Four-membered fused ring compounds and methods for their preparation and use

Abstract

The present invention relates to 4-membered fused ring compounds, and methods for their preparation and use, in particular to 4-membered fused ring compounds, methods for their preparation and pharmaceutical compositions containing therapeutically effective amounts of said compounds and their use as tyrosine kinase inhibitors, in particular in the preparation of medicaments that inhibit the tyrosine kinase activity of a protein selected from the group consisting of the ABL1 protein, the ABL2-related proteins and the chimeric protein BCR-ABL1. TIFF2024534707000043.tif47164

Description

[Technical field]

[0001] The present invention relates to the field of medical biology, specifically to a 4-membered fused ring compound, and its preparation method and use.The present invention further relates to the use of its pharmaceutically acceptable salt and pharmaceutical composition in the treatment of cancer and other related diseases. [Background technology]

[0002] The tyrosine kinase activity of the ABL1 protein is normally tightly regulated, in which the N-terminal capping region of the SH3 domain plays a key role. One of the control mechanisms involves myristoylation of the N-terminal capping glycine 2 residue, which in turn interacts with the myristic acid binding site of the SH1 catalytic domain. A marker of chronic myeloid leukemia (CML) is the Philadelphia chromosome (Ph), which is formed by a reciprocal translocation of the t(9,22) chromosome in hematopoietic stem cells. This chromosome harbors the BCR-ABL1 oncogene, which encodes a chimeric BCR-ABL1 protein lacking the N-terminal cap and with a constitutively active tyrosine kinase domain. Tyrosine kinase inhibitors (TKIs) of the BCR-ABL1 protein are the standard of care for CML patients, and imatinib, nilotinib, and dasatinib are approved for the treatment of newly diagnosed CML patients.

[0003] However, some patients develop drug-resistant clones in which mutations in the SHI domain impair inhibitor binding. Although both nilotinib and dasatinib retain efficacy against many imatinib-resistant variants of BCR-ABL1, a mutation in which the threonine 315 residue is replaced by isoleucine (T315I) is insensitive to all three drugs and may be responsible for treatment resistance in CML patients. Thus, inhibition of BCR-ABL1 mutations such as T315I remains an unmet medical need. In addition to CML, the BCR-ABL1 fusion protein also causes a certain proportion of acute lymphoblastic leukemia. Agents targeting ABL kinase activity can also be used for this indication. Thus, there is a clinical need for more BCR-ABL1 inhibitors. Summary of the Invention

[0004] The object of the present invention is to provide a compound represented by formula (I), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, [ka] During the ceremony, Ring A is C 3~6 Cycloalkyl, 4-7 membered heterocyclyl, C 6~10 aryl or 5- to 7-membered heteroaryl; R1 is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Alkylthio or C 1~6 haloalkoxy; M1 is N or CR a is selected from M2 is NR a or C(R a )2 is selected, M3 is N or CR a is selected from R a are each independently hydrogen, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Alkylthio or C 1~6 haloalkoxy; R2 and R3 each independently represent hydrogen, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~6 Haloalkoxy, C 3~6 Cycloalkyl, 4-7 membered heterocyclyl, C 6~10 aryl or 5- to 7-membered heteroaryl; n is 0, 1, or 2.

[0005] In a preferred embodiment of the present invention, there is provided a compound of formula (I), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, wherein: Ring A is C 6~10 aryl or 5- to 6-membered heteroaryl; R1 is C 1~3 Alkyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 13 Alkylthio or C 1~3 haloalkoxy; M1 is selected from N or CH; M2 is selected from NH or CH2; M3 is selected from N or CH; R2 or R3 are each independently C 1~3 Alkyl, C 1~3Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Alkylthio or C 1~3 haloalkoxy.

[0006] In a preferred embodiment of the present invention, the compound of formula (I) is further as described in general formula (II): [ka]

[0007] In a preferred embodiment of the present invention, the compound of formula (I) is further as illustrated by general formula (II-a). [ka]

[0008] In a preferred embodiment of the present invention, the compound of formula (I) is further as illustrated by general formula (II-b). [ka]

[0009] In a more preferred embodiment of the present invention, ring A is phenyl or pyridyl; R1 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy or C 1~3 haloalkoxy; M1 is N; M2 is NH; M3 is N; R2 and R3 each independently represent hydrogen, C 1~3 Alkyl or C 1~3 haloalkyl.

[0010] In a further preferred embodiment of the invention, R1 is selected from -CF2, -CF3, -CF2Cl, -OCF2, -OCF3 or -OCF2Cl; Each of R2 or R3 is independently selected from -CH3, -CF2, -CF3, or -CF2Cl.

[0011] Further preferred embodiments of the present invention include the following specific compounds: [ka]

[0012] In a preferred embodiment of the invention, the pharma- ceutically acceptable salt is selected from sulfate, hydrochloride, ethylsulfonate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, hydroxyethylsulfonate or 1,5-naphthalenedisulfonate, more preferably p-toluenesulfonate.

