wherein R d and R e each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

[0053] L is 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)-;

[0054] R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently unsubstituted or substituted with halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, oxo, -OR d 、-C(O)R d 、-CO2R d 、-CONR d R e 、-NR d R e , cycloalkyl, cycloalkylalkyl, aryl, heteroaryl and heterocyclic groups, wherein R d and R e each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, and alkoxyalkyl;

[0055] R 3 is a non-aromatic fused bicyclic heterocyclic group, R 3 is unsubstituted or substituted by one or more of the following groups: oxo, halogen, cyano, -OR d 、-C(O)R d 、-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 heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently substituted with halogen, alkyl, cyano, carbamoyl, alkoxy, hydroxy, cycloalkyl and heteroaryl, wherein R d and R e Each is independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkenyl or cycloalkyl.

[0056] In some embodiments, L 1 It is -C(O)- or -SO2-.

[0057] In some embodiments, L 1 -C(=NR a )-, where R a is H, CN or hydroxyl.

[0058] In some embodiments, T is -CR a =CR b R c 、-C≡CR b , alkyl or heterocyclic, wherein Ra and Rb are as defined in formula (I).

[0059] In some embodiments, T is -CR a =CR b R c or -C≡CR b , where R a is hydrogen, deuterium, cyano, halogen, hydroxyl or alkyl, R b and R c Each is independently hydrogen; halogen; unsubstituted alkyl; hydroxyl, halogen, NR x R y or an alkyl group substituted with a heterocyclic group; an unsubstituted aryl or heteroaryl group; an aryl or heteroaryl group substituted with an alkyl group, a hydroxyl group or a halogen group, wherein R x and R y Preferably, in the above embodiment, the aryl group is a phenyl group which is unsubstituted or substituted by halogen, hydroxyl or C 1-3 Preferably, in the above embodiment, the heteroaryl group is thiazolyl, oxazolyl, pyridyl or pyrimidinyl, which is unsubstituted or substituted by halogen, hydroxyl or C 1-3 One or two of the alkyl groups are substituted.

[0060] In some embodiments, 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 to which they are attached, form an unsaturated 5- to 8-membered ring that is unsubstituted or substituted with one or two of hydroxy, halogen, alkyl, hydroxyalkyl, haloalkyl, or alkoxy. In some embodiments, T is -CR a =CR b R c , where R a With R b or R a With R c , together with the carbon atoms to which they are attached, form an unsaturated 5-, 6-, 7- or 8-membered carbocyclic ring, which is unsubstituted or substituted by one or two of hydroxyl, halogen, alkyl, hydroxyalkyl, haloalkyl or alkoxy. Preferably, the unsaturated 5-, 6-, 7- or 8-membered carbocyclic ring is a cyclopentene ring, a cyclohexene ring, a cycloheptene ring or a cyclooctene ring.

[0061] In some embodiments, T is alkyl, which is unsubstituted or substituted with halogen, hydroxy, NR x R y , CN, haloalkyl, hydroxyalkyl, alkoxy or heterocyclic, wherein R x and R y Preferably, the heterocyclic group in the above embodiment is a 4- to 8-membered heterocyclic ring containing one or two members selected from oxygen, nitrogen and sulfur, such as azetidine, pyrrolidine, piperidinyl, morpholinyl.

[0062] In some embodiments, T is a heterocyclyl group which is unsubstituted or substituted with halogen, hydroxy, NR x R y , CN, alkyl, haloalkyl, hydroxyalkyl or alkoxy, wherein R x and R y Each is independently hydrogen or alkyl. Preferably, T is a 3- to 8-membered heterocyclic ring containing one member selected from oxygen, nitrogen and sulfur, such as unsubstituted or methyl-substituted propylene oxide.

[0063] In some embodiments, L 1 is -C(O)- or -SO2-, and T is -CH=CH2.

[0064] In some embodiments, L is -O-CH2- or -O-.

[0065] In some embodiments, L is -O-CH2-, and R 2 is a heterocyclic group, which is unsubstituted or substituted by one or more of halogen and alkyl. Preferably, L is -O-CH2-, and R 2 is a heterocyclic group, wherein the heterocyclic group contains 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, sulfur and is a 4- to 8-membered monocyclic ring, wherein the heterocyclic group is unsubstituted or substituted by one or more of halogen and alkyl. More preferably, the heterocyclic group is azetidinyl, pyrrolidinyl or piperidinyl, wherein the ring is unsubstituted or substituted by one or two halogen or alkyl. In a further preferred embodiment, LR 2 for

[0066] In some embodiments, L is -O-, and R 2 is a heterocyclic group, which is unsubstituted or substituted by one or more of halogen and alkyl. Preferably, L is -O-, and R 2is a heterocyclic group, wherein the heterocyclic group is a 7- to 12-membered fused bicyclic heterocyclic group containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and the heterocyclic group is unsubstituted or substituted with one or more of halogen and alkyl. More preferably, the heterocyclic group is a non-aromatic 7- to 12-membered fused bicyclic heterocyclic group containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and the heterocyclic group is unsubstituted or substituted with one or more of halogen and alkyl. In a preferred embodiment, the heterocyclic group is tetrahydro

[0067] Pyrrolizine, more preferably tetrahydro-1H-pyrrolizine-7a-yl In a further preferred embodiment, L-R2 is 2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yloxy

[0068] In some embodiments, R 3 is aryl, wherein the aryl is phenyl or naphthyl, and the phenyl or naphthyl is unsubstituted or substituted with 1, 2 or 3 of the following substituents: halogen; cyano; -OR d , where R d is hydrogen, alkyl or haloalkyl; -CONR d R e , where R d and R e Each is 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 is unsubstituted or substituted with halogen, cycloalkyl, hydroxy or alkoxy; cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with alkyl, cyano or carbamoyl; alkynyl; -NR d R e , where R d and R e Each is independently hydrogen or alkyl; or heteroaryl.

[0069] In some embodiments, R 3 is a partially hydrogenated naphthyl group which is unsubstituted or substituted by hydroxy, alkyl, hydroxyalkyl, haloalkyl or halogen. 3 is 1,2,3,4-tetrahydronaphthyl, which is unsubstituted or substituted by hydroxy, alkyl, hydroxyalkyl, haloalkyl, halogen, amino, alkylamino or dialkylamino.

[0070] In some embodiments, R 3 is a heteroaryl group, which is unsubstituted or substituted by 1, 2 or 3 of the following substituents: oxo, halogen; cyano; -ORd , where R d is hydrogen, alkyl or haloalkyl; -CONR d R e , where R d and R e Each is independently hydrogen, alkyl or cycloalkyl; -NR d COR e , where R d and R e each independently hydrogen, alkyl, or alkenyl; alkyl, wherein the alkyl is unsubstituted or substituted with halogen, cycloalkyl, hydroxy, or alkoxy; cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with alkyl, cyano, or carbamoyl; alkynyl; or -NR d R e , where R d and R e Each is independently hydrogen or alkyl. Preferably, the above heteroaryl is a monocyclic heteroaryl, such as thiophene, thiazole, pyrazole, pyridine or pyrimidine, which is unsubstituted or substituted as described above. Preferably, the above heteroaryl is a bicyclic heteroaryl, such as

[0071] It is unsubstituted or substituted as described above.

[0072] In some embodiments, R 3 is a heterocyclic group, preferably a non-aromatic fused bicyclic heterocyclic group, which is unsubstituted or substituted by 1, 2 or 3 of the following substituents: oxo, halogen; cyano; -OR d , where R d is hydrogen, alkyl or haloalkyl; -CONR d R e , where R d and R e Each is independently hydrogen, alkyl or cycloalkyl; -NR d COR e , where R d and R e each independently hydrogen, alkyl, or alkenyl; alkyl, wherein the alkyl is unsubstituted or substituted with halogen, cycloalkyl, hydroxy, or alkoxy; cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with alkyl, cyano, or carbamoyl; alkynyl; or -NR d R e , where R d and R e Each is independently hydrogen or alkyl. In another embodiment, R 3is a non-aromatic fused bicyclic heterocyclic group which is unsubstituted or substituted with 1, 2 or 3 of the following substituents: oxo, halogen; hydroxyl, alkoxy and alkyl; preferably, the substituent is oxo, halogen, hydroxyl, methoxy or methyl. In a further embodiment, R 3 is a non-aromatic fused bicyclic heterocyclic group, which is

[0073]

[0074] It is unsubstituted or substituted with 1, 2 or 3 of the following substituents: oxo, halogen; hydroxyl, alkoxy and alkyl; preferably, the substituent is oxo, halogen, hydroxyl, methoxy or methyl, wherein X, Y and Z are each independently N or CR 9 , where R 9 is hydrogen, hydroxy, cyano, alkyl, haloalkyl, halogen, hydroxyalkyl, alkoxyalkyl or alkylsulfonyl.

[0075] In some embodiments, the compound of formula (I) is

[0076]

[0077] in:

[0078] R 3 for

[0079] Where X, Y, Z are selected from N or CR 9 , and the remaining variables are as defined for formula (I).

[0080] In some embodiments, the compound of formula (I) is represented by formula (I-3), (I-4), (I-5), (I-6), (I-7), and (I-8):

[0081]

[0082] where R a and R b are independently hydrogen, methyl or trifluoromethyl, or R a and R b The composition is C=O.

[0083] In some embodiments, when Q is CR 11 When R 11 and R 4Together with the atoms to which they are attached, they form a 5- to 8-membered ring containing 0, 1 or 2 atoms selected from O, S and NR d The ring is unsubstituted or replaced by oxo, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, haloalkyl, hydroxyalkyl and -NR d R e One or more substitutions, wherein R d and R e are independently hydrogen, alkyl, hydroxyalkyl, haloalkyl and alkoxyalkyl. 11 and R 4 Together with the atoms to which they are attached, they form a 6-membered ring, said ring containing one additional N atom, said ring being unsubstituted or substituted by oxo. More preferably, R 11 and R 4 Together with the atoms to which they are attached, they form a 6-membered ring containing an amide bond, i.e. -C(O)-NH-, which is unsubstituted or substituted with oxo. Preferably, the compound of formula (I) is wherein R 4 With R 11 The cyclic compound (I-5-A) composed of the following:

[0084]

[0085] Where m is 0, 1 or 2; Z 2 O or NR 2 , R 2 is hydrogen or alkyl; R a and R b is independently hydrogen or alkyl; or when Z 2 NR 2 When R a With R b The composition is C=O.

[0086] In some embodiments, R 1 -W is wherein the piperazine ring is optionally additionally substituted with one or more R 4 Replacement, R 4 As defined in formula (I). In some embodiments, R 4 C 1- C3 alkyl, wherein the alkyl group is unsubstituted or substituted with cyano.

[0087] In some embodiments, R in the compound of formula (I) 1 -W is

[0088]

[0089] In some embodiments, R 1 For groups:

[0090]

[0091]

[0092] In a preferred embodiment, R 1 -W is In some embodiments, LR 2 for

[0093]

[0094] In a preferred embodiment, LR 2 for More preferably

[0095] In some embodiments, R 3 for

[0096]

[0097]

[0098] In a preferred embodiment, R 3 for

[0099] More preferably

[0100] In some embodiments, R 11 is hydrogen, nitro, hydroxy, halogen, cyano, alkyl, haloalkyl, alkoxy or alkoxyalkyl; preferably hydrogen, halogen, cyano, trifluoromethyl or nitro.

[0101] In some embodiments, R 12 is hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl, C1-C6 haloalkyl, aryl or heteroaryl, wherein the aryl and heteroaryl are each unsubstituted or substituted with one or more of C1-C3 alkyl, halogen, C1-C3 haloalkyl and C3-C6 cycloalkyl.

[0102] In some embodiments, R 12 for

[0103]

[0104] In some embodiments, the compound of formula (I) is in

[0105] R 1 -W is R 3 for

[0106] Preferably as well as

[0107] LR 2 for More preferably

[0108] In some embodiments, the compound of formula (I) is in

[0109] R 3 for as well as

[0110] R 2 for The remaining variables are as defined for the compounds of formula (I).

[0111] In some embodiments, the compound of formula (I) is in

[0112] R 3 for Preferably and LR 2 for

[0113] Preferably The remaining variables are as defined in formula (I).

[0114] In some embodiments, the compound of formula (I) is

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155] Another aspect of the present invention provides an exemplary preparation method of the compound of formula (I) or its pharmaceutically acceptable salt, tautomer or stereoisomer:

[0156] Preparation method 1:

[0157]

[0158] Where: R 1 , R 2 , R 3, L is as defined herein; the base used in the first step can be sodium carbonate, potassium carbonate, or sodium hydroxide; PG and PG' are amino protecting groups, such as tert-butyloxycarbonyl, TEOC, benzyl, benzyloxycarbonyl, and other commonly used amino protecting groups. When it is tert-butyloxycarbonyl, the protecting group can be removed with trifluoroacetic acid, hydrochloric acid, or the like; when it is TEOC, the protecting group can be removed with trifluoroacetic acid, cesium fluoride, potassium fluoride, or the like; when the protecting group is a benzyl or benzyloxycarbonyl protecting group, catalytic hydrogenation can be selected to remove the protecting group; the palladium catalyst used in the Buchwald reaction is Pd2(dba)3, and the ligands are XPhos, BrettPhos, tBuBret tPhos or DavePhos; the copper catalyst used in the Ullmann reaction is cuprous iodide, and the ligand can be but is not limited to 1,10-phenanthrolinone; the oxidant is but is not limited to potassium monopersulfate and m-chloroperbenzoic acid; when a free amino group or alcohol undergoes a substitution reaction, the base can be an organic base (such as potassium bis(trimethylsilylamide), triethylamine, diisopropylethylamine, pyridine, potassium tert-butoxide, etc.) or an inorganic base (sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, etc.); the acylation reaction can adopt an acid amine condensation method or an acyl chloride method; the condensation is carried out in the presence of a condensing agent (such as HOBT, EDCI, HATU, TBTU, etc.).

[0159] Preparation method 2:

[0160]

[0161] Where: R 1 , R 2 , R 3 , L is as defined herein; PG and PG' are amino protecting groups, such as tert-butyloxycarbonyl, TEOC, benzyl, benzyloxycarbonyl and other commonly used amino protecting groups. When it is tert-butyloxycarbonyl, the protecting group can be removed with trifluoroacetic acid, hydrochloric acid and the like. When it is TEOC, the protecting group can be removed with trifluoroacetic acid, cesium fluoride, potassium fluoride and the like. When the protecting group is a benzyl or benzyloxycarbonyl protecting group, catalytic hydrogenation can be selected to remove the protecting group. The palladium catalyst used in the Buchwald reaction is Pd2(dba)3, and the ligand is XPhos, BrettPhos, tBuBrettPhos or Dave Phos; the copper catalyst used in the Ullmann reaction is cuprous iodide, and the ligand can be, but is not limited to, 1,10-phenanthrolinone; the oxidant can be, but is not limited to, potassium monopersulfate and m-chloroperbenzoic acid; when a free amino group or alcohol undergoes a substitution reaction, the base can be an organic base (such as potassium bis(trimethylsilylamide), triethylamine, diisopropylethylamine, pyridine, potassium tert-butoxide, etc.) or an inorganic base (sodium carbonate, potassium carbonate, sodium bicarbonate, etc.); the acylation reaction can adopt an acid-amine condensation method or an acyl chloride method; and the condensation reaction is carried out in the presence of a condensing agent (such as HOBT, EDCI, HATU, TBTU, etc.).

[0162] Preparation method 3:

[0163]

[0164] Where: R a , R b , R 1 , R 2 , R 3 , L is as defined herein; when a free amino group or alcohol is substituted, the base can be an organic base (such as triethylamine, diisopropylethylamine, pyridine, etc.) or an inorganic base (sodium carbonate, potassium carbonate, sodium bicarbonate, etc.); the reducing agent for reductive amination is but not limited to sodium cyanoborohydride, sodium acetate borohydride, sodium borohydride, and the acid used for reductive amination is but not limited to acetic acid and trifluoroacetic acid; the oxidizing agent is but not limited to m-chloroperoxybenzoic acid; PG is an amino protecting group, such as tert-butyloxycarbonyl, TEOC, benzyloxycarbonyl, etc. Common amino protecting groups include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. When it is tert-butyloxycarbonyl, the protecting group can be removed with trifluoroacetic acid, hydrochloric acid, etc. When it is TEOC, the protecting group can be removed with trifluoroacetic acid, cesium fluoride, potassium fluoride, etc. When the protecting group is benzyl or benzyloxycarbonyl, catalytic hydrogenation can be selected to remove the protecting group; the acylation reaction can adopt the acid amine condensation method or the acyl chloride method; the condensation is carried out in the presence of a condensing agent (HOBT, EDCI, HATU, TBTU, etc.).

[0165] Preparation method 4:

[0166]

[0167] Among them, R 1 , R 2 , R 3 , L, W are as defined above. PG is an amino protecting group, such as Boc-, Cbz, etc., and X is a group such as F, Cl, Br, I, OTf, etc. The first step is a substitution reaction under alkaline conditions (such as triethylamine, diisopropylethylamine, etc.); the second step is an oxidation reaction under oxidizing agent conditions (such as m-chloroperbenzoic acid, etc.) to obtain an intermediate sulfoxide; the third step is a substitution reaction of the intermediate sulfoxide under alkaline conditions (triethylamine, sodium hydride, sodium tert-butoxide, etc.) to obtain the target intermediate; the fourth step is the selective removal of the protecting group under hydrogenation (Pd / C, hydrogen, methanol) conditions; the fifth step is a Buchwald reaction with R 3 -X-EU coupling reaction to obtain an intermediate; the sixth step is to remove the protecting group (such as Boc); the seventh step is to react with the corresponding acid or acyl chloride to obtain the target compound.

[0168] Preparation method 5:

[0169]

[0170] Among them, R1 , R 2 , R 11 , R 12 , L, W are as defined above. PG is an amino protecting group, such as Boc-, Cbz, etc., and X is a group such as F, Cl, Br, I, OTf, etc. The first step is to undergo a substitution reaction with a compound containing a naked amino group under alkaline conditions (triethylamine, diisopropylethylamine, etc.); the second step is to prepare an intermediate under alkaline conditions (triethylamine, sodium hydride, sodium tert-butoxide, etc.); the third step is to selectively remove the protecting group (such as hydrogenation-Pd / C); the fourth step is a Buchwald reaction with R 3 -X-EU coupling reaction to obtain an intermediate; the fifth step is to remove the protecting group (such as Boc) under acidic conditions to obtain the intermediate; the sixth step is to react with the corresponding acid or acyl chloride to obtain the target compound.

[0171] Preparation method 6:

[0172]

[0173] Where: R 1 , R 2 , R 3 , R 12 , L is as defined herein; the base used in the sNAr reaction can be sodium hydride, potassium bis(trimethylsilyl)amide, or diisopropylethylamine; the palladium catalyst used in the Buchwald reaction is Pd2(dba)3, and the ligand is XPhos, BrettPhos, tBuBrettPhos, or DavePhos; the copper catalyst used in the Ullmann reaction is cuprous iodide, and the ligand can be, but is not limited to, 1,10-phenanthrolinone; PG is an amino protecting group, such as Common amino protecting groups include tert-butyloxycarbonyl and benzyloxycarbonyl. When it is tert-butyloxycarbonyl, the protecting group can be removed with trifluoroacetic acid, hydrochloric acid, etc. When it is TEOC, the protecting group can be removed with trifluoroacetic acid, cesium fluoride, potassium fluoride, etc. When the protecting group is a benzyloxycarbonyl or other protecting group, catalytic hydrogenation can be selected to remove the protecting group. The acylation reaction can adopt the acid amine condensation method or the acid chloride method. The acid amine condensation method is to carry out the condensation reaction in the presence of a condensing agent (HOBT, EDCI, HATU, TBTU, etc.).

[0174] Preparation method 7:

[0175]

[0176] Where: R 1 , R 2 , R 3 , R 12, L is as defined herein; the first step is to carry out SNAr substitution reaction with a piperazine derivative. If the product contains exposed amino groups, an additional step of amino protection is required; PG is an amino protecting group, such as tert-butyloxycarbonyl, TEOC, benzyl, benzyloxycarbonyl and other commonly used amino protecting groups. When it is tert-butyloxycarbonyl, the protecting group can be removed with trifluoroacetic acid, hydrochloric acid and the like. When it is TEOC, the protecting group can be removed with trifluoroacetic acid, cesium fluoride, potassium fluoride and the like. When the protecting group is benzyl or benzyloxycarbonyl, the protecting group can be removed by catalytic hydrogenation; free amino or alcohol When performing substitution reaction, the base can be an organic base (such as triethylamine, diisopropylethylamine, pyridine, etc.) or an inorganic base (sodium hydrogen hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, etc.); the halogenating agent is but not limited to NCS, NBS, NIS; the palladium catalyst used in Suzik coupling reaction is but not limited to Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(dppf), etc.; the acylation reaction can adopt the acid amine condensation method or the acyl chloride method; the condensation is carried out in the presence of a condensing agent (HOBT, EDCI, HATU, TBTU, etc.).

[0177] Preparation method 8:

[0178]

[0179] Where: R 1 , R 2 , R 3 , R 4 , R 13 , L is as defined herein; the chlorination reagent is but not limited to phosphorus oxychloride; PG is an amino protecting group, such as tert-butyloxycarbonyl, benzyl, benzyloxycarbonyl and other commonly used amino protecting groups. When it is tert-butyloxycarbonyl, the protecting group can be removed by trifluoroacetic acid, hydrochloric acid and the like. When the protecting group is benzyl or benzyloxycarbonyl, catalytic hydrogenation can be selected to remove the protecting group; the reducing agent for reducing the nitro group is iron powder, and the acidic reagent can be acetic acid or ammonium chloride; when the free amino group or alcohol is subjected to the substitution reaction, the base can be an organic base (such as triethylamine, diisopropylethylamine, pyridine, etc.) or an inorganic base (sodium hydrogen, sodium carbonate, potassium carbonate, sodium bicarbonate, etc.); the acylation reaction can adopt the acid amine condensation method or the acyl chloride method; the condensation is carried out in the presence of a condensing agent (HOBT, EDCI, HATU, TBTU and other condensing agents).

[0180] Preparation method 9:

[0181]

[0182] Where: R 1 , R 2 , R 3 , R 4, L is as defined herein; when a free amino group or alcohol is subjected to a substitution reaction, the base can be an organic base (such as triethylamine, diisopropylethylamine, pyridine, etc.) or an inorganic base (sodium hydrogen hydride, sodium carbonate, potassium carbonate, etc.); PG, PG' are amino protecting groups, such as commonly used amino protecting groups such as tert-butyloxycarbonyl, TEOC, benzyl, benzyloxycarbonyl, etc. When it is tert-butyloxycarbonyl, the protecting group can be removed with trifluoroacetic acid, hydrochloric acid, etc.; when it is TEOC, the protecting group can be removed with trifluoroacetic acid, cesium fluoride, potassium fluoride, etc.; when the protecting group is a protecting group such as benzyl or benzyloxycarbonyl, catalytic hydrogenation can be selected to remove the protecting group; the acylation reaction can be carried out by an acid amine condensation method or an acyl chloride method; the condensation is carried out in the presence of a condensing agent (such as HOBT, EDCI, HATU, TBTU, etc.).

[0183] Preparation method 10:

[0184]

[0185] Where: R 1 , R 2 , R 3 As defined herein; the first step is a ring-enhancing reaction in which BF3.Et2O and ethyl diazoacetate react with 1-tert-butyloxycarbonyl-4-piperidone to obtain the target intermediate; the second step is a cyclization reaction under the action of a base (the base can be sodium methoxide, sodium ethoxide, sodium hydride, etc.); the third step is the addition of OTf under the action of a base (the base can be triethylamine, diisopropylethylamine, etc.); the fourth step is a nucleophilic substitution reaction under the action of a base (the base can be triethylamine, diisopropylethylamine, etc.); the fifth step is an oxidation reaction, and the oxidant is preferably an oxidant such as m-CPBA; the sixth step is the addition of OTf under the action of a base ( The seventh step is the selective removal of the amino protecting group, such as the removal of the amino protecting group tert-butyloxycarbonyl with trifluoroacetic acid; the eighth step is a coupling reaction, such as the Buchwald coupling reaction or the Ullmann coupling reaction; the ninth step is the removal of the amino protecting group under hydrogenation or acidic conditions; the tenth step is an acylation reaction, which can adopt the acid amine condensation method or the acid chloride method. The acid amine condensation method is a condensation reaction in the presence of a condensing agent (such as HOBT, EDCI, HATU, TBTU, etc.) to obtain the target compound.

[0186] Preparation method 11:

[0187]

[0188] The first step is to add OTf under the action of a base (the base can be triethylamine, diisopropylethylamine, etc.); the second step is to cause a nucleophilic substitution reaction under the action of a base (the base can be triethylamine, diisopropylethylamine, etc.); the third step is an oxidation reaction, and the oxidant is preferably an oxidant such as m-CPBA; the fourth step is to cause a nucleophilic substitution reaction under the action of a base (sodium tert-butoxide, potassium tert-butoxide, sodium hydride or cesium carbonate, etc.); the fifth step is to selectively remove the amino protecting group, such as using trifluoroacetic acid to remove the amino protecting group tert-butyloxycarbonyl; the sixth step is a coupling reaction such as a Buchwald coupling reaction or an Ullmann coupling reaction; the seventh step is to remove the amino protecting group under hydrogenation or acidic conditions; the eighth step is an acylation reaction, which can adopt an acid amine condensation method or an acyl chloride method. The acid amine condensation method is to carry out a condensation reaction in the presence of a condensing agent (such as HOBT, EDCI, HATU, TBTU, etc.) to obtain the target compound.

[0189] Preparation method 12:

[0190]

[0191] Where: R 1 , R 2 , R 3 , L is as defined herein; the palladium catalyst used in the first step of the Buchwald reaction is Pd2(dba)3, and the ligand is XPhos, BrettPhos, tBuBrettPhos or DavePhos; the oxidant used in the second step is but not limited to potassium monopersulfate, m-chloroperbenzoic acid; the base used in the third step of the substitution reaction can be an organic base (such as potassium bis(trimethylsilylamide), diisopropylethylamine, pyridine, potassium tert-butoxide, etc.) or an inorganic base (sodium hydride, cesium carbonate, carbonate potassium, etc.); PG is an amino protecting group, such as tert-butyloxycarbonyl, TEOC, benzyloxycarbonyl, etc. When it is tert-butyloxycarbonyl, the protecting group can be removed with trifluoroacetic acid, hydrochloric acid, etc. When it is TEOC, the protecting group can be removed with trifluoroacetic acid, cesium fluoride, potassium fluoride, etc. When the protecting group is benzyloxycarbonyl, catalytic hydrogenation can be selected to remove the protecting group; the fifth step acylation reaction can adopt the acid amine condensation method or the acid chloride method, and the condensation reaction is carried out in the presence of a condensing agent (EDCI / HOBt, HATU, TBTU, etc.).

[0192] Other general synthetic methods are provided in the Examples. It will be apparent to one of ordinary skill in the art that compounds of Formula (I) can be prepared according to one or more methods or by other means known in the art. It will be apparent that, in general, when following the general routes described herein, various substituted starting materials and / or protecting groups will be required to obtain the desired compounds. Various substituents may also be added at various points in the synthetic route to prepare the desired compounds.

[0193] The present invention relates to pharmaceutical compositions of compounds of formula (I) or pharmaceutically acceptable salts, prodrugs and solvates thereof.

[0194] Another aspect of the present invention provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions associated with G12 KRAS, HRAS, or NRAS mutations (e.g., cancers). Cancers mediated by G12C mutations include pancreatic cancer, lung cancer, colorectal cancer, peritoneal cancer, colorectal cancer, small intestine cancer, biliary tract cancer, endometrial cancer, ovarian cancer, reproductive tract cancer, gastrointestinal cancer, cervical cancer, gastric cancer, urinary tract cancer, and hematopoietic and lymphoid cancers.

[0195] The compound of formula (I) of the present invention has good physicochemical properties and safety and toxicity parameters, and can be used for treating cancer and inflammation in mammals.

[0196] In other embodiments, there is also provided a method of inhibiting proliferation of a cell population, the method comprising contacting the cell population with any one of the compounds of structure (I).

[0197] Other embodiments relate to pharmaceutical compositions. The pharmaceutical compositions comprise any one (or more) of the aforementioned compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions are formulated for oral administration. In other embodiments, the pharmaceutical compositions are formulated for injection. In further embodiments, the pharmaceutical compositions comprise a compound disclosed herein and another therapeutic agent (e.g., an anticancer agent). Non-limiting examples of such therapeutic agents are described below.

[0198] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection. DETAILED DESCRIPTION

[0199] Unless otherwise indicated, the following definitions are used throughout the disclosure of this invention:

[0200] As used herein, including the appended claims, singular forms such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0201] The term "prodrug" refers to any derivative that can be converted into the corresponding active pharmaceutical compound in vivo. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert into the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.

[0202] "Pharmaceutically acceptable salts" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, or the like, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base functional group with a suitable organic acid or by reacting an acidic group with a suitable base.

[0203] The term "solvate" refers to a complex molecular compound formed in solution when solute molecules or ions attract adjacent solvent molecules through intermolecular forces such as Coulombic forces, van der Waals forces, charge transfer forces, hydrogen bonds, etc. In one embodiment, the solvent is water, i.e., the compounds of the present invention form hydrates.

[0204] The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may therefore produce enantiomers, diastereomers and other stereoisomeric forms, which are defined as (R)- or (S)-, or as (D)- or (L)- configurations with respect to the absolute stereochemical configuration of the amino acids. The present invention is intended to include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be obtained using chiral synthesis or chiral preparation, or resolved using conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, and resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). The present invention provides pure isomers and isomer mixtures, as well as methods for their preparation and use, and compositions comprising them. For the sake of simplicity, they are referred to hereinafter as compounds of the formula (I), which refers both to the pure optical isomers and, if appropriate, to mixtures of isomers in varying ratios.

[0205] The compounds of the present invention may exist in specific forms. Unless otherwise indicated, the term "tautomer" or "tautomeric form" means that at room temperature, different functional group isomers are in dynamic equilibrium and can quickly convert into each other. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (proton tautomers) (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence isomers (valencetautomers) include interconversions performed by the reorganization of some bonding electrons.

