A highly active hpk1 kinase inhibitor

Abstract

A compound of formula (I) having an inhibitory effect on HPK1 kinase activity, and a pharmaceutical composition comprising said compound. Use of said compound in the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases, or immune-mediated diseases is also provided.

Description

[0001] This application claims priority to Chinese Patent Application No. 202011168944.1, entitled “A Highly Active HPK1 Kinase Inhibitor,” filed with the Chinese Patent Office on October 28, 2020, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] This invention relates to a heterocyclic compound, and more particularly to a highly active HPK1 kinase inhibitor and its uses. Background Technology

[0003] HPK1, a member of the MAP4K family, is primarily expressed in hematopoietic cells and acts as a negative intracellular regulator of T cell proliferation and signal transduction. Antigen stimulation of T cells recruits the cytoplasmic adaptor protein SLP-76 to the lipid membrane TCR complex, providing a binding site for signal transduction-related kinases (RTKs) to facilitate TCR-mediated signal transduction and induce T cell activation. During this process, HPK1 is activated by phosphorylation of tyrosine kinases Lck and Zap70, participating in the regulation of T cell receptor protein interactions. HPK1 phosphorylates the Ser376 site of the adaptor protein SLP-76, causing SLP-76 to bind to scaffold protein 14-3-3ε, which is then degraded via the proteasome. This effect reduces the binding of SLP-76 to RCKs, blocking TCR signal transduction and subsequently inhibiting T cell activation and proliferation. On the other hand, HPK1 also participates in regulating the maturation and activation of dendritic cells (DCs), particularly by inhibiting the expression of proteins related to T cell activation, such as CD80, CD86, and the MHC complex, within DCs, thereby affecting the role of DCs in regulating T cell activation. The presentation of tumor antigens by activated DCs and the collaboration between DCs and T cells are among the most important aspects of the anti-tumor immune system. Furthermore, the tumor microenvironment contains numerous immunosuppressive molecules such as PGE2 and TGF-β, and the immunosuppressive effects mediated by these factors are also closely related to HPK1. Overall, small molecule compounds that specifically target and inhibit HPK1 can exert their anti-tumor immune effects and inhibit tumor growth through multiple pathways, including primarily improving T cell function, enhancing DC cell function, and simultaneously reversing the tumor immunosuppressive microenvironment. Summary of the Invention

[0004] This invention provides a compound that inhibits HPK1 kinase activity, as well as a pharmaceutically acceptable salt, isotope derivative, or stereoisomer.

[0005]

[0006] Where R1 represents hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C1-C6)alkoxy.

[0007] Where R2 represents hydrogen, halogen, hydroxyl, (C1-C6)alkyl, (C2-C6)alkenyl, -(C0-C6 alkylene)(C1-C6)alkoxy, -(C0-C6 alkylene)(C6-C 10 aryl, -(C0-C6 alkylene)(5-10) heteroaryl, -(C0-C6 alkylene)(4-10) heterocycloalkyl, -(C0-C6 alkylene)(C3-C8) cycloalkyl, -NR L R L’ -OR L’ -SR L， R3 represents hydrogen, halogen, hydroxyl, (C1-C6)alkyl, (C2-C6)alkenyl, -(C0-C6 alkylene)(C3-C8)cycloalkyl, -(C0-C6 alkylene)(4-8-membered)heterocyclic alkyl, (C1-C6)alkoxy, -(C0-C6 alkylene)(C3-C8)cycloalkyloxy, -(C0-C6 alkylene)(4-8-membered)heterocyclic alkyloxy;

[0008] In this context, R4 and R4' each independently represent hydrogen, C1-C6 alkyl, (C2-C6) alkenyl, and halogen, respectively.

[0009] Or R4 and R 4’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may also contain 0, 1, or 2 heteroatoms selected from N, O, and S.

[0010] Wherein, R5 represents hydrogen, C1-C6 alkyl, (C3-C6) alkenyl, (C3-C8) cycloalkyl, and (4-8) heterocyclic alkyl;

[0011] Among them, R6 and R 6’ Each can independently represent hydrogen, C1-C6 alkyl, (C2-C6) alkenyl, or halogen;

[0012] Or R6 and R 6’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may also contain 0, 1, or 2 heteroatoms selected from N, O, and S.

[0013] Where X1 represents N or CH;

[0014] Where X2 represents N or CR7;

[0015] Where X3 represents N or CR8;

[0016] Wherein, R7 represents hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, and (C1-C6)alkoxy.

[0017] Wherein, R8 represents hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, -(C0-C6 alkylene)(C3-C8)cycloalkyl, -(C0-C6 alkylene)(4-10 quinary)heterocyclic alkyl, -(C0-C6 alkylene)(C6-C 10 )aryl, -(C0-C6 alkylene)(5-10) heteroaryl,

[0018] Alternatively, R8 can form a (5-10) cycloalkyl or a (5-10) heterocycloalkyl with the adjacent R3;

[0019] Among them, R L and R L’ Each can independently represent hydrogen, (C1-C6)alkyl, (C3-C6)alkenyl, (C3-C6)cycloalkyl, (C0-C6 alkylene) (C6-C6) 10 )aryl, -(C0-C6 alkylene)(5-10) heteroaryl, -(C0-C6) alkylene-(CR M R M’ -(C0-C6)alkyl, -(C0-C6)alkylene-(CR M R M’ )-halogen;

[0020] Or R L and R L’ Together with the nitrogen atom attached thereto, they form a 4-8 membered ring, which may additionally contain 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, and sulfur;

[0021] The ring can also be optionally fused to another 5-6 membered carbon ring, 5-6 cyclic heterane, 5-6 membered aromatic heterocycle or benzene ring to form a fused ring bicyclic system;

[0022] Alternatively, the ring can be linked to another (4-6 member) ring carbon ring or (4-6 member) hetero ring to form a spirocyclic bicyclic system;

[0023] The fused-ring bicyclic system or spiro-ring bicyclic system may optionally be composed of 0, 1, 2, or 3 radicals selected from halogen, cyano, (C1-C6) alkyl, (C2-C6) alkenyl, or -NR. a R a’ -OR a -SR a -(C1-C6 alkylene)hydroxyl, -C(O)R a -N(R) a )C(O)Ra -N(R) a )C(O)OR a -N(R) a SO2R a -C(O)OR a -C(O)NR a R a '、-S(O)2N R a R a '、-S(O)R a -S(O)2R a Replaced;

[0024] Where R M and R M’ Each can be used independently to represent hydrogen or C1-C6 alkyl groups;

[0025] Or, R M R M’ Together with the carbon atom attached thereto, they form a 3-8 membered ring, which may also contain 0, 1, or 2 heteroatoms selected from N, O, and S.

[0026] For the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups defined above, they may be substituted by any of the following 0, 1, 2, or 3 substituents: (C1-C6)alkyl, (C2-C6)alkenyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, -(C1-C6 alkylene)-O-(C1-C6)alkyl, (C3-C8)cycloalkyl, halo(C3-C8)cycloalkyl, halogen, -CN, oxo, -NR a R a’ -OR a -SR a -(C1-C6 alkylene)hydroxyl, -C(O)R a -N(R) a )C(O)R a -NR a C(O)OR a -NR a SO2R a -C(O)OR a -C(O)NR a R a’ -S(O)2N R a R a’ -S(O)R a -S(O)2R a -P(O)R a R a’ ;

[0027] Among them, Ra R a’ Each independently represents hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl; or when R a and R a’ Together they are attached to the N atom, and together they can form 4-7 membered cyclic alkanes with the attached N atom;

[0028] Where m and n represent 0, 1, 2, and 3, respectively.

[0029] In addition, the present invention also provides a compound or pharmaceutically acceptable salt, isotope derivative, or stereoisomer having the structure of formula (II) as follows:

[0030]

[0031] Among them, R1, R2, R3, R4, R 4’ R5, R 5’ R6, R 6’ X1, X2, and X3 are defined by equation (I).

[0032] In a preferred embodiment of the present invention, R2 represents (C1-C6)alkyl, -(C0-C6)alkylene (C6-C6)alkylene (C0 ... 10 )aryl, -(C0-C6 alkylene)(5-10) heteroaryl, -(C0-C6 alkylene)(4-10) heterocycloalkyl, -(C0-C6 alkylene)(C3-C8) cycloalkyl; wherein, the alkyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl groups may be arbitrarily replaced by 0, 1, or 2 groups selected from halogens, C1-C6 alkyl groups, -OR a -SR a -(C1-C6 alkylene)hydroxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, -(C1-C6 alkylene)-O-(C1-C6)alkyl, C3-C6 cycloalkyl, oxo, -NR a R a’ C(O)R a -N(R) a )C(O)R a -NR a C(O)OR a -NR a SO2R a -C(O)OR a -C(O)NR a Ra'、-S(O)2NR a R a '、-S(O)R a -S(O)2R a -P(O)Ra R a 'replaced'

[0033] In a preferred embodiment of the present invention, R2 represents NR. L R L’ , where R L Indicates hydrogen or C1-C6 alkyl; R L’ This indicates C1-C6 alkyl, (C3-C6)cycloalkyl, (C0-C6)alkylene (C6-C6)alkylene (C6-C6)alkylene (C3 ... 10 )aryl, -(C0-C6 alkylene)(5-10) heteroaryl, wherein, the R L and R L’ It can be independently and optionally separated by 0, 1, or 2 elements selected from halogen, hydroxyl, C1-C6 alkyl, halo(C1-C6)alkyl, OR a It is replaced by substituents of cyano groups.

[0034] In a preferred embodiment of the present invention, R2 represents NR. L R L’ , wherein, the R L R L’ Together with the nitrogen atom attached thereto, they form a 4-8 membered ring, which may additionally contain 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, and sulfur;

[0035] The ring can also be optionally fused to another 5-6 membered carbon ring, 5-6 cyclic heterane, 5-6 membered aromatic heterocycle or benzene ring to form a fused ring bicyclic system;

[0036] Alternatively, the ring can be linked to another (4-6 member) ring carbon ring or (4-6 member) hetero ring to form a spirocyclic bicyclic system;

[0037] The fused-ring bicyclic system or spiro-ring bicyclic system may optionally be composed of 0, 1, 2, or 3 elements selected from halogen, cyano, (C1-C6) alkyl, (C2-C6) alkenyl, oxo, or -NR. a R a’ -OR a -SR a -C(O)R a -N(R) a )C(O)R a -N(R) a )C(O)OR a -N(R) a SO2R a -C(O)OR a -C(O)NR a R a '、-S(O)2NR aR a '、-S(O)R a -S(O)2R a What it replaced.

[0038] In a preferred embodiment of the present invention, R2 represents NR. L R L’ , where R L Indicates hydrogen or C1-C6 alkyl; R L’ It represents -(C0-C6 alkylene)-(CR M R M’ -(C0-C6)alkyl, -(C0-C6 alkylene)-(CR M R M’ -(C0-C6)alkyl, -(C0-C6 alkylene)-(CR M R M’ )-halogen, where R M and R M’ Each can be used independently to represent hydrogen or C1-C6 alkyl groups;

[0039] Or, R M R M’ Together with the carbon atom it is attached to, they form a 3-8 membered ring, which may also contain 0, 1, or 2 heteroatoms selected from N, O, S, or oxo- or -NR. a Group.

[0040] In a preferred embodiment of the present invention, R1 represents hydrogen, C1-C6 alkyl, halogen, or OR. a NR a R a’ , cyano, -SO2R a Halogenated (C1-C6)alkyl, (C3-C6)cycloalkyl; preferably hydrogen, C1-C6 alkyl, halogen, halogenated (C1-C6) alkyl; more preferably hydrogen, C1-C6 alkyl.

[0041] In a preferred embodiment of the present invention, X2 represents CR7, and R7 represents hydrogen, halogen, hydroxyl, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, or halogenated (C1-C6)alkyl.

[0042] In addition, the present invention also provides a compound or pharmaceutically acceptable salt, isotope derivative, or stereoisomer having the structure of formula (III).

[0043]

[0044] Wherein, R1 represents hydrogen, halogen, hydroxyl, (C1-C6)alkyl, (C2-C6)alkenyl, and (C1-C6)alkoxy; wherein, R2 represents hydrogen, halogen, hydroxyl, (C1-C6)alkyl, (C2-C6)alkenyl, -(C0-C6 alkylene)(C1-C6)alkoxy, -(C0-C6 alkylene)(C6-C 10 aryl, -(C0-C6 alkylene)(5-10) heteroaryl, -(C0-C6 alkylene)(4-10) heterocycloalkyl, -(C0-C6 alkylene)(C3-C8) cycloalkyl, -NR L R L’ -OR L -SR L ;

[0045] Wherein, R3 represents hydrogen, halogen, hydroxyl, (C1-C6)alkyl, (C2-C6)alkenyl, halo(C1-C6)alkyl, -(C0-C6 alkylene)(C3-C8)cycloalkyl, -(C0-C6 alkylene)(4-8-membered)heterocyclic alkyl, (C1-C6)alkoxy, -(C0-C6 alkylene)(C3-C8)cycloalkyloxy, -(C0-C6 alkylene)(4-8-membered)heterocyclic alkyloxy;

[0046] Among them, R4 and R 4’ Each can independently represent hydrogen, C1-C6 alkyl, (C2-C6) alkenyl, or halogen;

[0047] Or R4 and R 4’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may also contain 0, 1, or 2 heteroatoms selected from N, O, and S.

[0048] Wherein, R5 represents hydrogen, C1-C6 alkyl, (C3-C6) alkenyl, (C3-C8) cycloalkyl, and (4-8) heterocyclic alkyl;

[0049] Among them, R6 and R 6’ Each can independently represent hydrogen, C1-C6 alkyl, (C2-C6) alkenyl, or halogen;

[0050] Or R6 and R 6’ Together with the carbon atom attached thereto, they form a 3-6 membered ring, which may also contain 0, 1, or 2 heteroatoms selected from N, O, and S.

[0051] Where X1 represents N or CH;

[0052] Where X2 represents N or CR7;

[0053] Wherein, R7 represents hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, and (C1-C6)alkoxy.

[0054] Wherein, R9 represents hydrogen, (C1-C6)alkyl, (C3-C6)alkenyl, -(C0-C6 alkylene)(C3-C8)cycloalkyl, -(C0-C6 alkylene)(4-10 quinary)heterocyclic alkyl, -(C0-C6 alkylene)(C6-C 10 )aryl, -(C0-C6 alkylene)(5-10) heteroaryl;

[0055] Among them, R L and R L’ Each can independently represent hydrogen, (C1-C6)alkyl, (C3-C6)alkenyl, (C3-C6)cycloalkyl, (C0-C6 alkylene) (C6-C6) 10 )aryl, -(C0-C6 alkylene)(5-10) heteroaryl, -(C0-C6) alkylene-(CR M R M’ -(C0-C6)alkyl, -(C0-C6)alkylene-(CR M R M’ )-halogen;

[0056] Or R L and R L’ Together with the nitrogen atom it is attached to, they form a 4-8 membered ring, which may additionally contain 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, sulfur, or oxo- or -NR. a Groups; and the ring may optionally be fused to another 5-6 membered carbon ring, 5-6 cyclic heterane, 5-6 membered aromatic heterocycle or benzene ring to form a fused ring bicyclic system;

[0057] Alternatively, the ring can be linked to another (4-6 member) ring carbon ring or (4-6 member) hetero ring to form a spirocyclic bicyclic system;

[0058] Where R M and R M’ Each can be used independently to represent hydrogen or C1-C6 alkyl groups;

[0059] Or, R M R M’ Together with the carbon atom it is attached to, they form a 3-8 membered ring, which may also contain 0, 1, or 2 heteroatoms selected from N, O, S, or oxo- or -NR. a Group;

[0060] For the alkyl, cyclo, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups defined above, they may be substituted by any of the following 0, 1, 2, or 3 substituents: (C1-C6)alkyl, (C2-C6)alkenyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C8)cycloalkyl, -(C1-C6 alkylene)-O-(C1-C6)alkyl, halo(C3-C8)cycloalkyl, halogen, -CN, oxo, -NR a R a’ -OR a -SR a -(C1-C6 alkylene)hydroxyl, -C(O)R a -N(R) a )C(O)R a -NR a C(O)OR a -NR a SO2R a -C(O)OR a -C(O)NR a R a’ -S(O)2N R a R a’ -S(O)R a -S(O)2R a -P(O)R a R a’ ;

[0061] Among them, R a R a’ Each can independently represent hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, or R a and R a’ It can form 4-7 membered cyclic hexaalkanes together with the N atom it is attached to;

[0062] Where m and n represent 0, 1, 2, and 3, respectively.

[0063] In addition, the present invention also provides a compound or pharmaceutically acceptable salt, isotope derivative, or stereoisomer having the structure of formula (IV).

[0064]

[0065] Among them, R1, R2, R3, R4, R 4’ R5, R 5’ R6, R 6’ R9, X1, X2, have the characteristics defined as in equation (I).

[0066] In the above preferred technical solution, R2 represents (C1-C6)alkyl, -(C0-C6 alkylene)(C6-C 10 )aryl, -(C0-C6 alkylene)(5-10) heteroaryl, -(C0-C6 alkylene)(4-10) heterocycloalkyl, -(C0-C6 alkylene)(C3-C8) cycloalkyl; wherein, the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups may be arbitrarily replaced by 0, 1, or 2 groups selected from halogens, C1-C6 alkyl groups, -OR a -SR a , Halo-(C1-C6)alkyl, Halo-(C1-C6)alkoxy, -(C1-C6 alkylene)-O-(C1-C6)alkyl, C3-C6 cycloalkyl, -NR a R a’ C(O)R a -N(R) a )C(O)R a -NR a C(O)OR a -NR a SO2R a -C(O)OR a -C(O)NR a Ra ’ -S(O)2NR a R a’ -S(O)R a -S(O)2R a -P(O)R a R a’ What it replaced.

[0067] In the above preferred technical solution, R2 represents NR L R L’ , where R L Indicates hydrogen or C1-C6 alkyl; R L’ This indicates C1-C6 alkyl, (C3-C6)cycloalkyl, (C0-C6)alkylene (C6-C6)alkylene (C6-C6)alkylene (C3 ... 10 )aryl, -(C0-C6 alkylene)(5-10) heteroaryl, wherein, the R L and R L’ It can be independently and optionally separated by 0, 1, or 2 elements selected from halogen, hydroxyl, C1-C6 alkyl, halo(C1-C6)alkyl, OR a The cyano group is replaced by a substituent, where R a It represents hydrogen and (C1-C6) alkyl.

[0068] In the above preferred technical solution, R2 represents NR L R L’, wherein, the R L R L’ Together with the nitrogen atom it is attached to, they form a 4-8 membered ring, which may additionally contain 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, sulfur, or oxo- or -NR. a Group;

[0069] The ring can also be optionally fused to another 5-6 membered carbon ring, 5-6 cyclic heterane, 5-6 membered aromatic heterocycle or benzene ring to form a fused ring bicyclic system;

[0070] Alternatively, the ring can be linked to another (4-6 member) ring carbon ring or (4-6 member) hetero ring to form a spirocyclic bicyclic system;

[0071] The ring may optionally be composed of 0, 1, 2, or 3 radicals selected from halogen, cyano, (C1-C6) alkyl, oxo, or -NR. a R a’ -OR a -SR a -C(O)R a -N(R) a )C(O)R a -N(R) a )C(O)OR a -N(R) a SO2R a -C(O)OR a -C(O)NR a R a’ -S(O)2N R a R a’ -S(O)R a -S(O)2R a Replaced, of which R a R a’ Each can be used independently to represent hydrogen or (C1-C6) alkyl groups.

[0072] In the above preferred technical solution, R2 represents -(C0-C6 alkylene)(C6-C 10 aryl, -(C0-C6 alkylene)(5-10) heteroaryl, -(C0-C6 alkylene)(4-10) heterocycloalkyl, -(C0-C6 alkylene)(C3-C8) cycloalkyl, wherein R2 can be arbitrarily selected from 0, 1, or 2 alkyl groups selected from halogen, C1-C6 alkyl, -OR a -SR a -(C1-C6 alkylene)hydroxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, -(C1-C6 alkylene)-O-(C1-C6)alkyl, C3-C6 cycloalkyl, -NRa R a’ -C(O)R a -N(R) a )C(O)R a -NR a C(O)OR a -NR a SO2R a -C(O)OR a -C(O)NR a R a’ -S(O)2NR a R a’ -S(O)R a -S(O)2R a -P(O)R a R a’ Replaced, of which R a R a’ Each can be used independently to represent hydrogen or (C1-C6) alkyl groups.

[0073] In the above preferred technical solution, R2 represents a halogenated, C1-C6 alkyl, or -OR a -C(O)OR a -C(O)NR a Ra ’ -(C1-C6 alkylene)hydroxyl, halo(C1-C6)alkoxy-substituted (C6-C 10 ) aryl, (5-10) heteroaryl, wherein R a R a’ Each can be used independently to represent hydrogen or (C1-C6) alkyl groups.

[0074] In the above preferred technical solution, R2 represents phenyl, pyridyl, pyrazolyl, or...

[0075]

[0076]

[0077] The dashed lines represent connection sites, where R2 can be arbitrarily selected from halogens, C1-C6 alkyl groups, and OR. a SR a C1-C6 alkylene hydroxyl, -(C1-C6 alkylene)-O-(C1-C6)alkyl, -C(O)R a -C(O)OR a -C(O)NR a R a’ -S(O)2NR a R a’ -S(O)Ra It is substituted by halogenated (C1-C6) alkyl groups and halogenated (C1-C6) alkoxy groups.

[0078] In the above preferred technical solution, R2 represents NR L R L’ , where R L Indicates hydrogen or C1-C6 alkyl; R L’ It represents -(C0-C6 alkylene)-(CR M R M’ -(C0-C6)alkyl, -(C0-C6 alkylene)-(CR M R M’ -(C0-C6)alkyl, -(C0-C6 alkylene)-(CR M R M’ )-halogen, where R M and R M’ Each can be used independently to represent hydrogen or C1-C6 alkyl groups;

[0079] Or, R M R M’ Together with the carbon atom it is attached to, they form a 3-8 membered ring, which may also contain 0, 1, or 2 heteroatoms selected from N, O, S, or oxo- or -NR. a Group.

