Inhibitors of RNA methyltransferase

Abstract

The present invention relates to compounds according to Formula (I), and their use as inhibitors of RNA methyltransferase.

Description

[0001] Inhibitors of RNA methyltransferase

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to compounds according to Formula I, and compositions comprising compound according to Formula I, dosage forms comprising said compositions, compounds according to Formula I for use in treatment, kits comprising compounds according to Formula I, and processes for manufacturing compounds according to Formula I.

[0004] BACKGROUND TO THE INVENTION

[0005] Post-translational modifications can significantly affect the function of coding and non-coding RNA sequences and thus play a key regulatory role in disease occurrence and progression. In particular, such post-translational modifications may include RNA methylation, such as m5C (5 -methylcytosine) and m6A (N6-methyladenosine). These methylation processes are typically catalysed by RNA methyltransferases .

[0006] However, RNA methyltransferases remain a class of enzymes that is currently underexplored. Nevertheless, the development of inhibitors of RNA methyltransferase may be useful for the treatment of various cancers.

[0007] SUMMARY OF THE INVENTION

[0008] According to an aspect of the present invention, there is provided a composition comprising a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient: wherein: each of X1to X4is independently selected from N, CH and CR3, at least one of X6and X7comprise a nitrogen atom such that X5, X6and X7form a structure selected from any one of Formulae 1-1, 1-2 and 1-3:

[0009] Formula 1-1 : Formula I-2: Formula I-3: wherein in Formula 1-1, X5is selected from NR4, O and C(R5)(R6), wherein in Formula 1-2, X5is N, wherein in Formula 1-3, X5is NR8, represents a connection point to the rest of Formula I,

[0010] R1is selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, - (optionally substituted alkylene)-(optionally substituted cycloalkyl), -(optionally substituted alkylene) -(optionally substituted heterocyclyl), -(optionally substituted alkylene) -(optionally substituted aryl), -(optionally substituted alkylene)-(optionally substituted heteroaryl), -(NH)- (optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH)-(optionally substituted heterocyclyl), -(NH)-(optionally substituted aryl), -(NH) -(optionally substituted heteroaryl), -(O) -(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O)- (optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), and -(O) -(optionally substituted heteroaryl), each R2is independently selected from hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino, each R3is independently selected from hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, -(NH) -(optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH) -(optionally substituted heterocyclyl), -(NH) -(optionally substituted aryl), - (NH) -(optionally substituted heteroaryl), -(O)-(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O) -(optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), -(O) -(optionally substituted heteroaryl), -(CO)-(optionally substituted alkyl), -(CO)- (optionally substituted cycloalkyl), -(CO)-(optionally substituted heterocyclyl), -(CO)- (optionally substituted alkoxy), -(CO)-(optionally substituted aryl), -(CO) -(optionally substituted heteroaryl), -(CO) -(optionally substituted amino), and -COOH,

[0011] R4is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, each of R5and R6is independently selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino,

[0012] R7is selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, - (NH) -(optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH)- (optionally substituted heterocyclyl), -(NH) -(optionally substituted aryl), -(NH) -(optionally substituted heteroaryl), -(O) -(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O)-(optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), -(O)- (optionally substituted heteroaryl), -(CO)-(optionally substituted alkyl), -(CO)-(optionally substituted cycloalkyl), -(CO) -(optionally substituted heterocyclyl), -(CO)-(optionally substituted alkoxy), -(CO) -(optionally substituted aryl), -(CO)-(optionally substituted heteroaryl), -(CO)-(optionally substituted amino), and -COOH,

[0013] R8is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, m is an integer selected from 0 to 9, n is an integer selected from 0 to 4, and with the proviso that when X5, X6and X7form a structure according to Formula 1-3, X1is N and each of X2to X4is independently selected from CH and CR3.

[0014] In one aspect, R1may be selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, - (optionally substituted alkylene) -(optionally substituted heterocyclyl), -(optionally substituted alkylene) -(optionally substituted aryl), -(optionally substituted alkylene) -(optionally substituted heteroaryl), and -(NH) -(optionally substituted aryl). In one aspect, R1may be selected from optionally substituted C1-C12 alkyl, optionally substituted C3- C10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C1-C12 alkoxy, optionally substituted 5-14 membered heteroaryl, -(optionally substituted C1-C12 alkylene)- (optionally substituted 3-10 membered heterocyclyl), -(optionally substituted C1-C12 alkylene)- (optionally substituted Ce-Ci4 aryl), -(optionally substituted C1-C12 alkylene)-(optionally substituted 5- 14 membered heteroaryl), and -(NH) -(optionally substituted Ce-Ci4 aryl).

[0015] In one aspect, R1may be selected from -(optionally substituted alkylene) -(optionally substituted aryl), and -(optionally substituted alkylene) -(optionally substituted heteroaryl).

[0016] In one aspect, R1may be -(optionally substituted alkylene) -(optionally substituted aryl).

[0017] In one aspect, the optionally substituted heterocyclyl group for R1may be selected from optionally substituted tetrahydrothiophenyl (e.g. tetrahydrothiophenyl dioxide), and optionally substituted 2- thiaspiro[3.3]heptanyl (e.g. 2-thiaspiro[3.3]heptanyl 2,2-dioxide).

[0018] In one aspect, the optionally substituted heteroaryl group for R1may be optionally substituted indazolyl.

[0019] In one aspect, the -(optionally substituted alkylene)-(optionally substituted heterocyclyl) group for R1may be -(optionally substituted alkylene) -(optionally substituted thiazolidinyl).

[0020] In one aspect, the -(optionally substituted alkylene) -(optionally substituted heteroaryl) group for R1may be selected from -(optionally substituted alkylene) -(optionally substituted thiophenyl), -(optionally substituted alkylene)-(optionally substituted indolyl), -(optionally substituted alkylene) -(optionally substituted pyridyl), -(optionally substituted alkylene) -(optionally substituted isoxazolyl), -(optionally substituted alkylene)-(optionally substituted pyrazolyl), -(optionally substituted alkylene) -(optionally substituted tetrazolyl), -(optionally substituted alkylene) -(optionally substituted imidazolyl), and - (optionally substituted alkylene) -(optionally substituted pyrimidinyl).

[0021] In one aspect, the optionally substituted aryl group of the -(optionally substituted alkylene) -(optionally substituted aryl) group for R1may have the following structure: wherein * represents a connection point to the optionally substituted alkylene group, and each Rlais independently selected from halogen, cyano, alkyl, haloalkyl, and alkoxy.

[0022] In one aspect, each R2may be independently selected from hydroxy, optionally substituted alkyl, and optionally substituted alkoxy. In one aspect, each R3may be independently selected from hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted amino, -(NH) -(optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), - (NH) -(optionally substituted heterocyclyl), -(CO)-(optionally substituted alkoxy), -(CO) -(optionally substituted amino), and -COOH.

[0023] In one aspect, each R3may be independently optionally substituted amino.

[0024] In one aspect, R4may be selected from hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl.

[0025] In one aspect, R4may be optionally substituted alkyl.

[0026] In one aspect, R5may be selected from hydrogen, halogen, and optionally substituted alkyl.

[0027] In one aspect, R6may be selected from hydrogen, halogen, and optionally substituted alkyl.

[0028] In one aspect, R7may be selected from optionally substituted alkoxy, optionally substituted amino, - (O) -(optionally substituted heterocyclyl), and -COOH.

[0029] In one aspect, R8may be hydrogen.

[0030] In one aspect, X1may be N.

[0031] In one aspect, X1may be CH or CR3.

[0032] In one aspect, X2may be N.

[0033] In one aspect, X2may be CH or CR3.

[0034] In one aspect, X3may be N.

[0035] In one aspect, X3may be CH or CR3.

[0036] In one aspect, X4may be N.

[0037] In one aspect, X4may be CH or CR3.

[0038] In one aspect, X1may be N, and each of X2to X4may be independently selected from CH and CR3.

[0039] In one aspect, X2may be N, and each of X1, X3and X4may be independently selected from CH and CR3.

[0040] In one aspect, X3may be N, and each of X1, X2and X4may be independently selected from CH and CR3.

[0041] In one aspect, X4may be N, and each of X1to X3may be independently selected from CH and CR3. In one aspect, X2and X4may be N, and each of X1and X3may be independently selected from CH and CR3.

[0042] In one aspect, each of X1to X4may be independently selected from CH and CR3.

[0043] In one aspect, X2may be CR3, and each of X1, X3and X4may be CH.

[0044] In one aspect, m may be 0 or 1.

[0045] In one aspect, m may be 0.

[0046] In one aspect, n may be 0, 1 or 2.

[0047] In one aspect, n may be 1.

[0048] In one aspect, the compound according to Formula I has a structure according to Formula la: wherein each of X1to X7, R1to R8, m and n are as defined herein.

[0049] In one aspect, the compound according to Formula I may have a structure according to Formula lb: wherein each of X1to X7, R1to R8, m and n are as defined herein.

[0050] In one aspect, the compound according to Formula I may have a structure according to Formula II- 1:

[0051] wherein X5is selected from NR4, O and C(R5)(R6), and each of X1to X4, R1to R6, m and n are as defined herein.

[0052] In one aspect, X5may be NR4.

[0053] In one aspect, X5may be O.

[0054] In one aspect, X5may be C(R5)(R6).

[0055] In one aspect, the compound according to Formula I may have a structure according to Formula II-2:

[0056] 11-2 wherein X5is N, and each of X1to X4, R1to R3, R7, m and n are as defined herein.

[0057] In one aspect, the compound according to Formula I may have a structure according to Formula II-3:

[0058] wherein X5is NR8, and each of R1to R3, R8, m and n are as defined herein.

[0059] According to a further aspect of the present invention, there is provided a dosage form comprising a composition as described herein.

[0060] According to a further aspect of the present invention, there is provided a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof: wherein each of X1to X7, R1to R8, m and n are as defined herein; or a composition as described herein; or a dosage form as described herein; for use in the treatment of a disease modulated by RNA methyltransferase.

[0061] In one aspect, the disease modulated by RNA methyltransferase may be a cancer.

[0062] In one aspect, the cancer may be selected from liver cancer (e.g. hepatocellular carcinoma), gastric cancer, intestinal cancer, colorectal cancer, glioma (e.g. glioblastoma), breast cancer, bladder cancer (e.g. urothelial carcinoma of the bladder), prostate cancer, renal cancer (e.g. clear cell renal cell carcinoma), gall bladder carcinoma, lung cancer (e.g. lung squamous cell carcinoma), skin cancer (e.g. cutaneous melanoma), throat cancer (e.g. oesophageal squamous cell carcinoma, hypopharyngeal squamous cell carcinoma), head and neck cancer (e.g. head and neck squamous cell carcinoma), and pancreatic cancer. According to a further aspect of the present invention, there is provided a kit comprising a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof: wherein each of X1to X7, R1to R8, m and n are as defined herein; or a composition as described herein; or a dosage form as described herein; and a pharmaceutically acceptable carrier or excipient, and / or instructions for use of the compound, the composition or the dosage form in the treatment of a disease modulated by RNA methyltransferase.

[0063] According to a further aspect of the present invention, there is provided a process for manufacturing a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein the process comprises a step of coupling a compound according to Formula Int-A to a compound according to Formula Int-B:

[0064] Int-A wherein each of X1to X7, R1to R8, m and n are as defined herein.

[0065] According to a further aspect of the present invention, there is provided a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof:

[0066] wherein: each of X1to X4is independently selected from N, CH and CR3, at least one of X6and X7comprise a nitrogen atom such that X5, X6and X7form a structure selected from any one of Formulae 1-1, 1-2 and 1-3:

[0067] Formula 1-1 : Formula 1-2: Formula I-3: wherein in Formula 1-1, X5is selected from NR4, O and C(R5)(R6), wherein in Formula 1-2, X5is N, wherein in Formula 1-3, X5is NR8, represents a connection point to the rest of Formula I,

[0068] R1is selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, - (optionally substituted alkylene)-(optionally substituted cycloalkyl), -(optionally substituted alkylene) -(optionally substituted heterocyclyl), -(optionally substituted alkylene) -(optionally substituted aryl), -(optionally substituted alkylene)-(optionally substituted heteroaryl), -(NH)- (optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH)-(optionally substituted heterocyclyl), -(NH)-(optionally substituted aryl), -(NH) -(optionally substituted heteroaryl), -(O) -(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O)- (optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), and -(O) -(optionally substituted heteroaryl), each R2is independently selected from hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino, each R3is independently selected from hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, -(NH) -(optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH) -(optionally substituted heterocyclyl), -(NH) -(optionally substituted aryl), - (NH) -(optionally substituted heteroaryl), -(O)-(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O) -(optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), -(O) -(optionally substituted heteroaryl), -(CO)-(optionally substituted alkyl), -(CO)- (optionally substituted cycloalkyl), -(CO)-(optionally substituted heterocyclyl), -(CO)- (optionally substituted alkoxy), -(CO)-(optionally substituted aryl), -(CO) -(optionally substituted heteroaryl), -(CO) -(optionally substituted amino), and -COOH,

[0069] R4is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, each of R5and R6is independently selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino,

[0070] R7is selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, - (NH) -(optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH)- (optionally substituted heterocyclyl), -(NH) -(optionally substituted aryl), -(NH) -(optionally substituted heteroaryl), -(O) -(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O)-(optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), -(O)- (optionally substituted heteroaryl), -(CO)-(optionally substituted alkyl), -(CO)-(optionally substituted cycloalkyl), -(CO) -(optionally substituted heterocyclyl), -(CO)-(optionally substituted alkoxy), -(CO) -(optionally substituted aryl), -(CO)-(optionally substituted heteroaryl), -(CO)-(optionally substituted amino), and -COOH,

[0071] R8is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, m is an integer selected from 0 to 9, n is an integer selected from 0 to 4, with the proviso that when X5, X6and X7form a structure according to Formula 1-1 and X5is NR4, X4is CH or CR3, with the proviso that when X5, X6and X7form a structure according to Formula 1-1 and X5is NR4and X2is N, when X1is CR3, R3for CR3is not optionally substituted amino, with the proviso that when X5, X6and X7form a structure according to Formula 1-2, R7is selected from optionally substituted alkoxy, optionally substituted amino, -(O)-(optionally substituted heterocyclyl), and -COOH, with the proviso that when X5, X6and X7form a structure according to Formula 1-3, X1is N and each of X2to X4is independently selected from CH and CR3, and with the proviso that the compound is not any one of the compounds as described in Tables I, II, III, and IV.

[0072] In one aspect, each of X1to X7, R1to R8, m and n may be as defined herein.

[0073] BRIEF DESCRIPTION OF THE DRAWINGS

[0074] The present invention is further described in the following non -limiting figures.

[0075] Figure 1 shows binding of Compound 130 ((S)-5-amino-l-(l-(2-(3-chloro-5- fluorophenyl)acetyl)piperidin-3-yl)-3-methyl-l,3-dihydro-2H-benzo[d]imidazol-2-one) to RNMT, cocrystallised with S -adenosylhomocysteine (SAH).

[0076] Figure 2 shows superposition of Compound 130 and Compound 68 ((S)-6-amino-l-(l-(2-(3-chloro-5- fluorophenyl)acetyl)piperidin-3 -yl)- 1 ,3 -dihydro-2H-benzo [d] imidazol-2-one) .

[0077] Figure 3 shows tests of Compound 133 and Compound 151 on glioblastoma cell lines: (A) tests on G7 cell line; (B) tests on E2 cell line.

[0078] DETAILED DESCRIPTION OF THE INVENTION

[0079] The following apply to all aspects of the present invention. General chemical definitions

[0080] The term “halo” or “halogen” as used herein refers to any radical of fluorine, chlorine, bromine or iodine.

[0081] The term “alkyl” as used herein refers to both straight and branched chain radicals of up to twelve carbons. For example, an alkyl group may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Non-limiting examples of C1-C12 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups. Preferably, the term “alkyl” as used herein may refer to a straight or branched chain radical comprising from one to eight carbon atoms, more preferably one to six carbon atoms and even more preferably one to four carbon atoms. An “optionally substituted alkyl” group may include the substituents as described below for the term “optionally substituted”. For example, an “optionally substituted alkyl” group may include a “haloalkyl” group.

[0082] The term “haloalkyl” as used herein refers to both straight and branched chain radicals of up to twelve carbon atoms, comprising at least one halogen atom. For example, a haloalkyl group may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Preferably, the term “haloalkyl” as used herein may refer to a straight or branched chain radical comprising from one to eight carbon atoms, more preferably one to six carbon atoms and even more preferably one to four carbon atoms, and comprising at least one halogen atom.

[0083] For example, a “haloalkyl” group may be a fluoroalkyl or perfluoroalkyl group.

[0084] Preferably, a “haloalkyl” group may be a Ci-Ce fluoroalkyl group, or a Ci-Ce perfluoroalkyl group.

[0085] Even more preferably, a “haloalkyl” group may be a C1-C4 fluoroalkyl group, or a C1-C4 perfluoroalkyl group. For example, a “haloalkyl” group may include difluoromethyl, trifluoromethyl or pentafluoroethyl.

[0086] The term “cycloalkyl” as used herein refers to an alkyl group comprising a closed ring comprising from 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms. For example, a cycloalkyl group may contain 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, (cyclohexyl)methyl, (cyclohexyl)ethyl, and tetralinyl. An “optionally substituted cycloalkyl” group may include the substituents as described below for the term “optionally substituted”.

[0087] The term “heterocyclyl” as used herein refers to a saturated or partially saturated 3 to 7 membered monocyclic, or 7 to 10 membered spirocyclic or bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms may be optionally oxidised, the nitrogen may be optionally quatemised, and includes any bicyclic group in which any of the above-defined rings is fused to a benzene ring, and wherein the ring may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Non -limiting examples of common saturated or partially saturated heterocyclyl groups include azetinyl, oxetanyl, tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, thiazolidinyl, tetronoyl, tetramoyl, thietanyl (e.g. thietanyl dioxide), tetrahydrothiophenyl (e.g. tetrahydrothiophenyl dioxide), tetrahydrothiopyranyl (e.g. tetrahydrothiopyranyl dioxide), 2-thiaspiro[3.3]heptanyl (e.g. 2-thiaspiro[3.3]heptanyl 2,2-dioxide) groups. An “optionally substituted heterocyclyl” group may include the substituents as described below for the term “optionally substituted”.

[0088] The term “alkoxy” as used herein refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. For example, an alkoxy group may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Preferably, the “alkoxy” as used herein, by itself or as part of another group, may refer to a straight or branched chain radical comprising from one to eight carbon atoms, more preferably one to six carbon atoms and even more preferably one to four carbon atoms, appended to the parent molecular moiety through an oxygen atom. Non -limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, 2 -propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. An “optionally substituted alkoxy” group may include the substituents as described below for the term “optionally substituted”. For example, an “optionally substituted alkoxy” group may include a “haloalkoxy” group.

[0089] The term “haloalkoxy” as used herein refers to both straight and branched chain radicals of up to twelve carbon atoms, comprising at least one halogen atom and being appended to the parent molecular moiety through an oxygen atom. For example, a haloalkoxy group may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Preferably, the term "haloalkoxy" as used herein, by itself or as part of another group, may refer to a straight or branched chain radical comprising from one to eight carbon atoms, more preferably one to six carbon atoms and even more preferably one to four carbon atoms, comprising at least one halogen atom and being appended to the parent molecular moiety through an oxygen atom.

[0090] For example, a “haloalkoxy” group may be a fluoroalkoxy or perfluoroalkoxy group.

[0091] Preferably, a “haloalkoxy” group may be a Ci-Ce fluoroalkoxy group, or a Ci-Ce perfluoroalkoxy group.

[0092] Even more preferably, a “haloalkoxy” group may be a C1-C4 fluoroalkoxy group, or a C1-C4 perfluoroalkoxy group. For example, a “haloalkyloxy” group may include difluoromethoxy, trifluoromethoxy or pentafluoroethoxy.

[0093] The term “aryl” as used herein refers to monocyclic, bicyclic or tricyclic aromatic groups containing from 6 to 14 carbon atoms in the ring. Common aryl groups include Ce-Ci4 aryl, for example, Ce-Cio aryl. Non-limiting examples of Ce-Ci4 aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups. An “optionally substituted aryl” group may include the substituents as described below for the term “optionally substituted”.

[0094] The term “heteroaryl” as used herein refers to aromatic groups having 5 to 14 ring atoms (for example, 5 to 10 ring atoms) and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms. Examples of heteroaryl groups include thienyl (thiophenyl), benzo [6]thienyl, naphtho [2,3 - / |thicnyl. thianthrenyl, furyl (furanyl), benzofuranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, including without limitation 2H-pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl (pyridinyl), including without limitation 2-pyridyl, 3 -pyridyl, and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H- quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, |3-carbohnyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, pyrazolo[l,5-a]pyrimidinyl, including without limitation pyrazolo [ 1 ,5 -a]pyrimidin-3 -yl, 1 ,2-benzoisoxazol-3 -yl, benzimidazolyl, 2- oxindolyl and 2-oxobenzimidazolyl. Where the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide. An “optionally substituted heteroaryl” group may include the substituents as described below for the term “optionally substituted”.

[0095] The term “amino” as used herein refers to the group -NR’ 2, wherein R’ is hydrogen or an optional substituent. An “optionally substituted amino” group may include the substituents as described below for the term “optionally substituted”.

[0096] The term “alkylene” as used herein refers to both divalent straight and branched chain radicals of up to twelve carbons. For example, an alkylene group may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Non-limiting examples of C1-C12 alkylene groups include methylene, ethylene, propylene, isopropylene, butylene, sec-butylene, tert-butylene, 3-pentylene, hexylene and octylene groups. Preferably, the term “alkylene” as used herein may refer to a divalent straight or branched chain radical comprising from one to eight carbon atoms, more preferably one to six carbon atoms and even more preferably one to four carbon atoms. An “optionally substituted alkylene” group may include the substituents as described below for the term “optionally substituted”.

[0097] As described herein, compounds may contain “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogen atoms of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisaged by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0098] For example, the term “optionally substituted” as used herein may refer to when at least one substituent is selected from non-limiting examples such as oxo, hydroxy, halogen, cyano, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, haloalkoxy, -CO-(optionally substituted alkyl), -CO-(optionally substituted alkoxy), -S-(optionally substituted alkyl), -SO-(optionally substituted alkyl), -SO2-(optionally substituted alkyl), -SO2-(optionally substituted amino), optionally substituted amino, mono(optionally substituted alkyl) amino, di(optionally substituted alkyl) amino, -COOH, optionally substituted aryl and optionally substituted heteroaryl.

[0099] Preferably, the term “optionally substituted” as used herein may refer to when at least one substituent is selected from oxo, hydroxy, halogen, cyano, alkyl, -(alkylene)-OH, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, haloalkoxy, -CO-(alkyl), -CO-(alkoxy), -S-(optionally substituted alkyl), -SO- (optionally substituted alkyl), -SC>2-(alkyl), -SO2-(amino), amino, mono(alkyl) amino, di(alkyl) amino, -COOH, aryl and heteroaryl.

[0100] More preferably, the term “optionally substituted” as used herein may refer to when at least one substituent is selected from oxo, hydroxy, halogen, cyano, Ci-Ce alkyl, -(Ci-Ce alkylene)-OH, Ci-Ce haloalkyl, Cs-Ce cycloalkyl, 3-10 membered heterocyclyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -CO-(Ci- C6alkyl), -CO-(Ci-C6alkoxy), -S-(Ci-C6alkyl), -SO-(Ci-C6alkyl), -SO2-(Ci-C6alkyl), -SO2-(amino), amino, mono(Ci-Ce alkyl) amino, di(Ci-Ce alkyl) amino, -COOH, Ce-Ci4 aryl and 5-14 membered heteroaryl.

[0101] The conjugates of the present invention may be provided in “salt” form. The term “salt” as used herein refers to salts of the compounds as described herein that are derived from suitable inorganic and organic acids and bases. Examples of salts of a basic group include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as trifluoroacetic acid, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2 -hydroxy-ethane sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2 -naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(CI-C4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate.

[0102] Certain compounds of the present disclosure may exist in unsolvated forms as well as solvated forms, including hydrated forms. “Hydrate” refers to a complex formed by combination of water molecules with molecules or ions of the solute. “Solvate” refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. The solvent may be an organic compound, an inorganic compound, or a mixture of both. Solvate is meant to include hydrate. Some examples of solvents include, but are not limited to, methanol, acetonitrile, N,N -dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist as solid material in e.g. multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0103] “Tautomer” means compounds produced by the phenomenon wherein a proton of one atom of a molecule shifts to another atom (See, Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pages 69-74 (1992)). The tautomers also refer to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. Examples include keto-enol tautomers, such as acetone / propen-2- ol, imine-enamine tautomers and the like, ring-chain tautomers, such as glucose / 2,3,4,5,6- pentahydroxy-hexanal and the like, the tautomeric forms of heteroaryl groups containing a -N=C(H)- NH- ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism (‘tautomerism’) may occur. The compounds described herein may have one or more tautomers and therefore include various isomers. A skilled person would recognise that other tautomeric ring atom arrangements are possible. All such isomeric forms of these compounds are expressly included in the present disclosure.

[0104] “Isomers” mean compounds having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. “Stereoisomer” and “stereoisomers” refer to compounds that exist in different stereoisomeric forms if they possess one or more asymmetric centres or a double bond with asymmetric substitution and, therefore, may be produced as individual stereoisomers or as mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer may be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or laevorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound may exist as either individual enantiomers or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of Advanced Organic Chemistry, 6th edition J. March, John Wiley and Sons, New York, 2007) differ in the chirality of one or more stereocentres.

[0105] The disclosure also embraces isotopically-labelled compounds of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to2H (deuterium, D),3H (tritium),nC,13C,14C,15N,18F,31P,32P,35S,36C1, and125I. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition or its isotopes, such as deuterium (D) or tritium (3H). Certain isotopically-labelled compounds of the present disclosure (e.g., those labelled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon- 14 (i.e.,14C) and fluorine-18 (i.e.,18F) isotopes are useful fortheir ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of the present disclosure may generally be prepared by following procedures analogous to those described herein, by substituting an isotopically labelled reagent for a non-isotopically labelled reagent.

[0106] Compounds

[0107] In another embodiment of the present invention, provided herein is a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof:

[0108] wherein: each of X1to X4is independently selected from N, CH and CR3, at least one of X6and X7comprise a nitrogen atom such that X5, X6and X7form a structure selected from any one of Formulae 1-1, 1-2 and 1-3:

[0109] Formula 1-1 : Formula 1-2: Formula I-3: wherein in Formula 1-1, X5is selected from NR4, O and C(R5)(R6), wherein in Formula 1-2, X5is N, wherein in Formula 1-3, X5is NR8, represents a connection point to the rest of Formula I,

[0110] R1is selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, - (optionally substituted alkylene)-(optionally substituted cycloalkyl), -(optionally substituted alkylene) -(optionally substituted heterocyclyl), -(optionally substituted alkylene) -(optionally substituted aryl), -(optionally substituted alkylene)-(optionally substituted heteroaryl), -(NH)- (optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH)-(optionally substituted heterocyclyl), -(NH)-(optionally substituted aryl), -(NH) -(optionally substituted heteroaryl), -(O) -(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O)- (optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), and -(O) -(optionally substituted heteroaryl), each R2is independently selected from hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino, each R3is independently selected from hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, -(NH) -(optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH) -(optionally substituted heterocyclyl), -(NH) -(optionally substituted aryl), - (NH) -(optionally substituted heteroaryl), -(O)-(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O) -(optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), -(O) -(optionally substituted heteroaryl), -(CO)-(optionally substituted alkyl), -(CO)- (optionally substituted cycloalkyl), -(CO)-(optionally substituted heterocyclyl), -(CO)- (optionally substituted alkoxy), -(CO)-(optionally substituted aryl), -(CO) -(optionally substituted heteroaryl), -(CO) -(optionally substituted amino), and -COOH,

[0111] R4is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, each of R5and R6is independently selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino,

[0112] R7is selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, - (NH) -(optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH)- (optionally substituted heterocyclyl), -(NH) -(optionally substituted aryl), -(NH) -(optionally substituted heteroaryl), -(O) -(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O)-(optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), -(O)- (optionally substituted heteroaryl), -(CO)-(optionally substituted alkyl), -(CO)-(optionally substituted cycloalkyl), -(CO) -(optionally substituted heterocyclyl), -(CO)-(optionally substituted alkoxy), -(CO) -(optionally substituted aryl), -(CO)-(optionally substituted heteroaryl), -(CO)-(optionally substituted amino), and -COOH,

[0113] R8is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, m is an integer selected from 0 to 9, n is an integer selected from 0 to 4, and with the proviso that when X5, X6and X7form a structure according to Formula 1-3, X1is N and each of X2to X4is independently selected from CH and CR3.

[0114] Compounds according to Formula I may have high binding affinity to RNA methyltransferase. Thus, compounds according to Formula I may be useful as potent inhibitors of RNA methyltransferase.

[0115] As used herein, the term (R2)mrefers to R2substituents that may replace a hydrogen atom in the piperidine ring of Formula I. Thus, when m is 0, there are no R2substituents. When m is 1, there is one R2substituent replacing one of the nine hydrogen atoms on the piperidine ring of Formula I; similarly, when m is 2, there are two R2substituents replacing two of the nine hydrogen atoms on the piperidine ring of Formula I; similar considerations apply for where m is 3, 4, 5, 6, 7, 8 and 9.

[0116] As used herein, the term (R3)nrefers to R3substituents that may replace a hydrogen atom in X1to X4(when X1to X4are not nitrogen atoms). Thus, when n is 0, all of X1to X4are N or CH and as such there are no R3substituents. When n is 1, one of X1to X4is CR3, and the remaining are N or CH. When n is 2, two of X1to X4are CR3, and the remaining are N or CH. When n is 3, three of X1to X4are CR3, and the remaining is N or CH. When n is 4, all of X1to X4are CR3.

[0117] In Formula I, R1is selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, -(optionally substituted alkylene)- (optionally substituted cycloalkyl), -(optionally substituted alkylene) -(optionally substituted heterocyclyl), -(optionally substituted alkylene) -(optionally substituted aryl), -(optionally substituted alkylene) -(optionally substituted heteroaryl), -(NH) -(optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH) -(optionally substituted heterocyclyl), -(NH) -(optionally substituted aryl), -(NH) -(optionally substituted heteroaryl), -(O)-(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O)-(optionally substituted heterocyclyl), -(O) -(optionally substituted aryl), and -(O) -(optionally substituted heteroaryl).

[0118] Preferably, R1may be selected from hydrogen, hydroxy, optionally substituted C1-C12 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C1-C12 alkoxy, optionally substituted Ce-Ci4 aryl, optionally substituted 5-14 membered heteroaryl, optionally substituted amino, -(optionally substituted C1-C12 alkylene) -(optionally substituted C3-C10 cycloalkyl), -(optionally substituted C1-C12 alkylene)-(optionally substituted 3-10 membered heterocyclyl), -(optionally substituted C1-C12 alkylene) -(optionally substituted Ce-Ci4 aryl), -(optionally substituted C1-C12 alkylene)-(optionally substituted 5-14 membered heteroaryl), -(NH)- (optionally substituted C1-C12 alkyl), -(NH) -(optionally substituted C3-C10 cycloalkyl), -(NH)- (optionally substituted 3-10 membered heterocyclyl), -(NH) -(optionally substituted Ce-Ci4 aryl), -(NH)- (optionally substituted 5-14 membered heteroaryl), -(O) -(optionally substituted C1-C12 alkyl), -(O)- (optionally substituted C3-C10 cycloalkyl), -(O)-(optionally substituted 3-10 membered heterocyclyl), - (O) -(optionally substituted Ce-Ci4 aryl), and -(O)-(optionally substituted 5-14 membered heteroaryl).

[0119] More preferably, R1may be selected from hydrogen, hydroxy, optionally substituted Ci-Ce alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ce-Cio aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted amino, -(optionally substituted Ci-Ce alkylene) -(optionally substituted C3-C6 cycloalkyl), -(optionally substituted Ci-Ce alkylene)-(optionally substituted 3-7 membered heterocyclyl), -(optionally substituted Ci-Ce alkylene)-(optionally substituted Ce-Cio aryl), - (optionally substituted Ci-Ce alkylene)-(optionally substituted 5-10 membered heteroaryl), -(NH)- (optionally substituted Ci-Ce alkyl), -(NH)-(optionally substituted C3-C6 cycloalkyl), -(NH)-(optionally substituted 3-7 membered heterocyclyl), -(NH) -(optionally substituted Ce-Cio aryl), -(NH) -(optionally substituted 5-10 membered heteroaryl), -(O)-(optionally substituted Ci-Ce alkyl), -(O) -(optionally substituted C3-C6 cycloalkyl), -(O) -(optionally substituted 3-7 membered heterocyclyl), -(O)- (optionally substituted Ce-Cio aryl), and -(O)-(optionally substituted 5-10 membered heteroaryl).

[0120] In a preferred embodiment, R1may be selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, -(optionally substituted alkylene) -(optionally substituted heterocyclyl), -(optionally substituted alkylene)-(optionally substituted aryl), -(optionally substituted alkylene) -(optionally substituted heteroaryl), and -(NH) -(optionally substituted aryl).

[0121] Preferably, R1may be selected from optionally substituted C1-C12 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C1-C12 alkoxy, optionally substituted 5-14 membered heteroaryl, -(optionally substituted C1-C12 alkylene) -(optionally substituted 3-10 membered heterocyclyl), -(optionally substituted C1-C12 alkylene) -(optionally substituted Ce-Ci4 aryl), -(optionally substituted C1-C12 alkylene)-(optionally substituted 5-14 membered heteroaryl), and -(NH) -(optionally substituted Ce-Ci4 aryl).

[0122] More preferably, R1may be selected from optionally substituted Ci-Ce alkyl, optionally substituted C3- Ce cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted Ci-Ce alkoxy, optionally substituted 5-10 membered heteroaryl, -(optionally substituted Ci-Ce alkylene) -(optionally substituted 3-7 membered heterocyclyl), -(optionally substituted Ci-Ce alkylene) -(optionally substituted Ce-Cio aryl), -(optionally substituted Ci-Ce alkylene) -(optionally substituted 5-10 membered heteroaryl), and -(NH) -(optionally substituted Ce-Cio aryl).

[0123] In a further preferred embodiment, R1may be selected from -(optionally substituted alkylene)- (optionally substituted aryl), and -(optionally substituted alkylene)-(optionally substituted heteroaryl).

[0124] Preferably, R1may be selected from -(optionally substituted C1-C12 alkylene) -(optionally substituted Ce-Ci4 aryl), and -(optionally substituted C1-C12 alkylene) -(optionally substituted 5-14 membered heteroaryl).

[0125] More preferably, R1may be selected from -(optionally substituted Ci-Ce alkylene) -(optionally substituted Ce-Cio aryl), and -(optionally substituted Ci-Ce alkylene) -(optionally substituted 5-10 membered heteroaryl).

[0126] In some embodiments, the optionally substituted heterocyclyl group for R1may be selected from optionally substituted tetrahydrothiophenyl (e.g. tetrahydrothiophenyl dioxide), and optionally substituted 2-thiaspiro[3.3]heptanyl (e.g. 2-thiaspiro[3.3]heptanyl 2,2-dioxide). This definition may not apply to the options of -(optionally substituted alkylene) -(optionally substituted heterocyclyl), -(NH)- (optionally substituted heterocyclyl), -(O) -(optionally substituted heterocyclyl) for R1.

[0127] In some embodiments, the optionally substituted heteroaryl group for R1may be optionally substituted indazolyl. This definition may not apply to the options of -(optionally substituted alkylene) -(optionally substituted heteroaryl), -(NH) -(optionally substituted heteroaryl), -(O) -(optionally substituted heteroaryl) for R1.

[0128] In some embodiments, the -(optionally substituted alkylene) -(optionally substituted heterocyclyl) group for R1may be -(optionally substituted alkylene) -(optionally substituted thiazolidinyl); preferably - (optionally substituted C1-C12 alkylene)-(optionally substituted thiazolidinyl); more preferably - (optionally substituted Ci-Ce alkylene) -(optionally substituted thiazolidinyl).

[0129] In some embodiments, the -(optionally substituted alkylene)-(optionally substituted heteroaryl) group for R1is selected from -(optionally substituted alkylene) -(optionally substituted thiophenyl), - (optionally substituted alkylene) -(optionally substituted indolyl), -(optionally substituted alkylene)- (optionally substituted pyridyl), -(optionally substituted alkylene) -(optionally substituted isoxazolyl), - (optionally substituted alkylene) -(optionally substituted pyrazolyl), -(optionally substituted alkylene)- (optionally substituted tetrazolyl), -(optionally substituted alkylene)-(optionally substituted imidazolyl), and -(optionally substituted alkylene) -(optionally substituted pyrimidinyl); preferably - (optionally substituted C1-C12 alkylene) -(optionally substituted thiophenyl), -(optionally substituted Ci- C12 alkylene) -(optionally substituted indolyl), -(optionally substituted C1-C12 alkylene) -(optionally substituted pyridyl), -(optionally substituted C1-C12 alkylene) -(optionally substituted isoxazolyl), - (optionally substituted C1-C12 alkylene) -(optionally substituted pyrazolyl), -(optionally substituted Ci- C12 alkylene) -(optionally substituted tetrazolyl), -(optionally substituted C1-C12 alkylene) -(optionally substituted imidazolyl), and -(optionally substituted C1-C12 alkylene) -(optionally substituted pyrimidinyl); more preferably -(optionally substituted Ci-Ce alkylene) -(optionally substituted thiophenyl), -(optionally substituted Ci-Ce alkylene)-(optionally substituted indolyl), -(optionally substituted Ci-Ce alkylene)-(optionally substituted pyridyl), -(optionally substituted Ci-Ce alkylene)- (optionally substituted isoxazolyl), -(optionally substituted Ci-Ce alkylene) -(optionally substituted pyrazolyl), -(optionally substituted Ci-Ce alkylene) -(optionally substituted tetrazolyl), -(optionally substituted Ci-Ce alkylene) -(optionally substituted imidazolyl), and -(optionally substituted Ci-Ce alkylene) -(optionally substituted pyrimidinyl).

