5-amino-1h-pyrrolo [3, 2-b] pyridine-2-carboxamide derivatives as MTA synergistic inhibitors of PRMT5

Abstract

Provided herein are compounds containing 5-amino-1H-pyrrolo [3, 2-b] pyridine-2-carboxamide derivatives as MTA synergistic inhibitors of PRMT5, their use for the selective inhibition of the activity of PRM T5 synergistic MTA in tumors carrying MTAPDEL mutations, and pharmaceutical compositions comprising said compounds for the treatment of various diseases, including cancer.

Description

Field of the Invention

[0001] The present disclosure provides a compound containing a 5-amino-1H-pyrrolo[3,2-b]pyridine-2-carboxamide derivative as an MTA co-inhibitor of PRMT5, which is used for selectively inhibiting PRMT5 co-inhibiting MTA in the presence of MTAP. DEL The present invention relates to a pharmaceutical composition comprising the compound for treating various diseases including cancer and a method for treating a variety of diseases including cancer. Background of the Invention

[0003] Epigenetic modification is a process that can modify genetic output, thereby changing the original DNA sequence. Epigenetic modification plays an important role in many aspects such as gene expression and regulation, protein production and cell differentiation. Generally, this process is reversible and selective to DNA, its regulatory proteins such as histones and other proteins such as transcription factors [Bradbury, EM, BioEssays, 1992, 14 (1): pp. 9-16]. PMT (protein methyltransferase) is the main participant of epigenetic modification, consisting of two subfamilies, i.e. PKMT (protein lysine methyltransferase) and PRMT (protein arginine methyltransferase) [Copel and RA et al., Oncogene, 2012.32 (8): pp. 939-46]. PMT is associated with a variety of human diseases and is considered to be a potential therapeutic target [Copel and RA et al., Oncogene, 2012, 32 (8): pp. 939-46].

[0004] As the name implies, PRMT catalyzes the methylation of protein arginine residues. In addition to its main function of methylating histone tails, PRMT also targets other cellular proteins, such as NAB2p, FOXO1, PABP1, Sm D1, etc. [Bedford, MT et al., Molecular Cell, 2005, 18 (3): p. 263-72]. According to the product classification, the nine mammalian PRMTs can be divided into three subtypes: type I (PRMT1, PRMT2, PRMT3, PRMT4, PRMT6 and PRMT8) catalyzes the formation of aDMA (asymmetric dimethylated arginine); type II (PRMT5, PRMT9) catalyzes sDMA (symmetric dimethylated arginine); and type III (PRMT7) catalyzes the formation of MMA (monomethylated arginine) [Yang, Y. et al., Nature Reviews Cancer, 2012, 13 (1): p. 37-50]. In addition, type I / II PRMTs can also catalyze the formation of MMA as intermediates of aDMA and sDMA. PRMTs contain a pocket that interacts with their cofactor SAM (S-adenosylmethionine) and an adjacent pocket that interacts with arginine residues on proteins, namely the SAM pocket and the substrate pocket. The methylation process involves the transfer of an activated methyl group from the cofactor SAM to the guanidinium group on the arginine residue. N 2. [Bedford, MT et al., Molecular Cell, 2005, 18(3): p. 263-72] A byproduct of the process is SAH (S-adenosyl-L-homocysteine).

[0005] For Arg:aDMA:MMA:sDMA, the total arginine level in the cell is approximately 1500:3:2:1, and PRMT5 accounts for the vast majority of sDMA formation [Dhar, S. et al., Scientific Reports, 2013, 3:1311]. In contrast to PRMT1 (the main type I PRMT that functions on its own in cells), PRMT5 binds to MEP50 (methyltransferase complex protein 50) to form a heterocomplex that is often elevated in cancer cells and is associated with poor patient survival [Gao, G. et al., Nucleic Acids Research, 2019, 47(10): p. 5038-48]. PRMT5 promotes tumorigenesis by multiple mechanisms. PRMT5 is a strong repressor of many genes; when PRMT5 methylates histones H2a and H4 on Arg3 and histone H3 on Arg8, it inhibits gene transcripts involved in differentiation, transformation, cell cycle progression, and tumor suppression [Karkhanis, V. et al., Trends in Biochemical Sciences, 2011, 36(12): p. 633-41]. In addition to its epigenetic effects, PRMT5 may also regulate RNA binding proteins, such as splicing factors. For example, reproducible events were observed in PRMT5 knockout mice, in which exon 6 skipping of MDM4 (mouse double minute 4) occurred and p53 was released to upregulate the p53 pathway [Gerhart, SV et al., Scientific Reports, 2018, 8: 9711]. In addition, PRMT5 can directly affect key proliferation pathways by directly methylating p53 [Jansson, M. et al., Nature Cell Biology, 2008, 10(12): p1431-9], EGFR [Hsu, J.-M. et al., Nature Cell Biology, 2011, 13(2): p174-81], PI3K [Wei, T.-YW, et al., Cellular Signaling, 2014, 26(12): p2940-50], etc. Therefore, PRMT5 is likely to become a clinically relevant target.

[0006] On the other hand, PRMT5 is an essential gene in normal tissues, and systemic inhibition of PRMT5 may lead to significant adverse consequences, especially hematological toxicity [Ahnert, JR et al., Journal of Clinical Oncology, 2021, 39(15 Suppl): p. 3019]. Therefore, for safer treatment, strategies to selectively block PRMT5 activity in tumor cells are needed.

[0007] Homozygous deletion of the tumor suppressor CDKN2A (cyclin-dependent kinase inhibitor 2A) occurs in approximately 15% of all tumor types. Interestingly, this mutation frequently involves co-deletion of neighboring genes present in 9p21, including the gene encoding MTAP (methylthioadenosine phosphorylase) [Firestone, RS et al., Journal of American Chemical Society, 2017, 139(39): p. 13754-60]. Due to MTAP deletion, MTAP's substrate MTA (methylthioadenosine) accumulates. MTA is structurally related to SAM and is a weak ligand / inhibitor of PRMT5 that occupies the same pocket as SAM. The formation of the MTA-PRMT5 complex provides an opportunity to further inhibit PRMT5 by forming a tertiary complex. In this way, the correlation between the MTAP null state and PRMT5 dependence is established by MTA concentration levels to provide precise tumor treatment.

[0008] Currently, most clinical-stage PRMT5 inhibitors cannot distinguish between normal and cancer cells based on SAM / MTA competition mechanisms (JNJ64619178, PF06939999, PRT543, and PRT811) or non-MTA synergistic mechanisms (GSK3326595). Therefore, there is still an unmet and ongoing medical need for potent and selective MTA-synergistic PRMT5 inhibitors. Summary of the Invention

[0009] One object of the present invention is to provide compounds and derivatives that act as PRMT5 inhibitors, as well as methods for their preparation and use.

[0010] Aspect 1. A compound of formula (X):

[0011]

[0012] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, wherein:

[0013] Z 1 , Z 2 , Z 3 and Z 4 Each independently selected from N or CR Z ;

[0014] At each occurrence, R Z are independently selected from hydrogen, halogen, -C 1-4 Alkyl or -C 1-4 Alkoxy; wherein the -C 1-4 Alkyl or -C1-4 Each of the alkoxy groups is optionally substituted with at least one substituent selected from halogen;

[0015] Ar is selected from phenyl or 5- to 6-membered heteroaryl, each of which is optionally substituted with at least one substituent R Ar replace,

[0016] R Ar are each independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy or -CN; wherein the -C 1-4 Alkyl, -C 1-4 Each of alkoxy, -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted with at least one substituent selected from halogen;

[0017] R X It is R 1 or

[0018] R 1 Each independently selected from -C 1-8 Alkyl, -C3-C8 cycloalkyl (preferably single, bridged, fused or spiral cycloalkyl) or 3- to 8-membered saturated heterocyclic group (preferably single, bridged, fused or spiral heterocyclic group); wherein the -C 1-8 Each of alkyl, -C3-C8 cycloalkyl (preferably mono-, bridged, fused or spiro cycloalkyl) or 3- to 8-membered saturated heterocyclic group (preferably mono-, bridged, fused or spiro heterocyclic group) is optionally substituted with at least one substituent R 1a replace;

[0019] R 1a are each independently selected from halogen, -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3-membered to 6-membered saturated heterocyclic group, -C 1-4 Alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo; wherein the -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3-membered to 6-membered saturated heterocyclic group, -C 1-4 Each of the alkoxy or -C3-C6 cycloalkoxy groups is optionally substituted by at least one selected from halogen, -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3-membered to 6-membered saturated heterocyclic group, -C 1-4 Alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo substituents;

[0020] G is selected from CH2, O or NH, provided that when G is NH and NH is replaced by R5 When substituted, R 5 Not halogen;

[0021] Z 5 , Z 6 , Z 7 and Z 8 Each independently selected from N or CR 1 , the prerequisite is that 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 Not at the same time N;

[0022] At each occurrence, R Z1 are independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy; wherein the -C 1-4 Alkyl, -C 1-4 Each of -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted by at least one selected from halogen, -C 1-4 Alkoxy, -CN, -OH, -NH2 or oxo substituents;

[0023] At each occurrence, R 5 are independently selected from hydrogen, halogen, -C 1-4 Alkyl or -C3-C6 cycloalkyl, wherein -C 1-4 Alkyl or -C3-C6 cycloalkyl is optionally substituted by at least one selected from halogen, -C 1-4 Alkoxy, -CN, -OH, -NH2 or oxo substituents; or

[0024] Two geminal R 5 Together with the carbon atoms to which they are attached, they form a 3- to 5-membered carbocyclic ring; wherein the ring is optionally substituted with at least one selected from halogen, -C 1-4 Alkoxy, -CN, -OH, -NH2 or oxo substituents;

[0025] n is 0, 1, 2, 3, or 4;

[0026] r is 0 or 1;

[0027] R 2 Selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy or -CN; wherein the -C1-4 Alkyl, -C 1-4 Each of -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted by at least one selected from halogen, -C 1-4 Alkoxy or -C3-C6 cycloalkoxy substituents;

[0028] R 3 Selected from hydrogen, halogen, -C 1-4 Alkyl or -CN, where -C 1-4 The alkyl group is optionally substituted with at least one selected from hydrogen, halogen, -C 1-4 Alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2 or oxo substituents;

[0029] R 4 Selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy, wherein the -C 1-4 Alkyl, -C 1-4 Each of -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted by at least one selected from halogen, -C 1-4 The substituents are substituted with alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo.

[0030] In aspect A1, the compound is of formula (AI):

[0031]

[0032] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, wherein:

[0033] Z 1 , Z 2 , Z 3 and Z 4 Each independently selected from N or CR Z ;

[0034] At each occurrence, R Z are independently selected from hydrogen, halogen, -C 1-4 Alkyl or -C 1-4 Alkoxy; wherein the -C 1-4 Alkyl or -C 1-4 Each of the alkoxy groups is optionally substituted with at least one substituent selected from halogen;

[0035] Ar is selected from phenyl or 5- to 6-membered heteroaryl, each of which is optionally substituted with at least one substituent RAr replace,

[0036] R Ar are each independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy or -CN; wherein the -C 1-4 Alkyl, -C 1-4 Each of alkoxy, -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted with at least one substituent selected from halogen;

[0037] G is selected from CH2, O or NH, provided that when G is NH and NH is replaced by R 5 When substituted, R 5 Not halogen;

[0038] Z 5 , Z 6 , Z 7 and Z 8 Each independently selected from N or CR 1 , the prerequisite is that 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 Not at the same time N;

[0039] At each occurrence, R Z1 are independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy; wherein the -C 1-4 Alkyl, -C 1-4 Each of -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted by at least one selected from halogen, -C 1-4 Alkoxy, -CN, -OH, -NH2 or oxo substituents;

[0040] R 2 Selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy or -CN; wherein the -C 1-4 Alkyl, -C 1-4 Each of -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted by at least one selected from halogen, -C 1-4Alkoxy or -C3-C6 cycloalkoxy substituents;

[0041] R 3 Selected from hydrogen, halogen, -C 1-4 Alkyl or -CN, where -C 1-4 The alkyl group is optionally substituted with at least one selected from hydrogen, halogen, -C 1-4 Alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2 or oxo substituents;

[0042] R 4 Selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy, wherein the -C 1-4 Alkyl, -C 1-4 Each of -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted by at least one selected from halogen, -C 1-4 Alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo substituents;

[0043] At each occurrence, R 5 are independently selected from hydrogen, halogen, -C 1-4 Alkyl or -C3-C6 cycloalkyl, wherein -C 1-4 Alkyl or -C3-C6 cycloalkyl is optionally substituted by at least one selected from halogen, -C 1-4 Alkoxy, -CN, -OH, -NH2 or oxo substituents; or

[0044] Two geminal R 5 Together with the carbon atoms to which they are attached, they form a 3- to 5-membered carbocyclic ring; wherein the ring is optionally substituted with at least one selected from halogen, -C 1-4 Alkoxy, -CN, -OH, -NH2 or oxo substituents;

[0045] n is 0, 1, 2, 3, or 4;

[0046] r is 0 or 1.

[0047] Aspect A2. The compound of Aspect 1, wherein the compound is selected from Formula (AIIa), (AIIb), (AIIc) or (AIId):

[0048]

[0049] Among them, R 2 、R 3 、R 4 、R 5 , Z 1 , Z2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Ar, G and n are as defined in aspect 1.

[0050] In some embodiments, the compound is selected from Formula (AIIe), (AIIf), (AIIg), (AIIh), (AIIi), (AIIj), (AIIk), (AIIl), (AIIm), or (AIIn):

[0051]

[0052]

[0053] Among them, R Z1 、R 2 、R 3 、R 4 、R 5 , Z 1 , Z 2 , Z 3 , Z 4 , Ar and n are as defined in aspect 1.

