A PI5P4Kγ inhibitor compound, pharmaceutical composition, and preparation method and application thereof

Abstract

The present invention provides a compound having PI5P4Kγ inhibitory activity, and its pharmaceutically acceptable salts, hydrates, solvates or prodrugs, as well as a preparation method of such compounds and their applications in anti-tumor drugs.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a PI5P4Kγ inhibitor compound, a pharmaceutical composition, and a preparation method and application thereof. Background Art

[0002] Type II phosphatidylinositol-5-phosphate-4-kinases (PI5P4Ks) play multiple regulatory roles in the occurrence and development of tumors, and are involved in the regulation of important physiological processes such as tumor cell survival, metastasis, lipid metabolism, mitochondrial function homeostasis, autophagy, and tumor immunity. Three PI5P4K subtypes, α, β, and γ, have been identified in mammals, and their corresponding encoding genes are PIP4K2A, PIP4K2B, and PIP4K2C, respectively. Another γ subtype among the three PI5P4K subtypes has lagged in the research on its biological functions due to its weak kinase activity. However, in recent years, with the confirmation of the important regulatory roles of PI5P4Kγ in physiological processes such as cell survival, autophagy, and immunity, it has gradually attracted the attention of new drug researchers. When knocking out PIP4K2C, it does not affect the normal metabolism, growth and development, and normal lifespan of gene knockout mice, indicating that PI5P4Kγ has good potential as a target for safety. Researchers have also found that knocking out PIP4K2C in normal mice will activate NK cell and T cell immunity, and significantly improve the immune function of mice. PIP4K2C plays a key role in maintaining the proliferation, survival, and immunosuppressive function of Treg cells. Inhibiting PI5P4Kγ can induce the death of Treg cells and activate T cells, thereby inhibiting the immune escape of tumor cells. Knocking out or inhibiting PIP4K2C can selectively eliminate tumor cells with TP53 mutations and KRAS mutations without affecting the survival of normal cells. Therefore, inhibiting PI5P4Kγ may be an effective intervention method for tumors with TP53 and KRAS mutations or overexpression of PI5P4Kγ. In addition, PI5P4Kγ has also been found to be closely related to abnormal changes in signal pathways related to tumor survival, proliferation, metastasis, and drug resistance, such as RTKs, mTOR, Wnt, Nrf2, p53 / Rb, Notch, Myc, and Hippo / YAP. In summary, PI5P4Kγ is a safe and effective new anti-tumor target.

[0003] However, there has been relatively little research on selective inhibitors of PI5P4Kγ. The currently reported PI5P4Kγ inhibitors mainly include ARUK2001607 acting on the orthosteric site, NIH-12848, Compound 40, NCT-504 and its structural derivative PI5P4Kγ-IN-1 acting on the allosteric pocket, as well as proteolysis-targeting chimeras JWZ-1-80, TMX-4102 and TMX-4153. Among them, the orthosteric inhibitor ARUK2001607, the allosteric inhibitor PI5P4Kγ-IN-1 and the proteolysis-targeting chimera TMX-4153 all have good target-binding affinity, with Kd values lower than 50 nM. However, these compounds only have target inhibitory activity, and there is no in vivo anti-tumor efficacy data. For in vitro activity research, there is only a report that the compounds can induce changes in downstream related proteins at a concentration in the micromolar range (1.0 - 10 μM). Due to the lack of anti-tumor efficacy data, the applicant investigated the proliferation inhibitory activity of ARUK2001607, TMX-4102 and NIH-12848 against the lung adenocarcinoma cell line HCC827 with high expression of PI5P4Kγ, and found that their IC 50 values were between 6 - 10 μM, indicating that their anti-tumor activity still needs to be improved. In summary, there is still a need to develop a large number of more novel PI5P4Kγ inhibitors, further improve their anti-tumor activity, and explore the potential of PI5P4Kγ as a novel anti-tumor target. SUMMARY OF THE INVENTION

[0004] To address the above technical problems, the present invention provides a compound represented by formula (I), its tautomer, stereoisomer, isotope-labeled substance, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

[0005]

[0006] Wherein:

[0007] Y is selected from N or CR y ;

[0008] Z is selected from N or CR z ;

[0009] A is selected from N or CR a ;

[0010] D is selected from N or CR d ;

[0011] E is selected from N or CR e ;

[0012] G is selected from N or CR g ;

[0013] R y 、R z 、Ra , R d , R e , R g are the same or different and are each independently selected from H, halogen, CN, C 1-6 -alkyl, C 1-6 -heteroalkyl;

[0014] R1 is selected from H, unsubstituted or optionally substituted by one, two or more R 11 and is one of the following groups: C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, C 3-10 -heterocycloalkyl, C 6-10 -aryl, 5- to 10-membered heteroaryl; each R 11 is the same or different and is each independently selected from CN, halogen, C2-6 alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, C 3-10 -heterocycloalkyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, C 1-6 -alkyl-C 6-10 -aryl;

[0015] R2 is selected from H, OH, NH2, halogen, C 1-6 -alkyl, C 1-6 -heteroalkyl, halo-C 1-6 -alkyl, halo-C 1-6 -heteroalkyl;

[0016] R 31 , R 32 are the same or different and are each independently selected from H, halogen, CN, C 1-6 -alkyl, C 1-6 -heteroalkyl, halo-C 1-6 -alkyl, halo-C1-6 heteroalkyl;

[0017] R4 and R5 are the same or different and are each independently selected from H, unsubstituted or optionally substituted by one, two or more R 41 and is one of the following groups: NH2, C 1-6 -alkyl, C 1-6 -heteroalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, C 3-10 -heterocycloalkyl, C 6-10 -aryl, 5- to 10-membered heteroaryl; each R 41 is the same or different and is each independently selected from H, OH, CN, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 heterocyclic group, C 6-10 aryl, 5 - 10 - membered heteroaryl, C 1-6 alkyl - C 6-10 aryl -, C 1-6 alkoxy - C 6-10 aryl -, halo - C 6-10 aryl -, C 6-10 aryl - C 1-6 alkyl -, C 1-6 alkyl - NH -;

[0018] Alternatively, R4, R5 and the atoms to which they are attached form an unsubstituted or optionally substituted by one, two or more R 51 substituted 3 - 10 - membered lactam; each R 51 is the same or different and is independently selected from H, OH, CN, oxo(=O), halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 heterocyclic group, C 6-10 aryl, 5 - 10 - membered heteroaryl.

[0019] According to an embodiment of the present invention, Y is selected from N or CH.

[0020] According to an embodiment of the present invention, Z is selected from N or CH.

[0021] According to an embodiment of the present invention, A is selected from N or CR a ; R a is selected from H, F, CN, methyl, methoxy;

[0022] According to an embodiment of the present invention, A is selected from N, CH, CCH3 or CF.

[0023] According to an embodiment of the present invention, D is selected from N or CR d ; R d is selected from H, F, CN, methyl, methoxy;

[0024] According to an embodiment of the present invention, D is selected from N, CH, CF or COCH3.

[0025] According to an embodiment of the present invention, E is selected from N or CR e ; R e is selected from H, F, CN, methyl, methoxy;

[0026] According to an embodiment of the present invention, E is selected from N, CH, CCH3 or CF.

[0027] According to an embodiment of the present invention, G is selected from N or CR g ; R g is selected from H, F, CN, methyl, methoxy;

[0028] According to an embodiment of the present invention, G is selected from N, CH, CCH3 or CF.

[0029] According to an embodiment of the present invention, R1 is selected from H, C 1-6 alkyl, C 2-6 alkynyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl, C 1-6 alkyl-C 6-10 aryl-C 1-6 alkyl;

[0030] According to an embodiment of the present invention, R1 is selected from H, the following groups which are unsubstituted or optionally substituted by F, cyclopropyl, cyclobutyl or phenyl: methyl, ethyl, propyl, butyl, pentyl, propynyl;

[0031] According to an embodiment of the present invention, R1 is selected from H,

[0032] According to an embodiment of the present invention, R2 is selected from H, OH, halogen, NH2, C 1-6 alkyl, C 1-6 heteroalkyl;

[0033] According to an embodiment of the present invention, R2 is selected from H, OH, NH2, methyl.

[0034] According to an embodiment of the present invention, R 31 , R 32 are the same or different and are independently selected from H, halogen, C 1-6 alkyl, C 1-6 heteroalkyl.

[0035] According to an embodiment of the present invention, R 31 is selected from H; R 32 is selected from H.

[0036] According to an embodiment of the present invention, R4 is H.

[0037] According to an embodiment of the present invention, R5 is selected from C 1-6 alkyl, halo C1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, halo-C 6-10 Aryl, C 3-8 Cycloalkyl-C 1-6 Alkyl, C 1-6 Alkyl-NH-C 1-6 Alkyl, C 1-6 Alkyl-NH-, C 6-10 Aryl-NH-, C1-6 alkyl-C 6-10 Aryl-NH-, C 1-6 Alkoxy-C 6-10 Aryl-NH-, halo-C 6-10 Aryl-NH-, C 6-10 Aryl-C 1-6 Alkyl-NH-;

[0038] According to an embodiment of the present invention, R5 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more of F, butyl, cyclopropyl, cyclobutyl, phenyl, tolyl, benzyl, fluorophenyl, methoxyphenyl, ethylamino: methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, amino, phenyl, pyridyl;

[0039] According to an embodiment of the present invention, R5 is selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-fluorophenyl, 4-pyridyl, cyclopropylmethyl, cyclobutylmethyl,

[0040]

[0041] According to an embodiment of the present invention, R4, R5 and the atoms to which they are respectively attached form the following groups which are unsubstituted or optionally substituted by one, two or more R 51 substituted: Each R 51 is the same or different and is independently selected from H, oxo(=O), methyl, ethyl.

[0042] According to an embodiment of the present invention, is selected from (such as ).

[0043] According to an embodiment of the present invention, the compound represented by formula (I) has the structure represented by formula (II)

[0044]

[0045] Among them, Y, Z, A, D, E, G, R1, R2, R4, and R5 have the definitions described above.

[0046] According to an embodiment of the present invention, the compound represented by formula (I) has the structure represented by formula (III)

[0047]

[0048] Among them, Y, Z, A, D, E, G, R1, R2, and R5 have the definitions described above.

[0049] According to an embodiment of the present invention, the compound represented by formula (I) is selected from the structures shown below:

[0050]

[0051]

[0052]

[0053]

[0054] According to an embodiment of the present invention, the compound represented by formula (I) is selected from:

[0055] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)acetamide (r1)

[0056] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)propanamide (r2)

[0057] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)hexanamide (r3)

[0058] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)butyramide (r4)

[0059] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)butyramide (r4)

[0060] 4-fluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)benzamide (r6)

[0061] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)cyclopropanecarboxamide (r7)

[0062] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)cyclobutanecarboxamide (r8)

[0063] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)isonicotinamide (r9)

[0064] N-(5-(2-ethyl-1-oxo-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r10)

[0065] N-(5-(2-butyl-1-oxo-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r11)

[0066] N-(5-(2-(cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r12)

[0067] N-(5-(2-benzyl-1-oxo-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r13)

[0068] N-(5-(2-(4-methylbenzyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r14)

[0069] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrazin-2-yl)pentanamide (r15)

[0070] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r16)

[0071] N-(2-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-5-yl)pentanamide (r17)

[0072] N-(4-fluoro-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r18)

[0073] N-(2-fluoro-4-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)phenyl)pentanamide (r19)

[0074] N-(2-methoxy-4-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)phenyl)pentanamide (r20)

[0075] 4,4-difluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r21)

[0076] N-(5-(2-(Cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)-4,4-difluoropentanamide (r22) 4-Fluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r23)

[0077] N-(5-(2-(Cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)-4-fluoropentanamide (r24)

[0078] 3,3-Difluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r25)

[0079] 3-Fluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r26)

[0080] N-(5-(2-(Cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r27)

[0081] N-(5-(6-(Cyclopropylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridin-3-yl)pyridin-2-yl)pentanamide (r28) N-(5-(2-Amino-4-oxo-3-propyl-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)pyridin-2-yl)pentanamide (r29) N-(5-(4-oxo-3-propyl-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)pyridin-2-yl)pentanamide (r30)

[0082] N-(5-(2-Hydroxy-4-oxo-3-propyl-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)pyridin-2-yl)pentanamide (r31) N-(5-(3-(Cyclopropylmethyl)-2-hydroxy-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r32) N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)benzamide (r33)

[0083] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)butanamide (r34)

[0084] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r35)

[0085] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)hexanamide (r36)

[0086] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)cyclobutanecarboxamide (r37)

[0087] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)cyclopentanecarboxamide (r38)

[0088] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)cyclohexanecarboxamide (r39)

[0089] N-(5-(3-Ethyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r40)

[0090] N-(5-(3-Isopentyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r41)

[0091] N-(5-(3-(Cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r42)

[0092] N-(5-(3-(Cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)hexanamide (r43)

[0093] N-(5-(3-(Cyclobutylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r44)

[0094] N-(5-(4-Oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)benzamide (r45)

[0095] N-(5-(4-Oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r46)

[0096] N-(5-(4-Oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)hexanamide (r47)

[0097] N-(5-(1-Oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r48)

[0098] N-(5-(1-Oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r49)

[0099] N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyrimidin-2-yl)pentanamide (r50)

[0100] N-(4-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)phenyl)pentanamide (r51)

[0101] N-(5-(5-oxo-6-propyl-5,6-dihydropyrido[1,6-a]pyridin-3-yl)pyridin-2-yl)pentanamide (r52)

[0102] 2-cyclopropyl-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)acetamide (r53)

[0103] 2-cyclobutyl-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)acetamide (r54)

[0104] N-(6-fluoro-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r55)

[0105] N-(5-(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r56)

[0106] N-(5-(2-hydroxy-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r57)

[0107] N-(5-(3-(2-fluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r58)

[0108] 2-(ethylamino)-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)acetamide (r59)

[0109] N-(5-(2-amino-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r60)

[0110] N-(5-(2-amino-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4,4-difluoropentanamide (r61)

[0111] N-(5-(2-amino-3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4,4-difluoropentanamide (r62)

[0112] N-(5-(4-Oxo-3-(prop-2-yn-1-yl)-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r63)

[0113] N-(5-(3-Cyclopropyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r64)

[0114] N-(5-(3-(2-Fluoropropyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r65)

[0115] 4,4-Difluoro-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r66)

[0116] N-(5-(3-(Cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4-fluoropentanamide (r67)

[0117] N-(5-(3-(Cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4,4-difluoropentanamide (r68)

[0118] N-(5-(3-(Cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3,3-difluoropentanamide (r69)

[0119] N-(5-(3-(Cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-fluoropentanamide (r70)

[0120] 3,3-Difluoro-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r71)

[0121] N-(5-(4-Oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyrazin-2-yl)pentanamide (r72)

[0122] N-(6-(4-Oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-3-yl)pentanamide (r73)

[0123] N-(2-(4-Oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyrimidin-5-yl)pentanamide (r74)

[0124] N-(3-Methyl-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r75)

[0125] N-(4-Methyl-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r76)

[0126] N-(6-Methyl-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r77)

[0127] N-(3-Fluoro-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r78)

[0128] 1-(5-(3-Benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(o-tolyl)urea (r79)

[0129] 1-(5-(3-Benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(m-tolyl)urea (r80)

[0130] 1-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-phenylurea (r81)

[0131] 1-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(4-fluorophenyl)urea (r82)

[0132] 1-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(4-methoxyphenyl)urea (r83)

[0133] 1-Benzyl-3-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)urea (r84)

[0134] 1-Butyl-3-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)urea (r85)

[0135] 1-(tert-Butyl)-3-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)urea (r86)

[0136] 6-(6-(2-Oxopyrrolidin-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (r87)

[0137] 6-(6-(2-Oxopiperidin-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (r88)

[0138] 6-(6-(2-Oxazepan-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (r89)

[0139] 6-(6-(4-Methyl-2-oxopiperidin-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (r90)

[0140] (S)-6-(6-(4-Ethyl-2-oxazepan-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (r91).

[0141] The present invention also provides a method for preparing the compound of formula (I), including the following Scheme 1 or Scheme 2:

[0142] Scheme 1: Reacting compound M1 with M1-1 to obtain the compound of formula (I);

[0143]

[0144] Scheme 2: Reacting compound M1 with M1-2 to obtain compound M2; Reacting compound M2 with compound M2-1 to obtain the compound of formula (I); M2-1 is

[0145]

[0146] Wherein, Y, Z, A, D, E, G, R1, R2, R 31 、R 32 、R4, R5 independently of one another have the definitions described above;

[0147] According to an embodiment of the present invention, the preparation method can be carried out in the presence of a solvent such as an organic solvent. For example, the organic solvent can be selected from at least one of the following: alcohols such as methanol, ethanol, isopropanol, n-butanol; ethers such as ethyl propyl ether, n-butyl ether, anisole, phenetole, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl ethylene glycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, dichloroethyl ether, and polyethers of ethylene oxide and / or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons such as pentane, hexane, heptane, octane, nonane, and those that may be substituted by fluorine and chlorine atoms such as methylene chloride, dichloromethane, chloroform, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, bromobenzene, xylene; esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate and dimethyl carbonate, dibutyl carbonate or ethylene carbonate.

[0148] The present invention also provides intermediate compounds represented by the following formula M1 or M2:

[0149]

[0150] Wherein Y, Z, A, D, E, G, R1, R2, R 31 、R 32 、R4, and R5 independently of one another have the definitions described above.

[0151] The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the compound represented by formula (I), its tautomer, stereoisomer, isotope-labeled compound, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

[0152] According to an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0153] The present invention also provides the use of the compound represented by formula (I), its tautomer, stereoisomer, isotope-labeled compound, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition in the preparation of a drug, for example, in the preparation of a drug related to PI5P4Kγ inhibition.

[0154] According to an embodiment of the present invention, the pharmaceutical composition or the drug is used for preventing and / or treating diseases related to PI5P4Kγ inhibition, such as cancer.

[0155] According to an embodiment of the present invention, the cancer is selected from solid tumor cancers or hematological cancers, and the solid tumor cancers are selected from lung cancer, breast cancer, cervical cancer, ovarian cancer, liver cancer, gastric cancer, kidney cancer, colorectal cancer, prostate cancer, pancreatic cancer, bladder cancer, blood cancer, bone cancer, brain cancer, central nervous system cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, genital cancer, urogenital cancer, head cancer, laryngeal cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosal cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, testicular cancer and / or thyroid cancer; for example, lung adenocarcinoma cells resistant to EGFR-TKI, tumors with TP53 mutation, TTN mutation and KRAS mutation; the hematological tumor cancers are, for example, blood cancers.

[0156] The present invention also provides a compound represented by formula (I), its tautomer, stereoisomer, isotope-labeled compound, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition for preventing and / or treating diseases related to PI5P4Kγ inhibition.

[0157] The present invention also provides a method for preventing and / or treating a disease (such as cancer) related to PI5P4Kγ inhibition, including administering to a patient a therapeutically effective amount of the compound represented by formula (I), its tautomer, stereoisomer, isotope-labeled substance, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or at least one of the said pharmaceutical compositions.

[0158] According to an embodiment of the present invention, the cancer is selected from solid tumor cancers or hematological cancers, and the solid tumor cancers are selected from lung cancer, breast cancer, cervical cancer, ovarian cancer, liver cancer, gastric cancer, kidney cancer, colorectal cancer, prostate cancer, pancreatic cancer, bladder cancer, blood cancer, bone cancer, brain cancer, central nervous system cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, genital cancer, urogenital cancer, head cancer, laryngeal cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosa cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, testicular cancer and / or thyroid cancer; for example, lung adenocarcinoma cells resistant to EGFR-TKI, tumors with TP53 mutation, TTN mutation and KRAS mutation; the hematological tumor cancers are, for example, blood cancers.

[0159] When preparing the drug or pharmaceutical composition of the present invention, the compound of the present invention, its tautomer, stereoisomer, isotope-labeled substance, hydrate, solvate, pharmaceutically acceptable salt or prodrug can be combined or formulated with appropriate pharmaceutically acceptable excipients (such as carriers, diluents or excipients) to prepare, and can be formulated into preparations in solid, semi-solid, liquid or gas forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. The administration routes include oral, intraperitoneal, transdermal, subcutaneous, intravenous or intramuscular injection, inhalation, topical, intralesional, infusion; liposome-mediated delivery; local, intrathecal, gingival pocket, rectal, bronchial, nasal, transmucosal, intestinal, ophthalmic or otic delivery, or any other method known in the art, all of which can achieve the treatment of tumors.

[0160] The therapeutically effective amount or dose of the present invention will vary according to several factors, including the selected administration route, the formulation of the composition, the patient's response, the severity of the condition, the weight of the subject and the judgment of the prescribing doctor, for example, 1-200 mg / kg, 40-150 mg / kg, such as 50 mg / kg. The dose can be increased or decreased over time as needed for individual patients. In some cases, the patient is initially given a low dose and then increased to an effective dose that the patient can tolerate. In addition, the patient can be given multiple doses over a determined period of time, especially at time intervals (such as daily, weekly, bi-weekly, monthly, quarterly, biennially or the like).

[0161] Beneficial effects

[0162] The present invention provides a compound of formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, which has an inhibitory effect on PI5P4Kγ and can be used for preventing and / or treating cancer. The crystal structure of the complex of the compound of the present invention with PI5P4Kγ shows that such compounds act on both the orthosteric site and the allosteric site of PI5P4Kγ simultaneously, and the in vivo anti-tumor efficacy is significantly higher than that of the known PI5P4Kγ inhibitors. This type of PI5P4Kγ inhibitor has a novel structure, a unique target acting mode, and remarkable anti-tumor efficacy. Description of the Drawings

[0163] Figure 1 Inhibitory activity of compound r46 against PI5P4Kγ and selectivity for two other subtypes.

[0164] Figure 2 Selectivity of compound r46 for 486 kinases.

[0165] Figure 3 Co-crystallization structure of compound r46 with PI5P4Kγ and its key interactions.

[0166] Figure 4 In vivo anti-tumor efficacy of compound r46.

[0167] Figure 5 Acute toxicity experiment of compound r46 on mice.

[0168] Figure 6 Compound r46 has no mutagenic effect on strains such as TA100, TA102, TA98 and TA97a.

[0169] Figure 7 Inhibitory activity of compound r46 against hERG.

[0170] Figure 8 Subacute toxicity of compound r46 on mice.

[0171] Term Definitions and Explanations

[0172] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be combined and combined with each other arbitrarily. The group definitions and compound structures after such combination and combination should be understood to be within the scope recorded in the specification and / or claims of this application.

[0173] Unless otherwise specified, the numerical ranges recited in this specification and the claims are equivalent to at least reciting each specific integer value therein. For example, the numerical range "1-10" is equivalent to reciting each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0174] It should be understood that in the description of one, two or more, "more" should mean greater than 2, for example, an integer greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0175] Used in the context of the present invention represents a chemical bond.

[0176] The term "C 1-6 alkyl" means a straight-chain or branched-chain saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. The C 1-6 alkyl includes C 1-3 alkyl, C 3-6 alkyl, etc. The alkyl is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers.

[0177] The term "C 2-6 alkenyl" should be understood to mean a straight-chain or branched-chain monovalent hydrocarbon group that contains one or more double bonds and has 2, 3, 4, 5 or 6 carbon atoms, for example, having 2 or 3 carbon atoms (i.e., C 2-3(alkenyl). It should be understood that when the alkenyl contains more than one double bond, the double bonds can be separated or conjugated with each other. The alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0178] The term "C 2-6 alkynyl" should be understood to mean a straight-chain or branched monovalent hydrocarbon group that contains one or more triple bonds and has 2, 3, 4, 5, or 6 carbon atoms, such as having 2 or 3 carbon atoms ("C 2-3"alkynyl"). The alkynyl is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl.

[0179] The term "C 1-6 heteroalkyl" means a straight-chain or branched-chain saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms and containing at least 1 heteroatom selected from O, S, N. The C 1-6 heteroalkyl includes -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 ether group, C 1-6 thioether group. For example, selected from methoxy, ethoxy, methylthio, methylamino, dimethylamino, diethylamino.

[0180] The term "C 3-10 cycloalkyl" means a saturated monovalent monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The C 3-10 cycloalkyl includes C 3-8 cycloalkyl, C 3-5 cycloalkyl, C 6-8 cycloalkyl, C 3-4 cycloalkyl, C 5-6 cycloalkyl, C6 cycloalkyl, etc. The C 3-10The cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as bornyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or a tricyclic hydrocarbon group such as adamantyl.

[0181] The term "3- to 10-membered heterocyclic group" means a saturated or unsaturated non-aromatic ring or ring system and contains at least one heteroatom selected from O, S and N. The heterocyclic group may be linked to the rest of the molecule through any one of the carbon atoms or a nitrogen atom (if present). The heterocyclic group may include fused or bridged rings as well as spiro rings. In particular, the heterocyclic group may include, but is not limited to: 3-membered rings such as aziridinyl, oxiranyl; 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuryl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, for example but not limited to 5,5-membered rings such as hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or 5,6-membered bicyclic rings such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as but not limited to dihydrofuryl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[1,4]thiazinyl, or, it may be benzo-fused, such as but not limited to dihydroisoquinolinyl. When the 3- to 10-membered heterocyclic group is linked to other groups to form the compounds of the present invention, it may be the carbon atom on the 3- to 10-membered heterocyclic group that is linked to other groups, or it may be a heteroatom (such as an N atom) on the 3- to 10-membered heterocyclic ring that is linked to other groups. For example, when the 3- to 10-membered heterocyclic group is selected from piperazinyl, tetrahydropyrrolyl, it may be the nitrogen atom or carbon atom on piperazinyl that is linked to other groups. Or when the 3- to 10-membered heterocyclic group is selected from piperidinyl, it may be the nitrogen atom on the piperidinyl ring or the carbon atom at its ortho, meta or para position that is linked to other groups.

[0182] The term "C 6-10"Aryl" should preferably be understood to mean a monocyclic, bicyclic or tricyclic hydrocarbon ring that is monovalent, aromatic or partially aromatic and has 6, 7, 8, 9 or 10 carbon atoms, especially a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. When the C 6-10 aryl is substituted, it can be mono-substituted or multi-substituted. Also, there is no restriction on the substitution site, for example, it can be ortho-substituted, para-substituted or meta-substituted.

