5-Amino-1H-pyrrolo[3,2-b]pyridine-2-carboxamide derivatives as MTA-cooperative inhibitors of PRMT5

Abstract

The present disclosure provides compounds comprising 5-amino-1H-pyrrolo[3,2-b]pyridine-2-carboxamide derivatives as MTA-cooperative inhibitors of PRMT5, MTAP DEL and their use to selectively inhibit the activity of PRMT5 in combination with MTA in tumors harboring the mutation, and pharmaceutical compositions containing the compounds as treatments for various diseases, including cancer.One object of the present invention is to provide compounds and derivatives that function as PRMT5 inhibitors, as well as methods for their preparation and use.

Description

[Technical Field]

[0001] The present disclosure provides compounds comprising 5-amino-1H-pyrrolo[3,2-b]pyridine-2-carboxamide derivatives as MTA-cooperative inhibitors of PRMT5, MTAP DEL Their use to selectively inhibit the activity of PRMT5 in combination with MTA in tumors harboring the mutation, and pharmaceutical compositions containing the compounds as treatments for various diseases, including cancer, are provided. [Background technology]

[0002] Epigenetic modification is a process that can alter genetic output by altering the primary DNA sequence. Epigenetic modification plays an important role in gene expression and regulation, protein production at multiple levels, and cell differentiation. Typically, this process is reversible and selective in DNA, its regulatory proteins (e.g., histones), and other proteins (e.g., transcription factors) [Bradbury, EM, BioEssays, 1992, 14(1):pp.9-16]. PMTs (protein methyltransferases), consisting of two subfamilies named PKMTs (protein lysine methyltransferases) and PRMTs (protein arginine methyltransferases), are central players in epigenetic modification [Copeland, RA, et al., Oncogene, 2012, 32(8):pp.939-46]. PMT is considered a potential therapeutic target for various human diseases and related deaths [Copeland, RA, et al., Oncogene, 2012.32(8):pp.939-46].

[0003] As its name suggests, PRMTs catalyze the methylation of arginine residues in proteins. In addition to their primary function of methylating histone tails, PRMTs also target other cellular proteins, such as NAB2p, FOXO1, PABP1, and Sm D1 [Bedford, MT, et al., Molecular Cell, 2005, 18(3):pp.263-72]. The nine mammalian PRMTs, classified by product, can be divided into three subtypes: type I (PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8) catalyze the formation of asymmetric dimethylated arginine (aDMA), type II (PRMT5 and PRMT9) catalyze the formation of symmetric dimethylated arginine (sDMA), and type III (PRMT7) catalyze the formation of monomethylated arginine (MMA) [Yang, Y., et al., Nature Reviews Cancer, 2012, 13(1):pp.37-50]. In addition, type I / II PRMTs can also catalyze the formation of MMA as an intermediate to aDMA and sDMA. PRMTs contain a pocket that interacts with the coenzyme SAM (S-adenosylmethionine) and adjacent pockets that interact with arginine residues on proteins, i.e., the SAM pocket and the substrate pocket. The methylation process involves the transfer of an activated methyl group from the coenzyme SAM to the guanidino group on an arginine residue, S N It involves two mechanisms [Bedford, MT, et al., Molecular Cell, 2005, 18(3): pp. 263-72]. A by-product of this process is SAH (S-adenosyl-L-homocysteine).

[0004] The overall arginine content in cells is approximately 1500:3:2:1 (Arg:aDMA:MMA:sDMA), and PRMT5 accounts for the overwhelming majority of sDMA formation [Dhar, S., et al., Scientific Reports, 2013, 3:1311]. In contrast to PRMT1, the major type I PRMT that functions intact in cells, PRMT5 binds to MEP50 (methylosomal protein 50) to form a heterocomplex that is often elevated in cancer cells and correlates with poor patient survival [Gao, G., et al., Nucleic Acids Research, 2019, 47(10):pp.5038-48]. PRMT5 promotes tumorigenesis through multiple mechanisms. PRMT5 is a potent repressor of multiple genes. When PRMT5 methylates histones H2a and H4 at Arg3 and histone H3 at Arg8, it represses gene transcripts involved in differentiation, transformation, cell cycle progression, and tumor suppression [Karkhanis, V., et al., Trends in Biochemical Sciences, 2011, 36(12):pp.633-41]. In addition to its epigenetic role, PRMT5 also regulates RNA-binding proteins, such as splicing factors. For example, a reproducible event was observed in PRMT5 knockout mice, in which exon 6 skipping of MDM4 (Murine Double Minute 4) resulted in the release of p53 and upregulation of the p53 pathway [Gerhart, SV, et al., Scientific Reports, 2018, 8:9711]. In addition, PRMT5 can directly affect key proliferation pathways by direct methylation, such as p53 [Jansson, M., et al., Nature Cell Biology, 2008, 10(12): pp. 1431-9], EGFR [Hsu, J.-M., et al., Nature Cell Biology, 2011, 13(2): pp. 174-81], and PI3K [Wei, T.-YW, et al., Cellular Signaling, 2014, 26(12): pp. 2940-50].Therefore, PRMT5 may well be a clinically relevant target.

[0005] On the other hand, PRMT5 is an essential gene present in normal tissues, and systemic inhibition of PRMT5 can result in significant disease liability, especially hematologic toxicity [Ahnert, JR, et al., Journal of Clinical Oncology, 2021, 39(15-suppl):p.3019]. Therefore, strategies to selectively block PRMT5 activity in tumor cells are needed for safer therapies.

[0006] Homozygous deletion of the tumor-decreasing factor CDKN2A (cyclin-dependent kinase inhibitor 2A) occurs in approximately 15% of all tumor types. Interestingly, mutations are frequently accompanied by concomitant deletion of proximal genes on 9p21, including the gene encoding MTAP (methylthioadenosine phosphorylase) [Firestone, RS, et al., Journal of American Chemical Society, 2017, 139(39):pp.13754-60]. MTAP deletion results in the accumulation of MTA (methylthioadenosine), a substrate of MTAP. MTA is structurally related to SAM and occupies the same pocket as SAM, making it a weak ligand / inhibitor of PRMT5. Formation of the MTA-PRMT5 complex provides an opportunity for further PRMT5 inhibition through the formation of a tertiary complex. In this way, correlation between MTAP absence and PRMT5 dependence can be established by MTA concentration levels, leading to precise oncological treatment strategies. Currently, most clinical-stage PRMT5 inhibitors are based on either SAM / MTA-competitive mechanisms (JNJ64619178, PF06939999, PRT543, and PRT811) or non-MTA-competitive mechanisms (GSK3326595), and are unable to differentiate normal cells from cancer cells. Therefore, there remains an unmet medical need for potent and selective MTA-cooperative PRMT5 inhibitors. [Prior art documents] [Non-patent literature]

[0007]

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[0008] One object of the present invention is to provide compounds and derivatives that function as PRMT5 inhibitors, as well as methods for their preparation and use.

[0009] Aspect 1. A compound of formula (X): [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof. (In the formula, Z 1 , Z 2 , Z 3 and Z 4 are each independently N or CR Z Selected from: In each of its occurrences, R Z are independently hydrogen, halogen, -C 1-4 Alkyl or -C 1-4 alkoxy, wherein the aforementioned -C 1-4 Alkyl or -C 1-4 each alkoxy is optionally substituted with at least one substituent selected from halogen; Ar is selected from phenyl or 5- to 6-membered heteroaryl, each of said phenyl or 5- to 6-membered heteroaryl being selected from at least one substituent R Ar optionally substituted with R Ar are each independently hydrogen, halogen, or -C 1-4 Alkyl, -C 1-4 alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy, or -CN, wherein the aforementioned -C 1-4 Alkyl, -C 1-4 each of the alkoxy, -C3-C6 cycloalkyl, or -C3-C6 cycloalkoxy is optionally substituted with at least one substituent selected from halogen; R X is R 1 or [ka] That is, R 1 are each independently -C 1-8 alkyl, -C3-C8 cycloalkyl (preferably mono-, bridged, fused, or helical cycloalkyl), or 3- to 8-membered saturated heterocyclyl (preferably mono-, bridged, fused, or helical heterocyclyl), wherein the aforementioned -C 1-8 Each of the alkyl, -C3-C8 cycloalkyl (preferably mono-, bridged, fused, or helical cycloalkyl), or 3- to 8-membered saturated heterocyclyl (preferably mono-, bridged, fused, or helical heterocyclyl) may contain at least one substituent R 1a optionally substituted with R 1a are each independently a halogen, -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered saturated heterocyclyl, -C 1-4 alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo, wherein the aforementioned -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered saturated heterocyclyl, -C1-4 Each of the alkoxy, or -C3-C6 cycloalkoxy is selected from the group consisting of halogen, -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered saturated heterocyclyl, -C 1-4 optionally substituted with at least one substituent selected from alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo; G is selected from CH, O, or NH, provided that G is NH and NH is R 5 If replaced by R 5 is not a halogen, Z 5 , Z 6 , Z 7 and Z 8 are each independently N or C R1 are selected from, where Z 5 , Z 6 , Z 7 and Z 8 At least one of them is N and the others are CR Z1 and Z 5 and Z 8 is not N at the same time, In each of its occurrences, R Z1 are independently hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 alkoxy, -C3-C6 cycloalkyl, or -C3-C6 cycloalkoxy, wherein the aforementioned -C 1-4 Alkyl, -C 1-4 Each of alkoxy, -C3-C6 cycloalkyl, or -C3-C6 cycloalkoxy is selected from the group consisting of halogen, -C 1-4 optionally substituted with at least one substituent selected from alkoxy, -CN, -OH, -NH2 or oxo; In each of its occurrences, R 5 are independently hydrogen, halogen, -C 1-4 alkyl, or -C3-C6 cycloalkyl, wherein -C 1-4 Alkyl or -C3-C6 cycloalkyl is not halogen, -C 1-4optionally substituted with at least one substituent selected from alkoxy, -CN, -OH, -NH2 or oxo; Two Germinal R 5 and the carbon atoms to which they are attached form a 3- to 5-membered carbocyclic ring, wherein said ring is optionally substituted with halogen, -C 1-4 optionally substituted with at least one substituent selected from alkoxy, -CN, -OH, -NH2 or oxo; n is 0, 1, 2, 3 or 4; r is 0 or 1; R 2 is hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy, or -CN, wherein the aforementioned -C 1-4 Alkyl, -C 1-4 Each of alkoxy, -C3-C6 cycloalkyl, or -C3-C6 cycloalkoxy is selected from the group consisting of halogen, -C 1-4 optionally substituted with at least one substituent selected from -alkoxy, -C3-C6 cycloalkoxy; R 3 is hydrogen, halogen, -C 1-4 alkyl, or -CN, where -C 1-4 Alkyl is a group that can contain hydrogen, halogen, -C 1- optionally substituted with at least one substituent selected from: -C3-C6 alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2 or oxo; R 4 is hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 alkoxy, -C3-C6 cycloalkyl, or -C3-C6 cycloalkoxy, wherein the aforementioned -C 1-4 Alkyl, -C 1-4 Each of alkoxy, -C3-C6 cycloalkyl, or -C3-C6 cycloalkoxy is selected from the group consisting of halogen, -C 1-4Optionally substituted with at least one substituent selected from alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2, or oxo.

[0010] In aspect A1, the compound has the formula (AI): [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof. (In the formula, Z 1 , Z 2 , Z 3 and Z 4 are each independently N or CR Z Selected from: In each of its occurrences, R Z are independently hydrogen, halogen, -C 1-4 Alkyl or -C 1-4 alkoxy, wherein the aforementioned -C 1-4 Alkyl or -C 1-4 each alkoxy is optionally substituted with at least one substituent selected from halogen; Ar is selected from phenyl or 5- to 6-membered heteroaryl, each of said phenyl or 5- to 6-membered heteroaryl being selected from at least one substituent R Ar optionally substituted with R Ar are each independently hydrogen, halogen, or -C 1-4 Alkyl, -C 1-4 alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy, or -CN, wherein the aforementioned -C 1-4 Alkyl, -C 1-4 each of the alkoxy, -C3-C6 cycloalkyl, or -C3-C6 cycloalkoxy is optionally substituted with at least one substituent selected from halogen; G is selected from CH, O, or NH, provided that G is NH and NH is R5 If replaced by R 5 is not a halogen, Z 5 , Z 6 , Z 7 and Z 8 are each independently N or C R1 are selected from, where Z 5 , Z 6 , Z 7 and Z 8 At least one of them is N and the others are CR Z1 and Z 5 and Z 8 is not N at the same time, In each of its occurrences, R Z1 are independently hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 alkoxy, -C3-C6 cycloalkyl, or -C3-C6 cycloalkoxy, wherein the aforementioned -C 1-4 Alkyl, -C 1-4 Each of alkoxy, -C3-C6 cycloalkyl, or -C3-C6 cycloalkoxy is selected from the group consisting of halogen, -C 1-4 optionally substituted with at least one substituent selected from alkoxy, -CN, -OH, -NH2 or oxo; R 2 is hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy, or -CN, wherein the aforementioned -C 1-4 Alkyl, -C 1-4 Each of alkoxy, -C3-C6 cycloalkyl, or -C3-C6 cycloalkoxy is selected from the group consisting of halogen, -C 1-4 optionally substituted with at least one substituent selected from -alkoxy, -C3-C6 cycloalkoxy; R 3 is hydrogen, halogen, -C 1-4 alkyl, or -CN, where -C 1-4 Alkyl is a group that can contain hydrogen, halogen, -C 1-optionally substituted with at least one substituent selected from: -C3-C6 alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2 or oxo; R 4 is hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 alkoxy, -C3-C6 cycloalkyl, or -C3-C6 cycloalkoxy, wherein the aforementioned -C 1-4 Alkyl, -C 1-4 Each of alkoxy, -C3-C6 cycloalkyl, or -C3-C6 cycloalkoxy is selected from the group consisting of halogen, -C 1-4 optionally substituted with at least one substituent selected from alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo; In each of its occurrences, R 5 are independently hydrogen, halogen, -C 1-4 alkyl, or -C3-C6 cycloalkyl, wherein -C 1-4 Alkyl or -C3-C6 cycloalkyl is not halogen, -C 1-4 optionally substituted with at least one substituent selected from alkoxy, -CN, -OH, -NH2 or oxo; Two Germinal R 5 and the carbon atoms to which they are attached form a 3- to 5-membered carbocyclic ring, wherein said ring is optionally substituted with halogen, -C 1-4 optionally substituted with at least one substituent selected from alkoxy, -CN, -OH, -NH2 or oxo; n is 0, 1, 2, 3 or 4; r is 0 or 1.)

[0011] Aspect A2. A compound according to aspect 1, wherein the compound is selected from formula (AIIa), (AIIb), (AIIc), or (AIId). [ka] (In the formula, R 2 , R 3, R 4 , R 5 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Ar, G, and n are defined as in embodiment 1.

[0012] In some embodiments, the compound is selected from formula (AIIe), (AIIf), (AIIg), (AIIh), (AIIi), (AIIj), (AIIk), (AIIl), (AIIm), or (AIIn). [ka] [ka] (In the formula, R Z1 , R 2 , R 3 , R 4 , R 5 , Z 1 , Z 2 , Z 3 , Z 4 , Ar and n are defined in the same manner as in embodiment 1.)

[0013] Aspect A3. The compound of aspect 1, wherein the compound is of formula (AIIIa), (AIIIb), (AIIIc), (AIIId), (AIIIe), (AIIIf), or (AIIIg). [ka] (In the formula, R 2 , R 3 , R 4 , R 5 , R Z , Z 5 , Z 6 , Z 7 , Z 8 , G, n, and r are defined as in embodiment 1.

[0014] Aspect A4. A compound according to aspect 1, wherein the compound is of formula (AIVa), (AIVb), (AIVc). [ka] (In the formula, X 1 , X 2 and X 3 are each independently selected from N or CH, with the proviso that X 1 , X 2 or X 3 If any one of is CH, CH is R Ar optionally substituted with X 4 are each independently selected from N, O or S; R 2 , R 3 , R 4 , R 5 , R Ar , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , G, and n and r are defined as in embodiment 1.)

[0015] Aspect A5.R Z1is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy or cyclohexoxy (wherein the aforementioned methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl)

[0023] The compound of any one of the preceding aspects, wherein each of cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, -CN, -OH, -NH, or oxo.

[0016] Aspect A6.R Z1 is selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.

[0017] In some embodiments, R Z1 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopropoxy or hydroxypropyl [ka] is selected from.

[0018] Aspect A7.R 2 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, or -CN (wherein methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), butyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy.

[0019] In some embodiments, R 2 is selected from hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopropoxy, cyclobutoxy, or —CN, wherein methyl, ethyl is optionally substituted with at least one substituent selected from —F, —Cl, —Br, —I, methoxy, ethoxy, propoxy, cyclopropoxy, or cyclobutoxy.

[0020] In some embodiments, R 2 is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy or -CN.

[0021] Aspect A8.R 2

[0023] The compound according to any one of the preceding embodiments, wherein is selected from hydrogen, methyl, ethyl, or -CN.

[0022] Aspect A9.R 3 is selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), or —CN, wherein methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl) is optionally substituted with at least one substituent selected from hydrogen, —F, —Cl, —Br, —I, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CN, —OH, —NH, or oxo.

[0023] In some embodiments, R 3 is selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl) or —CN.

[0024] Aspect A10.R 3

[0023] The compound of any one of the preceding embodiments, wherein is selected from hydrogen, -F, -Cl, -Br, -I, or -CN.

[0025] Aspect A11.R 4is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy, where methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, -CN, -OH, -NH, or oxo), a compound according to any one of the preceding aspects.

[0026] In some embodiments, R 4 is selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, propyl (isopropyl or n-propyl), methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopropoxy, or cyclobutoxy, wherein methyl, ethyl, propyl (isopropyl or n-propyl), methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopropoxy, or cyclobutoxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, cyclopropoxy, cyclobutoxy, -CN, -OH, -NH, or oxo.

[0027] In some embodiments, R 4 is selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl).

[0028] Aspect A12.R 4 The compound of any one of the preceding embodiments, wherein is selected from hydrogen, —F, —Cl, —Br, —I, methyl, and ethyl.

[0029] Aspect A13.R 5 is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, -CN, -OH, -NH, or oxo.

[0030] In some embodiments, R 5 is selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl) or butyl (n-butyl, sec-butyl, isobutyl or tert-butyl).

[0031] In some embodiments, R 5 is selected from hydrogen, —F, —Cl, —Br, methyl, ethyl.

[0032] Aspect A14. Two Germinal R 5 and the carbon atoms to which they are attached form a 3-, 4-, or 5-membered carbocyclic ring, wherein said ring is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, -CN, -OH, -NH, or oxo.

[0033] In some embodiments, two geminal R 5 and the carbon atoms to which they are attached form a 3-, 4-, or 5-membered carbocyclic ring.

[0034] In some embodiments, two geminal R 5 and the carbon atoms to which they are attached form a three-membered carbocyclic ring.

[0035] Aspect A15.Z 1 , Z 2 , Z 3 and Z 4 At most two of them are N and R Z are each independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), methoxy, ethoxy, propoxy, or butoxy, wherein each of said ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), methoxy, ethoxy, propoxy, or butoxy is optionally substituted with at least one substituent selected from —F, —Cl, —Br, or —I.

[0036] In some embodiments, R Z are each independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), methoxy, ethoxy, propoxy, or butoxy.

[0037] In some embodiments, R Z are each independently selected from hydrogen, —F, —Cl, —Br, methyl, or ethyl.

