Crystal form of a derivative of aryl phosphine oxide free base, and preparation method and application thereof

Abstract

The application relates to a crystal form of a free base of an aryl phosphine oxide derivative, a preparation method and application thereof, and particularly relates to a crystal form of a compound shown in a general formula (I), a preparation method, a pharmaceutical composition containing a therapeutically effective amount of the compound or the crystal form, and a use of the compound as an EGFR inhibitor in preparation of a medicine for treating cancer-related diseases.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of biological medicine, and particularly relates to a crystal form of aryl phosphine oxide derivative free base, a preparation method and application thereof. BACKGROUND

[0002] EGFR (Epidermal Growth Factor Receptor) is a member of transmembrane receptor tyrosine kinase ErbB family, which is activated by binding with its ligand epidermal growth factor (EGF) or transforming growth factor alpha (TGFa). The activated EGFR forms homodimers on the cell membrane, or forms heterodimers with other receptors (such as ErbB-2, ErbB-3, or ErbB-4) in the family, causing phosphorylation of key tyrosine residues in the cell, thereby activating the downstream signaling pathway in the cell, playing an important role in cell proliferation, survival and anti-apoptosis. The activation mutation, overexpression or gene amplification of EGFR can lead to the overactivation of EGFR, promote the transformation of cells to tumor cells, and play an important role in the proliferation, invasion, metastasis and vascular formation of tumor cells. It is an important target for the development of anti-cancer drugs, especially lung cancer treatment drugs.

[0003] The first generation of small molecule EGFR inhibitors includes gefitinib (Iressa) and erlotinib (Tarceva), which show good efficacy in the treatment of lung cancer and have been used as first-line drugs for the treatment of non-small cell lung cancer (NSCLC) with EGFR activating mutations (including L858R and delE746_A750). However, after 10-12 months of treatment with the first generation of small molecule EGFR inhibitors, almost all NSCLC patients develop resistance to the first generation of small molecule inhibitors, and more than half of the resistance mechanisms are due to the secondary mutation of EGFR gatekeeper residue T790M.

[0004] Osimertinib (AZD9291) is a third-generation EGFR TKI inhibitor, which has a high response rate and good therapeutic effect on drug resistance caused by EGFR T790M mutation, and was approved for marketing by the US FDA in November 2015. It can effectively treat patients with advanced non-small cell lung cancer with EGFR T790M drug-resistant mutation in clinic. Although Osimertinib has made great success in the treatment of non-small cell lung cancer with EGFR T790M mutation in clinic, drug resistance still occurs after 9-14 months of treatment. Studies have shown that up to 20-40% of drug-resistant patients are due to EGFR C797S mutation. EGFR C797S mutation changes the 797th half-amino acid to serine, which prevents Osimertinib from forming a covalent bond with the EGFR protein, thereby causing drug resistance. At present, there is no effective inhibitor for EGFR C797S drug-resistant mutation in clinic. Therefore, it is urgent to develop new EGFR inhibitors with high activity to solve the problem of drug resistance caused by EGFR C797S mutation.

[0005] Novartis reported a compound EAI0450 against EGFR C797S drug resistance, which is an EGFR allosteric inhibitor. When combined with EGFR monoclonal antibody drugs such as cetuximab, it showed good antitumor effect in a mouse in vivo pharmacodynamic model of L858R / T790M / C797S mutation, but the compound had no effect as a single drug and could not inhibit C797S drug resistance containing deIE746_A750, and failed to enter clinical research. In 2017, Ken Uchibori et al. reported that Brigatinib (AP26113) combined with EGFR monoclonal antibody (such as cetuximab) can overcome the third-generation EGFR inhibitor drug resistance caused by C797S mutation, and shows good antitumor effect in PC9 (EGFR-C797S / T790M / de119) mouse pharmacodynamic model, but Brigatinib also faces the problems of low in vitro activity and no significant antitumor activity in vivo, and also has no further clinical research.

[0006] Lung cancer is a major disease that threatens human health, and the mortality rate of lung cancer has ranked first among all malignant tumors. In China, the incidence of lung cancer is increasing year by year, with about 700,000 new cases each year. In China, cases of lung cancer with EGFR activating mutation account for about 35% of all NSCLC, and the use of first-generation or third-generation EGFR inhibitors can achieve good therapeutic effect, but new drug-resistant mutations will occur in the later stage. Therefore, the development of a new generation of EGFR inhibitors against drug resistance has great clinical and market value. SUMMARY

[0007] All contents involved in patents PCT / CN2020 / 097362 and PCT / CN2020 / 097369 are added to the present application by citation.

[0008] The present application aims to provide a crystal form of a compound represented by general formula (I),

[0009]

[0010] wherein:

[0011] R1is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, alkylthio, halogenated alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0012] R2is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, alkylthio, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0013] Alternatively, any two R2s are linked with the carbon atom to which they are attached to form a cycloalkyl or heterocyclyl;

[0014] Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0015] R a is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, cyanoalkyl, alkoxy, halogenated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n OR aa , -(CH2) n NR aa R bb , -(CH2) n C(O)R aa or -(CH2) n S(O) m R aa ;

[0016] R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0017] x is an integer from 0 to 4;

[0018] y is an integer from 0 to 4;

[0019] t is an integer from 0 to 1;

[0020] m is an integer from 0 to 2; and

[0021] n is an integer from 0 to 2.

[0022] In a preferred embodiment of the present application, the crystalline form of the compound of formula (I) is wherein ring A is selected from 3-12 membered heterocyclyl; preferably 3-8 membered heterocyclyl; more preferably 3-8 membered monocyclic heterocyclyl or fused heterocyclyl containing 1-2 N or O atoms; further preferably from the following group:

[0023]

[0024] In a preferred embodiment of the present application, the crystalline form of the compound of formula (I) is wherein R a is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CH2) n OR aa , -(CH2) n NR aa R bb , -(CH2) n C(O)R aa or -(CH2) n S(O) m R aa ;

[0025] preferably hydrogen, deuterium, halogen, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 cyanoalkyl, C 1-3 alkoxy, -(CH2) n OR aa , -(CH2) n NR aa R bb , -(CH2) n C(O)R aa or -(CH2) n S(O) m R aa ;

[0026] more preferably hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, isopropyl, -(CH2)2F, -CH2OH, -C(CH3)2OH, -CH2CN, -OCH2CH3, -CH2OCH3, -C(O)CH3, -S(O)2CH3, -N(CH3)2, -NCH3(CH2CH3), or

[0027] R aa and R bb are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 alkoxy, halogenated alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0028] preferably hydrogen, methyl, ethyl, or oxetanyl;

[0029] x is an integer from 0 to 2.

[0030] In a preferred embodiment of the present application, the crystalline form of the compound of general formula (I), wherein R1is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 alkoxy, or C 1-6 alkylthio;

[0031] preferably hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-3 halogenated alkyl, or C 1-3 alkylthio;

[0032] more preferably fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, or methylthio;

[0033] most preferably chlorine, bromine, trifluoromethyl, or methylthio.

[0034] In a preferred embodiment of the present application, the crystalline form of the compound of general formula (I), wherein R2is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-6 alkenyl, or C 2-6 alkynyl;

[0035] preferably hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 2-4 alkynyl;

[0036] more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, methoxy or ethynyl;

[0037] most preferably hydrogen, fluorine, methyl, ethyl, trifluoromethyl, methoxy or ethynyl;

[0038] or, any two R2and the carbon atom to which they are attached link to form a 3-8 membered heterocyclyl; preferably a 5-6 membered heterocyclyl containing 1-2 N or O atoms; more preferably tetrahydrofuranyl;

[0039] y is an integer from 0 to 3.

[0040] In a further preferred embodiment of the present application, the crystal form of the compound represented by general formula (I) has the following specific structure:

[0041]

[0042]

[0043]

[0044]

[0045] In a more preferred aspect of the present application, there are provided the compounds (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide; (6-((5-chloro-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide;

[0046] 2-(1-(1-(4-((5-bromo-4-((5-(dimethylphosphanyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidin-3-yl)acetonitrile;

[0047] (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-l-yl)piperidin-l- yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[B][l,4]dioxin-5- yl)dimethylphosphine oxide.

[0048] Most preferred are crystalline forms H, N, O and I of (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-l-yl)piperidin-l-yl)-5-methylphenyl)amino)pyrimidin-4- yl)amino)-2,3-dihydrobenzo[B][l,4]dioxin-5-yl)dimethylphosphine oxide, wherein:

[0049] In a further preferred embodiment of the present application, crystalline form H of (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-l-yl)piperidin-l-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[B][l,4]dioxin-5-yl)dimethylphosphine oxide.

[0050] The X-ray powder diffractogram of crystalline form H has a diffraction peak at 2-theta 4.8±0.2°; or at 21.7±0.2°; or at 24.2±0.2°; or at 11.4±0.2°; or at 22.9±0.2°; or at 23.8±0.2°; or at 14.7±0.2°; or at 12.9±0.2°; or at 26.4±0.2°; or at 8.0±0.2°; or at 10.8±0.2°; or at 24.9±0.2°; or at 12.0±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks; more preferably comprising any 6, 7 or 8 thereof;

[0051] The X-ray powder diffractogram of crystalline form H comprises at least one or more of the diffraction peaks at 2-theta 21.7±0.2°, 24.2±0.2°, 11.4±0.2°, preferably two, more preferably three thereof; optionally further comprising at least one of the diffraction peaks at 2-theta 22.9±0.2°, 23.8±0.2°, 14.7±0.2°, 12.9±0.2°, 26.4±0.2°, preferably 2, 3, 4 or 5 thereof; for example,

[0052] 21.7 ± 0.2°, 24.2 ± 0.2°;

[0053] 24.2 ± 0.2°, 11.4 ± 0.2°;

[0054] 21.7 ± 0.2°, 24.2 ± 0.2°, 11.4 ± 0.2°;

[0055] 24.2 ± 0.2°, 11.4 ± 0.2°, 22.9 ± 0.2°;

[0056] 21.7 ± 0.2°, 24.2 ± 0.2°, 11.4 ± 0.2°, 22.9 ± 0.2°;

[0057] 24.2 ± 0.2°, 11.4 ± 0.2°, 22.9 ± 0.2°, 23.8 ± 0.2°;

[0058] 21.7 ± 0.2°, 24.2 ± 0.2°, 11.4 ± 0.2°, 22.9 ± 0.2°, 23.8 ± 0.2°;

[0059] 24.2 ± 0.2°, 11.4 ± 0.2°, 22.9 ± 0.2°, 23.8 ± 0.2°, 14.7 ± 0.2°;

[0060] The X-ray powder diffraction pattern of crystalline Form H optionally further comprises one or more of diffraction peaks at 2Θ of 21.7 ± 0.2°, 24.2 ± 0.2°, 11.4 ± 0.2°, 22.9 ± 0.2°, 23.8 ± 0.2°, 14.7 ± 0.2°, 12.9 ± 0.2°, 26.4 ± 0.2°, 8.0 ± 0.2°, 10.8 ± 0.2°; preferably at least 2-3, or 4-5, or 6-7 of any of these; further preferably, at least 2, 3, 4, 5, 6, or 7 of any of these; for example,

[0061] 21.7 ± 0.2°, 24.2 ± 0.2°, 11.4 ± 0.2°, 22.9 ± 0.2°, 23.8 ± 0.2°, 14.7 ± 0.2°;

[0062] 24.2 ± 0.2°, 11.4 ± 0.2°, 22.9 ± 0.2°, 23.8 ± 0.2°, 14.7 ± 0.2°, 12.9 ± 0.2°;

[0063] 21.7 ± 0.2°, 24.2 ± 0.2°, 11.4 ± 0.2°, 22.9 ± 0.2°, 23.8 ± 0.2°, 14.7 ± 0.2°, 12.9 ± 0.2°, 26.4 ± 0.2°;

[0064] 24.2 ± 0.2°, 11.4 ± 0.2°, 22.9 ± 0.2°, 23.8 ± 0.2°, 14.7 ± 0.2°, 12.9 ± 0.2°, 26.4 ± 0.2°, 8.0 ± 0.2°;

[0065] 24.2 ± 0.2°, 11.4 ± 0.2°, 22.9 ± 0.2°, 23.8 ± 0.2°, 14.7 ± 0.2°, 12.9 ± 0.2°, 26.4 ± 0.2°, 4.8 ± 0.2°;

[0066] The X-ray powder diffraction pattern of crystalline Form H comprises one or more of the diffraction peaks at 21.7 ± 0.2°, 24.2 ± 0.2°, 11.4 ± 0.2°, 22.9 ± 0.2°, 23.8 ± 0.2°, 14.7 ± 0.2°, 12.9 ± 0.2°, 26.4 ± 0.2°, 8.0 ± 0.2°, 10.8 ± 0.2°, 24.9 ± 0.2°, 12.0 ± 0.2°, 32.5 ± 0.2°, 31.3 ± 0.2°, 17.0 ± 0.2°, 4.8 ± 0.2°, preferably, any 4, 5, 6, 8 or 10 of the diffraction peaks; for example,

[0067] 21.7 ± 0.2°, 22.9 ± 0.2°, 23.8 ± 0.2°, 14.7 ± 0.2°;

[0068] 24.2 ± 0.2°, 23.8 ± 0.2°, 14.7 ± 0.2°, 12.9 ± 0.2°;

[0069] 11.4 ± 0.2°, 12.9 ± 0.2°, 26.4 ± 0.2°, 8.0 ± 0.2°, 10.8 ± 0.2°;

[0070] 22.9 ± 0.2°, 8.0 ± 0.2°, 10.8 ± 0.2°, 24.9 ± 0.2°, 32.5 ± 0.2°;

[0071] 11.4 ± 0.2°, 22.9 ± 0.2°, 23.8 ± 0.2°, 14.7 ± 0.2°, 12.9 ± 0.2°, 26.4 ± 0.2°;

[0072] 22.9 ± 0.2°, 23.8 ± 0.2°, 14.7 ± 0.2°, 12.9 ± 0.2°, 26.4 ± 0.2°, 8.0 ± 0.2°;

[0073] 21.7 ± 0.2°, 22.9 ± 0.2°, 23.8 ± 0.2°, 14.7 ± 0.2°, 12.9 ± 0.2°, 26.4 ± 0.2°, 8.0 ± 0.2°, 10.8 ± 0.2°;

[0074] 24.2 ± 0.2°, 23.8 ± 0.2°, 14.7 ± 0.2°, 12.9 ± 0.2°, 26.4 ± 0.2°, 8.0 ± 0.2°, 10.8 ± 0.2°, 24.9 ± 0.2°;

[0075] 11.4 ± 0.2°, 22.9 ± 0.2°, 23.8 ± 0.2°, 14.7 ± 0.2°, 12.9 ± 0.2°, 26.4 ± 0.2°, 8.0 ± 0.2°, 10.8 ± 0.2°, 24.9 ± 0.2°, 12.0 ± 0.2°;

[0076] 21.7 ± 0.2°, 23.8 ± 0.2°, 14.7 ± 0.2°, 12.9 ± 0.2°, 26.4 ± 0.2°, 8.0 ± 0.2°, 10.8 ± 0.2°, 24.9 ± 0.2°, 12.0 ± 0.2°, 32.5 ± 0.2°;

[0077] X-ray characteristic diffraction peaks using Cu-Ka radiation, expressed in terms of 2 theta angle and interplanar distance d value, are shown in Table 1.

[0078] Table 1

[0079]

[0080] The crystalline form H of (6-((5-bromo-2-((2-methoxy-4-(4-(3- (methoxymethyl)azetidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4- yl)amino)-2,3-dihydrobenzo[B][1,4]dioxin-5-yl)dimethylphosphine oxide according to the present application has an X-ray powder diffractogram substantially as shown in Figure 1 The DSC pattern of the crystalline form H of (6-((5-bromo-2-((2-methoxy-4-(4-(3- (methoxymethyl)azetidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4- yl)amino)-2,3-dihydrobenzo[B][1,4]dioxin-5-yl)dimethylphosphine oxide according to the present application is substantially as shown in Figure 2 The TGA pattern of the crystalline form H of (6-((5-bromo-2-((2-methoxy-4-(4-(3- (methoxymethyl)azetidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4- yl)amino)-2,3-dihydrobenzo[B][1,4]dioxin-5-yl)dimethylphosphine oxide according to the present application is substantially as shown in Figure 3

[0081] In a further preferred embodiment of the present application, the crystalline form N of (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)-5- methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[B][1,4]dioxin-5-yl)dimethyl- phosphine oxide.

[0082] ​The X-ray powder diffraction pattern of Form N has a diffraction peak at 6.7±0.2°; or at 8.5±0.2°; or at 9.0±0.2°; or at 18.7±0.2°; or at 21.8±0.2°; or at 12.3±0.2°; or at 12.7±0.2°; or at 14.5±0.2°; or at 15.0±0.2°; or at 22.3±0.2°; or at 18.5±0.2°; or at 24.6±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks; more preferably comprising any 6, 7 or 8 of the above diffraction peaks;

[0083] The X-ray powder diffraction pattern of Form N has at least one diffraction peak at 6.7±0.2°, 8.5±0.2°, 9.0±0.2°, preferably two, more preferably three; optionally, further comprising at least one diffraction peak at 18.7±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°, preferably 2, 3, 4 or 5 of the above peaks; for example,

[0084] 6.7±0.2°, 8.5±0.2°;

[0085] 9.0±0.2°, 18.7±0.2°;

[0086] 6.7±0.2°, 8.5±0.2°, 9.0±0.2°;

[0087] 9.0±0.2°, 18.7±0.2°, 21.8±0.2°;

[0088] 6.7±0.2°, 8.5±0.2°, 9.0±0.2°, 18.7±0.2°;

[0089] 9.0±0.2°, 18.7±0.2°, 21.8±0.2°, 12.3±0.2°;

[0090] 6.7±0.2°, 8.5±0.2°, 9.0±0.2°, 18.7±0.2°, 21.8±0.2°;

[0091] 9.0±0.2°, 18.7±0.2°, 21.9±0.2°, 12.3±0.2°, 12.7±0.2°;

[0092] The X-ray powder diffraction pattern of crystalline Form N optionally further comprises one or more of diffraction peaks at 6.7 ± 0.2°, 8.5 ± 0.2°, 9.0 ± 0.2°, 18.7 ± 0.2°, 21.8 ± 0.2°, 12.3 ± 0.2°, 12.7 ± 0.2°, 14.5 ± 0.2°, 15.0 ± 0.2°, 22.3 ± 0.2° in terms of 2-theta; preferably at least any 2 to 3 thereof, or 4 to 5 thereof, or 6 to 7 thereof; further preferably, at any 2, 3, 4, 5, 6, 7 thereof; for example,

[0093] 6.7 ± 0.2°, 8.5 ± 0.2°, 9.0 ± 0.2°, 18.7 ± 0.2°, 21.8 ± 0.2°, 12.3 ± 0.2°;

[0094] 9.0 ± 0.2°, 18.7 ± 0.2°, 21.8 ± 0.2°, 12.3 ± 0.2°, 12.7 ± 0.2°, 14.5 ± 0.2°;

[0095] 9.0 ± 0.2°, 18.7 ± 0.2°, 21.8 ± 0.2°, 12.3 ± 0.2°, 12.7 ± 0.2°, 14.5 ± 0.2°, 15.0 ± 0.2°;

[0096] 18.7 ± 0.2°, 21.8 ± 0.2°, 12.3 ± 0.2°, 12.7 ± 0.2°, 14.5 ± 0.2°, 15.0 ± 0.2°, 22.3 ± 0.2°;

[0097] 6.7 ± 0.2°, 8.5 ± 0.2°, 9.0 ± 0.2°, 18.7 ± 0.2°, 21.8 ± 0.2°, 12.3 ± 0.2°, 12.7 ± 0.2°, 14.5 ± 0.2°;

[0098] 8.5 ± 0.2°, 9.0 ± 0.2°, 18.7 ± 0.2°, 21.8 ± 0.2°, 12.3 ± 0.2°, 12.7 ± 0.2°, 14.5 ± 0.2°, 15.0 ± 0.2°;

