A crystal form of a free base of an indole derivative and a preparation method and application thereof

Abstract

The present application relates to a kind of indole derivative free base crystal form and its preparation method and application.It is specifically related to a kind of compound shown in general formula (I), its crystal form, preparation method and the pharmaceutical composition containing therapeutically effective amount of the compound or its crystal form and its use as kinase inhibitor, especially as receptor tyrosine kinase inhibitor (TKI), more specifically, as EGFR or HER2 inhibitor in the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS and other related diseases, the compound of the present application shows good inhibitory activity in EGFR and HER2 20 exon mutation.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a crystal form of a free base containing an indole derivative, a preparation method and application thereof. BACKGROUND

[0002] There are multiple signal pathways in cells that interact with each other to control cell proliferation, growth, migration and apoptosis. Abnormal activation of signal pathways can lead to the occurrence of tumors. Receptor tyrosine kinases play an important role in cell regulation. Epidermal growth factor receptor (EGFR) is a member of the transmembrane protein tyrosine kinase ErbB receptor family (including ErbB1, ErbB2, ErbB3, and ErbB4). Through binding with its ligand epidermal growth factor (EGF), EGFR can form a homodimer on the membrane or form a heterodimer with other receptors (such as ErbB2, ErbB3, and ErbB4) in the ErbB family, leading to activation of EGFR tyrosine kinase activity. Activated EGFR can phosphorylate different substrates, thereby activating downstream PI3K-AKT and RAS-MAPK pathways, and playing a role in cell survival, proliferation and apoptosis.

[0003] Disorders of the EGFR signaling pathway, including increased expression of ligands and receptors, EGFR gene amplification and mutations, etc., can promote malignant transformation of cells, thereby leading to the occurrence of various tumors. About 35% of non-small cell lung cancer (NSCLC) patients in China have EGFR mutations, among which the most common mutation types are exon 19 deletion mutation (Del19) and exon 21 L858R activating mutation, which account for about 80% of EGFR mutations. EGFR exon 20 insertion mutation is another major mutation of EGFR, accounting for 4% to 10% of EGFR mutations in NSCLC, and there are dozens of mutation types, with common mutation types being Ex20Ins D770_N771InsSVD, Ex20Ins V769_D770InsASV, etc.

[0004] Over the years, a large number of targeted drugs have been developed for EGFR mutations in NSCLC, such as the first-generation reversible tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib for classic Del19 mutations and L858R mutations, the second-generation irreversible covalent binding inhibitor afatinib, and the third-generation inhibitor osimertinib for drug-resistant mutation EGFR T790M, all of which have very good clinical effects. However, the EGFR inhibitors currently on the market have very poor effects on EGFR exon 20 insertion mutations, and the survival period of patients is very short. There is a great clinical need for more specific inhibitors for this target.

[0005] HER2 as another member of the ErbB family, its amplification and mutation occur in a variety of cancers. Among them, the mutation of HER2 in NSCLC accounts for about 4%, and about 90% of HER2 mutations are 20 exon insertion mutations, of which the most common mutation type is p.A775_G776insYVMA, and the currently marketed EGFR inhibitors have general effects.

[0006] Currently, many domestic and foreign pharmaceutical companies have carried out active research on EGFR & HER2 20 exon insertion mutations, among which Spectrum's Poziotinib, Takeda's TAK-788 and Rain Therapeutics' Tarloxotinib have entered clinical research, and in addition, Cullinan & Taiho's compound TAS-6417 also showed good activity in preclinical experiments. Because many EGFR inhibitors have strong inhibitory effect on wild-type EGFR, leading to skin rash and other side effects in clinical practice, and the inhibitory activity of EGFR 20 exon insertion mutation and HER2 20 exon insertion mutation target needs to be improved, therefore, there is still a great demand for compounds with obvious effect on EGFR and HER2 20 exon mutation and high selectivity for wild-type EGFR, which has a good market prospect.

[0007] Patent PCT / CN2020 / 091558 discloses a series of structures of indole-containing derivative inhibitors, and in subsequent research and development, in order to facilitate the handling, filtration and drying of products, suitable crystals that are easy to store, long-term stable and have high bioavailability are sought, and the free base crystal form of the above-mentioned compounds is comprehensively studied. SUMMARY

[0008] All the contents involved in patent PCT / CN2020 / 091558 are added to the present application by reference.

[0009] The purpose of the present application is to provide a crystal form of a compound represented by general formula (I),

[0010]

[0011] Among them:

[0012] R1 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)NR aa (CH2) n R bb or -(CH2) n N=S(O)R aa Rbb ; and each R is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; said amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally, further substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0013] R2is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0014] R3is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0015] R aa and R bb are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; said amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally, further substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0016] x is an integer from 0 to 4; and

[0017] n is an integer from 0 to 4.

[0018] In preferred embodiments of the present application, the crystalline form of 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 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C(O)NR aa (CH2) n R bb or -(CH2) n N=S(O)R aa R bb ; and each R is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; said amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally, further substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; 1-6 alkyl, C 1-6deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally, further substituted by one or more substituents selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;

[0019] Preferably, R1is selected from hydrogen, deuterium, halogen, cyano, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, 5-6 membered heteroaryl, -C(O)NR aa (CH2) n R bb or -(CH2) n N=S(O)R aa R bb , said C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and 5-6 membered heteroaryl, optionally, further substituted by one or more substituents selected from deuterium, halogen, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy and C 1-6 haloalkoxy;

[0020] More preferably, R1is selected from hydrogen, deuterium, cyano, 5-6 membered heteroaryl, -C(O)NR aa (CH2) n R bb or -(CH2) n N=S(O)R aa R bb , said 5-6 membered heteroaryl, optionally, further substituted by one or more substituents selected from deuterium, halogen, C 1-3 alkyl and C1-3 one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C

[0021] Most preferably, R1is selected from hydrogen, cyano, oxazolyl, pyrazolyl,

[0022] R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, optionally, further substituted with one or more substituents selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;

[0023] x is an integer from 0 to 2; and

[0024] n is an integer from 0 to 2.

[0025] In a preferred aspect of the present application, the crystal form of general formula (I) wherein R2is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, or 3-8 membered heterocyclyl;

[0026] preferably hydrogen, deuterium, halogen, cyano, C 1-3 alkyl, C 1-3 deuteroalkyl, C1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups;

[0027] More preferably, hydrogen, deuterium, methyl, ethyl, propyl, cyclopropyl, or oxetyl;

[0028] The preferred compounds are hydrogen, methyl, cyclopropyl, or oxetine.

[0029] In a preferred embodiment of the present invention, the crystal form represented by general formula (I), R3 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 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0030] Preferred elements include hydrogen, deuterium, halogen, cyano, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0031] More preferably hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, or ethoxy;

[0032] The preferred materials are hydrogen, fluorine, or methoxy.

[0033] In a more preferred embodiment of the present invention, the compound is N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or N-(5-((5-cyano-4-(6-methoxy-1-(oxetanebut-3-yl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) Acrylamide, N-(5-((5-cyano-4-(1-cyclopropyl-5-fluoro-6-methoxy-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-5-(oxazol-2-yl)pyrimidin-2-yl)amino)phenyl)acrylamide.

[0034] In a more preferred aspect of the present application, there is provided a crystalline form of the compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.

[0035] In a further preferred embodiment of the present application, there is provided a crystalline form A of the compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Example 1).

[0036] The X-ray powder diffraction pattern of the crystalline form A comprises at least one of the diffraction peaks at 2-theta of 7.1±0.2°, 14.1±0.2°, 18.9±0.2°, preferably comprises two of them, more preferably comprises three of them; optionally, further comprising at least one of the diffraction peaks at 2-theta of 22.7±0.2°, 20.4±0.2°, 22.3±0.2°, 13.4±0.2°, 12.9±0.2°, preferably comprises two, three, four or five of them;

[0037] The X-ray powder diffraction pattern of the crystalline form A optionally further comprises one or more of the diffraction peaks at 2-theta of 17.5±0.2°, 20.8±0.2°, 9.6±0.2°, 22.0±0.2°, 25.6±0.2°, 14.9±0.2°, 15.6±0.2°; preferably at least two, three, four, five or six of them; more preferably, two, three, four, five or six of them;

[0038] The X-ray powder diffraction pattern of the crystalline form A comprises one or more of the diffraction peaks at 2-theta of 7.1±0.2°, 14.1±0.2°, 18.9±0.2°, 22.7±0.2°, 20.4±0.2°, 22.3±0.2°, 13.4±0.2°, 12.9±0.2, 17.5±0.2°, 20.8±0.2°, 9.6±0.2°, 22.0±0.2°, 25.6±0.2°, 14.9±0.2°, 15.6±0.2°, 28.1±0.2°, 9.4±0.2°, 24.1±0.2°, 16.2±0.2°, 19.3±0.2°; preferably, four, five, six, eight or ten of them;

[0039] Most preferably, the X-ray characteristic diffraction peaks, expressed in terms of 2-theta angle and interplanar spacing d value, are as shown in Table 1, using Cu-Ka radiation.

[0040] Table 1

[0041]

[0042] Further preferably, there is provided a crystalline form A of the compound N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide as shown in Figure 1, having an X-ray powder diffraction pattern substantially as shown in Figure 1; a DSC pattern substantially as shown in Figure 2; and a TGA pattern substantially as shown in Figure 3. Figure 1 Figure 2 Figure 3

[0043] In a further preferred embodiment of the application, there is provided a crystalline form B of the compound N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Example 1).

