EA046877B1 - IMIDAZOLIDINONE COMPOUND, METHOD OF ITS PREPARATION AND ITS APPLICATION - Google Patents

Abstract

An imidazolidinone compound represented by formula (I), or a stereoisomer thereof, a geometric isomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, a method for synthesizing it, and a use thereof.

Description

Field to which the invention relates

The present invention relates to imidazolidinone compounds which play a role by participating in the regulation of a variety of processes such as cell proliferation, apoptosis, migration and angiogenesis. The present invention also relates to pharmaceutical compositions containing such compounds, and the use of these compounds for the treatment of a disease mediated by PI3K.

Prerequisites for creating the invention

The PI3K pathway is important for regulating intracellular activities such as growth, proliferation, survival, differentiation, metastasis and apoptosis. It is called the PI3K/Akt/mTOR signaling pathway because PI3K, Akt, and mTOR are key proteins in this pathway. In recent years, PI3K inhibitor has been the focus of anticancer drug research.

Once activated by RTK or Ras, PI3K catalyzes phosphoinositide 3,4-bisphosphate (PIP2) to phosphoinositide 3,4,5-trisphosphate (PIP3). PIP3 binds to protein kinases such as Akt and 3-phosphoinositide (PIP)-dependent protein kinase (PDK), phosphorylates and activates Akt, and then translocates Akt from the cytoplasm to the nucleus. Activated Akt further phosphorylates downstream effector substrates, affecting cell survival, cell cycle, growth, and other cellular activities. (Ma K, Cheung SM, Marshall AJ etc., Cell Signal, 2008, 20:684-694). Therefore, activation of the PI3K/Akt/mTOR signaling pathway can inhibit cell apoptosis, enhance cell tolerance, promote cell survival, proliferation and participate in angiogenesis, promote tumor growth and metastasis.

Phosphatidylinositol 3-kinase (PI3K) belongs to the lipid kinase family, which is divided into class I, class II and class III based on the mechanism of activation and structural features (Vanhaesebroeck B, Waterfield MD; Exp Cell Res, 1999, 253:239-254) . The best studied currently are the class I PI3Ks. Class I PI3Ks are further subdivided into isoforms IA and IB, which receive signals from receptor tyrosine kinase (RTK) and G protein-coupled receptors (GPCRs), respectively (Wu P, Liu T, Hu Y; Curr Med Chem 2009, 16:916-930). Class IA PI3Ks include three isoforms, designated PI3Ka, PI3Ke and PI3Ki5„ Class IB PI3Ks contain only one isoform (PI3Ky). Class II PI3Ks are divided into three catalytic isoforms, designated PI3KC2a, PI3KC2e, and PI3KC2y, based on different C-terminal structures. However, little is known about their substrates in vivo, and understanding of their mechanisms of action and specific function is relatively limited. (Falasca M, T Muffucci; Biochem Soc Trans, 2007, 35:211-214). Class III PI3Ks include only one member, Vps34 (Vacuolar Protein Sorting 34), which acts as a calibrator at the protein level in regulating downstream mTOR signaling cascades (Schu P, Takegawa. K, Fry. M etc., Science, 1993, 260: 88-91).

Of the four class I PI3K isoforms, PI3Ka and PI3Ke are expressed in various organs, and PI3K<5 and PI3KY are mainly distributed in bone marrow cells (Kong D, Yamori T; cancer Sci, 2008, 99:17341740). The PI3Ka isoform is most closely associated with tumor development, the gene encoding the p110a catalytic subunit of PI3Ka is called PIK3CA, and its mutation is often observed in various malignancies, including breast, colon, endometrial, gastric, ovarian and lung cancer, etc. (Steelman. LS, Chappell. WH, Abrams. SLet al., Aging, 2011, 3:192-222). Aberrant activation of PI3Ka up-regulates and activates the PI3K signaling pathway, which can promote cell hyperproliferation, overgrowth and metastasis, and then tumor formation. Although the other three isoforms PI3Ke, PI3I<i3 and PI3Ky play roles in thrombosis, immune function, allergic and inflammatory responses, respectively, they are also important in tumor development, influencing catalytic activity, physicochemical properties, interactions and recognition.

The most studied early stage PI3K inhibitors are wortmannin and LY294002, which play important roles in studying the physiological functions and mechanisms of action of the PI3K signaling pathway. These are called first-generation PI3K inhibitors and provide an important basis for subsequent research. Based on wortmannin and LY294002, a second generation of PI3K inhibitors, such as morpholine aryls, imidazopyridines and imidazoquinolines, with new structures, higher activities and better pharmacokinetic properties were discovered, providing new hope for tumor therapy. The dozens of PI3K inhibitors in clinical trials mainly include pan-PI3K inhibitors, dual PI3K/mTOR inhibitors, and PI3K isoform-specific inhibitors.

Alpelisib (BYL719) is the first selective PI3Ka inhibitor developed by Norvartis with p110a inhibitory activity at 5 nM. Preclinical data show that BYL719 inhibits Akt phosphorylation, blocks the PI3K signaling pathway, and inhibits the proliferation of breast cancer cells harboring PIK3CA mutations. (Dejan Juric etc., cancer Res, 2012, 72:1). The drug was approved by the US Food and Drug Administration (FDA) on May 24, 2019 for the treatment of postmenopausal women and men with advanced or metastatic HR+/HER2- breast cancer with PIK3CA mutations and disease progression during or after regimens endocrine therapy. At the same time, previous studies

- 1 046877 indicate that a P13Ka-specific small molecule inhibitor shows promising therapeutic effects in head and neck cancer, ovarian cancer, triple negative breast cancer, HER2+ breast cancer and a spectrum of overgrowth syndromes associated with the PIK3 CA mutation (PROS) . Expanding the drug's indications will create enormous economic and social benefits.

To achieve better tumor treatment effect, better fit the market and provide an alternative for clinical use, we have developed a new generation PI3K inhibitor with higher activity, better pharmacokinetic properties and less toxicity.

Brief description of the invention

The present invention provides a series of imidazolidinone compounds as PI3K inhibitor.

The present invention relates to a compound of formula I or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof:

Where

X is selected from O and S;

R1 is selected from H or C _1-6 -alkyl, optionally substituted with one or more halogens;

R2 is selected from H, C _1-6 -alkyl, C _3-6 -cycloalkyl, C _3-6 -heterocyclyl, C ₆ - ₈ -aryl and C _5-8 -heteroaryl; where C _1-6 -alkyl, C _3-6 -cycloalkyl, C _3-6 -heterocyclyl, C ₆ -8-aryl and C5-8-heteroaryl are each optionally substituted with one or more substituents selected from halogen, CN, -OH, C _1-6 -αalkyl, C _1-6 -halogenαalkyl and -NRaRb; and wherein C _3-6 heterocyclyl contains from 1 to 3 heteroatoms selected from N, O or S, and C _5-8 heteroaryl contains from 1 to 4 heteroatoms selected from N, O or S;

R3 is selected from H C _1-6 -alkyl and C _2-6 -alkenyl;

R ₄ represents H;

R ₅ represents H;

R6 is selected from H, halogen, oxo, C _1-6 -alkyl, C _3-6 -cycloalkyl, C ₆ -8-aryl, -ORa, -NR _a R _b ;

R _a and R _b are independently selected from H and C _1-6 -αalkyl;

m is selected from 0, 1, 2, 3 and 4;

n is selected from 0, 1, 2 and 3;

y is selected from 0, 1, 2, 3, 4, 5 and 6.

The present invention provides certain preferred technical solutions regarding the compound of formula (I) or its stereoisomer, geometric isomer or tautomer.

In some embodiments, the compound of formula (I) is additionally a compound of formula (V):

Where

R1 is selected from C _1-6 -αalkyl and C _1-6 -halogenαalkyl;

R2 is selected from H, C _1-6 -alkyl, C _3-6 -cycloalkyl, C _3-6 -heterocyclyl, C ₆ -aryl and C _5-6 -heteroaryl; where C _1-6 -alkyl, C _3-6 -cycloalkyl, C _3-6 -heterocyclyl, C ₆ -aryl and C _5-6 -heteroaryl are each optionally substituted with one or more substituents selected from halogen, -CN, -OH, -No-(CH ₃ ) ₂ , C _1-6 alkyl and C _1-6 haloalkyl.

In some embodiments, the compound of formula (I) is additionally a compound of formula (VI):

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Where

R1 is selected from C _1-6 -alkyl and C _1-6 -haloalkyl;

R2 is selected from H, C _1-6 -alkyl, C _{3 -6} -cycloalkyl, C _3-6 -heterocyclyl, C ₆ -aryl and C _5-6 -heteroaryl; where C _1-6 -alkyl, C _3-6 -cycloalkyl, C _3-6 -heterocyclyl, C ₆ -aryl and C _3-6 -heteroaryl are optionally substituted with one or more substituents selected from halogen, -CN, -OH, -K-(CH ₃ ) ₂ , C _1-6 -alkyl and C _1-6 -haloalkylα.

In some embodiments, the compound of formula (I) is additionally a compound of formula (VII):

where R2 is selected from H, C _1-6 -alkyl, C _3-6 -cycloalkyl, C _3-6 -heterocyclyl, C ₆ -aryl and C _5-6 -heteroaryl; and said R2 is optionally substituted with halogen.

In some embodiments, R2 is selected from _-CH3 , -CH2CH3, -CH( _CH3 ) ₂ , -CH2CF3, cyclopropyl, cyclobutyl, phenyl, and pyridyl; where -CH3, -CH2CH3, -CH(CH3)2, -CH2CF3, cyclopropyl, cyclobutyl, phenyl and pyridyl are each optionally substituted with halogen.

In some embodiments, R2 is selected from -CH ₃ , -CH(CH ₃ ) ₂ , cyclopropyl, phenyl, and halogenated phenyl.

In some embodiments, R ₂ is selected from -CH(CH ₃ ) ₂ and cyclopropyl.

The present invention provides the most preferred technical solutions for a compound of formula (I) or a stereoisomer, geometric isomer or tautomer thereof, the compounds being the following:

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1) (2S)-1 -(2-(5-isopropyl-3-methyl-2,4-dioxoimidazolidin-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4] oxazepin-9-yl)pyrrolidin-2-carboxamide;

2) (2S)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4] oxazepin-9-yl)pyrrolidin-2-carboxamide;

3) (28)-1-(2-(5-isopropyl-2,4-dioxo-3-(2,2,2-trifluoroethyl)imidazolidin-1-yl) 5,6-dihydrobenzo[1]imidazo[ 1.2h1][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide;

4) (2S)-1-(2-(3-(4-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [ 1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide;

5) (28)-1-(2-(5-cyclopropyl-3-methyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4] oxazepin-9-yl)pyrrolidin-2-carboxamide;

6) (2S)-1-(2-(3-cyclobutyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4] oxazepin-9-yl)pyrrolidin-2-carboxamide;

7) (2S)-1-(2-(3-ethyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4] oxazepin-9-yl)pyrrolidin-2-carboxamide;

8) (2S)-1-(2-(5-difluoromethyl-3-methyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4] oxazepin-9-yl)pyrrolidin-2-carboxamide;

9) (28)-1-(2-(5-isopropyl-2,4-dioxo-3-phenylimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4] oxazepin-9-yl)pyrrolidin-2-carboxamide;

10) (S)-1 -(2-((8)-5-isopropyl-2,4-dioxo-3-phenylimidazolidin-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [ 1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide;

11) (S)-1 -(2-((K)-5-isopropyl-2,4-dioxo-3-phenylimidazolidin-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [ 1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide;

12) (28)-1-(2-(5-isopropyl-2,4-dioxo-3-(4-(trifluoromethyl)phenyl)imide azolidin-1-yl)-5,6-dihydrobenzo[1]imidazo[ 1,2-d][1,4]oxazepin-9yl)pyrrolidine-2-carboxamide;

13) (2S)-1 -(2-(5-isopropyl-2,4-dioxo-3-propylimidazolidin-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4] oxazepin-9-yl)pyrrolidin-2-carboxamide;

14) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4 ]oxazepin-9-yl)-2-methylpyrrolidine-2carboxamide;

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15) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4 ]thiazepin-9-yl)-4,4-difluoropyrrolidine-2carboxamide;

16) (2S)-1 -(2-(5-isopropyl-3-(1 -methyl-1H-1,2,4-triazol-5-yl)-2,4dioxoimid azolidin-1 -yl)-5, 6-dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepin-9yl)pyrrolidine-2-carboxamide;

