PI5p4kγ inhibitor compound, pharmaceutical composition, preparation method therefor, and use thereof

Abstract

Provided are a compound having PI5P4Kγ inhibitory activity, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, a preparation method for such a compound, and a use thereof in an anti-tumor drug.

Description

A PI5P4K gamma inhibitor compound, pharmaceutical composition and preparation method and application thereof

[0001] The present application claims priority from the prior application of Patent Application No. 202410894555.9, filed on July 4, 2024, with the State Intellectual Property Office of China, entitled "A PI5P4K gamma inhibitor compound, pharmaceutical composition and preparation method and application thereof". The prior application is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The present application belongs to the field of medicine, and particularly relates to a PI5P4K gamma inhibitor compound, pharmaceutical composition and preparation method and application thereof. BACKGROUND

[0003] Type II phosphatidylinositol-5-phosphate-4-kinases (PI5P4Ks) have multiple regulatory effects on 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. In mammals, three PI5P4K subtypes, alpha, beta and gamma, have been identified, and their corresponding coding genes are PIP4K2A, PIP4K2B and PIP4K2C. Another gamma subtype in the three subtypes of PI5P4Ks has weak kinase activity, and its biological function-related research has lagged behind. However, in recent years, with the confirmation of the important regulatory effects of PI5P4K gamma on cell survival, autophagy and immune physiological processes, it has gradually attracted the attention of new drug researchers. When PIP4K2C is knocked out, it does not affect the normal metabolism, growth and development and normal lifespan of the gene knockout mice, indicating that PI5P4K gamma has good target safety potential. Researchers have also found that knocking out PIP4K2C in normal mice will activate NK cell and T cell immunity, significantly improving the immune function of the mice. PIP4K2C plays a key role in maintaining Treg cell proliferation, survival and immune suppression function, and inhibiting PI5P4K gamma can induce Treg cell death and activate T cells, thereby inhibiting the immune escape of tumor cells. Knocking out or inhibiting PIP4K2C can selectively eliminate TP53 mutant and KRAS mutant tumor cells without affecting the survival of normal cells. Therefore, inhibiting PI5P4K gamma may be an effective intervention method for tumors with TP53 and KRAS mutations or PI5P4K gamma overexpression. In addition, PI5P4K gamma has also been found to be closely related to the abnormal changes of 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, PI5P4K gamma is a safe and effective new anti-tumor target.

[0004] However, there are few selective PI5P4Kγ inhibitors. The 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, and protein degraders JWZ-1-80, TMX-4102 and TMX-4153. Among them, the orthosteric inhibitor ARUK2001607, the allosteric inhibitor PI5P4Kγ-IN-1 and the protein degrader TMX-4153 all have good target binding force, and the Kd values are all less than 50 nM. However, these compounds only have target inhibition activity, and there is no in vivo anti-tumor efficacy data, and the in vitro activity research only reports that the compounds can induce changes in downstream related proteins at a concentration of 1.0-10 μM. Due to the lack of anti-tumor efficacy data, the applicant investigated the proliferation inhibition activity of ARUK2001607, TMX-4102 and NIH-12848 on lung adenocarcinoma cell line HCC827 with high expression of PI5P4Kγ, and found that the IC 50 values were between 6-10 μM, suggesting that the anti-tumor activity still needs to be improved. In summary, there is still a need to develop a large number of new PI5P4Kγ inhibitors to further improve their anti-tumor activity and explore the potential of PI5P4Kγ as a new anti-tumor target. SUMMARY

[0005] To improve the above technical problems, the present application provides a compound represented by (I), a tautomer, a stereoisomer, an isotopically labeled substance, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:

[0006] wherein:

[0007] W is selected from O or S;

[0008] M is selected from O or S;

[0009] Y is selected from N or CR y ;

[0010] Z is selected from N or CR z ;

[0011] A is selected from N or CR a ;

[0012] D is selected from N or CR d ;

[0013] E is selected from N or CR e ;

[0014] G is selected from N or CR g ;

[0015] R y R z R a R d R e R g They may be the same or different, and are independently selected from H, halogens, CN, and C. 1-6 Alkyl, C 1-6 Heteroalkyl;

[0016] R1 is selected from H, is unsubstituted, or is optionally composed of one, two, or more R1s. 11 The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl, 5-10 quinone heteroaryl; each R 11 They may be the same or different, and are independently selected from CN, halogen, C2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl, C 1-6 Alkyl-C 6-10 Aryl;

[0017] R2 is selected from H, OH, NH2, halogens, and C. 1-6 Alkyl, C 1-6 Heteroalkyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Heteroalkyl, -NH-C(O)O-C1-6alkyl or -OC(O)OC 1-6 alkyl;

[0018] Alternatively, R1, R2, and their respective attached atoms can form unsubstituted or optionally substituted atoms with one, two, or more R atoms. 13 Substituted 6-membered heterocyclic group; each R 13 They are either the same or different, and are independently selected from H, OH, CN, oxo (=O), halogen, and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl;

[0019] R 31 R 32 They may be the same or different, and are independently selected from H, halogens, CN, and C.1-6 Alkyl, C 1-6 Heteroalkyl, halogenated C 1-6 Alkyl groups, halo-C1-6 heteroalkyl groups;

[0020] R4 and R5 may be the same or different, and are independently selected from H, without substitution, or optionally by one, two, or more Rs. 41 The following groups are substituted: NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl, 5-10 quinone heteroaryl; each R 41 They may be the same or different, and are independently selected from H, OH, CN, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C2-6 ynyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl, 5-10 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-, C 1-6 Alkyl-NH-;

[0021] Alternatively, R4 and R5, together with their respective atoms, can form unsubstituted or optionally substituted atoms with one, two, or more R atoms. 51 Substituted 3-10 β-lactams; each R 51 They are either the same or different, and are independently selected from H, OH, CN, oxo (=O), halogen, and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl.

[0022] According to an embodiment of the present invention, W is selected from O or S.

[0023] According to an embodiment of the present invention, M is selected from O or S.

[0024] According to an embodiment of the present application, Y is selected from N or CH.

[0025] According to an embodiment of the present application, Z is selected from N or CH.

[0026] According to an embodiment of the present application, A is selected from N or CR a ; R a is selected from H, F, CN, methyl, methoxy;

[0027] According to an embodiment of the present application, A is selected from N, CH, CCH3or CF.

[0028] According to an embodiment of the present application, D is selected from N or CR d ; R d is selected from H, F, CN, methyl, methoxy;

[0029] According to an embodiment of the present application, D is selected from N, CH, CF or COCH3.

[0030] According to an embodiment of the present application, E is selected from N or CR e ; R e is selected from H, F, CN, methyl, methoxy;

[0031] According to an embodiment of the present application, E is selected from N, CH, CCH3or CF.

[0032] According to an embodiment of the present application, G is selected from N or CR g ; R g is selected from H, F, CN, methyl, methoxy;

[0033] According to an embodiment of the present application, G is selected from N, CH, CCH3or CF.

[0034] According to an embodiment of the present application, R1is selected from H, C 1-6 alkyl, C 2-6 alkynyl, haloC 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;

[0035] According to an embodiment of the present application, R1is selected from H, no substitution or the following groups, which are optionally substituted with F, cyclopropyl, cyclobutyl or phenyl: methyl, ethyl, propyl, butyl, pentyl, propynyl;

[0036] According to an embodiment of the present application, R1is selected from H,

[0037] According to an embodiment of the present application, R2is selected from H, OH, halogen, NH2, C 1-6 alkyl, C 1-6 heteroalkyl, -NH-C(O)O-C 1-6 alkyl, or -O-C(O)O-C 1-6 alkyl;

[0038] According to an embodiment of the present application, R2is selected from H, OH, NH2, methyl,

[0039] According to an embodiment of the present application, R1, R2and the atoms to which each is attached form, together with the carbon atom to which they are attached, a 5-10 membered heterocycloalkyl ring, which is unsubstituted or optionally substituted by one, two or more R 13 substituents:

[0040] According to an embodiment of the present application, is selected from for example

[0041] According to an embodiment of the present application, each R 13 is the same or different and independently from each other selected from H, oxo (=0), C 1-6 alkyl.

[0042] According to an embodiment of the present application, each R 13 is the same or different and independently from each other selected from H, oxo (=0), methyl, ethyl.

[0043] According to an embodiment of the present application, R 31 , R 32 is the same or different and independently from each other selected from H, halogen, C 1-6 alkyl, C 1-6 heteroalkyl.

[0044] According to an embodiment of the present application, R 31 is selected from H; R 32 is selected from H.

[0045] According to an embodiment of the present application, R4is H.

[0046] According to an embodiment of the present application, R5is 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, halogenated C 1-6Alkoxy-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-, C 1-6 Alkyl-C 6-10 Aryl-NH-, C 1-6 Alkoxy-C 6-10 Aryl-NH-, haloC 6-10 Aryl-NH-, C 6-10 Aryl-C 1-6 Alkyl-NH-;

[0047] According to an embodiment of the present application, R5is selected from the following groups, which are unsubstituted or optionally substituted by one, two or more F, butyl, cyclopropyl, cyclobutyl, phenyl, tolyl, benzyl, fluorophenyl, methoxyphenyl, ethylamino, trifluoromethoxy: methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, amino, phenyl, pyridyl, isoxazolyl;

[0048] According to an embodiment of the present application, R5is selected from the following groups: methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-fluorophenyl, 3-fluorophenyl, 2-trifluoromethoxyphenyl, 5-isoxazolyl, 4-pyridyl, cyclopropylmethyl, cyclobutylmethyl,

[0049] According to an embodiment of the present application, R4, R5and the atoms to which each of them is attached form the following groups, which are unsubstituted or optionally substituted by one, two or more R 51 substituents: each R 51 is the same or different, independently of one another, selected from H, oxo (=0), methyl, ethyl.

[0050] According to an embodiment of the present application, is selected from (as ).

[0051] According to an embodiment of the present application, the compound of formula (I) has the structure of formula (I-1)

[0052] wherein Y, Z, A, D, E, G, R1, R2, R4, R5, R 31 , R 32having the definitions described above.

[0053] According to an embodiment of the application, the compound of formula (I) has the structure of formula (II)

[0054] wherein W, M, Y, Z, A, D, E, G, R1, R2, R4, R5 have the definitions described above.

[0055] According to an embodiment of the application, the compound of formula (I) has the structure of formula (II-1)

[0056] wherein Y, Z, A, D, E, G, R1, R2, R4, R5 have the definitions described above.

[0057] According to an embodiment of the application, the compound of formula (I) has the structure of formula (III)

[0058] wherein W, M, Y, Z, A, D, E, G, R1, R2, R5 have the definitions described above.

[0059] According to an embodiment of the application, the compound of formula (I) has the structure of formula (III-1)

[0060] wherein Y, Z, A, D, E, G, R1, R2, R5 have the definitions described above.

[0061] According to an embodiment of the application, the compound of formula (I) is selected from the following structures:

[0062] According to an embodiment of the application, the compound of formula (I) is selected from:

[0063] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)acetamide (r1)

[0064] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)propionamide (r2)

[0065] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)hexanamide (r3)

[0066] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)butyramide (r4)

[0067] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)butanamide (r4)

[0068] 4-fluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)benzamide (r6)

[0069] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)cyclopropanecarboxamide (r7)

[0070] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)cyclobutanecarboxamide (r8)

[0071] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)isonicotinamide (r9)

[0072] N-(5-(2-ethyl-1-oxo-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r10)

[0073] N-(5-(2-butyl-1-oxo-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r11)

[0074] N-(5-(2-(cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r12)

[0075] N-(5-(2-benzyl-1-oxo-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r13)

[0076] N-(5-(2-(4-methylbenzyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r14)

[0077] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrazin-2-yl)pentanamide (r15)

[0078] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r16)

[0079] N-(2-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-5-yl)pentanamide (r17)

[0080] N-(4-fluoro-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)pentanamide (r18)

[0081] N-(2-fluoro-4-(l-oxo-2-propyl-l,2-dihydroisoquinolin-7-yl)phenyl)pentanamide (r19)

[0082] N-(2-methoxy-4-(l-oxo-2-propyl-l,2-dihydroisoquinolin-7-yl)phenyl)pentanamide (r20)

[0083] 4,4-difluoro-N-(5-(l-oxo-2-propyl-l,2-dihydroisoquinolin-7-yl)pyridin-2- yl)pentanamide (r21)

[0084] N-(5-(2-(cyclopropylmethyl)-l-oxo-l,2-dihydroisoquinolin-7-yl)pyridin-2-yl)-4,4- difluoropentanamide (r22)

[0085] 4-fluoro-N-(5-(l-oxo-2-propyl-l,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r23)

[0086] N-(5-(2-(cyclopropylmethyl)-l-oxo-l,2-dihydroisoquinolin-7-yl)pyridin-2-yl)-4- fluoropentanamide (r24)

[0087] 3,3-difluoro-N-(5-(l-oxo-2-propyl-l,2-dihydroisoquinolin-7-yl)pyridin-2- yl)pentanamide (r25)

[0088] 3-fluoro-N-(5-(l-oxo-2-propyl-l,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r26)

[0089] N-(5-(2-(cyclopropylmethyl)-l-oxo-l,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r27)

[0090] N-(5-(6-(cyclopropylmethyl)-5-oxo-5,6-dihydro-l,6-naphthyridin-3-yl)pyridin-2- yl)pentanamide (r28)

[0091] N-(5-(2-amino-4-oxo-3-propyl-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)pyridin-2- yl)pentanamide (r29)

[0092] N-(5-(4-oxo-3-propyl-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)pyridin-2-yl)pentanamide (r30)

[0093] N-(5-(2-hydroxy-4-oxo-3-propyl-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)pyridin-2- yl)pentanamide (r31)

[0094] N-(5-(3-(cyclopropylmethyl)-2-hydroxy-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)pentanamide (r32)

[0095] N-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)benzamide (r33)

[0096] N-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)butanamide (r34)

[0097] N-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r35)

[0098] N-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)hexanamide (r36)

[0099] N-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)cyclobutanecarboxamide (r37)

[0100] N-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)cyclopentanecarboxamide (r38)

[0101] N-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)cyclohexanecarboxamide (r39)

[0102] N-(5-(3-ethyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r40)

[0103] N-(5-(3-isopentyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r41)

[0104] N-(5-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r42)

[0105] N-(5-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)hexanamide (r43)

[0106] N-(5-(3-(cyclobutylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)pentanamide (r44)

[0107] N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)benzamide (r45)

[0108] N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r46)

[0109] N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)hexanamide (r47)

[0110] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r48)

[0111] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r49)

[0112] N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyrimidin-2-yl)pentanamide (r50)

[0113] N-(4-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)phenyl)pentanamide (r51)

[0114] N-(5-(5-oxo-6-propyl-5,6-dihydro-1,6-naphthyridin-3-yl)pyridin-2-yl)pentanamide (r52)

[0115] 2-cyclopropyl-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)acetamide (r53)

[0116] 2-cyclobutyl-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)acetamide (r54)

[0117] N-(6-fluoro-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r55)

[0118] N-(5-(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r56)

[0119] N-(5-(2-hydroxy-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r57)

[0120] N-(5-(3-(2-fluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r58)

[0121] 2-(ethylamino)-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)acetamide (r59)

[0122] N-(5-(2-amino-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r60)

[0123] N-(5-(2-amino-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4,4- difluoropentanamide (r61)

[0124] N-(5-(2-amino-3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)-4,4-difluoropentanamide (r62)

[0125] N-(5-(4-oxo-3-(prop-2-yn-1-yl)-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r63)

[0126] N-(5-(3-cyclopropyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r64)

[0127] N-(5-(3-(2-fluoropropyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r65)

[0128] 4,4-difluoro-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r66)

[0129] N-(5-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4- fluoropentanamide (r67)

[0130] N-(5-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4,4- difluoropentanamide (r68)

[0131] N-(5-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3,3- difluoropentanamide (r69)

[0132] N-(5-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3- fluoropentanamide (r70)

[0133] 3,3-Difluoro-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r71)

[0134] N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyrazin-2-yl)pentanamide (r72)

[0135] N-(6-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-3-yl)pentanamide (r73)

[0136] N-(2-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyrimidin-5-yl)pentanamide (r74)

[0137] N-(3-methyl-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r75)

[0138] N-(4-methyl-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r76)

[0139] N-(6-methyl-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r77)

[0140] N-(3-fluoro-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r78)

[0141] 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(o-tolyl)urea (r79)

[0142] 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(m-tolyl)urea (r80)

[0143] 1-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-phenylurea (r81)

[0144] 1-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(4-fluorophenyl)urea (r82)

[0145] 1-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(4-methoxyphenyl)urea (r83)

[0146] 1-Benzyl-3-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)urea (r84)

[0147] 1-Butyl-3-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)urea (r85)

[0148] 1-(tert-butyl)-3-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)urea(r86)

[0149] 6-(6-(2-oxopyrrolidone-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (r87)

[0150] 6-(6-(2-oxopiperidin-1-yl)pyridin-3-yl)-3-propylquinazoline-4(3H)-one (r88)

[0151] 6-(6-(2-oxazacycloheptane-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (r89)

[0152] 6-(6-(4-methyl-2-oxopiperidin-1-yl)pyridin-3-yl)-3-propylquinazoline-4(3H)-one (r90)

[0153] (S)-6-(6-(4-ethyl-2-oxoazacycloheptan-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (r91)

[0154] N-(5-(3-methyl-6-oxo-1,3,4,6-tetrahydro-2H-pyrimidino[2,1-b]quinazolin-8-yl)pyridin-2-yl)pentanamide (r92)

[0155] N-(5-(3,3-dimethyl-6-oxo-1,3,4,6-tetrahydro-2H-pyrimidino[2,1-b]quinazolin-8-yl)pyridin-2-yl)pentanamide (r93)

[0156] N-(5-(3-propyl-4-thionone-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r94)

[0157] N-(5-(2-amino-3-(cyclopropylmethyl)-4-thionone-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4,4-difluoropentanamide (r95)

[0158] N-(5-(2-amino-3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)pentanamide (r96)

[0159] 3-fluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)benzamide (r97)

[0160] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)benzamide (r98)

[0161] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)-2-(trifluoromethoxy)benzamide (r99)

[0162] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)isoxazole-5-carboxamide (r100).

[0163] N-(5-(3-propyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)thiopentanamide (z1)

[0164] N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)thiopentanamide (z2)

[0165] N-(5-(2-amino-3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4,4- difluorothio pentanamide (z3)

[0166] N-(5-(2-amino-3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)thiopentanamide (z4)

[0167] Ethyl (3-(cyclopropylmethyl)-6-(6-(4,4-difluoropentylamino)pyridin-3-yl)-4-oxo-3,4- dihydroquinazolin-2-yl)carbamate (ag1)

[0168] Ethyl (3-(cyclopropylmethyl)-6-(6-(4,4-difluoropentylthioamino)pyridin-3-yl)-4-oxo-3,4- dihydroquinazolin-2-yl)carbamate (ah1)

[0169] The present application also provides a preparation method of the compound represented by formula (I), a tautomer, a stereoisomer, an isotopically labeled substance, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, comprising the following steps:

[0170] Scheme one or scheme two:

[0171] Scheme one: compound M1 reacts with M1-1 to obtain the compound shown in formula (I);

[0172] Scheme two: compound M1 reacts with M1-2 to obtain compound M2; compound M2 reacts with compound M2-1 to obtain the compound shown in formula (I); M2-1 is

[0173] wherein, W, M, Y, Z, A, D, E, G, R1, R2, R 31 , R 32 , R4, R5 independently have the definition described above.

[0174] According to the embodiment of the present application, the preparation method comprises the following steps:

[0175] Scheme one or scheme two:

[0176] Scheme one: compound M1a reacts with M1-1a to obtain the compound shown in formula (I-1);

[0177] Scheme two: compound M1a reacts with M1-2a to obtain compound M2a; compound M2a reacts with compound M2-1a to obtain the compound shown in formula (I-1); M2-1a is

[0178] wherein, Y, Z, A, D, E, G, R1, R2, R 31 , R 32 , R4, R5 independently have the definition described above.

[0179] According to embodiments of the present application, 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, phenetol, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl glycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, dichlorodiethyl ether, and polyethers of ethylene oxide and / or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, and the like that can be substituted with fluorine and chlorine atoms, such as methylene chloride, dichloromethane, trichloromethane, 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.

[0180] The present application also provides an intermediate compound represented by the following formula M1 or M2:

[0181] wherein W, M, Y, Z, A, D, E, G, R1, R2, R 31 , R 32 , R4, R5, independently of each other, have the definitions described above. The present application also provides an intermediate compound represented by the following formula M1-1 or M2-1:

[0182] wherein Y, Z, A, D, E, G, R1, R2, R 31 , R 32 , R4, R5, independently of each other, have the definitions described above.