[0044] The X-ray powder diffraction pattern of crystalline form B has a diffraction peak at 6.5±0.2°; or at 20.7±0.2°; or at 20.9±0.2°; or at 21.0±0.2°; or at 21.4±0.2°; or at 15.6±0.2°; or at 23.8±0.2°; or at 21.6±0.2°; or at 9.2±0.2°; or at 25.1±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 thereof;

[0045] The X-ray powder diffraction pattern of crystalline form B comprises at least one or more of the diffraction peaks at 6.5±0.2°, 20.7±0.2°, 20.9±0.2°, preferably two, more preferably three thereof; optionally, further comprising at least one of 21.0±0.2°, 21.4±0.2°, 15.6±0.2°, 23.8±0.2°, 21.6±0.2°, preferably 2, 3, 4 or 5 thereof;

[0046] ​​​The X-ray powder diffraction pattern of crystalline Form B optionally further comprises one or more of the diffraction peaks at 2Θ of 9.2 ± 0.2°, 25.1 ± 0.2°, 10.7 ± 0.2°, 12.4 ± 0.2°, 17.4 ± 0.2°, 17.6 ± 0.2°, 14.5 ± 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;

[0047] The X-ray powder diffraction pattern of crystalline Form B comprises one or more of the diffraction peaks at 2Θ of 6.5 ± 0.2°, 20.7 ± 0.2°, 20.9 ± 0.2°, 21.0 ± 0.2°, 21.4 ± 0.2°, 15.6 ± 0.2°, 23.8 ± 0.2°, 21.6 ± 0.2°, 9.2 ± 0.2°, 25.1 ± 0.2°, 10.7 ± 0.2°, 12.4 ± 0.2°, 17.4 ± 0.2°, 17.6 ± 0.2°, 14.5 ± 0.2°, 23.4 ± 0.2°, 20.5 ± 0.2°, 13.5 ± 0.2°, 16.9 ± 0.2°, 24.7 ± 0.2°; preferably, any 4, 5, 6, 8, 10 thereof;

[0048] Most preferably, the X-ray characteristic diffraction peaks, expressed in terms of 2Θ angle and interplanar spacing d-value, are as shown in Table 2, using Cu-Kα radiation.

[0049] Table 2

[0050]

[0051]

[0052] Further preferably, crystalline Form B of the compound N-(5-((5-cyano-4-(l- cyclopropyl-lH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl)acrylamide, as shown in Example 1, has an X-ray powder diffraction pattern substantially as shown in Figure 4 Further preferably, crystalline Form B of the compound N-(5-((5-cyano-4-(l- cyclopropyl-lH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl)acrylamide, as shown in Example 1, has an X-ray powder diffraction pattern substantially as shown in Figure 5 Further preferably, crystalline Form B of the compound N-(5-((5-cyano-4-(l- cyclopropyl-lH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl)acrylamide, as shown in Example 1, has an X-ray powder diffraction pattern substantially as shown in Figure 6 Further preferably, crystalline Form B of the compound N-(5-((5-cyano-4-(l- cyclopropyl-lH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl)acrylamide, as shown in Example 1, has an X-ray powder diffraction pattern substantially as shown in

[0053] In a further preferred embodiment of the application, there is provided crystalline Form C of the compound N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Example 1).

[0054] The X-ray powder diffraction pattern of Form C has a diffraction peak at 7.1±0.2°; or at 18.1±0.2°; or at 9.0±0.2°; or at 22.7±0.2°; or at 14.1±0.2°; or at 18.9±0.2°; or at 22.5±0.2°; or at 20.3±0.2°; or at 22.2±0.2°; or at 23.2±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 them;

[0055] The X-ray powder diffraction pattern of Form C comprises at least one or more of the diffraction peaks at 7.1±0.2°, 18.1±0.2°, 9.0±0.2°, preferably two of them, more preferably three; optionally, further comprising at least one of 22.7±0.2°, 14.1±0.2°, 18.9±0.2°, 22.5±0.2°, 20.3±0.2°, preferably 2, 3, 4 or 5 of them;

[0056] The X-ray powder diffraction pattern of Form C optionally further comprises one or more of the diffraction peaks at 22.2±0.2°, 23.2±0.2°, 23.1±0.2°, 20.7±0.2°, 22.0±0.2°, 17.5±0.2°, 12.9±0.2°; preferably at least 2-3, or 4-5, or 6-7 of them; more preferably, any 2, 3, 4, 5, 6, 7 of them;

[0057] The X-ray powder diffraction pattern of Form C comprises one or more of the diffraction peaks at 7.1±0.2°, 18.1±0.2°, 9.0±0.2°, 22.7±0.2°, 14.1±0.2°, 18.9±0.2°, 22.5±0.2°, 20.3±0.2°, 22.2±0.2°, 23.2±0.2°, 23.1±0.2°, 20.7±0.2°, 22.0±0.2°, 17.5±0.2°, 12.9±0.2°, 12.9±0.2°, 21.9±0.2°, 13.4±0.2°, 10.7±0.2°; preferably, 4, 5, 6, 8 or 10 of them;

[0058] Most preferably, the X-ray characteristic diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d value, are as shown in Table 3 using Cu-Kα radiation.

[0059] Table 3

[0060]

[0061] Further preferably, there is provided a crystalline form C of the compound N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide as shown in Figure 7 Further preferably, there is provided a crystalline form C of the compound N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide as shown in Figure 8 Further preferably, there is provided a crystalline form C of the compound N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide as shown in Figure 9 Further preferably, there is provided a crystalline form C of the compound N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide as shown in

[0062] In a further preferred embodiment of the present application, there is provided a crystalline form D of the compound N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Example 1).

[0063] The X-ray powder diffraction pattern of the crystalline form D has a diffraction peak at 2-theta of 26.2±0.2°; or at 22.2±0.2°; or at 10.6±0.2°; or at 14.5±0.2°; or at 21.3±0.2°; or at 15.9±0.2°; or at 7.0±0.2°; or at 9.0±0.2°; or at 19.0±0.2°; or at 8.3±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;

[0064] The X-ray powder diffraction pattern of the crystalline form D comprises at least one or more of the diffraction peaks at 2-theta of 26.2±0.2°, 22.2±0.2°, 10.6±0.2°, preferably two, more preferably three thereof; optionally, further comprising at least one of 14.5±0.2°, 21.3±0.2°, 15.9±0.2°, 7.0±0.2°, 9.0±0.2°, preferably 2, 3, 4 or 5 thereof;

[0065] The X-ray powder diffractogram of crystalline Form D optionally further comprises one or more of the following peaks: at 19.0 ± 0.2°, 8.3 ± 0.2°, 26.9 ± 0.2°, 18.1 ± 0.2°, 20.1 ± 0.2°, 21.8 ± 0.2°, 19.8 ± 0.2° in terms of angles 2 theta and interplanar spacing d; preferably, at least any 2 to 3, or 4 to 5, or 6 to 7 thereof; further preferably, at least any 2, 3, 4, 5, 6, 7 thereof;

[0066] The X-ray powder diffractogram of crystalline Form D comprises one or more of the following peaks: at 26.2 ± 0.2°, 22.2 ± 0.2°, 10.6 ± 0.2°, 14.5 ± 0.2°, 21.3 ± 0.2°, 15.9 ± 0.2°, 7.0 ± 0.2°, 9.0 ± 0.2°, 19.0 ± 0.2°, 8.3 ± 0.2°, 26.9 ± 0.2°, 18.1 ± 0.2°, 20.1 ± 0.2°, 21.8 ± 0.2°, 19.8 ± 0.2°, 18.3 ± 0.2° in terms of angles 2 theta and interplanar spacing d; preferably, at least any 4, 5, 6, 8, or 10 thereof;

[0067] Most preferably, the X-ray characteristic diffraction peaks, expressed in terms of angles 2 theta and interplanar spacing d, are as shown in Table 4, using Cu-K alpha radiation.

[0068] Table 4

[0069]

[0070] Further preferably, crystalline Form D of the compound N-(5-((5-cyano-4-(1- cyclopropyl-1 H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl)acrylamide has an X-ray powder diffractogram substantially as shown in Figure 10 Further preferably, crystalline Form D of the compound N-(5-((5-cyano-4-(1- cyclopropyl-1 H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl)acrylamide has an X-ray powder diffractogram substantially as shown in Figure 11 Further preferably, crystalline Form D of the compound N-(5-((5-cyano-4-(1- cyclopropyl-1 H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl)acrylamide has an X-ray powder diffractogram substantially as shown in Figure 12 Further preferably, crystalline Form D of the compound N-(5-((5-cyano-4-(1- cyclopropyl-1 H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl)acrylamide has an X-ray powder diffractogram substantially as shown in

[0071] In a further preferred embodiment of the application, there is provided crystalline Form E of the compound N-(5-((5-cyano-4-(1-cyclopropyl-1 H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Example 1).