[0038] The embodiment A16.Ar is independently selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, oxazolyl, furanyl, thiazolyl, or thiophenyl, wherein each of said phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, oxazolyl, furanyl, thiazolyl, or thiophenyl is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, oxazolyl, furanyl, thiazolyl, and thiophenyl. Ar is optionally replaced by R Ar are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, or -CN, wherein each of said methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, or -I; The compound according to any one of the preceding aspects.

[0039] The embodiment A17.Ar is independently selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, or 1,2,4-triazolyl, wherein each of said phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, or 1,2,4-triazolyl is selected from the group consisting of at least one substituent R Ar is optionally replaced by R Arare each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, -CF3, or -CN; The compound according to any one of the preceding aspects.

[0040] In some embodiments, Ar is independently selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, or 1,2,4-triazolyl, wherein each of said phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, or 1,2,4-triazolyl is selected from the group consisting of at least one substituent R Ar is optionally replaced by R Ar are each independently selected from hydrogen, —F, —Cl, —Br, methyl, ethyl, methoxy, ethoxy, —CF 3 , or —CN.

[0041] Aspect A18. A compound according to any one of the preceding aspects, wherein G is selected from CH2, O, NH.

[0042] In some embodiments, G is selected from CH2 or O.

[0043] Aspect A19. The compound of any one of the preceding aspects, wherein the compound is selected from: [ka] [ka] [ka] [ka] [ka] [ka]

[0044] Aspect A20. A pharmaceutical composition comprising a compound of any one of Aspects A1-A19, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, in combination with a pharmaceutically acceptable excipient.

[0045] Aspect A21. A method for reducing PRMT5 activity by inhibition, comprising administering to an individual a compound according to any one of Aspects A1 to A19, or a pharmaceutically acceptable salt thereof, including a compound of formula (I) or a specific compound exemplified herein.

[0046] Aspect A22. The method of aspect A21, wherein the disease is selected from cancer.

[0047] Aspect A23. Use of a compound according to any one of aspects A1 to A19, or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, in the preparation of a medicament for treating a disease modulated by PRMT5.

[0048] Aspect A24. The use according to aspect A23, wherein the disease is cancer.

[0049] Aspect A25. The use according to aspect A24, wherein the disease is an MTAP-deficient solid tumor, including but not limited to lung cancer, bladder cancer, melanoma, pancreatic cancer, esophageal cancer, gastric adenocarcinoma, breast cancer or glioblastoma.

[0050] In aspect B1, the compound has formula (BI): [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof. (In the formula, Z1 , Z 2 , Z 3 and Z 4 are each independently N or CR Z Selected from: In each of its occurrences, R Z are each independently hydrogen, halogen, or -C 1-4 Alkyl or -C 1-4 alkoxy, wherein the aforementioned -C 1-4 Alkyl or -C 1-4 each alkoxy is optionally substituted with at least one substituent selected from halogen; Ar is independently selected from phenyl or 5- to 6-membered heteroaryl, wherein each of said phenyl or 5- to 6-membered heteroaryl is selected from at least one substituent R Ar optionally substituted with R Ar are each independently hydrogen, halogen, or -C 1-4 Alkyl, -C 1-4 alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy, or -CN, wherein the aforementioned -C 1-4 Alkyl, -C 1-4 each of the alkoxy, -C3-C6 cycloalkyl, or -C3-C6 cycloalkoxy is optionally substituted with at least one substituent selected from halogen; R 1 are each independently -C 1-8 alkyl, -C3-C8 cycloalkyl (preferably mono-, bridged, fused, or helical cycloalkyl), or 3- to 8-membered saturated heterocyclyl (preferably mono-, bridged, fused, or helical heterocyclyl), wherein the aforementioned -C 1-8 Each of the alkyl, -C3-C8 cycloalkyl (preferably mono-, bridged, fused, or helical cycloalkyl), or 3- to 8-membered saturated heterocyclyl (preferably mono-, bridged, fused, or helical heterocyclyl) may contain at least one substituent R 1a optionally substituted with R1a are each independently a halogen, -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered saturated heterocyclyl, -C 1-4 alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo, wherein the aforementioned -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered saturated heterocyclyl, -C 1-4 Each of the alkoxy, or -C3-C6 cycloalkoxy is selected from the group consisting of halogen, -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered saturated heterocyclyl, -C 1-4 optionally substituted with at least one substituent selected from alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo; R 2 is hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy, or -CN, wherein the aforementioned -C 1-4 Alkyl, -C 1-4 Each of alkoxy, -C3-C6 cycloalkyl, or -C3-C6 cycloalkoxy is selected from the group consisting of halogen, -C 1-4 optionally substituted with at least one substituent selected from -alkoxy, -C3-C6 cycloalkoxy; R 3 is hydrogen, halogen, -C 1-4 alkyl, or -CN, where -C 1-4 Alkyl is a group that can contain hydrogen, halogen, -C 1- optionally substituted with at least one substituent selected from: -C3-C6 alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2 or oxo; R 4 is hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 alkoxy, -C3-C6 cycloalkyl, or -C3-C6 cycloalkoxy, wherein the aforementioned -C 1-4 Alkyl, -C 1-4Each of alkoxy, -C3-C6 cycloalkyl, or -C3-C6 cycloalkoxy is selected from the group consisting of halogen, -C 1-4 Optionally substituted with at least one substituent selected from alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2, or oxo.

[0051] Aspect B2. A compound according to aspect B1 wherein the compound is of formula (BIIa), (BIIb), (BIIc), (BIId), (BIIe), (BIIf) or (BIIg). [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R Z , Ar is defined as in embodiment B1.

[0052] Aspect B3. A compound according to aspect B1, wherein the compound is of formula (BIIIa), (BIIIb), (BIIIc). [ka] (In the formula, X 1 , X 2 and X3 are each independently selected from N or CH, with the proviso that X 1 , X 2 or X 3 If any one of is CH, CH is R Ar optionally substituted with X 4 are each independently selected from NH, O, or S, with the proviso that X 4 If any one of is NH, then NH is R Ar optionally substituted with R 1 , R 2 , R 3 , R 4 , R Ar , Z 1 , Z 2, Z 3 and Z 4 is defined as in embodiment B1.)

[0053] In some embodiments, the compound is of Formula (BIIId), (BIIIe), (BIIIf), (BIIIg), (BIIIh), or (BIIIi). [ka] (In the formula, Ring A is -C3-C8 cycloalkyl (preferably mono-, bridged, fused, or helical cycloalkyl) or 3- to 8-membered saturated heterocyclyl (preferably mono-, bridged, fused, or helical heterocyclyl), wherein each of said -C3-C8 cycloalkyl (preferably mono-, bridged, fused, or helical cycloalkyl) or 3- to 8-membered saturated heterocyclyl (preferably mono-, bridged, fused, or helical heterocyclyl) contains at least one substituent R 1a optionally substituted with X 1 , X 2 and X3 are each independently selected from N or CH, with the proviso that X 1 , X 2 or X 3 If any one of is CH, CH is R Ar optionally substituted with X 4 are each independently selected from NH, O, or S, with the proviso that X 4 If any one of is NH, then NH is R Ar optionally substituted with R 1a , R 2 , R 3 , R 4 , R Ar , Z 1 , Z 2 , Z 3 and Z 4 is defined as in embodiment B1.)

[0054] Aspect B4. A compound according to any one of the preceding aspects, wherein R 1 is selected from methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-, 4-, 5-, 6-, 7- or 8-membered saturated monoheterocyclyl, 5-, 6-, 7- or 8-membered saturated bridged heterocyclyl, 4-, 5-, 6-, 7- or 8-membered saturated fused heterocyclyl, or 5-, 6-, 7- or 8-membered saturated helical heterocyclyl, wherein each of 3-, 4-, 5-, 6-, 7-, or 8-membered saturated monoheterocyclyl, 5-, 6-, 7-, or 8-membered saturated bridged heterocyclyl, 4-, 5-, 6-, 7-, or 8-membered saturated fused heterocyclyl, or 5-, 6-, 7-, or 8-membered saturated helical heterocyclyl may contain at least one substituent R 1a is optionally replaced by Each R1a is independently selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-, 4-, 5- or 6-membered saturated heterocyclyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, -CN, -OH, -NH2, or oxo, wherein the aforementioned methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl each of sil, 3-, 4-, 5-, or 6-membered saturated heterocyclyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-, 4-, 5-, or 6-membered saturated heterocyclyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, -CN, -OH, -NH, or oxo; The aforementioned compounds.

[0055] Aspect B5. A compound according to any one of the preceding aspects, wherein R 1is selected from methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-, 4-, 5-, 6-, 7- or 8-membered saturated monoheterocyclyl, 5-, 6-, 7- or 8-membered saturated bridged heterocyclyl, 4-, 5-, 6-, 7- or 8-membered saturated fused heterocyclyl, or 5-, 6-, 7- or 8-membered saturated helical heterocyclyl, each of the foregoing being selected from at least one substituent R 1a is optionally replaced by R1a are each independently optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-, 4-, 5- or 6-membered saturated heterocyclyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, -CN, -OH, -NH2, or oxo; The aforementioned compounds.

[0056] In some embodiments, R 1 is selected from methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl or pyrrolidinyl, wherein each of said methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl or pyrrolidinyl is selected from the group consisting of methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl or pyrrolidinyl, and 1a is optionally replaced by Each R1a is independently selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, -CN, -OH, -NH2, or oxo.

[0057] Aspect B6.R 1 but, [ka] The compound of any one of the preceding aspects, selected from:

[0058] Aspect B7.R 2 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, or -CN (wherein methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), butyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy.

[0059] In some embodiments, R 2is selected from hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopropoxy, cyclobutoxy, or —CN, wherein methyl, ethyl is optionally substituted with at least one substituent selected from —F, —Cl, —Br, —I, methoxy, ethoxy, propoxy, cyclopropoxy, or cyclobutoxy.

[0060] In some embodiments, R 2 is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy or -CN.

[0061] Aspect B8.R 2

[0023] The compound according to any one of the preceding embodiments, wherein is selected from hydrogen, methyl, ethyl, or -CN.

[0062] Aspect B9.R 3 is selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), or —CN, wherein methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl) is optionally substituted with at least one substituent selected from hydrogen, —F, —Cl, —Br, —I, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CN, —OH, —NH, or oxo.

[0063] In some embodiments, R 3is selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl) or —CN.

[0064] Aspect B10. A compound according to any one of the preceding aspects wherein R3 is selected from hydrogen, -F, -Cl, -Br, -I or -CN.

[0065] Aspect B11.R 4 is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy, where methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, -CN, -OH, -NH, or oxo), a compound according to any one of the preceding aspects.

[0066] In some embodiments, R 4is selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, propyl (isopropyl or n-propyl), methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopropoxy, or cyclobutoxy, wherein methyl, ethyl, propyl (isopropyl or n-propyl), methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopropoxy, or cyclobutoxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, cyclopropoxy, cyclobutoxy, -CN, -OH, -NH, or oxo.

[0067] In some embodiments, R 4 is selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl).

[0068] Aspect B12.R 4 The compound of any one of the preceding embodiments, wherein is selected from hydrogen, —F, —Cl, —Br, —I, methyl, and ethyl.

[0069] Aspect B13.Z 1 , Z 2 , Z 3 and Z 4 At most two of them are N and R Z are each independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), methoxy, ethoxy, propoxy, or butoxy, wherein each of said ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), methoxy, ethoxy, propoxy, or butoxy is optionally substituted with at least one substituent selected from —F, —Cl, —Br, or —I.

[0070] In some embodiments, R Z are each independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), methoxy, ethoxy, propoxy, or butoxy.

[0071] In some embodiments, R Z are each independently selected from hydrogen, —F, —Cl, —Br, methyl, or ethyl.

[0072] Embodiment B14. Ar is independently selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, oxazolyl, furanyl, thiazolyl, or thiophenyl, and each of said phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, oxazolyl, furanyl, thiazolyl, or thiophenyl is selected from the group consisting of at least one substituent R Ar is optionally replaced by R Arare each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, or -CN, wherein each of said methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, or -I; The compound according to any one of the preceding aspects.

[0073] The embodiment B15.Ar is independently selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, or 1,2,4-triazolyl, wherein each of said phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, or 1,2,4-triazolyl is selected from the group consisting of at least one substituent R Ar is optionally replaced by R Ar are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, -CF3, or -CN; The compound according to any one of the preceding aspects.

[0074] In some embodiments, Ar is independently selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, or 1,2,4-triazolyl, wherein each of said phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, or 1,2,4-triazolyl is selected from the group consisting of at least one substituent R Ar where R Ar are each independently selected from hydrogen, —F, —Cl, —Br, methyl, ethyl, methoxy, ethoxy, —CF 3 , or —CN.

[0075] Aspect B16. The compound of any one of the preceding aspects, wherein the compound is selected from: [ka] [ka] [ka] [ka] [ka] [ka]

[0076] Aspect B17. A pharmaceutical composition comprising a compound of any one of Aspects B1-B16, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, in combination with a pharmaceutically acceptable excipient.

[0077] Aspect B18. A method for reducing PRMT5 activity by inhibition, comprising administering to an individual a compound according to any one of Aspects B1 to B16, or a pharmaceutically acceptable salt thereof, including a compound of Formula (I) or a specific compound exemplified herein.

[0078] Aspect B19. The method of aspect B18, wherein the disease is selected from cancer.

[0079] Aspect B20. Use of a compound according to any one of aspects B1 to B16, or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, in the preparation of a medicament for treating a disease modulated by PRMT5.

[0080] Aspect B21. The use of aspect B20, wherein the disease is cancer.

[0081] Aspect B22. The use of aspect B21 wherein the disease is an MTAP-deficient solid tumor, including but not limited to lung cancer, bladder cancer, melanoma, pancreatic cancer, esophageal cancer, gastric adenocarcinoma, breast cancer or glioblastoma. DETAILED DESCRIPTION OF THE INVENTION

[0082] The following terms have the meanings indicated throughout this specification.

[0083] Unless otherwise defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0084] The following terms have the meanings indicated throughout this specification.

[0085] As used in this specification, including the appended claims, singular words such as "a," "an," and "the" include their corresponding plural references unless the context clearly dictates otherwise.

[0086] The term "or" means, and is used interchangeably with, the term "and / or," unless context clearly dictates otherwise.

[0087] The term "alkyl" includes hydrocarbon groups selected from linear and branched saturated hydrocarbon groups containing 1 to 18, for example, 1 to 12, further 1 to 10, further 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C 1-6 Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0088] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0089] The term "butyl" includes 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), and 1,1-dimethylethyl or t-butyl ("t-Bu").

[0090] The term "pentyl" includes 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl.

[0091] The term "hexyl" includes 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0092] The term "alkylene" refers to a divalent alkyl group formed by removing two hydrogens from an alkane. Alkylene includes, but is not limited to, methylene, ethylene, propylene, and the like.

[0093] The term "halogen" includes fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0094] The term "alkenyl" includes hydrocarbon groups selected from straight-chain and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18, such as 2 to 8, further such as 2 to 6 carbon atoms. Alkenyl groups, such as C 2-6 Examples of alkenyl include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

[0095] The term "alkenylene" refers to a divalent alkenyl group formed by removing two hydrogens from an alkene. Alkenylene includes, but is not limited to, vinylidene, butenylene, and the like.

[0096] The term "alkynyl" includes hydrocarbon groups selected from straight-chain and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18, such as 2 to 8, further such as 2 to 6 carbon atoms. Alkynyl groups, such as C 2-6Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0097] The term "alkynylene" refers to a divalent alkynyl group formed by removing two hydrogens from an alkyne. Alkenylene includes, but is not limited to, ethynylene, and the like.

[0098] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyls.

[0099] For example, the cycloalkyl group may contain 3 to 12, such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Further, for example, the cycloalkyl group may be selected from monocyclic groups containing 3 to 12, such as 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. Specifically, saturated monocyclic cycloalkyl groups, such as C 3-8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, cycloalkyl is a monocyclic ring (C 3-6Examples of bicyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0100] The term "spirocycloalkyl" includes cyclic structures containing carbon atoms and formed by at least two rings that share one atom.

[0101] The term "fused cycloalkyl" includes bicyclic cycloalkyl groups, as defined herein, that are saturated and formed by two or more rings sharing two adjacent atoms.

[0102] The term "bridged cycloalkyl" includes a cyclic structure containing carbon atoms and formed by two rings sharing two non-adjacent atoms. The term "7- to 10-membered bridged cycloalkyl" includes a cyclic structure containing 7 to 12 carbon atoms and formed by two rings sharing two non-adjacent atoms.

[0103] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and 3- to 8-membered benzocycloalkyl, benzoC 4-6Examples include, but are not limited to, cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8- to 9-membered fused rings, which refers to ring structures containing 8 to 9 ring atoms in the above examples.

[0104] The term "aryl," used alone or in combination with other terms, includes groups selected from: 5- and 6-membered carbocyclic aromatic rings, such as phenyl, bicyclic ring systems, such as 7- to 12-membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example naphthyl and indanyl, and - Tricyclic ring systems, such as 10-15 membered tricyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example fluorenyl.

[0105] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 Aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0106] Specifically, the term "bicyclic fused aryl" includes bicyclic aryl rings as defined herein. An exemplary bicyclic fused aryl is naphthalene.

[0107] The term "heteroaryl" includes groups selected from: a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom, for example, 1 to 4, or in some embodiments 1 to 3, and in some embodiments 1 to 2 heteroatoms selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring atoms being carbon; - 7- to 12-membered bicyclic rings containing at least one heteroatom, for example, 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and - An 11- to 14-membered tricyclic ring containing at least one heteroatom, for example, 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon, wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0108] When the total number of S and O atoms in the heteroaryl group exceeds 1, the heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is 1 or less. When a heteroaryl group contains two or more heteroatom ring members, the heteroatoms can be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group can be oxidized to form an N-oxide.

[0109] Specifically, the term "bicyclic fused heteroaryl" includes 7- to 12-membered, preferably 7- to 10-membered, and more preferably 9- or 10-membered fused bicyclic heteroaryl rings, as defined herein. Typically, bicyclic fused heteroaryls are 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclics. The group may be attached to the remainder of the molecule via either ring.

[0110] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and include non-aromatic heterocyclyl groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spirocyclic groups, i.e., monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclyl groups.

[0111] The term "at least one substituent" as disclosed herein includes, for example, 1 to 4, such as 1 to 3, and further such as 1 or 2 substituents, provided that valence theory is satisfied. For example, "at least one substituent F" as disclosed herein includes 1 to 4, such as 1 to 3, and further such as 1 or 2 substituents F.

[0112] The term "divalent" refers to a linking group that can form covalent bonds with two other moieties. For example, a "divalent cycloalkyl group" refers to a cycloalkyl group obtained by removing two hydrogens from the corresponding cycloalkane to form the linking group. The terms "divalent aryl group," "divalent heterocyclyl group," or "divalent heteroaryl group" should be understood similarly.

[0113] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. When the compounds disclosed herein have two or more asymmetric centers, they may further exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All such possible stereoisomers are intended to be included, including substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. Unless otherwise specified, a reference to one isomer applies to any possible isomer. Whenever an isomeric composition is not specified, all possible isomers are included.

[0114] When compounds disclosed herein contain olefinic double bonds, unless otherwise specified, such double bonds are meant to include both E- and Z-geometric isomers.

[0115] When the compounds disclosed herein contain a disubstituted cyclic ring system, the substituents found on such ring systems may adopt cis and trans configurations. A cis configuration means that both substituents are found on the upper side of the arrangement of the two substituents on the carbon, while trans means that they are on opposite sides. For example, a disubstituted cyclic ring system may be a cyclohexyl ring or a cyclobutyl ring.