[0080] In the above preferred technical solutions, R1 represents hydrogen, C1-C6 alkyl, halogen, OR a NR a R a’ , cyano, -SO2R a , halogenated (C1-C6)alkyl, (C3-C6)cycloalkyl, wherein, R a R a’ Each of the following can be independently represented as hydrogen or (C1-C6)alkyl; preferably hydrogen, C1-C6 alkyl, halogen, or halogenated (C1-C6)alkyl; more preferably hydrogen or C1-C6 alkyl.

[0081] In the above preferred technical solution, X2 represents CR7, and R7 represents hydrogen, halogen, hydroxyl, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, or halogenated (C1-C6)alkyl.

[0082] Specifically, the present invention provides compounds having the following structures:

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095] It is particularly noteworthy that, in this article, when referring to a "compound" having a specific structural formula, it generally also includes its stereoisomers, diastereomers, enantiomers, racemic mixtures, and isotopic derivatives.

[0096] As is known to those skilled in the art, the salts, solvates, and hydrates of a compound are alternative forms of the compound, and they can all be converted into the compound under certain conditions. Therefore, it is particularly noteworthy that when a compound is mentioned herein, its pharmaceutically usable salts are generally also included, and consequently its solvates and hydrates are also included.

[0097] Similarly, when referring to a compound in this article, its prodrug, metabolites, and nitrogen oxides are generally also included.

[0098] The pharmaceutically acceptable salts described in this invention can be formed using, for example, inorganic or organic acids: “Pharmaceutically acceptable salt” means a salt that, within a reasonable medical judgment, is suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and has a reasonable benefit / risk ratio. The salts can be prepared in situ during the final separation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent, as outlined below. For example, the free base function can react with a suitable acid. Furthermore, when the compounds of this invention contain an acidic moiety, suitable pharmaceutically acceptable salts may include metal salts, such as alkali metal salts (e.g., sodium or potassium salts); and alkaline earth metal salts (e.g., calcium or magnesium salts). Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed using other methods in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disaccharide, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-enolate, glyceryl phosphate, gluconate, hernisulfate, heptaate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pyrate, pectinate, persulfate, 3-phenylpropionate, phosphate, bitter salts, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically usable salts include (where appropriate) non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed by counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0099] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example by dissolving the compounds of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol, and acetonitrile), adding an excess of an aqueous solution of an organic or inorganic acid to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid, and then separating the precipitated salt.

[0100] The precursors or metabolites described in this invention can be precursors or metabolites known in the art, as long as they are metabolized and transformed in vivo to form compounds. For example, "prodrug" refers to those prodrugs of the compounds of this invention that, within a reasonable medical judgment, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and have a reasonable benefit / risk ratio and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to produce the parent compound of the above formula, for example, through in vivo metabolism, or through N-demethylation of the compounds of this invention.

[0101] The term "solvate" as used in this invention refers to the physical association of the compound of this invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0102] The "stereoisomerism" described in this invention is divided into conformational isomerism and configurational isomerism. Configurational isomerism can be further divided into cis-trans isomerism and optical isomerism. Conformational isomerism refers to the phenomenon where organic molecules with a certain configuration undergo different spatial arrangements of atoms or groups of atoms due to the rotation or twisting of carbon or carbon single bonds. Common examples include the structures of alkanes and cycloalkanes, such as the chair conformation and boat conformation in the cyclohexane structure. "Stereoisomers" refer to compounds of this invention containing one or more asymmetric centers, thus allowing them to exist as racemic mixtures and racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. The compounds of this invention have asymmetric centers, each of which produces two optical isomers. The scope of this invention includes all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds. The compounds of this invention can exist as tautomers, which have different hydrogen bonding sites through one or more double bond shifts. For example, ketones and their enol forms are ketone-enol tautomers. All tautomers and mixtures thereof are included in the compounds of this invention. All enantiomers, diastereomers, racemates, mesomates, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof of all compounds of formula (I) are included within the scope of this invention.

[0103] The "isotope derivative" of this invention refers to a molecule in which the compound is isotopically labeled. Commonly used isotopes for isotopic labeling are hydrogen isotopes. 2 H and 3 H; Carbon isotopes: 11 C, 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially deuterium. 3 H and carbon 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 Substitution with H can enhance metabolic stability and prolong the half-life, thereby reducing the dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0104] The present invention also provides the use of the compounds of the present invention in the preparation of medicaments for the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

[0105] Furthermore, the present invention provides pharmaceutical compositions for the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases, or immune-mediated diseases, comprising compounds of the present invention as active ingredients.

[0106] Furthermore, the present invention provides a method for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases, or immune-mediated diseases, comprising administering the compound of the present invention to a mammal in need of such treatment.

[0107] Representative examples of inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other inflammatory joint conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung diseases, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic inflammatory lung disease, chronic obstructive pulmonary disease (COPD), cardiovascular diseases, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjögren's syndrome, and autoimmune thyroid diseases. Diseases, urticaria (rubella), multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

[0108] Representative examples of cancers or tumors may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer, colon cancer, familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, kidney cancer, renal parenchymal carcinoma, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral thyroid cancer. Neuroectodermal tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, or plasmacytoma.

[0109] When the compounds of the present invention or their pharmaceutically acceptable salts are administered in combination with other anticancer agents or immune checkpoint inhibitors used to treat cancer or tumors, the compounds of the present invention or their pharmaceutically acceptable salts may provide enhanced anticancer effects.

[0110] Representative examples of anticancer agents used to treat cancer or tumors may include, but are not limited to, cell signal transduction inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dextrin, doxorubicin, epirubicin, doxorubicin, mitoxantrone, bleomycin, mitomycin C, and ixazolidin. Piperon, Tamoxifen, Flutamide, Gonarelin Analog, Medroxyprogesterone, Prednisone, Dexamethasone, Methylprednisolone, Thalidomide, Interferon Alpha, Calcium Leucovorin, Sirolimus, Sirolimus Lipids, Everolimus, Afatinib, Alisertib, Amuvatinib, Apatinib, Axitinib, Bortezomib, Bosutinib, Brinib, Cabozantinib, Sildenafil, Crenolanib, Crizotinib, Dabrafenib, Dacomitinib, Danusertib, Dasatinib, Dovitinib, Erlotinib, Foretinib, Ganetespib, Gefitinib, Ibrutinib, Icotinib, Icotinib, Icotinib Matinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masaitinib, momelotinib, motisanib, lenatatinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, rigosertib, rucaparib, ruxolitinib, cicatinib, saridegib, sorafenib, sunitinib, tilatinib, tivantinib Tivozani, Tofacitinib, Trametinib, Vandetanib, Veripani, Vemurafenib, Vemmodega, Volasertib, Alemumab, Bevacizumab, Belentoumab, Vidotin, Caputsuzumab, Cetuximab, Denoxin, Gemtuzumab, Ipilimumab, Nimotuzumab, Ophamumab, Panitumab, Rituximab, Tosimomab, Trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and / or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, and anti-CTLA-4 antibodies, or any combination thereof.

[0111] When the compounds of the present invention or their pharmaceutically acceptable salts are administered in combination with other therapeutic agents for treating inflammatory diseases, autoimmune diseases and immune-mediated diseases, the compounds of the present invention or their pharmaceutically acceptable salts may provide enhanced therapeutic effects.

[0112] Representative examples of therapeutic agents for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, steroidal drugs (e.g., prednisone, prednisolone hydrochloride, prednisolone methylhydrochloride, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα agents (e.g., etanercept, infliximab, adalimumab, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.), and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one of these therapeutic agents may be included in the pharmaceutical compositions of the present invention.

[0113] The compounds of the present invention, or their pharmaceutically acceptable salts, can be administered orally or parenterally as active ingredients in an effective range of 0.1 to 2,000 mg / kg body weight / day, preferably 1 to 1,000 mg / kg body weight / day, in mammals, including humans (weighing about 70 kg), and in a single or four divided dose daily, or administered with / without following a predetermined schedule. The dosage of the active ingredient can be adjusted based on several relevant factors, such as the condition of the patient, the type and severity of the disease, the rate of administration, and physician's opinion. In some cases, amounts lower than the above doses may be appropriate. Amounts higher than the above doses may be used if no harmful side effects are caused, and this amount may be administered in divided doses daily.

[0114] In addition, the present invention provides a method for preventing and / or treating tumors, cancer, viral infections, organ transplant rejection, neurodegenerative diseases, attention-related diseases, or autoimmune diseases, comprising administering the compounds of the present invention or the pharmaceutical compositions of the present invention to mammals in need of such treatment.

[0115] The pharmaceutical compositions of the present invention can be formulated into dosage forms for oral or parenteral administration (including intramuscular, intravenous, and subcutaneous routes, and intratumoral injection) according to any of the conventional methods, such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions, or suspensions.

[0116] The pharmaceutical compositions of the present invention for oral administration can be prepared by mixing the active ingredient with, for example, a carrier including cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspending agent, emulsifier, and diluent. Examples of carriers used in the injectable compositions of the present invention are water, saline solution, glucose solution, glucose-like solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, glycerol ester, surfactant, suspending agent, and emulsifier.

[0117] Other features of the invention will become apparent as the exemplary embodiments are described. The embodiments are given to illustrate the invention and are not intended to be limiting. The following examples use the methods disclosed in the invention to prepare, separate, and characterize.

[0118] The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. They can be synthesized using the methods described below, as well as synthetic methods known in the field of organic synthetic chemistry, or by variations thereof understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the kit materials used and suitable for the transformation achieved. Those skilled in the art of organic synthesis will understand that the functionalities present on the molecule are consistent with the proposed transformation. This sometimes necessitates determining whether to change the order of synthetic steps or the starting materials to obtain the desired compound of the present invention. Detailed Implementation

[0119] the term

[0120] Unless otherwise specified, the terms used in this application, including the specification and claims, are defined as follows. It must be noted that in the specification and appended claims, unless otherwise clearly indicated, the singular form "a" includes the plural meaning. Unless otherwise specified, conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used. In this application, unless otherwise specified, "or" or "and" refers to "and / or".

[0121] In the specification and claims, a given chemical formula or name shall cover all stereoisomers and optical isomers and racemates in which such isomers are present. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Many geometric isomers of C═C double bonds, C═N double bonds, ring systems, etc. may also be present in the compounds, and all such stable isomers are covered by the present invention. The present invention describes the cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, and they can be separated into mixtures of isomers or separate isomer forms. The compounds of the present invention can be separated in optically active or racemic forms. All methods for preparing the compounds of the present invention and intermediates prepared therein are considered part of the present invention. When preparing enantiomeric or diastereomeric products, they can be separated by conventional methods (such as by chromatography or fractional crystallization). Depending on the method conditions, the end products of the present invention are obtained in free (neutral) or salt form. Both the free form and salts of these end products are within the scope of the present invention. If desired, one form of the compound can be converted into another form. The free base or acid can be converted into a salt; the salt can be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention can be separated into individual isomers. The compounds of the present invention, their free forms and salts can exist in a variety of tautomeric forms, in which a hydrogen atom is transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all tautomeric forms that can exist are included in the present invention.

[0122] Unless otherwise defined, the definitions of the substituents of the present invention are each independent and not interrelated, for example for the substituent R a (or R a ’), which is independent in the definitions of different substituents. Specifically, for R a (or R a ’) when selecting a definition in one substituent, it does not mean that this R a (or R a ’) has the same definition in other substituents. More specifically, for example (only listing non-exhaustively) for NR a R a ’, when the definition of R a (or R a ’) is selected from hydrogen, it does not mean that in -C(O)-NR a R a ’, R a (or R a ’) must necessarily be hydrogen.

[0123] Unless otherwise defined, when a substituent is labeled “optionally substituted,” the substituent is selected from, for example, alkyl, cycloalkyl, aryl, heterocyclic, halogen, hydroxyl, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine group (where the two amino substituents are selected from alkyl, aryl, or arylalkyl), alkanoylamino, arylanoylamino, arylalkylamino, substituted alkanoylamino, substituted arylamino, substituted arylalkylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl Alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamide (e.g., -SO2NH2), substituted sulfonamide, nitro, cyano, carboxyl, carbamoyl (e.g., -CONH2), substituted carbamoyl (e.g., -CONHalkyl), -CONHaryl, -CONHarylalkyl, or having two substituents selected from alkyl, aryl, or arylalkyl on nitrogen, alkoxycarbonyl, aryl, substituted aryl, guanidine, heterocyclic, such as indolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazine, homopiperazine, etc., and substituted heterocyclic groups.

[0124] As used herein, the terms “alkyl” or “alkylene” are intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, “C1-C6 alkyl” means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).

[0125] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. For example, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc.

[0126] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds and typically ranging from 2 to 20 carbon atoms in length. For example, "C2-C6 alkynyl" contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, and 1-butynyl.

[0127] The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C1-C6 alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. Similarly, "alkylthio" or "thioalkoxy" indicates an alkyl group as defined above that has a specified number of carbon atoms and is linked by a sulfur bridge; for example, methyl-S- and ethyl-S-.

[0128] The term "carbonyl" refers to an organic functional group (C=O) formed by carbon and oxygen atoms linked by a double bond.

[0129] The term "aryl," alone or as part of a larger group such as "aralkyl," "aralkyloxy," or "aryloxyalkyl," refers to a monocyclic, bicyclic, or tricyclic ring system having a total of 5 to 12 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. In some embodiments of the invention, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, etc. Fused aryl groups can be attached to another group at a suitable position on a cycloalkyl ring or an aromatic ring. Example: Dashed lines drawn from a ring system indicate that the bond can be attached to any suitable ring atom.

[0130] The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group. Monocyclic cyclic alkyl groups refer to C3-C8 cyclic alkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornel. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Bicyclic cyclic alkyl groups include cycloalkyl groups with bridged rings, spiro rings, or fused rings.

[0131] The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl group. Monocyclic cyclic alkenyl groups refer to C3-C8 cyclic alkenyl groups, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norcamphenyl. Branched cyclic alkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl." Bicyclic cyclic alkenyl groups include cyclic alkenyl groups with bridged rings, spirorings, or fused rings.

[0132] "Halogen" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Halogenated alkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more halogens. Examples of halogenated alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of halogenated alkyl groups also include "fluoroalkyl" groups intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more fluorine atoms.

[0133] "Haloalkoxy" or "haloalkyloxy" means a haloalkyl group as defined above that is oxygen-bridged and has a specified number of carbon atoms. For example, "haloC1-C6 alkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" means a haloalkyl group as defined above that is sulfur-bridged and has a specified number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0134] In this disclosure, C is used when referring to certain substituent groups. x1 -C x2 The expression indicates that the number of carbon atoms in the substituent group can be x1 to x2. For example, C0-C8 indicates that the group contains 0, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C1-C8 indicates that the group contains 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C2-C8 indicates that the group contains 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C3-C8 indicates that the group contains 3, 4, 5, 6, 7, or 8 carbon atoms; C4-C8 indicates that the group contains 4, 5, 6, 7, or 8 carbon atoms; C0-C6 indicates that the group contains 0, 1, 2, 3, 4, 5, or 6 carbon atoms; C1-C6 indicates that the group contains 1, 2, 3, 4, 5, or 6 carbon atoms; C2-C6 indicates that the group contains 2, 3, 4, 5, or 6 carbon atoms; and C3-C6 indicates that the group contains 3, 4, 5, or 6 carbon atoms.

[0135] In this disclosure, when referring to cyclic groups (e.g., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), the expression "x1-x2 membered ring" is used, indicating that the number of ring atoms in the group can be x1 to x2. For example, the 3-12 membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; a 3-6 membered ring indicates that the cyclic group can be a 3, 4, 5, or 6 membered ring, and its number of ring atoms can be 3, 4, 5, or 6; a 3-8 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, or 8 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, or 8; a 3-9 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, 8, or 9 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; 8 or 9; 4-7 membered ring indicates that the cyclic group can be a 4, 5, 6, or 7 membered ring, and its number of ring atoms can be 4, 5, 6, or 7; 5-8 membered ring indicates that the cyclic group can be a 5, 6, 7, or 8 membered ring, and its number of ring atoms can be 5, 6, 7, or 8; 5-12 membered ring indicates that the cyclic group can be a 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 5, 6, 7, 8, 9, 10, 11, or 12; 6-12 membered ring indicates that the cyclic group can be a 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 6, 7, 8, 9, 10, 11, or 12. The ring atoms can be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more cyclic heteroatoms, for example heteroatoms selected from N, O and S.

[0136] In this disclosure, one or more halogens may be independently selected from fluorine, chlorine, bromine and iodine.

[0137] The term "heteroaryl" refers to a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic or bicyclic, or 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic polycyclic heterocycle that is fully unsaturated or partially unsaturated and contains a carbon atom and one, two, three, or four heteroatoms independently selected from N, O, and S; and includes any of the following polycyclic groups, wherein any heterocycle defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or, if defined, another substituent). The heterocycle may be attached to its side group at any heteroatom or carbon atom to obtain a stable structure. If the resulting compound is stable, the heterocyclic group described herein may be substituted at a carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1. When the term "heterocycle" is used, it is intended to include heteroaryl groups.Examples of aromatic heteroyl groups include, but are not limited to, acridine, aziridine, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophene, benzooxazolyl, benzooxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisooxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazole, 4aH-carbazole, carbolinyl, chromanyl, chromenyl, cenyl, decahydroquinolinyl, 2H,6H-1,5,2-diathiazinyl, dihydrofurano[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazoalkyl, imidazolinyl, imidazolyl, 1H-indazole, imidazopyridyl, indolenyl, and dihydroindolenyl. Indazinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochoryl, isoindazoleyl, isodihydroindolyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, diazanaphthyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolylalkyl, oxazolyl, oxazolopyridyl, naphthalene-intercalated diazaphenyl, hydroxyindolyl, pyrimidinyl, phenanthidyl, phenanthrololinyl, phenazinyl, phenothiazinyl, phenothiazinyl, phenothiazinyl Phthalasinyl, Piperazinyl, Piperidinyl, Piperidinoneyl, 4-Piperidinoneyl, Piperinyl, Pteridinyl, Puryl, Pyranyl, Pyrazinyl, Pyrazoloalkyl, Pyrazolinyl, Pyrazolopyridyl, Pyrazolyl, Pyridazinyl, Pyridoxazolyl, Pyridoimidazolyl, Pyridothiazolyl, Pyridinyl, Pyrimidinyl, Pyrrolylyl, Pyrrololinyl, 2-Pyrrolidoneyl, 2H-Pyrrolyl, Pyrrolyl, Quinazolinyl, Quinolinyl, 4H-Quinazinyl, Quinoxalinyl, Quinoxalinyl, Quininecycloyl, Tetrazolyl, Tetrahydrofuranyl, Tetrahydroisoquinolinyl, Tetrahydroquinolinyl, 6H-1,2,5-Thiadiazinyl, 1,2,3-Thiadiazinyl, 1,2,4-Thiadiazinyl, 1,2,5-Thiadiazinyl, 1,3,4-Thiadiazinyl Thianyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl-pyridyl, thiazolyl-thiazolyl, thiazolyl-oxazolyl, thiazolyl-imidazolyl, thiazolyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthonyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indoleyl, isoindoleyl, dihydroindoleyl, 1H-inzolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.The term "heteroaryl" may also include biaryl structures formed by an "aryl" as defined above and a monocyclic "heteroaryl", such as, but not limited to, "-phenylbipyridinyl-", "-phenylbipyrimidinyl", "-pyridylbiphenyl", "-pyridylbipyrimidinyl-", and "-pyrimidinylbiphenyl-"; wherein the present invention also includes fused-ring and spirocyclic compounds containing, for example, the heterocycles described above.

[0138] As used herein, the term "heterocyclic alkyl" refers to a monocyclic heterocyclic alkyl system or a bicyclic heterocyclic alkyl system, and also includes spirocyclic or bridged heterocyclic alkyl systems. A monocyclic heterocyclic alkyl system refers to a 3- to 8-membered cyclic alkyl system containing at least one saturated or unsaturated but non-aromatic cyclic alkyl group selected from O, N, S, and P. A bicyclic heterocyclic alkyl system refers to a heterocyclic alkyl group fused to a phenyl group, or a cycloalkyl group, or a cycloalkenyl group, or a heterocyclic alkyl group, or a heteroaryl group.

[0139] The term "bridged cycloalkyl" as used in this article refers to polycyclic compounds that share two or more carbon atoms. They can be divided into bicyclic bridged hydrocarbons and polycyclic bridged hydrocarbons. The former consists of two alicyclic rings sharing two or more carbon atoms; the latter consists of bridged hydrocarbons composed of three or more rings.

[0140] The term "spirocycloalkyl" as used in this article refers to polycyclic hydrocarbons in which a single carbon atom (called a spiro atom) is shared between monocyclic rings.

[0141] The term "bridged heterocycle" as used in this article refers to a polycyclic compound sharing two or more carbon atoms, wherein at least one of the carbon atoms is selected from O, N, or S. Bridged heterocycles can be classified into bicyclic bridged heterocycles and polycyclic bridged heterocycles.

[0142] The term “heterospirocyclic group” used in this article refers to a polycyclic hydrocarbon in which the monocyclic rings share a single carbon atom (called a spiro atom), and the ring contains at least one atom selected from O, N, or S.

[0143] As used herein, the term "substitution" means the replacement of at least one hydrogen atom with a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound. The cyclic double bond used herein refers to a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0144] In cases where nitrogen atoms (e.g., amines) are present on the compounds of the present invention, these nitrogen atoms can be converted into N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the present invention. Therefore, the nitrogen atoms shown and claimed are considered to encompass both the shown nitrogen and its N-oxides to obtain derivatives of the present invention.

[0145] When any variable appears more than once in any composition or formula of a compound, its definition for each occurrence is independent of its definition for each other occurrence. Thus, for example, if a substituent group is shown to have 0-3 R groups, the substituent group may optionally be substituted with up to three R groups, and each occurrence of R is independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are only permitted if such combinations produce a stable compound.

[0146] As used herein, the term "patient" refers to an organism treated by the method of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., rodents, apes / monkeys, horses, cattle, pigs, dogs, cats, etc.), and most preferably, humans.