[0206] The term "alkyl" herein refers to a hydrocarbon group selected from a straight chain saturated hydrocarbon group and a branched chain saturated hydrocarbon group, which contains 1 to 18 (such as 1 to 12, further such as 1 to 10, further such as 1 to 8 or 1 to 6 or 1 to 4) carbon atoms. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0207] The term "halogen" as used herein refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0208] The term "haloalkyl" herein refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms, such as fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). Examples of haloalkyl groups include halo C 1-8 Alkyl, halogenated C 1-6 Alkyl or halogenated C 1-4 Alkyl groups include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0209] The term "alkenyl" herein refers to a hydrocarbon group selected from a straight chain hydrocarbon group and a branched hydrocarbon group, which contains at least one C=C double bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Examples of alkenyl groups are C 2-6 Alkenyl groups include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl.

[0210] The term "alkynyl" herein refers to a hydrocarbon group selected from a straight chain hydrocarbon group and a branched hydrocarbon group, which contains at least one C≡C triple bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Examples of alkynyl groups are C 2-6Alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl.

[0211] The term "alkoxy" herein refers to an alkyl group as defined above bonded to oxygen, represented by -Oalkyl. Examples of alkoxy groups are C 1-6 Alkoxy or C 1-4 Alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0212] The term "cycloalkyl" herein refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, comprising monocycles and polycyclic (e.g., bicyclic and tricyclic) groups. For example, cycloalkyl can contain 3 to 12 (e.g., 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5 or 3 to 4) carbon atoms. Even further, for example, cycloalkyl can be selected from monocyclic groups containing 3 to 12 (e.g., 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms. The example of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. In particular, examples of saturated monocyclic cycloalkyl groups are C 3-8 Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In a preferred embodiment, a cycloalkyl is a monocyclic ring (abbreviated as C 3-6 Cycloalkyl) including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyls include those having 7 to 12 ring atoms arranged as a bicycle selected from [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, or a bridged bicycle selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Other examples of bicyclic cycloalkyls include those arranged as a bicycle selected from [5,6] and [6,6] ring systems, such as wherein the wavy line indicates the point of attachment. The ring may be saturated or have at least one double bond (ie, partially unsaturated), but is not fully conjugated and is not aromatic as aromatic is defined herein.

[0213] The term "aryl" used alone or in combination with other terms refers to a group selected from:

[0214] a. 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0215] b. bicyclic ring systems, such as 7- to 12-membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, such as naphthyl; and

[0216] c. Tricyclic ring systems, such as 10- to 15-membered tricyclic ring systems, wherein at least one ring is carbocyclic and aromatic, for example fluorenyl.

[0217] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably in the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring carbon atoms (i.e., C 5-10 Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a benzene ring. In some embodiments, the aromatic hydrocarbon ring is a benzene ring.

[0218] The term "heteroaryl" herein refers to a group selected from:

[0219] a. a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, in some embodiments 1 to 2 heteroatoms, selected from nitrogen (N), sulfur (S), and oxygen (O) (as one or more ring atoms), the remaining ring atoms being carbon;

[0220] b. a 7- to 12-membered bicyclic ring containing at least one heteroatom, e.g., 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, selected from N, O, and S (as one or more ring atoms), the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0221] c. an 11- to 14-membered tricyclic ring containing at least one heteroatom, e.g., 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, selected from N, O, and S (as one or more ring atoms), the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0222] In preferred embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group containing one nitrogen atom and 0 or 1 additional heteroatom selected from N, O, and S, including but not limited to pyridyl, isoxazolyl, and oxazolyl.

[0223] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group is no greater than 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is no greater than 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. A nitrogen atom in one or more rings of a heteroaryl group may be oxidized to form an N-oxide.

[0224] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably in the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9 or 10 ring members, wherein 1, 2, 3 or 4 heteroatom ring members are independently selected from nitrogen (N), sulfur (S) and oxygen (O), and the remaining ring members are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a 5-6 membered heteroaryl ring, which is a monocyclic ring and has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is an 8-10 membered heteroaryl ring, which is a bicyclic ring and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

[0225] Examples of heteroaryl or monocyclic or bicyclic aromatic heterocycles include, but are not limited to (numbered from the attachment position designated priority 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), tetrazolyl, ... yl, thienyl (such as thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl (furyl or furanyl), benzofuranyl, benzimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl or 1,3, 4-triazolyl), quinolyl, isoquinolyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazolyl, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4-oxadiazolyl, 1-thiazolyl -2,3-oxadiazolyl, 1-thia-2,4-oxadiazolyl, 1-thia-2,5-oxadiazolyl, 1-thia-3,4-oxadiazolyl, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzophenylthio, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl) and 5,6,7,8-tetrahydroisoquinoline.

[0226] The term "heterocyclic" or "heterocycle" or "heterocyclyl" herein refers to a ring selected from 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered monocyclic, bicyclic and tricyclic saturated and partially unsaturated rings containing at least one carbon atom and at least one heteroatom, such as 1 to 4 heteroatoms, further such as 1 to 3 heteroatoms or further such as 1 or 2 heteroatoms, these heteroatoms being selected from nitrogen (N), sulfur (S), oxygen (O), -SO- or -SO2 (as one or more ring atoms).

[0227] In some embodiments, the heterocyclyl group is a 4-, 5-, 6-, 7-, or 8-membered monocyclic ring having at least one heteroatom selected from N, O, and S. In some preferred embodiments, the heterocyclyl group is a 4-, 5-, 6-, 7-, or 8-membered saturated monocyclic ring containing one nitrogen heteroatom. Exemplary heterocyclyl groups are azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, and azocanyl. In other embodiments, the heterocyclyl group is a 5-, 6-, 7-, or 8-membered saturated monocyclic ring containing one nitrogen atom and one additional heteroatom selected from -NH, -O-, -S-, -SO-, or -SO2-. Exemplary heterocyclyl groups are morpholino, morpholinyl, or piperazinyl rings. In some embodiments, the heterocyclyl group is a 7- to 12-membered saturated bicyclic ring containing one nitrogen atom and 0, 1, or 2 additional heteroatoms selected from -NH, -O-, -S-, -SO-, or -SO2-. In some preferred embodiments, the heterocyclyl group is a bicyclic bridged ring or a spirocycle.

[0228] As used herein, "heterocycle" also refers to a 5- to 7-membered heterocyclic ring containing at least one heteroatom selected from N, O, and S, fused to a 5-, 6-, and / or 7-membered cycloalkyl, carbocyclic aromatic, or heteroaromatic ring, provided that the entire ring structure is non-aromatic. The heterocyclic ring is not a heteroaryl group as defined herein. In a preferred embodiment, the heterocyclic group is a 5- to 6-membered heterocyclic group containing one nitrogen atom and 0 or 1 additional heteroatom selected from N, O, and S, including but not limited to pyrrolyl, dihydropyridine, morpholino, morpholinyl, and tetrahydropyranyl.

[0229] Examples of heterocycles include, but are not limited to (numbering from the attachment position designated as priority 1), 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thioethanethiol, azetidinyl, oxetanyl, thietanyl, 1,2-di ... 3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl and 1,4- diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl 1-oxo-1-thiomorpholinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, and azabicyclo[2.2.2]hexyl. Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.

[0230] In some embodiments, the heterocyclyl is a non-aromatic fused bicyclic heterocyclyl, such as the fused bicyclic heterocycles listed above; and for example, the following non-aromatic fused bicyclic heterocyclyls, namely

[0231] Where X, Y, Z are selected from N or CR 9 , and the remaining variables are as defined for formula (I).

[0232] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0233] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as 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 be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0234] When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with up to two R, and R in each case has independent options. In addition, combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds. The term "substituted with one or more ... or less groups" disclosed herein includes, for example, 1 to 5 (such as 1 to 4, further such as 1, 2 or 3) substituents, provided that valence permits.

[0235] Unless otherwise specified, the term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched chain alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom, or heteroatom group. 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 heteroatom group 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 group is C1-C6 heteroalkyl; in other embodiments, the heteroalkyl group is C1-C3 heteroalkyl. The heteroatom or heteroatom group may be placed at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule, but the terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are conventional expressions and refer to those alkyl groups that are attached to the remainder of the molecule through an oxygen, amino, or sulfur atom, respectively. Examples of heteroalkyl groups include, but are not limited to, -OCH, -OCHCH, -OCHCHCH, -OCH(CH), -CH-CH-O-CH, -NHCH, -N(CH), -NHCHCH, -N(CH)(CHCH), -CH-CH-NH-CH, -CH-CH-N(CH)-CH, -SCH, -SCHCH, -SCHCHCH, -SCH(CH), -CH-SCH-CH, -CH-CH, -S(=O)-CH, -CH-CH-S(=O)-CH, -CH=CH-O-CH, -CH-CH=N-OCH, and -CH=CH(N-CH)-CH. Up to two heteroatoms can be consecutive, for example, -CH-NH-OCH.

[0236] Unless otherwise indicated, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, etc. moieties described herein may each independently be optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, nitro, trifluoromethyl, azido, amino, carboxyl, and thiol.

[0237] synthesis

[0238] Suitable solvents commonly used in organic reactions can be used in each step of the following preparation method of the present invention, for example, but not limited to: aliphatic and aromatic, optional hydrocarbons or halogenated hydrocarbons (such as pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, volatile oil, benzene, toluene, xylene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene), aliphatic and aromatic, optional alcohols (such as methanol, ethanol, propanol, isopropanol, tert-butyl alcohol), alcohol, ethylene glycol, etc.), ethers (such as diethyl ether and dibutyl ether, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether, tetrahydrofuran and dioxane, etc.), esters (such as methyl acetate or ethyl acetate, etc.), nitriles (such as acetonitrile or propionitrile, etc.), ketones (such as acetone, butanone, etc.), amides (such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, etc.), as well as dimethyl sulfoxide, tetramethylene sulfone, hexamethylphosphoric triamide and N,N-dimethylpropylene urea (DMPU), etc.

[0239] The present invention uses the following abbreviations: DCM represents dichloromethane; CHCl3 represents chloroform; 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 lithium hexamethyldisilazide; CDI represents 1,1'-carbonylimidazole; MS represents mass spectrometry; NMR represents nuclear magnetic resonance; TFA represents trifluoroacetic acid; BINAP represents (2R,3S)-2,2'-diphenylphosphine-1,1'-difluoromethane Naphthalene; BOC stands for tert-butyloxycarbonyl; Cbz stands for benzyloxycarbonyl; DBU stands for dicyclo-1,5-diaza-5-undecene; DCC stands for 1,3-dicyclohexylcarbodiimide; DCE stands for 1,2-dichloroethane; DMAP stands for 4-dimethylaminopyridine; dppf stands for bis(diphenylphosphino)ferrocene; LiAlH4 stands for lithium aluminum hydride; LDA stands for lithium diisopropylamide; m-CPBA stands for m-chloroperbenzoic acid; MTM stands for dimethyl sulfide; NBS stands for N-bromosuccinimide; NCS stands for N-chlorosuccinimide; NIS stands for N -iodosuccinimide; PCC stands for pyridine dichromate; TBAF stands for tetrabutylammonium fluoride; THP stands for tetrahydropyranyl; TMEDA stands for tetramethylethylenediamine; TMS stands for trimethylsilyl; TMP stands for 2,2,6,6-tetramethylpiperidine; Ts stands for p-toluenesulfonyl; Pd(PPh3)4 stands for tetrakistriphenylphosphine palladium; PdCl2(dppf) stands for 1,1'-bis(diphenylphosphinodiphenylphosphinodichloropalladium); Pd2(dba)3 stands for tris(dibenzylideneacetone)dipalladium; HOBT stands for 1-hydroxybenzotriazole; HATU stands for 2-(7-oxobenzotriazole) Benzotriazole )-N,N,N',N'- TetramethylureaHexafluorophosphate; TBTU represents O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate; Tf2O represents trifluoroacetic anhydride; Pd(OAc)2 represents palladium diacetate; RuPhos represents 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl; Pd(PPh3)2Cl2 represents bistriphenylphosphine palladium dichloride; Sphos represents 3,2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl; XantPhos represents 4,5-bisdiphenylphosphino-9,9-dimethylxanthene; MeONa represents sodium methoxide; n-BuLi represents n-butyl lithium; 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 represents urea; POCl3 represents phosphorus oxychloride; BBr3 represents boron tribromide; NH4Cl represents ammonium chloride; MeI represents iodomethane; NMP represents N-methylpyrrolidone; K3PO4 represents potassium phosphate; chromatographic separation represents column chromatography; Ac represents acetyl; Bn represents benzyl; Fmoc represents fluorenylmethyloxycarbonyl; Cy represents cyclohexyl; Tf represents trifluoromethanesulfonyl; PDC represents pyridinium dichromate.

[0240] Synthesis Example:

[0241] Example 1: Synthesis of (S)-1-(4-(6-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0242]

[0243] Step 1: Synthesis of tert-butyl 2-(methylthio)-4-oxo-3,4,5,7-tetrahydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0244] Dissolve ethyl N-BOC-4-oxo-3-pyrrolidinecarboxylate (3.5 g, 13.6 mmol) in water (50 mL), add S-methylisothiourea sulfate (7.6 g, 27.2 mmol) and sodium carbonate (5.8 g, 54.4 mmol), and stir at room temperature for 15 hours. TLC indicates the reaction is complete. Extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (dichloromethane / methanol = 30 / 1) to obtain a white solid (2 g, yield: 52.6%). 1 H NMR (400MHz, CDCl3) δ4.59-4.46 (m, 4H), 2.59 (dd, J = 11.3, 1.7Hz, 3H), 1.58-1.47 (m, 9H).

[0245] Step 2: Synthesis of 2-(methylthio)-3,5,6,7-tetrahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one

[0246] Dissolve tert-butyl 2-(methylthio)-4-oxo-3,4,5,7-tetrahydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (2 g, 7.1 mmol) in dichloromethane (50 mL). Add trifluoroacetic acid (10 mL) and stir at room temperature for 2 hours. TLC confirms the reaction is complete. Concentrate to dryness, add aqueous sodium bicarbonate (20 mL), extract with dichloromethane (50 mL), dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain a light yellow solid (850 mg, yield: 65.9%).

[0247] Step 3: Synthesis of 2-(methylthio)-6-(2,2,2-trifluoroacetyl)-3,5,6,7-tetrahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one

[0248] Dissolve 2-(Methylthio)-3,5,6,7-tetrahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one (800 mg, 4.4 mmol) in dichloromethane (50 mL), add triethylamine (883 mg, 8.8 mmol), and dropwise add trifluoroacetic anhydride (1.4 g, 6.6 mmol). Stir at room temperature for 2 hours. TLC confirms the reaction is complete. Concentrate to dryness, add aqueous sodium bicarbonate (20 mL), extract with dichloromethane (50 mL), dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain a light yellow solid (650 mg, yield: 53%).

[0249] Step 4: Synthesis of 2-(methylthio)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate

[0250] Dissolve 2-(Methylthio)-6-(2,2,2-trifluoroacetyl)-3,5,6,7-tetrahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one (650 mg, 2.3 mmol) in dichloromethane (50 mL), add DIPEA (601 mg, 4.6 mmol), and dropwise add trifluoromethanesulfonic anhydride (1.3 g, 4.6 mmol). Stir at room temperature for 1 hour. The reaction is complete by TLC. Concentrate to dryness and use directly in the next reaction (945 mg, yield: 100%).

[0251] Step 5: Synthesis of tert-butyl 4-(2-(methylthio)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0252] 2-(Methylthio)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate (900 mg, 2.2 mmol) was dissolved in DMF (50 mL), and DIPEA (567 mg, 4.4 mmol) and Boc-piperazine (818 mg, 4.4 mmol) were added. The mixture was heated to 80°C for 5 hours. TLC confirmed the reaction was complete. The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol = 30 / 1) to afford a white solid (850 mg, yield: 86.5%). 1 HNMR(400MHz, CDCl3)δ5.00(d,J=46.0Hz,2H),4.75(d,J=50.8Hz,2H),3.73(dd,J=7 .0,3.6Hz,4H),3.55(td,J=5.5,5.1,3.1Hz,4H),2.53(d,J=3.6Hz,3H),1.51(s,9H).

[0253] Step 6: Synthesis of tert-butyl 4-(2-(methylsulfinyl)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0254] Dissolve tert-butyl 4-(2-(methylthio)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (850 mg, 1.9 mmol) in dichloromethane (50 mL) and mCPBA (410 mg, 1.9 mmol). Stir at room temperature for 1 hour. TLC confirms the reaction is complete. Add aqueous sodium bicarbonate (20 mL), extract with dichloromethane (50 mL), concentrate to dryness, and use directly in the next reaction (880 mg, yield: 100%). 1 H NMR (400MHz, CDCl3) δ5.10 (d, J = 47.3Hz, 2H), 4.90 (d, J = 53.4Hz, 2H), 3.82 (q, J = 4.1Hz, 4H), 3.59 (q, J = 5.6Hz, 4H), 2.93 (d, J = 3.3Hz, 2H), 1.51 (s, 9H).

[0255] Step 7: Synthesis of tert-butyl (S)-4-(2-(((1-methylpyrrolidin-2-yl)methoxy)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0256] Tert-butyl 4-(2-(methylsulfinyl)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (880 mg, 1.9 mmol) was dissolved in toluene (50 mL). Sodium tert-butoxide (365 mg, 3.8 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (437 mg, 3.8 mmol) were added under ice-cooling. The mixture was stirred at room temperature for 1 hour. The reaction was complete as determined by TLC. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to afford a white solid (600 mg, yield: 61.5%).

[0257] Step 8: Synthesis of tert-butyl (S)-4-(2-(((1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0258] (S)-tert-Butyl 4-(2-(((1-methylpyrrolidin-2-yl)methoxy)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (600 mg, 1.2 mmol) was dissolved in methanol (50 mL) and potassium carbonate (497 mg, 3.6 mmol). The mixture was stirred at room temperature for 10 hours. TLC indicated that the reaction was complete. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol = 30 / 1) to give a white solid (300 mg, yield: 60%).

[0259] Step 9: Synthesis of tert-butyl (S)-4-(6-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0260] Tert-butyl (S)-4-(2-(((1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (300 mg, 0.72 mmol) was dissolved in toluene (50 mL), and Pd2(dba)3 (66 mg, 0.072 mmol), XPhos (68 mg, 0.144 mmol), and Cs2CO3 (469 mg, 1.44 mmol) were added. The mixture was heated to 100°C for 15 hours under nitrogen protection. The reaction was complete after TLC. The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give a white solid (210 mg, yield: 50.5%).

[0261] Step 10: Synthesis of (S)-6-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine

[0262] Dissolve (S)-tert-butyl 4-(6-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (210 mg, 0.36 mmol) in dichloromethane (20 mL). Add trifluoroacetic acid (5 mL) and stir at room temperature for 2 hours. The reaction is complete as determined by TLC. The mixture is concentrated to dryness, and aqueous sodium bicarbonate (20 mL) is added. Extraction is performed with dichloromethane (50 mL), and the organic phase is dried over anhydrous sodium sulfate. The organic phase is concentrated to obtain a light yellow solid (150 mg, yield: 86.7%).

[0263] Step 11: Synthesis of (S)-1-(4-(6-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0264] (S)-6-(8-Chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (150 mg, 0.31 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (106 mg, 1.04 mmol) was added. Acryloyl chloride (28 mg, 0.31 mmol) was then added under ice-cooling. The reaction was complete by TLC. Aqueous sodium bicarbonate (10 mL) was added, and the mixture was extracted with dichloromethane (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified on a preparative plate (dichloromethane / methanol = 10 / 1) to afford a pale yellow solid (75 mg, yield: 44.9%). 1H NMR (400MHz, CDCl3) δ8.34-8.15(m,1H),7.95-7.80(m,1H),7.62(d,J=8.2Hz,1H),7.5 4-7.51(m,1H),7.45(t,J=7.8Hz,1H),7.33-7.28(m,1H),6.58(dd,J=16.8,10.5Hz,1H ),6.35(dd,J=16.8,1.9Hz,1H),5.77(dd,J=10.5,2.0Hz,1H),4.94-4.73(m,2H),4.59 -4.45(m,2H),3.94-3.36(m,10H),2.89(s,4H),2.38-1.93(m,6H); MSm / z:533.2[M+H]

[0265] Example 2: Synthesis of 2-((S)-1-acryloyl-4-(6-(8-chloronaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0266]

[0267] Step 1: Synthesis of tert-butyl 2-(methylthio)-4-oxo-3,4,5,7-tetrahydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0268] Dissolve ethyl N-BOC-4-oxo-3-pyrrolidinecarboxylate (3.5 g, 13.6 mmol) in water (50 mL), add S-methylisothiourea sulfate (7.6 g, 27.2 mmol) and sodium carbonate (5.8 g, 54.4 mmol), and stir at room temperature for 15 hours. TLC indicates the reaction is complete. Extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (dichloromethane / methanol = 30 / 1) to obtain a white solid (2 g, yield: 52.6%). 1 H NMR (400MHz, CDCl3) δ4.59-4.46 (m, 4H), 2.59 (dd, J = 11.3, 1.7Hz, 3H), 1.58-1.47 (m, 9H).

[0269] Step 2: Synthesis of 2-(methylthio)-3,5,6,7-tetrahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one

[0270] Dissolve tert-butyl 2-(methylthio)-4-oxo-3,4,5,7-tetrahydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (2 g, 7.1 mmol) in dichloromethane (50 mL). Add trifluoroacetic acid (10 mL) and stir at room temperature for 2 hours. TLC confirms the reaction is complete. Concentrate to dryness, add aqueous sodium bicarbonate (20 mL), extract with dichloromethane (50 mL), dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain a light yellow solid (850 mg, yield: 65.9%).

[0271] Step 3: Synthesis of 2-(methylthio)-6-(2,2,2-trifluoroacetyl)-3,5,6,7-tetrahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one

[0272] Dissolve 2-(Methylthio)-3,5,6,7-tetrahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one (800 mg, 4.4 mmol) in dichloromethane (50 mL), add triethylamine (883 mg, 8.8 mmol), and dropwise add trifluoroacetic anhydride (1.4 g, 6.6 mmol). Stir at room temperature for 2 hours. TLC confirms the reaction is complete. Concentrate to dryness, add aqueous sodium bicarbonate (20 mL), extract with dichloromethane (50 mL), dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain a light yellow solid (650 mg, yield: 53%).

[0273] Step 4: Synthesis of 2-(methylthio)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate

[0274] 2-(Methylthio)-6-(2,2,2-trifluoroacetyl)-3,5,6,7-tetrahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one (100 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL), DIPEA (92 mg, 0.71 mmol) was added, and trifluoromethanesulfonic anhydride (151.7 mg, 0.53 mmol) was added dropwise. The mixture was stirred at room temperature for 20 min. The reaction was complete after TLC detection. The mixture was concentrated to dryness and used directly in the next reaction.

[0275] Step 5: Synthesis of (S)-2-(4-(2-(methylthio)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0276] 2-(Methylthio)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate (147 mg, 0.36 mmol) was dissolved in DMF (10 mL), and DIPEA (92 mg, 0.71 mmol) and (S)-2-(piperazin-2-yl)acetonitrile hydrochloride (71 mg, 0.36 mmol) were added. The mixture was reacted at room temperature for 5 hours. The reaction was complete when detected by TLC, and the product was used directly in the next reaction.

[0277] Step 6: Synthesis of (S) tert-butyl 2-(cyanomethyl)-4-(2-(methylthio)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0278] To the previous reaction mixture, add Boc2O (314 mg, 1.44 mmol) and DIPEA (139 mg, 0.108 mmol). Allow to react at room temperature for 2 hours. TLC indicates the reaction is complete. Extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and purify with column chromatography (dichloromethane / methanol = 30 / 1) to obtain a white solid (100 mg, yield: 57.1%). 1 H NMR (400MHz, CDCl3) δ4.97 (d, J = 4.2 Hz, 2H), 4.80 (s, 2H), 3.55-3.12 (m, 5H), 2.78-2.54 (m, 4H), 2.52 (d, J = 1.2Hz, 3H), 1.50 (s, 9H).

[0279] Step 7: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(2-(methylsulfinyl)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0280] (S) tert-Butyl 2-(cyanomethyl)-4-(2-(methylthio)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.20 mmol) was dissolved in dichloromethane (10 mL) and mCPBA (46 mg, 0.22 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was complete after TLC detection. Aqueous sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL). The mixture was concentrated to dryness and used directly in the next reaction. 1H NMR (400MHz, CDCl3) δ5.10 (d, J=6.4Hz, 2H), 4.98 (s, 2H), 3.64 (q, J=12.4Hz, 2H), 3.49 (t, J= 11.9Hz,3H),2.94(d,J=4.1Hz,3H),2.79(s,2H),2.63(dd,J=16.8,5.9Hz,2H),1.53(s,9H).

[0281] Step 8: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0282] Dissolve (S)-tert-Butyl 2-(cyanomethyl)-4-(2-(methylsulfinyl)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (110 mg, 0.22 mmol) in toluene (10 mL). Add sodium tert-butoxide (42 mg, 0.44 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (44 mg, 0.38 mmol) under ice-cooling. Stir at room temperature for 1 hour. The reaction is complete as determined by TLC. Extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (dichloromethane / methanol = 20 / 1) to afford a white solid (60 mg, yield: 49.6%).

[0283] Step 9: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0284] (S)-tert-Butyl 2-(cyanomethyl)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(2,2,2-trifluoroacetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in methanol (10 mL). Potassium carbonate (15 mg, 0.22 mmol) was added and stirred at room temperature for 10 hours. The reaction was complete as determined by TLC. The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give a white solid (30 mg, yield: 60%).

[0285] Step 10: Synthesis of tert-butyl (S)-4-(6-(8-chloronaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolidin[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0286] Tert-butyl (S)-2-(cyanomethyl)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (70 mg, 0.15 mmol) was dissolved in toluene (20 mL), and 1-bromo-8-chloronaphthalene (48 mg, 0.20 mmol), Pd2(dba)3 (28 mg, 0.03 mmol), XPhos (22 mg, 0.045 mmol), and Cs2CO3 (125 mg, 0.38 mmol) were added. The mixture was heated to 100°C under nitrogen for 15 hours. The reaction was complete as determined by TLC. The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give a white solid (30 mg, yield: 31.7%). 1 H NMR (400MHz, CDCl3) δ8.31-8.21(m,1H),7.90-7.83(m,1H),7.61(d,J=8.2Hz,1H),7.55-7.51(m, 1H),7.45(t,J=7.8Hz,1H),7.41-7.34(m,1H),4.78(q,J=14.1,11.0Hz,2H),4.57(d,J=7.1Hz,2H) ,4.03(d,J=12.6Hz,1H),3.72(d,J=29.3Hz,1H),3.55-3.02(m,6H),2.92(d,J=21.8Hz,3H),2.81- 2.68(m,2H),2.66-2.51(m,2H),2.38-2.13(m,3H),2.13-1.92(m,3H),1.50(p,J=5.8,4.6Hz,9H).

[0287] Step 11: Synthesis of 2-((S)-4-(6-(8-chloronaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolidin[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0288] Tert-butyl (S)-4-(6-(8-chloronaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolidin[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (30 mg, 0.048 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (5 mL) was added and stirred at room temperature for 2 hours. The reaction was complete as determined by TLC. The mixture was concentrated to dryness and aqueous sodium bicarbonate (10 mL) was added. The mixture was extracted with dichloromethane (20 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a light yellow solid (20 mg, yield: 80%).

[0289] Step 12: Synthesis of 2-((S)-1-acryloyl-4-(6-(8-chloronaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0290] 2-((S)-4-(6-(8-chloronaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolidin[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (20 mg, 0.039 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (5 mg, 0.05 mmol) was added. Acryloyl chloride (3.84 mg, 0.042 mmol) was added under ice-cooling. The reaction was complete by TLC. Aqueous sodium bicarbonate (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified on a preparative plate (dichloromethane / methanol = 10 / 1) to afford a pale yellow solid (5 mg, yield: 22.7%). 1 H NMR (400MHz, CDCl3) δ8.33-8.20(m,1H),7.93-7.83(m,1H),7.85-7.73(m,1H),7.70-7.63(m,1H ),7.45(t,J=7.8Hz,1H),7.37(t,J=7.7Hz,1H),6.56(s,1H),6.39(d,J=16.7Hz,1H),5.83(d,J=1 0.6Hz,1H),4.87(d,J=11.9Hz,2H),4.65-4.51(m,2H),4.31-4.10(m,1H),3.94(s,1H),3.61(s,6 H),2.88(d,J=14.8Hz,3H),2.72(s,4H),2.23(d,J=28.7Hz,3H),2.04(s,3H); MSm / z:572.2[M+H]

[0291] Example 3: Synthesis of (S)-1-(4-(6-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propyl-2-en-1-one

[0292]

[0293] Step 1: Synthesis of tert-butyl 2-(methylthio)-4-oxo-3,4,5,7-tetrahydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0294] Dissolve ethyl N-BOC-4-oxo-3-pyrrolidinecarboxylate (8.0 g, 31.1 mmol) in water (150 mL), add S-methylisothiourea sulfate (6.49 g, 46.6 mmol) and sodium carbonate (13.2 g, 124 mmol), and stir at room temperature for 15 hours. TLC indicates the reaction is complete. Add hydrochloric acid (6 N) with vigorous stirring to a pH of 6-7. Slowly add dilute hydrochloric acid (1 N) to a pH of 3. Collect the solid by filtration, rinse with water (20 mL x 2), and dry under reduced pressure. Slurry the mixture with ethyl acetate (15 mL), collect the solid by filtration, and rotary evaporation to obtain a light yellow solid (5 g, yield: 57%). 1 H NMR (400MHz, CDCl3) δ4.59-4.46 (m, 4H), 2.59 (dd, J = 11.3, 1.7Hz, 3H), 1.58-1.47 (m, 9H).

[0295] Step 2: Synthesis of tert-butyl 2-(methylthio)-4-((trifluoromethyl)sulfonyl)oxy)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0296] Dissolve tert-butyl 2-(methylthio)-4-oxo-3,4,5,7-tetrahydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (2.83 g, 10 mmol) in dichloromethane (100 mL) and add DIPEA (3.3 mL, 20 mmol). Add trifluoromethanesulfonic anhydride (2.19 mL, 13 mmol) dropwise in an ice-water bath. Stir at room temperature for 1 hour. The reaction is complete as determined by TLC. Concentrate the mixture to obtain a dark brown viscous product, which is used directly in the next step.