[0130] In an even further preferred embodiment, R1may be -(optionally substituted alkylene) -(optionally substituted aryl). When R1is -(optionally substituted alkylene) -(optionally substituted aryl), compounds according to Formula I may have enhanced binding affinity to RNA methyltransferase.

[0131] Preferably, R1may be -(optionally substituted C1-C12 alkylene) -(optionally substituted Ce-Ci4 aryl).

[0132] More preferably, R1may be -(optionally substituted Ci-Ce alkylene)-(optionally substituted Ce-Cio aryl).

[0133] Even more preferably, R1may be -(optionally substituted Ci-Ce alkylene) -(optionally substituted phenyl).

[0134] In some embodiments, the optionally substituted aryl group of the -(optionally substituted alkylene)- (optionally substituted aryl) group for R1may have the following structure: wherein * represents a connection point to the optionally substituted alkylene group, and each Rlamay be independently selected from halogen, cyano, alkyl, haloalkyl, and alkoxy. Preferably, each Rlamay be independently halogen. More preferably, each Rlamay be independently selected from fluoro and chloro. Even more preferably, each Rlamay be chloro.

[0135] In Formula I, each R2is independently selected from hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino. Preferably, each R2may be independently selected from hydroxy, halogen, optionally substituted Ci- C12 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C1-C12 alkoxy, optionally substituted Ce-Ci4 aryl, optionally substituted 5-14 membered heteroaryl, and optionally substituted amino.

[0136] More preferably, each R2may be independently selected from hydroxy, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Cs-Ce cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ce-Cio aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted amino.

[0137] In a preferred embodiment, each R2may be independently selected from hydroxy, optionally substituted alkyl, and optionally substituted alkoxy.

[0138] Preferably, each R2may be independently selected from hydroxy, optionally substituted C1-C12 alkyl, and optionally substituted C1-C12 alkoxy.

[0139] More preferably, each R2may be independently selected from hydroxy, optionally substituted Ci-Ce alkyl, and optionally substituted Ci-Ce alkoxy.

[0140] In Formula I, each R3is independently selected from hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, - (NH) -(optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH) -(optionally substituted heterocyclyl), -(NH) -(optionally substituted aryl), -(NH)-(optionally substituted heteroaryl), -(O) -(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O) -(optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), -(O) -(optionally substituted heteroaryl), -(CO)- (optionally substituted alkyl), -(CO) -(optionally substituted cycloalkyl), -(CO)-(optionally substituted heterocyclyl), -(CO)-(optionally substituted alkoxy), -(CO) -(optionally substituted aryl), -(CO)- (optionally substituted heteroaryl), -(CO)-(optionally substituted amino), and -COOH.

[0141] Preferably, each R3may be independently selected from hydroxy, halogen, cyano, optionally substituted C1-C12 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C1-C12 alkoxy, optionally substituted Ce-Ci4 aryl, optionally substituted 5-14 membered heteroaryl, optionally substituted amino, -(NH)-(optionally substituted Ci- C12 alkyl), -(NH)-(optionally substituted C3-C10 cycloalkyl), -(NH)-(optionally substituted 3-10 membered heterocyclyl), -(NH) -(optionally substituted Ce-Ci4 aryl), -(NH) -(optionally substituted 5-14 membered heteroaryl), -(O)-(optionally substituted C1-C12 alkyl), -(O) -(optionally substituted C3-C10 cycloalkyl), -(O)-(optionally substituted 3-10 membered heterocyclyl), -(O)-(optionally substituted Ce- C14 aryl), -(O) -(optionally substituted 5-14 membered heteroaryl), -(CO)-(optionally substituted C1-C12 alkyl), -(CO)-(optionally substituted C3-C10 cycloalkyl), -(CO)-(optionally substituted 3-10 membered heterocyclyl), -(CO)-(optionally substituted C1-C12 alkoxy), -(CO)-(optionally substituted Ce-Ci4 aryl), -(CO)-(optionally substituted 5-14 membered heteroaryl), -(CO)-(optionally substituted amino), and - COOH.

[0142] More preferably, each R3may be independently selected from hydroxy, halogen, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Cs-Ce cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ce-Cio aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted amino, -(NH)-(optionally substituted Ci- Ce alkyl), -(NH) -(optionally substituted Cs-Ce cycloalkyl), -(NH)-(optionally substituted 3-7 membered heterocyclyl), -(NH) -(optionally substituted Ce-Cio aryl), -(NH) -(optionally substituted 5-10 membered heteroaryl), -(O) -(optionally substituted Ci-Ce alkyl), -(O)-(optionally substituted Cs-Ce cycloalkyl), - (O) -(optionally substituted 3-7 membered heterocyclyl), -(O) -(optionally substituted Ce-Cio aryl), -(O)- (optionally substituted 5-10 membered heteroaryl), -(CO) -(optionally substituted Ci-Ce alkyl), -(CO)- (optionally substituted Cs-Ce cycloalkyl), -(CO)-(optionally substituted 3-7 membered heterocyclyl), - (CO)-(optionally substituted Ci-Ce alkoxy), -(CO)-(optionally substituted Ce-Cio aryl), -(CO)- (optionally substituted 5-10 membered heteroaryl), -(CO) -(optionally substituted amino), and -COOH.

[0143] In a preferred embodiment, each R3may be independently selected from hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted amino, -(NH) -(optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH)-(optionally substituted heterocyclyl), -(CO)-(optionally substituted alkoxy), -(CO)- (optionally substituted amino), and -COOH.

[0144] Preferably, each R3may be independently selected from hydroxy, halogen, cyano, optionally substituted C1-C12 alkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C1-C12 alkoxy, optionally substituted amino, -(NH) -(optionally substituted C1-C12 alkyl), -(NH) -(optionally substituted C3-C10 cycloalkyl), -(NH) -(optionally substituted 3-10 membered heterocyclyl), -(CO)-(optionally substituted C1-C12 alkoxy), -(CO) -(optionally substituted amino), and -COOH.

[0145] More preferably, each R3may be independently selected from hydroxy, halogen, cyano, optionally substituted Ci-Ce alkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted Ci-Ce alkoxy, optionally substituted amino, -(NH)-(optionally substituted Ci-Ce alkyl), -(NH) -(optionally substituted C3-C6 cycloalkyl), -(NH) -(optionally substituted 3-7 membered heterocyclyl), -(CO)- (optionally substituted Ci-Ce alkoxy), -(CO)-(optionally substituted amino), and -COOH.

[0146] In a further preferred embodiment, each R3may be independently optionally substituted amino. When R3is optionally substituted amino, compounds according to Formula I may have enhanced binding affinity to RNA methyltransferase. Preferably, each R3may be independently -NH2.

[0147] In Formula I, R4is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0148] Preferably, R4may be selected from hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted Ce-Ci4 aryl, and optionally substituted 5-14 membered heteroaryl.

[0149] More preferably, R4may be selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted CY-C'e cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted Ce-Cio aryl, and optionally substituted 5-10 membered heteroaryl.

[0150] In a preferred embodiment, R4may be selected from hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl.

[0151] Preferably, R4may be selected from hydrogen, optionally substituted C1-C12 alkyl, and optionally substituted C3-C10 cycloalkyl.

[0152] More preferably, R4may be selected from hydrogen, optionally substituted Ci-Ce alkyl, and optionally substituted C3-C6 cycloalkyl.

[0153] In a further preferred embodiment, R4may be optionally substituted alkyl.

[0154] Preferably, R4may be optionally substituted C1-C12 alkyl.

[0155] More preferably, R4may be optionally substituted Ci-Ce alkyl.

[0156] Even more preferably, R4may be optionally substituted C1-C4 alkyl.

[0157] Yet even more preferably, R4may be methyl.

[0158] In Formula I, R5is independently selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino.

[0159] Preferably, R5may be independently selected from hydrogen, hydroxy, halogen, optionally substituted C1-C12 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C1-C12 alkoxy, optionally substituted Ce-Ci4 aryl, optionally substituted 5-14 membered heteroaryl, and optionally substituted amino. More preferably, R5may be independently selected from hydrogen, hydroxy, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Cs-Ce cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ce-Cio aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted amino.

[0160] In a preferred embodiment, R5may be selected from hydrogen, halogen, and optionally substituted alkyl.

[0161] Preferably, R5may be selected from hydrogen, halogen, and optionally substituted C1-C12 alkyl.

[0162] More preferably, R5may be selected from hydrogen, halogen, and optionally substituted Ci-Ce alkyl.

[0163] In Formula I, R6is independently selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino.

[0164] Preferably, R6may be independently selected from hydrogen, hydroxy, halogen, optionally substituted C1-C12 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C1-C12 alkoxy, optionally substituted Ce-Ci4 aryl, optionally substituted 5-14 membered heteroaryl, and optionally substituted amino.

[0165] More preferably, R6may be independently selected from hydrogen, hydroxy, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Cs-Ce cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ce-Cio aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted amino.

[0166] In a preferred embodiment, R6may be selected from hydrogen, halogen, and optionally substituted alkyl.

[0167] Preferably, R6may be selected from hydrogen, halogen, and optionally substituted C1-C12 alkyl.

[0168] More preferably, R6may be selected from hydrogen, halogen, and optionally substituted Ci-Ce alkyl.

[0169] In Formula I, R7is selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, -(NH) -(optionally substituted alkyl), -(NH)-(optionally substituted cycloalkyl), -(NH)-(optionally substituted heterocyclyl), -(NH)-(optionally substituted aryl), -(NH) -(optionally substituted heteroaryl), -(O)- (optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O)-(optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), -(O) -(optionally substituted heteroaryl), -(CO)- (optionally substituted alkyl), -(CO) -(optionally substituted cycloalkyl), -(CO)-(optionally substituted heterocyclyl), -(CO)-(optionally substituted alkoxy), -(CO) -(optionally substituted aryl), -(CO)- (optionally substituted heteroaryl), -(CO)-(optionally substituted amino), and -COOH.

[0170] Preferably, R7may be selected from hydrogen, hydroxy, halogen, optionally substituted C1-C12 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C1-C12 alkoxy, optionally substituted Ce-Ci4 aryl, optionally substituted 5-14 membered heteroaryl, optionally substituted amino, -(NH) -(optionally substituted C1-C12 alkyl), -(NH) -(optionally substituted C3-C10 cycloalkyl), -(NH) -(optionally substituted 3-10 membered heterocyclyl), -(NH)- (optionally substituted Ce-Ci4 aryl), -(NH) -(optionally substituted 5-14 membered heteroaryl), -(O)- (optionally substituted C1-C12 alkyl), -(O)-(optionally substituted C3-C10 cycloalkyl), -(O) -(optionally substituted 3-10 membered heterocyclyl), -(O)-(optionally substituted Ce-Ci4 aryl), -(O) -(optionally substituted 5-14 membered heteroaryl), -(CO) -(optionally substituted C1-C12 alkyl), -(CO) -(optionally substituted C3-C10 cycloalkyl), -(CO) -(optionally substituted 3-10 membered heterocyclyl), -(CO)- (optionally substituted C1-C12 alkoxy), -(CO)-(optionally substituted Ce-Ci4 aryl), -(CO)-(optionally substituted 5-14 membered heteroaryl), -(CO)-(optionally substituted amino), and -COOH.

[0171] More preferably, R7may be selected from hydrogen, hydroxy, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ce-Cio aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted amino, -(NH) -(optionally substituted Ci-Ce alkyl), -(NH)- (optionally substituted C3-C6 cycloalkyl), -(NH) -(optionally substituted 3-7 membered heterocyclyl), - (NH) -(optionally substituted Ce-Cio aryl), -(NH) -(optionally substituted 5-10 membered heteroaryl), - (O) -(optionally substituted Ci-Ce alkyl), -(O)-(optionally substituted C3-C6 cycloalkyl), -(O)- (optionally substituted 3-7 membered heterocyclyl), -(O) -(optionally substituted Ce-Cio aryl), -(O)- (optionally substituted 5-10 membered heteroaryl), -(CO) -(optionally substituted Ci-Ce alkyl), -(CO)- (optionally substituted C3-C6 cycloalkyl), -(CO)-(optionally substituted 3-7 membered heterocyclyl), - (CO)-(optionally substituted Ci-Ce alkoxy), -(CO)-(optionally substituted Ce-Cio aryl), -(CO)- (optionally substituted 5-10 membered heteroaryl), -(CO) -(optionally substituted amino), and -COOH.

[0172] In a preferred embodiment, R7may be selected from optionally substituted alkoxy, optionally substituted amino, -(O) -(optionally substituted heterocyclyl), and -COOH.

[0173] Preferably, R7may be selected from optionally substituted C1-C12 alkoxy, optionally substituted amino, -(O) -(optionally substituted 3-10 membered heterocyclyl), and -COOH.

[0174] More preferably, R7may be selected from optionally substituted Ci-Ce alkoxy, optionally substituted amino, -(O) -(optionally substituted 3-7 membered heterocyclyl), and -COOH. In Formula I, R8is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0175] Preferably, R8may be selected from hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted Ce-Ci4 aryl, and optionally substituted 5-14 membered heteroaryl.

[0176] More preferably, R8may be selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Cs-Ce cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted Ce-Cio aryl, and optionally substituted 5-10 membered heteroaryl.

[0177] In a preferred embodiment, R8may be hydrogen.

[0178] In Formula I, X1is selected from N, CH and CR3(unless X5, X6and X7form a structure according to Formula 1-3).

[0179] In some embodiments, X1may be N. In other embodiments, X1may be CH or CR3.

[0180] In Formula I, X2is selected from N, CH and CR3(unless X5, X6and X7form a structure according to Formula 1-3).

[0181] In some embodiments, X2may be N. In other embodiments, X2may be CH or CR3.

[0182] In Formula I, X3is selected from N, CH and CR3(unless X5, X6and X7form a structure according to Formula 1-3).

[0183] In some embodiments, X3may be N. In other embodiments, X3may be CH or CR3.

[0184] In Formula I, X4is selected from N, CH and CR3(unless X5, X6and X7form a structure according to Formula 1-3).

[0185] In some embodiments, X4may be N. In other embodiments, X4may be CH or CR3. In some embodiments, X1may be N, and each of X2to X4may be independently selected from CH and CR3. Preferably, X1may be N, each of X2and X3may be independently selected from CH and CR3, and X4may be CH.

[0186] In some embodiments, X2may be N, and each of X1, X3and X4may be independently selected from CH and CR3(unless X5, X6and X7form a structure according to Formula 1-3). Preferably, X2may be N, X1and X4may be CH, and X3may be selected from CH and CR3.

[0187] In some embodiments, X3may be N, and each of X1, X2and X4may be independently selected from CH and CR3(unless X5, X6and X7form a structure according to Formula 1-3). Preferably, X2may be N, and X1, X2and X4may be CH.

[0188] In some embodiments, X4may be N, and each of X1to X3may be independently selected from CH and CR3(unless X5, X6and X7form a structure according to Formula 1-3). Preferably, X4may be N, and X1, X2and X3may be CH.

[0189] In some embodiments, X2and X4are N, and each of X1and X3is independently selected from CH and CR3(unless X5, X6and X7form a structure according to Formula 1-3). Preferably, X2and X4may be N, and X1and X3may be CH.

[0190] In some embodiments, each of X1to X4may be independently selected from CH and CR3(unless X5, X6and X7form a structure according to Formula 1-3). Preferably, X2may be CR3, and each of X1, X3and X4may be independently selected from CH and CR3; or X3may be CR3, and each of X1, X2and X4may be independently selected from CH and CR3. More preferably, X2may be CR3, and each of X1, X3and X4may be CH; or X3may be CR3, and each of X1, X2and X4may be CH.

[0191] In Formula I, at least one of X6and X7comprise a nitrogen atom such that X5, X6and X7form a structure selected from any one of Formulae 1-1, 1-2 and 1-3: Formula 1-1 : Formula 1-2: Formula I-3: wherein in Formula 1-1, X5is selected from NR4, O and C(R5)(R6), wherein in Formula 1-2, X5is N, wherein in Formula 1-3, X5is NR8, and

[0192] - represents a connection point to the rest of Formula I.

[0193] In Formula 1-1, in some embodiments, X5may be NR4(where R4is as defined herein). In other embodiments, X5may be O. In yet other embodiments, X5may be C(R5)(R6) (where R5and R6are as defined herein). It is especially preferred that X5is NR4(where R4is as defined herein).

[0194] In Formula I, m is an integer selected from 0 to 9.

[0195] Preferably, m may be an integer selected from 0 to 4.

[0196] More preferably, m may be 0 or 1.

[0197] In some embodiments, m may be 0. In other embodiments, m may be 1. It is especially preferred that m is 0.

[0198] In Formula I, n is an integer selected from 0 to 4.

[0199] Preferably, n may be 0, 1 or 2.

[0200] In some embodiments, n may be 0. In other embodiments, n may be 1. In yet other embodiments, n may be 2. It is especially preferred that n is 1.

[0201] In some embodiments, the compound according to Formula I may have a structure according to Formula la:

[0202] wherein each of X1to X7, R1to R8, m and n are as defined herein.

[0203] In other embodiments, the compound according to Formula I may have a structure according to Formula lb: wherein each of X1to X7, R1to R8, m and n are as defined herein.

[0204] In some embodiments, the compound according to Formula I (in particular, where X5, X6and X7form a structure according to Formula 1-1) may have a structure according to Formula II- 1 :

[0205] wherein X5is selected from NR4, O and C(R5)(R6), and each of X1to X4, R1to R6, m and n are as defined herein. When the compound according to Formula I has a structure according to Formula II- 1, compounds according to Formula I may have enhanced binding affinity to RNA methyltransferase.

[0206] In Formula II- 1, in some embodiments, X5may be NR4(where R4is as defined herein). In other embodiments, X5may be O. In yet other embodiments, X5may be C(R5)(R6) (where R5and R6are as defined herein). It is especially preferred that X5is NR4(where R4is as defined herein).

[0207] In some preferred embodiments, the compound according to Formula I (in particular, where X5, X6and

[0208] X7form a structure according to Formula 1-1) may have a structure according to Formula IIa-1: wherein X5is selected from NR4, O and C(R5)(R6), and each of X1to X4, R1to R6, m and n are as defined herein.

[0209] In Formula IIa-1, in some embodiments, X5may be NR4(where R4is as defined herein). In other embodiments, X5may be O. In yet other embodiments, X5may be C(R5)(R6) (where R5and R6are as defined herein). It is especially preferred that X5is NR4(where R4is as defined herein). In other preferred embodiments, the compound according to Formula I (in particular, where X5, X6and

[0210] X7form a structure according to Formula 1-1) may have a structure according to Formula IIb-1: wherein X5is selected from NR4, O and C(R5)(R6), and each of X1to X4, R1to R6, m and n are as defined herein.

[0211] In Formula IIb-1, in some embodiments, X5may be NR4(where R4is as defined herein). In other embodiments, X5may be O. In yet other embodiments, X5may be C(R5)(R6) (where R5and R6are as defined herein). It is especially preferred that X5is NR4(where R4is as defined herein).

[0212] In other embodiments, the compound according to Formula I (in particular, where X5, X6and X7form a structure according to Formula 1-2) may have a structure according to Formula II-2: wherein X5is N, and each of X1to X4, R1to R3, R7, m and n are as defined herein.

[0213] In some preferred embodiments, the compound according to Formula I (in particular, where X5, X6and

[0214] X7form a structure according to Formula 1-2) may have a structure according to Formula IIa-2:

[0215]

[0216] Ila-2 wherein X5is N, and each of X1to X4, R1to R3, R7, m and n are as defined herein.

[0217] In other preferred embodiments, the compound according to Formula I (in particular, where X5, X6and

[0218] X7form a structure according to Formula 1-2) may have a structure according to Formula IIb-2: llb-2 wherein X5is N, and each of X1to X4, R1to R3, R7, m and n are as defined herein.

[0219] In yet other embodiments, the compound according to Formula I (in particular, where X5, X6and X7form a structure according to Formula 1-3) may have a structure according to Formula II-3:

[0220] wherein X5is NR8, and each of R1to R3, R8, m and n are as defined herein.

[0221] In some preferred embodiments, the compound according to Formula I (in particular, where X5, X6and

[0222] X7form a structure according to Formula 1-3) may have a structure according to Formula IIa-3: wherein X5is NR8, and each of R1to R3, R8, m and n are as defined herein.

[0223] In other preferred embodiments, the compound according to Formula I (in particular, where X5, X6and

[0224] X7form a structure according to Formula 1-3) may have a structure according to Formula IIb-3: llb-3 wherein X5is NR8, and each of R1to R3, R8, m and n are as defined herein.

[0225] Preferably, the compound according to Formula I may be selected from any one of Compounds 1 to 41, 64 to 232 and 234, 236 to 241, 243, and 245 to 269.

[0226] More preferably, the compound according to Formula I may be selected from any one of Compounds 130 to 137, and 151.

[0227] Even more preferably, the compound according to Formula I may be selected from any one of Compounds 130 to 137.

[0228] Yet even more preferably, the compound according to Formula I may be Compound 133.

[0229] In embodiments relating to compounds of the present invention, the compounds per se are limited with the proviso that when X5, X6and X7form a structure according to Formula 1-1 and X5is NR4, X4is CH or CR3. However, as described herein, this proviso may not apply to compositions as described herein, dosage forms as described herein, compounds as described herein (or compositions as described herein, or dosage forms as described herein) for use in treatment, uses of compounds (or compositions as described herein, or dosage forms as described herein) in the manufacture of a medicament for treatment as described herein, methods of treatment as described herein, kits as described herein, or processes for manufacture as described herein.

[0230] In embodiments relating to compounds of the present invention, the compounds per se are limited with the proviso that when X5, X6and X7form a structure according to Formula 1-1 and X5is NR4and X2is N, when X1is CR3, R3for CR3is not optionally substituted amino. However, as described herein, this proviso may not apply to compositions as described herein, dosage forms as described herein, compounds as described herein (or compositions as described herein, or dosage forms as described herein) for use in treatment, uses of compounds (or compositions as described herein, or dosage forms as described herein) in the manufacture of a medicament for treatment as described herein, methods of treatment as described herein, kits as described herein, or processes for manufacture as described herein.

[0231] In embodiments relating to compounds of the present invention, the compounds per se are limited with the proviso that when X5, X6and X7form a structure according to Formula 1-2, R7is selected from optionally substituted alkoxy, optionally substituted amino, -(O)-(optionally substituted heterocyclyl), and -COOH. However, as described herein, this proviso may not apply to compositions as described herein, dosage forms as described herein, compounds as described herein (or compositions as described herein, or dosage forms as described herein) for use in treatment, uses of compounds (or compositions as described herein, or dosage forms as described herein) in the manufacture of a medicament for treatment as described herein, methods of treatment as described herein, kits as described herein, or processes for manufacture as described herein.

[0232] In embodiments relating to compounds of the present invention, the compounds per se are limited with the proviso that the compound is not any one of the compounds as described in Tables I, II, III, and IV. However, as described herein, this proviso may not apply to compositions as described herein, dosage forms as described herein, compounds as described herein (or compositions as described herein, or dosage forms as described herein) for use in treatment, uses of compounds (or compositions as described herein, or dosage forms as described herein) in the manufacture of a medicament for treatment as described herein, methods of treatment as described herein, kits as described herein, or processes for manufacture as described herein.

[0233] In embodiments relating to compounds of the present invention, the compounds per se may be limited with the proviso that the compound is not any one of the following compounds: However, as described herein, this proviso may not apply to compositions as described herein, dosage forms as described herein, compounds as described herein (or compositions as described herein, or dosage forms as described herein) for use in treatment, uses of compounds (or compositions as described herein, or dosage forms as described herein) in the manufacture of a medicament for treatment as described herein, methods of treatment as described herein, kits as described herein, or processes for manufacture as described herein.

[0234] Compositions

[0235] In another embodiment of the present invention, provided herein is a composition comprising a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient: wherein each of X1to X7, R1to R8, m and n are as defined herein.

[0236] Characteristics of compounds according to Formula I have already been described herein and these considerations apply equally to compositions comprising a compound of Formula I. For example, the compound according to Formula I may have a structure according to any one of Formulae la, lb, II- 1, IIa-1, IIb-1, II-2, IIa-2, IIb-2, II-3, IIa-3 or IIb-3.

[0237] Preferably, the compound according to Formula I may be selected from any one of Compounds 1 to 269.

[0238] More preferably, the compound according to Formula I may be selected from any one of Compounds 130 to 137, and 151.

[0239] Even more preferably, the compound according to Formula I may be selected from any one of Compounds 130 to 137.

[0240] Yet even more preferably, the compound according to Formula I may be Compound 133. In embodiments relating to compositions comprising a compound of Formula I as described herein, when X5, X6and X7form a structure according to Formula 1-1 and X5is NR4, X4may be CH or CR3. However, the compositions provided herein are not necessarily limited thereto.

[0241] In embodiments relating to compositions comprising a compound of Formula I as described herein, when X5, X6and X7form a structure according to Formula 1-1 and X5is NR4and X2is N, when X1is CR3, R3for CR3may not be optionally substituted amino. However, the compositions provided herein are not necessarily limited thereto.

[0242] In embodiments relating to compositions comprising a compound of Formula I as described herein, when X5, X6and X7form a structure according to Formula 1-2, R7may be selected from optionally substituted alkoxy, optionally substituted amino, -(O) -(optionally substituted heterocyclyl), and - COOH. However, the compositions provided herein are not necessarily limited thereto.

[0243] In embodiments relating to compositions comprising a compound of Formula I as described herein, the compound may not be any one of the compounds described in Tables I, II, III, and IV. However, the compositions provided herein are not necessarily limited thereto.

[0244] In embodiments relating to compositions comprising a compound of Formula I as described herein, the compound may not be any one of the compounds:

[0245] However, the compositions provided herein are not necessarily limited thereto.

[0246] Pharmaceutically acceptable carriers or excipients may include fillers, binders, disintegrants, glidants, lubricants, complexing agents, solubilizers, and surfactants, which may be chosen to facilitate administration of the compound by a particular route. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, and the like. Carriers also include physiologically compatible liquids as solvents or for suspensions, including, for example, sterile solutions of water for injection (WFI), saline solution, dextrose solution, Hank’s solution, Ringer’s solution, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, and the like . Excipients may also include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethyl cellulose, cross-linked sodium carboxymethylcellulose, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated cotton seed oil, castor seed oil mineral oil, polyethylene glycol (e.g. PEG 400 or PEG 4000-8000), polyoxyethylene glycol, poloxamers, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, methacrylic acid divinylbenzene copolymer, sodium docusate, cyclodextrins (e.g. 2-hydroxypropyl-.delta. -cyclodextrin), polysorbates (e.g. polysorbate 80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ethers, di-fatty acid ester of polyethylene glycols, or a polyoxyalkylene sorbitan fatty acid ester (e.g., polyoxyethylene sorbitan ester Tween®), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid ester, e.g. a sorbitan fatty acid ester from a fatty acid such as oleic, stearic or palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, lactose monohydrate or lactose spray dried, sucrose, fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrates, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, simethicone, polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl methyl celluloses), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, and the like.

[0247] In some embodiments, oral administration may be used. Pharmaceutical preparations for oral use can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops. Compounds of Formula I described herein may be combined with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e.g. aqueous, alcoholic, or oily solutions) and the like. Suitable excipients are, in particular, fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, com starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and / or polyvinylpyrrolidone (PVP: povidone); oily excipients, including vegetable and animal oils, such as sunflower oil, olive oil, or codliver oil. The oral dosage formulations may also contain disintegrating agents, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate; a lubricant, such as talc or magnesium stearate; a plasticizer, such as glycerol or sorbitol; a sweetening such as sucrose, fructose, lactose, or aspartame; a natural or artificial flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring; or dye-stuffs or pigments, which may be used for identification or characterization of different doses or combinations. Also provided are dragee cores with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, poly-vinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.

[0248] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin (“gelcaps”), as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, active components, such as compounds of Formula I, may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.

[0249] In some embodiments, injection (parenteral administration) may be used, e.g., intramuscular, intravenous, intraperitoneal, and / or subcutaneous. Compounds of Formula I described herein for injection may be formulated in sterile liquid solutions, preferably in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. Dispersions may also be prepared in non-aqueous solutions, such as glycerol, propylene glycol, ethanol, liquid polyethylene glycols, triacetin, and vegetable oils. Solutions may also contain a preservative, such as methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In addition, compounds of Formula I described herein may be formulated in solid form, including, for example, lyophilized forms, and redissolved or suspended prior to use.

[0250] In some embodiments, transmucosal, topical or transdermal administration may be used. In such formulations of compounds of Formula I described herein, penetrants appropriate to the barrier to be permeated are used. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays or suppositories (rectal or vaginal). Compositions of compounds of Formula I described herein for topical administration may be formulated as oils, creams, lotions, ointments, and the like by choice of appropriate carriers known in the art. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C12). In some embodiments, carriers are selected such that the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Creams for topical application are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of solvent (e.g., an oil), is admixed. Additionally, administration by transdermal means may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents known in the art. To be administered in the form of a transdermal delivery system, the dosage administration will be continuous rather than intermittent throughout the dosage regimen. In some embodiments, compounds of Formula I, or compositions thereof, are administered as an inhalant. Compounds of Formula I described herein may be formulated as dry powder or a suitable solution, suspension, or aerosol. Powders and solutions may be formulated with suitable additives known in the art. For example, powders may include a suitable powder base such as lactose or starch, and solutions may comprise propylene glycol, sterile water, ethanol, sodium chloride and other additives, such as acid, alkali and buffer salts. Such solutions or suspensions may be administered by inhaling via spray, pump, atomizer, or nebulizer, and the like.

[0251] Dosage forms

[0252] In another embodiment of the present invention, provided herein is a dosage form comprising a composition as described herein.

[0253] The dosage form may be as a unit dose or single dose form, e.g., single dose pills, capsules, or the like.

[0254] Medical uses

[0255] In another embodiment of the present invention, provided herein is a compound according to Formula

[0256] I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof: wherein each of X1to X7, R1to R8, m and n are as defined herein; or a composition as defined herein; or a dosage form as defined herein; for use in the treatment of a disease modulated by RNA methyltransferase (e.g. RNMT).

[0257] In another embodiment of the present invention, provided herein is a use of a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof:

[0258] wherein each of X1to X7, R1to R8, m and n are as defined herein; or a composition as defined herein; or a dosage form as defined herein; in the manufacture of a medicament for the treatment of a disease modulated by RNA methyltransferase (e.g. RNMT).

[0259] In another embodiment of the present invention, provided herein is a method of treating a disease modulated by RNA methyltransferase (e.g. RNMT) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof: wherein each of X1to X7, R1to R8, m and n are as defined herein; or a composition as defined herein; or a dosage form as defined herein.

[0260] Characteristics of compounds according to Formula I have already been described herein and these considerations apply equally to compounds as described herein (or compositions as described herein, or dosage forms as described herein) for use in treatment, uses of compounds (or compositions as described herein, or dosage forms as described herein) in the manufacture of a medicament for treatment as described herein, or methods of treatment as described herein. For example, the compound according to Formula I may have a structure according to any one of Formulae la, lb, II- 1, IIa-1, IIb-1, II-2, Ila- 2, IIb-2, II-3, IIa-3 or IIb-3. Preferably, the compound according to Formula I may be selected from any one of Compounds 1 to 269.

[0261] More preferably, the compound according to Formula I may be selected from any one of Compounds 130 to 137, and 151.

[0262] Even more preferably, the compound according to Formula I may be selected from any one of Compounds 130 to 137.

[0263] Yet even more preferably, the compound according to Formula I may be Compound 133.

[0264] In embodiments relating to compounds as described herein (or compositions as described herein, or dosage forms as described herein) for use in treatment, uses of compounds (or compositions as described herein, or dosage forms as described herein) in the manufacture of a medicament for treatment as described herein, or methods of treatment as described herein, when X5, X6and X7form a structure according to Formula 1-1 and X5is NR4, X4may be CH or CR3. However, the compounds (or compositions / dosage forms) for use in treatment, uses of compounds (or compositions / dosage forms) in the manufacture of a medicament for treatment, or methods of treatment provided herein are not necessarily limited thereto.

[0265] In embodiments relating to compounds as described herein (or compositions as described herein, or dosage forms as described herein) for use in treatment, uses of compounds (or compositions as described herein, or dosage forms as described herein) in the manufacture of a medicament for treatment as described herein, or methods of treatment as described herein, when X5, X6and X7form a structure according to Formula I- 1 and X5is NR4and X2is N, when X1is CR3, R3for CR3may not be optionally substituted amino. However, the compounds (or compositions / dosage forms) for use in treatment, uses of compounds (or compositions / dosage forms) in the manufacture of a medicament for treatment, or methods of treatment provided herein are not necessarily limited thereto.

[0266] In embodiments relating to compounds as described herein (or compositions as described herein, or dosage forms as described herein) for use in treatment, uses of compounds (or compositions as described herein, or dosage forms as described herein) in the manufacture of a medicament for treatment as described herein, or methods of treatment as described herein, when X5, X6and X7form a structure according to Formula 1-2, R7may be selected from optionally substituted alkoxy, optionally substituted amino, -(O) -(optionally substituted heterocyclyl), and -COOH. However, the compounds (or compositions / dosage forms) for use in treatment, uses of compounds (or compositions / dosage forms) in the manufacture of a medicament for treatment, or methods of treatment provided herein are not necessarily limited thereto.

[0267] In embodiments relating to compounds as described herein (or compositions as described herein, or dosage forms as described herein) for use in treatment, uses of compounds (or compositions as described herein, or dosage forms as described herein) in the manufacture of a medicament for treatment as described herein, or methods of treatment as described herein, the compound may not be any one of the compounds described in Tables I, II, III, and IV. However, the compounds (or compositions / dosage forms) for use in treatment, uses of compounds (or compositions / dosage forms) in the manufacture of a medicament for treatment, or methods of treatment provided herein are not necessarily limited thereto .

[0268] In embodiments relating to compounds as described herein (or compositions as described herein, or dosage forms as described herein) for use in treatment, uses of compounds (or compositions as described herein, or dosage forms as described herein) in the manufacture of a medicament for treatment as described herein, or methods of treatment as described herein, the compound may not be any one of the compounds:

[0269] However, the compounds (or compositions / dosage forms) for use in treatment, uses of compounds (or compositions / dosage forms) in the manufacture of a medicament for treatment, or methods of treatment provided herein are not necessarily limited thereto. Preferably, the disease modulated by RNA methyltransferase (e.g. RNMT) may be cancer.

[0270] More preferably, the cancer may be selected from liver cancer (e.g. hepatocellular carcinoma), gastric cancer, intestinal cancer, colorectal cancer, glioma (e.g. glioblastoma), breast cancer, bladder cancer (e.g. urothelial carcinoma of the bladder), prostate cancer, renal cancer (e.g. clear cell renal cell carcinoma), gall bladder carcinoma, lung cancer (e.g. lung squamous cell carcinoma), skin cancer (e.g. cutaneous melanoma), throat cancer (e.g. oesophageal squamous cell carcinoma, hypopharyngeal squamous cell carcinoma), head and neck cancer (e.g. head and neck squamous cell carcinoma), and pancreatic cancer

[0271] As used herein, the terms “treat” and “treatment” and like terms refer to the administration of material, e.g., any one or more compound(s) as described herein in an amount effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or condition, i.e., indication, and / or to prolong the survival of the subject being treated.

[0272] In some cases, one or more compound(s) as described herein may be used in combination (for example, in a composition as described herein) with one or more pharmaceutically active compounds. As used herein, the term “therapeutically effective” or "effective amount" indicates that a compound or amount of the compound of Formula I when administered is sufficient or effective to prevent, alleviate, or ameliorate one or more symptoms of a disease, disorder or medical condition being treated, and / or to prolong the survival of the subject being treated. The therapeutically effective amount will vary depending on the compound, the disease, disorder or condition and its severity and the age, weight, etc., of the mammal to be treated. In general, satisfactory results in subjects are indicated to be obtained at a daily dosage of from about 0.1 to about 10 g / kg subject body weight. In some embodiments, a daily dose ranges from about 0.10 to lO.O mg / kg of body weight, from about 1.0 to 3.0 mg / kg of body weight, from about 3 to 10 mg / kg of body weight, from about 3 to 150 mg / kg of body weight, from about 3 to 100 mg / kg of body weight, from about 10 to 100 mg / kg of body weight, from about 10 to 150 mg / kg of body weight, or from about 150 to 1000 mg / kg of body weight. The dosage can be conveniently administered, e.g., in divided doses up to four times a day or in sustained-release form.

[0273] As used herein, the term “modulating” or “modulate” refers to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule. For example, an inhibitor of a particular biomolecule modulates the activity of that biomolecule, e.g., an enzyme, by decreasing the activity of the biomolecule, such as an enzyme. Such activity is typically indicated in terms of an inhibitory concentration (IC50) or pKd of the compound for an inhibitor with respect to, for example, an enzyme.

[0274] As used herein, the term “subject” refers to a living organism that is treated with compounds as described herein, including, but not limited to, any mammal, such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats.

[0275] As used herein, the term “administering” refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.).

[0276] The compounds for use herein are typically used in therapy for human subjects. However, they may also be used to treat similar or identical indications in other animal subjects. Compounds of Formula I described herein can be administered by different routes, including injection (i.e. parenteral, including intravenous, intraperitoneal, subcutaneous, and intramuscular), oral, transdermal, transmucosal, rectal, or inhalant. Such dosage forms allow the compound to reach target cells. Other factors are well known in the art, and include considerations such as toxicity and dosage forms that retard the compound or composition from exerting its effects. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy, 21stedition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005.

[0277] Kits

[0278] In another embodiment of the present invention, provided herein is a kit comprising a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof: wherein each of X1to X7, R1to R8, m and n are as defined herein; or a composition as described herein; or a dosage form as described herein; and a pharmaceutically acceptable carrier or excipient, and / or instructions for use of the compound, the composition or the dosage form in the treatment of a disease modulated by RNA methyltransferase (e.g. RNMT).

