4-(Aminomethyl)-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-1(2H)-one derivatives as MTA-cooperative inhibitors of PRMT5

Abstract

The present disclosure relates to a compound containing the structure 4-(aminomethyl)-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-1(2H)-one, MTAP. DEL Their use to selectively inhibit the activity of PRMT5 in combination with MTA in tumors bearing the mutations, and pharmaceutical compositions containing the compounds as therapeutic agents for various diseases, including cancer, are provided.

Description

[Technical field]

[0001] The present disclosure relates to a compound containing the structure 4-(aminomethyl)-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-1(2H)-one, MTAP. DEL Their use to selectively inhibit the activity of PRMT5 in combination with MTA in tumors bearing the mutations, and pharmaceutical compositions containing the compounds as therapeutic agents for various diseases, including cancer, are provided. [Background technology]

[0002] Epigenetic modifications are processes that can alter the genetic output by changing the primary DNA sequence. Epigenetic modifications play an important role in gene expression and regulation, protein production in multiple dimensions, and cell differentiation. Typically, the process is reversible and selective in DNA, its regulatory proteins (such as histones), and other proteins (such as transcription factors) [Bradbury,EM,BioEssays,1992,14(1):pp.9-16]. PTMs (protein methyltransferases) are central players in epigenetic modifications, consisting of two subfamilies named PKMTs (protein lysine methyltransferases) and PRMTs (protein arginine methyltransferases) [Copeland,RA,et al.,Oncogene,2012.32(8):pp.939-46]. PMT is thought to be a potential therapeutic target for various human diseases and associated deaths [Copeland, RA, et al., Oncogene, 2012.32(8): pp.939-46].

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

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

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

[0006] Homozygous deletion of the tumor-decreasing factor CDKN2A (cyclin-dependent kinase inhibitor 2A) occurs in approximately 15% of all tumor types. Interestingly, the mutation is frequently accompanied by the concomitant deletion of proximal genes present at 9p21, including the gene encoding MTAP (methylthioadenosine phosphorylase) [Firestone, RS, et al., Journal of American Chemical Society, 2017, 139(39): p.13754-60]. MTAP deletion results in the accumulation of MTA (methylthioadenosine), a substrate of MTAP. MTA is a weak ligand / inhibitor of PRMT5 that is structurally related to SAM and occupies the same pocket as SAM. The formation of the MTA-PRMT5 complex provides an opportunity for further PRMT5 inhibition by the formation of a tertiary complex. In this way, a correlation between MTAP absence and PRMT5 dependence is established by MTA concentration levels, leading to precise oncological treatment strategies.

[0007] Currently, most of the clinical-stage PRMT5 inhibitors are based on SAM / MTA competitive mechanisms (JNJ64619178, PF06939999, PRT543, and PRT811) or non-MTA competitive mechanisms (GSK3326595) and are unable to differentiate normal cells and cancer cells. Therefore, there is a continuing unmet medical need for potent and selective MTA-cooperative PRMT5 inhibitors. Summary of the Invention [Problem to be solved by the invention]

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

[0009] Aspect 1. A compound of formula (I): [ka] or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof. [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , and R 12 are each independently hydrogen, halogen, or -C 1-8 Alkyl, -C3-C8 cycloalkyl, -CN, -OR 1a , -NR 1a R 1b , -COR 1a , -CO2R 1a , -CONR 1a R 1b , or -NR 1a COR 1b -C 1-8 Each of alkyl and -C3-C8 cycloalkyl is selected from halogen, -C 1-8 Alkoxy, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -OR 1c , -SO2R 1c , -SO2NR1c R 1d , -COR 1c , -CO2R 1c , -CONR 1c R 1d , -NR 1c R 1d , -NR 1c COR 1d , -NR 1c CO2R 1d , or -NR 1c SO2R 1d and optionally substituted with at least one substituent selected from R 1a and R 1b are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Each aryl or 5- to 12-membered heteroaryl is at least one halogen, -OH, -C 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Optionally substituted with aryl, or 5-12 membered heteroaryl; R 1c and R 1d are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl,1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Each aryl or 5- to 12-membered heteroaryl is at least one halogen, -OH, -C 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Optionally substituted with aryl, or 5-12 membered heteroaryl; R 9 and R 10 are each independently hydrogen, halogen, or -C 1-8 Alkyl, C3-C8 cycloalkyl, -CN, -OR 9a , -NR 9a R 9b , or -NR 9a COR 9b -C 1-8 Each of the alkyl and C3-C8 cycloalkyl groups may have at least one substituent R 9d or R 9 and R 10 together with the carbon atom to which they are attached form a 5-6 membered saturated or partially or fully unsaturated (preferably fully unsaturated, i.e. aromatic) ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring containing at least one substituent R 9e is optionally substituted with; R 9e is, in each occurrence, independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, oxo, 3-8 membered heterocyclyl, C6-C 12Aryl, 5-12 membered heteroaryl, -CN, -SO2R 9a , -SO2NR 9a R 9b , -COR 9a , -CO2R 9a , -CONR 9a R 9b , -NR 9a R 9b , -NR 9a COR 9b , -NR 9a CO2R 9b , or -NR 9a SO2R 9b and -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups may have at least one substituent R 9d and optionally substituted with R 9a and R 9b are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Alkyl-, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Alkyl-, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups may have at least one substituent R 9f and optionally substituted with R 9d and R 9f each occurrence independently represents a halogen, -OH, -C1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; R 13 , R 14 , R 15 , and R 16 are each independently hydrogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, or -C6-C 12 aryl; 1-8 Alkyl, -C3-C8 cycloalkyl, and -C6-C 12 Each aryl is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -NR 13a R 13b , -OR 13a , oxo, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 optionally substituted with at least one substituent selected from aryl, 5-12 membered heteroaryl, or -CN; R 13a and R 13b are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups may have at least one substituent R 13c and optionally substituted with R 13c are independently halogen, hydroxy, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, 5-12 membered heteroaryl, or -CN, 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl is selected from the group consisting of at least one hydrogen, halogen, hydroxyl, -C 1-8 Alkyl, -C 1-8 optionally substituted with alkoxy, -CN, -NH2, or oxo.

[0010] Aspect 2. The compound according to aspect 1, wherein the compound is selected from formula (IIa) or (IIb) [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are each as defined in aspect 1; In each of its occurrences, R 17 is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12Aryl, 5-12 membered heteroaryl, -CN, -SO2R 17a , -SO2NR 17a R 17b , -COR 17a , -CO2R 17a , -CONR 17a R 17b , -OR 17a , -NR 17a R 17b , -NR 17a COR 17b , -NR 17a CO2R 17b , or -NR 17a SO2R 17b are selected independently from -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Each of the aryl, aryl, and 5- to 12-membered heteroaryl is selected from the group consisting of halogen, -C 1-8 Alkoxy, -C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -OR 17c , -SO2R 17c , -SO2NR 17c R 17d , -COR 17c , -CO2R 17c , -CONR 17c R 17d , -NR 17c R 17d , -NR 17c COR 17d , -NR 17c CO2R 17d , or -NR 17c SO2R 17d and optionally substituted with R 17a and R 17b are each independently hydrogen, -C 1-8 Alkyl, -C 2-8Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Each aryl or 5- to 12-membered heteroaryl is at least one halogen, -OH, -C 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Optionally substituted with aryl, or 5-12 membered heteroaryl; R 17c and R 17d are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Each aryl or 5- to 12-membered heteroaryl is at least one halogen, -OH, -C 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Optionally substituted with aryl, or 5-12 membered heteroaryl; n is 0, 1, 2, 3, or 4; m is 0, 1, or 2].

[0011] Aspect 3. The compound according to aspect 1 or aspect 2, wherein the compound is selected from formula (IIIa) or (IIIb) [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are as defined in aspect 1 and as defined in aspect 2, respectively; R 17 , n, and m are each as defined in embodiment 2.

[0012] Aspect 4. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 12 each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -COR 1a , -CO2R 1a , -CONR 1a R 1b , -OR 1a , -NR 1a R 1b , or -NR 1a COR 1bwherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl is selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -OR 1c , -SO2R 1c , -SO2NR 1c R 1d , -COR 1c , -CO2R 1c , -CONR 1c R 1d , -NR 1c R 1d , -NR 1c COR 1d , -NR 1c CO2R 1d , or -NR 1c SO2R 1d and optionally substituted with R 1a , R 1b , R 1c , and R 1d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, as defined above for methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl is selected from the group consisting of halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 The compound of any one of the preceding aspects, optionally substituted with at least one substituent selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0013] Aspect 5. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 12 each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -COR 1a , -CO2R 1a , -CONR 1a R 1b , -OR 1a , -NR 1a R 1b , or -NR 1a COR 1b is selected from R 1a and R 1b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8The compound according to any one of the preceding embodiments, which is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0014] Aspect 6. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 12 are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, preferably R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 12 are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and more preferably, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 12 The compound of any one of the preceding aspects, wherein each is independently selected from hydrogen.

[0015] Aspect 7. R 7 are independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -COR 1a , -CO2R 1a , -CONR 1a R 1b , -OR 1a , -NR 1a R 1b , or -NR1a COR 1b wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl is selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -OR 1c , -SO2R 1c , -SO2NR 1c R 1d , -COR 1c , -CO2R 1c , -CONR 1c R 1d , -NR 1c R 1d , -NR 1c COR 1d , -NR 1c CO2R 1d , or -NR 1c SO2R 1d and optionally substituted with R 1a and R 1b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, as defined above for methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may contain at least one halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, optionally substituted; R 1c and R 1d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, as defined above for methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may contain at least one halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8The compound of any one of the preceding embodiments, optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0016] Aspect 8. R 7 are independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -COR 1a , -CO2R 1a , -CONR 1a R 1b , -OR 1a , -NR 1a R 1b , or -NR 1a COR 1b is selected from R 1a and R 1b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 The compound according to any one of the preceding embodiments, which is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0017] Aspect 9. R 7 is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, preferably R 7 are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, more preferably R 7is independently selected from hydrogen, -F, -Cl, -Br, or -I.

[0018] Aspect 10. R 8 are independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -COR 1a , -CO2R 1a , -CONR 1a R 1b , -OR 1a , -NR 1a R 1b , or -NR 1a COR 1b wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl is selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -OR 1c , -SO2R 1c , -SO2NR 1c R 1d , -COR 1c , -CO2R 1c , -CONR 1c R 1d , -NR 1c R 1d , -NR 1c COR 1d , -NR 1c CO2R 1d , or -NR 1c SO2R 1dand optionally substituted with R 1a and R 1b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, as defined above for methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may contain at least one halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, optionally substituted; R 1c and R 1d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, as defined above for methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may contain at least one halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 The compound of any one of the preceding embodiments, optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0019] Aspect 11. R 8 are independently hydrogen, -F, -Cl, -Br, -I, -CH2F, -CHF2, -CF3, -C2F5, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -COR 1a , -CO2R 1a , -CONR 1a R 1b , -OR 1a , -NR 1a R 1b , or -NR 1a COR 1b is selected from R 1a and R 1b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 The compound according to any one of the preceding embodiments, which is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0020] Aspect 12. R 8 are independently selected from hydrogen, -F, -Cl, -Br, -I, -CHF, -CHF, -CF, -C2F5, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, preferably R 8 are each independently selected from hydrogen, -F, -Cl, -Br, -I, -CHF, -CHF, -CF, -CF, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, more preferably, R 8 is independently selected from hydrogen, -CH2F, -CHF2, -CF3, -C2F5, or -I.

