Compounds as BCR-ABL inhibitors

Abstract

A field of pharmaceutical chemistry, a compound as a BCR-ABL inhibitor, namely a compound of formula (I), or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and its use in preparing a drug for treating BCR-ABL related diseases. #imgabs0#

Description

[0001] Citation of Related Applications

[0002] This application claims the rights and priority of the Chinese invention patent application with application number 202010062317.3 filed with the Intellectual Property Office of the People's Republic of China on January 19, 2020, and the rights and priority of the Chinese invention patent application with application number 202011246125.4 filed with the Intellectual Property Office of the People's Republic of China on November 10, 2020, and the entire contents of which are hereby incorporated by reference into this document in their entirety. Technical Field

[0003] The present application belongs to the field of pharmaceutical chemistry, and provides a compound as a BCR-ABL inhibitor and a preparation method thereof, a pharmaceutical composition containing the compound, and relates to the use of the compound in the preparation of a drug for treating BCR-ABL related diseases. Background Art

[0004] Chronic myeloid leukemia (CML) is the main type of chronic leukemia in my country, accounting for about 70% of chronic leukemia. More than 90% of the cases of this disease have chromosomal abnormalities. The main abnormality is the long arm translocation of chromosomes 9 and 22, forming the Bcr-Abl fusion gene and expressing the protein p-210. The tyrosine kinase activity of p-210 is much stronger than that of p-150 (the normal c-Abl gene expression product), causing abnormal proliferation and differentiation of hematopoietic stem cells, and ultimately causing CML.

[0005] Imatinib is the first Bcr-Abl targeted therapeutic drug to be marketed. It is currently used as a first-line treatment for all stages of CML. Nilotinib, dasatinib, and bosutinib (second-generation Bcr-Abl inhibitors) are approved for the treatment of CML that is resistant or intolerant to imatinib. The efficacy of second-generation Bcr-Abl inhibitors is better than imatinib, and they are effective against almost all types of imatinib-resistant mutations, but the problem of T315I (gatekeeper) mutation resistance has not yet been solved. Among patients who are resistant to first- and second-generation Bcr-Abl inhibitors, T315I mutations account for about 20%. The launch of ponatinib (third-generation Bcr-Abl inhibitor) alleviates the dilemma of patients with T315I resistance mutations who have no medicine to treat, and is the only option for patients who have failed first- and second-generation Bcr-Abl inhibitors.

[0006] ABL001 is a Bcr-Abl allosteric inhibitor developed by Novartis, which is disclosed in WO2013171639 and is currently in Phase III clinical trials. ABL001 is a potent and selective BCR-ABL inhibitor that is active against most mutants, such as T315I. (Andrew A. Wylie et al. (2017) Nature 543, 733-737).

[0007]

[0008] At present, there is no BCR-ABL allosteric inhibitor on the market. There is an urgent need for efficient, low-toxic Bcr-Abl inhibitors that are effective against T315I in clinical practice. It is necessary to further develop new BCR-ABL allosteric inhibitors. Summary of the invention

[0009] In one aspect, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0010]

[0011] in,

[0012] R 1 Selected from or

[0013] R 2 is selected from hydrogen, 3-10 membered heterocyclyl or amino, wherein the 3-10 membered heterocyclyl or amino is optionally substituted by one or more R a replace;

[0014] R a Selected from hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, di(C 1-6 alkyl)amino, or one or more hydroxyl or C 1-6 Alkoxy substituted C 1-6 alkyl;

[0015] R 3 is selected from -OCF2H, wherein said -OCF2H is optionally substituted with halogen;

[0016] R 4 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-10 membered heterocyclic group, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-10 membered heterocyclic group is optionally substituted by one or more R b replace;

[0017] R b Selected from deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl, amino, mono(C 1-6 alkyl)amino or di(C 1-6 Alkyl)amino;

[0018] R 5 Selected from C 1-6 alkyl;

[0019] Ring A is selected from 5-6 membered heteroaryl or phenyl.

[0020] In some embodiments, R a Selected from hydroxyl, halogen, C 1-6 Alkyl, di(C 1-6 alkyl)amino, or C 1-6 Alkyl; R b Selected from hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl, amino, mono(C 1-6 alkyl)amino or di(C 1-6 Alkyl)amino.

[0021] In some embodiments, R 1 Selected from Other variables are as defined in this application.

[0022] In some embodiments, R 1 Selected from Other variables are as defined in this application.

[0023] In some embodiments, R 2 is selected from hydrogen, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl or amino, wherein the 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl or amino is optionally substituted by one or more R a Substitution; other variables are as defined in this application.

[0024] In some embodiments, R 2 is selected from hydrogen, 4-6 membered heterocyclyl, 7-9 membered spiro heterocyclyl or amino, wherein the 4-6 membered heterocyclyl, 7-9 membered spiro heterocyclyl or amino is optionally substituted by one or more R a Substitution; other variables are as defined in this application.

[0025] In some embodiments, R 2 is selected from hydrogen, 4-6 membered heterocyclyl or amino, wherein the 4-6 membered heterocyclyl or amino is optionally substituted by one or more R a Substitution; other variables are as defined in this application.

[0026] In some embodiments, R 2 is selected from hydrogen, 4-6 membered heterocycloalkyl, 6 membered heterocycloalkenyl, 7 or 9 membered spiro heterocycloalkyl or amino, wherein the 4-6 membered heterocycloalkyl, 6 membered heterocycloalkenyl, 7 or 9 membered spiro heterocycloalkyl or amino is optionally replaced by one or more R a Substitution; other variables are as defined in this application.

[0027] In some embodiments, R 2 is selected from 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]heptanyl 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]heptanyl or amino is optionally substituted by one or more R a Substitution; other variables are as defined in this application.

[0028] In some embodiments, R 2 is selected from hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 3,4-dihydropyranyl or amino, wherein the pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 3,4-dihydropyranyl or amino is optionally replaced by one or more R a Substitution; other variables are as defined in this application.

[0029] In some embodiments, R 2 Selected from hydrogen, or amino, wherein the or amino groups are optionally replaced by one or more R a Substitution; other variables are as defined in this application.

[0030] In some embodiments, R a Selected from hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-3 Alkoxy, di(C 1-3 alkyl)amino or one or more hydroxyl or C 1-3 Alkoxy substituted C 1-4 alkyl; other variables are as defined herein.

[0031] In some embodiments, R aSelected from hydroxyl, halogen, C 1-3 Alkyl, di(C 1-3 alkyl)amino, or C 1-3 alkyl; other variables are as defined herein.

[0032] In some embodiments, R a Selected from hydroxyl, cyano, fluorine, methyl, methoxy, 2-hydroxyethyl, 2-methoxyethyl, 2-methyl-2-hydroxypropyl, di(methyl)amino or hydroxymethyl; other variables are as defined herein.

[0033] In some embodiments, R a is selected from hydroxy, fluoro, methyl, 2-hydroxyethyl, di(methyl)amino or hydroxymethyl; other variables are as defined in the present application.

[0034] In some embodiments, R 2 is selected from 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]heptanyl or amino, wherein the pyrrolidinyl is optionally substituted by one hydroxyl, cyano, fluoro, The invention relates to a piperazinyl, piperidinyl or morpholinyl group, wherein the piperazinyl, piperidinyl or morpholinyl group is optionally substituted with one or two hydroxyl groups or methyl groups, wherein the azetidinyl group is optionally substituted with one or two hydroxyl groups, fluoro groups, cyano groups, methyl groups, methoxy groups or hydroxymethyl groups, wherein the amino group is optionally substituted with one or more 2-hydroxyethyl groups, methyl groups, 2-methoxyethyl groups or 2-methyl-2-hydroxypropyl groups; and other variables are as defined herein.

[0035] In some embodiments, R 2 is selected from hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 3,4-dihydropyranyl or amino, wherein the pyrrolidinyl is optionally substituted with one hydroxyl, fluoro or di(methyl)amino, wherein the piperazinyl or piperidinyl is optionally substituted with one methyl, wherein the azetidinyl is optionally substituted with one hydroxyl or hydroxymethyl, wherein the amino is optionally substituted with one or more 2-hydroxyethyl or methyl; other variables are as defined herein.

[0036] In some embodiments, R 2 Selected from hydrogen, Other variables are as defined in this application.

[0037] In some embodiments, R 2 Selected from hydrogen, Other variables are as defined in this application.

[0038] In some embodiments, R 3 is selected from -OCF3 or -OCF2Cl; other variables are as defined in this application.

[0039] In some embodiments, R 4 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more R b Substitution; other variables are as defined in this application.

[0040] In some embodiments, R 4 Selected from hydrogen, C 1-5 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl, wherein C 1-5 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with one or more R b Substitution; other variables are as defined in this application.

[0041] In some embodiments, R 4 Selected from hydrogen, C 1-5 Alkyl, cyclopropyl or 6-membered heterocycloalkyl, wherein C 1-5 Alkyl, cyclopropyl or 6-membered heterocycloalkyl is optionally substituted by one or more R b Substitution; other variables are as defined in this application.

[0042] In some embodiments, R 4 is selected 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 replaced by one or more R b Substitution; other variables are as defined in this application.

[0043] In some embodiments, R 4 is selected from hydrogen, methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, Among them, methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, Optionally one or more R b Substitution; other variables are as defined in this application.

[0044] In some embodiments, R b Selected from deuterium, hydroxyl, C 1-3 Alkoxy, C 1-3 Alkyl, amino, mono(C 1-3 alkyl)amino or di(C 1-3 other variables are as defined herein.

[0045] In some embodiments, R b Selected from hydroxyl, C 1-3 Alkoxy, C 1-3 Alkyl, amino, mono(C 1-3 alkyl)amino or di(C 1-3 other variables are as defined herein.

[0046] In some embodiments, R b is selected from deuterium, hydroxyl, methoxy, methyl or di(ethyl)amino; other variables are as defined in the present application.

[0047] In some embodiments, R b is selected from hydroxy, methoxy, methyl or di(ethyl)amino; other variables are as defined in the present application.

[0048] In some embodiments, R 4 is selected from hydrogen, methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, tetrahydropyranyl or piperidinyl, wherein the methyl group is optionally substituted with three deuterium groups, wherein the ethyl group is optionally substituted with one hydroxyl group, methoxy or di(ethyl)amino, wherein the 2-methylpropyl or 3-methylbutyl group is optionally substituted with one hydroxyl group, wherein the piperidinyl group is optionally substituted with one methyl group; and the other variables are as defined herein.

[0049] In some embodiments, R 4 is selected from hydrogen, methyl, d3-methyl, cyclopropyl, Other variables are as defined in this application.

[0050] In some embodiments, R 4 is selected from hydrogen; and the other variables are as defined herein.

[0051] In some embodiments, R 4 is selected from methyl or cyclopropyl; other variables are as defined herein.

