CN114728943A

CN114728943A - Compounds as BCR-ABL inhibitors

Info

Publication number: CN114728943A
Application number: CN202180006423.2A
Authority: CN
Inventors: 张寅生; 陆鹏; 李久香; 杨加举; 秦慧; 叶嘉炜; 诸丽娟; 汪纪楠; 施伟; 王晓金
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2020-01-19
Filing date: 2021-01-19
Publication date: 2022-07-08
Also published as: WO2021143927A1

Abstract

The field of pharmaceutical chemistry, compounds serving as BCR-ABL inhibitors, namely compounds shown as a formula (I) or pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition containing the compounds, and application of the compounds in preparing medicines for treating BCR-ABL related diseases.

Description

Compounds as BCR-ABL inhibitors

Reference to related applications

This application claims the benefit and priority of the chinese patent application having application number 202010062317.3 filed on 19.01.2020 to the intellectual property office of the people's republic of china and the benefit and priority of the chinese patent application having application number 202011246125.4 filed on 10.11.2020 to the intellectual property office of the people's republic of china, the entire contents of which are hereby incorporated by reference in their entirety.

Technical Field

The application belongs to the field of pharmaceutical chemistry, and provides a compound serving as a BCR-ABL inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound in preparation of medicines for treating BCR-ABL related diseases.

Background

Chronic Myelocytic Leukemia (CML) is the main disease species of chronic leukemia in China, and accounts for about 70% of chronic leukemia. Chromosome abnormalities are present in more than 90% of the cases. Mainly translocate the long arm of chromosome 9 and 22 to form Bcr-Abl fusion gene and express protein p-210. The tyrosine kinase activity of p-210 is much stronger than that of p-150 (normal c-Abl gene expression product), which causes abnormal proliferation and differentiation of hematopoietic stem cells, and finally triggers CML.

Imatinib is the first Bcr-Abl targeted therapeutic drug on the market and is currently used as a first-line therapeutic drug for the treatment of various stages of CML. Nilotinib, dasatinib and bosutinib (second generation Bcr-Abl inhibitors) are approved for the treatment of imatinib-resistant or intolerant CML. The second generation Bcr-Abl inhibitors all have superior potency to imatinib and are effective against almost all imatinib resistant mutant types, but still do not address the problem of mutant resistance of T315I (gatekeeper). The T315I mutation accounts for about 20% of patients with drug resistance of the first and second generation Bcr-Abl inhibitors, and the marketing of ponatinib (third generation Bcr-Abl inhibitor) relieves the predicament that patients with T315I drug resistance mutation can not be treated with drugs, and is the only choice for patients with failure of the first and second generation Bcr-Abl inhibitor treatment.

ABL001 is a Bcr-ABL allosteric inhibitor developed by noval, which is disclosed in WO2013171639, currently in phase III clinical research. ABL001 is a potent, selective inhibitor of BCR-ABL, active against most mutants, such as T315I. (Andrew A. Wylie et al (2017) Nature 543, 733-737).

At present, no BCR-ABL allosteric inhibitor is on the market, so that a high-efficiency and low-toxicity Bcr-ABL inhibitor for T315I is needed in clinic, and a new BCR-ABL allosteric inhibitor needs to be further developed.

Disclosure of Invention

In one aspect, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein,

R ¹is selected from

Or alternatively

R ²Selected from hydrogen, 3-10 membered heterocyclyl or amino, wherein said 3-10 membered heterocyclyl or amino is optionally substituted with one or more R^aSubstitution;

R ^aselected from hydroxy, cyano, halogen,

C _1-6Alkyl radical, C_1-6Alkoxy, di (C)_1-6Alkyl) amino, or substituted by one or more hydroxy or C_1-6Alkoxy-substituted C_1-6An alkyl group;

R ³is selected from-OCF₂H, wherein said-OCF₂H is optionally substituted with halogen;

R ⁴selected from hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl or 3-10 membered heterocyclyl, wherein C_1-6Alkyl radical, C_3-6Cycloalkyl or 3-10 membered heterocyclyl is optionally substituted with one or more R^bSubstitution;

R ^bselected from deuterium, hydroxy, C_1-6Alkoxy radical, C_1-6Alkyl, amino, mono (C)_1-6Alkyl) amino or di (C)_1-6Alkyl) amino;

R ⁵is selected from C_1-6An alkyl group;

ring a is selected from 5-6 membered heteroaryl or phenyl.

In some embodiments, R^aSelected from hydroxy, halogen, C_1-6Alkyl, di (C) _1-6Alkyl) amino, or C substituted by one or more hydroxy groups_1-6An alkyl group; r^bSelected from hydroxy, C_1-6Alkoxy radical, C_1-6Alkyl, amino, mono (C)_1-6Alkyl) amino or di (C)_1-6Alkyl) amino.

In some embodiments, R¹Is selected from

Other variables are as defined herein.

In some embodiments, R¹Is selected from

Other variables are as defined herein.

In some embodiments, R²Selected from hydrogen, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl or amino, wherein said 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl or amino is optionally substituted with one or more R^aSubstitution; other variables are as defined herein.

In some embodiments, R²Selected from hydrogen, 4-6 membered heterocyclyl, 7-9 membered spiroheterocyclyl or amino, wherein said 4-6 membered heterocyclyl, 7-9 membered spiroheterocyclyl or amino is optionally substituted with one or more R^aSubstitution; other variables are as defined herein.

In some embodiments, R²Selected from hydrogen, 4-6 membered heterocyclyl or amino, wherein said 4-6 membered heterocyclyl or amino is optionally substituted with one or more R^aSubstitution; other variables are as defined herein.

In some embodiments, R²Selected from hydrogen, 4-6 membered heterocycloalkyl, 6 membered heterocycloalkenyl, 7 or 9 membered spiroheterocycloalkyl or amino, wherein said 4-6 membered heterocycloalkyl, 6 membered heterocycloalkenyl, 7 or 9 membered spiroheterocycloalkyl or amino is optionally substituted with one or more R ^aSubstitution; other variables are as defined herein.

In some embodiments, R²Selected from the group consisting of hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 1,2,3, 6-tetrahydropyridinyl, tetrahydropyranyl, 3, 4-dihydropyranyl, 3, 6-dihydropyranyl, 2-oxa-7-azaspiro [3.5]]Nonyl, 2-oxa-6-azaspiro [3.3]]Heptalkyl or amino, wherein the pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 1,2,3, 6-tetrahydropyridinyl, tetrahydropyranyl, 3, 4-dihydropyranyl, 3, 6-dihydropyranyl, 2-oxa-7-azaspiro [3.5]]Nonanyl, 2-oxa-6-azaspiro [3.3]Heptylalkyl or amino optionally substituted with one or more R^aSubstitution; other variables are as defined herein.

In some embodiments, R²Selected from hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 3, 4-dihydropyranyl, or amino, wherein said pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 3, 4-dihydropyranyl, or amino is optionally substituted with one or more R^aSubstitution; other variables are as defined herein.

In some embodiments, R²Selected from hydrogen,

Or an amino group, wherein

Or amino optionally substituted with one or more R^aSubstitution; othersThe variables are as defined herein.

In some embodiments, R^aSelected from hydroxy, cyano, halogen,

C _1-4Alkyl radical, C_1-3Alkoxy, di (C)_1-3Alkyl) amino groups or substituted by one or more hydroxy groups or C_1-3Alkoxy-substituted C_1-4An alkyl group; other variables are as defined herein.

In some embodiments, R^aSelected from hydroxy, halogen, C_1-3Alkyl, di (C)_1-3Alkyl) amino, or C substituted by one or more hydroxy groups_1-3An alkyl group; other variables are as defined herein.

In some embodiments, R^aSelected from hydroxy, cyano, fluoro,

Methyl, methoxy, 2-hydroxyethyl, 2-methoxyethyl, 2-methyl-2-hydroxypropyl, di (methyl) amino or hydroxymethyl; other variables are as defined herein.

In some embodiments, R^aSelected from hydroxy, fluoro, methyl, 2-hydroxyethyl, di (methyl) amino or hydroxymethyl; other variables are as defined herein.

In some embodiments, R²Selected from the group consisting of hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 1,2,3, 6-tetrahydropyridinyl, tetrahydropyranyl, 3, 4-dihydropyranyl, 3, 6-dihydropyranyl, 2-oxa-7-azaspiro [3.5]]Nonanyl, 2-oxa-6-azaspiro [3.3]Heptaalkyl or amino, wherein said pyrrolidinyl is optionally substituted with one hydroxy, cyano, fluoro, cyano, nitro, or a pharmaceutically acceptable salt thereof,

Methoxy or di (methyl) amino, wherein the piperazinyl, piperidinyl or morpholinyl is optionally substituted with one or two hydroxy or methyl groups, wherein the azetidinyl is optionally substituted with one or two hydroxy, fluoro, cyano, methyl, methoxy or hydroxymethyl groups, wherein the amino is optionally substituted with one or more 2-hydroxyethyl, methyl, 2-methoxyethyl or 2-methyl-2-hydroxypropyl groups; other variables are as defined herein.

In some embodiments, R²Selected from hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 3, 4-dihydropyranyl, or amino, wherein said pyrrolidinyl is optionally substituted with one hydroxy, fluoro, or di (methyl) amino, wherein said piperazinyl or piperidinyl is optionally substituted with one methyl, wherein said azetidinyl is optionally substituted with one hydroxy or hydroxymethyl, wherein said amino is optionally substituted with one or more 2-hydroxyethyl or methyl; other variables are as defined herein.

In some embodiments, R²Selected from hydrogen,

Other variables are as defined herein.

In some embodiments, R²Selected from hydrogen,

Other variables are as defined herein.

In some embodiments, R³Is selected from-OCF₃or-OCF₂Cl; other variables are as defined herein.

In some embodiments, R⁴Selected from hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl or 3-to 10-membered heterocycloalkyl, wherein C_1-6Alkyl radical, C_3-6Cycloalkyl or 3-10 membered heterocycloalkyl optionally substituted with one or more R^bSubstitution; other variables are as defined herein.

In some embodiments, R⁴Selected from hydrogen, C_1-5Alkyl radical, C_3-6Cycloalkyl or 4-6 membered heterocycloalkyl, wherein C_1-5Alkyl radical, C_3-6Cycloalkyl or 4-6 membered heterocycloalkyl optionally substituted with one or more R^bSubstitution; other variables are as defined herein.

In some embodiments, R⁴Selected from hydrogen, C_1-5Alkyl, cyclopropyl or 6-membered heterocycloalkyl, wherein C_1-5Alkyl, cyclopropyl or 6-membered heterocycloalkyl optionally substituted with one or more R^bSubstitution; other variables are as defined herein.

In some embodiments, R⁴Selected from hydrogen, methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, tetrahydropyranyl or piperidinyl, wherein methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, tetrahydropyranyl or piperidinyl is optionally substituted by one or more R^bSubstitution; other variables are as defined herein.

In some embodiments, R⁴Selected from hydrogen, methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropylA base,

Wherein methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, methyl, ethyl, propyl, isopropyl, and the like,

Optionally substituted by one or more R^bSubstitution; other variables are as defined herein.

In some embodiments, R^bSelected from deuterium, hydroxy, C_1-3Alkoxy radical, C_1-3Alkyl, amino, mono (C)_1-3Alkyl) amino or di (C)_1-3Alkyl) amino; the other variables are as defined herein.

In some embodiments, R^bSelected from hydroxy, C_1-3Alkoxy radical, C_1-3Alkyl, amino, mono (C)_1-3Alkyl) amino or di (C)_1-3Alkyl) amino; other variables are as defined herein.

In some embodiments, R^bSelected from deuterium, hydroxy, methoxy, methyl or di (ethyl) amino; other variables are as defined herein.

In some embodiments, R^bSelected from hydroxy, methoxy, methyl or di (ethyl) amino; other variables are as defined herein.

In some embodiments, R⁴Selected from hydrogen, methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, tetrahydropyranyl or piperidinyl, wherein methyl is optionally substituted with three deuterium groups, wherein ethyl is optionally substituted with one hydroxy, methoxy or di (ethyl) amino group, wherein 2-methylpropyl or 3-methylbutyl is optionally substituted with one hydroxy group, wherein piperidineOptionally substituted with one methyl group; other variables are as defined herein.

In some embodiments, R⁴Selected from hydrogen, methyl, d₃-methyl, cyclopropyl,

Other variables are as defined herein.

In some embodiments, R⁴Selected from hydrogen; other variables are as defined herein.

In some embodiments, R⁴Selected from methyl or cyclopropyl; the other variables are as defined herein.

In some embodiments, R⁵Is selected from C_1-3An alkyl group; other variables are as defined herein.

In some embodiments, R⁵Is selected from methyl; other variables are as defined herein.

In some embodiments, ring a is selected from a 5-6 membered nitrogen containing heteroaryl or phenyl; other variables are as defined herein.

In some embodiments, ring a is selected from pyrrolyl, pyridinyl, or phenyl; other variables are as defined herein.

In some embodiments, ring a is selected from pyrrolyl; other variables are as defined herein.

In some embodiments, a building block

Is selected from

Other variables are as defined herein.

In some embodiments, a building block

Is selected from

Is further selected from

Other variables are as defined herein.

In some embodiments, R¹Is selected from

Or

R ^aselected from hydroxy, halogen, C_1-6Alkyl, di (C)_1-6Alkyl) amino or C substituted by one or more hydroxy groups_1-6An alkyl group;

R ³is selected from-OCF₂H, wherein said-OCF ₂H is optionally substituted with halo;

R ^bselected from hydroxy, C_1-6Alkoxy radical, C_1-6Alkyl, amino, mono (C)_1-6Alkyl) amino or di (C)_1-6Alkyl) amino;

R ⁵is selected from C_1-6An alkyl group;

ring a is selected from 5-6 membered heteroaryl or phenyl.

In another aspect, the present application provides a compound of formula (II) or a pharmaceutically acceptable salt thereof,

wherein,

R ³is selected from-OCF₃or-OCF₂Cl；

R ²、R ⁴And R^aAnd R^bAs defined above.

In another aspect, the present application provides a compound of formula (III), or a pharmaceutically acceptable salt thereof,

wherein,

structural unit

Is selected from

R ³Is selected from-OCF₃or-OCF₂Cl；

R ²And R^aAs defined above.

