Polycyclic anaplastic lymphoma kinase inhibitor

Abstract

A polycyclic anaplastic lymphoma kinase inhibitor represented by general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein R1, R2, R3, R4, R6, R7, Q, m, n and ring A are defined in the specification. The invention also relates to a preparation method of the compounds, a pharmaceutical preparation and a pharmaceutical composition containing the compounds, and application of the compounds, the pharmaceutically acceptable salts or the stereoisomers thereof in preparation of medicines for treating and / or preventing anaplastic lymphoma kinase mediated cancers or non-cancerous related diseases. # imgabs0 #

Description

Technical Field

[0001] Embodiments of the present invention provide a multi-ring anaplastic lymphoma kinase inhibitor, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, a preparation method of these compounds, a pharmaceutical preparation and a pharmaceutical composition containing these compounds, and an application of the compound, the pharmaceutically acceptable salt thereof or the stereoisomer thereof in the preparation of a drug for treating and / or preventing cancer or non-cancer related diseases mediated by anaplastic lymphoma kinase. Background Art

[0002] Anaplastic lymphoma kinase (ALK) is a member of the receptor tyrosine kinase family, which can recruit downstream proteins through autophosphorylation, and then express specific genes to regulate cell metabolism and growth. Anaplastic lymphoma kinase was first discovered in anaplastic large cell lymphoma (ALCL), and later it was found that it is also highly expressed in non-small cell lung cancer (NSCLC).

[0003] The abnormal expression of ALK in some ALCL / NSCLC results from different chromosomal translocations. These chromosomal translocations can all produce corresponding fusion proteins. Analysis of these fusion genes shows that they all contain the gene sequence encoding the intracellular kinase region at the 3' end of the ALK gene, while the gene fragments fused with ALK contain promoter elements and sequences encoding mediators of auto-dimerization, resulting in high expression and over-activation of the fusion protein with ALK kinase activity in cells, and causing malignant transformation of cells. Therefore, the activity of the ALK intracellular kinase region and the corresponding signal transduction pathway are important molecular mechanisms leading to the formation of ALCL. ROS1 is a currently popular target gene studied in lung adenocarcinoma after ALK. ROS1 is a member of the receptor tyrosine kinase family, and the incidence of ROS1 in NSCLC is about 1.7%. There is 49% homology between ROS1 and anaplastic lymphoma kinase ALK within the amino acid kinase domain, and 77% identity at the ATP binding site, which makes it possible to use ALK kinase inhibitors to treat ROS1 rearrangement-positive NSCLC.

[0004] Thus, it can be seen that developing small molecule inhibitors targeting ALK / ROS1 can effectively reduce the influence of mutant ALK / ROS1 genes on downstream proteins, and further affect the effects of tumor cell invasion, proliferation, etc., and ultimately affect the growth of tumor cells, playing an anti-tumor role. Summary of the Invention

[0005] To develop small molecule inhibitors against ALK, embodiments of the present invention provide polycyclic anaplastic lymphoma kinase inhibitors that have good effects on treating and / or preventing ALK-mediated cancers or non-cancerous related diseases. The technical solutions are as follows:

[0006] Scheme 1. The compound of general formula (I), its pharmaceutically acceptable salt or its stereoisomer:

[0007]

[0008] Wherein,

[0009] R 1 is selected from -SO2R 5 or -SO2NRR 5 ;

[0010] R 2 , R 6 R 7 are each independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, carboxy, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl;

[0011] R 3 is selected from a 5-6 membered heteroaryl optionally substituted with 1-3 substituents W, or a 3-8 membered heterocyclic group optionally substituted with 1-3 substituents W;

[0012] Or R 2 and R 7 together with the carbon atom to which they are attached form a 5-6 membered cycloalkyl, 5-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl optionally substituted with 1-3 substituents W1;

[0013] Or R 2 and R 3 together with the carbon atom to which they are attached form a 5-6 membered cycloalkyl, 5-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl optionally substituted with 1-3 substituents W2;

[0014] R 4 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkoxy, C 1-6 alkyl, halo C 1-6 alkyl, halo C1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylcarbonyl or C 1-6 alkylcarbonyloxy;

[0015] or R 4 and R 6 together with the carbon atom to which they are attached form a 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl optionally substituted by 1 to 3 substituents W3;

[0016] W, W1, W2, W3 are each independently selected from hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkylsulfonamido, C 1-6 alkylaminosulfonyl or C 1-6 alkylsulfonyl;

[0017] R is selected from hydrogen, C 1-6 alkyl, hydroxy C 1-6 alkyl or a 3- to 8-membered carbocyclic ring;

[0018] R 5 is selected from hydrogen, hydroxy C 1-6 alkyl or a 3- to 8-membered carbocyclic ring;

[0019] Ring A is selected from 5- to 6-membered heterocyclic groups containing 2 O, S and / or N atoms;

[0020] Q is selected from hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy;

[0021] n is an integer from 0 to 5;

[0022] m is 0, 1 or 2.

[0023] Scheme 2. The compound according to Scheme 1, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

[0024] wherein, R 1 is selected from -SO2R 5 ;

[0025] R 5 is selected from hydrogen or hydroxy C 1-6 alkyl.

[0026] Compound, its pharmaceutically acceptable salt or its stereoisomer as described in Scheme 1 or 2:

[0027] wherein, R 2 , R 6 , R 7 are each independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C 1-6 alkyl, C 1-6 alkoxy.

[0028] Compound, its pharmaceutically acceptable salt or its stereoisomer as described in Scheme 1 or 2:

[0029] wherein, R 2 , R 6 , R 7 are each independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C 1-4 alkyl, C 1-4 alkoxy.

[0030] Compound, its pharmaceutically acceptable salt or its stereoisomer as described in Scheme 1 or 2:

[0031] wherein, R 2 , R 6 , R 7 are each independently selected from a hydrogen atom, a halogen atom, nitro, cyano, amino, hydroxyl, carboxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy.

[0032] Compound, its pharmaceutically acceptable salt or its stereoisomer as described in Scheme 1 or 2:

[0033] wherein, R 2 , R 6 , R 7 are each independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy.