[0183] According to embodiments of the present application, the intermediate compound is selected from the group consisting of compounds k1 to k30, compounds m1 to m47, compounds o1 to o47, and compounds q1.

[0184] The present application also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the compound represented by the formula (I), a tautomer, a stereoisomer, an isotopically labeled, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof.

[0185] According to embodiments of the present application, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0186] The present application also provides use of the compound represented by Formula (I), a tautomer, a stereoisomer, an isotopically-labeled material, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, or the pharmaceutical composition in the preparation of a medicament, for example, in the preparation of a medicament related to PI5P4K gamma inhibition.

[0187] According to embodiments of the present application, the pharmaceutical composition or the medicament is for preventing and / or treating a disease related to PI5P4K gamma inhibition, for example, a cancer.

[0188] According to embodiments of the present application, the cancer is selected from a solid tumor cancer 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, genitourinary tract cancer, head cancer, laryngeal cancer, muscle tissue cancer, neck cancer, oral or nasal mucosa cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, testicular cancer, and / or thyroid cancer; for example, EGFR-TKI-resistant lung adenocarcinoma cells, tumors with TP53 mutation, TTN mutation and KRAS mutation; the hematological cancer is, for example, a blood cancer.

[0189] The present application also provides a compound represented by Formula (I), a tautomer, a stereoisomer, an isotopically-labeled material, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, or the pharmaceutical composition for preventing and / or treating a disease related to PI5P4K gamma inhibition.

[0190] The present application also provides a method for preventing and / or treating a disease related to PI5P4K gamma inhibition, for example, a cancer, comprising administering to a patient a therapeutically effective amount of at least one of a compound represented by Formula (I), a tautomer, a stereoisomer, an isotopically-labeled material, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, or the pharmaceutical composition.

[0191] According to embodiments of the present application, the cancer is selected from a solid tumor cancer 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, genitourinary tract cancer, head cancer, laryngeal cancer, muscle tissue cancer, neck cancer, oral or nasal mucosa cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, testicular cancer, and / or thyroid cancer; for example, EGFR-TKI-resistant lung adenocarcinoma cells, tumors with TP53 mutation, TTN mutation and KRAS mutation; the hematological cancer is, for example, a blood cancer.

[0192] In preparing the medicaments or pharmaceutical compositions of the present invention, the compounds of the present invention, their tautomers, stereoisomers, isotope-labeled substances, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs can be combined or formulated with suitable pharmaceutically acceptable excipients (such as carriers, diluents, or excipients). The formulations can be prepared in solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalers, gels, microspheres, and aerosols. Administration routes include oral, intraperitoneal, transdermal, subcutaneous, intravenous, or intramuscular injection, inhalation, local, intralesional, infusion; liposome-mediated delivery; local, intrathecal, gingival pocket, rectal, bronchial, nasal, transmucosal, intestinal, ocular, or ear delivery, or any other method known in the art, all capable of achieving therapeutic effects on tumors.

[0193] The therapeutically effective dose or dosage described in this invention will vary depending on several factors, including the chosen route of administration, the formulation of the composition, patient response, severity of the condition, the subject's weight, and the prescribing physician's judgment, for example, 1-200 mg / kg, 40-150 mg / kg, such as 50 mg / kg. The dosage may be increased or decreased over time, as needed by individual patients. In some cases, patients are initially given a low dose, which is then increased to an effective dose that the patient can tolerate. Furthermore, patients may be given multiple doses over defined time periods, particularly in time increments (e.g., daily, weekly, bi-weekly, monthly, quarterly, bi-annual, or similar). Beneficial effects

[0194] This invention provides a compound of formula (I), its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, which exhibit PI5P4Kγ inhibitory activity and can be used for the prevention and / or treatment of cancer. The crystal structure of the complex of the compound of this invention with PI5P4Kγ indicates that these compounds act simultaneously on both the ortho- and allosteric sites of PI5P4Kγ, exhibiting significantly higher in vivo antitumor efficacy than known PI5P4Kγ inhibitors. This class of PI5P4Kγ inhibitors possesses novel structures, unique target mechanisms of action, and significant antitumor therapeutic effects. Attached Figure Description

[0195] Figure 1 shows the inhibitory activity of compound r46 on PI5P4Kγ and the selectivity of the other two isoforms.

[0196] Figure 2 shows the selectivity of compound r46 for 486 kinases.

[0197] Figure 3 shows the co-crystallization structure of compound r46 and the PI5P4Kγ complex and its key interactions.

[0198] Figure 4 shows the in vivo antitumor efficacy of compound r46 (H1975-OR).

[0199] Figure 5 Anti-tumor efficacy of compound r46 in vivo (Mia PACA-2).

[0200] Figure 6 Anti-tumor efficacy of compound r46 in vivo (HCC827).

[0201] Figure 7 Acute toxicity of compound r46 in mice.

[0202] Figure 8 Compound r46 has no mutagenic effect on TA100, TA102, TA98 and TA97a strains.

[0203] Figure 9 Inhibition activity of compound r46 on hERG.

[0204] Figure 10 Subacute toxicity of compound r46 in mice.

[0205] Definitions of terms and explanations

[0206] Unless otherwise indicated, the definitions of groups and terms recited in the specification and claims hereof, including definitions of examples, illustrative examples, preferred definitions, definitions recited in tables, definitions of specific compounds in examples, etc., can be combined and / or interchanged with each other. The group and compound structures after such combination and interchanging should be understood as within the scope recited in the specification and / or claims.

[0207] Unless otherwise indicated, numerical ranges recited in the specification and claims hereof are inclusive of the integers within the recited ranges. For example, a range of "1 to 10" is inclusive of the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0208] It should be understood that herein, when describing one, two, or more, "more" shall mean greater than 2, e.g., an integer greater than or equal to 3, e.g., 3, 4, 5, 6, 7, 8, 9, or 10.

[0209] As used in the context of the present application represents a chemical bond.

[0210] The term "C 1-6 "alkyl" means a straight 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 3-6Alkyl groups, etc. The alkyl group 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 isomers thereof.

[0211] Term "C" 2-6 "Alkenyl" should be understood as referring to a straight-chain or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, or 6 carbon atoms, for example, having 2 or 3 carbon atoms (i.e., C40, C50, C6 ... 2-3 Alkenyl). It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. The alkenyl group 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)- Pentyl-1-enyl, (Z)-pentyl-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-methyl But-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.

[0212] Term "C" 2-6"Alkynyl" is understood to mean a straight-chain or branched monovalent hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5 or 6 carbon atoms, for example 2 or 3 carbon atoms ("C2-3-alkynyl", "C2-alkynyl", "C3-alkynyl"). The alkynyl group 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. 2-3 "Alkynyl" is understood to mean a straight-chain or branched monovalent hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5 or 6 carbon atoms, for example 2 or 3 carbon atoms ("C2-3-alkynyl", "C2-alkynyl", "C3-alkynyl"). The alkynyl group 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.

[0213] The term "C 1-6 "Heteroalkyl" denotes a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, and containing at least one 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, C 1-6 thioether. For example selected from methoxy, ethoxy, methylthio, methylamino, dimethylamino, diethylamino.

[0214] The term "C 3-10 "Cycloalkyl" denotes a saturated monovalent monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic hydrocarbon ring or a 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, C6cycloalkyl and the like. The C 3-10Cycloalkyl can be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or a bicyclic hydrocarbon group such as a bornyl group, an indolyl group, a hexahydroindolyl group, a tetrahydronaphthyl group, a decahydronaphthyl group, a bicyclo[2.1.1]hexyl group, a bicyclo[2.2.1]heptyl group, a bicyclo[2.2.1]heptenyl group, a 6,6-dimethylbicyclo[3.1.1]heptyl group, a 2,6,6-trimethylbicyclo[3.1.1]heptyl group, a bicyclo[2.2.2]octyl group, a 2,7-diazaspiro[3.5]nonanyl group, a 2,6-diazaspiro[3.4]octanyl group, or a tricyclic hydrocarbon group such as an adamantyl group.

[0215] The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S, and N. The heterocyclyl group can be attached to the rest of the molecule by any of the carbon atoms or the nitrogen atom, if present. The heterocyclyl group can include fused or bridged rings as well as spirocyclic rings. In particular, the heterocyclyl group can include, but is not limited to: a 3-membered ring such as aziridinyl, oxiridinyl; a 4-membered ring such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl group can be benzo-fused. The heterocyclyl group can be bicyclic, for example, but not limited to, a 5,5 membered ring such as hexahydrocyclopenta[c]pyrrol-2(lH)-yl ring, or a 5,6 membered bicyclic ring such as hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl ring. The heterocyclyl group can be partially unsaturated, i.e., it can contain one or more double bonds, for example, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-lH-pyrrolyl, 4H-[l,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[l,4]thiazinyl, or it can be benzo-fused, for example, but not limited to, dihydroisoquinolinyl. When the 3-10 membered heterocyclyl group is attached to other groups to form a compound of the invention, it can be attached to other groups through a carbon atom on the 3-10 membered heterocyclyl group, or it can be attached to other groups through a heteroatom (e.g., N atom) on the 3-10 membered heterocyclyl ring. For example, when the 3-10 membered heterocyclyl group is selected from piperazinyl, tetrahydropyrrolyl, it can be attached to other groups through a nitrogen atom or a carbon atom on the piperazinyl group. Or when the 3-10 membered heterocyclyl group is selected from piperidinyl, it can be attached to other groups through a nitrogen atom on the piperidinyl ring or a carbon atom ortho, meta, or para to the nitrogen atom.

[0216] The term "C 6-10"Aryl" is to be understood as preferably denoting a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9 or 10 carbon atoms, in particular a ring having 6 carbon atoms ("C6-aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9-aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C10-aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. When the C6-aryl, C9-aryl or C10-aryl group is substituted, it can be mono- or polysubstituted. Also, there is no restriction on the substitution site, e.g. ortho, meta or para substitution is possible. 10 "Aryl" is to be understood as preferably denoting a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9 or 10 carbon atoms, in particular a ring having 6 carbon atoms ("C6-aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9-aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C10-aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. When the C6-aryl, C9-aryl or C10-aryl group is substituted, it can be mono- or polysubstituted. Also, there is no restriction on the substitution site, e.g. ortho, meta or para substitution is possible. 6-10 "Aryl" is to be understood as preferably denoting a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9 or 10 carbon atoms, in particular a ring having 6 carbon atoms ("C6-aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9-aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C10-aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. When the C6-aryl, C9-aryl or C10-aryl group is substituted, it can be mono- or polysubstituted. Also, there is no restriction on the substitution site, e.g. ortho, meta or para substitution is possible.

[0217] The term "5-10 membered heteroaryl" denotes a monovalent or polyvalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9 or 10 ring atoms, and of which the ring atoms comprise 1 to 5 heteroatoms independently selected from N, O and S, which bicyclic and tricyclic aromatic ring systems can be fused, spiro or bridged. The 5-10 membered heteroaryl has 1 to 5, preferably 1 to 3 heteroatoms. In addition, in each case the 5-10 membered heteroaryl can be benzo-fused. The 5-10 membered heteroaryl includes 5-8 membered heteroaryl, 5-9 membered heteroaryl, 5-10 membered heteroaryl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, 6 membered heteroaryl, etc. Examples of heteroaryl include, but are not limited to: 5 membered rings, such as oxazolyl, pyrazolyl, thienyl, thiazolyl, triazolyl, imidazolyl, etc.; 6 membered rings, such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. The heterocyclyl can be bicyclic, including but not limited to: 5,5 membered rings, such as tetrahydrocyclopentapyrazole; 5,6 membered rings, such as tetrahydroindole, tetrahydropyrazolopyridine, tetrahydroimidazopyridine, tetrahydrobenzisoxazole, tetrahydrobenzoxazole, tetrahydrobenzothiazole, tetrahydrobenzisothiazole, dihydrofuroazolyl, tetrahydrobenzofuran, dihydrobenzofuran, tetrahydrobenzothiophene; 6,6 membered rings, such as tetrahydroquinoline; 5,7 membered rings, such as tetrahydrocycloheptylthiazole, tetrahydrocycloheptylfuran. The heterocyclyl can be tricyclic, including but not limited to: 6,7-dihydrospiro[cyclopropane-1,5-pyrrolo[1,2-c]imidazole]. When the 5-10 membered heteroaryl is substituted, it can be mono- or polysubstituted. Also, there is no restriction on the substitution site, e.g. the hydrogen attached to a carbon atom on the heteroaryl ring can be substituted, or the hydrogen attached to a heteroatom on the heteroaryl ring can be substituted.

[0218] The term "3-10 membered lactam" denotes a cyclic group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and of which the formed ring comprises -C(O)NH-. The "3-10 membered lactam" includes 3-8 membered lactam, 4-6 membered lactam. For example, selected from Other groups are attached to either the C atom or the N atom in the 3-10 membered lactam.

[0219] The term "spiro" refers to a ring system in which two rings share one ring-forming atom.

[0220] The term "fused ring" refers to a ring system in which two rings share two ring-forming atoms.

[0221] The term "bridged ring" refers to a ring system in which two rings share three or more ring-forming atoms.

[0222] The term "halogen" denotes fluorine, chlorine, bromine, or iodine.

[0223] "Halo" means substituted with one or more halogens.

[0224] The term "oxo (=0)" means that a hydrogen or lone pair of electrons on a non-oxygen atom is replaced by an oxygen, for example, after being oxo after being oxo

[0225] The term "haloC 1-6 alkyl" means an alkyl group as defined above which is substituted with one or more halogens as defined above, preferably "haloC 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.

[0226] Crystallization often produces solvates of the compounds of the application, and as used herein, the term "solvate" means a combination of a compound of the application with one or more solvent molecules.

[0227] The solvent can be water, in which case the solvate is a hydrate. It can also be an organic solvent. Thus, the compounds of the application can exist as a hydrate, including a monohydrate, a dihydrate, a hemihydrate, a trihydrate, a tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the application can be true solvates, but in other cases the compounds of the application can be only adventitiously associated with water or a mixture of water and some other solvent. The compounds of the application can be reacted in one solvent or precipitated or crystallized from one solvent. Solvates of the compounds of the application are included within the scope of this application.

[0228] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0229] The term "pharmaceutically acceptable" as used herein means a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds of the present application, and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0230] It will be appreciated by those skilled in the art that the compounds of the present application can exist in various pharmaceutically acceptable salt forms. If these compounds have basic centers, they can form acid addition salts; if these compounds have acidic centers, they can form base addition salts; and if these compounds contain both acidic and basic centers (for example, carboxyl and amino groups), they can also form inner salts. The compounds of the present application can be prepared in the form of salts with various inorganic or organic acids or bases. Such salts include, but are not limited to, those derived from inorganic bases such as ammonium, potassium, sodium, and calcium salts; and salts derived from organic bases such as amines, quaternary amines, and the like. Such salts include, but are not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like; and salts derived from organic acids such as acetic, propionic, glycolic, pyruvic, oxalic, malic, malonic, benzoic, citric, cinnamic, mandelic, salicylic, and the like.

[0231] The term "tautomer" refers to isomeric forms of a functional group resulting from the rapid movement of an atom between two positions in a molecule. The compounds of the present application can exhibit tautomerism. Compounds that tautomerize can exist in two or more interconvertible forms. Proton-shift tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present application encompasses all tautomeric forms of the compounds.

[0232] Depending on their molecular structure, the compounds of the present application can be chiral and, therefore, can exist in various enantiomeric forms. The compounds can thus exist in racemic or optically active forms. The compounds of the present application encompass the isomers in which each chiral carbon is in the R or S configuration or mixtures thereof, racemates. The compounds of the present application or intermediates thereto can be separated into the enantiomeric compounds or used as mixtures in the synthesis by chemical or physical methods known to those skilled in the art. In the case of racemic amines, the diastereomeric forms are prepared from the mixture by reaction with optically active resolving agents. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids, for example N-benzoylproline or N-benzenesulfonylproline, or various optically active camphorsulfonic acids. Chromatographic separation of the enantiomeric compounds on silica gel with a suitable stationary phase, for example, on di-nitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatizing agents, can also be advantageously used. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0233] In the present application, "pharmaceutical composition" refers to a preparation of a compound of the present application with a medium conventionally accepted in the art for the delivery of a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration of the organism, to facilitate absorption of the active ingredient, and to thereby facilitate biological activity.

[0234] In the present application, "pharmaceutically acceptable excipient" includes, but is not limited to, any ingredient, carrier, adjuvant, vehicle, sweetener, diluent, preservative, dye / colorant, flavor, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsor that is accepted in the art for use in the manufacture of a preparation for use in humans or animals.

[0235] In the present application, the term "solvate" refers to a compound of the present application or a salt thereof, including stoichiometric or non-stoichiometric amounts of a solvent, which is bound by intermolecular non-covalent forces, when the solvent is water, then it is a hydrate.

[0236] In the present application, the term "prodrug" refers to a compound of the present application that can be converted to a biologically active compound of the present application under physiological conditions or by solvolysis. A prodrug of the present application is prepared by modifying a functional group in the compound in a manner that is reversible under the conditions of administration or within the mammalian organism. The prodrug includes a compound of the present application in which a hydroxyl or amino group is attached to any group, and when the prodrug of the compound of the present application is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group, a free amino group, respectively.

[0237] "Isotope" is all isotopes of atoms occurring in the present application. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for inclusion in the present application are hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, for example, and include 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 31 P, 32 P, 35 S, 18 F and 36 C1. Isotopically-labeled compounds of the present application can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagent in place of the non- isotopically labeled reagent. Such compounds have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds have the potential to alter the biological, pharmacological, or pharmacokinetic properties of the molecule.

[0238] The term "tumor" herein includes benign tumors and malignant tumors (e.g., cancers).

[0239] The terms "treatment" and other similar terms herein include the following meanings:

[0240] (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed or at risk to developing the disease or condition but has not yet been diagnosed as having it;

[0241] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0242] (iii) relieving the disease or condition, i.e., causing the state of the disease or condition to regress; or

[0243] (iv) alleviating the symptoms of the disease or condition.

[0244] The term "patient" means any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine; cattle, sheep, horses, or primates, and most preferably humans.

[0245] The term "therapeutically effective amount" means the amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, and includes one or more of the following: (1) preventing the disease: for example, preventing a disease, disorder or condition from occurring in an individual that is predisposed or at risk to developing the disease, disorder or condition but has not yet been diagnosed with a pathology or symptoms of the disease; (2) inhibiting the disease: for example, inhibiting a disease, disorder or condition (i.e., arresting the further development of a pathology and / or symptoms) in an individual that is already experiencing or has already developed the pathology or symptoms of the disease, disorder or condition; (3) relieving the disease: for example, relieving a disease, disorder or condition (i.e., reversing a pathology and / or symptoms) in an individual that is already experiencing or has already developed the pathology or symptoms of the disease, disorder or condition. DETAILED DESCRIPTION

[0246] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively and explain the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of protection intended by the present application.

[0247] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0248] The synthesis methods and steps of the compounds described in the present application include:

[0249] S1, synthesis of intermediate k or kk with compound a, c and h as substrates, the reaction scheme is as follows:

[0250] The specific reaction process is:

[0251] Potassium carbonate is added to the acetone solution of raw material a and compound b, and the reaction is carried out for 5-8 hours. After the reaction is completed, column chromatography is carried out after concentration to obtain intermediate compound k.

[0252] Lawesson's reagent is added to the toluene solution of intermediate compound k, and the temperature is raised to 110°C overnight. After the reaction is completed, the temperature is cooled to room temperature, and column chromatography is carried out after concentration to obtain the corresponding intermediate compound kk.

[0253] The specific reaction process is:

[0254] Compound d is added to the pyridine solution of compound c, and the reaction is carried out at 50°C overnight. After the reaction is completed, the temperature 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 column chromatography is carried out to obtain intermediate compound e;

[0255] Compound f is added to the isopropanol solution of intermediate compound e, and the mixture is stirred at 85°C for 3-5 hours. After the reaction is completed, the temperature is cooled to room temperature, and column chromatography is carried out after concentration to obtain the corresponding intermediate compound g.

[0256] Concentrated hydrochloric acid is added to the dimethyl sulfoxide solution of intermediate compound g, and the temperature is raised to 100°C for 1-3 hours. After the reaction is completed, 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 over sodium sulfate, and column chromatography is carried out after concentration to obtain intermediate compound k;

[0257] The specific reaction process is:

[0258] 1N aqueous sodium hydroxide solution is added to the tetrahydrofuran solution of compound h, and the reaction is carried out for 15-24 hours. After the reaction is completed, the temperature is cooled to 0°C, the pH of the reaction system is adjusted to 5 with acetic acid, and the solid is collected by filtration to obtain intermediate compound i;

[0259] Potassium carbonate is added to the acetone solution of intermediate compound i and compound b, and the reaction is carried out for 5-8 hours. After the reaction is completed, the filtrate is concentrated and column chromatography is carried out to obtain intermediate compound j;

[0260] Intermediate compound j and cesium fluoride in dimethyl sulfoxide are reacted at 150°C for 5-8 hours. After the reaction is completed, the temperature is cooled to room temperature, water is added, the solid is collected, dried, and column chromatography is carried out to obtain intermediate compound k.