[0054] Aspect A3. The compound of Aspect 1, wherein the compound is of Formula (AIIIa), (AIIIb), (AIIIc), (AIIId), (AIIIe), (AIIIf) or (AIIIg):

[0055]

[0056] Among them, R 2 、R 3 、R 4 、R 5 、R Z , Z 5 , Z 6 , Z 7 , Z 8 , G, n and r are as defined in aspect 1.

[0057] Aspect A4. The compound of Aspect 1, wherein the compound is of formula (AIVa), (AIVb), (AIVc):

[0058]

[0059] Among them, X 1 、X 2 and X 3Each independently selected from N or CH, provided that when X 1 、X 2 or X 3 When any one of is CH, CH is optionally replaced by R Ar replace;

[0060] X 4 are each independently selected from N, O or S;

[0061] 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, n and r are as defined in aspect 1.

[0062] Aspect A5. A compound according to any of the preceding aspects, wherein R Z1 wherein each of the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, -CN, -OH, -NH or oxo.

[0063] Aspect A6. A compound according to any of the preceding aspects, wherein R Z1 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl.

[0064] In some embodiments, R Z1Selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopropyloxy or hydroxypropyl

[0065] Aspect A7. A compound according to any of the preceding aspects, wherein 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or -CN; 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy;

[0066] In some embodiments, R 2 is selected from hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy or -CN; wherein methyl, ethyl is optionally substituted by at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, cyclopropyloxy or cyclobutyloxy.

[0067] 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or -CN.

[0068] Aspect A8. A compound according to any of the preceding aspects, wherein R 2 is selected from hydrogen, methyl, ethyl or -CN.

[0069] Aspect A9. The compound of any of the preceding aspects, wherein 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, 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, -NH2 or oxo.

[0070] 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.

[0071] Aspect A10. The compound of any of the preceding aspects, wherein R 3 is selected from hydrogen, -F, -Cl, -Br, -I or -CN.

[0072] Aspect A11. A compound according to any of the preceding aspects, wherein R 4 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy, wherein 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -CN, -OH, -NH2 or oxo.

[0073] In some embodiments, R 4 is selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, propyl (isopropyl or n-propyl), methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopropyloxy or cyclobutyloxy, wherein methyl, ethyl, propyl (isopropyl or n-propyl), methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopropyloxy or cyclobutyloxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, cyclopropyloxy, cyclobutyloxy, -CN, -OH, -NH2 or oxo.

[0074] In some embodiments, R 4is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl) or butyl (n-butyl, sec-butyl, isobutyl or tert-butyl).

[0075] Aspect A12. The compound of any of the preceding aspects, wherein R 4 Selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl.

[0076] Aspect A13. A compound according to any of the preceding aspects, wherein 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, -NH2 or oxo.

[0077] 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).

[0078] In some embodiments, R 5 Selected from hydrogen, -F, -Cl, -Br, methyl, ethyl.

[0079] Aspect A14. The compound according to any of the preceding aspects, wherein the two geminal R 5 Together with the carbon atom to which they are attached, they form a 3-, 4- to 5-membered carbocyclic ring; wherein the ring is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, -CN, -OH, -NH2 or oxo.

[0080] In some embodiments, the two geminal R 5 Together with the carbon atoms to which they are attached, they form a 3-, 4- or 5-membered carbocyclic ring.

[0081] In some embodiments, the two geminal R 5 Together with the carbon atom to which they are attached, they form a 3-membered carbocyclic ring.

[0082] Aspect A15. The compound of any of the preceding aspects, wherein Z 1 , Z 2 , Z 3 and Z 4 At most two of them are N; RZ Each is 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 the 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, -I.

[0083] In some embodiments, R Z Each is 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.

[0084] In some embodiments, R Z Each is independently selected from hydrogen, -F, -Cl, -Br, methyl or ethyl.

[0085] Aspect A16. A compound according to any of the preceding aspects, wherein 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 thienyl; each of said phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, oxazolyl, furanyl, thiazolyl or thienyl is optionally substituted with at least one substituent R Ar replace;

[0086] R Ar 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or -CN; wherein each of the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or -CN is optionally substituted with at least one substituent selected from -F, -Cl, -Br or -I;

[0087] Aspect A17. A compound according to any of the preceding aspects, wherein 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 is optionally substituted with at least one substituent R Ar replace;

[0088] R Ar Each is 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -CF3 or -CN.

[0089] In some embodiments, 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 is optionally substituted with at least one substituent R Ar replace;

[0090] R Ar Each is independently selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, methoxy, ethoxy, -CF3 or -CN.

[0091] Aspect A18. The compound of any of the preceding aspects, wherein G is selected from CH2, O, NH.

[0092] In some embodiments, G is selected from CH2 or O.

[0093] Aspect A19. The compound of any of the preceding aspects, wherein the compound is selected from

[0094]

[0095]

[0096]

[0097]

[0098]

[0099] Aspect A20. A pharmaceutical composition comprising a compound according to any one of Aspects A1 to A19, or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, and a pharmaceutically acceptable excipient.

[0100] Aspect A21. A method of reducing PRMT5 activity by inhibition, comprising administering to a subject a compound according to any one of Aspects A1-A19, or a pharmaceutically acceptable salt thereof, including the compound of Formula (I) or a specific compound exemplified herein.

[0101] Aspect A22. The method according to aspect A21, wherein the disease is selected from cancer.

[0102] 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.

[0103] Aspect A24. Use according to Aspect A23, wherein the disease is cancer.

[0104] 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.

[0105] In aspect B1, the compound is of formula (BI):

[0106]

[0107] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, wherein:

[0108] Z 1 , Z 2 , Z 3 and Z 4 Each independently selected from N or CR Z ;

[0109] At each occurrence, R Z are each independently selected from hydrogen, halogen, -C 1-4 Alkyl or -C 1-4 Alkoxy; wherein the -C 1-4 Alkyl or -C 1-4 Each of the alkoxy groups is optionally substituted with at least one substituent selected from halogen;

[0110] Ar is independently selected from phenyl or 5- to 6-membered heteroaryl, wherein each of said phenyl or 5- to 6-membered heteroaryl is optionally substituted with at least one substituent R Ar replace,

[0111] R Ar are each independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C1-4 Alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy or -CN; wherein the -C 1-4 Alkyl, -C 1-4 Each of alkoxy, -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted with at least one substituent selected from halogen;

[0112] R 1 Each independently selected from -C 1-8 Alkyl, -C3-C8 cycloalkyl (preferably single, bridged, fused or spiral cycloalkyl) or 3- to 8-membered saturated heterocyclic group (preferably single, bridged, fused or spiral heterocyclic group); wherein the -C 1-8 Each of alkyl, -C3-C8 cycloalkyl (preferably mono-, bridged, fused or spiro cycloalkyl) or 3- to 8-membered saturated heterocyclic group (preferably mono-, bridged, fused or spiro heterocyclic group) is optionally substituted with at least one substituent R 1a replace;

[0113] R 1a are each independently selected from halogen, -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3-membered to 6-membered saturated heterocyclic group, -C 1-4 Alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo; wherein the -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3-membered to 6-membered saturated heterocyclic group, -C 1-4 Each of the alkoxy or -C3-C6 cycloalkoxy groups is optionally substituted by at least one selected from halogen, -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3-membered to 6-membered saturated heterocyclic group, -C 1-4 Alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo substituents;

[0114] R 2 Selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy or -CN; wherein the -C 1-4 Alkyl, -C 1-4 Each of -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted by at least one selected from halogen, -C 1-4 Alkoxy or -C3-C6 cycloalkoxy substituents;

[0115] R 3 Selected from hydrogen, halogen, -C 1-4 Alkyl or -CN, where -C 1-4 The alkyl group is optionally substituted with at least one selected from hydrogen, halogen, -C1-4 Alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2 or oxo substituents;

[0116] R 4 Selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy, wherein the -C 1-4 Alkyl, -C 1-4 Each of -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted by at least one selected from halogen, -C 1-4 The substituents are substituted with alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo.

[0117] Aspect B2. The compound of Aspect B1, wherein the compound is of Formula (BIIa), (BIIb), (BIIc), (BIId), (BIIe), (BIIf), or (BIIg):

[0118]

[0119] Among them, R 1 、R 2 、R 3 、R 4 、R Z , Ar are as defined in aspect B1.

[0120] Aspect B3. The compound according to Aspect B1, wherein the compound is of formula (BIIIa), (BIIIb), (BIIIc):

[0121]

[0122] Among them, X 1 、X 2 and X 3 are independently selected from N or CH; provided that, when X 1 、X 2 or X 3 When any one of is CH, CH is optionally replaced by R Ar replace;

[0123] X 4 Each independently selected from NH, O or S; provided that, when X 4 When any one of is NH, NH is optionally replaced by R Ar replace;

[0124] R 1 、R 2 、R 3、R 4 、R Ar , Z 1 , Z 2 , Z 3 and Z 4 As defined in aspect B1.

[0125] In some embodiments, the compound is of Formula (BIIId), (BIIIe), (BIIIf), (BIIIg), (BIIIh), or (BIIIi):

[0126]

[0127] wherein Ring A is -C3-C8 cycloalkyl (preferably a mono-, bridged, fused or spiro cycloalkyl) or a 3- to 8-membered saturated heterocyclyl (preferably a mono-, bridged, fused or spiro heterocyclyl); wherein each of said -C3-C8 cycloalkyl (preferably a mono-, bridged, fused or spiro cycloalkyl) or a 3- to 8-membered saturated heterocyclyl (preferably a mono-, bridged, fused or spiro heterocyclyl) is optionally substituted with at least one substituent R 1a replace;

[0128] X 1 、X 2 and X 3 are independently selected from N or CH; provided that, when X 1 、X 2 or X 3 When any one of is CH, CH is optionally replaced by R Ar replace;

[0129] X 4 Each independently selected from NH, O or S; provided that, when X 4 When any one of is NH, NH is optionally replaced by R Ar replace;

[0130] R 1a 、R 2 、R 3 、R 4 、R Ar , Z 1 , Z 2 , Z 3 and Z 4 As defined in aspect B1.

[0131] Aspect B4. A compound according to any 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, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered saturated monoheterocyclic group, a 5-membered, 6-membered, 7-membered or 8-membered saturated bridged heterocyclic group, a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered saturated fused heterocyclic group, or a 5-membered, 6-membered, 7-membered or 8-membered saturated spiral heterocyclic group; wherein the methyl, ethyl Each of the following substituents R, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered saturated monoheterocyclyl, a 5-membered, 6-membered, 7-membered or 8-membered saturated bridged heterocyclyl, a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered saturated fused heterocyclyl, or a 5-membered, 6-membered, 7-membered or 8-membered saturated spiroheterocyclyl is optionally substituted with at least one substituent R 1a replace;

[0132] R 1a Each 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-membered, 4-membered, 5-membered or 6-membered saturated heterocyclic group, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -CN, -OH, -NH2 or oxo; wherein the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-membered, 4-membered or 5-membered saturated heterocyclic group Each of the 3-, 4-, 5- or 6-membered saturated heterocyclic group, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy 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 heterocyclic group, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -CN, -OH, -NH2 or oxo.

[0133] Aspect B5. A compound according to any 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, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered saturated monoheterocyclic group, a 5-membered, 6-membered, 7-membered or 8-membered saturated bridged heterocyclic group, a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered saturated fused heterocyclic group, or a 5-membered, 6-membered, 7-membered or 8-membered saturated spiroheterocyclic group, each of which is optionally substituted with at least one substituent R 1a replace;

[0134] R 1a Each 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-membered, 4-membered, 5-membered or 6-membered saturated heterocyclic group, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -CN, -OH, -NH2 or oxo.

[0135] 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 the 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 optionally substituted by at least one substituent R 1a replace;

[0136] R 1a Each 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -CN, -OH, -NH2 or oxo.

[0137] Aspect B6. A compound according to any of the preceding aspects, wherein R 1 Selected from

[0138] CH2CH2OCH3,

[0139] Aspect B7. A compound according to any of the preceding aspects, wherein R 2 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or -CN; 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

[0140] In some embodiments, R 2 is selected from hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy or -CN; wherein methyl, ethyl is optionally substituted by at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, cyclopropyloxy or cyclobutyloxy.

[0141] 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or -CN.

[0142] Aspect B8. A compound according to any of the preceding aspects, wherein R 2 is selected from hydrogen, methyl, ethyl or -CN.

[0143] Aspect B9. A compound according to any of the preceding aspects, wherein 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, -NH2 or oxo.

[0144] 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.

[0145] Aspect B10. The compound of any one of the preceding aspects, wherein R 3 is selected from hydrogen, -F, -Cl, -Br, -I or -CN.

[0146] Aspect B11. A compound according to any of the preceding aspects, wherein R 4 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy, wherein 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -CN, -OH, -NH2 or oxo.

[0147] In some embodiments, R 4 is selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, propyl (isopropyl or n-propyl), methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopropyloxy or cyclobutyloxy, wherein methyl, ethyl, propyl (isopropyl or n-propyl), methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopropyloxy or cyclobutyloxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, cyclopropyloxy, cyclobutyloxy, -CN, -OH, -NH2 or oxo.

[0148] 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).

[0149] Aspect B12. The compound of any of the preceding aspects, wherein R 4 Selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl.

[0150] Aspect B13. The compound of any of the preceding aspects, wherein Z 1 , Z 2 , Z3 and Z 4 At most two of them are N; R Z Each is 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 the 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, -I.

[0151] In some embodiments, R Z Each is 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.

[0152] In some embodiments, R Z Each is independently selected from hydrogen, -F, -Cl, -Br, methyl or ethyl.