In some embodiments, the present application provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein,

R ¹is selected from

Or

R ²Selected from hydrogen, 4-10 membered heterocyclyl or amino containing 1-3 heteroatoms selected from N or O or S, wherein said 4-10 membered heterocyclyl or amino is optionally substituted with one or more R^aSubstitution;

R ^aselected from hydroxy, cyano, halogen,

R ³is selected from-OCF₃、-OCF ₂Cl or-OCF₂Br；

R ⁴Selected from hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, or a 5-to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N or O or S, wherein C_1-6Alkyl radical, C_3-6Cycloalkyl or 5-7 membered heterocyclyl is optionally substituted with one or more R^bSubstitution;

R ^bselected from deuterium, hydroxy, C_1-6Alkoxy radical, C_1-6An alkyl group;

R ⁵is selected from C_1-6An alkyl group;

ring a is selected from 5-6 membered heteroaryl or phenyl containing 1-3 heteroatoms selected from N or O or S.

R ¹is selected from

Or

R ²Selected from hydrogen, a 4-9 membered heterocyclyl or amino group containing 1-3 (e.g. 1,2 or 3) heteroatoms selected from N or O or S (preferably N or O), wherein said 4-9 membered heterocyclyl or amino group is optionally substituted by 1 or 2R^aSubstitution;

R ^aselected from hydroxy, cyano, halogen (preferably F),

C _1-3Alkyl (preferably methyl, ethyl), C_1-3Alkoxy (preferably methoxy, ethoxy), di (C)_1-6Alkyl) amino, or by a hydroxy or C group_1-3Alkoxy (preferably methoxy, ethoxy) substituted C_1-4An alkyl group;

R ³is selected from-OCF₃or-OCF₂Cl；

R ⁴Selected from hydrogen, C_1-4Alkyl, aryl, heteroaryl, and heteroaryl,C ₃Cycloalkyl, or a 6-membered heterocyclic group containing 1-2 (preferably 1) heteroatoms selected from N or O or S, wherein C is_1-4Alkyl radical, C₃Cycloalkyl or 6-membered heterocyclyl is optionally substituted with one or more R^bSubstitution;

R ^bselected from deuterium, hydroxy and C_1-3Alkoxy (e.g., methoxy, ethoxy, propoxy);

R ⁵is selected from C_1-3Alkyl (e.g., methyl, ethyl, propyl);

ring a is selected from 5-6 membered heteroaryl or phenyl containing 1-2 (preferably 1) N heteroatoms.

R ¹is selected from

Or

R ^aselected from hydroxy, cyano, halogen (preferably F),

R ³is-OCF₂Cl；

R ⁴Selected from hydrogen, C_1-3Alkyl (preferably methyl, ethyl), C₃Cycloalkyl, or a 6-membered heterocyclic group containing 1 heteroatom selected from N or O (preferably O heteroatom), wherein C_1-3Alkyl is optionally substituted by one or more R^bSubstitution;

R ^bis selected from deuterium;

R ⁵is selected from C_1-3Alkyl (preferably methyl, ethyl);

ring a is a 5-membered heteroaryl or phenyl group containing 1-2 (preferably 1) N heteroatoms.

R ¹is selected from

Or

R ²Is selected from

R ³Is selected from-OCF₃or-OCF₂Cl；

R ⁴Selected from hydrogen, methyl, ethyl, propylCyclopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxy 2-methylpropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl,

Wherein methyl, ethyl and propyl are optionally substituted with one or more deuterium;

R ⁵selected from methyl, ethyl and propyl;

ring a is selected from pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl or phenyl.

R ¹is selected from

Or

R ²Is selected from

R ³is-OCF₂Cl；

R ⁴Selected from hydrogen, methyl, d₃-methyl, cyclopropyl or

R ⁵Is selected from methyl;

ring A is selected from pyrrolyl or phenyl.

In the present application, there are also embodiments derived from any combination of the above variables.

In another aspect, the present application provides a compound, or a pharmaceutically acceptable salt thereof,

in another aspect, the present application also provides a pharmaceutical composition comprising a compound of the present application, or a pharmaceutically acceptable salt thereof, as described above. In some embodiments, the pharmaceutical compositions of the present application further comprise a pharmaceutically acceptable excipient.

In another aspect, the present application also provides a method for treating and/or preventing BCR-ABL related diseases, comprising administering to a mammal, preferably a human, in need thereof a therapeutically effective amount of the above-described compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

In another aspect, the present application also provides a use of the above compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present application in the preparation of a medicament for treating and/or preventing BCR-ABL related diseases.

In another aspect, the present application also provides the use of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment and/or prevention of BCR-ABL related diseases.

In another aspect, the present application also provides a compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating and/or preventing BCR-ABL related diseases.

In some embodiments, the BCR-ABL associated disease is selected from cancer, for example leukemia (such as chronic myeloid leukemia).

Technical effects

The compound or the pharmaceutically acceptable salt thereof can show a proliferation inhibition effect on K562 cells and Ba/F3 cells transfected by BCR-ABL T315I, has good cell activity, and can show good in vivo pharmacokinetic properties.

Definition of

The following terms used in the present application have the following meanings, unless otherwise specified. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.

When a covalent bond in some structural unit or group is not attached to a particular atom in this application, it is meant that the covalent bond can be attached to any atom in the structural unit or group, as long as the valence bond attachment rules are not violated.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., ═ O), meaning that two hydrogen atoms are substituted, oxo does not occur on the aryl.

The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. When a group is "optionally" substituted, it means that the group may be unsubstituted or substituted, e.g., ethyl "optionally" is substituted with halo, meaning that ethyl may be unsubstituted (CH)₂CH ₃) Monosubstituted (e.g. CH)₂CH ₂F) Polysubstituted (e.g. CHFCH)₂F、CH ₂CHF ₂Etc.) or completely substituted (CF)₂CF ₃). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.

Herein C_m-nIt is the moiety that has an integer number of carbon atoms in the given range. E.g. "C_1-6By "is meant that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. E.g. C_1-3Meaning that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms.

When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 2R, then there are separate options for each R.

When the number of one linking group is 0, e.g. - (CH)₂) ₀-, denotes that the linking group is a covalent bond。

When one of the variables is selected from a covalent bond, it means that the two groups to which it is attached are directly linked, for example, in A-L '-Z where L' represents a covalent bond, it means that the structure is actually A-Z.

When a substituent's bond is cross-linked to two atoms on a ring, such substituent may be bonded to any atom on the ring. For example, a structural unit

Meaning that it may be substituted at any position on the cyclohexyl or cyclohexadiene.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "hydroxy" refers to an-OH group.

The term "amino" refers to-NH₂A group.

The term "cyano" refers to the group — CN.

The term "alkyl" refers to a group of formula C_nH _2n+1A hydrocarbon group of (2). The alkyl group may be linear or branched. For example, the term "C_1-6Alkyl "means an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio groups have the same definitions as above. Also for example, the term "C_1-3Alkyl "refers to alkyl groups containing 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).

The term "alkoxy" refers to-O-alkyl.

The term "alkylamino" refers to-NH-alkyl.

The term "dialkylamino" refers to-N (alkyl)₂。

The term "cycloalkyl" means fully saturated and may be in the form ofMonocyclic, bridged or spiro carbon rings. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring, such as a 3,4, 5, 6, 7, 8, 9 or 10 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1 ] n]Heptyl), bicyclo [2.2.2]Octyl, adamantyl, bicyclo [1.1.1]Pent-1-yl and the like. E.g. C_3-4Cycloalkyl groups include cyclopropyl and cyclobutyl.

The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3-to 10-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen, or a 4-to 6-membered ring, for example, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring or a 9-membered ring. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuranyl, 3, 4-dihydropyranyl, 3, 6-dihydropyranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, 2-oxa-7-azaspiro [3.5] nonanyl, 2-oxa-6-azaspiro [3.3] heptanyl, and the like.

The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 10 membered ring, or a 4 to 6 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxiranyl, thietanyl, cycloazenyl, non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thiabutinyl, examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, examples of tetrahydropyrazolyl, 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thialkyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, and examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, thiepanyl. Monocyclic heterocycloalkyl groups having 5 or 6 ring atoms are preferred.

The term "heterocycloalkenyl" refers to a non-aromatic ring that is partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 10 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen, or a 4 to 6 membered ring. Non-limiting examples of heterocycloalkenyl include, but are not limited to, dihydrofuranyl, 3, 4-dihydropyranyl, 3, 6-dihydropyranyl, dihydropyrrolyl, 4H-pyranyl, and the like.

The term "spiroheterocyclyl" refers to a fully saturated or partially unsaturated (but not fully saturated) spirocyclic ring in which one or more ring atoms are heteroatoms (preferably 1 or 2 heteroatoms) selected from sulfur, oxygen and/or nitrogen, the remaining ring atoms being carbon. Preferably 6 to 14, more preferably 6 to 10. Spiroheterocycles are classified as mono-, di-or polyspiroheterocycles, preferably mono-or di-spiroheterocycles, more preferably 4-or 5-or 6-membered mono-spiroheterocycles, depending on the number of spiro atoms shared between the rings. Non-limiting examples of spiroheterocycles include

The term "spiroheterocycloalkyl" refers to a completely saturated spiroheterocyclyl group.

The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing as ring atoms at least one (e.g., 1-4, 1-3, or 1-2, e.g., 1,2, or 3) heteroatom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryl groups have a single 5 to 8 membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.

The term "treating" means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) inhibiting the disease or disease state, i.e., arresting its development;

(ii) alleviating the disease or condition, i.e., causing regression of the disease or condition.

The term "preventing" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes: prevention of a disease or condition occurs in a mammal, particularly when such mammal is susceptible to the disease condition, but has not yet been diagnosed as having the disease condition.

The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art with their own knowledge and this disclosure.

The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like can be mentioned.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

The term "pharmaceutically acceptable adjuvants" refers to those adjuvants which do not have a significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

The word "comprise" or "comprises", and variations such as "comprises" or "comprising", will be understood in an open, non-exclusive sense, i.e., "including but not limited to", meaning that elements, components, and steps other than those listed may be included.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

Unless otherwise indicated, "(D)" or "(+)" means dextrorotation, "(L)" or "(-) -means levorotation," (DL) "or" (±) "means racemization.

Using solid wedge keys, unless otherwise indicated

And wedge dotted bond

Showing the absolute configuration of a solid centre, by means of straight solid keys

And straight dotted line bond

Showing the relative configuration of the centres of solids, by wavy lines

Representing solid-line keys of wedge shape

Or wedge dotted bond

Or by wavy lines

Indicating straight solid-line keys

And straight dotted bond

Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).

The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (A), (B), (C) and C)³H) Iodine-125 (¹²⁵I) Or C-14(¹⁴C) .1. the As another example, deuterium can be substituted for hydrogen with deuterium to form a deuterated drug, such as d₃The-methyl represents that three hydrogen atoms on the methyl are all replaced by deuterium atoms, the bond formed by deuterium and carbon is firmer than the bond formed by common hydrogen and carbon, and compared with an un-deuterated drug, the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life period of the drug and the like. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The present application also includes isotopically-labeled compounds of the present application, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Can be incorporated into this applicationExamples of isotopes of compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as respectively²H、 ³H、 ¹¹C、 ¹³C、 ¹⁴C、 ¹³N、 ¹⁵N、 ¹⁵O、 ¹⁷O、 ¹⁸O、 ³¹P、 ³²P、 ³⁵S、 ¹⁸F、 ¹²³I、 ¹²⁵I and³⁶cl, and the like.

Certain isotopically-labelled compounds of the present application (e.g. with³H and¹⁴c-labeled ones) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation)³H) And carbon-14 (i.e.¹⁴C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as¹⁵O、 ¹³N、 ¹¹C and¹⁸f can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

In addition, heavier isotopes are used (such as deuterium (i.e., deuterium)²H) Substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium, all such forms of the compounds being encompassed within the scope of the present application.

The compounds of the present application may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.

The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.

Typical routes of administration of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.

In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These adjuvants enable the compounds of the present application to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.

Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid adjuvants, optionally the mixture obtained is milled, if desired with further suitable adjuvants, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.

The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

Therapeutic dosages of the compounds of the present application may be determined, for example, by: the particular use of the treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the present application in the pharmaceutical composition may not be fixed, depending on a variety of factors including dosage, chemical properties (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present application can be provided for parenteral administration by a physiological buffered aqueous solution containing about 0.1-10% w/v of the compound. Some typical dosage ranges are from about 1. mu.g/kg to about 1g/kg body weight/day. In certain embodiments, the dosage range is from about 0.01mg/kg to about 100mg/kg of body weight per day. The dosage will likely depend on such variables as the type and extent of progression of the disease or disorder, the general health status of the particular patient, the relative biological efficacy of the selected compound, the excipient formulation and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

In this document, unless the context clearly dictates otherwise, singular terms encompass plural referents and vice versa.

All patents, patent applications, and other established publications are herein expressly incorporated by reference for the purpose of description and disclosure. These publications are provided solely for their disclosure prior to the filing date of the present application. All statements as to the date of these documents or representation as to the contents of these documents is based on the information available to the applicant and does not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Moreover, any reference herein to such publications in any country does not constitute an admission that the publications form part of the common general knowledge in the art.

The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application.

The chemical reactions of the embodiments herein are carried out in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.

An important consideration in the art of synthetic route planning is the selection of suitable protecting Groups for reactive functional Groups (e.g., amino Groups as used herein), for example, see Greene's Protective Groups in Organic Synthesis (4th Ed.) Hoboken, New Jersey: John Wiley & Sons, Inc.

The compounds of general formula (I) of the present application can be prepared by a person skilled in the art of organic synthesis by the following route:

synthesis of intermediate (i):

wherein,

R ²、R ³is as defined above, and R²Is not hydrogen.

Synthesis of intermediate (ii):

wherein,

R ³as defined above, R²Is hydrogen.

Synthesis of intermediate (iii):

the first scheme is as follows:

scheme II:

wherein,

R ⁴、R ⁵and ring a is as defined above.

Preparation of the target compound:

wherein,

R ²、R ³、R ⁴、R ⁵and ring a is as defined above.

The following abbreviations are used in this application:

SOCl ₂represents thionyl chloride; TEA stands for triethylamine; oxone represents Oxone complex salt; NBS represents N-bromosuccinimide; pd (PPh)₃) ₄Represents tetrakis (triphenylphosphine) palladium; PdCl₂(dppf) represents 1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; DCM represents dichloromethane; DMSO represents dimethyl sulfoxide; DMF stands for N, N-dimethylformamide.

Detailed Description

For clarity, the invention is further illustrated by examples, which are not intended to limit the scope of the application. It will be apparent to those skilled in the art that various changes and modifications can be made in the specific embodiments of the invention without departing from the spirit and scope of the invention. All reagents used herein were commercially available and were used without further purification.

