METTL3 inhibitor compounds, pharmaceutical compositions thereof and uses thereof

Abstract

The present invention provides the use of compounds represented by the following formula I, I', or I'', or tautomers, stereoisomers, or pharmaceutically acceptable salts of these compounds as METTL3 inhibitors. The compounds have excellent regulatory and inhibitory effects on METTL3 / METTL14 and AML-related cell lines. They are significantly superior to compounds disclosed in the prior art in terms of enzymatic activity and cellular activity (in the same assay, the enzymatic activity and cellular activity of the compounds of the present invention are significantly improved compared to similar compounds of the prior art). Therefore, the compounds provided by the present invention can be used to treat diseases and conditions associated with METTL3 / METTL14 methyltransferase activity. In addition, the compounds of the present invention can be prepared simply, and have good potential for future applications. TIFF2025530847000337.tif84170

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to a prior application filed with the State Intellectual Property Office of China on September 16, 2022, bearing patent application number 202211132234.2 and entitled "METTL3 inhibitor compounds, pharmaceutical compositions thereof and use thereof," and a prior application filed with the State Intellectual Property Office of China on February 20, 2023, bearing patent application number 202310138424.3 and entitled "METTL3 inhibitor compounds, preparation methods thereof and use thereof," the entire contents of which are incorporated herein by reference. [Technical Field]

[0002] The present invention belongs to the technical field of medicine, and particularly relates to METTL3 inhibitor compounds, pharmaceutical compositions and uses thereof. [Background technology]

[0003] N6-methyladenosine (m6A) is the most common and abundant covalent modification of messenger RNA (mRNA). Methyltransferases can modify specific sites on mRNA to synthesize m6A. Approximately 0.1%–0.5% of all mRNAs are m6A-modified. Cellular experimental data indicate that the m6A modification affects various aspects of mRNA biology, primarily mRNA expression, splicing, stability, localization, and translation. The m6A modification is tissue-specific, with significant differences in its occurrence in non-diseased and diseased tissues and cells, such as the brain, heart, and kidney. m6A-related proteins, such as FTO, ALKBH5, methyltransferase 3 (METTL3), and methyltransferase 14 (METTL14), are associated with major diseases, including solid organ cancers, leukemia, type 2 diabetes, neuropsychiatric behavioral disorders, and depression.

[0004] METTL3 is the primary enzyme catalyzing RNA m6A modification and exists as a heterotrimeric complex with METTL14 and Wilms' tumor-associated protein (WTAP). METTL3 is catalytically active and transfers one methyl group from the cofactor adenosylmethionine to the substrate RNA. METTL14 promotes substrate RNA binding, and WTAP localizes the complex to specific RNA sites. METTL3 has been reported to play an important role in many aspects of cancer development. Knockdown of METTL3 expression in lung cancer cell lines (A549, H1299, and H1792) and HeLa cells inhibits the growth, survival, and invasion of human lung cancer cells. Researchers have observed significantly increased METTL3 expression in human bladder cancer, and knockdown of the METTL3 gene significantly reduces bladder cancer cell proliferation, invasion, in vitro viability, and in vivo carcinogenicity.

[0005] METTL3 also plays an important role in regulating the myeloid differentiation of normal hematopoietic cells and leukemia cells in mammals. High expression of METTL3 can promote the proliferation and inhibit the differentiation of CD34+ hematopoietic stem cells from human umbilical cord blood. Knockdown of METTL3 promotes this differentiation and inhibits cell proliferation. In the absence of METTL3, downregulation of m6A levels on interferon-stimulated gene (ISG) mRNA leads to upregulation of the gene protein levels, inhibiting viral replication. Therefore, METTL3 inhibitors may provide a new therapeutic approach for a range of infectious and inflammatory diseases. m6A modification affects the division and differentiation of embryonic stem cells and various tissue progenitor / stem cells via NANOG, SOX2, NR5A2, and MYC.

[0006] Although METTL3 inhibitors have been reported in the relevant literature, the activity of these inhibitors needs to be further improved. Summary of the Invention

[0007] In order to solve the above technical problems, the present invention provides compounds represented by the following formula I, formula I', or formula I''; tautomers, stereoisomers, or pharmaceutically acceptable salts of these three compounds. TIFF2025530847000338.tif18170 (wherein A is selected from -NH-(Ci_12 alkyl)-C3_20 cycloalkyl, 3-20 membered heterocyclyl, -3-20 membered heterocyclyl-3-20 membered heterocyclyl, -5-20 membered heteroaryl-5-20 membered heteroaryl, -NH-(Ci_12 alkyl)-3-20 membered heterocyclyl, C3_20 cycloalkyl, or -N(Z)CO-5-20 membered heteroaryl, which are unsubstituted or optionally substituted by one, two or more Ra; X1, X2, X3 are the same or different and are independently selected from C, O, or N, with the proviso that X1, X2, and X3 are not simultaneously heteroatoms (i.e., not simultaneously N and / or O); X4 is selected from a -5-20 membered heteroaryl-5-20 membered heteroaryl group, a -5-20 membered heteroaryl-C6-20 aryl group, a -N(Z)CO-5-20 membered heteroaryl group, a -CON(Z)-5-20 membered heteroaryl group, a -5-20 membered heteroaryl-COC1-12 alkyl group, a -NH-(C1-12 alkyl)-C3-20 cycloalkyl group, a 3-20 membered heterocyclyl group, or a -COO-5-20 membered heteroaryl group, which are unsubstituted or optionally substituted with one, two or more Rb; R is selected from H or a C alkyl group; Ra is selected from a nitro group, an amino group, a halogen, —CHN(Ci_12 alkyl)2, —N(Ci_12 alkyl)2, —O—(Ci_12 alkyl-O)2-Ci_12 alkyl group, a 3-20 membered heterocyclyl group, a —Ci_12 alkyl substituted 3-20 membered heterocyclyl group, a —Se—Ci_12 alkyl group, a —S—Ci_12 alkyl group, a 5-20 membered heteroaryl group, a Ci_12 alkoxy group, or a Ci_12 alkyl group; Rb is selected from H, halogen, NO2, -CHO, OH, NH2, =O, -S-Ci-i2 alkyl group, -NH-Ci-i2 alkyl group, -N(Ci-i2 alkyl)2, a 3-20 membered heterocyclyl group, a Ci-i2 alkoxy group, -O-(Ci-i2 alkyl-O)2-Ci-i2 alkyl group, -S(O)2-Ci-i2 alkyl group, -Se-Ci-i2 alkyl group, -N(Ci-i2 alkyl-OH)2, -N(Ci-i2 alkyl-Cl)2, a Ci-i2 alkyl group, -NHC(O)Ci-i2 alkyl group, -N(Z)CO-5-20 membered heteroaryl group, -OC(O)Ci-i2 alkyl group, -N(CD3)2, a 5-20 membered heteroaryl group, unsubstituted or optionally substituted by one, two or more Rd; Z is selected from H or a C alkyl group; Rd is selected from halogen, cyano, C alkyl group, —S—C alkyl group, —NH—C alkyl group, and —N(C alkyl) TIFF2025530847000339.tif18170 (in formula I', R1 is -NH-(C1-12 alkyl)-bicyclo[1.1.1]pentane-(Ra)n, -NH-(C1-12 alkyl)-C6-20 aryl-(Ra)n, -NH-(C1-12 alkyl)-(Ra)n, -NH-(C1-12 alkyl)-C3-20 cycloalkyl-(R a)n, -NH-(Ci_12 alkyl)-3-20 membered heterocyclyl-(Ra)n, -3-20 membered heterocyclyl-(Ra)n, -NH-(Ci_12 alkyl)-5-20 membered heteroaryl-(Ra)n, -NH-(Ci_12 alkyl)-bicyclo[2.2.2]octane-(Ra)n, -NH-(Ci_12 alkyl)-cubane-(Ra)n; Ra is selected from H, OH, halogen, a haloC alkyl group, a C alkyl group, CN, or a C alkynyl group; n is the number of Ra substituents and is selected from 1, 2, 3, 4, or 5; In -NH-(C1-3 alkyl)-C3-12 cycloalkyl-(Ra)n, Ra is optionally substituted on the C3-12 cycloalkyl group or on the carbon atom at the bonding position between the C3-12 cycloalkyl group and the C1-3 alkyl group; R2 is selected from H, a C1-12 alkyl group, or CN; R3 is selected from -5-20 membered heteroaryl-Rb, -OC(O)-5-20 membered heteroaryl-Rb, or -NC(O)-5-20 membered heteroaryl-Rb; Rb is selected from a 5- to 20-membered heteroaryl-Rc, a 3- to 20-membered heterocyclyl group, or a halogen; m is 1, 2, or 3; Rc is selected from -3-20 membered heterocyclyl-Rd, -5-20 membered heteroaryl-Rd, and -O(Ci_i2 alkylO)m-Ci_i2 alkyl group; Rd is selected from H, deuterium, halogen, OH, CN, a haloC1-12 alkyl group, a C1-12 alkyl group, or ═O. TIFF2025530847000340.tif21170 (in Formula I″, R1 is —NH—(C1-12 alkyl)-bicyclo[1.1.1]pentane-(Ra)n, —NH—(C1-12 alkyl)-C6-20 aryl-(Ra)n, —NH—(C1-12 alkyl)-(Ra)n, —NH—(C1-12 alkyl)-C3-20 cycloalkyl-( -NH-(Ci_12 alkyl)-3-20 membered heterocyclyl-(Ra)n, -3-20 membered heterocyclyl-(Ra)n, -NH-(Ci_12 alkyl)-5-20 membered heteroaryl-(Ra)n, -NH-(Ci_12 alkyl)-bicyclo[2.2.2]octane-(Ra)n, -NH-(Ci_12 alkyl)-cubane-(Ra)n; Ra is selected from H, OH, halogen, a haloC alkyl group, a C alkyl group, CN, or a C alkynyl group; n is the number of Ra substituents and is selected from 1, 2, 3, 4, or 5; In -NH-(C1-3 alkyl)-C3-12 cycloalkyl-(Ra)n, Ra is optionally substituted on the C3-12 cycloalkyl group or on the carbon atom at the bonding position between the C3-12 cycloalkyl group and the C1-3 alkyl group; R2 is selected from H, a C1-12 alkyl group, or CN; R3 is selected from -OC(O)-5-12 membered heteroaryl-Rm, or -NC(O)-5-12 membered heteroaryl-Rm, where Rm is selected from -NH-(Ci_12 alkyl), -N(Ci_12 alkyl)2, or a 3-12 membered heterocyclyl group.

[0008] According to an embodiment of the present invention, the compound of formula I is It does not contain the specific compound TIFF2025530847000341.tif67170.

[0009] According to an embodiment of the present invention, the compound of formula I' is It is not the compound represented by TIFF2025530847000342.tif117170.

[0010] According to an embodiment of the present invention, in the compound of formula I, A is selected from: -NH-(Ci_12 alkyl)-C3_20 cycloalkyl group, a 3-20 membered heterocyclyl group, a -3-20 membered heterocyclyl-3-20 membered heterocyclyl group, a -5-20 membered heteroaryl-5-20 membered heteroaryl group, a -NH-(Ci_12 alkyl)-3-20 membered heterocyclyl group, a C3_20 cycloalkyl group, or a -N(Z)CO-5-20 membered heteroaryl group, which are unsubstituted or optionally substituted by one, two or more Ra; X1, X2, X3 are the same or different and are independently selected from C, O, or N, with the proviso that X1, X2, and X3 are not simultaneously heteroatoms (i.e., not simultaneously N and / or O); X4 is selected from a -5-20 membered heteroaryl-5-20 membered heteroaryl group, a -5-20 membered heteroaryl-C6-20 aryl group, a -N(Z)CO-5-20 membered heteroaryl group, a -CON(Z)-5-20 membered heteroaryl group, a -5-20 membered heteroaryl-COC1-12 alkyl group, a -NH-(C1-12 alkyl)-C3-20 cycloalkyl group, a 3-20 membered heterocyclyl group, or a -COO-5-20 membered heteroaryl group, which are unsubstituted or optionally substituted with one, two or more Rb; R is selected from H or a C alkyl group; Ra is selected from a nitro group, an amino group, a halogen, —CHN(Ci_12 alkyl)2, —N(Ci_12 alkyl)2, —O—(Ci_12 alkyl-O)2-Ci_12 alkyl group, a 3-20 membered heterocyclyl group, a —Ci_12 alkyl substituted 3-20 membered heterocyclyl group, a —Se—Ci_12 alkyl group, a —S—Ci_12 alkyl group, a 5-20 membered heteroaryl group, a Ci_12 alkoxy group, or a Ci_12 alkyl group; Rb is selected from H, halogen, NO2, -CHO, OH, NH2, =O, -S-Ci-i2 alkyl group, -NH-Ci-i2 alkyl group, -N(Ci-i2 alkyl)2, a 3-20 membered heterocyclyl group, a Ci-i2 alkoxy group, -O-(Ci-i2 alkyl-O)2-Ci-i2 alkyl group, -S(O)2-Ci-i2 alkyl group, -Se-Ci-i2 alkyl group, -N(Ci-i2 alkyl-OH)2, -N(Ci-i2 alkyl-Cl)2, a Ci-i2 alkyl group, -NHC(O)Ci-i2 alkyl group, -N(Z)CO-5-20 membered heteroaryl group, -OC(O)Ci-i2 alkyl group, -N(CD3)2, a 5-20 membered heteroaryl group, unsubstituted or optionally substituted by one, two or more Rd; Z is selected from H or a C alkyl group; Rd is selected from halogen, cyano, C alkyl group, —S—C alkyl group, —NH—C alkyl group, and —N(C alkyl); and A is selected from -NH-(Ci_i2 alkyl)-C3_20 cycloalkyl groups, X1 and X2 are N, X3 is C, and R is selected from H, then X4 is TIFF2025530847000343.tif39170 Or, when Ra is selected from halogen, A is selected from -NH-(C1-12 alkyl)-C3-20 cycloalkyl groups, X1 and X2 are N, X3 is C, and R is selected from H, X4 is Not TIFF2025530847000344.tif38170.

[0011] According to a preferred embodiment of the present invention, in formula I, A is selected from an —NH—(Ci_6 alkyl)-C3_12 cycloalkyl group, a 3-12 membered heterocyclyl group, a -3-12 membered heterocyclyl-3-12 membered heterocyclyl group, a -5-12 membered heteroaryl-5-12 membered heteroaryl group, a —NH—(Ci_6 alkyl)-3-12 membered heterocyclyl group, a C3_12 cycloalkyl group, or a —N(Z)CO-5-12 membered heteroaryl group, which are unsubstituted or optionally substituted by one, two or more Ra; X1, X2, X3 are the same or different and are independently selected from C, O or N, provided that X1, X2, X3 are not simultaneously heteroatoms; X4 is selected from a -5-12 membered heteroaryl-5-12 membered heteroaryl group, a -5-12 membered heteroaryl-C6-12 aryl group, a -N(Z)CO-5-12 membered heteroaryl group, a -CON(Z)-5-12 membered heteroaryl group, a -5-12 membered heteroaryl-COC1-6 alkyl group, a -NH-(C1-3 alkyl)-C3-12 cycloalkyl group, a 3-12 membered heterocyclyl group, or a -COO-5-12 membered heteroaryl group, which are unsubstituted or optionally substituted by one, two or more Rb; R is selected from H or a C alkyl group; Ra is selected from NO2, NH2, halogen, —CH2N(C1-3 alkyl)2, —N(C1-6 alkyl)2, —O—(C1-6 alkyl-O)2-C1-6 alkyl group, a 3-12 membered heterocyclyl group, a C1-6 alkyl substituted 3-12 membered heterocyclyl group, —Se—C1-6 alkyl group, —S—C1-6 alkyl group, a 5-12 membered heteroaryl group, a C1-6 alkoxy group, or a C1-6 alkyl group; Rb is selected from H, halogen, NO2, -CHO, OH, NH2, =O, -S-C1-6 alkyl group, -NH-C1-6 alkyl group, -N(C1-6 alkyl)2, a 3- to 12-membered heterocyclyl group, a C1-6 alkoxy group, -O-(C1-6 alkyl-O)2-C1-6 alkyl group, -S(O)2-C1-6 alkyl group, -Se-C1-6 alkyl group, -N(C1-6 alkyl-OH)2, -N(C1-6 alkyl-Cl)2, a C1-6 alkyl group, -NHC(O)C1-6 alkyl group, -N(Z)CO-5- to 12-membered heteroaryl group, -OC(O)C1-6 alkyl group, -N(CD3)2, a 5- to 12-membered heteroaryl group, unsubstituted or optionally substituted by one, two or more Rd; Z is selected from H or a C alkyl group; Rd is selected from halogen, CN, a C1-6 alkyl group, a -S-C1-6 alkyl group, a -NH-C1-6 alkyl group, and a -N(C1-6 alkyl)2 group.

[0012] According to a preferred embodiment of the present invention, in formula I, A is TIFF2025530847000345.tif75170X4 TIFF2025530847000346.tif238170

[0013] Y, Y1, and Y2 are the same or different and are each independently selected from H, NH2, CN, CHO, OH, ═O, —S—C1-6 alkyl group, I, NH2, —NH—C1-6 alkyl group, —N(C1-6 alkyl)2, a 3- to 6-membered heterocyclyl group, Cl, Br, a C1-6 alkoxy group, —O—(C1-6 alkyl-O)2—C1-6 alkyl group, —S(O)2—C1-6 alkyl group, —Se—C1-6 alkyl group, —N (Ci_6 alkyl-OH)2, -N(Ci_6 alkyl-Cl)2, a Ci_6 alkyl group, -NHC(O)Ci_6 alkyl group, -OC(O)Ci_6 alkyl group, -CHO, OH, -N(CD3)2, a 5- to 6-membered heteroaryl group, NO2, F, wherein the 3- to 6-membered heterocyclyl group or the 5- to 6-membered heteroaryl group is optionally substituted by one, two or three groups selected from F, Cl, Br and I; R1, R2 are the same or different and are independently selected from H, F, or a C1-6 alkyl group; Z are the same or different and are independently selected from H or a C1-6 alkyl group.

[0014] According to a preferred embodiment of the present invention, in formula I: TIFF2025530847000347.tif13170X1, X2, and X3 are the same or different and independently selected from C or N, with the proviso that X1, X2, and X3 are not simultaneously heteroatoms, and X4 is TIFF2025530847000348.tif34170 wherein Y1 and Y2 are the same or different and are independently selected from H, -S-C1-6 alkyl group, I, Cl, Br, NH2, -NH-C1-6 alkyl group, -N(C1-6 alkyl)2, a 3-6 membered heterocyclyl group, -Se-C1-6 alkyl group, C1-6 alkyl group, and a 3-6 membered heterocyclyl group, and R1 is selected from H, F, or a C1-6 alkyl group.

[0015] According to a preferred embodiment of the present invention, in formula I: TIFF2025530847000349.tif13170X1, X2, and X3 are the same or different and independently selected from C or N, provided that X1, X2, and X3 are not simultaneously heteroatoms, and X4 is TIFF2025530847000350.tif29170 Wherein Y is selected from Cl, Br, a C1-6 alkyl group, or a C1-6 alkoxy group.

[0016] According to a preferred embodiment of the present invention, in formula I: TIFF2025530847000351.tif13170X1, X2, and X3 are the same or different and independently selected from C or N, with the proviso that X1, X2, and X3 are not simultaneously heteroatoms; A is TIFF2025530847000352.tif34170 wherein Y1 and Y2 are the same or different and are independently selected from H, NH2, —NH—C1-6 alkyl group, —N(C1-6 alkyl)2, and C1-6 alkyl group; R1 is selected from H, F, or a C1-6 alkyl group; wherein Y is selected from H or a 3- to 6-membered heterocyclyl group; and Z is selected from H or a C1-6 alkyl group; Y is selected from a 3-6 membered heterocyclyl group and Z is selected from H or a C1-6 alkyl group.

[0017] According to a preferred embodiment of the present invention, in formula I: TIFF2025530847000353.tif13170X1, X2, and X3 are the same or different and independently selected from C or N, provided that X1, X2, and X3 are not simultaneously heteroatoms, and X4 is TIFF2025530847000354.tif34170Y, Y1, and Y2 are the same or different and are independently selected from H, a 3- to 6-membered heterocyclyl group, and a C1-6 alkyl-substituted 3- to 6-membered heterocyclyl group.

[0018] According to a preferred embodiment of the present invention, in formula I: TIFF2025530847000355.tif16170X1, X2, and X3 are the same or different and independently selected from C or N, with the proviso that X1, X2, and X3 are not simultaneously heteroatoms, and X4 is TIFF2025530847000356.tif34170 wherein Y1 and Y2 are the same or different and independently selected from H, I, -S-C1-6 alkyl group, -NH-C1-6 alkyl group, -N(C1-6 alkyl)2, -Se-C1-6 alkyl group, R1 is selected from H, F, or a C1-6 alkyl group, Y is selected from a 3- to 6-membered heterocyclyl group, and Z is selected from H or a C1-6 alkyl group.

[0019] According to a preferred embodiment of the present invention, in formula I: TIFF2025530847000357.tif17170X1, X2, and X3 are the same or different and are independently selected from C or N, provided that X1, X2, and X3 are not simultaneously heteroatoms; TIFF2025530847000358.tif34170 wherein Y1 and Y2 are the same or different and independently selected from H, a 3-6 membered heterocyclyl group, -NH-C1-6 alkyl group, -N(C1-6 alkyl)2, -Se-C1-6 alkyl group, and R1 is selected from H, F, or a C1-6 alkyl group.

[0020] According to a preferred embodiment of the present invention, in formula I: TIFF2025530847000359.tif17170X1, X2, and X3 are the same or different and independently selected from C or N, with the proviso that X1, X2, and X3 are not simultaneously heteroatoms, and X4 is TIFF2025530847000360.tif34170Y, Y1, and Y2 are the same or different and are independently selected from H, a 3- to 6-membered heterocyclyl group, and a C1-6 alkyl-substituted 3- to 6-membered heterocyclyl group.

[0021] According to a preferred embodiment of the present invention, in formula I: TIFF2025530847000361.tif17170X1, X2, and X3 are the same or different and are independently selected from C or N, provided that X1, X2, and X3 are not simultaneously heteroatoms; TIFF2025530847000362.tif34170Y, Y1, and Y2 are the same or different and independently selected from H, a 3-6 membered heterocyclyl group, a C1-6 alkyl-substituted 3-6 membered heterocyclyl group, -NH-C1-6 alkyl group, and -N(C1-6 alkyl)2, and Z is selected from H or a C1-6 alkyl group.

[0022] According to a preferred embodiment of the present invention, in formula I: TIFF2025530847000363.tif19170X1, X2, and X3 are the same or different and independently selected from C or N, with the proviso that X1, X2, and X3 are not simultaneously heteroatoms, and X4 is TIFF2025530847000364.tif34170 wherein Y1 and Y2 are the same or different and independently selected from H, I, NH2, -S-C1-6 alkyl group, -NH-C1-6 alkyl group, -N(C1-6 alkyl)2, -Se-C1-6 alkyl group, 3-6 membered heterocyclyl group, and R1 is selected from H, F, or C1-6 alkyl group.

[0023] According to a preferred embodiment of the present invention, in formula I: TIFF2025530847000365.tif19170X1, X2, and X3 are the same or different and are independently selected from C or N, with the proviso that X1, X2, and X3 are not simultaneously heteroatoms; A is TIFF2025530847000366.tif34170 wherein Y1 and Y2 are the same or different and independently selected from H, I, NH2, -S-C1-6 alkyl group, -NH-C1-6 alkyl group, -N(C1-6 alkyl)2, -Se-C1-6 alkyl group, 3-6 membered heterocyclyl group, and R1 is selected from H, F, or C1-6 alkyl group.

[0024] According to a preferred embodiment of the present invention, in formula I: TIFF2025530847000367.tif13170X1, X2, and X3 are the same or different and independently selected from C or N, with the proviso that X1, X2, and X3 are not simultaneously heteroatoms; A is TIFF2025530847000368.tif34170 wherein Y, Y1, Y2 are the same or different and are independently selected from H, a 3-6 membered heterocyclyl group, and Z is selected from H or a C1-6 alkyl group.

[0025] According to a preferred embodiment of the present invention, in formula I: TIFF2025530847000369.tif13170X1, X2, and X3 are the same or different and independently selected from C or N, with the proviso that X1, X2, and X3 are not simultaneously heteroatoms, and X4 is TIFF2025530847000370.tif34170 wherein Y, Y1, Y2 are the same or different and are independently selected from H, a 3- to 6-membered heterocyclyl group.

[0026] According to a preferred embodiment of the present invention, in formula I: TIFF2025530847000371.tif16170X1, X2, and X3 are the same or different and independently selected from C or N, provided that X1, X2, and X3 are not simultaneously heteroatoms, and X4 is TIFF2025530847000372.tif34170 wherein Y, Y1, and Y2 are the same or different and independently selected from H, a 3-6 membered heterocyclyl group, -NH-C1-6 alkyl group, and -N(C1-6 alkyl)2, wherein the 3-6 membered heterocyclyl group is optionally substituted by one, two, or three groups selected from F, Cl, Br, and I, and Z is selected from H or a C1-6 alkyl group.

[0027] According to a preferred embodiment of the present invention, in formula I: TIFF2025530847000373.tif17170X1, X2, and X3 are the same or different and are independently selected from C or N, with the proviso that X1, X2, and X3 are not simultaneously heteroatoms; A is TIFF2025530847000374.tif34170 wherein Y, Y1, and Y2 are the same or different and independently selected from H, a 3-6 membered heterocyclyl group, an -NH-C1-6 alkyl group, and an -N(C1-6 alkyl)2 group, wherein the 3-6 membered heterocyclyl group is optionally substituted by one, two, or three groups selected from F, Cl, Br, and I.

[0028] In one embodiment, the compound of formula I is TIFF2025530847000375.tif159170A is TIFF2025530847000376.tif18170Y1, Y2, Y3, and Y4 are the same or different and independently represent H, I, Br, Cl, F, NH2, a 3- to 6-membered heterocyclyl group, -Se-C1-6 alkyl group, -S-C1-6 alkyl group, -N(C1-6 alkyl)2, -NH-C1-6 alkyl group, -N(C1-3 alkyl-Cl)2, or a difluoro 3- to 6-membered heterocyclyl group. TIFF2025530847000377.tif13170Fluoro 3-6-membered heterocyclyl group TIFF2025530847000378.tif131705-6-membered heteroaryl group, C1-6 alkyl-substituted 3-6-membered heterocyclyl group TIFF2025530847000379.tif17170C1-6 alkyl group, or C1-6 alkoxy group.

[0029] In one embodiment, the 3- to 6-membered heterocyclyl group is TIFF2025530847000380.tif14170

[0030] In one example, a compound of formula I is TIFF2025530847000381.tif222170TIFF2025530847000382.tif233170TIFF2025530847000383.tif 237170TIFF2025530847000384.tif223170TIFF2025530847000385.tif252170TIFF20255308470003 Selected from 86.tif224170TIFF2025530847000387.tif220170TIFF2025530847000388.tif221170TIFF2025530847000389.tif224170TIFF2025530847000390.tif226170TIFF2025530847000391.tif40170

[0031] According to an embodiment of the invention, the pharmaceutically acceptable salt is an HCl or TFA salt.

[0032] In one example, a compound of formula I is The compound is selected from the TFA salt or the HCl salt of compound TIFF2025530847000392.tif113170.

[0033] According to an embodiment of the present invention, in formula I', R1 is selected from -NH-(Ci_3 alkyl)-bicyclo[1.1.1]pentane-(Ra), -NH-(Ci_3 alkyl)-C6-12 aryl-(Ra), -NH-(Ci_3 alkyl)-(Ra), -NH-(Ci_3 alkyl)-C3-12 cycloalkyl-(Ra), -NH-(Ci_3 alkyl)-3-12 membered heterocyclyl-(Ra), -3-12 membered heterocyclyl-(Ra), -NH-(Ci_3 alkyl)-5-12 membered heteroaryl-(Ra), -NH-(Ci_3 alkyl)-bicyclo[2.2.2]octane-(Ra), -NH-(Ci_3 alkyl)-cubane-(Ra), Ra is selected from H, OH, halogen, haloC1-3 alkyl group, C1-3 alkyl group, CN, or C2-6 alkynyl group; n is the number of Ra substituents and is selected from 1, 2, 3, 4, or 5; In -NH-(C1-3 alkyl)-C3-12 cycloalkyl-(Ra)n, Ra is optionally substituted on the C3-12 cycloalkyl group or on the carbon atom at the bonding position between the C3-12 cycloalkyl group and the C1-3 alkyl group; R2 is selected from H, a C1-3 alkyl group, or CN; R3 is selected from -5-12 membered heteroaryl-Rb, -OC(O)-5-12 membered heteroaryl-Rb, or -NC(O)-5-12 membered heteroaryl-Rb; Rb is selected from a 5- to 12-membered heteroaryl-Rc, a 3- to 12-membered heterocyclyl group, or a halogen; m is 1, 2, or 3; Rc is selected from -3-20 membered heterocyclyl-Rd, -5-12 membered heteroaryl-Rd, or -O(Ci_3 alkylO)m-Ci_3 alkyl group; Rd is selected from H, deuterium, halogen, OH, CN, a haloC1-3 alkyl group, a C1-3 alkyl group, or =0.

[0034] In one embodiment, in Formula I', R1 is TIFF2025530847000393.tif102170Rf and Rh are the same or different and are independently selected from H, F, Cl, a methyl group, a trifluoromethyl group, or CN; m and n are the same or different and are independently selected from 1, 2, 3, 4, or 5.

[0035] In one embodiment, in Formula I': TIFF2025530847000394.tif244170TIFF2025530847000395.tif191170

[0036] In one preferred embodiment, the compound of formula I' is TIFF2025530847000396.tif138170A is TIFF2025530847000397.tif17170Y1, Y2, Y3, Y4, Y5, Y6, and Y7 are the same or different and are independent of each other. TIFF2025530847000398.tif19170

[0037] In some embodiments of the present invention, the compound represented by I'-a is prepared by the following method: TIFF2025530847000399.tif45170Compound I-a1 is reacted with compound R1H to obtain a compound represented by formula I'-a; However, Y1 and R1 have the same definitions as above.

[0038] In some embodiments of the present invention, the compound represented by I'-b is prepared by the following method: TIFF2025530847000400.tif28170Compound I-b1 is reacted with compound R1H to obtain a compound represented by formula I'-b; However, Y2 and R1 have the same definitions as above.

[0039] In some embodiments of the present invention, compounds represented by I'-c are prepared by the following method: TIFF2025530847000401.tif37170Compound I-c1 is reacted with compound I-c2 to obtain a compound represented by formula I'-c; However, Y3 and R1 have the same definitions as above.

[0040] In some embodiments of the present invention, the compound represented by I'-d is prepared by the following method: TIFF2025530847000402.tif35170Compound Id-1 and compound Id-2 are reacted to obtain a compound represented by formula I'-d; However, Y4 and R1 have the same definitions as above.

[0041] In some embodiments of the present invention, the compound represented by I'-e is prepared by the following method: TIFF2025530847000403.tif37170Compound IE'-1 and compound IE'-2 are reacted to obtain a compound represented by formula I'-e; However, Y5 and R1 have the same definitions as above.

[0042] In some embodiments of the present invention, the compound represented by I'-f is prepared by the following method: TIFF2025530847000404.tif46170Compound If-1 is reacted with Lawesson's reagent to obtain a compound represented by formula I'-f; However, Y6 and R1 have the same definitions as above.

[0043] In some embodiments of the present invention, the compound represented by I'-h is prepared by the following method: TIFF2025530847000405.tif41170Compound Ih-1 is reacted with compound R1H to obtain a compound represented by formula I'-h; However, Y7 and R1 have the same definitions as above.

[0044] In one example, the compound of formula I' is Selected from TIFF2025530847000406.tif228170TIFF2025530847000407.tif240170TIFF2025530847000408.tif250170TIFF2025530847000409.tif225170TIFF2025530847000410.tif239170TIFF2025530847000411.tif244170

[0045] According to an embodiment of the present invention, the compound of formula I' is selected from the TFA or HCl salts of the following compounds: TIFF2025530847000412.tif211170TIFF2025530847000413.tif47170

[0046] According to an embodiment of the present invention, in formula I″, R1 is TIFF2025530847000414.tif17170R2 is selected from a C1-6 alkyl group, and R3 is selected from -OC(O)-5-6 membered heteroaryl-Rm, or -NC(O)-5-6 membered heteroaryl-Rm, and Rm is selected from -NH-(C1-3 alkyl), -N(C1-3 alkyl)2, or a 3-6 membered heterocyclyl group.

[0047] According to an embodiment of the present invention, in formula I″, R1 is TIFF2025530847000415.tif17170R2 is selected from a C1-3 alkyl group, such as a methyl group or an ethyl group, and R3 is TIFF2025530847000416.tif31170

[0048] According to an embodiment of the present invention, the compound of formula I″ is Selected from TIFF2025530847000417.tif234170.

[0049] According to an embodiment of the invention, the pharmaceutically acceptable salt is an HCl or TFA salt.

[0050] According to an embodiment of the present invention, as is clear from the above-mentioned compounds and the general formula structure of the compounds of the present application, the compounds of the present application further have a chiral center, and therefore the enantiomers of the above compounds also fall within the scope of protection of the present application. The present invention further provides the use of at least one of the compounds represented by the above formula I, formula I', or formula I" or a tautomer, stereoisomer, or pharmaceutically acceptable salt of the three compounds in the preparation of a METTL3 inhibitor.

[0051] According to an embodiment of the present invention, the disease, illness or condition prevented, alleviated and / or treated by the METTL3 inhibitor comprises a solid tumor, leukemia, an autoimmune disease, a nervous system disease, an inflammatory disease or an infectious disease.

[0052] By way of example, the disease, illness or condition prevented, alleviated and / or treated by the METTL3 inhibitor includes a hematological malignancy, AML leukemia, chronic myeloid leukemia, a solid tumor, or a viral disease.

[0053] The present invention further provides a pharmaceutical composition comprising a compound represented by Formula I, Formula I', or Formula I'' above, or a tautomer, stereoisomer, or pharmaceutically acceptable salt of said three compounds.

[0054] According to an embodiment of the present invention, the pharmaceutical composition is used for treating, alleviating and / or preventing a disease, illness or condition associated with abnormal function of METTL3.

[0055] According to embodiments of the present invention, the pharmaceutical composition may be administered by oral, rectal, topical, buccal, parenteral, intramuscular, intradermal, intravenous and transdermal routes of administration.

[0056] The present invention further provides methods for treating, alleviating and / or preventing abnormalities in the function of METTL3, comprising administering the above-described compounds to an individual in need thereof.

[0057] According to an embodiment of the present invention, the disease, illness or condition in which METTL3 function is abnormal includes solid tumor, leukemia, autoimmune disease, nervous system disease, inflammatory disease or infectious disease.

[0058] According to an embodiment of the invention, the disease, illness or condition comprises a hematological malignancy, AML leukemia, chronic myeloid leukemia, a solid tumor, or a viral disease.

[0059] The present invention further provides a method for treating, alleviating and / or preventing a disease, illness or condition comprising administering the above-described compound to an individual in need thereof, wherein the disease, illness or condition comprises a solid tumor, leukemia, an autoimmune disease, a nervous system disease, an inflammatory disease, or an infectious disease.

[0060] According to an embodiment of the invention, the disease, illness or condition comprises a hematological malignancy, AML leukemia, chronic myeloid leukemia, a solid tumor, or a viral disease.

[0061] Beneficial effects The compounds of the present invention have excellent regulatory and inhibitory effects on METTL3 / METTL14 and AML-related cell lines. They have significant advantages over compounds disclosed in the prior art (e.g., WO2022074379A1) in terms of enzymatic and cellular activity (in the same assay, the enzymatic and cellular activities of the compounds of the present invention are significantly improved compared to similar compounds in the prior art). Therefore, the compounds provided by the present invention can be used to treat diseases and conditions associated with METTL3 / METTL14 methyltransferase activity. Furthermore, the preparation method of the compounds of the present invention is simple, and they have good future applicability.

[0062] Define and explain terms Unless otherwise specified, the definitions of groups and terms described in the specification and claims of this application, including illustrative definitions, exemplary definitions, preferred definitions, definitions given in tables, definitions of specific compounds in the examples, etc., can be combined with each other in any way, and such combined group definitions and compound structures should fall within the scope described in the specification of this application.

[0063] In this specification, the terms "comprises," "has," and / or "contains" are open-ended terms, i.e., they include what is specified in the present invention, but do not exclude other contents.

[0064] In this specification, when one / one kind, two / two kinds, or more / more kinds are described, "more / more kinds" shall refer to a number greater than two, for example, an integer greater than or equal to three, such as 3, 4, 5, 6, 7, 8, 9, or 10 pieces / kinds.

[0065] In this specification, the term "optional" means that the characteristic may or may not be present, meaning that the event described below may occur but does not necessarily occur, and thus includes both the occurrence and non-occurrence of the event. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may be present but is not necessarily present, and thus includes heterocyclyl groups substituted with alkyl groups and heterocyclyl groups not substituted with alkyl groups.

[0066] In this application, the "*" in some substituents indicates the attachment site, for example, in Formula I, TIFF2025530847000418.tif12170, then Formula I The structure is represented by TIFF2025530847000419.tif14170. The same applies to other groups.

[0067] In this specification, the term "halogen" refers to fluorine, chlorine, bromine and / or iodine. Correspondingly, the term "halo" refers to fluoro, chloro, bromo and / or iodo. Within the scope of this specification, when an atom, residue, group or moiety is halogenated, the atom at the halogenated position may be mono-, di-, poly- or fully substituted by halogen atoms.

[0068] The term "C alkyl group" is understood to denote a linear or branched saturated monovalent hydrocarbon group having from 1 to 12 carbon atoms, preferably a C alkyl group. A "C alkyl group" is understood to denote a linear or branched saturated monovalent hydrocarbon group having preferably 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of the alkyl group include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, and 1,2-dimethylbutyl, and isomers thereof. In particular, the group has 1, 2, or 3 carbon atoms ("C alkyl group"), such as methyl, ethyl, n-propyl, or isopropyl.

[0069] The term "C2-12 alkynyl group" is understood to denote a linear or branched monovalent hydrocarbon group containing one or more triple bonds and having 2 to 12 carbon atoms, preferably a "C2-C10 alkynyl group". The term "C2-C10 alkynyl group" is understood to denote a linear or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, in particular 2 or 3 carbon atoms ("C2-C3-alkynyl group"). Examples of the alkynyl group include an ethynyl group, a prop-1-ynyl group, a prop-2-ynyl group, a but-1-ynyl group, a but-2-ynyl group, a but-3-ynyl group, a pent-1-ynyl group, a pent-2-ynyl group, a pent-3-ynyl group, a pent-4-ynyl group, a hex-1-ynyl group, a hex-2-ynyl group, a hex-3-ynyl group, a hex-4-ynyl group, a hex-5-ynyl group, a 1-methylprop-2-ynyl group, a 2-methylbut-3-ynyl group, a 1-methylbut-3-ynyl group, a 1-methylbut-2-ynyl group, a 3-methylbut-1-ynyl group, a 1-ethylprop-2-ynyl group, a 3-methylpent-4-ynyl group, a 2-methyl Examples of the alkynyl group include pent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, and 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl, or prop-2-ynyl. The term "C3-20 cycloalkyl group" is understood to denote a saturated monovalent monocyclic, bicyclic, or polycyclic hydrocarbon ring (also called fused hydrocarbon ring) having from 3 to 20 carbon atoms.Bicyclic or polycyclic cycloalkyl groups include fused-ring cycloalkyl groups, bridged cycloalkyl groups, and spirocyclic cycloalkyl groups, where the fused ring refers to a fused ring structure formed by two or more cyclic structures sharing two adjacent ring atoms (i.e., sharing one bond) with each other. The bridged ring refers to a fused ring structure formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other. The spirocyclic ring refers to a fused ring structure formed by two or more cyclic structures sharing one ring atom with each other. For example, the C3-20 cycloalkyl group may be a C3-8 monocyclic cycloalkyl group such as a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, or cyclooctyl group, or a C7-12 fused-ring cycloalkyl group such as a decalin ring. TIFF2025530847000420.tif19170C7-12 It may also be a bridged ring cycloalkyl group or a spirocycloalkyl group.

[0070] The term "3- to 20-membered heterocyclyl group" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5 heteroatoms independently selected from N, O, and S, and preferably includes a "3- to 12-membered heterocyclyl group." The term "3- to 12-membered heterocyclyl group" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3, heteroatoms selected from N, O, and S. The heterocyclyl group can be attached to the remainder of the molecule through any of the carbon atoms or nitrogen atoms (if present). In particular, the heterocyclyl group can include, but is not limited to, a 4-membered ring such as azetidinyl or oxetanyl, a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, or pyrrolinyl, a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl group can be benzo-fused. The heterocyclyl group can also be bicyclic, for example, but is not limited to, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The nitrogen atom-containing ring may be partially unsaturated, i.e., contain one or more double bonds, such as, but not limited to, a 2,5-dihydro-1H-pyrrolyl group, a 4H-[1,3,4]thiadiazinyl group, a 4,5-dihydrooxazolyl group, or a 4H-[1,4]thiazinyl group, or it may be benzo-fused, such as, but not limited to, a dihydroisoquinolinyl group. According to the present invention, the heterocyclyl group is non-aromatic. According to the present invention, the heterocyclyl group is not a spirocycloalkyl group, such as, but not limited to, a It could also be TIFF2025530847000421.tif18170.

[0071] The term "C6-20 aryl group" is understood to denote a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having from 6 to 20 carbon atoms, preferably a "C6-14 aryl group". The term "C aryl group" is understood to denote a monovalent aromatic or partially aromatic mono-, bi- or tricyclic hydrocarbon ring ("C aryl group"), preferably having 6, 7, 8, 9, 10, 11, 12 carbon atoms, in particular a ring having 6 carbon atoms ("C aryl group"), such as a phenyl or biphenyl group, or a ring having 9 carbon atoms ("C aryl group"), such as an indanyl or indenyl group, or a ring having 10 carbon atoms ("C aryl group"), such as a tetrahydronaphthyl, dihydronaphthyl or naphthyl group, or a ring having 13 carbon atoms ("C aryl group"), such as a fluorenyl group, or a ring having 14 carbon atoms ("C aryl group"), such as an anthryl group.