[0153] Aspect B14. A compound according to any of the preceding aspects, wherein 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 thienyl; each of said phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, oxazolyl, furanyl, thiazolyl or thienyl is optionally substituted with at least one substituent R Ar replace;

[0154] R Ar 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or -CN; wherein each of the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or -CN is optionally substituted with at least one substituent selected from -F, -Cl, -Br or -I;

[0155] Aspect B15. A compound according to any of the preceding aspects, wherein 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 is optionally substituted with at least one substituent R Ar replace;

[0156] R Ar Each is 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -CF3 or -CN.

[0157] In some embodiments, 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 is optionally substituted with at least one substituent R Ar substituted; wherein R Ar Each is independently selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, methoxy, ethoxy, -CF3 or -CN.

[0158] Aspect B16. The compound of any of the preceding aspects, wherein the compound is selected from

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165] Aspect B17. A pharmaceutical composition comprising a compound according to any one of Aspects B1 to B16, or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, and a pharmaceutically acceptable excipient.

[0166] Aspect B18. A method of reducing PRMT5 activity by inhibition, comprising administering to a subject a compound according to any one of Aspects B1-B16, or a pharmaceutically acceptable salt thereof, including the compound of Formula (I) or a specific compound exemplified herein.

[0167] Aspect B19. The method according to aspect B18, wherein the disease is selected from cancer.

[0168] 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.

[0169] Aspect B21. Use according to Aspect B20, wherein the disease is cancer.

[0170] Aspect B22. The use according to 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

[0171] The following terms have the indicated meanings throughout the specification:

[0172] Unless otherwise defined herein, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0173] The following terms have the indicated meanings throughout the specification:

[0174] As used herein, including the appended claims, singular forms of words such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0175] Unless the context clearly dictates otherwise, the term "or" is used to mean, and is used interchangeably with, the term "and / or."

[0176] The term "alkyl" includes hydrocarbon groups selected from straight and branched chain saturated hydrocarbon groups containing 1 to 18 (such as 1 to 12, further such as 1 to 10, further such as 1 to 8, or 1 to 6, or 1 to 4) carbon atoms. 1-6Examples of alkyl groups 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 sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-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.

[0177] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0178] The term "butyl" includes 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu").

[0179] 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.

[0180] 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.

[0181] The term "alkylene" refers to a divalent alkyl group produced by removing two hydrogens from an alkane. Alkylene includes, but is not limited to, methylene, ethylene, propylene, and the like.

[0182] The term "halogen" includes fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0183] The term "alkenyl" includes hydrocarbon groups selected from straight 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. 2-6Examples of alkenyl groups 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 hex-1,3-dienyl.

[0184] The term "alkenylene" refers to a divalent alkenyl group generated by removing two hydrogen atoms from an alkene. Alkenylene groups include, but are not limited to, vinylene, butenylene, and the like.

[0185] The term "alkynyl" includes hydrocarbon groups selected from straight 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. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl.

[0186] The term "alkynylene" refers to a divalent alkynyl group generated by removing two hydrogen atoms from an alkyne. Alkynylenes include, but are not limited to, ethynylene and the like.

[0187] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups, including fused, bridged or spiro-connected cycloalkyl groups.

[0188] For example, cycloalkyl can comprise 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. Even further for example, cycloalkyl can be selected from the monocyclic group comprising 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms. The example of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. In particular, saturated monocyclic cycloalkyl (for example, C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In a preferred embodiment, a cycloalkyl group is a monocyclic ring (abbreviated as C 3-6Cycloalkyl) includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of bicyclic cycloalkyls include those with 7 to 12 ring atoms, arranged as fused bicyclic rings selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems, or arranged as bridged bicyclic rings selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Other examples of bicyclic cycloalkyls include those arranged as bicyclic rings selected from [5,6] and [6,6] ring systems.

[0189] The term "spirocycloalkyl" includes cyclic structures containing carbon atoms and formed by at least two rings that share one atom.

[0190] 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.

[0191] The term "bridged cycloalkyl" includes a cyclic structure containing carbon atoms and formed by two rings, the two rings sharing two atoms that are not adjacent to each other. The term "7- to 10-membered bridged cycloalkyl" includes a cyclic structure containing 7 to 12 carbon atoms and formed by two rings, the two rings sharing two atoms that are not adjacent to each other.

[0192] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl groups include, but are not limited to, 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 benzo[3- to 8-membered cycloalkyl, benzo[C] 4-6 Cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8- to 9-membered fused rings, which in the above examples refer to cyclic structures containing 8 to 9 ring atoms.

[0193] The term "aryl" used alone or in combination with other terms includes groups selected from:

[0194] - 5- and 6-membered carbocyclic aromatic rings, for example, phenyl;

[0195] - 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

[0196] - a tricyclic ring system, such as a 10- to 15-membered tricyclic ring system, wherein at least one ring is carbocyclic and aromatic, for example, fluorenyl.

[0197] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring carbon atoms (i.e., C 5-10 Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0198] Specifically, the term "bicyclic fused aryl" includes bicyclic aryl rings as defined herein. A typical bicyclic fused aryl is naphthalene.

[0199] The term "heteroaryl" includes groups selected from:

[0200] - a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), for example, 1 to 4 (or in some embodiments, 1 to 3, in some embodiments, 1 to 2) heteroatoms, the remaining ring atoms being carbon;

[0201] a 7- to 12-membered bicyclic ring containing at least one heteroatom selected from N, O, and S, such as 1 to 4 (or in some embodiments, 1 to 3, or in other embodiments, 1 or 2) heteroatoms, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0202] - an 11- to 14-membered tricyclic ring comprising at least one heteroatom selected from N, O, and S, e.g., 1 to 4 (or in some embodiments, 1 to 3, or in other embodiments, 1 or 2) heteroatoms, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.

[0203] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. The nitrogen atoms in one or more rings of the heteroaryl group can be oxidized to form N-oxides.

[0204] Specifically, the term "bicyclic fused heteroaryl" includes 7- to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused bicyclic heteroaryl rings as defined herein. Typically, the bicyclic fused heteroaryl is a 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic ring. The group may be attached to the rest of the molecule via either ring.

[0205] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and include non-aromatic heterocyclic groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, the remaining ring members being carbon, including monocyclic, fused, bridged, and spirocyclic rings, i.e., containing monocyclic heterocyclyls, bridged heterocyclyls, spiro heterocyclyls, and fused heterocyclyls.

[0206] The term "at least one substituent" disclosed herein includes, for example, 1 to 4 (such as 1 to 3, further such as 1 or 2) substituents, provided that it complies with valence theory. For example, "at least one substituent F" disclosed herein includes 1 to 4 (such as 1 to 3, further such as 1 or 2) substituents F.

[0207] The term "divalent" refers to a linking group capable of forming a covalent bond with two other moieties. For example, a "divalent cycloalkyl" refers to a cycloalkyl group obtained by removing two hydrogen atoms from a corresponding cycloalkane to form a linking group. The terms "divalent aryl," "divalent heterocyclyl," or "divalent heteroaryl" should be understood in a similar manner.

[0208] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other. In the case where the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a wider range of stereoisomer categories. It is intended to include all such possible stereoisomers in the form of substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. It is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically noted, reference to an isomer is applicable to any possible isomer. As long as the isomer composition is not specified, all possible isomers are included.

[0209] Unless stated otherwise, when compounds disclosed herein contain olefinic double bonds, such double bonds are intended to include both E and Z geometric isomers.

[0210] When the compounds disclosed herein contain a disubstituted cyclic ring system, the substituents found on such ring systems can take the cis and trans forms. The cis form means that both substituents are found on the upper side of the carbon 2 substituent positions, while the trans form means that they are found on opposite sides. For example, the disubstituted cyclic ring system can be a cyclohexyl ring or a cyclobutyl ring.

[0211] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired product of each step or series of steps is separated and / or purified (hereinafter separated) to a desired degree of uniformity by techniques commonly used in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve many methods, including, for example: reverse phase and normal phase chromatography; size exclusion chromatography; ion exchange chromatography; high pressure, medium pressure, and low pressure liquid chromatography methods and apparatus; small-scale analytical chromatography; simulated moving bed ("SMB") chromatography and preparative thin or thick layer chromatography, as well as small-scale thin layer and flash chromatography techniques. Those skilled in the art can select and apply the technology most likely to achieve the desired separation.

[0212] "Diastereoisomers" refer to stereoisomers of compounds with two or more chiral centers but that are not mirror images of each other. A diastereomeric mixture can be separated into its single diastereoisomers based on its physicochemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomer mixtures can be converted into diastereoisomer mixtures by reacting with suitable optically active compounds (e.g., chiral auxiliary agents, such as chiral alcohols or Mosher's acid chlorides), separating diastereomers and converting (e.g., hydrolyzing) single diastereomers into corresponding pure enantiomers, and separating enantiomers. Enantiomers can also be separated by using chiral HPLC columns.

[0213] Single stereoisomers (e.g., substantially pure enantiomers) can be obtained by resolving the racemic mixture using a method such as the formation of diastereomers using an optically active resolving agent (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3) (1975): pp. 283-302). Racemic mixtures of the chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) forming ionic diastereomeric salts with chiral compounds and separating them by fractional crystallization or other methods, (2) forming diastereomeric compounds with chiral derivatizing agents, separating the diastereomers and converting them to pure stereoisomers, and (3) separating the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., ed., Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0214] Some of the compounds disclosed herein may exist with different points of hydrogen attachment, known as tautomers. For example, a compound comprising a carbonyl -CH2C(O)- group (keto form) may undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Where applicable, both the individual keto and enol forms, as well as mixtures thereof, are also intended to be included.

[0215] "Prodrug" refers to a derivative of an active agent that requires a transformation in vivo to release the active agent. In some embodiments, the transformation is enzymatic. The prodrug is generally (but not necessarily) pharmacologically inactive prior to conversion to the active agent.

[0216] "Pharmaceutically acceptable salts" refers to those salts which are, 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, and which are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can 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 by reacting 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.

[0217] In addition, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, can be prepared according to conventional methods for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

[0218] As used herein, the terms "administration," "administering," "treating," and "treatment" refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, a human, a subject, a cell, a tissue, an organ, or a biological fluid. Treatment of cells encompasses contact of an agent with a cell, as well as contact of an agent with a fluid, wherein the fluid is in contact with the cell. The terms "administering" and "treating" also refer to in vitro and ex vivo treatment of a cell, for example, by an agent, a diagnostic agent, a binding compound, or by another cell. The term "subject" herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0219] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient (such as a compound) that is sufficient to affect treatment for a disease, disorder or symptom when administered to a subject to treat a disease, or at least one clinical symptom of a disease or condition. The term "therapeutically effective amount" may vary with the compound, the disease, disorder, and / or symptoms of the disease or condition, the severity of the disease, disorder and / or symptoms of the disease or condition, the age of the subject to be treated and / or the weight of the subject to be treated. In any given case, the appropriate amount may be obvious to one skilled in the art or may 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, as defined herein, that is effective to "treat" the disease or condition of the subject. In the case of combination therapy, the term "therapeutically effective amount" refers to the total amount of the combination subject used to effectively treat the disease, disorder or condition.

[0220] The term "disease" refers to any illness, ailment, ailment, symptom, or indication, and is interchangeable with the terms "disorder" or "condition."

[0221] Throughout the specification and the appended claims, unless the context requires otherwise, the term "comprise" and variations such as "comprises" and "comprising" are intended to specify the presence of the following features, but do not preclude the presence or addition of one or more other features. When used herein, the term "comprise" may be replaced by the terms "contains," "includes," or sometimes "having."

[0222] Throughout the specification and appended claims, the term “C n-m " indicates a range including the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 、C 1-6 wait.

[0223] Unless otherwise defined herein, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0224] Example

[0225] General synthesis

[0226] 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.

[0227] The reactions for preparing the compounds disclosed herein can be carried out in suitable solvents, which can be readily selected by those skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with starting materials, intermediates, or products at temperatures within the boiling temperature range of the solvent, for example. A given reaction can be carried out in a solvent or a mixture of solvents.

[0228] The selection of suitable protecting group can be easily determined by those skilled in the art.In the synthetic scheme, some protection / deprotection steps are not shown, and can be introduced before, after or between any step.Based on reaction conditions, may use or may not use the protecting group shown in the synthetic scheme.The order of reaction may change and provide similar result.

[0229] Can monitor reaction according to any suitable method known in the art, described method such as NMR, UV, HPLC, LC-MS and TLC.Compound can be purified by several methods, including preparative HPLC and silica gel chromatography.Unless otherwise stated, preparative HPLC uses buffered acetonitrile / water system, and silica gel chromatography (including column chromatography and preparative TLC) uses PE / EtOAc or DCM / MeOH system as mobile phase.Use Bruker or Varian instrument recording NMR spectrum with preset pulse sequence.

[0230] Solution AI

[0231]

[0232] For example, compounds of formula (I) can be formed as shown in Scheme 1. Compound (iii) can be formed by amine alkylation between compound (i) and compound (ii) or between compound (i') and compound (ii'). Compound (iv) can undergo an enamine-Heck reaction with pyruvate to provide compound (v). Compound (v) can be protected to provide compound (vi). Compound (vi) can react with an amine via a transition metal-catalyzed reaction or substitution to provide compound (vii). Compound (vii) can be substituted to provide compound (viii). Compound (viii) can be saponified to provide compound (ix). Compound (ix) can be coupled with compound (iii) under amide coupling conditions to provide compound (x). Compound (x) can be unmasked to provide compound (xi) [i.e., formula (I)].