[0013] In another aspect, the present invention provides a toluenesulfonate compound represented by formula (III): [ka] During the ceremony, Ring A is C 3~6 Cycloalkyl, 4-7 membered heterocyclyl, C 6~10 aryl or 5- to 7-membered heteroaryl; R1 is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Alkylthio or C 1~6 haloalkoxy; M1 is N or CR a is selected from M2 is NRa or C(R a )2 is selected, M3 is N or CR a is selected from R a are each independently hydrogen, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Alkylthio or C 1~6 haloalkoxy; R2 and R3 each independently represent hydrogen, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~6 Haloalkoxy, C 3~6 Cycloalkyl, 4-7 membered heterocyclyl, C 6~10 aryl or 5- to 7-membered heteroaryl; n is 0, 1, or 2.

[0014] In a preferred embodiment of the present invention, ring A is 6~10 aryl or 5- to 6-membered heteroaryl; R1 is C 1~3 Alkyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 13 Alkylthio or C 1~3 haloalkoxy; M1 is selected from N or CH; M2 is selected from NH or CH2; M3 is selected from N or CH; R2 or R3 are each independently C 1~3 Alkyl, C 1~3 Deuterated alkyl, C1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Alkylthio or C 1~3 haloalkoxy.

[0015] In a preferred embodiment of the present invention, formula (III) is further as described in general formula (IV) or (IV-a): [ka]

[0016] In a preferred embodiment of the invention, ring A is phenyl or pyridyl; R1 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy or C 1~3 haloalkoxy; M1 is N; M2 is NH; M3 is N; R2 and R3 each independently represent hydrogen, C 1~3 Alkyl or C 1~3 haloalkyl.

[0017] In a preferred embodiment of the invention, R1 is selected from -CF2, -CF3, -CF2Cl, -OCF2, -OCF3 or -OCF2Cl; R2 or R3 are each independently selected from -CH3, -CH2CH3, -CF2, -CF3, or -CF2Cl.

[0018] In a preferred embodiment of the invention, the p-toluenesulfonate salt is selected from the following compounds: [ka] [ka]

[0019] It is a further object of the present invention to provide a process for preparing a compound of formula (II), its stereoisomer or a pharma- ceutically acceptable salt thereof, comprising the steps of: [ka] wherein compound 1 and compound 2 are substituted to prepare compound 3, compound 5 is prepared under the action of boronic acid compound 4, compound 5 is adjusted to cyclic compound 6 under acidic conditions, which is then condensed with compound 7 to prepare compound (II), its stereoisomer or its pharma- ceutically acceptable salt; Optionally, compound (II) is reacted with an acid to prepare a salt compound; X is selected from halogens; The definitions of ring A, R1 to R3, and M1 to M3 are as defined in formula (II). The acid is preferably p-toluenesulfonic acid.

[0020] It is a further object of the present invention to provide a process for preparing a compound of formula (II), its stereoisomer or a pharma- ceutically acceptable salt thereof, comprising the steps of: [ka] Compound 1-a is substituted with compound 2 to prepare compound 3-a, which is reacted with 3-b to prepare compound 5-a, compound 6-a is prepared from compound 5-a under the action of boronic acid compound 4, and compound 6-a and compound 7 are condensed to prepare compound (II); Optionally, compound (II) is reacted with an acid to prepare a salt compound; X1, X2 and X3 are each independently selected from halogen; The definitions of ring A, R1 to R3, and M1 to M3 are as defined in formula (II), and preferably, M3 is N. The acid is preferably p-toluenesulfonic acid.

[0021] It is a further object of the present application to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers or excipients.

[0022] The present invention further provides the use of the compounds of formula (I), their stereoisomers or pharma- ceutically acceptable salts thereof, and pharmaceutical compositions in the preparation of a medicament for inhibiting the tyrosine kinase enzymatic activity of a protein selected from Abelson protein (ABL1), Abelson-related protein (ABL2) and the chimeric protein BCR-ABL1.

[0023] The present invention further provides the use of a compound of formula (I), its stereoisomer or a pharma- ceutically acceptable salt thereof, and pharmaceutical composition thereof, in the preparation of a medicament for the treatment of a leukemia-related disease.

[0024] In a preferred embodiment of the invention, the leukemia is chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), or acute lymphoblastic leukemia (ALL).

[0025] In a more preferred embodiment of the invention, the CML is refractory to treatment with one or more standard therapies, such as imatinib, nilotinib and dasatinib, and the AML is secondary AML developing after myelodysplastic syndrome (MDS) or myeloproliferative disorder (MPN).

[0026] Detailed Description of the Invention Terms used in the specification and claims have the following meanings unless otherwise specified.

[0027] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 8 carbon atoms, more preferably an alkyl group of from 1 to 6 carbon atoms, and most preferably an alkyl group of from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof.More preferred are lower alkyls containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl may be substituted or unsubstituted, and if substituted, the substituent may be substituted at any available point of attachment. The substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate. In the present invention, methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxyl-substituted alkyl are preferred.