[0052] In some embodiments, R 5 Selected from C 1-3alkyl; other variables are as defined herein.

[0053] In some embodiments, R 5 is selected from methyl; other variables are as defined herein.

[0054] In some embodiments, Ring A is selected from a 5-6 membered nitrogen-containing heteroaryl or phenyl; the other variables are as defined herein.

[0055] In some embodiments, Ring A is selected from pyrrolyl, pyridinyl, or phenyl; the other variables are as defined herein.

[0056] In some embodiments, Ring A is selected from pyrrolyl; the other variables are as defined herein.

[0057] In some embodiments, the structural unit Selected from Other variables are as defined in this application.

[0058] In some embodiments, the structural unit Selected from Further selected from Other variables are as defined in this application.

[0059] In some embodiments, R 1 Selected from or

[0060] R 2 is selected from hydrogen, 3-10 membered heterocyclyl or amino, wherein the 3-10 membered heterocyclyl or amino is optionally substituted by one or more R a replace;

[0061] R a Selected from hydroxyl, halogen, C 1-6 Alkyl, di(C 1-6 alkyl)amino or C substituted by one or more hydroxyl groups 1-6 alkyl;

[0062] R 3 is selected from -OCF2H, wherein said -OCF2H is optionally substituted with halogen;

[0063] R 4 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-10 membered heterocyclic group, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-10 membered heterocyclic group is optionally substituted by one or more R b replace;

[0064] R b Selected from hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl, amino, mono(C 1-6 alkyl)amino or di(C 1-6 Alkyl)amino;

[0065] R 5 Selected from C 1-6 alkyl;

[0066] Ring A is selected from 5-6 membered heteroaryl or phenyl.

[0067] On the other hand, the present application provides a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0068]

[0069] in,

[0070] R 3 Selected from -OCF3 or -OCF2Cl;

[0071] R 2 , R 4 and R a and R b The definition of is as mentioned above.

[0072] On the other hand, the present application provides a compound of formula (III) or a pharmaceutically acceptable salt thereof,

[0073]

[0074] in,

[0075] Structural unit Selected from

[0076] R 3 Selected from -OCF3 or -OCF2Cl;

[0077] R 2 and R a The definition of is as mentioned above.

[0078] In some embodiments, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0079] R 1 Selected from or

[0080] R 2is selected from hydrogen, a 4-10 membered heterocyclyl or amino group containing 1-3 heteroatoms selected from N or O or S, wherein the 4-10 membered heterocyclyl or amino group is optionally substituted by one or more R a replace;

[0081] R a Selected from hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, di(C 1-6 alkyl)amino, or one or more hydroxyl or C 1-6 Alkoxy substituted C 1-6 alkyl;

[0082] R 3 Selected from -OCF3, -OCF2Cl or -OCF2Br;

[0083] R 4 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, or a 5-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl or 5-7 membered heterocyclic group is optionally substituted by one or more R b replace;

[0084] R b Selected from deuterium, hydroxyl, C 1-6 Alkoxy, C 1-6 alkyl;

[0085] R 5 Selected from C 1-6 alkyl;

[0086] Ring A is selected from a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S or a phenyl group.

[0087] In some embodiments, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0088] R 1 Selected from or

[0089] R 2 A 4-9 membered heterocyclyl or amino group selected from hydrogen, containing 1-3 (e.g. 1, 2 or 3) heteroatoms selected from N or O or S (preferably N or O), wherein the 4-9 membered heterocyclyl or amino group is optionally replaced by 1 or 2 R a replace;

[0090] R aSelected from hydroxyl, cyano, halogen (preferably F), C 1-3 Alkyl (preferably methyl, ethyl), C 1-3 Alkoxy (preferably methoxy, ethoxy), di(C 1-6 alkyl)amino, or a hydroxyl or C 1-3 Alkoxy (preferably methoxy, ethoxy) substituted C 1-4 alkyl;

[0091] R 3 Selected from -OCF3 or -OCF2Cl;

[0092] R 4 Selected from hydrogen, C 1-4 alkyl, C3 cycloalkyl, or a 6-membered heterocyclic group containing 1-2 (preferably 1) heteroatoms selected from N, O or S, wherein C 1-4 Alkyl, C3 cycloalkyl or 6-membered heterocyclic group is optionally substituted by one or more R b replace;

[0093] R b Selected from deuterium, hydroxyl and C 1-3 Alkoxy (e.g., methoxy, ethoxy, propoxy);

[0094] R 5 Selected from C 1-3 Alkyl (e.g., methyl, ethyl, propyl);

[0095] Ring A is selected from 5-6 membered heteroaryl containing 1-2 (preferably 1) N heteroatoms or phenyl.

[0096] In some embodiments, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0097] R 1 Selected from or

[0098] R 2 A 4-9 membered heterocyclyl or amino group selected from hydrogen, containing 1-3 (e.g. 1, 2 or 3) heteroatoms selected from N or O or S (preferably N or O), wherein the 4-9 membered heterocyclyl or amino group is optionally replaced by 1 or 2 R a replace;

[0099] R a Selected from hydroxyl, cyano, halogen (preferably F), C 1-3 Alkyl (preferably methyl, ethyl), C 1-3 Alkoxy (preferably methoxy, ethoxy), di(C 1-6 alkyl)amino, or a hydroxyl or C1-3 Alkoxy (preferably methoxy, ethoxy) substituted C 1-4 alkyl;

[0100] R 3 is -OCF2Cl;

[0101] R 4 Selected from hydrogen, C 1-3 Alkyl (preferably methyl, ethyl), C3 cycloalkyl, or a 6-membered heterocyclic group containing 1 heteroatom selected from N or O (preferably O heteroatom), wherein C 1-3 The alkyl group is optionally substituted with one or more R b replace;

[0102] R b Selected from deuterium;

[0103] R 5 Selected from C 1-3 Alkyl (preferably methyl, ethyl);

[0104] Ring A is a 5-membered heteroaryl group containing 1 to 2 (preferably 1) N heteroatoms or a phenyl group.

[0105] In some embodiments, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0106] R 1 Selected from or

[0107] R 2 Selected from

[0108] R 3 Selected from -OCF3 or -OCF2Cl;

[0109] R 4 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, 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;

[0110] R 5 is selected from methyl, ethyl and propyl;

[0111] Ring A is selected from pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl or phenyl.

[0112] In some embodiments, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0113] R 1 Selected from or

[0114] R 2 Selected from

[0115] R 3 is -OCF2Cl;

[0116] R 4 is selected from hydrogen, methyl, d3-methyl, cyclopropyl or

[0117] R 5 Selected from methyl;

[0118] Ring A is selected from pyrrolyl or phenyl.

[0119] There are also some embodiments of the present application which are obtained by any combination of the above variables.

[0120] On the other hand, the present application provides the following compound or a pharmaceutically acceptable salt thereof,

[0121]

[0122]

[0123]

[0124]

[0125] On the other hand, the present application provides the following compound or a pharmaceutically acceptable salt thereof,

[0126]

[0127]

[0128] On the other hand, the present application also provides a pharmaceutical composition, which comprises the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

[0129] On the other hand, the present application also provides a method for treating and / or preventing BCR-ABL related diseases, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a mammal, preferably a human in need thereof.

[0130] On the other hand, the present application also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating and / or preventing BCR-ABL related diseases.

[0131] On the other hand, the present application also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, or its pharmaceutical composition in the treatment and / or prevention of BCR-ABL related diseases.

[0132] On the other hand, the present application also provides the above-mentioned compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating and / or preventing BCR-ABL related diseases.

[0133] In some embodiments, the BCR-ABL-related disease is selected from cancer, such as leukemia (eg, chronic myeloid leukemia).

[0134] Technical Effects

[0135] The compound of the present application or a pharmaceutically acceptable salt thereof can exhibit a proliferation inhibitory effect on K562 cells and Ba / F3 cells transfected with BCR-ABL T315I, has good cell activity, and can exhibit good in vivo pharmacokinetic properties.

[0136] definition

[0137] Unless otherwise specified, the following terms used in this application have the following meanings. A particular term should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient.

[0138] When a covalent bond in certain structural units or groups in the present application is not connected to a specific atom, it means that the covalent bond can be connected to any atom in the structural unit or group as long as it does not violate the valence bond connection rules.

[0139] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo will not occur on an aromatic group.

[0140] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. When a certain group is "optionally" substituted, it means that the group can be unsubstituted or substituted, for example, ethyl is "optionally" substituted by halogen, which means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.) or completely substituted (CF2CF3). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced.

[0141] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. For example, C 1-3 It means that the group may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0142] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 2 R's, each R has an independent choice.

[0143] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0144] When one of the variables is selected from a covalent bond, it means that the two groups it connects are directly connected. For example, when L' in A-L'-Z represents a covalent bond, it means that the structure is actually AZ.

[0145] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0146] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0147] The term "hydroxy" refers to an -OH group.

[0148] The term "amino" refers to a -NH2 group.

[0149] The term "cyano" refers to a -CN group.

[0150] The term "alkyl" refers to a group of the formula C n H2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6 The term "alkyl" refers to an alkyl group containing 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, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above. For another example, the term "C 1-3 The term "alkyl" refers to an alkyl group containing 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, and isopropyl).

[0151] The term "alkoxy" refers to an -O-alkyl group.

[0152] The term "alkylamino" refers to an -NH-alkyl group.

[0153] The term "dialkylamino" refers to -N(alkyl)2.

[0154] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 3 to 10 rings, such as 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-rings. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, bicyclo [1.1.1] penta-1-yl, etc. For example, C 3-4 Cycloalkyl groups include cyclopropyl and cyclobutyl.

[0155] The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged or spirocyclic 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, such as 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, oxirane, tetrahydrofuranyl, dihydrofuranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, and the like.

[0156] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle 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. Examples of 3-membered heterocycloalkyls include, but are not limited to, oxirane, thioethane, and cyclonitroethane. Non-limiting examples of 4-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxadiazine, and thiadinyl. Examples of 5-membered heterocycloalkyls include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl. Examples of 6-membered heterocycloalkyls include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl. Examples of 7-membered heterocycloalkyls include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Preferably, the monocyclic heterocycloalkyl has 5 or 6 ring atoms.

[0157] The term "heterocycloalkenyl" refers to a non-aromatic ring that is partially unsaturated (but not completely unsaturated heteroaromatic) and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 10 ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen, or a 4 to 6 ring. Non-limiting examples of heterocycloalkenyl include, but are not limited to, dihydrofuranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, dihydropyrrolyl, 4H-pyranyl, etc.