[0072] The term "5- to 20-membered heteroaryl group" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1-5 heteroatoms independently selected from N, O and S, such as "5- to 12-membered heteroaryl groups". The term "5- to 12-membered heteroaryl group" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1-5, preferably 1-3 heteroatoms independently selected from N, O and S, and furthermore which may in each case be benzo-fused. In particular, heteroaryl groups include thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzimidazole, benzotriazolyl, indazolyl, indolyl, and isoindolyl. groups, or a pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, etc. and benzo derivatives thereof, for example, quinoline group, quinazolinyl group, isoquinoline group, etc., or an azocinyl group, indolizinyl group, purinyl group, etc. and benzo derivatives thereof, or a cinnolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, naphthyridinyl group, pteridinyl group, carbazolyl group, acridinyl group, phenazinyl group, phenothiazinyl group, phenoxazinyl group, etc.

[0073] Unless otherwise specified, heterocyclyl, heteroaryl, or heteroarylene groups include all possible isomers thereof, for example, positional isomers thereof. Thus, as some illustrative, non-limiting examples, pyridyl or pyridylene groups include pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl, and thienyl or thienylidenyl groups include thien-2-yl, thienylidene-2-yl, thien-3-yl, and thienylidene-3-yl.

[0074] The above definition of the term "C1-12 alkyl group" is also applicable to other terms that contain "C1-12 alkyl group", such as "haloC1-12 alkyl group", "C1-12 alkoxy group", "halogenated N(C1-12 alkyl)2", etc.

[0075] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is safe and effective for use in mammals and possesses the desired biological activity.

[0076] Pharmaceutically acceptable salts include acid addition salts of the compounds of the present invention that have nitrogen atoms in the chain or ring and are sufficiently basic. Alternatively, basic nitrogen-containing groups can be converted to quaternary ammonium salts using reagents such as lower alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl groups); dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate); long-chain halides (e.g., chlorides, bromides, and iodides of decyl, lauryl, myristyl, and stearyl groups); and aralkyl halides (e.g., bromides of benzyl and phenethyl groups). Illustrative physiologically / pharmaceutically acceptable salts include, but are not limited to, hydrochlorides, sulfates, nitrates, hydrogen sulfates, hydrobromides, acetates, oxalates, citrates, methanesulfonates, formates, and meglumine salts.

[0077] Since the compound of the present invention may have multiple salt-forming sites, the physiologically / pharmaceutically acceptable salts include not only salts formed at one salt-forming site of the compound of the present invention but also salts formed at two, three or all of the salt-forming sites thereof. Therefore, in the physiologically / pharmaceutically acceptable salts, the molar ratio of the compound of formula (I) to the acid ion (anion) or base cation necessary for salt formation can vary within a wide range, for example, 4:1-1:4, e.g., 3:1, 2:1, 1:1, 1:2, 1:3, etc. DETAILED DESCRIPTION OF THE INVENTION

[0078] The technical solutions of the present invention will be described in more detail below in combination with specific examples. The following examples are only intended to exemplify and explain the present invention, and should not be construed as limiting the scope of protection of the present invention. Any technology realized based on the above content of the present invention is included in the scope of protection of the present invention.

[0079] Unless otherwise stated, all raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0080] In the following examples, a solution of HCl in 1,4-dioxane is used to remove the amino protecting group. Those skilled in the art will appreciate that free hydrochloric acid can form a salt with an electron-donating amino group in a compound during the removal of the protecting group, thereby obtaining a hydrochloride salt of the compound. Therefore, although some compounds in the following examples are not shown as hydrochlorides, those skilled in the art will recognize that they should have hydrochloride structures. The number of hydrochloride salts is determined by the number of salt-forming amino groups in the structure. Similarly, when other acids, such as TFA, are used to remove the protecting group, the corresponding salts are formed.

[0081] 1.1 Preparation of intermediates for compounds corresponding to formula I Intermediate I-1: Synthesis of tert-butyl ((2-(azidomethyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate TIFF2025530847000422.tif53170 Intermediate 1-a: 1-(6-chloropyridin-3-yl)-N-(cyclobutylmethyl)methanamine To a solution of 6-chloronicotinaldehyde (2.5 g, 16.779 mmol, 1.00 eq), 1-cyclobutylmethylamine hydrochloride (1.8 g, 20.082 mmol, 1.20 eq), and magnesium sulfate (1.06 g, 8.366 mmol, 0.50 eq) in 1,2-dichloroethane (30 mL) was added a solution of sodium borohydride (2.21 g, 55.494 mmol, 3.31 eq) in MeOH (2 mL) portionwise with stirring, and the resulting mixture was stirred at 40 °C under a nitrogen atmosphere for 4 h. The mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM (3 × 30 mL). The combined organic phase was washed with brine (3 × 10 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography eluting with DCM / EtOAc (1:7) to give intermediate 1-a (1.38 g, 37.78%) as a yellow oil. LC-MS (ESI): m / z 210.7 [M+H]+. Intermediate 1-b: tert-butyl((6-chloropyridin-3-yl)methyl)(cyclobutylmethyl)carbamate Intermediate 1-a (1.38 g, 6.340 mmol, 1.00 eq) and di-tert-butyl dicarbonate (1.51 g, 6.573 mmol, 1.04 eq) were dissolved in MeCN (15 mL) at 25° C., and the resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (7:1) to give intermediate 1-b (1.87 g, 93.19%) as a yellow oil.

[0082] LC-MS (ESI): m / z 310.8 [M+H]+. Intermediate 1-c: tert-butyl((6-aminopyridin-3-yl)methyl)(cyclobutylmethyl)carbamate Intermediate 1-b (1.87 g, 5.908 mmol, 1.00 eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (563.29 mg, 1.123 mmol, 0.19 eq), and tris(dibenzylideneacetone)dipalladium (284.74 mg, 0.295 mmol, 0.05 eq) were dissolved in THF (20 mL). The reaction mixture was deoxygenated with nitrogen for 30 min. LiHMDS (45.5 mL, 45.5 mmol, 7.70 eq) was added dropwise at 0 °C under nitrogen atmosphere, and the resulting mixture was stirred at 70 °C under nitrogen atmosphere for 2 h. The resulting mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (1:3) to give Intermediate 1-c (1.0 g, 53.56%) as a yellow solid.

[0083] LC-MS (ESI): m / z 291.4 [M+H]+. Intermediate 1-d: tert-butyl ((2-(chloromethyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Intermediate 1-c (1.0 g, 3.164 mmol, 1.00 eq) and 1,3-dichloroacetone (537.97 mg, 4.025 mmol, 1.27 eq) were dissolved in 1,2-dimethoxyethane (10 mL), and the resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1.5 h. The mixture was quenched with saturated sodium bicarbonate solution and extracted with EtOAc (3 × 30 mL). The combined organic phase was washed with brine (3 × 10 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (1:1) to give intermediate 1-d (420 mg, 32.39%) as a yellow solid.

[0084] LC-MS (ESI): m / z 363.8 [M+H]+. Intermediate I-1: tert-butyl ((2-(azidomethyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate To a solution of intermediate 1-d (1.12 g, 2.770 mmol, 1 eq) and sodium iodide (60 mg, 0.380 mmol, 0.14 eq) in DMF (10 mL, 129.218 mmol, 46.65 eq) was added sodium azide (500 mg, 7.307 mmol, 2.64 eq), and the resulting mixture was stirred at 25 °C under a nitrogen atmosphere for 2 h. The mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (3 × 30 mL). The combined organic phase was washed with brine (3 × 10 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (3:1) to give intermediate I-1 (900 mg, 79.20%) as a purple oil.

[0085] LC-MS (ESI): m / z 370.46 [M+H]+. Intermediate I-2: Synthesis of 4-ethynyl-6-nitro-1-(tetrahydro2H-pyran-2-yl)-1H-indazole TIFF2025530847000423.tif26170 Intermediate 2-a: 4-Bromo-6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole To a stirred solution of 4-bromo-6-nitro-1H-indazole (1 g, 3.925 mmol, 1.00 eq) in DCM (15 mL) at 25 °C, p-toluenesulfonic acid (78.26 mg, 0.432 mmol, 0.11 eq) and dihydropyran (1.10 mL, 12.442 mmol, 3.17 eq) were added dropwise. Under a nitrogen atmosphere, the resulting mixture was stirred at 25 °C for 2 h. The mixture was quenched with saturated sodium bicarbonate solution, and the combined organic layers were washed with DCM (2 × 30 mL) and dried over anhydrous sodium sulfate. Filtration and concentration gave intermediate 2-a (1 g, crude product) as a yellow oil.

[0086] LC-MS (ESI): m / z326.15 [M+H]+. Intermediate 2-b: 6-nitro-1-(tetrahydro2H-pyran-2-yl)-4-((trimethylsilyl)ethynyl)-1H-indazole To a stirred solution of intermediate 2-a (1 g, 2.809 mmol, 1.00 eq) and trimethylsilylacetylene (468.78 mg, 4.534 mmol, 2.00 eq) in DMF (10 mL) was added copper iodide (56.30 mg, 0.281 mmol, 0.10 eq) and bis(triphenylphosphine)palladium(II) chloride (207.51 mg, 0.281 mmol, 0.10 eq), and the resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 3 h. The reaction mixture was extracted with ethyl acetate (2 × 80 mL), and the combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (2:1) to give intermediate 2-b (600 mg, 59%) as a pale yellow solid.

[0087] LC-MS (ESI): m / z343.46 [M+H]+. Intermediate I-2: 4-ethynyl-6-nitro-1-(tetrahydro2H-pyran-2-yl)-1H-indazole To a stirred solution of intermediate 2-b (600 mg, 1.660 mmol, 1 eq) in methanol (8 mL) at 25° C., potassium carbonate (242 mg, 1.663 mmol, 1.00 eq) was added, and the resulting mixture was stirred at 25° C. under a nitrogen atmosphere for 3 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (5:1) to give intermediate I-2 (390 mg, 84.55%) as a pale yellow solid.

[0088] LC-MS (ESI): m / z271.28 [M+H]+. Intermediate I-3: Synthesis of 6-bromo-4-ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole TIFF2025530847000424.tif26170 Intermediate 3-a: 6-Bromo-4-iodo-1-(tetrahydro2H-pyran-2-yl)-1H-indazole Intermediate 3-a (4.52 g, 93.00%) was prepared as an off-white solid from 6-bromo-4-iodo-1H-indazole and 3,4-dihydro-2H-pyran by the method described for intermediate 2-a.

[0089] LC-MS (ESI): m / z407.05 [M+H]+. Intermediate 3-b: 6-bromo-1-(tetrahydro2H-pyran-2-yl)-4-((trimethylsilyl)ethynyl)-1H-indazole Intermediate 3-b (910 mg, 75.80%) was prepared as a brown starch syrup from Intermediate 3-a by the method described for Intermediate 2-b.

[0090] LC-MS (ESI): m / z 377.1 [M+H]+. Intermediate I-3: 6-Bromo-4-ethynyl-1-(tetrahydro2H-pyran-2-yl)-1H-indazole Intermediate I-3 (540 mg, 95.08%) was prepared as an off-white solid from Intermediate 3-b in the manner described for Intermediate I-3.

[0091] LC-MS (ESI): m / z 305.0 [M+H]+. Intermediate I-4: Synthesis of (2-(azidomethyl)imidazo[1,2-a]pyridin-6-yl)methanol TIFF2025530847000425.tif58170 Intermediate 4-a: 2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester Intermediate 4-a (70.0 g, 52.7%) was prepared as a yellow solid from methyl 6-aminonicotinate by the method described for intermediate 1-d.

[0092] 1H NMR (400 MHz, CDCl3): δ 8.89 - 8.91 (m, 1 H) 7.76 - 7.81 (m, 1 H) 7.71 - 7.74 (m, 1 H) 7.59 - 7.63 (m, 1 H) 4.77 - 4.82 (m, 2 H) 3.98 - 4.00 (m, 3H). Intermediate 4-b: (2-(chloromethyl)imidazo[1,2-a]pyridin-6-yl)methanol To a stirred solution of 2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (40.0 g, 178 mmol, 1.00 eq) in THF (1.20 L) was added DIBAL-H (1.00 M, 445 mL, 2.50 eq) at 0 °C under a nitrogen atmosphere, and the resulting mixture was stirred at 0 °C for 2 h. The mixture was quenched with methanol (2 L) and extracted with DCM (4 L). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography with petroleum ether / EtOAc (3:1) to give intermediate 4-b (10.0 g, 25.7%) as a yellow solid.

[0093] LC-MS (ESI): m / z196.63 [M+H]+. Intermediate 4-c: (2-(azidomethyl)imidazo[1,2-a]pyridin-6-yl)methanol Intermediate 4-c (540 mg, crude product) was prepared as a yellow solid from intermediate 4-b by the method described for intermediate I-1.

[0094] LC-MS (ESI): m / z203.21 [M+H]+. Intermediate 4-d: (2-((4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methanol To a stirred solution of intermediate 4-c (540 mg, 1.616 mmol, 1.00 eq) and (2-(azidomethyl)imidazo[1,2-a]pyridin-6-yl)methanol (439.47 mg, 2.076 mmol, 1.10 eq) in DMF (18 mL) and water (6 mL) was added copper(II) sulfate (63.26 mg, 0.396 mmol, 0.21 eq) and sodium ascorbate (435.16 mg, 2.076 mmol, 1.10 eq). The resulting mixture was stirred at 25 °C under a nitrogen atmosphere for 1 h. The reaction was diluted with saturated ammonium chloride (20 mL) and stirred for 35 min. The precipitate was collected by filtration, washed with water (2 × 50 mL), and concentrated to give intermediate 4-d (0.87 g, 99.05%) as an off-white solid.

[0095] LC-MS (ESI): m / z 423.3 [M+H]+. Intermediate I-4: 2-((4-(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carbaldehyde To a solution of intermediate 4-d (0.87 g, 1.601 mmol, 1.00 eq) in DCM (58 mL) was added Dess-Martin reagent (1.61 g, 3.602 mmol, 2.25 eq), and the resulting mixture was stirred at 25 °C for 30 min. The mixture was diluted with 1 M sodium hydroxide (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (1:1) to give intermediate I-4 (720 mg, 84.54%) as a yellow solid.

[0096] LC-MS (ESI): m / z 506.3 [M+H]+. Intermediate I-5: Synthesis of tert-butyl(cyclobutylmethyl)((2-(2-hydrazino-2-oxoethyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate TIFF2025530847000426.tif24170 Intermediate 5-a: 2-(6-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)acetate To a stirred solution of intermediate 1-c (400 mg, 1.371 mmol, 1 eq) in ethanol (4.44 mL) at 25° C., ethyl 4-chloro-3-oxobutanoate (237.58 mg, 1.371 mmol, 1.00 eq) was added, and the resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 3 hours. The mixture was concentrated, and the residue was purified by reverse-phase flash chromatography to give intermediate 5-a (210 mg, 31.56%) as a light brown starch syrup.

[0097] LC-MS (ESI): m / z 402.3 [M+H]+. Intermediate I-5: tert-butyl(cyclobutylmethyl)((2-(2-hydrazino-2-oxoethyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate To a stirred solution of intermediate 5-a (210 mg, 0.433 mmol, 1 eq) in ethanol (4 mL) at 25° C., hydrazine hydroxide (104.02 mg, 2.598 mmol, 6.00 eq) was added dropwise, and the resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 12 h. The mixture was concentrated, and the residue was purified by reverse-phase flash chromatography to give intermediate I-5 (170 mg, 94.94%) as a light brown starch syrup.

[0098] LC-MS (ESI): m / z 388.4 [M+H]+. Intermediate I-6: Synthesis of tert-butyl ((2-((4-(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Intermediate I-6 (3.70 g, 83.6%) was prepared as a yellow solid from Intermediate I-1 and Intermediate I-3 by the method described for Intermediate 4-d in TIFF2025530847000427.tif47170.

[0099] LC-MS (ESI): m / z 677.2 [M+H]+. Intermediate I-7: Synthesis of tert-butyl 6-(azidomethyl)-2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate TIFF2025530847000428.tif62170 Intermediate 7-a: tert-Butyl (cyclobutylmethyl) (prop-2-yn-1-yl)carbamate To a stirred solution of tert-butyl prop-2-yn-1-ylcarbamate (20.0 g, 129 mmol, 1.00 eq) in DMF (200 mL) was added sodium hydride (5.67 g, 141 mmol, 60% purity, 1.10 eq) in portions at 0 °C. Next, (bromomethyl)cyclobutane (21.1 g, 141 mmol, 15.9 mL, 1.10 eq) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 16 h. The mixture was poured into ice-water (1000 mL) and extracted with tert-butyl methyl ether (200 mL × 3). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=50 / 1 to 20 / 1) to give intermediate 7-a (17.0 g, 59.1%) as a yellow oil.

[0100] 1H NMR (400 MHz, chloroform-d): δ 3.94 (s, 2H), 3.29 (d, J = 7.3 Hz, 2H), 2.51 (td, J = 7.7, 15.3 Hz, 1H), 2.11 (t, J = 2.4 Hz, 1H), 1.97 - 1.91 (m, 2H), 1.86 - 1.75 (m, 2H), 1.72 - 1.61 (m, 2H), 1.40 (s, 9H). Intermediate 7-b: Methyl 4-iodo-3-(2,2,2-trifluoroacetamido)benzoate To a stirred solution of methyl 3-amino-4-iodobenzoate (25.0 g, 90.2 mmol, 1.00 eq) in DCM (250 mL) was added trifluoroacetic anhydride (56.8 g, 271 mmol, 37.6 mL, 3.00 eq) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at 25 °C under a nitrogen atmosphere for 16 h. The mixture was adjusted to pH = 8 with saturated sodium bicarbonate solution at 0 °C, then extracted with DCM (3 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give intermediate 7-b (30.0 g, 89.1%) as a white solid.

[0101] LC-MS (ESI): m / z 374.2 [M+H]+. Intermediate 7-c: 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-6-carboxylic acid methyl ester To a solution of intermediate 7-b (2.00 g, 5.36 mmol, 1.00 eq) and 7-atert-butyl(cyclobutylmethyl)(prop-2-yn-1-yl)carbamate (1.20 g, 5.36 mmol, 1.00 eq) in 1,4-dioxane (20 mL), triphenylphosphine (422 mg, 1.61 mmol, 0.30 eq), cuprous iodide (153 mg, 804 μmol, 0.15 eq), and tripotassium phosphate (2 eq) were added, and the mixture was stirred at 110° C. for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=50 / 1 to 20 / 1) to give intermediate 7-c (0.50 g, 25.0%) as a yellow solid.

[0102] LC-MS (ESI): m / z 373.3 [M+H]+. Intermediate 7-d: 1-(tert-butyl) 6-methyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1,6-dicarboxylate Intermediate 7-d (0.55 g, 86.7%) was prepared as a yellow solid from intermediate 7-c by the method described for intermediate 1-b.

[0103] LC-MS (ESI): m / z 473.3 [M+H]+. Intermediate 7-e: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-(hydroxymethyl)-1H-indole-1-carboxylate Intermediate 7-e (0.50 g, 77.3%) was prepared as a yellow oil from intermediate 7-d in the manner described for intermediate 4-b.

[0104] LC-MS (ESI): m / z 444.3 [M+H]+. Intermediate I-7: tert-butyl 6-(azidomethyl)-2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate To a stirred solution of intermediate 7-e (0.10 g, 180 μmol, 1.00 eq) in DMF (1.00 mL) at 20 °C, DBU (54.8 mg, 360 μmol, 54.2 μL, 2.00 eq) was added. The mixture was then cooled to 0 °C, and diphenylphosphoryl azide (DPPA) (99.0 mg, 360 μmol, 78.0 μL, 2.00 eq) was added at 0 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (2 mL x 3). The combined organic layers were washed with brine (5 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 5 / 1) to give intermediate I-7 (0.06 g, 71.0%) as a yellow oil.

[0105] LC-MS (ESI): m / z469.5 [M+H]+ . 1H NMR (400 MHz, chloroform-d): δ 8.03 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.09 (s, 1H), 6.22 (d, J = 15.8 Hz, 1H), 4.66 (d, J = 16.6 Hz, 2H), 4.35 (br s, 2H), 3.31 (d, J = 11.1 Hz, 2H), 2.51 (s, 1H), 2.00 - 1.92 (m, 2H), 1.83 - 1.75 (m, 2H), 1.72 - 1.66 (m, 2H), 1.62 (s, 9H), 1.51 - 1.41 (m, 9H). Intermediate I-8: Synthesis of tert-butyl 6-((4-(6-bromo-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-formyl-1H-indole-1-carboxylate TIFF2025530847000429.tif67170 Intermediate 8-a: 1-(tert-butyl) 2-methyl 6-bromo-1H-indole-1,2-dicarboxylate Intermediate 8-a (6.40 g, 91.8%) was prepared as a colorless oil from methyl 6-bromo-1H-indole-2-carboxylate by the method described for intermediate 1-b.

[0106] 1H NMR (400 MHz, chloroform-d): δ 8.23 ​​(d, J = 0.6 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.32 - 7.27 (m, 1H), 6.96 (s, 1H), 3.95 - 3.66 (m, 3H), 1.54 (s, 9H). Intermediate 8-b: 6-(hydroxymethyl)-1H-indole-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester To a solution of intermediate 8-a (5.00 g, 14.1 mmol, 1 eq) in 1,4-dioxane (50 mL) was added (tributylstannyl)methanol (9.07 g, 28.2 mmol, 2 eq) and tetrakis(triphenylphosphine)palladium (1.63 g, 1.41 mmol, 0.1 eq) under a nitrogen atmosphere. The mixture was stirred at 100° C. for 16 h under a nitrogen atmosphere. The mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1 to 0 / 1) to give intermediate 8-b (3.60 g, 83.5%) as a colorless oil.

[0107] 1H NMR (400 MHz, DMSO-d6): δ 8.02 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.38 - 7.14 (m, 2H), 4.76 - 4.55 (m, 2H), 3.95 - 3.75 (m, 3H), 1.70 - 1.45 (m, 9H). Intermediate 8-c: 1-(tert-butyl) 2-methyl 6-(((methylsulfonyl)oxy)methyl)-1H-indole-1,2-dicarboxylate To a stirred solution of 1-(tert-butyl) 2-methyl 6-(hydroxymethyl)-1H-indole-1,2-dicarboxylate (3.60 g, 11.8 mmol, 1.00 eq) and triethylamine (5.97 g, 59.0 mmol, 8.21 mL, 5.00 eq) in DCM (36 mL) was added methanesulfonyl chloride (3.21 g, 28.0 mmol, 2.17 mL, 2.38 eq) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 25 °C under a nitrogen atmosphere for 3 h. The mixture was concentrated, and the residue was diluted with ice water (30 mL) and extracted with DCM (40.0 mL x 2). The combined organic layers were washed with brine (30 mL) and dried over anhydrous sodium sulfate. Filtration and concentration afforded intermediate 8-c (4.50 g, crude product) as a yellow solid.

[0108] LC-MS (ESI): m / z 383.4 [M+H]+. Intermediate 8-d: 6-(azidomethyl)-1H-indole-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester To a stirred solution of intermediate 8-c (4.50 g, 11.7 mmol, 1 eq) in DMF (45 mL) at 25 °C, sodium azide (1.53 g, 23.5 mmol, 2 eq) was added, and the mixture was stirred at 25 °C for 16 h. The mixture was diluted with saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (50 mL × 3). The organic layer was washed with brine (30 mL) and dried over anhydrous sodium sulfate. Filtration and concentration gave intermediate 8-d (6.70 g, crude product) as a yellow oil.

[0109] 1H NMR (400 MHz, DMSO-d6): δ 8.02 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.29 (s, 1H), 4.64 - 4.48 (m, 2H), 3.88 (s, 3H), 1.57 (s, 9H). Intermediate 8-e: 1-(tert-butyl) 2-methyl 6-((4-(6-bromo-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1,2-dicarboxylate Intermediate 8-e (1.50 g, crude product) was prepared as a yellow oil from Intermediate 8-d and Intermediate I-3 by the method described for Intermediate 4-d.

[0110] 1H NMR (400 MHz, DMSO-d6): δ 9.04 (s, 1H), 8.64 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.82 (d, J = 1.4 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 1.3, 8.1 Hz, 1H), 7.29 (s, 1H), 5.92 (dd, J= 2.1, 9.6 Hz, 1H), 5.86 (s, 2H), 3.85 (s, 3H), 3.82 - 3.74 (m, 1H), 2.47 - 2.29 (m, 2H), 2.04 (d, J = 4.1 Hz, 1H), 1.96 (d, J = 2.8 Hz, 1H), 1.82 - 1.67 (m, 1H), 1.58 (d, J= 3.8 Hz, 2H), 1.51 (s, 9H). Intermediate 8-f: tert-butyl 6-((4-(6-bromo-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-(hydroxymethyl)-1H-indole-1-carboxylate Intermediate 8-f (1.10 g, 76.7%) was prepared as a white solid from intermediate 8-e in the manner described for intermediate 4-b.

[0111] LC-MS (ESI): m / z 607.5 [M+H]+. Intermediate I-8: tert-butyl 6-((4-(6-bromo-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-formyl-1H-indole-1-carboxylate Intermediate I-8 (0.700 g, 63.9%) was prepared as a white solid from intermediate 8-f in the manner described for intermediate I-4.

[0112] LC-MS (ESI): m / z605.48 [M+H]+. Intermediate I-9: Synthesis of tert-butyl ((2-((4-(6-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)carbamate TIFF2025530847000430.tif55170 Intermediate 9-a: (2-((4-(6-nitro-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methanol Intermediate 9-a (1.10 g, crude product) was prepared as a white solid from intermediate 4-c in the manner described for intermediate 4-d.

[0113] LC-MS (ESI): m / z 390.4 [M+H]+. Intermediate 9-b: 2-((4-(6-nitro-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carbaldehyde Intermediate 9-b (0.90 g, crude product) was prepared as a yellow oil from intermediate 9-a by the method described for intermediate I-4.

[0114] LC-MS (ESI): m / z 472.5 [M+H]+. Intermediate 9-c: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((2-((4-(6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Intermediate 9-c (650 mg, 54, 7%) was prepared as a yellow solid from intermediate 9-b and (3-fluorobicyclo[1.1.1]pentan-1-yl)methanamine in the manner described for intermediate E6-1.

[0115] LC-MS (ESI): m / z 572.2 [M+H]+. Intermediate 9-d: tert-butyl((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)((2-((4-(6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate 9-d (200 mg, 30.9%) was prepared as a yellow solid from intermediate 9-c by the method described for intermediate 1-b.

[0116] LC-MS (ESI): m / z 672.4 [M+H]+. Intermediate I-9: tert-butyl ((2-((4-(6-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)carbamate Intermediate I-9 (220 mg, crude) was prepared as a yellow solid from intermediate 9-d in the manner described for intermediate E3-2.

[0117] LC-MS (ESI): m / z 642.5 [M+H]+. Intermediate I-10: Synthesis of tert-butyl ((2-(aminomethyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate TIFF2025530847000431.tif33170 Intermediate I-10: tert-butyl ((2-(aminomethyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate At 20° C., triphenylphosphine (850 mg, 3.24 mmol, 3.00 eq) and water (195 mg, 10.8 mmol, 195 μL, 10 eq) were added to a solution of tert-butyl ((2-(azidomethyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate (400 mg, 1.08 mmol, 1.00 eq) in THF (8.00 mL), and the mixture was stirred at 20° C. for 16 h. The resulting mixture was concentrated, and the residue was purified by preparative TLC (petroleum ether / EtOAc=1 / 3) to give intermediate I-10 (290 mg, 78.0%) as a yellow oil.

[0118] LC-MS (ESI): m / z 345.3 [M+H]+. 1H NMR (400 MHz, chloroform-d): δ 7.83 - 8.02 (m, 1 H) 7.42 - 7.54 (m, 2 H) 7.01 - 7.14 (m, 1 H) 4.31 - 4.44 (m, 2 H) 3.99 - 4.09 (m, 2 H) 3.14 - 3.38 (m, 2 H) 2.44 - 2.60 (m, 1 H) 1.97 - 2.03 (m, 2 H) 1.80 - 1.89 (m, 2 H) 1.63 - 1.74 (m, 2 H) 1.44 - 1.55 (m, 9 H). 1.2 Preparation and Activity Testing of Compounds Corresponding to Formula I

[0119] Example 1: Synthesis of E-1: 1-cyclobutyl-N-((2-((4-(6-(methylthio)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000432.tif63170E1-1: 1-(2-((4-(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine To a stirred solution of intermediate I-4 (324 mg, 0.609 mmol, 1.00 eq) in DCM (10 mL) at 25 °C under a nitrogen atmosphere, 1-cyclobutylmethylamine (109.15 mg, 1.218 mmol, 2.00 eq) was added. The resulting mixture was stirred at 50 °C for 10 min. After cooling to room temperature, sodium triacetoxyborohydride (407.52 mg, 1.827 mmol, 3.00 eq) was added, and the resulting mixture was stirred at 50 °C for 3 h under a nitrogen atmosphere. The reaction was quenched with saturated sodium bicarbonate solution (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography eluting with DCM / MeOH (5:1) to give intermediate E1-1 (250 mg, 69.58%) as a yellow solid.

[0120] LC-MS: [M+H]+= 575.4. E1-2: 1-Cyclobutyl-N-((2-((4-(6-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine To a solution of intermediate E1-1 (150 mg, 0.254 mmol, 1 eq) and (methylsulfanyl)sodium (56.24 mg, 0.762 mmol, 3.00 eq) in DMF (7.5 mL) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35.60 mg, 0.058 mmol, 0.23 eq) and tris(dibenzylideneacetone)dipalladium (56.34 mg, 0.058 mmol, 0.23 eq) while stirring at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 180 °C under a nitrogen atmosphere for 1 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (1:1) to give intermediate E1-2 (120 mg, 68.67%) as a light brown solid.

[0121] LC-MS: [M+H]+= 543.6. E-1: 1-Cyclobutyl-N-((2-((4-(6-(methylthio)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine To a stirred solution of intermediate E1-2 (120 mg, 0.175 mmol, 1 eq) in methanol (6 mL) at 25° C. under a nitrogen atmosphere, a solution of hydrochloric acid in 1,4-dioxane (1.20 mL, 4.8 mmol, 27 eq, 4 M) was added. The resulting mixture was stirred at 25° C. under a nitrogen atmosphere for 2 hours. The mixture was concentrated, and the residue was purified by preparative HPLC to give compound E-1 (50.9 mg, 56.39%) as a yellow solid.

[0122] LC-MS: [M+H]+= 459.2. 1H NMR (300 MHz, DMSO-d6): 9.78 (br s, 2H), 9.20-9.10 (m, 2H), 8.62 (s, 1H), 8.53 (s, 1H), 8.26 (d, J = 9.3 Hz, 1H), 8.03 (d, J = 9.3 Hz, 1H), 7.52 (s, 1H), 7.31 (s, 1H), 6.11 (s, 2H), 4.31-4.21 (m, 2H), 2.98-2.88 (m, 2H), 2.78-2.68 (m, 1H), 2.58 (s, 3H), 2.15-2.00 (m, 2H), 1.91-1.73 (m, 4H).

[0123] Example 2: Synthesis of E-2: 1-cyclobutyl-N-((2-((4-(6-iodo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000433.tif26170E2-1: tert-Butyl(cyclobutylmethyl)((2-((4-(6-iodo-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate To a stirred solution of intermediate E3-2 (200 mg, 0.309 mmol, 1 eq) in AcOH (4.00 mL) under an argon atmosphere at 0° C., sulfuric acid (220 μL, 6.393 mmol, 20.69 eq) and sodium nitrite (35 mg, 0.482 mmol, 1.56 eq) were added. After stirring at 0° C. for 1 h under an argon atmosphere at 0° C., the resulting mixture was added with iodomethane (1 mL, 17.168 mmol, 55.57 eq) and subsequently stirred at 0° C. for 2 h. The solution was adjusted to pH = 8-9 with saturated aqueous sodium bicarbonate, the mixture was diluted with water (70 mL) and extracted with ethyl acetate (3 × 30 mL), the combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative TLC with petroleum ether / EtOAc (1:4) to give intermediate E2-1 (310 mg, 87.06%) as a red oil.

[0124] LC-MS: [M+H]+= 722.6. E-2: 1-Cyclobutyl-N-((2-((4-(6-iodo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-2 (9.5 mg, 19.73%) was prepared as a light brown solid from intermediate E2-1 by the method described for compound E-1.

[0125] LC-MS: [M+H]+= 538.30. 1H NMR (300 MHz, DMSO-d6): δ 13.29 (s, 1H), 8.95 (s, 1H), 8.59 (s, 1H), 8.43 (s, 1H), 7.98 (s, 1H), 7.94-7.88 (m, 2H), 7.46 (d, J = 9.3 Hz, 1H), 7.26 (d, J = 9.3 Hz, 1H), 5.78 (s, 2H), 3.66 (s, 2H), 2.55-2.30 (m, 3H), 2.05-1.89 (m, 2H), 1.88-1.69 (m, 2H), 1.67-1.59 (m, 2H), 1.29-1.18 (m, 1H).

[0126] Example 3: Synthesis of E-3: 4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-amine TIFF2025530847000434.tif81170

[0127] E3-1: tert-Butyl(cyclobutylmethyl)((2-((4-(6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E3-1 (670 mg, 88.51%) was prepared as a yellow solid from intermediate I-2 in the manner described for intermediate 4-d.

[0128] LC-MS: [M+H]+= 641.7. E3-2: tert-butyl ((2-((4-(6-amino-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Intermediate E3-1 (200 mg, 0.285 mmol, 1 eq), ammonium chloride (83.35 mg, 1.480 mmol, 5.19 eq), and Fe (69.81 mg, 1.188 mmol, 4.16 eq) were added to ethanol (2 mL) and water (1 mL) at 25 °C, and the mixture was reacted at 80 °C under a nitrogen atmosphere for 1 h. The mixture was concentrated, and the residue was dissolved in EtOAc (20 mL), diluted with EtOAc (30 mL), washed with brine (3 × 10 mL), and dried over anhydrous sodium sulfate. Filtration and concentration gave intermediate E3-2 (120 mg, crude product) as a yellow solid.

[0129] LC-MS: [M+H]+= 611.8. E-3: 4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-amine To a solution of intermediate E3-2 (120 mg, 0.128 mmol, 1 eq) in DCM (2.5 mL) stirred at 25° C., a solution of HCl in 1,4-dioxane (3 mL, 12 mmol, 4 M) was added dropwise, and the resulting mixture was reacted at 25° C. under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated, and the residue was purified by preparative HPLC to give compound E-3 (41.8 mg, 52.06%) as a white solid.

[0130] LC-MS: [M+H]+= 427.20. 1H NMR (300 MHz, DMSO-d6): δ 12.41 (s, 1H), 8.67 (s, 1H), 8.42 (s, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.46 (d, J = 9.3 Hz, 1H), 7.25 (d, J = 9.3, 1H), 7.06 (s, 1H), 6.51 (s, 1H), 5.76 (s, 2H), 5.31 (s, 2H), 3.65 (s, 2H), 2.55-2.18 (m, 3H), 205-1.50 (m, 6H).

[0131] Example 4: Synthesis of E-4: 4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-methyl-1H-indazol-6-amine TIFF2025530847000435.tif24170

[0132] E4-1: tert-Butyl (cyclobutylmethyl) ((2-((4-(6-(methylamino)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate To a solution of intermediate E3-2 (50 mg, 0.071 mmol, 1 eq) and sodium methoxide (44.13 mg, 0.777 mmol, 10.95 eq) in MeOH (2 mL) was added POM (12.27 mg, 0.123 mmol, 1.73 eq) at 25 °C, and the resulting mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. Sodium borohydride (6.18 mg, 0.155 mmol, 2.19 eq) was then added portionwise at 0 °C under a nitrogen atmosphere, and the resulting mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 5 mL) and dried over anhydrous sodium sulfate. Filtration and concentration afforded intermediate E4-1 (50 mg, 98.32%) as a white solid.

[0133] LC-MS: [M+H]+ = 625.8. E-4: 4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-methyl-1H-indazol-6-amine Compound E-4 (11.4 mg, 36.50%) was prepared as a light brown solid from intermediate E4-1 by the method described for compound E-3.

[0134] LC-MS: [M+H]+= 442.30. 1H NMR (300 MHz, DMSO-d6): δ 12.50 (s, 1H), 8.71 (s, 1H), 8.42 (s, 1H), 8.21 (s, 1H), 7.95 (s, 1H), 7.46 (d, J = 9.3 Hz, 1H), 7.25 (dd, J = 9.3 Hz, 1H), 7.08 (s, 1H), 6.30 (s, 1H), 6.02-5.92 (m, 1H), 5.76 (s, 2H), 3.65 (s, 2H), 2.78-2.70 (m, 3H), 2.55-2.39 (m, 3H), 2.05-1.55 (m, 6H).

[0135] Example 5: Synthesis of E-5: 4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethyl-1H-indazol-6-amine TIFF2025530847000436.tif28170

[0136] E5-1: tert-butyl(cyclobutylmethyl)((2-((4-(6-(dimethylamino)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate To a stirred solution of intermediate E3-2 (150 mg, 0.232 mmol, 1 eq) in DCM (5 mL) at 25 °C, formaldehyde (35.66 mg, 0.476 mmol, 2.05 eq) was added and the mixture was stirred at 25 °C under a nitrogen atmosphere for 30 min. Sodium triacetoxyborohydride (19.47 mg, 0.295 mmol, 1.27 eq) was then added portionwise, and the resulting mixture was stirred at 25 °C under a nitrogen atmosphere for 2 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with EtOAc / MeOH (10:1) to give intermediate E5-1 (130 mg, 70%) as a white solid.

[0137] LC-MS: [M+H]+= 639.8. E-5: 4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethyl-1H-indazol-6-amine Compound E-5 (18.0 mg, 34.11%) was prepared as a white solid from intermediate E5-1 by the method described for compound E-1.

[0138] LC-MS: [M+H]+= 456.20. 1H NMR (300 MHz, DMSO-d6): δ 12.60 (s, 1H), 8.85 (s, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 7.96 (s, 1H), 7.46 (d, J = 9.3 Hz, 1H), 7.30-7.20 (m, 2H), 6.54 (s, 1H), 5.77 (s, 2H), 3.64 (s, 2H), 3.00 (s, 6H), 2.55-2.20 (m, 3H), 2.04-1.55 (m, 6H).

[0139] Example 6: Synthesis of E-6: 1-(2-((4-(6-(aziridin-1-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine TIFF2025530847000437.tif55170

[0140] E6-1: tert-butyl ((2-((4-(6-((2-chloroethyl)amino)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Intermediate E3-2 (0.50 g, 817 μmol, 1.00 eq), AcOH (226 mg, 81 μmol, 1.00 eq), 2-chloroacetic acid (192 mg, 981 μmol, 158 μL, 1.20 eq), and sodium cyanoborohydride (128 mg, 2.04 mmol, 2.50 eq) were dissolved in MeOH (5.00 mL) at 25 °C under a nitrogen atmosphere, and the resulting mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (5.00 mL) and extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with brine (3.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc (1:10)) to give Intermediate E6-1 (0.420 g, 76.2%) as a yellow solid.

[0141] LC-MS: [M+H]+= 674.5. E6-2: N-(2-chloroethyl)-4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-amine Intermediate E6-2 (0.05 g, crude product) was prepared as a yellow oil from intermediate E6-1 in the manner described for compound E-1.

[0142] LC-MS: [M+H]+= 490.4. E-6: 1-(2-((4-(6-(aziridin-1-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine At 0° C., sodium hydride (20.4 mg, 510 μmol, 60% purity, 5.00 eq) was added to a solution of intermediate E6-2 (0.05 g, 102 μmol, 1.00 eq) in DMF (1.00 mL), and the resulting mixture was stirred at 25° C. for 2 hours. The mixture was quenched with water at 0° C. and concentrated. The residue was purified by preparative HPLC to give compound E-6 (12.5 mg, 26.2%) as a white solid.

[0143] LC-MS: [M+H]+= 454.2. 1H NMR (400 MHz, DMSO-d6): δ 12.90 (s, 1H), 8.86 (s, 1H), 8.43 (s, 2H), 7.97 (s, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.39 (d, J = 1.7 Hz, 1H), 7.28 - 7.24 (m, 1H), 6.94 (s, 1H), 5.77 (s, 2H), 3.65 (s, 2H), 2.39 (t, J = 7.3, 15.0 Hz, 2H), 2.15 (s, 4H), 1.97 (d, J = 7.6 Hz, 3H), 1.86 - 1.73 (m, 2H), 1.67 - 1.59 (m, 2H).

[0144] Example 7: Synthesis of E-7: 1-(2-((5-(6-chloro-1H-indazol-4-yl)-1,3,4-thiadiazol-2-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine TIFF2025530847000438.tif51170

[0145] E7-1: 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carboxylic acid methyl ester Intermediate E7-1 (1.52 g, 83.19%) was prepared as a pale yellow solid from 6-chloro-1H-indazole-4-carboxylic acid methyl ester in the manner described for intermediate 2-a.

[0146] LC-MS: [M+H]+= 295.1. E7-2: 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carboxylic acid To a solution of intermediate E7-1 (1.52 g, 3.752 mmol, 1 eq) in THF (15 mL) was added lithium hydroxide (507.19 mg, 11.481 mmol, 3.06 eq) and water (15 mL) at 25 °C, and the resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 3 h. The pH was adjusted to 3 with HCl (3N) solution, and the mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-TLC (petroleum ether / EtOAc = 1:1) to give intermediate E7-2 (1.0 g, 94%) as an off-white solid.

[0147] LC-MS: [M+H]+= 281.1. E7-3: tert-butyl ((2-(2-(2-(6-chloro-1-(tetrahydro2H-pyran-2-yl)-1H-indazole-4-carbonyl)hydrazino)-2-oxoethyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate To a stirred solution of intermediate E7-2 (128.56 mg, 0.436 mmol, 1.20 eq) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (217.67 mg, 0.544 mmol, 1.50 eq) in DMF (6 mL) was added tert-butyl(cyclobutylmethyl)((2-(2-hydrazino-2-oxoethyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate (150 mg, 0.363 mmol, 1 eq) and triethylamine (115.86 mg, 1.089 mmol, 3.00 eq) at 25 °C under a nitrogen atmosphere for 16 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (5:1) to give intermediate E7-3 (140 mg, 46.83%) as a brown starch syrup.