[0279] Characteristics of compounds according to Formula I have already been described herein and these considerations apply equally to kits comprising a compound of Formula I. For example, the compound according to Formula I may have a structure according to any one of Formulae la, lb, II- 1, IIa-1, IIb-1, II -2, IIa-2, IIb-2, II-3, IIa-3 or IIb-3.

[0280] Preferably, the compound according to Formula I may be selected from any one of Compounds 1 to 269.

[0281] More preferably, the compound according to Formula I may be selected from any one of Compounds 130 to 137, and 151.

[0282] Even more preferably, the compound according to Formula I may be selected from any one of Compounds 130 to 137.

[0283] Yet even more preferably, the compound according to Formula I may be Compound 133. In embodiments relating to kits as described herein, when X5, X6and X7form a structure according to Formula 1-1 and X5is NR4, X4may be CH or CR3. However, the kits provided herein are not necessarily limited thereto.

[0284] In embodiments relating to kits as described herein, when X5, X6and X7form a structure according to Formula 1-1 and X5is NR4and X2is N, when X1is CR3, R3for CR3may not be optionally substituted amino. However, the kits provided herein are not necessarily limited thereto.

[0285] In embodiments relating to kits as described herein, when X5, X6and X7form a structure according to Formula 1-2, R7may be selected from optionally substituted alkoxy, optionally substituted amino, -(O)- (optionally substituted heterocyclyl), and -COOH. However, the kits provided herein are not necessarily limited thereto.

[0286] In embodiments relating to kits as described herein, the compound may not be any one of the compounds described in Tables I, II, III, and IV. However, the kits provided herein are not necessarily limited thereto.

[0287] In embodiments relating to kits as described herein, the compound may not be any one of the compounds:

[0288] However, the kits provided herein are not necessarily limited thereto. The disease modulated by RNA methyltransferase (e.g. RNMT) may be a disease as defined herein.

[0289] Processes for manufacture

[0290] In another embodiment of the present invention, provided herein is a process for manufacturing a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein the process comprises a step of coupling a compound according to Formula Int-A to a compound according to Formula Int-B:

[0291] Int-A wherein each of X1to X7, R1to R8, m and n are as defined herein.

[0292] Characteristics of compounds according to Formula I have already been described herein and these considerations apply equally to processes for manufacturing a compound of Formula I. For example, the compound according to Formula I may have a structure according to any one of Formulae la, lb, II- 1, IIa-1, IIb-1, II-2, IIa-2, IIb-2, II-3, IIa-3 or IIb-3.

[0293] Preferably, the compound according to Formula I may be selected from any one of Compounds 1 to 269.

[0294] More preferably, the compound according to Formula I may be selected from any one of Compounds 130 to 137, and 151.

[0295] Even more preferably, the compound according to Formula I may be selected from any one of Compounds 130 to 137.

[0296] Yet even more preferably, the compound according to Formula I may be Compound 133.

[0297] In embodiments relating to processes for manufacture as described herein, when X5, X6and X7form a structure according to Formula 1-1 and X5is NR4, X4may be CH or CR3. However, the processes for manufacture provided herein are not necessarily limited thereto.

[0298] In embodiments relating to processes for manufacture as described herein, when X5, X6and X7form a structure according to Formula 1-1 and X5is NR4and X2is N, when X1is CR3, R3for CR3may not be optionally substituted amino. However, the processes for manufacture provided herein are not necessarily limited thereto.

[0299] In embodiments relating to processes for manufacture as described herein, when X5, X6and X7form a structure according to Formula 1-2, R7may be selected from optionally substituted alkoxy, optionally substituted amino, -(O)-(optionally substituted heterocyclyl), and -COOH. However, the processes for manufacture provided herein are not necessarily limited thereto. In embodiments relating to processes for manufacture as described herein, the compound may not be any one of the compounds described in Tables I, II, III, and IV. However, the processes for manufacture provided herein are not necessarily limited thereto.

[0300] In embodiments relating to processes for manufacture as described herein, the compound may not be any one of the compounds:

[0301] However, the processes for manufacture provided herein are not necessarily limited thereto. The type of coupling reaction is not particularly limited and methods of conducting amidation reactions are known to persons of skill in the art.

[0302] In some embodiments, the coupling reaction may involve the use of a peptide coupling agent. Nonlimiting examples of peptide coupling agents include phosphonic acid anhydrides (e.g. propanephosphonic acid anhydride (T3P)), carbodiimides (e.g. dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl -(N’,N’-dimethylamino)propylcarbodiimide hydrochloride (EDCI)), acyl imidazoles (e.g. carbonyldiimidazole (CDI)), chlorinating reagents (e.g. oxalyl chloride, thionyl chloride, phosphorus chlorides including PCI3 and PCI5, cyanuric chloride), anhydrides, phosphonium salts (e.g. (benzotriazol- l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol- l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7- azabenzotriazol- 1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), PyOxim), and aminium / uronium salts (e.g. O-(benzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU), O- (benzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-l- yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU), O-(7-azabenzotriazol-l-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TATU), O-(6-chlorobenzotriazol-l-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (HCTU), TOTU, COMU, O-(N-succinimidyl)-l, 1,3,3- tetramethyluronium tetrafluoroborate (TSTU), O-(5-norbomene-2,3-dicarboximido)-N,N,N’,N’- tetramethyluronium tetrafluoroborate (TNTU) and O-(l,2-dihydro-2-oxo-l-pyridyl-N,N,N’,N’- tetramethyluronium tetrafluoroborate (TPTU)). Preferably, the peptide coupling agent is a phosphonic acid anhydride (e.g. propanephosphonic acid anhydride (T3P)).

[0303] The present invention is further described in the following non -limiting examples. EXAMPLES

[0304] Synthesis Examples

[0305] General Procedure 1 for Amide Coupling:

[0306] To a solution of Int-A (0.251 mmol, HC1 salt), Int-B (0.228 mmol), and DIPEA (117.7 mg, 0.911 mmol) in DMF (2 mL) was added T3P (159.4 mg, 0.251 mmol, 50% purity) slowly at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction was monitored by LCMS. The reaction mixture was then directly purified by prep-HPLC and / or prep-TLC. l-(l-(2-(4-fluorophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0307] (Compound 1):

[0308] To a solution of l-(3-piperidyl)-3H-imidazo[4,5-b]pyridin-2-one (110 mg, 0.504 mmol), in DMF (4 mL) was added 2-(4-fluorophenyl)acetic acid (T1.7 mg, 0.504 mmol), HBTU (210.2 mg, 0.5544 mmol) and TEA (0.26 mL, 1.512 mmol). The resulting mixture was stirred at ambient temperature overnight. The mixture was then poured into water (60mL) and extracted with EtOAc (3x40mL). The combined organics were then washed with brine, dried over MgSCL and concentrated in vacuo. Purification was done using mass-directed autoprep HPLC (acidic). l-[l-[2-(4-fluorophenyl)acetyl]-3-piperidyl]-3H- imidazo[4,5-b]pyridin-2-one, 67 mg, 35.6 % yield. 'H NMR (400 MHz, CDC13) 5 8.40 (s, 1H), 8.02 (dd, J= 5.2, 1.3 Hz, 1H), 7.21 (d, J= 8.3 Hz, 2.5H), 7.10 - 6.93 (m, 3H), 6.76 (d, J= 8.2 Hz, 0.5H), 4.76 (d, J= 14.9 Hz, 1H), 4.06 - 3.86 (m, 1.5H), 3.84 - 3.63 (m, 3H), 3.31 (t, J= 12.2 Hz, 0.5H), 3.05 (d, J= 13.3 Hz, 0.5H), 2.68 - 2.37 (m, 2H), 2.09 - 1.78 (m, 2H), 1.40 (s, 0.5H). MS m / z 355.1579 l-(l-(2-(thiophen-3-yl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0309] (Compound 2):

[0310] Prepared using the same protocol as was used for the synthesis of Compound 1, however 2-(4- fluorophenyl)acetic acid was replaced with 2-(3-thienyl)acetic acid (71.6 mg, 0.504mmol). l-(l-(2- (thiophen-3-yl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, 40 mg, 22 % yield. ’HNMR (400 MHz, CDC13) 5 9.63 (s, 1H), 8.04 (dd, J= 5.3, 1.3 Hz, 1H), 7.33 (dd, J= 4.8, 3.0 Hz, 1H), 7.14 - 6.96 (m, 3H), 6.87 (d, J= 7.8 Hz, 1H), 4.78 (t, J= 13.4 Hz, 1H), 4.08 - 3.89 (m, 2H), 3.86 - 3.66 (m, 3H), 3.33 (t, J= 12.1 Hz, 0.5H), 3.07 (t, J= 12.4 Hz, 0.5H), 2.67 - 2.35 (m, 2H), 2.07 - 1.80 (m, 2H), 1.63 - 1.50 (m, 0.5H), 1.37 (q, J= 13.3 Hz, 0.5H). MS m / z 343.1237 l-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0311] (Compound 3):

[0312] Prepared using the same protocol that was used for the synthesis of Compound 1, however 2-(4- fluorophenyl)acetic acid was replaced with 2-(3-methoxyphenyl)acetic acid (83.7 mg, 0.504 mmol). 1- (l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, 47mg, 24% yield. 'H NMR (400 MHz, CDC13) 5 9.41 (s, 1H), 8.02 (t, J = 6.4 Hz, 1H), 7.22 (d, J = 7.9 Hz, 0.5H), 6.96 (ddd, J= 35.0, 7.8, 5.2 Hz, 1H), 6.88 - 6.77 (m, 3H), 6.61 (d, J= 7.8 Hz, 0.5H), 4.79 (t, J = 14.4 Hz, 1H), 3.98 (dd, J= 36.4, 13.0 Hz, 1.5H), 3.82 (s, 1.5H), 3.76 (s, 1.5H), 3.73 (s, 2H), 3.63 - 3.53 (m, 0.5H), 3.31 (t,J= 12.1 Hz, 0.5H), 3.04 (t, J= 13.1 Hz, 0.5H), 2.61 (t,J= 13.0 Hz, 0.5H), 2.48 (qd, J= 12.8, 4.2 Hz, 0.5H), 2.06 - 1.77 (m, 2H), 1.57 (t,J= 13.6 Hz, 0.5H), 1.38 (t,J= 13.2 Hz, 0.5H).

[0313] MS m / z 367.1775

[0314] (S)-l-(l-(2-(4-fluorophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0315] (Compound 4): l-[(3S)-3-piperidyl]-3H-imidazo[4,5-b]pyridin-2-one (50 mg, 0.23 mmol) was dissolved in DCM (2 mL) and TEA (0.13 mL, 0.9163 mmol) followed by 2-(4-fluorophenyl)acetyl chloride (43.4mg,0.252mmol). The resulting mixtures were stirred at ambient temperature for 3h. The reactions were quenched by subsequent addition of water (ImL), aq. sat. NaHCO3 (ImL), diluted with DCM (2mL) and the layers separated using a phase separator. Purification by mass-directed Autoprep HPLC. Further purification by Gilson HPLC (basic) to afford l-[(3S)-l-[2-(4-fluorophenyl)acetyl]-3- piperidyl]-3H-imidazo[4,5-b]pyridin-2-one (15mg,0.0402mmol), 17.5% yield. 'H NMR (400 MHz, CDCh) 5 8.04 (d, J= 5.2 Hz, 1H), 7.21 (dd, J = 9.0, 5.5 Hz, 2.5H), 7.08 - 6.92 (m, 3H), 6.79 (d, J = 7.9 Hz, 0.5H), 4.77 (dt, J= 17.2, 8.6 Hz, 1H), 4.08 - 3.87 (m, 1.5H), 3.75 (dd, J= 17.2, 9.3 Hz, 3H), 3.33 (t, J = 12.1 Hz, 0.5H), 3.07 (td, J = 13.4, 2.7 Hz, 0.5H), 2.67 - 2.35 (m, 1.5H), 2.06 - 1.79 (m, 2H), 1.64 - 1.49 (m, 0.5H), 1.49 - 1.32 (m, 0.5H). MS m / z 355.1578

[0316] (S)-l-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-imidazo[4,5-b]pyri din-2- one (Compound 5):

[0317] Prepared using the same protocol that was used for the synthesis of Compound 4, however 2-(4- fluorophenyl)acetyl chloride (43.4mg,0.252mmol) was replaced with 2-(3-methoxyphenyl)acetyl chloride (46.5mg,0 ,252mmol) . 1 -[(3 S)- 1 - [2 -(3 -methoxyphenyl)acetyl] -3 -piperidyl] -3H-imidazo [4,5- b]pyridin-2-one (19mg,0.049mmol), 21.5% yield. 'H NMR (400 MHz, CDCh) 5 8.03 (t, J = 5.5 Hz, 1H), 7.25 - 7.18 (m, 1H), 6.99 (dd, J = 7.9, 5.3 Hz, 0.5H), 6.94 - 6.75 (m, 4H), 6.63 (d, J = 7.9 Hz, 0.5H), 4.78 (t, J= 13.1 Hz, 1H), 4.11 - 3.89 (m, 1.5H), 3.85 - 3.66 (m, 5H), 3.60 (ddt, J= 17.9, 14.3, 4.2 Hz, 0.5H), 3.32 (t, J= 12.1 Hz, 0.5H), 3.04 (td, J= 13.3, 2.7 Hz, 0.5H), 2.66 - 2.40 (m, 2H), 2.04 - 1.76 (m, 2H), 1.62 - 1.49 (m, 0.5H), 1.44 - 1.28 (m, 0.5H). MS m / z 367.1750

[0318] (R)-l-(l-(2-(4-fluorophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0319] (Compound 6):

[0320] Prepared using the same protocol that was used for the synthesis of Compound 4, however l-[(3S)-3- piperidyl]-3H-imidazo[4,5-b]pyridin-2-one was replaced with l-[(3R)-3-piperidyl]-3H-imidazo[4,5- b]pyridin-2-one (50mg,0.23mmol). l-[(3R)-l-[2-(4-fluorophenyl)acetyl]-3-piperidyl]-3H- imidazo[4,5-b]pyridin-2-one (13mg,0.035mmol), 15.2% yield. 'H NMR (400 MHz, CDCh) 8 8.05 (d, J= 5.2 Hz, 1H), 7.22 (dd, J= 9.0, 5.5 Hz, 2.5H), 7.07 - 6.92 (m, 3H), 6.79 (d, J= 7.8 Hz, 0.5H), 4.78 (dt, J= 17.5, 8.7 Hz, 1H), 4.09 - 3.86 (m, 1.5H), 3.76 (dd, J= 18.4, 9.5 Hz, 3H), 3.33 (t, J= 12.1 Hz, 0.5H), 3.07 (td, J= 13.3, 2.7 Hz, 0.5H), 2.68 - 2.37 (m, 1.5H), 2.07 - 1.79 (m, 2H), 1.64 - 1.49 (m, 0.5H), 1.47 - 1.31 (m, 0.5H). MS m / z 355.1545

[0321] (R)-l-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-imidazo[4,5-b]pyri din-2- one (Compound 7): Prepared using the same protocol that was used for the synthesis of Compound 5, however l-[(3S)-3- piperidyl]-3H-imidazo[4,5-b]pyridin-2-one was replaced with l-[(3R)-3-piperidyl]-3H-imidazo[4,5- b]pyridin-2-one (50mg,0.23mmol). l-[(3R)-l-[2-(3-methoxyphenyl)acetyl]-3-piperidyl]-3H- imidazo[4,5-b]pyridin-2-one (21mg,0.054mmol), 23.7% yield. 'H NMR (400 MHz, CDCls) 8 8.03 (t, J= 5.5 Hz, 1H), 7.27 - 7.19 (m, 1.5H), 6.99 (dd, J= 7.9, 5.3 Hz, 0.5H), 6.91 (dd, J= 7.9, 5.3 Hz, 0.5H), 6.82 (tt, J= 11.9, 6.6 Hz, 3H), 6.63 (d, J= 7.8 Hz, 0.5H), 4.85 - 4.72 (m, 1H), 4.10 - 3.89 (m, 1.5H), 3.86 - 3.70 (m, 5H), 3.60 (ddd, J= 20.1, 10.6, 4.1 Hz, 0.5H), 3.32 (t, J= 12.1 Hz, 0.5H), 3.04 (td, J = 13.3, 2.7 Hz, 0.5H), 2.66 - 2.40 (m, 2H), 2.04 - 1.78 (m, 2H), 1.64 - 1.48 (m, 0.5H), 1.44 - 1.28 (m, 0.5H). MS m / z 367.1774 l-(l-(2-(4-fluorophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0322] (Compound 8):

[0323] 3-(3-piperidyl)-lH-benzimidazol-2-one (60mg,0.2762mmol) was dissolved in DCM (2mL) and TEA (111.8mg,1.105mmol) followed by 2-(4-fhiorophenyl)acetyl chloride (0.042 m , 0.304mmol). The mixture was stirred at ambient temperature for 3h, before being quenched by addition of water (Im) and aq. sat. NaHCO3 (ImL). After dilution with DCM (2mL) the layers were separated using a phase separator. Purification by mass-directed Autoprep HPLC. 3-[l-[2-(4-fluorophenyl)acetyl]-3-piperidyl]- lH-benzimidazol-2-one (3 lmg,0.0807mmol), 29.2% yield.1H NMR (400 MHz, CDC13) 8 9.96 - 9.60 (m, 1H), 7.31 - 7.16 (m, 2H), 7.14 - 6.94 (m, 5.5H), 6.71 - 6.62 (m, 0.5H), 4.79 (dt, J= 16.9, 8.5 Hz, 1H), 4.17 - 4.04 (m, 0.5H), 4.01 - 3.80 (m, 2H), 3.74 (appd, J = 14.0 Hz, 2H), 3.39 (t, J= 12.2 Hz, 0.5H), 3.14 - 3.01 (m, 0.5H), 2.64 (td, J = 13.1, 2.8 Hz, 0.5H), 2.59 - 2.43 (m, 1H), 2.07 - 1.82 (m, 2H), 1.67 - 1.50 (m, 0.5H), 1.51 - 1.34 (m, 0.5H). MS m / z 355.1652 l-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0324] (Compound 9):

[0325]

[0326] 3-(3-piperidyl)-lH-benzimidazol-2-one (60mg,0.2762mmol) was dissolved in DCM (2mL) and TEA (111.8mg,1.1046mmol) followed by 2-(3-methoxyphenyl)acetyl chloride (0.047 mL, 0.3038mmol). The mixture was stirred at ambient temperature for 3h, before being quenched by addition of water (Im) and aq. sat. NaHCO3 (ImL). After dilution with DCM (2mL) the layers were separated using a phase separator. Purification by mass-directed Autoprep HPLC. 3-[l-[2-(3-methoxyphenyl)acetyl]-3- piperidyl]-lH-benzimidazol-2-one (25mg,0.0616mmol), 22.3% yield. 'H NMR (400 MHz, CDCE) 8 10.08 (s, 1H), 7.29 - 7.17 (m, 1H), 7.11 - 6.95 (m, 3.5H), 6.90 - 6.75 (m, 3H), 6.54 (d, J = 7.7 Hz, 0.5H), 4.80 (dt, J= 16.7, 8.4 Hz, 1H), 4.19 - 4.05 (m, 0.5H), 3.95 (dd, J= 13.1, 4.3 Hz, 0.5H), 3.88 (d, J = 11.2 Hz, 0.5H), 3.83 - 3.67 (m, 6H), 3.42 - 3.32 (m, 0.5H), 3.11 - 2.99 (m, 0.5H), 2.63 (td, J = 13.0, 2.6 Hz, 0.5H), 2.56 - 2.43 (m, 1H), 2.02 - 1.77 (m, 1.5H), 1.66 - 1.50 (m, 0.5H), 1.47 - 1.31 (m, 0.5H). MS m / z 366.1819 l-(l-(2-(3-(methylthio)phenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0327] (Compound 10):

[0328] 10 l-[3-(2-aminoanilino)-l-piperidyl]-2-(3-methylsulfanylphenyl)ethanone (240mg,0.67mmol) was dissolved in MeCN (15mL), and l,l'-carbonyl -diimidazole (383.1mg,2.36mmol), and DIPEA (0.59 mL, 3.38mmol) were added. The resulting mixture was stirred at ambient temperature overnight. Another portion of l,l'-carbonyl -diimidazole (383.1mg,2.36mmol) and DIPEA (0.59 mL, 3.38mmol) was added and the resulting mixture stirred at ambient temperature overnight. The mixture was concentrated in vacuo, the residue taken up in EtOAc and water, the aqueous further extracted with EtOAc (2x50mL), the combined organics dried over MgSO4, and concentrated in vacuo. Purification by mass directed Autoprep HPLC (acidic) afforded two portions of the title compound. 3-[l-[2-(3- methylsulfanylphenyl)acetyl]-3-piperidyl]-lH-benzimidazol-2-one (93mg,0.22mmol), 32.5% yield and 3-[l-[2-(3-methylsulfanylphenyl)acetyl]-3-piperidyl]-lH-benzimidazol-2-one (55mg,0.13mmol), 19.2% yield. 'HNMR (400 MHz, CDC13) 59.85 (d, J= 14.5 Hz, 1H), 7.30 - 7.12 (m, 3H), 7.12 - 6.96 (m, 4.5H), 6.58 (d, J= 7.6 Hz, 0.5H), 4.80 (dt, J= 15.4, 7.8 Hz, 1H), 4.22 - 4.02 (m, 0.5H), 3.98 - 3.80 (m, 2H), 3.75 (d, J= 12.4 Hz, 2H), 3.39 (t, J= 12.2 Hz, 0.5H), 3.06 (t, J= 13.1 Hz, 0.5H), 2.64 (t, J = 12.9 Hz, 0.5H), 2.60 - 2.35 (m, 4H), 2.07 - 1.78 (m, 2H), 1.67 - 1.52 (m, 0.5H), 1.49 - 1.28 (m, 0.5H). MS m / z 382.1567 l-(l-(2-(3-bromophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0329] (Compound 11):

[0330] Prepared using the same protocol that was used for the synthesis of Compound 10, however l-[3-(2- aminoanilino)-l -piperidyl] -2-(3-methylsulfanylphenyl)ethanone was replaced with l-[3-(2- aminoanilino)-l -piperidyl] -2-(3-bromophenyl)ethanone (262.1mg,0.67mmol). This gave 3-[l-[2-(3- bromophenyl)acetyl]-3-piperidyl]-lH-benzimidazol-2-one (116mg,0.25mmol), 37.3% yield and 3-[l- [2-(3-bromophenyl)acetyl]-3-piperidyl]-lH-benzimidazol-2-one (57mg,0.12mmol), 18.3% yield. 'H NMR (400 MHz, CDCh) 5 9.58 (d, J= 28.0 Hz, 1H), 7.47 - 7.37 (m, 2H), 7.20 (dd, J= 18.0, 4.7 Hz, 2H), 7.13 - 7.00 (m, 3.5H), 6.68 (d, J= 7.2 Hz, 0.5H), 4.85 - 4.73 (m, 1H), 4.18 -4.03 (m, 0.5H), 3.94 - 3.83 (m, 2H), 3.74 (d, J= 13.2 Hz, 2H), 3.41 (t, J= 12.2 Hz, 0.5H), 3.20 - 2.95 (m, 0.5H), 2.82 - 2.61 (m, 0.5H), 2.60 -2.44 (m, 1H), 2.00 (d,J= 1.4 Hz, 1H), 1.90 (t,J= 15.8 Hz, 1H), 1.77 - 1.54 (m, 0.5H), 1.45 (q, J= 13.4 Hz, 0.5H). MS m / z 416.0773

[0331] 3-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5- carboxylic acid (Compound 12):

[0332]

[0333] Methyl 3-[ 1 - [2-(3 -methoxyphenyl)acetyl]-3 -piperidyl] -2 -oxo- IH-benzimidazole -5 -carboxylate

[0334] (215mg,0.5077mmol) was dissolved in THF (4mL) and Water (ImL) and lithium hydroxide (42.608mg,1.0154mmol) were added. The mixture was stirred at ambient temperature overnight. More lithium hydroxide was added (420mg) and the mixture heated to 60 °C and stirred overnight. The mixture was cooled to ambient temperature, acidified with 2M HC1 and extracted with DCM (3x40mL), the combined organics were dried over Na2SO4 and concentrated in vacuo. Purification by mass- directed autoprep HPLC (acidic) followed by purification by Gilson HPLC (acidic) to afford 3-[l-[2- (3 -methoxyphenyl)acetyl] -3 -piperidyl] -2-oxo- lH-benzimidazole-5 -carboxylic acid

[0335] (20mg,0.0464mmol), 9.1% yield as a white powder. 'H NMR (400 MHz, DMSO) 8 11.26 (d, J = 7.2 Hz, 1H), 7.73 (s, 0.5H), 7.67 (dd, J = 8.1, 2.0 Hz, 0.5H), 7.29 - 7.12 (m, 1H), 7.04 (t, J = 7.7 Hz, 1H), 6.90 - 6.69 (m, 3H), 4.47 (t, J = 11.1 Hz, 1H), 4.16 - 3.88 (m, 2H), 3.90 - 3.56 (m, 6H), 3.28 - 3.15 (m, 2H), 3.05 (t, J = 12.8 Hz, 1H), 2.57 (t, J = 12.9 Hz, 1H), 2.44 - 2.18 (m, 1H), 1.96 - 1.68 (m, 2H), 1.58 - 1.34 (m, 1H). [M+H]+ 410.1713.

[0336] 7-amino-l-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2- one (Compound 13):

[0337] Crude l-[3-(2,6-diaminoanilino)-l-piperidyl]-2-(3-methoxyphenyl)ethanone (354.0mg,0.99mmol) was dissolved in MeCN (20mL) and l,l'-carbonyl-diimidazole (404.9mg,2.49mmol) and DIPEA (0.87 mL, 4.99mmol) were added. The resulting mixture was stirred at ambient temperature overnight. Another portion of l,l'-carbonyl -diimidazole (404.9mg,2.49mmol) and DIPEA (0.87 mL, 4.99mmol) added and stirring continued. Worked up. The residue was redissolved in EtOAc (30mL) washed with water (50mL), aqueous layer extracted with EtOAc (2x30mL), combined organics, washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by mass-directed autoprep HPLC (basic) afforded impure material. Further purification by mass-directed autoprep HPLC (acidic). The compound was received as off-white solid. 4-amino-3-[l-[2-(3-methoxyphenyl)acetyl]-3-piperidyl]- lH-benzimidazol-2-one (5 mg, 0.012 mmol), 1.18% yield. 'H NMR (400 MHz, DMSO) 8 10.62 (d, J = 11.4 Hz, 1H), 7.20 (dt, J= 14.5, 7.8 Hz, 1H), 6.87 - 6.65 (m, 4H), 6.44 (dd, J= 15.6, 8.0 Hz, 1H), 6.34 (t, J = 7.4 Hz, 1H), 4.68 (d, J = 8.7 Hz, 2H), 4.57 (d, J = 12.0 Hz, 0.5H), 4.44 (d, J = 12.0 Hz, 1.5H), 4.11 - 4.00 (m, 0.5H), 3.95 (d, J = 13.6 Hz, 0.5H), 3.90 - 3.79 (m, 1H), 3.78 - 3.65 (m, 5H), 3.32 (s, 0.5H), 2.93 (t, J = \l.l z, 0.5H), 2.71 - 2.38 (m, 1H), 1.90 (t, J = 14.8 Hz, 1H), 1.72 (t, J = 16.6 Hz, 1H), 1.45 (d, J= 13.0 Hz, 0.5H), 1.31 (d, J= 13.7 Hz, 0.5H). MS m / z 381.1964

[0338] 7-amino-l-(l-(2-(4-fluorophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one (Compound 14):

[0339] 14

[0340] Crude l-[3-(2,6-diaminoanilino)-l-piperidyl]-2-(4-fluorophenyl)ethanone (342mg,0.99mmol) was dissolved in MeCN (20mL) and l,l'-carbonyl -diimidazole (404.9mg,2.49mmol) and DIPEA (0.87 mL, 4.99mmol) were added. The resulting mixtures were stirred at ambient temperature overnight. The residue was redissolved in EtOAc (30mL) washed with water (50mL), aqueous layer extracted with EtOAc (2x30mL), combined organics, washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by mass-directed autoprep HPLC (basic) afforded impure material. Further purification by mass-directed autoprep HPLC (acidic). The compound was received as white solid. 4- amino-3-[ 1 -[2-(4-fluorophenyl)acetyl] -3-piperidyl] - lH-benzimidazol-2-one ( 10mg,0.024mmol),

[0341] 2.45% yield. ’H NMR (400 MHz, DMSO) 8 10.63 (d, J= 13.9 Hz, 1H), 7.32 - 7.25 (m, 1H), 7.21 (t, J = 7.0 Hz, 1H), 7.16 - 7.03 (m, 2H), 6.72 (q, J= 7.6 Hz, 1H), 6.44 (dd, J= 19.2, 8.0 Hz, 1H), 6.35 (t, J = 8.7 Hz, 1H), 4.87 - 4.56 (m, 2.5H), 4.43 (d, J= 11.6 Hz, 1.5H), 4.14 - 3.94 (m, 1H), 3.94 - 3.65 (m, 3H), 3.33 (t, J= 12.7 Hz, 0.5H), 2.96 (t, J = 13.0 Hz, 0.5H), 2.66 - 2.41 (m, 1H), 1.92 (t, J= 14.5 Hz, 1H), 1.73 (d, J= 13.5 Hz, 1H), 1.44 (dt, J= 28.6, 13.5 Hz, 1H). MS m / z 369.1733

[0342] 6-amino-l-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2- one (Compound 15):

[0343] Tert-butyl N-[3-[l-[2-(3-methoxyphenyl)acetyl]-3-piperidyl]-2-oxo-lH-benzimidazol-5-yl]carbamate (20mg,0.0416mmol) was dissolved in DCM (3mL) and TFA (0.5 mL, 0.0416mmol) was added. The mixture was stirred at ambient temperature for 2h, before being concentrated in vacuo. Purification by Gilson HPLC (acidic) afforded 5-amino-3-[l-[2-(3-methoxyphenyl)acetyl]-3-piperidyl]-lH- benzimidazol-2-one (2mg,0.0047mmol), 11.37% yield as a white powder. 1H NMR (400 MHz, DMSO) 5 10.93 (s, 1H), 7.22 (dt, J = 14.9, 7.8 Hz, 1H), 7.07 (s, 1H), 6.99 - 6.89 (m, 2H), 6.87 - 6.82 (m, 3H), 4.58 - 4.39 (m, 1H), 4.15 - 3.89 (m, 2H), 3.79 - 3.65 (m, 5H), 3.17 (t, J = 12.0 Hz, 1H), 3.00 (t, J = 13.3 Hz, 1H), 2.39 - 2.20 (m, 1H), 1.91 - 1.74 (m, 2H), 1.53 - 1.33 (m, 1H). [M+H]+ 381.1938.

[0344] (S)-l-(l-(2-(3-bromophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0345] (Compound 16):

[0346] T3P in EtOAc (351.47mg,0.5523mmol) was added to a stirred solution of 3-[(3S)-3-piperidyl]-lH- benzimidazol-2-one (100mg,0.4603mmol), 2-(3-bromophenyl)acetic acid (118.8mg,0.55mmol) and DIPEA (69.9mg,0.69mmol) in DCM (6mL). The mixture allowed to stir overnight. Water was added to the reaction mixture and stirred vigorously for 5 mins. The mixture was passed through a phase separator and the filtrate concentrated under reduced pressure. The material was redissolved in DMS0:ACN:H20 and purified by the Water's mass directed autoprep HPLC (0.1 % NH3 in ACN : H2O (95 - 5%). The desired fractions were collected and concentrated under reduced pressure. 3-[(3S)- l-[2-(3-bromophenyl)acetyl]-3-piperidyl]-lH-benzimidazol-2-one (43 mg, 0.098 mmol), 21.4% yield.1H NMR (400 MHz, DMSO) 5 10.87 (s, 1H), 7.49 (s, 0.5H), 7.46 - 7.42 (m, 1H), 7.37 - 7.21 (m, 2H), 7.19 - 7.10 (m, 0.5H), 6.99 (d, J = 3.3 Hz, 2H), 4.51 - 4.34 (m, 1H), 4.18 - 3.95 (m, 2H), 3.90 - 3.69 (m, 2H), 3.14 (t, J = 13.1 Hz, 1H), 2.73 - 2.56 (m, 1H), 2.45 - 2.27 (m, 1H), 1.89 - 1.65 (m, 2H), 1.61

[0347] - 1.40 (m, 1H). MS m / z 416.0

[0348] (S)-l-(l-(2-(naphthalen-2-yl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0349] (Compound 17):

[0350] 3-[(3S)-3-piperidyl]-lH-benzimidazol-2-one (45mg,0.21mmol) was added to a stirred solution of 2- (naphthalen-2-yl)acetic acid, T3P in EtOAc (158. lmg,0.25mmol) and DIPEA (31.4mg,0.31mmol) in DCM (2mL). The mixture allowed to stir for 6 days. Water was added to the reaction mixture and stirred vigorously for 5 mins. The mixture was passed through a phase separator and the fdtrate concentrated under reduced pressure. The material was redissolved in DMSO:ACN:H2O and purified by a mixture of Gilson prep HPLC (0. 1 % NH3 in ACN : H2O (95 - 5%) and Water Mass directed autoprep. Fractions were collected and dried overnight on the HT4 genevac. (S)-l-(l-(2- (naphthalen-2-yl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one 35.4mg, 0.091 mmol, 44.3%. 1H NMR (500 MHz, DMSO) 5 10.94 - 10.72 (m, 1H), 7.99 - 7.83 (m, 1H), 7.81 - 7.70 (m, 0.5H), 7.55 - 7.48 (m, 1H), 7.47 - 7.37 (m, 0.5H), 7.34 (s, 0.5H), 7.03 - 6.96 (m, 0.5H), 6.95 - 6.90 (m, 0.5H), 6.75 - 6.68 (m, 0.5H), 4.59 - 4.39 (m, 1H), 4.20 - 4.03 (m, 1H), 3.99 - 3.76 (m, 2H), 3.14 (t, J = 13.1 Hz, 0.5H), 2.68 - 2.58 (m, 0.5H), 2.40 - 2.33 (m, 1H), 1.88 - 1.68 (m, 2H), 1.58 - 1.37 (m, 1H).