[0147] As used herein, the term "effective amount" means the amount of a drug or agent (i.e., the compound of the present invention) that will elicit a biological or medical response in a tissue, system, animal, or human, as sought by, for example, a researcher or clinician. Furthermore, the term "therapeutic effective amount" means an amount that, compared to a corresponding subject who has not received the aforementioned amount, results in improved treatment, cure, prevention, or reduction of a disease, symptom, or side effect, or a slower rate of progression of a disease or symptom. Effective amounts may be administered, applied, or dosed in one or more ways and are not intended to be limited to a particular formulation or route of administration. The term also includes effective amounts within its scope that enhance normal physiological function.

[0148] The term “treatment” as used in this article includes any effect that results in improvement of a condition, disease, disorder, etc., such as reducing, decreasing, regulating, improving or eliminating, or improving its symptoms.

[0149] The term "pharmaceutical" as used herein refers to compounds, substances, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, and / or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0150] As used herein, the phrase "pharmaceutical carrier" refers to a pharmaceutical substance, composition, or medium, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate, zinc stearate, or stearic acid), or solvent encapsulation substance, relating to the carrying or delivery of a subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of compatibility with other components of the formulation and harmlessness to the patient.

[0151] The term "pharmaceutical composition" means a composition comprising the compounds of the present invention and at least one other pharmaceutical carrier. "Pharmaceutical carrier" refers to a medium commonly accepted in the art for delivering a bioactive agent to an animal (specifically a mammal), including (i) adjuvants, excipients, or mediators such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form.

[0152] Specific pharmaceutical and medical terminology

[0153] The term “acceptable,” as used herein, means that a prescription component or active ingredient does not have an excessively harmful effect on health for general therapeutic purposes.

[0154] The term "cancer," as used in this article, refers to an uncontrolled abnormal growth of cells that, under certain conditions, can metastasize (spread). This type of cancer includes, but is not limited to, solid tumors (such as those of the bladder, intestines, brain, chest, uterus, heart, kidneys, lungs, lymphoid tissue (lymphoma), ovaries, pancreas or other endocrine organs (such as the thyroid), prostate, skin (melanoma), or hematologic malignancies (such as nonleukemic leukemia).

[0155] The term “combined administration” or similar terms, as used herein, refers to the administration of several selected therapeutic agents to a patient in the same or different manners of administration at the same or different times.

[0156] The terms "enhancement" or "synergistic effect," as used herein, refer to the expected increase or prolongation of either potency or duration of effect. Therefore, in terms of enhancing the therapeutic effect of a drug, the term "synergistic effect" refers to the ability of a drug in a system to increase or prolong its potency or duration of effect. The term "synergistic value," as used herein, refers to the ability of an ideal system to maximize the enhancement of another therapeutic agent.

[0157] The term "immune disease" refers to a disease or symptom that results from an adverse or harmful reaction to endogenous or exogenous antigens. The result is often impaired cell function, or damage to cells leading to dysfunction, or damage to organs or tissues that may produce immune symptoms.

[0158] The terms "reagent kit" and "product packaging" are synonyms.

[0159] The terms "subject" or "patient" include both mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as orangutans, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, and pigs; livestock such as rabbits and dogs; and laboratory animals including rodents such as rats, mice, and guinea pigs. Non-mammals include, but are not limited to, birds and fish. In a preferred embodiment, the selected mammal is a human.

[0160] The terms “treatment,” “treatment process,” or “therapy” as used herein include alleviating, suppressing, or improving symptoms or conditions of a disease; suppressing the development of complications; improving or preventing underlying metabolic syndrome; suppressing the development of a disease or symptom, such as controlling the progression of a disease or condition; reducing a disease or symptom; reducing a disease or symptom; reducing complications arising from a disease or symptom, or preventing and / or treating signs arising from a disease or symptom.

[0161] As used herein, a compound or pharmaceutical composition, when administered, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. This may be attributable to or related to the administration, whether the administration is fixed or intermittent, continuous or discontinuous.

[0162] route of administration

[0163] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, ocular, nasal, and topical administration. Furthermore, for illustrative purposes only, parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary, ventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0164] In one respect, the compounds described herein are administered via local rather than systemic routes of administration. In specific embodiments, long-acting formulations are administered via implantation (e.g., subcutaneous or intramuscular) or via intramuscular injection. Furthermore, in another embodiment, the drug is administered via a targeted drug delivery system, such as liposomes encapsulated by organ-specific antibodies. In this embodiment, the liposomes are selectively directed to a specific organ and absorbed.

[0165] Drug composition and dosage

[0166] The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the present invention formulated with one or more pharmaceutical carriers (additives) and / or diluents, and optionally one or more of the other therapeutic agents described above. The compounds of the present invention can be administered in any suitable manner for any of the above-described uses, such as orally, in tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; sublingually; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to a nasal membrane, such as by inhalation sprays; topically, such as in the form of creams or ointments; or rectally, such as in the form of suppositories; or intratumorally. They can be administered alone, but are typically administered using a pharmaceutical carrier chosen based on the selected route of administration and standard pharmaceutical practice.

[0167] Pharmaceutical carriers are formulated based on a number of factors known to those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to whom the composition containing the active agent is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutical carriers include aqueous and non-aqueous liquid media as well as various solid and semi-solid dosage forms.

[0168] The aforementioned carriers may include a variety of different components and additives besides the active agent. These other components are included in the formulation for various reasons known to those skilled in the art, such as stabilizing agents, binders, etc. Descriptions of suitable pharmaceutical carriers and the factors involved in carrier selection can be found in several readily available sources, such as Allen LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0169] Of course, the dosage regimen of the compounds of the present invention varies depending on known factors, such as the pharmacodynamic properties of the specific pharmaceutical agent and its administration mode and route; the recipient's species, age, sex, health status, medical condition, and weight; the nature and severity of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration; the patient's renal and hepatic function; and the desired effect. According to general guidelines, when used for a specified effect, the daily oral dose of each active ingredient should be from about 0.001 mg / day to about 10-5000 mg / day, preferably from about 0.01 mg / day to about 1000 mg / day, and most preferably from about 0.1 mg / day to about 250 mg / day. During constant-rate infusion, the most preferred intravenous dose should be from about 0.01 mg / kg / min to about 10 mg / kg / min. The compounds of the present invention can be administered as a single daily dose, or as a total daily dose administered in two, three, or four separate doses daily.

[0170] The compound is typically administered in the form of a mixture with a suitable drug diluent, excipient, or carrier (collectively referred to herein as a drug carrier) appropriately selected according to the intended form of administration (e.g., oral tablets, capsules, elixirs, and syrups) and consistent with routine pharmaceutical practice.

[0171] Suitable dosage forms (pharmaceutical compositions) may contain from about 1 mg to about 2000 mg of active ingredient per dose unit. In these pharmaceutical compositions, the active ingredient will typically be present in an amount of about 0.1-95% by weight, based on the total weight of the composition.

[0172] Typical capsules for oral administration contain at least one compound of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60-mesh sieve and packaged into No. 1 gelatin capsules.

[0173] A typical injectable formulation can be prepared as follows: at least one compound of the present invention (250 mg) is aseptically placed in a vial, aseptically lyophilized, and sealed. For use, the vial contents are mixed with 2 mL of physiological saline to produce an injectable formulation.

[0174] The scope of this invention includes (alone or in combination with a drug carrier) pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of the invention as an active ingredient. Optionally, the compounds of the invention may be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agents (e.g., anticancer agents or other pharmaceutically active substances).

[0175] Regardless of the chosen route of administration, the compounds of the present invention (which may be used in a suitable hydrated form) and / or the pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms using conventional methods known to those skilled in the art.

[0176] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be altered to obtain an amount of active ingredient that is effective and non-toxic to patients in achieving the desired therapeutic response, composition, and administration mode for a particular patient.

[0177] The selected dose level will depend on a variety of factors, including the activity of the specific compound of the present invention or its ester, salt or amide; route of administration; time of administration; excretion rate of the specific compound; absorption rate and extent; duration of treatment; other drugs, compounds and / or substances used in combination with the specific compound; and medically known factors such as the age, sex, weight, condition, general health and prior medical history of the patient being treated.

[0178] Physicians or veterinarians with ordinary skills in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, to achieve the desired therapeutic effect, a physician or veterinarian may begin with a dose of the compound of the invention used in the pharmaceutical composition at a level below the required level and gradually increase the dose until the desired effect is achieved. Typically, the appropriate daily dose of the compound of the invention will be the amount of the lowest dose of the compound that effectively produces a therapeutic effect. This effective dose typically depends on the factors described above. Typically, the oral, intravenous, intraventricular, and subcutaneous doses of the compound of the invention for a patient range from about 0.01 to about 50 mg / kg body weight / day. If desired, the effective daily dose of the active compound may be administered in two, three, four, five, six, or more subdose at appropriate intervals throughout the day, optionally in unit dosage form. In some aspects of the invention, the medication is administered once daily.

[0179] Although the compounds of the present invention can be administered alone, they are preferably administered in the form of pharmaceutical formulations (compositions).

[0180] Reagent kit / product packaging

[0181] For use in treating the aforementioned indications, the kit / product packaging is also described herein. These kits may consist of a delivery system, a medicine bag, or a container box, which may be divided into multiple compartments to hold one or more containers, such as tubular bottles, test tubes, and the like, each containing a single component of the method. Suitable containers include bottles, tubular bottles, syringes, and test tubes. Containers are made of acceptable materials such as glass or plastic.

[0182] For example, the container may contain one or more of the compounds described herein, which may be present as pharmaceutical components or as mixtures with other ingredients described herein. The container may have a sterile outlet (e.g., the container may be an intravenous infusion pack or bottle, with a stopper that can be punctured by a hypodermic needle). Such a kit may come with one compound and instructions, labeling, or operating instructions for use as described herein.

[0183] A typical kit may include one or more containers, each containing one or more materials (such as reagents, concentrated stock solutions, and / or instruments) to suit commercial applications and user needs for compound use. These materials include, but are not limited to, buffer solutions, diluents, filters, needles, syringes, delivery systems, packs, containers, bottles, and / or test tubes, accompanied by a list of contents and / or instructions for use. Instructions for use are also included with the inner packaging. The complete set of instructions must be included.

[0184] Labels may be displayed on or closely associated with containers. Labels on containers refer to labels whose letters, numbers, or other features are affixed, molded, or engraved onto the container; labels may also appear inside container boxes or shipping boxes containing multiple containers, such as in product inserts. A label can indicate a specific therapeutic use of the contents. Labels may also indicate instructions for use of the contents, such as those described in the methods above.

[0185] All features described in this specification (including any claims, abstracts, and figures), and / or all steps involved in any method or process, may exist in any combination unless certain features or steps are mutually exclusive in the same combination.

[0186] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0187] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.

[0188] The units used in weight-volume percentages in this invention are well known to those skilled in the art, for example, referring to the weight of the solute in 100 ml of solution. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0189] Example

[0190] General process

[0191] When the preparation method is not specified, all raw materials and reagents used in this invention are known products that can be synthesized according to methods known in the art, or can be obtained by purchasing commercially available products. None of the commercially available reagents used require further purification. Room temperature refers to 20-30°C.

[0192] Unless otherwise specified in the reaction examples, all reactions were carried out under a nitrogen atmosphere. A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon of approximately 1L.

[0193] Hydrogenation reactions are typically carried out under vacuum, filled with hydrogen gas, and repeated three times. A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon of approximately 1L.

[0194] Microwave reaction use Initiator + Microwave Reactor.

[0195] The structure of the compounds of this invention was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) were expressed in terms of 10⁻¹⁰. -6 The measurements are given in units of (ppm). NMR determinations are performed using (Bruker Ascend) TM A Model 500 NMR spectrometer was used. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). The following abbreviations are used for NMR signal multiplicity: s = singlet, brs = broad peak, d = doublet, t = triplet, m = multiplet. Coupling constants are listed in J values ​​and measured in Hz.

[0196] LC-MS was performed using a Thermo UltiMate 3000+MSQ PLUS system. HPLC was performed using a Thermo UltiMate 3000 high-performance liquid chromatograph. Reversed-phase preparative chromatography was performed using a Thermo UltiMate 3000 reversed-phase preparative chromatograph. Rapid column chromatography was performed using an Agilent FS-9200T automated column press, and pre-packed silica gel columns were obtained from Sante. Pre-packed column. Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The thickness used for thin-layer chromatography separation and purification of products is 0.4mm to 0.5mm.

[0197] The synthesis methods of some intermediates in this invention are as follows:

[0198]

[0199] Intermediate 1 is prepared by the following steps:

[0200]

[0201] Step 1: 1-Methyl-3,5-dinitropyridin-2-one Int-1a (1.0 g, 5.02 mmol) was dissolved in methanol (50 mL), followed by the addition of ammonia-methanol solution (7 mol / L, 8.61 mL, 60.27 mmol) and 1-methylpiperidin-4-one Int-1b (625 mg, 5.52 mmol). The reaction mixture was heated to 50 °C and stirred for 5 hours. After cooling to room temperature, the mixture was allowed to stand for 48 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added to ethyl acetate (50 mL) and filtered. The filtrate was concentrated under reduced pressure to give a red solid Int-1c (1.0 g), which was used directly in the next step of the reaction. ESI-MS (m / z): 194.4 [M+H] + ; 1 HNMR (500MHz, DMSO-d6) δ9.14 (d, J = 2.5 Hz, 1H), 8.36 (d, J = 2.5 Hz, 1H), 3.64 (s, 2H), 3.02 (t, J = 6.0 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.39 (s, 3H).

[0202] Step 2: The compound Int-1c (1.0 g) obtained in the previous step was dissolved in methanol (30 mL), and 10% Pd-C (400 mg) was added. The reaction was carried out at room temperature for 6 hours under a hydrogen atmosphere. The palladium on carbon was removed by filtration, and the filtrate was concentrated to give a yellow solid Int-1 (800 mg, yield 94.70%). ESI-MS (m / z): 164.2 [M+H] + .

[0203] Intermediate 2

[0204]

[0205] Intermediate 2 is prepared by the following steps:

[0206]

[0207] Step 1: Compound Int-1 (100 mg, 0.61 mmol) was dissolved in acetic acid (3 mL), and N-bromosuccinimide (109 mg, 0.61 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution until no more bubbles were produced. The aqueous phase was extracted with methanol / dichloromethane (1 / 20, 50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound Int-2a (38 mg, 25% yield). ESI-MS (m / z): 242.3 [M+H] + ; 1 HNMR (500MHz, DMSO-d6) δ6.77(s,1H),5.25(s,2H),3.37(s,2H),2.69(t,J=6.0Hz,2H),2.60(t,J=6.0Hz,2H),2.32(s,3H).

[0208] Step 2: Compound Int-2a (37 mg, 0.15 mmol) was dissolved in methanol (1 mL), and cuprous iodide (3 mg, 0.015 mmol), 1,10-phenanthroline (3 mg, 0.03 mmol), and cesium carbonate (99 mg, 0.30 mmol) were added. The reaction mixture was purged with nitrogen and then microwaved to 100 °C with stirring for 2 hours. The reaction mixture was cooled to room temperature, concentrated, and the residue was purified by preparative thin-layer chromatography (methanol / dichloromethane / triethylamine = 1 / 10 / 0.1) to give a yellow solid Int-2 (20 mg, yield 67%). ESI-MS (m / z): 194.5 [M+H] + ; 1 HNMR (500MHz, DMSO-d6) δ6.54 (s, 1H), 4.68 (s, 2H), 3.80 (s, 3H), 3.30 (s, 2H), 2.64 (t, J = 5.6Hz, 2H), 2.59 (t, J = 5.7Hz, 2H), 2.31 (s, 3H).

[0209] Intermediate 3

[0210]

[0211] Intermediate 3 is prepared by the following steps:

[0212]

[0213] Step 1: Compound Int-2a (230 mg, 0.94 mmol) was dissolved in ethanol (2 mL), and cuprous iodide (18 mg, 0.095 mmol), 1,10-phenanthroline (34 mg, 0.18 mmol), and cesium carbonate (619 mg, 1.90 mmol) were added. The reaction mixture was purged with nitrogen and then microwaved to 100 °C with stirring for 5 hours. The reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methanol / dichloromethane / triethylamine = 1 / 50 / 0.1) to give a yellow solid Int-3 (113 mg, yield 57%). ESI-MS (m / z): 208.5 [M+H] + .

[0214] Intermediate 4

[0215]

[0216] Intermediate 4 is prepared by the following steps:

[0217]

[0218] Step 1: Compound Int-2a (200 mg, 0.82 mmol) was dissolved in isopropanol (2 mL), and cuprous iodide (15 mg, 0.082 mmol), 1,10-phenanthroline (29 mg, 0.16 mmol), and cesium carbonate (538 mg, 1.65 mmol) were added. The reaction mixture was purged with nitrogen and then microwaved to 110 °C with stirring for 5 hours. After cooling to room temperature, the reaction solution was concentrated, and the residue was separated by preparative thin-layer chromatography (methanol / dichloromethane / triethylamine = 1 / 10 / 0.1) to give yellow oil Int-4 (21 mg, yield 11%). ESI-MS (m / z): 222.5 [M+H] + .

[0219] Intermediate 5

[0220]

[0221] Intermediate 5 is prepared by the following steps:

[0222]

[0223] Step 1: Under ice bath conditions at 0°C, 20% sodium methanethiol aqueous solution (1.58 g, 4.52 mmol) was added dropwise to a DMF (10 mL) solution of 2-chloro-8-bromoquinazoline Int-5a (1.0 g, 4.11 mmol). The reaction mixture was stirred dropwise under ice bath conditions for 30 minutes, and then water (100 mL) was added. The reaction mixture was filtered, the filter cake was washed with cold water, and dried to give a yellow solid Int-5b (1.02 g, yield 97%). ESI-MS (m / z): 255.2 [M+H] + .

[0224] Step 2: Under ice bath conditions at 0°C, m-chloroperoxybenzoic acid (1.95 g, 85% purity, 9.59 mmol) was added to a dichloromethane (20 mL) suspension of compound Int-5b (1.02 g, 4.00 mmol). The reaction mixture was then stirred at room temperature for 2 hours. The reaction solution was diluted with water, and the mixture was extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 100% ethyl acetate) to give a white solid Int-5 (1.05 g, 91% yield). ESI-MS (m / z): 287.1 [M+H] + .

[0225] Intermediate 6

[0226]

[0227] Intermediate 6 is prepared by the following steps:

[0228]

[0229] Step 1: Formic acid (2.14 g, 46.57 mmol, 1.76 mL) was added dropwise to acetic anhydride (3.17 g, 31.05 mmol, 2.93 mL) under ice bath conditions at 0 °C, and then stirred at room temperature for 1 hour. The mixture was then recooled to 0 °C and added dropwise to a tetrahydrofuran (10 mL) solution (0 °C) containing Int-2 (500 mg, 2.59 mmol), and stirred at room temperature for 30 minutes. The reaction mixture was diluted with dichloromethane and washed three times with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give a white solid Int-6 (550 mg, 96% yield). ESI-MS (m / z): 222.5 [M+H] + .

[0230] Intermediate 7

[0231]

[0232] Intermediate 7 is prepared by the following steps:

[0233]

[0234] Step 1: Under 0°C ice bath conditions, sodium hydride (45 mg, 60% purity, 1.13 mmol) was added to an anhydrous DMF (5 mL) solution of Int-6 (250 mg, 1.13 mmol). The mixture was stirred at room temperature for 20 minutes, then cooled to 0°C. An anhydrous DMF (5 mL) solution of Int-5 (356 mg, 1.24 mmol) was added, and the mixture was brought to room temperature and stirred for another 2 hours. Then, 2N sodium hydroxide aqueous solution (3 mL) and methanol (3 mL) were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with 50 mL of water, filtered, the filter cake was washed with water, and dried to obtain a yellow solid Int-7 (440 mg, 97% yield). ESI-MS (m / z): 400.2 [M+H] + .

[0235] Intermediate 8

[0236]

[0237] Intermediate 8 is prepared by the following steps:

[0238]

[0239] Step 1: Compound Int-8a (300 mg, 1.42 mmol) was dissolved in dichloromethane (10 mL). m-CPBA (604 mg, 85% purity, 2.98 mmol) was added under ice bath conditions. After the addition was complete, the reaction was continued under ice bath conditions for 4 hours. LC-MS analysis confirmed complete reaction of the starting material. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain a pale yellow solid Int-8 (300 mg, 86% yield). ESI-MS (m / z): 244.3 [M+H] + .

[0240] Intermediate 9

[0241]

[0242] Intermediate 9 is prepared by the following steps:

[0243]

[0244] Step 1: Compound Int-6 (230 mg, 1.04 mmol) was dissolved in anhydrous DMF (10 mL), and NaH (42 mg, 60% purity, 1.04 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 30 minutes, then cooled to 0°C, and a DMF solution of Int-8 (244 mg, 1.14 mmol) was added dropwise (3 mL). After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours, and LCMS analysis confirmed complete reaction of the starting material. 0.1 N NaOH solution (1 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was then poured into water (40 mL), resulting in the precipitation of a yellow solid. The solid was collected by filtration and dried to obtain Int-9 (230 mg, 62% yield). ESI-MS (m / z): 357.2 [M+H] + .

[0245] Intermediate 10

[0246]

[0247] Intermediate 10 is prepared by the following steps:

[0248]

[0249] Step 1: Sodium hydride (45 mg, 60%, 1.13 mmol) was added to an anhydrous DMF (5 mL) solution of Int-6 (250 mg, 1.13 mmol) under 0°C ice bath conditions. The reaction mixture was stirred at room temperature for 20 minutes, then cooled to 0°C, and an anhydrous DMF (5 mL) solution of Int-5 (356 mg, 1.24 mmol) was added. The reaction mixture was then warmed to room temperature and stirred for another 2 hours. The reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a yellow solid Int-10 (380 mg, 78% yield). ESI-MS (m / z): 428.2 [M+H] + .

[0250] Intermediate 11

[0251]

[0252] Intermediate 11 is prepared by the following steps:

[0253]

[0254] Step 1: Compound Int-2a (100 mg, 0.41 mmol) and trimethylcycloborane (148 mg, 1.19 mmol) were dissolved in dioxane (1.5 mL) and water (0.15 mL). Potassium carbonate (171 mg, 1.24 mmol) and Pd(dppf)Cl2 (30 mg, 0.041 mmol) were added. The reaction system was purged with nitrogen and then heated to 140 °C in a microwave oven with stirring for 1 hour. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 20) to give a yellow solid Int-11 (50 mg, yield 68%). ESI-MS (m / z): 178.6 [M+H] + .