[0072] The X-ray powder diffraction pattern of Form E has a diffraction peak at 6.3 ± 0.2°; or at 12.6 ± 0.2°; or at 9.9 ± 0.2°; or at 21.1 ± 0.2°; or at 13.2 ± 0.2°; or at 26.2 ± 0.2°; or at 20.0 ± 0.2°; or at 16.9 ± 0.2°; or at 15.5 ± 0.2°; or at 25.3 ± 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 them;

[0073] The X-ray powder diffraction pattern of Form E has at least one diffraction peak at 6.3 ± 0.2°, 12.6 ± 0.2°, 9.9 ± 0.2°, preferably two, more preferably three; optionally, further comprising at least one of 21.1 ± 0.2°, 13.2 ± 0.2°, 26.2 ± 0.2°, 20.0 ± 0.2°, 16.9 ± 0.2°; preferably comprising 2, 3, 4 or 5 of them;

[0074] The X-ray powder diffraction pattern of Form E optionally further comprises one or more diffraction peaks at 15.5 ± 0.2°, 25.3 ± 0.2°, 27.4 ± 0.2°; preferably comprising at least 2-3 of them; more preferably, comprising any 2 or 3 of them;

[0075] The X-ray powder diffraction pattern of Form E comprises one or more diffraction peaks at 6.3 ± 0.2°, 12.6 ± 0.2°, 9.9 ± 0.2°, 21.1 ± 0.2°, 13.2 ± 0.2°, 26.2 ± 0.2°, 20.0 ± 0.2°, 16.9 ± 0.2°, 15.5 ± 0.2°, 25.3 ± 0.2°, 27.4 ± 0.2°; preferably, comprising optionally 4, 5, 6, 8 or 10 of them;

[0076] Most preferably, the X-ray characteristic diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d value, are as shown in Table 5, using Cu-Kα radiation.

[0077] Table 5

[0078]

[0079] Further preferably, the crystalline form E of the compound N-(5-((5-cyano-4-(1- cyclopropyl-1 H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl) amino)-4-methoxyphenyl)acrylamide has an X-ray powder diffraction pattern substantially as shown in Figure 13 ; a DSC pattern substantially as shown in Figure 14 ; and a TGA pattern substantially as shown in Figure 15 .

[0080] In further preferred embodiments of the present application, the relative peak intensity of the top ten peaks in the X-ray powder diffraction pattern of the crystalline form A, the crystalline form B, the crystalline form C, the crystalline form D, the crystalline form E of the compound N-(5-((5-cyano-4-(1-cyclopropyl-1 H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide are within ±0.2° to ±0.5°, preferably within ±0.2° to ±0.3°, most preferably within ±0.2° of the corresponding positions of the diffraction peaks of Figure 1 , Figure 4 , Figure 7 , Figure 10 and Figure 13 .

[0081] In preferred embodiments of the present application, the crystalline form of any of the compounds of general formula (I) is a crystalline form with or without solvent, wherein the solvent is one or more selected from the group consisting of water, methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, n-propanol, t-butyl alcohol, 2-butanone, 3-pentanone, n-heptane, heptane, ethyl formate, isopropyl acetate, cyclohexane, methyl t-butyl ether or isopropyl ether.

[0082] In preferred embodiments of the present application, the number of solvents in the crystalline form of any of the compounds of general formula (I) 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.

[0083] In preferred embodiments of the present application, the crystalline form of the compound of general formula (I) is a non-solvent crystalline form, preferably an anhydrous crystalline form.

[0084] In preferred embodiments of the present application, the crystalline form of the compound of general formula (I) is a hydrate crystalline form, and the number of water 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.

[0085] In a more preferred embodiment of the present application, the crystalline form of the compound N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide is a non-solvated compound, preferably an anhydrate or a hydrate.

[0086] In a more preferred embodiment of the present application, the number of water molecules in the hydrate crystalline form of the compound N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide 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.

[0087] It is well known to those of ordinary skill in the art that XRPD can have some shift and intensity deviation due to the detection method, condition and instrument. As a specific example of the crystalline form of the present application, its XRPD is shown in Figure X, but those of ordinary skill understand that when the key characteristic peak shifts 2Θ deviation is about ±0.5, especially ±0.2, it can be identified as the same crystalline form.

[0088] In another aspect, the present application also relates to a method for preparing the crystalline form of the compound of general formula (I), which specifically comprises the following steps:

[0089] 1) A certain amount of free base is weighed and suspended in a poor solvent, and the suspension density is preferably 50-200 mg / mL;

[0090] 2) The above obtained suspension is shaken at a certain temperature for a certain time, and the temperature is preferably 0-50°C and the time is preferably 1-15 days;

[0091] 3) The above suspension is quickly centrifuged, the supernatant is removed, and the remaining solid is dried to constant weight to obtain the target product, for example, placed in a vacuum drying oven at 45-55°C to dry to constant weight to obtain the target product;

[0092] Wherein:

[0093] The poor solvent is selected from one or more of methanol, acetone, ethyl acetate, tetrahydrofuran, acetonitrile, ethanol, 88% acetone, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, methyl tert-butyl ether, n-heptane, benzene, toluene, chlorobenzene, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-propyl alcohol, ethyl formate, isopropyl acetate, tert-butyl alcohol, 2-butanone and 3-pentanone; preferably one or more of toluene, 1,4-dioxane, 3-pentanone, ethyl acetate, methanol and ethyl formate.

[0094] The present application also relates to a method for preparing the crystal form of the compound of general formula (I), which specifically comprises the following steps:

[0095] 1) an appropriate amount of free base is weighed and dissolved in a good solvent;

[0096] 2) an anti-solvent is added to the above obtained solution, and stirred until the solid precipitates; preferably the anti-solvent is added to the above obtained solution at a temperature of 0-50°C;

[0097] 3) the above suspension is quickly centrifuged, the supernatant is removed, and the remaining solid is dried to constant weight to obtain the target product, for example, placed in a vacuum drying oven at 45-55°C to dry to constant weight;

[0098] wherein:

[0099] The good solvent is selected from one or more of methanol, acetone, ethyl acetate, tetrahydrofuran, acetonitrile, ethanol, 88% acetone, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, chlorobenzene, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-propyl alcohol, ethyl formate, isopropyl acetate, tert-butyl alcohol, 2-butanone and 3-pentanone; preferably one or more of dichloromethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, acetonitrile and 2-butanone.

[0100] The poor solvent is selected from one or more of methanol, ethanol, ethyl acetate, acetone, isopropyl alcohol, toluene, n-heptane, water, isopropyl acetate, cyclohexane, methyl tert-butyl ether and isopropyl ether; preferably one or more of water, n-heptane, cyclohexane and methyl tert-butyl ether.

[0101] The present application also provides a pharmaceutical composition containing a therapeutically effective amount of the crystal form of the compound of general formula (I) and one or more pharmaceutically acceptable carriers or excipients.

[0102] The present application also provides the use of the crystal form of the compound of general formula (I) and the pharmaceutical composition in the preparation of a kinase inhibitor drug.

[0103] The present application also provides a crystalline form of N-(5-((5-cyano-4-(1- cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl)acrylamide of the compound of general formula (I) and the use of the pharmaceutical composition in the preparation of a kinase inhibitor drug.

[0104] 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.

[0105] The present application provides a crystalline form of the compound of general formula (I) 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.

[0106] The present application also provides a crystalline form of N-(5-((5-cyano-4-(1- cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl)acrylamide of the compound of general formula (I) 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.

[0107] 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.

[0108] The third generation EGFR inhibitor mainly inhibits EGFR activating mutants and T790M drug resistance mutants, and the compound of the present application has the following significant advantages over the third generation EGFR inhibitor in terms of EGFR and / or HER2 20 exon insertion mutant target points:

[0109] 1. significantly higher inhibitory activity in Ba / F3 EGFR mutant cell lines, preferably the activity of the compound is more than 10-fold, even 20-fold higher;

[0110] 2. higher selectivity in the proliferation inhibitory activity in Ba / F3 EGFR mutant cell lines and A431 cell lines, preferably the compound is more than 3-fold, even 10-fold higher;

[0111] 3. also shows significant advantage in the in vivo efficacy tumor inhibition rate in the mouse pro-B cell Ba / F3 EGFR-D770-N771ins_SVD xenograft model.

[0112] Detailed description of the invention

[0113] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0114] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, which are straight-chain or branched groups, preferably alkyl groups containing 1 to 20 carbon atoms, more preferably 1 to 8 carbon atoms, most preferably 1 to 6 carbon atoms, and in particular 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 and various branched isomers thereof, and the like.

[0115] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl.

[0116] The term "heterocyclyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, which comprise 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein 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, 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; and most preferably 3 to 6 ring atoms. Non-limiting examples of heterocyclyl groups include oxetanyl, thietanyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl.

[0117] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings which share adjacent pairs of carbon atoms) ring systems having a conjugated pi-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably phenyl.

[0118] 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. Heteroaryl 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.

[0119] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy.

[0120] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halogens.

[0121] "Haloalkoxy" refers to an alkoxy group as defined above substituted with one or more halogens.

[0122] "Hydroxy" refers to an -OH group.

[0123] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0124] "Amino" refers to -NH2.

[0125] "Cyano" refers to -CN.

[0126] "Nitro" refers to -NO2.

[0127] "Carboxy" refers to -C(O)OH.

[0128] "THF" refers to tetrahydrofuran.

[0129] "MeOH" refers to methanol.

[0130] "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium.

[0131] The phrases "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 are used in the same sense and are intended to convey the same meaning, i.e., that X can be any one of A, B, or C, or any combination thereof.

[0132] Any hydrogen atom described herein can be replaced by its isotope deuterium, and any hydrogen atom in the compounds of the embodiments described herein can be replaced by deuterium.

[0133] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0134] "Substituted" refers to one or more hydrogen atoms in the group, preferably up to five, more preferably one to three hydrogen atoms, independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene). Optional substituents include one or more substituents from the following groups: deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl, preferably deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl compounds.

[0135] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0136] "Medicinal salts" refers to salts of the compounds of this invention that are safe and effective when used in mammals and have the appropriate biological activity. Attached Figure Description

[0137] Figure 1 XRPD diagram of N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide crystal form A.

[0138] Figure 2 A DSC pattern for N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form A.

[0139] Figure 3 A TGA pattern for N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form A.

[0140] Figure 4 An XRPD pattern for N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form B.