[0351] (S)-l-(l-(2-(4-chloro-3-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol- 2-one (Compound 18):

[0352]

[0353] T3P in EtOAc (0.148 mL, 0.2485mmol) was added to a stirred solution of 2-(4-chloro-3- methoxyphenyl)acetic acid (11.2mg,0.25mmol), 3-[(3S)-3-piperidyl]-lH-benzimidazol-2-one (45mg,0.207mmol) and DIPEA (0.043 mL, 0.31mmol) in DCM (2mL). The mixture allowed to stir for 2 days. Water was added to the reaction mixture and stirred vigorously for 5 mins. The mixture was passed through a phase separator and the fdtrate concentrated under reduced pressure in the EZ-2 genevac. The material was redissolved in DMSO:ACN:H2O and purified by the Gilson prep HPLC (0. 1 % NH3 in ACN : H2O (95 - 5%). Fractions were collected and dried overnight on the HT4 genevac. (S)- 1 -( 1 -(2-(4-chloro-3 -methoxyphenyl)acetyl)piperidin-3 -yl)- 1 ,3 -dihydro-2H-benzo [d] imidazol-2-one 7.1 mg, 0.018mmol 8.6% yield. 1H NMR (5OO MHz, DMSO) 5 10.90 - 10.74 (m, 1H), 7.41 - 7.28 (m, 1.5H), 7.07 (s, 0.5H), 7.04 - 6.93 (m, 4H), 6.88 - 6.78 (m, 1H), 4.57 - 4.33 (m, 1H), 4.14 - 3.96 (m, 1.5H), 3.94 - 3.58 (m, 3H), 3.17 - 3.08 (m, 0.5H), 2.67 - 2.57 (m, 0.5H), 2.42 - 2.28 (m, 1.5H), 2.08 (s, 1.5H), 1.89 (s, 0.5H), 1.84 - 1.78 (m, 2H), 1.52 - 1.39 (m, 1H). MS m / z 401.1

[0354] (S)-l-(l-(2-(l-methyl-lH-indol-3-yl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2- one (Compound 19):

[0355] 19

[0356] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with 2-(l-methyl-lH-indol-3-yl)acetic acid. 3-[(3S)-l-[2-(l-methylindol-3-yl)acetyl]-3- piperidyl]-lH-benzimidazol-2-one (40.7mg,0.099mmol), 48.057% yield. 1H NMR (500 MHz, DMSO) 5 10.89 - 10.82 (m, 1H), 7.58 (dd, J = 18.5, 7.9 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.32 - 7.28 (m, 0.5H), 7.24 (s, 0.5H), 7.19 - 7.12 (m, 1.5H), 7.06 - 6.90 (m, 4H), 6.80 (d, J = 7.5 Hz, 0.5H), 4.55 - 4.41 (m, 1H), 4.10 - 4.05 (m, 1.5H), 3.91 - 3.79 (m, 1.5H), 3.80 - 3.63 (m, 4H), 3.10 (t, J = 13.0 Hz, 0.5H), 2.59 (t, J = 12.8 Hz, 0.5H), 2.38 - 2.29 (m, 1H), 1.80 - 1.74 (m, 2H), 1.45 - 1.36 (m, 1H). MS m / z 389.1

[0357] (S)-l-(l-(2-(2,6-difluorophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0358] (Compound 20):

[0359] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with 2-(2,6-difluorophenyl)acetic acid. 3-[(3S)-l-[2-(3-methoxyphenyl)acetyl]-3-piperidyl]- lH-benzimidazol-2-one 34.6 mg, 0.093 mmol, 44.9% yield. 1H NMR (500 MHz, DMSO) 8 10.91- 10.83 (m, 1H), 7.42-7.29 (m, 2H), 7.13 - 6.92 (m, 4H), 4.44-4.32 (1H), 4.29-4.22 (m, 0.5H), 4.15-4.05 (m, 1.5H), 3.90 - 3.72 (m, 2H), 3.33-3.21 (m, 1H), 2.72-2.62 (m, 0.5H), 2.46 - 2.30 (m, 1.5H), 1.96 - 1.78 (m, 2H), 1.66-1.48 (m, 1H). MS m / z 372.1

[0360] (S)-l-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0361] (Compound 21):

[0362] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with 2-(3-methoxyphenyl)acetic acid (34.1 mg, 0.088mmol, 42.8% yield). 'H NMR (500 MHz, DMSO) 8 10.89 - 10.83 (m, 1H), 7.36 - 7.30 (m, 0.5H), 7.28 - 7.19 (m, 0.5H), 7.01 - 6.93 (m, 4H), 6.87 - 6.77 (m, 3H), 4.54 - 4.36 (m, 1H), 4.15 - 3.84 (m, 2.5H), 3.82 - 3.59 (m, 4H), 3.26 - 3.21 (m, 0.5H), 3.18 (d, J = 5.3 Hz, 1H), 3.10 (t, J = 13.1 Hz, 0.5H), 2.65 - 2.56 (m, 0.5H), 2.42 - 2.30 (m, 1H), 1.84 - 1.74 (m, 2H), 1.50 - 1.36 (m, 1H). MS m / z 366.1 (S)-l-(l-(2-(pyridin-2-yl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0363] (Compound 22):

[0364] 22

[0365] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with 2-(pyridin-2-yl)acetic acid. (S)-l-(l-(2-(pyridin-2-yl)acetyl)piperidin-3-yl)-l,3-dihydro- 2H-benzo[d]imidazol-2-one (l.lmg, 0.003mmol, 1.6% yield). 'HNMR (500 MHz, CDC13) 8 8.55 (dd, J = 32.0, 4.9 Hz, 1H), 8.24 (d, J = 27.2 Hz, 1H), 7.73 - 7.65 (m, 1H), 7.39 (dd, J = 13.8, 7.8 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.11 - 7.03 (m, 3H), 6.94 - 6.89 (m, 1H), 4.79 (t, J = 13.2 Hz, 1H), 4.40 - 4.16 (m, 1H), 4.13 - 3.87 (m, 3H), 3.41 (t, J = 12.2 Hz, 1H), 3.14 - 3.06 (m, 1H), 2.70 - 2.64 (m, 1H), 2.60 - 2.45 (m, 1H), 2.04 - 1.98 (m, 1H), 1.95 - 1.86 (m, 1H), 1.52 - 1.41 (m, 1H). MS m / z 337.1 l-((S)-l-((S)-2-(4-fluorophenyl)propanoyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2- one (Compound 23):

[0366] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with (S)-2-(4-fluorophenyl)propanoic acid. l-((S)-l-((S)-2-(4- fluorophenyl)propanoyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one (30.6 mg, 0.083 mmol, 40.2% yield). ’H NMR (500 MHz, DMSO) 8 10.88 (s, 1H), 7.45 - 7.14 (m, 4H), 7.07 (t, J = 8.6 Hz, 1H), 7.01 - 6.96 (m, 3H), 4.51-4.44 (m, 1H), 4.21-4.17 (m, 1H), 4.01-3.81 (m, 1.5H), 3.51 (t, J = 12.3 Hz, 0.5H), 3.14-3.07 (m, 1H), 2.33-2.26 (m, 1H), 1.86-1.78 (m, 2H), 1.66 (d, J = 13.0 Hz, 1H), 1.53 (d, J = 13.0 Hz, 2H), 1.33-1.26 (m, 3H), 0.61 (m, 1H). MS m / z 368.1 (S)-l-(l-(2-(naphthalen-l-yl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0367] (Compound 24):

[0368] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with 2-(naphthalen-l-yl)acetic acid (5mg, 0.012mmol, 5.95%). 'H NMR (500 MHz, CDC13) 5 8.79 - 8.74 (m, 1H), 8.08 - 7.99 (m, 1H), 7.94 - 7.74 (m, 2H), 7.64 - 7.37 (m, 4H), 7.12 - 6.87 (m, 3.5H), 6.54 (d, J = 7.9 Hz, 0.5H), 4.88 (t, J = 15.0 Hz, 1H), 4.42 - 4.07 (m, 2.5H), 4.05 - 3.71 (m, 2H), 3.46 (t, J = 12.2 Hz, 0.5H), 3.10 (t, J = 13.0 Hz, 0.5H), 2.71 (t, J = 13.0 Hz, 0.5H), 2.61 - 2.49 (m, 1H), 1.98 - 1.76 (m, 1H), 1.74 - 1.33 (m, 2H). MS m / z 386.18

[0369] (S)-l-(l-(2-(3-bromo-4-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-

[0370] 2-one (Compound 25):

[0371] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with 2-(3-bromo-4-methoxyphenyl)acetic acid (8.3mg, 0.019 mmol, 9.02% yield). 'H NMR (500 MHz, DMSO) 5 10.88 (s, 1H), 7.51 - 7.40 (m, 1H), 7.36 - 7.16 (m, 1.5H), 7.12 - 6.92 (m, 3.5H), 4.61 - 4.32 (m, 1H), 4.18 - 3.93 (m, 1.5H), 3.87 - 3.79 (m, 3H), 3.78 - 3.60 (m, 1.5H), 3.12 (t, J = 13.0 Hz, 1H), 2.68 - 2.56 (m, 0.5H), 2.41 - 2.30 (m, 1.5H), 2.08 (s, 0.5H), 1.90 (s, 0.5H), 1.86 - 1.74 (m, 1.5H), 1.59 - 1.37 (m, 0.5H). MS m / z 401.1 l-((S)-l-((S)-l,2,3,4-tetrahydronaphthalene-l-carbonyl)piperidin-3-yl)-l,3-dihydro-2H- benzo[d]imidazol-2-one (Compound 26):

[0372]

[0373] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with (S)-l,2,3,4-tetrahydronaphthalene-l-carboxylic acid (6.4 mg, 0.016 mmol, 7.8% yield).

[0374] 1H NMR (400 MHz, DMSO) 8 10.89 (s, 1H), 7.35 (d, J = 16.8 Hz, 1H), 7.14 - 6.96 (m, 6.5H), 6.84 (d,

[0375] J = 7.0 Hz, 0.5H), 4.55 - 4.40 (in, 1H), 4.31 -- 4. 1 1 (m, 3H), 3.97 - 3.86 (m, 0.5H), 3.23 (br s, 0.5H),

[0376] 2.78 -- 2.65 (m, 3H), 2.49 2.36 (m, 1.5H), 2.08 1.38 (m, 7.5H). MS m / z 375.9

[0377] (S)-l-(l-(2-(3-chloro-4-fluorophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2- one (Compound 27):

[0378] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with 2-(3-chloro-4-fluorophenyl)acetic acid (8.3mg, 0.021mmol, 10.3% yield). 'H NMR (500 MHz, DMSO) 8 10.88 (s, 1H), 7.52 - 7.41 (m, 1H), 7.37 - 7.30 (m, 1.5H), 7.30 - 7.14 (m, 1.5H), 7.03 - 6.93 (m, 3H), 4.53 - 4.33 (m, 1H), 4.14 - 3.98 (m, 2H), 3.87 - 3.67 (m, 2H), 3.15 (t, J = 13.2 Hz, 0.5H), 2.67 - 2.58 (m, 0.5H), 2.45 - 2.28 (m, 1H), 1.91 - 1.71 (m, 2H), 1.61 - 1.41 (m, 1H). MS m / z 388.1

[0379] (S)-l-(l-(2-(3-(trifluoromethoxy)phenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- benzo[d]imidazol-2-one (Compound 28):

[0380]

[0381] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with 2-(3-(trifluoromethoxy)phenyl)acetic acid (30.4mg, 0.072mmol, 34.9% yield). 'HNMR (500 MHz, CDC13) 5 10.03 - 9.79 (m, 1H), 7.44 - 7.31 (m, 1H), 7.29 - 7.22 (m, 1H), 7.21 - 7.14 (m, 2H), 7.12 - 7.00 (m, 4H), 6.72 (d, J = 7.7 Hz, 1H), 4.87 - 4.77 (m, 1H), 4.18 - 4.07 (m, 1H), 3.98 - 3.88 (m, 2H), 3.86 - 3.76 (m, 2H), 3.44 (t, J = 12.2 Hz, 1H), 3.17 - 3.08 (m, 1H), 2.73 - 2.63 (m, 1H), 2.62 - 2.49 (m, 1H), 2.07 - 2.00 (m, 2H), 1.97 - 1.84 (m, 1H), 1.70 - 1.37 (m, 1H). MS m / z 420.1

[0382] (S)-l-(l-(2-phenylacetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one (Compound 29):

[0383] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with 2-phenylacetic acid (23.3mg, 0.069 mmol, 33.5% yield). 'H NMR (500 MHz, DMSO) 8 10.85 (d, J = 12.7 Hz, 1H), 7.36 - 7.19 (m, 5H), 7.00 - 6.94 (m, 4H), 4.49-4.35 (m, 1H), 4.16 - 3.84 (m, 2H), 3.82 - 3.66 (m, 2.5H), 3.25-3.20 (m, 0.5H), 3.10 (t, J = 13.0 Hz, 0.5H), 2.60 (t, J = 13.0 Hz, 0.5H), 2.41 - 2.17 (m, 1H), 1.79-1.76 (m, 2H), 1.48-1.32 (m, 1H). MS m / z 336.1

[0384] (S)-l-(l-(2-(3,5-dimethoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0385] (Compound 30):

[0386]

[0387] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with 2-(3,5-dimethoxyphenyl)acetic acid (7.8mg, 0.020mmol, 9.5% yield). 'H NMR (500 MHz, DMSO) 5 10.96-10.80 (m, 1H), 7.33 (s, 1H), 7.21 - 6.78 (m, 3H), 6.80 - 6.21 (m, 3H), 4.53 - 4.36 (m, 1H), 4.21 - 3.82 (m, 2H), 3.78 - 3.65 (m, 7H), 3.63 - 3.58 (m, 1H), 3.10 (t, J = 13.0 Hz, 0.5H), 2.72 - 2.55 (m, 0.5H), 2.44 - 2.20 (m, 2H), 1.91 - 1.70 (m, 2H), 1.55 - 1.34 (m, 1H). MS m / z 396.1

[0388] (S)-l-(l-(2-(3-fluorophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0389] (Compound 31):

[0390] 31

[0391] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with 2-(3-fluorophenyl)acetic acid (13.4 mg, 0.038mmol, 18.3% yield). 'H NMR (500 MHz, CDC13) 5 9.59 - 9.35 (m, 1H), 7.38 - 7.25 (m, 2H), 7.16 - 6.92 (m, 6H), 6.70 (d, J = 7.7 Hz, 1H), 4.81 (t, J = 13.2 Hz, 1H), 4.18 - 4.08 (m, 1H), 3.98 - 3.89 (m, 2H), 3.83 - 3.76 (m, 2H), 3.47 - 3.39 (m, 1H), 3.16 - 3.06 (m, 1H), 2.72 - 2.62 (m, 1H), 2.62 - 2.49 (m, 1H), 1.98 - 1.86 (m, 1H), 1.67 - 1.39 (m, 1H). MS m / z 354.1

[0392] (S)-l-(l-(2-(3-ethoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0393] (Compound 32):

[0394]

[0395] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with 2-(3-ethoxyphenyl)acetic acid (6.0mg, 0.016 mmol, 7.63% yield). 'H NMR (500 MHz, CDC13) 5 9.36 - 9.24 (m, 1H), 7.29 - 7.19 (m, 1H), 7.14 - 6.97 (m, 3.5H), 6.95 - 6.75 (m, 3H), 6.54 (d, J = 7.8 Hz, 0.5H), 4.91 - 4.64 (m, 1H), 4.18 - 4.04 (m, 1.5H), 4.02 - 3.85 (m, 2.5H), 3.83 - 3.70 (m, 2.5H), 3.40 (t, J = 12.1 Hz, 0.5H), 3.06 (td, J = 13.2, 2.7 Hz, 0.5H), 2.78 - 2.44 (m, 1.5H), 1.99 - 1.88 (m, 1.5H), 1.85 - 1.54 (m, 2H), 1.48 - 1.33 (m, 3.5H). MS m / z 380.1

[0396] (S)-l-(l-(2-(3-(difluoromethoxy)phenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-

[0397] 2-one (Compound 33):

[0398] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with 2-(3-(difluoromethoxy)phenyl)acetic acid (11.0 mg, 0.027 mmol, 13.2% yield). 'HNMR (500 MHz, CDC13) 5 9.48 - 9.20 (m, 1H), 7.42 - 7.29 (m, 1H), 7.22 - 6.99 (m, 6H), 6.74 - 6.25 (m, 1H), 4.82 (dt, J = 16.2, 8.2 Hz, 1H), 4.17 - 4.07 (m, 1H), 3.95 - 3.85 (m, 2H), 3.83 - 3.73 (m, 2H), 3.43 (t, J = 12.2 Hz, 1H), 3.17 - 3.07 (m, 1H), 2.67 (td, J = 13.0, 2.8 Hz, 1H), 2.62 - 2.49 (m, 1H), 1.99 - 1.82 (m, 1H), 1.65 - 1.41 (m, 1H). MS m / z 402.1 l-((S)-l-((R)-2-(4-fluorophenyl)propanoyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2- one (Compound 34):

[0399] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with (R)-2-(4-fluorophenyl)propanoic acid (30.5mg, 0.083 mmol, 40.1%yield). 'HNMR(500 MHz, DMSO) 5 10.88-10.71 (m, 1H), 7.35-7.22 (m, 3H), 7.12 (q, J = 9.0 Hz, 2H), 7.00 - 6.84 (m, 3H), 6.40 (d, J = 7.9 Hz, 0.5H), 4.66 - 4.29 (m, 1H), 4.23-4.12 (m, 2H), 4.02 - 3.85 (m, 1H), 3.76 (t, J = 12.3 Hz, 0.5H), 3.19-3.14 (m, 1H), 2.79 (t, J = 12.5 Hz, 0.5H), 2.66 - 2.53 (m, 0.5H), 2.37 - 2.26 (m, 1H), 1.88 - 1.56 (m, 1H), 1.35-1.19 (m, 3H). MS m / z 368.0 tert-butyl (S)-3-(6-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-l-carboxylate (Compound 35):

[0400] CDI (0.6504g, 4.0109mmol) and DIPEA (579.8mg,5.73mmol) was added to a stirred solution of tertbutyl (3S)-3-(2-amino-5-methyl-anilino)piperidine-l-carboxylate (1.15mmol) in MeCN (lOmL) . The resulting mixture was stirred at rt overnight. Analysis by LCMS showed remaining starting material, the reaction allowed to stir at rt overnight. The reaction mixture was concentrated under reduced pressure. The crude material was dissolved in DCM and quenched with Sat Sodium Bicarb (aq). The mixture was extracted with DCM (2 x 25 m ). The combined organic extracts were dried (phase sep) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (silica, 24 g) eluting with 0 - 80% EtOAc in Heptane. The desired fractions were combined and concentrated under reduced pressure. ’H NMR (500 MHz, DMSO) 8 10.72 (s, 1H), 7. 14 (s, 1H), 6.85 (d, J= 7.8 Hz, 1H), 6.79 (d, J= 8.0 Hz, 1H), 4.14 - 4.05 (m, 1H), 3.97 (d, J = 13.1 Hz, 1H), 3.90 (s, 1H), 3.42 (s, 1H), 2.82 (s, 1H), 2.32 (s, 3H), 2.29 (d, J= 11.3 Hz, 1H), 1.79 (d, J= 12.1 Hz, 2H), 1.51 (d, J= 13.5 Hz, 1H), 1.41 (s, 9H). MS m / z 332.2 tert-butyl (S)-3-(6-cyano-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-l-carboxylate (Compound 36):

[0401] CDI (1.22g,7.52mmol) and DIPEA (1087.4mg,10.74mmol) was added to a stirred solution of tert-butyl (3S)-3-(2-amino-5-cyano-anilino)piperidine-l-carboxylate (2.15mmol) in MeCN (lOmL). The resulting mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure. The crude material was dissolved in DCM and quenched with Sat Sodium Bicarb (aq). The mixture was extracted with DCM (2 x 25 mL). The combined organic extracts were dried (phase sep) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (silica, 24 g) eluting with 0 - 100%EtOAc in Heptane. The desired fractions were combined and concentrated under reduced pressure. ’H NMR (500 MHz, DMSO) 8 11.48 (s, 1H), 7.91 (s, 1H), 7.46 (dd, J= 8.1, 1.4 Hz, 1H), 7.13 (d, J= 8.1 Hz, 1H), 4.23 - 4.15 (m, 1H), 3.96 (d, J= 14.9 Hz, 2H), 3.45 (s, 1H), 2.88 (s, 1H), 2.36 - 2.25 (m, 1H), 1.81 (t, J= 14.0 Hz, 2H), 1.52 (d, J= 13.4 Hz, 1H), 1.42 (s, 9H).MS m / z 287.0 (loss oftBu) tert-butyl (S)-3-(3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-l-carboxylate (Compound 37): lodomethane (447.2mg,3.15mmol) and NaOH (132.21mg,3.15mmol) (in H2O) was added to a stirred solution of tert-butyl (3S)-3-(2-oxo-3H-benzimidazol-l-yl)piperidine-l-carboxylate (0.63mmol) in THF (8mL) . The resulting mixture was stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure. Water was added, no precipitate was observed as suggested by the lit procedure. DCM was added and the mixture was extracted with DCM (2 x 25 mL). The combined organic extracts were dried (phase sep) and concentrated under reduced pressure, tert-butyl (3S)-3-(3- methyl-2-oxo-benzimidazol-l-yl)piperidine-l -carboxylate (0.217g,0.622mmol), 98.711% yield. 'H NMR (500 MHz, DMSO) 5 7.38 (dd, J= 7.2, 1.7 Hz, 1H), 7.16 (dd, J= 7.1, 1.8 Hz, 1H), 7.07 (pd, J = 7.5, 1.5 Hz, 2H), 5.76 (s, 1H), 4.18 (tt, J= 11.8, 4.3 Hz, 1H), 3.98 (d, J= 14.5 Hz, 1H), 3.42 (s, 1H), 3.32 (s, 3H), 2.83 (s, 1H), 2.37 - 2.29 (m, 1H), 1.87 - 1.76 (m, 2H), 1.59 - 1.47 (m, 1H), 1.42 (s, 9H). MS m / z 276.1348 (loss oftBu)

[0402] (S)-6-bromo-l-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-

[0403] 2-one (Compound 38):

[0404] T3P in EtOAc (1487.8mg, 2.3379mmol) was added to a stirred solution of 5-bromo-3-[(3S)-3- piperidyl]-lH-benzimidazol-2-one (577mg,1.9483mmol), 2-(3-methoxyphenyl)acetic acid (388.49 mg, 2.34 mmol) and DIPEA (295.72 mg, 2.92 mmol) in DCM (20mL). The mixture was allowed to stir overnight. Water was added to the reaction mixture and stirred vigourously for 5 mins. The mixture was passed through a phase seperator and the fdtrate concentrated under reduced pressure. The crude material was purified by flash column chromatography (silica, 12 g) eluting with 50 - 100% EtOAc in Heptane. The desired fractions were combined and concentrated under reduced pressure. 5-bromo-3- [(3S)-l-[2-(3-methoxyphenyl)acetyl]-3-piperidyl]-lH-benzimidazol-2-one (654mg,1.39mmol), 71.7% yield. 'H NMR (500 MHz, CDC13) 5 8.03 (d, J= 22.1 Hz, 1H), 7.26 - 7.23 (m, 1.5H), 7.17 (d, J= 10.4 Hz, 1.5H), 6.95 - 6.79 (m, 4H), 4.77 (t, J = 13.8 Hz, 1H), 4.07 - 3.88 (m, 2H), 3.87 - 3.71 (m, 5H), 3.45 (s, 0.5H), 3.36 (t, J= 12.2 Hz, 0.5H), 3.04 (t, J= 13.2 Hz, 0.5H), 2.61 (t, J= 12.4 Hz, 0.5H), 2.51 - 2.35 (m, 1H), 1.99 - 1.93 (m, 0.5H), 1.92 - 1.78 (m, 1.5H), 1.60 - 1.52 (m, 0.5H), 1.46 - 1.32 (m, 0.5H). MS m / z 446.0892

[0405] (S)-l-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-6-methyl-l,3-dihydro-2H-benzo[d]imidazol-

[0406] 2-one (Compound 39):

[0407]

[0408] T3P in EtOAc (115.56 mg, 0.18 mmol) was added to a stirred solution of 5-methyl-3-[(3S)-3-piperidyl]- lH-benzimidazol-2-one (35 mg, 0.1513 mmol) , 2-(3-methoxyphenyl)acetic acid (30.2 mg, 0.1816 mmol) and DIPEA (22.9 mg, 0.227 mmol) in DCM (20mL). The mixture allowed to stir overnight. Additional portions of T3P, DIPEA and Acid were added and the mixture allowed to stir at rt for a further 4 h. Water was added to the reaction mixture and stirred vigorously for 5 mins. The mixture was passed through a phase separator and the filtrate concentrated under reduced pressure. The material was redissolved in DMSO ACRFEO and purified by the Water's mass directed autoprep HPLC (0.1 % NH3 in ACN : H2O (95 - 5%). Fractions were collected and dried overnight on the HT4 genevac. 3-[(3S)-l- [2-(3 -methoxyphenyl)acetyl] -3 -piperidyl] -5 -methyl- lH-benzimidazol-2 -one (54 ,9mg,0. 1374mmol), 90.83% yield. ’H NMR (500 MHz, CDC13) 5 8.28 (d, J= 26.9 Hz, 1H), 7.21 - 7.17 (m, 1.5H), 7.13 (t, J= 7.7 Hz, 0.5H), 6.87 - 6.82 (m, 1H), 6.82 - 6.72 (m, 4H), 4.71 (t, J= 11.9 Hz, 1H), 4.03 - 3.92 (m,

[0409] 0.5H), 3.92 - 3.79 (m, 1.5H), 3.79 - 3.53 (m, 5.5H), 3.32 (t, J= 12.1 Hz, 0.5H), 2.97 (t, J= 13.1 Hz,

[0410] 0.5H), 2.60 - 2.51 (m, 0.5H), 2.51 - 2.36 (m, 1H), 2.31 (s, 3H), 1.94 - 1.69 (m, 2H), 1.50 - 1.47 (m,

[0411] 0.5H), 1.39 - 1.27 (m, 0.5H). MS m / z 380.1974

[0412] (S)-3-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5- carbonitrile (Compound 40):

[0413] T3P in EtOAc (0.1002 mL, 0.1684 mmol) was added to a stirred solution of 2-(3-methoxyphenyl)acetic acid (27.983 mg, 0.1684 mmol), 2-oxo-3-[(3S)-3-piperidyl]-lH-benzimidazole-5-carbonitrile (34 mg ,0.1403 mmol) and DIPEA (0.0293 mL, 0.2105 mmol) in DCM (20mL). The mixture allowed to stir overnight. Additional portions of T3P, DIPEA and Acid were added and the mixture allowed to stir at rt for a further 4 h. Water was added to the reaction mixture and stirred vigourously for 5 mins. The mixture was passed through a phase seperator and the fdtrate concentrated under reduced pressure. The material was redissolved in DMS0:ACN:H20 and purified by the Water's mass directed autoprep HPLC (0. 1 % NH3 in ACN : H2O (95 - 5%). Fractions were collected and dried overnight on the HT4 genevac . 3 -[(3 S)- 1 - [2 -(3 -methoxyphenyl)acetyl] -3 -piperidyl] -2 -oxo- lH-benzimidazole-5 -carbonitrile (10.5 mg, 0.0255 mmol), 18.205% yield. ’H NMR (400 MHz, DMSO) 5 11.46 (d, J = 11.1 Hz, 1H), 7.91 (s, 0.5H), 7.52 - 7.41 (m, 1.5H), 7.30 - 7.17 (m, 1H), 7.11 (t,J= 7.4 Hz, 1H), 6.87 - 6.74 (m, 3H), 4.44 (t, J= 15.6 Hz, 1H), 4.20 - 3.88 (m, 1.5H), 3.84 - 3.63 (m, 5H), 3.33 - 3.22 (m, 0.5H), 3.21 - 3.09 (m, 1.5H), 2.70 - 2.56 (m, 0.5H), 2.39 - 2.25 (m, 1H), 1.87 - 1.71 (m, 2H), 1.53 - 1.30 (m, 1H). MS m / z 391.1764

[0414] (S)-l-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-3-methyl-l,3-dihydro-2H-benzo[d]imidazol- 2-one (Compound 41):

[0415] 41

[0416] T3P in EtOAc (125.46mg,0.1972mmol) was added to a stirred solution of l-methyl-3-[(3S)-3- piperidyl]benzimidazol-2-one (38 mg, 0.1643 mmol) , 2-(3-methoxyphenyl)acetic acid (32.761 mg, 0.1972 mmol) and DIPEA (24.938mg,0.2464mmol) in DCM (20mL). The mixture allowed to stir overnight. Water was added to the reaction mixture and stirred vigourously for 5 mins. The mixture was passed through a phase seperator and the filtrate concentrated under reduced pressure. The material was redissolved in DMSO:ACN:H2O and purified by the Water's mass directed autoprep HPLC (0.1 % NH3 in ACN : H2O (95 - 5%). Fractions were collected and dried overnight on the HT4 genevac. 1-[(3S)-1- [2-(3-methoxyphenyl)acetyl]-3-piperidyl]-3-methyl-benzimidazol-2-one (46.1 mg,0.1154 mmol), 70.249% yield. 'H NMR (400 MHz, CDCh) 5 7.28 - 7.17 (m, 1H), 7.10 - 7.03 (m, 2H), 7.02 - 6.91 (m, 1.5H), 6.88 - 6.75 (m, 3H), 6.49 (d, J= 7.8 Hz, 0.5H), 4.82 - 4.70 (m, 1H), 4.12 - 3.99 (m, 0.5H), 3.95 - 3.83 (m, 1.5H), 3.83 - 3.64 (m, 5H), 3.50 - 3.31 (m, 4H), 3.08 - 2.96 (m, 0.5H), 2.66 - 2.43 (m, 1.5H), 2.00 - 1.74 (m, 2H), 1.64 - 1.49 (m, 0.5H), 1.44 - 1.29 (m, 0.5H). MS m / z 380.1952

[0417] (S)-6-amino-l-(l-(2-(3-methoxy-5-(trifluoromethyl)phenyl)acetyl)piperidin-3-yl)-l,3-dihydro- 2H-benzo[d]imidazol-2-one (Compound 64):

[0418]

[0419] General synthetic procedure: reagent 1 (appr. 1 eq.) Reagent 2 (appr. 1.1 eq ), l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) (appr. 1.3 eq ), and l-Hydroxy-7-azabenzotriazole (HOAt) (appr. 1.3 eq.) were mixed in dry DMF (appr. 0.7 ml per 100 mg of product). The reaction mixture was sealed and left at ambient temperature for 16 hours. Then the cleavage cocktail (CC) (Trifluoroacetic acid, Triisopropylsilane, water (93:5:2; v / v), appr. 1 ml per 100 mg of product) was added in one portion. The mixture was stirred for 6 hours at ambient temperature and evaporated under reduced pressure and the residue was dissolved in the DMSO (appr. 1 ml up to 300 mg of product). DMSO solution was filtered, analyzed by LCMS and transferred for HPLC purification. 6-amino-l-[(3S)-l-{2-[3-methoxy-5-(trifluoromethyl)phenyl]acetyl}piperidin-3-yl]-2,3-dihydro-lH- 1,3- benzodiazol-2-one was obtained by the above general synthetic procedure with using 81 mg (0.244 mmol) of tert-butyl N-{2-oxo-3-[(3S)-piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5-yl}carbamate (Reagent 1), 61 mg (0.26 mmol) of 2-[3-methoxy-5-(trifluoromethyl)phenyl]acetic acid (Reagent 2), 47.8 mg (0.308 mmol) of EDC, and 41.9 mg (0.308 mmol) of HOAt. Purified by HPLC. Yield: 46.6 mg (43.9 %). Green powder. El MS m / z: pos. 449.2 (MH+). 'H NMR (400 MHz, d6-DMSO) 5 10.31 - 10.17 (m, 1H), 7.20 - 6.96 (m, 3H), 6.63 (d, J = 8.1 Hz, 1H), 6.53 - 6.35 (m, 1H), 6.29 - 6.16 (m, 1H), 4.61 - 4.41 (m, 1H), 4.31 (s, 2H), 4.09 - 3.89 (m, 2H), 3.89 - 3.70 (m, 4.5H), 3.27 (t, J= 12.1 Hz, 0.5H), 3.23 - 3.16 (m, 1H), 3.14 - 3.05 (m, 0.5H), 2.68 - 2.54 (m, 0.5H), 2.49 - 2.33 (m, 1H), 1.94 - 1.79 (m, 2H), 1.64 - 1.46 (m, 1H).

[0420] (S)-6-amino-l-(l-(2-(3-(trifluoromethoxy)phenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- benzo [d]imidazol-2-one (Compound 65):

[0421]

[0422] 65

[0423] 6-amino-l-[(3S)-l-{2-[3-(trifluoromethoxy)phenyl]acetyl}piperidin-3-yl]-2,3-dihydro-lH-l,3- benzodiazol-2-one was obtained by the general synthetic procedure for Compound 64, using 78 mg (0.235 mmol) of tert-butyl N-{2-oxo-3-[(3S)- piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5- yl}carbamate (Reagent 1), 57 mg (0.259 mmol) of 2-[3- (trifluoromethoxy )phenyl] acetic acid (Reagent 2), and 46.5 mg (0.3 mmol) of EDC. Purified by HPLC. Yield: 43.9 mg (43.9 %). Brown powder. El MS m / z: pos. 435.2. 'HNMR (400 MHz, d6-DMSO) 5 10.31 - 10.19 (m, 1H), 7.46 - 7.33 (m, 1H), 7.31 - 7.09 (m, 3H), 6.63 (d, J= 8.1 Hz, 1H), 6.48 (s, 0.5H), 6.36 (s, 0.5H), 6.22 (d, J= 7.9 Hz, 1H), 4.61 - 4.41 (m, 1H), 4.30 (s, 2H), 4.06 - 3.86 (m, 2H), 3.86 - 3.69 (m, 1.5H), 3.33 - 3.17 (m, 1H), 2.64 - 2.51 (m, 0.5H), 2.43 (d, J= 12.6 Hz, 1H), 1.85 (s, 2H), 1.59 - 1.42 (m, 1H).

[0424] 6-amino-l-((S)-l-((S)-2-phenylpropanoyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2- one (Compound 66):

[0425] 6-amino- 1 - [(3 S) - 1 -[(2S)-2-phenylpropanoyl]piperidin-3-yl] -2,3-dihydro- 1H- 1 ,3 -benzodiazol-2-one was obtained by general synthetic procedure for Compound 64 using 90 mg (0.271 mmol) of tert-butyl N-{2-oxo-3-[(3S)-piperidin-3-yl]- 2,3-dihydro-lH-l,3-benzodiazol-5-yl}carbamate (Reagent 1), 47 mg (0.313 mmol) of (2S)-2 -phenylpropanoic acid (Reagent 2), 55.4 mg (0.357 mmol) of EDC, and 48.6 mg (0.357 mmol) of HO At. Purified by HPLC. Yield: 49.7 mg (49.7 %). Brown powder. El MS m / z: pos. 365.0 (MH+). ’HNMR (500 MHz, d6-DMSO) 5 10.36 (s, 1H), 7.43 - 7.14 (m, 5H), 6.64 (dd, J= 8.1, 1.8 Hz, 1H), 6.58 - 6.48 (m, 0.5H), 6.24 (dd, J= 8.3, 2.0 Hz, 1H), 4.74 - 4.59 (m, 2H), 4.59 - 4.40 (m, 1H), 4.19 - 4.05 (m, 1H), 4.05 - 3.90 (m, 1H), 3.70 (s, 0.5H), 3.18 (t, J= 12.0 Hz, 1H), 2.98 (t,J= 13.2 Hz, 1H), 2.23 (t, J= 12.5 Hz, 1H), 1.81 (d, J= 12.4 Hz, 1H), 1.59 (d, J= 12.5 Hz, 1H), 1.53 - 1.40 (m, 1H), 1.37 - 1.22 (m, 3H), 0.48 (d, J= 13.9 Hz, 0.5H).

[0426] (S)-6-amino-l-(l-(2-(3-(difluoromethoxy)phenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- benzo[d]imidazol-2-one (Compound 67):

[0427] 6-amino-l-[(3S)-l-{2-[3-(difluoromethoxy)phenyl]acetyl}piperidin-3-yl]-2,3-dihydro-lH-l,3- benzodiazol-2-one was obtained by synthetic procedure for Compound 64 with using 79 mg (0.238 mmol) of tert-butyl N-{2-oxo-3- [(3S)-piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5- yl}carbamate (Reagent 1), 55 mg (0.272 mmol) of 2 -[3 -(difluoromethoxy )phenyl] acetic acid (Reagent 2), 49.9 mg (0.321 mmol) of EDC and 43.8 mg (0.322 mmol) of HOAt. Purified by HPLC. Yield: 17.4 mg (16.9 %). Brown sticky oil. El MS m / z: pos. 417.0 (MH+). 'H NMR (500 MHz, d6-DMSO) 5 10.36 (s, 1H), 7.43 - 7.32 (m, 1H), 7.18 - 6.99 (m, 3H), 6.65 (d, J= 8.2 Hz, 1H), 6.59 - 6.40 (m, 1H), 6.25 (d, J= 8.2 Hz, 1H), 4.64 (s, 2H), 4.54 - 4.35 (m, 1H), 4.06 - 3.84 (m, 2H), 3.84 - 3.69 (m, 2H), 3.19 (t, J= 11.9 Hz, 1H), 3.02 (t, J= 13.3 Hz, 1H), 2.70 - 2.58 (m, 1H), 2.39 - 2.25 (m, 1H), 1.86 - 1.74 (m, 2H), 1.50 - 1.36 (m, 1H).

[0428] (S)-6-amino-l-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- benzo [d]imidazol-2-one (Compound 68):

[0429] 6-amino-l-[(3S)-l-[2-(3-chloro-5-fluorophenyl)acetyl]piperidin-3-yl]-2,3-dihydro-lH-l,3- benzodiazol-2-one was obtained by using the general synthetic procedure for Compound 64 using 116 mg (0.349 mmol) of tert-butyl N-{2-oxo-3- [(3S)-piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5- yl}carbamate (Reagent 1), 73 mg (0.387 mmol) of 2-(3- chloro-5-fluorophenyl)acetic acid (Reagent 2), 71 mg (0.457 mmol) of EDC, and 62.3 mg (0.458 mmol) of HOAt. Purified by HPLC. Yield: 31.3 mg (22.1 %). Brown powder. El MS m / z: pos. 403.2 (MH+). 'H NMR (400 MHz, d6-DMSO) 5 10.32 - 10.17 (m, 1H), 7.11 (d, J = 7.0 Hz, 1H), 7.04 - 6.92 (m, 2H), 6.70 - 6.60 (m, 1H), 6.44 (d, J = 25.7 Hz, 1H), 6.29 - 6.17 (m, 1H), 4.65 - 4.42 (m, 1H), 4.03 - 3.87 (m, 2H), 3.87 - 3.63 (m, 3H), 3.30 (t,J = 12.0 Hz, 1H), 3.09 (t,J= 13.0 Hz, 1H), 2.59 (t, J= \l.l z, 0.5H), 2.49 -2.38 (m, 1.5H), 1.97 - 1.81 (m, 2H), 1.67 - 1.50 (m, 1H).

[0430] 6-amino-l-((S)-l-((S)-2-phenylbutanoyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one (Compound 69):

[0431] 6-amino-l-[(3S)-l-[(2S)-2-phenylbutanoyl]piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-2-one was obtained using the general synthetic procedure for Compound 64 using 81 mg (0.244 mmol) of tert-butyl N-{2-oxo-3-[(3S)-piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5-yl}carbamate

[0432] (Reagent 1), 46 mg (0.28 mmol) of (2S)-2 -phenylbutanoic acid (Reagent 2), 51.4 mg (0.331 mmol) of EDC, and 45.1 mg (0.331 mmol) of HOAt. Purified by HPLC. Yield: 31.9 mg (33.1 %). White powder. El MS m / z: pos. 379.2 (MH+). 'HNMR (500 MHz, d6-DMSO) 5 10.41 - 10.30 (m, 1H), 7.45 - 7.15 (m, 5H), 6.70 - 6.59 (m, 1H), 6.59 - 6.47 (m, 1H), 6.24 (d, J= 8.1 Hz, 1H), 4.73 - 4.59 (m, 2H), 4.59 - 4.41 (m, 1H), 4.07 (d,J= 13.9 Hz, 1H), 3.90 (d,J = 7.4 Hz, 1H), 3.72 - 3.61 (m, 1H), 3.48 - 3.41 (m, 1H), 3.19 (t, J= 12.1 Hz, 1H), 3.00 (t, J= 13.1 Hz, 0.5H), 2.30 - 2.16 (m, 1H), 2.03 - 1.90 (m, 1H), 1.82 (d, J= 12.7 Hz, 1H), 1.66 - 1.53 (m, 1H), 1.52 - 1.40 (m, 1H), 0.91 - 0.72 (m, 3H), 0.52 - 0.35 (m, 0.5H).