[0099] 6.7 ± 0.2°, 9.0 ± 0.2°, 18.7 ± 0.2°, 21.8 ± 0.2°, 12.3 ± 0.2°, 12.7 ± 0.2°, 14.5 ± 0.2°, 15.0 ± 0.2°;

[0100] 9.0 ± 0.2°, 18.7 ± 0.2°, 21.8 ± 0.2°, 12.3 ± 0.2°, 12.7 ± 0.2°, 14.5 ± 0.2°, 15.0 ± 0.2°, 22.3 ± 0.2°;

[0101] 6.7±0.2°, 8.5±0.2°, 9.0±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°, 15.0±0.2°;

[0102] The X-ray powder diffraction pattern of Form N comprises one or more of the diffraction peaks at 2-theta = 6.7±0.2°, 8.5±0.2°, 9.0±0.2°, 18.7±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°, 15.0±0.2°, 22.3±0.2°, 18.5±0.2°, 24.6±0.2°, 18.0±0.2°, 23.7±0.2°, 17.8±0.2°, preferably, any 4, 5, 6, 8 or 10 thereof; for example,

[0103] 6.7±0.2°, 18.7±0.2°, 21.8±0.2°, 12.3±0.2°;

[0104] 8.5±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°;

[0105] 6.7±0.2°, 18.7±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°;

[0106] 8.5±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°, 15.0±0.2°;

[0107] 6.7±0.2°, 18.7±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°, 15.0±0.2°, 22.3±0.2°;

[0108] 8.5±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°, 15.0±0.2°, 22.3±0.2°, 18.5±0.2°;

[0109] 18.7±0.2°, 12.7±0.2°, 14.5±0.2°, 15.0±0.2°, 22.3±0.2°, 18.5±0.2°, 24.6±0.2°, 18.0±0.2°;

[0110] 21.8 ± 0.2°, 14.5 ± 0.2°, 15.0 ± 0.2°, 22.3 ± 0.2°, 18.5 ± 0.2°, 24.6 ± 0.2°, 18.0 ± 0.2°, 23.7 ± 0.2°;

[0111] 6.7 ± 0.2°, 18.7 ± 0.2°, 21.8 ± 0.2°, 12.3 ± 0.2°, 12.7 ± 0.2°, 14.5 ± 0.2°, 15.0 ± 0.2°, 22.3 ± 0.2°, 18.5 ± 0.2°, 24.6 ± 0.2°;

[0112] 8.5 ± 0.2°, 21.9 ± 0.2°, 12.3 ± 0.2°, 12.7 ± 0.2°, 14.5 ± 0.2°, 15.0 ± 0.2°, 22.3 ± 0.2°, 18.5 ± 0.2°, 24.6 ± 0.2°, 18.0 ± 0.2°;

[0113] 18.7 ± 0.2°, 6.7 ± 0.2°, 18.7 ± 0.2°, 21.8 ± 0.2°, 12.3 ± 0.2°, 12.7 ± 0.2°, 14.5 ± 0.2°, 15.0 ± 0.2°, 22.3 ± 0.2°, 18.5 ± 0.2°;

[0114] 21.8 ± 0.2°, 9.0 ± 0.2°, 18.7 ± 0.2°, 21.8 ± 0.2°, 12.3 ± 0.2°, 12.7 ± 0.2°, 14.5 ± 0.2°, 15.0 ± 0.2°, 22.3 ± 0.2°, 18.5 ± 0.2°;

[0115] The X-ray powder diffraction pattern of crystalline Form N comprises one or more of the diffraction peaks at 2-theta = 6.7 ± 0.2°, 8.5 ± 0.2°, 10.8 ± 0.2°, 9.0 ± 0.2°, 18.7 ± 0.2°, 21.8 ± 0.2°, 12.3 ± 0.2°, 12.7 ± 0.2°, 13.7 ± 0.2°, 14.5 ± 0.2°, 15.0 ± 0.2°, 20.1 ± 0.2°, 21.4 ± 0.2°, 21.9 ± 0.2°, 22.3 ± 0.2°, 18.5 ± 0.2°, 24.6 ± 0.2°, 18.0 ± 0.2°, 23.7 ± 0.2°, 17.8 ± 0.2°.

[0116] Crystalline Form N of (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[B][1,4]dioxin-5-yl)dimethyl phosphine oxide of the present application has an X-ray powder diffraction pattern substantially as shown in Figure 4as shown; its DSC pattern is substantially as shown in Figure 5 as shown; its TGA pattern is substantially as shown in Figure 6 as shown.

[0117] In a further preferred embodiment of the present application, the crystalline form O of (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[B][1,4]dioxin-5-yl)dimethyl phosphine oxide.

[0118] The X-ray powder diffraction pattern of the crystalline form O has a diffraction peak at 5.0±0.2°; or at 6.2±0.2°; or at 7.2±0.2°; or at 8.7±0.2°; or at 12.9±0.2°; or at 17.3±0.2°; or at 17.9±0.2°; or at 20.4±0.2°; or at 14.4±0.2°; or at 12.4±0.2°; or at 19.7±0.2°; or at 18.7±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks; more preferably comprising any 6, 7 or 8 of the above diffraction peaks;

[0119] The X-ray powder diffraction pattern of the crystalline form O comprises at least one or more of the diffraction peaks at 5.0±0.2°, 6.2±0.2°, 7.2±0.2°, preferably comprising two of them, more preferably comprising three of them; optionally, further comprising at least one of the diffraction peaks at 8.7±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, preferably comprising 2, 3, 4 or 5 of them; for example,

[0120] 5.0±0.2°, 6.2±0.2°;

[0121] 6.2±0.2°, 7.2±0.2°;

[0122] 5.0±0.2°, 6.2±0.2°, 7.2±0.2°;

[0123] 6.2±0.2°, 7.2±0.2°, 8.7±0.2°;

[0124] 5.0±0.2°, 6.2±0.2°, 7.2±0.2°, 8.7±0.2°;

[0125] 6.2 ± 0.2°, 7.2 ± 0.2°, 8.7 ± 0.2°, 12.9 ± 0.2°;

[0126] 5.0 ± 0.2°, 6.2 ± 0.2°, 7.2 ± 0.2°, 8.7 ± 0.2°, 12.9 ± 0.2°;

[0127] 6.2 ± 0.2°, 7.2 ± 0.2°, 8.7 ± 0.2°, 12.9 ± 0.2°, 17.3 ± 0.2°;

[0128] The X-ray powder diffraction pattern of Form O optionally further comprises one or more of the diffraction peaks at 2Θ of 5.0 ± 0.2°, 6.1 ± 0.2°, 7.2 ± 0.2°, 8.7 ± 0.2°, 12.9 ± 0.2°, 17.3 ± 0.2°, 17.9 ± 0.2°, 20.4 ± 0.2°, 14.4 ± 0.2°, 12.4 ± 0.2°; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, 7 thereof; for example,

[0129] 5.0 ± 0.2°, 7.2 ± 0.2°, 8.7 ± 0.2°, 12.9 ± 0.2°, 17.3 ± 0.2°;

[0130] 7.2 ± 0.2°, 8.7 ± 0.2°, 12.9 ± 0.2°, 17.3 ± 0.2°, 17.9 ± 0.2°;

[0131] 8.7 ± 0.2°, 12.9 ± 0.2°, 17.3 ± 0.2°, 17.9 ± 0.2°, 20.4 ± 0.2°;

[0132] 5.0 ± 0.2°, 6.2 ± 0.2°, 7.2 ± 0.2°, 8.7 ± 0.2°, 12.9 ± 0.2°, 17.3 ± 0.2°, 17.9 ± 0.2°, 20.4 ± 0.2°;

[0133] 6.2 ± 0.2°, 7.2 ± 0.2°, 8.7 ± 0.2°, 12.9 ± 0.2°, 17.3 ± 0.2°, 17.9 ± 0.2°, 20.4 ± 0.2°, 14.4 ± 0.2°;

[0134] The X-ray powder diffraction pattern of Form O comprises one or more of the diffraction peaks at 5.0±0.2°, 6.1±0.2°, 7.2±0.2°, 8.7±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, 14.4±0.2°, 12.4±0.2°, 19.7±0.2°, 18.7±0.2°, 24.9±0.2°, 20.1±0.2°, 24.9±0.2°, preferably, any 4, 5, 6, 8 or 10 of the diffraction peaks; for example,

[0135] 5.0±0.2°, 8.7±0.2°, 12.9±0.2°, 17.3±0.2°;

[0136] 6.1±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°;

[0137] 5.0±0.2°, 8.7±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°;

[0138] 6.1±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, 14.4±0.2°;

[0139] 5.0±0.2°, 8.7±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, 14.4±0.2°, 12.4±0.2°;

[0140] 6.1±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, 14.4±0.2°, 12.4±0.2°, 19.7±0.2°;

[0141] 5.0±0.2°, 8.7±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, 14.4±0.2°, 12.4±0.2°, 19.7±0.2°, 18.7±0.2°;

[0142] 6.1±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, 14.4±0.2°, 12.4±0.2°, 19.7±0.2°, 18.7±0.2°, 24.9±0.2.

[0143] The present application (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[B][1,4]dioxin-5-yl)dimethyl phosphine oxide, Form I, has an X-ray powder diffraction pattern substantially as shown in Figure 7 ; and a DSC pattern substantially as shown in Figure 8 In a further preferred embodiment of the present application, (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[B][1,4]dioxin-5-yl)dimethyl phosphine oxide, Form I.

[0144] The X-ray powder diffraction pattern of Form I has a diffraction peak at 2-theta of 20.8±0.2°; or at 13.7±0.2°; or at 12.7±0.2°; or at 14.4±0.2°; or at 17.2±0.2°; or at 11.3±0.2°; or at 20.2±0.2°; or at 25.1±0.2°; or at 22.5±0.2°; or at 14.6±0.2°; or at 22.2±0.2°; or at 26.0±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks; more preferably comprising any 6, 7 or 8 of them;

[0145] The X-ray powder diffraction pattern of Form I comprises at least one or more of the diffraction peaks at 2-theta of 20.8±0.2°, 13.7±0.2°, 12.7±0.2°, preferably two of them, more preferably three of them; optionally, further comprising at least one of the diffraction peaks at 2-theta of 14.4±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, preferably 2, 3, 4 or 5 of them; for example,

[0146] 20.8±0.2°, 13.7±0.2°;

[0147] 13.7±0.2°, 12.7±0.2°;

[0148] 20.8±0.2°, 13.7±0.2°, 12.7±0.2°;

[0149] 13.7 ± 0.2°, 12.7 ± 0.2°, 14.4 ± 0.2°;

[0150] 20.8 ± 0.2°, 13.7 ± 0.2°, 12.7 ± 0.2°, 14.4 ± 0.2°;

[0151] 13.7 ± 0.2°, 12.7 ± 0.2°, 14.4 ± 0.2°, 17.2 ± 0.2°;

[0152] 20.8 ± 0.2°, 13.7 ± 0.2°, 12.7 ± 0.2°, 14.4 ± 0.2°, 17.2 ± 0.2°;

[0153] 13.7 ± 0.2°, 12.7 ± 0.2°, 14.4 ± 0.2°, 17.2 ± 0.2°, 11.3 ± 0.2°;

[0154] The X-ray powder diffraction pattern of Form I optionally further comprises one or more of the diffraction peaks at 2Θ of 20.8 ± 0.2°, 13.7 ± 0.2°, 12.7 ± 0.2°, 14.4 ± 0.2°, 17.2 ± 0.2°, 11.3 ± 0.2°, 20.2 ± 0.2°, 25.1 ± 0.2°, 22.5 ± 0.2°; preferably at least 2-3, or 4-5, or 6-7 of any of these; further preferably, 2, 3, 4, 5, 6, or 7 of any of these; for example,

[0155] 20.8 ± 0.2°, 13.7 ± 0.2°, 12.7 ± 0.2°, 14.4 ± 0.2°, 17.2 ± 0.2°, 11.3 ± 0.2°;

[0156] 13.7 ± 0.2°, 12.7 ± 0.2°, 14.4 ± 0.2°, 17.2 ± 0.2°, 11.3 ± 0.2°, 20.2 ± 0.2°;

[0157] 20.8 ± 0.2°, 13.7 ± 0.2°, 12.7 ± 0.2°, 14.4 ± 0.2°, 17.2 ± 0.2°, 11.3 ± 0.2°, 20.2 ± 0.2°;

[0158] 13.7 ± 0.2°, 12.7 ± 0.2°, 14.4 ± 0.2°, 17.2 ± 0.2°, 11.3 ± 0.2°, 20.2 ± 0.2°, 25.1 ± 0.2°;

[0159] The X-ray powder diffraction pattern of Form I comprises one or more of the diffraction peaks at 20.8±0.2°, 13.7±0.2°, 12.7±0.2°, 14.4±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, 22.5±0.2°, 14.6±0.2°, 22.2±0.2°, 26.0±0.2°, 23.4±0.2°, 17.6±0.2°, 8.5±0.2°, preferably, 4, 5, 6, 8 or 10 of the optional peaks; for example,

[0160] 20.8±0.2°, 14.4±0.2°, 17.2±0.2°, 11.3±0.2°;

[0161] 13.7±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°;

[0162] 12.7±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, 22.5±0.2°;

[0163] 20.8±0.2°, 20.2±0.2°, 25.1±0.2°, 22.5±0.2°, 14.6±0.2°;

[0164] 12.7±0.2°, 14.4±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°;

[0165] 20.8±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, 22.5±0.2°;

[0166] 13.7±0.2°, 14.4±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, 22.5±0.2°, 14.6±0.2°;

[0167] 12.7±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, 22.5±0.2°, 14.6±0.2°, 22.2±0.2°;

[0168] 14.4±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, 22.5±0.2°, 14.6±0.2°, 22.2±0.2°, 26.0±0.2°, 8.5±0.2°;

[0169] 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, 22.5±0.2°, 14.6±0.2°, 22.2±0.2°, 26.0±0.2°, 23.4±0.2°, 17.6±0.2°;

[0170] The X-ray characteristic diffraction peak using Cu-Kα radiation, expressed in 2θ angle and interplanar spacing d value, is shown in Table 2.

[0171] Table 2

[0172]

[0173] The crystal form I of the present application (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[B][1,4]dioxin-5-yl)dimethyl phosphine oxide has an X-ray powder diffraction pattern substantially as shown in Figure 9 ; and a DSC pattern substantially as shown in Figure 10 .

[0174] In a further preferred aspect of the present application, the crystal form is an anhydrate or a hydrate; when the crystal form is a hydrate, the number of water molecules is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3; preferably, the crystal form is an anhydrate.

[0175] In a further preferred aspect of the present application, the relative peak intensity of the X-ray powder diffraction pattern of the crystal form H, the crystal form N, the crystal form O and the crystal form I is that the position of the diffraction peak of the top ten peaks is respectively corresponding to Figure 1 、 Figure 4 、 Figure 7 and Figure 9 the 2θ error of the diffraction peak is ±0.2°-±0.5°, preferably ±0.2°-±0.3°, most preferably ±0.2°.

[0176] In a further preferred aspect of the present application, the preparation method of the crystal form of the compound represented by the general formula (I) comprises the following steps:

[0177] 1) weigh an appropriate amount of free base, and dissolve by heating with a good solvent;

[0178] 2) adding a poor solvent to the above obtained solution dropwise;

[0179] 3) cooling the above suspension, removing the supernatant, and drying the remaining solid to obtain the target product;

[0180] wherein:

[0181] The good solvent is selected from methanol, ethanol, acetone, sec-amyl alcohol, n-butanol, n-octanol, n-hexanol, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl alcohol, n-butanol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, t-butyl alcohol, 2-butanone or 3-pentanone; preferably methanol, ethanol, acetone, sec-amyl alcohol, n-butanol, n-octanol or n-hexanol.

[0182] The poor solvent is selected from heptane, water, methyl tert-butyl ether, toluene, isopropyl ether.

[0183] In a further preferred embodiment of the present application, the preparation method of the crystal form of the compound of general formula (I) comprises the following steps:

[0184] 1) weighing an appropriate amount of free base and suspending it with a poor solvent, preferably with a suspension density of 50-200 mg / mL;

[0185] 2) shaking the above obtained suspension, preferably at a temperature of 0-60°C for 0-10 days;

[0186] 3) quickly centrifuging the suspension, removing the supernatant, and drying the remaining solid to obtain the target product;

[0187] wherein:

[0188] The poor solvent is selected from acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl alcohol, n-butanol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, t-butyl alcohol, 2-butanone or 3-pentanone, methyl tert-butyl ether, water; preferably acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, toluene, isopropyl alcohol, 2-butanone, 3-pentanone, methyl tert-butyl ether or water.

[0189] In a further preferred embodiment of the present application, the preparation method of the crystal form of the compound of general formula (I) comprises the following steps:

[0190] 1) weighing an appropriate amount of free base and suspending it with a poor solvent, preferably with a suspension density of 50-200 mg / mL;

[0191] 2) shaking the above obtained suspension, preferably at a temperature of 0-60°C for 0-10 days;

[0192] 3) rapidly centrifuging the above suspension, removing the supernatant, and drying the remaining solid to obtain the target product;

[0193] wherein:

[0194] the poor solvent is selected from acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butyl alcohol, 2-butanone or 3-pentanone, methyl tert-butyl ether, water; preferably acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, toluene, isopropyl alcohol, 2-butanone, 3-pentanone, methyl tert-butyl ether or water.

[0195] The present application also provides a crystalline form of the compound of formula (I) (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[B][1,4]dioxin-5-yl)dimethyl phosphine oxide, and use of the pharmaceutical composition in the preparation of a kinase inhibitor drug.

[0196] The kinase inhibitor is a MEK inhibitor;

[0197] The kinase inhibitor is a receptor tyrosine kinase inhibitor, preferably a HER2 inhibitor, an EGFR inhibitor and an EGFR mAb and their combination related drugs, more preferably a HER2 20 exon mutant inhibitor, an EGFR 20 exon mutant inhibitor and an EGFR 20 exon mutant mAb and their combination related drugs.

[0198] The present application provides a crystalline form of the compound of formula (I) and use of the pharmaceutical composition in the preparation of a drug for treating cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS related diseases, preferably the cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS related diseases are diseases mediated by HER2 20 exon mutation and / or EGFR 20 exon mutation.

[0199] The application also provides the crystalline form of the compound of formula (I) (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[B][1,4]dioxin-5-yl)dimethyl phosphine oxide and the use of the pharmaceutical composition in the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS-related diseases, preferably the cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS-related diseases are diseases mediated by HER2 20 exon mutation and / or EGFR 20 exon mutation.

[0200] The cancer is selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, glioblastoma, leukemia, lymphoma, myeloma and non-small cell lung cancer.

[0201] The third generation EGFR inhibitor mainly inhibits EGFR activating mutants and T790M drug-resistant mutants, and the compound of the application has the following significant advantages over the third generation EGFR inhibitor in terms of EGFR and / or HER2 20 exon insertion mutation target:

[0202] 1. Significantly improve the inhibition activity of Ba / F3 EGFR mutant cell lines, preferably the activity of the compound is more than 10 times higher, even 20 times;

[0203] 2. Improve the selectivity of proliferation inhibition activity in Ba / F3 EGFR mutant cell lines and A431 cell lines, preferably the compound is more than 3 times higher, even 10 times;

[0204] 3. The in vivo efficacy of tumor inhibition rate in the mouse B cell Ba / F3 EGFR-D770-N771ins_SVD xenograft model also shows significant advantages.

[0205] Detailed description of the invention

[0206] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0207] The term "alkyl" refers to saturated aliphatic hydrocarbon groups which are straight-chain or branched-chain groups containing 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, and are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate, with methyl, ethyl, i-propyl, t-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxyl-substituted alkyl being preferred.

[0208] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further replaced by a substituent, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1- propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0209] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms, more preferably comprising 3 to 8 carbon atoms, most preferably comprising 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0210] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, or S(O) m (m is an integer from 0 to 2) but excluding ring moieties of -O-O-, -O-S-, or -S-S-, the remaining ring atoms being carbon. Preferably, the heterocyclyl group comprises 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, the heterocyclyl group comprises 3 to 8 ring atoms; most preferably, the heterocyclyl group comprises 3 to 6 ring atoms.