[0141] Figure 5 A DSC pattern for N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form B.

[0142] Figure 6 A TGA pattern for N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form B.

[0143] Figure 7 An XRPD pattern for N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form C.

[0144] Figure 8 A DSC pattern for N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form C.

[0145] Figure 9A TGA pattern of N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form C.

[0146] Figure 10 An XRPD pattern of N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form D.

[0147] Figure 11 A DSC pattern of N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form D.

[0148] Figure 12 A TGA pattern of N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form D.

[0149] Figure 13 An XRPD pattern of N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form E.

[0150] Figure 14 A DSC pattern of N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form E.

[0151] Figure 15 A TGA pattern of N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form E. DETAILED DESCRIPTION

[0152] The application is further described in connection with the following examples which are not intended to limit the scope of the application.

[0153] I. Preparation of Compounds

[0154] Examples

[0155] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shifts (δ) are given in parts per million (ppm). The NMR is determined by using a Bruker AVANCE-400 NMR spectrometer, and the solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

[0156] The LC-MS is determined by using an Agilent 1200 Infinity Series mass spectrometer. The HPLC is determined by using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150x4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150x4.6mm column).

[0157] The thin layer chromatography silica gel plate is Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specification of TLC is 0.15mm-0.20mm, and the specification of thin layer chromatography separation and purification product is 0.4mm-0.5mm. The column chromatography generally uses 200-300 mesh Yantai Huanghai silica gel as the carrier.

[0158] The starting materials in the embodiments of the present application are known and can be purchased on the market, or can be synthesized by using the methods known in the art.

[0159] Unless otherwise specified, all the reactions of the present application are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature unit is Celsius.

[0160] Example 1

[0161] N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0162]

[0163] First step: preparation of 2-chloro-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidine-5- carbonitrile

[0164]

[0165] Dissolve 2,4-dichloropyrimidine-5-carbonitrile (2 g, 12 mmol) in dichloroethane (30 mL), cool to 0°C, add iron trichloride (3.9 g, 24 mmol), stir the reaction at room temperature for half an hour, add 1-cyclopropyl-1H-indole (2.17 g, 14 mmol), stir the reaction at 60°C for 2 hours. Add water (30 mL), filter, extract the filtrate with dichloromethane (30 mL x 2), dry the combined organic phases with anhydrous sodium sulfate, filter, spin dry, purify the crude product by column chromatography (petroleum ether / ethyl acetate: 100 / 1 to 3 / 1) to obtain 2-chloro-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidine-5-carbonitrile (1.6 g, yield: 47%) as a brown solid.

[0166] Second step: Preparation of 4-(1-cyclopropyl-1H-indol-3-yl)-2-((4-fluoro-2-methoxy-5- nitrophenyl)amino)pyrimidine-5-carbonitrile

[0167]

[0168] Dissolve 2-chloro-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidine-5-carbonitrile (1 g, 3.4 mmol), 4-fluoro-2-methoxy-5-nitroaniline (0.7 g, 3.7 mmol) and p-toluenesulfonic acid (0.7 g, 3.7 mmol) in 2-pentanol (40 mL), stir the reaction at 100°C overnight. Cool to room temperature, add water (50 mL), extract with dichloromethane (50 mL x 2), dry the organic phase with anhydrous sodium sulfate, filter, spin dry, purify the crude product by column chromatography (petroleum ether / ethyl acetate: 100 / 1 to 1 / 1 to dichloromethane / ethyl acetate: 100 / 1 to 10 / 1) to obtain 4-(1-cyclopropyl-1H-indol-3-yl)-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carbonitrile (1 g, 67%) as a brown solid.

[0169] Third step: Preparation of 4-(1-cyclopropyl-1H-indol-3-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carbonitrile

[0170]

[0171] To a solution of 4-(1-cyclopropyl-1H-indol-3-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5- carbonitrile (0.48 g, 0.97 mmol) in ethanol (20 mL) was added saturated sodium bicarbonate solution (10 mL) and iron powder (0.54 g, 9.7 mmol) and the reaction stirred at 80 °C for 2 h. Cooled to room temperature, the reaction was filtered and the filtrate extracted with dichloromethane (20 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1- cyclopropyl-1H-indol-3-yl)pyrimidine-5-carbonitrile (0.4 g, 88% yield) as a yellow solid.

[0172] Fourth Step: Preparation of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidine-5-carbonitrile

[0173]

[0174] To a solution of 4-(1-cyclopropyl-1H-indol-3-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5- carbonitrile (0.48 g, 0.97 mmol) in ethanol (20 mL) was added saturated sodium bicarbonate solution (10 mL) and iron powder (0.54 g, 9.7 mmol) and the reaction stirred at 80 °C for 2 h. Cooled to room temperature, the reaction was filtered and the filtrate extracted with dichloromethane (20 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1- cyclopropyl-1H-indol-3-yl)pyrimidine-5-carbonitrile (0.4 g, 88% yield) as a yellow solid.

[0175] Fifth Step: Preparation of N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0176]

[0177] N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)-5-(oxazol-2-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0178] MS m / z (ESI): 551.4 [M+H] + .

[0179] 1 H NMR (400 MHz, CDC13) δ 10.08 (s, 1H), 9.42 (s, 1H), 8.68 (s, 1H), 8.49-8.47 (m, 2H), 7.76 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.30-7.26 (m, 2H), 6.81 (s, 1H), 6.39 (s, 2H), 5.69-5.67 (m, 1H), 3.89 (s, 3H), 3.48-3.44 (m, 1H), 2.93-2.91 (m, 2H), 2.73 (s, 3H), 2.35-2.30 (m, 8H), 1.17-1.11 (m, 4H).

[0180] Example 2

[0181] N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)-5-(oxazol-2-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0182]

[0183] Example 2 was prepared according to the procedure of Example 1 with the synthetic route as follows:

[0184]

[0185] MS m / z (ESI): 593.1 [M+H] + .

[0186] 1 H NMR (400 MHz, CDC13) δ 9.65 (s, 1H), 8.86 (s, 1H), 8.14 - 7.98 (m, 1H), 7.76 (s, 1H), 7.57 - 7.44 (m, 2H), 7.21 - 7.12 (m, 2H), 7.02 - 6.94 (m, 1H), 6.73 (s, 1H), 6.47 (d, J = 17.2 Hz, 1H), 5.73 (d, J = 11.7 Hz, 1H), 5.40 - 5.22 (m, 1H), 3.88 (s, 3H), 3.43 - 3.36 (m, 1H), 3.22 - 3.04 (m, 2H), 2.88 (s, 2H), 2.73 (s, 3H), 2.70 - 2.35 (m, 6H), 2.25 - 2.18 (m, 1H), 2.05 - 1.96 (m, 1H), 1.15 - 1.01 (m, 4H).

[0187] Example 6

[0188] N-(5-((5-cyano-4-(l-(oxetan-3-yl)-lH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0189]

[0190]

[0191] First Step: Preparation of 3-(5-bromo-2-chloropyrimidin-4-yl)-lH-indole

[0192]

[0193] Indole (5.0 g, 54.86 mmol) was dissolved in 2-methyltetrahydrofuran (50 mL) under ice bath, then methylmagnesium bromide (3.0 M in 2-methyltetrahydrofuran, 18.3 mL, 54.86 mmol) was added dropwise, maintaining the internal temperature below 30 °C. After the addition was completed, the reaction was stirred at room temperature for 30 minutes. Then 2,4-dichloro-5-bromopyrimidine in 2-methyltetrahydrofuran (5.0 g, 21.94 mmol, 10 mL solvent) was added dropwise, after the addition was completed, the reaction was stirred at room temperature for half an hour, then heated to 70 °C, and reacted for 14 hours. Cooled to room temperature, the reaction was poured into saturated aqueous ammonium chloride solution, a solid precipitated, filtered to obtain a solid. The obtained solid was re-suspended in water, ultrasonic, filtered to obtain a solid, dried to obtain the product 3-(5-bromo-2-chloropyrimidin-4-yl)-1H-indole (4.0 g, yield: 59%, yellow solid).

[0194] MS m / z (ESI): 308.0 [M+H] + .

[0195] 1 H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 8.86 (s, 1H), 8.80 (s, 1H), 8.46 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.30-7.23 (m, 2H).

[0196] Second Step: Preparation of 5-bromo-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H- indol-3-yl)pyrimidin-2-amine

[0197]

[0198] 3-(5-bromo-2-chloropyrimidin-4-yl)-1H-indole (0.50 g, 1.62 mmol), 4-fluoro-2-methoxy-5-nitroaniline (0.33 g, 1.78 mmol) and p-toluenesulfonic acid (0.34 g, 1.78 mmol) were dissolved in 2-pentanol (25 mL), and reacted at 100 °C for 14 hours. Cooled to room temperature, the reaction was neutralized with saturated sodium bicarbonate solution, stirred at room temperature for 20 minutes, filtered, the filter cake was washed with 2-pentanol, and finally washed with petroleum ether, and the filter cake was dried to obtain 5-bromo-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (0.40 g, 54%, tan solid).

[0199] MS m / z (ESI): 458.0, 460.0 [M+H] + .