[0021] Aspect 13. R 9 and R 10 each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -OR 9a , -NR 9a R 9b , or -NR 9a COR 9b wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl is selected from at least one substituent R 9d and optionally substituted with R 9a and R 9b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; and the above-mentioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Each of alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may be selected from the group consisting of at least one substituent R 9f and optionally substituted with R 9d and R 9f each occurrence independently represents -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 The compound according to any one of the preceding embodiments, which is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0022] Aspect 14. R 9 and R 10are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, and cyclooctoxy; Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, and cyclooctoxy are -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 The compound of any one of the preceding aspects, optionally substituted with at least one substituent selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0023] Aspect 15. R 9 and R 10are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, and cyclooctoxy.

[0024] Aspect 16.R 9 and R 10 together with the carbon atom to which they are attached form a 5- or 6-membered saturated or partially or fully unsaturated (preferably fully unsaturated, i.e. aromatic) ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring containing at least one substituent R 9e is optionally substituted with; R 9e each occurrence independently represents -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxo, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -CN, -SO2R 9a , -SO2NR 9a R 9b , -COR 9a , -CO2R 9a , -CONR 9a R 9b , -NR 9a R 9b , -NR 9a COR 9b , -NR 9a CO2R 9b , or -NR 9a SO2R9b methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxo, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may be selected from the group consisting of at least one substituent R 9d and optionally substituted with R 9a and R 9b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; and the above-mentioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Each of alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may be selected from the group consisting of at least one substituent R 9f and optionally substituted with R 9d and R 9f each occurrence independently represents -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C2-8 Alkenyl, -C 2-8 The compound according to any one of the embodiments 1 to 12, which is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0025] Aspect 17.R 9 and R 10 together with the carbon atom to which they are attached form a 5- or 6-membered aromatic ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring containing at least one substituent R 9e and optionally substituted with R 9e each occurrence independently represents -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxo, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxo, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl may contain at least one substituent -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C2-8 Alkenyl, -C 2-8 17. A compound according to any one of embodiments 1-12, or 16, optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0026] Aspect 18. R 9 and R 10 together with the carbon atom to which they are attached form a phenyl ring, said ring containing at least one substituent R 9e and optionally substituted with R 9e each occurrence independently represents -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 The compound according to any one of aspects 1-12, or 16-17, wherein the aryl group is alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxo, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -CN.

[0027] Aspect 19. R 11 are independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -COR 1a , -CO2R 1a , -CONR 1a R 1b , or -NR 1a COR 1bwherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl is selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -OR 1c , -SO2R 1c , -SO2NR 1c R 1d , -COR 1c , -CO2R 1c , -CONR 1c R 1d , -NR 1c R 1d , -NR 1c COR 1d , -NR 1c CO2R 1d , or -NR 1c SO2R 1d and optionally substituted with R 1a and R 1b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, as defined above for methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may contain at least one halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, optionally substituted; R 1c and R 1d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, as defined above for methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may contain at least one halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8The compound of any one of the preceding embodiments, optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0028] Aspect 20. R 11 are independently hydrogen, -F, -Cl, -Br, -I, -CH2F, -CHF2, -CF3, -C2F5, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -COR 1a , -CO2R 1a , -CONR 1a R 1b , or -NR 1a COR 1b is selected from R 1a and R 1b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 The compound according to any one of the preceding embodiments, which is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0029] Aspect 21. R 11 are independently selected from hydrogen, -F, -Cl, -Br, -I, -CHF, -CHF, -CF, -C2F5, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or -CN, preferably, R 11 are each independently selected from hydrogen, -F, -Cl, -Br, -I, -CHF, -CHF, -CF, -CF, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or -CN, more preferably, R11 The compound of any one of the preceding embodiments, wherein is -CN.

[0030] Aspect 22. R 13 , R 14 , R 15 , R 16 are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or phenyl, and each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and phenyl is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -NR 13a R 13b , -OR 13a , oxo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, or -CN; R 13a and R 13b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and is selected from the above-mentioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may be selected from the group consisting of at least one substituent R 13c and optionally substituted with R 13c are independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, or -CN, and the above-mentioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 The compound of any one of the preceding aspects, wherein each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionally substituted with at least one hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -CN, -NH2, or oxo.

[0031] Aspect 23. R 13 , R 14 , R 15 , R 16are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or phenyl, and each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and phenyl is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -NR 13a R 13b , -OR 13a , oxo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, or -CN; R 13a and R 13b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 The compound according to any one of the preceding embodiments, wherein the aryl is selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0032] Aspect 24. R 13 , R 14 , R 15 , R 16 are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or phenyl; preferably, R 13 , R 14 , R 15 , R 16are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, more preferably R 13 , R 14 , R 15 , R 16 are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0033] Aspect 25. R 13 , R 14 , R 15 , R 16 are each independently selected from hydrogen and methyl, preferably R 13 is methyl, R 14 , R 15 , and R 16 The compound of any one of the preceding aspects, wherein each is hydrogen.

[0034] Aspect 26. R 17 are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -CN, -SO2R 17a , -SO2NR 17a R 17b , -COR 17a , -CO2R 17a , -CONR 17a R 17b , -OR 17a , -NR 17a R 17b , -NR 17a COR 17b , -NR 17a CO2R 17b , or -NR 17a SO2R 17bmethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl is selected from the group consisting of -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, oxo, -CN, -OR 17c , -SO2R 17c , -SO2NR 17c R 17d , -COR 17c , -CO2R 17c , -CONR 17c R 17d , -NR 17c R 17d , -NR 17c COR 17d , -NR 17c CO2R 17d , or -NR 17c SO2R 17d and optionally substituted with R 17a and R 17b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, as defined above for methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is selected from the group consisting of at least one of -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, optionally substituted; R 17c and R 17d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, as defined above for methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is selected from the group consisting of at least one of -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8The compound of any one of the preceding embodiments, optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0035] Aspect 27. R 17 are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -CN, -SO2R 17a , -SO2NR 17a R 17b , -COR 17a , -CO2R 17a , -CONR 17a R 17b , -OR 17a , -NR 17a R 17b , -NR 17a COR 17b , -NR 17a CO2R 17b , or -NR 17a SO2R 17b is selected from R 17a and R 17b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, as defined above for methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is selected from the group consisting of at least one of -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 The compound of any one of the preceding embodiments, optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0036] Aspect 28. R 17 is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, -CN, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, cyclooctoxy.

[0037] Aspect 29. [ka] The part is [ka] The compound of any one of the preceding aspects,

[0038] Aspect 30. [ka] The part is [ka] The compound of any one of the preceding aspects,

[0039] Aspect 31. [ka] The part is [ka] The compound of any one of the preceding aspects,

[0040] Embodiment 32. The compound according to any one of the preceding embodiments, wherein the compound is selected from the following: [ka]

[0041] Aspect 33. A pharmaceutical composition comprising a compound according to any one of aspects 1 to 32, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, together with a pharma- ceutically acceptable excipient.

[0042] Aspect 34. A method of reducing PRMT5 activity by inhibition, comprising administering to an individual a compound of formula (I) or a compound according to any one of aspects 1 to 33, including the specific compounds exemplified herein, or a pharma- ceutically acceptable salt thereof.

[0043] Embodiment 35. The method of embodiment 34, wherein the disease is selected from cancer.

[0044] Embodiment 36. Use of a compound according to any one of embodiments 1 to 32, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, in the preparation of a medicament for treating a disease modulated by PRMT5.

[0045] Embodiment 37. The use according to embodiment 36, wherein the disease is cancer.

[0046] Aspect 38. The use according to aspect 37, wherein the disease is an MTAP-null solid tumor, including but not limited to lung cancer, bladder cancer, melanoma, pancreatic cancer, esophageal cancer, gastric adenocarcinoma, breast cancer, glioblastoma, etc. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] The following terms have the meanings indicated throughout this specification: Unless specifically defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0048] The following terms have the meanings indicated throughout this specification: As used in this specification, including the appended claims, singular words such as "a," "an," and "the" include their corresponding plural references unless the context clearly dictates otherwise.

[0049] The term "or" means, and is used interchangeably with, the term "and / or," unless context clearly dictates otherwise.

[0050] The term "alkyl" includes hydrocarbon groups selected from linear and branched saturated hydrocarbon groups containing 1 to 18, for example 1 to 12, further 1 to 10, further 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. Alkyl containing 1 to 6 carbon atoms (i.e., C 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 s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0051] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0052] The term "butyl" includes 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), and 1,1-dimethylethyl or t-butyl ("t-Bu").

[0053] 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.

[0054] 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.

[0055] The term "alkylene" refers to a divalent alkyl group formed by removing two hydrogens from an alkane. Alkylene includes, but is not limited to, methylene, ethylene, propylene, and the like.

[0056] The term "halogen" includes fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0057] The term "alkenyl" includes hydrocarbon groups selected from linear and branched chain hydrocarbon groups containing at least one C=C double bond and 2 to 18, such as 2 to 8, further such as 2 to 6, carbon atoms. Alkenyl groups, such as C 2-6 Examples of alkenyl include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl groups.

[0058] The term "alkenylene" refers to a divalent alkenyl group formed by removing two hydrogens from an alkene. Alkenylene includes, but is not limited to, vinylidene, butenylene, and the like.

[0059] The term "alkynyl" includes hydrocarbon groups selected from linear and branched chain hydrocarbon groups containing at least one C≡C triple bond and 2 to 18, such as 2 to 8, further such as 2 to 6, carbon atoms. Alkynyl groups, such as C 2-6 Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0060] The term "alkynylene" refers to a divalent alkynyl group formed by removing two hydrogens from an alkyne. Alkenylene includes, but is not limited to, ethynylene, and the like.

[0061] 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 spirocycloalkyls.

[0062] For example, the cycloalkyl group may contain 3 to 12, such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Further, for example, the cycloalkyl group may be selected from monocyclic groups containing 3 to 12, such as 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, saturated monocyclic cycloalkyl (e.g., C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, cycloalkyl is a monocyclic ring containing 3 to 6 carbon atoms (C), including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3-6 Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0063] The term "spirocycloalkyl" includes cyclic structures containing carbon atoms and formed by at least two rings which share one atom.

