Phenyltriazole MLL1-WDR5 protein-protein interaction inhibitors

Abstract

Described herein are phenyltriazole MLL1-WDR5 protein-protein interaction inhibitors, pharmaceutical compositions, and methods of use.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 319,582, filed March 14, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to the field of medicinal chemistry, more specifically to phenyltriazole compounds that inhibit MLL1-WDR5 protein-protein interaction, and their preparation and medical use. [Background technology]

[0003] Translocations and rearrangements of the histone H3K4 methyltransferase MLL1 gene can cause mixed lineage leukemia (MLL1, acute myeloid leukemia, and acute lymphoblastic leukemia). Rearrangements of the MLL1 gene are observed in approximately 10% of leukemia patients. Upon rearrangement, the MLL1 gene fuses with other chaperone genes to form fusion genes, resulting in the expression of oncogenic MLL fusion proteins. These fusion proteins can interact with RNA polymerase II (Pol II)-associated elongation factors to form super-elongation complexes (SECs). This complex can lead to the aberrant expression of Hox genes regulated by MLL1 via Pol II, which can cause a series of serious consequences that lead to the development of MLL1 leukemia.

[0004] Chromosomal translocations of the MLL1 gene are monoallelic, resulting in the presence of wild-type MLL1. When the wild-type MLL1 allele is knocked out, the MLL1 fusion protein alone does not cause leukemia; however, the enzymatic activity of wild-type MLL1 is required for the MLL1 fusion protein to induce leukemia. Therefore, specific inhibition of wild-type MLL1 enzymatic activity can be used to treat leukemia.

[0005] MLL1 alone has very weak catalytic activity for H3K4 methylation, producing only a single methylation; however, this enzyme's catalytic activity, particularly for H3K4me2, is significantly improved upon formation of the MLL1 core catalytic complex. The C-terminal WIN motif of MLL can bind to WDR5, RbBP5, Ash2L, and DPY30 to form a complex. MLL1 directly interacts with WDR5 via the C-terminal WIN motif and mediates the interaction between the catalytic domain of MLL1SET and other protein complexes. Knockout of WDR5 reduces H3K4me2 / 3 levels, downregulating Hox gene expression.

[0006] Therefore, using small molecule inhibitors to disrupt the MLL1-WDR5 protein-protein interaction is an effective method for inhibiting MLL1 enzymatic activity and downregulating the expression of Hox and Meis-1 genes to prevent leukemia progression. MLL1-WDR5 protein-protein interaction inhibitors are described in WO2019205687A1, which is incorporated herein by reference in its entirety. Additional MLL1-WDR5 protein-protein interaction inhibitors with additional and / or improved properties are needed. Summary of the Invention

[0007] The aforementioned needs and additional needs are met by the embodiments described herein. Provided herein are small molecule compounds and compositions capable of modulating the MLL1-WDR5 protein-protein interaction, as well as methods of using the compounds and compositions. Inhibitors of the MLL1-WDR5 protein-protein interaction inhibit the enzymatic catalytic activity of MLL1, downregulating H3K4 methylation levels and gene expression levels of Hox and Meis-1 genes, thereby inducing apoptosis in leukemia cells. Thus, the compounds and compositions described herein can be used to treat cancers, such as, but not limited to, leukemia.

[0008] Some embodiments described herein are phenyltriazole compounds, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the compounds are listed in Table 1, Table 2, Table 3, or Table 4.

[0009] Some embodiments described herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers, diluents, and excipients.

[0010] Some embodiments provided herein are methods of treating or preventing acute leukemia in a patient in need thereof, comprising administering to the patient a therapeutically acceptable dose of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein are methods of treating or preventing acute leukemia in a patient in need thereof, comprising administering to the patient a pharmaceutical composition described herein. In some embodiments, the acute leukemia is acute leukemia associated with an MLL1 gene rearrangement.

[0011] Other objects, features, and advantages of the methods and compositions described herein will become apparent from the following detailed description. However, while this detailed description and specific examples indicate particular embodiments, it should be understood that such embodiments are given by way of example only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description.

[0012] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0013] Various aspects of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings, in which: DETAILED DESCRIPTION OF THE INVENTION

[0014] The phenyltriazole and aniline compounds described herein have potent inhibitory activity against MLL1-WDR5 protein-protein interaction, can reduce the catalytic activity of MLL1 at the cellular level, downregulate the expression of Hox and Meis-1 genes, and induce apoptosis in leukemia cells. Furthermore, the compounds described herein exhibit good water solubility and pharmaceutical safety, and can be used to treat cancers such as, but not limited to, leukemia.

[0015] compound In some embodiments, described herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: [ka] During the ceremony, Y is absent, -O-, -S-, -C(O)-, -CHO-, -(CO)O-, -O(CO)-, -NR 10 -, -C(O)NR 11 -or-NR 12 C(O)-, where R 10 , R 11 , and R 12 are each independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or substituted or unsubstituted phenyl {wherein phenyl is substituted with one, two, or three of halogen, amino, cyano, hydroxyl, trifluoro, -C1-C4 alkyl, C1-C4 alkoxy, carboxyl, or imidazolyl}; R 1is hydrogen, hydroxyl, thiol, carboxyl, cyano, C1-C4 alkyl, substituted C1-C4 alkyl, substituted or unsubstituted phenyl, {wherein the substituent is C1-C4 alkoxy}, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted nitrogen- or oxygen-containing 3- to 7-membered heterocycle, or substituted or unsubstituted 3- to 7-membered heterocycle containing both nitrogen and oxygen, where the substituents on the heterocyclic ring can optionally be on the heteroatom; unsaturated heterocycloalkyl containing nitrogen or oxygen or both, -NR 13 COR 14 , -OR 17 -, -C(O)OR 17 , -O(CO)OR 17 -C(O)NR 15 R 16 or -NR 15 R 16 In this case, R 13 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, substituted or unsubstituted phenyl, R 14 is hydrogen, amino, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing or oxygen-containing 3- to 7-membered heterocycle, wherein the substituents on the heterocycle can be on the heteroatom; R 15 and R 16 are each independently hydrogen, C1-C4 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted nitrogen or oxygen, or a 3- to 7-membered heterocycle containing both, wherein the heterocycle may be aryl, partially unsaturated, or fully saturated, and the substituents on the heterocycle may be on the heteroatom; or R 15 and R 16together form a nitrogen-, oxygen-, or nitrogen and oxygen-, or nitrogen and nitrogen, or oxygen and oxygen-containing 3- to 7-membered heterocycle, wherein the heterocycle is optionally substituted with 1, 2, or 3 substituents which are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, hydroxyl, thiol, carboxyl, cyano, trifluoromethyl, or imidazolyl; wherein the substituents on the heterocycle can be on the heteroatom; R 17 is C1-C4 alkyl, C1-C4 haloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted nitrogen- or oxygen-, or both-containing 3- to 7-membered heterocycle, and substituents on the heterocycle can be on heteroatoms; R 2 and R 3 are independently hydrogen, halogen, methyl, methoxy, difluoromethoxy, or trifluoromethoxy; R 4 , R 5 and R 6 are each independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 7 and R 8 are independently hydrogen, halogen, amino, cyano, hydroxy, thiol, nitro, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C3-C7 cycloalkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, hydroxy-(C1-C6)alkyl, amino-(C1-C6)alkyl, or -C(O)NR 1A R 1B (wherein R 1A and R 1B are each independently hydrogen or C1-C6 alkyl; m is an integer from 0 to 5; n is an integer from 0 to 2; and p is an integer of 0 to 3.

[0016] In some embodiments, R 7 is hydrogen, halogen, amino, thiol, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, nitro, or cyano. 7 and R8 is independently hydrogen, chloro, fluoro, bromo, amino, cyano, methyl, methoxy, trifluoromethyl, difluoromethyl, or trifluoromethyl. 7 is -Cl, -F, -OH, -CF, -CH, -CF, or -OCH. In some embodiments, R 7 is —NO or —NH. In some embodiments, R 7 is -NH. In some embodiments, R 7 is —C(O)NH. In some embodiments, R 7 is -OH, -SH, -OMe, -SMe, or -NMe.

[0017] In some embodiments, each R 8 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, amino, nitro, or cyano. 8 is independently hydrogen, chloro, fluoro, bromo, amino, cyano, methyl, methoxy, trifluoromethyl, difluoromethyl, or trifluoromethyl. 8 is independently -Cl, -F, -OH, -CF, -CH, or -OCH. In some embodiments, each R 8 is independently —CH, —Cl, or —F. In some embodiments, each R 9 is independently -OCF or -CF. In some embodiments, each R 8 are independently hydrogen. In some embodiments, R 8is independently —C(O)NH. In some embodiments, each R 7 are independently -OH, -SH, -OMe, -SMe, or -NMe;

[0018] In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, m is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 0.

[0019] In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 0.

[0020] In some embodiments, the substituted phenyl is not 4-chloro-2-fluoro-3-methylaniline.

[0021] In some embodiments, the substituted phenyl is 4-chloro-2-fluoro-3-methylaniline.

[0022] Some embodiments of the compounds of Formula (I) are inhibitors of the MLL1-WDR5 protein-protein interaction.

[0023] In some embodiments, the compound of Formula (I) has the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof: [ka] wherein, unless otherwise defined herein, the variables have the definitions provided in formula (I).

[0024] In some embodiments, Y is —O—, —S—, —C(O)—, —CHO—, —NR 10 -, -C(O)NR 11 -, or -NR 12 In some embodiments, Y is —C(O)— or —NR10 In some embodiments, Y is —O— or —NR 10 -, wherein R 10 is hydrogen or C1-C4 alkyl. In some embodiments, Y is -O-. In some embodiments, Y is -NR 10 In some embodiments, Y is -NH-. In some embodiments, Y is -NCH-. In some embodiments, Y is -S-. In some embodiments, Y is -C(O)-. In some embodiments, Y is -CHO.

[0025] In some embodiments, Y is —C(O)NR 11 In some embodiments, Y is —C(O)NR 11 -, wherein R 11 is hydrogen or C1-C4 alkyl. In some embodiments, Y is -C(O)NH-. In some embodiments, Y is -C(O)N(CH3)-. In some embodiments, Y is -NR 12 In some embodiments, Y is —C(O)—. 12 C(O)—, where R 11 is hydrogen or C1-C4 alkyl. In some embodiments, Y is -NHC(O)-. In some embodiments, Y is -N(CH3)C(O)-.

[0026] In some embodiments, Y is absent.

[0027] Some embodiments of the compounds of Formula (II) are inhibitors of the MLL1-WDR5 protein-protein interaction.

[0028] In some embodiments, the compound has the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof: [ka] During the ceremony, X is -O- or -NR 17 - in which R 17 is hydrogen or C1-C6 alkyl.

[0029] In some embodiments, X is -O-. In some embodiments, X is -NR 1A In some embodiments, X is -NH-. In some embodiments, X is -N(CH3)-.

[0030] In some embodiments, m is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6.

[0031] In some embodiments, when m is greater than 1, R b can be linked via any C atom in the linkage. In some embodiments, R b is hydrogen, C1-C6 alkyl, substituted or unsubstituted C3-C6 heterocycloalkyl, {wherein the substituent is C1-C6 alkyl and the substituent can optionally be on the heteroatom}.

[0032] In some embodiments, R 1 is amino, hydroxyl, thiol, carboxyl, cyano, C1-C4 alkyl, C1-C6 alkoxy, substituted or unsubstituted phenyl, or a substituted or unsubstituted nitrogen- or oxygen-containing 3- to 7-membered heterocycle. 1 is hydrogen. In some embodiments, R 1 is hydroxyl, thiol, carboxyl, cyano, C1-C4 alkyl, or C1-C6 alkoxy. In some embodiments, R 1 is —OH, —SH, —CN, —CH, or —OCH. In some embodiments, R 1is phenyl.

[0033] In some embodiments, R 1 is a substituted or unsubstituted nitrogen- or oxygen-containing 3- to 7-membered heterocycle. In some embodiments, the nitrogen- or oxygen-containing 3- to 7-membered heterocycle is pyrrolidine, piperidine, piperazine, or morpholine. In some embodiments, the nitrogen- or oxygen-containing 3- to 7-membered heterocycle is pyrrolidine. In some embodiments, the 3- to 7-membered ring is piperidine. In some embodiments, the 3- to 7-membered ring is piperazine. In some embodiments, the 3- to 7-membered ring is morpholine.

[0034] In some embodiments, R 1 Ha-NR 13 COR 14 , -C(O)NR 15 R 16 , or -NR 15 R 16 In some embodiments, R 1 Ha-NR 13 COR 14 In some embodiments, R 1 is -C(O)NR 15 R 16 In some embodiments, R 1 Ha-NR 15 R 16 is.

[0035] In some embodiments, R 1 Ha-NR 15 R 16 and R 15 and R 16 are joined together with the nitrogen to which they are attached to form a nitrogen- or oxygen-containing 3- to 7-membered heterocycle. In some embodiments, the 3- to 7-membered ring is piperazine or morpholine. In some embodiments, the 3- to 7-membered ring is piperazine. In some embodiments, the 3- to 7-membered ring is morpholine.

[0036] In some embodiments, R 1is preferably —C(O)OR a In this case, R a is hydrogen, C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, {wherein the substituent is C1-C6 alkyl}, substituted or unsubstituted C3-C6 heterocycloalkyl, {wherein the substituent is C1-C6 alkyl and the substituent may optionally be on the heteroatom}.

[0037] In some embodiments, R 4 and R 5 are each independently C3-C6 cycloalkyl. In some embodiments, R 4 and R 5 are each independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0038] In some embodiments, R 4 and R 5 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 4 and R 5 are each independently C1-C6 alkyl. In some embodiments, R 4 and R 5 are each independently methyl, ethyl, or isopropyl. In some embodiments, R 4 and R 5 Each is methyl. In some embodiments, R 4 and R 5 are hydrogen atoms.

[0039] In some embodiments, R 4 is hydrogen; R 5 is C3-C6 cycloalkyl or C1-C6 alkyl. In some embodiments, R 4 is hydrogen; R 5 is C1-C6 alkyl. In some embodiments, R 4 is hydrogen; R 5 is methyl, ethyl, or isopropyl. In some embodiments, R 4is hydrogen; R 5 is methyl. In some embodiments, R 4 is C3-C6 cycloalkyl or C1-C6 alkyl; R 5 is hydrogen. In some embodiments, R 4 is C1-C6 alkyl; R 5 is hydrogen. In some embodiments, R 4 is methyl, ethyl, or isopropyl; R 5 is hydrogen. In some embodiments, R 4 is methyl; R 5 is hydrogen.

[0040] In some embodiments, R 6 is C-C cycloalkyl. In some embodiments, R 6 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 6 is cyclopropyl. In some embodiments, R 6 is cyclobutyl. In some embodiments, R 6 is cyclopentyl. In some embodiments, R 6 is cyclohexyl.

[0041] In some embodiments, R 6 is hydrogen or C1-C6 alkyl. In some embodiments, R 6 is C1-C6 alkyl. In some embodiments, R 6 is methyl. In some embodiments, R 6 is methyl, ethyl, propyl, isopropyl, sec-butyl, isobutyl, or tert-butyl. In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is tert-butyl. In some embodiments, R 6 is hydrogen.

[0042] In some embodiments, R 2 and R 3 is independently hydrogen, halogen, methyl, or methoxy. In some embodiments, R 2 and R 3 is independently hydrogen, chloro, fluoro, bromo, iodo, methyl, or methoxy. In some embodiments, R 2 and R 3 is independently hydrogen, chloro, fluoro, or methyl. In some embodiments, R 2 and R 3 is independently difluoromethoxy or trifluoromethoxy.

[0043] In some embodiments, R 2 and R 3 Each R is hydrogen, halogen, or methyl. 2 and R 3 is hydrogen. In some embodiments, R 2 and R 3 Each is a halogen. In some embodiments, R 2 and R 3 are each methyl.

[0044] In some embodiments, R 2 is halogen or methyl; R 3 is hydrogen. In some embodiments, R 2 is chloro, fluoro, or methyl; R 3 is hydrogen. In some embodiments, R 2 is hydrogen; R 3 is halogen or methyl. In some embodiments, R 2 is hydrogen; R 3 is chloro, fluoro, or methyl.

[0045] Some embodiments of the compounds of Formula (III) are inhibitors of the MLL1-WDR5 protein-protein interaction.

[0046] In some embodiments, the compound 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate methyl; 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid; 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)-N,N-dimethyl-1H-1,2,3-triazole-4-carboxamide; 5-amino-2-chloro-4-fluoro-3-methyl-N-(2-(4-methylpiperazin-1-yl)-5-(4-(morpholine-4-carbonyl)-1H-1,2,3-triazol-1-yl)phenyl)benzamide; 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazole-4-carboxamide; 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)-N-(1-methylpiperidin-4-yl)-1H-1,2,3-triazole-4-carboxamide; 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide; 5-amino-2-chloro-4-fluoro-3-methyl-N-(2-(4-methylpiperazin-1-yl)-5-(4-(4-methylpiperazine-1-carbonyl)-1H-1,2,3-triazol-1-yl)phenyl)benzamide; 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)-N-(2-morpholinoethyl)-1H-1,2,3-triazole-4-carboxamide; 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-aminopropyl)-1H-1,2,3-triazole-4-carboxamide; Tert-butyl (1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)carbamate; N-(1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazolopyridin-4-yl)-1-methylpiperidine-4-carboxamide; N-(1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazolopyridin-4-yl)piperidine-4-carboxamide; 5-amino-N-(5-(4-(4-aminobutyrylamino)-1H-1,2,3-triazol-1-yl)-2-(4-methylpiperazin-1-yl)phenyl)-2-chloro-4-fluoro-3-methylbenzamide; or It is not a pharmaceutically acceptable salt or solvate thereof.

[0047] In some embodiments, the compound has the structure of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof: [ka] wherein X1 to X5 are independently C, CH, or N; R 1 , R 2 and R 3are the same as or different from each other and are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, nitro, halogen, cyano, aldehyde, hydroxyl, or amino; R 4 represents an unsubstituted, mono-substituted, di- or tri-substituted morpholinyl, an unsubstituted, mono-substituted, di- or tri-substituted piperazinyl, or an unsubstituted, mono-substituted, di- or tri-substituted homopiperazinyl, wherein the mono-, di- or tri-substituted morpholinyl, piperazinyl, or homopiperazinyl is each substituted with 1, 2, or 3 substituents, each of which is independently C1-C4 alkyl, 3- to 7-membered cycloalkyl, hydroxyalkyl, or phenyl; represents an unsubstituted, mono-, di-, or tri-substituted -N- or / and -O-containing 3- to 7-membered heterocycle, each of which is independently C1-C4 alkyl, 3- to 7-membered cycloalkyl, hydroxyalkyl, or phenyl; R 5 does not exist, or R 5 is hydrogen; C1-C6 alkyl, substituted C1-C6 alkyl {wherein each substituent is a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycle containing nitrogen or oxygen, or a 3- to 7-membered heterocycle containing both nitrogen and oxygen}; an unsubstituted, mono-substituted, di- or tri-substituted 3- to 7-membered heterocycle containing nitrogen, oxygen, or both {wherein the heterocycle is aromatic, partially unsaturated, or fully saturated, and each substituent is independently C1-C6 alkyl (e.g., -CH3, -CH2CH3, or -CH(CH3)2) or NR 1 0R 11};-NHCOR 9 ;-CONR 10 R 11 ;-COR 12 ;OR 15 and R 9is hydrogen; C1-C6 alkyl; 3- to 7-membered cycloalkyl; 3- to 7-membered heterocycloalkyl containing nitrogen, oxygen, or both, or substituted C1-C6 alkyl {wherein the substituent is 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclic ring containing nitrogen or oxygen, or 3- to 7-membered heterocyclic ring containing both nitrogen and oxygen}; R 10 , R 11 are each independently hydrogen; C1-C6 alkyl; phenyl or substituted phenyl; a substituted or unsubstituted 3- to 7-membered heterocycle containing nitrogen, oxygen, or both; or a substituted C1-C6 alkyl, 10 and R 11 each of the above substituents is independently a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycle containing nitrogen or oxygen, or a 3- to 7-membered heterocycle containing both nitrogen and oxygen; R 12 is C1-C6 alkyl; C1-C6 substituted alkyl (wherein the substituent is C3-C6 cycloalkyl); or NR 10 R 11 (In this case, R 10 and R 11 is defined in the immediately preceding paragraph); R 15 is C1-C6 alkyl; C1-C6 substituted alkyl (wherein the substituent is C3-C6 cycloalkyl); R 6 represents hydrogen, halogen, methyl, trifluoromethyl, amino, substituted amino, wherein the substituent is C1-C4 alkyl or allyl, or R 12 is C1-C6 alkyl -OR 12 or a substituted C1-C6 alkyl in which the substituent is a C3-C6 cycloalkyl; R 7 does not exist, or R 7 is hydrogen, halogen, methyl, trifluoromethyl, amino, substituted amino, and the substituent is C1-C4 alkyl or allyl; R 8represents absent or hydrogen; C1-C6 alkyl; C1-C6 substituted alkyl, where each alkyl substituent is selected from the group consisting of NR 13 R 14 [In that case, R 13 and R 14 each independently represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or a 5- or 6-membered aromatic heterocycle containing oxygen or nitrogen, or R 13 and R 14 are linked together with the N to form an optionally substituted 5- to 7-membered heterocycle containing nitrogen, oxygen, or both nitrogen and oxygen, where the optional substituents may be 1, 2, or 3 C1-C4 alkyl (e.g., -CH3, -CH2CH3, or -CH(CH3)2); a 3- to 7-membered cycloalkyl; a 3- to 7-membered heterocycle containing nitrogen or oxygen, or a 3- to 7-membered heterocycle containing both nitrogen and oxygen; -OR 12 {where, R 12 is C1-C6 alkyl, substituted C1-C6 alkyl (wherein the substituent is C3-C6 cycloalkyl); -NR 13 R 14 {In that case, R 1 3 and R 14 each independently represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, a 5- to 6-membered aromatic heterocycle containing oxygen or nitrogen or both; or R 13 and R 14are linked together with N to form an optionally substituted 5- to 7-membered heterocyclic ring containing nitrogen, oxygen, or both (wherein the optional substituents may be 1, 2, or 3 C1-C4 alkyl (e.g., -CH3, -CH2CH3, or -CH(CH3)2)); a substituted 5- to 6-membered aromatic heterocycle containing oxygen or nitrogen {wherein the substituents are C1-C4 alkyl, alkylamino, or substituted alkylamino [wherein the substituents are C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl containing N or O, or both]}; an unsubstituted or substituted 3- to 6-membered heterocycle containing oxygen or nitrogen, or both (wherein the substituents are C1-C4 alkyl); In the formula, p is an integer of 0 to 4.

[0048] In some embodiments of the compound of Formula (IV), R 1 is H, F or CH3 (more preferably H), and R 2 is halo (preferably F, Cl or Br, more preferably Cl), and R 3 is NH2, NHCH3 or N(CH3)2 (more preferably NH2).

[0049] In some embodiments of the compound of Formula (IV), R 4 or R 1 is mono-, di-, or trisubstituted piperazinyl, where each substituent is C1-C3 alkyl (preferably methyl). 4 is 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3,4,5-trimethylpiperazinyl, 2,4-dimethylpiperazinyl, or 2,4,6-trimethylpiperazinyl. 4 is a mono-, di-, or tri-substituted homopiperazinyl, where each substituent is a C1-C3 alkyl (preferably, methyl). 4is N-methylhomopiperazinyl, 3,4-dimethylhomopiperazinyl, 3,4,5-trimethylhomopiperazinyl, 3,4,6-trimethylhomopiperazinyl, 3,4,7-trimethylhomopiperazinyl, 2,4-dimethylhomopiperazinyl, 2,4,6-trimethylhomopiperazinyl, or 2,4,7-trimethylhomopiperazinyl. 4 is an N-linked morpholino, 2-methylmorpholino, 3-methylmorpholino, 2,6-dimethylmorpholino, or 3,5-dimethylmorpholino.

[0050] Some embodiments of the compounds of Formula (IV) are inhibitors of the MLL1-WDR5 protein-protein interaction.

[0051] In some embodiments, the compound has the formula (V) or Its pharmaceutically acceptable salts or solvates have the structure: [ka] In the formula, R 1 , R 2 and R 3 are the same or different, and each independently represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, nitro, halogen, cyano, aldehyde, or hydroxyl; R 4 represents a substituted or unsubstituted morpholinyl, a substituted or unsubstituted piperazinyl, a 4-substituted piperazinyl, a 4-substituted homopiperazinyl, a 3-substituted piperazinyl, or a 2-substituted piperazinyl, wherein the substituents are C1-C4 alkyl, a 3- to 7-membered cycloalkyl, a hydroxyalkyl, or a phenyl; R 5 does not exist, or R 5 is nitro, amino, phenyl, substituted phenyl, a 5- or 6-membered aromatic heterocycle containing oxygen or nitrogen, a substituted 5- or 6-membered aromatic heterocycle containing oxygen or nitrogen, -CONR 13 R 14 In this case, R13 , R 14 represents hydrogen, C1-C6 alkyl, phenyl, or substituted phenyl, a substituted or unsubstituted 3- to 7-membered heterocyclic ring containing nitrogen, oxygen, or both, or R 13 and R 14 Together, R 13 and R 14 forming a 3- to 7-membered heterocycle containing nitrogen, oxygen, or both; R 6 represents hydrogen, halogen, methyl, trifluoromethyl, amino, or substituted amino, and the substituent is C1-C4 alkyl or allyl.

[0052] In some embodiments of compounds of Formula (V), R 1 is H, F or CH3 (preferably H), and R 2 is halo (preferably F, Cl or Br, more preferably Cl), and R 3 is -NH2, -NHCH3 or -N(CH3)2 (preferably -NH2).

[0053] Some embodiments of the compounds of Formula (V) are inhibitors of the MLL1-WDR5 protein-protein interaction.

[0054] In some embodiments, the compound has the structure of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof: [ka] In the formula, R 1 , R 2 and R 4 are the same as or different from each other and are each independently selected from Cl, F, Br, I, or —NH; R 3represents substituted or unsubstituted morpholinyl, substituted or unsubstituted piperazinyl, 4-substituted piperazinyl, 4-substituted homopiperazinyl, 3-substituted piperazinyl, or 2-substituted piperazinyl, {wherein the substituents are C1-C4 alkyl, 3- to 7-membered cycloalkyl, hydroxyalkyl, or phenyl}; R 5 is a substituted 5- to 6-membered aromatic heterocycle containing oxygen, nitrogen, or both {wherein each substituent is independently C1-C4 alkyl, substituted C1-C4 alkyl {wherein the substituent is -NR 6 R 7 (wherein R 6 and R 7 are independently C1-C4 alkyl or a 3- to 7-membered heterocycle containing nitrogen or oxygen or both), or (R 6 and R 7 are linked together to form a 3- to 7-membered heterocycle containing nitrogen, oxygen, or both.

[0055] In some embodiments of the compound of Formula (VI), R 1 is H, F or CH3 (preferably H), and R 2 is halo (preferably F, Cl or Br, more preferably Cl), and R 3 is NH2, NHCH3 or N(CH3)2 (preferably NH2).

[0056] Some embodiments of the compounds of Formula (VI) are inhibitors of the MLL1-WDR5 protein-protein interaction.

[0057] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0058] In some embodiments, compounds described herein include, but are not limited to, compounds in Table 1, Table 2, Table 3, or Table 4, or a pharmaceutically acceptable salt or solvate thereof.

[0059] In some embodiments, the compounds described herein do not include compounds of formula A or DDO-2093 and formula B or DDO-2213, represented by formula III and formula IV, respectively, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, compounds of formula I, formula II, formula III, and / or formula V exclude compounds of formula A (DDO-2093). In some embodiments, compounds of formula IV exclude compounds of formula B (DDO-2213). [ka] [Table 1] TIFF2025509846000009.tif235159TIFF2025509846000010.tif193159TIFF2025509846000011.tif187159 TIFF2025509846000012.tif239159TIFF2025509846000013.tif196159TIFF2025509846000014.tif199159 TIFF2025509846000015.tif198159TIFF2025509846000016.tif235159TIFF2025509846000017.tif207159 TIFF2025509846000018.tif197159TIFF2025509846000019.tif204159TIFF2025509846000020.tif140159 [Table 2] TIFF2025509846000022.tif205159TIFF2025509846000023.tif209159TIFF2025509846000024.tif210159TIFF2025509846000025.tif209159TIFF2025509846000026.tif208159TIFF2025509846000027.tif192159TIFF2025509846000028.tif208159TIFF2025509846000029.tif199159TIFF2025509846000030.tif201159TIFF2025509846000031.tif194159TIFF2025509846000032.tif190159TIFF2025509846000033.tif188159

Table 3

Table 4

[0060] In some embodiments, the compound is a compound selected from Table 1, or a pharmaceutically acceptable salt, solvate, polymorph, or prodrug thereof. In some embodiments, the compound is a compound selected from Table 2, or a pharmaceutically acceptable salt, solvate, polymorph, or prodrug thereof. In some embodiments, the compound is a compound selected from Table 3, or a pharmaceutically acceptable salt, solvate, polymorph, or prodrug thereof. In some embodiments, the compound is a compound selected from Table 4, or a pharmaceutically acceptable salt, solvate, polymorph, or prodrug thereof.

[0061] Further forms of the compound In some embodiments, the compounds disclosed herein possess one or more stereocenters, and each stereocenter independently exists in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as appropriate mixtures thereof. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In some embodiments, diastereomers are separated by separation / resolution techniques based on differences in solubility. In some embodiments, separation of stereoisomers is carried out by chromatography or by formation of diastereomeric salts, and separation is carried out by recrystallization, chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0062] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. For example, a prodrug may be orally bioavailable, whereas the parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the prodrug design enhances effective water solubility. Examples of prodrugs include, but are not limited to, the compounds described herein, which are administered as esters ("prodrugs") to facilitate crossing cell membranes where water solubility is disadvantageous, but which are metabolically hydrolyzed to the active carboxylic acid once inside cells where water solubility is advantageous. Further examples of prodrugs include short peptides (polyamino acids) bonded to an acid group, where the peptide is metabolized to reveal the active moiety. In some embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In some embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

[0063] In some embodiments, prodrugs are designed to alter the metabolic stability or transport properties of a drug, to mask side effects or toxicity, to improve the flavor of a drug, or to alter other characteristics or properties of a drug. Knowledge of in vivo pharmacokinetics, pharmacodynamic processes, and drug metabolism allows for the design of prodrugs of a pharmaceutically active compound once that compound is known. (For example, Nogrady (1985), Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Aesop Cho, “Recent Advances in Oral Prodrug Discovery”, Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series).

[0064] In some embodiments, some of the compounds described herein may be a prodrug for another derivative or active compound.

[0065] In some embodiments, sites on the aromatic ring portion of the compounds described herein are susceptible to various metabolic reactions. Therefore, incorporating appropriate substituents on the aromatic ring structure will reduce, minimize, or eliminate this metabolic pathway. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions include, for example, halogens or alkyl groups.

[0066] In another embodiment, the compounds described herein are isotopically labeled (e.g., with a radioisotope) or labeled by other means, including, but not limited to, the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0067] The compounds described herein include isotopically labeled compounds that are identical to those recited in the various formulas and structures presented herein, but in fact have one or more atoms replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Cl, and 125 In some embodiments, the isotopically labeled compounds described herein, e.g., 3 H and 14 Compounds incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. In some embodiments, substitution with isotopes such as deuterium may offer certain therapeutic advantages resulting from, for example, greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0068] In some embodiments, the compounds described herein are metabolized upon administration to an organism in need thereof to produce a metabolic product, which is then used to produce a desired effect, including a desired therapeutic effect.

[0069] As used herein, the term "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and that is relatively non-toxic, i.e., the substance may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0070] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound disclosed herein with an acid. Pharmaceutically acceptable salts can also be obtained by reacting a compound disclosed herein with a base to form a salt.

[0071] The compounds described herein may be formed as and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include: (1) salts of the free base form of the compound with pharmaceutically acceptable inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, etc.; or salts of, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1- (2) acid addition salts formed by reaction with organic acids such as carboxylic acids, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, etc.; (3) salts formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium or calcium), or an aluminum ion. In some embodiments, the compounds described herein may be coordinated with organic bases such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In some embodiments, the compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like.Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0072] It should be understood that a reference to a pharmaceutically acceptable salt includes solvent addition forms, particularly solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and may be formed during the process of crystallization with a pharmaceutically acceptable solvent, such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholate is formed. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0073] Pharmaceutical Composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. The gist of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, PA: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosure.

[0074] As used herein, a pharmaceutical composition refers to a mixture of a compound disclosed herein with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as, for example, a carrier, excipient, binder, filler, suspending agent, flavoring agent, sweetener, disintegrant, dispersant, surfactant, lubricant, colorant, diluent, solubilizer, wetting agent, plasticizer, stabilizer, penetration enhancer, humectant, antifoaming agent, antioxidant, preservative, or one or more combinations thereof. A pharmaceutical composition facilitates administration of the compound to an organism.

[0075] The pharmaceutical formulations described herein may be administered to a subject in a variety of ways by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intracerebroventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, buccal, topical, or transdermal routes of administration. The pharmaceutical formulations described herein include, but are not limited to, aqueous dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolving formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and combination immediate and controlled release formulations.

[0076] In some embodiments, the compounds disclosed herein are administered orally.

[0077] In some embodiments, the compounds disclosed herein are administered topically.In such embodiments, the compounds disclosed herein are formulated into various topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, ointments, medicated sticks, medicated bandages, balms, creams, or ointments.In some embodiments, the compounds disclosed herein are administered topically to the skin.

[0078] In some embodiments, the compounds disclosed herein are administered by inhalation.

[0079] In some embodiments, the compounds disclosed herein are formulated for intranasal administration, including nasal sprays, nasal mists, and the like.

[0080] In some embodiments, the compounds disclosed herein are formulated as eye drops.

[0081] In any of the foregoing embodiments, there are further embodiments in which an effective amount of a compound disclosed herein is (a) administered systemically to a mammal; and / or (b) administered orally to a mammal; and / or (c) administered intravenously to a mammal; and / or (d) administered by inhalation to a mammal; and / or (e) administered by nasal administration to a mammal; and / or (f) administered by injection to a mammal; and / or (g) administered topically to a mammal; and / or (h) administered by ocular administration; and / or (i) administered rectally to a mammal; and / or (j) administered non-systemically or topically to a mammal.

[0082] In any of the foregoing embodiments, there are further embodiments that comprise a single administration of an effective amount of a compound disclosed herein, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times during the day; (iii) the compound is administered continuously; or (iv) the compound is administered continuously.

[0083] In any of the foregoing embodiments, there are further embodiments comprising multiple administrations of an effective amount of a compound disclosed herein, including further embodiments in which (i) the compound is administered continuously or intermittently, such as a single dose; (ii) the interval between multiple doses is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; or (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday, during which administration of a compound disclosed herein is temporarily suspended or the dose of the compound administered is temporarily reduced, and administration of the compound is resumed at the end of the drug holiday. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0084] In some embodiments, the compounds disclosed herein are administered locally rather than systemically.

[0085] In some embodiments, the compounds disclosed herein are administered locally. In some embodiments, the compounds disclosed herein are administered systemically.

[0086] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, the pharmaceutical formulation of the compounds disclosed herein is in the form of a capsule.

[0087] In some embodiments, the dosage form of the liquid formulation for oral administration is in the form of an aqueous suspension or solution selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.

[0088] For administration by inhalation, the compounds disclosed herein are formulated for use as an aerosol, mist, or powder.

[0089] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.

[0090] In some embodiments, the compounds disclosed herein are formulated as transdermal dosage forms.

[0091] In some embodiments, the compounds disclosed herein are formulated into pharmaceutical compositions suitable for intramuscular, subcutaneous, or intravenous injection.

[0092] In some embodiments, the compounds disclosed herein are administered topically and can be formulated into a variety of topically administrable compositions such as, for example, a solution, suspension, lotion, gel, paste, medicated stick, balm, cream, or ointment.

[0093] In some embodiments, the compounds disclosed herein are formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas.

[0094] Dosage and Treatment Regimen In some embodiments, the compounds disclosed herein are used in the preparation of a medicament for treating a disease or condition described herein. Additionally, a method of treating any of the diseases or conditions described herein in a subject in need of such treatment comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one compound disclosed herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or solvate thereof.

[0095] In some embodiments, compositions containing the compounds disclosed herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially halt at least one symptom of the disease or condition. The amount effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation clinical trials.

[0096] In prophylactic applications, compositions containing the compounds disclosed herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.

[0097] In some embodiments, the dose of the administered drug may be temporarily reduced or even temporarily stopped for a period of time (ie, a "drug holiday").