17) (28.48)-4-amino-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin 1 -yl)-5,6-dihydrobenzo[1]imidazo[1,2 -d][1,4]oxazepin-9-yl)pyrrolidine-2carboxamide;

18) (28)-1-(2-(3-(2-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [ 1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide;

19) (2 S)-1 -(2-(3 -(4-chlorophenyl)-5 -isopropyl-2,4-dioxoimid azolide in-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2- d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide;

20) (28)-4-(tert-butoxy)-1-(2-(3-cyclopropyl-5-isopropyl-2,4dioxoimidazolidin-1 -yl)-5,6-dihydrobenzo[1]imidazo[1,2]- d][1,4]oxazepin-9yl)pyrrolidine-2-carboxamide;

21) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4 ]oxazepin-9-yl)-4,4-dimethylpyrrolidine-2carboxamide;

22) (2 S)-1 -(2-(3 -(2,2-difluoroethyl)-5 -isopropyl-2,4-dioxoimidazolidin-1 -yl)5,6-dihydrobenzo[1]imidazo[1,2 -b][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide;

23) (2S)-1 -(2-(3,5-diisopropyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepine- 9-yl)pyrrolidin-2-carboxamide;

24) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4 ]oxazepin-9-yl)-4-phenylpyrrolidine-2carboxamide;

25) (28)-1-(2-(3-(3-chloro-5-cyanophenyl)-5-isopropyl-2,4-dioxoimidazolidin-1yl)-5,6-dihydrobenzo[1]imidazo[1,2 -b][1,4]thiazepin-9-yl)pyrrolidin-2-carboxamide;

26) (2S)-1 -(2-(3,5-diisopropyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]thiazepine- 9-yl)pyrrolidin-2-carboxamide;

27) (28)-1-(2-(3-azetidin-3-yl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [ 1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide;

28) (28)-1-(2-(3-methyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepine- 9-yl)pyrrolidin-2-carboxamide;

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29) (2S)-1 -(2-(5-tert-butyl-3-methyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[T]-imidazo[1,2-d] [1,4 ]oxazepin-9-yl)pyrrolidin-2-carboxamide;

30) (S)-1 -(2-((R)-3-(4-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidin-1 -yl)5,6-dihydrobenzo[T]imidazo[1, 2]^][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide;

31) (S)-1 -(2-((8)-3-(4-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidin-1 -yl)5,6-dihydrobenzo[1]imidazo[1, 2]^][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide;

32) (2S)-l-(2-((5R)-3-cycloπpoπyl-5-isoπpoπyl-2,4-dioκcoimidazolidin-l-yl)5,6-dihydrobenzo[T]imidazo[1.2h1][1 ,4]oxazepin-9-yl)pyrrolidin-2-carboxamide;

33) (2S)-1-(2-((58)-3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)5,6-dihydrobenzo[T]imidazo[1.2h1][1 ,4]oxazepin-9-yl)pyrrolidin-2-carboxamide;

4) (2 S)-1 -(2-(3 -(2-hydroxyethyl)-5 -isopropyl-2,4-dioxoimid azolide in-1 -yl)5,6-dihydrobenzo[T]imidazo[1.2h1 ][1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide;

35) (2S)-1-(2-(3-(2-fluoroethyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[T]imidazo[1,2-d] [ 1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide;

36) (28)-1-(2-(3-(2-(dimethylamino)ethyl)-5-)isopropyl-2,4-dioxoimidazolidin1 -yl)-5,6-dihydrobenzo[1 ^: ]imidazo[ 1, 2-d][1,4]oxazepin-9-yl)pyrrolidine-2carboxamide;

37) (2S)-1 -(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4 ]thiazepin-9-yl)pyrrolidin-2-carboxamide;

38) (2S)-1 -(2-(3-(6-fluoropyridin-3-yl)-5-isopropyl-2,4-dioxoimidazolidin-1 yl)-5,6-dihydrobenzo[1 ^: ]imidazo[ 1 ,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide;

39) (28)-1-(2-(3-(5-fluoropyridin-3-yl)-5-isopropyl-2,4-dioxoimidazolidin-1yl)-5,6-dihydrobenzo[1 ^: ]imidazo[1, 2]h1][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide;

40) (28)-1-(2-(3-(3-cyano-5-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidin-1yl)-5,6-dihydrobenzo[1 ^: ]imidazo[ 1, 2-d][1,4]oxazepin-9-yl)-4-fluoropyrrolidine-2carboxamide;

41) (2 S)-1 -(2-(3 -(3-chloropyrimidin-2-yl)-5 -isopropyl-2,4-dioxoimidazolidin1 -yl)-5,6-dihydrobenzo[1]imidazo[ 1, 2-d][1,4]oxazepin-9-yl)pyrrolidine-2carboxamide;

42) (2S)-1 -(2-(3-cyclopentyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4] oxazepin-9-yl)pyrrolidin-2-carboxamide;

43) (28)-1-(2-(3-(cyanomethyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1, 4]oxazepin-9-yl)pyrrolidin-2-carboxamide;

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44) (28)-1-(2-(5-isopropyl-3-methyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[1]imidazo[1,2-d] [1, 4]thiazepin-9-yl)pyrrolidin-2-carboxamide;

45) (28)-1-(2-(3-(2,2-difluoroethyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-

5,6-dihydrobenzo[1G]imidazo[1,2-(1][1,4]thiazepin-9-yl)pyrrolidin-2-carboxamide;

46) (2S)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-3-vinyl-5,6-dihydrobenzo[1]imidazo[1,2-d ] [ 1,4]oxazepin-9-yl)pyrrolidin-2carboxamide;

47) (2S)-1 -(3-chloro-2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1 - yl)-5,6-dihydrobenzo[1]imidazo[1,2-d ] [ 1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide;

48) (28)-1-(2-(3-cyclopropyl-5-(difluoromethyl)-2,4-dioxoimidazolidin-1-yl)-

5,6-dihydrobenzo[1]imidazo[1,2^][1,4]thiazepin-9-yl)pyrrolidin-2-carboxamide;

49) (2S,3 S)-l-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-

5,6-dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepin-9-yl)-3-hydroxypyrrolidine-2carboxamide;

50) (28)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-3-methyl-5,6-dihydrobenzo[1]imidazo[1,2^] [1,4]oxazepin-9-yl)-4-oxopyrrolidine-2carboxamide;

51) (2 8)-4-cyclohexyl-1 -(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimide azolidin-1-yl)-5,6-dihydrobenzo[1]imidazo[1,2 -d][1,4]oxazepin-9yl)pyrrolidine-2-carboxamide;

52) (2S)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[1]imidazo[1,2^][1,4 ]thiazepin-9-yl)-5-oxopyrrolidine-2-carboxamide.

The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of at least one compound of formula (I) and at least one pharmaceutically acceptable excipient.

The present invention further provides a pharmaceutical composition, wherein said compound of formula (I) in the composition has a weight ratio of about 0.0001-10 with said excipient.

The present invention provides the use of a compound of formula (I) or a pharmaceutical composition containing a compound of formula (I) for the manufacture of a medicament.

The present invention further provides preferred technical solutions for the specified application:

Preferably, the drug is used to treat, prevent, delay or stop the onset or progression of cancer or cancer metastasis.

Preferably, the drug is used to treat cancer.

Preferably, the drug is used as a PI3K inhibitor.

Preferably, the drug is used to treat a PI3K-mediated disease.

Preferably, PI3K includes PI3Ka, PI3Ke, ΡΙ3Κδ and/or ΡΙ3Κγ.

Preferably the PI3K is PI3Ka.

Preferably, the PI3K-mediated disease is cancer.

Preferably, the cancer is selected from sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer , uterine cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharyngeal cancer, laryngeal cancer, lymphoma, basal cell carcinoma, polycythemia vera, essential thrombocythemia.

The present invention also provides a method of treating or preventing a PI3K-mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition containing a compound of formula (I).

Preferably, in the above method, said PI3K includes PI3Ka, PI3Ke, ΡΙ3Κδ and/or ΡΙ3Κγ.

Preferably, in the above method, said PI3K is PI3Ka.

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Preferably, in the above method, said PI3Kα-mediated disease is cancer.

Preferably, in the above method, said cancer is sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma, cancer kidney, bladder cancer, uterine cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharyngeal cancer, laryngeal cancer, lymphoma, basal cell carcinoma, polycythemia vera, essential thrombocythemia.

The present invention also provides a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutical composition containing a compound of formula (I), wherein said cancer is sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, uterine cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharyngeal cancer, laryngeal cancer, lymphoma, basal cell carcinoma, polycythemia vera, essential thrombocythemia.

Preferably, in the above method, the subject is a human.

The present invention relates to a compound used as a PI3K inhibitor and the manufacture of a medicament comprising the same compound for the treatment and prevention of a PI3K mediated disease. This compound acts as an active ingredient and has the characteristics of good therapeutic effect, high selectivity and high bioavailability. As a drug that will soon be available on the market, the compound has the characteristics of low cost and convenient administration, which is more advantageous for the widespread use of the drug and is more effective in helping the needy subject overcome pain and improve his quality of life.

The terms used in the present invention have the following meanings.

As used herein, the term alkyl, unless otherwise specified, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties. For example, alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, N-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, cyclopentyl, and cyclohexyl. Likewise, C _1-4 , as in C _1-4 alkyl, is defined as a group having 1, 2, 3 or 4 carbon atoms in a linear, branched or cyclic arrangement.

The term cycloalkyl refers to a cyclic saturated monovalent alkyl chain. Likewise, _C3-6 , as in _C3-6 -cycloalkyl, is defined as a group having 3, 4, 5 or 6 carbon atoms in a cyclic saturated monovalent alkyl chain. Typical cycloalkyl includes, but is not limited to, cyclopropane, cyclobutane, cyclopentane. or cyclohexane, etc.

As used herein, the term heterocyclyl, unless otherwise indicated, refers to unsubstituted or substituted non-aromatic 3-6 membered monocyclic systems containing carbon atoms and 1-3 atoms selected from N, O or S. In this case, nitrogen or sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. A heterocyclyl group can be attached to any heteroatom or carbon atom, resulting in a stable structure. Representative heterocyclyl includes, but is not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, omorpholinyl, thiomorpholin sulfonyl, thiamorpholinyl sulfone and oxadiazolyl.

The term halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferably, halogen means fluorine, chlorine and bromine.

The term halogen refers to a fluorine, chlorine, bromo or iodine group.

The term substituted refers to a group in which one or more hydrogen atoms are each independently replaced by the same substituent or different substituents. Typical substituents include, but are not limited to, halogen, amino, hydroxyl, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, aryl, haloaryl, arylalkyl, arylalkenyl, heterocyclyl, cycloalkoxy, alkylamino.

As used herein, the term aryl, unless otherwise specified, refers to an unsubstituted or substituted mono- or polycyclic ring system containing carbon atoms in the ring. A preferred aryl is phenyl.

As used herein, the term heteroaryl, unless otherwise specified, represents an unsubstituted or substituted stable five to six membered monocyclic aromatic ring system, or an unsubstituted or substituted nine to ten membered fused heteroaromatic ring system or a bicyclic heteroaromatic ring system,

- 8 046877 which consists of carbon atoms and one to four heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. A heteroaryl group can be attached to any heteroatom or carbon atom, resulting in a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, angry , benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.

The term compound as used in the present invention includes the compound shown in formula (I) and its pharmaceutically acceptable forms, which include its salt, solvent, non-covalent complex, chelate, tereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, isotopic -labeled compounds, tautomers, prodrugs or any mixtures of the above compounds.

The term enantiomer refers to a pair of stereoisomers that are not superimposed and are mirror images of each other, and a 1:1 mixture of a pair of enantiomers is a racemic mixture. When indicating the stereochemistry of the compounds of the present invention, the conventional RS system is used. (For example, (1S, 2S) denotes one stereoisomer of known relative and absolute configuration with two chiral centers).

The term diastereomers represents stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other. When compounds are pure enantiomers, the stereochemistry of each chiral carbon may be designated R or S.

An isolated compound of unknown absolute configuration may be designated (+) or (-) depending on the direction of rotation of the plane-polarized light (right-handed or left-handed) at the sodium D-line wavelength. Or the isolated compound can be determined by the retention time of the corresponding enantiomers/diastereoisomers for chiral HPLC.