Example 1: preparation of Compound 1

Step A: preparation of Compound 1-1

Adding 300mL of toluene and 5-bromo-6-chloronicotinic acid (15.0g) into a 500mL three-necked bottle in sequence, dropwise adding thionyl chloride (14.79g) into the system at room temperature, heating to 70-80 ℃ after the addition, reacting for 4 hours, stopping the reaction, and concentrating under reduced pressure to obtain brown oily matter; dichloromethane (300mL) was added thereto, stirring was turned on and 4- (chlorodifluoromethoxy) aniline (12.28g) was added dropwise to the system; after the dropwise addition, triethylamine (12.58g) was added dropwise; after dropping, the reaction is carried out for 4h at room temperature. Adding 100mL of saturated sodium bicarbonate water solution into the reaction solution, stirring for 10min, filtering and collecting a filter cake; and separating the mother liquor to obtain an organic phase, adding 100mL of saturated sodium chloride aqueous solution, stirring, separating to obtain the organic phase, adding the filter cake into the organic phase, concentrating under reduced pressure to obtain a residue, and purifying by column chromatography to obtain 20.44g of the compound 1-1.

And B, step B: preparation of Compounds 1-2

Adding isopropanol (10mL), the compound 1-1(2.0g) obtained in the step A, (R) -3-pyrrolidinol (0.498g), N, N-diisopropylethylamine (1.229g) and magnetons into a 50mL sealed tube in sequence, sealing the tube, and placing the sealed tube into a microwave reactor to react for 30min at 130 ℃. Concentrating the reaction solution under reduced pressure to obtain brown residue, adding anhydrous ethanol (4mL) into the brown residue, pulping for 10min, filtering, leaching the filter cake with a small amount of anhydrous ethanol, and collecting the filter cake; the filter cake was placed in a vacuum oven and dried under vacuum at 50 ℃ to constant weight to obtain 1.744g of compound 1-2.

MS(ESI,[M+H] ⁺)m/z:462.0/464.0.

And C: preparation of Compounds 1-3

To a 25mL single-neck flask were added in sequence dimethyl sulfoxide (5mL), 2, 5-dibromopyridine (100mg), 2-methyl-2-mercapto urea sulfate (120mg), and cesium carbonate (550mg), and after completion of the addition, the temperature was raised to 75-85 ℃ for reaction for 4 hours. Cooling to room temperature, filtering to obtain light yellow mother liquor, adding 20mL of water, extracting with 10mL of dichloromethane for 2 times, mixing organic phases, adding 10mL of saturated sodium chloride aqueous solution, stirring, washing, separating liquid to obtain an organic phase, drying with anhydrous sodium sulfate, performing suction filtration, and concentrating under reduced pressure to obtain 153mg of compound 1-3; the product was used in the next reaction without purification.

MS(ESI,[M+H] ⁺)m/z:203.9.

Step D: preparation of Compounds 1-4

To a 250mL three-necked flask were added isopropanol (90mL) and water (30mL) in this order, and 5-bromo-2- (methylthio) pyridine (3.2g) prepared according to the method in step C was added to the system with stirring, followed by addition of Oxone (Oxone, complex salt of potassium hydrogen persulfate, 22.17g) in portions. After the addition, the reaction was kept at room temperature. Cooling to room temperature, filtering to obtain white mother liquor, and concentrating under reduced pressure; adding 50mL of ethyl acetate and 30mL of water for washing, extracting the water phase for 1 time by using 50mL of ethyl acetate, combining organic phases, adding 30mL of saturated sodium chloride aqueous solution for washing, separating liquid to obtain an organic phase, and concentrating under reduced pressure to obtain 3.70g of a compound 1-4.

MS(ESI,[M+H] ⁺)m/z:224.1.

Step E: preparation of Compounds 1-5

And (3) sequentially adding 1, 4-dioxane (10mL), the 5-bromo-2-methylsulfonylpyridine (100mg) obtained in the step D, the pinacol diboron diboride (164mg), potassium acetate (85mg) and the [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (10mg) into a 25mL three-necked flask, reacting for 4 hours after the addition and nitrogen replacement, heating to 80-90 ℃, stopping the reaction, cooling to room temperature, and directly using for the next reaction without separation and purification.

Step F: preparation of Compound 1

To the reaction solution obtained in the above step E, the compound 1-2(163mg) obtained in the above step B, potassium carbonate (146mg), deionized water (1.5mL), tetrakis (triphenylphosphine) palladium (10mg) were added in this order; after the addition, nitrogen is replaced, and the temperature is raised to 80-90 ℃ for reaction for 4 h. Cooling to room temperature, filtering the reaction, collecting mother liquor, adding 15mL ethyl acetate, stirring, separating liquid, adding 15mL saturated sodium chloride aqueous solution, stirring, separating liquid, and purifying by column chromatography to obtain 60mg of compound 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.22(s,1H),8.88(m,1H),8.81(d,J＝2.3Hz,1H),8.17-8.11(m,3H),7.93–7.82(m,2H),7.35(d,J＝8.8Hz,2H),4.91(d,J＝3.5Hz,1H),4.27–4.18(m,1H),3.46–3.37(m,1H),3.36(s,3H),3.28–3.19(m,2H),2.86(d,J＝11.4Hz,1H),1.91–1.81(m,1H),1.81–1.71(m,1H).

MS(ESI,[M+H] ⁺)m/z:539.2/541.1.

Example 2: preparation of Compound 2

Step A: preparation of Compound 2-1

Trifluoromethyl benzene (30mL), 5-bromo-2-methylnicotinic acid ethyl ester (3.0g), N-bromosuccinimide (2.62g) and azobisisobutyronitrile (0.395g) are sequentially added into a 50mL single-neck bottle, and after the addition is finished, the temperature is raised to 70-80 ℃ for reaction for 6 hours after nitrogen replacement. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography to give 1.731g of Compound 2-1.

MS(ESI,[M+H] ⁺)m/z:321.9/323.9.

And B: preparation of Compound 2-2

Adding 30mL of ammonia isopropanol solution (2mol/L) into a 100mL single-neck bottle in sequence to obtain a compound 2-1(1.484g) obtained in the step A, and reacting at room temperature for 6h after the addition is finished; concentrating the reaction solution under reduced pressure; the obtained residue was subjected to column chromatography to give 768mg of the compound 2-2.

¹H NMR(500MHz,DMSO-d ₆):δ8.93(s,1H),8.87(s,1H),8.28(s,1H),4.39(s,2H).

And C: preparation of Compounds 2-3

Referring to the procedure of step E of example 1, a reaction solution containing compound 2-3 was prepared using compound 2-2 obtained in step B, cooled to room temperature, and used in the next reaction without separation and purification.

Step D: preparation of Compound 2

Compound 2 was prepared by the method of step F of example 1 using the reaction mixture obtained in step C above and compound 1-2 obtained in step B of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.19(s,1H),8.92(s,1H),8.81-8.76(m,2H),8.11–8.05(m,2H),7.86(d,J＝8.8Hz,2H),7.33(d,J＝8.6Hz,2H),4.87(d,J＝3.4Hz,1H),4.51(s,2H),4.21–4.16(m,1H),3.41–3.39(m,1H),3.25–3.15(m,2H),2.88(d,J＝11.4Hz,1H),1.87–1.79(m,1H),1.76–1.69(m,1H).

MS(ESI,[M+H] ⁺)m/z:516.2/518.2.

Example 3: preparation of Compound 3

Compound 3 was prepared by the method referenced to step F of example 1, using compound 1-2 and 3-methanesulfonylphenylboronic acid, obtained in step B of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.23(s,1H),8.78(d,J＝2.3Hz,1H),8.06(d,J＝2.4Hz,1H),7.96–7.91(m,2H),7.90–7.84(m,2H),7.79–7.73(m,2H),7.34(d,J＝8.7Hz,2H),4.86(d,J＝3.3Hz,1H),4.19(q,J＝3.6Hz,1H),3.45–3.36(m,1H),3.29(s,3H),3.27–3.22(m,1H),3.21–3.14(m,1H),2.85(d,J＝11.4Hz,1H),1.88–1.79(m,1H),1.77–1.70(m,1H).

MS(ESI,[M+H] ⁺)m/z:538.1/540.1.

Example 4: preparation of Compound 4

Step A: preparation of Compound 4-1

Compound 4-1 was prepared by reacting compound 1-1 with N-methylpiperazine according to the preparation method of step B of example 1.

MS(ESI,[M+H] ⁺)m/z:475.1/477.1.

And B: preparation of Compound 4

Compound 4 was prepared by reacting the reaction mixture containing Compound 2-3 obtained in step C of example 2 with Compound 4-1 of step A described above, according to the preparation method of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.37(s,1H),9.05(s,1H),8.94(s,1H),8.83(d,J＝1.8Hz,1H),8.35(s,1H),8.23(s,1H),7.90(d,J＝8.9Hz,2H),7.39(d,J＝8.7Hz,2H),4.54(s,2H),3.17(t,J＝4.7Hz,4H),2.28(t,J＝4.7Hz,4H),2.17(s,3H).

MS(ESI,[M+H] ⁺)m/z:529.3.

Example 5: preparation of Compound 5

Step A: preparation of Compound 5-1

Compound 5-1 was prepared by reacting compound 1-1 with morpholine according to the procedure for the preparation of step B of example 1.

MS(ESI,[M+H] ⁺)m/z:462.0/464.0.

And B: preparation of Compound 5

Compound 5 was prepared by reacting the reaction mixture containing Compound 2-3 obtained in step C of example 2 with Compound 5-1 of step A described above, according to the preparation method of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.29(s,1H),8.98(s,1H),8.85(s,1H),8.75(s,1H),8.28(s,1H),8.15(s,1H),7.80(d,J＝8.5Hz,2H),7.29(d,J＝8.6Hz,2H),4.44(s,2H),3.63–3.36(m,4H),3.18–2.89(m,4H).

MS(ESI,[M+H] ⁺)m/z:516.2.

Example 6: preparation of Compound 6

Step A: preparation of Compound 6-1

Referring to the preparation method of step B of example 1, compound 6-1 was prepared by reacting compound 1-1 with (R) -3-dimethylaminopyrrolidine.

MS(ESI,[M+H] ⁺)m/z:489.3/491.3.

And B: preparation of Compound 6

Referring to the preparation method of step F of example 1, compound 6 was prepared by reacting compound 6-1 of step A with the reaction solution containing compound 2-3 obtained in step C of example 2.

¹H NMR(500MHz,DMSO-d ₆)δ10.23(s,1H),8.92(s,1H),8.86–8.74(m,2H),8.18–8.06(m,2H),7.87(d,J＝9.0Hz,2H),7.34(d,J＝8.7Hz,2H),4.51(s,2H),3.26–3.09(m,2H),3.09–2.93(m,1H),2.77–2.60(m,1H),2.12(s,6H),2.03–1.94(m,1H),1.72–1.59(m,2H).

MS(ESI,[M+H] ⁺)m/z:543.3.

Example 7: preparation of Compound 7

Step A: preparation of Compound 7-1

Referring to the preparation method of step B of example 1, compound 7-1 is prepared by reacting compound 1-1 with azetidine.

MS(ESI,[M+H] ⁺)m/z:448.1/450.1.

And B: preparation of Compound 7

Referring to the preparation method of step F of example 1, compound 7 was prepared by reacting the reaction solution containing compound 2-3 obtained in step C of example 2 with compound 7-1 of step A described above.

¹H NMR(500MHz,DMSO-d ₆)δ10.24(s,1H),8.93(s,1H),8.83(s,1H),8.79(s,1H),8.17–8.07(m,2H),7.87(d,J＝8.4Hz,2H),7.35(d,J＝8.2Hz,2H),5.57(d,J＝5.8Hz,1H),4.52(s,2H),4.45–4.31(m,1H),3.94–3.81(m,2H),3.53–3.43(m,2H).

MS(ESI,[M+H] ⁺)m/z:502.1.

Example 8: preparation of Compound 8

Step A: preparation of Compound 8-1

Referring to the preparation method of step B of example 1, compound 8-1 is prepared by reacting compound 1-1 with tetrahydropyrrole.

MS(ESI,[M+H] ⁺)m/z:446.0/448.0.

And B: preparation of Compound 8

Referring to the preparation method of step F of example 1, compound 8 was prepared by reacting the reaction solution containing compound 2-3 obtained in step C of example 2 with compound 8-1 of step A described above.

¹H NMR(500MHz,DMSO-d ₆)δ10.17(s,1H),8.90(s,1H),8.79(d,J＝2.5Hz,1H),8.78(d,J＝2.4Hz,1H),8.12–8.05(m,2H),7.92–7.77(m,2H),7.33(d,J＝8.6Hz,2H),4.50(s,2H),3.19–3.04(m,4H),1.85–1.65(m,4H).

MS(ESI,[M-H] ^-)m/z:498.1/500.1.

Example 9: preparation of Compound 9

Step A: preparation of Compound 9-1

Compound 9-1 was prepared according to the method of example 1, step a, using 5-bromo-6-chloronicotinic acid and 4-trifluoromethoxyaniline.

MS(ESI,[M-H] ^-)m/z:393.0.

And B: preparation of Compound 9-2

Compound 9-2 is prepared using compound 9-1 obtained in the above step A and (R) -3-pyrrolidinol, by a method similar to step B of example 1.

MS(ESI,[M+H] ⁺)m/z:446.1.

And C: preparation of Compound 9

Compound 9 was prepared by the method of step F of example 1 using the reaction solution containing Compound 2-3 obtained in step C of example 2 and Compound 9-2 obtained in step B above.

¹H NMR(500MHz,DMSO-d ₆)δ10.18(s,1H),8.92(s,1H),8.86–8.72(m,2H),8.16–8.01(m,2H),7.86(d,J＝8.7Hz,2H),7.35(d,J＝8.4Hz,2H),4.94–4.82(m,1H),4.52(s,2H),4.19(s,1H),3.44–3.37(m,1H),3.28–3.15(m,2H),2.95–2.83(m,1H),1.90–1.79(m,1H),1.79–1.67(m,1H).

MS(ESI,[M+H] ⁺)m/z:500.2.

Example 10: preparation of Compound 10

Step A: preparation of Compound 10-2

Referring to the preparation method of step B of example 2, compound 10-2 was prepared by substituting an ethanol solution of methylamine (30% -35%, m/m) for an isopropanol solution of ammonia (2 mol/L).

MS(ESI,[M+H] ⁺)m/z:227.1/229.1.