[0098] Doses employed for adult human treatment are typically in the range of 0.01 mg to 5000 mg per day, or within the range of about 0.01 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in single or divided doses.

[0099] Treatment methods Provided herein are methods for treating MLL1-mediated diseases through inhibition of the MLL1-WDR5 protein-protein interaction, where diseases, e.g., MLL gene fusion leukemia, can be treated through inhibition of the enzymatic activity of MLL1. In some embodiments, described herein are methods for treating a disease or condition, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein.

[0100] In some embodiments, the disease or condition being treated is cancer, hi some embodiments, the cancer is a hematological cancer.

[0101] leukemia Leukemia is characterized by an abnormal increase in white blood cells in the blood or bone marrow. Among all types of cancer, the incidence of leukemia is highest in patients under 35 years of age. More than 70% of childhood leukemia patients have a translocation involving chromosome 11, resulting in the fusion of the MLL1 gene with another gene (Nat. Rev. Cancer., 2007, 7(11):823-833). MLL1 translocations are also found in approximately 10% of adult acute myeloid leukemia (AML) patients previously treated with topoisomerase II inhibitors for other types of cancer.

[0102] MLL1 enzymatic activity is determined by the protein-protein interaction between MLL1 and WDR5; MLL1 enzymatic activity affects the H3K4 methylation level. H3K4 methylation levels are abnormally elevated in MLL fusion leukemia, and the expression levels of downstream Hox and Meis-1 genes are abnormally upregulated. Inhibition of the MLL1-WDR5 protein-protein interaction reduces MLL1 catalytic activity, reduces H3K4 methylation levels, downregulates Hox and Meis-1 gene expression, and inhibits leukemia cell proliferation.

[0103] In some embodiments, the cancer is leukemia. In some embodiments, the leukemia is acute leukemia. In some embodiments, the acute leukemia is acute leukemia with MLL1 gene rearrangement.

[0104] Acute myeloid leukemia (AML) The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of a short (30 kDa) CCAAT-enhancer-binding protein (C / EBPa) translational isoform, termed p30, represents the most common type of CEBPA mutation in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. Studies have shown that C / EBPa p30, but not the normal p42 isoform, preferentially interacts with WDR5, a key component of the SET / MLL (SET domain / mixed lineage leukemia) histone methyltransferase complex. Accordingly, p30-bound genomic regions are enriched for MLL-dependent H3K4me3 marks. Downregulation of the latter inhibited proliferation and restored differentiation in p30-dependent AML models, demonstrating that WDR5 was required for the p30-dependent increase in autologous proliferation and suppression of myeloid differentiation. A small-molecule inhibitor of WDR5-MLL binding selectively inhibited proliferation and induced differentiation in p30-expressing human AML cells, revealing a mechanism for p30-dependent transformation and establishing the p30 cofactor WDR5 as a therapeutic target in CEBPA-mutated AML (Nat. Chem. Biol. 2015;11(8):571-8).

[0105] In some embodiments, the leukemia is AML leukemia.

[0106] MYCN-amplified neuroblastoma MYCN gene amplification in neuroblastoma drives a gene expression program that strongly correlates with aggressive disease. Mechanistically, trimethylation of histone H3 lysine 4 (H3K4) at target gene promoters is a prerequisite for the execution of the transcriptional program. WDR5 is a histone H3K4 presenter that has been found to play an essential role in H3K4 trimethylation. We investigated the relationship between WDR5-mediated H3K4 trimethylation and the N-Myc transcriptional program in neuroblastoma cells. N-Myc upregulated WDR5 expression in neuroblastoma cells. Gene expression analysis revealed that WDR5 target genes, such as those with MYC-binding elements in their promoters, include MDM2. WDR5 has been shown to form a protein complex with N-Myc, but not p53, at the MDM2 promoter, resulting in histone H3K4 trimethylation and activation of MDM2 transcription (Cancer Res. 2015;75(23);5143-54). RNAi-mediated attenuation of WDR5 upregulated wild-type, but not mutant, p53 expression, an effect associated with growth inhibition and apoptosis. Similarly, a small molecule antagonist of WDR5 reduced N-Myc / WDR5 complex formation, N-Myc target gene expression, and cell proliferation in neuroblastoma cells. In MYCN transgenic mice, WDR5 was overexpressed in premalignant ganglia and neuroblastoma cells compared with normal ganglion cells. Clinically, elevated WDR5 levels in neuroblastoma specimens are an independent predictor of poor overall survival. WDR5 has been identified as a cofactor involved in N-Myc-regulated transcriptional activation and tumorigenesis and as a novel therapeutic target for MYCN-amplified neuroblastoma (Cancer Res. 2015;75(23);5143-54, Mol. Cell. 2015;58(3):440-52).

[0107] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is neuroblastoma.

[0108] definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise. Moreover, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0109] As used herein, the following terms have the following meanings unless otherwise indicated.

[0110] "Oxo" refers to the =O substituent.

[0111] "Alkyl" refers to a straight or branched hydrocarbon chain radical having from 1 to 20 carbon atoms and attached to the rest of the molecule by a single bond. Alkyl containing up to 10 carbon atoms is C1-C 10 Similarly, for example, an alkyl containing up to 6 carbon atoms is a C1-C6 alkyl. Alkyl groups containing other numbers of carbon atoms (and other moieties defined herein) are similarly represented. Alkyl groups include C1-C 10 Examples of alkyl include, but are not limited to, alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl, and C4-C8 alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethylpropyl, and the like. In some embodiments, alkyl is methyl or ethyl. Unless otherwise stated herein, alkyl groups may be optionally substituted as described below.

[0112] "Alkylene" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group. In some embodiments, alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, alkylene is -CH2-. In some embodiments, alkylene is -CH2CH2-. In some embodiments, alkylene is -CH2CH2CH2-. In some embodiments, alkylene is -CH2CH2CH2-.

[0113] "Alkoxy" refers to a radical of the formula -OR, where R is an alkyl radical as defined herein. Unless stated otherwise in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and pentoxy. In some embodiments, the alkoxy is methoxy. In some embodiments, the alkoxy is ethoxy.

[0114] "Heteroalkyl" refers to an alkyl radical as defined above in which one or more carbon atoms of the alkyl has been replaced with an O, N (i.e., NH, N-alkyl), or S atom. "Heteroalkylene" refers to a straight or branched divalent heteroalkyl chain connecting the remainder of the molecule to the radical group. Unless stated otherwise in the specification, a heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkyl groups include, but are not limited to, -OCHOMe, -OCHCHOMe, or -OCHCHOCHCHNH. Representative heteroalkylene groups include, but are not limited to, -OCHCHO-, -OCHCHOCHCHO-, or -OCHCHOCHCHOCHCHO-.

[0115] "Alkylamino" refers to a radical of the formula -NHR or -NRR, where each R is independently an alkyl radical as defined above. Unless stated otherwise in the specification, an alkylamino group may be optionally substituted as described below.

[0116] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2π electrons, where n is an integer. Aromatic compounds can be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0117] "Aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. An aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, an aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise herein, the term "aryl" or the prefix "ar-" (e.g., "aralkyl") is meant to include aryl radicals that are optionally substituted.

[0118] "Carboxy" refers to -CO2H. In some embodiments, the carboxy moiety may be replaced with a "carboxylic acid bioisostere," which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as the carboxylic acid moiety. Carboxylic acid bioisosteres have biological properties similar to those of the carboxylic acid group. A compound bearing a carboxylic acid moiety can have the carboxylic acid moiety replaced with a carboxylic acid bioisostere and have similar physical and / or biological properties compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere ionizes to approximately the same extent as a carboxylic acid group at physiological pH. Examples of carboxylic acid bioisosteres include: [ka] These include, but are not limited to:

[0119] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. The cycloalkyl may be saturated or partially unsaturated. The cycloalkyl may be fused to an aromatic ring (in which case the cycloalkyl is attached through a carbon atom of the non-aromatic ring). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, bicyclic, or polycyclic. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbornyl, decalinyl, and adamantyl. In some embodiments, the cycloalkyl is monocyclic. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl is bicyclic. Bicyclic cycloalkyl groups include fused bicyclic cycloalkyl groups, spiro bicyclic cycloalkyl groups, and bridged bicyclic cycloalkyl groups.In some embodiments, the cycloalkyl group is selected from spiro[2.2]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbornyl, 3,4-dihydronaphthalen-1(2H)-one, and decalinyl. In some embodiments, the cycloalkyl is polycyclic. Polycyclic radicals include, for example, adamantyl. In some embodiments, the polycyclic cycloalkyl is adamantyl. Unless otherwise specified herein, the cycloalkyl group may be optionally substituted.

[0120] "Fused" refers to any ring structure described herein that is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or fused heteroaryl ring may be replaced with a nitrogen atom.

[0121] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

[0122] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise in the specification, a haloalkyl group may be optionally substituted.

[0123] "Haloalkoxy" refers to an alkoxy radical, as defined above, that is substituted with one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, etc. Unless stated otherwise in the specification, a haloalkoxy group may be optionally substituted.

[0124] "Heterocycloalkyl" or "heterocyclyl" or "heterocycle" refers to a stable 3- to 14-membered non-aromatic ring radical containing 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless otherwise stated herein, a heterocycloalkyl radical can be monocyclic, bicyclic (including fused bicyclic heterocycloalkyls (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom)), bridged heterocycloalkyl, or spiroheterocycloalkyl), or polycyclic. In some embodiments, a heterocycloalkyl is monocyclic. In some embodiments, a heterocycloalkyl is bicyclic. The nitrogen, carbon, or sulfur atom in a heterocyclyl radical can be optionally oxidized. The nitrogen atom can be optionally quaternized. The heterocycloalkyl radical can be partially or fully saturated. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise noted, heterocycloalkyls have 2-10 carbons in the ring. In some embodiments, heterocycloalkyls have 2-8 carbons in the ring. In some embodiments, heterocycloalkyls have 2-8 carbons and 1 or 2 N atoms in the ring.In some embodiments, a heterocycloalkyl has 2-10 carbons, 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heterocycloalkyl has 2-10 carbons, 1-2 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) comprising the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise in this specification, a heterocycloalkyl group may be optionally substituted.

[0125] "Heteroaryl" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryls are monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furyl. In some embodiments, heteroaryls contain 0 to 4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl is a C1-C9 heteroaryl. In some embodiments, a monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, a monocyclic heteroaryl is a 5- or 6-membered heteroaryl.In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.

[0126] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C-C alkylalkyne, halogen, acyl, acyloxy, -COH, -COalkyl, nitro, and amino (including mono- and di-substituted amino groups (e.g., -NH, -NHR, -NR)), and protected derivatives thereof. In some embodiments, the optional substituents are independently selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, -CN, -NH, -NH(CH), N(CH), -OH, -COH, and -COalkyl. In some embodiments, optional substituents are independently selected from fluoro, chloro, bromo, iodo, -CH, -CHCH, -CF, -OCH, and -OCF. In some embodiments, substituted groups are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0127] "Tautomer" refers to the migration of a proton from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by the migration of a hydrogen atom, accompanied by the interchange of a single bond with an adjacent double bond. In bonding configurations where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomer interconversions include the following: [ka]

[0128] "Co-administration" and like terms, as used herein, are meant to encompass the administration of selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0129] The term "effective amount" or "therapeutically effective amount," as used herein, refers to the administration of an amount of an agent or compound sufficient to relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or pathogenesis of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound as disclosed herein required to produce a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case may be determined using techniques such as dose escalation studies. An "effective amount" is an amount sufficient for the compound to achieve its stated purpose (e.g., achieve the administered effect, treat the disease, decrease enzyme activity, increase enzyme activity, decrease a signal transduction pathway, or alleviate one or more symptoms of the disease or condition) compared to the absence of the compound. An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom(s) of a disease, which may also be referred to as a "therapeutically effective amount." "Alleviating" a symptom(s) (and grammatical equivalents of this phrase) means reducing the severity or frequency of the symptom(s), or eliminating the symptom(s). A "prophylactically effective amount" of a drug is an amount of drug that, when administered to a subject, has an intended prophylactic effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, condition, or illness, or reducing the likelihood of the onset (or recurrence) of an injury, disease, condition, or illness, or their symptoms. A complete prophylactic effect does not necessarily occur with the administration of a single dose, but may occur only after the administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. "Activity-reducing amount," as used herein, refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of the antagonist. "Function-disrupting amount," as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein compared to the absence of the antagonist.The actual amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0130] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combining of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound of Formula (I) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "unfixed combination" means that the active ingredients, e.g., a compound of Formula (I) and a co-agent, are administered to a patient as separate entities simultaneously, simultaneously, or sequentially without any specific time constraint, such that such administration provides effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0131] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, humans. In some embodiments, the mammal is a human.

[0132] As used herein, the terms "treat," "treating," or "treatment" include alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, e.g., arresting the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating symptoms caused by a disease or condition, or prophylactically and / or therapeutically arresting a symptom of a disease or condition.

[0133] Synthesis method In some embodiments, synthesis of the compounds described herein is achieved using means described in the chemical literature, using methods described herein, or by a combination thereof. In addition, solvents, temperatures, and other reaction conditions presented herein may be varied.

[0134] In other embodiments, the starting materials and reagents used in the synthesis of the compounds described herein are synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fisher Scientific (Fisher Chemicals), and Acros Organics.

[0135] In further embodiments, the compounds described herein, and other related compounds with different substituents, are synthesized using the techniques and materials described herein, as well as art-recognized methods such as those described in, for example, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley, 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum, 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley, 1999), all of which are incorporated by reference into such disclosures. General methods for the preparation of the compounds disclosed herein may be obtained from reactions which may be modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the formulae as provided herein. The following synthetic methods may be used as a guide.

[0136] In the reactions described, it may be necessary to protect reactive functional groups, such as hydroxy, amino, imino, thio, or carboxy groups, which are desired in the final product to prevent their undesired participation in the reaction. A detailed description of techniques applicable to the creation of protecting groups and their removal is provided in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure. It is understood that other similar procedures and reagents may be used and that these schemes are intended as non-limiting examples only. [Example]

[0137] Preparation of compounds Abbreviation DCM: dichloromethane DIEA: Diisopropylethylamine DMF: dimethylformamide DMSO: dimethyl sulfoxide ESI: electrospray ionization HPLC: High-performance liquid chromatography HRMS: High resolution mass spectrometry h or hr(s): hour(s) HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide min(s): minutes m / z: mass-to-charge ratio 1 H NMR: proton nuclear magnetic resonance 13 C NMR: Carbon nuclear magnetic resonance RT: room temperature

[0138] Example 1. Synthesis of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-(2-ethoxyethyl)-1H-1,2,3-triazole-4-carboxamide (Compound 1, Table 1) [ka] The title compound was synthesized according to Schemes 1-3 (Example 2) starting from 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (80 mg, 163.96 μmol, 1 equiv.) and 2-ethoxyethanol (22 mg, 245.94 μmol, 23.83 μL, 1.5 equiv.) in DMF (1 mL), to which was added DMAP (24 mg, 196.76 μmol, 1.2 equiv.), 2-chloro-1-methyl-pyridin-1-ium iodide (50 mg, 196.76 μmol, 1.2 equiv.), and EtN (33 mg, 327.93 μmol, 45.64 μL, 2 equiv.) in one portion. The mixture was stirred at 30°C for 12 hours. The residue was concentrated under reduced pressure to remove DMF. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; 7.8 min;). Example 1 (20.7mg, 36.40μmol, 22.20% yield, 98.471% purity) was obtained as a white solid.

[0139] 1 H NMR: (DMSO-d6, 400 MHz) δ H=9.56-9.45(m,2H),8.65(s,1H),7.74(dd,J=2.8,8.8Hz,1H),7.43(d,J= 8.8Hz,1H),6.88(d,J=9.2Hz,1H),5.53(s,2H),4.48-4.41(m,2H),3.74- 3.68(m,2H),3.51(q,J=6.8Hz,3H),3.00(s,4H),2.69(s,3H),2.40-2.30 (m,3H),2.26(d,J=2.4Hz,3H),1.15-1.10(m,1H),1.12(t,J=7.2Hz,2H).

[0140] HPLC:R t =3.556 mins in 8 min chromatography, Xbridge C18 2.1*50mm 5μm, 8um, purity 98.41%.

[0141] LCMS:R t = 0.693 min in 1.5 min chromatography, Agilent Pursit 5 C18 20*2.0 mm, 8 μm, 100% purity, 559.21 [M+H] + MS ESI calculated for 560.21, found 560.1.

[0142] Example 2. Synthesis of isobutyl 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (Compound 2, Table 1) Scheme 1. Synthesis of 2-chloro-4-fluoro-3-methyl-5-nitrobenzoyl chloride (Intermediate 3). [ka]

[0143] Step 1: To a mixture of 2-chloro-4-fluoro-3-methylbenzoic acid (10 g, 53.03 mmol, 1 equiv.) in H2SO4 (100 mL) was added HNO3 (5.65 g, 58.33 mmol, 4.04 mL, 65% purity, 1.1 equiv.) dropwise at 0 °C. The mixture was warmed to 25 °C and stirred for 2 h. The mixture was poured into ice water. The mixture was filtered through filter paper, and the filter cake was dried under reduced pressure. The product was used directly in the next step without further purification. 2-Chloro-4-fluoro-3-methyl-5-nitrobenzoic acid (10 g, 34.79 mmol, 65.61% yield, 81.27% purity) was obtained as an off-white solid.

[0144] 1 H NMR: (DMSO-d6, 400 MHz) δ H =8.36(d,J=8.0Hz,1H),2.39(d,J=2.8Hz,1H).

[0145] HPLC:R t =2.60 min with 8 min chromatography, final XB-C18 3.0*50mm, 3μm, purity 81.27%.

[0146] LCMS: Rt=4min chromatography 1.284min, Xtimate C18, 3μm, 2.1*30mm, purity 81.30%.

[0147] Step 2: To a solution of 2-chloro-4-fluoro-3-methyl-5-nitrobenzoic acid (500 mg, 2.14 mmol, 1 equiv) and DMF (7.82 mg, 107.03 μmol, 8.23 ​​μL, 0.05 equiv) in DCM (5 mL) was added (COCl) (408 mg, 3.21 mmol, 281.07 μL, 1.5 equiv) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 1 h to give a yellow solution. The reaction mixture was concentrated to dryness. The crude product, 2-chloro-4-fluoro-3-methyl-5-nitrobenzoyl chloride (500 mg, crude), was obtained as a yellow oil and used in the next step without further purification.

[0148] Scheme 2. Synthesis of intermediate compound 5, methyl 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (intermediate 8). [ka]

[0149] Step 1: To a mixture of 4-fluoro-3-nitroaniline (50 g, 320.28 mmol, 1 eq.) and 1-methylpiperazine (64.16 g, 640.56 mmol, 71.05 mL, 2 eq.) in CHCN (500 mL) was added DIEA (82.79 g, 640.56 mmol, 111.57 mL, 2 eq.). The mixture was stirred at 90 °C for 12 h. The mixture was diluted with DCM (200 mL) and washed with brine (50 mL * 3). The combined organic layers were dried over NaSO and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel (DCM:MeOH = 20:1). 4-(4-Methylpiperazin-1-yl)-3-nitroaniline (72 g, 302.15 mmol, 94.34% yield, 99.15% purity) was obtained as a red solid.

[0150] 1 H NMR: (DMSO-d6, 400 MHz) δ H =7.16(d,J=8.8Hz,1H),6.68(d,J=2.4Hz,1H),6.78(dd,J=2.8,8.8Hz,1H),5.43(s,2H),2.82-2.79(m,4H),2.50-2.34(m,4H),2.19(s,3H).

[0151] Step 2: To a mixture of 4-(4-methylpiperazin-1-yl)-3-nitroaniline (35 g, 148.14 mmol, 1 equiv.) in HCl (2 M, 875.00 mL, 11.81 equiv.) was added dropwise a solution of NaNO (15.33 g, 222.20 mmol, 1.5 equiv.) in HO (90 mL) at 0 °C. After 0.5 h, a solution of NaN (19.26 g, 296.27 mmol, 2 equiv.) in HO (90 mL) was added to the mixture. After 0.5 h, the mixture was warmed to 25 °C and stirred for 2 h. The pH of the mixture was adjusted to approximately 9 with 2 N NaOH. The mixture was filtered through filter paper. The filter cake was obtained as a red solid. The product was used directly in the next step without further purification. 1-(4-Azido-2-nitrophenyl)-4-methylpiperazine (30 g, 109.33 mmol, 73.80% yield, 95.58% purity) was obtained as a red solid.

[0152] 1 H NMR: (DMSO-d6, 400 MHz) δ H =7.56(d,J=2.0Hz,1H),7.39-7.32(m,2H),2.95-2.92(m,4H),2.41-2.38(m,4H),2.20(s,3H).

[0153] Step 3: To a mixture of 1-(4-azido-2-nitrophenyl)-4-methylpiperazine (30 g, 114.39 mmol, 1 equiv.) and methyl prop-2-ynoate (28.85 g, 343.16 mmol, 28.57 mL, 3 equiv.) in MeOH (1500 mL), CuI (6.54 g, 34.32 mmol, 0.3 equiv.) and DIEA (2.96 g, 22.88 mmol, 3.98 mL, 0.2 equiv.) were added. The mixture was stirred at 65 °C for 48 h. The mixture was diluted with DCM (2000 mL) and washed with 2N NH3.HO (1000 mL*2) and brine (500 mL*2). The combined organic layer was dried over Na2SO4 and concentrated to give the crude product. The product was purified by column chromatography on silica gel (DCM:MeOH=10:1) to give methyl 1-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (32 g, 84.28 mmol, 73.68% yield, 91.22% purity) as a red solid.

[0154] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.54(s,1H),8.45(d,J=2.4Hz,1H),8.15(dd,J=2.8,9.2Hz,1H),7.51(d,J= 8.8Hz,1H),3.90(s,3H),3.12-3.09(m,4H),2.50-2.45(m,4H),2.24(s,3H).

[0155] Step 4: To a solution of methyl 1-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (10 g, 28.87 mmol, 1 equiv.) in MeOH (100 mL) was added Pd / C (1 g, 10% purity) under N atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred under H (15 Psi) at 30 °C for 12 h. The mixture was filtered through a Celite pad, and the pad was washed with MeOH (100 mL*3). The filtrate was concentrated to give the desired product. Methyl 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (6.1 g, 19.09 mmol, 66.11% yield, 99% purity) was obtained as a red solid.

[0156] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.28(s,1H),7.26(d,J=2.0Hz,1H),7.08-7.02(m,2H),5.15(s,2H),3.88(s,3H),2.85(s,4H),2.56-2.51(m,4H),2.24(s,3H).

[0157] Scheme 2. Synthesis of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (final intermediate 11) and compound 2. [ka]

[0158] Step 5: To a solution of methyl 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (3.8 g, 12.01 mmol, 1 equiv.) and 2-chloro-4-fluoro-3-methyl-5-nitrobenzoyl chloride (3.33 g, 13.21 mmol, 1.1 equiv.) in DCM (50 mL) at 0 °C was added EtN (6.08 g, 60.06 mmol, 8.36 mL, 5 equiv.). The reaction mixture was stirred at 15 °C for 2 h to give a brown mixture. The reaction mixture was concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluting with a 0-10% MeOH / DCM ether gradient at 60 mL / min). The product, methyl 1-(3-(2-chloro-4-fluoro-3-methyl-5-nitrobenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (3.3 g, 4.34 mmol, 36.14% yield, 70.2% purity), was obtained as a yellow solid.

[0159] 1 H NMR: (CDCl3, 400 MHz) δ H =9.36(s,1H),9.00-8.89(m,1H),8.62-8.55(m,1H),8.32(d,J=7.6Hz,1H),7.76-7.65(m,1H ),7.48-7.39(m,1H),4.01(s,3H),3.04-2.92(m,4H),2.78-2.47(m,7H),2.46-2.31(m,3H).

[0160] Step 6: To a solution of methyl 1-(3-(2-chloro-4-fluoro-3-methyl-5-nitrobenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (5 g, 9.40 mmol, 1 equiv.) in 100 mL of EtOAc was added SnCl2.2H2O (8.48 g, 37.60 mmol, 4 equiv.). The reaction mixture was stirred at 80 °C for 3 h to give a yellow mixture. The reaction mixture was adjusted to pH 8 with aqueous NaHCO3. The resulting mixture was filtered, and the filter cake was washed with EtOAc (50 mL × 3). The filtrate was concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluting with a 0–10% MeOH / DCM ether gradient at 60 mL / min). The product, methyl 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (2.5 g, 4.27 mmol, 45.46% yield, 85.8% purity), was obtained as a yellow solid.

[0161] 1 H NMR: (CDCl3, 400 MHz) δ H =9.39(s,1H),8.97(d,J=2.4Hz,1H),8.58(s,1H),7.66(dd,J=2.8,8.8Hz,1H),7.39(d,J=8.8Hz,1H),7.0 6(d,J=9.2Hz,1H),4.00(s,3H),3.88(s,2H),2.97(t,J=4.8Hz,4H),2.75-2.48(m,4H),2.43-2.31(m,6H).

[0162] Step 7: To a mixture of methyl 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (1.4 g, 2.79 mmol, 1 equiv.) in THF (20 mL) and HO (2 mL) was added LiOH.HO (234.09 mg, 5.58 mmol, 2 equiv.). The reaction mixture was stirred at 15 °C for 2 h to give a yellow mixture. The reaction mixture was then adjusted to pH 5 with aqueous HCl (1 N). The resulting mixture was concentrated to dryness. The crude product, 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (1.6 g, crude) was obtained as a yellow solid, which was used in the next step without further purification.

[0163] 1 H NMR: (DMSO-d6, 400 MHz) δ H =11.23-11.01(m,1H),9.65(s,1H),9.39(s,1H),8.65(s,1H),7.76(dd,J=2.8,8.8Hz,1H),7.43(d,J=8.8Hz,1H),6.88( d,J=9.2Hz,1H),3.71-3.61(m,2H),3.51-3.43(m,2H),3.28-3.18(m,6H),2.81(d,J=3.6Hz,3H),2.27(d,J=2.4Hz,3H).

[0164] Step 8: 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (150 mg, 30 To a mixture of 2-methylpropan-1-ol (34.18 mg, 461.15 μmol, 42.62 μL, 1.5 eq.) and 2-methylpropan-1-ol (34.18 mg, 461.15 μmol, 42.62 μL, 1.5 eq.) was added DMAP (45.07 mg, 368.92 μmol, 1.2 eq.), EtN (62.22 mg, 614.86 μmol, 85.58 μL, 2 eq.), and 2-chloro-1-methyl-pyridin-1-ium; iodide (157.09 mg, 614.86 μmol, 2 eq.). The reaction mixture was stirred at 30 °C for 12 h to give a yellow mixture. Water (10 mL) was added to the reaction mixture. The resulting mixture was extracted with DCM (10 mL * 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80*40mm*3μm; condition: water (0.05% ammonia hydroxide v / v)-ACN; start B: 40%, end B: 70%; gradient time (min): 20 min). Product Example 2 (20.2 mg, 36.63 μmol, yield 11.91%, purity 99.14%) was obtained as an off-white solid.

[0165] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.48(s,1H),9.45(s,1H),8.65(s,1H),7.73(dd,J=2.8,8.8Hz,1H),7.43(d,J=8.8Hz,1H),6.90(d,J=9.6Hz,1H),5.53(s,2H) ,4.12(d,J=6.6Hz,2H),2.93(t,J=4.3Hz,4H),2.49-2.40(m,4H),2.30-2.18(m,6H),2.10-1.95(m,1H),0.99(d,J=6.8Hz,6H).

[0166] HPLC: Rt=8 min chromatography 4.08 min, Ultimate XB-C18 3.0*50 mm, 3 μm, purity 99.14%.

[0167] LCMS:R t = 0.868 min in 4 min chromatography, Chromolith Flash RP-18, 5 μm, 3.0*25 mm, purity 100%, 543.22 [M+H] + MS ESI calculated for 544.22, found 544.2.

[0168] Example 3. Synthesis of methoxybenzyl 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (Compound 3, Table 1) [ka] The title compound was synthesized according to Schemes 1-3 (Example 2). To a mixture of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (51 mg, 368.92 μmol, 45.92 μL, 1.2 equiv.) and 4-methoxyphenyl)methanol (150 mg, 307.43 μmol, 1 equiv.) in DMF (1 mL) was added DMAP (45 mg, 368.92 μmol, 1.2 equiv.), 2-chloro-1-methyl-pyridin-1-ium iodide (157 mg, 614.86 μmol, 2 equiv.), and TEA (62 mg, 614.86 μmol, 85.58 μL, 2 equiv.) in one portion. The mixture was stirred at 30°C for 12 hours. The residue was poured into water (20 mL). The aqueous phase was extracted with DCM (10 mL * 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80 * 40 mm * 3 μm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 42% ~ 72%; 11 min). Example 3 (40.7 mg, 66.70 μmol, yield 21.70%, purity 99.647%) was obtained as a white solid.

[0169] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.49-9.44(m,2H),8.65(s,1H),7.72(dd,J=2.8,8.8Hz,1H),7.48-7.38(m,3H),7.01-6.85(m,3 H),5.52(s,2H),5.33(s,2H),3.76(s,3H),2.92(t,J=4.4Hz,4H),2.47(s,4H),2.30-2.17(m,6H).

[0170] HPLC:R t =3.049 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, 4 μm, purity 99.647%.

[0171] LCMS:Rt = 2.425 min in 4 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, 4 μm, purity 99.821%, 608.06 [M+H] + MS ESI calculated for 609.06, found 608.4.

[0172] Example 4. Synthesis of (S)-1-ethoxy-1-oxopropan-2-yl 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (Compound 4, Table 1) [ka] The title compound was synthesized according to Schemes 1-3 (Example 2). To a mixture of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (150 mg, 307.43 μmol, 1 equiv.) and ethyl (2S)-2-hydroxypropanoate (54 mg, 461.15 μmol, 52.89 μL, 1.5 equiv.) in DMF (1 mL) was added DMAP (45 mg, 368.92 μmol, 1.2 equiv.), TEA (62 mg, 614.86 μmol, 85.58 μL, 2 equiv.), and 2-chloro-1-methyl-pyridin-1-ium iodide (157 mg, 614.86 μmol, 2 equiv.) in one portion. The mixture was stirred at 30°C for 12 hours. The residue was poured into water (5 mL). The aqueous phase was extracted with DCM (5 mL * 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 * 25 mm * 5 μm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN] B%: 42% ~ 75%; 11 min). Example 4 (58.14 mg, 88.49 μmol, 28.78% yield, 98.546% purity) was obtained as a white solid.

[0173] 1H NMR: (DMSO-d6, 400 MHz) δ H =9.51(d,J=16.4Hz,2H),8.66(s,1H),7.74(dd,J=2.4,8.6Hz,1H),7.44(d,J=8.8Hz,1H),6.89(d,J=9.6Hz,1H),5.53(s,2H),5.29(q,J=7. 2Hz,1H),4.18(q,J=7.2Hz,2H),2.93(d,J=4.4Hz,4H),2.49-2.45(m,4H),2.29-2.18(m,6H),1.57(d,J=7.2Hz,3H),1.21(t,J=7.2Hz,3H).

[0174] HPLC:R t =2.817 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, 5 μm, purity 98.546%.

[0175] LCMS:R t = 2.257 minutes in 4 minute chromatography, XBridge Shield RP18, 5μm, 2.1*50mm, 5um, purity 99.059%, 587.21 [M+H] + MS ESI calculated for 588.21, found 588.3.

[0176] Example 5. (1-methylcyclohexyl)methyl 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (Compound 5, Table 1) [ka] The title compound was synthesized according to Schemes 1-3 (Example 2). To a mixture of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (80 mg, 163.96 μmol, 1 equiv.) and (1-methylcyclohexyl)methanol (32 mg, 245.94 μmol, 1.5 equiv.) in DMF (1 mL) was added DMAP (24 mg, 196.76 μmol, 1.2 equiv.), TEA (33 mg, 327.93 μmol, 45.64 μL, 2 equiv.), and 2-chloro-1-methyl-pyridin-1-ium iodide (50 mg, 196.76 μmol, 1.2 equiv.) in one portion. The mixture was stirred at 30° C. for 12 h. The residue was poured into water (5 mL). The aqueous phase was extracted with DCM (5 mL * 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 100 * 40 mm * 3 μm; mobile phase: [water (0.225% FA) -ACN]; 10 min). Example 5 (13 mg, 21.66 μmol, yield 13.21%, purity 99.65%) was obtained as a white solid.

[0177] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.46(d,J=17.6Hz,2H),8.65(s,1H),8.18(s,1H),7.77-7.68(m,1H),7.44(d,J=8.4Hz,1H),6.90(d,J=9.2Hz,1 H),5.52(s,2H),4.10(s,2H),3.32(s,4H),2.93(s,4H),2.24(d,J=13.6Hz,6H),1.54-1.23(m,10H),1.01(s,3H).

[0178] HPLC:R t =3.48 min for 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, 10μm, purity 99.01%.

[0179] LCMS:Rt = 2.076 minutes in 4 minute chromatography, Xtimate C18, 3μm, 2.1*30mm, 10um, purity 99.882%, 597.26 [M+H] + MS ESI calculated value 598.26, found value 598.4.

[0180] Example 6. Synthesis of (1-methylpiperidin-4-yl)methyl 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (Compound 6, Table 1) [ka] The title compound was synthesized according to Schemes 1-3 (Example 2). To a mixture of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (80 mg, 163.96 μmol, 1 equiv.) and (1-methyl-4-piperidyl)methanol (32 mg, 245.94 μmol, 1.5 equiv.) in DMF (1 mL) was added DMAP (24 mg, 196.76 μmol, 1.2 equiv.), TEA (33 mg, 327.93 μmol, 45.64 μL, 2 equiv.), and 2-chloro-1-methyl-pyridin-1-ium iodide (50 mg, 196.76 μmol, 1.2 equiv.) in one portion. The mixture was stirred at 30° C. for 12 h. The residue was poured into water (5 mL). The aqueous phase was extracted with DCM (5 mL * 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 * 25 mm * 5 μm; mobile phase: [water (0.05% ammonia hydroxide v / v) -ACN]; 7.8 min;). Example 6 (10 mg, 16.59 μmol, yield 10.12%, purity 99.37%) was obtained as a white solid.

[0181] 1 H NMR: (DMSO-d6, 400 MHz) δ H=9.46(d,J=17.6Hz,2H),8.65(s,1H),8.18(s,1H),7.77-7.68(m,1H),7.44(d,J=8.4Hz,1H),6.90(d,J=9.2Hz,1 H),5.52(s,2H),4.10(s,2H),3.32(s,4H),2.93(s,4H),2.24(d,J=13.6Hz,6H),1.54-1.23(m,10H),1.01(s,3H).

[0182] HPLC:R t =4.067 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, 5 μm, purity 96.881%.

[0183] LCMS:R t = 1.852 min in 4 min chromatography, XBridge Shield RP-18, 5 μm, 2.1*50 mm, 40 μm, purity 97.972%, 598.26 [(M+2H) / 2] + MS ESI calculated for 300.13, found 300.2.

[0184] Example 7. Synthesis of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (Compound 7, Table 1) [ka] The title compound was synthesized according to Schemes 1-3 (Example 2). To a mixture of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (300 mg, 614.86 μmol, 1 equiv.) and 1-methylcyclobutanol (79 mg, 922.29 μmol, 1.5 equiv.) in DMF (1 mL) was added DMAP (180 mg, 1.48 mmol, 2.4 equiv.), TEA (124 mg, 1.23 mmol, 171.16 μL, 2 equiv.), and 2-chloro-1-methyl-pyridin-1-ium iodide (314 mg, 1.23 mmol, 2 equiv.) in one portion. The mixture was stirred at 100° C. for 12 h. The residue was poured into water (20 mL). The aqueous phase was extracted with DCM (10 mL * 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80 * 40 mm * 3 μm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 45%-80%; 13 min). Example 7 (10.5 mg, 18.77 μmol, 3.05% yield, 99.39% purity) was obtained as a white solid.

[0185] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.52-9.33(m,2H),8.65(s,1H),7.71(d,J=6.8Hz,1H),7.43(d,J=8.4Hz,1H),6.89(d,J=9.2Hz,1H),5.53(s,2H),4.64- 3.96(m,1H),2.93(s,4H),2.48-2.36(m,5H),2.24(d,J=16.8Hz,8H),1.90-1.69(m,2H),1.64(s,2H),1.48-0.81(m,1H).

[0186] HPLC:R t =3.044 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, 10 μm, purity 99.39%.

[0187] LCMS:R t = 2.443 minutes in 4 minute chromatography, XBridge Shield RP18, 5μm, 2.1*50mm, 6μm, purity 99.676%, 555.22 [M+H] + MS ESI calculated for 556.22, found 556.4.