[0116] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter, "separated") to the desired degree of homogeneity by techniques common in the art. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may involve any number of methods, including, for example, reverse-phase and normal-phase, size-exclusion, ion-exchange, high-pressure, medium-pressure, and low-pressure liquid chromatography methods and apparatus, small-scale analytical, simulated moving bed ("SMB"), and preparative thin- or thick-layer chromatography, as well as small-scale thin-layer and flash chromatography techniques. One skilled in the art can select and apply the techniques most likely to achieve the desired separation.

[0117] "Diastereomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereoisomers to the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column.

[0118] Single stereoisomers, e.g., substantially pure enantiomers, may be obtained by resolving racemic mixtures using methods such as the formation of diastereomers with optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lchmuller, C.H., et al. "Chromatographic resolution of enantiomers: Selective review," J. Chromatogr., 113(3)(1975): pp. 283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of the diastereomers, and conversion to pure stereoisomers, and (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions. See Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0119] Some of the compounds disclosed herein may exist with different points of attachment of hydrogen, called tautomers. For example, compounds containing a carbonyl -CHC(O)- group (keto form) may undergo tautomerization to form a hydroxyl -CH=C(OH)- group (enol form). Where applicable, both the keto and enol forms, individually and mixtures thereof, are intended to be included.

[0120] "Prodrug" refers to a derivative of an active drug that requires conversion within the body to release the active drug. In certain embodiments, the conversion is enzymatic. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the active drug.

[0121] "Pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base functional group with a suitable organic acid, or an acidic group with a suitable base. The term also includes salts of stereoisomers (such as enantiomers and / or diastereomers), tautomers, and prodrugs of the compounds of the invention.

[0122] Furthermore, if a compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, may be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic, pharmaceutically acceptable addition salts.

[0123] As used herein, the terms "administration," "administering," "treating," and "treatment," when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to contacting an exogenous pharmaceutical, therapeutic agent, diagnostic agent, or composition with an animal, human, experimental subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contacting a reagent with a cell, and contacting a reagent with a fluid (when a fluid is in contact with a cell). The terms "administration" and / or "treatment" also refer to in vitro and ex vivo treatments, e.g., of a cell, with a reagent, diagnostic agent, binding compound, or with another cell. As used herein, the term "subject" includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0124] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient, such as a compound, that, when administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or condition. The term "therapeutically effective amount" may vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any given instance will be apparent to one of ordinary skill in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer, tautomer, or prodrug thereof, and / or at least one pharmaceutically acceptable salt thereof, effective to "treat" a disease or disorder, as defined herein, in a subject. In the case of a combination therapy, the term "therapeutically effective amount" refers to the total amount of the combined components to effectively treat a disease, disorder, or condition.

[0125] The term "disease" refers to any disease, ailment, illness, symptom or sign, and is interchangeable with the terms "disorder" or "condition."

[0126] Throughout this specification and the claims that follow, unless the context requires otherwise, the term "comprise," as well as variations such as "comprises" and "comprising," are intended to specify the presence of the subsequent feature but do not exclude the presence or addition of one or more other features. As used herein, the term "comprising" can be interchanged with the terms "containing," "including," or, in some cases, "having."

[0127] Throughout this specification and the claims that follow, the term "C n-m " indicates a range inclusive of the endpoints, and n and m are integers indicating the number of carbon atoms. Examples include C 1-8 , C 1-6 Examples include:

[0128] Unless specifically defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. [Example]

[0129] General Synthesis The compounds disclosed herein (including salts thereof) can be prepared using known organic synthesis techniques, and can be synthesized according to any of a number of possible synthetic routes.

[0130] The reactions for preparing the compounds disclosed herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials, intermediates, or products at the temperature at which the reaction is carried out, for example, at a temperature that can range from the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of solvents.

[0131] The selection of an appropriate protecting group can be easily determined by one skilled in the art. In the synthetic scheme, some protection / deprotection steps are not shown and can be incorporated before, after, or between any steps. The protecting groups shown in the synthetic scheme may or may not be used based on the reaction conditions. The order of the reactions may be different, but will achieve similar results.

[0132] Reactions can be monitored by any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. Compounds can be purified by various methods, including preparative HPLC and silica gel chromatography. Unless otherwise specified, preparative HPLC uses a buffered acetonitrile / water system, and silica gel chromatography (including column chromatography and preparative TLC) uses a PE / EtOAc or DCM / MeOH system as the mobile phase. NMR spectra are recorded using Bruker or Varian instruments with preset pulse sequences.

[0133] Scheme AI [ka]

[0134] For example, a compound of formula (I) can be formed as shown in Scheme I. Compound (iii) can be formed by amine alkylation between compound (i) and compound (ii), or compound (i') and compound (ii'). Compound (iv) can undergo an enamine-Heck reaction with pyruvate to give compound (v). Compound (v) can be protected to give compound (vi). Compound (vi) can react with an amine via a transition metal catalyzed reaction or a substitution reaction to give compound (vii). Compound (vii) can be substituted to give compound (viii). Compound (viii) can be saponified to give compound (ix). Compound (ix) can be coupled with compound (iii) under amide coupling conditions to give compound (x). Compound (x) can be deprotected to give compound (xi) [i.e., formula (I)].

[0135] Scheme AII [ka]

[0136] For example, a compound of formula (I) can be formed as shown in Scheme II. Compound (iii) can be formed by amine alkylation between compound (i) and compound (ii), or compound (i') and compound (ii'). Compound (iv) can undergo Claisen-type condensation with oxalate to give compound (v). Compound (v) can be reduced and cyclized to give compound (vi). Compound (vi) can be substituted to give compound (vii). Compound (vii) can be saponified to give compound (viii). Compound (viii) can be coupled with compound (iii) under amide coupling conditions to give compound (ix). Compound (ix) can be deprotected to give compound (x) [i.e., formula (I)].

[0137] Scheme BI [ka]

[0138] For example, a compound of formula (I) can be formed as shown in Scheme I. Compound (iii) can be formed by amine alkylation between compound (i) and compound (ii), or compound (i') and compound (ii'). Compound (iv) can undergo an enamine-Heck reaction with pyruvate to give compound (v). Compound (v) can be protected to give compound (vi). Compound (vi) can react with an amine via a transition metal catalyzed reaction or a substitution reaction to give compound (vii). Compound (vii) can be substituted to give compound (viii). Compound (viii) can be saponified to give compound (ix). Compound (ix) can be coupled with compound (iii) under amide coupling conditions to give compound (x). Compound (x) can be deprotected to give compound (xi) [i.e., formula (I)].

[0139] Scheme BII [ka]

[0140] For example, a compound of formula (I) can be formed as shown in Scheme II. Compound (iii) can be formed by amine alkylation between compound (i) and compound (ii), or compound (i') and compound (ii'). Compound (iv) can undergo Claisen-type condensation with oxalate to give compound (v). Compound (v) can be reduced and cyclized to give compound (vi). Compound (vi) can be substituted to give compound (vii). Compound (vii) can be saponified to give compound (viii). Compound (viii) can be coupled with compound (iii) under amide coupling conditions to give compound (ix). Compound (ix) can be deprotected to give compound (x) [i.e., formula (I)].

[0141] [Table 2]

[0142] Example A1: (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0143] Step 1: 5-chloro-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid [ka]

[0144] A mixture of 2,6-dichloro-5-methylpyridin-3-amine (10.0 g, 56.5 mmol), pyruvic acid (14.9 g, 169 mmol), Pd(OAc) (0.94 g, 5.65 mmol), and PPh (11.8 g, 45.2 mmol) in DMF (100 mL) was stirred at 110 °C for 24 h. The mixture was cooled to room temperature, and the volatiles were removed in vacuo. Aqueous KCO (24 g in 200 mL of water) and MTBE (300 mL) were added, and the mixture was stirred for 10 min. The solids were removed by filtration. The aqueous phase was separated, and the pH was adjusted to 3–4 with aqueous HCl (6 M). The mixture was extracted with EtOAc (500 mL × 2). The combined organic layers were washed with brine (300 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by C18 chromatography (MeCN:0.03% formic acid in water, 0:1 to 1:1) to give the title compound (4.0 g, 34%). LC-MS (M+H) + =211.

[0145] Step 2: Methyl 5-chloro-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate [ka]

[0146] To a mixture of 5-chloro-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (8.5 g, 40.3 mmol) in MeOH (100 mL) was added concentrated H2SO4 (10 mL) dropwise at 0 °C. The mixture was stirred at reflux overnight. The mixture was cooled to room temperature, and most of the volatiles were removed in vacuo. The mixture was quenched with ice water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 8 / 1) to give the title compound (7.6 g, 84%). LC-MS (M+H) + =225.0.

[0147] Step 3: 5-chloro-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate methyl ester [ka]

[0148] A mixture of methyl 5-chloro-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (7.6 g, 33.9 mmol), SEMCl (11.3 g, 67.8 mmol), and DIPEA (13.1 g, 101.7 mmol) in THF (120 mL) was stirred overnight at 70 °C under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE / EtOAc = 10 / 1) to give the title compound (6.8 g, 71%). LC-MS (M+H) + =355.1.

[0149] Step 4: Methyl 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate [ka]

[0150] A solution of methyl 5-chloro-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (2.8 g, 7.89 mmol), diphenylmethanimine (2.14 g, 11.8 mmol), Pd(dba) (361 mg, 0.39 mmol), BINAP (0.492 g, 0.79 mmol), and KPO (5.0 g, 23.7 mmol) in dioxane (50 mL) was stirred at 100 °C under N overnight. The mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 4 / 1) to give the title compound (3.0 g, 76%). LC-MS (M+H) + =500.2.

[0151] Step 5: 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid [ka]

[0152] To a mixture of methyl 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (3.0 g, 6.0 mmol) in THF (50 mL) / water (50 mL) was added LiOH·HO (0.75 g, 18 mol). The mixture was stirred at 60 °C for 4 h. The mixture was cooled to room temperature, and the pH was adjusted to 7-8 with aqueous HCl (1 M). The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (2.5 g, 86%). LC-MS (M+H) + =486.2.

[0153] Step 6: 5-(2,6-difluorophenyl)picolinaldehyde [ka]

[0154] To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinaldehyde (62 g, 266 mmol) and 1,3-difluoro-2-iodobenzene (95.8 g, 399 mmol) in dioxane (600 mL), toluene (300 mL), and water (300 mL) was added Pd(dppf)Cl (9.73 g, 13.3 mmol) and KPO (141 g, 665 mmol). The mixture was stirred at 85 °C for 16 h, cooled to room temperature, and poured into water (1000 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (800 mL × 2). The combined organic layers were washed with brine (500 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EtOAc = 50:1 to 5:1) to give the title compound (30 g, 51%). LC-MS (M+H) + =220.2.

[0155] Step 7: (R)—N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine [ka]

[0156] To a solution of (R)-5,6,7,8-tetrahydroquinolin-8-amine (1.35 g, 9.12 mmol) in DCM (20 mL) were added 5-(2,6-difluorophenyl)picolinaldehyde (2.0 g, 9.12 mmol), MeOH (2 mL), and NaBH(OAc) (5.80 g, 27.4 mmol). The mixture was stirred at room temperature for 1 h and quenched with saturated NaHCO (50 mL). The organic layer was separated, and the aqueous phase was extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EtOAc = 1:0 to 0:1) to give the title compound (582 mg, 18%). LC-MS (M+H) + =352.1.

[0157] Step 8: (R)—N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0158] To a solution of 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (40 mg, 0.08 mmol) in DMF (3 mL) was added HATU (34.5 mg, 0.09 mmol), (R)—N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (35 mg, 0.1 mmol), and DIPEA (21 mg, 0.16 mmol). The mixture was stirred at 55° C. for 16 h. The mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (50 mL). The organic layer was separated, washed with brine (50 mL × 2), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM:MeOH=20:1) to give the title compound (55 mg, 82%). LC-MS (M+H) + =819.1.

[0159] Step 9: (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide.

[0160] To a solution of (R)—N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (55 mg, 0.07 mmol) in DCM (6 mL) was added TFA (6 mL). The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. HCl (4 M in MeOH, 4 mL) was added and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, and KCO (37 mg, 0.27 mmol), water (2 mL), and MeOH (10 mL) were added. The mixture was stirred at 50° C. for 2 hours. The mixture was concentrated in vacuo and purified by preparative HPLC to give Example 2 (21 mg, 60%). 1H NMR(500MHz,DMSO-d6)δ11.65-11.16(m,1H), 8.77-8.49(m,1H), 8.49-8.30(m,1H), 8.07-7.47(m,4H), 7.39-7.10(m,4H), 6. 75-6.08(m,1H), 6.01-5.37(m,1H), 5.29(s,2H), 5.25-4.70(m,1H), 3.97-3.41(m,1H), 2.96-2.68(m,2H), 2.46-1.69(m,7H). LC-MS(M+H) + =525.3.

[0161] Example A2: (R)-5-amino-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0162] Step 1: (R)—N-((5-phenylpyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine [ka]

[0163] The title compound (300 mg, 44%) was prepared from (R)-5,6,7,8-tetrahydroquinolin-8-amine and 5-phenylpicolinaldehyde in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =316.3.

[0164] Step 2: (R)-5-((diphenylmethylene)amino)-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0165] The title compound (30 mg, 47%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)—N-((5-phenylpyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine in a manner similar to Step 8 of Example 1. LC-MS (M+H) + =783.6.

[0166] Step 3: (R)-5-amino-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide.

[0167] Example 2 (3 mg, 16%) was prepared from (R)-5-((diphenylmethylene)amino)-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Step 9 of Example 1. 1 H NMR(500MHz,DMSO-d6)δ11.60-11.26(m,1H), 9.07-8.76(m,1H), 8.56-8. 35(m,1H), 8.24-8.02(m,1H), 7.97-7.34(m,8H), 7.33-7.17(m,1H), 6.77- 6.19(m,1H), 6.06-5.44(m,1H), 5.44-5.28(m,2H), 5.28-4.87(m,1H), 4. 86-3.50(m,1H), 2.98-2.72(m,2H), 2.54-2.39(m,1H), 2.36-1.73(m,6H). LC-MS (M+H) + =489.4.

[0168] Example A3: (R)-5-amino-N-((3',5'-difluoro-[3,4'-bipyridin]-6-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0169] Step 1: 3',5'-Difluoro-[3,4'-bipyridine]-6-carbaldehyde [ka]

[0170] To a mixture of 3,5-difluoro-4-iodopyridine (0.85 g, 3.53 mmol) in dioxane (17 mL), toluene (8.5 mL), and water (8.5 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinaldehyde (1.64 g, 7.05 mmol), KPO (2.25 g, 10.6 mmol), and Pd(dppf)Cl (258 mg, 0.35 mmol) at 20 °C. The mixture was stirred at 85 °C for 3 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: EtOAc = 1:0 to 1:1) to give the title compound (0.70 g, 90%). LC-MS (M+H) + =221.2.

[0171] Step 2: (R)—N-((3',5'-difluoro-[3,4'-bipyridin]-6-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine [ka]

[0172] To a solution of (R)-5,6,7,8-tetrahydroquinolin-8-amine (525 mg, 3.54 mmol) in DCM (13 mL) was added NaBH(OAc) (939 mg, 4.43 mmol), MeOH (0.13 mL), and 3',5'-difluoro-[3,4'-bipyridine]-6-carbaldehyde (0.65 g, 2.95 mmol). The mixture was stirred at 20 °C for 1 h and then poured into saturated NaHCO (50 mL). The mixture was extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (216 mg, 21%). LC-MS (M+H) + =353.2.

[0173] Step 3: 5-Amino-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid [ka]

[0174] To a solution of ethyl 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (900 mg, 1.75 mmol) in THF (20 mL) / water (5 mL) was added LiOH (126 mg, 5.30 mmol). The mixture was stirred at 60° C. for 3 hours. The mixture was cooled to room temperature, and the pH was adjusted to 2 with 1 M HCl. The mixture was stirred at 80° C. for 2 hours, cooled to room temperature, and then concentrated under reduced pressure. The residue was purified by C18 chromatography (MeCN:water = 0:1 to 3:2) to give the title compound (380 mg, 70%). LC-MS (M+H) + =322.15.

[0175] Step 4: (R)-5-amino-N-((3',5'-difluoro-[3,4'-bipyridin]-6-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0176] To a solution of 5-amino-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (36 mg, 0.11 mmol) in DMF (1 mL) was added (R)-N-((3',5'-difluoro-[3,4'-bipyridin]-6-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (47 mg, 0.13 mmol), HATU (47 mg, 0.12 mmol), and DIPEA (0.08 mL, 0.45 mmol). The mixture was stirred at 50 °C for 2 h. The mixture was cooled to room temperature, diluted with water (10 mL), and extracted with EtOAc (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=20:1) to give the title compound (34 mg, 47%). LC-MS (M+H) + =656.3.

[0177] Step 5: (R)-5-amino-N-((3',5'-difluoro-[3,4'-bipyridin]-6-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0178] A mixture of (R)-5-amino-N-((3',5'-difluoro-[3,4'-bipyridin]-6-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (34 mg, 0.05 mmol) in DCM (3 mL) / TFA (1 mL) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and then redissolved in MeOH (5 mL), followed by the addition of K2CO3 (14 mg). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (10 mg, 37%). 1 H NMR(500MHz,DMSO-d6)δ11.48-11.16(m,1H), 8.85-7.46(m,7H), 7.37-7.27(m,1H), 7.27-7.13(m,1H), 6.73- 6.07(m,1H), 6.02-5.39(m,1H), 5.37-4.72(m,3H), 3.95-3.50(m,1H), 2.92-2.66(m,2H), 2.44-1.69(m,7H). LC-MS(M+H) + =526.4.

[0179] Example A4: (R)-5-amino-N-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0180] Step 1: 5-(1,4-dimethyl-1H-pyrazol-5-yl)picolinaldehyde [ka]

[0181] To a mixture of 5-bromopicolinaldehyde (2.0 g, 10.8 mmol) in dioxane (20 mL), water (10 mL), and toluene (10 mL) was added 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.9 g, 12.9 mmol), Pd(dppf)Cl (787 mg, 1.1 mmol), and KPO (6.85 g, 32.3 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: EtOAc = 1:0 to 0:1) to give the title compound (0.98 g, 45%). LC-MS (M+H) + =202.3.

[0182] Step 2: (R)—N-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine [ka]

[0183] The title compound (220 mg, 33%) was prepared from (R)-5,6,7,8-tetrahydroquinolin-8-amine and 5-(1,4-dimethyl-1H-pyrazol-5-yl)picolinaldehyde in a manner similar to that of Step 7 of Example 1. LC-MS (M+H) + =334.3.

[0184] Step 3: (R)—N-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0185] The title compound (20 mg, 50%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)—N-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine in a manner similar to Step 8 of Example 1. LC-MS (M+H) + =801.6.

[0186] Step 4: (R)-5-amino-N-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0187] Example 4 (2.5 mg, 20%) was prepared from (R)—N-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Step 9 of Example 1. 1 H NMR(500MHz,DMSO-d6)δ11.56-11.08(m,1H), 8.73-8.46(m,1H), 8.46-8.29(m,1H), 7.99-7.45(m,3H), 7.43-7.27(m,2H), 7.27-7.07(m,1H), 6. 76-6.19(m,1H), 6.02-5.33(m,1H), 5.30(s,2H), 5.23-4.74(m,1H), 4.0 2-3.58(m,4H), 2.93-2.66(m,2H), 2.49-2.42(m,1H), 2.26-1.69(m,9H). LC-MS (M+H) + =507.4.

[0188] Example A5: (R)-5-amino-3-bromo-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0189] Step 1: 3-Bromo-5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid [ka]

[0190] To a solution of 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (150 mg, 0.31 mmol) in DMF (2 mL) was added NBS (66 mg, 0.37 mmol). The mixture was stirred at room temperature for 1 h. Water (10 mL) was added and the mixture was extracted with EtOAc (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (DCM:MeOH=15:1) to give the title compound (130 mg, 75%). LC-MS (M+H) + =564.1.