[0261] The specific reaction process is as follows:

[0262] The compound s is added to the dichloromethane solution of the compound c, and the reaction is carried out at room temperature for 5 hours. After the reaction is completed, the mixture is concentrated under reduced pressure, and column chromatography is performed to obtain the intermediate compound t.

[0263] The compound u is added to the tetrahydrofuran solution of the intermediate compound t, and the reaction is stirred at room temperature for 3-5 hours. After the reaction is completed, concentration and column chromatography are performed to obtain the corresponding intermediate compound k.

[0264] The specific reaction process is as follows:

[0265] The compound f, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine are added to the N,N-dimethylformamide solution of the compound v, and the reaction is carried out at room temperature for 3-5 hours. After the reaction is completed, water and ethyl acetate are used for extraction, the organic extract is concentrated, and column chromatography is performed to obtain the intermediate compound w.

[0266] Lawesson's reagent is added to the toluene solution of the intermediate compound w, and the reaction is carried out at 110°C overnight. After the reaction is completed, the temperature is cooled to room temperature, and concentration and column chromatography are performed to obtain the corresponding intermediate compound x.

[0267] Reduced iron powder and ammonium chloride are added to the ethanol and water solution of the intermediate compound x, and the reaction is carried out at 60°C for 1-3 hours. After the reaction is completed, the temperature is cooled to room temperature, water and dichloromethane are used for extraction, the organic extract is concentrated, and column chromatography is performed to obtain the intermediate compound y.

[0268] Tricyanogen chloride and sodium bicarbonate are added to the acetonitrile and water solution of the intermediate compound y, and the reaction is carried out at 80°C for 2-6 hours. After the reaction is completed, the temperature is cooled to room temperature, water and ethyl acetate are used for extraction, the organic extract is concentrated, and column chromatography is performed to obtain the intermediate compound k.

[0269] S2, using the intermediate k obtained in S1 to synthesize the target compound r, the reaction route is as follows:

[0270] At room temperature, different substituted acyl chlorides are added to the toluene solution of N,N-diisopropylethylamine and the compound l, and the reaction is carried out at 110°C for 3-5 hours. After the reaction is completed, concentration and column chromatography are performed to obtain the intermediate compound m; or different substituted isocyanates are added to the 1,4-dioxane solution of triethylamine and the intermediate compound l in batches, and the reaction is carried out at 110°C for 4-8 hours. After the reaction is completed, concentration and column chromatography are performed to obtain the intermediate compound m.

[0271] Pd[1,1'-bis(diphenylphosphino)ferrocene]dichloride is added to a solution of intermediate compound m, bis(pinacolato)diboron and potassium acetate in 1,4-dioxane and the reaction is allowed to proceed for 3-6 hours. After the reaction is complete, the reaction is cooled to room temperature and the solvent is removed in vacuo. Dichloromethane and methanol are added to dissolve the crude product and the potassium carbonate is removed by suction filtration. The filtrate is concentrated and chromatographed to yield the corresponding intermediate compound o.

[0272] Pd[1,1'-bis(diphenylphosphino)ferrocene]dichloride is added to a solution of intermediate compound o, intermediate compound k and potassium carbonate in a mixture of 1,4-dioxane and water and the reaction is allowed to proceed for 0.5-3 hours. After the reaction is complete, the reaction is cooled to room temperature and the solvent is removed in vacuo. Dichloromethane and methanol are added to dissolve the crude product and the potassium carbonate is removed by suction filtration. The filtrate is concentrated and chromatographed to yield the target compound r.

[0273] Lawesson's reagent is added to a solution of compound r in toluene and the reaction is allowed to proceed overnight at 110°C. After the reaction is complete, the reaction is cooled to room temperature and concentrated. The residue is chromatographed to yield the corresponding target compound z.

[0274] Pd[1,1'-bis(diphenylphosphino)ferrocene]dichloride is added to a solution of intermediate compound o, intermediate compound w and potassium carbonate in a mixture of 1,4-dioxane and water and the reaction is allowed to proceed for 2-5 hours. After the reaction is complete, the reaction is cooled to room temperature and the solvent is removed in vacuo. Dichloromethane and methanol are added to dissolve the crude product and the potassium carbonate is removed by suction filtration. The filtrate is concentrated and chromatographed to yield intermediate compound aa.

[0275] Lawesson's reagent is added to a solution of intermediate compound aa in toluene and the reaction is allowed to proceed overnight at 110°C. After the reaction is complete, the reaction is cooled to room temperature and concentrated. The residue is chromatographed to yield the corresponding intermediate compound ab.

[0276] Reduced iron powder and ammonium chloride are added to a solution of intermediate compound ab in ethanol and water and the reaction is allowed to proceed for 1-3 hours at 60°C. After the reaction is complete, the reaction is cooled to room temperature and extracted with water and dichloromethane. The organic extract is concentrated and chromatographed to yield intermediate compound ac.

[0277] Cyanogen trihalide and sodium bicarbonate are added to a solution of intermediate compound ac in acetonitrile and water and the reaction is allowed to proceed for 2-6 hours at 80°C. After the reaction is complete, the reaction is cooled to room temperature and extracted with water and ethyl acetate. The organic extract is concentrated and chromatographed to yield the target compound z.

[0278] To a solution of intermediate compound o, intermediate compound c and potassium carbonate in a mixture of 1,4-dioxane and water, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium was added and the reaction was allowed to proceed for 2-5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. Dichloromethane and methanol were added to dissolve the crude product. The potassium carbonate was removed by suction filtration and the filtrate was concentrated and purified by column chromatography to obtain intermediate compound ad.

[0279] To a solution of intermediate ad in acetonitrile, ethyl isothiocyanate was added and the reaction was allowed to proceed for 0.5-2 hours at room temperature. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography to obtain the corresponding intermediate compound ae.

[0280] To a solution of intermediate ae and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride in acetone, f was added and the reaction was allowed to proceed for 6-12 hours at room temperature. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography to obtain the corresponding compound ag.

[0281] To a solution of intermediate ac in acetonitrile, ethyl isothiocyanate was added and the reaction was allowed to proceed for 1-3 hours at room temperature. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography to obtain the corresponding intermediate compound af.

[0282] To a solution of af in acetone, triethylamine was added followed by the addition of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride. The reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography to obtain the corresponding compound ah.

[0283] To a solution of ah in tetrahydrofuran, tetrabutylammonium fluoride was added and the reaction was allowed to proceed for 4-8 hours at reflux. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated and purified by column chromatography to obtain the corresponding compound z.

[0284] To a solution of intermediate compound p, intermediate compound k and potassium carbonate in 1,4-dioxane, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium was added and the reaction was allowed to proceed for 1.5 hours. Water was added and the reaction was allowed to proceed for an additional 0.5-2.5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. Dichloromethane and methanol were added to dissolve the crude product. The potassium carbonate was removed by suction filtration and the filtrate was concentrated and purified by column chromatography to obtain intermediate compound q.

[0285] To a solution of intermediate compound q, variously substituted 5-7 membered cyclic lactams, N,N'-dimethylethylenediamine and potassium carbonate in toluene, copper iodide was added and the reaction was allowed to proceed for 4-6 hours at 110°C. After the reaction was completed, the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. Dichloromethane and methanol were added to dissolve the crude product. The potassium carbonate was removed by suction filtration and the filtrate was concentrated and purified by column chromatography to obtain the target compound r.

[0286] Intermediate Preparation Example 1: The specific synthesis of intermediate k is as follows:

[0287] 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) and reacted at 65 °C for 5 h, cooled to room temperature, filtered to remove potassium carbonate, the solvent was removed under vacuum, and the product was purified by column chromatography on silica gel using dichloromethane as eluent to give 7-bromo-2-propylisoquinolin-1(2H)-one (k1) as a white solid (2044 mg, 7.68 mmol, 86% yield), ESI-MS: m / z 267.1 [M+H] + .

[0288] In a similar manner, compounds k2-21 were prepared using compounds a2-5 and different halogenated compounds b.

[0289] Compound k2, 7-bromo-2-ethylisoquinolin-1(2H)-one, was obtained as a white solid with 83% yield, ESI-MS: m / z 253.1 [M+H] + .

[0290] Compound k3, 7-bromo-2-butylisoquinolin-1(2H)-one, was obtained as a white solid with 80% yield, ESI-MS: m / z 281.2 [M+H] + .

[0291] Compound k4, 7-bromo-2-(cyclopropylmethyl)isoquinolin-1(2H)-one, was obtained as a white solid with 81% yield, ESI-MS: m / z 279.1 [M+H] + .

[0292] Compound k5, 2-benzyl-7-bromoisoquinolin-1(2H)-one, was obtained as a white solid with 85% yield, ESI-MS: m / z 315.2 [M+H] + .

[0293] Compound k6, 7-bromo-2-(4-methylbenzyl)isoquinolin-1(2H)-one, was obtained as a white solid with 84% yield, ESI-MS: m / z 329.2 [M+H] + .

[0294] Compound k7, 3-benzyl-6-bromoquinazolin-4(3H)-one, was obtained as a white solid with 90% yield, ESI-MS: m / z 316.1 [M+H] + .

[0295] Compound k8, 6-bromo-3-butylquinazolin-4(3H)-one, white solid, yield 75%, ESI-MS: m / z 282.1 [M+H] + .

[0296] Compound k9, 6-bromo-3-(cyclopropylmethyl)quinazolin-4(3H)-one, white solid, yield 73%, ESI-MS: m / z 280.2 [M+H] + .

[0297] Compound k10, 6-bromo-3-isopentylquinazolin-4(3H)-one, white solid, yield 78%, ESI-MS: m / z 296.1 [M+H] + .

[0298] Compound k11, 6-bromo-3-ethylquinazolin-4(3H)-one, white solid, yield 82%, ESI-MS: m / z 254.1 [M+H] + .

[0299] Compound k12, 6-bromo-3-propylquinazolin-4(3H)-one, white solid, yield 85%, ESI-MS: m / z 268.1 [M+H] + .

[0300] Compound k13, 6-bromo-3-(2-fluoroethyl)quinazolin-4(3H)-one, white solid, yield 83%, ESI-MS: m / z 272.1 [M+H] + .

[0301] Compound k14, 6-bromo-3-(2-fluoropropyl)quinazolin-4(3H)-one, white solid, yield 78%, ESI-MS: m / z 286.1 [M+H] + .

[0302] Compound k15, 6-bromo-3-(cyclobutylmethyl)quinazolin-4(3H)-one, white solid, yield 83%, ESI-MS: m / z 294.2 [M+H] + .

[0303] Compound k16, 6-bromo-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one, white solid, yield 77%, ESI-MS: m / z 264.1 [M+H] + .

[0304] Compound k17, 6-bromo-3-cyclopropylquinazolin-4(3H)-one, white solid, yield 70%, ESI-MS: m / z 266.1 [M+H] + .

[0305] Compound k18, 6-bromo-2-methyl-3-propylquinazolin-4(3H)-one, white solid, yield 86%, ESI-MS: m / z 282.0 [M+H] + .

[0306] Compound k19, 3-bromo-6-propyl-1,6-naphthyridin-5(6H)-one, white solid, yield 82%, ESI-MS: m / z 268.1 [M+H] + .

[0307] Compound k20, 3-bromo-6-(cyclopropylmethyl)-1,6-naphthyridin-5(6H)-one, white solid, yield 85%, ESI-MS: m / z 280.1 [M+H] + .

[0308] Compound k21, 6-bromo-3-propylpyrido[2,3-d]pyrimidin-4(3H)-one, white solid, yield 81%, ESI-MS: m / z 269.1 [M+H] + .

[0309] Lawesson's reagent (809 mg, 2 mmol) was added to a solution of intermediate compound k12 (534 mg, 2 mmol) in toluene (15 mL) and the mixture was heated to 110 °C overnight. After the reaction was completed, the mixture was cooled to room temperature and the solvent was removed in vacuo. The product was purified by column chromatography on silica gel using petroleum ether: ethyl acetate = 25:1 as eluent to give 6-bromo-3-propylquinazoline-4(3H)-thione (kk1) as a yellow solid (442 mg, 1.56 mmol, 78% yield), ESI-MS: m / z 283.2 [M+H] + .

[0310] Compound d (5000 mg, 20.99 mmol) was added to a solution of methyl 5-bromoaminobenzoate cl (3450 mg, 14.99 mmol) in pyridine (30 mL) and reacted at 50 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, extracted with 5% potassium carbonate solution (200 mL) and dichloromethane, the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed using petroleum ether: ethyl acetate = 3: 1 as eluent to obtain methyl 5-bromo-2-((cyanamido(phenoxy)methylidene)amino)benzoate (compound el) as a white solid (3140 mg, 8.39 mmol, 56% yield), ESI-MS: m / z 375.2 [M+H] + ;

[0311] N-propylamine f (316 mg, 5.35 mmol) was added to a solution of intermediate compound el (1 g, 2.67 mmol) in isopropanol (15 mL) and stirred at 85 °C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, the solvent was removed under vacuum, and the product was column chromatographed on silica gel using petroleum ether: ethyl acetate = 3: 1 as eluent to obtain N-(6-bromo-4-oxo-3-propyl-3,4-dihydroquinazolin-2-yl) cyanamide (gl) as a white solid (651 mg, 2.12 mmol, 80% yield), ESI-MS: m / z 308.2 [M+H] + .

[0312] To a solution of intermediate compound gl (821 mg, 2.67 mmol) in dimethyl sulfoxide (9.4 mL) was added concentrated hydrochloric acid (18.7 mL), and the mixture was heated to 100 °C for 1 hour. After the reaction was completed, the mixture was poured into water (100 mL) and treated with potassium carbonate until no gas bubbles were generated, and then extracted with dichloromethane (3 x 75 mL). The solvent was removed under reduced pressure, the residue was dissolved in acetic acid (75 mL), washed with water, brine, dried over sodium sulfate, and concentrated to obtain 2-amino-6-bromo-3-propylquinazolin-4(3H)-one (compound k22) as a white solid (640 mg, 2.27 mmol, 85% yield), ESI-MS: m / z 283.1 [M+H] + .

[0313] In a similar manner, compounds k23-24 were prepared using compound c.

[0314] Compound k23, 2-amino-6-bromo-3-(cyclopropylmethyl)quinazolin-4(3H)-one, was obtained as a white solid in a yield of 86%, ESI-MS: m / z 295.2 [M+H] + .

[0315] To obtain compound k24, 2-amino-6-bromo-3-propylpyrido[2,3-d]pyrimidin-4(3H)-one, white solid, yield 80%, ESI-MS: m / z 284.1 [M+H] + .

[0316] To a solution of compound h1 (500 mg, 1.80 mmol) in tetrahydrofuran, 1 N sodium hydroxide aqueous solution (1.8 mL) was added at room temperature, the reaction was carried out for 15 hours, cooled to 0 °C, adjusted to Ph = 5 with acetic acid, the white solid precipitated was collected, washed with water, dried in vacuum, the crude product was purified by column chromatography on silica gel using dichloromethane as eluent to obtain intermediate compound 6-bromo-2-chloroquinazolin-4(3H)-one (compound i1), white solid (444 mg, 1.71 mmol, yield 95%), ESI-MS: m / z 260.4 [M+H] + .

[0317] 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), the reaction was carried out at 65 °C for 5 hours, cooled to room temperature, filtered to remove potassium carbonate, the solvent was removed in vacuum, the product was purified by column chromatography on silica gel using dichloromethane as eluent to obtain 6-bromo-2-chloro-3-propylquinazolin-4(3H)-one (compound j1), white solid (344 mg, 1.14 mmol, yield 74%), ESI-MS: m / z 302.3 [M+H] + .

[0318] Cesium fluoride (304 mg, 2.00 mmol) was added to a solution of compound j1 (302 mg, 1.00 mmol) in dimethyl sulfoxide, after the reaction was carried out at 150 °C for 5 hours, water (25 mL) was added to the reaction mixture, the reaction mixture was stirred for 10 minutes until no white solid precipitated. The solid was filtered, washed with water (25 mL), dried in vacuum, the crude product was purified by column chromatography on silica gel using dichloromethane:methanol = 30:1 as eluent to obtain intermediate compound 6-bromo-2-hydroxy-3-propylquinazolin-4(3H)-one (compound k25), white solid (184 mg, 0.65 mmol, yield 65%), ESI-MS: m / z 284.1 [M+H] + .

[0319] In a similar manner, compounds k26-27 were prepared from compound h.

[0320] Compound k26, 6-bromo-3-(cyclopropylmethyl)-2-hydroxyquinazolin-4(3H)-one, was obtained as a white solid in 62% yield, ESI-MS: m / z 296.1 [M+H] + .

[0321] Compound k27, 6-bromo-2-hydroxy-3-propylpyrido[2,3-d]pyrimidin-4(3H)-one, was obtained as a white solid in 61% yield, ESI-MS: m / z 285.1 [M+H] + .

[0322] Compound s (834 mg, 4.00 mmol) was added to a solution of compound 5-bromo- methyl benzoate cl (460 mg, 2 mmol) in dichloromethane (15 mL) and the reaction was allowed to proceed at room temperature for 5 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The product was purified by column chromatography on silica gel using petroleum ether: ethyl acetate = 20: 1 as eluent to give (Z)-5-bromo-2-((4-chloro-5H-1,2,3- dithiazol-5-ylidene)amino)benzoic acid methyl ester (t) as a yellow solid (622 mg, 1.70 mmol, 85% yield), ESI-MS: m / z 365.5 [M+H] + ;

[0323] Compound 2-methyl-1,3-propanediamine ul (157 mg, 1.78 mmol) was added to a solution of intermediate compound t (500 mg, 1.37 mmol) in tetrahydrofuran (15 mL) and the reaction was allowed to proceed at room temperature for 3 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The product was purified by column chromatography on silica gel using dichloromethane:methanol = 100:1 as eluent to give 8-bromo-3-methyl-1,2,3,-tetrahydro-6H-pyrimido[2,1-b]quinazolin-6-one (k28) as a white solid (330 mg, 1.12 mmol, 82% yield), ESI-MS: m / z 294.2 [M+H] + ;

[0324] In a similar manner, compound k29 was prepared.

[0325] Compound k29, 8-bromo-3,3-dimethyl-1,2,3,-tetrahydro-6H-pyrimido[2,1-b]quinazolin-6-one (k29), was obtained as a white solid in 85% yield, ESI-MS: m / z 308.2 [M+H] + .

[0326] The specific reaction process is as follows:

[0327] To a solution of compound 5-bromo-2-nitrobenzoic acid v1 (496 mg, 2.01 mmol) in N,N-dimethylformamide (20 mL) was added compound cyclopropylmethylamine f (215 mg, 3.02 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1148 mg, 3.02 mmol) and N,N-diisopropylethylamine (521 mg, 4.03 mmol) and the reaction was allowed to proceed at room temperature for 3 h. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and ethyl acetate (50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography using dichloromethane as eluent to give 5-bromo-N-(cyclopropylmethyl)-2-nitrobenzamide (compound w1) as a white solid (529 mg, 1.77 mmol, 88% yield), ESI-MS: m / z 299.1 [M+H] + ;

[0328] To a solution of intermediate compound w1 (512 mg, 1.71 mmol) in toluene (20 mL) was added Lawesson's reagent (692 mg, 1.71 mmol) and the reaction was allowed to proceed at 110 °C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The product was purified by column chromatography using petroleum ether: ethyl acetate = 15:1 as eluent to give 5-bromo-N-(cyclopropylmethyl)-2-nitrothiobenzamide (x1) as a yellow solid (377 mg, 1.20 mmol, 70% yield), ESI-MS: m / z 315.2 [M+H] + .

[0329] To a solution of intermediate compound x1 (300 mg, 0.95 mmol) in ethanol (12 mL) and water (3 mL) was added iron powder (531 mg, 9.5 mmol) and ammonium chloride (508 mg, 9.5 mmol) and the reaction was allowed to proceed at 60 °C for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with water (100 mL) and dichloromethane (100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography using dichloromethane as eluent to give 2-amino-5-bromo-N-(cyclopropylmethyl)thiobenzamide (compound y1) as a yellow solid (163 mg, 0.57 mmol, 60% yield), ESI-MS: m / z 285.2 [M+H] + ;

[0330] To a solution of intermediate compound yl (300 mg, 1.05 mmol) in acetonitrile (20 mL) and water (5 mL) was added cyanuric chloride (194 mg, 1.05 mmol) and sodium bicarbonate (265 mg, 3.16 mmol) and the reaction mixture was heated to 80 °C for 2-6 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and ethyl acetate (100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol = 100:1 as eluent to give 2-amino-6-bromo-3- (cyclopropylmethyl) quinazoline-4(3H)-thione (compound k30) as a yellow solid (202 mg, 0.65 mmol, 62% yield), ESI-MS: m / z 310.2 [M+H] + .