[0034] Compound, its pharmaceutically acceptable salt or its stereoisomer as described in any one of Schemes 1-6:

[0035] wherein, R 3 is selected from a 4-6 membered heterocyclic group containing 1-2 N atoms optionally substituted by 1-2 substituents W; W is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6(alkyl)2amino, halo-C 1-6 alkyl, halo-C 1-6 alkoxy.

[0036] Embodiment 8. A compound as described in any one of Embodiments 1-6, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0037] wherein, R 3 is selected from pyridyl, dihydropyridyl, tetrahydropyridyl, azetidinyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, pyrazolyl, dihydropyrazolyl, tetrahydropyrazolyl, imidazolyl, dihydroimidazolyl, tetrahydroimidazolyl, pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, piperidinyl, piperazinyl or morpholinyl, which is optionally substituted by 1-2 substituents W.

[0038] Embodiment 9. A compound as described in any one of Embodiments 1-6, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0039] wherein, R 3 is selected from pyridyl, dihydropyridyl, tetrahydropyridyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl.

[0040] Embodiment 10. A compound as described in any one of Embodiments 1-6, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0041] wherein, R 3 is selected from azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl or morpholinyl.

[0042] Embodiment 11. A compound as described in any one of Embodiments 1-6, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0043] wherein, R 4 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, C 1-6 alkoxy, C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy.

[0044] Embodiment 12. A compound as described in any one of Embodiments 1-6, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0045] wherein, R 4 is selected from hydrogen, halogen, cyano, C 1-6 alkoxy, C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy.

[0046] Compound, pharmaceutically acceptable salt thereof or stereoisomer thereof according to any one of Schemes 1 - 6:

[0047] wherein, R 4 is selected from halogen, preferably fluorine atom, bromine atom or chlorine atom.

[0048] Compound, pharmaceutically acceptable salt thereof or stereoisomer thereof according to any one of Schemes 1 - 13:

[0049] wherein, R is selected from hydrogen, C 1-6 alkyl or hydroxy C 1-6 alkyl;

[0050] R 5 is selected from hydrogen or hydroxy C 1-6 alkyl.

[0051] Compound, pharmaceutically acceptable salt thereof or stereoisomer thereof according to any one of Schemes 1 - 13:

[0052] wherein, R is selected from C 1-4 alkyl or hydroxy C 1-4 alkyl;

[0053] R 5 is selected from hydroxy C 1-4 alkyl.

[0054] Compound, pharmaceutically acceptable salt thereof or stereoisomer thereof according to any one of Schemes 1 - 13:

[0055] wherein, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert - butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxyisobutyl or hydroxytert - butyl;

[0056] R 5 is selected from hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxyisobutyl or hydroxytert - butyl.

[0057] Compound, pharmaceutically acceptable salt thereof or stereoisomer thereof according to any one of Schemes 1 - 16:

[0058] wherein, ring A is selected from 5 - to 6 - membered heterocyclic group containing 2 O atoms;

[0059] Q is selected from hydroxy, amino, carboxyl, cyano, nitro, halogen or C 1-6 alkyl;

[0060] n is an integer from 0 to 4;

[0061] m is 0, 1 or 2.

[0062] Compound, pharmaceutically acceptable salt or stereoisomer thereof according to any one of Schemes 1-16:

[0063] Wherein, ring A is selected from a 6-membered heteroaryl group containing 2 O atoms;

[0064] Q is selected from hydroxy, amino, carboxy, cyano, nitro, halogen or C 1-4 alkyl;

[0065] n is an integer from 0 to 3;

[0066] m is 0, 1 or 2.

[0067] Compound, pharmaceutically acceptable salt or stereoisomer thereof according to any one of Schemes 1-16:

[0068] Wherein, ring A is selected from a 6-membered heteroaryl group containing 2 O atoms;

[0069] Q is selected from hydroxy, amino, carboxy, cyano, nitro, halogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;

[0070] n is 1, 2, 3;

[0071] m is 0, 1 or 2.

[0072] Compound, pharmaceutically acceptable salt or stereoisomer thereof according to any one of Schemes 1-19:

[0073] Wherein, R 1 is selected from -SO2R 5 or -SO2NRR 5 ;

[0074] R 2 , R 6 , R 7 are each independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, carboxy or C 1-6 alkyl, C 1-6 alkoxy;

[0075] R 3 is selected from a 5-6-membered nitrogen-containing heteroaryl group optionally substituted by 1-3 substituents W, or a 4-6-membered nitrogen-containing heterocyclic group optionally substituted by 1-2 substituents W; W is selected from hydroxy, amino, carboxy, cyano, nitro, halogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy;

[0076] R 4 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, C 1-6 alkoxy, C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy;

[0077] R is selected from hydrogen, C 1-6 alkyl or hydroxy-C 1-6 alkyl;

[0078] R 5 is selected from hydrogen or hydroxy-C 1-6 alkyl;

[0079] Ring A is selected from 5- to 6-membered heterocyclic groups containing 2 O atoms;

[0080] Q is selected from hydroxy, amino, carboxy, cyano, nitro, halogen or C 1-6 alkyl;

[0081] n is an integer from 0 - 4;

[0082] m is 0, 1 or 2.

[0083] Embodiment 21. A compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of Embodiments 1 - 20:

[0084] R 1 is selected from -SO2R 5 or -SO2NRR 5 ;

[0085] R 2 , R 6 , R 7 are each independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, carboxy, C 1-4 alkyl, C 1-4 alkoxy;

[0086] R 3 is selected from pyridyl, dihydropyridyl, tetrahydropyridyl, azetidinyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, pyrazolyl, dihydropyrazolyl, tetrahydropyrazolyl, imidazolyl, dihydroimidazolyl, tetrahydroimidazolyl, pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, piperidinyl, piperazinyl or morpholinyl optionally substituted by 1 - 2 substituents W;

[0087] R 4 is selected from halogen;

[0088] R is selected from C 1-4 alkyl or hydroxy-C 1-4 alkyl;

[0089] R5 Selected from hydroxy C 1-4 alkyl;

[0090] Ring A is selected from 6-membered heterocyclic groups containing 2 O atoms;

[0091] Q is selected from hydroxy, amino, carboxy, cyano, nitro, halogen or C 1-4 alkyl;

[0092] n is an integer from 0 to 3;

[0093] m is 0, 1 or 2.