[0297] Step 3: Synthesis of tert-butyl 2-(methylthio)-4-(4-((2-(trimethylsilyl)ethoxy)carbonyl)piperazin-1-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0298] The crude product of tert-butyl 2-(methylthio)-4-((trifluoromethyl)sulfonyl)oxy)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate obtained in the previous step was dissolved in DMF (35 mL). DIPEA (3.3 mL, 20 mmol) and ethyl 2-(trimethylsilyl)piperazine-1-carboxylate (2.3 g, 10 mmol) were added at room temperature. The mixture was heated to 80°C and reacted for 16 hours. TLC indicated that the reaction was complete. After cooling to room temperature, ethyl acetate (250 mL) and saturated aqueous ammonium chloride (200 mL) were added. After shaking and separating the layers, the aqueous phase was extracted with ethyl acetate (100 mL). The organic phases were combined, washed with saturated aqueous sodium bicarbonate (50 mL), water (50 mL x 2), and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to yield a brown solid (5 g, crude product) that was used directly in the next reaction.

[0299] Step 4: Synthesis of tert-butyl 2-(methylsulfoxy)-4-(4-((2-(trimethylsilyl)ethoxy)carbonyl)piperazin-1-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0300] To a solution of tert-butyl 2-(methylthio)-4-(4-((2-(trimethylsilyl)ethoxy)carbonyl)piperazin-1-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (5 g, crude product) in dichloromethane (100 mL) was slowly added a solution of mCPBA (2.23 g, 1.9 mmol) in dichloromethane (50 mL) in an ice-water bath. The mixture was stirred at room temperature for 1 hour, and the reaction was complete as determined by TLC. The reaction solvent was washed with aqueous sodium bicarbonate (50 mL), then with saturated brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting solid was purified by column chromatography (silica gel, methanol:dichloromethane = 1:40) to afford a light yellow powder (3.3 g, 59% yield over three steps). 1 H NMR(400MHz,CDCl3)δ4.82and 4.80(s,AB,2H),4.62and 4.58(s,AB,2H),4.23(t,J=8.0Hz,2H),3.78-3.76(m,4H),3.61-3.54(m,4H),2.88(s,3H),1.52(s,9H),1.03(t,J=8.0Hz,2H),0.05(s,9H).

[0301] Step 5: Synthesis of (S)-tert-butyl 2-((1-methylpyrrolidin-2-yl)methoxy)-4-(4-((2-(trimethylsilyl)ethoxy)carbonyl)piperazin-1-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0302] To a solution of (S)-(1-methylpyrrolidin-2-yl)methanol (553 mg, 4.8 mmol) in tetrahydrofuran was added a solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (4.5 mL, 4.5 mmol) dropwise in an ice-water bath. The resulting white cloudy solution was stirred in an ice-water bath for 20 minutes, and tert-butyl 2-(methylsulfoxy)-4-(4-((2-(trimethylsilyl)ethoxy)carbonyl)piperazin-1-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (1.54 g, 3.0 mmol) was added all at once. The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into stirred water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (silica gel, dichloromethane / methanol = 10 / 1) to give a yellow foamy solid (900 mg, 1.6 mmol, yield: 53%).

[0303] Step 6: Synthesis of 2-(trimethylsilyl)ethyl (S)-4-(2-((1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0304] A mixture of (S)-tert-butyl 2-((1-methylpyrrolidin-2-yl)methoxy)-4-(4-((2-(trimethylsilyl)ethoxy)carbonyl)piperazin-1-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (500 mg, 0.89 mmol) and formic acid (8 mL) was stirred at room temperature for 12 hours. The formic acid was removed by concentration under reduced pressure, and aqueous sodium hydroxide (30 mL) and dichloromethane (50 mL) were added to the residue. After shaking and separation, the aqueous phase was extracted with dichloromethane (50 mL + 20 mL). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting orange viscous material was purified by column chromatography (silica gel, dichloromethane / methanol = 8 / 1, 0.6% aqueous ammonia) to afford a light brown solid (295 mg, yield: 72%).

[0305] Step 7: Synthesis of 2-(trimethylsilyl)ethyl 4-(6-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0306] (S)-2-(Trimethylsilyl)ethyl 4-(2-((1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid (80 mg, 0.17 mmol) was dissolved in toluene (50 mL), and 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (75 mg, 0.22 mmol), Pd2(dba)3(32 mg, 0.034 mmol), XPhos(25 mg, 0.051 mmol), Cs2CO3(140 mg, 0.43 mmol), under nitrogen protection, heated to 100°C for 15 hours. The reaction was completed as detected by TLC. The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol=10 / 1) to give a brown solid. 1 H NMR (400MHz, CDCl3) δ8.08 (s, 1H), 7.12 (d, J = 8.5Hz, 1H), 5.60 (dd, J = 9.1, 2.7Hz, 1H), 5.06 (t, J = 2.5Hz, 2H),4.91-4.80(m,2H),4.74(s,1H),4.50-4.37(m,1H),4.30-4.12(m,2H),4.08-3.97(m,1H),3.83-3.6 7(m, 4H), 3.57(t, J=5.0Hz, 4H), 3.48(s, 1H), 2.78(s, 3H), 2.57-2.45(m, 1H), 2.31-1.88(m, 6H), 1.78-1.63(m, 2H), 1.27(d, J=7.8Hz, 2H), 1.11-0.97(m, 2H), 0.92-0.74(m, 2H), 0.06(s, 9H).(50mg, yield: 41.1%).

[0307] Step 8: Synthesis of (S)-6-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine

[0308] 2-(Trimethylsilyl)ethyl 4-(6-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid (50 mg, 0.07 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (6 mL) was added and stirred at room temperature for 2 hours. The reaction was complete as determined by TLC. The mixture was concentrated to dryness, and aqueous sodium bicarbonate (10 mL) was added. The mixture was extracted with dichloromethane (20 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a light yellow solid (34 mg, yield: 100%).

[0309] Step 9: Synthesis of (S)-1-(4-(6-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propyl-2-en-1-one

[0310] (S)-6-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (34 mg, 0.07 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (9.1 mg, 0.09 mmol) was added. Acryloyl chloride (7 mg, 0.077 mmol) was added under ice-cooling. The reaction was complete by TLC. Aqueous sodium bicarbonate (10 mL) was added, and the mixture was extracted with dichloromethane (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified on a preparative plate (dichloromethane / methanol = 10 / 1) to afford a pale yellow solid (6 mg, yield: 15.9%). 1 H NMR (400MHz, CDCl3) δ8.12(s,1H),6.93(d,J=8.2Hz,1H),6.61(dd,J=16.8,10.5Hz,1H),6. 38(dd,J=16.8,1.9Hz,1H),5.79(dd,J=10.5,1.9Hz,1H),5.14(s,2H),4.85(s,2H),4.66(s, 1H),4.34(dd,J=11.2,4.9Hz,1H),3.76(d,J=29.3Hz,8H),3.48(d,J=19.1Hz,1H),3.11(s,1 H),2.78(s,3H),2.69-2.48(m,2H),2.14(d,J=47.6Hz,2H),1.95(s,2H);MSm / z:541.2[M+H]

[0311] Example 4-29 was prepared by the method of Example 1

[0312]

[0313]

[0314]

[0315] Example 30: Synthesis of (S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0316]

[0317] Step 1: Synthesis of tert-butyl 2-(methylthio)-4-oxo-3,4,5,7-tetrahydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0318] Dissolve ethyl N-BOC-4-oxo-3-pyrrolidinecarboxylate (9.7 g, 37.7 mmol) in water (250 mL), add S-methylisothiourea sulfate (7.86 g, 56.5 mmol) and sodium carbonate (16.0 g, 151 mmol), and stir at room temperature for 15 hours. TLC indicates the reaction is complete. Add hydrochloric acid (170 mL, 1 N) with vigorous stirring until the pH reaches 3. Collect the solid by filtration, rinse with water (20 mL x 3), and drain. Slurry the mixture with ethyl acetate / petroleum ether (20 mL, V:V = 1:1), collect the solid by filtration, rinse with ethyl acetate / petroleum ether (10 mL x 2, V:V = 1:1), and rotary evaporation to obtain a light yellow powder (6.6 g, yield: 62%). 1 H NMR (400MHz, CDCl3) δ4.59-4.46 (m, 4H), 2.59 (dd, J = 11.3, 1.7Hz, 3H), 1.58-1.47 (m, 9H).

[0319] Step 2: Synthesis of tert-butyl 2-(methylthio)-4-((trifluoromethyl)sulfonyl)oxy)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0320] Dissolve tert-butyl 2-(methylthio)-4-oxo-3,4,5,7-tetrahydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (1.55 g, 5.48 mmol) in dichloromethane (55 mL) and add DIPEA (1.82 mL, 11 mmol). Add trifluoromethanesulfonic anhydride (1.20 mL, 7.12 mmol) dropwise in an ice-water bath. Stir at room temperature for 1.5 hours. The reaction is complete as determined by TLC. Concentrate under reduced pressure to obtain a dark brown viscous product, which is used directly in the next step.

[0321] Step 3: Synthesis of tert-butyl 2-(methylthio)-4-(4-((2-(trimethylsilyl)ethoxy)carbonyl)piperazin-1-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

[0322] The crude product of tert-butyl 2-(methylthio)-4-((trifluoromethyl)sulfonyl)oxy)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate obtained in the previous step was dissolved in DMF (20 mL). DIPEA (1.82 mL, 11 mmol) and ethyl 2-(trimethylsilyl)piperazine-1-carboxylate (1.39 g, 6.03 mmol) were added at room temperature. The mixture was heated to 80°C and reacted for 16 hours. TLC confirmed the reaction was complete. After cooling to room temperature, ethyl acetate (100 mL) and saturated aqueous ammonium chloride (100 mL) were added. After shaking and separating the layers, the aqueous phase was extracted with ethyl acetate (100 mL). The organic phases were combined, washed with saturated aqueous sodium bicarbonate (50 mL), water (50 mL x 2), and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to yield a brown solid (2.2 g, crude product) that was used directly in the next reaction.

[0323] Step 4: Synthesis of 2-(trimethylsilyl)ethyl 4-(2-(methylthio)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0324] The crude product of tert-butyl 2-(methylthio)-4-(4-((2-(trimethylsilyl)ethoxy)carbonyl)piperazin-1-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (2 g) obtained in the previous step was dissolved in ethanol (50 mL) and anhydrous p-toluenesulfonic acid (1.87 g, 10.8 mmol) at room temperature. The mixture was heated to 80°C and reacted for 16 hours. TLC confirmed the reaction was complete. After cooling to room temperature, ethyl acetate (100 mL) and saturated aqueous sodium carbonate solution (100 mL) were added. After shaking and separation, the aqueous phase was extracted with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a brown solid. Purification by column chromatography (silica gel, methanol / dichloromethane = 1 / 20) afforded a brown solid (750 mg, three-step yield: 36%).

[0325] Step 5: Synthesis of 2-(trimethylsilyl)ethyl 4-(2-(methylthio)-6-(naphthalen-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0326] To a reaction flask, add 2-(trimethylsilyl)ethyl 4-(2-(methylthio)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (750 mg, 1.9 mmol), 2-bromonaphthalene (471 mg, 2.28 mmol), tris(dibenzylideneacetone)dipalladium (348 mg, 0.38 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (181 mg, 0.38 mmol), and cesium carbonate (1.24 g, 3.8 mmol). After replacing the atmosphere with argon, pre-deoxygenated anhydrous toluene (20 mL) was added. The reaction mixture was heated at 110°C for 16 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was rinsed with ethyl acetate (10 mL x 2). The combined filtrates were concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:4) to give a dark purple solid (620 mg, 1.19 mmol, yield: 63%). MS m / z: 522.2 [M+H] +.

[0327] Step 6: Synthesis of 2-(trimethylsilyl)ethyl 4-(2-(methylsulfoxy)-6-(naphthalen-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0328] To a mixture of 2-(trimethylsilyl)ethyl 4-(2-(methylthio)-6-(naphthalen-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (490 mg, 0.94 mmol), sodium bicarbonate (331 mg, 3.94 mmol), acetone (20 mL), dichloromethane (5 mL), and water (10 mL) was added potassium monopersulfate (750 mg, 1.22 mmol). The reaction mixture was stirred at room temperature for 16 hours. Ethyl acetate (100 mL) and water (50 mL) were added. After shaking and separation, the mixture was washed with saturated aqueous sodium carbonate solution (20 mL), saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a brown viscous product. The residue was purified by column chromatography (silica gel, methanol / dichloromethane = 1 / 50) to give a light brown solid (263 mg, 0.3 mmol, yield: 32%).

[0329] Step 7: Synthesis of 2-(trimethylsilyl)ethyl (S)-4-(2-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0330] To a solution of (S)-(1-methylpyrrolidin-2-yl)methanol (56 mg, 0.48 mmol) in tetrahydrofuran was added dropwise a solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (0.45 mL, 0.45 mmol) in an ice-water bath. The resulting white cloudy solution was stirred in an ice-water bath for 20 minutes, and 2-(trimethylsilyl)ethyl 4-(2-(methylsulfoxy)-6-(naphthalen-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (163 mg, 0.30 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into stirred water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified on a preparative TLC plate (dichloromethane / methanol = 8 / 1) to give a white foamy solid (120 mg, 0.204 mmol, yield: 68%).

[0331] Step 8: Synthesis of (S)-6-(3-bromonaphthalen-2-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine

[0332] To a solution of (S)-2-(trimethylsilyl)ethyl 4-(2-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (50 mg, 0.085 mmol) in DMF (1.5 mL) was added cesium fluoride (64 mg, 0.425 mmol). The mixture was stirred at 60°C for 3 hours. After cooling to room temperature, dichloromethane (20 mL) and saturated aqueous sodium carbonate solution (20 mL) were added. After shaking and separation, the aqueous phase was extracted with dichloromethane (20 mL). The organic phases were combined, washed with water (10 mL × 3), washed with saturated brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain a light brown viscous product that was used directly in the next reaction.

[0333] Step 9: Synthesis of (S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0334] In an ice-water bath, slowly add a solution of (S)-6-(3-bromonaphthalen-2-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (crude) and triethylamine (0.036 mL, 0.255 mmol) in dichloromethane (2 mL) with acryloyl chloride (0.01 mL, 0.128 mmol) in dichloromethane (1 mL). Remove the ice-water bath, and stir the reaction mixture at room temperature for 30 minutes. Add dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL), shake, separate, and extract the aqueous phase with dichloromethane (10 mL). Combine the organic phases, wash with saturated brine (10 mL), dry over sodium sulfate, and rotary evaporation to obtain a viscous product. Purify by preparative TLC (methanol:dichloromethane = 1:8) to obtain a white solid. (22 mg, total yield of two steps: 21%) 1H NMR (400MHz, CDCl3) δ7.81(d,J=8.0Hz,1H),7.73(t,J=8.0Hz,2H),7.42(t,J=8.0Hz,1 H),7.25-7.23(m,1H),7.07(d,J=8.0Hz,1H),6.87(s,1H),6.63(dd,J=16.8,10.5Hz,1 H),6.39(dd,J=16.8,1.9Hz,1H),5.80(dd,J=10.5,2.0Hz,1H),4.84-4.80(m,2H),4.5 9-4.54(m,2H),3.94-3.36(m,10H),2.89(s,4H),2.38-1.93(m,6H); MSm / z:499.3[M+H]

[0335] Examples 31-33 were prepared using the method of Example 1

[0336]

[0337] Example 34: Synthesis of 1-(4-(7-(5-chloro-6-fluoro-1H-indazole-4-carbonyl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0338]

[0339] Step 1: Synthesis of tert-butyl (2-(4,6-dichloro-2-(methylthio)pyrimidin-5-yl)ethyl)carbamate

[0340] 4,6-Dichloro-2-(methylthio)pyrimidine (3.1 g, 15.9 mmol) and tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (4.2 g, 19 mmol) were placed in a 100 ml two-necked flask and the atmosphere was evacuated and replaced with nitrogen three times. Ultra-dry THF was added and stirred to dissolve. 1 mol / L LiHMDS (47.7 ml, 47.7 mmol) was added at -78°C and stirred overnight. After the reaction was complete, excess citric acid solution was added to the reaction system and stirring continued for half an hour. The reaction system was extracted, separated, and dried to obtain the crude product, which was then separated by column chromatography (silica gel, EA:PET = 1:10) to afford a pale yellow solid (1.76 g, 33% yield).

[0341] Step 2: Synthesis of 4-chloro-2-(methylthio)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine

[0342] Dissolve tert-butyl 2-(4,6-dichloro-2-(methylthio)pyrimidin-5-yl)ethyl)carbamate (1.76 g, 5.2 mmol) in a co-solvent of DCM and CF3COOH and stir at room temperature for 0.5 h. After the reaction, remove the solvent under reduced pressure. Add DIEPA (1.73 ml, 10.4 mmol) and 20 ml of acetonitrile solution to the reaction system. The reaction is allowed to proceed at 50°C overnight. After the reaction, remove the solvent under reduced pressure to yield a light yellow solid (1.0 g, 96% yield). 1 H NMR (400MHz, CDCl3) δ6.20(s,1H),3.55(t,2H),3.03(t,2H),2.50(s,2H). ESI-MSm / z:202.01[M+H] +

[0343] Step 3: Synthesis of tert-butyl 4-(2-(methylthio)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0344] 4-Chloro-2-(methylthio)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (1.0 g, 5 mmol) and tert-butyl piperazine-1-carboxylate (1.02 g, 5.5 mmol) were dissolved in 20 ml of 1,4-dioxane, and DIEPA (1.7 ml, 10 mmol) was added. The reaction system was reacted at 50°C for 3 h. The solvent was removed under reduced pressure, and the desired product (1.50 g, 85% yield) was obtained by column chromatography (silica gel, EA:PET = 1:10). 1 H NMR (400MHz, CDCl3) δ6.20(s,1H),3.73(t,4H),3.55(t,2H),3.32(t,4H),3.01(t,2H),2.50(s,2H),1.42(s,9H). ESI-MS m / z:352.17[M+H] +

[0345] Step 4: Synthesis of tert-butyl 4-(7-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-2-(methylthio)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0346] tert-Butyl 4-(2-(methylthio)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.50 g, 4.25 mmol) and 5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl chloride (1.6 g, 5.1 mmol) were dissolved in 30 ml of ultra-dry THF. t-BuOK (1.2 g, 10.6 mmol) was added and the reaction was stirred at room temperature overnight. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure, and the mixture was separated by column chromatography (silica gel, EA:PET = 1:10) to obtain the desired product as a pale yellow solid (1.8 g, yield: 67%). ESI-MS m / z: 632.21 [M+H] +

[0347] Step 5: Synthesis of tert-butyl 4-(7-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0348] The compound tert-butyl 4-(7-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-2-(methylthio)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.8 g, 2.7 mmol) was dissolved in 40 ml of DCM, and m-CPBA (11.6 g, 6.75 mmol) was added. The reaction was stirred at room temperature overnight. After completion of the reaction, an appropriate amount of water was added to the reaction system. After washing, the organic phase was washed three times with saturated sodium bicarbonate solution. After drying, the organic solvent was removed under reduced pressure to obtain the desired product (1.4 g, 77% yield). ESI-MS m / z: 664.20 [M+H] +

[0349] Step 6: Synthesis of tert-butyl 4-(7-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-2-(((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0350] The compound tert-butyl 4-(7-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.4 g, 2.1 mmol) and 2-methyl-5-hydroxy-1,2,3,4-tetrahydroisoquinoline (513 mg, 3.15 mmol) were dissolved in 30 ml of ultra-dry THF. 1 mol / L LiHMDS (3.2 ml, 3.2 mmol) was added in an ice-water bath. The reaction was allowed to return to room temperature and the reaction was complete. EA was added to the reaction system, and the mixture was washed three times with appropriate amounts of water. The organic phase was dried, and the organic solvent was removed under reduced pressure. The crude product was separated by column chromatography (silica gel, EA:PET = 1:10) to obtain a yellow solid (1.1 g, 68% yield). ESI-MS m / z:747.31[M+H] +

[0351] Step 7: Synthesis of (5-chloro-6-fluoro-1H-indazol-4-yl)(2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-4-(piperazin-1-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methanone

[0352] The compound tert-butyl 4-(7-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-2-(((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid (1.1 g, 1.4 mmol) was dissolved in a co-solvent of DCM and CF3COOH (3:1) and stirred at room temperature for two hours. The organic solvent was removed under reduced pressure to obtain the target product as a yellow oily solid (803 mg, yield 100%).

[0353] Step 8: Synthesis of 1-(4-(7-(5-chloro-6-fluoro-1H-indazole-4-carbonyl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0354] The compound (5-chloro-6-fluoro-1H-indazol-4-yl)(2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-4-(piperazin-1-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methanone (800 mg, 1.4 mmol) and DIEPA (0.35 ml, 2.1 mmol) were dissolved in 20 ml of DCM, and acryloyl chloride (127 mg, 1.4 mmol) was added dropwise in an ice-water bath. After the reaction, the solvent was removed under reduced pressure, and the crude product was separated by column chromatography (silica gel, EA:PET = 1:5) to obtain the target product (475 mg, yield 55%). 1 H NMR(400MHz, CDCl3)δ8.20(s,1H),7.50(d,1H),6.98-6,95(m,3H),6.62(m,1H),6.04(m,1H) ,5.58(m,1H),3.73-3.70(m,8H),3.32(m,4H),3.08(m,2H),2.96-2.83(m,4H),2.26(s,3H). ESI-MSm / z:617.21[M+H] +

[0355] Example 35-83 was prepared by the method of Example 34

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363] Example 84: Synthesis of 1-(4-(8-(5-chloro-6-fluoro-1H-indole-4-carbonyl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:

[0364]

[0365] Step 1: Synthesis of tert-butyl (3-(4,6-dichloro-2-(methylthio)pyrimidin-5-yl)propyl)carbamate:

[0366] 4,6-Dichloro-2-(methylthio)pyrimidine (3.00 g, 15.38 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). The atmosphere was replaced with nitrogen, and LiHMDS (1 M, 23.07 mL, 23.07 mmol) was added dropwise in a dry ice-ethanol bath. The mixture was stirred at -78°C for 30 minutes. A solution of tert-butyl 1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (4.01 g, 16.92 mmol) in tetrahydrofuran (10 mL) was then added dropwise. After the addition was complete, the mixture was slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the reaction was quenched with saturated 1 M citric acid and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford an off-white solid (2.1 g, yield: 39%). 1 HNMR (400MHz, CDCl3) δ4.62 (s, 1H), 3.22 (d, J = 5.8Hz, 2H), 2.90-2.76 (m, 2H), 2.55 (s, 3H), 1.84-1.72 (m, 2H), 1.45 (s, 9H).

[0367] Step 2: Synthesis of 3-(4,6-dichloro-2-(methylthio)pyrimidin-5-yl)propan-1-amine

[0368] Dissolve tert-butyl (3-(4,6-dichloro-2-(methylthio)pyrimidin-5-yl)propyl)carbamate (2.1 g, 5.96 mmol) in trifluoroacetic acid (15 mL) and stir at room temperature for 30 minutes. After completion of the reaction, concentrate the reaction mixture to obtain a brown oil, which was used directly in the next step.

[0369] Step 3: Synthesis of 4-chloro-2-(methylthio)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine:

[0370] Dissolve 3-(4,6-dichloro-2-(methylthio)pyrimidin-5-yl)propan-1-amine (1.5 g, 5.95 mmol) in anhydrous acetonitrile (15 mL), add triethylamine (2.41 g, 23.79 mmol), and heat to 80°C with stirring for 30 minutes. After completion, cool to room temperature, dilute the reaction solution with water, and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain a white solid (1.0 g, yield: 78%). 1H NMR (400MHz, CDCl3) δ5.47 (s, 1H), 3.40 (td, J = 5.8, 2.7Hz, 2H), 2.69 (t, J = 6.4Hz, 2H), 2.47 (s, 3H), 2.00-1.86 (m, 2H).

[0371] Step 4: Synthesis of tert-butyl 4-(2-(methylthio)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate:

[0372] Dissolve 4-chloro-2-(methylthio)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine (1.0 g, 4.64 mmol) in anhydrous DMF (10 mL). Add DIEA (0.90 g, 6.95 mmol) and tert-butyl piperazine-1-carboxylate (1.04 g, 5.56 mmol). Heat to 80°C and stir for 4 hours. After completion, cool to room temperature, dilute the reaction solution with saturated brine, and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield an off-white solid (1.6 g, 94% yield). 1 H NMR (400MHz, CDCl3) δ5.40 (s, 1H), 3.46-3.30 (m, 6H), 2.88-2.75 (m, 4H), 2.69 (t, J = 6.4Hz, 2H), 2.47 (s, 3H), 1.98-1.88 (m, 2H), 1.46 (s, 9H).

[0373] Step 5: Synthesis of tert-butyl 4-(8-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate:

[0374] tert-Butyl 4-(2-(methylthio)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.2 g, 0.55 mmol) and 5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl chloride (209 mg, 0.66 mmol) were dissolved in anhydrous THF (10 ml). t-BuOK (148 mg, 1.31 mmol) was added and stirred at room temperature overnight. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure, and the mixture was separated by column chromatography (dichloromethane / methanol = 50 / 1) to obtain the desired product as a pale yellow solid (220 mg, yield: 62%).

[0375] Step 6: Synthesis of tert-butyl 4-(8-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-2-(methanesulfonyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate:

[0376] The compound 4-(8-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (220 mg, 0.34 mmol) was dissolved in dichloromethane (10 mL). 85% m-chloroperbenzoic acid (83 mg, 0.41 mmol) was added under ice-water cooling and stirred for 30 minutes under ice-water cooling. After completion of the reaction, the reaction was quenched with saturated sodium thiosulfate and extracted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate and brine in sequence, dried over anhydrous sodium sulfate, and concentrated to obtain an off-white solid which was used directly in the next step. (220 mg, yield: 97%)

[0377] Step 7: Synthesis of tert-butyl 4-(8-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate:

[0378] The compound tert-butyl 4-(8-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-2-(methanesulfonyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (220 mg, 0.33 mol) was dissolved in anhydrous toluene (5 mL), 2-methyl-1,2,3,4-tetrahydroisoquinolin-5-ol (65 mg, 0.40 mmol) was added, and sodium tert-butoxide (48 mg, 0.50 mmol) was added under ice-water cooling. The mixture was stirred under ice-water cooling for 3 hours. After completion of the reaction, the reaction was quenched with cold water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 20 / 1) to obtain an off-white solid. (150 mg, yield: 59%).

[0379] Step 8: Synthesis of (5-chloro-6-fluoro-1H-indazol-4-yl)(2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-4-(piperazin-1-yl)-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl)methanone:

[0380] Dissolve tert-butyl 4-(8-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (150 mg, 0.20 mmol) in dichloromethane (5 mL). Add trifluoroacetic acid (2 mL) and stir at room temperature for 1 hour. After completion of the reaction, concentrate the reaction solution to obtain a brown oil (113 mg, 100% yield) that was used directly in the next step.

[0381] Step 9: Synthesis of 1-(4-(8-(5-chloro-6-fluoro-1H-indazole-4-carbonyl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:

[0382] The compound (113 mg, 0.20 mmol) was dissolved in dichloromethane (5 mL). DIEA (31 mg, 0.23 mmol) was added dropwise under ice-water cooling, followed by the dropwise addition of acryloyl chloride (18 mg, 0.20 mmol). The mixture was stirred under ice-water cooling for 30 minutes. After completion of the reaction, the reaction solution was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 10 / 1) to afford an off-white solid (55 mg, yield: 44.5%). 1 HNMR (400MHz, CDCl3) δ8.48 (s, 1H), 7.56 (d, J = 16.1Hz, 1H), 6.97 (q, J = 5.9Hz, 3H), 6.12-5.91 (m, 2H), 5.53 (dd, J = 26.3, 11.6Hz, 1H), 3.99 (t, J = 10. 6Hz,4H),3.88(t,J=10.4Hz,2H),3.70(s,2H),3.32(t,J=10.6Hz,4H),3. 03-2.86(m,4H),2.88-2.72(m,2H),1.76-1.52(m,2H); MSm / z:631.1[M+H] + .

[0383] Example 85: Synthesis of 1-(4-(8-(1-(5-chloro-6-fluoro-1H-indazol-4-yl)ethyl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0384]

[0385] Step 1: Synthesis of 2-(trimethylsilyl)ethyl 4-(2-(methylthio)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0386] To a solution of 4-chloro-2-(methylthio)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine (863 mg, 4.00 mmol) in tetrahydrofuran (25 mL) were added nitrogen, nitrogen-diisopropylethylamine (1.03 g, 8.00 mmol) and ethyl 2-(trimethylsilyl)piperazine-1-carboxylate (1.11 g, 4.8 mmol). The reaction mixture was heated under reflux for 6 hours. After cooling to room temperature, the reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate:petroleum ether = 2:1) to afford a white solid (711 mg, yield: 67%). MS m / z: 409.6 [M+H]+.

[0387] Step 2: Synthesis of 2-(trimethylsilyl)ethyl 4-(8-(1-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)ethyl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0388] To a solution of 2-(trimethylsilyl)ethyl 4-(2-(methylthio)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (711 mg, 2.69 mmol) and 1-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)ethan-1-one (798 mg, 2.69 mmol) in dichloromethane (25 mL) was added trifluoroacetic acid (307 mg, 2.69 mmol) and sodium acetate borohydride (1.14 g, 5.38 mmol). The reaction mixture was stirred at room temperature for 16 hours. Saturated aqueous sodium bicarbonate (20 mL) and dichloromethane (15 mL) were added. After shaking and separating the layers, the aqueous phase was extracted with dichloromethane (20 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, and then evaporated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate:petroleum ether = 1:2) to afford a khaki solid (150 mg, yield: 8.1%). MS m / z: 690.4 [M+H]+.