[0028] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 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 monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, and polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0029] The term "spirocycloalkyl" refers to a 5-20 membered polycyclic group in which the monocyclic rings share a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably, it is 6-14 membered, more preferably 7-10 membered. Depending on the number of spiro atoms shared between the rings, spirocycloalkyls are divided into monospirocycloalkyls, bispirocycloalkyls or polyspirocycloalkyls, preferably monospirocycloalkyls and bispirocycloalkyls. More preferably, they are 3-membered / 6-membered, 3-membered / 5-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospirocycloalkyls. Non-limiting examples of spirocycloalkyls include: [ka]

[0030] Also included are monospirocycloalkyls and spirocycloalkyls where the heterocycloalkyls share a spiro atom, non-limiting examples include: [ka]

[0031] The term "fused cycloalkyl" refers to a 5-20 membered all-carbon polycyclic group, where each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, and one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably, it is 6-14 membered, more preferably 7-10 membered. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl include: [ka]

[0032] The term "bridged cycloalkyl" refers to a 5-20 membered all-carbon polycyclic group, in which any two rings share two carbon atoms that are not directly bonded, and may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably, it has 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include: [ka]

[0033] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, in which one or more of the ring atoms is selected from the group consisting of nitrogen, oxygen, C(O) or S(O). m(m is an integer of 0 to 2), but the remaining ring atoms are carbon, except for the -OO-, -OS-, or -SS- ring moiety. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably contains 3 to 8 ring atoms, most preferably contains 3 to 8 ring atoms, and even more preferably is a 3-8 membered heterocyclyl containing 1 to 3 nitrogen atoms, and is optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups. It includes nitrogen-containing monocyclic heterocyclyl, nitrogen-containing spiroheterocyclyl, and nitrogen-containing fused heterocyclyl.

[0034] Non-limiting examples of monocyclic heterocyclyls include oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl, or tetrahydrothiopyranyl dioxide, and the like; preferably, oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl, or tetrahydrothiopyranyl dioxide, and the like. and more preferably piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, oxetanyl or azetidinyl. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls, which are optionally connected to other groups via single bonds or further connected to other cycloalkyls, heterocyclyls, aryls and heteroaryls via any two or more atoms on the ring.

[0035] The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group in which a single ring shares one atom (called a spiro atom) and one or more of the ring atoms is a nitrogen, oxygen, or S(O) atom. m (m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 5-12 membered, more preferably 7-10 membered. Depending on the number of spiro atoms shared between the rings, spiroheterocyclyl is divided into monospiroheterocyclyl, bispiroheterocyclyl or polyspiroheterocyclyl, preferably monospiroheterocyclyl and bispiroheterocyclyl. More preferably, it is 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include: [ka]

[0036] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and one or more ring atoms is nitrogen, oxygen, or S(O) m (m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6-14 membered, more preferably 7-10 membered. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl include: [ka]

[0037] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, and may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and one or more ring atoms is not nitrogen, oxygen, or S(O) m (m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 6 to 10-membered. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyls, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyls include: [ka]

[0038] The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, where the ring connected to the parent structure is a heterocyclyl, non-limiting examples of which include: [ka]

[0039] A heterocyclyl may be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0040] The term "aryl" refers to a 6- to 14-membered, preferably 6- to 10-membered, all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, such as phenyl and naphthyl. More preferably, it is phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo-3- to 8-membered cycloalkyl, benzo-3- to 8-membered heteroalkyl, preferably benzo-3- to 6-membered cycloalkyl, benzo-3- to 6-membered heteroalkyl, heterocyclyl is a heterocyclic group containing 1 to 3 nitrogen, oxygen and sulfur atoms, or also including a 3-membered nitrogen-containing fused ring containing a benzene ring, and the ring connected to the parent structure is an aryl ring.

[0041] Aryl may be substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0042] The term "heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms, the heteroatoms being selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5-10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl, more preferably pyrazolyl and oxazolyl. Heteroaryl rings may be fused to aryl, heterocyclyl, or cycloalkyl rings, where the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include: [ka]

[0043] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. An alkoxy may be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0044] The term "haloalkyl" refers to an alkyl substituted with one or more halogens, where alkyl is defined above.

[0045] The term "haloalkoxy" refers to an alkoxy substituted with one or more halogens, where alkoxy is as defined above.

[0046] The term "hydroxyalkyl" refers to an alkyl substituted with a hydroxyl, where alkyl is as defined above.

[0047] The term "alkylthio" refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkylthio include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, and cyclohexylthio. Alkylthio can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0048] "Alkenyl" refers to alkenyl, also known as alkylene group, which is a straight or branched chain group containing 2 to 20 carbon atoms, preferably an alkenyl containing 2 to 8 carbon atoms, more preferably an alkenyl containing 2 to 6 carbon atoms, and most preferably an alkenyl containing 2 to 4 carbon atoms. Alkenyl may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0049] The term "alkynyl" refers to straight or branched chain groups containing 2 to 20 carbon atoms, preferably alkynyl containing 2 to 8 carbon atoms, more preferably alkynyl containing 2 to 6 carbon atoms, and most preferably alkynyl containing 2 to 4 carbon atoms. Alkynyl may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0050] "Hydroxyl" refers to the -OH group.