[0233] Plan AII

[0234]

[0235] For example, compounds of formula (I) can be formed as shown in Scheme II. Compound (iii) can be formed by amine alkylation between compounds (i) and (ii) or between compounds (i') and (ii'). Compound (iv) can undergo a Claisen-type condensation with an oxalate to provide compound (v). Compound (v) can be reduced and cyclized to provide compound (vi). Compound (vi) can be substituted to provide compound (vii). Compound (vii) can be saponified to provide compound (viii). Compound (viii) can be coupled with compound (iii) under amide coupling conditions to provide compound (ix). Compound (ix) can be unmasked to provide compound (x) [i.e., formula (I)].

[0236] Solution BI

[0237]

[0238] For example, compounds of formula (I) can be formed as shown in Scheme 1. Compound (iii) can be formed by amine alkylation between compound (i) and compound (ii) or between compound (i') and compound (ii'). Compound (iv) can be subjected to an enamine-Heck reaction with pyruvate to provide compound (v). Compound (v) can be protected to provide compound (vi). Compound (vi) can be reacted with an amine via a transition metal-catalyzed reaction or substitution to provide compound (vii). Compound (vii) can be substituted to provide compound (viii). Compound (viii) can be saponified to provide compound (ix). Compound (ix) can be coupled with compound (iii) under amide coupling conditions to provide compound (x). Compound (x) can be unmasked to provide compound (xi) [i.e., formula (I)].

[0239] Plan BII

[0240]

[0241] For example, compounds of formula (I) can be formed as shown in Scheme II. Compound (iii) can be formed by amine alkylation between compounds (i) and (ii) or between compounds (i') and (ii'). Compound (iv) can undergo a Claisen-type condensation with an oxalate to provide compound (v). Compound (v) can be reduced and cyclized to provide compound (vi). Compound (vi) can be substituted to provide compound (vii). Compound (vii) can be saponified to provide compound (viii). Compound (viii) can be coupled with compound (iii) under amide coupling conditions to provide compound (ix). Compound (ix) can be unmasked to provide compound (x) [i.e., formula (I)].

[0242] Abbreviations NMR Nuclear Magnetic Resonance UV Ultraviolet HPLC High Performance Liquid Chromatography prep Preparative LC-MS Liquid Chromatography Mass Spectrometry TLC Thin Layer Chromatography PE Petroleum Ether Et Ethyl Ac Acetyl Ph Phenyl DMF N,N-Dimethylformamide MTBE Methyl tert-butyl ether DCM Dichloromethane Me Methyl DMSO Dimethyl sulfoxide Boc tert-Butoxycarbonyl SEM 2-(Trimethylsilyl)ethoxymethyl DIPEA Diisopropylethylamine THF Tetrahydrofuran dba Dibenzylideneacetone BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl dppf 1,1'-Bis(diphenylphosphino)ferrocene TFA, trifluoroacetic acid, NBS, N-bromosuccinimide, BPD, bis(pinacol)diboron, m-CPBA, m-chloroperbenzoic acid, DMP, Dess-Martin periodinane, SPhos, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, DIBAL-H, diisobutylaluminum hydride, DMAP, 4-dimethylaminopyridine

[0243] 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

[0244]

[0245] Step 1: 5-Chloro-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid

[0246]

[0247] A mixture of 2,6-dichloro-5-methylpyridine-3-amine (10.0 g, 56.5 mmol), pyruvic acid (14.9 g, 169 mmol), Pd(OAc)2 (0.94 g, 5.65 mmol), PPh3 (11.8 g, 45.2 mmol) in DMF (100 mL) was stirred at 110 ° C for 24 hours. The mixture was cooled to room temperature and volatiles were removed in vacuo. K2CO3 aqueous solution (24 g in 200 mL water) and MTBE (300 mL) were added and the mixture was stirred for 10 minutes. The solid was removed by filtration. The aqueous layer was separated and the pH was adjusted to 3-4 with HCl aqueous solution (6 M). The mixture was extracted with EtOAc (500 mL × 2). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by C18 chromatography (MeCN: 0.03% aqueous formic acid, 0:1 to 1:1) to give the title compound (4.0 g, 34%). LC-MS (M+H) + =211.

[0248] Step 2: 5-Chloro-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methyl ester

[0249]

[0250] 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 under 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 × 2). The combined organic layer was 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.

[0251] Step 3: 5-chloro-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b] Methyl pyridine-2-carboxylate

[0252]

[0253] A mixture of 5-chloro-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methyl ester (7.6 g, 33.9 mmol), SEMCl (11.3 g, 67.8 mmol), DIPEA (13.1 g, 101.7 mmol) in THF (120 mL) was stirred overnight at 70 ° C under nitrogen. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude material 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.

[0254] Step 4: 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methane 1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methyl ester

[0255]

[0256] A mixture of 5-chloro-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methyl ester (2.8 g, 7.89 mmol), diphenylmethylamine (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 overnight at 100 ° C under N2. 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.

[0257] Step 5: 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methane 1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid

[0258]

[0259] 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) and water (50 mL) was added LiOH. .H2O (0.75 g, 18 mol). The mixture was stirred at 60°C for 4 hours. 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 x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2.5 g, 86%). LC-MS (M+H) + =486.2.

[0260] Step 6: 5-(2,6-difluorophenyl)picolinaldehyde

[0261]

[0262] To a mixture 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)Cl2 (9.73 g, 13.3 mmol) and K3PO4 (141 g, 665 mmol). The mixture was stirred at 85 ° C for 16 hours, 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 layer was washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under vacuum. 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.

[0263] Step 7: (R)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0264]

[0265] To a solution of (R)-5,6,7,8-tetrahydroquinolin-8-amine (1.35 g, 9.12 mmol) in DCM (20 mL) was added 5-(2,6-difluorophenyl)picolinaldehyde (2.0 g, 9.12 mmol), MeOH (2 mL) and NaBH(OAc)3 (5.80 g, 27.4 mmol). The mixture was stirred at room temperature for 1 hour and quenched with saturated NaHCO3 (50 mL). The organic layer was separated and the aqueous layer was extracted with DCM (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. 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.

[0266] 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[2-(trimethylsilyl)ethoxy)methyl]- [3,2-b]pyridine-2-carboxamide

[0267]

[0268] 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 hours. The mixture was cooled to room temperature, diluted with water (50 mL), and then extracted with EtOAc (50 mL). The organic layer was separated and washed with brine (50 mL×2), dried over Na2SO4, filtered and concentrated under vacuum. 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.

[0269] 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

[0270] 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 under vacuum. HCl (4 M in MeOH, 4 mL) was added and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum and then 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 under vacuum and purified by preparative HPLC to give Example 2 (21 mg, 60%). 1 H 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.

[0271] 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

[0272]

[0273] Step 1: (R)-N-((5-phenylpyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0274]

[0275] The title compound (300 mg, 44%) was prepared in a manner similar to that of Example 1, Step 7, from (R)-5,6,7,8-tetrahydroquinolin-8-amine and 5-phenylpyridinecarboxaldehyde. LC-MS (M+H) + =316.3.

[0276] 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]pyrrolidone Pyridine-2-carboxamide

[0277]

[0278] The title compound (30 mg, 47%) was prepared in a manner analogous to Example 1, Step 8, 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. LC-MS (M+H) + =783.6.

[0279] Step 3: (R)-5-amino-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline (1H-pyrrolo[3,2-b]pyridine-2-carboxamide)

[0280] Example 2 (3 mg, 16%) was prepared in a manner analogous to Example 1, Step 9, 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. 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.

[0281] Example A3: (R)-5-amino-N-((3',5'-difluoro-[3,4'-bipyridyl]-6-yl)methyl)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0282]

[0283] Step 1: 3',5'-difluoro-[3,4'-bipyridine]-6-carbaldehyde

[0284]

[0285] 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), K3PO4 (2.25 g, 10.6 mmol) and Pd(dppf)Cl2 (258 mg, 0.35 mmol) at 20 ° C. The mixture was stirred at 85 ° C for 3 hours. 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.

[0286] Step 2: (R)-N-((3',5'-difluoro-[3,4'-bipyridyl]-6-yl)methyl)-5,6,7,8-tetrahydroquinoline-8- amine

[0287]

[0288] 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)3 (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 hour and then poured into saturated NaHCO3 (50 mL). The mixture was extracted with DCM (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound (216 mg, 21%). LC-MS (M+H) + =353.2.

[0289] Step 3: 5-amino-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxylic acid

[0290]

[0291] 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) and 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 1M 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.

[0292] Step 4: (R)-5-amino-N-((3',5'-difluoro-[3,4'-bipyridyl]-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-Formamide

[0293]

[0294] 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'-bipyridyl]-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 hours. The mixture was cooled to room temperature and diluted with water (10 mL), then 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.

[0295] Step 5: (R)-5-amino-N-((3',5'-difluoro-[3,4'-bipyridyl]-6-yl)methyl)-6-methyl-N-(5, 6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0296] A mixture of (R)-5-amino-N-((3',5'-difluoro-[3,4'-bipyridyl]-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) and TFA (1 mL) was stirred at room temperature for 1 hour. 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 hour. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (10 mg, 37%). 1 HNMR(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.

[0297] 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

[0298]

[0299] Step 1: 5-(1,4-Dimethyl-1H-pyrazol-5-yl)pyridinecarboxaldehyde

[0300]

[0301] 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)Cl2 (787 mg, 1.1 mmol) and K3PO4 (6.85 g, 32.3 mmol). The mixture was stirred at 80 ° C for 12 hours. 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). The title compound (0.98 g, 45%) was obtained. LC-MS (M+H) + =202.3.

[0302] Step 2: (R)-N-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydro Quinolin-8-amine

[0303]

[0304] 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 Example 1, Step 7. LC-MS (M+H) + =334.3.

[0305] Step 3: (R)-N-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-5-((diphenyl (2-(trimethylsilyl)ethoxy)methyl)amino)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) 1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0306]

[0307] The title compound (20 mg, 50%) was prepared in a manner analogous to Example 1, Step 8, 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. LC-MS (M+H) + =801.6.

[0308] 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

[0309] Example 4 (2.5 mg, 20%) was prepared in a manner analogous to Example 1, Step 9, 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. 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.

[0310] 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

[0311]

[0312] Step 1: 3-Bromo-5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy) (2-Methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid

[0313]

[0314] 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 hour. 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.

[0315] 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

[0316]

[0317] The title compound (20 mg, 20%) was prepared in a manner analogous to Example 1, Step 8, 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. LC-MS (M+H) + =897.2.

[0318] 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

[0319] Example 5 (10 mg, 77%) was prepared in a manner analogous to Example 1, Step 9, 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. 1 HNMR(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.

[0320] 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

[0321]

[0322] Step 1: tert-Butyl ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamate

[0323]

[0324] 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) Cl2 (1.27 g, 1.74 mmol) and KOAc (4.27 g, 43.5 mmol). The mixture was stirred at 85 ° C for 12 hours. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The crude material was redissolved in dioxane (25 mL), toluene (12 mL) and water (12 mL), followed by the addition of 1,3-difluoro-2-iodobenzene (4.28 g, 17.8 mmol), K3PO4 (6.32 g, 29.8 mmol) and Pd (dppf) Cl2 (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 × 3). The combined organic layer was washed with brine (10 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 obtain 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.

[0325] Step 2: (5-(2,6-Difluorophenyl)pyridin-2-yl)methanamine

[0326]

[0327] A mixture of tert-butyl ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamate (3.0 g, 9.37 mmol) in HCl methanol solution (4 M, 50 mL) was stirred for 2 hours at 25 ° C., and the mixture was then neutralized to pH 7 with NaOH methanol solution (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 under vacuum 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.

[0328] Step 3: 4-Methoxy-5,6,7,8-tetrahydroquinoline

[0329]

[0330] To a solution of PtO2 (3.71 g, 16.3 mmol) in TFA (200 mL) was added 4-methoxyquinoline (20 g, 126 mmol) under nitrogen. The suspension was degassed and purged with hydrogen 3 times. The mixture was stirred at 50 ° C under hydrogen (50 psi) for 3 hours. The filtrate was collected by filtration, concentrated to about 50 mL and diluted with water (100 mL). The pH of the mixture was adjusted to 9 with an aqueous NaOH solution (1 M). The mixture was extracted with DCM (50 mL × 3). The combined organic layer was 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.

[0331] Step 4: 4-Bromo-5,6,7,8-tetrahydroquinoline

[0332]

[0333] To a solution of 4-methoxy-5,6,7,8-tetrahydroquinoline (17g, 104mmol) in DMF (170mL) was added POBr3 (89.6g, 312mmol) at 0°C. The mixture was heated to 100°C and stirred for 12 hours. The reaction mixture was cooled to 0°C and slowly added to ice water (300mL). The mixture was extracted with EtOAc (100mL×3). The combined organic layers were washed with brine (50mL×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 (15g). LC-MS (M+H) + =212.1.

[0334] Step 5: 4-Bromo-5,6,7,8-tetrahydroquinoline 1-oxide

[0335]

[0336] 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 hours 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 layer was 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.

[0337] Step 6: 4-Bromo-5,6,7,8-tetrahydroquinolin-8-yl acetate

[0338]

[0339] 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 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.

[0340] Step 7: 4-Bromo-5,6,7,8-tetrahydroquinolin-8-ol

[0341]

[0342] Four identical reactions were set up in parallel as described below. 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 K2CO3 (5.8 g, 42.2 mmol). The mixture was stirred at 25°C for 2 hours.

[0343] The four reaction mixtures 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.

[0344] Step 8: 4-Bromo-6,7-dihydroquinolin-8(5H)-one

[0345]

[0346] 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.

[0347] Step 9: 4-cyclopropyl-6,7-dihydroquinolin-8(5H)-one

[0348]

[0349] 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) and toluene (9 mL) was added SPhos (145 mg, 0.35 mmol), Pd(OAc)2 (99 mg, 0.44 mmol) and K3PO4 (2.35 g, 11.1 mmol). The mixture was stirred at 90 ° C for 12 hours 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 Na2SO4, 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.