[0211] Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, thietanyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably oxetanyl, pyrrolidinonyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl. Polycyclic heterocyclyl groups include spirocyclic, fused, and bridged heterocyclyl groups; wherein the spirocyclic, fused, and bridged heterocyclyl groups involved are optionally connected to other groups by a single bond, or further annelated to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups through any two or more atoms on the ring.

[0212] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0213]

[0214] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0215] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo3- to 8-membered cycloalkyl and benzo3- to 8-membered heteroalkyl, preferably benzo3- to 6-membered cycloalkyl and benzo3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen, oxygen, and sulfur atoms; or may further comprise a ternary nitrogen-containing fused ring containing a benzene ring, wherein the ring connected to the parent structure is an aryl ring.

[0216] Non-limiting examples include:

[0217]

[0218] wait.

[0219] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0220] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 membered, more preferably 5 or 6 membered, for example imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl and oxazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heteroaryl ring.

[0221] Non-limiting examples thereof include:

[0222]

[0223] and the like.

[0224] The term "alkoxy" refers to -O-(alkyl) and -O-(non-substituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group can be optionally substituted or non-substituted, when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.

[0225] The term "alkylthio" refers to -S-(alkyl) and -S-(non-substituted cycloalkyl), wherein alkyl is as defined above. Preferably alkyl contains 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms. Non-limiting examples of alkylthio groups include methylthio, ethylthio, propylthio, butylthio. The alkylthio group can be optionally substituted or non-substituted, when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.

[0226] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halogens.

[0227] "Hydroxyalkyl" refers to an alkyl group as defined above substituted with one or more hydroxy groups.

[0228] "Cyanoalkyl" means an alkyl group substituted with one or more cyano groups, wherein alkyl is as defined above.

[0229] "Haloalkoxy" means an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0230] "Alkenyl" means an alkenyl group, also called an alkene group, preferably an alkyl group containing 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, most preferably 2 to 3 carbon atoms. The alkenyl group can be further substituted with other relevant groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0231] "Alkynyl" means (CH≡C-), preferably an alkyl group containing 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, most preferably 2 to 3 carbon atoms. The alkynyl group can be further substituted with other relevant groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0232] "Hydroxyl" means an -OH group.

[0233] "Halogen" means fluorine, chlorine, bromine, or iodine.

[0234] "Amino" means -NH2.

[0235] "Cyano" means -CN.

[0236] "Nitro" means -NO2.

[0237] "Carboxyl" means -C(O)OH.

[0238] "THF" means tetrahydrofuran.

[0239] "EtOAc" means ethyl acetate.

[0240] "MeOH" means methanol.

[0241] "DMF" means N,N-dimethylformamide.

[0242] "DIPEA" means diisopropylethylamine.

[0243] "TFA" means trifluoroacetic acid.

[0244] "MeCN" means acetonitrile.

[0245] “DMA” means N,N-dimethylacetamide.

[0246] “Et20” means diethyl ether.

[0247] “DCE” means 1,2 dichloroethane.

[0248] “DIPEA” means N,N-diisopropylethylamine.

[0249] “NBS” means N-bromosuccinimide.

[0250] “NIS” means N-iodosuccinimide.

[0251] “Cbz-Cl” means benzyl chloroformate.

[0252] “Pd2(dba)3” means tris(dibenzylideneacetone)dipalladium.

[0253] “Dppf” means 1,1’-bis(diphenylphosphino)ferrocene.

[0254] “HATU” means 2-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate.

[0255] “KHMDS” means potassium hexamethyldisilazide.

[0256] “LiHMDS” means lithium bis(trimethylsilyl)amide.

[0257] “MeLi” means methyl lithium.

[0258] “n-BuLi” means n-butyllithium.

[0259] “NaBH(OAc)3” means sodium triacetoxyborohydride.

[0260] “DMAP” means 4-dimethylaminopyridine.

[0261] “SEM-Cl” means chloromethyltrimethylsilylether.

[0262] “Xantphos” means 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0263] “DCM” means dichloromethane.

[0264] The different expressions “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C”, and the like all express the same meaning, i.e. that X can be any one or several of A, B, C.

[0265] The hydrogen atoms described herein can be replaced by their isotopes deuterium. Any of the hydrogen atoms in the compounds of the embodiments described herein can also be replaced by deuterium.

[0266] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl can or can not be present, and that the description includes instances where the heterocyclyl is substituted with alkyl and instances where the heterocyclyl is not substituted with alkyl.

[0267] "Substituted" means that one or more hydrogen atoms, preferably up to five, more preferably one to three, of the group are each, independently of one another, replaced with a corresponding number of substituents. It goes without saying that the substituents are only present in their possible chemical positions, which can or cannot be possible (experimentally or theoretically) to a person skilled in the art without undue effort. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated (e.g., olefinic) bond. Optional substituents include one or more of deuterium, halogen, amino, hydroxyl, cyano, oxo, thioxo, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, alkylthio, halogenated alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, preferably deuterium, halogen, amino, hydroxyl, cyano, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 halogenated alkoxy, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl.

[0268] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, and to facilitate absorption, thereby facilitating biological activity.

[0269] "Pharmaceutically acceptable salt" refers to those salts of the compounds of the present application which are safe and effective for use in a mammal, and possess the desired biological activity. BRIEF DESCRIPTION OF DRAWINGS

[0270] Figure 1 XRPD pattern of Form H free base is shown.

[0271] Figure 2 DSC pattern of Form H as a free base.

[0272] Figure 3 TGA pattern of Form H as a free base.

[0273] Figure 4 XRPD pattern of Form N as a free base.

[0274] Figure 5 DSC pattern of Form N as a free base.

[0275] Figure 6 TGA pattern of Form N as a free base.

[0276] Figure 7 XRPD pattern of Form O as a free base.

[0277] Figure 8 DSC pattern of Form O as a free base.

[0278] Figure 9 XRPD pattern of Form I as a free base.

[0279] Figure 10 DSC pattern of Form I as a free base. DETAILED DESCRIPTION

[0280] The application will be further described in the following examples, which are not intended to limit the scope of the application.

[0281] I. Preparation of Compounds

[0282] Examples

[0283] The structure of the compounds of the present application was determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed on a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0284] Liquid chromatography-mass spectrometry (LC-MS) measurements were performed on an Agilent 1200 Infinity Series Mass Spectrometer. HPLC measurements were performed using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

[0285] Thin layer chromatography silica gel plates were used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, TLC used specifications are 0.15mm-0.20mm, thin layer chromatography separation and purification of products used specifications are 0.4mm-0.5mm. Column chromatography generally uses 200-300 mesh Yantai Huanghai silica gel as the carrier.

[0286] The starting materials in the embodiments of the present application are known and commercially available, or can be synthesized by methods known in the art.

[0287] Unless otherwise specified, all reactions of the present application were carried out under continuous magnetic stirring, under a dry nitrogen or argon atmosphere, with dry solvents, and the reaction temperature unit is Celsius.

[0288] Preparation of intermediates

[0289] Preparation of (6-amino-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethyl phosphine oxide

[0290]

[0291] First step: preparation of 2-bromo-6-methoxy-3-nitrophenol

[0292]

[0293] To a solution of 2-methoxy-5-nitrophenol (2 g, 11.8 mmol) in DCM (20 mL) was added NBS (2.1 g, 11.8 mmol), stirred at room temperature for one hour, then added CH2Cl2 and water to the reaction, the organic phase was concentrated under reduced pressure, and then column chromatography to obtain the title compound 2-bromo-6-methoxy-3-nitrophenol (1.5 g, yield: 51%).

[0294] MS m / z (ESI): 245.9 [M-H] - .

[0295] Second step: preparation of 3-bromo-4-nitrobenzene-1,2-diol

[0296]

[0297] To a solution of 2-bromo-6-methoxy-3-nitrophenol (500 mg, 2.0 mmol) in dichloromethane (5 mL) was added BBr3(1 M, 2.6 mL, 2.6 mmol) at -78 °C. After stirring for 2 h, the reaction was slowly warmed to room temperature and stirred overnight. The reaction was cooled to 0 °C and MeOH (5 mL) was added slowly. The organic phase was concentrated under reduced pressure and the title compound 3-bromo-4-nitrobenzene-1,2-diol (410 mg, yield: 87%) was isolated by column chromatography.

[0298] MS m / z (ESI): 231.9 [M-H] - .

[0299] Third step: Preparation of 5-bromo-6-nitro-2,3-dihydrobenzo[b][1,4]dioxin

[0300]

[0301] 3-bromo-4-nitrobenzene-1,2-diol (410 mg, 1.75 mmol), potassium carbonate (0.73 g, 5.26 mmol), 1,2-dibromoethane (1.32 g, 7.0 mmol) were mixed in DMF (5 mL) and stirred at 90 °C overnight. The reaction was cooled and diluted with a large amount of ethyl acetate. The organic phase was washed several times with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure and the title compound 5-bromo-6-nitro-2,3-dihydrobenzo[b][1,4]dioxin (200 mg, yield: 44%) was isolated by column chromatography.

[0302] MS m / z (ESI): 257.9 [M-H] - .

[0303] Fourth step: Preparation of 5-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-amine

[0304]

[0305] 5-bromo-6-nitro-2,3-dihydrobenzo[b][1,4]dioxin (200 mg, 0.77 mmol) was dissolved in ethanol (9 mL) and water (3 mL). Iron powder (343 mg, 6.1 mmol) and ammonium chloride (82 mg, 1.5 mmol) were added and the reaction was refluxed for 3 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the title compound 5-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-amine (170 mg, yield: 96%).

[0306] MS m / z (ESI): 230.2 [M+H] + .

[0307] Fifth step: Preparation of (6-amino-2,3-dihydrobenzo[b][l,4]dioxin-5- yl)dimethylphosphine oxide

[0308]

[0309] 5-Bromo-2,3-dihydrobenzo[b][l,4]dioxin-6-amine (0.16 g, 0.7 mmol), dimethylphosphine oxide (108 mg, 1.39 mmol), potassium phosphate (295 mg, 1.39 mmol) were mixed in N,N-dimethylformamide (5 mL), palladium acetate (31 mg, 0.14 mmol) and Xantphos (161 mg, 0.28 mmol) were added, deoxygenated under N2for 5 min, then heated to 145 °C for 3 h in microwave. The reaction was cooled to room temperature, concentrated under reduced pressure and purified by column chromatography to give the title compound (6-amino-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide (83 mg, yield: 52%).

[0310] 1 H NMR (400 MHz, CDC13) δ 1.72 (s, 3H), 1.75 (s, 3H), 4.09-4.13 (m, 2H), 4.15-4.23 (m, 2H), 5.41-5.85 (m, 2H), 6.07-6.15 (m, 1H), 6.72 (d, J = 6.8, 1H);

[0311] MS m / z (ESI): 228.2 [M+H] + .

[0312] Preparation of intermediate 2

[0313] 2-Methoxy-5-methyl-4-(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)aniline

[0314]

[0315] First step: Preparation of 8-(5-methoxy-2-methyl-4-nitrophenyl)-l,4-dioxa-8- azaspiro[4.5]decane

[0316]

[0317] To a solution of 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (1.1 g, 5.9 mmol) and 4-piperidinone ethylene glycol (3.4 g, 23.9 mmol) in DMSO (15 mL) was added K2CO3 (1.6 g, 11.9 mmol) and stirred at 120 °C overnight. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound 8-(5-methoxy-2-methyl-4-nitrophenyl)-1,4-dioxa-8- azaspiro[4.5]decane (1.3 g, yield: 71%).

[0318] MS m / z (ESI): 309.2 [M+H] + .

[0319] Second Step: Preparation of 2-methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]dec-8- yl)aniline

[0320]

[0321] 8-(5-methoxy-2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (500 mg, 1.62 mmol) was dissolved in methanol (10 mL) and tetrahydrofuran (3 mL), and Pd / C (100 mg) was added. The reaction was stirred at room temperature under hydrogen atmosphere for 5 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the title compound 2-methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)aniline (433 mg, yield: 96%).

[0322] MS m / z (ESI): 279.2 [M+H] + .

[0323] Example 1

[0324] Preparation of (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide

[0325]

[0326] First Step: Preparation of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide

[0327]

[0328] To a stirred solution of 5-bromo-2,4-dichloropyrimidine (2.27 g, 10 mmol), (6-amino-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethyl phosphine oxide (2.27 g, 10 mmol), potassium phosphate (2.76 g, 20 mmol) in tert-amyl alcohol (20 mL) was heated to 90 °C for 1 h in microwave. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethyl phosphine oxide (3.25 g, yield: 78%).

[0329] 1 H NMR (400 MHz, DMSO-d6) δ 1.81 (s, 3H), 1.85 (s, 3H), 4.24-4.39 (m, 4H), 7.13 (d, J = 9.2 Hz, 1H), 7.89-7.98 (m, 1H), 8.44 (d, J = 1.8 Hz, 1H), 12.26 (s, 1H); 6 ) δ 1.81 (s, 3H), 1.85 (s, 3H), 4.24-4.39 (m, 4H), 7.13 (d, J = 9.2 Hz, 1H), 7.89-7.98 (m, 1H), 8.44 (d, J = 1.8 Hz, 1H), 12.26 (s, 1H);

[0330] MS m / z (ESI): 417.9 [M+H] + .

[0331] Second Step: Preparation of (6-((5-bromo-2-((2-methoxy-5-methyl-4-(l,4-dioxa-8- azaspiro[4.5]dec-8-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5- yl)dimethyl phosphine oxide

[0332]

[0333] (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5- yl)dimethylphosphine oxide (1.0 g, 2.4 mmol), 2-methoxy-5-methyl-4-(l,4-dioxa-8- azaspiro[4.5]dec-8-yl)aniline (1.0 g, 3.6 mmol), p-toluenesulfonic acid (0.62 g, 3.6 mmol) were mixed in ethylene glycol (40 mL) and heated to 90 °C for 2 h. The reaction was cooled to room temperature, saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate, the organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, filtered over the drying agent and the organic solvent was concentrated under reduced pressure. The title compound (6-((5-bromo-2-((2-methoxy-5-methyl-4-(l,4-dioxa-8- azaspiro[4.5]dec-8-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin- 5-yl)dimethylphosphine oxide (1.34 g, yield: 85%) was isolated by column chromatography.

[0334] 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.74-1.85 (m, 10H), 2.14 (s, 3H), 2.91 (t, J = 5.4 Hz, 4H), 3.77 (s, 3H), 3.93 (s, 4H), 4.24 (s, 2H), 4.32 (s, 2H), 6.73 (s, 1H), 6.81 (d, J = 9.2 Hz, 1H), 7.46 (s, 1H), 7.94 (d, J = 15.0 Hz, 2H), 8.10 (s, 1H), 11.62 (s, 1H);

[0335] MS m / z (ESI): 660.2 [M+H] + .

[0336] Third Step: Preparation of l-(4-((5-bromo-4-((5-(dimethylphosphino)-2,3- dihydrobenzo[b][l,4]dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2- methylphenyl)piperidin-4-one

[0337]

[0338] (6-((5-bromo-2-((2-methoxy-5-methyl-4-(l,4-dioxa-8-azaspiro[4.5]dec-8- yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5- yl)dimethylphosphine oxide (1.34 g, 2.03 mmol) was mixed in acetic acid / water (12 mL / 12 mL) and heated to 90 °C for 2 h. The reaction was cooled to room temperature, concentrated under reduced pressure, and saturated aqueous sodium bicarbonate was added. The mixture was extracted with ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure, and the title compound, l-(4-((5-bromo-4-((5-(dimethylphosphino)-2,3- dihydrobenzo[b][l,4]dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2- methylphenyl)piperidin-4-one (1.2 g, yield: 96%) was isolated by column chromatography.

[0339] MS m / z (ESI): 616.2 [M+H] + .

[0340] Fourth Step: Preparation of (6-((5-bromo-2-((2-methoxy-4-(4-(3- (methoxymethyl)azetidin-l-yl)piperidin-l-yl)-5-methylphenyl)amino)pyrimidin-4- yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide

[0341]

[0342] l-(4-((5-bromo-4-((5-(dimethylphosphino)-2,3-dihydrobenzo[b][l,4]dioxin-6- yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-one (0.8 g, 1.3 mmol), 3-(methoxymethyl)azetidine trifluoroacetate (0.42 g, 1.95 mmol), and acetic acid (0.1 mL) were mixed in dichloroethane (20 mL) and stirred for 30 min. Sodium triacetoxyborohydride (0.55 g, 2.6 mmol) was added, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added, and the mixture was extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The title compound, (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-l-yl)piperidin-l-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide (0.56 g, yield: 62%) was isolated by column chromatography.

[0343] 1H NMR (400 MHz, DMSO-d 6 ) δ 1.26-1.38 (m, 2H), 1.69-1.77 (m, 2H), 1.78 (s, 3H), 1.81 (s, 3H), 2.07-2.22 (m, 4H), 2.56-2.66 (m, 3H), 2.83-2.92 (m, 1H), 2.96-3.05 (m, 2H), 3.15-3.19 (m, 2H), 3.23-3.27 (m, 3H), 3.42-3.46 (m, 2H), 3.76 (s, 3H), 4.07-4.13 (m, 1H), 4.24 (s, 2H), 4.32 (s, 2H), 6.69 (s, 1H), 6.80 (d, J = 9.0 Hz, 1H), 7.43 (s, 1H), 7.91-7.98 (m, 2H), 8.10 (s, 1H), 11.62 (s, 1H);

[0344] MS m / z (ESI): 701.2 [M+H] + .

[0345] Example 2

[0346] Preparation of (6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-5- ethyl-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)dimethylphosphine oxide

[0347]

[0348] First Step: Preparation of tert-butyl 4-(3-(dimethylamino)azetidin-1-yl)piperidine-1- carboxylate

[0349]

[0350] Tert-butyl 4-carbonylpiperidine-1-carboxylate (500 mg, 2.51 mmol) and N,N- dimethylazetidin-3-amine (302 mg, 3.01 mmol) were dissolved in 1,2-dichloroethane (15 mL) at room temperature, 2 drops of acetic acid was added, stirred for 5 minutes, sodium triacetoxyborohydride (1.06 g, 5.02 mmol) was added, stirred at room temperature overnight, then the reaction was quenched by adding saturated sodium bicarbonate solution, extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered off the drying agent and the organic solvent was concentrated under reduced pressure and the title compound tert-butyl 4-(3-(dimethylamino)azetidin-1-yl)piperidine-1-carboxylate (610 mg, yield: 86%) was isolated by column chromatography.

[0351] 1 H NMR (400 MHz, CDC13) δ 1.14-1.23 (m, 2H), 1.44 (s, 9H), 1.62-1.70 (m, 2H), 2.12 (s, 6H), 2.81-2.89 (m, 6H), 3.48-3.53 (m, 2H), 4.03-3.87 (m, 2H);

[0352] MS m / z (ESI): 284.1 [M+H] + .

[0353] Second Step: Preparation of N,N-dimethyl-1-(piperidin-4-yl)azetidin-3-amine

[0354]

[0355] N,N-dimethyl-1-(piperidin-4-yl)azetidin-3-amine crude product was obtained by stirring tert-butyl 4-(3-(dimethylamino)azetidin-1-yl)piperidine-1-carboxylate (610 mg, 2.16 mmol) in hydrochloric acid dioxane (10 mL) at room temperature overnight, and then concentrating the organic solvent under reduced pressure. The title compound was directly used in the next reaction.

[0356] MS m / z (ESI): 284.1 [M+H] + .

[0357] Third Step: Preparation of 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-N,N-dimethylazetidin-3-amine

[0358]

[0359] N,N-dimethyl-1-(piperidin-4-yl)azetidin-3-amine crude product was obtained by stirring tert-butyl 4-(3-(dimethylamino)azetidin-1-yl)piperidine-1-carboxylate (610 mg, 2.16 mmol) in hydrochloric acid dioxane (10 mL) at room temperature overnight, and then concentrating the organic solvent under reduced pressure. The title compound was directly used in the next reaction.