[0148] LC-MS: [M+H]+= 650.4. E7-4: tert-butyl ((2-((5-(6-chloro-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1,3,4-thiadiazol-2-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Lawesson's reagent (73.58 mg, 0.173 mmol, 1.50 eq) was added to a solution of intermediate E7-3 (95 mg, 0.115 mmol, 1 eq) in toluene (2 mL) at 25° C., and the resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 5 h. The mixture was concentrated, and the residue was purified by reverse-phase chromatography to give intermediate E7-4 (45 mg, 49.71%) as a light brown solid.

[0149] LC-MS: [M+H]+= 648.6 E-7: 1-(2-((5-(6-chloro-1H-indazol-4-yl)-1,3,4-thiadiazol-2-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine Compound E-7 (7.5 mg, 38.78%) was prepared as a pale yellow solid from intermediate E7-4 by the method described for compound E-1.

[0150] LC-MS: [M+H]+ = 464.1. 1H NMR (400 MHz, Kai-d4): 9.03 (s, 1H), 8.63 (s, 1H), 8.39 (s, 1H), 8.13 (d, J= 9.2 Hz, 1H), 8.00 (d, J = 9.3 Hz, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 4.99 (s, 2H), 4.42 (s, 2H), 3.22-3.16 (m, 2H), 2.81-2.71 (m, 1H), 2.21-2.11 (m, 2H), 1.98-1.85 (m, 4H).

[0151] Example 8: Synthesis of E-8: 1-(2-((5-(6-bromo-1H-indazol-4-yl)-1,3,4-thiadiazol-2-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine TIFF2025530847000439.tif47170

[0152] E8-1: 6-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carboxylic acid methyl ester Intermediate E8-1 (1.5 g, 72%) was prepared as a white solid from 6-bromo-1H-indazole-4-carboxylic acid methyl ester in the manner described for intermediate 2-a.

[0153] LC-MS: [M+H]+= 339.2. E8-2: 6-Bromo-1-(tetrahydro2H-pyran-2-yl)-1H-indazole-4-carboxylic acid Intermediate E8-2 (1.25 g, 96%) was prepared as a white solid from intermediate E8-1 in the manner described for intermediate E7-2.

[0154] LC-MS: [M+H]+= 325.2. E8-3: tert-butyl ((2-(2-(2-(6-bromo-1-(tetrahydro2H-pyran-2-yl)-1H-indazole-4-carbonyl)hydrazino)-2-oxoethyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Intermediate E8-3 (170 mg, 33.22%) was prepared as a pale yellow solid from intermediate E8-2 in the manner described for intermediate E7-3.

[0155] LC-MS: [M+H]+= 694.5. E8-4: tert-butyl ((2-((5-(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1,3,4-thiadiazol-2-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Intermediate E8-4 (50 mg, 44.19%) was prepared as a light brown starch syrup from intermediate E8-3 by the method described for intermediate E7-4.

[0156] LC-MS: [M+H]+= 692.4. E-8: 1-(2-((5-(6-bromo-1H-indazol-4-yl)-1,3,4-thiadiazol-2-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine Compound E-8 (19.0 mg, 51.53%) was prepared as an off-white solid from intermediate E8-4 in the manner described for compound E-1.

[0157] LC-MS: [M+H]+= 508.1. 1H NMR (300 MHz, DMSO-d6) 9.77 (s, 1H), 9.13 (s, 1H), 8.60-8.49 (m, 2H), 8.27 (d, J = 9.4 Hz, 1H), 8.10-8.01 (m, 2H), 7.82 (s, 1H), 5.02 (s, 2H), 4.27 (s, 2H), 3.01-2.90 (m, 2H), 2.2.80-2.68 (m, 1H), 2.10-1.95 (m, 2H), 1.96-1.75 (m, 4H).

[0158] Example 9: Synthesis of E-9: 1-cyclobutyl-N-((2-((5-(6-methoxy-1H-indazol-4-yl)-1,3,4-thiadiazol-2-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000440.tif52170

[0159] E9-1: 4-bromo-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole Intermediate E9-1 (740 mg, 44.21%) was prepared as a yellow solid from 4-bromo-6-methoxy-1H-indazole in the manner described for intermediate 2-a.

[0160] LC-MS: [M+H]+ = 311.2. E9-2: 6-Methoxy-1-(tetrahydro2H-pyran-2-yl)-1H-indazole-4-carboxylic acid To a solution of intermediate E9-1 (620 mg, 1.955 mmol, 1 eq) in THF (10 mL) was added n-butyllithium (0.86 mL, 2.151 mmol, 1.1 eq) dropwise at −78°C under a nitrogen atmosphere, and the mixture was stirred at −78°C under a nitrogen atmosphere for 30 min. Dry carbon dioxide was then introduced within 10 min, and the resulting mixture was stirred at −78°C for 30 min and then at 25°C under a nitrogen atmosphere for 16 h. The mixture was concentrated, and ether was added to precipitate the residue, yielding intermediate E9-2 (220 mg, 35%) as an off-white solid.

[0161] LC-MS: [M+H]+= 277.2. E9-3: tert-Butyl (cyclobutylmethyl) ((2-(2-(2-(6-methoxy-1-(tetrahydro2H-pyran-2-yl)-1H-indazole-4-carbonyl)hydrazino)-2-oxoethyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E9-3 (140 mg, 72.76%) was prepared as a pale yellow starch syrup from intermediate E9-2 by the method described for intermediate E7-3.

[0162] LC-MS: [M+H]+= 646.4. E9-4: tert-butyl (2-((5-(6-methoxy-1H-indazol-4-yl)-1,3,4-thiadiazol-2-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E9-4 (70 mg, 61%) was prepared from intermediate E9-3 by the method described for intermediate E7-4.

[0163] LC-MS: [M+H]+= 560.4. E-9: 1-Cyclobutyl-N-((2-((5-(6-methoxy-1H-indazol-4-yl)-1,3,4-thiadiazol-2-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-9 (12.7 mg, 35.38%) was prepared as a pale yellow solid from intermediate E9-4 by the method described for compound E-1.

[0164] LC-MS: [M+H]+= 460.1. 1H NMR (300 MHz, Kou-d4) δ 9.08 (s, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 8.18 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 9.1 Hz, 1H), 7.37 (s, 1H), 7.19 (s, 1H), 4.97 (s, 2H), 4.43 (s, 2H), 3.95 (s, 3H), 3.25-3.15 (m, 2H), 2.90-2.70 (m, 1H), 2.30-2.10 (m, 2H), 2.09-1.91 (m, 4H).

[0165] Example 10: Synthesis of E-10: 1-cyclobutyl-N-((2-((4-(6-(hexyloxy)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine hydrochloride TIFF2025530847000441.tif74170

[0166] E10-1: tert-butyl(cyclobutylmethyl)((2-((4-(6-hydroxy-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate To a stirred solution of intermediate E1-1 (500 mg, 740 μmol, 1.00 eq) in water (1.00 mL) and dioxane (5.00 mL) at 25° C., potassium hydroxide (166 mg, 2.96 mmol, 4.00 eq), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (31.4 mg, 74.0 μmol, 0.10 eq), and tris(dibenzylideneacetone)dipalladium (33.9 mg, 37.0 μmol, 0.05 eq) were added, and the resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 16 h. The mixture was diluted with water (20 mL) and extracted with tert-butyl methyl ether (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC with petroleum ether / EtOAc (0:1) to give intermediate E10-1 (40 mg, 88.2%) as a red oil.

[0167] LC-MS: [M+H]+= 613.5. E10-2: tert-Butyl (cyclobutylmethyl) ((2-((4-(6-(hexyloxy)-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl) imidazo[1,2-a]pyridin-6-yl)methyl)carbamate To a solution of intermediate E10-1 (100 mg, 163 μmol, 1 eq) and 1-bromohexane (40.4 mg, 245 μmol, 34.2 μL, 1.5 eq) in DMF (2 mL) were added potassium iodide (2.71 mg, 16.3 μmol, 0.1 eq) and potassium carbonate (45.1 mg, 326 μmol, 2 eq), and the resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 16 h. The mixture was quenched with water (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate E10-2 (100 mg, crude product) as a white solid.

[0168] LC-MS: [M+H]+= 697.5. E-10: 1-Cyclobutyl-N-((2-((4-(6-(hexyloxy)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine hydrochloride Compound E-10 (34.0 mg, 45.8%) was prepared as a white solid from intermediate E10-2 by the method described for compound E-1.

[0169] LC-MS: [M+H]+= 549.2. 1H NMR (400 MHz, DMSO-d6): δ 9.56 (brs, 2 H) 9.03 (s, 2 H) 8.51 (s, 1 H) 8.45 (s, 1 H) 8.04 - 8.14 (m, 1 H) 7.96 (d, J = 9.29 Hz, 1 H) 7.25 (d, J = 1.83 Hz, 1 H) 6.92 (d, J = 0.73 Hz, 1 H) 6.03 (s, 2 H) 4.23 (t, J = 4.77 Hz, 2 H) 4.05 (t, J = 6.42 Hz, 2 H) 2.89 - 2.99 (m, 2 H) 2.64 - 2.74 (m, 1 H) 1.98 - 2.10 (m, 2 H) 1.70 - 1.84 (m, 6 H) 1.40 - 1.50 (m, 2 H) 1.28 - 1.35 (m, 4 H) 0.84 - 0.91 (m, 3 H)

[0170] Example 11: Synthesis of E-11: 1-cyclobutyl-N-((2-((4-(6-(2-(2-methoxyethoxy)ethoxy)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000442.tif74170

[0171] E11-1: 1-Cyclobutyl-N-((2-((4-(6-(hexyloxy)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine hydrochloride Intermediate E11-1 (100 mg, crude) was prepared as a white solid from intermediate E10-1 in the manner described for intermediate E10-2.

[0172] LC-MS: [M+H]+= 715.6. E-11: 1-Cyclobutyl-N-((2-((4-(6-(2-(2-methoxyethoxy)ethoxy)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-11 (37.4 mg, 49.8%) was prepared as a yellow solid from intermediate E11-1 by the method described for compound E-1.

[0173] LC-MS: [M+H]+= 531.2. 1H NMR (400 MHz, Kou-d4): δ 9.02 (s, 1 H) 8.75 (s, 1 H) 8.56 (s, 1 H) 8.48 (s, 1 H) 8.12 (d, J = 9.41 Hz, 1 H) 7.99 (d, J = 9.29 Hz, 1 H) 7.36 (d, J = 1.96 Hz, 1 H) 7.03 (s, 1 H) 6.11 (s, 2 H) 4.40 (s, 2 H) 4.22 - 4.28 (m, 2 H) 3.87 - 3.94 (m, 2 H) 3.69 - 3.75 (m, 2H) 3.55 - 3.60 (m, 2 H) 3.36 (s, 3 H) 3.18 (d, J = 7.46 Hz, 2 H) 2.74 (d, J = 15.19, 7.50 Hz, 1 H) 2.15 - 2.25 (m, 2 H) 1.85 - 2.03 (m, 4 H)

[0174] Example 12: Synthesis of E-12: N-(1-(6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)ethyl)-5-(dimethylamino)nicotinamide TIFF2025530847000443.tif113170

[0175] E12-1: tert-Butyl (cyclobutylmethyl) ((2-(hydroxymethyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate To a solution of 1-d (2.00 g, 5.50 mmol, 1.00 eq) in DMSO (20.0 mL) and water (20.0 mL), sodium bicarbonate (1.39 g, 16.5 mmol, 641 μL, 3.00 eq) was added, and the resulting mixture was stirred at 120 °C for 1 h. The reaction mixture was cooled to 20 °C, diluted with water (100 mL), and extracted with DCM (30.0 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:methanol = 50 / 1 to 10 / 1) to obtain E12-1 (1.20 g, 63.2%) as a yellow solid.

[0176] LC-MS: [M+H]+= 346.2. E12-2: tert-Butyl(cyclobutylmethyl)((2-formylimidazo[1,2-a]pyridin-6-yl)methyl)carbamate E12-2 (940 mg, 78.8%) was prepared as a yellow solid from E12-1 by the method described for E54-2.

[0177] 1H NMR: (400 MHz, CDCl3): δ 10.14 (s, 1H), 8.11 (s, 1H), 8.00 (d, J= 1.3 Hz, 1H), 7.64 (d, J = 9.4 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 4.40 (s, 2H), 3.26 (br s, 2H), 2.61-2.43 (m, 1H), 2.03-1.94 (m, 2H), 1.91-1.81 (m, 2H), 1.75-1.67 (m, 2H), 1.49 (s, 9H). E12-3: tert-Butyl(cyclobutylmethyl)((2-(1-hydroxyethyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Methylmagnesium bromide (3M, 1.82 mL, 2.00 eq) was added dropwise to a solution of E12-2 in THF (20.0 mL) at -60 °C under a nitrogen atmosphere, and the resulting mixture was stirred at 20 °C for 15 h. The mixture was quenched with saturated ammonium chloride solution (5.00 mL) at 0 °C, diluted with water (20.0 mL), and extracted with DCM (10.0 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 50 / 1 to 10 / 1) to give E12-3 (0.75 g, 76.2%) as a yellow solid.

[0178] LC-MS: [M+H]+= 360.2. E12-4: tert-butyl((2-acetylimidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate E12-4 (200 mg, crude product) was prepared as a brown solid from E12-3 by the method described for E54-2.

[0179] LC-MS: [M+H]+= 358.2. E12-5: tert-butyl(2-(1-aminoethyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate To a solution of E12-4 (0.20 g, 560 μmol, 1.00 eq) in MeOH (6.00 mL) was added NHOAc (431 mg, 5.60 mmol, 10.0 eq), and the mixture was stirred at 30 °C for 0.5 h. NaBHCN (70.3 mg, 1.12 mmol, 2.00 eq) was then added, and the mixture was stirred at 30 °C for 15.5 h. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate (5.00 mL × 3). The organic phase was washed with brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give E12-5 (0.20 g, crude product) as a yellow solid.

[0180] LC-MS: [M+H]+= 359.2. E12-6: tert-Butyl (cyclobutylmethyl) ((2-(1-(5-(dimethylamino)nicotinamido)ethyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate E12-6 (30 mg, 42.5%) was prepared as a yellow solid from E12-5 by the method described for E36-2.

[0181] LC-MS: [M+H]+= 507. E-12: N-(1-(6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)ethyl)-5-(dimethylamino)nicotinamide hydrochloride E-12 (11.0 mg, 40.8%) was prepared as a yellow solid from E12-6 by the method described for E-1.

[0182] LC-MS: [M+H]+= 407.2. 1H NMR (400 MHz, DMSO-d6): δ 9.75 (d, J = 7.4 Hz, 1H), 9.53 (br s, 2H), 8.99 (s, 1H), 8.53 (s, 1H), 8.45 (s, 1H), 8.31 (d, J= 2.9 Hz, 1H), 8.12 (d, J = 9.5 Hz, 1H), 8.07 (br s, 1H), 7.99 (d, J = 9.3 Hz, 1H), 5.48 (t, J = 7.0 Hz, 1H), 4.26 (t, J = 5.0 Hz, 2H), 3.10 (s, 6H), 2.98-2.93 (m, 2H), 2.73-2.67 (m, 1H), 2.54 (s, 1H), 2.08-2.00 (m, 2H), 1.88-1.76 (m, 4H), 1.70 (d, J = 7.0 Hz, 3H).

[0183] Example 13: Synthesis of E-13: 1-cyclobutyl-N-((2-((4-(6-(methylsulfonyl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000444.tif28170

[0184] E13-1: 1-Cyclobutyl-N-((2-((4-(6-(methylsulfonyl)-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Intermediate E1-2 (100 mg, 0.097 mmol, 1 eq) and m-CPBA (53 mg, 0.291 mmol, 3 eq) were dissolved in DCM (2 mL) and stirred at 25 °C under a nitrogen atmosphere for 1 h. The mixture was diluted with water (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (8:1) to give intermediate E13-1 (45 mg, 10%) as a yellow solid.

[0185] LC-MS: [M+H]+= 575.35. E-13: 1-Cyclobutyl-N-((2-((4-(6-(methylsulfonyl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-13 (3.7 mg, 69%) was prepared as a white solid from intermediate E13-1 by the method described for compound E-1.

[0186] LC-MS: [M+H] += 491.2. 1H NMR (400 MHz, Kou-d4): δ9.15-8.95 (m, 2H), 8.75 (s, 1H), 8.54 (s, 1H), 8.22-8.10 (m, 2H), 8.05-7.95 (m, 1H), 6.18 (s, 2H), 4.43 (s, 2H), 3.30-3.10 (m, 5H), 2.82-2.72 (m, 1H), 2.23-2.15 (m, 2H), 2.06-1.85 (m, 5H), 1.30 (s, 1H).

[0187] Example 14: Synthesis of E-14: 1-cyclobutyl-N-((2-((4-(6-(methylsilanyl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000445.tif58170

[0188] E14-1: tert-butyl (2-((4-(6-selenocyano-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate To a stirred solution of intermediate E3-2 (0.200 g, 327 μmol, 1.00 eq) in ACN (2.00 mL) at 25 °C, potassium selenocyanate (47.1 mg, 326.94 μmol, 1.00 eq) and tert-butyl nitrite (40.5 mg, 392 μmol, 46.7 μL, 1.20 eq) were added dropwise, and the mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate E14-1 (0.220 g, crude product) as a yellow solid.

[0189] LC-MS: [M+H] += 702.2. E14-2: tert-Butyl (cyclobutylmethyl) ((2-((4-(6-(methylsilanyl)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl) imidazo[1,2-a]pyridin-6-yl)methyl)carbamate To a solution of intermediate E14-1 (0.220 g, 314 μmol, 1.00 eq) and CHCl (89.1 mg, 628 μmol, 39.9 eq) in MeOH (2.2 mL) was added NaBH (23.8 mg, 628 μmol, 2.00 eq) at 0 °C, and the mixture was stirred at 25 °C for 2 h. The mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with petroleum ether (2 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography eluting with EtOAc / petroleum ether (1:0) to give intermediate E14-2 (0.0700 g, 32.3%) as a white solid.

[0190] LC-MS: [M+H] += 691.2. E-14: 1-Cyclobutyl-N-((2-((4-(6-(methylsilanyl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-14 (0.016 g, 35.0%) was prepared as a white solid from intermediate E14-2 by the method described for compound E-1.

[0191] LC-MS: [M+H] += 507.1. 1H NMR (400 MHz, Kou-d4): δ 8.65 (s, 1H), 8.49 (s, 1H), 8.36 (s, 1H), 7.98 - 7.90 (m, 1H), 7.68 (d, J = 1.1 Hz, 1H), 7.55 (s, 1H), 7.51 (d, J = 9.3 Hz, 1H), 7.38 (d, J = 1.6, 9.3 Hz, 1H), 5.84 (s, 2H), 3.76 (s, 2H), 2.66 - 2.59 (m, 2H), 2.57 - 2.49 (m, 1H), 2.47 - 2.44 (m, 3H), 2.14 - 2.03 (m, 2H), 1.98 - 1.80 (m, 2H), 1.75 - 1.63 (m, 2H).

[0192] Example 15: Synthesis of E-15: 1-cyclobutyl-N-((2-((4-(6-(pyrrolidin-1-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine hydrochloride TIFF2025530847000446.tif29170

[0193] E15-1: tert-butyl (2-((4-(6-(pyrrolidin-1-yl)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate To a solution of intermediate I-6 (200 mg, 296 μmol, 1 eq) and pyrrolidine (421 mg, 5.92 mmol, 494 μL, 20.0 eq) in toluene (4.00 mL) was added tris(dibenzylideneacetone)dipalladium (27.1 mg, 29.6 μmol, 0.100 eq), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (11.6 mg, 29.6 μmol, 0.1 eq), and sodium tert-butoxide (42.7 mg, 444 μmol, 1.5 eq) at 20 °C under a nitrogen atmosphere, and the resulting mixture was stirred at 80 °C for 3 h. The mixture was concentrated, and the residue was purified by preparative thin-layer chromatography eluting with EtOAc / petroleum ether (5:1) to afford intermediate E15-1 (140 mg, 210 μmol, 71.0% yield) as a yellow solid.

[0194] LC-MS: [M+H]+= 666.4. E-15: 1-Cyclobutyl-N-((2-((4-(6-(pyrrolidin-1-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine hydrochloride Compound E-15 (70.9 mg, 64.9%) was prepared as a pale yellow solid from intermediate E15-1 by the method described for compound E-1.

[0195] LC-MS: [M+H] += 482.4. 1H NMR (400 MHz, DMSO-d6): δ 9.70 (brs, 2H), 9.23 - 9.02 (m, 2H), 8.65 - 8.41 (m, 2H), 8.21 (d, J = 1.2, 9.3 Hz, 1H), 8.01 (d, J = 9.3 Hz, 1H), 7.27 (s, 1H), 6.59 (s, 1H), 6.09 (s, 2H), 4.27 - 4.24 (m, 2H), 3.41 (s, 4H), 3.02 - 2.87 (m, 2H), 2.80 - 2.62 (m, 1H), 2.17 - 1.95 (m, 6H), 1.90 - 1.73 (m, 4H)

[0196] Example 16: Synthesis of E-16: 2,2'-((4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-yl)azanediyl)bis(ethan-1-ol) TIFF2025530847000447.tif28170

[0197] E16-1: tert-butyl (2-((4-(6-(bis(2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate To a stirred solution of intermediate E3-2 (200 mg, 326 μmol, 1.00 eq) and tert-butyl(2-iodoethoxy)dimethylsilane (2.00 mL) in DMF (2.00 mL) at 20 °C, cesium carbonate (372 mg, 1.14 mmol, 3.50 eq) was added, and the resulting mixture was stirred at 80 °C for 3 h. The mixture was diluted with water (8 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography eluting with EtOAc / petroleum ether (1:0) to give intermediate E16-1 (60.0 mg, 64.6 μmol, 19.7% yield) as a dark brown solid.

[0198] LC-MS: [M+H] += 928.7. E-16: 2,2'-((4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-yl)azanediyl)bis(ethan-1-ol) Compound E-16 (70.9 mg, 64.9%) was prepared as a yellow solid from intermediate E16-1 by the method described for compound E-1.

[0199] 1H NMR (400 MHz, DMSO-d6): δ 9.27 - 9.47 (m, 2 H) 9.02 (s, 1 H) 8.93 - 8.96 (m, 1 H) 8.46 (s, 1 H) 8.36 (s, 1 H) 7.94 - 8.00 (m, 1 H) 7.87 - 7.93 (m, 1 H) 7.37 (s, 1 H) 6.66 - 6.96 (m, 1 H) 6.00 (s, 2 H) 4.22 (t, J= 5.26 Hz, 2 H) 3.38 (s, 8 H) 2.93 - 2.97 (m, 2 H) 2.63 - 2.66 (m, 1H) 2.01 (s, 2 H) 1.79 - 1.89 (m, 2 H) 1.75 - 1.79 (m, 2 H) LC-MS: [M+H] += 516.2.

[0200] Example 17: Synthesis of E-17: N,n-bis(2-chloroethyl)-4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-amine hydrochloride TIFF2025530847000448.tif33170

[0201] Under a nitrogen gas atmosphere, compound E-16 (30.0 mg, 58.1 μmol, 1.00 eq) was added with phosphorus oxychloride (1.5 mL), and the resulting mixture was stirred at 80° C. for 1 h. The mixture was diluted with ice water (1.5 mL) and purified by prep-HPLC to give compound E-17 (4.00 mg, 12.4%) as a white solid.

[0202] LC-MS: [M+H] += 552.4. 1H NMR (400 MHz, DMSO-d6): δ 9.42 (br s, 2 H) 9.01 - 9.05 (m, 1 H) 8.95 - 9.00 (m, 1 H) 8.43 - 8.51 (m, 1 H) 8.30 - 8.37 (m, 1 H) 7.98 - 8.06 (m, 1 H) 7.88 - 7.96 (m, 1 H) 7.26 (s, 1 H) 6.66 (s, 1 H) 6.02 (s, 2 H) 4.22 (s, 2 H) 3.82 - 3.86 (m, 4 H) 3.80 (d, J = 5.13 Hz, 4 H) 2.94 (d, J = 4.25 Hz, 2 H) 2.64 - 2.70 (m, 1 H) 2.01 - 2.08 (m, 2 H) 1.72 - 1.85 (m, 4 H).

[0203] Example 18: Synthesis of E-18: 1-cyclobutyl-N-((2-((4-(6-methyl-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000449.tif73170

[0204] E18-1: tert-Butyl (cyclobutylmethyl) ((2-((4-(6-methyl-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate I-6 (100 mg, 148 μmol, 1.00 eq) and trimethylboroxine (74.3 mg, 592 μmol, 82.8 μL, 4.00 eq) were dissolved in water (1.00 mL) and 1,4-dioxane (2.00 mL). Cesium carbonate (145 mg, 444 μmol, 3.00 eq) and tetrakis(triphenylphosphine)palladium (17.1 mg, 14.8 μmol, 0.10 eq) were added under a nitrogen atmosphere, and the resulting mixture was stirred at 100 °C for 16 h. The mixture was diluted with water (10.00 mL) and extracted with EtOAc (3 × 2.00 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography eluting with EtOAc / petroleum ether (1:0) to give compound E18-1 (50.0 mg, 27.7%) as a white solid.

[0205] LC-MS: [M+H] += 611.3. E-18: 1-Cyclobutyl-N-((2-((4-(6-methyl-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-18 (70.9 mg, 64.9%) was prepared as a white solid from intermediate E18-1 by the method described for compound E-1.

[0206] LC-MS: [M+H] += 427.4. 1H NMR (400 MHz, DMSO-d6): δ 8.79 - 8.82 (m, 1 H) 8.46 - 8.50 (m, 1 H) 8.40 - 8.45 (m, 1 H) 7.95 - 7.99 (m, 1 H) 7.45 - 7.50 (m, 2 H) 7.24 - 7.30 (m, 2 H) 5.76 - 5.79 (m, 2 H) 3.64 - 3.67 (m, 2 H) 3.30 - 3.31 (m, 2 H) 2.47 (s, 5 H) 1.94 - 2.00 (m, 2 H) 1.67 - 1.93 (m, 3 H) 1.58 - 1.65 (m, 2 H) .

[0207] Example 19: Synthesis of E-19: N-(4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-yl)acetamide TIFF2025530847000450.tif65170

[0208] E19-1: tert-butyl (2-((4-(6-acetylamino-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate To a solution of intermediate E3-2 (0.02 g, 32.7 μmol, 1.00 eq) and triethylamine (6.62 mg, 65.4 μmol, 9.10 μL, 2.00 eq) in DCM (1.00 mL) was added glacial acetic acid (5.01 mg, 49.0 μmol, 4.59 μL, 1.50 eq) at 0 °C, and the resulting mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (1.00 mL) and extracted with DCM (3 × 2.00 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography eluting with EtOAc / petroleum ether (1:0) to give intermediate E19-1 (10.0 mg, 46.8%) as a yellow oil.

[0209] LC-MS: [M+H]+= 654.5. E-19: N-(4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-yl)acetamide Compound E-19 (70.9 mg, 64.9%) was prepared as a yellow viscous material from intermediate E19-1 in the manner described for compound E-3.

[0210] LC-MS: [M+H] += 470.0. 1H NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 9.22 (br s, 2H), 8.85 (s, 1H), 8.81 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 8.08 (s, 1H), 7.74 (s, 1H), 7.78 - 7.71 (m, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.70 - 7.68 (m, 1H), 5.91 (s, 2H), 4.14 (t, J = 5.3 Hz, 2H), 2.91 (br d, J = 4.8 Hz, 2H), 2.65 - 2.61 (m, 1H), 2.06 (s, 3H), 2.03 - 1.97 (m, 2H), 1.78 - 1.68 (m, 4H).

[0211] Example 20: Synthesis of E-20: 4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-yl acetate TIFF2025530847000451.tif65170

[0212] E20-1: 4-(1-((6-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-6-yl acetate To a solution of intermediate E10-1 (120 mg, 196 μmol, 1.00 eq) and pyridine (15.5 mg, 196 μmol, 15.8 μL, 1.00 eq) in toluene (6.00 mL) and tetrahydrofuran (1.20 mL) was added glacial acetic acid (30.0 mg, 294 μmol, 27.5 μL, 1.50 eq) at 0 °C, and the resulting mixture was stirred at 20 °C for 12 h. The mixture was diluted with water (10.00 mL) and extracted with EtOAc (3 × 3.00 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate E20-1 (0.120 g, crude product) as a red solid.

[0213] LC-MS: [M+H]+= 655.5. E-20: 4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-yl acetate To a solution of intermediate E20-1 (70.00 mg, 106.91 μmol, 1 eq) in DCM (1.40 mL) was added TFA (0.35 mL, 2.000 mmol, 20 eq), and the resulting mixture was stirred at 0-25 °C for 2 h. The mixture was concentrated, and the residue was purified by prep-HPLC to give compound E-20 (0.0011 g, 5.08%) as a white solid.

[0214] LC-MS: [M+H] += 471.2. 1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1 H) 8.92 (s, 1 H) 8.74 (s, 1 H) 8.64 (br s, 1 H) 8.11 (br s, 1 H) 7.74 (d, J = 1.13 Hz, 1 H) 7.61 (d, J = 9.26 Hz, 1 H) 7.33 - 7.38 (m, 2 H) 5.80 - 5.83 (m, 2 H) 4.12 (br s, 2 H) 2.96 (d, J = 6.38 Hz, 2 H) 2.70 (s, 3 H) 2.54 (d, J = 3.88 Hz, 1 H) 2.04 (d, J = 8.13 Hz, 2 H) 1.80 (br s, 2 H) 1.76 (br s, 2 H).

[0215] Example 21: Synthesis of E-21: 1-cyclobutyl-N-((2-((4-(6-(piperidin-1-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000452.tif25170

[0216] E21-1: tert-butyl (2-((4-(6-(piperidin-1-yl)-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E21-1 (120 mg, 79.5%) was prepared as a yellow solid from intermediate I-6 in the manner described for intermediate E15-1.

[0217] LC-MS: [M+H]+= 780.4. E-21: 1-Cyclobutyl-N-((2-((4-(6-(piperidin-1-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-21 (58.4 mg, 62.2%) was prepared as a white solid from intermediate E21-1 by the method described for compound E-1.

[0218] LC-MS: [M+H]+= 496.1. 1H NMR (400 MHz, DMSO-d6): δ 9.62 (br s, 2H), 9.16 (s, 1H), 9.03 (s, 1H), 8.67 (s, 1H), 8.51 (s, 1H), 8.14 (br s, 2H), 8.07 (d, J = 9.4 Hz, 1H), 7.93 (d, J = 9.4 Hz, 1H), 6.08 (s, 2H), 4.26 - 4.20 (m, 2H), 3.62 (br s, 4H), 2.98 - 2.90 (m, 2H), 2.76 - 2.64 (m, 1H), 2.17 - 1.93 (m, 6H), 1.87 - 1.65 (m, 6H).

[0219] Example 22: Synthesis of E-22: 1-cyclobutyl-N-((6-((4-(6-(methylthio)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine TIFF2025530847000453.tif24170

[0220] E22-1: tert-butyl 2-(((cyclobutylmethyl)amino)methyl)-6-((4-(6-(methylthio)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Under a nitrogen atmosphere, intermediate E34-1 (0.02 g, 29.7 μmol, 1.00 eq) and tributyl(methylthio)stannane (30.0 mg, 88.9 μmol, 3.00 eq) were dissolved in DMF (1.00 mL), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (2.17 mg, 2.96 μmol, 0.1 eq) was added. The mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The resulting mixture was diluted with water (3 mL) and extracted with EtOAc (2 mL * 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (petroleum ether / EtOAc = 3 / 1) to give intermediate E22-1 (0.01 g, crude product) as a yellow solid.

[0221] LC-MS: [M+H]+ = 642.3. E-22: 1-Cyclobutyl-N-((6-((4-(6-(methylthio)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine Compound E-22 (1.2 mg, 15.8%) was prepared as a white solid from intermediate E22-1 in the manner described for compound E-34.

[0222] LC-MS: [M+H]+= 457.4. 1H NMR (400 MHz, DMSO-d6): δ 11.38 (s, 1H), 9.09 (s, 2H), 8.98 (s, 1H), 8.51 (s, 1H), 7.58 (d,J = 8.3 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.29 (s, 1H), 7.17 - 7.09 (m, 1H), 6.61 (s, 1H), 5.75 (s, 2H), 4.27 (t, J = 5.2 Hz, 2H), 2.99 - 2.94 (m, 2H), 2.65 - 2.61 (m, 1H), 2.58 (s, 3H), 2.09 - 2.00 (m, 2H), 1.89 - 1.75 (m, 4H)

[0223] Example 23: Synthesis of E-23: 4-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethyl-1H-indazol-6-amine TIFF2025530847000454.tif29170

[0224] E23-1: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(6-(dimethylamino)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E23-1 (70.0 mg, 77.9%) was prepared as a white solid from intermediate E33-1 in the manner described for intermediate E5-1.

[0225] LC-MS: [M+H]+= 738.4 E-23: 4-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethyl-1H-indazol-6-amine Compound E-23 (13.8 mg, 35.6%) was prepared as a yellow oil from intermediate E23-1 in the manner described for compound E-1.

[0226] LC-MS: [M+H]+= 455.2. 1H NMR (400 MHz, DMSO-d6): δ 11.56 (s, 1H), 9.37 (br s, 2H), 8.94 (s, 1H), 8.57 (s, 1H), 7.77 (br s, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.47 (s, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.58 (s, 1H), 5.76 (s, 2H), 4.24 (t, J= 5.0 Hz, 2H), 3.12 (s, 6H), 2.94 - 2.86 (m, 2H), 2.63 (td, J = 7.4, 14.7 Hz, 1H), 2.05 - 1.96 (m, 2H), 1.86 - 1.77 (m, 1H), 1.77 - 1.70 (m, 2H), 1.77 - 1.70 (m, 1H).

[0227] Example 24: Synthesis of E-24: 1-cyclobutyl-N-((6-((4-(6-iodo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine TIFF2025530847000455.tif28170

[0228] E24-1: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(6-iodo-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate To a solution of intermediate E34-1 (0.10 g, 129 μmol, 1.00 eq) in 1,4-dioxane (3.00 mL) was added sodium iodide (58.0 mg, 387 μmol, 3.00 eq), cuprous iodide (12.3 mg, 64.5 μmol, 0.50 eq), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (18.3 mg, 129 μmol, 1.00 eq) at 20 °C, and the mixture was stirred at 110 °C under a nitrogen atmosphere for 16 h. The resulting mixture was concentrated, and the residue was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1) to give intermediate E24-1 (65.0 mg, 61.2%) as a yellow solid.

[0229] E-24: 1-Cyclobutyl-N-((6-((4-(6-iodo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine Compound E-24 (32.0 mg, 69.0%) was prepared as a yellow solid from intermediate E24-1 by the method described for compound E-1.

[0230] LC-MS (ESI): m / z 538.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 13.31 (s, 1H), 11.35 (s, 1H), 9.10 - 8.98 (m, 3H), 8.59 (s, 1H), 7.91 (d, J = 3.2 Hz, 2H), 7.58 (d, J = 8.2 Hz, 1H), 7.50 (s, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.61 (s, 1H), 5.75 (s, 2H), 4.30 - 4.23 (m, 2H), 3.01 - 2.94 (m, 2H), 2.65 - 2.58 (m, 1H), 2.09 - 2.00 (m, 2H), 1.91 - 1.83 (m, 1H), 1.82 - 1.73 (m, 3H).

[0231] Example 25: Synthesis of E-25: 1-cyclobutyl-N-((6-((4-(5-(2-(2-methoxyethoxy)ethoxy)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine TIFF2025530847000456.tif48170

[0232] E25-1: 3-bromo-5-(2-(2-methoxyethoxy)ethoxy)pyridine Intermediate E25-1 (32.0 mg, 69.0%) was prepared as a yellow oil from 5-bromopyridin-3-ol in the manner described for intermediate E10-2.

[0233] LC-MS (ESI): m / z 276.0 [M+H]+. E25-2: 3-(2-(2-methoxyethoxy)ethoxy)-5-((trimethylsilyl)ethynyl)pyridine To a solution of 3-bromo-5-(2-(2-methoxyethoxy)ethoxy)pyridine (2.00 g, 7.24 mmol, 1.00 eq) and ethynyltrimethylsilane (854 mg, 8.69 mmol, 1.20 mL, 1.20 eq) in ethyl acetate (20 mL) was added dichlorobis(triphenylphosphine)palladium(II) (254 mg, 362 μmol, 0.05 eq), cuprous iodide (138 mg, 724 μmol, 0.10 eq), and triethylamine (2.93 g, 29.0 mmol, 4.03 mL, 4.00 eq), and the mixture was stirred at 75 °C for 20 h. The resulting mixture was filtered, washed with EtOAc (20 mL), and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to obtain intermediate E25-2 (1.80 g, 84.6%) as a black oil.

[0234] LC-MS (ESI): m / z294.2 [M+H]+ . E25-3: 3-ethynyl-5-(2-(2-methoxyethoxy)ethoxy)pyridine Intermediate E25-3 (1.00 g, 73.7%) was prepared as a yellow oil from intermediate E25-2 in the manner described for intermediate I-2.

[0235] LC-MS (ESI): m / z222.1 [M+H]+ . E25-4: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(5-(2-(2-methoxyethoxy)ethoxy)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E25-4 (0.08 g, 54.4%) was prepared as a yellow solid from intermediate E25-3 in the manner described for intermediate 4-d.

[0236] LC-MS (ESI): m / z 691.6 [M+H]+ . E-25: 1-Cyclobutyl-N-((6-((4-(5-(2-(2-methoxyethoxy)ethoxy)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine Compound E-25 (22.0 mg, 35.8%) was prepared as a yellow oil from intermediate E25-4 in the manner described for compound E-1.

[0237] LC-MS (ESI): m / z 491.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ11.55 (s, 1H), 9.33 (s, 2H), 8.85 (s, 1H), 8.78 (s, 1H), 8.43 (d, J= 2.4 Hz, 1H), 8.14 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.45 (s, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.59 (s, 1H), 5.74 (s, 2H), 4.33 - 4.21 (m, 4H), 3.75 (s, 1H), 3.56 (d, J= 5.0 Hz, 3H), 3.45 - 3.39 (m, 2H), 3.20 (s, 3H), 2.91 (d, J = 4.8 Hz, 2H), 2.66 - 2.60 (m, 1H), 2.02 (d, J = 6.8 Hz, 2H), 1.86 - 1.69 (m, 4H).

[0238] Example 26: Synthesis of E-26: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((2-((4-(6-iodo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000457.tif28170

[0239] E26-1: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((2-((4-(6-iodo-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Intermediate E26-1 (0.06 g, 62.8%) was prepared as a brown solid from intermediate E27-1 in the manner described for intermediate E24-1.

[0240] LC-MS: [M+H]+= 653.5. E-26: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((2-((4-(6-iodo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-26 (5.20 mg, 15.3%) was prepared as a yellow solid from intermediate E26-1 by the method described for compound E-1.

[0241] LC-MS: [M+H]+= 569.1. 1H NMR (400 MHz, DMSO-d6): δ 8.95 (s, 1H), 8.78 (s, 1H), 8.57 (s, 1H), 8.40 (s, 1H), 8.01 - 7.91 (m, 4H), 6.08 (s, 2H), 4.43 (s, 2H), 3.50 (s, 2H), 2.19 (d, J = 2.3 Hz, 6H).

[0242] Example 27: Synthesis of E-27: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((2-((4-(6-(methylthio)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000458.tif62170

[0243] E27-1: 1-(2-((4-(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)methanamine Intermediate E27-1 (0.15 g, 41.8%) was prepared as a yellow solid from intermediate I-4 and (3-fluorobicyclo[1.1.1]pentan-1-yl)methanamine hydrochloride in the manner described for intermediate E6-1.

[0244] LC-MS: [M+H]+ = 605.3. E27-2: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((2-((4-(6-(methylthio)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Intermediate E27-2 (0.07 g, 52.5%) was prepared as a yellow solid from intermediate E27-1 in the manner described for intermediate E1-2.

[0245] LC-MS: [M+H]+= 573.3. E-27: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((2-((4-(6-(methylthio)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-27 (32.8 mg, 50.5%) was prepared as a yellow solid from intermediate E27-2 by the method described for compound E-1.

[0246] LC-MS: [M+H]+= 489.1. 1H NMR (400 MHz, DMSO-d6): δ 9.67 (s, 2H), 9.05 (s, 1H), 9.00 (s, 1H), 8.49 (s, 2H), 8.06 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 9.4 Hz, 1H), 7.49 (d, J = 1.3 Hz, 1H), 7.28 (s, 1H), 6.02 (s, 2H), 4.26 (s, 2H), 3.29 - 3.20 (m, 2H), 2.55 (s, 3H), 2.10 (d, J= 2.4 Hz, 6H).

[0247] Example 28: Synthesis of E-28: 4-(1-((6-((((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethyl-1H-indazol-6-amine TIFF2025530847000459.tif29170

[0248] E28-1: tert-butyl ((2-((4-(6-(dimethylamino)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)carbamate Intermediate E28-1 (100 g, crude) was prepared as a yellow solid from intermediate I-9 in the manner described for intermediate E5-1.

[0249] LC-MS: [M+H]+= 670.3. E-28: 4-(1-((6-((((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethyl-1H-indazol-6-amine Compound E-28 (35.9 mg, 45.8%) was prepared as a yellow solid from intermediate E28-1 by the method described for compound E-1.

[0250] LC-MS: [M+H]+= 486.3. 1H NMR (400 MHz, DMSO-d6): δ 9.07 (s, 1 H) 9.00 (s, 1 H) 8.77 (s, 1 H) 8.52 (s, 1 H) 8.15 (dd, J= 9.42, 1.55 Hz, 1 H) 8.00 (d, J = 9.30 Hz, 1 H) 7.90 (s, 1 H) 7.67 (br s, 1 H) 6.15 (s, 2 H) 4.46 (s, 2 H) 3.51 (s, 2 H) 3.39 (s, 6 H) 2.19 (d, J = 2.38 Hz, 6 H).