And B: preparation of Compound 10-3

Referring to the procedure of step E of example 1, a reaction solution containing compound 10-3 was prepared using compound 10-2 obtained in step A, cooled to room temperature, and used in the next reaction without separation and purification.

Step C: preparation of Compound 10

Compound 10 was prepared by the method of step F of example 1 using the reaction solution containing compound 10-3 obtained in step B above and compound 1-2 obtained in step B of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.18(s,1H),8.78(d,J＝2.4Hz,1H),8.76(d,J＝2.1Hz,1H),8.07(d,J＝2.4Hz,1H),8.05(d,J＝2.1Hz,1H),7.97–7.80(m,2H),7.34(d,J＝8.7Hz,2H),4.86(d,J＝3.5Hz,1H),4.53(s,2H),4.21–4.15(m,1H),3.34(s,3H),3.25–3.13(m,2H),3.07–2.95(m,1H),2.87(d,J＝11.3Hz,1H),1.88–1.78(m,1H),1.76–1.68(m,1H).

MS(ESI,[M+H] ⁺)m/z:530.2/532.2.

Example 11: preparation of Compound 11

Step A: preparation of Compound 11-1

To a 100mL single-necked flask were sequentially added 20mL of absolute ethanol, cyclopropylamine (532mg), and compound 2-1(600mg), prepared by the method of step A in example 2. After 6 hours of reaction at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue obtained was subjected to column chromatography to give 405mg of compound 11-1.

¹H NMR(500MHz,DMSO-d ₆)δ8.86(d,J＝2.3Hz,1H),8.27(d,J＝2.1Hz,1H),4.43(s,2H),3.01–2.93(m,1H),0.91–0.85(m,2H),0.85–0.77(m,2H).

MS(ESI,[M+H] ⁺)m/z:253.0/255.0.

And B: preparation of Compound 11-2

Referring to the procedure of step E of example 1, a reaction solution containing compound 11-2 was prepared using compound 11-1 obtained in the above step A, cooled to room temperature, and used in the next step without isolation and purification.

And C: preparation of Compound 11

Compound 11 was prepared by the method of step F of example 1 using the reaction solution containing Compound 11-2 obtained in step B above and Compound 1-2 obtained in step B of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.19(s,1H),8.78(d,J＝2.4Hz,1H),8.77(d,J＝2.1Hz,1H),8.08(d,J＝2.4Hz,1H),8.06(d,J＝2.1Hz,1H),7.93–7.80(m,2H),7.34(d,J＝8.6Hz,2H),4.86(d,J＝3.5Hz,1H),4.60(s,2H),4.21–4.15(m,1H),3.41–3.35(m,1H),3.36-3.30(m,2H),3.24–3.16(m,2H),3.16-3.11(m,3H),2.87(d,J＝11.3Hz,1H),1.88–1.77(m,1H),1.76–1.68(m,1H).

MS(ESI,[M+H] ⁺)m/z:556.3/558.2.

Example 12: preparation of Compound 12

Step A: preparation of Compound 12-1

Referring to the procedure of step A of example 1, 5-bromo-6-chloronicotinic acid was replaced with 5-bromonicotinic acid to give compound 12-1

¹H NMR(500MHz,DMSO-d ₆)δ10.68(s,1H),9.07(d,J＝1.9Hz,1H),8.92(d,J＝2.2Hz,1H),8.55(t,J＝2.1Hz,1H),7.96–7.83(m,2H),7.44–7.33(m,2H).

MS(ESI,[M+H] ⁺)m/z:377.0/379.0/381.0.

Step B preparation of Compound 12

Compound 12 was prepared by the method of step F of example 1 using the reaction solution containing compound 2-3 obtained in step C of example 2 and compound 12-1 obtained in step A above.

¹H NMR(500MHz,DMSO-d ₆)δ10.68(s,1H),9.28–9.21(m,2H),9.13(s,1H),8.93(s,1H),8.74(s,1H),8.56(s,1H),7.91(d,J＝8.6Hz,2H),7.40(d,J＝8.6Hz,2H),4.52(s,2H).

MS(ESI,[M-H] ^-)m/z:429.0/431.0.

Example 13: preparation of Compound 13

Step A: preparation of Compound 13-1

A25 mL single-necked flask was charged with 5mL of absolute ethanol, compound 2-1 prepared in step A of example 2 (0.15g), and 2-methoxyethylamine (0.18g) in this order, and reacted at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to column chromatography to give 0.12g of compound 13-1.

MS(ESI,[M+H] ⁺)m/z:271.0.

And B: preparation of Compound 13-2

Referring to the procedure of step E of example 1, a reaction solution containing compound 13-2 was prepared using compound 13-1 obtained in the above step A, cooled to room temperature, and used in the next step without isolation and purification.

And C: preparation of Compound 13

Compound 13 was prepared by the method of step F of example 1 using the reaction solution containing compound 13-2 obtained in the above step B and compound 12-1 obtained in step A of example 12.

¹H NMR(500MHz,DMSO-d ₆)δ10.69(s,1H),9.25(s,2H),9.14(s,1H),8.75(s,1H),8.58(s,1H),7.92(d,J＝9.0Hz,2H),7.41(d,J＝8.8Hz,2H),4.67(s,2H),3.76-3.78(m,2H),3.61-3.64(m,2H),3.30(s,3H).

MS(ESI,[M+H] ⁺)m/z:489.2.

Example 14: preparation of Compound 14

Step A: preparation of Compound 14-1

Compound 14-1 was prepared according to the procedure of example 13, step a, substituting starting ethanolamine for 2-methoxyethylamine.

MS(ESI,[M+H] ⁺)m/z:257.2/259.2.

And B: preparation of Compound 14-2

Referring to the procedure of step E of example 1, using compound 14-1 obtained in the above step A, a reaction solution containing compound 14-2 was prepared, cooled to room temperature, and used in the next reaction without separation and purification.

And C: preparation of Compound 14

Compound 14 was prepared by the method of step F of example 1 using the reaction solution containing compound 14-2 obtained in step B above and compound 12-1 obtained in step A of example 12.

¹H NMR(500MHz,DMSO-d ₆)δ10.69(s,1H),9.25(s,2H),9.14(s,1H),8.75(s,1H),8.58(s,1H),7.92(d,J＝9.1Hz,2H),7.41(d,J＝9.0Hz,2H),4.87-4.89(m,1H),4.69(s,2H),3.66-3.69(m,4H).

MS(ESI,[M+H] ⁺)m/z:475.1.

Example 15: preparation of Compound 15

Step A: preparation of Compound 15-1

Compound 15-1 was prepared according to the procedure of example 13, step a, substituting the starting material, 1-amino-2-methyl-2-propanol, for 2-methoxyethylamine.

MS(ESI,[M+H] ⁺)m/z:285.0/287.0.

And B, step B: preparation of Compound 15-2

Referring to the procedure of step E of example 1, using compound 15-1 obtained in the above step A, a reaction solution containing compound 15-2 was prepared, cooled to room temperature, and used in the next reaction without separation and purification.

And C: preparation of Compound 15

Compound 15 was obtained by the method of step F of example 1 using the reaction solution containing compound 15-2 obtained in the above step B and compound 12-1 obtained in step A of example 12.

¹H NMR(500MHz,DMSO-d ₆):δ10.69(s,1H),9.25(s,2H),9.14(s,1H),8.76(s,1H),8.59(s,1H),7.93(d,J＝8.5Hz,2H),7.41(d,J＝8.5Hz,2H),4.80(s,2H),4.74(s,1H),3.53(s,2H),1.16(s,6H).

MS(ESI,[M-H] ^-)m/z:501.1.

Example 16: preparation of Compound 16

Step A: preparation of Compound 16-1

Compound 16-1 was prepared according to the procedure of example 13, step a, substituting the starting material, 4-aminotetrahydropyran, for 2-methoxyethylamine.

MS(ESI,[M+H] ⁺)m/z:297.0/299.0.

And B: preparation of Compound 16-2

Referring to the procedure of step E of example 1, a reaction solution containing compound 16-2 was prepared using compound 16-1 obtained in the above step A, cooled to room temperature, and used in the next step without isolation and purification.

And C: preparation of Compound 16

Compound 16 was prepared by the method of step F of example 1 using the reaction solution containing compound 16-2 obtained in step B above and compound 12-1 obtained in step A of example 12.

¹H NMR(500MHz,DMSO-d ₆):δ11.21(s,1H),9.44(m,2H),9.33(s,1H),9.17(m,1H),8.73(d,J＝2.0Hz,1H),8.05(d,J＝9.0Hz,2H),7.47(d,J＝8.5Hz,2H),4.72(s,2H),4.42(m,1H),4.03(m,2H),3.53(m,2H),1.95(m,2H),1.79(m,2H).

MS(ESI,[M-H] ^-)m/z:513.1.

Example 17: preparation of Compound 17

Step A: preparation of Compound 17-1

Compound 17-1 was prepared by the method of example 1, step B, substituting the starting material, 3-hydroxyazetidine hydrochloride, for (R) -3-pyrrolidinol.

And B, step B: preparation of Compound 17

Compound 17 was obtained by the method of step F of example 1 using the reaction solution containing compound 11-2 obtained in step B of example 11 and the reaction solution containing compound 17-1 obtained in step A.

¹H NMR(500MHz,DMSO-d ₆)δ10.23(s,1H),8.79(d,J＝4.8Hz,2H),8.07(s,2H),7.86(d,J＝8.8Hz,2H),7.35(d,J＝8.5Hz,2H),5.54(d,J＝6.1Hz,1H),4.53(s,2H),4.36-4.37(m,1H),3.84-3.88(m,2H),3.45-3.48(m,2H),3.02(s,1H),0.82-0.84(m,4H).

MS(ESI,[M+H] ⁺)m/z:542.1.

Example 18: preparation of Compound 18

Step A: preparation of Compound 18-1

Compound 18-1 was prepared by the method of example 1, step B, substituting starting morpholine for (R) -3-pyrrolidinol.

And B: preparation of Compound 18

Compound 18 was prepared by the method of step F of example 1 using the reaction solution containing compound 10-3 obtained in step B of example 10 and the reaction solution containing compound 18-1 obtained in step A described above.

¹H NMR(500MHz,DMSO-d ₆)δ10.36(s,1H),9.02(d,J＝2.0Hz,1H),8.82(s,1H),8.34(s,1H),8.21(s,1H),7.87(d,J＝9.1Hz,2H),7.36(d,J＝9.0Hz,2H),4.60(s,2H),3.52-3.53(m,4H),3.14(s,3H),3.13-3.14(m,4H).

MS(ESI,[M+H] ⁺)m/z:530.1.

Example 19: preparation of Compound 19

Step A: preparation of Compound 19

Compound 19 was obtained by the method referred to step F of example 1, using the reaction solution containing compound 10-3 obtained in step B of example 10 and compound 17-1 obtained in step A of example 17.

¹H NMR(500MHz,DMSO-d ₆)δ10.23(s,1H),8.78-8.80(m,2H),8.09(s,2H),7.85-7.87(m,2H),7.34-7.36(m,2H),5.54(d,J＝6.2Hz,1H),4.60(s,2H),4.33-4.39(m,1H),3.85-3.88(m,2H),3.44-3.48(m,2H), 3.15(s,3H).

MS(ESI,[M+H] ⁺)m/z:516.1.

Example 20: preparation of Compound 20

Step A: preparation of Compound 20-1

Compound 20-1 was prepared by the method of step B of example 1, substituting the starting material, 2-oxa-7-azaspiro [3.5] nonane, for (R) -3-pyrrolidinol.

And B: preparation of Compound 20

Compound 20 was prepared by the method of step F of example 1 using the reaction solution containing compound 10-3 obtained in step B of example 10 and the reaction solution containing compound 20-1 obtained in step A described above.

¹H NMR(500MHz,DMSO-d ₆)δ10.33(s,1H),8.99(s,1H),8.79(s,1H),8.30(s,1H),8.18(s,1H),7.86(d,J＝8.9Hz,2H),7.36(d,J＝8.7Hz,2H),4.61(s,2H),4.27(s,4H),3.14(s,3H),3.07(s,4H),1.70(s,4H).

MS(ESI,[M+H] ⁺)m/z:570.2.

Example 21: preparation of Compound 21

Step A: preparation of Compound 21-1

Referring to the procedure for the preparation of step B of example 1, compound 1-1 and 2-oxa-6-aza-spiro [3.3] heptane were reacted to give compound 21-1.

MS(ESI,[M+H] ⁺)m/z:474.1.

And B, step B: preparation of Compound 21

Compound 21 was prepared by reacting the reaction mixture containing compound 10-3 obtained in step B of example 10 with compound 21-1 obtained in step A described above, according to the procedure of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.23(s,1H),8.79(s,2H),8.08(s,2H),7.86(d,J＝8.0Hz,2H),7.35(d,J＝7.7Hz,2H),4.62(s,2H),4.57(s,4H),3.88(s,4H),3.16(s,3H).

MS(ESI,[M+H] ⁺)m/z:542.3/544.2.

Example 22: preparation of Compound 22

Step A: preparation of Compound 22-1

Compound 22-1 was prepared by reacting compound 1-1 with 3-cyanoazetidine hydrochloride according to the procedure for the preparation of step B of example 1.

MS(ESI,[M-H] ^-)m/z:455.0/457.0.

And B: preparation of Compound 22

Compound 22 can be prepared by reacting compound 22-1 obtained in step A with the reaction mixture containing compound 10-3 obtained in step B of example 10 according to the procedure of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.30(s,1H),8.90–8.74(m,2H),8.19–8.06(m,2H),7.86(d,J＝8.7 Hz,2H),7.35(d,J＝8.6Hz,2H),4.60(s,2H),3.96(t,J＝8.8Hz,2H),3.88–3.81(m,2H),3.74–3.66(m,1H),3.15(s,3H).

MS(ESI,[M-H] ^-)m/z:523.2.0/525.2.

Example 23: preparation of Compound 23

Step A: preparation of Compound 23

Compound 23 was prepared by the method of step F of example 1, using the reaction mixture containing Compound 11-2 obtained in step B of example 11 and Compound 22-1 obtained in step A of example 22.

¹H NMR(500MHz,DMSO-d ₆)δ10.30(s,1H),9.01–8.70(m,2H),8.29–8.00(m,2H),7.86(d,J＝8.7Hz,2H),7.35(d,J＝8.6Hz,2H),4.53(s,2H),3.96(t,J＝8.8Hz,2H),3.84(t,J＝7.1Hz,2H),3.76–3.64(m,1H),3.09–2.93(m,1H),0.99–0.89(m,2H),0.88–0.77(m,2H).

MS(ESI,[M-H] ^-)m/z:549.2/551.1.