[0191] Step 2: (R)-3-bromo-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0192] The title compound (20 mg, 20%) was prepared from 3-bromo-5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)—N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine in a manner similar to Step 8 of Example 1. LC-MS (M+H) + =897.2.

[0193] Step 3: (R)-5-amino-3-bromo-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0194] Example 5 (10 mg, 77%) was prepared from (R)-3-bromo-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Step 9 of Example 1. 1 H NMR(500MHz,DMSO-d6)δ11.70(s,1H), 8.56(s,1H), 8.44(d,J=3.9Hz,1H), 7.94(d,J=7.9Hz,1 H), 7.73(d,J=8.1Hz,1H), 7.59-7.47(m,2H), 7.33(s,1H), 7.28(t,J=7.9Hz,2H), 7.21(dd,J=7 .3,4.9Hz,1H), 5.61(s,2H), 5.23-5.20(m,1H), 4.97-4.94(m,1H), 3.94-3.91(m,1H), 2.85-2. 80(m,1H), 2.68-2.64(m,1H), 2.57(s,1H), 2.14(s,3H), 2.06-1.90(m,2H), 1.75-1.60(m,1H). LC-MS(M+H) + =603.1.

[0195] Example A6: 5-amino-N-(4-cyclopropyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0196] Step 1: tert-butyl ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamate [ka]

[0197] To a solution of tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate (5.0 g, 17.4 mmol) in dioxane (50 mL) was added BPD (5.31 g, 20.9 mmol), Pd(dppf)Cl (1.27 g, 1.74 mmol), and KOAc (4.27 g, 43.5 mmol). The mixture was stirred at 85 °C for 12 h. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude product was redissolved in dioxane (25 mL) / toluene (12 mL) / water (12 mL), followed by the addition of 1,3-difluoro-2-iodobenzene (4.28 g, 17.8 mmol), KPO (6.32 g, 29.8 mmol), and Pd(dppf)Cl (871 mg, 1.19 mmol). The mixture was stirred at 85°C for 3 hours. The mixture was cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: EtOAc = 1:0 to 5:1) to give the title compound (3.0 g, 54%). 1H NMR(400MHz,CDCl3)δ8.64(s,1H), 7.78(d,J=8.4Hz,1H), 7.39(d,J=8.4Hz,1H), 7.36-7.28(m,1H), 7.06-6.96(m,1H), 5.62(br s,1H), 4.50(d,J=5.6Hz,2H), 7.47(s,9H). LC-MS(M+H) + =321.1.

[0198] Step 2: (5-(2,6-difluorophenyl)pyridin-2-yl)methanamine [ka]

[0199] A mixture of tert-butyl ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamate (3.0 g, 9.37 mmol) in methanolic HCl (4 M, 50 mL) was stirred at 25 °C for 2 h, after which the mixture was neutralized to pH 7 with methanolic NaOH (1 M). The mixture was concentrated to dryness under reduced pressure, and the residue was triturated with DCM / MeOH (10 / 1, 10 mL). The filtrate was collected by filtration and concentrated in vacuo to give the title compound (1.5 g, 73%). 1 H NMR (400MHz, CD3OD) δ8.72(s,1H), 7.97(d,J=6.0Hz,1H), 7.60(d,J=6.0Hz,1H), 7.54-7.45(m,1H), 7.20-7.10(m,1H), 4.37(s,2H). LC-MS(M+H) + =221.1.

[0200] Step 3: 4-Methoxy-5,6,7,8-tetrahydroquinoline [ka]

[0201] To a solution of PtO2 (3.71 g, 16.3 mmol) in TFA (200 mL) was added 4-methoxyquinoline (20 g, 126 mmol) under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen (50 psi) at 50 °C for 3 h. The filtrate was collected by filtration, concentrated to approximately 50 mL, and diluted with water (100 mL). The pH of the mixture was adjusted to 9 with aqueous NaOH (1 M). The mixture was extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (20 g, 98%). 1 H NMR (400MHz, CD3OD) δ8.40(d,J=6.4Hz,1H), 7.30(d,J=6.4Hz,1H), 4.11(s,3H), 2.96(t,J=6.2Hz,2H), 2.71(t,J=6.2Hz,2H), 1.96-1.83(m,4H). LC-MS(M+H) + =164.2.

[0202] Step 4: 4-Bromo-5,6,7,8-tetrahydroquinoline [ka]

[0203] To a solution of 4-methoxy-5,6,7,8-tetrahydroquinoline (17 g, 104 mmol) in DMF (170 mL) was added POBr (89.6 g, 312 mmol) at 0 °C. The mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was cooled to 0 °C and slowly added to ice water (300 mL). The mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: EtOAc = 1:0 to 5:1) to give the title compound (15 g). LC-MS (M+H) + =212.1.

[0204] Step 5: 4-Bromo-5,6,7,8-tetrahydroquinoline 1-oxide [ka]

[0205] To a solution of 4-bromo-5,6,7,8-tetrahydroquinoline (15 g, 70.7 mmol) in DCM (195 mL) was added m-CPBA (80%, 30.5 g, 141 mmol). The mixture was stirred at 42 °C for 2 h and then cooled to room temperature. The mixture was washed with water (100 mL), and the aqueous phase was extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: EtOAc = 1:0 to 3:1) to give the title compound (14 g, 87%). LC-MS (M+H) + =228.2.

[0206] Step 6: 4-Bromo-5,6,7,8-tetrahydroquinolin-8-yl acetate [ka]

[0207] A mixture of 4-bromo-5,6,7,8-tetrahydroquinoline 1-oxide (14 g, 61.4 mmol) in AcO (70 mL) was stirred at 55 °C for 2 hours and then cooled to room temperature. The filtrate was collected by filtration and concentrated under reduced pressure to give the title compound (14 g, 84%). LC-MS (M+H) + =270.1.

[0208] Step 7: 4-Bromo-5,6,7,8-tetrahydroquinolin-8-ol [ka]

[0209] Four identical reactions were set up in parallel as follows: To a solution of 4-bromo-5,6,7,8-tetrahydroquinolin-8-yl acetate (3.0 g, 11.1 mmol) in MeOH (15 mL) was added KCO (5.8 g, 42.2 mmol). The mixture was stirred at 25 °C for 2 h.

[0210] The four batches of reaction mixture were combined. The filtrate was collected by filtration and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: EtOAc = 1:0 to 1:1) to give the title compound (5.2 g, 51%). LC-MS (M+H) + =228.2.

[0211] Step 8: 4-Bromo-6,7-dihydroquinolin-8(5H)-one [ka]

[0212] To a solution of 4-bromo-5,6,7,8-tetrahydroquinolin-8-ol (5.0 g, 21.9 mmol) in DCM (260 mL) was added DMP (16.7 g, 39.5 mmol). The mixture was stirred at 25° C. for 8 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: EtOAc = 1:0 to 1:1) to give the title compound (4.0 g, 81%). LC-MS (M+H) + =226.1.

[0213] Step 9: 4-Cyclopropyl-6,7-dihydroquinolin-8(5H)-one [ka]

[0214] To a solution of 4-bromo-6,7-dihydroquinolin-8(5H)-one (1.0 g, 4.42 mmol) and cyclopropylboronic acid (950 mg, 11.1 mmol) in water (1 mL) / toluene (9 mL) was added SPhos (145 mg, 0.35 mmol), Pd(OAc) (99 mg, 0.44 mmol), and KPO (2.35 g, 11.1 mmol). The mixture was stirred at 90 °C for 12 h and cooled to room temperature. The mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (15 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc = 1:0 to 1:1) to give the title compound (0.20 g, 24%). LC-MS (M+H) + =188.3.

[0215] Step 10: 4-Cyclopropyl-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine [ka]

[0216] The title compound (0.30 g, 29%) was prepared from 4-cyclopropyl-6,7-dihydroquinolin-8(5H)-one and (5-(2,6-difluorophenyl)pyridin-2-yl)methanamine in a manner similar to that of Example 10, Step 3. LC-MS (M+H) + =392.2.

[0217] Step 11: N-(4-cyclopropyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0218] The title compound (20 mg, 42%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and 4-cyclopropyl-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine in a manner similar to that of Example 1, Step 8. LC-MS (M+H) + =859.3.

[0219] Step 12: 5-amino-N-(4-cyclopropyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0220] Example 6 (5 mg, 38%) was prepared from N-(4-cyclopropyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Example 1, Step 9. 1 H NMR(500MHz,DMSO-d6)δ11.29-11.23(m,1H), 8.63-8.46(m,1H), 8.24-8.15(m,1H), 7.92-7. 69(m,1H), 7.47(d,J=6.9Hz,2H), 7.28-7.20(m,3H), 6.80-6.46(m,1H), 6.07-5.84(m,1H), 5 .22(s,1H), 4.76-4.72(m,1H), 3.74-3.71(m,1H), 2.90-2.87(m,1H), 2.75(s,1H), 2.36(s,1 H), 2.15-2.05(m,3H), 2.0-1.85(m,3H), 1.72(s,1H), 1.02-0.87(m,2H), 0.73-0.58(m,2H). LC-MS(M+H) + =565.2.

[0221] Example A7: 5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(4-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinolin-8-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0222] Step 1: Methyl 5,6,7,8-tetrahydroquinoline-4-carboxylate [ka]

[0223] To a solution of 4-bromo-5,6,7,8-tetrahydroquinoline (2.0 g, 9.43 mmol) in MeOH (40 mL) was added EtN (2.86 g, 28.3 mmol) and Pd(dppf)Cl·DCM (770 mg, 943 μmol) under a nitrogen atmosphere. After the mixture was degassed and purged with CO three times, the mixture was stirred under CO (50 psi) at 50 °C for 12 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 3 / 1) to give the title compound (0.76 g, 42%). LC-MS (M+H) + =192.3.

[0224] Step 2: 2-(5,6,7,8-tetrahydroquinolin-4-yl)propan-2-ol [ka]

[0225] To a solution of MeMgBr (3 M in THF, 3.1 mL, 9.3 mmol) in THF (6 mL) was added dropwise a solution of methyl 5,6,7,8-tetrahydroquinoline-4-carboxylate (0.60 g, 3.14 mmol) in THF (3 mL) at 0 °C under a nitrogen atmosphere. The mixture was warmed to room temperature and stirred for 2 h. Aqueous HCl (0.05 M, 10 mL) was slowly added to the reaction mixture, and the mixture was extracted with EtOAc (2 mL × 3). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 1 / 1) to give the title compound (0.40 g, 67%). 1 H NMR(400MHz,DMSO-d6)δ8.19(d,J=5.2Hz,1H), 7.20(d,J=5.2Hz,1H), 5.08(s,1H) ), 3.02(t,J=6.0Hz,1H), 2.84(t,J=6.6Hz,1H), 1.83-1.65(m,4H), 1.48(s,6H). LC-MS(M+H) + =192.3.

[0226] Step 3: 4-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinoline 1-oxide [ka]

[0227] The title compound (0.30 g, 92%) was prepared from 2-(5,6,7,8-tetrahydroquinolin-4-yl)propan-2-ol in a manner similar to Example 6, Step 5. 1 H NMR(400MHz,DMSO-d6)δ8.05(d,J=6.8Hz,1H), 7.27(d,J=6.8Hz,1H), 5.17(s,1H) ), 3.02(t,J=6.0Hz,1H), 2.85(t,J=6.6Hz,1H), 1.82-1.60(m,4H), 1.48(s,6H). LC-MS(M+H) + =208.3.

[0228] Step 4: 4-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinolin-8-yl acetate [ka]

[0229] The title compound (0.48 g, 100%) was prepared from 4-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinoline 1-oxide in a similar manner to Step 6 of Example 6. LC-MS (M+H) + =250.3.

[0230] Step 5: 4-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinolin-8-ol [ka]

[0231] The title compound (0.48 g, 100%) was prepared from 4-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinolin-8-yl acetate in a manner similar to that of Example 6, Step 7. 1 H NMR(400MHz,DMSO-d6)δ8.31(d,J=5.2Hz,1H), 7.31(d,J=5.2Hz,1H), 5.13(s,1H), 4.98(d,J=3.6 Hz,1H), 4.59-4.53(m,1H), 3.22-3.10(m,1H), 2.97-2.85(m,1H), 1.98-1.60(m,4H), 1.48(s,6H). LC-MS(M+H) + =208.3.

[0232] Step 6: 4-(2-hydroxypropan-2-yl)-6,7-dihydroquinolin-8(5H)-one [ka]

[0233] To a solution of 4-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinolin-8-ol (0.26 g, 1.25 mmol) in DCM (10 mL) was added MnO (1.09 g, 12.5 mmol). The mixture was stirred at 40 °C for 12 h and cooled to room temperature. The solid was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 0 / 1) to give the title compound (0.20 g, 78%). 1 H NMR(400MHz,DMSO-d6)δ8.53(d,J=4.8Hz,1H), 7.58(d,J=4.8Hz,1H), 5.33(s, 1H), 3.29-3.22(m,2H), 2.68(t,J=6.4Hz,2H), 2.06-1.99(m,2H), 1.53(s,6H). LC-MS(M+H) + =206.1.

[0234] Step 7: 2-(8-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)amino)-5,6,7,8-tetrahydroquinolin-4-yl)propan-2-ol [ka]

[0235] The title compound (0.10 g, 33%) was prepared from 4-(2-hydroxypropan-2-yl)-6,7-dihydroquinolin-8(5H)-one and (5-(2,6-difluorophenyl)pyridin-2-yl)methanamine in a manner similar to that of Step 3 of Example 10. LC-MS (M+H) + =410.2.

[0236] Step 8: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-N-(4-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinolin-8-yl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0237] In a manner similar to that of Example 1, Step 8, the title compound (10 mg, 28%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and 2-(8-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)amino)-5,6,7,8-tetrahydroquinolin-4-yl)propan-2-ol. LC-MS (M+H) + =877.4.

[0238] Step 9: 5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(4-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinolin-8-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0239] Example 7 (2 mg, 30%) was prepared from N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-N-(4-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinolin-8-yl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Example 1, Step 9. 1 H NMR(500MHz,DMSO-d6)δ11.50-11.23(m,1H), 8.77-8.50(m,1H), 8.43-8.18(m,1H), 8.01-7.23(m,7H), 6.66-6.09(m,1H), 6. 00-5.35(m,1H), 5.33-4.70(m,5H), 3.95-3.34(m,1H), 3.05-2.81(m,1H), 2.47-2.38(m,1H), 2.21-1.60(m,7H), 1.50(s,6H). LC-MS(M+H) + =583.4.

[0240] Example A8: (R)-5-amino-N-((4-chloro-5-phenylpyridin-2-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0241] Step 1: Methyl 4-amino-5-phenylpicolinate [ka]

[0242] To a solution of methyl 4-amino-5-iodopicolinate (2.0 g, 7.2 mmol) and phenylboronic acid (1.05 g, 8.6 mmol) in dioxane (16 mL) / water (4 mL) was added Pd(dppf)Cl (526 mg, 0.72 mmol) and KPO (3.05 g, 14.4 mmol). The mixture was stirred at 100 °C for 2 h and cooled to room temperature. The mixture was diluted with water (10 mL) and extracted with EtOAc (8 mL × 2). The combined organic layers were washed with brine (5.0 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EtOAc = 50:1 to 5:1) to give the title compound (400 mg, 24%). LC-MS (M+H) + =229.2.

[0243] Step 2: Methyl 4-chloro-5-phenylpicolinate [ka]

[0244] To a mixture of CuCl2 (509 mg, 3.79 mmol) in MeCN (2 mL) was added tert-butyl nitrite (488 mg, 4.73 mmol). The mixture was stirred at room temperature for 15 minutes and then cooled to 0 °C. A solution of methyl 4-amino-5-phenylpicolinate (360 mg, 1.58 mmol) in MeCN (2 mL) was added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 1 hour and at room temperature for 16 hours. The mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography (PE:EtOAc = 50:1 to 3:1) to give the title compound (160 mg, 41%). 1 H NMR (400MHz, DMSO-d6) δ8.79(s,1H), 8.27(s,1H), 7.68-7.53(m,5H), 3.99(s,3H). LC-MS(M+H) + =248.2.

[0245] Step 3: 4-Chloro-5-phenylpicolinaldehyde [ka]

[0246] To a solution of methyl 4-chloro-5-phenylpicolinate (160 mg, 0.65 mmol) in THF (2 mL) was added DIBAL-H (1 M in toluene, 840 μL) at −70° C. The mixture was stirred at −70° C. for 1 h. The mixture was poured into water (10 mL), and the mixture was extracted with EtOAc (8 mL × 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EtOAc = 50:1 to 5:1) to give the title compound (130 mg, 92%). 1 H NMR (400MHz, DMSO-d6) δ10.09(s,1H), 8.91(s,1H), 8.18(s,1H), 7.70-7.52(m,5H). LC-MS(M+H) + =218.2.

[0247] Step 4: (R)—N-((4-chloro-5-phenylpyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine [ka]

[0248] The title compound (150 mg, 75%) was prepared from (R)-5,6,7,8-tetrahydroquinolin-8-amine and 4-chloro-5-phenylpicolinaldehyde in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =350.2.

[0249] Step 5: (R)—N-((4-chloro-5-phenylpyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0250] The title compound (10 mg, 30%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)—N-((4-chloro-5-phenylpyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine in a manner similar to Step 8 of Example 1. LC-MS (M+H) + =817.4.

[0251] Step 6: (R)-5-amino-N-((4-chloro-5-phenylpyridin-2-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0252] Example 8 (1 mg, 16%) was prepared from (R)—N-((4-chloro-5-phenylpyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Step 9 of Example 1. 1 H NMR(500MHz,DMSO-d6)δ11.30(s,1H), 8.47-8.30(m,2H), 7.63-7.44(m,8H), 7.37-7.29(m,1H), 7.26-7.13(m,1H), 5.2 9(s,2H), 4.79-3.92(m,1H), 2.92-2.81(m,2H), 2.78-2.71(m,2H), 2.14(s,3H), 2.03-1.93(m,2H), 1.85-1.72(m,2H). LC-MS(M+H) + =523.3.

[0253] Example A9: 5-amino-6-methyl-N-((6-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0254] Step 1: tert-butyl ((5-bromo-6-methylpyridin-2-yl)methyl)carbamate [ka]

[0255] To a solution of 5-bromo-6-methylpicolinonitrile (5.0 g, 25.4 mmol), BocO (11.1 g, 50.8 mmol), and NiCl (987 mg, 7.61 mmol) in MeOH (75 mL) was added NaBH (3.84 g, 102 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for 2 h. The mixture was slowly added to ice water (100 mL). After the effervescence subsided, the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EtOAc = 1:0 to 3:1) to give the title compound (1.3 g, 17%). LC-MS (M+H) + =301.2.

[0256] Step 2: (5-bromo-6-methylpyridin-2-yl)methanamine [ka]

[0257] A mixture of tert-butyl ((5-bromo-6-methylpyridin-2-yl)methyl)carbamate (1.3 g, 4.32 mmol) in HCl (4 M in MeOH, 20 mL) was stirred at room temperature for 2 hours. The mixture was neutralized to pH 7 with 1 M NaOH in MeOH and concentrated under vacuum. The solid was triturated with a DCM (10 mL) / MeOH (1 mL) mixture. The solid was filtered and the filtrate was concentrated under reduced pressure to give the title compound (0.80 g, 92%). LC-MS (M+H) + =201.1.

[0258] Step 3: N-((5-bromo-6-methylpyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine [ka]

[0259] The title compound (0.50 g, 47%) was prepared from 6,7-dihydroquinolin-8(5H)-one and (5-bromo-6-methylpyridin-2-yl)methanamine in a similar manner to Step 3 of Example 10. LC-MS (M+H) + =332.2.