[0051] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0052] "Amino" refers to -NH2.

[0053] "Cyano" refers to -CN.

[0054] "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" are different expressions that mean the same thing, that is, X is one or more of A, B, and C.

[0055] A hydrogen atom described in the present invention can be replaced with its deuterium isotope, and any hydrogen atom in the exemplary compounds involved in the present invention can also be replaced with a deuterium atom.

[0056] "Optional" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "a heterocyclic group optionally substituted with an alkyl" means that the alkyl may, but does not have to, be present, and includes cases where the heterocyclic group is substituted with an alkyl and cases where the heterocyclic group is not substituted with an alkyl.

[0057] By "substituted" is meant that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced with the corresponding number of substituents. Needless to say, the substituents are present only at possible chemical positions, and the skilled artisan can determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond (such as an olefinic bond). Optional substituents include one or more of deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~6 Haloalkoxy, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl.

[0058] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / pharmaceutical acceptable salts or prodrugs with other chemical components and other components such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living body and promote absorption of the active ingredient to exert a biological activity.

[0059] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is safe and effective when used in mammals and possesses the desired biological activity. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0060] The invention will be further described below with reference to examples which should not be construed as limiting the scope of the invention.

[0061] Example 1 (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide p-toluenesulfonate [ka] Method 1: Step 1: Synthesis of methyl 7-bromo-2-(difluoromethyl)-1H-difluoromethyl-benzo[d]imidazole-5-carboxylate [ka] In a 100mL reaction flask, 20g of methyl 3,4-diamino-5-bromobenzoate and 60mL of difluoroacetic acid were added, stirred for 10-30 minutes, and subjected to nitrogen purge three times. The temperature was heated to 70°C, and the reaction was stirred for 18-20 hours. After the reaction was completed, 100mL of ethyl acetate was added, the organic phase was adjusted to pH=7 with aqueous sodium bicarbonate solution, and the mixture was stirred for 5-10 minutes. The organic phase was collected, and the aqueous phase was discarded. The organic phase was washed by adding 50mL of sodium chloride solution, and dried over anhydrous sodium sulfate. The system was filtered, concentrated to dryness, and subjected to column chromatography to obtain 22.3g of product in a yield of 90%.

[0062] Step 2: Synthesis of methyl (R)-7-bromo-2-(difluoromethyl)-1-[1-hydroxyprop-2-yl]-1H-benzo[d]imidazole-5-carboxylate [ka] In a 500 mL reaction flask, 20 g of methyl 7-bromo-2-(difluoromethyl)-1H-difluoromethyl-benzo[d]imidazole-5-carboxylate, 4.8 g of cetyltrimethylammonium bromide, 18.1 g of potassium carbonate, and 200 mL of acetonitrile were added, and 9.3 g / 50 mL of (S)-2-chloro-1-propanol / acetonitrile solution was added dropwise at room temperature while stirring. After the addition was completed, the mixture was heated to reflux and reacted for 8 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and poured into ice water to precipitate the solid, which was purified by column chromatography to obtain 16.3 g of product in a yield of 60%.

[0063] Step 3: Synthesis of methyl (R)-2-(difluoromethyl)-1-[1-hydroxyprop-2-yl]-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylate [ka] In a 250 mL three-neck flask, 15 g of methyl (R)-7-bromo-2-(difluoromethyl)-1-[1-hydroxyprop-2-yl]-1H-benzo[d]imidazole-5-carboxylate, 16.2 g of potassium acetate, 7.9 g of potassium fluoride, 105 mL of 1,4-dioxane, and 15 mL of water were added, and the system was subjected to nitrogen purge three times. 2.4 g of Pd(PPh3)4 was added, nitrogen purge three times, the system was heated to 80°C, and a solution of 5-pyrimidineboronic acid in tetrahydrofuran (6.1 g / 15 mL) was added dropwise. After the addition was completed, the reaction was stirred for another 5 hours, and the system was cooled to room temperature after TLC monitoring showed that the raw materials were completely reacted. 250mL of water, 120mL of ethyl acetate, and 3g of N-acetylcysteine ​​were added to the reaction system, and the system was stirred for 0.5 hours, after which 3L of saturated sodium bicarbonate solution was added. The system was phase-separated, and the aqueous phase was extracted with 120mL of ethyl acetate. The organic phases were combined, washed with 5L of saturated sodium chloride solution, concentrated to dryness, and purified by column chromatography to obtain 10.3g of product in 69% yield.

[0064] Step 4: Synthesis of methyl (3R)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxylate [ka] In a 250 mL reaction flask, 10 g of methyl (R)-2-(difluoromethyl)-1-[1-hydroxypropyl-2-yl]-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylate, 2.6 g of methanesulfonic acid, and 150 mL of methylene chloride were added, stirred at room temperature for 1 hour, filtered, and dried to give 11.5 g of product, 91% yield.