[0255] Intermediate 12

[0256]

[0257] Starting from Int-3, using reaction steps similar to those of intermediates 6 and 7, Int-12 can be obtained. ESI-MS (m / z): 414.2 [M+H] + .

[0258] Intermediate 13

[0259]

[0260] Starting from Int-11, and using reaction steps similar to those of intermediates 6 and 7, Int-13 can be obtained. ESI-MS (m / z): 384.2 [M+H] + .

[0261] Intermediate 14

[0262]

[0263] Intermediate 14 is prepared by the following steps:

[0264]

[0265] Step 1: Compound Int-14a (5 g, 25.09 mmol) and tetrahydropyrrole (2.68 g, 37.64 mmol, 3.13 mL) were dissolved in toluene (50 mL), and the mixture was heated under reflux for 18 hours using a water separator. The reaction mixture was concentrated, and the residue was dissolved in 1,4-dioxane (50 mL). Diethyl ethoxymethylene malonate (5.97 g, 27.60 mmol, 5.53 mL) was added, and the reaction mixture was heated under reflux and stirred for 6 hours. After the reaction mixture cooled to room temperature, ammonium acetate (3.29 g, 42.66 mmol) was added, and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give a yellow solid compound Int-14b (2.3 g, 28% yield). ESI-MS (m / z): 323.4 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ11.99(s,1H),7.90(s,1H),4.25(s,2H),4.19(q,J=7.1Hz,2 H), 3.54 (t, J = 5.8Hz, 2H), 2.60 (t, J = 5.9Hz, 2H), 1.42 (s, 9H), 1.25 (t, J = 7.1Hz, 3H).

[0266] Step 2: Compound Int-14b (1.1 g, 3.41 mmol) was dissolved in DMF (20 mL), and cesium carbonate (1.67 g, 5.12 mmol) and methyl iodide (484 mg, 3.41 mol) were added sequentially in an ice bath at 0 °C. The mixture was heated to room temperature and stirred for 1 hour. After the reaction was complete, the reaction was quenched with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oily liquid compound Int-14c (1.1 g, 95% yield). ESI-MS (m / z): 337.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ7.84(s,1H),4.28(s,2H),4.19(q,J=7.1Hz,2H),3.57(t,J= 5.9Hz, 2H), 3.40 (s, 3H), 2.80 (t, J = 5.9Hz, 2H), 1.41 (s, 9H), 1.24 (t, J = 7.1Hz, 3H).

[0267] Step 3: Compound Int-14c (1.1 g, 3.27 mmol) was dissolved in ethanol (10 mL), and 1 N sodium hydroxide aqueous solution (9.8 mL) was added. The mixture was stirred at room temperature for 2 hours. The pH was adjusted to 6 with 6 N hydrochloric acid aqueous solution, and then diluted with water (100 mL). The precipitate was filtered, the filter cake was washed with water, and dried to give a yellow solid compound Int-14d (830 mg, yield 82%). ESI-MS (m / z): 309.3 [M+H] + .

[0268] Step 4: Compound Int-14d (830 mg, 2.69 mmol) was dissolved in toluene (10 mL), and diphenyl azidophosphate (2.22 g, 8.08 mmol), benzyl alcohol (873 mg, 8.08 mmol), and N,N-diisopropylethylamine (1.39 mg, 10.77 mmol) were added. The reaction mixture was heated to 120 °C and stirred for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a yellow solid compound Int-14e (930 mg, yield 83%). ESI-MS (m / z): 414.3 [M+H] + ; 1 H NMR(500MHz,methanol-d4)δ7.84(s,1H),7.48-7.31(m,6H),5.21(s,2H),4.3 6(s,2H),3.71(t,J=6.3Hz,2H),3.56(s,3H),2.80-2.77(m,2H),1.50(s,9H).

[0269] Step 5: Compound Int-14e (930 mg, 2.25 mmol) was dissolved in dichloromethane (10 mL), and hydrochloric acid / dioxane solution (4 N, 2.25 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was dissolved in methanol (10 mL). Formaldehyde aqueous solution (1.09 g, 11.25 mmol, 35%) and sodium triacetoxyborohydride (1.43 g, 6.75 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, diluted with water (50 mL), and the aqueous phase was extracted with a mixed solvent of dichloromethane and methanol (v / v = 10 / 1). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid compound Int-14f (700 mg, 95% yield). ESI-MS (m / z): 328.3 [M+H] + ; 1H NMR(500MHz,DMSO-d6)δ8.29(s,1H),7.58(s,1H),7.44-7.31(m,5H),5.15(s,2H),3.4 5(s,3H),3.26-3.22(m,2H),2.73(t,J=5.7Hz,2H),2.60(t,J=5.8Hz,2H),2.31(s,3H).

[0270] Step 6: Compound Int-14f (700 mg, 2.14 mmol) was dissolved in methanol (10 mL), and 10% palladium on carbon (70 mg) was added. The mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The palladium on carbon was removed by filtration with diatomaceous earth, the filter cake was washed with methanol, and the filtrate was concentrated to give a yellow solid compound Int-14 g (380 mg, yield 92%). ESI-MS (m / z): 194.4 [M+H] + .

[0271] Step 7: Dissolve 100 mg (0.52 mmol) of compound Int-14 in 2 mL of formic acid. Stir the reaction mixture at 100 °C for 30 min. After the reaction is complete, concentrate the reaction mixture, and separate the residue by column chromatography (DCM / MeOH = 20:1) to obtain compound Int-14 (90 mg, 0.41 mmol), yield 78%, as a pale yellow solid. ESI-MS (m / z): 222.5 [M+H] + .

[0272] Intermediate 15

[0273]

[0274] Intermediate 15 is prepared by the following steps:

[0275]

[0276] Step 1: Dissolve Int-14 (82 mg, 0.37 mmol) in DMF (3 mL), and add NaH (30 mg, 0.74 mmol) under ice bath conditions. Stir the reaction mixture at 0 °C for 1 h. Then add a DMF (1 mL) solution of Int-8 (90 mg, 0.37 mmol), and stir the reaction mixture at room temperature for 1 h. After the reaction is complete, pour the reaction mixture into water (50 mL), filter, and dry to obtain compound Int-15 (85 mg, 0.24 mmol), yield 64.5%, as a pale yellow solid. ESI-MS (m / z): 357.2 [M+H] + .

[0277] Intermediate 16

[0278]

[0279] Intermediate 16 is prepared by the following steps:

[0280]

[0281] Compound Int-9 (500 mg, 1.4 mmol) was dissolved in dichloromethane (20 mL). A dichloromethane solution of BBr3 (1 M, 1.68 mL, 4.2 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the mixture was slowly brought to room temperature overnight. The reaction was monitored by LC-MS to ensure complete reaction of the starting material. The reaction solution was quenched with methanol, concentrated, and the residual solid was slurried with ethyl acetate, filtered, and dried to give 550 mg of compound Int-16 (HBr salt), a brown solid, with a yield of 92.64%. ESI-MS (m / z): 343.3 [M+H]. + .

[0282] Intermediate 17

[0283]

[0284] Intermediate 17 is prepared by the following steps:

[0285]

[0286] Step 1: Int-14e (200 mg, 0.48 mmol) was added to hydrochloric acid / dioxane (3 mL), and the reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was concentrated to obtain Int-17a (160 mg, 0.46 mmol), 94% yield, as a pale yellow solid. ESI-MS (m / z): 314.3 [M+H] + .

[0287] Step 2: Int-17a (160 mg, 0.46 mmol) was dissolved in acetonitrile (5 mL), and potassium carbonate (190 mg, 1.38 mmol) and benzyl 2-bromoethyl ether (198 mg, 0.92 mmol) were added. The reaction mixture was stirred at 70 °C for 16 h. After the reaction was complete, water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (DCM / MeOH = 30 / 1) to give compound Int-17b (160 mg, 0.36 mmol), 78% yield, as a pale yellow solid. ESI-MS (m / z): 448.2 [M+H] + .

[0288] Step 3: Compound Int-17b (160 mg, 0.36 mmol) was dissolved in a mixed solution of ethyl acetate (3 mL) and ammonia / methanol (3 mL), and palladium on carbon (32 mg, 20% wt) was added. The mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After the reaction was complete, the palladium on carbon was removed by filtration with diatomaceous earth, the filter cake was washed with methanol, and the filtrate was concentrated to give compound Int-17c (100 mg, 0.32 mmol), in 89.2% yield, as a pale yellow solid. ESI-MS (m / z): 314.3 [M+H] + .

[0289] Step 4: Compound Int-17c (100 mg, 0.32 mmol) was dissolved in formic acid (2 mL), and the reaction mixture was stirred at 100 °C for 30 min. After the reaction was complete, the reaction mixture was concentrated, and the residue was separated by column chromatography (DCM:MeOH = 20:1) to give compound Int-17d (75 mg, 0.22 mmol), yield 68.8%, as a pale yellow solid. ESI-MS (m / z): 342.3 [M+H] + .

[0290] Step 5: Dissolve Int-17d (75 mg, 0.22 mmol) in DMF (3 mL), and add NaH (44 mg, 1.10 mmol) under ice bath conditions. Stir the reaction mixture at 0 °C for 1 h. Then add a DMF (1 mL) solution of Int-8 (53.5 mg, 0.22 mmol), and stir the reaction mixture at room temperature for 1 h. After the reaction is complete, pour the reaction mixture into water (50 mL), filter, and dry to obtain compound Int-17 (85 mg, 0.18 mmol), yield 81%, as a pale yellow solid. ESI-MS (m / z): 477.1 [M+H] + .

[0291] Intermediate 18

[0292]

[0293] Intermediate 18 is prepared by the following steps:

[0294]

[0295] Step 1: Compound Int-14e (1.28 g, 3.97 mmol) was dissolved in DMF (15 mL), and bis(trimethylsilylaminolithium) (1 mol / L in THF, 4.76 mL) was added dropwise under an ice bath at 0 °C. The mixture was stirred at 0 °C for 30 min. Then, 1-iodo-2-methoxyethane (739 mg, 3.97 mmol) was added, and the mixture was heated to 50 °C and stirred for 16 h. After the reaction was complete, the reaction was quenched with water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE / EA = 1 / 2) to give compound Int-18a (600 mg, 1.58 mmol), 39.7%, as a pale yellow solid. ESI-MS (m / z): 381.6 [M+H] + .

[0296] Step 2: Compound Int-18a (850 mg, 2.23 mmol) was dissolved in ethanol (10 mL), and 1 N sodium hydroxide aqueous solution (6.7 mL) was added. The mixture was stirred at room temperature for 2 hours. The pH was adjusted to 6 with 6 N hydrochloric acid aqueous solution, and then diluted with water (60 mL). The precipitate was filtered, the filter cake was washed with water, and dried to give a yellow solid compound Int-18b (700 mg, 1.99 mmol), yield 88.9%, pale yellow solid. ESI-MS (m / z): 353.3 [M+H] + .

[0297] Step 3: Compound Int-18b (700 mg, 1.99 mmol) was dissolved in toluene (10 mL), and diphenyl azidophosphate (1.64 g, 5.96 mmol), benzyl alcohol (644 mg, 5.96 mmol), and N,N-diisopropylethylamine (1.03 g, 7.95 mmol) were added. The mixture was heated to 120 °C and stirred for 16 hours. The reaction solution was concentrated, and the residue was separated by column chromatography (PE / EA = 2 / 3) to give compound Int-18c (650 mg, 1.42 mmol), a pale yellow solid, in 71.5% yield. ESI-MS (m / z): 458.4 [M+H] + .

[0298] Step 4: Compound Int-18c (650 mg, 1.42 mmol) was dissolved in dichloromethane (5 mL), and hydrochloric acid / dioxane solution (4 mol / L, 1.42 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was dissolved in methanol (5 mL). Formaldehyde aqueous solution (415 mg, 4.26 mmol, 35% purity) and sodium triacetoxyborohydride (903 mg, 4.26 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, diluted with water (30 mL), and the aqueous phase was extracted with a mixed solvent of dichloromethane and methanol (v / v = 10 / 1). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid compound Int-18d (500 mg, 1.35 mmol), yield 94.7%, pale yellow solid. ESI-MS (m / z): 372.4 [M+H] + .

[0299] Step 5: Compound Int-18d (500 mg, 1.09 mmol) was dissolved in methanol (10 mL), and 10% palladium on carbon (50 mg, 10% wt) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The palladium on carbon was removed by filtration with diatomaceous earth, the filter cake was washed with methanol, and the filtrate was concentrated to give a yellow solid compound Int-18f (250 mg, 1.05 mmol), yield 96.4%, pale yellow solid. ESI-MS (m / z): 238.6 [M+H] + .

[0300] Step 6: Dissolve compound Int-18f (120 mg, 0.51 mmol) in formic acid (2 mL), and stir the reaction solution at 100 °C for 30 min. After the reaction is complete, concentrate the reaction solution, and separate the residue by silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound Int-18 (70 mg, 0.26 mmol), yield 52.2%, as a pale yellow solid. ESI-MS (m / z): 266.4 [M+H] + .

[0301] The synthesis method of the compounds in the embodiments of this invention is as follows:

[0302] Example 1

[0303] N-(2-Methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-phenylquinoline-2-amine

[0304]

[0305] Compound 1 was prepared by the following steps:

[0306]

[0307] Step 1: 2-Chloro-8-bromoquinazoline 1a (200 mg, 0.82 mmol) and phenylboronic acid (120 mg, 0.98 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL). Sodium carbonate (348 mg, 3.29 mmol) and Pd(dppf)Cl2 (30 mg, 0.041 mmol) were added. The reaction system was purged with nitrogen and heated to 90 °C with stirring for 18 hours. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give a yellow solid 1b (170 mg, 85% yield). ESI-MS (m / z): 241.3 [M+H] + .

[0308] Step 2: Compound 1b (18 mg, 0.077 mmol) and Int-2 (15 mg, 0.077 mmol) were dissolved in 1,4-dioxane (3 mL), and BrettPhos Pd G3 (7 mg, 7.7 μmol), BrettPhos (8 mg, 15 μmol), and cesium carbonate (50 mg, 0.15 mmol) were added. The reaction system was purged with nitrogen and heated to 100 °C with stirring for 18 hours. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by Prep-HPLC to give a white solid 1 (8 mg, 25% yield). ESI-MS (m / z): 398.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.38(s,1H),8.25(s,1H),8.14(s,1H),7.97(dd,J=8.0,1.4Hz,1H),7.83(dd,J=7.2,1.5Hz,1H), 7.68-7.63(m,2H),7.55-7.43(m,4H),3.90(s,3H),3.14(s,2H),2.72(t,J=5.9Hz,2H),2.62(t,J=5.9Hz,2H),2.37(s,3H).

[0309] Example 2

[0310] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(pyrazolo[1,5-a]pyridin-3-yl)quinazolin-2-amine

[0311]

[0312] Compound 2 was obtained by replacing the phenylboronic acid in the first step of Example 1 with pyrazolo[1,5-a]pyridine-3-boronic acid pinacol ester, using a similar method and reaction steps. ESI-MS (m / z): 437.4 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.40(s,1H),8.83(d,J=7.0Hz,1H),8.42(s,1H),8.20(s,1H),8.07(s,1H),8.00-7.91(m,2H),7.59(d,J=8.9Hz,1H),7.5 2(t,J=7.6Hz,1H),7.22-7.15(m,1H),6.98(t,J=6.7Hz,1H),3.89(s,3H) ,2.91(s,2H),2.70(t,J=5.9Hz,2H),2.59(t,J=5.8Hz,2H),2.34(s,3H).

[0313] Example 3

[0314] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(1-methyl-1H-indazol-5-yl)quinazolin

[0315] -2-amine

[0316]

[0317] By replacing the phenylboronic acid in the first step of Example 1 with 1-methylinazole-5-boronic acid, and using a similar method and reaction steps, compound 3 can be obtained. ESI-MS (m / z): 452.2 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.38(s,1H),8.13-8.09(m,3H),7.97-7.93(m,2H),7.86(dd,J=7.2,1.4Hz,1H),7.78(d,J=8.6Hz,1H),7.65(dd ,J=8.5,1.5Hz,1H),7.51(t,J=7.6Hz,1H),4.14(s,3H),3.89(s,3H),2.66(t,J=6.0Hz,2H),2.54(s,2H),2.53-2.52(m,2H),2.18(s,3H).

[0318] Example 4

[0319] 8-(2-Fluorophenyl)-N-(2-Methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)quinazolin-2-amine

[0320]

[0321] By replacing the phenylboronic acid in the first step of Example 1 with 2-fluorophenylboronic acid, and using a similar method and reaction steps, compound 4 can be obtained. ESI-MS (m / z): 416.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.40(s,1H),8.14(s,1H),8.10(s,1H),8.04(d,J=8.0Hz,1H),7.84(d,J=7.0Hz,1H),7.60- 7.50(m,3H),7.46-7.35(m,2H),3.91(s,3H),3.08(s,2H),2.71(d,J=5.9Hz,2H),2.62(t,J=5.9Hz,2H),2.39(s,3H).

[0322] Example 5

[0323] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(2-methoxyphenyl)quinazolin-2-amine

[0324]

[0325] By replacing the phenylboronic acid in the first step of Example 1 with 2-methoxyphenylboronic acid, and using a similar method and reaction steps, compound 5 can be obtained. ESI-MS (428.2): m / z [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.35(s,1H),8.11(s,1H),8.01(s,1H),7.99-7.94(m,1H),7.72(d,J=7.1Hz,1H),7.50-7.45(m,2H),7.29(dd,J=7.4,1.6Hz ,1H),7.21(d,J=8.3Hz,1H),7.11(t,J=7.4Hz,1H),3.91(s,3H),3.61(s,3 H), 3.06 (s, 2H), 2.70 (t, J = 5.9Hz, 2H), 2.60 (t, J = 5.9Hz, 2H), 2.39 (s, 3H).

[0326] Example 6

[0327] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(3-methoxyphenyl)quinazolin-2-amine

[0328]

[0329] By replacing the phenylboronic acid in the first step of Example 1 with 3-methoxyphenylboronic acid, and using a similar method and reaction steps, compound 6 can be obtained. ESI-MS (m / z): 428.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.38(s,1H),8.32(s,1H),8.14(s,1H),7.98(d,J=8.1Hz,1H),7.84(d,J=7.0Hz,1H),7.55-7.43(m,2H),7.20(s,2H),7.05(br s,1H),3.91(s,3H),3.77(s,3H),3.16(s,2H),2.74(br s,2H),2.66(brs,2H),2.39(s,3H).

[0330] Example 7

[0331] 8-(3,6-dihydro-2H-pyran-4-yl)-N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthid-3-yl)quinazolin-2-amine

[0332]

[0333] By replacing the phenylboronic acid in the first step of Example 1 with 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester, and using a similar method and reaction steps, compound 7 can be obtained. ESI-MS (m / z): 404.1 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.30(s,1H),8.33(s,1H),8.30(s,1H),7.85(dd,J=8.0,1.4Hz,1H),7.65(dd,J=7.2,1.4Hz,1H),7.37(t,J=7.6Hz,1H),6.04( s,1H),4.25(q,J=2.7Hz,2H),3.90(s,3H),3.83(t,J=5.4Hz,2H),3.50(s,2 H), 2.79 (t, J = 6.0Hz, 2H), 2.68 (t, J = 5.9Hz, 2H), 2.60 (s, 2H), 2.37 (s, 3H).

[0334] Example 8

[0335] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)quinazolino

[0336] -2-amine

[0337]

[0338] By replacing the phenylboronic acid in the first step of Example 1 with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentoboran-2-yl)-1H-pyrazole, compound 8 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 402.3 (M+H) + ; 1 HNMR(500MHz,DMSO-d6)δ9.28(s,1H),8.65(s,1H),8.28(s,1H),8.07(s,1H),8.06-8.00(m,2H),7.76(d,J=7.5Hz,1H), 7.36(t,J=7.5Hz,1H),3.87(s,3H),3.85(s,3H),3.46(s,2H),2.83(t,J=6.0Hz,2H),2.70(t,J=6.0Hz,2H),2.38(s,3H).

[0339] Example 9

[0340] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(pyridin-3-yl)quinazolin-2-amine

[0341]

[0342] By replacing the phenylboronic acid in the first step of Example 1 with pyridine-3-boronic acid, and using a similar method and reaction steps, compound 9 can be obtained. ESI-MS (m / z): 399.2 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.41(s,1H),8.88(s,1H),8.66(d,J=5.0Hz,1H),8.25(s,1H),8.16(s,1H),8.08(d,J=7.5Hz,1H),8.03(d,J=8. 0Hz,1H),7.92(d,J=7.0Hz,1H),7.58-7.52(m,2H),3.91(s,3H),3.23(s,2H),2.74(t,J=6.0Hz,2H),2.65(t,J=6.0Hz,2H),2.40(s,3H).

[0343] Example 10

[0344] 5-(2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)amino)quinazolin-8-yl)-1-methylpyridine

[0345] -2(1H)-keto

[0346]

[0347] By replacing the phenylboronic acid in the first step of Example 1 with 1-methyl-6-oxo-1,6-dihydropyridine-3-boronate pinacol ester, compound 10 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 429.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.36(s,1H),8.29(s,1H),8.26(s,1H),7.99(d,J=2.5H z,1H),7.93(dd,J=8.0,1.5Hz,1H),7.83(dd,J=7.0,1.5Hz,1H),7.80(dd,J=9.5, 2.5Hz,1H),7.46(dd,J=8.0,7.5Hz,1H),6.48(d,J=9.5Hz,1H),3.91(s,3H),3.4 8(s,3H),3.24(s,2H),2.76(t,J=6.0Hz,2H),2.64(t,J=6.0Hz,2H),2.36(s,3H).

[0348] Example 11

[0349] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(tetrahydro-2H-pyran-4-yl)quinazolin-2-

[0350] amine

[0351]

[0352] Compound 11 was prepared by the following steps:

[0353]

[0354] Step 1: Compound 7 (25 mg, 61 μmol) was dissolved in 2 mL of methanol, and 15 mg of 10% palladium on carbon was added. The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by Prep-HPLC to give compound 11 (1.83 mg, yield 7%). ESI-MS (m / z): 406.1 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.30(d,J=2.8Hz,1H),8.52(s,1H),8.24(s,1H),7.80(d,J=8.1Hz,1 H),7.73(d,J=6.7Hz,1H),7.39(t,J=7.7Hz,1H),4.05(d,J=11.3Hz,2H),3.93(s,3H),3.79(br s,1H),3.56(br s,4H),2.79(br s,2H),2.70(br s,2H),2.39(s,3H),1.80(br s,4H).