[0183] The term "5- to 10-membered heteroaryl" refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9 or 10 ring atoms, and the ring atoms thereof include 1 to 5 heteroatoms independently selected from N, O and S. The bicyclic and tricyclic aromatic ring systems can be fused rings, spiro rings or bridged rings. The number of heteroatoms in the 5- to 10-membered heteroaryl is 1 to 5, preferably 1 to 3. Additionally, in each case, the 5- to 10-membered heteroaryl can be benzo-fused. The 5- to 10-membered heteroaryl includes 5- to 8-membered heteroaryl, 5- to 9-membered heteroaryl, 5- to 10-membered heteroaryl, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl, 6-membered heteroaryl, etc. Examples of heteroaryl include, but are not limited to: 5-membered rings, such as oxazolyl, pyrazolyl, thienyl, thiazolyl, triazole, imidazolyl, etc.; 6-membered rings, such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. The heterocyclic group can be bicyclic, including, but not limited to: 5,5-membered rings, such as tetrahydrocyclopentanopyrazole; 5,6-membered rings, such as tetrahydroindole, tetrahydropyrazolopyridine, tetrahydroimidazopyridine, tetrahydrobenzisoxazole, tetrahydrobenzoxazole, tetrahydrobenzothiazole, tetrahydrobenzisothiazole, dihydrofuranopyrazole, tetrahydrobenzofuran, dihydrobenzofuran, tetrahydrobenzothiophene; 6,6-membered rings, such as tetrahydroquinoline; 5,7-membered rings, such as tetrahydrocycloheptathiazole, tetrahydrocycloheptafuran. The heterocyclic group can be tricyclic, including, but not limited to: 6,7-dihydrospiro[cyclopropane-1,5-pyrrolo[1,2-c]imidazole]. When the 5- to 10-membered heteroaryl is substituted, it can be mono-substituted or multi-substituted. Also, there is no restriction on the substitution site, for example, a hydrogen atom connected to a carbon atom on the heteroaryl ring can be substituted, or a hydrogen atom connected to a heteroatom on the heteroaryl ring can be substituted.

[0184] The term "3- to 10-membered lactam" refers to a cyclic group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms and including -C(O)NH- in the formed ring. The "3- to 10-membered lactam" includes 3- to 8-membered lactams, 4- to 6-membered lactams. For example, selected from Other groups are attached to the C atom or N atom in the 3- to 10-membered lactam.

[0185] The term "spiro" refers to a ring system in which two rings share one ring-forming atom.

[0186] The term "fused ring" refers to a ring system in which two rings share two ring-forming atoms.

[0187] The term "bridged ring" refers to a ring system in which two rings share more than three ring-forming atoms.

[0188] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0189] "Halogenated" means substituted by one or more halogens.

[0190] The term "oxo(=O)" means that the hydrogen on a non-oxygen atom is substituted or the lone pair of electrons is replaced by oxygen. For example, after being oxo-substituted is after being oxo-substituted is

[0191] The term "halo-C 1-6 alkyl" refers to an alkyl group as defined above, which is substituted by one or more halogens as defined above, preferably "halo-C 1-3 alkyl". The haloalkyl group includes but is not limited to monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.

[0192] Crystallization often produces solvates of the compounds of the present invention. As used herein, the term "solvate" refers to an entity formed by the combination of one or more molecules of the compounds of the present invention and one or more solvent molecules.

[0193] The solvent can be water, in which case the solvate is a hydrate. It can also be an organic solvent. Therefore, the compounds of the present invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, etc., as well as the corresponding solvated forms. The compounds of the present invention can be true solvates, but in some other cases, the compounds of the present invention may only accidentally retain water or a mixture of water and some other solvents. The compounds of the present invention can react in a solvent or precipitate or crystallize in a solvent. The solvates of the compounds of the present invention are also included within the scope of the present invention.

[0194] As used herein, the term "acceptable" in relation to a formulation, composition or ingredient means that it has no continuing adverse effect on the overall health of the treated subject.

[0195] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing adverse biological reactions or interacting in an adverse manner with any of the components contained in the composition.

[0196] Those skilled in the art will understand that the compounds of the present invention can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (such as a carboxyl group) and a basic center (such as an amino group), they can also form internal salts.

[0197] The term "tautomer" refers to functional group isomers resulting from the rapid movement of a particular atom within a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Prototrophic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in an equilibrium form, and attempting to isolate a single tautomer usually results in a mixture whose physical and chemical properties are consistent with those of a mixture of compounds. The position of the equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0198] Depending on their molecular structure, the compounds of the present invention may be chiral and thus may exist in various enantiomeric forms. Consequently, these compounds can exist in racemic form or in optically active form. The compounds of the present invention encompass isomers or mixtures thereof, racemates, in which each chiral carbon has the R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art or can be used in synthesis in this form. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (such as N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids. Chromatographic enantiomeric resolution can also be advantageously carried out with the aid of an optically active resolving agent (such as dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0199] In the present application, "pharmaceutical composition" refers to a preparation of the compounds of the present invention and a medium commonly accepted in the art for delivering bioactive compounds to mammals (such as humans). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, facilitate the absorption of the active ingredient and thereby exert its biological activity.

[0200] In the present application, "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifying agents that are permitted by the relevant government regulatory authorities for use in humans or livestock.

[0201] In the present application, the term "solvate" refers to a stoichiometric or non-stoichiometric solvent in which the compounds or salts of the present invention are bound by intermolecular non-covalent forces, and when the solvent is water, it is a hydrate.

[0202] In the present application, the term "prodrug" refers to a compound that can be converted into a bioactive compound of the present invention under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying the functional groups in the compound, and this modification can be removed by conventional operations or in vivo to obtain the parent compound. Prodrugs include compounds formed by connecting a hydroxyl group or an amino group in the compounds of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.

[0203] "Isotope" refers to all isotopes of the atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example but not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 31 P, 32 P, 35 S, 18 F and 36 C1. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples using appropriate isotopically labeled reagents in place of non-isotopically labeled reagents. Such compounds have various potential uses, for example as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.

[0204] As used herein, the term "tumor" includes both benign tumors and malignant tumors (e.g., cancers).

[0205] The terms "treatment" and other similar synonyms used herein include the following meanings:

[0206] (i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder but has not been diagnosed as having the disease or disorder;

[0207] (ii) Inhibiting a disease or disorder, i.e., arresting its development;

[0208] (iii) Alleviating a disease or disorder, i.e., causing the state of the disease or disorder to regress; or

[0209] (iv) Relieving the symptoms caused by the disease or disorder.

[0210] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0211] The term "therapeutically effective amount" refers to the amount of an active compound or drug that a researcher, veterinarian, physician or other clinician is seeking to elicit a biological or medical response in a tissue, system, animal, individual or human, and it includes one or more of the following: (1) Preventing a disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or manifested the disease pathology or symptoms. (2) Inhibiting a disease: e.g., inhibiting a disease, disorder or condition in an individual who is experiencing or manifesting the disease pathology or symptoms of the disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms). (3) Alleviating a disease: e.g., alleviating a disease, disorder or condition in an individual who is experiencing or manifesting the disease pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and / or symptoms). Detailed Description of the Invention

[0212] The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only illustrative of and for the purpose of explaining the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection of the present invention.

[0213] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products, or can be prepared by known methods.

[0214] The synthesis methods and steps of the compounds of the present invention include:

[0215] S1. Using compounds a, c, and h as substrates to synthesize intermediate k, the reaction route is as follows:

[0216]

[0217] The specific reaction process is as follows:

[0218] Potassium carbonate is added to the acetone solution of raw material a and compound b and reacted for 5 - 8 hours. After the reaction, it is concentrated and purified by column chromatography to obtain intermediate compound k.

[0219]

[0220] The specific reaction process is as follows:

[0221] Compound d is added to the pyridine solution of compound c and reacted at 50 °C overnight. After the reaction, it is cooled to room temperature, the mixture is concentrated under reduced pressure, extracted with 5% potassium carbonate solution and dichloromethane, the organic extract is concentrated, and purified by column chromatography to obtain intermediate compound e;

[0222] Compound f is added to the isopropanol solution of intermediate compound e and stirred at 85 °C for 3 - 5 hours. After the reaction, it is cooled to room temperature, concentrated and purified by column chromatography to obtain the corresponding intermediate compound g.

[0223] Concentrated hydrochloric acid is added to the dimethyl sulfoxide solution of intermediate compound g, and the temperature is raised to 100 °C and reacted for 1 - 3 hours. Then the mixture is poured into water, treated with potassium carbonate until no bubbles are generated, and then extracted with dichloromethane. The solvent is removed under reduced pressure, the residue is dissolved in acetic acid, washed with water and brine, dried with sodium sulfate, concentrated and purified by column chromatography to obtain intermediate compound k;

[0224]

[0225] The specific reaction process is as follows:

[0226] 1N aqueous sodium hydroxide solution is added to the tetrahydrofuran solution of compound h and reacted for 15 - 24 hours. After the reaction, it is cooled to 0 °C, and the pH of the reaction system is adjusted to 5 with acetic acid. The solid is collected by filtration to obtain intermediate compound i;

[0227] Potassium carbonate is added to the acetone solution of intermediate compound i and compound b and reacted for 5 - 8 hours. After the reaction, it is filtered by suction, the filtrate is concentrated and purified by column chromatography to obtain intermediate compound j;

[0228] The dimethyl sulfoxide solution of intermediate compound j and cesium fluoride is reacted at 150 °C for 5 - 8 hours. After the reaction is completed, it is cooled to room temperature, water is added, the solid is collected, dried and purified by column chromatography to obtain intermediate compound k.

[0229] S2. Use the intermediate k obtained in S1 to synthesize the target compound r, and the reaction route is as follows:

[0230]

[0231] At room temperature, add acyl chlorides with different substituents to the toluene solution of N,N - diisopropylethylamine and compound l, heat to 110 °C and react for 3 - 5 hours. After the reaction, concentrate and perform column chromatography to obtain intermediate compound m; or add isocyanates with different substituents in batches to the 1,4 - dioxane solution of triethylamine and intermediate compound l, heat to 110 °C and react for 4 - 8 hours. After the reaction, concentrate and perform column chromatography to obtain intermediate compound m.

[0232] Add [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium to the solution of intermediate compound m, bis(pinacolato)diboron n and potassium acetate in 1,4 - dioxane and react for 3 - 6 hours. After the reaction, cool to room temperature, remove the solvent under vacuum, add dichloromethane and methanol to dissolve the crude product, filter off potassium carbonate by suction, concentrate the filtrate and perform column chromatography to obtain the corresponding intermediate compound o.

[0233] Add [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium to the mixed solution of intermediate compound o, intermediate compound k and potassium carbonate in 1,4 - dioxane and water and react for 0.5 - 3 hours. After the reaction, cool to room temperature, remove the solvent under vacuum, add dichloromethane and methanol to dissolve the crude product, filter off potassium carbonate by suction, concentrate the filtrate and perform column chromatography to obtain the target compound r.

[0234]

[0235] Add [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium to the solution of intermediate compound p, intermediate compound k and potassium carbonate in 1,4 - dioxane and react for 1.5 hours, then add water and continue to react for 0.5 - 2.5 hours. After the reaction, cool to room temperature, remove the solvent under vacuum, add dichloromethane and methanol to dissolve the crude product, filter off potassium carbonate by suction, concentrate the filtrate and perform column chromatography to obtain intermediate compound q.

[0236] Add copper(I) iodide to the toluene solution of intermediate compound q, 5 - 7 - membered cyclic lactams with different substituents, N,N'-dimethylethylenediamine and potassium carbonate, heat to 110 °C and react for 4 - 6 hours. After the reaction, cool to room temperature, remove the solvent under vacuum, add dichloromethane and methanol to dissolve the crude product, filter off potassium carbonate by suction, concentrate the filtrate and perform column chromatography to obtain the target compound r.

[0237] Intermediate k is selected from the following compounds:

[0238]

[0239]

[0240] The intermediate m is selected from the following compounds:

[0241]

[0242]

[0243] The intermediate o is selected from the following compounds:

[0244]

[0245]

[0246] The structure of intermediate q is as follows:

[0247] The target compound r is selected from the following compounds:

[0248]

[0249]

[0250]

[0251] Preparation Example 1 of Intermediate: The specific synthesis method of intermediate k is as follows:

[0252]

[0253] Potassium carbonate (2468 mg, 17.86 mmol) was added to a solution of 7-bromo-1-hydroxyisoquinoline a1 (2000 mg, 8.93 mmol) and iodopropane b1 (2277 mg, 13.40 mmol) in acetone (50 mL). The reaction was carried out at 65 °C for 5 hours, cooled to room temperature, and potassium carbonate was removed by filtration. The solvent was removed under vacuum. The product was purified by silica gel column chromatography using dichloromethane as the eluent to obtain 7-bromo-2-propylisoquinolin-1(2H)-one (k1), which was a white solid (2044 mg, 7.68 mmol, yield 86%). ESI-MS: m / z 267.1 [M+H] + .

[0254] In a similar manner, the corresponding compounds k2-21 were prepared using compounds a2-5 and different halogenated compounds b.

[0255] Compound k2, namely 7-bromo-2-ethylisoquinolin-1(2H)-one, was obtained as a white solid with a yield of 83%. ESI-MS: m / z 253.1 [M+H] + .

[0256] Compound k3, namely 7-bromo-2-butylisoquinolin-1(2H)-one, is a white solid with a yield of 80%. ESI-MS: m / z 281.2 [M+H] + .

[0257] Compound k4, namely 7-bromo-2-(cyclopropylmethyl)isoquinolin-1(2H)-one, is a white solid with a yield of 81%. ESI-MS: m / z 279.1 [M+H] + .

[0258] Compound k5, namely 2-benzyl-7-bromoisoquinolin-1(2H)-one, is a white solid with a yield of 85%. ESI-MS: m / z 315.2 [M+H] + .

[0259] Compound k6, namely 7-bromo-2-(4-methylbenzyl)isoquinolin-1(2H)-one, is a white solid with a yield of 84%. ESI-MS: m / z 329.2 [M+H] + .

[0260] Compound k7, namely 3-benzyl-6-bromoquinazolin-4(3H)-one, is a white solid with a yield of 90%. ESI-MS: m / z 316.1 [M+H] + .

[0261] Compound k8, namely 6-bromo-3-butylquinazolin-4(3H)-one, is a white solid with a yield of 75%. ESI-MS: m / z 282.1 [M+H] + .

[0262] Compound k9, namely 6-bromo-3-(cyclopropylmethyl)quinazolin-4(3H)-one, is a white solid with a yield of 73%. ESI-MS: m / z 280.2 [M+H] + .

[0263] Compound k10, namely 6-bromo-3-isopentylquinazolin-4(3H)-one, is a white solid with a yield of 78%. ESI-MS: m / z 296.1 [M+H] + .

[0264] Compound k11, namely 6-bromo-3-ethylquinazolin-4(3H)-one, is a white solid with a yield of 82%. ESI-MS: m / z 254.1 [M+H] + .

[0265] Compound k12, namely 6-bromo-3-propylquinazolin-4(3H)-one, is a white solid with a yield of 85%. ESI-MS: m / z 268.1 [M+H]+ .

[0266] Compound k13, namely 6-bromo-3-(2-fluoroethyl)quinazolin-4(3H)-one, was obtained as a white solid in 83% yield. ESI-MS: m / z 272.1 [M+H] + .

[0267] Compound k14, namely 6-bromo-3-(2-fluoropropyl)quinazolin-4(3H)-one, was obtained as a white solid in 78% yield. ESI-MS: m / z 286.1 [M+H] + .

[0268] Compound k15, namely 6-bromo-3-(cyclobutylmethyl)quinazolin-4(3H)-one, was obtained as a white solid in 83% yield. ESI-MS: m / z 294.2 [M+H] + .

[0269] Compound k16, namely 6-bromo-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one, was obtained as a white solid in 77% yield. ESI-MS: m / z 264.1 [M+H] + .

[0270] Compound k17, namely 6-bromo-3-cyclopropylquinazolin-4(3H)-one, was obtained as a white solid in 70% yield. ESI-MS: m / z 266.1 [M+H] + .

[0271] Compound k18, namely 6-bromo-2-methyl-3-propylquinazolin-4(3H)-one, was obtained as a white solid in 86% yield. ESI-MS: m / z 282.0 [M+H] + .

[0272] Compound k19, namely 3-bromo-6-propyl-1,6-naphthyridin-5(6H)-one, was obtained as a white solid in 82% yield. ESI-MS: m / z 268.1 [M+H] + .

[0273] Compound k20, namely 3-bromo-6-(cyclopropylmethyl)-1,6-naphthyridin-5(6H)-one, was obtained as a white solid in 85% yield. ESI-MS: m / z 280.1 [M+H] + .

[0274] Compound k21, namely 6-bromo-3-propylpyrido[2,3-d]pyrimidin-4(3H)-one, was obtained as a white solid in 81% yield. ESI-MS: m / z 269.1 [M+H] + .

[0275]

[0276] Compound d (5000 mg, 20.99 mmol) was added to a solution of methyl 5-bromoanthranilate c1 (3450 mg, 14.99 mmol) in pyridine (30 mL). The reaction was carried out overnight at 50 °C. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was extracted with 5% potassium carbonate solution (200 mL) and dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using petroleum ether:ethyl acetate = 3:1 as the eluent to obtain methyl 5-bromo-2-((cyanamino(phenoxy)methylene)amino)benzoate (Compound e1) as a white solid (3140 mg, 8.39 mmol, yield 56%). ESI-MS: m / z 375.2 [M+H] + ;

[0277] n-Propylamine f (316 mg, 5.35 mmol) was added to a solution of intermediate compound e1 (1 g, 2.67 mmol) in isopropanol (15 mL). The mixture was stirred at 85 °C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and the solvent was removed under vacuum. The product was purified by silica gel column chromatography using petroleum ether:ethyl acetate = 3:1 as the eluent to obtain N-(6-bromo-4-oxo-3-propyl-3,4-dihydroquinazolin-2-yl)cyanamide (g1) as a white solid (651 mg, 2.12 mmol, yield 80%). ESI-MS: m / z 308.2 [M+H] + 。

[0278] Concentrated hydrochloric acid (18.7 mL) was added to a solution of intermediate compound g1 (821 mg, 2.67 mmol) in dimethyl sulfoxide (9.4 mL). The temperature was raised to 100 °C and the reaction was carried out for 1 hour. Then the mixture was poured into water (100 mL), treated with potassium carbonate until no more bubbles were generated, and then extracted with dichloromethane (3 × 75 mL). The solvent was removed under reduced pressure. The residue was dissolved in acetic acid (75 mL), washed with water and brine, dried over sodium sulfate, and purified by column chromatography to obtain 2-amino-6-bromo-3-propylquinazolin-4(3H)-one (Compound k22) as a white solid (640 mg, 2.27 mmol, yield 85%). ESI-MS: m / z 283.1 [M+H] + 。

[0279] Compounds k23 - 24 were prepared from compound c in a similar manner.

[0280] Compound k23, namely 2-amino-6-bromo-3-(cyclopropylmethyl)quinazolin-4(3H)-one, was obtained as a white solid with a yield of 86%. ESI-MS: m / z 295.2 [M+H]+ .

[0281] Compound k24, namely 2-amino-6-bromo-3-propylpyrido[2,3-d]pyrimidin-4(3H)-one, was obtained as a white solid with a yield of 80%. ESI-MS: m / z 284.1 [M+H] + .

[0282] At room temperature, 1N aqueous sodium hydroxide solution (1.8 mL) was added to a solution of 6-bromo-2,4-dichloroquinazoline h1 (500 mg, 1.80 mmol) in tetrahydrofuran, and the reaction was carried out for 15 hours. After cooling to 0 °C, the pH was adjusted to 5 with acetic acid, and the precipitated white solid was collected, washed with water, and dried in vacuo. The crude product was purified by silica gel column chromatography using dichloromethane as the eluent to obtain the intermediate compound 6-bromo-2-chloroquinazolin-4(3H)-one (Compound i1) as a white solid (444 mg, 1.71 mmol, yield 95%). ESI-MS: m / z 260.4 [M+H] + .

[0283] Potassium carbonate was added to a solution of Compound i1 (400 mg, 1.54 mmol) and iodopropane b (524 mg, 3.08 mmol) in acetone (15 mL), and the reaction was carried out at 65 °C for 5 hours. After cooling to room temperature, potassium carbonate was filtered off, and the solvent was removed in vacuo. The product was purified by silica gel column chromatography using dichloromethane as the eluent to obtain 6-bromo-2-chloro-3-propylquinazolin-4(3H)-one (Compound j1) as a white solid (344 mg, 1.14 mmol, yield 74%). ESI-MS: m / z 302.3 [M+H] + .

[0284] Cesium fluoride (304 mg, 2.00 mmol) was added to a solution of Compound j1 (302 mg, 1.00 mmol) in dimethyl sulfoxide, and the reaction was carried out at 150 °C for 5 hours. Then, water (25 mL) was added to the reaction mixture, and the mixture was stirred for an additional 10 minutes until no white solid precipitate formed. The solid was filtered, washed with water (25 mL), and dried in vacuo. The crude product was purified by silica gel column chromatography using dichloromethane:methanol = 30:1 as the eluent to obtain the intermediate compound 6-bromo-2-hydroxy-3-propylquinazolin-4(3H)-one (Compound k25) as a white solid (184 mg, 0.65 mmol, yield 65%). ESI-MS: m / z 284.1 [M+H] + .

[0285] Compounds k26-27 were prepared from Compound h in a similar manner.

[0286] Compound k26, namely 6-bromo-3-(cyclopropylmethyl)-2-hydroxyquinazolin-4(3H)-one, was a white solid with a yield of 62%, ESI-MS: m / z 296.1 [M+H] + 。

[0287] Compound k27, namely 6-bromo-2-hydroxy-3-propylpyrido[2,3-d]pyrimidin-4(3H)-one, was a white solid with a yield of 61%, ESI-MS: m / z 285.1 [M+H] + 。

[0288] Preparation Example 1 of the target compound: The specific synthesis method of the target compound r was as follows:

[0289]

[0290] At room temperature, acetyl chloride (1015 mg, 12.93 mmol) was added to a toluene (35 mL) solution of N,N-diisopropylethylamine (2228 mg, 17.24 mmol) and 2-amino-5-bromopyrimidine (1500 mg, 8.62 mmol). The temperature was raised to 110 °C and the reaction was carried out for 3 - 5 hours. After the reaction was completed, the solvent was removed under vacuum. The crude product was purified by silica gel column chromatography using petroleum ether:ethyl acetate = 20:1 as the eluent to obtain N-(5-bromopyrimidin-2-yl)acetamide (Compound m1), which was a white solid (1508 mg, 6.98 mmol, yield 81%), ESI-MS: m / z 217.1 [M+H] + 。

[0291] Intermediate compounds m2 - 36 were prepared in a similar manner using different acyl chlorides and aromatic amine compound l.

[0292] Compound m2, namely N-(5-bromopyrimidin-2-yl)propanamide, was a white solid with a yield of 71%, ESI-MS: m / z 231.1 [M+H] + 。

[0293] Compound m3, namely N-(5-bromopyrimidin-2-yl)hexanamide, was a white solid with a yield of 68%, ESI-MS: m / z 273.1 [M+H] + 。

[0294] Compound m4, namely N-(5-bromopyrimidin-2-yl)butanamide, was a white solid with a yield of 81%, ESI-MS: m / z 245.1 [M+H] + 。

[0295] Compound m5, namely N-(5-bromopyrimidin-2-yl)benzamide, was a white solid with a yield of 78%, ESI-MS: m / z 279.1 [M+H]+ .

[0296] Compound m6, namely N-(5-bromopyrimidin-2-yl)-4-fluorobenzamide, was obtained as a white solid with a yield of 79%, ESI-MS: m / z 297.1 [M+H] + .

[0297] Compound m7, namely N-(5-bromopyrimidin-2-yl)cyclopropanecarboxamide, was obtained as a white solid with a yield of 67%, ESI-MS: m / z 243.1 [M+H] + .

[0298] Compound m8, namely N-(5-bromopyrimidin-2-yl)cyclobutanecarboxamide, was obtained as a white solid with a yield of 68%, ESI-MS: m / z 257.1 [M+H] + .

[0299] Compound m9, namely N-(5-bromopyrimidin-2-yl)isonicotinamide, was obtained as a white solid with a yield of 80%, ESI-MS: m / z 280.1 [M+H] + .

[0300] Compound m10, namely N-(5-bromopyrimidin-2-yl)pentanamide, was obtained as a white solid with a yield of 83%, ESI-MS: m / z 259.1 [M+H] + .

[0301] Compound m11, namely N-(5-bromopyrazin-2-yl)pentanamide, was obtained as a white solid with a yield of 85%, ESI-MS: m / z 259.1 [M+H] + .

[0302] Compound m12, namely N-(6-bromopyridin-3-yl)pentanamide, was obtained as a white solid with a yield of 77%, ESI-MS: m / z 258.1 [M+H] + .

[0303] Compound m13, namely N-(2-bromopyrimidin-5-yl)pentanamide, was obtained as a white solid with a yield of 76%, ESI-MS: m / z 259.1 [M+H] + .

[0304] Compound m14, namely N-(4-bromo-2-fluorophenyl)pentanamide, was obtained as a white solid with a yield of 65%, ESI-MS: m / z 275.1 [M+H] + .

[0305] Compound m15, namely N-(4-bromo-2-methoxyphenyl)pentanamide, was obtained as a white solid with a yield of 63%, ESI-MS: m / z 287.2 [M+H]+ .

[0306] Compound m16, namely N-(5-bromopyridin-2-yl)-4,4-difluoropentanamide, was obtained as a white solid with a yield of 87%. ESI-MS: m / z 294.1 [M+H] + .

[0307] Compound m17, namely N-(5-bromopyridin-2-yl)-3-fluoropentanamide, was obtained as a white solid with a yield of 82%. ESI-MS: m / z 276.1 [M+H] + .