[0158] The term "spiro heterocyclic group" refers to a fully saturated or partially unsaturated (but not fully saturated) spiro ring in which one or more ring atoms are selected from sulfur, oxygen and / or nitrogen heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 6 to 10 members. According to the number of shared spiro atoms between rings, the spiro heterocycle is divided into a monospiro heterocycle, a bispiro heterocycle or a polyspiro heterocycle, preferably a monospiro heterocycle or a bispiro heterocycle, more preferably a 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member or 5-member / 6-member monospiro heterocycle. Non-limiting examples of spiro heterocycles include

[0159] The term "spiroheterocycloalkyl" refers to a fully saturated spiroheterocyclyl group.

[0160] The term "heteroaryl" refers to a monocyclic or fused polycyclic system containing at least one (e.g., 1-4, 1-3 or 1-2, such as 1, 2 or 3) heteroatom selected from N, O, S as a ring atom, the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls 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 heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

[0161] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0162] (i) inhibiting a disease or disease state, i.e. arresting its development;

[0163] (ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

[0164] The term "prevention" means administering the compounds or formulations described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0165] The term "therapeutically effective amount" means an amount of the compound of the present application that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of the 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 based on their own knowledge and the present disclosure.

[0166] The term "pharmaceutically acceptable" refers 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 problems or complications, commensurate with a reasonable benefit / risk ratio.

[0167] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0168] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0169] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients 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, etc.

[0170] The word "comprise" or "comprises" and its English variations such as comprises or comprising or equivalents should be understood as an open, non-exclusive meaning, that is, "including but not limited to", meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

[0171] 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, and racemic mixtures 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. All of these isomers and their mixtures are included within the scope of the present invention.

[0172] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0173] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Represents a straight solid bond and straight dashed key

[0174] 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 enantiomer 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 (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (e.g., carbamate formation from an amine).

[0175] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14( 14 C). For another example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen, such as d3-methyl, which means that all three hydrogen atoms on the methyl group are replaced by deuterium atoms. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention. "Optional" or "optionally" means that the event or situation described later may but does not necessarily occur, and the description includes the case where the event or situation occurs and the case where the event or situation does not occur.

[0176] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35S. 18 F. 123 I. 125 I and 36C l etc.

[0177] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes such as 15 O. 13 N. 11 C and 18 F 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 Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0178] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may provide certain therapeutic advantages arising from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of compounds are included within the scope of the present application.

[0179] The compounds of the present application may be asymmetric, for example, 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 may be separated in optically pure form or in racemic form. Optically pure forms may be separated from racemic mixtures or synthesized by using chiral raw materials or chiral reagents.

[0180] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0181] Typical routes of administration of the compounds of the present application or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0182] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0183] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0184] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0185] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0186] The therapeutic dose of the compounds of the present application may be determined, for example, based on the specific use of the treatment, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compounds 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 route of administration. For example, the compounds of the present application may be provided by a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg body weight / day. In certain embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage is likely to depend on such variables as the type and degree of development of the disease or condition, the general health status of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration. The effective dose can be obtained by extrapolation of a dose-response curve derived from an in vitro or animal model test system.

[0187] Herein, singular terms include plural referents and vice versa unless the context clearly dictates otherwise.

[0188] For the purpose of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements regarding the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any reference to these publications herein does not constitute an admission that the publications are part of the common general knowledge in the art in any country.

[0189] The compounds of the present application can 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 combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0190] The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, which must be suitable for the chemical changes of the present application and the reagents and materials required. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0191] An important consideration in the planning of synthetic routes in the art is to select a suitable protecting group for a reactive functional group (such as an amino group in the present application). For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0192] The compound of the general formula (I) of the present application can be prepared by a person skilled in the art of organic synthesis through the following route:

[0193] Synthesis of intermediates (I):

[0194]

[0195] in,

[0196] R 2 , R 3 The definition of is as above, and R 2 Not hydrogen.

[0197] Synthesis of intermediates (II):

[0198]

[0199] in,

[0200] R 3 The definition of R is as mentioned above. 2 For hydrogen.

[0201] Synthesis of intermediates (III):

[0202] Solution 1:

[0203]

[0204] Option 2:

[0205]

[0206] in,

[0207] R 4 , R 5 And Ring A is as defined above.

[0208] Preparation of target compound:

[0209]

[0210] in,

[0211] R 2 , R 3 , R 4 , R 5 And Ring A is as defined above.

[0212] This application uses the following abbreviations:

[0213] SOCl2 represents thionyl chloride; TEA represents triethylamine; Oxone represents potassium persulfate complex salt; NBS represents N-bromosuccinimide; Pd(PPh3)4 represents tetrakis(triphenylphosphine)palladium; PdCl2(dppf) represents 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium; DCM represents dichloromethane; DMSO represents dimethyl sulfoxide; DMF represents N,N-dimethylformamide. DETAILED DESCRIPTION

[0214] For the sake of clarity, the present invention is further described with examples, but the examples are not intended to limit the scope of the present application. It will be apparent to those skilled in the art that various changes and modifications will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. All reagents used in the present application are commercially available and can be used without further purification.

[0215] Example 1: Preparation of Compound 1

[0216]

[0217]

[0218] Step A: Preparation of Compound 1-1

[0219] Add 300mL toluene and 5-bromo-6-chloronicotinic acid (15.0g) to a 500mL three-necked flask in sequence, then drop thionyl chloride (14.79g) into the system at room temperature, heat to 70-80℃ and react for 4h, stop the reaction, and concentrate under reduced pressure to obtain a brown oil; add dichloromethane (300mL), start stirring and drop 4-(chlorodifluoromethoxy)aniline (12.28g) into the system; then drop triethylamine (12.58g); react at room temperature for 4h. Add 100mL saturated sodium bicarbonate aqueous solution to the above reaction solution, stir for 10min, filter and collect the filter cake; separate the mother liquor to obtain an organic phase, add 100mL saturated sodium chloride aqueous solution, stir and separate to obtain an organic phase, add the filter cake to the organic phase and concentrate under reduced pressure to obtain a residue, purify by column chromatography to obtain 20.44g of compound 1-1.

[0220] Step B: Preparation of Compound 1-2

[0221] Isopropanol (10 mL), compound 1-1 (2.0 g) obtained in step A, (R)-3-pyrrolidinol (0.498 g), N,N-diisopropylethylamine (1.229 g) and a magnet were added to a 50 mL sealed tube in sequence, and the sealed tube was placed in a microwave reactor for reaction at 130°C for 30 min. The reaction solution was concentrated under reduced pressure to obtain a brown residue, to which anhydrous ethanol (4 mL) was added for slurrying for 10 min, and filtered, and the filter cake was rinsed with a small amount of anhydrous ethanol and collected; the filter cake was placed in a vacuum drying oven at 50°C and vacuum dried to constant weight to obtain 1.744 g of compound 1-2.

[0222] MS (ESI, [M+H] + )m / z:462.0 / 464.0.

[0223] Step C: Preparation of Compound 1-3

[0224] Add dimethyl sulfoxide (5 mL), 2,5-dibromopyridine (100 mg), 2-methyl-2-mercaptosulfuric acid urea (120 mg), and cesium carbonate (550 mg) to a 25 mL single-mouth bottle in sequence. After the addition is complete, heat to 75-85 ° C and react for 4 hours. Cool to room temperature and filter to obtain a light yellow mother liquor. Add 20 mL of water and extract twice with 10 mL of dichloromethane. Combine the organic phases and add 10 mL of saturated sodium chloride aqueous solution to stir and wash, then separate to obtain an organic phase, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 153 mg of compound 1-3; use it directly in the next step without purification.

[0225] MS (ESI, [M+H] + )m / z:203.9.

[0226] Step D: Preparation of Compound 1-4

[0227] Add isopropanol (90mL) and water (30mL) to a 250mL three-necked flask in sequence, start stirring and add 5-bromo-2-(methylthio)pyridine (3.2g) prepared according to the method in step C to the system, and then add Oxone (potassium persulfate complex salt, 22.17g) in batches. After addition, keep the reaction at room temperature. After cooling to room temperature, filter to obtain a white mother liquor, which is concentrated under reduced pressure; add 50mL of ethyl acetate and 30mL of water for washing, and then extract the aqueous phase with 50mL of ethyl acetate once, combine the organic phases, add 30mL of saturated sodium chloride aqueous solution for washing, and then separate the liquids to obtain the organic phase, which is concentrated under reduced pressure to obtain 3.70g of compound 1-4.

[0228] MS (ESI, [M+H] + )m / z:224.1.

[0229] Step E: Preparation of Compound 1-5

[0230] To a 25 mL three-necked flask, 1,4-dioxane (10 mL), 5-bromo-2-methylsulfonylpyridine (100 mg) obtained in the above step D, biboric acid pinacol ester (164 mg), potassium acetate (85 mg), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (10 mg) were added in sequence. After the addition, the atmosphere was replaced with nitrogen and the temperature was raised to 80-90° C. for reaction for 4 h. The reaction was stopped and the temperature was lowered to room temperature. The mixture was directly used in the next step without separation or purification.

[0231] Step F: Preparation of Compound 1

[0232] To the reaction solution obtained in the above step E, compound 1-2 (163 mg) obtained in the above step B, potassium carbonate (146 mg), deionized water (1.5 mL), and tetrakis(triphenylphosphine)palladium (10 mg) were added in sequence; after the addition, the temperature was raised to 80-90°C and reacted for 4 hours after nitrogen replacement. After cooling to room temperature, the above reaction was filtered, the mother liquor was collected, 15 mL of ethyl acetate was added, stirred and washed, and then separated. The organic phase was added with 15 mL of saturated sodium chloride aqueous solution, stirred and washed, and then separated. Purification by column chromatography obtained a total of 60 mg of compound 1.

[0233] 1H NMR (500MHz, DMSO-d6) 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).

[0234] MS (ESI, [M+H] + )m / z:539.2 / 541.1.

[0235] Example 2: Preparation of Compound 2

[0236]

[0237] Step A: Preparation of Compound 2-1

[0238] Trifluoromethylbenzene (30 mL), 5-bromo-2-methylnicotinate ethyl ester (3.0 g), N-bromosuccinimide (2.62 g), and azobisisobutylcyanide (0.395 g) were added to a 50 mL single-mouth bottle in sequence. After the addition, the temperature was raised to 70-80°C and reacted for 6 hours after nitrogen replacement. After cooling to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography to obtain 1.731 g of compound 2-1.

[0239] MS (ESI, [M+H] + )m / z:321.9 / 323.9.

[0240] Step B: Preparation of compound 2-2

[0241] Add 30 mL of isopropanol solution of ammonia (2 mol / L) and compound 2-1 (1.484 g) obtained in step A to a 100 mL single-necked bottle, and react at room temperature for 6 h. Concentrate the reaction solution under reduced pressure. The residue is purified by column chromatography to obtain 768 mg of compound 2-2.