[0360] MS m / z (ESI): 284.1 [M+H] + .

[0361] Step 4: Preparation of 1-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)-N,N- dimethylazetidin-3-amine

[0362]

[0363] To a solution of 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-N,N- dimethylazetidin-3-amine (430 mg, 1.04 mmol), vinylpotassium trifluoroborate (279 mg, 2.08 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (76 mg, 0.104 mmol), cesium carbonate (1.01 g, 3.12 mmol) in dioxane / water (10 mL / 1.5 mL) under nitrogen, the reaction mixture was stirred at 90 °C overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3x). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound 1-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)-N,N-dimethylazetidin-3-amine (230 mg, yield: 61%).

[0364] MS m / z (ESI): 361.1 [M+H] + .

[0365] Step 5: Preparation of 1-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-N,N- dimethylazetidin-3-amine

[0366]

[0367] To a solution of 1-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)-N,N- dimethylazetidin-3-amine (230 mg, 0.64 mmol) in methanol (10 mL) under nitrogen, palladium on carbon (46 mg) was added. The reaction mixture was stirred at room temperature under hydrogen overnight. The catalyst was removed by filtration, and the organic solvent was concentrated under reduced pressure to give the title compound 1-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-N,N-dimethylazetidin-3-amine (210 mg, yield: 98%).

[0368] MS m / z (ESI): 333.1 [M+H] + .

[0369] Reference Example 1, Step 2, the prepared 1-(1-(4-amino-2-ethyl-5- methoxyphenyl)piperidin-4-yl)-N,N-dimethylazetidin-3-amine was reacted with (6- ((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide to prepare the target product (6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidin- 1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide.

[0370] 1 H NMR (400 MHz, CD3OD) δ 0.98-1.07 (m, 3H), 1.47-1.60 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.96-2.05 (m, 2H), 2.24 (s, 6H), 2.50-2.59 (m, 2H), 2.71-2.83 (m, 4H), 3.03-3.10 (m, 2H), 3.12-3.19 (m, 1H), 3.47-3.58 (m, 2H), 3.84 (d, J = 1.7 Hz, 2H), 3.90-3.97 (m, 2H), 4.26-4.32 (m, 2H), 4.33-4.39 (m, 2H), 6.77 (s, 1H), 6.88-6.94 (m, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.79-7.84 (m, 1H), 8.07 (s, 1H);

[0371] MS m / z (ESI): 714.2 [M+H] + .

[0372] Example 3

[0373] Preparation of (6-((5-bromo-2-((4-(4-(3-(2-fluoroethyl)-3-hydroxyazetidin-1-yl)piperidin-1- yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)dimethyl phosphine oxide

[0374]

[0375] The preparation method of (6-((5-bromo-2-((4-(4-(3-(2-fluoroethyl)-3-hydroxyazetidin-1-yl)piperidin-1- yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)dimethyl phosphine oxide refers to Example 1.

[0376] 1 H NMR (400 MHz, CD3OD) δ 1.56-1.67 (m, 2H), 1.88 (s, 3H), 1.92 (s, 3H), 2.03-2.11 (m, 2H), 2.12-2.18 (m, 4H), 2.20-2.26 (m, 1H), 2.73 (t, J = 11.7 Hz, 3H), 3.11-3.20 (m, 2H), 3.81-3.89 (m, 4H), 4.08-4.14 (m, 2H), 4.25-4.31 (m, 2H), 4.33-4.38 (m, 2H), 4.55-4.66 (m, 3H), 4.75 (t, J = 5.6 Hz, 1H), 6.72 (s, 1H), 6.92 (d, J = 9.2 Hz, 1H), 7.72 (s, 1H), 7.87-7.93 (m, 1H), 8.07 (s, 1H);

[0377] MS m / z (ESI): 719.2 [M+H] + .

[0378] Example 4

[0379] Preparation of (6-((5-bromo-2-((5-ethyl-4-(4-(3-fluoro-3-(2-hydroxypropan-2-yl)azetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide

[0380]

[0381] The method of preparing (6-((5-bromo-2-((5-ethyl-4-(4-(3-fluoro-3-(2-hydroxypropan-2-yl)azetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide is according to Example 2.

[0382] 1H NMR (400 MHz, CD3OD) δ 1.03 (t, J = 7.6 Hz, 3H), 1.23-1.26 (m, 6H), 1.60-1.65 (m, 2H), 1.91-1.93 (m, 6H), 2.03-2.05 (m, 2H), 2.56-2.58 (m, 2H), 2.75-2.78 (m, 3H), 3.08-3.12 (m, 2H), 3.78-3.96 (m, 5H), 4.12-4.16 (m, 2H), 4.22-4.48 (m, 4H), 6.78 (s, 1H), 6.91-6.93 (m, 1H), 7.63-7.90 (m, 2H), 8.08 (s, 1H);

[0383] MS m / z (ESI): 747.2 [M+H] + .

[0384] Example 5

[0385] (6-((5-bromo-2-((5-ethyl-3-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1- yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)dimethylphosphine oxide

[0386] Preparation of (6-((5-bromo-2-((5-ethyl-3-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1- yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)dimethylphosphine oxide

[0387]

[0388] (6-((5-bromo-2-((5-ethyl-3-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1- yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)dimethylphosphine oxide

[0389] MS m / z (ESI): 732.2 [M+H] + .

[0390] Example 6

[0391] (6-((5-bromo-2-((3-ethyl-2-fluoro-6-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1- yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)dimethylphosphine oxide

[0392] Preparation of (6-((5-bromo-2-((3-ethyl-2-fluoro-6-methoxy-4-(4-(4-methylpiperazin-1- yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)dimethylphosphine oxide

[0393]

[0394] Reference Example 1. MS m / z (ESI): 696.2 [M+H]

[0395] MS m / z (ESI): 732.2 [M+H] + .

[0396] Example 7

[0397] Preparation of (5-((5-bromo-2-((5-ethynyl-2-methoxy-4-(4-(4- methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxol-4- yl)dimethylphosphine oxide

[0398]

[0399] Reference Example 1. MS m / z (ESI): 696.2 [M+H] + .

[0400] Example 8

[0401] Preparation of (6-((5-bromo-2-((4-(4-(3-fluoro-3-(2-hydroxypropan-2-yl)azetidin-1-yl)piperidin-1-yl)- 2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxol-5- yl)dimethylphosphine oxide

[0402]

[0403] Reference Example 1. MS m / z (ESI): 696.2 [M+H]

[0404] 1H NMR (400 MHz, CD3OD) δ 1.23-1.25 (m, 6H), 1.63-1.65 (m, 2H), 1.89-1.91 (m, 6H), 2.02-2.21 (m, 5H), 2.71-2.73 (m, 2H), 3.12-3.16 (m, 3H), 3.84 (s, 3H), 4.11-4.13 (m 2H), 4.36-4.39 (m, 6H), 6.72 (s, 1H), 6.91-6.93 (m, 1H), 7.72 (s, 1H), 7.87-7.89 (m, 1H), 8.06 (s, 1H);

[0405] MS m / z (ESI): 733.2 [M+H] + .

[0406] Example 9

[0407] Preparation of (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5- methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)piperidin-l-yl)phenyl)amino)pyrimidin-4- yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide

[0408]

[0409] The preparation of (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5- methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)piperidin-l-yl)phenyl)amino)pyrimidin-4- yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide was performed according to Example 1.

[0410] MS m / z (ESI): 726.3 [M+H] + .

[0411] Example 10

[0412] Preparation of (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5- methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)piperidin-l-yl)phenyl)amino)pyrimidin-4- yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide

[0413]

[0414] The preparation of (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5- methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)piperidin-l-yl)phenyl)amino)pyrimidin-4- yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide is described in reference to Example 1.

[0415] MS m / z (ESI): 682.3 [M+H] + .

[0416] Example 11

[0417] The preparation of (6-((2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5- methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)piperidin-l-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide is described in reference to Example 1.

[0418] Preparation of (6-((2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5- methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)piperidin-l-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide is described in reference to Example 1.

[0419]

[0420] The preparation of (6-((2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5- methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)piperidin-l-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide is described in reference to Example 1.

[0421] MS m / z (ESI): 716.3 [M+H] + .

[0422] Example 12

[0423] The preparation of 2-(l-(l-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2,3- dihydrobenzo[b][l,4]dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2- methylphenyl)piperidin-4-yl)azetidin-3-yl)acetonitrile is described in reference to Example 1.

[0424]

[0425] A process for preparing 2-(l-(l-(4-((5-bromo-4-((5-(dimethylphosphino)-2,3- dihydrobenzo[b][l,4]dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2- methylphenyl)piperidin-4-yl)azetidin-3-yl)acetonitrile is described in Reference Example 1.

[0426] 1 H NMR (400 MHz, CD3OD) δ 1.49 - 1.51 (m, 3H), 1.91 - 1.93 (m, 9H), 2.12 (s, 3H), 2.57 - 2.59 (m, 1H), 2.69 - 2.72 (m, 2H), 2.78 - 2.80 (m, 2H), 2.89 - 2.93 (m, 1H), 3.12 - 3.15 (m, 2H), 3.78 - 3.81 (m, 2H), 3.84 (s, 3H), 4.33 - 4.36 (m, 4H), 6.72 (s, 1H), 6.91 - 6.95 (m, 1H), 7.70 - 7.76 (m, 1H), 7.88 - 7.91 (m, 1H), 8.06 (s, 1H);

[0427] MS m / z (ESI): 696.2 [M+H] + .

[0428] Example 13

[0429] A process for preparing 2-(l-(l-(4-((5-bromo-4-((5-(dimethylphosphino)-2,3- dihydrobenzo[b][l,4]dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2- methylphenyl)piperidin-4-yl)azetidin-3-yl)acetonitrile is described in Reference Example 1.

[0430]

[0431] A process for preparing 2-(l-(l-(4-((5-bromo-4-((5-(dimethylphosphino)-2,3- dihydrobenzo[b][l,4]dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2- methylphenyl)piperidin-4-yl)azetidin-3-yl)acetonitrile is described in Reference Example 1.

[0432] 1H NMR (400 MHz, CD3OD) δ 1.46-1.49 (m, 2H), 1.90-1.93 (m, 8H), 2.15-2.19 (m, 3H), 2.37-2.39 (m, 1H), 2.62-2.78 (m, 4H), 2.85-2.89 (m, 1H), 3.06-3.21 (m, 4H), 3.63-3.66 (m, 2H), 3.83 (s, 3H), 4.32-4.38 (m, 4H), 6.72 (s, 1H), 6.89-6.91 (m, 1H), 7.69-7.73 (m, 1H), 7.96-8.10 (m, 2H);

[0433] MS m / z (ESI): 652.3 [M+H] + .

[0434] Example 14

[0435] Preparation of 2-(1-(1-(4-((4-((5-(dimethylphosphino)-2,3-dihydrobenzo[b][1,4]dioxin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin- 4-yl)azetidin-3-yl)acetonitrile

[0436]

[0437] The preparation of 2-(1-(1-(4-((4-((5-(dimethylphosphino)-2,3-dihydrobenzo[b][1,4]dioxin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin- 4-yl)azetidin-3-yl)acetonitrile follows the procedure of Example 1.

[0438] MS m / z (ESI): 686.3 [M+H] + .

[0439] Example 15

[0440] Preparation of (6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2- methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)dimethylphosphine oxide

[0441]

[0442] Reference Example 1 for the preparation of (6-((5-bromo-2-((4-(4-(3- (dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin- 4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide.

[0443] 1 H NMR (400 MHz, CD3OD) δ 1.54-1.61 (m, 2H), 1.89-1.91 (m, 6H), 2.07-2.08 (m, 2H), 2.12 (s, 3H), 2.30 (s, 6H), 2.72-2.79 (m, 2H), 3.04-3.06 (m, 2H), 3.15-3.18 (m, 2H), 3.82-3.88 (m, 5H), 4.05-4.18 (m, 2H), 4.32-4.39 (m, 4H), 6.71 (s, 1H), 6.90-6.93 (m, 1H), 7.71 (s, 1H), 7.88-7.92 (m, 1H), 8.06 (s, 1H);

[0444] MS m / z (ESI): 700.2 [M+H] + .

[0445] Example 16

[0446] (6-((5-bromo-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxy-5- methylphenyl)amino)

[0447] the preparation of (6-((5-bromo-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2- methoxy-5-methylphenyl)amino)

[0448]

[0449] Reference Example 1 for the preparation of (6-((5-bromo-2-((4-(4-(3- (dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin- 4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide.

[0450] 1H NMR (400 MHz, CD3OD) δ 1.22 (t, J = 7.0 Hz, 3H), 1.53 - 1.64 (m, 2H), 1.87 (s, 3H), 1.90 (s, 3H), 2.00 - 2.08 (m, 2H), 2.11 (s, 3H), 2.64 - 2.75 (m, 2H), 2.91 - 3.01 (m, 1H), 3.11 - 3.18 (m, 2H), 3.48 - 3.57 (m, 2H), 3.73 - 3.79 (m, 2H), 3.83 (s, 3H), 4.15 - 4.23 (m, 2H), 4.25 - 4.38 (m, 5H), 6.70 (s, 1H), 6.89 (d, J = 9.1 Hz, 1H), 7.71 (s, 1H), 7.84 - 7.91 (m, 1H), 8.05 (s, 1H);

[0451] MS m / z (ESI): 701.2 [M+H] + .

[0452] Example 17

[0453] Preparation of (S)-(6-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide

[0454]

[0455] The method of preparing (S)-(6-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide is described in Example 1.

[0456] 1 H NMR (400 MHz, CD3OD) δ 1.80 - 1.83 (m, 2H), 1.88 - 1.90 (m, 6H), 2.09 - 2.11 (m, 6H), 2.30 (s, 1H), 2.62 (s, 6H), 2.72 - 2.79 (m, 3H), 3.14 - 3.18 (m, 4H), 3.25 - 3.29 (m, 1H), 3.34 - 3.47 (m, 2H), 3.83 (s, 3H), 4.31 - 4.33 (m, 4H), 6.69 (s, 1H), 6.88 - 6.91 (m, 1H), 7.70 (s, 1H), 7.87 - 7.89 (m, 1H), 8.05 (s, 1H);

[0457] MS m / z (ESI): 714.2 [M+H] + .

[0458] Example 18

[0459] Preparation of (R)-(6-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide

[0460]

[0461] The method of preparing (R)-(6-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide is described in Example 1.

[0462] 1 H NMR (400 MHz, CD3OD) δ 1.80-1.83 (m, 2H), 1.88-1.90 (m, 6H), 2.09-2.11 (m, 6H), 2.30 (s, 1H), 2.62 (s, 6H), 2.72-2.79 (m, 3H), 3.14-3.18 (m, 4H), 3.25-3.29 (m, 1H), 3.34-3.47 (m, 2H), 3.83 (s, 3H), 4.31-4.33 (m, 4H), 6.69 (s, 1H), 6.88-6.91 (m, 1H), 7.70 (s, 1H), 7.87-7.89 (m, 1H), 8.05 (s, 1H);

[0463] MS m / z (ESI): 714.2 [M+H] + .

[0464] Example 19

[0465] Preparation of (S)-(6-((5-bromo-2-((4-(4-(3-ethoxypyrrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide

[0466]

[0467] A process for the preparation of (S)-(6-((5-bromo-2-((4-(4-(3-ethoxypyrrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide is described in reference example 1.

[0468] 1 H NMR (400 MHz, CD3OD) δ 1.22 (t, J = 7.0 Hz, 3H), 1.90-1.96 (m, 8H), 2.15 (s, 3H), 2.22-2.28 (m, 4H), 2.75-2.82 (m, 2H), 3.18-3.22 (m, 3H), 3.41-3.46 (m, 3H), 3.50-3.59 (m, 4H), 3.84 (s, 3H), 4.25-4.38 (m, 5H), 6.71 (s, 1H), 6.91-6.96 (m, 1H), 7.73 (s, 1H), 7.90-7.93 (m, 1H), 8.06 (s, 1H);

[0469] MS m / z (ESI): 715.2 [M+H] + .

[0470] Example 20

[0471] A process for the preparation of (R)-(6-((5-bromo-2-((4-(4-(3-ethoxypyrrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide is described in reference example 1.

[0472]

[0473] A process for the preparation of (R)-(6-((5-bromo-2-((4-(4-(3-ethoxypyrrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide is described in reference example 1.

[0474] 1H NMR (400 MHz, CD3OD) δ 1.22 (t, J = 7.0 Hz, 3H), 1.90-1.96 (m, 8H), 2.15 (s, 3H), 2.22-2.28 (m, 4H), 2.75-2.82 (m, 2H), 3.18-3.22 (m, 3H), 3.41-3.46 (m, 3H), 3.50-3.59 (m, 4H), 3.84 (s, 3H), 4.25-4.38 (m, 5H), 6.71 (s, 1H), 6.91-6.96 (m, 1H), 7.73 (s, 1H), 7.90-7.93 (m, 1H), 8.06 (s, 1H);

[0475] MS m / z (ESI): 715.2 [M+H] + .

[0476] Example 21

[0477] Preparation of (6-((5-chloro-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide

[0478]

[0479] The method for preparing (6-((5-chloro-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide is according to Example 1.

[0480] 1 H NMR (400 MHz, CD3OD) δ 1.22 (t, J = 7.0 Hz, 3H), 1.90-1.96 (m, 8H), 2.15 (s, 3H), 2.22-2.28 (m, 4H), 2.75-2.82 (m, 2H), 3.18-3.22 (m, 3H), 3.41-3.46 (m, 3H), 3.50-3.59 (m, 4H), 3.84 (s, 3H), 4.25-4.38 (m, 5H), 6.71 (s, 1H), 6.91-6.96 (m, 1H), 7.73 (s, 1H), 7.90-7.93 (m, 1H), 8.06 (s, 1H);

[0481] MS m / z (ESI): 715.2 [M+H] + .

[0482] Example 22

[0483] Preparation of (6-((5-chloro-2-((4-(4-(3-ethoxyazetidin-l-yl)piperidin-l-yl)-2- methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5- yl)dimethylphosphine oxide

[0484]

[0485] The preparation of (6-((5-chloro-2-((4-(4-(3-ethoxyazetidin-l-yl)piperidin-l-yl)-2- methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5- yl)dimethylphosphine oxide follows the procedure of Example 1.

[0486] MS m / z (ESI): 657.2 [M+H] + .

[0487] Example 23

[0488] Preparation of (S)-(6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-l-yl)piperidin-l-yl)- 2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5- yl)dimethylphosphine oxide

[0489]

[0490] The preparation of (S)-(6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-l-yl)piperidin-l- yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin- 5-yl)dimethylphosphine oxide follows the procedure of Example 1.

[0491] MS m / z (ESI): 670.2 [M+H] + .

[0492] Example 24

[0493] Preparation of (R)-(6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-l-yl)piperidin-l-yl)- 2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5- yl)dimethylphosphine oxide

[0494]

[0495] The preparation of (R)-(6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1- yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide is described in Reference Example 1.

[0496] MS m / z (ESI): 670.2 [M+H] + .

[0497] Example 25

[0498] The preparation of (R)-(6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1- yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide is described in Reference Example 1.

[0499]

[0500] The preparation of (R)-(6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1- yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide is described in Reference Example 1.

[0501] MS m / z (ESI): 671.2 [M+H] + .

[0502] Example 26

[0503] The preparation of (R)-(6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1- yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide is described in Reference Example 1.

[0504]

[0505] The preparation of (R)-(6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1- yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide is described in Reference Example 1.

[0506] MS m / z (ESI): 671.2 [M+H] + .

[0507] Example 27

[0508] Preparation of (6-((2-((4-(4-(3-(dimethylamino)azetidin-l-yl)piperidin-l- yl)-2-methoxy-5-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide

[0509]

[0510] The method of preparing (6-((2-((4-(4-(3-ethoxyazetidin-l-yl)piperidin-l-yl)-2- methoxy-5-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide refers to Example 1.