[0065] Step 5: Synthesis of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide [ka] In a 250 mL reaction flask, 10 g of compound 1-8, 5.8 g of 4-(chlorodifluoromethoxy)aniline, and 100 mL of tetrahydrofuran were added, and 44 mL of lithium bistrimethylsilylamide (1.0 M in THF) was added dropwise at 5-10 °C. After the addition was completed, the reaction was stirred at room temperature for 15 hours. The reaction mixture was quenched by adding 100 mL of saturated aqueous ammonium chloride solution dropwise, extracted by adding 200 mL of ethyl acetate, and the organic phase was concentrated to dryness. 100 mL of ethyl acetate was added to the concentrate, the concentrate was heated to 50 °C, stirred for 0.5 hours, and 50 mL of n-heptane was slowly added dropwise. The system was stirred for another 0.5 hours, then cooled to 20-30 °C, stirred for 3 hours, filtered, and dried under vacuum to give 9.1 g of off-white solid, in 82% yield.

[0066] Step 6: Synthesis of (3R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-3-methyl-3,4,5a,6-tetrahydro-5-oxa-1,2a,6,8-tetraazabenzo[4,5]cyclooctyl[1,2,3-cd]indene-11-carboxamide 4-methylbenzenesulfonate [ka] 9 g of compound 1-10 was weighed out, 90 mL of acetonitrile was added, and the mixture was heated to 50°C and stirred for 30 minutes. A solution of p-toluenesulfonic acid in ethanol (4 g / 20 mL) was added, and then the system was incubated to react for 22-24 hours. The mixture was filtered, and the filter cake was vacuum dried at 50°C for 24 hours to obtain 10.1 g of product, with a yield of 84%.

[0067] 1 HNMR(400Hz,DMSO-d6)δ10.51(s,1H),8.68(s,1H),8.35(s,1H),8.58-8.59(d,J=1.6Hz,1H),7.9 2-7.95(d,J=9.2Hz,2H),7.84-7.85(d,J=1.6Hz,1H),7.58-7.62(m,1H),7.56(t,J=52.0Hz,1H), 7.48-7.50(d,J=7.6Hz,2H),7.36-7.38(d,J=9.2Hz,2H),7.11-7.13(d,J=7.6Hz,2H),6.93(br,1 H),5.05(s,1H),4.34-4.39(m,1H),3.47-3.60(m,2H),2.29(s,3H),1.36-1.38(d,J=7.2Hz,3H).

[0068] MS(ESI,m / z):524.2[M-C7H8O3S+H] + .

[0069] Method 2: [ka] In a 500mL reaction flask, 20g of methyl 4-amino-3-bromo-5-nitrobenzoate (compound 1), 5.30g of cetyltrimethylammonium bromide, 20.07g of potassium carbonate, and 200mL of acetonitrile were added. 10.3g / 50mL of (S)-2-chloro-1-propanol / acetonitrile solution was added dropwise at room temperature with stirring. After the addition was completed, the mixture was heated to reflux and reacted for 8 hours. After the reaction was completed, the reaction mixture was concentrated to dryness, and ethyl acetate and water were added to the residue to extract the mixture. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The system was filtered, and the filtrate was purified by column chromatography to obtain 13.32g of compound 3 in a yield of 55%.

[0070] In a 100 mL reaction flask, 10 g of methyl (R)-3-bromo-4-[(1-hydroxyisopropan-2-yl)amino]-5-nitrobenzoic acid (compound 3) and 38 mL of difluoroacetic acid were added, and 16.76 g of iron powder was added at room temperature, and the mixture was heated to 40-50°C and reacted for 3 hours. The reaction system was cooled, and ethyl acetate was added thereto. The reaction system was filtered. The filtrate was washed once each with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and directly put into the next reaction step.

[0071] In a 250 mL three-neck flask, 15 g of methyl (R)-7-bromo-2-(difluoromethyl)-1-[1-hydroxyprop-2-yl]-1H-benzo[d]imidazole-5-carboxylate (compound 4), 16.2 g of potassium acetate, 7.9 g of potassium fluoride, 105 mL of 1,4-dioxane, and 15 mL of water were added, and the system was subjected to nitrogen purge three times. 2.4 g of Pd(PPh3)4 was added, nitrogen purge three times, the system was heated to 80° C., and a solution of 5-pyrimidineboronic acid in tetrahydrofuran (6.1 g / 15 mL) was added dropwise. After the addition was completed, the reaction was stirred for another 5 hours, and the system was cooled to room temperature after TLC monitoring showed that the raw materials were completely reacted. 250mL of water, 120mL of ethyl acetate, and 3g of N-acetylcysteine ​​were added to the reaction system, and the system was stirred for 0.5 hours, after which 3L of saturated sodium bicarbonate solution was added. The system was phase-separated, and the aqueous phase was extracted with 120mL of ethyl acetate. The organic phases were combined, washed with 5L of saturated sodium chloride solution, concentrated to dryness, and purified by column chromatography to obtain 10.3g of compound 6 in 69% yield.