[0331] The target compound was prepared according to the following procedure:

[0332] To a solution of N,N-diisopropyl ethylamine (2228 mg, 17.24 mmol) and 2-amino-5- bromopyrimidine (1500 mg, 8.62 mmol) in toluene (35 mL) was added acetyl chloride (1015 mg, 12.93 mmol) at room temperature. The reaction mixture was heated to 110 °C for 3-5 h. After completion of the reaction, the solvent was removed under vacuum. The crude product was purified by column chromatography using petroleum ether: ethyl acetate = 20:1 as eluent to give N-(5-bromopyrimidin-2-yl)acetamide (compound ml) as a white solid (1508 mg, 6.98 mmol, 81% yield), ESI-MS: m / z 217.1 [M+H] + .

[0333] In a similar manner, intermediate compounds m2-36, 45-47 were prepared using different acyl chlorides and aromatic amine compound l.

[0334] Compound m2, N-(5-bromopyrimidin-2-yl)propanamide was obtained as a white solid in 71% yield, ESI-MS: m / z 231.1 [M+H] + .

[0335] Compound m3, N-(5-bromopyrimidin-2-yl)hexanamide was obtained as a white solid in 68% yield, ESI-MS: m / z 273.1 [M+H] + .

[0336] Compound m4, N-(5-bromopyrimidin-2-yl)butanamide was obtained as a white solid in 81% yield, ESI-MS: m / z 245.1 [M+H] + .

[0337] Compound m5, N-(5-bromopyrimidin-2-yl)benzamide, was obtained as a white solid in 78% yield, ESI-MS: m / z 279.1 [M+H] + .

[0338] Compound m6, N-(5-bromopyrimidin-2-yl)-4-fluorobenzamide, was obtained as a white solid in 79% yield, ESI-MS: m / z 297.1 [M+H] + .

[0339] Compound m7, N-(5-bromopyrimidin-2-yl)cyclopropanecarboxamide, was obtained as a white solid in 67% yield, ESI-MS: m / z 243.1 [M+H] + .

[0340] Compound m8, N-(5-bromopyrimidin-2-yl)cyclobutanecarboxamide, was obtained as a white solid in 68% yield, ESI-MS: m / z 257.1 [M+H] + .

[0341] Compound m9, N-(5-bromopyrimidin-2-yl)isonicotinamide, was obtained as a white solid in 80% yield, ESI-MS: m / z 280.1 [M+H] + .

[0342] Compound m10, N-(5-bromopyrimidin-2-yl)pentanamide, was obtained as a white solid in 83% yield, ESI-MS: m / z 259.1 [M+H] + .

[0343] Compound m11, N-(5-bromopyrazin-2-yl)pentanamide, was obtained as a white solid in 85% yield, ESI-MS: m / z 259.1 [M+H] + .

[0344] Compound m12, N-(6-bromopyridin-3-yl)pentanamide, was obtained as a white solid in 77% yield, ESI-MS: m / z 258.1 [M+H] + .

[0345] Compound m13, N-(2-bromopyrimidin-5-yl)pentanamide, was obtained as a white solid in 76% yield, ESI-MS: m / z 259.1 [M+H] + .

[0346] Compound m14, N-(4-bromo-2-fluorophenyl)pentanamide, was obtained as a white solid in 65% yield, ESI-MS: m / z 275.1 [M+H] + .

[0347] Compound m15, N-(4-bromo-2-methoxyphenyl)pentanamide, was obtained as a white solid in 63% yield, ESI-MS: m / z 287.2 [M+H] + .

[0348] Compound m16, N-(5-bromopyridin-2-yl)-4,4-difluoropentanamide, was obtained as a white solid in 87% yield, ESI-MS: m / z 294.1 [M+H] + .

[0349] Compound m17, N-(5-bromopyridin-2-yl)-3-fluoropentanamide, was obtained as a white solid in 82% yield, ESI-MS: m / z 276.1 [M+H] + .

[0350] Compound m18, N-(5-bromopyridin-2-yl)-4-fluoropentanamide, was obtained as a white solid in 83% yield, ESI-MS: m / z 276.1 [M+H] + .

[0351] Compound m19, N-(5-bromopyridin-2-yl)pentanamide, was obtained as a white solid in 69% yield, ESI-MS: m / z 258.1 [M+H] + .

[0352] Compound m20, N-(5-bromopyridin-2-yl)-3,3-difluoropentanamide, was obtained as a white solid in 72% yield, ESI-MS: m / z 294.1 [M+H] + .

[0353] Compound m21, N-(5-bromopyridin-2-yl)benzamide, was obtained as a white solid in 74% yield, ESI-MS: m / z 278.1 [M+H] + .

[0354] Compound m22, N-(5-bromopyridin-2-yl)butanamide, was obtained as a white solid in 65% yield, ESI-MS: m / z 244.1 [M+H] + .

[0355] Compound m23, N-(5-bromopyridin-2-yl)hexanamide, was obtained as a white solid in 67% yield, ESI-MS: m / z 272.2 [M+H] + .

[0356] Compound m24, N-(5-bromopyridin-2-yl)cyclobutanecarboxamide, was obtained as a white solid in 62% yield, ESI-MS: m / z 256.1 [M+H] +.

[0357] Compound m25, N-(5-bromopyridin-2-yl)cyclopentanecarboxamide, was obtained as a white solid in 80% yield, ESI-MS: m / z 270.1 [M+H] + .

[0358] Compound m26, N-(5-bromopyridin-2-yl)cyclohexanecarboxamide, was obtained as a white solid in 81% yield, ESI-MS: m / z 284.2 [M+H] + .

[0359] Compound m27, N-(4-bromophenyl)pentanamide, was obtained as a white solid in 71% yield, ESI-MS: m / z 257.1 [M+H] + .

[0360] Compound m28, N-(5-bromopyridin-2-yl)-2-cyclopropylethanamide, was obtained as a white solid in 75% yield, ESI-MS: m / z 256.1 [M+H] + .

[0361] Compound m29, N-(5-bromopyridin-2-yl)-2-cyclobutylethanamide, was obtained as a white solid in 76% yield, ESI-MS: m / z 270.1 [M+H] + .

[0362] Compound m30, N-(5-bromo-6-fluoropyridin-2-yl)pentanamide, was obtained as a white solid in 81% yield, ESI-MS: m / z 276.1 [M+H] + .

[0363] Compound m31, N-(5-bromo-3-fluoropyridin-2-yl)pentanamide, was obtained as a white solid in 86% yield, ESI-MS: m / z 276.2 [M+H] + .

[0364] Compound m32, N-(5-bromo-4-fluoropyridin-2-yl)pentanamide, was obtained as a white solid in 87% yield, ESI-MS: m / z 276.1 [M+H] + .

[0365] Compound m33, N-(5-bromo-3-methylpyridin-2-yl)pentanamide, was obtained as a white solid in 84% yield, ESI-MS: m / z 272.1 [M+H] + .

[0366] Compound m34, N-(5-bromo-4-methylpyridin-2-yl)pentanamide, was obtained as a white solid in 82% yield, ESI-MS: m / z 272.2 [M+H] + .

[0367] Compound m35, 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] + .

[0368] Compound m36, 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] + .

[0369] Compound m45, N-(5-bromopyridin-2-yl)-3-fluorobenzamide, was obtained as a white solid in 82% yield, ESI-MS: m / z 295.1 [M+H] + .

[0370] Compound m46, N-(5-bromopyridin-2-yl)-2-(trifluoromethoxy)benzamide, was obtained as a white solid in 86% yield, ESI-MS: m / z 361.2 [M+H] + .

[0371] Compound m47, N-(5-bromopyridin-2-yl)isoxazole-5-carboxamide, was obtained as a white solid in 88% yield, ESI-MS: m / z 268.1 [M+H] + .

[0372] or o-tolyl isocyanate (2039 mg, 17.34 mmol) was added 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) in portions, and the reaction was heated to 110 °C for 6 h. After the reaction was completed, the reaction 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 eluent to give 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] + .

[0373] In a similar manner, intermediate compounds m38-44 were prepared using different isocyanates and aromatic amine compound l.

[0374] Compound m38, 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] + .

[0375] Compound m39, 1-(5-bromopyridin-2-yl)-3-phenylurea, was obtained as a white solid in 83% yield, ESI-MS: m / z 293.1 [M+H] + .

[0376] Compound m40, 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] + .

[0377] Compound m41, 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] + .

[0378] Compound m42, 1-benzyl-3-(5-bromopyridin-2-yl)urea, was obtained as a white solid in 82% yield, ESI-MS: m / z 307.2 [M+H] + .

[0379] Compound m43, 1-(5-bromopyridin-2-yl)-3-butylurea, was obtained as a white solid in 65% yield, ESI-MS: m / z 273.2 [M+H] + .

[0380] Compound m44, 1-(5-bromopyridin-2-yl)-3-(tert-butyl)urea, was obtained as a white solid in 64% yield, ESI-MS: m / z 273.2 [M+H] + .

[0381] 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) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (237 mg, 0.324 mmol) and the reaction was stirred at 80 °C for 4 h. After the reaction was completed, the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The crude product was dissolved in dichloromethane and methanol, and the potassium carbonate was removed by suction filtration. The filtrate was concentrated and the crude product was purified by column chromatography on silica gel using dichloromethane as the eluent to give N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)acetamide (compound o1) as a colorless oil (639 mg, 2.43 mmol, 75% yield), ESI-MS: m / z 364.1 [M+H] + .

[0382] In a similar manner, intermediate compounds o2-47 were prepared from intermediate compound m.

[0383] Compound o2, N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)propanamide, was obtained as a colorless oil in 72% yield, ESI-MS: m / z 277.1 [M+H] + .

[0384] Compound o3, N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)hexanamide, was obtained as a colorless oil in 78% yield, ESI-MS: m / z 319.2 [M+H] + .

[0385] Compound o4, N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)butanamide, was obtained as a colorless oil in 74% yield, ESI-MS: m / z 291.1 [M+H] + .

[0386] Compound o5, N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)benzamide, was obtained as a colorless oil in 71% yield, ESI-MS: m / z 325.2 [M+H] + .

[0387] Compound o6, 4-fluoro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2- yl)benzamide, colorless oil, yield 74%, ESI-MS: m / z 343.2 [M+H] + .

[0388] Compound o7, N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)cyclopropane carboxamide, colorless oil, yield 73%, ESI-MS: m / z 289.1 [M+H] + .

[0389] Compound o8, N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)cyclobutane carboxamide, colorless oil, yield 71%, ESI-MS: m / z 303.2 [M+H] + .

[0390] Compound o9, N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)isonicotinamide, colorless oil, yield 72%, ESI-MS: m / z 326.2 [M+H] + .

[0391] Compound o10, N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)pentanamide, colorless oil, yield 71%, ESI-MS: m / z 305.2 [M+H] + .

[0392] Compound o11, N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)pentanamide, colorless oil, yield 73%, ESI-MS: m / z 305.2 [M+H] + .

[0393] Compound o12, N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)pentanamide, colorless oil, yield 71%, ESI-MS: m / z 304.2 [M+H] + .

[0394] Compound o13, N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-5-yl)pentanamide, colorless oil, yield 76%, ESI-MS: m / z 305.2 [M+H] + .

[0395] Compound o14, N-(2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pentanamide, colorless oil, yield 70%, ESI-MS: m / z 321.2 [M+H] + .

[0396] Compound o15, N-(2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pentanamide, colorless oil, yield 71%, ESI-MS: m / z 333.2 [M+H] + .

[0397] Compound o16, 4,4-difluoro-N-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl)pentanamide, colorless oil, yield 74%, ESI-MS: m / z 340.2 [M+H] + .

[0398] Compound o17, 3-fluoro-N-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin- 2-yl)pentanamide, colorless oil, yield 71%, ESI-MS: m / z 322.2 [M+H] + .

[0399] Compound o18, 4-fluoro-N-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin- 2-yl)pentanamide, colorless oil, yield 73%, ESI-MS: m / z 322.2 [M+H] + .

[0400] Compound o19, N-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yl)pentanamide, colorless oil, yield 77%, ESI-MS: m / z 304.2 [M+H] + .

[0401] Compound o20, 3,3-difluoro-N-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl)pentanamide, colorless oil, yield 73%, ESI-MS: m / z 340.2 [M+H] + .

[0402] Compound o21, N-(5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyridin-2- yl)benzamide, colorless oil, yield 75%, ESI-MS: m / z 324.2 [M+H] + .

[0403] Compound o22, N-(5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyridin-2- yl)butanamide, colorless oil, yield 73%, ESI-MS: m / z 290.2 [M+H] + .

[0404] Compound o23, N-(5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyridin-2- yl)hexanamide, colorless oil, yield 77%, ESI-MS: m / z 318.2 [M+H] + .

[0405] Compound o24, N-(5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyridin-2- yl)cyclobutanamide, colorless oil, yield 77%, ESI-MS: m / z 302.2 [M+H] + .

[0406] Compound o25, N-(5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyridin-2- yl)cyclopentanamide, colorless oil, yield 74%, ESI-MS: m / z 316.2 [M+H] + .

[0407] Compound o26, N-(5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyridin-2- yl)cyclohexanecarboxamide, colorless oil, yield 75%, ESI-MS: m / z 330.2 [M+H] + .

[0408] Compound o27, N-(4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenyl)pentanamide, colorless oil, yield 76%, ESI-MS: m / z 303.2 [M+H] + .

[0409] Compound o28, 2-cyclopropyl-N-(5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2- yl)pyridin-2-yl)acetamide, colorless oil, yield 73%, ESI-MS: m / z 302.2 [M+H] + .

[0410] Compound o29, 2-cyclobutyl-N-(5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2- yl)pyridin-2-yl)acetamide, colorless oil, yield 71%, ESI-MS: m / z 316.2 [M+H] + .

[0411] Compound o30, N-(6-fluoro-5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2- yl)pyridin-2-yl)pentanamide, colorless oil, yield 74%, ESI-MS: m / z 323.2 [M+H] + .

[0412] Compound o31, N-(3-fluoro-5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2- yl)pyridin-2-yl)pentanamide, colorless oil, yield 66%, ESI-MS: m / z 323.1 [M+H] + .

[0413] Compound o32, N-(4-fluoro-5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2- yl)pyridin-2-yl)pentanamide, colorless oil, yield 69%, ESI-MS: m / z 323.2 [M+H] + .

[0414] Compound o33, N-(3-methyl-5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2- yl)pyridin-2-yl)pentanamide, colorless oil, yield 65%, ESI-MS: m / z 319.2 [M+H] + .

[0415] Compound o34, N-(4-methyl-5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2- yl)pyridin-2-yl)pentanamide, colorless oil, yield 75%, ESI-MS: m / z 319.2 [M+H] + .

[0416] Compound o35, N-(6-methyl-5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2- yl)pyridin-2-yl)pentanamide, colorless oil, yield 76%, ESI-MS: m / z 319.3 [M+H] + .

[0417] Compound o36, 2-(ethylamino)-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-yl)acetamide, was obtained as colorless oil in 67% yield, ESI-MS: m / z 306.2 [M+H] + .

[0418] Compound o37, 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3- (o-tolyl)urea, was obtained as colorless oil in 76% yield, ESI-MS: m / z 354.2 [M+H] + .

[0419] Compound o38, 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3- (m-tolyl)urea, was obtained as colorless oil in 77% yield, ESI-MS: m / z 354.2 [M+H] + .

[0420] Compound o39, 1-phenyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- yl)urea, was obtained as colorless oil in 72% yield, ESI-MS: m / z 340.2 [M+H] + .

[0421] Compound o40, 1-(4-fluorophenyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-yl)urea, was obtained as colorless oil in 76% yield, ESI-MS: m / z 358.2 [M+H] + .

[0422] Compound o41, 1-(4-methoxyphenyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-yl)urea, was obtained as colorless oil in 73% yield, ESI-MS: m / z 370.2 [M+H] + .

[0423] Compound o42, 1-benzyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- yl)urea, was obtained as colorless oil in 79% yield, ESI-MS: m / z 354.2 [M+H] + .

[0424] Compound o43, 1 -butyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-yl)urea, was obtained as colorless oil in 71 % yield, ESI-MS: m / z 320.2 [M+H] + .

[0425] Compound o44, 1 -(tert-butyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-yl)urea, was obtained as colorless oil in 80% yield, ESI-MS: m / z 320.2 [M+H] + .

[0426] Compound o45, 3-fluoro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin- 2-yl)benzamide, was obtained as colorless oil in 74% yield, ESI-MS: m / z 343.2 [M+H] + .

[0427] Compound o46, N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-2- (trifluoromethoxy)benzamide, was obtained as colorless oil in 68% yield, ESI-MS: m / z 408.2 [M+H] + .

[0428] Compound o47, N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)isoxazole- 5-carboxamide, was obtained as colorless oil in 80% yield, ESI-MS: m / z 316.1 [M+H] + .

[0429] To a solution of N-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2- yl)acetamide o1 (1038 mg, 3.95 mmol), 7-bromo-2-propylisoquinolin-l(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) was added [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium (192 mg, 0.26 mmol) and the reaction was stirred for 2 h. After the reaction was completed, the reaction was cooled to room temperature and the solvent was removed in vacuo. The crude product was dissolved in dichloromethane and methanol, the potassium carbonate was removed by suction filtration and the filtrate was concentrated. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol = 100:1 as eluent to give N-(5-(l-oxo-2-propyl-l,2-dihydroisoquinolin-7-yl)pyrimidin-2- yl)acetamide (compound r1) as a white solid (644 mg, 2.00 mmol, 76% yield). 1 H 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 C 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.

[0430] In a similar manner, the target compounds r2-86, 92-100 were prepared from different substituted aromatic amine compounds l.

[0431] N-(5-(l-oxo-2-propyl-l,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)acetamide (compound r1)

[0432] White solid, 75% yield.1 H 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). 13 C 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.

[0433] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)hexanamide (r3)

[0434] White solid, yield 77%. 1 H 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). 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, 372 129; found, 379.2123.

[0435] N-(5-(1 -oxo-2-propyl- 1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)butanamide (r4)

[0436] White solid, yield 78%. 1 H NMR (600 MHz, DMSO-d6) δ 9.70 (s, 1 H), 8.87 (s, 2H), 8.25 (d, J = 1.3 Hz, 1 H), 7.85 (d, J = 7.5 Hz, 1 H), 7.83 (dd, J = 7.5, 1.4 Hz, 1 H), 6.93 (d, J = 1 1.0 Hz, 1 H), 6.60 (d, J = 10.9 Hz, 1 H), 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.

[0437] N-(5-(1 -oxo-2-propyl- 1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)butanamide (r4)

[0438] White solid, yield 81 %. 1H 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). 13 C 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.

[0439] 4-Fluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)benzamide (r6)

[0440] White solid, yield 71%. 1 H 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). 13CNMR (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 F NMR (565 MHz, Chloroform-d) δ -110.07. HRMS (ESI): calcd for C 23 H 20 FN4O2[M+H] + m / z, 403.1565; found, 403.1561.

[0441] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)cyclopropanecarboxamide (r7)

[0442] 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.

[0443] N-(5-(l-oxo-2-propyl-l,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)cyclobutanecarboxamide (r8)

[0444] 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). 13 C 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.

[0445] N-(5-(l-oxo-2-propyl-l,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)isonicotinamide (r9)

[0446] White solid, yield 79%. 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). 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.

[0447] N-(5-(2-ethyl-l-oxo-l,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r10)

[0448] White solid, yield 77%. 1 H 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 C 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.

[0449] N-(5-(2-butyl-l-oxo-l,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r11)

[0450] White solid, yield 73%. 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). 13 C 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.

[0451] N-(5-(2-(Cyclopropylmethyl)-l-oxo-l,2-dihydroisoquinolin-7-yl)pyrimidin-2- yl)pentanamide (r12)

[0452] White solid, yield 78%. 1 H 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 = 7.5 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). 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.

[0453] N-(5-(2-benzyl-l-oxo-l,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r13)

[0454] 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.