[0200] Step 3: Preparation of N1-(5-bromo-4-(1H-indol-3-yl)pyrimidin-2-yl)-N4-(2- (dimethylamino)ethyl)-2-methoxy-N4-methyl-5-nitrobenzene-1,4-diamine

[0201]

[0202] N1-(5-bromo-4-(1H-indol-3-yl)pyrimidin-2-yl)-N4-(2-(dimethylamino)ethyl)-2- methoxy-N4-methyl-5-nitrobenzene-1,4-diamine (0.40 g, 0.87 mmol) was dissolved in acetonitrile (20 mL), potassium carbonate (0.36 g, 2.61 mmol) and N1,N1,N2- trimethylethane-1,2-diamine (0.10 g, 0.96 mmol) were added and the reaction was stirred at 80 °C for two hours. Cooled to room temperature, the reaction was diluted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to yield N1-(5-bromo-4-(1H-indol-3-yl)pyrimidin-2-yl)-N4-(2- (dimethylamino)ethyl)-2-methoxy-N4-methyl-5-nitrobenzene-1,4-diamine (0.40 g, yield: 87%, red solid).

[0203] MS m / z (ESI): 540.2, 542.2 [M+H] + .

[0204] Step 4: Preparation of N1-(5-bromo-4-(1-(oxetan-3-yl)-1H-indol-3-yl)pyrimidin-2-yl)- N4-(2-(dimethylamino)ethyl)-2-methoxy-N4-methyl-5-nitrobenzene-1,4-diamine

[0205]

[0206] N1-(5-bromo-4-(1-(oxetan-3-yl)-1H-indol-3-yl)pyrimidin-2-yl)-N4-(2- (dimethylamino)ethyl)-2-methoxy-N4-methyl-5-nitrobenzene-1,4-diamine (0.12 g, 0.20 mmol), Pd2(dba)3(18.4 mg, 0.02 mmol), X-Phos (19 mg, 0.04 mmol), zinc cyanide (23.5 mg, 0.20 mmol) and zinc powder (13 mg, 0.20 mmol) were dissolved in N,N-dimethylacetamide (3 mL) at room temperature, purged with nitrogen and microwaved at 110 °C for 1.5 hours. Cooled to room temperature, filtered, the solid washed with ethyl acetate and the organic phase concentrated under reduced pressure. The crude product was separated on a preparative plate (dichloromethane:methanol:20:1) to give 2-((4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-4-(1-(oxetan-3-yl)- 1H-indol-3-yl)pyrimidine-5-carbonitrile (0.096 g, yield: 88%, yellow solid).

[0207] MS m / z (ESI): 596.0 [M+H] + .

[0208] Fifth step: Preparation of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxy-5-nitrophenyl)amino)-4-(1-(oxetan-3-yl)-1H-indol-3-yl)pyrimidine-5- carbonitrile

[0209]

[0210] N1-(5-bromo-4-(1-(oxetan-3-yl)-1H-indol-3-yl)pyrimidin-2-yl)-N4-(2- (dimethylamino)ethyl)-2-methoxy-N4-methyl-5-nitrobenzene-1,4-diamine (0.12 g, 0.20 mmol), Pd2(dba)3(18.4 mg, 0.02 mmol), X-Phos (19 mg, 0.04 mmol), zinc cyanide (23.5 mg, 0.20 mmol) and zinc powder (13 mg, 0.20 mmol) were dissolved in N,N-dimethylacetamide (3 mL) at room temperature, purged with nitrogen and microwaved at 110 °C for 1.5 hours. Cooled to room temperature, filtered, the solid washed with ethyl acetate and the organic phase concentrated under reduced pressure. The crude product was separated on a preparative plate (dichloromethane:methanol:20:1) to give 2-((4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-4-(1-(oxetan-3-yl)- 1H-indol-3-yl)pyrimidine-5-carbonitrile (0.096 g, yield: 88%, yellow solid).

[0211] MS m / z (ESI): 543.1 [M+H] + .

[0212] Step 6: Preparation of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-4-(1-(oxetan-3-yl)-1H-indol-3-yl)pyrimidine-5-carbonitrile

[0213]

[0214] To a solution of 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5- nitrophenyl)amino)-4-(1-(oxetan-3-yl)-1H-indol-3-yl)pyrimidine-5-carbonitrile (0.12 g, 0.22 mmol) in ethanol (10 mL) was added ammonium chloride aqueous solution (0.06 g, 1.1 mmol, water, 2 mL) and iron powder (0.12 g, 2.2 mmol) and the reaction was stirred at 80 °C for 2 hours. Cooled to room temperature, the reaction was filtered, the filter cake was washed with dichloromethane, the organic solvent was removed under reduced pressure, the residue was dissolved with dichloromethane and water, the layers were separated, the aqueous phase was extracted with dichloromethane (20 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-(oxetan-3-yl)-1H-indol-3-yl)pyrimidine-5-carbonitrile (0.095 g, yield: 83.8%, yellow oil).

[0215] MS m / z (ESI): 513.2 [M+H] + .

[0216] Step 7: Preparation of N-(5-((5-cyano-4-(1-(oxetan-3-yl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0217]

[0218] To a solution of 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-4-(1-(oxetan-3-yl)-1H-indol-3-yl)pyrimidine-5-carbonitrile (0.075 g, 0.146 mmol) in dichloromethane (5 mL) was cooled to 0 °C, triethylamine (0.03 g, 0.292 mmol) was added, followed by 3-chloropropanoyl chloride (0.024 g, 0.19 mmol). The reaction was stirred at 0 °C for 1 h. Upon completion, it was concentrated, the crude was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude was dissolved in acetonitrile (5 mL), followed by the addition of aqueous sodium hydroxide (0.058 g, 1.46 mmol, in water, 0.5 mL), and the reaction was stirred at 40 °C for 2 h. Upon completion, it was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude was purified by preparative chromatography to give N-(5-((5-cyano-4-(1-(oxetan-3-yl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (0.04 g, 48% yield, yellow solid).

[0219] MS m / z (ESI): 567.2 [M+H] + .

[0220] 1 H NMR (400 MHz, CDCl3) δ 10.15-9.82 (br, 1H), 9.45 (s, 1H), 8.69 (s, 2H), 8.55-8.38 (br, 1H) 7.80 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.33-7.29 (m, 2H), 6.78 (s, 1H), 6.42-6.38 (m, 1H), 5.72-5.66 (m, 2H), 5.28-5.13 (m, 5H), 3.90 (s, 3H), 3.13-2.95 (br, 2H), 2.74 (s, 3H), 2.61-2.24 (br, 6H), 1.85-1.53 (m, 2H).

[0221] Example 9

[0222] N-(5-((5-cyano-4-(1-(oxetan-3-yl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-6-methoxy-pyridin-3-yl)acrylamide

[0223]

[0224]

[0225] First Step: Preparation of 6-chloro-2-methoxy-pyridin-3-amine

[0226]

[0227] 6-chloro-2-methoxy-3-nitro-pyridine (5 g, 26.6 mmol) was dissolved in ethanol (100 mL) and water (30 mL), ammonium chloride (7.0 g, 133 mmol) was added, iron powder (7.5 g, 133 mmol) was added portionwise, the reaction was stirred at 85 °C for 2 hours. The reaction was cooled to room temperature, filtered through celite, the filtrate was added to ethyl acetate (150 mL) and saturated brine (120 mL), the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-chloro-2-methoxy-pyridin-3-amine (4 g, yield: 95%) as a brown solid.

[0228] MS m / z (ESI): 159.1 [M+H] + .

[0229] Second Step: Preparation of N-(6-chloro-2-methoxy-pyridin-3-yl)acetamide

[0230]

[0231] 6-chloro-2-methoxy-pyridin-3-amine (4.0 g, 25.0 mmol) was dissolved in dichloromethane (100 mL), diisopropylethylamine (4.8 g, 37.5 mmol) was added, cooled to 0 °C, acetyl chloride (2.4 g, 30.0 mmol) was added, and stirring was continued for 2 hours. The reaction was washed with 80 mL water, 80 mL 1 N hydrochloric acid, and 80 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give N-(6-chloro-2-methoxy-pyridin-3-yl)acetamide (4.0 g, yield: 79%) as a brown solid.

[0232] MS m / z (ESI): 201.1 [M+H] + .

[0233] Third Step: Preparation of N-(6-chloro-2-methoxy-5-nitro-pyridin-3-yl)acetamide

[0234]

[0235] N-(6-chloro-2-methoxy-5-nitropyridin-3-yl)acetamide (1.6 g, 6.5 mmol) was dissolved in acetonitrile (30 mL), N1,N1,N2-trimethylethane-1,2-diamine (1 g, 9.8 mmol) was added and the reaction was stirred at 80 °C for 3 hours. The solvent was evaporated and the crude was purified by column chromatography (dichloromethane / methanol: 100 / 1 to 10 / 1) to give N-(6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitropyridin-3-yl)acetamide (0.9 g, yield: 45%) as a brown solid.

[0236] MS m / z (ESI): 244.1 [M-H] + .

[0237] Fourth step: Preparation of N-(6-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxy-5-nitropyridin-3-yl)acetamide

[0238]

[0239] N-(6-chloro-2-methoxy-5-nitropyridin-3-yl)acetamide (1.6 g, 6.5 mmol) was dissolved in acetonitrile (30 mL), N1,N1,N2-trimethylethane-1,2-diamine (1 g, 9.8 mmol) was added and the reaction was stirred at 80 °C for 3 hours. The solvent was evaporated and the crude was purified by column chromatography (dichloromethane / methanol: 100 / 1 to 10 / 1) to give N-(6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitropyridin-3-yl)acetamide (0.9 g, yield: 45%) as a brown solid.

[0240] MS m / z (ESI): 312.1 [M+H] + .