[0072] In a 250 mL reaction flask, 10 g of compound 6, 5.8 g of 4-(chlorodifluoromethoxy)aniline, and 100 mL of tetrahydrofuran were added, and 44 mL of lithium bistrimethylsilylamide (1.0 M in THF) was added dropwise at 5-10 °C. After the addition was completed, the system was stirred and reacted at room temperature for 15 hours. 100 mL of saturated aqueous ammonium chloride was added dropwise to the reaction mixture to quench the reaction, 200 mL of ethyl acetate was added to extract, and the organic phase was concentrated to dryness. 100 mL of ethyl acetate was added to the concentrate, the concentrate was heated to 50 °C, stirred for 0.5 hours, and 50 mL of n-heptane was slowly added dropwise. The system was stirred for another 0.5 hours, then cooled to 20-30 °C, stirred for 3 hours, filtered, and dried under vacuum to obtain 9.1 g of off-white solid, with a yield of 82%.

[0073] 1 HNMR (400 Hz, acetone-d6) δ 10.13 (s, 1H), 9.51 (s, 1H), 9.37 (s, 1H), 9.09-9.10 (d, J = 2.4 Hz, 1H), 7.90-7.92 (m, 3H), 7.7.81 (s, 1H), 7.74 (t, J = 52.4 Hz, 1H), 7.27-7.29 (d, J = 8.4 Hz, 2H), 6.04 (s, 1H), 4.66-4.67 (m, 1H), 3.98-4.04 (m, 1H), 3.73-3.77 (m, 1H), 1.56-1.58 (d, J = 6.8 Hz, 3H).

[0074] For the preparation of other examples, see Example 1. [Table 1]

[0075] Biological Test Evaluation The present invention is further described and illustrated below with reference to test examples, which are not intended to limit the scope of the invention.

[0076] I. Study on the inhibitory activity of the compounds of the present invention against ABL1WT kinase 1. Purpose of the study The in vitro inhibitory activity of the compounds of the present invention against ABL1WT kinase is evaluated.

[0077] 2. Test Method Capillary electrophoresis was used to detect the phosphorylation conversion rate of the substrate peptide and the IC of test compounds that inhibit the kinase (ABL1-WT) 50 The values ​​were determined. The maximum concentration of the compounds tested in this study was 1000 nM, with 3-fold dilutions, resulting in a total of 12 concentrations (1000-0.0056 nM). First, the enzyme reaction system (the concentration of the enzyme ABL1-WT was 1.3 nM, the concentration of the substrate FLPeptide2 was 1.5 μM, and the reaction factor was 10 mM MgCl2) was prepared. After incubation at room temperature for 30 minutes, 5 μL of 4×ATP solution was added to start the enzyme reaction. After reacting at room temperature for 90 minutes, the reaction was stopped by adding stop buffer (containing 0.5 M EDTA). The samples were analyzed using an EZ reader (analysis conditions: pressure - 1.5 PSI, maximum voltage current - 2250 V, minimum voltage current - 500 V, separation time 40 seconds, and system delay 100.0 seconds).

[0078] 3. Data Processing The residual activity was calculated from the conversion rate read by the EZ Reader according to the following formula.

number

[0079] 4. Test Results [Table 2] In vitro enzyme tests show that the compounds of the present invention exhibit good inhibitory activity against ABL1WT kinase.

[0080] II. Study on the inhibitory activity against proliferation of BaF3 cell lines overexpressing different BCR-ABL1 fusion mutations 1. Purpose of the study The inhibitory activity of the compounds of the present invention against proliferation of primary B cells in vitro cultured murine Ba / F3 BCR-ABL1-T315I, Ba / F3 BCR-ABL1-E255K, Ba / F3 BCR-ABL1-E255V, and Ba / F3 BCR-ABL1-G250E mutant models is evaluated.

[0081] 2. Cell lines [Table 3]

[0082] 3. Test Method The CellTiter-Glo® Luminescent Cell Viability Assay was used to detect the inhibitory effect of drugs on tumor cell proliferation and growth. Overnight cultured cells in logarithmic growth phase were directly harvested, infused, mixed and counted, cell density was adjusted according to different cell density requirements, cells were prepared into cell suspensions and seeded into 96-well plates. Different concentrations of drugs were added, and three replicate wells were set up for each concentration, along with corresponding vehicle controls. The maximum test concentration in Ba / F3 BCR-ABL1-T315I cells and Ba / F3 BCR-ABL1-E255K cells was 10000nM, with 3.16-fold gradient dilution, a total of nine concentrations (10000-1.0058nM). The maximum concentration of the compound detected in other cells was 500nM, with 3.16-fold gradient dilution, a total of nine concentrations (500-0.0503nM). The compound-loaded cells were cultured for an additional 72 hours at 37° C. and 5% CO2. The culture plate and its contents were equilibrated to room temperature, CellTiter-Glo® reagent was added, the contents were mixed on a shaker for 5 minutes to induce cell lysis, the culture plate was incubated in the dark at room temperature for an additional 20 minutes, and luminescence was read on a microplate reader.