[0242] 1 H NMR (500MHz, DMSO-d6): δ8.93 (s, 1H), 8.87 (s, 1H), 8.28 (s, 1H), 4.39 (s, 2H).

[0243] Step C: Preparation of Compound 2-3

[0244] Referring to the method of step E of Example 1, the compound 2-2 obtained in step B was used to prepare a reaction solution containing compound 2-3, which was cooled to room temperature and directly used in the next reaction without separation or purification.

[0245] Step D: Preparation of Compound 2

[0246] Referring to the method of step F of Example 1, compound 2 was prepared using the reaction solution obtained in step C above and compound 1-2 obtained in step B of Example 1.

[0247] 1 H NMR (500MHz, DMSO-d6) 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).

[0248] MS (ESI, [M+H] + )m / z:516.2 / 518.2.

[0249] Example 3: Preparation of Compound 3

[0250]

[0251] Referring to the method of step F of example 1, compound 3 was prepared using compound 1-2 obtained in step B of example 1 and 3-methylsulfonylphenylboronic acid.

[0252] 1H NMR (500MHz, DMSO-d6) 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).

[0253] MS (ESI, [M+H] + )m / z:538.1 / 540.1.

[0254] Example 4: Preparation of Compound 4

[0255]

[0256] Step A: Preparation of Compound 4-1

[0257] Referring to the preparation method of step B of Example 1, compound 1-1 was reacted with N-methylpiperazine to prepare compound 4-1.

[0258] MS (ESI, [M+H] + )m / z:475.1 / 477.1.

[0259] Step B: Preparation of Compound 4

[0260] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 4-1 in the above step A to prepare compound 4.

[0261] 1 H NMR (500MHz, DMSO-d6) 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).

[0262] MS (ESI, [M+H] + )m / z:529.3.

[0263] Example 5: Preparation of Compound 5

[0264]

[0265] Step A: Preparation of compound 5-1

[0266] Referring to the preparation method of step B in Example 1, compound 1-1 was reacted with morpholine to prepare compound 5-1.

[0267] MS (ESI, [M+H] + )m / z:462.0 / 464.0.

[0268] Step B: Preparation of Compound 5

[0269] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 5-1 of the above step A to prepare compound 5.

[0270] 1 H NMR (500MHz, DMSO-d6) δ10.29 (s, 1H), 8.98 (s, 1H), 8.85 (s, 1H), 8.75 (s, 1H), 8.28 (s, 1H), 8.15 (s, 1 H), 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).

[0271] MS (ESI, [M+H] + )m / z:516.2.

[0272] Example 6: Preparation of Compound 6

[0273]

[0274] Step A: Preparation of Compound 6-1

[0275] Referring to the preparation method of step B of Example 1, compound 1-1 and (R)-3-dimethylaminopyrrolidine were reacted to prepare compound 6-1.

[0276] MS (ESI, [M+H] + )m / z:489.3 / 491.3.

[0277] Step B: Preparation of Compound 6

[0278] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 6-1 in the above step A to prepare compound 6.

[0279] 1 H NMR (500MHz, DMSO-d6) 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=8.7H z, 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).

[0280] MS (ESI, [M+H] + )m / z:543.3.

[0281] Example 7: Preparation of Compound 7

[0282]

[0283] Step A: Preparation of Compound 7-1

[0284] Referring to the preparation method of step B of Example 1, compound 1-1 was reacted with azetidine to prepare compound 7-1.

[0285] MS (ESI, [M+H] + )m / z:448.1 / 450.1.

[0286] Step B: Preparation of Compound 7

[0287] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 7-1 in the above step A to prepare compound 7.

[0288] 1 H NMR (500MHz, DMSO-d6) 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).

[0289] MS (ESI, [M+H] + )m / z:502.1.

[0290] Example 8: Preparation of Compound 8

[0291]

[0292] Step A: Preparation of Compound 8-1

[0293] Referring to the preparation method of step B of Example 1, compound 1-1 was reacted with tetrahydropyrrole to prepare compound 8-1.

[0294] MS (ESI, [M+H] + )m / z:446.0 / 448.0.

[0295] Step B: Preparation of Compound 8

[0296] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 8-1 in the above step A to prepare compound 8.

[0297] 1 H NMR (500MHz, DMSO-d6) 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).

[0298] MS (ESI, [MH] - )m / z:498.1 / 500.1.

[0299] Example 9: Preparation of Compound 9

[0300]

[0301] Step A: Preparation of compound 9-1

[0302] Referring to the method of step A of example 1, compound 9-1 was prepared using 5-bromo-6-chloronicotinic acid and 4-trifluoromethoxyaniline.

[0303] MS (ESI, [MH] - )m / z:393.0.

[0304] Step B: Preparation of compound 9-2

[0305] Referring to the method of step B of Example 1, compound 9-2 was prepared using compound 9-1 obtained in step A above and (R)-3-pyrrolidinol.

[0306] MS (ESI, [M+H] + )m / z:446.1.

[0307] Step C: Preparation of Compound 9

[0308] Referring to the method of step F of Example 1, compound 9 was prepared using the reaction solution containing compound 2-3 obtained in step C of Example 2 and compound 9-2 obtained in the above step B.

[0309] 1 H NMR (500MHz, DMSO-d6) 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).

[0310] MS (ESI, [M+H] + )m / z:500.2.

[0311] Example 10: Preparation of Compound 10

[0312]

[0313] Step A: Preparation of Compound 10-2

[0314] Referring to the preparation method of step B of Example 2, compound 10-2 was prepared by replacing the isopropanol solution of ammonia (2 mol / L) with the ethanol solution of methylamine (30%-35%, m / m).

[0315] MS (ESI, [M+H] + )m / z:227.1 / 229.1.

[0316] Step B: Preparation of compound 10-3

[0317] Referring to the method of step E of Example 1, the compound 10-2 obtained in step A was used to prepare a reaction solution containing compound 10-3, which was cooled to room temperature and directly used in the next reaction without separation or purification.

[0318] Step C: Preparation of Compound 10

[0319] Referring to the method of step F of Example 1, compound 10 was prepared using the reaction solution containing compound 10-3 obtained in the above step B and compound 1-2 obtained in step B of Example 1.

[0320] 1 H NMR (500MHz, DMSO-d6) 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, 2 H), 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).

[0321] MS (ESI, [M+H] + )m / z:530.2 / 532.2.

[0322] Example 11: Preparation of Compound 11

[0323]

[0324] Step A: Preparation of Compound 11-1

[0325] 20 mL of anhydrous ethanol, cyclopropylamine (532 mg), and compound 2-1 (600 mg) prepared by the method of step A in Example 2 were added to a 100 mL single-necked bottle in sequence. After reacting at room temperature for 6 h, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 405 mg of compound 11-1.

[0326] 1 H NMR (500MHz, DMSO-d6) 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).

[0327] MS (ESI, [M+H] + )m / z:253.0 / 255.0.

[0328] Step B: Preparation of compound 11-2

[0329] Referring to the method of step E of Example 1, the compound 11-1 obtained in step A was used to prepare a reaction solution containing compound 11-2, which was cooled to room temperature and directly used in the next reaction without separation or purification.

[0330] Step C: Preparation of Compound 11

[0331] Referring to the method of step F of Example 1, compound 11 was prepared using the reaction solution containing compound 11-2 obtained in the above step B and compound 1-2 obtained in step B of Example 1.

[0332] 1 H NMR (500MHz, DMSO-d6) 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).

[0333] MS (ESI, [M+H] + )m / z:556.3 / 558.2.

[0334] Example 12: Preparation of Compound 12

[0335]

[0336] Step A: Preparation of Compound 12-1

[0337] Referring to the method of step A of Example 1, 5-bromo-6-chloronicotinic acid was replaced with 5-bromonicotinic acid to obtain compound 12-1

[0338] 1H NMR (500MHz, DMSO-d6) 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).

[0339] MS (ESI, [M+H] + )m / z:377.0 / 379.0 / 381.0.

[0340] Step B: Preparation of Compound 12

[0341] Referring to the method of step F of Example 1, compound 12 was prepared using the reaction solution containing compound 2-3 obtained in step C of Example 2 and compound 12-1 obtained in the above step A.

[0342] 1 H NMR (500MHz, DMSO-d6) 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).

[0343] MS (ESI, [MH] - )m / z:429.0 / 431.0.

[0344] Example 13: Preparation of Compound 13

[0345]

[0346] Step A: Preparation of Compound 13-1

[0347] 5 mL of anhydrous ethanol, compound 2-1 (0.15 g) prepared in step A of Example 2, and 2-methoxyethylamine (0.18 g) were added to a 25 mL single-mouth bottle in sequence and reacted at room temperature for 6 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 0.12 g of compound 13-1.

[0348] MS (ESI, [M+H] + )m / z:271.0.

[0349] Step B: Preparation of compound 13-2

[0350] Referring to the method of step E of Example 1, the compound 13-1 obtained in step A was used to prepare a reaction solution containing compound 13-2, which was cooled to room temperature and directly used in the next reaction without separation or purification.

[0351] Step C: Preparation of Compound 13

[0352] Referring to the method of step F of Example 1, compound 13 was prepared using the reaction solution containing compound 13-2 obtained in step B above and compound 12-1 obtained in step A of Example 12.

[0353] 1 H NMR (500MHz, DMSO-d6) 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).

[0354] MS (ESI, [M+H] + )m / z:489.2.

[0355] Example 14: Preparation of Compound 14

[0356]

[0357] Step A: Preparation of Compound 14-1

[0358] Referring to the method of step A of Example 13, compound 14-1 was prepared by using ethanolamine as the raw material instead of 2-methoxyethylamine.

[0359] MS (ESI, [M+H] + )m / z:257.2 / 259.2.

[0360] Step B: Preparation of compound 14-2

[0361] Referring to the method of step E of Example 1, the compound 14-1 obtained in step A was used to prepare a reaction solution containing compound 14-2, which was cooled to room temperature and directly used in the next reaction without separation or purification.

[0362] Step C: Preparation of Compound 14

[0363] Referring to the method of step F of Example 1, compound 14 was prepared using the reaction solution containing compound 14-2 obtained in step B above and compound 12-1 obtained in step A of Example 12.

[0364] 1 H NMR (500MHz, DMSO-d6) 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).

[0365] MS (ESI, [M+H] + )m / z:475.1.

[0366] Example 15: Preparation of Compound 15

[0367]

[0368]

[0369] Step A: Preparation of Compound 15-1

[0370] Referring to the method of step A of example 13, compound 15-1 was prepared by using 1-amino-2-methyl-2-propanol as the raw material instead of 2-methoxyethylamine.

[0371] MS (ESI, [M+H] + )m / z:285.0 / 287.0.