[0064] 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.

[0065] The term "bridged cycloalkyl" includes cyclic structures containing carbon atoms and formed by two rings sharing two atoms that are not adjacent to each other. The term "7-10 membered bridged cycloalkyl" includes cyclic structures containing 7-12 carbon atoms and formed by two rings sharing two atoms that are not adjacent to each other.

[0066] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo 3-8 membered cycloalkyl, benzo C 4-6 Examples include, but are not limited to, cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8-9 membered fused rings, which refers to ring structures containing 8-9 ring atoms within the scope of the preceding examples.

[0067] The term "aryl", used alone or in combination with other terms, - 5 and 6 membered carbocyclic aromatic rings, for example phenyl; Bicyclic ring systems, for example 7-12 membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example naphthyl and indanyl, and - Tricyclic ring systems, such as 10-15 membered tricyclic ring systems, in which at least one ring is carbocyclic and aromatic, e.g., fluorenyl The present invention includes a group selected from the group consisting of

[0068] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0069] Specifically, the term "bicyclic fused aryl" includes bicyclic aryl rings as defined herein. An exemplary bicyclic fused aryl is naphthalene.

[0070] The term "heteroaryl" includes groups selected from: - a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom, e.g., 1-4, or in some embodiments 1-3, and in some embodiments 1-2 heteroatoms, selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring atoms being carbon; - 7-12 membered bicyclic rings containing at least one heteroatom selected from N, O, and S, e.g., 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being in the aromatic ring; and - An 11-14 membered tricyclic ring containing at least one heteroatom, e.g., 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2 heteroatoms, selected from N, O, and S, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being in the aromatic ring.

[0071] When the total number of S and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in a heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is 1 or less. When a heteroaryl group contains two or more heteroatom ring members, the heteroatoms may be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group may be oxidized to form an N-oxide.

[0072] In particular, the term "bicyclic fused heteroaryl" includes 7-12 membered, preferably 7-10 membered, more preferably 9 or 10 membered fused bicyclic heteroaryl rings as defined herein. Typically, bicyclic fused heteroaryls are 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclics. Groups can be attached to the remainder of the molecule via either ring.

[0073] "Heterocyclyl", "heterocycle", or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclyl group containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, and including monocyclic, fused, bridged, and spirocyclic rings, i.e., including monocyclic, heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclic groups.

[0074] The term "at least one substituent" as disclosed herein includes, for example, 1 to 4 substituents, such as 1 to 3, further 1 or 2, as long as valence theory is satisfied. For example, "at least one substituent F" as disclosed herein includes, for example, 1 to 3, further 1 or 2, 1 to 4 substituents selected from the list of F disclosed herein.

[0075] The term "divalent" refers to a linking group capable of forming a covalent bond with two other moieties. For example, a "divalent cycloalkyl group" refers to a cycloalkyl group obtained by removing two hydrogens from a corresponding corresponding cycloalkyl group to form a linking group. The terms "divalent aryl group," "divalent heterocyclyl group," or "divalent heteroaryl group" should be understood in a similar manner.

[0076] The compounds disclosed herein may have asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. When the compounds disclosed herein have two or more asymmetric centers, they may further exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All such possible stereoisomers are intended to be included, such as substantially purely resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharma-ceutically acceptable salts are intended to be included. Unless otherwise specified, a reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is not specified, all possible isomers are included.

[0077] When compounds disclosed herein contain olefinic double bonds, unless otherwise specified, such double bonds are intended to include both E and Z geometric isomers.

[0078] When the compounds disclosed herein comprise a disubstituted cyclic ring system, the substituents found in such ring system can adopt cis and trans configuration.Cis configuration means that both substituents are found on the top side of the arrangement of two substituents on carbon, while trans means that they are on the opposite side.For example, the disubstituted cyclic ring system can be a cyclohexyl or cyclobutyl ring.

[0079] It may be advantageous to separate reaction products from each other and / or from starting materials. The desired products of each step or series of steps may be separated and / or purified (hereinafter separated) to the desired degree of homogeneity by techniques common in the art. Typically, such separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include any number of methods, including, for example, reverse and normal phase, size exclusion, ion exchange, high, medium, and low pressure liquid chromatography methods and apparatus, small scale analytical, simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as small scale thin layer and flash techniques. One skilled in the art will be able to select and apply the techniques most likely to achieve the desired separation.

[0080] "Diastereomers" refers to stereoisomers of a compound that have two or more chiral centers, but are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional recrystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by the use of chiral HPLC columns.

[0081] Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by resolution of racemic mixtures using methods such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H., et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3)(1975): pp.283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of diastereomers, and conversion to pure stereoisomers, and (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions. See Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0082] Some of the compounds disclosed herein may exist at different points of hydrogen attachment, called tautomers. For example, compounds containing a carbonyl -CH2C(O)- group (keto form) may undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Where applicable, both keto and enol forms, as well as mixtures thereof, are intended to be included.

[0083] "Prodrug" refers to a derivative of an active drug that requires a transformation in the body to release the active drug. In some embodiments, the transformation is enzymatic. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to an active drug.

[0084] "Pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, and the like, within the scope of sound medical judgment, and that correspond to 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 function with a suitable organic acid, or by reacting an acidic group with a suitable base. The term also includes salts of stereoisomers (enantiomers and / or diastereomers), tautomers, and prodrugs of the compounds of the invention.

[0085] In addition, when the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, such as a pharma- ceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize a variety of synthetic methods that can be used without undue experimentation to prepare non-toxic pharma-ceutically acceptable addition salts.

[0086] The terms "administration," "administering," "treat," and "treatment," as used herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to the contact of an exogenous pharmaceutical, therapeutic, diagnostic, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent with the cell, as well as contact of a reagent with a fluid, where the fluid contacts the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatments, e.g., of a cell, with a reagent, diagnostic, binding compound, or with another cell. The term "subject" as used herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0087] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient, such as a compound, that, when administered to a subject to treat a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or condition. A "therapeutically effective amount" can vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. The appropriate amount in any given case may be apparent to one of ordinary skill in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer, tautomer, or prodrug thereof, and / or at least one pharma- ceutically acceptable salt thereof, which is effective for "treating" a disease or disorder in a subject, as defined herein. In the case of a combination therapy, the term "therapeutically effective amount" refers to the total amount of the combination objects for effective treatment of a disease, disorder, or condition.

[0088] The term "disease" refers to any disease, ailment, disorder, symptom or indication, and may be interchangeable with the term "disorder" or "condition."

[0089] Throughout this specification and the claims that follow, unless the context otherwise requires, the term "comprise," as well as variations such as "comprises" and "comprising," are intended to specify the presence of the subsequent feature but do not exclude the presence or addition of one or more other features. As used herein, the term "comprising" can be substituted with the terms "containing," "including," or, in some cases, "having."

[0090] Throughout this specification and the following claims, "C n-mThe term "inclusive" denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. Examples include 1-8 , C 1-6 etc.

[0091] Unless specifically defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. EXAMPLES

[0092] General Synthesis The compounds disclosed herein and their salts can be prepared using known organic synthesis techniques, or can be synthesized according to any of a number of possible synthetic routes.

[0093] The reaction for preparing the compounds disclosed herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.A suitable solvent can be substantially non-reactive with starting materials, intermediates, or products at the temperature at which the reaction is carried out, for example, at a temperature that can vary from the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of solvents.

[0094] The selection of appropriate protecting groups can be readily determined by one of ordinary skill in the art. In the synthetic schemes, some protection / deprotection steps are not shown and can be incorporated before, after, or between any steps.

[0095] The reaction can be monitored according to any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. The compound can be purified by various methods, including preparative HPLC and silica gel chromatography. Unless otherwise specified, preparative HPLC uses a buffered acetonitrile / water system, and silica gel chromatography (including column chromatography and preparative TLC) uses a PE / EtOAc or DCM / MeOH system as a mobile phase.

[0096] Chiral analytical HPLC was used for retention time analysis of various chiral examples, and the conditions were divided into the following methods according to the column, mobile phase, and solvent ratio used:

[0097] Scheme I [ka] For example, a compound of formula (I) can be formed as shown in Scheme I. Compound (i) and compound (ii) can be coupled by a transition metal catalyzed reaction to give compound (iii); the compound can be halogenated to give compound (iv). In parallel, compound (vi) can be boronated to give compound (vii). Compound (iv) and compound (vi) can be coupled by a transition metal catalyzed reaction to give compound (vii) [i.e., formula (I)].

[0098] Scheme II [ka] For example, compounds of formula (I) can be formed as shown in Scheme I. Compounds (i) and (ii) can be coupled by a transition metal catalyzed reaction to give compound (iii); the compound can be halogenated to give compound (iv). In parallel, compound (vi) can be boronated to give compound (vii). Compounds (iv) and (vi) can be coupled by a transition metal catalyzed reaction to give compound (vii) [i.e., formula (IIIa)].

[0099] Scheme III [ka] For example, compounds of formula (I) can be formed as shown in Scheme I. Compounds (i) and (ii) can be coupled by a transition metal catalyzed reaction to give compound (iii); the compound can be halogenated to give compound (iv). In parallel, compound (vi) can be boronated to give compound (vii). Compounds (iv) and (vi) can be coupled by a transition metal catalyzed reaction to give compound (vii) [i.e., formula (IIIb)].

[0100] TIFF2025509404000014.tif187138

[0101] Example 1: 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthonitrile [ka]

[0102] Step 1: Methyl 4-bromo-2-(dicyanomethyl)benzoate [ka] A mixture of methyl 4-bromo-2-iodobenzoate (6.0 g, 17.6 mmol), malononitrile (1.4 g, 21.2 mmol), (S)-proline (400 mg, 3.5 mmol), CuI (660 mg, 3.5 mmol), and K2CO3 (3.6 g, 26.1 mmol) in DMSO (60 mL) was heated to 60 °C and stirred for 3 h. After the mixture was cooled to room temperature and diluted with water (300 mL), concentrated HCl was added to adjust the pH of the mixture to 5-6. The mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE:EtOAc = 4:1) to give the title compound (3.7 g, 76%). LC-MS (M+H) +=278.9.

[0103] Step 2: tert-Butyl ((6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)carbamate [ka] To a solution of methyl 4-bromo-2-(dicyanomethyl)benzoate (500 mg, 1.8 mg) in ethanol (10 mL) was added Raney nickel (100 mg) and ammonia solution (25%, 2 mL). The mixture was heated to 50° C. under 4 atm of hydrogen overnight. The solid was filtered off and the solvent was evaporated in vacuum. The residue was dissolved in DCM (10 mL) and then triethylamine (0.5 mL, 12.2 mmol) and Boc2O (780 mg, 9.1 mmol) were added. The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=10:1) to give the title compound (50 mg, 8%). LC-MS (M+H) + =353.0.