Those skilled in the art will recognize that the compounds of the present invention contain chiral centers and thus may exist in various isomeric forms. Unless otherwise indicated, the compounds of the present invention are intended to include all such possible isomers, including racemic mixtures, optically pure forms, and mixtures of isomers in any ratio. The compound of example of formula (VIII) includes the compound of example 2, the compound of example 32, the compound of example 33, and any mixture ratio of example 32 and example 33. The optically active (R)- and (b)-isomers can be prepared synthetically from using optically active starting materials, or prepared using chiral reagents, or separated using conventional techniques (eg, separated on a chiral SFC or HPLC column).

Pharmaceutically acceptable refers to those agents that are known to be useful in the treatment of animals, particularly humans.

The term composition as used herein is intended to cover a product containing the specified ingredients in the specified amounts, as well as any product that is directly or indirectly the result of combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as an active ingredient, as well as methods for preparing the compounds of the present invention are also part of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs and are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or with common organic solvents, and such solvates are also included within the scope of the present invention.

The term therapeutically effective amount in the present invention refers to the amount of a compound that is active when used to treat and prevent or inhibit at least one clinical symptom of a disease, condition, symptom, sign and/or discomfort. The specific therapeutically effective amount will vary as the compound, route of administration, age of the patient, weight of the patient, type of disease or discomfort being treated, symptoms and severity will vary. In any case, the appropriate dosage will be obvious to those skilled in the art and can be assessed by routine experimentation.

The compounds of the present invention may also exist in the form of pharmaceutically acceptable salts. The medicinal salts of the compounds of this invention are non-toxic pharmaceutically acceptable salts. Pharmaceutically acceptable salt forms include pharmaceutically acceptable acid/anionic or basic/cationic salts. The pharmaceutically acceptable acid/anionic salt typically takes a form in which the basic nitrogen is protonated with an inorganic or organic acid. Typical organic or inorganic acids include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric,

- 9 046877 nitrogen, phosphorus, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, almond, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamic, 2-naphthalene sulfonic, p-toluene sulfonic, cyclohexane sulfonic , salicylic, saccharin or trifluoroacetic. Pharmaceutically acceptable basic/cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc salts.

The present invention includes prodrugs of the compounds. Typically, such prodrugs are functional derivatives of compounds that are readily converted in vivo to the desired compound. Thus, in the treatment methods of the present invention, the term administration means the treatment of various described disorders with a compound specifically described in the invention, or a compound that may not be specifically described, but which is converted to the specified compound in vivo after administration to a subject. Typical techniques for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

The definition of any substituent or variable at a particular location in a molecule is assumed to be independent of its definitions elsewhere in that molecule. It will be understood that one of ordinary skill in the art can select substituents and substitution schemes for the compounds of the present invention that result in chemically stable compounds that can be readily synthesized by methods known in the art, as well as by methods described later herein.

When a compound of formula I and its pharmaceutically acceptable salts exist in the form of solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used.

The term pharmaceutically acceptable salts refers to salts derived from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be easily prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric iron, ferrous iron, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc, etc. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine , N-ethylmorpholine, Nethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

If the compound of the present invention is basic, its corresponding salt can be easily prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucinic, nitric, pamic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and the like. Preferred are citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids, with formic and hydrochloric acids particularly preferred. Since the compounds of formula I are intended for pharmaceutical use, they are preferably presented in sufficiently pure form, for example at least 60% pure, more preferably at least 75% pure, in particular at least 98% pure (% based). on mass).

The pharmaceutical compositions of the present invention contain the compound represented by Formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. The compositions include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most appropriate route in any particular case will depend on the particular host and the nature and severity of the conditions for which the active substance is administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

In practice, the compounds represented by Formula I, or their prodrugs, or metabolites, or

- 10 046877 The pharmaceutically acceptable salts of the present invention can be combined as the active ingredient in a uniform mixture with a pharmaceutical carrier in accordance with conventional methods of pharmaceutical compositions. The carrier may take a variety of forms depending on the form of preparation desired for administration, for example, oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention may be presented in discrete units suitable for oral administration, such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient. In addition, the compositions may be presented as a powder, as a granule, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a liquid water-in-oil emulsion. In addition to the conventional dosage forms mentioned above, the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, can also be administered via controlled release delivery agents and/or devices. The compositions can be prepared using any of the pharmaceutical methods. Typically, such methods include the step of binding the active ingredient to a carrier that represents one or more of the required ingredients. Typically, compositions are prepared by uniformly and intimately mixing the active ingredient with liquid carriers or finely divided solid carriers, or both. Then, if necessary, the product is shaped into the desired formulation.

Thus, the pharmaceutical compositions of the present invention may include a pharmaceutically acceptable carrier and a compound of Formula I or a pharmaceutically acceptable salt thereof. The compounds of Formula I or pharmaceutically acceptable salts thereof may also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

The pharmaceutical carrier used may be, for example, a solid, liquid or gas. Examples of solid carriers include, for example, lactose, gypsum, sucrose, talc, gelatin, agar, pectin, gum acacia, magnesium stearate and stearic acid. Examples of liquid carriers include sugar syrup, peanut butter, olive oil and water. Examples of gaseous carriers include, for example, carbon dioxide and nitrogen. When preparing compositions for oral dosage form, any suitable pharmaceutical vehicle can be used. For example, water, glycols, oils, alcohols, flavorings, preservatives, dyes, etc. can be used to prepare oral liquid preparations such as suspensions, elixirs and solutions; at the same time, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants and the like can be used for the preparation of oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage unit forms using solid pharmaceutical carriers. Optionally, the tablets can be coated using standard aqueous or non-aqueous technologies.

A tablet containing the composition of this invention may be prepared by compression or molding, optionally together with one or more auxiliary ingredients or adjuvants. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or disintegrant. Molded tablets can be prepared by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of active ingredient, and each sachet or capsule preferably contains from about 0.05 mg to about 5 g of active ingredient. For example, a formulation intended for oral administration to humans may contain from about 0.5 mg to about 5 g of active agent formulated with a suitable and convenient amount of carrier material, which may be from about 5 to about 95 percent by weight of the total composition. Unit dosage forms typically contain from about 1 mg to about 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

The pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant may be included, such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerin, liquid polyethylene glycols and mixtures thereof in oils. In addition, a preservative may be included to prevent harmful microbial growth.

Pharmaceutical compositions of the present invention suitable for injection include sterile aqueous solutions or dispersions. In addition, the compositions may be in the form of sterile powders for subsequent preparation of such sterile injectable solutions or dispersions. In all cases, the final injection form must be sterile and must

- 11 046877 be effectively fluid for easy drawing into a syringe. Pharmaceutical compositions must be stable under manufacturing and storage conditions; thus, preferably, they should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerin, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical compositions of the present invention may be in a form suitable for topical administration, such as, for example, an aerosol, cream, ointment, lotion, powder, and the like. In addition, the compositions may be in a form suitable for use in transdermal devices. These preparations can be prepared using the compound represented by Formula I of the present invention, or a pharmaceutically acceptable salt thereof, by conventional processing methods. For example, a cream or ointment is prepared by mixing a hydrophilic material and water together with about 5 wt.% to about 10 wt.% of the compound to obtain a cream or ointment having the desired consistency.

The pharmaceutical compositions of this invention may be in a form suitable for rectal administration, in which the carrier is a solid. Preferably, the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with softened or melted carrier(s), followed by cooling and molding.

In addition to the above-mentioned carrier ingredients, the pharmaceutical compositions described above may contain, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavorings, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. In addition, other adjuvants may be included to make the composition isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be prepared in the form of a powder or liquid concentrate.

Examples

In the present invention, the following examples will be used to illustrate the preparation of the compound of formula (I), but the present invention is not limited to them.

The following examples are offered for illustrative purposes to enable those skilled in the art to understand the present invention, but are not intended to limit the invention in any way. Unless otherwise indicated, the technical solutions or methods in the examples in the present inventions are generally accepted. Unless otherwise indicated, all parts and percentages are by weight and all temperatures are in degrees Celsius of the present invention.

The following abbreviations are used in the examples:

DCM: dichloromethane

DMF: N,N-dimethylcarboxamide

DIEA: Ν,Ν-diisopropylethylamine

PE: petroleum ether

EA: ethyl acetate

NIS: N-iodosuccinimide

LCMS or LC-MS: liquid chromatography-mass spectrometry

THF: tetrahydrofuran

DMSO: dimethyl sulfoxide

Et ₃ N or TEA: triethylamine

HATU: 2-(7-azobenzotriazole)-HNK',N-tetramethylurea hexafluorophosphate

Hex: n-hexane h, hr or hrs: hour

LiHMDS: lithium bis(trimethylsilyl)amide

[PdCE (dppf)]CH2C12: [1,1 '-bis(diphenylphosphine)ferrocene]dichloropalladium(P), complexed with dichloromethane

Vos: tert-butoxycarbonyl min: minute rt or RT: room temperature.

- 12 046877

General method.

The compound of formula (VI) was prepared as follows:

Preparation of intermediate compound M-5.

Step 1: synthesis of compound M-2.

4-Bromo-2-hydroxybenzaldehyde (40 g) and MeOH (400 ml) were added to a 1000 ml one-neck flask, ammonia (136.50 g) was added while stirring in an ice bath, and then the reaction was carried out in an oil bath at 35°C. When LC-MS analysis indicated completion of the reaction, the reaction mixture was concentrated and diluted with water, extracted with EA four times, and then the organic layers were combined, dried and concentrated. The residue was purified by column chromatography (PE:EA=3:1) and concentrated to give compound M-2 (34.55 g).

LC-MS [M+H+]: 239.

Step 2: synthesis of compound M-3.

Compound M-2 (34.55 g), Cs ₂ CO ₃ (133 g) and DMF (300 ml) were added to a 1000 ml one-neck flask, stirred at room temperature for 20 minutes, and then 1.2 was added dropwise -dibromoethane (54.30 g), after addition was completed, the mixture was placed in an oil bath at 80° C. to reflux. When LC-MS analysis indicated completion of the reaction, the reaction mixture was concentrated and diluted with water, extracted 3 times with EA, and then the organic layers were combined, dried, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=70:30) and concentrated to give compound M-3 (21.37 g).

LC-MS [M+H+]: 265.

^1H NMR (500 MHz, Chloroform-d) δ 8.38 (d, J=8.5 Hz, 1H), 7.30-7.15 (m, 3H), 6.99 (s, 1H), 4.47-4.43 (m, 2H), 4.41 -4.35 (m, 2H).

Step 3: synthesis of compound M-4.

Compound M-3 (21.37 g) and DMF (100 ml) were added to a 1000 ml one-neck flask, stirred until dissolved, and NIS (50.78 g) dissolved in DMF (100 ml) was added dropwise after addition was completed. the reaction mixture was placed in an oil bath at 60°C and left to react overnight. When LC-MS analysis indicated completion of the reaction, water was added to the reaction mixture, the resulting precipitate was collected by vacuum filtration, and the filter cake was dried to give compound M-4 (35 g).

LC-MS [M+H+]: 517.

¹ H NMR (500 MHz, Chloroform-d) δ 8.30 (d, J=8.6 Hz, 1H), 7.25-7.16 (m, 2H), 4.46 -4.41 (m, 2H), 4.364.32 (m, 2H) .

Step 4: synthesis of compound M-5.

Compound M-4 (35 g) and THF (150 ml) were added to a 500 ml three-neck flask, 100 ml of ethylmagnesium bromide (1 M solution in THF) was added dropwise at -40°C under a protective nitrogen atmosphere, after completion of the addition the reaction mixture was stirred at -40°C. When LC-MS analysis indicated

- 13 046877 completion of the reaction, the reaction mixture was quenched with a saturated solution of ammonium chloride in an ice bath, extracted 3 times with EA, and then the organic layers were combined, dried, concentrated to obtain a residue, which was suspended in methyl tert-butyl ether, the suspension was filtered by vacuum suction and the filter cake was dried to obtain compound M-5 (19.8 g).

LC-MS [M+H+]:391.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.22 (d, J=8.6 Hz, 1H), 7.55 (s, 1H), 7.31 -7.23 (m, 2H), 4.47 -4.39 (m, 4H).

Example 1. Synthesis of (2S)-1-(2-(5-isopropyl-3-methyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[£]imidazo[1,2^] [1 ,4]oxazepin-9-yl)pyrrolidin-2-carboxamide (compound 1).

Step 1: synthesis of compound 1-3.