[0251] Example 29: Synthesis of E-29: 4-(1-((6-((6-azaspiro[3.4]octan-6-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-iodo-1H-indazole TIFF2025530847000460.tif27170

[0252] E29-1: 4-(1-((6-((6-azaspiro[3.4]octan-6-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-iodo-1-(tetrahydro2H-pyran-2-yl)-1H-indazole Intermediate E29-1 (30.0 mg, 34.8%) was prepared as a yellow solid from intermediate E30-1 in the manner described for intermediate E24-1.

[0253] LC-MS: [M+H]+= 649.5. E-29: 4-(1-((6-((6-azaspiro[3.4]octan-6-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-iodo-1H-indazole Compound E-29 (4.00 mg, 15.1%) was prepared as a yellow solid from intermediate E29-1 in the manner described for compound E-3.

[0254] LC-MS: [M+H]+= 565.0. 1H NMR (400 MHz, DMSO-d6): δ (br s, 1 H) 9.09 (s, 1 H) 9.03 (s, 1 H) 8.56 (s, 1 H) 8.45 (s, 1 H) 8.11 (d, J= 8.99 Hz, 1 H) 7.90 - 7.94 (m, 2 H) 7.88 (s, 1 H) 6.02 (s, 2 H) 4.44 - 4.50 (m, 1 H) 4.37 - 4.43 (m, 1 H) 3.36 (d, J = 11.51, 5.37 Hz, 2 H) 3.10 - 3.17 (m, 1H) 3.06 (d, J = 11.40, 7.02 Hz, 1 H) 2.04 - 2.12 (m, 2 H) 1.93 - 2.04 (m, 3 H) 1.78 - 1.89 (m, 2 H) 1.69 - 1.76 (m, 1 H).

[0255] Example 30: Synthesis of E-30: 4-(1-((6-((6-azaspiro[3.4]octan-6-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-(methylthio)-1H-indazole TIFF2025530847000461.tif55170

[0256] E30-1: 4-(1-((6-((6-azaspiro[3.4]octan-6-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-bromo-1-(tetrahydro2H-pyran-2-yl)-1H-indazole To a solution of intermediate I-4 (300 mg, 592 μmol, 1.00 eq) and 6-azaspiro[3.4]octane (131 mg, 1.18 mmol, 2.00 eq) in MeOH (15.0 mL) was added AcOH (3.56 mg, 59.2 μmol, 3.39 μL, 0.100 eq), and the resulting mixture was stirred at 25 °C under a nitrogen atmosphere for 30 min. Sodium triacetoxyborohydride (74.4 mg, 1.18 mmol, 2.00 eq) was then added to the mixture at 25 °C. The mixture was stirred at 50 °C under a nitrogen atmosphere for 2 h. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (DCM / MeOH=10 / 1) to give intermediate E30-1 (220 mg, 61.7%) as a yellow oil.

[0257] LC-MS: [M+H]+= 603.2. 1H NMR (400 MHz, DMSO-d6): δ 8.95 (s, 1 H) 8.62 (s, 1 H) 8.41 (s, 1 H) 7.98 (s, 1 H) 7.95 (s, 1 H) 7.80 (d, J = 1.53 Hz, 1 H) 7.43 (d, J = 9.65 Hz, 1 H) 7.18 (dd, J = 9.43, 1.32 Hz, 1 H) 5.86 - 5.91 (m, 1 H) 5.75 (s, 2 H) 5.72 (s, 2 H) 3.71 - 3.87 (m, 2 H) 3.48 (d, J = 0.88 Hz, 2 H) 3.28 (s, 2 H) 2.49 (d, J = 1.75 Hz, 2 H) 2.28 - 2.41 (m, 2 H) 1.86 - 1.88 (m, 2 H) 1.65 - 1.81 (m, 6 H) 1.53 - 1.57 (m, 2 H).

[0258] E30-2: 4-(1-((6-((6-azaspiro[3.4]octan-6-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-(methylthio)-1-(tetrahydro2H-pyran-2-yl)-1H-indazole Intermediate E30-2 (34.0 mg, 35.9%) was prepared as a yellow solid from intermediate E30-1 in the manner described for intermediate E1-2.

[0259] LC-MS: [M+H]+= 569.3. 1H NMR (400 MHz, DMSO-d6): δ 8.94 (s, 1 H) 8.87 (s, 1 H) 8.63 (s, 1 H) 8.56 (s, 1 H) 8.45 (s, 1 H) 7.98 (s, 1 H) 7.58 (d, J = 1.31 Hz, 1 H) 7.53 (s, 1 H) 7.45 (s, 1 H) 7.23 (d, J = 1.31 Hz, 1 H) 1.91 (d, J = 7.51 Hz, 4 H) 1.73 - 1.84 (m, 6 H) 1.60 (d, J = 2.86Hz, 2H) 1.24 (s, 2 H) E-30: 4-(1-((6-((6-azaspiro[3.4]octan-6-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-(methylthio)-1H-indazole Compound E-30 (13.2 mg, 45.5%) was prepared as a colorless oil from intermediate E30-2 in the manner described for compound E-3.

[0260] LC-MS: [M+H]+= 485.2. 1H NMR (400 MHz, DMSO-d6): δ 13.11 (s, 1 H) 8.93 (s, 1 H) 8.52 (s, 1 H) 8.45 (s, 1 H) 7.98 (s, 1 H) 7.52 (d, J = 1.34 Hz, 1 H) 7.46 (d, J = 9.29 Hz, 1 H) 7.28 (s, 1 H) 7.22 (dd, J = 9.29, 1.47 Hz, 1 H) 5.78 (s, 2 H) 3.52 (s, 2 H) 3.33 (s, 2 H) 2.58 (s, 3 H) 1.87 - 1.97 (m, 4 H) 1.81 (t, J = 6.97 Hz, 2 H) 1.68 - 1.77 (m, 2 H).

[0261] Example 31: Synthesis of E-31: 4-(1-((6-((6-azaspiro[3.4]octan-6-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethyl-1H-indazol-6-amine TIFF2025530847000462.tif50170

[0262] E31-1: 4-(1-((6-((6-azaspiro[3.4]octan-6-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-nitro-1-(tetrahydro2H-pyran-2-yl)-1H-indazole Intermediate E31-1 (0.29 g, 34.4%) was prepared as a yellow solid from intermediate 9-b in the manner described for intermediate E30-1.

[0263] LC-MS: [M+H]+= 568.4. E31-2: 4-(1-((6-((6-azaspiro[3.4]octan-6-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine Intermediate E31-2 (30 mg, 34.4%) was prepared as a yellow solid from intermediate E31-1 in the manner described for intermediate E3-2.

[0264] LC-MS: [M+H]+= 538.5. E31-3: 4-(1-((6-((6-azaspiro[3.4]octan-6-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethyl-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-6-amine Intermediate E31-3 (crude product) was prepared as a yellow oil from intermediate E31-2 in the manner described for intermediate E5-1.

[0265] LC-MS: [M+H]+ = 566.5. E-31: 4-(1-((6-((6-azaspiro[3.4]octan-6-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethyl-1H-indazol-6-amine Compound E-31 (23.3 mg, 20.7%) was prepared as a yellow oil from intermediate E31-3 in the manner described for compound E-3.

[0266] LC-MS: [M+H]+= 482.1. 1H NMR (400 MHz, DMSO-d6): δ 12.52 - 12.80 (m, 1 H) 9.82 - 10.01 (m, 1 H) 8.90 (s, 1 H) 8.73 (s, 1 H) 8.32 (s, 1 H) 8.15 (s, 1 H) 7.67 (d, J = 9.38 Hz, 1 H) 7.43 (d, J = 9.26 Hz, 1 H) 7.29 (d, J = 1.50 Hz, 1 H) 6.58 (br s, 1 H) 5.84 (s, 2 H) 4.32 - 4.40 (m, 2 H) 3.42 (dd, J = 11.57, 5.44 Hz, 2 H) 3.16 - 3.23 (m, 1 H) 3.12 (dd, J = 11.57, 7.07 Hz, 1 H) 3.01 (s, 6 H) 2.07 - 2.21 (m, 2 H) 2.00 - 2.06 (m, 2 H) 1.95 - 2.00 (m, 1 H) 1.86 - 1.92 (m, 1 H) 1.71 - 1.86 (m, 2 H).

[0267] Example 32: Synthesis of E-32: 1-cyclobutyl-N-((6-((4-(6-nitro-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine TIFF2025530847000463.tif30170

[0268] E32-1: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(6-nitro-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E32-1 (0.07 g, 73.9%) was prepared as a yellow solid from intermediate I-7 by the method described for intermediate 4-d.

[0269] LC-MS: [M+H]+= 741.4. E-32: 1-Cyclobutyl-N-((6-((4-(6-nitro-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine Compound E-32 (28.1 mg, 52.2%) was prepared as a yellow solid from intermediate E32-1 by the method described for compound E-1.

[0270] LC-MS: [M+H]+= 457.1. 1H NMR (400 MHz, DMSO-d6): δ 13.96 (s, 1H), 11.35 (s, 1H), 9.20 (s, 1H), 9.03 (s, 2H), 8.80 (s, 1H), 8.39 (s, 2H), 7.55 (d, J = 8.3 Hz, 1H), 7.49 (s, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.58 (s, 1H), 5.76 (s, 2H), 4.24 (t, J= 5.0 Hz, 2H), 2.93 (d, J = 5.5 Hz, 2H), 2.63 - 2.54 (m, 1H), 2.05 - 1.96 (m, 2H), 1.87 - 1.70 (m, 4H).

[0271] Example 33: Synthesis of E-33: 4-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-amine TIFF2025530847000464.tif24170

[0272] E33-1: tert-butyl 6-((4-(6-amino-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate Intermediate E33-1 (0.07 g, 73.9%) was prepared as a yellow solid from intermediate E32-1 in the manner described for intermediate E3-2.

[0273] LC-MS: [M+H]+= 711.4. E-33: 4-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-amine Compound E-33 (4.00 mg, 12.3%) was prepared as a brown solid from intermediate E33-1 by the method described for compound E-1.

[0274] LC-MS: [M+H]+= 427.2. 1H NMR (400 MHz, DMSO-d6): δ 11.44 (s, 1H), 9.18 (s, 2H), 8.95 (s, 1H), 8.49 (s, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.28 (s, 1H), 7.11 (d, J= 8.1 Hz, 1H), 6.58 (s, 1H), 5.73 (s, 2H), 4.27 - 4.21 (m, 2H), 2.94 - 2.89 (m, 2H), 2.64 - 2.58 (m, 1H), 2.04 - 1.96 (m, 2H), 1.82 - 1.69 (m, 4H).

[0275] Example 34: Synthesis of E-34: 1-(6-((4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine TIFF2025530847000465.tif24170

[0276] E34-1: tert-butyl 6-((4-(6-bromo-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-(((cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate Intermediate E34-1 (200 mg, 59.8%) was prepared as a yellow solid from intermediate I-8 in the manner described for intermediate E30-1.

[0277] LC-MS: [M+H]+= 674.6. E-34: 1-(6-((4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine To a stirred solution of intermediate E34-1 (30.0 mg, 44.5 μmol, 1.00 eq) in 1,4-dioxane (1.00 mL) was added HCl in 1,4-dioxane (4 M, 222 μL, 20 eq), and the mixture was stirred at 25° C. for 2 h. The mixture was concentrated and purified by preparative HPLC to give compound E-34 (12.2 mg, 50.3%) as a yellow oil.

[0278] LC-MS: [M+H]+= 490.4. 1H NMR (400 MHz, DMSO-d6): δ 13.37 (br s, 1H), 11.41 (s, 1H), 9.14 (br s, 2H), 9.02 (s, 1H), 8.59 (s, 1H), 7.79 - 7.68 (m, 2H), 7.55 (d, J = 8.1 Hz, 1H), 7.47 (s, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.58 (s, 1H), 5.73 (s, 2H), 4.31 - 4.18 (m, 2H), 3.00 - 2.86 (m, 2H), 2.62 (d, J = 7.9, 15.8 Hz, 1H), 2.05 - 1.97 (m, 2H), 1.88 - 1.79 (m, 1H), 1.78 - 1.69 (m, 3H).

[0279] Example 35: Synthesis of E-35: 5-(dimethylamino)-N-((6-(((((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)nicotinamide TIFF2025530847000466.tif31170

[0280] E-35 (7.0 mg, 26.2%) was prepared as a yellow solid from E102-7 by the method described for E30-1.

[0281] LC-MS: [M+H]+= 423.1. 1H NMR (400 MHz, DMSO-d6): δ 9.10 (t, J = 5.7 Hz, 1H), 8.36 (s, 2H), 8.22 (d, J = 2.9 Hz, 1H), 7.76 (s, 1H), 7.50-7.46 (m, 1H), 7.42 (d, J= 9.1 Hz, 1H), 7.20 (dd, J = 1.4, 9.2 Hz, 1H), 4.56 (d, J = 5.8 Hz, 2H), 3.66 (s, 2H), 2.97 (s, 6H), 2.74 (s, 2H), 1.92 (d, J = 2.6 Hz, 6H).

[0282] Example 36: Synthesis of E-36: N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-5-(dimethylamino)nicotinamide TIFF2025530847000467.tif57170

[0283] E36-1: 5-(dimethylamino)nicotinic acid methyl ester Intermediate E36-1 (2.20 g, 41.3%) was prepared as a yellow oil from methyl 5-aminonicotinate in the manner described for intermediate E5-1.

[0284] LC-MS: [M+H]+= 181.0. E36-2: 5-(dimethylamino)nicotinic acid Intermediate E36-2 (200 mg, 68.4%) was prepared as a yellow solid from intermediate E36-1 in the manner described for intermediate E7-2.

[0285] LC-MS: [M+H]+= 167.1. E36-3: tert-Butyl (cyclobutylmethyl) ((2-((5-(dimethylamino)nicotinamido)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E36-3 (40.0 mg, 59.4%) was prepared as a yellow solid from intermediates E36-2 and I-10 in the manner described for intermediate E7-3.

[0286] LC-MS: [M+H]+= 493.3. E-36: N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-5-(dimethylamino)nicotinamide Compound E-36 (9.20 mg, 28.8%) was prepared as a white solid from intermediate E36-3 in the manner described for compound E-3.

[0287] LC-MS: [M+H]+= 393.2. 1H NMR (400 MHz, DMSO-d6):δ 9.10 (t, J = 5.69 Hz, 1 H) 8.36 (d, J = 1.63 Hz, 2 H) 8.21 (d, J = 2.88 Hz, 1 H) 7.77 (s, 1 H) 7.46 - 7.50 (m, 1 H) 7.43 (d, J = 9.13 Hz, 1 H) 7.21 (d, J = 9.26 Hz, 1 H) 4.56 (d, J = 5.63 Hz, 2 H) 3.66 (s, 2 H) 2.97 (s, 5 H) 2.94 (br s, 1 H) 2.52 (br d, J= 1.75 Hz, 1 H) 2.52 - 2.53 (m, 1 H) 2.33 - 2.44 (m, 1 H) 1.91 - 2.01 (m, 2 H) 1.71 - 1.86 (m, 2 H) 1.54 - 1.68 (m, 2 H).

[0288] Example 37: Synthesis of E-37: 1-cyclobutyl-N-((2-((4-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000468.tif61170

[0289] E37-1: 3-Methoxy-5-((trimethylsilyl)ethynyl)pyridine Intermediate E37-1 (2.00 g, 91.5%) was prepared as a red oil from 3-bromo-5-methoxypyridine in the manner described for intermediate 2-b.

[0290] LC-MS: [M+H]+= 206.1. E37-2: 3-ethynyl-5-methoxypyridine Intermediate E37-2 (0.90 g, 69.0%) was prepared as a yellow solid from intermediate E37-1 in the manner described for intermediate I-2.

[0291] 1H NMR: (400 MHz, CDCl3-d):δ 8.32 (dd, J = 2.1, 19.0 Hz, 2H), 7.29 - 7.28 (m, 1H), 3.87 (s, 3H), 3.22 (s, 1H). E37-3: tert-butyl (2-((4-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E37-3 (0.06 g, 44.1%) was prepared as a yellow solid from intermediate E37-2 in the manner described for intermediate 4-d.

[0292] LC-MS: [M+H]+= 504.4. E-37: 1-Cyclobutyl-N-((2-((4-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-37 (26.5 mg, 50.4%) was prepared as a yellow solid from intermediate E37-3 by the method described for compound E-1.

[0293] LC-MS: [M+H]+= 404.2. 1H NMR (400 MHz, DMSO-d6): δ 9.62 (br s, 2H), 9.07 - 8.99 (m, 2H), 8.82 (d, J = 1.2 Hz, 1H), 8.48 (s, 2H), 8.15 (br s, 1H), 8.06 (d, J= 9.2 Hz, 1H), 7.92 (d, J= 9.4 Hz, 1H), 6.04 (s, 2H), 4.23 (br s, 2H), 3.97 (s, 3H), 2.95 (d, J= 4.5 Hz, 2H), 2.76 - 2.66 (m, 1H), 2.10 - 2.00 (m, 2H), 1.90 - 1.74 (m, 4H).

[0294] Example 38: Synthesis of E-38: 5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethylpyridin-3-amine TIFF2025530847000469.tif49170

[0295] E38-1: 5-Bromo-N,N-dimethylpyridin-3-amine Intermediate E38-1 (4.34 g, 76.0%) was prepared as a red oil from 3-bromo-5-fluoropyridine in the manner described for intermediate E16-1.

[0296] LC-MS: [M+H]+ = 203.0. E38-2: N,N-dimethyl-5-((trimethylsilyl)ethynyl)pyridin-3-amine Intermediate E38-2 (1.37 g, 63.1%) was prepared as a brown solid from intermediate E38-1 in the manner described for intermediate 2-b.

[0297] LC-MS: [M+H]+ = 219.2. E38-3: 5-ethynyl-N,N-dimethylpyridin-3-amine Intermediate E38-3 (800 mg, 87.2%) was prepared as a pale yellow solid from intermediate E38-2 in the manner described for intermediate I-2.

[0298] LC-MS: [M+H]+= 147.2. E38-4: tert-butyl (2-((4-(5-(dimethylamino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E38-4 (0.22 g, crude) was prepared as a black solid from intermediate E38-3 in the manner described for intermediate 4-d.

[0299] LC-MS: [M+H]+ = 517.5. E-38: 5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethylpyridin-3-amine Compound E-38 (26.2 mg, 36.0%) was prepared as a yellow solid from intermediate E38-4 by the method described for compound E-3.

[0300] LC-MS: [M+H]+= 417.5. 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1 H) 9.00 (s, 1 H) 8.54 (br s, 1 H) 8.50 (s, 1 H) 8.15 - 8.21 (m, 2 H) 8.12 (d, J = 2.50 Hz, 1 H) 8.01 (d, J = 9.38 Hz, 1 H) 6.14 (s, 2 H) 4.41 - 4.42 (m, 1 H) 4.42 (s, 1 H) 3.20 (s, 6 H) 3.18 (s, 2 H) 2.76 (dt, J = 15.26, 7.75 Hz, 1 H) 2.18 - 2.24 (m, 2 H) 1.93 - 2.05 (m, 2 H) 1.87 - 1.92 (m, 2 H).

[0301] Example 39: Synthesis of E-39: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((2-((4-(6-(methylsilanyl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000470.tif65170

[0302] E39-1: tert-butyl((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)((2-((4-(6-selenocyano-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E39-1 (220 mg, crude) was prepared as a red solid from intermediate I-9 in the manner described for intermediate E14-1.

[0303] LC-MS: [M+H]+= 732.2.LC-MS: [M+H]+= 732.2. E39-2: tert-butyl((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)((2-((4-(6-(methylsilanyl)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E39-2 (40.0 mg, 14.3%) was prepared as a yellow solid from intermediate E39-1 in the manner described for intermediate E14-2.

[0304] LC-MS: [M+H]+ = 721.2. E-39: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((2-((4-(6-(methylsilanyl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-39 (10.2 mg, 27.6%) was prepared as a yellow solid from intermediate E39-2 in the manner described for compound E-3.

[0305] LC-MS: [M+H]+= 537.0. 1H NMR (400 MHz, DMSO-d6): δ 9.81 (br s, 2 H) 9.03 - 9.14 (m, 2 H) 8.53 (d, J= 2.13 Hz, 2 H) 8.14 (d, J = 9.26 Hz, 1 H) 7.97 (d, J = 9.26 Hz, 1 H) 7.65 (s, 1 H) 7.49 (s, 1 H) 6.06 (s, 2 H) 4.28 (br s, 2 H) 3.24 - 3.29 (m, 2 H) 2.46 (s, 3 H) 2.12 (d, J = 2.38 Hz, 6H).

[0306] Example 40: Synthesis of E-40: 1-cyclobutyl-N-((6-((4-(6-(methylsilanyl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine TIFF2025530847000471.tif59170

[0307] E40-1: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(6-selenocyano-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E40-1 (220 mg, crude) was prepared as a red solid from intermediate E33-1 in the manner described for intermediate E14-1.

[0308] LC-MS: [M+H]+ = 801.3. E40-2: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(6-(methylsilanyl)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E40-2 (30.0 mg, 15.2%) was prepared as a yellow solid from intermediate E40-1 in the manner described for intermediate E14-2.

[0309] LC-MS: [M+H]+=790.5. E-40: 1-Cyclobutyl-N-((6-((4-(6-(methylsilanyl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine Compound E-40 (11.8 mg, 55.6%) was prepared as a yellow solid from intermediate E40-2 in the manner described for compound E-3.

[0310] LC-MS: [M+H]+= 505.9. 1H NMR (400 MHz, DMSO-d6): δ 12.98 - 13.32 (m, 1 H) 11.29 - 11.47 (m, 1 H) 8.99 - 9.15 (m, 2 H) 8.97 (s, 1 H) 8.52 (s, 1 H) 7.63 (d, J= 1.07 Hz, 1 H) 7.57 (d, J = 8.23 ​​Hz, 1 H) 7.47 (d, J = 12.52 Hz, 2 H) 7.12 (d, J = 8.23 ​​Hz, 1 H) 6.60 (s, 1 H) 5.75 (s, 2 H) 4.26 (t, J= 5.07 Hz, 2 H) 2.96 (d, J = 4.77 Hz, 2 H) 2.58 - 2.64 (m, 1 H) 2.40 - 2.46 (m, 3 H) 1.99 - 2.11 (m, 2 H) 1.70 - 1.89 (m, 4 H).

[0311] Example 41: Synthesis of E-41: 1-cyclobutyl-N-((6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine TIFF2025530847000472.tif50170

[0312] E41-1: 6-Methoxy-1-(tetrahydro2H-pyran-2-yl)-4-((trimethylsilyl)ethynyl)-1H-indazole Intermediate E41-1 (0.06 g, 56.8%) was prepared as a red oil from intermediate E9-1 in the manner described for intermediate 2-b.

[0313] LC-MS: [M+H]+ = 329.2. E41-2: 4-ethynyl-6-methoxy-1-(tetrahydro 2H-pyran-2-yl)-1H-indazole Intermediate E41-2 (20.0 mg, 42.7%) was prepared as a yellow solid from intermediate E41-1 in the manner described for intermediate I-2.

[0314] 1H NMR: (400 MHz, CDCl3): δ 7.95 (d, J = 6.8 Hz, 1H), 6.91 (dd, J = 5.6, 12.2 Hz, 2H), 5.57 (s, 1H), 3.91 (s, 1H), 3.81 (d, J = 7.4 Hz, 3H), 3.66 (s, 1H), 3.24 (d, J = 7.4 Hz, 1H), 2.48 (br s, 1H), 2.08 (br s, 1H), 2.14 - 2.05 (m, 1H), 1.99 (d, J = 12.6 Hz, 1H), 1.18 (d, J = 5.5 Hz, 2H). E41-3: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(6-methoxy-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E41-3 (0.04 g, 64.7%) was prepared as a yellow oil from intermediate E41-2 in the manner described for intermediate 4-d.

[0315] LC-MS: [M+H]+ = 726.5. E-41: 1-Cyclobutyl-N-((6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine Compound E-41 (18.6 mg, 70.1%) was prepared as a yellow solid from intermediate E41-3 by the method described for compound E-1.

[0316] LC-MS: [M+H]+= 442.2. 1H NMR (400 MHz, DMSO-d6): δ 11.43 (s, 1H), 9.16 (br s, 2H), 8.94 (s, 1H), 8.45 (s, 1H), 7.57 (d, J= 8.2 Hz, 1H), 7.49 (s, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.92 (s, 1H), 6.61 (s, 1H), 5.75 (s, 2H), 4.30 - 4.24 (m, 1H), 4.27 (t, J = 5.1 Hz, 1H), 3.85 (s, 3H), 2.99 - 2.92 (m, 2H), 2.66 - 2.59 (m, 1H), 2.09 - 2.00 (m, 2H), 1.92 - 1.82 (m, 1H), 1.81 - 1.72 (m, 3H).

[0317] Example 42: Synthesis of E-42: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((6-((4-(6-nitro-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine TIFF2025530847000473.tif51170

[0318] E42-1: 1-(tert-butyl) 2-methyl 6-((4-(6-nitro-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1,2-dicarboxylate Intermediate E42-1 (1.50 g, 78.4%) was prepared as a yellow solid from intermediate 8-d by the method described for intermediate 4-d.

[0319] LC-MS: [M+H]+ = 602.5. E42-2: tert-butyl 2-(hydroxymethyl)-6-((4-(6-nitro-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E42-2 (0.650 g, 48.8%) was prepared as a yellow solid from intermediate E42-1 in the manner described for intermediate 4-b.

[0320] 1H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 1 H) 8.86 (s, 1 H) 8.72 (s, 1 H) 8.47 (d, J = 1.75 Hz, 1 H) 8.09 (s, 1 H) 7.59 (d, J = 7.88 Hz, 1 H) 7.32 (dd, J = 8.00, 1.38 Hz, 1 H) 6.67 (s, 1 H) 6.18 (dd, J = 9.38, 2.13 Hz, 1 H) 5.83 (s, 2 H) 5.34 (t, J = 5.75 Hz, 1 H) 4.76 (d, J = 5.25 Hz, 2H) 3.82 - 3.93 (m, 2 H) 2.45 (br s, 2 H) 2.02 - 2.08 (m, 2 H) 1.61 (br s, 2 H) 1.57 (s, 9 H). E42-3: tert-butyl 2-formyl-6-((4-(6-nitro-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E42-3 (500 mg, 77.2%) was prepared as a yellow solid from intermediate E42-2 in the manner described for intermediate I-4.

[0321] LC-MS: [M+H]+= 572.5. E42-4: tert-butyl 2-((((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)-6-((4-(6-nitro-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E42-4 (0.290 g, 49.4%) was prepared as a yellow solid from intermediate E42-3 in the manner described for intermediate E30-1.

[0322] LC-MS: [M+H]+= 671.3. E-42: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((6-((4-(6-nitro-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine Compound E-42 (16.2 mg, 44.1%) was prepared as a yellow solid from intermediate E42-4 in the manner described for compound E-3.

[0323] LC-MS: [M+H]+= 487.1. 1H NMR (400 MHz, DMSO-d6): δ 13.92 - 14.07 (m, 1 H) 11.42 (s, 1 H) 9.32 (br s, 2 H) 9.24 (s, 1 H) 8.82 (s, 1 H) 8.42 (s, 2 H) 7.58 (d, J = 8.19 Hz, 1 H) 7.52 (s, 1 H) 7.12 - 7.17 (m, 1 H) 6.61 (s, 1 H) 5.78 (s, 2 H) 4.31 (t, J = 4.71 Hz, 2 H) 3.24 - 3.30 (m, 2 H) 2.10 (d, J = 2.57 Hz, 6 H).

[0324] Example 43: Synthesis of E-43: 4-(1-((2-((((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-amine TIFF2025530847000474.tif27170

[0325] E43-1: tert-butyl 6-((4-(6-amino-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-((((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)-methyl)-1H-indole-1-carboxylate Intermediate E43-1 (56.0 mg, 58.6%) was prepared as a yellow solid from intermediate E42-4 in the manner described for intermediate E3-2.

[0326] LC-MS: [M+H]+= 641.5. E-43: 4-(1-((2-((((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-amine Compound E-43 (12.4 mg, 30.1%) was prepared as a yellow oil from intermediate E43-1 in the manner described for compound E-3.

[0327] LC-MS: [M+H]+= 457.1. 1H NMR (400 MHz, DMSO-d6): δ 11.57 (s, 1 H) 9.55 (br s, 2 H) 9.05 (s, 1 H) 8.60 (s, 1 H) 7.55 - 7.60 (m, 2 H) 7.50 - 7.55 (m, 2 H) 7.14 (dd, J = 8.19, 1.10 Hz, 1 H) 6.61 (s, 1 H) 5.77 (s, 2 H) 4.31 (br s, 2 H) 3.21 - 3.29 (m, 2 H) 2.11 (d, J = 2.57 Hz, 6 H).

[0328] Example 44: Synthesis of E-44: 5-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethylpyridin-3-amine TIFF2025530847000475.tif30170

[0329] E44-1: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(5-(dimethylamino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E44-1 (0.10 g, 76.2%) was prepared as a yellow solid from intermediates I-7 and E38-3 in the manner described for intermediate 4-d.

[0330] LC-MS: [M+H]+= 616.6. E-44: 5-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethylpyridin-3-amine Compound E-44 (55.5 mg, 72.0%) was prepared as a yellow solid from intermediate E44-1 by the method described for compound E-1.

[0331] LC-MS: [M+H]+= 416.3. 1H NMR (400 MHz, DMSO-d6): δ 11.67 (s, 1H), 9.47 (s, 2H), 9.00 (s, 1H), 8.51 (s, 1H), 8.15 (d, J = 2.6 Hz, 1H), 8.06 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.48 (s, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.62 (s, 1H), 5.79 (s, 2H), 4.28 (t, J= 5.0 Hz, 2H), 3.11 (s, 6H), 2.97 - 2.89 (m, 2H), 2.72 - 2.64 (m, 1H), 2.09 - 2.00 (m, 2H), 1.89 - 1.73 (m, 4H).

[0332] Example 45: Synthesis of E-45: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-bromo-1H-indazole TIFF2025530847000476.tif25170

[0333] E45-1: tert-butyl 2-((6-azaspiro[3.4]octan-6-yl)methyl)-6-((4-(6-bromo-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E45-1 (140 mg, 60.5%) was prepared as a yellow solid from intermediate I-8 in the manner described for intermediate E5-1.

[0334] 1H NMR (400 MHz, chloroform-d): δ 8.59 (s, 1H), 8.09 (s, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.54 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 6.73 - 6.51 (m, 1H), 5.70 (s, 2H), 5.69 - 5.65 (m, 1H), 4.01 (d, J = 11.6 Hz, 1H), 3.80 - 3.67 (m, 1H), 2.68 (br s, 2H), 2.51 (d, J = 7.5 Hz, 2H), 2.13 (s, 1H), 2.00 - 1.87 (m, 7H), 1.76 (d,J = 9.4 Hz, 1H), 1.25 - 1.22 (m, 9H), 0.89 - 0.81 (m, 7H). E-45: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-bromo-1H-indazole Compound E-45 (12.4 mg, 51.1%) was prepared as a white solid from intermediate E45-1 in the manner described for compound E-34.

[0335] LC-MS: [M+H]+= 516.2. 1H NMR (400 MHz, DMSO-d6): δ 11.53 (s, 1H), 11.18 (s, 1H), 9.06 (s, 1H), 8.62 (d, J = 0.6 Hz, 1H), 7.81 - 7.70 (m, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.50 (s, 1H), 7.14 (dd, J = 1.2, 8.2 Hz, 1H), 6.68 (s, 1H), 5.77 (s, 2H), 4.54 - 4.38 (m, 2H), 3.48 - 3.33 (m, 2H), 3.20 - 3.11 (m, 2H), 2.15 - 2.05 (m, 2H), 2.04 - 1.92 (m, 3H), 1.89 - 1.70 (m, 3H).

[0336] Example 46: Synthesis of E-46: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-nitro-1H-indazole TIFF2025530847000477.tif30170

[0337] E46-1: tert-butyl 2-((6-azaspiro[3.4]octan-6-yl)methyl)-6-((4-(6-nitro-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E46-1 (0.907 g, 51.8%) was prepared as a yellow solid from intermediate E42-3 in the manner described for intermediate E30-1.

[0338] LC-MS: [M+H]+ = 667.5. E-46: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-nitro-1H-indazole Compound E-46 (32.5 mg, 41.1%) was prepared as a yellow solid from intermediate E46-1 in the manner described for compound E-3.

[0339] LC-MS: [M+H]+= 483.3. 1H NMR (400 MHz, DMSO-d6): δ 13.96 (s, 1 H) 11.36 (s, 1 H) 10.26 - 10.44 (m, 1 H) 9.23 (s, 1 H) 8.82 (s, 1 H) 8.42 (s, 2 H) 7.57 - 7.64 (m, 1 H) 7.50 (s, 1 H) 7.13 - 7.20 (m, 1 H) 6.66 (s, 1 H) 5.79 (s, 2 H) 4.46 (s, 2 H) 3.43 (d, J = 11.44, 5.44 Hz, 2 H) 3.22 (br s, 2 H) 2.05 - 2.11 (m, 2 H) 1.98 - 2.04 (m, 2 H) 1.88 (d, J= 5.63 Hz, 2 H) 1.85 (br s, 2 H).

[0340] Example 47: Synthesis of E-47: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-(methylthio)-1H-indazole TIFF2025530847000478.tif27170

[0341] E47-1: tert-butyl 2-((6-azaspiro[3.4]octan-6-yl)methyl)-6-((4-(6-(methylthio)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E47-1 (10 mg, 15.0%) was prepared as a yellow solid from intermediate E45-1 in the manner described for intermediate E22-1.

[0342] LC-MS: [M+H]+= 668.3. E-47: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-(methylthio)-1H-indazole Compound E-47 (1.3 mg, 16.6%) was prepared as a white solid from intermediate E47-1 in the manner described for compound E-34.

[0343] LC-MS: [M+H]+= 484.1. 1H NMR (400 MHz, DMSO-d6): δ 13.14 (br s, 1H), 11.41 (s, 1H), 10.62 (br s, 1H), 8.99 (s, 1H), 8.51 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 1.1 Hz, 1H), 7.49 (s, 1H), 7.29 (s, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.67 (s, 1H), 5.76 (s, 2H), 4.54 - 4.40 (m, 2H), 3.44 (d, J = 6.1 Hz, 2H), 3.27 - 3.11 (m, 2H), 2.58 (s, 3H), 2.14 - 1.96 (m, 5H), 1.91 - 1.68 (m, 3H).

[0344] Example 48: Synthesis of E-48: 4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3-fluoro-N,n-dimethyl-1H-indazol-6-amine TIFF2025530847000479.tif74170

[0345] E48-1: 4-Bromo-3-fluoro-6-nitro-1H-indazole To a solution of 4-bromo-6-nitro-1H-indazole (5.00 g, 20.7 mmol, 1.00 eq) in MeCN (50.0 mL) and AcOH (10.0 mL) was added a selective fluorination reagent (7.32 g, 20.7 mmol, 1.00 eq), and the resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was concentrated, and the residue was diluted with water (30.0 mL) and extracted with ethyl acetate (10.0 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (50 / 1 to 3 / 1)) to give intermediate E48-1 (2.00 g, 37.2%) as a yellow solid.

[0346] LC-MS: [M-H] = 259.0. E48-2: 4-Bromo-3-fluoro-6-nitro-1-(tetrahydro 2H-pyran-2-yl)-1H-indazole Intermediate E48-2 (1.10 g, 41.6%) was prepared as a yellow solid from intermediate E48-1 in the manner described for intermediate 2-a.

[0347] 1H NMR (400 MHz, chloroform-d): δ 8.45 (t, J = 1.75 Hz, 1 H), 8.19 (d, J = 1.63 Hz, 1 H), 5.68 (dt, J = 8.60, 2.20 Hz, 1 H), 3.96 - 4.01 (m, 1 H), 3.73 - 3.80 (m, 1 H), 2.36 - 2.45 (m, 1 H), 2.09 - 2.18 (m, 2 H), 1.68 - 1.76 (m, 3 H). E48-3: 3-Fluoro-6-nitro-1-(tetrahydro2H-pyran-2-yl)-4-((trimethylsilyl)ethynyl)-1H-indazole Intermediate E48-3 (200 mg, 54.0%) was prepared as a brown solid from intermediate E48-2 in the manner described for intermediate 2-b.

[0348] LC-MS: [M+H]+ = 362.1. E48-4: 4-ethynyl-3-fluoro-6-nitro-1-(tetrahydro 2H-pyran-2-yl)-1H-indazole Intermediate E48-4 (130 mg, 81.2%) was prepared as a yellow solid from intermediate E48-3 in the manner described for intermediate I-2.

[0349] LC-MS: [M+H]+= 290.0. E48-5: tert-butyl (2-((4-(3-fluoro-6-nitro-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E48-5 (150 mg, 50.6%) was prepared as a yellow solid from intermediate E48-4 in the manner described for intermediate 4-d.

[0350] LC-MS: [M+H]+= 660.3. E48-6: tert-butyl (2-((4-(6-amino-3-fluoro-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Intermediate E48-6 (100 mg, 69.8%) was prepared as a yellow solid from intermediate E48-5 in the manner described for intermediate E3-2.

[0351] LC-MS: [M+H]+= 630.4. E48-7: tert-Butyl (cyclobutylmethyl) ((2-((4-(6-(dimethylamino)-3-fluoro-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl) imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E48-7 (60 mg, 57.4%) was prepared as a yellow solid from intermediate E48-6 in the manner described for intermediate E5-1.

[0352] LC-MS: [M+H]+ = 658.4. E-48: 4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3-fluoro-N,n-dimethyl-1H-indazol-6-amine Compound E-48 (24.6 mg, 52.5%) was prepared as a white solid from intermediate E48-7 in the manner described for compound E-1.

[0353] LC-MS: [M+H]+= 474.3. 1H NMR (400 MHz, DMSO-d6): δ 12.44 (brs, 1 H) 9.68 (br s, 2 H) 9.07 (s, 1 H) 8.75 (s, 1 H) 8.52 (s, 1 H) 8.15 - 8.22 (m, 1 H) 7.99 (d, J = 9.26 Hz, 1 H) 7.50 (br s, 1 H) 6.66 - 6.98 (m, 1 H) 6.10 (s, 2 H) 4.24 (t, J= 5.25 Hz, 2 H) 3.06 (s, 6 H) 2.90 - 2.97 (m, 2 H) 2.65 - 2.76 (m, 1 H) 2.00 - 2.09 (m, 2 H) 1.71 - 1.90 (m, 4 H).

[0354] Example 49: Synthesis of E-49: 4-(1-((6-(6-(6-azaspiro[3.4]octan-6-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole TIFF2025530847000480.tif50170

[0355] E49-1: 4-(1-((6-((6-azaspiro[3.4]octan-6-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-selenocyano-1-(tetrahydro2H-pyran-2-yl)-1H-indazole Intermediate E31-2 (0.03 g, 55.8 μmol, 1.00 eq) was dissolved in HCl (8 M, 1.00 mL), and NaNO (3 M, 37.2 μL, 2.00 eq) was added. The resulting mixture was stirred at 0 °C for 1 hour. Saturated sodium acetate was then added dropwise to the mixture to adjust the pH to 6 at 0 °C, and potassium selenocyanate (32.2 mg, 223 μmol, 4.00 eq) was added. The resulting mixture was then stirred at 0 °C for 10 minutes. The mixture was quenched with water (1.00 mL) at 0 °C and extracted with EtOAc (2.00 mL * 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate E49-1 (0.03 g, crude product) as a brown oil.

[0356] LC-MS: [M+H]+ = 628. E49-2: 4-(1-((6-((6-azaspiro[3.4]octan-6-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-(methylsilanyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole Intermediate E49-2 (100 mg, 69.8%) was prepared as a yellow solid from intermediate E49-1 in the manner described for intermediate E14-2.

[0357] LC-MS: [M+H]+= 616. E-49: 4-(1-((6-((6-azaspiro[3.4]octan-6-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-(methylsilanyl)-1H-indazole Compound E-49 (100 mg, 69.8%) was prepared as a yellow solid from intermediate E49-2 in the manner described for compound E-1.

[0358] LC-MS: [M+H]+= 533.1. 1H NMR (400 MHz, DMSO-d6): δ 11.83 (br, J = 5.6 Hz, 1H), 9.28 - 9.02 (m, 2H), 8.68 - 8.47 (m, 2H), 8.28 (dd, J= 1.1, 9.4 Hz, 1H), 8.02 (d, J = 9.3 Hz, 1H), 7.64 (d, J = 1.1 Hz, 1H), 7.49 (s, 1H), 6.10 (s, 2H), 4.49 (br, J= 5.6, 13.9 Hz, 2H), 3.51 - 3.32 (m, 2H), 3.24 - 3.04 (m, 2H), 2.47 - 2.44 (m, 3H), 2.19 - 2.08 (m, 2H), 2.07 - 1.96 (m, 3H), 1.91 - 1.84 (m, 1H), 1.83 - 1.67 (m, 2H).

[0359] Example 50: Synthesis of E-50: 1-cyclobutyl-N-((6-((4-(6-methyl-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine TIFF2025530847000481.tif30170

[0360] E50-1: tert-butyl 2-(((cyclobutylmethyl)amino)methyl)-6-((4-(6-methyl-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E50-1 (0.053 g, 67.3%) was prepared as a white solid from intermediate E34-1 in the manner described for intermediate E18-1.

[0361] LC-MS: [M+H]+= 610.3. E-50: 1-Cyclobutyl-N-((6-((4-(6-methyl-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine Compound E-50 (16.2 mg, 40.2%) was prepared as a yellow solid from intermediate E50-1 in the manner described for compound E-3.