[0094] Embodiment 22. A compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of Embodiments 1-21:

[0095] wherein, R 1 is selected from -SO2R 5 ;

[0096] R 2 , R 6 , R 7 are each independently selected from a hydrogen atom, a halogen atom, a nitro group, a cyano group, an amino group, a hydroxy group, a carboxy group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group;

[0097] R 3 is selected from pyridyl, dihydropyridyl, tetrahydropyridyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, azetidinyl, piperidyl, piperazinyl or morpholinyl;

[0098] R 4 is selected from a fluorine atom, a bromine atom or a chlorine atom;

[0099] R 5 is selected from hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxyisobutyl or hydroxytert-butyl;

[0100] Ring A is selected from 6-membered heterocyclic groups containing 2 O atoms;

[0101] Q is selected from hydroxy, amino, carboxy, cyano, nitro, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;

[0102] n is 1, 2, 3;

[0103] m is 0, 1 or 2.

[0104] Embodiment 23. A compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of Embodiments 1-22, having the structure represented by formula (II):

[0105]

[0106] Among them, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、Q, m, and ring A are defined as described in any one of the foregoing technical solutions.

[0107] Solution 23-1. The compound, its pharmaceutically acceptable salt or its stereoisomer as described in any one of Solutions 1-22 has the structure represented by formula (II'):

[0108]

[0109] Among them, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、Q, and m are defined as described in any one of the foregoing technical solutions.

[0110] Solution 24. The compound, its pharmaceutically acceptable salt or its stereoisomer as described in any one of Solutions 1-22 has the structure represented by formula (III):

[0111]

[0112] R 2 、R 3 、R 4 、R 6 、R 7 、ring A, Q, and m are defined as described in any one of the foregoing technical solutions.

[0113] Solution 25. The compound, its pharmaceutically acceptable salt or its stereoisomer as described in any one of Solutions 1-22 has the structure represented by formula (IV):

[0114]

[0115] Among them, R 2 、R 3 、R 4 、R 6 、R 7 、Q, and m are defined as described in any one of the foregoing technical solutions.

[0116] Solution 26. The compound, its pharmaceutically acceptable salt or its stereoisomer as described in any one of Solutions 1-22 has the structure represented by formula (V):

[0117]

[0118] Among them, R 2 , R 3 , R 4 are defined as described in any one of the foregoing technical solutions.

[0119] Solution 27. A compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described in any one of Solutions 1-26:

[0120] Among them, R 2 , R 6 , R 7 are each independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy;

[0121] R 3 is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

[0122] R 4 is selected from a fluorine atom, a bromine atom or a chlorine atom;

[0123] R 5 is selected from hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxyisobutyl or hydroxytert-butyl.

[0124] Some of the compounds in the embodiments of the present invention

[0125]

[0126] Detailed implementation manners

[0127] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the described embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0128] As used herein, the "halogen atom" includes a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.

[0129] As used herein, "C 1-6 alkyl" means a straight-chain or branched-chain alkyl containing 1-6 carbon atoms, including, for example, "C 1-4 alkyl", "C 1-3Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, and the like.

[0130] The “C 2-8 "Alkenyl" refers to a linear or branched or cyclic alkenyl group with 2 to 8 carbon atoms containing at least one double bond, including, for example, "C 2-6 Alkenyl", "C 2-4 Alkenyl", "C 2-3 Alkenyl", "C 3-6 Examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 1-methyl-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1,1-dimethyl-3-butenyl , 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-1-butenyl, 2-ethyl-1-butenyl, 2-ethyl-3-butenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 4-octenyl, 1,3-butadienyl, 2,4-pentadienyl, 1,4-hexadienyl, 2,4-hexadienyl, 1,5-heptadienyl, 2,5-heptadienyl, 2,6-octadienyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl, cycloheptenyl, 1,4-cycloheptadienyl, cyclooctenyl, etc.

[0131] The “C 2-8 "Alkynyl" refers to a straight or branched chain alkynyl group having 2 to 8 carbon atoms and containing a triple bond, including, for example, "C 2-6 Alkynyl", "C 2-4 Alkynyl", "C 2-3"Alkynyl", etc. Examples include, but are not limited to: ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1,1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, 2-heptynyl, 3-heptynyl, 4-methyl-2-hexynyl, 5-methyl-2-hexynyl, 2-methyl-3-hexynyl, 5-methyl-3-hexynyl, 2-methyl-4-hexynyl, 4-methyl-5-hexynyl, 2-octynyl, 3-octynyl, 4-octynyl, 4-methyl-2-heptynyl, 5-methyl-3-heptynyl, 6-methyl-3-heptynyl, 2-methyl-4-heptynyl, 2-methyl-5-heptynyl, 3-methyl-6-heptynyl, etc.

[0132] "C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonylamino, C 1-6 alkylaminosulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylcarbonyloxy" means a group formed in the manner of C 1-6 alkyl-O-, C 1-6 alkyl-NH-, (C 1-6 alkyl)2-N-, C 1-6 alkyl-C(O)-, C 1-6 alkyl-SO2NH-, C 1-6 alkyl-NHSO2-, C 1-6 alkyl-SO2-, C 1-6 alkyl-C(O)-O-, where the definition of "C 1-6 alkyl" is as described above.

[0133] "C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl)2amino, C 1-4 alkylcarbonyl, C 1-4 alkylsulfonylamino, C 1-4 alkylaminosulfonyl, C 1-4 alkylsulfonyl, C 1-4 alkylcarbonyloxy" means a group formed in the manner of C 1-4 alkyl-O-, C 1-4 alkyl-NH-, (C 1-4(alkyl)2-N-, C 1-4 alkyl-C(O)-, C 1-4 alkyl-SO2NH-, C 1-4 alkyl-NHSO2-, C 1-4 alkyl-SO2-, C 1-4 a group formed in the manner of alkyl-C(O)-O-, wherein "C 1-4 alkyl" is as defined above.