Compound 1-1 (9 g), Compound 1-2 (16.8 g), DCM (200 ml) and HATU (31.25 g) were added to a 500 ml three-neck flask and TEA (50 g) was added dropwise into an ice bath. ,21 g), after the addition was completed, the reaction was left to proceed at room temperature. When LC-MS analysis indicated completion of the reaction, the reaction was quenched by adding water, the organic layers were separated, washed with water, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (PE:EA=50:50) to obtain compound 1-3 (9.2 g).

LC-MS [M-Voc+H]+: 131.

Step 2: synthesis of compound 1-4.

To a solution of compound 1-3 (1.3 g) in dichloromethane (10 ml) was added HCl/dioxane (10 ml, 4.0 mol/L), stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated to obtain compound 1-4 (0.9 g), which was used directly in the next reaction without further purification.

LC-MS [M+H]+: 131.

Step 3: synthesis of compound 1-5.

Compound 1-4 (900 mg) and TEA (4.19 g) were dissolved in THF (50 ml). Triphosgene (802 mg) in THF (10 ml) was slowly added to the reaction mixture in an ice bath, the reaction mixture was naturally warmed to room temperature and stirred for 12 h. When LC-MS analysis indicated completion of the reaction, the reaction was quenched by adding water ( 5 ml), the reaction mixture was concentrated, extracted and partitioned with dichloromethane/water. The organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (PE:EA=1:1) to obtain compound 1-5 (732 mg).

LC-MS [M+H]+: 157.

Step 4: synthesis of compound 1-6.

Compound 1-5 (177 mg), Compound M-5 (443 mg), CuI (64.75 mg), TpaHC-N,N'dimethylcyclohexane-1,2-diamine (48.36 mg) and K3PO4 (721, 68 mg) was dissolved in DMF (5 ml), the atmosphere was replaced with nitrogen three times, the reaction mixture was heated to 110°C and allowed to react for 2 hours. When LC-MS analysis indicated completion of the reaction, the reaction mixture was diluted with EA (100 ml ), washed with water. The organic layers were combined, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (PE:EA=70:30) to obtain compound 1-6 (350 mg).

LC-MS [M+H]+:419.

Step 5: synthesis of compound 1-7.

Compound 1-6 (350 mg), L-proline (290 mg), K3PO4 (848 mg), CuI (79.8 mg) and DMSO (5 ml) were added to a 100 ml one-neck flask, and the reaction mixture was stirred at 120° From within 3 hours per

- 14 046877 protective atmosphere of nitrogen. When LC-MS analysis indicated completion of the reaction, the reaction mixture was filtered, the filter cake was washed with DMSO (3 ml), and the filtrate was used directly in the next step.

LC-MS [M+H]+: 454.

Step 6: synthesis of compound 1.

To the filtrate obtained in step 5, DCM (12 ml), NH ₄ Cl (445 mg) and DIEA (2.17 g) were added under a protective nitrogen atmosphere, cooled to 0° C., HATU (1.27 d) in an ice bath, stirred at 0°C for 20 minutes. When LC-MS analysis indicated completion of the reaction, the reaction mixture was diluted with DCM, washed with water, and the organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting crude product was purified by column chromatography (PE:EA=100:0-0:100) to obtain compound 1 (300 mg).

LC-MS [M+H] ⁺ :453.

¹ H NMR (500 MHz, DMSO-d6) δ 8.04 (d, J=8.9 Hz, 1H), 7.41 (s, 1H), 7.24 (s, 1H), 7.05 (s, 1H), 6.32 (d, J =8.7 Hz, 1H), 6.03 (s, 1H), 4.62-4.51 (m, 1H), 4.45 -4.30 (m, 4H), 3.94 (d, J=8.7 Hz, 1H), 3.55 (t, J= 7.3 Hz, 1H), 3.23 (q, J=7.2 Hz, 1H), 2.92 (s, 3H), 2.68 (m, 1H), 2.26-2.12 (m, 1H), 1.96 (m, 3H), 1.16 ( d, J=7.0 Hz, 3H), 0.74 (d, J=6.8 Hz, 3H).

Example 2. Synthesis of (2S)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[£]imidazo[1,2^][1,4 ]oxazepin-9-yl)pyrrolidin-2-carboxamide (compound 2).

C.I.

N NN

Η I

n ⁰ NS'Dioxane "P"4

L2-diamine

TEA

Step 1: synthesis of compound 2-2.

Compound 1-1 (5.0 g), DCM (100 mL) and HATU (9.55 g) under a protective nitrogen atmosphere, TEA (8.15 g) were added to a 250 mL one-neck flask, and TEA (8.15 g) was added to the reaction mixture under ice. Compound 2-1 (1.45 g) was added to the bath and allowed to react at room temperature for 2 hours. When LC-MS analysis indicated completion of the reaction, the reaction mixture was concentrated, diluted with EA, washed with water, dried over anhydrous Na2SO4 and concentrated to give compound 2-2 (5.0 g), which was used directly in the next step.

LC-MS [M-Voc+H] ⁺ : 157.

^1H NMR (500 MHz, DMSO-d ₆ ) δ 7.91 (s, 1H), 6.54 (d, J=9.0 Hz, 1H), 3.69-3.58 (m, 1H), 2.65-2.55 (m, 1H), 1.88-1.80 (m, 1H), 1.37 (s, 9H), 0.79 (d, J=6.0 Hz, 6H), 0.62-0.58 (m, 2H), 0.42-0.30 (m, 2H).

Step 2: synthesis of compound 2-3.

Compound 2-2 (5 g), DCM (20 mL), and HCl/dioxane (20 mL, 4.0 mol/L) were added to a 250 mL one-neck flask and allowed to react at room temperature for 2 hours. When LC-MS analysis indicated completion of the reaction, the reaction mixture was concentrated to give compound 2-3 (3.75 g).

LC-MS [M+H] ⁺ : 157.

Step 3: synthesis of compound 2-4.

Compound 2-3 (2.0 g), DCM (50 mL) and TEA (4.20 g) were added to a 250 mL one-neck flask under a nitrogen blanket, and triphosgene (1.54 g) was added to the reaction system in an ice bath. , dissolved in DCM (50 ml), the mixture was stirred in an ice bath for 2 hours. When LC-MS analysis indicated completion of the reaction, the reaction was quenched with ice water in an ice bath, the reaction mixture was concentrated, extracted with ethyl acetate, dried over anhydrous Na ₂ SO ₄ was concentrated to give the crude product. The crude product was purified by column chromatography (PE:EA=100:050:50) to give compound 2-4 (810 mg).

LC-MS [M+H] ⁺ : 183/185.

1H NMR (500 MHz, Chloroform-d) δ 6.28 (s, 1H), 3.85 (d, J=3.6 Hz, 1H), 2.66 -2.48 (m, J=3.7 Hz, 1H), 2.25-2.15 (m, 1H), 1.03 (d, J=6.5 Hz, 3H), 0.98-0.91 (m, 4H), 0.88 (d, J=7.0 Hz, 3H).

- 15 046877

Step 4: synthesis of compound 2-5.

Compound 2-4 (431 mg), compound M-5 (700 mg), DMF (10 ml), CuI (102 mg), trans-NiNi-dimethylcyclohexane-1,2-diamine (77) were added to a 50 ml one-neck flask. mg) and K ₃ PO ₄ (760 mg) under a protective nitrogen atmosphere, the reaction mixture was heated to 120°C and stirred for 2 hours. When LC-MS analysis indicated completion of the reaction, the reaction mixture was diluted with EA, washed with water, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (PE:EA=100:0-60:40) to give compound 2-5 (642 mg).

LC-MS [M+H]+: 445/447.

^1H NMR (500 MHz, Chloroform-d) δ 8.23 (d, J=8.5 Hz, 1H), 7.27 (s, 1H), 7.22 (d, J=8.7 Hz, 1H), 7.20 (s, 1H), 4.63-4.59 (m, 1H), 4.51-4.38 (m, 2H), 4.36 (t, J=4.3 Hz, 2H), 2.79-2.71 (m, 1H), 2.68-2.60 (m, 1H), 1.24 ( d, J=7.1 Hz, 3H), 1.02-0.94 (m, 4H), 0.81 (d, J=6.9 Hz, 3H).

Step 5: synthesis of compound 2-6.

Compound 2-5 (642 mg), Compound M-12 (415 mg), K3PO4 (919 mg) and DMSO (10 ml) were added to a 30 ml microwave vial, purged with nitrogen, CuI (83 mg) was added, the reaction mixture was heated to 120°C and allowed to react in the microwave reactor for 1 hour. When LCMS analysis indicated completion of the reaction, the reaction mixture was used directly in the next step.

LC-MS [M+H]+: 480.

Step 6: synthesis of compound 2.

The reaction mixture obtained in step 5 was added to a 50 ml one-neck flask, the atmosphere was replaced with nitrogen, DCM (10 ml), NH ₄ Cl (462 mg) and TEA (1.46 g) were added, the reaction system was cooled to 0°C HATU (3.28 g) was added in an ice bath, the reaction mixture was stirred at 0°C for 1 hour. When LC-MS analysis indicated completion of the reaction, the reaction mixture was diluted with DCM, washed with water, and the organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by preparative Pre-HPLC (C18 column, H ₂ O:MeOH=95:5-50:50) to give compound 2 (85 mg).

LC-MS [M+H]+: 479.

^1H NMR (500 MHz, DMSO-d ₆ ) δ 8.03 (d, J=9.0 Hz, 1H), 7.40 (s, 1H), 7.24 (s, 1H), 7.05 (s, 1H), 6.32 (d, J=8.9 Hz, 1H), 6.03 (d, J=2.6 Hz, 1H), 4.48 (s, 1H), 4.41 -4.29 (m, 4H), 3.94 (d, J=8.8 Hz, 1H), 3.55 ( t, J=8.1 Hz, 1H), 3.25-3.19 (m, 1H), 2.74 -2.55 (m, 2H), 2.25-2.14 (m, 1H), 2.07-1.85 (m, 3H), 1.13 (d, J=7.0 Hz, 3H), 0.88 (d, J=7.2 Hz, 2H), 0.81 (d, J=3.9 Hz, 2H), 0.71 (d, J=6.8 Hz, 3H).

Step 7: Preparation of compound 32 and compound 33.

In the present examples, compound 32 (front peak) and compound 33 (back peak) were prepared by resolving compound 2 on the next chiral column.

HPLC conditions on a chiral column.

Column CHIRALPAK IA Speaker characteristics 3 cm x 25 cm, 5 microns Injected sample volume 4.0 ml Mobile phase (Hex:DCM =3:1):EUN=50:50 (v/v) Flow rate 35 ml/min Wavelength UV 220 nm Temperature 25°C Sample solution EtOH:DCM=3:1(12.3 mg/ml) Pre-HPLC Prep-HPLC-flash

Compound 32: LC-MS [M+H]+: 479.

1H NMR (500 MHz, DMSO-d6) δ 8.03 (d, J=9.0 Hz, 1H), 7.40 (s, 1H), 7.24 (s, 1H), 7.05 (s, 1H), 6.32 (d, J= 8.9 Hz, 1H), 6.03 (d, J=2.6 Hz, 1H), 4.48 (s, 1H), 4.41 - 4.29 (m, 4H), 3.94 (d, J=8.8 Hz, 1H), 3.55 (t, J=8.1 Hz, 1H), 3.25-3.19 (m, 1H), 2.74-2.55 (m, 2H), 2.25-2.14 (m, 1H), 2.07-1.85 (m, 3H), 1.13 (d, J= 7.0 Hz, 3H), 0.88 (d, J=7.2 Hz, 2H), 0.81 (d, J=3.9 Hz, 2H), 0.71 (d, J=6.8 Hz, 3H).

Compound 33: LC-MS [M+H]+: 479.

1H NMR (500 MHz, DMSO-d6) δ 8.03 (d, J=9.0 Hz, 1H), 7.40 (s, 1H), 7.24 (s, 1H), 7.05 (s, 1H), 6.32 (d, J= 8.9 Hz, 1H), 6.03 (d, J=2.6 Hz, 1H), 4.48 (s, 1H), 4.41 - 4.29 (m, 4H), 3.94 (d, J=8.8 Hz, 1H), 3.55 (t, J=8.1 Hz, 1H), 3.25-3.19 (m, 1H), 2.74 - 2.55 (m, 2H), 2.25-2.14 (m, 1H), 2.07-1.85 (m, 3H), 1.13 (d, J= 7.0 Hz, 3H), 0.88 (d, J=7.2 Hz, 2H), 0.81 (d, J=3.9 Hz, 2H), 0.71 (d, J=6.8 Hz, 3H).