[0308] Compound m18, namely N-(5-bromopyridin-2-yl)-4-fluoropentanamide, was obtained as a white solid with a yield of 83%. ESI-MS: m / z 276.1 [M+H] + .

[0309] Compound m19, namely N-(5-bromopyridin-2-yl)pentanamide, was obtained as a white solid with a yield of 69%. ESI-MS: m / z258.1 [M+H] + .

[0310] Compound m20, namely N-(5-bromopyridin-2-yl)-3,3-difluoropentanamide, was obtained as a white solid with a yield of 72%. ESI-MS: m / z 294.1 [M+H] + .

[0311] Compound m21, namely N-(5-bromopyridin-2-yl)benzamide, was obtained as a white solid with a yield of 74%. ESI-MS: m / z 278.1 [M+H] + .

[0312] Compound m22, namely N-(5-bromopyridin-2-yl)butanamide, was obtained as a white solid with a yield of 65%. ESI-MS: m / z244.1 [M+H] + .

[0313] Compound m23, namely N-(5-bromopyridin-2-yl)hexanamide, was obtained as a white solid with a yield of 67%. ESI-MS: m / z272.2 [M+H] + .

[0314] Compound m24, namely N-(5-bromopyridin-2-yl)cyclobutanecarboxamide, was obtained as a white solid with a yield of 62%. ESI-MS: m / z 256.1 [M+H] + .

[0315] Compound m25, namely N-(5-bromopyridin-2-yl)cyclopentanecarboxamide, is a white solid with a yield of 80%, ESI-MS: m / z 270.1 [M+H] + .

[0316] Compound m26, namely N-(5-bromopyridin-2-yl)cyclohexanecarboxamide, is a white solid with a yield of 81%, ESI-MS: m / z 284.2 [M+H] + .

[0317] Compound m27, namely N-(4-bromophenyl)pentanamide, is a white solid with a yield of 71%, ESI-MS: m / z 257.1 [M+H] + .

[0318] Compound m28, namely N-(5-bromopyridin-2-yl)-2-cyclopropylethanamide, is a white solid with a yield of 75%, ESI-MS: m / z 256.1 [M+H] + .

[0319] Compound m29, namely N-(5-bromopyridin-2-yl)-2-cyclobutylethanamide, is a white solid with a yield of 76%, ESI-MS: m / z 270.1 [M+H] + .

[0320] Compound m30, namely N-(5-bromo-6-fluoropyridin-2-yl)pentanamide, is a white solid with a yield of 81%, ESI-MS: m / z 276.1 [M+H] + .

[0321] Compound m31, namely N-(5-bromo-3-fluoropyridin-2-yl)pentanamide, is a white solid with a yield of 86%, ESI-MS: m / z 276.2 [M+H] + .

[0322] Compound m32, namely N-(5-bromo-4-fluoropyridin-2-yl)pentanamide, is a white solid with a yield of 87%, ESI-MS: m / z 276.1 [M+H] + .

[0323] Compound m33, namely N-(5-bromo-3-methylpyridin-2-yl)pentanamide, is a white solid with a yield of 84%, ESI-MS: m / z 272.1 [M+H] + .

[0324] Compound m34, namely N-(5-bromo-4-methylpyridin-2-yl)pentanamide, is a white solid with a yield of 82%, ESI-MS: m / z 272.2 [M+H] + .

[0325] Compound m35, namely N-(5-bromo-6-methylpyridin-2-yl)pentanamide, was obtained as a white solid in 88% yield. ESI-MS: m / z 272.1 [M+H] + .

[0326] Compound m36, namely N-(5-bromopyridin-2-yl)-2-(ethylamino)acetamide, was obtained as a white solid in 75% yield. ESI-MS: m / z 259.1 [M+H] + .

[0327] Alternatively, o-tolyl isocyanate (2039 mg, 17.34 mmol) was added portionwise to a solution of triethylamine (1755 mg, 17.34 mmol) and 2-amino-5-bromopyridine l2 (1500 mg, 8.67 mmol) in 1,4-dioxane (30 mL). The temperature was raised to 110 °C and the reaction was carried out for 6 hours. After completion of the reaction, the mixture was cooled to room temperature and the solvent was removed under vacuum. The crude product was purified by silica gel column chromatography using dichloromethane as the eluent to obtain 1-(5-bromopyridin-2-yl)-3-(o-tolyl)urea (Compound m37) as a white solid (2263 mg, 7.37 mmol, 85% yield). ESI-MS: m / z 307.2 [M+H] + .

[0328] Intermediate compounds m38-44 were prepared in a similar manner using different isocyanates and aromatic amine compounds l.

[0329] Compound m38, namely 1-(5-bromopyridin-2-yl)-3-(m-tolyl)urea, was obtained as a white solid in 80% yield. ESI-MS: m / z 307.2 [M+H] + .

[0330] Compound m39, namely 1-(5-bromopyridin-2-yl)-3-phenylurea, was obtained as a white solid in 83% yield. ESI-MS: m / z 293.1 [M+H] + .

[0331] Compound m40, namely 1-(5-bromopyridin-2-yl)-3-(4-fluorophenyl)urea, was obtained as a white solid in 78% yield. ESI-MS: m / z 311.2 [M+H] + .

[0332] Compound m41, namely 1-(5-bromopyridin-2-yl)-3-(4-methoxyphenyl)urea, was obtained as a white solid in 79% yield. ESI-MS: m / z 323.2 [M+H] + .

[0333] Compound m42, namely 1-benzyl-3-(5-bromopyridin-2-yl)urea, was a white solid with a yield of 82%, ESI-MS: m / z 307.2 [M+H] + 。

[0334] Compound m43, namely 1-(5-bromopyridin-2-yl)-3-butylurea, was a white solid with a yield of 65%, ESI-MS: m / z 273.2 [M+H] + 。

[0335] Compound m44, namely 1-(5-bromopyridin-2-yl)-3-(tert-butyl)urea, was a white solid with a yield of 64%, ESI-MS: m / z 273.2 [M+H] + 。

[0336] [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium (237 mg, 0.324 mmol) was added to a solution of N-(5-bromopyrimidin-2-yl)acetamide m1 (700 mg, 3.24 mmol), bis(pinacolato)diboron n (1234 mg, 4.86 mmol) and potassium acetate (636 mg, 6.48 mmol) in 1,4-dioxane (30 mL), and the mixture was reacted for 4 hours. After the reaction, it was cooled to room temperature, the solvent was removed under vacuum, dichloromethane and methanol were added to dissolve the crude product, potassium carbonate was removed by filtration, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography using dichloromethane as the eluent to obtain N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)acetamide (Compound o1), which was a colorless oil (639 mg, 2.43 mmol, yield 75%), ESI-MS: m / z 364.1 [M+H] + 。

[0337] Intermediate compound o2-44 was prepared from intermediate compound m in a similar method.

[0338] Compound o2, namely N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)propanamide, was a colorless oil with a yield of 72%, ESI-MS: m / z 277.1 [M+H] + 。

[0339] Compound o3, namely N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)hexanamide, was a colorless oil with a yield of 78%, ESI-MS: m / z 319.2 [M+H] + 。

[0340] Compound o4, i.e., N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)butanamide, was obtained as a colorless oil with a yield of 74%. ESI-MS: m / z 291.1 [M+H] + .

[0341] Compound o5, i.e., N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)benzamide, was obtained as a colorless oil with a yield of 71%. ESI-MS: m / z 325.2 [M+H] + .

[0342] Compound o6, i.e., 4-fluoro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)benzamide, was obtained as a colorless oil with a yield of 74%. ESI-MS: m / z 343.2 [M+H] + .

[0343] Compound o7, i.e., N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)cyclopropanecarboxamide, was obtained as a colorless oil with a yield of 73%. ESI-MS: m / z 289.1 [M+H] + .

[0344] Compound o8, i.e., N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)cyclobutanamide, was obtained as a colorless oil with a yield of 71%. ESI-MS: m / z 303.2 [M+H] + .

[0345] Compound o9, i.e., N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)isonicotinamide, was obtained as a colorless oil with a yield of 72%. ESI-MS: m / z 326.2 [M+H] + .

[0346] Compound o10, i.e., N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)pentanamide, was obtained as a colorless oil with a yield of 71%. ESI-MS: m / z 305.2 [M+H] + .

[0347] Compound o11, i.e., N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)pentanamide, was obtained as a colorless oil with a yield of 73%. ESI-MS: m / z 305.2 [M+H] + .

[0348] Compound o12, namely N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)pentanamide, was obtained as a colorless oil in 71% yield. ESI-MS: m / z 304.2 [M+H] + 。

[0349] Compound o13, namely N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-5-yl)pentanamide, was obtained as a colorless oil in 76% yield. ESI-MS: m / z 305.2 [M+H] + 。

[0350] Compound o14, namely N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pentanamide, was obtained as a colorless oil in 70% yield. ESI-MS: m / z 321.2 [M+H] + 。

[0351] Compound o15, namely N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pentanamide, was obtained as a colorless oil in 71% yield. ESI-MS: m / z 333.2 [M+H] + 。

[0352] Compound o16, namely 4,4-difluoro-N-(5-(4,4,5,5-tetramethyldioxaborolan-2-yl)pyridin-2-yl)pentanamide, was obtained as a colorless oil in 74% yield. ESI-MS: m / z 340.2 [M+H] + 。

[0353] Compound o17, namely 3-fluoro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pentanamide, was obtained as a colorless oil in 71% yield. ESI-MS: m / z 322.2 [M+H] + 。

[0354] Compound o18, namely 4-fluoro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pentanamide, was obtained as a colorless oil in 73% yield. ESI-MS: m / z 322.2 [M+H] + 。

[0355] Compound o19, namely N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pentanamide, was obtained as a colorless oil in 77% yield. ESI-MS: m / z 304.2 [M+H]+ .

[0356] Compound o20, namely 3,3-difluoro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pentanamide, is a colorless oil with a yield of 73%, ESI-MS: m / z 340.2 [M+H] + .

[0357] Compound o21, namely N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)benzamide, is a colorless oil with a yield of 75%, ESI-MS: m / z 324.2 [M+H] + .

[0358] Compound o22, namely N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)butanamide, is a colorless oil with a yield of 73%, ESI-MS: m / z 290.2 [M+H] + .

[0359] Compound o23, namely N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)hexanamide, is a colorless oil with a yield of 77%, ESI-MS: m / z 318.2 [M+H] + .

[0360] Compound o24, namely N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclobutanamide, is a colorless oil with a yield of 77%, ESI-MS: m / z 302.2 [M+H] + .

[0361] Compound o25, namely N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclopentanamide, is a colorless oil with a yield of 74%, ESI-MS: m / z 316.2 [M+H] + .

[0362] Compound o26, namely N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclohexanecarboxamide, is a colorless oil with a yield of 75%, ESI-MS: m / z 330.2 [M+H] + .

[0363] Compound o27, namely N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pentanamide, was obtained as a colorless oil with a yield of 76%, ESI-MS: m / z 303.2 [M+H] + 。

[0364] Compound o28, namely 2-cyclopropyl-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide, was obtained as a colorless oil with a yield of 73%, ESI-MS: m / z 302.2 [M+H] + 。

[0365] Compound o29, namely 2-cyclobutyl-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide, was obtained as a colorless oil with a yield of 71%, ESI-MS: m / z 316.2 [M+H] + 。

[0366] Compound o30, namely N-(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pentanamide, was obtained as a colorless oil with a yield of 74%, ESI-MS: m / z 323.2 [M+H] + 。

[0367] Compound o31, namely N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pentanamide, was obtained as a colorless oil with a yield of 66%, ESI-MS: m / z 323.1 [M+H] + 。

[0368] Compound o32, namely N-(4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pentanamide, was obtained as a colorless oil with a yield of 69%, ESI-MS: m / z 323.2 [M+H] + 。

[0369] Compound o33, namely N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pentanamide, was obtained as a colorless oil with a yield of 65%, ESI-MS: m / z 319.2 [M+H] + 。

[0370] Compound o34, namely N-(4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pentanamide, was a colorless oil with a yield of 75%, ESI-MS: m / z 319.2 [M+H] + .

[0371] Compound o35, namely N-(6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pentanamide, was a colorless oil with a yield of 76%, ESI-MS: m / z 319.3 [M+H] + .

[0372] Compound o36, namely 2-(ethylamino)-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide, was a colorless oil with a yield of 67%, ESI-MS: m / z 306.2 [M+H] + .

[0373] Compound o37, namely 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3-(o-tolyl)urea, was a colorless oil with a yield of 76%, ESI-MS: m / z 354.2 [M+H] + .

[0374] Compound o38, namely 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3-(m-tolyl)urea, was a colorless oil with a yield of 77%, ESI-MS: m / z 354.2 [M+H] + .

[0375] Compound o39, namely 1-phenyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea, was a colorless oil with a yield of 72%, ESI-MS: m / z 340.2 [M+H] + .

[0376] Compound o40, namely 1-(4-fluorophenyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea, was a colorless oil with a yield of 76%, ESI-MS: m / z 358.2 [M+H] + .

[0377] Compound o41, namely 1-(4-methoxyphenyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea, was a colorless oil with a yield of 73%. ESI-MS: m / z 370.2 [M+H] + .

[0378] Compound o42, namely 1-benzyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea, was a colorless oil with a yield of 79%. ESI-MS: m / z 354.2 [M+H] + .

[0379] Compound o43, namely 1-butyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea, was a colorless oil with a yield of 71%. ESI-MS: m / z 320.2 [M+H] + .

[0380] Compound o44, namely 1-(tert-butyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea, was a colorless oil with a yield of 80%. ESI-MS: m / z 320.2 [M+H] + .

[0381] [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium (192 mg, 0.26 mmol) was added to a solution of N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)acetamide o1 (1038 mg, 3.95 mmol), 7-bromo-2-propylisoquinolin-1(2H)-one k1 (700 mg, 2.63 mmol) and potassium carbonate (767 mg, 5.26 mmol) in 1,4-dioxane (24 mL) and water (6 mL), and the mixture was reacted for 2 hours. After the reaction, it was cooled to room temperature, the solvent was removed under vacuum, dichloromethane and methanol were added to dissolve the crude product, potassium carbonate was removed by filtration, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography using dichloromethane:methanol = 100:1 as the eluent to obtain N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)acetamide (Compound r1), which was a white solid (644 mg, 2.00 mmol, yield 76%). 11H NMR (600 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.86 (s, 2H), 8.27 (d, J = 1.6 Hz, 1H), 7.85 (dd, J = 7.5, 0.7 Hz, 1H), 7.82 (dd, J = 7.5, 1.4 Hz, 1H), 6.95 (d, J = 11.0 Hz, 1H), 6.60 (d, J = 10.9 Hz, 1H), 3.75 (t, J = 7.0 Hz, 2H), 2.33 (s, 3H), 1.65–1.59 (m, 2H), 0.93 (t, J = 8.0 Hz 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 165.69, 161.21, 155.95, 150.01, 136.73, 135.19, 134.22, 130.00, 127.93, 127.38, 126.88, 125.71, 103.31, 49.83, 23.81, 21.76, 10.91. HRMS (ESI): calcd for C 18 H 19 N4O2 [M+H] + m / z, 323.1503; found, 323.1506.

[0382] The target compound r2-86 was prepared from the aromatic amine compound l with different substitutions in a similar method.

[0383] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)propanamide (r2)

[0384] White solid, yield 75%. 1 1H NMR (600 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.88 (s, 2H), 8.25 (d, J = 1.3 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.83 (dd, J = 7.5, 1.4 Hz, 1H), 6.94 (d, J = 10.8 Hz, 1H), 6.60 (d, J = 10.9 Hz, 1H), 3.75 (t, J = 7.2 Hz, 2H), 2.44 (q, J = 8.0 Hz, 2H), 1.70–1.56 (m, 2H), 1.10 (t, J = 8.0 Hz, 3H), 0.93 (t, J = 8.0 Hz, 3H). 1313C NMR (151 MHz, DMSO-d6) δ 171.41, 164.21, 155.96, 150.02, 136.75, 135.20, 134.47, 129.90, 127.67, 127.05, 126.90, 126.64, 103.11, 50.15, 29.49, 21.76, 10.92, 9.74. HRMS (ESI): calcd for C 19 H 21 N4O2 [M + H] + m / z, 337.1659; found, 337.1654.

[0385] N-(5-(1-Oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)hexanamide (r3)

[0386] White solid, yield 77%. 1 1H NMR (600 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.89 (s, 2H), 8.29 (d, J = 1.6 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.81 (dd, J = 7.4, 1.5 Hz, 1H), 6.93 (d, J = 11.0 Hz, 1H), 6.60 (d, J = 10.9 Hz, 1H), 3.75 (t, J = 7.0 Hz, 2H), 2.51 (t, J = 7.1 Hz, 2H), 1.69–1.56 (m, 4H), 1.37–1.31 (m, 2H), 1.34–1.28 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H), 0.91 (t, J = 8.0 Hz 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 171.71, 164.21, 156.62, 150.24, 136.85, 134.44, 134.42, 130.40, 127.67, 127.52, 127.26, 126.84, 103.11, 50.25, 36.87, 31.73, 24.53, 23.21, 21.76, 13.98, 10.92. HRMS (ESI): calcd for C 22 H 27 N4O2 [M + H] + m / z, 372129; found, 379.2123.

[0387] N-(5-(1-Oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)butanamide (r4)

[0388] White solid, yield 78%. 1 H NMR (600 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.87 (s, 2H), 8.25 (d, J = 1.3 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.83 (dd, J = 7.5, 1.4 Hz, 1H), 6.93 (d, J = 11.0 Hz, 1H), 6.60 (d, J = 10.9 Hz, 1H), 3.76 (t, J = 7.1 Hz, 2H), 2.49 (t, J = 7.1 Hz, 2H), 1.70–1.56 (m, 4H), 0.98–0.90 (m, 6H) 13 C NMR (151 MHz, DMSO-d6) δ 171.70, 164.21, 156.47, 150.06, 136.75, 134.79, 134.71, 129.77, 127.67, 127.10, 126.90, 126.60, 103.01, 50.49, 37.23, 21.76, 19.00, 13.84, 10.91. HRMS (ESI): calcd for C 20 H 23 N4O2 [M + H] + m / z, 351.1816; found, 351.1813.

[0389] N-(5-(1-Oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)benzamide (r5)

[0390] White solid, yield 81%. 1 H NMR (600 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.84 (s, 2H), 8.29 (d, J = 1.6 Hz, 1H), 7.99–7.94 (m, 2H), 7.83 (dd, J = 7.6, 0.7 Hz, 1H), 7.77 (dd, J = 7.6, 1.4 Hz, 1H), 7.60–7.54 (m, 1H), 7.51–7.45 (m, 2H), 6.90 (d, J = 11.0 Hz, 1H), 6.62–6.57 (m, 1H), 3.74 (t, J = 7.0 Hz, 2H), 1.66–1.59 (m, 2H), 0.93 (t, J = 8.0 Hz, 3H). 13¹³C NMR (151 MHz, DMSO-d6) δ 167.45, 164.21, 156.95, 150.27, 136.85, 134.42, 134.37, 133.69, 132.10, 130.19, 128.38, 128.13, 127.92, 127.67, 127.46, 126.84, 103.11, 50.25, 21.76, 10.92. HRMS (ESI): calcd for C 23 H 21 N4O2 [M+H] + m / z, 385.1659; found, 385.1654.

[0391] 4-Fluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)benzamide (r6)

[0392] White solid, yield 71%. 1 ¹H NMR (600 MHz, Chloroform-d) δ 11.25 (s, 1H), 8.89 (s, 2H), 8.17 (d, J = 1.5 Hz, 1H), 8.14–8.08 (m, 2H), 7.79 (d, J = 7.3 Hz, 1H), 7.66 (dd, J = 7.4, 1.5 Hz, 1H), 7.32–7.25 (m, 2H), 6.99 (d, J = 10.8 Hz, 1H), 6.78 (d, J = 10.6 Hz, 1H), 3.65 (t, J = 7.2 Hz, 2H), 1.69–1.61 (m, 2H), 0.94 (t, J = 8.0 Hz, 3H). 13 ¹³C NMR (150 MHz, Chloroform-d) δ 167.00, 164.39, 164.28 (d, J = 252.1 Hz), 157.00, 150.27, 136.55, 135.02, 134.44, 130.49, 130.37 (d, J = 8.0 Hz), 129.96 (d, J = 2.8 Hz), 128.35, 128.25, 127.67, 126.34, 115.40 (d, J = 20.0 Hz), 103.11, 49.92, 21.76, 10.92. 19 ¹⁹F NMR (565 MHz, Chloroform-d) δ -110.07. HRMS (ESI): calcd for C 23 H 20 F N4O2 [M+H] + m / z, 403.1565; found, 403.1561.

[0393] N-(5-(1-Oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)cyclopropanecarboxamide (r7)

[0394] White solid, yield 79%. 1 H NMR (600 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.87 (s, 2H), 8.25 (d, J = 1.3 Hz, 1H), 7.86–7.80 (m, 2H), 6.93 (d, J = 11.0 Hz, 1H), 6.60 (d, J = 10.9 Hz, 1H), 3.76 (t, J = 7.1 Hz, 2H), 2.37–2.30 (m, 1H), 1.66–1.59 (m, 2H), 0.99–0.92 (m, 3H), 0.95–0.88 (m, 4H). 13 C NMR (151 MHz, DMSO-d6) δ 172.82, 164.21, 156.14, 150.08, 136.73, 134.71, 129.77, 127.67, 127.10, 126.84, 126.59, 103.01, 50.49, 21.76, 17.27, 10.92, 8.65. HRMS (ESI): calcd for C 20 H 21 N4O2 [M+H] + m / z, 349.1659; found, 349.1658.

[0395] N-(5-(1-Oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)cyclobutanecarboxamide (r8)

[0396] White solid, yield 76%. 1 H NMR (600 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.87 (s, 2H), 8.29 (d, J = 1.6 Hz, 1H), 7.86–7.79 (m, 2H), 6.93 (d, J = 11.0 Hz, 1H), 6.59 (s, 1H), 3.76 (t, J = 7.0 Hz, 2H), 3.26–3.15 (m, 1H), 2.33–2.21 (m, 4H), 1.94–1.86 (m, 2H), 1.65–1.55 (m, 2H), 0.93 (t, J = 8.0 Hz, 3H). 1313C NMR (151 MHz, DMSO-d6) δ 173.54, 164.21, 156.38, 150.08, 136.85, 134.61, 134.44, 130.56, 127.52, 127.46, 126.84, 103.11, 50.25, 40.10, 27.82, 21.76, 19.69, 10.92. HRMS (ESI): calcd for C 21 H 23 N4O2 [M+H] + m / z, 363.1816; found, 363.1812.

[0397] N-(5-(1-Oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)isonicotinamide (r9)

[0398] White solid, yield 79%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.84 (s, 2H), 8.77 (d, J = 8.0 Hz, 2H), 8.29 (d, J = 1.5 Hz, 1H), 7.96 (d, J = 7.7 Hz, 2H), 7.81 (d, J = 7.4 Hz, 1H), 7.77 (dd, J = 7.5, 1.3 Hz, 1H), 6.90 (d, J = 11.0 Hz, 1H), 6.60 (d, J = 10.6 Hz, 1H), 3.74 (t, J = 7.0 Hz, 2H), 1.66–1.58 (m, 2H), 0.93 (t, J = 8.0 Hz, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 167.49, 164.21, 156.95, 150.27, 149.87, 138.01, 136.85, 134.42, 134.37, 130.19, 127.94, 127.67, 127.46, 126.84, 121.72, 103.11, 50.25, 21.76, 10.92. HRMS (ESI): calcd for C 22 H 20 N5O2 [M+H] + m / z, 386.1612; found, 386.1610.

[0399] N-(5-(2-Ethyl-1-oxo-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r10)

[0400] White solid, yield 77%. 11H NMR (600 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.87 (s, 2H), 8.25 (d, J = 1.2 Hz, 1H), 7.86–7.80 (m, 2H), 6.76 (d, J = 10.8 Hz, 1H), 6.59 (d, J = 11.2 Hz, 1H), 3.75 (q, J = 7.9 Hz, 2H), 2.51 (t, J = 7.1 Hz, 2H), 1.62–1.52 (m, 2H), 1.38–1.30 (m, 2H), 1.24 (t, J = 8.0 Hz, 3H), 0.92 (t, J = 8.0 Hz, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 171.71, 164.09, 156.47, 150.06, 136.27, 134.79, 134.71, 129.77, 127.67, 127.10, 127.02, 126.60, 103.15, 44.70, 36.11, 26.94, 21.86, 14.38, 13.80. HRMS (ESI): calcd for C 20 H 23 N4O2 [M+H] + m / z, 351.1816; found, 351.1817.

[0401] N-(5-(2-Butyl-1-oxo-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r11)

[0402] White solid, yield 73%. 1 1H NMR (600 MHz, Chloroform-d) δ 10.84 (s, 1H), 8.88 (s, 2H), 8.16 (d, J = 1.5 Hz, 1H), 7.80 (d, J = 7.1 Hz, 1H), 7.66 (dd, J = 7.7, 1.5 Hz, 1H), 7.00 (d, J = 11.0 Hz, 1H), 6.78 (d, J = 11.2 Hz, 1H), 3.66 (t, J = 7.1 Hz, 2H), 2.51 (t, J = 7.1 Hz, 2H), 1.62 (m, 4H), 1.43–1.32 (m, 4H), 0.95 (t, J = 7.9 Hz, 3H), 0.92 (t, J = 8.0 Hz, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 171.71, 164.36, 156.36, 150.14, 136.54, 135.18, 134.44, 130.40, 128.34, 127.67, 127.61, 126.35, 103.11, 46.95, 36.29, 31.05, 26.75, 21.89, 19.10, 13.81, 13.56. HRMS (ESI): calcd for C 22 H 27 N4O2 [M+H] + m / z, 379.2129; found, 379.2128.