[0188] Example 8. Synthesis of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-methyl-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 8, Table 1) [ka] The title compound was synthesized according to Schemes 1-3 (Example 2) and Scheme 4.

[0189] Scheme 4. Synthesis of N-methyl-3-morpholinopropan-1-amine (intermediate compound 4A). [ka]

[0190] Step 1: To a mixture of tert-butyl (3-hydroxypropyl)(methyl)carbamate (200 mg, 1.06 mmol, 1 equiv.), TEA (1.07 g, 10.57 mmol, 1.47 mL, 10 equiv.), and DMSO (247.71 mg, 3.17 mmol, 247.71 μL, 3 equiv.) in DCM (5 mL) was added SO3.Py (504.61 mg, 3.17 mmol, 3 equiv.) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 4 h. The mixture was extracted with DCM (10 mL * 3). The combined organic phase was washed with NaHCO3 (10 mL * 3) and brine (10 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The product was directly concentrated for the next reaction. tert-Butyl methyl(3-oxopropyl)carbamate (200 mg, crude) was obtained as a yellow oil.

[0191] Step 2: To a mixture of tert-butyl methyl(3-oxopropyl)carbamate (200 mg, 1.07 mmol, 1 equiv.) and morpholine (93.06 mg, 1.07 mmol, 94.00 μL, 1 equiv.) in DCM (10 mL) was added NaBH(OAc) (679.17 mg, 3.20 mmol, 3 equiv.). The reaction mixture was stirred at 25 °C for 10 h. The mixture was extracted with DCM (10 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The product was directly concentrated for the next reaction. tert-Butyl methyl(3-morpholinopropyl)carbamate (200 mg, crude) was obtained as a yellow oil.

[0192] Step 3: A mixture of tert-butyl methyl(3-morpholinopropyl)carbamate (200 mg, 774.13 μmol, 1 equiv.) in HCl / dioxane (5 mL) under N2. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The product was directly concentrated for the next reaction. N-methyl-3-morpholinopropan-1-amine (200 mg, crude, HCl) was obtained as a white solid.

[0193] Step 4: To a mixture of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (250 mg, 512.39 μmol, 1 equiv.) and N-methyl-3-morpholinopropan-1-amine (199.52 mg, 1.02 mmol, 2 equiv., HCl)) in DMF (2 mL) was added HATU (389.65 mg, 1.02 mmol, 2 equiv.) and DIEA (198.66 mg, 1.54 mmol, 267.74 μL, 3 equiv.). The reaction mixture was stirred at 25° C. for 10 hours. The mixture was extracted with DCM (10 mL*3). The combined organic phase was washed with brine (10 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The reaction mixture was concentrated to dryness. The crude product was purified by reverse-phase HPLC (column: Phenomenex Gemini-NX C18 75 * 30 mm * 3 μm; condition: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3) -ACN]; B: 19% - 49%, 11 min). Example 8 (22 mg, 34.89 μmol, yield 6.81%, purity 99.63%) was obtained as a white solid.

[0194] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.47(s,1H),9.14(d,J=5.3Hz,1H),8.65(s,1H),7.68(dd,J=2.4,8.8Hz,1H),7.42 (d,J=8.8Hz,1H),6.89(d,J=9.2Hz,1H),5.53(s,2H),3.81(t,J=7.2Hz,1H),3.57(s, 2H),3.53-3.43(m,5H),3.53-3.43(m,1H),3.36(s,2H),3.01(s,2H),2.92(s,4H),2. 48-2.43(m,3H),2.33(dd,J=8.0,15.2Hz,3H),2.29-2.19(m,6H),1.85-1.75(m,2H).

[0195] HPLC:R t=2.33 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 99.62%.

[0196] LCMS:R t = 1.877 min in 4 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 99.52%, 627.28 [M+H] + MS ESI calculated for 628.28, found 628.7.

[0197] Example 9. Synthesis of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-hydroxypropyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (Compound 9, Table 1) [ka] The title compound was synthesized according to Schemes 1-3 (Example 2). To a mixture of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (100 mg, 204.95 μmol, 1 equiv.) and 3-(methylamino)propan-1-ol (80 mg, 409.91 μmol, 2 equiv., HCl) in DMF (1 mL) was added HATU (156 mg, 409.91 μmol, 2 equiv.) and DIEA (79 mg, 614.86 μmol, 107.10 μL, 3 equiv.). The reaction mixture was stirred at 25° C. for 10 hours. The mixture was extracted with DCM (10 mL*3). The combined organic phase was washed with brine (10 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The reaction mixture was concentrated to dryness. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 80 * 40 mm * 3 μm; conditions: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3) -ACN]; B: 10% to 50%, 12 min). Example 9 (15.8 mg, 36.77 μmol, yield 17.94%, purity 97.43%) was obtained as a white solid.

[0198] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.48(s,1H),9.16(d,J=8.4Hz,1H),8.66(s,1H),7.70(dd,J=2.8,8.8Hz,1H ),7.43(d,J=8.8Hz,1H),6.90(d,J=9.2Hz,1H),5.54(s,2H),4.53(q,J=4.8Hz ,1H),3.83(t,J=7.2Hz,1H),3.58-3.40(m,3H),3.36(s,4H),3.03(s,1H),2. 93(t,J=4.4Hz,4H),2.49-2.46(m,2H),2.31-2.18(m,6H),1.87-1.70(m,2H).

[0199] HPLC:R t =3.041 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 97.43%.

[0200] LCMS:R t =2.353 min in 4 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 97.73%, MS ESI calculated 559.23 for 558.23 [M+H]+, found 559.4.

[0201] Example 10. Synthesis of (S)-1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(3,4-dimethylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 10, Table 1) [ka] The title compound was synthesized in a manner similar to Schemes 1-3.

[0202] Step 1: To a solution of 4-fluoro-3-nitroaniline (5 g, 32.03 mmol, 1 equiv.) in CH3CN (50 mL) was added (2R)-1,2-dimethylpiperazine (3.66 g, 32.03 mmol, 1 equiv.) and DIEA (8.28 g, 64.06 mmol, 11.16 mL, 2 equiv.). The mixture was stirred at 80 °C for 2 h. The reaction mixture was partitioned between EtOAc (30 mL) and HO (30 mL * 2). The organic phase was separated, washed with brine (20 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluting with a 0-8% dichloromethane / methanol gradient at 58 mL / min). (S)-4-(3,4-dimethylpiperazin-1-yl)-3-nitroaniline (4.03 g, 16.10 mmol, 50.27% yield) was obtained as a reddish-brown oil.

[0203] 1 H NMR: (DMSO-d6, 400 MHz) δ H =7.14(d,J=8.8Hz,1H),6.85(d,J=2.8Hz,1H),6.80-6.75(m,1H),5.43(s,2H),2.80(dd,J=2.8, 7.6Hz,4H),2.46(d,J=9.6Hz,1H),2.22-2.13(m,4H),2.11-2.03(m,1H),0.95(d,J=6.4Hz,3H).

[0204] Step 2: To a mixture of (S)-4-(3,4-dimethylpiperazin-1-yl)-3-nitroaniline (5.3 g, 21.17 mmol, 1 equiv) in HCl (2 M, 125 mL, 11.81 equiv) was added dropwise a solution of NaNO (2.19 g, 31.76 mmol, 1.5 equiv) in HO (15 mL) at 0 °C. After 0.5 h, a solution of NaN (2.75 g, 42.35 mmol, 2 equiv) in HO (15 mL) was added to the mixture. After 0.5 h, the mixture was warmed to 25 °C and stirred for 2 h. The pH of the mixture was adjusted to approximately 9 with 2 N NaOH. The mixture was extracted with DCM (200 mL*3). The combined organic layers were dried over NaSO and concentrated to give the crude product. (S)-4-(4-azido-2-nitrophenyl)-1,2-dimethylpiperazine (5.5 g, 19.45 mmol, 91.88% yield) was obtained as a red oil.

[0205] Step 3: To a mixture of (S)-4-(4-azido-2-nitrophenyl)-1,2-dimethylpiperazine (4.5 g, 16.29 mmol, 1 equiv.) in MeOH (140 mL) was added CuI (3.10 g, 16.29 mmol, 1 equiv.), DIEA (1.05 g, 8.14 mmol, 1.42 mL, 0.5 equiv.), and methyl prop-2-ynoate (8.22 g, 97.72 mmol, 8.13 mL, 6 equiv.). The mixture was stirred at 65 °C for 2 h. The mixture was diluted with DCM (50 mL) and washed with 2N NH3.HO (20 mL) and brine (20 mL * 2). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel (PE: EtOAc = 5:1). (S)-methyl 1-(4-(3,4-dimethylpiperazin-1-yl)-3-nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (4.5 g, 11.05 mmol, 67.86% yield) was obtained as a yellow solid.

[0206] 1 H NMR: (DMSO-d6, 400 MHz) δ H=7.58(d,J=2.0Hz,1H),7.41-7.32(m,2H),3.03-2.89(m,3H),2.79-2.71(m,1H),2.59-2.51(m,1H),2.25-2.09(m,5H),0.98(d,J=2.4Hz,3H).

[0207] Step 4: To a mixture of (S)-1-(4-(3,4-dimethylpiperazin-1-yl)-3-nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (1 g, 2.77 mmol, 1 equiv.) in MeOH (10 mL) and HO (2 mL) was added SnCl.2HO (1.57 g, 6.94 mmol, 2.5 equiv.). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched by adding NaHCO (100 mL) and then extracted with DCM (100 mL * 3). The combined organic layers were concentrated under reduced pressure to give a residue. The crude product was purified by silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a 0-15% MeOH / DCM ether gradient at 60 mL / min). (S)-methyl 1-(3-amino-4-(3,4-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (650 mg, 1.81 mmol, 65.23% yield) was obtained as a yellow solid.

[0208] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.28(s,1H),7.25(d,J=2.4Hz,1H),7.07-6.99(m,2H),5.14(s,2H),3.87(s,3H),3.01 -2.91(m,2H),2.82-2.68(m,2H),2.42-2.27(m,3H),2.23(s,3H),1.01(d,J=6.0Hz,3H).

[0209] Step 5: To a solution of (S)-1-(3-amino-4-(3,4-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-methyl carboxylate, Intermediate 8 (200 mg, 605.36 μmol, 1 equiv.), and 2-chloro-4-fluoro-3-methyl-5-nitrobenzoyl chloride (168 mg, 665.89 μmol, 1.1 equiv.) in DCM (15 mL) at −20° C., EtN (306 mg, 3.03 mmol, 421.29 μL, 5 equiv.) was added. The reaction mixture was warmed to 15° C. and stirred for 12 h to give a brown mixture. The reaction mixture was concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluting with a 0–20% MeOH / DCM ether gradient at 20 mL / min). The product, (S)-1-(3-(2-chloro-4-fluoro-3-methyl-5-nitrobenzamido)-4-(3,4-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (190 mg, 271.11 μmol, 44.78% yield), was obtained as a yellow solid.

[0210] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.96(s,1H),9.47(s,1H),8.56(s,1H),8.35(d,J=7.6Hz,1H),7.77(dd,J=2.6,8.6Hz,1H),7.37 (d,J=8.8Hz,1H),3.90(s,3H),3.13-3.02(m,2H),2.94-2.74(m,2H),2.48-2.34(m,5H),2.21(br s,4H),1.01(d,J=5.9Hz,3H).

[0211] Step 6: To a mixture of (S)-1-(3-(2-chloro-4-fluoro-3-methyl-5-nitrobenzamido)-4-(3,4-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (490 mg, 897.52 μmol, 1 equiv.) in MeOH (10 mL) and HO (3 mL) was added SnCl.2HO (607 mg, 2.69 mmol, 3 equiv.). The reaction mixture was stirred at 80° C. for 2 h to give a brown mixture. The reaction mixture was then adjusted to pH 8 with aqueous NaHCO. The resulting mixture was extracted with DCM (60 mL*3). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluting with a 0-20% DCM / MeOH ether gradient at 20 mL / min) to afford the product (S)-1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(3,4-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (300 mg, 473.87 μmol, 52.80% yield) as a yellow solid.

[0212] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.48(s,2H),8.65(s,1H),7.71(dd,J=2.8,8.8Hz,1H),7.42(d,J=8.8Hz,1H),6.88(d,J=9.6Hz,1H),5.52(s,2H) ,3.89(s,3H),3.17(d,J=5.6Hz,3H),3.05-2.75(m,4H),2.26(d,J=2.4Hz,3H),2.21(s,3H),0.99(d,J=6.4Hz,3H).

[0213] Step 7: To a solution of (S)-1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(3,4-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (300 mg, 581.43 μmol, 1 equiv.) in THF (3 mL) and HO (1 mL) was added LiOH.HO (48.79 mg, 1.16 mmol, 2 equiv.). The mixture was stirred at 25 °C for 2 h. The reaction mixture was adjusted to pH 5 with 1 N aqueous HCl and concentrated under reduced pressure to give a residue. The product was used directly in the next step without further purification. Final intermediate 9 (S)-1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(3,4-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (291 mg, crude) was obtained as a brown solid.

[0214] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.57(s,1H),9.19(s,1H),8.66-8.56(m,1H),7.71(dd,J=2.4,8.8Hz,1H),7.40(d,J=8.8Hz,1H),6.90(d,J=9.2Hz,1H ),5.54(s,2H),3.12(s,5H),2.95(s,1H),2.91-2.82(m,2H),2.53(s,3H),2.24(d,J=2.0Hz,3H),1.19(d,J=6.4Hz,3H).

[0215] Step 8: To a solution of final intermediate 9 (140 mg, 278.92 μmol, 1 equiv.) and 3-morpholinopropan-1-amine (60.34 mg, 418.38 μmol, 61.13 μL, 1.5 equiv.) in DMF (3 mL) was added HATU (212.11 mg, 557.84 μmol, 2 equiv.) and DIEA (108.14 mg, 836.75 μmol, 145.74 μL, 3 equiv.). The mixture was stirred at 25° C. for 3 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm, mobile phase A: purified water (0.04% NH3H2O ​​+ 10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 15 to 55% B in 11 min). Example 10 (98 mg, 154.44 μmol, yield 55.37%, purity 98.99%) was obtained as a white solid.

[0216] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.49-9.40(m,1H),9.20(s,1H),8.88-8.79(m,1H),8.71-8.62(m,1H),7.70(dd,J=2.4 ,8.4Hz,1H),7.40(d,J=8.8Hz,1H),6.90(d,J=9.2Hz,1H),5.52(s,2H),3.61(s,4H),3. 39-3.35(m,2H),3.01-2.73(m,4H),2.55-2.50(m,2H),2.41-2.32(m,6H),2.32-2.28(m ,1H),2.26(d,J=1.6Hz,3H),2.20(s,3H),1.71(d,J=6.8Hz,2H),0.98(d,J=6.0Hz,3H).

[0217] HPLC:R t = 2.460 min with 8 min of chromatography, Ultimate XB-C18 (3 × 50 mm, 3 μm), purity 98.99%.

[0218] LCMS:R t= 1.999 min in 4 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 99.06%, 627.28 [M+H] + MS ESI calculated for 628.28, found 628.5.

[0219] Example 11. Synthesis of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 11, Table 1) [ka] The title compound was synthesized in a manner similar to Schemes 1-3.

[0220] Step 1: To a mixture of 4-fluoro-3-nitroaniline (5 g, 32.03 mmol, 1 equiv.) and (2S,6R)-1,2,6-trimethylpiperazine (4.93 g, 38.43 mmol, 1.2 equiv.) in CH3CN (10 mL) under N2 at 25 °C, DIEA (4.2 g, 32.03 mmol, 5.58 mL, 1 equiv.) was added in one portion. The mixture was heated to 80 °C and stirred for 10 h. The residue was poured into water (40 mL). The aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with brine (20 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column weight: 20 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 7:3). 3-Nitro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)aniline (6.8 g, 25.62 mmol, 79.98% yield, 99.57% purity) was obtained as a yellow oil.

[0221] 1 H NMR: (CDCl3-d6, 400 MHz) δ H=7.07-7.01(m,2H),6.81(dd,J=2.8,8.6Hz,1H),3.73(br s,2H),2.99-2.92(m,2H),2.62(t,J=10.8Hz,2H),2.47-2.36(m,2H),2.31(s,3H),1.10(d,J=6.4Hz,6H).

[0222] Step 2: To a mixture of 3-nitro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)aniline (6.8 g, 25.73 mmol, 1 equiv) in HCl (2 M, 155.43 mL, 12.08 equiv) was added a solution of NaNO (2.66 g, 38.59 mmol, 1.5 equiv) in HO (21 mL) dropwise at 0 °C. After 0.5 h, a solution of NaN (3.34 g, 51.45 mmol, 2 equiv) in HO (21 mL) was added to the mixture. After 0.5 h, the mixture was warmed to 25 °C and stirred for 2 h. The pH of the mixture was adjusted to approximately 9 with 2 N NaOH. The mixture was extracted with DCM (200 mL*3). The combined organic layers were dried over NaSO and concentrated to give the crude product. The crude product was used directly in the next step without further purification to give (2S,6R)-4-(4-azido-2-nitrophenyl)-1,2,6-trimethylpiperazine (7.3 g, 24.53 mmol, 95.34% yield, 97.54% purity) as a red solid.

[0223] LCMS:R t = 0.640 min in 2 min chromatography, Ultimate XB-C18, 3 μm, 3.0*50 mm, purity 97.54%, 290.15 [M+H] + MS ESI calculated for 291.15, found 290.9.

[0224] Step 3: To a mixture of (2S,6R)-4-(4-azido-2-nitrophenyl)-1,2,6-trimethylpiperazine (6 g, 20.67 mmol, 1 equiv.) and methyl propionate (2.09 g, 24.80 mmol, 2.06 mL, 1.2 equiv.) in THF (70 mL) was added CuI (1.18 g, 6.20 mmol, 0.3 equiv.) and DIEA (8.01 g, 62.00 mmol, 10.80 mL, 3 equiv.) under N. The reaction mixture was stirred at 25 °C for 10 h. The reaction mixture was filtered. The filter cake was washed with CHCN (200 mL * 3). The filtrate was concentrated. The product was directly concentrated for the next reaction. Methyl 1-(3-nitro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (9 g, 19.23 mmol, 93.05% yield) was obtained as a yellow solid.

[0225] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.54(s,1H),8.44(d,J=2.4Hz,1H),8.13(dd,J=2.8,8.8Hz,1H),7.49(d,J=9.2Hz,1H),3.89(s,3H), 3.11(d,J=12.0Hz,2H),2.72(t,J=11.2Hz,2H),2.30-2.23(m,2H),2.19(s,3H),1.02(d,J=6.4Hz,6H).

[0226] Step 4: To a mixture of methyl 1-(3-nitro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (6 g, 20.67 mmol, 1 equiv.) in MeOH (100 mL) and HO (20 mL) was added SnCl.2HO (16.27 g, 72.12 mmol, 3 equiv.). The mixture was stirred at 80 °C for 10 h. The reaction mixture was quenched by adding NaHCO (200 mL) and then extracted with DCM (100 mL * 3). The combined organic layers were concentrated under reduced pressure to give a residue. The crude product was purified by silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, elution with a 0-15% MeOH / DCM ether gradient at 100 mL / min). Methyl 1-(3-amino-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate, Intermediate 11 (4.4 g, 12.02 mmol, 50.02% yield) was obtained as a yellow solid.

[0227] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.28(s,1H),7.26(d,J=2.4Hz,1H),7.08-7.03(m,1H),7.01-6.96(m,1H),5.15(s,2H),3. 87(s,3H),2.96(d,J=7.6Hz,2H),2.37(d,J=5.6Hz,4H),2.22(s,3H),1.03(d,J=5.2Hz,6H).

[0228] Step 5: To a solution of methyl 1-(3-amino-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (700 mg, 2.03 mmol, 1 equiv.) and TEA (1.03 g, 10.16 mmol, 1.41 mL, 5 equiv.) in DCM (20 mL) was added a solution of 2-chloro-4-fluoro-3-methyl-5-nitrobenzoyl chloride (461 mg, 1.83 mmol, 0.9 equiv.) in DCM (5 mL) dropwise at −20° C. The reaction mixture was warmed to 20° C. and stirred for 3 h to give a brown mixture. Water (20 mL) was added to the reaction mixture. The resulting mixture was extracted with DCM (20 mL*3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluting with a 0–15% MeOH / DCM ether gradient at 30 mL / min) to give the product, methyl 1-(3-(2-chloro-4-fluoro-3-methyl-5-nitrobenzamido)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (900 mg, 663.78 μmol, 32.66% yield, 41.3% purity), as a brown solid.

[0229] LCMS:R t = 0.796 min in 1.5 min chromatography, Chromolith Flash RP-18, 5 μm, 3.0*25 mm, purity 41.3%, 559.17 [M+H] + MS ESI calculated for 560.17, found 560.1.

[0230] Step 6: To a solution of methyl 1-(3-(2-chloro-4-fluoro-3-methyl-5-nitrobenzamido)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (900 mg, 1.61 mmol, 1 equiv.) in MeOH (20 mL) and HO (6 mL) was added SnCl.2HO (1.09 g, 4.82 mmol, 3 equiv.). The mixture was stirred at 80 °C for 2 h. The mixture was adjusted to pH 9 with NaHCO and filtered to remove insoluble materials. The filtrate was concentrated in vacuo. The mixture was diluted with DMC (50 mL*3) and washed with brine (20 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, elution with 0–13% MeOH / DCM at 35 mL / min) to afford 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (640 mg, 941.90 μmol, 58.60% yield) as a yellow oil.

[0231] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.49-9.47(m,1H),8.69-8.61(m,1H),7.75-7.68(m,1H),7.43-7.37(m,1H),6.93-6.85(m,1H),5.51(s,2H),3.90(s,3H),3.00-2.93( m,2H),2.89(s,1H),2.77-2.75(m,1H),2.77-2.72(m,1H),2.36-2.29(m,2H),2.26(d,J=2.4Hz,3H),2.20(s,3H),1.03(d,J=6.4Hz,6H).

[0232] Step 7: To a solution of methyl 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (300 mg, 566.05 μmol, 1 equiv.) in THF (4 mL) and HO (2 mL) was added LiOH.HO (48 mg, 1.13 mmol, 2 equiv.). The mixture was stirred at 25 °C for 2 h. The reaction mixture was adjusted to pH 5 with 1 N aqueous HCl and concentrated under reduced pressure to give a residue. The product was used directly in the next step without further purification. 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid, final intermediate 12 (300 mg, crude) was obtained as a brown solid.

[0233] 1 H NMR: (DMSO-d6, 400 MHz) δ H =11.45-11.29(m,1H),9.78(s,1H),9.39(s,1H),8.64-8.57(m,1H),7.82-7.74(m,1H),7.43-7.37(m,1H),7.12-7.04(m,1H),3.57- 3.43(m,2H),3.31-3.16(m,4H),2.96(s,1H),2.79(d,J=4.8Hz,3H),2.65-2.59(m,1H),2.28(d,J=2.0Hz,3H),1.40(d,J=6.4Hz,6H).

[0234] Step 8: To a solution of final intermediate 8 (300 mg, 581.43 μmol, 1 equiv.) and 3-morpholinopropan-1-amine (126 mg, 872.15 μmol, 127.43 μL, 1.5 equiv.) in DMF (4 mL) was added HATU (442 mg, 1.16 mmol, 2 equiv.) and DIEA (225.44 mg, 1.74 mmol, 303.83 μL, 3 equiv.). The mixture was stirred at 25 °C for 12 h. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*5 μm, mobile phase A: purified water (0.04% NH3H2O ​​+ 10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 0 to 70% B in 12 min). Example 11 (33.6 mg, 51.91 μmol, 41.67% yield, 99.21% purity) was obtained as a white solid.

[0235] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.47(s,1H),9.20(s,1H),8.82(t,J=5.6Hz,1H),8.65(s,1H),7.69(dd,J=2.8, 8.8Hz,1H),7.38(d,J=8.8Hz,1H),6.89(d,J=9.2Hz,1H),5.50(s,2H),3.61(t,J =4.8Hz,4H),3.36(s,2H),2.94(d,J=10.8Hz,2H),2.58-2.52(m,2H),2.41-2.27 (m,8H),2.25(d,J=2.6Hz,3H),2.18(s,3H),1.70(s,2H),1.02(d,J=6.2Hz,6H).

[0236] HPLC:R t =3.540 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 99.21%.

[0237] LCMS:R t = 2.712 minutes in 4 minute chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 99.72%, 641.30 [M+H] +MS ESI calculated for 642.30, found 642.5.

[0238] Example 12. Synthesis of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 12, Table 1) [ka] The title compound was synthesized in a manner similar to Schemes 1-3.

[0239] Step 1: To a solution of 4-fluoro-3-nitro-aniline (10 g, 64.06 mmol, 1 equiv) in CHCN (100 mL) was added 1-methyl-1,4-diazepane (7.31 g, 64.06 mmol, 7.97 mL, 1 equiv) and DIEA (16.56 g, 128.11 mmol, 22.31 mL, 2 equiv). The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with HO (200 mL), extracted with EtOAc (500 mL), and washed with brine (300 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0–14% MeOH / DCM at 80 mL / min). 4-(4-methyl-1,4-diazepan-1-yl)-3-nitroaniline (12.6 g, 49.33 mmol, 77.02% yield) was obtained as a reddish-brown oil.

[0240] 1 H NMR: (DMSO-d6, 400 MHz) δ H =7.08(d,J=8.8Hz,1H),6.84(d,J=2.8Hz,1H),6.78(dd,J=2.8,8.8Hz,1H),5.2 4(s,2H),3.12-3.04(m,4H),2.57-2.52(m,4H),2.26(s,3H),1.77-1.67(m,2H).

[0241] Step 2: To a mixture of 4-(4-methyl-1,4-diazepan-1-yl)-3-nitroaniline (13 g, 51.94 mmol, 1 equiv.) in HCl (2 M, 259.69 mL, 10 equiv.) was added dropwise a solution of NaNO (5.38 g, 77.91 mmol, 1.5 equiv.) in HO (40 mL) at 0 °C. After 0.5 h, a solution of NaN (6.75 g, 103.88 mmol, 2 equiv.) in HO (40 mL) was added to the mixture. The mixture was warmed to 20 °C and stirred for 1 h to give a brown mixture. The pH of the mixture was adjusted to approximately 9 with 2 N NaOH. The resulting mixture was extracted with DCM (200 mL*3). The combined organic phase was washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated. The product 1-(4-azido-2-nitrophenyl)-4-methyl-1,4-diazepane (12.3 g, 42.34 mmol, 81.51% yield) was obtained as a brown oil and used in the next step without further purification.

[0242] 1 H NMR: (CDCl3, 400 MHz) δ H =7.42(s,1H),7.06(d,J=1.6Hz,2H),3.47-3.39(m,2H),3.33-3.22(m,2H),2. 75-2.67(m,2H),2.65-2.56(m,2H),2.38(s,3H),1.95(td,J=5.6,10.8Hz,2H).

[0243] Step 3: To a mixture of 1-(4-azido-2-nitrophenyl)-4-methyl-1,4-diazepane (9 g, 32.57 mmol, 1 equiv.) and methyl prop-2-ynoate (8.22 g, 97.72 mmol, 8.13 mL, 3 equiv.) in MeOH (450 mL), CuI (1.86 g, 9.77 mmol, 0.3 equiv.) and DIEA (842 mg, 6.51 mmol, 1.13 mL, 0.2 equiv.) were added. The mixture was stirred at 65 °C for 10 h. The mixture was diluted with DCM (500 mL) and washed with 2N NH3.HO (200 mL) and brine (200 mL * 2). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel (DCM:MeOH = 3:1). Methyl 1-(4-(4-methyl-1,4-diazepan-1-yl)-3-nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (7 g, 16.87 mmol, 51.78% yield) was obtained as a yellow solid.

[0244] LCMS:R t = 0.995 min in 2 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 86.55%, 360.15 [M+H] + MS ESI calculated for 361.15, found 361.0.

[0245] Step 4: To a mixture of methyl 1-(4-(4-methyl-1,4-diazepan-1-yl)-3-nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (6 g, 16.65 mmol, 1 equiv.) in EtOH (60 mL) and HO (20 mL) was added Fe (2.79 g, 49.95 mmol, 3 equiv.) and NHCl (4.45 g, 83.25 mmol, 5 equiv.). The reaction mixture was stirred at 80 °C for 10 h to give a brown mixture. The reaction mixture was filtered and washed with DCM (200 mL*3). The combined organic phase was washed with brine (200 mL*2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, elution with a 0-20% MeOH / DCM ether gradient at 100 mL / min) to give crude ethyl 1-(3-amino-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (2.1 g, crude) as a brown solid.

[0246] LCMS:R t = 1.185 min in 2 min chromatography, Xtimate C18, 3um, 2.1*30mm, purity 62.16%, 344.20 [M+H] + MS ESI calculated for 345.20, found 345.3.

[0247] Step 5: To a mixture of ethyl 1-(3-amino-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (1.8 g, 5.23 mmol, 1 equiv.) and 2-chloro-4-fluoro-3-methyl-5-nitrobenzoyl chloride (1.45 g, 5.75 mmol, 1.1 equiv.) in DCM (100 mL) was added TEA (2.64 g, 26.13 mmol, 3.64 mL, 5 equiv.) in one portion at 0 °C. The mixture was stirred at 25 °C for 12 hours. The residue was poured into water (100 mL). The aqueous phase was extracted with DCM (70 mL*3). The combined organic phase was washed with brine (100 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column weight: 20 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 5:1) to obtain 1-(3-(2-chloro-4-fluoro-3-methyl-5-nitrobenzamido)-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (1.2 g, 1.29 mmol, 24.60% yield) as a yellow solid.

[0248] LCMS:R t = 0.753 min in 2 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 49.76%, 559.17 [M+H] + MS ESI calculated for 560.17, found 560.0.

[0249] Step 6: To a mixture of 1-(3-(2-chloro-4-fluoro-3-methyl-5-nitrobenzamido)-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (1.2 g, 2.14 mmol, 1 equiv.) in EtOH (30 mL) and HO (10 mL) was added SnCl.2HO (1.45 g, 6.43 mmol, 3 equiv.). The reaction mixture was stirred at 80 °C for 2 h to give a brown mixture. After cooling, the reaction mixture was adjusted to pH 8 with aqueous NaHCO. Then, DCM was added until a solid formed. The mixture was filtered, and the cake was washed with EtOH (50 mL × 2). The filtrate was concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, elution with a 0–20% MeOH / DCM ether gradient at 30 mL / min) to afford impure product 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (670 mg, 816.65 μmol, 38.11% yield) as a yellow solid.

[0250] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.85(s,1H),9.49-9.35(m,1H),8.55-8.44(m,1H),7.74-7.61(m,1H),7.41-7.33(m,1H),6.86(d,J=9.2Hz,1H),5 .53(s,2H),4.37(q,J=7.2Hz,2H),4.21-4.02(m,2H),3.31-3.19(m,7H),2.37-2.16(m,7H),1.35(t,J=7.2Hz,3H).

[0251] Step 7: To a mixture of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (650 mg, 1.23 mmol, 1 equiv.) in THF (15 mL) and HO (5 mL) was added LiOH.HO (103 mg, 2.45 mmol, 2 equiv.). The reaction mixture was stirred at 15 °C for 2 h to give a brown mixture. The pH of the reaction mixture was adjusted to 5 with 1 N HCl. The reaction mixture was then concentrated. The crude product 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (660 mg, crude) was obtained as a brown solid, which was used in the next step without further purification.

[0252] 1 H NMR: (DMSO-d6, 400 MHz) δ H =11.23(s,1H),9.84(s,1H),9.36(s,1H),8.40(s,1H),7.73(dd,J=2.8,8.8Hz,1H),7.40(d,J=8.8H z,1H),6.88(d,J=9.2Hz,1H),5.54(s,2H),3.26-3.08(m,4H),2.84-2.71(m,6H),2.34-2.23(m,6H).

[0253] Step 8: To a solution of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (150 mg, 298.84 μmol, 1 equiv.) and 3-morpholinopropan-1-amine (65 mg, 448.26 μmol, 65.50 μL, 1.5 equiv.) in DMF (1.5 mL) was added HATU (228 mg, 597.68 μmol, 2 equiv.) and DIEA (116 mg, 896.52 μmol, 156.16 μL, 3 equiv.). The mixture was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm, mobile phase A: purified water (0.04% NH3H2O ​​+ 10 mM NH4HCO3), mobile phase B: acetonitrile; gradient: 14 to 54% B in 11 min) to give Example 12 (16.1 mg, 25.42 μmol, 8.50% yield, 99.16% purity) as a pale yellow solid.

[0254] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.86(s,1H),9.16(s,1H),8.85-8.78(m,1H),8.55-8.48(m,1H),7.70-7.59(m,1 H),7.41-7.31(m,1H),6.92-6.82(m,1H),5.51(s,2H),3.64-3.57(m,4H),3.33-3 .32(m,1H),3.27-3.18(m,5H),2.65-2.59(m,2H),2.58-2.53(m,2H),2.40-2.33( m,6H),2.25(d,J=2.4Hz,3H),2.14(s,3H),1.84-1.75(m,2H),1.75-1.66(m,2H).

[0255] HPLC:R t = 2.934 min in 8-min chromatography, Ultimate XB-C18 (3 × 50 mm, 3 μm), purity 99.16%.

[0256] LCMS:R t= 1.636 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 99.65%, 627.28 [M+H] + MS ESI calculated for 628.28, found 628.4.

[0257] Example 13. Synthesis of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 13, Table 1) Scheme 5. Synthesis of methyl 1-(5-amino-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (common intermediate 18) [ka]

[0258] Step 1: To a mixture of 1-bromo-2,4-difluoro-5-nitrobenzene (10 g, 42.02 mmol, 1 equiv.) and 1-methylpiperazine (4 g, 42.02 mmol, 4.66 mL, 1 equiv.) in CH3CN (200 mL) was added DIEA (11 g, 84.04 mmol, 14.64 mL, 2 equiv.) in one portion at 25 °C. The mixture was stirred at 25 °C for 12 h. The residue was concentrated under reduced pressure. The residue was purified by silica gel chromatography (column weight: 80 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1). 1-(4-bromo-5-fluoro-2-nitrophenyl)-4-methylpiperazine (13 g, 40.80 mmol, 97.09% yield) was obtained as a yellow oil.

[0259] 1 H NMR: (DMSO-d6, 400 MHz) δ H =8.21(d,J=7.2Hz,1H),7.32(d,J=11.6Hz,1H),3.07-2.98(m,4H),2.44-2.36(m,4H),2.20(s,3H).

[0260] Step 2: To a mixture of 1-(4-bromo-5-fluoro-2-nitrophenyl)-4-methylpiperazine (13 g, 40.86 mmol, 1 equiv.) and diphenylmethanimine (11 g, 61.29 mmol, 10.29 mL, 1.5 equiv.) in dioxane (200 mL) under N was added Pd(OAc) (917 mg, 4.09 mmol, 0.1 equiv.), Xantphos (4 g, 6.13 mmol, 0.15 equiv.), and CsCO (27 g, 81.72 mmol, 2 equiv.) in one portion at 25 °C. The mixture was stirred at 100 °C for 12 h. The mixture was filtered through filter paper and diatomaceous earth. The residue was purified by silica gel chromatography (column weight: 80 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1) to obtain N-(diphenylmethylene)-2-fluoro-4-(4-methylpiperazin-1-yl)-5-nitroaniline (18.3 g, 34.96 mmol, 85.56% yield) as a yellow oil.

[0261] 1 H NMR: (DMSO-d6, 400 MHz) δ H =7.67(d,J=7.6Hz,1H),7.61-7.55(m,1H),7.51-7.46(m,3H),7.41-7.38(m,3H),7.36(d,J=8.6Hz,1 H),7.22-7.18(m,2H),7.06(d,J=12.6Hz,1H),2.91-2.84(m,4H),2.37(d,J=4.2Hz,4H),2.18(s,3H).

[0262] Step 3: To a mixture of N-(diphenylmethylene)-2-fluoro-4-(4-methylpiperazin-1-yl)-5-nitroaniline (18 g, 34.96 mmol, 79.95% purity, 1 equiv.) in THF (200 mL) was added HCl (12 M, 29.13 mL, 10 equiv.) in one portion. The mixture was stirred at 25 °C for 12 h. The residue was poured into water (200 mL). The aqueous phase was washed with ethyl acetate (100 mL*3). The pH of the aqueous phase was adjusted to about 8 by the slow addition of solid NaHCO3. The aqueous phase was then extracted with DCM (100 mL*3). The combined organic phase was washed with brine (100 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was used in the next step without further purification. 2-Fluoro-4-(4-methylpiperazin-1-yl)-5-analine (8.9 g, 27.06 mmol, 77.40% yield) was obtained as a yellow oil.