Example 3. Synthesis of (2S)-1-(2-(5-isopropyl-2,4-dioxo-3-(2,2,2-trifluoroethyl)imidazolidin-1-yl)-5,6dihydrobenzo[2]imidazo[ 1,2^][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide (compound 3).

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Step 1: synthesis of compound 3-2.

To a solution of compound 3-0 (2 g) and compound 3-1 (583 mg) in DCM (100 ml), HATU (2.67 g) and DIEA (2.28 g) were added successively, and the mixture was stirred at room temperature for 12 hours Water was added and the reaction mixture was separated and concentrated to give a residue. EA (25 ml) was added to the residue, and then the residue was washed with water and brine. The organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated to give 1.8 g of product.

LC-MS [M+H]+:421.

Step 2: synthesis of compound 3-3.

To a solution of compound 3-2 (1.8 g) dissolved in DCM (10 ml), diethylamine (10 ml) was added, stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a residue, and the residue was purified by column chromatography to obtain compound 3-3 (0.70 g).

LC-MS [M+H]+: 199.

Step 3: synthesis of compound 3-4.

Compound 3-3 (200 mg), CH3CN (10 ml), NaHCO ₃ (254 mg) was added to a 50 ml three-neck flask, the atmosphere was replaced with nitrogen 3 times, p-nitrophenyl chloroformate (203 mg) was added and the mixture was stirred at room temperature in for 2 hours. Water (6 ml) was added to the reaction system and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue, and the residue was diluted with EA, the organic layers were washed successively with water, aqueous carbonate solution potassium and brine, and dried over anhydrous Na ₂ SO ₄ , concentrated to give the crude product. The crude product was purified by column chromatography (PE:EA=60:40) to give compound 3-4 (195 mg).

LC-MS [M+H]+:225.

Step 4: synthesis of compound 3-5.

Compound 3-4 (138 mg), Compound M-5 (200 mg), CuI (39 mg), trans-HNi-dimethylcyclohexane-1,2diamine (29 mg), K3PO4 (326 mg) in DMF (5 ml) , the atmosphere was replaced with nitrogen 3 times, the reaction mixture was heated to 110°C for 2 hours. Upon completion of the reaction, the reaction mixture was diluted with EA, washed once with water and three times with saturated saline, the organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (PE:EA=100:0-70:30) to obtain compound 3-5 (180 mg).

LC-MS [M+H+]: 487/489.

Step 5: synthesis of compound 3-6.

Compound 3-5 (117 mg), compound M-12 (138 mg), K3PO4 (356 mg), CuI (46 mg) and DMSO (3 ml) were added to a 50 ml one-neck flask, the atmosphere was replaced with nitrogen 3 times, the reaction the mixture was heated to 120°C and stirred for 3 hours. Upon completion of the reaction, the reaction mixture was filtered, the filter cake was washed with DMSO (3 ml), and the filtrate was used directly in the next step.

LC-MS [M+H]+: 522.

Step 6: synthesis of compound 3.

DCM (6 ml), NH ₄ Cl (127 mg), DIEA (613 mg) were added to the filtrate obtained in step 5 under a protective nitrogen atmosphere, the reaction mixture was cooled to 0°C, HATU (447 mg) was added in portions in ice cold bath, stirred at 0°C for 20 minutes. After completion of the reaction, the reaction mixture

- 17 046877 diluted with dichloromethane, washed with water and brine, the organic layers were dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative Pre-HPLC to give compound 3 (85 mg).

LC-MS [M+H] ⁺ : 521.

1H NMR (500 MHz, DMSO-d6) δ 8.05 (d, J=8.5 Hz, 1H), 7.41 (s, 1H), 7.29 (s, 1H), 7.06 (s, 1H), 6.33 (d, J= 9 Hz, 1H), 6.04 (s, 1H), 4.71 - 4.70 (m, 1H), 4.38 - 4.24 (m, 6H), 3.95 (d, J=8.5 Hz, 1H), 3.55 (t, J=7.3 Hz, 1H), 3.28-3.20 (m, 1H), 2.70 (brs, 1H), 2.25-2.15(m, 1H), 2.00-1.94(m, 3H), 1.17 (d, J=7.0 Hz, 3H) , 0.75 (d, J=7

Hz, 3H).

Example 4. Synthesis of ^)-1-(2-(3-(4-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[£]imidazo[1,2^][ 1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide (compound 4).

Step 1: synthesis of compound 4-1.

To a solution of compound 1-1 (1.5 g) and p-fluoroaniline (921 mg) in DCM (50 ml) were added HATU (3.39 g) and DIEA (2.68 g). The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted with water, separated, the organic layers were washed successively with 1N HCl, saturated aqueous NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ , concentrated to obtain the crude product. The crude product was purified by column chromatography (EA/PE=0-30%) to give compound 4-1 (2.1 g).

LC-MS [M-Boc+H] ⁺ :211

Step 2: synthesis of compound 4-2.

Compound 4-1 (2.1 g) was added to HCl/dioxane solution (10 mL, 4 M) and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to give Compound 4-2 (1.64 g ), which was used directly in the next step without further purification.

LC-MS [M+H] ⁺ :211.

Step 3: synthesis of compound 4-3.

Compound 4-2 (500 mg), CH3CN (30 ml), NaHCO ₃ (681 mg) was added to a 50 ml three-neck flask, the atmosphere was replaced with nitrogen 3 times, p-nitrophenyl chloroformate (449 mg) was added, stirred at room temperature for 2 hours. Water (18 ml) was added to the reaction mixture and stirred at room temperature for 3 hours.

Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was diluted with EA (100 ml), the organic layers were washed successively with water (50 ml), 5% aqueous K2CO3 (50 ml) and brine, separated, and the organic layers were dried. over anhydrous Na ₂ SO ₄ , concentrated to give the crude product. The crude product was purified by column chromatography (EA/PE=0-40%) to give compound 4-3 (447 mg).

LC-MS [M+H] ⁺ :237.

Step 4: synthesis of compound 4-4.

Compound 4-3 (144 mg), Compound M-5 (200 mg), CuI (39 mg), trans-Ni-dimethylcyclohexane-1,2diamine (29 mg), K3PO4 (326 mg) were dissolved in DMF (5 ml ), the atmosphere was replaced with nitrogen 3 times, the reaction mixture was heated to 110°C and left to react for 2 hours. Upon completion of the reaction, EA (100 ml) was added to dilute the reaction mixture. The organic layers were washed with water (60 ml) and brine (60 ml), dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (PE:EA=100:0-70:30) to give compound 4-4 (215 mg).

LC-MS [M+H] ⁺ : 499.

Step 5: synthesis of compound 4-5.

Compound 4-4 (120 mg), Compound M-12 (138 mg), K3PO4 (356 mg), CuI (46 mg) and DMSO (3 ml) were added to a 100 ml one-neck flask, the atmosphere was replaced with nitrogen 3 times, the reaction the mixture was heated to 120°C, stirred and left to react for 3 hours. Upon completion

- 18 046877 reactions, the reaction mixture was filtered, the filter cake was washed with 3 ml of DMSO, the filtrate was used directly in the next step.

LC-MS [M+H+]: 534.

Step 6: synthesis of compound 4.

To the filtrate obtained in step 5, DCM (12 ml), NH ₄ Cl (445 mg) and DIEA (2.17 g) were added under a protective nitrogen atmosphere, the reaction mixture was cooled to 0° C., HATU (1.27 d) in an ice bath and stirred at 0°C for 20 minutes. Upon completion of the reaction, the reaction mixture was diluted with DCM (50 ml), the organic layers were washed with water (40 ml) and brine (40 ml), dried over anhydrous Na ₂ SO ₄ , concentrated to obtain the crude product. The crude product was purified by column chromatography (PE:EA=100:0-0:100) to obtain compound 4 (89 mg).

LC-MS [M+H]+: 533.

^1H NMR (500 MHz, DMSO-d ₆ ) δ 8.08 (d, J=8.9 Hz, 1H), 7.45-7.41 (m, 3H), 7.38-7.35 (m, 2H), 7.28 (s, 1H), 7.06 (s, 1H), 6.34 (d, J=8.9 Hz, 1H), 6.04 (s, 1H), 4.76 (s, 1H), 4.40-4.37 (m, 4H), 3.95 (d, J=8.8 Hz , 1H), 3.60-3.52 (m, 1H), 3.24 (q, J=8.5, 7.7 Hz, 1H), 2.75 (s, 1H), 2.26-2.14 (m, 1H), 2.00-1.93 (m, 3H ), 1.22 (d, J=7.1 Hz, 3H), 0.88 (d, J=6.8 Hz, 3H).

Compound 30 and Compound 31 were prepared according to procedures similar to those described in Step 7 of Example 2.

Example 5. Synthesis of (2S)-1-(2-(5-cyclopropyl-3-methyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[£]imidazo[1,2^] [1,4 ]oxazepin-9-yl)pyrrolidin-2-carboxamide (compound 5).

By replacing compound 1-1 with compound 5-0 and p-fluoroaniline with methylamine hydrochloride, compound 5 was obtained following procedures similar to those described in Example 4.

LC-MS [M+H]+:451.

Example 6. Synthesis of (2S)-1-(2-(3-cyclobutyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6dihydrobenzo[£]imidazo[1,2^] [1,4 ]oxazepin-9-yl)pyrrolidin-2-carboxamide (compound 6).

By replacing p-fluoroaniline with cyclobutylamine, compound 6 was prepared following procedures similar to those described in example 4.

LC-MS [M+H]+:493.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.04 (d, J=9 Hz, 1H), 7.41 (s, 1H), 7.25 (s, 1H), 7.05 (s, 1H), 6.32 (d, J=9 Hz, 1H), 6.03 (s, 1H), 4.52 - 4.48 (m, 1H), 4.37 - 4.35 (m, 4H), 3.94 (d, J=8.5 Hz, 1H), 3.55 (t, J =7 Hz, 1H), 3.23 (q, J=7.2 Hz, 1H), 2.80-2.65 (m, 3H), 2.14-2.12 (m, 3H), 1.96-1.94 (m, 3H), 1.79-1.71 ( m, 3H), 1.15 (d, J=7 Hz, 3H) 0.74 (d, J=6.5 Hz, 3H).

Example 7 Synthesis of (2S)-1-(2-(3-ethyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydroben

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3o[f]uMuga3o[1,2-d][1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide (compound 7).

By replacing compound 3-1 with compound 7-1, compound 7 was prepared following procedures similar to those described in Example 3.

LC-MS [M+H]+: 467.

Connections in the table 1 was prepared in accordance with the synthesis protocols set forth in Examples 17 using appropriate starting materials and suitable reagents.