[0403] N-(5-(2-(Cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r12)

[0404] White solid, yield 78%. 1 1H NMR (600 MHz, Chloroform-d) δ 10.84 (s, 1H), 8.89 (s, 2H), 8.16 (d, J = 1.5 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.66 (dd, J = 7.7, 1.5 Hz, 1H), 7.00 (d, J = 11.0 Hz, 1H), 6.80–6.75 (m, 1H), 3.65 (d, J = 7.1 Hz, 2H), 2.51 (t, J = 7.1 Hz, 2H), 1.76–168 (m, 1H), 1.63–1.53 (m, 2H), 1.43–1.35 (m, 4H), 1.38–1.30 (m, 2H), 0.92 (t, J = 7.9 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 171.71, 164.55, 156.36, 150.14, 136.79, 135.18, 134.44, 130.40, 128.34, 128.27, 127.67, 126.30, 103.17, 49.71, 36.29, 26.75, 21.89, 13.81, 9.88, 6.25. HRMS (ESI): calcd for C 22 H 25 N4O2 [M+H] + m / z, 377.1972; found, 377.1970.

[0405] N-(5-(2-Benzyl-1-oxo-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r13)

[0406] White solid, yield 79%. 1 H NMR (600 MHz, Chloroform-d) δ 10.68 (s, 1H), 8.92 (s, 2H), 8.30 (d, J = 1.5 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.77 (dd, J = 7.4, 1.5 Hz, 1H), 7.31 (d, J = 4.6 Hz, 4H), 7.26–7.15 (m, 1H), 6.94 (d, J = 11.0 Hz, 1H), 6.63 (d, J = 10.9 Hz, 1H), 5.20 (s, 2H), 2.51 (t, J = 7.1 Hz, 2H), 1.61–1.50 (m, 2H), 1.38 (m, 2H), 0.92 (t, J = 7.9 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 171.78, 164.39, 156.57, 150.31, 137.59, 137.05, 135.34, 134.27, 130.64, 128.59, 128.35, 128.35, 128.27, 127.67, 127.48, 126.38, 102.53, 51.53, 36.29, 26.71, 21.86, 13.81. HRMS (ESI): calcd for C 25 H 25 N4O2 [M+H] + m / z, 413.1972; found, 413.1970.

[0407] N-(5-(2-(4-Methylbenzyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r14)

[0408] White solid, yield 73%. 11H NMR (600 MHz, Chloroform-d) δ 10.94 (s, 1H), 8.90 (s, 2H), 8.18 (d, J = 1.5 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.66 (dd, J = 7.6, 1.4 Hz, 1H), 7.17 (d, J = 7.6, 1.1 Hz, 2H), 7.13 (d, J = 7.0 Hz, 2H), 7.03 (d, J = 10.8 Hz, 1H), 6.82 (d, J = 10.5 Hz, 1H), 5.21 (s, 2H), 2.52 (t, J = 7.1 Hz, 2H), 2.33 (s, 3H), 1.60–1.52 (m, 2H), 1.43–1.33 (m, 2H), 0.91 (t, J = 8.1 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 171.85, 164.39, 156.51, 150.75, 137.28, 137.05, 135.49, 135.09, 134.17, 130.53, 128.98, 128.58, 128.35, 127.74, 127.67, 126.38, 102.53, 51.46, 36.55, 26.71, 21.86, 21.01, 13.81. HRMS (ESI): calcd for C 26 H 27 N4O2 [M + H] + m / z, 427.2129; found, 427.2126.

[0409] N-(5-(1-Oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrazin-2-yl)pentanamide (r15)

[0410] White solid, yield 67%. 1 1H NMR (600 MHz, Chloroform-d) δ 10.32 (s, 1H), 8.77 (s, 1H), 8.36 (d, J = 1.5 Hz, 1H), 7.92–7.88 (m, 1H), 7.90 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.02 (d, J = 11.0 Hz, 1H), 6.76 (d, J = 11.3 Hz, 1H), 3.68 (t, J = 7.1 Hz, 2H), 2.42 (t, J = 7.1 Hz, 2H), 1.68–1.64 (m, 2H), 1.62–1.52 (m, 2H), 1.39–1.30 (m, 2H), 0.94 (t, J = 8.0 Hz, 3H), 0.92 (t, J = 8.0 Hz, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 171.82, 164.46, 147.74, 147.65, 140.26, 136.55, 135.69, 134.91, 134.65, 131.28, 127.79, 126.80, 126.22, 103.11, 50.22, 36.63, 26.77, 21.88, 21.76, 13.81, 10.92. HRMS (ESI): calcd for C 21 H 25 N4O2 [M+H] + m / z, 365.1972; found, 365.1970.

[0411] N-(5-(1-Oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r16)

[0412] White solid, yield 67%. 1 1H NMR (600 MHz, Chloroform-d) δ 10.26 (s, 1H), 8.37 (d, J = 1.6 Hz, 1H), 8.11 (d, J = 1.5 Hz, 1H), 8.00 (dd, J = 7.5, 1.4 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.78–7.73 (m, 1H), 7.62 (dd, J = 7.5, 1.5 Hz, 1H), 7.02 (d, J = 11.0 Hz, 1H), 6.80–6.75 (m, 1H), 3.67 (t, J = 7.0 Hz, 2H), 2.41 (t, J = 7.1 Hz, 2H), 1.68–1.63 (m, 2H), 1.62–1.53 (m, 2H), 1.44–1.34 (m, 2H), 0.94 (t, J = 8.0 Hz, 3H), 0.92 (t, J = 8.0 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 171.85, 164.40, 150.75, 146.61, 137.85, 136.55, 134.62, 134.07, 132.86, 130.73, 128.64, 126.95, 126.78, 112.51, 103.11, 50.22, 36.63, 26.77, 21.88, 21.76, 13.81, 10.92. HRMS (ESI): calcd for C 22 H 26 N3O2 [M+H] + m / z, 364.2020; found, 364.2022.

[0413] N-(2-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-5-yl)pentanamide (r17)

[0414] White solid, yield 69%. 1 H NMR(600MHz,Chloroform-d)δ9.79(s,1H),9.21(s,2H),8.13(d,J = 1.5Hz,1H),8.05(dd,J = 7.7,1.5Hz,1H),7.80(dd,J = 7.6,0.7Hz,1H),7.02(d,J = 10.8Hz,1H),6.55–6.50(m,1H),3.68(t,J = 7.1Hz,2H),2.30(t,J = 7.0Hz,2H),1.72–1.63(m,2H),1.62–1.51(m,2H),1.43–1.34(m,2H),0.94(t,J = 8.0Hz,3H),0.92(t,J = 8.1Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ171.70,164.53,159.46,148.32,136.55,135.90,135.19,133.56,132.12,128.17,126.24,125.54,103.11,50.22,36.71,26.76,21.88,21.76,13.81,10.92.HRMS(ESI):calcd for C 21 H 25 N4O2[M+H] + m / z,365.1972;found,365.1970.

[0415] N-(4-fluoro-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r18)

[0416] White solid, yield 73%. 11H NMR (600 MHz, Chloroform-d) δ 8.81 (s, 1H), 8.43 (d, J = 2.3 Hz, 1H), 8.20 (s, 1H), 8.09 (s, 1H), 7.93–7.85 (m, 2H), 7.74–7.71 (m, 1H), 3.94 (t, J = 7.4 Hz, 2H), 2.41 (t, J = 7.6 Hz, 2H), 1.82 (h, J = 7.4 Hz, 2H), 1.70 (p, J = 7.6 Hz, 2H), 1.41 (h, J = 7.4 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 171.65, 161.17, 161.00 (d, J = 243.4 Hz), 149.31 (d, J = 7.4 Hz), 147.14, 146.02, 145.77 (d, J = 8.4 Hz), 132.13 (d, J = 6.4 Hz), 127.84 (d, J = 2.4 Hz), 127.76 (d, J = 2.6 Hz), 122.24, 121.35, 119.13 (d, J = 26.2 Hz), 105.27 (d, J = 28.4 Hz), 47.80, 37.56, 25.43, 22.90, 22.76, 13.92, 11.39. 19 19F NMR (565 MHz, Chloroform-d) δ -105.52. HRMS (ESI): calcd for C 21 H 24 N4O2 [M + H] + m / z, 383.1878; found, 383.1879.

[0417] N-(2-Fluoro-4-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)phenyl)pentanamide (r19)

[0418] White solid, yield 62%. 11H NMR (600 MHz, Chloroform-d) δ 9.41 (s, 1H), 8.09 (d, J = 1.4 Hz, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.55–7.47 (m, 3H), 7.43 (dd, J = 8.0, 1.5 Hz, 1H), 7.02 (d, J = 11.0 Hz, 1H), 6.78 (d, J = 11.3 Hz, 1H), 3.67 (t, J = 7.1 Hz, 2H), 2.32 (t, J = 7.1 Hz, 2H), 1.72–1.65 (m, 2H), 1.65–1.59 (m, 2H), 1.43–1.34 (m, 2H), 0.94 (t, J = 8.0 Hz, 3H), 0.92 (t, J = 8.0 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 172.04 (d, J = 11.7 Hz), 164.40, 154.94 (d, J = 252.1 Hz), 138.24 (d, J = 3.1 Hz), 136.55, 134.62, 132.85 (d, J = 8.0 Hz), 130.80, 128.64, 128.29 (d, J = 20.0 Hz), 126.58, 125.67, 123.19 (d, J = 2.8 Hz), 122.35 (d, J = 8.0 Hz), 114.10 (d, J = 20.0 Hz), 103.11, 49.92, 36.43, 26.75, 21.89, 21.76, 13.81, 10.92. 19 19F NMR (565 MHz, Chloroform-d) δ -122.21. HRMS (ESI): calcd for C 23 H 26 FN2O2 [M + H] + m / z, 381.1973; found, 381.1970.

[0419] N-(2-Methoxy-4-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)phenyl)pentanamide (r20)

[0420] White solid, yield 61%. 11H NMR (600 MHz, Chloroform-d) δ 8.96 (s, 1H), 8.13 (d, J = 1.5 Hz, 1H), 7.94 (d, J = 7.4 Hz, 1H), 7.69 (dd, J = 7.4, 0.6 Hz, 1H), 7.53 (dd, J = 7.4, 1.5 Hz, 1H), 7.46 (dd, J = 7.4, 1.5 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 7.02 (d, J = 11.0 Hz, 1H), 6.78 (d, J = 11.3 Hz, 1H), 3.87 (s, 3H), 3.65 (t, J = 7.2 Hz, 2H), 2.32 (t, J = 7.0 Hz, 2H), 1.73–1.65 (m, 2H), 1.62–1.50 (m, 2H), 1.38–1.30 (m, 2H), 0.94 (t, J = 8.0 Hz, 3H), 0.92 (t, J = 7.9 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 172.11, 164.40, 148.53, 139.45, 136.55, 134.88, 134.62, 131.07, 129.47, 128.61, 126.46, 125.38, 121.63, 121.50, 110.29, 103.11, 56.05, 49.92, 36.40, 26.71, 21.88, 21.76, 13.81, 10.92. HRMS (ESI): calcd for C 24 H 29 N2O3 [M + H] + m / z, 393.2173; found, 393.2170.

[0421] 4,4-Difluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r21)

[0422] White solid, yield 79%. 11H NMR (600 MHz, Chloroform-d) δ 10.32 (s, 1H), 8.38 (d, J = 1.2 Hz, 1H), 8.15 (d, J = 1.5 Hz, 1H), 8.07 (dd, J = 7.5, 1.4 Hz, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.74 (dd, J = 7.5, 0.7 Hz, 1H), 7.60 (dd, J = 7.4, 1.5 Hz, 1H), 7.02 (d, J = 11.0 Hz, 1H), 6.80–6.75 (m, 1H), 3.65 (t, J = 7.2 Hz, 2H), 2.68–2.56 (m, 2H), 2.58–2.51 (m, 2H), 1.94 (t, J = 20.9 Hz, 3H), 1.73–1.64 (m, 2H), 0.94 (t, J = 8.0 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 171.54 (t, J = 30.0 Hz), 164.40, 150.98, 146.62, 137.78, 136.55, 134.62, 134.17, 132.69, 130.77, 128.53, 127.33, 126.22, 122.65 (t, J = 268.1 Hz), 112.68, 103.11, 49.92, 34.79 (t, J = 26.9 Hz), 31.49 (t, J = 10.0 Hz), 21.76, 21.63 (t, J = 27.0 Hz), 10.92. 19 19F NMR (565 MHz, Chloroform-d) δ -92.82. HRMS (ESI): calcd for C 22 H 24 F2N3O2 [M+H] + m / z, 400.1831; found, 400.1834.

[0423] N-(5-(2-(Cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)-4,4-difluoropentanamide (r22)

[0424] White solid, yield 79%. 11H NMR (600 MHz, Chloroform-d) δ 10.27 (s, 1H), 8.38 (d, J = 1.3 Hz, 1H), 8.15 (d, J = 1.5 Hz, 1H), 8.06 (dd, J = 7.4, 1.5 Hz, 1H), 7.97 (d, J = 7.4 Hz, 1H), 7.77–7.72 (m, 1H), 7.62 (dd, J = 7.4, 1.5 Hz, 1H), 6.91 (d, J = 11.0 Hz, 1H), 6.79 (d, J = 10.9 Hz, 1H), 3.65 (d, J = 7.1 Hz, 2H), 2.66–2.56 (m, 2H), 2.55–2.51 (m, 2H), 1.93 (t, J = 20.9 Hz, 3H), 1.76–1.66 (m, 1H), 1.48–1.37 (m, 4H). 13 13C NMR (151 MHz, Chloroform-d) δ 171.63 (t, J = 30.0 Hz), 164.69, 150.75, 146.58, 138.32, 136.92, 135.52, 134.54, 131.44, 130.86, 128.53, 127.78, 126.38, 122.65 (t, J = 268.1 Hz), 112.59, 103.17, 49.97, 34.79 (t, J = 26.9 Hz), 31.49 (t, J = 10.0 Hz), 21.71 (t, J = 27.0 Hz), 9.88, 6.35. 19 19F NMR (565 MHz, Chloroform-d) δ -92.82. HRMS (ESI): calcd for C 23 19 24 19F2N3O2 [M + H] + m / z, 412.1831; found, 412.1831.

[0425] 4-Fluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r23)

[0426] White solid, yield 77%. 11H NMR (600 MHz, Chloroform-d) δ 10.31 (s, 1H), 8.38 (d, J = 1.2 Hz, 1H), 8.14 (d, J = 1.5 Hz, 1H), 8.06 (dd, J = 7.4, 1.5 Hz, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.75 (d, J = 7.1 Hz, 1H), 7.62 (dd, J = 7.5, 1.4 Hz, 1H), 7.02 (d, J = 11.0 Hz, 1H), 6.80–6.75 (m, 1H), 4.55 (dp, J = 46.4, 6.9 Hz, 1H), 3.76–3.66 (m, 2H), 2.58–2.46 (m, 2H), 2.00–1.78 (m, 2H), 1.72–1.63 (m, 2H), 1.44 (dd, J = 25.3, 6.8 Hz, 3H), 0.94 (t, J = 8.0 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 171.66 (d, J = 30.0 Hz), 164.40, 150.98, 146.62, 137.78, 136.55, 134.62, 134.26, 132.86, 130.44, 128.53, 126.95, 126.43, 112.68, 103.11, 86.38 (d, J = 268.1 Hz), 49.92, 33.54 (d, J = 26.9 Hz), 33.27 (d, J = 10.0 Hz), 21.76, 20.19 (d, J = 26.9 Hz), 10.92. 19 19F NMR (565 MHz, Chloroform-d) δ -174.48. HRMS (ESI): calcd for C 22 H 25 FN3O2 [M + H] + m / z, 382.1925; found, 382.1920.

[0427] N-(5-(2-(Cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)-4-fluoropentanamide (r24)

[0428] White solid, yield 71%. 11H NMR (600 MHz, Chloroform-d) δ 10.25 (s, 1H), 8.38 (d, J = 1.3 Hz, 1H), 8.15 (d, J = 1.5 Hz, 1H), 8.07 (dd, J = 7.7, 1.5 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.60 (dd, J = 7.4, 1.5 Hz, 1H), 6.91 (d, J = 11.0 Hz, 1H), 6.79 (d, J = 10.5 Hz, 1H), 4.64–4.47 (m, 1H), 3.65 (d, J = 7.1 Hz, 2H), 2.52 (t, J = 7.0 Hz, 2H), 1.97–1.80 (m, 2H), 1.80–1.71 (m, 1H), 1.44 (dd, J = 25.3, 6.8 Hz, 3H), 1.45–1.38 (m, 4H). 13 13C NMR (151 MHz, Chloroform-d) δ 172.05 (d, J = 30.0 Hz), 164.55, 150.78, 146.66, 137.78, 136.79, 134.62, 134.10, 132.69, 130.81, 128.53, 127.76, 126.38, 112.68, 103.17, 86.38 (d, J = 268.1 Hz), 49.87, 33.48 (d, J = 27.2 Hz), 33.27 (d, J = 10.0 Hz), 20.19 (d, J = 26.9 Hz), 9.88, 6.28. 19 19F NMR (565 MHz, Chloroform-d) δ -174.48. HRMS (ESI): calcd for C 23 H 25 FN3O2 [M + H] + m / z, 394.1925; found, 394.1922.

[0429] 3,3-Difluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r25)

[0430] White solid, yield 73%. 11H NMR (600 MHz, Chloroform-d) δ 10.32 (s, 1H), 8.38 (d, J = 1.3 Hz, 1H), 8.15 (d, J = 1.5 Hz, 1H), 8.08 (dd, J = 7.7, 1.5 Hz, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.60 (dd, J = 7.4, 1.5 Hz, 1H), 7.02 (d, J = 11.0 Hz, 1H), 6.78 (d, J = 11.3 Hz, 1H), 3.65 (t, J = 7.2 Hz, 2H), 2.81 (t, J = 20.9 Hz, 2H), 2.02–1.73 (m, 2H), 1.73–1.64 (m, 2H), 0.98–0.91 (m, 6H). 13 13C NMR (151 MHz, Chloroform-d) δ 170.03 (t, J = 6.0 Hz), 164.40, 151.16, 146.62, 137.78, 136.55, 134.62, 134.17, 132.69, 130.77, 128.53, 127.33, 126.22, 123.26 (t, J = 268.1 Hz), 112.68, 103.11, 49.92, 42.74 (t, J = 27.0 Hz), 30.08 (t, J = 27.0 Hz), 21.76, 10.92, 7.48 (t, J = 10.0 Hz). HRMS (ESI): calcd for C 22 H 24 F2N3O2 [M + H] + m / z, 400.1831; found, 400.1830.

[0431] 3-Fluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r26)

[0432] White solid, yield 73%. 11H NMR (600 MHz, Chloroform-d) δ 10.35 (s, 1H), 8.38 (d, J = 1.3 Hz, 1H), 8.14 (d, J = 1.5 Hz, 1H), 8.07 (dd, J = 7.7, 1.5 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.62 (dd, J = 7.5, 1.4 Hz, 1H), 7.02 (d, J = 11.0 Hz, 1H), 6.78 (d, J = 11.3 Hz, 1H), 4.89–4.73 (m, 1H), 3.86–3.65 (m, 2H), 2.69–2.47 (m, 2H), 1.71–1.65 (m, 2H), 1.65–1.44 (m, 2H), 0.94–0.80 (m, 6H). 13 13C NMR (151 MHz, Chloroform-d) δ 170.94 (d, J = 6.0 Hz), 164.40, 151.03, 146.62, 137.78, 136.55, 134.62, 134.26, 132.86, 130.44, 128.53, 126.95, 126.43, 112.68, 103.11, 90.32 (d, J = 268.1 Hz), 49.92, 40.92 (d, J = 27.2 Hz), 28.44 (d, J = 27.2 Hz), 21.76, 10.92, 9.59 (d, J = 10.0 Hz). 19 19F NMR (565 MHz, Chloroform-d) δ -185.24. HRMS (ESI): calcd for C 22 H 25 FN3O2 [M + H] + m / z, 382.1925; found, 382.1921.

[0433] N-(5-(2-(Cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r27)

[0434] White solid, yield 75%. 11H NMR (600 MHz, Chloroform-d) δ 10.26 (s, 1H), 8.38 (d, J = 1.4 Hz, 1H), 8.14 (d, J = 1.5 Hz, 1H), 8.05 (dd, J = 7.7, 1.5 Hz, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.62 (dd, J = 7.6, 1.4 Hz, 1H), 7.00 (d, J = 11.0 Hz, 1H), 6.79 (d, J = 10.6 Hz, 1H), 3.65 (d, J = 7.1 Hz, 2H), 2.41 (t, J = 7.1 Hz, 2H), 1.76–1.66 (m, 1H), 1.63–1.54 (m, 2H), 1.48–1.40 (m, 4H), 1.43–1.34 (m, 2H), 0.92 (t, J = 8.0 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 171.85, 164.55, 150.98, 146.62, 137.69, 136.79, 134.62, 134.26, 132.86, 130.57, 128.64, 126.95, 126.38, 112.70, 103.17, 49.71, 36.43, 26.75, 21.89, 13.81, 9.88, 6.25. HRMS (ESI): calcd for C 23 H 26 N3O2 [M + H] + m / z, 376.2020; found, 376.2023.

[0435] N-(5-(6-(Cyclopropylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridin-3-yl)pyridin-2-yl)pentanamide (r28)

[0436] White solid, yield 75%. 11H NMR (600 MHz, Chloroform-d) δ 10.26 (s, 1H), 8.64 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.6 Hz, 1H), 8.40 (d, J = 1.5 Hz, 1H), 8.09 (dd, J = 7.4, 1.5 Hz, 1H), 7.97 (d, J = 7.4 Hz, 1H), 7.02 (d, J = 11.0 Hz, 1H), 6.33 (d, J = 10.8 Hz, 1H), 3.53 (d, J = 6.9 Hz, 2H), 2.41 (t, J = 7.1 Hz, 2H), 1.78–1.68 (m, 1H), 1.63–1.53 (m, 2H), 1.50–1.42 (m, 4H), 1.45–1.34 (m, 2H), 0.92 (t, J = 7.9 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 171.85, 164.01, 151.06, 150.51, 148.26, 146.68, 140.30, 135.96, 130.86, 129.90, 128.19, 124.55, 113.46, 103.28, 49.71, 36.43, 26.75, 21.89, 13.81, 9.88, 6.25. HRMS (ESI): calcd for C 22 H 25 N4O2 [M + H] + m / z, 377.1972; found, 377.1879.

[0437] N-(5-(2-Amino-4-oxo-3-propyl-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)pyridin-2-yl)pentanamide (r29)

[0438] White solid, yield 63%. 11H NMR (600 MHz, Chloroform-d) δ 10.27 (s, 1H), 8.63 (d, J = 1.3 Hz, 1H), 8.59 (d, J = 1.3 Hz, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.09 (dd, J = 7.6, 1.4 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.25 (d, J = 6.2 Hz, 1H), 6.89 (d, J = 6.2 Hz, 1H), 3.92 (t, J = 7.0 Hz, 2H), 2.41 (t, J = 7.1 Hz, 2H), 1.68–1.63 (m, 2H), 1.63–1.53 (m, 2H), 1.39 (m, 2H), 0.96 (t, J = 8.0 Hz, 3H), 0.92 (t, J = 7.9 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 171.85, 160.13, 154.84, 154.76, 152.26, 151.06, 146.79, 136.24, 130.09, 129.34, 127.81, 114.53, 113.46, 43.55, 36.43, 26.75, 21.89, 21.43, 13.81, 11.22. HRMS (ESI): calcd for C 20 H 25 N6O2 [M + H] + m / z, 381.2034; found, 381.2030.

[0439] N-(5-(4-Oxo-3-propyl-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)pyridin-2-yl)pentanamide (r30)

[0440] White solid, yield 67%. 1 1H NMR (600 MHz, Chloroform-d) δ 10.27 (s, 1H), 8.94 (s, 1H), 8.91 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.46 (d, J = 1.3 Hz, 1H), 7.97 (dd, J = 7.6, 1.4 Hz, 1H), 7.93 (d, J = 7.5 Hz, 1H), 4.03 (t, J = 7.0 Hz, 2H), 2.41 (t, J = 7.1 Hz, 2H), 1.73–1.65 (m, 2H), 1.62–1.53 (m, 2H), 1.44–1.34 (m, 2H), 0.94 (t, J = 8.0 Hz, 3H), 0.92 (t, J = 8.0 Hz, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 171.85, 160.56, 153.96, 151.57, 150.81, 147.80, 146.68, 136.24, 130.25, 129.18, 128.36, 118.16, 113.26, 48.56, 36.63, 26.77, 21.88, 21.79, 13.81, 10.92. HRMS (ESI): calcd for C 20 H 24 N5O2 [M+H] + m / z, 366.1925; found, 366.1929.

[0441] N-(5-(2-Hydroxy-4-oxo-3-propyl-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)pyridin-2-yl)pentanamide (r31)

[0442] White solid, yield 67%. 1 1H NMR (600 MHz, Chloroform-d) δ 10.27 (s, 1H), 8.78 (d, J = 1.5 Hz, 1H), 8.62 (d, J = 1.5 Hz, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.17 (s, 1H), 8.09 (dd, J = 7.6, 1.4 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 4.11 (t, J = 7.0 Hz, 2H), 2.41 (t, J = 7.1 Hz, 2H), 1.71–1.64 (m, 2H), 1.63–1.52 (m, 2H), 1.39–1.39 (m, 2H), 0.96 (t, J = 8.0 Hz, 3H), 0.92 (t, J = 7.9 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 171.85, 161.43, 154.21, 153.06, 152.80, 151.06, 146.79, 136.24, 130.09, 129.21, 128.01, 113.65, 113.46, 42.56, 36.43, 26.75, 21.89, 21.48, 13.81, 11.22. HRMS (ESI): calcd for C 20 H 24 N5O3 [M+H] + m / z, 382.1874; found, 382.1871.