[0389] Step 3: Synthesis of 2-(trimethylsilyl)ethyl 4-(8-(1-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)ethyl)-2-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0390] To a solution of 2-(trimethylsilyl)ethyl 4-(8-(1-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)ethyl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (150 mg, 0.217 mmol) in dichloromethane (10 mL) was added m-chloroperbenzoic acid (112 mg, 0.65 mmol) at room temperature. The reaction mixture was stirred for 12 hours. Dichloromethane (10 mL) and saturated aqueous sodium sulfite solution (10 mL) were added, shaken, and the layers separated. The organic phase was washed with saturated aqueous sodium carbonate solution (10 mL), saturated brine, and dried over sodium sulfate. The light yellow solid was dried under reduced pressure and used directly in the next step. (150 mg, yield: 96%) MS m / z: 722.3 [M+H] +.

[0391] Step 4: Synthesis of 2-(trimethylsilyl)ethyl 4-(8-(1-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)ethyl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0392] To a solution of 2-methyl-1,2,3,4-tetrahydroisoquinolin-5-ol (51 mg, 0.312 mmol) in N,N-dimethylformamide (3 mL) in an ice-water bath, sodium hydride (13 mg, 0.312 mmol) was added. The reaction mixture was stirred in the ice-water bath for 30 minutes. Then, 2-(trimethylsilyl)ethyl 4-(8-(1-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)ethyl)-2-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (150 mg, 0.208 mmol) was added. The ice-water bath was removed and the mixture was stirred at room temperature for 16 hours. Ethyl acetate (30 mL) and saturated sodium carbonate (10 mL) were added and the mixture was shaken to separate the layers. The organic phase was washed with water (5 mL x 3) and saturated brine (5 mL), dried over sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by TLC (methanol:dichloromethane = 1:10) to afford a white solid (35 mg, yield: 21%). MS m / z: 805.5 [M+H]+.

[0393] Step 5: Synthesis of 8-(1-(5-chloro-6-fluoro-1H-indazol-4-yl)ethyl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine

[0394] In an ice-water bath, trifluoroacetic acid (1 mL) was slowly added to a solution of 2-(trimethylsilyl)ethyl 4-(8-(1-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)ethyl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (35 mg, 0.0435 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 3 hours. Anhydrous dichloromethane (10 mL) was added to dilute the mixture and evaporated to dryness under reduced pressure. The resulting light yellow viscous product was used directly in the next step. (35 mg, yield: 100%) MS m / z: 577.1 [M+H]+.

[0395] Step 6: Synthesis of 1-(4-(8-(1-(5-chloro-6-fluoro-1H-indazol-4-yl)ethyl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0396] To a mixed solution of 8-(1-(5-chloro-6-fluoro-1H-indazol-4-yl)ethyl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine (35 mg, crude) and acrylic acid (4.7 mg, 0.0653 mmol) in N,N-dimethylformamide (0.5 mL) and dichloromethane (1.5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.4 mg, 0.07 mmol), 4-dimethylaminopyridine (0.9 mg, 0.007 mmol), and triethylamine (19 mg, 0.19 mmol). The reaction was stirred at room temperature for 12 hours. Add dichloromethane (30 mL), wash with saturated sodium bicarbonate solution (10 mL), wash with saturated brine (5 mL), and dry over sodium sulfate. The residue was dried under reduced pressure and analyzed by TLC (methanol:dichloromethane = 1:12) to obtain an off-white solid (3 mg, yield: 11%). 1H NMR (400MHz, DMSO) δ8.21 (s, 1H), 7.22 (d, J = 8.0Hz, 1H), 7.00 (t, J = 7.5Hz, 1H), 6.94-6.91 (m, 2H), 6 .78(dd,J=16.8,10.0Hz,1H),6.08(dd,J=2.1,16.8Hz,1H),5.68(dd,J=2.1,10.0Hz,1H),4.91(s,1 H),4.45-4.23(m,2H),4.08(q,J=6.8Hz,1H),3.74-3.68(m,6H),3.22-3.15(m,4H),3.14-3.12(m,2 H),3.00-2.74(m,6H),2.36(s,3H),1.85-1.81(m,2H),1.28(d,J=6.8Hz,3H).MSm / z:631.1[M+H]+.

[0397] Compound 86-119 was prepared using the method of Example 85

[0398]

[0399]

[0400]

[0401]

[0402]

[0403] Example 120: Synthesis of 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0404]

[0405] Step 1: Synthesis of tert-butyl 4-hydroxy-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:

[0406] Dissolve 1-(tert-butyl)-4-methyl 3-oxopiperidine-1,4-dicarboxylate (20 g, 77.73 mmol) in anhydrous methanol (160 mL). Add 30% sodium methoxide solution (42.0 g, 233.20 mmol) and thiourea (8.88 g, 116.60 mmol). Heat to 80°C for 2 hours. After the reaction is complete, cool to room temperature and add iodomethane (13.79 g, 6.10 mL, 97.17 mmol) dropwise. Stir at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution, dissolve the residue in water, adjust the pH to 6-7 with glacial acetic acid, and filter to obtain a white solid (22 g, 95% yield). 1 HNMR (400MHz, CDCl3) δ11.40 (s, 1H), 4.33 (s, 2H), 3.60 (t, J = 5.5Hz, 2H), 2.56 (s, 5H), 1.49 (s, 9H).

[0407] Step 2: Synthesis of 2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol:

[0408] Dissolve tert-butyl 4-hydroxy-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (22 g, 73.98 mmol) in dichloromethane (200 mL). Add trifluoroacetic acid (50 mL) and stir at room temperature for 3 hours. After the reaction is complete, condense the reaction solution and add saturated sodium bicarbonate aqueous solution and dichloromethane to the resulting residue. Extract with dichloromethane. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain a crude product that is used directly in the next step (14.6 g, yield: 100%).

[0409] Step 3: Synthesis of benzyl 4-hydroxy-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:

[0410] Dissolve 2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (14.5 g, 73.51 mmol) in anhydrous tetrahydrofuran (150 mL). Add triethylamine (15.37 mL, 110.26 mmol) under ice-water cooling, then slowly add benzyloxycarbonyl chloride (13.79 g, 80.86 mmol) dropwise. Stir under ice-water for 1 hour. After completion of the reaction, dilute the reaction solution with water and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the title compound (24 g, 98.5%).

[0411] Step 4: Synthesis of benzyl 2-(methylthio)-4-(((trifluoromethyl)sulfonyl)oxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:

[0412] Dissolve benzyl 4-hydroxy-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (24.0 g, 72.42 mmol) in dichloromethane (300 mL). Add DIEA (14.04 g, 108.63 mmol) under ice-water cooling. Then slowly add trifluoromethanesulfonic anhydride (22.48 g, 79.66 mol) dropwise. After the addition is complete, continue stirring in an ice-water bath for 1 hour. After completion of the reaction, concentrate the reaction solution to obtain an oily crude product, which is used directly in the next step.

[0413] Step 5: Synthesis of (S)-4-(4-(tert-butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester:

[0414] Dissolve benzyl 2-(methylthio)-4-(((trifluoromethyl)sulfonyl)oxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (72.42 mmol) obtained in the previous step in anhydrous DMF (300 mL). Add DIEA (46.80 g, 362.07 mmol) and (S)-2-(piperazin-2-yl)acetonitrile-2 hydrochloride (14.35 g, 72.42 mmol). Heat to 80°C and stir for 1 hour. After completion of the reaction, add di-tert-butyl dicarbonate (47.42 g, 217.26 mmol) and continue stirring for 1 hour. After completion of the reaction, cool to room temperature, dilute the reaction solution with saturated brine, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography to obtain an off-white solid (37 g, yield: 95%). 1 HNMR (400MHz, CDCl3) δ7.37(t,J=6.3Hz,5H),5.18(s,2H),4.69(d,J=18.8Hz,1H),4.59(s,1H),4.45(d,J=19 .0Hz,1H),3.94(s,4H),3.43(s,1H),3.25(s,2H),2.97(s,1H),2.81-2.56(m,4H),2.50(s,3H),1.50(s,9H).

[0415] Step 6: Synthesis of benzyl 4-((S)-4-(tert-butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylsulfinyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:

[0416] Dissolve benzyl (S)-4-(4-(tert-butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (37 g, 68.69 mmol) in dichloromethane (300 mL). Add 85% m-chloroperbenzoic acid (16.73 g, 82.43 mmol) under ice-water cooling. Stir and react for 30 minutes under ice-water cooling. After completion, quench the reaction with saturated sodium thiosulfate solution, extract with dichloromethane, and wash the organic phase sequentially with saturated sodium bicarbonate and saturated brine, dry over anhydrous sodium sulfate, and concentrate to yield an off-white solid (37.5 g, 98% yield).

[0417] Step 7: Synthesis of benzyl 4-((S)-4-(tert-butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:

[0418] Benzyl 4-((S)-4-(tert-butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylsulfinyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (20 g, 36.06 mmol) was dissolved in anhydrous toluene (200 mL). (S)-(1-methylpyrrolidin-2-yl)methanol (7.27 g, 63.10 mmol) was added in an ice-water bath. Sodium tert-butoxide (6.93 g, 72.12 mmol) was added portionwise and stirred for 20 minutes under ice-water cooling. After completion, the reaction was quenched with cold water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to afford an off-white solid (13.5 g, yield: 62%). 1H NMR(400MHz, CDCl3)δ7.36(d,J=9.8Hz,5H),5.18(s,2H),4.66(d,J=18.9Hz,1H), 4.57(s,1H),4.44(d,J=18.9Hz,2H),4.21(s,1H),3.86(d,J=84.9Hz,4H),3.43(s ,1H),3.23(d,J=13.9Hz,3H),2.95(s,1H),2.84(s,1H),2.79-2.60(m,4H),2.57( s,3H),2.41(s,2H),2.09(d,J=8.4Hz,1H),1.90(s,1H),1.81(s,2H),1.50(s,9H).

[0419] Step 8: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:

[0420] Benzyl 4-((S)-4-(tert-butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (13.5 g, 22.29 mmol) was dissolved in methanol (150 mL) and a 6M methanolic ammonia solution (4 mL). 10% wet Pd / C (1.35 g) was added under a nitrogen atmosphere to displace the hydrogen. The mixture was stirred at room temperature for 5 hours. After completion of the reaction, the mixture was filtered through celite and washed with methanol. The methanol phase was collected and concentrated to yield an off-white solid (10.5 g, 99% yield). 1 H NMR (400MHz, CDCl3) δ4.58 (s, 1H), 4.34 (dd, J = 10.5, 5.0 Hz, 1H), 4.11 (dd, J = 10 .5,6.9Hz,1H),3.95(d,J=9.7Hz,3H),3.83(d,J=12.8Hz,1H),3.20(dd,J=13.7 ,3.7Hz,2H),3.09(dd,J=15.1,9.9Hz,2H),3.02-2.87(m,2H),2.81-2.51(m,5H ),2.47(s,3H),2.32-2.21(m,1H),2.05(s,1H),1.86-1.63(m,7H),1.50(s,9H).

[0421] Step 9: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:

[0422] Tert-butyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.21 mmol) and 5-bromo-1,2,3,4-tetrahydronaphthalene (54 mg, 0.25 mmol) were dissolved in anhydrous toluene (5 mL). Cesium carbonate (173 mg, 0.53 mmol), RuPhos (20 mg, 0.04 mmol), and Pd2(dba)3 (39 mg, 0.04 mmol) were added. The atmosphere was purged with nitrogen three times and the mixture was heated to 100°C with stirring for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, filtered, and the filtrate concentrated. The resulting off-white solid was isolated by column chromatography (63 mg, yield: 49.4%). 1 H NMR (400MHz, CDCl3) δ7.12(t,J=7.7Hz,2H),6.90(t,J=7.3Hz,2H),4.67-4.52(m,2H),4.20-3.97(m,4H),3.96-3.84(m,2H ),3.35-2.95(m,7H),2.92-2.63(m,10H),2.35-2.10(m,3H),2.10-1.86(m,3H),1.80(dt,J=12.2,7.1Hz,4H),1.51(s,9H).

[0423] Step 10: Synthesis of 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0424] Compound (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (60 mg, 0.10 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the resulting residue was added with saturated sodium bicarbonate solution and dichloromethane, followed by extraction with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product that was used directly in the next step. (50 mg, yield: 100%)

[0425] Step 11: Synthesis of 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0426] The compound 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (50 mg, 0.10 mmol) was dissolved in dichloromethane (3 mL). DIEA (16 mg, 0.12 mmol) was added under ice-water cooling, followed by acryloyl chloride (12 mg, 0.13 mmol). The mixture was stirred under ice-water cooling for 10 minutes. After completion, the reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 15 / 1) to obtain an off-white solid. 1 H NMR (400MHz, CDCl3) δ7.12(t,J=7.7Hz,2H),6.91(t,J=7.3Hz,2H),6.66 -6.56(m,1H),6.36(d,J=16.7Hz,1H),5.80(d,J=10.6Hz,1H),4.67-4.52(m,2H),4.20-3.97(m,4H),3.96-

[0427] 3.84(m,2H),3.35-2.95(m,7H),2.92-2.63(m,10H),2.35-2.10(m,3H),2.10-1.86(m,3H),1.80(dt,J=12.2,7.1Hz,4H).MSm / z:556.59[M+H] + .

[0428] Example 121: Synthesis of 2-((S)-1-(2-fluoroacryloyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0429]

[0430] Compound 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (50 mg, 0.10 mmol) was dissolved in dichloromethane (3 mL). 2-Fluoroacrylic acid (14 mg, 0.15 mmol), HATU (60 mg, 0.15 mmol), and DIEA (20 mg, 0.15 mmol) were added and stirred under ice-water cooling for 3 hours. After completion of the reaction, the reaction solution was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 20 / 1) to afford an off-white solid (35 mg, yield: 61.21%). MSm / z:574.59[M+H] + .

[0431] Examples 122-166 were prepared using the preparation methods of Examples 120 and 121.

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442] Example 198: Synthesis of 2-((S)-1-acryloyl-4-(7-(1,3-dioxoisoindolin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0443]

[0444] Step 1: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(7-(2-(4-methoxybenzyl)-1,3-dioxoisoindolin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0445] (S)-tert-Butyl 2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (50 mg, 0.11 mmol) and 4-bromo-2-(4-methoxybenzyl)isoindoline-1,3-dione (44 mg, 0.13 mmol) were dissolved in anhydrous toluene (5 mL). Cesium carbonate (87 mg, 0.27 mmol), RuPhos (10 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) were added. The atmosphere was replaced with nitrogen, and the mixture was stirred at 100°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and separated by TLC to yield a yellow solid (78 mg, yield: 100%). 1 H NMR (400MHz, CDCl3) δ7.58(d,J=7.9Hz,1H),7.41(d,J=7.0Hz,1H),7.37(d,J=8.7Hz,2H),7.19(d,J=8.3Hz,1H),6.84(d,J=8.7Hz,2H),4.77 (s,2H),4.62(s,1H),4.34(s,2H),4.18-3.97(m,5H),3.80-3.71(m,4H),3.55-3.44(m,3H),3.31(d,J=10.9Hz,3H),3.12-3.03(m,3H),2.94 -2.90(m,2H),2.82 -2.68(m,4H),2.24 -2.20(m,1H),2.03 -1.99(m,2H),1.52(s,9H).

[0446] Step 2: Synthesis of 2-((S)-4-(7-(1,3-dioxoisoindolin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0447] Compound (S)-tert-butyl 2-(cyanomethyl)-4-(7-(2-(4-methoxybenzyl)-1,3-dioxoisoindolin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (78 mg, 0.11 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid / trifluoromethanesulfonic acid (2 / 1) (1.5 mL) and anisole (0.5 mL) were added and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was slowly added dropwise to cooled saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic phase was dried over sodium sulfate, concentrated, and separated by TLC (dichloromethane / methanol = 10 / 1) to afford a yellow solid (12 mg, yield: 22%). MSm / z:517.53[M+H] + .

[0448] Step 3: Synthesis of 2-((S)-1-acryloyl-4-(7-(1,3-dioxoisoindolin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0449] The compound 2-((S)-4-(7-(1,3-1,3-dioxoisoindolin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (12 mg, 0.02 mmol) was dissolved in dichloromethane (3 mL). DIEA (4 mg, 0.02 mmol) was added under ice-water cooling, followed by a dichloromethane solution (1 mL). The mixture was stirred under ice-water for 10 minutes. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by TLC (dichloromethane / methanol = 10 / 1) to afford a yellow solid (8 mg, yield: 60%). MS m / z: 571.27 [M+H] + .

[0450] The compounds of Examples 199-200 were prepared by the method of Example 198.

[0451]

[0452] Example 201: Synthesis of 2-((S)-1-(2-fluoroacryloyl)-4-(7-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0453]

[0454] Step 1: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(7-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:

[0455] Compound (S)-tert-butyl 2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.21 mmol) and 8-bromo-1-methyl-1,2,3,4-tetrahydroquinoline (72 mg, 0.32 mmol) were dissolved in anhydrous toluene (5 mL). Cesium carbonate (173 mg, 0.53 mmol), XantPhos (20 mg, 0.04 mmol), and Pd2(dba)3 (39 mg, 0.04 mmol) were added. The atmosphere was purged with nitrogen three times, and the mixture was heated to 100°C with stirring for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, filtered, and the filtrate was concentrated. The filtrate was separated by column chromatography (dichloromethane / methanol = 30 / 1) to obtain an off-white solid. (70 mg, yield: 53.5%)

[0456] Step 2: Synthesis of 2-((S)-4-(7-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0457] Compound (S)-2-(cyanomethyl)-4-(7-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (70 mg, 0.11 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the resulting residue was added with saturated sodium bicarbonate solution and dichloromethane, followed by extraction with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product that was used directly in the next step. (56 mg, yield: 95%)

[0458] Step 3: Synthesis of 2-((S)-1-(2-fluoroacryloyl)-4-(7-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0459] The compound 2-((S)-4-(7-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (56 mg, 0.11 mmol) was dissolved in dichloromethane (5 mL). 2-Fluoroacrylic acid (15 mg, 0.16 mmol), HATU (61 mg, 0.16 mmol), and DIEA (21 mg, 0.16 mmol) were added and stirred under ice-water cooling for 3 hours. After completion of the reaction, the reaction solution was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 20 / 1) to afford an off-white solid (25 mg, yield: 39%). 1H NMR (400MHz, CDCl3) δ6.45-6.35(m,1H),6.27(dt,J=14.6,3.4Hz,2H),5.42(d,J=45.1Hz,1H),5.25(d ,J=16.8Hz,1H),5.02-4.93(m,2H),4.61(s,1H),4.31(p,J=14.7Hz,1H),4.04-3.87(m,2H),3.81-3.44 (m,4H),3.44-3.29(m,4H),3.29-3.19(m,2H),3.15-3.03(m,3H),2.95(dq,J=17.1,9.2Hz,1H),2.87-2 .68(m,6H),2.53-2.29(m,2H),2.26(s,3H),2.07-1.87(m,2H),1.78-1.38(m,4H); MSm / z:589.34[M+H] + .

[0460] The preparation method of Example 201 was used to prepare Examples 202-250

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469] Example 251: Synthesis of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile:

[0470]

[0471] Step 1: Synthesis of 1-tert-butyl 4-ethyl 5-amino-3,6-dihydro-2H-pyridine-1,4-dicarboxylate:

[0472] Dissolve 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (20 g, 73.72 mmol) in a 2M ethanolic ammonia solution (80 mL, 160 mmol) and heat to 60°C with stirring for 3 hours. After completion of the reaction, cool to room temperature and concentrate to obtain a yellow solid (19 g, 95% yield). MS (ES+): m / z = 271 (M+1).

[0473] Step 2: Synthesis of 1-tert-butyl 4-ethyl 5-(2-methoxycarbonyl-acetylamino)-3,6-dihydro-2H-pyridine-1,4-dicarboxylate:

[0474] Dissolve 1-tert-butyl 4-ethyl 5-amino-3,6-dihydro-2H-pyridine-1,4-dicarboxylate (19 g, 70.28 mmol) in dichloromethane (150 mL). Add triethylamine (10.78 mL, 77.31 mmol). Cool in an ice-water bath, then add methyl 3-chloro-3-oxopropanoate (10.56 g, 77.31 mmol) dropwise. After the addition is complete, warm the mixture to room temperature and stir for 12 hours. After completion, dilute the reaction solution with water and extract with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield a yellow solid, which is used directly in the next step (26 g, yield: 100%). MS (ES-): m / z = 369 (M-1).

[0475] Step 3: Synthesis of 7-tert-butyl 3-methyl 2,4-dihydroxy-5,8-dihydro-1,7-naphthyridine-3,7(6H)-dicarboxylate:

[0476] Dissolve 1-tert-butyl 4-ethyl 5-(2-methoxycarbonyl-acetylamino)-3,6-dihydro-2H-pyridine-1,4-dicarboxylate (26 g, 70.19 mmol) in anhydrous methanol (100 mL). Add 30% sodium methoxide methanol solution (63.20 g, 350.97 mmol). Heat under reflux under nitrogen for 3 hours. After completion, cool to room temperature, concentrate the reaction mixture, dissolve in ice water, adjust the pH to 5-6 with glacial acetic acid, and filter the precipitated solid. The filter cake is washed with water and dried under vacuum to yield an off-white solid (13.7 g, 60%). 1 H NMR (400MHz, DMSO) δ4.26 (s, 2H), 3.81 (s, 3H), 3.52 (t, J = 5.56Hz, 2H), 2.38 (t, J = 5.56Hz, 2H), 1.41 (s, 9H)

[0477] Step 4: Synthesis of 5,6,7,8-tetrahydro-1,7-naphthyridine-2,4-diol hydrochloride

[0478] Dissolve 7-tert-butyl 3-methyl 2,4-dihydroxy-5,8-dihydro-1,7-naphthyridine-3,7(6H)-dicarboxylate (5 g, 15.42 mmol) in concentrated hydrochloric acid (20 mL) and heat under reflux for 12 hours. After completion, cool to room temperature and concentrate to obtain an off-white solid (3.12 g, 100% yield), which was used directly in the next step. 1 H NMR (400MHz, DMSO) δ12.38(s,1H),9.76(s,2H),6.25(s,1H),4.10(s,2H),3.30(s,2H),2.62(t,J=5.8Hz,2H).

[0479] Step 5: Synthesis of 2,4-dihydroxy-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylic acid benzyl ester:

[0480] Dissolve 5,6,7,8-tetrahydro-1,7-naphthyridine-2,4-diol hydrochloride (3.12 g, 15.42 mmol) in dichloromethane (100 mL), add triethylamine (6.44 mL, 46.21 mmol), and add benzyloxycarbonyl chloride (3.94 g, 23.11 mmol) dropwise under ice-water cooling. Stir at room temperature overnight. After completion of the reaction, concentrate the mixture, dissolve the residue in methanol (50 mL), add potassium carbonate (6.37 g, 46.21 mmol), and stir at room temperature for 2 hours. Concentrate the reaction mixture, dissolve the residue in water, and adjust the pH to 5-6 with glacial acetic acid. Filter the precipitated solid to obtain an off-white solid (3.1 g, yield: 67%). 1 H NMR (400MHz, DMSO) δ12.01(s,2H),7.37(t,J=9.5Hz,5H),6.12(d,J=15.4Hz,1H),5.13(s,2H),4.43(s,3H),2.44(s,2H).

[0481] Step 6: Synthesis of benzyl 2,4-bis(((trifluoromethyl)sulfonyl)oxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate:

[0482] Dissolve the compound 2,4-dihydroxy-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylic acid benzyl ester (1.0 g, 3.33 mmol) in anhydrous dichloromethane (15 mL). Add triethylamine (0.74 g, 7.33 mmol) under ice-water cooling, followed by dropwise addition of trifluoromethanesulfonic anhydride (1.97 g, 6.99 mmol). Stir and react for 30 minutes under ice-water cooling. After completion of the reaction, dilute the reaction solution with dichloromethane, wash the organic phase with 1M hydrochloric acid and saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain a brown oil, which is used directly in the next step. (1.88 g, yield: 100%)

[0483] Step 7: Synthesis of (S)-benzyl 4-(4-(tert-butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((trifluoromethyl)sulfonyl)oxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate:

[0484] Dissolve the compound 2,4-bis(((trifluoromethyl)sulfonyl)oxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylic acid benzyl ester (1.88g, 3.33mmol) in anhydrous acetonitrile (20mL). Add triethylamine (405mg, 4.00mmol) under ice-water cooling, then add (S)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (751mg, 3.33mmol). The mixture is naturally warmed to room temperature and stirred for 12 hours. After the reaction is complete, dilute the reaction solution with ethyl acetate and wash with water. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain an off-white solid (1.05g, 49%).

[0485] Step 8: Synthesis of benzyl 4-((S)-4-(tert-butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate:

[0486] Compound (S)-4-(4-(tert-butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((trifluoromethyl)sulfonyl)oxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (1.05 g, 1.64 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (284 mg, 2.46 mmol) were dissolved in anhydrous toluene (15 mL), and sodium tert-butoxide (394 mg, 4.10 mmol), BINAP (103 mg, 0.16 mmol) and palladium acetate (37 mg, 0.16 mmol) were added. The atmosphere was replaced with nitrogen, and the mixture was heated to 80°C under a nitrogen atmosphere with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 10 / 1) to obtain an off-white solid (850 mg, yield: 86%).

[0487] Step 9: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate:

[0488] Benzyl 4-((S)-4-(tert-butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (850 mg, 1.41 mmol) was dissolved in methanol (50 mL) and a 2M methanolic ammonia solution (1 mL). 10% wet Pd / C (100 mg) was added under a nitrogen atmosphere to displace the hydrogen. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, the Pd / C was removed by filtration, washed with methanol, and the organic phase was concentrated to yield an off-white solid (650 mg, 98% yield).

[0489] Step 10: Synthesis of tert-butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:

[0490] The compound (S)-tert-butyl 2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate (100 mg, 0.21 mmol) and 1-bromo-8-chloronaphthalene (77 mg, 0.32 mmol) were dissolved in anhydrous toluene (3 mL). Cesium carbonate (173 mg, 0.53 mmol), RuPhos (20 mg, 0.04 mmol), and Pd2(dba)3 (37 mg, 0.04 mmol) were added. The nitrogen atmosphere was replaced three times, and the mixture was heated to 100°C under a nitrogen atmosphere with stirring for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, filtered to remove insoluble matter, and the organic phase was concentrated and separated by column chromatography (dichloromethane / methanol = 20 / 1) to obtain a brown solid. (50 mg, yield: 37%)

[0491] Step 11: Synthesis of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazin-2-yl)acetonitrile:

[0492] Compound (S)-tert-butyl 4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (50 mg, 0.08 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which was used directly in the next step. (40 mg, yield: 95%)

[0493] Step 12: Synthesis of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0494] The compound 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazin-2-yl)acetonitrile (40 mg, 0.07 mmol) and 2-fluoroacrylic acid (10 mg, 0.11 mmol) were dissolved in dichloromethane. HATU (42 mg, 0.11 mmol) and DIEA (15 mg, 0.11 mmol) were added and stirred at room temperature for 3 hours. After completion, the reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 10 / 1) to afford an off-white solid (21 mg, yield: 46%). 1 H NMR(400MHz, CDCl3) δ7.66(dt,J=14.9,3.0Hz,1H),7.60-7.38(m,4H),7.31(t,J=14.9Hz,1H),5.90(s,1H),5. 23(d,J=30.6Hz,1H),5.06(dd,J=13.4,4.2Hz,1H),5.00-4.97(m,1H),4.19-3.96(m,2H),3.89(dd,J=24.7,14. 9Hz,1H),3.73-3.32(m,7H),3.29-3.19(m,2H),3.09(t,J=11.2Hz,2H),3.02-2.88(m,1H),2.86-2.69(m,1H),2 .58(dd,J=24.8,6.5Hz,1H),2.39(dt,J=24.6,14.1Hz,1H),2.26(s,3H),1.79-1.32(m,4H);MSm / z:603.2[M+H] + .

[0495] Example 252-301 was prepared using the preparation method of Example 251

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503] Example 302: Synthesis of 7-(8-chloronaphth-1-yl)-4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-methyl

[0504]

[0505] Step 1: Synthesis of 1-tert-butyl 4-ethyl 5-(2-cyanoacetamido)-3,6-dihydropyridine-1,4(2H)-dicarboxylate:

[0506] Dissolve 1-tert-butyl 4-ethyl 5-amino-3,6-dihydro-2H-pyridine-1,4-dicarboxylate (15 g, 55.49 mmol) in dichloromethane (150 mL). Add triethylamine (8.51 mL, 61.04 mmol). Cool in an ice-water bath and add 2-cyanoacetyl chloride (6.32 g, 61.04 mmol) dropwise. After the addition is complete, warm the mixture to room temperature and stir for 12 hours. After completion, dilute the reaction solution with water and extract with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield a yellow solid that is used directly in the next step (18.72 g, 100% yield). 1 HNMR (400MHz, CDCl3) δ12.14(s,1H),4.74(s,2H),4.25(q,J=7.1Hz,2H),3.59-3.41(m,4H),2.45(s,2H),1.47(s,9H),1.31(t,J=7.1Hz,3H).

[0507] Step 2: Synthesis of tert-butyl 3-cyano-2,4-hydroxy-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate:

[0508] Dissolve 1-tert-butyl 4-ethyl 5-(2-cyanoacetamido)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (3.0 g, 8.89 mmol) in anhydrous tetrahydrofuran (30 mL). Add 60% NaH (1.42 g, 35.57 mmol) portionwise under ice-water cooling. Heat to 70°C and react for 6 hours. After completion, quench the reaction with saturated ammonium chloride under ice-water cooling. Extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography (dichloromethane / methanol = 50 / 1) to afford a yellow solid (1.7 g, yield: 66%). 1HNMR (400MHz, DMSO) δ12.18(s,1H),11.72(s,1H),4.26(s,2H),3.49(s,3H),2.37(s,2H),1.41(s,9H).

[0509] Step 3: Synthesis of 2,4-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile:

[0510] Dissolve tert-butyl 3-cyano-2,4-hydroxy-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (1.7 g, 5.84 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (6 mL), and stir at room temperature for 1 hour. After completion of the reaction, concentrate to obtain a brown oil, which is used directly in the next step (1.12 g, yield: 100%).