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Table 1

No. Structure Chemical name LCMS[M+H] ⁺ approx. 8 ^vAAp_N sAy ^F NH ₂ 0 F (2 S)-1 -(2 -(5-difluoromethyl-3-methyl2,4-dioxoimidazolid in-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepine- 9-yl)pyrrolidine-2carboxamide 461 9 , AR- O' ⁿ y ^; v ^NHs ο ' (28)-1-(2-(5-isopropyl-2,4-dioxo3-phenylimide azolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepine-9 -yl)pyrrolidine-2carboxamide 515 10 ofb-p Q-γγ ° (S)-1 -(2-((8)-5-isopropyl-2,4dioxo-3-phenylimide azolidin-1 yl)-5,6-dihydrobenzo[£]imidazo[1,2d] [1,4] Oxazepin-9-yl)pyrrolidine2-carboxamide 515 AND 0¼ < 0' (S)-l-(2-((R)-5-isopropyl-2,4dioxo-3-phenylimide azolidin-1 yl)-5,6-dihydrobenzo[1]imidazo[1,2d] [1,4] Oxazepin-9-yl)pyrrolidine2-carboxamide 515 12 ^c-OVr ^ΝΗ! 0 ¹ (28)-1-(2-(5-isopropyl-2,4-dioxo3 -(4-(trifluoromethyl)phenyl)imide azolidin-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4]oxazepin-9-yl)pyrrolidin-2carboxamide 583 13 ο ifb-p -Al _χ °=< Λ ^ΝΗ2 0 ' (28)-1-(2-(5-isopropyl-2,4-dioxo3-propylimide azolide in-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepine- 9-yl)pyrrolidine-2carboxamide 481

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14 UY? AY (2 S)-1-(2-(3-cyclopropyl-5isopropyl)-2,4dioxoimid azolide in-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepine- 9-yl)-2methylpyrrolidin-2-carboxamide 493 15 \7Уу nh ₂ (2 S)-1-(2-(3-cyclopropyl-5isopropyl)-2,4dioxoimid azolide in-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]thiazepine- 9-yl)-4,4difluoropyrrolidine-2-carboxamide 531 16 ί^° .l/% ^ι Άγ· °< (2 S)-1 -(2-(5 -isopropyl-3 -(1 -methyl1H-1,2,4-triazol-5-yl)-2,4dioxoimidazolidin-1-yl)-5,6 dihydrobenzo[1 ]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidin-2carboxamide 520 17 (28.48)-4-amino-1-(2-(3cyclopropyl-5-isopropyl-2,4dioxoimid azolide in-1-yl)-5,6dihydrobenzo[1] imidazo [1,2-d] [1, 4]oxazepin-9-yl)pyrrolidin-2carboxamide 494 18 o _b /ybp Q7V < (28)-1-(2-(3-(2-fluorophenyl)-5isopropyl-2,4dioxoimid azolide in-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4] Oxazepin-9-yl)pyrrolidin-2carboxamide 533 19 _v j£bp «-Q-γγ (2 S)-1 -(2-(3 -(4-chlorophenyl)-5isopropyl-2,4dioxoimide azolide in-1 -yl)-5,6- 549

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dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidin-2carboxamide 20 \/ ^Γ ^ ^Ν ΥΤ ^{/ ΝΗ} 2 0 ' (2 8)-4-(tert-butoxy)-1-(2-(3cyclopropyl-5-isopropyl-2,4dioxoimide azolide in-1-yl)-5,6dihydrobenzo[1] imidazo [l,2]-d] [ 1,4]oxazepin-9-yl)pyrrolidin-2carboxamide 551 21 F° <y irbyAо=/ ^ΝΗζ 0 ' (2 S)-1 -(2-(3 -cyclopropyl-5 isopropyl)-2,4dioxoimide azolide in-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepine -9-yl)-4,4dimethylpyrrolidin-2-carboxamide 507 22 I yN 0=( ^NHz 0 ' (2 S)-1 -(2-(3 -(2,2-difluoroethyl)-5isopropyl-2,4dioxoimid azolide in-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2^ ] [ 1, 4]oxazepin-9-yl)pyrrolidin-2carboxamide 503 23 ^NH2 o' (2 S)-1 -(2-(3,5-diisopropyl-2,4dioxoimide azolide in-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepine-9 -yl)pyrrolidine-2carboxamide 481 24 _o [guAl >уу °=<& T ^NH 2 (2 S)-1 -(2-(3-cyclopropyl-5isopropyl)-2,4dioxoimide azolide in-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepine- 9-yl)-4phenylpyrrolidine-2-carboxamide 555

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25 ο ΡΥΥ ^ΝΗ2 CI (2 S)-1 -(2-(3 -(3 -chloro-5 -cyanophenyl)5-isopropyl-2,4dioxoimide azolide in-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2-d ][1,4]thiazepin-9-yl)pyrrolidin-2carboxamide 590 26 r^~ ^s l-LAr ^ ^Η 2 Ο ' (2 S)-1 -(2-(3,5-diisopropyl-2,4dioxoimide azolide in-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]thiazepine-9 -yl)pyrrolidine-2carboxamide 497 27 ^ΗΝ < /Υ ^ΝΗ2 0 ' (2 S)-1 -(2-(3 -azetidin-3 -yl)-5 isopropyl-2,4dioxoimide azolide in-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1 ,4]oxazepin-9-yl)pyrrolidin-2carboxamide 494 28 DD ΝΗ ₂ 0 (2 S)-1 -(2-(3 -methyl-2,4dioxoimide azolide in-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepin-9-yl )pyrrolidine-2carboxamide 411 29 νΑ^Ρ Ά ⁰ * (2 S)-1 -(2-(5 -tert-butyl-3-methyl-2,4dioxoimide azolide in-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepine -9-yl)pyrrolidin-2carboxamide 467 thirty .ΝΑ? f-O'Vy ^νΗ2 0 ¹ (S)-1 -(2-((R)-3 -(4-fluorophenyl)-5isopropyl-2,4dioxoimide azolide in-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2]h1] [ 1,4]oxazepin-9-yl)pyrrolidin-2carboxamide 533

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31 NV ^NH2 0' (S)-l -(2-((S)-3 -(4-fluorophenyl)-5isopropyl-2,4dioxoimid azolide in-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2]-с1] [ 1,4]oxazepin-9-yl)pyrrolidin-2carboxamide 533 32 ΥΥ V ^r ' ^N y ⁾ ' ^/ < ^NH2 0 ' (28)-1-(2-((5K)-3-cyclopropyl-5isopropyl-2,4dioxoimid azolide in-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4] Oxazepin-9-yl)pyrrolidin-2carboxamide 479 33 Yr ^nh 2 0 ' (2S)-1 -(2-((5S)-3-cyclopropyl-5isopropyl-2,4dioxoimide azolide in-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4] Oxazepin-9-yl)pyrrolidin-2carboxamide 479 34 0' (28)-1-(2-(3-(2-hydroxyethyl)-5isopropyl-2,4dioxoimid azolide in-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4] Oxazepin-9-yl)pyrrolidin-2carboxamide 483 35 o flrb-p _F -\ o=Z nh ₂ 0 ' (2 S)-1 -(2-(3 -(2-fluoroethyl)-5isopropyl-2,4dioxoimide azolide in-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4 ]oxazepin-9-yl)pyrrolidin-2carboxamide 485 36 \ % YhA ^NX =/ \J W θ=( ₀ T ^NH 2 (28)-1-(2-(3-(2- (dimethylamino)ethyl)-5-)isopropyl2,4-dioxoimidazolidin-1-yl)-5,6- 510

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dihydrobenzo[1]imidazo[1,2-d] [ 1,4]oxazepin-9-yl)pyrrolidin-2carboxamide 37 J/? ^ΝΗ 2 0 ' (2 S)-1-(2-(3-cyclopropyl-5isopropyl)-2,4dioxoimid azolide in-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]thiazepine- 9-yl)pyrrolidine-2carboxamide 495 38 ^F ν 0 (2 S)-1 -(2-(3 -(6-fluoropyridin-3 -yl)5-isopropyl-2,4dioxoimide azolide in-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2- d] [ 1,4]oxazepin-9-yl)pyrrolidin-2carboxamide 534 39 {'''Ο _F ·Μ °=( />Yy ^ΝΗι (2 S)-1 -(2-(3 -(5 -fluoropyridin-3 -yl)5-isopropyl-2,4dioxoimidazolidin 1 -yl)-5,6dihydrobenzo[1]imidazo[1,2]-4] [ 1,4]oxazepin-9-yl)pyrrolidin-2carboxamide 534 40 » iCb-o-' NC _0=< Η F (2 S)-1 -(2-(3 -(3 -cyano-5-fluorophenyl)5-isopropyl-2,4dioxoimide azolide in-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2-d ] [1,4]oxazepin-9-yl)-4fluoropyrrolidine-2-carboxamide 576 41 » ifb-p еХГУТ “ ^H1 (2 S)-1 -(2-(3 -(3-chloropyrimidin-2yl)-5-isopropyl-2,4dioxoimid azolide in-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [ 1,4]oxazepin-9-yl)pyrrolidin-2carboxamide 551

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42 C^Vi ^NHz (2 S)-1 -(2-(3-cyclopentyl-5 isopropyl-2,4dioxoimid azolide in-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepine- 9-yl)pyrrolidine-2carboxamide 507 43 " ifb-p NC bN ₀ =< ^NH 2 0 ' (2S)-1 -(2-(3 -(cyanomethyl)-5isopropyl-2,4dioxoimid azolide in-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4]oxazepine- 9-yl)pyrrolidine-2carboxamide 478 44 Air -- nh ₂ o ' (2 S)-1-(2-(5-isopropyl-3-methyl-2,4dioxoimide azolide in-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]thiazepine -9-yl)pyrrolidin-2carboxamide 469 45 ^ ^N V ^X y ^{/ NH} 2 0 ' (2 S)-1 -(2-(3 -(2,2-d iforoethyl)-5 isopropyl-2,4dioxoimid azolide in-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4]thiazepin-9-yl)pyrrolidin-2carboxamide 519 46 \U yV NH ₂ 0 ' (2 S)-1-(2-(3-cyclopropyl-5isopropyl-2,4dioxoimid azolide in-1-yl)-3 vinyl-5,6dihydrobenzo[1]imidazo[1,2-d] [1,4] Oxazepin-9-yl)pyrrolidin-2carboxamide 505 47 ^0 ^0| ^ ^ν χ_/Α^ уЛ “o=p Η/Υ nh ₂ 0 ' (2 S)-1 -(3 -chloro-2-(3 -cyclopropyl -5isopropyl-2,4dioxoimide azolide in-1 -yl)-5,6- 513

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dihydrobenzo[1]imidazo[1,2-d] [ 1,4]oxazepin-9-yl)pyrrolidin-2carboxamide 48 About F (2 S)-1-(2-(3-cyclopropyl-5(difluoromethyl)-2,4dioxoimide azolide in-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-b] [1, 4] thiazepin-9-yl)pyrrolidin-2carboxamide 503 49 o.irb-p, У-N 0=7 OH 'У'УА-У ^NH ₂ о' (28.38)-1-(2-(3-cyclopropyl-5isopropyl-2,4- dioxoimide azolide in-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepin-9-yl)-3-hydroxypyrrolidine-2-carboxamide 495 50 yo „ \\ /~ ^N / zn '— ZN 0=/ nh ₂ 0 ' (2 8)-1-(2-(3-cyclopropyl-5isopropyl-2,4dioxoimid azolide in-1-yl)-3 methyl-5,6- Dihydrobenzo[1]imidazo[1.2h1][1,4]oxazepin-9-yl)-4ohopyrrolidin-2-carboxamide 507 51 _G o >-N 0=7 V ^r ' ^N y4 ^{/ NH} * O ' (2 8)-4-cyclohexyl-1 -(2-(3 cyclopropyl-5-isopropyl-2,4dioxoimid azolide in-1 -yl)-5,6dihydrobenzo[1]imidazo[1,2-d] [ 1,4]oxazepin-9-yl)pyrrolidin-2carboxamide 561 52 t^~ ^S \__ o „ i K / ^N / °v A~ ⁿ '— z Z~N ₀₌ 7 nh ₂ 0 ' (2 8)-1-(2-(3-cyclopropyl-5isopropyl-2,4dioxoimid azolide in-1-yl)-5,6dihydrobenzo[G]imidazo[1,2-d][1,4]thiazepine-9 -yl)-5-oxopyrrolidine- 509 2-carboxamide

All racemic compounds in the table. 1 can be synthesized using appropriate chiral raw materials to obtain the corresponding enantiomers, or the enantiomers are separated on a chiral column substantially in accordance with the method described in Example 2, Step 7.

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Control connection.

table 2

Example Connection name Structure 1 (2 S)-1 -(2-((4K)-4-methyl-2- Oxooxazolidin-3-yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidin-2carboxamide ..... ^NH 2 2 (2 S)-1 -(2-((2K)-2-(hydroxymethyl)5-oxopyrrolidin-1-yl)-5,6dihydrobenzo[1]imidazo[1,2-d][1,4]oxazepine- 9-yl)pyrrolidine-2carboxamide 7~N O=\ SC ^nh * he 3 (2S)-1 -(2-(2-(1,1,1-trifluoro-2methylrgorap-2-yl)pyridin-4-yl)5,6-dihydrobenzo[1]imidazo[1,2^] [ 1 ,4]oxazepin-9-yl)pyrrolidin-2carboxamide -Λ—CF ₃

Control compound 1 (Example 102 in WO 2017001658) and control compound 2 were prepared according to the synthesis protocols set out in WO 2017001658 using appropriate starting materials, intermediates and agents. The method for obtaining control compound 3 is as follows.

Obtaining control connection 3.

stage 9 control connection stage 3

PdidppfK'l. dioxide stage ί dioxane, H?O

Step 1: synthesis of compound D3-2.

Compound D3-1 (2000 g) and oxalyl chloride (2019 g) were dissolved in dichloromethane (8 L). DMF (5 ml) was slowly added to the reaction mixture and refluxed for 6 hours. The reaction system was concentrated to obtain 2245 g of a suspension containing a yellow solid, which was used directly in the next step.

Step 2: synthesis of compound D3-3.