[0263] 1 H NMR: (DMSO-d6, 400 MHz) δ H =7.22(d,J=9.2Hz,1H),7.15(d,J=12.8Hz,1H),5.46(s,2H),2.83(t,J=4.8Hz,4H),2.38(s,4H),2.19(s,3H).

[0264] Step 4: To a mixture of 2-fluoro-4-(4-methylpiperazin-1-yl)-5-nitroanaline (8.9 g, 35.00 mmol, 1 equiv.) in HCl (2 M, 175.02 mL, 10 equiv.) was added dropwise a solution of NaNO (3.62 g, 52.51 mmol, 1.5 equiv.) in HO (20 mL) at 0 °C. After 0.5 h, a solution of NaN (3.47 g, 53.38 mmol, 1.52 equiv.) in HO (20 mL) was added to the mixture. The mixture was warmed to 15 °C and stirred for 1 h to give a brown mixture. The pH of the mixture was adjusted to approximately 9 with 2 N NaOH. The resulting mixture was extracted with DCM (150 mL*3). The combined organic phase was washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated. The product 1-(4-azido-5-fluoro-2-nitrophenyl)-4-methylpiperazine (8.7 g, 31.04 mmol, 88.68% yield) was obtained as a brown solid and used in the next step without further purification.

[0265] 1 H NMR: (DMSO-d6, 400 MHz) δ H =7.82(d,J=8.8Hz,1H),7.32(d,J=13.6Hz,1H),3.03-2.94(m,4H),2.45-2.35(m,4H),2.20(s,3H).

[0266] Step 5: To a mixture of 1-(4-azido-5-fluoro-2-nitrophenyl)-4-methylpiperazine (8.2 g, 29.26 mmol, 1 equiv.) and methyl prop-2-ynoate (3 g, 35.11 mmol, 2.92 mL, 1.2 equiv.) in THF (250 mL) was added CuI (2 g, 8.78 mmol, 0.3 equiv.) and DIEA (11 g, 87.78 mmol, 15.29 mL, 3 equiv.) in one portion at 25 °C for 2 h. The mixture was filtered through filter paper and diatomaceous earth and concentrated under reduced pressure. The mixture was then poured into water (100 mL), and the aqueous phase was extracted with DCM (70 mL * 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was used in the next step without further purification. Methyl 1-(2-fluoro-4-(4-methylpiperazin-1-yl)-5-nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (12.3 g, crude) was obtained as a yellow solid.

[0267] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.24(s,1H),8.41(d,J=7.6Hz,1H),7.49(d,J=13.2Hz,1H),3.88(s,3H),3.16(t,J=4.6Hz,4H),2.44(s,4H),2.23(s,3H).

[0268] Step 6: To a mixture of SnCl·2H O (11 g, 49.41 mmol, 3 equiv.) in MeOH (100 mL) and H O (25 mL), methyl 1-(2-fluoro-4-(4-methylpiperazin-1-yl)-5-nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (6 g, 16.47 mmol, 1 equiv.) was added in one portion, and the mixture was then heated to 80 °C for 4 h. The pH was adjusted to approximately 8 by the slow addition of NaHCO (40 mL). DCM (200 mL) was then added to the mixture and stirred for 5 min. The mixture was filtered through filter paper. The combined organic phase was washed with brine (100 mL*2), dried over anhydrous Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column weight: 40 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1) to obtain 1-(5-amino-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (2.7 g, 7.29 mmol, 44.29% yield) as a yellow solid.

[0269] 1 H NMR: (DMSO-d6, 400 MHz) δ H =8.55(d,J=2.4Hz,1H),7.31(d,J=7.2Hz,1H),6.90(d,J=12.4Hz,1H),4.06(s,2H),3.98(s,3H),2.98(s,4H),2.76-2.51(m,4H),2.38(s,3H).

[0270] Scheme 6. Synthesis of the common intermediate 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (common intermediate 21) and compound 13 [ka]

[0271] Step 7: A mixture of 1-(5-amino-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (200 mg, 598.18 μmol, 1 equiv) and TEA (303 mg, 2.99 mmol, 416.29 μL, 5 equiv) in DCM (5 mL) was stirred at 0 °C for 10 min, and then 2-chloro-4-fluoro-3-methyl-5-nitrobenzoyl chloride (136 mg, 538.36 μmol, 0.9 equiv) was added in one portion at 0 °C. The mixture was stirred for 12 h. The residue was poured into water (20 mL). The aqueous phase was extracted with DCM (15 mL * 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column weight: 12 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1) to obtain methyl 1-(5-(2-chloro-4-fluoro-3-methyl-5-nitrobenzamido)-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (220 mg, 256.04 μmol, 42.80% yield) as a yellow solid.

[0272] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.10(d,J=8.0Hz,1H),8.99(s,1H),8.30(d,J=7.6Hz,1H),8.02(s,1H),7.23-7.18(m,1H),4.02(s,3H) ),3.00(d,J=4.8Hz,4H),2.55(d,J=2.8Hz,2H),2.53(d,J=2.8Hz,3H),2.46-2.42(m,2H),2.37(s,3H).

[0273] Step 8: To a mixture of methyl 1-(5-(2-chloro-4-fluoro-3-methyl-5-nitrobenzamido)-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (220 mg, 400.06 μmol, 1 equiv.) in MeOH (10 mL) and HO (3 mL) was added SnCl.2HO (271 mg, 1.20 mmol, 3 equiv.) in one portion. The mixture was heated to 80° C. and stirred for 4 h. The pH was adjusted to about 8 by the slow addition of NaHCO (40 mL). Then, DCM (200 mL) was added to the mixture and stirred for 5 min. The mixture was filtered through filter paper. The combined organic phase was washed with brine (100 mL*2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column weight: 12 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1) to obtain methyl 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (130 mg, 240.03 μmol, 60.00% yield) as a yellow solid.

[0274] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.13(d,J=8.0Hz,1H),9.05(s,1H),8.57-8.51(m,1H),7.16(d,J=11.6Hz,1H),7.08(d,J=9.2Hz,1H), 4.01(s,3H),3.89(s,2H),3.01-2.98(m,3H),2.97(s,3H),2.61(s,3H),2.44-2.40(m,2H),2.38(s,3H).

[0275] Step 9: To a mixture of methyl 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (130 mg, 250.03 μmol, 1 equiv.) in THF (5 mL) and HO (2 mL) at 25 °C, LiOH.HO (21 mg, 500.07 μmol, 2 equiv.) was added in one portion and stirred for 12 h. The pH of the mixture was adjusted to approximately 4 with 2 N HCl. The mixture was then concentrated to remove THF. The crude product was used in the next step without further purification. 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (190 mg, crude) was obtained as a yellow solid.

[0276] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.76(s,1H),9.14(d,J=1.2Hz,1H),8.30(d,J=8.0Hz,1H),7.45(d,J=12.0Hz,1H),6.85(d,J=9.2Hz,1H),4.10(br s,2H),3.45-3.33(m,3H),3.22(br d,J=11.6Hz,4H),2.80(br d,J=4.4Hz,3H),2.34-2.29(m,2H),2.25(d,J=2.0Hz,3H).

[0277] Step 10: To a mixture of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (190 mg, 375.57 μmol, 1 equiv.) and 3-morpholinopropan-1-amine (54 mg, 375.57 μmol, 54.88 μL, 1 equiv.) in DMF (3 mL) was added DIEA (146 mg, 1.13 mmol, 196.25 μL, 3 equiv.) and HATU (171 mg, 450.68 μmol, 1.2 equiv.) in one portion. The mixture was stirred at 25° C. for 12 hours. The residue was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 21%~51%; 11 min) to give Example 13 (42.2 mg, 65.68 μmol, yield 17.49%, purity 98.38%) as a pale yellow solid.

[0278] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.58(s,1H),8.96(s,1H),8.84(t,J=5.6Hz,1H),8.25(d,J=8.0Hz,1H),7.38(d,J=12.4Hz,1H),6.83(d,J=9.2Hz,1H),5.50(s,2H),3.60( t,J=4.4Hz,4H),3.38-3.34(m,2H),2.99(s,4H),2.49-2.44(m,4H),2.41-2.32(m,6H),2.25(s,3H),2.23(s,3H),1.70(quintet,J=6.8Hz,2H).

[0279] HPLC:R t =2.340 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, 5 μm, purity 98.380%.

[0280] LCMS:R t= 1.891 min in 4 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, 5 μm, purity 96.336%, 631.26 [M+H] + MS ESI calculated for 631.26, found 632.4.

[0281] Example 14. Synthesis of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(3,4-dimethylpiperazin-1-yl)-2-fluorophenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 14, Table 1) [ka] The title compound was synthesized according to Schemes 5 and 6 (Example 13).

[0282] Step 1: To a mixture of 1-bromo-2,4-difluoro-5-nitrobenzene (5 g, 21.01 mmol, 1 equiv.) and 1,2-dimethylpiperazine (2 g, 21.01 mmol, 1 equiv.) in CH3CN (150 mL) was added DIEA (5 g, 42.02 mmol, 7.32 mL, 2 equiv.) in one portion. The mixture was stirred at 25 °C for 12 h. The residue was concentrated under reduced pressure to remove THF. The residue was purified by silica gel chromatography (column weight: 40 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1). 4-(4-bromo-5-fluoro-2-nitrophenyl)-1,2-dimethylpiperazine (6.5 g, 19.54 mmol, 93.00% yield) was obtained as a yellow solid.

[0283] 1 H NMR: (DMSO-d6, 400 MHz) δ H=8.21(d,J=7.6Hz,1H),7.31(d,J=11.2Hz,1H),3.10-3.03(m,2H),3.01-2.92(m,1H),2.73(td,J=2.6,11.6Hz ,1H),2.62(dd,J=9.6,12.3Hz,1H),2.25-2.20(m,1H),2.19(s,3H),2.16-2.08(m,1H),0.97(d,J=6.4Hz,3H).

[0284] Step 2: To a mixture of 4-(4-bromo-5-fluoro-2-nitrophenyl)-1,2-dimethylpiperazine (6.5 g, 19.57 mmol, 1 equiv.) and diphenylmethanimine (5.3 g, 29.35 mmol, 4.93 mL, 1.5 equiv.) in dioxane (100 mL) under N was added Pd(OAc) (439.33 mg, 1.96 mmol, 0.1 equiv.), Xantphos (1.70 g, 2.94 mmol, 0.15 equiv.), and CsCO (12.75 g, 39.14 mmol, 2 equiv.) in one portion at 25 °C. The mixture was heated to 100 °C and stirred for 12 h. The residue was poured into water (200 mL). The aqueous phase was extracted with DCM (100 mL * 3). The combined organic phase was washed with brine (100 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column weight: 80 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1). 4-(3,4-dimethylpiperazin-1-yl)-N-(diphenylmethylene)-2-fluoro-5-nitroaniline (6.66 g, 9.58 mmol, 48.95% yield) was obtained as a yellow oil.

[0285] 1 H NMR: (DMSO-d6, 400 MHz) δ H=7.67(d,J=7.2Hz,2H),7.52-7.46(m,3H),7.41-7.38(m,3H),7.36(d,J=8.4Hz,1H),7.20(dd,J=2.8,6.4Hz,2H),7 .05(d,J=12.4Hz,1H),2.97-2.79(m,3H),2.77-2.58(m,2H),2.17(s,3H),2.15-2.05(m,2H),0.94(d,J=6.4Hz,3H).

[0286] Step 3: To a mixture of 4-(3,4-dimethylpiperazin-1-yl)-N-(diphenylmethylene)-2-fluoro-5-nitroaniline (6.66 g, 15.40 mmol, 1 equiv.) in THF (100 mL) was added HCl (12 M, 12.83 mL, 10 equiv.) in one portion. The reaction mixture was stirred at 25 °C for 12 h. The residue was poured into water (200 mL). The aqueous phase was washed with ethyl acetate (100 mL*3). The pH was adjusted to about 8 by the slow addition of solid NaHCO3. The aqueous phase was then extracted with DCM (100 mL*3). The combined organic phase was washed with brine (100 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was used in the next step without further purification. 4-(3,4-Dimethylpiperazin-1-yl)-2-fluoro-5-nitroaniline (4.6 g, 11.20 mmol, 72.71% yield) was obtained as a yellow gum.

[0287] 1 H NMR: (DMSO-d6, 400 MHz) δ H =7.22(d,J=9.2Hz,1H),7.13(d,J=12.8Hz,1H),5.45(s,2H),3.11-3.02(m,1H),2.89-2.79(m,3 H),2.72(d,J=10.8Hz,1H),2.48-2.42(m,1H),2.19(s,3H),2.13(s,1H),0.96(d,J=6.4Hz,3H).

[0288] Step 4: To a mixture of 4-(3,4-dimethylpiperazin-1-yl)-2-fluoro-5-nitroaniline (4.6 g, 17.15 mmol, 1 equiv.) in HCl (2 M, 85.73 mL, 10 equiv.) was added dropwise a solution of NaNO (1.77 g, 25.72 mmol, 1.5 equiv.) in HO (20 mL) at 0 °C. After 0.5 h, a solution of NaN (1.86 g, 28.61 mmol, 1.67 equiv.) in HO (20 mL) was added to the mixture. The mixture was warmed to 15 °C and stirred for 1 h to give a brown mixture. The pH of the mixture was adjusted to approximately 9 with 2 N NaOH. The resulting mixture was extracted with DCM (100 mL*3). The combined organic phase was washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated. The product 1-(4-azido-5-fluoro-2-nitrophenyl)-4-methylpiperazine (3 g, 7.89 mmol, 46.02% yield) was obtained as a brown solid.

[0289] 1 H NMR: (DMSO-d6, 400 MHz) δ H =7.82(d,J=8.8Hz,1H),7.31(d,J=13.6Hz,1H),3.09-2.88(m,3H),2.74(td,J=2.8 ,11.6Hz,1H),2.59(dd,J=9.6,12.0Hz,1H),2.27-2.11(m,4H),1.03-0.92(m,3H).

[0290] Step 5: To a mixture of 1-(4-azido-5-fluoro-2-nitrophenyl)-4-methylpiperazine (2.8 g, 9.51 mmol, 1 equiv.) and methyl prop-2-ynoate (960 mg, 11.42 mmol, 950.40 μL, 1.2 equiv.) in THF (150 mL) was added CuI (543.62 mg, 2.85 mmol, 0.3 equiv.) and DIEA (3.7 g, 28.54 mmol, 4.97 mL, 3 equiv.) in one portion at 25 °C and stirred for 12 h. The mixture was filtered through filter paper and diatomaceous earth and concentrated under reduced pressure. The mixture was then poured into water (50 mL), and the aqueous phase was extracted with DCM (30 mL * 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was used in the next step without further purification to give 1-(4-(3,4-dimethylpiperazin-1-yl)-2-fluoro-5-nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (5.7 g, crude) as a yellow solid.

[0291] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.24(d,J=0.8Hz,1H),8.41(d,J=8.0Hz,1H),7.50(d,J=13.2Hz,1H),3.89(s,3H),3.14 -3.05(m,3H),3.00-2.92(m,1H),2.79-2.73(m,3H),2.22(s,3H),1.01(d,J=6.0Hz,3H).

[0292] Step 6: To a mixture of SnCl.2HO (10.33 g, 45.80 mmol, 4 equiv.) in MeOH (100 mL) and HO (30 mL), 1-(4-(3,4-dimethylpiperazin)-1-yl)-2-fluoro-5-nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (5.7 g, 11.45 mmol, 76% purity, 1 equiv.) was added in one portion, and the mixture was then heated to 80 °C and stirred for 4 h. The pH was adjusted to about 8 by the slow addition of NaHCO (40 mL). DCM (200 mL) was then added to the mixture and stirred for 5 min. The mixture was filtered through filter paper. The combined organic phase was washed with brine (100 mL*2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column weight: 40 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1) to obtain 1-(5-amino-4-(3,4-dimethylpiperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate (2.5 g, 6.64 mmol, 58.01% yield) as a yellow solid.

[0293] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.10(d,J=2.0Hz,1H),7.06-6.99(m,2H),4.99(s,2H),3.87(s,3H),3.16(d,J=4.8Hz,1H), 3.08-2.99(m,2H),2.98-2.89(m,1H),2.82-2.66(m,3H),2.23(s,3H),1.01(d,J=6.0Hz,3H).

[0294] Step 7: To a solution of 2-chloro-4-fluoro-3-methyl-5-nitrobenzoyl chloride (506.40 mg, 2.01 mmol, 1 equiv) and 1-(5-amino-4-(3,4-dimethylpiperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate (700 mg, 2.01 mmol, 1 equiv) in DCM (20 mL) was added TEA (1.02 g, 10.05 mmol, 1.40 mL, 5 equiv) at -20 °C. The reaction mixture was warmed to 20 °C and stirred for 3 h to give a brown mixture. Water (20 mL) was added to the reaction mixture. The resulting mixture was extracted with DCM (20 mL * 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluting with a 0–15% DCM / MeOH ether gradient at 25 mL / min) to afford the impure product, methyl 1-(5-(2-chloro-4-fluoro-3-methyl-5-nitrobenzamido)-4-(3,4-dimethylpiperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate (460 mg, 415.19 μmol, 20.66% yield), as a brown solid.

[0295] LCMS: Rt=1.5 min chromatography 0.807 min, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 50.91%, MS ESI calculated 564.15 for 563.15 [M+H]+, found 564.0.

[0296] Step 8: To a mixture of methyl 1-(5-(2-chloro-4-fluoro-3-methyl-5-nitrobenzamido)-4-(3,4-dimethylpiperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate (460 mg, 815.69 μmol, 1 equiv.) in MeOH (20 mL) and HO (6 mL) was added SnCl·2HO (552 mg, 2.45 mmol, 3 equiv.) in one portion. The mixture was heated at 80° C. for 4 h. The pH was adjusted to approximately 8 by the slow addition of NaHCO (40 mL). Then, DCM (100 mL) was added to the mixture and stirred for 5 min. The mixture was filtered through filter paper. The combined organic phase was washed with brine (70 mL*2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column weight: 12 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1) to obtain 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(3,4-dimethylpiperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate (180 g, 286.84 mmol, 35.17% yield) as a yellow solid.

[0297] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.25(br s,1H),7.85(dd,J=6.4,8.8Hz,1H),7.01(dd,J=2.4,10.6Hz,1H),6.96-6.89(m,1H),6.83-6.79(m,1H),3.89(s,2H) ),3.32-3.28(m,3H),3.19-3.04(m,1H),3.02-2.87(m,3H),2.84-2.72(m,3H),2.24(s,6H),0.98(d,J=6.0Hz,3H).

[0298] Step 9: To a mixture of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(3,4-dimethylpiperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate (180 mg, 337.11 μmol, 1 equiv.) in THF (3 mL) and HO (1 mL) was added LiOH.HO (28.29 mg, 674.21 μmol, 2 equiv.) in one portion. The mixture was stirred at 25 °C for 2 h. The pH of the mixture was adjusted to approximately 4 with 2 N HCl. The mixture was concentrated to remove THF. The crude product was used in the next step without further purification. 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(3,4-dimethylpiperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid (240 mg, 148.77 μmol, 44.13% yield) was obtained as a yellow solid.

[0299] LCMS:R t = 1.891 min in 4 min chromatography, Chromolith Flash RP-18, 5um, 3.0*25mm, purity 35.469%, 519.16 [M+H] + MS ESI calculated for 520.16, found 520.1.

[0300] Step 10: To a mixture of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(3,4-dimethylpiperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid (240 mg, 461.60 μmol, 1 equiv.) and 3-morpholinopropan-1-amine (67 mg, 461.60 μmol, 67.45 μL, 1 equiv.) in DMF (3 mL) was added DIEA (179 mg, 1.38 mmol, 241.21 μL, 3 equiv.) and HATU (263 mg, 692.40 μmol, 1.5 equiv.) in one portion. The mixture was stirred at 25° C. for 12 hours. The residue was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 20%~60%; 11 min) to give Example 14 (28.7 mg, 44.13 μmol, yield 9.56%, purity 99.34%) as a yellow solid.

[0301] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.56(s,1H),8.96(s,1H),8.84(s,1H),8.25(d,J=8.0Hz,1H),7.36(d,J=1 2.0Hz,1H),6.83(d,J=9.2Hz,1H),5.48(s,2H),3.60(s,4H),3.37-3.34(m, 3H),3.15-3.01(m,2H),2.88(t,J=10.4Hz,1H),2.78(d,J=10.8Hz,1H),2.3 6(s,8H),2.23(d,J=13.6Hz,6H),1.76-1.65(m,2H),1.00(d,J=5.6Hz,3H).

[0302] HPLC:R t =1.79 min with 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 99.34%.

[0303] LCMS:R t= 1.891 min in 4 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 98.051%, 645.28 [M+H] + MS ESI calculated for 646.28, found 646.4.

[0304] Example 15. Synthesis of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 15, Table 1) [ka] To a mixture of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (120 mg, 224.74 μmol, 1 equiv.), 3-morpholinopropan-1-amine (48.62 mg, 337.11 μmol, 49.26 μL, 1.5 equiv.), and DIEA (87 mg, 674.21 μmol, 117.44 μL, 3 equiv.) in DMF (4 mL) was added HATU (128 mg, 337.11 μmol, 1.5 equiv.). The reaction mixture was stirred at 20° C. for 2 hours to give a brown mixture. The reaction mixture was concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; condition: water (0.04% NH3H2O+10 mM NH4HCO3)-ACN; start B: 20%; end B: 60%; gradient time (min): 12 min). The product Example 15 (17.2 mg, 25.82 μmol, yield 11.49%, purity 99.11%) was obtained as a white solid.

[0305] 1 H NMR: (DMSO-d6, 400 MHz) δ H=9.59(s,1H),8.95(s,1H),8.84(t,J=5.6Hz,1H),8.24(d,J=8.0Hz,1H),7.33(d,J=12.4Hz,1H),6.82(d,J=9.2Hz,1H),5.47(s,2H),3.6 0(s,4H),3.08(d,J=10.8Hz,2H),2.61-2.51(m,4H),2.36(s,8H),2.24(s,3H),2.19(s,3H),1.70(t,J=6.8Hz,2H),1.02(d,J=6.0Hz,6H).

[0306] HPLC:R t =3.524 minutes in 8 minute chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 99.12%.

[0307] LCMS:R t = 2.699 minutes in 4 minute chromatography, XBridge Shield RP18, 5μm, 2.1*50mm, purity 99.47%, 659.29 [M+H] + MS ESI calculated for 660.29, found 660.5.

[0308] Example 16. Synthesis of 1-(3-(4-fluoro-3,5-dimethylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 16, Table 1) Scheme 7. Representative synthesis of compound 16 [ka]

[0309] Step 1: To a mixture of methyl 1-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (10 g, 28.87 mmol, 1 equiv.) in THF (60 mL) and HO (30 mL) was added LiOH.HO (6 g, 144.37 mmol, 5 equiv.). The mixture was stirred at 25 °C for 10 h. The mixture was concentrated to remove THF. The pH of the mixture was adjusted to about 4 with 2 N HCl. The mixture was filtered through filter paper. The filter cake was dried under reduced pressure. The product was used directly in the next step without further purification. 1-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)-1H-1,2,3-triazole-4-carboxylic acid (7 g, 19.41 mmol, 67.23% yield) was obtained as a yellow solid.

[0310] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.45(s,1H),8.51(d,J=2.4Hz,1H),8.21(dd,J=2.4,9.0Hz,1H),7.59(d,J=9.2Hz,1H),3.37-3.30(m,4H),3.03(s,4H),2.63(s,3H).

[0311] Step 2: To a mixture of 1-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)-1H-1,2,3-triazole-4-carboxylic acid (5 g, 15.05 mmol, 1 equiv.) and 3-morpholinopropan-1-amine (2 g, 15.05 mmol, 2.20 mL, 1 equiv.) in DMF (70 mL) was added DIEA (6 g, 45.14 mmol, 7.86 mL, 3 equiv.) in one portion at 25 °C, followed by HATU (7 g, 18.06 mmol, 1.2 equiv.). The mixture was stirred at 25 °C for 10 h. The mixture was concentrated to remove DMF. The residue was triturated with CHCN (50 mL) to give a yellow solid (3 g). The residue was purified by silica gel chromatography (column weight: 40 g, 100-200 mesh silica gel, dichloromethane:methanol=7:3) to give 1-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (3 g, crude) as a yellow solid.

[0312] 1 H NMR: MeOD-d4, 400 MHz) δ H =9.00(s,1H),8.47(d,J=2.4Hz,1H),8.17(dd,J=2.4,8.8Hz,1H),7.62(d,J=9.2Hz,1H),3.89(s,4H),3.55(t ,J=6.4Hz,2H),3.40(d,J=4.4Hz,4H),3.30-3.25(m,4H),3.14-2.99(m,6H),2.87(s,3H),2.08-2.00(m,2H).

[0313] Step 3: To a mixture of 1-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (2 g, 4.36 mmol, 1 equiv.) in MeOH (80 mL) was added wet Pd / C (590 mg, 4.36 mmol, 10% purity, 1 equiv.). The reaction mixture was degassed and back-filled with H. The reaction mixture was stirred under H (15 psi) at 30° C. for 12 h to give a black mixture. The reaction mixture was filtered to remove Pd / C, and the filter cake was washed with MeOH (30 mL). The filtrate was then concentrated. The crude product 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (1.9 g, crude) was obtained as a yellow solid and used in the next step without further purification.

[0314] 1 H NMR: (MeOD, 400 MHz) δ H =8.71(s,1H),8.52(d,J=3.6Hz,1H),8.18(d,J=7.6Hz,1H),7.24(d,J=2.8Hz,1H),3.81-3.70(m, 6H),3.51(t,J=6.8Hz,2H),3.22-3.11(m,7H),2.75(s,3H),2.70-2.61(m,6H),1.93-1.86(m,2H).

[0315] Step 4: To a mixture of 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (180 mg, 420.04 μmol, 1 equiv.) and 4-fluoro-3,5-dimethyl-benzoic acid (71 mg, 420.04 μmol, 1 equiv.) in pyridine (1 mL) under N was added EDCI (121 mg, 630.06 μmol, 1.5 equiv.) in one portion at 25° C. The mixture was stirred at 100° C. for 12 hours. The residue was concentrated under reduced pressure to remove pyridine. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 15%~65%; 15 min) to give Example 16 (14.7 mg, 25.05 μmol, yield 5.96%, purity 98.61%) as a pale yellow solid.

[0316] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.66(s,1H),9.21(s,1H),8.85(t,J=5.6Hz,1H),8.71(d,J=2.4Hz,1H),7.75-7.68(m,3H),7.46(d,J=8.8Hz,1H),3.61(t,J=4 .4Hz,4H),2.94(t,J=4.4Hz,4H),2.55-2.51(m,6H),2.36(t,J=6.8Hz,6H),2.33(s,6H),2.25(s,3H),1.70(quintuple line,J=6.8Hz,2H).

[0317] HPLC:R t =2.739 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, 8 μm, purity 98.61%.

[0318] LCMS:R t = 2.199 min in 4 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, 8 μm, purity 98.58%, 578.31 [M+H] +MS ESI calculated for 579.31, found 579.5.

[0319] Example 17. Synthesis of 1-[3-[(2-chloro-4-fluoro-3-methyl-benzoyl)amino]-4-(4-methylpiperazin-1-yl)phenyl]-N-(3-morpholinopropyl)triazole-4 - carboxamide (compound 17, Table 1) [ka] The title compound was synthesized according to Scheme 7 (Example 16) and Scheme 8.

[0320] Scheme 8. Synthesis of 2-chloro-4-fluoro-3-methylbenzoic acid (Intermediate 5C). [ka]

[0321] Step 1: To a mixture of 1-chloro-3-fluoro-2-methylbenzene (10 g, 69.17 mmol, 8.40 mL, 1 equiv.) and AlCl (18.45 g, 138.34 mmol, 7.56 mL, 2 equiv.) in DCM (100 mL) was added acetyl chloride (5.43 g, 69.17 mmol, 4.94 mL, 1 equiv.) dropwise at 0 °C. The mixture was warmed to 25 °C and stirred for 2 h. The mixture was poured into ice water and acidified to pH 4 with 2 N HCl. The mixture was extracted with DCM (100 mL*3) and washed with brine (100 mL*3). The combined organic layers were dried over Na SO and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel (PE: EtOAc = 50:1). 1-(2-chloro-4-fluoro-3-methyl-phenyl)ethanone (8 g, 42.87 mmol, 61.98% yield) was obtained as a yellow oil.

[0322] 1 H NMR: (DMSO-d6, 400 MHz) δ H=7.42-7.35(m,1H),7.03(t,J=8.8Hz,1H),2.63(s,3H),2.35(d,J=2.4Hz,3H).

[0323] Step 2: To a solution of NaOH (8.57 g, 214.35 mmol, 10 equiv) in HO (40 mL) was added Br (10.28 g, 64.30 mmol, 3.31 mL, 3 equiv) dropwise at 10 °C. A solution of Br (4 g, 21.43 mmol, 1 equiv) in dioxane (40 mL) was added dropwise at 0 °C. The mixture was warmed to 25 °C and stirred for 2 h. The mixture was extracted with DCM (50 mL * 2). The pH of the aqueous phase was adjusted to about 4 with 2 N HCl. The mixture was filtered through filter paper, and the filter cake was dried under reduced pressure. The product was used directly in the next step without further purification. 2-Chloro-4-fluoro-3-methyl-benzoic acid 5C (4 g, 21.21 mmol, 98.95% yield) was obtained as a white solid.

[0324] 1 H NMR: (DMSO-d6, 400 MHz) δ H =7.70-7.64(m,1H),7.28(m,J=8.8Hz,1H),2.30(d,J=2.4Hz,3H).

[0325] Step 3: To a solution of 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (150 mg, 350.03 μmol, 1 equiv.) and 2-chloro-4-fluoro-3-methyl-benzoic acid (66 mg, 350.03 μmol, 1 equiv.) in pyridine (1 mL) was added EDCI (101 mg, 525.05 μmol, 1.5 equiv.). The reaction mixture was stirred at 100° C. for 12 hours to give a yellow mixture. The reaction mixture was concentrated to dryness. Water (15 mL) was added to the reaction mixture. The resulting mixture was extracted with DCM (15 mL*3). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (column: Gemini NX C18 30 × 150 mm, 5 μm; conditions: water (0.05% ammonia, v / v)-ACN; start B: 30%; end B: 70%; gradient time (min): 11 min). Example 17 (9.5 mg, 15.68 μmol, yield 4.48%, purity 98.9%) was obtained as a white solid.

[0326] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.66(s,1H),9.20(s,1H),8.90-8.78(m,1H),8.65-8.54(m,1H),7.72(d,J=8.8Hz,1H),7.56(t,J=7.2Hz,1H),7. 45-7.31(m,2H),4.04-3.45(m,4H),3.00-2.90(m,4H),2.46-2.32(m,13H),2.24-2.13(m,5H),1.80-1.63(m,2H).

[0327] HPLC:R t =2.85 in 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 98.95%.

[0328] LCMS:R t = 1.688 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 99.76%, 598.26 [M+H]+ MS ESI calculated for 599.26, found 599.

[0329] Example 18. 1-[3-[(2-chloro-4-fluoro-3-methyl-5-nitro-benzoyl)amino]-4-(4-methylpiperazin-1-yl)phenyl]-N-(3-morpholinopropyl)triazole-4-carboxamide (Compound 18, Table 1) [ka] The title compound was synthesized according to Scheme 7 (Example 16). To a solution of 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (150 mg, 350.03 μmol, 1 eq.) and pyridine (55.4 mg, 700.07 μmol, 56.51 μL, 2 eq.) in DCM (5 mL) was added 2-chloro-4-fluoro-3-methyl-5-nitrobenzoyl chloride (133 mg, 525.05 μmol, 1.5 eq.) in DCM (5 mL). The reaction mixture was stirred at 0° C. for 0.5 hours, resulting in a brown mixture. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC (column: Xtimate C18 30 × 100 mm; 3 μm; conditions: water (0.225% formic acid, v / v)-ACN; start B: 2%, end B: 32%; gradient time (min): 8 min). Example 18 (36.3 mg, 53.98 μmol, yield 15.42%, purity 99.2%, 0.5FA) was obtained as a white solid.

[0330] 1 H NMR: (DMSO-d6, 400 MHz) δ H=9.97(s,1H),9.20(s,1H),8.84(t,J=5.6Hz,1H),8.55(d,J=2.0Hz,1H),8.38(d,J=7.6Hz,1H),8.14(s,1H),7.76(dd,J=2.8,8.8Hz,1H),7.38( d,J=8.8Hz,1H),3.65-3.57(m,3H),3.42-3.37(m,3H),3.02-2.95(m,4H ),2.62-2.56(m,4H),2.46-2.37(m,9H),2.28(s,3H),1.78-1.66(m,2H).

[0331] HPLC: Rt=8 min chromatography 2.92 min, Ultimate XB-C18 3.0*50 mm, 3 μm, purity 99.21%.

[0332] LCMS:R t = 1.715 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 99.31%, 643.24 [M+H] + MS ESI calculated for 644.24, found 644.3.

[0333] Example 19. Synthesis of 1-(3-(4-fluoro-3-nitrobenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 19, Table 1) [ka] The title compound was synthesized according to Scheme 7 (Example 16). To a solution of 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (150 mg, 350.03 μmol, 1 equiv.) in DCM (1.5 mL) was added 4-fluoro-3-nitrobenzoyl chloride (107 mg, 525.04 μmol, 1.5 equiv.), followed by N,N-diethylethanamine (106 mg, 1.05 mmol, 146.16 μL, 3 equiv.). The mixture was stirred at 25° C. for 14 hours. The mixture was diluted with DCM (100 mL) and washed with brine (50 mL×3). The organic layer was extracted with Na 2S The mixture was dried over 0, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Gemini NX C18 80 × 40 mm, 3 μm, mobile phase A: purified water (0.05% ammonia, v / v, 10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 29 to 53% B in 8 min). Example 19 (43 mg, 69.90 μmol, 19.97% yield, 96.83% purity) was obtained as a white solid.

[0334] 1 H NMR: (DMSO-d6, 400 MHz) δ H =10.05(s,1H),9.21(s,1H),8.84(t,J=5.6Hz,1H),8.72(dd,J=2.4,7.2Hz,1H),8.56(d,J=2.8Hz,1H),8.43-8.36(m,1H),7.89-7.74(m,2H) ,7.44(d,J=8.8Hz,1H),3.61(t,J=4.8Hz,4H),2.96(t,J=4.8Hz,4H),2.58-2.51(m,6H),2.41-2.34(m,6H),2.25(s,3H),1.77-1.65(m,2H).

[0335] HPLC:R t =2.65 min with 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 96.83%.

[0336] LCMS:R t= 1.571 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 98.96%, 595.27 [M+H] + MS ESI calculated for 596.27, found 596.3.

[0337] Example 20. Synthesis of 1-(3-(4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 20, Table 1) [ka] The title compound was synthesized according to Scheme 7 (Example 16). To a solution of 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (150 mg, 350.03 μmol, 1 equiv.) in pyridine (1.5 mL) was added 4-fluoro-3-methyl-benzoic acid (54 mg, 350.03 mmol, 1 equiv.) and EDCI (101 mg, 525.04 μmol, 1.5 equiv.). The mixture was stirred at 100° C. for 14 hours. The mixture was diluted with DCM (100 mL) and washed with brine (50 mL×3). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Gemini NX C18 80 × 40 mm, 3 μm, mobile phase A: water (0.05% ammonia, v / v, 10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 33 to 55% B in 8 min). Example 20 (32.6 mg, 56.16 μmol, 16.05% yield, 97.28% purity) was obtained as a white solid.

[0338] 1 H NMR: (DMSO-d6, 400 MHz) δ H=9.68(s,1H),9.21(s,1H),8.84(t,J=5.6Hz,1H),8.69(d,J=2.4Hz,1H),7.95-7.84(m,2H),7.72(dd,J=2.8,8.8Hz,1H),7.49-7 .35(m,2H),3.62(t,J=4.8Hz,4H),2.95(t,J=4.8Hz,4H),2.61-2.52(m,6H),2.41-2.34(m,9H),2.26(s,3H),1.77-1.65(m,2H).

[0339] HPLC: Rt=8 min chromatography 2.80 min, Ultimate XB-C18 3.0*50 mm, 3 μm, purity 97.28%.

[0340] LCMS:R t = 1.677 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 96.272%, 564.30 [M+H] + MS ESI calculated for 565.30, found 565.4.