[0511] Step 4: Synthesis of 3-cyano-2,4-hydroxy-5,8-hydrogen-1,7-naphthyridine-7(6H)-carboxylic acid benzyl ester:

[0512] Dissolve 2,4-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (1.12 g, 5.84 mmol) in anhydrous tetrahydrofuran (15 mL), add triethylamine (1.78 g, 17.57 mmol), and add benzyloxycarbonyl chloride (1.10 g, 6.44 mmol) dropwise under ice-water cooling. Stir and react at room temperature for 12 hours. After completion of the reaction, dilute the reaction solution with water and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 50 / 1) to obtain an off-white solid (1.53 g, yield: 80%).

[0513] Step 5: Synthesis of benzyl 3-cyano-2,4-bis(((trifluoromethyl)sulfonyl)oxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate:

[0514] Dissolve 3-cyano-2,4-hydroxy-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylic acid benzyl ester (1.53 g, 4.70 mmol) in dichloromethane (20 mL). Add triethylamine (714 mg, 7.05 mmol) and trifluoromethanesulfonic anhydride (1.46 g, 5.17 mmol) under ice-water cooling. Stir and react in an ice-water bath for 30 minutes. After completion of the reaction, concentrate the reaction solution and use it directly in the next step. (2.77 g, yield: 100%)

[0515] Step 6: Synthesis of (S)-4-(4-(tert-Butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-3-cyano-2-(((trifluoromethyl)sulfonyl)oxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylic acid benzyl ester:

[0516] Dissolve benzyl 3-cyano-2,4-bis(((trifluoromethyl)sulfonyl)oxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (2.77 g, 4.70 mmol) in anhydrous acetonitrile (30 mL). Add triethylamine (571 mg, 6.64 mmol) while cooling in an ice-water bath, followed by tert-butyl (S)-2-(cyanomethyl)piperazine-1-carboxylate (1.06 mg, 4.70 mmol). The mixture is allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction, dilute the reaction solution with ethyl acetate and wash with water. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 50 / 1) to afford an off-white solid.

[0517] (1.32g, 42%)

[0518] Step 7: Synthesis of 4-((S)-4-(tert-Butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylic acid benzyl ester:

[0519] Compound (S)-4-(4-(tert-Butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-3-cyano-2-(((trifluoromethyl)sulfonyl)oxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylic acid benzyl ester (1.32 g, 1.99 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (343 mg, 2.98 mmol) were dissolved in anhydrous toluene (15 mL), and sodium tert-butoxide (477 mg, 4.96 mmol), BINAP (125 mg, 0.20 mmol) and palladium acetate (45 mg, 0.20 mmol) were added. The atmosphere was replaced with nitrogen, and the mixture was heated to 80°C under a nitrogen atmosphere with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 20 / 1) to obtain an off-white solid (1.1 g, yield: 87%).

[0520] Step 8: Synthesis of tert-butyl (S)-4-(3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:

[0521] Benzyl 4-((S)-4-(tert-Butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (1.1 g, 1.75 mmol) was dissolved in methanol (50 mL) and a 2M methanolic ammonia solution (2 mL). 10% wet Pd / C (110 mg) was added under a nitrogen atmosphere to displace the hydrogen atmosphere. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, the Pd / C was removed by filtration, washed with methanol, and the organic phase was concentrated to yield an off-white solid (850 mg, 98% yield).

[0522] Step 9: Synthesis of tert-butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:

[0523] Compound (S)-tert-butyl 4-(3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (100 mg, 0.20 mmol) and 1-bromo-8-chloronaphthalene (73 mg, 0.30 mmol) were dissolved in anhydrous toluene (5 mL). Cesium carbonate (165 mg, 0.50 mmol), RuPhos (20 mg, 0.04 mmol), and Pd2(dba)3 (37 mg, 0.04 mmol) were added. The atmosphere was purged with nitrogen three times and the mixture was heated to 100°C under a nitrogen atmosphere with stirring for 12 hours. After completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate. The insoluble matter was removed by filtration. The organic phase was concentrated and separated by column chromatography (dichloromethane / methanol = 20 / 1) to obtain a brown solid. (60 mg, yield: 45%)

[0524] Step 10: Synthesis of 7-(8-chloronaphthyl)-4-((S)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile:

[0525] Compound (S)-4-(7-(8-chloronaphthalen-1-yl)-3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (60 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which was used directly in the next step. (46 mg, yield: 90%)

[0526] Step 11: Synthesis of 7-(8-chloronaphth-1-yl)-4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-3-methyl

[0527] The compound 7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (46 mg, 0.08 mmol) and 2-fluoroacrylic acid (11 mg, 0.12 mmol) were dissolved in dichloromethane. HATU (43 mg, 0.12 mmol) and DIEA (16 mg, 0.12 mmol) were added and stirred at room temperature for 3 hours. After completion, the reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 10 / 1) to afford an off-white solid (21 mg, yield: 46%). 1 H NMR (400MHz, CDCl3) δ7.66 (dt, J=14.8, 3.0Hz, 1H), 7.61-7.51 (m, 1H), 7.51-7.39 (m, 3H) ,7.31(t,J=14.9Hz,1H),5.30-5.17(m,2H),5.11-4.97(m,2H),4.39(p,J=14.2Hz,1H),4 .09-3.94(m,2H),3.84-3.32(m,6H),3.30-2.89(m,6H),2.79(dt,J=24.9,13.1Hz,1H),2 .52-2.30(m,2H),2.26(s,3H),1.82-1.64(m,1H),1.61-1.35(m,3H); MSm / z:628.2[M+H] + .

[0528] Examples 303-375 were prepared using the preparation method of Example 302.

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539] Example 376: Synthesis of 2-((S)-1-acryloyl-4-(3-((((S)-1-methylpyrrolidin-2-yl)methoxy)-6)-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-2-yl)acetonitrile

[0540]

[0541] Step 1: Synthesis of (S)-benzyl 7-chloro-5-(3-(cyanomethyl)piperazin-1-yl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate

[0542] To a solution of (S)-2-(piperazin-2-yl)acetonitrile (557 mg, 4.45 mmol) in N,N-dimethylformamide (25 mL) in an ice-water bath, sodium hydride (178 mg, 4.45 mmol) was added. The reaction mixture was stirred in an ice-water bath for 30 minutes, followed by the addition of benzyl 5,7-dichloro-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (1.5 g, 4.45 mmol). The reaction mixture was stirred at 60°C for 12 hours. After cooling to room temperature, the reaction mixture was used directly in the next step. MS m / z: 426.2 [M+H]+.

[0543] Step 2: Synthesis of (S)-5-(4-(tert-Butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-chloro-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylic acid benzyl ester

[0544] To a crude solution of (S)-7-chloro-5-(3-(cyanomethyl)piperazin-1-yl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylic acid benzyl ester was added di-tert-butyl dicarbonate (970 mg, 4.45 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate (150 mL) and saturated aqueous ammonium chloride (50 mL) were added and stirred vigorously for 20 minutes. The mixture was separated, and the organic phase was washed with water (30 mL x 3) and saturated brine (30 mL), then dried over sodium sulfate. After vacuum drying, the residue was purified by column chromatography (silica gel, ethyl acetate:petroleum ether = 1:5) to afford a light brown viscous product (880 mg, total yield for two steps: 38%). MS m / z: 526.2 [M+H]+.

[0545] Step 3: Synthesis of benzyl 5-((S)-4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate

[0546] To a reaction flask, (S)-benzyl 5-(4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-chloro-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (880 mg, 1.67 mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (385 mg, 3.34 mmol), tris(dibenzylideneacetone)dipalladium (15 mg, 0.0167 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (16 mg, 0.0334 mmol), and sodium tert-butoxide (321 mg, 3.34 mmol) were added. After purging the atmosphere with argon, deoxygenated anhydrous toluene (15 mL) was added. The reaction mixture was heated at 110°C for 16 hours. After cooling to room temperature, ethyl acetate (50 mL) and water (50 mL) were added, shaken, and the layers separated. The organic phase was washed with saturated brine (10 mL), dried over sodium sulfate, and then dried under reduced pressure. The residue was purified by column chromatography (silica gel, methanol:dichloromethane = 1:12) to obtain a light brown viscous product (330 mg, yield: 33%). MS m / z: 605.3 [M+H]+.

[0547] Step 4: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate

[0548] Under a hydrogen balloon atmosphere, a suspension of benzyl 5-((S)-4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (171 mg, 0.282 mmol) and palladium / carbon (300 mg, 0.0282 mmol) in ethyl acetate (3 mL) and tetrahydrofuran (3 mL) was stirred for 6 hours. The solid was filtered and the filter cake was rinsed with ethyl acetate. The combined filtrates were evaporated under reduced pressure to afford a gray viscous product (108 mg, 81% yield). MS m / z: 471.3 [M+H]+.

[0549] Step 5: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate

[0550] To a reaction flask, tert-butyl (S)-2-(cyanomethyl)-4-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate (108 mg, 0.228 mmol), 5-bromo-1,2,3,4-tetrahydronaphthalene (72 mg, 0.342 mmol), tris(dibenzylideneacetone)dipalladium (23 mg, 0.025 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (24 mg, 0.05 mmol), and cesium carbonate (147 mg, 0.45 mmol) were added. After argon replacement, deoxygenated anhydrous toluene (4 mL) was added. The reaction solution was heated at 110°C for 16 hours. After cooling to room temperature, ethyl acetate (30 mL) and water (15 mL) were added, and the mixture was shaken to separate the layers. The organic phase was washed with saturated brine (10 mL), dried over sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, methanol:dichloromethane = 1:10) to afford a light brown viscous product (80 mg, yield: 58%). MS m / z: 601.4 [M+H]+.

[0551] Step 6: Synthesis of 2-((S)-4-(3-((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-2-yl)acetonitrile

[0552] In an ice-water bath, trifluoroacetic acid (1 mL) was added to a solution of (S)-2-(cyanomethyl)-4-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylic acid tert-butyl ester (80 mg, 0.133 mmol) in dichloromethane (3 mL). The resulting solution was stirred at room temperature for 3 hours. The reaction solution was evaporated to dryness under reduced pressure to obtain a white viscous material which was used directly in the next reaction. MS m / z: 501.3 [M+H]+.

[0553] Step 7: Synthesis of 2-((S)-1-acryloyl-4-(3-((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-2-yl)acetonitrile

[0554] In an ice-water bath, slowly add a solution of acryloyl chloride (33 mg, 0.36 mmol) in dichloromethane (1 mL) to a solution of ((S)-4-(3-((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-2-yl)acetonitrile (crude) and triethylamine (119 mg, 1.18 mmol) in dichloromethane (10 mL). Remove the ice-water bath, and stir the reaction mixture at room temperature for 15 minutes. Rotary evaporation under reduced pressure and purification of the residue by preparative TLC (methanol:dichloromethane = 1:10) yield a light yellow solid (15 mg, total yield over two steps: 20%). 1 H NMR (400MHz, CDCl3) δ7.12(t,J=7.7Hz,2H),6.91(t,J=7.3Hz,2H),6.66 -6.56(m,1H),6.45(s,1H),6.36(d,J=16.7Hz,1H),5.80(d,J=10.6Hz,1H),4.67-4.52(m,2H),4.20 -3.97(m,4H),3.96-3.84(m,2H),3.35-2.95(m,7H),2.92-2.63(m,10H),2.35-2. 10(m,3H),2.10-1.86(m,3H),1.80(dt,J=12.2,7.1Hz,4H).MSm / z:555.34[M+H]+.

[0555] The method of Example 376 was used to prepare the compounds of Examples 377-428.

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562] Example 429: Synthesis of 2-((2S)-4-(4-(2,4-dimethylpyridin-3-yl)-6-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-3-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0563]

[0564] Step 1: Synthesis of benzyl 5-((S)-4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-8-iodo-7-((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate

[0565] To a solution of benzyl 5-((S)-4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-7-((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (330 mg, 0.546 mmol) in N,N-dimethylformamide (5 mL) was added nitrogen-iodosuccinimide (149 mg, 0.66 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. Ethyl acetate (50 mL) and saturated aqueous sodium carbonate solution (20 mL) were added. After shaking and separation, the organic phase was washed with saturated aqueous sodium sulfite solution (10 mL), water (10 mL × 2), and saturated brine (10 mL), dried over sodium sulfate, and dried under reduced pressure to obtain a yellow viscous product. The crude product was used directly in the next step. (280 mg, yield: 70%) MS m / z: 730.7 [M+H] +.

[0566] Step 2: Synthesis of benzyl 5-((S)-4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-8-(2,4-dimethylpyridin-3-yl)-7-((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate

[0567] To a reaction flask, benzyl 5-((S)-4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-8-iodo-7-((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (280 mg, 0.383 mmol), (2,4-dimethylpyridin-3-yl)boronic acid (116 mg, 0.766 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (28 mg, 0.038 mmol), and potassium phosphate (163 mg, 0.766 mmol) were added. After nitrogen replacement, pre-deoxygenated 1,4-dioxane (8 mL) and water (2 mL) were added. The reaction mixture was stirred at 80°C for 4 hours. Ethyl acetate (50 mL) and water (20 mL) were added. After shaking and separating the layers, the organic phase was washed with saturated aqueous sodium carbonate (10 mL) and saturated brine (10 mL), dried over sodium sulfate, and then dried under reduced pressure. The residue was purified by column chromatography (silica gel, methanol:dichloromethane = 1:10) to yield a white solid (200 mg, yield: 74%). MS m / z: 709.9 [M+H]+.

[0568] Step 3: Synthesis of tert-butyl (2S)-2-(cyanomethyl)-4-(4-(2,4-dimethylpyridin-3-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate

[0569] Under a hydrogen balloon atmosphere, a suspension of benzyl 5-((S)-4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-8-(2,4-dimethylpyridin-3-yl)-7-((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (200 mg, 0.282 mmol) and palladium / carbon (300 mg, 0.0282 mmol) in ethyl acetate (4 mL) and tetrahydrofuran (4 mL) was stirred for 3 hours. The solid was filtered and the filter cake was rinsed with ethyl acetate. The combined filtrates were evaporated to dryness under reduced pressure to afford a gray viscous product (131 mg, 81% yield). MS m / z: 575.7 [M+H].

[0570] Step 4: Synthesis of tert-butyl (2S)-2-(cyanomethyl)-4-(4-(2,4-dimethylpyridin-3-yl)-6-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-3-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate

[0571] To a reaction flask were added tert-butyl (2S)-2-(cyanomethyl)-4-(4-(2,4-dimethylpyridin-3-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate (131 mg, 0.228 mmol), 8-bromo-1-methyl-1,2,3,4-tetrahydroquinoline (77 mg, 0.342 mmol), tris(dibenzylideneacetone)dipalladium (23 mg, 0.025 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (24 mg, 0.05 mmol), and cesium carbonate (147 mg, 0.45 mmol). After argon replacement, deoxygenated anhydrous toluene (4 mL) was added. The reaction solution was heated at 110°C for 16 hours. After cooling to room temperature, ethyl acetate (30 mL) and water (15 mL) were added, shaken, and the layers separated. The organic phase was washed with saturated brine (10 mL), dried over sodium sulfate, and then dried under reduced pressure. The residue was purified by column chromatography (silica gel, methanol:dichloromethane = 1:10) to obtain a light brown viscous product (28 mg, yield: 17%). MS m / z: 721.0 [M+H]+.

[0572] Step 5: Synthesis of 2-((2S)-4-(4-(2,4-dimethylpyridin-3-yl)-6-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-3-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-2-yl)acetonitrile

[0573] To a solution of (2S)-tert-butyl 2-(cyanomethyl)-4-(4-(2,4-dimethylpyridin-3-yl)-6-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-3-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate (28 mg, 0.0388 mmol) in dichloromethane (3 mL) was slowly added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 3 hours. Anhydrous dichloromethane (15 mL) was added for dilution and the mixture was evaporated to dryness under reduced pressure. The resulting light yellow viscous product was used directly in the next step. (44 mg, yield: 100%) MS m / z: 620.8 [M+H]+.

[0574] Step 6: Synthesis of 2-((2S)-4-(4-(2,4-dimethylpyridin-3-yl)-6-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-3-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

[0575] To a solution of 2-((2S)-4-(4-(2,4-dimethylpyridin-3-yl)-6-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-3-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-2-yl)acetonitrile (44 mg, crude) and 2-fluoroacrylic acid (7 mg, 0.0776 mmol) in dichloromethane (5 mL) was added 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (29 mg, 0.075 mmol) and nitrogen, nitrogen-diisopropylethylamine (20 mg, 0.155 mmol). The reaction was stirred at room temperature for 12 hours. Add dichloromethane (30 mL), wash with saturated sodium bicarbonate solution (10 mL), wash with saturated brine (10 mL), and dry over sodium sulfate. The residue was dried under reduced pressure and analyzed by TLC (methanol:dichloromethane = 1:10) to obtain a yellow solid (2 mg, yield: 7.4%). 1 H NMR (400MHz, DMSO) δ8.49(d,J=5.6Hz,1H),7.48(d,J=5.6Hz,1H),6.40(t,J=7.5Hz,1H),6.29 -6.26(m,2H),5.44-5.26(m,2H),5.26(s,2H),5.18(d,J=3.6,16.8Hz,1H),3.68-3.50(m,5H), 3.37-3.32(m,3H),3.24-3.01(m,8H),3.03(s,3H),2.79-2.73(m,3H),2.75(s,3H),2.68(s,3H ),2.46-2.32(m,3H),2.36(s,3H),1.94-1.91(m,2H),1.68-1.51(m,4H).MSm / z:692.9[M+H]+.

[0576] Examples 430-443 were prepared using the method of Example 429.

[0577]

[0578]

[0579]

[0580] Example 444: Synthesis of (8aR,11R)-10-acryloyl-3-(8-chloronaphthalen-1-yl)-7,11-dimethyl-6-((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,4,7,9,10,11,12-octahydro-1H-pyrazino[1',2:4,5]pyrazino[2,3-c][1,7]naphthyridin-8(8aH)-one

[0581]

[0582] Step 1: Synthesis of 4-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyridin-2(1H)-one

[0583] A mixture of 3-methyl 4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1,7-naphthyridine-3,7(1H)-dicarboxylate (3.0 g, 9.26 mmol) and hydrochloric acid (2N, 60 mL) was heated under reflux for 24 hours. After cooling to room temperature, the reaction mixture was used directly in the next step. MS m / z: 166.1 [M+H] + .

[0584] Step 2: Synthesis of benzyl 4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1,7-naphthyridine-7(1H)-carboxylate

[0585] In an ice-water bath, add sodium hydroxide to a solution of crude 4-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyridin-2(1H)-one until the pH reaches 11. Add tetrahydrofuran (50 mL). Add benzyl chloroformate (1.57 g, 9.26 mmol) slowly dropwise. Stir the reaction mixture at room temperature for 12 hours. Add methanol (5 mL) and stir for 30 minutes. Remove most of the tetrahydrofuran by rotary evaporation. Add hydrochloric acid (6 N) until the pH reaches 2. Collect the solid by filtration, wash with water, and dry to obtain a light yellow solid (900 mg, yield: 32%). MS m / z: 300.1 [M+H] + .

[0586] Step 3: Synthesis of benzyl 4-hydroxy-3-nitro-2-oxo-2,5,6,8-tetrahydro-1,7-naphthyridine-7(1H)-carboxylate

[0587] A mixture of benzyl 4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1,7-naphthyridine-7(1H)-carboxylate (900 mg, 3 mmol) and concentrated sulfuric acid (5 mL) was vigorously stirred. Concentrated nitric acid (1 mL) was slowly added dropwise. After stirring for 5 hours, the reaction mixture was slowly poured into ice water (200 mL). The solid was collected by filtration, washed with water (5 mL x 2), and dried to obtain an orange solid (600 mg, yield: 58%). MS m / z: 345.1 [M+H] + .

[0588] Step 4: Synthesis of benzyl 2,4-dichloro-3-nitro-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate

[0589] A mixture of 4-hydroxy-3-nitro-2-oxo-2,5,6,8-tetrahydro-1,7-naphthyridine-7(1H)-carboxylic acid benzyl ester (600 mg, 1.74 mmol) and phosphorus oxychloride (6 mL) was heated at 100°C for 6 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. Anhydrous toluene (10 mL) was added and the mixture was concentrated again. This process was repeated twice. The resulting yellow viscous material was used directly in the next step. (600 mg, crude product) MS m / z: 381.0 [M+H] + .

[0590] Step 5: Synthesis of 3-methyl (3R,6R)-4-(7-((phenoxy)carbonyl)-2-chloro-3-nitro-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate 1-(tert-butyl) ester

[0591] To a solution of benzyl 2,4-dichloro-3-nitro-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (600 mg, crude) in tetrahydrofuran (20 mL) were added diisopropylethylamine (774 mg, 6.0 mmol) and 3-methyl (3R,6R)-6-methylpiperazine-1,3-dicarboxylate (1-(tert-butyl) ester) (539 mg, 2.09 mmol). The reaction mixture was heated at 65°C for 2 hours. After cooling to room temperature, ethyl acetate (100 mL) and saturated aqueous ammonium chloride (50 mL) were added. After shaking and separating the layers, the organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and evaporated to dryness under reduced pressure to obtain a yellow viscous product, which was used directly in the next step. (300 mg, total yield for two steps: 29%) MS m / z: 602.3 [M+H] + .

[0592] Step 6: Synthesis of 3-methyl 1-(tert-butyl)-3-(3R,6R)-4-(7-((phenoxy)carbonyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-3-nitro-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate

[0593] To a solution of (3R,6R)-4-(7-((phenoxy)carbonyl)-2-chloro-3-nitro-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester (300 mg, 0.5 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (58 mg, 0.5 mmol) in N,N-dimethylformamide (4 mL) was added nitrogen-diisopropylethylamine (129 mg, 1.0 mmol). The reaction mixture was heated at 80°C for 12 hours. Ethyl acetate (50 mL) and saturated aqueous sodium carbonate solution (30 mL) were added. After shaking and separation, the organic phase was washed with water (10 mL × 3) and saturated brine (10 mL), dried over sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, methanol: dichloromethane = 1:10) to give a yellow solid (290 mg, yield: 85%). MS m / z: 682.3 [M+H] + .

[0594] Step 7: Synthesis of (8aR,11R)-11-methyl-6-((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-1,4,7,8,8a,9,11,12-octahydro-3H-pyrazino[1',2:4,5]pyrazino[2,3-c][1,7]naphthyridine-3,10(2H)-dicarboxylic acid 3-benzyl ester 10-(tert-butyl) ester

[0595] To a solution of 1-(tert-butyl)-3-methyl (3R,6R)-4-(7-(phenoxy)carbonyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-3-nitro-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate (290 mg, 0.425 mmol) in ethanol (15 mL) were added ammonium chloride (228 mg, 4.3 mmol) and iron powder (123 mg, 2.2 mmol). The reaction mixture was heated under reflux for 8 hours. After cooling to room temperature, it was filtered and the solid was rinsed with ethanol. The filtrate was concentrated under reduced pressure to obtain a dark brown solid which was used directly in the next step. (165 mg, yield: 63%) MS m / z: 620.3 [M+H] + .

[0596] Step 8: Synthesis of (8aR,11R)-7,11-dimethyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-1,4,7,8,8a,9,11,12-octahydro-3H-pyrazino[1',2:4,5]pyrazino[2,3-c][1,7]naphthyridine-3,10(2H)-dicarboxylic acid 3-benzyl ester 10-(tert-butyl) ester

[0597] To a solution of (8aR,11R)-11-methyl-6-((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-1,4,7,8,8a,9,11,12-octahydro-3H-pyrazino[1',2:4,5]pyrazino[2,3-c][1,7]naphthyridine-3,10(2H)-dicarboxylic acid 3-benzyl ester 10-(tert-butyl) ester (165 mg, 0.266 mmol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (73 mg, 0.53 mmol) and iodomethane (121 mg, 0.85 mmol). The reaction mixture was stirred at 40°C for 12 hours. After cooling to room temperature, ethyl acetate (50 mL) and water (30 mL) were added. After shaking and separating, the organic phase was washed with water (10 mL x 2), saturated brine (10 mL), dried over sodium sulfate, and dried under reduced pressure. A brown solid was obtained and used directly in the next step. (99 mg, yield: 59%) MS m / z: 634.4 [M+H] + .

[0598] Step 9: Synthesis of tert-butyl (8aR,11R)-7,11-dimethyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-1,2,3,4,7,8,8a,9,11,12-decahydro-10H-pyrazino[1',2:4,5]pyrazino[2,3-c][1,7]naphthyridine-10-carboxylate

[0599] Under a hydrogen balloon atmosphere, a suspension of (8aR,11R)-7,11-dimethyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-1,4,7,8,8a,9,11,12-octahydro-3H-pyrazino[1',2:4,5]pyrazino[2,3-c][1,7]naphthyridine-3,10(2H)-dicarboxylic acid 3-benzyl ester 10-(tert-butyl) ester (99 mg, 0.156 mmol) and palladium on carbon (170 mg, 0.016 mmol) in ethyl acetate (2 mL) and tetrahydrofuran (2 mL) was stirred for 3 hours. The solid was filtered and the filter cake was rinsed with ethyl acetate. The combined filtrates were evaporated to dryness under reduced pressure. The residue was purified by TLC (methanol:ethyl acetate = 1:1) to afford a yellow solid. (65 mg, yield: 83%) MS m / z: 500.3 [M+H] + .

[0600] Step 10: Synthesis of tert-butyl (8aR,11R)-3-(8-chloronaphthalen-1-yl)-7,11-dimethyl-6-((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-1,2,3,4,7,8,8a,9,11,12-decahydro-10H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,7]naphthyridine-10-carboxylate

[0601] To a reaction flask, tert-butyl (8aR,11R)-7,11-dimethyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-1,2,3,4,7,8,8a,9,11,12-decahydro-10H-pyrazino[1',2:4,5]pyrazino[2,3-c][1,7]naphthyridine-10-carboxylate (65 mg, 0.13 mmol), 1-bromo-8-chloronaphthalene (48 mg, 0.20 mmol), tris(dibenzylideneacetone)dipalladium (12 mg, 0.013 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (12 mg, 0.026 mmol), and cesium carbonate (85 mg, 0.26 mmol) were added. After argon replacement, deoxygenated anhydrous toluene (3 mL) was added. The reaction mixture was heated at 110°C for 16 hours. After cooling to room temperature, ethyl acetate (30 mL) and water (30 mL) were added, shaken, and the layers separated. The organic phase was washed with saturated brine (10 mL), dried over sodium sulfate, and dried under reduced pressure. The residue was purified by TLC (methanol:dichloromethane = 1:10) to obtain a light brown viscous product (22 mg, yield: 23%). MS m / z: 660.3 [M+H] + .

[0602] Step 11: Synthesis of (8aR,11R)-3-(8-chloronaphthalen-1-yl)-7,11-dimethyl-6-((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,4,7,9,10,11,12-octahydro-1H-pyrazino[1',2:4,5]pyrazino[2,3-c][1,7]naphthyridin-8(8aH)-one

[0603] To a solution of (8aR,11R)-3-(8-chloronaphthalen-1-yl)-7,11-dimethyl-6-((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-1,2,3,4,7,8,8a,9,11,12-decahydro-10H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,7]naphthyridine-10-carboxylic acid tert-butyl ester (22 mg, 0.030 mmol) in dichloromethane (3 mL) was slowly added trifluoroacetic acid (1 mL). The reaction solution was stirred at room temperature for 3 hours. Anhydrous dichloromethane (10 mL) was added for dilution and the mixture was dried under reduced pressure. The resulting light yellow viscous material was used directly in the next step. MSm / z:560.3[M+H] + .

[0604] Step 12: Synthesis of (8aR,11R)-10-acryloyl-3-(8-chloronaphthalen-1-yl)-7,11-dimethyl-6-((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,4,7,9,10,11,12-octahydro-1H-pyrazino[1',2:4,5]pyrazino[2,3-c][1,7]naphthyridin-8(8aH)-one

[0605] In an ice-water bath, slowly add a solution of acryloyl chloride (2.7 mg, 0.03 mmol) in dichloromethane (1 mL) to a solution of (8aR,11R)-3-(8-chloronaphthalen-1-yl)-7,11-dimethyl-6-((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,4,7,9,10,11,12-octahydro-1H-pyrazino[1',2:4,5]pyrazino[2,3-c][1,7]naphthyridin-8(8aH)-one and nitrogen, nitrogen-diisopropylethylamine (39 mg, 0.3 mmol) in dichloromethane (3 mL). Remove the ice-water bath, and stir the reaction mixture at room temperature for 15 minutes. Evaporate under reduced pressure and purify the residue by TLC (methanol:dichloromethane = 1:10) to yield a light yellow solid (3 mg, total yield for two steps: 16%). 1H NMR (400MHz, DMSO) δ7.72-7.64(m,1H),7.53(t,J=7.2Hz,1H),7.48(t,J=7.2Hz,1H),7.35(t d,J=7.8,13.2Hz,1H),7.28-7.20(m,2H),6.92-6.78(m,1H),6.20(brd,J=16.2Hz,1H),5.79- 5.72(m,1H),4.35-4.31(m,1H),3.68-3.50(m,6H),3.42(s,3H),3.37-3.32(m,1H),3.24-3.0 1(m,7H),2.46-2.32(m,2H),2.36(s,3H),1.68-1.51(m,4H),1.31(s,3H).MSm / z:614.3[M+H] + .

[0606] Examples 445-487 were prepared using the method of Example 444.

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614] Example 488: Synthesis of 1-((8aR,11R)-3-(8-chloronaphthalen-1-yl)-11-methyl-6-((S)-1-methylpyrrolidin-2-yl)methoxy)-1,2,3,4,8a,9,11,12-octylhydropyrazino[1',2:4,5][1,4]oxazino[2,3-c][1,7]naphthyridin-10(8H)-yl)prop-2-en-one

[0615]

[0616]

[0617] Step 1: Synthesis of benzyl 4-((2R,5R)-4-(tert-butoxycarbonyl)-2-(hydroxymethyl)-5-methylpiperazin-1-yl)-2-chloro-3-nitro-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate

[0618] A solution of 2,4-dichloro-3-nitro-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (535 mg, 1.40 mmol), benzyl tert-butyl (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (345 mg, 1.5 mmol), and diisopropylethylamine (258 mg, 2 mmol) in DMF (15 mL) was stirred at 75°C for 4 hours. After cooling to room temperature, ethyl acetate (150 mL) and saturated aqueous ammonium chloride (100 mL) were added. After shaking and separating the layers, the aqueous phase was extracted with ethyl acetate (50 mL). The organic phases were combined, washed with water (40 mL x 3) and saturated brine (40 mL), dried over sodium sulfate, and evaporated to dryness under reduced pressure to obtain a brown viscous product. Column chromatography (silica gel, ethyl acetate / petroleum ether = 1 / 1) gave a viscous product (400 mg, 0.69 mmol, yield: 49%).