[0350] Step 10: 4-cyclopropyl-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline- 8-Amine

[0351]

[0352] 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 in Example 10, step 3. LC-MS (M+H) + =392.2.

[0353] Step 11: N-(4-cyclopropyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-((5-(2,6-difluorophenyl)pyridine-2-yl)- (2-(trimethylsilyl)ethoxy)methyl)-5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- Pyrrolo[3,2-b]pyridine-2-carboxamide

[0354]

[0355] The title compound (20 mg, 42%) was prepared in a manner analogous to Example 1, Step 8, 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. LC-MS (M+H) + =859.3.

[0356] 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

[0357] Example 6 (5 mg, 38%) was prepared in a manner analogous to Example 1, Step 9 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. 1HNMR(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, 1H),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.

[0358] 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

[0359]

[0360] Step 1: Methyl 5,6,7,8-tetrahydroquinoline-4-carboxylate

[0361]

[0362] To a solution of 4-bromo-5,6,7,8-tetrahydroquinoline (2.0 g, 9.43 mmol) in MeOH (40 mL) under nitrogen was added Et3N (2.86 g, 28.3 mmol) and Pd(dppf)Cl2 . DCM (770 mg, 943 μmol). The mixture was degassed and purged with CO 3 times, then stirred at 50 ° C under CO (50 psi) for 12 hours. 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.

[0363] Step 2: 2-(5,6,7,8-Tetrahydroquinolin-4-yl)propan-2-ol

[0364]

[0365] To a solution of MeMgBr (3M in THF, 3.1mL, 9.3mmol) in THF (6mL) was added dropwise a solution of 5,6,7,8-tetrahydroquinoline-4-carboxylic acid methyl ester (0.60g, 3.14mmol) in THF (3mL) at 0°C under nitrogen. The mixture was warmed to room temperature and stirred for 2 hours. Aqueous HCl solution (0.05M, 10mL) was slowly added to the reaction mixture, and the mixture was extracted with EtOAc (2mL×3). The combined organic layer was washed with brine (2mL), 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 (0.40g, 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.

[0366] Step 3: 4-(2-Hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinoline 1-oxide

[0367]

[0368] The title compound (0.30 g, 92%) was prepared in a manner analogous to Example 6, Step 5 from 2-(5,6,7,8-tetrahydroquinolin-4-yl)propan-2-ol. 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.

[0369] Step 4: 4-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinolin-8-yl acetate

[0370]

[0371] The title compound (0.48 g, 100%) was prepared from 4-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinoline 1-oxide in a manner similar to that of Example 6, Step 6. LC-MS (M+H) + =250.3.

[0372] Step 5: 4-(2-Hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinolin-8-ol

[0373]

[0374] The title compound (0.48 g, 100%) was prepared in a manner analogous to Example 6, Step 7 from 4-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinolin-8-yl acetate. 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.

[0375] Step 6: 4-(2-Hydroxypropan-2-yl)-6,7-dihydroquinolin-8(5H)-one

[0376]

[0377] 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 MnO2 (1.09 g, 12.5 mmol). The mixture was stirred at 40 ° C for 12 hours 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.

[0378] Step 7: 2-(8-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)amino)-5,6,7,8-tetrahydroquinoline- 4-amino)propan-2-ol

[0379]

[0380] The title compound (0.10 g, 33%) was prepared in a manner similar to that in Step 3 of Example 10 from 4-(2-hydroxypropan-2-yl)-6,7-dihydroquinolin-8(5H)-one and (5-(2,6-difluorophenyl)pyridin-2-yl)methanamine. LC-MS (M+H) + =410.2.

[0381] 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) (2-Methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0382]

[0383] The title compound (10 mg, 28%) was prepared in a manner analogous to Example 1, Step 8, 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.

[0384] Step 9: 5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(4-(2-hydroxypropan-2-yl)- 1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0385] Example 7 (2 mg, 30%) was prepared in a manner analogous to Example 1, Step 9, 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. 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.

[0386] 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

[0387]

[0388] Step 1: Methyl 4-amino-5-phenylpicolinate

[0389]

[0390] 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) and water (4 mL) was added Pd (dppf) Cl2 (526 mg, 0.72 mmol) and K3PO4 (3.05 g, 14.4 mmol). The mixture was stirred at 100 ° C for 2 hours and cooled to room temperature. The mixture was diluted with water (10 mL) and extracted with EtOAc (8 mL × 2). The combined organic layer was washed with brine (5.0 mL), dried over Na2SO4, filtered and concentrated under vacuum. 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.

[0391] Step 2: Methyl 4-chloro-5-phenylpicolinate

[0392]

[0393] To CuCl(509mg, 3.79mmol) in a mixture of MeCN (2mL) tert-butyl nitrite (488mg, 4.73mmol) was added. The mixture was stirred at room temperature for 15 minutes and then cooled to 0°C. A solution of methyl 4-amino-5-phenylpicolinate (360mg, 1.58mmol) in MeCN (2mL) was added dropwise. After the addition was completed, 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 obtain the title compound (160mg, 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.

[0394] Step 3: 4-Chloro-5-phenylpyridinecarboxaldehyde

[0395]

[0396] 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 hour. The mixture was poured into water (10.0 mL) and extracted with EtOAc (8 mL × 2). The combined organic layers were washed with brine (5.0 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.

[0397] Step 4: (R)-N-((4-chloro-5-phenylpyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0398]

[0399] The title compound (150 mg, 75%) was prepared in a manner similar to that of Example 1, Step 7, from (R)-5,6,7,8-tetrahydroquinolin-8-amine and 4-chloro-5-phenylpyridinecarboxaldehyde. LC-MS (M+H) + =350.2.

[0400] 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

[0401]

[0402] The title compound (10 mg, 30%) was prepared in a manner analogous to Example 1, Step 8, 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. LC-MS (M+H) + =817.4.

[0403] Step 6: (R)-5-amino-N-((4-chloro-5-phenylpyridin-2-yl)methyl)-6-methyl-N-(5,6,7,8-tetrakis (quinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0404] Example 8 (1 mg, 16%) was prepared in a manner analogous to Example 1, Step 9, 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. 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.

[0405] 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

[0406]

[0407] Step 1: tert-Butyl ((5-bromo-6-methylpyridin-2-yl)methyl)carbamate

[0408]

[0409] To a solution of 5-bromo-6-methylpicolinonitrile (5.0 g, 25.4 mmol), Boc2O (11.1 g, 50.8 mmol) and NiCl2 (987 mg, 7.61 mmol) in MeOH (75 mL) was added NaBH4 (3.84 g, 102 mmol) at 0 ° C, the mixture was warmed to room temperature and stirred for 2 hours. The mixture was slowly added to ice water (100 mL). After bubbling stopped, the mixture was extracted with EtOAc (50 mL × 3). The combined organic layer was washed with brine (20 ml × 3), dried over Na2SO4, 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.

[0410] Step 2: (5-Bromo-6-methylpyridin-2-yl)methanamine

[0411]

[0412] 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 then concentrated under vacuum. The solid was triturated with a mixture of DCM (10 mL) and MeOH (1 mL). The solid was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (0.80 g, 92%). LC-MS (M+H) + =201.1.

[0413] Step 3: N-((5-bromo-6-methylpyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0414]

[0415] 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 manner similar to that in Example 10, step 3. LC-MS (M+H) + =332.2.

[0416] Step 4: N-((6-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)methane 1-Methyl-5,6,7,8-tetrahydroquinolin-8-amine

[0417]

[0418] To a mixture 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) and water (2 mL) was added K PO (1.28 g, 6.0 mmol) and Pd(dppf)Cl (176 mg, 0.24 mmol). The mixture was stirred at 90° C. for 12 hours 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.

[0419] Step 5: 5-((diphenylmethylene)amino)-6-methyl-N-((6-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)- 1-((2-(trimethylsilyl)-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)- ... (alkyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0420]

[0421] The title compound (30 mg, 42%) was prepared in a manner analogous to Example 1, Step 8, 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. LC-MS (M+H) + =871.4.

[0422] 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

[0423] Example 9 (6 mg, 26%) was prepared in a manner analogous to Example 1, Step 9, 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. 1 HNMR(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.

[0424] 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

[0425]

[0426] Step 1: tert-Butyl ((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)carbamate

[0427]

[0428] 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) and water (40 mL) was added K3PO4 (33.3 g, 157 mmol) and Pd(dppf)Cl2 (4.59 g, 6.27 mmol) under nitrogen. The mixture was stirred at 85°C for 12 hours 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 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 (9.0 g, 41%). LC-MS (M+H) + =353.1.

[0429] Step 2: (5-(2,6-Dichlorophenyl)pyridin-2-yl)methanamine

[0430]

[0431] A mixture of tert-butyl ((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)carbamate (9.0 g, 25.5 mmol) in methanolic HCl solution (4 M, 90 mL) was stirred at 25 ° C for 1 hour, and then the mixture was neutralized to pH 7 with methanolic NaOH solution (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 under vacuum 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).

[0432] Step 3: N-((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0433]

[0434] 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) and MeOH (1.4 mL) was added NaBH(OAc) (18.1 g, 85.6 mmol). The mixture was stirred at 25 ° C for 2 hours. The mixture was poured into saturated NaHCO (100 mL). The mixture was extracted with DCM (50 mL × 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under vacuum. 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.

[0435] 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

[0436]

[0437] 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 hours. The mixture was cooled to room temperature, diluted into water (50 mL), and then extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under vacuum. 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.

[0438] Step 5: 5-amino-N-((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)-6-methyl-N-(5,6,7,8-tetrakis (quinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0439] 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 solution was concentrated under vacuum, and HCl (4 M in MeOH, 5 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, 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 under vacuum. The residue was purified by silica gel chromatography (DCM:MeOH=20:1) to give the title compound (277 mg, 70.4%). 1H 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.

[0440] 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

[0441]

[0442] Step 1: 5-(Perfluorophenyl)picolinaldehyde

[0443]

[0444] To a mixture 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) and water (5 mL) was added Pd(dppf)Cl2 (249 mg, 0.34 mmol) and K3PO4 (3.61 g, 17.0 mmol). The mixture was stirred at 85 ° C for 16 hours 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 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 (0.80 mg, 43%).

[0445] Step 2: (R)-N-((5-(perfluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0446]

[0447] 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 Example 1, Step 7. LC-MS (M+H) + =406.1.

[0448] Step 3: (R)-5-((diphenylmethylene)amino)-6-methyl-N-((5-(perfluorophenyl)pyridin-2-yl)methane yl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3, 2-b]pyridine-2-carboxamide

[0449]

[0450] The title compound (44 mg, 62%) was prepared in a manner analogous to Example 1, Step 8, 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. LC-MS (M+H) + =873.4.

[0451] Step 4: (R)-5-amino-6-methyl-N-((5-(perfluorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetra ... (quinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0452] Example 11 (2 mg, 8%) was prepared in a manner analogous to Example 1, Step 9, 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. 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.

[0453] 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

[0454]

[0455] Step 1: tert-Butyl (3-bromo-6-methyl-5-nitropyridin-2-yl)(tert-butoxycarbonyl)carbamate

[0456]

[0457] To a solution of 3-bromo-6-methyl-5-nitropyridine-2-amine (55g, 237mmol) and DMAP (2.90g, 23.7mmol) in THF (500mL) was added Boc2O (129g, 593mmol) at room temperature. After 12 hours, the mixture was diluted with water (2.5L) and extracted with EtOAc (400mL×3). The combined organic layers were washed with brine (100ml×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 (80g, 78%). 1 H NMR (400MHz, DMSO-d6) δ8.87(s,1H),2.70(s,3H),1.38(s,18H).

[0458] Step 2: 3-(5-Bromo-6-((tert-Butoxycarbonyl)amino)-3-nitropyridin-2-yl)-2-hydroxypropenoic acid ester

[0459]

[0460] 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 this mixture. The mixture was stirred at 0°C for 0.5 hours, followed by the dropwise addition 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 hours. 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 HNMR (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).

[0461] Step 3: 5-(bis(tert-butoxycarbonyl)amino)-6-bromo-1H-pyrrolo[3,2-b]pyridine-1,2-dicarboxylic acid 1- 2-Ethyl (tert-butyl) ester

[0462]

[0463] To a mixture of ethyl 3-(5-bromo-6-((tert-butoxycarbonyl)amino)-3-nitropyridine-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 hours. The mixture was cooled to room temperature and filtered. The filter cake was rinsed 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 the pH reached 7. The mixture was extracted with EtOAc (50 mL × 4). The combined organic layer was 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 Boc O (1.34 g, 6.16 mmol). The mixture was stirred at room temperature for 2 hours. 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 Na SO , 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).

[0464] Step 4: 6-Bromo-1-(tert-butoxycarbonyl)-5-((tert-butoxycarbonyl)amino)-1H-pyrrolo[3,2-b]pyrrolidone 2-pyridinecarboxylic acid

[0465]

[0466] 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. . H2O (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 about 4 with HCl methanol solution (1 M). 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.

[0467] Step 5: (R)-6-Bromo-5-((tert-butoxycarbonyl)amino)-2-(((5-(2,6-difluorophenyl)pyridin-2-yl) tert-Butyl (methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

[0468]

[0469] The title compound (40 mg, 18%) was prepared in a manner analogous to Example 1, Step 8, 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. LC-MS (M+H) + =789.2.

[0470] 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

[0471] A mixture of (R)-tert-butyl 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 h. 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.

[0472] 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

[0473]

[0474] Step 1: 2-(1,3-dioxolan-2-yl)-5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridine

[0475]

[0476] To a mixture of (6-(1,3-dioxolane-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), K3PO4 (6.53 g, 30.8 mmol) and Pd(dppf)Cl2 (751 mg, 1.0 mmol). The mixture was stirred at 80 ° C for 12 hours 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.