[0455] N-(5-(2-(4-methylbenzyl)-1-oxo-1,2-dihydroisoquinoline-7-yl)pyrimidin-2-yl)pentanamide (r14)

[0456] White solid, yield 73%. 1 H NMR(600MHz,Chloroform-d)δ10.94(s,1H),8.90(s,2H),8.18(d,J=1.5Hz,1H),7.79 (d,J=7.7Hz,1H),7.66(dd,J=7.6,1.4Hz,1H),7.17(d,J=7.6,1.1Hz,2H),7.13(d,J= 7.0Hz,2H),7.03(d,J=10.8Hz,1H),6.82(d,J=10.5Hz,1H),5.21(s,2H),2.52(t,J=7 .1Hz,2H),2.33(s,3H),1.60–1.52(m,2H),1.43–1.33(m,2H),0.91(t,J=8.1Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ171.85,164.39,156.51,150.75,137.28,137.05,135.49,135.09,134.17,130.53,12 8.98,128.58,128.35,127.74,127.67,126.38,102.53,51.46,36.55,26.71,21.86,21.01,13.81.HRMS(ESI):calcd for C 26 H 27 N4O2[M+H] + m / z,427.2129; found,427.2126.

[0457] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinoline-7-yl)pyrazin-2-yl)pentanamide (r15)

[0458] White solid, yield 67%. 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). 13 C 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.

[0459] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r16)

[0460] White solid, yield 67%. 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 C 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.

[0461] N-(2-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-5-yl)pentanamide (r17)

[0462] White solid, yield 69%. 1H NMR (600 MHz, Chloroform-d) δ 9.79 (s, 1H), 9.21 (s, 2H), 8.13 (d, J = 1.5 Hz, 1H), 8.05 (dd, J = 7.7, 1.5 Hz, 1H), 7.80 (dd, J = 7.6, 0.7 Hz, 1H), 7.02 (d, J = 10.8 Hz, 1H), 6.55 - 6.50 (m, 1H), 3.68 (t, J = 7.1 Hz, 2H), 2.30 (t, J = 7.0 Hz, 2H), 1.72 - 1.63 (m, 2H), 1.62 - 1.51 (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, 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.

[0463] N-(4-Fluoro-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r18)

[0464] White solid, yield 73%. 1 H 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). 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 F 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.

[0465] N-(2-Fluoro-4-(l-oxo-2-propyl-l,2-dihydroisoquinolin-7-yl)phenyl)pentanamide (r19)

[0466] White solid, yield 62%. 1 H 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). 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 F NMR (565 MHz, Chloroform-d) δ -122.21. HRMS (ESI): calcd for C 23 H 26 F N2O2 [M+H] + m / z, 381.1973; found, 381.1970.

[0467] N-(2-methoxy-4-(l-oxo-2-propyl-l,2-dihydroisoquinolin-7-yl)phenyl)pentanamide (r20)

[0468] White solid, yield 61%. 1 H 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). 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. HRMS (ESI): calcd for C 24 H 29 N2O3[M+H] + m / z, 393.2173; found, 393.2170.

[0469] 4,4-Difluoro-N-(5-(l-oxo-2-propyl-l,2-dihydroisoquinolin-7-yl)pyridin-2- yl)pentanamide (r21)

[0470] White solid, yield 79%. 1 H 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 C 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. HRMS (ESI): calcd for C 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.

[0471] N-(5-(2-(Cyclopropylmethyl)-l-oxo-l,2-dihydroisoquinolin-7-yl)pyridin-2- yl)-4,4-difluoropentanamide (r22)

[0472] White solid, yield 79%. 1 H 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 C 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 F NMR (565 MHz, Chloroform-d) δ -92.82. HRMS (ESI): calcd for C 23 H 24 F2N3O2[M+H] + m / z, 412.1831 ; found, 412.1831.

[0473] 4-fluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r23)

[0474] White solid, yield 77%. 1 H 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 C 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 F 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.

[0475] N-(5-(2-(cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)-4- fluoro pentanamide (r24)

[0476] White solid, yield 71%. 1H 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 C 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 F 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.

[0477] 3,3-Difluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r25)

[0478] White solid, yield 73%. 1H 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 C 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.

[0479] 3-Fluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r26)

[0480] White solid, yield 73%. 1H 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 C 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 F 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.

[0481] N-(5-(2-(Cyclopropylmethyl)-l-oxo-l,2-dihydroisoquinolin-7-yl)pyridin-2- yl)pentanamide (r27)

[0482] White solid, yield 75%. 1H 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 CNMR (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.

[0483] N-(5-(6-(cyclopropylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridin-3-yl)pyridin-2- yl)pentanamide (r28)

[0484] White solid, yield 75%. 1H 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 C 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.

[0485] N-(5-(2-amino-4-oxo-3-propyl-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)pyridin-2- yl)pentanamide (r29)

[0486] White solid, yield 63%. 1H 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 C 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.

[0487] N-(5-(4-oxo-3-propyl-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)pyridin-2-yl)pentanamide (r30)

[0488] White solid, yield 67%. 1 H 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 = 8.0 Hz, 3H). 13C 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.

[0489] N-(5-(2-hydroxy-4-oxo-3-propyl-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)pyridin-2- yl)pentanamide (r31)

[0490] White solid, yield 67%. 1 H 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 C 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.

[0491] N-(5-(3-(cyclopropylmethyl)-2-hydroxy-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)pentanamide (r32)

[0492] White solid, yield 67%. 1 H NMR (600 MHz, Chloroform-d) δ 10.25 (s, 1H), 8.41 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 1.4 Hz, 1H), 8.03 (dd, J = 7.7, 1.5 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.83 (s, 1H), 7.77 (dd, J = 7.4, 1.5 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 3.76 (d, J = 6.9 Hz, 2H), 2.41 (t, J = 7.1 Hz, 2H), 1.96 - 1.87 (m, 1H), 1.62 (p, J = 7.1 Hz, 2H), 1.57 - 1.46 (m, 4H), 1.43 - 1.34 (m, 2H), 0.92 (t, J = 8.0 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 171.88, 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.

[0493] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)benzamide (r33)

[0494] White solid, yield 60%. 1H 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 C 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.

[0495] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)butanamide (r34)

[0496] White solid, yield 72%. 1 H 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). 13C 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.

[0497] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r35)

[0498] White solid, yield 67%. 1 H 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 C 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.

[0499] N-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)cyclohexanecarboxamide (r37)

[0500] 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.

[0501] N-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)cyclohexanecarboxamide (r37)

[0502] White solid, yield 73%. 1H 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 C 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.

[0503] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)cyclopentanecarboxamide (r38)

[0504] White solid, yield 75%. 1H 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 C 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.

[0505] N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)cyclohexanecarboxamide (r39)

[0506] White solid, yield 56%. 1H 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 C 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.

[0507] N-(5-(3-ethyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r40)

[0508] White solid, yield 72%. 1H 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 C 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.

[0509] N-(5-(3-Isopentyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r41)

[0510] White solid, yield 74%. 1 H 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). 13C 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.

[0511] N-(5-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)pentanamide (r42)

[0512] White solid, yield 78%. 1 H NMR (600 MHz, Chloroform-d) δ 8.58 (d, J = 2.5 Hz, 1 H), 8.52 (s, 1 H), 8.50 (d, J = 2.2 Hz, 1 H), 8.34 (d, J = 8.7 Hz, 1 H), 8.12 (s, 1 H), 8.00 (dd, J = 8.7, 2.4 Hz, 1 H), 7.94 (dd, J = 8.4, 2.2 Hz, 1 H), 7.79 (d, J = 8.5 Hz, 1 H), 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, 1 H), 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 C 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.

[0513] N-(5-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)hexanamide (r43)

[0514] 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.

[0515] N-(5-(3-(cyclobutylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)pentanamide (r44)

[0516] White solid, yield 75%. 1H 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 C 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.

[0517] N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)benzamide (r45)

[0518] White solid, yield 82%. 1 H 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). 13C 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.

[0519] N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r46)

[0520] White solid, yield 76%. 1 H NMR (600 MHz, Chloroform-d) δ 8.59 (d, J = 2.5 Hz, 1 H), 8.50 (d, J = 2.2 Hz, 1 H), 8.37 (s, 1 H), 8.34 (d, J = 8.6 Hz, 1 H), 8.05 (s, 1 H), 8.01 (dd, J = 8.6, 2.5 Hz, 1 H), 7.94 (dd, J = 8.4, 2.2 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 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 C 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.

[0521] N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)hexanamide (r47)

[0522] 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.

[0523] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)pentanamide (r48)

[0524] White solid, yield 79%. 1H 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 CNMR (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.

[0525] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyrimidin-2-yl)pentanamide (r49)

[0526] White solid, yield 77%. 1H 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 C 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.

[0527] N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyrimidin-2-yl)pentanamide (r50)

[0528] White solid, yield 66%. 1 H 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). 13C 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.

[0529] N-(4-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)phenyl)pentanamide (r51)

[0530] White solid, yield 74%. 1 H 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 C 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.

[0531] N-(5-(5-oxo-6-propyl-5,6-dihydro-1,6-naphthyridin-3-yl)pyridin-2-yl)pentanamide (r52)

[0532] 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.

[0533] 2-cyclopropyl-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)acetamide (r53)

[0534] White solid, yield 59%. 1H NMR(600MHz,Chloroform-d)δ8.59(d,J=2.3Hz,1H),8.53(s,1H),8.50(d,J=2.2Hz,1H),8 .36(d,J=8.6Hz,1H),8.05(s,1H),8.01(dd,J=8.6,2.5Hz,1H),7.94(dd,J=8.5,2.2Hz,1H ),7.79(d,J=8.4Hz,1H),4.01–3.97(m,2H),2.38(d,J=7.2Hz,2H),1.85(h,J=7.4Hz,2H), 1.17–1.07(m,1H),1.01(t,J=7.4Hz,3H),0.76–0.68(m,2H),0.31(dt,J=6.0,4.6Hz,2H). 13 C NMR(151MHz,Chloroform-d)δ171.32,161.13,151.02,147.70,146.92,146.13,137.04,136.49,132.5 9,131.46,128.46,124.41,122.72,113.99,48.82,42.76,22.76,11.25,7.21,4.90.HRMS(ESI):calcd for C 21 H 23 N4O2[M+H] + m / z,363.1816; found,363.1816.

[0535] 2-Cyclobutyl-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)acetamide (r54)

[0536] White solid, yield 55%. 1 H NMR(600MHz,Chloroform-d)δ8.58(d,J=2.5Hz,1H),8.50(d,J=2.2Hz,1H),8.37(s,1H) ,8.32(d,J=8.7Hz,1H),8.05(s,1H),7.99(dd,J=8.7,2.5Hz,1H),7.93(dd,J=8.4,2.2H z,1H),7.78(d,J=8.4Hz,1H),3.99(t,J=7.4Hz,2H),2.84–2.75(m,1H),2.54(d,J=7.6H z,2H),2.24–2.14(m,2H),1.96–1.81(m,4H),1.81–1.73(m,2H),1.00(t,J=7.4Hz,3H).13 C NMR (151 MHz, 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.

[0537] N-(6-fluoro-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r55)

[0538] White solid, yield 70%. 1 H NMR (600 MHz, Chloroform-d) δ 8.45 (d, J = 2.2 Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.99 - 7.91 (m, 2H), 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). 13C 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 F 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.

[0539] N-(5-(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r56)

[0540] White solid, yield 78%. 1 H 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). 13C 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.

[0541] N-(5-(2-hydroxy-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r57)

[0542] Yellow solid, yield 75%. 1 H 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 = 8.5, 2.2 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 C 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.

[0543] N-(5-(3-(2-fluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r58)

[0544] 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.

[0545] 2-(Ethylamino)-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)acetamide (r59)

[0546] White solid, yield 73%. 1H 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 C 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.

[0547] N-(5-(2-amino-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r60)

[0548] White solid, yield 51%. 1 H 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). 13C 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.

[0549] N-(5-(2-amino-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4,4- difluoropentanamide (r61)

[0550] White solid, yield 54%. 1 H 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 C 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. 19F NMR (565 MHz, DMSO-d6) δ -89.20. HRMS (ESI): calcd for C 21 H 24 F2N5O2[M+H] + m / z, 416.1893; found, 416.1989.

[0551] N-(5-(2-amino-3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)-4,4-difluoropentanamide (r62)

[0552] White solid, yield 50%. 1 H 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 C 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 F NMR (565 MHz, DMSO-d6) δ -89.22. HRMS (ESI): calcd for C 22 H 24 F2N5O2[M+H] + m / z, 428.1893; found, 428.1888.

[0553] N-(5-(4-oxo-3-(prop-2-yn-1 -yl)-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r63)

[0554] 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.

[0555] N-(5-(3-cyclopropyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r64)

[0556] White solid, yield 72%. 1H 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 C 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.

[0557] N-(5-(3-(2-fluoropropyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)pentanamide (r65)

[0558] White solid, yield 66%. 1 H 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.

[0559] 4,4-Difluoro-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)pentanamide (r66)

[0560] 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). 13C NMR (151 MHz, DMSO-d6) δ 170.76, 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 = 237.7 Hz), 123.03, 122.00, 113.34, 47.53, 32.51 (32.68, 32.51, 32.34, t, J = 25.5 Hz), 29.43 (29.46, 29.43, 29.40, t, J = 4.5 Hz), 23.00 (23.18, 23.00, 22.82, t, J = 27.0 Hz), 21.93, 10.84. 19 F NMR (565 MHz, DMSO-d6) δ -89.19. HRMS (ESI): calcd for C 21 H 23 F2N4O2[M+H] + m / z, 401.1784; found, 401.1782.

[0561] N-(5-(3-(Cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4- fluoropentanamide (r67)

[0562] White solid, yield 63%. 1 H 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), 4.08 - 3.92 (m, 1H), 3.91 (d, J = 7.2 Hz, 2H), 2.63 (t, J = 18.6 Hz, 2H), 1.85 - 1.78 (m, 2H), 1.36 (d, J = 14.6 Hz, 3H), 1.32 (tt, J = 7.6, 4.8 Hz, 1H), 0.69 - 0.63 (m, 2H), 0.46 (dt, J = 6.1, 4.8 Hz, 2H). 13CNMR (151 MHz, 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 = 164.8 Hz), 52.36, 41.66 (41.74, 41.59, d, J = 22.4 Hz), 34.42 (34.43, 34.41, d, J = 3.4 Hz), 19.92 (20.01, 19.83, d, J = 26.8 Hz), 11.98, 4.67. 19 F NMR (565 MHz, Chloroform-d) δ -189.34. HRMS (ESI): calcd for C 22 H 24 FN4O2[M+H] + m / z, 394.1802; found, 394.1800.

[0563] N-(5-(3-(Cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4,4- difluoropentanamide (r68)

[0564] White solid, yield 69% 1 H NMR (600 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.74 (t, J = 1.7 Hz, 1H), 8.45 (s, 1H), 8.39 (d, J = 2.3 Hz, 1H), 8.23 - 8.18 (m, 2H), 8.17 (dd, J = 8.5, 2.3 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 3.86 (d, J = 7.2 Hz, 2H), 2.65 - 2.61 (m, 2H), 2.28 - 2.20 (m, 2H), 1.64 (t, J = 18.9 Hz, 3H), 1.31 - 1.26 (m, 1H), 0.53 - 0.49 (m, 2H), 0.45 - 0.42 (m, 2H). 13C 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 F 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.

[0565] N-(5-(3-(Cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3,3- difluoropentanamide (r69)

[0566] White solid, yield 68%. 1 H NMR (600 MHz, Chloroform-d) δ 8.65 (d, J = 2.5 Hz, 1 H), 8.57 (s, 1 H), 8.54 (d, J = 2.2 Hz, 1 H), 8.39 (d, J = 8.7 Hz, 1 H), 8.15 (s, 1 H), 8.07 (dd, J = 8.7, 2.5 Hz, 1 H), 7.86 (dd, J = 8.4, 2.2 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 1 H), 3.95 (d, J = 7.2 Hz, 2 H), 2.68 (s, 2 H), 1.82 (q, J = 12.6 Hz, 2 H), 1.31 - 1.37 (m, 1 H), 0.95 (t, J = 10.5 Hz, 3 H), 0.68 - 0.61 (m, 2 H), 0.45 - 0.50 (m, 2 H). 13C 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 F 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.

[0567] N-(5-(3-(Cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3- fluoropentanamide (r70)

[0568] White solid, yield 65%. 1 H 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). 13C 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 F 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.

[0569] 3,3-Difluoro-N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r71)

[0570] White solid, yield 71%. 1 H 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). 13C 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 F 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.

[0571] N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyrazin-2-yl)pentanamide (r72)

[0572] White solid, yield 71%. 1 H 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). 13C 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.

[0573] N-(6-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-3-yl)pentanamide (r73)

[0574] White solid, yield 74%. 1 H 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 C 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.

[0575] N-(2-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyrimidin-5-yl)pentanamide (r74)

[0576] 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.

[0577] N-(3-methyl-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r75)

[0578] 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). 13C 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.

[0579] N-(4-methyl-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r76)

[0580] White solid, yield 77%. 1 H 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 C 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.

[0581] N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r76)

[0582] White solid, yield 67%. 1 H NMR (600 MHz, Chloroform-d) δ 8.24 (d, J = 2.0 Hz, 1 H), 8.17 - 8.08 (m, 2 H), 8.06 (s, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.70 - 7.65 (m, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 3.98 (t, J = 7.3 Hz, 2 H), 2.42 - 2.37 (m, 5 H), 1.83 (h, J = 7.4 Hz, 2 H), 1.71 (p, J = 7.6 Hz, 2 H), 1.39 (h, J = 7.4 Hz, 2 H), 1.00 (t, J = 7.4 Hz, 3 H), 0.93 (t, J = 7.4 Hz, 3 H). 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.

[0583] N-(3-Fluoro-5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r78)

[0584] White solid, yield 70%. 1H 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 C 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 F 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.

[0585] 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(o-tolyl)urea (r79)

[0586] White solid, yield 81%. 1H 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 C 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.

[0587] 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(m-tolyl)urea (r80)

[0588] White solid, yield 84%. 1 H 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). 13C 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.

[0589] 1-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-phenylurea (r81)

[0590] White solid, yield 85%. 1 H 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 C 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 24 H 24 N5O2[M+H] + m / z, 414.1925; found, 414.1925.

[0591] 1 -(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(4- methoxyphenyl)urea (r83)

[0592] 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.

[0593] 1 -(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(4- methoxyphenyl)urea (r83)

[0594] White solid, yield 80%. 1H 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 C 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.

[0595] 1 -Benzyl-3-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)urea (r84)

[0596] White solid, yield 77%. 1 H 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). 13C 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.

[0597] 1 -Butyl-3-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)urea (r85)

[0598] White solid, yield 62%. 1 H 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 C 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.

[0599] 1 -(tert-butyl)-3-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)urea (r86)

[0600] White solid, yield 59%. 1 H NMR (600 MHz, Chloroform-d) δ 9.48 (s, 1 H), 9.27 (s, 1 H), 8.50 (d, J = 2.5 Hz, 1 H), 8.46 (d, J = 2.2 Hz, 1 H), 8.03 (s, 1 H), 7.95 - 7.89 (m, 2H), 7.77 (d, J = 8.5 Hz, 1 H), 7.06 (d, J = 8.6 Hz, 1 H), 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 CNMR (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.

[0601] N-(5-(3-methyl-6-oxo-1,3,4,6-tetrahydro-2H-pyrimido[2,1 -b]quinazolin-8-yl)pyridin-2- yl)pentanamide (r92)

[0602] White solid, yield 79%. 1H NMR (600 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.62 (d, J = 2.5 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 8.13 (d, J = 2.3 Hz, 1H), 8.10 (dd, J = 8.7, 2.6 Hz, 1H), 8.04 (s, 1H), 7.90 (dd, J = 8.6, 2.3 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 3.70 (s, 2H), 3.05 (s, 2H), 2.41 (t, J = 7.4 Hz, 2H), 2.20 - 2.13 (m, 1H), 1.56 (p, J = 7.4 Hz, 2H), 1.30 (h, J = 7.4 Hz, 2H), 1.05 - 0.99 (m, 3H), 0.88 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, DMSO) δ 172.22, 161.40, 151.11, 149.26, 145.21, 135.61, 132.42, 130.31, 129.55, 123.76, 123.48, 115.91, 113.32, 50.13, 49.58, 35.81, 27.10, 26.82, 23.43, 21.75, 13.74. HRMS (ESI): calcd for C 22 H 26 N5O2[M+H] + m / z, 392.2081; found, 392.2075.