[0083] 4. Test Results [Table 4] The compounds of the present invention can significantly inhibit the proliferation of Ba / F3 BCR-ABL1-T315I, E255K, E255V, and G250E mutant cells.

[0084] III. Study on the inhibitory activity against the proliferation of tumor cell lines harboring BCR-ABL1 fusion mutations 1. Purpose of the study The inhibitory activity of the compounds of the present invention against the proliferation of in vitro cultured human erythroleukemia cells K562, human peripheral blood basophilic leukemia cells Ku812, and human chronic myeloid leukemia cells KCL22-s and KCL22-r is evaluated.

[0085] 2. Cell lines [Table 5]

[0086] 3. Test Method The CellTiter-Glo® Luminescent Cell Viability Assay was used to detect the inhibitory effect of drugs on tumor cell proliferation and growth. The cells in the logarithmic growth phase cultured overnight were directly harvested, infused, mixed and counted, the cell density was adjusted according to different cell density requirements, the cells were prepared into cell suspensions and seeded into 96-well plates. Different concentrations of drugs were added, and three replicate wells were set up for each concentration, along with corresponding solvent controls. The maximum concentration of the detected compound was 500 nM, with 3-fold gradient dilutions, a total of nine concentrations (500-0.076 nM). The cells with the added compounds were cultured for an additional 72 h at 37°C and 5% CO2. The culture plate and its contents were equilibrated to room temperature, CellTiter-Glo® reagent was added, the contents were mixed on a shaker for 3 min to induce cell lysis, the culture plate was incubated for an additional 10 min at room temperature in the dark, and the chemiluminescence signal values ​​were determined by a microplate reader (BioTek SynergyH1).

[0087] 4. Test Results [Table 6] The test results show that the compounds of the present invention can significantly inhibit the proliferation of tumor cells carrying BCR-ABL1 fusion mutation.

[0088] IV. Study on the efficacy of the drug in xenograft tumor models of human chronic myeloid leukemia cell line KCL22-s 1 Purpose of the experiment: The efficacy of test compounds against the human chronic myeloid leukemia cell line KCL22-s in a BALB / c nude mouse subcutaneous xenograft tumor model is evaluated.

[0089] 2. Experimental Procedures and Data Processing: 2.1 Animals BALB / c nude mice, 8–10 weeks old. 2.2 Preparation of cell culture medium and cell suspension a, KCL22-s cell line was taken out from the cell bank and resuscitated with RPMI-1640 medium (RPMI-1640+10%FBS+1%P / S). The resuscitated cells were placed in a cell culture flask (cell type, date, cultivator name, etc. were written on the flask wall) and then placed in a CO2 incubator (incubator temperature was 37°C, CO2 concentration was 5%) and incubated. b, The cells were passaged. After passage, the cells were continued to be cultured in a CO2 incubator. This process was repeated until the cell number met the in vivo drug efficacy requirement. c, The cultured cells were harvested and counted using an automated cell counter. According to the counting results, the cells were resuspended in PBS to prepare a cell suspension (density of 5 × 107 / mL) and placed in an icebox for later use. 2.3 Cell inoculation a, Before inoculation, nude mice were labeled with disposable ear tags for mice and rats. b, During inoculation, the cell suspension was mixed uniformly, and 0.1–1 mL of cell suspension was taken with a 1 mL syringe. After removing air bubbles, the syringe was placed on an ice pack for later use. c) The nude mouse was fixed with the left hand, and the area around the right shoulder on the right side of the nude mouse's back (inoculation site) was disinfected with 75% alcohol, and inoculation was started 30 seconds later. d, Experimental nude mice were inoculated sequentially (0.1 mL of cell suspension was inoculated for each mouse). 2.4 Tumor Measurement, Grouping and Dosing of Tumor-Bearing Mice a, Tumors were measured and tumor size was calculated on day 15 after inoculation based on tumor growth. Calculation of tumor volume: tumor volume (mm3) = length (mm) x width (mm) x width (mm) / 2 b, Based on the body weight and tumor size of tumor-bearing mice, the mice were grouped using a random grouping method. c. Based on the grouping results, administration of the test drug was started (administration route: oral administration; dose: 1.5, 3, 7.5 mg / kg; administration volume: 10 mL / kg; administration frequency: 1 to 2 times / day; administration cycle: 15 days; vehicle: 0.5% HPMC K4M). d, After the start of administration of the test drug, tumors were measured and weighed twice a week. e, Animals were euthanized after the experiment. f, Data was processed using Excel and other software. Calculation of compound tumor inhibition rate TGI(%): If tumor regression is not observed, TGI(%)=[1-(mean tumor volume at the end of treatment in a treatment group-mean tumor volume at the start of treatment in that treatment group) / (mean tumor volume at the end of treatment in vehicle control group-mean tumor volume at the start of treatment in vehicle control group)]×100%. If tumor regression is present, TGI(%)=[1-(mean tumor volume at the end of treatment in a particular treatment group-mean tumor volume at the start of treatment in that treatment group) / mean tumor volume at the start of treatment in that treatment group]×100%.