[0372] Step B: Preparation of compound 15-2

[0373] Referring to the method of step E of Example 1, the compound 15-1 obtained in step A was used to prepare a reaction solution containing compound 15-2, which was cooled to room temperature and directly used in the next reaction without separation or purification.

[0374] Step C: Preparation of Compound 15

[0375] Referring to the method of step F of Example 1, compound 15 was prepared using the reaction solution containing compound 15-2 obtained in step B above and compound 12-1 obtained in step A of Example 12.

[0376] 1 H NMR (500MHz, DMSO-d6): 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).

[0377] MS (ESI, [MH] - )m / z:501.1.

[0378] Example 16: Preparation of Compound 16

[0379]

[0380] Step A: Preparation of Compound 16-1

[0381] Referring to the method of step A of example 13, compound 16-1 was prepared by using 4-aminotetrahydropyran as the raw material instead of 2-methoxyethylamine.

[0382] MS (ESI, [M+H] + )m / z:297.0 / 299.0.

[0383] Step B: Preparation of compound 16-2

[0384] Referring to the method of step E of Example 1, the compound 16-1 obtained in step A was used to prepare a reaction solution containing compound 16-2, which was cooled to room temperature and directly used in the next reaction without separation or purification.

[0385] Step C: Preparation of Compound 16

[0386] Referring to the method of step F of Example 1, compound 16 was prepared using the reaction solution containing compound 16-2 obtained in step B above and compound 12-1 obtained in step A of Example 12.

[0387] 1 H NMR (500MHz, DMSO-d6): 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).

[0388] MS (ESI, [MH] - )m / z:513.1.

[0389] Example 17: Preparation of Compound 17

[0390]

[0391] Step A: Preparation of Compound 17-1

[0392] Referring to the method of step B of Example 1, compound 17-1 was prepared by using 3-hydroxyazetidine hydrochloride as the raw material instead of (R)-3-pyrrolidinol.

[0393] Step B: Preparation of Compound 17

[0394] Referring to the method of step F of Example 1, compound 17 was prepared 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 the above step A.

[0395] 1 H NMR (500MHz, DMSO-d6) 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).

[0396] MS (ESI, [M+H] + )m / z:542.1.

[0397] Example 18: Preparation of Compound 18

[0398]

[0399] Step A: Preparation of Compound 18-1

[0400] Referring to the method of step B of Example 1, compound 18-1 was prepared by using morpholine as the raw material instead of (R)-3-pyrrolidinol.

[0401] Step B: Preparation of Compound 18

[0402] Referring to the method of step F of Example 1, compound 18 was prepared 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 the above step A.

[0403] 1H NMR (500MHz, DMSO-d6) 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).

[0404] MS (ESI, [M+H] + )m / z:530.1.

[0405] Example 19: Preparation of Compound 19

[0406]

[0407] Step A: Preparation of Compound 19

[0408] Referring to the method of step F of Example 1, compound 19 was prepared 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.

[0409] 1 H NMR (500MHz, DMSO-d6) 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).

[0410] MS (ESI, [M+H] + )m / z:516.1.

[0411] Example 20: Preparation of Compound 20

[0412]

[0413] Step A: Preparation of Compound 20-1

[0414] Referring to the method of step B of Example 1, compound 20-1 was prepared by using 2-oxa-7-azaspiro[3.5]nonane as the raw material instead of (R)-3-pyrrolidinol.

[0415] Step B: Preparation of Compound 20

[0416] Referring to the method of step F of Example 1, compound 20 was prepared 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 the above step A.

[0417] 1 H NMR (500MHz, DMSO-d6) 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).

[0418] MS (ESI, [M+H] + )m / z:570.2.

[0419] Example 21: Preparation of Compound 21

[0420]

[0421] Step A: Preparation of Compound 21-1

[0422] Referring to the preparation method of step B of Example 1, compound 1-1 and 2-oxa-6-aza-spiro[3.3]heptane were reacted to prepare compound 21-1.

[0423] MS (ESI, [M+H] + )m / z:474.1.

[0424] Step B: Preparation of Compound 21

[0425] Referring to the method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 21-1 obtained in the above step A to prepare compound 21.

[0426] 1 H NMR (500MHz, DMSO-d6) 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).

[0427] MS (ESI, [M+H] + )m / z:542.3 / 544.2.

[0428] Example 22: Preparation of Compound 22

[0429]

[0430] Step A: Preparation of Compound 22-1

[0431] Referring to the preparation method of step B of Example 1, compound 1-1 and 3-cyanoazetidine hydrochloride were reacted to prepare compound 22-1.

[0432] MS (ESI, [MH] - )m / z:455.0 / 457.0.

[0433] Step B: Preparation of Compound 22

[0434] Referring to the method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 22-1 obtained in the above step A to prepare compound 22.

[0435] 1 H NMR (500MHz, DMSO-d6) δ10.30 (s, 1H), 8.90-8.74 (m, 2H), 8.19-8.06 (m, 2H), 7.86 (d, J=8.7Hz, 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).

[0436] MS (ESI, [MH] - )m / z:523.2.0 / 525.2.

[0437] Example 23: Preparation of Compound 23

[0438]

[0439] Step A: Preparation of Compound 23

[0440] Referring to the method of step F of Example 1, the reaction solution containing compound 11-2 obtained in step B of Example 11 was reacted with compound 22-1 obtained in step A of Example 22 to prepare compound 23.

[0441] 1H NMR (500MHz, DMSO-d6) 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).

[0442] MS (ESI, [MH] - )m / z:549.2 / 551.1.

[0443] Example 24: Preparation of Compound 24

[0444]

[0445] Step A: Preparation of Compound 24-1

[0446] Referring to the preparation method of step B of Example 1, compound 1-1 and 3-methoxyazetidine were reacted to prepare compound 24-1.

[0447] MS (ESI, [MH] - )m / z:460.1 / 462.1.

[0448] Step B: Preparation of Compound 24

[0449] Referring to the method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 24-1 obtained in the above step A to prepare compound 24.

[0450] 1 H NMR (500MHz, DMSO-d6) 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).

[0451] MS (ESI, [MH] - )m / z:527.91 / 529.90.

[0452] Example 25: Preparation of Compound 25

[0453]

[0454] Step A: Preparation of Compound 25-1

[0455] Referring to the preparation method of step B of Example 1, compound 1-1 was reacted with 2-methoxyethylamine to prepare compound 25-1.

[0456] MS (ESI, [MH] - )m / z:448.08 / 450.05.

[0457] Step B: Preparation of compound 25

[0458] Referring to the method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 25-1 obtained in the above step A to prepare compound 25.

[0459] 1 H NMR (500MHz, DMSO-d6) 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), 7.90-7.8 0 (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).

[0460] MS (ESI, [MH] - )m / z:516.2 / 518.2.

[0461] Example 26: Preparation of Compound 26

[0462]

[0463] Step A: Preparation of Compound 26-1

[0464] Referring to the preparation method of step B of Example 1, compound 1-1 and 1-amino-2-methyl-2-propanol were reacted to prepare compound 26-1.

[0465] MS (ESI, [MH] - )m / z:462.0.

[0466] Step B: Preparation of Compound 26

[0467] Referring to the method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 26-1 obtained in the above step A to prepare compound 26.

[0468] 1 H NMR (500MHz, DMSO-d6) 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).

[0469] MS (ESI, [MH] - )m / z:530.3 / 532.3.

[0470] Example 27: Preparation of Compound 27

[0471]

[0472] Step A: Preparation of Compound 27-1

[0473] Referring to the preparation method of step B of Example 1, compound 1-1 was reacted with N-methyl-2-hydroxyethylamine to prepare compound 27-1.

[0474] 1 H NMR (500MHz, DMSO-d6) δ10.68 (s, 1H), 9.00 (d, J = 2.3Hz, 1H), 8.98 (d, J = 2.0Hz, 1H), 8.95 (s, 1H), 8.5 3 (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).

[0475] Step B: Preparation of Compound 27

[0476] Referring to the method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 27-1 obtained in the above step A to prepare compound 27.

[0477] 1H NMR (500MHz, DMSO-d6) 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).

[0478] MS (ESI, [MH] - )m / z:516.2 / 518.1.

[0479] Example 28: Preparation of Compound 28

[0480]

[0481] Step A: Preparation of Compound 28-1

[0482] Referring to the preparation method of step B of Example 1, compound 1-1 was reacted with azetidine hydrochloride to prepare compound 28-1.

[0483] 1 H NMR (500MHz, DMSO-d6) δ10.24 (s, 1H), 8.68 (d, J = 2.0Hz, 1H), 8.29 (d, J = 2.0Hz, 1H), 7.8 5 (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).

[0484] Step B: Preparation of Compound 28

[0485] Referring to the method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 28-1 obtained in the above step A to prepare compound 28.

[0486] 1 H NMR (500MHz, DMSO-d6) 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).

[0487] MS (ESI, [MH] - )m / z:484.16 / 486.14.

[0488] Example 29: Preparation of Compound 29

[0489]

[0490] Step A: Preparation of Compound 29-1

[0491] Referring to the preparation method of step B of Example 1, compound 1-1 and 3-fluoroazetidine hydrochloride were reacted to prepare compound 29-1.

[0492] Step B: Preparation of Compound 29

[0493] Referring to the method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 29-1 obtained in the above step A to prepare compound 29.

[0494] 1 H NMR (500MHz, DMSO-d6) 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).

[0495] MS (ESI, [MH] - )m / z:502.20 / 504.25.

[0496] Example 30: Preparation of Compound 30

[0497]

[0498] Step A: Preparation of compound 30

[0499] Referring to the method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 28-1 obtained in step A of Example 28 to prepare compound 30.

[0500] 1H NMR (500MHz, DMSO-d6) 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).

[0501] MS (ESI, [MH] - )m / z:498.14 / 500.10.

[0502] Example 31: Preparation of Compound 31

[0503]

[0504] Step A: Preparation of compound 31

[0505] Referring to the method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 29-1 obtained in step A of Example 29 to prepare compound 31.

[0506] 1 H NMR (500MHz, DMSO-d6) 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).

[0507] MS (ESI, [MH] - )m / z:516.13 / 518.11.

[0508] Example 32: Preparation of Compound 32

[0509]

[0510] Step A: Preparation of compound 32

[0511] Referring to the method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 8-1 obtained in step A of Example 8 to prepare compound 32.

[0512] 1 H NMR (500MHz, DMSO-d6) 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).

[0513] MS (ESI, [MH] - )m / z:512.20 / 514.16.

[0514] Example 33: Preparation of Compound 33

[0515]

[0516] Step A: Preparation of compound 33-1

[0517] Referring to the preparation method of step B of Example 1, compound 1-1 and (S)-3-hydroxymethyltetrahydropyrrole hydrochloride were reacted to prepare compound 33-1.

[0518] 1 H NMR (500MHz, DMSO-d6) 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).