[0260] Step 4: N-((6-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine [ka]

[0261] To a solution of N-((5-bromo-6-methylpyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (0.80 g, 2.4 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.67 g, 6.0 mmol) in dioxane (4 mL) / toluene (2 mL) / water (2 mL) was added KPO (1.28 g, 6.0 mmol) and Pd(dppf)Cl (176 mg, 0.24 mmol). The mixture was stirred at 90 °C for 12 h and then cooled to room temperature. The reaction was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EtOAc = 1:0 to 1:1) to give the title compound (139 mg, 14% yield). LC-MS (M+H) + =404.2.

[0262] Step 5: 5-((diphenylmethylene)amino)-6-methyl-N-((6-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0263] The title compound (30 mg, 42%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-((6-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine in a manner similar to Step 8 of Example 1. LC-MS (M+H) + =871.4.

[0264] Step 6: 5-amino-6-methyl-N-((6-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0265] Example 9 (6 mg, 26%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-N-((6-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Step 9 of Example 1. 1H NMR(500MHz,DMSO-d6)δ12.37(s,1H), 11.38(s,1H), 8.46-8.31(m,1H), 8.00-7.83(m ,2H), 7.82-7.67(m,2H), 7.61-7.53(m,1H), 7.52-7.14(m,3H), 6.67-6.58(m,0.5H),6 .20-5.86(m,1H), 5.31-5.04(m,2H), 4.83-3.65(m,1H), 2.88-2.67(m,2H), 2.65-2.5 8(m,2H), 2.43-2.34(m,1H), 2.17-2.09(m,4H), 1.97-1.90(m,2H), 1.80-1.69(m,1H). LC-MS(M+H) + =493.3.

[0266] Example A10: 5-amino-N-((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0267] Step 1: tert-butyl ((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)carbamate [ka]

[0268] To a solution of tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate (18.0 g, 62.7 mmol) and (2,6-dichlorophenyl)boronic acid (23.9 g, 125 mmol) in dioxane (80 mL) / toluene (40 mL) / water (40 mL) was added KPO (33.3 g, 157 mmol) and Pd(dppf)Cl (4.59 g, 6.27 mmol) under a nitrogen atmosphere. The mixture was stirred at 85 °C for 12 h and cooled to room temperature. The mixture was diluted with water (150 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc = 1:0 to 5:1) to give the title compound (9.0 g, 41%). LC-MS (M+H) + =353.1.

[0269] Step 2: (5-(2,6-dichlorophenyl)pyridin-2-yl)methanamine [ka]

[0270] A mixture of tert-butyl ((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)carbamate (9.0 g, 25.5 mmol) in methanolic hydrochloric acid (4 M, 90 mL) was stirred at 25 °C for 1 h, after which the mixture was neutralized to pH 7 with a solution of NaOH in methanol (1 M). The mixture was concentrated to dryness under reduced pressure, and the residue was triturated with DCM / MeOH (10 / 1, 10 mL). The filtrate was collected by filtration and concentrated in vacuo to give the title compound (6.0 g, 93%). 1 H NMR (400MHz, CDCl3) δ8.45(s,1H), 7.66-7.58(m,1H), 7.54(d,J=8.0Hz,1H), 7.38(d,J=8.0Hz,2H), 7.30-7.24(m,1H), 4.58(s,2H).

[0271] Step 3: N-((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine [ka]

[0272] To a solution of (5-(2,6-dichlorophenyl)pyridin-2-yl)methanamine (10.8 g, 42.8 mmol) and 6,7-dihydroquinolin-8(5H)-one (7.0 g, 47.6 mmol) in DCM (140 mL) / MeOH (1.4 mL) was added NaBH(OAc) (18.1 g, 85.6 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was poured into saturated NaHCO (100 mL). The mixture was extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EtOAc = 1:0 to 0:1) to give the title compound (5.5 g, 30%). 1 H NMR(400MHz,CD3OD)δ8.43-8.35(m,2H), 7.78-7.70(m,1H), 7.66(d,J=8.0Hz,1H), 7.58-7.50(m,3H), 7.44-7.36(m,1H), 7.25-7.17 (m,1H), 4.73-4.56(m,2H), 3.90(dd,J=7.6,6.4Hz,1H), 2.95-2.76(m,2H), 2.33-2.23(m,1H), 2.12-2.03(m,2H), 1.93-1.72(m,2H). LC-MS(M+H) + =384.0.

[0273] Step 4: N-((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0274] To a solution of 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (430 mg, 0.88 mmol) in DMF (15 mL) was added HATU (370 mg, 0.97 mmol), N-((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (408 mg, 1.06 mmol), and DIPEA (228 mg, 1.77 mmol). The solution was stirred at 55 °C for 16 h. The mixture was cooled to room temperature, diluted in water (50 mL), and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL × 2), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM:MeOH=20:1) to give the title compound (600 mg, 80%). LC-MS (M+H) + =851.2.

[0275] Step 5: 5-amino-N-((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0276] To a solution of N-((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (600 mg, 0.71 mmol) in DCM (8 mL) was added TFA (8 mL). The mixture was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo, and HCl (4 M in MeOH, 5 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, and KCO (390 mg, 2.82 mmol), water (3 mL), and MeOH (15 mL) were added. The mixture was stirred at 60° C. for 3 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM:MeOH=20:1) to give the title compound (277 mg, 70.4%). 1 H NMR(500MHz,DMSO-d6)δ11.64-11.19(m,1H), 8.67-8.19(m,2H), 8.06-7.06(m,8H), 6.91-6.12(m,1H), 6.05- 5.07(m,3H), 5.07-3.71(m,2H), 3.02-2.65(m,2H), 2.49-2.40(m,1H), 2.31-1.89(m,5H), 1.86-1.64(m,1H). LC-MS(M+H) + =557.3.

[0277] Example A11: (R)-5-amino-6-methyl-N-((5-(perfluorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0278] Step 1: 5-(perfluorophenyl)picolinaldehyde [ka]

[0279] To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinaldehyde (4.76 g, 20.4 mmol) and 1,2,3,4,5-pentafluoro-6-iodobenzene (2.0 g, 6.80 mmol) in dioxane (10 mL) / toluene (5 mL) / water (5 mL) was added Pd(dppf)Cl (249 mg, 0.34 mmol) and KPO (3.61 g, 17.0 mmol). The mixture was stirred at 85 °C for 16 h and then cooled to room temperature. The mixture was diluted with water (10 mL) and extracted with EtOAc (8 mL × 2). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EtOAc = 50:1 to 5:1) to give the title compound (0.80 mg, 43%).

[0280] Step 2: (R)—N-((5-(perfluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine [ka]

[0281] The title compound (0.20 g, 45%) was prepared from (R)-5,6,7,8-tetrahydroquinolin-8-amine and 5-(perfluorophenyl)picolinaldehyde in a manner similar to that of Step 7 of Example 1. LC-MS (M+H) + =406.1.

[0282] Step 3: (R)-5-((diphenylmethylene)amino)-6-methyl-N-((5-(perfluorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0283] The title compound (44 mg, 62%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)—N-((5-(perfluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine in a manner similar to Step 8 of Example 1. LC-MS (M+H) + =873.4.

[0284] Step 4: (R)-5-amino-6-methyl-N-((5-(perfluorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0285] Example 11 (2 mg, 8%) was prepared from (R)-5-((diphenylmethylene)amino)-6-methyl-N-((5-(perfluorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Step 9 of Example 1. 1 H NMR(500MHz,DMSO-d6)δ11.54-11.20(m,1H), 8.82-8.53(m,1H), 8.49-8.31(m,1H), 8.12-7.44(m,3H), 7.39-7.27(m,1H), 7.27-7.12(m,1 H), 6.72-6.07(m,1H), 6.00-5.35(m,1H), 5.36-5.26(m,2H), 5.26-4.76(m,1H), 4.00-3.35(m,1H), 2.98-2.69(m,2H), 2.28-1.69(m,7H). LC-MS(M+H) + =579.4.

[0286] Example A12: (R)-5-amino-6-bromo-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0287] Step 1: tert-butyl (3-bromo-6-methyl-5-nitropyridin-2-yl) (tert-butoxycarbonyl)carbamate [ka]

[0288] To a solution of 3-bromo-6-methyl-5-nitropyridin-2-amine (55 g, 237 mmol) and DMAP (2.90 g, 23.7 mmol) in THF (500 mL) was added BocO (129 g, 593 mmol) at room temperature. After 12 h, the mixture was diluted with water (2.5 L) and extracted with EtOAc (400 mL × 3). The combined organic layers were washed with brine (100 mL × 4), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give the title compound (80 g, 78%). 1 H NMR (400MHz, DMSO-d6) δ8.87(s,1H), 2.70(s,3H), 1.38(s,18H).

[0289] Step 2: Ethyl 3-(5-bromo-6-((tert-butoxycarbonyl)amino)-3-nitropyridin-2-yl)-2-hydroxyacrylate [ka]

[0290] EtONa (20% in EtOH, 23.6 g, 69.4 mmol) was dissolved in THF (150 mL) at 0 °C, and diethyl oxalate (15.2 g, 104 mmol) was added to the mixture. The mixture was stirred at 0 °C for 0.5 h, followed by the dropwise addition of a solution of tert-butyl (3-bromo-6-methyl-5-nitropyridin-2-yl) (tert-butoxycarbonyl)carbamate (15 g, 34.7 mmol) in THF (100 mL). The mixture was warmed to room temperature and stirred for 24 h. The mixture was diluted with water (2 L) and extracted with EtOAc (300 mL × 4). The combined organic layers were washed with brine (100 mL × 4), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give the title compound (5.0 g, 33% yield). 1 H NMR (400MHz, DMSO-d6) δ13.15(s,1H), 9.57(s,1H), 8.79(s,1H), 7.26(s,1H), 4.29(q,J=7.0Hz,2H), 1.52(s,9H), 1.31(t,J=7.0Hz,3H).

[0291] Step 3: 1-(tert-butyl) 2-ethyl 5-(bis(tert-butoxycarbonyl)amino)-6-bromo-1H-pyrrolo[3,2-b]pyridine-1,2-dicarboxylate [ka]

[0292] To a mixture of ethyl 3-(5-bromo-6-((tert-butoxycarbonyl)amino)-3-nitropyridin-2-yl)-2-hydroxyacrylate (2.5 g, 5.78 mmol) in AcOH (30 mL) was added iron powder (1.94 g, 34.7 mmol), and the mixture was stirred at 80 °C for 12 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with THF (20 mL × 2). The filtrate was concentrated under reduced pressure. The residue was diluted with water (10 mL) and neutralized with saturated NaHCO3 until pH was 7. The mixture was extracted with EtOAc (50 mL × 4). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue (0.50 g) was redissolved in THF (5 mL), and DIPEA (1.14 g, 8.80 mmol) and DMAP (21.5 mg, 0.18 mmol) were added, followed by BocO (1.34 g, 6.16 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (5 mL × 3), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give the title compound (0.55 g, 16%). 1 H NMR (400MHz, DMSO-d6) δ8.58(s,1H), 7.39(s,1H), 4.37(q,J=7.0Hz,2H), 1.59(s,9H), 1.40-1.25(m,21H).

[0293] Step 4: 6-Bromo-1-(tert-butoxycarbonyl)-5-((tert-butoxycarbonyl)amino)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid [ka]

[0294] To a mixture of 1-(tert-butyl) 2-ethyl 5-(bis(tert-butoxycarbonyl)amino)-6-bromo-1H-pyrrolo[3,2-b]pyridine-1,2-dicarboxylate (100 mg, 0.17 mmol) in THF (1 mL), MeOH (0.3 mL), and water (0.1 mL) was added LiOH·HO (11 mg, 0.26 mmol). The mixture was stirred at 40 °C for 0.5 h and then cooled to room temperature. The pH of the mixture was carefully adjusted to approximately 4 with a 1 M solution of hydrochloric acid in methanol. The mixture was concentrated in vacuo. The residue was triturated with a mixture of DCM (10 mL) and MeOH (2 mL). The solid was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (78 mg, 100%). LC-MS (MH) - =454.3.

[0295] Step 5: tert-butyl (R)-6-bromo-5-((tert-butoxycarbonyl)amino)-2-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ka]

[0296] The title compound (40 mg, 18%) was prepared from 6-bromo-1-(tert-butoxycarbonyl)-5-((tert-butoxycarbonyl)amino)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)—N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine in a manner similar to Step 8 of Example 1. LC-MS (M+H) + =789.2.

[0297] Step 6: (R)-5-amino-6-bromo-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0298] A mixture of tert-butyl (R)-6-bromo-5-((tert-butoxycarbonyl)amino)-2-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (40 mg, 51 μmol) and HCl (1 M in MeOH, 5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give Example 12 (3 mg, 10%). 1 H NMR(500MHz,DMSO-d6)δ11.72-11.61(m,1H), 8.78-8.52(m,1H), 8.49-8.31(m,1H), 8.00-7.73(m,2H), 7.59-7.50(m,2H), 7.34- 7.13(m,3H), 6.73-6.20(m,1H), 5.88-5.38(m,3H), 5.25-4.76(m,1H), 3.96-3.30(m,1H), 2.93-2.64(m,2H), 2.49-1.77(m,4H). LC-MS(M+H) + =589.1.

[0299] Example A13: (R)-5-amino-6-methyl-N-((5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0300] Step 1: 2-(1,3-dioxolan-2-yl)-5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridine [ka]

[0301] To a mixture of (6-(1,3-dioxolan-2-yl)pyridin-3-yl)boronic acid (2.0 g, 10.3 mmol) in dioxane (20 mL), toluene (10 mL), and water (10 mL) was added 5-bromo-1-methyl-1H-1,2,4-triazole (1.66 g, 10.3 mmol), KPO (6.53 g, 30.8 mmol), and Pd(dppf)Cl (751 mg, 1.0 mmol). The mixture was stirred at 80 °C for 12 h and cooled to room temperature. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: EtOAc = 5:1 to 0:1) to give the title compound (1.3 g, 55%). LC-MS (M+H) + =233.3.

[0302] Step 2: 5-(1-methyl-1H-1,2,4-triazol-5-yl)picolinaldehyde [ka]

[0303] To a mixture of 2-(1,3-dioxolan-2-yl)-5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridine (1.2 g, 5.17 mmol) in water (6 mL) / dioxane (12 mL) was added concentrated hydrochloric acid (6.5 mL), and the mixture was stirred at 60 °C for 3 h. The mixture was cooled to room temperature and neutralized with saturated NaHCO until the pH reached 7-8. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give the title compound (0.60 g, 62%). LC-MS (M+H) + =189.3.

[0304] Step 3: (R)—N-((5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine [ka]

[0305] The title compound (0.28 g, 25%) was prepared from (R)-5,6,7,8-tetrahydroquinolin-8-amine and 5-(1-methyl-1H-1,2,4-triazol-5-yl)picolinaldehyde in a manner similar to that of Step 7 of Example 1. LC-MS (M+H) + =321.1.

[0306] Step 4: (R)-5-((diphenylmethylene)amino)-6-methyl-N-((5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0307] The title compound (30 mg, 46%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)—N-((5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine in a manner similar to Step 8 of Example 1. LC-MS (M+H) + =788.4.

[0308] Step 5: (R)-5-amino-6-methyl-N-((5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0309] Example 13 (12 mg, 64%) was prepared from (R)-5-((diphenylmethylene)amino)-6-methyl-N-((5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Step 9 of Example 1. 1 H NMR(500MHz,DMSO-d6)δ11.54-11.10(m,1H), 9.13-8.73(m,1H), 8.49-8.32(m,1H), 8.29-8.09(m,1H), 8.07-7.44(m,3H), 7.38-7.09(m,2) H), 6.74-6.11(m,1H), 6.01-5.35(m,1H), 5.32-5.23(m,2H), 4.92-4.70(m,1H), 4.06-3.80(m,4H), 2.93-2.67(m,2H), 2.26-1.69(m,7H). LC-MS(M+H) + =494.4.

[0310] Example A14: 5-amino-N-((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0311] Step 1: tert-butyl ((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)carbamate [ka]

[0312] The title compound (180 mg, 69%) was prepared from tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate and 1-chloro-3-fluoro-2-iodobenzene in a similar manner to Step 1 of Example 6. LC-MS (M+H) + =337.2.

[0313] Step 2: (5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methanamine [ka]

[0314] The title compound (140 mg, 99%) was prepared from tert-butyl ((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)carbamate in a similar manner to Example 6, Step 2. LC-MS (M+H) + =237.1.

[0315] Step 3: N-((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine [ka]

[0316] The title compound (78 mg, 29%) was prepared from (5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methanamine and 6,7-dihydroquinolin-8(5H)-one in a manner similar to that of Example 10, Step 3. LC-MS (M+H) + =368.1.

[0317] Step 4: 5-Amino-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid [ka]

[0318] A mixture of 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (1.7 g, 3.5 mmol) in TFA (10 mL) / DCM (10 mL) was stirred at 30 °C for 4 h. The mixture was concentrated under reduced pressure and treated with aqueous hydrochloric acid (1 M, 15 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was treated with aqueous K2CO3 (1 M, 10 mL) and MeOH (10 mL), and the mixture was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure, and the crude was purified by C18 chromatography (10% aqueous MeCN with 0.03% formic acid) to give the title compound (0.60 g, 90%). LCMS (M+H) + =192.2.

[0319] Step 5: 5-amino-N-((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0320] To a solution of 5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (20 mg, 0.10 mmol) in DMF (4 mL) was added HATU (44 mg, 0.11 mmol), N-((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (42 mg, 0.12 mmol), and DIPEA (27 mg, 0.21 mmol). The mixture was stirred at room temperature for 3 hours, and then aqueous NaOH (1 M, 3 mL) was added and stirred at room temperature for 1 hour. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL × 2), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give Example 14 (3 mg, 5%). 1H NMR(500MHz,DMSO-d6)δ11.51-11.16(m,1H), 8.72-8.26(m,2H), 8.05-6.56(m,9H), 6.31- 5.77(m,1H), 5.57-3.66(m,4H), 2.97-2.67(m,2H), 2.45-1.85(m,6H), 1.86-1.67(m,1H). LC-MS(M+H) + =541.3.

[0321] Example A15: 5-amino-N-((5-(2-cyano-6-fluorophenyl)pyridin-2-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0322] Step 1: tert-butyl ((5-(2-cyano-6-fluorophenyl)pyridin-2-yl)methyl)carbamate [ka]

[0323] The title compound (308 mg, 77%) was prepared from tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate and 3-fluoro-2-iodobenzonitrile in a manner similar to that in Example 6, Step 1. 1 H NMR(400MHz,DMSO-d6)δ8.65(s,1H), 8.00(d,J=8.0Hz,1H), 7.89(d,J=6.8Hz,1H), 7.82-7.73(m,1H), 7.73-7 .66(m,1H), 7.56-7.50(m,1H), 7.44(d,J=8.0Hz,1H), 4.36-4.28(m,2H), 4.50(d,J=5.6Hz,2H), 1.40(s,9H).

[0324] Step 2: 2-(6-(aminomethyl)pyridin-3-yl)-3-fluorobenzonitrile [ka]

[0325] The title compound (0.20 g, 96%) was prepared from tert-butyl ((5-(2-cyano-6-fluorophenyl)pyridin-2-yl)methyl)carbamate in a manner similar to Example 6, Step 2.

[0326] Step 3: 3-Fluoro-2-(6-(((5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)pyridin-3-yl)benzonitrile [ka]

[0327] The title compound (212 mg, 34%) was prepared from 2-(6-(aminomethyl)pyridin-3-yl)-3-fluorobenzonitrile and 6,7-dihydroquinolin-8(5H)-one in a manner similar to that of Step 3 of Example 10. LC-MS (M+H) + =359.1.