[0433] (S)-6-amino-l-(l-(2-(3-fluorophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2- one (Compound 70):

[0434]

[0435] 6-amino-l-|(3S)-l-|2-(3-fliiorophcnyl)acctyl|pipcridin-3-yl |-2.3-dihydro-I H-l.3-bcnzodiazol-2-onc was obtained by synthetic procedure for Compound 64 with using 91 mg (0.274 mmol) of tert-butyl N- {2-oxo-3-[(3S)-piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5-yl}carbamate (Reagent 1), 44 mg (0.285 mmol) of 2-(3- fluorophenyl)acetic acid (Reagent 2), and 54.8 mg (0.353 mmol) of EDC. Purified by HPLC. Yield: 45.8 mg (45.8 %). Violet powder. El MS m / z: pos. 369.1 (MH+). 'H NMR (400 MHz, d6-DMSO) 5 10.32 - 10.17 (m, 1H), 7.39 - 7.21 (m, 1H), 7.13 - 6.88 (m, 3H), 6.69 - 6.57 (m, 1H), 6.49 (s, 0.5H), 6.35 - 6.18 (m, 1.5H), 4.62 - 4.42 (m, 1H), 4.32 (s, 2H), 4.05 - 3.85 (m, 2H), 3.85 - 3.64 (m, 2.5H), 3.33 - 3.17 (m, 0.5H), 2.64 - 2.53 (m, 1H), 2.47 - 2.34 (m, 1H), 1.95 - 1.76 (m, 2H), 1.60 - 1.39 (m, 1H).

[0436] (S)-6-amino-l-(l-(2-(3-chloro-4-fluorophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- benzo [d]imidazol-2-one (Compound 71):

[0437] 6-amino-l-[(3S)-l-[2-(3-chloro-4-fluorophenyl)acetyl]piperidin-3-yl]-2,3-dihydro-lH-l,3- benzodiazol-2-one was obtained by the general synthetic procedure for Compound 64 using 84 mg (0.253 mmol) of tert-butyl N-{2-oxo-3-[(3S)- piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5- yl}carbamate (Reagent 1), 50 mg (0.265 mmol) of 2-(3-chloro- 4-fluorophenyl)acetic acid (Reagent 2), and 50.1 mg (0.323 mmol) of EDC. Purified by HPLC. El MS m / z: pos. 403.1 (MH+). 'HNMR (400 MHz, d6-DMSO) 5 10.25 (d, J= 16.1 Hz, 1H), 7.45 - 7.33 (m, 1H), 7.28 - 7.11 (m, 2H), 6.71 - 6.58 (m, 1H), 6.46 (d, J= 14.0 Hz, 1H), 6.22 (t, J= 7.0 Hz, 1H), 4.60 - 4.41 (m, 1H), 4.32 (brs, 2H), 4.07 - 3.87 (m, 2H), 3.87 - 3.63 (m, 2H), 3.34 - 3.16 (m, 1.5H), 2.65 -2.55 (m, 0.5H), 2.47 -2.34 (m, 1H), 1.86 (d, J = 12.6 Elz, 2H), 1.62 - 1.45 (m, 1H).

[0438] (S)-6-amino-l-(l-(2-(3,5-dimethylphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- benzo [d]imidazol-2-one (Compound 72):

[0439] 72

[0440] 6-amino-l-[(3S)-l-[2-(3,5-dimethylphenyl)acetyl]piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-2- one obtained by the general synthetic procedure for Compound 64 using 88 mg (0.265 mmol) of tertbutyl N-{2-oxo-3-[(3S)- piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5-yl}carbamate (Reagent 1), 47 mg (0.286 mmol) of 2 -(3, 5- dimethylphenyl)acetic acid (Reagent 2), and 53.3 mg (0.343 mmol) of EDC. Purified by HPLC. Yield: 53.4 mg (53.4 %). Light brown powder. El MS m / z: pos. 379.2 (MH+). 'H NMR (400 MHz, d6-DMSO) 5 10.23 (s, 1H), 6.89 - 6.76 (m, 3H), 6.65 - 6.59 (m, 1H), 6.48 (s, 0.5H), 6.25 - 6.19 (m, 1H), 6.11 (s, 0.5H), 4.61 - 4.43 (m, 1H), 4.28 (s, 2H), 4.02 - 3.84 (m, 1.5H), 3.84 - 3.66 (m, 1H), 3.66 - 3.52 (m, 2H), 3.30 - 3.17 (m, 1H), 2.57 - 2.53 (m, 0.5H), 2.47 - 2.35 (m, 1H), 2.35 - 2.22 (m, 6H), 1.91 - 1.76 (m, 2H), 1.55 - 1.37 (m, 1H).

[0441] (S)-6-amino-l-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-

[0442] 6-amino-l-[(3S)-l-[2-(3-methoxyphenyl)acetyl]piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-2- one was obtained by general synthetic procedure for Compound 64 using 86 mg (0.259 mmol) of tertbutyl N-{2-oxo-3-[(3S)-piperidin- 3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5-yl}carbamate (Reagent 1), 51 mg (0.307 mmol) of 2-(3- methoxyphenyl)acetic acid (Reagent 2), and 53 mg (0.341 mmol) of EDC. Purified by HPLC. Yield: 41.4 mg (41.4 %). Brown powder. El MS m / z: pos. 381.2 (MH+), 403.0. 'H NMR (400 MHz, d6-DMSO) 5 10.23 (s, 1H), 7.24 - 7.16 (m, 1H), 6.85 - 6.72 (m, 3H), 6.66 - 6.59 (m, 1H), 6.48 (s, 0.5H), 6.25 - 6.19 (m, 1H), 6.15 (s, 0.5H), 4.63 -4.44 (m, 1H), 4.29 (brs, 2H), 4.02 - 3.85 (m, 1.5H), 3.82 - 3.61 (m, 5.5H), 3.30 - 3.17 (m, 1.5H), 2.61 - 2.53 (m, 0.5H), 2.41 (d, J= 12.9 Hz, 1H), 1.82 (d,J= 10.4 Hz, 2H), 1.44 (dd, J= 34.0, 14.9 Hz, 1H).

[0443] (S)-6-amino-l-(l-(2-(4-chloro-3-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- benzo [d]imidazol-2-one (Compound 74):

[0444] 6-amino-l-[(3S)-l-[2-(4-chloro-3-methoxyphenyl)acetyl]piperidin-3-yl]-2,3-dihydro-lH-l,3- benzodiazol-2-one was obtained by general synthetic procedure for Compound 64 using 82 mg (0.247 mmol) of tert-butyl N-{2-oxo-3-[(3S)- piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5- yl}carbamate (Reagent 1), 53 mg (0.264 mmol) of 2-(4-chloro- 3-methoxyphenyl)acetic acid (Reagent 2), 48.6 mg (0.313 mmol) of EDC, and 42.6 mg (0.313 mmol) ofHOAt. Purified by HPLC. Yield: 29.4 mg (29.4 %). Violet sticky oil. El MS m / z: pos. 415.2 (MH+). 'H NMR (600 MHz, d6-DMSO) 5 10.48 - 10.24 (m, 1H), 7.38 - 7.29 (m, 1H), 7.09 - 6.99 (m, 1H), 6.87 - 6.78 (m, 1H), 6.67 - 6.61 (m, 1H), 6.57 - 6.43 (m, 1H), 6.28 - 6.22 (m, 1H), 4.69 - 4.57 (m, 2H), 4.52 - 4.33 (m, 1H), 4.03 (d, J= 13.4 Hz, 1H), 3.92 (t, J= 12.2 Hz, 1H), 3.87 - 3.76 (m, 4H), 3.76 - 3.67 (m, 1H), 3.18 (t, J= 12.0 Hz, 1H), 3.01 (t, J= 13.2 Hz, 1H), 2.30 (dd, J= 13.4, 9.4 Hz, 1H), 1.79 (d, J= 11.8 Hz, 2H), 1.41 (s, 1H).

[0445] (S)-6-amino-l-(l-(2-(3-chlorophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2- one (Compound 75):

[0446]

[0447] 75

[0448] 6-amino-l-[(3S)-l-[2-(3-chlorophenyl)acetyl]piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-2-one was obtained by general synthetic procedure for Compound 64 using 85 mg (0.256 mmol) of tert-butyl N-{2-oxo-3-[(3S)-piperidin- 3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5-yl}carbamate (Reagent 1), 49 mg (0.287 mmol) of 2-(3- chlorophenyl)acetic acid (Reagent 2), and 52.4 mg (0.338 mmol) of EDC. Purified by HPLC. Yield: 30.8 mg (30.8 %). Violet sticky oil. El MS m / z: pos. 385.2 (MH+). ’HNMR (600 MHz, d6-DMSO) 5 10.37 (s, 1H), 7.39 - 7.27 (m, 3H), 7.27 - 7.13 (m, 1H), 6.64 (d, J= 8.1 Hz, 1H), 6.57 - 6.44 (m, 1H), 6.24 (d, J= 8.0 Hz, 1H), 4.70 - 4.59 (m, 2H), 4.51 - 4.34 (m, 1H), 4.07 - 3.89 (m, 2H), 3.86 - 3.71 (m, 2H), 3.19 (t, J= 12.0 Hz, 1H), 3.03 (t, J= 13.1 Hz, 1H), 2.37 - 2.26 (m, 1H), 1.85 - 1.76 (m, 2H), 1.52 - 1.36 (m, 1H).

[0449] (S)-6-amino-l-(l-(2-(3,5-dimethoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- benzo[d]imidazol-2-one (Compound 76):

[0450] 6-amino-l-[(3S)-l-[2-(3,5-dimethoxyphenyl)acetyl]piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol- 2-one was obtained by general synthetic procedure for Compound 64 with using 80 mg (0.241 mmol) of tert-butyl N-{2-oxo-3-[(3S)- piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5-yl}carbamate (Reagent 1), 52 mg (0.265 mmol) of 2 -(3, 5- dimethoxyphenyl)acetic acid (Reagent 2), and 49.2 mg (0.317 mmol) of EDC. Purified by HPLC. Yield: 27.4 mg (27.4 %). Beige powder. LCEI MS m / z: pos. 411.2 (MH+). ’H NMR (600 MHz, d6-DMSO) 5 10.41 - 10.32 (m, 1H), 6.64 (t, J = 7.3 Hz, 1H), 6.58 - 6.52 (m, 1H), 6.48 - 6.32 (m, 3H), 6.24 (d, J= 8.2 Hz, 1H), 4.69 - 4.57 (m, 2H), 4.52 - 4.36 (m, 1H), 4.04 - 3.81 (m, 2H), 3.77 - 3.63 (m, 8H), 3.16 (t, J= 12.1 Hz, 1H), 2.98 (t, J= 13.1 Hz, 1H), 2.36 - 2.23 (m, 1H), 1.85 - 1.74 (m, 2H), 1.46 - 1.32 (m, 1H).

[0451] (S)-6-amino-l-(l-(2-(m-tolyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0452] (Compound 77):

[0453] 6-amino-l-[(3S)-l-[2-(3-methylphenyl)acetyl]piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-2-one was obtained by general synthetic procedure for Compound 64 using 93 mg (0.28 mmol) of tert-butyl N-{2-oxo-3-[(3S)-piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5-yl}carbamate (Reagent 1), 47 mg (0.313 mmol) of 2-(3- methylphenyl)acetic acid (Reagent 2), and 55.4 mg (0.357 mmol) of EDC. Purified by HPLC. Yield: 30.4 mg (30.4 %). Light brown sticky oil. El MS m / z: pos. 365.0 (MH+). 'H NMR (600 MHz, d6-DMSO) 5 10.38 - 10.34 (m, 1H), 7.24 - 7.15 (m, 1H), 7.10 - 6.98 (m, 3H), 6.64 (t, J= 7.4 Hz, 1H), 6.58 - 6.52 (m, 0.5H), 6.32 (s, 0.5H), 6.24 (dd, J= 8.2, 1.9 Hz, 1H), 4.63 (d, J = 23.0 Hz, 2H), 4.52 - 4.36 (m, 1H), 4.06 - 3.94 (m, 1H), 3.95 - 3.78 (m, 1H), 3.77 - 3.63 (m, 2H), 3.17 (t, J= 12.0 Hz, 1H), 2.99 (t, J= 13.2 Hz, 1H), 2.33 - 2.21 (m, 4H), 1.84 - 1.73 (m, 2H), 1.45 - 1.32 (m, 1H).

[0454] (S)-6-amino-l-(l-(2-(3-chloro-5-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- benzo [d]imidazol-2-one (Compound 78):

[0455] 6-amino-l-[(3S)-l-[2-(3-chloro-5-methoxyphenyl)acetyl]piperidin-3-yl]-2,3-dihydro-lH-l,3- benzodiazol-2-one was obtained by general synthetic procedure for Compound 64 with using 79 mg (0.238 mmol) of tert-butyl N-{2-oxo-3- [(3S)-piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5- yl}carbamate (Reagent 1), 56 mg (0.279 mmol) of 2-(3- chloro-5-methoxyphenyl)acetic acid (Reagent 2), and 48.6 mg (0.313 mmol) of EDC. Purified by HPLC. Light brown powder. El MS m / z: pos. 415.0 (MH+).1H NMR (600 MHz, d6-DMSO) 5 10.37 (s, 1H), 6.93 - 6.75 (m, 3H), 6.64 (d, J= 8.2 Hz, 1H), 6.58 - 6.45 (m, 1H), 6.28 - 6.21 (m, 1H), 4.64 (s, 2H), 4.51 - 4.34 (m, 1H), 4.08 - 3.88 (m, 2H), 3.83 - 3.65 (m, 5.5H), 3.18 (t, J= 12.0 Hz, 0.5H), 3.02 (t, J= 13.0 Hz, 0.5H), 2.59 - 2.53 (m, 0.5H), 2.37 - 2.25 (m, 1H), 1.89 - 1.76 (m, 2H), 1.52 - 1.39 (m, 1H).

[0456] (S)-6-amino-l-(l-(2-(3-fluoro-5-(trifluoromethyl)phenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- benzo [d]imidazol-2-one (Compound 79):

[0457] 79

[0458] 6-amino-l-[(3S)-l-{2-[3-fhioro-5-(trifluoromethyl)phenyl]acetyl}piperidin-3-yl]-2,3-dihydro-lH-l,3- benzodiazol-2-one was obtained by general synthetic procedure for Compound 64 using 108 mg (0.325 mmol) of tert-butyl N-{2- oxo-3-[(3S)-piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5- yl}carbamate (Reagent 1), 81 mg (0.365 mmol) of 2-[3-fhroro-5-(trifhroromethyl)phenyl]acetic acid (Reagent 2), 66.9 mg (0.431 mmol) of EDC, and 58.7 mg (0.431 mmol) of HOAt. Purified by HPLC. Yield: 54.2 mg (37.5 %). Brown sticky oil. El MS m / z: pos. 437.0 (MH+). 'H NMR (500 MHz, d6- DMSO) 5 10.37 (d, J= 7.2 Hz, 1H), 7.60 - 7.34 (m, 3H), 6.65 (dd, J= 8.4, 2.3 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.25 (d, J = 7.8 Hz, 1H), 4.64 (s, 2H), 4.52 - 4.32 (m, 1H), 4.11 - 3.84 (m, 4H), 3.82 - 3.73 (m, 0.5H), 3.26 - 3.16 (m, 0.5H), 3.07 (t, J= 13.1 Hz, 0.5H), 2.67 - 2.55 (m, 0.5H), 2.40 - 2.24 (m, 1H), 1.90 - 1.76 (m, 2H), 1.62 - 1.40 (m, 1H).

[0459] 6-amino-l-((S)-l-((R)-l,2,3,4-tetrahydronaphthalene-l-carbonyl)piperidin-3-yl)-l,3-dihydro- 2H-benzo[d]imidazol-2-one (Compound 80):

[0460] 6-amino-l-[(3S)-l-[(lR)-l,2,3,4-tetrahydronaphthalene-l-carbonyl]piperidin-3-yl]-2,3-dihydro-lH- 1,3- benzodiazol-2-one was obtained by general synthetic procedure for Compound 64 using 114 mg (0.343 mmol) of tert-butyl N-{2-oxo-3-[(3S)-piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5- yl}carbamate (Reagent 1), 66 mg (0.375 mmol) of (lR)-l,2,3,4-tetrahydronaphthalene-l-carboxylic acid (Reagent 2), 68.7 mg (0.443 mmol) of EDC, and 60.2 mg (0.442 mmol) of HOAt. Purified by HPLC. Yield: 48.7 mg (36.6 %). Brown sticky oil. El MS m / z: pos. 391.2 (MH+). ’HNMR(400 MHz, d6-DMSO) 5 10.23 (s, 1H), 7.18 - 6.86 (m, 4H), 6.64 (d, J= 8.2 Hz, 1H), 6.54 (s, 1H), 6.23 (d, J= 8.1 Hz, 1H), 4.68 - 4.29 (m, 2.5H), 4.29 - 3.86 (m, 3.5H), 3.79 (d, J= 12.6 Hz, 0.5H), 3.42 - 3.16 (m, 1H), 2.86 - 2.60 (m, 2.5H), 2.11 - 1.81 (m, 5 5H), 1.81 - 1.49 (m, 2.5H).

[0461] (S)-6-amino-l-(l-(2-(l-methyl-lH-indol-3-yl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- benzo [d]imidazol-2-one (Compound 81):

[0462] 6-amino-l-[(3S)-l-[2-(l-methyl-lH-indol-3-yl)acetyl]piperidin-3-yl]-2,3-dihydro-lH-l,3- benzodiazol-2-one was obtained by general synthetic procedure for Compound 64 with using 82 mg (0.247 mmol) of tert-butyl N-{2-oxo-3-[(3S)-piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5- yl}carbamate (Reagent 1), 54 mg (0.285 mmol) of 2-(l- methyl- lH-indol-3-yl)acetic acid (Reagent 2), 52.4 mg (0.338 mmol) of EDC, 0 mg (0 mmol) of DIPEA, and 45.9 mg (0.337 mmol) of HOAt. Purified by HPLC. Yield: 19.4 mg (18.5 %). Violet sticky oil. El MS m / z: pos. 404.2 (MH+). 'HNMR (500 MHz, d6-DMSO) 5 10.35 (s, 1H), 7.58 (t, J = 10.4 Hz, 1H), 7.38 (s, 1H), 7.26 - 7.10 (m, 2H), 7.08 - 6.96 (m, 1H), 6.68 - 6.60 (m, 1H), 6.57 - 6.28 (m, 1H), 6.28 - 6.19 (m, 1H), 4.61 (d, J= 23.2 Hz, 2H), 4.54 - 4.37 (m, 1H), 4.13 - 4.03 (m, 1H), 3.96 - 3.63 (m, 5H), 3.16 (t, J= 12.1 Hz, 0.5H), 2.99 (t, J= 13.2 Hz, 0.5H), 2.34 - 2.18 (m, 1H), 2.07 (d, J= 2.3 Hz, 2H), 1.81 - 1.67 (m, 2H), 1.47 - 1.27 (m, 1H).

[0463] (S)-5-amino-3-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-l-methyl-l,3-dihydro-2H- benzo[d]imidazol-2-one (Compound 82):

[0464] 82

[0465] Sodium hydride (60 mg, 1.5 mmol, 60% dispersion in oil) was added to a stirred solution of Compound 73 (380 mg, 1 mmol) in DMF (1 mL). The reaction mixture was left for 1 h. at rt. lodomethane (426 mg, 3 mmol) was added to the reaction mixture. The reaction mixture was left at rt overnight. The residue was analyzed by LCMS and then subjected to chromatographic purification by HPLC. The product, 5 -amino-3 - [(3 S)- 1 - [2 -(3 -methoxyphenyl)acetyl]piperidin-3 -yl] - 1 -methyl -2, 3 -dihydro- 1H- l,3-benzodiazol-2-one, was obtained in 180 mg amount (45 % yield). Orange powder. El MS m / z: pos. 395.2 (MH+). 'H NMR (400 MHz, d6-DMSO) 5 7.29 - 7.18 (m, 1H), 6.88 - 6.74 (m, 4H), 6.60 (s, 0.5H), 6.42 - 6.29 (m, 1.5H), 4.71 (s, 2H), 4.45 (dd, J= 35.6, 12.2 Hz, 1H), 4.09 - 3.81 (m, 2H), 3.80 - 3.62 (m, 5.5H), 3.26 - 3.13 (m, 3.5H), 2.99 (t, J= 13.2 Hz, 0.5H), 2.59 - 2.54 (m, 0.5H), 2.39 - 2.22 (m, 1H), 1.79 (s, 2H), 1.50 - 1.30 (m, 1H).

[0466] (S)-6-amino-l-(l-(2-(3-fluoro-5-methylphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- benzo[d]imidazol-2-one (Compound 83):

[0467] 6-amino-l-[(3S)-l-[2-(3-fluoro-5-methylphenyl)acetyl]piperidin-3-yl]-2,3-dihydro-lH-l,3- benzodiazol-2-one was obtained by general synthetic procedure for Compound 64 using 82 mg (0.247 mmol) of tert-butyl N-{2-oxo-3-[(3S)-piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5-yl}carbamate (Reagent 1), 46 mg (0.274 mmol) of 2-(3-fluoro-5-methylphenyl)acetic acid (Reagent 2), 50.2 mg (0.323 mmol) of EDC, 0 mg (0 mmol) of DIPEA, and 44 mg (0.323 mmol) ofHOAt. Purified by HPLC. Yield: 42.6 mg (44.8 %). Brown sticky oil. El MS m / z: pos. 383.2 (MH+). 'H NMR (400 MHz, DMSO) 5 10.38 (s, 1H), 6.96 - 6.80 (m, 3H), 6.64 (d, J= 8.2 Hz, 1H), 6.59 - 6.40 (m, 1H), 6.30 - 6.21 (m, 1H), 4.70 - 4.57 (m, 2H), 4.52 - 4.33 (m, 1H), 4.07 - 3.84 (m, 2H), 3.81 - 3.68 (m, 2.5H), 3.18 (t, J= 12.0 Hz, 0.5H), 3.01 (t, J= 13.1 Hz, 0.5H), 2.62 - 2.53 (m, 0.5H), 2.38 - 2.22 (m, 4H), 1.80 (d, J= 11.8 Hz, 2H), 1.48 - 1.37 (m, 1H). l-((3S)-l-(2-(3-chlorophenyl)propanoyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0468] (Compound 84):

[0469] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with 2-(3-chlorophenyl)propanoic acid. ’H NMR (500 MHz, CDC13) 8 10.05 - 9.57 (m, 1H), 7.48 - 6.92 (m, 7.5H), 6. 19 (d, J = 7.9 Hz, 0.5H), 4.89 - 4.80 (m, 1H), 4.45 - 4.11 (m, 0.5H), 4.09 - 3.82 (m, 2H), 3.59 - 3.18 (m, 1H), 3.14 - 2.99 (m, 0.5H), 2.92 - 2.37 (m, 1.5H), 2.08 - 2.04 (m, 0.5H), 1.99 - 1.81 (m, 2H), 1.71 - 1.61 (m, 0.5H), 1.54 - 1.33 (m, 3.5H), 0.91 - 0.73 (m, 0.5H). MS m / z 384.1 l-((3S)-l-(3-hydroxy-2-phenylpropanoyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2- one (Compound 85):

[0470] 85

[0471] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with 3 -hydroxy-2 -phenylpropanoic acid. HI NMR (400 MHz, DMSO) 8 10.93 - 10.73 (ni. 1H), 7.43 - 7.13 (m, 5.7H), 7.05 - 6.73 (m, 3H), 6.17 (d, J = 7.8 Hz, 0.3H), 5.00 - 4.38 (m, 2H), 4.34

[0472] 3.70 (m, 2H), 3.59 - 3.35 (m, 2H), 3.29 - 3.08 (m, 0.8H), 2.86 (t, J = 13.1 Hz, 0.2H), 2.60 (d, J = 11.7

[0473] Hz, 0.4H), 2.45 2.15 (m, 2.6H), 1.98 - 1.22 (m, 2H). MS m / z 366.1

[0474] 1-((3S)-l-(2-(3,5-dimethoxyphenyl)propanoyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-

[0475] 2-one (Compound 86):

[0476] Prepared the same method as Compound 18, except that 2-(4-chloro-3-methoxyphenyl)acetic acid was replaced with 2-(3,5-dimethoxyphenyl)propanoic acid. ’H NMR (500 MHz, DMSO) 8 10.88 (s, 1H), 7.37 - 7.24 (m, 1H), 6.98 (d, J = 3.1 Hz, 3H), 6.56 - 6.28 (m, 3H), 4.49 (t, J = 16.9 Hz, 1H), 4.21 (s, 0.5H), 4.11 - 3.94 (m, 2H), 3.90 (s, 0.5H), 3.70 (d, J= 52.5 Hz, 6H), 3.46 (d, J= 12.3 Hz, 0.5H), 3.24 - 3.21 (m, 1H), 3.10 (t, J= 13.1 Hz, 0.5H), 2.62 - 2.55 (m, 0.5H), 2.35 - 2.22 (m, 1H), 1.87 - 1.73 (m, 0.5H), 1.65 (d, J = 12.8 Hz, 0.5H), 1.51 (d, J = 13.5 Hz, 1H), 1.33 - 1.23 (m, 3H), 0.70 - 0.54 (m, 0.5H). MS m / z 410.1

[0477] (S)-l-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2- one (Compound 87):

[0478] 3-[(3S)-3-piperidyl]-lH-benzimidazol-2-one (45mg, 0.207 Immol) was added to a stirred solution of 2- (3-chloro-5-fluorophenyl)acetic acid, T3P in EtOAc (158.1mg,0.25mmol) and DIPEA (31.4mg,0.31mmol) in DCM (2mL). The mixture allowed to stir overnight. Water was added to the reaction mixture and stirred vigourously for 5 mins. The mixture was passed through a phase seperator and the filtrate dried in the EZ-2 genevac. The material was redissolved in DMS0:ACN:H20 and purified by the Gilson prep HPLC (0. 1 % NH3 in ACN : H2O (95 - 5%). Fractions were collected and dried overnight on the HT4 genevac. 3-[(3S)-l-[2-(3,5-dimethylphenyl)acetyl]-3-piperidyl]-lH- benzimidazol-2-one (43.2mg,0.1129mmol), 54.519% yield. 'H NMR (500 MHz, DMSO) 8 10.87 (s, 1H), 7.36 - 7.08 (m, 4H), 6.98 (d, J= 3.1 Hz, 3H), 4.50 - 4.36 (m, 1H), 4.14 - 4.05 (m, 1H), 4.01 (d, J = 13.3 Hz, 1H), 3.93 - 3.76 (m, 2.5H), 3.16 (t, J= 13.2 Hz, 1H), 2.68 - 2.60 (m, 1H), 2.44 - 2.33 (m, 1.5H), 1.88 - 1.78 (m, 2H), 1.60 - 1.41 (m, 1H). MS m / z 364.1

[0479] (S)-l-(l-(2-(3-fluoro-5-methylphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2- one (Compound 88):

[0480] 3-[(3S)-3-piperidyl]-lH-benzimidazol-2-one (45mg,0.2071mmol) was added to a stirred solution of 2- (3-fluoro-5-methylphenyl)acetic acid, T3P in EtOAc (158.16mg,0.25mmol) and DIPEA (31.4mg,0.31mmol) in DCM (2mL). The mixture allowed to stir overnight. Water was added to the reaction mixture and stirred vigourously for 5 mins. The mixture was passed through a phase seperator and the filtrate dried in the EZ-2 genevac. The material was redissolved in DMSO:ACN:H2O and purified by the Gilson prep HPLC (0.1 % NH3 in ACN : H2O (95 - 5%). Fractions were collected and dried overnight on the HT4 genevac. 3-[(3S)-l-[2-(3-fluoro-5-methyl-phenyl)acetyl]-3-piperidyl]-lH- benzimidazol-2-one (21.4mg,0.0553mmol), 26.715% yield. 'H NMR (500 MHz, DMSO) 8 10.86 (s, 1H), 7.32 (s, 0.5H), 7.10 - 6.79 (m, 6.5H), 4.53 - 4.36 (m, 1H), 4.13 - 4.03 (m, 0.5H), 4.03 - 3.92 (m, 1.5H), 3.83 - 3.60 (m, 1.5H), 3.20 - 3.06 (m, 2.5H), 2.63 - 2.57 (m, 0.5H), 2.36 (t, J= 12.8 Hz, 1H), 2.28 (d, J= 23.1 Hz, 3H), 1.86 - 1.74 (m, 2H), 1.54 - 1.38 (m, 1H). MS m / z 368.1 l-((S)-l-((S)-2-phenylbutanoyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0481] (Compound 89):

[0482]

[0483] 3-[(3S)-3-piperidyl]-lH-benzimidazol-2-one (45mg,0.2071mmol) was added to a stirred solution of (S)-2 -phenylbutanoic acid, T3P in EtOAc (158.1mg,0.25mmol) and DIPEA

[0484] (31.4mg,0.31mmol) in DCM (2mL). 3-[(3S)-l-[(2S)-2-phenylbutanoyl]-3-piperidyl]-lH- benzimidazol-2-one (25.5mg,0.0667mmol), 32.182% yield 'H NMR (500 MHz, DMSO) 8 10.87 (s, 1H), 7.42 - 7.14 (m, 6H), 6.98 (d, J= 3.7 Hz, 3H), 4.54 - 4.43 (m, 1H), 4.24 - 4.01 (m, 1H), 3.89 (t, J = 6.6 Hz, 1H), 3.80 (td, J= 9.8, 5.3 Hz, 0.5H), 3.51 (t, J= 12.3 Hz, 0.5H), 3.27 - 3.18 (m, 0.5H), 3.11 (t, J= 13.0 Hz, 0.5H), 2.59 - 2.53 (m, 1H), 2.40 - 2.21 (m, 1H), 2.05 - 1.91 (m, 1H), 1.83 (t, J= 15.4 Hz, 1H), 1.65 - 1.56 (m, 1.5H), 1.47 (d, J = 13.6 Hz, 1H), 0.89 - 0.74 (m, 3H), 0.55 - 0.41 (m, 0.5H). MS m / z 364.1

[0485] (S)-6-amino-l-(l-(2-(3,5-difluorophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- benzo[d]imidazol-2-one (Compound 90):

[0486] 6-amino-l-[(3S)-l-[2-(3,5-difluorophenyl)acetyl]piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-2- one was obtained using the general procedure for compound 64 using 138 mg (0.415 mmol) of tertbutyl N-{2-oxo-3-[(3S)- piperidin-3-yl]-2,3-dihydro-lH-l,3-benzodiazol-5-yl}carbamate (Reagent 1), 76 mg (0.442 mmol) of 2 -(3, 5- difluorophenyl)acetic acid (Reagent 2), 81 mg (0.522 mmol) of EDC, and 71 mg (0.522 mmol) of HOAt. Purified by HPLC. Yield: 30.6 mg (19.7 %). Brown powder. El MS m / z: pos. 387.1 (MH+). 'H NMR (400 MHz, d6-DMSO) 8 10.31 - 10.17 (m, 1H), 6.97 - 6.85 (m, 2H), 6.85 - 6.77 (m, 1H), 6.63 (d,J= 8.1 Hz, 1H), 6.53 - 6.38 (m, 1H), 6.28 - 6.18 (m, 1H), 4.61 -4.41 (m, 1H), 4.31 (s, 2H), 4.06 - 3.88 (m, 2H), 3.86 - 3.67 (m, 3H), 3.27 (t, J= 12.2 Hz, 0.5H), 2.65 -2.57 (m, 0.5H), 2.46 - 2.35 (m, 1H), 1.87 (d, J= 12.3 Hz, 2H), 1.63 - 1.46 (m, 1H). l-((3S,5R)-5-hydroxy-l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (Compound 91):

[0487] To a solution of tert-butyl ((3S,5R)-5-hydroxypiperidin-3-yl)carbamate (500 mg, 2.31 mmol), 2-(3- methoxyphenyl)acetic acid (384 mg, 2.31 mmol) and DIEA (1.21 mL, 6.94 mmol) in THF (10 mL) was added drop wise T3P (1.37 mL, 2.31 mmol, 50% purity of ethyl acetate solution) at 0 °C. After addition, the mixture was warmed to 25 °C and stirred for 1 hour. The mixture was poured into a saturated aqueous solution of NaHCOs (5 mL), extracted with ethyl acetate (5 mL x 3), the combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum. The residue was purified by prep-TLC (Dichloromethane: Methanol=20: l) to afford the title compound tert-butyl ((3S,5R)-5-hydroxy-l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl) carbamate as yellow gum (530 mg, 62.9% yield), m / z 365.0 (M+H)+(ES+); SFC 100% de, 'H NMR (400 MHz, CDCh) <5 7.26 - 7.19 (m, 1H), 6.92 - 6.73 (m, 3H), 6.07 (br d, J= 6.8 Hz, 1H), 4.47 (d, J = 13.2 Hz, 1H), 4.09 (s, 1H), 3.99 (d, J= 14.8 Hz, 1H), 3.79 (s, 3H), 3.70 (d, J= 3.2 Hz, 2H), 3.53 - 3.34 (m, 1H), 3.18 (d, J = 13.6 Hz, 1H), 3.02 (s, 1H), 2.97 (d, J = 13.6 Hz, 1H), 1.88 (d, J = 2.8 Hz, 2H), 1.46 (s, 9H).

[0488] A solution of tert-butyl ((3S,5R)-5-hydroxy-l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)carbamate (520 mg, 1.43 mmol) in HCl / MeOH (4 M, 10 mL) was stirred at 25 °C for 1 hour. Then the mixture was evaporated under reduced pressure to afford the title compound l-((3S,5R)-3-amino-5- hydroxypiperidin-l-yl)-2-(3-methoxyphenyl)ethan-l-one hydrochloride as a yellow solid (530 mg, crude), m / z 264.9 (M+H)+(ES+); 'H NMR (400 MHz, D2O) d 7.57 - 7.21 (m, 1H), 6.93 (dd, J= 2.4, 8.0 Hz, 1H), 6.87 (d, J= 7.6 Hz, 1H), 6.84 (d, J= 2.4 Hz, 1H), 3.99 - 3.82 (m, 4H), 3.80 (s, 3H), 3.32 (s, 4H), 2.33 - 2.14 (m, 1H), 1.92 - 1.71 (m, 1H).

[0489] A solution of l-((3S,5R)-3-amino-5-hydroxypiperidin-l-yl)-2-(3-methoxyphenyl)ethan-l-one hydrochloride (520 mg, 1.73 mmol) and 3 -fluoro-2 -nitro-pyridine (270 mg, 1.90 mmol) in DIEA (59.71 mmol, 10.40 mL) and DMSO (5 mL) was stirred at 120 °C for 16 hours. The mixture was then cooled to room temperature, and poured into water (50 mL), extracted with ethyl acetate (25 mL x 3), the combined organic layers were washed with brine (5 mb), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-TLC (Dichloromethane: Methanol=10: l) to afford the title compound l-((3R,5S)-3-hydroxy-5-((2-nitropyridin-3- yl)amino)piperidin-l-yl)-2-(3-methoxyphenyl)ethan-l-one as a yellow solid (600 mg, 89.3% yield), m / z 387.0 (M+H)+(ES+); SFC 100% de; 'H NMR (400 MHz, DMSO-d6) <5 8.63 (d, J= 8.0 Hz, 0.6H), 8.29 (d, J= 8.0 Hz, 0.4H), 7.79 (dd, J= 1.6, 3.6 Hz, 1H), 7.71 - 7.63 (m, 0.6H), 7.61 - 7.55 (m, 0.6H), 7.52 (dd, J= 4.0, 8.4 Hz, 0.4H), 7.37 (d, J= 8.0 Hz, 0.4H), 7.16 (t, J= 7.6 Hz, 0.6H), 7.05 (t, J= 8.0 Hz, 0.4H), 6.75 (dd, J= 2.0, 8.0 Hz, 0.6H), 6.72 - 6.65 (m, 1.5H), 6.60 - 6.56 (m, 0.7H), 5.51 (br d, J = 2.4 Hz, 0.6H), 5.34 (br s, 0.4H), 4.09 (d, J= 13.2 Hz, 0.6H), 4.05 - 3.93 (m, 0.6H), 3.90 (s, 0.6H), 3.81 - 3.58 (m, 6H), 3.55 - 3.47 (m, 1.5H), 3.45 - 3.38 (m, 1H), 3.13 (dd, J= 1.6, 12.8 Hz, 0.5H), 2.13 - 2.00 (m, 1H), 1.90 - 1.85 (m, 0.6H), 1.77 - 1.70 (m, 0.4H).VT NMR (400 MHz, DMSO-d6) <5 8.23 - 7.95 (m, 1H), 7.82 - 7.77 (m, 1H), 7.59 - 7.41 (m, 2H), 7.22 - 7.05 (m, 1H), 6.83 - 6.59 (m, 3H), 5.06 (br s, 1H), 3.90 - 3.78 (m, 2H), 3.77 - 3.69 (m, 4H), 3.68 - 3.43 (m, 5H), 2.13 (td, J = 4.0, 13.2 Hz, 1H), 1.85 - 1.73(m, 1H).

[0490] To a solution of l-((3R,5S)-3-hydroxy-5-((2-nitropyridin-3-yl)amino)piperidin-l-yl)-2- (3- methoxyphenyl) ethan-l-one (600 mg, 1.54 mmol) in methanol (20 mb) was added Pd / C (100 mg, 10% weight on activated charcoal) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 2 hours, then fdtered through celite. The fdtrate was concentrated in vacuum to afford the title compound l-((3S,5R)-3-((2- aminopyridin-3-yl)amino)-5-hydroxypiperidin-l-yl)-2-(3-methoxyphenyl) ethan-l-one as a yellow solid (510 mg, 92.3% yield), m / z 357.2 (M+H)+(ES+); SFC 96.7% de; 'H NMR (400 MHz, DMSO- d6) 37.29 - 7.23 (m, 2H), 6.90 - 6.79 (m, 2H), 6.76 - 6.71 (m, 1H), 6.68 (d, J= 7.2 Hz, 0.5H), 6.44 (dd, J= 4.8, 7.6 Hz, 0.5H), 6.31 (dd, J= 4.8, 7.6 Hz, 0.5H), 6.07 (d, J= 7.2 Hz, 0.5H), 5.41 (d, J= 16.8 Hz, 2H), 5.20 - 5.01 (m, 1H), 4.69 - 4.44 (m, 2H), 4.05 - 3.85 (m, 1H), 3.80 - 3.59 (m, 5H), 3.52 - 3.35 (m, 2.5H), 3.29 - 3.04 (m, 2.5H), 2.26 - 2.01 (m, 2H).