[0443] N-(5-(3-(Cyclopropylmethyl)-2-hydroxy-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r32)

[0444] White solid, yield 67%. 1 H NMR(600MHz,Chloroform-d)δ10.25(s,1H),8.41(d,J=1.6Hz,1H),8.28(d,J=1.4Hz,1H),8.03(dd,J=7.7,1.5Hz,1H),7.91(d,J=7.5Hz,1H),7.83(s,1H),7.77(dd,J=7.4,1.5Hz,1H),7.60(d,J=7.4Hz,1H),3.76(d,J=6.9Hz,2H),2.41(t,J=7.1Hz,2H),1.96–1.87(m,1H),1.62(p,J=7.1Hz,2H),1.57–1.46(m,4H),1.43–1.34(m,2H),0.92(t,J=8.0Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ171.88,161.75,152.33,150.78,146.66,143.76,134.62,134.21,133.15,132.01,128.00,127.43,121.05,112.68,45.18,36.43,26.71,21.86,13.81,9.95,6.18.HRMS(ESI):calcd for C 22 H 25 N4O3[M+H] + m / z,393.1921;found,393.1925.

[0445] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)benzamide (r33)

[0446] White solid, yield 60%. 11H NMR (600 MHz, Chloroform-d) δ 8.95 (s, 1H), 8.57 (s, 1H), 8.55–8.49 (m, 3H), 8.10–8.04 (m, 2H), 7.98–7.93 (m, 3H), 7.80 (d, J = 8.4 Hz, 1H), 7.62–7.56 (m, 1H), 7.54–7.49 (m, 2H), 4.03 (t, J = 7.4 Hz, 2H), 1.80 (p, J = 7.4 Hz, 2H), 1.43 (h, J = 7.5 Hz, 2H), 0.98 (t, J = 7.4 Hz, 4H). 13 13C NMR (151 MHz, Chloroform-d) δ 165.94, 161.13, 151.28, 147.76, 146.94, 146.21, 137.17, 136.40, 134.27, 132.59, 132.53, 131.64, 129.03, 128.50, 127.43, 124.45, 122.76, 114.25, 47.06, 31.55, 20.02, 13.79. HRMS (ESI): calcd for C 24 H 23 N4O2 [M+H] + m / z, 399.1816; found, 399.1818.

[0447] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)butyramide (r34)

[0448] White solid, yield 72%. 1 1H NMR (600 MHz, Chloroform-d) δ 8.58 (d, J = 2.4 Hz, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.40 (s, 1H), 8.35 (d, J = 8.6 Hz, 1H), 8.05 (s, 1H), 8.01 (dd, J = 8.6, 2.4 Hz, 1H), 7.94 (dd, J = 8.5, 2.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 4.03 (t, J = 7.4 Hz, 2H), 2.41 (t, J = 7.4 Hz, 2H), 1.83–1.71 (m, 4H), 1.42 (h, J = 7.4 Hz, 2H), 1.01 (t, J = 7.4 Hz, 4H), 0.97 (t, J = 7.4 Hz, 4H). 13¹³C NMR (151 MHz, Chloroform-d) δ 171.90, 161.14, 151.14, 147.70, 146.89, 146.07, 137.06, 136.48, 132.57, 131.36, 128.46, 124.39, 122.72, 114.05, 47.04, 39.78, 31.53, 20.00, 18.93, 13.85, 13.77. HRMS (ESI): calcd for C 21 H 25 N4O2 [M+H] + m / z, 365.1972; found, 365.1974.

[0449] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r35)

[0450] White solid, yield 67%. 1 ¹H NMR (600 MHz, Chloroform-d) δ 8.58 (d, J = 2.5 Hz, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.36 (s, 1H), 8.34 (d, J = 8.7 Hz, 1H), 8.05 (s, 1H), 8.01 (dd, J = 8.7, 2.4 Hz, 1H), 7.94 (dd, J = 8.5, 2.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 4.03 (t, J = 7.4 Hz, 2H), 2.43 (t, J = 7.6 Hz, 2H), 1.82–1.76 (m, 2H), 1.75–1.70 (m, 2H), 1.45–1.37 (m, 4H), 0.97 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H). 13 ¹³C NMR (151 MHz, Chloroform-d) δ 172.07, 161.14, 151.14, 147.69, 146.89, 146.06, 137.08, 136.48, 132.58, 131.36, 128.46, 124.39, 122.73, 114.04, 47.05, 37.68, 31.53, 27.55, 22.46, 20.01, 13.93, 13.77. HRMS (ESI): calcd for C 22 H 27 N4O2 [M+H] + m / z, 379.2129; found, 379.2130.

[0451] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)hexanamide (r36)

[0452] White solid, yield 70%. 1 H NMR (600 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.53 (s, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.34 (d, J = 8.7 Hz, 1H), 8.04 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.93 (dd, J = 8.5, 2.2 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 4.02 (t, J = 7.4 Hz, 2H), 2.42 (t, J = 7.5 Hz, 2H), 1.79 (q, J = 7.5 Hz, 2H), 1.73 (q, J = 7.4 Hz, 2H), 1.41 (h, J = 7.4 Hz, 2H), 1.36–1.29 (m, 4H), 0.96 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.5 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 172.12, 161.13, 151.24, 147.68, 146.88, 146.09, 137.03, 136.48, 132.55, 131.32, 128.44, 124.37, 122.71, 114.09, 47.03, 37.88, 31.51, 31.47, 25.18, 22.52, 19.99, 14.02, 13.75. HRMS (ESI): calcd for C 23 H 29 N4O2 [M+H] + m / z, 393.2285; found, 393.2284.

[0453] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)cyclobutanecarboxamide (r37)

[0454] White solid, yield 73%. 11H NMR (600 MHz, Chloroform-d) δ 8.57 (d, J = 2.4 Hz, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.36 (d, J = 8.6 Hz, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 8.01 (dd, J = 8.6, 2.4 Hz, 1H), 7.94 (dd, J = 8.5, 2.2 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 4.02 (t, J = 7.4 Hz, 2H), 3.23 (p, J = 8.6 Hz, 1H), 2.45–2.37 (m, 2H), 2.28–2.21 (m, 2H), 2.06–1.98 (m, 1H), 1.96–1.89 (m, 1H), 1.79 (p, J = 7.4 Hz, 2H), 1.42 (h, J = 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 173.79, 161.13, 151.17, 147.69, 146.88, 146.06, 137.05, 136.48, 132.56, 131.30, 128.46, 124.37, 122.72, 113.95, 47.04, 40.95, 31.52, 25.29, 20.00, 18.13, 13.77. HRMS (ESI): calcd for C 22 H 25 N4O2 [M+H] + m / z, 377.1972; found, 377.1973.

[0455] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)cyclopentanecarboxamide (r38)

[0456] White solid, yield 75%. 11H NMR (600 MHz, Chloroform-d) δ 8.57 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.37 (s, 1H), 8.34 (d, J = 8.7 Hz, 1H), 8.04 (s, 1H), 7.99 (dd, J = 8.7, 2.5 Hz, 1H), 7.93 (dd, J = 8.4, 2.2 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 4.02 (t, J = 7.4 Hz, 2H), 2.77 (p, J = 8.1 Hz, 1H), 1.99–1.87 (m, 4H), 1.82–1.74 (m, 4H), 1.67–1.57 (m, 2H), 1.41 (h, J = 7.4 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 175.22, 161.12, 151.31, 147.65, 146.86, 146.03, 137.00, 136.49, 132.54, 131.22, 128.42, 124.33, 122.70, 113.99, 47.01, 46.93, 31.50, 30.48, 26.12, 19.98, 13.75. HRMS (ESI): calcd for C 23 H 27 N4O2 [M+H]+ + m / z, 391.2129; found, 391.2130.

[0457] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)cyclohexanecarboxamide (r39)

[0458] White solid, yield 56%. 11H NMR (600 MHz, Chloroform-d) δ 8.58 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.35 (d, J = 8.7 Hz, 1H), 8.25 (s, 1H), 8.04 (s, 1H), 8.00 (dd, J = 8.7, 2.5 Hz, 1H), 7.94 (dd, J = 8.4, 2.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 4.02 (t, J = 7.4 Hz, 2H), 2.30 (tt, J = 11.7, 3.5 Hz, 1H), 2.01–1.95 (m, 2H), 1.86–1.76 (m, 4H), 1.72–1.67 (m, 1H), 1.59–1.51 (m, 2H), 1.42 (h, J = 7.4 Hz, 2H), 1.34–1.22 (m, 3H), 0.97 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 174.98, 161.13, 151.27, 147.69, 146.88, 146.05, 137.03, 136.49, 132.55, 131.30, 128.46, 124.36, 122.73, 114.04, 47.04, 46.63, 31.53, 29.60, 25.75, 25.70, 20.00, 13.77. HRMS (ESI): calcd for C 24 H 29 N4O2 [M+H] + m / z, 405.2285; found, 405.2292.

[0459] N-(5-(3-Ethyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r40)

[0460] White solid, yield 72%. 11H NMR (600 MHz, Chloroform-d) δ 8.59 (d, J = 2.5 Hz, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.34 (d, J = 8.6 Hz, 2H), 8.08 (s, 1H), 8.01 (dd, J = 8.6, 2.5 Hz, 1H), 7.94 (dd, J = 8.4, 2.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 2.43 (t, J = 7.6 Hz, 2H), 1.76–1.70 (m, 2H), 1.44 (t, J = 7.2 Hz, 3H), 1.43–1.36 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 172.06, 161.00, 151.14, 147.76, 146.58, 146.06, 137.09, 136.50, 132.59, 131.35, 128.49, 124.34, 122.75, 114.03, 42.40, 37.69, 27.55, 22.46, 15.03, 13.94. HRMS (ESI): calcd for C 20 H 23 N4O2 [M+H] + m / z, 351.1816; found, 351.1820.

[0461] N-(5-(3-Isopentyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r41)

[0462] White solid, yield 74%. 1 1H NMR (600 MHz, Chloroform-d) δ 8.57 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 2.2 Hz, 2H), 8.34 (d, J = 8.7 Hz, 1H), 8.05 (s, 1H), 8.00 (dd, J = 8.7, 2.5 Hz, 1H), 7.93 (dd, J = 8.4, 2.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 4.03 (t, J = 7.6 Hz, 2H), 2.43 (t, J = 7.6 Hz, 2H), 1.76–1.70 (m, 2H), 1.70–1.63 (m, 3H), 1.39 (h, J = 7.4 Hz, 2H), 0.99 (d, J = 6.1 Hz, 6H), 0.92 (t, J = 7.4 Hz, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 172.09, 161.09, 151.20, 147.67, 146.79, 146.04, 137.03, 136.47, 132.54, 131.31, 128.44, 124.34, 122.70, 114.08, 45.61, 38.39, 37.64, 27.54, 25.90, 22.48, 22.44, 13.91. HRMS (ESI): calcd for C 23 H 29 N4O2 [M+H] + m / z, 393.2285; found, 393.2289.

[0463] N-(5-(3-(Cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r42)

[0464] White solid, yield 78%. 1 1H NMR (600 MHz, Chloroform-d) δ 8.58 (d, J = 2.5 Hz, 1H), 8.52 (s, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.34 (d, J = 8.7 Hz, 1H), 8.12 (s, 1H), 8.00 (dd, J = 8.7, 2.4 Hz, 1H), 7.94 (dd, J = 8.4, 2.2 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 3.89 (d, J = 7.2 Hz, 2H), 2.43 (t, J = 7.6 Hz, 2H), 1.72 (m, 2H), 1.39 (h, J = 7.4 Hz, 2H), 1.30 (tt, J = 7.6, 4.8 Hz, 1H), 0.92 (t, J = 7.4 Hz, 3H), 0.67–0.61 (m, 2H), 0.43 (dt, J = 6.1, 4.8 Hz, 2H). 13 13C NMR (151 MHz, Chloroform-d) δ 172.10, 161.26, 151.21, 147.69, 146.60, 146.05, 137.03, 136.44, 132.57, 131.31, 128.44, 124.42, 122.74, 114.07, 51.36, 37.63, 27.53, 22.44, 13.91, 10.95, 4.27. HRMS (ESI): calcd for C 22 H 25 N4O2 [M+H] + m / z, 377.1972; found, 377.1979.

[0465] N-(5-(3-(Cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)hexanamide (r43)

[0466] White solid, yield 72%. 1 H NMR (600 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.51 (d, J = 2.2 Hz, 1H), 8.46 (s, 1H), 8.39–8.31 (m, 1H), 8.13 (s, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.96–7.92 (m, 1H), 7.79 (d, J = 8.4 Hz, 1H), 3.90 (d, J = 7.2 Hz, 2H), 2.43 (t, J = 7.6 Hz, 2H), 1.74 (p, J = 7.3 Hz, 2H), 1.38–1.32 (m, 4H), 1.30 (dt, J = 7.6, 4.6 Hz, 1H), 0.91–0.86 (m, 3H), 0.67–0.62 (m, 2H), 0.46–0.41 (m, 2H). 13 C NMR (151 MHz, Chloroform-d) δ 172.12, 161.28, 151.22, 147.71, 146.62, 146.10, 137.08, 136.47, 132.58, 131.38, 128.46, 124.44, 122.76, 114.09, 51.37, 37.93, 31.47, 25.19, 22.53, 14.03, 10.96, 4.28. HRMS (ESI): calcd for C 23 H 27 N4O2 [M + H] + m / z, 391.2129; found, 391.2129.

[0467] N-(5-(3-(Cyclobutylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r44)

[0468] White solid, yield 75%. 11H NMR (600 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.38 (s, 1H), 8.34 (d, J = 8.7 Hz, 1H), 8.04 (s, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 4.05 (d, J = 7.4 Hz, 2H), 2.83 (m, 1H), 2.43 (t, J = 7.6 Hz, 2H), 2.10–2.07 (m, 2H), 1.96–1.88 (m, 2H), 1.86–1.80 (m, 2H), 1.73 (m, 2H), 1.41 (h, J = 7.6 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 172.06, 161.20, 151.15, 147.65, 146.79, 146.07, 137.07, 136.45, 132.57, 131.36, 128.44, 124.46, 122.75, 114.04, 51.82, 37.68, 35.03, 27.55, 26.17, 22.46, 18.29, 13.93. HRMS (ESI): calcd for C 23 H 27 N4O2 [M + H] + m / z, 391.2129; found, 391.2129.

[0469] N-(5-(4-Oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)benzamide (r45)

[0470] White solid, yield 82%. 1 1H NMR (600 MHz, Chloroform-d) δ 9.16 (s, 1H), 8.51 (d, J = 8.6 Hz, 1H), 8.47 (d, J = 2.2 Hz, 2H), 8.05 (m, 2H), 7.97–7.93 (m, 2H), 7.91 (dd, J = 8.4, 2.2 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.60–7.53 (m, 1H), 7.49 (t, J = 7.6 Hz, 2H), 3.98 (t, J = 7.4 Hz, 2H), 1.84 (h, J = 7.4 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 166.10, 161.08, 151.36, 147.71, 146.93, 146.23, 137.07, 136.35, 134.38, 132.53, 132.46, 131.51, 128.96, 128.43, 127.47, 124.40, 122.71, 114.25, 48.79, 22.75, 11.24. HRMS (ESI): calcd for C 23 H 21 N4O2 [M+H] + m / z, 385.1659; found, 385.1659.

[0471] N-(5-(4-Oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r46)

[0472] White solid, yield 76%. 1 1H NMR (600 MHz, Chloroform-d) δ 8.59 (d, J = 2.5 Hz, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.37 (s, 1H), 8.34 (d, J = 8.6 Hz, 1H), 8.05 (s, 1H), 8.01 (dd, J = 8.6, 2.5 Hz, 1H), 7.94 (dd, J = 8.4, 2.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 3.99 (t, J = 7.4 Hz, 2H), 2.43 (t, J = 7.6 Hz, 2H), 1.85 (h, J = 7.4 Hz, 2H), 1.76–1.70 (m, 2H), 1.41 (h, J = 7.4 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 172.06, 161.14, 151.16, 147.71, 146.92, 146.09, 137.07, 136.49, 132.59, 131.36, 128.47, 124.41, 122.73, 114.04, 48.82, 37.68, 27.55, 22.77, 22.46, 13.93, 11.25. HRMS (ESI): calcd for C 21 H 25 N4O2 [M+H] + m / z, 365.1972; found, 365.1977.

[0473] N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)hexanamide (r47)

[0474] White solid, yield 75%. 1 H NMR (600 MHz, Chloroform-d) δ 8.58 (d, J = 2.5 Hz, 1H), 8.51 (s, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.34 (d, J = 8.7 Hz, 1H), 8.05 (s, 1H), 8.00 (dd, J = 8.7, 2.5 Hz, 1H), 7.93 (dd, J = 8.4, 2.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 3.99 (t, J = 7.3 Hz, 2H), 2.42 (t, J = 7.6 Hz, 2H), 1.84 (h, J = 7.4 Hz, 2H), 1.76–1.70 (m, 2H), 1.37–1.30 (m, 4H), 1.00 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 172.11, 161.13, 151.22, 147.69, 146.91, 146.07, 137.04, 136.48, 132.57, 131.32, 128.44, 124.39, 122.71, 114.08, 48.81, 37.88, 31.47, 25.18, 22.75, 22.52, 14.02, 11.24. HRMS (ESI): calcd for C 22 H 27 N4O2 [M + H] + m / z, 379.2129; found, 379.2129.

[0475] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r48)

[0476] White solid, yield 79%. 11H NMR (600 MHz, Chloroform-d) δ 8.67 (d, J = 2.0 Hz, 1H), 8.60 (s, 1H), 8.56 (s, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.00 (dd, J = 8.6, 2.2 Hz, 1H), 7.81 (dd, J = 8.2, 2.0 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 7.3 Hz, 1H), 6.51 (d, J = 7.3 Hz, 1H), 3.99 (t, J = 7.4 Hz, 2H), 2.42 (t, J = 7.6 Hz, 2H), 1.82 (h, J = 7.4 Hz, 2H), 1.71 (p, J = 7.6 Hz, 2H), 1.39 (h, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 172.10, 162.19, 151.02, 146.09, 136.93, 136.42, 135.92, 132.22, 131.89, 130.48, 126.90, 126.86, 125.68, 114.03, 105.65, 51.16, 37.61, 27.57, 22.66, 22.45, 13.91, 11.32. HRMS (ESI): calcd for C 22 H 26 N3O2 [M + H] + m / z, 364.2020; found, 364.2019.

[0477] N-(5-(1-Oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r49)

[0478] White solid, yield 77%. 11H NMR (600 MHz, Chloroform-d) δ 9.30 (s, 1H), 8.95 (s, 2H), 8.67 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.2, 2.0 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 7.3 Hz, 1H), 6.54 (d, J = 7.3 Hz, 1H), 3.99 (t, J = 7.4 Hz, 2H), 2.77 (t, J = 7.6 Hz, 2H), 1.83 (h, J = 7.4 Hz, 2H), 1.73 (p, J = 7.6 Hz, 2H), 1.43 (h, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 162.05, 156.94, 156.44, 136.94, 132.66, 132.62, 130.07, 128.52, 127.30, 126.96, 125.67, 105.61, 51.22, 37.42, 27.27, 22.65, 22.52, 13.99, 11.32. HRMS (ESI): calcd for C 21 H 25 N4O2 [M+H] + m / z, 365.1972; found, 365.1971.

[0479] N-(5-(4-Oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyrimidin-2-yl)pentanamide (r50)

[0480] White solid, yield 66%. 1 1H NMR (600 MHz, Chloroform-d) δ 9.49 (s, 1H), 8.94 (s, 2H), 8.50 (d, J = 2.2 Hz, 1H), 8.08 (s, 1H), 7.93 (dd, J = 8.4, 2.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 3.99 (t, J = 7.4 Hz, 2H), 2.80 (t, J = 7.4 Hz, 2H), 1.84 (h, J = 7.4 Hz, 2H), 1.74 (p, J = 7.6 Hz, 2H), 1.43 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 160.93, 157.15, 156.49, 148.10, 147.27, 133.23, 132.15, 128.85, 127.90, 124.38, 122.88, 48.85, 37.41, 27.21, 22.72, 22.51, 13.98, 11.22. HRMS (ESI): calcd for C 20 H 24 N5O2 [M+H] + m / z, 366.1925; found, 366.1925.

[0481] N-(4-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)phenyl)pentanamide (r51)

[0482] White solid, yield 74%. 1 1H NMR (600 MHz, Chloroform-d) δ 8.46 (d, J = 2.2 Hz, 1H), 8.02 (s, 1H), 7.95 (dd, J = 8.4, 2.2 Hz, 1H), 7.83 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 3.99 (t, J = 7.4 Hz, 2H), 2.39 (t, J = 7.6 Hz, 2H), 1.84 (h, J = 7.4 Hz, 2H), 1.72 (p, J = 7.6 Hz, 2H), 1.39 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 171.86, 161.33, 147.19, 146.47, 139.65, 138.22, 135.15, 132.92, 128.03, 127.77, 124.12, 122.45, 120.33, 48.77, 37.61, 27.80, 22.77, 22.51, 13.95, 11.24. HRMS (ESI): calcd for C 22 H 26 N3O2 [M+H] + m / z, 364.2020; found, 364.2020.

[0483] N-(5-(5-oxo-6-propyl-5,6-dihydro-1,6-naphthyridin-3-yl)pyridin-2-yl)pentanamide (r52)

[0484] White solid, yield 72%. 1 H NMR (600 MHz, Chloroform-d) δ 9.10 (d, J = 2.4 Hz, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.68 (s, 1H), 8.60 (d, J = 2.5 Hz, 1H), 8.37 (d, J = 8.6 Hz, 1H), 8.00 (dd, J = 8.6, 2.5 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 4.00 (t, J = 7.4 Hz, 2H), 2.44 (t, J = 7.6 Hz, 2H), 1.82 (h, J = 7.4 Hz, 2H), 1.71 (p, J = 7.6 Hz, 2H), 1.39 (h, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 172.25, 162.24, 152.69, 152.67, 151.69, 146.18, 136.87, 135.75, 133.53, 131.34, 128.75, 121.97, 114.25, 107.60, 51.21, 37.56, 27.50, 22.63, 22.44, 13.92, 11.27. HRMS (ESI): calcd for C 21 H 25 N4O2 [M+H] + m / z, 365.1972; found, 365.1972.

[0485] 2-Cyclopropyl-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)acetamide (r53)

[0486] White solid, yield 59%. 11H NMR (600 MHz, Chloroform-d) δ 8.59 (d, J = 2.3 Hz, 1H), 8.53 (s, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.36 (d, J = 8.6 Hz, 1H), 8.05 (s, 1H), 8.01 (dd, J = 8.6, 2.5 Hz, 1H), 7.94 (dd, J = 8.5, 2.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 4.01–3.97 (m, 2H), 2.38 (d, J = 7.2 Hz, 2H), 1.85 (h, J = 7.4 Hz, 2H), 1.17–1.07 (m, 1H), 1.01 (t, J = 7.4 Hz, 3H), 0.76–0.68 (m, 2H), 0.31 (dt, J = 6.0, 4.6 Hz, 2H). 13 13C NMR (151 MHz, Chloroform-d) δ 171.32, 161.13, 151.02, 147.70, 146.92, 146.13, 137.04, 136.49, 132.59, 131.46, 128.46, 124.41, 122.72, 113.99, 48.82, 42.76, 22.76, 11.25, 7.21, 4.90. HRMS (ESI): calcd for C 21 H 23 N4O2 [M + H] + m / z, 363.1816; found, 363.1816.

[0487] 2-Cyclobutyl-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)acetamide (r54)

[0488] White solid, yield 55%. 1 1H NMR (600 MHz, Chloroform-d) δ 8.58 (d, J = 2.5 Hz, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.37 (s, 1H), 8.32 (d, J = 8.7 Hz, 1H), 8.05 (s, 1H), 7.99 (dd, J = 8.7, 2.5 Hz, 1H), 7.93 (dd, J = 8.4, 2.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 3.99 (t, J = 7.4 Hz, 2H), 2.84–2.75 (m, 1H), 2.54 (d, J = 7.6 Hz, 2H), 2.24–2.14 (m, 2H), 1.96–1.81 (m, 4H), 1.81–1.73 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H).13 C NMR(151MHz, Chloroform-d) δ 171.05, 161.13, 151.14, 147.69, 146.90, 146.09, 137.01, 136.49, 132.57, 131.33, 128.45, 124.38, 122.71, 114.04, 48.81, 44.81, 32.63, 28.47, 22.75, 18.75, 11.24. HRMS(ESI): calcd for C 22 H 25 N4O2 [M + H] + m / z, 377.1972; found, 377.1972.

[0489] N-(6-Fluoro-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r55)

[0490] White solid, yield 70%. 1 H NMR(600MHz, Chloroform-d) δ 8.45 (d, J = 2.2Hz, 1H), 8.21 (d, J = 8.2Hz, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.99–7.91 (m, 2H), 7.79–7.74 (m, 1H), 3.99 (t, J = 7.4Hz, 2H), 2.43 (t, J = 7.6Hz, 2H), 1.84 (h, J = 7.4Hz, 2H), 1.71 (p, J = 7.6Hz, 2H), 1.40 (h, J = 7.4Hz, 2H), 1.00 (t, J = 7.4Hz, 3H), 0.93 (t, J = 7.4Hz, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 172.08, 161.01, 158.43 (159.23, 157.62, d, J = 242.7 Hz), 149.15 (149.20, 149.10, d, J = 14.3 Hz), 147.73, 147.23, 143.21 (143.22, 143.20, d, J = 4.2 Hz), 134.42 (134.44, 134.41, d, J = 3.7 Hz), 132.86 (132.87, 132.84, d, J = 5.0 Hz), 127.95, 126.55 (126.56, 126.54, d, J = 2.5 Hz), 122.49, 117.17 (117.25, 117.08, d, J = 26.4 Hz), 111.37 (111.39, 111.36, d, J = 4.3 Hz), 48.83, 37.52, 27.42, 22.74, 22.39, 13.89, 11.23. 19 19F NMR (565 MHz, Chloroform-d) δ -72.67. HRMS (ESI): calcd for C 21 H 24 N4O2 [M+H] + m / z, 383.1878; found, 383.1878.