[0511] MS m / z (ESI): 690.2 [M+H] + .

[0512] Example 28

[0513] Preparation of (6-((2-((4-(4-(3-ethoxyazetidin-l-yl)piperidin-l-yl)-2- methoxy-5-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide

[0514]

[0515] The method of preparing (6-((2-((4-(4-(3-ethoxyazetidin-l-yl)piperidin-l-yl)-2- methoxy-5-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide refers to Example 1.

[0516] MS m / z (ESI): 691.2 [M+H] + .

[0517] Example 29

[0518] Preparation of (S)-(6-((2-((4-(4-(3-(dimethylamino)pyrrolidin-l-yl)piperidin-l- yl)-2-methoxy-5-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide

[0519]

[0520] The preparation of (S)-(6-((2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide is described in reference example 1.

[0521] MS m / z (ESI): 704.2 [M+H] + .

[0522] Example 30

[0523] The preparation of (R)-(6-((2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide

[0524]

[0525] The preparation of (R)-(6-((2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide is described in reference example 1.

[0526] MS m / z (ESI): 704.2 [M+H] + .

[0527] Example 31

[0528] The preparation of (S)-(6-((2-((4-(4-(3-ethoxypyrrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide

[0529]

[0530] The preparation of (S)-(6-((2-((4-(4-(3-ethoxypyrrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide is described in reference example 1.

[0531] MS m / z (ESI): 705.2 [M+H] + .

[0532] Example 32

[0533] Preparation of (R)-(6-((2-((4-(4-(3-ethoxypyrrrolidin-1-yl)piperidin-1-yl)-2- methoxy-5-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide

[0534]

[0535] The preparation of (R)-(6-((2-((4-(4-(3-ethoxypyrrrolidin-1-yl)piperidin-1-yl)-2- methoxy-5-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide follows the procedure of Example 1.

[0536] MS m / z (ESI): 705.2 [M+H] + .

[0537] Example 33

[0538] Preparation of (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(3-(methyl(oxetan-3- yl)amino)azetidin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide

[0539]

[0540] The preparation of (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(3-(methyl(oxetan-3- yl)amino)azetidin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide follows the procedure of Example 1.

[0541] 1H NMR (400 MHz, CD3OD) δ 1.50-1.65 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.99-2.07 (m, 2H), 2.11 (s, 3H), 2.22 (s, 3H), 2.64-2.74 (m, 2H), 2.90-3.00 (m, 1H), 3.08-3.18 (m, 2H), 3.37-3.46 (m, 1H), 3.73-3.81 (m, 3H), 3.83 (s, 3H), 3.95-4.04 (m, 2H), 4.24-4.39 (m, 4H), 4.60-4.70 (m, 4H), 6.69 (s, 1H), 6.89 (d, J = 9.1 Hz, 1H), 7.71 (s, 1H), 7.84-7.91 (m, 1H), 8.05 (s, 1H);

[0542] MS m / z (ESI): 742.2 [M+H] + .

[0543] Example 34

[0544] Preparation of (5-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxol-4-yl)dimethylphosphine oxide

[0545]

[0546] The method for preparing (5-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxol-4-yl)dimethylphosphine oxide is described in Example 1.

[0547] 1 H NMR (400 MHz, CD3OD) δ 1.50-1.65 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.99-2.07 (m, 2H), 2.11 (s, 3H), 2.22 (s, 3H), 2.64-2.74 (m, 2H), 2.90-3.00 (m, 1H), 3.08-3.18 (m, 2H), 3.37-3.46 (m, 1H), 3.73-3.81 (m, 3H), 3.83 (s, 3H), 3.95-4.04 (m, 2H), 4.24-4.39 (m, 4H), 4.60-4.70 (m, 4H), 6.69 (s, 1H), 6.89 (d, J = 9.1 Hz, 1H), 7.71 (s, 1H), 7.84-7.91 (m, 1H), 8.05 (s, 1H);

[0548] MS m / z (ESI): 687.2 [M+H] + .

[0549] Example 35

[0550] (5-((5-bromo-2-((4-(4-(3-ethoxyazetidin-l-yl)piperidin-l-yl)-2-methoxy-5- methylphenyl)amino)pyrimidin-4-yl)amino)benzo[d][l,3]dioxol-4-yl)dimethyl phosphine oxide

[0551] (5-((5-bromo-2-((4-(4-(3-ethoxyazetidin-l-yl)piperidin-l-yl)-2-methoxy-5- methylphenyl)amino)pyrimidin-4-yl)amino)benzo[d][l,3]dioxol-4-yl)dimethyl phosphine oxide

[0552]

[0553] (5-((5-bromo-2-((4-(4-(3-ethoxyazetidin-l-yl)piperidin-l-yl)-2-methoxy-5- methylphenyl)amino)pyrimidin-4-yl)amino)benzo[d][l,3]dioxol-4-yl)dimethyl phosphine oxide

[0554] 1 H NMR (400 MHz, CD3OD) δ 1.23 (t, J = 7.1 Hz, 3H), 1.53 - 1.64 (m, 2H), 1.84 (s, 3H), 1.88 (s, 3H), 2.03 - 2.14 (m, 5H), 2.72 (t, J = 11.7 Hz, 2H), 3.06 - 3.19 (m, 3H), 3.49 - 3.58 (m, 2H), 3.84 (s, 3H), 3.88 - 3.95 (m, 2H), 4.25 - 4.38 (m, 3H), 6.07 (s, 2H), 6.71 (s, 1H), 6.93 (d, J = 8.7 Hz, 1H), 7.71 (s, 1H), 7.74 - 7.81 (m, 1H), 8.08 (s, 1H);

[0555] MS m / z (ESI): 687.2 [M+H] + .

[0556] Example 36

[0557] (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-((3aR,6aS)-5-(methylsulfonyl)hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)piperidin-l-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4] dioxin-5-yl)dimethyl phosphine oxide

[0558]

[0559] Reference Example 1 for the preparation of (6-((5-bromo-2-((2-methoxy-5-methyl-4- (4-((3aR,6aS)-5-(methylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)piperidin-l- yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethyl- phosphine oxide.

[0560] MS m / z (ESI): 804.2 [M+H] + .

[0561] Example 37

[0562] Reference Example 1 for the preparation of (6-((5-bromo-2-((2-methoxy-5-methyl-4- (4-((3aR,6aS)-5-(methylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)piperidin-l- yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethyl- phosphine oxide.

[0563]

[0564] Reference Example 1 for the preparation of (6-((5-bromo-2-((2-methoxy-5-methyl-4- (4-((3aR,6aS)-5-(methylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)piperidin-l- yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethyl- phosphine oxide.

[0565] 1 H NMR (400 MHz, CD3OD) δ 1.85 - 1.97 (m, 8H), 2.14 (s, 3H), 2.17 - 2.30 (m, 2H), 2.74 (t, J = 11.9 Hz, 2H), 2.96 (s, 3H), 3.04 - 3.26 (m, 7H), 3.34 - 3.49 (m, 3H), 3.80 - 3.91 (m, 5H), 4.28 (d, J = 4.9 Hz, 2H), 4.35 (d, J = 4.9 Hz, 2H), 6.70 (s, 1H), 6.90 (d, J = 9.1 Hz, 1H), 7.72 (s, 1H), 7.88 (dd, J = 9.5, 4.4 Hz, 1H), 8.06 (s, 1H);

[0566] MS m / z (ESI): 790.2 [M+H] + .

[0567] Example 38

[0568] Preparation of (6-((5-bromo-2-((4-(4-(3-(ethyl(methyl)amino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide

[0569]

[0570] The method of preparing (6-((5-bromo-2-((4-(4-(3-(ethyl(methyl)amino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide refers to Example 1.

[0571] 1 H NMR (400 MHz, CD3OD) δ 1.14 (t, J = 7.2 Hz, 3H), 1.52-1.63 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.99-2.09 (m, 2H), 2.12 (s, 3H), 2.29 (s, 3H), 2.48-2.57 (m, 2H), 2.66-2.77 (m, 2H), 2.83-2.93 (m, 1H), 3.08-3.18 (m, 2H), 3.38-3.45 (m, 1H), 3.63-3.71 (m, 2H), 3.84 (s, 3H), 4.00-4.07 (m, 2H), 4.22-4.40 (m, 4H), 6.71 (s, 1H), 6.88-6.95 (m, 1H), 7.71 (s, 1H), 7.85-7.92 (m, 1H), 8.06 (s, 1H);

[0572] MS m / z (ESI): 714.2 [M+H] + .

[0573] Example 39

[0574] Preparation of (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide

[0575]

[0576] A process for the preparation of (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4- methyl-1,4-diazepan-1 -yl)piperidin-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)- 2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide is described in reference example 1.

[0577] 1 H NMR (400 MHz, CD3OD) δ 1.73-1.84 (m, 2H), 1.85-1.97 (m, 8H), 2.00-2.10 (m, 2H), 2.14 (s, 3H), 2.64-2.74 (m, 2H), 2.78-2.86 (m, 4H), 3.01-3.07 (m, 2H), 3.09-3.18 (m, 4H), 3.19-3.23 (m, 2H), 3.25-3.29 (m, 2H), 3.83 (s, 3H), 4.25-4.39 (m, 4H), 6.70 (s, 1H), 6.90 (d, J = 9.1 Hz, 1H), 7.68 (s, 1H), 7.86-7.93 (m, 1H), 8.05 (s, 1H);

[0578] MS m / z (ESI): 714.2 [M+H] + .

[0579] Example 40

[0580] (6-((2-((4-(4-(1,4-oxazepan-4-yl)piperidin-1 -yl)-2-methoxy-5-methylphenyl)amino)- 5-bromopyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide

[0581] Preparation of (6-((2-((4-(4-(1,4-oxazepan-4-yl)piperidin-1 -yl)-2-methoxy-5- methylphenyl)amino)-5-bromopyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)dimethylphosphine oxide

[0582]

[0583] A process for the preparation of (6-((2-((4-(4-(1,4-oxazepan-4-yl)piperidin-1 -yl)-2-methoxy-5-methylphenyl)amino)-5-bromopyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide is described in reference example 1.

[0584] 1H NMR (400 MHz, CD3OD) δ 1.84 - 1.94 (m, 8H), 2.02 - 2.10 (m, 4H), 2.15 (s, 3H), 2.69 - 2.79 (m, 2H), 3.08 - 3.26 (m, 7H), 3.80 - 3.88 (m, 7H), 4.26 - 4.39 (m, 4H), 6.72 (s, 1H), 6.91 (d, J = 9.1 Hz, 1H), 7.70 (s, 1H), 7.86 - 7.92 (m, 1H), 8.06 (s, 1H);

[0585] MS m / z (ESI): 701.2 [M+H] + .

[0586] Example 41

[0587] Preparation of (6-((2-((4-(4-(3-(dimethylamino)azetidin-l-yl)piperidin-l-yl)-5- ethyl-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide

[0588]

[0589] The method of preparing (6-((2-((4-(4-(3-(dimethylamino)azetidin-l-yl)piperidin-l-yl)-5- ethyl-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide is described in Example 2.

[0590] 1 H NMR (400 MHz, CD3OD) δ 0.94 - 1.04 (m, 3H), 1.51 - 1.60 (m, 2H), 1.84 (s, 3H), 1.88 (s, 3H), 1.98 - 2.07 (m, 2H), 2.26 (s, 6H), 2.46 - 2.55 (m, 2H), 2.70 - 2.81 (m, 2H), 3.04 - 3.12 (m, 2H), 3.17 - 3.23 (m, 2H), 3.57 - 3.65 (m, 2H), 3.84 (s, 3H), 3.99 (t, J = 8.1 Hz, 2H), 4.26 - 4.33 (m, 2H), 4.33 - 4.41 (m, 2H), 6.77 (s, 1H), 6.89 (d, J = 9.1 Hz, 1H), 7.54 - 7.64 (m, 1H), 7.72 (s, 1H), 8.25 (s, 1H);

[0591] MS m / z (ESI): 704.2 [M+H]+ .

[0592] Example 42

[0593] 2-(1-(1-(4-((4-((5-(dimethylphosphino)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5- (methylthio)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidin-3- yl)acetonitrile

[0594]

[0595] The method of preparing 2-(1-(1-(4-((4-((5-(dimethylphosphino)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5-(methylthio)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidin-3-yl)acetonitrile is described in Example 1.

[0596] 1 H NMR (400 MHz, CD3OD) δ 1.51-1.61 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.99-2.07 (m, 2H), 2.13 (s, 3H), 2.29 (s, 3H), 2.67-2.76 (m, 2H), 2.81-2.95 (m, 3H), 3.07-3.19 (m, 3H), 3.65-3.73 (m, 2H), 3.85 (s, 3H), 4.02-4.10 (m, 2H), 4.26-4.31 (m, 4H), 6.72 (s, 1H), 6.91 (d, J = 9.1 Hz, 1H), 7.75 (s, 1H), 7.89-7.96 (m, 1H), 8.11 (s, 1H);

[0597] MS m / z (ESI): 664.2 [M+H] + .

[0598] Example 43

[0599] (6-((2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)-5-(methylthio)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide

[0600]

[0601] Reference Example 2 for the preparation of (6-((2-((4-(4-(3-(dimethylamino)azetidin-l-yl)piperidin-l-yl)-5- ethyl-2-methoxyphenyl)amino)-5-(methylthio)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5- yl)dimethylphosphine oxide.

[0602] 1 H NMR (400 MHz, CD3OD) δ 1.01 (t, J = 7.5 Hz, 3H), 1.51 - 1.63 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.99 - 2.08 (m, 2H), 2.24 - 2.32 (m, 9H), 2.50 - 2.58 (m, 2H), 2.70 - 2.80 (m, 2H), 2.85 - 2.96 (m, 1H), 3.03 - 3.13 (m, 2H), 3.20 - 3.28 (m, 1H), 3.64 - 3.71 (m, 2H), 3.85 (s, 3H), 3.98 - 4.08 (m, 2H), 4.25 - 4.40 (m, 4H), 6.77 (s, 1H), 6.91 (d, J = 9.1 Hz, 1H), 7.79 - 7.88 (m, 2H), 8.12 (s, 1H);

[0603] MS m / z (ESI): 682.2 [M+H] + .

[0604] Example 44

[0605] Preparation of (6-((5-bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-l-yl)piperidin-l-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide

[0606]

[0607] Reference Example 2 for the preparation of (6-((2-((4-(4-(3-(dimethylamino)azetidin-l-yl)piperidin-l-yl)-5- ethyl-2-methoxyphenyl)amino)-5-(methylthio)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5- yl)dimethylphosphine oxide.

[0608] MS m / z (ESI): 710.2 [M+H] + .

[0609] Example 45

[0610] Preparation of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(3- (methoxymethyl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)- 2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide

[0611]

[0612] The method of preparing (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(3- (methoxymethyl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)- 2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide is described in Reference Example 2.

[0613] 1 H NMR (400 MHz, CD3OD) δ 1.02 (t, J = 7.5 Hz, 3H), 1.53 - 1.64 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 2.02 - 2.09 (m, 2H), 2.49 - 2.60 (m, 2H), 2.71 - 2.81 (m, 2H), 2.97 - 3.13 (m, 4H), 3.44 (s, 3H), 3.52 (d, J = 4.5 Hz, 2H), 3.84 (s, 3H), 3.87 - 3.91 (m, 2H), 4.08 (t, J = 9.4 Hz, 2H), 4.26 - 4.33 (m, 2H), 4.33 - 4.40 (m, 2H), 6.77 (s, 1H), 6.91 (d, J = 9.2 Hz, 1H), 7.77 (s, 1H), 7.79 - 7.84 (m, 1H), 8.07 (s, 1H);

[0614] MS m / z (ESI): 715.2 [M+H] + .

[0615] Example 46

[0616] Preparation of 2-(1-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5- methoxyphenyl)piperidin-4-yl)azetidin-3-yl)acetonitrile

[0617]

[0618] A process for the preparation of 2-(l-(l-(4-((5-bromo-4-((5-(dimethylphosphino)-2,3- dihydrobenzo[b][l,4]dioxin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5- methoxyphenyl)piperidin-4-yl)azetidin-3-yl)acetonitrile is described in reference to Example 2.

[0619] 1 H NMR (400 MHz, CD3OD) δ 1.01 (t, J = 7.5 Hz, 3H), 1.50-1.60 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.96-2.04 (m, 2H), 2.50-2.58 (m, 2H), 2.71-2.79 (m, 2H), 2.80-2.87 (m, 3H), 3.03-3.12 (m, 3H), 3.58-3.68 (m, 2H), 3.84 (s, 3H), 3.97-4.06 (m, 2H), 4.25-4.31 (m, 4H), 6.76 (s, 1H), 6.90 (d, J = 9.1 Hz, 1H), 7.74-7.83 (m, 2H), 8.07 (s, 1H);

[0620] MS m / z (ESI): 710.2 [M+H] + .

[0621] Example 47

[0622] Preparation of (6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidin-l-yl)piperidin-l-yl)-2- methoxy-5-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5- yl)dimethylphosphine oxide

[0623]

[0624] A process for the preparation of (6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidin-l-yl)piperidin-l-yl)-2- methoxy-5-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5- yl)dimethylphosphine oxide is described in reference to Example 1.

[0625] 1H NMR (400 MHz, CD3OD) δ 1.51 - 1.62 (m, 2H), 1.88 (s, 3H), 1.91 (s, 3H), 2.00 - 2.07 (m, 2H), 2.28 (s, 6H), 2.85 (t, J= 11.3 Hz, 2H), 2.91 - 3.02 (m, 1H), 3.04 - 3.12 (m, 2H), 3.21 - 3.27 (m, 1H), 3.67 - 3.75 (m, 2H), 3.94 (s, 3H), 4.02 - 4.08 (m, 2H), 4.26 - 4.32 (m, 2H), 4.33 - 4.39 (m, 2H), 6.89 (d, J= 9.1 Hz, 1H), 7.07 (s, 1H), 7.81 - 7.86 (m, 1H), 8.13 (s, 1H), 8.21 (s, 1H);

[0626] MS m / z (ESI): 754.2 [M+H] + .

[0627] Example 48

[0628] Preparation of (5-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2- methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxol-4- yl)dimethylphosphine oxide

[0629]

[0630] The method of preparing (5-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2- methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxol-4- yl)dimethylphosphine oxide is described in Example 1.

[0631] 1H NMR (400 MHz, CD3OD) δ 1.58 - 1.61 (m, 2H), 1.86 - 1.88 (m, 6H), 1.90 - 1.92 (m, 1H), 2.04 - 2.07 (m, 2H), 2.12 - 2.15 (m, 3H), 2.20 - 2.37 (m, 6H), 2.70 - 2.75 (m, 2H), 2.92 - 2.95 (m, 1H), 3.13 - 3.16 (m, 2H), 3.61 - 3.77 (m, 2H), 3.84 (s, 3H), 3.97 - 4.14 (m, 2H), 6.07 (s, 2H), 6.71 (s, 1H), 6.92 - 6.95 (m, 1H), 7.70 (s, 1H), 7.74 - 7.87 (m, 1H), 8.07 (s, 1H);

[0632] MS m / z (ESI): 686.2 [M+H] + .

[0633] Example 49

[0634] (5-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-5- ethyl-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxol-4- yl)dimethylphosphine oxide

[0635] Process for the preparation of (5-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidin-1- yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3] dioxol-4-yl)dimethylphosphine oxide

[0636]

[0637] Process for the preparation of (5-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidin-1- yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3] dioxol-4-yl)dimethylphosphine oxide

[0638] 1 H NMR (400 MHz, CD3OD) δ 1.58 - 1.61 (m, 2H), 1.86 - 1.88 (m, 6H), 1.90 - 1.92 (m, 1H), 2.04 - 2.07 (m, 2H), 2.12 - 2.15 (m, 3H), 2.20 - 2.37 (m, 6H), 2.70 - 2.75 (m, 2H), 2.92 - 2.95 (m, 1H), 3.13 - 3.16 (m, 2H), 3.61 - 3.77 (m, 2H), 3.84 (s, 3H), 3.97 - 4.14 (m, 2H), 6.07 (s, 2H), 6.71 (s, 1H), 6.92 - 6.95 (m, 1H), 7.70 (s, 1H), 7.74 - 7.87 (m, 1H), 8.07 (s, 1H);

[0639] MS m / z (ESI): 700.2 [M+H] + .