[0341] Example 21. Synthesis of 1-(3-(4-fluoro-3-(trifluoromethyl)benzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 21, Table 1) [ka] The title compound was synthesized according to Scheme 7 (Example 16). To a solution of 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (150 mg, 350.03 μmol, 1 equiv.) in pyridine (1.5 mL) was added 4-fluoro-3-(trifluoromethyl)benzoic acid (73 mg, 350.03 mmol, 1 equiv.) and EDCI (101 mg, 525.04 μmol, 1.5 equiv.). The mixture was stirred at 100° C. for 14 hours. The mixture was diluted with DCM (100 mL) and washed with brine (50 mL×3). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Gemini NX C18 30 × 150 mm, 5 μm; mobile phase A: purified water (0.05% ammonia, v / v); mobile phase B: acetonitrile; gradient: 40 to 60% B in 11 min) to give Example 21 (30.9 mg, 48.84 μmol, 13.95% yield, 97.78% purity) as a white solid.

[0342] 1 H NMR: (DMSO-d6, 400 MHz) δ H =10.03-9.95(m,1H),9.21(s,1H),8.85(t,J=5.6Hz,1H),8.59(d,J=2.4Hz,1H),8.40-8.27(m,2H),7.83-7.72(m,2H),7.44(d,J =8.8Hz,1H),3.62(t,J=4.8Hz,4H),2.96(t,J=4.4Hz,4H),2.56-2.52(m,6H),2.41-2.33(m,6H),2.24(s,3H),1.81-1.63(m,2H).

[0343] HPLC:R t =3.01 min in 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 97.78%.

[0344] LCMS:R t= 1.799 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 98.318%, 618.27 [M+H] + MS ESI calculated for 619.27, found 619.

[0345] Example 22. Synthesis of 1-(3-(4-hydroxy-2-(trifluoromethyl)benzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 22, Table 1) [ka] The title compound was synthesized according to Scheme 7 (Example 16). To a solution of 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (150 mg, 350.03 μmol, 1 equiv.) in DCM (2 mL) was added 4-hydroxy-2-(trifluoromethyl)benzoyl chloride (117.91 mg, 525.05 μmol, 1.5 equiv.) and pyridine (138 mg, 1.75 mmol, 141.26 μL, 5 equiv.). The mixture was stirred at 25° C. for 14 hours. The mixture was diluted with DCM (100 mL) and washed with brine (50 mL×3). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase A: purified water (0.05% NH3H2O ​​+ 10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 18 to 48% B in 10 min). Example 22 (3 mg, 4.66 μmol, yield 1.33%, purity 95.78%) was obtained as a white solid.

[0346] 1 H NMR: (DMSO-d6, 400 MHz) δ H=9.40(s,1H),9.19(s,1H),8.85-8.80(m,1H),8.60-8.57(m,1H),7.73-7.68(m,1H),7.62(s,1H),7.42(d,J=8.8Hz,1H),7.18(d,J=2.4H) z,2H),3.61(t,J=4.8Hz,4H),2.92(t,J=4.8Hz,4H),2.50-2.42(m,6H),2.40-2.34(m,6H),2.40-2.33(m,1H),2.21(s,3H),1.71(s,2H).

[0347] HPLC:R t =2.54 min in 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 95.78%.

[0348] LCMS:R t = 1.542 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 97.77%, 616.63 [M+H] + MS ESI calculated for 617.63, found 617.4.

[0349] Example 23. Synthesis of 1-(3-(3,5-dimethylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 23, Table 1) [ka] The title compound was synthesized according to Scheme 7 (Example 16). To a mixture of 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (150 mg, 350.03 μmol, 1 equiv.) and 3,5-dimethylbenzoic acid (53 mg, 350.03 μmol, 1 equiv.) in pyridine (1 mL) was added EDCI (101 mg, 525.05 μmol, 1.5 equiv.) in one portion at 25° C. The mixture was stirred at 25° C. for 5 minutes, then heated to 80° C. and stirred for 10 hours. The mixture was concentrated to remove pyridine. The residue was purified by preparative HPLC (column: Gemini NX C18 30 × 150 mm, 5 μm; mobile phase A: [purified water (0.05% ammonia, v / v)]; mobile phase B: ACN; B%: 33-63%; 11 min) to give Example 23 (21.1 mg, 36.42 μmol, 10.41% yield, 96.79% purity) as a yellow solid.

[0350] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.68(s,1H),9.20(s,1H),8.87-8.78(m,2H),7.68(dd,J=2.8,8.8Hz,1H),7.57(s,2H),7.48(d,J=8.8Hz,1H),7.30(s,1H),3.60(t, J=4.8Hz,4H),3.37(s,2H),2.94(t,J=4.8Hz,4H),2.53(d,J=10.4Hz,4H),2.42-2.31(m,12H),2.25(s,3H),1.70(quintet,J=6.8Hz,2H).

[0351] HPLC: Rt=8 min chromatography 2.89 min, Ultimate XB-C18 3.0*50 mm, 3 μm, purity 96.79%.

[0352] LCMS:R t = 2.73 minutes in 4 minute chromatography, XBridge Shield RP18, 5μm, 2.1*50mm, purity 99.431%, 560.32 [M+H] +MS ESI calculated for 561.32, found 561.4.

[0353] Example 24. Synthesis of 1-(3-(3,5-dichlorobenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 24, Table 1) [ka] The title compound was synthesized according to Scheme 7 (Example 16). To a solution of 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (150 mg, 350.03 μmol, 1 equiv.) in pyridine (2 mL) was added 3,5-dichlorobenzoic acid (74 mg, 385.04 mmol, 1.1 equiv.) and EDCI (101 mg, 525.05 μmol, 1.5 equiv.). The mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove pyridine and give a residue. The residue was purified by preparative HPLC (column: Gemini NX C18 30 × 150 mm, 5 μm, mobile phase A: purified water (0.05% ammonia, v / v); mobile phase B: acetonitrile, gradient: 25 to 80% B in 11 min) to give Example 24 (22.3 mg, 36.76 μmol, yield 10.50%, purity 99.17%) as a white solid.

[0354] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.94(s,1H),9.20(s,1H),8.84(t,J=5.6Hz,1H),8.53(d,J=2.4Hz,1H),8.02-7.89(m,3H),7.76(dd,J=2.4,8.8Hz,1H),7.43(d ,J=8.8Hz,1H),3.62(t,J=4.4Hz,5H),3.44-3.39(m,2H),3.05-2.85(m,5H),2.47-2.30(m,8H),2.24(s,3H),1.77-1.65(m,2H).

[0355] HPLC: Rt=8 min chromatography 2.99 min, Ultimate XB-C18 3.0*50 mm, 3 μm, purity 99.17%.

[0356] LCMS:R t = 1.865 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 99.157%, 600.21 [M+H] + MS ESI calculated for 601.21, found 601.3.

[0357] Example 25. Synthesis of 1-(3-(3-hydroxy-5-(trifluoromethyl)benzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 25, Table 1) [ka] The title compound was synthesized according to Scheme 7 (Example). To a mixture of 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (150 mg, 350.03 μmol, 1 equivalent) and 3-hydroxy-5-(trifluoromethyl)benzoyl chloride (118 mg, 525.04 μmol, 1.5 equivalents) in DCM (5 mL) was added pyridine (55 mg, 700.06 μmol, 56.50 μL, 2 equivalents) in one portion at 0° C. The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated to remove DCM and pyridine. The residue was purified by preparative HPLC (column: Xtimate C18 30 × 100 mm, 3 μm; mobile phase A: [purified water (0.225% formic acid, v / v)]; mobile phase B: ACN; B%: 2-32%; 8 min) to obtain Example 25 (51.6 mg, 82.94 μmol, yield 23.70%, purity 99.12%) as a yellow solid.

[0358] 1 H NMR: (DMSO-d6, 400 MHz) δ H=9.88(s,1H),9.21(s,1H),8.68(d,J=2.5Hz,1H),8.14(s,1H),7.73(dd,J=2.8,8.8Hz,1H),7.69(s,1H),7.62(s,1H),7.47(d,J=8.8Hz,1H),7 .31(s,1H),3.63-3.60(m,6H),3.38-3.31(m,2H),2.96(t,J=4.4Hz,4H) ,2.56(s,3H),2.43-2.35(m,6H),2.26(s,3H),1.71(quintet,J=6.8Hz,2H).

[0359] HPLC: Rt=8 min chromatography 2.83 min, Ultimate XB-C18 3.0*50 mm, 3 μm, purity 99.12%.

[0360] LCMS:R t = 1.688 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 99.215%, 616.27 [M+H] + MS ESI calculated for 617.27, found 617.4.

[0361] Example 26. Synthesis of 1-(3-(2,3-difluoro-5-hydroxybenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 26, Table 1) [ka] The title compound was synthesized according to Scheme 7 (Example 16). To a mixture of 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (150 mg, 350.03 μmol, 1 equivalent) and 2,3-difluoro-5-hydroxybenzoyl chloride (91.4 mg, 525.05 μmol, 1.5 equivalents) in DMF (2 mL) was added pyridine (55.4 mg, 700.07 μmol, 56.51 μL, 2 equivalents) in one portion at 0° C. The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure to remove pyridine and DMF. The residue was purified by preparative HPLC (column: Xtimate C18 30 × 100 mm, 3 μm; mobile phase: [purified water (0.225% formic acid, v / v)-ACN]; B%: 0-30%; 8 min) to give Example 26 (35 mg, 59.46 μmol, yield 16.99%, purity 98.75%) as a brown solid.

[0362] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.20(s,1H),8.88-8.80(m,2H),7.69(dd,J=2.8,8.8Hz,1H),7.46-7.36(m,2H),6.80(d,J=6.4Hz,1H),3.62(t,J=4. 8Hz,3H),3.34-3.33(m,5H),2.97(s,3H),2.71-2.65(m,3H),2.53(s,2H),2.45-2.31(m,9H),1.72(quintet,J=6.8Hz,2H).

[0363] HPLC:R t =2.69 min in 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 98.75%.

[0364] LCMS:R t = 1.638 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 97.878%, 584.27 [M+H] + MS ESI calculated for 585.27, found 585.4.

[0365] Example 27. Synthesis of 1-methyl-N-(2-(4-methylpiperazin-1-yl)-5-(4-((3-morpholinopropyl)carbamoyl)-1H-1,2,3-triazol-1-yl)phenyl)-1H-indazole-3-carboxamide (Compound 27, Table 1) [ka] The title compound was synthesized according to Scheme 7 (Example 16). To a mixture of 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (150 mg, 350.03 μmol, 1 equivalent) and 1-methylindazole-3-carboxylic acid (62 mg, 350.03 μmol, 1 equivalent) in pyridine (1 mL) was added EDCI (101 mg, 525.05 μmol, 1.5 equivalents) in one portion at 25° C. The mixture was heated to 100° C. and stirred for 10 hours. The mixture was concentrated to remove pyridine. The residue was purified by preparative HPLC (column: Gemini NX C18 30 × 150 mm, 5 μm; mobile phase A: [purified water (0.05% ammonia, v / v)-ACN]; B%: 33-63%; 11 min) to give Example 27 (24 mg, 40.40 μmol, 11.54% yield, 98.34% purity) as a yellow solid.

[0366] 1 H NMR: (DMSO-d6, 400 MHz) δ H=10.19(s,1H),9.23(s,1H),9.07(d,J=2.4Hz,1H),8.87(t,J=5.6Hz,1H),8.27(d,J=8 Hz,1H),7.84(d,J=8.8Hz,1H),7.67(dd,J=2.8,8.8Hz,1H),7.60-7.48(m,2H),7.39(t, J=7.6Hz,1H),4.24(s,3H),3.63(t,J=4.8Hz,4H),3.33-3.30(m,3H),2.98(t,J=4.8Hz, 4H), 2.76-2.60(m, 3H), 2.43-2.30(m, 8H), 2.13-2.05(m, 1H), 1.72 (quintuple line, J=6.8Hz, 2H).

[0367] HPLC:R t =3.561 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, 3 μm, purity 98.397%.

[0368] LCMS:R t = 2.726 minutes in 4 minute chromatography, XBridge Shield RP18, 5μm, 2.1*50mm, purity 96.722%, 586.31 [M+H] + MS ESI calculated for 587.31, found 587.5.

[0369] Example 28. Synthesis of 1-(5-(2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (Compound 28, Table 1) [ka] Step 1: To a mixture of methyl 1-(5-amino-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (100 mg, 275.94 μmol, 1 equiv.) in DCM (10 mL) at 0 °C, TEA (140 mg, 1.38 mmol, 192.03 μL, 5 equiv.) and 2-chloro-4-fluoro-3-methylbenzoyl chloride (115 mg, 555.48 μmol, 2.01 equiv.) were added in one portion. The mixture was stirred at 0 °C for 12 h. The residue was concentrated under reduced pressure. The residue was purified by silica gel chromatography (column weight: 12 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1). 1-(5-(2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (120 mg, 161.26 μmol) was obtained as a yellow solid.

[0370] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.97(s,1H),8.49(s,1H),8.42(d,J=5.2Hz,1H),8.34(d,J=8.0Hz,1H),7.19(d,J=13.2Hz,1H),7.03-6.96( m,1H),3.21-3.17(m,2H),3.16(s,6H),3.11-3.06(m,2H),2.94-2.78(m,4H),2.58-2.51(m,3H),1.31(s,6H).

[0371] Step 2: To a mixture of 1-(5-(2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (120 mg, 225.15 μmol, 1 equiv.) in THF (5 mL) and HO (1 mL) was added LiOH.HO (19 mg, 450.31 μmol, 2 equiv.) in one portion. The mixture was stirred at 25 °C for 12 h. The residue was concentrated under reduced pressure. The crude product was used in the next step without further purification. 1-(5-(2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (100 mg, 130.30 μmol) was obtained as a yellow solid.

[0372] Step 3: To a mixture of 1-(5-(2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (100 mg, 192.70 μmol, 1 equiv.) and 3-morpholinopropan-1-amine (28 mg, 192.70 μmol, 28.16 μL, 1 equiv.) in DMF (3 mL), DIEA (75 mg, 578.10 μmol, 100.69 μL, 3 equiv.) and HATU (125 mg, 327.59 μmol, 1.7 equiv.) were added in one portion. The mixture was stirred at 25 °C for 12 hours. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 23%~63%; 11 min). Example 28 (17.2 mg, 26.27 μmol, yield 13.63%, purity 98.54%) was obtained as a pale yellow solid.

[0373] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.79(s,1H),8.96(d,J=1.6Hz,1H),8.85(t,J=5.6Hz,1H),8.24(d,J=8.0Hz,1 H),7.50(dd,J=6.4,8.0Hz,1H),7.39-7.26(m,2H),3.60(t,J=4.8Hz,4H),3.34 -3.33(m,3H),3.13(d,J=11.2Hz,2H),2.57-2.52(m,2H),2.36(t,J=6.8Hz,7H) ,2.32(d,J=1.6Hz,3H),2.18(s,3H),1.75-1.65(m,2H),1.03(d,J=6.0Hz,6H).

[0374] HPLC:R t =2.06 min in 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 98.54%.

[0375] LCMS:R t = 0.918 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 98.477%, 644.28 [M+H] + MS ESI calculated for 645.28, found 645.4.

[0376] Example 29. Synthesis of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-N,N-diethyl-1H-1,2,3-triazole-4-carboxamide (Compound 29, Table 1) [ka] To a solution of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (100 mg, 187.28 μmol, 1 equiv.) and N-ethylethanamine (27 mg, 374.56 μmol, 38.58 μL, 2 equiv.) in DMF (5 mL) was added HATU (107 mg, 280.92 μmol, 1.5 equiv.) and DIEA (73 mg, 561.84 μmol, 97.86 μL, 3 equiv.). The mixture was stirred at 25° C. for 12 h. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm, mobile phase A: purified water (0.04% NH3H2O ​​+ 10 mM NH4HCO3), mobile phase B: acetonitrile; gradient: 29 to 69% B in 11 min) to give Example 29 (10 mg, 16.82 μmol, 8.98% yield, 99.101% purity) as a red solid.

[0377] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.61(s,1H),8.93(d,J=1.6Hz,1H),8.23(d,J=8.0Hz,1H),7.33(d,J=12.4Hz,1H) ,6.81(d,J=9.2Hz,1H),5.49(s,2H),3.75(q,J=6.8Hz,2H),3.47(q,J=7.2Hz,2H), 3.08(d,J=10.8Hz,2H),2.58-2.51(m,2H),2.39-2.28(m,2H),2.24(d,J=2.4Hz,3H ),2.19(s,3H),1.24(t,J=6.8Hz,3H),1.16(t,J=7.2Hz,3H),1.02(d,J=6.0Hz,6H).

[0378] HPLC:R t =2.973 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 99.10%.

[0379] LCMS:R t= 2.368 min in 4 min chromatography, XBridge Shield RP18, 5 μm, 2.1 × 50 mm, purity 98.77%, 588.25 [M+H] + MS ESI calculated for 589.25, found 589.3.

[0380] Example 30. Synthesis of 5-amino-2-chloro-4-fluoro-N-(4-fluoro-5-(4-(morpholine-4-carbonyl)-1H-1,2,3-triazol-1-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-3-methylbenzamide (Compound 30, Table 1) [ka] To a solution of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (120 mg, 224.74 μmol, 1 equiv.) and morpholine (39 mg, 449.47 μmol, 39.55 μL, 2 equiv.) in DMF (5 mL) was added HATU (128 mg, 337.11 μmol, 1.5 equiv.) and DIEA (87 mg, 674.21 μmol, 117.44 μL, 3 equiv.). The mixture was stirred at 25° C. for 12 h. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm, mobile phase A: purified water (0.05% NH3H2O ​​+ 10 mM NH4HCO3), mobile phase B: acetonitrile; gradient: 20 to 60% B in 11 min) to give Example 30 (18 mg, 29.34 μmol, yield 13.06%, purity 98.3%) as a white solid.

[0381] 1 H NMR: (DMSO-d6, 400 MHz) δ H=9.60(s,1H),8.98(d,J=1.2Hz,1H),8.23(d,J=8.0Hz,1H),7.34(d,J=12.4Hz,1H),6.81(d,J=9.2Hz,1H),5.48(s,2H),4. 03(s,2H),3.67(s,6H),3.09(d,J=10.8Hz,2H),2.59-2.52(m,2H),2.35(s,2H),2.27-2.15(m,6H),1.03(d,J=6.0Hz,6H).

[0382] HPLC:R t =3.551 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 98.31%.

[0383] LCMS:R t = 2.719 minutes in 4 minute chromatography, XBridge Shield RP18, 5μm, 2.1*50mm, purity 98.70%, 602.23 [M+H] + MS ESI calculated for 603.23, found 603.4.

[0384] Example 31. Synthesis of 5-amino-2-chloro-4-fluoro-N-(4-fluoro-5-(4-(4-methylpiperazine-1-carbonyl)-1H-1,2,3-triazol-1-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-3-methylbenzamide (Compound 31, Table 1) [ka] To a solution of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (100 mg, 187.28 μmol, 1 equiv.) and 1-methylpiperazine (38 mg, 374.56 μmol, 41.55 μL, 2 equiv.) in DMF (5 mL) was added HATU (107 mg, 280.92 μmol, 1.5 equiv.) and DIEA (73 mg, 561.84 μmol, 97.86 μL, 3 equiv.). The mixture was stirred at 25° C. for 12 h. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm, mobile phase A: purified water (0.04% NH3H2O ​​+ 10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 26 to 66% B in 11 min). Example 31 (13.2 mg, 20.57 μmol, yield 10.98%, purity 96.02%) was obtained as a yellow solid.

[0385] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.62(s,1H),8.96(d,J=1.2Hz,1H),8.22(d,J=8.0Hz,1H),7.33(d,J=12.4Hz,1H),6.81(d,J=9.2Hz,1H),5.49(s,2H),3.98(s,2H),3.6 6(s,2H),3.08(d,J=10.8Hz,2H),2.58-2.52(m,2H),2.38(t,J=4.8Hz,4H),2.35-2.29(m,2H),2.26-2.17(m,9H),1.02(d,J=6.0Hz,6H).

[0386] HPLC:R t =3.439 min in 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 96.02%.

[0387] LCMS:R t= 2.636 minutes in 4 minute chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 97.89%, 615.26 [M+H] + MS ESI calculated for 616.26, found 616.3. Example 32. Synthesis of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-N-cyclohexyl-1H-1,2,3-triazole-4-carboxamide (Compound 32, Table 1) [ka] To a solution of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (100 mg, 187.28 μmol, 1 equiv.) and cyclohexanamine (27.86 mg, 280.92 μmol, 32.15 μL, 1.5 equiv.) in DMF (1 mL) was added HATU (142.42 mg, 374.56 μmol, 2 equiv.) and DIEA (72.61 mg, 561.84 μmol, 97.86 μL, 3 equiv.). The reaction mixture was stirred at 25° C. for 10 hours. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; condition: [water (0.04% NH3H2O ​​+ 10mM NH4HCO3) ACN]; B: 33%-73%, 11 min). Example 32 (20mg, 31.73umol, yield 16.94%, purity 97.60%) was obtained as a red solid. 1 H NMR (DMSO-d6, 400 MHz) δ H=9.59(s,1H),8.96(s,1H),8.40(d,J=8.0Hz,1H),8.23(d,J=8.0Hz,1H),7.33 (d,J=12.0Hz,1H),6.82(d,J=8.8Hz,1H),5.48(s,2H),3.85-3.73(m,1H),3.12 -3.04(m,2H),2.60-2.50(m,2H),2.40-2.30(m,2H),2.24(s,3H),2.19(s,3H), 1.85-1.68(m,4H),1.65-1.55(m,4H),1.45-1.30(m,5H),1.02(d,J=6.0Hz,6H) HPLC R t = 3.394 min in 8-min chromatography, Xtimate C18 (2.1 × 30 mm, 3 μm), purity 97.599%. LCMS R t = 2.230 min in 4-minute chromatography, Xtimate C18 (2.1 × 30 mm, 3 μm), purity 97.826%, 614.27 [M+H] + MS ESI calculated for 615.27, found 615.4.

[0388] Example 33. Synthesis of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 33, Table 1) [ka] To a solution of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (150 mg, 280.92 μmol, 1 equiv.) and tetrahydro-2H-pyran-4-amine (42.62 mg, 421.38 μmol, 1.5 equiv.) in DMF (3 mL) was added HATU (213.63 mg, 561.84 μmol, 2 equiv.) and DIEA (108.92 mg, 842.76 μmol, 146.79 μL, 3 equiv.). The mixture was stirred at 25° C. for 12 hours. Concentration under reduced pressure provided a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm, mobile phase A: purified water (0.04% NH3H2O ​​+ 10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 23 to 63% B in 10 min). Example 33 (16 mg, 25.49 μmol, yield 9.07%, purity 98.31%) was obtained as a white solid.

[0389] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.59(s,1H),8.98(s,1H),8.61(d,J=8.0Hz,1H),8.24(d,J=8.0Hz,1H),7. 33(d,J=12.4Hz,1H),6.82(d,J=9.2Hz,1H),5.47(s,2H),4.11-3.98(m,1H) ,3.88(d,J=10.8Hz,2H),3.14-2.96(m,3H),2.60-2.51(m,3H),2.38-2.29( m,2H),2.24(s,3H),2.18(s,3H),1.78-1.61(m,4H),1.02(d,J=6.0Hz,6H).

[0390] HPLC:R t =3.525 min for 8 min chromatography, XBridge Shield RP18, 5um, 2.1*50mm, purity 98.31%.

[0391] LCMS:R t= 2.709 minutes in 4 minute chromatography, XBridge Shield RP18, 5um, 2.1*50mm, purity 98.77%, 616.25 [M+H] + MS ESI calculated for 617.25, found 316.

[0392] Example 34. Synthesis of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 34, Table 1) [ka] To a solution of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (150 mg, 280.92 μmol, 1 equiv.) and 1-methylpiperidin-4-amine (48.12 mg, 421.38 μmol, 1.5 equiv.) in DMF (3 mL) was added HATU (213.63 mg, 561.84 μmol, 2 equiv.) and DIEA (108.92 mg, 842.76 μmol, 146.79 μL, 3 equiv.). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um, mobile phase A: purified water (0.04% NH3H2O ​​+ 10mM NH4HCO3); mobile phase B: acetonitrile; gradient: 25 to 65% B in 10 min). Example 34 (17.3 mg, 26.93 μmol, yield 9.59%, purity 98.08%) was obtained as a white solid.

[0393] 1 H NMR: (DMSO-d6, 400 MHz) δ H=9.60(s,1H),8.98(s,1H),8.51(d,J=8.0Hz,1H),8.25(d,J=8.0Hz,1H),7.34(d,J= 12.4Hz,1H),6.83(d,J=9.2Hz,1H),5.48(s,2H),3.85-3.71(m,1H),3.08(d,J=10.8 Hz,2H),2.77(d,J=11.2Hz,2H),2.59-2.54(m,2H),2.34(s,2H),2.25(s,3H),2.18( d,J=11.6Hz,6H),1.95(t,J=10.8Hz,2H),1.81-1.59(m,4H),1.03(d,J=6.0Hz,6H).

[0394] HPLC:R t =3.630 min for 8 min chromatography, XBridge Shield RP18, 5um, 2.1*50mm, purity 98.08%.

[0395] LCMS:R t = 2.804 minutes in 4 minute chromatography, XBridge Shield RP18, 5um, 2.1*50mm, purity 98.535%, 629.28 [M+H] + MS ESI calculated for 630.28, found 630.3.

[0396] Example 35. Synthesis of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-N-(3-(4-methylpiperazin-1-yl)propyl)-1H-1,2,3-triazole-4-carboxamide (Compound 35, Table 1) [ka] To a solution of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (150 mg, 280.92 μmol, 1 equiv.) and 3-(4-methylpiperazin-1yl)propan-1-amine (66.27 mg, 421.38 μmol, 1.5 equiv.) in DMF (3 mL) was added HATU (213.63 mg, 561.84 μmol, 2 equiv.) and DIEA (108.92 mg, 842.76 μmol, 146.79 μL, 3 equiv.). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm, mobile phase A: purified water (0.04% NH3H2O ​​+ 10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 15 to 80% B in 10 min). Example 35 (14.5 mg, 21.18 μmol, 7.54% yield, 98.32% purity) was obtained as a white solid.

[0397] 1 H NMR: (DMSO-d6, 400 MHz) δ H =9.60(s,1H),8.95(d,J=1.6Hz,1H),8.81(t,J=5.6Hz,1H),8.23(d,J=8.0Hz ,1H),7.33(d,J=12.4Hz,1H),6.82(d,J=9.2Hz,1H),5.48(s,2H),3.34-3.29( m,4H),3.12-3.03(m,2H),2.57-2.51(m,3H),2.38-2.29(m,8H),2.24(d,J=2. 4Hz,4H),2.18(s,3H),2.14(s,3H),1.73-1.64(m,2H),1.02(d,J=6.4Hz,6H).

[0398] HPLC:R t =2.544 minutes in 8 minute chromatography, XBridge Shield RP18, 5um, 2.1*50mm, purity 98.33%.

[0399] LCMS:Rt = 2.680 minutes in 4 minute chromatography, XBridge Shield RP18, 5um, 2.1*50mm, purity 97.12%, 672.32 [M+H] + MS ESI calculated for 673.32, found 673.

[0400] Example 36. Synthesis of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-N-(cyclohexylmethyl)-1H-1,2,3-triazole-4-carboxamide (Compound 36, Table 1) [ka] To a solution of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (150 mg, 280.92 μmol, 1 equiv.) and cyclohexylmethanamine (47.70 mg, 421.38 μmol, 54.83 μL, 1.5 equiv.) in DMF (3 mL) was added HATU (213.63 mg, 561.84 μmol, 2 equiv.) and DIEA (108.92 mg, 842.76 μmol, 146.79 μL, 3 equiv.). The mixture was stirred at 25° C. for 12 h. The mixture was heated to 100° C. and stirred for 10 h. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm, mobile phase A: purified water (0.04% NH3H2O ​​+ 10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 50 to 80% B in 10 min). Example 36 (15.5 mg, 24.21 μmol, yield 8.62%, purity 98.29%) was obtained as a white solid.

[0401] 1 H NMR: (DMSO-d6, 400 MHz) δ H=9.61(s,1H),8.96(d,J=1.6Hz,1H),8.66(t,J=6.0Hz,1H),8.24(d,J=8.0Hz,1 H),7.34(d,J=12.4Hz,1H),6.83(d,J=9.2Hz,1H),5.49(s,2H),3.18-3.04(m,5 H),2.39-2.29(m,3H),2.25(d,J=2.4Hz,3H),2.19(s,3H),1.74-1.65(m,4H),1 .64-1.53(m,2H),1.27-1.11(m,3H),1.03(d,J=6.0Hz,6H),0.98-0.87(m,2H).

[0402] HPLC:R t =3.433 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 98.29%.

[0403] LCMS:R t = 2.715 minutes in 4 minute chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 97.88%, 628.29 [M+H] + MS ESI calculated for 629.39, found 629.3.

[0404] Example 37. Synthesis of (S)-5'-((5-amino-6-chloropyrimidin-4-yl)amino)-4'-(3,4 dimethylpiperazin-1-yl)-2'-fluoro-N,N-dimethyl-[1,1'-biphenyl]-4-carboxamide (Compound 123, Table 3) [ka]

[0405] Step 1: (S)-4-(4-bromo-5-fluoro-2-nitrophenyl)-1,2-dimethylpiperazine (Compound 2) [ka] To a solution of compound 1 (2 g, 8.40 mmol, 1 equiv.) in CH3CN (20 mL) was added (2S)-1,2-dimethylpiperazine (959 mg, 8.40 mmol, 1 equiv.) and DIEA (2.17 g, 16.81 mmol, 2.93 mL, 2 equiv.). The mixture was stirred at 30 °C for 2 h. The mixture was diluted with DCM (100 mL) and washed with brine (50 mL * 3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound 2 (2.43 g, 6.51 mmol, 77.47% yield) was obtained as a yellow solid. The product was used directly in the next step without further purification.

[0406] 1 H NMR (CDCl3, 400 MHz) δ H =8.05(d,J=7.2Hz,1H),6.82(d,J=10.0Hz,1H),3.26-2.95(m,4H),2.91- 2.81(m,1H),2.67-2.54(m,2H),2.44-2.42(m,3H),1.16(d,J=6.4Hz,3H).

[0407] Step 2: (S)-5-bromo-2-(3,4-dimethylpiperazin-1-yl)-4-fluoroaniline (compound 3) [ka]

[0408] To a solution of compound 2 (2.43 g, 7.32 mmol, 1 equiv.) in EtOH (22.5 mL) and HO (7.5 mL) was added Fe (1.23 g, 21.95 mmol, 3 equiv.) and NH4Cl (1.96 g, 36.58 mmol, 5 equiv.). The mixture was stirred at 80 °C for 2 h. The mixture was filtered to remove insoluble material. The filtrate was concentrated in vacuo. The mixture was diluted with DCM (100 mL) and washed with NaHCO3 (50 mL * 3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® silica flash column, eluent: 0-10% methanol / dichloromethane at 30 mL / min). Compound 3 (1.42 g, 4.14 mmol, 56.65% yield) was obtained as an orange oil.

[0409] 1 H NMR (DMSO-d6, 400 MHz) δ H =6.92-6.82(m,2H),4.79(s,2H),3.35(s,1H),2.93(s,2H),2.80-2.59(m,2H),2.37-2.24(m,2H),2.21(s,3H),0.99(d,J=6.0Hz,3H).

[0410] Step 3: (S)—N-(5-bromo-2-(3,4-dimethylpiperazin-1-yl)-4-fluorophenyl)-6-chloro-5-nitropyrimidin-4-amine (Compound 4) [ka]

[0411] To a solution of compound 3 (1.42 g, 4.70 mmol, 1 equiv.) and 4,6-dichloro-5-nitro-pyrimidine (1.09 g, 5.64 mmol, 1.2 equiv.) in THF (15 mL) was added TEA (951 mg, 9.40 mmol, 1.31 mL, 2 equiv.). The mixture was stirred at 25 °C for 3 h. The mixture was diluted with DCM (100 mL) and washed with brine (50 mL*3). The organic layer was dried over NaSO and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0–10% methanol / dichloromethane at 30 mL / min). Compound 4 (530 mg, 1.11 mmol, 23.55% yield) was obtained as an orange oil.

[0412] 1 H NMR (DMSO-d6, 400 MHz) δ H =10.27-9.91(m,1H),8.59(s,1H),8.09(d,J=7.6Hz,1H),7.24(d,J=10.4Hz,1H),3.42-3.24(m,2H) ,2.96(d,J=11.6Hz,2H),2.88-2.77(m,2H),2.49-2.43(m,1H),2.23(s,3H),0.98(d,J=6.0Hz,3H).

[0413] Step 4: (S)—N4-(5-bromo-2-(3,4-dimethylpiperazin-1-yl)-4-fluorophenyl)-6-chloropyrimidine-4,5-diamine (Compound 5) [ka]

[0414] To a solution of compound 4 (530 mg, 1.15 mmol, 1 equiv) in EtOH (50 mL) was added PtO2 (26 mg, 115.29 μmol, 0.1 equiv). The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 25 °C for 5 h. The mixture was filtered to remove insoluble material. The filtrate was concentrated in vacuo. The reaction mixture was diluted with DCM (100 mL) and washed with brine (50 mL*3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0–15% methanol / dichloromethane at 30 mL / min). Compound 5 (200 mg, 331.85 μmol, 28.78% yield) was obtained as a yellow solid.

[0415] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.14(s,1H),7.89(s,1H),7.21-7.15(m,1H),5.76(s,2H),5.36(s,2H),3.17(s,1H),2.93-2.85 (m,2H),2.80-2.72(m,2H),2.50-2.40(m,2H),2.37-2.29(m,1H),2.22(s,3H),0.99-0.94(m,3H).

[0416] Step 5: (S)-5'-((5-amino-6-chloropyrimidin-4-yl)amino)-4'-(3,4-dimethylpiperazin-1-yl)-2'-fluoro-N,N-dimethyl-[1,1'-biphenyl]-4-carboxamide (DDO-2213_001) [ka]

[0417] A mixture of compound 5 (200 mg, 465.42 μmol, 1 equiv.), [4-(dimethylcarbamoyl)phenyl]boronic acid (90 mg, 465.42 μmol, 1 equiv.), Pd(dppf)Cl.CHCl (38 mg, 46.54 μmol, 0.1 equiv.), and CsCO (303.29 mg, 930.84 μmol, 2 equiv.) in dioxane (4 mL) and HO (0.8 mL) was degassed and purged with N three times, then the mixture was stirred at 100 °C under a N atmosphere for 12 h. The mixture was filtered to remove insoluble material. The filtrate was concentrated in vacuo. The reaction mixture was diluted with DCM (100 mL) and washed with brine (20 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*30 mm*3 μm; mobile phase A: purified water (0.04% NH3H2O ​​+ 10 mM NH4HCO3); mobile phase B: MeOH; gradient: 39 to 69% B in 11 min). DDO-2213_001 (40.5 mg, 79.07 μmol, 16.99% yield, 97.23% purity) was obtained as a white solid.

[0418] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.10(s,1H),7.95-7.89(m,1H),7.81(s,1H),7.61-7.55(m,2H),7.49(d,J=8.0Hz,2H),7.08(d,J=12.4Hz,1H),5.3 6(s,2H),3.04-2.90(m,8H),2.76(s,2H),2.47-2.41(m,1H),2.34-2.25(m,1H),2.19(s,4H),0.96(d,J=6.4Hz,3H).

[0419] HPLC: Rt=8 min chromatography 2.90 min, Ultimate XB-C18 3.0*50 mm, 3 μm, purity 97.23%.

[0420] LCMS R t= 1.983 min in 4 min chromatography, Xtimate C18, 3 μm, 3.0*50 mm, purity 95.90%, 497.21 [M+H] + MS ESI calculated for 498.21, found 498.1.

[0421] Example 38. Synthesis of 4-[5-[(5-amino-6-chloro-pyrimidin-4-yl)amino]-2-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-N,N-dimethyl-benzamide (Compound 124, Table 3) [ka]

[0422] Step 1: (2S,6R)-4-(4-bromo-5-fluoro-2-nitrophenyl)-1,2,6-trimethylpiperazine (compound 2) [ka] To a solution of compound 1 (10 g, 42.02 mmol, 1 equiv.) in MeCN (200 mL) was added (2S,6R)-1,2,6-trimethylpiperazine (5.66 g, 44.12 mmol, 1.05 equiv.) and DIEA (10.86 g, 84.04 mmol, 14.64 mL, 2 equiv.). The reaction mixture was stirred at 30 °C for 2 h to give a brown mixture. The reaction mixture was concentrated to dryness. Water (200 mL) and DCM (100 mL) were added. The resulting mixture was extracted with DCM (150 mL * 2). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. Compound 2 (14 g, 33.52 mmol, 79.78% yield, 82.9% purity) was obtained as a yellow solid.

[0423] 1 H NMR (CDCl3, 400 MHz) δ H =8.13(d,J=7.2Hz,1H),6.92-6.77(m,1H),3.17-3.00(m,2H),3.00-1.98(m,7H),1.33-1.05(m,6H).