To a solution of 4-methoxy-3-buten-2-one (642 g) in anhydrous THF (16 L), 6.42 L of LiHMDS (1 mol/L) dissolved in THF was added dropwise at -78°C. After stirring at -78°C for 2 hours, the suspension obtained in step 1, dissolved in THF (1 L), was slowly added to the reaction system, stirred at -78°C for 1-2 hours, the reaction mixture was warmed to room temperature temperature and stirred for 16 hours. The resulting reaction mixture was used directly after

- 29 046877 blowing stage.

LC-MS [M+H]+: 239.

Step 3: synthesis of compound D3-4.

The reaction mixture obtained in step 2 was quenched by adding water (500 ml) in an ice bath, and then trifluoroacetic acid (50 ml) was added and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated and extracted with EA. The organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (Hex/EA 100:1-10:1) to give a brown solid. The brown solid was washed with a mixed solvent of HEX and EA (50:1 v/v), the reaction mixture was filtered with suction, and the filtrate was collected and concentrated to give D3-4 (395 g).

LC-MS [M+H]+: 207.

1H NMR (MeOD-d6): 1.59 (s, 6H), 6.39-6.41 (m, 1H), 6.53-6.54 (m, 1H), 8.12-8.14 (m, 1H).

Step 4: synthesis of compound D3-5.

Compound D3-4 (395 g) was added to 2 L of ammonia (30%), stirred and refluxed for 2 hours. The reaction mixture was cooled, concentrated to obtain 343.00 g of Compound D3-5, which was used immediately next stages.

LC-MS [M+H]+: 206.

Step 5: synthesis of compound D3-6.

A mixture of compound D3-5 (343 g) and phosphorus oxybromide (966.68 g) was heated to 120° C. and stirred for 1 hour. The reaction mixture was poured into ice water while it was hot. Sodium bicarbonate was added to adjust the pH to neutral, and the reaction mixture was extracted with EA. The organic layers were dried and concentrated. The residue was purified by column chromatography (Hex/EA=100:1) to give compound D3-6 (305 g).

LC-MS [M+H] ⁺ : 269.

¹ H NMR (MeOD-d6): 1.59 (s, 6H), 7.52-7.54 (m, 1H), 7.78 (s, 1H), 8.41-8.42 (m, 1H).

Step 6: synthesis of compound D3-7.

Bis(pinacolato)diborane (710.45 mg), compound D3-6 (500 mg), potassium acetate (1.88 g), [PdCl ₂ (dppf)]CH ₂ Cl ₂ (152.32 mg) and dioxane ( 20 ml) was added to a one-neck flask under a protective nitrogen atmosphere, the reaction proceeded in an oil bath at 90°C for 4 hours. The reaction mixture was concentrated. The residue was purified by column chromatography (Hex/EA=3:1) to obtain compound D3-7 (450 mg).

LC-MS [M+H] ⁺ :316.

Step 7: synthesis of compound D3-8.

[PdCl ₂ (dppf)]CH ₂ Cl ₂ (233.22 mg), potassium carbonate (394.70 mg), compound D3-7 (450 mg), compound M-5 (586 .25 mg), dixon (3 ml) and H ₂ O (0.5 ml), refluxed in an oil bath at 70°C for 15 hours. The reaction mixture was concentrated. The residue was purified by column chromatography (PE:EA=50:50) to obtain compound D3-8 (130 mg).

LC-MS [M+H] ⁺ : 452.

Step 8: synthesis of compound D3-9.

Compound D3-9 was prepared according to the synthesis protocols outlined in step 5 of Example 2.

LC-MS [M+H] ⁺ : 487.

Step 9: Synthesis of control compound 3.

Control compound 3 was prepared according to the synthesis protocols outlined in step 6 of Example 2.

LC-MS [M+H] ⁺ : 486.

Pharmacological experiment.

The following experiments showed that the preferred compounds of the present invention effectively inhibit PI3Ka kinase activities in vitro. The antiproliferative activities against tumor cells bearing PI3Ka mutants and the pharmacokinetic profile of the preferred compound of the present invention are superior to those of the control compound with significant superiority.

Example A: experiment with kinases.

The kinases PI3Ka, PI3Ke, PI3Ky undergo enzymatic reactions with their substrates ATP and PIP2:3PS, and the amount of product detected using the ADP-Glo agent and the luminescence method was used to reflect the enzymatic activities of PI3Ka, PI3Ke, PI3Ky (final ATP concentration is 10 µM). The above methods were used to test the inhibitory activity of a certain compound of the present invention against PI3Ka, PI3Ke and PI3Ky kinase.

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Method.

Agent: basic kinase buffer (pH 7.5); solutions of kinases ΡΙ3Κα, ΡΙ3Κβ, ΡΙ3Κγ; PIP2:3PS and ATP solutions; ADP-Glo kit (containing 10 mM MgCl ₂ ).

The composition of the buffer is: 50 mM Hepes (pH 7.2-7.5), 3 mM MgCl ₂ , 1 mM EGTA, 0.03% CHAPS, 100 mM NaCl, 2 mM DTT;

Compound Preparation: The test compound was diluted to a specified concentration with 100%DMSO.

Methodology.

1) The protein solution of PI3Ka, PI3Ke or PI3Ky was applied to a 384-well assay plate (6008280, PerkinElmer) and centrifuged at 1000 rpm for 1 min.

2) The test compound, DMSO as a negative control or BYL719 as a positive control was added to the above 384-well kinase assay plate, centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 15 minutes.

3) PIP2:3PS&ATP solution was added to the above 384-well assay plate, centrifuged at 1000 rpm for 1 min, incubated at 25°C for 60 min.

4) 5 μl of ADP-Glo agent (containing 10 mM MgCl2) was transferred to a 384-well assay plate, centrifuged at 1000 rpm for 1 min, and incubated at 25°C for 40 min.

5) 10 μl of the detection agent was transferred to a 384-well assay plate, centrifuged at 1000 rpm for 1 min, and incubated at 25°C for 40 min.

6) The RLU (relative luminescence unit) value was measured using an Envision multifunctional tablet reader. The RLU value was used to characterize the degree of reaction between the enzyme and substrate and calculate the IC ₅₀ value.

7) Data analysis.

Inhibition rate of compound (% ir) (Negative control RLU - Test compound RLU)/(Negative control RLU - Positive control RLU) * 100%

The IC ₅₀ (half inhibitory concentration) value of a compound was obtained using the following nonlinear fitting formula:

Y=minimum degree of inhibition+(maximum degree of inhibition - minimum degree of inhibitionU^+Y^^odGS^-X^Slope)); where X is the logarithm of the concentration of the test compound, Y is the degree of inhibition of the test compound (% ing).

The results of some examples of the present invention are shown in table. 3. In the above table, A represents an IC ₅₀ value of <5 nM; B represents an IC ₅₀ value of 5~20 nM; C represents an IC ₅₀ value of 300~600 nM; D represents IC ₅₀ value > 600 nM.

Table 3

Example ICso connections to PI3K (nM) A β Υ Example 1 A D D Example 2 A D WITH Example 3 A / / Example 4 IN D D Example 5 IN / / Example 6 IN / / Example 7 V / / Example 9 V / / Example 23 A / / Example 32 A WITH WITH Example 33 A D D

Note: / means not tested.

As shown in table. 3, the compound provided by the present invention has favorable PI3Ka kinase inhibitory activities and good selectivity for PI3Ke and PI3Ky isoforms, thereby avoiding potential adverse effects caused by multi-target inhibition.

Example B: Cell Proliferation Assay.

Method. The antiproliferative effects of certain compounds of the present invention on MCF-7 and HGC27 human tumor cells were assessed using the CellTiter Glo assay.

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Detection method: MCF-7 cells were suspended in DMEM culture medium, the cell concentration in which was adjusted to 25,000 cells/ml; HGC27 cells were suspended in RPMI-1640 culture medium, the cell concentration in which was adjusted to 5000 cells/ml. 100 μl of cell suspension was applied to a 96-well assay plate and placed in a CO ₂ incubator overnight. Test compounds were dissolved in DMSO and 3-fold serial dilutions were performed to obtain 10 different concentrations. The resulting 10 different concentrations of the test compound or negative control were transferred into a well containing 100 μl of culture medium, respectively, incubated at 37°C, 5% CO ₂ , HGC27 cells were incubated for 96 hours, MCF-7 cells were incubated for 120 hours. Then, 100 μL of CellTiter-Glo agent was added to the above-mentioned 96-well assay plate and incubated at room temperature for 10 min to ensure a stable luminescence signal. A VICTOR TM X5 instrument was used to record RLU (relative luminescence unit) and then IC ₅₀ values were calculated.

Inhibition rate for a compound (% ing) = 100% - (RLU in the presence of test compound - RLU of blank control)/(RLU of negative control - RLU of blank control) * 100%

Negative control: DMSO.

Blank control: Blank culture medium without compound or cells.

The IC ₅₀ (half maximal inhibitory concentration) value of a compound was obtained using the following nonlinear fitting formula:

Y=minimum degree of inhibition + (maximum degree of inhibition - minimum degree of inhibition)/(1+10 ^l ((Bod1C ₅₀ -X)*Slope)); where X: logarithm of the concentration of the test compound; Y: degree of inhibition of the test compound (% ing).

The experimental data are presented in table. 4 and table. 5.

Table 4

IC ₅₀ value for compounds from MCF cell examples

Example ICso(mkM) compounds on MCF cells Control connection 1 0.444 Control connection 2 0.549 Control connection 3 0.519 Example 1 0.176 Example 2 0.070 Example 5 0.373 Example 9 0.142 Example 23 0.074 Example 28 0.468 Example 32 0.107 Example 33 0.047

Table 5

IC ₅₀ value for compounds exemplified in HGC-27 cells

Example ICso(mkM) compounds on HGC-27 cells Control connection 1 1,579 Control connection 3 2,067 Example 2 0.361 Example 5 4,071 Example 28 3.921 Example 32 0.415 Example 33 0.267

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From the above table, it can be seen that the compounds provided in the present invention have higher cell proliferation inhibitory activities for cell lines bearing PI3Ka point mutations than control compounds and have higher antitumor effects at the same concentration. Thus, it can be expected that the compound provided by the present invention will be a PI3Kα kinase inhibitor having superior antitumor effects.

Example C: pharmacokinetic test.

Method: 42 male SD rats, weight: 150-300 g. Randomly divided into 7 groups, 6 rats in each group. Of the 6 rats in each group, three were administered a single intravenous injection of 2 mg/ml of the Example Compound, the other three were intragastrically administered 10 mg/ml of the Example Compound, blood was collected from the orbital venous plexus at specific time points, and plasma was separated and stored in a refrigerator at - 80°C for subsequent use.

The resulting plasma protein was precipitated with acetonitrile, the supernatant was extracted and mixed with water in a 1:1 ratio, 10 μl was taken for detection by LC-MS/MS, and the average value was calculated. The results are presented in table. 6.

Table 6

Pharmacokinetic Test Results for Example Compounds

No. Connection Intravenous injection Gastric tube Dose (mg/kg) C.L. (ml/min/kg) Dose (mg/kg) Stakh (ng/ml) AUC (h*ng/ml) Control connection 1 2 16.6 10 1963 7882 Example 2 2 1.98 10 4340 52993 Example 4 2 4.75 10 2690 29080 Example 23 2 8.76 10 1833 18563 Example 32 2 1.5 10 5033 66414 Example 33 2 ID 10 1597 19832

According to relevant statistics (Kola I, Landis J. Nat Rev Drug Discov. 2004 Aug;3(8):711-5.), in the early 1990s, about 40% of drug candidates failed clinical trials due to poor pharmacokinetics/ bioavailability, therefore pharmacokinetics/bioavailability plays a very important role in clinical trials of drug candidates.

The above table shows that the compounds provided by the present invention have unexpectedly higher oral exposure and lower in vivo clearance compared to control compounds, resulting in higher systemic exposure at the same dose. The compound of the present invention achieves the same antitumor effects at a lower dose level, thereby reducing the likelihood of toxicity and safety risks, as well as increasing the medicinal usefulness of the compound.