[0640] Example 50

[0641] Preparation of (6-((2-((5-bromo-4-(4-(3-(dimethylamino)acetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation

[0642]

[0643] The preparation method of (6-((2-((5-bromo-4-(4-(3-(dimethylamino)acetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation is as described in Example 1.

[0644] MS m / z(ESI): 720.2 [M+H] + .

[0645] Example 51

[0646] (6-((2-((5-bromo-4-(4-(3-ethoxyacryl-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidine

[0647] Preparation of 4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation

[0648]

[0649] The preparation method of (6-((2-((5-bromo-4-(4-(3-ethoxyacryl-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation is described in Example 1.

[0650] MS m / z (ESI): 721.2 [M+H] + .

[0651] Example 52

[0652] Preparation of (6-((5-chloro-2-((4-(4-(3-(dimethylamino)azetidin-l-yl)piperidin-l- yl)-5-ethyl-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4] dioxin-5- yl)dimethylphosphine oxide

[0653]

[0654] The method of preparing (6-((5-chloro-2-((4-(4-(3-(dimethylamino)azetidin-l-yl)piperidin-l- yl)-5-ethyl-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4] dioxin-5- yl)dimethylphosphine oxide is described in Reference Example 2.

[0655] 1 H NMR (400 MHz, CD3OD) δ 0.96 - 1.11 (m, 3H), 1.48 - 1.63 (m, 2H), 1.88 (s, 3H), 1.91 (s, 3H), 1.99 - 2.08 (m, 2H), 2.27 (s, 6H), 2.50 - 2.64 (m, 2H), 2.66 - 2.96 (m, 4H), 3.04 - 3.12 (m, 2H), 3.16 - 3.25 (m, 2H), 3.55 - 3.66 (m, 2H), 3.85 (s, 3H), 3.94 - 4.05 (m, 2H), 4.23 - 4.31 (m, 2H), 4.33 - 4.40 (m, 2H), 6.78 (s, 1H), 6.86 - 6.93 (m, 1H), 7.76 (d, J = 4.4 Hz, 1H), 7.93 - 8.01 (m, 2H);

[0656] MS m / z (ESI): 670.2 [M+H] + .

[0657] Example 53

[0658] Preparation of (6-((5-chloro-2-((4-(4-(3-(dimethylamino)azetidin-l-yl)piperidin-l- yl)-5-ethyl-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4] dioxin-5- yl)dimethylphosphine oxide

[0659]

[0660] Reference Example 1 for the preparation of (6-((5-bromo-2-((4-(4-(3-fluoro-3- (hydroxymethyl)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin- 4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide.

[0661] 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.35-1.38 (m, 2H), 1.79-1.81 (m, 8H), 2.11 (s, 3H), 2.22-2.25 (m, 1H), 2.58-2.71 (m, 3H), 2.96-3.01 (m, 5H), 3.68-2.71 (m, 2H), 3.76 (s, 3H), 4.28-4.31 (m, 4H), 6.70 (s, 1H), 6.80-6.83 (m, 1H), 7.43 (s, 1H), 7.93-7.95 (m 2H), 8.10 (s, 1H), 11.62 (s, 1H);

[0662] MS m / z (ESI): 705.2 [M+H] + .

[0663] Example 54

[0664] Reference Example 2 for the preparation of (6-((5-bromo-2-((5-ethyl-4-(4-(3-fluoro-3- (hydroxymethyl)azetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)- 2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide.

[0665]

[0666] Reference Example 2 for the preparation of (6-((5-bromo-2-((5-ethyl-4-(4-(3-fluoro-3- (hydroxymethyl)azetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)- 2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide.

[0667] 1H NMR (400 MHz, CD3OD) δ 1.02 (t, J = 7.6 Hz, 3H), 1.49 - 1.64 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 2.00 (d, J = 13.4 Hz, 2H), 2.54 (q, J = 7.5 Hz, 2H), 2.75 (t, J = 11.5 Hz, 3H), 3.07 (d, J = 11.7 Hz, 2H), 3.71 - 3.85 (m, 7H), 3.97 (dd, J = 15.7, 10.4 Hz, 2H), 4.29 (s, 2H), 4.36 (s, 2H), 6.77 (s, 1H), 6.90 (d, J = 9.1 Hz, 1H), 7.75 (s, 1H), 7.81 (dd, J = 9.2, 4.5 Hz, 1H), 8.07 (s, 1H);

[0668] MS m / z (ESI): 719.2 [M+H] + .

[0669] Example 55

[0670] 1-((3aR,6aS)-5-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxin-6- yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-yl)ethan-1-one

[0671] Preparation of 1-((3aR,6aS)-5-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxin-6- yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-yl)ethan-1-one

[0672]

[0673] The method of preparation of 1-((3aR,6aS)-5-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxin-6- yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-yl)ethan-1-one is described in Example 2.

[0674] 1H NMR (400 MHz, CD3OD) δ 1.02 (t, J = 7.7 Hz, 3H), 1.81 - 1.93 (m, 8H), 2.09 (s, 3H), 2.18 (d, J = 10.5 Hz, 2H), 2.56 (q, J = 7.5 Hz, 2H), 2.78 (t, J = 11.6 Hz, 2H), 2.95 - 3.20 (m, 7H), 3.52 - 3.68 (m, 5H), 3.77 (d, J = 9.6 Hz, 1H), 3.84 (s, 3H), 4.29 (s, 2H), 4.36 (s, 2H), 6.76 (s, 1H), 6.90 (d, J = 9.2 Hz, 1H), 7.79 - 7.83 (m, 2H), 8.07 (s, 1H);

[0675] MS m / z (ESI): 768.2 [M+H] + .

[0676] Example 56

[0677] 1-((3aR,6aS)-5-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxin-6- yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-yl)ethan-1-one

[0678] Preparation of 1-((3aR,6aS)-5-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxin-6- yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-yl)ethan-1-one

[0679]

[0680] The preparation of 1-((3aR,6aS)-5-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxin-6- yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-yl)ethan-1-one

[0681] 1H NMR (400 MHz, CD3OD) δ 1.78 - 1.90 (m, 5H), 1.91 (s, 3H), 2.09 (s, 3H), 2.12 - 2.22 (m, 5H), 2.73 (t, J=11.8 Hz, 2H), 2.97 - 3.23 (m, 7H), 3.54 - 3.67 (m, 5H), 3.75 - 3.82 (m, 1H), 3.84 (s, 3H), 4.25 - 4.32 (m, 2H), 4.33 - 4.39 (m, 2H), 6.71 (s, 1H), 6.91 (d, J=9.1 Hz, 1H), 7.72 (s, 1H), 7.87 - 7.92 (m, 1H), 8.06 (s, 1H);

[0682] MS m / z (ESI): 754.2 [M+H] + .

[0683] Example 57

[0684] Preparation of (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)- tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)piperidin-l-yl)phenyl)amino)pyrimidin-4- yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide

[0685]

[0686] First Step: Preparation of (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)- tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)piperidin-l-yl)phenyl)amino)pyrimidin-4- yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethylphosphine oxide

[0687]

[0688] (0.25 g, 0.41 mmol), (3aR,6aS)-hexahydro-lH-furo[3,4-c]pyrrole (0.07 g, 0.61 mmol) and acetic acid (3 drops) were dissolved in dichloroethane (10 mL) at room temperature, stirred for 30 minutes, sodium triacetoxyborohydride (0.17 g, 0.81 mmol) was added, stirred at room temperature overnight, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with dichloromethane, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure, and column chromatography was performed to isolate the title compound (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)piperidin-l-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethyl phosphine oxide (0.17 g, yield: 58%).

[0689] 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.49-1.62 (m, 2H), 1.78 (s, 3H), 1.81 (s, 3H), 1.89-1.95 (m, 2H), 2.04-2.15 (m, 4H), 2.38-2.43 (m, 2H), 2.58-2.72 (m, 6H), 3.02-3.07 (m, 2H), 3.35-3.43 (m, 2H), 3.72-3.80 (m, 5H), 4.24 (s, 2H), 4.32 (s, 2H), 6.70 (s, 1H), 6.80 (d, J=8.8 Hz, 1H), 7.43 (s, 1H), 7.91-7.97 (m, 2H), 8.10 (s, 1H), 11.62 (s, 1H);

[0690] MS m / z (ESI): 713.2 [M+H] + .

[0691] Example 58

[0692] Preparation of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-((3aR,6aS)-tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)piperidin-l-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)dimethyl phosphine oxide

[0693]

[0694] The preparation method of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrolo-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation is described in Example 2.

[0695] 1 H NMR (400MHz, CD3OD) δ1.03(t,J=7.6Hz,3H),1.87-1.91(m,8H),2.17-2.19(m,2H),2.56-2.58(m,2H),2.77-2.79(m,2H),2.90(s,3H),3. 08-3.11(m4H),3.65-3.68(m,4H),3.83-3.86(m,5H),4.32-4.35(m,4H),6.76(s,1H),6.91-6.93(m,1H),7.80-7.83(m,2H),8.07(s,1H);

[0696] MS m / z (ESI): 727.2 [M+H] + .

[0697] Example 59

[0698] Preparation of (6-((5-bromo-2-((5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation

[0699]

[0700] Step 1: Preparation of 5-methyl-2,3-dihydrobenzofuran

[0701]

[0702] Pd / C (300 mg, 10 wt%) was added to a methanol solution (3.0 g, 22.7 mmol) of 5-methylbenzofuran (3.0 g, 22.7 mmol) and stirred overnight under a hydrogen atmosphere at room temperature and pressure. Insoluble matter was removed by filtration with diatomaceous earth, and the organic solvent was concentrated under reduced pressure. The solution was then separated by column chromatography to obtain the title compound 5-methyl-2,3-dihydrobenzofuran (2.70 g, yield: 89%).

[0703] Step 2: Preparation of 5-methyl-7-nitro-2,3-dihydrobenzofuran

[0704]

[0705] To a solution of 5-methyl-2,3-dihydrobenzofuran (2.70 g, 20.1 mmol) in TFA (40 mL) was added NaNO2(1.36 g, 19.7 mmol) portion wise under ice water bath and the reaction was stirred for another 2 h under ice water bath. To the reaction was added ice water and the reaction was extracted with DCM several times. The organic layers were combined and washed with saturated aqueous NaHC03solution and saturated brine solution successively. The organic layer was dried over anhydrous Na2S04, filtered and the organic solvent was concentrated under reduced pressure. The title compound, 5-methyl-7-nitro-2,3-dihydrobenzofuran (900 mg, yield: 25%) was isolated by column chromatography.

[0706] Step 3: Preparation of 5-methyl-2,3-dihydrobenzofuran-7-amine

[0707]

[0708] To a solution of 5-methyl-7-nitro-2,3-dihydrobenzofuran (900 mg, 5.03 mmol) in MeOH (30 mL) was added Pd / C (100 mg, 10 wt%) and the reaction was stirred under hydrogen atmosphere at room temperature and pressure overnight. The insoluble materials were filtered off using celite and the filtrate was concentrated. The title compound, 5-methyl-2,3-dihydrobenzofuran-7-amine (670 mg, yield: 89%) was isolated by column chromatography.

[0709] MS m / z (ESI): 150.1 [M+H] + .

[0710] Step 4: Preparation of 4-bromo-5-methyl-2,3-dihydrobenzofuran-7-amine

[0711]

[0712] To a solution of 5-methyl-2,3-dihydrobenzofuran-7-amine (650 mg, 4.36 mmol) in DMF (20 mL) was added NBS (466 mg, 2.62 mmol) portion wise at -30 °C and the reaction was allowed to warm to room temperature and stirred at room temperature for another 2 h. The reaction was diluted with EtOAc and washed with saturated brine solution several times. The filtrate was dried over anhydrous Na2S04, concentrated under reduced pressure and the title compound, 4-bromo-5-methyl-2,3-dihydrobenzofuran-7-amine (600 mg, yield: 60%) was isolated by column chromatography.

[0713] MS m / z (ESI): 228.0 [M+H]+ .

[0714] Step 5: Preparation of N-(4-bromo-5-methyl-2,3-dihydrobenzofuran-7- yl)acetamide

[0715]

[0716] To a solution of 4-bromo-5-methyl-2,3-dihydrobenzofuran-7-amine (400 mg, 1.75 mmol) in dichloromethane (10 mL) was added acetic anhydride (0.233 mL, 2.46 mmol) and DIPEA (0.864 mL, 5.25 mmol) dropwise under ice water bath. The reaction was then slowly warmed to room temperature and stirred at room temperature for another 2 hours. The reaction was concentrated under reduced pressure and purified by column chromatography to give the title compound N-(4-bromo-5-methyl-2,3-dihydrobenzofuran-7-yl)acetamide (385 mg, yield: 81%).

[0717] MS m / z (ESI): 270.0 [M+H] + .

[0718] Step 6: Preparation of N-(5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)- 2,3-dihydrobenzofuran-7-yl)acetamide

[0719]

[0720] To a solution of N-(4-bromo-5-methyl-2,3-dihydrobenzofuran-7-yl)acetamide (385 mg, 1.43 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (783 mg, 4.28 mmol) in THF (10 mL) was added palladium acetate (48 mg, 0.215 mmol), Johnphos (128 mg, 0.430 mmol) and LiHMDS (1 M in THF, 4.3 mL) successively. The reaction was stirred at 115 °C for 2 hours under microwave. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound N-(5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7- yl)acetamide (225 mg, yield: 42%).

[0721] MS m / z (ESI): 373.3 [M+H] + .

[0722] Step 7: Preparation of 5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3- dihydrobenzofuran-7-amine

[0723]

[0724] To a solution of N-(5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3- dihydrobenzofuran-7-yl)acetamide (125 mg, 0.336 mmol) in ethanol (10 mL) was added carefully concentrated sulfuric acid (1 mL) and stirred at reflux for one hour, cooled, concentrated, dissolved in DCM, washed with saturated aqueous sodium bicarbonate, saturated brine, dried, and column chromatographed to give the title compound 5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3- dihydrobenzofuran-7-amine (80 mg, yield: 72%).

[0725] MS m / z (ESI): 331.2 [M+H] + .

[0726]

[0727] The preparation method of (6-((5-bromo-2-((5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl phosphine oxide was referred to Example 1.

[0728] 1 H NMR (400 MHz, CD3OD) δ 1.70 (d, J = 12.0 Hz, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 2.00 (d, J = 13.2 Hz, 3H), 2.16 (s, 3H), 2.53 (s, 3H), 2.60 - 2.65 (m, 1H), 2.73 - 3.17 (m, 13H), 4.27 (s, 2H), 4.34 (d, J = 4.3 Hz, 2H), 4.48 (t, J = 8.6 Hz, 2H), 6.84 (d, J = 9.3 Hz, 1H), 7.30 (s, 1H), 7.97 (d, J = 9.3 Hz, 1H), 8.03 (s, 1H);

[0729] MS m / z (ESI): 712.2 [M+H] + .

[0730] two, Biological test evaluation

[0731] The application is further described and explained with reference to the following test examples, which are not meant to limit the scope of the application.

[0732] Test Example 1, determination of the inhibitory activity of the compounds of the present application on EGFR wild type, EGFR del746-750 / T790M / C797S and EGFR L858R / T790M / C797S mutant kinases

[0733] Purpose of the experiment: the purpose of this test example is to test the inhibitory activity of the compounds on EGFR wild type, EGFR del746-750 / T790M / C797S and EGFR L858R / T790M / C797S mutant kinases.

[0734] Experimental instruments: centrifuge (5810R) purchased from Eppendorf company, pipette purchased from Eppendorf or Rainin company, microplate reader purchased from BioTek company in the United States, model SynergyH1 full-featured microplate reader.

[0735] Experimental method: this experiment adopts the HTRF kinase determination method of Cisbio company (Cisbio #62TK0PEB), the substrate polypeptide TK and ATP catalyze the reaction in the presence of tyrosine kinase EGFR wild type, EGFR del746-750 / T790M / C797S or EGFR L858R / T790M / C797S mutant, the substrate is phosphorylated, the content of the phosphorylated substrate generated in the reaction is determined to characterize the activity of the kinase, and the half inhibitory concentration IC50 of the compound on the EGFR wild type, EGFR del746-750 / T790M / C797S or EGFR L858R / T790M / C797S mutant kinase activity inhibition is obtained. 50 .

[0736] The specific experimental operation is as follows:

[0737] Kinase reaction was performed in white 384-well plates (Perkin Elmer #6008280) by adding 1-5 μL of different concentrations of compounds diluted with ddH2O containing 1% DMSO to each well, 1-5 μL of ddH2O containing 1% DMSO to positive control wells, then 1-5 μL of 0.5-5 nM 4x EGFR wild type, EGFR del746-750 / T790M / C797S or EGFR L858R / T790M / C797S mutant kinase solution diluted with Dilution buffer (5x kinase buffer, MgCl2 6.65 mM, MnCl2 1.33 mM, DTT 1.33 mM) to each well, 1-5 μL of Dilution buffer to negative control wells, 1-5 μL of 4 μM 4x substrate TK solution prepared with 10x Dilution buffer to all wells, and finally 1-5 μL of 24 μM 4x ATP solution diluted with Dilution buffer to start the reaction. After reaction at room temperature for 120 minutes, 10 μL of detection solution (TK antibody 16 nM, XL665 0.5 μM) was added to each well, and the chemiluminescence value was detected by BioTek Synergy H1 microplate reader after reaction at room temperature for 20 minutes in the dark.

[0738] Experimental data processing method:

[0739] The percentage inhibition data of the wells treated with compounds was calculated by the positive control wells (DMSO control wells) and the negative control wells (without adding kinase) on the plate {% inhibition = 100-[(test compound value-negative control value)] / (positive control value-negative control value) x 100}. The IC 50 values were calculated by fitting different concentrations and corresponding percentage inhibition data to the 4-parameter nonlinear logistic formula using GraphPad prism, and the specific data are shown in the following table:

[0740]

[0741]

[0742] Experimental conclusion:

[0743] It is concluded from the above scheme that the compounds of the embodiments of the present application have strong inhibitory effect on the kinase activity of EGFR mutants, and have small inhibitory effect on the kinase activity of EGFR wild type. It can be known from the comparison data that the compounds of the series of embodiments of the present application have high selectivity in inhibiting the kinase activity of EGFR mutants / wild type.

[0744] Test Example 2, Determination of the kinase inhibitory activity of the compounds of the present application against EGFR del746-750 / C797S and EGFR L858R / C797S mutations

[0745] Purpose of the experiment: The purpose of this test example is to test the inhibitory activity of the compounds against the EGFR del746-750 / C797S and EGFR L858R / C797S mutant kinases.

[0746] Experimental instruments: centrifuge (5810R) purchased from Eppendorf, pipettor purchased from Eppendorf or Rainin, microplate reader purchased from BioTek, Synergy H1 full-featured microplate reader, USA.

[0747] Experimental method: In this experiment, the HTRF kinase assay method of Cisbio (Cisbio #62TK0PEB) was used. The substrate polypeptide TK and ATP catalyze the reaction in the presence of the tyrosine kinase EGFR del746-750 / C797S or EGFR L858R / C797S mutant, and the substrate is phosphorylated. The activity of the kinase is characterized by determining the content of the phosphorylated substrate generated in the reaction, and the half inhibitory concentration IC50 of the compound against the EGFR del746-750 / C797S or EGFR L858R / C797S mutant kinase activity is obtained. 50 .