[0134] "halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, halo C 1-6 alkoxy" means a group formed by substituting one or more, for example 1-4, 1-3, 1-2 halogen atoms, hydroxy groups, amino groups, carboxyl groups, C 1-6 alkoxy for the hydrogen atoms of C 1-6 alkyl, C 1-6 alkoxy respectively.

[0135] "halo C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, halo C 1-4 alkoxy" means a group formed by substituting one or more, for example 1-4, 1-3, 1-2 halogen atoms, hydroxy groups, amino groups, carboxyl groups, C 1-4 alkoxy for the hydrogen atoms of C 1-4 alkyl, C 1-4 alkoxy respectively.

[0136] "3-8 membered cycloalkyl" as described herein means a monocyclic cyclic alkyl derived by removing one hydrogen atom from the alkane moiety of 3-8 carbon atoms, including for example "3-6 membered cycloalkyl", "4-7 membered cycloalkyl", "4-6 membered cycloalkyl", "5-6 membered cycloalkyl", etc. Examples include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl, dimethylcyclohexyl, etc.

[0137] As used herein, the "5- or 6-membered heteroaryl" refers to a heteroaryl having 5 to 6 ring atoms containing at least one heteroatom, said heteroatoms including nitrogen, oxygen, sulfur, etc., and also including the case where carbon atoms, nitrogen atoms and sulfur atoms are oxo-substituted. For example, it may be "5- or 6-membered heteroaryl containing 1 to 3 O, S and / or N", "5- or 6-membered heteroaryl containing 1 to 2 O, S and / or N", "5- or 6-membered nitrogen-containing heteroaryl", "5- or 6-membered heteroaryl containing 1 to 2 N".

[0138] Examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridone, 4-pyridone, pyrimidinyl, 1,4-dioxanyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl.

[0139] As used herein, the term "3- to 8-membered heterocyclic group" refers to a group obtained by removing one hydrogen atom from a saturated or partially saturated monocyclic heterocyclic compound containing 3 to 8 ring atoms and at least one heteroatom (e.g., 1, 2, 3, 4, or 5 heteroatoms). It includes, for example, "3- to 7-membered heterocyclic group", "3- to 6-membered heterocyclic group", "3- to 5-membered heterocyclic group", "4- to 7-membered heterocyclic group", "4- to 6-membered heterocyclic group", "4- to 5-membered heterocyclic group", "5- to 6-membered heterocyclic group", "5- to 7-membered heterocyclic group", "5- to 8-membered heterocyclic group", "6- to 7-membered heterocyclic group", "6- to 8-membered heterocyclic group", etc. For example, it can be: "4- to 6-membered nitrogen-containing heterocyclic group", "3- to 5-membered heterocyclic group containing 2 O, S, and / or N atoms", "6- to 8-membered heterocyclic group containing 1-2 O, S, and / or N atoms", "4- to 6-membered heterocyclic group containing 1-2 O, S, and / or N", "4- to 5-membered heterocyclic group containing 2 O, S, and / or N atoms", "6- to 7-membered heterocyclic group containing 1-2 O, S, and / or N atoms", "5-membered heterocyclic group containing 2 O, S, and / or N atoms", "6-membered heterocyclic group containing 1-2 O, S, and / or N atoms", "5-membered heterocyclic group containing 2 N atoms", "6-membered heterocyclic group containing 1-2 N atoms", "5-membered heterocyclic group containing 2 O atoms", "6-membered heterocyclic group containing 1-2 O atoms", "6-membered heterocyclic group containing 2 O atoms", "5- to 6-membered heterocyclic group containing 2 O atoms", "6-membered heterocyclic group containing 1 O, S, and / or N atom", "4- to 6-membered heterocyclic group containing 1-2 N atoms". A 3- to 8-membered partially saturated monocyclic heterocyclic group refers to a cyclic group containing a double bond and a heteroatom. A 3- to 8-membered saturated monocyclic heterocyclic group refers to a cyclic group containing a heteroatom with all saturated bonds. Examples include but are not limited to: aziridinyl, 2H-aziridinyl, diaziridinyl, 3H-diazirinyl, azetidinyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxadienyl, tetrahydrofuryl, dihydropyridyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, dihydropyrimidinyl, tetrahydropyrimidinyl, piperidinyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, 2H-1,2-oxazinyl, 6H-1,3-oxazinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-one, 3,4-dihydro-2H-pyranyl, 2,5-dihydrothienyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-4H-1,3-oxazinyl, 1,2,3,6-tetrahydropyridyl, 1,2,3,4-tetrahydropyridyl, 2,3,4,5-tetrahydropyridyl, etc., and preferably "5- to 6-membered heterocyclic group".

[0140] The "heteroatom" described herein refers to N, O, C(O), S, SO, and / or SO2, etc., preferably N, O, S, and more preferably N, O.

[0141] The "3-8 membered carbocyclic ring" described herein refers to a saturated, partially saturated or unsaturated monocyclic compound containing 3-8 carbon atoms. It includes, for example, "3-7 membered carbocyclic ring", "3-6 membered carbocyclic ring", "4-7 membered carbocyclic ring", "4-6 membered carbocyclic ring", "5-6 membered carbocyclic ring", etc. Examples include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl, cycloheptenyl, 1,4-cycloheptadienyl, cyclooctenyl, phenyl, etc. Preferably, it is a "5-6 membered saturated or partially saturated carbocyclic ring".

[0142] The "partially saturated" described herein means that the ring part includes at least one double bond or triple bond.

[0143] The embodiments of the present invention also provide a preparation method of the above compounds, but not limited to the following methods. The reaction equations are as follows:

[0144]

[0145] Step 1 Preparation of Intermediate 1, Intermediate 2, Intermediate 5, and Intermediate 7

[0146] Purchase or prepare Intermediate 1, Intermediate 2, Intermediate 5, and Intermediate 7.