[0090] 3 Experimental results: [Table 7] The compounds of the present invention have significant tumor-inhibitory effects on human chronic myeloid leukemia cell line KCL22-s xenograft tumor model.

Claims

1. Formula (I): 【Chemical 1】 [In the formula, Ring A is C ３～６ cycloalkyl, 4- to 7-membered heterocyclyl, C ６～１０ aryl or 5- to 7-membered heteroaryl; R １ is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Deuterated alkyl, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio or C １～６ haloalkoxy, M １ is N or CR ａ and M ２ is NR ａ or C(R ａ ) ２ and M ３ is N or CR ａ and R ａ are each independently hydrogen, C １～６ Alkyl, C １～６ Deuterated alkyl, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio or C １～６ haloalkoxy, R ２ or R ３ are each independently hydrogen, C １～６ Alkyl, C １～６ Deuterated alkyl, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio, C １～６ Haloalkoxy, C ３～６ cycloalkyl, 4- to 7-membered heterocyclyl, C ６～１０ aryl or 5- to 7-membered heteroaryl; n is 0, 1, or 2. or a stereoisomer or a pharmaceutically acceptable salt thereof.

2. Ring A is C ６～１０ aryl or 5- to 6-membered heteroaryl; R １ But C １～３ Alkyl, C １～３ Deuterated alkyl, C １～３ Haloalkyl, C １～３ Hydroxyalkyl, C １～３ Alkoxy, C １～３ Alkylthio or C １～３ haloalkoxy, M １ is N or CH; M ２ is NH or CH ２ and M ３ is N or CH; R ２ or R ３ However, each independently, C １～３ Alkyl, C １～３ Deuterated alkyl, C １～３ Haloalkyl, C １～３ Hydroxyalkyl, C １～３ Alkoxy, C １～３ Alkylthio or C １～３ haloalkoxy, 2. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the formula (I) is further as described in general formula (II) or (II-a), or a stereoisomer or a pharmaceutically acceptable salt thereof: 【Chemistry 2】

4. Ring A is phenyl or pyridyl, R １ But C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy or C １～３ haloalkoxy, M １ is N, M ２ is NH, M ３ is N, R ２ or R ３ are each independently hydrogen, C １～３ Alkyl or C １～３ haloalkyl, 4. The compound of claim 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

5. R １ But -CHF ２ , -CF ３ , -CF ２ Cl, -OCHF ２ , -OCF ３ or -OCF ２ Cl, R ２ or R ３ are each independently —CH ３ , -CH ２ CH ３ , -CHF ２ , -CF ３ or -CF ２ Cl, 2. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

6. The structure of the compound is 【Chemistry 3】 2. The compound of claim 1, wherein:

7. The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a sulfate, hydrochloride, ethylsulfonate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, isethionate, or 1,5-naphthalenedisulfonate.

8. A pharmaceutical composition comprising the compound of claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

9. An ABL1 and / or BCR-ABL1 tyrosine kinase inhibitor comprising the compound according to any one of claims 1 to 7, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8.

10. A therapeutic agent for leukemia, comprising the compound according to any one of claims 1 to 7, or a stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8.

11. Methods for preparing compounds of formula (II): 【Chemistry 4】 wherein compound 1 and compound 2 are substituted to prepare compound 3, compound 5 is prepared under the action of boronic acid compound 4, compound 5 is adjusted to cyclic compound 6 under acidic conditions, which is then condensed with compound 7 to prepare compound (II), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein X is a halogen; M 3 is N; Ring A, R １ , R2, R ３ , M １ and M2 is as defined in claim 1. or 【Chemistry 5】 [wherein compound 1-a is substituted with compound 2 to prepare compound 3-a, which is reacted with 3-b to prepare compound 5-a, compound 6-a is prepared from compound 5-a under the action of boric acid compound 4, and compound 6-a and compound 7 are condensed to prepare compound (II), wherein: X １ , X ２ and X ３ are each independently a halogen; M 3 is N; Ring A, R １ , R2, R ３ , M １ and M2 is as defined in claim 1].

12. The method according to claim 11, wherein compound (II) is reacted with an acid to prepare a salt compound of compound (II).

13. The method of claim 12, wherein the acid is p-toluenesulfonic acid.

14. The method described in claim 10, wherein the leukemia is chronic myeloid leukemia.

15. The method described in claim 10, wherein the leukemia is acute myeloid leukemia.

16. The method described in claim 10, wherein the leukemia is acute lymphoblastic leukemia.

17. The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is p-toluenesulfonate.

18. The structure of the compound is 【Chemistry 6】 2. The compound of claim 1, wherein:

19. A pharmaceutical composition comprising the compound of claim 18, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

20. An ABL1 and / or BCR-ABL1 tyrosine kinase inhibitor comprising the compound of claim 18, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 19.

21. A therapeutic agent for a leukemia-related disease, comprising the compound of claim 18, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 19.

22. The pharmaceutically acceptable salt of claim 1, 【Chemistry 7】 2. The compound of claim 1, wherein:

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