[0355] Example 12

[0356] 2-(2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)amino)quinazolin-8-yl)-N-methylbenzamide

[0357]

[0358] Compound 12 was prepared by the following steps:

[0359]

[0360] Step 1: 2-Chloro-8-bromoquinazoline 1a (100 mg, 0.41 mmol) and 2-(methoxycarbonyl)phenylboronic acid 12a (88 mg, 0.49 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL). Sodium carbonate (87 mg, 0.82 mmol) and Pd(dppf)Cl2 (15 mg, 0.020 mmol) were added. The reaction system was purged with nitrogen and heated to 90 °C with stirring for 18 hours. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a white solid 12b (55 mg, yield 44%). ESI-MS (m / z): 299.2 [M+H] + .

[0361] Step 2: Compound 12b (45 mg, 0.15 mmol) and Int-2 (29 mg, 0.15 mmol) were dissolved in 1,4-dioxane (5 mL), and BrettPhos Pd G3 (13 mg, 15 μmol), BrettPhos (8 mg, 15 μmol), and cesium carbonate (98 mg, 0.30 mmol) were added. The reaction system was purged with nitrogen and heated to 100 °C with stirring for 18 hours. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by Prep-TLC (dichloromethane / methanol = 10 / 1) to give compound 12c (15 mg, 21% yield). ESI-MS (m / z): 456.2 [M+H] + .

[0362] Step 3: Compound 12c (15 mg, 32 μmol) was dissolved in a mixed solvent of methanol (0.5 mL) and tetrahydrofuran (0.5 mL), and 0.2 mL of 1 N NaOH aqueous solution was added. The reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated to obtain compound 12d (10 mg, crude product), which was directly used in the next step of the reaction. ESI-MS (m / z): 442.2 [M+H] + .

[0363] Step 4: Compound 12d (10 mg) obtained in the previous step was dissolved in DMF (2 mL), and HATU (10 mg, 27 μmol) and DIPEA (29 mg, 226 μmol) were added. The reaction mixture was stirred at room temperature for 5 minutes, and then methylamine hydrochloride (7.6 mg, 113 μmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to give compound 12 (1 mg, 10% yield). ESI-MS (m / z): 455.2 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ9.34(s,1H),8.11(s,1H),8.06(s,1H),7.93(d,J=8.0H z,1H),7.77-7.73(m,1H),7.68(d,J=7.5Hz,1H),7.62(d,J=7.5Hz,1H),7.58(t ,J=7.5Hz,1H),7.52(t,J=7.5Hz,1H),7.49-7.42(m,2H),3.90(s,3H),3.11(s, 2H), 2.73-2.70 (m, 2H), 2.65-2.62 (m, 2H), 2.43 (d, J = 4.5Hz, 3H), 2.39 (s, 3H).

[0364] Example 13

[0365] 3-(2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)amino)quinazolin-8-yl)methyl benzoate

[0366]

[0367] By replacing the phenylboronic acid in the first step of Example 1 with 3-(methoxycarbonyl)phenylboronic acid, and using a similar method and reaction steps, compound 13 can be obtained. ESI-MS (m / z): 456.2 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ9.41(s,1H),8.24(t,J=2.0Hz,1H),8.20(s,1H),8.10(s,1H) ,8.08(dt,J=7.5,1.5Hz,1H),8.02(dd,J=8.0,1.5Hz,1H),7.92(dt,J=7.5,1.5Hz,1H ),7.88(dd,J=7.0,1.5Hz,1H),7.71(t,J=7.5Hz,1H),7.53(t,J=7.5Hz,1H),3.90(s, 3H), 3.85 (s, 3H), 2.98 (s, 2H), 2.72 (t, J = 6.0Hz, 2H), 2.66-2.60 (m, 2H), 2.35 (s, 3H).

[0368] Example 14

[0369] 3-(2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)amino)quinazolin-8-yl)-N-methylbenzamide

[0370]

[0371] By replacing reactant 12c in step 3 of Example 12 with compound 13, and using a similar method and reaction steps, compound 14 can be obtained. ESI-MS (m / z): 455.2 [M+H] + ; 1HNMR(500MHz,DMSO-d6)δ9.40(s,1H),8.52(q,J=4.5Hz,1H),8.16(s,1H),8.15(s,1H ),8.13(t,J=1.5Hz,1H),8.02-7.97(m,2H),7.87(dd,J=7.0,1.5Hz,1H),7.80(dt,J= 7.5,1.5Hz,1H),7.62(t,J=7.5Hz,1H),7.53(t,J=7.5Hz,1H),3.90(s,3H),3.01(s,2 H), 2.79 (d, J = 4.5Hz, 3H), 2.70 (t, J = 6.0Hz, 2H), 2.58 (t, J = 6.0Hz, 2H), 2.34 (s, 3H).

[0372] Example 15

[0373] 4-(2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)amino)quinazolin-8-yl)-3,6-dihydropyridine-1(2H)-formate tert-butyl ester

[0374]

[0375] By replacing the phenylboronic acid in the first step of Example 1 with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, compound 15 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 503.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.29(s,1H),8.44(s,1H),8.12(s,1H),7.85(dd,J=8.0,1 .6Hz,1H),7.64(dd,J=7.4,1.7Hz,1H),7.35(t,J=7.6Hz,1H),5.96(s,1H),4.00(br s,2H),3.89(s,3H),3.50(t,J=5.6Hz,2H),3.45(s,2H),2.80(t,J=6.1Hz,2H),2.69(t,J=6.0Hz,2H),2.58(br s,2H),2.37(s,2H),1.45(s,9H).

[0376] Example 16

[0377] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(prop-1-en-2-yl)quinazolin-2-amine

[0378]

[0379] By replacing the phenylboronic acid in the first step of Example 1 with pinacol isopropenylboronic acid, and using a similar method and reaction steps, compound 16 can be obtained. ESI-MS (m / z): 362.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.31(s,1H),8.54(s,1H),8.26(s,1H),7.87(dd,J=8.0,1.5Hz,1H),7.68(dd,J=7.2,1.5Hz,1H),7.38(t,J=7.6Hz,1H) ,5.35(t,J=1.9Hz,1H),5.20(d,J=2.2Hz,1H),3.92(s,3H),3.46(s,2H) ,2.79(t,J=6.0Hz,2H),2.68(t,J=5.9Hz,2H),2.40(s,3H),2.26(s,3H).

[0380] Example 17

[0381] 1-(4-(2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)amino)quinazolin-8-yl)-3,6-dihydropyridin-1(2H)-yl)ethane-1-one

[0382]

[0383] Compound 17 was prepared by the following steps:

[0384]

[0385] Step 1: 2-Chloro-8-bromoquinazoline 1a (220 mg, 0.90 mmol) and compound 17a (307 mg, 0.99 mmol) were dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (0.4 mL). Sodium carbonate (191 mg, 1.81 mmol) and Pd(dppf)Cl2 (66 mg, 90 μmol) were added. The reaction system was purged with nitrogen and heated to 90 °C with stirring for 16 hours. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was separated by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 17b (260 mg, yield 83%). ESI-MS (m / z): 346.3 [M+H] + .

[0386] Step 2: Compound 17b (200 mg, 0.57 mmol) was dissolved in dichloromethane (2 mL), and dioxane hydrochloride solution (4 N, 0.72 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to obtain compound 17c (160 mg, crude product), which was directly used in the next step of the reaction.

[0387] Step 3: Compound 17c (160 mg) obtained in the previous step was dissolved in tetrahydrofuran (5 mL). N,N-diisopropylethylamine (219 mg, 1.70 mmol, 0.29 mL) and acetyl chloride (67 mg, 0.85 mmol) were added sequentially at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water, and the organic phase was dried over anhydrous sodium sulfate and concentrated by filtration. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 17d (120 mg, 72% yield in two steps). ESI-MS (m / z): 288.3 [M+H] + .

[0388] Step 4: Compound 17d (44 mg, 0.15 mmol) and Int-2 (20 mg, 0.10 mmol) were dissolved in 1,4-dioxane (2 mL), and BrettPhos Pd G3 (9 mg, 10 μmol), BrettPhos (11 mg, 20 μmol), and cesium carbonate (67 mg, 0.20 mmol) were added. The reaction system was purged with nitrogen and heated to 100 °C with stirring for 16 hours. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by Prep-TLC, and the crude product was further purified by Prep-HPLC to obtain compound 17 (1.45 mg, yield 3%). ESI-MS (m / z): 445.4 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.29(d,J=1.7Hz,1H),8.40(s,0.5H),8.35(s,0.5H),8.18(s,0.5H),8.14(s,0.5H),7.9 1-7.81(m,1H),7.65(t,J=6.1Hz,1H),7.37(dd,J=7.7,3.4Hz,1H),5.96(d,J=3.4Hz,1H),4.17(brs,1H),4.09(br s,1H),3.89(s,3H),3.62(t,J=5.7Hz,1H),3.58(t,J=5.6Hz,1H),3.40( s,2H),2.84-2.74(m,2H),2.70-2.55(m,4H),2.36(s,3H),2.08(s,3H).

[0389] Example 18

[0390] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(2-trifluoromethoxy)phenyl)quinazolin-2-

[0391] amine

[0392]

[0393] By replacing the phenylboronic acid in the first step of Example 1 with 2-(trifluoromethoxy)phenylboronic acid, and using a similar method and reaction steps, compound 18 can be obtained. ESI-MS (m / z): 482.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.40(s,1H),8.11(s,1H),8.04(dd,J=8.0,1.5Hz,1H),7.99(s,1H),7.80-7.77(m,1H),7.6 8-7.63(m,1H),7.60-7.51(m,4H),3.90(s,3H),3.00(s,2H),2.70(t,J=6.0Hz,2H),2.64-2.60(m,2H),2.39(s,3H).

[0394] Example 19

[0395] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(2-(methylthio)phenyl)quinazolin-2-amine

[0396]

[0397] By replacing the phenylboronic acid in the first step of Example 1 with 2-methylthiophenylboronic acid, and using a similar method and reaction steps, compound 19 can be obtained. ESI-MS (m / z): 444.2 [M+H] + ; 1HNMR(500MHz,DMSO-d6)δ9.37(s,1H),8.08(s,1H),8.04(s,1H),8.00(dd,J=8.0,1.5Hz,1H),7.72(dd,J=7.5,1.5Hz,1H),7.53-7.47(m,3H), 7.35-7.31(m,1H),7.26(d,J=7.5Hz,1H),3.90(s,3H),3.08-2.99(m,2 H), 2.69 (t, J = 6.0Hz, 2H), 2.63-2.58 (m, 2H), 2.40 (s, 3H), 2.29 (s, 3H).

[0398] Example 20

[0399] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(2-phenoxyphenyl)quinazolin-2-amine

[0400]

[0401] By replacing the phenylboronic acid in the first step of Example 1 with 2-phenoxyphenylboronic acid, and using a similar method and reaction steps, compound 20 can be obtained. ESI-MS (m / z): 490.4 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.32(s,1H),8.22(s,1H),8.10(s,1H),7.92(d,J=8.0 Hz,1H),7.77(d,J=7.0Hz,1H),7.53-7.48(m,2H),7.42(t,J=7.5Hz,1H),7.35( t,J=7.5Hz,1H),7.11-7.05(m,3H),6.91(t,J=7.5Hz,1H),6.73(d,J=8.0Hz,2H ),3.93(s,3H),3.09(s,2H),2.77-2.72(m,2H),2.70-2.61(m,2H),2.39(s,3H).

[0402] Example 21

[0403] 8-(2-fluoro-6-methoxyphenyl)-N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)quinazolin-2-

[0404] amine

[0405]

[0406] By replacing the phenylboronic acid in the first step of Example 1 with 2-fluoro-6-methoxyphenylboronic acid, and using a similar method and reaction steps, compound 21 can be obtained. ESI-MS (m / z): 446.2 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.37(s,1H),8.06(s,1H),8.03(s,1H),8.01(d,J=8.0Hz,1H),7.75(d,J=7.0Hz,1H),7.54-7.48(m,2H),7.08(d ,J=8.0Hz,1H),7.01(t,J=8.5Hz,1H),3.91(s,3H),3.65(s,3H),3.06(s,2H),2.70(t,J=6.0Hz,2H),2.60(t,J=6.0Hz,2H),2.40(s,3H).

[0407] Example 22

[0408] 8-(2-(benzyloxy)phenyl)-N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)quinazolin-2-amine

[0409]

[0410] By replacing the phenylboronic acid in the first step of Example 1 with 2-benzyloxyphenylboronic acid, and using a similar method and reaction steps, compound 22 can be obtained. ESI-MS (m / z): 504.4 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ9.36(s,1H),8.13(s,1H),8.02(s,1H),7.96(dd,J=8.0,1.5H z,1H),7.78-7.75(m,1H),7.50-7.43(m,2H),7.34(dd,J=7.5,1.5Hz,1H),7.25(d,J= 8.0Hz,1H),7.16-7.09(m,2H),7.08-7.04(m,2H),6.98(d,J=7.5Hz,2H),4.97(s,2H) ,3.90(s,3H),2.97(s,2H),2.69(t,J=6.0Hz,2H),2.58(t,J=6.0Hz,2H),2.36(s,3H).

[0411] Example 23

[0412] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(2-methoxypyridin-3-yl)quinazolin-2-

[0413] amine

[0414]

[0415] Compound 23 was prepared by the following steps:

[0416]

[0417] Step 1: Int-7 (20 mg, 49 μmol) and 2-methoxypyridyl-3-boronic acid (9 mg, 59 μmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL). Potassium carbonate (13 mg, 99 μmol) and Pd(dppf)Cl2 (3 mg, 5 μmol) were added. The reaction system was purged with nitrogen and heated to 80 °C with stirring overnight. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by Prep-HPLC to give a yellow solid 23 (10 mg, yield 49.88%). ESI-MS (m / z): 429.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.37(s,1H),8.34-8.31(m,1H),8.08(s,1H),8.03(s,1H),8.00(d,J=8.0Hz,1H),7.80(d,J=7.0Hz,1H),7.74(dd,J=7.0,2. 0Hz,1H),7.50(t,J=7.5Hz,1H),7.21-7.16(m,1H),3.91(s,3H),3.72(s,3 H), 3.14 (s, 2H), 2.71 (t, J = 6.0Hz, 2H), 2.62 (t, J = 6.0Hz, 2H), 2.40 (s, 3H).

[0418] Example 24

[0419] 1-(2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)amino)quinazolin-8-yl)pyrrolidine-2-one

[0420]

[0421] Compound 24 was prepared by the following steps:

[0422]

[0423] Step 1: Int-7 (50 mg, 0.12 mmol) and 2-pyrrolidone (12 mg, 0.15 mmol) were dissolved in DMF (5 mL). XantPhos (14 mg, 25 μmol), Pd2(dba)3 (11 mg, 12 μmol), and potassium carbonate (34 mg, 0.25 mmol) were added. The reaction system was purged with nitrogen and heated to 100 °C overnight. Product formation was monitored by LCMS. The reaction solution was concentrated, and the residue was purified by Prep-TLC to obtain the crude product, which was then purified by Prep-HPLC to obtain compound 24 (4 mg, yield 9%). ESI-MS (m / z): 405.1 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.35(d,J=2.3Hz,1H),8.47(s,1H),8.20(s,1H),7.91(d,J=8.0Hz, 1H),7.76(d,J=7.5Hz,1H),7.42(t,J=8.1Hz,1H),3.94-3.83(m,5H),2.80(brs,2H),2.70(br s,2H),2.44-2.33(m,5H),2.16(br s,2H).

[0424] Example 25

[0425] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(2-methoxyphenyl)pyrido[3,4-d]

[0426] Pyrimidine-2-amine

[0427]

[0428] Compound 25 was prepared by the following steps:

[0429]

[0430] Step 1: Int-9 (50 mg, 0.14 mmol) and 2-methoxyphenylboronic acid (32 mg, 0.21 mmol) were dissolved in a mixed solution of THF (10 mL) and water (2 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (11 mg, 14 μmol) and sodium carbonate (29 mg, 0.28 mmol) were added. The reaction system was purged with nitrogen and heated to 60 °C with stirring overnight. Product formation was detected by LCMS. The reaction solution was concentrated, and the residue was purified by Prep-HPLC to give a yellow solid 25 (24 mg, yield 41%). ESI-MS (m / z): 429.1 [M+H] + ;1 HNMR(500MHz,DMSO-d6)δ9.49(s,1H),8.55(d,J=5.3Hz,1H),8.33(s,1H),8 .05(s,1H),7.85(d,J=5.4Hz,1H),7.58-7.50(m,1H),7.34(dd,J=7.4,1.6H z,1H),7.23(d,J=8.3Hz,1H),7.14(t,J=7.4Hz,1H),3.90(s,3H),3.59(s,3 H), 3.08 (s, 2H), 2.71 (t, J = 5.9Hz, 2H), 2.61 (t, J = 5.9Hz, 2H), 2.40 (s, 3H).

[0431] Example 26

[0432] 8-(3,6-dihydro-2H-pyran-4-yl)-N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthid-3-yl)pyrido[3,4-d]pyrimidino-2-amine

[0433]

[0434] By replacing 2-methoxyphenylboronic acid in the first step of Example 25 with 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester, compound 26 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 404.1 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.40(s,1H),8.90(s,1H),8.41(d,J=5.1Hz,1H),7.98(s,1H),7.67(d,J=5.1Hz,1H),7.21(s,1H),4.24(q,J=2.9Hz, 2H), 3.87 (s, 3H), 3.83 (t, J = 5.4Hz, 2H), 3.47 (s, 2H), 2.82 (t, J = 6.0Hz, 2H), 2.70 (t, J = 5.9Hz, 2H), 2.66 (dt, J = 8.2, 4.2Hz, 2H), 2.38 (s, 3H).

[0435] Example 27

[0436] 5-(2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)amino)pyrido[3,4-d]pyrimidino-8-

[0437] 1-Methylpyridin-2(1H)-one

[0438]

[0439] By replacing 2-methoxyphenylboronic acid in the first step of Example 25 with 1-methyl-6-oxo-1,6-dihydropyridine-3-boronic acid pinacol ester, compound 27 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 430.1 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.44(s,1H),9.08(s,1H),8.81(br s,1H),8.45(d,J=5.0Hz,1H),8.32(dd,J=9.9,2.5Hz,1H),7.89(s,1H),7.71(d,J=5.0Hz,1H),6.44(d,J=9. 5Hz, 1H), 3.85 (s, 3H), 3.38 (s, 3H), 3.36 (s, 2H), 2.82 (t, J = 6.0Hz, 2H), 2.68 (t, J = 6.0Hz, 2H), 2.36 (s, 3H).

[0440] Example 28

[0441] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-morpholinoquinazoline-2-amine

[0442]

[0443] Compound 28 was prepared by the following steps:

[0444]

[0445] Step 1: Int-7 (40 mg, 99 μmol) was dissolved in toluene (5 mL), and Pd2(dba)3 (4 mg, 4.9 μmol), BINAP (9 mg, 14.9 μmol), sodium tert-butoxide (19 mg, 199 μmol), and morpholine (13 mg, 149 μmol) were added sequentially. The reaction system was purged with nitrogen and heated to 100 °C with stirring overnight. The reaction solution was concentrated, and the residue was purified by Prep-TLC (dichloromethane / methanol = 10 / 1) to obtain the crude product, which was then purified by Prep-HPLC to obtain a yellow solid 28 (23 mg, yield 57%). ESI-MS (m / z): 407.0 [M+H] + ; 1HNMR(500MHz,DMSO-d6)δ9.25(s,1H),8.30(s,1H),8.24(s,1H),7.52(dd,J=8.0,1.5Hz,1H),7.31(t,J=7.5Hz,1H),7.24(dd,J=7.5,1.5H z,1H),3.90(s,3H),3.79(t,J=4.5Hz,4H),3.52(s,2H),3.23(t,J=4.5Hz,4H),2.81(t,J=6.0Hz,2H),2.70(t,J=6.0Hz,2H),2.39(s,3H).

[0446] Example 29

[0447] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(piperidin-1-yl)quinazolin-2-amine

[0448]

[0449] By replacing morpholine in the first step of Example 28 with piperidine, compound 29 can be obtained using a similar method and reaction steps. MS(ESI): m / z 405.2 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.23(s,1H),8.49(s,1H),8.17(s,1H),7.49(dd,J=7.5,1.5Hz,1H),7.30(t,J=7.5Hz,1H),7.25(dd,J=7.5,1.5Hz,1H), 3.92(s,3H),3.51(s,2H),3.15(t,J=5.0Hz,4H),2.80(t,J=6.0Hz,2H),2 .69(t,J=6.0Hz,2H),2.38(s,3H),1.76-1.70(m,4H),1.62-1.57(m,2H).

[0450] Example 30

[0451] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(1-methyl-1H-pyrazol-3-yl)quinazolino

[0452] -2-amine

[0453]

[0454] By replacing 2-methoxy-3-pyridineboronic acid in the first step of Example 23 with 1-methylpyrazole-3-boronic acid pinacol ester, compound 30 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 402.2 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.32(s,1H),8.38(s,1H),8.37(s,1H),8.27(dd,J=7.5,1.5Hz,1H),7.89(dd,J=7.5,1.5Hz,1H),7.78(d,J=2.0Hz,1H) ,7.43(t,J=7.5Hz,1H),7.11(d,J=2.0Hz,1H),3.95(s,3H),3.90(s,3H) ,3.43(s,2H),2.80(t,J=6.0Hz,2H),2.70(t,J=6.0Hz,2H),2.42(s,3H).

[0455] Example 31

[0456] N2-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-N8-((tetrahydro-2H-pyran-4-yl)methyl)quinazolin-2,8-diamine

[0457]

[0458] By replacing the morpholine in the first step of Example 28 with 4-aminomethyltetrahydropyran, and using a similar method and reaction steps, compound 31 can be obtained. ESI-MS (m / z): 435.0 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ9.18(s,1H),8.34(s,1H),8.21(s,1H),7.21(t,J=8.0Hz,1H),7.10 (dd,J=8.0,1.0Hz,1H),6.82(d,J=7.5Hz,1H),5.67(t,J=6.0Hz,1H),3.93(s,3H),3.92-3. 88(m,2H),3.48(s,2H),3.37-3.34(m,2H),3.14(t,J=6.0Hz,2H),2.79(t,J=6.0Hz,2H),2. 68(t,J=6.0Hz,2H),2.39(s,3H),2.01-1.92(m,1H),1.76-1.70(m,2H),1.39-1.29(m,2H).