[0147] Step 2 Preparation of Intermediate 3

[0148] Intermediate 1 is dissolved in a suitable solvent (such as N,N-dimethylformamide), Intermediate 2 and a basic substance (such as potassium carbonate) are added, and the mixture is heated (such as 70°C - 80°C) for reaction (such as 10 - 20 hours). After cooling to room temperature, the reaction is quenched with water, and the mixture is extracted with an organic solvent (such as ethyl acetate). The organic phase is washed with saturated brine, dried, concentrated, and purified by an appropriate method (such as silica gel column chromatography) to obtain Intermediate 3.

[0149] Step 3 Preparation of Intermediate 4

[0150] Intermediate 3 is dissolved in a suitable solvent (such as dichloromethane), an oxidizing agent (such as p-methoxyperbenzoic acid) is added, and the mixture is reacted (such as 10 - 20 hours). After washing, drying, and filtering, it is purified by an appropriate method (such as silica gel column chromatography) to obtain Intermediate 4.

[0151] Step 4 Preparation of Intermediate 6

[0152] Dissolve Intermediate 4 in a suitable solvent (e.g., N,N-dimethylformamide), add NaH under an ice bath, stir, add an organic solution of Intermediate 5 (e.g., N,N-dimethylformamide), react (e.g., for 10 - 20 hours), quench the reaction with water, extract with an organic solvent (e.g., ethyl acetate), dry, filter, and purify by a suitable method (e.g., silica gel column chromatography) to obtain Intermediate 6.

[0153] Preparation of Intermediate 8 in Step 5

[0154] Dissolve Intermediate 6, Intermediate 7 and an organic acid (e.g., p-toluenesulfonic acid) in a solvent (e.g., sec-amyl alcohol), react at 70°C - 80°C (e.g., for 10 - 20 hours), purify by a suitable method (e.g., silica gel column chromatography) or directly proceed to the next step.

[0155] Preparation of the compound of general formula (II) of the present invention in Step 6

[0156] Dissolve Intermediate 8 in a solvent (e.g., dichloromethane), add a desilylating reagent (e.g., tetrabutylammonium fluoride), react (e.g., for 10 - 20 hours), wash, dry, concentrate, and purify by a suitable method (e.g., silica gel column chromatography) to obtain the compound of general formula (II) of the present invention.

[0157] In the reaction equation, R 5‘ is such that the hydrogen in R 5 is replaced by tert-butyldiphenylchlorosilane, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and ring A are defined as in any one of the foregoing technical solutions.

[0158] An intermediate for preparing a compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof as shown in any one of the above technical solutions, having the following structure:

[0159]

[0160] Wherein, R 5‘ is such that the hydrogen in R 5 is replaced by tert-butyldiphenylchlorosilane, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and ring A are defined as in any one of the foregoing technical solutions.

[0161] "Stereoisomers" of the compounds of formula (I) herein refer to enantiomers that are generated when there are asymmetric carbon atoms in the compounds of formula (I), cis-trans isomers that are generated when there are carbon-carbon double bonds or cyclic structures in the compounds, and tautomers that are generated when there are ketones or oximes in the compounds. All enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of the compounds of formula (I) are included within the scope of the present invention.

[0162] If the compound obtained by synthesizing any of the compounds represented by the general formula (I) herein is a racemate, the desired enantiomerically pure compound can be obtained by chiral resolution methods: by chromatography with a chiral stationary phase (such as high-pressure preparative liquid chromatography, supercritical fluid chromatography). Chiral packings include, but are not limited to: Chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H.

[0163] The pharmaceutically acceptable salts of any of the compounds represented by the general formula (I) herein refer to salts prepared from pharmaceutically acceptable, non-toxic bases or acids, including organic acid salts, inorganic acid salts, organic base salts, and inorganic base salts.

[0164] The examples of the present invention further provide a pharmaceutical composition comprising any of the compounds represented by the above formula (I), its pharmaceutically acceptable salt or its stereoisomer and one or more pharmaceutical carriers and / or diluents, which can be made into any pharmaceutically acceptable dosage form. It is administered to a patient in need of such treatment by oral, parenteral, rectal or pulmonary administration, etc. When used for oral administration, it can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When making oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. When used for parenteral administration, it can be made into injections, including injection solutions, sterile powders for injection and concentrated solutions for injection. When making injections, it can be produced by conventional methods in the existing pharmaceutical field. When formulating injections, additives may not be added, or suitable additives can be added according to the properties of the drug. When used for rectal administration, it can be made into suppositories, etc. When used for pulmonary administration, it can be made into inhalants or sprays, etc.

[0165] Embodiments of the present invention further provide a pharmaceutical composition comprising any one of the compounds of formula (I) described above, a pharmaceutically acceptable salt thereof or a stereoisomer thereof and one or more other anti-tumor agents and / or immunosuppressants. The anti-tumor agent and / or immunosuppressant is an antimetabolite selected from capecitabine, gemcitabine, pemetrexed disodium; or the anti-tumor agent and / or immunosuppressant is a growth factor inhibitor selected from pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib; or the anti-tumor agent and / or immunosuppressant is an antibody selected from Herceptin, bevacizumab; or the anti-tumor agent and / or immunosuppressant is a mitotic inhibitor selected from paclitaxel, vinorelbine, docetaxel, doxorubicin; or the anti-tumor agent and / or immunosuppressant is an anti-tumor hormone selected from letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; or the anti-tumor agent and / or immunosuppressant is an alkylating agent selected from cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, carmustine, temozolomide; or the anti-tumor agent and / or immunosuppressant is a metal platinum compound selected from carboplatin, cisplatin, oxaliplatin; or the anti-tumor agent and / or immunosuppressant is an immunosuppressive agent selected from everolimus, sirolimus, tacrolimus; or the anti-tumor agent and / or immunosuppressant is a purine analogue selected from 6-mercaptopurine, 6-thioguanine, azathioprine; or the anti-tumor agent and / or immunosuppressant is an antibiotic selected from actinomycin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, plicamycin; or the anti-tumor agent and / or immunosuppressant is a platinum complex selected from cisplatin, carboplatin; or the anti-tumor agent and / or immunosuppressant is an adrenocortical inhibitor selected from aminoglutethimide; or the anti-tumor agent and / or immunosuppressant is an enzyme inhibitor selected from cytarabine, methotrexate, hydroxyurea, hydroxycamptothecin, camptothecin, topotecan, irinotecan.