[0424] Step 2: 5-Bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)aniline (Compound 3) [ka]

[0425] To a mixture of compound 2 (13 g, 37.55 mmol, 1 equiv.) and NH4Cl (10.04 g, 187.76 mmol, 5 equiv.) in EtOH (150 mL) and HO (50 mL) was added Fe (6.29 g, 112.65 mmol, 3 equiv.). The reaction mixture was stirred at 80 °C for 2 h to give a brown mixture. After cooling, the mixture was filtered and the cake was washed with EtOH (100 mL × 2). The filtrate was concentrated to dryness. Aqueous NaHCO3 solution (200 mL) was added to the residue. The resulting mixture was extracted with DCM (200 mL * 3). The combined organic phase was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, elution with a 0-15% DCM / MeOH ether gradient at 60 mL / min) to give compound 3 (8 g, 22.94 mmol, 61.09% yield, 90.68% purity) as a brown oil.

[0426] 1 H NMR (DMSO-d6, 400 MHz) δ H =6.88(d,J=7.6Hz,1H),6.82(d,J=10.4Hz,1H),4.79(s,2H),2.93(d,J=9.6Hz,2H),2.36-2.24(m,4H),2.19(s,3H),1.01(d,J=5.6Hz,6H).

[0427] Step 3: N-[5-bromo-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-chloro-5-nitro-pyrimidin-4-amine (Compound 4) [ka]

[0428] To a solution of compound 3 (8 g, 25.30 mmol, 1 equiv.) and TEA (5.12 g, 50.60 mmol, 7.04 mL, 2 equiv.) in THF (100 mL) was added 4,6-dichloro-5-nitro-pyrimidine (5.89 g, 30.36 mmol, 1.2 equiv.). The reaction mixture was stirred at 15 °C for 12 h to give a brown mixture. Water (200 mL) was added to the reaction mixture. The resulting mixture was extracted with DCM (200 mL * 3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluting with a 0-15% DCM / MeOH ether gradient at 60 mL / min). Compound 4 (5 g, 7.99 mmol, 31.58% yield, 75.7% purity) was obtained as a brown solid.

[0429] 1 H NMR (DMSO-d6, 400 MHz) δ H =10.26-9.92(m,1H),8.58(s,1H),8.08(d,J=7.6Hz,1H),7.39-7.09(m,1H),3 .07-2.85(m,2H),2.61-2.51(m,2H),2.43-2.03(m,5H),1.02(d,J=6.0Hz,6H).

[0430] Step 4: N4-[5-bromo-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-chloro-pyrimidine-4,5-diamine (Compound 5) [ka]

[0431] To a mixture of compound 4 (500 mg, 1.06 mmol, 1 equiv.) in EtOH (20 mL) and HO (2 mL) was added SnCl2.2HO (476 mg, 2.11 mmol, 2 equiv.). The reaction mixture was stirred at 80 °C for 2 h, resulting in a brown mixture. After cooling to room temperature, the reaction mixture was then adjusted to pH 8 with saturated aqueous NaHCO3. The resulting mixture was extracted with DCM (20 mL * 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0–15% DCM / MeOH ether gradient at 25 mL / min). The product compound 5 (170 mg, 358.09 μmol, 33.93% yield, 93.47% purity) was obtained as a yellow solid.

[0432] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.20-8.08(m,2H),7.89(s,1H),7.16(d,J=10.4Hz,1H),5.35(s,2H),2.9 0(d,J=10.8Hz,2H),2.47-2.28(m,4H),2.20(s,3H),0.98(d,J=6.0Hz,6H).

[0433] Step 5: 4-[5-[(5-amino-6-chloro-pyrimidin-4-yl)amino]-2-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-N,N-dimethyl-benzamide (DDO-2213_002) [ka]

[0434] To a mixture of compound 5 (100 mg, 225.36 μmol, 1 equiv.) and [4-(dimethylcarbamoyl)phenyl]boronic acid (52.19 mg, 270.43 μmol, 1.2 equiv.) in dioxane (4 mL) and HO (0.8 mL) under N was added Pd(dppf)Cl.CHCl (18 mg, 22.54 μmol, 0.1 equiv.) and CsCO (147 mg, 450.71 μmol, 2 equiv.). The reaction mixture was stirred at 100 °C for 2 h, resulting in a black mixture. After cooling, water (10 mL) was added to the reaction mixture. The resulting mixture was extracted with DCM (10 mL * 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80*40 mm*3 μm; condition: water (0.05% ammonia hydroxide v / v)-ACN; start B: 27%, end B: 67%; gradient time (min): 13 min). DDO-2213_002 (23.2 mg, 44.81 μmol, yield 19.89%, purity 98.9%) was obtained as an off-white solid.

[0435] 1 H NMR (DMSO-d6, 400 MHz) δ H =9.66(s,1H),9.20(s,1H),8.90-8.78(m,1H),8.65-8.54(m,1H),7.72(d,J=8.8Hz,1H),7.56(t,J=7.2Hz,1H) ,7.45-7.31(m,2H),4.04-3.45(m,4H),2.94(s,4H),2.46-2.32(m,13H),2.24-2.13(m,5H),1.80-1.63(m,2H).

[0436] HPLC: Rt=8 min chromatography 2.97 min, Ultimate XB-C18 3.0*50 mm, 3 μm, purity 98.98%.

[0437] LCMS R t = 0.788 min in 2 min chromatography, Chromolith Flash RP-18.5 μm, 3.0*25 mm, purity 100%, 511.23 [M+H]+ MS ESI calculated for 512.23, found 512.2.

[0438] Example 39. 5'-((5-amino-6-chloropyrimidin-4-yl)amino)-2'-fluoro-N,N-dimethyl-4'-(4-methyl-1,4-diazepan-1-yl)-[1,1'-biphenyl]-4-carboxamide (Compound 125, Table 3) [ka]

[0439] Step 1: 1-(4-bromo-5-fluoro-2-nitrophenyl)-4-methyl-1,4-diazepane (Compound 2) [ka] To a solution of compound 1 (6 g, 25.21 mmol, 1 equiv.) in CH3CN (30 mL) was added 1-methyl-1,4-diazepane (2.88 g, 25.21 mmol, 3.14 mL, 1 equiv.) and DIEA (6.52 g, 50.42 mmol, 8.78 mL, 2 equiv.). The mixture was stirred at 20 °C for 2 h. The mixture was diluted with DCM (100 mL) and washed with brine (50 mL*3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent 0–15% methanol / dichloromethane at 50 mL / min). Compound 2 (7.24 g, 20.00 mmol, 79.31% yield) was obtained as a yellow oil.

[0440] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.11(d,J=7.6Hz,1H),7.19(d,J=12.4Hz,1H),3.33(d,J=1.6Hz,2H),3.25-3.1 9(m,2H),2.65-2.60(m,2H),2.50-2.45(m,2H),2.23(s,3H),1.89-1.81(m,2H).

[0441] Step 2: 5-Bromo-4-fluoro-2-(4-methyl-1,4-diazepan-1-yl)aniline (Compound 3) [ka]

[0442] To a solution of compound 2 (4 g, 12.04 mmol, 1 equiv.) in EtOH (30 mL) and HO (3 mL) was added SnCl2.2HO (8.15 g, 36.13 mmol, 3 equiv.). The mixture was stirred at 80 °C for 4 h. The mixture was adjusted to pH 9 with aqueous NaHCO3. Insoluble materials were removed by filtration. The filtrate was concentrated in vacuo. The mixture was diluted with DCM (300 mL) and washed with brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0–14% methanol / dichloromethane at 40 mL / min). Compound 3 (3.32 g, 10.20 mmol, 84.67% yield) was obtained as a black-brown solid.

[0443] 1 H NMR (DMSO-d6, 400 MHz) δ H =6.99-6.87(m,2H),5.03-4.93(m,2H),3.00(d,J=6.0Hz,8H),2.57(s,3H),2.04-1.94(m,2H).

[0444] Step 3: N-(5-bromo-4-fluoro-2-(4-methyl-1,4-diazepan-1-yl)phenyl)-6-chloro-5-nitropyrimidin-4-amine (Compound 4) [ka]

[0445] To a solution of compound 3 (2 g, 6.62 mmol, 1 equiv.) and 4,6-dichloro-5-nitro-pyrimidine (1.54 g, 7.94 mmol, 1.2 equiv.) in THF (10 mL) was added TEA (1.34 g, 13.24 mmol, 1.84 mL, 2 equiv.). The mixture was stirred at 25 °C for 3 h. The mixture was filtered to remove insoluble material. The filtrate was concentrated in vacuo. The reaction mixture was diluted with DCM (300 mL) and washed with brine (50 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0–13% MeOH / DCM at 40 mL / min). Compound 4 (520 mg, 932.09 μmol, 14.08% yield) was obtained as a brown solid.

[0446] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.54(s,1H),7.84(d,J=8.0Hz,1H),7.21(d,J=11.2Hz,1H),5.77(s,2H),3.24-3.02(m,5H),2.77(s,3H),2.10(s,3H),1.19(t,J=7.2Hz,1H).

[0447] Step 4: N4-(5-bromo-4-fluoro-2-(4-methyl-1,4-diazepan-1-yl)phenyl)-6-chloropyrimidine-4,5-diamine (Compound 5) [ka]

[0448] To a solution of compound 4 (500 mg, 1.09 mmol, 1 equiv.) in EtOH (10 mL) and HO (3 mL) was added SnCl2.2HO (736 mg, 3.26 mmol, 3 equiv.). The mixture was stirred at 80 °C for 2 h. The mixture was adjusted to pH 9 with aqueous NaHCO3. Insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The mixture was diluted with DCM (150 mL) and washed with brine (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0–16% MeOH / DCM at 40 mL / min). Compound 5 (300 mg, 628.32 μmol, 57.77% yield) was obtained as a yellow oil.

[0449] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.28-8.18(m,1H),7.83-7.75(m,2H),7.11(d,J=11.2Hz,1H),5.41(s,2 H),3.20-3.09(m,4H),2.75-2.64(m,4H),2.34(s,3H),1.87-1.79(m,2H).

[0450] Step 5: 5'-((5-amino-6-chloropyrimidin-4-yl)amino)-2'-fluoro-N,N-dimethyl-4'-(4-methyl-1,4-diazepan-1-yl)-[1,1'-biphenyl]-4-carboxamide (DDO-2213_003) [ka]

[0451] A mixture of compound 5 (150 mg, 349.07 μmol, 1 equiv.), [4-(dimethylcarbamoyl)phenyl]boronic acid (81 mg, 418.88 μmol, 1.2 equiv.), Pd(dppf)Cl.CHCl (29 mg, 34.91 μmol, 0.1 equiv.), and CsCO (228 mg, 698.13 μmol, 2 equiv.) in dioxane (5 mL) and HO (1 mL) was degassed and purged with N three times, after which the mixture was stirred at 100 °C under a N atmosphere for 12 h. The reaction mixture was diluted with HO (10 mL), extracted with DCM (30 mL * 2), and washed with brine (20 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm, mobile phase A: purified water (0.04% NH3H2O ​​+ 10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 7 to 47% B in 12 min). DDO-2213_003 (18 mg, 35.56 μmol, yield 10.19%, purity 98.39%) was obtained as a white solid.

[0452] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.16(s,1H),7.74(s,1H),7.57(s,3H),7.49-7.44(m,2H),7.02-6.95(m,1H),5.35(s,2H) ,3.23-3.16(m,4H),3.03-2.92(m,6H),2.61-2.52(m,4H),2.24(s,3H),1.84-1.74(m,2H).

[0453] HPLC: Rt=8min chromatography 2.852min, XBridge Shield RP18, 5μm, 2.1*50mm, purity 98.39%.

[0454] LCMS R t = 2.357 min in 4 min chromatography, X Bridge Shield RP18, 5 μm, 2.1*50 mm, purity 100.00%, 497.21 [M+H] +MS ESI calculated for 498.21, found 498.3.

[0455] Example 40. 5'-((5-amino-6-chloropyrimidin-4-yl)amino)-2'-fluoro-N-isopropyl-4'-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-4-carboxamide (Compound 126, Table 3) [ka]

[0456] Step 1: 5'-((5-amino-6-chloropyrimidin-4-yl)amino)-2'-fluoro-N-isopropyl-4'-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-4-carboxamide (DDO-2213_004) [ka] Compound 1 was synthesized as described in Example 38 above. To a mixture of compound 1 (200 mg, 450.71 μmol, 1 eq.) and compound 1A (112 mg, 540.85 μmol, 1.2 eq.) in dioxane (4 mL) and HO (0.5 mL) under N was added Pd(dppf)Cl (33 mg, 45.07 μmol, 0.1 eq.) and CsCO (294 mg, 901.42 μmol, 2 eq.). The reaction mixture was stirred at 100° C. for 2 hours. The mixture was extracted with DCM (200 mL*3). The combined organic phase was washed with brine (100 mL*2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80*40 mm*3 μm; conditions: [water (0.05% NH3 HO)-ACN)]; B: 46%-76%, 11 min) to give DDO-2213_004 (70 mg, 127.69 μmol, 28.33% yield, 95.96% purity) as a white solid.

[0457] 1H NMR (DMSO-d6, 400 MHz) δ H =8.31-8.09(m,2H),7.97-7.77(m,4H),7.60(d,J=7.2Hz,2H),7.04(d,J=12.0Hz,1H),5.35(s,2H),4.20-4.01(m ,1H),2.97(d,J=10.4Hz,2H),2.48-2.41(m,2H),2.30-2.05(m,5H),1.17(d,J=6.0Hz,6H),0.97(d,J=5.2Hz,6H).

[0458] HPLC:R t =2.36 min in 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 95.96%.

[0459] LCMS R t = 1.124 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 98.51%, 525.24 [M+H] + MS ESI calculated for 526.24, found 526.4.

[0460] Example 41. (S)—N-(5′-((5-amino-6-chloropyrimidin-4-yl)amino)-4′-(3,4-dimethylpiperazin-1-yl)-2′-fluoro-[1,1′-biphenyl]-4-yl)cyclohexanecarboxamide (Compound 127, Table 3) [ka]

[0461] Step 1: N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexanecarboxamide (Compound 1A) [ka] To a solution of compound A (1 g, 4.56 mmol, 1 equiv.) and EtN (924 mg, 9.13 mmol, 1.27 mL, 2 equiv.) in DCM (15 mL) at 0 °C was added cyclohexanecarbonyl chloride (736 mg, 5.02 mmol, 669 μL, 1.1 equiv.). The reaction mixture was stirred at 0 °C for 1 h to give a brown mixture. Water (30 mL) was added to the reaction mixture. The reaction mixture was then adjusted to pH 8 with aqueous NaHCO solution. The resulting mixture was extracted with DCM (20 mL * 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. Compound 1A (1.3 g, 2.87 mmol, 62.89% yield) was obtained as a brown solid, which was used in the next step without further purification.

[0462] 1 H NMR (DMSO-d6, 400 MHz) δ H =9.92(s,1H),7.60(q,J=8.8Hz,4H),3.17-2.99(m,1H),2.37-2.27(m,1H ),1.80-1.63(m,5H),1.43-1.34(m,2H),1.27(s,12H),1.21-1.14(m,2H).

[0463] Step 2: (S)—N-(5′-((5-amino-6-chloropyrimidin-4-yl)amino)-4′-(3,4-dimethylpiperazin-1-yl)-2′-fluoro-[1,1′-biphenyl]-4-yl)cyclohexanecarboxamide (DDO-2213_005) [ka]

[0464] Compound 1 is synthesized as shown in Example 37. To a mixture of compound 1 (150 mg, 349.07 μmol, 1 eq.) and compound 1A (138 mg, 418.88 μmol, 1.2 eq.) in dioxane (4 mL) and HO (0.5 mL) under N2, Pd(dppf)Cl2 (26 mg, 34.91 μmol, 0.1 eq.) and Cs2CO3 (228 mg, 698.14 μmol, 2 eq.) were added. The reaction mixture was stirred at 100 °C for 2 h. The mixture was extracted with DCM (20 mL * 3). The combined organic phase was washed with brine (20 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80*40 mm*3 μm; conditions: [water (0.04% NH3H2O) + 10 mM NH4HCO3-ACN)]; B: 40% to 70%, 11 min) to obtain DDO-2213_005 (47.9 mg, 85.78 μmol, yield 24.57%, purity 98.87%) as a white solid.

[0465] 1 H NMR (DMSO-d6, 400 MHz) δ H =9.92(s,1H),8.10(s,1H),7.85(d,J=8.8Hz,1H),7.81(s,1H),7.69(d,J=8.8Hz,2H), 7.44(d,J=7.6Hz,2H),7.03(d,J=12.4Hz,1H),5.35(s,2H),2.97-2.87(m,2H),2.80-2 .71(m,2H),2.44(t,J=10.4Hz,1H),2.38-2.24(m,2H),2.18(s,3H),1.84-1.73(m,4H) ,1.65(d,J=10.8Hz,1H),1.48-1.36(m,2H),1.33-1.11(m,4H),0.95(d,J=6.4Hz,3H).

[0466] HPLC:R t =3.93 min for 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 98.87%.

[0467] LCMS Rt = 2.162 minutes in 4 minute chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 99.87%, 551.26 [M+H] + MS ESI calculated for 552.26, found 552.4.

[0468] Example 42. N-(5'-((5-amino-6-chloropyrimidin-4-yl)amino)-2'-fluoro-4'-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)cyclohexanecarboxamide (Compound 128, Table 3) [ka]

[0469] Step 1: N-(5'-((5-amino-6-chloropyrimidin-4-yl)amino)-2'-fluoro-4'-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)cyclohexanecarboxamide (DDO-2213_006) [ka] Compound 1 is synthesized as shown in Example 38, and compound 3A is synthesized as shown in Example 41. To a mixture of compound 1 (200 mg, 450.71 μmol, 1 eq.) and compound 3A (178 mg, 540.85 μmol, 1.2 eq.) in dioxane (4 mL) and HO (0.5 mL) under N2, Pd(dppf)Cl2 (33 mg, 45.07 μmol, 0.1 eq.) and Cs2CO3 (294 mg, 901.42 μmol, 2 eq.) were added. The reaction mixture was stirred at 100 °C for 2 h. The mixture was extracted with DCM (200 mL * 3). The combined organic phase was washed with brine (100 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80*40 mm*3 μm; conditions: [water (0.05% NH3 HO)-ACN)]; B: 50%-75%, 16 min) to give DDO-2213_006 (52 mg, 91.28 μmol, 20.25% yield, 99.37% purity) as a white solid.

[0470] 1 H NMR (DMSO-d6, 400 MHz) δ H =9.91(s,1H),8.12(s,1H),7.86(d,J=8.8Hz,1H),7.81(s,1H),7.69(d,J=8.8Hz,2H),7.44(br d,J=7.6Hz,2H),7.00(d,J=12.4Hz,1H),5.33(s,2H),2.93(d,J=10.8Hz,2H),2.45(t,J=10.8Hz, 2H),2.38-2.22(m,3H),2.17(s,3H),1.85-1.62(m,5H),1.48-1.15(m,5H),0.97(d,J=6.0Hz,6H).

[0471] HPLC:R t =4.00 min with 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 99.37%.

[0472] LCMS R t= 2.045 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 99.27%, 565.27 [M+H] + MS ESI calculated for 566.27, found 566.4.

[0473] Example 43. N-(5'-((5-amino-6-chloropyrimidin-4-yl)amino)-2'-fluoro-4'-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)butyramide (Compound 129, Table 3) [ka]

[0474] Step 1: N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyramide (Compound 2A) [ka] To a mixture of compound 1A (1 g, 4.56 mmol, 1 equiv.) and EtN (924 mg, 9.13 mmol, 1.27 mL, 2 equiv.) in DCM (15 mL) at 0 °C was added butanoyl chloride (535 mg, 5.02 mmol, 524.48 μL, 1.1 equiv.). The reaction mixture was stirred at 0 °C for 1 h to give a brown mixture. Water (30 mL) was added to the reaction mixture. The reaction mixture was then adjusted to pH 8 with aqueous NaHCO solution. The resulting mixture was extracted with DCM (20 mL * 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The product compound 2A (1.1 g, 3.18 mmol, 69.75% yield) was obtained as a brown solid, which was used in the next step without further purification.

[0475] 1 H NMR (DMSO-d6, 400 MHz) δ H=10.00(s,1H),7.66-7.54(m,4H),3.13-3.01(m,2H),1.68-1.54(m,2H),1.27(s,12H),0.91(t,J=7.6Hz,3H).

[0476] Step 2: N-(5'-((5-amino-6-chloropyrimidin-4-yl)amino)-2'-fluoro-4'-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)butyramide (DDO-2213_007) [ka]

[0477] Compound 1 is synthesized as shown in Example 38. To a mixture of compound 1 (200 mg, 450.71 μmol, 1 eq.) and compound 2A (156 mg, 540.85 μmol, 1.2 eq.) in dioxane (4 mL) and HO (0.5 mL) under N2, Pd(dppf)Cl2 (33 mg, 45.07 μmol, 0.1 eq.) and Cs2CO3 (294 mg, 901.42 μmol, 2 eq.) were added. The reaction mixture was stirred at 100 °C for 2 h. The mixture was extracted with DCM (200 mL * 3). The combined organic phase was washed with brine (100 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80*40 mm*3 μm; conditions: [water (0.05% NH₃·H₂O)-ACN)]; B: 40% to 80%, 16 min) to obtain DDO-2213_007 (33.7 mg, 63.13 μmol, 14.01% yield, 98.54% purity) as a white solid.

[0478] 1 H NMR (DMSO-d6, 400 MHz) δ H=9.98(s,1H),8.12(s,1H),7.89-7.80(m,2H),7.68(d,J=8.0Hz,2H),7.45(d,J=8.0Hz,2H),7.01(d,J=12.4Hz,1H),5.33(s,2H) ,3.33(s,3H),2.93(d,J=10.4Hz,2H),2.46-2.41(m,1H),2.33-2.25(m,3H),2.17(s,2H),1.68-1.57(m,2H),1.01-0.88(m,9H).

[0479] HPLC:R t =2.45 min with 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 98.54%.

[0480] LCMS R t = 1.221 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, 100% purity, 525.24 [M+H] + MS ESI calculated for 526.24, found 526.3.

[0481] Example 44. (S)-6-chloro-N4-(5-(2-(cyclopropylmethoxy)pyridin-4-yl)-2-(3,4-dimethylpiperazin-1-yl)-4-fluorophenyl)pyrimidine-4,5-diamine (Compound 130, Table 3) [ka]

[0482] Step 1: 4-Bromo-2-(cyclopropylmethoxy)pyridine (Compound 1B) [ka] To a mixture of cyclopropylmethanol (492 mg, 6.82 mmol, 539.11 μL, 1.2 equiv) in THF (30 mL) was added NaH (273 mg, 6.82 mmol, 60% purity, 1.2 equiv) in one portion under N2 at 0 °C and stirred for 10 min. Then, compound 1A (1 g, 5.68 mmol, 1 equiv) was added in one portion under N2 at 0 °C. The mixture was stirred at 25 °C for 12 h. The residue was poured into water (50 mL). The aqueous phase was extracted with DCM (30 mL * 3). The combined organic phase was washed with brine (20 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column weight: 4 g, diameter: 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate = 5:1). Compound 1B (1 g, 4.22 mmol, 74.33% yield) was obtained as a colorless oil.

[0483] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.04(d,J=5.6Hz,1H),7.22-7.17(m,1H),7.14-7.10(m,1H),4.09(d,J=7.2Hz,2H),1.28-1.16(m,1H),0.57-0.50(m,2H),0.34-0.27(m,2H).

[0484] Step 2: 2-(cyclopropylmethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound 1C) [ka]

[0485] To a mixture of compound 1B (1 g, 4.38 mmol, 1 equiv.) in dioxane (10 mL) under N2 at 25 °C, AcOK (861 mg, 8.77 mmol, 2 equiv.), Pin2B2 (1.34 g, 5.26 mmol, 1.2 equiv.), and Pd(dppf)Cl2 (321 mg, 438.43 μmol, 0.1 equiv.) were added in one portion. The mixture was stirred at 100 °C for 12 h. The residue was poured into water (100 mL). The aqueous phase was extracted with DCM (70 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column weight: 20 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1). Compound 1C (1.2 g, 3.73 mmol, 85.03% yield) was obtained as a brown oil.

[0486] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.16(d,J=4.8Hz,1H),7.10(d,J=5.2Hz,1H),6.92(s,1H),4.08(d,J=7.2Hz ,2H),1.29(s,12H),1.24-1.17(m,1H),0.57-0.48(m,2H),0.34-0.26(m,2H).

[0487] Step 3: (S)-6-chloro-N4-(5-(2-(cyclopropylmethoxy)pyridin-4-yl)-2-(3,4-dimethylpiperazin-1-yl)-4-fluorophenyl)pyrimidine-4,5-diamine (DDO-2213_008) [ka]

[0488] DDO-2213_001_5 was synthesized as shown in Example 37. To a mixture of DDO-2213_001_5 (150 mg, 349.07 μmol, 1 equiv.) and compound 1C (96 mg, 349.07 μmol, 1 equiv.) in dioxane (5 mL) and HO (0.8 mL) under N at 25 °C, Pd(dppf)Cl (26 mg, 34.91 μmol, 0.1 equiv.) and CsCO (114 mg, 349.07 μmol, 1 equiv.) were added in one portion. The mixture was heated to 100 °C and stirred for 12 h. The residue was filtered through a paper filter and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 27%~67%; 11 min) to obtain DDO-2213_008 (19 mg, 37.83 μmol, 10.84% ​​yield, 99.16% purity) as a white solid.

[0489] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.18(d,J=5.6Hz,1H),8.09(s,1H),7.93(d,J=8.8Hz,1H),7.81(s,1H),7.12(d,J=5.6H z,1H),7.06(d,J=12.8Hz,1H),6.92(s,1H),5.36(s,2H),4.12(d,J=7.2Hz,2H),3.04-2.9 3(m,2H),2.83-2.70(m,2H),2.48-2.42(m,1H),2.34-2.22(m,1H),2.18(s,3H),2.17-2. 10(m,1H),1.32-1.19(m,1H),0.95(d,J=6.4Hz,3H),0.60-0.49(m,2H),0.37-0.28(m,2H)

[0490] HPLC: Rt=8 min chromatography 3.095 min, XBridge Shield RP18, 5 μm, 2.1*50 mm, 8 μm, purity 99.16%.

[0491] LCMS R t= 2.480 min in 4 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, 8 μm, purity 99.89%, 497.21 [M+H] + MS ESI calculated for 498.21, found 498.3.

[0492] Example 45. 6-chloro-N4-(5-(2-(cyclopropylmethoxy)pyridin-4-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidine-4,5-diamine (Compound 131, Table 3) [ka]

[0493] Step 1: 6-chloro-N4-(5-(2-(cyclopropylmethoxy)pyridin-4-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidine-4,5-diamine (DDO-2213_009) [ka] DDO-2213_002_5 was synthesized as described in Example 38, and compound 1C was synthesized as described in Example 44. To a mixture of DDO-2213_002_5 (150 mg, 338.03 μmol, 1 equiv.) and compound 1C (93 mg, 338.03 μmol, 1 equiv.) in dioxane (5 mL) and HO (0.8 mL) under N was added Pd(dppf)Cl (25 mg, 33.80 μmol, 0.1 equiv.) and CsCO (110 mg, 338.03 μmol, 1 equiv.) in one portion at 25 °C. The mixture was heated to 100 °C and stirred for 12 h. The residue was filtered through a paper filter and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 35%~74%; 11 min) to obtain DDO-2213_009 (17.7 mg, 34.45 μmol, 10.19% yield, 99.66% purity) as a white solid.

[0494] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.18(d,J=5.6Hz,1H),8.11(s,1H),7.92(d,J=8.6Hz,1H),7.81(s,1H),7.12(d ,J=5.6Hz,1H),7.03(d,J=12.8Hz,1H),6.92(s,1H),5.34(s,2H),4.12(d,J=7.2H z,2H),2.99(d,J=11.2Hz,2H),2.48-2.42(m,2H),2.30-2.19(m,2H),2.16(s,3H) ,1.31-1.20(m,1H),0.96(d,J=6.4Hz,6H),0.58-0.52(m,2H),0.35-0.30(m,2H).

[0495] HPLC:R t =3.268 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, 8 μm, purity 99.66%.

[0496] LCMS R t= 2.611 min in 4 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, 8 μm, purity 99.52%, 511.23 [M+H] + MS ESI calculated for 512.23, found 512.4. Example 46. (1-(5-((5-amino-6-chloropyrimidin-4-yl)amino)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)(morpholino)methanone (Compound 132, Table 3) [ka] Step 1: Synthesis of methyl 1-(5-amino-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (HYBI_028_5) Step 1A: Synthesis of compound 2 as seen in the scheme below. [ka] To a mixture of compound 1 (8.4 g, 24.26 mmol, 1 equiv.) and diphenylmethanimine (6.60 g, 36.40 mmol, 6.11 mL, 1.5 equiv.) in dioxane (300 mL) under N2 at 25 °C, Pd(OAc)2 (545 mg, 2.43 mmol, 0.1 equiv.), Xantphos (2.11 g, 3.64 mmol, 0.15 equiv.), and Cs2CO3 (15.81 g, 48.53 mmol, 2 equiv.) were added in one portion. The mixture was heated to 100 °C and stirred for 12 h. The mixture was filtered through filter paper and diatomaceous earth. The residue was purified by silica gel chromatography (column weight: 80 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1) to give the intermediate. To the intermediate (13.3 g, 20.03 mmol, 1 equiv.) in THF (150 mL) was added HCl (12 M, 16.69 mL, 10 equiv.) in one portion. The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (200 mL). The aqueous phase was washed with ethyl acetate (100 mL * 3). The pH of the aqueous phase was adjusted to about 8 by slowly adding solid NaHCO3. The aqueous phase was then extracted with DCM (100 mL * 3). The combined organic phase was washed with brine (100 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was used in the next step without further purification. Compound 2 (4.5 g, 9.06 mmol, 45.22% yield) was obtained as a yellow oil. 1 H NMR (DMSO-d6, 400 MHz) δ H =7.23(d,J=9.0Hz,1H),7.12(d,J=12.8Hz,1H),5.46(s,2H),3.31(s,1H),3.1 7(d,J=5.6Hz,3H),2.84(d,J=9.2Hz,2H),2.17(s,3H),0.99(d,J=4.4Hz,6H). Step 1B: (2S,6R)-4-(4-azido-5-fluoro-2-nitrophenyl)-1,2,6-trimethylpiperazine [ka] To a mixture of compound 2 (4.5 g, 15.94 mmol, 1 equiv.) in HCl (2 M, 79.70 mL, 10 equiv.) was added dropwise a solution of NaNO (1.65 g, 23.91 mmol, 1.5 equiv.) in HO (20 mL) at 0 °C. After 0.5 h, a solution of NaN (1.7 g, 26.15 mmol, 1.64 equiv.) in HO (20 mL) was added to the mixture. The mixture was warmed to 15 °C and stirred for 1 h to give a brown mixture. The pH of the mixture was adjusted to approximately 9 with 2 N NaOH. The solid formed was filtered, and the cake was washed with HO (50 mL × 2). The cake was then dried to give the product. The product, compound 3 (4 g, 10.53 mmol, 66.09% yield), was obtained as a brown solid, which was used in the next step without further purification. 1 H NMR (DMSO-d6, 400 MHz) δ H =7.82(d,J=8.6Hz,1H),7.30(d,J=13.4Hz,1H),3.01(d,J=12.0Hz,2H),2.6 3(t,J=11.3Hz,2H),2.30-2.21(m,2H),2.18(s,3H),1.00(d,J=6.1Hz,6H). Step 1C: methyl 1-(2-fluoro-5-nitro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate [ka] To a mixture of compound 3 (3.9 g, 12.65 mmol, 1 equiv.) and methyl prop-2-ynoate (1.28 g, 15.18 mmol, 1.26 mL, 1.2 equiv.) in CH3CN (40 mL) under N2, CuI (723 mg, 3.79 mmol, 0.3 equiv.) and DIEA (4.90 g, 37.95 mmol, 6.61 mL, 3 equiv.) were added. The reaction mixture was stirred at 25 °C for 10 h. The reaction mixture was filtered. The filter cake was washed with CH3CN (100 mL × 3). The filtrate was concentrated. The product was directly concentrated for the next reaction. Crude compound 4 (6 g, crude) was obtained as a black-brown solid. 1 H NMR (DMSO-d6, 400 MHz) δH =9.25(s,1H),8.43(d,J=8.0Hz,1H),7.51(d,J=13.2Hz,1H),3.92-3.79(m,2H),3.5 0(s,1H),3.29-3.06(m,4H),2.82(t,J=11.6Hz,2H),2.24(s,3H),1.08-1.01(m,6H). Step 1D: methyl 1-(5-amino-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate [ka] To a solution of compound 4 (6 g, 15.29 mmol, 1 equiv.) in MeOH (60 mL) and HO (12 mL) was added SnCl2.2HO (10.35 g, 45.87 mmol, 3 equiv.). The mixture was stirred at 70 °C for 10 h. The reaction mixture was quenched by adding NaHCO3 (200 mL) and then extracted with DCM (100 mL * 3). The combined organic layers were concentrated under reduced pressure to give a residue. The crude product was purified by silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-15% MeOH / DCM ether gradient at 60 mL / min). Compound 5 (2 g, 4.75 mmol, 31.04% yield) was obtained as a brown solid. 1 H NMR (DMSO-d6, 400 MHz) δ H =9.10(d,J=1.6Hz,1H),7.08-6.95(m,2H),5.00(s,2H),3.91-3.85(m,3H),3 .04(d,J=8.4Hz,2H),2.43-2.32(m,4H),2.22(s,3H),1.03(d,J=5.6Hz,6H).

[0497] Step 2: Methyl 1-(5-((6-chloro-5-nitropyrimidin-4-yl)amino)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (Compound 1) [ka]

[0498] To a solution of HYBI_028_5 (300 mg, 827.81 μmol, 1 equiv.) and 4,6-dichloro-5-nitro-pyrimidine (321 mg, 1.66 mmol, 2 equiv.) in THF (10 mL) was added TEA (251 mg, 2.48 mmol, 345.67 μL, 3 equiv.). The mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with DCM (100 mL * 2) and washed with brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0–5% MeOH / DCM at 20 mL / min). Compound 1 (240 mg, 349.44 μmol, 42.21% yield) was obtained as a brown solid.

[0499] 1 H NMR (DMSO-d6, 400 MHz) δ H =4.11(d,J=5.2Hz,2H),4.08-3.99(m,1H),3.91-3.88(m,1H),3.57(s,1H),3.32(s,3H),3.17(d,J=5.2Hz, 6H),2.68(s,1H),2.57-2.52(m,4H),1.99(s,1H),1.29-1.22(m,1H),1.21-1.14(m,1H),1.13-0.98(m,1H).

[0500] Step 3: Methyl 1-(5-((5-amino-6-chloropyrimidin-4-yl)amino)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (Compound 2) [ka]

[0501] To a solution of compound 2 (240 mg, 461.61 μmol, 1 equiv.) in MeOH (10 mL) and HO (4 mL) was added SnCl2.2HO (313 mg, 1.38 mmol, 3 equiv.). The mixture was stirred at 80 °C for 3 h. The mixture was adjusted to pH 9 with NaHCO3 and filtered to remove insoluble materials. The filtrate was concentrated in vacuo. The reaction mixture was diluted with DCM (50 mL*3) and washed with brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0–8% MeOH / DCM at 25 mL / min). The product compound 2 (130 mg, 202.46 μmol, 43.86% yield) was obtained as a yellow oil.

[0502] 1 H NMR (DMSO-d6, 400 MHz) δ H =9.23(d,J=1.6Hz,1H),8.29-8.19(m,2H),7.85(s,1H),7.35-7.25(m,1H),5.40(s,2H),3.88( s,3H),3.33(s,2H),3.06-2.97(m,2H),2.31-2.22(m,2H),2.17(s,3H),0.98(d,J=6.0Hz,6H).

[0503] Step 4: 1-(5-((5-amino-6-chloropyrimidin-4-yl)amino)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (Compound 3) [ka]

[0504] To a solution of compound 2 (130 mg, 265.34 μmol, 1 equiv.) in THF (4 mL) and HO (1 mL) was added LiOH.HO (22 mg, 530.68 μmol, 2 equiv.). The mixture was stirred at 25° C. for 2 h. The reaction mixture was adjusted to pH 5 with 1N aqueous HCl and concentrated under reduced pressure to give a residue. The product was used directly in the next step without further purification. Compound 3 (120 mg, crude) was obtained as a yellow solid.