[0459] Example 32

[0460] 2-(2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)amino)quinazolin-8-yl)isoindoline-1-

[0461] ketone

[0462]

[0463] By replacing the 2-pyrrolidone in the first step of Example 24 with isoindolin-1-one, compound 32 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 453.1 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.43(s,1H),8.34(s,1H),8.11(s,1H),8.02(dd,J= 8.1,1.4Hz,1H),7.97(dd,J=7.4,1.5Hz,1H),7.88(d,J=7.5Hz,1H),7.78-7. 70(m,2H),7.66-7.61(m,1H),7.53(t,J=7.7Hz,1H),5.08(s,2H),3.89(s,3H ),3.42-3.35(m,2H),2.65(t,J=6.0Hz,2H),2.49-2.45(m,2H),2.12(s,3H).

[0464] Example 33

[0465] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(piperidin-1-yl)pyrido[3,4-d]pyrimidine

[0466] -2-amine

[0467]

[0468] Compound 33 was prepared by the following steps:

[0469]

[0470] Step 1: Int-9 (50 mg, 140 μmol) was dissolved in N-methylpyrrolidone (5 mL), and piperidine (178 mg, 2.1 mmol) was added. The reaction mixture was heated to 120 °C and stirred for 2 hours. The reaction was confirmed to be complete by LC-MS. The reaction mixture was concentrated, and the residue was purified by Prep-HPLC to give a yellow solid 33 (31 mg, yield 55%). ESI-MS (m / z): 406.5 [M+H] + ; 1HNMR(500MHz,DMSO-d6)δ9.23(s,1H),8.59(s,1H),8.01-7.90(m,2H),7.12(d,J=5.4Hz,1H),3.87(s,3H),3.69(br s, 4H), 3.48 (s, 2H), 2.80 (t, J = 6.0Hz, 2H), 2.68 (t, J = 6.0Hz, 2H), 2.38 (s, 3H), 1.59 (br s, 6H).

[0471] Example 34

[0472] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(2-methoxypyridin-3-yl)pyridin

[0473] [3,4-d]pyrimidin-2-amine

[0474]

[0475] By replacing piperidine in the first step of Example 25 with 2-methoxypyridyl-3-boronic acid, and using a similar method and reaction steps, compound 34 can be obtained. ESI-MS (m / z): 430.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.51(d,J=1.9Hz,1H),8.57(dd,J=5.3,1.9Hz,1H),8.42(d,J=2 .0Hz,1H),8.38(dt,J=4.1,2.0Hz,1H),7.99(s,1H),7.89(dd,J=5.4,2.0Hz,1H),7.82(dt ,J=7.0,2.0Hz,1H),7.21(ddd,J=7.1,5.0,1.9Hz,1H),3.90(d,J=1.9Hz,3H),3.71(d,J= 1.9Hz, 3H), 3.16 (s, 2H), 2.71 (d, J = 6.1Hz, 2H), 2.66–2.60 (m, 2H), 2.41 (d, J = 2.0Hz, 3H).

[0476] Example 35

[0477] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-morpholinopyrido[3,4-d]pyrimidin-2-amine

[0478]

[0479] By replacing piperidine in the first step of Example 33 with morpholine, compound 35 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 408.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.27(s,1H),8.73(s,1H),7.97(d,J=5.4Hz,1H),7.85(s,1H),7.20(d,J=5.4Hz,1H),3 .86(s,3H),3.70(dt,J=8.8,4.6Hz,8H),3.48(s,2H),2.81(t,J=5.9Hz,2H),2.69(t,J=5.9Hz,2H),2.38(s,3H).

[0480] Example 36

[0481] 1-(2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyrrolidine-2-one

[0482]

[0483] By replacing Int-7 in the first step of Example 24 with Int-9, and using a similar method and reaction steps, compound 36 can be obtained. ESI-MS (m / z): 405.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.49(s,1H),8.69(s,1H),8.34(d,J=5.3Hz,1H),8.32(s,1H),7.80(d,J=5.3Hz,1H),3.96(t,J=6.9Hz,2H) ,3.91(s,3H),3.49(s,2H),2.80(t,J=6.0Hz,2H),2.69(t,J=5.9Hz,2H),2.54(t,J=8.0Hz,2H),2.39(s,3H),2.21(t,J=7.4Hz,2H).

[0484] Example 37

[0485] N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(pyridin-2-yl)quinazolin-2-amine

[0486]

[0487] Compound 37 was prepared by the following steps:

[0488]

[0489] Step 1: Dissolve Int-10 (40 mg, 93 μmol) and pinacol diboronate (28 mg, 0.11 mmol) in 1,4-dioxane (4 mL), and add potassium acetate (27 mg, 0.28 mmol) and Pd(dppf)Cl2 (6 mg, 9 μmol). After purging with nitrogen, heat the reaction mixture to 100 °C and stir for 3 hours. Once the reaction mixture has cooled to room temperature, filter it through diatomaceous earth and wash the filter cake with 1,4-dioxane (1 mL). The filtrate containing compound 37a is used directly in the next step without further purification.

[0490] Step 2: Add 2-bromopyridine (14 mg, 93 μmol) and water (0.5 mL) to the filtrate of compound 37a obtained in the previous step, followed by potassium carbonate (25 mg, 186 μmol) and Pd(dppf)Cl2 (6 mg, 9 μmol). After purging the reaction system with nitrogen, heat to 100 °C and stir overnight. Once the reaction solution has cooled to room temperature, filter it through diatomaceous earth and concentrate the filtrate. Purify the residue using Prep-HPLC to obtain compound 37 (6 mg, 17% yield). ESI-MS (m / z): 399.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.39(s,1H),8.77-8.74(m,1H),8.32(s,1H),8.19(s, 1H),8.17(dd,J=7.5,1.5Hz,1H),8.10(d,J=8.0Hz,1H),8.03(dd,J=8.0,1.5Hz, 1H),7.89(td,J=7.5,2.0Hz,1H),7.53(t,J=7.5Hz,1H),7.47-7.43(m,1H),3.90 (s,3H),3.23(s,2H),2.76(t,J=6.0Hz,2H),2.65(t,J=6.0Hz,2H),2.38(s,3H).

[0491] Example 38

[0492] N8-Benzyl-N2-(2-Methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)quinazolin-2,8-diamine

[0493]

[0494] By replacing morpholine in the first step of Example 28 with benzylamine, compound 38 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 427.3 [M+H] +; 1 HNMR(500MHz,DMSO-d6)δ9.20(s,1H),8.25(s,1H),8.20(s,1H),7.46(d,J=7.5Hz,2 H),7.41-7.36(m,2H),7.32-7.28(m,1H),7.19(t,J=8.0Hz,1H),7.13(dd,J=8.0,2. 0Hz,1H),6.83(dd,J=7.5,2.0Hz,1H),6.08(t,J=5.5Hz,1H),4.48(d,J=5.5Hz,2H), 3.92(s,3H),3.26(s,2H),2.76(t,J=6.0Hz,2H),2.64(t,J=6.0Hz,2H),2.34(s,3H).

[0495] Example 39

[0496] N8-Isobutyl-N2-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)quinazolin-2,8-diamine

[0497]

[0498] By replacing the morpholine in the first step of Example 28 with isobutylamine, compound 39 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 393.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.18(s,1H),8.33(s,1H),8.25(s,1H),7.20(t,J=8. 0Hz,1H),7.09(dd,J=8.0,1.0Hz,1H),6.79(d,J=7.5Hz,1H),5.68(t,J=6.0Hz ,1H),3.92(s,3H),3.49(s,2H),3.07(t,J=6.0Hz,2H),2.79(t,J=6.0Hz,2H), 2.68(t,J=6.0Hz,2H),2.37(s,3H),2.04-1.97(m,1H),1.03(d,J=6.5Hz,6H).

[0499] Example 40

[0500] 8-(6-chloropyridin-2-yl)-N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)quinazolin-2-amine

[0501]

[0502] By replacing the 2-bromopyridine in step 2 of Example 37 with 2-bromo-6-chloropyridine, and using a similar method and reaction steps, compound 40 can be obtained. ESI-MS (m / z): 433.2 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.40(s,1H),8.45(s,1H),8.19-8.15(m,2H),8.09(s,1H),8.06(dd,J=8.0,2.0Hz,1H),7.94(t,J=8.0Hz,1H ), 7.58 (d, J = 8.0Hz, 1H), 7.53 (t, J = 7.5Hz, 1H), 3.89 (s, 3H), 3.27 (s, 2H), 2.77 (t, J = 6.0Hz, 2H), 2.67 (t, J = 6.0Hz, 2H), 2.39 (s, 3H).

[0503] Example 41

[0504] N2-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-N8-neopentylpyridino[3,4-d]pyrimidine

[0505] -2,8-diamine

[0506]

[0507] By replacing piperidine in the first step of Example 33 with neopentylamine, and using a similar method and reaction steps, compound 41 can be obtained. ESI-MS (m / z): 408.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.18(s,1H),8.56(s,1H),8.22(s,1H),7.78(d,J=5.7Hz,1H),6.86(d,J=5.7Hz,1H),6.64-6.60(m, 1H), 3.91 (s, 3H), 3.47 (s, 2H), 3.38 (d, J = 6.3Hz, 2H), 2.79 (t, J = 5.9Hz, 2H), 2.68 (d, J = 5.8Hz, 2H), 2.35 (s, 3H), 0.98 (s, 9H).

[0508] Example 42

[0509] (S)-N8-(3,3-dimethylbut-2-yl)-N2-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)pyrido[3,4-d]pyrimidin-2,8-diamine

[0510]

[0511] By replacing the 2-pyrrolidone in the first step of Example 24 with (S)-3,3-dimethyl-2-butanamine, compound 42 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 422.4 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.18(s,1H),8.65(s,1H),8.10(s,1H),7.78(d,J=5.7Hz,1H),6.85(d,J=5.6Hz,1H),6.33(d,J=9.6Hz,1H),4.18- 4.10(m,1H),3.90(s,3H),3.50-3.42(m,2H),2.80(t,J=5.9Hz,2H),2.68(t,J=5.9Hz,2H),2.36(s,3H),1.13(d,J=6.6Hz,3H),0.97(s,9H).

[0512] Example 43

[0513] 8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)pyrido[3,4-d]pyrimidin-2-amine

[0514]

[0515] By replacing 2-methoxyphenylboronic acid in the first step of Example 25 with 1,3-dimethyl-1H-pyrazole-5-boronic acid pinacol ester, compound 43 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 417.2 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.49(s,1H),8.77(s,1H),8.57(d,J=5.2Hz,1H),8.20(s,1H),7.85(d,J=5.3Hz,1H),6.71(s ,1H),3.90(s,3H),3.85(s,3H),3.39(s,2H),2.79(t,J=5.9Hz,2H),2.67(t,J=5.9Hz,2H),2.39(s,3H),2.26(s,3H).

[0516] Example 44

[0517] N-(2-ethoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(2-methoxyphenyl)quinazolin-2-amine

[0518]

[0519] By replacing the phenylboronic acid in the first step of Example 1 with 2-methoxyphenylboronic acid, and then replacing Int-2 in the second step with Int-3, compound 44 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 442.2 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.36(s,1H),8.12(s,1H),7.99-7.92(m,2H),7.73(dd,J =7.1,1.6Hz,1H),7.52-7.46(m,2H),7.30(dd,J=7.4,1.7Hz,1H),7.22(d,J=8.1Hz ,1H),7.12(td,J=7.4,1.0Hz,1H),4.35(q,J=7.0Hz,2H),3.61(s,3H),3.06(s,2H) ,2.69(t,J=5.8Hz,2H),2.60(t,J=5.8Hz,2H),2.40(s,3H),1.37(t,J=7.0Hz,3H).

[0520] Example 45

[0521] 8-(2-Methoxyphenyl)-N-(6-Methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)quinazolin-2-amine

[0522]

[0523] By replacing the phenylboronic acid in the first step of Example 1 with 2-methoxyphenylboronic acid, and then replacing Int-2 in the second step with Int-1, compound 45 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 398.2 [M+H] + ; 1 HNMR(500MHz,Chloroform-d)δ9.12(s,1H),8.23-8.19(m,1H),8.16-8.12(m,1H),7.79-7.74(m,2H),7.50-7.42(m,2H),7.37(dd,J=7. 4,1.7Hz,1H),7.30-7.28(m,1H),7.15-7.08(m,2H),3.67(s,3H),3.40-3.26(m,2H),3.03-2.95(m,2H),2.87-2.75(m,2H),2.55(s,3H).

[0524] Example 46

[0525] N-(2,6-dimethyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(2-methoxyphenyl)quinazolin-2-amine

[0526]

[0527] By replacing the phenylboronic acid in the first step of Example 1 with 2-methoxyphenylboronic acid, and then replacing Int-2 in the second step with Int-11, compound 46 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 412.2 [M+H] + ; 1 H NMR(500MHz,Chloroform-d)δ9.12(s,1H),8.34(s,1H),7.78-7.74(m,2H),7.48-7.41(m,2H),7.36(d,J=7.4Hz,1H), 7.14-7.06(m,2H),3.65(s,3H),3.22(s,2H),2.94(t,J=5.9Hz,2H),2.74(t,J=5.6Hz,2H),2.55(s,3H),2.50(s,3H).

[0528] Example 47

[0529] N-(2-ethoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(2-methoxypyridin-3-yl)quinazolin-2-amine

[0530]

[0531] Compound 47 was prepared by the following steps:

[0532]

[0533] Int-12 (30 mg, 74 μmol) and 2-methoxypyridyl-3-boronic acid (14 mg, 94 μmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL). Sodium carbonate (23 mg, 217 μmol) and Pd(dppf)Cl2 (5 mg, 7 μmol) were added. The reaction system was purged with nitrogen and heated to 90 °C with stirring overnight. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by Prep-HPLC to give a yellow solid 47 (9 mg, yield 28%). ESI-MS (m / z): 443.2 [M+H] + ; 1HNMR(500MHz,DMSO-d6)δ9.36(s,1H),8.32(d,J=5.0Hz,1H),8.03(s,1H),8.01- 7.98(m,2H),7.79(d,J=7.1Hz,1H),7.73(d,J=7.2Hz,1H),7.49(t,J=7.6Hz,1H) ,7.18(dd,J=7.1,5.1Hz,1H),4.34(q,J=7.0Hz,2H),3.71(s,3H),3.12(s,2H),2 .69(t,J=5.7Hz,2H),2.60(t,J=5.8Hz,2H),2.40(s,3H),1.36(t,J=7.0Hz,3H).

[0534] Example 48

[0535] N-(2,6-dimethyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(2-methoxypyridin-3-yl)quinazolin-2-amine

[0536]

[0537] By replacing Int-7 in the first step of Example 23 with Int-13 and using a similar method and reaction steps, compound 47 can be obtained. ESI-MS (m / z): 413.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.34(s,1H),8.78(s,1H),8.24(d,J=5.0Hz,1H),7 .94(d,J=8.0Hz,1H),7.83(s,1H),7.73(d,J=7.1Hz,1H),7.69(d,J=7.2Hz,1 H),7.43(t,J=5.0Hz,1H),7.09(dd,J=7.2,5.0Hz,1H),3.72(s,3H),3.25(s, 2H), 2.76 (t, J=5.8Hz, 2H), 2.63 (t, J=5.9Hz, 2H), 2.41 (s, 3H), 2.39 (s, 3H).

[0538] Example 49

[0539] 6-Methyl-3-((8-morpholinopyrido[3,4-d]pyrimidin-2-yl)amino)-5,6,7,8-tetrahydro-1,6-naphthyl-2(1H)-

[0540] ketone

[0541]

[0542] Compound 49 was prepared by the following steps:

[0543]

[0544] Step 1: Compound 35 (20 mg, 0.049 mmol) was dissolved in 1,4-dioxane (5 mL), and concentrated hydrochloric acid (0.2 mL) was added. The reaction was carried out at 100 °C for 2 hours. LC-MS showed that the starting material reacted completely. The reaction solution was directly concentrated, and the residue was purified by Prep-HPLC to give compound 49 (8 mg, yield 42%). ESI-MS (m / z): 394.2 [M+H] + ; 1 HNMR(500Hz,DMSO-d6)δ11.95(br s,1H),9.33(s,1H),8.47(s,1H),8.06(d,J=5.4Hz,1H),7.98(s,1H),7.28(d,J=5.4Hz,1H) ,3.88-3.83(m,4H),3.79-3.74(m,4H),3.35-3.32(m,2H),2.63-2.58(m,4H),2.37(s,3H).

[0545] Example 50

[0546] (S)-N8-(3,3-dimethylbut-2-yl)-N2-(2-ethoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthid-3-yl)-6-

[0547] Methylpyrido[3,4-d]pyrimidine-2,8-diamine

[0548]

[0549] Compound 50 was prepared by the following steps:

[0550]

[0551] Step 1: 8-Chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine 50a (50 mg, 0.22 mmol) and (S)-3,3-dimethyl-2-butylamine 50b (112 mg, 1.11 mmol) were dissolved in N-methylpyrrolidone (4 mL), and diisopropylethylamine (143 mg, 1.11 mmol) was added. The reaction mixture was heated to 130 °C in a microwave oven for 5 hours, and the product formation was detected by LCMS. The reaction solution was poured into water (15 mL), extracted with ethyl acetate (10 mL * 2), and the organic phases were combined, washed three times with saturated brine, dried over sodium sulfate, filtered, and concentrated to give compound 50c (60 mg, 93% yield). ESI-MS (m / z): 291.4 [M+H] + .

[0552] Step 2: Compound 50c (60 mg, 0.20 mmol) was dissolved in dichloromethane (10 mL), and m-CPBA (105 mg, 85% purity, 0.51 mmol) was added under ice bath conditions. The mixture was then allowed to react overnight at room temperature. LC-MS analysis confirmed complete reaction of the starting material. The reaction solution was concentrated, and the residue was purified by Prep-TLC to give compound 50d (16 mg, 22% yield). ESI-MS (m / z): 323.4 [M+H] + .

[0553] Step 3: Compound 50d (16 mg, 0.07 mmol) was dissolved in anhydrous DMF (3 mL). NaH (3 mg, 60% purity, 0.07 mmol) was added under ice bath conditions. After stirring for 30 minutes under ice bath conditions, a DMF solution of Int-3 (15 mg, 0.047 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 2 hours after the addition was complete. LC-MS analysis confirmed complete reaction of the starting material. Compound 50 (2 mg, 11% yield) was directly prepared by Prep-HPLC. ESI-MS (m / z): 450.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.10(s,1H),8.39(s,1H),8.16(s,1H),6.69(d,J=1 .0Hz,1H),6.29(d,J=9.4Hz,1H),4.36(qd,J=7.0,1.0Hz,2H),4.15(dd,J=9.5 ,6.7Hz,1H),3.57-3.40(m,2H),2.78(t,J=5.8Hz,2H),2.69(d,J=6.0Hz,2H), 2.38-2.35(m,6H),1.33(t,J=7.1Hz,3H),1.14(d,J=6.7Hz,3H),0.98(s,9H).

[0554] Example 51

[0555] N2-(2-ethoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-6-methyl-N8-neopentylpyridino[3,4-d]

[0556] Pyrimidine-2,8-diamine

[0557]

[0558] By replacing (S)-3,3-dimethyl-2-butylamine in the first step of Example 50 with neopentylamine, compound 51 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 436.2 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.10(s,1H),8.31(s,1H),8.26(s,1H),6.69(d,J=1.0Hz,1H),6.55(t,J=6.1Hz,1H),4.36(q,J=7.0Hz,2H) ,3.46(s,2H),3.37(d,J=6.2Hz,2H),2.77(t,J=5.9Hz,2H),2.66(t,J=5.8Hz,2H),2.35(s,6H),1.34(t,J=6.6Hz,3H),0.99(s,9H).

[0559] Example 52

[0560] N2-(2-ethoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-N8-neopentylpyridino[3,4-d]pyrimidine

[0561] -2,8-diamine

[0562]

[0563] In Example 50, the two reactants in the first step, (S)-3,3-dimethyl-2-butylamine and 8-chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine, were replaced with neopentylamine and 8-chloro-2-(methylthioalkyl)pyrido[3,4-d]pyrimidine, respectively. Compound 52 was obtained using a similar method and reaction steps. ESI-MS (m / z): 422.3 [M+H] + ; 1HNMR(500MHz,DMSO-d6)δ9.19(s,1H),8.46(s,1H),8.25(s,1H),7.79(d,J=5.6Hz,1H),6.87(d,J=5.7Hz,1H),6.63(t,J=6.3Hz,1H),4.37(q,J =7.0Hz,2H),3.47(s,2H),3.39(d,J=6.3Hz,2H),2.77(t,J=5.9Hz,2H),2.67(t,J=5.9Hz,2H),2.35(s,3H),1.33(t,J=7.0Hz,3H),0.98(s,9H).

[0564] Example 53

[0565] 8-(1,5-dimethyl-1H-pyrazol-4-yl)-N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)quinazolin-2-amine

[0566]

[0567] By replacing 2-methoxy-3-pyridineboronic acid in the first step of Example 23 with 1,5-dimethyl-1H-pyrazole-4-boronic acid pinacol ester, compound 53 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 416.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.34(s,1H),8.41(s,1H),8.13(s,1H),7.89(dd,J=8.0,1.5Hz,1H),7.71(dd,J=7.0,1.5Hz,1H),7.65(s,1H),7. 46(dd,J=8.0,7.0Hz,1H),3.91(s,3H),3.86(s,3H),3.34(s,2H),2.76(t,J=6.0Hz,2H),2.66(t,J=6.0Hz,2H),2.40(s,3H),2.19(s,3H).