[0477] Step 2: 5-(1-methyl-1H-1,2,4-triazol-5-yl)picolinaldehyde

[0478]

[0479] To a mixture of 2-(1,3-dioxolane-2-yl)-5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridine (1.2 g, 5.17 mmol) in water (6 mL) and dioxane (12 mL) was added concentrated HCl (6.5 mL) and the mixture was stirred at 60 ° C for 3 hours. The mixture was cooled to room temperature and neutralized with saturated NaHCO 3 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 Na 2 SO 4 , filtered and concentrated in vacuo to give the title compound (0.60 g, 62%). LC-MS (M+H) + =189.3.

[0480] Step 3: (R)-N-((5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrakis Hydroquinolin-8-amine

[0481]

[0482] 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 Example 1, Step 7. LC-MS (M+H) + =321.1.

[0483] Step 4: (R)-5-((diphenylmethylene)amino)-6-methyl-N-((5-(1-methyl-1H-1,2,4-triazole- (5-(trimethylsilyl)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

[0484]

[0485] The title compound (30 mg, 46%) was prepared in a manner analogous to Example 1, Step 8, 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. LC-MS (M+H) + =788.4.

[0486] 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

[0487] Example 13 (12 mg, 64%) was prepared in a manner analogous to Example 1, Step 9, 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. 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.

[0488] 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

[0489]

[0490] Step 1: tert-Butyl ((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)carbamate

[0491]

[0492] The title compound (180 mg, 69%) was prepared in a manner similar to that in Example 6, step 1, from tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate and 1-chloro-3-fluoro-2-iodobenzene. LC-MS (M+H) + =337.2.

[0493] Step 2: (5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methanamine

[0494]

[0495] The title compound (140 mg, 99%) was prepared in a manner similar to that in Example 6, step 2, from tert-butyl ((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)carbamate. LC-MS (M+H) + =237.1.

[0496] Step 3: N-((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0497]

[0498] 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 in Example 10, step 3. LC-MS (M+H) + =368.1.

[0499] Step 4: 5-Amino-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid

[0500]

[0501] 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) and DCM (10 mL) was stirred at 30 ° C for 4 hours. The mixture was concentrated under reduced pressure and treated with aqueous HCl (1 M, 15 mL). The mixture was stirred at room temperature for 1 hour 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 hours. The mixture was concentrated under reduced pressure, and the crude material was purified by C18 chromatography (10% MeCN / water containing 0.03% formic acid) to give the title compound (0.60 g, 90%). LCMS (M+H) + =192.2.

[0502] 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

[0503] 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, then an aqueous NaOH solution (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 Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC to give Example 14 (3 mg, 5%). 1 H 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.

[0504] 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

[0505]

[0506] Step 1: tert-Butyl ((5-(2-cyano-6-fluorophenyl)pyridin-2-yl)methyl)carbamate

[0507]

[0508] The title compound (308 mg, 77%) was prepared in a manner analogous to Example 6, step 1, from tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate and 3-fluoro-2-iodobenzonitrile. 1 HNMR(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).

[0509] Step 2: 2-(6-(Aminomethyl)pyridin-3-yl)-3-fluorobenzonitrile

[0510]

[0511] The title compound (0.20 g, 96%) was prepared in a manner analogous to Example 6, step 2, from tert-butyl ((5-(2-cyano-6-fluorophenyl)pyridin-2-yl)methyl)carbamate.

[0512] Step 3: 3-Fluoro-2-(6-(((5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)pyridin-3-yl)benzonitrile

[0513]

[0514] 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 Example 10, Step 3. LC-MS (M+H) + =359.1.

[0515] 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

[0516] Example 15 (6 mg, 11%) was prepared in a manner analogous 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. 1 H 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.

[0517] Example A16: N-([2,3'-bipyridyl]-6'-ylmethyl)-5-amino-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0518]

[0519] Step 1: tert-Butyl ([2,3'-bipyridyl]-6'-ylmethyl)carbamate

[0520]

[0521] The title compound (0.40 g, 59%) was prepared in a manner analogous to Example 6, Step 1, from tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate and 2-bromopyridine. LC-MS (M+H) + =286.3.

[0522] Step 2: [2,3'-Bipyridyl]-6'-ylmethylamine

[0523]

[0524] To a solution of tert-butyl ([2,3'-bipyridyl]-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 reached 8. 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), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 mg, 77%). LC-MS (M+H) + =186.3.

[0525] Step 3: N-([2,3'-bipyridyl]-6'-ylmethyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0526]

[0527] The title compound (0.30 g, 29%) was prepared in a manner similar to that in Example 10, Step 3, from 6,7-dihydroquinolin-8(5H)-one and [2,3'-bipyridyl]-6'-ylmethanamine. LC-MS (M+H) + =317.1.

[0528] Step 4: N-([2,3'-bipyridyl]-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-Formamide

[0529]

[0530] The title compound (22 mg, 43%) was prepared in a manner analogous to Example 1, Step 8, from 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-([2,3'-bipyridyl]-6'-ylmethyl)-5,6,7,8-tetrahydroquinolin-8-amine. LC-MS (M+H) + =784.2.

[0531] Step 5: N-([2,3'-bipyridyl]-6'-ylmethyl)-5-amino-6-methyl-N-(5,6,7,8-tetrahydroquinolin- 8-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0532] Example 16 (7 mg, 51%) was prepared in a manner analogous to Example 1, Step 9, from N-([2,3'-bipyridyl]-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. 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.

[0533] 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

[0534]

[0535] Step 1: 5-((diphenylmethylene)amino)-3-fluoro-6-methyl-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

[0536]

[0537] 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 NaHCO3 (168 mg, 2.0 mmol) and (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 Na2SO4, 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.

[0538] Step 2: 5-((diphenylmethylene)amino)-3-fluoro-6-methyl-1-((2-(trimethylsilyl)ethoxy) (2-Methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid

[0539]

[0540] The title compound (13 mg, 89%) was prepared in a manner similar to that in Step 5 of Example 1 from methyl 5-((diphenylmethylene)amino)-3-fluoro-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate. LC-MS (M+H) + =504.3.

[0541] 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

[0542]

[0543] 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 (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 layers were 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.

[0544] 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

[0545] Example 17 (1.5 mg, 23%) was prepared in a manner analogous to Example 1, Step 9, 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. 1 HNMR(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.

[0546] 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

[0547]

[0548] Step 1: 4-(1,4-Dimethyl-1H-pyrazol-5-yl)-2-fluorobenzaldehyde

[0549]

[0550] 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), K2CO3 (900 mg, 6.5 mmol) was added to dioxane (10 mL) and water (1 mL) under nitrogen. 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.

[0551] Step 2: N-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-fluorobenzyl)-5,6,7,8-tetrahydroquinolin-8-yl amine

[0552]

[0553] 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 Example 1, Step 7. LC-MS (M+H) + =351.3.

[0554] Step 3: N-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-fluorobenzyl)-5-((diphenylmethylene)amino) ... 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolidone)-6-methyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolidone)- Pyrrolidine-2-carboxamide

[0555]

[0556] The title compound (40 mg, 48%) was prepared in a manner analogous to Step 8 of Example 1 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. LC-MS (M+H) + =818.5.

[0557] 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

[0558] Example 18 (15 mg, 59%) was prepared in a manner analogous to Example 1, Step 9, 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. 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.

[0559] 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

[0560]

[0561] Step 1: 5-((diphenylmethylene)amino)-3-iodo-6-methyl-1-((2-(trimethylsilyl)ethoxy) (2-Methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid

[0562]

[0563] 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 and isopropanol (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.

[0564] 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

[0565]

[0566] The title compound (134 mg, 58%) was prepared in a manner analogous to Example 1, Step 8, 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. LC-MS (M+H) + =945.3

[0567] 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

[0568] Example 19 (0.5 mg, 7%) was prepared in a manner analogous to Example 1, Step 9, 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. 1HNMR(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.

[0569] Example B1: 5-amino-N-cyclobutyl-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0570]

[0571] Step 1: 5-Chloro-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid

[0572]

[0573] A mixture of 2,6-dichloro-5-methylpyridine-3-amine (10.0 g, 56.5 mmol), pyruvic acid (14.9 g, 169 mmol), Pd(OAc)2 (0.94 g, 5.65 mmol), PPh3 (11.8 g, 45.2 mmol) in DMF (100 mL) was stirred at 110 ° C for 24 hours. The mixture was cooled to room temperature and volatiles were removed in vacuo. K2CO3 aqueous solution (24 g in 200 mL water) and MTBE (300 mL) were added and the mixture was stirred for 10 minutes. The solid was removed by filtration. The aqueous layer was separated and the pH was adjusted to 3-4 with HCl aqueous solution (6 M). The mixture was extracted with EtOAc (500 mL × 2). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by C18 chromatography (MeCN: 0.03% aqueous formic acid, 0:1 to 1:1) to give the title compound (4.0 g, 34%). LC-MS (M+H) + =211.

[0574] Step 2: 5-Chloro-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methyl ester

[0575]

[0576] 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 under 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 × 2). The combined organic layer was 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.

[0577] Step 3: 5-chloro-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b] Methyl pyridine-2-carboxylate

[0578]

[0579] A mixture of 5-chloro-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methyl ester (7.6 g, 33.9 mmol), SEMCl (11.3 g, 67.8 mmol), DIPEA (13.1 g, 101.7 mmol) in THF (120 mL) was stirred overnight at 70 ° C under nitrogen. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude material 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.

[0580] Step 4: 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methane 1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methyl ester

[0581]

[0582] A mixture of 5-chloro-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methyl ester (2.8 g, 7.89 mmol), diphenylmethylamine (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 overnight at 100 ° C under N2. 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.

[0583] Step 5: 5-((diphenylmethylene)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methane 1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid

[0584]

[0585] 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) and water (50 mL) was added LiOH. .H2O (0.75 g, 18 mol). The mixture was stirred at 60°C for 4 hours. 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 x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2.5 g, 86%). LC-MS (M+H) + =486.2.

[0586] Step 6: N-((5-phenylpyridin-2-yl)methyl)cyclobutaneamine

[0587]

[0588] To a solution of 5-phenylpyridinecarboxaldehyde (300 mg, 1.64 mmol) and cyclobutylamine (233 mg, 3.28 mmol) in DCM (2 mL) and MeOH (0.2 mL) was added NaBH (OAc) 3 (694 mg, 3.28 mmol). The mixture was stirred at room temperature for 1 hour and then carefully added dropwise to water (100 mL) under vigorous stirring. The mixture was extracted with EtOAc (200 mL). The organic layer was separated and washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound (100 mg, 26%). LC-MS (M+H) + =239.2.

[0589] Step 7: N-cyclobutyl-5-((diphenylmethylene)amino)-6-methyl-N-((5-phenylpyridin-2-yl)methane 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0590]

[0591] 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 nitrogen. 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.

[0592] Step 8: 5-amino-N-cyclobutyl-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide

[0593] 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 hour 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 hour and then concentrated under reduced pressure. The residue was redissolved in MeOH (2 mL) and water (0.2 mL), followed by the addition of KCO (39 mg, 0.285 mmol). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The mixture was wet-ground 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%). 1 H 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.

[0594] 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

[0595]

[0596] Step 1: tert-Butyl ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamate

[0597]

[0598] 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) Cl2 (1.27 g, 1.74 mmol) and KOAc (4.27 g, 43.5 mmol). The mixture was stirred at 85 ° C for 12 hours. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The crude material was redissolved in dioxane (25 mL), toluene (12 mL) and water (12 mL), followed by the addition of 1,3-difluoro-2-iodobenzene (4.28 g, 17.8 mmol), K3PO4 (6.32 g, 29.8 mmol) and Pd (dppf) Cl2 (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 × 3). The combined organic layer was washed with brine (10 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 obtain 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.

[0599] Step 2: (5-(2,6-Difluorophenyl)pyridin-2-yl)methanamine

[0600]

[0601] A mixture of tert-butyl ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamate (3.0 g, 9.37 mmol) in HCl methanol solution (4 M, 50 mL) was stirred for 2 hours at 25 ° C., and the mixture was then neutralized to pH 7 with NaOH methanol solution (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 under vacuum to give the title compound (1.5 g, 73%). 1H 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.

[0602] Step 3: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-1,3-dimethoxypropan-2-amine

[0603]

[0604] The title compound (0.20 g, 76%) was prepared in a manner analogous to Example 1, Step 6 from 1,3-dimethoxypropan-2-one and (5-(2,6-difluorophenyl)pyridin-2-yl)methanamine. 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.60-7.48 (m, 2H), 7.32-7.22 (m, 2H), 3.94 (s, 2H), 3.34 (d, J = 5.6 Hz, 4H), 3.24 (s, 6H), 2.89 (quintet, J = 5.6 Hz, 1H). LC-MS (M+H) + =323.2.

[0605] 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)

[0606] methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0607]

[0608] The title compound (30 mg, 76%) was prepared in a manner analogous to Step 7 of Example 1 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. LC-MS (M+H) + =790.6.

[0609] Step 5: 5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(1,3-dimethoxypropan-2-yl)- 1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0610] Example 2 (9 mg, 47%) was prepared in a manner analogous to Example 1, Step 8 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. 1 H 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.

[0611] 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

[0612]

[0613] Step 1: 5-(2,6-difluorophenyl)picolinaldehyde

[0614]

[0615] To a mixture 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)Cl2 (9.73 g, 13.3 mmol) and K3PO4 (141 g, 665 mmol). The mixture was stirred at 85 ° C for 16 hours, 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 layer was washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under vacuum. 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.

[0616] Step 2: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-3,3-difluorocyclobutan-1-amine

[0617]

[0618] 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 Example 1, Step 6. LC-MS (M+H) + =311.1.