[0491] To a solution of l-((3S,5R)-3-((2-aminopyridin-3-yl)amino)-5-methoxypiperidin-l-yl)-2-(3- methoxyphenyl)ethanone (80.0 mg, 0.216 mmol) in tetrahydrofuran (2 mb) was added CDI (175 mg, 1.08 mmol) at 25 °C. The mixture was stirred for 5 hours at 25 °C under nitrogen, concentrated in vacuum. The residue was purified by prep-HPLC to afford the title compound l-((3S,5R)-5-methoxy- l-(2-(3-methoxyphenyl)acetyl) piperidin-3-yl)-lH-imidazo[4,5-b]pyridin-2(3H)-one as a white solid (46.5 mg, 0.115 mmol, 53.5% yield), m / z 397.2 (M+H)+(ES+); SFC 100% de- 'H NMR (400 MHz, DMSO-t e) 3 11.60 (s, 1H), 7.92-7.90 (m, 1H), 7.71 (d, J= 7.6 Hz, 0.5H), 7.36 (d, J= 7.6 Hz, 0.5H), 7.26 (t, J = 8.4 Hz, 0.5H), 7.21(t, J= 8.0 Hz, 0.5H), 7.01-6.96 (m, 1H), 6.87-6.78 (m, 3H), 4.70 (dd, J = 4.0, 11.2 Hz, 0.5H), 4.39 (dd, J= 2.8, 11.2 Hz, 0.5H), 4.17-3.98 (m, 2H), 3.86-3.68 (m, 5H), 3.30 (s, 1H), 3.27-3.13 (m, 3H), 3.01-2.88 (m, 1H), 2.43 (t, J= 7.2 Hz, 1H), 2.28-1.98 (m, 2H). VT NMR (400 MHz, DMSO- e) <5 10.41 (br.s, 1H), 7.92-7.89 (m, 1H), 7.73-7.30 (m, 1H), 7.26-7.21 (m, 1H), 6.99- 6.95 (m, 1H), 6.90-6.81 (m, 3H), 4.57-4.09 (m, 3H), 3.75 (s, 5H), 3.28-3.17 (m, 1H), 3.04 (s, 4H), 2.27- 2.11 (m, 3H). l-((3S,5R)-5-methoxy-l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (Compound 92):

[0492] To a solution of tert-butyl ((3S,5R)-5-hydroxypiperidin-3-yl)carbamate (50.0 mg, 0.231 mmol) and sodium bicarbonate (29.1 mg, 0.346 mmol) in THF (2 mb) and water (1 mL) at 0 °C was added drop wise benzyl chloroformate (41.4 mg, 0.243 mmol). The resultant mixture was warmed to 25 °C and stirred for 3 hrs. The mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL x 3), the combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-TLC (Dichloromethane: Methanol = 10: 1) to afford (3S,5R)-benzyl 3-((tert-butoxycarbonyl)amino)-5-hydroxypiperidine-l-carboxylate as a white solid (70.0 mg, 86.4% yield), m / z 372.9 (M+Na)+(ES+); 'H NMR (400 MHz, CDC13) <5 7.63 - 7.29 (m, 5H), 5.83 (br s, 1H), 5.27 - 5.02 (m, 2H), 4.18 - 3.95 (m, 2H), 3.86 - 3.69 (m, 1H), 3.30 - 3.10 (m, 1H), 2.03 - 1.98 (m, 1H), 1.93 - 1.83 (m, 1H), 1.40 (s, 9H).

[0493] To a slurry of benzyl (3S,5R)-benzyl 3 -((tert-butoxycarbonyl)amino)-5 -hydroxypiperidine -1- carboxylate (280 mg, 0.799 mmol), silver oxide (370 mg, 1.60 mmol) in THF (5 mL) was added methyl iodide (226 mg, 1.60 mmol) at 0 °C. The mixture was then warmed to 25 °C and stirred for 16 hours, then heated to 60 °C and stirred for 24 hours. The mixture was filtered, and the filtrate was concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 5 : 1) to afford the title compound (3S,5R)-benzyl 3-((tert-butoxycarbonyl)amino)-5-methoxypiperidine-l-carboxylate as yellow oil (200 mg, 66.6% yield), m / z 265.2 (M-Boc+H)+(ES+); 'H NMR (400 MHz, CDCL) <5 7.43 - 7.28 (m, 5H), 5.71 (br s, 1H), 5.30 - 5.04 (m, 2H), 4.26 - 4.21 (m, 0.5H), 4.06 - 3.88 (m, 1H), 3.80 - 3.72 (m, 1H), 3.41 (s, 3H), 3.29 - 3.21 (m, 1H), 3.17 - 3.10 (m, 1H), 3.04 - 2.97 (m, 0.5H), 1.93 - 1.81 (m, 2H), 1.39 (s, 9H). To a solution of benzyl (3S,5R)-benzyl 3 -((tert-butoxycarbonyl)amino)-5 -methoxy piperidine-1- carboxylate (150 mg, 0.411 mmol) in tetrahydrofuran (10 mL) was added Pd / C (20.0 mg, 10% weight on activated charcoal) under nitrogen. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under hydrogen (15 psi) at 25 °C for 12 hours. The mixture was fdtered and concentrated in vacuum to afford the title compound tert-butyl ((3S,5R)-5- methoxypiperidin-3-yl)carbamate as a white solid (110 mg, crude). ‘H NMR (400 MHz, CDCh) <5 5.52 (br.s, 1H), 3.68 (s, 1H), 3.38 (s, 3H), 3.35-3.30 (m, 1H), 2.95-2.76 (m, 4H), 2.05-1.95 (m, 1H), 1.74- 1.70 (m, 1H), 1.45 (s, 9H).

[0494] To a solution of tert-butyl ((3S,5R)-5-methoxypiperidin-3-yl)carbamate (90.0 mg, 0.390 mmol), 2-(3- methoxyphenyl)acetic acid (68.2 mg, 0.410 mmol) and diisopropylethylamine (151.52 mg, 1.17 mmol, 3 eq.) in tetrahydrofuran (2 mL) was added T3P (273 mg, 0.429 mmol, 50% purity in ethyl acetate) at 25 °C. The resultant mixture was stirred for 1 hour at 25 °C, then poured into water (20 mL), extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum. The residue was purified by prep- TLC (Petroleum ether: Ethyl acetate = 1 : 1) to afford the title compound tert-butyl ((3S,5R)-5-methoxy- l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)carbamate as yellow oil (120 mg, 81.1% yield), m / z 379.3 (M+H)+(ES+); SFC 100% de; 'H NMR (400 MHz, DMSO-d6) <5 7.26-7.18 (m, 1H), 6.85-6.72 (m, 4H), 4.28-4.11 (m, 1H), 4.06-3.97 (m, 1H), 3.92-3.77 (m, 1H), 3.72 (s, 3H), 3.68-3.63 (m, 1H), 3.27 (s, 1H), 3.19-3.15 (m, 1H), 3.11 (s, 1H), 2.93-2.87 (m, 1H), 2.85-2.72 (m, 1H), 2.67-2.60 (m, 1H), 2.35- 2.29 (m, 1H), 2.12-2.02 (m, 1H), 1.38 (s, 9H).

[0495] A solution of tert-butyl ((3S,5R)-5-methoxy-l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)carbamate (100 mg, 0.264 mmol) in HCl / l,4-dioxane (2 mL) was stirred for 0.5 hour at 25 °C. The mixture was concentrated in vacuum to afford the title compound l-((3S,5R)-3-amino-5-methoxypiperidin-l-yl)-2- (3-methoxyphenyl)ethanone as a white solid (80.0 mg, crude), m / z 279.2 (M+H)+(ES+); SFC 100% de; 'H NMR (400 MHz, DMSO-d6) <5 8.06 (br.s, 3H), 7.25-7.21 (m, 1H), 6.82-6.80 (m, 3H), 4.29 (d, J = 10.4 Hz, 1H), 3.92-3.78 (m, 2H), 3.71 (s, 3H), 3.69-3.63 (m, 2H), 3.28 (s, 2H), 3.02-2.97 (m, 1H), 2.20-2.12 (m, 1H), 1.68-1.48 (m, 1H).

[0496] To a solution of l-((3S,5R)-3-amino-5-methoxypiperidin-l-yl)-2-(3-methoxyphenyl) ethanone (80.0 mg, 0.254 mmol) and diisopropylethylamine (742 mg, 5.74 mmol) in dimethylsulfoxide (0.5 mL) was added 3 -fluoro-2 -nitro-pyridine (39.7 mg, 0.279 mmol) at 25 °C. The mixture was stirred at 120 °C for 12 hours under nitrogen atmosphere. The mixture was cooled to 25 °C and poured into ice-water (30 mL), extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, fdtered and concentrated in vacuum. The residue was purified by prep-TLC (Ethyl acetate) to afford l-((3R,5S)-3-methoxy-5-((2-nitropyridin-3-yl)amino) piperidin-l-yl)-2-(3-methoxyphenyl)ethanone as yellow oil (100 mg, 97.9% yield), m / z 401.2 (M+H)+(ES+); SFC 100% de; 'H NMR (400 MHz, DMSO-d6) <5 8.49 (dd, J= 8.0, 18.4 Hz, 1H), 7.82-7.79 (m, 1H) ,7.69(d, J= 48.0 Hz, 0.5 H), 7.60 (q, J= 2.0, 8.8 Hz, 0.5H), 7.57-7.50 (m, 1H), 6.97 (t, J= 8.0 Hz, 0.5H), 6.76 (dd, J = 1.6, 8.0 Hz, 0.5H), 6.72-6.70 (m, 1H), 6.60(dd, J= 1.6, 8.0 Hz, 0.5H), 6.50-6.46 (m, 1H), 4.44 (d, J = 12.8 Hz, 0.5 H), 4.19 (d, J = 12.8 Hz, 0.5 H), 4.05-4.01 (m, 1H), 3.98-3.93 (m, 1H), 7.36-3.58 (m, 5H), 3.44-3.34 (m, 1H), 3.37-3.35 (m, 3H), 3.12-3.04 (m, 1H), 2.13-2.10 (m, 0.5H), 2.10-2.06 (m,lH), 1.99-1.97 (m, 0.5H).

[0497] To a solution of l-((3R,5S)-3-methoxy-5-((2-nitropyridin-3-yl)amino)piperidin-l-yl) -2-(3- methoxyphenyl)ethanone (100 mg, 0.249 mmol) in methanol (2 mL) was added Pd / C (10.0 mg, 10% weight on activated charcoal) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25 °C for 14 hours. The mixture was fdtered through celite and the fdtrate was concentrated in vacuum to afford the title compound l-((3S,5R)-3-((2-aminopyridin-3-yl)amino)-5-methoxypiperidin-l-yl)-2-(3- methoxyphenyl)ethanone as yellow oil (80.0 mg, 83.3% yield), m / z 371.2 (M+H)+(ES+); SFC 100% de; 'H NMR (400 MHz, DMSO-d6) <5 (7.30-7.22 (m, 2H), 6.86-6.81 (m, 2H), 6.73-6.68 (m, 1.5H), 6.46 (dd, J= 5.2, 7.6 Hz, 0.5H), 6.33 (dd, J= 4.8, 7.6 Hz, 0.5H), 6.11 (d, J= 7.2 Hz, 0.5H), 5.44 (s, 1H), 5.37 (s, 1H), 4.67-4.53 (m, 2H), 4.19-4.11 (m, 0.5H), 3.89-3.84 (m, 0.5H), 3.78-3.77 (m, 0.5H), 3.72 (d, J= 10.8 Hz, 3H), 3.70-3.69 (m, 0.5H), 3.62-3.58 (m, 2H), 3.21-3.10 (m, 0.5H), 3.09-2.93 (m, 0.5H), 2.71-2.66 (m, 1H), 2.33-2.19 (m, 2H), 1.77-1.72 (m, 3H).

[0498] To a solution of l-((3S,5R)-3-((2-aminopyridin-3-yl)amino)-5-methoxypiperidin-l-yl) -2-(3- methoxyphenyl)ethanone (80.0 mg, 0.216 mmol) in tetrahydrofuran (2 mL) was added CDI (175 mg, 1.08 mmol) at 25 °C. The mixture was stirred for 5 hours at 25 °C under nitrogen, concentrated in vacuum. The residue was purified by prep-HPLC to afford the title compound l-((3S,5R)-5-methoxy- l-(2-(3-methoxyphenyl)acetyl) piperidin-3-yl)-lH-imidazo[4,5-b]pyridin-2(3H)-one as a white solid (46.5 mg, 0.115 mmol, 53.5% yield), m / z 397.2 (M+H)+(ES+); SFC 100% de; 'H NMR (400 MHz, DMSO-t e) <5 11.60 (s, 1H), 7.92-7.90 (m, 1H), 7.71 (d, J= 7.6 Hz, 0.5H), 7.36 (d, J = 7.6 Hz, 0.5H), 7.26 (t, J = 8.4 Hz, 0.5H), 7.21(t, J= 8.0 Hz, 0.5H), 7.01-6.96 (m, 1H), 6.87-6.78 (m, 3H), 4.70 (dd, J = 4.0, 11.2 Hz, 0.5H), 4.39 (dd, J= 2.8, 11.2 Hz, 0.5H), 4.17-3.98 (m, 2H), 3.86-3.68 (m, 5H), 3.30 (s, 1H), 3.27-3.13 (m, 3H), 3.01-2.88 (m, 1H), 2.43 (t, J= 7.2 Hz, 1H), 2.28-1.98 (m, 2H). VT NMR (400 MHz, DMSO-t e) <5 10.41 (br.s, 1H), 7.92-7.89 (m, 1H), 7.73-7.30 (m, 1H), 7.26-7.21 (m, 1H), 6.99- 6.95 (m, 1H), 6.90-6.81 (m, 3H), 4.57-4.09 (m, 3H), 3.75 (s, 5H), 3.28-3.17 (m, 1H), 3.04 (s, 4H), 2.27- 2.11 (m, 3H). l-((3S,4R)-l-(2-(3-methoxyphenyl)acetyl)-4-methylpiperidin-3-yl)-l,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one and l-((3R,4S)-l-(2-(3-methoxyphenyl)acetyl)-4-methylpiperidin-3-yl)-l,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (Compounds 93 and 94):

[0499] (R)-tert-butyl 4-(methoxy(methyl)carbamoyl)-2,2-dimethyloxazolidine-3-carboxylate

[0500] To a suspension of N,O-dimethylhydroxylamine hydrochloride (9.40 g, 96.4 mmol) in tetrahydrofuran (100 mL) was added isopropylmagnesium chloride (2 M, 96.4 mL, 193 mmol) at -78 °C under nitrogen. After stirring for 10 minutes, a solution of (R) -3 -tert-butyl 4-methyl 2,2-dimethyloxazolidine-3,4- dicarboxylate (10.0 g, 38.6 mmol) in tetrahydrofuran (30 mL) was dropped into it. The resultant mixture was stirred for 2 hours at -78 °C, then poured into a saturated aqueous solution of ammonium chloride (500 mL), extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiCL, Petroleum ether: Ethyl acetate= 10: 1 to 5: 1) to afford the title compound tert-butyl (4R)-4-[methoxy(methyl)carbamoyl]-2,2-dimethyl- oxazolidine-3- carboxylate (10.0 g, 87.2% yield) as yellow oil. m / z 311.3 (M+Na)+(ES+); SFC 100% de,1H NMR (400 MHz, CDCh) <5 4.82-4.71 (m, 1H), 4.22-4.15 (m, 1H), 3.99-3.91 (m, 1H), 3.75 (s, 1.5H), 3.70 (s, 1.5H), 3.21(s, 3H), 1.71(s, 1.5H), 1.68 (s, 1.5H), 1.57 (s, 1.5H), 1.52 (s, 1.5H), 1.50 (s, 4.5H), 1.41 (s, 4.5H).

[0501] (R)-tert-butyl 4-acetyl-2,2-dimethyloxazolidine-3-carboxylate

[0502] To a solution of (R)-tert-butyl 4-(methoxy(methyl)carbamoyl)-2,2-dimethyloxazolidine-3- carboxylate (10.0 g, 34.7 mmol) in tetrahydrofuran (100 mL) was added methylmagnesium bromide (3 M, 23.12 mL) at -78 °C under nitrogen atmosphere. The resultant mixture was stirred for 1 hour at -78 °C, then warmed to 25 °C for 12 hours. The mixture was quenched with an aqueous saturated solution of ammonium chloride (200 mL), extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (80 mL x 3), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum. The residue was purified by column chromatography (SiCL, Petroleum ether: Ethyl acetate = 10: 1 to 5: 1) to afford (R) -tert-butyl 4-acetyl-2,2-dimethyloxazolidine-3-carboxylate as yellow oil (6.00 g, 71.1% yield). 'H NMR (400 MHz, CDC13): <5 4.50-4.25 (m, 1H), 4.18-4.12 (m ,1H), 3.99-3.92 (m, 1H), 2.20 (s, 3H), 1.71+1.65 (s+s, 3H, retainers), 1.56+1.53 (s+s, 3H, retainers), 1.51+1.42 (s+s, 9H, retainers).

[0503] (S)-tert-butyl 2,2-dimethyl-4-(prop-l-en-2-yl)oxazolidine-3-carboxylate

[0504] To a suspension of (R)-tert-butyl 4-acetyl-2,2-dimethyloxazolidine-3-carboxylate (6.00 g, 24.7 mmol) and methyltriphenylphosphonium iodide (19.9 g, 49.3 mmol) in tetrahydrofuran (100 mL) was added dropwise potassium tert-butoxide (1 M in THF, 49.32 mL) at 0 C under nitrogen atmosphere. The icebath was moved, and the resultant mixture was warmed to 25 C with water bath and stirred for 20 min, then poured into brine (100 mL), extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum.The residue was purified by column chromatography (SiCL, Petroleum ether: Ethyl acetate = 10: 1 to 5: 1) to afford the title compound (S)-tert-butyl 2,2-dimethyl-4-(prop-l-en-2-yl)oxazolidine-3- carboxylate as yellow oil (5.20 g, 78.6% yield). ’H NMR (400 MHz, CDCL): <5 4.91 (s, 1H), 4.85 (s, 1H), 4.37-4.24 (m, 1H), 4.07 (dd, J= 12, 8.8 Hz, 1H), 3.75 (dd, J= 2.8, 8.8 Hz, 1H), 1.73 (s, 3H), 1.61 (s, 3H), 1.51 (s, 3H), 1.49 +1.41 (s+s,9H, retainers).

[0505] (S)-tert-butyl (l-hydroxy-3-methylbut-3-en-2-yl)carbamate

[0506] To a solution of (S)-tert-butyl 2,2-dimethyl-4-(prop-l-en-2-yl)oxazolidine-3 -carboxylate (5.00 g, 20.7 mmol) and toluene-4-sulfonic acid (393 mg, 2.28 mmol) in methanol (100 mL) was stirred for 12 hours at 70 C. After cooling to 25C, triethylamine (1.05 g, 10.36 mmol) and BOC2O (2.26 g, 10.4 mmol) were added into it. The resultant mixture was stirred for 2 hours at 25 C then concentrated in vacuum. The residue was purified by column chromatography (SiCL, Petroleum ether: Ethyl acetate = 10: 1 to 3: 1) to afford (S)-tert-butyl (1 -hydroxy-3 -methylbut-3-en-2-yl) carbamate as a white solid (4.00 g, 91.1% yield), m / z 224.2 (M+H)+(ES+); 'H NMR (400 MHz, CDCL) <5 5.00 (br.s, 1H), 4.97 (d, J= 15.6 Hz, 2H), 4.14-4.10 (m, 1H), 3.71 (d, J = 4.8 Hz, 2H), 1.80 (s, 3H), 1.46 (s, 9H).

[0507] (S)-2-((tert-butoxycarbonyl)amino)-3-methylbut-3-en-l-yl methanesulfonate

[0508] To a solution of (S)-tert-butyl (1 -hydroxy-3 -methylbut-3-en-2-yl)carbamate (4.00 g, 19.9 mmol) and triethylamine (4.02 g, 39.8 mmol) in dichloromethane (50 mL) at 0 C was added methane sulfonyl chloride (4.89 g, 42.7 mmol) under nitrogen. The mixture was stirred for 1 hour at 25 C, then poured into water (50 mL), extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with brine (20 mL*3), dried with anhydrous sodium sulfate, fdtered and concentrated in vacuum. The residue was purified by column chromatography (SiC>2, Petroleum ether: Ethyl acetate = 5: 1 to 1: 1) to afford (S)-2-((tert-butoxycarbonyl)amino)-3-methylbut-3-en-l-yl methanesulfonate as yellow oil (4.00 g, 72.1% yield).1!! NMR (400 MHz, CDC13): <5 5.01 (d, J= 12.8 Hz, 2H), 4.90 (br.s, 1H), 4.33-4.10 (m, 3H), 3.04 (s, 3H), 1.81 (s, 3H), 1.27 (s, 9H).

[0509] (S)-tert-butyl (l-(allylamino)-3-methylbut-3-en-2-yl)carbamate

[0510] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-methylbut-3-en-l-yl methane sulfonate (4.00g, 14.3 mmol) in prop-2-en-l -amine (66 mL) was stirred for 12 hours at 60 C under nitrogen. The mixture was concentrated in vacuum, the residue was poured into ice-water (100 mL), extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to afford the crude product (S) -tert-butyl (l-(allylamino)-3-methylbut-3-en-2-yl)carbamate (3.00 g, crude) as yellow oil, which was used for the next step without further purification. ’H NMR (400 MHz, CDCL): <5 5.89-5.78 (m, 1H), 5.15-5.03 (m, 2H), 4.92 (s, 2H), 3.88-3.81 (m, 1H), 3.62-3.53 (m, 1H), 3.25-3.23 (m, 2H), 3.14-3.10 (m, 1H), 1.75 (s, 3H), 1.44 (s, 9H).

[0511] (S)-tert-butyl (l-(N-allyl-2,2,2-trifluoroacetamido)-3-methylbut-3-en-2-yl)carbamate

[0512] To a solution of (S)-tert-butyl (l-(allylamino)-3-methylbut-3-en-2-yl)carbamate (3.00 g, 12.48 mmol) and triethylamine (6.32 g, 62.41 mmol) in dichloromethane (30 mL) was added trifluoroacetic anhydride (7.86 g, 37.5 mmol) at 25 C. The resultant mixture was stirred for 0.5 hours at 25 C then poured into a saturated aqueous solution of sodium bicarbonate (80 mL), extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiC>2, Petroleum ether: Ethyl acetate = 10: 1 to 5: 1) to afford (S) -tert-butyl ( l-(N-allyl -2,2,2- trifluoroacetamido)-3-methylbut -3-en-2-yl)carbamate as yellow oil (2.50 g, 52.7% yield), m / z 281.2 (M-tBu+H)+(ES+); 'H NMR (400 MHz, CDC13) <5 5.78-5.69 (m, 1 H), 5.33-5.19 (m, 3 H), 5.11 (s, 1 H), 4.92 (s, 1 H), 4.19-4.14 (m, 1 H), 3.96-3.79 (m, 2 H) ,1.75 (s, 3 H), 1.52 (s, 9 H).19F NMR (400 MHz, CDCh): <5 -69.327 ppm

[0513] (S)-tert-butyl(4-methyl-l-(2,2,2-trifluoroacetyl)-l,2,3,6-tetrahydropyridin-3-yl)carbamate

[0514] To a solution of (S)-tert-butyl (l-(N-allyl-2,2,2-trifluoroacetamido)-3-methylbut-3-en-2-yl) carbamate (1.50 g, 4.46 mmol) in dichloromethane (200 mL) was added Grubb’s II (367 mg, 0.445 mmol) at 25 C. The mixture was then heated to 40 C and stirred for 12 hours under nitrogen. The mixture was concentrated in vacuum. The residue was purified by column chromatography (Si O2- Petroleum ether: Ethyl acetate = 10: 1 to 5: 1) to afford (S)-tert-butyl (4-methyl-l-(2,2,2-trifluoroacetyl)-l,2,3,6- tetrahydropyridin-3-yl)carbamate as ayellow solid (1.20 g, 84.6% yield), m / z 209.2 (M-tBu+H)+(ES+); 'H NMR (400 MHz, CDCh) <5 5.61-5.52 (m, 1H), 4.57-453 (m, 2H), 4.18-4.15 (m, 1H), 4.12-3.91 (m, 1H), 3.62 (d,J= 18.8 Hz, 1H), 3.34 (dd, J= 2.8, 13.6 Hz, 1H), 1.81(d, J = 1.6 Hz, 3H), 1.45 (s, 9H).19F NMR (400 MHz, CDCh): <5 -68.066 ppm tert-butyl ((3S,4R)-4-methyl-l-(2,2,2-trifluoroacetyl)piperidin-3-yl)carbamate and tert-butyl ((3S,4S)-4-methyl-l-(2,2,2-trifluoroacetyl) piperidin-3-yl) carbamate. To a solution of (S)-tert-butyl (4-methyl-l-(2,2,2-trifluoroacetyl)-l,2,3,6-tetrahydropyridin-3-yl)carbamate (0.700 g, 2.27 mmol) in methanol (30 mL) was added Pd / C (150 mg, 10% weight on activated charcoal) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25 °C for 12 hours, then filtered and the filtrate was concentrated in vacuum. The residue was purified by prep-TLC (SiC>2, Petroleum ether: Ethyl acetate=5: 1, Separation of three times) to afford Tert-butyl ((3 S,4R)-4-methyl- 1 -(2,2,2-trifluoroacetyl)piperidin-3-yl)carbamate (0.400 g, 1.27 mmol, 55.7% yield) as a white solid and Tert-butyl ((3S,4S)-4-methyl-l-(2,2,2- trifluoroacetyl) piperidin-3-yl) carbamate (0.300 g, 0.967 mmol, 42.6% yield) as yellow oil.

[0515] Trans isomer: m / z 211.1 (M-Boc+H)+(ES+); SFC: 100% de; 'H NMR (400 MHz, CDCh) <5 4.53- 4.26(m, 2H), 4.05-3.83 (m, 1H), 3.32-3.11 (m, 1H), 3.02(t, J= 12.4 Hz, 1H), 2.86-2.55 (m, 1H), 1.81- 1.75 (m, 2H), 1.38 (s, 9H), 1.32-1.18 (m, 1H), 0.99-0.97 (m, 3H);19F NMR (400 MHz, CDCh): <5 - 68.942 ppm.

[0516] Cis isomer: m / z 211.1 (M-Boc+H)+(ES+); 'H NMR (400 MHz, CDCh) <5 6.23 (br. s, 1H), 4.28-4.16 (m, 1H), 4.04-3.98 (m,lH), 3.92-3.77 (m, 3H), 3.58-3.69 (m, 1H), 3.38-3.24 (m, 1H), 2.05-2.01 (m, 1H), 1.77 (s, 3H), 0.95 (d, J= 6.8 Hz, 3H). l-((3S,4R)-3-amino-4-methylpiperidin-l-yl)-2,2,2-trifluoroethanone hydrochloride

[0517] A solution of tert-butyl ((3S,4R)-4-methyl-l-(2,2,2-trifluoroacetyl)piperidin-3-yl)carbamate (0.400 g, 1.29 mmol) in HCl / l,4-dioxane (5 mL) was stirred for 30 min at 25 C. The mixture was concentrated in vacuum to afford l-((3S,4R)-3-amino-4-methylpiperidin-l-yl) -2,2,2-trifluoroethanone hydrochloride (0.300 g, crude) as a white solid, m / z 211.2 (M+H)+(ES+); ’H NMR (400 MHz, DMSO- d6) <5 8.30 (br.s, 2H), 4.47(d, J = 10.4 Hz, 1H), 4.13(d, J= 13.2 Hz, 1H), 3.77 (d,J= 14.8 Hz, 1H), 3.34- 3.20 (m, 1H), 2.98-2.87 (m, 2H), 1.86-1.82 (m, 1H), 1.32-1.26(m, 1H), 1.02 (d, J = 6.4 Hz, 3H).19F NMR (400 MHz, DMSO-d6): <5 -68.096 ppm.

[0518] 2,2,2-trifluoro-l-((3S,4R)-4-methyl-3-((2-nitropyridin-3-yl)amino)piperidin-l-yl)ethanone

[0519] To a solution of l-((3S,4R)-3-amino-4-methylpiperidin-l-yl)-2,2,2-trifluoroethanone hydrochloride (0.300 g, 1.22 mmol) in diisopropylethylamine (6 mL) and dimethylsulfoxide (3 mL) was added 3- fluoro-2-nitro-pyridine (190 mg, 1.34 mmol) at 25 C. The mixture was heated to 120 C and stirred for 12 hours under nitrogen, then poured into ice-water (30 mL), extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with 0.5 M HC1 (20 mL), followed by a saturated aqueous solution of sodium bicarbonate (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum. The residue was purified by column chromatography (SiCL, Petroleum ether: Ethyl acetate = 10: 1 to 3: 1) to afford 2,2,2-trifluoro-l-((3S,4R)-4-methyl-3-((2- nitropyridin-3-yl)amino) piperidin-l-yl)ethanone (0.400 g, 95.6%yield) as a yellow oil. m / z 333.2 (M+H)+(ES+); SFC: 0.2% de; 'H NMR (400 MHz, CDC13) d 7.99-7.96 (m, 1H), 7.78-7.63 (m, 1H), 7.56-7.48 (m, 2H), 4.79-4.57 (m, 1H), 4.32-4.01 (m, 1H), 3.30-3.17 (m, 2H), 3.00-2.86 (m, 1H), 2.62- 2.51 (m, 1H), 1.92-1.87 (m, 1H), 1.52-1.44 (m, 1H), 1.15-1.10 (m, 3H).19F NMR (400 MHz, CDCh): <5 -68.771 ppm; l-((3S,4R)-3-((2-aminopyridin-3-yl)amino)-4-methylpiperidin-l-yl)-2,2,2-trifluoroethanone

[0520] To a solution of 2,2,2-trifhioro-l-((3S,4R)-4-methyl-3-((2-nitropyridin-3-yl)amino) piperidin-1- yl)ethanone (0.400 g, 1.20 mmol) in methanol (5 mL) was added Pd / C (40.0 mg, 10% weight on activated charcoal) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25 C for 2 hours, then fdtered and concentrated in vacuum to afford l-((3S,4R)-3-((2-aminopyridin-3-yl)amino)-4- methylpiperidin-l-yl)-2,2,2-trifluoroethanone (310 mg, crude) as yellow oil. m / z 303.2 (M+H)+(ES+); 'H NMR (400 MHz, DMSO-d6) <57.32 (dd, J= 1.2, 4.8 Hz, 1H), 6.74-6.65 (m, 1H), 6.49-6.45 (m, 1H), 5.30 (br.s, 2H), 4.45 (dd, J= 8.4 Hz, 1H), 4.43-4.24 (m, 1H), 3.93-3.85 (m, 1H), 3.31-3.10 (m, 1H), 2.98-2.93 (m, 1H), 1.98-1.90 (m, 1H), 1.84- 1.77 (m, 1H), 1.98-1.30 (m, 1H), 1.03 (d, J= 6.4 Hz, 3H); VT NMR (400 MHz, DMSO-d6): <5 7.32 (dd, J= 1.2, 4.8 Hz, 1H), 6.34-6.65 (m, 1H), 6.49-6.45 (m, 1H), 5.30 (br.s, 2H), 4.45 (d, J= 8.4 Hz, 1H), 4.29-4.25 (m ,1H), 3.94-3.85 (m, 1H), 3.31-3.20 (m, 1H), 3.04-2.92 (m, 1H), 1.99-1.90 (m, 1H), 1.82-1.76 (m, 1H), 1.39-1.29 (m, 1H), 1.04 (d, J= 6.4 Hz, 3H).19F NMR (400 MHz, CDCh): d -68.826 ppm; l-((3S,4R)-4-methyl-l-(2,2,2-trifluoroacetyl)piperidin-3-yl)-l,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one

[0521] To a solution of l-((3S,4R)-3-((2-aminopyridin-3-yl)amino)-4-methylpiperidin-l-yl)-2,2,2- trifluoroethanone (0.300 g, 0.992 mmol) in tetrahydrofuran (5 mL) was added CDI (804 mg, 4.96 mmol) at 25 C. The mixture was stirred at 25 C for 12 hours then poured into water (30 mL), extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum. The residue was purified by column chromatography (SiCL, Petroleum ether: Ethyl acetate = 10: 1 to 5: 1) to afford l-((3S,4R)-4-methyl-l- (2,2,2-trifluoroacetyl)piperidin-3-yl)-lH-imidazo[4,5-b]pyridin-2(3H)-one (0.300 g, 88.6% yield) as yellow oil. m / z 329.1 (M+H)+(ES+); SFC: 0.83% de; 'H NMR (400 MHz, DMSO-d6): <5 11.61 (br.s, 1H), 7.94-7.92 (m, 1H), 7.74-7.60 (m, 1H), 7.08-7.00 (m, 1H), 4.37- 4.28 (m, 1H), 4.00-3.83 (m, 2.5H), 3.56-3.41 (m,lH), 3.08-3.04 (m, 0.5 H), 2.61-2.51 (m, 1H), 1.98-1.89 (m, 1H), 1.45-1.33 (m, 1H), 0.73 (d, J= 6.4 Hz, 3H); VT NMR (400 MHz, DMSO-d6): <5 11.43 (br.s, 1H), 7.93 (dd, J= 1.2, 4.8 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.00 (dd, J = 5.2, 7.6 Hz, 1H), 4.40-4.32 (m, 2H), 3.96-3.85 (m, 2H), 3.55- 3.42 (m, 1H), 2.67-2.52 (m, 2H), 1.99-1.94 (m, 1H), 1.46-1.14 (m, 1H), 0.77 (d, J= 6.4 Hz, 3H). l-((3S,4R)-4-methylpiperidin-3-yl)-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0522] To a solution of l-((3S,4R)-4-methyl-l-(2,2,2-trifluoroacetyl)piperidin-3-yl)-lH-imidazo[4,5- b]pyridin-2(3H)-one (0.300 g, 0.913 mmol) in methanol (5 mL) and water (1 mL) was added potassium carbonate (6.31 mg, 0.457 mmol) at 25 C. The mixture was stirred for 2 hours at 25 C, then concentrated in vacuum. The residue was purified by reversed-phase HPLC (0.1% NHMTO) to afford 1-((3S,4R)- 4-methylpiperidin-3-yl) -lH-imidazo[4,5-b]pyridin-2(3H)-one (0.200 g, 91.3% yield) as yellow oil. m / z 233.2 (M+H)+(ES+); SFC: 0.74% de; 'H NMR (400 MHz, DMSO-d6): <58.57 (s, 1H), 7.62-7.52(m, 1H), 6.94 (br.s, 1H), 6.41-6.34 (m, 1H), 4.11 (d, J= 12.0 Hz, 1H), 3.96 (dd,J= 3.2, 11.6 Hz, 1H), 3.85- 3.73 (m, 1H), 2.96-2.82 (m, 1H), 2.71-2.51 (m, 1H), 2.27-2.21 (m, 1H), 1.75-1.59 (m, 1H), 1.33-1.07 (m, 1H), 0.62-0.59 (m, 3H).VT NMR (400 MHz, DMSO-d6): <5 8.63 (s, 1H), 7.54 (d, J= 4.0 Hz, 1H), 6.8-6.86 (m, 1H), 6.34 (dd, J = 5.2, 6.8 Hz, 1H), 4.18-4.13 (m, 1H), 4.04-4.01 (m, 1H), 4.00-3.70 (m, 1H), 3.19-3.01 (m, 1H), 2.57-2.51 (m, 1H), 2.49-2.29 (m, 1H), 1.73-1.61 (m, 1H), 1.18-1.15 (m, 1H), 0.65 (d, J = 5.4 Hz, 3H). l-((3S,4R)-l-(2-(3-methoxyphenyl)acetyl)-4-methylpiperidin-3-yl)-l,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one

[0523] To a solution of l-((3S,4R)-4-methylpiperidin-3-yl)-lH-imidazo[4,5-b]pyridin-2(3H)-one (180 mg, 0.774 mmol) and diisopropylethylamine (300 mg, 2.32 mmol) and 2-(3-methoxyphenyl)acetic acid (135 mg, 0.813 mmol) in dimethyl formamide (2 mL) was added T3P (493.13 mg, 0.775 mmol, 50% purity in ethyl acetate) at 25 °C. The mixture was stirred for 1 hour at 25 °C then concentrated in vacuum. The residue was purified by prep-HPLC to afford the racemate as a white solid, which was separated by prep-SFC to afford the two single isomers.

[0524] Isomer in peak 1: (26.3 mg, 17.8% yield) as a white solid, m / z 381.2 (M+H)+(ES+); SFC: 100% de; 'H NMR (400 MHz, DMSO-d6): d 11.62 (br.s, 1H), 7.91 (t, J= 4.0 Hz, 1H), 7.69-7.31 (m, 1H), 7.26- 7.18 (m, 1H), 7.00-6.94 (m, 1H), 6.84-6.77 (m, 3H), 4.49-4.39 (m, 1H), 4.02 (t, J= 14.0 Hz, 1H), 3.78- 3.61 (m, 7H), 3.17 (t, J = 12.0 Hz, 1H), 2.49-2.3 3(m, 1H), 1.79 (t,J= 11.2 Hz, 1H), 1.23-1.11 (m, 1H), 0.68 (t, J = 6.8 Hz, 3H).