[0362] LC-MS: [M+H]+= 426.2. 1H NMR (400 MHz, DMSO-d6): δ11.49 (s, 1 H) 9.27 (br s, 2 H) 8.88 (s, 1 H) 8.49 (d, J= 0.75 Hz, 1 H) 7.57 (d, J = 8.25 Hz, 1 H) 7.49 (d, J = 12.51 Hz, 2 H) 7.29 (s, 1 H) 7.08 - 7.16 (m, 1 H) 6.61 (s, 1 H) 5.75 (s, 2 H) 4.27 (t, J= 4.94 Hz, 2 H) 2.91 - 2.97 (m, 2 H) 2.61 - 2.70 (m, 1 H) 2.47 (s, 3 H) 1.99 - 2.08 (m, 2 H) 1.82 - 1.89 (m, 1 H) 1.74 - 1.81 (m, 3 H).

[0363] Example 51: Synthesis of E-51: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-(methylsilanyl)-1H-indazole TIFF2025530847000482.tif55170

[0364] E51-1: tert-butyl 2-((6-azaspiro[3.4]octan-6-yl)methyl)-6-((4-(6-selenocyano-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E51-1 (0.14 g, crude) was prepared as a pink solid from intermediate E61-1 in the manner described for intermediate E49-1.

[0365] LC-MS: [M+H]+ = 643.2. E51-2: tert-butyl 2-((6-azaspiro[3.4]octan-6-yl)methyl)-6-((4-(6-(methylsilanyl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E51-2 (50 mg, 36.3%) was prepared as a yellow solid from intermediate E51-1 in the manner described for intermediate E14-2.

[0366] LC-MS: [M+H]+= 632.2. E-51: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-(methylsilanyl)-1H-indazole Compound E-51 (11.8 mg, 26.2%) was prepared as a yellow solid from intermediate E51-2 by the method described for compound E-1.

[0367] LC-MS: [M+H]+= 532.1. 1H NMR (400 MHz, DMSO-d6): δ 11.44 (s, 1 H) 10.72 - 10.85 (m, 1 H) 8.99 (s, 1 H) 8.53 (s, 1 H) 7.65 (d, J= 1.10 Hz, 1 H) 7.60 (d, J = 8.19 Hz, 1 H) 7.48 (d, J = 8.07 Hz, 2 H) 7.11 - 7.19 (m, 1 H) 6.67 (s, 1 H) 5.77 (s, 2 H) 4.46 (s, 2 H) 3.42 (dd, J = 11.80, 5.93Hz, 2H) 3.10 - 3.25 (m, 2 H) 2.42 - 2.48 (m, 3 H) 2.06 - 2.14 (m, 2 H) 2.05 (br s, 2 H) 1.97 (s, 2 H) 1.84 (d, J= 6.85 Hz, 2 H).

[0368] Example 52: Synthesis of E-52: 1-(6-((4-(6-(aziridin-1-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine TIFF2025530847000483.tif60170

[0369] E52-1: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(6-((2-chloroethyl)amino)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E52-1 (90 mg, 82.7%) was prepared as a yellow solid from intermediate E33-1 in the manner described for intermediate E6-1.

[0370] LC-MS: [M+H]+ = 773.6. E52-2: N-(2-chloroethyl)-4-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-amine Intermediate E52-2 (15 mg, 29.3%) was prepared as a pink solid from intermediate E52-1 in the manner described for compound E-1.

[0371] LC-MS: [M+H]+ = 489.2. E-52: 1-(6-((4-(6-(aziridin-1-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine Compound E-52 (2.6 mg, 27.8%) was prepared as a white solid from intermediate E52-2 in the manner described for compound E-6.

[0372] LC-MS: [M+H]+= 453.3. 1H NMR (400 MHz, DMSO-d6): δ 12.90 (s, 1H), 11.00 (s, 1H), 8.88 (s, 1H), 8.50 - 8.24 (m, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 1.7 Hz, 2H), 7.03 (d, J = 8.1 Hz, 1H), 6.92 (s, 1H), 6.23 (s, 1H), 5.70 (s, 2H), 3.77 (s, 2H), 2.52 - 2.51 (m, 2H), 2.42 - 2.35 (m, 1H), 2.13 (s, 4H), 1.96 (d, J = 7.8 Hz, 2H), 1.81 - 1.75 (m, 2H), 1.64 - 1.57 (m, 2H).

[0373] Example 53: Synthesis of E-53: 4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-7-fluoro-N,n-dimethyl-1H-indazol-6-amine hydrochloride TIFF2025530847000484.tif126170

[0374] E53-1: 5-Bromo-2,3-difluoroaniline Intermediate E53-1 (7.8 g, 52.5%) was prepared as a yellow oil from 5-bromo-1,2-difluoro-3-nitrobenzene in the manner described for intermediate E3-2.

[0375] LC-MS: [M+H]+= 208.1. E53-2: 5-Bromo-2,3-difluoro-N,N-dimethylaniline Intermediate E53-2 (6.4 g, 72.3%) was prepared as a brown oil from intermediate E53-1 in the manner described for compound E-6.

[0376] LC-MS: [M+H]+= 236.1. E53-3: 6-Bromo-4-(dimethylamino)-2,3-difluorobenzaldehyde Under a nitrogen atmosphere, DMF (2.58 g, 35.3 mmol, 2.71 mL, 1.30 eq) and phosphorus oxychloride (4.99 g, 32.5 mmol, 3.02 mL, 1.20 eq) were added to a solution of intermediate E53-2 (6.40 g, 27.1 mmol, 1.00 eq) in toluene (64.0 mL), and the resulting mixture was stirred at 100 °C for 20 h. The reaction was quenched by the addition of 2N NaOH (60.0 mL) at 0 °C, diluted with ice water (40 mL), and extracted with ethyl acetate (40.0 mL*3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (100 / 1 to 10 / 1)) to give intermediate E53-3 (1.4 g, 19.6%) as a white solid.

[0377] LC-MS: [M+H]+ = 264.1. E53-4: 4-Bromo-7-fluoro-N,N-dimethyl-1H-indazol-6-amine To a solution of intermediate E53-3 (1.80 g, 6.82 mmol, 1.00 eq) in 1,4-dioxane (18.0 mL), hydrazine hydrate (1.44 g, 28.8 mmol, 1.40 mL, 4.22 eq) was added, and the resulting mixture was stirred at 110 °C for 48 h. The mixture was cooled to room temperature and concentrated. The residue was diluted with water (50.0 mL) and extracted with ethyl acetate (20.0 mL*3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to give intermediate E53-4 (1.40 g, 79.6%) as a yellow solid.

[0378] LC-MS: [M+H]+ = 257.8. E53-5: 4-Bromo-7-fluoro-N,n-dimethyl-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-6-amine Intermediate E53-5 (300 mg, 82.9%) was prepared as a green oil from intermediate E53-4 in the manner described for intermediate 2-a.

[0379] LC-MS: [M+H]+ = 342.2. E53-6: 7-Fluoro-N,n-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-((trimethylsilyl)ethynyl)-1H-indazol-6-amine To a solution of intermediate E53-5 (330 mg, 847 μmol, 1 eq) and trimethylsilylethynyl ether (416 mg, 4.24 mmol, 587 μL, 5 eq) in triethylamine (3.3 mL) was added copper iodide (16.1 mg, 84.7 μmol, 0.10 eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (62.0 mg, 84.7 μmol, 0.10 eq) at 25 °C. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 16 h. The mixture was quenched with water (5.00 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (3:1) to give intermediate E53-6 (280 mg, 80.7%) as a brown oil.

[0380] LC-MS: [M+H]+= 360.2. E53-7: 4-ethynyl-7-fluoro-N,n-dimethyl-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-6-amine Intermediate E53-7 (200 mg, 89.4%) was prepared as a brown oil from intermediate E53-6 in the manner described for intermediate I-2.

[0381] LC-MS: [M+H]+ = 288.1. E53-8: tert-Butyl (cyclobutylmethyl) ((2-((4-(6-(dimethylamino)-7-fluoro-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl) imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E53-8 (90 mg, 86.5%) was prepared as a brown oil from intermediate E53-7 in the manner described for intermediate 4-d.

[0382] LC-MS: [M+H]+ = 658.3. E-53: 4-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-7-fluoro-N,n-dimethyl-1H-indazol-6-amine hydrochloride Intermediate E-53 (14.4 mg, 99.4%) was prepared as a white solid from intermediate E53-8 in the manner described for compound E-1.

[0383] LC-MS: [M+H]+= 474.2. 1H NMR (400 MHz, DMSO-d6): δ 9.29 (d, J = 4.00 Hz, 2 H) 8.98 (s, 1 H) 8.90 (s, 1 H) 8.49 (d, J = 3.38 Hz, 1 H) 8.39 (s, 1 H) 7.86 (br s, 2 H) 7.41 (d, J = 6.88 Hz, 1 H) 5.97 (s, 2 H) 4.20 (t, J = 5.25 Hz, 4 H) 2.95 (br s, 1 H) 2.93 (s, 6 H) 2.63 - 2.70 (m, 1 H) 2.01 - 2.07 (m, 2 H) 1.75 - 1.86 (m, 4 H).

[0384] Example 54: Synthesis of E-54: 1-(4-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-yl)-N,N-dimethylmethanamine TIFF2025530847000485.tif123170

[0385] E54-1: (4-bromo-1H-indazol-6-yl)methanol A solution of 4-bromo-1H-indazole-6-carboxylic acid methyl ester (6.00 g, 23.5 mmol, 1.00 eq) in THF (60.0 mL) was added to a solution of LAH (1.34 g, 35.3 mmol, 1.50 eq) in THF (30.0 mL) at 0 °C under a nitrogen atmosphere, and the resulting mixture was stirred at 25 °C for 0.5 h. The mixture was quenched with 15% aqueous NaOH (4.20 mL) and water (4.2 mL) at 0 °C. The resulting mixture was filtered and concentrated to give intermediate E54-1 (4.80 g, crude product) as a white solid.

[0386] LC-MS: [M+H]+= 226.9. E54-2: 4-Bromo-1H-indazole-6-carbaldehyde To a stirred solution of intermediate E54-1 (4.30 g, 18.9 mmol, 1.00 eq) in DCM (43.0 mL) was added manganese dioxide (16.5 g, 189 mmol, 10.0 eq), and the resulting mixture was stirred at 25 °C for 16 h. The mixture was filtered and washed with ethyl acetate (50.0 mL * 4). The combined filtrate was concentrated to give intermediate E54-2 (2.50 g, crude product) as a white solid.

[0387] LC-MS: [M+H]+= 225.0. E54-3: 1-(4-bromo-1H-indazol-6-yl)-N,N-dimethylmethanamine To a stirred solution of intermediate E54-2 (900 mg, 4.00 mmol, 1.00 eq) in DCM (9.00 mL) was added dimethylamine (541 mg, 4.80 mmol, 608 μL, 40% purity, 1.20 eq), and the mixture was stirred at 25 °C under a nitrogen atmosphere for 0.5 h. Sodium cyanoborohydride (319 mg, 5.08 mmol, 1.27 eq) was then added, and the resulting mixture was stirred at 25 °C for 2 h. The mixture was quenched with water (10.0 mL) and extracted with DCM (5.00 mL*3). The combined organic layers were washed with brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH (5:1)) to give intermediate E54-3 (270 mg, 26.6%) as a white solid.

[0388] LC-MS: [M+H]+= 254.0. E54-4: 1-(4-bromo-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-6-yl)-N,N-dimethylmethanamine Intermediate E54-4 (90 mg, 86.5%) was prepared as a yellow solid from intermediate E54-3 in the manner described for intermediate 2-a.

[0389] LC-MS: [M+H]+= 338.0. E54-5: N,N-dimethyl-1-(1-(tetrahydro2H-pyran-2-yl)-4-((trimethylsilyl)ethynyl)-1H-indazol-6-yl)methanamine Intermediate E54-5 (90 mg, 86.5%) was prepared as a brown oil from intermediate E54-4 in the manner described for intermediate E53-6.

[0390] LC-MS: [M+H]+ = 356.3. E54-6: 1-(4-ethynyl-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-6-yl)-N,n-dimethylmethanamine Intermediate E54-6 (37 mg, 46.4%) was prepared as a brown oil from intermediate E54-5 in the manner described for intermediate I-2.

[0391] LC-MS: [M+H]+ = 284.1. E54-7: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(6-((dimethylamino)methyl)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E54-7 (30 mg, 30.5%) was prepared as a brown oil from intermediate E54-6 in the manner described for intermediate 4-d.

[0392] LC-MS: [M+H]+ = 753.5. E-54: 1-(4-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-yl)-N,N-dimethylmethanamine Intermediate E-54 (7.80 mg, 38.1%) was prepared as a yellow solid from intermediate E54-7 in the manner described for compound E-1.

[0393] LC-MS: [M+H]+= 469.0. 1H NMR (400 MHz, DMSO-d6):δ 13.50 - 13.60 (m, 1 H) 11.63 (br s, 1 H) 10.62 - 10.77 (m, 1 H) 9.44 (br s, 2 H) 8.85 (s, 1 H) 8.61 (br s, 1 H) 7.84 (s, 1 H) 7.76 (s, 1 H) 7.56 (d, J = 8.07 Hz, 1 H) 7.49 (s, 1 H) 7.10 (d, J = 8.07 Hz, 1 H) 6.60 (s, 1 H) 5.77 (s, 2 H) 4.42 (d, J = 2.57 Hz, 2 H) 4.26 (br s, 2 H) 2.91 (d, J = 3.30 Hz, 2 H) 2.71 (d, J = 2.69 Hz, 6 H) 2.66 (br s, 1 H) 2.00 - 2.06 (m, 2 H) 1.74 - 1.84 (m, 4H).

[0394] Example 55: Synthesis of E-55: 6-(aziridin-1-yl)-4-(1-((2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazole TIFF2025530847000486.tif51170

[0395] E55-1: 4-(1-((2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole Intermediate E55-1 (180 mg, 18.1%) was prepared as a brown oil from intermediate E42-4 in the manner described for intermediate E30-1.

[0396] LC-MS: [M+H]+= 569.4. E55-2: 4-(1-((2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine Intermediate E55-2 (66 mg, 53.6%) was prepared as a brown oil from intermediate E55-1 in the manner described for intermediate E3-2.

[0397] LC-MS: [M+H]+ = 539.4. E55-3: N-(2-chloroethyl)-4-(1-((2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-6-amine Intermediate E55-3 (46 mg, 62.5%) was prepared as a yellow solid from intermediate E55-2 in the manner described for intermediate E6-1.

[0398] LC-MS: [M+H]+ = 601.4. E55-4: N-(2-chloroethyl)-4-(1-((2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-6-amine Intermediate E55-4 (39 mg, crude) was prepared as a red oil from intermediate E55-3 in the manner described for compound E-1.

[0399] LC-MS: [M+H]+= 517.3. E-55: 6-(aziridin-1-yl)-4-(1-((2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazole Intermediate E-55 (5.8 mg, 17%) was prepared as a yellow solid from intermediate E55-4 in the manner described for compound E-6.

[0400] LC-MS: [M+H]+= 481.4. 1H NMR (400 MHz, DMSO-d6): δ 12.78 - 12.96 (m, 1 H) 11.05 (s, 1 H) 8.88 (s, 1 H) 8.42 (s, 1 H) 7.44 (d, J = 8.13 Hz, 1 H) 7.35 - 7.38 (m, 2 H) 7.03 (dd, J = 8.19, 1.31 Hz, 1 H) 6.92 (s, 1 H) 6.24 (d, J = 0.75 Hz, 1 H) 5.70 (s, 2 H) 3.57 (s, 2 H) 2.33 (d, J = 4.00Hz, 4H) 2.13 (s, 4 H) 1.31 (t, J = 5.44 Hz, 4 H) 0.87 (s, 6 H).

[0401] Example 56: Synthesis of E-56: 1-(6-((4-(6-(aziridin-1-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)methanamine TIFF2025530847000487.tif69170

[0402] E56-1: tert-butyl 2-(((tert-butoxycarbonyl)((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)-6-((4-(6-((2-chloroethyl)amino)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E56-1 (80 mg, 73.8%) was prepared as a yellow solid from intermediate E60-2 in the manner described for intermediate E6-1.

[0403] LC-MS: [M+H]+ = 803.5. E56-2: N-(2-chloroethyl)-4-(1-((2-(((((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-amine Intermediate E56-2 (50 mg, crude) was prepared as a yellow solid from intermediate E56-1 in the manner described for compound E-1.

[0404] LC-MS: [M+H]+ = 519.4. E-56: 1-(6-((4-(6-(aziridin-1-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)methanamine Compound E-56 (5.7 mg, 12.9%) was prepared as a yellow solid from intermediate E56-2 in the manner described for compound E-6.

[0405] LC-MS: [M+H]+= 483.3. 1H NMR (400 MHz, DMSO-d6): δ 12.89 (s, 1 H) 11.00 (s, 1 H) 8.87 (s, 1 H) 8.42 (s, 1 H) 7.44 (d, J= 8.13 Hz, 1 H) 7.36 (s, 2 H) 7.03 (d, J = 8.25 Hz, 1 H) 6.92 (s, 1 H) 6.24 (s, 1 H) 5.70 (s, 2 H) 3.81 (br s, 2 H) 2.75 (br s, 2 H) 2.42 - 2.47 (m, 1 H) 2.13 (s, 4H) 1.92 (d, J = 2.63 Hz, 6 H).

[0406] Example 57: Synthesis of E-57: 4-(1-((2-((((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethyl-1H-indazol-6-amine TIFF2025530847000488.tif29170

[0407] E57-1: tert-butyl 2-(((tert-butoxycarbonyl)((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)-6-((4-(6-(dimethylamino)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E57-1 (50 mg, 48.2%) was prepared as a white solid from intermediate E60-2 in the manner described for intermediate E5-1.

[0408] LC-MS: [M+H]+= 769.6. E-57: 4-(1-((2-((((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethyl-1H-indazol-6-amine Compound E-57 (6.7 mg, 21.3%) was prepared as a yellow solid from intermediate E57-1 by the method described for compound E-1.

[0409] LC-MS: [M+H]+= 485.3. 1H NMR (400 MHz, DMSO-d6): δ 12.59 (s, 1 H) 10.99 (s, 1 H) 8.86 (s, 1 H) 8.32 (s, 1 H) 7.44 (d, J= 8.13 Hz, 1 H) 7.35 (s, 1 H) 7.25 (d, J = 1.88 Hz, 1 H) 6.98 - 7.09 (m, 1 H) 6.53 (s, 1 H) 6.24 (s, 1 H) 5.70 (s, 2 H) 3.81 (s, 2 H) 2.99 (s, 6 H) 2.74 (s, 2 H) 1.98 - 2.13 (m, 1 H) 1.92 (d, J = 2.75 Hz, 6 H).

[0410] Example 58: Synthesis of E-58: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethyl-1H-indazol-6-amine TIFF2025530847000489.tif33170

[0411] E58-1: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine Intermediate E58-1 (15 mg, 19.7%) was prepared as a yellow solid from intermediate E61-1 in the manner described for intermediate E5-1.

[0412] LC-MS: [M+H]+ = 665.3. E-58: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethyl-1H-indazol-6-amine Compound E-58 (2.7 mg, 20.7%) was prepared as a yellow solid from intermediate E58-1 by the method described for compound E-1.

[0413] LC-MS: [M+H]+= 481.2. 1H NMR (400 MHz, DMSO-d6): δ 11.28 - 11.67 (m, 1 H) 10.78 - 11.16 (m, 1 H) 8.85 - 9.05 (m, 1 H) 8.27 - 8.53 (m, 1 H) 7.54 - 7.66 (m, 1 H) 7.37 - 7.54 (m, 2 H) 7.08 - 7.17 (m, 1 H) 6.63 - 6.70 (m, 1 H) 5.68 - 5.84 (m, 2 H) 4.43 - 4.48 (m, 2 H) 3.34 - 3.46 (m, 2H) 3.11 - 3.23 (m, 2 H) 3.10 (s, 6 H) 1.97 - 2.12 (m, 4 H) 1.65 - 1.95 (m, 4 H).

[0414] Example 59: Synthesis of E-59: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-(aziridin-1-yl)-1H-indazole TIFF2025530847000490.tif68170

[0415] E59-1: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-(2-chloroethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine Intermediate E59-1 (60 mg, 54.9%) was prepared as a yellow solid from intermediate E61-1 in the manner described for intermediate E6-1.

[0416] LC-MS: [M+H]+ = 699.4. E59-2: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-(2-chloroethyl)-1H-indazol-6-amine Intermediate E59-2 (50 mg, crude) was prepared as a yellow solid from intermediate E59-1 in the manner described for compound E-1.

[0417] LC-MS: [M+H]+ = 515.4. E-59: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-(aziridin-1-yl)-1H-indazole Compound E-59 (5.4 mg, 12.6%) was prepared as a yellow solid from intermediate E59-2 in the manner described for compound E-6.

[0418] LC-MS: [M+H]+= 479.3. 1H NMR (400 MHz, DMSO-d6): δ 12.93 (s, 1 H) 11.12 - 11.15 (m, 1 H) 8.91 (s, 1 H) 8.44 - 8.46 (m, 1 H) 7.46 (d, J = 7.82 Hz, 1 H) 7.38 (d, J = 4.52 Hz, 2 H) 7.06 (d, J = 7.95 Hz, 1 H) 6.94 (s, 1 H) 6.26 (s, 1 H) 5.72 (s, 2 H) 3.67 (s, 2 H) 2.16 (s, 4 H) 1.94 (s, 2H) 1.90 - 1.93 (m, 2 H) 1.85 - 1.90 (m, 2 H) 1.82 - 1.85 (m, 2 H) 1.76 - 1.81 (m, 2 H) 1.65 - 1.76 (m, 2 H).

[0419] Example 60: Synthesis of E-60: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((6-((4-(6-(methylsilanyl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine TIFF2025530847000491.tif55170

[0420] E60-1: tert-butyl 2-(((tert-butoxycarbonyl)((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)-6-((4-(6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E60-1 (90 mg, 65.3%) was prepared as a yellow solid from intermediate E42-4 in the manner described for intermediate 1-b.

[0421] LC-MS: [M+H]+= 771.4. E60-2: tert-butyl 6-((4-(6-amino-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-(((tert-butoxycarbonyl)((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)-1H-indole-1-carboxylate Intermediate E60-2 (75 mg, 86.7%) was prepared as a white solid from intermediate E60-1 in the manner described for intermediate E3-2.

[0422] LC-MS: [M+H]+ = 741.4. E60-3: tert-butyl 2-(((tert-butoxycarbonyl)((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)-6-((4-(6-selenocyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E60-3 (100 mg, crude) was prepared as a brown solid from intermediate E60-2 in the manner described for intermediate E14-1.

[0423] LC-MS: [M+H]+ = 831.3. E60-4: tert-butyl 2-(((tert-butoxycarbonyl)((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)-6-((4-(6-(methylsilyl)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E60-4 (50.0 mg, 50.7%) was prepared as a yellow solid from intermediate E60-3 in the manner described for intermediate E14-2.

[0424] LC-MS: [M+H]+ = 820.3. E-60: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((6-((4-(6-(methylsilanyl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine Compound E-60 (7.8 mg, 22.1%) was prepared as a yellow solid from intermediate E60-4 in the manner described for compound E-3.

[0425] LC-MS: [M+H]+= 536.1. 1H NMR (400 MHz, DMSO-d6): δ 11.40 (s, 1 H) 9.31 (br s, 2 H) 8.99 (s, 1 H) 8.53 (s, 1 H) 7.64 (d, J= 1.10 Hz, 1 H) 7.58 (d, J = 8.19 Hz, 1 H) 7.50 (s, 1 H) 7.46 (s, 1 H) 7.13 (dd, J = 8.19, 1.22 Hz, 1 H) 6.62 (s, 1 H) 5.63 - 5.88 (m, 2 H) 4.21 - 4.38 (m, 2 H) 3.20 - 3.32 (m, 2 H) 2.45 (s, 3 H) 2.11 (d, J= 2.57 Hz, 6 H).

[0426] Example 61: Synthesis of E-61: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-amine TIFF2025530847000492.tif32170

[0427] E61-1: tert-butyl 2-((6-azaspiro[3.4]octan-6-yl)methyl)-6-((4-(6-amino-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E61-1 (60.0 mg, 62.8%) was prepared as a yellow solid from intermediate E46-1 in the manner described for intermediate E3-2.

[0428] LC-MS: [M+H]+ = 637.5. E-61: 4-(1-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-6-amine Compound E-61 (31.7 mg, 68.8%) was prepared as a dark brown oil from intermediate E61-1 in the manner described for compound E-3.

[0429] LC-MS: [M+H]+= 453.3. 1H NMR (400 MHz, DMSO-d6): δ 11.61 (s, 1 H) 11.33 (d, J = 5.38 Hz, 1 H) 9.11 (s, 1 H) 8.65 (s, 1 H) 7.59 - 7.66 (m, 3 H) 7.53 (s, 1 H) 7.18 (dd, J= 8.25, 1.16 Hz, 1 H) 6.69 (s, 1 H) 5.80 (s, 2 H) 4.48 (t, J = 5.75 Hz, 2 H) 3.40 (dd, J = 10.15, 4.52 Hz, 2 H) 3.10 - 3.24 (m, 2 H) 2.06 - 2.16 (m, 2 H) 1.98 - 2.05 (m, 2 H) 1.86 - 1.98 (m, 2 H) 1.74 - 1.85 (m, 2 H).

[0430] Example 62: Synthesis of E-62: 5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-amine TIFF2025530847000493.tif50170

[0431] E62-1: 3-nitro-5-((trimethylsilyl)ethynyl)pyridine Intermediate E62-1 (9.8 g, 45.2%) was prepared as a black solid from 3-bromo-5-nitropyridine in the manner described for intermediate 2-b.

[0432] LC-MS (ESI): m / z 221.1 [M+H]+. E62-2: 3-ethynyl-5-nitropyridine Intermediate E62-2 (5.1 g, 77.4%) was prepared as a yellow solid from intermediate E62-1 in the manner described for intermediate I-2.

[0433] LC-MS (ESI): m / z 149.2 [M+H] +. E62-3: tert-butyl (2-((4-(5-nitropyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E62-3 (1.2 g, 76.2%) was prepared as a yellow solid from intermediate E62-2 by the method described for intermediate 4-d.

[0434] LC-MS (ESI): m / z 519.4 [M+H] +. E62-4: tert-butyl (2-((4-(5-aminopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Intermediate E62-4 (0.18 g, crude) was prepared as a yellow solid from intermediate E62-3 in the manner described for intermediate E3-2.

[0435] 1H NMR (400 MHz, chloroform-d): δ 8.27 (s, 1H), 7.97 (d, J = 5.3 Hz, 2H), 7.87 (s, 1H), 7.56 - 7.42 (m, 3H), 7.09 (s, 1H), 5.67 (s, 2H), 4.31 (s, 2H), 3.71 (s, 2H), 3.16 (s, 2H), 2.44 (s, 1H), 1.90 (s, 2H), 1.77 (d, J = 7.5 Hz, 2H), 1.62 (d, J = 8.0 Hz, 2H), 1.41 (s, 9H). E-62: 5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-amine Compound E-62 (0.18 g, crude) was prepared as a white solid from intermediate E62-4 in the manner described for compound E-1.

[0436] LC-MS (ESI): m / z 389.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ9.70 - 9.58 (m, 1H), 9.64 (br s, 1H), 9.06 - 8.99 (m, 2H), 8.46 (d, J = 6.6 Hz, 2H), 8.12 (s, 1H), 8.08 - 8.01 (m, 2H), 7.91 (d, J = 9.4 Hz, 1H), 6.04 (s, 2H), 4.26 - 4.20 (m, 1H), 4.26 - 4.19 (m, 1H), 2.99 - 2.92 (m, 2H), 2.78 - 2.70 (m, 1H), 2.10 - 2.01 (m, 2H), 1.91 - 1.77 (m, 4H).

[0437] Example 63: Synthesis of E-63: 1-(2-((4-(5-bromopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine TIFF2025530847000494.tif72170

[0438] E63-1: 3-Bromo-5-((trimethylsilyl)ethynyl)pyridine Intermediate E63-1 (20.0 g, 89.4%) was prepared as a black solid from 3-bromo-5-iodopyridine in the manner described for intermediate 2-b.

[0439] LC-MS (ESI): m / z 256.0 [M+H]+. E63-2: 3-Bromo-5-ethynylpyridine Intermediate E63-2 (5.1 g, 77.4%) was prepared as a yellow solid from intermediate E63-1 in the manner described for intermediate I-2.

[0440] LC-MS (ESI): m / z 181.9 [M+H]+. E63-3: tert-butyl (2-((4-(5-bromopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Intermediate E63-3 (3.3 g, 82.0%) was prepared as a purple solid from intermediate E63-2 by the method described for intermediate 4-d.

[0441] LC-MS (ESI): m / z 552.1 [M+H]+ . E-63: 1-(2-((4-(5-bromopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine Compound E-63 (35.0 mg, 49.5%) was prepared as a white solid from intermediate E63-3 by the method described for compound E-1.

[0442] LC-MS (ESI): m / z 452.0 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 9.01 (s, 1 H) 8.92 (s, 1 H) 8.82 (s, 1 H) 8.66 (d, J = 1.88 Hz, 1 H) 8.44 (t, J = 2.00 Hz, 1 H) 8.42 (s, 1 H) 7.96 - 8.00 (m, 1 H) 7.88 - 7.92 (m, 1 H) 6.01 (s, 2 H) 4.24 (s, 2 H) 2.99 (d, J= 7.50 Hz, 2 H) 2.60 (dt, J = 15.17, 7.61 Hz, 1 H) 1.98 - 2.06 (m, 2 H) 1.76 - 1.88 (m, 2 H) 1.70 - 1.75 (m, 2 H).

[0443] Example 64: Synthesis of E-64: 5-(1-((6-((4,4-dimethylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethylpyridin-3-amine TIFF2025530847000495.tif79170

[0444] E64-1: (2-((4-(5-(dimethylamino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methanol Intermediate E64-1 (0.60 g, 41.8%) was prepared as a yellow solid from intermediate E38-3 in the manner described for intermediate 4-d.

[0445] LC-MS (ESI): m / z 350.2 [M+H]+ . E64-2: 2-((4-(5-(dimethylamino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carbaldehyde Intermediate E64-2 (180 mg, 60.3%) was prepared as a yellow solid from intermediate E64-1 in the manner described for intermediate E54-2.

[0446] LC-MS (ESI): m / z 348.1 [M+H]+ . E-64: 5-(1-((6-((4,4-dimethylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethylpyridin-3-amine Compound E-64 (47.0 mg, 38.3%) was prepared as a brown solid from compound E-62 in the manner described for intermediate E30-1.

[0447] LC-MS (ESI): m / z 445.3 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ8.70 (s, 1H), 8.44 (s, 1H), 8.37 (d, J= 1.6 Hz, 1H), 8.07 (d, J = 2.8 Hz, 1H), 7.96 (s, 1H), 7.49 - 7.44 (m, 2H), 7.21 (dd, J = 1.5, 9.4 Hz, 1H), 5.74 (s, 2H), 3.44 (s, 2H), 2.98 (s, 6H), 2.34 (d, J = 3.9 Hz, 4H), 1.31 (t, J = 5.4 Hz, 4H), 0.89 (s, 6H).

[0448] Example 65: Synthesis of E-65: N-((6-((((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-5-(pyrrolidin-1-yl)nicotinamide TIFF2025530847000496.tif23170

[0449] E-65 (15.1 mg, 39.4%) was prepared as a white solid from E123-3 by the method described for E30-1.

[0450] LC-MS: [M+H]+= 449.1. 1H NMR (400 MHz, DMSO-d6): δ 9.07 (t, J = 5.7 Hz, 1H), 8.36 (s, 1H), 8.31 (d, J = 1.6 Hz, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.75 (s, 1H), 7.46-7.37 (m, 1H), 7.33-7.28 (m, 1H), 7.20 (dd, J= 1.6, 9.3 Hz, 1H), 4.56 (d, J = 5.8 Hz, 2H), 3.66 (s, 2H), 3.31-3.28 (m, 4H), 2.74 (s, 2H), 2.00-1.95 (m, 4H), 1.94-1.90 (m, 6H).

[0451] Example 66: Synthesis of E-66: 1-(6-((4-(5-bromopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine hydrochloride TIFF2025530847000497.tif25170

[0452] E66-1: tert-butyl 6-((4-(5-bromopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate Intermediate E66-1 (320 mg, 76.9%) was prepared as a white solid from intermediate I-7 in the manner described for intermediate 4-d.

[0453] LC-MS (ESI): m / z652.2 [M+H]+ . E-66: 1-(6-((4-(5-bromopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine hydrochloride Compound E-66 (20.3 mg, 38.3%) was prepared as a white solid from intermediate E66-1 in the manner described for compound E-3.

[0454] LC-MS (ESI): m / z 453.0 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ11.36 (br s, 1 H) 9.05 (d, J = 1.75 Hz, 2 H) 8.83 (s, 1 H) 8.66 (d, J = 2.13 Hz, 1 H) 8.46 (t, J = 1.94 Hz, 1 H) 7.57 (d, J = 8.00 Hz, 1 H) 7.46 (s, 1 H) 7.07 (d, J = 8.25 Hz, 1 H) 6.60 (s, 1 H) 5.74 (s, 2 H) 4.26 (t, J = 5.19Hz, 2H) 2.94 - 2.99 (m, 2 H) 2.64 (br s, 1 H) 1.99 - 2.10 (m, 2 H) 1.78 - 1.90 (m, 2 H) 1.72 - 1.78 (m, 2 H).

[0455] Example 67: Synthesis of E-67: 1-cyclobutyl-N-((2-((4-(5-morpholinopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000498.tif22170

[0456] E67-1: tert-butyl (2-((4-(5-morpholinopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E67-1 (70 mg, 69.2%) was prepared as a yellow solid from intermediate E63-3 in the manner described for intermediate E15-1.

[0457] LC-MS (ESI): m / z 559.3 [M+H]+ . E-67: 1-Cyclobutyl-N-((2-((4-(5-morpholinopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-67 (41.4 mg, 66.3%) was prepared as a white solid from intermediate E67-1 in the manner described for compound E-34.

[0458] LC-MS (ESI): m / z 459.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 9.66 (br s, 2H), 9.14 (s, 1H), 9.01 (s, 1H), 8.64 (s, 1H), 8.51 - 8.41 (m, 2H), 8.35 (s, 1H), 8.00 (d, J = 9.3 Hz, 1H), 7.87 (d, J = 9.3 Hz, 1H), 6.02 (s, 2H), 4.21 (t, J = 5.2 Hz, 2H), 3.81 - 3.72 (m, 4H), 3.48 - 3.40 (m, 4H), 3.00 - 2.88 (m, 2H), 2.72 (td, J = 7.5, 14.9 Hz, 1H), 2.11 - 2.01 (m, 2H), 1.89 - 1.74 (m, 4H).

[0459] Example 68: Synthesis of E-68: 1-cyclobutyl-N-((2-((4-(5-(piperidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000499.tif23170

[0460] E68-1: tert-butyl (2-((4-(5-(piperidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E68-1 (50 mg, 49.6%) was prepared as a yellow solid from intermediate E63-3 in the manner described for intermediate E15-1.

[0461] LC-MS (ESI): m / z 557.3 [M+H]+ . E-68: 1-Cyclobutyl-N-((2-((4-(5-(piperidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-68 (22.4 mg, 50.6%) was prepared as a yellow solid from intermediate E68-1 by the method described for compound E-1.

[0462] 1H NMR (400 MHz, DMSO-d6): δ 9.58 (br s, 2 H) 9.12 (s, 1 H) 8.95 (s, 1 H) 8.53 (s, 1 H) 8.37 - 8.43 (m, 2 H) 8.30 (s, 1 H) 7.88 - 7.95 (m, 1 H) 7.79 - 7.85 (m, 1 H) 5.98 (s, 2 H) 4.19 (t, J= 5.25 Hz, 2 H) 3.48 (br s, 4 H) 2.89 - 2.98 (m, 2 H) 2.65 - 2.76 (m, 1 H) 2.00 - 2.10 (m, 2 H) 1.75 - 1.88 (m, 4 H) 1.62 (br s, 6 H). LC-MS (ESI): m / z 457.2 [M+H]+ .

[0463] Example 69: Synthesis of E-69: 1-cyclobutyl-N-((2-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000500.tif27170

[0464] E69-1: tert-butyl (2-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E69-1 (70 mg, 71.3%) was prepared as a yellow solid from intermediate E63-3 in the manner described for intermediate E15-1.

[0465] LC-MS (ESI): m / z 543.3 [M+H]+ . E-69: 1-Cyclobutyl-N-((2-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-69 (26.6 mg, 42.7%) was prepared as a white solid from intermediate E69-1 in the manner described for compound E-34.

[0466] LC-MS (ESI): m / z 443.3 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 9.62 (br s, 2H), 9.14 (s, 1H), 9.00 (s, 1H), 8.46 (d, J = 9.9 Hz, 2H), 8.06 (d, J = 2.5 Hz, 1H), 7.99 (d, J = 9.1 Hz, 1H), 7.94 (s, 1H), 7.87 (d, J = 9.4 Hz, 1H), 6.02 (s, 2H), 4.21 (t, J = 5.3 Hz, 2H), 3.42 (br t, J = 6.4 Hz, 4H), 2.98 - 2.91 (m, 2H), 2.80 - 2.64 (m, 1H), 2.09 - 2.00 (m, 6H), 1.89 - 1.76 (m, 4H).

[0467] Example 70: Synthesis of E-70: 5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-methylpyridin-3-amine TIFF2025530847000501.tif21170

[0468] E70-1: tert-butyl (2-((4-(5-(methylamino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E70-1 (60 mg, 29.1%) was prepared as a yellow solid from intermediate E62-4 in the manner described for intermediate E5-1.

[0469] LC-MS (ESI): m / z 503.3 [M+H]+ . E-70: 5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-methylpyridin-3-amine Compound E-70 (40.9 mg, 78.0%) was prepared as a white solid from intermediate E70-1 by the method described for compound E-1.

[0470] LC-MS (ESI): m / z 403.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ9.65 (br s, 2 H), 9.07 (s, 1 H), 9.00 (s, 1 H), 8.45 (d, J = 6.65 Hz, 2 H), 7.98 - 8.07 (m, 3 H), 7.87 (d, J = 9.29 Hz, 1 H), 6.02 (s, 2 H), 4.21 (t, J = 5.21 Hz, 2 H), 2.91 - 2.98 (m, 2 H), 2.85 (s, 3 H), 2.72 (dt, J= 15.00, 7.43 Hz, 1H), 2.00 - 2.10 (m, 2 H), 1.73 - 1.89 (m, 4 H).

[0471] Example 71: Synthesis of E-71: 1-cyclobutyl-N-((2-((4-(5-(methylthio)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000502.tif46170

[0472] E71-1: 3-Bromo-5-(methylthio)pyridine Intermediate E71-1 (8.30 g, crude) was prepared as a yellow solid from 3,5-dibromopyridine in the manner described for intermediate E1-2.

[0473] LC-MS (ESI): m / z204.0 [M+H]+ . E71-2: 3-(methylthio)-5-((trimethylsilyl)ethynyl)pyridine Intermediate E71-2 (4.9 g, 61.8%) was prepared as a yellow oil from intermediate E71-1 in the manner described for intermediate 2-b.

[0474] LC-MS (ESI): m / z222.1 [M+H]+ . E71-3: 3-ethynyl-5-(methylthio)pyridine Intermediate E71-3 (2.9 g, 76.8%) was prepared as a colorless oil from intermediate E71-2 in the manner described for intermediate I-2.

[0475] LC-MS (ESI): m / z 150.0 [M+H]+ . E71-4: tert-butyl (2-((4-(5-(methylthio)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E71-4 (110 mg, 78.4%) was prepared as a yellow solid from intermediate E71-3 by the method described for intermediate 4-d.

[0476] LC-MS (ESI): m / z 520.3 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ9.32 (br s, 2 H) 8.88 - 8.92 (m, 2 H) 8.86 (d, J = 1.75 Hz, 1 H) 8.48 (d, J = 2.25 Hz, 1 H) 8.36 (s, 1 H) 8.17 (t, J = 2. E-71: 1-cyclobutyl-N-((2-((4-(5-(methylthio)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)m1-cyclobutyl-N-((2-((4-(5-(methylthio)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanaminemethyl)imidazo[1,2-a]pyridin-6-yl Compound E-71 (63.9 mg, 60.1%) was prepared as a white solid from intermediate E71-4 by the method described for compound E-1.

[0477] LC-MS (ESI): m / z 420.1 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ9.32 (br s, 2 H) 8.88 - 8.92 (m, 2 H) 8.86 (d, J = 1.75 Hz, 1 H) 8.48 (d, J = 2.25 Hz, 1 H) 8.36 (s, 1 H) 8.17 (t, J = 2.00 Hz, 1 H) 7.80 - 7.89 (m, 2 H) 5.95 (s, 2 H) 4.19 (t, J = 5.00 Hz, 2 H) 2.91 - 2.97 (m, 2 H) 2.66 - 2.71 (m, 1H) 2.59 - 2.60 (m, 3 H) 2.00 - 2.08 (m, 2 H) 1.81 - 1.88 (m, 1 H) 1.74 - 1.81 (m, 3 H).

[0478] Example 72: Synthesis of E-72: 1-(2-((4-(5-(aziridin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine TIFF2025530847000503.tif67170

[0479] E72-1: tert-butyl (2-((4-(5-((2-chloroethyl)amino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Intermediate E72-1 (0.15 g, 26.6%) was prepared as a yellow solid from intermediate E62-4 in the manner described for intermediate E6-1.

[0480] LC-MS (ESI): m / z551.3 [M+H]+ . E72-2: N-(2-chloroethyl)-5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-amine Intermediate E72-2 (0.12 g, 90.4%) was prepared as a yellow solid from intermediate E72-1 in the manner described for compound E-1.

[0481] LC-MS (ESI): m / z451.2 [M+H]+ . E-72: 1-(2-((4-(5-(aziridin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine Intermediate E-72 (33.0 mg, 44.7%) was prepared as a yellow solid from intermediate E72-2 in the manner described for compound E-6.

[0482] LC-MS (ESI): m / z 415.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 8.71 (s, 1H), 8.66 (d, J = 1.6 Hz, 1H), 8.42 (s, 1H), 8.25 (d, J = 2.5 Hz, 1H), 7.97 (s, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.46 (d, J = 9.1 Hz, 1H), 7.26 (d, J = 9.3 Hz, 1H), 5.75 (s, 2H), 3.65 (s, 2H), 2.49 (br s, 2H), 2.44 - 2.37 (m, 1H), 2.17 (s, 4H), 2.01 - 1.93 (m, 2H), 1.86 - 1.77 (m, 2H), 1.66 - 1.58 (m, 1H).