[0748] The specific experimental operation is as follows:

[0749] Kinase reaction was performed in white 384-well plates (Perkin Elmer #6008280) by adding 1-5 μL of different concentrations of compounds diluted with ddH2O containing 1% DMSO to each well, 1-5 μL of ddH2O containing 1% DMSO to positive control wells, then 1-5 μL of 0.5-5 nM 4x EGFR del746-750 / C797S or EGFR L858R / C797S mutant kinase solution diluted with Dilution buffer (5x kinase buffer, MgCl26.65 mM, MnCl21.33 mM, DTT 1.33 mM) to each well, 1-5 μL of Dilution buffer to negative control wells, 1-5 μL of 4 μM 4x substrate TK solution prepared with 10x Dilution buffer to all wells, and finally 1-5 μL of 24 μM 4x ATP solution diluted with Dilution buffer to start the reaction. After reaction at room temperature for 120 min, 10 μL of detection solution (TK antibody 16 nM, XL665 0.5 μM) was added to each well, and the chemiluminescence value was detected by BioTek Synergy H1 microplate reader after reaction at room temperature for 20 min in the dark.

[0750] Experimental data processing method:

[0751] The percentage inhibition data of the wells treated with compounds was calculated by the positive control wells (DMSO control wells) and the negative control wells (without adding kinase) on the plate {the inhibition rate = 100-[(test compound value-negative control value)] / (positive control value-negative control value) x 100}. The IC values were calculated by fitting the different concentrations and the corresponding percentage inhibition data to the 4-parameter nonlinear logistic formula using GraphPad prism, and the specific data are shown in the following table: 50

[0752]

[0753]

[0754] Experimental conclusion:

[0755] It is concluded from the above scheme that the compounds of the embodiments shown in the present application have strong inhibitory effect on the kinase activity of EGFR del746-750 / C797S or EGFR L858R / C797S mutant

[0756] Test Example 3: Cell proliferation inhibition experiment

[0757] Purpose of the experiment: The purpose of this test example is to test the cell proliferation inhibition activity of the compounds.

[0758] ​Experimental instruments: pipette was purchased from Eppendorf company, CO2 incubator was purchased from Thermo company in the United States, and enzyme marker was purchased from BioTek company in the United States, model was SynergyH1 full function enzyme marker.

[0759] Experimental method: CTG (CELL TITER-GLO) luminescence method was used to detect the proliferation inhibition activity of the compound on A431 cells and Ba / F3 (EGFR del746-750 / T790M / C797S) cells, and the half inhibitory concentration IC 50 .

[0760] Specific experimental operation is as follows:

[0761] For A431 cells: on the first day, 90 μL of A431 cell suspension was plated in a 96-well detection plate, and the number of cells in each well was 3000, and the negative control was not added with cells. The plate was placed in a 37℃ incubator containing 5% CO2 and cultured overnight. On the second day, 10 μL of gradient diluted compound solution was added to each well, and only 10 μL of culture medium containing DMSO was added to the positive and negative control wells. The plate was placed in a carbon dioxide incubator for incubation for 72 hours. After 72 hours of culture, 50 μL of CellTiter Glo was added to each well of the cell plate, and the light was shaken for 2 min and then placed for 10 min. Then the luminescence value was detected by BioTek Synergy H1 enzyme marker. The inhibition rate was calculated by the chemiluminescence signal value, and the IC 50 .

[0762] For Ba / F3 (EGFR del746-750 / T790M / C797S) suspension cells:

[0763] In a 96-well detection plate, 90 μL of Ba / F3 cell suspension was plated, and the number of cells in each well was 3000, and the negative control was not added with cells. After standing for 2 h, 10 μL of gradient diluted compound solution was added to each well, and only 10 μL of culture medium containing DMSO was added to the positive and negative control wells. After 72 hours of culture in a carbon dioxide incubator, the CTG detection was carried out in the same way as the A431 cells described above.

[0764] Experimental data processing method:

[0765] The percent inhibition data for the wells treated with compounds was calculated by the on-plate positive control well (DMSO control well) and negative control well (no cells added) { % inhibition = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) x 100}. The IC 50 values were calculated using GraphPad Prism to fit the different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic equation, with the specific data shown in the table below:

[0766]

[0767]

[0768] Experimental conclusion:

[0769] It is concluded from the above scheme that the example compounds of the present application have good inhibitory effect on the proliferation activity of Ba / F3 (EGFR del746-750 / T790M / C797S) mutant cells, and have weak inhibitory effect on A431 cells. It can be known from the comparison data that the example compounds of the present application have high selectivity for inhibiting the proliferation activity of Ba / F3 (EGFR del746-750 / T790M / C797S) mutant cells.

[0770] Test Example 4, determination of the inhibitory effect of the compounds of the present application on cell EGFR phosphorylation

[0771] Experimental purpose: the purpose of this test example is to test the inhibitory activity of the compounds on cell EGFR phosphorylation.

[0772] Experimental instruments: microplate shaker (88880024) is purchased from Thermo Scientific company, centrifuge (5702R) is purchased from Eppendorf company, pipette is purchased from Eppendorf company, microplate reader is purchased from Biotech company in the United States, and the model is SynergyH1 full-function microplate reader. TM

[0773] ​Experimental reagents: Phospho-EGFR (Tyr1068) LANCE Ultra TR-FRET Cellular Detection Kit (Perkin Elmer TRF4016C) contains (5X) LANCE Ultra Lysis Buffer 1, LANCE Ultra Eu-labeled Anti-EGFR (Y1068) Antibody, LANCE Ultra ULight-labeled Anti-EGFR Antibody, EGF (Thermo fisher PHG0311);

[0774] Experimental method: In this experiment, Ba / F3 (EGFR del746-750 / T790M / C797S) cell line was used to activate the EGFR signaling pathway by EGF stimulation, and the inhibitory activity of the compound on the downstream EGFR (Y1068) phosphorylation was detected, and the half inhibitory concentration IC50 of the compound on the EGFR signaling pathway activity was obtained. 50 .

[0775] Specific experimental operation is as follows:

[0776] Ba / F3 (EGFR del746-750 / T790M / C797S) cells were plated in 384-well test plates at 3-12 μL per well, and the number of cells per well was 100-300K. 2 μL of gradient diluted compound solution was added, and incubated at room temperature, 350 rpm, for 2 hours. 2 hours later, 2 μL of EGF was added, and the final concentration of EGF was 50 nM. Shake at room temperature for 15 min. Add 2-5 μL (5X) LANCE Ultra Lysis Buffer 1 solution, shake at room temperature for 2 h. 2 h later, add 5 μL of LANCE Ultra Eu-labeled Anti-EGFR (Y1068) Antibody (Perkin Elmer) solution with a final concentration of 0.5 nM and 5 μL of LANCE Ultra ULight-labeled Anti-EGFR Antibody (Perkin Elmer) solution with a final concentration of 5 nM, and incubate at room temperature overnight. The fluorescence signal value of each well of the plate was measured by the enzyme label instrument, and the inhibition rate was calculated by the fluorescence signal value. According to the inhibition rate of different concentrations, the IC50 of the compound was obtained by curve fitting. 50 .

[0777] Experimental data processing method:

[0778] The percent inhibition data for the wells treated with compounds was calculated by subtracting the values for the positive control wells (DMSO control wells) and the negative control wells (no cells added) from the values for the wells treated with compounds {Percent Inhibition = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) x 100}. The data for the different concentrations and the corresponding percent inhibition were fitted to a 4-parameter nonlinear logistic equation using GraphPad Prism to calculate IC 50 values.

[0779]

[0780]

[0781] Experimental Conclusion:

[0782] According to the above scheme, it is shown that the compound of the embodiment of the present application has a good inhibitory effect on the EGFR phosphorylation of Ba / F3 (EGFR del746-750 / T790M / C797S) cells.

[0783] Test Example 5: Pharmacokinetic determination in Balb / C mice

[0784] 5.1 Purpose of the study:

[0785] The pharmacokinetic behavior of the compound of the embodiment in the plasma of mice was studied by orally administering the compound of the embodiment to Balb / C mice at a dose of 5 mg / kg.

[0786] 5.2 Test protocol

[0787] 5.2.1 Test drug:

[0788] The compound of the embodiment of the present application was self-prepared.

[0789] 5.2.2 Test animals:

[0790] Balb / C Mouse (6 per example), male, Shanghai Jiesijie Experimental Animal Co., Ltd., Animal Production License No. (SCXK (Shanghai) 2013-0006N0.311620400001794).

[0791] 5.2.3 Formulation prescription:

[0792] 0.5% CMC-Na (1% Tween 80), ultrasonic dissolution, prepared into a clear solution or a uniform suspension.

[0793] 5.2.4 Administration:

[0794] Balb / C Mouse (6 per example), male; after fasting overnight, p.o. at a dose of 5 mg / kg, and the administration volume was 10 mL / kg.

[0795] 5.2.5 Sample collection:

[0796] Before and after administration of the drug, 0.1 mL of blood was collected from the eye socket of the mice at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours, and placed in an EDTA-K2 test tube. The plasma was separated by centrifugation at 6000 rpm for 6 min at 4°C and stored at -80°C.

[0797] 5.2.6 Sample processing:

[0798] 1) 40 μL of plasma sample was added to 160 μL of acetonitrile for precipitation, and then centrifuged at 3500 x g for 5-20 min.

[0799] 2) 100 μL of the supernatant after treatment was taken for LC / MS / MS analysis of the concentration of the test compound.

[0800] 5.2.7 Liquid analysis

[0801] • Liquid phase conditions: Shimadzu LC-20AD pump

[0802] • Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0803] • Chromatographic column: phenomenex Gemiu 5um C18 50x4.6mm

[0804] • Mobile phase: A liquid is 0.1% formic acid aqueous solution, B liquid is acetonitrile

[0805] • Flow rate: 0.8 mL / min

[0806] • Elution time: 0-4.0 min, eluent as follows:

[0807]

[0808] 5.3 Test results and analysis

[0809] The main pharmacokinetic parameters were calculated using WinNonlin 6.1, and the results of the mouse pharmacokinetic experiment are shown in the table below:

[0810]

[0811]

[0812] Note: FA is the formate salt of the corresponding compound.

[0813] Experimental conclusion:

[0814] From the mouse pharmacokinetic experiment results in the table, it can be seen that the compound of the embodiment of the application shows good metabolic properties, and the exposure AUC and the maximum blood drug concentration C max All show good.

[0815] Test Example 6: In-vivo pharmacodynamic test of the compound of the embodiment of the application

[0816] 6.1 Purpose of the experiment

[0817] Through the in-vivo pharmacodynamic test, the compound with more obvious pharmacodynamic effect and less toxic side effect is screened out.

[0818] 6.2 Main instruments and materials of the experiment

[0819] 6.2.1 Instruments:

[0820] Instrument Supplier Model Analytical balance Mettler XS 105 Analytical balance Mettler AL204 Digital caliper Sylvac 0-150mm Electronic balance OHAUS Scout pro Pipette RANIN 100ul-1ml Pipette RANIN 20ul-200ul Electric suction device Pipet-Lite M20 Biological safety cabinet Sujing Antai BSC-1604IIA2 CO2 incubator SANYO MCO-18AIC Table centrifuge Thermo Fisher ST16R Biological safety cabinet Sujing Antai BHC-1300IIA2

[0821] 6.2.2 Reagents:

[0822] Reagent Supplier Part No. Matrigel Corning 354234 FBS Gibco 10099-141C Trypsin Gibco 25200-072 RPMI1640 Hyclone SH30809.01 Puromycin Gibco A11138-03 HPMC Sigma H3785

[0823] 6.2.3 Animals:

[0824] NOD / SCID mice, 6-8 weeks, ♀, purchased from Jiangsu Jizhuangkang Biotechnology Co., Ltd.

[0825] 6.3 Experimental steps

[0826] 6.3.1 Cell culture

[0827] PC9 (EGFR Del19 / T790M / C797S) cells were cultured in RPMI1640 culture solution containing 10% fetal bovine serum. Exponentially growing PC9 (EGFR Del19 / T790M / C797S) cells were collected.

[0828] 6.3.2 Cell inoculation

[0829] The experimental mice were inoculated with 1×10 7 PC9 (EGFR Del19 / T790M / C797S) cells were resuspended in 1:1 PBS and Matrigel (0.1 ml per mouse), and the tumor growth was observed regularly. The day of tumor cell inoculation was defined as day 0.

[0830] 6.3.3 Tumor-bearing mice, grouping, and drug administration

[0831] a, day 7 tumor volume data were measured, and mice with tumor volume in the range of 100-200 mm 3 a, day 7 tumor volume data were measured, and mice with tumor volume in the range of 100-200 mm 3, according to tumor size and mouse weight randomly grouped administration.

[0832] c, according to the grouping results, start to give the test drug (administration method: oral administration; administration volume: 10 mL / kg; administration frequency: 1 / time / day; administration period: 21 days; solvent: 0.5% HPMC).

[0833] d, start to give the test drug every week twice tumor, weighing.

[0834] e, after the end of the experiment, euthanize the animals.

[0835] f, use Excel and other software to process data. Compound tumor inhibition rate TGI (%) calculation: TGI% = [1-(T i -T0) / (C i -C0)]x100%; wherein, T i is the tumor volume of the administration group on the i day, T0 is the tumor volume of the administration group on the grouping day, C i is the tumor volume of the solvent control group on the i day, C0 is the tumor volume of the solvent control group on the grouping day.

[0836] 6.4 Test data as follows:

[0837]

[0838] 6.5 Experimental results

[0839] From the above results, it can be seen that the above-mentioned compounds of the present patent have good tumor inhibition rate and good safety.

[0840] III. Crystal form research

[0841] 1. Experimental instruments

[0842] 1.1 Some parameters of physical and chemical detection instruments

[0843]

[0844]

[0845] 1.2 Instruments and liquid phase analysis conditions

[0846] 1.2.1 Instruments and equipment

[0847] Instrument name Model Analytical balance Sartorius BSA224S-CW Water purifier Milli-Q Plus, Millipore High performance liquid chromatograph Agilent 1260 Pump Agilent G1311B Sampler G1329B Column oven G1316A Detector G1315D

[0848] 1.2.2 Chromatographic conditions

[0849] Chromatographic column: ZORBAX (SB-C8, 3.5 μm, 4.6*75 mm)

[0850] Flow rate: 1 mL / min

[0851] Column temperature: 40 °C

[0852] Detection wavelength: 235 nm

[0853] Injection volume: 5.0 μL

[0854] Run time: 15 min

[0855] Diluent: ACN-water (v / v, 1 : 1)

[0856] Mobile phase: A: water (0.05% trifluoroacetic acid); B: acetonitrile (0.05% trifluoroacetic acid)

[0857] T(min) A(％) B(％) 0.00 90 10 3.00 70 30 10.00 50 50 12.00 30 70 12.01 90 10 15.00 90 10

[0858] 2. Preparation of the crystal form

[0859] 1. Preparation of the crystal form H

[0860] About 20 mg of the crude amorphous free base was weighed into a 2 mL glass bottle, 100 μL of organic solvent (the organic solvent can be selected from Acetone, ACN and EA) was added, and the slurry was prepared at room temperature for 12 h. Finally, the solid was rapidly centrifuged, the supernatant was removed, and vacuum drying was performed at 40 °C to obtain the crystal form H. The crystal form H was detected and analyzed to have an XRPD pattern as shown in FIG. 1, a DSC pattern as shown in FIG. 2, and a TGA pattern as shown in FIG. 3. Figure 1 Figure 2 Figure 3

[0861] 2. Preparation of the crystal form N

[0862] About 250.0 g of the free base was weighed into 2.0 L (8.0 V) of n-octanol, and the temperature was increased to 90 °C while stirring. While controlling the temperature at 80-90 °C, 16.0 L (64.0 V) of n-heptane was added dropwise. After the addition, the temperature was naturally cooled to 20-30 °C in an oil bath, and stirring was performed for 16 h. Filtration was performed, and vacuum drying was performed at 60 °C to obtain the crystal form N.

[0863] Alternatively, about 1.0 g of the free base was weighed into 8.0 mL (8.0 V) of n-hexanol, and the temperature was increased to 90 °C while stirring. While controlling the temperature at 80-90 °C, 60.0 mL (64.0 V) of n-heptane was added dropwise. After the addition, the temperature was naturally cooled to 20-30 °C in an oil bath, and stirring was performed for 16 h. Filtration was performed, and vacuum drying was performed at 60 °C to obtain the crystal form N. The crystal form N was detected and analyzed to have an XRPD pattern as shown in FIG. 4, a DSC pattern as shown in FIG. 5, and a TGA pattern as shown in FIG. 6. Figure 4 Figure 5 Figure 6

[0864] 3. Preparation of the crystal form O

[0865] ​​​​​​about 1.0 g of the free base was added to 14.0 mL (14.0 V) of sec-amyl alcohol, and the mixture was stirred to dissolve at 90°C. While maintaining the temperature at 80-90°C, 84.0 mL (84.0 V) of n-heptane was added dropwise. After the addition was completed, the mixture was naturally cooled to 20-30°C in an oil bath, stirred for 16 h, filtered, and dried at 60°C under vacuum to obtain Form O. The Form O was analyzed by XRPD, and the results are shown in FIG. 1, and by DSC, and the results are shown in FIG. 2. Figure 7 Figure 8

[0866] about 1.0 g of the free base was added to 14.0 mL (14.0 V) of sec-amyl alcohol, and the mixture was stirred to dissolve at 90°C. While maintaining the temperature at 80-90°C, 84.0 mL (84.0 V) of n-heptane was added dropwise. After the addition was completed, the mixture was naturally cooled to 20-30°C in an oil bath, stirred for 16 h, filtered, and dried at 60°C under vacuum to obtain Form O. The Form O was analyzed by XRPD, and the results are shown in FIG. 1, and by DSC, and the results are shown in FIG. 2. Figure 7 Figure 8

[0867] about 1.0 g of the free base was added to 14.0 mL (14.0 V) of sec-amyl alcohol, and the mixture was stirred to dissolve at 90°C. While maintaining the temperature at 80-90°C, 84.0 mL (84.0 V) of n-heptane was added dropwise. After the addition was completed, the mixture was naturally cooled to 20-30°C in an oil bath, stirred for 16 h, filtered, and dried at 60°C under vacuum to obtain Form O. The Form O was analyzed by XRPD, and the results are shown in FIG. 1, and by DSC, and the results are shown in FIG. 2. Figure 7 Figure 8

[0868] 4. Preparation of Form I

[0869] about 20 mg of the free base Form H was added to 200 μL of THF, and the mixture was stirred to dissolve at 50°C. The mixture was cooled to room temperature, and 600 μL of water was added. The mixture was stirred for a certain period of time, and a large amount of white solid was precipitated. The solid was centrifuged, and the supernatant was removed. The solid was dried at 40°C under vacuum to obtain Form I. The Form I was analyzed by XRPD, and the results are shown in FIG. 3, and by DSC, and the results are shown in FIG. 4. Figure 9 Figure 10

[0870] 3. Competition experiment of crystal forms

[0871] a. Competition experiment of Form H and Form O

[0872] about 0.2 g of Form H and about 0.2 g of Form O were added to 3.0 mL of methyl tert-butyl ether, and the mixture was slurried at 20-30°C for 16 h. The mixture was filtered, and the solid was dried at 60°C under vacuum to obtain 0.35 g of a solid. The solid was analyzed by XRD, and the results showed that Form H was converted to Form O.

[0873] b. Competition experiment of Form H and Form N ​​​​​​​​

[0874] Take 0.2 g of sample of Form H and 0.2 g of sample of Form N, add 3.0 mL of methyl tert-butyl ether, beat at 20-30 °C for 16 h, filter, and dry at 60 °C under vacuum to obtain 0.30 g of solid. XRD detection shows that Form H is converted to Form N.

[0875] The above experiments show that Form N and Form O are more stable and are easier to prepare after scale-up.

[0876] 4. Solid stability experiment

[0877] 4.1 Purpose of the experiment:

[0878] The physical and chemical stability of the free base Form H at high temperature 60 °C was investigated to provide a basis for crystal form screening and storage of the compound.

[0879] 4.2 Experimental procedure:

[0880] Take about 2 mg of free base Form H and place it in an oven at 60 °C. Investigate for 5 days and 10 days, and determine the content by HPLC using the external standard method. Calculate the change in related substances by the chromatographic peak area normalization method.