[0166] Embodiments of the present invention also provide the use of the compound shown in formula (I) herein, its pharmaceutically acceptable salt or its stereoisomer in the preparation of a medicament for treating and / or preventing ALK-mediated cancer or non-cancer related diseases, wherein the cancer-related diseases are selected from brain tumors, lung cancer, non-small cell lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, hepatoblastoma, papillary renal cell carcinoma, head and neck squamous cell carcinoma, Wilms tumor, renal cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, non-Hodgkin lymphoma, central nervous system tumors, female genital tract cancer, carcinoma in situ, lymphoma, neuroblastoma, neurofibromatosis, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small cell lung cancer, gastrointestinal stromal tumors, prostate tumors, mast cell tumors, multiple myeloma, melanoma, glioma, astrocytoma, neuroblastoma, sarcoma or glioblastoma; non-cancer related diseases, selected from benign hyperplasia of the skin or prostate.

[0167] The compounds provided by the embodiments of the present invention have the following advantages:

[0168] (1) The compound of formula (I) herein, its pharmaceutically acceptable salt or its stereoisomer has excellent ALK / ROS1 inhibitory activity, and has good inhibitory activity against cells such as NCI-H3122, NCI-H2228, Karpas-299, etc.;

[0169] (2) The compound of formula (I) herein, its pharmaceutically acceptable salt or its stereoisomer shows good biological stability, has a longer-lasting effect and high bioavailability;

[0170] (3) The preparation process of the compound provided by the embodiments of the present invention is simple, the drug purity is high, the quality is stable, and it is easy to carry out large-scale industrial production.

[0171] The beneficial effects of the compounds provided by the embodiments of the present invention are further elaborated through experiments below, but this should not be understood as the compounds provided by the embodiments of the present invention only having the following beneficial effects.

[0172] The meanings represented by the abbreviations in the following experiments are as follows:

[0173] DMSO: Dimethyl sulfoxide

[0174] DTT: DL-Dithiothreitol

[0175] ALK: Anaplastic Lymphoma Kinase

[0176] HEPES: 4-Hydroxyethylpiperazineethanesulfonic acid

[0177] Brij-35: Dodecyl Polyglycol Ether

[0178] EDTA: Ethylenediaminetetraacetic acid

[0179] The full English name comes from the kit instructions

[0180] In vitro ALK / ROS kinase inhibition activity experiment of the compound provided by the embodiment of the present invention in Experimental Example 1

[0181] Test sample: the compound provided in the examples of the present invention. For its chemical name and preparation method, please refer to the preparation example of each compound.

[0182] Experimental Methods: Inhibitory activity of ALK and ROS kinases was measured using the Caliper Mobility Shift method

[0183] 1.1x kinase buffer preparation:

[0184] Take HEPES at pH 7.5, Brij-35 at a concentration of 30%, MgCl2 solution at a mother solution concentration of 1M, and DTT at a mother solution concentration of 1M respectively, add ultrapure water and mix well to make the final concentration of HEPES to 50mM, the final concentration of Brij-35 to 0.0015%, the final concentration of MgCl2 to 10mM, and the final concentration of DTT to 2mM.

[0185] 2. Preparation of Stop Solution

[0186] Take coating solution Coating Reagent #3 with a stock concentration of 4% (the coating solution comes with the 12-sipper chip used by the Caliper instrument), HEPES with a stock concentration of 1000mM pH 7.5, EDTA with a stock concentration of 0.5M, and Brij-35 with a stock concentration of 30%, add ultrapure water and mix well to make the final concentration of Coating Reagent #3 0.2%, the final concentration of HEPES 100mM, the final concentration of EDTA 50mM, and the final concentration of Brij-35 0.015%.

[0187] Preparation of 3.5 times the test solution:

[0188] Preparation of DMSO stock solution of test samples: Weigh appropriate amount of compound respectively, add appropriate amount of DMSO to dissolve, mix well and set aside.

[0189] Take the DMSO stock solution of the test sample and dilute it with DMSO to make a solution with a concentration of 50 μM as the stock solution. Dilute the stock solution four times with DMSO, and then dilute each concentration 10 times with 1x kinase buffer to make a 5x test sample solution.

[0190] 4. Preparation of various other reagents

[0191] Prepare the required 2.5-fold ALK kinase solution and 2.5-fold polypeptide solution with 1-fold kinase buffer respectively for standby use.

[0192] 5. Enzymatic reaction:

[0193] 1) Add 5 μL of the prepared 5-fold test article solution and 10 μL of the prepared 2.5-fold kinase solution to the corresponding wells in a 384-well plate, and incubate at room temperature for 10 minutes.

[0194] 2) Then add 10 μL of the prepared 2.5-fold polypeptide solution to the corresponding wells respectively, so that the final concentrations of the test substances are 1000 nM, 250 nM, 63 nM, 16 nM, 4 nM, 1 nM, 0.2 nM, 0.1 nM, 0.02 nM, and 0.004 nM. Start the enzymatic reaction and incubate at 28 °C for 1 hour.

[0195] 6. Enzymatic detection:

[0196] Add 25 μL of the termination solution to each corresponding well to terminate the reaction. Read the data with a Caliper instrument and calculate the inhibition rate through the data.

[0197] Inhibition rate (%) = (maximum value - sample value) / (maximum value - minimum value) × 100. Use XLFIT software for curve fitting to obtain the IC50 value.

[0198] Maximum value: positive control without test substance, minimum value: negative control without enzyme.

[0199] Experimental results and conclusions:

[0200] Table 1 In vitro enzymatic inhibition activities of the compounds provided in the examples of the present invention

[0201]

[0202] The test results show that the compounds provided in the examples of the present invention have good inhibitory activities against both ALK kinase and ROS kinase, and can be used for the treatment of diseases related to ALK kinase and ROS kinase, especially ALK kinase- and ROS kinase-mediated disorders or conditions, with significant clinical significance.