[0483] Example 73: Synthesis of E-73: 1-cyclobutyl-N-((2-((4-(5-(piperazin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine hydrochloride TIFF2025530847000504.tif24170

[0484] E73-1: tert-butyl 4-(5-(1-((6-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperazine-1-carboxylate Intermediate E73-1 (100 mg, 42.0%) was prepared as a yellow solid from intermediate E63-3 in the manner described for intermediate E15-1.

[0485] LC-MS (ESI): m / z 658.4 [M+H]+ . E-73: 1-Cyclobutyl-N-((2-((4-(5-(piperazin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-73 (19.3 mg, 25.7%) was prepared as a yellow solid from intermediate E73-1 by the method described for compound E-1.

[0486] LC-MS (ESI): m / z 458.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 9.59 - 9.79 (m, 4 H) 9.19 (s, 1 H) 9.06 (s, 1 H) 8.66 (s, 1 H) 8.51 (s, 2 H) 8.42 (s, 1 H) 8.09 (d, J= 9.18 Hz, 1 H) 7.92 (d, J = 9.42 Hz, 1 H) 6.06 (s, 2 H) 4.22 (t, J = 5.19 Hz, 2 H) 3.70 - 3.82 (m, 4 H) 3.22 (br s, 4 H) 2.90 - 2.98 (m, 2 H) 2.66 - 2.78 (m, 1 H) 2.00 - 2.09 (m, 2 H) 1.72 - 1.91 (m, 4 H).

[0487] Example 74: Synthesis of E-74: 1-cyclobutyl-N-((6-((4-(5-(methylthio)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine TIFF2025530847000505.tif29170

[0488] E74-1: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(5-(methylthio)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E74-1 (50 mg, 37.9%) was prepared as a yellow solid from intermediate E71-3 by the method described for intermediate 4-d.

[0489] LC-MS (ESI): m / z 619.3 [M+H]+ . E-74: 1-Cyclobutyl-N-((6-((4-(5-(methylthio)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine Compound E-74 (23.8 mg, 64.3%) was prepared as a white solid from intermediate E74-1 in the manner described for compound E-1.

[0490] LC-MS (ESI): m / z 419.1 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ9.32 (br s, 2 H) 8.88 - 8.92 (m, 2 H) 8.86 (d, J =1.75 Hz, 1 H) 8.48 (d, J =2.25 Hz, 1 H) 8.36 (s, 1 H) 8.17 (t, J=2.00 Hz, 1 H) 7.80 - 7.89 (m, 2 H) 5.95 (s, 2 H) 4.19 (t, J=5.00 Hz, 2 H) 2.91 - 2.97 (m, 2 H) 2.66 - 2.71 (m, 1 H) 2.59 - 2.60 (m, 3 H) 2.00 - 2.08 (m, 2 H) 1.81 - 1.88 (m, 1 H) 1.74 - 1.81 (m, 3 H).

[0491] Example 75: Synthesis of E-75: 1-cyclobutyl-N-((6-((4-(5-iodopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine TIFF2025530847000506.tif30170

[0492] E75-1: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(5-iodopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E75-1 (80 mg, 74.6%) was prepared as a yellow oil from intermediate E66-1 in the manner described for intermediate E24-1.

[0493] LC-MS (ESI): m / z 699.3 [M+H]+ . E-75: 1-Cyclobutyl-N-((6-((4-(5-iodopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine Compound E-75 (26.7 mg, 43.6%) was prepared as a yellow solid from intermediate E75-1 in the manner described for compound E-3.

[0494] LC-MS (ESI): m / z 499.0 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 11.40 (s, 1 H) 9.12 (br s, 1 H) 9.04 (d, J = 1.75 Hz, 1 H) 8.81 (s, 1 H) 8.76 (d, J = 1.88 Hz, 1 H) 8.60 (t, J = 1.88 Hz, 1 H) 7.57 (d, J = 8.25 Hz, 1 H) 7.46 (s, 1 H) 7.06 (d, J = 8.25 Hz, 1 H) 6.60 (s, 1 H) 5.73 (s, 2 H) 4.25 - 4.28 (m, 2 H) 2.92 - 2.99 (m, 2 H) 2.59 - 2.64 (m, 1 H) 2.00 - 2.07 (m, 2 H) 1.79 - 1.91 (m, 2 H) 1.74 - 1.78 (m, 2 H).

[0495] Example 76: Synthesis of E-76: 1-cyclobutyl-N-((2-((4-(5-iodopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000507.tif27170

[0496] E76-1: tert-butyl (2-((4-(5-iodopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E76-1 (80 mg, 73.7%) was prepared as a yellow solid from intermediate E63-3 in the manner described for intermediate E24-1.

[0497] LC-MS (ESI): m / z 600.2 [M+H]+ . E-76: 1-Cyclobutyl-N-((2-((4-(5-iodopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-76 (59.6 mg, 83.3%) was prepared as a white solid from intermediate E76-1 in the manner described for compound E-1.

[0498] LC-MS (ESI): m / z 500.1 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ9.60 (br s, 2 H) 9.06 (d, J = 1.83 Hz, 1 H) 9.01 (s, 1 H) 8.94 (s, 1 H) 8.79 (d, J= 1.96 Hz, 1 H) 8.61 (t, J = 1.96 Hz, 1 H) 8.45 (s, 1 H) 8.05 (d, J = 9.29 Hz, 1 H) 7.91 (d, J = 9.29 Hz, 1 H) 6.00 (s, 2 H) 4.22 (t, J = 5.38 Hz, 2H) 2.90 - 2.98 (m, 2 H) 2.65 - 2.77 (m, 1 H) 1.99 - 2.10 (m, 2 H) 1.71 - 1.91 (m, 4 H).

[0499] Example 77: Synthesis of E-77: N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-5-(dimethylamino)nicotinamide TIFF2025530847000508.tif61170

[0500] E77-1: tert-butyl 6-(aminomethyl)-2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate Intermediate E77-1 (60 mg, 63.5%) was prepared as a yellow oil from intermediate I-7 in the manner described for intermediate I-10.

[0501] LC-MS (ESI): m / z442.6 [M+H]+ . E77-2: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((5-(dimethylamino)nicotinamido)methyl)-1H-indole-1-carboxylate Intermediate E77-2 (80 mg, 99.9%) was prepared as a yellow oil from intermediate E77-1 in the manner described for intermediate E7-3.

[0502] LC-MS (ESI): m / z592.3 [M+H]+ . E-77: N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-5-(dimethylamino)nicotinamide Compound E-77 (14.6 mg, 25.0%) was prepared as a white solid from intermediate E77-2 in the manner described for compound E-3.

[0503] LC-MS (ESI): m / z 392.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 8.28 (s, 1H), 8.15 (br s, 1H), 7.54 (s, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.35 (s, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.36 (s, 1H), 4.66 (s, 2H), 3.94 (s, 2H), 3.04 (s, 6H), 2.71 (d, J = 7.3 Hz, 2H), 2.53 (td, J = 7.7, 15.3 Hz, 1H), 2.15 - 2.04 (m, 2H), 1.98 - 1.78 (m, 2H), 1.76 - 1.64 (m, 2H).

[0504] Example 78: Synthesis of E-78: 1-(5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidine-2-carbonitrile TIFF2025530847000509.tif103170

[0505] E78-1: (5-bromopyridin-3-yl)proline E78-1 (1.4 g, 59.5%) was prepared as a white solid from proline by the method described for E16-1.

[0506] LC-MS: [M+H]+= 271.0. E78-2: 1-(5-bromopyridin-3-yl)pyrrolidine-2-carboxamide To a solution of E78-1 (1.40 g, 5.16 mmol, 1.00 eq) and ammonium chloride (414 mg, 7.75 mmol, 1.50 eq) in pyridine (14.0 mL) was added EDCI (1.98 g, 10.3 mmol, 2.00 eq), and the resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by adding water (50.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give E78-2 (0.82 g, 58.8%) as a yellow solid.

[0507] LC-MS: [M+H]+= 271.9. E78-3: 1-(5-bromopyridin-3-yl)pyrrolidine-2-carbonitrile To a solution of E78-2 (0.35 g, 1.30 mmol, 1.00 eq) in THF (7.00 mL) was added triethylamine (408 mg, 1.94 mmol, 270 μL, 1.50 eq) at 0 °C, and the resulting mixture was stirred at 25 °C for 3 h. Next, sodium carbonate (549 mg, 5.18 mmol, 4.00 eq) was added to the reaction mixture at 0 °C, and the mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated, and the residue was diluted with water (10.0 mL) and extracted with ethyl acetate (3.00 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to give E78-3 (0.30 g, 91.8%) as a yellow solid.

[0508] LC-MS: [M+H]+= 253.9. E78-4: 1-(5-((trimethylsilyl)ethynyl)pyridin-3-yl)pyrrolidine-2-carbonitrile E78-4 (270 mg, 84.2%) was prepared as a yellow solid from E78-3 by the method described for E53-6.

[0509] LC-MS: [M+H]+= 270.2. E78-5: 1-(5-ethynylpyridin-3-yl)pyrrolidine-2-carbonitrile E78-5 (40 mg, crude) was prepared as a yellow solid from E78-4 by the method described for I-2.

[0510] LC-MS: [M+H]+= 198.2. E78-6: tert-butyl (2-((4-(5-(2-cyanopyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate E78-6 (50 mg, 43.4%) was prepared as a yellow solid from E78-5 by the method described for 4-d.

[0511] LC-MS: [M+H]+= 568.4. E-78: 1-(5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidine-2-carbonitrile E-78 (6.40 mg, 37.0%) was prepared as a yellow solid from E78-6 by the method described for E-94.

[0512] LC-MS: [M+H]+= 468.2. 1H NMR (400 MHz, DMSO-d6): δ 8.72 (s, 1H), 8.50 (d, J = 1.4 Hz, 1H), 8.42 (s, 1H), 8.07 (d, J = 2.8 Hz, 1H), 7.97 (s, 1H), 7.55-7.52 (m, 1H), 7.46 (d, J= 9.3 Hz, 1H), 7.26 (dd, J = 1.4, 9.3 Hz, 1H), 5.75 (s, 2H), 5.01 (dd, J= 2.7, 6.7 Hz, 1H), 3.64 (s, 2H), 3.50-3.38 (m, 2H), 2.48 (br s, 2H), 2.42 (s, 1H), 2.36-2.25 (m, 2H), 2.20-2.04 (m, 2H), 2.02-1.89 (m, 2H), 1.84-1.70 (m, 2H), 1.66-1.54 (m, 2H).

[0513] Example 79: E-79: Synthesis of 1-cyclobutyl-N-((6-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine hydrochloride TIFF2025530847000510.tif29170

[0514] E79-1: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E79-1 (30 mg, 30.5%) was prepared as a white solid from intermediate E66-1 in the manner described for intermediate E15-1.

[0515] LC-MS (ESI): m / z642.2 [M+H]+ . E-79: 1-Cyclobutyl-N-((6-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine hydrochloride Compound E-79 (1.3 mg, 6.18%) was prepared as a yellow solid from intermediate E79-1 in the manner described for compound E-1.

[0516] LC-MS (ESI): m / z 442.1 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 11.55 (s, 1 H) 9.30 (d, J = 3.00 Hz, 2 H) 8.94 (s, 1 H) 8.45 (br s, 1 H) 8.01 (br s, 1 H) 7.86 (s, 1 H) 7.57 (d, J = 8.13 Hz, 1 H) 7.48 (s, 1 H) 7.06 (dd, J = 8.19, 1.19 Hz, 1 H) 6.60 (s, 1 H) 5.77 (s, 2 H) 4.27 (t, J = 5.07Hz, 2H) 3.38 - 3.41 (m, 4 H) 2.89 - 2.97 (m, 2 H) 2.61 - 2.70 (m, 1 H) 1.98 - 2.08 (m, 6 H) 1.73 - 1.88 (m, 4 H) .

[0517] Example 80: Synthesis of E-80: 1-cyclobutyl-N-((6-((4-(5-(methylsilyl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine TIFF2025530847000511.tif41170

[0518] E80-1: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(5-nitropyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E80-1 (1.10 g, 83.6%) was prepared as a yellow solid from intermediate I-7 by the method described for intermediate 4-d.

[0519] 1H NMR: (400 MHz, CDCl3): δ 9.17 - 9.32 (m, 2 H), 8.79 (t, J = 2.13 Hz, 1 H), 8.13 (br s, 1 H), 7.72 (br s, 1 H), 7.43 (d, J= 7.25 Hz, 1 H), 7.13 (br s, 1 H), 6.22 (br s, 1 H), 5.64 (br s, 2 H), 4.59 - 4.72 (m, 2 H), 3.30 (d, J = 6.25 Hz, 2 H), 2.43 - 2.57 (m, 1 H), 1.95 (br s, 2 H), 1.74 - 1.84 (m, 2 H), 1.63 - 1.72 (m, 2 H), 1.59 (br s, 9 H), 1.29 - 1.46 (m, 9 H). E80-2: tert-butyl 6-((4-(5-aminopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate Intermediate E80-2 (1 g, 86.0%) was prepared as a yellow solid from intermediate E80-1 in the manner described for intermediate E3-2.

[0520] 1H NMR: (400 MHz, CDCl3): δ8.17 - 8.24 (m, 1 H), 8.06 (br s, 1 H), 7.95 (d, J = 2.38 Hz, 1 H), 7.58 (br s, 1 H), 7.48 (br s, 1 H), 7.41 (d, J = 6.00 Hz, 1 H), 7.05 - 7.16 (m, 1 H), 6.23 (d, J = 14.26 Hz, 1 H), 5.60 (br s, 2 H), 4.65 (d, J = 16.76 Hz, 2 H), 3.69 (br s, 2 H), 3.29 (d, J = 6.50 Hz, 2 H), 2.51 (br s, 1 H), 1.95 (br s, 2 H), 1.74 - 1.83 (m, 2 H), 1.63 - 1.71 (m, 2 H), 1.57 (s, 9 H), 1.28 - 1.46 (m, 9 H). E80-3: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(5-selenocyanopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E80-3 (0.11 g, crude) was prepared as a red solid from intermediate E80-2 in the manner described for intermediate E14-1.

[0521] LC-MS (ESI): m / z 677.2 [M+H]+. E80-4: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(5-(methylsilyl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E80-4 (70 mg, 64.7%) was prepared as a yellow oil from intermediate E80-3 in the manner described for intermediate E14-2.

[0522] 1H NMR: (400 MHz, CDCl3): δ 8.66 (br s, 1 H), 8.48 (br s, 1 H), 8.16 (br s, 1 H), 8.03 - 8.10 (m, 1 H), 7.58 - 7.71 (m, 1 H), 7.41 (d, J= 7.38 Hz, 1 H), 7.06 - 7.18 (m, 2 H), 6.18 - 6.31 (m, 1 H), 5.61 (br s, 2 H), 4.58 - 4.71 (m, 2 H), 3.29 (d, J = 6.00 Hz, 2 H), 2.45 - 2.56 (m, 1 H), 2.32 - 2.37 (m, 3 H), 2.15 - 2.16 (m, 1 H), 1.94 (d, J= 5.63 Hz, 2 H), 1.73 - 1.84 (m, 2 H), 1.63 - 1.70 (m, 2 H), 1.58 (s, 9 H), 1.29 - 1.47 (m, 7 H). E-80: 1-Cyclobutyl-N-((6-((4-(5-(methylsilanyl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine Compound E-80 (17.5 mg, 32.6%) was prepared as a white solid from intermediate E80-4 in the manner described for compound E-1.

[0523] LC-MS (ESI): m / z 467.0 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ11.59 (s, 1 H), 9.39 (br s, 2 H), 8.96 (d, J = 1.88 Hz, 1 H), 8.87 (s, 1 H), 8.63 (d, J = 2.13 Hz, 1 H), 8.44 (t, J = 1.88 Hz, 1 H), 7.57 (d, J = 8.13 Hz, 1 H), 7.47 (s, 1 H), 7.07 (dd, J = 8.13, 1.38 Hz, 1 H), 6.61 (d, J = 1.00 Hz, 1 H), 5.76 (s, 2 H), 4.27 (t, J = 5.32 Hz, 2 H), 2.89 - 2.98 (m, 2 H), 2.62 - 2.72 (m, 1 H), 2.50 (br s, 3 H), 1.98 - 2.11 (m, 2 H), 1.72 - 1.90 (m, 4 H).

[0524] Example 81: Synthesis of E-81: 1-cyclobutyl-N-((2-((4-(5-(methylsilyl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000512.tif66170

[0525] E81-1: tert-butyl (2-((4-(5-selenocyanopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E81-1 (30 mg, 8.46%) was prepared as a yellow solid from intermediate E62-4 in the manner described for intermediate E14-1.

[0526] LC-MS (ESI): m / z 579.2 [M+H]+ . E81-2: tert-butyl (2-((4-(5-(methylsilanyl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E81-2 (20 mg, 67.9%) was prepared as a yellow solid from intermediate E81-1 in the manner described for intermediate E14-2.

[0527] LC-MS (ESI): m / z 568.1 [M+H]+ . E-81: 1-Cyclobutyl-N-((2-((4-(5-(methylsilanyl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-81 (11.5 mg, 61.0%) was prepared as a white solid from intermediate E81-2 by the method described for compound E-1.

[0528] LC-MS (ESI): m / z 468.1 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 9.27 (s, 2 H) 8.92 (d, J = 1.67 Hz, 1 H) 8.89 (s, 1 H) 8.87 (s, 1 H) 8.59 (d, J = 1.91 Hz, 1 H) 8.33 (d, J =2.03 Hz, 2 H) 7.80 (s, 2 H) 5.93 (s, 2 H) 4.19 (t, J = 5.36 Hz, 2 H) 2.96 (d, J = 5.13 Hz, 2 H) 2.62 - 2.74 (m, 1 H) 2.48 (s, 3 H) 2.02 - 2.09 (m, 2 H) 1.80 (s, 2 H) 1.78 (s, 2 H) .

[0529] Example 82: Synthesis of E-82: 1-(2-((4-(4-chloro-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)methanamine TIFF2025530847000513.tif93170

[0530] E82-1: 3-bromo-4-chloro-5-(pyrrolidin-1-yl)pyridine E82-1 (500 mg, 44.6%) was prepared as a white solid from 3-bromo-4-chloro-5-fluoropyridine in the manner described for E16-1.

[0531] LC-MS: [M+H]+= 262.9. E82-2: 4-chloro-3-(pyrrolidin-1-yl)-5-((trimethylsilyl)ethynyl)pyridine E82-2 (180 mg, 60.8%) was prepared as a brown solid from E82-1 by the method described for E53-6.

[0532] LC-MS: [M+H]+= 279.0. E82-3: 4-chloro-3-ethynyl-5-(pyrrolidin-1-yl)pyridine A solution of E82-3 (140 mg, crude product) was prepared from E82-2 by the method described for I-2.

[0533] LC-MS: [M+H]+= 207.1. E82-4: (2-((4-(4-chloro-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methanol E82-4 (60 mg, 81.8%) was prepared as a yellow solid from E82-3 by the method described for 4-d.

[0534] LC-MS: [M+H]+= 410.1. E82-5: 2-((4-(4-chloro-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carbaldehyde E82-5 (15 mg, 37.6%) was prepared as a gray solid from E82-4 by the method described for E143-2.

[0535] LC-MS: [M+H]+= 408.1. E-82: 1-(2-((4-(4-chloro-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)methanamine E-82 (1.40 mg, 7.45%) was prepared as a yellow oil from E82-5 by the method described for E6-1.

[0536] LC-MS: [M+H]+= 507.2. 1H NMR (400 MHz, DMSO-d6): δ 8.71 (s, 1H), 8.52 (s, 1H), 8.42 (s, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.46 (d, J= 9.4 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 5.78 (s, 2H), 3.67 (s, 2H), 3.43-3.39 (m, 4H), 2.74 (s, 2H), 1.97-1.87 (m, 10H).

[0537] Example 83: Synthesis of E-83: 6-((2,2-dimethylpiperidin-1-yl)methyl)-2-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine hydrochloride TIFF2025530847000514.tif29170

[0538] E83-1: 6-(bromomethyl)-2-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine E83-1 (400 mg, crude) was prepared as a brown solid from E134-1 in the manner described for E141-2.

[0539] LC-MS: [M+H]+= 438.1. E-83: 6-((2,2-dimethylpiperidin-1-yl)methyl)-2-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine hydrochloride E-83 (0.80 mg, 1.38%) was prepared as a yellow solid from E83-1 by the method described for E16-1.

[0540] LC-MS: [M+H]+= 471.3. 1H NMR (400 MHz, DMSO-d6): δ9.88-9.57 (m, 1H), 8.96 (s, 1H), 8.83 (s, 1H), 8.50-8.44 (m, 1H), 8.17 (s, 1H), 8.02 (d, J= 2.6 Hz, 1H), 7.83 (br s, 1H), 7.69-7.60 (m, 1H), 7.52 (d, J = 9.3 Hz, 1H), 5.85 (s, 2H), 4.68-4.60 (m, 1H), 3.96 (dd, J = 8.7, 13.3Hz, 1H), 3.11-3.05 (m, 2H), 2.96-2.88 (m, 2H), 2.56-2.54 (m, 2H), 2.02 (t, J = 6.6 Hz, 4H), 1.94-1.87 (m, 1H), 1.77-1.63 (m, 3H), 1.61 (s, 3H), 1.59 (br s, 2H), 1.40 (s, 3H).

[0541] Example 84: Synthesis of E-84: 2-((4,4-dimethylpiperidin-1-yl)methyl)-6-((4-(5-(2-methylpyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole TIFF2025530847000515.tif61170

[0542] E84-1: 3-bromo-5-(2-methylpyrrolidin-1-yl)pyridine E84-1 (250 mg, 18.0%) was prepared as a white solid from 2-methylpyrrolidine and 3-bromo-5-fluoropyridine in the manner described for E16-1.

[0543] LC-MS: [M+H]+= 240.9. E84-2: 3-(2-methylpyrrolidin-1-yl)-5-((trimethylsilyl)ethynyl)pyridine E84-2 (70 mg, 40.8%) was prepared as a brown solid from E84-1 by the method described for E53-6.

[0544] LC-MS: [M+H]+= 259.3. E84-3: 3-ethynyl-5-(2-methylpyrrolidin-1-yl)pyridine E84-3 (50.4 mg, crude product) was prepared as a brown solid from E84-2 by the method described for I-2.

[0545] LC-MS: [M+H]+= 187.4. E-84: 2-((4,4-dimethylpiperidin-1-yl)methyl)-6-((4-(5-(2-methylpyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole E-84 (3.60 mg, 2.66%) was prepared as a yellow solid from E84-3 by the method described for 4-d.

[0546] LC-MS: [M+H]+= 484.3. 1H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 8.67 (s, 1H), 8.26 (s, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (s, 1H), 7.27 (s, 1H), 6.98 (d, J = 7.3 Hz, 1H), 6.25 (s, 1H), 5.67 (s, 2H), 3.97 (br s, 1H), 3.57 (s, 2H), 3.47-3.40 (m, 1H), 3.21-3.13 (m, 1H), 2.34 (br s, 4H), 2.10-1.92 (m, 3H), 1.69 (br s, 1H), 1.31 (t, J = 5.5 Hz, 4H), 1.12 (d, J = 6.1 Hz, 3H), 0.87 (s, 6H).

[0547] Example 85: Synthesis of E-85: (6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl 5-(dimethylamino)nicotinic acid TIFF2025530847000516.tif25170

[0548] E85-1: (6-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl 5-(dimethylamino)nicotinic acid E85-1 (30.0 mg, 44.2%) was prepared as a yellow oil from 1-d by the method described for E16-1.

[0549] LC-MS: [M+H]+= 494.3. E-85: (6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl 5-(dimethylamino)nicotinic acid E-85 (18.3 mg, 75.2%) was prepared as a yellow solid from E85-1 by the method described for E-1.

[0550] LC-MS: [M+H]+= 394.1. 1H NMR (400 MHz, DMSO-d6): δ 9.67 (d, J = 1.6 Hz, 2H), 9.07 (s, 1H), 8.57 (s, 1H), 8.52 (s, 1H), 8.39 (d, J = 2.8 Hz, 1H), 8.17 (d, J = 9.4 Hz, 1H), 8.02 (d, J = 9.3 Hz, 1H), 7.86 (br s, 1H), 5.68 (s, 2H), 4.27-4.23 (m, 2H), 3.08 (s, 6H), 2.98-2.92 (m, 2H), 2.71 (td, J= 7.5, 15.0 Hz, 1H), 2.09-2.01 (m, 2H), 1.88-1.75 (m, 4H).

[0551] Example 86: Synthesis of E-86: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((2-((4-(5-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000517.tif86170

[0552] E86-1: 3-bromo-5-(3-fluoropyrrolidin-1-yl)pyridine E86-1 (300.0 mg, 48.3%) was prepared as a gray solid from 3-fluoropyrrolidine and 3,5-dibromopyridine in the manner described for E130-1.

[0553] LC-MS: [M+H]+= 247.0. E86-2: 3-(3-fluoropyrrolidin-1-yl)-5-((trimethylsilyl)ethynyl)pyridine E86-2 (250.0 mg, 77.8%) was prepared as a black solid from E86-1 by the method described for E53-6.

[0554] LC-MS: [M+H]+= 263.7. E86-3: 3-ethynyl-5-(3-fluoropyrrolidin-1-yl)pyridine E86-3 (181.0 mg, crude product) was prepared as a yellow oil from E86-2 by the method described for I-2.

[0555] LC-MS: [M+H]+= 191.2. E86-4: (2-((4-(5-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methanol E86-4 (84.0 mg, 45.1%) was prepared as a yellow solid from E86-3 by the method described for 4-d.

[0556] LC-MS: [M+H]+= 394.4. E86-5: 2-((4-(5-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carbaldehyde E86-5 (14.0 mg, crude product) was prepared as a yellow solid from E86-4 by the method described for E54-2.

[0557] LC-MS: [M+H]+= 392.2. E-86: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((2-((4-(5-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine E-86 (4.20 mg, 23.8%) was prepared as a yellow solid from E86-5 by the method described for E6-1.

[0558] LC-MS: [M+H]+= 491.5. 1H NMR (400 MHz, DMSO-d6): δ 8.69 (s, 1H), 8.46-8.33 (m, 2H), 7.95 (d, J = 12.9 Hz, 2H), 7.47 (d, J = 9.4 Hz, 1H), 7.35 (br s, 1H), 7.26 (d, J = 9.3 Hz, 1H), 5.75 (s, 2H), 5.59-5.40 (m, 1H), 3.68 (s, 2H), 3.65-3.61 (m, 1H), 3.55 (br s, 2H), 3.42 (d, J = 7.6 Hz, 2H), 2.74 (s, 2H), 2.35-2.24 (m, 2H), 1.93 (d, J = 1.3 Hz, 6H).

[0559] Example 87: Synthesis of E-87: 1-(2-((4-(5-(2,5-dihydro-1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)methanamine hydrochloride TIFF2025530847000518.tif70170

[0560] E87-1: tert-butyl (2-((4-(5-(2,5-dihydro-1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)carbamate E87-1 (12.0 mg, 18.4%) was prepared as a white solid from E141-2 by the method described for 7-a.

[0561] LC-MS: [M+H]+= 571.3. E-87: 1-(2-((4-(5-(2,5-dihydro-1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)methanamine hydrochloride E-87 (3.50 mg, 31.1%) was prepared as a white solid from E87-1 by the method described for E-34.

[0562] LC-MS: [M+H]+= 471.2. 1H NMR (400 MHz, DMSO-d6): δ 9.53 (d, J = 1.6 Hz, 2H), 9.05 (s, 1H), 8.85 (s, 1H), 8.54 (s, 1H), 8.29 (s, 1H), 8.05 (d, J = 2.5 Hz, 1H), 7.92 (s, 1H), 7.73 (s, 2H), 6.09 (s, 2H), 5.92 (s, 2H), 4.26 (s, 4H), 4.21 (br s, 2H), 3.30-3.25 (m, 2H), 2.12 (d, J = 2.4 Hz, 6H).

[0563] Example 88: Synthesis of E-88: 6-((4,4-dimethylpiperidin-1-yl)methyl)-2-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine TIFF2025530847000519.tif53170

[0564] E88-1: (2-((4-(5-bromopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methanol Intermediate E88-1 (1.30 g, 61.3%) was prepared as a yellow solid from intermediate E63-2 in the manner described for intermediate 4-d.

[0565] LC-MS (ESI): m / z385.2 [M+H]+ . E88-2: 2-((4-(5-bromopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carbaldehyde Intermediate E88-2 (0.80 g, 73.1%) was prepared as a yellow solid from intermediate E88-1 in the manner described for intermediate E54-2.

[0566] LC-MS (ESI): m / z383.2 [M+H]+ . E88-3: 2-((4-(5-bromopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-6-((4,4-dimethylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine Intermediate E88-3 (0.22 g, 58.5%) was prepared as a brown solid from intermediate E88-2 in the manner described for intermediate E30-1.

[0567] LC-MS (ESI): m / z480.3 [M+H]+ . E-88: 6-((4,4-dimethylpiperidin-1-yl)methyl)-2-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine Intermediate E-88 (6.4 mg, 12.7%) was prepared as a yellow solid from intermediate E88-3 in the manner described for intermediate E15-1.

[0568] LC-MS (ESI): m / z 471.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 8.68 (s, 1 H), 8.44 (s, 1 H), 8.31 (d, J = 1.50 Hz, 1 H), 8.18 (s, 1 H), 7.96 (s, 1 H), 7.89 (d, J= 2.75 Hz, 1 H), 7.47 (d, J = 9.26 Hz, 1 H), 7.26 - 7.33 (m, 1 H), 7.21 (dd, J= 9.26, 1.50 Hz, 1 H), 5.74 (s, 2 H), 3.44 - 3.46 (m, 2 H), 3.29 - 3.33 (m, 4 H), 2.32 - 2.40 (m, 4 H), 1.94 - 2.01 (m, 4 H), 1.32 (t, J = 5.44 Hz, 4 H), 0.89 (s, 6 H).

[0569] Example 89: Synthesis of E-89: 5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-diethylpyridin-3-amine TIFF2025530847000520.tif28170

[0570] E89-1: tert-butyl (2-((4-(5-(diethylamino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E89-1 (70 mg, 71.0%) was prepared as a white solid from intermediate E63-3 in the manner described for intermediate E15-1.

[0571] LC-MS (ESI): m / z 545.3 [M+H]+ . E-89: 5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-diethylpyridin-3-amine Compound E-89 (26.6 mg, 64.3%) was prepared as a white solid from intermediate E89-1 by the method described for compound E-1.

[0572] LC-MS (ESI): m / z 445.4 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 9.62 (br s, 2H), 9.18 (s, 1H), 9.00 (s, 1H), 8.44 (d, J = 2.3 Hz, 2H), 8.17 (d, J = 2.6 Hz, 1H), 8.08 - 7.96 (m, 2H), 7.87 (d, J = 9.4 Hz, 1H), 6.02 (s, 2H), 4.20 (t, J = 5.2 Hz, 2H), 3.53 (q, J = 7.0 Hz, 4H), 3.00 - 2.87 (m, 2H), 2.79 - 2.62 (m, 1H), 2.12 - 1.96 (m, 2H), 1.92 - 1.68 (m, 4H), 1.14 (t, J = 7.0 Hz, 6H).

[0573] Example 90: Synthesis of E-90: 5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-bis(methyl-d3)pyridin-3-amine hydrochloride TIFF2025530847000521.tif29170

[0574] E90-1: tert-butyl (2-((4-(5-(bis(methyl-d3)amino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Intermediate E90-1 (30 mg, 31.7%) was prepared as a white solid from intermediate E63-3 in the manner described for intermediate E15-1.

[0575] LC-MS (ESI): m / z523.3 [M+H]+ . E-90: 5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-bis(methyl-d3)pyridin-3-amine hydrochloride Compound E-90 (8.30 mg, 31.2%) was prepared as a white solid from intermediate E90-1 in the manner described for compound E-1.

[0576] LC-MS (ESI): m / z 423.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 9.37 (br s, 2H), 9.07 (s, 1H), 8.86 (s, 1H), 8.52 (s, 1H), 8.31 (s, 1H), 8.16 (d, J = 2.7 Hz, 1H), 8.05 (s, 1H), 7.75 (br s, 2H), 5.93 (s, 2H), 4.17 (br s, 2H), 2.94 (d, J = 4.8 Hz, 2H), 2.75 - 2.62 (m, 1H), 2.05 (d, J = 5.7 Hz, 2H), 1.93 - 1.68 (m, 4H).

[0577] Example 91: Synthesis of E-91: 2-((4-(5-(azetidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-6-((4,4-dimethylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine TIFF2025530847000522.tif38170

[0578] E-91: 2-((4-(5-(azetidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-6-((4,4-dimethylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine Compound E-91 (2.00 mg, 2.08%) was prepared as a yellow solid from intermediate E88-3 in the manner described for intermediate E15-1.

[0579] LC-MS (ESI): m / z 457.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ8.68 (s, 1 H), 8.36 - 8.47 (m, 2 H), 7.96 (s, 1 H), 7.75 (d, J = 2.75 Hz, 1 H), 7.46 (d, J = 9.26 Hz, 1 H), 7.18 - 7.26 (m, 2 H), 5.74 (s, 2 H), 3.92 (t, J = 7.25 Hz, 4 H), 3.42 - 3.47 (m, 2 H), 2.30 - 2.42 (m, 5 H), 1.32 (t, J= 5.44 Hz, 4 H), 0.89 (s, 6 H).

[0580] Example 92: Synthesis of E-92: 5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-ethyl-N-methylpyridin-3-amine TIFF2025530847000523.tif28170

[0581] E92-1: tert-butyl (2-((4-(5-(ethyl(methyl)amino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E92-1 (70 mg, crude) was prepared as a white solid from intermediate E63-3 in the manner described for intermediate E15-1.

[0582] LC-MS (ESI): m / z 531.3 [M+H]+ . E-92: 5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-ethyl-N-methylpyridin-3-amine Compound E-92 (5.70 mg, 9.00%) was prepared as a white solid from intermediate E92-1 in the manner described for compound E-1.

[0583] LC-MS (ESI): m / z 431.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 9.53 (br s, 2H), 9.12 (s, 1H), 8.93 (s, 1H), 8.48 (s, 1H), 8.37 (s, 1H), 8.18 (d, J = 2.3 Hz, 1H), 8.07 (s, 1H), 7.86 (br s, 1H), 7.83 - 7.76 (m, 1H), 5.97 (s, 2H), 4.18 (br s, 2H), 3.57 (br s, 2H), 3.06 (s, 3H), 2.94 (d, J = 4.8 Hz, 2H), 2.77 - 2.63 (m, 1H), 2.11 - 1.99 (m, 2H), 1.89 - 1.74 (m, 4H), 1.11 (t, J = 7.0 Hz, 3H).

[0584] Example 93: Synthesis of E-93: 1-(2-((4-(6-fluoro-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)methanamine TIFF2025530847000524.tif97170

[0585] E93-1: 5-bromo-2-fluoro-3-(pyrrolidin-1-yl)pyridine To a solution of 5-bromo-2-fluoropyridin-3-amine (200 mg, 1.05 mmol, 1.00 eq) in THF (4.00 mL) and MeOH (4.00 mL) was added a solution of sulfuric acid (408 mg, 4.08 mmol, 222 μL, 98% purity, 3.90 eq) in water (1.78 g, 98.8 mmol, 1.78 mL, 95.0 eq), followed by the addition of 2,5-dimethoxytetrahydrofuran (416 mg, 3.15 mmol, 405 μL, 3.00 eq) and NaBH (119 mg, 3.15 mmol, 3.00 eq) portionwise at 0 °C. The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (3.00 mL) at 0 °C, adjusted to pH 8 with saturated sodium bicarbonate at 0 °C, and extracted with ethyl acetate (5.00 mL × 3). The combined organic layer was washed with brine (2.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate=20:1) to give E93-1 (0.10 g, 39.0%) as a white solid.

[0586] LC-MS: [M+H]+= 245.0. E93-2: 2-fluoro-3-(pyrrolidin-1-yl)-5-((trimethylsilyl)ethynyl)pyridine E93-2 (70.0 mg, 26.2%) was prepared as a yellow solid from E93-1 by the method described for E53-6.

[0587] LC-MS: [M+H]+= 263.2. E93-3: 5-ethynyl-2-fluoro-3-(pyrrolidin-1-yl)pyridine E93-3 (20.0 mg, crude product) was prepared as a yellow solid from E93-2 by the method described for I-2.

[0588] LC-MS: [M+H]+= 191.1. E93-4: (2-((4-(6-fluoro-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methanol E93-4 (130.0 mg, crude product) was prepared as a brown solid from E93-3 by the method described for 4-d.

[0589] LC-MS: [M+H]+= 394.1. E93-5: 2-((4-(6-fluoro-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carbaldehyde E93-5 (70.0 mg, 43.3%) was prepared as a brown solid from E93-4 by the method described for E54-2.

[0590] LC-MS: [M+H]+= 392.1. E-93: 1-(2-((4-(6-fluoro-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)methanamine E-93 (4.20 mg, 10.3%) was prepared as a yellow solid from E93-5 by the method described for E6-1.

[0591] LC-MS: [M+H]+= 491.1. 1H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.42 (s, 1H), 7.96 (s, 1H), 7.88 (s, 1H), 7.46 (d, J= 9.8 Hz, 2H), 7.30-7.22 (m, 1H), 5.73 (s, 2H), 3.68 (s, 2H), 3.40 (d, J= 2.0 Hz, 4H), 2.74 (s, 2H), 1.99-1.87 (m, 10H).

[0592] Example 94: Synthesis of E-94: 1-(2-((4-(5-(azetidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine TIFF2025530847000525.tif23170

[0593] E94-1: tert-butyl (2-((4-(5-(azetidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Intermediate E94-1 (50 mg, 52.3%) was prepared as a yellow solid from intermediate E63-3 in the manner described for intermediate E15-1.

[0594] LC-MS (ESI): m / z 529.3 [M+H]+ . E-94: 1-(2-((4-(5-(azetidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine To a stirred solution of intermediate E94-1 (30.0 mg, 56.8 μmol, 1.00 eq) in DCM (0.60 mL) at 25° C., TFA / DCM (V / V=1 / 50, 35.0 eq) was added, and the resulting mixture was stirred for 16 hours at 25° C. The mixture was concentrated, and the residue was purified by preparative HPLC to give compound E-94 (3.30 mg, 13.3%) as a yellow solid.

[0595] LC-MS (ESI): m / z 429.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1 H) 8.41 (s, 1 H) 8.38 (d, J = 1.43 Hz, 1 H) 7.95 (s, 1 H) 7.90 - 8.01 (m, 1 H) 7.74 (d, J= 2.50 Hz, 1 H) 7.45 (d, J = 9.18 Hz, 1 H) 7.25 (dd, J = 9.30, 1.43 Hz, 1 H) 7.20 (t, J = 2.15 Hz, 1 H) 5.73 (s, 2 H) 3.91 (t, J = 7.27 Hz, 4 H) 3.64 (s, 2 H) 3.29 (s, 2 H) 2.37 - 2.41 (m, 3 H) 1.90 - 2.03 (m, 3 H) 1.71 - 1.87 (m, 3 H) 1.55 - 1.66 (m, 2 H).

[0596] Example 95: Synthesis of E-95: 1-(2-((4-(2-fluoro-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)methanamine TIFF2025530847000526.tif101170

[0597] E95-1: 3-Bromo-2-fluoro-5-(pyrrolidin-1-yl)pyridine E95-1 (100.0 mg, 39.1%) was prepared as a white solid from 5-bromo-6-fluoropyridin-3-amine in the manner described for E93-1.

[0598] LC-MS: [M+H]+= 264.9. E95-2: 2-fluoro-5-(pyrrolidin-1-yl)-3-((trimethylsilyl)ethynyl)pyridine E95-2 (70.0 mg, 81.7%) was prepared as a gray solid from E95-1 by the method described for E53-6.

[0599] LC-MS: [M+H]+= 263.2. E95-3: 3-ethynyl-2-fluoro-5-(pyrrolidin-1-yl)pyridine E95-3 (50.7 mg, crude product) was prepared as a yellow oil from E95-2 by the method described for I-2.

[0600] LC-MS: [M+H]+= 191.1. E95-4: (2-((4-(2-fluoro-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methanol E95-4 (70.0 mg, 58.8%) was prepared as a yellow solid from E95-3 by the method described for 4-d.

[0601] LC-MS: [M+H]+= 394.4. E95-5: 2-((4-(2-fluoro-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carbaldehyde E95-5 (30.0 mg, 30.2%) was prepared as a brown solid from E95-4 by the method described for E143-2.

[0602] LC-MS: [M+H]+= 392.2. E-95: 1-(2-((4-(2-fluoro-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)methanamine E-95 (1.80 mg, 9.34%) was prepared as a yellow solid from E95-5 by the method described for E6-1.

[0603] LC-MS: [M+H]+= 491.2. 1H NMR (400 MHz, DMSO-d6): δ 8.47 (d, J = 3.6 Hz, 1H), 8.41 (s, 1H), 7.94 (s, 1H), 7.65 (dd, J = 2.9, 8.2 Hz, 1H), 7.46 (d, J = 9.4 Hz, 1H), 7.43 (br s, 1H), 7.25 (d, J = 9.4 Hz, 1H), 5.78 (s, 2H), 3.67 (s, 2H), 3.30 (d, J = 6.6 Hz, 4H), 2.73 (s, 2H), 1.98 (t, J = 6.4 Hz, 4H), 1.92 (d, J = 2.6 Hz, 6H).

[0604] Example 96: Synthesis of E-96: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((2-((4-(2-methyl-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000527.tif94170

[0605] E96-1: 3-bromo-2-methyl-5-(pyrrolidin-1-yl)pyridine E96-1 (400 mg, 31.6%) was prepared as a yellow solid from 5-bromo-6-methylpyridin-3-amine in the manner described for E93-1.