[0104] Step 3: tert-Butyl ((1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydroisoquinolin-4-yl)methyl)carbamate [ka] To a solution of tert-butyl ((6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)carbamate (100 mg, 0.28 mmol) in dioxane (1 mL) was added Pd(dppf)Cl2 (20.72 mg, 0.028 mmol), BPD (79 mg, 0.31 mmol), and KOAc (83 mg, 0.85 mmol). The mixture was heated to 100° C. and stirred for 12 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC to give the title compound (53 mg, 46%). LC-MS (M+H) + =401.0.

[0105] Step 4: 5-Bromo-7-fluoro-9-methyl-1,4-dihydro-1,4-epiminonaphthalene [ka] To a solution of 1,3-dibromo-2-chloro-5-fluorobenzene (30.5 g, 105.9 mmol) and 1-methylpyrrole (17.2 g, 211.8 mol) in toluene (750 mL) was added n-BuLi (2.5 M in hexanes, 44.5 mL, 111 mol) dropwise at -30°C under nitrogen. The mixture was stirred for 30 min at -30°C and then warmed to room temperature. After 12 h, the mixture was quenched with water (10 mL) and concentrated under reduced pressure. The residue was diluted with EtOAc (500 mL), washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EtOAc=3:2) to give the title compound (15 mg, 60%). LC-MS (M+H) + =254.1.

[0106] Step 5: 1-Bromo-3-fluoronaphthalene [ka] To a solution of 5-bromo-7-fluoro-9-methyl-1,4-dihydro-1,4-epimino-naphthalene (9.3 g, 36.8 mmol) in chloroform (250 mL) was carefully added m-CPBA (75%, 17 g, 73.5 mmol) in small portions while maintaining the internal temperature below 40° C. After 26 h, the solids were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (7.3 g, 89%). LC-MS (M+H) + =225.1.

[0107] Step 6: 3-Fluoro-1-naphthonitrile [ka] A mixture of 1-bromo-3-fluoronaphthalene (4.4 g, 19.6 mmol), Pd2(dba)3 (1.8 g, 1.96 mmol), zinc cyanide (5.7 g, 49 mmol), dppf (2.2 g, 3.9 mmol), and Zn powder (127 mg, 1.96 mmol) in DMF (50 mL) was purged with N2 and then stirred at 115 °C for 4 h. The mixture was cooled to room temperature, filtered, and the filtrate was diluted with EtOAc (200 mL), washed with brine (200 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 (3.1 g, 92%). LC-MS (M + H) + =172.1.

[0108] Step 7: 3-Fluoro-2-iodo-1-naphthonitrile [ka] n-BuLi (2.5M in hexanes, 7.7 mL, 19.2 mol) was added to a solution of N-isopropylpropan-2-amine (2.3 g, 22.7 mmol) in THF (50 mL) at -78 °C and stirred for 15 min. 3-Fluoro-1-naphthonitrile (3.0 g, 17.4 mmol) in THF (40 mL) was added to the mixture and stirred at -78 °C for 30 min. Then, a solution of iodine (5.7 g, 22.7 mmol) in THF (40 mL) was added to the mixture and stirred for 30 min at -78 °C. The mixture was allowed to warm to room temperature and stirred for an additional 10 h. The mixture was quenched with saturated NH4Cl (40 mL) and extracted with EtOAc (150 mL). The organic layer was washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column (PE:EtOAc=10:1) to give the title compound (2.6 g, 50%).

[0109] Step 8: 3-Fluoro-2-(1-methyl-1H-pyrazol-5-yl)-1-naphthonitrile [ka] To a solution of 3-fluoro-2-iodo-1-naphthonitrile (1.6 g, 5.4 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.5 g, 11.9 mmol) in dioxane (20 mL) and water (2 mL), Pd(dtbpf)Cl2 (352 mg, 0.54 mmol) and NaHCO3 (1.4 g, 16.2 mmol) were added and then stirred at 80 °C for 12 h. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed successively with water (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EtOAc = 2: 1) to give the title compound (840 mg, 62%). LC-MS (M + H) + =252.2.

[0110] Step 9: 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthonitrile [ka] To a solution of 3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)-1-naphthonitrile (560 mg, 2.2 mmol) in MeCN (10 mL) was added NBS (713 mg, 4.0 mmol) and the mixture was stirred for 3 h at room temperature. The mixture was diluted with EtOAc (30 mL), washed successively with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EtOAc=3:1) to give the title compound (640 mg, 87%). LC-MS (M+H) + =330.1.

[0111] Step 10: tert-Butyl ((6-(5-(1-cyano-3-fluoronaphthalen-2-yl)-1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)carbamate [ka] A mixture of tert-butyl ((1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydroisoquinolin-4-yl)methyl)carbamate, 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthonitrile (53 mg, 0.14 mmol), Pd(dppf)Cl2 (10 mg, 0.01 mmol), K2CO3 (39 mg, 0.28 mmol) in dioxane (5 mL) and water (1 mL) was heated to reflux under nitrogen for 8 h. After the mixture was cooled to room temperature, it was partitioned between water (20 mL) and EtOAc (20 mL). The separated organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (50 mg, 33%). LC-MS (M+H) + =524.2.

[0112] Step 11: 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthonitrile [ka] Solid tert-butyl ((6-(5-(1-cyano-3-fluoronaphthalen-2-yl)-1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)carbamate (50 mg, 0.96 mmol) was added to HCl in dioxane (4.0 M, 6 mL). The mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The crude product was purified by preparative TLC to give Example 1 (6 mg, 15%). LC-MS (M+H) + =424.2. 1H NMR(400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.51 (d, J = 10.2 Hz, 1H), 8.24 (d, J = 7.0 Hz, 2H), 8.14 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.89-7.84 (m, 2H), 7.41 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.97 (s, 1H), 3.80 (s, 3H), 3.31 (s, 2H).

[0113] Example 2: 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxybenzonitrile hydrochloride [ka]

[0114] Step 1: 2-Bromo-4-chloro-6-fluoronitrile [ka] To a solution of 2-bromo-4-chloro-6-fluoroaniline (15 g, 67 mmol) in anhydrous DCM (60 mL) was added nitrosonium tetrafluoroborate (8.6 g, 74 mmol) and the mixture was stirred at 25 °C for 1 h. The reaction mixture was then cooled to 0 °C. KCN (9.3 g, 143 mmol) was added to the mixture followed by dropwise addition of CuSO4·5H2O (33 g, 134 mmol) in water (300 mL). After stirring at 0 °C for 40 min, the reaction mixture was warmed to 25 °C and stirred for an additional 1 h. The reaction mixture was diluted with DCM (100 mL) and saturated NaHCO3 solution was added slowly until gas evolution ceased. The heterogeneous mixture was filtered through a celite pad. The organic layer was separated, washed with brine (50 mL × 2), dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc=1:0→50:1) to give the title compound (3.7 g, 24%).

[0115] Step 2: 2-Bromo-4-chloro-6-cyclopropoxybenzonitrile [ka] To a solution of 2-bromo-4-chloro-6-fluoronitrile (3.7 g, 16 mmol), cyclopropanol (1.37 g, 23.7 mmol) in DMF (15 mL) was added Cs2CO3 (12.9 g, 39.5 mmol). The mixture was stirred at 25° C. for 4 h and then quenched with water (45 mL). The mixture was extracted with EtOAc (45 mL×3). 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 column chromatography (PE:EtOAc=1:0→1:1) to give the title compound (1.5 g, 35%). LC-MS (M+H) + =272.0.

[0116] Step 3: 4-Chloro-2-cyclopropoxy-6-(1-methyl-1H-pyrazol-5-yl)benzonitrile [ka] To a solution of 2-bromo-4-chloro-6-cyclopropoxybenzonitrile (1.3 g, 4.77 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (993 mg, 4.77 mmol) in dioxane (1 mL) and water (0.2 mL) was added NaHCO3 (1.0 g, 12 mmol) and Pd(t-Bu3P)2 (244 mg, 0.48 mmol). The mixture was stirred at 80 °C for 12 h. The mixture was cooled to room temperature and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 → 0:1) to give the title compound (0.4 g, 31%). 1H NMR(400MHz,CDCl3)δ 7.55 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 1.2 Hz, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.45 (d, J = 1.6 Hz, 1H), 3.96-3.81 (m, 4H), 3.74 (s, 3H), 1.01-0.88 (m, 4H), 0.88-0.75 (m, 2H). LC-MS(M+H) + =274.1.

[0117] Step 4: 4-Chloro-2-cyclopropoxy-6-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile [ka] To a solution of 4-chloro-2-cyclopropoxy-6-(1-methyl-1H-pyrazol-5-yl)benzonitrile (0.35 g, 1.28 mmol) in AcOH (3.5 mL) was added NIS (575 mg, 2.56 mmol). The mixture was stirred at 60° C. for 4 h. After adding PE (5.0 mL) to the mixture, the precipitate was collected by filtration. The solid was washed with PE (5 mL) to give the title compound (0.10 g, 20%). LC-MS (M+H) + =400.0.

[0118] Step 5: tert-Butyl ((6-(5-(5-chloro-2-cyano-3-cyclopropoxyphenyl)-1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)carbamate [ka] To a solution of 4-chloro-2-cyclopropoxy-6-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile (80 mg, 0.20 mmol) and tert-butyl ((1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydroisoquinolin-4-yl)methyl)carbamate (40 mg, 0.10 mmol) in dioxane (1 mL) and water (0.2 mL) was added Na2CO3 (42 mg, 0.40 mmol) and Pd(dppf)Cl2 (15 mg, 0.02 mmol). The mixture was stirred at 80° C. for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC to give the title compound (20 mg, 37%). LC-MS (M+H) + =546.2.

[0119] Step 6: 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxybenzonitrile hydrochloride [ka] To a solution of tert-butyl ((6-(5-(5-chloro-2-cyano-3-cyclopropoxyphenyl)-1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)carbamate (20 mg, 0.037 mmol) in MeOH (0.5 mL) was added HCl / MeOH (4 M, 0.3 mL). The mixture was stirred at 25° C. for 0.5 h and then concentrated under reduced pressure. The crude product was purified by preparative HPLC using water (HCl) / MeCN system to give Example 2 (7 mg, 38%). 1H NMR(400MHz,DMSO-d6) δ 11.50-11.40 (m, 1H), 8.48-8.20 (m, 4H), 8.06 (d, J = 8.4 Hz, 1H), 7.82-7.73 (m, 2H), 7.49-7.43 (m, 1H), 7.40 (d, J = 6.0 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.27-4.19 (m, 1H), 4.17-4.00 (m, 2H), 3.74 (s, 3H), 0.99-0.88 (m, 2H), 0.88-0.75 (m, 2H). LC-MS (M-NH2) + = 429.0.