[0568] Example 54

[0569] 5-(2-((2-ethoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)amino)quinazolin-8-yl)-1-methylpyridine

[0570] -2(1H)-keto

[0571]

[0572] By replacing 2-methoxy-3-pyridineboronic acid in the first step of Example 47 with 1-methyl-6-oxo-1,6-dihydropyridine-3-boronic acid pinacol ester, compound 54 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 443.3 [M+H] + ; 1 HNMR(500MHz,Chloroform-d)δ9.12(s,1H),8.48(s,1H),7.86(s,1H),7.78(d,J=9. 3Hz,1H),7.74(d,J=8.0Hz,1H),7.69(d,J=7.2Hz,1H),7.60(d,J=2.3Hz,1H),7.38(t ,J=7.6Hz,1H),6.71(d,J=9.4Hz,1H),4.45(q,J=7.1Hz,2H),3.63(s,3H),3.36(s,2 H), 2.89 (t, J = 5.9Hz, 2H), 2.76 (t, J = 5.8Hz, 2H), 2.55 (s, 3H), 1.43 (t, J = 7.1Hz, 3H).

[0573] Example 55

[0574] 8-(1,5-dimethyl-1H-pyrazol-4-yl)-N-(2-ethoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)quinazolin-2-amine

[0575]

[0576] By replacing 2-methoxy-3-pyridineboronic acid in the first step of Example 47 with 1,5-dimethyl-1H-pyrazole-4-boronic acid pinacol ester, compound 54 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 430.2 [M+H] + ; 1 HNMR(500MHz,Chloroform-d)δ9.11(s,1H),8.58(s,1H),7.84(s,1H),7.76(s,1H),7.70(d,J=8.0Hz,1H),7.66(d,J=7.1Hz,1H),7.38(t,J=7.6Hz, 1H),4.44(q,J=7.1Hz,2H),3.94(s,3H),3.50(s,2H),2.90(t,J=5.8Hz,2H ), 2.80 (t, J = 5.9Hz, 2H), 2.55 (s, 3H), 2.24 (s, 3H), 1.43 (t, J = 7.1Hz, 3H).

[0577] Example 56

[0578] N2-(2-ethoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-N8-isobutylquinazoline-2,8-diamine

[0579]

[0580] Compound 56 was prepared by the following steps:

[0581]

[0582] Step 1: Int-12 (40 mg, 96 μmol) was dissolved in toluene (5 mL), and Pd2(dba)3 (4 mg, 4.9 μmol), BINAP (9 mg, 14.9 μmol), sodium tert-butoxide (18 mg, 193 μmol), and isobutylamine (11 mg, 144 μmol) were added sequentially. The reaction system was purged with nitrogen and heated to 100 °C with stirring overnight. The reaction solution was concentrated, and the residue was purified by Prep-TLC (dichloromethane / methanol = 10 / 1) to obtain the crude product, which was then purified by Prep-HPLC to obtain a yellow solid 56 (23 mg, yield 59%). ESI-MS (m / z): 407.2 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ9.19(s,1H),8.37(s,1H),8.15(s,1H),7.21(t,J=8.0Hz,1H ),7.10(d,J=8.0Hz,1H),6.80(d,J=7.5Hz,1H),5.67(t,J=6.0Hz,1H),4.38(q,J=7. 0Hz,2H),3.48(s,2H),3.07(t,J=6.0Hz,2H),2.77(t,J=6.0Hz,2H),2.67(t,J=6.0H z, 2H), 2.37 (s, 3H), 2.04-1.96 (m, 1H), 1.36 (t, J = 7.0Hz, 3H), 1.03 (d, J = 6.5Hz, 6H).

[0583] Example 57

[0584] (R)-2-((2-((2-ethoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)amino)pyrido[3,4-d]pyrimidine

[0585] -8-yl)amino)-3,3-dimethylbut-1-ol

[0586]

[0587] In Example 50, the two reactants in the first step, (S)-3,3-dimethyl-2-butamine and 8-chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine, were replaced with D-tert-leucine and 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine, respectively. Compound 57 was obtained using a similar method and reaction steps. ESI-MS (m / z): 452.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.20(s,1H),8.44(s,1H),8.30(s,1H),7.78(d,J=5.4Hz,1 H), 6.86 (d, J = 5.4Hz, 1H), 6.72 (d, J = 9.8Hz, 1H), 4.73 (t, J = 5.0Hz, 1H), 4.37 (q, J = 7. 0Hz,2H),4.15(dd,J=9.7,4.7Hz,1H),3.73-3.60(m,2H),3.53-3.38(m,2H),2.81-2. 73(m,2H),2.70-2.62(m,2H),2.36-2.33(m,3H),1.35(t,J=7.0Hz,3H),1.01(s,9H).

[0588] Example 58

[0589] (R)-N8-(3,3-dimethylbut-2-yl)-N2-(2-ethoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)pyrido[3,4-d]pyrimidin-2,8-diamine

[0590]

[0591] In Example 50, the two reactants in the first step, (S)-3,3-dimethyl-2-butamine and 8-chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine, were replaced with (R)-3,3-dimethyl-2-butamine and 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine, respectively. Compound 58 was obtained using a similar method and reaction steps. ESI-MS (m / z): 436.1 [M+H] + ; 1HNMR(500MHz,DMSO-d6)δ9.18(s,1H),8.53(s,1H),8.13(s,1H),7.79(d,J=5.7 Hz,1H),6.86(d,J=5.7Hz,1H),6.32(d,J=9.5Hz,1H),4.36(q,J=6.9Hz,2H),4.1 6(q,J=9.4,6.5Hz,1H),3.53-3.39(m,2H),2.78(t,J=5.8Hz,2H),2.67(t,J=5.6 Hz, 2H), 2.36 (s, 3H), 1.32 (t, J = 7.0Hz, 3H), 1.14 (d, J = 6.6Hz, 3H), 0.98 (s, 9H).

[0592] Example 59

[0593] 8-Benzyl-N-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthid-3-yl)quinazolin-2-amine

[0594]

[0595] Compound 59 was prepared by the following steps:

[0596]

[0597] Step 1: Int-7 (30 mg, 74 μmol) was dissolved in a mixed solvent of toluene / 1,4-dioxane / water (10 / 1 / 1, 6 mL), and potassium carbonate (31 mg, 0.22 mmol), Pd(dppf)Cl2 (5 mg, 7 μmol), and 2-benzyl-4,4,5,5-tetramethyl-1,3,2-diazepineborane 59a (32 mg, 0.14 mmol) were added. The reaction system was purged with nitrogen and heated to 90 °C with stirring overnight. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by Prep-TLC (dichloromethane / methanol = 20 / 1) to obtain the crude product, which was then separated by Prep-HPLC to obtain a white solid 59 (6 mg, yield 21%). ESI-MS (m / z): 412.3 [M+H] + ; 1HNMR(500MHz,DMSO-d6)δ9.31(s,1H),8.40(s,1H),8.25(s,1H),7.84(dd,J=8.0,1.5Hz,1H),7.72(dd,J=7.0,1.5Hz,1H),7.37(t,J=7.5Hz, 1H),7.25-7.19(m,4H),7.17-7.13(m,1H),4.41(s,2H),3.92(s,3H),3 .28(s,2H),2.76(t,J=6.0Hz,2H),2.64(t,J=6.0Hz,2H),2.34(s,3H).

[0598] Example 60

[0599] N2-(2-ethoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-N8-((3-methyloxetane-3-yl)methyl)quinazolin-2,8-diamine

[0600]

[0601] In Example 56, the morpholine in the first step was replaced with 3-methyl-3-aminomethyl-1-oxecyclobutane. Compound 60 was obtained using a similar method and reaction steps. ESI-MS (m / z): 435.1 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.20(s,1H),8.34(s,1H),8.14(s,1H),7.24(t,J=8.0Hz,1H ),7.14(dd,J=8.0,1.5Hz,1H),6.94(dd,J=7.5,1.5Hz,1H),5.85(t,J=6.0Hz,1H),4. 51(d,J=5.5Hz,2H),4.40-4.35(m,4H),3.47(s,2H),3.45(d,J=6.0Hz,2H),2.77(t,J =6.0Hz,2H),2.67(t,J=6.0Hz,2H),2.37(s,3H),1.39(s,3H),1.36(t,J=7.0Hz,3H).

[0602] Example 61

[0603] 3-((8-(1,5-dimethyl-1H-pyrazol-4-yl)quinazolin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidine

[0604] -2(1H)-keto

[0605]

[0606] Compound 61 was prepared by the following steps:

[0607]

[0608] Step 1: Compound 56 (30 mg, 69 μmol) was dissolved in 1,4-dioxane (5 mL), and concentrated hydrochloric acid (0.2 mL) was added. The reaction mixture was heated to 100 °C and stirred for 3 hours. The reaction solution was concentrated, and the residue solid was washed with ethyl acetate and then purified by Prep-HPLC to obtain compound 61 (3 mg, yield 12%). ESI-MS (m / z): 402.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ11.83(br s,1H),9.35(s,1H),8.23(d,J=9.3Hz,2H),7.90(d,J=8.0Hz,1H),7.72(d,J=7.2Hz,1H),7.67(s ,1H),7.50–7.43(m,1H),3.87(s,3H),3.14(s,2H),2.60-2.55(m,4H),2.37(s,3H),2.23(s,3H).

[0609] Example 62

[0610] 3-((8-(2-methoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro-1,6-naphthylidine

[0611] -2(1H)-keto

[0612]

[0613] By replacing reactant 56 in the first step of Example 61 with compound 25, and using a similar method and reaction steps, compound 62 can be obtained. ESI-MS (m / z): 415.0 [M+H] + .

[0614] Example 63

[0615] 6-Methyl-3-((8-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)-5,6,7,8-tetrahydro-1,6-naphthylidine

[0616] -2(1H)-keto

[0617]

[0618] By replacing reactant 35 in the first step of Example 49 with compound 33, and using a similar method and reaction steps, compound 63 can be obtained. ESI-MS (m / z): 392.0 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ11.95(br s,1H),9.29(s,1H),8.41(s,1H),8.18(s,1H),8.10(s,1H),8.03(d,J=5.3Hz,1H),7.20(d,J=5 .3Hz,1H),3.80-3.70(m,4H),3.32(s,2H),2.65-2.56(m,4H),2.36(s,3H),1.80-1.60(m,6H).

[0619] Example 64

[0620] 6-Methyl-3-((8-(neopentylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)-5,6,7,8-tetrahydro-1,6-naphthylidine

[0621] -2(1H)-keto

[0622]

[0623] Replacing reactant 35 in the first step of Example 49 with compound 41, and using a similar method and reaction steps, yields compound 64. ESI-MS (m / z): 394.1 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ11.94(s,1H),9.22(s,1H),8.43(s,1H),8.21(s,1H),7.83(d,J=5.6 Hz,1H),6.89(d,J=5.6Hz,1H),6.77-6.74(m,1H),3.43(d,J=6.2Hz,2H),3.28(s,2H),2.59(br s,4H),2.32(s,3H),1.01(s,9H).

[0624] Example 65

[0625] 8-(3,3-dimethylazacyclobutane-1-yl)-N-(2-ethoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)pyrido[3,4-d]pyrimidin-2-amine

[0626]

[0627] In Example 50, the two reactants in the first step, (S)-3,3-dimethyl-2-butamine and 8-chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine, were replaced with 3,3-dimethylazacyclobutane and 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine, respectively. Compound 65 was obtained using a similar method and reaction steps. ESI-MS (m / z): 420.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ8.41(s,1H),8.02(s,1H),7.83(d,J=5.5Hz,1H),6.93(d,J=5.5Hz,1H),4.34(q,J=7.0Hz,2H),3.99(br s,4H),3.44(s,2H),2.78(t,J=6.0Hz,2H),2.67(t,J=5.9Hz,2H),2.37(s,4H),1.32(t,J=7.0Hz,3H),1.29(s,6H).

[0628] Example 66

[0629] N-(2-ethoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(7-oxa-2-azaspiro[3,5]non-2-yl)pyrido[3,4-d]pyrimidin-2-amine

[0630]

[0631] In Example 50, the two reactants in the first step, (S)-3,3-dimethyl-2-butamine and 8-chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine, were replaced with 7-oxa-2-azaspiro[3,5]nonane and 8-chloro-2-(methylthioalkyl)pyrido[3,4-d]pyrimidine, respectively. Compound 66 was obtained using a similar method and reaction steps. ESI-MS (m / z): 462.2 [M+H] + ;1H NMR (500MHz, DMSO-d6) δ9.17(d,J=1.9Hz,1H),8.48(s,1H),7.95(s,1H),7.82(d,J=5.5Hz,1H),6.92(d,J=5.5Hz,1H),4.33(q,J=7.0Hz,2H),4.02(br s,4H),3.60-3.52(m,4H),3.47(s,2H),2.78(t,J=5.9Hz,2H),2.68(t,J=5.9Hz,2H),2.37(s,3H),1.76-1.72(m,4H),1.30(t,J=7.0Hz,3H).

[0632] Example 67

[0633] N-(2-ethoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-8-(1,3,5-trimethyl-1H-pyrazol-4-yl)quinazolin-2-amine

[0634]

[0635] By replacing 2-methoxy-3-pyridineboronic acid in the first step of Example 47 with 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester, compound 67 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 444.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ9.36(s,1H),8.34(s,1H),8.01(s,1H),7.94(d,J=8 .1Hz,1H),7.68(d,J=7.1Hz,1H),7.48(t,J=6.1Hz,1H),4.36(q,J=7.0Hz,2H ),3.80(s,3H),3.42-3.37(m,1H),3.22-3.15(m,1H),2.77-2.70(m,2H),2.6 8-2.58(m,2H),2.40(s,3H),2.07(s,3H),1.94(s,3H),1.37(t,J=7.0Hz,3H).

[0636] Example 68

[0637] 1,6-Dimethyl-3-((8-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)-5,6,7,8-tetrahydro-1,6-naphthylidine

[0638] -2(1H)-keto

[0639]

[0640] Compound 68 was prepared by the following steps:

[0641]

[0642] Step 1: Int-15 (25 mg, 70 μmol) was dissolved in N-methylpyrrolidone (0.5 mL), and piperidine (30 mg, 0.35 mmol) was added. The reaction mixture was heated to 160 °C and stirred for 6 hours. The reaction was confirmed to be complete by LCMS. The reaction mixture was concentrated, and the residue was purified by Prep-HPLC to give a yellow solid 68 (8 mg, yield 28%). ESI-MS (m / z): 405.4 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.30 (s, 1H), 8.51 (s, 1H), 8.11 (s, 1H), 8.03 (d, J = 5.3Hz, 1H), 7.21 (d, J = 5.3Hz, 1H), 3.73 (t, J = 5.3Hz, 4H),3.53(s,3H),3.35(s,2H),2.78(t,J=5.8Hz,2H),2.65(t,J=5.8Hz,2H),2.36(s,3H),1.76-1.71(m,4H),1.70-1.65(m,2H).

[0643] Example 69

[0644] 1,6-Dimethyl-3-((8-morpholinylpyridino[3,4-d]pyrimidin-2-yl)amino)-5,6,7,8-tetrahydro-1,6-naphthylidine

[0645] -2(1H)-keto

[0646]

[0647] By replacing piperidine in the first step of Example 68 with morpholine, compound 69 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 408.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.34(s,1H),8.56(s,1H),8.07(d,J=5.3Hz,1H),7.99(s,1H),7.29(d,J=5.4Hz,1H),3.85( t, 4H), 3.77 (t, J = 4.8Hz, 4H), 3.53 (s, 3H), 3.36 (s, 2H), 2.79 (t, J = 6.0Hz, 2H), 2.65 (t, J = 5.9Hz, 2H), 2.38 (s, 3H).

[0648] Example 70

[0649] 3-((8-((3-hydroxy-2,2-dimethylpropyl)aminopyridino[3,4-d]pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-

[0650] Tetrahydro-1,6-naphthidin-2(1H)-one

[0651]

[0652] Compound 70 was prepared by the following steps:

[0653]

[0654] Step 1: Int-16 (50 mg, 118 μmol, HBr salt) was dissolved in N-methylpyrrolidone (4 mL), and 3-amino-2,2-dimethyl-1-propanol (61 mg, 0.59 mmol) and N,N-diisopropylethylamine (76 mg, 0.59 mmol) were added. The reaction mixture was heated to 150 °C and stirred for 4 hours in a microwave reactor. The reaction was confirmed to be complete by LCMS. The reaction mixture was concentrated, and the residue was purified by Prep-HPLC to give 70 (16 mg, 33% yield) of a yellow solid. ESI-MS (m / z): 410.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ11.91(s,1H),9.22(s,1H),8.42(s,1H),8.22(s,1H),7.81(d,J=5.5Hz,1H),7.23(s,1H),6.88(d,J=5.5 Hz,1H),5.06(t,J=5.6Hz,1H),3.44(d,J=5.8Hz,2H),3.34(s,2H),3.28(d,J=5.0Hz,2H),2.59(s,4H),2.33(s,3H),0.95(s,6H).

[0655] Example 71

[0656] (R)-6-methyl-3-((8-(2-methylmorpholinyl)pyrido[3,4-d]pyrimidin-2-yl)amino)-5,6,7,8-tetrahydro-1,6-

[0657] Naphthid-2(1H)-one

[0658]

[0659] By replacing 3-amino-2,2-dimethyl-1-propanol in the first step of Example 70 with (R)-2-methylmorpholine, compound 71 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 408.2 [M+H]+ ; 1 H NMR (500MHz, DMSO-d6) δ11.96(s,1H),9.32(s,1H),8.46(s,1H),8.10-7.91(m,2H),7.27(d,J=5.4Hz,1H),4.56-4.40(m,2H),3.97(d,J=10.4H z,1H),3.86-3.72(m,2H),3.35-3.30(m,2H),3.02(t,J=12.0Hz,1H),2. 76-2.66(m,1H),2.63-2.52(m,4H),2.37(s,3H),1.15(d,J=6.2Hz,3H).

[0660] Example 72

[0661] 6-Methyl-3-((8-thiomorpholinylpyridino[3,4-d]pyrimidin-2-yl)amino)-5,6,7,8-tetrahydro-1,6-naphthylidine

[0662] -2(1H)-keto

[0663]

[0664] By replacing 3-amino-2,2-dimethyl-1-propanol in the first step of Example 70 with thiomorpholine, compound 72 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 410.2 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ11.96(s,1H),9.33(s,1H),8.45(s,1H),8.10-8.02(m,2H),7.26 (d, J=5.4Hz, 1H), 4.09 (d, J=5.4Hz, 4H), 2.80 (d, J=5.0Hz, 4H), 2.60 (s, 4H), 2.36 (s, 4H).

[0665] Example 73

[0666] 3-((8-(azacycloheptan-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro-1,6-naphthidium-2(1H)-one

[0667]

[0668] By replacing 3-amino-2,2-dimethyl-1-propanol in the first step of Example 70 with cycloheximine, compound 73 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 405.4 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ9.11(s,1H),8.12(s,1H),7.90(d,J=5.5Hz,1H),6.92(d,J=5.5Hz,1H),4.2 0-4.13(m,4H),3.46(s,2H),2.82-2.72(m,4H),2.51(s,3H),1.91-1.84(m,4H),1.65-1.58(m,4H).

[0669] Example 74

[0670] 3-((8-(4,4-difluoropiperidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro-1,6-

[0671] Naphthid-2(1H)-one

[0672]

[0673] By replacing 3-amino-2,2-dimethyl-1-propanol in the first step of Example 70 with 4,4-difluoropiperidine, compound 74 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 428.2 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ12.03(s,1H),9.35(s,1H),8.49(s,1H),8.09-8.06(m,2H),7.31 (d,J=5.5Hz,1H),3.95-3.89(m,4H),2.65-2.57(m,4H),2.36(s,3H),2.22-2.12(m,4H).

[0674] Example 75

[0675] 3-((8-(cyclohexyl-1-en-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyl

[0676] -2(1H)-keto

[0677]

[0678] Compound 75 was prepared by the following steps:

[0679]

[0680] Step 1: Int-16 (50 mg, 118 μmol, HBr salt) and pinacol cyclohexene-1-borate (27 mg, 129 μmol) were dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (2 mL). Sodium carbonate (25 mg, 236 μmol) and Pd(dppf)Cl2 (10 mg, 12 μmol) were added. The reaction system was purged with nitrogen and heated to 60 °C with stirring overnight. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by Prep-HPLC to give 75 μL (1.1 mg, yield 2%) of yellow solid. ESI-MS (m / z): 389.3 [M+H] + ; 1 HNMR(500MHz,DMSO-d6)δ12.01(br s,1H),9.43(s,1H),8.48-8.45(m,2H),8.32(s,1H),7.70(d,J=5.2Hz,1H),6.6 8(s,1H),3.30(s,2H),2.65-2.58(m,6H),2.40-2.30(m,5H),1.86-1.70(m,4H).

[0681] Example 76

[0682] (R)-6-methyl-3-((8-(2-methylpiperidin-1-yl)pyrido[3,4-d]piperidin-2-yl)amino)-5,6,7,8-tetrahydro

[0683] -1,6-Naphthidin-2(1H)-one

[0684]

[0685] By replacing 3-amino-2,2-dimethyl-1-propanol in the first step of Example 70 with R-2-methylpiperidine, compound 76 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 405.4 [M+H] + ; 1H NMR (500MHz, DMSO-d6) δ11.97(s,1H),9.30(s,1H),8.41(s,1H),8.08(s,1H),8.03(d,J=5.3Hz,1H),7.19(d,J=5.3Hz,1H),5.13(br s,1H),4.15-4.06(m,1H),3.28-3.22(m,2H),2.65-2.55(m,4H),2.35(s,3H),2 .02-1.94(m,1H),1.80-1.75(m,2H),1.70-1.57(m,3H),1.10(d,J=6.8Hz,3H).

[0686] Example 77

[0687] 6-Methyl-3-((8-((((1-methylcyclopropyl)methyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)-5,6,7,8-tetrahydro-1,6-naphthidium-2(1H)-one

[0688]

[0689] By replacing 3-amino-2,2-dimethyl-1-propanol in the first step of Example 70 with 1-methylcyclopropylethylamine, compound 77 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 392.2 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ11.95(s,1H),9.23(s,1H),8.42(s,1H),8.23(s,1H),7.83(d,J=5.6Hz,1H),6.90(d,J=5.7Hz,1H),6.74(br s,1H),3.45(d,J=5.7Hz,2H),3.34(s,2H),2.64-2.56(m,4H),2.34(s,3H),1.17(s,3H),0.63-0.57(m,2H),0.36-0.32(m,2H).