[0519] Step B: Preparation of compound 33

[0520] Referring to the method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 33-1 obtained in the above step to prepare compound 33.

[0521] 1H NMR (500MHz, DMSO-d6) 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=8.7 Hz, 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).

[0522] MS (ESI, [MH] - )m / z:542.19 / 544.20.

[0523] Example 34: Preparation of Compound 34

[0524]

[0525] Step A: Preparation of compound 34

[0526] Referring to the method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 33-1 obtained in step A of Example 33 to prepare compound 34.

[0527] 1 H NMR (500MHz, DMSO-d6) 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).

[0528] MS (ESI, [MH] - )m / z:528.18 / 530.22.

[0529] Example 35: Preparation of Compound 35

[0530]

[0531] Step A: Preparation of compound 35-1

[0532] Referring to the preparation method of step B of Example 1, compound 1-1 and (S)-3-cyanopyrrolidine hydrochloride were reacted to prepare compound 35-1.

[0533] 1 H NMR (500MHz, DMSO-d6) 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).

[0534] Step B: Preparation of compound 35

[0535] Referring to the method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 35-1 obtained in the above step to prepare compound 35.

[0536] 1 H NMR (500MHz, DMSO-d6) 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, 2 H), 7.35 (d, J=8.9Hz, 2H), 4.61 (s, 2H), 3.57-3.48 (m, 1H), 3.46-3.36 (m, 2 H), 3.26-3.17(m, 2H), 3.15(s, 3H), 2.23-2.13(m, 1H), 2.11-2.02(m, 1H).

[0537] MS (ESI, [MH] - )m / z:537.18 / 539.19.

[0538] Example 36: Preparation of Compound 36

[0539]

[0540] Step A: Preparation of compound 36

[0541] Referring to the method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 35-1 obtained in step A of Example 35 to prepare compound 36.

[0542] 1 H NMR (500MHz, DMSO-d6) 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).

[0543] MS (ESI, [MH] - )m / z:523.18 / 525.18.

[0544] Example 37: Preparation of Compound 37

[0545]

[0546] Step A: Preparation of Compound 37-1

[0547] Referring to the preparation method of step B of Example 1, compound 1-1 and ethyl 4-aminobutyrate hydrochloride were reacted to prepare compound 37-1.

[0548] 1 H NMR (500MHz, DMSO-d6) 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).

[0549] Step B: Preparation of compound 37-2

[0550] Add compound 37-1 (660 mg) prepared in step A above and 1M sodium hydroxide aqueous solution (10 mL) to a 50 mL single-mouth bottle, heat to 80°C and react for 2 h. Adjust the pH to 5 with 6M dilute hydrochloric acid, add 10 mL of water to dilute, and extract with ethyl acetate three times. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain 600 mg of compound 37-2.

[0551] 1 H NMR (500MHz, DMSO-d6) 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, 2 H), 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).

[0552] Step C: Preparation of Compound 37-3

[0553] Add compound 37-2 (600 mg) obtained in step B above, DMF (20 mL), triethylamine (162 mg) to a 50 mL single-mouth bottle, add pentafluorophenyl diphenyl phosphate (482 mg) in DMF (5 mL) dropwise at room temperature, heat to 50 ° C for reaction, and after the reaction is complete. Add 150 mL of water, extract three times with ethyl acetate, combine the organic phases, and wash the organic phases three times with saturated sodium chloride aqueous solution. The organic phase is dried over anhydrous sodium sulfate and concentrated, and the crude product is purified by column chromatography to obtain 489 mg of compound 37-3.

[0554] 1 H NMR (500MHz, DMSO-d6) δ10.68 (s, 1H), 8.97 (d, J = 1.8Hz, 1H), 8.66 (d, J = 1.8Hz, 1H), 7.88 (d, J = 9.0 Hz, 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).

[0555] Step D: Preparation of compound 37

[0556] Referring to the method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 37-3 obtained in the above step to prepare compound 37.

[0557] 1H NMR (500MHz, DMSO-d6) 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).

[0558] MS (ESI, [M+H] + )m / z:528.3 / 530.2.

[0559] Example 38: Preparation of Compound 38

[0560]

[0561] Step A: Preparation of compound 38-1

[0562] Referring to the preparation method of step B of Example 1, compound 1-1 was reacted with (R)-3-methoxypyrrolidine to prepare compound 38-1.

[0563] Step B: Preparation of compound 38

[0564] Referring to the method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 38-1 obtained in the above step A to prepare compound 38.

[0565] 1 H NMR (500MHz, DMSO-d6) 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).

[0566] MS (ESI, [M+H] + )m / z:530.1.

[0567] Example 39: Preparation of Compound 39

[0568]

[0569] Step A: Preparation of compound 39

[0570] Referring to the method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 38-1 obtained in step 38 of Example to prepare compound 39.

[0571] 1 H NMR (500MHz, DMSO-d6) 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).

[0572] MS (ESI, [M+H] + )m / z:544.2.

[0573] Example 40: Preparation of Compound 40

[0574]

[0575] Step A: Preparation of Compound 40-1

[0576] Referring to the preparation method of step B of Example 1, compound 1-1 was reacted with (R)-3-cyanopyrrolidine to prepare compound 40-1.

[0577] Step B: Preparation of compound 40

[0578] Referring to the method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 40-1 obtained in the above step A to prepare compound 40.

[0579] 1 H NMR (500MHz, DMSO-d6) 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).

[0580] HRMS (ESI, [M+H] + )m / z:525.1.

[0581] Example 41: Preparation of Compound 41

[0582]

[0583] Step A: Preparation of Compound 41

[0584] Referring to the method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 40-1 obtained in step A of Example 40 to prepare compound 41.

[0585] 1 H NMR (500MHz, DMSO-d6) 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).

[0586] HRMS (ESI, [M+H] + )m / z:539.1418.

[0587] Example 42: Preparation of Compound 42

[0588]

[0589] Step A: Preparation of Compound 42-1

[0590] In a 25 mL three-necked flask, compound 2-2 (0.931 g) obtained in step B of Example 2, 1,4-dioxane (20 mL), biboric acid pinacol ester (1.664 g), PdCl2 (dppf) (0.266 g), potassium acetate (1.072 g) were added in sequence. After the addition was completed, the temperature was raised to 90°C for reaction for 2 h after N2 protection. After the reaction was complete, the reaction system was cooled to room temperature, and compound 1-1 (1.5 g) obtained in step A of Example 1, potassium carbonate (1.509 g), Pd (Ph3P) 4 (0.421 g), and water (5 mL) were added in sequence to the system. After the addition was completed, the temperature was raised to 110°C for reaction for 2 h after nitrogen replacement. After the reaction was complete, the filtrate was filtered and the filtrate was collected. Ethyl acetate (50 mL) and saturated brine (25 mL) were added to the filtrate for washing and separation. The organic phase was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by column chromatography to obtain 0.5 g of compound 42-1.

[0591] 1H NMR (500MHz, DMSO-d6) δ10.68 (s, 1H), 9.00 (d, J = 2.3Hz, 1H), 8.98 (d, J = 2.0Hz, 1H), 8.95 (s, 1H), 8.5 3 (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).

[0592] MS (ESI, [M+H] - )m / z:463.1.

[0593] Step B: Preparation of compound 42-2

[0594] Compound 42-2 (0.3 g), 1,4-dioxane (20 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.199 g), bis(tri-tert-butylphosphine)palladium(0) (0.033 g), cesium carbonate (0.420 g) and water (4.00 mL) were added to a 35 mL microwave tube in sequence, and the reaction system was placed in a microwave reactor under the microwave conditions of 150° C. for 30 min. After the reaction was complete, 50 mL of ethyl acetate and 20 mL of water were added to the reaction solution, the organic phase was separated and collected, and the organic phase was washed three times with 20 mL of saturated sodium chloride aqueous solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to obtain 210 mg of compound 42-2.

[0595] 1 H NMR (500MHz, DMSO-d6) 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).

[0596] MS (ESI, [M+Na] + )m / z:634.3.

[0597] Step C: Preparation of Compound 42

[0598] In a 25 mL single-necked bottle, compound 42-2 (50 mg) obtained in the above step and 4 M hydrogen chloride in 1,4-dioxane solution (5 mL) were added in sequence, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated to remove the solvent, and the crude product was purified by column chromatography to obtain 40 mg of compound 42.

[0599] 1 H NMR (500MHz, DMSO-d6) 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).

[0600] MS (ESI, [M+H] + )m / z:512.1.

[0601] Example 43: Preparation of Compound 43

[0602]

[0603] Referring to the method of step B of Example 42, compound 42-1 obtained in step A of Example 42 was reacted with 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester to prepare compound 43.

[0604] 1 H NMR (500MHz, DMSO-d6) 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).

[0605] HRMS (ESI, [M+H] + )m / z:513.1174.

[0606] Example 44: Preparation of Compound 44

[0607]

[0608] Step A: Preparation of Compound 44-1

[0609] Referring to the method of step A of Example 42, 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.

[0610] 1 H NMR (500MHz, DMSO-d6) 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).

[0611] MS (ESI, [M+H] + )m / z:479.2.

[0612] Step B: Preparation of Compound 44-2

[0613] Referring to the method of step B of Example 42, compound 44-1 obtained in step A was reacted with 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester to prepare compound 44-2.

[0614] MS (ESI, [M+H] + )m / z:527.3.

[0615] Step C: Preparation of Compound 44

[0616] In a 100 mL single-mouth bottle, compound 44-2 (150 mg) obtained in the above step, methanol (20 mL), and Pd / C (1.671 mg) were added in sequence, and hydrogen was replaced three times, and stirred at room temperature overnight. After the reaction was complete, the mixture was filtered, and the crude product obtained by concentrating the filtrate was purified by column chromatography to obtain 88 mg of compound 44.

[0617] 1H NMR (500MHz, DMSO-d6) 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).

[0618] MS (ESI, [M+H] + )m / z:529.1.

[0619] Example 45: Preparation of Compound 45

[0620]

[0621] Step A: Preparation of Compound 45-1

[0622] Referring to the preparation method of step B of Example 1, compound 1-1 was reacted with 4-hydroxypiperidine to prepare compound 45-1.

[0623] MS (ESI, [M+H] + )m / z:476.1 / 478.1.

[0624] Step B: Preparation of compound 45

[0625] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 45-1 obtained in the above step A to prepare compound 45.

[0626] 1H NMR (500MHz, DMSO-d6) 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, 2 H), 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).

[0627] MS (ESI, [M+H] + )m / z:544.1.

[0628] Example 46: Preparation of Compound 46

[0629]

[0630] Step A: Preparation of Compound 46

[0631] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 11-2 obtained in step B of Example 11 was reacted with compound 45-1 obtained in step A of Example 45 to prepare compound 46.