[0120] Example 3: 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride [ka]

[0121] Step 1: 4-Chloro-2-cyclopropoxy-5-fluorobenzonitrile [ka] To a solution of 4-chloro-2,5-difluoro-benzonitrile (45.0 g, 259 mmol), cyclopropanol (18.0 g, 311 mmol) in DMF (150 mL) was added Cs2CO3 (168 g, 518 mmol). The mixture was stirred at 25° C. for 12 h. The mixture was quenched with water (1500 mL) and extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=1:0→1:1) to give the title compound (70.0 g, 64%).

[0122] Step 2: 4-Chloro-6-cyclopropoxy-3-fluoro-2-iodobenzonitrile [ka] To a solution of 4-chloro-2-cyclopropoxy-5-fluorobenzonitrile (68.5 g, 323 mmol) in THF (316 mL) was added LDA (2.0 M in THF / heptane, 194 mL) dropwise at −78° C. over 0.5 h. Iodine (98.5 g, 388 mmol) in THF (95.0 mL) was added dropwise at −78° C. over 1.5 h. The residue was poured into saturated NH4Cl (100 mL) and stirred for 30 min. The mixture was extracted with ethyl acetate (150 mL×3). The combined organic layers were washed with 10% Na2SO3 (150 mL), brine (50.0 mL×2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EtOAc=1:0→1:1) to give the title compound (60.0 g, 55%).

[0123] Step 3: 4-Chloro-6-cyclopropoxy-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile [ka] To a mixture of 4-chloro-6-cyclopropoxy-3-fluoro-2-iodobenzonitrile (50.0 g, 148 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40.0 g, 192 mmol), and KF (21.5 g, 370 mmol) in dioxane (250 mL) and water (50 mL) was added bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (10.4 g, 14.8 mmol). The mixture was stirred at 60° C. for 16 hours. The mixture was poured into water (150 mL) and extracted with EtOAc (500 mL×2). The combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc=20:1→3:1) to give the title compound (30.0 g, 49%). LC-MS (M+H) + =292.0.

[0124] Step 4: 4-Chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile [ka] To a solution of 4-chloro-6-cyclopropoxy-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile (30.0 g, 102 mmol) in AcOH (180 mL) was added NIS (46.2 g, 205 mmol). The mixture was stirred at 60° C. for 3.5 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=20:1→3:1) to give the title compound (24.5 g, 57%). LC-MS (M+H) + =418.0.

[0125] Step 5: tert-Butyl ((6-(5-(3-chloro-6-cyano-5-cyclopropoxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)carbamate [ka] To a solution of 4-chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile (20 mg, 0.048 mmol), tert-butyl ((1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydroisoquinolin-4-yl)methyl)carbamate (20 mg, 0.048 mmol) in dioxane (1 mL) and water (0.2 mL) was added Na2CO3 (10 mg, 0.096 mmol) and Pd(dppf)Cl2 (3.5 mg, 0.005 mmol). The mixture was stirred at 80° C. for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC to give the title compound (20 mg, 74%). LC-MS (M+H) + =564.3.

[0126] Step 6: 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile hydrochloride [ka] To a solution of tert-butyl ((6-(5-(3-chloro-6-cyano-5-cyclopropoxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)carbamate (20 mg, 0.035 mmol) in MeOH (0.5 mL) was added HCl in MeOH (4.0 M, 4.0 mL). The mixture was stirred at 25° C. for 0.5 h and then concentrated under reduced pressure. The crude product was purified by preparative HPLC using water (HCl) / MeCN system to give Example 3 (7 mg, 45%). 1H NMR(400MHz,DMSO-d6)δ 11.48 (d, J = 5.6 Hz, 1H), 8.41 (s, 1H), 8.40-8.20 (br s, 3H), 8.08 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.83 (s, 1H), 7.41 (d, J = 6.0 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.28-4.22 (m, 1H), 4.20-4.02 (m, 2H), 3.77 (s, 3H), 0.98-0.87 (m, 2H), 0.87-0.76 (m, 2H). LC-MS (M-NH2) + = 447.0.

[0127] Example 4: 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-methyl-1-naphthonitrile hydrochloride [ka]

[0128] Step 1: 2-Iodo-4-methyl-1-naphthonitrile [ka] To a solution of 4-methyl-1-naphthonitrile (9.0 g, 53.8 mmol) in DCE (54 mL) was added NIS (14.5 g, 64.6 mmol), TsOH (4.63 g, 26.9 mmol), and Pd(OAc)2 (1.21 g, 5.38 mmol). The mixture was stirred at 70° C. for 12 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc=1 / 0→0 / 1) to give the title compound (3.50 g) as an impure mixture. LC-MS (M+H) + =294.0.

[0129] Step 2: 4-Methyl-2-(1-methyl-1H-pyrazol-5-yl)-1-naphthonitrile [ka] To a solution of 2-iodo-4-methyl-1-naphthonitrile (3.50 g, directly from step 1) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.48 g, 11.9 mmol) in dioxane (20 mL) and water (4 mL) was added Na2CO3 (2.53 g, 23.9 mmol) and Pd(dtbpf)Cl2 (778 mg, 1.19 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were concentrated under vacuum and the residue was purified by silica column chromatography (PE: EtOAc = 100: 1 -> 0: 1) to give the title compound (80 mg, 0.6% over two steps). LC-MS (M + H) + =248.0.

[0130] Step 3: 2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-4-methyl-1-naphthonitrile [ka] To a solution of 4-methyl-2-(1-methyl-1H-pyrazol-5-yl)-1-naphthonitrile (80 mg, 0.32 mmol) in HOAc (1 mL) was added NIS (87 mg, 0.39 mmol). The mixture was stirred at 20° C. for 12 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (80 mg, 66%). LC-MS (M+H) + =374.1.

[0131] Step 4: tert-Butyl ((6-(5-(1-cyano-4-methylnaphthalen-2-yl)-1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)carbamate [ka] To a solution of 2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-4-methyl-1-naphthonitrile (60 mg, 0.16 mmol) and tert-butyl ((1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydroisoquinolin-4-yl)methyl)carbamate (32 mg, 0.08 mmol) in dioxane (2 mL) and water (0.4 mL) was added Na2CO3 (43 mg, 0.40 mmol) and Pd(dppf)Cl2 (12 mg, 0.016 mmol). The mixture was stirred at 80 °C for 3 h, cooled to room temperature and diluted with water (2 mL). The mixture was extracted with EtOAc (2 mL x 2) and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (10 mg, 12%). LC-MS (M+H) + =520.0.

[0132] Step 5: 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-methyl-1-naphthonitrile hydrochloride [ka] To a solution of tert-butyl ((6-(5-(1-cyano-4-methylnaphthalen-2-yl)-1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)carbamate (10 mg, 0.019 mmol) in MeOH (2 mL) was added HCl / MeOH (4 M, 0.005 mL). The mixture was stirred at 20° C. for 2 h and then concentrated under reduced pressure to give Example 4 (4 mg, 54%). 1H NMR (400 MHz, CD3OD) δ 8.37-8.31 (m, 1H), 8.24-8.17 (m, 2H), 8.04 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.88-7.82 (m, 2H), 7.62 (s, 1H), 7.38 (s, 1H), 7.04 (dd, J = 8.8, 1.2 Hz, 1H), 4.28-4.18 (m, 2H), 3.85 (s, 3H), 2.88 (s, 3H).LC-MS (M-NH2) + = 403.0.

[0133] Example 5: 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-1-naphthonitrile hydrochloride [ka]

[0134] Step 1: 4-Chloro-2-iodo-1-naphthonitrile [ka] To a solution of 4-chloro-1-naphthonitrile (4.0 g, 21.3 mmol) in DCE (24 mL) was added NIS (5.28 g, 23.5 mmol), TsOH (1.84 g, 10.7 mmol), and Pd(OAc)2 (479 mg, 2.13 mmol). The mixture was stirred at 70° C. for 12 h, cooled to room temperature, and concentrated in vacuo. The residue was purified by preparative TLC to give the title compound (2.0 g, 30%).

[0135] Step 2: 4-Chloro-2-(1-methyl-1H-pyrazol-5-yl)-1-naphthonitrile [ka] To a solution of 4-chloro-2-iodo-1-naphthonitrile (0.50 g, 1.59 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (332 mg, 1.59 mmol) in dioxane (5 mL) and water (1 mL) was added NaHCO3 (268 mg, 3.19 mmol) and Pd(dtbpf)Cl2 (104 mg, 0.16 mmol). The mixture was stirred at 80 °C for 12 h. The mixture was cooled to room temperature, diluted with water (5 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were concentrated under vacuum. The residue was purified by preparative TLC to give the title compound (50 mg, 12%). LC-MS (M+H) + =268.0.

[0136] Step 3: 4-Chloro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-1-naphthonitrile [ka] To a solution of 4-chloro-2-(1-methyl-1H-pyrazol-5-yl)-1-naphthonitrile (0.30 g, 1.12 mmol) in HOAc (2 mL) was added NIS (302 mg, 1.34 mmol). The mixture was stirred at 20° C. for 12 h and then concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (0.2 g, 45%). LC-MS (M+H) + =393.9.

[0137] Step 4: tert-Butyl ((6-(5-(4-chloro-1-cyanonaphthalen-2-yl)-1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)carbamate [ka] To a solution of 4-chloro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-1-naphthonitrile (50 mg, 0.13 mmol) and tert-butyl ((1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydroisoquinolin-4-yl)methyl)carbamate (25 mg, 0.063 mmol) in dioxane (1 mL) and water (0.2 mL) was added Na2CO3 (34 mg, 0.32 mmol) and Pd(dppf)Cl2 (9 mg, 0.013 mmol). The mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with water (2 mL) and extracted with EtOAc (2 mL x 2). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel chromatography to give the title compound (12 mg, 18%). LC-MS (M+H) + =540.2.

[0138] Step 5: 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-1-naphthonitrile hydrochloride [ka] To a solution of tert-butyl ((6-(5-(4-chloro-1-cyanonaphthalen-2-yl)-1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)carbamate (10 mg, 0.019 mmol) in MeOH (2 mL) was added HCl in MeOH (4.0 M, 2 mL). The mixture was stirred at 20° C. for 3 h. The reaction mixture was concentrated in vacuo to give Example 5 (6 mg, 72%). 1 H NMR(400MHz,CD3OD) δ 8.56-8.49 (m, 1H), 8.32-8.23 (m, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.4, 1H), 7.98-7.88 (m, 4H), 7.38 (s, 1H), 7.05 (d, J = 8.4, 1H), 4.30-4.21 (m, 2H), 3.88 (s, 3H). LC-MS (M-NH2)+ = 423.0.