[0619] Step 2: Synthesis of benzyl 4-((2R,5R)-4-(tert-butoxycarbonyl)-2-(hydroxymethyl)-5-methylpiperazin-1-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-3-nitro-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate

[0620] To a solution of benzyl 4-((2R,5R)-4-(tert-butoxycarbonyl)-2-(hydroxymethyl)-5-methylpiperazin-1-yl)-2-chloro-3-nitro-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (311 mg, 0.54 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (67 mg, 0.58 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (129 mg, 1.0 mmol). The reaction mixture was heated at 60°C for 12 hours. After cooling to room temperature, ethyl acetate (50 mL) and saturated aqueous sodium carbonate solution (30 mL) were added. After shaking and separation, the organic phase was washed with water (10 mL × 3) and saturated brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a dark brown solid that was used directly in the next reaction.

[0621] Step 3: Synthesis of (8aR,11R)-11-methyl-6-((S)-1-methylpyrrolidin-2-yl)methoxy)-1,4,8a,9,11,12-hexahydropyrazino[1',2:4,5][1,4]oxazino[2,3-c][1,7]naphthyridine-3,10(2H,8H)-dicarboxylic acid 3-benzyl ester 10-tert-butyl ester

[0622] In an ice-water bath, sodium hydride (24 mg, 0.60 mmol) was added to a solution of benzyl 4-((2R,5R)-4-(tert-butoxycarbonyl)-2-(hydroxymethyl)-5-methylpiperazin-1-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-3-nitro-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in N,N-dimethylformamide (5 mL). The reaction mixture was stirred in an ice-water bath for 15 minutes, heated to 120°C and stirred for 24 hours. After cooling to room temperature, ethyl acetate (50 mL) and water (30 mL) were added. After shaking and separation, the organic phase was washed with water (10 mL × 2), saturated brine (10 mL), dried over sodium sulfate, and evaporated to dryness under reduced pressure to obtain a brown solid. Column chromatography (silica gel, methanol / dichloromethane = 1 / 10) gave a yellow solid (195 mg, 0.32 mmol, two-step yield: 59%). MS m / z: 608.3 [M+H] + .

[0623] Step 4: Synthesis of tert-butyl (8aR,11R)-11-methyl-6-((S)-1-methylpyrrolidin-2-yl)methoxy)-1,2,3,4,8a,9,11,12-octylhydropyrazino[1',2:4,5][1,4]oxazino[2,3-c][1,7]naphthyridine-10(8H)-carboxylate

[0624] Under a hydrogen balloon atmosphere, a suspension of (8aR,11R)-11-methyl-6-((S)-1-methylpyrrolidin-2-yl)methoxy)-1,4,8a,9,11,12-hexahydropyrazino[1',2:4,5][1,4]oxazino[2,3-c][1,7]naphthyridine-3,10(2H,8H)-dicarboxylic acid 3-benzyl ester 10-tert-butyl ester (178 mg, 0.293 mmol) and palladium on carbon (319 mg, 0.03 mmol) in ethyl acetate (8 mL) and tetrahydrofuran (8 mL) was stirred for 3 hours. The solid was filtered off, and the filter cake was rinsed with ethyl acetate (10 mL x 2). The combined filtrates were evaporated to dryness under reduced pressure. The residue was purified by preparative TLC (methanol:ethyl acetate = 1:1) to afford a yellow solid (125 mg, 0.26 mmol, yield: 90%). MSm / z:474.3[M+H] + .

[0625] Step 5: Synthesis of tert-butyl (8aR,11R)-3-(8-chloronaphthalen-1-yl)-11-methyl-6-((S)-1-methylpyrrolidin-2-yl)methoxy)-1,2,3,4,8a,9,11,12-octahydropyrazino[1',2:4,5][1,4]oxazino[2,3-c][1,7]naphthyridine-10(8H)-carboxylate

[0626] To a reaction flask, tert-butyl (8aR,11R)-11-methyl-6-((S)-1-methylpyrrolidin-2-yl)methoxy)-1,2,3,4,8a,9,11,12-octylhydropyrazino[1',2:4,5][1,4]oxazino[2,3-c][1,7]naphthyridine-10(8H)-carboxylate (119 mg, 0.25 mmol), 1-bromo-8-chloronaphthalene (72 mg, 0.3 mmol), tris(dibenzylideneacetone)dipalladium (28 mg, 0.03 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (14 mg, 0.03 mmol), and cesium carbonate (163 mg, 0.5 mmol) were added. After purging the atmosphere with argon, deoxygenated anhydrous toluene (5 mL) was added. The reaction mixture was heated at 110°C for 16 hours. After cooling to room temperature, the mixture was filtered and the filter cake was rinsed with ethyl acetate (10 mL x 2). The filtrates were combined and dried under reduced pressure. The residue was purified by preparative TLC (methanol:dichloromethane = 1:10) to obtain a light brown viscous product (35 mg, 0.055 mmol, yield: 22%). MS m / z: 634.3 [M+H] + .

[0627] Step 6: Synthesis of (8aR,11R)-3-(8-chloronaphthalen-1-yl)-11-methyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,2,3,4,8,8a,9,10,11,12-decahydropyrazino[1',2:4,5][1,4]oxazino[2,3-c][1,7]naphthyridine

[0628] To a solution of (8aR,11R)-3-(8-chloronaphthalen-1-yl)-11-methyl-6-((S)-1-methylpyrrolidin-2-yl)methoxy)-1,2,3,4,8a,9,11,12-octahydropyrazino[1',2:4,5][1,4]oxazino[2,3-c][1,7]naphthyridine-10(8H)-carboxylic acid tert-butyl ester (28 mg, 0.063 mmol) in dichloromethane (3 mL) was slowly added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2 hours. Anhydrous dichloromethane (10 mL) was added to dilute the mixture and evaporated to dryness under reduced pressure. The resulting light yellow viscous product was used directly in the next step.

[0629] Step 7: Synthesis of 1-((8aR,11R)-3-(8-chloronaphthalen-1-yl)-11-methyl-6-((S)-1-methylpyrrolidin-2-yl)methoxy)-1,2,3,4,8a,9,11,12-octylhydropyrazino[1',2:4,5][1,4]oxazino[2,3-c][1,7]naphthyridin-10(8H)-yl)prop-2-en-one

[0630] In an ice-water bath, a solution of acryloyl chloride (8.1 mg, 0.09 mmol) in dichloromethane (1 mL) was slowly added to a solution of ((8aR,11R)-3-(8-chloronaphthalen-1-yl)-11-methyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,2,3,4,8,8a,9,10,11,12-decahydropyrazino[1',2:4,5][1,4]oxazino[2,3-c][1,7]naphthyridine and triethylamine (39 mg, 0.3 mmol) in dichloromethane (3 mL) was added dropwise. The ice-water bath was removed, and the reaction mixture was stirred at room temperature for 15 minutes. The residue was evaporated under reduced pressure and purified by preparative TLC (methanol:dichloromethane = 1:10) to give a light yellow solid (4 mg, 0.0068 mmol, total yield for two steps: 11%). 1 HNMR(400MHz,DMSO)δ7.72-7.64(m,1H),7.53(t,J=7.2Hz,1H),7.48(t,J=7.2Hz,1H) ,7.35(td,J=7.8,13.2Hz,1H),7.28-7.20(m,2H),6.92-6.78(m,1H),6.20(brd,J=16 .2Hz,1H),5.79-5.72(m,1H),3.68-3.50(m,6H),3.37-3.32(m,3H),3.24-3.01(m,8H ),2.46-2.32(m,2H),2.36(s,3H),1.68-1.51(m,4H),1.31(s,3H).MSm / z:614.3[M+H] + .

[0631] Examples 489-525 were prepared using the method of Example 488.

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639] Example 526: Synthesis of (S)-1-(4-(7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazin-1-yl)prop-2-en-1-one:

[0640]

[0641] Step 1: Synthesis of 1-tert-butyl 4-ethyl 5-oxaheptane-1,4-dicarboxylate

[0642] Dissolve 1-tert-butyloxycarbonyl-4-piperidone (10 g, 50.19 mmol) in diethyl ether (100 mL). Add BF3.Et2O (7 mL, 55.21 mmol) under ice-water cooling. Then slowly add ethyl diazoacetate (6.85 mL, 55.21 mmol) dropwise. After the addition is complete, continue stirring and react for 1 hour. After the reaction is complete, quench with 30% aqueous sodium carbonate solution and water, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography (dichloromethane / methanol = 50 / 1) to obtain an oil (14 g, yield: 97%). 1 H NMR (400MHz, CDCl3): 4.25-2.03 (m, 11H), 1.47-1.45 (d, J = 7.8Hz, 9H), 1.31-1.24 (m, 3H).

[0643] Step 2: Synthesis of 4-hydroxy-2-(methylthio)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-tert-butyl ester

[0644] Dissolve the compound 5-oxaheptane-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (14g, 49.06mmol) in anhydrous methanol (80mL), add 30% sodium methoxide solution (26.5g, 147.18mmol) and thiourea (5.60g, 73.60mmol), and heat to 80°C for 2 hours. After the reaction is completed, cool to room temperature, add iodomethane (8.7g, 3.82mL, 61.33mmol) dropwise to the reaction solution, and stir at room temperature for 1 hour. After the reaction is completed, concentrate the reaction solution, dissolve the residue in water, adjust the pH to 6-7 with glacial acetic acid, precipitate the solid, and filter to obtain a white solid (13.1g, yield: 85%). 1 HNMR (400MHz, CDCl3) δ10.98 (s, 1H), 3.56 (d, J = 30.3Hz, 4H), 2.88 (d, J = 32.7Hz, 4H), 2.56 (s, 3H), 1.48 (s, 9H).

[0645] Step 3:

[0646] Dissolve tert-butyl 4-hydroxy-2-(methylthio)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate (5.0 g, 16.06 mmol) in anhydrous dichloromethane (50 mL). Add DIEA (3.11 g, 24.08 mmol) and trifluoromethanesulfonic anhydride (5.44 g, 19.27 mmol) under ice-water cooling. Stir and react for 30 minutes under ice-water cooling. After completion of the reaction, concentrate the reaction solution to obtain the crude product (7.12 g, 100% yield) which is used directly in the next step.

[0647] Step 4: Synthesis of tert-butyl 4-(4-(benzyloxy)carbonyl)piperazin-1-yl)-2-(methylthio)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate

[0648] The crude product (3.0 g, 6.77 mmol) obtained in the previous step was dissolved in anhydrous DMF (30 mL). DIEA (1.31 g, 10.15 mmol) and benzyl piperazine-1-carboxylate (1.79 g, 8.12 mmol) were then added. The mixture was heated to 80°C and stirred for one hour. After completion of the reaction, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 50 / 1) to afford an off-white solid (2.62 g, yield: 75%). 1 HNMR (400MHz, CDCl3) δ7.39-7.30 (m, 5H), 5.16 (s, 2H), 3.61 (d, J = 4.9Hz, 6H), 3.51(s,2H),3.24(s,4H),2.97(s,2H),2.74(s,2H),2.50(s,3H),1.48(s,9H).

[0649] Step 5: Synthesis of tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-(methylsulfinyl)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate:

[0650] The compound 4-(4-(benzyloxy)carbonyl)piperazin-1-yl)-2-(methylthio)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylic acid tert-butyl ester (1.0 g, 1.95 mmol) was dissolved in dichloromethane (20 mL), and 85% m-chloroperbenzoic acid (0.41 g, 2.34 mmol) was added under ice-water cooling and stirred for 30 minutes. After the reaction was completed, the reaction was quenched with saturated sodium thiosulfate solution, extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated to obtain an off-white solid. (1.0 g, yield: 97%)

[0651] Step 6: Synthesis of tert-butyl (S)-4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate

[0652] The compound tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-(methylsulfinyl)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate (1.0 g, 1.89 mmol) was dissolved in anhydrous toluene (10 mL). (S)-(1-methylpyrrolidin-2-yl)methanol (380 mg, 3.30 mmol) and sodium tert-butoxide (363 mg, 3.78 mmol) were added under ice-water cooling. The mixture was stirred under ice-water cooling for 4 hours. After completion of the reaction, the reaction was quenched with cold water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 30 / 1) to obtain an off-white solid (0.85 g, yield: 77%).

[0653] Step 7: Synthesis of (S)-benzyl 4-(2-((1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazine-1-carboxylate:

[0654] Compound (S)-tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate (0.85 g, 1.45 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated, then dissolved in dichloromethane, washed with saturated sodium bicarbonate, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain an off-white solid (700 mg, yield: 99.5%).

[0655] Step 8: Synthesis of (S)-benzyl 4-(7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazine-1-carboxylate:

[0656] Compound (S)-benzyl 4-(2-((1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazine-1-carboxylate (100 mg, 0.21 mmol) and 1-bromo-8-methylnaphthalene (92 mg, 0.42 mmol) were added to a reaction flask. Cesium carbonate (172 mg, 0.53 mmol), X-phos (20 mg, 0.04 mmol), and Pd2(dba)3 (37 mg, mol 0.04 mol) were also added. Anhydrous toluene (5 mL) was added, and the nitrogen atmosphere was replaced three times. The reaction mixture was heated to 100°C and stirred under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, concentrated, and separated by TLC (dichloromethane / methanol = 20 / 1) to obtain a light yellow solid.

[0657] (40 mg, yield: 31%)

[0658] Step 9: Synthesis of (S)-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepane:

[0659] Compound (S)-4-(7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazine-1-carboxylic acid benzyl ester (40 mg, 0.06 mmol) was dissolved in methanol (10 mL). 10% wet Pd / C (10 mg) was added under a nitrogen atmosphere to replace the hydrogen gas. The mixture was stirred under a hydrogen atmosphere for 3 hours. After the reaction was completed, the Pd / C was removed by filtration, and the organic phase was concentrated to obtain an off-white solid (30 mg, yield: 96%).

[0660] Step 10: Synthesis of (S)-1-(4-(7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazin-1-yl)prop-2-en-1-one:

[0661] Compound (S)-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepane (mg, mmol) was dissolved in dichloromethane (5 mL). DIEA (mg, mmol) was added under ice-water cooling, followed by the dropwise addition of acryloyl chloride (mg, mmol). The mixture was stirred under ice-water cooling for 10 minutes. After completion of the reaction, saturated aqueous sodium bicarbonate was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by TLC (dichloromethane / methanol = 10 / 1) to obtain an off-white solid. 1 H NMR (400MHz, CDCl3) δ7.61(dt,J=15.0,2.9Hz,1H),7.55-7.41(m,2H),7.37-7.24(m,2H),6.87(dd,J=14.9,3.0H z,1H),6.14(dd,J=33.0,20.0Hz,1H),6.00(dd,J=20.0,4.9Hz,1H),5.53(dd,J=33.0,4.9Hz,1H),4.12(td,J=9.7 ,8.0Hz,2H),3.99(t,J=10.4Hz,4H),3.65(dd,J=24.8,10.2Hz,1H),3.47-3.24(m,9H),3.15(t,J=9.8Hz,2H),3. 03-2.90(m,4H),2.79(dt,J=24.9,14.0Hz,1H),2.40(dt,J=24.8,14.1Hz,1H),2.26(s,3H),1.81-1.32(m,4H);MS m / z:541.3[M+H] + .

[0662] Example 527: Synthesis of (S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazin-1-yl)prop-2-en-1-one:

[0663]

[0664] Step 1: Synthesis of (S)-benzyl 4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazine-1-carboxylate:

[0665] Compound (S)-4-(2-((1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazine-1-carboxylic acid benzyl ester (100 mg, 0.21 mmol) and 1-bromonaphthalene (92 mg, 0.42 mmol) were added to a reaction flask. Cesium carbonate (172 mg, 0.53 mmol), X-phos (20 mg, 0.04 mmol), and Pd2(dba)3 (37 mg, 0.04 mol) were also added. Anhydrous toluene (5 mL) was added, and the nitrogen atmosphere was replaced three times. The mixture was heated to 100°C under a nitrogen atmosphere and stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated, and separated by TLC (dichloromethane / methanol = 20 / 1) to obtain a light yellow solid (40 mg, yield: 31%).

[0666] Step 2: (S)-2-((1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepane

[0667] Compound (S)-4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazine-1-carboxylic acid benzyl ester (40 mg, 0.06 mmol) was dissolved in methanol (10 mL). 10% wet Pd / C (10 mg) was added under a nitrogen atmosphere to replace the hydrogen gas. The mixture was stirred under a hydrogen atmosphere for 3 hours. After the reaction was completed, the Pd / C was removed by filtration, and the organic phase was concentrated to obtain an off-white solid (30 mg, yield: 96%).

[0668] Step 3: (S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazin-1-yl)prop-2-en-1-one

[0669] Compound (S)-2-((1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepane (mg, mmol) was dissolved in dichloromethane (5 mL). DIEA (mg, mmol) was added under ice-water cooling, followed by the dropwise addition of acryloyl chloride (mg, mmol). The mixture was stirred under ice-water for 10 minutes. After completion of the reaction, saturated aqueous sodium bicarbonate was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by TLC (dichloromethane / methanol = 10 / 1) to afford an off-white solid. 1HNMR(400MHz, CDCl3)δ8.32(d,J=7.8Hz,1H),7.85(d,J=7.3Hz,1H),7.61-7.45(m,3H),7.39(t,J =7.7Hz,1H),7.08(d,J=7.1Hz,1H),6.60(dd,J=16.6,10.4Hz,1H),6.32(d,J=16.8Hz,1H),5.74( d,J=11.7Hz,1H),5.12(s,1H),4.60(d,J=11.4Hz,1H),3.96(s,1H),3.69(d,J=35.6Hz,6H),3.28 (d,J=15.0Hz,9H),3.04(s,5H),2.95-2.82(m,1H),2.34(s,2H),2.20(s,2H); MSm / z:527.3[M+H] + .

[0670] Example 528: Synthesis of 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazin-2-yl)acetonitrile:

[0671]

[0672] Step 1: Synthesis of tert-butyl (S)-4-(3-(cyanomethyl)piperazin-1-yl)-2-(methylthio)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate:

[0673] Dissolve tert-butyl 2-(methylthio)-4-(((trifluoromethyl)sulfonyl)oxy)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate (2 g, 4.51 mmol) in anhydrous DMF (10 mL). Add DIEA (2.04 g, 15.80 mmol) and (S)-2-(piperazin-2-yl)acetonitrile-2 hydrochloride (980 mg, 4.96 mmol). Heat to 60°C and stir for 2 hours. After the reaction is complete, cool to room temperature, dilute the reaction solution with water, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain a crude product that is used directly in the next step (1.9 g, yield: 100%).

[0674] Step 2: Synthesis of tert-butyl (S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylthio)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate:

[0675] The crude product from the previous step (1.89 g, 4.51 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and DIEA (874 mg, 6.77 mmol) and Cbz-Cl (846 mg, 4.96 mmol) were added. The reaction was stirred at room temperature for 2 hours. After completion, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 50 / 1) to obtain an off-white solid (1.84 g, yield: 74%).

[0676] Step 3: Synthesis of tert-butyl 4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylsulfinyl)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate:

[0677] Compound (S)-tert-butyl 4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylthio)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate (1.84 g, 3.33 mmol) was dissolved in dichloromethane (20 mL). 85% m-CPBA (0.74 g, 3.66 mmol) was added under ice-water cooling. The mixture was stirred under ice-water cooling for 30 minutes. After completion of the reaction, the reaction was quenched with saturated sodium thiosulfate solution and extracted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to obtain an off-white solid (1.89 g, yield: 100%).

[0678] Step 4: Synthesis of tert-butyl 4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate:

[0679] Dissolve tert-butyl 4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylsulfinyl)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate (1.89 g, 3.32 mmol) in anhydrous toluene (20 mL). Add (S)-(1-methylpyrrolidin-2-yl)methanol (672 mg, 5.83 mmol). Add sodium tert-butoxide (638 mg, 6.64 mmol) under ice-water cooling, and stir under ice-water cooling for 4 hours. After completion of the reaction, quench with cold water, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography (dichloromethane / methanol = 30 / 1) to obtain an off-white solid (1.8 g, yield: 87%).

[0680] Step 5: Synthesis of benzyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazine-1-carboxylate

[0681] The compound 4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylic acid tert-butyl ester (1.8 g, 2.90 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (5 mL) was added, and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was added with saturated sodium bicarbonate and extracted with dichloromethane. The organic phase was washed with saturated water, dried over anhydrous sodium sulfate, and concentrated to obtain an off-white solid. (1.5 g, yield: 99%)

[0682] Step 6: Synthesis of (S)-benzyl 2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazine-1-carboxylate:

[0683] Benzyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazine-1-carboxylate (200 mg, 0.38 mmol) and 1-bromonaphthalene (160 mg, 0.77 mmol) were added to a reaction flask. Cesium carbonate (372 mg, 1.14 mmol), X-Phos (36 mg, 0.08 mmol), and Pd2(dba)3 (70 mg, 0.08 mmol) were also added. The atmosphere was replaced with nitrogen and the reaction was stirred at 100°C for 12 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered, and the organic phase was concentrated and separated by column chromatography (dichloromethane / methanol = 20 / 1) to obtain a light yellow solid (70 mg, yield: 28%).

[0684] Step 7: Synthesis of 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazin-2-yl)acetonitrile:

[0685] Compound (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazine-1-carboxylic acid benzyl ester (70 mg, 0.11 mmol) was dissolved in methanol (10 mL). 10% wet Pd / C (20 mg) was added under a nitrogen atmosphere to replace the hydrogen gas. The mixture was stirred under a hydrogen atmosphere for 3 hours. After completion of the reaction, the mixture was filtered through celite and the filtrate was concentrated to obtain an off-white solid (50 mg, yield: 90%).

[0686] Step 8: Synthesis of 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazin-2-yl)acetonitrile:

[0687] The compound 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazin-2-yl)acetonitrile (50 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL). DIEA (20 mg, 0.15 mmol) and acryloyl chloride (10 mg, 0.11 mmol) were added under ice-water cooling. The mixture was stirred under ice-water cooling for 10 minutes. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was washed with saturated water. The organic phase was separated by column chromatography (dichloromethane / methanol = 10 / 1) to obtain an off-white solid (25 mg, yield: 45%). 1 H NMR (400MHz, CDCl3) δ8.50(dd,J=11.1,6.9Hz,1H),7.78(ddd,J=11.0,6.9,2.8Hz,1H),7.60-7.28(m,5H),6.26(d d,J=33.3,20.0Hz,1H),6.00(dd,J=20.0,4.4Hz,1H),5.53(dd,J=33.4,4.5Hz,1H),4.22-4.10(m,2H),4.01(ddd, J=43.2,22.5,12.1Hz,2H),3.71-3.51(m,4H),3.48-3.19(m,8H),3.11(t,J=9.8Hz,2H),3.02-2.89(m,1H),2.79( dt,J=24.8,14.1Hz,1H),2.41(dt,J=24.8,14.1Hz,1H),2.29-2.14(m,4H),1.80-1.31(m,4H); MSm / z:566.8[M+H] + .

[0688] Example 529: Synthesis of 2-((S)-1-acryloyl-4-(7-(8-naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazin-2-yl)acetonitrile:

[0689]

[0690] Further prepared by replacing 1-bromonaphthalene with 1-bromo-8-methylnaphthalene in step 6 of Example 528. MS m / z: 580.8 [M+H] + .

[0691] Example 530: Synthesis of 2-((S)-1-acryloyl-4-(7-(8-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazin-2-yl)acetonitrile:

[0692]

[0693] Further prepared by replacing 1-bromonaphthalene with 1-bromo-8-fluoronaphthalene in step 6 of Example 528. MS m / z: 584.7 [M+H] + .

[0694] Example 531: Synthesis of 2-((S)-1-acryloyl-4-(7-(4-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazin-2-yl)acetonitrile:

[0695]

[0696] Further prepared by replacing 1-bromonaphthalene with 1-bromo-4-fluoronaphthalene in step 6 of Example 528. MS m / z: 584.8 [M+H] + .

[0697] Example 532: Synthesis of 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazin-2-yl)acetonitrile:

[0698]

[0699] Step 1: Synthesis of 2-(methylthio)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-ol

[0700] Dissolve tert-butyl 4-hydroxy-2-(methylthio)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate (5.0 g, 16.06 mmol) in dichloromethane (30 mL). Add trifluoroacetic acid (10 mL) and stir at room temperature for 3 hours. After completion of the reaction, concentrate the reaction mixture to obtain a crude brown oil that was used directly in the next step.

[0701] Step 2: Synthesis of benzyl 4-hydroxy-2-(methylthio)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate:

[0702] The oil obtained in the previous step (16.06 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and triethylamine (4.88 g, 48.18 mmol) was added. Benzyloxycarbonyl chloride (3.0 g, 17.67 mmol) was then added under ice-water cooling and stirred for 30 minutes. After completion, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed sequentially with 1M hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield an off-white solid (half oil, half solid). (4.6 g, yield: 83%)

[0703] Step 3: Synthesis of benzyl 2-(methylthio)-4-(((trifluoromethyl)sulfonyl)oxy)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate:

[0704] Dissolve benzyl 4-hydroxy-2-(methylthio)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate (4.6 g, 13.32 mmol) in anhydrous dichloromethane (50 mL). Add DIEA (2.58 g, 19.98 mmol). Add trifluoromethanesulfonic anhydride (4.13 g, 14.65 mmol) under ice-water cooling. Stir the mixture under ice-water cooling for 30 minutes, concentrate, and separate by column chromatography (dichloromethane / methanol = 80 / 1) to obtain an oil (4.8 g, yield: 75%).

[0705] Step 4: Synthesis of (S)-benzyl 4-(4-(tert-butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylthio)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate

[0706] Benzyl 2-(methylthio)-4-(((trifluoromethyl)sulfonyl)oxy)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate (4.8 g, 10.05 mmol) was dissolved in anhydrous DMF (30 mL). DIEA (1.95 g, 15.08 mmol) and (S)-2-(piperazin-2-yl)acetonitrile-2 hydrochloride (1.99 g, 10.05 mmol) were added. The mixture was heated to 80°C and stirred for 1 hour. After the reaction was complete, DIEA (1.95 g, 15.08 mmol) and di-tert-butyl dicarbonate (6.58 g, 30.15 mmol) were added and the reaction was continued with stirring for 1 hour. After the reaction was complete, the mixture was cooled to room temperature and diluted with saturated brine. 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 (dichloromethane / methanol = 50 / 1) to obtain an off-white solid (4.5 g, yield: 81%).

[0707] Step 5: Synthesis of (S)-4-(4-(tert-butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methanesulfonyl)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylic acid benzyl ester:

[0708] Compound (S)-4-(4-(tert-butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylthio)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate (4.5 g, 8.14 mmol) was dissolved in dichloromethane (50 mL). 85% m-chloroperbenzoic acid (1.82 g, 8.95 mmol) was added under ice-water cooling and stirred for 30 minutes. After completion of the reaction, the reaction was quenched with saturated sodium thiosulfate solution and extracted with dichloromethane. The organic phase was washed sequentially with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain an off-white solid (4.6 g, yield: 99%).

[0709] Step 6: Synthesis of benzyl 4-((S)-4-(tert-butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate:

[0710] Benzyl (S)-4-(4-(tert-butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methanesulfonyl)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylate (4.6 g, 8.09 mmol) was dissolved in anhydrous toluene (30 mL). (S)-(1-methylpyrrolidin-2-yl)methanol (1.63 g, 14.16 mmol) was added. Sodium tert-butoxide (1.55 g, 16.18 mmol) was added under ice-water cooling. The mixture was stirred under ice-water cooling for 4 hours. After completion of the reaction, the reaction was quenched with cold water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 30 / 1) to obtain an off-white solid (4.1 g, yield: 82%).

[0711] Step 7: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazine-1-carboxylate:

[0712] The compound 4-((S)-4-(tert-butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepane-7-carboxylic acid benzyl ester (4.1 g, 6.62 mmol) was dissolved in methanol (50 mL). 10% wet Pd / C (410 mg) was added under a nitrogen atmosphere to replace the hydrogen gas. The reaction was stirred under a hydrogen atmosphere for 6 hours. After the reaction was completed, the mixture was filtered through celite and the filtrate was concentrated to obtain an off-white solid (3.05 g, yield: 95%).

[0713] Step 8: Synthesis of tert-butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:

[0714] The compound (S)-tert-butyl 2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazine-1-carboxylate (100 mg, 0.21 mmol) and 1-bromonaphthalene (75 mg, 0.31 mmol) were added to a reaction flask. Cesium carbonate (168 mg, 0.52 mmol), RuPhos (10 mg, 0.02 mmol), and Pd2(dba)3 (19 mg, 0.02 mmol) were also added. The atmosphere was replaced with nitrogen and heated to 100°C with stirring for 12 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered, and the organic phase was concentrated and separated by column chromatography (dichloromethane / methanol = 20 / 1) to obtain a light yellow solid (45 mg, yield: 34%).

[0715] Step 9: Synthesis of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazin-2-yl)acetonitrile:

[0716] Dissolve (S)-tert-butyl 4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (45 mg, 0.07 mmol) in dichloromethane (3 ml), add trifluoroacetic acid (1 mL), and stir at room temperature for 1 hour. After completion of the reaction, concentrate the reaction solution to obtain the crude product, which was used directly in the next step (38 mg, yield: 100%).