[0606] LC-MS: [M+H]+= 241.1. E96-2: 2-methyl-5-(pyrrolidin-1-yl)-3-((trimethylsilyl)ethynyl)pyridine E96-2 (150.0 mg, 73.7%) was prepared as a brown solid from E96-1 by the method described for E53-6.

[0607] LC-MS: [M+H]+= 259.2. E96-3: 3-ethynyl-2-methyl-5-(pyrrolidin-1-yl)pyridine E96-3 (108 mg, crude product) was prepared as a yellow oil from E96-2 as described for I-2.

[0608] LC-MS: [M+H]+= 187.3. E96-4: (2-((4-(2-methyl-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methanol E96-4 (200 mg, crude product) was prepared as a brown solid from E96-3 by the method described for 4-d.

[0609] LC-MS: [M+H]+= 390.1. E96-5: 2-((4-(2-methyl-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carbaldehyde E96-5 (25.0 mg, 10.9%) was prepared as a yellow solid from E96-4 by the method described for E143-2.

[0610] LC-MS: [M+H]+= 388.2. E-96: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((2-((4-(2-methyl-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine E-96 (11.40 mg, 22.7%) was prepared as a yellow solid from E96-5 by the method described for E6-1.

[0611] LC-MS: [M+H]+= 487.2. 1H NMR (400 MHz, DMSO-d6): δ 8.50 (s, 1H), 8.41 (s, 1H), 7.93 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 9.4 Hz, 1H), 7.25 (d, J = 9.3 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 5.75 (s, 2H), 3.67 (s, 2H), 3.31 (br s, 3H), 3.26 (br s, 4H), 2.74 (s, 2H), 1.96 (br s, 4H), 1.93 (d, J = 2.4 Hz, 6H).

[0612] Example 97: Synthesis of E-97: N-(1-(6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)ethyl)-5-(pyrrolidin-1-yl)nicotinamide TIFF2025530847000528.tif97170

[0613] E97-1: tert-butyl(cyclobutylmethyl)((2-(1-(5-(pyrrolidin-1-yl)nicotinamido)ethyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate E97-1 (15.0 mg, 19.6%) was prepared as a white solid from E12-5 by the method described for E101-2.

[0614] LC-MS: [M+H]+= 533.3. E-97: N-(1-(6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)ethyl)-5-(pyrrolidin-1-yl)nicotinamide E-97 (4.50 mg, 33.8%) was prepared as a yellow solid from E97-1 by the method described for E-3.

[0615] LC-MS: [M+H]+= 433.2. 1H NMR (400 MHz, DMSO-d6): δ 9.78 (d, J = 7.3 Hz, 1H), 9.61 (br s, 2H), 9.00 (s, 1H), 8.49 (s, 1H), 8.47-8.42 (m, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 9.1 Hz, 1H), 7.98 (d, J = 9.4 Hz, 1H), 7.95 (br s, 1H), 5.48 (t, J = 7.1 Hz, 1H), 4.25 (br s, 2H), 3.45-3.43 (m, 4H), 2.95 (d, J = 4.4 Hz, 2H), 2.73-2.66 (m, 1H), 2.10-2.03 (m, 2H), 2.02-1.97 (m, 4H), 1.90-1.76 (m, 4H), 1.70 (d, J = 7.0 Hz, 3H).

[0616] Example 98: Synthesis of E-98: 1-(2-((4-(5-(1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine TIFF2025530847000529.tif31170

[0617] E98-1: tert-butyl (2-((4-(5-(1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Intermediate E98-1 (0.07 g, 72.6%) was prepared as a white solid from intermediate E63-3 in the manner described for intermediate E15-1.

[0618] LC-MS (ESI): m / z539.2 [M+H]+ . E-98: 1-(2-((4-(5-(1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine Compound E-98 (25.6 mg, 39.5%) was prepared as a white solid from intermediate E98-1 in the manner described for compound E-1.

[0619] LC-MS (ESI): m / z 439.1 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 8.96 (s, 1 H) 8.92 (s, 1 H) 8.89 - 8.91 (m, 1 H) 8.87 - 8.89 (m, 1 H) 8.44 - 8.47 (m, 1 H) 8.38 - 8.40 (m, 1 H) 7.85 (s, 2 H) 7.55 (s, 2 H) 6.36 (s, 2 H) 5.99 (s, 2 H) 4.21 - 4.24 (m, 2 H) 2.98 (s, 2 H) 2.62 (br s, 1 H) 2.04 (s, 2 H) 1.73 - 1.84 (m, 4 H) .

[0620] Example 99: Synthesis of E-99: N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-5-(pyrrolidin-1-yl)nicotinamide hydrochloride TIFF2025530847000530.tif65170

[0621] E99-1: 5-(pyrrolidin-1-yl)nicotinic acid Intermediate E99-1 (0.40 g, crude) was prepared as a yellow solid from methyl 5-bromonicotinate in the manner described for intermediate E15-1.

[0622] LC-MS (ESI): m / z193.0 [M+H]+ . E99-2: tert-butyl (2-((5-(pyrrolidin-1-yl)nicotinamido)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E99-2 (35.0 mg, 23.2%) was prepared as a yellow solid from intermediates E99-1 and I-10 in the manner described for intermediate E7-3.

[0623] LC-MS (ESI): m / z519.5 [M+H]+ . E-99: N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-5-(pyrrolidin-1-yl)nicotinamide hydrochloride Compound E-99 (5.60 mg, 18.2%) was prepared as a white solid from intermediate E99-2 in the manner described for compound E-1.

[0624] LC-MS (ESI): m / z 419.4 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ9.99 (br s, 1H), 9.55 (br s, 2H), 9.01 (s, 1H), 8.46 (s, 1H), 8.40 (s, 1H), 8.18 (d, J = 2.5 Hz, 1H), 8.12 (d, J = 9.4 Hz, 1H), 8.01 - 7.92 (m, 2H), 4.76 (d, J = 5.4 Hz, 2H), 4.24 (br s, 2H), 3.42 - 3.39 (m, 4H), 3.01 - 2.92 (m, 2H), 2.76 - 2.68 (m, 1H), 2.07 - 1.99 (m, 6H), 1.87 - 1.76 (m, 4H).

[0625] Example 100: Synthesis of E-100: 5-(1-((2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,n-dimethylpyridin-3-amine TIFF2025530847000531.tif29170

[0626] E100-1: tert-butyl 6-((4-(5-(dimethylamino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E100-1 (0.10 g, 28.5%) was prepared as a white solid from intermediate E38-3 in the manner described for intermediate E7-3.

[0627] LC-MS (ESI): m / z 544.4 [M+H]+ . E-100: 5-(1-((2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylpyridin-3-amine Compound E-100 (14.5 mg, 16.4%) was prepared as a yellow solid from intermediate E100-1 in the manner described for compound E-1.

[0628] LC-MS (ESI): m / z 444.1 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ11.58 - 11.67 (m, 1 H) 10.69 - 10.85 (m, 1 H) 8.98 - 9.01 (m, 1 H) 8.49 - 8.53 (m, 1 H) 8.14 - 8.18 (m, 1 H) 8.04 - 8.07 (m, 1 H) 7.57 - 7.63 (m, 1 H) 7.47 - 7.51 (m, 1 H) 7.07 - 7.12 (m, 1 H) 6.64 - 6.68 (m, 1 H) 5.76 - 5.81 (m, 2 H) 4.49 (s, 2 H) 3.16 - 3.21 (m, 2 H) 3.11 (s, 6 H) 3.03 - 3.08 (m, 2 H) 1.67 - 1.75 (m, 2 H) 1.48 - 1.54 (m, 2 H) 0.93 - 0.99 (m, 6 H) .

[0629] Example 101: Synthesis of E-101: N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-5-(pyrrolidin-1-yl)nicotinamide hydrochloride TIFF2025530847000532.tif73170

[0630] E101-1: tert-butyl 6-(aminomethyl)-2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate Intermediate E101-1 (840 mg, 59.3%) was prepared as a yellow oil from intermediate I-7 in the manner described for intermediate I-10.

[0631] LC-MS (ESI): m / z443.7 [M+H]+ . E101-2: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((5-(pyrrolidin-1-yl)nicotinamido)methyl)-1H-indole-1-carboxylate To a stirred solution of intermediate E99-2 (43.3 mg, 225 μmol, 1.00 eq) and E101-1 (100 mg, 225 μmol, 1.00 eq) in pyridine (2.00 mL) was added EDCI (64.8 mg, 338 μmol, 1.50 eq). The resulting mixture was stirred at 25 °C under a nitrogen atmosphere for 16 h. The mixture was quenched by the addition of water (5.00 mL) and extracted with ethyl acetate (2.00 mL*3). The combined organic layers were washed with brine (2.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography on silica gel eluting with DCM:MeOH (10:1) to give intermediate E101-2 (0.07 g, 50.3%) as a brown oil.

[0632] LC-MS (ESI): m / z 618.5 [M+H]+ . E-101: N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-5-(pyrrolidin-1-yl)nicotinamide hydrochloride Compound E-101 (37.6 mg, 67.2%) was prepared as a yellow oil from intermediate E101-2 in the manner described for compound E-1.

[0633] LC-MS (ESI): m / z 418.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ11.46 (s, 1 H) 9.70 (t, J = 5.92 Hz, 1 H) 9.35 - 9.45 (m, 2 H) 8.44 (s, 1 H) 8.17 (d, J = 2.63 Hz, 1 H) 7.99 (s, 1 H) 7.50 (d, J = 8.11 Hz, 1 H) 7.38 (s, 1 H) 7.04 (dd, J = 8.11, 1.32 Hz, 1 H) 6.57 (s, 1 H) 4.60 (d, J = 5.92 Hz, 2H) 4.25 (t, J = 5.26 Hz, 2 H) 3.40 (t, J = 6.36 Hz, 4 H) 2.88 - 2.95 (m, 2 H) 2.62 - 2.70 (m, 1 H) 1.97 - 2.05 (m, 6 H) 1.73 - 1.84 (m, 4 H).

[0634] Example 102: Synthesis of E-102: 5-(dimethylamino)-N-((6-((4,4-dimethylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)nicotinamide TIFF2025530847000533.tif84170

[0635] E102-1: (6-aminopyridin-3-yl)methanol Intermediate E102-1 (9.50 g, crude) was prepared as a yellow solid from methyl 6-aminonicotinate in the manner described for intermediate E54-1.

[0636] LC-MS (ESI): m / z 125.0 [M+H]+ . E102-2: 5-((tert-butyldimethyloxy)methyl)pyridin-2-amine To a solution of intermediate E102-1 (9.50 g, 76.5 mmol, 1.00 eq) in DCM (250 mL) were added imidazole (5.73 g, 84.1 mmol, 1.10 eq) and TBSCl (11.5 g, 76.5 mmol, 9.38 mL, 1.00 eq). The resulting mixture was stirred at 25 °C for 16 h. The mixture was quenched with water (100 mL) and extracted with DCM (30.0 mL). The combined organic layers were washed with brine (2.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give intermediate E102-2 (8.00 g, 43.8%) as a white solid.

[0637] LC-MS (ESI): m / z 239.0 [M+H]+ . E102-3: 6-(((tert-butyldimethylsilyloxy)methyl)-2-(chloromethyl)imidazo[1,2-a]pyridine To a suspension of intermediate E102-2 (8.00 g, 33.6 mmol, 1.00 eq) in MeCN (80.0 mL) at 20 °C, 1,3-dichloropropan-2-one (8.52 g, 67.1 mmol, 8.35 mL, 2.00 eq) was added, and the resulting mixture was stirred at 80 °C for 16 h. The mixture was quenched with 2 M sodium bicarbonate (100.0 mL) and extracted with DCM (30.0 mL *3). The combined organic layers were washed with brine (2.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give intermediate E102-3 (1.00 g, 9.60%) as a pink solid.

[0638] LC-MS (ESI): m / z 311.1 [M+H]+ . E102-4: (6-(((tert-butyldimethylsilyl)oxy)methyl)imidazo[1,2-a]pyridin-2-yl)methanamine Intermediate E102-3 (1.00 g, 3.22 mmol, 1.00 eq) was added with a solution of NH in MeOH (7 M, 30.0 mL) and stirred at 50 °C for 12 h. The solution was concentrated. The residue was purified by column chromatography (DCM / MeOH = 50 / 1 to 5 / 1) to give intermediate E102-4 (0.50 g, 53.3%) as a yellow solid.

[0639] LC-MS (ESI): m / z 292.1 [M+H]+ . E102-5: N-((6-(((tert-butyldimethylsilyl)oxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-5-(dimethylamino)nicotinamide Intermediate E102-5 (0.32 g, 42.4%) was prepared as a yellow solid from intermediate E102-4 in the manner described for intermediate E7-3.

[0640] LC-MS (ESI): m / z 440.2 [M+H]+ . E102-6: 5-(dimethylamino)-N-((6-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)nicotinamide To a solution of intermediate E102-5 (0.27 g, 614 μmol, 1.00 eq) in THF (5.50 mL) was added TBAF (1 M, 1.23 mL, 2.00 eq) at 20 °C. The resulting mixture was stirred at 25 °C for 2 h. The mixture was concentrated. The residue was purified by preparative thin-layer chromatography (DCM / MeOH = 5 / 1) to give intermediate E102-6 (0.120 g, 60.0%) as a brown solid.

[0641] LC-MS (ESI): m / z 326.2 [M+H]+ . E102-7: 5-(dimethylamino)-N-((6-formylimidazo[1,2-a]pyridin-2-yl)methyl)nicotinamide Intermediate E102-7 (30 mg, crude) was prepared as a red solid from intermediate E102-6 in the manner described for intermediate I-4.

[0642] LC-MS (ESI): m / z 323.4 [M+H]+ . E-102: 5-(dimethylamino)-N-((6-((4,4-dimethylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)nicotinamide Compound E-102 (2.80 mg, 7.00%) was prepared as a yellow solid from intermediate E102-7 in the manner described for intermediate E30-1.

[0643] LC-MS (ESI): m / z 421.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ9.08 - 9.14 (m, 1 H), 8.34 - 8.41 (m, 2 H), 8.20 - 8.25 (m, 1 H), 7.76 - 7.80 (m, 1 H), 7.47 - 7.49 (m, 1 H), 7.43 (d, J = 9.38 Hz, 1 H), 7.13 - 7.18 (m, 1 H), 4.52 - 4.60 (m, 2 H), 3.39 - 3.47 (m, 2 H), 2.96 - 3.01 (m, 6 H), 2.32 - 2.37 (m, 4 H), 1.29 - 1.36 (m, 4 H), 0.87 - 0.91 (m, 6 H).

[0644] Example 103: Synthesis of E-103: 5-(dimethylamino)-N-((2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)nicotinamide TIFF2025530847000534.tif93170

[0645] E103-1: tert-butyl 6-(aminomethyl)-2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E103-1 (26.0 mg, 37.0%) was prepared as a white solid from intermediate E109-5 in the manner described for intermediate I-10.

[0646] LC-MS (ESI): m / z372.2 [M+H]+ . E103-2: tert-butyl 6-((5-(dimethylamino)nicotinamido)methyl)-2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E103-2 (30.0 mg, 18.8%) was prepared as a white solid from intermediate E103-1 in the manner described for intermediate E7-3.

[0647] LC-MS (ESI): m / z520.5 [M+H]+ . E-103: 5-(dimethylamino)-N-((2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)nicotinamide Compound E-103 (16.4 mg, 30.7%) was prepared as a white solid from intermediate E103-2 in the manner described for intermediate E-1.

[0648] LC-MS (ESI): m / z 420.3 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 11.42 (s, 1 H) 10.54 - 10.67 (m, 1 H) 9.59 - 9.66 (m, 1 H) 8.47 (s, 1 H) 8.30 (s, 1 H) 8.04 - 8.07 (m, 1 H) 7.52 - 7.56 (m, 1 H) 7.40 (s, 1 H) 7.05 - 7.09 (m, 1 H) 6.61 - 6.63 (m, 1 H) 4.60 (s, 2 H) 4.47 (s, 2 H) 3.16 (s, 2H) 3.10 (s, 6 H) 3.03 - 3.08 (m, 2 H) 1.65 - 1.72 (m, 2 H) 1.52 (s, 2 H) 0.96 (d, J= 10.38 Hz, 6 H) .

[0649] Example 104: Synthesis of E-104: 1-(2-((4-(5-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)methanamine TIFF2025530847000535.tif74170

[0650] E104-1: (2-((4-(5-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methanol E104-1 (70.0 mg, 42.5%) was prepared as a yellow solid from E131-4 and 4-c by the method described for 4-d.

[0651] LC-MS: [M+H]+= 412.3. E104-2: 2-((4-(5-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carbaldehyde E104-2 (49 mg, crude) was prepared as a white solid from E104-1 by the method described for E54-2.

[0652] LC-MS: [M+H]+= 410.2. E-104: 1-(2-((4-(5-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)methanamine E-104 (37.5 mg, 59.2%) was prepared as a yellow solid from E104-2 by the method described for E6-1.

[0653] LC-MS: [M+H]+= 509.2. 1H NMR (400 MHz, DMSO-d6): δ8.69 (s, 1H), 8.47-8.41 (m, 2H), 7.98-7.95 (m, 2H), 7.47 (d, J = 9.3 Hz, 1H), 7.40 (s, 1H), 7.28 (s, 1H), 5.75 (s, 2H), 3.80 (s, 2H), 3.68 (s, 2H), 3.58 (s, 2H), 2.74 (s, 2H), 2.61-2.56 (m, 2H), 1.93 (d, J= 2.6 Hz, 6H).

[0654] Example 105: Synthesis of E-105: 1-(6-((4-(5-(1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine TIFF2025530847000536.tif63170

[0655] E105-1: 3-bromo-5-(1H-pyrrol-1-yl)pyridine Intermediate E105-1 (1.10 g, 86.8%) was prepared as a white solid from 3-bromo-5-fluoropyridine in the manner described for intermediate E16-1.

[0656] LC-MS (ESI): m / z 223.2 [M+H]+ . E105-2: 3-(1H-pyrrol-1-yl)-5-((trimethylsilyl)ethynyl)pyridine Intermediate E105-2 (0.90 g, 83.5%) was prepared as a brown solid from intermediate E105-1 in the manner described for intermediate 2-b.

[0657] LC-MS (ESI): m / z 241.3 [M+H]+ . E105-3: 3-ethynyl-5-(1H-pyrrol-1-yl)pyridine Intermediate E105-3 (0.12 g, 85.8%) was prepared as a brown solid from intermediate E105-2 in the manner described for intermediate I-2.

[0658] LC-MS (ESI): m / z 169.1 [M+H]+ . E105-4: tert-butyl 6-((4-(5-(1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate Intermediate E105-4 (0.08 g, 70.3%) was prepared as a white solid from intermediate E105-3 in the manner described for intermediate 4-d.

[0659] LC-MS (ESI): m / z638.6 [M+H]+ . E-105: 1-(6-((4-(5-(1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine Compound E-105 (26.3 mg, 44.2%) was prepared as a white solid from intermediate E105-4 in the manner described for intermediate E-1.

[0660] LC-MS (ESI): m / z 438.1 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ11.55 (d, J = 0.66 Hz, 1 H) 9.27 - 9.35 (m, 2 H) 8.98 (s, 1 H) 8.92 (s, 1 H) 8.87 (s, 1 H) 8.49 (t, J = 1.86 Hz, 1 H) 7.55 - 7.60 (m, 3 H) 7.48 (s, 1 H) 7.07 (dd, J = 8.22, 1.21 Hz, 1 H) 6.61 (s, 1 H) 6.35 (t, J = 2.08 Hz, 2 H) 5.78 (s, 2 H) 4.27 (t, J = 5.26 Hz, 2 H) 2.90 - 2.97 (m, 2 H) 2.61 - 2.70 (m, 1 H) 2.00 - 2.08 (m, 2 H) 1.73 - 1.85 (m, 4 H).

[0661] Example 106: Synthesis of E-106: 1-cyclobutyl-N-((6-((4-(5-(2,5-dihydro-1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine TIFF2025530847000537.tif55170

[0662] E106-1: 3-Bromo-5-(2,5-dihydro-1H-pyrrol-1-yl)pyridine Intermediate E106-1 (1.00 g, 33.4%) was prepared as a black solid from 3-bromo-5-fluoropyridine in the manner described for intermediate E16-1.

[0663] LC-MS (ESI): m / z224.9 [M+H]+ . E106-2: 3-(2,5-dihydro-1H-pyrrol-1-yl)-5-((trimethylsilyl)ethynyl)pyridine Intermediate E106-2 (0.95 g, 67.8%) was prepared as a black solid from intermediate E106-1 in the manner described for intermediate 2-b.

[0664] LC-MS (ESI): m / z 243.2 [M+H]+ . E106-3: 3-(2,5-dihydro-1H-pyrrol-1-yl)-5-ethynylpyridine Intermediate E106-3 (55.0 mg, 63.8%) was prepared as a black solid from intermediate E106-2 in the manner described for intermediate I-2.

[0665] LC-MS (ESI): m / z171.0 [M+H]+ . E106-4: tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(5-(2,5-dihydro-1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E106-4 (0.08 g, 41.1%) was prepared as a yellow solid from intermediate E106-3 in the manner described for intermediate 4-d.

[0666] LC-MS (ESI): m / z 638.5 [M+H]+ . E-106: 1-Cyclobutyl-N-((6-((4-(5-(2,5-dihydro-1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine Compound E-106 (21.6 mg, 31.3%) was prepared as a yellow solid from intermediate E106-4 in the manner described for intermediate E-1.

[0667] LC-MS (ESI): m / z 440.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 11.62 (s, 1H), 9.39 (s, 2H), 8.96 (s, 1H), 8.51 (s, 1H), 8.03 (d, J = 2.15 Hz, 1H), 7.88 (s, 1H), 7.58 (d, J = 8.11 Hz, 1H), 7.49 (s, 1H), 7.07 (d, J = 8.23 ​​Hz, 1H), 6.62 (s, 1 H), 6.09 (s, 2H), 5.78 (s, 2H), 4.28 (s, 2H), 4.25 (s, 4H), 2.98-2.89 (m, 2H), 2.67 (s, 1H), 2.09-2.02 (m, 2H), 1.83-1.72 (m, 4H).

[0668] Example 107: Synthesis of E-107: 1-cyclobutyl-N-((2-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000538.tif28170

[0669] E107-1: tert-butyl (2-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E107-1 (0.08 g, 41.1%) was prepared as a yellow solid from intermediate I-1 by the method described for intermediate 4-d.

[0670] LC-MS (ESI): m / z 473.3 [M+H]+ . E-107: 1-Cyclobutyl-N-((2-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-107 (34.6 mg, 49.8%) was prepared as a white solid from intermediate E107-1 in the manner described for intermediate E-1.

[0671] LC-MS (ESI): m / z 373.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ9.72-9.64 (m, 2H), 9.05-9.02 (m, 1H), 8.79 (s, 1H), 8.47 (s, 1H), 8.13-8.08 (m, 1H), 7.96-7.91 (m, 1H), 7.84 (s, 2H), 7.46 (s, 2H), 7.38-7.32 (m, 1H), 6.00 (s, 2H), 4.22 (d, J = 4.88 Hz, 2H), 2.97-2.91 (m, 2H), 2.71 (s, 1H), 2.05 (d, J = 6.63 Hz, 2H), 1.83-1.74 (m, 4H).

[0672] Example 108: Synthesis of E-108: 1-cyclobutyl-N-((2-((4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000539.tif27170

[0673] E108-1: tert-Butyl (cyclobutylmethyl) ((2-((4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E108-1 (42.0 mg, 46.9%) was prepared as a white solid from intermediate I-1 by the method described for intermediate 4-d.

[0674] LC-MS (ESI): m / z474.4 [M+H]+ . E-108: 1-Cyclobutyl-N-((2-((4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-108 (21.1 mg, 62.9%) was prepared as a white solid from intermediate E108-1 in the manner described for intermediate E-1.

[0675] LC-MS (ESI): m / z 374.1 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ9.07 (d, J = 1.25 Hz, 1H), 8.74 (s, 1H), 8.53 (dd, J = 4.75, 1.50 Hz, 1H), 8.42 (s, 1H), 8.23 ​​(t, J = 7.91, 1.80 Hz, 1H), 7.97 (s, 1H), 7.50-7.44 (m, 2H), 7.26 (dd, J = 9.26, 1.25 Hz, 1H), 5.76 (s, 2H), 3.65 (s, 2H), 3.33 (s, 2H), 2.45-2.35 (m, 1H), 2.02-1.95 (m, 2H), 1.80 (d, J = 8.13 Hz, 2H), 1.63 (d, J = 9.51 Hz, 2H).

[0676] Example 109: Synthesis of E-109: 6-((4-(5-(azetidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indole TIFF2025530847000540.tif87170

[0677] E109-1: (6-bromo-1H-indol-2-yl)methanol Intermediate E109-1 (17.0 g, crude) was prepared as a brown solid from methyl 6-bromo-1H-indole-2-carboxylate in the manner described for intermediate E54-1.

[0678] LC-MS (ESI): m / z225.9 [M+H]+ . E109-2: 6-Bromo-1H-indole-2-carbaldehyde Intermediate E109-2 (5.80 g, 34.4%) was prepared as a yellow solid from intermediate E109-1 in the manner described for intermediate E54-2.

[0679] LC-MS (ESI): m / z 224.0 [M+H]+ . E109-3: 6-bromo-2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indole Intermediate E109-3 (3.10 g, crude) was prepared as a pink solid from intermediate E109-2 in the manner described for intermediate E30-1.

[0680] LC-MS (ESI): m / z 321.1 [M+H]+ . E109-4: tert-butyl 6-bromo-2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indole-1-carboxylate To a solution of intermediate E109-3 (3.90 g, 12.1 mmol, 1.00 eq) in THF (40.0 mL) at 0 °C, BocO (10.6 g, 48.5 mmol, 11.1 mL, 4.00 eq) and LiHMDS (1.00 M, 36.4 mL, 3.00 eq) were added, and the resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 16 h. The mixture was quenched with water (100 mL) and extracted with ethyl acetate (30.0 mL). The combined organic layers were washed with brine (30.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with DCM:MeOH = 50:1 to 10:1 to give intermediate E109-4 (4.50 g, 87.9%) as a red oil.

[0681] LC-MS (ESI): m / z421.1 [M+H]+ . E109-5: tert-butyl 2-((4,4-dimethylpiperidin-1-yl)methyl)-6-(hydroxymethyl)-1H-indole-1-carboxylate Intermediate E109-5 (430 mg, 41.3%) was prepared as a yellow solid from intermediate E109-4 in the manner described for intermediate 8-b.

[0682] LC-MS (ESI): m / z373.3 [M+H]+ . E109-6: tert-butyl 6-(azidomethyl)-2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E109-6 (0.30 g, 53.2%) was prepared as a colorless oil from intermediate E109-5 in the manner described for intermediate I-7.

[0683] LC-MS (ESI): m / z 398.3 [M+H]+ . E109-7: tert-butyl 6-((4-(5-(azetidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E109-7 (0.05 g, 14.8%) was prepared as a yellow solid from intermediate E109-6 in the manner described for intermediate 4-d.

[0684] LC-MS (ESI): m / z556.3 [M+H]+ . E-109: 6-((4-(5-(azetidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indole Compound E-109 (8.10 mg, 19.0%) was prepared as a yellow solid from intermediate E109-7 in the manner described for intermediate E-94.

[0685] LC-MS (ESI): m / z 456.3 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ11.06 (s, 1H), 8.66 (s, 1H), 8.37 (s, 1H), 7.73 (s, 1H), 7.43 (d, J= 8.2 Hz, 1H), 7.31 (s, 1H), 7.19-7.16 (m, 1H), 6.97 (dd, J = 1.5, 8.1 Hz, 1H), 6.25 (d, J = 1.1 Hz, 1H), 5.67 (s, 2H), 3.90 (t, J = 7.3 Hz, 4H), 3.57 (s, 2H), 2.39-2.29 (m, 6H), 1.31 (t, J= 5.4 Hz, 4H), 0.87 (s, 6H).

[0686] Example 110: Synthesis of E-110: 1-cyclobutyl-N-((2-((4-(3-(pyrrolidin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000541.tif70170

[0687] E110-1: 1-(3-((trimethylsilyl)ethynyl)phenyl)pyrrolidine Intermediate E110-1 (0.18 g, 66.1%) was prepared as a yellow solid from 1-(3-bromophenyl)pyrrolidine in the manner described for intermediate E53-6.

[0688] LC-MS (ESI): m / z 244.1 [M+H]+ . E110-2: 1-(3-ethynylphenyl)pyrrolidine Intermediate E110-2 (0.06 g, 60.0%) was prepared as a brown solid from intermediate E110-1 in the manner described for intermediate I-2.

[0689] LC-MS (ESI): m / z172.3 [M+H]+ . E110-3: tert-butyl (2-((4-(3-(pyrrolidin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E110-3 (0.15 g, 79.0%) was prepared as a brown solid from intermediate E110-2 in the manner described for intermediate 4-d.

[0690] LC-MS (ESI): m / z542.4 [M+H]+ . E-110: 1-Cyclobutyl-N-((2-((4-(3-(pyrrolidin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-110 (96.4 mg, 72.8%) was prepared as a yellow solid from intermediate E110-3 in the manner described for intermediate E-1.

[0691] LC-MS (ESI): m / z 442.4 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 9.76 (br s, 2 H), 9.11 (s, 1 H), 8.80 (s, 1 H), 8.56 (s, 1 H), 8.24 (d, J = 9.30 Hz, 1 H), 8.01 (d, J = 9.42 Hz, 1 H), 7.24 - 7.32 (m, 1 H), 7.19 (br s, 2 H), 6.71 (d, J = 2.98 Hz, 1 H), 6.03 (s, 2 H), 4.25 (br t, J = 5.01 Hz, 2 H), 3.33 (br s, 4 H), 2.85 - 3.03 (m, 2 H), 2.64 - 2.79 (m, 1 H), 1.92 - 2.12 (m, 6 H), 1.69 - 1.90 (m, 4 H).

[0692] Example 111: Synthesis of E-111: 2-((4,4-dimethylpiperidin-1-yl)methyl)-6-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole TIFF2025530847000542.tif62170

[0693] E111-1: 3-bromo-5-(pyrrolidin-1-yl)pyridine Intermediate E111-1 (7.70 g, 80.3%) was prepared as a yellow solid from 3,5-dibromopyridine in the manner described for intermediate E15-1.

[0694] LC-MS (ESI): m / z227.0 [M+H]+ . E111-2: 3-(pyrrolidin-1-yl)-5-((trimethylsilyl)ethynyl)pyridine Intermediate E111-2 (6.80 g, 83.1%) was prepared as a brown solid from intermediate E111-1 in the manner described for intermediate E53-6.

[0695] LC-MS (ESI): m / z 245.3 [M+H]+ . E111-3: 3-ethynyl-5-(pyrrolidin-1-yl)pyridine Intermediate E111-3 (4.00 g, 83.5%) was prepared as a white solid from intermediate E111-2 in the manner described for intermediate I-2.

[0696] LC-MS (ESI): m / z173.3 [M+H]+ . E111-4: tert-butyl 2-((4,4-dimethylpiperidin-1-yl)methyl)-6-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E111-4 (0.03 g, 30.2%) was prepared as a brown oil from intermediate E111-3 in the manner described for intermediate 4-d.

[0697] LC-MS (ESI): m / z 570.4 [M+H]+ . E-111: 2-((4,4-dimethylpiperidin-1-yl)methyl)-6-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole Compound E-111 (7.40 mg, 26.2%) was prepared as a yellow solid from intermediate E111-4 in the manner described for intermediate E-1.

[0698] LC-MS (ESI): m / z 470.3 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ11.55 (s, 1 H), 10.56 (d, J = 1.38 Hz, 1 H), 8.93 (s, 1 H), 8.44 (s, 1 H), 8.00 (d, J = 2.50 Hz, 1 H), 7.82 (s, 1 H), 7.60 (d, J = 8.25 Hz, 1 H), 7.49 (s, 1 H), 7.08 (dd, J = 8.19, 1.06 Hz, 1 H), 6.65 (s, 1 H), 5.78 (s, 2 H), 4.47 (d, J = 4.63 Hz, 2 H), 3.39 (t, J = 6.38 Hz, 4 H), 3.15 - 3.20 (m, 2 H), 3.01 - 3.09 (m, 2 H), 1.98 - 2.03 (m, 4 H), 1.62 - 1.73 (m, 2 H), 1.50 (d, J = 14.13 Hz, 2 H), 0.95 (d, J = 11.38 Hz, 6 H).

[0699] Example 112: Synthesis of E-112: 1-(6-((4-(5-(azetidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine TIFF2025530847000543.tif60170

[0700] E112-1: 3-(azetidin-1-yl)-5-bromopyridine Intermediate E112-1 (1.00 g, 75.1%) was prepared as a white solid from 3-bromo-5-fluoropyridine in the manner described for intermediate E16-1.

[0701] LC-MS (ESI): m / z212.9 [M+H]+ . E112-2: 3-(azetidin-1-yl)-5-((trimethylsilyl)ethynyl)pyridine Intermediate E112-2 (0.30 g, 92.5%) was prepared as a brown solid from intermediate E112-1 in the manner described for intermediate 2-b.

[0702] LC-MS (ESI): m / z231.2 [M+H]+ . E112-3: 3-(azetidin-1-yl)-5-ethynylpyridine Intermediate E112-3 (100.0 mg, 67.7%) was prepared as a white solid from intermediate E112-2 in the manner described for intermediate I-2.

[0703] LC-MS (ESI): m / z159.1 [M+H]+ . E112-4: tert-butyl 6-((4-(5-(azetidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate Intermediate E112-4 (0.10 g, 84.0%) was prepared as a white solid from intermediate E112-3 in the manner described for intermediate 4-d.

[0704] LC-MS (ESI): m / z 628.3 [M+H]+ . E-112: 1-(6-((4-(5-(azetidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine Compound E-112 (12.0 mg, 52.9%) was prepared as a white solid from intermediate E112-4 in the manner described for intermediate E-1.

[0705] LC-MS (ESI): m / z 428.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ11.03 (s, 1H), 8.69 (s, 1H), 8.39 (d, J= 1.7 Hz, 1H), 7.75 (d, J = 2.7 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.34 (s, 1H), 7.20 (d, J = 2.2 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.25 (s, 1H), 5.69 (s, 2H), 3.92 (t, J= 7.2 Hz, 4H), 3.80 (s, 2H), 2.49-2.29 (m, 4H), 2.06-1.90 (m, 3H), 1.89-1.73 (m, 2H), 1.70-1.53 ​​(m, 2H).

[0706] Example 113: Synthesis of E-113: 1-cyclobutyl-N-((2-((4-(5-(2,5-dihydro-1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000544.tif30170

[0707] E113-1: tert-Butyl (cyclobutylmethyl) ((2-((4-(5-(2,5-dihydro-1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E113-1 (0.03 g, 28.9%) was prepared as a yellow solid from intermediate E106-3 by the method described for intermediate 4-d.

[0708] LC-MS (ESI): m / z 541.2 [M+H]+ . E-113: 1-Cyclobutyl-N-((2-((4-(5-(2,5-dihydro-1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-113 (10.7 mg, 39.4%) was prepared as a yellow solid from intermediate E113-1 by the method described for compound E-1.

[0709] LC-MS (ESI): m / z 441.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 9.42 (br s, 2H), 9.07 (s, 1H), 8.88 (s, 1H), 8.54 (s, 1H), 8.32 (s, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.94 (s, 1H), 7.80-7.73 (m, 2H), 6.10 (s, 2H), 5.95 (s, 2H), 4.27 (s, 4H), 4.19-4.16 (m, 2H), 2.97-2.92 (m, 2H), 2.72-2.68 (m, 1H), 2.12-2.02 (m, 2H), 1.89-1.76 (m, 4H).

[0710] Example 114: Synthesis of E-114: 1-(2-((4-(5-(1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)methanamine TIFF2025530847000545.tif59170

[0711] E114-1: (2-((4-(5-(1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methanol E114-1 (180 mg, crude) was prepared as a yellow solid from E105-3 and 4-c by the method described for 4-d.

[0712] LC-MS: [M+H]+= 372.2. E114-2: 2-((4-(5-(1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carbaldehyde E114-2 (152 mg, crude) was prepared as a white solid from E114-1 in the manner described for E54-2.

[0713] LC-MS: [M+H]+= 370.2. E-114: 1-(2-((4-(5-(1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)methanamine E-114 (32.5 mg, 42.1%) was prepared as a yellow solid from E114-2 by the method described for E6-1.

[0714] LC-MS: [M+H]+= 469.0. 1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.88-8.85 (m, 1H), 8.83 (s, 1H), 8.42 (d, J = 14.6 Hz, 2H), 8.02-7.99 (m, 1H), 7.56 (s, 2H), 7.48 (d, J= 9.4 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 6.34 (s, 2H), 5.79 (s, 2H), 3.69 (br s, 2H), 2.75 (br s, 2H), 1.94 (d, J = 2.6 Hz, 6H).

[0715] Example 116: Synthesis of E-116: 3-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-5-nitropyridin-4-amine TIFF2025530847000546.tif60170

[0716] E116-1: 3-nitro-5-((trimethylsilyl)ethynyl)pyridin-4-amine Intermediate E116-1 (8.50 g, 78.8%) was prepared as a black solid from 3-bromo-5-nitropyridin-4-amine in the manner described for intermediate 2-b.

[0717] LC-MS (ESI): m / z236.1 [M+H]+ . E116-2: 3-ethynyl-5-nitropyridin-4-amine Intermediate E116-2 (5.20 g, 88.2%) was prepared as a black solid from intermediate E116-1 in the manner described for intermediate I-2.

[0718] LC-MS (ESI): m / z 164.1 [M+H]+ . E116-3: tert-butyl (2-((4-(4-amino-5-nitropyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Intermediate E116-3 (1.30 g, 90.3%) was prepared as a white solid from intermediate E116-2 in the manner described for intermediate 4-d.

[0719] LC-MS (ESI): m / z534.2 [M+H]+ . E-116: 3-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-5-nitropyridin-4-amine Compound E-116 (40.2 mg, 22.8%) was prepared as a yellow solid from intermediate E116-3 by the method described for compound E-1.

[0720] LC-MS (ESI): m / z 434.1 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ9.51 (br s, 2H), 9.23 (s, 1H), 9.12 (s, 1H), 8.95 (s, 1H), 8.84 (s, 1H), 8.43 (s, 1H), 7.9-7.89 (m, 1H), 7.87-7.82 (m, 1H), 6.04 (s, 2H), 4.20 (br s, 2H), 3.04-2.84 (m, 2H), 2.77-2.59 (m, 1H), 2.12-1.98 (m, 2H), 1.90-1.69 (m, 4H)..

[0721] Example 119: Synthesis of E-119: N-((2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)-5-(pyrrolidin-1-yl)nicotinamide TIFF2025530847000547.tif53170

[0722] E119-1: tert-butyl 6-(aminomethyl)-2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E119-1 (0.07 g, 37.5%) was prepared as a white solid from intermediate E109-5 in the manner described for intermediate I-10.

[0723] LC-MS (ESI): m / z372.4 [M+H]+ . E119-2: tert-butyl 2-((4,4-dimethylpiperidin-1-yl)methyl)-6-((5-(pyrrolidin-1-yl)nicotinamido)methyl)-1H-indole-1-carboxylate Intermediate E119-2 (0.05 g, 48.6%) was prepared as a white solid from intermediate E119-1 in the manner described for intermediate E101-2.

[0724] LC-MS (ESI): m / z 546.1 [M+H]+. E-119: N-((2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)-5-(pyrrolidin-1-yl)nicotinamide Compound E-119 (12.7 mg, 30.8%) was prepared as a white solid from intermediate E119-2 in the manner described for compound E-1.

[0725] LC-MS (ESI): m / z 446.3 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ10.88 (s, 1H), 9.04 (t, J= 5.9 Hz, 1H), 8.31 (d, J = 1.6 Hz, 1H), 8.03 (d, J = 2.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.30-7.26 (m, 2H), 6.93 (dd, J = 1.3, 8.0 Hz, 1H), 6.20 (s, 1H), 4.53 (d, J = 5.9 Hz, 2H), 3.56 (s, 2H), 3.30-3.27 (m, 4H), 2.36-2.32 (m, 4H), 1.99-1.94 (m, 4H), 1.32 (t, J = 5.6 Hz, 4H), 0.87 (s, 6H).

[0726] Example 120: Synthesis of E-120: 5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridine-3,4-diamine TIFF2025530847000548.tif30170

[0727] E-120: 5-(1-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridine-3,4-diamine Compound E-120 (14.9 mg, 38.2%) was prepared as a white solid from compound E-116 by the method described for intermediate E3-2.

[0728] LC-MS (ESI): m / z 404.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ8.64 (s, 1H), 8.45 (s, 1H), 8.21 (br s, 1H), 8.05- 7.91 (m, 2H), 7.61 (s, 1H), 7.47 (d, J = 9.3 Hz, 1H), 7.27 (d, J = 9.4 Hz, 1H), 6.53 (br s, 2H), 5.75 (s, 2H), 3.71 (s, 2H), 2.55 (d, J= 6.8 Hz, 2H), 2.46-2.37 (m, 1H), 2.03-1.92 (m, 2H), 1.87-1.73 (m, 2H), 1.69-1.56 (m, 2H).

[0729] Example 121: Synthesis of E-121: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((6-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine TIFF2025530847000549.tif45170

[0730] E121-1: 1-(tert-butyl) 2-methyl 6-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1,2-dicarboxylate Intermediate E121-1 (0.95 g, 56.4%) was prepared as a white solid from intermediate 8-d in the manner described for intermediate 4-d.

[0731] LC-MS (ESI): m / z503.3 [M+H]+ . E121-2: tert-butyl 2-(hydroxymethyl)-6-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E121-2 (95.0 mg, 44.6%) was prepared as a white solid from intermediate E121-1 by the method described for intermediate 4-b.

[0732] LC-MS (ESI): m / z 475.1 [M+H]+ . E121-3: tert-butyl 2-formyl-6-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E121-3 (0.07 g, 57.8%) was prepared as a white solid from intermediate E121-2 in the manner described for intermediate E54-2.

[0733] LC-MS (ESI): m / z 473.1 [M+H]+ . E121-4: tert-butyl 2-((((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)-6-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E121-4 (20.0 mg, 25.6%) was prepared as a yellow solid from intermediate E121-3 in the manner described for intermediate E6-1.