[0241] Fifth step: Preparation of N2-(2-(dimethylamino)ethyl)-6-methoxy-N2-methyl-3- nitropyridine-2,5-diamine

[0242]

[0243] N-(6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitropyridin-3-yl)acetamide (0.9 g, 2.9 mmol) was dissolved in methanol (30 mL) and concentrated hydrochloric acid (5 mL), and the reaction was stirred at 60 °C for 3 hours. The solvent was evaporated to dryness, and dichloromethane (50 mL) and saturated sodium bicarbonate (50 mL) were added. The mixture was stirred until no bubbles precipitated, and the organic layer was separated. The organic layer was dried with anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was purified by column chromatography (dichloromethane / methanol: 100 / 1 to 10 / 1) to give N2-(2-(dimethylamino)ethyl)-6-methoxy-N2-methyl-3-nitropyridin-2,5-diamine (0.15 g, yield: 19%) as a brown solid.

[0244] MS m / z(ESI): 270.1 [M+H] + .

[0245] Step 6: Preparation of 4-(1-cyclopropyl-1H-indol-3-yl)-2-((6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitropyridin-3-yl)amino)pyrimidine-5-carboxynitrile

[0246]

[0247] N2-(2-(dimethylamino)ethyl)-6-methoxy-N2-methyl-3-nitropyridine-2,5-diamine (0.11 g, 0.41 mmol), 2-chloro-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-5-carboxynitrile (0.12 g, 0.41 mmol), tris(dibenzylideneacetone)dipalladium (0.18 g, 0.2 mmol), x-phos (0.2 g, 0.41 mmol), and sodium tert-butoxide (0.12 g, 1.2 mmol) were dissolved in dioxane (5 mL), and nitrogen gas was purged. The reaction was stirred in a microwave at 140 °C for 1 hour. The reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness. The crude product was separated by prep-TLC (dichloromethane / methanol: 20 / 1) to give 4-(1-cyclopropyl-1H-indol-3-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxynitrile (0.1 g, yield: 47%) as a yellow solid.

[0248] MS m / z (ESI): 528.1 [M+H] + .

[0249] Step 7: Preparation of 2-((5-amino-6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxypyridin-3-yl)amino)-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidine-5-carboxynitrile)

[0250]

[0251] To a solution of 4-(l-cyclopropyl-lH-indol-3-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5- carbonitrile (80 mg, 0.15 mmol) in methanol (10 mL) was added Raney nickel (80 mg) and 85% hydrazine hydrate (90 mg, 1.5 mmol) at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction was filtered, the filtrate was concentrated, water (15 mL) was added, and the mixture was extracted with dichloromethane (15 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-((5-amino-6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxypyridin-3-yl)amino)-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidine-5- carbonitrile (80 mg, yield: 100% crude) as a brown solid.

[0252] MS m / z (ESI): 498.1 [M+H] + .

[0253] Eighth Step: Preparation of N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-6-methoxypyridin-3- yl)acrylamide

[0254]

[0255] To a solution of 2-((5-amino-6-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxy-pyridin-3-yl)amino)-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidine-5-carbonitrile (80 mg, 0.16 mmol) in dichloromethane (10 mL) was cooled to 0 °C, triethylamine (24 mg, 0.24 mmol) was added, followed by 3-chloropropanoyl chloride (25 mg, 0.19 mmol). The reaction was stirred at 0 °C for 1 h. Water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Tetrahydrofuran (5 mL) was added, followed by sodium hydroxide (64 mg, 1.6 mmol) in water (0.5 mL). The reaction was stirred at 40 °C overnight. Water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated by prep-HPLC to give N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-6-methoxy-pyridin-3-yl)acrylamide (0.9 mg, yield: 0.7%) as a yellow solid.

[0256] MS m / z (ESI): 552.1 [M+H] + .

[0257] The preparation methods of other embodiments are as follows:

[0258]

[0259]

[0260]

[0261]

[0262] two, Biological test evaluation

[0263] The present application is further described in connection with the following test examples, which are not meant to limit the scope of the present application.

[0264] 1. Enzymatic Assay

[0265] Test Example 1, Determination of the Inhibitory Effect of Compounds of the Invention on EGFR 20 Exon Insertion Mutant Kinase Activity

[0266] Purpose of the Experiment: The purpose of this test example is to measure the ability of compounds to inhibit EGFR 20 exon insertion mutant kinase activity.

[0267] Experimental instruments: centrifuge (Eppendorf 5810R), microplate reader (BioTek Synergy H1), pipette (Eppendorf & Rainin)

[0268] Experimental method: In this experiment, the TR-FRET (time-resolved fluorescence resonance energy transfer) method was used to study the inhibitory activity of the compound on the EGFR 20 exon insertion mutant kinase. The experiment was carried out in a 384-well plate, and the experimental buffer (50 mM HEPES, 1 mM EGTA, 10 mM MgCl2, 2 mM DTT, 0.01% Tween-20) was prepared. The compound gradient was diluted to different concentrations using the experimental buffer, and 2.5 μL was added to each well of the 384-well plate. Then 2.5 μL of diluted EGFR kinase solution (0.001-0.5 nM) was added, and incubated at room temperature for 10 minutes. Then 5 μL of ULight-poly GT / ATP mixed solution was added, and incubated at room temperature for 30-60 minutes. Then 5 μL of EDTA was added to terminate the reaction, and 5 μL of Eu-labeled antibody detection solution was added. Incubate at room temperature for 1 hour, and measure the fluorescence signal value of each well of the plate at 665 nm using a microplate reader.

[0269] Experimental data processing method:

[0270] The inhibition rate was calculated using the fluorescence signal value at 665 nm ((positive control well value-sample well value) / (positive control well value-negative control well value))*100%, and the concentration and inhibition rate were subjected to nonlinear regression curve fitting using Graphpad Prism software to obtain the IC 50 value, as shown in Table 1 below:

[0271] Table 1 Inhibitory activity IC 50

[0272]

[0273] Experimental conclusion:

[0274] Through the above scheme, it is found that the compound of the embodiment of the present application has good inhibitory effect in the EGFR 20 exon insertion mutant kinase activity inhibition experiment.

[0275] Test Example 2, determination of the inhibitory effect of the compound of the present application on the activity of EGFR wild-type kinase

[0276] Experimental purpose: The purpose of this test example is to measure the inhibitory ability of the compound on the activity of EGFR wild-type kinase.

[0277] Experimental instruments: centrifuge (Eppendorf 5810R), microplate reader (BioTek Synergy H1), pipette (Eppendorf & Rainin)

[0278] Experimental method: In this experiment, the TR-FRET (time-resolved fluorescence resonance energy transfer) method was used to study the inhibitory activity of the compound on EGFR wild-type kinase. The experiment was carried out in a 384-well plate, and the experimental buffer (50 mM HEPES, 1 mM EGTA, 10 mM MgCl2, 2 mM DTT, 0.01% Tween-20) was prepared. The compound gradient was diluted to different concentrations using the experimental buffer, 2 μL per well was added to the 384-well plate, and 4 μL of diluted EGFR kinase solution (0.001-0.5 nM) was added. Incubate at room temperature for 10 minutes, add 4 μL of ULight-poly GT / ATP mixed solution, incubate at room temperature for 30-60 minutes, add 5 μL of EDTA to terminate the reaction and 5 μL of Eu-labeled antibody detection solution, incubate at room temperature for 1 hour, and measure the fluorescence signal value of each well of the plate at 665 nm using a microplate reader.

[0279] Experimental data processing method:

[0280] The inhibition rate was calculated using the fluorescence signal value at 665 nm ((positive control well value - sample well value) / (positive control well value - negative control well value))*100%, and the concentration and inhibition rate were subjected to nonlinear regression curve fitting using Graphpad Prism software to obtain the IC 50 value, as shown in Table 2 below:

[0281] Table 2 Inhibitory activity IC 50

[0282]

[0283] Experimental conclusion:

[0284] Through the above scheme, it is found that the compound of the embodiment of the present application has less inhibitory effect in the EGFR wild-type kinase inhibition test.

[0285] Test Example 3, determination of the inhibitory effect of the compound of the present application on the proliferation of Ba / F3 EGFR mutant cell lines and A431 cell lines

[0286] Experimental purpose: The purpose of this test example is to measure the inhibitory effect of the compound on the proliferation activity of Ba / F3 EGFR mutant cell lines and A431 cell lines.

[0287] Experimental instruments: microplate reader (BioTek Synergy H1), pipette (Eppendorf & Rainin)

[0288] Experimental method:

[0289] When the Ba / F3 EGFR mutant cells were cultured to the appropriate density, the cells were collected, the cells were adjusted to the appropriate cell concentration using complete culture medium, the cell suspension was plated in a 96-well plate at 90 μL per well, and was placed in a 37°C, 5% CO2 incubator overnight. DMSO and culture medium were used to prepare compound solutions of different concentrations, a solvent control was set, the compound solutions were added to the 96-well plate at 10 μL per well, and was placed in a 37°C, 5% CO2 incubator for continued culture for 72-144 h. Then, CellTiter-Glo solution was added, mixed uniformly by shaking, and incubated in the dark for 10 min. The BioTek Synergy H1 microplate reader was used for reading.

[0290] Experimental method:

[0291] When the A431 cells were cultured to the appropriate density, the cells were collected, the cells were adjusted to the appropriate cell concentration using complete culture medium, the cell suspension was plated in a 96-well plate at 90 μL per well, and was placed in a 37°C, 5% CO2 incubator overnight. DMSO and culture medium were used to prepare compound solutions of different concentrations, a solvent control was set, the compound solutions were added to the 96-well plate at 10 μL per well, and was placed in a 37°C, 5% CO2 incubator for continued culture for 72 h. Then, CellTiter-Glo solution was added, mixed uniformly by shaking, and incubated in the dark for 10 min. The BioTek Synergy H1 microplate reader was used for reading.