[0525] Isomer in peak 2: (25.7 mg, 17.1% yield,) as a white solid, m / z 381.2 (M+H)+(ES+); SFC: 100% de; 'H NMR (400 MHz, DMSO-d6): d 11.62 (br.s, 1H), 7.91 (t, J= 4.0 Hz, 1H), 7.69-7.31 (m, 1H), 7.26- 7.18 (m, 1H), 7.00-6.94 (m, 1H), 6.84-6.77 (m, 3H), 4.49-4.39 (m, 1H), 4.02 (t, J= 14.0 Hz, 1H), 3.78- 3.61 (m, 7H), 3.17 (t,J= 12.0 Hz, 1H), 2.49-2.33 (m, 1H), 1.79 (t,J= 11.2 Hz, 1H), 1.23-1.11 (m, 1H), 0.68 (t, J= 6.8 Hz, 3H). l-((3S,4S)-l-(2-(3-methoxyphenyl)acetyl)-4-methylpiperidin-3-yl)-l,3-dihydro-2H-imidazo[4,5- b] pyridin-2-one and 1 -((3R,4R)- l-(2-(3-methoxyphenyl)acetyl)-4-methylpiperidin-3-yl)- 1 ,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (Compounds 95 and 96): l-((3S,4S)-3-amino-4-methylpiperidin-l-yl)-2,2,2-trifluoroethan-l-one. A solution of tert-butyl ((3S,4S)-4-methyl-l-(2,2,2-trifluoroacetyl) piperidin-3-yl) carbamate (0.300 g, 0.967 mmol) in HCl / l,4-dioxane (5 mL) was stirred for 1 hour at 25 C. The mixture was concentrated in vacuum to afford l-((3S,4S)-3-amino- 4-methylpiperidin-l-yl)-2,2,2-trifluoroethanone hydrochloride (240 mg, crude) as a white solid, m / z 211.2 (M+H)+(ES+); SFC: 12.78% de; 'H NMR (400 MHz, DMSO-d6): <5 8.19 (br. s, 3H), 4.32-4.27 (m, 1H), 4.09-3.69 (m, 3H), 3.49-3.45 (m, 1H), 2.14-2.12 (m, 1H), 1.90-1.85 (m, 1H), 1.06-0.98 (m, 3H).19F NMR (400 MHz, DMSO-d6): <5 -67.708 ppm.

[0526] 2,2,2-trifluoro-l-((3S,4S)-4-methyl-3-((2-nitropyridin-3-yl)amino)piperidin-l-yl)ethanone

[0527] To a solution of l-((3S,4S)-3-amino-4-methylpiperidin-l-yl)-2,2,2-trifluoroethanone hydrochloride (205 mg, 973 umol) in diisopropylethylamine (3 mL) and dimethylsulfoxide (1.5 mL) was added 3- fluoro-2-nitro-pyridine (152 mg, 1.07 mmol) at 25 C. The mixture was heated to 120 C and stirred for 12 hours under nitrogen, then cooled to 25 C, and poured into water (20 mL), extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiCL, Petroleum ether: Ethyl acetate = 1: 1) to afford 2,2,2-trifhioro-l-((3S,4S)-4-methyl-3-((2-nitropyridin- 3-yl) amino)piperidin-l-yl)ethanone (110 mg, 32.2% yield) as yellow oil. m / z 333.1 (M+H)+(ES+); SFC: 3.0% de; 'H NMR (400 MHz, DMSO-d6): <5 7.89-7.83 (m, 2H), 7.69-7.60 (m, 2H), 4.31-4.26 (m, 1H), 4.26-4.14 (m, 1H), 3.86 (d, J= 14.8 Hz,lH), 3.55-3.50 (m, 0.5H), 3.44-3.37 (m, 0.5 H), 3.22 (d, J = 12.8 Hz, 0.5H), 3.10-3.03 (m, 0.5H), 2.24-2.19 (m, 1H), 1.82-1.74 (m, 1H), 1.45-1.15 (m, 1H), 0.96- 0.93 (m, 3H). l-((3S,4S)-3-((2-aminopyridin-3-yl)amino)-4-methylpiperidin-l-yl)-2,2,2-trifluoroethanone

[0528] To a solution of 2,2,2-trifhioro-l-((3S,4S)-4-methyl-3-((2-nitropyridin-3-yl)amino) piperidin-1- yl)ethanone (100 mg, 301 umol) in methanol (2 mL) was added Pd / C (10.0 mg, 10% weight on activated charcoal) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25 C for 3 hours then filtered and the filtrate was concentrated to afford l-((3S,4S)-3-((2-aminopyridin-3-yl)amino)-4-methylpiperidin-l-yl)- 2,2,2-trifhroroethanone (90.0 mg, 87.4% yield) as yellow oil. m / z 303.2 (M+H)+(ES+); SFC: 3.1% de; 'H NMR (400 MHz, DMSO-d6): <5 7.28 (dd, J= 4.0, 10.8 Hz, 1H), 6.70 (t, J= 6.0 Hz, 1H), 5.63 (d, J = 12.8 Hz, 2H), 4.20 (d, J= 9.2 Hz, 0.5H), 4.15-4.11 (m, 1H), 4.00-3.93 (m, 0.5H), 3.79-3.69 (m, 1H), 3.61-3.58 (m, 1H), 3.23-2.99 (m, 1H), 2.33-2.06 (m, 1H), 1.84-1.75 (m, 1H), 1.74-1.52 (m, 1H), 0.93 (dd, J= 6.8, 18.0 Hz, 3H). l-((3S,4S)-4-methyl-l-(2,2,2-trifluoroacetyl)piperidin-3-yl)-lH-imidazo[4,5-b]pyridin-2(3H)-one

[0529] To a solution of l-((3S,4S)-3-((2-aminopyridin-3-yl)amino)-4-methylpiperidin-l-yl) -2,2,2- trifluoroethanone (90.0 mg, 297 umol) in tetrahydrofuran (2 mL) was added CDI (241 mg, 1.49 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 hours then concentrated in vacuum. The residue was purified by prep-TLC (SiCE, Petroleum ether: Ethyl acetate = 1: 1) to afford l-[(3S,4S)-4-methyl-l- (2,2,2-trifluoroacetyl)-3-piperidyl]-3H-imidazo[4,5-b] pyridine-2-one (90.0 mg, 91.0% yield) as yellow oil. m / z 329.1 (M+H)+(ES+); SFC: 0.38% de; 'H NMR (400 MHz, DMSO-d6): d 8.07 (s, 1H), 7.29(s, 1H), 7.11 (s, 1H), 4.75-4.48 (m, 1H), 4.35-4.31 (m, 2H), 4.14-4.10 (m, 0.5 H), 3.86-3.82 (m, 1H), 3.64- 3.57 (m, 1H), 3.40-3.33 (m, 0.5 H), 2.64-2.52 (m, 1H), 2.01-1.85 (m, 1H), 1.20-1.10 (m, 3H). l-((3S,4S)-4-methylpiperidin-3-yl)-lH-imidazo[4,5-b]pyridin-2(3H)-one

[0530] To a solution of l-((3S,4S)-4-methyl-l-(2,2,2-trifluoroacetyl)piperidin-3-yl)-lH-imidazo [4,5- b]pyridin-2(3H)-one (70.0 mg, 21 umol) in methanol (1 mL) and water (0.2 mL) was added potassium carbonate (2.95 mg, 21.3 umol) at 25 C. The mixture was stirred for 2 hours at 25 C then concentrated in vacuum. The residue was triturated with a solution of dichloromethane / methanol (v / v= 20 / 1, 50 mL), fdtered and the fdtrate was concentrated in vacuum to afford l-((3S,4S)-4-methylpiperidin-3-yl)-lH- imidazo[4,5-b]pyridin-2(3H)-one (50.0 mg, crude) as a yellow oil. m / z 233.0 (M+H)+(ES+); ’H NMR (400 MHz, DMSO- e): <5 7.83-7.75 (m, 2H), 6.87 (q, J= 2.4 Hz, 1H), 4.38-4.34 (m, 1H), 3.48 (q, J = 4.0 Hz,lH), 2.90-2.8 5(m, 2H), 2.67-3.65 (m, 1H), 2.21-2.13 (m, 1H), 1.67-.62 (m, 1H). l-((3S,4S)-l-(2-(3-methoxyphenyl)acetyl)-4-methylpiperidin-3-yl)-l,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one

[0531] To a solution of l-((3S,4S)-4-methylpiperidin-3-yl)-lH-imidazo[4,5-b]pyridin-2(3H)-one (50.0 mg, 215 umol) and 2-(3-methoxyphenyl)acetic acid (42.9 mg, 258 nmol) and diisopropylethylamine (83.5 mg, 645 umol) in tetrahydrofuran (2 mL) was added T3P (137 mg, 215 umol, 50% purity in Ethyl acetate) at 0 C. The mixture was stirred for 12 hours at 25 C then concentrated in vacuum. The residue was purified by prep-HPLC to afford the racemate as a white solid, which was separated by prep-SFC to afford two single isomers.

[0532] Isomer in peak 1: (14.3 mg, 17. 1% yield) as a white solid, m / z 381.2 (M+H)+(ES+); SFC: 100% de; 'H NMR (400 MHz, DMSO-d6): <5 11.55(br.s, 1H), 7.89 (d, J= 4.8 Hz, 1H), 7.53 (d, J= 7.6 Hz, 0.5H), 7.33 (d, J=8.0 Hz, 0.5 H), 7.24 (t, J = 8.4 Hz, 0.5H), 7.15 (t, J= 8.0 Hz, 0.5H), 6.97-6.92 (m, 1H) , 6.84- 6.70 (m, 3H), 4.34-4.37 (m, 0.5H), 4.27-4.16 (m, 1H), 4.08-3.97 (m,2H), 3.85-3.78 (m, 0.5H), 3.77- 3.62 (m, 5H), 3.47-3.37 (m, 0.5H), 3.12 (t, J= 10.4 Hz, 0.5H), 2.33-2.26 (m, 1H), 1.72-1.64 (m, 1H), 1.61-1.54 (m, 1H), 0.95-0.92 (m, 3H); VT NMR (400 MHz, DMSO-d6): <5 11.25 (br.s, 1H), 7.90-7.88 (m, 1H), 7.34-7.37 (m, 1H), 7.25-7.05 (m, 1H), 6.96-6.90 (m, 1H), 6.80-6.60 (m, 3H), 4.22-4.07 (m, 3H), 3.90-3.81 (m, 1H), 3.80-3.71 (m, 5H), 3.41-3.37 (m, 1H), 2.32 (s, 1H), 1.75-1.64 (m, 2H), 0.96- 0.93 (m, 3H).

[0533] Isomer in peak 2: (13.9 mg, 16.6% yield) as a white solid, m / z 381.2 (M+H)+(ES+); SFC: 100% de;1H NMR (400 MHz, DMSO-d6): <5 11.55 (br. s, 1H), 7.89 (d, J= 7.6 Hz, 1H), 7.52 (d, J= 7.6 Hz, 0.5H), 7.33 (d, J= 7.6 Hz, 0.5H), 7.24 (t, J= 8.4 Hz, 0.5H), 7.15 (t, J= 8.0 Hz, 0.5H), 6.97-6.92 (m, 1H), 6.84- 6.70 (m, 3H), 4.34-4.37 (m, 0.5H), 4.27-4.16 (m, 1H), 4.08-3.97 (m,2H), 3.85-3.78 (m, 0.5H), 3.77- 3.62 (m, 5H), 3.47-3.37 (m, 0.5H), 3.12 (t, J= 10.4 Hz, 0.5H), 2.33-2.26 (m, 1H), 1.72-1.64 (m, 1H), 1.61-1.54 (m, 1H), 0.95-0.92 (m, 3H); VTNMR (400 MHz, DMSO-d6): d 11.27 (br.s, 1H), 7.90-7.88 (m, 1H), 7.39-7.36 (m, 1H), 7.19-7.17 (m, 1H), 6.95-6.91 (m, 1H), 6.67-6.68 (m, 3H), 4.38-4.00 (m, 3H), 391-3.79 (m, 1H), 3.78-3.60 (m, 5H), 3.45-3.32 (m, 1H), 2.42-2.22 (m, 1H), 1.77-1.65 (m, 2H), 0.94 (d, J=6.8 Hz, 3H).

[0534] (S)-3-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one

[0535] (Compound 97):

[0536]

[0537] CDI (0.0884g, 0.5449mmol) and DIPEA (78.771mg,0.7785mmol) was added to a stirred solution of 2- (3 -methoxyphenyl)- 1 -[-(3 S)-3 -[(4-amino-3 -pyridyl)amino] - 1 -piperidyl] ethanone

[0538] (0.053g,0.1557mmol) in MeCN (5mL) . The resulting mixture was stirred atrtfor 18 h. Another portion of CDI was added and the reaction stirred for a further 18 h. The reaction mixture was concentrated under reduced pressure. The crude material was dissolved in DCM and quenched with Sat Sodium Bicarb (aq). The mixture was extracted with DCM (2 x 25 mL). The combined organic extracts were dried (phase sep) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (silica, 24 g) eluting with 0 - 100% EtOAc - heptane. The desired fractions were combined and concentrated under reduced pressure. The material was purified by flash column chromatography (silica, 24 g) eluting with 0 - 80% EtOAc - heptane. The desired fractions were combined and concentrated under reduced pressure. The material was redissolved in DMSO:ACN:H2O and purified by the Gilson prep HPLC (0.1 % NH3 in ACN : H2O (95 - 5%). Fractions were collected and dried overnight on the HT4 genevac. 7.6 mg 12.6 % yield. 'H NMR (500 MHz, CDCE) 8 8.43 - 8.38 (m, 1H), 8.07 (s, 1H), 7.40 (dt, J = 14.9, 7.9 Hz, 1H), 7.17 (dd, J= 11.0, 5.2 Hz, 1H), 7.04 - 6.92 (m, 3H), 4.96 (dd, J= 32.6, 12.8 Hz, 1H), 4.42 - 4.30 (m, 0.5H), 4.18 - 4.10 (m, 1H), 4.02 - 3.84 (m, 6H), 3.49 (t, J= 12.1 Hz, 0.5H), 3.21 (dd, J= 14.5, 11.8 Hz, 0.5H), 2.84 - 2.74 (m, 0.5H), 2.66 - 2.49 (m, 1H), 2.24 - 2.11 (m, 1H), 2.04 (dd, J = 30.0, 13.8 Hz, 1H), 1.77 (t, J= 13.3 Hz, 0.5H), 1.65 - 1.54 (m, 0.5H). MS m / z 367.1

[0539] (S)-5-amino-l-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol- 2-one (Compound 98): 2,2,2-trifluoroacetic acid (0.1085 mL, 1.4171mmol) was added to a stirred solution of tert-butyl N-[2- oxo- 1 -[(3 S)- 1 - [2 -( 3 -methoxyphenyl)acetyl] -3 -piperidyl] -3H-benzimidazol-5 -yl]carbamate (68.1mg,0.1417mmol) in DCM (2mL) The resulting mixture was stirred for 18 h. The reaction mixture was passed through a SCX cartridge and washed with MeOH (15 mL). The cartridge was then washed with 2 M NH3 in MeOH (15 mL). the fdtrate was concentrated under reduced pressure. The filtrate was concentrated under reduced pressure. The material was redissolved in DMS0:ACN:H20 and purified by the Gilson prep HPLC (0.1 % NH3 in ACN : H2O (95 - 5%). Fractions were collected and dried overnight on the HT4 genevac. 6-amino-3-[(3S)-l-[2-(3-methoxyphenyl)acetyl]-3-piperidyl]-lH- benzimidazol-2-one (20.1mg,0.0502mmol), 35.419% yield. 'H NMR (500 MHz, DMSO) 8 10.43 (d, J = 13.4 Hz, 1H), 7.22 (dt, J= 14.1, 7.8 Hz, 1H), 6.95 (d, J= 8.4 Hz, 0.5H), 6.86 - 6.71 (m, 3H), 6.62 (d, J= 8.3 Hz, 0.5H), 6.34 - 6.17 (m, 2H), 4.70 (s, 2H), 4.45 (s, 0.5H), 4.37 (d, J= 12.8 Hz, 0.5H), 4.01 - 3.87 (m, 2H), 3.76 - 3.67 (m, 6H), 3.16 (t, J= 12.0 Hz, 0.5H), 3.12 - 3.00 (m, 0.5H), 2.33 - 2.20 (m, 1H), 1.75 (s, 2H), 1.36 (s, 1H). MS m / z 381.1

[0540] (S)-5-amino-l-(l-(2-(3-methoxyphenyl)acetyl)piperidin-3-yl)-3-methyl-l,3-dihydro-2H- benzo [d]imidazol-2-one (Compound 99): lodomethane (107.8 lmg,0.7595mmol) and NaOH (31.87mg,0.7595mmol) (in H2O) was added to a stirred solution of tert-butyl N-[2-oxo-l-[(3S)-l-[2-(3-methoxyphenyl)acetyl]-3-piperidyl]-3H- benzimidazol-5-yl]carbamate (0.1519mmol) in THF (4mL). The resulting mixture was stirred at rt for 18 h.The reaction mixture was concentrated under reduced pressure. DCM was added and the mixture was extracted with DCM (2 x 25 mL). The combined organic extracts were dried (phase sep) and concentrated under reduced pressure. The crude material was dissolved in DCM (2mL) and 2,2,2- trifluoroacetic acid (0.1163 mL, 1.5191mmol) was added. The resulting mixture was stirred at rt for 2 h. The reaction mixture was passed through a SCX2 column and washed with DCM (15 mL). The product was eluted off with 7 M NH3 in MeOH (15 mL). The SCX2 layer was concentrated under reduced pressure. The material was redissolved in DMSO:ACN:H2O and purified by the Gilson prep HPLC (0. 1 % NH3 in ACN : H2O (95 - 5%). Fractions were collected and dried overnight on the HT4 genevac. 5 mg, 7.9%. ’H NMR (400 MHz, DMSO) 8 7.22 (q, J = 8.6 Hz, 1H), 7.02 (d, J = 8.3 Hz, 0.5H), 6.89 - 6.75 (m, 3H), 6.67 (d, J = 8.3 Hz, 0.5H), 6.39 - 6.20 (m, 2H), 4.80 (s, 2H), 4.54 - 4.32 (m, 1H), 4.08 - 3.80 (m, 2H), 3.79 - 3.57 (m, 5.5H), 3.22 - 3.15 (m, 3H), 3.14 - 3.02 (m, 1H), 2.39 -

[0541] 2.21 (m, 1.5H), 1.83 - 1.70 (m, 2H), 1.48 - 1.30 (m, 1H). MS m / z 395.2 l-((3S)-l-(2-(naphthalen-l-yl)propanoyl)piperidin-3-yl)-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0542] (Compound 100):

[0543] 3-[(3S)-3-piperidyl]-lH-benzimidazol-2-one (45mg, 0.207 Immol) was added to a stirred solution of alpha-Methyl- 1 -naphthaleneacetic acid (67.275mg,0.336mmol), T3P in EtOAc

[0544] (158.16mg,0.2485mmol) and DIPEA (31.437mg,0.3107mmol) in DCM (2mL). The mixture allowed to stir for 2 days. 25.4 mg, 17.9% yield. 1H NMR (400 MHz, DMSO) 8 11.01 - 10.47 (m, 1H), 8.35 -

[0545] 7.17 (m, 10.5H), 6.81 - 6.71 (m, 0.5H), 4.98 - 4.48 (m, 2H), 4.39 - 3.84 (in, 1H), 3.74 - 3.51 (m, 1H),

[0546] 3.29 (s, 0.3H), 3.10 2.99 (m, 0.7H), 2.77 2.55 (m, 0.7H), 2.46 - 2.05 (m, 1H), 1.97 - 1.53 (m, 2.3H),

[0547] 1.51 - 1.28 (in, 3.6H), 1.19 (d, J = 13.3 Hz, 0.4H). MS m / z 400.1

[0548] (S)-l-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-3-methyl-6-(methylamino)-l,3- dihydro- 2H-imidazo [4, 5-b]pyridin-2-one (Compound 101):

[0549] To a solution of 5-bromo-3-fluoropicolinonitrile (20.0 g, 99.5 mmol, 1.00 eq) in DMSO (200 mL) was added tert-butyl (S)-3-aminopiperidine-l-carboxylate (20.9 g, 104 mmol, 1.05 eq), then the mixture was stirred at 110 °C for 2 hrs. The mixture was poured into water (700 mL) and extracted with ethyl acetate (500 mL * 2), the combined organic layer was washed with brine (500 mL * 2), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to get a residue. The residue was used to next step without further purification. The tert-butyl (S)-3-((5-bromo-2-cyanopyridin-3- yl)amino)piperidine-l -carboxylate (38.7 g, crude) was obtained as a brown gum. m / z = 325.1 (M- 55+H)+. 'H NMR (400 MHz, CDC13) 5 8.01 (d, J = 1.8 Hz, 1H), 7.27 (s, 1H), 4.70 (br d, J = 6.8 Hz, 1H), 3.93 (dd, J= 13.4, 3.5 Hz, 1H), 3.71 (br s, 1H), 3.41 (br s, 1 H), 3.11 - 3.16 (m, 1H), 3.01 (br dd, J= 12.6, 8.4 Hz, 1H), 2.02 - 2.06 (m, 1H), 1.76 - 1.82 (m, 1H), 1.58 -1.67 (m, 2H), 1.47 (s, 9H).

[0550] To a solution of tert-butyl (S)-3-((5-bromo-2-cyanopyridin-3-yl)amino)piperidine-l-carboxylate (38.7 g, 102 mmol, Crude purity, 1.00 eq) in EtOH (194 m ) was added NaOH (5.00 M, 71.1 m , 3.50 eq), then the mixture was stirred at 90 °C for 12 hrs. The mixture was poured into water (1.00 E), the aqueous phase was adjusted to pH = 1 - 2 with 5 N HC1 (120 mb) and extracted with ethyl acetate (800 mb * 2), the combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get a residue. The residue was used to next step without further purification. The (S)-5-bromo-3-((l-(tert-butoxycarbonyl)piperidin-3-yl)amino)picolinic acid (38.4 g, 85.4 mmol, 84.1% yield, 89.0% purity) was obtained as a yellow solid, m / z = 344.1 (M-55+H)+. ’H NMR (400 MHz, CDCh) 5 7.83 - 7.86 (m, 1H), 7.36 (br s, 1H), 3.98 (dd, J = 13.3, 3.4 Hz, 1H), 3.78 (br s, 1H), 3.42 (br s, 1H), 3.08 (br s, 1H), 2.96 (br dd, J= 11.9, 9.2 Hz, 1H), 2.06 - 2.09 (m, 1 H), 1.80 - 1.82 (m, 1H), 1.60 - 1.68 (m, 2H), 1.47 (s, 9H).

[0551] To a solution of (S)-5-bromo-3-((l-(tert-butoxycarbonyl)piperidin-3-yl)amino)picolinic acid (33.0 g, 73.4 mmol, 89.0% purity, 1.00 eq) and TEA (29.7 g, 294 mmol, 40.9 mb, 4.00 eq) in DME (330 mb) was added dropwise DPPA (40.4 g, 147 mmol, 31.8 mb, 2.00 eq), then the mixture was stirred at 80 °C for 16 hrs. The mixture was poured into water (1.50 E), adjusted to pH = 4 - 5 with IN HC1 (160 mb) and extracted with ethyl acetate (1.00 E * 2), the combined organic layer was washed with brine (1.00 E * 2), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to get a residue. The mixture was triturated with MTBE (100 mb) at 15 °C for 30 mins, filtered and the filter cake was triturated with ethyl acetate (50.0 mb) at 70 °C for 1 hr to get tert-butyl (S)-3-(6-bromo-2- oxo-2, 3-dihydro-lH-imidazo[4,5-b]pyridin-l-yl)piperidine-l-carboxylate (11.5 g, 28.4 mmol, 38.7% yield, 98.0% purity) as a off - white solid, m / z = 341.1 (M-55+H)+. 'HNMR (400 MHz, DMSO) 8 11.85 (s, 1H), 8.00 (s, 2H), 4.12 - 4.18 (m, 1H), 3.93 (br d, J= 9.5 Hz, 2H), 3.36 - 3.44 (m, 1H), 2.83 - 2.89 (m, 1H), 2.17 - 2.27 (m, 1H), 1.75 - 1.84 (m, 2H), 1.46 - 1.53 (m, 1H), 1.40 (s, 9H).

[0552] (S)-tert-butyl 3-(6-bromo-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-l- yl)piperidine-l-carboxylate

[0553] To a solution of (S)-tert-butyl 3-(6-bromo-2-oxo-2,3-dihydro-lH-imidazo[4,5-b] pyridin-l-yl) piperidine- 1 -carboxylate (3 g, 7.55 mmol) in DMb (30 mb) was added NaH (604 mg, 15.10 mmol, 60% purity) at 0°C in one portion. The mixture was stirred at 20°C for 0.5 hours. Then CH3I (1.61 g, 11.33 mmol) was added to the mixture. The resulting mixture was stirred at 20°C for another 1.5 hours. TEC (petroleum ether: ethyl acetate = 1 : 1) showed starting material was consumed and a new spot formed. The reaction mixture was quenched with saturated NH4CI aqueous solution (200 mL) at 0°C and extract with EtOAc (120 mL*3). The combined organic phases were washed with brine (100 mL*4), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum to afford (S)-tert-butyl 3-(6-bromo-3- methyl-2 -oxo-2, 3-dihydro-lH-imidazo[4,5-b] pyridin-l-yl) piperidine- 1 -carboxylate as a yellow solid (3.0 g, 95.43% yield), m / z 411.2 (M+H)+(ES+); 'H NMR (400 MHz, CDCI3) d 8.10 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 4.24 - 4.13 (m, 2H), 3.46 (s, 3H), 3.36 (t, J = 12.0 Hz, 1H), 2.85 - 2.67 (m, 1H), 2.37 - 2.21 (m, 1H), 2.04 - 1.95 (m, 1H), 1.92 - 1.82 (m, 1H), 1.71 -1.63 (m, 1H), 1.48 (s, 9H), 1.33 - 1.28 (m, 1H).

[0554] (S)-tert-butyl 3-(3-methyl-6-(methylamino)-2-oxo-2,3-dihydro-lH-imidazo [4,5-b] pyridin-1- yl)piperidine-l-carboxylate

[0555] To a mixture of (S)-tert-butyl 3-(6-bromo-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b] pyridin-l- yl) piperidine- 1 -carboxylate (700 mg, 1.70 mmol) and MebTE (575 mg, 8.51 mmol, HC1 salt) in dioxane (15 mL) was added CS2CO3 (4.16 g, 12.76 mmol) and BrettPhos Pd G3 (154 mg, 0.170 mmol). The mixture was degassed and purged with N2 for 3 times, then stirred at 100°C for 8 hours. TLC (petroleum ether: ethyl acetate = 1: 1) showed the reaction was completed. The reaction mixture was cooled to 20°C, diluted with DCM (50 mL) and fdtered. The fdter cake was washed with DCM (20 mL*2). The fdtrate was concentrated in vacuum to give a residue, which was purified by column chromatography (SiCE, petroleum ether: ethyl acetate= 5: 1 to 1:3) to afford (S) -tert-butyl 3-(3-methyl- 6-(methylamino)-2 -oxo-2, 3-dihydro- lH-imidazo[4,5 -b]pyridin- 1 -yl)piperidine- 1 -carboxylate as a yellow solid (1.45 g, 73.39% yield), m / z 362.3 (M+H)+(ES+); 'H NMR (400 MHz, CDCI3) d 7.49 (d, J= 2.0 Hz, 1H), 6.65 (d, J= 2.4 Hz, 1H), 4.24 - 4.14 (m, 2H), 3.59 (br s, 1H), 3.46 - 3.37 (m, 4H), 2.89 (s, 3H), 2.80 - 2.69 (m, 1H), 2.42 - 2.25 (m, 1H), 2.03 - 1.94 (m, 1H), 1.90 - 1.82 (m, 1H), 1.69 - 1.59 (m, 2H), 1.47 (s, 9H).

[0556] (S)-3-methyl-6-(methylamino)-l-(piperidin-3-yl)-lH-imidazo[4,5-b]pyridin-2(3H)-one

[0557] To a solution of (S)-tert-butyl 3-(3-methyl-6-(methylamino)-2-oxo-2,3-dihydro-lH-imidazo[4,5-b] pyridin-l-yl)piperidine-l -carboxylate (1.45 g, 4.01 mmol) in dioxane (10 mL) was added HCl / dioxane (4 M, 20 mL). The mixture was stirred at 20°C for 0.5 hours. TLC (petroleum ether: ethyl acetate = 0: 1) showed the reaction was completed. The reaction mixture was concentrated in vacuum to afford (S)-3- methyl-6-(methylamino)-l-(piperidin-3-yl)-lH-imidazo[4,5-b]pyridin-2(3H)-one as a yellow solid (1.58 g, 99.34% yield, HC1 salt), m / z 262.2 (M+H)+(ES+); 'H NMR (400 MHz, CD3OD) d 8.19 (d, J = 2.4 Hz, 1H), 8.80 (d, J= 2.4 Hz, 1H), 4.79 - 4.71 (m, 1H), 3.84 - 3.76 (m, 1H), 3.58 - 3.53 (m, 1H), 3.47 (s, 3H), 3.44 - 3.38(m, 1H), 3.28 - 3.22 (m, 1H), 3.18 (s, 3H), 2.52 - 2.42 (m, 1H), 2.16 - 2.07 (m, 2H), 2.05 - 1.96 (m, 1H). (S)-l-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-3-methyl-6-(methylamino)-lH- imidazo[4,5-b]pyridin-2(3H)-one

[0558] To a solution of (S)-3-methyl-6-(methylamino)-l-(piperidin-3-yl)-lH-imidazo[4,5-b]pyridin-2(3H)- one (83 mg, 0.223 mmol, HC1 salt) and 2-(3-chloro-5-fluoro-phenyl)acetic acid (40 mg, 0.212 mmol) in DMF (3 mL) was added DIEA (164 mg, 1.27 mmol), followed by T3P (142 mg, 0.223 mmol, 50% purity) at 20°C. The mixture was stirred at 20°C for 2 hours. LCMS showed starting material was consumed and desired mass was detected. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*3). The combined organic phases were washed with brine (30 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC to afford (S)-l-(l-(2-(3-chloro-5-fluorophenyl)acetyl) piperidin-3-yl)-3- methyl-6- (methylamino)-lH-imidazo[4,5-b]pyridin-2(3H)-one as a yellow solid (25.07 mg, 27.01% yield), m / z 432.1 (M+H)+(ES+); 'H NMR (400 MHz, CD3OD) d 7.44 (s, 1H), 7.19 - 7.06 (m, 2H), 705 - 6.96 (m, 1.5H), 6.88 - 6.85 (m, 0.5H), 4.64 - 4.57 (m, 1H), 4.18 - 4.04 (m, 2H), 3.90 - 3.79 (m, 2.5H), 3.40 - 3.35 (m, 3.5H), 3.20 - 3.14 (m, 0.5H), 2.85 - 2.78 (m, 3H), 2.77 - 2.70 (m, 0.5H), 2.51 - 2.35 (m, 1H), 2.01 - 1.88 (m, 2H), 1.68 - 1.53 (m, 1H). l-((S)-l-((S)-2-(3-chloro-5-fluorophenyl)propanoyl)piperidin-3-yl)-3-methyl-6-(methylamino)- l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (Compound 102):

[0559] 102

[0560] 2-(3-chloro-5-fluorophenyl)acetic pivalic anhydride

[0561] To a solution of 2-(3-chloro-5-fluorophenyl)acetic acid (2 g, 10.61 mmol) in THF (25 mL) was added TEA (1.18 g, 11.67 mmol), followed by pivaloyl chloride (1.34 g, 11.14 mmol) dropwise at 0°C. The mixture was stirred at 0°C for 30 min. TLC (petroleum ether: ethyl acetate = 3: 1) showed starting material was consumed and a new spot formed. The reaction mixture was diluted with THF (30 mL) and filtered. The filter cake was washed with THF (5 mL*2). The filtrate was concentrated in vacuum to afford 2-(3-chloro-5-fluorophenyl)acetic pivalic anhydride as yellow oil (2.9 g, crude), which was used for the next step directly without further purification.

[0562] (S)-4-benzyl-3-(2-(3-chloro-5-fluorophenyl)acetyl)oxazolidin-2-one To a solution of (S)-4-benzyloxazolidin-2-one (1.97 g, 11. 13 mmol) in THF (20 mL) was added n-BuLi (2.5 M, 4.66 mL) dropwise at -70°C. The mixture was stirred at -70°C for 30 minutes. Then The mixture was added to a solution of 2-(3-chloro-5-fluorophenyl)acetic pivalic anhydride (2.89 g, 10.60 mmol) in THF (30 mL) at -70°C dropwise. The resulting mixture was stirred at -70°C for 30 minutes, then warmed to 20°C and stirred for another 12 hours. LCMS showed starting material was consumed and desired mass was detected. The reaction mixture was quenched with saturated NH4CI aqueous solution (100 mL) and extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with brine (50 mL*2), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum to give a residue, which was purified by column chromatography (SiCL, petroleum ether: ethyl acetate = 1:0 to 3: 1) to give a product. Then the product was purified by reverse phase combiflash to afford (S)-4- benzyl-3-(2-(3-chloro-5-fluorophenyl)acetyl)oxazolidin-2-one as yellow oil (1.0 g, 23.25% yield), m / z 348.0 (M+H)+(ES+); 'H NMR (400 MHz, CDCh) <5 7.36 - 7.28 (m, 3H), 7.19 - 7.13 (m, 3H), 7.05 (dt, J = 8.4, 2.0 Hz, 1H), 7.01 - 6.96 (m, 1H), 4.74 - 4.66 (m, 1H), 4.35 - 4.20 (m, 4H), 3.28 (dd, J = 13.2, 3.2 Hz, 1H), 2.83 - 2.76 (m, 1H).

[0563] (S)-4-benzyl-3-((S)-2-(3-chloro-5-fluorophenyl)propanoyl)oxazolidin-2-one

[0564] To a solution of (S)-4-benzyl-3-(2-(3-chloro-5-fluorophenyl)acetyl)oxazolidin-2-one (400 mg, 0.986 mmol) in THF (10 mL) was added NaHMDS (1 M, 1.48 mL) dropwise at -70°C under N2. The mixture was stirred at -70°C for 1 hour. Then CH3I (700 mg, 4.93 mmol) was added to the mixture at -70°C. The resulting mixture was warmed to 0°C and stirred for 0.5 hours. LCMS showed starting material was consumed and desired mass was detected. The reaction mixture was quenched with saturated NH4CI aqueous solution (60 mL) and extracted with EtOAc (40 mL*3). The combined organic phases were washed with brine (40 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue, which was purified by reverse phase combiflash to afford (S)-4-benzyl-3- ((S)-2-(3-chloro-5-fluorophenyl)propanoyl)oxazolidin-2-one as yellow oil (220 mg, 61.32% yield), m / z 362.1 (M+H)+(ES+); 'H NMR (400 MHz, CDCh) <5 7.39 - 7.28 (m, 3H), 7.24 - 7.20 (m, 2H), 7.19 - 7.14 (m, 1H), 7.04 - 6.97 (m, 2H), 5.11 (q, J = 6.8 Hz, 1H), 4.68 - 4.60 (m, 1H), 4.18 - 4.12 (m, 2H), 3.34 (dd, J = 13.2, 3.2 Hz, 1H), 2.86 - 2.77 (m, 1H), 1.54 (d, J = 7.2 Hz, 3H).

[0565] (S)-2-(3-chloro-5-fluorophenyl)propanoic acid

[0566] To a solution of (S)-4-benzyl-3-((S)-2-(3-chloro-5-fluorophenyl)propanoyl)oxazolidin-2-one (220 mg, 0.608 mmol) in THF (4.5 mL) was added a solution of LiOH.H2O (51 mg, 1.22 mmol) in H2O (1.5 mL), followed by H2O2 (552 mg, 4.86 mmol, 30% purity) dropwise at 0°C. The mixture was stirred at 0°C for 3 hours. TLC (petroleum ether: ethyl acetate = 3: 1) showed the reaction was completed. The reaction mixture was poured into water (40 mL) and extracted with DCM (30 mL). Then the aqueous solution was acidified to pH=4 by 1 M HC1 aqueous solution. The mixture was extracted with EtOAc (30 mL*3). The combined organic phases were washed with brine (30 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford (S)-2-(3-chloro-5-fluorophenyl)propanoic acid as yellow oil (120 mg, 93.02% yield). 'H NMR (400 MHz, DMSO-6) <5 12.58 (br.s, 1H), 7.32 (dt, J= 8.8, 2.0 Hz, 1H), 7.25 -7.21 (m, 1H), 7.32 (dt, J= 8.8, 2.0 Hz, 1H), 3.77 (q, J= 7.2 Hz, 1H), 1.37 (d, J = 7.2 Hz, 3H). l-((S)-l-((S)-2-(3-chloro-5-fluorophenyl)propanoyl)piperidin-3-yl)-3-methyl-6-(methylamino)- lH-imidazo[4,5-b]pyridin-2(3H)-one

[0567] To a solution of (S)-3-methyl-6-(methylamino)-l-(piperidin-3-yl)-lH-imidazo[4,5-b]pyridin-2(3H)- one (137 mg, 0.370 mmol, HC1 salt) and (S)-2-(3-chloro-5-fluorophenyl)propanoic acid (75 mg, 0.370 mmol) in DMF (3 mb) was added DIEA (287 mg, 2.22 mmol) and T3P (247 mg, 0.389 mmol, 50% purity in EtOAc) dropwise at 0°C. After addition, the mixture was warmed to 20°C and stirred for 2 hours. LCMS showed the reaction was completed. The reaction mixture was poured into water (30 mb) and extracted with EtOAc (20 mL*3). The combined organic phases were washed with brine (30 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC and SFC separation to afford the two single isomers.

[0568] Isomer in peak 1: l-((S)-l-((S)-2-(3-chloro-5-fluorophenyl)propanoyl)piperidin-3-yl)-3-methyl-6- (methylamino)-lH-imidazo[4,5-b] pyridin-2(3H)-one as a white solid (60.71 mg, 36.37% yield), m / z 446.1 (M+H)+(ES+); SFC: 100% de; 'H NMR (400 MHz, CD3OD) d 7.46 - 7.41 (m, 1H), 7.26 (s, 0.5H), 7.17 - 7.03 (m, 1.5H), 7.06 - 6.90 (m, 2H), 4.69- 4.60 (m, 1H), 4.39- 4.29 (m, 0.5H), 4.27 - 4.18 (m, 1H), 4.14 - 4.05 (m, 1H), 4.02 - 3.93 (m, 0.5H), 3.63 - 3.54 (m, 0.5H), 3.40 - 3.34 (m, 3.5H), 3.20 - 3.13 (m, 0.5H), 2.81 (s, 3H), 2.74 - 2.65 (m, 0.5H), 2.45 - 2.32 (m, 1H), 2.05 - 1.83 (m, 1.5H), 1.78 - 1.59 (m, 1H), 1.42 (t, J = 7.2 Hz, 3H), 1.00 - 0.89 (m, 0.5H).