[0328] Step 4: 5-amino-N-((5-(2-cyano-6-fluorophenyl)pyridin-2-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0329] Example 15 (6 mg, 11%) was prepared in a similar manner to Example 14, Step 5 from 5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and 3-fluoro-2-(6-(((5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)pyridin-3-yl)benzonitrile. 1H NMR(500MHz,DMSO-d6)δ11.44-11.20(m,1H), 8.90-8.52(m,1H), 8.49-8.27(m,1H), 8.14-6.56(m,9 H), 6.31-5.58(m,1H), 5.56-3.77(m,4H), 2.97-2.68(m,2H), 2.47-1.88(m,6H), 1.87-1.66(m,1H). LC-MS(M+H) + =532.4.

[0330] Example A16: N-([2,3'-bipyridin]-6'-ylmethyl)-5-amino-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0331] Step 1: tert-butyl ([2,3'-bipyridin]-6'-ylmethyl)carbamate [ka]

[0332] The title compound (0.40 g, 59%) was prepared from tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate and 2-bromopyridine in a similar manner to Step 1 of Example 6. LC-MS (M+H) + =286.3.

[0333] Step 2: [2,3'-bipyridine]-6'-ylmethanamine [ka]

[0334] To a solution of tert-butyl ([2,3'-bipyridin]-6'-ylmethyl)carbamate (400 mg, 1.40 mmol) in DCM (4 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 1 hour. The mixture was neutralized with aqueous NaHCO3 until the pH was 8. The mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (200 mg, 77%). LC-MS (M+H) + =186.3.

[0335] Step 3: N-([2,3'-bipyridin]-6'-ylmethyl)-5,6,7,8-tetrahydroquinolin-8-amine [ka]

[0336] The title compound (0.30 g, 29%) was prepared from 6,7-dihydroquinolin-8(5H)-one and [2,3'-bipyridine]-6'-ylmethanamine in a similar manner to Step 3 of Example 10. LC-MS (M+H) + =317.1.

[0337] Step 4: N-([2,3'-bipyridin]-6'-ylmethyl)-5-((diphenylmethylene)amino)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0338] The title compound (22 mg, 43%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-([2,3'-bipyridin]-6'-ylmethyl)-5,6,7,8-tetrahydroquinolin-8-amine in a manner similar to that of Example 1, Step 8. LC-MS (M+H) + =784.2.

[0339] Step 5: N-([2,3'-bipyridin]-6'-ylmethyl)-5-amino-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0340] Example 16 (7 mg, 51%) was prepared from N-([2,3'-bipyridin]-6'-ylmethyl)-5-((diphenylmethylene)amino)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Example 1, Step 9. 1 H NMR(500MHz,CD3OD)δ9.27-8.93(m,1H), 8.73-8.23(m,3H), 8.02-7.84(m,2H), 7.81-7.47(m,3H), 7.46-7.11(m,2H), 6.89-6. 44(m,1H), 6.08-5.43(m,1H), 5.28-4.96(m,1H), 4.22-3.34(m,1H), 2.97-2.75(m,2H), 2.49-1.93(m,6H), 1.86-1.73(m,1H). LC-MS(M+H) + =490.3.

[0341] Example A17: (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-3-fluoro-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0342] Step 1: methyl 5-((diphenylmethylene)amino)-3-fluoro-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate [ka]

[0343] To a solution of methyl 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (500 mg, 1.0 mmol) in MeCN (5 mL) was added NaHCO (168 mg, 2.0 mmol) and Selectfluor® (886 mg, 2.50 mmol). The mixture was stirred at room temperature for 16 hours, diluted with water (5 mL), and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (15 mg, 3%). LC-MS (M+H) + =518.3.

[0344] Step 2: 5-((diphenylmethylene)amino)-3-fluoro-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid [ka]

[0345] The title compound (13 mg, 89%) was prepared from methyl 5-((diphenylmethylene)amino)-3-fluoro-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate in a manner similar to that of Example 1, Step 5. LC-MS (M+H) + =504.3.

[0346] Step 3: (R)—N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-3-fluoro-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0347] To a solution of (R)—N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (6 mg, 18 μmol) and 5-((diphenylmethylene)amino)-3-fluoro-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (9 mg, 18 μmol) in THF (1 mL) was added PyBroP® (9 mg, 20 μmol) and DIPEA (6 mg, 45 μmol). The mixture was stirred at room temperature for 12 hours. The mixture was diluted with water (3 mL) and extracted with DCM (3 mL × 3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE: EtOAc = 1:1) to give the title compound (10 mg, 67%). LC-MS (M+H) + =837.5.

[0348] Step 4: (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-3-fluoro-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0349] Example 17 (1.5 mg, 23%) was prepared from (R)—N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-3-fluoro-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Step 9 of Example 1. 1 H NMR(400MHz,CDCl3)δ9.76(s,1H), 8.76-8.23(m,2H), 7.79-7.68(m,1H), 7.63-7.31(m,3H), 7.18-6.94(m,4H), 5.68-5.47(m,1H), 5.16-5.04(m, 1H), 4.46(s,2H), 4.28-4.01(m,1H), 2.97-2.80(m,1H), 2.80-2.63(m,1H ), 2.50-2.33(m,1H), 2.26(s,3H), 2.16-1.97(m,2H), 1.89-1.70(m,1H). LC-MS (M+H) + =543.1.

[0350] Example A18: 5-amino-N-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-fluorobenzyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0351] Step 1: 4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-fluorobenzaldehyde [ka]

[0352] A mixture of (3-fluoro-4-formylphenyl)boronic acid (435 mg, 2.6 mmol), 5-bromo-1,4-dimethyl-1H-pyrazole (450 mg, 2.6 mmol), Pd(PPh3)4 (300 mg, 0.10 mmol), and K2CO3 (900 mg, 6.5 mmol) was added to dioxane (10 mL) and water (1 mL) under a nitrogen atmosphere. The mixture was stirred at 90 °C overnight. The mixture was cooled to room temperature and diluted with EtOAc (50 mL). The mixture was washed successively with water (30 mL) and brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE: EtOAc = 2:1) to give the title compound (400 mg, 73%). LC-MS (M+H) + =219.2.

[0353] Step 2: N-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-fluorobenzyl)-5,6,7,8-tetrahydroquinolin-8-amine [ka]

[0354] The title compound (120 mg, 48%) was prepared from 5,6,7,8-tetrahydroquinolin-8-amine and 4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-fluorobenzaldehyde in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =351.3.

[0355] Step 3: N-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-fluorobenzyl)-5-((diphenylmethylene)amino)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0356] The title compound (40 mg, 48%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-fluorobenzyl)-5,6,7,8-tetrahydroquinolin-8-amine in a manner similar to Step 8 of Example 1. LC-MS (M+H) + =818.5.

[0357] Step 4: 5-amino-N-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-fluorobenzyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0358] Example 18 (15 mg, 59%) was prepared from N-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-fluorobenzyl)-5-((diphenylmethylene)amino)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Example 1, Step 9. 1 H NMR(500MHz,DMSO-d6)δ11.37(s,1H), 8.41(s,1H), 8.02-7.47(m,2H), 7.40-7.10(m,5H), 6.66(s,1H), 6.23-5.85(m,1H), 5.29(s,2H), 4.83-4.6 8(m,1H), 3.90-3.79(m,1H), 3.70(s,3H), 2.92-2.79(m,1H), 2.78-2.68 (m,1H), 2.15(s,3H), 2.09-2.01(m,1H), 1.97(s,3H), 1.84-1.70(m,1H). LC-MS (M+H) + =524.3.

[0359] Example A19: (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-3-iodo-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0360] Step 1: 5-((diphenylmethylene)amino)-3-iodo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid [ka]

[0361] To a solution of 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (200 mg, 0.41 mmol) in MeCN (10 mL) was added NIS (110 mg, 0.49 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with chloroform / isopropyl alcohol (3:1, 40 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (175 mg, 70%). LC-MS (M+H) + =612.1.

[0362] Step 2: (R)—N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-3-iodo-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0363] The title compound (134 mg, 58%) was prepared from 5-((diphenylmethylene)amino)-3-iodo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)—N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine in a manner similar to that of Example 1. LC-MS (M+H) + =945.3.

[0364] Step 3: (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-3-iodo-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0365] Example 19 (0.5 mg, 7%) was prepared from (R)—N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-3-iodo-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Step 9 of Example 1. 1H NMR(500MHz,CD3OD)δ8.62-7.90(m,1H), 7.88-7.37(m,3H), 7.31-7.07(m,3H), 5.68-4. 93(m,2H), 4.77-4.07(m,1H), 3.01-2.30(m,2H), 2.30-2.17(m,3H), 2.14-1.52(m,3H). LC-MS(M+H) + =651.3.

[0366] Example B1: 5-Amino-N-cyclobutyl-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0367] Step 1: 5-chloro-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid [ka]

[0368] A mixture of 2,6-dichloro-5-methylpyridin-3-amine (10.0 g, 56.5 mmol), pyruvic acid (14.9 g, 169 mmol), Pd(OAc) (0.94 g, 5.65 mmol), and PPh (11.8 g, 45.2 mmol) in DMF (100 mL) was stirred at 110 °C for 24 h. The mixture was cooled to room temperature, and the volatiles were removed in vacuo. Aqueous KCO (24 g in 200 mL of water) and MTBE (300 mL) were added, and the mixture was stirred for 10 min. The solids were removed by filtration. The aqueous phase was separated, and the pH was adjusted to 3–4 with aqueous HCl (6 M). The mixture was extracted with EtOAc (500 mL × 2). The combined organic layers were washed with brine (300 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by C18 chromatography (MeCN:0.03% formic acid in water, 0:1 to 1:1) to give the title compound (4.0 g, 34%). LC-MS (M+H) + =211.

[0369] Step 2: Methyl 5-chloro-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate [ka]

[0370] To a mixture of 5-chloro-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (8.5 g, 40.3 mmol) in MeOH (100 mL) was added concentrated H2SO4 (10 mL) dropwise at 0 °C. The mixture was stirred at reflux overnight. The mixture was cooled to room temperature, and most of the volatiles were removed in vacuo. The mixture was quenched with ice water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 8 / 1) to give the title compound (7.6 g, 84%). LC-MS (M+H) + =225.0.

[0371] Step 3: 5-chloro-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate methyl ester [ka]

[0372] A mixture of methyl 5-chloro-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (7.6 g, 33.9 mmol), SEMCl (11.3 g, 67.8 mmol), and DIPEA (13.1 g, 101.7 mmol) in THF (120 mL) was stirred overnight at 70 °C under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE / EtOAc = 10 / 1) to give the title compound (6.8 g, 71%). LC-MS (M+H) + =355.1.

[0373] Step 4: Methyl 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate [ka]

[0374] A solution of methyl 5-chloro-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (2.8 g, 7.89 mmol), diphenylmethanimine (2.14 g, 11.8 mmol), Pd(dba) (361 mg, 0.39 mmol), BINAP (0.492 g, 0.79 mmol), and KPO (5.0 g, 23.7 mmol) in dioxane (50 mL) was stirred at 100 °C under N overnight. The mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 4 / 1) to give the title compound (3.0 g, 76%). LC-MS (M+H) + =500.2.

[0375] Step 5: 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid [ka]

[0376] To a mixture of methyl 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (3.0 g, 6.0 mmol) in THF (50 mL) / water (50 mL) was added LiOH·HO (0.75 g, 18 mol). The mixture was stirred at 60 °C for 4 h. The mixture was cooled to room temperature, and the pH was adjusted to 7-8 with aqueous HCl (1 M). The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (2.5 g, 86%). LC-MS (M+H) + =486.2.

[0377] Step 6: N-((5-phenylpyridin-2-yl)methyl)cyclobutanamine [ka]

[0378] To a solution of 5-phenylpicolinaldehyde (300 mg, 1.64 mmol) and cyclobutanamine (233 mg, 3.28 mmol) in DCM (2 mL) / MeOH (0.2 mL) was added NaBH(OAc) (694 mg, 3.28 mmol). The mixture was stirred at room temperature for 1 h and then carefully added dropwise to water (100 mL) with vigorous stirring. The mixture was extracted with EtOAc (200 mL). The organic layer was separated, washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (100 mg, 26%). LC-MS (M+H) + =239.2.

[0379] Step 7: N-cyclobutyl-5-((diphenylmethylene)amino)-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0380] A mixture of 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (40 mg, 0.082 mmol), N-((5-phenylpyridin-2-yl)methyl)cyclobutanamine (20 mg, 0.082 mmol), HATU (31 mg, 0.082 mmol), and DIPEA (21 mg, 0.164 mmol) in DMF (1.5 mL) was stirred overnight at 60°C under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to give the title compound (40 mg, 69%). LC-MS (M+H) + =706.6.

[0381] Step 8: 5-amino-N-cyclobutyl-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0382] To a solution of N-cyclobutyl-5-((diphenylmethylene)amino)-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (40 mg, 0.057 mmol) in methanol (2 mL) was added aqueous HCl (6 M, 0.5 mL). The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was redissolved in DCM (2 mL) and TFA (1 mL) was added. The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was redissolved in MeOH (2 mL) / water (0.2 mL) followed by the addition of KCO (39 mg, 0.285 mmol). The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The mixture was triturated with DCM (5 mL) and the solid was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC to give Example 1 (6 mg, 26%). 1H NMR(500MHz,DMSO-d6)δ11.29(s,1H), 8.87(s,1H), 8.13-7.97(m,1H), 7.79-7.66(m,2H), 7.50(t,J=7.6Hz,2H), 7.42(t,J =7.3Hz,1H), 7.39-7.27(m,2H), 6.74-6.07(m,1H), 5.32(s,2H), 5.18-4.85(m,3H), 2.26-2.05(m,7H), 1.71-1.49(m,2H). LC-MS(M+H) + =412.3.

[0383] Example B2: 5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(1,3-dimethoxypropan-2-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0384] Step 1: tert-butyl ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamate [ka]

[0385] To a solution of tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate (5.0 g, 17.4 mmol) in dioxane (50 mL) was added BPD (5.31 g, 20.9 mmol), Pd(dppf)Cl (1.27 g, 1.74 mmol), and KOAc (4.27 g, 43.5 mmol). The mixture was stirred at 85 °C for 12 h. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude product was redissolved in dioxane (25 mL) / toluene (12 mL) / water (12 mL), followed by the addition of 1,3-difluoro-2-iodobenzene (4.28 g, 17.8 mmol), KPO (6.32 g, 29.8 mmol), and Pd(dppf)Cl (871 mg, 1.19 mmol). The mixture was stirred at 85°C for 3 hours. The mixture was cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: EtOAc = 1:0 to 5:1) to give the title compound (3.0 g, 54%). 1 H NMR(400MHz,CDCl3)δ8.64(s,1H), 7.78(d,J=8.4Hz,1H), 7.39(d,J=8.4Hz,1H), 7.36-7.28(m,1H), 7.06-6.96(m,1H), 5.62(br s,1H), 4.50(d,J=5.6Hz,2H), 7.47(s,9H). LC-MS(M+H) + =321.1.

[0386] Step 2: (5-(2,6-difluorophenyl)pyridin-2-yl)methanamine [ka]

[0387] A mixture of tert-butyl ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamate (3.0 g, 9.37 mmol) in methanolic HCl (4 M, 50 mL) was stirred at 25 °C for 2 h, after which the mixture was neutralized to pH 7 with methanolic NaOH (1 M). The mixture was concentrated to dryness under reduced pressure, and the residue was triturated with DCM / MeOH (10 / 1, 10 mL). The filtrate was collected by filtration and concentrated in vacuo to give the title compound (1.5 g, 73%). 1 H NMR (400MHz, CD3OD) δ8.72(s,1H), 7.97(d,J=6.0Hz,1H), 7.60(d,J=6.0Hz,1H), 7.54-7.45(m,1H), 7.20-7.10(m,1H), 4.37(s,2H). LC-MS(M+H) + =221.1.

[0388] Step 3: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-1,3-dimethoxypropan-2-amine [ka]

[0389] The title compound (0.20 g, 76%) was prepared from 1,3-dimethoxypropan-2-one and (5-(2,6-difluorophenyl)pyridin-2-yl)methanamine in a manner similar to that of Example 1, Step 6. 1 H NMR(400MHz,DMSO-d6)δ8.57(s,1H), 7.87(d,J=8.4Hz,1H), 7.60-7.48(m,2H), 7.32-7 .22(m,2H), 3.94(s,2H), 3.34(d,J=5.6Hz,4H), 3.24(s,6H), 2.89(quin,J=5.6Hz,1H). LC-MS(M+H) + =323.2.

[0390] Step 4: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(1,3-dimethoxypropan-2-yl)-5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0391] The title compound (30 mg, 76%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-1,3-dimethoxypropan-2-amine in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =790.6.

[0392] Step 5: 5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(1,3-dimethoxypropan-2-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0393] Example 2 (9 mg, 47%) was prepared from N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(1,3-dimethoxypropan-2-yl)-5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Step 8 of Example 1. 1H NMR(500MHz,DMSO-d6)δ11.22(s,1H), 8.59(s,1H), 7.88(s,1H), 7.75-7.43(m,2H), 7.35-7.21(m,3H), 6.7 1(s,1H), 5.32(s,2H), 5.21-4.65(m,3H), 3.68-3.55(m,2H), 3.53-3.45(m,2H), 3.16(s,6H), 2.14(s,3H). LC-MS(M+H) + =496.3.

[0394] Example B3: 5-amino-N-(3,3-difluorocyclobutyl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0395] Step 1: 5-(2,6-difluorophenyl)picolinaldehyde [ka]

[0396] To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinaldehyde (62 g, 266 mmol) and 1,3-difluoro-2-iodobenzene (95.8 g, 399 mmol) in dioxane (600 mL), toluene (300 mL), and water (300 mL) was added Pd(dppf)Cl (9.73 g, 13.3 mmol) and KPO (141 g, 665 mmol). The mixture was stirred at 85 °C for 16 h, cooled to room temperature, and poured into water (1000 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (800 mL × 2). The combined organic layers were washed with brine (500 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EtOAc = 50:1 to 5:1) to give the title compound (30 g, 51%). LC-MS (M+H) + =220.2.

[0397] Step 2: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-3,3-difluorocyclobutan-1-amine [ka]

[0398] The title compound (50 mg, 35%) was prepared from 5-(2,6-difluorophenyl)picolinaldehyde and 3,3-difluorocyclobutan-1-amine in a manner similar to that of Step 6 of Example 1. LC-MS (M+H) + =311.1.

[0399] Step 3: N-(3,3-difluorocyclobutyl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0400] The title compound (35 mg, 55%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-3,3-difluorocyclobutan-1-amine in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =778.1.

[0401] Step 4: 5-amino-N-(3,3-difluorocyclobutyl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0402] To a solution of N-(3,3-difluorocyclobutyl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (35 mg, 0.04 mmol) in DCM (6 mL) was added TFA (6 mL). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The mixture was then treated with HCl (4 M in methanol, 4 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, and the residue was redissolved in MeOH (10 mL) / water (2 mL), followed by the addition of KCO (31 mg, 0.20 mmol). The mixture was stirred at 50° C. for 2 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC to give Example 3 (3 mg, 14%). 1 H NMR(500MHz,DMSO-d6)δ11.34(s,1H), 8.66(s,1H), 8.04-7.85(m,1H), 7.52(s,2H), 7.37- 7.21(m,3H), 6.37(s,1H), 5.35(s,2H), 5.20-4.44(m,3H), 3.04-2.84(m,4H), 2.14(s,3H). LC-MS(M+H) + =484.3.