[0505] 1 H NMR (DMSO-d6, 400 MHz) δ H =11.21(s,1H),9.14-9.06(m,2H),8.09(d,J=8.0Hz,1H),7.82(s,1H),7.39-7.32(m,1H),3.4 5(s,4H),3.18-3.10(m,2H),2.76(d,J=4.8Hz,3H),1.35(d,J=6.4Hz,6H),1.28-1.19(m,2H).

[0506] Step 5: (1-(5-((5-amino-6-chloropyrimidin-4-yl)amino)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)(morpholino)methanone (DDO-2213_010) [ka]

[0507] To a solution of compound 3 (120 mg, 252.15 μmol, 1 equiv.) and morpholine (44 mg, 504.30 μmol, 44.38 μL, 2 equiv.) in DMF (5 mL) was added HATU (144 mg, 378.23 μmol, 1.5 equiv.) and DIEA (98 mg, 756.45 μmol, 131.76 μL, 3 equiv.). The mixture was stirred at 25 °C for 12 h. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*5 μm, mobile phase A: purified water (0.04% NH3H2O ​​+ 10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 10 to 50% B in 11 min). DDO-2213_010 (33 mg, 60.40 μmol, 23.95% yield, 99.75% purity) was obtained as a white solid.

[0508] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.97(s,1H),8.25(d,J=8.0Hz,2H),7.86(s,1H),7.30(d,J=12.4Hz,1H),5.39(s,2H),4.04(s,2H),3.33(s ,6H),3.00(d,J=11.2Hz,2H),2.54-2.51(m,2H),2.29(d,J=6.4Hz,2H),2.17(s,3H),0.98(d,J=6.0Hz,6H).

[0509] HPLC:R t =2.947 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 99.75%.

[0510] LCMS R t = 2.268 minutes in 4 minute chromatography, XBridge Shield RP18, 5μm, 2.1*50mm, purity 99.24%, 544.22 [M+H] + MS ESI calculated for 545.22, found 545.4.

[0511] Example 47. (S)-3'-((5-amino-6-chloropyrimidin-4-yl)amino)-4'-(3,4-dimethylpiperazin-1-yl)-2'-fluoro-N-(2-morpholinoethyl))-[1,1'-biphenyl]-4-carboxamide (Compound 133, Table 3) [ka]

[0512] Step 1: (S)-4-(4-bromo-3-fluoro-2-nitrophenyl)-1,2-dimethylpiperazine (Compound 2) [ka] To a solution of compound 1 (2 g, 8.40 mmol, 1 equiv.) in CH3CN (20 mL) was added (2S)-1,2-dimethylpiperazine (960 mg, 8.40 mmol, 1 equiv.) and DIEA (2.17 g, 16.81 mmol, 2.93 mL, 2 equiv.). The mixture was diluted with DCM (200 mL) and washed with brine (50 mL*3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0–3% methanol / dichloromethane at 40 mL / min). Compound 2 (2.66 g, 7.59 mmol) was obtained as a yellow solid.

[0513] 1 H NMR (DMSO-d6, 400 MHz) δ H =7.84(d,J=8.8Hz,1H),7.16(J=1.6,9.2Hz,1H),3.03(s,3H),2.78-2.71(m,1H),2.66-2.58(m,1H),2.22-2.07(m,5H),0.97(d,J=6.4Hz,3H).

[0514] Step 2: (S)-3-Bromo-6-(3,4-dimethylpiperazin-1-yl)-2-fluoroaniline (Compound 3) [ka]

[0515] To a solution of compound 2 (2.66 g, 8.01 mmol, 1 equiv.) in EtOH (40 mL) and HO (4 mL) was added SnCl.2HO (4.52 g, 20.02 mmol, 2.5 equiv.). The mixture was stirred at 80 °C for 3 h. The reaction mixture was adjusted to pH 9 with 1 N aqueous NaHCO. The filtrate was diluted with DCM (100 mL) and washed with brine (50 mL * 2). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0–14% MeOH / DCM at 40 mL / min). The product compound 3 (1.45 g, 4.53 mmol, 56.52% yield) was obtained as a yellow solid.

[0516] 1 H NMR (DMSO-d6, 400 MHz) δ H =6.82-6.75(m,1H),6.73-6.67(m,1H),4.89(s,2H),2.89(d,J=11.2Hz,2H),2.77(d,J=1 1.2Hz,1H),2.68(d,J=2.4Hz,1H),2.41-2.24(m,3H),2.22(s,3H),1.00(d,J=6.0Hz,3H).

[0517] Step 3: (S)—N-(3-bromo-6-(3,4-dimethylpiperazin-1-yl)-2-fluorophenyl)-6-chloro-5-nitropyrimidin-4-amine (Compound 4) [ka]

[0518] To a solution of compound 3 (900 mg, 2.98 mmol, 1 equiv.) and 4,6-dichloro-5-nitro-pyrimidine (1.16 g, 5.96 mmol, 2 equiv.) in THF (9 mL) was added TEA (905 mg, 8.93 mmol, 1.24 mL, 3 equiv.). The mixture was stirred at 40 °C for 12 h. The reaction mixture was diluted with DCM (100 mL * 2) and washed with brine (50 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0–8% MeOH / DCM at 30 mL / min). Compound 4 (830 mg, 1.44 mmol, 48.50% yield) was obtained as a brown solid.

[0519] 1 H NMR (DMSO-d6, 400 MHz) δ H =9.89(s,1H),8.46(s,1H),7.69-7.56(m,1H),6.98-6.87(m,1H),3.27-3.18(m, 2H),3.01-2.86(m,2H),2.83-2.67(m,3H),2.66-2.54(m,3H),1.15-1.08(m,3H).

[0520] Step 4: (S)—N4-(3-bromo-6-(3,4-dimethylpiperazin-1-yl)-2-fluorophenyl)-6-chloropyrimidine-4,5-diamine (Compound 5) [ka]

[0521] To a solution of compound 4 (830 mg, 1.81 mmol, 1 equiv.) in EtOH (20 mL) and HO (6 mL) was added SnCl2.2HO (1.22 g, 5.42 mmol, 3 equiv.). The mixture was stirred at 80 °C for 3 h. The reaction mixture was adjusted to pH 9 with 1 N aqueous NaHCO3. The filtrate was diluted with DCM (100 mL) and washed with brine (50 mL * 2). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0–16% MeOH / DCM at 40 mL / min). Compound 5 (460 mg, 873.51 μmol, 48.38% yield) was obtained as a yellow solid.

[0522] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.06(s,1H),7.73(s,1H),7.49(s,1H),6.86(dd,J=1.2,8.8Hz,1H),5.48(s,2H),3.44-3.26(m,1H),3.20 -3.15(m,1H),2.99-2.90(m,2H),2.73-2.66(m,2H),2.45-2.37(m,1H),2.17(s,3H),0.90(d,J=6.4Hz,3H).

[0523] Step 5: (S)-3'-((5-amino-6-chloropyrimidin-4-yl)amino)-4'-(3,4-dimethylpiperazin-1-yl)-2'-fluoro-N-(2-morpholinoethyl)-[1,1'-biphenyl]-4-carboxamide (DDO-2213_012) [ka]

[0524] A mixture of compound 5 (150 mg, 349.07 μmol, 1 equiv.), [4-(2-morpholinoethylcarbamoyl)phenyl]boronic acid (68 mg, 244.35 μmol, 0.7 equiv.), Pd(dppf)Cl.CHCl (29 mg, 34.91 μmol, 0.1 equiv.), and CsCO (228 mg, 698.13 μmol, 2 equiv.) in dioxane (4 mL) and HO (0.8 mL) was degassed and purged with N three times, after which the mixture was stirred at 100 °C under a N atmosphere for 12 h. The reaction mixture was diluted with DCM (50 mL) and washed with brine (50 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm, mobile phase A: purified water (0.04% NH3H2O ​​+ 10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 10 to 50% B in 11 min). The crude product DDO-2213_012 (26.1 mg, 43.16 μmol, yield 12.36%, purity 96.42%) was obtained as a white solid.

[0525] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.46(s,1H),8.03(s,1H),7.90(d,J=8.4Hz,2H),7.71(s,1H),7.59(d,J=7.6Hz,2H),7.40(t,J=8.4 Hz,1H),6.97(d,J=8.4Hz,1H),5.45(s,2H),3.57(d,J=4.0Hz,4H),3.40(q,J=6.4Hz,2H),3.36-3.30( m,7H),3.00(dd,J=12.0,17.2Hz,1H),3.07-2.93(m,1H),2.82-2.64(m,2H),2.52-2.48(m,20H),2.48 -2.44(m,3H),2.42(s,4H),2.22-2.17(m,1H),2.15(s,3H),2.11-2.02(m,1H),0.90(d,J=6.0Hz,3H).

[0526] HPLC:R t=2.029 min in 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 96.42%.

[0527] LCMS R t = 1.658 min in 4 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 97.15%, 582.26 [M+H] + MS ESI calculated for 583.26, found 583.5.

[0528] Example 48. N-(3'-((5-amino-6-chloropyrimidin-4-yl)amino)-2'-fluoro-4'-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]yl)cyclohexanecarboxamide (Compound 134, Table 3) [ka]

[0529] Step 1: (2S,6R)-4-(4-bromo-3-fluoro-2-nitrophenyl)-1,2,6-trimethylpiperazine (Compound 1) [ka] To a mixture of compound 1 (2 g, 8.40 mmol, 1 eq.) and compound 1A (1.08 g, 8.40 mmol, 1 eq.) in CH3CN (20 mL) was added DIEA (2.17 g, 16.80 mmol, 2.93 mL, 2 eq.). The reaction mixture was stirred at 25 °C for 4 hours. The reaction mixture was extracted with DCM (100 mL * 3). The combined organic phase was washed with brine (100 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The reaction mixture was concentrated to dryness. The crude product was purified by silica chromatography (DCM:MeOH = 5%). Compound 2 (2.9 g, 8.26 mmol, 98.32% yield) was obtained as a yellow oil.

[0530] 1 H NMR (DMSO-d6, 400 MHz) δH =7.83(dd,J=8.0,9.2Hz,1H),7.14(dd,J=1.6,9.2Hz,1H),3.04-2.97(m,2H),2.63(t,J =11.2Hz,2H),2.22-2.17(m,1H),2.16(s,3H),2.15-2.12(m,1H),0.98(d,J=6.0Hz,6H).

[0531] Step 2: 3-Bromo-2-fluoro-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)aniline (Compound 3) [ka]

[0532] To a mixture of compound 2 (2.9 g, 8.38 mmol, 1 equiv.) in EtOH (30 mL) and HO (5 mL) was added SnCl2.2HO (5.67 g, 25.13 mmol, 3 equiv.). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched by adding NaHCO3 (150 mL) and then extracted with DCM (100 mL * 3). The combined organic layers were concentrated under reduced pressure to give a residue. The crude product was purified by silica gel chromatography (5% MeOH in DCM). Compound 3 (1.6 g, 5.01 mmol, 59.87% yield) was obtained as a brown oil.

[0533] 1 H NMR (DMSO-d6, 400 MHz) δ H =6.81-6.75(m,1H),6.71-6.66(m,1H),4.90(s,2H),2.90(d,J=9.2Hz,2H),2.42-2.30(m,4H),2.21(s,3H),1.01(d,J=5.6Hz,6H).

[0534] Step 3: N-[3-bromo-2-fluoro-6-((3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl)-6-chloro-5-nitropyrimidin-4-amine (Compound 4) [ka]

[0535] To a mixture of compound 3A (1.23 g, 6.32 mmol, 2 eq.) and TEA (960 mg, 9.49 mmol, 1.32 mL, 3 eq.) in THF (5 mL) was added a mixture of compound 3 (1 g, 3.16 mmol, 1 eq.) in THF (5 mL). The reaction mixture was stirred at 40 °C for 2 h. The mixture was extracted with DCM (50 mL * 3). The combined organic phase was washed with brine (50 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (5% MeOH in DCM). Compound 4 (1.3 g, 2.22 mmol, 70.18% yield) was obtained as a yellow oil.

[0536] 1 H NMR (DMSO-d6, 400 MHz) δ H =9.16-8.89(m,1H),8.48-8.44(m,1H),7.65(t,J=8.0Hz,1H),6.96(d,J=8.8Hz,1 H),3.34(s,2H),3.09(q,J=7.2Hz,4H),2.88-2.66(m,3H),1.18(t,J=7.2Hz,6H).

[0537] Step 4: N4-[3-bromo-2-fluoro-6-((3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl)-6-chloropyrimidine-4,5-diamine (Compound 5) [ka]

[0538] To a mixture of compound 4 (1.30 g, 2.74 mmol, 1 equiv.) in EtOH (10 mL) and HO (2 mL) was added SnCl2.2HO (1.86 g, 8.23 ​​mmol, 3 equiv.). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched by adding NaHCO3 (150 mL) and then extracted with DCM (100 mL * 3). The combined organic layers were concentrated under reduced pressure to give a residue. The crude product was purified by silica gel chromatography (5% MeOH in DCM). Compound 5 (640 mg, 1.34 mmol, 48.76% yield) was obtained as a yellow oil.

[0539] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.11(s,1H),7.73(s,1H),7.55-7.48(m,1H),6.87(d,J=8.4Hz,1H),5.47(s,2H), 4.11(q,J=5.2Hz,2H),3.10(q,J=7.2Hz,4H),2.38-2.11(m,3H),1.09-0.91(m,6H).

[0540] Step 5: N-(3'-((5-amino-6-chloropyrimidin-4-yl)amino)-2'-fluoro-4'-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)cyclohexanecarboxamide (DDO-2213_014) [ka]

[0541] Compound 5A is synthesized as shown in Example 42. To a mixture of compound 5 (150 mg, 338.03 μmol, 1 eq.) and compound 5A (134 mg, 405.64 μmol, 1.2 eq.) in dioxane (4 mL) and HO (0.5 mL) under N was added Pd(dppf)Cl (25 mg, 33.80 μmol, 0.1 eq.) and CsCO (220 mg, 676.07 μmol, 2 eq.). The reaction mixture was stirred at 100° C. for 2 hours. The mixture was extracted with DCM (20 mL*3). The combined organic phase was washed with brine (10 mL*2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by reverse-phase HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; conditions: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B: 33%-73%, 12 min). DDO-2213_014 (6.3 mg, 20.05 μmol, yield 5.93%, purity 96.20%) was obtained as a white solid.

[0542] 1 H NMR (DMSO-d6, 400 MHz) δ H =9.91(s,1H),8.04(s,1H),7.70-7.66(m,3H),7.42(d,J=7.6Hz,2H),7.32(t,J=8.8Hz,1H),6.92(d,J=8.4Hz,1H),5.45 (s,2H),3.04(s,2H),2.39-2.13(m,6H),1.78(t,J=15.2Hz,5H),1.65(d,J=10.8Hz,1H),1.48-1.12(m,6H),0.96(s,6H).

[0543] HPLC:R t =2.78 min in 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 96.20%.

[0544] LCMS R t = 1.515 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 95.33%, 565.27 [M+H] +MS ESI calculated for 566.27, found 566.4.

[0545] Example 49. N-(3'-((5-amino-6-chloropyrimidin-4-yl)amino)-2'-fluoro-4'-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)-2-cyclohexylacetamide (Compound 135, Table 3) [ka] Step 1: 2-Cyclohexyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (DDO-2213_015) [ka]

[0546] To a mixture of compound 1A (1 g, 4.56 mmol, 1 eq.) and 2-cyclohexylacetyl chloride (953 mg, 5.93 mmol, 1.3 eq.) in DCM (20 mL) was added TEA (924 mg, 9.13 mmol, 1.27 mL, 2 eq.) in one portion at 0 °C. The mixture was stirred at 25 °C for 4 h. The residue was poured into water (50 mL). The aqueous phase was extracted with DCM (20 mL * 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was used in the next step without further purification. Compound 2A (1.7 g, 4.28 mmol, 93.75% yield, 86.4% purity) was obtained as a pale yellow solid.

[0547] 1 H NMR (DMSO-d6, 400 MHz) δ H =9.97(s,1H),7.63-7.54(m,4H),2.19(d,J=7.0Hz,2H),1.72-1.55(m,7H),1.27(s,12H),1.21-1.15(m,2H),1.01-0.92(m,2H).

[0548] Step 2: N-(3'-((5-amino-6-chloropyrimidin-4-yl)amino)-2'-fluoro-4'-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)-2-cyclohexylacetamide (DDO-2213_015) [ka]

[0549] Compound 1 can be synthesized as shown in Example 48. To a mixture of compound 1 (155 mg, 349.07 μmol, 1 eq.) and compound 1A (144 mg, 418.88 μmol, 1.2 eq.) in dioxane (4 mL) and HO (0.5 mL) under N was added Pd(dppf)Cl (26 mg, 34.91 μmol, 0.1 eq.) and CsCO (227.47 mg, 698.13 μmol, 2 eq.). The reaction mixture was stirred at 100° C. for 2 hours. The mixture was extracted with DCM (20 mL*3). The combined organic phase was washed with brine (10 mL*2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; conditions: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B: 33% to 73%, 12 min) to give DDO-2213_015 (48.1 mg, 92.79 μmol, yield 26.58%, purity 96.82%) as a white solid.

[0550] 1 H NMR (DMSO-d6, 400 MHz) δ H=9.96(s,1H),8.01(s,1H),7.72-7.64(m,3H),7.43(d,J=8.0Hz,2H),7.32(t,J=8.8Hz,1H),6.91(d,J=8.8Hz,1H),5.44(s,2H),3.00(d,J =10.8Hz,2H),2.42(t,J=11.2Hz,2H),2.24-2.06(m,7H),1.85-1.57(m,6H),1.31-1.10(m,3H),1.04-0.95(m,2H),0.92(d,J=6.0Hz,6H).

[0551] HPLC:R t =2.95 min with 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 96.82%.

[0552] LCMS R t = 1.616 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 99.41%, 579.29 [M+H] + MS ESI calculated for 580.29, found 580.4.

[0553] Example 50. (S)-5'-((5-amino-6-chloropyrimidin-4-yl)amino)-4'-(3,4-dimethylpiperazin-1-yl)-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-[1,1'-biphenyl]-4-carboxamide (Compound 136, Table 3) [ka]

[0554] Step 1: N-((tetrahydro-2H-pyran-4-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Compound 3A) [ka] To a mixture of compound 1A (2 g, 8.06 mmol, 1 equiv.) and compound 2A (1.11 g, 9.67 mmol, 1.2 equiv.) in DMF (20 mL) was added HATU (4.60 g, 12.09 mmol, 1.5 equiv.) and TEA (1.63 g, 16.12 mmol, 2.24 mL, 2 equiv.). The mixture was extracted with DCM (100 mL * 3). The combined organic phase was washed with brine (100 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, elution with a 0-20% MeOH / DCM ether gradient at 40 mL / min). Compound 3A (3.5 g, 7.55 mmol, 93.63% yield) was obtained as a white solid.

[0555] 1 H NMR (DMSO-d6, 400 MHz) δ H =7.85(d,J=8.0Hz,2H),7.74(d,J=8.4Hz,2H),3.87-3.81(m,,2H),3.35(s, 1H),3.29-3.21(m,2H),3.17-3.12(m,2H),1.30(s,12H),1.19-1.16(m,5H).

[0556] Step 2: (S)-5'-((5-amino-6-chloropyrimidin-4-yl)amino)-4'-(3,4-dimethylpiperazin-1-yl)-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-[1,1'-biphenyl]-4-carboxamide (DDO-2213_016) [ka]

[0557] Compound 1 is synthesized as shown in Example 37. To a mixture of compound 1 (150 mg, 349.07 μmol, 1 eq.) and compound 3A (145 mg, 418.88 μmol, 1.2 eq.) in dioxane (4 mL) and HO (0.5 mL) under N2, Pd(dppf)Cl2 (26 mg, 34.91 μmol, 0.1 eq.) and Cs2CO3 (227 mg, 698.13 μmol, 2 eq.) were added. The reaction mixture was stirred at 100 °C for 2 h. The mixture was extracted with DCM (200 mL * 3). The combined organic phase was washed with brine (100 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; conditions: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B: 23%~53%, 11 min) to give DDO-2213_016 (28 mg, 47.66 μmol, yield 13.65%, purity 96.70%) as a white solid.

[0558] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.53(t,J=5.6Hz,1H),8.11(s,1H),7.92(dd,J=2.4,8.4Hz,3H),7.81(s,1H),7.61(d,J=7.2Hz ,2H),7.07(d,J=12.4Hz,1H),5.36(s,2H),3.92-3.81(m,2H),3.31-3.22(m,3H),3.17(t,J=6.4 Hz,2H),3.01-2.91(m,2H),2.82-2.71(m,2H),2.48-2.42(m,1H),2.35-2.24(m,1H),2.19(s,3H) ),1.80(dt,J=3.6,7.2Hz,1H),1.60(d,J=13.2Hz,2H),1.27-1.14(m,2H),0.96(d,J=6.0Hz,3H).

[0559] HPLC:R t =3.371 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 96.70%.

[0560] LCMS:R t = 2.598 minutes in 4 minute chromatography, XBridge Shield RP18, 5μm, 2.1*50mm, purity 97.59%, 567.25 [M+H] + MS ESI calculated for 568.25, found 568.4.

[0561] Example 51. N-(5'-((5-amino-6-chloropyrimidin-4-yl)amino)-2'-fluoro-4'-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)butyramide (Compound 137, Table 3) [ka]

[0562] Step 1: N-(5'-((5-amino-6-chloropyrimidin-4-yl)amino)-2'-fluoro-4'-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)butyramide (DDO-2213_017) [ka] Compound 1 is synthesized as shown in Example 38, and compound 1A is synthesized as shown in Example 50. To a mixture of compound 1 (200 mg, 450.71 μmol, 1 eq.) and compound 1A (187 mg, 540.85 μmol, 1.2 eq.) in dioxane (4 mL) and HO (0.5 mL) under N was added Pd(dppf)Cl (33 mg, 45.07 μmol, 0.1 eq.) and CsCO (294 mg, 901.42 μmol, 2 eq.). The reaction mixture was stirred at 100° C. for 2 hours. The mixture was extracted with DCM (50 mL*3). The combined organic phase was washed with brine (50 mL*2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80*40 mm*3 μm; conditions: [water (0.05% NH3H2O) + 10 mM NH4HCO3-ACN)]; B: 42% to 72%, 8 min) to obtain DDO-2213_017 (15.3 mg, 26.03 μmol, yield 5.78%, purity 99.05%) as a white solid.

[0563] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.54(t,J=5.6Hz,1H),7.96-7.88(m,3H),7.80(s,1H),7.61(d,J=7.6Hz,2H),7 .04(d,J=12.4Hz,1H),5.36(s,2H),3.90-3.79(m,3H),3.17(t,J=6.0Hz,2H),2. 97(d,J=10.4Hz,2H),2.48-2.41(m,2H),2.27(d,J=6.4Hz,3H),2.16(s,3H),1.8 7-1.74(m,1H),1.60(d,J=12.8Hz,2H),1.26-1.14(m,3H),0.97(d,J=6.0Hz,6H).

[0564] HPLC:R t =2.16 min for 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 99.05%.

[0565] LCMS Rt = 1.711 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 96.71%, 581.27 [M+H] + MS ESI calculated for 582.27, found 582.4.

[0566] Example 52. 6-chloro-N4-(6-fluoro-4'-(morpholinomethyl)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)pyrimidine-4,5-diamine (Compound 138, Table 3) [ka]

[0567] Step 1: 6-chloro-N4-(6-fluoro-4'-(morpholinomethyl)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)pyrimidine-4,5-diamine (DDO-2213_018) [ka] DDO-2213_002_5 is synthesized as shown in Example 38. A mixture of DDO-2213_002_5 (200 mg, 450.71 μmol, 1 equiv.), 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (164 mg, 540.85 μmol, 1.2 equiv.), Pd(dppf)Cl.CHCl (37 mg, 45.07 μmol, 0.1 equiv.), and CsCO (294 mg, 901.42 μmol, 2 equiv.) in dioxane (4 mL) and HO (0.8 mL) was degassed and purged with N three times, and then the mixture was stirred at 100 °C under a N atmosphere for 12 h. The mixture was diluted with DCM (50 mL) and washed with brine (20 mL*3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80*40 mm*3 μm, mobile phase A: purified water (0.05% ammonia hydroxide v / v), mobile phase B: acetonitrile, gradient: 43 to 73% in 11 min). DDO-2213_018 (50.8 mg, 91.44 μmol, 20.29% yield, 97.21% purity) was obtained as a white solid.

[0568] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.14(s,1H),7.91(d,J=8.4Hz,1H),7.82(s,1H),7.53-7.36(m,4H),7.03(d,J=12.4Hz,1H),5.34(s,2H),3.59(t,J=4.4Hz,4H ),3.50(s,2H),3.00-2.90(m,2H),2.49-2.43(m,2H),2.42-2.34(m,4H),2.32-2.23(m,2H),2.18(s,3H),0.98(d,J=6.0Hz,6H).

[0569] HPLC:R t =2.72 in 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 97.21%.

[0570] LCMS Rt = 1.513 minutes in 4 minute chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 97.66%, 540.07 [M+H] + MS ESI calculated for 541.07, found 540.4.

[0571] Example 53. 6-chloro-N4-(6-fluoro-3'-(morpholinomethyl)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)pyrimidine-4,5-diamine (Compound 139, Table 3) [ka]

[0572] Step 1: 6-chloro-N4-(6-fluoro-3'-(morpholinomethyl)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)pyrimidine-4,5-diamine (DDO-2213_019) [ka] DDO-2213_002_5 is synthesized as shown in Example 38. A mixture of DDO-2213_002_5 (200 mg, 450.71 μmol, 1 equiv.), 4-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (164 mg, 540.85 μmol, 1.2 equiv.), Pd(dppf)Cl.CHCl (37 mg, 45.07 μmol, 0.1 equiv.), and CsCO (294 mg, 901.42 μmol, 2 equiv.) in dioxane (4 mL) and HO (0.8 mL) was degassed and purged with N three times, and then the mixture was stirred at 100 °C under a N atmosphere for 12 h. The reaction mixture was diluted with DCM (100 mL) and washed with brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex luna C18 80*40 mm*3 μm; water (0.05% ammonia hydroxide)-ACN). DDO-2213_019 (41.5 mg, 75.17 μmol, 16.68% yield, 97.82% purity) was obtained as a white solid.

[0573] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.13(s,1H),7.88(d,J=8.4Hz,1H),7.81(s,1H),7.46(s,1H),7.43-7.38(m,2H),7.34-7.28(m,1H),7.02(d,J=12.4Hz,1H),5.34(s ,2H),3.57(s,4H),3.52(s,2H),3.00-2.90(m,2H),2.46(s,2H),2.37(s,4H),2.31-2.22(m,2H),2.17(s,3H),0.97(d,J=6.0Hz,6H).

[0574] HPLC:R t =2.82 min in 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 97.82%.

[0575] LCMS R t= 1.574 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 99.81%, 539.26 [M+H] + MS ESI calculated for 540.26, found 540.4.

[0576] Example 54. (Table 3 shows this compound as...) (S)-6-chloro-N4-(2-(3,4-dimethylpiperazin-1-yl)-4-fluoro-5-(2-morpholinopyrimidin-5-yl)phenyl)pyrimidine-4,5-diamine (Compound 140, Table 3) [ka]

[0577] Step 1: (S)-6-chloro-N4-(2-(3,4-dimethylpiperazin-1-yl)-4-fluoro-5-(2-morpholinopyrimidin-5-yl)phenyl)pyrimidine-4,5-diamine (DDO-2213_020) [ka] DDO-2213_001_5 is synthesized as shown in Example 37. A mixture of DDO-2213_001_5 (150 mg, 349.07 μmol, 1 equiv.), 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine (122 mg, 418.88 μmol, 1.2 equiv.), Pd(dppf)Cl.CHCl (28 mg, 34.91 μmol, 0.1 equiv.), and CsCO (227 mg, 698.13 μmol, 2 equiv.) in dioxane (4 mL) and HO (0.8 mL) was degassed and purged with N three times, after which the mixture was stirred at 100 °C under a N atmosphere for 12 h. The reaction mixture was diluted with DCM (100 mL) and washed with brine (50 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm, mobile phase A: purified water (0.05% NHH0 + 10 mM NHHCO); mobile phase B: acetonitrile; gradient: 30 to 60% B in 11 min). DDO-2213_020 (69.3 mg, 133.60 μmol, 38.27% yield, 99.09% purity) was obtained as a white solid.

[0578] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.55(s,2H),8.11(s,1H),7.90(d,J=8.8Hz,1H),7.81(s,1H),7.11-7.01(m,1H),5.35(s,2H),3.77-3.63(m,8H) ,2.99-2.86(m,2H),2.80-2.69(m,2H),2.47-2.39(m,1H),2.31-2.23(m,1H),2.18(s,4H),0.95(d,J=6.0Hz,3H).

[0579] HPLC:R t =3.487 min in 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 99.09%.

[0580] LCMS Rt = 2.674 minutes in 4 minute chromatography, XBridge Shield RP18, 5μm, 2.1*50mm, purity 99.49%, 513.22 [M+H] + MS ESI calculated for 514.22, found 514.3.

[0581] Example 55. 6-chloro-N4-(4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidine-4,5-diamine (Compound 141, Table 3) [ka]

[0582] Step 1: 6-chloro-N4-(4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidine-4,5-diamine (DDO-2213_021) [ka] DDO-2213_002_5 is synthesized as shown in Example 38. A mixture of DDO-2213_002_5 (200 mg, 450.71 μmol, 1 equiv.), 4-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine (157 mg, 540.85 μmol, 1.2 equiv.), Pd(dppf)Cl.CHCl (37 mg, 45.07 μmol, 0.1 equiv.), and CsCO (294 mg, 901.42 μmol, 2 equiv.) in dioxane (4 mL) and HO (0.8 mL) was degassed and purged with N three times, and then the mixture was stirred at 100 °C under a N atmosphere for 12 h. The reaction mixture was diluted with DCM (100 mL) and washed with brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0-10% methanol / dichloromethane at 30 mL / min). The product was purified by recrystallization from MeOH (5 mL) at 20 °C. DDO-2213_021 (45 mg, 81.45 μmol, 18.07% yield, 95.57% purity) was obtained as a white solid.

[0583] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.55(s,2H),8.18-8.07(m,1H),7.93-7.86(m,1H),7.84-7.78(m,1H),7.10-6.99(m,1H),5.35(s,2H),3.8 1-3.59(m,8H),2.97-2.87(m,2H),2.48-2.38(m,2H),2.31-2.20(m,2H),2.16(s,3H),0.96(d,J=6.0Hz,6H).

[0584] HPLC:R t =3.06 min in 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 95.57%.

[0585] LCMS Rt = 2.000 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 97.83%, 527.23 [M+H] + MS ESI calculated for 528.23, found 528.3.

[0586] Example 56. 6-chloro-N4-(5-(6-(cyclopropylmethoxy)pyridin-3-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidine-4,5-diamine (Compound 142, Table 3) [ka]

[0587] Step 1: 6-chloro-N4-(5-(6-(cyclopropylmethoxy)pyridin-3-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidine-4,5-diamine (DDO-2213_022) [ka] DDO-2213_002_5 was synthesized as shown in Example 38. To a mixture of DDO-2213_002_5 (200 mg, 450.71 μmol, 1 equiv.) and 2-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (124 mg, 450.71 μmol, 1 equiv.) in dioxane (4 mL) and HO (0.8 mL) was added Pd(dppf)Cl.CHCl (37 mg, 45.07 μmol, 0.1 equiv.) and CsCO (147 mg, 450.71 μmol, 1 equiv.) in one portion under N. The mixture was heated to 100 °C and stirred for 12 h. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80*40 mm*3 μm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 45%-95%; 20 min). DDO-2213_022 (35.9 mg, 69.70 μmol, yield 15.46%, purity 99.41%) was obtained as a white solid.

[0588] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.27(s,1H),8.13(s,1H),7.89(d,J=8.4Hz,1H),7.85(d,J=9.4Hz,1H),7.81(s, 1H),7.04(d,J=12.4Hz,1H),6.92(d,J=8.8Hz,1H),5.35(s,2H),4.12(d,J=7.2Hz, 2H),2.94(d,J=10.8Hz,2H),2.45(t,J=10.8Hz,2H),2.31-2.22(m,2H),2.16(s,3 H),1.32-1.20(m,1H),0.96(d,J=6.4Hz,6H),0.60-0.51(m,2H),0.37-0.29(m,2H)

[0589] HPLC:R t=2.83 minutes for 8 minutes of chromatography, Ultimate XB-C18 3.0*50mm, 3μm, 8μm, purity 99.41%.

[0590] LCMS R t = 1.701 min in 4 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, 8 μm, purity 99.85%, 512.23 [M+H] + MS ESI calculated for 513.23, found 512.3.

[0591] Example 57. Chloro-N4-(5-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-2-((S)-3,4-dimethylpiperazin-1-yl)-4-fluorophenyl)pyrimidine-4,5-diamine (Compound 143, Table 3) [ka]

[0592] Step 1: (2S,6R)-4-(5-bromopyrimidin-2-yl)-2,6-dimethylmorpholine (compound 2A) [ka] To a solution of compound 1A (1 g, 5.17 mmol, 1 equiv.) and (2S,6R)-2,6-dimethylmorpholine (595 mg, 5.17 mmol, 1 equiv.) in MeCN (15 mL) was added DIEA (1.34 g, 10.34 mmol, 1.80 mL, 2 equiv.). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (20 mL), extracted with DCM (100 mL), and washed with brine (20 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0–2% methanol / dichloromethane at 40 mL / min). Compound 2A (1.4 g, 5.02 mmol, 97.02% yield) was obtained as a white solid.

[0593] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.46(s,2H),4.41(dd,J=1.6,13.2Hz,2H),3.54(dd,J=2.4,4.4Hz,2H),2.58-2.51(m,2H),1.14(d,J=6.4Hz,6H).

[0594] Step 2: (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine (compound 3A) [ka]

[0595] To a mixture of compound 2A (1 g, 3.67 mmol, 1 equiv.) in dioxane (17 mL) under N2, AcOK (721 mg, 7.35 mmol, 2 equiv.), Pin2B2 (1.12 g, 4.41 mmol, 1.2 equiv.), and Pd(dppf)Cl2 (269 mg, 367.46 μmol, 0.1 equiv.) were added. The reaction mixture was stirred at 100 °C for 2 h. The mixture was diluted with HO (20 mL) and extracted with DCM (100 mL * 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0–5% ethyl acetate / DCM at 30 mL / min). Compound 3A (1.1 g, 3.10 mmol, 84.40% yield) was obtained as a brown oil.

[0596] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.51-8.48(m,1H),8.49(s,1H),4.61-4.54(m,2H),3.56-3.49(m,2H),3.56-3.49(m,1H),2.60-2.53(m,2H),1.16(s,12H),1.07(s,6H).

[0597] Step 3: 6-chloro-N4-(5-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-2-((S)-3,4-dimethylpiperazin-1-yl)-4-fluorophenyl)pyrimidine-4,5-diamine (DDO-2213_023) [ka]

[0598] Compound 5 can be synthesized as shown in Example 37. A mixture of compound 5 (70 mg, 162.90 μmol, 1 equiv.), compound 3A (63 mg, 195.48 μmol, 1.2 equiv.), Pd(dppf)Cl.CHCl (13 mg, 16.29 μmol, 0.1 equiv.), and CsCO (106 mg, 325.80 μmol, 2 equiv.) in dioxane (4 mL) and HO (0.8 mL) was degassed and purged with N three times, after which the mixture was stirred at 100 °C under a N atmosphere for 12 h. The reaction mixture was diluted with HO (10 mL), extracted with DCM (50 mL), and washed with brine (20 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm, mobile phase A: purified water (0.04% NH3H2O ​​+ 10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 40 to 70% B in 11 min). Compound DDO-2213_023 (15.1 mg, 27.77 μmol, yield 17.05%, purity 99.7%) was obtained as a white solid.

[0599] 1 H NMR (DMSO-d6, 400 MHz) δ H=8.53(s,2H),8.10(s,1H),7.88(d,J=8.8Hz,1H),7.81(s,1H),7.06(d,J=12 .4Hz,1H),5.35(s,2H),4.60-4.48(m,2H),3.63-3.50(m,2H),2.98-2.86(m, 2H),2.81-2.70(m,2H),2.62-2.52(m,2H),2.43(s,1H),2.31-2.22(m,1H),2 .18(s,3H),2.16-2.11(m,1H),1.16(d,J=6.0Hz,6H),0.95(d,J=6.0Hz,3H).

[0600] HPLC:R t =2.997 min in 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 99.78%.

[0601] LCMS R t = 2.406 minutes in 4 minute chromatography, X Bridge Shield RP18, 5μm, 2.1*50mm, purity 99.78%, 541.25 [M+H] + MS ESI calculated for 542.25, found 542.4.