[0603] N-(5-(3,3-dimethyl-6-oxo-1,3,4,6-tetrahydro-2H-pyrimido[2,1-b]quinazolin-8-yl)pyridin-2- yl)pentanamide (r93)

[0604] White solid, yield 81%. 1 H NMR (600 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.62 (d, J = 2.5 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 8.13 (d, J = 2.3 Hz, 1H), 8.10 (dd, J = 8.7, 2.6 Hz, 1H), 8.04 (s, 1H), 7.90 (dd, J = 8.6, 2.3 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 3.70 (s, 2H), 3.05 (s, 2H), 2.41 (t, J = 7.4 Hz, 2H), 2.20 - 2.13 (m, 1H), 1.56 (p, J = 7.4 Hz, 2H), 1.30 (h, J = 7.4 Hz, 2H), 1.05 - 0.99 (m, 3H), 0.88 (t, J = 7.3 Hz, 3H). 13C NMR (151MHz, DMSO) δ172.23,161.41,151.10,149.27,145.20,135.60,132.43,130.30,129.53,123.7 5,123.47,115.90,113.31,50.12,49.57,35.80,27.12,26.86,23.44,21.78,13.75.HRMS(ESI):calcd for C 23 H 28 N5O2[M+H] + m / z,406.2238; found,406.2233.

[0605] N-(5-(3-propyl-4-thionone-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)pentanamide (r94)

[0606] Yellow solid, yield 76%. 1 H NMR (600MHz, DMSO-d6) δ10.62(s,1H),8.86(d,J=2.2Hz,1H),8.70(s,1H),8.68(d,J=2.1 Hz,1H),8.22(d,J=8.7Hz,1H),8.19(dd,J=8.5,2.2Hz,1H),8.13(dd,J=8.7,2.6Hz,1H), 7.78(d,J=8.4Hz,1H),4.52–4.45(m,2H),2.42(t,J=7.5Hz,2H),1.84(h,J=7.4Hz,2H),1 .58(p,J=7.5Hz,2H),1.32(h,J=7.4Hz,2H),0.93(t,J=7.4Hz,3H),0.89(t,J=7.4Hz,3H). 13 C NMR (151MHz, DMSO) δ185.15,172.38,151.95,146.85,145.94,141.90,136.91,136.40,132.81,129.47 ,129.12,128.89,126.66,113.33,54.41,35.82,27.07,21.78,20.50,13.74,10.75.HRMS(ESI):calcd for C 21 H 25 N4OS[M+H] + m / z,381.1744; found,381.1739.

[0607] N-(5-(2-amino-3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)-4,4-difluoropentanamide (r95)

[0608] Yellow solid, yield 74%. 1 H NMR (600 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.64 (d, J = 2.5 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.10 (dd, J = 8.7, 2.6 Hz, 1H), 7.99 (dd, J = 8.6, 2.3 Hz, 1H), 7.46 (s, 2H), 7.34 (d, J = 8.5 Hz, 1H), 4.88 - 4.73 (m, 2H), 2.62 (t, J = 7.7 Hz, 2H), 2.28 - 2.19 (m, 2H), 1.64 (t, J = 18.9 Hz, 3H), 1.49 - 1.44 (m, 1H), 0.60 - 0.57 (m, 2H), 0.49 - 0.46 (m, 2H). 13 C NMR (151 MHz, DMSO) δ 188.74, 170.68, 151.21, 151.16, 145.41, 135.93, 133.08, 131.40, 130.45, 128.74, 125.48, 124.70 (126.27, 124.70, 123.13, t, J = 237.5 Hz), 124.29, 113.43, 51.16, 32.53 (32.70, 32.53, 32.36, t, J = 25.5 Hz), 29.42 (29.45, 29.42, 29.39, t, J = 6.0 Hz), 23.00 (23.18, 23.00, 22.83, t, J = 26.8 Hz), 9.17, 3.55. 19 F NMR (565 MHz, DMSO) δ -89.16. HRMS (ESI): calcd for C 23 H 24 F2N5OS[M+H] + m / z, 444.1664; found, 444.1661.

[0609] N-(5-(2-amino-3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)-4,4-difluoropentanamide (r95)

[0610] Yellow solid, yield 74%. 1H NMR (600 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.67 (d, J = 2.3 Hz, 1H), 8.63 (d, J = 2.6 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.09 (dd, J = 8.7, 2.6 Hz, 1H), 7.99 (dd, J = 8.6, 2.3 Hz, 1H), 7.53 (s, 2H), 7.35 (d, J = 8.5 Hz, 1H), 4.86 - 4.74 (m, 2H), 2.41 (t, J = 7.4 Hz, 2H), 1.58 (p, J = 7.5 Hz, 2H), 1.49 - 1.43 (m, 1H), 1.35 - 1.29 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H), 0.61 - 0.56 (m, 2H), 0.50 - 0.45 (m, 2H). 13 C NMR (151 MHz, DMSO) δ 188.78, 172.31, 151.32, 151.10, 145.29, 135.92, 133.12, 131.56, 130.24, 128.70, 125.11, 124.23, 113.40, 51.17, 35.81, 27.10, 21.78, 13.75, 9.15, 3.56. HRMS (ESI): calcd for C 22 H 26 N5OS[M+H] + m / z, 408.1853; found, 408.1848.

[0611] 3-Fluoro-N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)benzamide (r97)

[0612] White solid, yield 82%. 1H NMR (600 MHz, Chloroform-d) δ 9.08 (s, 1H), 8.68 (s, 1H), 8.65 (s, 1H), 8.51 (d, J = 8.6 Hz, 1H), 8.12 (dd, J = 8.6, 2.1 Hz, 1H), 7.86 (dd, J = 8.2, 1.8 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.31 - 7.27 (m, 1H), 7.11 (d, J = 7.2 Hz, 1H), 6.54 (d, J = 7.2 Hz, 1H), 4.01 (t, J = 7.3 Hz, 2H), 1.84 (p, J = 7.3 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, CDC13) δ 163.87, 162.22, 150.72, 145.84, 137.43, 136.64, 136.48, 135.56, 132.57, 132.43, 130.70, 130.65, 130.46, 127.03, 126.96, 125.84, 122.91, 122.89, 119.63, 119.49, 115.13, 114.98, 114.51, 105.62, 51.23, 22.70, 11.37. HRMS (ESI): calcd for C 24 H 21 FN3O2[M+H] + m / z, 402.1614; found, 402.1612.

[0613] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)benzamide (r98)

[0614] White solid, yield 78%. 1H NMR (600 MHz, Chloroform-d) δ 9.22 (s, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.65 (d, J = 2.4 Hz, 1H), 8.56 (d, J = 8.6 Hz, 1H), 8.16 - 8.11 (m, 1H), 8.04 - 7.99 (m, 2H), 7.86 (dd, J = 8.2, 2.0 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.61 - 7.57 (m, 1H), 7.56 - 7.48 (m, 2H), 7.11 (d, J = 7.3 Hz, 1H), 6.54 (d, J = 7.3 Hz, 1H), 4.03 - 3.98 (m, 2H), 1.85 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, CDC13) δ 166.00, 162.20, 151.03, 145.62, 137.47, 136.61, 135.63, 132.52, 132.40, 130.47, 128.99, 127.59, 127.02, 125.80, 114.56, 105.63, 51.24, 22.70, 11.38. HRMS (ESI): calcd for C 21 H 22 N3O2[M+H] + m / z, 348.1707; found, 3478.1707.

[0615] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)-2- (trifluoromethoxy)benzamide (r99)

[0616] White solid, yield 76%. 1H NMR (600 MHz, Chloroform-d) δ 9.43 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.43 (d, J = 2.3 Hz, 1H), 8.07 (dd, J = 8.6, 2.5 Hz, 1H), 7.99 (dd, J = 7.7, 1.8 Hz, 1H), 7.80 (dd, J = 8.2, 2.0 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.48 - 7.42 (m, 1H), 7.38 - 7.33 (m, 1H), 7.10 (d, J = 7.3 Hz, 1H), 6.53 (d, J = 7.3 Hz, 1H), 4.02 - 3.96 (m, 2H), 1.83 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 167.34, 163.68, 150.30, 148.78, 144.71, 138.57, 137.25, 135.66, 135.55, 133.69, 130.69, 130.20, 128.98, 128.10, 124.90, 124.46, 122.72, 118.49, 118.27, 117.15, 110.59, 109.34, 47.42, 23.43, 11.69. HRMS (ESI): calcd for C 25 H 21 F3N3O3 [M+H] + m / z, 468.1527; found, 468.1530.

[0617] N-(5-(1-oxo-2-propyl-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)isoxazole-5- carboxamide (r100)

[0618] White solid, yield 80%. 1H NMR (600 MHz, Chloroform-d) δ 9.15 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.39 (d, J = 8.6 Hz, 1H), 8.09 (dd, J = 8.6, 2.5 Hz, 1H), 7.85 (dd, J = 8.2, 2.0 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.12 - 7.07 (m, 2H), 6.53 (d, J = 7.3 Hz, 1H), 3.99 (t, J = 7.3 Hz, 2H), 1.86 - 1.81 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, CDC13) δ 162.49, 162.13, 153.70, 151.44, 149.58, 146.68, 137.06, 136.64, 135.50, 133.15, 132.44, 130.47, 127.00, 126.90, 125.90, 114.48, 107.76, 105.58, 51.19, 22.67, 11.35. HRMS (ESI): calcd for C 21 H 19 N4O3[M+H] + m / z, 375.1452; found, 375.1450.

[0619] Lawesson's reagent (555 mg, 1.37 mmol) was added to a solution of compound r46 (500 mg, 1.37 mmol) in toluene (20 mL) and heated to 110 °C overnight. After the reaction was completed, it was cooled to room temperature and the solvent was removed under vacuum. The product was purified by column chromatography on silica gel using petroleum ether: ethyl acetate = 3: 1 as eluent to give N-(5-(3-propyl-4-thioxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)thiopentanamide (zl) as a yellow solid (299 mg, 0.75 mmol, 55% yield) and N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)thiopentanamide (z2) as a yellow solid (104 mg, 0.27 mmol, 20% yield).

[0620] N-(5-(3-Propyl-4-thioxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)thiopentanamide (zl)

[0621] Yellow solid, 45% yield. 1H NMR (600 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.58 (d, J = 8.6 Hz, 1H), 8.55 (d, J = 2.5 Hz, 1H), 8.12 - 8.06 (m, 2H), 7.94 (dd, J = 8.6, 2.6 Hz, 1H), 7.88 (dd, J = 8.5, 2.3 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 3.63 (t, J = 7.2 Hz, 2H), 2.52 (t, J = 7.6 Hz, 2H), 1.43 - 1.33 (m, 4H), 1.02 (h, J = 7.3 Hz, 2H), 0.58 - 0.53 (m, 6H). 13 C NMR (151 MHz, DMSO) δ 205.66, 185.18, 151.85, 148.43, 147.50, 146.35, 135.82, 135.12, 132.66, 131.81, 128.08, 123.41, 122.11, 116.10, 47.63, 47.12, 31.70, 21.90, 21.48, 13.79, 10.75. HRMS (ESI): calcd for C 21 H 25 N4S2[M+H] + m / z, 397.1515; found, 397.1514.

[0622] N-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)thiopentanamide (z2)

[0623] Yellow solid, yield 41%. 1 H NMR (600 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.58 (d, J = 8.6 Hz, 1H), 8.55 (d, J = 2.5 Hz, 1H), 8.12 - 8.06 (m, 2H), 7.94 (dd, J = 8.6, 2.6 Hz, 1H), 7.88 (dd, J = 8.5, 2.3 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 3.63 (t, J = 7.2 Hz, 2H), 2.52 (t, J = 7.6 Hz, 2H), 1.43 - 1.33 (m, 4H), 1.02 (h, J = 7.3 Hz, 2H), 0.58 - 0.52 (m, 6H). 13C NMR (151 MHz, DMSO) δ 205.65, 160.08, 151.84, 148.42, 147.49, 146.31, 135.80, 135.02, 132.56, 131.78, 128.04, 123.51, 122.01, 116.09, 47.57, 47.06, 31.72, 21.92, 21.44, 13.77, 10.84. HRMS (ESI): calcd for C 21 H 25 N4OS[M+H] + m / z, 381.1744; found, 381.1740.

[0624] To a solution of intermediate compound aa (502 mg, 1.16 mmol) in toluene (20 mL) was added Lawesson's reagent (938 mg, 2.32 mmol) and the reaction mixture was heated to 110 °C overnight. After the reaction was completed, the reaction 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 = 5: 1 as eluent to give N-(cyclopropylmethyl)-5-(6-(4,4-difluoropentylsulfanyl amino)pyridin-3-yl)-2-nitrothiobenzamide (ab) as a yellow solid (404 mg, 0.87 mmol, 75% yield), ESI-MS: m / z 465.2 [M+H] + .

[0625] To a solution of intermediate compound aa (502 mg, 1.16 mmol) in toluene (20 mL) was added Lawesson's reagent (938 mg, 2.32 mmol) and the reaction mixture was heated to 110 °C overnight. After the reaction was completed, the reaction 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 = 5: 1 as eluent to give N-(cyclopropylmethyl)-5-(6-(4,4-difluoropentylsulfanyl amino)pyridin-3-yl)-2-nitrothiobenzamide (ab) as a yellow solid (404 mg, 0.87 mmol, 75% yield), ESI-MS: m / z 465.2 [M+H] + .

[0626] To a solution of compound ab (512 mg, 1.10 mmol) in ethanol (16 mL) and water (4 mL) was added reduced iron powder (614 mg, 11.00 mmol) and ammonium chloride (588 mg, 11.00 mmol) and the reaction mixture was heated to 60 °C for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and dichloromethane (100 mL), the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography using dichloromethane as eluent to afford 2-amino-N-(cyclopropylmethyl)-5-(6-(4,4-difluoropentylthioamino)pyridin-3-yl)thiobenzamide (compound ac) as a yellow solid (287 mg, 0.66 mmol, 60% yield), ESI-MS: m / z 435.6 [M+H] + ;

[0627] To a solution of intermediate compound ac (500 mg, 1.15 mmol) in acetonitrile (32 mL) and water (8 mL) was added cyanogen chloride (212 mg, 1.15 mmol) and sodium bicarbonate (290 mg, 3.45 mmol) and the reaction mixture was heated to 80 °C for 4 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and ethyl acetate (100 mL), the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol = 100:1 as eluent to afford N-(5-(2-amino-3-(cyclopropylmethyl)-4-thioxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4,4-difluoropentanethioamide (compound z3) as a yellow solid (381 mg, 0.83 mmol, 55% yield). 1 H NMR (600 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.5 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.11 (dd, J = 8.7, 2.6 Hz, 1H), 8.00 (dd, J = 8.6, 2.3 Hz, 1H), 7.47 (s, 2H), 7.35 (d, J = 8.5 Hz, 1H), 4.87 - 4.72 (m, 2H), 2.61 (t, J = 7.7 Hz, 2H), 2.27 - 2.18 (m, 2H), 1.63 (t, J = 18.9 Hz, 3H), 1.50 - 1.45 (m, 1H), 0.61 - 0.58 (m, 2H), 0.49 - 0.47 (m, 2H). 13C NMR (151 MHz, DMSO) δ 205.48, 188.74, 151.25, 151.18, 145.43, 135.94, 133.07, 131.41, 130.46, 128.75, 125.50, 124.70 (126.27, 124.70, 123.13, t, J = 237.7 Hz), 124.29, 113.43, 51.16, 32.53 (32.70, 32.53, 32.36, t, J = 25.3 Hz), 29.42 (29.46, 29.42, 29.38, t, J = 5.9 Hz), 23.00 (23.17, 23.00, 22.84, t, J = 26.6 Hz), 9.15, 3.56. 19 F NMR (565 MHz, DMSO) δ -89.17. HRMS (ESI): calcd for C 22 H 24 F2N5S2[M+H] + m / z, 460.1436; found, 460.1429.

[0628] In a similar manner, the target compound z4 was prepared.

[0629] N-(5-(2-amino-3-(cyclopropylmethyl)-4-thioxo-3,4-dihydroquinazolin-6-yl)pyridin-2- yl)thiopentanamide (z4).

[0630] Yellow solid, yield 54%. 1 H NMR (600 MHz, DMSO-d6) δ 12.12 (s, 1H), 8.88 (d, J = 8.6 Hz, 1H), 8.78 (d, J = 2.5 Hz, 1H), 8.72 (d, J = 2.3 Hz, 1H), 8.18 (dd, J = 8.7, 2.6 Hz, 1H), 8.03 (dd, J = 8.6, 2.3 Hz, 1H), 7.52 (s, 2H), 7.36 (d, J = 8.6 Hz, 1H), 4.86 - 4.75 (m, 2H), 2.85 (t, J = 7.6 Hz, 2H), 1.79 - 1.71 (m, 2H), 1.49 - 1.44 (m, 1H), 1.36 (h, J = 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H), 0.61 - 0.57 (m, 2H), 0.50 - 0.46 (m, 2H). 13C NMR (151 MHz, DMSO) d 205.46, 188.78, 151.38, 151.25, 145.76, 145.26, 135.24, 133.23, 132.47, 131.08, 129.21, 125.41, 124.28, 116.36, 51.17, 46.98, 31.71, 21.44, 13.78, 9.15, 3.56. HRMS (ESI): calcd for C 22 H 26 N5S2[M+H] + m / z, 424.1624; found, 424.1620.

[0631] To a mixture of intermediate compound o16 (1117 mg, 3.29 mmol), methyl 5- bromoaminobenzoate c1 (504 mg, 2.19 mmol) and potassium carbonate (605 mg, 4.38 mmol) in 1,4-dioxane (32 mL) and water (8 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (161 mg, 0.22 mmol) and the reaction was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The crude product was dissolved in dichloromethane and methanol, the potassium carbonate was removed by suction filtration and the filtrate was concentrated. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol = 200:1 as eluent to give methyl 2-amino-5-(6-(4,4-difluoropentylamino)pyridin-3- yl)benzoate ad1 as a white solid (589 mg, 1.62 mmol, 74% yield), ESI-MS: m / z 364.3 [M+H] + .

[0632] To a solution of intermediate ad1 (200 mg, 0.55 mmol) in acetonitrile (15 mL) was added ethyl isothiocyanate (94 mg, 0.72 mmol) and the reaction was stirred at room temperature for 1 h. After completion of the reaction, the solvent was removed under vacuum and the product was purified by column chromatography on silica gel using dichloromethane:methanol = 200:1 as eluent to give methyl 5-(6-(4,4-difluoropentylamino)pyridin-3-yl)-2-(3- (ethoxycarbonyl)thioureido)benzoate ae1 as a white solid (218 mg, 0.44 mmol, 80% yield), ESI-MS: m / z 495.2 [M+H] + .

[0633] To a solution of intermediate ae1 (495 mg, 1.00 mmol) and l-ethyl-(3- dimethylaminopropyl)carbodiimide hydrochloride (383 mg, 2.00 mmol) in acetone (25 mL) was added cyclopropylmethylamine fl (107 mg, 1.50 mmol) and the reaction was stirred at room temperature for 12 h. After completion of the reaction, the solvent was removed under vacuum and the product was purified by column chromatography on silica gel using dichloromethane:methanol = 200:1 as eluent to give (3-(cyclopropylmethyl)-6-(6-(4,4-difluoropiperidin-l- yl)pyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)carbamic acid ethyl ester (agl) as a white solid (400 mg, 0.80 mmol, 80% yield). 1 H NMR (600 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.73 (t, J = 1.7 Hz, 1H), 8.37 (d, J = 2.3 Hz, 1H), 8.21 - 8.17 (m, 2H), 8.13 (dd, J = 8.5, 2.3 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 4.28 - 4.23 (m, 2H), 3.94 (t, J = 7.7 Hz, 2H), 2.64 - 2.60 (m, 2H), 2.25 - 2.20 (m, 2H), 1.64 (t, J = 18.8 Hz, 3H), 1.45 - 1.39 (m, 3H), 1.32 - 1.28 (m, 1H), 0.54 - 0.50 (m, 2H), 0.45 - 0.4 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 172.35, 161.81, 155.23, 152.16, 151.15, 149.33, 145.25, 135.77, 132.34, 130.53, 129.86, 124.72 (126.29, 124.70, 123.16, t, J = 237.8 Hz), 124.65, 123.68, 116.45, 113.38, 64.45, 47.57, 32.55 (32.73, 32.53, 32.37, t, J = 25.5 Hz), 29.48 (29.50, 29.48, 29.46, t, J = 4.3 Hz), 23.04 (23.23, 23.04, 22.85, t, J = 27.1 Hz), 14.85, 10.82, 3.54. 19 F NMR (565 MHz, DMSO) δ -89.17. HRMS (ESI): calcd for C 25 H 28 F2N5O4[M+H] + m / z, 500.2014; found, 500.2011.

[0634] Ethyl isothiocyanate (196 mg, 1.50 mmol) was added to a solution of intermediate ac1 (500 mg, 1.15 mmol) in acetonitrile (20 mL) and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the solvent was removed in vacuo and the product was purified by column chromatography on silica gel using dichloromethane:methanol = 200:1 as eluent to give intermediate compound af1 as a yellow solid (533 mg, 0.94 mmol, 82% yield), ESI-MS: m / z 566.2 [M+H] + .