[0403] Example B4: 5-amino-N-cyclopropyl-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0404] Step 1: N-((5-phenylpyridin-2-yl)methyl)cyclopropanamine [ka]

[0405] The title compound (150 mg, 61%) was prepared from 5-phenylpicolinaldehyde and cyclopropylamine in a similar manner to Step 6 of Example 1. LC-MS (M+H) + =225.1.

[0406] Step 2: N-cyclopropyl-5-((diphenylmethylene)amino)-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0407] The title compound (20 mg, 70%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-((5-phenylpyridin-2-yl)methyl)cyclopropanamine in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =692.3.

[0408] Step 3: 5-amino-N-cyclopropyl-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0409] Example 4 (1.6 mg, 14%) was prepared from N-cyclopropyl-5-((diphenylmethylene)amino)-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Step 8 of Example 1. 1H NMR(500MHz,DMSO-d6)δ11.17(s,1H), 8.83(d,J=1.9Hz,1H), 8.05(dd,J=8.2,2.3Hz,1H), 7.72(d,J=7.3Hz,2H), 7.50(t,J=7.6Hz,2 H), 7.45-7.33(m,3H), 6.93(s,1H), 5.34(s,2H), 4.88(s,2H), 2.16(s,3H), 2.04-1.91(m,1H), 1.33-1.23(m,2H), 0.95-0.82(m,2H). LC-MS(M+H) + =398.3.

[0410] Example B5: 5-amino-N-(cyclopropylmethyl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0411] Step 1: 1-Cyclopropyl-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)methanamine [ka]

[0412] The title compound (36 mg, 14%) was prepared from 5-(2,6-difluorophenyl)picolinaldehyde and cyclopropylmethanamine in a manner similar to Step 6 of Example 1. LC-MS (M+H) + =275.1.

[0413] Step 2: N-(cyclopropylmethyl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0414] The title compound (13 mg, 24%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and 1-cyclopropyl-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)methanamine in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =742.3.

[0415] Step 3: 5-amino-N-(cyclopropylmethyl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0416] Example 5 (1.6 mg, 14%) was prepared from N-(cyclopropylmethyl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Step 8 of Example 1. 1 H NMR(500MHz,CD3OD)δ8.82-8.50(m,1H), 7.95(s,1H), 7.58(d,J=8.1Hz,1H), 7.52(s,1H), 7.47(dt,J=14.9,7.6Hz,1H), 7.14(t,J=8.0Hz,2H) , 6.0Hz,2H), 6.59(s,1H), 5.39-4.98(m,2H), 3.97-3.44(m,2H), 2.25( s,3H), 1.22-1.07(m,1H), 0.54(d,J=7.3Hz,2H), 0.26(d,J=4.7Hz,2H). LC-MS(M+H) + =448.3.

[0417] Example B6 and Example B7: 5-amino-N-((1r,3r)-3-methoxycyclobutyl)-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide and 5-amino-N-((1s,3s)-3-methoxycyclobutyl)-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0418] Step 1: tert-butyl ((5-phenylpyridin-2-yl)methyl)carbamate [ka]

[0419] To a solution of 5-phenylpicolinonitrile (12.0 g, 66.6 mmol), BocO (29.1 g, 133 mmol), and NiCl (1.73 g, 13.3 mmol) in MeOH (150 mL) was added NaBH (15.1 g, 400 mmol) slowly at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature for 12 h and then slowly added to ice water (1 L). The mixture was extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1) to give the title compound (6.0 g, 32%). LC-MS (M+H) + =285.1.

[0420] Step 2: (5-phenylpyridin-2-yl)methanamine [ka]

[0421] The title compound (1.93 g, 99%) was prepared from tert-butyl ((5-phenylpyridin-2-yl)methyl)carbamate in a similar manner to Step 2 of Example 2. LC-MS (M+H) + =185.3.

[0422] Step 3: 3-Methoxy-N-((5-phenylpyridin-2-yl)methyl)cyclobutan-1-amine [ka]

[0423] The title compound (90 mg, 19%) was prepared from (5-phenylpyridin-2-yl)methanamine and 3-methoxycyclobutan-1-one in a manner similar to that of Step 6 of Example 1. LC-MS (M+H) + =269.2.

[0424] Step 4: 5-((diphenylmethylene)amino)-N-(3-methoxycyclobutyl)-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0425] The title compound (20 mg, 26%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and 3-methoxy-N-((5-phenylpyridin-2-yl)methyl)cyclobutan-1-amine in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =736.3.

[0426] Step 5. 5-Amino-N-((1r,3r)-3-methoxycyclobutyl)-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide, and 5-amino-N-((1s,3s)-3-methoxycyclobutyl)-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0427] Example 6 (2 mg, 17%) and Example 7 (1.6 mg, 13%) were prepared from 5-((diphenylmethylene)amino)-N-(3-methoxycyclobutyl)-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Example 1, Step 8.

[0428] Example 6: 1 H NMR(500MHz,DMSO-d6)δ11.23(s,1H), 8.81(s,1H), 8.01(d,J=7.6Hz,1H), 7.68(d ,J=7.4Hz,2H), 7.44(t,J=7.6Hz,2H), 7.35(t,J=7.3Hz,1H), 7.30(d,J=7.7Hz,1H ), 7.26(s,1H), 6.49-6.06(m,1H), 5.24(s,2H), 4.89(s,2H), 4.69-4.37(m,1H), 3 .60-3.48(m,1H), 3.03(s,3H), 2.56-2.47(m,2H), 2.07(s,3H), 1.98-1.85(m,2H). LC-MS(M+H) + =442.3.

[0429] Example 7: 1H NMR(500MHz,DMSO-d6)δ11.23(s,1H), 8.80(s,1H), 8.00(d,J=7.0Hz,1H), 7.67 (d,J=7.2Hz,2H), 7.44(t,J=7.5Hz,2H), 7.35(t,J=7.3Hz,1H), 7.29(d,J=8.0Hz ,1H), 7.26(s,1H), 6.45-6.14(m,1H), 5.37-5.03(m,3H), 4.89(s,2H), 3.84-3.7 3(m,1H), 3.09-3.01(m,3H), 2.36-2.25(m,2H), 2.23-2.14(m,2H), 2.07(s,3H). LC-MS(M+H) + =442.4.

[0430] Example B8: 5-amino-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-N-(tetrahydro-2H-pyran-3-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0431] Step 1: N-((5-phenylpyridin-2-yl)methyl)tetrahydro-2H-pyran-3-amine [ka]

[0432] The title compound (25 mg, 41%) was prepared from (5-phenylpyridin-2-yl)methanamine and dihydro-2H-pyran-3(4H)-one in a manner similar to that of Step 6 of Example 1. LC-MS (M+H) + =269.2.

[0433] Step 2: 5-((diphenylmethylene)amino)-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-N-(tetrahydro-2H-pyran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0434] The title compound (50 mg, 82%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-((5-phenylpyridin-2-yl)methyl)tetrahydro-2H-pyran-3-amine in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =736.6.

[0435] Step 3: 5-amino-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-N-(tetrahydro-2H-pyran-3-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0436] Example 8 (13 mg, 44%) was prepared from 5-((diphenylmethylene)amino)-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-N-(tetrahydro-2H-pyran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Example 1, Step 8. 1 H NMR(500MHz,DMSO-d6)δ11.30(s,1H), 8.88(s,1H), 8.07(d,J=5.7Hz,1H), 7.75(d,J=7.4Hz,2H), 7.52-7.41(m,5H), 7.34(s,1H), 5.30(s,2H), 4.93( s,2H), 4.51(s,1H), 3.87(s,1H), 3.74(d,J=9.4Hz,1H), 3.44(t,J=10.3Hz ,1H), 3.24(t,J=10.9Hz,1H), 2.14(s,3H), 2.01-1.77(m,2H), 1.65(s,2H). LC-MS (M+H) + =442.3.

[0437] Example B9: 5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0438] Step 1: (3R,4R)-3-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)amino)tetrahydro-2H-pyran-4-ol [ka]

[0439] To a solution of (3R,4R)-3-aminotetrahydro-2H-pyran-4-ol (120 mg, 1.02 mmol) and 5-(2,6-difluorophenyl)picolinaldehyde (224 mg, 1.02 mmol) in DCM (10 mL) was added NaBH(OAc)3 (430 mg, 2.03 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 1 / 1) to give the title compound (200 mg, 61%). LCMS (M+H) + =321.1.

[0440] Step 2: tert-butyl ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl) ((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate [ka]

[0441] To a solution of (3R,4R)-3-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)amino)tetrahydro-2H-pyran-4-ol (200 mg, 0.62 mmol) in DCM (10 mL) was added BocO (164 mg, 0.75 mmol) and EtN (188 mg, 1.86 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 2 / 1) to give the title compound (230 mg, 88%). LCMS (M+H) + =421.1.

[0442] Step 3: tert-butyl ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)carbamate [ka]

[0443] To a mixture of tert-butyl ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl) ((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate (230 mg, 0.55 mmol) and MeI (78 mg, 0.55 mmol) in DMF (10 mL) was added NaH (60%, 29 mg, 0.72 mmol) at 0 °C. The mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The mixture was diluted with ice water (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 2 / 1) to give the title compound (230 mg, 96%). LCMS (M+H) + =435.1.

[0444] Step 4: (3R,4R)—N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-4-methoxytetrahydro-2H-pyran-3-amine hydrochloride [ka]

[0445] A mixture of tert-butyl ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl) ((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)carbamate (230 mg, 0.53 mmol) in HCl (4 M in MeOH, 5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (180 mg, 92%). LCMS (M+H) + =335.1.

[0446] Step 5: 5-Amino-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid [ka]

[0447] A mixture of 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (1.7 g, 3.5 mmol) in TFA (10 mL) / DCM (10 mL) was stirred at 30 °C for 4 h. The mixture was concentrated under reduced pressure and treated with aqueous hydrochloric acid (1 M, 15 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was treated with aqueous K2CO3 (1 M, 10 mL) and MeOH (10 mL), and the mixture was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure, and the crude was purified by C18 chromatography (10% aqueous MeCN with 0.03% formic acid) to give the title compound (0.60 g, 90%). LCMS (M+H) + =192.2.

[0448] Step 6: 5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0449] A mixture of 5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (50 mg, 0.26 mmol) in SOCl (2 mL) was stirred at 60 °C under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in DCM (5 mL), cooled to room temperature, and (3R,4R)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-4-methoxytetrahydro-2H-pyran-3-amine hydrochloride (96 mg, 0.26 mmol) and EtN (131 mg, 1.3 mmol) were added under a nitrogen atmosphere. The mixture was warmed to room temperature and stirred for 3 hours. The mixture was diluted with water (10 mL) and extracted with DCM (10 mL × 2). The combined organic layers were washed with brine (10 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (15 mg, 11%). 1 H NMR(500MHz,DMSO-d6)δ11.54-11.20(m,1H), 8.80-8.48(m,1H), 8.02-7. 75(m,1H), 7.72-7.43(m,2H), 7.43-7.33(m,1H), 7.32-7.12(m,2H), 6.77- 6.16(m,1H), 5.74-5.32(m,2H), 5.22-4.43(m,3H), 4.29-4.03(m,1H), 3. 92-3.48(m,3H), 3.15-3.10(m,3H), 2.22-2.08(m,4H), 1.45-1.20(m,1H). LCMS(M+H) + =508.3.

[0450] Example B10: 5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(1-methoxy-3,3-dimethylbutan-2-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0451] Step 1: tert-butyl (1-hydroxy-3,3-dimethylbutan-2-yl)carbamate [ka]

[0452] To a solution of 2-amino-3,3-dimethylbutan-1-ol (1.0 g, 8.55 mmol) in DCM (20 mL) were added EtN (1.72 g, 17.1 mmol) and BocO (2.79 g, 12.8 mmol) at 0 °C. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL). The organic layer was washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EtOAc = 10:1) to give the title compound (1.6 g, 86%). LC-MS (M+H) + =218.2.

[0453] Step 2: tert-butyl (1-methoxy-3,3-dimethylbutan-2-yl)carbamate [ka]

[0454] To a solution of tert-butyl (1-hydroxy-3,3-dimethylbutan-2-yl)carbamate (700 mg, 3.22 mmol) in MeCN (8 mL) was added AgO (1.19 g, 5.16 mmol) and MeI (2.29 g, 16.1 mmol). The mixture was stirred in a sealed tube at 70 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL × 2), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EtOAc = 10:1) to give the title compound (600 mg, 80%).

[0455] Step 3: 1-Methoxy-3,3-dimethylbutan-2-amine hydrochloride [ka]

[0456] To tert-butyl (1-methoxy-3,3-dimethylbutan-2-yl)carbamate (600 mg, 2.60 mmol) was added HCl (4 M in dioxane), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo to give the title compound (440 mg, 100%). LC-MS (M+H) + =132.1.

[0457] Step 4: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-1-methoxy-3,3-dimethylbutan-2-amine [ka]

[0458] To a mixture of 1-methoxy-3,3-dimethylbutan-2-amine hydrochloride (150 mg, 0.90 mmol) in DCM (5 mL) was added 5-(2,6-difluorophenyl)picolinaldehyde (198 mg, 0.90 mmol), EtN (91 mg, 0.90 mmol), and NaBH(OAc) (383 mg, 1.81 mmol). The mixture was stirred at room temperature for 16 h. The mixture was carefully added to saturated NaHCO (50 mL) and then extracted with DCM (50 mL). The organic layer was washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM:MeOH = 10:1) to give the title compound (200 mg, 66%). LC-MS (M+H) + =335.3.

[0459] Step 5: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-N-(1-methoxy-3,3-dimethylbutan-2-yl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide [ka]

[0460] To a solution of 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (50 mg, 0.10 mmol) in DCM (6 mL) was added DMF (2 drops) and (COCl) (25 mg, 0.20 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was transferred to a solution of N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-1-methoxy-3,3-dimethylbutan-2-amine (40 mg, 0.12 mmol) and DIPEA (25 mg, 0.2 mmol) in DCM (6 mL). The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was purified by silica gel chromatography (DCM:MeOH=20:1) to give the title compound (55 mg, 667%). LC-MS (M+H)+ = 802.2.

[0461] Step 6: 5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(1-methoxy-3,3-dimethylbutan-2-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0462] Example 10 (17 mg, 49%) was prepared from N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenylmethylene)amino)-N-(1-methoxy-3,3-dimethylbutan-2-yl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to Example 1, Step 8. 1 H NMR(500MHz,DMSO-d6)δ11.30-11.11(m,1H), 8.66-8.52(m,1H), 7.94-7.80(m,1H), 7.61-7.44(m,2H), 7.38-7.18(m,3 H), 6.80-6.23(m,1H), 5.45-4.48(m,5H), 3.76-3.41(m,2H), 3.26-2.88(m,3H), 2.20-2.07(m,3H), 1.11-0.87(m,9H). LC-MS(M+H) + =508.4.

[0463] Cytotoxicity of compounds in HCT116 isogenic pairs The HCT116 cell line was obtained from ATCC (CCL-247). This cell line contains a mutation at codon 13 of the ras proto-oncogene and can be used as a positive control for PCR assays of mutations at this codon. HCT116-MTAP-KO is a HCT116 cell line in which the MTAP gene has been knocked out; one single clone was passaged for this assay. HCT116-mock-RNA-KO is a knockout-mock-gene-based HCT116 cell line containing the wild-type MTAP gene. The base medium for the isogenic pair of HCT116 is RPMI 1640 and HEPES (Gibco, 22400105). To make complete growth medium, add the following components to the base medium: fetal bovine serum to a final concentration of 10% (Gibco, 10099-141C). Cell lines were grown at 37°C in a humidified 5% CO2 atmosphere and periodically tested for the presence of mycoplasma using the MycoAlert™ PLUS Mycoplasma Detection Kit (Lonza, LT07-710).

[0464] experiment HCT116-mock-RNA-KO cells (400 / well) or HCT116-MTAP-KO cells (400 / well) were seeded into a 96-well plate (Greiner: 655090) at 100 μL / well. Incubate overnight at 37°C and 5% CO2. Add 50 μL of fresh growth medium containing serially diluted compounds to each well, resulting in final compound concentrations ranging from 0 to 10 μM. Incubate at 37°C and 5% CO2 for 6 days. Cell viability was detected using Cell Titer-Glo (Promega, G7573). Add 70 μL of CellTiter-Glo® reagent to each well. Incubate at room temperature for 10 minutes to stabilize the luminescent signal. Analyze with a microplate reader (TECAN, SPARK) and use Prism® 9 for IC50 Adapt the

[0465] The compounds disclosed herein exhibited cell killing activity values ​​as shown in Table 1. [Table 1]

Claims

1. A compound of formula (X), 【Chemistry 171】 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof. (In the formula, Z １ , Z ２ , Z ３ and Z ４ are each independently N or CR Ｚ Selected from: In each of its occurrences, R Ｚ are independently hydrogen, halogen, -C １－４ Alkyl or -C １－４ alkoxy, wherein said -C １－４ Alkyl or -C １－４ each alkoxy is optionally substituted with at least one substituent selected from halogen; Ar is selected from phenyl or 5- to 6-membered heteroaryl, each of said phenyl or 5- to 6-membered heteroaryl having at least one substituent R Ａｒ optionally substituted with R Ａｒ are each independently hydrogen, halogen, or —C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ Cycloalkyl, —C ３ -C ６ cycloalkoxy, or —CN, wherein said —C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ cycloalkyl, or —C ３ -C ６ Each cycloalkoxy is optionally substituted with at least one substituent selected from halogen; R Ｘ is R １ or 【Chemistry 172】 That is, R １ are each independently -C １－８ Alkyl, -C ３ -C ８ cycloalkyl (preferably mono-, bridged, fused, or helical cycloalkyl), or 3- to 8-membered saturated heterocyclyl (preferably mono-, bridged, fused, or helical heterocyclyl), wherein said -C １－８ Alkyl, -C ３ -C ８ Each cycloalkyl (preferably mono-, bridged, fused, or helical cycloalkyl) or 3- to 8-membered saturated heterocyclyl (preferably mono-, bridged, fused, or helical heterocyclyl) may contain at least one substituent R １ａ optionally substituted with R １ａ are each independently a halogen, —C １－４ Alkyl, -C ３ -C ６ cycloalkyl, 3- to 6-membered saturated heterocyclyl, —C １－４ Alkoxy, -C ３ -C ６ Cycloalkoxy, —CN, —OH, —NH ２ or oxo, wherein said -C １－４ Alkyl, -C ３ -C ６ cycloalkyl, 3- to 6-membered saturated heterocyclyl, —C １－４ Alkoxy, or -C ３ -C ６ Each cycloalkoxy is selected from the group consisting of halogen, —C １－４ Alkyl, -C ３ -C ６ cycloalkyl, 3- to 6-membered saturated heterocyclyl, —C １－４ Alkoxy, -C ３ -C ６ Cycloalkoxy, —CN, —OH, —NH ２ or oxo, G is CH ２ , O, or NH, provided that G is NH and NH is R ５ When substituted with ５ is not a halogen, Z ５ , Z ６ , Z ７ and Z ８ are each independently N or C Ｒ１ is selected from the group consisting of ５ , Z ６ , Z ７ and Z ８ At least one of them is N and the others are CR Ｚ１ and Z ５ and Z ８ is not N at the same time, In each of its occurrences, R Ｚ１ are independently hydrogen, halogen, -C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ cycloalkyl, or —C ３ -C ６ cycloalkoxy, wherein said -C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ cycloalkyl, or —C ３ -C ６ Each cycloalkoxy is selected from the group consisting of halogen, —C １－４ Alkoxy, -CN, -OH, -NH ２ or oxo, In each of its occurrences, R ５ are independently hydrogen, halogen, -C １－４ Alkyl, or -C ３ -C ６ cycloalkyl, wherein —C １－４ Alkyl or -C ３ -C ６ Cycloalkyl is substituted with halogen, —C １－４ Alkoxy, -CN, -OH, -NH ２ or oxo, or Two Germinal R ５ and the carbon atoms to which they are attached form a 3- to 5-membered carbocyclic ring, wherein the ring is free of halogen, —C １－４ Alkoxy, -CN, -OH, -NH ２ or oxo, n is 0, 1, 2, 3 or 4; r is 0 or 1; R ２ is hydrogen, halogen, -C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ Cycloalkyl, —C ３ -C ６ cycloalkoxy, or —CN, wherein said —C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ Cycloalkyl or -C ３ -C ６ Each cycloalkoxy is selected from the group consisting of halogen, —C １－４ Alkoxy, or -C ３ -C ６ optionally substituted with at least one substituent selected from cycloalkoxy; R ３ is hydrogen, halogen, -C １－４ alkyl, or —CN, where —C １－４ Alkyl is hydrogen, halogen, -C １－ 4 alkoxy, -C ３ -C ６ Cycloalkyl, —CN, —OH, —NH ２ or oxo, R ４ is hydrogen, halogen, -C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ cycloalkyl, or —C ３ -C ６ cycloalkoxy, wherein said -C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ cycloalkyl, or —C ３ -C ６ Each cycloalkoxy is selected from the group consisting of halogen, —C １－４ Alkoxy, -C ３ -C ６ Cycloalkoxy, —CN, —OH, —NH ２ or oxo.