[0690] Example 78

[0691] 1,6-Dimethyl-3-((8-thiomorpholinylpyridino[3,4-d]pyrimidin-2-yl)amino)-5,6,7,8-tetrahydro-1,6-naphthylidine

[0692] -2(1H)-keto

[0693]

[0694] By replacing piperidine in the first step of Example 68 with thiomorpholine, compound 78 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 424.3 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ9.32(s,1H),8.53(s,1H),8.08(s,1H),8.05(d,J=5.5Hz,1H),7.26(d,J=5.5Hz ,1H),4.13-4.06(m,4H),3.53(s,3H),3.37(s,2H),2.83-2.74(m,6H),2.68-2.62(m,2H),2.37(s,3H).

[0695] Example 79

[0696] 3-((8-(4,4-difluoropiperidin-1-yl)piperidino[3,4-d]pyrimidin-2-yl)amino)-1,6-dimethyl-5,6,7,8-tetrahydro

[0697] -1,6-Naphthidin-2(1H)-one

[0698]

[0699] By replacing the piperidine in the first step of Example 68 with 4,4-difluoropiperidine, and using a similar method and reaction steps, compound 79 can be obtained. ESI-MS (m / z): 442.3 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ9.35(s,1H),8.56(s,1H),8.09(s,1H),8.07(d,J=5.5Hz,1H),7.31(d,J=5.5Hz,1H),3.96 -3.89(m,4H),3.53(s,3H),3.35(s,2H),2.83-2.75(m,2H),2.65(t,J=6.0Hz,2H),2.35(s,3H),2.24-2.12(m,4H).

[0700] Example 80

[0701] 3-((8-(azacycloheptane-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)-1,6-dimethyl-5,6,7,8-tetrahydro

[0702] -1,6-Naphthidin-2(1H)-one

[0703]

[0704] By replacing piperidine in the first step of Example 68 with cycloheximine, compound 79 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 420.3 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ9.11(s,1H),8.12(s,1H),7.90(d,J=5.5Hz,1H),6.92(d,J=5.5Hz,1H),4.2 0-4.13(m,4H),3.46(s,2H),2.82-2.72(m,4H),2.51(s,3H),1.91-1.84(m,4H),1.65-1.58(m,4H).

[0705] Example 81

[0706] 3-((8-(cyclohexyl-1-en-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)-1,6-dimethyl-5,6,7,8-tetrahydro-1,6-

[0707] Naphthid-2(1H)-one

[0708]

[0709] By replacing Int-16 in the first step of Example 75 with Int-15, and using a similar method and reaction steps, compound 81 can be obtained. ESI-MS (m / z): 403.2 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.44(s,1H),8.56(s,1H),8.46(d,J=5.5Hz,1H),8.34(s,1H),7.70(d,J=5.5Hz,1H),6.70-6.65(m,1H),3.54(s,3H),3. 36-3.34(m,2H),2.83-2.76(m,2H),2.68-2.64(m,2H),2.64-2.58(m,2H ),2.36(s,3H),2.35-2.30(m,2H),1.86-1.80(m,2H),1.80-1.73(m,2H).

[0710] Example 82

[0711] 3-((8-(4,4-difluoropiperidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)-6-(2-hydroxyethyl)-1-methyl-5,6,7,8-tetrahydro-1,6-naphthidium-2(1H)-one

[0712]

[0713] Compound 82 was prepared by the following steps:

[0714]

[0715] Step 1: Int-17 (40 mg, 83 μmol) was dissolved in N-methylpyrrolidone (2 mL), and 4,4-difluoropiperidine (61 mg, 0.59 mmol) and N,N-diisopropylethylamine (54 mg, 0.42 mmol) were added. The reaction mixture was heated to 150 °C and stirred for 4 hours in a microwave reactor. The reaction was confirmed to be complete by LCMS. The reaction mixture was cooled to room temperature, and water (50 mL) was added. The resulting yellow solid was filtered and dried to give compound 82a (35 mg, 74% yield). ESI-MS (m / z): 562.2 [M+H] + .

[0716] Step 2: Intermediate 82a (10 mg, 17 μmol) was dissolved in 1 mL of 48% hydrobromic acid aqueous solution. The reaction mixture was stirred at 50 °C for 30 min, and the reaction was monitored for completeness by LC-MS. After cooling to room temperature, the pH was adjusted to 7 with 1 N NaOH aqueous solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase preparative HPLC to give a yellow solid 82 (4.9 mg, yield 58%). ESI-MS (m / z): 472.2 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ9.36(s,1H),8.57(s,1H),8.11(s,1H),8.08(d,J=5.5Hz,1H),7.32(d,J=5.5Hz,1H),4.53-4.49(m,1H) ,3.95-3.89(m,4H),3.62-3.57(m,2H),3.53(s,3H),3.46(s,2H),2.80-2.73(m,4H),2.58(t,J=6.0Hz,2H),2.25-2.14(m,4H).

[0717] Example 83

[0718] 6-(2-hydroxyethyl)-1-methyl-3-((8-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)-5,6,7,8-tetrahydro

[0719] -1,6-Naphthidin-2(1H)-one

[0720]

[0721] By replacing 4,4-difluoropiperidine in the first step of Example 82 with piperidine, and using a similar method and reaction steps, compound 81 can be obtained. ESI-MS (m / z): 435.9 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ9.29(s,1H),8.50(s,1H),8.12(s,1H),8.03(d,J=5.5Hz,1H),7.21(d,J=5.5Hz,1H),4.59-4.49(m,1H),3.73-3.67 (m,4H),,3.59(t,J=6.0Hz,2H),3.52(s,3H),3.46(s,2H),2.79-2.73(m,4H),2.58(t,J=6.0Hz,2H),1.79-1.71(m,4H),1.70-1.62(m,2H).

[0722] Example 84

[0723] 6-(2-hydroxyethyl)-1-methyl-3-((8-thiomorpholinylpyridino[3,4-d]pyrimidin-2-yl)amino)-5,6,7,8-tetrahydro

[0724] -1,6-Naphthidin-2(1H)-one

[0725]

[0726] By replacing 4,4-difluoropiperidine in the first step of Example 82 with thiomorpholine, compound 81 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 454.2 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.31(s,1H),8.52(s,1H),8.08(s,1H),8.05(d,J=5.5Hz,1H),7.25(d,J=5.5Hz,1H),4.55-4.50(m,1 H),4.11-4.00(m,4H),3.64-3.57(m,2H),3.52(s,3H),3.47(s,2H),2.84-2.78(m,4H),2.78-2.72(m,4H),2.62-2.57(m,2H).

[0727] Example 85

[0728] 3-((8-(3,3-difluoropyrrolidone-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)-1,6-dimethyl-5,6,7,8-tetrahydro-1,6-naphthidium-2(1H)-one

[0729]

[0730] By replacing piperidine in the first step of Example 68 with 3,3-difluoropyrrolidine, and using a similar method and reaction steps, compound 85 can be obtained. ESI-MS (m / z): 404.5 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.27(s,1H),8.43(s,1H),7.97(d,J=5.5Hz,1H),7.90(s,1H),7.09(d,J=5.5Hz,1H),4.47-4. 40(m,2H),4.04(t,J=7.0Hz,2H),3.51(s,2H),2.80-2.75(m,2H),2.66-2.61(m,2H),2.33(s,3H),2.04-1.95(m,1H).

[0731] Example 86

[0732] 3-((8-(3-azabicyclo[3.1.0]hex-3-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)-1,6-dimethyl

[0733] -5,6,7,8-Tetrahydro-1,6-naphthidium-2(1H)-one

[0734]

[0735] By replacing piperidine in the first step of Example 68 with 3-aza-bicyclo[3.1.0]hexane, compound 86 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 404.5 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.21(s,1H),8.32(s,1H),7.98(s,1H),7.92(d,J=5.5Hz,1H),6.99(d,J=5.5Hz,1H),4.45(d,J=11.5Hz,2H),3.69-3.66 (m,2H),3.52(s,3H),3.36(s,2H),2.80-2.75(m,2H),2.67-2.62(m,2H) ,2.36(s,3H),1.71-1.67(m,2H),0.75-0.70(m,1H),0.36-0.32(m,1H).

[0736] Example 87

[0737] 3-((8-(4,4-difluoropiperidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)-1-(2-methoxyethyl)-6-methyl

[0738] -5,6,7,8-Tetrahydro-1,6-naphthidium-2(1H)-one

[0739]

[0740] Example 88

[0741] 3-((8-(4,4-difluoropiperidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)-1-(2-hydroxyethyl)-6-methyl

[0742] -5,6,7,8-Tetrahydro-1,6-naphthidium-2(1H)-one

[0743]

[0744] Compounds 87 and 88 were prepared by the following steps:

[0745]

[0746] Step 1: Int-8a (300 mg, 1.42 mmol) was dissolved in NMP (5 mL), and 4,4-difluoropiperidine (343 mg, 2.84 mmol) and N,N-diisopropylethylamine (548 mg, 4.25 mmol) were added. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL * 2). The organic phases were combined and washed with saturated brine (50 mL). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a pale yellow solid compound 87a (350 mg, yield 83%). MS (ESI): m / z 297.2 [M+H] + .

[0747] Step 2: Compound 87a (350 mg, 1.18 mmol) was dissolved in dichloromethane (5 mL). Under ice bath conditions, m-chloroperoxybenzoic acid (600 mg, 84% purity, 2.95 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the solution was diluted with water (30 mL) and extracted with dichloromethane (30 mL x 2). The combined organic phases were washed with saturated sodium thiosulfate solution (30 mL), saturated sodium carbonate solution (30 mL), and saturated brine solution (30 mL), respectively. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a pale yellow solid, compound 87b (300 mg, 77% yield). MS (ESI): m / z 329.2 [M+H] + .

[0748] Step 3: Compound Int-18 (70 mg, 0.26 mmol) was dissolved in DMF (5 mL), and NaH (53 mg, 60% purity, 1.32 mmol) was added under ice bath conditions. The reaction system was stirred at 0 °C for 1 hour. Then, a DMF solution of compound 87b (87 mg, 0.26 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was poured into water (50 mL), and the resulting solid was filtered and dried to obtain the crude product. The crude product was purified by reverse-phase preparative HPLC to obtain a pale yellow solid compound 87 (35 mg, yield 27%). ESI-MS (m / z): 486.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.36(s,1H),8.55(s,1H),8.10(s,1H),8.08(d,J=5.5Hz,1H),7.32(d,J=5.5Hz,1H),4.22(t,J=5.5Hz,2H),3.9 8-3.90(m,4H),3.62(t,J=5.5Hz,2H),3.36(s,2H),3.25(s,3H),2.92-2.84(m,2H),2.69-2.61(m,2H),2.35(s,3H),2.24-2.12(m,4H).

[0749] Step 4: Compound 87 (30 mg, 0.062 mmol) was dissolved in dichloromethane (5 mL). NaI (9 mg, 0.062 mmol), 15-crown-5 (14 mg, 0.062 mmol), and boron tribromide (31 mg, 0.124 mmol) were added to the solution under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (50 mL) was added, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase preparative HPLC to give a white solid compound 88 (2 mg, yield 6.9%). ESI-MS (m / z): 472.4 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.35(s,1H),8.55(s,1H),8.10(s,1H),8.07(d,J=5.5Hz,1H),7.31(d,J=5.5Hz,1H),4.96(s,1H),4.11(t,J=5. 5Hz,2H),3.96-3.90(m,4H),3.67(t,J=6.0Hz,2H),3.36(s,2H),2.93-2.89(m,2H),2.66-2.62(m,2H),2.35(s,3H),2.23-2.13(m,4H).

[0750] Based on the synthetic route and intermediate synthesis method described in the above embodiments, the following embodiments were obtained.

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758] Example 112

[0759] (R)-2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)-3-methylbut-1-ol

[0760]

[0761] Compound 112 was prepared by the following steps:

[0762]

[0763] Step 1: Compound 112a (1.0 mg, 5.2 mmol) was dissolved in formic acid (10 mL), and the reaction mixture was stirred at 100 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction mixture was concentrated, and the residue was dissolved in dichloromethane. Ammonia-methanol solution (7 M) was added, and the insoluble matter was removed by filtration. The filtrate was concentrated to obtain compound 112b (1.1 g, yield 96%, pale yellow solid). ESI-MS (m / z): 221.4 [M+H] + .

[0764] Step 2: Compound 112b (950 mg, 4.31 mmol) was dissolved in 5 mL of dry DMF. Sodium hydride (314 mg, 60% purity, 8.21 mmol) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 1 hour, then cooled under ice bath conditions. Int-18 (1.0 g, 4.10 mmol, dissolved in 3 mL of dry DMF) was added. The reaction mixture was stirred for another 1 hour, and the reaction was monitored for completion by LCMS. The reaction solution was diluted with 100 mL of water, and the resulting yellow solid was collected by filtration and dried to give compound 112c (800 mg, 54% yield). ESI-MS (m / z): 356.3 [M+H] + .

[0765] Step 3: Compound 112c (50 mg, 140 μmol) was dissolved in N-methylpyrrolidone (3 mL), and D-valine (73 mg, 702 μmol) and N,N-diisopropylethylamine (91 mg, 702 μmol) were added. The reaction mixture was heated to 150 °C and stirred for 5 hours in a microwave reactor. The reaction was confirmed to be complete by LCMS. After cooling to room temperature, the reaction mixture was directly purified by reverse-phase preparative HPLC to obtain compound 112 (17 mg, formate, yield 26%). ESI-MS (m / z): 423.5 [M+H] + ; 1H NMR(500MHz,DMSO-d6)δ9.15(s,1H),8.39(s,1H),8.17(s,1H),7.94(s,1H),7.76 (d,J=5.6Hz,1H),6.85(d,J=5.6Hz,1H),6.82(s,1H),6.59(d,J=9.1Hz,1H),4.12 -4.04(m,1H),3.84(s,3H),3.67-3.63(m,1H),3.55-3.50(m,2H),2.81(t,J=5.9H z, 2H), 2.62 (t, J = 6.0Hz, 2H), 2.36 (s, 3H), 2.16-2.06 (m, 1H), 1.00-0.94 (m, 6H).

[0766] Biological screening and results of HPK1 inhibitors

[0767] Example 1: Detection of the inhibitory effect of compounds on HPK1 kinase activity (Method 1)

[0768] The reagents required are as follows:

[0769]

[0770] Experimental steps

[0771] The specific procedures are as follows: Prepare the enzyme reaction system buffer (10mM MOPS, pH 7.2, 5mM β-glycerol-phosphate, 10mM MgCl2, 0.8mM EDTA, 2mM EGTA, 0.1mM DTT); dilute the test compound (compound stock solution in 1mM DMSO) with buffer to a maximum concentration of 60μM (containing 6% DMSO), and prepare a gradient concentration of 8 points of compound starting at 60μM and then performing 5-fold dilutions with buffer containing 6% DMSO; then dilute HPK1 kinase to 30nM with buffer. Add 2 μl of HPK1 kinase dilution to each well of a Greiner 384-well microplate (catalog number: 784075), and add 2 μl of buffer to each control well. After brief centrifugation, add 1 μl of the diluted compound to each reaction well, and add 1 μl of buffer containing 6% DMSO to each control well. After brief centrifugation, incubate at 25°C for 20 min in a constant temperature incubator (Shanghai Yiheng Scientific Instruments Co., Ltd., catalog number: LRH-150). Add 3 μl of reaction substrate (10 μM MBP and 20 μM ATP dissolved in distilled water) to each well, briefly centrifuge, and incubate at 25°C for 60 min. Enzymatic activity was detected using the ADP-Glo ​​Kinase Assay Kit, and all ADP-Glo ​​Kinase Assay Kit assays were performed according to the kit's instructions. Data are described using the half-maximal inhibitory concentration (IC50) of the compound.

[0772]

[0773]

[0774]

[0775] Experimental Example 2: Detection of the agonistic effect of the compound on the interleukin-2 (IL-2) cytokine secreted by Jurkat cells (Method 2)

[0776] The required reagents and cells are as follows:

[0777] Experimental reagents:

[0778]

[0779] Experimental cells:

[0780]

[0781] Experimental steps

[0782] The specific procedure is as follows: Dissolve the compound powder in DMSO to 10 mM. Take 2 μl of the compound and add it to 998 μl of RPMI 1640 medium (containing 10% FBS in this experiment). Vortex mix well; this is the highest concentration point. Gradually dilute the compound solution 3-fold with 0.2% DMSO medium, resulting in 8 concentration points. RPMI 1640 medium solution containing 0.1% DMSO serves as a control. Add 1×10⁻⁶ ppm of the compound to each well of a Corning 96-well cell culture plate (catalog number: 3599). 5 Jurkat E6-1 cells were incubated with an equal volume of the compound dilution solution, while the control group was incubated with RPMI 1640 medium containing 0.2% DMSO. The cells were then incubated at 37°C in a Thermo Fisher Scientific (model 3111) for 1 hour. Anti-human CD3 antibody and anti-human CD28 antibody antibodies were then added to a final concentration of 1 μg / ml, and the cells were incubated at 37°C for 24 hours. The IL-2 content in the cell supernatant was detected using the Human IL-2 DuoSet ELISA Kit, performed according to the kit's instructions. Data are described as the fold-over ratio of the compound's stimulus signal to the signal from 0.1% DMSO.

[0783]

[0784]

[0785]

[0786] NA: Indicates that no enhanced IL-2 release was detected.

[0787] Experimental Example 3: Detection of the agonistic effect of the compound on the secretion of the cytokine interleukin-2 (IL-2) by mouse spleen cells (Method 3)

[0788] The required reagents and cells are as follows:

[0789] Experimental reagents:

[0790]

[0791] Laboratory animals:

[0792]

[0793]

[0794] Experimental steps

[0795] The specific procedures are as follows: Dissolve the compound powder in DMSO to 10 mM. Take 2 μl of the compound and add it to 998 μl of RPMI 1640 medium (containing 10% FBS in this experiment). Vortex mix well; this is the highest concentration point. Gradually dilute the compound solution 3-fold with 0.2% DMSO medium, resulting in 8 concentration points. RPMI 1640 medium solution containing 0.1% DMSO serves as a control. Add 10 mice to each well of a Corning 96-well cell culture plate (catalog number: 3599). 5 Spleen cells were added, followed by an equal volume of the compound diluent. The control group was added to RPMI 1640 medium containing 0.2% DMSO. Cells were incubated at 37°C in a Thermo Fisher Scientific (model 3111) for 1 hour. Then, Concanavalin A was added to a final concentration of 0.4 μg / ml, and the cells were incubated at 37°C for 24 hours. The IL-2 content in the cell supernatant was detected using the Mouse IL-2 DuoSet ELISA kit, performed according to the kit's instructions. Data are described as the fold-over ratio of the compound's stimulus signal to the signal from 0.1% DMSO.

[0796]

[0797]

[0798] NA: Indicates that no enhanced IL-2 release was detected.

[0799] Experimental Example 4: Detection of the agonistic effect of the compound on the secretion of the cytokine interleukin-6 (IL-6) by DC2.4 cells (Method 3)

[0800] The required reagents and cells are as follows:

[0801] Experimental reagents:

[0802]

[0803] Experimental cells:

[0804]

[0805] Experimental steps

[0806] The specific procedure is as follows: Dissolve the compound powder in DMSO to a concentration of 10 mM. Take 2 μl of the compound and add it to 998 μl of RPMI 1640 medium (containing 10% FBS in this experiment). Vortex mix well; this is the highest concentration point. Gradually dilute the compound solution 3-fold with 0.2% DMSO medium, resulting in 8 concentration points. RPMI 1640 medium solution containing 0.1% DMSO serves as a control. Add 10 μL of the compound powder to each well of a Corning 96-well cell culture plate (catalog number: 3599). 5 DC2.4 cells were incubated with an equal volume of the compound dilution solution, while the control group was incubated with RPMI 1640 medium containing 0.2% DMSO. The cells were then incubated at 37°C in a Thermo Fisher Scientific (model 3111) for 1 hour. LPS was then added to a final concentration of 3.2 ng / ml, and the cells were incubated at 37°C for 24 hours. The IL-2 content in the cell supernatant was detected using the Mouse IL-6 DuoSet ELISA kit, performed according to the kit's instructions. Data are described as the fold-over ratio of the compound's stimulus signal to the signal from 0.1% DMSO.

[0807]

[0808]

[0809]

[0810] NA: Indicates that no enhanced release of IL-6 was detected.

[0811] Example 5: Detection of the agonistic effect of the compound on the PBMC-secreted cytokine interleukin-2 (IL-2) (Method 5)

[0812] The required reagents and cells are as follows:

[0813] Experimental reagents:

[0814]

[0815] Experimental cells:

[0816]

[0817] Experimental steps

[0818] The specific procedure is as follows: Dissolve the compound powder in DMSO to 10 mM. Take 2 μl of the compound and add it to 998 μl of RPMI 1640 medium (containing 10% FBS in this experiment). Vortex mix well; this is the highest concentration point. Gradually dilute the compound solution 3-fold with 0.2% DMSO medium, resulting in 8 concentration points. RPMI 1640 medium solution containing 0.1% DMSO serves as a control. Add 1×10⁻⁶ ppm of the compound to each well of a Corning 96-well cell culture plate (catalog number: 3599). 5 PBMC cells were incubated with an equal volume of the compound dilution solution, while the control group was incubated with RPMI 1640 medium containing 0.2% DMSO. The cells were then incubated at 37°C in a Thermo Fisher Scientific (model 3111) for 1 hour. Subsequently, 0.1 μg / ml Anti-human CD3 Antibody and 1 μg / ml Anti-human CD28 Antibody antibodies were added, and the cells were incubated at 37°C for 24 hours. The IL-2 content in the cell supernatant was detected using the Human IL-2 DuoSet ELISA Kit, performed according to the kit's instructions. Data are described as the fold-over ratio of the compound's stimulus signal to the signal from 0.1% DMSO.

[0819]

[0820]

[0821] NA: Indicates that no enhanced IL-2 release was detected.

Claims

1. Compounds or pharmaceutically acceptable salts or stereoisomers having the following structures:

2. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically usable carrier.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or pharmaceutical composition of claim 2 in the preparation of a medicament for the prevention and / or treatment of tumors, inflammatory diseases, autoimmune diseases, or immune-mediated diseases.

4. Use of the compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer thereof, or the pharmaceutical composition of claim 2 in the preparation of a medicament for the prevention and / or treatment of cancer.

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