[0602] Example 58. 6-chloro-N4-(4-fluoro-5-(2-morpholinopyrimidin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidine-4,5-diamine (Compound 144, Table 3) [ka]

[0603] Step 1: (2S,6R)-4-(5-fluoro-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,6-trimethylpiperazine (DDO-2213_024_2) [ka] DDO-2213_024_1 can be synthesized as shown in Example 38. To a mixture of DDO-2213_024_1 (5 g, 14.44 mmol, 1 equiv.) in dioxane (20 mL) under N2 at 25 °C, AcOK (2.83 g, 28.89 mmol, 2 equiv.), Pin2B2 (4.40 g, 17.33 mmol, 1.2 equiv.), and Pd(dppf)Cl2 (1.06 g, 1.44 mmol, 0.1 equiv.) were added in one portion. The mixture was heated to 100 °C and stirred for 12 h. The residue was filtered through a paper filter and concentrated under reduced pressure. DDO-2213_024_2 (8.7 g, crude) was obtained as a yellow solid. The crude product was used in the next step without further purification.

[0604] LCMS R t = 0.900 min in 2 min chromatography, Xtimate C18, 3 μm, 2.1*30 mm, purity 50.97%, 393.22 [M+H] + MS ESI calculated for 394.22, found 312.2.

[0605] Step 2: 2-chloro-4-(2-fluoro-5-nitro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidine (DDO-2213_024_3) [ka]

[0606] To a mixture of DDO-2213_024_2 (8.7 g, 15.49 mmol, 70% purity, 1 equiv.) and 2,4-dichloropyrimidine (2.31 g, 15.49 mmol, 1 equiv.) in CH3CN (100 mL) and HO (30 mL) was added NaHCO3 (3.90 g, 46.46 mmol, 1.81 mL, 3 equiv.) and Pd(PPh3)4 (894.75 mg, 774.30 μmol, 0.05 equiv.) in one portion under N2 at 25 °C. The mixture was heated to 80 °C and stirred for 16 h. The mixture was filtered through a paper filter and concentrated under reduced pressure. The residue was purified by silica gel chromatography (column weight: 20 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1). DDO-2213_024_3 (1.8 g, 4.72 mmol, 30.48% yield) was obtained as a yellow solid.

[0607] 1 H NMR (chloroform-d, 400 MHz) δ H =8.85(d,J=8.4Hz,1H),8.63(d,J=5.2Hz,1H),7.73(d,J=5.6Hz,1H),6.77(d,J=14.4Hz,1H),3.16(d,J=12. 4Hz,2H), 2.88(t,J=11.6Hz,2H),2.51-2.41(m,2H),2.33(s,3H),1.20-1.09(m,1H),1.15(d,J=6.4Hz,5H).

[0608] Step 3: 5-(2-chloropyrimidin-4-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)aniline (DDO-2213_024_4) [ka]

[0609] To a mixture of SnCl2.2HO (3.21 g, 14.22 mmol, 3 equiv.) in MeOH (20 mL) and HO (6 mL), DDO-2213_024_3 (1.8 g, 4.74 mmol, 1 equiv.) was added in one portion, and the mixture was then heated to 80 °C for 4 h. The pH was adjusted to approximately 8 by the gradual addition of NaHCO3 (10 mL). DCM (50 mL) was then added to the mixture and stirred for 5 min. The mixture was filtered through filter paper. The combined organic phase was washed with brine (20 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column weight: 4 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1). DDO-2213_024_3 (1.1 g, 2.81 mmol, 59.32% yield) was obtained as a yellow solid.

[0610] 1 H NMR (chloroform-d, 400 MHz) δ H =8.57(d,J=5.6Hz,1H),7.78(d,J=5.2Hz,1H),7.59(d,J=7.6Hz,1H),6.74(d,J=13.2Hz,1H),3.85(s,2H) ),3.17(d,J=11.2Hz,2H),2.56-2.48(m,2H),2.43(d,J=6.0Hz,2H),2.35(s,3H),1.17(d,J=6.0Hz,6H).

[0611] Step 4: 5-(2-chloropyrimidin-4-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)aniline (DDO-2213_024_5) [ka]

[0612] To a mixture of DDO-2213_024_4 (400 mg, 1.14 mmol, 1 equiv.) and morpholine (398 mg, 4.57 mmol, 402.48 μL, 4 equiv.) in CH3CN (20 mL) was added DIEA (591 mg, 4.57 mmol, 796.62 μL, 4 equiv.) in one portion. The mixture was stirred at 80 °C for 12 h. The residue was concentrated under reduced pressure. The residue was purified by silica gel chromatography (column weight: 12 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1). DDO-2213_024_5 (430 mg, 985.91 μmol, 86.23% yield) was obtained as a yellow solid.

[0613] 1 H NMR (chloroform-d, 400 MHz) δ H =8.34(d,J=5.2Hz,1H),7.46(d,J=7.6Hz,1H),7.08(dd,J=2.0,5.2Hz,1H),6.74(d,J=12.8Hz,1H),3.90-3.86(m,4 H),3.82-3.79(m,4H),3.12(d,J=11.2Hz,2H),2.56-2.48(m,2H),2.43(s,2H),2.35(s,3H),1.17(d,J=6.0Hz,6H).

[0614] Step 5: 6-chloro-N-(4-fluoro-5-(2-morpholinopyrimidin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-5-nitropyrimidin-4-amine (DDO-2213_024_6) [ka]

[0615] To a mixture of DDO-2213_024_5 (430 mg, 1.07 mmol, 1 equiv.) and 4,6-dichloro-5-nitro-pyrimidine (417 mg, 2.15 mmol, 2 equiv.) in THF (10 mL) was added TEA (325.93 mg, 3.22 mmol, 448.33 μL, 3 equiv.) in one portion. The mixture was stirred at 25 °C for 12 h. The residue was poured into water (20 mL). The aqueous phase was extracted with DCM (20 mL * 3). The combined organic phases were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column weight: 12 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1). DDO-2213_024_6 (420 mg, 584.08 μmol, 54.40% yield) was obtained as a yellow solid.

[0616] 1 H NMR (chloroform-d, 400 MHz) δ H =9.98(s,1H),9.23(d,J=8.0Hz,1H),8.51(s,1H),8.41(d,J=5.2Hz,1H),7.11(dd,J=2.0,5.2Hz,1H),7.02(d,J=12.0Hz, 1H),3.90(d,J=5.2Hz,4H),3.82(d,J=5.2Hz,4H),2.93(d,J=9.6Hz,3H),2.80(s,3H),2.51(s,3H),1.23(d,J=4.4Hz,6H).

[0617] Step 6: 6-chloro-N4-(4-fluoro-5-(2-morpholinopyrimidin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidine-4,5-diamine (DDO-2213_024) [ka] To a mixture of DDO-2213_024_6 (420 mg, 752.68 μmol, 1 equiv.) in MeOH (20 mL) and HO (6 mL) was added SnCl2.2HO (509 mg, 2.26 mmol, 3 equiv.) in one portion. The mixture was heated to 80 °C and stirred for 4 h. The pH was adjusted to approximately 8 by the slow addition of NaHCO3 (20 mL). DCM (50 mL) was then added to the mixture and stirred for 5 min. The mixture was filtered through filter paper. The combined organic phase was washed with brine (50 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 26%~66%; 13 min) to give DDO-2213_024 (79 mg, 149.03 μmol, yield 19.80%, purity 99.611%) as a pale yellow solid.

[0618] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.43(d,J=5.2Hz,1H),8.40(d,J=8.4Hz,1H),8.15(s,1H),7.77(s,1H),7.08-7.04(m,1H),6.97(d,J=13.6Hz,1H),5.33(s,2H),3.74(d, J=4.0Hz,4H),3.67(d,J=4.0Hz,4H),3.07(d,J=11.2Hz,2H),2.49-2.41(m,3H),2.17(d,J=6.8Hz,1H),2.14(s,3H),0.95(d,J=6.0Hz,6H).

[0619] HPLC:R t =2.802 min in 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 99.611%.

[0620] LCMS R t = 2.272 min in 4 min chromatography, XBridge Shield RP18, 5 μm, 2.1 × 50 mm, purity 96.704%, 527.23 [M+H]+ MS ESI calculated for 528.23, found 528.3.

[0621] Example 59. 6-chloro-N4-(4-fluoro-5-(1-(5-(morpholinomethyl)pyrimidin-2-yl)-1,2,5,6-tetrahydropyridin-3-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidine-4,5-diamine (Compound 145, Table 3) [ka]

[0622] Step 1: 4-((2-(3-(2-fluoro-5-nitro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-5,6-dihydropyridin-1(2H)-yl)pyrimidin-5-yl)methyl)morpholine (Compound 6) [ka] Compound DDO-2213_414_5 can be synthesized as shown in Example 64. To a solution of compound DDO-2213_414_5 (500 mg, 1.10 mmol, 1 eq.) and morpholine (288 mg, 3.30 mmol, 290.43 μL, 3 eq.) in DCM (10 mL) was added NaBH(OAc) (700 mg, 3.30 mmol, 3 eq.) and TEA (557 mg, 5.50 mmol, 765.61 μL, 5 eq.). The mixture was stirred at 25 °C for 12 h. Water (30 mL) was added to the mixture, and the resulting mixture was extracted with DCM (50 mL * 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0–18% MeOH / DCM at 25 mL / min) to give compound 6 (550 mg, 920.82 μmol, 83.70% yield, 88% purity) as a brown oil.

[0623] 1H NMR (DMSO-d6,400MHz)δH=8.29(s,1H),8.32-8.29(m,1H),7.88(d,J=8.0Hz,1H),7.14(d,J=13.6Hz,1H) ,6.18(s,1H),5.75(s,1H),3.65(s,6H),3.16(s,6H),3.10(s,4H),1.92-1.91(m,9H),1.27-1.23(m,6H).

[0624] Step 2: 4-Fluoro-5-(1-(5-(morpholinomethyl)pyrimidin-2-yl)-1,2,5,6-tetrahydropyridin-3-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)aniline (Compound 7) [ka]

[0625] To a solution of compound 6 (550 mg, 1.05 mmol, 1 equiv.) in MeOH (10 mL) and HO (5 mL) was added SnCl.2HO (708 mg, 3.14 mmol, 3 equiv.). The mixture was stirred at 80 °C for 3 h. The reaction mixture was adjusted to pH 9 with 1 N aqueous NaHCO. The filtrate was diluted with DCM (100 mL) and washed with brine (50 mL*2). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The product was used in the next step without further purification. Compound 7 (230 mg, crude) was obtained as a brown oil.

[0626] LCMS R t = 0.667 min in 1.5 min chromatography, XBridge Shield RP18, 5 μm, 3.0*25 mm, purity 64.39%, 495.31 [M+H] + MS ESI calculated for 496.31, found 496.3.

[0627] Step 3: 6-chloro-N-(4-fluoro-5-(1-(5-(morpholinomethyl)pyrimidin-2-yl)-1,2,5,6-tetrahydropyridin-3-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-5-nitropyrimidin-4-amine (Compound 8) [ka]

[0628] To a solution of compound 7 (110 mg, 221.94 μmol, 1 equiv.) in THF (5 mL) was added TEA (67.37 mg, 665.81 μmol, 92.67 μL, 3 equiv.) and compound 7A (47.36 mg, 244.13 μmol, 1.1 equiv.). The mixture was stirred at 25° C. for 12 h. The reaction mixture was directly concentrated. The product was used in the next step without further purification. Compound 8 (144 mg, 100.49 μmol, 45.28% yield) was obtained as a brown solid.

[0629] Step 5: 6-chloro-N4-(4-fluoro-5-(1-(5-(morpholinomethyl)pyrimidin-2-yl)-1,2,5,6-tetrahydropyridin-3-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidine-4,5-diamine (DDO-2213_026) [ka]

[0630] To a solution of compound 8 (144 mg, 220.47 μmol, 1 equiv.) in MeOH (10 mL) and HO (4 mL) was added SnCl2.2HO (248.74 mg, 1.10 mmol, 5 equiv.). The mixture was stirred at 80 °C for 3 h. The reaction mixture was adjusted to pH 9 with NaHCO3. The resulting mixture was extracted with DCM (10 mL * 3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 * 30 mm * 3 μm; mobile phase A: water (0.04% NH3HO + 10 mM NH4HCO3)-ACN; mobile phase B: 30%-60%; 11 min). DDO-2213_026 (15.2 mg, 23.98 μmol, 10.88% yield, 98.3% purity) was obtained as a white solid.

[0631] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.28(s,2H),8.10(s,1H),7.82(s,1H),7.72(d,J=8.0Hz,1H),6.93(d,J=12.8Hz,1H),6.09(s,1H),5.31(s,2H),4.49(s,2H),3.92(s, 2H),3.54(s,4H),3.30(s,2H),2.92(d,J=10.4Hz,2H),2.43-2.37(m,2H),2.32(s,6H),2.23(s,2H),2.15(s,3H),0.95(d,J=5.8Hz,6H).

[0632] HPLC:R t =3.828 min in 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 98.30%.

[0633] LCMS R t = 2.938 min in 4 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 96.62%, 622.31 [M+H] + MS ESI calculated for 623.31, found 623.3.

[0634] Example 60. 6-chloro-N4-(4-fluoro-5-(2-(4-isopropylpiperazin-1-yl)pyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidine-4,5-diamine (Compound 146, Table 3) [ka]

[0635] Step 1: 5-Bromo-2-(4-isopropylpiperazin-1-yl)pyrimidine (Compound 2A) [ka] To a solution of compound 1A (1.2 g, 6.20 mmol, 1 equiv.) and 1-isopropylpiperazine (795 mg, 6.20 mmol, 887.75 μL, 1 equiv.) in MeCN (15 mL) was added DIEA (1.60 g, 12.41 mmol), 2.16 mL, 2 equiv.). The mixture was stirred at 20 °C for 12 h. The mixture was concentrated in vacuo. The reaction mixture was diluted with HO (20 mL), extracted with DCM (50 mL*3), and washed with brine (50 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0–4% MeOH / DCM at 40 mL / min). Compound 2A (1.54 g, 4.86 mmol, 78.34% yield) was obtained as a yellow solid.

[0636] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.53(s,2H),4.87-4.41(m,1H),3.77-3.28(m,6H),3.02(s,2H),1.24(s,6H).

[0637] Step 2: 2-(4-isopropylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (Compound 3A) [ka]

[0638] To a mixture of compound 2A (1.54 g, 5.40 mmol, 1 equiv.) in dioxane (20 mL) under N2, AcOK (1.06 g, 10.80 mmol, 2 equiv.), Pin2B2 (1.65 g, 6.48 mmol, 1.2 equiv.), and Pd(dppf)Cl2 (395 mg, 540.00 μmol, 0.1 equiv.) were added. The reaction mixture was stirred at 80 °C for 12 h. The mixture was extracted with DCM (100 mL * 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0–10% EtOAc / DCM at 30 mL / min). Compound 3A (1.34 g, 2.42 mmol, 44.81% yield, 60% purity) was obtained as a brown solid.

[0639] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.47(s,1H),8.34(d,J=4.8Hz,1H),3.81-3.65(m,4H),2.76-2.63(m,1H) ,2.50-2.44(m,4H),1.91(s,1H),1.28(s,6H),0.99(dd,J=3.2,6.4Hz,6H).

[0640] Step 3: 6-chloro-N4-(4-fluoro-5-(2-(4-isopropylpiperazin-1-yl)pyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidine-4,5-diamine (DDO-2213_027)

[0641] [ka]

[0642] Compound 5 can be synthesized as shown in Example 38. A mixture of compound 5 (200 mg, 450.71 μmol, 1 equiv.), compound 3A (150 mg, 450.71 μmol, 1 equiv.), Pd(dppf)Cl.CHCl (37 mg, 45.07 μmol, 0.1 equiv.), and CsCO (294 mg, 901.42 μmol, 2 equiv.) in dioxane (4 mL) and HO (0.8 mL) was degassed and purged with N three times, after which the mixture was stirred at 100 °C under a N atmosphere for 12 h. The reaction mixture was diluted with HO (20 mL), extracted with DCM (50 mL × 2), and washed with brine (50 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm, mobile phase A: purified water (0.05% NH3H2O ​​+ 10 mM NH4HCO3); mobile phase B: acetonitrile; gradient: 43 to 63% B in 10 min). Compound DDO-2213_027 (35 mg, 61.25 μmol, yield 13.59%, purity 99.6%) was obtained as a white solid.

[0643] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.51(d,J=0.8Hz,2H),8.22-8.06(m,1H),7.89(d,J=8.4Hz,1H),7.81(s,1H),7.03(d,J=12.4Hz,1H),5.34(s,2H),3.80-3.70(m,4H),3 .34-3.28(m,4H),2.97-2.89(m,2H),2.73-2.64(m,1H),2.47-2.40(m,2H),2.30-2.20(m,2H),2.16(s,3H),0.97(dd,J=6.4,12.0Hz,12H)

[0644] HPLC:R t=3.572 min for 8 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 99.63%.

[0645] LCMS R t = 2.503 min in 4 min chromatography, XBridge Shield RP18, 5 μm, 2.1*50 mm, purity 99.46%, 568.30 [M+H] + MS ESI calculated for 569.30, found 569.5.

[0646] Example 61. 6-chloro-N4-(4-fluoro-5-(2-((S)-2-methylmorpholino)pyrimidin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidine-4,5-diamine (Compound 148, Table 3) [ka]

[0647] Step 1: 4-Fluoro-5-(2-((S)-2-methylmorpholino)pyrimidin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)aniline (DDO-2213_029_1) [ka] DDO-2213_024_4 can be synthesized as shown in Example 58. DIEA (517 mg, 4.00 mmol, 697.06 μL, 4 equiv.) was added in one portion to a mixture of DDO-2213_024_4 (350 mg, 1.00 mmol, 1 equiv.) and (2S)-2-methylmorpholine (405 mg, 4.00 mmol, 4 equiv.) in CH3CN (5 mL). The mixture was stirred at 80 °C for 12 h. The residue was concentrated under reduced pressure. The residue was purified by silica gel chromatography (column weight: 12 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1). DDO-2213_029_1 (400 mg, 823.80 μmol, 82.34% yield) was obtained as a yellow oil.

[0648] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.37(d,J=5.2Hz,1H),7.41(d,J=8.0Hz,1H),6.98(dd,J=2.0,5.2Hz,1H),6.74(d,J= 13.6Hz,1H),4.71(s,2H),4.60-4.46(m,2H),3.91(dd,J=2.4,11.6Hz,1H),3.56-3.50 (m,2H),3.08(d,J=8.8Hz,2H),2.96(dt,J=3.2,12.4Hz,1H),2.64(dd,J=10.4,12.8Hz ,1H),2.33(d,J=7.6Hz,4H),2.21(s,3H),1.17(d,J=6.4Hz,3H),1.03(d,J=4.8Hz,6H).

[0649] Step 2: 6-chloro-N-(4-fluoro-5-(2-((S)-2-methylmorpholino)pyrimidin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-5-nitropyrimidin-4-amine (DDO-2213_029_2) [ka]

[0650] To a mixture of DDO-2213_029_1 (400 mg, 964.98 μmol, 1 equiv.) and 4,6-dichloro-5-nitro-pyrimidine (374 mg, 1.93 mmol, 2 equiv.) in THF (10 mL) was added TEA (293 mg, 2.89 mmol, 402.94 μL, 3 equiv.) in one portion. The mixture was stirred at 25 °C for 12 h. The residue was concentrated under reduced pressure. The residue was purified by silica gel chromatography (column weight: 40 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1). DDO-2213_029_2 (390 mg, 580.33 μmol, 60.14% yield) was obtained as a yellow solid.

[0651] 1H NMR (DMSO-d6, 400 MHz) δ H =8.49(s,1H),8.45(d,J=5.2Hz,1H),8.32(d,J=7.2Hz,1H),7.12(d,J=13.2Hz,1H),7.07(dd,J=2.0,5.2Hz,1H),4.57-4.43(m,2H),3.92(dd,J=2 .4,11.6Hz,1H),3.58-3.46(m,2H),3.31-3.19(m,2H),3.03-2.91(m,2H) ),2.71-2.61(m,3H),2.53(s,3H),1.21-1.11(m,9H),1.10-1.02(m,2H).

[0652] Step 3: 6-chloro-N4-(4-fluoro-5-(2-((S)-2-methylmorpholino)pyrimidin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidine-4,5-diamine (DDO-2213_029) [ka]

[0653] To a mixture of DDO-2213_029_2 (390 mg, 681.78 μmol, 1 equiv.) in MeOH (5 mL) and HO (2 mL) was added SnCl2.2HO (462 mg, 2.05 mmol, 3 equiv.) in one portion. The mixture was stirred at 80 °C for 4 h. The pH was adjusted to approximately 8 by the slow addition of NaHCO3 (5 mL). Then, DCM (50 mL) was added to the mixture and stirred for 5 min. The mixture was filtered through filter paper. The combined organic phase was washed with brine (20 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 28%~68%; 11 min) to obtain DDO-2213_029 (11.5 mg, 20.90 μmol, yield 3.06%, purity 98.49%) as a white solid.

[0654] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.46-8.42(m,2H),8.15(s,1H),7.78(s,1H),7.06(dd,J=2.0,5.2Hz,1H),6.98(d,J =13.6Hz,1H),5.34(s,2H),4.58-4.43(m,2H),3.91(dd,J=2.4,11.6Hz,1H),3.57-3. 46(m,2H),3.07(d,J=11.2Hz,2H),3.02-2.92(m,1H),2.70-2.60(m,1H),2.48-2.41( m,2H),2.23-2.17(m,2H),2.15(s,3H),1.15(d,J=6.4Hz,3H),0.96(d,J=6.0Hz,6H).

[0655] HPLC:R t =3.095 min with 8 min chromatography, Ultimate XB-C18 3.0*50mm, 3μm, purity 98.49%.

[0656] LCMS R t = 2.480 minutes in 4 minute chromatography, Xtimate C18.3μm, 2.1*30mm, purity 98.102%, 542.05 [M+H] + MS ESI calculated for 543.05, found 542.4.

[0657] Example 62. 6-Chloro-N4-(5'-((cyclohexylamino)methyl)-2'-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)pyrimidine-4,5-diamine (Compound 149, Table 3) [ka]

[0658] Step 1: N-(3-bromo-4-fluorobenzyl)cyclohexanamine (Compound 3A) [ka] To a mixture of compound 2A (977 mg, 9.85 mmol, 1.13 mL, 1 equiv.) and compound 1A (2 g, 9.85 mmol, 1 equiv.) in DCM (20 mL) was added NaBH(OAc) (6.26 g, 29.56 mmol, 3 equiv.) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h to give a brown mixture. The mixture was extracted with DCM (100 mL * 3). The combined organic phase was washed with brine (100 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0-20% MeOH / DCM ether gradient at 40 mL / min). Compound 3A (3 g, 9.49 mmol, 96.33% yield) was obtained as a white solid.

[0659] 1 H NMR (DMSO-d6, 400 MHz) δ H =7.68(dd,J=2.0,6.8Hz,1H),7.40-7.35(m,1H),7.32-7.26(m,1H),2.40-2.33(m,1H),1.88(s, 3H),1.83(d,J=12.4Hz,2H),1.70-1.61(m,2H),1.53(dd,J=3.2,8.8Hz,1H),1.23-0.98(m,5H).

[0660] Step 2: N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)cyclohexanamine (Compound 4A) [ka]

[0661] To a mixture of compound 3A (1 g, 3.49 mmol, 1 equiv.) in dioxane (10 mL) under N2, AcOK (686 mg, 6.99 mmol, 2 equiv.), Pin2B2 (1.06 g, 4.19 mmol, 1.2 equiv.), and Pd(dppf)Cl2 (256 mg, 349.43 μmol, 0.1 equiv.) were added. The reaction mixture was stirred at 100 °C for 2 h. The mixture was extracted with DCM (80 mL * 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluting with a 0-20% MeOH / DCM ether gradient at 20 mL / min). Compound 4A (890 mg, 2.06 mmol, 58.85% yield) was obtained as a black oil.

[0662] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.72(s,1H),7.83(dd,J=2.4,5.6Hz,1H),7.75-7.69(m,1H),7.24(t,J=8.8Hz,1H),4.20-4.14(m,1H),3.47-3.41( m,,1H),2.10(d,J=10.4Hz,1H),1.81-1.74(m,1H),1.61(d,J=12.4Hz,1H),1.31(s,6H),1.15(s,2H),1.06(s,12H).

[0663] Step 3: (2S,6R)-4-(4-bromo-2-nitrophenyl)-1,2,6-trimethylpiperazine (compound 2) [ka]

[0664] To a solution of compound 1 (2 g, 9.09 mmol, 1.12 mL, 1 equiv.) in CH3CN (20 mL) was added (2R,6S)-1,2,6-trimethylpiperazine (1.17 g, 9.09 mmol, 1 equiv.) and DIEA (2.35 g, 18.18 mmol, 3.17 mL, 2 equiv.). The mixture was stirred at 30 °C for 12 h. The reaction mixture was diluted with water (100 mL), extracted with DCM (100 mL), and washed with brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The product was used directly in the next step without further purification. Compound 2 (2.9 g, 7.72 mmol, 84.95% yield) was obtained as an orange solid.

[0665] 1 H NMR (DMSO-d6, 400 MHz) δ H =7.97(d,J=2.4Hz,1H),7.64(dd,J=2.0,8.8Hz,1H),7.13(d,J=8.4Hz,1H),3.42-3.22 (m,2H),3.15(d,J=12.4Hz,2H),3.06-2.89(m,2H),2.66(s,3H),1.42(d,J=6.0Hz,6H).

[0666] Step 4: 5-Bromo-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)aniline (Compound 3) [ka]

[0667] To a solution of compound 2 (2.9 g, 8.84 mmol, 1 equiv.) in EtOAc (22.5 mL) and HO (7.5 mL) was added Fe (1.48 g, 26.51 mmol, 3 equiv.) and NH4Cl (2.36 g, 44.18 mmol, 5 equiv.). The mixture was stirred at 80 °C for 4 h. The mixture was filtered to remove insoluble material. The filtrate was concentrated in vacuo. The reaction mixture was diluted with aqueous NaHCO3 (100 mL), extracted with DCM (100 mL), and washed with brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® silica flash column, eluent: 0–10% methanol / dichloromethane at 30 mL / min). Compound 3 (2.32 g, 7.53 mmol, 85.23% yield) was obtained as an orange oil.

[0668] 1 H NMR (DMSO-d6, 400 MHz) δ H =6.82(d,J=2.4Hz,1H),6.76(d,J=8.4Hz,1H),6.64(dd,J=2.4,8.4Hz,1H),4.99(s ,2H),2.86(d,J=8.4Hz,2H),2.37-2.27(m,4H),2.20(s,3H),1.01(d,J=5.6Hz,6H).

[0669] Step 5: N-(5-bromo-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl)-6-chloro-5-nitropyrimidin-4-amine (Compound 4) [ka]

[0670] To a solution of compound 3 (2.32 g, 7.78 mmol, 1 equiv.) and 4,6-dichloro-5-nitro-pyrimidine (1.81 g, 9.34 mmol, 1.2 equiv.) in THF (24 mL) was added TEA (1.57 g, 15.56 mmol, 2.17 mL, 2 equiv.). The mixture was stirred at 25 °C for 3 h. The mixture was filtered to remove insoluble material. The filtrate was concentrated in vacuo. The reaction mixture was diluted with water (100 mL), extracted with DCM (100 mL), and washed with brine (100 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0–10% methanol / dichloromethane at 30 mL / min). Compound 4 (1.56 g, 1.23 mmol, 15.84% yield) was obtained as a brown solid.

[0671] 1 H NMR (DMSO-d6, 400 MHz) δ H =8.90(s,1H),8.66(s,1H),7.39(d,J=6.0Hz,2H),3.17(d,J=4.4Hz,3H),3.11-3.04(m,7H),1.30-1.25(m,6H).

[0672] Step 6: 6-chloro-N4-(5'-((cyclohexylamino)methyl)-2'-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)pyrimidine-4,5-diamine (Compound 5) [ka]

[0673] To a solution of compound 4 (1.56 g, 3.42 mmol, 1 equiv.) in EtOH (10 mL) and HO (1 mL) was added SnCl.2HO (1.54 g, 6.85 mmol, 2 equiv.). The mixture was stirred at 80 °C for 2 h. The mixture was adjusted to pH 9 with aqueous NaHCO. DCM was added to the mixture until a precipitate formed, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0–13% MeOH / DCM at 35 mL / min). Compound 5 (640 mg, 941.90 μmol, 58.60% yield) was obtained as a yellow oil.

[0674] 1 H NMR (DMSO-d 6, 400MHz)δ H =8.41-8.29(m,2H),7.99(s,1H),7.21(dd,J=2.4,8.4Hz,1H),7.14-7.07(m,1H),5.31(s,2H),3.20-3.15(m,1H),3.18 (d,J=2.8Hz,1H),2.80(d,J=10.8Hz,2H),2.49-2.42(m,2H),2.38(d,J=6.4Hz,2H),2.20(s,3H),0.99(d,J=6.0Hz,6H).

[0675] Step 7: 6-chloro-N4-(5'-((cyclohexylamino)methyl)-2'-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)pyrimidine-4,5-diamine (DDO-2213_030) [ka]

[0676] A mixture of compound 5 (200 mg, 469.76 μmol, 1 equiv.), compound 4A (157 mg, 469.76 μmol, 1 equiv.), Pd(dppf)Cl.CHCl (38 mg, 46.98 μmol, 0.1 equiv.), and CsCO (306 mg, 939.51 μmol, 2 equiv.) in dioxane (4 mL) and HO (0.8 mL) was degassed and purged with N three times, after which the mixture was stirred at 100 °C under a N atmosphere for 12 h. The reaction mixture was diluted with water (20 mL), extracted with DCM (50 mL), and washed with brine (20 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 150*30mm*5μm, mobile phase A: purified water (0.05% HCl); mobile phase B: acetonitrile; gradient: 10 to 40% B in 10 min). DDO-2213_030 (15.7 mg, 26.38 μmol, yield 5.62%, purity 98.89%, HCl) was obtained as a yellow solid.

[0677] 1 H NMR (DMSO-d6, 400 MHz) δ H =11.70-10.88(m,1H),9.49-9.16(m,2H),8.96-8.61(m,1H),8.23-7.99(m,1 H),7.90-7.79(m,2H),7.62(d,J=2.4Hz,1H),7.47-7.27(m,3H),4.18(s,2H), 3.49-3.23(m,3H),3.10(s,3H),2.79(d,J=4.8Hz,3H),2.20-2.05(m,2H),1. 85-1.70(m,2H),1.66-1.55(m,1H),1.36(d,J=6.4Hz,7H),1.31-1.13(m,5H).

[0678] HPLC:R t = 3.398 min in 8-min chromatography, Ultimate XB-C18 (3 × 50 mm, 3 μm), purity 98.89%.

[0679] LCMS R t= 1.883 min in 4 min chromatography, X Bridge Shield RP18, 5 μm, 2.1*50 mm, purity 97.55%, 551.29 [M+H] + MS ESI calculated for 552.29, found 552.4.

[0680] Example 63. 6-chloro-N4-(5-(2-(dimethylamino)pyrimidin-4-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidine-4,5-diamine (Compound 147, Table 3)

[0681] Step 1: 4-(5-amino-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-N,N-dimethylpyrimidin-2-amine (DDO-2213_028_1) [ka] DDO-2213_024_4 was synthesized as shown in Example 58. DIEA (1.03 g, 8.00 mmol, 1.39 mL, 8 equiv.) was added in one portion to a mixture of DDO-2213_024_4 (350 mg, 1.00 mmol, 1 equiv.) and N-methylmethanamine (408 mg, 5.00 mmol, 458.33 μL, 5 equiv., HCl) in CH3CN (10 mL). The mixture was heated to 80 °C and stirred for 12 h. The residue was concentrated under reduced pressure. The residue was purified by silica gel chromatography (column weight: 12 g, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane:methanol = 10:1). DDO-2213_028_1 (330 mg, 865.10 μmol, 86.47% yield) was obtained as a yellow solid.

[0682] 1 H NMR (DMSO-d6, 400 MHz) δ H=8.34(d,J=5.2Hz,1H),7.45(d,J=8.0Hz,1H),6.91(dd,J=2.0,5.2Hz,1H),6.79(d,J=12.8Hz,1H),4.87(s ,2H),3.62-3.53(m,2H),3.17(s,6H),3.09(d,J=7.2Hz,2H),2.67-2.58(m,2H),2.50(s,3H),1.28(s,6H).

[0683] Step 2: 4-(5-((6-chloro-5-nitropyrimidin-4-yl)amino)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-N,N-dimethylpyrimidin-2-amine (DDO-2213_028_2) [ka]

[0684] To a mixture of DDO-2213_028_1 (330 mg, 920.62 μmol, 1 equiv.) and 4,6-dichloro-5-nitro-pyrimidine (358 mg, 1.84 mmol, 2 equiv.) in THF (5 mL) was added TEA (279 mg, 2.76 mmol, 384.41 μL, 3 equiv.) in one portion. The mixture...

Claims

1. A compound having the structure of formula I or a pharmaceutically acceptable salt thereof, wherein formula I is 【Chemistry 1】 And in the formula, Y is either absent, -O-, -S-, -C(O)-, -CH₂O-, -(CO)O-, -O(CO)-, -NR₁₀-, -C(O)NR₁₁₁-, or -NR₁₂C(O)-, where R₁₀, R₁₁₁, and R₁₂C(O)-, each independently being hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or substituted or unsubstituted phenyl {where phenyl is substituted with one, two, or three of halogens, amino, cyano, hydroxyl, trifluoro, -C₁-C₄ alkyl, C₁-C₄ alkoxy, carboxyl, or imidazolyl}; R1 is hydrogen, hydroxyl, thiol, carboxyl, cyano, C1-C4 alkyl, substituted C1-C4 alkyl, substituted or unsubstituted phenyl {where the substituent is C1-C4 alkoxy}, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted nitrogen or oxygen-containing 3-7 membered heterocycle or substituted or unsubstituted 3-7 membered heterocycle containing both nitrogen and oxygen (where the substituent on the heterocycle may optionally be located on a heteroatom); unsaturated heterocycloalkyl containing nitrogen or oxygen or both, -NR13COR14, -OR17-, -C(O)O-R17, -O(CO)O-R17-C(O)NR15R16 or -NR15R16, where, R13 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, substituted or unsubstituted phenyl. R 14 is hydrogen, amino, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing or oxygen-containing 3-7 membered heterocycle (where substituents on the heterocycle may be located on heteroatoms), R15 and R16 are each independently a 3-7 membered heterocycle containing hydrogen, a C1-C4 alkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted nitrogen or oxygen, or both {wherein the heterocycle may be aryl, partially unsaturated or fully saturated, and substituents on the heterocycle may be located on heteroatoms}, Alternatively, R15 and R16 together form a 3- to 7-membered heterocycle containing nitrogen, oxygen, or nitrogen and oxygen or nitrogen and nitrogen or oxygen and oxygen, wherein the heterocycle may be optionally independently substituted with 1, 2, or 3 substituents which are halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, hydroxyl, thiol, carboxyl, cyano, trifluoromethyl, or imidazolyl, wherein the substituents on the heterocycle may be located on heteroatoms; R17 is a 3-7 membered heterocycle containing a C1-C4 alkyl, a C1-C4 haloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted nitrogen or oxygen, or both, where substituents on the heterocycle may be located on heteroatoms; R2 and R3 are independently hydrogen, halogen, methyl, methoxy, difluoromethoxy, or trifluoromethoxy; R4, R5, and R6 are each independently hydrogen, a C1-C6 alkyl, or a C3-C6 cycloalkyl; Each R7 and R8 is independently hydrogen, halogen, amino, cyano, hydroxy, thiol, nitro, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C3-C7 cycloalkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, hydroxy-(C1-C6)alkyl, amino-(C1-C6)alkyl, or -C(O)NR1A R1B, where R1A and R1B are independently hydrogen or C1-C6 alkyl; m is an integer between 0 and 5; n is an integer between 0 and 2; p is an integer between 0 and 3; A compound or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula I and the compound is selected from Table 1, Table 1 is Table 1 A compound or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the compound does not have the structure of DDO-2093.

4. The compound according to claim 1, wherein the compound does not have the structure of DDO-2213.

5. The aforementioned compound is given by formula: 【Chemistry 2】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the above.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

7. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for the treatment or prevention of acute leukemia.

8. The use according to claim 7, wherein the acute leukemia is acute leukemia involving MLL1 gene rearrangement.

9. A composition for use in the treatment or prevention of acute leukemia, comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

10. The composition according to claim 9, wherein the acute leukemia is an acute leukemia involving MLL1 gene rearrangement.

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