Claims (52)

1. A compound of formula (I) or a stereoisomer, geometric isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof Formula (I) where X is selected from O and S; R ₁ is selected from H or C _1-6 -αalkyl, optionally substituted with one or more halogens; R ₂ is selected from H, C _1-6 -alkyl, C _3-6 -cycloalkyl, C _3-6 -heterocyclyl, C _6-8 -aryl and C _5-8 -heteroaryl; where C _1-6 -αalkyl, C _3-6 -cycloalkyl, C _3-6 -heterocyclyl, C _6-8 -aryl and ^^-heteroaryl are each optionally substituted with one or more substituents selected from halogen, CN, - HE, - 33 046877 C _1-6 -alkyl, C _1-6 -haloalkyl and -NRaRb; and wherein C _3-6 -heterocyclyl contains from 1 to 3 heteroatoms selected from N, O or S, and C _5-8 -heteroaryl contains from 1 to 4 heteroatoms selected from N, O or S; R3 is selected from H, C _1-6 -alkyl and C _2-6 -alkenyl; R4 is H; R ₅ represents H; R6 is selected from H, halogen, oxo, C _1-6 -alkyl, C _3-6 -cycloalkyl, C _6-8 -aryl, -ORa, -NRaRb,; Ra and Rb are independently selected from H and C _1-6 -alkyl; m is selected from 0, 1, 2, 3 and 4; n is selected from 0, 1, 2 and 3; y is selected from 0, 1, 2, 3, 4, 5 and 6. 2. A compound according to claim 1 or a stereoisomer, geometric isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (V): NH ₂ o Formula (V), where R ₁ is selected from C _1-6 -alkyl and C _1-6 -haloalkyl; R2 is selected from H, C _1-6 -alkyl, C _3-6 -cycloalkyl, C _3-6 -heterocyclyl, C ₆ -aryl and C _5-6 -heteroaryl; where C _1-6 -alkyl, C _3-6 -cycloalkyl, C _3-6 -heterocyclyl, C ₆ -aryl and C _5-6 -heteroaryl are each optionally substituted with one or more substituents selected from halogen, -CN, -OH, -^(CH3^, C1. ₆ -alkyl and C _1-6 -haloalkyl. 3. A compound according to claim 1 or a stereoisomer, geometric isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (VII): o ¹ Formula (VII) where R2 is selected from H, C _1-6 -αalkyl, C _3-6 -cycloalkyl, C _3-6 -heterocyclyl, C ₆ -aryl and C5 _-6 -1'heteroaryl; and said R ₂ is optionally substituted with halogen. 4. A compound according to any one of claims 1 to 3 or its stereoisomer, geometric isomer or tautomer, or a pharmaceutically acceptable salt thereof, where R2 is selected from _-CH3 , -CH2CH3, -CH( _CH3 ) ₂ , -CH2CF3, cyclopropyl, cyclobutyl, phenyl and pyridyl; where -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CF ₃ , cyclopropyl, cyclobutyl, phenyl and pyridyl are each optionally substituted with halogen. 5. A compound according to any one of claims 1 to 4, or a stereoisomer, geometric isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R ₂ is selected from -CH ₃ , -CH(CH ₃ ) ₂ , cyclopropyl, phenyl and halogenated phenyl. 6. A compound according to any one of claims 1 to 5, or a stereoisomer, geometric isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R ₂ is selected from -CH(CH ₃ ) ₂ and cyclopropyl. 7. A compound according to claim 1, or a stereoisomer, geometric isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following: 1) (2S)-1-(2-(5-isopropyl-3-methyl-2,4-diokCOimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1.20][1.4] oxazepin-9-yl)pyrrolidin-2-carboxamide; 2) (2S)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxCOimidαzolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2^][1,4 ]oxazepin-9-yl)pyrrolidin-2-carboxamide; 3) ^)-1-(2-(5-isopropyl-2,4-dioxo-3-(2,2,2-trifluoroethyl)imidazolidin-1-yl)-5,6-dihydrobenzo[1]imidazo [1,2^][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide; 4) ^)-1-(2-(3-(4-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[1]imidazo[1,2^][ 1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide; 5) DO)-1-(2-(5-cyclopropyl-3-methyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[1]imidazo[1,20][1,4]oxazepine -9-yl)pyrrolidin-2-carboxamide; 6) ^)-1-(2-(3-cyclobutyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[1]imidazo[1,2b][1,4]oxazepine -9-yl)pyrrolidin-2-carboxamide; 7) DO)-1-(2-(3-ethyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[1]imidazo[1,2- b][1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide; - 34 046877 8) (2S)-1-(2-(5-difluoromethyl-3-methyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2d][1,4] oxazepin-9-yl)pyrrolidin-2-carboxamide; 9) (^)-1-(2-(5-isopropyl-2.4-dioxo-3-(|)enylimidazolidin-1-yl)-5.6-dihydrobenzo[G|imidazo[1.2d][1,4]oxazepin- 9-yl)pyrrolidin-2-carboxamide; 10) (b)-1-(2-((b)-5-isopropyl-2.4-dioxo-3-(|)enylimidazolidin-1-yl)-5.6-dihydrobenzo[G|imidaz,o[1.2- d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide; 11) (B)-1-(2-((K)-5-isopropyl-2.4-dioxo-3-(|)enylimidazolidin-1-yl)-5.6-dihydrobenzo[G|imidaz,o[1.2d][ 1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide; 12) (2S)-1-(2-(5-isopropyl-2,4-dioxo-3-(4-(trifluoromethyl)phenyl)-imidazolidin-1-yl)-5,6-dihydrobenzo [G|imidazo[ 1.2-d|[1,4]oxazepin-9-yl)-pyrrolidine-2-carboxamide; 13) (2S)-1-(2-(5-isopropyl-2,4-dioxo-3-propylimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide; 14) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazoPD-DPM]oxazepin-9-yl) -2-methylpyrrolidine-2-carboxamide; 15) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f|imidazo[1,2-d][1 ,4]thiazepin-9-yl)-4,4-difluoropyrrolidine-2-carboxamide; 16) (^)-1-(2-(5-isopropyl-3-(1-methyl-1H-1.2.4-triaz,ol-5-yl)-2.4-dioxoimidazolidin-1-yl)-5.6-dihydrobenzo [H]imidazo[V-dHM]oxazepin-9-yl)pyrrolidine-2-carboxamide; 17) (2S,4S)-4-amino-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[G|imidazo[1.2-d |[ 1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide; 18) (2S)-1-(2-(3-(2-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f|imidazo[1,2-d ][1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide; 19) (2S)-1-(2-(3-(4-chlorophenyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f|imidazo[1,2-d ][1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide; 20) (^)-4-(tert-butoxy)-1-(2-(3-cyclopropyl-5-is,oppropyl-2.4-dioxoimidazolidin-1-yl)-5.6-dihydrobenzo [G|imidazo [1,2 -d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide; 21) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1 ,4]oxazepin-9-yl)-4,4-dimethylpyrrolidine-2-carboxamide; 22) (2S)-1-(2-(3-(2,2-difluoroethyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1.2-d |[1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide; 23) (^)-1-(2-(3.5-diis,oppropyl-2.4-dioxoimidazolidin-1-yl)-5.6-dihydrobenzo[G|imidazo[1.2- d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide; 24) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1 ,4]oxazepin-9-yl)-4-phenylpyrrolidine-2-carboxamide; 25) (2S)-1-(2-(3-(3-chloro-5-cyanophenyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo [G|imidazo [1.2 -d|[1,4]thiazepin-9-yl)pyrrolidin-2-carboxamide; 26) (^)-1-(2-(3.5-diisopropyl-2.4-dioxoimidazolidin-1-yl)-5.6-dihydrobenzo[G|imidazo[1.2-d|[1,4]thiazepin-9-yl)pyrrolidin- 2-carboxamide; 27) (2S)-1-(2-(3-azetidin-3-yl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[G|imidazo[1.2-d| [ 1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide; 28) (2S)-1-(2-(3-methyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f|imidazo[1,2-d][1,4]oxazepine9- yl)pyrrolidine-2-carboxamide; 29) (2S)-1-(2-(5-tert-butyl-3-methyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2d][1,4] oxazepin-9-yl)pyrrolidin-2-carboxamide; 30) (S)-1-(2-((R)-3-(4-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f|imidazo[1.2 |-d|[1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide; 31) (S)-1-(2-((S)-3-(4-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f|imidazo [1.2 ^^1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide; 32) (2S)-1-(2-((5R)-3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d ][1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide; 33) (2S)-1-(2-((5S)-3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo [1.2-D|[ 1.4|oxazepin-9-yl)pyrrolidin-2-carboxamide; 34) (2S)-1-(2-(3-(2-hydroxyethyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f|imidazo[1,2-d ][1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide; 35) (2S)-1-(2-(3-(2-fluoroethyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo [1.2-d|[ 1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide; 36) (2S)-1-(2-(3-(2-(dimethylamino)ethyl)-5-)isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[G|imidazo[1.2 -d|[1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide; 37) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f|imidazo[1.2-d| [1,4]thiazepin-9-yl)pyrrolidin-2-carboxamide; 38) (2S)-1-(2-(3-(6-fluoropyridin-3-yl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo [G|imidazo [1.2 -d|[1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide; - 35 046877 39) (2S)-1-(2-(3-(5-fluoropyridin-3-yl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[G]imvdazo [1 ,2]-d][ 1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide; 40) (^)-1-(2-(3-(3-cyano-5-(|)tor(|)enyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6- dihydroben'u[Pimidazo[1,2D][1,4]oxazepin-9-yl)-4-(|)torpyrrolidine-2-carboxamide; 41) (2S)-1-(2-(3-(3-chloropyrimidin-2-yl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[£]imidazo [1 ,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide; 42) (2S)-1-(2-(3-cyclopentyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo [1,2-d] [1, 4]oxazepin-9-yl)pyrrolidin-2-carboxamide; 43) (2S)-1-(2-(3-(cyanomethyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo [1,2-d] [ 1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide; 44) (2S)-1-(2-(5-isopropyl-3-methyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2d] [1,4] thiazepin-9-yl)pyrrolidin-2-carboxamide; 45) DO)-1-(2-(3-(2,2-difluoroethyl)-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[:G]imidazo[1,2 -d][1,4]thiazepin-9-yl)pyrrolidin-2-carboxamide; 46) (2S)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-3-vinyl-5,6-dihydrobenzo[G]imidazo[1,2-d ][ 1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide; 47) (2S)-1-(3-chloro-2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[G]imidazo[1,2-d ][ 1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide; 48) (^)-1-(2-C3-cyclopropyl-5-(di(|)tormethyl)-2.4-dioxoimidazolidin-1-yl)-5.6-dihydrobenzo[G]imidazo[1,2-d] [1 ,4]thiazepin-9-yl)pyrrolidin-2-carboxamide; 49) DO^)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[:G]imidazo[1,2-d] [1,4]oxazepin-9-yl)-3-hydroxypyrrolidine-2-carboxamide; 50) (2S)-1 -(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1 -yl)-3-methyl-5,6-dihydrobenzo[G]imidazo[1,2-d ][ 1,4]oxazepin-9-yl)-4-oxopyrrolidine-2-carboxamide; 51) (2S)-4-cyclohexyl-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d ][1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide; And 52) DO)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[:G]imidazo[1,2-d][ 1,4]thiazepin-9-yl)-5-oxopyrrolidine-2-carboxamide. 8. A pharmaceutical composition which contains a therapeutically effective amount of at least one compound according to any one of claims 1 to 7 or a stereoisomer, geometric isomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 9. The pharmaceutical composition according to claim 8, wherein the weight ratio of said compound or its stereoisomer, geometric isomer or tautomer, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is 0.0001-10. 10. A method of treating or preventing a PI3K-mediated disease, comprising administering to said subject in need thereof a therapeutically effective amount of a compound according to any one of claims. 1-7 or a pharmaceutical composition according to claim 8 or 9, wherein the disease is cancer. 11. The method according to claim 10, where the PI3Ks include ΡΙ3Κα, ΡΙ3Κβ, ΡΙ3Κδ and/or ΡΙ3Κγ. 12. The method according to claim 10, where PI3K is PI3Ka. 13. The method of claim 10, wherein the cancer is sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer , melanoma, kidney cancer, bladder cancer, uterine cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharyngeal cancer, laryngeal cancer, lymphoma, basal cell carcinoma, polycythemia vera, essential thrombocythemia. 14. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 or 9, wherein the cancer is sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, uterine cancer, vaginal cancer, ovarian cancer, multiple myeloma, cancer esophagus, leukemia, brain cancer, cancer of the oral cavity and pharynx, laryngeal cancer, lymphoma, basal cell carcinoma, polycythemia vera, essential thrombocythemia. 15. The method according to claim 14, where the subject is a person.