Example 24: preparation of Compound 24

Step A: preparation of Compound 24-1

Referring to the preparation method of step B of example 1, compound 24-1 is prepared by reacting compound 1-1 with 3-methoxyazetidine.

MS(ESI,[M-H] ^-)m/z:460.1/462.1.

And B, step B: preparation of Compound 24

Compound 24 was prepared by reacting the reaction mixture containing compound 10-3 obtained in step B of example 10 with compound 24-1 obtained in step A described above, according to the procedure of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.25(s,1H),8.90–8.71(m,2H),8.19–8.05(m,2H),7.86(d,J＝8.6Hz,2H),7.35(d,J＝8.6Hz,2H),4.60(s,2H),4.16–4.07(m,1H),3.92–3.79(m,2H),3.58–3.46(m,2H),3.14(s,3H),3.12(s,3H).

MS(ESI,[M-H] ^-)m/z:527.91/529.90.

Example 25: preparation of Compound 25

Step A: preparation of Compound 25-1

Referring to the preparation method of step B of example 1, compound 25-1 was prepared by reacting compound 1-1 with 2-methoxyethylamine.

MS(ESI,[M-H] ^-)m/z:448.08/450.05.

And B, step B: preparation of Compound 25

Compound 25 was prepared by reacting compound 25-1 obtained in step A with the reaction solution containing compound 10-3 obtained in step B of example 10 according to the procedure in step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.15(s,1H),8.78(d,J＝2.0Hz,1H),8.74(d,J＝2.3Hz,1H),8.09(d,J＝2.1Hz,1H),7.93(d,J＝2.4Hz,1H),7.90–7.80(m,2H),7.33(d,J＝8.7Hz,2H),6.70(t,J＝5.6Hz,1H),4.60(s,2H),3.55(q,J＝5.9Hz,2H),3.47(t,J＝6.0Hz,2H),3.25(s,3H),3.15(s,3H).

MS(ESI,[M-H] ^-)m/z:516.2/518.2.

Example 26: preparation of Compound 26

Step A: preparation of Compound 26-1

Referring to the preparation method of step B of example 1, compound 26-1 was prepared by reacting compound 1-1 with 1-amino-2-methyl-2-propanol.

MS(ESI,[M-H] ^-)m/z:462.0.

And B: preparation of Compound 26

Compound 26 can be prepared by reacting compound 26-1 obtained in step A with the reaction solution containing compound 10-3 obtained in step B of example 10 according to the procedure in step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.16(s,1H),8.85(d,J＝2.1Hz,1H),8.71(d,J＝2.4Hz,1H),8.17(d,J＝2.1Hz,1H),7.96(d,J＝2.4Hz,1H),7.89–7.78(m,2H),7.33(d,J＝8.7Hz,2H),6.22(t,J＝5.8Hz,1H),4.69(s,1H),4.61(s,2H),3.42(d,J＝5.8Hz,2H),3.15(s,3H),1.10(s,6H).

MS(ESI,[M-H] ^-)m/z:530.3/532.3.

Example 27: preparation of Compound 27

Step A: preparation of Compound 27-1

Referring to the preparation method of step B of example 1, compound 27-1 was prepared by reacting compound 1-1 with N-methyl-2-hydroxyethylamine.

¹H NMR(500MHz,DMSO-d ₆)δ10.68(s,1H),9.00(d,J＝2.3Hz,1H),8.98(d,J＝2.0Hz,1H),8.95(s,1H),8.53(d,J＝2.3Hz,1H),8.34(d,J＝2.0Hz,1H),7.88(d,J＝9.1Hz,2H),7.40(d,J＝8.9Hz,2H),4.55(s,2H).

And B: preparation of Compound 27

Compound 27 was prepared by reacting compound 27-1 obtained in the above step A with the reaction solution containing compound 10-3 obtained in step B of example 10, according to the procedure of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.25(s,1H),8.85(s,1H),8.76(s,1H),8.17(s,1H),8.12(s,1H),7.86(d,J＝8.7Hz,2H),7.35(d,J＝8.4Hz,2H),4.66(t,J＝4.7Hz,1H),4.59(s,2H),3.53(t,J＝5.7Hz,2H),3.43(t,J＝6.0Hz,2H),3.14(s,3H),2.71(s,3H).

MS(ESI,[M-H] ^-)m/z:516.2/518.1.

Example 28: preparation of Compound 28

Step A: preparation of Compound 28-1

Referring to the preparation method of step B of example 1, compound 28-1 is prepared by reacting compound 1-1 with azetidine hydrochloride.

¹H NMR(500MHz,DMSO-d ₆)δ10.24(s,1H),8.68(d,J＝2.0Hz,1H),8.29(d,J＝2.0Hz,1H),7.85(d,J＝9.1Hz,2H),7.34(d,J＝9.0Hz,2H),4.31(t,J＝7.6Hz,4H),2.27(p,J＝7.6Hz,2H).

And B: preparation of Compound 28

Compound 28 was prepared by reacting the reaction mixture containing Compound 2-3 obtained in step C of example 2 with Compound 28-1 obtained in step A described above, according to the procedure of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ8.96(d,J＝1.9Hz,1H),8.76(d,J＝2.1Hz,1H),8.50(d,J＝2.1Hz,1H), 8.31(d,J＝1.9Hz,1H),7.96(d,J＝9.1Hz,2H),7.37(d,J＝8.9Hz,2H),5.59(s,4H),4.56(s,2H),2.56(p,J＝1.9Hz,1H).

MS(ESI,[M-H] ^-)m/z:484.16/486.14.

Example 29: preparation of Compound 29

Step A: preparation of Compound 29-1

Compound 29-1 was prepared by reacting compound 1-1 with 3-fluoroazetidine hydrochloride according to the procedure for the preparation of step B of example 1.

And B, step B: compound 29 preparation

Compound 29 can be prepared by reacting compound 29-1 obtained in step A above with the reaction mixture containing compound 2-3 obtained in step C of example 2 by the method described in step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.28(s,1H),8.94(s,1H),8.86(d,J＝2.0Hz,1H),8.82(d,J＝2.2Hz,1H),8.15(d,J＝2.2Hz,1H),8.14(d,J＝2.0Hz,1H),7.88(d,J＝9.1Hz,2H),7.36(d,J＝8.9Hz,2H),5.47–5.16(m,1H),4.52(s,2H),4.10–3.96(m,2H),3.83–3.68(m,2H).

MS(ESI,[M-H] ^-)m/z:502.20/504.25.

Example 30: preparation of Compound 30

Step A: preparation of Compound 30

Compound 30 was prepared by the method of step F of example 1, using the reaction mixture containing Compound 10-3 obtained in step B of example 10 and Compound 28-1 obtained in step A of example 28.

¹H NMR(500MHz,DMSO-d ₆)δ10.69(s,1H),9.25(d,J＝2.1Hz,1H),9.14(d,J＝2.0Hz,1H),8.75(t,J＝2.1Hz,1H),8.57(d,J＝2.1Hz,1H),7.92(d,J＝9.1Hz,2H),7.41(d,J＝9.0Hz,2H),4.64(s,2H),3.70–3.60(m,2H),3.43–3.37(m,2H),3.25(s,3H),1.95–1.84(m,2H).

MS(ESI,[M-H] ^-)m/z:498.14/500.10.

Example 31: preparation of Compound 31

Step A: preparation of Compound 31

Compound 31 can be prepared by reacting the reaction mixture containing compound 10-3 obtained in step B of example 10 with compound 29-1 obtained in step A of example 29, according to the procedure of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.28(s,1H),8.83(d,J＝2.0Hz,1H),8.82(d,J＝2.2Hz,1H),8.14(d,J＝2.2Hz,1H),8.12(d,J＝2.0Hz,1H),7.87(d,J＝9.1Hz,2H),7.36(d,J＝8.9Hz,2H),5.41–5.22(m,1H),4.61(s,2H),4.11–3.96(m,2H),3.81–3.67(m,2H),3.15(s,3H).

MS(ESI,[M-H] ^-)m/z:516.13/518.11.

Example 32: preparation of Compound 32

Step A: preparation of Compound 32

Compound 32 was prepared by reacting the reaction mixture containing compound 10-3 obtained in step B of example 10 with compound 8-1 obtained in step A of example 8, according to the procedure of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.19(s,1H),8.78(d,J＝2.3Hz,1H),8.77(d,J＝2.0Hz,1H),8.08(d,J＝2.2Hz,1H),8.07(d,J＝1.9Hz,1H),7.87(d,J＝9.1Hz,2H),7.34(d,J＝8.8Hz,2H),4.59(s,2H),3.14(s,3H),3.13–3.04(m,4H),1.82–1.67(m,4H).

MS(ESI,[M-H] ^-)m/z:512.20/514.16.

Example 33: preparation of Compound 33

Step A: preparation of Compound 33-1

Referring to the preparation method of step B of example 1, compound 33-1 was prepared by reacting compound 1-1 with (S) -3-hydroxymethyltetrahydropyrrole hydrochloride.

¹H NMR(500MHz,DMSO-d ₆)δ10.23(s,1H),8.69(d,J＝2.1Hz,1H),8.35(d,J＝2.1Hz,1H),7.86(d,J＝9.1Hz,2H),7.34(d,J＝9.0Hz,2H),3.78–3.66(m,4H),1.97–1.83(m,4H).

And B: preparation of Compound 33

Compound 33 can be produced by reacting the reaction mixture containing compound 10-3 obtained in step B of example 10 with compound 33-1 obtained in the above-mentioned step by the method described in step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.20(s,1H),8.79(d,J＝1.9Hz,1H),8.78–8.74(m,1H),8.10(d,J＝1.9Hz,1H),8.08(d,J＝2.1Hz,1H),7.87(d,J＝9.0Hz,2H),7.34(d,J＝8.7Hz,2H),4.60(s,2H),3.94–3.80(m,1H),3.31–3.25(m,1H),3.25–3.17(m,2H),3.16(s,3H),3.15(s,3H),3.12–3.06(m,1H),1.95–1.88(m,1H),1.88–1.79(m,1H).

MS(ESI,[M-H] ^-)m/z:542.19/544.20.

Example 34: preparation of Compound 34

Step A: preparation of Compound 34

Compound 34 was obtained by reacting the reaction mixture containing compound 2-3 obtained in step C of example 2 with compound 33-1 obtained in step A of example 33 in accordance with the procedure in step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.20(s,1H),8.92(s,1H),8.82–8.76(m,2H),8.11(d,J＝2.3Hz,1H),8.10–8.07(m,1H),7.87(d,J＝9.1Hz,2H),7.35(d,J＝8.9Hz,2H),4.51(s,2H),3.90(p,J＝4.8,2.3Hz,1H),3.31–3.26(m,1H),3.26–3.17(m,2H),3.16(s,3H),3.13–3.05(m,1H),1.96–1.89(m,1H),1.89–1.77(m,1H).

MS(ESI,[M-H] ^-)m/z:528.18/530.22.

Example 35: preparation of Compound 35

Step A: preparation of Compound 35-1

Referring to the preparation method of step B of example 1, compound 1-1 and (S) -3-cyanopyrrolidine hydrochloride should be prepared to give compound 35-1.

¹H NMR(500MHz,DMSO-d ₆)δ10.30(s,1H),8.72(d,J＝1.9Hz,1H),8.41(d,J＝1.9Hz,1H),7.87(d,J＝9.0Hz,2H),7.35(d,J＝8.8Hz,2H),4.05–3.97(m,1H),3.95–3.86(m,2H),3.85–3.77(m,1H),3.53(p,J＝6.4Hz,1H),2.38–2.28(m,1H),2.27–2.16(m,1H).

And B: preparation of Compound 35

Compound 35 was prepared by reacting the reaction mixture containing Compound 10-3 obtained in step B of example 10 with Compound 35-1 obtained in the above-mentioned step, according to the procedure of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.26(s,1H),8.81(d,J＝2.3Hz,1H),8.79(d,J＝2.0Hz,1H),8.14(d,J＝2.3Hz,1H),8.12(d,J＝2.0Hz,1H),7.87(d,J＝9.1Hz,2H),7.35(d,J＝8.9Hz,2H),4.61(s,2H),3.57–3.48(m,1H),3.46–3.36(m,2H),3.26–3.17(m,2H),3.15(s,3H),2.23–2.13(m,1H),2.11–2.02(m,1H).

MS(ESI,[M-H] ^-)m/z:537.18/539.19.

Example 36: preparation of Compound 36

Step A: preparation of Compound 36

Compound 36 can be prepared by reacting the reaction mixture containing Compound 2-3 obtained in step C of example 2 with Compound 35-1 obtained in step A of example 35, according to the procedure of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.25(s,1H),8.93(s,1H),8.81(d,J＝2.1Hz,2H),8.17–8.12(m,2H),7.87(d,J＝9.1Hz,2H),7.35(d,J＝8.9Hz,2H),4.52(s,2H),3.58–3.50(m,1H),3.47–3.37(m,2H),3.28–3.12(m,2H),2.25–2.13(m,1H),2.13–2.03(m,1H).

MS(ESI,[M-H] ^-)m/z:523.18/525.18.

Example 37: preparation of Compound 37

Step A: preparation of Compound 37-1

Referring to the preparation method of step B of example 1, compound 37-1 was prepared by reacting compound 1-1 with ethyl 4-aminobutyrate hydrochloride.

¹H NMR(500MHz,DMSO-d ₆)δ10.19(s,1H),8.70–8.62(m,1H),8.29(d,J＝2.0Hz,1H),7.86(d,J＝9.1Hz,2H),7.34(d,J＝8.9Hz,2H),7.08(t,J＝5.8Hz,1H),4.05(q,J＝7.1Hz,2H),3.47(q,J＝6.6Hz,2H), 2.34(t,J＝7.4Hz,2H),1.84(q,J＝7.1Hz,2H),1.17(t,J＝7.1Hz,3H).

And B, step B: preparation of Compound 37-2

A50 mL single-neck flask was charged with compound 37-1(660mg) obtained in step A and 1M aqueous sodium hydroxide solution (10mL), and heated to 80 ℃ for 2 hours. The pH was adjusted to 5 with 6M dilute hydrochloric acid, diluted with 10mL of water and extracted 3 times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give 600mg of compound 37-2.

¹H NMR(500MHz,DMSO-d ₆)δ12.06(s,1H),10.20(s,1H),8.66(d,J＝2.0Hz,1H),8.29(d,J＝2.0Hz,1H),7.86(d,J＝9.1Hz,2H),7.34(d,J＝8.9Hz,2H),7.08(t,J＝5.7Hz,1H),3.46(q,J＝6.6Hz,2H),2.27(t,J＝7.4Hz,2H),1.81(p,J＝7.2Hz,2H).