[0734] LC-MS (ESI): m / z572.2 [M+H]+ . E-121: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((6-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine Compound E-121 (4.00 mg, 22.5%) was prepared as a yellow solid from intermediate E121-4 in the manner described for compound E-3.

[0735] LC-MS (ESI): m / z 472.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 11.64 (s, 1H), 9.63 (br s, 2H), 8.97 (s, 1H), 8.45 (s, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.88 (s, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.48 (s, 1H), 7.07 (dd, J = 1.3, 8.3 Hz, 1H), 6.62 (s, 1H), 5.77 (s, 2H), 4.32 (br s, 2H), 3.44 (br s, 2H), 3.24 (br s, 4H), 2.11 (d, J = 2.5 Hz, 6H), 2.00 (t, J = 6.6 Hz, 4H).

[0736] Example 122: Synthesis of E-122: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((2-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000550.tif53170

[0737] E122-1: (2-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methanol Intermediate E122-1 (240.0 mg, crude product) was prepared as a brown solid from intermediate E111-3 by the method described for intermediate 4-d.

[0738] LC-MS (ESI): m / z376.0 [M+H]+ . E122-2: 2-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carbaldehyde Intermediate E122-2 (0.04 g, 20.1%) was prepared as a yellow solid from intermediate E122-1 in the manner described for intermediate E54-2.

[0739] LC-MS (ESI): m / z374.3 [M+H]+ . E-122: 1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((2-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-122 (11.3 mg, 14.8%) was prepared as a pink solid from intermediate E122-2 in the manner described for intermediate E6-1.

[0740] LC-MS (ESI): m / z 473.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ8.67 (s, 1H), 8.42 (s, 1H), 8.30 (d, J= 1.4 Hz, 1H), 7.95 (s, 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.46 (d, J = 9.1 Hz, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.27-7.23 (m, 1H), 5.73 (s, 2H), 3.67 (s, 2H), 3.31-3.28 (m, 4H), 2.74 (s, 2H), 1.97 (t, J = 6.4 Hz, 4H), 1.93 (d, J = 2.8 Hz, 6H).

[0741] Example 123: Synthesis of E-123: N-((6-((4,4-dimethylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-5-(pyrrolidin-1-yl)nicotinamide TIFF2025530847000551.tif40170

[0742] E123-1: N-((6-(((tert-butyldimethylsilyl)oxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-5-(pyrrolidin-1-yl)nicotinamide Intermediate E123-1 (0.16 g, 33.4%) was prepared as a brown solid from intermediates E102-4 and E99-2 in the manner described for intermediate E101-2.

[0743] LC-MS (ESI): m / z466.0 [M+H]+ . E123-2: N-((6-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-5-(pyrrolidin-1-yl)nicotinamide Intermediate E123-2 (0.07 g, 58.0%) was prepared as a white solid from intermediate E123-1 in the manner described for intermediate E102-6.

[0744] LC-MS (ESI): m / z352.0 [M+H]+ . E123-3: n-((6-formylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(pyrrolidin-1-yl)nicotinamide Intermediate E123-3 (0.03 g, 43.1%) was prepared as a white solid from intermediate E123-2 in the manner described for intermediate I-4.

[0745] LC-MS (ESI): m / z350.0 [M+H]+ . E-123: N-((6-((4,4-dimethylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-5-(pyrrolidin-1-yl)nicotinamide Compound E-123 (16.4 mg, 30.7%) was prepared as a white solid from intermediate E123-3 in the manner described for intermediate E30-1.

[0746] LC-MS (ESI): m / z 447.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ9.09 (t, J = 5.7 Hz, 1H), 8.37 (s, 1H), 8.31 (d, J = 1.6 Hz, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.76 (s, 1H), 7.42 (d, J = 9.3 Hz, 1H), 7.31-7.28 (m, 1H), 7.15 (dd, J = 1.6, 9.2 Hz, 1H), 4.55 (d, J = 5.6 Hz, 2H), 3.42 (s, 2H), 3.31-3.28 (m, 4H), 2.33 (br s, 4H), 2.00-1.93 (m, 4H), 1.31 (t, J = 5.5 Hz, 4H), 0.88 (s, 6H).

[0747] Example 124: Synthesis of E-124: N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-5-(piperidin-1-yl)nicotinamide TIFF2025530847000552.tif29170

[0748] E124-1: tert-butyl (2-((5-(piperidin-1-yl)nicotinamido)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E124-1 (0.08 g, 49.0%) was prepared as a white solid from intermediate I-10 in the manner described for intermediate E101-2.

[0749] LC-MS (ESI): m / z 533.1 [M+H]+ . E-124: N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-5-(piperidin-1-yl)nicotinamide Compound E-124 (33.8 mg, 48.0%) was prepared as a yellow solid from intermediate E124-1 in the manner described for compound E-3.

[0750] LC-MS (ESI): m / z 433.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 10.06 (t, J = 5.3 Hz, 1H), 9.65 (br s, 2H), 9.04 (s, 1H), 8.54 (d, J = 2.8 Hz, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.35 (br s, 1H), 8.18 (d, J = 9.3 Hz, 1H), 8.01 (d, J = 9.3 Hz, 1H), 4.77 (d, J = 5.4 Hz, 2H), 4.25 (t, J = 5.3 Hz, 2H), 3.46 (br s, 4H), 3.00-2.91 (m, 2H), 2.77-2.66 (m, 1H), 2.09-2.00 (m, 2H), 1.79 (dd, J = 5.0, 8.4 Hz, 4H), 1.62 (br s, 6H).

[0751] Example 125: Synthesis of E-125: N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-5-fluoronicotinamide TIFF2025530847000553.tif64170

[0752] E125-1: 5-Fluoronicotinic acid Intermediate E125-1 (1.50 g, crude) was prepared as a white solid from methyl 5-fluoronicotinate in the manner described for intermediate E7-2.

[0753] LC-MS (ESI): m / z142.1 [M+H]+ . E125-2: tert-butyl(cyclobutylmethyl)((2-((5-fluoronicotinamido)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E125-2 (0.16 g, 54.3%) was prepared as a yellow solid from intermediate E125-1 in the manner described for intermediate E101-2.

[0754] LC-MS (ESI): m / z 468.0 [M+H]+ . E-125: N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-5-fluoronicotinamide Compound E-125 (5.4 mg, 17.2%) was prepared as a yellow solid from intermediate E125-2 in the manner described for compound E-3.

[0755] LC-MS (ESI): m / z 367.9 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 9.32 (t, J = 5.6 Hz, 1H), 8.94 (s, 1H), 8.78-8.73 (m, 1H), 8.75 (d, J = 2.6 Hz, 1H), 8.35 (s, 1H), 8.17-8.09 (m, 1H), 7.81 (s, 1H), 7.43 (d, J = 9.1 Hz, 1H), 7.21 (d, J = 9.3 Hz, 1H), 4.59 (d, J = 5.6 Hz, 2H), 3.64 (s, 2H), 2.49-2.47 (m, 2H), 2.39 (td, J = 7.6, 14.8 Hz, 1H), 2.02-1.92 (m, 2H), 1.86-1.73 (m, 2H), 1.66-1.56 (m, 2H).

[0756] Example 127: Synthesis of E-127: 1-(6-((4-(5-(1H-pyrazol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine TIFF2025530847000554.tif55170

[0757] E127-1: 3-bromo-5-(1H-pyrazol-1-yl)pyridine To a solution of 3,5-dibromopyridine (2.00 g, 8.44 mmol, 1.00 eq) and 1H-pyrazole (632 mg, 9.29 mmol, 1.10 eq) in DMF (40 mL) was added KCO (2.92 g, 21.1 mmol, 2.50 eq), CuI (161 mg, 844 μmol, 0.10 eq), and 1,10-phenanthroline (304 mg, 1.69 mmol, 0.20 eq), and the resulting mixture was stirred at 120 °C for 16 h under a nitrogen atmosphere. The mixture was quenched with water (200 mL) and extracted with DCM (50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography eluting with EtOAc / petroleum ether (1:10) to afford intermediate E127-1 (0.50 g, 26.4%) as a yellow solid.

[0758] LC-MS (ESI): m / z 224.0 [M+H]+ . E127-2: 3-(1H-pyrazol-1-yl)-5-((trimethylsilyl)ethynyl)pyridine Intermediate E127-2 (0.45 g, 83.6%) was prepared as a yellow solid from intermediate E127-1 in the manner described for intermediate 2-b.

[0759] LC-MS (ESI): m / z242.1 [M+H]+ . E127-3: 3-ethynyl-5-(1H-pyrazol-1-yl)pyridine Intermediate E127-3 (0.23 g, 92.3%) was prepared as a yellow solid from intermediate E127-2 in the manner described for intermediate I-2.

[0760] LC-MS (ESI): m / z 170.1 [M+H]+ . E127-4: tert-butyl 6-((4-(5-(1H-pyrazol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate Intermediate E127-4 (0.06 g, 88.2%) was prepared as a brown solid from intermediate E127-3 in the manner described for intermediate 4-d.

[0761] LC-MS (ESI): m / z 639.3 [M+H]+ . E-127: 1-(6-((4-(5-(1H-pyrazol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine Compound E-127 (17.9 mg, 40.1%) was prepared as a white solid from intermediate E127-4 in the manner described for compound E-1.

[0762] LC-MS (ESI): m / z 438.9 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 11.62 (br s, 1H), 9.43 (br s, 2H), 9.12 (d, J = 2.4 Hz, 1H), 9.03 (d, J = 1.8 Hz, 1H), 8.93 (s, 1H), 8.77 (d, J = 1.9 Hz, 1H), 8.73 (d, J = 2.5 Hz, 1H), 7.87 (d, J = 1.4 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.49 (s, 1H), 7.08 (dd, J = 1.3, 8.1 Hz, 1H), 6.66-6.63 (m, 1H), 6.61 (s, 1H), 5.77 (s, 2H), 4.27 (t, J = 5.2 Hz, 2H), 2.96-2.87 (m, 2H), 2.66 (td, J = 7.5, 14.6 Hz, 1H), 2.09-1.98 (m, 2H), 1.87-1.72 (m, 4H).

[0763] Example 129: Synthesis of E-129: N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-methyl-5-(pyrrolidin-1-yl)nicotinamide hydrochloride TIFF2025530847000555.tif59170

[0764] E129-1: Methyl-5-(pyrrolidin-1-yl)nicotinamide Intermediate E129-1 (0.06 g, 54.8%) was prepared as a white solid from intermediate E99-2 in the manner described for intermediate E101-2.

[0765] LC-MS (ESI): m / z 206.2 [M+H]+ . E129-2: tert-butyl (2-((N-methyl-5-(pyrrolidin-1-yl)nicotinamido)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E129-2 (0.10 g, 91.5%) was prepared as a yellow solid from intermediate E129-1 in the manner described for intermediate 7-a.

[0766] LC-MS (ESI): m / z 533.0 [M+H]+. E-129: N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-methyl-5-(pyrrolidin-1-yl)nicotinamide hydrochloride Compound E-129 (14.9 mg, 32.8%) was prepared as a yellow solid from intermediate E129-2 in the manner described for compound E-3.

[0767] LC-MS (ESI): m / z 433.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 9.71-9.49 (m, 2H), 9.14-8.91 (m, 1H), 8.58-8.36 (m, 1H), 8.30-7.90 (m, 4H), 7.88-7.72 (m, 1H), 5.01-4.67 (m, 2H), 4.27 (br s, 2H), 3.39 (br s, 4H), 3.04 (s, 2H), 3.02-2.93 (m, 3H), 2.78-2.68 (m, 1H), 2.11-1.94 (m, 6H), 1.80 (dd, J = 5.3, 8.4 Hz, 4H).

[0768] Example 130: Synthesis of E-130: 1-cyclobutyl-N-((2-((4-(4-methyl-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000556.tif56170

[0769] E130-1: 3-bromo-4-methyl-5-(pyrrolidin-1-yl)pyridine To a solution of 3,5-dibromo-4-methylpyridine (4.50 g, 17.9 mmol, 1.00 eq) and pyrrolidine (1.28 g, 17.9 mmol, 1.50 mL, 1.00 eq) in dioxane (45.0 mL), t-BuONa (3.45 g, 35.9 mmol, 2.00 eq), BINAP (558 mg, 897 μmol, 0.0500 eq), and Pd(dba) (657 mg, 717 μmol, 0.04 eq) were added, and the resulting mixture was stirred at 25 °C for 16 h. The mixture was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to give intermediate E130-1 (2.00 g, 46.2%) as a yellow solid.

[0770] 1H NMR (400 MHz, chloroform-d): δ 8.20-8.15 (m, 1H), 8.03-7.97 (m, 1H), 3.15 ( t, J = 6.44 Hz, 4H), 2.35-2.27 (m, 3H), 1.94-1.84 (m, 4H). E130-2: 4-methyl-3-(pyrrolidin-1-yl)-5-((trimethylsilyl)ethynyl)pyridine Intermediate E130-2 (0.60 g, 56.0%) was prepared as a brown oil from intermediate E130-1 in the manner described for intermediate E53-6.

[0771] LC-MS (ESI): m / z259.1 [M+H]+ . E130-3: 3-ethynyl-4-methyl-5-(pyrrolidin-1-yl)pyridine Intermediate E130-3 (0.05 g, 69.4%) was prepared as a yellow solid from intermediate E130-2 in the manner described for intermediate I-2.

[0772] 1H NMR (400 MHz, chloroform-d): δ 8.43-7.91 (m, 2H), 3.29-3.25 (m, 1H), 3.17 (t, J = 6.50 Hz, 4H), 2.39-2.32 (m, 3H), 1.94-1.84 (m, 4H). E130-4: tert-butyl (2-((4-(4-methyl-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E130-4 (0.10 g, 66.5%) was prepared as a yellow solid from intermediate E130-3 in the manner described for intermediate 4-d.

[0773] LC-MS (ESI): m / z557.3 [M+H]+ . E-130: 1-Cyclobutyl-N-((2-((4-(4-methyl-5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-130 (54.1 mg, 59.3%) was prepared as a yellow solid from intermediate E130-4 by the method described for compound E-1.

[0774] LC-MS (ESI): m / z 457.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 9.51-9.35 (m, 2H), 8.92-8.87 (m, 1H), 8.87-8.83 (m, 1H), 8.55-8.52 (m, 1H), 8.37-8.32 (m, 1H), 8.20-8.16 (m, 1H), 7.90-7.72 (m, 2H), 6.01-5.95 (m, 2H), 4.19 (t, J= 5.1 Hz, 2H), 3.46-3.36 (m, 4H), 3.01-2.91 (m, 2H), 2.71-2.65 (m, 1H), 2.56 (s, 3H), 2.10-2.01 (m, 2H), 2.01-1.91 (m, 4H), 1.89-1.73 (m, 4H).

[0775] Example 131: Synthesis of E-131: 1-cyclobutyl-N-((2-((4-(5-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine TIFF2025530847000557.tif55170

[0776] E131-1: 3-bromo-5-(3,3-difluoropyrrolidin-1-yl)pyridine Intermediate E131-1 (0.17 g, 76.5%) was prepared as a brown solid from 3,5-dibromopyridine in the manner described for intermediate E130-1.

[0777] LC-MS (ESI): m / z262.9 [M+H]+ . E131-2: 3-(3,3-difluoropyrrolidin-1-yl)-5-((trimethylsilyl)ethynyl)pyridine Intermediate E131-2 (0.15 g, 88.0%) was prepared as a brown solid from intermediate E131-1 in the manner described for intermediate E53-6.

[0778] LC-MS (ESI): m / z281.1 [M+H]+ . E131-3: 3-(3,3-difluoropyrrolidin-1-yl)-5-ethynylpyridine Intermediate E131-3 (0.04 g, crude product) was prepared as a black liquid from intermediate E131-2 in the manner described for intermediate I-2.

[0779] LC-MS (ESI): m / z209.0 [M+H]+ . E131-4: tert-butyl (2-((4-(5-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E131-4 (0.10 g, 89.9%) was prepared as a white solid from intermediate E131-3 in the manner described for intermediate 4-d.

[0780] LC-MS (ESI): m / z579.0 [M+H]+ . E-131: 1-Cyclobutyl-N-((2-((4-(5-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)methanamine Compound E-131 (29.8 mg, 33.3%) was prepared as a white solid from intermediate E131-4 in the manner described for compound E-1.

[0781] LC-MS (ESI): m / z 479.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 9.40 (br s, 2H), 9.05 (s, 1H), 8.89 (s, 1H), 8.60 (s, 1H), 8.35 (s, 1H), 8.14 (d, J= 2.5 Hz, 1H), 7.98 (s, 1H), 7.84-7.76 (m, 2H), 5.96 (s, 2H), 4.18 (t, J = 5.3 Hz, 2H), 3.95 (s, 2H), 3.70 (br s, 2H), 2.97-2.92 (m, 2H), 2.73-2.64 (m, 2H), 2.61 (d, J = 7.0 Hz, 1H), 2.08-2.01 (m, 2H), 1.87-1.74 (m, 4H).

[0782] Example 132: Synthesis of E-132: 5-(azetidin-1-yl)-N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)nicotinamide TIFF2025530847000558.tif25170

[0783] E132-1: tert-butyl((2-((5-(azetidin-1-yl)nicotinamido)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Intermediate E132-1 (0.05 g, 42.5%) was prepared as a yellow solid from intermediate E125-2 in the manner described for intermediate E16-1.

[0784] LC-MS (ESI): m / z505.0 [M+H]+ . E-132: 5-(azetidin-1-yl)-N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)nicotinamide Compound E-132 (4.00 mg, 9.53%) was prepared as a yellow solid from intermediate E132-1 in the manner described for compound E-94.

[0785] LC-MS (ESI): m / z 405.2 [M+H]+ .1H NMR (400 MHz, DMSO-d6): δ 9.09 (t, J = 5.8 Hz, 1H), 8.41-8.34 (m, 2H), 7.90 (d, J = 2.8 Hz, 1H), 7.76 (s, 1H), 7.42 (d, J = 9.3 Hz, 1H), 7.25-7.18 (m, 2H), 4.55 (d, J = 5.8 Hz, 2H), 3.91 (t, J = 7.3 Hz, 4H), 3.64 (s, 2H), 2.49 (br s, 2H), 2.42-2.31 (m, 3H), 2.02-1.92 (m, 2H), 1.86-1.72 (m, 2H), 1.67-1.56 (m, 2H).

[0786] Example 133: Synthesis of E-133: 1-(6-((4-(5-(1H-imidazol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine TIFF2025530847000559.tif68170

[0787] E133-1: 3-bromo-5-(1H-imidazol-1-yl)pyridine Intermediate E133-1 (0.15 g, 58.9%) was prepared as a yellow solid from 3-bromo-5-fluoropyridine in the manner described for intermediate E16-1.

[0788] LC-MS (ESI): m / z 223.9 [M+H]+ . E133-2: 3-ethynyl-5-(1H-imidazol-1-yl)pyridine Intermediate E133-2 (0.03 g, 22.5%) was prepared as a yellow solid from intermediate E133-1 in the manner described for intermediate 2-b.

[0789] LC-MS (ESI): m / z 170.1 [M+H]+ . E133-3: tert-butyl 6-((4-(5-(1H-imidazol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate Intermediate E133-3 (0.02 g, 56.1%) was prepared as a brown solid from intermediate E133-2 by the method described for intermediate 4-d.

[0790] LC-MS (ESI): m / z 639.5 [M+H]+ . E-133: 1-(6-((4-(5-(1H-imidazol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine Compound E-133 (3.20 mg, 20.9%) was prepared as a white solid from intermediate E133-3 in the manner described for compound E-1.

[0791] LC-MS (ESI): m / z 439.1 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 11.63 (s, 1H), 9.83 (s, 1H), 9.42 (br s, 2H), 9.22 (d, J= 1.6 Hz, 1H), 9.01 (d, J = 2.5 Hz, 1H), 8.85 (s, 1H), 8.72 (t, J = 2.1 Hz, 1H), 8.41 (t, J = 1.6 Hz, 1H), 7.96 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.07 (dd, J = 1.3, 8.2 Hz, 1H), 6.61 (s, 1H), 5.79 (s, 2H), 4.27 (t, J = 5.2 Hz, 2H), 2.96-2.89 (m, 2H), 2.68-2.64 (m, 1H), 2.08-2.00 (m, 2H), 1.87-1.71 (m, 4H).

[0792] Example 134: Synthesis of E-134: 6-(piperidin-1-ylmethyl)-2-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine TIFF2025530847000560.tif79170

[0793] E134-1: (2-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methanol Intermediate E134-1 (0.4 g, crude) was prepared as a brown solid from intermediate E111-3 in the manner described for intermediate 4-d.

[0794] LC-MS (ESI): m / z376.0 [M+H]+ . E134-2: 2-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carbaldehyde Intermediate E134-2 (0.07 g, 35.2%) was prepared as a yellow solid from intermediate E134-1 in the manner described for intermediate I-4.

[0795] LC-MS (ESI): m / z374.0 [M+H]+ . E-134: 6-(piperidin-1-ylmethyl)-2-((4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine Compound E-134 (6.40 mg, 17.4%) was prepared as a yellow solid from intermediate E134-2 in the manner described for intermediate E30-1.

[0796] LC-MS (ESI): m / z 443.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.43 (s, 1H), 8.31 (d, J= 1.8 Hz, 1H), 7.95 (s, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.46 (d, J = 9.3 Hz, 1H), 7.32-7.27 (m, 1H), 7.21 (dd, J= 1.6, 9.3 Hz, 1H), 5.73 (s, 2H), 3.39 (s, 2H), 3.31-3.27 (m, 4H), 2.33 (d, J= 1.8 Hz, 4H), 2.01-1.94 (m, 4H), 1.48 (td, J = 5.3, 10.5 Hz, 4H), 1.38 (d, J = 5.4 Hz, 2H).

[0797] Example 136: Synthesis of E-136: 1-(6-((4-(5-(4H-1,2,4-triazol-4-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine TIFF2025530847000561.tif59170

[0798] E136-1: 3-Bromo-5-(4H-1,2,4-triazol-4-yl)pyridine A solution of 5-bromopyridin-3-amine (1.00 g, 5.78 mmol, 1.00 eq) and N'-formylformohydrazide (509 mg, 5.78 mmol, 1.00 eq) was added to a sealed tube. The resulting mixture was stirred at 140 °C for 16 hours under a nitrogen atmosphere. The mixture was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to give intermediate E136-1 (300 mg, 23.1%) as a brown solid.

[0799] LC-MS (ESI): m / z226.9 [M+H]+ . E136-2: 3-(4H-1,2,4-triazol-4-yl)-5-((trimethylsilyl)ethynyl)pyridine Intermediate E136-2 (0.08 g, 74.3%) was prepared as a brown oil from intermediate E136-1 in the manner described for intermediate 2-b.

[0800] LC-MS (ESI): m / z 243.2 [M+H]+. E136-3: 3-ethynyl-5-(4H-1,2,4-triazol-4-yl)pyridine Intermediate E136-3 (35.00 mg, crude product) was prepared as a black solution from intermediate E136-2 in the manner described for intermediate I-2.

[0801] LC-MS (ESI): m / z171.2 [M+H]+ . E136-4: tert-butyl 6-((4-(5-(4H-1,2,4-triazol-4-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate Intermediate E136-4 (50 mg, 38.0%) was prepared as a brown solid from intermediate E136-3 by the method described for intermediate 4-d.

[0802] LC-MS (ESI): m / z 640.4 [M+H]+ . E-136: 1-(6-((4-(5-(4H-1,2,4-triazol-4-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine Compound E-136 (9.30 mg, 25.0%) was prepared as a yellow solid from intermediate E136-4 by the method described for compound E-1.

[0803] LC-MS (ESI): m / z 440.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ11.53 (s, 1H), 9.33 (s, 2H), 9.28 (br s, 2H), 9.15-9.08 (m, 1H), 8.95 (d, J = 2.4 Hz, 1H), 8.80 (s, 1H), 8.60 (t, J = 2.0 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.48 (s, 1H), 7.09-7.05 (m, 1H), 6.61 (s, 1H), 5.78 (s, 2H), 4.27 (t, J = 5.0 Hz, 2H), 2.98-2.90 (m, 2H), 2.68-2.62 (m, 1H), 2.07-2.00 (m, 2H), 1.86-1.73 (m, 4H).

[0804] Example 139: Synthesis of E-139: 1-(2-((4-(1H-imidazo[4,5-c]pyridin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine TIFF2025530847000562.tif57170

[0805] E139-1: tert-butyl (2-((4-(4,5-diaminopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)carbamate Intermediate E139-1 (0.15 g, crude) was prepared as a brown solid from intermediate E116-3 in the manner described for intermediate E3-2.

[0806] LC-MS (ESI): m / z504.5 [M+H]+ . E139-2: tert-butyl (2-((4-(1H-imidazo[4,5-c]pyridin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methyl)(cyclobutylmethyl)carbamate Intermediate E139-1 (100 mg, 199 μmol, 1.00 eq) and diethoxyethoxyethane (1.00 mL) were stirred at 140 °C for 40 h. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (3.00 mL * 3). The combined organic layer was washed with brine (2.00 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (ethyl acetate:methanol = 10:1) to give intermediate E139-2 (50.0 mg, 49.0%) as a black oil.

[0807] LC-MS (ESI): m / z514.5 [M+H]+ . E-139: 1-(2-((4-(1H-imidazo[4,5-c]pyridin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-6-yl)-N-(cyclobutylmethyl)methanamine Compound E-139 (12.9 mg, 25.0%) was prepared as a white solid from intermediate E139-2 by the method described for compound E-1.

[0808] LC-MS (ESI): m / z 414.1 [M+H]+ .1H NMR (400 MHz, DMSO-d6): δ 9.39 (br s, 1H), 9.13 (s, 2H), 8.95 (br s, 1H), 8.87 (br s, 2H), 8.71 (s, 1H), 8.21 (s, 1H), 7.65 (d, J = 9.4 Hz, 1H), 7.43 (dd, J = 1.4, 9.4 Hz, 1H), 5.95 (s, 2H), 4.16 (br s, 2H), 2.98 (d, J = 3.3 Hz, 2H), 2.60 (td, J = 7.5, 15.2 Hz, 1H), 2.11-2.00 (m, 2H), 1.91-1.71 (m, 4H).

[0809] Example 140: Synthesis of E-140: 6-((4-(5-(2,5-dihydro-1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indole TIFF2025530847000563.tif39170

[0810] E140-1: tert-butyl 6-((4-(5-(2,5-dihydro-1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-((4,4-dimethylpiperidin-1-yl)methyl)-1H-indole-1-carboxylate Intermediate E140-1 (0.02 g, 24.1%) was prepared as a yellow solid from intermediate E106-3 in the manner described for intermediate 4-d.

[0811] LC-MS (ESI): m / z568.4 [M+H]+ . E-140: 6-((4-(5-(2,5-dihydro-1H-pyrrol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-((4,4-...

Claims

1. A compound represented by formula I, or formula I', or formula I'', and a tautomer, stereoisomer, or pharmaceutically acceptable salt of these three compounds. (however, A is unsubstituted or —NH—(C １－１２ alkyl)-C ３－２０ a cycloalkyl group, a 3- to 20-membered heterocyclyl group, a -3- to 20-membered heterocyclyl-3- to 20-membered heterocyclyl group, a -5- to 20-membered heteroaryl-5- to 20-membered heteroaryl group, —NH—(C １－１２ alkyl)-3-20-membered heterocyclyl group, C ３－２０ a cycloalkyl group, or a —N(Z)CO-5-20 membered heteroaryl group; X １ , X ２ , X ３ are the same or different and are independently selected from C, O or N, with the proviso that X １ , X ２ , X ３ is not a heteroatom at the same time, X ４ is a -5-20 membered heteroaryl-5-20 membered heteroaryl group, -5-20 membered heteroaryl-C, which is unsubstituted or optionally substituted with one, two or more Rb. ６ - ２０ Aryl group, —N(Z)CO-5-20 membered heteroaryl group, —CON(Z)-5-20 membered heteroaryl group, -5-20 membered heteroaryl-COC １－１２ Alkyl group, —NH—(C １－１２ alkyl)-C ３－２０ a cycloalkyl group, a 3- to 20-membered heterocyclyl group, or a —COO-5- to 20-membered heteroaryl group; R is H or C １－１２ alkyl groups, Ra is a nitro group, an amino group, a halogen, or —CH ２ N (C １－１２ alkyl) ２ , -N(C １－１２ alkyl) ２ , —O—(C １－１２ alkyl-O) ２ -C １－１２ alkyl group, 3-20 membered heterocyclyl group, C １－１２ Alkyl-substituted 3- to 20-membered heterocyclyl group, -Se-C １－１２ Alkyl group, —S—C １－１２ alkyl group, 5-20 membered heteroaryl group, C １－１２ an alkoxy group, or C １－１２ alkyl groups, Rb is H, halogen, NO ２ , -CHO, OH, NH ２ , ═O, —S—C which is unsubstituted or optionally substituted with one, two or more Rd １－１２ Alkyl group, —NH—C １－１２ Alkyl group, —N(C １－１２ alkyl) ２ , 3- to 20-membered heterocyclyl group, C １－１２ Alkoxy group, —O—(C １－１２ alkyl-O) ２ -C １－１２ Alkyl group, —S(O) ２ -C １－１２ Alkyl group, -Se-C １－１２ Alkyl group, —N(C １－１２ alkyl-OH) ２ , -N(C １－１２ alkyl-Cl) ２ , C １－１２ Alkyl group, —NHC(O)C １－１２ Alkyl group, —N(Z)CO-5-20 membered heteroaryl group, —OC(O)C １－１２ Alkyl group, -N(CD ３ ) ２ , 5-20 membered heteroaryl groups; Z is H or C １－１２ alkyl groups, Rd is a halogen, a cyano group, C １－１２ Alkyl group, —S—C １－１２ Alkyl group, —NH—C １－１２ alkyl group, —N(C １－１２ alkyl) ２ (selected from (In Formula I′, R １ is -NH-(C １－１２ alkyl)-bicyclo[1.1.1]pentane-(Ra)n, -NH-(C １－１２ alkyl)-C ６－２０ Aryl-(Ra), —NH—(C １－１２ alkyl)-(Ra)n, -NH-(C １－１２ alkyl)-C ３－２０ Cycloalkyl-(Ra), —NH—(C １－１２ alkyl)-3-20-membered heterocyclyl-(Ra)n, -3-20-membered heterocyclyl-(Ra)n, -NH-(C １－１２ alkyl)-5-20-membered heteroaryl-(Ra)n, —NH—(C １－１２ alkyl)-bicyclo[2.2.2]octane-(Ra)n, —NH—(C １－１２ alkyl)-cubane-(Ra)n; Ra is H, OH, halogen, haloC １－１２ Alkyl group, C １－１２ alkyl group, CN, or C ２－１２ alkynyl groups, n is the number of Ra substituents and is selected from 1, 2, 3, 4, or 5; -NH-(C １－３ alkyl)-C ３－１２ In cycloalkyl-(Ra)n, Ra is C ３－１２ on the cycloalkyl group, or C ３－１２ Cycloalkyl groups and C １－３ optionally substituted on the carbon atom at the attachment point of the alkyl group, R ２ is H, C １－１２ alkyl group, or CN; R ３ is selected from -5-20-membered heteroaryl-Rb, -OC(O)-5-20-membered heteroaryl-Rb, or -NC(O)-5-20-membered heteroaryl-Rb; Rb is selected from a 5- to 20-membered heteroaryl-Rc, a 3- to 20-membered heterocyclyl group, or a halogen; m is 1, 2, or 3; Rc is -3-20 membered heterocyclyl-Rd, -5-20 membered heteroaryl-Rd, -O(C １－１２ AlkylO)m-C １－１２ alkyl groups, Rd is H, deuterium, halogen, OH, CN, haloC １－１２ Alkyl group, C １－１２ an alkyl group, or ═O) (In Formula I″, R １ is -NH-(C １－１２ alkyl)-bicyclo[1.1.1]pentane-(Ra)n, -NH-(C １－１２ alkyl)-C ６－２０ Aryl-(Ra), —NH—(C １－１２ alkyl)-(Ra)n, -NH-(C １－１２ alkyl)-C ３－２０ Cycloalkyl-(Ra), —NH—(C １－１２ alkyl)-3-20-membered heterocyclyl-(Ra)n, -3-20-membered heterocyclyl-(Ra)n, -NH-(C １－１２ alkyl)-5-20-membered heteroaryl-(Ra)n, —NH—(C １－１２ alkyl)-bicyclo[2.2.2]octane-(Ra)n, —NH—(C １－１２ alkyl)-cubane-(Ra)n; Ra is H, OH, halogen, haloC １－１２ Alkyl group, C １－１２ alkyl group, CN, or C ２－１２ alkynyl groups, n is the number of Ra substituents and is selected from 1, 2, 3, 4, or 5; -NH-(C １－３ alkyl)-C ３－１２ In cycloalkyl-(Ra)n, Ra is C ３－１２ on the cycloalkyl group, or C ３－１２ Cycloalkyl groups and C １－３ optionally substituted on the carbon atom at the attachment point of the alkyl group, R ２ is H, C １－１２ alkyl group, or CN; R ３ is selected from —OC(O)-5-12 membered heteroaryl-R m or —NC(O)-5-12 membered heteroaryl-R m , where R m is —NH—(C １－１２ alkyl), -N(C １－１２ alkyl) ２ or a 3- to 12-membered heterocyclyl group

2. In formula I, A is —NH—(C １－６ alkyl)-C ３－１２ a cycloalkyl group, a 3- to 12-membered heterocyclyl group, a -3- to 12-membered heterocyclyl-3- to 12-membered heterocyclyl group, a -5- to 12-membered heteroaryl-5- to 12-membered heteroaryl group, —NH—(C １－６ alkyl)-3-12 membered heterocyclyl group, C ３－１２ a cycloalkyl group, or a —N(Z)CO-5-12 membered heteroaryl group; X １ , X ２ , X ３ are the same or different and are independently selected from C, O or N, with the proviso that X １ , X ２ , X ３ is not a heteroatom at the same time, X ４ is a -5-12 membered heteroaryl-5-12 membered heteroaryl group, -5-12 membered heteroaryl-C, which is unsubstituted or optionally substituted by one, two or more Rb. ６ - １２ Aryl group, —N(Z)CO-5-12 membered heteroaryl group, —CON(Z)-5-12 membered heteroaryl group, -5-12 membered heteroaryl-COC １－６ Alkyl group, —NH—(C １－３ alkyl)-C ３－１２ a cycloalkyl group, a 3- to 12-membered heterocyclyl group, or a —COO-5- to 12-membered heteroaryl group; R is H or C １－６ alkyl groups, Ra is NO ２ , N.H. ２ , halogen, -CH ２ N (C １－３ alkyl) ２ , -N(C １－６ alkyl) ２ , —O—(C １－６ alkyl-O) ２ -C １－６ alkyl group, 3-12 membered heterocyclyl group, C １－６ Alkyl-substituted 3- to 12-membered heterocyclyl group, -Se-C １－６ Alkyl group, —S—C １－６ alkyl group, 5-12 membered heteroaryl group, C １－６ an alkoxy group, or C １－６ alkyl groups, Rb is H, halogen, NO ２ , -CHO, OH, NH ２ , ═O, —S—C which is unsubstituted or optionally substituted with one, two or more Rd １－６ Alkyl group, —NH—C １－６ alkyl group, —N(C １－６ alkyl) ２ , 3-12 membered heterocyclyl group, C １－６ Alkoxy group, —O—(C １－６ alkyl-O) ２ -C １－６ Alkyl group, —S(O) ２ -C １－６ Alkyl group, -Se-C １－６ alkyl group, —N(C １－６ alkyl-OH) ２ , -N(C １－６ alkyl-Cl) ２ , C １－６ Alkyl group, —NHC(O)C １－６ alkyl group, —N(Z)CO-5-12-membered heteroaryl group, —OC(O)C １－６ Alkyl group, -N(CD ３ ) ２ , 5-12 membered heteroaryl groups; Z is H or C １－６ alkyl groups, Rd is halogen, CN, C １－６ Alkyl group, —S—C １－６ Alkyl group, —NH—C １－６ Alkyl group, —N(C １－６ alkyl) ２ is selected from Preferably, in formula I′, R １ is -NH-(C １－３ alkyl)-bicyclo[1.1.1]pentane-(Ra)n, —NH—(C １－３ alkyl)-C ６ - １２ Aryl-(Ra), —NH—(C １－３ alkyl)-(Ra)n, -NH-(C １－３ alkyl)-C ３－１２ Cycloalkyl-(Ra), —NH—(C １－３ alkyl)-3-12-membered heterocyclyl-(Ra)n, -3-12-membered heterocyclyl-(Ra)n, -NH-(C １－３ alkyl)-5-12 membered heteroaryl-(Ra)n, —NH—(C １－３ alkyl)-bicyclo[2.2.2]octane-(Ra)n, —NH—(C １－３ alkyl)-cubane-(Ra)n; Ra is H, OH, halogen, haloC １－３ Alkyl group, C １－３ alkyl group, CN, or C ２－６ alkynyl groups, n is the number of Ra substituents and is selected from 1, 2, 3, 4, or 5; -NH-(C １－３ alkyl)-C ３－１２ In cycloalkyl-(Ra)n, Ra is C ３－１２ on the cycloalkyl group, or C ３－１２ Cycloalkyl groups and C １－３ optionally substituted on the carbon atom at the attachment point of the alkyl group, R ２ is H, C １－３ alkyl group, or CN; R ３ is selected from -5-12 membered heteroaryl-Rb, -OC(O)-5-12 membered heteroaryl-Rb, or -NC(O)-5-12 membered heteroaryl-Rb; Rb is selected from a 5-12 membered heteroaryl-Rc, a 3-12 membered heterocyclyl group, or a halogen; m is 1, 2, or 3; Rc is -3-20 membered heterocyclyl-Rd, -5-12 membered heteroaryl-Rd, or -O(C １－３ AlkylO)m-C １－３ alkyl groups, Rd is H, deuterium, halogen, OH, CN, haloC １－３ Alkyl group, C １－３ an alkyl group, or ═O; Preferably, in formula I″, R １ teeth, R ２ is C １－６ alkyl groups, R ３ is selected from —OC(O)-5-6 membered heteroaryl-R m or —NC(O)-5-6 membered heteroaryl-R m , where R m is —NH—(C １－３ alkyl), -N(C １－３ alkyl) ２ or a 3- to 6-membered heterocyclyl group.

3. In formula I, A is X ４ teeth, Y, Y １ , Y ２ are the same or different and independently represent H, NH ２ ,CN,CHO,OH,=O,-S-C １－６ Alkyl group, I, NH ２ , —NH—C １－６ Alkyl group, —N(C １－６ alkyl) ２ , 3-6 membered heterocyclyl group, Cl, Br, C １－６ Alkoxy group, —O—(C １－６ alkyl-O) ２ -C １－６ Alkyl group, —S(O) ２ -C １－６ Alkyl group, -Se-C １－６ Alkyl group, —N(C １－６ alkyl-OH) ２ , -N(C １－６ alkyl-Cl) ２ , C １－６ Alkyl group, —NHC(O)C １－６ Alkyl group, —OC(O)C １－６ Alkyl group, -CHO, OH, -N(CD ３ ) ２ , 5-6 membered heteroaryl group, NO ２ and F, wherein the 3- to 6-membered heterocyclyl group or the 5- to 6-membered heteroaryl group is optionally substituted by one, two or three groups selected from F, Cl, Br, and I; R １ , R ２ are the same or different and independently represent H, F, or C. １－６ alkyl groups, Z are the same or different and independently represent H or C. １－６ alkyl groups, Preferably, in formula I′, R １ teeth, Rf and Rh are the same or different and are independently selected from H, F, Cl, a methyl group, a trifluoromethyl group, or CN; m and n are the same or different and are independently selected from 1, 2, 3, 4, or 5; In formula I', Preferably, in formula I″, R １ teeth, R ２ is C １－３ alkyl groups, R ３ teeth, 3. The compound according to claim 1 or 2.

4. Compounds of formula I are A is, Y １ , Y ２ , Y ３ , Y ４ are the same or different and independently represent H, I, Br, Cl, F, NH ２ , 3-6 membered heterocyclyl group, -Se-C １－６ Alkyl group, —S—C １－６ alkyl group, —N(C １－６ alkyl) ２ , —NH—C １－６ alkyl group, —N(C １－３ alkyl-Cl) ２ , difluoro 3-6 membered heterocyclyl group Fluoro 3-6 membered heterocyclyl group 5-6 membered heteroaryl group, C １－６ Alkyl-substituted 3-6-membered heterocyclyl group C １－６ Alkyl group, or C １－６ alkoxy groups, Preferably, the compound of formula I' is A is, Y １ , Y ２ , Y ３ , Y ４ , Y ５ , Y ６ , Y ７ are the same or different and, independently of each other, Preferably, in formula I″, R １ teeth, R ２ The compound according to any one of claims 1 to 3, wherein is selected from the group consisting of a methyl group and an ethyl group.

5. Compounds of formula I are is selected from Preferably, the compound of formula I is and the compound is selected from the group consisting of a TFA salt and an HCl salt of the compound Preferably, the compound of formula I' is is selected from Preferably, the compound of formula I' is and the compound is selected from the group consisting of a TFA salt and an HCl salt of the compound Preferably, the compound of formula I″ is is selected from.

6. The compound according to any one of claims 1 to 5, wherein the pharmaceutically acceptable salt is an HCl or TFA salt.

7. Use of at least one compound of formula I, I', or I'' according to any one of claims 1 to 6, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of said three compounds in the preparation of a METTL3 inhibitor.

8. the disease, condition or condition prevented, alleviated and / or treated by the METTL3 inhibitor comprises a solid tumor, leukemia, an autoimmune disease, a nervous system disease, an inflammatory disease or an infectious disease; Preferably, the disease, illness or condition prevented, alleviated and / or treated by the METTL3 inhibitor comprises a hematological malignancy, AML leukemia, chronic myeloid leukemia, a solid tumor, or a viral disease.

9. A pharmaceutical composition comprising at least one of a compound represented by formula I, formula I', or formula I'' according to any one of claims 1 to 6, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of said three compounds.

10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is used for treating, alleviating and / or preventing a disease, illness or condition associated with abnormal function of METTL3.

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