[0139] Example 6: 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-cyclopropoxybenzonitrile hydrochloride [ka]

[0140] Step 1: 2-Bromo-6-cyclopropoxybenzonitrile [ka] To a solution of 2-bromo-6-fluorobenzonitrile (2.0 g, 10 mmol) and cyclopropanol (697 mg, 12 mmol) in DMF (50 mL) was added Cs2CO3 (8.15 g, 25 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 4 h. The mixture was poured into water (150 mL) and successively extracted with EtOAc (200 mL×2). The combined organic layers were concentrated under vacuum to give the title compound (1.5 g, 63% yield).

[0141] Step 2: 2-Cyclopropoxy-6-(1-methyl-1H-pyrazol-5-yl)benzonitrile [ka] To a solution of 2-bromo-6-cyclopropoxybenzonitrile (1.0 g, 4.20 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.1 g, 5.04 mmol) in dioxane (10 mL) and water (2 mL) was added NaHCO3 (0.88 g, 10.5 mmol) and Pd(dtbpf)Cl2 (0.27 g, 0.42 mmol). The mixture was stirred at 80° C. for 16 h under nitrogen, cooled to room temperature and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography (PE:EtOAc=100:1→2:1) to give the title compound (0.75 g, 71%). LC-MS (M+H) + =240.3.

[0142] Step 3: 2-Cyclopropoxy-6-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile [ka] To a solution of 2-cyclopropoxy-6-(1-methyl-1H-pyrazol-5-yl)benzonitrile (0.70 g, 2.93 mmol) in AcOH (4.2 mL) was added NIS (790 mg, 3.51 mmol). The mixture was stirred at 75° C. for 12 h, cooled to room temperature and poured into water (10 mL). The suspension was stirred for 1 h at room temperature, filtered, washed with water (10 mL) and dried under reduced pressure to give the title compound (0.50 g, 45%). LC-MS (M+H) + =366.0.

[0143] Step 4: tert-Butyl ((6-(5-(2-cyano-3-cyclopropoxyphenyl)-1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)carbamate [ka] To a solution of 2-cyclopropoxy-6-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile (100 mg, 0.27 mmol) and tert-butyl ((1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydroisoquinolin-4-yl)methyl)carbamate (55 mg, 0.14 mmol) in dioxane (1 mL) and water (0.2 mL) was added Na2CO3 (45 mg, 0.43 mmol) and Pd(dppf)Cl2 (20 mg, 0.027 mmol). The mixture was stirred at 85 °C for 16 h, cooled to room temperature and filtered. The filtrate was concentrated under vacuum and the residue was purified by preparative TLC to give the title compound (20 mg, 14%). LC-MS (M+H) + =512.0.

[0144] Step 5: 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-cyclopropoxybenzonitrile hydrochloride [ka] To a solution of tert-butyl ((6-(5-(2-cyano-3-cyclopropoxyphenyl)-1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)carbamate (20 mg, 0.039 mmol) in MeOH (0.1 mL) was added HCl in MeOH (4.0 M, 0.05 mL). The mixture was stirred at 20° C. for 4 hours and then concentrated under vacuum. The residue was purified by preparative HPLC using water (HCl) / MeCN system to give Example 6 (11 mg, 66%). 1 H NMR (400 MHz, CD3OD) δ 8.18-8.11 (m, 2H), 7.88-7.82 (m, 2H), 7.75-7.67 (m, 1H), 7.40 (s, 1H), 7.59-7.53 (m, 1H), 7.14-7.07 (m, 1H), 4.32-4.20 (m, 2H), 4.10-4.02 (m, 1H), 3.79 (s, 3H). LC-MS (M-NH2)+ = 395.0.

[0145] Example 7: 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-cyclopropoxy-4-(trifluoromethyl)benzonitrile hydrochloride [ka]

[0146] Step 1: 2-Bromo-6-fluoro-4-(trifluoromethyl)aniline [ka] To a solution of 2-fluoro-4-(trifluoromethyl)aniline (20.0 g, 112 mmol) in MeCN (30 mL) was added NBS (21.9 g, 123 mmol) at 15° C. The mixture was warmed to 85° C. and stirred for 3 h. The residue was partitioned between EtOAc (100 mL) and water (50 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (20.0 g, 69%).

[0147] Step 2: 2-Bromo-6-fluoro-4-(trifluoromethyl)benzonitrile [ka] To a solution of 2-bromo-6-fluoro-4-(trifluoromethyl)aniline (20.0 g, 77.5 mmol) in DCM (100 mL) was added nitronium tetrafluoroborate (10.0 g, 85.3 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 h. KCN (15.1 g, 233 mmol) was added to the mixture, followed by CuSO4 (24.74 g, 155 mmol) in water (100 mL). The mixture was allowed to warm to room temperature and stirred for 12 h. The mixture was carefully concentrated under reduced pressure, and the residue was partitioned between EtOAc (100 mL) and water (50 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=1:0→0:1) to give the title compound (3.0 g, 14%).

[0148] Step 3: 2-Bromo-6-cyclopropoxy-4-(trifluoromethyl)benzonitrile [ka] To a solution of 2-bromo-6-fluoro-4-(trifluoromethyl)benzonitrile (3.0 g, 11.2 mmol) in DMF (15 mL), Cs2CO3 (9.12 g, 28.0 mmol) and cyclopropanol (650 mg, 11.2 mmol) were added at 15° C., and the mixture was stirred for 2 h. The mixture was partitioned between ethyl acetate (30 mL) and water (50 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=1:0→0:1) to give the title compound (1.0 g, 2.9%).

[0149] Step 4: 2-Cyclopropoxy-6-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)benzonitrile [ka] To a solution of 2-bromo-6-cyclopropoxy-4-(trifluoromethyl)benzonitrile (1.0 g, 3.27 mmol) in dioxane (1 mL) and water (0.1 mL) was added NaHCO3 (823 mg, 9.80 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (680 mg, 3.27 mmol), and Pd(dtbpf)Cl2 (106 mg, 0.16 mmol). The mixture was stirred at 80 °C for 12 h, cooled to room temperature, and partitioned between EtOAc (30 mL) and water (50 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc = 1:0 → 0:1) to give the title compound (500 mg, 50%). 1 H NMR(400MHz,DMSO-d6) δ 7.86 (s, 1H), 7.66 (s, 1H), 7.58 (s, 1H), 6.58 (s, 1H), 4.32-4.27 (m, 1H), 3.78 (s, 3H), 1.00-0.88 (m, 2H), 0.87-0.80 (m, 2H).

[0150] Step 5: 2-Cyclopropoxy-6-(4-iodo-1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)benzonitrile [ka] To a solution of 2-cyclopropoxy-6-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)benzonitrile (400 mg, 1.30 mmol) in AcOH (2 mL) was added NIS (586 mg, 2.60 mmol) at 15° C. The mixture was stirred for 12 h and then concentrated under reduced pressure. The residue was partitioned between EtOAc (5 mL) and water (5 mL). The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The crude product was triturated with MTBE (2 mL) for 30 min, filtered, and dried under vacuum to give the title compound (100 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 4.40-4.28 (m, 1H), 3.76 (s, 3H), 1.01-0.81 (m, 4H). LC-MS(M+H) + =434.0.

[0151] Step 6: tert-Butyl ((6-(5-(2-cyano-3-cyclopropoxy-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)carbamate [ka] To a solution of 2-cyclopropoxy-6-(4-iodo-1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)benzonitrile (90 mg, 0.21 mmol) in dioxane (1 mL) and water (0.2 mL) was added tert-butyl ((1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydroisoquinolin-4-yl)methyl)carbamate (42 mg, 0.10 mmol), Pd(dppf)Cl2 (15 mg, 0.021 mmol), and NaHCO3 (52 mg, 0.62 mmol) under N2. The mixture was stirred at 80 °C for 3 h, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by preparative TLC to give the title compound (20 mg, 17%). LC-MS (M+H) + =580.2.

[0152] Step 7: 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-cyclopropoxy-4-(trifluoromethyl)benzonitrile hydrochloride [ka] To a solution of tert-butyl ((6-(5-(2-cyano-3-cyclopropoxy-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)carbamate (20 mg, 0.035 mmol) in MeOH (1 mL) was added HCl in MeOH (4.0 M, 0.01 mL) at 15° C., the mixture was stirred at 15° C. for 2 hours, and concentrated under reduced pressure. The residue was purified by preparative HPLC using water (HCl) / MeCN system to give Example 7 (2 mg, 10%). 1 H NMR (400 MHz, CD3OD) δ 8.24-8.17 (m, 2H), 7.92-7.88 (m, 2H), 7.60 (s, 1H), 7.42 (s, 1H), 7.03 (dd, J = 8.4, 1.2 Hz, 1H), 4.34-4.27 (m, 2H), 4.23-4.15 (m, 1H), 3.82 (s, 3H), 1.02-0.94 (m, 2H), 0.92-0.83 (m, 2H). LC-MS (M-NH2) + = 463.0.

[0153] PRMT5 biochemical assay This assay measures the methylation activity of purified human PRMT5 / MEP50 enzyme against histone H4-R3. The PRMT5 TR-FRET assay kit (BPS Bioscience), which contains a highly specific antibody that recognizes methylated substrates, was used to test the inhibition of PRMT5 / MEP50 of the compounds disclosed herein.

[0154] The assay was performed in a 384-well low volume black plate in a reaction mixture containing 10 nM PRMT5 / MEP50 complex, biotinylated histone H4 peptide, 3 μM S-adenosylmethionine, and 0-10 μM compound in a buffer containing 50 mM Tris-HCl buffer (pH 8.5), 0.005% BSA, 1 mM TCEP, and 0.002% Tween-20. PRMT5 / MEP50 enzyme was incubated with the compounds disclosed herein and biotinylated histone H4 peptide for 20 minutes at room temperature. The reaction was started by adding S-adenosylmethionine. After 120 minutes at room temperature, a detection solution containing Eu-labeled antibody and dye-labeled acceptor in detection buffer was added to the reaction mixture. Plates were sealed and incubated at room temperature for 60 min and the TR-FRET signal (excitation 337 nm, emission 665 / 620 nm) was recorded on a PHERAstar FSX plate reader (BMG Labtech). The percentage of inhibition of PRMT5 / MEP50 activity in the presence of increasing concentrations of compounds was calculated based on the ratio of fluorescence at 665 nm to fluorescence at 620 nm. The IC for each compound was calculated based on the ratio of fluorescence at 665 nm to fluorescence at 620 nm. 50 Values ​​were derived by fitting the dose-response percent inhibition data to a four-parameter logistic model in Dotmatics, and compounds were tested in the presence and absence of MTA to assess whether they exhibited MTA synergistic activity. [Table 1]