[0632] 1 H NMR (500MHz, DMSO-d6) 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).

[0633] MS (ESI, [M+H] +)m / z:570.2.

[0634] Example 47: Preparation of Compound 47

[0635]

[0636] Step A: Preparation of Compound 47-1

[0637] Referring to the preparation method of step B of Example 1, compound 1-1 and 3-methylhydroxyazetidine hydrochloride were reacted to prepare compound 47-1.

[0638] MS (ESI, [MH] - )m / z:460.0 / 462.0.

[0639] Step B: Preparation of compound 47

[0640] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 47-1 obtained in the above step A to prepare compound 47.

[0641] 1 H NMR (500MHz, Methanol-d4) 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).

[0642] MS (ESI, [M+H] + )m / z:530.1.

[0643] Example 48: Preparation of Compound 48

[0644]

[0645] Step A: Preparation of Compound 48

[0646] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 11-2 obtained in step B of Example 11 was reacted with compound 47-1 obtained in step A of Example 47 to prepare compound 48.

[0647] 1H NMR (500MHz, DMSO-d6) 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).

[0648] MS (ESI, [M+H] + )m / z:556.2.

[0649] Example 49: Preparation of Compound 49

[0650]

[0651] Step A: Preparation of Compound 49-1

[0652] Referring to the preparation method of step B of Example 1, compound 1-1 was reacted with cis-2,6-dimethylmorpholine to prepare compound 49-1.

[0653] MS (ESI, [M+H] + )m / z:490.0 / 492.0.

[0654] Step B: Preparation of compound 49

[0655] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 49-1 obtained in the above step A to prepare compound 49.

[0656] 1 H NMR (500MHz, DMSO-d6) 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 = 9.1H z, 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).

[0657] MS (ESI, [M+H] + )m / z:558.2.

[0658] Example 50: Preparation of Compound 50

[0659]

[0660] Step A: Preparation of Compound 50-1

[0661] Referring to the preparation method of step B of Example 1, compound 1-1 and 3-methyl-3-acridinol hydrochloride were reacted to prepare compound 50-1.

[0662] MS (ESI, [M+H] - )m / z:460.0 / 462.0.

[0663] Step B: Preparation of Compound 50

[0664] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 11-2 obtained in step B of Example 11 was reacted with compound 50-1 obtained in the above step A to prepare compound 50.

[0665] 1 H NMR (500MHz, DMSO-d6) 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).

[0666] MS (ESI, [M+H] + )m / z:556.2.

[0667] Example 51: Preparation of Compound 51

[0668]

[0669] Step A: Preparation of Compound 51-1

[0670] Under nitrogen protection, (S)-(-)-2-carboxycyclobutylamine (200 mg), tetrahydrofuran (10 mL), and borane tetrahydrofuran complex (425 mg) were added to a 50 mL sealed tube in sequence. After sealing, the sealed tube was placed in an oil bath and heated to 72°C, stirred and reacted overnight. Methanol (5 mL) was added to the reaction solution and stirred for 10 min. The reaction solution was concentrated under reduced pressure to obtain a light yellow residue 51-1, which was directly used in the next step without separation and purification.

[0671] Step B: Preparation of Compound 51-2

[0672] Referring to the preparation method of step B of Example 1, compound 51-1 obtained in step A above was reacted with compound 1-1 to prepare compound 51-2.

[0673] MS (ESI, [MH] - )m / z:460.0 / 462.0.

[0674] Step C: Preparation of Compound 51

[0675] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 51-2 in step B to prepare compound 51.

[0676] 1 H NMR (500MHz, DMSO-d6) 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).

[0677] MS (ESI, [MH] - )m / z:528.2.

[0678] Example 52: Preparation of Compound 52

[0679]

[0680] Step A: Preparation of Compound 52-1

[0681] Referring to the preparation method of step A of Example 51, (R)-(-)-2-carboxycyclobutylamine and borane tetrahydrofuran complex were reacted to prepare compound 52-1.

[0682] Step B: Preparation of compound 52-2

[0683] Referring to the preparation method of step B of Example 1, compound 52-1 obtained in step A above was reacted with compound 1-1 to prepare compound 52-2.

[0684] MS (ESI, [M+H] + )m / z:462.1 / 464.1.

[0685] Step C: Preparation of Compound 52

[0686] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 52-2 obtained in the above step B to prepare compound 52.

[0687] 1 H NMR (500MHz, DMSO-d6) 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, 5.1 Hz, 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).

[0688] MS (ESI, [M+H] + )m / z:530.3.

[0689] Example 53: Preparation of Compound 53

[0690]

[0691] Step A: Preparation of Compound 53-1

[0692] Referring to the preparation method of step B of Example 1, compound 1-1 was reacted with (R)-3-fluoropyrrolidine to prepare compound 53-1.

[0693] MS (ESI, [M+H] + )m / z:464.0 / 466.0.

[0694] Step B: Preparation of Compound 53

[0695] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 53-1 obtained in the above step A to prepare compound 53.

[0696] 1 H NMR (500MHz, DMSO-d6) 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).

[0697] MS (ESI, [MH] - )m / z:516.16 / 518.20.

[0698] Example 54: Preparation of Compound 54

[0699]

[0700] Step A: Preparation of Compound 54

[0701] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 53-1 obtained in step A of Example 53 to prepare compound 54.

[0702] 1 H NMR (500MHz, DMSO-d6) 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).

[0703] MS (ESI, [MH]- )m / z:530.16 / 532.14.

[0704] Example 55: Preparation of Compound 55

[0705]

[0706] Step A: Preparation of Compound 55-1

[0707] Referring to the preparation method of step B of Example 1, compound 1-1 was reacted with (S)-3-fluoropyrrolidine to prepare compound 55-1.

[0708] MS (ESI, [M+H] + )m / z:464.3 / 466.3.

[0709] Step B: Preparation of Compound 55

[0710] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 55-1 in step A to prepare compound 55.

[0711] 1 H NMR (500MHz, DMSO-d6) 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).

[0712] MS (ESI, [M+H] + )m / z:518.3 / 520.3.

[0713] Example 56: Preparation of Compound 56

[0714]

[0715] Step A: Preparation of Compound 56

[0716] Referring to the preparation method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 55-1 obtained in step A of Example 55 to prepare compound 56.

[0717] 1H NMR (500MHz, DMSO-d6) 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).

[0718] MS (ESI, [M+H] + )m / z:532.3 / 534.2.

[0719] Example 57: Preparation of Compound 57

[0720]

[0721] Step A: Preparation of Compound 57-1

[0722] To a 50 mL single-necked bottle, 10 mL of anhydrous ethanol, the compound 2-1 (400 mg) obtained in step A of Example 2, diisopropylethylamine (428 mg), and deuterated methylamine hydrochloride (97 mg) were added in sequence, and the mixture was reacted at room temperature for 6 h. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 57-1.

[0723] MS (ESI, [M+H] + )m / z:230.1 / 231.9.

[0724] Step B: Preparation of Compound 57-2

[0725] Referring to the method of step E of Example 1, the compound 57-1 obtained in step A was used to prepare a reaction solution containing compound 57-2, which was cooled to room temperature and directly used in the next reaction without separation or purification.

[0726] Step C: Preparation of Compound 57

[0727] Referring to the method of step F of Example 1, compound 57 was prepared using the reaction solution containing compound 57-2 obtained in step B above and compound 33-1 obtained in step A of Example 33.

[0728] 1H NMR (500MHz, DMSO-d6) 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), 7.90-7.8 2 (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).

[0729] MS (ESI, [MH] - )m / z:545.2 / 547.2.

[0730] Example 58: Preparation of Compound 58

[0731]

[0732] Step A: Preparation of Compound 58

[0733] Referring to the method of step F of example 1, compound 58 was prepared by reacting compound 5-1 obtained in step A of example 5 with (3-(methylsulfonyl)phenyl)boronic acid.

[0734] 1 H NMR (500MHz, DMSO-d6) 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).

[0735] MS (ESI, [M+H] + )m / z:538.3 / 540.2.

[0736] Example 59: Preparation of Compound 59

[0737]

[0738] Step A: Preparation of Compound 59-1

[0739] 1,4-dioxane (15 mL), 1-tert-butyloxycarbonyl-pyrrole-2-boric acid (423 mg), compound 1-2 (700 mg) obtained in step B of Example 1, potassium carbonate (626 mg), tetrakis(triphenylphosphine)palladium (87 mg), purified water (3 mL) and a magnetron were added to a 20 mL microwave tube in sequence. After nitrogen purging, the mixture was placed in a microwave reactor and reacted at 130° C. for 1.5 h. The mixture was concentrated under reduced pressure and the crude product was purified by column chromatography to obtain 500 mg of compound 59-1.

[0740] MS (ESI, [MH] - )m / z:447.16 / 449.14.

[0741] Step B: Preparation of compound 59-2

[0742] Add ultra-dry tetrahydrofuran (15 mL), compound 59-1 (400 mg) obtained in step A and azobisisobutyronitrile (21 mg) to a 100 mL single-mouth bottle, and cool to -78 ° C under nitrogen protection; start to add dibromohydantoin (94 mg) to the system in batches, and keep warm for 2 hours after addition. Concentrate under reduced pressure, and the crude product is purified by column chromatography to obtain 370 mg of compound 59-2.

[0743] MS (ESI, [MH] - )m / z:525.1 / 527.1.

[0744] Step C: Preparation of Compound 59-3

[0745] 1,4-dioxane (15 mL), compound 59-2 (370 mg) obtained in step B, N,N-diisopropylethylamine (94 mg), sodium thiomethoxide (51.0 mg), tris(dibenzyl-BASE acetone)dipalladium (50 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (63 mg) and a magnetron were added to a 20 mL microwave tube, and the mixture was placed in a microwave reactor at 130° C. for 2 h after nitrogen purge. The mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain 250 mg of compound 59-3.

[0746] MS (ESI, [MH] - )m / z:493.2 / 495.2.

[0747] Step D: Preparation of compound 59

[0748] Isopropanol (5 mL), purified water (1.5 mL), compound 59-3 obtained in step C (230 mg) and potassium peroxymonosulfonate (195 mg) were added to a 25 mL single-mouth bottle in sequence, and the mixture was reacted at room temperature for 0.5 h. Ethyl acetate was added to the reaction system for extraction three times, and the organic phases were combined and washed with saturated sodium sulfite aqueous solution and saturated brine twice each in sequence. The organic phases were collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 20 mg of compound 59.

[0749] 1 H NMR (500MHz, DMSO-d6) 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, 1 H), 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).

[0750] MS (ESI, [MH] - )m / z:525.2 / 527.2.

[0751] Example 60: Preparation of Compound 60

[0752]

[0753] Step A: Preparation of Compound 60-1

[0754] Referring to the method of step B in Example 1, the target compound 60-1 was prepared using compound 1-1 obtained in step A in Example 1 and 2-(methylamino)ethan-1-ol.