[0619] Step 3: N-(3,3-difluorocyclobutyl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenyl (2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyrrolidone)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyrrolidone Pyridine-2-carboxamide

[0620]

[0621] The title compound (35 mg, 55%) was prepared in a manner analogous to Step 7 of Example 1 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. LC-MS (M+H) + =778.1.

[0622] 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

[0623] 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 stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, and the residue was redissolved in MeOH (10 mL) and water (2 mL), followed by the addition of K2CO3 (31 mg, 0.20 mmol). The mixture was stirred at 50 ° C for 2 hours. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by preparative HPLC to give Example 3 (3 mg, 14%). 1HNMR(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.

[0624] Example B4: 5-amino-N-cyclopropyl-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0625]

[0626] Step 1: N-((5-phenylpyridin-2-yl)methyl)cyclopropylamine

[0627]

[0628] The title compound (150 mg, 61%) was prepared in a manner similar to that of Example 1, Step 6, from 5-phenylpicolinaldehyde and cyclopropylamine. LC-MS (M+H) + =225.1.

[0629] Step 2: N-cyclopropyl-5-((diphenylmethylene)amino)-6-methyl-N-((5-phenylpyridin-2-yl)methane 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0630]

[0631] The title compound (20 mg, 70%) was prepared in a manner similar to that in Example 1, Step 7, 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)cyclopropylamine. LC-MS (M+H) + =692.3.

[0632] Step 3: 5-amino-N-cyclopropyl-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-1H-pyrrolo[3,2- b]pyridine-2-carboxamide

[0633] Example 4 (1.6 mg, 14%) was prepared in a manner analogous to Example 1, Step 8, 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. 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.

[0634] 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

[0635]

[0636] Step 1: 1-cyclopropyl-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)methanamine

[0637]

[0638] The title compound (36 mg, 14%) was prepared in a manner similar to that in Example 1, Step 6, from 5-(2,6-difluorophenyl)picolinaldehyde and cyclopropylmethylamine. LC-MS (M+H) + =275.1.

[0639] Step 2: N-(cyclopropylmethyl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5-((diphenyl methyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2- Formamide

[0640]

[0641] The title compound (13 mg, 24%) was prepared in a manner analogous to Step 7 of Example 1 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. LC-MS (M+H) + =742.3.

[0642] 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

[0643] Example 5 (1.6 mg, 14%) was prepared in a manner analogous to Example 1, Step 8 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. 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=8.0H z,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.

[0644] 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

[0645]

[0646] Step 1: tert-Butyl ((5-phenylpyridin-2-yl)methyl)carbamate

[0647]

[0648] To a solution of 5-phenylpyridinecarbonitrile (12.0 g, 66.6 mmol), Boc2O (29.1 g, 133 mmol) and NiCl2 (1.73 g, 13.3 mmol) in MeOH (150 mL) was slowly added NaBH4 (15.1 g, 400 mmol) at 0 ° C under nitrogen. The mixture was stirred at room temperature for 12 hours 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 Na2SO4, filtered and concentrated under vacuum. 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.

[0649] Step 2: (5-phenylpyridin-2-yl)methanamine

[0650]

[0651] The title compound (1.93 g, 99%) was prepared in a manner similar to that in Example 2, Step 2, from tert-butyl ((5-phenylpyridin-2-yl)methyl)carbamate. LC-MS (M+H) + =185.3.

[0652] Step 3: 3-Methoxy-N-((5-phenylpyridin-2-yl)methyl)cyclobutan-1-amine

[0653]

[0654] The title compound (90 mg, 19%) was prepared in a manner similar to that of Example 1, Step 6, from (5-phenylpyridin-2-yl)methanamine and 3-methoxycyclobutan-1-one. LC-MS (M+H) + =269.2.

[0655] Step 4: 5-((diphenylmethylene)amino)-N-(3-methoxycyclobutyl)-6-methyl-N-((5-phenylpyrrolidone)amino)-N-(3-methoxycyclobutyl)-6-methyl-N- ...3-methoxycyclobutyl)- pyridine-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid amine

[0656]

[0657] The title compound (20 mg, 26%) was prepared in a manner analogous to Step 7 of Example 1 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. LC-MS (M+H) + =736.3.

[0658] Step 5: 5-amino-N-((1r,3r)-3-methoxycyclobutyl)-6-methyl-N-((5-phenylpyridin-2-yl)methane yl)-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

[0659] 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 analogous to Example 1, Step 8.

[0660] Example 6: 1H 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.

[0661] Example 7: 1 H 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.

[0662] 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

[0663]

[0664] Step 1: N-((5-phenylpyridin-2-yl)methyl)tetrahydro-2H-pyran-3-amine

[0665]

[0666] 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 Example 1, Step 6. LC-MS (M+H) + =269.2.

[0667] Step 2: 5-((diphenylmethylene)amino)-6-methyl-N-((5-phenylpyridin-2-yl)methyl)-N-(tetramethyl Hydrogen-2H-pyran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid Amide

[0668]

[0669] The title compound (50 mg, 82%) was prepared in a manner analogous to Step 7 of Example 1 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. LC-MS (M+H) + =736.6.

[0670] 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

[0671] Example 8 (13 mg, 44%) was prepared in a manner analogous to Example 1, Step 8, 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. 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.

[0672] 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

[0673]

[0674] Step 1: (3R,4R)-3-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)amino)tetrahydro-2H-pyran- 4-ol

[0675]

[0676] 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.

[0677] Step 2: ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)- tert-Butyl)carbamate

[0678]

[0679] 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 Boc2O (164 mg, 0.75 mmol) and Et3N (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.

[0680] Step 3: ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)((3R,4R)-4-methoxytetrahydro-2H-pyran- tert-Butyl 3-amino)carbamate

[0681]

[0682] 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 nitrogen for 5 hours. The mixture was diluted with ice water (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were 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.

[0683] Step 4: (3R,4R)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-4-methoxytetrahydro-2H-piperidin Phenylan-3-amine hydrochloride

[0684]

[0685] 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 (4M 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.

[0686] Step 5: 5-Amino-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid

[0687]

[0688] 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) and DCM (10 mL) was stirred at 30 ° C for 4 hours. The mixture was concentrated under reduced pressure and treated with aqueous HCl (1 M, 15 mL). The mixture was stirred at room temperature for 1 hour 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 hours. The mixture was concentrated under reduced pressure, and the crude material was purified by C18 chromatography (10% MeCN / water containing 0.03% formic acid) to give the title compound (0.60 g, 90%). LCMS (M+H) + =192.2.

[0689] Step 6: 5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-((3R,4R)-4-methoxy Tetrahydro-2H-pyran-3-yl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0690] A mixture of 5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (50 mg, 0.26 mmol) in SOCl2 (2 mL) was stirred at 60 ° C under nitrogen 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 Et3N (131 mg, 1.3 mmol) were added under nitrogen. 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 layer was washed with brine (10 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain 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.

[0691] 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

[0692]

[0693] Step 1: tert-Butyl (1-hydroxy-3,3-dimethylbutan-2-yl)carbamate

[0694]

[0695] To a solution of 2-amino-3,3-dimethylbutan-1-ol (1.0 g, 8.55 mmol) in DCM (20 mL) was added Et3N (1.72 g, 17.1 mmol) and Boc2O (2.79 g, 12.8 mmol) at 0°C. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (50 mL) and then extracted with DCM (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. 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.

[0696] Step 2: tert-Butyl (1-methoxy-3,3-dimethylbutan-2-yl)carbamate

[0697]

[0698] 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 Ag2O (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 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and then extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL × 2), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EtOAc = 10: 1) to give the title compound (600 mg, 80%).

[0699] Step 3: 1-Methoxy-3,3-dimethylbutan-2-amine hydrochloride

[0700]

[0701] 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 under vacuum to give the title compound (440 mg, 100%). LC-MS (M+H) + =132.1.

[0702] Step 4: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-1-methoxy-3,3-dimethylbutan-2-amine

[0703]

[0704] 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), Et3N (91 mg, 0.90 mmol) and NaBH(OAc)3 (383 mg, 1.81 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was carefully added to saturated NaHCO3 (50 mL) and then extracted with DCM (50 mL). The organic layer was washed with brine (50 ml), dried over Na2SO4, filtered and concentrated under vacuum. 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.

[0705] 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)

[0706] (ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0707]

[0708] 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 under vacuum. 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.

[0709] Step 6: 5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(1-methoxy-3,3-dimethoxy 2-Methyl-6-(2-butyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

[0710] Example 10 (17 mg, 49%) was prepared in a manner similar to Example 1, Step 8, 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; 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.

[0711] Compound cell killing in HCT116 isogenic pairs

[0712] HCT116 cell line is available from ATCC (CCL-247). It has sudden change in codon 13 of ras proto-oncogene, and can be used as the positive control of the PCR assay of the sudden change in this codon.HCT116-MTAP-KO is the knockout MTAP gene based on HCT116, and a monoclonal body is measured by this.HCT116-mock-RNA-KO is the knockout mock gene based on HCT116 with MTAP wild-type genotype.The basal culture medium of HCT116 isogenic right is RPMI 1640, HEPES (Gibco, 22400105).In order to make complete growth medium, in basal culture medium, add following component: fetal calf serum, final concentration is 10% (Gibco, 10099-141C). This cell line was grown at 37° C. in a humidified 5% CO 2 atmosphere and tested regularly for the presence of mycoplasma using the MycoAlert™ PLUS Mycoplasma Detection Kit (Lonza, LT07-710).

[0713] experiment

[0714] HCT116-mock-RNA-KO (400 cells / well) or HCT116-MTAP-KO (400 cells / well) cells were seeded into 96-well plates (Greiner: 655090) at 100 μL / well.

[0715] Incubate overnight at 37°C, 5% CO2.

[0716] • Add 50 μL of fresh growth medium containing serial dilutions of compound to each well, with a final compound concentration of 0-10 μM.

[0717] Incubate at 37°C, 5% CO2 for 6 days.

[0718] · Cell viability was detected by CellTiter-Glo (Promega, G7573). 70 μL was added to each well. Reagents.

[0719] Incubate at room temperature for 10 minutes to stabilize the luminescent signal.

[0720] · Analyze with a microplate reader (TECAN, SPARK) and use 9 Fitting IC 50 .

[0721] The compounds disclosed herein exhibited cell killing activity values ​​as shown in Table 1

[0722] Table 1: Cell killing IC of compounds disclosed herein 50 (nM)

[0723]

[0724] *No complete IC for more than 50% inhibition of activity at the concentrations tested 50 Determination curve.

Claims

1. A compound of formula (X): or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, wherein: Z 1 , Z 2 , Z 3 and Z 4 Each independently selected from N or CR Z ; At each occurrence, R Z are independently selected from hydrogen, halogen, -C 1-4 Alkyl or -C 1-4 Alkoxy; wherein the -C 1-4 Alkyl or -C 1-4 Each of the alkoxy groups is optionally substituted with at least one substituent selected from halogen; Ar is selected from phenyl or 5- to 6-membered heteroaryl, each of which is optionally substituted with at least one substituent R Ar replace, R Ar are each independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy or -CN; wherein the -C 1-4 Alkyl, -C 1-4 Each of alkoxy, -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted with at least one substituent selected from halogen; R X It is R 1 or R 1 Each independently selected from -C 1-8 Alkyl, -C3-C8 cycloalkyl (preferably single, bridged, fused or spiral cycloalkyl) or 3- to 8-membered saturated heterocyclic group (preferably single, bridged, fused or spiral heterocyclic group); wherein the -C 1-8 Each of alkyl, -C3-C8 cycloalkyl (preferably mono-, bridged, fused or spiro cycloalkyl) or 3- to 8-membered saturated heterocyclic group (preferably mono-, bridged, fused or spiro heterocyclic group) is optionally substituted with at least one substituent R 1a replace; R 1a are each independently selected from halogen, -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3-membered to 6-membered saturated heterocyclic group, -C 1-4 Alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo; wherein the -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3-membered to 6-membered saturated heterocyclic group, -C 1-4 Each of the alkoxy or -C3-C6 cycloalkoxy groups is optionally substituted by at least one selected from halogen, -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3-membered to 6-membered saturated heterocyclic group, -C 1-4 Alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo substituents; G is selected from CH2, O or NH, provided that when G is NH and NH is replaced by R 5 When substituted, R 5 Not halogen; Z 5 , Z 6 , Z 7 and Z 8 Each independently selected from N or CR 1 , the prerequisite is that 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 Not at the same time N; At each occurrence, R Z1 are independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy; wherein the -C 1-4 Alkyl, -C 1-4 Each of -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted by at least one selected from halogen, -C 1-4 Alkoxy, -CN, -OH, -NH2 or oxo substituents; At each occurrence, R 5 are independently selected from hydrogen, halogen, -C 1-4 Alkyl or -C3-C6 cycloalkyl, wherein -C 1-4 Alkyl or -C3-C6 cycloalkyl is optionally substituted by at least one selected from halogen, -C 1-4 Alkoxy, -CN, -OH, -NH2 or oxo substituents; or Two geminal R 5 Together with the carbon atoms to which they are attached, they form a 3- to 5-membered carbocyclic ring; wherein the ring is optionally substituted with at least one selected from halogen, -C 1-4 Alkoxy, -CN, -OH, -NH2 or oxo substituents; n is 0, 1, 2, 3, or 4; r is 0 or 1; R 2 Selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy or -CN; wherein the -C 1-4 Alkyl, -C 1-4 Each of -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted by at least one selected from halogen, -C 1-4 Alkoxy or -C3-C6 cycloalkoxy substituents; R 3 Selected from hydrogen, halogen, -C 1-4 Alkyl or -CN, where -C 1-4 The alkyl group is optionally substituted with at least one selected from hydrogen, halogen, -C 1-4 Alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2 or oxo substituents; R 4 Selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy, wherein the -C 1-4 Alkyl, -C 1-4 Each of -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted by at least one selected from halogen, -C 1-4 The substituents are substituted with alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo.