[0491] N-(5-(2-Methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r56)

[0492] White solid, yield 78%. 1 1H NMR (600 MHz, Chloroform-d) δ 8.57 (d, J = 2.5 Hz, 1H), 8.45 (s, 1H), 8.43 (d, J = 2.2 Hz, 1H), 8.32 (d, J = 8.6 Hz, 1H), 7.99 (dd, J = 8.6, 2.5 Hz, 1H), 7.89 (dd, J = 8.5, 2.2 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 4.10–4.03 (m, 2H), 2.66 (s, 3H), 2.42 (t, J = 7.6 Hz, 2H), 1.78 (h, J = 7.6 Hz, 2H), 1.71 (p, J = 7.6 Hz, 2H), 1.39 (h, J = 7.4 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 172.05, 162.07, 154.54, 151.05, 146.84, 146.02, 136.93, 135.54, 132.59, 131.51, 127.62, 124.47, 121.04, 114.02, 46.32, 37.64, 27.55, 23.33, 22.45, 22.09, 13.91, 11.49. HRMS (ESI): calcd for C 22 H 27 N4O2 [M+H] + m / z, 379.2129; found, 379.2129.

[0493] N-(5-(2-Hydroxy-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r57)

[0494] Yellow solid, yield 75%. 1 1H NMR (600 MHz, DMSO-d6) δ 11.52 (s, 1H), 10.56 (s, 1H), 8.63 (d, J = 2.5 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 8.08 (dd, J = 8.7, 2.5 Hz, 1H), 7.99 (dd, J = 8.5, 2.2 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 3.86 (t, J = 7.4 Hz, 2H), 2.40 (t, J = 7.6 Hz, 2H), 1.63–1.54 (m, 4H), 1.31 (h, J = 7.4 Hz, 2H), 0.91–0.86 (m, 6H). 13 13C NMR (151 MHz, DMSO-d6) δ 172.30, 161.81, 151.47, 150.05, 145.43, 138.81, 135.86, 133.00, 131.18, 129.65, 124.46, 116.00, 114.26, 113.27, 41.60, 35.82, 27.12, 21.80, 20.71, 13.77, 11.25. HRMS (ESI): calcd for C 21 H 25 N4O3 [M+H] + m / z, 381.1921; found, 381.1922.

[0495] N-(5-(3-(2-Fluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r58)

[0496] White solid, yield 71%. 1 H NMR (600 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.74 (d, J = 2.7 Hz, 1H), 8.41–8.35 (m, 2H), 8.24–8.17 (m, 3H), 7.77 (dd, J = 8.5, 2.2 Hz, 1H), 4.81–4.77 (m, 1H), 4.73–4.69 (m, 1H), 4.40–4.36 (m, 1H), 4.36–4.32 (m, 1H), 2.42 (t, J = 7.6 Hz, 2H), 1.61–1.55 (m, 2H), 1.35–1.29 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 172.40, 160.21, 151.84, 148.18, 147.24, 145.99, 136.41, 135.64, 132.59, 129.53, 128.13, 123.01, 121.93, 113.30, 81.31 (81.86, 80.76, d, J = 166.2 Hz), 46.36 (46.43, 46.30, d, J = 19.9 Hz), 35.84, 27.11, 21.80, 13.77. 19 F NMR (565 MHz, DMSO-d6) δ -208.23. HRMS (ESI): calcd for C 20 H 22 FN4O2 [M+H] + m / z, 369.1721; found, 369.1721.

[0497] 2-(Ethylamino)-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)acetamide (r59)

[0498] White solid, yield 73%. 11H NMR (600 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.72 (t, J = 1.7 Hz, 1H), 8.41 (s, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.24–8.19 (m, 2H), 8.14 (dd, J = 8.5, 2.3 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 3.95 (t, J = 7.4 Hz, 2H), 3.34 (s, 2H), 2.58 (q, J = 7.1 Hz, 2H), 1.72 (h, J = 7.4 Hz, 2H), 1.05 (t, J = 7.1 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 171.26, 160.11, 150.85, 148.24, 147.35, 146.15, 136.62, 135.31, 132.31, 130.04, 128.05, 123.08, 122.00, 112.85, 52.46, 47.55, 43.44, 21.94, 15.15, 10.86. HRMS (ESI): calcd for C 20 H 24 N5O2 [M+H] + m / z, 366.1925; found, 366.1925.

[0499] N-(5-(2-Amino-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r60)

[0500] White solid, yield 51%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.63 (d, J = 2.5 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 2.3 Hz, 1H), 8.08 (dd, J = 8.7, 2.5 Hz, 1H), 7.90 (dd, J = 8.5, 2.3 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 7.11 (s, 2H), 3.96 (t, J = 7.7 Hz, 2H), 2.40 (t, J = 7.4 Hz, 2H), 1.67–1.53 (m, 4H), 1.31 (h, J = 7.4 Hz, 2H), 0.93–0.86 (m, 6H). 1313C NMR (151 MHz, DMSO) δ 172.32, 161.81, 152.14, 151.14, 149.32, 145.30, 135.71, 132.32, 130.48, 129.84, 124.61, 123.66, 116.43, 113.39, 42.59, 35.87, 27.19, 21.84, 20.49, 13.80, 10.99. HRMS (ESI): calcd for C 21 H 26 N5O2 [M+H] + m / z, 380.2081; found, 380.2068.

[0501] N-(5-(2-Amino-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4,4-difluoropentanamide (r61)

[0502] White solid, yield 54%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.70 (t, J = 1.7 Hz, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.18 (d, J = 1.7 Hz, 2H), 8.13 (dd, J = 8.5, 2.3 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.10 (s, 2H), 3.96 (t, J = 7.7 Hz, 2H), 2.63–2.60 (m, 2H), 2.27–2.20 (m, 2H), 1.73–1.69 (m, 2H), 1.65 (t, J = 19.0 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 172.31, 161.80, 152.12, 151.13, 149.30, 145.26, 135.70, 132.30, 130.49, 129.81, 124.70 (126.28, 124.70, 123.12, t, J = 238.2 Hz), 124.60, 123.64, 116.41, 113.36, 47.54, 32.53 (32.70, 32.53, 32.37, t, J = 25.4 Hz), 29.46 (29.49, 29.46, 29.43, t, J = 4.5 Hz), 23.06 (23.24, 23.06, 22.88, t, J = 27.2 Hz), 21.87, 10.97. 1919F NMR (565 MHz, DMSO-d6) δ -89.20. HRMS (ESI): calculated for C 21 H 24 F2N5O2 [M+H] + m / z, 416.1893; found, 416.1989.

[0503] N-(5-(2-Amino-3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4,4-difluoropentanamide (r62)

[0504] White solid, yield 50%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.71 (t, J = 1.7 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.20–8.16 (m, 2H), 8.14 (dd, J = 8.5, 2.3 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.11 (s, 2H), 3.95 (t, J = 7.7 Hz, 2H), 2.64–2.61 (m, 2H), 2.26–2.21 (m, 2H), 1.65 (t, J = 18.8 Hz, 3H), 1.32–1.27 (m, 1H), 0.55–0.51 (m, 2H), 0.46–0.43 (m, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 172.34, 161.82, 152.14, 151.16, 149.31, 145.27, 135.73, 132.33, 130.51, 129.84, 124.72 (126.30, 124.70, 123.15, t, J = 237.8 Hz), 124.62, 123.66, 116.44, 113.39, 47.56, 32.55 (32.72, 32.53, 32.38, t, J = 25.6 Hz), 29.48 (29.51, 29.48, 29.45, t, J = 4.4 Hz), 23.04 (23.22, 23.04, 22.87, t, J = 27.0 Hz), 10.84, 3.56. 19 19F NMR (565 MHz, DMSO-d6) δ -89.22. HRMS (ESI): calculated for C 22 H 24 F2N5O2 [M+H] + m / z, 428.1893; found, 428.1888.

[0505] N-(5-(4-Oxo-3-(prop-2-yn-1-yl)-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r63)

[0506] White solid, yield 76%. 1 H NMR (600 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.73 (d, J = 2.3 Hz, 1H), 8.48 (s, 1H), 8.39 (d, J = 2.3 Hz, 1H), 8.25–8.16 (m, 3H), 7.77 (d, J = 8.5 Hz, 1H), 4.85 (d, J = 2.5 Hz, 2H), 3.44 (t, J = 2.4 Hz, 1H), 2.42 (t, J = 7.4 Hz, 2H), 1.58 (p, J = 7.5 Hz, 2H), 1.32 (h, J = 7.4 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 172.38, 159.45, 151.85, 147.11, 147.08, 145.98, 136.38, 135.81, 132.67, 129.44, 128.17, 123.01, 121.88, 113.27, 78.47, 75.72, 35.83, 35.27, 27.09, 21.78, 13.74. HRMS (ESI): calcd for C 21 H 21 N4O2 [M+H] + m / z, 361.1659; found, 361.1649.

[0507] N-(5-(3-Cyclopropyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r64)

[0508] White solid, yield 72%. 11H NMR (600 MHz, Chloroform-d) δ 8.57 (d, J = 2.5 Hz, 1H), 8.53 (s, 1H), 8.51 (d, J = 2.2 Hz, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.10 (s, 1H), 8.03 (dd, J = 8.7, 2.4 Hz, 1H), 7.96 (dd, J = 8.4, 2.2 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 2.58 (tt, J = 7.6, 4.8 Hz, 1H), 2.41 (t, J = 7.6 Hz, 2H), 1.74 (m, 2H), 1.37 (h, J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H), 0.65–0.59 (m, 2H), 0.45 (dt, J = 6.1, 4.8 Hz, 2H). 13 13C NMR (151 MHz, Chloroform-d) δ 172.19, 161.29, 151.31, 147.70, 146.66, 146.10, 137.08, 136.46, 132.59, 131.35, 128.54, 124.49, 122.78, 114.17, 37.66, 30.31, 27.55, 22.49, 13.90, 4.23. HRMS (ESI): calcd for C 21 H 23 N4O2 [M+H] + m / z, 363.1816; found, 363.1813.

[0509] N-(5-(3-(2-Fluoropropyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r65)

[0510] White solid, yield 66%. 1 1H NMR (600 MHz, Chloroform-d) δ 8.58 (d, J = 2.5 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.35 (s, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.04 (s, 1H), 8.00 (dd, J = 8.6, 2.5 Hz, 1H), 7.95 (dd, J = 8.4, 2.3 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 4.20–4.10 (m, 2H), 3.44–3.37 (m, 1H), 2.43 (t, J = 7.6 Hz, 2H), 1.76–1.70 (m, 2H), 1.51 (d, J = 12.5 Hz, 3h), 1.41 (h, J = 7.4 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H).13 C NMR (151 MHz, Chloroform-d) δ 172.20, 161.15, 151.17, 147.75, 146.25, 146.11, 137.09, 136.52, 132.58, 131.37, 128.47, 124.40, 122.71, 114.08, 93.52 (94.08, 92.97, d, J = 168.4 Hz), 59.42 (59.51, 59.34, d, J = 25.6 Hz), 37.66, 27.57, 22.74 (22.83, 22.65, d, J = 27.2 Hz) 22.40, 13.89. 19 F NMR (282 MHz, Chloroform-d); δ -181.3; HRMS (ESI): calcd for C 21 H 24 FN4O2 [M + H] + m / z, 383.1833; found, 383.1831.

[0511] 4,4-Difluoro-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r66)

[0512] White solid, yield 67%. 1 H NMR (600 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.73 (t, J = 1.7 Hz, 1H), 8.41 (s, 1H), 8.37 (d, J = 2.3 Hz, 1H), 8.19 (d, J = 1.7 Hz, 2H), 8.16 (dd, J = 8.5, 2.3 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 3.96 (t, J = 7.2 Hz, 2H), 2.65–2.61 (m, 2H), 2.28–2.20 (m, 2H), 1.75–1.71 (m, 2H), 1.64 (t, J = 18.9 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H). 1313C NMR(151MHz,DMSO-d6)δ170.76,160.12,151.61,148.21,147.32,145.97,136.41,135.38,132.30,129.78,128.04,124.68(126.26,124.68,123.11,t,J=237.7Hz),123.03,122.00,113.34,47.53,32.51(32.68,32.51,32.34,t,J=25.5Hz),29.43(29.46,29.43,29.40,t,J=4.5Hz),23.00(23.18,23.00,22.82,t,J=27.0Hz),21.93,10.84. 19 19F NMR(565MHz,DMSO-d6)δ-89.19.HRMS(ESI):calcd for C 21 H 23 F2N4O2[M+H] + m / z,401.1784;found,401.1782.

[0513] N-(5-(3-(Cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4-fluoropentanamide (r67)

[0514] White solid, yield 63%. 1 1H NMR(600MHz,Chloroform-d)δ8.60(d,J=2.5Hz,1H),8.54(s,1H),8.50(d,J=2.2Hz,1H),8.36(d,J=8.7Hz,1H),8.14(s,1H),8.04(dd,J=8.7,2.5Hz,1H),7.96(dd,J=8.4,2.2Hz,1H),7.82(d,J=8.5Hz,1H),4.08–3.92(m,1H),3.91(d,J=7.2Hz,2H),2.63(t,J=18.6Hz,2H),1.85–1.78(m,2H),1.36(d,J=14.6Hz,3H),1.32(tt,J=7.6,4.8Hz,1H),0.69–0.63(m,2H),0.46(dt,J=6.1,4.8Hz,2H). 13CNMR(151MHz, Chloroform-d) δ 174.20, 163.56, 150.91, 148.99, 147.60, 146.85, 137.93, 137.44, 132.97, 131.61, 129.44, 125.42, 121.74, 115.97, 101.51(102.06, 100.96, d, J=164.8Hz), 52.36, 41.66(41.74, 41.59, d, J=22.4Hz), 34.42(34.43, 34.41, d, J=3.4Hz), 19.92(20.01, 19.83, d, J=26.8Hz), 11.98, 4.67. 19 F NMR(565MHz, Chloroform-d) δ -189.34. HRMS(ESI): calcd for C 22 H 24 FN4O2 [M+H] + m / z, 394.1802;found, 394.1800.

[0515] N-(5-(3-(Cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4,4-difluoropentanamide (r68)

[0516] White solid, yield 69% 1 H NMR(600MHz, DMSO-d6) δ 10.75(s, 1H), 8.74(t, J=1.7Hz, 1H), 8.45(s, 1H), 8.39(d, J=2.3Hz, 1H), 8.23–8.18(m, 2H), 8.17(dd, J=8.5, 2.3Hz, 1H), 7.76(d, J=8.5Hz, 1H), 3.86(d, J=7.2Hz, 2H), 2.65–2.61(m, 2H), 2.28–2.20(m, 2H), 1.64(t, J=18.9Hz, 3H), 1.31–1.26(m, 1H), 0.53–0.49(m, 2H), 0.45–0.42(m, 2H). 1313C NMR (151 MHz, DMSO-d6) δ 170.79, 160.24, 151.64, 148.09, 147.37, 146.01, 136.44, 135.41, 132.37, 129.77, 128.07, 124.72 (126.29, 124.72, 123.14, t, J = 237.5 Hz), 123.07, 122.05, 113.35, 50.17, 32.52 (32.69, 32.52, 32.35, t, J = 25.7 Hz), 29.45 (29.48, 29.45, 29.41, t, J = 4.4 Hz), 23.02 (23.20, 23.02, 22.85, t, J = 27.1 Hz), 10.82, 3.54. 19 19F NMR (565 MHz, DMSO-d6) δ -89.22. HRMS (ESI): calcd for C 22 H 23 F2N4O2 [M+H] + m / z, 413.1784; found, 413.1774.

[0517] N-(5-(3-(Cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3,3-difluoropentanamide (r69)

[0518] White solid, yield 68%. 1 1H NMR (600 MHz, Chloroform-d) δ 8.65 (d, J = 2.5 Hz, 1H), 8.57 (s, 1H), 8.54 (d, J = 2.2 Hz, 1H), 8.39 (d, J = 8.7 Hz, 1H), 8.15 (s, 1H), 8.07 (dd, J = 8.7, 2.5 Hz, 1H), 7.86 (dd, J = 8.4, 2.2 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 3.95 (d, J = 7.2 Hz, 2H), 2.68 (s, 2H), 1.82 (q, J = 12.6 Hz, 2H), 1.31–1.37 (m, 1H), 0.95 (t, J = 10.5 Hz, 3H), 0.68–0.61 (m, 2H), 0.45–0.50 (m, 2H). 1313C NMR (151 MHz, Chloroform-d) δ 174.10, 163.58, 150.93, 148.89, 145.63, 146.95, 137.98, 137.54, 132.87, 131.51, 129.49, 125.43, 121.71, 115.87, 111.58 (112.38, 110.78, d, J = 242.2 Hz), 53.26, 47.82 (47.91, 47.73, d, J = 27.6 Hz), 38.52 (38.61, 38.44, d, J = 26.2 Hz), 11.88, 5.11 (5.12, 5.10, d, J = 3.4 Hz), 4.77. 19 19F NMR (565 MHz, Chloroform-d) δ -102.28. HRMS (ESI): calcd for C 22 H 23 F2N4O2 [M+H] + m / z, 413.1784; found, 413.1781.

[0519] N-(5-(3-(Cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-fluoropentanamide (r70)

[0520] White solid, yield 65%. 1 1H NMR (600 MHz, Chloroform-d) δ 8.60 (d, J = 2.5 Hz, 1H), 8.54 (s, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.36 (d, J = 8.7 Hz, 1H), 8.14 (s, 1H), 8.04 (dd, J = 8.7, 2.5 Hz, 1H), 7.96 (dd, J = 8.4, 2.2 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 4.01–3.84 (m, 1H), 3.91 (d, J = 7.2 Hz, 2H), 2.63 (d, J = 17.6 Hz, 2H), 1.75–1.68 (m, 2H), 1.32 (tt, J = 7.6, 4.8 Hz, 1H), 0.96 (t, J = 8.6 Hz, 3H), 0.68–0.61 (m, 2H), 0.45–0.50 (m, 2H). 1313C NMR (151 MHz, Chloroform-d) δ 172.14 (172.15, 172.13, d, J = 3.4 Hz), 163.59, 150.90, 148.89, 147.69, 146.87, 137.97, 137.49, 132.99, 131.51, 129.54, 125.62, 121.64, 115.87, 100.82 (101.38, 100.27, d, J = 166.4 Hz), 52.46, 40.26 (40.34, 40.18, d, J = 24.4 Hz), 30.48 (30.56, 30.41, d, J = 23.4 Hz), 12.06 (12.07, 12.05, d, J = 3.6 Hz), 11.91, 4.57. 19 19F NMR (565 MHz, Chloroform-d) δ -165.78. HRMS (ESI): calcd for C 22 H 24 FN4O2 [M+H] + m / z, 394.1802; found, 394.1802.

[0521] 3,3-Difluoro-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r71)

[0522] White solid, yield 71%. 1 1H NMR (600 MHz, Chloroform-d) δ 8.86 (s, 1H), 8.62 (d, J = 2.5 Hz, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.30 (d, J = 8.6 Hz, 1H), 8.05 (s, 1H), 8.01 (dd, J = 8.6, 2.5 Hz, 1H), 7.94 (dd, J = 8.5, 2.3 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 4.00 (t, J = 7.3 Hz, 2H), 3.05 (t, J = 15.3 Hz, 2H), 2.12–2.03 (m, 2H), 1.85 (h, J = 7.4 Hz, 2H), 1.08 (t, J = 7.5 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 164.90, 161.19, 150.74, 147.77, 146.96, 146.32, 137.04, 136.39, 132.65, 131.90, 128.48, 124.53, 123.31 (124.91, 123.31, 121.70, t, J = 242.5 Hz), 122.72, 114.28, 48.84, 45.11 (45.29, 45.11, 44.93, t, J = 26.9 Hz), 29.72 (29.89, 29.72, 29.56, t, J = 24.9 Hz), 22.75, 11.23, 6.65 (6.69, 6.65, 6.61, t, J = 5.3 Hz). 19 19F NMR (565 MHz, Chloroform-d) δ -95.36. HRMS (ESI): calcd for C 21 H 23 F2N4O2 [M+H] + m / z, 401.1784; found, 401.1775.

[0523] N-(5-(4-Oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyrazin-2-yl)pentanamide (r72)

[0524] White solid, yield 71%. 1 1H NMR (600 MHz, Chloroform-d) δ 10.32 (s, 1H), 8.80 (s, 1H), 8.75 (s, 1H), 8.47 (d, J = 1.5 Hz, 1H), 8.36 (dd, J = 7.5, 1.4 Hz, 1H), 7.90 (s, 1H), 7.64 (d, J = 7.4 Hz, 1H), 4.06 (t, J = 7.0 Hz, 2H), 2.42 (t, J = 7.1 Hz, 2H), 1.73–1.65 (m, 2H), 1.66–1.58 (m, 2H), 1.44–1.34 (m, 2H), 0.94 (t, J = 8.0 Hz, 3H), 0.92 (t, J = 8.0 Hz, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 171.82, 160.18, 148.15, 147.74, 147.54, 145.62, 140.26, 135.69, 132.89, 132.20, 127.65, 126.78, 122.68, 48.59, 36.63, 26.77, 21.88, 21.79, 13.81, 10.92. HRMS (ESI): calcd for C 20 H 24 N5O2 [M+H] + m / z, 366.1925; found, 366.1927.

[0525] N-(6-(4-Oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-3-yl)pentanamide (r73)

[0526] White solid, yield 74%. 1 1H NMR (600 MHz, Chloroform-d) δ 9.87 (s, 1H), 9.31 (d, J = 1.3 Hz, 1H), 8.75 (s, 1H), 8.32 (d, J = 1.5 Hz, 1H), 8.24 (dd, J = 7.4, 1.5 Hz, 1H), 7.83–7.77 (m, 2H), 7.62 (d, J = 7.5 Hz, 1H), 4.06 (t, J = 7.0 Hz, 2H), 2.30 (t, J = 7.1 Hz, 2H), 1.73–1.65 (m, 2H), 1.66–1.58 (m, 2H), 1.44–1.34 (m, 2H), 0.94 (t, J = 8.0 Hz, 3H), 0.92 (t, J = 8.1 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 171.77, 160.18, 153.47, 147.54, 145.55, 142.59, 135.07, 134.85, 132.26, 126.92, 126.83, 126.68, 122.84, 122.38, 48.59, 36.74, 26.76, 21.88, 21.79, 13.81, 10.92. HRMS (ESI): calcd for C 21 H 25 N4O2 [M+H] + m / z, 365.1972; found, 365.1976.

[0527] N-(2-(4-Oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyrimidin-5-yl)pentanamide (r74)

[0528] White solid, yield 72%. 1 H NMR (600 MHz, Chloroform-d) δ 9.79 (s, 1H), 9.21 (s, 2H), 8.75 (s, 1H), 8.23 (d, J = 1.5 Hz, 1H), 8.05 (dd, J = 7.7, 1.5 Hz, 1H), 7.62 (d, J = 7.4 Hz, 1H), 4.06 (t, J = 7.0 Hz, 2H), 2.30 (t, J = 7.0 Hz, 2H), 1.73–1.64 (m, 2H), 1.65–1.58 (m, 2H), 1.43–1.34 (m, 2H), 0.94 (t, J = 8.0 Hz, 3H), 0.92 (t, J = 8.1 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 171.70, 160.28, 160.18, 148.32, 147.54, 145.99, 133.56, 132.83, 132.80, 126.81, 126.28, 122.95, 48.59, 36.71, 26.76, 21.88, 21.79, 13.81, 10.92. HRMS (ESI): calcd for C 20 H 24 N5O2 [M + H] + m / z, 366.1925; found, 366.1927.

[0529] N-(3-Methyl-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r75)

[0530] White solid, yield 76%. 1 H NMR (600 MHz, Chloroform-d) δ 8.59 (d, J = 2.5 Hz, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.37 (s, 1H), 8.05 (s, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.94 (dd, J = 8.4, 2.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 3.99 (t, J = 7.4 Hz, 2H), 2.52 (s, 3H), 2.43 (t, J = 7.6 Hz, 2H), 1.85 (h, J = 7.4 Hz, 2H), 1.76–1.70 (m, 2H), 1.41 (h, J = 7.4 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H). 13¹³C NMR (151 MHz, Chloroform-d) δ 171.53, 160.97, 149.31, 147.14, 145.66, 139.70, 133.99, 132.48, 129.25, 129.21, 128.44, 127.74, 122.60, 120.56, 47.57, 37.55, 25.41, 22.91, 22.77, 16.24, 13.95, 11.39. HRMS (ESI): calcd for C 22 H 27 N4O2 [M+H] + m / z, 379.2129; found, 379.2125.

[0531] N-(4-Methyl-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r76)

[0532] White solid, yield 77%. 1 ¹H NMR (600 MHz, Chloroform-d) δ 8.65 (s, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 8.06 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 8.4, 2.1 Hz, 1H), 3.98 (t, J = 7.3 Hz, 2H), 2.41 (t, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.84 (h, J = 7.4 Hz, 2H), 1.70 (p, J = 7.5 Hz, 2H), 1.38 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). 13 ¹³C NMR (151 MHz, Chloroform-d) δ 172.20, 161.07, 151.06, 147.64, 147.58, 147.48, 147.00, 136.97, 135.42, 132.84, 127.68, 127.22, 122.28, 115.17, 48.80, 37.59, 27.57, 22.74, 22.43, 20.58, 13.90, 11.23. HRMS (ESI): calcd for C 22 H 27 N4O2 [M+H] + m / z, 379.2129; found, 379.2129.

[0533] N-(6-Methyl-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r77)

[0534] White solid, yield 67%. 1 H NMR (600 MHz, Chloroform-d) δ 8.24 (d, J = 2.0 Hz, 1H), 8.17–8.08 (m, 2H), 8.06 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.70–7.65 (m, 1H), 7.58 (d, J = 8.4 Hz, 1H), 3.98 (t, J = 7.3 Hz, 2H), 2.42–2.37 (m, 5H), 1.83 (h, J = 7.4 Hz, 2H), 1.71 (p, J = 7.6 Hz, 2H), 1.39 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 171.95, 161.07, 153.99, 150.19, 147.34, 146.95, 139.99, 138.74, 135.26, 131.67, 127.67, 127.02, 122.22, 111.31, 48.79, 37.68, 27.57, 23.04, 22.74, 22.44, 13.91, 11.24. HRMS (ESI): calcd for C 22 H 27 N4O2 [M+H] + m / z, 379.2129; found, 379.2128.