[0635] Triethylamine (267 mg, 2.64 mmol) was added to a solution of af1 (500 mg, 0.88 mmol) in acetone (20 mL), followed by the addition of l-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg, 1.14 mmol) and the reaction was stirred at room temperature overnight. After the reaction was completed, the solvent was removed in vacuo and the product was purified by column chromatography on silica gel using dichloromethane:methanol = 300:1 as eluent to give (3-(cyclopropylmethyl)-6-(6-(4,4-difluoropentylthioamino)pyridin-3-yl)-4-thioxo-3,4-dihydroquinazolin-2-yl)carbamic acid ethyl ester (ah1) as a yellow solid (533 mg, 0.94 mmol, 82% yield), ESI-MS: m / z 532.5 [M+H] + .

[0636] Tetrabutylammonium fluoride (523 mg, 2.00 mmol) was added to a solution of ah1 (532 mg, 1.00 mmol) in tetrahydrofuran (30 mL) and the reaction was refluxed for 6 h. After the reaction was completed, the solvent was removed in vacuo and the product was purified by column chromatography on silica gel using dichloromethane:methanol = 100:1 as eluent to give N-(5-(2-amino-3-(cyclopropylmethyl)-4-thioxo-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-4,4-difluoropentanethioamide (z3) as a yellow solid (391 mg, 0.85 mmol, 85% yield). 1H NMR (600 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.5 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.11 (dd, J = 8.7, 2.6 Hz, 1H), 8.00 (dd, J = 8.6, 2.3 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 5.08 - 4.98 (m, 2H), 4.87 - 4.72 (m, 2H), 2.61 (t, J = 7.7 Hz, 2H), 2.27 - 2.18 (m, 2H), 1.63 (t, J = 18.9 Hz, 3H), 1.57 - 1.51 (m, 3H), 1.50 - 1.45 (m, 1H), 0.61 - 0.58 (m, 2H), 0.49 - 0.47 (m, 2H). 13 C NMR (151 MHz, DMSO) δ 205.47, 188.75, 155.24, 151.23, 151.19, 145.45, 135.96, 133.06, 131.40, 130.48, 128.77, 125.52, 124.70 (126.28, 124.70, 123.12, t, J = 237.6 Hz), 124.27, 113.41, 64.47, 51.15, 32.53 (32.71, 32.53, 32.35, t, J = 25.5 Hz), 29.42 (29.44, 29.42, 29.40, t, J = 5.8 Hz), 23.00 (23.16, 23.00, 22.85, t, J = 26.5 Hz), 14.86, 9.14, 3.55. 19 F NMR (565 MHz, DMSO) δ -89.17. HRMS (ESI): calcd for C 25 H 28 F2N5O2S2[M+H] + m / z, 532.1647; found, 532.1649.

[0637] To a solution of 2-bromo-5-(4,4,5,5-tetramethyl-l,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) was added [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium (137 mg, 0.19 mmol) and the reaction was allowed to proceed for 1.5 h. Water (5 mL) was added and the reaction was allowed to proceed for an additional 0.5-2.5 h. Upon completion, the reaction was cooled to room temperature and the solvent was removed in vacuo. The crude product was dissolved in dichloromethane and methanol, the potassium carbonate was removed by suction filtration and the filtrate was concentrated. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol = 50:1 as eluent to give 6-(6-bromopyridin-3-yl)-3-propylquinazolin-4(3H)-one (compound q1) as a white solid (489 mg, 1.42 mmol, 76% yield), ESI-MS: m / z 345.3 [M+H] + .

[0638] To a solution of 6-(6-bromopyridin-3-yl)-3-propylquinazolin-4(3H)-one q1 (300 mg, 0.87 mmol), 2-pyrrolidinone (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) was added cuprous iodide (3.8 mg, 0.02 mmol) and the reaction was allowed to proceed at 110 °C for 4 h. Upon completion, the reaction was cooled to room temperature and the solvent was removed in vacuo. The crude product was dissolved in dichloromethane and methanol, the potassium carbonate was removed by suction filtration and the solvent was removed in vacuo. The product was purified by column chromatography on silica gel using dichloromethane:methanol = 80:1 as eluent to give 6-(6-(2-oxopyrrolidin-l-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (compound r87) as a white solid (237 mg, 0.68 mmol, 78% yield). 1H 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 C 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.

[0639] In a similar manner, compounds r88-91 were prepared using different compound p and different compound k.

[0640] 6-(6-(2-oxopiperidin-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (r88)

[0641] White solid, yield 78%. 1 H 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). 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 21 H 23 N4O2[M+H] + m / z, 363.1816; found, 363.1805.

[0642] 6-(6-(2-oxoazepan-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (r89)

[0643] White solid, yield 75%. 1 H 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 C 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.

[0644] 6-(6-(4-methyl-2-oxopiperidin-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (r90)

[0645] White solid, yield 80%. 1H 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 C 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.

[0646] (S)-6-(6-(4-ethyl-2-oxoazepan-1-yl)pyridin-3-yl)-3-propylquinazolin-4(3H)-one (r91)

[0647] White solid, yield 77%. 1 H 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). 13C 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.

[0648] Test Example 1: Proliferation inhibition activity of the compounds of the present application on various tumor cells

[0649] The lung cancer, breast cancer, cervical cancer, ovarian cancer, leukemia, liver cancer, gastric cancer, renal cancer, colorectal cancer, prostate cancer and pancreatic cancer cells were cultured in a cell culture medium containing 10% fetal bovine serum at 37°C in a 5% carbon dioxide saturated incubator. The cells in the logarithmic growth phase were inoculated in a 96-well plate (MMT or CCK8 method for measuring OD value) or a 12-well plate (cytometry counting method), and after adhering, the corresponding concentration of drug was added and cultured for 72 hours. The OD value was measured at 450 nm or 490 nM after directly counting or adding MTT or CCK8 for a corresponding time, and the inhibition rate was calculated.

[0650] As shown in Tables 1, 2 and 3, the compounds used in the present application showed very strong proliferation inhibition activity on lung cancer, breast cancer, cervical cancer, ovarian cancer, leukemia, liver cancer, gastric cancer, renal cancer, colorectal cancer, prostate cancer and pancreatic cancer, lung adenocarcinoma with EGFR-TKI resistance, TP53 mutation, TTN mutation and KRAS mutation, and related tumor cells with high expression of PI5P4Kγ, and the IC 50 of most of the compounds was below 50 nM.

[0651] The proliferation inhibition activity of the compounds in Table 1 on various tumor cells is expressed by IC 50 value (unit: μM), which is the average of three data.

[0652] The proliferation inhibition activity of the compounds in Table 2 on various tumor cells is expressed by IC 50 value (unit: μM), which is the average of three data.

[0653] The inhibitory activity of the compounds on the proliferation of Mia PACA-2 cells is shown in Table 3 as IC 50 values (in μM) are the average of three data.

[0654] Test Example 2: Cytotoxicity test of some compounds of the present application on normal cells (PBMC)

[0655] Human peripheral blood mononuclear cells (PMBC) were used to test the toxicity of the compounds used in the present application. As shown in Table 4, the IC 50 values of most of the compounds were greater than 40 μM, higher than the positive control ARUK2001607, comparable to Compound 40, which indicated that these compounds had high safety.

[0656] The inhibitory activity of some compounds on the proliferation of normal cells (PBMC) is shown in Table 4 as IC 50 values (in μM) are the average of three data.

[0657] Test Example 3: PI5P4Kγ inhibitory activity of the compounds of the present application

[0658] The PI5P4Kγ inhibitory activity test of the compounds was mainly completed in the KINOMEscan screening platform of Eurofins. The platform reflects the inhibitory activity of the compounds by determining the ability of the compounds to compete with the ligand of PI5P4Kγ. When the compounds compete with the ligand to bind to the kinase site, or hinder the binding of the ligand to PI5P4Kγ after binding to PI5P4Kγ, the inhibitory activity is exhibited. The inhibition rate reflects the affinity strength of the compound to the target.

[0659] The target binding inhibition activity test was conducted on the compounds of the present application, and it was found that the compounds in the present application all showed strong binding activity to 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, r71, r94-100 and z1-4 to PI5P4Kγ all exceeded 90%, and the inhibition rates of r61, r62, r66, r68, r95, r96, z3 and z4 to PI5P4Kγ reached 100%. In addition, the inhibition rates of r28, r30, r44, r45, r49, r72 and r78 all exceeded 85%. It can be seen that the PI5P4Kγ inhibitors r61, r62, r66, r68, r95, r96, z3 and z4 with stronger target inhibition activity were obtained by further structural optimization of r46. The results are shown in Table 5.

[0660] Table 5 Inhibition activity of some compounds to PI5P4Kγ.

[0661] Test Example 4: Target inhibition activity of compound r46

[0662] (1) Subtype selectivity test method: The kinase inhibition activity of r46 to PI5P4Kα was completed by using the Kinase Profiler platform of Eurofins Company (using radioisotope labeling method, which is the gold standard for kinase activity test). The binding inhibition activity of r46 to PI5P4Kβ and PI5P4Kγ was completed by using the ScanMax platform of Eurofins Company (determination of target binding activity (Kd value), which can identify allosteric inhibitors of kinases).

[0663] (2) ITC experimental method: isothermal titration calorimetry (ITC) technique is the "gold standard" for verifying direct intermolecular interactions, and the ITC experimental results directly reflect the thermodynamic conditions of intermolecular interactions, and the results have high reliability. The present application uses the ITC method to investigate the main interaction type of r46 and PI5P4Kγ. The full-length protein of PI5P4Kγ is purified, then dialyzed in a buffer containing 20 mM sodium phosphate, pH 8, 150 mM sodium chloride and 10% (v / w) glycerol, then frozen in about 300 μL of liquid nitrogen at 1-4 μM, and stored at -80°C. The buffer is added to the sample protein, and the reference material and the test material 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 material is injected into the sample, and the baseline value of the heat effect signal is recorded. The test material 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 complete. According to the measurement results, calculate the thermodynamic parameters such as thermodynamic equilibrium constant, enthalpy change and entropy change. All experiments were carried out in 20 mM sodium phosphate, 150 mM sodium chloride, 10% glycerol, 0.5 mg / mL BSA, 0.1% (v / v) DMSO, pH 8 buffer. The ligand is dissolved in DMSO and then diluted into the buffer immediately before the experiment. All experiments were carried out at 30°C with high feedback mode and stirring speed of 806 rpm. (Malvern VP-ITC) or 750 pm. (Malvern ITC-200), filter time is 1 second. In order to establish a flat baseline, a long pre-injection delay (~1000 s) was used. The inhibition kinetics ITC experiment was 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 was added to the cell solution to avoid substrate depletion. The initialization ITC kinetics experiment was carried out by adding TRH in the reaction cell and PI5P4Kγ / inhibitor in the syringe. The syringe solution was equilibrated at 30°C for about 2 hours before starting the experiment. The ligand is dissolved in DMSO and then diluted into the buffer immediately before the experiment. DMSO was added to the cell solution to match the syringe solution in order to minimize the heat of dilution. In order to correct the tilted baseline, a baseline correction procedure was implemented for the inhibition kinetics and initialization experiments, which is a common artifact in ITC experiments. This process includes fitting a line to the final flat portion of each injection (typically lasting about 200 seconds). Each line was extrapolated to the beginning of the respective injection in order to establish a complete baseline for each injection. The complete baseline was then subtracted from the raw data of each injection to obtain baseline-corrected data.

[0664] (3) Kinase profiling method: The selective binding of compound r46 to 486 kinds of kinases was investigated using the ScanMax platform of Eurofins (determination of target binding activity (Kd value), capable of identifying allosteric inhibitors of kinases).

[0665] Co-crystal structure analysis experimental method: PI5P4Kγ was expressed in E. coli BL21 (DE3) Gold using pET28b vector. The expression was induced by 0.1 mM IPT, cultured at 18°C for 16 h, and harvested by centrifugation. The protein consists of His32 to Ala421 residues, with the region between residues 300-341 deleted. The tev-cleaved protein was purified by affinity chromatography and size exclusion chromatography (Superdex 75). The structure of the complex of ligand and receptor was generated by co-crystallization of human PI5P4Kγ and target compound solution. The purified protein was incubated overnight at 4°C in 20 mM N-(2-hydroxyethyl) piperazine-N'-sulfamic acid (HEPES) pH 7.5, 150 mM NaCl and 0.5 mM tris(2-carboxyethyl)-phosphine [15.5 mg / mL] with 10 mM target compound. The complex crystals were formed in 22% w / v Peg 3350, 0.3 M ammonium tartrate and 100 mM PCPT (propionic acid sodium, sodium acetate trihydrate and bis-tripropylamine) solution at pH 7.5 at 20°C. When AMP-PNP was used, the protein was first incubated with 4 mM AMP-PNP (buffer) for 2 hours, then with 10 mM 40 overnight, and then the crystallization plate was set. X-ray data collection, rapid freezing, and X-ray diffraction data collection at 100 k. Data processing was performed using XDS and Aimless software. Diamond Light Source synchrotron facility, Oxford, UK, beamlines (I03 and I24 for 7QIE and 7QPN, respectively). Data processing was performed using XDS and Aimless software. The phases required for the determination and analysis of the structure were obtained by molecular replacement (PHASER, CCP4) using the previously solved structure of human PI5P4Kγ (PDB code: 2GK9) as the search model. Subsequent model building and refinement were performed according to standard protocols of the CCP4 and COOT software packages. TLS was improved (REFMAC5, CCP4) to make the electron density map lower in r factor and higher in quality. Ligand parameterization and generation of the corresponding library file were performed using ACEDRG (CCP4). The final model Ramachandran plot showed that for 7QIE and 7QPN, the residues in the most favorable region were 91.3% and 92.3%, respectively, and the residues in the additional allowed region were 7.0% and 5.0%, respectively.

[0666] After the good anti-tumor activity of the above-mentioned compound was confirmed, the target inhibition activity of r46 was further investigated. As shown in FIG. 1, the ScanMAX platform test results showed that the Kd value of r46 was 6.55 nM. In addition, the Kd values of compound r46 for PI5P4Ks of other two subtypes PI5P4Kα and PI5P4Kβ were both greater than 20 μM, indicating that r46 had strong subtype selectivity for PI5P4Kγ. In order to investigate the interaction type of r46 and PI5P4Kγ, the ITC method was used to investigate the interaction thermodynamics. As shown in FIG. 1, the Kd value of r46 binding to PI5P4Kγ was 123 nM, ΔH = -5.76 ± 0.02 Kcal / mol, indicating that the interaction of r46 and PI5P4Kγ was mainly driven by enthalpy, and the interaction was usually generated by hydrogen bond, ionic bond and van der Waals force.

[0667] In order to further confirm the inhibition activity of compound r46 to other kinases, the binding inhibition activity of 1 μM r46 to 486 kinds of kinases was screened. As shown in FIG. 2, r46 could selectively inhibit PI5P4Kγ, and the inhibition rate reached 99%, while there was no obvious inhibition activity to other 485 kinds of kinases. In summary, r46 is a high selectivity and high activity PI5P4Kγ inhibitor.

[0668] To determine the binding mode of r46 to PI5P4Kγ, the crystal structure of the complex was further determined. As shown in Figure 3, the N1of the quinazolinone, the N atom on the pyridine ring, and the carbonyl of the amide side chain at C6form three key hydrogen bonds with Met206, Lys152, and Ile375, respectively. The 6-(pyridin-3-yl)quinazolin-4(3H)-one nucleus forms six interactions with the Met162, Leu201, Phe207, Lys216, and Leu376, etc. of the hydrophobic pocket of the active site of PI5P4Kγ, including π-π T shaped, π-sigma, π-sulfur, and van der Waals forces. In addition, the amide side chain on the pyridine ring reaches into a hydrophobic allosteric pocket that is a subversion of the orthosteric site. Unlike r46, the only known orthosteric inhibitor of PI5P4Kγ, ARUK2001607, was found to not interact with the hydrophobic allosteric pocket. During the crystal structure determination, it was found that the alkyl chain on the pyridine ring of r46, although there is a high-energy conformation, does not cause its electron cloud to be unclear, indicating that its binding conformation in the binding pocket is relatively stable, which is likely due to the key interactions with multiple amino acids such as Met162 and Leu201 that stabilize its binding conformation. However, the presence of a high-energy conformation can lose some binding energy, affecting the activity of the compound. Therefore, by stabilizing the active conformation in subsequent structural modifications, further improving the target inhibition activity of the compound, more active compounds r61, r62, r66, and r68 were obtained. In summary, compound r46 is a new PI5P4Kγ inhibitor that acts on both the orthosteric site and the allosteric site of PI5P4Kγ.

[0669] Test Example 5: In vivo efficacy test

[0670] The nude mice fed with basal feed were put into a sterile feeding room, and it was found that their activities, food and water intake were normal, and their body weight was about 20 g. Five groups (6 mice in each group) were set up, including a control group, high, medium and low dose groups of r46, and a positive control group (known PI5P4Kγ inhibitor ARUK2001607). After 3 days of adaptive feeding, a nude mouse xenograft tumor model of H1975-OR cells was established. The cells in the logarithmic growth phase (after subculture 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, the cells were resuspended with 1xPBS and adjusted to the appropriate density. In a sterile operating table, a syringe was used to extract 0.2 mL of the above prepared cell suspension and inoculate it into the right axillary of the nude mice sterilized with 75% alcohol. After inoculation, a lump-like protrusion could be seen at the inoculation site. About 3 days after inoculation, tumors could be seen growing subcutaneously at the inoculation site. After 10 days, the tumors grew to an average of about 80 mm3, and oral administration was started for 3 weeks. According to the measurement results, the relative tumor volume (RTV) was calculated, 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 antitumor activity is the relative tumor proliferation rate T / C (%), T / C (%) = TRTV / CRTV x 100%. TRTV: RTV of the treatment group; CRTV: RTV of the negative control group; the evaluation criteria for efficacy are: T / C % > 40% is ineffective; T / C % ≤ 40%, and p < 0.05 after statistical processing is effective. Tumor inhibition rate (%) = (1 - average tumor weight of the drug group / average tumor weight of the negative control group) x 100%. Tumor growth inhibition rate < 40% is ineffective; tumor growth inhibition rate ≥ 40%, and p < 0.05 after statistical processing is effective. After the end of the experiment, the experimental animals were sacrificed by anesthesia, the tumors were peeled off, the tumor weight was measured, and the tumor inhibition rate was calculated.

[0671] As shown in Figure 4, 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 has high target inhibition activity and selectivity, but also has strong in vivo and in vitro anti-tumor activity. Compound r46 can effectively inhibit the growth of H1975OR cell subcutaneous xenograft tumors and their lung metastasis. H1975OR cells are TP53 mutant and EGFR-TKI resistant non-small cell lung cancer cells, which further verify the in vivo efficacy of r46 on TP53 mutant and EGFR-TKI resistant tumors.

[0672] To clarify the in vivo anti-tumor activity of r46 on TP53 and KRAS double-mutated pancreatic cancer, we selected TP53 and KRAS double-mutated pancreatic cancer cell line Mia PACA-2 to construct a xenograft tumor model to investigate the in vivo anti-tumor efficacy of r46. The results showed that, as shown in Figure 5, the tumor inhibition rate of r46 at 20 mg / kg reached 59.2%, which was stronger than that of the positive control drug gemcitabine at the same dose, and the in vivo anti-tumor activity was significant.

[0673] In addition to the above two models, we also investigated the anti-tumor activity of r46 on HCC827 cells, which are currently known to have the highest expression of PI5P4kγ. As shown in Figure 6, the tumor inhibition rate of r46 at 20 mg / kg reached 65.69%, which was better than that of PI5P4Kγ inhibitor ARUK2001607 at the same dose.