And C: preparation of Compound 37-3

A50 mL single-neck flask was charged with the compound 37-2(600mg) obtained in the above step B, DMF (20mL) and triethylamine (162mg), and a DMF (5mL) solution of pentafluorophenyl diphenyl phosphate (482mg) was added dropwise at room temperature, and the mixture was heated to 50 ℃ to react, after completion of the reaction. 150mL of water was added, extracted three times with ethyl acetate, the organic phases were combined and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by column chromatography to give 489mg of compound 37-3.

¹H NMR(500MHz,DMSO-d ₆)δ10.68(s,1H),8.97(d,J＝1.8Hz,1H),8.66(d,J＝1.8Hz,1H),7.88(d,J＝9.0Hz,2H),7.39(d,J＝8.8Hz,2H),3.90(t,J＝6.9Hz,2H),2.49(d,J＝8.1Hz,2H),2.18(p,J＝7.4Hz,2H).

Step D: preparation of Compound 37

Compound 37 can be obtained by reacting the reaction mixture containing Compound 10-3 obtained in step B of example 10 with Compound 37-3 obtained in the above-mentioned step by the method described in step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.63(s,1H),9.01(d,J＝2.2Hz,1H),8.84(d,J＝1.9Hz,1H),8.49–8.42(m,1H),8.20(d,J＝2.0Hz,1H),7.89(d,J＝9.1Hz,2H),7.40(d,J＝8.9Hz,2H),4.59(s,2H),4.14(t,J＝6.8Hz,2H),3.14(s,3H),2.18(t,J＝7.7Hz,2H),2.07(p,J＝8.0,7.4Hz,2H).

MS(ESI,[M+H] ⁺)m/z:528.3/530.2.

Example 38: preparation of Compound 38

Step A: preparation of Compound 38-1

Referring to the preparation method of step B of example 1, compound 38-1 was prepared by reacting compound 1-1 with (R) -3-methoxypyrrolidine.

And B: preparation of Compound 38

Compound 38 can be prepared by reacting the reaction mixture containing compound 2-3 obtained in step C of example 2 with compound 38-1 obtained in step A described above, by the method described in step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.20(s,1H),8.92(s,1H),8.79(d,J＝2.5Hz,2H),8.10(m,2H),7.86(d,J＝8.0Hz,2H),7.53(d,J＝7.5Hz,2H),4.51(s,2H),3.89(s,1H),3.25(m,3H),3.17(s,3H),3.10(m,1H),1.85(m,2H).

MS(ESI,[M+H] ⁺)m/z:530.1.

Example 39: preparation of Compound 39

Step A: preparation of Compound 39

Compound 39 can be prepared by reacting the reaction mixture containing Compound 10-3 obtained in step B of example 10 with Compound 38-1 obtained in step 38 of example 1 by the method described in step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.20(s,1H),8.78(m,2H),8.08(m,2H),7.86(d,J＝9.0Hz,2H),7.34(d, J＝8.5Hz,2H),4.60(s,2H),3.89(s,1H),3.25(m,3H),3.20(s,3H),3.18(s,3H),3.12(m,1H),1.85(m,2H).

MS(ESI,[M+H] ⁺)m/z:544.2.

Example 40: preparation of Compound 40

Step A: preparation of Compound 40-1

Referring to the preparation method of step B of example 1, compound 40-1 is prepared by reacting compound 1-1 with (R) -3-cyanopyrrolidine.

And B: preparation of Compound 40

Compound 40 was prepared by reacting the reaction mixture containing Compound 2-3 obtained in step C of example 2 with Compound 40-1 obtained in step A described above, according to the procedure of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.25(s,1H),8.92(s,1H),8.81(s,2H),8.14(d,J＝1.5Hz,2H),7.86(d,J＝8.5Hz,2H),7.35(d,J＝8.5Hz,2H),4.52(s,2H),3.52(m,1H),3.39(m,2H),3.18(m,2H),2.12(m,2H).

HRMS(ESI,[M+H] ⁺)m/z:525.1.

EXAMPLE 41 preparation of Compound 41

Step A: preparation of Compound 41

Compound 41 was prepared by reacting the reaction mixture containing Compound 10-3 obtained in step B of example 10 with Compound 40-1 obtained in step A of example 40 according to the procedure in step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.26(s,1H),8.79(d,J＝5.0Hz,2H),8.12(d,J＝8.0Hz,2H),7.86(d,J＝8.5Hz,2H),7.34(d,J＝8.5Hz,2H),4.61(s,2H),3.52(s,1H),3.40(d,J＝7.0Hz,2H),3.18(m,2H),3.15(s,3H),2.12(m,2H).

HRMS(ESI,[M+H] ⁺)m/z:539.1418.

Example 42: preparation of Compound 42

Step A: preparation of Compound 42-1

To a 25mL three-necked flask, 2-2(0.931g) of the compound obtained in step B of example 2 was charged,1, 4-dioxane (20mL), pinacol diboron ester (1.664g), PdCl₂(dppf) (0.266g), potassium acetate (1.072g), after addition, N₂After protection, the temperature is raised to 90 ℃ for reaction for 2 h. After the reaction was completed, the reaction system was cooled to room temperature, and the compound 1-1(1.5g) obtained in step A of example 1, potassium carbonate (1.509g), Pd (Ph) were sequentially added to the system₃P) ₄(0.421g) and water (5mL) were added, the mixture was replaced with nitrogen, and the mixture was heated to 110 ℃ to react for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was collected, washed with ethyl acetate (50mL) and saturated brine (25mL), separated, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to give 0.5g of compound 42-1.

MS(ESI,[M+H] ^-)m/z:463.1.

And B: preparation of Compound 42-2

To a 35mL microwave tube, compound 42-2(0.3g), 1, 4-dioxane (20mL), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (0.199g), bis (tri-tert-butylphosphine) palladium (0) (0.033g), cesium carbonate (0.420g) and water (4.00mL) were added in this order, the reaction was placed in a microwave reactor under microwave conditions: at 150 deg.C for 30 min. After the reaction was completed, 50mL of ethyl acetate and 20mL of water were added to the reaction solution, the organic phase was collected by liquid separation, and washed three times with 20mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to give 210mg of compound 42-2.

¹H NMR(500MHz,DMSO-d ₆)δ10.62(s,1H),9.12(d,J＝2.5Hz,1H),8.90(s,1H),8.83(d,J＝2.0Hz,1H),8.40(d,J＝2.5Hz,1H),8.24(d,J＝2.0Hz,1H),7.89(m,2H),7.39(d,J＝8.5Hz,2H),5.63(s,1H),4.50(s,2H),4.28(s,2H),3.35(s,2H),1.98(s,2H),1.41(s,9H).

MS(ESI,[M+Na] ⁺)m/z:634.3.

And C: preparation of Compound 42

To a 25mL single-necked flask, compound 42-2(50mg) obtained in the above step and a solution of 4M hydrogen chloride in 1, 4-dioxane (5mL) were added in this order, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to remove the solvent, and the obtained crude product was purified by column chromatography to obtain 40mg of compound 42.

¹H NMR(500MHz,DMSO-d ₆)δ10.87(s,1H),9.48(s,2H),9.15(d,J＝2.0Hz,1H),8.94(s,2H),8.47(d,J＝2.0Hz,1H),8.33(d,J＝2.0Hz,1H),7.94(d,J＝8.5Hz,2H),7.39(d,J＝8.5Hz,2H),5.66(s,1H),5.51(s,2H),4.15(s,2H),3.11(d,J＝4.0Hz,2H),2.17(s,2H).

MS(ESI,[M+H] ⁺)m/z:512.1.

Example 43: preparation of Compound 43

Compound 43 was prepared by reacting compound 42-1 obtained in step a of example 42 with 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester according to the procedure of example 42, step B.

¹H NMR(500MHz,DMSO-d ₆)δ10.62(s,1H),9.12(d,J＝2.0Hz,1H),8.91(s,1H),8.83(d,J＝1.5Hz,1H),8.39(d,J＝1.5Hz,1H),8.21(d,J＝1.5Hz,1H),7.89(d,J＝8.0Hz,2H),7.39(d,J＝7.5Hz,2H),5.64(s,1H),4.52(s,2H),3.95(d,J＝2.0Hz,2H),3.72(t,J＝5.5Hz,2H),2.45(s,2H).

HRMS(ESI,[M+H] ⁺)m/z:513.1174.

Example 44: preparation of Compound 44

Step A: preparation of Compound 44-1

Compound 44-1 was prepared by reacting compound 1-1 obtained in step a of example 1 with compound 10-2 obtained in step a of example 10, according to the procedure of step a of example 42.

¹H NMR(500MHz,DMSO-d ₆)δ10.69(s,1H),8.97(m,2H),8.56(d,J＝2.0Hz,1H),8.32(d,J＝2.0Hz,1H),7.86(d,J＝9.5Hz,2H),7.05(d,J＝9.0Hz,2H),4.64(s,2H),3.15(s,3H).

MS(ESI,[M+H] ⁺)m/z:479.2.

And B: preparation of Compound 44-2

Referring to the procedure of step B of example 42, compound 44-2 was prepared using the reaction of compound 44-1 obtained in the above step A with 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester.

MS(ESI,[M+H] ⁺)m/z:527.3.

And C: preparation of Compound 44

To a 100mL single-necked flask, 44-2(150mg) obtained in the above procedure and methanol (20mL) were sequentially added, Pd/C (1.671mg) was added, and hydrogen gas was substituted three times, followed by stirring at room temperature overnight. Filtering after the reaction is completed, concentrating the filtrate to obtain a crude product, and purifying by column chromatography to obtain 88mg of the compound 44.

¹H NMR(500MHz,DMSO-d ₆)δ10.59(s,1H),9.15(d,J＝2.0Hz,1H),8.83(d,J＝1.5Hz,1H),8.19(m,2H),7.88(d,J＝9.0Hz,2H),7.38(d,J＝8.5Hz,2H),4.64(s,2H),3.86(dd,J＝3.5Hz,11Hz,2H),3.22(t,J＝11.5Hz,2H),3.16(s,3H),3.00(m,1H),1.95(m,2H),1.60(d,J＝12.5Hz,2H).

MS(ESI,[M+H] ⁺)m/z:529.1.

Example 45: preparation of Compound 45

Step A: preparation of Compound 45-1

Referring to the preparation method of step B of example 1, compound 45-1 is prepared by reacting compound 1-1 with 4-hydroxypiperidine.

MS(ESI,[M+H] ⁺)m/z:476.1/478.1.

And B: preparation of Compound 45

Compound 45 was prepared by reacting the reaction mixture containing Compound 10-3 obtained in step B of example 10 with Compound 45-1 obtained in step A described above, according to the preparation method of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.31(s,1H),8.98(d,J＝1.6Hz,1H),8.78(d,J＝2.1Hz,1H),8.32–8.24(m,1H),8.16(d,J＝2.0Hz,1H),7.86(d,J＝9.0Hz,2H),7.35(d,J＝8.7Hz,2H),4.67(d,J＝4.0Hz,1H),4.60(s,2H),3.58(dq,J＝8.3,4.1Hz,1H),3.44(d,J＝13.1Hz,2H),3.14(s,3H),2.86(t,J＝10.5Hz,2H),1.63(d,J＝9.8Hz,2H),1.28(d,J＝9.5Hz,2H).

MS(ESI,[M+H] ⁺)m/z:544.1.

Example 46: preparation of Compound 46

Step A: preparation of Compound 46

Referring to the preparation process of step F of example 1, compound 46 was prepared by reacting compound 45-1 obtained in step A of example 45 with the reaction solution containing compound 11-2 obtained in step B of example 11.

¹H NMR(500MHz,DMSO-d ₆)δ10.31(s,1H),8.99(d,J＝1.8Hz,1H),8.78(d,J＝2.2Hz,1H),8.27(d,J＝1.7Hz,1H),8.15(d,J＝2.1Hz,1H),7.86(d,J＝9.0Hz,2H),7.35(d,J＝8.8Hz,2H),4.67(d,J＝4.0Hz,1H),4.53(s,2H),3.58(dq,J＝8.4,4.2Hz,1H),3.45(d,J＝13.1Hz,2H),3.01(tt,J＝7.4,4.0Hz,1H),2.86(t,J＝10.5Hz,2H),1.64(d,J＝9.9Hz,2H),1.29(d,J＝9.5Hz,2H),0.92(d,J＝3.3Hz,2H),0.83(d,J＝5.3Hz,2H).

MS(ESI,[M+H] ⁺)m/z:570.2.

Example 47: preparation of Compound 47

Step A: preparation of Compound 47-1

Referring to the procedure for the preparation of step B of example 1, compound 47-1 was prepared by reacting compound 1-1 with 3-methylhydroxyazetidine hydrochloride.

MS(ESI,[M-H] ^-)m/z:460.0/462.0.

And B: preparation of Compound 47

Referring to the preparation process of step F of example 1, compound 47 was prepared by reacting compound 47-1 obtained in the above step A with the reaction solution containing compound 10-3 obtained in step B of example 10.

¹H NMR(500MHz,Methanol-d ₄)δ8.82(d,J＝1.9Hz,1H),8.78(d,J＝2.2Hz,1H),8.17(d,J＝1.9Hz,1H),8.05(d,J＝2.2Hz,1H),7.79(d,J＝9.0Hz,2H),7.27(d,J＝8.9Hz,2H),4.62(s,2H),3.84(t,J＝8.6Hz,2H),3.64–3.53(m,4H),3.26(s,3H),2.70(p,J＝8.0Hz,1H).

MS(ESI,[M+H] ⁺)m/z:530.1.

Example 48: preparation of Compound 48

Step A: preparation of Compound 48

Compound 48 can be obtained by reacting the reaction mixture containing Compound 11-2 obtained in step B of example 11 with Compound 47-1 obtained in step A of example 47 according to the preparation process in step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.21(s,1H),8.78(d,J＝8.4Hz,2H),8.06(d,J＝15.2Hz,2H),7.86(d,J＝8.6Hz,2H),7.34(d,J＝8.3Hz,2H),4.68(s,1H),4.53(s,2H),3.69(t,J＝7.9Hz,2H),3.43(dd,J＝11.6,6.0Hz,4H),3.01(s,1H),2.61(s,1H),0.92(s,2H),0.83(d,J＝5.5Hz,2H).

MS(ESI,[M+H] ⁺)m/z:556.2.