[0535] N-(3-Fluoro-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r78)

[0536] White solid, yield 70%. 11H NMR (600 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.45 (d, J = 2.2 Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.95–7.91 (m, 1H), 7.79–7.74 (m, 1H), 3.99 (t, J = 7.4 Hz, 2H), 2.43 (t, J = 7.6 Hz, 2H), 1.84 (h, J = 7.4 Hz, 2H), 1.71 (p, J = 7.6 Hz, 2H), 1.40 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 171.55, 160.97, 152.43 (d, J = 241.6 Hz), 147.42 (d, J = 21.2 Hz), 147.14, 145.66, 138.64 (d, J = 3.4 Hz), 133.99 (d, J = 2.3 Hz), 129.32 (d, J = 8.6 Hz), 128.13, 127.74, 122.60, 120.56, 117.84 (d, J = 26.5 Hz), 47.81, 37.55, 25.41, 22.91, 22.77, 13.94, 11.41. 19 19F NMR (565 MHz, Chloroform-d) δ -110.69. HRMS (ESI): calcd for C 21 H 24 N4O2 [M + H] + m / z, 383.1878; found, 383.1875.

[0537] 1-(5-(3-Benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(o-tolyl)urea (r79)

[0538] White solid, yield 81%. 11H NMR (600 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.97 (s, 1H), 8.72 (d, J = 2.5 Hz, 1H), 8.61 (s, 1H), 8.39 (d, J = 2.3 Hz, 1H), 8.22–8.16 (m, 2H), 8.07 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.44–7.34 (m, 5H), 7.30 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 6.97 (t, J = 7.4 Hz, 1H), 5.23 (s, 2H), 2.36 (s, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 160.10, 152.69, 152.20, 148.09, 147.23, 144.54, 137.33, 137.08, 136.83, 135.52, 132.42, 130.24, 128.68, 128.14, 127.80, 127.74, 127.02, 126.30, 122.99, 122.82, 122.12, 120.28, 112.05, 49.01, 18.24. HRMS (ESI): calcd for C 28 H 24 N5O2 [M + H]+ + m / z, 462.1925; found, 462.1926.

[0539] 1-(5-(3-Benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(m-tolyl)urea (r80)

[0540] White solid, yield 84%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.61 (s, 1H), 8.72 (d, J = 2.5 Hz, 1H), 8.60 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.20–8.15 (m, 2H), 7.78 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.39–7.33 (m, 6H), 7.31–7.27 (m, 1H), 7.19 (t, J = 7.7 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H), 5.23 (s, 2H), 2.29 (s, 3H). 1313C NMR (151 MHz, DMSO-d6) δ 160.10, 152.53, 152.03, 148.08, 147.20, 145.12, 138.93, 138.15, 136.83, 135.64, 132.36, 128.76, 128.68, 128.17, 128.01, 127.72, 123.30, 122.93, 122.14, 119.28, 115.95, 111.95, 48.99, 21.20. HRMS (ESI): calcd for C 28 H 24 N5O2 [M+H] + m / z, 462.1925; found, 462.1925.

[0541] 1-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-phenylurea (r81)

[0542] White solid, yield 85%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.59 (s, 1H), 8.71 (d, J = 2.5 Hz, 1H), 8.40 (s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.17 (dd, J = 8.7, 2.5 Hz, 1H), 8.14 (dd, J = 8.5, 2.2 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.57–7.53 (m, 2H), 7.34–7.30 (m, 2H), 7.05–7.00 (m, 1H), 3.98 (t, J = 7.4 Hz, 2H), 1.68 (p, J = 7.4 Hz, 2H), 1.31 (h, J = 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 160.11, 152.46, 152.06, 148.11, 147.23, 145.12, 139.02, 136.80, 135.42, 132.13, 128.92, 128.14, 128.06, 122.81, 122.56, 122.01, 118.79, 111.95, 45.77, 30.75, 19.32, 13.58. HRMS (ESI): calcdfor C 24 H 24 N5O2 [M+H] + m / z, 414.1925; found, 414.1925.

[0543] 1-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(4-fluorophenyl)urea (R82)

[0544] White solid, yield 81%. 1 H NMR (600 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.60 (s, 1H), 8.70 (d, J = 2.5 Hz, 1H), 8.40 (s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.17 (dd, J = 8.7, 2.5 Hz, 1H), 8.13 (dd, J = 8.5, 2.2 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.58–7.54 (m, 2H), 7.19–7.13 (m, 2H), 3.99 (t, J = 7.4 Hz, 2H), 1.68 (p, J = 7.4 Hz, 2H), 1.31 (h, J = 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 159.32 (160.10, 158.53, d, J = 238.1 Hz), 156.94, 152.42, 152.14, 148.12, 147.24, 145.07, 136.82, 135.40, 135.34 (135.34, 135.33, d, J = 2.5 Hz), 132.13, 128.14, 128.06, 122.80, 122.01, 120.58 (120.61, 120.56, d, J = 7.7 Hz), 115.44 (115.51, 115.36, d, J = 22.3 Hz), 111.96, 45.77, 30.75, 19.32, 13.58. 19 F NMR (565 MHz, DMSO-d6) δ -120.55. HRMS (ESI): calcd for C 24 H 23 FN5O2 [M + H] + m / z, 432.1830; found, 432.1833.

[0545] 1-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(4-methoxyphenyl)urea (R83)

[0546] White solid, yield 80%. 11H NMR (600 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.54 (s, 1H), 8.69 (d, J = 2.5 Hz, 1H), 8.40 (s, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 8.7, 2.5 Hz, 1H), 8.14 (dd, J = 8.5, 2.3 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.47–7.43 (m, 2H), 6.92–6.87 (m, 2H), 3.99 (t, J = 7.4 Hz, 2H), 3.73 (s, 3H), 1.68 (p, J = 7.4 Hz, 2H), 1.31 (h, J = 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 160.11, 154.93, 152.60, 152.17, 148.10, 147.21, 145.04, 136.76, 135.46, 132.13, 131.99, 128.05, 127.95, 122.78, 122.02, 120.57, 114.07, 111.90, 55.20, 45.77, 30.75, 19.32, 13.59. HRMS (ESI): calcd for C 25 H 26 N5O3 [M + H] + m / z, 444.2030; found, 444.2032.

[0547] 1-Benzyl-3-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)urea (r84)

[0548] White solid, yield 77%. 1 1H NMR (600 MHz, Chloroform-d) δ 9.49 (s, 1H), 8.60 (d, J = 2.5 Hz, 1H), 8.40 (s, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.15–8.09 (m, 2H), 7.73 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.40–7.30 (m, 4H), 7.29–7.21 (m, 1H), 4.43 (d, J = 5.9 Hz, 2H), 3.98 (t, J = 7.4 Hz, 2H), 1.68 (p, J = 7.4 Hz, 2H), 1.31 (h, J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 160.10, 154.77, 153.03, 148.09, 148.05, 147.15, 144.94, 139.93, 136.63, 135.56, 132.13, 128.44, 128.01, 127.59, 127.10, 126.85, 122.74, 122.69, 121.99, 111.74, 45.76, 42.68, 30.74, 19.31, 13.59. HRMS (ESI): calcd for C 25 H 26 N5O2 [M+H] + m / z, 428.2081; found, 428.2085.

[0549] 1-Butyl-3-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)urea (r85)

[0550] White solid, yield 62%. 1 1H NMR (600 MHz, Chloroform-d) δ 9.38 (s, 2H), 8.50 (d, J = 2.5 Hz, 1H), 8.46 (d, J = 2.2 Hz, 1H), 8.04 (s, 1H), 7.94–7.88 (m, 2H), 7.77 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 4.02 (t, J = 7.4 Hz, 2H), 3.46–3.39 (m, 2H), 1.83–1.75 (m, 2H), 1.67–1.59 (m, 2H), 1.50–1.37 (m, 4H), 1.00–0.94 (m, 6H). 13 13C NMR (151 MHz, Chloroform-d) δ 161.14, 156.42, 153.32, 147.46, 146.77, 144.42, 136.90, 136.65, 132.34, 128.37, 128.33, 124.00, 122.69, 112.43, 47.03, 39.73, 32.17, 31.52, 20.36, 20.00, 13.98, 13.76. HRMS (ESI): calcd for C 22 H 28 N5O2 [M+H] + m / z, 394.2238; found, 394.2241.

[0551] 1-(tert-Butyl)-3-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)urea (r86)

[0552] White solid, yield 59%. 1 H NMR (600 MHz, Chloroform-d) δ 9.48 (s, 1H), 9.27 (s, 1H), 8.50 (d, J = 2.5 Hz, 1H), 8.46 (d, J = 2.2 Hz, 1H), 8.03 (s, 1H), 7.95–7.89 (m, 2H), 7.77 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 4.02 (t, J = 7.4 Hz, 2H), 1.81–1.76 (m, 2H), 1.49 (s, 9H), 1.42 (h, J = 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 161.13, 155.26, 153.62, 147.46, 146.73, 144.39, 136.83, 136.74, 132.30, 128.37, 128.05, 123.97, 122.72, 112.32, 50.68, 47.01, 31.54, 29.39, 20.00, 13.78. HRMS (ESI): calcd for C 22 H 28 N5O2 [M + H] + m / z, 394.2238; found, 394.2238.

[0553]

[0554] Bis(diphenylphosphino)ferrocene palladium(II) dichloride (137 mg, 0.19 mmol) was added to a solution of 2-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine p1 (797 mg, 2.81 mmol), 6-bromo-3-propylquinazolin-4(3H)-one k2 (500 mg, 1.87 mmol) and potassium carbonate (517 mg, 3.74 mmol) in 1,4-dioxane (20 mL). After reacting for 1.5 h, water (5 mL) was added and the reaction was continued for 0.5 - 2.5 h. After the reaction was completed, it was cooled to room temperature, the solvent was removed under vacuum, dichloromethane and methanol were added to dissolve the crude product, potassium carbonate was removed by filtration, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography using dichloromethane:methanol = 50:1 as the eluent to obtain 6-(6-bromopyridin-3-yl)-3-propylquinazolin-4(3H)-one (Compound q1) as a white solid (489 mg, 1.42 mmol, yield 76%). ESI-MS: m / z 345.3 [M+H] + 。

[0555] Copper(I) iodide (3.8 mg, 0.02 mmol) was added to a solution of 6-(6-bromopyridin-3-yl)-3-propylquinazolin-4(3H)-one q1 (300 mg, 0.87 mmol), 2-pyrrolidone (111 mg, 1.30 mmol), N,N'-dimethylethylenediamine (8 mg, 0.09 mmol) and potassium carbonate (241 mg, 1.74 mmol) in toluene (5 mL). The temperature was raised to 110 °C and the reaction was carried out for 4 h. After the reaction was completed, it was cooled to room temperature, the solvent was removed under vacuum, dichloromethane and methanol were added to dissolve the crude product, potassium carbonate was removed by filtration, the solvent was removed under vacuum, and the product was purified by silica gel column chromatography using dichloromethane:methanol = 80:1 as the eluent to obtain 6-(6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (Compound r87) as a white solid (237 mg, 0.68 mmol, yield 78%). 11H NMR (600 MHz, DMSO-d6) δ 8.75 (d, J = 2.5 Hz, 1H), 8.41 (s, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.20 (dd, J = 8.8, 2.5 Hz, 1H), 8.13 (dd, J = 8.5, 2.3 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 4.04–4.00 (m, 2H), 3.99–3.90 (m, 2H), 2.60 (t, J = 8.0 Hz, 2H), 2.06 (p, J = 8.0 Hz, 2H), 1.73 (h, J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 174.74, 160.08, 151.14, 148.24, 147.35, 145.56, 135.98, 135.27, 132.32, 129.71, 128.03, 123.15, 121.98, 113.46, 47.54, 47.00, 33.07, 21.93, 17.15, 10.85. HRMS (ESI): calcd for C 20 H 21 N4O2 [M+H] + m / z, 349.1659; found, 349.1649.

[0556] Compound r88 - 91 was prepared with different compounds p and different compounds k in a similar method.

[0557] 6-(6-(2-Oxopiperidin-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (r88)

[0558] White solid, yield 78%. 1 1H NMR (600 MHz, DMSO-d6) δ 8.81 (d, J = 2.5 Hz, 1H), 8.43 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.19–8.15 (m, 2H), 7.86 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 3.98–3.94 (m, 2H), 3.92–3.88 (m, 2H), 2.52–2.50 (m, 2H), 1.91–1.86 (m, 2H), 1.86–1.81 (m, 2H), 1.73 (h, J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H). 1313C NMR (151 MHz, DMSO-d6) δ 170.38, 160.09, 153.79, 148.35, 147.50, 145.52, 135.27, 135.19, 132.52, 130.80, 128.08, 123.41, 122.01, 120.05, 47.56, 47.12, 33.29, 22.64, 21.93, 20.45, 10.86. HRMS (ESI): calcd for C 21 H 23 N4O2 [M+H] + m / z, 363.1816; found, 363.1805.

[0559] 6-(6-(2-Oxoazepan-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (r89)

[0560] White solid, yield 75%. 1 1H NMR (600 MHz, DMSO-d6) δ 8.80 (d, J = 2.5 Hz, 1H), 8.42 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 8.5, 2.3 Hz, 2H), 7.81–7.74 (m, 2H), 4.12–4.06 (m, 2H), 3.98–3.94 (m, 2H), 2.75–2.69 (m, 2H), 1.79–1.69 (m, 8H), 0.90 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 175.21, 160.07, 154.01, 148.33, 147.48, 145.64, 135.30, 135.23, 132.51, 130.74, 128.07, 123.40, 122.00, 120.22, 47.54, 47.37, 37.81, 28.68, 28.43, 23.16, 21.91, 10.84. HRMS (ESI): calcd for C 22 H 25 N4O2 [M+H] + m / z, 377.1972; found, 377.1962.

[0561] 6-(6-(4-Methyl-2-oxopiperidin-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (r90)

[0562] White solid, yield 80%. 11H NMR (600 MHz, DMSO-d6) δ 8.80 (d, J = 2.5 Hz, 1H), 8.41 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 4.00–3.94 (m, 3H), 2.59–2.47 (m, 3H), 2.09–2.02 (m, 1H), 1.90–1.85 (m, 1H), 1.73 (h, J = 7.4 Hz, 2H), 1.56–1.49 (m, 1H), 1.03 (d, J = 6.6 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 170.41, 160.24, 153.85, 148.44, 147.57, 145.60, 135.42, 135.30, 132.66, 130.97, 128.19, 123.51, 122.08, 120.14, 53.77, 47.69, 32.71, 28.59, 28.49, 22.01, 18.59, 10.93. HRMS (ESI): calcd for C 22 H 25 N4O2 [M+H] + m / z, 377.1972; found, 377.1962.

[0563] (S)-6-(6-(4-Ethyl-2-oxoazepan-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (r91)

[0564] White solid, yield 77%. 1 1H NMR (600 MHz, DMSO-d6) δ 8.82 (d, J = 2.5 Hz, 1H), 8.39 (s, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.15 (dd, J = 8.5, 2.3 Hz, 2H), 7.79–7.70 (m, 2H), 4.10–4.07 (m, 2H), 3.88–3.84 (m, 2H), 2.73–2.68 (m, 2H), 1.797–1.64 (m, 10H), 1.03 (t, J = 6.8 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). 1313C NMR (151 MHz, DMSO-d6) δ 172.20, 160.82, 146.99, 145.61, 144.58, 142.17, 136.37, 135.29, 129.93, 127.83, 126.99, 121.71, 117.96, 110.32, 47.63, 46.38, 42.19, 37.28, 26.92, 25.75, 24.86, 23.26, 11.89, 11.23. HRMS (ESI): calcd for C 24 H 28 N4O2 [M + H] + m / z, 405.2240; found, 405.2237.

[0565] Test Example 1: Proliferation Inhibitory Activity of the Compounds of the Present Invention against Various Tumor Cells

[0566] Cells such as lung cancer, breast cancer, cervical cancer, ovarian cancer, leukemia, liver cancer, gastric cancer, kidney cancer, colorectal cancer, prostate cancer, and pancreatic cancer were cultured in a cell culture medium containing 10% fetal bovine serum in a 5% carbon dioxide saturated incubator at 37°C. Cells in the logarithmic growth phase were inoculated into 96-well plates (OD values were measured by the MMT or CCK8 method) or 12-well plates (cell counting method by flow cytometry) for culture. After adherence, the corresponding concentration of the drug was added and cultured for 72 hours. OD values were measured at 450 nm or 490 nM after direct counting or incubation with MTT or CCK8 for the corresponding time, and the inhibition rate was calculated.

[0567] As shown in Table 1, the compounds used in the present invention showed strong proliferation inhibitory activity against EGFR-TKI-resistant lung adenocarcinoma, TP53 mutations, TTN mutations, and KRAS mutations, as well as related tumor cells with high expression of PI5P4Kγ, such as lung cancer, breast cancer, cervical cancer, ovarian cancer, leukemia, liver cancer, gastric cancer, kidney cancer, colorectal cancer, prostate cancer, and pancreatic cancer. Moreover, the IC 50 values of the vast majority of the compounds were all below 50 nM.

[0568] Table 1 Proliferation Inhibitory Activity of Compounds against Various Tumor Cells is Expressed by IC 50 values (unit: μM) and are the average of three data.

[0569]

[0570]

[0571]

[0572]

[0573] Test Example 2: PI5P4Kγ Inhibitory Activity of the Compounds of the Present Invention

[0574] The inhibitory activity test of the compounds against PI5P4Kγ was mainly completed on the KINOMEscan screening platform of Eurofins. This platform reflects the inhibitory activity by measuring the ligand competitive binding ability of the compounds to PI5P4Kγ. When the compound competes with the ligand for binding at the kinase site, or hinders the ligand from binding to PI5P4Kγ after binding to PI5P4Kγ, it shows inhibitory activity. The inhibition rate reflects the affinity strength between the compound and the target.

[0575] The target binding inhibitory activity test was carried out on the compounds of the present invention, and it was found that the compounds in the present invention showed strong binding activity against PI5P4Kγ at a concentration of 1.0 μM. Among them, the inhibition rates of compounds r15, r21, r22, r23, r24, r46, r48, r60, r61, r62, r66, r67, r68, r69, r70 and r71 against PI5P4Kγ all exceeded 90%, and the inhibition rates of r61, r62, r66 and r68 against PI5P4Kγ reached 100%. In addition, the inhibition rates of r28, r30, r44, r45, r49, r72 and r78 all exceeded 85%. Thus, it can be seen that by further structural optimization of r46, PI5P4Kγ inhibitors r61, r62, r66 and r68 with stronger target inhibitory activity were obtained. The results are shown in Table 2.

[0576] Table 2 Inhibitory Activity of Some Compounds against PI5P4Kγ

[0577] Compound Name Inhibition Rate (%) Compound Name Inhibition Rate (%) Compound Name Inhibition Rate (%) r15 99.16 r35 78.90 r66 100 r21 99.42 r41 72.81 r67 99.86 r22 99.48 r44 85.33 r68 100 r23 99.51 r45 88.30 r69 99.21 r24 99.53 r46 99.57 r70 93.28 r25 80.07 r48 93.01 r71 99.52 r26 82.03 r49 87.57 r78 85.14 r28 86.21 r56 71.08 r73 76.55 r29 78.99 r60 95.36 r75 75.38 r30 85.31 r61 100 r76 78.26 r31 79.54 r62 100 r72 86.23 r32 32.16 r63 77.23 r78 88.76 r33 73.11 r64 78.05 r81 83.75 r34 69.57 r65 79.28 r88 64.97

[0578] Test Example 3: Target Inhibitory Activity of Compound r46

[0579] (1) Subtype Selectivity Test Method: The kinase inhibitory activity of r46 against PI5P4Kα was completed on the KinaseProfiler platform of Eurofins (using the radioactive isotope labeling method, which is the gold standard for kinase activity testing). The binding inhibitory activity of r46 against PI5P4Kβ and PI5P4Kγ was completed on the ScanMax platform of Eurofins (the determination of the target binding activity (Kd value), which can identify allosteric inhibitors of kinases).

[0580] (2)ITC experimental method: Isothermal titration calorimetry (ITC) technology is the "gold standard" for verifying direct intermolecular interactions. The results of ITC experiments directly reflect the thermodynamics of intermolecular interactions, and the results are highly reliable. In this invention, the ITC method is used to investigate the main types of interactions between r46 and PI5P4Kγ. After the full-length protein of PI5P4Kγ is purified, it is dialyzed in a buffer containing 20 mM sodium phosphate, pH 8, 150 mM sodium chloride, and 10% (v / w) glycerol, and then quickly frozen in liquid nitrogen at 1 - 4 μM in approximately 300 μL of liquid and stored at -80 °C. The buffer is added to the sample protein, and the reference substance and the substance to be tested are added to the syringe. The sample and the syringe are placed in the ITC instrument, and the temperature is controlled at a constant temperature. The reference substance is injected into the sample, and the baseline value of the heat effect signal is recorded. The substance to be tested is added to the sample, and the change value of the heat effect signal is recorded. Steps 3 - 4 are repeated until the measurement is completed. Thermodynamic parameters such as the thermodynamic equilibrium constant, enthalpy change, and entropy change are calculated based on the measurement results. All experiments are carried out in a buffer containing 20 mM sodium phosphate, 150 mM sodium chloride, 10% glycerol, 0.5 mg / mL BSA, 0.1% (v / v) DMSO, and pH 8. The ligand is dissolved in DMSO and then diluted into the buffer immediately before the experiment. All experiments are carried out in the high feedback mode at 30 °C, with a stirring speed of 806 revolutions per minute. (Malvern VP-ITC) or 750 pm. (Malvern ITC-200), and the filtering time is 1 second. To establish a flat baseline, a long pre-injection delay (∼1000 s) is used. Inhibitory kinetic ITC experiments are carried out with PI5P4Kγ and TRH in the reaction cell and the syringe respectively. Immediately before loading the sample cell and initializing the experiment, PI5P4Kγ is added to the cell solution to avoid substrate depletion. TRH is added to the reaction cell, and PI5P4Kγ / inhibitor is added to the syringe to conduct the initialized ITC kinetic experiment. Before starting the experiment, the syringe solution is equilibrated at 30 °C for about 2 hours. The ligand is dissolved in DMSO and then diluted into the buffer immediately before the experiment. DMSO is added to the cell solution to match the syringe solution to minimize the heat of dilution. To correct the tilted baseline, an artifact common in ITC experiments, a baseline correction procedure is implemented for the inhibitory kinetic and starting experiments. This process involves fitting a line to the final flat part of each injection (usually lasting about 200 seconds). Each line is extrapolated to the start of its respective injection to establish a complete baseline for each injection. Then the complete baseline is subtracted from the original data of each injection to obtain the baseline-corrected data.

[0581] (3) Kinase profiling screening method: The selective binding of compound r46 to 486 kinases was investigated using the ScanMax platform of Eurofins (the determination of the target binding activity (Kd value), which can identify allosteric inhibitors of kinases) to complete.

[0582] Co-crystal structure analysis experimental method: PI5P4Kγ was expressed in Escherichia coli BL21(DE3)Gold using the pET28b vector. Induced expression with 0.1 mM IPT, cultured at 18 °C for 16 h, and harvested by centrifugation. This protein consists of residues His32 to Ala421, and the region between residues 300 - 341 was deleted. The tev-cleaved protein was purified by affinity chromatography and size exclusion chromatography (Superdex 75). The structure of the complex of the ligand and the receptor was generated by co-crystallization of human PI5P4Kγ and the target compound in solution. The purified protein was incubated overnight at 4 °C in 20 mM N-(2-hydroxyethyl)piperazine-N'-aminosulfonic acid (HEPES) pH 7.5, 150 mM NaCl and 0.5 mM tris(2-carboxyethyl)-phosphine [15.5 mg / mL] with 10 mM of the target compound. Complex crystals were formed in a solution of 22% w / v Peg3350, 0.3 M ammonium tartrate and 100 mM PCPT (sodium propionate, sodium acetate trihydrate and bis-tris propane) at pH 7.5 at 20 °C. When using AMP-PNP, first incubate with 4 mM AMP-PNP (buffer) for 2 hours, then incubate with 10 mM 40 overnight, and then set up the crystallization plate. X-ray data collection, rapid freezing, and X-ray diffraction data were collected at 100 k. Data processing was performed using XDS and Aimless software. Diamond Light Source synchrotron facility, Oxford, UK, beamlines (I03 and I24 were used for 7QIE and 7QPN respectively). Data processing was performed using XDS and Aimless software. Using the previously solved structure of human PI5P4Kγ (PDB code: 2GK9) as a search model, the phase information required to determine and analyze the structure was obtained by molecular replacement (PHASER, CCP4). Subsequent model building and refinement were carried out according to the standard protocols of the CCP4 and COOT software packages. TLS was refined (REFMAC5, CCP4) to give a lower r factor and higher quality electron density map. Ligand parameterization and the generation of the corresponding library files were carried out using ACEDRG (CCP4). The Ramachandran plots of the final models showed that for 7QIE and 7QPN, the residues in the most favorable regions were 91.3% and 92.3% respectively, and the residues in the additionally allowed regions were 7.0% and 5.0% respectively.

[0583] After confirming the good anti-tumor activity of the above compounds, the target inhibitory activity of r46 was further investigated. As attached Figure 1As shown, the test results of the ScanMAX platform indicate that the Kd value of r46 is 6.55 nM. In addition, the Kd values of compound r46 for the other two subtypes of PI5P4Ks, PI5P4Kα and PI5P4Kβ, are both greater than 20 μM, indicating that r46 has strong subtype selectivity for PI5P4Kγ. To investigate the interaction type between r46 and PI5P4Kγ, the thermodynamic situation of their interaction was investigated using the ITC method. As attached Figure 1 As shown, the Kd value for the binding of r46 to PI5P4Kγ is 123 nM, and ΔH = -5.76 ± 0.02 Kcal / mol, indicating that the interaction between r46 and PI5P4Kγ is mainly enthalpy-driven and usually generates interactions through hydrogen bonds, ionic bonds, and van der Waals forces.