[0717] Step 10: Synthesis of 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazin-2-yl)acetonitrile:

[0718] The compound 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepan-4-yl)piperazin-2-yl)acetonitrile (38 mg, 0.07 mmol) was dissolved in dichloromethane (5 mL). DIEA (23 mg, 0.18 mmol) was added under ice-water cooling, followed by acryloyl chloride (7 mg, 0.07 mmol). The mixture was stirred under ice-water cooling for 20 minutes. After completion, the reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by TLC (dichloromethane / methanol = 10 / 1) to afford an off-white solid (20 mg, yield: 48%). 1H NMR(400MHz, CDCl3)δ7.66(dt,J=14.8,3.0Hz,1H),7.60-7.52(m,1H),7.51-7.39(m,3H),7.31(t,J=14.9Hz,1H) ,6.25(dd,J=33.4,20.1Hz,1H),6.00(dd,J=20.1,4.5Hz,1H),5.53(dd,J=33.4,4.5Hz,1H),4.17-4.05(m,3H),4. 03-3.90(m,1H),3.70-3.46(m,4H),3.46-3.20(m,8H),3.15(t,J=9.8Hz,2H),2.96(tt,J=16.7,9.9Hz,1H),2.80( dt,J=24.8,14.2Hz,1H),2.41(dt,J=24.8,14.1Hz,1H),2.30-2.13(m,4H),1.79-1.33(m,4H); MSm / z:600.8[M+H] + .

[0719] Examples 533-576 were prepared using the preparation method of Example 532.

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727] Example 577: Synthesis of 1-(4-(8-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepan-4-yl)piperazin-1-yl)prop-2-en-1-one:

[0728] Step 1: Synthesis of 2-(methylthio)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepan-4-ol

[0729] Dissolve tert-butyl 4-hydroxy-2-(methylthio)-5,6,7,9-tetrahydro-8H-pyrimido[4,5-c]azepane-8-carboxylate (2 g, 6.42 mmol) in dichloromethane (30 mL). Add trifluoroacetic acid (10 mL) and stir at room temperature for 3 hours. After completion of the reaction, concentrate the reaction mixture to obtain a brown oil, which was used directly in the next step.

[0730] Step 2: Synthesis of benzyl 4-hydroxy-2-(methylthio)-5,6,7,9-tetrahydro-8H-pyrimido[4,5-c]azepane-8-carboxylate:

[0731] Dissolve the compound 2-(methylthio)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepan-4-ol (1.36 g, 6.42 mmol) in anhydrous tetrahydrofuran (30 mL). Add triethylamine (1.62 g, 16.05 mmol) and benzyloxycarbonyl chloride (1.21 g, 7.08 mmol) under ice-water cooling. Stir and react for 30 minutes under ice-water cooling. After completion of the reaction, dilute the reaction solution with water and extract with dichloromethane. The organic phase is washed with 1M hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product that is used directly in the next step (2.22 g, yield: 100%).

[0732] Step 3: Synthesis of benzyl 2-(methylthio)-4-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,9-tetrahydro-8H-pyrimido[4,5-c]azepane-8-carboxylate:

[0733] Dissolve benzyl 4-hydroxy-2-(methylthio)-5,6,7,9-tetrahydro-8H-pyrimido[4,5-c]azepane-8-carboxylate (2.22 g, 6.42 mmol) in dichloromethane (30 mL). Add DIEA (1.24 g, 9.63 mmol) and trifluoromethanesulfonic anhydride (1.99 g, 7.07 mmol) under ice-water cooling. Stir and react for 30 minutes under ice-water cooling. After completion of the reaction, concentrate the reaction solution to obtain a brown oil, which is used directly in the next step (3.07 g, yield: 100%).

[0734] Step 4: Synthesis of benzyl 4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-2-(methylthio)-5,6,7,9-tetrahydro-8H-pyrimido[4,5-c]azepane-8-carboxylate:

[0735] The compound 2-(methylthio)-4-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,9-tetrahydro-8H-pyrimido[4,5-c]azepane-8-carboxylic acid benzyl ester (3.07 g, 6.42 mmol) was dissolved in anhydrous DMF (20 mL), DIEA (1.66 g, 12,86 mmol) and tert-butyl piperazine-1-carboxylate (1.44 g, 7.72 mmol) were added, and the mixture was heated to 80°C and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled, diluted with saturated brine, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane / methanol = 30 / 1) to obtain an off-white solid (2.1 g, yield: 63%).

[0736] Step 5: Synthesis of benzyl 4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-2-(methanesulfonyl)-5,6,7,9-tetrahydro-8H-pyrimido[4,5-c]azepane-8-carboxylate:

[0737] Dissolve the compound 4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-2-(methylthio)-5,6,7,9-tetrahydro-8H-pyrimido[4,5-c]azepane-8-carboxylic acid benzyl ester (2.1 g, 4.09 mmol) in dichloromethane (30 mL). Add m-chloroperbenzoic acid (996 mg, 4.91 mmol) under ice-water cooling. Stir and react for 30 minutes under ice-water cooling. After completion of the reaction, quench with saturated sodium thiosulfate and extract with dichloromethane. The organic phase is washed sequentially with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product that is used directly in the next step (2.05 g, yield: 95%).

[0738] Step 6: Synthesis of benzyl 4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-5,6,7,9-tetrahydro-8H-pyrimido[4,5-c]azepane-8-carboxylate:

[0739] Benzyl 4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-2-(methanesulfonyl)-5,6,7,9-tetrahydro-8H-pyrimido[4,5-c]azepane-8-carboxylate (2.05 g, 3.87 mmol) was dissolved in anhydrous toluene (20 mL). 5-Hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (695 mg, 4.26 mmol) and sodium tert-butoxide (558 mg, 5.81 mmol) were added under ice-water cooling. The mixture was stirred at room temperature for 8 hours. After completion of the reaction, cold water was added to quench the reaction, and 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 (dichloromethane / methanol = 30 / 1) to obtain an off-white solid.

[0740] (2.1 g, yield: 86%)

[0741] Step 7: Synthesis of tert-butyl 4-(2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepan-4-yl)piperazine-1-carboxylate:

[0742] The compound 4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-5,6,7,9-tetrahydro-8H-pyrimido[4,5-c]azepane-8-carboxylic acid benzyl ester (2.1 g, 3.34 mmol) was dissolved in methanol (50 mL). 10% wet Pd / C (210 mg) was added under a nitrogen atmosphere to replace the hydrogen gas. The reaction was stirred under a hydrogen balloon for 3 hours. After the reaction was completed, the mixture was filtered through celite and washed with methanol. The mixture was concentrated to obtain an off-white solid (1.6 g, yield: 97%).

[0743] Step 8: Synthesis of tert-butyl 4-(8-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepan-4-yl)piperazine-1-carboxylate:

[0744] The compound tert-butyl 4-(2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepan-4-yl)piperazine-1-carboxylate (100 mg, 0.16 mmol) and 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (64 mg, 0.19 mmol) were dissolved in anhydrous toluene (5 mL), and RuPhos (15 mg, 0.03 mmol), cesium carbonate (130 mg, 0.40 mmol) and Pd2(dba)3 (28 mg, 0.03 mmol) were added. The nitrogen atmosphere was replaced three times and the mixture was heated to 110 ° C under a nitrogen atmosphere and stirred for 12 hours. After the reaction was complete, the reaction solution was cooled, diluted with ethyl acetate, filtered, concentrated, and separated by column chromatography (dichloromethane / methanol = 20 / 1) to obtain a light yellow solid (40 mg, yield: 34%).

[0745] Step 9: Synthesis of 8-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepane:

[0746] The compound 4-(8-(5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepan-4-yl)piperazine-1-carboxylic acid tert-butyl ester (40 mg, mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product which was directly used in the next step. (30 mg, yield: 99%)

[0747] Step 10: Synthesis of 1-(4-(8-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepan-4-yl)piperazin-1-yl)prop-2-en-1-one:

[0748] The compound 8-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepane (30 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL). DIEA (8 mg, 0.06 mmol) was added dropwise under ice-water cooling, followed by a solution of acryloyl chloride (5 mg, 0.05 mmol) in dichloromethane (2 mL). The mixture was stirred under ice-water for 30 minutes. After completion, the reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by TLC (dichloromethane / methanol = 10 / 1) to afford an off-white solid (15 mg, yield: 45%). 1 H NMR (400MHz, CDCl3) δ8.40(s,1H),7.03-6.84(m,4H),6.13-5.90(m,2H),5.51(dd,J=31.1,6.8Hz,1H),5.23(s,1H),5.05(s,1H),3.97(q,J=10 .2Hz,6H),3.69(s,2H),3.31(t,J=10.1Hz,4H),3.00-2.86(m,4H),2.87 -2.74(m,2H),2.25(s,3H),1.99(p,J=10.5Hz,2H); MSm / z:617.67[M+H] + .

[0749] The preparation method of Example 577 was used to prepare Examples 578-612

[0750]

[0751]

[0752]

[0753]

[0754]

[0755] Example 613: Synthesis of 2-((S)-1-acryloyl-4-(2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiochroman-8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0756]

[0757] Step 1: Synthesis of 3-((2-bromophenyl)thio)propionic acid

[0758] In an ice-water bath, acrylic acid (2.04 mL, 30 mmol) was added dropwise to a solution of 2-bromothiophenol (5.67 g, 30 mmol) and triethylamine (4.4 mL, 31.5 mmol) in anhydrous tetrahydrofuran (15 mL). The reaction mixture was slowly allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was evaporated to dryness under reduced pressure to obtain a colorless oil. Aqueous sodium hydroxide solution (2.0 g / 70 mL) was added and stirred. The aqueous solution was extracted with a mixture of ethyl acetate and petroleum ether (V:V = 1:1, 50 mL x 2). The remaining aqueous phase was cooled in an ice-water bath and hydrochloric acid (6 M) was added dropwise with stirring until the pH reached 1. The resulting milky white suspension was extracted with ethyl acetate (100 mL). After separation, the organic phase was washed with saturated brine (20 mL), dried over sodium sulfate, and evaporated to dryness under reduced pressure. The resulting solid was redissolved in dichloromethane (50 mL) and evaporated again under reduced pressure to dryness. After high vacuum treatment, a white solid was obtained. (7.6 g, 29.1 mmol, yield: 97%) MS m / z: 261.1 [M+H] + .

[0759] Step 2: Synthesis of 8-bromothiochroman-4-one

[0760] In an ice-water bath, 3-((2-bromophenyl)thio)propionic acid (7.6 g, 29.1 mmol) was added portionwise to concentrated sulfuric acid. The resulting dark red solution was stirred at room temperature overnight. The resulting viscous solution was slowly poured into rapidly stirred ice water (200 mL). The resulting pink suspension was extracted twice with ethyl acetate (200 mL + 100 mL). The organic phases were combined, washed with water (50 mL), saturated sodium bicarbonate aqueous solution (50 mL), and saturated brine (50 mL). After drying over sodium sulfate and vacuum drying, the residue was treated with high vacuum to obtain a colorless oil that was used directly in the next step. (4.2 g, 17.3 mmol, yield: 60%)

[0761] Step 3: Synthesis of 8-bromothiochroman

[0762] At room temperature, boron trifluoride etherate (15.5 mL, 123 mmol) was slowly added to a solution of 8-bromothiochroman-4-one (3.0 g, 12.3 mmol) in dichloromethane (120 mL). Triethylsilane (15.5 mL, 97.5 mmol) was added dropwise to the resulting bright yellow solution. The reaction mixture was stirred at room temperature for 16 hours. After cooling in an ice-water bath, water (100 mL) was slowly added and stirred for 20 minutes. After separation, the aqueous phase was extracted with dichloromethane (100 mL). The organic phases were combined, washed with saturated sodium bicarbonate aqueous solution (50 mL), washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated in vacuo (water bath temperature 38-45°C) to obtain a light yellow oil (1.9 g, crude yield: 100%).

[0763] Step 4: Synthesis of benzyl (S)-2-(cyanomethyl)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiochroman-8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0764] To a 10 mL single-necked vial was added benzyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (51 mg, 0.1 mmol), 8-bromothiochroman (46 mg, 0.2 mmol), tris(dibenzylideneacetone)dipalladium (28 mg, 0.03 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (19 mg, 0.04 mmol), and sodium tert-butoxide (16 mg, 0.17 mmol). After nitrogen replacement, deoxygenated anhydrous toluene (1 mL) was added. The reaction mixture was heated at 100°C for 16 hours. After cooling to room temperature, ethyl acetate (2 mL) and dichloromethane (2 mL) were added, and the mixture was filtered. The filter cake was rinsed with ethyl acetate / dichloromethane (4 mL, V:V = 1:1). The combined filtrates were vacuum-dried. The residue was purified by preparative TLC (silica gel, methanol:dichloromethane = 1:6) to obtain a khaki solid (26 mg, 0.04 mmol, yield: 40%). MS m / z: 654.7 [M+H] + .

[0765] Step 5: Synthesis of 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiochroman-8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0766] To a solution of benzyl (S)-2-(cyanomethyl)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiochroman-8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (36 mg, 0.04 mmol) in methanol (2 mL) were added a 7 M methanolic ammonia solution (2 mL) and wet palladium on carbon (70 mg, 5%). The hydrogen atmosphere was replaced with a hydrogen balloon and the mixture was stirred at room temperature for 18 hours. The solid was filtered and rinsed with methanol (4 mL). The combined organic phases were dried by vortexing. The residue was mixed with dichloromethane (10 mL) and dried by vortexing. The residue was mixed with ethyl acetate (10 mL) and dried by vortexing to give an off-white powder. This powder was used directly in the next reaction. MS m / z: 520.6 [M+H] + .

[0767] Step 6: Synthesis of 2-((S)-1-acryloyl-4-(2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiochroman-8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0768] To a solution of 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(thiochroman-8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile and triethylamine (31 μL, 0.22 mmol) in dichloromethane (2 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 15 minutes. Dichloromethane (20 mL) and saturated aqueous sodium carbonate solution (20 mL) were added, the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, and rotary evaporation to obtain a viscous product. Purification by preparative TLC (methanol: dichloromethane = 1:7) gave an off-white solid (7 mg, total yield for two steps: 22%). MS m / z: 574.7 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.00(d,J=8.0Hz,1H),6.94(d,J=8.0Hz,1H),6.87-6.85(m,1H),6.66 -6.56(m,1H),6.37(d,J=16.7Hz,1H),5.81(d,J=10.6Hz,1H),5.20-5.16(m1H),4.96-4.74(AB,J=68,20Hz,2H),4.58-4.55(m,1H),4.25-4 .22(m,1H),4.13(s,2H),4.01-3.77(m,1H),3.55-3.05(m,6H),3.00- 2.68(m,8H),2.35-2.26(m,3H),2.16-2.08(m,2H),1.98-1.92(m,6H).

[0769] The preparation method of Example 613 was used to prepare Examples 614-624

[0770]

[0771]

[0772]

[0773] Example 625: Synthesis of 2-((S)-1-acryloyl-4-(7-(isothiochroman-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0774]

[0775] Step 1: Synthesis of 2-((2-bromophenyl)thio)acetyl chloride

[0776] Combine thionyl chloride (0.29 mL, 4 mmol) and 2-((2-bromophenyl)thio)acetic acid (550 mg, 2 mmol) to give a light yellow solution. Heat in an 82°C oil bath for 2 hours. After cooling to room temperature, concentrate under reduced pressure and then treat under high vacuum to obtain a light yellow oil, which is used directly in the next reaction.

[0777] Step 2: Synthesis of 5-bromoisothiochroman

[0778] A suspension of aluminum trichloride (560 mg, 4.2 mmol) in anhydrous dichloromethane (1 mL) was cooled in an ice-water bath. A solution of 2-((2-bromophenyl)thio)acetyl chloride in anhydrous dichloromethane (2 mL) was slowly added dropwise. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reactants were poured into ice (20 g) and stirred vigorously for 5 minutes. The excess yellow suspension was extracted with methyl tert-butyl ether (20 mL x 2). The organic phases were combined, washed with saturated aqueous sodium carbonate (10 mL), washed with saturated brine (10 mL), dried over sodium sulfate, and dried under reduced pressure to obtain a yellow oil. Purification by column chromatography (silica gel, petroleum ether) gave a white solid (211 mg, 0.92 mmol, yield: 46%).

[0779] Step 3: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(7-(isothiomalo-5-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0780] To a 10 mL single-necked vial was added tert-butyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (66 mg, 0.14 mmol), 5-bromoisothiochroman (64 mg, 0.28 mmol), tris(dibenzylideneacetone)dipalladium (38 mg, 0.042 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (26 mg, 0.056 mmol), and sodium tert-butoxide (23 mg, 0.238 mmol). After nitrogen replacement, deoxygenated anhydrous toluene (2 mL) was added. The reaction mixture was heated at 100°C for 16 hours. After cooling to room temperature, ethyl acetate (2 mL) and dichloromethane (2 mL) were added, and the mixture was filtered. The filter cake was rinsed with ethyl acetate / dichloromethane (4 mL, V:V = 1:1). The combined filtrates were vacuum-dried. The residue was purified by preparative TLC (silica gel, methanol:dichloromethane = 1:8) to afford a light yellow solid (56 mg, 0.09 mmol, yield: 65%). MS m / z: 620.7 [M+H] + .

[0781] Step 4: Synthesis of 2-((S)-4-(7-(isothiomalo-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0782] To a solution of tert-butyl (S)-2-(cyanomethyl)-4-(7-(isothiomalo-5-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (20 mg, 0.032 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) dropwise at room temperature. The resulting solution was stirred at room temperature for 1 hour. Dichloromethane (7 mL) was added and the mixture was concentrated in vacuo. Dichloromethane (5 mL) was added to the resulting residue, and the mixture was concentrated again and this process was repeated once. The resulting yellow solid was used directly in the next step.

[0783] Step 5: Synthesis of 2-((S)-1-acryloyl-4-(7-(isothiochroman-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0784] To a solution of 2-((S)-4-(7-(isothio-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile and triethylamine (0.027 mL, 0.19 mmol) in dichloromethane (2 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 15 minutes. Dichloromethane (20 mL) and saturated aqueous sodium carbonate solution (20 mL) were added, the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, and rotary evaporation to obtain a viscous product. Purification by preparative TLC (methanol: dichloromethane = 1:8) gave a white solid (9.4 mg, total yield for two steps: 51%). MS m / z: 574.7 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.22-7.18(m,1H),7.03(d,J=8.0Hz,1H),6.97(d,J=8.0Hz,1H),6.66 -6.56(m,1H),6.40(d,J=16.7Hz,1H),5.83(d,J=10.6Hz,1H),5.10-5.00(m,1H),4.47-4.45(m,1H),4.22-4.19(m,1H),4.06-4.04 (m,1H),4.03(s,2H),3.76(s,2H),3.65-3.35(m,2H),3.24-3.04(m,5H),3.00-2.68(m,10H),2.35-2.15(m,4H),2.10-1.98(m,4H).

[0785] Example 626: Synthesis of 2-((S)-1-acryloyl-4-(7-(isochroman-8-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy))-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0786]

[0787] Step 1: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:

[0788] Compound (S)-2-(cyanomethyl)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.11 mmol) and 8-bromoisochroman (33.9 mg, 0.16 mmol) were dissolved in toluene. Under nitrogen atmosphere, Pd2(dba)3 (38.8 mg, 0.042 mmol), RuPhos (24.7 mg, 0.053 mmol) and t-BuONa (25.0 mg, 0.27 mmol) were added in sequence, and then heated to 100 ο C and stirred at this temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by PLC to obtain compound (S)-2-(cyanomethyl)-4-(7-(isochroman-8-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (22 mg, 34%). MS m / z: [M+H] +=604.3.

[0789] Step 2: Synthesis of 2-((S)-4-(7-(isochroman-8-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0790] Compound (S)-2-(cyanomethyl)-4-(7-(isochroman-8-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (22 mg, 0.036 mmol) was dissolved in CH2Cl2 (2.4 mL) and TFA (0.8 mL) was added dropwise. The reaction solution was stirred at room temperature until the reaction was complete. Then, the reaction solution was treated with 10% The pH was adjusted to 10 with aqueous NaOH solution, the layers were separated, extracted with CH2Cl2, washed with saturated brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to give 2-((S)-4-(7-(isochroman-8-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (18 mg, 100%). MS m / z: [M+H] + =504.7.

[0791] Step 3: Synthesis of 2-((S)-1-acryloyl-4-(7-(isochroman-8-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy))-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0792] Compound 2-((S)-4-(7-(isochroman-8-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (18 mg, 0.036 mmol) and triethylamine (10.8 mg, 0.11 mmol) were dissolved in CH2Cl2 (1.0 mL), and then acryloyl chloride (6.4 The reaction mixture was concentrated under pressure and purified by PLC to obtain the compound 2-((S)-1-acryloyl-4-(7-(isochroman-8-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy))-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (11.5 mg, 58%). MS m / z: [M+H] + =558.8.1 H NMR (400MHz, CDCl3) δ7.20 (t, J=7.7Hz, 1H), 6.96 (dd, J=19.1, 10.3Hz, 2H), 6. 58(m,1H),6.38(d,J=16.6Hz,1H),5.82(d,J=10.1Hz,1H),4.82(m,2H),4.73-4 .43(m,1H),4.33-4.17(m,1H),4.16-3.84(m,4H),3.36-2.97(m,7H),2.91-2.6 2(m,10H),2.35-2.10(m,3H),2.10-1.86(m,3H),1.80(dt,J=12.2,7.1Hz,4H).

[0793] Example 627: Synthesis of 2-((S)-1-acryloyl-4-(7-(isochroman-5-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0794]

[0795] Step 1: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(7-(isochroman-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0796] To a 10 mL single-necked vial was added tert-butyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (66 mg, 0.14 mmol), 5-bromoisochroman (60 mg, 0.28 mmol), tris(dibenzylideneacetone)dipalladium (38 mg, 0.042 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (26 mg, 0.056 mmol), and sodium tert-butoxide (23 mg, 0.238 mmol). After nitrogen replacement, deoxygenated anhydrous toluene (2.5 mL) was added. The reaction mixture was heated at 100°C for 16 hours. After cooling to room temperature, ethyl acetate (2 mL) and dichloromethane (2 mL) were added, and the mixture was filtered. The filter cake was rinsed with ethyl acetate / dichloromethane (4 mL, V:V = 1:1). The combined filtrates were vacuum-dried. The residue was purified by preparative TLC (silica gel, methanol:dichloromethane = 1:8) to afford a light yellow solid (37 mg, 0.062 mmol, yield: 44%). MS m / z: 604.7 [M+H] + .

[0797] Step 2: Synthesis of 2-((S)-4-(7-(isochroman-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0798] To a solution of (S)-2-(cyanomethyl)-4-(7-(isotryptamine-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (18 mg, 0.03 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) dropwise at room temperature. The resulting solution was stirred at room temperature for 1 hour. Dichloromethane (7 mL) was added and the mixture was concentrated under vacuum. Dichloromethane (5 mL) was added to the resulting residue, which was concentrated again and the process was repeated once. The resulting yellow solid was used directly in the next step.

[0799] Step 3: Synthesis of 2-((S)-1-acryloyl-4-(7-(isochroman-5-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0800] To a solution of 2-((S)-4-(7-(isotryptamine-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile and triethylamine (0.026 mL, 0.18 mmol) in dichloromethane (2 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 15 minutes. Dichloromethane (20 mL) and saturated aqueous sodium carbonate solution (20 mL) were added, the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, and rotary evaporation to obtain a viscous product. Purification by preparative TLC (methanol: dichloromethane = 11:80) gave a white solid (10 mg, total yield for two steps: 60%). MS m / z: 558.7 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.27-7.18(m,1H),6.95(d,J=8.0Hz,1H),6.79(d,J=8.0Hz,1H),6.66 -6.56(m,1H),6.40(d,J=16.7Hz,1H),5.83(d,J=10.6Hz,1H),5.20-5.02(m,2H),4.82(s,2H),4.56-4.53(m,1H),4.25-4.12 (m,1H),4.08-3.90(m,5H),3.65-3.35(m,2H),3.20-3.04(m,2H),3.00-2.68(m,10H),2.35-2.15(m,4H),2.10-1.98(m,4H).

[0801] The preparation method of Example 627 was used to prepare Examples 628-651

[0802]

[0803]

[0804]

[0805]

[0806] Example 652: 2-((S)-1-Acryloyl-4-(2-((((1R,2S)-2-(dimethylamino)cyclopentyl)oxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0807]

[0808] Step 1: Synthesis of tert-butyl 4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylsulfinyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

[0809] Tert-butyl 4-(4-(((benzyloxy)carbonyl)piperazin-1-yl)-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (538 mg, 1 mmol) was dissolved in 10 ml of dichloromethane. 85% m-chloroperbenzoic acid (m-CPBA) (244 mg, 1.2 mmol) was added in an ice-water bath. The reaction system was stirred in an ice-water bath for 30 min. After completion of the reaction, saturated sodium thiosulfate solution was added to quench the reaction. The mixture was extracted with dichloromethane, and the organic phase was washed sequentially with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford an off-white solid (550 mg, 100% yield). This solid was used in the next reaction without further treatment.

[0810] Step 2: Synthesis of tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-(((((1R,2S)-2-(dimethylamino)cyclopentyl)oxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

[0811] Dissolve tert-butyl 4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylsulfinyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate and (1S,2S)-2-(dimethylamino)cyclopentan-1-ol (550 mg, 1 mmol) in 10 ml of dry toluene. Add sodium tert-butoxide () in portions under an ice-water bath. Stirring is continued for one hour. After completion of the reaction, quench with cold water and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to afford an off-white solid (150 mg, yield: 35%).

[0812] Step 3: Synthesis of benzyl (S)-2-(cyanomethyl)-4-(2-((((1R,2S)-2-(dimethylamino)cyclopentyl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0813] Dissolve tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-(((((1R,2S)-2-(dimethylamino)cyclopentyl)oxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (150 mg, 0.3 mmol) in a co-solvent of TFA and DCM (DCM / TFA: 3 ml / 1 ml) and stir at room temperature for one hour. After completion of the reaction, condense the reaction solution and extract the resulting residue with saturated aqueous sodium bicarbonate and dichloromethane. Separate the layers, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product, which is used directly in the next step (130 mg, yield: 95%).

[0814] Step 4: Synthesis of benzyl(S)-2-(cyanomethyl)-4-(2-((((1R,2S)-2-(dimethylamino)cyclopentyl)oxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid

[0815] Benzyl (S)-2-(cyanomethyl)-4-(2-((((1R,2S)-2-(dimethylamino)cyclopentyl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (52 mg, 0.1 mmol) and 5-bromo-1,2,3,4-tetrahydronaphthalene (27 mg, 0.12 mmol) were dissolved in anhydrous toluene (5 mL). Cesium carbonate (81 mg, 0.25 mmol), RuPhos (8.3 mg, 0.02 mmol), and Pd2(dba)3 (9.1 mg, 0.01 mmol) were added. The atmosphere was purged with nitrogen three times and the mixture was heated to 100°C with stirring for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, filtered, and the filtrate concentrated. The resulting mixture was separated by column chromatography to afford an off-white solid (65 mg, yield: 49.4%).

[0816] Step 5: Synthesis of 2-((S)-4-(2-(((((1R,2S)-2-(dimethylamino)cyclopentyl)oxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0817] Benzyl (S)-2-(cyanomethyl)-4-(2-((((1R,2S)-2-(dimethylamino)cyclopentyl)oxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid (52 mg, 0.10 mmol) was dissolved in 5 ml of anhydrous methanol. Approximately 0.5 ml of a 7 M / L ammonia methanol solution and 10% Pd / C were added. After completion of the reaction, the reaction system was filtered through celite to afford an off-white solid (25 mg, 80% yield). The solid was used directly in the next step without any further treatment.

[0818] Step 6: Synthesis of 2-((S)-1-acryloyl-4-(2-((((1R,2S)-2-(dimethylamino)cyclopentyl)oxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0819] The compound 2-((S)-4-(2-(((((1R,2S)-2-(dimethylamino)cyclopentyl)oxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (25 mg, 0.10 mmol) was dissolved in dichloromethane (3 mL). DIEA (80 mg, 0.60 mmol) was added under ice-water cooling, followed by acryloyl chloride (18 mg, 0.13 mmol). The mixture was stirred under ice-water cooling for 10 minutes. After completion, the reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by PLC (dichloromethane / methanol = 15 / 1) to obtain an off-white solid (8.8 mg, yield: 45%). 1 HNMR(400MHz, CDCl3)δ7.27(m,1H),7.21(m,1H),7.02(m,1H),6.62(m,1H),6.04(m,1H),5.58(m,1H),3.65-3.40(m,3H),3 .38-3.13(m,4H),3.02-2.98(m,2H),2.85(m,1H),2.75-2.70(m,5H),2.50-2.30(m,3H),2.26(s,3H),1.74-1.41(m,8H).MS m / z:570.35[M+H] +

[0820] Example 653: Synthesis of (S)-2-(1-acryloyl-4-(2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0821]

[0822] Step 1: Synthesis of 2-methyl 1-(tert-butyl)-2-(3-chloropropyl)pyrrolidine-1,2-dicarboxylate:

[0823] Dissolve 1-(tert-butyl)-2-methyl pyrrolidine-1,2-dicarboxylate (5.8 g, 25.3 mmol) in tetrahydrofuran (25 mL), cool to -78°C, and add LiHMDS (1 M / L, 37.9 mmol) dropwise. After 30 minutes, add 1-bromo-3-chloropropane (19.9 g, 126 mmol). Allow to react at room temperature for 2 hours. Quench the reaction with saturated aqueous ammonium chloride, extract with ethyl acetate, concentrate, and purify by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain a clear oil (5.1 g, yield: 65.9%). 1 H NMR (400MHz, CDCl3) δ3.83-3.28 (m, 7H), 2.39-1.68 (m, 8H), 1.43 (d, J = 13.1Hz, 9H).

[0824] Step 2: Synthesis of methyl 2-(3-chloropropyl)pyrrolidine-2-carboxylate:

[0825] 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, and the mixture was reacted at room temperature for 1 hour. The mixture was concentrated to dryness and used directly in the next reaction.

[0826] Step 3: Synthesis of tetrahydro-1H-pyrrolizine 7a(5H)-carboxylic acid methyl ester:

[0827] Dissolve methyl 2-(3-chloropropyl)pyrrolidine-2-carboxylate (670 mg, 3.27 mmol) in methanol (10 mL), add potassium carbonate (1.35 g, 9.81 mmol) and potassium iodide (670 mg, 0.327 mmol), and react at room temperature for 2 hours. Filter the solid, concentrate the filtrate, and purify by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain a clear oil (400 mg, yield: 72.5%). 1H NMR (400MHz, CDCl3) δ3.72 (s, 3H), 3.21-3.11 (m, 2H), 2.64 (d, J = 10.2Hz, 2H), 2.38-2.24 (m, 2H), 1.86-1.76 (m, 4H), 1.72-1.66 (m, 2H).