[0674] Test Example 6: Inhibition of each subtype of P450 enzyme by compound r46

[0675] 1) Test method: Drug concentration: The drug was prepared into a stock solution with a mass concentration of 19.5 mg / m L using a Na2HPO4-Na H2PO4 (pH 7.4) solution, and then diluted with a Na2HPO4-Na H2PO4 solution to have a final mass concentration of 6.5, 32.5, 65.0, 325.0, 650.0, 3250.0, and 6500.0 μg / m L during incubation. Positive substrate: CYP1A2: phenacetin; CYP2C9: diclofenac; CYP2C19: mephenytoin; CYP3A4: midazolam or testosterone; CYP2D6: butoprozol; CYP2C8: paclitaxel; CYP2B6: bupropion. Detection method: LC-MS / MS. Metabolic probe product: CYP1A2: acetaminophen-D4; CYP2C9: 4'-hydroxydiclofenac-[13C6]; CYP2C19: hydroxymephenytoin-D3; CYP3A4: 1-hydroxy-midazolam-D4 or chenodeoxycholic acid; CYP2D6: 1-hydroxybutoprozol-[D9] maleate; CYP2C8: 6a-hydroxypaclitaxel-[D5]; CYP2B6: hydroxybupropion-D6. Source: human liver microsomes. Preparation: differential centrifugation method, the final mass concentration of mixed human liver microsomal protein was 0.3 mg / m L, all operations were carried out at 4°C, and the microsomal protein concentration was determined by the Lowry method using bovine serum albumin as a standard control. The prepared liver microsomes were stored in a-80°C refrigerator for standby use. Probe substrate concentration: 30 μM phenacetin; 10 μM diclofenac; 35 μM mephenytoin; 10 μM butoprozol; 5 μM midazolam or 80 μM testosterone; 10 μM paclitaxel; 70 μM bupropion. Inhibitor: CYP1A2: a-naphthoflavone; CYP2C9: sulfaphenazole; CYP2C19: omeprazole; CYP3A4: ketoconazole; CYP2D6: quinidine; CYP2C8: nicardipine; CYP2B6: clopidogrel. The experiment was divided into three groups, negative control: mixed human liver microsomes and blank Na2HPO4-NaH2PO4 buffer were pre-incubated at 37°C for 15 min, then the probe substrate of each CYP450 subenzyme and the coenzyme β-NADPH of CYP450 were added, and incubated at 37°C for 30 min. Positive control group: mixed human liver microsomes were pre-incubated with the selective inhibitor of each subenzyme at 37°C for 15 min, then the probe substrate of each subenzyme and β-NADPH were added, and incubated at 37°C for 30 min. Drug group: mixed human liver microsomes were pre-incubated with drugs (6.5, 32.5, 65.0, 325.0, 650.0, 3250.0, and 6500.0 μg / m L) at 37°C for 15 min, then the probe substrate of each subenzyme and β-NADPH were added, and incubated at 37°C for 30 min. Each group had three parallel samples.

[0676] 2) Experimental results: In general, if the IC 50 <1.0 μM is considered strong inhibitory activity, IC 50 = 1-10 μM is considered moderate inhibition, and IC 50 > 10 μM is considered mild inhibition or no inhibition. As shown in Table 6, the IC 50 > 30 μM for CYP450 enzymes 1A2, 2C19 and 2D6. The IC 50 > 20 μM for CYP450 enzymes 2C9 and 3A4. These results indicate that r46 has mild or no inhibition for each of the CYP450 subtypes.

[0677] Table 6 Inhibition of CYP450 enzymes by compound r46

[0678] Test Example 7: Acute toxicity evaluation of compound r46

[0679] 1) Experimental method: Kunming mice were divided into four groups according to gender and body weight, with half male and half female, and each group of 20 mice, divided into two cages. After 12 hours of fasting without water, the drug administration group was given 400 mg / kg, 200 mg / kg and 100 mg / kg by gavage once, and the blank control group was given the same volume of solvent (DMSO: Solutol HS-15: physiological saline = 5:10:85) by gavage. The LD 100 values (100% mortality), LD0values (0% mortality) and corresponding dose group interval r values were determined to determine the LD 50 values. Changes in body weight, activity, behavior, diet, fur color and death were observed within 14 days, and the entire set of tissues was collected, weighed, and subjected to systematic clinical pathology studies.

[0680] 2) Experimental results: As shown in Figure 7, after a single gavage administration of r46 at a concentration of 400 mg / kg or less, the mice in each group did not die after being fed for 14 days. In addition, the mice in the drug administration group had no significant effect on liver function indicators ALT and AST, kidney function indicators BUN, and heart function indicators LDH. The body weight and activity of the mice were also not affected after administration. The effects of 400 mg / kg treatment on the heart, liver, spleen, lung and kidney of the mice were analyzed using HE staining, and the results are shown in Figure 7E. The heart, liver, spleen, lung and kidney of the mice showed no obvious damage. These results indicate that r46 has good safety.

[0681] Test Example 8: Investigation of the genetic toxicity of compound r46 by Ames test

[0682] 1) Experimental procedure: Ames test was performed according to the recommendations of the OECD 471 test guideline. Bacteria of Salmonella typhimurium were incubated in nutrient broth for 10 hours with shaking (37°C, 150 rpm) until the exponential growth phase was reached and the treatment was completed within 3 hours after the end of the incubation to ensure that the bacteria were in a stable growth phase. The mutagenic evaluation was performed using the "Ames" plate incorporation method, where bacterial suspension (100 μl), test compound or vehicle (100 μl for plate incorporation, 50 μl for pre-incubation) or positive control (100 μl) were mixed with S9 mix (or phosphate buffer without S9-mix) (500 μl) and incubated directly in 2 ml top agar containing histidine, biotin and tryptophan (50°C) and the mixture was poured onto selective agar plates and incubated at 37°C for 3 days. Table 7 below lists the positive controls for each strain (including concentration) in the presence and absence of S9-mix. Colony counts were performed using an Ames colony counter and the Ames Study Manager software (Instem, UK) was used to generate tabular results. Two replicates were set up for each concentration level. The concentration gradient for r46 was: 1000 μg / well, 500 μg / well, 250 μg / well, 125 and 62.5 μg / well. (S9 metabolic activation system is a test system with cofactors and microsomal fraction extracted from liver treated with enzyme inducers).

[0683] Table 7 Ames test conditions for compound r46

[0684] 2) Experimental results: The results of the Ames test showed that compound r46 did not cause a significant increase in the number of revertant bacteria for the four strains TA98, TA100, TA97a and TA102 at the highest concentration of 1000.0 μg / well (concentration equivalent to 5000.0 μg / dish in standard Ames test) in the presence or absence of the S9 metabolic activation system. This indicates that the tested compound r46 does not have genotoxic effects on the four strains TA98, TA100, TA97a and TA102 in the presence or absence of the metabolic activation system (Figure 8). The above results of r46 indicate that the new PI5P4Kγ selective inhibitor compound r46 is a safe and efficient anti-tumor candidate compound.

[0685] Test example 9: Inhibition activity of r46 on hERG

[0686] 1) Experimental procedure: The cells used in this test were CHO cell lines stably expressing hERG channels transfected with hERG cDNA

[0687] CHO hERG cells were grown in flasks containing the following medium (all from Invitrogen): Hams F12 medium, 10% (v / v) inactivated fetal bovine serum, 100 μg / ml hygromycin B, 100 μg / ml Geneticin. CHO hERG cells were grown in flasks containing the above medium and incubated at 37°C in a 5% CO2incubator. Twenty-four to forty-eight hours prior to electrophysiological experiments, CHO / hERG cells were transferred to circular glass coverslips placed in flasks and grown under the same conditions as above. The density of CHO hERG cells on each circular coverslip was adjusted to meet the requirement that most cells be isolated and single. A manual patch clamp system (HEKA EPC-10 signal amplifier and digital conversion system, available from HEKA Electronics, Germany) was used to record whole-cell currents. Circular coverslips with CHO hERG cells growing on the surface were placed in an electrophysiological recording bath under an inverted microscope. The recording bath was continuously perfused with extracellular solution at a rate of approximately 1 ml / min. Conventional whole-cell patch clamp current recording techniques were used during experiments. Experiments were performed at room temperature (-25°C) unless otherwise stated. Cells were clamped at -80 mV. The clamping voltage was depolarized to +20 mV to activate the hERG potassium channel, and 5 seconds later, clamped to -50 mV to eliminate inactivation and generate tail currents. The peak of the tail current was used as the measure of the size of the hERG current. After the hERG potassium current recorded in the above steps reached a steady state under continuous perfusion of extracellular solution in the recording bath, the test drug was applied until the inhibition of the hERG current reached a steady state. The coincidence of the last three consecutive current recording lines was used as the criterion for a steady state. After reaching a steady state, the extracellular solution was used to wash until the hERG current returned to the size before the drug was applied. One or more drugs, or multiple concentrations of the same drug, could be tested on one cell, but extracellular solution was used to wash between different drugs. Cisapride (Sigma) was used as a positive control in experiments to ensure the quality of the cells used. Compound r46 was prepared as a 10 mM stock solution in DMSO. To obtain the IC50of the compound, a series of 2-fold dilutions were prepared in DMSO, and then diluted 1:100 in extracellular solution. The IC50was determined by measuring the current inhibition at each concentration of the compound and fitting the data to a logistic equation. The results are shown in Table 1. 50We selected the following concentrations (30, 10, 3, 1, 0.3 and 0.1 μM) for testing. Before the experiment, the stock solutions of 3, 1, 0.3 and 0.1 mM were diluted with DMSO in a gradient manner, and then diluted with extracellular solution to the final μM test concentration. The test concentration of positive control Cisapride was 0.1 μM. All compound solutions were routinely sonicated and shaken 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.

[0688] 2) Experimental results: As shown in Figure 9, the inhibition of hERG by compound r46 was weak, with an IC 50 >30 μM. Moreover, its inhibition rate on hERG at a concentration of 30 μM was still less than 40%. By calculation with SPSS software, the IC 50 value was 72.59 μM. In summary, compound r46 had no significant toxic side effects on the heart.

[0689] Test Example 10: Subacute toxicity experiment of r46

[0690] Half of the Kunming mice were divided into four groups according to gender and body weight, namely the control group (female and male groups) and the administration group (female and male groups), with 20 mice in each group. After fasting for 12 h without water, the administration group was given 300 mg / kg, 100 mg / kg, 30 mg / kg, respectively, by continuous gavage for 28 days, and the blank control group was given the same volume of solvent (DMSO: Solutol HS-15: physiological saline at 5:10:85) by gavage. The changes in body weight, activity, behavior, diet, fur color and whether there was death were observed within 28 days, and the complete set of tissues was collected, weighed, and subjected to systematic clinical pathology research.

[0691] As shown in Figure 10, after 28 days of continuous gavage administration of r46 at a concentration of 100 mg / kg and below, no mice in each group died. In addition, the administration group of mice had no significant effect on the liver function indicators ALT and AST, the kidney function indicators CREA and UREA, and the heart function indicators LDH and CK-MB. The body weight, eating and activity ability of the mice after administration were also not affected. The above results show that long-term administration of r46 at 100 mg / kg has good safety. Since the tumor inhibition rate of compound r46 at 20 mg / kg has reached 93.73%, the safety of r46 is good.

[0692] Test Example 11: Pharmacokinetic study

[0693] Healthy adult Kunming mice (body weight 20-22 g, half male and half female). Fasting for 12 hours before the experiment (free water). Single oral administration of 20 mg / kg, mixed with 5% DMSO and 95% olive oil, gavage volume 5 mL / kg. At 9 time points (0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h), 6 mice at each time point, whole blood was collected by the method of orbital blood collection. The blood samples were collected into heparin sodium anticoagulation tubes, centrifuged at 3000 rpm for 10 minutes at 4°C, the upper serum was collected, and stored in a -80°C refrigerator.

[0694] Agilent 1290UPLC-AB Sciex 6500+ mass spectrometry system was used. Chromatographic column: Agilent ZORBAX SB-C18 (2.1x50mm, 1.8μm). Mobile phase: acetonitrile-0.1% formic acid aqueous solution (gradient elution). Mass spectrometry conditions (AB SCIEX API5500 mass spectrometer, USA) are as follows: ion source mode is positive ion mode (ESI+); curtain gas (CUR) pressure 20 psi, collision gas (CAD) pressure 9 levels; ion spray voltage (IS) 5500V, ion source temperature (Tem) 500℃; ion source gas 1 (GS1) and ion source gas 2 (GS2) pressure are both 50 psi.

[0695] Take 20μL of plasma sample in an EP tube, add 20μL of dexamethasone internal standard solution with a concentration of 500ng / mL, then add 160μL of chromatographic grade methanol, vortex well, and centrifuge at 12000rpm for 10 minutes. After centrifugation, transfer the supernatant to the sample bottle, and analyze according to the above chromatography-mass spectrometry conditions, each sample is injected twice.

[0696] As shown in Table 8, compared with compound r46, after introducing amino at position 2 of compound r46 quinazolinone and double fluorine at position 4 of pentanamide, the C ax and AUC0-∞ increase, especially when the amide bond in the compound is replaced by sulfur, not only the C ax and AUC0-∞ increase significantly, and the t1 / 2 is also greatly extended. For example, compared with compound r46, the C ax and AUC0-∞ of r95 and z3 increase significantly, and the t 1 / 2 is also greatly extended. The above results show that the replacement of the amide bond in the compound in the present application significantly improves the oral bioavailability of the compound.

[0697] Table 8 Pharmacokinetic parameters of some compounds in the present application in mice

[0698] The above has exemplarily described the embodiments of the technical scheme of the present application. It should be understood that the protection scope of the present application is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principle of the present application shall be included in the protection scope of the claims of the present application.

Claims

1. A compound of formula (I), its tautomers, stereoisomers, isotopic labels, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs: wherein: W is selected from O or S; M is selected from O or S; Y is selected from N or 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 identical or different and independently of each other selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 1-6 heteroalkyl; R1 is selected from H, is unsubstituted, or is optionally composed of one, two, or more R1s. 11 The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl, 5-10 quinone heteroaryl; each R 11 They may be the same or different, and are independently selected from CN, halogen, C2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl, C 1-6 Alkyl-C 6-10 Aryl; R2is selected from H, OH, NH2, halo, C 1-6 alkyl, C 1-6 heteroalkyl, halo C 1-6 alkyl, halo C 1-6 heteroalkyl, -NH-C(O)O-C1-6alkyl or -O-C(O)O-C 1-6 alkyl; or R1, R2and the atoms to which they are each attached form an unsubstituted or optionally substituted 5- or 6-membered heterocyclyl ring 13 substituted 6-membered heterocyclyl; each R 13 are the same or different, each independently selected from the group consisting of H, OH, CN, oxo (=0), halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl; R 31 , R 32 are identical or different and independently of each other selected from H, halogen, CN, C 1-6 alkyl, C 1-6 heteroalkyl, halo C 1-6 alkyl, halo C1-6 heteroalkyl; R4, R5are the same or different, independently of one another, selected from the group consisting of H, unsubstituted or optionally substituted with one, two or more R 41 NH2, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl; each R 41 are the same or different, independently of one another, selected from the group consisting of H, OH, CN, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 2-6 alkenyl, C2-6alkynyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, 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-, C 1-6 alkyl-NH-; or R4, R5and the atoms to which they are each attached form an unsubstituted or optionally substituted 3-10 membered cycloalkane, cycloalkene, heterocycloalkane, heterocycloalkene, aryl, or heteroaryl 51 substituted 3-10 membered lactam; each R 51 the same or different, each independently selected from H, OH, CN, oxo (=0), halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl.

2. The compound of formula (I) according to claim 1, a tautomer, a stereoisomer, an isotopically labeled material, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, characterized in that, Y is selected from N or CH; Preferably, Z is selected from N or CH; Preferably, A is selected from N or CR a ; R a is selected from H, F, CN, methyl, methoxy; Preferably, A is selected from N, CH, CCH3or CF; Preferably, D is selected from N or CR d ; R d is selected from H, F, CN, methyl, methoxy; Preferably, D is selected from N, CH, CF or COCH3; Preferably, E is selected from N or CR e ; R e is selected from H, F, CN, methyl, methoxy; Preferably, E is selected from N, CH, CCH3or CF; Preferably, G is selected from N or CR g ; R g is selected from H, F, CN, methyl, methoxy; Preferably, G is selected from N, CH, CCH3or CF.

3. The compound of formula (I) according to claim 1 or 2, a tautomer, a stereoisomer, an isotopically labeled material, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, characterized in that, R1is selected from H, C 1-6 alkyl, C 2-6 alkynyl, haloC 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; Preferably, R1is selected from H, unsubstituted or optionally substituted with F, cyclopropyl, cyclobutyl or phenyl, methyl, ethyl, propyl, butyl, pentyl, propynyl; Preferably, R1is selected from H, R2is selected from H, OH, halogen, NH2, C 1-6 alkyl, C 1-6 heteroalkyl, -NH-C(O)O-C 1-6 alkyl or -O-C(O)O-C 1-6 alkyl; Preferably, R2is selected from H, OH, NH2, methyl, Preferably, R1, R2and the atoms to which each is attached form a substituted or unsubstituted 5-, 6- or 7-membered heterocyclyl ring having 1, 2 or 3 ring heteroatoms independently selected from N, O and S, wherein the heterocyclyl ring is optionally substituted with one, two or more R 13 substituted with one, two or more R Preferably, selected from the group consisting of For example Preferably, each R 13 identically or differently, independently of one another, are selected from H, oxo (=0), C 1-6 alkyl; Preferably, each R 13 are the same or different, independently of each other, selected from H, oxo (=0), methyl, ethyl; Preferably, R 31 R 32 They are either the same or different, and are independently selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Heteroalkyl; Preferably, R 31 selected from H; R 32 selected from H; Preferably, R4is H.

4. The compound of formula (I), a tautomer, a stereoisomer, an isotopically-labeled material, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof according to any one of claims 1-3, characterized in that, R5is selected from C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, haloC 6-10 aryl, haloC 1-6 alkoxy-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-, C 1-6 alkyl-C 6-10 aryl-NH-, C 1-6 alkoxy-C 6-10 aryl-NH-, haloC 6-10 aryl-NH-, C 6-10 aryl-C 1-6 alkyl-NH-; Preferably, R5is selected from unsubstituted or optionally substituted with one, two or more F, butyl, cyclopropyl, cyclobutyl, phenyl, tolyl, benzyl, fluorophenyl, methoxyphenyl, ethylamino, trifluoromethoxy, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, amino, phenyl, pyridyl, isoxazolyl; Preferably, R5 is selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-fluorophenyl, 3-fluorophenyl, 2-trifluoromethoxyphenyl, 5-isoxazolyl, 4-pyridyl, cyclopropylmethyl, cyclobutylmethyl, Preferably, R4, R5and the atoms to which they are each attached form an unsubstituted or optionally substituted 5- to 7-membered heterocyclyl ring 51 substituted with one, two, or more R Each R 51 They may be the same or different, and are independently selected from H, oxo (=O), methyl, and ethyl; Preferably, selected from the group consisting of (As )。 5. The compound of formula (I), a tautomer, a stereoisomer, an isotopically-labeled material, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof according to any one of claims 1-4, characterized in that, The compound of formula (I) has a structure represented by formula (I-1) wherein Y, Z, A, D, E, G, R1, R2, R4, R5, R 31 , R 32 have the definitions of any one of claims 1-4; Preferably, the compound of formula (I) has the structure of formula (II) wherein W, M, Y, Z, A, D, E, G, R1, R2, R4, R5have the definitions as described in any one of claims 1-4; Preferably, the compound of formula (I) has the structure of formula (II-1) wherein Y, Z, A, D, E, G, R1, R2, R4, R5have the definitions as described in any one of claims 1-4; Preferably, the compound of formula (I) has the structure of formula (III) wherein W, M, Y, Z, A, D, E, G, R1, R2, R5have the definitions as described in any one of claims 1-4; Preferably, the compound of formula (I) has the structure of formula (III-1) wherein Y, Z, A, D, E, G, R1, R2, R5have the definitions as described in any one of claims 1-4.

6. The compound of formula (I), a tautomer, a stereoisomer, an isotopically-labeled material, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof according to any one of claims 1-5, wherein, The compound of formula (I) is selected from the structures shown below: ​ 7. A process for the preparation of a compound of formula (I), a tautomer, a stereoisomer, an isotopically labeled material, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof according to any one of claims 1 to 6, characterized in that, comprising the following steps: the following scheme one or scheme two: Scheme one: compound M1 reacts with M1-1 to obtain the compound shown in formula (I); Scheme two: compound M1 reacts with M1-2 to obtain compound M2; compound M2 reacts with compound M2-1 to obtain the compound shown in formula (I); M2-1 is wherein W, M, Y, Z, A, D, E, G, R1, R2, R 31 , R 32 4, R5 independently of one another have the definitions according to any one of claims 1 to 6.

8. An intermediate compound of the following formula Ml or M2: wherein W, M, Y, Z, A, D, E, G, R1, R2, R 31 , R 32 , R4, R5 independently of one another have the definitions given in any of claims 1 to 6.

9. A pharmaceutical composition, wherein the pharmaceutical composition comprises a compound of Formula (I), a tautomer, a stereoisomer, an isotopically-labeled, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof as described in any one of claims 1-6.

10. Use of a compound of Formula (I), a tautomer, a stereoisomer, an isotopically-labeled, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof as described in any one of claims 1-6, or the pharmaceutical composition, in the manufacture of a medicament, for example, in the manufacture of a medicament related to PI5P4Kγ inhibition. Preferably, the pharmaceutical composition or the medicament is for preventing and / or treating a disease related to PI5P4Kγ inhibition, for example, a cancer. Preferably, the cancer is selected from a solid tumor cancer 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, genitourinary tract cancer, head cancer, laryngeal cancer, muscle tissue cancer, neck 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 cancer is, for example, a blood cancer.

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