[0584] To further confirm the inhibitory activity of compound r46 against other kinases, the binding inhibitory activity of 1 μM r46 against 486 kinases was screened. As attached Figure 2 As shown, r46 can selectively inhibit PI5P4Kγ with an inhibition rate of up to 99%, and has no obvious inhibitory activity against the other 485 kinases. In summary, r46 is a highly selective and highly active inhibitor of PI5P4Kγ.

[0585] To determine the binding mode of r46 to PI5P4Kγ, the crystal structure of the complex was further identified. As attached Figure 3As shown, the N1 of quinazolinone, the N atom on the pyridine ring, and the carbonyl group on the amide side chain at its C6 position respectively form three key hydrogen bonds with Met206, Lys152, and Ile375. The 6-(pyridin-3-yl)quinazolin-4(3H)-one nucleus forms six types of interactions including π-π T shaped, π-sigma, π-sulfur, and van der Waals forces with nearly 20 amino acids such as Met162, Leu201, Phe207, Lys216, and Leu376 in the hydrophobic pocket of the PI5P4Kγ active site. In addition, the amide side chain on the pyridine ring extends into a hydrophobic allosteric pocket where the orthosteric site mutates. Different from r46, it was found that ARUK2001607, the only known orthosteric inhibitor of PI5P4Kγ, does not form an interaction with this hydrophobic allosteric pocket. When performing crystal structure analysis, it was found that although there is a high-energy conformation in the alkane chain on the pyridine ring of r46, it does not cause its electron cloud to be unclear, indicating that its binding conformation in this binding pocket is relatively stable. This may be due to the formation of key interactions with multiple amino acids such as Met162 and Leu201, which stabilized its binding conformation. However, the existence of the high-energy conformation will lose some binding energy and affect the activity of the compound. Therefore, in subsequent structure modifications, by stabilizing this active conformation, the target inhibition activity of the compound was further improved, and compounds r61, r62, r66, and r68 with higher activity were obtained. In summary, compound r46 is a novel PI5P4Kγ inhibitor that acts on both the orthosteric site and the allosteric site of PI5P4Kγ.

[0586] Test Example 4: In Vivo Pharmacodynamic Test

[0587] Nude mice fed with basal diet were placed in a sterile breeding room. It was found that their activities, eating and drinking were normal, and their body weights were about 20 g. Five groups (6 mice in each group) were set up, namely the control group, the high, medium and low dose groups of r46, and the positive control group (the known PI5P4Kγ inhibitor ARUK2001607). After 3 days of adaptive feeding, a nude mouse xenograft tumor model of H1975-OR cells was established. Cells in the logarithmic growth phase (passaged to the 2nd generation) were digested with 0.05% trypsin containing EDTA, washed twice with serum-free culture medium, resuspended with serum-free culture medium and counted. After centrifugation, they were resuspended with 1×PBS and adjusted to an appropriate density. 0.2 mL of the above-prepared cell suspension was drawn with a syringe and inoculated into the right axilla of nude mice disinfected with 75% alcohol under aseptic operation. After inoculation, a lump-like protrusion could be clearly seen at the inoculation site. Tumors began to grow subcutaneously at the inoculation site about 3 days after inoculation. After 10 days, the tumors grew to an average of about 80 mm3 and oral administration was started for 3 weeks. The relative tumor volume (RTV) was calculated according to the measurement results, RTV = Vt / V0. Where V0 is the tumor volume measured at d0, and Vt is the tumor volume at each measurement. The evaluation index of anti-tumor activity was the relative tumor proliferation rate T / C (%) = TRTV / CRTV×100%. TRTV: RTV of the treatment group; CRTV: RTV of the negative control group. The efficacy evaluation criteria: T / C% > 40% is ineffective; T / C% ≤ 40%, and after statistical treatment p < 0.05 is effective. Tumor inhibition rate (%) = (1 - average tumor weight of the drug administration group / average tumor weight of the negative control group)×100%. Tumor growth inhibition rate < 40% is ineffective; tumor growth inhibition rate ≥ 40%, and after statistical treatment p < 0.05 is effective. After the experiment, the experimental animals were sacrificed by anesthesia, the tumors were dissected, the tumor weights were weighed and the tumor inhibition rate was calculated.

[0588] As shown in the appendix Figure 4 As shown, compound r46 also has strong in vivo anti-tumor activity, and the tumor inhibition rate of r46 at 20 mg / kg is 93.73%. The above experimental results show that r46 not only exhibits high target inhibition activity and selectivity, but also has strong anti-tumor activity in vitro and in vivo. Compound r46 can effectively inhibit the growth and lung metastasis of subcutaneous xenograft tumors of H1975OR cells. H1975OR cells are non-small cell lung cancer cells with TP53 mutation and EGFR-TKI resistance, further verifying the in vivo drug efficacy of r46 against TP53 mutation and EGFR-TKI resistant tumors.

[0589] Test Example 5: Inhibitory effect of compound r46 on each subtype of P450 enzyme

[0590] 1) Test method: Drug concentration: The drug was prepared into a stock solution with a mass concentration of 19.5 mg / mL using Na2HPO4-NaH2PO4 (pH 7.4) solution, and then diluted with Na2HPO4-NaH2PO4 solution to make the final mass concentrations during incubation be 6.5, 32.5, 65.0, 325.0, 650.0, 3250.0, and 6500.0 μg / mL respectively. Positive substrates: CYP1A2: phenacetin; CYP2C9: diclofenac; CYP2C19: mephenytoin; CYP3A4: midazolam or testosterone; CYP2D6: bufuralol; CYP2C8: paclitaxel; CYP2B6: bupropion. Detection method: LC-MS / MS. Metabolic probe products: CYP1A2: acetaminophen-D4; CYP2C9: 4'-hydroxydiclofenac-[13C6]; CYP2C19: hydroxymephenytoin-D3; CYP3A4: 1-hydroxy-midazolam-D4 or cholerythrin; CYP2D6: 1-hydroxybufuralol-[D9] maleate; CYP2C8: 6α-hydroxypaclitaxel-[D5]; CYP2B6: hydroxybupropion-D6. Source: human liver microsomes. Preparation was carried out by differential centrifugation method. The final mass concentration of the mixed human liver microsome protein was 0.3 mg / mL. All operations were carried out at 4°C. The microsome protein concentration was measured by the Lowry method using bovine serum albumin as a standard control. The prepared liver microsomes were aliquoted and stored at -80°C in a refrigerator for later use. Probe substrate concentrations: 30 μM phenacetin; 10 μM diclofenac; 35 μM mephenytoin; 10 μM bufuralol; 10 μM midazolam or 80 μM testosterone; 10 μM paclitaxel; 70 μM bupropion. Inhibitors: CYP1A2: α-naphthoflavone; CYP2C9: sulfaphenazole; CYP2C19: omeprazole; CYP3A4: ketoconazole; CYP2D6: quinidine; CYP2C8: nicardipine; CYP2B6: clopidogrel. The experiment was divided into 3 groups. Negative control: After pre-incubating the mixed human liver microsomes with blank Na2HPO4-NaH2PO4 buffer at 37°C for 15 min, the probe substrates of each CYP450 isoenzyme and the coenzyme β-NADPH of CYP450 were added, and co-incubated at 37°C for 30 min. Positive control group: After pre-incubating the mixed human liver microsomes with the selective inhibitors of each isoenzyme at 37°C for 15 min, the probe substrates of each isoenzyme and β-NADPH were added, and co-incubated at 37°C for 30 min. Drug group: After pre-incubating the mixed human liver microsomes with the drug (6.5, 32.5, 65.0, 325.0, 650.0, 3250.0, and 6500.0 μg / mL) at 37°C for 15 min, the probe substrates of each isoenzyme and β-NADPH were added, and co-incubated at 37°C for 30 min. Each group was set with 3 parallel samples.

[0591] 2) Experimental results: Under normal circumstances, if the IC 50 of a compound is < 1.0 μM, it is considered to have strong inhibitory activity. If the IC 50 is 1 - 10 μM, it is considered moderate inhibition. If the IC 50 > 10 μM, it is considered mild inhibition or no inhibition. As shown in Table 3, the IC 50 of r46 against CYP450 enzymes 1A2, 2C19, and 2D6 is > 30 μM. The IC 50 of compound r46 against CYP450 enzymes 2C9 and 3A4 is > 20 μM. The above results indicate that the inhibitory effect of r46 on each subtype of CYP450 is mild inhibition or no inhibition.

[0592] Table 3 Inhibitory effect of compound r46 on CYP450 enzymes

[0593]

[0594] Test Example 6: Acute toxicity evaluation of compound r46

[0595] 1) Experimental method: Kunming mice, with equal numbers of males and females, were divided into 4 groups according to gender and body weight, namely the control group (female and male groups), and the dosing groups (female and male groups), with 20 mice in each group, divided into two cages. After fasting for 12 h without water restriction, the dosing groups were given a single intragastric administration of 400 mg / kg, 200 mg / kg, and 100 mg / kg respectively, and the blank control group was given an equal volume of solvent (DMSO: Solutol HS - 15: normal saline at 5:10:85) by gavage. The LD 100 value (100% mortality), LD0 value (0% mortality), and the corresponding dose - group spacing r value were determined for each sample to measure the LD 50 value. The changes in body weight, activity, behavior, diet, hair color, etc. of the mice within 14 days were observed, and any deaths were noted. A complete set of tissues was collected, weighed, and a systematic clinical pathology study was conducted.

[0596] 2) Experimental results: As Figure 5 shown, after a single intragastric administration of r46 at a concentration of 400 mg / kg or less and continued feeding for 14 days, the mice in each group did not die. In addition, there were no significant effects on the liver function indicators ALT and AST, the kidney function indicator BUN, and the heart function indicator LDH in the dosing - group mice. The body weight and activity ability of the mice after dosing were also not affected. HE staining was used to analyze the effects on the heart, liver, spleen, lungs, and kidneys of the mice in the 400 mg / kg treatment group. The results are as Figure 5 shown in E, and no obvious damage was found in the heart, liver, spleen, lungs, and kidneys of the mice. The above results indicate that r46 has good safety.

[0597] Test Example 7: Ames test to investigate the genotoxicity of compound r46

[0598] 1) Experimental method: The Ames test was conducted according to the recommendations of the OECD 471 test guideline. Salmonella typhimurium bacteria were cultured in a nutrient solution with shaking (37 °C, 150 pm) for 10 hours until the exponential growth phase was reached, and the treatment was completed within 3 hours after the end of the culture to ensure that the bacteria were in the stable growth phase. The mutagenicity evaluation was carried out using the "Ames" plate incorporation method. The bacterial suspension (100 μl), the test compound or vehicle (100 μl for plate incorporation, 50 μl for pre-incubation) or the positive control (100 μl) was mixed and incubated with S9 (or phosphate buffer without S9-mix) (500 μl). In the plate incorporation method, these were directly mixed in 2 ml of molten top agar containing histidine, biotin, and tryptophan (50 °C), and the mixture was poured onto a selective agar plate and incubated at 37 °C for 3 days. The following table lists the positive controls for each strain (including concentrations) in the presence and absence of S9-mix. Colony counting was performed using an Ames colony counter, and tabular results were generated using Ames Study Manager software (Instem, UK). Two replicate samples were set at each concentration level. The concentration gradient of r46 was: 1000 μg / well, 500 μg / well, 250 μg / well, 125, and 62.5 μg / well. (The S9 metabolic activation system is a test system extracted from the liver treated with an enzyme inducer, with cofactors and microsomal fractions).

[0599] Table 4 Ames test conditions for compound r46

[0600] With S9-mix Concentration (Control Group) Without S9-mix Concentration (Control Group) TA97a 2-Aminoanthracene 20 μg / well (DMSO) Sodium Hinosolate 2 μg / well (DMSO) TA98 2-Aminofluorene 10 μg / well (DMSO) 2-Aminofluorene 2 μg / well (DMSO) TA100 2-Aminofluorene 10 μg / well (DMSO) Sodium Azide 2 μg / well (DMSO) TA102 2-Aminofluorene 100 μg / well (DMSO) 2-Aminofluorene 100 μg / plate (DMSO)

[0601] 2) Experimental results: The results of the Ames test showed that compared with the untreated group, at a dose with a maximum concentration of 1000.0 μg / well (the concentration is equivalent to 5000.0 μg / plate in the standard Ames test), for the four strains TA98, TA100, TA97a, and TA102 of compound r46, no significant increase in the number of bacterial reverse mutation colonies was found under the conditions of the presence or absence of the S9 metabolic activation system. This indicates that under the current test concentration conditions, the test compound r46 does not have a gene mutation-inducing effect on the four strains TA98, TA100, TA97a, and TA102 under the conditions of the presence or absence of the metabolic activation system (attached Figure 6 ). The above results of r46 indicate that the novel PI5P4Kγ selective inhibitor compound r46 is a safe and highly effective anti-tumor candidate compound.

[0602] Test Example 8: Inhibitory activity of r46 on hERG

[0603] 1) Experimental method: The cells used in this experiment were CHO cell lines transfected with hERG cDNA and stably expressing hERG channels

[0604] (provided by Sophion Bioscience, Denmark), and the cell passage number was P10. The cells were cultured in a medium containing the following components (all from Invitrogen): Hams F12 medium, 10% (v / v) inactivated fetal bovine serum, 100 μg / ml hygromycin B, and 100 μg / ml Geneticin. CHO hERG cells were grown in a culture dish containing the above culture medium and cultured in an incubator at 37 °C with 5% CO2. Twenty-four to forty-eight hours before the electrophysiological experiment, CHO / hERG cells were transferred to a round glass slide placed in a culture dish and grown under the same culture medium and culture conditions as above. The density of CHO hERG cells on each round glass slide needed to meet the requirement that the vast majority of cells were independent and single. In this experiment, a manual patch clamp system (HEKA EPC-10 signal amplifier and digital conversion system, purchased from HEKA Electronics, Germany) was used to record the whole-cell current. The round glass slide with CHO hERG cells growing on its surface was placed in an electrophysiological recording chamber under an inverted microscope. The recording chamber was continuously perfused with extracellular fluid (about 1 ml per minute). Conventional whole-cell patch clamp current recording techniques were used during the experiment. Unless otherwise specified, the experiments were carried out at a conventional room temperature (∼25 °C). The cells were clamped at a voltage of -80 mV. The cell clamping voltage was depolarized to +20 mV to activate the hERG potassium channel, and then clamped back to -50 mV after 5 seconds to remove inactivation and generate a tail current. The peak value of the tail current was used as the value of the hERG current magnitude. After the hERG potassium current recorded by the above steps reached stability under continuous perfusion of extracellular fluid in the recording chamber, the test drug could be perfused in addition until the inhibitory effect of the drug on the hERG current reached a steady state. Generally, the coincidence of the nearest three consecutive current recording lines was used as the criterion for judging whether it was in a steady state. After reaching a steady state, the cells were perfused and rinsed with extracellular fluid until the hERG current returned to the size before the addition of the drug. One or more drugs, or multiple concentrations of the same drug, could be tested on one cell, but the cells needed to be rinsed with extracellular fluid between different drugs. Cisapride (purchased from Sigma) was used as a positive control in the experiment to ensure the normal quality of the cells used. Compound r46 was prepared as a 10 mM DMSO stock solution. To obtain the IC 50, we selected the following concentrations (30, 10, 3, 1, 0.3 and 0.1 μM) for testing. Before the experiment, stock solutions of 3, 1, 0.3 and 0.1 mM were diluted with DMSO by gradient dilution and then diluted with extracellular fluid to the final μM test concentrations. The test concentration of the positive control Cisapride was 0.1 μM. All compound solutions were sonicated and shaken conventionally for 5 to 10 minutes to ensure complete dissolution of the compounds. The experimental data were analyzed by the data analysis software provided by HEKA Patchmaster (V2x73.2), Microsoft Excel and Graphpad Prism 5.0.

[0605] 2) Experimental results: As shown in the appendix Figure 7 As shown, compound r46 had a weak inhibitory effect on hERG, with an IC 50 > 30 μM. Moreover, its inhibition rate on hERG at a concentration of 30 μM was still less than 40%. Calculated by SPSS software, the IC 50 value was 72.59 μM. In summary, compound r46 had no significant toxic and side effects on the heart.

[0606] Test Example 8: Subacute toxicity experiment of r46

[0607] Male and female Kunming mice were divided into 4 groups according to gender and weight, namely the control group (female and male groups), the dosing group (female and male groups), with 20 mice in each group, divided into two cages. After fasting for 12 h without water deprivation, the dosing groups were given 300 mg / kg, 100 mg / kg, 30 mg / kg respectively by continuous gavage for 28 days, and the blank control group was gavaged with an equal volume of solvent (DMSO: Solutol HS-15: normal saline = 5:10:85). The changes in body weight, activity, behavior, diet, hair color, etc. of the mice and the presence of death were observed within 28 days, and a complete set of tissues were collected, weighed, and systematic clinical pathology studies were conducted.

[0608] As shown in the appendix Figure 8 As shown, after continuous gavage of r46 at a concentration of 100 mg / kg and below for 28 days, the mice in each group did not die. In addition, the liver function indexes ALT and AST, the kidney function indexes CREA and UREA, and the heart function indexes LDH and CK-MB of the mice in the dosing group were not significantly affected. The body weight, food intake and activity ability of the mice after dosing were also not affected. The above results indicate that long-term administration of r46 at 100 mg / kg has good safety. Since the tumor inhibition rate of compound r46 has reached 93.73% at 20 mg / kg, the safety of r46 is good.

[0609] The above has given an exemplary description of the implementation manner of the technical solution of the present invention. It should be understood that the protection scope of the present invention is not limited to the above implementation manner. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention shall be included within the protection scope of the claims of this application.

Claims

1. A compound represented by formula (I), its tautomer, stereoisomer or a pharmaceutically acceptable salt thereof: in: Y is selected from CR y ; Z is selected from N or CR z ; A is selected from N or CR a ; D is selected from N or CR d ; E is selected from N or CR e ; G is selected from N or CR g ; R y , R z , R a , R d , R e , R g are the same or different and are independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 heteroalkyl; R1 is selected from H, unsubstituted or optionally substituted with one, two or more R 11 Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; each R 11 are the same or different and are independently selected from CN, halogen, C2-6 alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Alkyl-C 6-10 Aryl; R2 is selected from H, OH, NH2, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 heteroalkyl; R 31 , R 32 are the same or different and are independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, halogenated C 1-6 Alkyl, halogenated C1-6 heteroalkyl; R4 is selected from H; R5 is selected from H, unsubstituted or optionally substituted with one, two or more R 41 Substituted with the following groups: NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C2-6 alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; each R 41 are the same or different and are independently selected from H, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Alkyl-C 6-10 Aryl-, C 1-6 Alkoxy-C 6-10 Aryl-, halogenated C 6-10 Aryl-, C 6-10 Aryl-C 1-6 Alkyl-, C1-6 alkyl-NH-; Alternatively, R4, R5 and the atoms to which they are attached form an unsubstituted or optionally substituted group with one, two or more R 51 Substituted 3-10 membered lactam; each R 51 are the same or different and are independently selected from H, OH, CN, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; or, Y is selected from N; Z is selected from N or CR z ; A is selected from N or CR a ; D is selected from N or CR d ; E is selected from N or CR e ; G is selected from N or CR g ; R z , R a , R d , R e , R g are the same or different and are independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 heteroalkyl; R1 is selected from unsubstituted or optionally substituted with one, two or more R 11 Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl; each R 11 are the same or different and are independently selected from CN, halogen, C 3-10 Cycloalkyl; R2 is selected from H, OH, NH2, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 heteroalkyl; R 31 , R 32 are the same or different and are independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, halogenated C 1-6 Alkyl, halogenated C1-6 heteroalkyl; R4 is selected from H; R5 is selected from H, unsubstituted or optionally substituted with one, two or more R 41 Substituted with the following groups: NH2, C 3-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; each R 41 are the same or different and are independently selected from H, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C1-6 alkyl-C 6-10 Aryl-, C 1-6 Alkoxy-C 6-10 Aryl-, halogenated C 6-10 Aryl-, C 6-10 Aryl-C 1-6 Alkyl-, C 1-6 Alkyl-NH-; Alternatively, R4, R5 and the atoms to which they are attached form an unsubstituted or optionally substituted group with one, two or more R 51 Substituted 3-10 membered lactam; each R 51 are the same or different and are independently selected from H, OH, CN, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl.

2. The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: Z is selected from N or CH; and / or, A is selected from N or CR a ; R a Selected from H, F, CN, methyl, methoxy; and / or, D is selected from N or CR d ; R d Selected from H, F, CN, methyl, methoxy; and / or, E is selected from N or CR e ; R e Selected from H, F, CN, methyl, methoxy; and / or, G is selected from N or CR g ; R g Selected from H, F, CN, methyl, methoxy.

3. The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: A is selected from N, CH, CCH3 or CF; and / or, D is selected from N, CH, CF or COCH3; and / or, E is selected from N, CH, CCH3 or CF; And / or, G is selected from N, CH, CCH3 or CF.

4. The compound represented by formula (I) according to claim 1 or 2, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: When Y is selected from CR y When; R1 is selected from H, C 1-6 Alkyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-C1-6 alkyl, C 6-10 Aryl-C 1-6 Alkyl, C 1-6 Alkyl-C 6-10 Aryl-C 1-6 alkyl; When Y is selected from N; R1 is selected from C 1-6 Alkyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-C 1-6 alkyl.

5. The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: When Y is selected from CR y When; R1 is selected from the following groups: H, unsubstituted or optionally substituted by F, cyclopropyl, cyclobutyl or phenyl: methyl, ethyl, propyl, butyl, pentyl, propynyl; When Y is selected from N; R1 is selected from the following groups which are unsubstituted or optionally substituted by F, cyclopropyl or cyclobutyl: methyl, ethyl, propyl, butyl, pentyl, propynyl.

6. The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: When Y is selected from CR y When; R1 is selected from H, When Y is selected from N; R1 is selected from 7. The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R2 is selected from H, OH, halogen, NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl.

8. The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R2 is selected from H, OH, NH2, methyl.

9. The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R 31 , R 32 are the same or different and are independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl.

10. The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R 31 Selected from H; R 32 Selected from H.

11. The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: When Y is selected from CR y When; R5 is selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogenated C 6-10 Aryl, C 3-8 Cycloalkyl-C 1-6 Alkyl, C 1-6 Alkyl-NH-C 1-6 Alkyl, C 1-6 Alkyl-NH-, C 6-10 Aryl-NH-, C1-6 alkyl-C 6-10 Aryl-NH-, C 1-6 Alkoxy-C 6-10 Aryl-NH-, halogenated C 6-10 Aryl-NH-, C 6-10 Aryl-C 1-6 Alkyl-NH-; When Y is selected from N; R5 is selected from C 3-6 Alkyl, halogenated C 3-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogenated C 6-10 Aryl, C 1-6 Alkyl-NH-, C 6-10 Aryl-NH-, C 1-6 Alkyl-C 6-10 Aryl-NH-, C 1-6 Alkoxy-C 6-10 Aryl-NH-, halogenated C 6-10 Aryl-NH-, C 6-10 Aryl-C 1-6 Alkyl-NH-.

12. The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: When Y is selected from CR y When; R5 is selected from the following groups which are unsubstituted or optionally substituted with one, two or more F, butyl, cyclopropyl, cyclobutyl, phenyl, tolyl, benzyl, fluorophenyl, methoxyphenyl, ethylamino: methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, amino, phenyl, pyridyl; When Y is selected from N; R5 is selected from the following groups which are unsubstituted or optionally substituted with one, two or more F, butyl, cyclopropyl, cyclobutyl, phenyl, tolyl, benzyl, fluorophenyl, methoxyphenyl, ethylamino: propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, amino, phenyl, pyridyl.

13. The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: When Y is selected from CR y When; R5 is selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-fluorophenyl, 4-pyridyl, cyclopropylmethyl, cyclobutylmethyl, When Y is selected from N; R5 is selected from n-propyl, n-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-fluorophenyl, 4-pyridyl, 14. The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R4, R5 and the atoms to which they are attached form an unsubstituted or optionally substituted group with one, two or more R 51 Substituted with the following groups: Each R 51 The same or different, are independently selected from H, oxo (=O), methyl, ethyl.

15. The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: Selected from 16. The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: Selected from 17. The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) has the structure represented by formula (II) Among them, Y, Z, A, D, E, G, R1, R2, R4, and R5 have the definitions described in claim 1.

18. The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) has the structure represented by formula (III) Among them, Y, Z, A, D, E, G, R1, R2, and R5 have the definitions described in claim 1.

19. The compound shown below, its tautomer, stereoisomer or a pharmaceutically acceptable salt thereof:

20. A method for preparing the compound according to any one of claims 1 to 19, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The following steps are involved: The following options are: Scheme 1: Compound M1 reacts with M1-1 to obtain a compound represented by formula (I); Scheme 2: Compound M1 reacts with M1-2 to obtain compound M2; compound M2 reacts with compound M2-1 to obtain a compound represented by formula (I); M2-1 is Among them, Y, Z, A, D, E, G, R1, R2, R 31 , R 32 , R4, and R5 independently have the definitions as described in any one of claims 1 to 19.

21. A pharmaceutical composition, wherein the pharmaceutical composition comprises the compound according to any one of claims 1 to 19, its tautomer, stereoisomer or a pharmaceutically acceptable salt thereof.

22. Use of the compound according to any one of claims 1 to 19, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 21 in the preparation of a medicament for preventing and / or treating diseases associated with PI5P4Kγ inhibition.

23. The use according to claim 22, characterized in that The disease is cancer.

24. The use according to claim 23, characterized in that The cancer is selected from solid tumor cancer or blood cancer, and the solid tumor cancer is selected from lung cancer, breast cancer, cervical cancer, ovarian cancer, liver cancer, stomach cancer, kidney cancer, colorectal cancer, prostate cancer, pancreatic cancer, bladder cancer, bone cancer, brain cancer, central nervous system cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, external genital cancer, urogenital tract cancer, head cancer, laryngeal cancer, muscle tissue cancer, neck cancer, oral or nasal mucosal cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, testicular cancer and / or thyroid cancer.

25. The use according to claim 24, characterized in that The solid tumor cancer is selected from EGFR-TKI-resistant lung adenocarcinoma cells, TP53 mutations, TTN mutations and KRAS mutations.

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