[0203] The above content of the present invention will be further described in detail below through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

[0204] The definitions represented by the following abbreviations are as follows:

[0205] DMF: N,N - dimethylformamide

[0206] Example 1 Preparation of 2 - ((2 - ((5 - chloro - 2 - ((7 - methyl - 8 - (piperidin - 4 - yl)-2,3 - dihydrobenzo[b][1,4]dioxin - 5 - yl)amino)pyrimidin - 4 - yl)amino)phenyl)sulfonyl)propan - 1 - ol (Compound 4)

[0207] 1. Preparation of 1 - ((tert - butyldiphenyl)silyloxy)propan - 2 - ol

[0208]

[0209] Dissolve 1,2 - propanediol (3.0 g, 39.5 mmol) in DMF (50 mL), add tert - butyldiphenylchlorosilane (11.9 g, 43.4 mmol) and imidazole (5.4 g, 79 mmol), and react at 25 °C for 16 h. Add 100 mL of water, extract with ethyl acetate (100 mL×3), combine the organic phases, wash the organic phase with saturated brine (200 mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain the title compound (12.3 g, yield 99.2%).

[0210] 2. Preparation of 1 - ((tert - butyldiphenyl)silyloxy)propan - 2 - yl methanesulfonate

[0211]

[0212] Dissolve 1 - ((tert - butyldiphenyl)silyloxy)propan - 2 - ol (12.3 g, 39 mmol) in dichloromethane (200 mL), add triethylamine (7.8 g, 77.1 mmol), and dropwise add methanesulfonyl chloride (5.4 g, 47.1 mmol) at 0 °C. After the addition is complete, react at 25 °C for 2 h. After the reaction is complete, add 200 mL of water, extract with dichloromethane (100 mL×3), combine the organic phases, wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the title compound (13 g, yield 85.0%).

[0213] 3. Preparation of 2 - ((1 - ((tert - butyldiphenyl)silyloxy)propan - 2 - yl)thio)aniline

[0214]

[0215] 1-((tert-Butyldiphenyl)oxy)propan-2-yl methanesulfonate (13 g, 33 mmol) was dissolved in DMF (200 mL), 2-aminobenzenethiol (4.5 g, 36 mmol) and potassium carbonate (9.1 g, 66 mmol) were added, and the mixture was heated to 80 °C and reacted for 16 hours. After the reaction was completed, it was cooled to room temperature, 200 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (12.6 g, yield 90.6%).

[0216] Preparation of 4.2-((1-((tert-Butyldiphenyl)oxy)propan-2-yl)sulfonyl)aniline

[0217]

[0218] 2-((1-((tert-Butyldiphenyl)oxy)propan-2-yl)thio)aniline (12.6 g, 29.9 mmol) was dissolved in dichloromethane (200 mL), meta-chloroperoxybenzoic acid (12.8 g, 74.4 mmol) was added, and the mixture was reacted at 25 °C for 16 hours. After the reaction was completed, it was washed with water (150 mL × 3), saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (10 g, yield 73.5%).

[0219] 5.Preparation of N-(2-((1-((tert-Butyldiphenyl)oxy)propan-2-yl)sulfonyl)phenyl)-2,5-dichloropyrimidin-4-amine

[0220]

[0221] 2-((1-((tert-Butyldiphenyl)oxy)propan-2-yl)sulfonyl)aniline (10 g, 22 mmol) was dissolved in DMF (100 mL), NaH (1.77 g, 44 mmol, 60%) was slowly added under ice bath, and the mixture was stirred for half an hour. Then a solution of 2,4,5-trichloropyrimidine (6 g, 33 mmol) in DMF (50 mL) was slowly added dropwise, and the mixture was reacted at 25 °C for 16 hours. After the reaction was completed, 200 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to obtain the crude product, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (3 g, yield 22.7%).

[0222] 6.N 4-(2-((1-((tert-Butyldiphenyl)oxy)propan-2-yl)sulfonyl)phenyl)-5-chloro-N 2 Preparation of -(7-Methyl-8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrimidine-2,4-diamine

[0223] tert-Butyl 4-(8-amino-6-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate (270 mg, 0.77 mmol, preparation method see ZL201580052631.0), N-(2-((1-((tert-butyldiphenyl)oxy)propan-2-yl)sulfonyl)phenyl)-2,5-dichloropyrimidin-4-amine (462 mg, 0.77 mmol) and p-toluenesulfonic acid (137 mg, 0.8 mmol) were dissolved in sec-amyl alcohol (20 mL), and the reaction was carried out at 80 °C for 16 hours. After the reaction was completed, it was concentrated and directly subjected to the next step without purification.

[0224] Preparation of 7.2-((2-((5-chloro-2-((7-methyl-8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)pyrimidin-4-yl)amino)phenyl)sulfonyl)propan-1-ol

[0225]

[0226] The crude product of the previous step of N 4 -(2-((1-((tert-Butyldiphenyl)oxy)propan-2-yl)sulfonyl)phenyl)-5-chloro-N 2 -(7-methyl-8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrimidine-2,4-diamine was dissolved in dichloromethane (20 mL), tetrabutylammonium fluoride (402 mg, 1.54 mmol) was added, and the reaction was carried out at 25 °C for 16 hours. After the reaction was completed, it was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The title compound (49 mg, two-step yield 11.1%) was obtained by silica gel column chromatography (dichloromethane:methanol = 10:1).

[0227] Molecular formula: C 27 H 32 ClN5O5S Molecular weight: 574.1 LC-MS (m / z): 574.2 [M + H] +

[0228] 1H-NMR (400 MHz, MeOD) δ: 8.49 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 7.95 (dd, J = 1.2 Hz, J = 8.0 Hz, 1H), 7.66 (t, J = 7.2 Hz, 1H), 7.32 - 7.36 (m, 2H), 4.29 (s, 4H), 3.86 (d, J = 4.8 Hz, 1H), 3.70 - 3.72 (m, 1H), 3.3 - 3.48 (m, 3H), 3.01 - 3.14 (m, 3H), 2.50 - 2.53 (m, 2H), 2.20 (s, 3H), 1.78 - 1.83 (m, 2H), 1.26 (d, J = 7.2 Hz, 3H).