[0881] 4.3 Experimental results:

[0882] Results of the physical and chemical stability of the free base Form H:

[0883]

[0884] The above experimental results show that the physical and chemical properties of Form H are relatively stable

[0885] 5. Dynamic hygroscopicity experiment

[0886] 5.1 Purpose of the experiment

[0887] The hygroscopicity of the free base Form H of the compound under different relative humidity conditions was investigated to provide a basis for crystal form screening and storage of the compound.

[0888] 5.2 Experimental procedure:

[0889] Place the free base Form H of the compound in saturated water vapor of different relative humidity, allow the compound and water vapor to reach dynamic equilibrium, and calculate the percentage weight gain of the compound after equilibrium.

[0890] 5.3 Experimental results:

[0891] After one cycle of hygroscopicity and desorption under 0-95% relative humidity, the XRPD spectrum of the free base Form H did not change, i.e., the crystal form did not change.

[0892] 6. Solubility experiment in different media

[0893] 6.1 Purpose of the experiment

[0894] To compare the solubility of free base Form H in water, simulated gastric fluid (SGF), fasted simulated intestinal fluid (FaSSIF) and non-fasted simulated intestinal fluid (FeSSIF), and to provide a basis for the evaluation of the drugability.

[0895] 6.2 Experimental protocol:

[0896] About 2 mg of free base Form H was suspended in different media for 2 hours, and the thermodynamic solubility of the compound at 37°C was determined by HPLC using an external standard method.

[0897] 6.3 Experimental results:

[0898]

[0899] The above experimental results show that Form H has good solubility at different pH values, making it suitable for drug development.

[0900] 7. Animal PK study

[0901] 7.1 Purpose of the experiment:

[0902] SD rats were used as test animals to study the pharmacokinetic behavior of free base Form H after single oral administration in rats (plasma), to compare the changes in exposure, and to calculate the bioavailability of free base Form H after oral administration.

[0903] 7.2 Experimental protocol:

[0904] Free base Form H was suspended in water containing 0.5% HPMC K4M and then administered orally to rats, with three rats in parallel. The dose was free base Form H (30 mg / kg, 100 mg / kg as a suspension).

[0905]

[0906] 8. Confirmation of stable crystal form experiment

[0907] 8.1 Purpose of the experiment:

[0908] A more stable crystal form of the compound was found through the crystal slurry experiment and the stability investigation experiment.

[0909] 8.2 Experimental protocol:

[0910] An organic solvent with certain solubility and water were selected, and Form H was suspended in the solvent system and stirred at a certain temperature. Form H was investigated under different conditions for crystal form changes. Finally, the solid was treated, and the XRPD of the solid was determined and compared.

[0911] 8.3 Experimental results:

[0912] Crystal form H in different solvents beating crystal form transition:

[0913] Solvent Crystal form H beating situation MeOH Still crystal form H at 50℃ for 1 day EtOH Still crystal form H at 50℃ for 1 day Acetone Still crystal form H at 50℃ for 1 day ACN Still crystal form H at 50℃ for 1 day THF Dissolved EA Still crystal form H at 50℃ for 1 day H2O Still crystal form H at 50℃ for 1 day

[0914] 8.4 Different crystal forms under different influence factors transition relationship:

[0915] Crystal form H and N were placed in different conditions to investigate the crystal transition:

[0916] Crystal form H stability test:

[0917] High temperature 60℃ Room temperature high humidity RH=92.5% High temperature 50℃ high humidity RH=75% Crystal form H No crystal transformation for 30 days No crystal transformation for 30 days No crystal transformation for 30 days

[0918] Crystal form N stability test:

[0919] (1) Influence factor test

[0920]

[0921] (2) Humidity, compression, and crystal form N stability after crushing

[0922] I. Humidity treatment: 0.992 g of raw material was granulated with 0.515 g of purified water, and then dried at 60°C for 60 min.

[0923] II. Pressure treatment: tablet weight / g: 0.150, hardness / kgf: 3.10, 1.48, 3.41.

[0924] III. Crushing: when the raw material was crushed, 50 g of raw material crystal form N was weighed, the screw speed was 5, and three speeds / rpm were investigated: 3000, 7500, and 12000.

[0925] The results are as follows:

[0926] Condition Crystal form Untreated Crystal form N Wet heat Crystal form N Pressure Crystal form N Crushing Crystal form N

[0927] (3) Crystal form comparison of raw materials and preparations

[0928] Raw material crystal form N was weighed and tablets were prepared according to the preparation process, and the stability of the raw material and the preparation sample was compared.

[0929] I. Crushing: the raw material crystal form N was crushed using a hammer crusher at 3000-5000 rpm.

[0930] II. Mixing: Set the mixing blade speed to 100 rpm and the granulating blade speed to 600 rpm according to the process requirements. Add the prescribed amount of microcrystalline cellulose, crystalline Form N raw material into the wet granulation kettle, and perform premix I for 5 min. Then add the prescribed amount of lactose, sodium carboxymethyl starch (internal), and pregelatinized starch in sequence, and perform premix II for 10 min.

[0931] III. Granulation: Set the relevant parameters according to the process requirements, start the equipment, and perform I-speed granulation (mixing blade speed 100 rpm, granulating blade speed 1000 rpm). Pump the wetting agent water into the wet mixing granulator at a constant speed through a peristaltic pump. After I-speed granulation, perform II-speed granulation (mixing blade speed 150 rpm, granulating blade speed 1500 rpm).

[0932] IV. Wet massing: Set the relevant parameters according to the process requirements, and perform wet massing treatment on the wet material through a 4750 μm square screen (massing blade speed 995.7 rpm).

[0933] V. Drying: Start the fan to begin drying. After the material temperature reaches 40°C, take a sample to measure the moisture content. If it is qualified, discharge the material. If it is not qualified, continue drying, take a sample every 5 min to detect and record the parameters, and control the granule moisture content to be below 3.0%.

[0934] VI. Dry massing: Perform massing treatment on the dried material through a 991 μm flat screen.

[0935] VII. Total mixing: Add the dry-massed material, sodium carboxymethyl starch (external), and magnesium stearate into the hopper mixer. Set the mixer speed to 10 rpm and the mixing time to 10 min according to the process requirements.

[0936] VIII. Tabletting:

[0937] 30 mg specification: Control the hardness to be 9.00 kgf.

[0938] IX. Coating

[0939] Use the prescribed amount of film coating premix (gastroresistant type) to perform the coating operation. The target weight gain is 3.0%

[0940] The results are as follows:

[0941] API Formulation sample (30mg tablet) Crystal form N Crystal form N

[0942] The above results show that crystalline Form H and crystalline Form N do not undergo crystalline transformation under the conditions of light, high temperature, high humidity, damp heat, sieving, tabletting, and preparation into a preparation product. Crystalline Form H and Form N are relatively stable.

Claims

1. A crystal form of the compound represented by formula (I), wherein the crystal form is crystal form H, crystal form N, crystal form O and crystal form I, wherein: The X-ray powder diffraction pattern of crystal form H shows diffraction peaks at any 7 or 8 locations within the range of 2θ values ​​of 21.7±0.2°, 24.2±0.2°, 11.4±0.2°, 22.9±0.2°, 23.8±0.2°, 14.7±0.2°, 12.9±0.2°, 26.4±0.2°, 8.0±0.2°, 10.8±0.2°, 24.9±0.2°, and 12.0±0.2°. The X-ray powder diffraction pattern of crystalline N shows diffraction peaks at any 7 or 8 locations within the range of 2θ: 6.7±0.2°, 8.5±0.2°, 9.0±0.2°, 18.7±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°, 15.0±0.2°, 22.3±0.2°, 18.5±0.2°, and 24.6±0.2°. The X-ray powder diffraction pattern of crystal form O shows diffraction peaks at any 7 or 8 locations within the range of 2θ values ​​of 5.0±0.2°, 6.2±0.2°, 7.2±0.2°, 8.7±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, 14.4±0.2°, 12.4±0.2°, 19.7±0.2°, and 18.7±0.2°. The X-ray powder diffraction pattern of crystal form I shows diffraction peaks at any 7 or 8 locations within the range of 2θ: 20.8±0.2°, 13.7±0.2°, 12.7±0.2°, 14.4±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, 22.5±0.2°, 14.6±0.2°, 22.2±0.2°, and 26.0±0.2°.

2. The crystal form of the compound according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form H contains at least one diffraction peak at 2θ of 21.7±0.2°, 24.2±0.2°, and 11.4±0.2°, and also contains four or five diffraction peaks at 2θ of 22.9±0.2°, 23.8±0.2°, 14.7±0.2°, 12.9±0.2°, and 26.4±0.2°. The X-ray powder diffraction pattern of crystalline N contains at least the diffraction peaks located at 2θ of 6.7±0.2°, 8.5±0.2°, and 9.0±0.2°, and also contains 4 or 5 of the diffraction peaks located at 2θ of 18.7±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, and 14.5±0.2°. The X-ray powder diffraction pattern of crystal form O contains at least one diffraction peak at 2θ of 5.0±0.2°, 6.2±0.2°, and 7.2±0.2°, and also contains four or five diffraction peaks at 2θ of 8.7±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, and 20.4±0.2°. The X-ray powder diffraction pattern of crystal form I contains at least the diffraction peaks located at 2θ of 20.8±0.2°, 13.7±0.2°, and 12.7±0.2°, and also contains 4 or 5 diffraction peaks located at 2θ of 14.4±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, and 25.1±0.2°.

3. The crystal form of the compound according to claim 1, characterized in that: The X-ray powder diffraction pattern of crystal form H includes diffraction peaks at 2θ of 21.7±0.2°, 24.2±0.2°, 11.4±0.2°, 22.9±0.2°, 23.8±0.2°, 14.7±0.2°, 12.9±0.2°, 26.4±0.2°, 8.0±0.2°, and 10.8±0.2°. The X-ray powder diffraction pattern of crystalline N contains diffraction peaks at 2θ of 6.7±0.2°, 8.5±0.2°, 9.0±0.2°, 18.7±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°, 15.0±0.2°, and 22.3±0.2°. The X-ray powder diffraction pattern of crystal form O includes diffraction peaks located at 2θ of 5.0±0.2°, 6.1±0.2°, 7.2±0.2°, 8.7±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, 14.4±0.2°, and 12.4±0.2°. The X-ray powder diffraction pattern of crystal form I contains diffraction peaks at 2θ of 20.8±0.2°, 13.7±0.2°, 12.7±0.2°, 14.4±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, and 22.5±0.2°.

4. The crystal form of the compound according to claim 1, characterized in that: The X-ray powder diffraction pattern of crystal form H contains 8 or 10 diffraction peaks located at 2θ values ​​of 21.7±0.2°, 24.2±0.2°, 11.4±0.2°, 22.9±0.2°, 23.8±0.2°, 14.7±0.2°, 12.9±0.2°, 26.4±0.2°, 8.0±0.2°, 10.8±0.2°, 24.9±0.2°, 12.0±0.2°, 32.5±0.2°, 31.3±0.2°, and 17.0±0.2°. The X-ray powder diffraction pattern of crystalline N contains 8 or 10 diffraction peaks located at 2θ of 6.7±0.2°, 8.5±0.2°, 9.0±0.2°, 18.7±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°, 15.0±0.2°, 22.3±0.2°, 18.5±0.2°, 24.6±0.2°, 18.0±0.2°, 23.7±0.2°, and 17.8±0.2°. The X-ray powder diffraction pattern of crystal form O contains 8 or 10 diffraction peaks located at 2θ of 5.0±0.2°, 6.1±0.2°, 7.2±0.2°, 8.7±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, 14.4±0.2°, 12.4±0.2°, 19.7±0.2°, 18.7±0.2°, 24.9±0.2°, 20.1±0.2°, and 24.9±0.2°. The X-ray powder diffraction pattern of crystal form I contains 8 or 10 diffraction peaks located at 2θ values ​​of 20.8±0.2°, 13.7±0.2°, 12.7±0.2°, 14.4±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, 22.5±0.2°, 14.6±0.2°, 22.2±0.2°, 26.0±0.2°, 23.4±0.2°, 17.6±0.2°, and 8.5±0.2°.

5. The crystal form of the compound according to claim 1, characterized in that: The X-ray powder diffraction pattern of crystal form H includes diffraction peaks located at 2θ of 24.2±0.2°, 11.4±0.2°, 22.9±0.2°, 23.8±0.2°, 14.7±0.2°, 12.9±0.2°, and 26.4±0.2°. Alternatively, it includes diffraction peaks located at 2θ of 11.4±0.2°, 22.9±0.2°, 23.8±0.2°, 14.7±0.2°, 12.9±0.2°, 26.4±0.2°, and 8.0±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 21.7±0.2°, 24.2±0.2°, 11.4±0.2°, 22.9±0.2°, 23.8±0.2°, 14.7±0.2°, 12.9±0.2°, and 26.4±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 24.2±0.2°, 11.4±0.2°, 22.9±0.2°, 23.8±0.2°, 14.7±0.2°, 12.9±0.2°, 26.4±0.2°, and 8.0±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 21.7±0.2°, 22.9±0.2°, 23.8±0.2°, 14.7±0.2°, 12.9±0.2°, 26.4±0.2°, 8.0±0.2°, and 10.8±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 24.2±0.2°, 23.8±0.2°, 14.7±0.2°, 12.9±0.2°, 26.4±0.2°, 8.0±0.2°, 10.8±0.2°, and 24.9±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 11.4±0.2°, 22.9±0.2°, 23.8±0.2°, 14.7±0.2°, 12.9±0.2°, 26.4±0.2°, 8.0±0.2°, 10.8±0.2°, 24.9±0.2°, and 12.0±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 21.7±0.2°, 23.8±0.2°, 14.7±0.2°, 12.9±0.2°, 26.4±0.2°, 8.0±0.2°, 10.8±0.2°, 24.9±0.2°, 12.0±0.2°, and 32.5±0.2°; The X-ray powder diffraction pattern of crystalline N contains diffraction peaks at 2θ of 9.0±0.2°, 18.7±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°, and 15.0±0.2°. Alternatively, it includes diffraction peaks located at 2θ of 18.7±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°, 15.0±0.2°, and 22.3±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 6.7±0.2°, 8.5±0.2°, 9.0±0.2°, 18.7±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, and 14.5±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 9.0±0.2°, 18.7±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°, 15.0±0.2°, and 22.3±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 6.7±0.2°, 18.7±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°, 15.0±0.2°, and 22.3±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 8.5±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°, 15.0±0.2°, 22.3±0.2°, and 18.5±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 6.7±0.2°, 18.7±0.2°, 21.8±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°, 15.0±0.2°, 22.3±0.2°, 18.5±0.2°, and 24.6±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 8.5±0.2°, 21.9±0.2°, 12.3±0.2°, 12.7±0.2°, 14.5±0.2°, 15.0±0.2°, 22.3±0.2°, 18.5±0.2°, 24.6±0.2°, and 18.0±0.2°; The X-ray powder diffraction pattern of crystal form O includes diffraction peaks located at 2θ of 7.2±0.2°, 8.7±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, and 14.4±0.2°. Alternatively, it includes diffraction peaks located at 2θ of 8.7±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, 14.4±0.2°, and 12.4±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 5.0±0.2°, 6.2±0.2°, 7.2±0.2°, 8.7±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, and 20.4±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 6.2±0.2°, 7.2±0.2°, 8.7±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, and 14.4±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 5.0±0.2°, 8.7±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, 14.4±0.2°, and 12.4±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 6.1±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, 14.4±0.2°, 12.4±0.2°, and 19.7±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 5.0±0.2°, 8.7±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, 14.4±0.2°, 12.4±0.2°, 19.7±0.2°, and 18.7±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 6.1±0.2°, 12.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.4±0.2°, 14.4±0.2°, 12.4±0.2°, 19.7±0.2°, 18.7±0.2°, and 24.9±0.2°; The X-ray powder diffraction pattern of crystal form I includes diffraction peaks located at 2θ of 13.7±0.2°, 12.7±0.2°, 14.4±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, and 25.1±0.2°. Alternatively, it includes diffraction peaks located at 2θ of 12.7±0.2°, 14.4±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, and 22.5±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 20.8±0.2°, 13.7±0.2°, 12.7±0.2°, 14.4±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, and 25.1±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 13.7±0.2°, 12.7±0.2°, 14.4±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, and 22.5±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 13.7±0.2°, 14.4±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, 22.5±0.2°, and 14.6±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 12.7±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, 22.5±0.2°, 14.6±0.2°, and 22.2±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 14.4±0.2°, 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, 22.5±0.2°, 14.6±0.2°, 22.2±0.2°, 26.0±0.2°, and 8.5±0.2°; Alternatively, it includes diffraction peaks located at 2θ of 17.2±0.2°, 11.3±0.2°, 20.2±0.2°, 25.1±0.2°, 22.5±0.2°, 14.6±0.2°, 22.2±0.2°, 26.0±0.2°, 23.4±0.2°, and 17.6±0.2°.

6. The crystal form of the compound according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form H is shown in Figure 1; the X-ray powder diffraction pattern of crystal form N is shown in Figure 4; the X-ray powder diffraction pattern of crystal form O is shown in Figure 7; and the X-ray powder diffraction pattern of crystal form I is shown in Figure 9.

7. The crystal form of the compound according to claim 1, characterized in that, The 2θ errors of the positions of the top ten diffraction peaks with the highest relative peak intensities in the X-ray powder diffraction patterns of crystal forms H, N, O, and I, respectively, compared with the corresponding diffraction peaks in Figures 1, 4, 7, and 9 are ±0.2° to ±0.5°.

8. The crystal form of the compound according to claim 1, characterized in that, The 2θ errors of the positions of the top ten diffraction peaks with the highest relative peak intensities in the X-ray powder diffraction patterns of crystal forms H, N, O, and I, respectively, compared with the corresponding diffraction peaks in Figures 1, 4, 7, and 9 are ±0.2° to ±0.3°.

9. The crystal form of the compound according to claim 1, characterized in that, Crystal form H has the DSC spectrum shown in Figure 2; or the TGA spectrum shown in Figure 3. Crystal form N has a DSC pattern as shown in Figure 5, or a TGA pattern as shown in Figure 6; Crystal form O has the DSC spectrum shown in Figure 8; Crystal form I has the DSC pattern shown in Figure 10.

10. The crystal form of the compound according to any one of claims 1-9, characterized in that, The crystal form is either anhydrous or hydrated.

11. The crystal form of the compound according to claim 10, characterized in that, When the crystal form is hydrate, the number of water molecules is 0.2-3.

12. The crystal form of the compound according to claim 10, characterized in that, When the crystal form is hydrate, the number of water molecules is 0.2, 0.5, 1, 1.5, 2, 2.5, or 3.

13. The crystal form of the compound according to any one of claims 1-9, characterized in that, The crystal form is anhydrous.

14. A method for preparing the crystal form of the compound according to any one of claims 1-13, specifically comprising the following steps: 1) Weigh an appropriate amount of free base and dissolve it by heating with a good solvent; 2) Add a poor solvent to the solution obtained above; 3) Cool the above suspension, remove the supernatant, and dry the remaining solid to obtain the target product; in: The good solvent is selected from methanol, ethanol, acetone, sec-pentanol, n-butanol, n-octanol, n-hexanol, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, or 3-pentanone; The unsuitable solvent is selected from heptane, water, methyl tert-butyl ether, toluene, or isopropyl ether.

15. A method for preparing the crystal form of the compound according to any one of claims 1-13, specifically comprising the following steps: 1) Weigh an appropriate amount of free base and suspend it in a poor solvent; 2) Shake the suspension; 3) The suspension was rapidly centrifuged to remove the supernatant, and the remaining solid was dried to obtain the target product; in: The unsuitable solvents are selected from acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone or 3-pentanone, methyl tert-butyl ether, and water.

16. A pharmaceutical composition comprising a therapeutically effective amount of the crystal form of any one of claims 1-13 and one or more pharmaceutically acceptable carriers or excipients.

17. Use of the crystal form of the compound according to any one of claims 1-13 in the preparation of a medicament for treating cancer; wherein the cancer is selected from non-small cell lung cancer.

18. Use of the pharmaceutical composition according to claim 16 in the preparation of a medicament for treating cancer; wherein the cancer is selected from non-small cell lung cancer.

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