[0828] Step 4: Synthesis of (tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol:

[0829] Methyl tetrahydro-1H-pyrrolizine 7a(5H)-carboxylate (400 mg, 2.37 mmol) was dissolved in tetrahydrofuran (10 mL). Lithium aluminum tetrahydride (270 mg, 7.10 mmol) was added portionwise under ice-cooling. After 1 hour, the reaction was complete as determined by TLC (petroleum ether / ethyl acetate = 10 / 1). Sodium sulfate decahydrate was added, the solid was filtered, and the filtrate was concentrated to obtain a clear oil (290 mg, yield: 87%). 1 HNMR (400MHz, MeOD) δ3.36-3.28 (m, 2H), 2.96 (dt, J = 10.4, 6.1Hz, 2H), 2.64 (ddd, J = 10. 5,7.3,6.0Hz,2H),1.97-1.81(m,4H),1.73(dt,J=12.6,6.8Hz,2H),1.64-1.52(m,2H).

[0830] Step 5: Synthesis of (S)-benzyl 4-(4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate:

[0831] Benzyl 4-((S)-4-(tert-Butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylsulfinyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (100 mg, 0.18 mmol) and tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (38 mg, 0.27 mmol) were dissolved in toluene (10 mL). Sodium tert-butoxide (34.6 mg, 0.36 mmol) was added under ice-cooling. The mixture was allowed to react for 1 hour, extracted with dichloromethane, and concentrated, then purified by column chromatography (dichloromethane / methanol = 10 / 1) to afford a light yellow oil (100 mg, yield: 88.5%). MS m / z: 632.6 [M+H] + .

[0832] Step 6: Synthesis of (S)-tert-butyl 2-(cyanomethyl)-4-(2-(((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:

[0833] Benzyl (S)-4-(4-(tert-Butyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (100 mg, 0.16 mmol) was dissolved in methanol (10 mL). Palladium on carbon (10%, 100 mg) was added and the mixture was reacted under a hydrogen balloon for 6 hours. The mixture was filtered and the filtrate was concentrated to obtain a transparent solid (70 mg, yield: 89.7%). MS m / z: 498.5 [M+H] + .

[0834] Step 7: Synthesis of (S)-tert-butyl 2-(cyanomethyl)-4-(2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:

[0835] Tert-butyl (S)-2-(cyanomethyl)-4-(2-(((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (74 mg, 0.15 mmol) was dissolved in toluene (5 mL), and 5-bromo-1,2,3,4-tetrahydronaphthalene (41 mg, 0.19 mmol) and Pd were added. 2(dba)3 (13.6 mg, 0.015 mmol), RuPhos (13.8 mg, 0.030 mmol), cesium carbonate (121 mg, 0.37 mmol), nitrogen atmosphere, heated to 100°C, reacted overnight, TLC monitoring reaction completion, solvent concentration, preparative plate purification (dichloromethane / methanol = 10 / 1) to give an off-white solid (20 mg, yield: 19.3%). MS m / z: 628.7 [M+H] + .

[0836] Step 8: Synthesis of (S)-2-(4-(2-(((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7]-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0837] Tert-butyl (S)-2-(cyanomethyl)-4-(2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (20 mg, 0.032 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The mixture was reacted at room temperature for 1 hour, concentrated to dryness, and aqueous sodium bicarbonate was added. The mixture was extracted with dichloromethane and concentrated to obtain a light yellow solid, which was used directly in the next reaction.

[0838] Step 9: Synthesis of (S)-2-(1-acryloyl-4-(2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0839] (S)-2-(4-(2-(((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7]-(5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (16.8 mg, 0.032 mmol) was dissolved in dichloromethane (5 mL), and DIPEA (8.8 mg, 0.068 mmol) was added. Acryloyl chloride (3 mg, 0.033 mmol) was then added under ice-cooling. The reaction was complete after ten minutes. Aqueous sodium bicarbonate was added, and the mixture was extracted with dichloromethane. The mixture was concentrated and purified on a preparative plate (dichloromethane / methanol = 10 / 1) to give a white solid (6 mg, yield: 32.4%). 1 H NMR (400MHz, CDCl3) δ7.09 (q, J=4.4, 3.9Hz, 2H), 6.77-6.56 (m, 2H), 6.18 (dd, J=13.7, 10.1Hz, 1H), 5.67 (d d,J=16.8,13.8Hz,1H),5.30(dd,J=17.2,2.7Hz,1H),4.93-4.78(m,1H),4.36-4.23(m,2H),4.02(td,J=12. 1,2.3Hz,1H),3.92(s,2H),3.89-3.62(m,3H),3.38-3.07(m,6H),3.01(dtd,J=9.6,7.0,4.4Hz,2H),2.97-2 .72(m,4H),2.53-2.25(m,3H),2.19-1.88(m,4H),1.88-1.58(m,6H),1.55-1.32(m,2H); MSm / z:582.3[M+H] + .

[0840] Examples 654-673 were prepared using the preparation method of Example 653.

[0841]

[0842]

[0843]

[0844] Example 674: Synthesis of 2-((S(-1-acryloyl-4-(7-(3-methyl-2,3-dihydro-1H-indan-4-yl)-2-((((S)-1-methylpyrrolidin-2-(yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0845]

[0846] Step 1: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(7-(3-methyl-2,3-dihydro-1H-indan-4-yl)-2-((((S)-1-methylpyrrolidinone-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:

[0847] Compound (S)-2-(cyanomethyl)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (83.8 mg, 0.18 mmol) and 7-bromo-1-methyl-2,3-dihydro-1H-indene (40 mg, 0.21 mmol) were dissolved in toluene (2.5 mL). Under a nitrogen atmosphere, Pd2(dba)3 (65.1 mg, 0.071 mmol), RuPhos (41.4 mg, 0.089 mmol) and t-BuONa (42.7 mg, 0.27 mmol) were added in sequence, and then heated to 100 ο C and stirred at this temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by PLC to obtain compound (S)-2-(cyanomethyl)-4-(7-(3-methyl-2,3-dihydro-1H-indan-4-yl)-2-((((S)-1-methylpyrrolidinone-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (48.1 mg, 45%). MS m / z: [M+H] + =602.4.

[0848] Step 2: Synthesis of 2-((S)-4-(7-(3-methyl-2,3-dihydro-1H-indan-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0849] Compound (S)-2-(cyanomethyl)-4-(7-(3-methyl-2,3-dihydro-1H-indan-4-yl)-2-((((S)-1-methylpyrrolidinone-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (48 mg, 0.080 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 completed. Then, the reaction solution was treated with 10% The pH was adjusted to 10 with aqueous NaOH solution, the layers were separated, extracted with CH2Cl2, washed with saturated brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to give 2-((S)-4-(7-(3-methyl-2,3-dihydro-1H-indan-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (38.5 mg, 96%). MS m / z: [M+H] + =502.3.

[0850] Step 3: Synthesis of 2-((S(-1-acryloyl-4-(7-(3-methyl-2,3-dihydro-1H-indan-4-yl)-2-((((S)-1-methylpyrrolidin-2-(yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0851] Compound 2-((S)-4-(7-(3-methyl-2,3-dihydro-1H-indan-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (38 mg, 0.076 mmol) and triethylamine (23 mg, 0.23 mmol) were dissolved in CH2Cl2 (1.0 mL), and then acryloyl chloride (13.7 The reaction mixture was concentrated under pressure and purified by PLC to give the compound 2-((S(-1-acryloyl-4-(7-(3-methyl-2,3-dihydro-1H-indan-4-yl)-2-((((S)-1-methylpyrrolidin-2-(yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (11.3 mg, 27%). MS m / z: [M+H] + =556.3. 1 H NMR (400MHz, CDCl3) δ7.20-7.09(m,1H),7.02-6.91(m,1H),6.88-6.81(m,1H),6.35(d,J=16.5Hz,1H),6.20-6.09(m,1H),5.78(d,J=10.1Hz,1H), 4.62-4.43(m,2H),4.41-3.84(m,4H),3.78-2.91(m,8H),2.90-2.44(m,1 0H),2.42-2.05(m,3H),2.07-1.84(m,4H),1.82(dt,J=12.1,7.0Hz,4H).

[0852] Example 675: Synthesis of 2-((S)-1-acryloyl-4-(7-(2,2-dimethyl-2,3-dihydro-1H-inden-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0853]

[0854] Step 1: Synthesis of 4-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one

[0855] In an ice-water bath, a solution of 4-bromo-2,3-dihydro-1H-inden-1-one (844 mg, 4.0 mmol) in tetrahydrofuran (5 mL) was added dropwise to a suspension of sodium hydroxide (368 mg, 9.2 mmol) in tetrahydrofuran (10 mL). The resulting brown suspension was slowly warmed to room temperature and stirred for 45 minutes. Iodomethane (1.0 mL, 16 mmol) was added dropwise. The resulting dark brown solution was stirred at room temperature for 1.5 hours. Water (2 mL) was slowly added to quench the reaction. Methyl tert-butyl ether (50 mL) and water (30 mL) were added. After shaking and separating the layers, the aqueous phase was extracted with methyl tert-butyl ether (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to obtain a brown oil (970 mg, crude product) which was used directly in the next reaction.

[0856] Step 2: Synthesis of 4-bromo-2,2-dimethyl-2,3-dihydro-1H-indene

[0857] At room temperature, boron trifluoride etherate (1.88 mL, 15 mmol) was slowly added to a solution of 4-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (359 mg, crude product) in dichloromethane (15 mL). Triethylsilane (1.9 mL, 12 mmol) was added dropwise to the resulting bright yellow solution. The reaction mixture was stirred at room temperature for 16 hours. After cooling in an ice-water bath, water (20 mL) was slowly added and stirred for 20 minutes. After separation, the aqueous phase was extracted with dichloromethane (20 mL). The organic phases were combined, washed with saturated sodium bicarbonate aqueous solution (10 mL), washed with saturated brine (10 mL), dried over sodium sulfate, and concentrated in vacuo (water bath temperature 38-45°C) to obtain a light yellow oil (152 mg, total yield over two steps: 46%).

[0858] Step 3: Synthesis of benzyl (S)-2-(cyanomethyl)-4-(7-(2,2-dimethyl-2,3-dihydro-1H-inden-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0859] To a 10 mL single-necked vial were added benzyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (51 mg, 0.1 mmol), 4-bromo-2,2-dimethyl-2,3-dihydro-1H-indene (30 mg, 0.13 mmol), tris(dibenzylideneacetone)dipalladium (27 mg, 0.03 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (19 mg, 0.04 mmol), and sodium tert-butoxide (16 mg, 0.17 mmol). After nitrogen replacement, deoxygenated anhydrous toluene (1.0 mL) was added. The reaction mixture was heated at 100°C for 16 hours. After cooling to room temperature, ethyl acetate (2 mL) and dichloromethane (2 mL) were added, and the mixture was filtered. The filter cake was rinsed with ethyl acetate / dichloromethane (4 mL, V:V = 1:1). The combined filtrates were vacuum-dried. The residue was purified by preparative TLC (silica gel, methanol:dichloromethane = 1:8) to afford a light yellow solid (16 mg, 0.0246 mmol, yield: 25%). MS m / z: 604.7 [M+H] + .

[0860] Step 4: Synthesis of 2-((S)-4-(7-(2,2-dimethyl-2,3-dihydro-1H-inden-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0861] To a solution of (S)-2-(cyanomethyl)-4-(7-(2,2-dimethyl-2,3-dihydro-1H-inden-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester (15 mg, 0.023 mmol) in methanol (1.5 mL) was added a methanolic ammonia solution (7 M, 1.5 mL) and wet palladium on carbon (33 mg, 5%). After replacing the hydrogen atmosphere with a hydrogen balloon, the mixture was stirred at room temperature for 4 hours. The solid was filtered off and rinsed with methanol (5 mL). The combined organic phases were dried by vortexing. The residue was mixed with dichloromethane (10 mL) and dried by vortexing. The residue was mixed with ethyl acetate (10 mL) and dried by vortexing to give an off-white powder. The powder was used directly in the next reaction.

[0862] Step 5: Synthesis of 2-((S)-1-acryloyl-4-(7-(2,2-dimethyl-2,3-dihydro-1H-inden-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0863] Acryloyl chloride (0.01 mL) was added dropwise to a solution of 2-((S)-4-(7-(2,2-dimethyl-2,3-dihydro-1H-inden-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile and triethylamine (0.040 mL, 0.28 mmol) in dichloromethane (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes. Dichloromethane (20 mL) and saturated aqueous sodium carbonate solution (20 mL) were added, the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, and rotary evaporated to obtain a viscous product. Purification by preparative TLC (methanol: dichloromethane = 1:8) gave a light yellow solid (7 mg, 0.123 mmol, total yield for two steps: 53%). MS m / z: 570.7 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.15-7.11(m,1H),6.90(d,J=8.0Hz,1H),6.76(d,J=8.0Hz,1H),6.66 -6.56(m,1H),6.40(d,J=16.7Hz,1H),5.83(d,J=10.6Hz,1H),5.20-5.02(m,2H),4.56-4.53(m,1H),4.26-3.78(m ,6H),3.65-3.49(m,2H),3.32-2.80(m,6H),2.78-2.58(m,6H),2.35-2.15(m,4H),2.10-1.98(m,4H),1.16(s,6H).

[0864] Example 676: Synthesis of 2-((2S)-1-acryloyl-4-(7-(2-methyl-2,3-dihydro-1H-inden-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0865]

[0866] Step 1: Synthesis of 4-bromo-2-methyl-2,3-dihydro-1H-inden-1-one

[0867] A solution of lithium bis(trimethylsilyl)amide (1M, 6 mL) in tetrahydrofuran (10 mL) was cooled to -70°C. A solution of 4-bromo-2,3-dihydro-1H-inden-1-one (1.27 g, 6 mmol) in tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was stirred at this temperature for 30 minutes. Iodomethane (0.37 mL, 6 mmol) was added. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction was quenched by the slow addition of saturated aqueous ammonium chloride (15 mL). Methyl tert-butyl ether (50 mL) and water (15 mL) were added. After shaking and separating the layers, the aqueous phase was extracted with methyl tert-butyl ether (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to obtain a brown oil. Purification by column chromatography (silica gel, ethyl acetate:petroleum ether = 1:40) afforded a colorless oil (125 mg, yield: 9.3%).

[0868] Step 2: Synthesis of 4-bromo-2-methyl-2,3-dihydro-1H-indene

[0869] At room temperature, boron trifluoride etherate (0.35 mL, 2.75 mmol) was slowly added to a solution of 4-bromo-2-methyl-2,3-dihydro-1H-inden-1-one (62 mg, 0.275 mmol) in dichloromethane (3 mL). Triethylsilane (0.35 mL, 2.18 mmol) was added dropwise to the resulting bright yellow solution. The reaction mixture was stirred at room temperature for 16 hours. After cooling in an ice-water bath, water (20 mL) and dichloromethane (17 mL) were slowly added and stirred for 20 minutes. After separation, the aqueous phase was extracted with dichloromethane (20 mL). The organic phases were combined, washed with saturated sodium bicarbonate aqueous solution (10 mL), washed with saturated brine (10 mL), dried over sodium sulfate, concentrated in vacuo, and treated under high vacuum to obtain a colorless oil. (47 mg, 0.223 mmol, yield: 81%)

[0870] Step 3: Synthesis of benzyl (2S)-2-(cyanomethyl)-4-(7-(2-methyl-2,3-dihydro-1H-inden-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0871] To a 10 mL single-necked vial were added benzyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (60 mg, 0.119 mmol), 4-bromo-2-methyl-2,3-dihydro-1H-indene (47 mg, 0.223 mmol), tris(dibenzylideneacetone)dipalladium (33 mg, 0.036 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (28 mg, 0.06 mmol), and sodium tert-butoxide (19 mg, 0.2 mmol). After nitrogen replacement, deoxygenated anhydrous toluene (1.5 mL) was added. The reaction mixture was heated at 100°C for 16 hours. After cooling to room temperature, ethyl acetate (2 mL) and dichloromethane (2 mL) were added, and the mixture was filtered. The filter cake was rinsed with ethyl acetate / dichloromethane (4 mL, V:V = 1:1). The combined filtrates were vacuum-dried. The residue was purified by preparative TLC (silica gel, methanol:dichloromethane = 1:8) to afford a light yellow solid (13 mg, 0.0204 mmol, yield: 17%). MS m / z: 604.7 [M+H] + .

[0872] Step 4: Synthesis of 2-((2S)-4-(7-(2-methyl-2,3-dihydro-1H-inden-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0873] To a solution of benzyl (2S)-2-(cyanomethyl)-4-(7-(2-methyl-2,3-dihydro-1H-inden-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (13 mg, 0.0204 mmol) in methanol (1.5 mL) were added ammonia in methanol (7 M, 1.5 mL) and wet palladium on carbon (33 mg, 5%). The hydrogen atmosphere was replaced with a hydrogen balloon and stirred at room temperature for 4 hours. The solid was filtered off and rinsed with methanol (5 mL). The combined organic phases were dried by vortexing. The residue was mixed with dichloromethane (10 mL) and dried by vortexing. The resulting residue was mixed with ethyl acetate (10 mL) and dried by vortexing to give an off-white powder. The powder was used directly in the next reaction.

[0874] Step 5: Synthesis of 2-((2S)-1-acryloyl-4-(7-(2-methyl-2,3-dihydro-1H-inden-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0875] To a solution of 2-((S)-4-(7-(5-methyl-5,6,7,8-tetrahydropyridino[3,2-d]pyrimidin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile and triethylamine (0.04 mL, 0.28 mmol) in dichloromethane (2 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 15 minutes. Dichloromethane (20 mL) and saturated aqueous sodium carbonate solution (20 mL) were added, the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, and rotary evaporation to obtain a viscous product. Purification by preparative TLC (methanol: dichloromethane = 1:5) gave a white solid (7 mg, 0.0126 mmol, total yield for two steps: 63%). MS m / z: 556.7 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.15-7.11(m,1H),6.93(d,J=8.0Hz,1H),6.77(d,J=8.0Hz,1H),6.66 -6.56(m,1H),6.40(d,J=16.7Hz,1H),5.83(d,J=10.6Hz,1H),5.10-4.80(m,2H),4.46-4.40(m,1H),4.26-3.88(m,6H),3.6 5-3.49(m,2H),3.32-2.78(m,4H),2.76-2.54(m,6H),2.52-2.49(m,3H),2.35-2.15(m,4H),2.10-1.98(m,4H),1.17(s,3H).

[0876] Examples 677-683 were prepared using the preparation method of Example 676.

[0877]

[0878]

[0879] Example 684: Synthesis of 2-((2S)-1-acryloyl-4-(7-(1-methyl-2,3-dihydro-1H-inden-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0880]

[0881]

[0882] Step 1: Synthesis of 4-bromo-1-methylene-2,3-dihydro-1H-indene

[0883] Methyltriphenylphosphonium iodide (808 mg, 2.0 mmol) was added to a solution of potassium tert-butoxide (1 M, 2 mL) in anhydrous tetrahydrofuran (5 mL) at room temperature. The resulting yellow suspension was stirred at room temperature for 40 minutes. 4-Bromo-2,3-dihydro-1H-indene-1-one (211 mg, 1.0 mmol) was added in one portion. The resulting cyan reaction solution was stirred at room temperature for 13 hours. The reaction solution was poured into water (30 mL) and methyl tert-butyl ether (30 mL). After shaking and layering, the aqueous phase was extracted with methyl tert-butyl ether (15 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over sodium sulfate, and dried under vacuum. The remaining purple-red oil was purified by column chromatography (silica gel, petroleum ether) to obtain a colorless oil. (150 mg, yield: 72%)

[0884] Step 2: Synthesis of benzyl (S)-2-(cyanomethyl)-4-(7-(1-methylene-2,3-dihydro-1H-inden-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0885] To a 10 mL single-necked vial were added benzyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (51 mg, 0.1 mmol), 4-bromo-1-methylene-2,3-dihydro-1H-indene (42 mg, 0.2 mmol), tris(dibenzylideneacetone)dipalladium (28 mg, 0.03 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (19 mg, 0.04 mmol), and sodium tert-butoxide (16 mg, 0.17 mmol). After nitrogen replacement, deoxygenated anhydrous toluene (1.5 mL) was added. The reaction mixture was heated at 100°C for 16 hours. After cooling to room temperature, ethyl acetate (2 mL) and dichloromethane (2 mL) were added, and the mixture was filtered. The filter cake was rinsed with ethyl acetate / dichloromethane (4 mL, V:V = 1:1). The combined filtrates were vacuum-dried. The residue was purified by preparative TLC (silica gel, methanol:dichloromethane = 1:8) to afford a light yellow solid (13 mg, 0.02 mmol, yield: 20%). MS m / z: 634.7 [M+H] + .

[0886] Step 3: Synthesis of 2-((2S)-4-(7-(1-methyl-2,3-dihydro-1H-inden-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0887] To a solution of (S)-2-(cyanomethyl)-4-(7-(1-methylene-2,3-dihydro-1H-inden-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester (13 mg, 0.02 mmol) in methanol (2 mL) was added a methanolic solution of ammonia (7 M, 2 mL) and wet palladium on carbon (29 mg, 5%). After replacing the hydrogen atmosphere with a hydrogen balloon, the mixture was stirred at room temperature for 3 hours. The solid was filtered off and rinsed with methanol (5 mL). The combined organic phases were dried by vortexing. The residue was mixed with dichloromethane (10 mL) and dried by vortexing. The resulting residue was mixed with ethyl acetate (10 mL) and dried by vortexing to give an off-white powder. The powder was used directly in the next reaction.

[0888] Step 4: Synthesis of 2-((2S)-1-acryloyl-4-(7-(1-methyl-2,3-dihydro-1H-inden-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0889] To a solution of 2-((2S)-4-(7-(1-methyl-2,3-dihydro-1H-inden-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile and triethylamine (0.04 mL, 0.287 mmol) in dichloromethane (2 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 15 minutes. Dichloromethane (20 mL) and saturated aqueous sodium carbonate solution (20 mL) were added, the mixture was shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, and rotary evaporation to obtain a viscous product. Purification by preparative TLC (methanol: dichloromethane = 1:8) gave a white powder (6 mg, total yield for two steps: 30%). MS m / z: 556.7 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.21-7.17(m,1H),6.93(d,J=8.0Hz,1H),6.80(d,J=8.0Hz,1H),6.66 -6.56(m,1H),6.40(d,J=16.7Hz,1H),5.83(d,J=10.6Hz,1H),5.10-5.00(m,1H),4.80-4.75(m,1H),4.46-4.40(m,1H),4.26-3.88(m ,6H),3.65-3.49(m,2H),3.32-2.78(m,4H),2.76-2.54(m,6H),2.52-2.49(m,3H),2.35-2.15(m,4H),2.10-1.98(m,4H),1.25(s,3H).

[0890] Example 685: Synthesis of 2-((2S)-1-acryloyl-4-(2-(((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4-methylthiochroman-8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0891]

[0892] Step 1: Synthesis of 8-bromo-4-methylenethiochroman

[0893] Methyltriphenylphosphonium iodide (808 mg, 2.0 mmol) was added to a solution of potassium tert-butoxide (1 M, 2 mL) in anhydrous tetrahydrofuran (5 mL) at room temperature. The resulting yellow suspension was stirred at room temperature for 30 minutes. 8-Bromo-thiochroman-4-one (243 mg, 1.0 mmol) was added in one portion. The resulting orange reaction solution was stirred at room temperature for 16 hours. The reaction solution was poured into water (30 mL) and methyl tert-butyl ether (30 mL). After shaking and layering, the aqueous phase was extracted with methyl tert-butyl ether (15 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over sodium sulfate, and dried under vacuum. The remaining purple-red oil was purified by column chromatography (silica gel, petroleum ether) to obtain a colorless oil. (31 mg, 0.129 mmol, yield: 13%)

[0894] Step 2: Synthesis of benzyl (S)-2-(cyanomethyl)-4-(7-(4-methylenethiochroman-8-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0895] To a 10 mL single-necked vial was added benzyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (66 mg, 0.13 mmol), 8-bromo-4-methylenethiochroman (42 mg, 0.174 mmol), tris(dibenzylideneacetone)dipalladium (36 mg, 0.039 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (30 mg, 0.065 mmol), and sodium tert-butoxide (21 mg, 0.221 mmol). After nitrogen replacement, deoxygenated anhydrous toluene (1.5 mL) was added. The reaction mixture was heated at 100°C for 16 hours. After cooling to room temperature, ethyl acetate (2 mL) and dichloromethane (2 mL) were added, and the mixture was filtered. The filter cake was rinsed with ethyl acetate / dichloromethane (4 mL, V:V = 1:1). The combined filtrates were vacuum-dried. The residue was purified by preparative TLC (silica gel, methanol:dichloromethane = 1:8) to afford a light yellow solid (17 mg, 0.0255 mmol, yield: 20%). MS m / z: 666.7 [M+H] + .

[0896] Step 3: Synthesis of 2-((2S)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4-methylthiochroman-8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0897] To a solution of (S)-2-(cyanomethyl)-4-(7-(4-methylenethiochroman-8-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester (17 mg, 0.0255 mmol) in methanol (2 mL) was added a methanol solution of ammonia (7 M, 2 mL) and wet palladium on carbon (29 mg, 5%). After replacing the hydrogen atmosphere with a hydrogen balloon, the mixture was stirred at room temperature for 3 hours. The solid was filtered off and rinsed with methanol (5 mL). The combined organic phases were dried by vortexing. The residue was mixed with dichloromethane (10 mL) and dried by vortexing. The resulting residue was mixed with ethyl acetate (10 mL) and dried by vortexing to give an off-white powder. The powder was used directly in the next reaction.

[0898] Step 4: Synthesis of 2-((2S)-1-acryloyl-4-(2-(((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4-methylthiochroman-8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0899] To a solution of 2-((2S)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4-methylthiochroman-8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile and triethylamine (0.04 mL, 0.287 mmol) in dichloromethane (2 mL) was added a solution of acryloyl chloride (0.01 mL, 0.122 mmol) in dichloromethane (1 mL) slowly at room temperature. The reaction mixture was stirred at room temperature for 16 hours. Dichloromethane (20 mL) and saturated aqueous sodium carbonate solution (20 mL) were added, shaken, separated, and the aqueous phase was extracted with dichloromethane (10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over sodium sulfate, and rotary evaporated to obtain a viscous product. Purification by preparative TLC (methanol:dichloromethane = 11:96) gave a light yellow powder (10 mg, 0.017 mmol, total yield for two steps: 67%). MS m / z: 588.7 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.06-7.01(m,1H),6.98-6.94(m,2H),6.66 -6.56(m,1H),6.40(d,J=16.7Hz,1H),5.83(d,J=10.6Hz,1H),5.10-5.00(m,1H),4.80-4.75(m,1H),4.46-4.40(m, 1H),4.26-3.88(m,6H),3.65-3.49(m,2H),3.32-2.98(m,4H),2.96-2.54(m,7H),2.23-1.98(m,10H),1.29(s,3H).

[0900] Example 686: Synthesis of 2-(((2S)-1-acryloyl-4-(2-((((S)-1-methylpyrrolidin-2-yl)methoxy))-7-(1a,2,3,7b-tetrahydro-1H-cyclopropane[a]naphthalen-7-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0901]

[0902] Step 1: Synthesis of 5-bromo-1,2-dihydronaphthalene:

[0903] Compound 8-bromo-1,2,3,4-tetrahydronaphthalen-1-ol (500 mg, 2.20 mmol) and triethylamine (267 mg, 2.64 mmol) were dissolved in dichloromethane (10 mL). ο C, a dichloromethane solution (6 mL) of trifluoromethanesulfonic anhydride (745 mg, 2.64 mmol) was added dropwise, and then ο C for 2h. ο At 4°C, saturated NaHCO₃ solution was added and the reaction was continued for 1 hour. Dichloromethane was added for dilution, and the layers were separated. The organic phase was washed with saturated brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain the compound 5-bromo-1,2-dihydronaphthalene (450 mg, 97%). 1 H NMR (400MHz, CDCl3) δ7.38(d,J=7.9Hz,1H),7.02(t,J=10.0Hz,1H),6.95(t,J=7.7Hz,1 H),6.84(d,J=9.8Hz,1H),6.24-6.10(m,1H),2.79(t,J=8.2Hz,2H),2.36-2.23(m,2H).

[0904] Step 2: Synthesis of 7-bromo-1a,2,3,7b-tetrahydro-1H-cyclopropane[a]naphthalene:

[0905] Dissolve 5-bromo-1,2-dihydronaphthalene (440 mg, 2.10 mmol) and diethylzinc (16.8 mL, 16.83 mmol, 1.0 M solution in toluene) in toluene (5 mL). Add diiodomethane (2.71 mL, 9.02 g, 33.67 mmol) dropwise to the solution at room temperature, then stir and react at room temperature for 24 hours. The reaction solvent is removed under pressure, and the resulting crude product is dissolved in dichloromethane (5.2 mL), followed by the addition of saturated NaHCO₃ solution (5.2 mL). ο m-CPBA (726 mg, 4.21 mmol) was added under conditions of 4% C, and the reaction was stirred at room temperature overnight. The layers were separated and extracted with dichloromethane. The organic phase was washed with saturated brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to obtain the crude product. PLC purification afforded the compound 7-bromo-1a,2,3,7b-tetrahydro-1H-cyclopropane[a]naphthalene (83.4 mg, 18%). 1 H NMR (400MHz, CDCl3) δ7.39 (d, J=7.8Hz, 1H), 7.01-6.86 (m, 2H), 2.60 (dd, J=16.0, 3.1Hz, 1H), 2...

Claims

1. A compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is in: R 1 -W is R 1 for LR 2 for and R 3 for 2. A compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is in: R 1 -W is R 1 for LR 2 for as well as R 3 for 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 for 4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 for 5. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 for 6. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 for 7. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 for 8. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein LR 2 for 9. A compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is 10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt or stereoisomer thereof.

11. Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt or stereoisomer thereof and the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating cancer mediated by KRAS G12C, HRAS G12C or NRAS G12 mutations.

12. The use according to claim 11, wherein the cancer is lung cancer, colorectal cancer or pancreatic cancer.

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