[0229] The above are only exemplary embodiments of the present invention and are not intended to limit the scope of protection of the present invention. The scope of protection of the present invention is determined by the appended claims.

Claims

1. A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: Wherein, R 1 selected from -SO2R 5 or -SO2NRR 5 ; R 2 、R 6 、R 7 are each independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, carboxy, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl; R 3 selected from a 5- to 6-membered heteroaryl optionally substituted with 1 to 3 substituents W, or a 3- to 8-membered heterocyclic group optionally substituted with 1 to 3 substituents W; or R 2 and R 7 together with the carbon atom to which it is attached forms a 5- or 6-membered cycloalkyl, 5- or 6-membered heterocyclic group, phenyl or 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents W1; or R 2 and R 3 together with the attached carbon atom form a 5- or 6-membered cycloalkyl, 5- or 6-membered heterocyclic group, phenyl or 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents W2; R 4 selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkoxy, C 1-6 alkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylcarbonyl or C 1-6 alkylcarbonyloxy; or R 4 and R 6 together with the carbon atom to which it is attached forms a 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl optionally substituted by 1 to 3 substituents W3; W, W1, W2, and W3 are each independently selected from hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkylsulfonamido, C 1-6 alkylaminosulfonyl or C 1-6 alkylsulfonyl; R is selected from hydrogen, C 1-6 alkyl, hydroxy C 1-6 alkyl or a 3- to 8-membered carbocyclic ring; R 5 selected from hydrogen, hydroxy C 1-6 alkyl or a 3- to 8-membered carbocyclic ring; Ring A is selected from 5- to 6-membered heterocyclic groups containing 2 O, S, and / or N atoms; Q is selected from a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen, C 1-6 alkyl, C 1-6 alkoxy; n is an integer from 0 to 5; m is 0, 1, or 2.

2. The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: Wherein, R 1 selected from -SO2R 5 or -SO2NRR 5 ; R 2 、R 6 、R 7 are each independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, carboxy or C 1-6 alkyl, C 1-6 alkoxy; R 3 selected from a 5- or 6-membered nitrogen-containing heteroaryl optionally substituted with 1 to 3 substituents W, or a 4- to 6-membered nitrogen-containing heterocyclic group optionally substituted with 1 or 2 substituents W; W is selected from hydroxy, amino, carboxy, cyano, nitro, a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy; R 4 Selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, C 1-6 alkoxy, C 1-6 alkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy; R is selected from hydrogen, C 1-6 alkyl or hydroxy C 1-6 alkyl; R 5 Selected from hydrogen or hydroxy C 1-6 alkyl; Ring A is selected from 5- to 6-membered heterocyclic groups containing 2 O atoms; Q is selected from a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen, or a C 1-6 alkyl group; n is an integer from 0 to 4; m is 0, 1, or 2.

3. The compound according to claim 2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: Wherein, R 1 selected from -SO2R 5 or -SO2NRR 5 ; R 2 、R 6 、R 7 are each independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, carboxy, C 1-4 alkyl or C 1-4 alkoxy; R 3 selected from pyridyl, dihydropyridyl, tetrahydropyridyl, azetidinyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, pyrazolyl, dihydropyrazolyl, tetrahydropyrazolyl, imidazolyl, dihydroimidazolyl, tetrahydroimidazolyl, pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, piperidinyl, piperazinyl or morpholinyl, which is optionally substituted by one or two substituents W; R 4 selected from halogens; R is selected from C 1-4 alkyl or hydroxy C 1-4 alkyl; R 5 Selected from hydroxy C 1-4 alkyl; Ring A is selected from 6-membered heterocyclic groups containing 2 O atoms; Q is selected from a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen, or a C 1-4 alkyl group; n is an integer from 0 to 3; m is 0, 1, or 2.

4. The compound according to claim 3, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: Wherein, R 1 selected from -SO2R 5 ; R 2 、R 6 、R 7 are each independently selected from a hydrogen atom, a halogen atom, a nitro group, a cyano group, an amino group, a hydroxyl group, a carboxyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group; R 3 selected from pyridyl, dihydropyridyl, tetrahydropyridyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, azetidinyl, piperidyl, piperazinyl or morpholinyl; R 4 selected from a fluorine atom, a bromine atom or a chlorine atom; R 5 selected from hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxyisobutyl or hydroxytert-butyl; Ring A is selected from 6-membered heterocyclic groups containing 2 O atoms; Q is selected from hydroxy, amino, carboxy, cyano, nitro, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; n is 1, 2, 3; m is 0, 1, or 2.

5. The compound according to any one of claims 1-4, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which has the structure represented by formula (II): Among them, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、Q, m, and the definition of ring A are as described in any one of claims 1-4.

6. The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound is selected from:

7. A pharmaceutical preparation prepared from the compound according to any one of claims 1-6, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more pharmaceutical carriers and / or diluents, which is any pharmaceutically acceptable dosage form.

8. A pharmaceutical composition containing the compound according to any one of claims 1-6, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and further containing one or more anti-tumor agents and / or immunosuppressive agents.

9. Use of the compound according to any one of claims 1-6, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, the pharmaceutical preparation according to claim 7, and the pharmaceutical composition according to claim 8 in the preparation of a drug for treating and / or preventing ALK-mediated cancer or non-cancerous related diseases, wherein the cancer-related diseases are selected from brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, non-Hodgkin lymphoma, central nervous system tumor, prostate cancer, thyroid cancer, small cell lung cancer, female genital tract cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, colon cancer, testicular cancer, non-small cell lung cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma, astrocytoma, neuroblastoma, sarcoma; the non-cancerous related diseases are selected from benign hyperplasia of the skin or prostate.

10. An intermediate for preparing the compound according to any one of claims 1-6, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which has the following structure: Among them, R 5’ is R 5 in which the hydrogen is replaced by tert-butyldiphenylchlorosilane, X is selected from halogens, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, m and ring A are as defined in any one of claims 1-6.

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