[0292] Experimental data processing method:

[0293] The luminescence signal value was used to calculate the inhibition rate, and the concentration and inhibition rate were subjected to non-linear regression curve fitting using Graphpad Prism software to obtain the IC 50 value. The specific data are shown in Table 3:

[0294] Table 3: IC 50

[0295]

[0296] Experimental conclusion:

[0297] The compound of the embodiment of the present application obtained by the above scheme has good inhibitory effect in the inhibition test of Ba / F3 EGFR mutant cell proliferation activity, and has poor inhibitory effect on A431 cells. It can be known from the comparison data that the series of embodiments of the present application have high selectivity in inhibiting the proliferation activity of Ba / F3 EGFR mutant cells.

[0298] III. Crystal form research

[0299] 1. Experimental instruments

[0300] 1.1 Some parameters of physical and chemical detection instruments

[0301]

[0302]

[0303] 2. Preparation of different crystal forms of compound N-(5-((5-cyano-4-(1- cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0304] 2.1 Preparation of crystal form A

[0305]

[0306] 4-(1-cyclopropyl-1H-indol-3-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carbonitrile 66.0 g, tetrahydrofuran 660 mL were added to a 2 L three-necked flask; palladium-carbon (6.6 g) was added, and N2 was bubbled under the liquid surface for half an hour; hydrogen was replaced for 3 times, heating to 35-40℃ for 20-24 h of reaction, filtration, and the filter cake was washed with tetrahydrofuran (100 mL); the filtrate was protected by N2 after filtration, and the temperature was lowered to 0-5℃; triethylamine (12.6 g) was added; the temperature was controlled at 0-5℃, and a solution of 3-chloropropionyl chloride (23.7 g) in tetrahydrofuran (120 mL) was added dropwise, which was completed in about 45 minutes; the temperature was maintained at 0-5℃ for 2-3 h of reaction, filtration, and the filter cake was washed with tetrahydrofuran (100 mL), followed by washing with 100 ml of n-heptane, to obtain N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) 3-chloropropionamide hydrochloride (98.9 g, yield 100%).

[0307] Into a 2L three-necked flask, was placed N-(5-((5-cyano-4-(1- cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) 3-chloropropanamide hydrochloride 50.0 g, THF 420 mL, and stirred; potassium hydroxide 42.0 g in water 42 mL was added dropwise, and the dropwise addition was completed in about 10 min, and the stirring was continued at room temperature for 30 min; the temperature was raised to 35-40 °C, and the reaction was carried out for 1 h, and the reaction was completed; the temperature was lowered to room temperature, and water 500 mL was added, and the stirring was continued for 10 min, and then the mixture was allowed to stand to separate into layers, and the organic layer was retained, and the aqueous layer was extracted with 2-methyltetrahydrofuran 300 mL; the organic layers were combined, and washed successively with water 200 mL and saturated brine 200 mL; activated carbon 2.5 g and anhydrous sodium sulfate 25 g were added to the organic layer, and the stirring was continued at room temperature (20 ± 5 °C) for 1 h; the mixture was filtered, and the filtrate was concentrated to give a yellow solid about 70 g; 2-methyltetrahydrofuran 150 mL was added, and the mixture was heated to 80 °C to reflux, and the stirring was continued for 1 h, and the mixture was allowed to cool to room temperature naturally; the mixture was cooled in an ice bath (0-5 °C), and the stirring was continued for 1 h, and the mixture was filtered, and the filter cake was washed with 2-methyltetrahydrofuran (50 mL) to give the target product N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) acrylamide Form A (24.0 g, yield 69.7%), which was 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

[0308] 2.2 Preparation of Form B

[0309] Into a 2L three-necked flask, was placed N-(5-((5-cyano-4-(1- cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) 3-chloropropanamide hydrochloride 50.0 g, THF 420 mL, and stirred; potassium hydroxide 42.0 g in water 42 mL was added dropwise, and the dropwise addition was completed in about 10 min, and the stirring was continued at room temperature for 30 min; the temperature was raised to 35-40 °C, and the reaction was carried out for 1 h, and the reaction was completed; the temperature was lowered to room temperature, and water 500 mL was added, and the stirring was continued for 10 min, and then the mixture was allowed to stand to separate into layers, and the organic layer was retained, and the aqueous layer was extracted with 2-methyltetrahydrofuran 300 mL; the organic layers were combined, and washed successively with water 200 mL and saturated brine 200 mL; activated carbon 2.5 g and anhydrous sodium sulfate 25 g were added to the organic layer, and the stirring was continued at room temperature (20 ± 5 °C) for 1 h; the mixture was filtered, and the filtrate was concentrated to give a yellow solid about 70 g; 2-methyltetrahydrofuran 150 mL was added, and the mixture was heated to 80 °C to reflux, and the stirring was continued for 1 h, and the mixture was allowed to cool to room temperature naturally; the mixture was cooled in an ice bath (0-5 °C), and the stirring was continued for 1 h, and the mixture was filtered, and the filter cake was washed with 2-methyltetrahydrofuran (50 mL) to give the target product N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) acrylamide Form A (24.0 g, yield 69.7%), which was 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 4 Figure 5 Figure 6

[0310] 2.3 Preparation of Form C

[0311] ​​​​​​10 mg of compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide crystal form A was weighed and added to 100 μL of 1,4-dioxane solvent. The mixture was stirred at 25°C for two weeks, centrifuged, and dried under vacuum at 50°C to constant weight to obtain compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide crystal form C. Analysis showed that it possessed the following properties... Figure 7 The XRPD pattern shown is as follows: Figure 8 The DSC spectrum shown is as follows: Figure 9 The TGA spectrum shown.

[0312] 2.4 Preparation of Crystal Form D

[0313] 10 mg of compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide crystal form A was weighed and added to 100 μL of ethyl formate solvent. The mixture was stirred at 25°C for two weeks, centrifuged, and dried under vacuum at 50°C to constant weight to obtain compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide crystal form D. Analysis revealed the following properties: Figure 10 The XRPD diagram shown is as follows: Figure 11 The DSC diagram shown and as follows Figure 12 The TGA diagram shown.

[0314] 2.5 Preparation of Crystal Form E

[0315] 10 mg of compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide crystal form A was weighed and added to 100 μL of ethyl formate solvent. The mixture was stirred at 50°C for one day, centrifuged, and dried under vacuum at 50°C to constant weight to obtain compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide crystal form E. Analysis revealed the following properties: Figure 13 The XRPD diagram shown is as follows: Figure 14 The DSC diagram shown and as follows Figure 15 The TGA diagram shown.

[0316] 3. Solid stability experiment

[0317] 3.1 Purpose of the experiment:

[0318] To investigate the physical and chemical stability of compound N-(5-((5-cyano-4-(1- cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl)acrylamide Form A under the conditions of light 5000lx, high temperature 60℃, high humidity 92.5% RH, high temperature and high humidity 50℃ 75% RH, to provide a basis for the storage of the compound.

[0319] 3.2 Instruments and liquid chromatography analysis conditions

[0320] 3.2.1 Instruments and equipment:

[0321] Instrument name Model Analytical balance Sartorius BSA224S-CW Pure water machine Milli-Q Plus, Millipore High performance liquid chromatograph Agilent 1260 Pump Agilent G1311B Sampler G1329B Column oven G1316A Detector G1315D

[0322] 3.2.2 Chromatography conditions:

[0323]

[0324] 3.3 Experimental protocol:

[0325] Take about 1 mg of compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form A, and investigate under the conditions of light 5000lx, high temperature 60℃, high humidity 92.5% RH, high temperature and high humidity 50℃ 75% RH for 5 days, 10 days, determine the content by HPLC using the external standard method, and calculate the changes in related substances using the chromatographic peak area normalization method.

[0326] 3.4 Experimental results:

[0327]

[0328] 3.5 Experimental conclusions:

[0329] The above data show that compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form A is relatively stable under light conditions, has degradation under the conditions of high temperature 60℃, high humidity 92.5% RH, high temperature and high humidity 50℃ 75% RH, and needs to be stored in a cool place during the later storage process.

[0330] 4. Dynamic moisture absorption experiment

[0331] 4.1 Purpose of the experiment:

[0332] To investigate the hygroscopicity of compound N-(5-((5-cyano-4-(1- cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl)acrylamide Form A under different relative humidity conditions, and to provide a basis for the storage of the compound.

[0333] 4.2 Experimental protocol:

[0334] Compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form A was placed in saturated water vapor of different relative humidity, allowing the compound to reach dynamic equilibrium with the water vapor, and the percentage of weight gain of the compound after equilibrium was calculated.

[0335] 4.3 Experimental results and conclusions:

[0336] Compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form A gained about 0.521% in weight under RH 80% conditions, showing slight hygroscopicity. After 2 cycles of hygroscopicity and desorption under 0-95% relative humidity conditions, the XRPD spectrum of Form A did not change, i.e., the crystal form did not convert.

[0337] 5. Solubility experiment in different media

[0338] 5.1 Purpose of the experiment:

[0339] To compare the solubility of compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form A in pH 1-8 USP buffer, artificial simulated gastric fluid (FaSSGF), fasted artificial simulated intestinal fluid (FaSSIF), non-fasted artificial simulated intestinal fluid (FeSSIF), fasted artificial simulated colonic fluid (FaSSCoF), non-fasted artificial simulated colonic fluid (FeSSCoF), and pure water, etc. media, to provide a basis for the evaluation of drugability.

[0340] 5.2 Experimental protocol:

[0341] Compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2- ((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form A 1 mg was suspended in different media for 24 hours, and the thermodynamic solubility of the compound at 37°C was determined by HPLC using an external standard method.