2. The compound of claim 1, wherein the compound is of formula (AI): or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, wherein: Z 1 、Z 2 、Z 3 and Z 4 Each independently selected from N or CR Z ; At each occurrence, R Z are independently selected from hydrogen, halogen, -C 1-4 Alkyl or -C 1-4 Alkoxy; wherein the -C 1-4 Alkyl or -C 1-4 Each of the alkoxy groups is optionally substituted with at least one substituent selected from halogen; Ar is selected from phenyl or 5- to 6-membered heteroaryl, each of which is optionally substituted with at least one substituent R Ar replace, R Ar are each independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy or -CN; wherein the -C 1-4 Alkyl, -C 1-4 Each of alkoxy, -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted with at least one substituent selected from halogen; G is selected from CH2, O or NH, provided that when G is NH and NH is replaced by R 5 When substituted, R 5 Not halogen; Z 5 、Z 6 、Z 7 and Z 8 Each independently selected from N or CR Z1 , the prerequisite is that Z 5 、Z 6 、Z 7 and Z 8 At least one of them is N, and the others are CR Z1 ; At each occurrence, R Z1 are independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy; wherein the -C 1-4 Alkyl, -C 1-4 Each of -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted by at least one selected from halogen, -C 1-4 Alkoxy, -CN, -OH, -NH2 or oxo substituents; R 2 Selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy or -CN; wherein the -C 1-4 Alkyl, -C 1-4 Each of -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted by at least one selected from halogen, -C 1-4 Alkoxy or -C3-C6 cycloalkoxy substituents; R 3 Selected from hydrogen, halogen, -C 1-4 Alkyl or -CN, where -C 1-4 The alkyl group is optionally substituted with at least one selected from hydrogen, halogen, -C 1-4 Alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2 or oxo substituents; R 4 Selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy, wherein the -C 1-4 Alkyl, -C 1-4 Each of -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted by at least one selected from halogen, -C 1-4 Alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo substituents; At each occurrence, R 5 are independently selected from hydrogen, halogen, -C 1-4 Alkyl or -C3-C6 cycloalkyl, wherein -C 1-4 Alkyl or -C3-C6 cycloalkyl is optionally substituted by at least one selected from halogen, -C 1-4 Alkoxy, -CN, -OH, -NH2 or oxo substituents; or Two geminal R 5 Together with the carbon atoms to which they are attached, they form a 3- to 5-membered carbocyclic ring; wherein the ring is optionally substituted with at least one selected from halogen, -C 1-4 Alkoxy, -CN, -OH, -NH2 or oxo substituents; n is 0, 1, 2, 3, or 4; r is 0 or 1.

3. The compound of any one of claims 1, wherein the compound is of formula (BI): or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, wherein: Z 1 、Z 2 、Z 3 and Z 4 Each independently selected from N or CR Z ; At each occurrence, R Z are each independently selected from hydrogen, halogen, -C 1-4 Alkyl or -C 1-4 Alkoxy; wherein the -C 1-4 Alkyl or -C 1-4 Each of the alkoxy groups 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 optionally substituted with at least one substituent R Ar replace, R Ar are each independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy or -CN; wherein the -C 1-4 Alkyl, -C 1-4 Each of alkoxy, -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted with at least one substituent selected from halogen; R 1 Each independently selected from -C 1-8 Alkyl, -C3-C8 cycloalkyl (preferably single, bridged, fused or spiral cycloalkyl) or 3- to 8-membered saturated heterocyclic group (preferably single, bridged, fused or spiral heterocyclic group); wherein the -C 1-8 Each of alkyl, -C3-C8 cycloalkyl (preferably mono-, bridged, fused or spiro cycloalkyl) or 3- to 8-membered saturated heterocyclic group (preferably mono-, bridged, fused or spiro heterocyclic group) is optionally substituted with at least one substituent R 1a replace; R 1a are each independently selected from halogen, -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3-membered to 6-membered saturated heterocyclic group, -C 1-4 Alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo; wherein the -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3-membered to 6-membered saturated heterocyclic group, -C 1-4 Each of the alkoxy or -C3-C6 cycloalkoxy groups is optionally substituted by at least one selected from halogen, -C 1-4 Alkyl, -C3-C6 cycloalkyl, 3-membered to 6-membered saturated heterocyclic group, -C 1-4 Alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo substituents; R 2 Selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl, -C3-C6 cycloalkoxy or -CN; wherein the -C 1-4 Alkyl, -C 1-4 Each of -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted by at least one selected from halogen, -C 1-4 Alkoxy or -C3-C6 cycloalkoxy substituents; R 3 Selected from hydrogen, halogen, -C 1-4 Alkyl or -CN, where -C 1-4 The alkyl group is optionally substituted with at least one selected from hydrogen, halogen, -C 1-4 Alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2 or oxo substituents; R 4 Selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy, wherein the -C 1-4 Alkyl, -C 1-4 Each of -C3-C6 cycloalkyl or -C3-C6 cycloalkoxy is optionally substituted by at least one selected from halogen, -C 1-4 The substituents are substituted by alkoxy, -C3-C6 cycloalkoxy, -CN, -OH, -NH2 or oxo.

4. The compound of claim 1, wherein the compound is selected from formula (AIIa), (AIIb), (AIIc) or (AIId): in, 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 as defined in claim 1.

5. The compound of claim 1, wherein the compound is selected from Formula (AIIe), (AIIf), (AIIg), (AIIh), (AIIi), (AIIj), (AIIk), (AIIl), (AIIm) or (AIIn): in, R Z1 、R 2 、R 3 、R 4 、R 5 、Z 1 、Z 2 、Z 3 、Z 4 , Ar and n are as defined in claim 1.

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

7. The compound of claim 1, wherein the compound is of formula (AIVa), (AIVb), (AIVc): in, X 1 、X 2 and X 3 Each independently selected from N or CH, provided that when X 1 、X 2 or X 3 When any one of is CH, CH is optionally replaced by R Ar replace; 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, n and r are as defined in claim 1.

8. The compound of claim 1, wherein the compound is of Formula (BIIa), (BIIb), (BIIc), (BIId), (BIIe), (BIIf), or (BIIg): in, R 1 、R 2 、R 3 、R 4 、R Z , Ar as defined in claim 1.

9. The compound of claim 1, wherein the compound is of formula (BIIIa), (BIIIb), or (BIIIc): in, X 1 、X 2 and X 3 are independently selected from N or CH; provided that, when X 1 、X 2 or X 3 When any one of is CH, CH is optionally replaced by R Ar replace; X 4 Each independently selected from NH, O or S; provided that, when X 4 When any one of is NH, NH is optionally replaced by R Ar replace; R 1 、R 2 、R 3 、R 4 、R Ar 、Z 1 、Z 2 、Z 3 and Z 4 As defined in claim 1.

10. The compound of claim 1, wherein the compound is of Formula (BIIId), (BIIIe), (BIIIf), (BIIIg), (BIIIh), or (BIIIi): in, Ring A is -C3-C8 cycloalkyl (preferably mono, bridged, fused or spiro cycloalkyl) or 3- to 8-membered saturated heterocyclyl (preferably mono, bridged, fused or spiro heterocyclyl); wherein each of said -C3-C8 cycloalkyl (preferably mono, bridged, fused or spiro cycloalkyl) or 3- to 8-membered saturated heterocyclyl (preferably mono, bridged, fused or spiro heterocyclyl) is optionally substituted with at least one substituent R 1a replace; X 1 、X 2 and X 3 are independently selected from N or CH; provided that, when X 1 、X 2 or X 3 When any one of is CH, CH is optionally replaced by R Ar replace; X 4 Each independently selected from NH, O or S; provided that, when X 4 When any one of is NH, NH is optionally replaced by R Ar replace; R 1a 、R 2 、R 3 、R 4 、R Ar , Z 1 , Z 2 , Z 3 and Z 4 As defined in claim 1.

11. A compound as claimed in any one of the preceding claims, wherein R Z1 wherein each of the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, -CN, -OH, -NH or oxo.

12. A compound as claimed in any one of the preceding claims, wherein R Z1 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl.

13. A compound as claimed in any one of the preceding claims, wherein R Z1 Selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopropyloxy or hydroxypropyl 14. A compound as claimed in any one of the preceding claims, wherein 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, -NH2 or oxo.

15. A compound as claimed in any one of the preceding claims, wherein 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 Selected from hydrogen, -F, -Cl, -Br, methyl, ethyl.

16. A compound as claimed in any one of the preceding claims, wherein the two geminal R 5 Together with the carbon atom to which they are attached, they form a 3-, 4- to 5-membered carbocyclic ring; wherein the ring is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, -CN, -OH, -NH2 or oxo.

17. A compound as claimed in any one of the preceding claims, wherein the two geminal R 5 Together with the carbon atoms to which they are attached, they form a 3-, 4- or 5-membered carbocyclic ring.

18. A compound as claimed in any one of the preceding claims, wherein the two geminal R 5 Together with the carbon atom to which they are attached, they form a 3-membered carbocyclic ring.

19. A compound as claimed in any one of the preceding claims, wherein G is selected from CH2, O or NH; Preferably, G is selected from CH2 or O.

20. A compound as claimed in 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, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered saturated monoheterocyclic group, a 5-membered, 6-membered, 7-membered or 8-membered saturated bridged heterocyclic group, a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered saturated fused heterocyclic group, or a 5-membered, 6-membered, 7-membered or 8-membered saturated spiral heterocyclic group; wherein the methyl, ethyl Each of the following substituents R, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered saturated monoheterocyclyl, a 5-membered, 6-membered, 7-membered or 8-membered saturated bridged heterocyclyl, a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered saturated fused heterocyclyl, or a 5-membered, 6-membered, 7-membered or 8-membered saturated spiroheterocyclyl is optionally substituted with at least one substituent R 1a replace; R 1a Each 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-membered, 4-membered, 5-membered or 6-membered saturated heterocyclic group, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -CN, -OH, -NH2 or oxo; wherein the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-membered, 4-membered or 5-membered saturated heterocyclic group Each of the 3-, 4-, 5- or 6-membered saturated heterocyclic group, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy 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 heterocyclic group, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -CN, -OH, -NH2 or oxo.

21. A compound as claimed in 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, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered saturated monoheterocyclic group, a 5-membered, 6-membered, 7-membered or 8-membered saturated bridged heterocyclic group, a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered saturated fused heterocyclic group, or a 5-membered, 6-membered, 7-membered or 8-membered saturated spiroheterocyclic group, each of which is optionally substituted with at least one substituent R 1a replace; R 1a Each 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-membered, 4-membered, 5-membered or 6-membered saturated heterocyclic group, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -CN, -OH, -NH2 or oxo.

22. A compound as claimed in 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 the 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 optionally substituted by at least one substituent R 1a replace; R 1a Each 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -CN, -OH, -NH2 or oxo.

23. A compound as claimed in any one of the preceding claims, wherein R 1 Selected from -CH2CH2OCH3, 24. A compound as claimed in any one of the preceding claims, wherein R 2 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or -CN; 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

25. A compound as claimed in any one of the preceding claims, wherein R 2 is selected from hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy or -CN; wherein methyl, ethyl is optionally substituted by at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, cyclopropyloxy or cyclobutyloxy.

26. A compound as claimed in any one of the preceding claims, wherein 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or -CN.

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

28. A compound as claimed in any one of the preceding claims, wherein 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, -NH2 or oxo.

29. A compound as claimed in any one of the preceding claims, wherein 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.

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

31. A compound as claimed in any one of the preceding claims, wherein R 4 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy, wherein 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -CN, -OH, -NH2 or oxo.

32. A compound as claimed in any one of the preceding claims, wherein R 4 is selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, propyl (isopropyl or n-propyl), methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopropyloxy or cyclobutyloxy, wherein methyl, ethyl, propyl (isopropyl or n-propyl), methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopropyloxy or cyclobutyloxy is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, cyclopropyloxy, cyclobutyloxy, -CN, -OH, -NH2 or oxo.

33. A compound as claimed in any one of the preceding claims, wherein 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. A compound as claimed in any one of the preceding claims, wherein R 4 Selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl.

35. A compound as claimed in any one of the preceding claims, wherein Z 1 、Z 2 、Z 3 and Z 4 At most two of them are N; R Z Each is 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 the 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, -I.

36. A compound as claimed in any one of the preceding claims, wherein R Z Each is 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. A compound as claimed in any one of the preceding claims, wherein R Z Each is independently selected from hydrogen, -F, -Cl, -Br, methyl or ethyl.

38. A compound as claimed in any one of the preceding claims, wherein Ar is independently selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, oxazolyl, furanyl, thiazolyl or thienyl; each of said phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, oxazolyl, furanyl, thiazolyl or thienyl is optionally substituted with at least one substituent R Ar replace; R Ar Each is 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or -CN; wherein each of the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or -CN is optionally substituted with at least one substituent selected from -F, -Cl, -Br or -I.

39. A compound as claimed in any one of the preceding claims, wherein Ar is independently selected from phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl or 1,2,4-triazolyl; each of said phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl or 1,2,4-triazolyl is optionally substituted with at least one substituent R Ar replace; R Ar Each is 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -CF3 or -CN.

40. A compound as claimed in any one of the preceding claims, wherein Ar is independently selected from phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl or 1,2,4-triazolyl; each of said phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl or 1,2,4-triazolyl is optionally substituted with at least one substituent R Ar Substitution; wherein R Ar Each is independently selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, methoxy, ethoxy, -CF3 or -CN.

41. A compound as claimed in any one of the preceding claims, wherein the compound is selected from 。 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, and a pharmaceutically acceptable excipient.

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

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

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

47. The use according to 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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