Claims

1. Compound of formula (I), 【Chemistry 1】 or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its deuterated analog. [In the formula, R ２ , ２ , ８ , １２ , １ｃ , ２ , １ａ , ２－８ , ２ , １ｃ , １ａ , １－８ , １ｃ , １ｄ , １ｂ , １ｃ , １ｃ , １ｄ , ３ , ２ , １－８ , ２ , １ｃ , １－８ , ８ , １ｃ , １ｄ , １ａ , １ｄ , ２－８ , １ｄ , ３ , １ｃ , １ｄ , １ｂ , ６ , １ｃ , １ｃ , R ２ , R ３ , R ４ , R ５ , R<000:006>, R ７ , R ８ , R １１ , and R １２ are each independently hydrogen, halogen, -C １－８ alkyl, -C ３ -C ８ cycloalkyl, -CN, -OR １ａ , -NR １ａ R １ｂ , -COR １ａ , -CO ２ R １ａ , -CONR １ａ R １ｂ , or -NR １ａ COR １ｂ from the group consisting of, -C １－８ alkyl and -C ３ -C ８ cycloalkyl, each of which is independently halogen, -C １－８ alkoxy, -C １－８ alkyl, -C ２－８ alkenyl, -C[[ID=s8]] ２－８ alkynyl, -C[[ID=so]] ３ -C ８ cycloalkyl, a 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, a 5- to 12-membered heteroaryl, oxo, -CN, -OR １ｃ , -SO ２ R １ｃ , -SO ２ NR １ｃ R １ｄ , -COR １ｃ , -CO ２ R １ｃ , -CONR １ｃ R １ｄ , -NR １ｃ R １ｄ , -NR １ｃ COR １ｄ , -NR １ｃ CO ２ R １ｄ , or -NR １ｃ SO ２ R １ｄ It is optionally substituted with at least one substituent selected from the following: R １ａ and R １ｂ These are, independently, hydrogen and -C. １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ The aryl or 5- to 12-membered heteroaryl, and the -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ Each aryl, or 5- to 12-membered heteroaryl, contains at least one halogen, -OH, and -C. １－８ Alkyl, -C １－８ Alkoxy, C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ It is optionally substituted with an aryl or a 5- to 12-membered heteroaryl. R １ｃ and R １ｄ are each independently hydrogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl, wherein the -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl is each optionally substituted with at least one halogen, -OH, -C １－８ alkyl, -C １－８ alkoxy, C １－８ alkoxy-C １－８ alkyl-, -C ２－８ alkenyl, -C ２－８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl, and is optionally substituted R ９ and R １０ These are, independently, hydrogen, halogen, and -C. １－８ Alkyl, C ３ -C ８ Cycloalkyl, -CN, -OR ９ａ , -NR ９ａ R ９ｂ , or -NR ９ａ COR ９ｂ Selected from, -C １－８ Alkyl and C ３ -C ８ Each cycloalkyl group has at least one substituent R ９ｄ It is either optionally replaced by, R ９ and R １０ Together with the carbon atoms to which they are bonded, they form a 5-6 member saturated, partially, or fully unsaturated (preferably fully unsaturated, i.e., aromatic) ring, the ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring comprising at least one substituent R ９ｅ It is optionally replaced by; R ９ｅ In each of their appearances, hydrogen, halogen, and -C appear independently. １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C １－８ Alkoxy, -C ３ -C ８ Cycloalkyl, oxo, 3-8 membered heterocyclyl, C ６ -C １２ Aryl, 5- to 12-membered heteroaryl, -CN, -SO ２ R ９ａ , -SO ２ NR ９ａ R ９ｂ , -COR ９ａ , -CO ２ R ９ａ , -CONR ９ａ R ９ｂ , -NR ９ａ R ９ｂ , -NR ９ａ COR ９ｂ , -NR ９ａ CO ２ R ９ｂ , or -NR ９ａ SO ２ R ９ｂ And, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C １－８ Alkoxy, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ Each aryl or 5- to 12-membered heteroaryl has at least one substituent R ９ｄ It is optionally replaced by R ９ａ and R ９ｂ These are, independently, hydrogen and -C. １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, C １－８ Alkoxy-C １－８ Alkyl-, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ The aryl or 5- to 12-membered heteroaryl, and the -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, C １－８ Alkoxy-C １－８ Alkyl-, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ Each aryl or 5- to 12-membered heteroaryl has at least one substituent R ９ｆ It is optionally replaced by R ９ｄ and R ９ｆ In each of their appearances, they are independently halogen, -OH, and -C. １－８ Alkyl, -C １－８ Alkoxy, C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ It is an aryl or a 5- to 12-membered heteroaryl. R １３ , R １４ , R １５ , and R １６ These are, independently, hydrogen and -C. １－８ Alkyl, -C ３ -C ８ Cycloalkyl, or -C ６ -C １２ Selected from the aryl group, -C １－８ Alkyl, -C ３ -C ８ Cycloalkyl and -C ６ -C １２ Each of the aryls is hydrogen, halogen, and -C. １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -NR １３ａ R １３ｂ , -OR １３ａ , oxo, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ It is optionally substituted with at least one substituent selected from aryl, 5- to 12-membered heteroaryl, or -CN. R １３ａ and R １３ｂ These are, independently, hydrogen and -C. １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ The aryl or 5- to 12-membered heteroaryl, and the -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ Each aryl or 5- to 12-membered heteroaryl has at least one substituent R １３ｃ It is optionally replaced by R １３ｃ These are independently halogen, hydroxyl, and -C １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ The aryl group is a 5- to 12-membered heteroaryl group, or -CN, and the -C １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ Each of the aryl and 5- to 12-membered heteroaryls contains at least one hydrogen, halogen, hydroxyl, or -C １－８ Alkyl, -C １－８ Alkoxy, -CN, -NH ２ [or optionally substituted with an oxo]

2. The compound is selected from formulas (IIa), (IIb), (IIIa), and (IIIb) according to claim 1. 【Chemistry 2】 【Transformation 3】 or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its deuterated analog [wherein, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R １１ , R １２ , R １３ , R １４ , R １５ , and R １６ Each of these is as defined in claim 1, In each of its appearances, R １７ is hydrogen, halogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ Aryl, 5- to 12-membered heteroaryl, -CN, -SO ２ R １７ａ , -SO ２ NR １７ａ R １７ｂ , -COR １７ａ , -CO ２ R １７ａ , -CONR １７ａ R １７ｂ , -OR １７ａ , -NR １７ａ R １７ｂ , -NR １７ａ COR １７ｂ , -NR １７ａ CO ２ R １７ｂ , or -NR １７ａ SO ２ R １７ｂ Selected independently from, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C １－８ Alkoxy, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ Each aryl, or 5- to 12-membered heteroaryl, is a halogen, -C １－８ Alkoxy, -C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ Aryl, 5-12 member heteroaryl, oxo, -CN, -OR １７ｃ , -SO ２ R １７ｃ , -SO ２ NR １７ｃ R １７ｄ , -COR １７ｃ , -CO ２ R １７ｃ , -CONR １７ｃ R １７ｄ , -NR １７ｃ R １７ｄ , -NR １７ｃ COR １７ｄ , -NR １７ｃ CO ２ R １７ｄ , or -NR １７ｃ SO ２ R １７ｄ It is optionally replaced by R １７ａ and R １７ｂ These are, independently, hydrogen and -C. １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ The aryl or 5- to 12-membered heteroaryl, and the -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ Each aryl, or 5- to 12-membered heteroaryl, contains at least one halogen, -OH, and -C. １－８ Alkyl, -C １－８ Alkoxy, C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ It is optionally substituted with an aryl or a 5- to 12-membered heteroaryl. R １７ｃ and R １７ｄ These are, independently, hydrogen and -C. １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ The aryl or 5- to 12-membered heteroaryl, and the -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ Each aryl, or 5- to 12-membered heteroaryl, contains at least one halogen, -OH, and -C. １－８ Alkyl, -C １－８ Alkoxy, C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ It is optionally substituted with an aryl or a 5- to 12-membered heteroaryl. n is 0, 1, 2, 3, or 4. m is 0, 1, or 2.

3. R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R １２ These are independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -COR １ａ , -CO ２ R １ａ , -CONR １ａ R １ｂ , -OR １ａ , -NR １ａ R １ｂ , or -NR １ａ COR １ｂ Selected from, Each of the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, cyclooctyl is -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C ６ -C １２ Aryl, 5-12 member heteroaryl, oxo, -CN, -OR １ｃ , -SO ２ R １ｃ , -SO ２ NR １ｃ R １ｄ , -COR １ｃ , -CO ２ R １ｃ , -CONR １ｃ R １ｄ , -NR １ｃ R １ｄ , -NR １ｃ COR １ｄ , -NR １ｃ CO ２ R １ｄ , or -NR １ｃ SO ２ R １ｄ It is optionally replaced by R １ａ , R １ｂ , R １ｃ , and R １ｄ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of the following is a halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl: C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ The compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, which is optionally substituted with at least one substituent selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl.

4. R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R １２ These are independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -COR １ａ , -CO ２ R １ａ , -CONR １ａ R １ｂ , -OR １ａ , -NR １ａ R １ｂ , or -NR １ａ COR １ｂ Selected from, R １ａ and R １ｂ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ The compound according to claim 1, which is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl, or its N-oxide, or a pharmaceutically acceptable salt thereof, or its stereoisomer, or its deuterated analog.

5. R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R １２ Each of these is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and is the compound according to claim 1, its N-oxide, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated analog thereof.

6. R ７ These are independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -COR １ａ , -CO ２ R １ａ , -CONR １ａ R １ｂ , -OR １ａ , -NR １ａ R １ｂ , or -NR １ａ COR １ｂ Selected from, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl is -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C ６ -C １２ Aryl, 5-12 member heteroaryl, oxo, -CN, -OR １ｃ , -SO ２ R １ｃ , -SO ２ NR １ｃ R １ｄ , -COR １ｃ , -CO ２ R １ｃ , -CONR １ｃ R １ｄ , -NR １ｃ R １ｄ , -NR １ｃ COR １ｄ , -NR １ｃ CO ２ R １ｄ , or -NR １ｃ SO ２ R １ｄ It is optionally replaced by R １ａ and R １ｂ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is at least one halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl are optionally substituted. R １ｃ and R １ｄ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is at least one halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ The compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, which is optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl.

7. R ７ These are independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -COR １ａ , -CO ２ R １ａ , -CONR １ａ R １ｂ , -OR １ａ , -NR １ａ R １ｂ , or -NR １ａ COR １ｂ Selected from, R １ａ and R １ｂ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ The compound according to claim 1, which is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl, or its N-oxide, or a pharmaceutically acceptable salt thereof, or its stereoisomer, or its deuterated analog.