Example 49: preparation of Compound 49

Step A: preparation of Compound 49-1

Compound 49-1 was prepared by reacting compound 1-1 with cis-2, 6-dimethylmorpholine according to the procedure for preparation of step B of example 1.

MS(ESI,[M+H] ⁺)m/z:490.0/492.0.

And B: preparation of Compound 49

Compound 49 can be prepared by reacting compound 49-1 obtained in step A with the reaction mixture containing compound 10-3 obtained in step B of example 10 according to the preparation process of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.35(s,1H),8.99(d,J＝1.8Hz,1H),8.80(d,J＝2.2Hz,1H),8.30(d,J＝1.8Hz,1H),8.20(d,J＝2.2Hz,1H),7.87(d,J＝9.1Hz,2H),7.36(d,J＝8.8Hz,2H),4.61(s,2H),3.50(d,J＝16.4Hz,2H),3.44(d,J＝12.6Hz,2H),3.15(s,3H),2.48–2.40(m,2H),0.96(d,J＝6.2Hz,6H).

MS(ESI,[M+H] ⁺)m/z:558.2.

Example 50: preparation of Compound 50

Step A: preparation of Compound 50-1

Referring to the preparation method of step B of example 1, Compound 50-1 was prepared by reacting compound 1-1 with 3-methyl-3-acridine alkoxide.

MS(ESI,[M+H] ^-)m/z:460.0/462.0.

And B: preparation of Compound 50

Compound 50 was prepared by reacting the reaction mixture containing Compound 11-2 obtained in step B of example 11 with Compound 50-1 obtained in step A described above, according to the preparation method of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.23(s,1H),8.79(dd,J＝7.3,1.9Hz,2H),8.07(dd,J＝4.7,2.0Hz,2H),7.86(d,J＝9.0Hz,2H),7.34(d,J＝8.8Hz,2H),5.48(s,1H),4.53(s,2H),3.62–3.48(m,4H),3.01(tt,J＝7.4,3.9Hz,1H),1.27(s,3H),0.92(d,J＝3.3Hz,2H),0.84(d,J＝5.3Hz,2H).

MS(ESI,[M+H] ⁺)m/z:556.2.

Example 51: preparation of Compound 51

Step A: preparation of Compound 51-1

Under the protection of nitrogen, (S) - (-) -2-carboxycyclobutylamine (200mg), tetrahydrofuran (10mL) and borane tetrahydrofuran complex (425mg) are sequentially added into a 50mL sealed tube, and after sealing, the sealed tube is placed into an oil bath pot and heated to 72 ℃ for stirring and reaction overnight. Methanol (5mL) was added to the reaction mixture and stirred for 10min, and the reaction mixture was concentrated under reduced pressure to give a pale yellow residue 51-1, which was used in the next reaction without separation and purification.

And B: preparation of Compound 51-2

Referring to the preparation method of step B of example 1, compound 51-2 was prepared by reacting compound 51-1 with compound 1-1 obtained in the above step A.

MS(ESI,[M-H] ^-)m/z:460.0/462.0.

And C: preparation of Compound 51

Compound 51 was prepared by reacting compound 51-2 of step B described above with the reaction solution containing compound 10-3 of step B of example 10 according to the preparation process of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.22(s,1H),8.85(d,J＝2.0Hz,1H),8.76(d,J＝2.3Hz,1H),8.14(d,J＝2.1Hz,1H),8.08(d,J＝2.3Hz,1H),7.86(d,J＝9.1Hz,2H),7.34(d,J＝9.0Hz,2H),4.88(s,1H),4.59(s,2H),4.44(tt,J＝7.5,4.1Hz,1H),3.69(dt,J＝10.6,5.1Hz,1H),3.55(dt,J＝11.2,5.7Hz,1H),3.19(q,J＝7.9Hz,1H),3.14(s,3H),2.12(q,J＝7.6Hz,2H).

MS(ESI,[M-H] ^-)m/z:528.2.

Example 52: preparation of Compound 52

Step A: preparation of Compound 52-1

Referring to the preparation method of example 51, step A, (R) - (-) -2-carboxycyclobutylamine and borane tetrahydrofuran complex were reacted to prepare compound 52-1.

And B: preparation of Compound 52-2

Referring to the preparation method of step B of example 1, compound 52-2 was prepared by reacting compound 52-1 obtained in the above step A with compound 1-1.

MS(ESI,[M+H] ⁺)m/z:462.1/464.1.

Step C: preparation of Compound 52

Compound 52 was obtained by reacting the reaction mixture containing Compound 10-3 obtained in step B of example 10 with Compound 52-2 obtained in step B described above, according to the preparation process in step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.22(s,1H),8.85(d,J＝2.0Hz,1H),8.76(d,J＝2.3Hz,1H),8.14(d,J＝2.1Hz,1H),8.08(d,J＝2.4Hz,1H),7.89–7.83(m,2H),7.34(d,J＝9.0Hz,2H),4.90(t,J＝5.8Hz,1H),4.59(s,2H),4.44(tt,J＝7.5,4.2Hz,1H),3.69(dt,J＝10.6,5.1Hz,1H),3.60–3.50(m,1H),3.19(q,J＝8.0Hz,1H),3.14(s,3H),2.12(q,J＝7.6Hz,2H).

MS(ESI,[M+H] ⁺)m/z:530.3.

Example 53: preparation of Compound 53

Step A: preparation of Compound 53-1

Referring to the preparation method of step B of example 1, compound 53-1 was prepared by reacting compound 1-1 with (R) -3-fluoropyrrolidine.

MS(ESI,[M+H] ⁺)m/z:464.0/466.0.

And B: preparation of Compound 53

Referring to the preparation process of step F of example 1, compound 53 was prepared by reacting compound 53-1 obtained in step A above with the reaction solution containing compound 2-3 obtained in step C of example 2.

¹H NMR(500MHz,DMSO-d ₆)δ10.23(s,1H),8.93(s,1H),8.82(d,J＝1.7Hz,1H),8.81(d,J＝2.3Hz,1H),8.13(d,J＝2.3Hz,1H),8.13–8.11(m,1H),7.88(s,1H),7.86(s,1H),7.36(s,1H),7.34(s,1H),5.41–5.16(m,1H),4.52(s,2H),3.54–3.42(m,1H),3.34–3.22(m,3H),2.14–1.91(m,2H).

MS(ESI,[M-H] ^-)m/z:516.16/518.20.

Example 54: preparation of Compound 54

Step A: preparation of Compound 54

Compound 54 can be obtained by reacting the reaction mixture containing Compound 10-3 obtained in step B of example 10 with Compound 53-1 obtained in step A of example 53 by the preparation method described in step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.23(s,1H),8.80(s,2H),8.11(d,J＝11.2Hz,2H),7.87(d,J＝8.8Hz,2H),7.35(d,J＝8.5Hz,2H),5.39–5.18(m,1H),4.60(s,2H),3.54–3.40(m,1H),3.33–3.19(m,3H),3.15(s,3H),2.14–1.89(m,2H).

MS(ESI,[M-H] ^-)m/z:530.16/532.14.

Example 55: preparation of Compound 55

Step A: preparation of Compound 55-1

Referring to the preparation method of step B of example 1, compound 55-1 was prepared by reacting compound 1-1 with (S) -3-fluoropyrrolidine.

MS(ESI,[M+H] ⁺)m/z:464.3/466.3.

And B: preparation of Compound 55

Compound 55 was prepared by reacting compound 55-1 of step A described above with the reaction solution containing compound 2-3 obtained in step C of example 2, according to the preparation method of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.23(s,1H),8.93(s,1H),8.81(s,2H),8.24–8.03(m,2H),7.87(d,J＝7.8Hz,2H),7.35(d,J＝7.6Hz,2H),5.40–5.16(m,1H),4.52(s,2H),3.57–3.41(m,1H),3.33–3.15(m,3H),2.20–1.87(m,2H).

MS(ESI,[M+H] ⁺)m/z:518.3/520.3.

Example 56: preparation of Compound 56

Step A: preparation of Compound 56

Compound 56 can be obtained by reacting the reaction mixture containing Compound 10-3 obtained in step B of example 10 with Compound 55-1 obtained in step A of example 55 according to the preparation process in step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.23(s,1H),8.86–8.76(m,2H),8.13(d,J＝2.3Hz,1H),8.12–8.06(m,1H),7.87(d,J＝9.1Hz,2H),7.35(d,J＝8.9Hz,2H),5.37–5.18(m,1H),4.60(s,2H),3.55–3.40(m,1H),3.34–3.19(m,3H),3.15(s,3H),2.17–1.88(m,2H).

MS(ESI,[M+H] ⁺)m/z:532.3/534.2.

Example 57: preparation of Compound 57

Step A: preparation of Compound 57-1

Adding 10mL of absolute ethyl alcohol, the compound 2-1(400mg) obtained in the step A of the example 2, diisopropylethylamine (428mg) and deuterated methylamine hydrochloride (97mg) into a 50mL single-neck flask in sequence, and reacting for 6h at room temperature after the addition is finished; concentrating the reaction solution under reduced pressure; the residue was subjected to column chromatography to give compound 57-1.

MS(ESI,[M+H] ⁺)m/z:230.1/231.9.

And B: preparation of Compound 57-2

Referring to the procedure of step E of example 1, a reaction solution containing compound 57-2 was prepared using compound 57-1 obtained in the above step A, cooled to room temperature, and used for the next reaction without separation and purification.

And C: preparation of Compound 57

Compound 57 was prepared by the method referenced as step F in example 1 using the reaction solution containing compound 57-2 obtained in the above step B and compound 33-1 obtained in step A in example 33.

¹H NMR(500MHz,DMSO-d ₆)δ10.20(s,1H),8.78(d,J＝2.4Hz,1H),8.77(d,J＝2.2Hz,1H),8.09(d,J＝2.3Hz,1H),8.07(d,J＝2.1Hz,1H),7.90–7.82(m,2H),7.34(d,J＝8.6Hz,2H),4.59(s,2H),3.93–3.85(m,1H),3.30–3.16(m,2H),3.15(s,3H),3.09(d,J＝11.9Hz,1H),1.95–1.78(m,2H).

MS(ESI,[M-H] ^-)m/z:545.2/547.2.

Example 58: preparation of Compound 58

Step A: preparation of Compound 58

Compound 58 was prepared by reacting compound 5-1, obtained in step a of example 5, with (3- (methylsulfonyl) phenyl) boronic acid, according to the procedure described in step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.42(s,1H),8.82(d,J＝2.3Hz,1H),8.27(s,1H),8.18(d,J＝2.3Hz,1H),8.04(d,J＝7.7Hz,1H),7.95(d,J＝7.8Hz,1H),7.88(d,J＝9.1Hz,2H),7.81(t,J＝7.8Hz,1H),7.36(d,J＝8.8Hz,2H),3.58–3.54(m,4H),3.30(s,3H),3.19–3.08(m,4H).

MS(ESI,[M+H] ⁺)m/z:538.3/540.2.

Example 59: preparation of Compound 59

Step A: preparation of Compound 59-1

1, 4-dioxane (15mL), 1-tert-butoxycarbonyl-pyrrole-2-boronic acid (423mg), the compound 1-2(700mg) obtained in step B of example 1, potassium carbonate (626mg), tetrakis (triphenylphosphine) palladium (87mg), purified water (3mL) and magnetite were sequentially added to a 20mL microwave tube, and after purging with nitrogen, the mixture was placed in a microwave reactor and reacted at 130 ℃ for 1.5 hours; vacuum concentrating, and purifying the crude product by column chromatography to obtain 500mg of compound 59-1.

MS(ESI,[M-H] ^-)m/z:447.16/449.14.

And B: preparation of Compound 59-2

Adding ultra-dry tetrahydrofuran (15mL), the compound 59-1(400mg) obtained in the step A and azobisisobutyronitrile (21mg) into a 100mL single-neck bottle, and cooling to-78 ℃ under the nitrogen protection condition after adding; dibromohydantoin (94mg) was added to the system in portions, and the reaction was incubated for 2h after the addition. Vacuum concentrating, and purifying the crude product by column chromatography to obtain 370mg of compound 59-2.

MS(ESI,[M-H] ^-)m/z:525.1/527.1.

And C: preparation of Compound 59-3

To a 20mL microwave tube were added 1, 4-dioxane (15mL), 59-2(370mg) of the compound obtained in step B, N-diisopropylethylamine (94mg), sodium thiomethoxide (51.0mg), tris (dibenzylidene-BASE acetone) dipalladium (50mg), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (63mg), and magnetite, and the mixture was placed in a microwave reactor after purging with nitrogen and reacted at 130 ℃ for 2 hours. Vacuum concentrating, and purifying by column chromatography to obtain 250mg of compound 59-3.

MS(ESI,[M-H] ^-)m/z:493.2/495.2.

Step D: preparation of Compound 59

To a 25mL single-neck flask were added isopropanol (5mL), purified water (1.5mL), compound 59-3 from step C (230mg), and potassium peroxymonosulfonate (195mg) in that order, and the reaction was carried out at room temperature for 0.5 h. Ethyl acetate was added to the reaction system to extract 3 times, and the organic phases were combined and washed with a saturated aqueous sodium sulfite solution and a saturated brine in this order 2 times each. The organic phase was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product was purified by column chromatography to give 20mg of compound 59.

¹H NMR(500MHz,DMSO-d ₆)δ12.50(s,1H),10.18(s,1H),8.76(d,J＝2.4Hz,1H),8.08(d,J＝2.4Hz,1H),7.93–7.81(m,2H),7.40–7.28(m,2H),6.80(dd,J＝3.6,2.4Hz,1H),6.28(dd,J＝3.7,2.3Hz,1H),4.88(d,J＝3.4Hz,1H),4.23(s,1H),3.52–3.42(m,1H),3.21(s,3H),2.97(d,J＝11.6Hz,1H),1.90–1.81(m,1H),1.80–1.72(m,1H).

MS(ESI,[M-H] ^-)m/z:525.2/527.2.

Example 60: preparation of Compound 60

Step A: preparation of Compound 60-1

The title compound 60-1 was prepared using compound 1-1 and 2- (methylamino) ethan-1-ol obtained in step A of example 1, according to the procedure of step B of example 1.

And B, step B: preparation of Compound 60

Compound 60 was prepared by reacting compound 60-1 obtained in step A above with the reaction solution containing compound 2-3 obtained in step C of example 2, according to the procedure of step F of example 1.

¹H NMR(500MHz,DMSO-d ₆)δ10.25(s,1H),8.91(s,1H),8.88(s,1H),8.76(s,1H),8.19(s,1H),8.14(s,1H),7.87(d,J＝8.8Hz,2H),7.35(d,J＝8.5Hz,2H),4.66(t,J＝4.9Hz,1H),4.51(s,2H),3.54(q,J＝5.7Hz,2H),3.44(t,J＝6.0Hz,2H),2.71(s,3H).