[0342] 5.3 Experimental results:

[0343] Sample name Crystalline form A solubility (mg / mL) pH 1 >1 pH 2 >1 pH 3 0.02 pH 4 0.01 pH 5 0.01 pH 6 0.00 pH 7 0.00 pH 8 0.00 H2O 0.00 FaSSGF >1 FaSSIF 0.16 FeSSIF >1 FaSSCoF 0.00 FeSSCoF 0.09

[0344] 5.4 Experimental conclusions:

[0345] The solubility of the comparative compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3- yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form A in different media was compared, and it was found that Form A had better solubility under acidic conditions.

[0346] 6. Thermodynamic stability experiment

[0347] 6.1 Purpose of the experiment:

[0348] Through polymorphic screening, a more stable compound, N-(5-((5-cyano-4-(1-cyclopropyl-1H- indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide Form, was found.

[0349] 6.2 Experimental protocol:

[0350] Organic solvents with certain solubility and water were selected, and different forms were suspended in the solvent system. After stirring and beating for 2 weeks or 1 day at 25°C, the supernatant was discarded after centrifugation, and the solid was dried at 50°C under vacuum (-0.1 Mpa) for 16 hours. The XRPD, DSC and TGA of the solid were determined and compared.

[0351] 6.3 Experimental results:

[0352]

[0353]

[0354] 6.4 Experimental conclusions:

[0355] Five crystal forms of compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide were obtained by beating, changing the crystallization solvent and the crystallization method, which were crystal form A, crystal form B, crystal form C, crystal form D and crystal form E. By comparing the DSC spectra of different crystal forms, it was determined that the thermodynamic stability of compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide crystal form A was better, and it was an anhydrate.

[0356] 7. Rat pharmacokinetic study

[0357] 7.1 Purpose of the experiment:

[0358] The rat pharmacokinetic parameters of compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide free base crystal form A were studied.

[0359] 7.2 Experimental instruments and reagents:

[0360] 7.2.1 Instruments:

[0361]

[0362] 7.2.2 Reagents:

[0363]

[0364]

[0365] 7.3 Experimental animals:

[0366] Animal species Strain Age Gender Supplier Rat SD 7 weeks, body weight 200 g Male Zhaoyan (Suzhou) New Drug Research Center Co., Ltd.

[0367] 7.4 Test compound:

[0368] Compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide free base crystal form A.

[0369] 7.5 Experimental scheme:

[0370] The compound N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide free base crystal form A was uniformly suspended with an aqueous solution containing 0.5% HPMC (hydroxypropyl methyl cellulose) K4M (1% Tween 80), and then was administered intragastrically to rats, with three rats in parallel, and the dose was 30 mg / kg, and the amount of the compound was all converted into the amount of the same free base.

[0371] 7.6 Experimental results:

[0372] Table 7.1 Rat pharmacokinetic experiment results

[0373]

[0374] 7.7 Experimental conclusion:

[0375] As can be seen from the rat pharmacokinetic experiment results in the table, at a dose of 30 mg / kg, the compound 5 N-(5-((5-cyano-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide free base crystal form A of the present application showed good metabolic properties.

Claims

1. A crystalline form of the compound N-(5-((5-cyano-4-(l-cyclopropyl-lH-indol-3- yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- methoxyphenyl)acrylamide characterized by, the crystal form is Form A, Form B, Form C, Form D, Form E, wherein: the X-ray powder diffraction pattern of Form A has diffraction peaks at 2-theta = 7.1 ± 0.2°, 14.1 ± 0.2°, 18.9 ± 0.2°, 22.7 ± 0.2°, 20.4 ± 0.2°, 22.3 ± 0.2°, 13.4 ± 0.2°, 12.9 ± 0.2, 9.6 ± 0.2°, 14.9 ± 0.2°; the X-ray powder diffraction pattern of Form B has diffraction peaks at 2-theta = 6.5 ± 0.2°, 20.7 ± 0.2°, 20.9 ± 0.2°, 21.0 ± 0.2°, 21.4 ± 0.2°, 15.6 ± 0.2°, 23.8 ± 0.2°, 21.6 ± 0.2°; the X-ray powder diffraction pattern of Form C has diffraction peaks at 2-theta = 7.1 ± 0.2°, 18.1 ± 0.2°, 9.0 ± 0.2°, 22.7 ± 0.2°, 14.1 ± 0.2°, 18.9 ± 0.2°, 22.5 ± 0.2°, 20.3 ± 0.2°, 23.2 ± 0.2°, 23.1 ± 0.2°; the X-ray powder diffraction pattern of Form D has diffraction peaks at 2-theta = 26.2 ± 0.2°, 22.2 ± 0.2°, 10.6 ± 0.2°, 14.5 ± 0.2°, 21.3 ± 0.2°, 15.9 ± 0.2°, 7.0 ± 0.2°, 9.0 ± 0.2°; the X-ray powder diffraction pattern of Form E has diffraction peaks at 2-theta = 6.3 ± 0.2°, 12.6 ± 0.2°, 9.9 ± 0.2°, 21.1 ± 0.2°, 13.2 ± 0.2°, 26.2 ± 0.2°, 20.0 ± 0.2°, 16.9 ± 0.2°.

2. The crystal form of the compound according to claim 1, wherein, the X-ray powder diffraction pattern of Form A optionally further comprises diffraction peaks at 2-theta = 17.5 ± 0.2°, 20.8 ± 0.2°, 22.0 ± 0.2°, 25.6 ± 0.2°, 15.6 ± 0.2°; the X-ray powder diffraction pattern of Form B optionally further comprises diffraction peaks at 2-theta = 9.2 ± 0.2°, 25.1 ± 0.2°, 10.7 ± 0.2°, 12.4 ± 0.2°, 17.4 ± 0.2°, 17.6 ± 0.2°, 14.5 ± 0.2°; the X-ray powder diffraction pattern of Form C optionally further comprises diffraction peaks at 2-theta = 22.2 ± 0.2°, 20.7 ± 0.2°, 22.0 ± 0.2°, 17.5 ± 0.2°, 12.9 ± 0.2°; the X-ray powder diffraction pattern of Form D optionally further comprises diffraction peaks at 2-theta = 19.0 ± 0.2°, 8.3 ± 0.2°, 26.9 ± 0.2°, 18.1 ± 0.2°, 20.1 ± 0.2°, 21.8 ± 0.2°, 19.8 ± 0.2°; the X-ray powder diffraction pattern of Form E optionally further comprises diffraction peaks at 2-theta = 6.3 ± 0.2°, 12.6 ± 0.2°, 9.9 ± 0.2°, 21.1 ± 0.2°, 13.2 ± 0.2°, 26.2 ± 0.2°, 20.0 ± 0.2°, 16.9 ± 0.2°. The X-ray powder diffraction pattern of the crystal form E optionally further comprises diffraction peaks at 2-theta of 15.5±0.2°, 25.3±0.2°, 27.4±0.2°.

3. The crystal form of the compound according to claim 1, wherein, The X-ray powder diffraction pattern of the crystal form A is shown in Figure 1. The X-ray powder diffraction pattern of the crystal form B is shown in Figure 4. The X-ray powder diffraction pattern of the crystal form C is shown in Figure 7. The X-ray powder diffraction pattern of the crystal form D is shown in Figure 10. The X-ray powder diffraction pattern of the crystal form E is shown in Figure 13.

4. The crystalline form of the compound according to claim 1, characterized in that, The relative peak intensity of the X-ray powder diffraction pattern of the crystal form A, the crystal form B, the crystal form C, the crystal form D and the crystal form E is within ±0.2° of the 2-theta value of the corresponding peak in Figure 1, Figure 4, Figure 7, Figure 10 and Figure 13, respectively.

5. A crystalline form of the compound of claim 1, characterized by, The crystal form A has a DSC pattern as shown in Figure 2 or a TGA pattern as shown in Figure 3; the crystal form B has a DSC pattern as shown in Figure 5 or a TGA pattern as shown in Figure 6; the crystal form C has a DSC pattern as shown in Figure 8 or a TGA pattern as shown in Figure 9; the crystal form D has a DSC pattern as shown in Figure 11 or a TGA pattern as shown in Figure 12; and the crystal form E has a DSC pattern as shown in Figure 14 or a TGA pattern as shown in Figure 15.

6. A pharmaceutical composition comprising a therapeutically effective amount of the crystal form of the compound according to any one of claims 1-5, and one or more pharmaceutically acceptable carriers or excipients.

7. Use of the crystal form of the compound according to any one of claims 1-5 and the pharmaceutical composition of claim 6 in the preparation of a kinase inhibitor medicament.

8. Use according to claim 7, characterized in that, The kinase inhibitor is a receptor tyrosine kinase inhibitor.

9. Use according to claim 7, characterized in that, The kinase inhibitor is a HER2 inhibitor, an EGFR inhibitor, an EGFR mAb and a combination thereof.

10. Use according to claim 7, characterized in that, The kinase inhibitor is a HER2 20 exon mutant inhibitor, an EGFR 20 exon mutant inhibitor, an EGFR 20 exon mutant mAb and a combination thereof.

11. Use of the crystal form of the compound according to any one of claims 1-5 and the pharmaceutical composition of claim 6 in the preparation of a medicament for treating cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS-related disease.

12. Use according to claim 11, characterized in that, The cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS-related disease is mediated by HER2 20 exon mutation and / or EGFR 20 exon mutation.

13. The use according to claim 11, characterized in that, 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 and myeloma.

14. The use according to claim 11, characterized in that, The cancer is non-small cell lung cancer.

Images