8. R ７ The compound according to claim 1, or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its deuterated analog, is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

9. R ８ These are independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -COR １ａ , -CO ２ R １ａ , -CONR １ａ R １ｂ , -OR １ａ , -NR １ａ R １ｂ , or -NR １ａ COR １ｂ Selected from, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl is -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C ６ -C １２ Aryl, 5-12 member heteroaryl, oxo, -CN, -OR １ｃ , -SO ２ R １ｃ , -SO ２ NR １ｃ R １ｄ , -COR １ｃ , -CO ２ R １ｃ , -CONR １ｃ R １ｄ , -NR １ｃ R １ｄ , -NR １ｃ COR １ｄ , -NR １ｃ CO ２ R １ｄ , or -NR １ｃ SO ２ R １ｄ It is optionally replaced by R １ａ and R １ｂ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is at least one halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl are optionally substituted. R １ｃ and R １ｄ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is at least one halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ The compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, which is optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl.

10. R ８ These are independently hydrogen, -F, -Cl, -Br, -I, and -CH ２ F, -CHF ２ , -CF ３ , -C ２ F ５ Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -COR １ａ , -CO ２ R １ａ , -CONR １ａ R １ｂ , -OR １ａ , -NR １ａ R １ｂ , or -NR １ａ COR １ｂ Selected from, R １ａ and R １ｂ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ The compound according to claim 1, which is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl, or its N-oxide, or a pharmaceutically acceptable salt thereof, or its stereoisomer, or its deuterated analog.

11. R ８ These are independently hydrogen, -F, -Cl, -Br, -I, and -CH ２ F, -CHF ２ , -CF ３ , -C ２ F ５ A compound according to claim 1, selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof.

12. R ９ and R １０ Each of these is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -OR ９ａ , -NR ９ａ R ９ｂ , or -NR ９ａ COR ９ｂ Selected from, each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl has at least one substituent R ９ｄ It is optionally replaced by R ９ａ and R ９ｂ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, C １－８ Alkoxy-C １－８ Selected from alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, C １－８ Alkoxy-C １－８ Each of alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl has at least one substituent R ９ｆ And it is being replaced by an arbitrary choice. R ９ｄ and R ９ｆ In each appearance, they are independently -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ The compound according to claim 1, which is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl, or its N-oxide, or a pharmaceutically acceptable salt thereof, or its stereoisomer, or its deuterated analog.

13. R ９ and R １０ Each is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, cyclooctoxy, and the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclo Each of the following is a compound: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, and cyclooctoxy, respectively, -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ The compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, which is optionally substituted with at least one substituent selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl.

14. R ９ and R １０ Each of these is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, cyclooctoxy, or the compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof.

15. R ９ and R １０ Together with the carbon atoms to which they are bonded, they form a 5 or 6-membered saturated, partially or fully unsaturated ring, the ring comprising 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; The ring has at least one substituent R ９ｅ It is optionally replaced by; R ９ｅ In their respective appearances, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C appear independently. ２－８ Alkenyl, -C ２－８ Alkinyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxo, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -CN, -SO ２ R ９ａ , -SO ２ NR ９ａ R ９ｂ , -COR ９ａ , -CO ２ R ９ａ , -CONR ９ａ R ９ｂ , -NR ９ａ R ９ｂ , -NR ９ａ COR ９ｂ , -NR ９ａ CO ２ R ９ｂ , or -NR ９ａ SO ２ R ９ｂ These are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Each of the alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxo, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl compounds has at least one substituent R ９ｄ It is optionally replaced by R ９ａ and R ９ｂ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, C １－８ Alkoxy-C １－８ Selected from alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, C １－８ Alkoxy-C １－８ Each of alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl has at least one substituent R ９ｆ And it is being replaced by an arbitrary choice. R ９ｄ and R ９ｆ In each appearance, they are independently -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ The compound according to claim 1, which is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl, or its N-oxide, or a pharmaceutically acceptable salt thereof, or its stereoisomer, or its deuterated analog.

16. R ９ and R １０ Together with the carbon atoms to which they are bonded, they form a 5 or 6-membered aromatic ring, the ring comprising 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring comprising at least one substituent R ９ｅ It is optionally replaced by R ９ｅ In their respective appearances, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C appear independently. ２－８ Alkenyl, -C ２－８ Alkinyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxo, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of the alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxo, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl has at least one substituent -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ The compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, which is optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl.

17. R ９ and R １０ Together with the carbon atoms to which they are bonded, they form a phenyl ring, and the ring has at least one substituent R ９ｅ It is optionally replaced by R ９ｅ In their respective appearances, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C appear independently. ２－８ Alkenyl, -C ２－８ The compound according to claim 1, wherein the compound is alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxo, a 3-8 member heterocyclyl, phenyl, a 5-12 member heteroaryl, or -CN, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof.

18. R １１ These are independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -COR １ａ , -CO ２ R １ａ , -CONR １ａ R １ｂ , or -NR １ａ COR １ｂ Selected from, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl is -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C ６ -C １２ Aryl, 5-12 member heteroaryl, oxo, -CN, -OR １ｃ , -SO ２ R １ｃ , -SO ２ NR １ｃ R １ｄ , -COR １ｃ , -CO ２ R １ｃ , -CONR １ｃ R １ｄ , -NR １ｃ R １ｄ , -NR １ｃ COR １ｄ , -NR １ｃ CO ２ R １ｄ , or -NR １ｃ SO ２ R １ｄ It is optionally replaced by R １ａ and R １ｂ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is at least one halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl are optionally substituted. R １ｃ and R １ｄ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is at least one halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ The compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, which is optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl.

19. R １１ These are independently hydrogen, -F, -Cl, -Br, -I, and -CH ２ F, -CHF ２ , -CF ３ , -C ２ F ５ Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -COR １ａ , -CO ２ R １ａ , -CONR １ａ R １ｂ , or -NR １ａ COR １ｂ Selected from, R １ａ and R １ｂ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ The compound according to claim 1, which is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl, or its N-oxide, or a pharmaceutically acceptable salt thereof, or its stereoisomer, or its deuterated analog.

20. R １１ These are independently hydrogen, -F, -Cl, -Br, -I, and -CH ２ F, -CHF ２ , -CF ３ , -C ２ F ５ A compound according to claim 1, selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or -CN, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof.

21. R １３ , R １４ , R １５ , R １６ Each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or phenyl, and each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and phenyl is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -NR １３ａ R １３ｂ , -OR １３ａ , optionally substituted with at least one substituent selected from oxo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, or -CN, R １３ａ and R １３ｂ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl compounds has at least one substituent R １３ｃ And it is being replaced by an arbitrary choice. R １３ｃ These are independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, or -CN, and the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２－８ Alkenyl, -C ２－８ Each of the following is an alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl: at least one hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -CN, -NH ２ The compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, which is optionally substituted with an oxo.

22. R １３ , R １４ , R １５ , R １６ Each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or phenyl, and each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and phenyl is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -NR １３ａ R １３ｂ , -OR １３ａ , optionally substituted with at least one substituent selected from oxo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, or -CN, R １３ａ and R １３ｂ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ A compound according to claim 1, selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof.

23. R １３ , R １４ , R １５ , R １６ Each of the compounds described in claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or phenyl.

24. R １３ , R １４ , R １５ , R １６ Each of these is independently selected from hydrogen and methyl, and is the compound according to claim 1, its N-oxide, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated analog thereof.

25. R １７ Each of these is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -CN, -SO ２ R １７ａ , -SO ２ NR １７ａ R １７ｂ , -COR １７ａ , -CO ２ R １７ａ , -CONR １７ａ R １７ｂ , -OR １７ａ , -NR １７ａ R １７ｂ , -NR １７ａ COR １７ｂ , -NR １７ａ CO ２ R １７ｂ , or -NR １７ａ SO ２ R １７ｂ Selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of the following is a heterocyclyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl: -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, oxo, -CN, -OR １７ｃ , -SO ２ R １７ｃ , -SO ２ NR １７ｃ R １７ｄ , -COR １７ｃ , -CO ２ R １７ｃ , -CONR １７ｃ R １７ｄ , -NR １７ｃ R １７ｄ , -NR １７ｃ COR １７ｄ , -NR １７ｃ CO ２ R １７ｄ , or -NR １７ｃ SO ２ R １７ｄ And it is being replaced by an arbitrary choice. R １７ａ and R １７ｂ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of the following is an alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl: at least one -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl are optionally substituted. R １７ｃ and R １７ｄ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one of -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C １－８ alkoxy-C １－８ alkyl-, -C ２－８ alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and is the compound according to claim 1, or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its deuterated analog.

26. R １７ Each of these is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -CN, -SO ２ R １７ａ , -SO ２ NR １７ａ R １７ｂ , -COR １７ａ , -CO ２ R １７ａ , -CONR １７ａ R １７ｂ , -OR １７ａ , -NR １７ａ R １７ｂ , -NR １７ａ COR １７ｂ , -NR １７ａ CO ２ R １７ｂ , or -NR １７ａ SO ２ R １７ｂ Selected from, R １７ａ and R １７ｂ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of the following is an alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl: at least one -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C １－８ Alkoxy-C １－８ Alkyl-, -C ２－８ Alkenyl, -C ２－８ The compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, which is optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl.

27. R １７ The compound according to claim 1, or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its deuterated analogue, is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, -CN, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, or cyclooctoxy.

28. The aforementioned 【Chemistry 4】 The part is, 【Transformation 5】 The compound according to claim 1, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, or its deuterated analog.

29. The aforementioned 【Transformation 6】 The part is, 【Transformation 7】 The compound according to claim 1, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, or its deuterated analog.

30. The aforementioned 【Transformation 8】 The part is, 【Chemistry 9】 The compound according to claim 1, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, or its deuterated analog. 【Request Item 31】 【Chemistry 10】 A compound, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, or its deuterated analog, selected from the above.

32. A pharmaceutical composition comprising, together with a pharmaceutically acceptable excipient, a compound according to any one of claims 1 to 31, its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, or a deuterated analog thereof.

33. A composition comprising a compound of formula (I), or a specific compound as illustrated herein, as described in any one of claims 1 to 31, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, wherein the composition is administered to an individual, for reducing PRMT5 activity by inhibition.

34. The composition according to claim 33, wherein the disease is selected from cancer.

35. Use of a compound according to any one of claims 1 to 31, or its N-oxide, a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, or a prodrug thereof, or a deuterated analog thereof, in the preparation of a drug for treating a disease regulated by PRMT5.

36. The use according to claim 35, wherein the disease is cancer.

37. The aforementioned diseases include lung cancer, bladder cancer, melanoma, pancreatic cancer, esophageal cancer, gastric adenocarcinoma, breast cancer, gliablastoma, etc. The use according to claim 35, including but not limited to MTAP null solid tumors.

38. A composition for treating a disease regulated by PRMT5, comprising a compound according to any one of claims 1 to 31, its N-oxide, a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, or a prodrug thereof, or a deuterated analog thereof.

39. The composition according to claim 38, wherein the disease is cancer.

40. The disease is lung cancer, bladder cancer, melanoma, pancreatic cancer, esophageal cancer, gastric adenocarcinoma, breast cancer, gliablastoma, etc. The composition according to claim 38, including, but not limited to, MTAP null solid tumors.

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