2. The compound has the formula (AI): 【Chemistry 173】 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof. (In the formula, Z １ , Z ２ , Z ３ and Z ４ are each independently N or CR Ｚ Selected from: In each of its occurrences, R Ｚ are independently hydrogen, halogen, -C １－４ Alkyl or -C １－４ alkoxy, wherein said -C １－４ Alkyl or -C １－４ each alkoxy is optionally substituted with at least one substituent selected from halogen; Ar is selected from phenyl or 5- to 6-membered heteroaryl, each of said phenyl or 5- to 6-membered heteroaryl having at least one substituent R Ａｒ optionally substituted with R Ａｒ are each independently hydrogen, halogen, or —C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ Cycloalkyl, —C ３ -C ６ cycloalkoxy, or —CN, wherein said —C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ cycloalkyl, or —C ３ -C ６ Each cycloalkoxy is optionally substituted with at least one substituent selected from halogen; G is CH ２ , O, or NH, provided that G is NH and NH is R ５ When substituted with ５ is not a halogen, Z ５ , Z ６ , Z ７ and Z ８ are each independently N or CR １ is selected from the group consisting of ５ , Z ６ , Z ７ and Z ８ At least one of them is N and the others are CR Ｚ１ That is, In each of its occurrences, R Ｚ１ are independently hydrogen, halogen, -C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ cycloalkyl, or —C ３ -C ６ cycloalkoxy, wherein said -C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ cycloalkyl, or —C ３ -C ６ Each cycloalkoxy is selected from the group consisting of halogen, —C １－４ Alkoxy, -CN, -OH, -NH ２ or oxo, R ２ is hydrogen, halogen, -C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ Cycloalkyl, —C ３ -C ６ cycloalkoxy, or —CN, wherein said —C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ Cycloalkyl or -C ３ -C ６ Each cycloalkoxy is selected from the group consisting of halogen, —C １－４ Alkoxy, or -C ３ -C ６ optionally substituted with at least one substituent selected from cycloalkoxy; R ３ is hydrogen, halogen, -C １－４ alkyl, or —CN, where —C １－４ Alkyl is hydrogen, halogen, -C １－ 4 alkoxy, -C ３ -C ６ Cycloalkyl, —CN, —OH, —NH ２ or oxo, R ４ is hydrogen, halogen, -C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ cycloalkyl, or —C ３ -C ６ cycloalkoxy, wherein said -C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ cycloalkyl, or —C ３ -C ６ Each cycloalkoxy is selected from the group consisting of halogen, —C １－４ Alkoxy, -C ３ -C ６ Cycloalkoxy, —CN, —OH, —NH ２ or oxo, In each of its occurrences, R ５ are independently hydrogen, halogen, -C １－４ Alkyl, or -C ３ -C ６ cycloalkyl, wherein —C １－４ Alkyl or -C ３ -C ６ Cycloalkyl is substituted with halogen, —C １－４ Alkoxy, -CN, -OH, -NH ２ or oxo, or Two Germinal R ５ and the carbon atoms to which they are attached form a 3- to 5-membered carbocyclic ring, wherein the ring is free of halogen, —C １－４ Alkoxy, -CN, -OH, -NH ２ or oxo, n is 0, 1, 2, 3 or 4; r is 0 or 1.

3. The compound has the formula (BI): 【Chemistry 174】 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof. (In the formula, Z １ , Z ２ , Z ３ and Z ４ are each independently N or CR Ｚ Selected from: In each of its occurrences, R Ｚ are each independently hydrogen, halogen, or —C １－４ Alkyl or -C １－４ alkoxy, wherein said -C １－４ Alkyl or -C １－４ each alkoxy is optionally substituted with at least one substituent selected from halogen; Ar is independently selected from phenyl or 5- to 6-membered heteroaryl, wherein each of said phenyl or 5- to 6-membered heteroaryl is selected from at least one substituent R Ａｒ optionally substituted with R Ａｒ are each independently hydrogen, halogen, or —C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ Cycloalkyl, —C ３ -C ６ cycloalkoxy, or —CN, wherein said —C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ cycloalkyl, or —C ３ -C ６ Each cycloalkoxy is optionally substituted with at least one substituent selected from halogen; R １ are each independently -C １－８ Alkyl, -C ３ -C ８ cycloalkyl (preferably mono-, bridged, fused, or helical cycloalkyl), or 3- to 8-membered saturated heterocyclyl (preferably mono-, bridged, fused, or helical heterocyclyl), wherein said -C １－８ Alkyl, -C ３ -C ８ Each cycloalkyl (preferably mono-, bridged, fused, or helical cycloalkyl) or 3- to 8-membered saturated heterocyclyl (preferably mono-, bridged, fused, or helical heterocyclyl) may contain at least one substituent R １ａ optionally substituted with R １ａ are each independently a halogen, —C １－４ Alkyl, -C ３ -C ６ cycloalkyl, 3- to 6-membered saturated heterocyclyl, —C １－４ Alkoxy, -C ３ -C ６ Cycloalkoxy, —CN, —OH, —NH ２ or oxo, wherein said -C １－４ Alkyl, -C ３ -C ６ cycloalkyl, 3- to 6-membered saturated heterocyclyl, —C １－４ Alkoxy, or -C ３ -C ６ Each cycloalkoxy is selected from the group consisting of halogen, —C １－４ Alkyl, -C ３ -C ６ cycloalkyl, 3- to 6-membered saturated heterocyclyl, —C １－４ Alkoxy, -C ３ -C ６ Cycloalkoxy, —CN, —OH, —NH ２ or oxo, R ２ is hydrogen, halogen, -C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ Cycloalkyl, —C ３ -C ６ cycloalkoxy, or —CN, wherein said —C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ Cycloalkyl or -C ３ -C ６ Each cycloalkoxy is selected from the group consisting of halogen, —C １－４ Alkoxy, or -C ３ -C ６ optionally substituted with at least one substituent selected from cycloalkoxy; R ３ is hydrogen, halogen, -C １－４ alkyl, or —CN, where —C １－４ Alkyl is hydrogen, halogen, -C １－ 4 alkoxy, -C ３ -C ６ Cycloalkyl, —CN, —OH, —NH ２ or oxo, R ４ is hydrogen, halogen, -C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ cycloalkyl, or —C ３ -C ６ cycloalkoxy, wherein said -C １－４ Alkyl, -C １－４ Alkoxy, -C ３ -C ６ cycloalkyl, or —C ３ -C ６ Each cycloalkoxy is selected from the group consisting of halogen, —C １－４ Alkoxy, -C ３ -C ６ Cycloalkoxy, —CN, —OH, —NH ２ or oxo.

4. 2. The compound of claim 1, wherein the compound is selected from formula (AIIa), (AIIb), (AIIc) or (AIId). 【Chemistry 175】 (In the formula, R ２ , R ３ , R ４ , R ５ , Z １ , Z ２ , Z ３ , Z ４ , Z ５ , Z ６ , Z ７ , Z ８ , Ar, G and n are defined as in claim 1.

5. 2. The compound of claim 1, wherein the compound is selected from formula (AIIe), (AIIf), (AIIg), (AIIh), (AIIi), (AIIj), (AIIk), (AIIl), (AIIm) or (AIIn). 【Chemistry 176-1】 【Chemistry 176-2】 (In the formula, R Ｚ１ , R ２ , R ３ , R ４ , R ５ , Z １ , Z ２ , Z ３ , Z ４ , Ar and n are defined as in claim 1.

6. 2. The compound of claim 1, wherein the compound is of formula (AIIIa), (AIIIb), (AIIIc), (AIIId), (AIIIe), (AIIIf) or (AIIIg). 【Chemistry 177】 (In the formula, R ２ , R ３ , R ４ , R ５ , R Ｚ , Z ５ , Z ６ , Z ７ , Z ８ , G, n and r are defined as in claim 1.

7. 2. The compound of claim 1, wherein the compound is of formula (AIVa), (AIVb), or (AIVc). 【Chemistry 178】 (In the formula, X １ , X ２ and X ３ are each independently selected from N or CH, with the proviso that X １ , X ２ or X ３の If any one is CH, CH is R Ａｒ optionally substituted with X ４ are each independently selected from N, O or S; R ２ , R ３ , R ４ , R ５ , R Ａｒ , Z １ , Z ２ , Z ３ , Z ４ , Z ５ , Z ６ , Z ７ , Z ８ , G, and n and r are defined as in claim 1.

8. 2. The compound of claim 1, wherein the compound is of formula (BIIa), (BIIb), (BIIc), (BIId), (BIIe), (BIIf) or (BIIg). 【Chemistry 179】 (In the formula, R １ , R ２ , R ３ , R ４ , R Ｚ , Ar are defined as in claim 1.

9. 2. The compound of claim 1, wherein the compound is of formula (BIIIa), (BIIIb), or (BIIIc). 【Chemistry 180】 (In the formula, X １ , X ２ and Ｘ３ are each independently selected from N or CH, with the proviso that X １ , X ２ or X ３ is CH, then CH is R Ａｒ optionally substituted with X ４ are each independently selected from NH, O, or S, with the proviso that X ４ is NH, then NH is Ａｒ optionally substituted with R １ , R ２ , R ３ , R ４ , R Ａｒ , Z １ , Z ２ , Z ３ and Z ４ is defined as in claim 1.)

10. 2. The compound of claim 1, wherein the compound is of formula (BIIId), (BIIIe), (BIIIf), (BIIIg), (BIIIh) or (BIIIi). 【Chemistry 181】 (In the formula, Ring A is -C ３ -C ８ cycloalkyl (preferably mono-, bridged, fused, or helical cycloalkyl), or 3- to 8-membered saturated heterocyclyl (preferably mono-, bridged, fused, or helical heterocyclyl), wherein said -C ３ -C ８ Each cycloalkyl (preferably mono-, bridged, fused, or helical cycloalkyl) or 3- to 8-membered saturated heterocyclyl (preferably mono-, bridged, fused, or helical heterocyclyl) may contain at least one substituent R １ａ optionally substituted with X １ , X ２ and Ｘ３ are each independently selected from N or CH, with the proviso that X １ , X ２ or X ３ is CH, then CH is R Ａｒ optionally substituted with X ４ are each independently selected from NH, O, or S, with the proviso that X ４ is NH, then NH is Ａｒ optionally substituted with R １ａ , R ２ , R ３ , R ４ , R Ａｒ , Z １ , Z ２ , Z ３ and Z ４ is defined as in claim 1.)

11. R Ｚ１ is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy or cyclohexoxy (wherein each of said methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy or cyclohexoxy is —F, —Cl, —Br, —I, methoxy, ethoxy, propoxy, butoxy, —CN, —OH, —NH ２ or oxo.

12. R Ｚ１ is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl.

13. R Ｚ１ is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopropoxy or hydroxypropyl 【Chemistry 182】 10. A compound according to any one of the preceding claims, selected from:

14. R ５ is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl (wherein methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl are not —F, —Cl, —Br, —I, methoxy, ethoxy, propoxy, butoxy, —CN, —OH, —NH ２ or oxo).

15. R ５ is selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl); More preferably, R ５ 10. A compound according to any one of the preceding claims, wherein is selected from hydrogen, -F, -Cl, -Br, methyl, ethyl.

16. Two Germinal R ５ and the carbon atoms to which they are attached form a 3-, 4-, or 5-membered carbocyclic ring, wherein said ring is selected from the group consisting of -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, -CN, -OH, -NH ２ or oxo.

17. Two Germinal R ５ and the carbon atoms to which they are attached form a 3-, 4- or 5-membered carbocyclic ring.

18. Two Germinal R ５ and the carbon atoms to which they are attached form a three-membered carbocyclic ring.

19. G is CH ２ , O, or NH; Preferably, G is CH ２ま or O, A compound according to any one of the preceding claims.

20. 10. A compound according to any one of the preceding claims, wherein R １ is selected from methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-, 4-, 5-, 6-, 7- or 8-membered saturated monoheterocyclyl, 5-, 6-, 7- or 8-membered saturated bridged heterocyclyl, 4-, 5-, 6-, 7- or 8-membered saturated fused heterocyclyl, or 5-, 6-, 7- or 8-membered saturated spiral heterocyclyl, wherein said methyl each of 3-, 4-, 5-, 6-, 7-, or 8-membered saturated monoheterocyclyl, 5-, 6-, 7-, or 8-membered saturated bridged heterocyclyl, 4-, 5-, 6-, 7-, or 8-membered saturated fused heterocyclyl, or 5-, 6-, 7-, or 8-membered saturated helical heterocyclyl may contain at least one substituent R １ａ is optionally replaced by Each R1a independently represents -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-, 4-, 5- or 6-membered saturated heterocyclyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, -CN, -OH, or -NH ２ or oxo, wherein each of said methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-, 4-, 5- or 6-membered saturated heterocyclyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy is selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-, 4-, 5- or 6-membered saturated heterocyclyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, -CN, -OH, -NH ２ or oxo, The compound.

21. 10. A compound according to any one of the preceding claims, wherein R １ is selected from methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-, 4-, 5-, 6-, 7- or 8-membered saturated monoheterocyclyl, 5-, 6-, 7- or 8-membered saturated bridged heterocyclyl, 4-, 5-, 6-, 7- or 8-membered saturated fused heterocyclyl, or 5-, 6-, 7- or 8-membered saturated spiral heterocyclyl, each of the foregoing being selected from at least one substituent R １ａ is optionally replaced by Each R1a independently represents -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-, 4-, 5- or 6-membered saturated heterocyclyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, -CN, -OH, or -NH ２ or oxo, The compound.

22. 10. A compound according to any one of the preceding claims, wherein R １ is selected from methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl or pyrrolidinyl, wherein each of said methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl or pyrrolidinyl is selected from the group consisting of methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl or pyrrolidinyl, and １ａ is optionally replaced by Each R1a independently represents -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, -CN, -OH, or -NH ２ or oxo, The compound.

23. R １ but, 【Chemistry 183】 Selected from: A compound according to any one of the preceding claims.

24. R ２ is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, or —CN (wherein methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl) is substituted or unsubstituted; 2. A compound according to any one of the preceding claims, wherein the aryl, aryl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy.

25. R ２ is selected from hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopropoxy, cyclobutoxy or -CN, where methyl, ethyl is selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, cyclopropoxy or cyclobutoxy.

26. R ２ is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy or -CN.

27. R ２ A compound according to any one of the preceding claims, wherein is selected from hydrogen, methyl, ethyl or -CN.

28. R ３ is selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), or —CN, wherein methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl or tert-butyl) is selected from hydrogen, —F, —Cl, —Br, —I, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CN, —OH, —NH ２ or oxo.

29. R ３ 10. A compound according to any one of the preceding claims, wherein is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl) or -CN.

30. R ３ A compound according to any one of the preceding claims, wherein is selected from hydrogen, -F, -Cl, -Br, -I or -CN.

31. R ４ is selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy, wherein methyl, ethyl, propyl (isopropyl or n-propyl) butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy or cyclohexoxy are -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, -CN, -OH, -NH ２ or oxo.

32. R ４ is selected from hydrogen, —F, —Cl, —Br, methyl, ethyl, propyl (isopropyl or n-propyl), methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopropoxy, or cyclobutoxy, where methyl, ethyl, propyl (isopropyl or n-propyl), methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopropoxy, or cyclobutoxy is selected from —F, —Cl, —Br, —I, methoxy, ethoxy, propoxy, cyclopropoxy, cyclobutoxy, —CN, —OH, —NH ２ or oxo.

33. R ４ is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl or tert-butyl).

34. R ４ A compound according to any one of the preceding claims, wherein is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl.

35. Z １ , Z ２ , Z ３ and Z ４ At most two of these are N, and R Ｚ are each independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), methoxy, ethoxy, propoxy, or butoxy, wherein each of said ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), methoxy, ethoxy, propoxy, or butoxy is optionally substituted with at least one substituent selected from —F, —Cl, —Br, or —I.

36. R Ｚ are each independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, or butoxy.

37. R Ｚ 5. A compound according to any one of the preceding claims, wherein each is independently selected from hydrogen, -F, -Cl, -Br, methyl or ethyl.

38. Ar is independently selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, oxazolyl, furanyl, thiazolyl, or thiophenyl, each of said phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, oxazolyl, furanyl, thiazolyl, or thiophenyl being selected from the group consisting of at least one substituent R Ａｒ is optionally replaced by R Ａｒ are each independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, or —CN, wherein each of said methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy is optionally substituted with at least one substituent selected from —F, —Cl, —Br, or —I; A compound according to any one of the preceding claims.

39. Ar is independently selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, or 1,2,4-triazolyl, each of said phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, or 1,2,4-triazolyl being selected from the group consisting of at least one substituent R Ａｒ is optionally replaced by R Ａｒ each independently represents hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, —CF ３ or -CN; A compound according to any one of the preceding claims.

40. Ar is independently selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, or 1,2,4-triazolyl, each of said phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, or 1,2,4-triazolyl containing at least one substituent R Ａｒ optionally substituted with, where R Ａｒ are each independently hydrogen, —F, —Cl, —Br, methyl, ethyl, methoxy, ethoxy, or —CF ３ 8. A compound according to any one of the preceding claims, wherein the compound is selected from -CN, or -CN.

41. 10. The compound of any one of the preceding claims, wherein the compound is selected from the following: 【Chemistry 184-1】 【Chemistry 184-2】 【Chemistry 184-3】 【Chemistry 184-4】 【Chemistry 184-5】 【Chemistry 184-6】 【Chemistry 184-7】 【Chemistry 184-8】 【Chemistry 184-9】 【Chemistry 184-10】 【Chemistry 184-11】 【Chemistry 184-12】

42. 42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, together with a pharmaceutically acceptable excipient.

43. 42. A method of reducing PRMT5 activity by inhibition, comprising administering to an individual a compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, including a compound of formula (I) or the specific compounds exemplified herein.

44. 44. The method of claim 43, wherein the disease is selected from cancer.

45. 42. Use of a compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, in the preparation of a medicament for treating a disease modulated by PRMT5.

46. 46. ​​The use of claim 45, wherein the disease is cancer.

47. 47. The use of claim 46, wherein the disease is an MTAP-deficient solid tumor, including but not limited to lung cancer, bladder cancer, melanoma, pancreatic cancer, esophageal cancer, gastric adenocarcinoma, breast cancer or glioblastoma.

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