[0755] 1 H NMR (500MHz, DMSO-d6) δ10.68 (s, 1H), 9.00 (d, J = 2.3Hz, 1H), 8.98 (d, J = 2.0Hz, 1H), 8.95 (s, 1H), 8.5 3 (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).

[0756] Step B: Preparation of Compound 60

[0757] Referring to the method of step F of Example 1, 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.

[0758] 1 H NMR (500MHz, DMSO-d6) 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).

[0759] MS (ESI, [M+H] + )m / z:504.2 / 506.2.

[0760] Example 61: Preparation of Compound 61

[0761]

[0762] Step A: Preparation of Compound 61-1

[0763] Referring to the method of step A of example 13, 1-tert-butoxycarbonyl-4-aminopiperidine was used instead of 2-methoxyethylamine to react with compound 2-1 to prepare compound 61-1.

[0764] Step B: Preparation of compound 61-2

[0765] Referring to the method of step E of Example 1, the compound 61-1 obtained in step A was used to prepare a reaction solution containing compound 61-2, which was cooled to room temperature and directly used in the next reaction without separation or purification.

[0766] Step C: Preparation of Compound 61-3

[0767] Referring to the method of step F of Example 1, compound 61-3 was prepared using the reaction solution containing compound 61-2 obtained in the above step B and compound 12-1 obtained in step A of Example 12.

[0768] MS (ESI, [MH] - )m / z:612.29 / 614.30.

[0769] Step D: Preparation of Compound 61

[0770] In a 50 mL round-bottom flask, add compound 61-3 (430 mg) obtained in step A above, dichloromethane (10 mL), and 6 M hydrogen chloride-dioxane solution (2.5 mL), stir at room temperature overnight, concentrate the reaction solution after the reaction is complete, then add ethyl acetate (10 mL) and stir at room temperature for 4 h. Filter, wash the filter cake with ethyl acetate. Collect the filter cake and dry it to obtain 60 mg of compound 61.

[0771] 1 H NMR (500MHz, DMSO-d6) 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).

[0772] MS (ESI, [M+H] + )m / z:514.3 / 516.4.

[0773] Experimental Example 1 Inhibitory Effect of Compounds on Proliferation of K562 Cells

[0774] Take K562 cells that are in good condition in the exponential growth phase, collect the cells into a centrifuge tube, centrifuge at a low speed tabletop centrifuge at 1000 rpm for 5 minutes, discard the supernatant, and use a pipette to add 5 mL of complete medium (RPMI 1640 basal medium + 10% FBS) to resuspend the cells. Count using a cell counter, dilute with complete medium, and adjust the cell density to 6×10 4 / mL, and then add an equal amount of RPMI 1640 basal medium to adjust the serum concentration to 5% and the cell density to 3×10 4 / mL. Use a multichannel pipette to inoculate on a 96-well plate, 100μL / well, and culture in a cell culture incubator at 37°C and 5% CO2 saturated humidity. After 24 hours of culture, use a nanoliter pipette to add compounds. Set 8 concentrations for each compound (1000nM, 250nM, 63nM, 16nM, 3.9nM, 0.98nM, 0.24nM, 0.061nM), set 2 replicates for each concentration, use cells without compound as negative control, and use culture medium without cells as blank control. After 72 hours, add CCK-8, 10μL / well, and detect its absorbance at 450nm with Envision microplate reader after 2 hours to calculate the inhibition rate. Inhibition rate (%) = (average value of negative control group - average value of experimental group) / (average value of negative control group - average value of blank group) × 100%, with the logarithm of compound concentration as the horizontal axis and inhibition rate as the vertical axis. Four-parameter analysis, fitting of dose-effect curve, calculation of IC 50 , the results are shown in Table 1.

[0775] Experimental Example 2 Inhibitory Effect of Compounds on Proliferation of Ba / F3 Cells Transfected with BCR-ABL T315I

[0776] Take Ba / F3-BCR-ABL1-T315I cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) in good exponential growth phase, collect the cells into centrifuge tubes, centrifuge at 1000 rpm for 5 min, discard the supernatant, and use a pipette to add 5 mL of complete medium (RPMI 1640 basal medium + 10% FBS) to resuspend the cells. Count using a cell counter, dilute with complete medium, and adjust the cell density to 6×10 4 / mL, and then add an equal amount of RPMI 1640 basal medium to adjust the serum concentration to 5% and the cell density to 3×10 4 / mL. Use a multichannel pipette to inoculate on a 96-well plate, 100μL / well, and culture in a cell culture incubator at 37°C and 5% CO2 saturated humidity. After 24 hours of culture, use a nanoliter pipette to add compounds, set 8 concentrations for each compound (1000nM, 250nM, 63nM, 16nM, 3.9nM, 0.98nM, 0.24nM, 0.061nM), set 2 replicates for each concentration, use cells without compound addition as negative control, and use culture medium without cell addition as blank control. After 72 hours, CCK-8 was added at 10 μL / well. Ba / F3-BCR-ABL1-T315I cells were placed at 37°C after adding CCK8. One hour later, the absorbance at 450 nm was detected using a microplate reader to calculate the inhibition rate. Inhibition rate (%) = (average value of negative control group - average value of experimental group) / (average value of negative control group - average value of blank group) × 100%. The logarithm of compound concentration was used as the horizontal axis and the inhibition rate was used as the vertical axis. Four-parameter analysis was performed to fit the dose-effect curve and calculate the IC 50 , the results are shown in Table 1.

[0777] Table 1

[0778]

[0779]

[0780] Experimental Example 3: Pharmacokinetic evaluation in mice

[0781] ICR mice (purchased from Shanghai Xipulbikai Experimental Animal Co., Ltd.) weighing 18-22g were randomly divided into groups after 3-5 days of adaptation, with 9 mice in each group, and each compound was administered by gavage at a dose of 10mg / kg. The test animals (ICR mice) were fasted overnight before administration, and food was given 4h after administration. Water was freely available before, during and after the experiment. After gavage, about 0.1mL of blood was collected from the eye sockets at 0.25h (15min), 0.5h (30min), 1h, 2h, 3h, 4h, 6h, 8h, 10h, and 24h (3-4 time points were collected for each mouse, and 3 mice were collected for each time point). After EDTA-K2 anticoagulation, the blood was transferred to 4℃, 4000rpm, and centrifuged for 10min to separate plasma within 30min. After collecting all the plasma, it was immediately stored at -20℃ for testing.

[0782] Pipette 30 μL of the plasma sample to be tested and the standard sample, add 300 μL of acetonitrile solution containing the internal standard (diazepam 20 ng / mL), shake and mix for 5 min, centrifuge at 13000 rpm for 10 min, take 70 μL of the supernatant, add 70 μL of ultrapure water to dilute, mix, and take 1 μL for LC / MS / MS determination, and record the chromatogram.

[0783] The oral exposure of the compound was evaluated 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.

[0784] Table 2

[0785]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, R 1 Selected from R 2 is selected from hydrogen, 4-6 membered heterocycloalkyl, 6 membered heterocycloalkenyl, 7 or 9 membered spiro heterocycloalkyl or amino, wherein the 4-6 membered heterocycloalkyl, 6 membered heterocycloalkenyl, 7 or 9 membered spiro heterocycloalkyl or amino is optionally replaced by one or more R a replace; R a Selected from hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-3 Alkoxy, di(C 1-3 alkyl)amino or one or more hydroxyl or C 1-3 Alkoxy substituted C 1-4 alkyl; R 3 Selected from -OCF3 or -OCF2Cl; R 4 Selected from hydrogen, C 1-5 Alkyl, cyclopropyl or 6-membered heterocycloalkyl, wherein C 1-5 Alkyl, cyclopropyl or 6-membered heterocycloalkyl is optionally substituted by one or more R b replace; R b Selected from deuterium, hydroxyl, C 1-3 Alkoxy, C 1-3 Alkyl, amino, mono(C 1-3 alkyl)amino or di(C 1-3 Alkyl)amino; R 5 Selected from C 1-3 alkyl.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R 2 is selected from 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]heptanyl 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]heptanyl or amino is optionally replaced by one or more R a replace.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R 2 Selected from hydrogen, 4. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R a Selected from hydroxyl, halogen, C 1-3 Alkyl, di(C 1-3 alkyl)amino or C substituted by one or more hydroxyl groups 1-3 alkyl.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R a Selected from hydroxyl, cyano, fluorine, methyl, methoxy, 2-hydroxyethyl, 2-methoxyethyl, 2-methyl-2-hydroxypropyl, di(methyl)amino or hydroxymethyl.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R 4 is selected 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 replaced by one or more R b replace.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R 4 is selected from hydrogen, methyl, d3-methyl, cyclopropyl, 8. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R b Selected from hydroxyl, C 1-3 Alkoxy, C 1-3 Alkyl, amino, mono(C 1-3 alkyl)amino or di(C 1-3 Alkyl)amino.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R b Selected from deuterium, hydroxy, methoxy, methyl or di(ethyl)amino.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 5 Selected from methyl.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit Selected from 12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is a compound of formula (II), in, R 3 Selected from -OCF3 or -OCF2Cl.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is a compound of formula (III), in, Structural unit Selected from R 3 Selected from -OCF3 or -OCF2Cl.

14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 Selected from R 2 is selected from hydrogen, a 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N or O or S, a 6 membered heterocycloalkenyl containing 1-3 heteroatoms selected from N or O or S, a 7 or 9 membered spiroheterocycloalkyl containing 1-3 heteroatoms selected from N or O or S, or an amino group, wherein the 4-6 membered heterocycloalkyl, 6 membered heterocycloalkenyl, 7 or 9 membered spiroheterocycloalkyl or amino group is optionally replaced by one or more R a replace; R a Selected from hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-3 Alkoxy, di(C 1-3 alkyl)amino or one or more hydroxyl or C 1-3 Alkoxy substituted C 1-4 alkyl; R 3 Selected from -OCF3 or -OCF2Cl; R 4 Selected from hydrogen, C 1-5 alkyl, cyclopropyl or a 6-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N or O or S, wherein C 1-5 Alkyl, cyclopropyl or 6-membered heterocycloalkyl is optionally substituted by one or more R b replace; R b Selected from deuterium, hydroxyl, C 1-3 Alkoxy, C 1-3 alkyl; R 5 Selected from C 1-3 alkyl.

15. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound of formula (I) is selected from:

16. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound of formula (I) is selected from:

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

18. Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating and / or preventing a BCR-ABL-related disease; the disease is selected from cancer.

19. The use according to claim 18, wherein the disease is selected from leukemia.

20. The use according to claim 19, wherein the disease is selected from chronic myeloid leukemia.

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