MS(ESI,[M+H] ⁺)m/z:504.2/506.2.

Example 61: preparation of Compound 61

Step A: preparation of Compound 61-1

Compound 61-1 was prepared by reacting compound 2-1 with 1-tert-butoxycarbonyl-4-aminopiperidine instead of 2-methoxyethylamine, according to the procedure as in step a of example 13.

And B: preparation of Compound 61-2

Referring to the procedure of step E of example 1, a reaction solution containing compound 61-2 was prepared using compound 61-1 obtained in the above step A, cooled to room temperature, and used in the next reaction without separation and purification.

Step C: preparation of Compound 61-3

Compound 61-3 was prepared by the method of step F of example 1 using the reaction solution containing compound 61-2 obtained in step B above and compound 12-1 obtained in step A of example 12.

MS(ESI,[M-H] ^-)m/z:612.29/614.30.

Step D: preparation of Compound 61

To a 50mL round-bottomed flask, compound 61-3(430mg) obtained in the above step A, methylene chloride (10mL) and a 6M hydrogen chloride-dioxane solution (2.5mL) were added, and the mixture was stirred at room temperature overnight, after completion of the reaction, the reaction mixture was concentrated, followed by addition of ethyl acetate (10mL) and stirring at room temperature for 4 hours. Filter and wash the filter cake with ethyl acetate. The filter cake was collected and dried to yield 60mg of compound 61.

¹H NMR(500MHz,DMSO-d ₆)δ9.50–9.45(m,1H),9.41(s,1H),9.38(d,J＝6.7Hz,1H),9.34(s,1H),8.74(s,1H),8.02(d,J＝9.0Hz,2H),7.40(d,J＝8.5Hz,2H),4.64(s,2H),4.41(d,J＝11.7Hz,1H),3.37(d,J＝12.1Hz,2H),3.07(t,J＝11.7Hz,2H),2.14(d,J＝13.3Hz,2H),1.95(d,J＝12.3Hz,2H).

MS(ESI,[M+H] ⁺)m/z:514.3/516.4.

Test example 1 proliferation inhibitory Effect of Compounds on K562 cells

Collecting K562 cells in exponential growth phase, collecting the cells to a centrifuge tube, centrifuging for 5min at a low-speed desk centrifuge at 1000 rpm, discarding the supernatant, and adding 5mL of complete culture medium (RPMI1640 basic medium + 10% FBS) to the pipette for cell resuspension. Counting with a cell counter, diluting the complete medium, adjusting the cell density to 6X 10⁴Adding equal amount of RPMI1640 basic culture medium to adjust serum concentration to 5% and cell density to 3 × 10⁴one/mL. Inoculating to 96-well plate with multi-channel pipette at 100 μ L/well, placing at 37 deg.C and 5% CO₂Culturing in a cell culture box with saturated humidity. After 24h incubation, compounds were loaded using a nanoliter loader, with 8 concentrations (1000nM,250nM,63nM,16nM,3.9nM,0.98nM,0.24nM,0.061nM) per compound, 2 duplicate wells per concentration, with cells without compound as negative controls and medium without cells as blank controls. After 72 hours, adding CCK-8 with 10 mu L/hole,detecting the light absorption value of the Envision microplate reader at 450nm after 2 hours, calculating the inhibition rate, wherein the inhibition rate (%) (negative control group average value-experimental group average value)/(negative control group average value-blank group average value) is multiplied by 100%, taking the logarithm of the concentration of the compound as the abscissa, the inhibition rate as the ordinate, analyzing four parameters, fitting a dose-effect curve, and calculating the IC₅₀The results are shown in Table 1.

Experimental example 2 proliferation inhibitory Effect of Compounds on Ba/F3 cells transfected with BCR-ABL T315I

The Ba/F3-BCR-ABL1-T315I cells (purchased from Bai Biotech Co., Ltd., Nanjing) in the exponential growth phase are taken, the cells are collected into a centrifuge tube, a low-speed desk type centrifuge is used for 1000 r/min, the centrifuge tube is centrifuged for 5min, the supernatant is discarded, and a pipettor is used for adding 5mL of complete culture medium (RPMI1640 basic medium + 10% FBS) for cell resuspension. Counting with a cell counter, diluting the complete medium, and adjusting the cell density to 6X 10⁴Adding the same amount of RPMI1640 basic medium to adjust the serum concentration to 5% and the cell density to 3 × 10⁴one/mL. Inoculating to 96-well plate with multi-channel pipette at 100 μ L/well, placing at 37 deg.C and 5% CO₂Culturing in a cell culture box with saturated humidity. After 24h incubation, compounds were loaded using a nanoliter loader at 8 concentrations (1000nM,250nM,63nM,16nM,3.9nM,0.98nM,0.24nM,0.061nM) per compound, 2 replicate wells per concentration, with cells without compound as negative controls and medium without cells as blank controls. Adding CCK-8 and 10 mu L/well after 72 hours, adding CCK8 into Ba/F3-BCR-ABL1-T315I cells, placing the cells at 37 ℃ after adding CCK8, detecting the light absorption value at 450nm by using an enzyme labeling instrument after 1 hour, calculating the inhibition rate, wherein the inhibition rate (%) (negative control group mean value-experimental group mean value)/(negative control group mean value-blank group mean value) x 100%, taking the logarithm of the compound concentration as the abscissa and the inhibition rate as the ordinate, performing four-parameter analysis, fitting a dose-effect curve, and calculating IC₅₀The results are shown in Table 1.

TABLE 1

Test example 3 evaluation of pharmacokinetics in mice

ICR mice (purchased from Shanghai Seipaibikai laboratory animals Co., Ltd.) weighed 18-22 g, were adapted for 3-5 days, and were randomly grouped, 9 mice per group, and each compound was administered by gavage at a dose of 10 mg/kg. The test animals (ICR mice) were fasted overnight before and food 4h after administration, and water was freely available both before and after and during the experiment. After the intragastric administration, 0.1mL of blood is collected from eye sockets for 0.25h (15min), 0.5h (30min), 1h, 2h, 3h, 4h, 6h, 8h, 10h and 24h (3-4 time points are collected from each mouse, 3 mice are collected at each time point), EDTA-K2 is anticoagulated, and the blood plasma is transferred to the conditions of 4 ℃, 4000rpm and 10min within 30min for centrifugal separation. All plasma was collected and immediately stored at-20 ℃ for testing.

Sucking 30 mu L of plasma sample to be detected and standard yeast sample, adding 300 mu L of acetonitrile solution containing an internal standard (diazepam 20ng/mL), shaking and uniformly mixing for 5min, centrifuging at 13000rpm for 10min, taking 70 mu L of supernatant, adding 70 mu L of ultrapure water for dilution, uniformly mixing, sucking 1 mu L of ultrapure water for LC/MS/MS determination, and recording a chromatogram.

Oral exposure of the compounds was assessed by in vivo pharmacokinetic experiments in mice. The relevant pharmacokinetic parameters were fitted using DAS3.2.5 software and the results are shown in Table 2.

TABLE 2

Claims

A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein,

R ¹is selected from
Or

R ²Selected from hydrogen, 3-10 membered heterocyclyl or amino, wherein said 3-10 membered heterocyclyl or amino is optionally substituted with one or more R^aSubstitution;

R ^aselected from hydroxy, cyano, halogen,
C _1-6Alkyl radical, C_1-6Alkoxy, di (C)_1-6Alkyl) amino, or substituted by one or more hydroxy or C_1-6Alkoxy-substituted C_1-6An alkyl group;

R ³is selected from-OCF₂H, wherein said-OCF₂H is optionally substituted with halogen;

R ⁴selected from hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl or 3-10 membered heterocyclyl, wherein C_1-6Alkyl radical, C_3-6Cycloalkyl or 3-10 membered heterocyclyl is optionally substituted with one or more R^bSubstitution;

R ^bselected from deuterium, hydroxy, C_1-6Alkoxy radical, C_1-6Alkyl, amino, mono (C)_1-6Alkyl) amino or di (C)_1-6Alkyl) amino;

R ⁵is selected from C_1-6An alkyl group;

ring a is selected from 5-6 membered heteroaryl or phenyl.
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R²Selected from hydrogen, 4-6 membered heterocyclyl, 7-9 membered spiroheterocyclyl or amino, wherein said 4-6 membered heterocyclyl, 7-9 membered spiroheterocyclyl or amino is optionally substituted with one or more R^aSubstitution; or, R²Selected from hydrogen, 4-6 membered heterocyclyl or amino, wherein said 4-6 membered heterocyclyl or amino is optionally substituted with one or more R^aSubstitution; or, R²Selected from hydrogen, 4-6 membered heterocycloalkyl, 6 membered heterocycloalkenyl, 7 or 9 membered spiroheterocycloalkyl or amino, wherein said 4-6 membered heterocycloalkyl, 6 membered heterocycloalkenyl, 7 or 9 membered spiroheterocycloalkyl or amino is optionally substituted with one or more R^aSubstitution; or, R²Selected from the group consisting of hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 1,2,3, 6-tetrahydropyridinyl, tetrahydropyranyl, 3, 4-dihydropyranyl, 3, 6-dihydropyranyl, 2-oxa-7-azaspiro [3.5]]Nonanyl, 2-oxa-6-azaspiro [3.3]Heptylalkyl group or amino group, wherein the pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 1,2,3, 6-tetrahydropyridinyl, tetrahydropyranyl, 3, 4-dihydropyranyl, 3, 6-dihydropyranyl, 2-oxa-7-azaspiro [3.5]]Nonanyl, 2-oxa-6-azaspiro [3.3]Heptylalkyl or amino optionally substituted with one or more R^aSubstitution; or, R²Selected from hydrogen,
A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2 wherein R^aSelected from hydroxy, halogen, C_1-6Alkyl, di (C)_1-6Alkyl) amino or C substituted by one or more hydroxy groups_1-6An alkyl group; or, R^aSelected from hydroxy, cyano, halogen,
C _1-4Alkyl radical, C_1-3Alkoxy, di (C)_1-3Alkyl) amino groups or substituted by one or more hydroxy groups or C_1-3Alkoxy-substituted C_1-4An alkyl group; or, R^aSelected from hydroxy, halogen, C_1-3Alkyl, di (C)_1-3Alkyl) amino or C substituted by one or more hydroxy groups_1-3An alkyl group; or, R^aSelected from hydroxy, cyano, fluoro,
Methyl, methoxy, 2-hydroxyethyl, 2-methoxyethyl, 2-methyl-2-hydroxypropyl, di (methyl) amino or hydroxymethyl.
A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-3, wherein R³Is selected from-OCF₃or-OCF₂Cl。
A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-4 wherein R⁴Selected from hydrogen, C_1-5Alkyl radical, C_3-6Cycloalkyl or 4-6 membered heterocycloalkyl, wherein C_1-5Alkyl radical, C_3-6Cycloalkyl or 4-6 membered heterocycloalkyl optionally substituted with one or moreR is^bSubstitution; or, R⁴Selected from hydrogen, C_1-5Alkyl, cyclopropyl or 6-membered heterocycloalkyl, wherein C_1-5Alkyl, cyclopropyl or 6-membered heterocycloalkyl optionally substituted with one or more R^bSubstitution; or, R⁴Selected from hydrogen, methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, tetrahydropyranyl or piperidinyl, wherein methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, tetrahydropyranyl or piperidinyl is optionally substituted by one or more R^bSubstitution; or, R⁴Selected from hydrogen, methyl, d₃-methyl, cyclopropyl,
A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-5 wherein R^bSelected from hydroxy, C_1-6Alkoxy radical, C_1-6Alkyl, amino, mono (C)_1-6Alkyl) amino or di (C)_1-6Alkyl) amino; or, R^bSelected from deuterium, hydroxy, C_1-3Alkoxy radical, C_1-3Alkyl, amino, mono (C)_1-3Alkyl) amino or di (C)_1-3Alkyl) amino; or, R^bSelected from hydroxy, C_1-3Alkoxy radical, C_1-3Alkyl, amino, mono (C)_1-3Alkyl) amino or di (C)_1-3Alkyl) amino; or, R^bSelected from deuterium, hydroxy, methoxy, methyl or di (ethyl) amino.
A compound of formula (I) as claimed in any one of claims 1 to 6 or a pharmaceutical thereofThe above acceptable salt, wherein R⁵Is selected from C_1-3An alkyl group; or, R⁵Selected from methyl.
A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-7 wherein ring a is selected from 5-6 membered nitrogen containing heteroaryl or phenyl; alternatively, ring a is selected from pyrrolyl, pyridyl or phenyl.
A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-8 wherein the structural unit
Is selected from
Or, a structural unit
Is selected from
Is further selected from
The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-9, which is a compound of formula (II) or a compound of formula (III),

wherein,

R ³is selected from-OCF₃or-OCF₂Cl; or

Wherein,

structural unit
Is selected from

R ³Is selected from-OCF₃or-OCF₂Cl。
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein,

R ¹is selected from
Or

R ²Selected from hydrogen, 4-10 membered heterocyclyl or amino containing 1-3 heteroatoms selected from N or O or S, wherein said 4-10 membered heterocyclyl or amino is optionally substituted with one or more R^aSubstitution;

R ^aselected from hydroxy, cyano, halogen,
C _1-6Alkyl radical, C_1-6Alkoxy, di (C)_1-6Alkyl) amino, or substituted by one or more hydroxy or C_1-6Alkoxy-substituted C_1-6An alkyl group;

R ³is selected from-OCF₃、-OCF ₂Cl or-OCF₂Br；

R ⁴Selected from hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, or 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N or O or S, wherein C_1-6Alkyl radical, C_3-6Cycloalkyl or 5-7 membered heterocyclyl is optionally substituted with one or more R^bSubstitution;

R ^bselected from deuterium, hydroxy, C_1-6Alkoxy radical, C_1-6An alkyl group;

R ⁵is selected from C_1-6An alkyl group;

ring A is selected from 5-6 membered heteroaryl or phenyl containing 1-3 heteroatoms selected from N or O or S.
A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11, wherein the compound of formula (I) is selected from:
a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-12, wherein the compound of formula (I) is selected from:
a pharmaceutical composition comprising a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof.
Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 14, for the manufacture of a medicament for the treatment and/or prevention of a BCR-ABL associated disease; optionally, the disease is selected from cancer; alternatively, the disease is selected from leukemia; alternatively, the disease is selected from chronic myeloid leukemia.