[0569] (S)-l-(l-(2-(3-chloro-5-methoxyphenyl)acetyl)piperidin-3-yl)-3-methyl-6-(methylamino)-l,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (Compound 103): l-chloro-3-(chloromethyl)-5-methoxybenzene To a solution of (3-chloro-5-methoxyphenyl)methanol (1.07 g, 6.20 mmol) and DMF (45 mg, 0.620 mmol) in DCM (15 mL) was added SOCh (5.90 g, 49.59 mmol). The mixture was stirred at 40°C for 2 hours. TLC (petroleum ether: ethyl acetate = 3: 1) showed the reaction was completed. The reaction mixture was concentrated in vacuum to afford l-chloro-3-(chloromethyl)-5-methoxybenzene as a yellow solid (1.2 g, crude). 'H NMR (400 MHz, CDCh) <5 6.99 (t, J= 1.6 Hz, 1H), 6.86 (t, J= 2.0 Hz, 1H), 6.84 - 6.81 (m, 1H), 4.51 (s, 2H), 3.82 (s, 3H).

[0570] 2-(3-chloro-5-methoxyphenyl)acetonitrile

[0571] To a solution of l-chloro-3-(chloromethyl)-5-methoxybenzene (1.2 g, 6.28 mmol) in MeCN (20 mL) was added TMSCN (935 mg, 9.42 mmol), followed by TBAF (1 M in THF, 9.42 mL) at 0°C. The mixture was warmed to 20°C and stirred for 12 hours. TLC (petroleum ether: ethyl acetate = 3: 1) showed the reaction was completed. The reaction mixture was concentrated in vacuum to remove the organic solvent, diluted with water (50 mL) and extracted with EtOAc (40 mL*3). The combined organic phases were washed with brine (40 mL*2), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum to give a residue, which was purified by column chromatography (SiCL, petroleum ether: ethyl acetate=l:0 to 10: 1) to afford 2-(3-chloro-5-methoxyphenyl)acetonitrile as yellow oil (1.07 g, 90.42% yield). 'H NMR (400 MHz, CDCh) <5 6.93 - 6.90 (m, 1H), 6.87 (t, J = 2.0 Hz, 1H), 6.79 - 6.76 (m, 1H), 3.82 (s, 3H), 3.70 (s, 2H).

[0572] 2-(3-chloro-5-methoxyphenyl)acetic acid

[0573] To a solution of 2-(3-chloro-5-methoxyphenyl)acetonitrile (600 mg, 3.30 mmol) in EtOH (6 mL) was added a solution of NaOH (33 mg, 8.26 mmol) in H2O (2 mL). The mixture was heated to 70°C and stirred for 6 hours. LCMS showed a main peak with desired mass was detected. The reaction mixture was cooled to 20°C, diluted with water (30 mL) and concentrated in vacuum to remove the organic solvent. The resulting mixture was extracted with DCM (30 mL). The aqueous phase was acidified to pH=4 by 1 M HC1 aqueous solution, then extracted with EtOAc (20 mL*3). The combined organic phases were washed with brine (30 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford 2-(3-chloro-5-methoxy-phenyl)acetic acid was obtained as a yellow solid (370 mg, 52.09% yield). 'H NMR (400 MHz, DMSO-6) <5 12.41 (br.s, 1H), 6.91 (d, J =1.6Hz, 2H), 6.81 (d, J = 1.6 Hz, 1H), 3.76 (s, 3H), 3.56 (s, 2H).

[0574] (S)-l-(l-(2-(3-chloro-5-methoxyphenyl)acetyl)piperidin-3-yl)-3-methyl-6-(methylamino)-lH- imidazo[4,5-b]pyridin-2(3H)-one

[0575] To a solution of (S)-3-methyl-6-(methylamino)-l-(piperidin-3-yl)-lH-imidazo[4,5-b] pyridin-2(3H)- one (97 mg, 0.262 mmol, HC1 salt) and 2-(3-chloro-5-methoxy-phenyl)acetic acid (50 mg, 0.249 mmol) in DMF (3 mL) was added DIEA (193 mg, 1.50 mmol) and T3P (167 mg, 0.262 mol, 50% purity) at 20°C. The mixture was stirred at 20°C for 2 hours. LCMS showed starting material was consumed and desired mass was detected. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*3). The combined organic phases were washed with brine (30 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue, which was purified by column chromatography (SiCh, petroleum ether: ethyl acetate=5: 1 to 0:1) and then purified by reverse phase combiflash to afford (S)-l-(l-(2-(3-chloro-5-methoxyphenyl)acetyl)piperidin-3-yl)-3-methyl- 6- (methylamino)-lH-imidazo[4,5-b]pyridin-2(3H)-one as a yellow solid (66.25 mg, 31.14% yield), m / z 444.2 (M+H)+(ES+); 'H NMR (400 MHz, CD3OD) d 7.44 (s, 1H), 7.02 - 6.69 (m, 4H), 4.66 - 4.58 (m, 1H), 4.18 - 4.03 (m, 1.5H), 3.94 - 3.85 (m, 1H), 3.86 - 3.77 (m, 3H), 3.76 - 3.67 (m, 2H), 3.41 - 3.36 (m, 3.5H), 3.20 - 3.10 (m, 0.5H), 2.86 - 2.78 (m, 3H), 2.76 - 2.66 (m, 0.5H), 2.50 - 2.29 (m, 1H), 2.01 - 1.84 (m, 2H), 1.65 - 1.46 (m, 1H).

[0576] (S)-l-(l-(2-(3-fluoro-5-(trifluoromethyl)phenyl)acetyl)piperidin-3-yl)-3-methyl-6- (methylamino)-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (Compound 104):

[0577] 104

[0578] To a solution of (S)-3-methyl-6-(methylamino)-l-(piperidin-3-yl)-lH-imidazo[4,5-b] pyridin-2(3H)- one (88 mg, 0.236 mmol, HC1 salt) and 2-(3-fhioro-5-(trifluoromethyl)phenyl)acetic acid (50 mg, 0.225 mmol) in DMF (3 mL) was added DIEA (175 mg, 1.35 mmol), followed by T3P (150 mg, 0.236 mmol, 50% purity) at 20°C. The mixture was stirred at 20°C for 2 hours. LCMS showed starting material was consumed and desired mass was detected. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*3). The combined organic phases were washed by brine (30 mL*3), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC to afford (S)-l-(l-(2-(3-fhioro-5-(trifluoromethyl)phenyl)acetyl)piperidin-3- yl)- 3-methyl-6-(methylamino)-lH-imidazo[4,5-b]pyridin-2(3H)-one as a yellow solid (37.39 mg, 34.48% yield), m / z 466.2 (M+H)+(ES+); 'H NMR (400 MHz, CD3OD) d 7.49 - 7.40 (m, 2H), 7.38 - 7.29 (m, 2H), 6.95 (dd, 1H), 4.64 - 4.57 (m, 1H), 4.22 - 4.08 (m, 2H), 3.99 - 3.85 (m, 2.5H), 3.39 - 3.34 (m, 3.5H), 3.21 - 3.17 (m, 0.5H), 2.86 - 2.79 (m, 3H), 2.77 - 2.69 (m, 0.5H), 2.53 - 2.37 (m, 1H), 2.00 - 1.90 (m, 2H), 1.70 - 1.57 (m, 1H). (S)-l-(l-(2-(3-chloro-4-fluorophenyl)acetyl)piperidin-3-yl)-3-methyl-6-(methylamino)-l,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (Compound 105):

[0579] To a solution of (S)-3-methyl-6-(methylamino)-l-(piperidin-3-yl)-lH-imidazo[4,5-b] pyridin-2(3H)- one (83 mg, 0.223 mmol, HC1 salt) and 2-(3-chloro-4-fluoro-phenyl)acetic acid (40 mg, 0.212 mmol) in DMF (3 mL) was added DIEA (164 mg, 1.27 mmol), followed by T3P (142 mg, 0.223 mmol, 50% purity) at 20°C. The mixture was stirred at 20°C for 2 hours. LCMS showed starting material was consumed and desired mass was detected. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*3). The combined organic phases were washed with brine (30 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC to afford (S)-l-(l-(2-(3-chloro-4-fluorophenyl)acetyl)piperidin-3-yl)-3-methyl- 6-(methylamino)-lH-imidazo[4,5-b]pyridin-2(3H)-one as ayellow solid (46.87 mg, 50.04% yield), m / z 432.1 (M+H)+(ES+); 'H NMR (400 MHz, CD3OD) d 7.47 - 7.32 (m, 2H), 7.27 - 7.14 (m, 2H), 7.00 - 6.84 (m, 1H), 4.67 - 4.56 (m, 1H), 4.20 - 4.04 (m, 2H), 3.91- 3.73 (m, 2.5H), 3.41 - 3.35 (m, 3.5H), 3.16 (t, J= 12.4 Hz, 0.5H), 2.86 - 2.79 (m, 3H), 2.77 - 2.66 (m, 0.5H), 2.51 - 2.33 (m, 1H), 2.03 - 1.87 (m, 2H), 1.70 - 1.50 (m, 1H).

[0580] (S)-l-(l-(2-(3,5-bis(trifluoromethyl)phenyl)acetyl)piperidin-3-yl)-3-methyl-6-(methylamino)-l,3- dihydro- 2H-imidazo [4, 5-b]pyridin-2-one (Compound 106):

[0581] 106 To a solution of (S)-3-methyl-6-(methylamino)-l-(piperidin-3-yl)-lH-imidazo[4,5-b] pyridin-2(3H)- one (86 mg, 0.232 mmol, HC1 salt) and 2-(3,5-bis(trifluoromethyl)phenyl)acetic acid (60 mg, 0.220 mmol) in DMF (2 mb) was added DIEA (171 mg, 1.32 mmol), followed by T3P (147 mg, 0.232 mmol, 50% purity) at 20°C. The mixture was stirred at 20°C for 1.5 hours. LCMS showed starting material was consumed and desired mass was detected. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*3). The combined organic phases were washed by brine (30 mL*3), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC to afford (S)-l-(l-(2-(3,5-bis(trifluoromethyl)phenyl)acetyl)piperidin-3-yl)-3- methyl-6-(methylamino)-lH-imidazo[4,5-b]pyridin-2(3H)-one as a yellow solid (25.27 mg, 21.21% yield), m / z 516.1 (M+H)+(ES+); 'H NMR (400 MHz, CD3OD) d 7.92 - 7.83 (m, 3H), 7.45 (dd, J= 5.6, 2.0 Hz, 1H), 6.98 (dd, J = 14.2, 2.4 Hz, 1H), 4.64- 4.59 (m, 1H), 4.32 - 4.11 (m, 2H), 4.09- 3.97 (m, 2H), 3.93 - 3.83 (m, 0.5H), 3.44 - 3.35 (m, 3.5H), 3.27 - 3.19 (m, 0.5H), 2.87 - 2.80 (m, 3H), 2.79 - 2.71 (m, 0.5H), 2.55 - 2.37 (m, 1H), 2.03 - 1.90 (m, 2H), 1.76 - 1.58 (m, 1H).

[0582] (S)-l-(l-(2-(3,5-dichlorophenyl)acetyl)piperidin-3-yl)-3-methyl-6-(methylamino)-l,3-dihydro-

[0583] 2H-imidazo[4,5-b]pyridin-2-one (Compound 107):

[0584] 107

[0585] To a solution of (S)-3-methyl-6-(methylamino)-l-(piperidin-3-yl)-lH-imidazo[4,5-b] pyridin-2(3H)- one (85 mg, 0.230 mmol, HC1 salt) and 2-(3,5-dichlorophenyl)acetic acid (45 mg, 0.219 mmol) in DMF (2 mL) was added DIEA (170 mg, 1.32 mmol), followed by T3P (147 mg, 0.230 mmol, 50% purity) at 20°C. The mixture was stirred at 20°C for 1.5 hours. LCMS showed starting material was consumed and desired mass was detected. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*3). The combined organic phases were washed with brine (30 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC to afford (S)-l-(l-(2-(3,5-dichlorophenyl)acetyl)piperidin-3-yl) -3-methyl-6- (methylamino)-lH-imidazo[4,5-b]pyridin-2(3H)-one (29.75 mg, 29.48% yield) as a yellow solid, m / z 448.1 (M+H)+(ES+). 'H NMR (400 MHz, CD3OD) d 7.45 - 740 (m, 1H), 7.37 - 7.18 (m, 3H), 6.99 - 6.85 (m, 1H), 4.63- 4.56 (m, 1H), 4.21 - 4.03 (m, 2H), 3.93 - 3.74 (m, 2.5H), 3.41 - 3.34 (m, 3.5H), 3.22 - 3.13 (m, 0.5H), 2.87 - 2.79 (m, 3H), 2.78 - 2.67 (m, 0.5H), 2.53 - 2.33 (m, 1H), 2.04 - 1.87 (m, 2H), 1.68 - 1.54 (m, 1H).

[0586] (S)-l-(l-(2-(3-chloro-5-(trifluoromethyl)phenyl)acetyl)piperidin-3-yl)-3-methyl-6- (methylamino)-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (Compound 108):

[0587] To a solution of (S)-3-methyl-6-(methylamino)-l-(piperidin-3-yl)-lH-imidazo[4,5-b] pyridin-2(3H)- one (90 mg, 0.242 mmol, HC1 salt) and 2-[3-chloro-5-(trifluoromethyl)phenyl]acetic acid (55 mg, 0.231 mmol) in DMF (2 mL) was added DIEA (179 mg, 1.38 mmol), followed by T3P (154 mg, 0.242 mmol, 50% purity) at 20°C. The mixture was stirred at 20°C for 1.5 hours. LCMS showed starting material was consumed, and desired mass was detected. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*3). The combined organic phases were washed with brine (30 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC to afford (S)-l-(l-(2-(3-chloro-5-(trifluoromethyl)phenyl)acetyl)piperidin -3- yl)-3-methyl-6-(methylamino)-lH-imidazo[4,5-b]pyridin-2(3H)-one as a yellow solid (39.74 mg, 34.70% yield), m / z 482.1 (M+H)+(ES+). 'H NMR (400 MHz, CD3OD) d 7.63 - 749 (m, 3H), 7.47 - 7.40 (m, 1H), 6.99 - 6.92 (m, 1H), 4.65- 4.55 (m, 1H), 4.24- 4.07 (m, 2H), 3.99 - 3.83 (m, 2.5H), 3.42 - 3.35 (m, 3.5H), 3.22 - 3.15 (m, 0.5H), 2.85 - 2.69 (m, 3.5H), 2.54 - 2.34 (m, 1H), 2.06 - 1.89 (m, 2H), 1.71 - 1.57 (m, 1H).

[0588] (S)-6-amino-l-(l-(2-(3-chloro-5-methoxyphenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (Compound 109):

[0589] 109

[0590] To a solution of (S)-6-amino-l-(piperidin-3-yl)-lH-imidazo[4,5-b]pyridin-2(3H)-one (108 mg, 0.314 mmol, HC1 salt) and 2-(3-chloro-5-methoxy-phenyl)acetic acid (60 mg, 0.299 mmol) in DMF (3 mL) was added DIEA (232 mg, 1.79 mmol), followed by T3P (200 mg, 0.314 mmol, 50% purity) at 20°C. The mixture was stirred at 20°C for 2 hours. LCMS showed starting material was consumed and desired mass was detected. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*3). The combined organic phase was washed by brine (30 mL*3), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC to give crude product. The crude product was further purified by prep-HPLC to give a solution (25 mL). The solution was concentrated in vacuum to remove the organic solvent, basified to pH=9 by saturated Na2COs aqueous solution. The mixture was extracted with DCM (20 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford (S)-6-amino-l-(l-(2-(3-chloro-5-methoxyphenyl)acetyl)piperidin-3-yl)-lH- imidazo [4,5-b]pyridin-2(3H)-one as a white solid (26.55 mg, 21.35% yield), m / z 416.1 (M+H)+(ES+); 'H NMR (400 MHz, CD3OD) d 7.48 (s, 1H), 7.66 (d, J = 2.0 Hz, 0.5H), 6.92 - 6.75 (m, 3.5H), 4.67- 4.60 (m, 1H), 4.14- 4.03 (m, 1.5H), 3.91 - 3.77 (m, 4.5H), 3.76 - 3.71 (m, 2H), 3.17 - 3.09 (m, 0.5H), 2.73 - 2.64 (m, 0.5H), 2.48 - 2.29 (m, 1H), 2.01 - 1.84 (m, 2H), 1.64 - 1.43 (m, 1H). l-((S)-l-((R)-2-(3-chloro-5-fluorophenyl)propanoyl)piperidin-3-yl)-3-methyl-6-(methylamino)- l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (Compound 110): Synthesised by the same procedure as Compound 102, with isomers purified by prep-HPLC and separated by SFC to afford the two single isomers.

[0591] Isomer in peak 1: l-((S)-l-((S)-2-(3-chloro-5-fluorophenyl)propanoyl)piperidin-3-yl)-3-methyl-6- (methylamino)-lH-imidazo[4,5-b] pyridin-2(3H)-one as a white solid (60.71 mg, 36.37% yield), m / z 446.1 (M+H)+(ES+); SFC: 100% de; 'H NMR (400 MHz, CD3OD) 3 7.46 - 7.41 (m, 1H), 7.26 (s, 0.5H), 7.17 - 7.03 (m, 1.5H), 7.06 - 6.90 (m, 2H), 4.69- 4.60 (m, 1H), 4.39- 4.29 (m, 0.5H), 4.27 - 4.18 (m, 1H), 4.14 - 4.05 (m, 1H), 4.02 - 3.93 (m, 0.5H), 3.63 - 3.54 (m, 0.5H), 3.40 - 3.34 (m, 3.5H), 3.20 - 3.13 (m, 0.5H), 2.81 (s, 3H), 2.74 - 2.65 (m, 0.5H), 2.45 - 2.32 (m, 1H), 2.05 - 1.83 (m, 1.5H), 1.78 - 1.59 (m, 1H), 1.42 (t, J = 7.2 Hz, 3H), 1.00 - 0.89 (m, 0.5H).

[0592] Isomer in peak 2: l-((S)-l-((R)-2-(3-chloro-5-fluorophenyl)propanoyl)piperidin-3-yl)-3-methyl-6- (methylamino)-lH-imidazo[4,5-b]pyridin-2(3H)-one as a yellow solid (5.72 mg, 3.40% yield), m / z 446.1 (M+H)+(ES+); SFC: 95.1% de- 'H NMR (400 MHz, CD3OD) 3 7.43 (dd, J= 12.4, 2.0 Hz, 1H), 7.19 - 7.06 (m, 2H), 7.05 - 6.97 (m, 1.5H), 6.44 (d, J= 2.0 Hz, 0.5H), 4.68 - 4.61 (m, 1H), 4.28 - 4.17 (m, 1H), 4.14 - 4.04 (m, 1.5H), 3.99 - 3.91 (m, 0.5H), 3.38 - 3.33 (m, 3.5H), 2.95 - 2.86 (m, 0.5H), 2.82 (d, J= 2.4 Hz, 3H), 2.75 - 2.66 (m, 0.5H), 2.47 - 2.37 (m, 0.5H), 2.33 - 2.23 (m, 0.5H), 2.01 - 1.83 (m, 2H), 1.77 - 1.66 (m, 0.5H), 1.53 - 1.44 (m, 0.5H), 1.42 - 1.34 (m, 3H).

[0593] (S)-6-amino-l-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (Compound 111):

[0594] To a solution of (S)-6-amino-l-(piperidin-3-yl)-lH-imidazo[4,5-b]pyridin-2(3H)-one (114 mg, 0.334 mmol, HC1 salt) and 2-(3-chloro-5-fluoro-phenyl)acetic acid (60 mg, 0.318 mmol) in DMF (3 mL) was added DIEA (247 mg, 1.91 mmol), followed by T3P (213 mg, 0.334 mmol, 50% purity) at 20°C. The mixture was stirred at 20°C for 2 hours. LCMS showed starting material was consumed and desired mass was detected. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*3). The combined organic phases were washed with brine (30 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC to afford (S)-6-amino- 1 -( 1 -(2-(3 -chloro-5 -fluorophenyl)acetyl)piperidin-3 -yl)- IH-imidazo [4,5 -b] pyridin-2(3H)-one as a yellow solid (39.51 mg, 30.07% yield), m / z 404.1 (M+H)+(ES+);1H NMR (400 MHz, CD3OD) 3 7.48 (s, 1H), 7.21 - 6.94 (m, 4H), 4.66- 4.56 (m, 1H), 4.16- 4.02 (m, 2H), 3.90 - 3.76 (m, 2.5H), 3.38 - 3.35 (m, 0.5H), 3.19 - 3.10 (m, 0.5H), 2.77 - 2.64 (m, 0.5H), 2.49 - 2.33 (m, 1H), 2.06 - 1.87 (m, 2H), 1.68 - 1.48 (m, 1H).

[0595] (S)-5-amino-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-isopropyl-l,3-dihydro-2H- benzo [d]imidazol-2-one (Compound 112):

[0596] To a stirred solution of tert-butyl A'-{3-|(3S)- l -|2-(3-chloro-5-fliiorophcnyl)acctyl |pipcridin-3-yl |-2- oxo- 1 -(propan-2-yl)-2.3-dihydro- IH- 1, 3 -benzodiazol -5 -yl (carbamate (45 mg, 0.08 mmol) in 1,4- dioxane (2 mL), 4M HC1 in dioxane (2 mL) was added. The reaction mixture was stirred at room temperature for 5 h. After completion, the reaction mixture was concentrated, washed with diethyl ether and dried to afford 5-amino-3-[(3S)-l-[2-(3-chloro-5-fluorophenyl)acetyl]piperidin-3-yl]-l-(propan-2- yl)-2.3-dihydro- IH- l .3-bcnzodiazol-2-onc as an off white solid HCl-Salt (1: 1) (32 mg, 0.066 mmol, 81%). ’H NMR (400 MHz, DMSO- 6) (Rotamers) 5 9.90 (br, 3 H), 7.40-7.36 (m, 2 H), 7.31-7.27 (m,

[0597] 1 H), 7.21-7.17 (m, 1 H), 7.13-7.07 (m, 1 H), 7.01 (d, J= 8.32 Hz, 1 H), 4.63-4.58 (m, 1 H), 4.44-4.41 (m, 1 H), 4.12-4.02 (m, 2 H), 3.85-3.67 (m, 2 H), 3.39-3.04 (m, 2 H), 2.50-2.32 (m, 1 H), 1.91-1.82 (m,

[0598] 2 H), 1.47-1.43 (m, 7 H) ppm; m / z 445.39 [M+H]+

[0599] (S)-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-5-(methylamino)-l,3- dihydro-2H-benzo[d]imidazol-2-one (Compound 113):

[0600] 113

[0601] To a solution of 4-bromo-2 -fluoro- 1 -nitrobenzene (10 g, 45.46 mmol) and TEA (11.50 g, 113.64 mmol) in MeCN (100 m ) was added (S)-tert-butyl 3-aminopiperidine-l-carboxylate (10.01 g, 50.00 mmol) at 20 °C. The mixture was heated to 80 °C and stirred for 12 hours. LCMS showed the starting materials were consumed and desired mass was detected. The reaction mixture was concentrated in vacuum to give a residue. The residue was diluted with water (150 m ) and extracted with EtOAc (80 mb * 3). The combined organic phases were washed with brine (80 mb * 2), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum to give a crude product, which was purified by silica gel chromatography (SiCE, petroleum ether : ethyl acetate = 100:0 to 20: 1) to afford (S)-tert-butyl3-((5- bromo-2-nitrophenyl) amino)piperidine-l-carboxylate as yellow oil (17.8 g, 97.83% yield).1H NMR (400 MHz, CDCh) d 8.15 (s, 1H), 8.08 - 8.02 (m, 1H), 7.09 (s, 1H), 6.82 - 6.75 (m, 1H), 3.96 - 3.88 (m, 1H), 3.69 - 3.56 (m, 2H), 3.30 - 3.17 (m, 2H), 1.84 - 1.63 (m, 4H), 1.47 (s, 9H).

[0602] (S)-tert-butyl 3-((2-amino-5-bromophenyl)amino)piperidine-l-carboxylate

[0603] To a mixture of (S)-tert-butyl 3-((5-bromo-2-nitrophenyl)amino)piperidine-l-carboxylate (10 g, 24.98 mmol) and NH4CI (4.01 g, 74.95 mmol) in EtOH (75 mb) and H2O (25 mb) was added Fe (4.19 g, 74.95 mmol). The mixture was heated to 100 °C and stirred for 2 hours. LCMS and TLC (petroleum ether: ethyl acetate = 1: 1) showed the reaction was completed. The reaction mixture was fdtered and the fdter cake was washed with EtOAc (60 mb * 2). The fdtrate was concentrated in vacuum to give a residue, which was diluted with water (100 mb) and extracted with EtOAc (80 mb * 3). The combined organic phases were washed with brine (60 mb * 2), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum to give a crude product, which was purified by silica gel chromatography (SiO2, petroleum ether ethyl acetate = 50:0 to 5: 1) to afford (S)-tert-butyl 3-((2-amino-5- bromophenyl)amino)piperidine-l -carboxylate as brown oil (8.87 g, 92.14% yield), m / z 370.1 (M+H)+(ES+); 'H NMR (400 MHz, CDCh) d 6.86 (s, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.67 (d, J=8.0 Hz, 1H), 3.94 (d, J=13.2 Hz, 1H), 3.76 - 3.26 (m, 2H), 3.24 - 2.89 (m, 2H), 2.05 - 1..94 (m, 1H), 1.82 - 1.73 (m, 1H), 1.68 - 1.56 (m, 2H), 1.46 (s, 9H). (S)-tert-butyl 3-(6-bromo-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-l-carboxylate To a solution of tert-butyl (3S)-3-(2-amino-5-bromo-anilino)piperidine-l-carboxylate (8.5 g, 22.96 mmol) and CDI (14.89 g, 91.82 mmol) in MeCN (40 mL) was added DIEA (14.83 g, 114.78 mmol) at 20 °C. The mixture was stirred at 20 °C for 12 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated in vacuum to give a residue. The residue was diluted with water (100 mL) and extracted with EtOAc (60 mL * 3). The combined organic phases were washed with brine (60 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a crude product, which was purified by silica gel chromatography (SiCL, petroleum ether : ethyl acetate = 50:0 to 1: 1) to afford (S)-tert-butyl 3-(6-bromo-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-l- carboxylate as yellow oil (8.1 g, 85.36% yield), m / z 296.1 (M-Boc+H)+(ES+);1H NMR (400 MHz, CDCh) <5 10.00 (s, 1H), 7.24 (s, 1H), 7.20 (d, J= 8.4 Hz, 1H), 7.00 (d, J= 8.4 Hz, 1H), 4.25 - 4.13 (m, 3H), 3.46 (t,J= 12.0 Hz, 1H), 2.85 - 2.72 (m, 1H), 2.45 - 2.32 (m, 1H), 2.03 - 1.95 (m, 1H), 1.93 - 1.83 (m, 1H), 1.72 - 1.60 (m, 1H), 1.49 (s, 9H).

[0604] (S)-6-bromo-l-(piperidin-3-yl)-lH-benzo[d]imidazol-2(3H)-one

[0605] To a solution of (S)-tert-butyl 3-(6-bromo-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine -1- carboxylate (500 mg, 1.26 mmol) in dioxane (3 mL) was added HCl / dioxane (4 M, 3 mL) at 20 °C. The mixture was stirred at 20°C for 1.5 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated in vacuum to afford (S)-6-bromo-l- (piperidin-3-yl)-lH-benzo[d]imidazol- 2(3H)-one as a white solid (420 mg, 94.07% yield, HC1 salt), m / z 295.9 (M+H)+(ES+); 'H NMR (400 MHz, CD3OD) d 7.49 (d, J= 1.2 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.64 - 4.55 (m, 1H), 3.83 - 3.76 (m, 1H), 3.54 - 3.48 (m, 1H), 3.40 - 3.33 (m, 1H), 3.27 - 3.19 (m, 1H), 2.44 - 2.33 (m, 1H), 2.13 - 1.89 (m, 3H).

[0606] (S)-6-bromo-l-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-lH-benzo[d]imidazol- 2(3H)-one

[0607] To a solution of 2-(3-chloro-5-fluorophenyl)acetic acid (1.52 g, 8.04 mmol) and (S)-6-bromo-l- (piperidin-3-yl)-lH-benzo[d]imidazol-2(3H)-one (2.5 g, 8.44 mmol) in DME (30 mL) was added DIEA (3.12 g, 24.12 mmol), followed by T3P (5.37 g, 8.44 mmol, 50% purity) at 0 °C. The mixture was warmed to 20 °C and stirred for 12 hours. LCMS showed the starting materials were consumed and the desired mass was detected. The reaction mixture was concentrated in vacuum to give a residue. The residue was diluted with water (100 mL) and extracted with EtOAc (80 mL * 3). The combined organic phases were washed with brine (60 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford (S)-6-bromo-l-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)- IH-benzo [d]imidazol-2(3H)-one as yellow oil (3.9 g, 95.94% yield), m / z 466.1 (M+H)+(ES+); ’H NMR (400 MHz, CDCI3) <5 9.80 - 9.45 (m, 1H), 7.25 - 7.16 (m, 2H), 7.13 - 6.86 (m, 4H), 4.82 - 4.72 (m, 1H), 4.10 - 4.02 (m, 0.5H), 3.98 - 3.77 (m, 2H), 3.76 - 3.68 (m, 2H), 3.42 (t, J = 12.4 Hz, 0.5H), 3.19 - 3.09 (m, 0.5H), 2.73 - 2.61 (m, 0.5H), 2.56 - 2.35 (m, 1H), 2.04 - 1.89 (m, 2H), 1.62 - 1.46 (m, 1H).

[0608] (S)-5-bromo-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH- benzo [d] imidazol-2(3H)-one

[0609] To a solution of (S)-6-bromo-l-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-lH-benzo[d] imidazol-2(3H)-one (400 mg, 0.857 mmol) in THF (6 mL) was added a solution ofNaOH (171.3 mg, 4.29 mmol) in H2O (0.5 mL), followed by CH3I (608.2 mg, 4.29 mmol) at 20 °C. The mixture was stirred at 20 °C for 12 hours. TLC (petroleum ether: ethyl acetate = 0: 1) showed the starting materials were consumed and a new spot formed. The reaction mixture was diluted with water (150 mL) and acidified to pH=6 by 1 N HC1 aqueous solution. The mixture was extracted with EtOAc (60 mL * 3). The combined organic phases were washed with brine (60 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue, which was purified by column chromatography (SiCL, petroleum ether : ethyl acetate = 5: 1 to 1:3) to afford (S)-5-bromo-3-(l-(2-(3- chloro-5-fluorophenyl)acetyl)piperidin-3-yl) -l-methyl-lH-benzo[d]imidazol-2(3H)-one as colorless oil (290 mg, 68.34% yield). The structure was confirmed by ID NOSEY and HSQC. m / z 479.9 (M+H)+(ES+); 'H NMR (400 MHz, CDCh) 7.25 - 7.17 (m, 1.5H), 7.12 - 6.98 (m, 2H), 6.96 - 6.82 (m, 2.5H), 4.75 (d, J= 12.4 Hz, 1H), 4.08 - 3.98 (m, 0.5H), 3.94 - 3.79 (m, 2H), 3.76 - 3.69 (m, 2H), 3.45 - 3.40 (m, 0.5H), 3.39 - 3.36 (m, 3H), 3.17 - 3.08 (m, 0.5H), 2.69 - 2.60 (m, 0.5H), 2.57 - 2.37 (m, 1H), 2.01 - 1.89 (m, 2H), 1.58 - 1.46 (m, 1H).

[0610] (S)-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-5-(methylamino)-lH- benzo [d] imidazol-2(3H)-one

[0611] To a mixture of (S)-5-bromo-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH- benzo[d]imidazol-2(3H)-one (120 mg, 0.249 mmol), methanamine hydrochloride (84.2 mg, 1.25 mmol) and CS2CO3 (609.9 mg, 1.87 mmol) in dioxane (4 mL) was added BrettPhos Pd G3 (22.6 mg, 0.025 mmol). The mixture was degassed and purged with N2 for 3 times, then heated to 100 °C and stirred for 12 hours. LCMS showed the starting materials were consumed and the desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated to give a residue, which was purified by column chromatography (SiCL, petroleum ether: ethyl acetate = 10: 1 to 1: 1) and then purified by prep- HPLC to afford (S)-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-5- (methylamino)-lH-benzo[d]imidazol-2(3H)-one as a white solid (32.47 mg, 28.95% yield), m / z 431.1 (M+H)+(ES+); 'H NMR (400 MHz, CD3OD) d 7.20 - 6.92 (m, 4H), 6.65 - 6.47 (m, 2H), 4.67 - 4.54 (m, 1H), 4.17 - 4.01 (m, 2H), 3.97 - 3.76 (m, 2.5H), 3.46 - 3.39 (m, 0.5H), 3.33 (s, 3H), 3.21 - 3.13 (m, 0.5H), 2.80 (d, J= 2.4 Hz, 3H), 2.77 - 2.67 (m, 0.5H), 2.58 - 2.40 (m, 1H), 2.00 - 1.88 (m, 2H), 1.69 - 1.52 (m, 1H). (S)-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-5-(ethylamino)-l-methyl-l,3-dihydro-

[0612] 2H-benzo[d]imidazol-2-one (Compound 114):

[0613] 114

[0614] To a mixture of (S)-5-bromo-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH- benzo[d]imidazol-2(3H)-one (150 mg, 0.312 mmol) and K3PO4 (463.6 mg, 2.18 mmol) in DMSO (6 mL) was added Cui (59.4 mg, 0.312 mmol) and L-proline (71.84 mg, 0.624 mmol), followed by ethanamine (127.2 mg, 1.56 mmol, HC1 salt). The mixture was degassed and purged with N2 for 3 times, then heated to 90 °C and stirred for 12 hours. LCMS showed the starting materials were consumed and the desired mass was detected. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (40 mL * 3). The combined organic phases were washed with brine (40 mL * 4), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue, which was purified by column chromatography (SiCL, petroleum ether: ethyl acetate = 5: 1 to 0: 1) and then purified by prep- HPLC to afford (S)-3-(l-(2-(3-chloro-5-fhiorophenyl)acetyl)piperidin-3-yl)-5-(ethylamino)-l-methyl- lH-benzo[d] imidazol-2(3H)-one as a yellow solid (40.87 mg, 29.29% yield), m / z 445.1 (M+H)+(ES+); 'H NMR (400 MHz, CD3OD) d 7.21 - 6.90 (m, 4H), 6.67 - 6.51 (m, 2H), 4.65 - 4.56 (m, 1H), 4.17 - 4.00 (m, 2H), 3.95 - 3.78 (m, 2.5H), 3.43 - 3.38 (m, 0.5H), 3.35 - 3.32 (m, 3H), 3.20 - 3.10 (m, 2.5H) 2.77 - 2.66 (m, 0.5H), 2.57 - 2.41 (m, 1H), 2.00 - 1.89 (m, 2H), 1.68 - 1.51 (m, 1H), 1.28 - 1.21 (m, 3H).

[0615] (S)-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-5-(isopropylamino)-l-methyl-l,3- dihydro-2H-benzo[d]imidazol-2-one (Compound 115):

[0616] 115

[0617] To a mixture of (S)-5-bromo-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH- benzo[d]imidazol-2(3H)-one (120 mg, 0.249 mmol), propan-2-amine (147.5 mg, 2.50 mmol) and K3PO4 (105.9 mg, 0.499 mmol) in DMSO (4 mL) was added L-proline (57.4 mg, 0.499 mmol) and Cui (47.5 mg, 0.249 mmol). The mixture was degassed and purged with N2 for 3 times, then heated to 90 °C and stirred for 12 hours. LCMS showed the starting materials were consumed and the desired mass was detected. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (30 mL * 3). The combined organic phases were washed with brine (30 mL * 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue, which was purified by column chromatography (SiCL, petroleum ether: ethyl acetate = 5:0 to 0: 1) and then purified by prep-HPLC to afford (S)-3 -( 1 -(2-(3 -chloro-5 -fluorophenyl)acetyl)piperidin-3 -y 1) -5 -(isopropylamino)- 1 -methyl- 1H- benzo[d]imidazol-2(3H)-one as a white solid (67.03 mg, 56.93% yield), m / z 459.2 (M+H)+(ES+); ‘H NMR (400MHz, CD3OD) d 122 - 6.86 (m, 4H), 6.74 - 6.49 (m, 2H), 4.67 - 4.55 (m, 1H), 4.18 - 4.00 (m, 2H), 3.94 - 3.75 (m, 2.5H), 3.67 - 3.54 (m, 1H), 3.43 - 3.32 (m, 3.5H), 3.20 - 3.12 (m, 0.5H), 2.77 - 2.63 (m, 0.5H), 2.57 - 2.39 (m, 1H), 2.00 - 1.87 (m, 2H), 1.69 - 1.51 (m, 1H), 1.24 - 1.14 (m, 6H).

[0618] (S)-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-5-((2,2,2- trifluoroethyl)amino)-l,3-dihydro-2H-benzo[d]imidazol-2-one (Compound 116):

[0619] 116 To a mixture of (S)-5-amino-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH- benzo[d]imidazol-2(3H)-one (150 mg, 0.359 mmol) in DCM (1 mL) and TFA (1 mL) was added 2,2,2- trifluoroacetaldehyde (56.4 mg, 0.431 mmol, 75% purity) at 0 °C. The mixture was stirred at 0 °C for 5 min. Then NaBHsCN (33.9 mg, 0.539 mmol) was added. The resulting mixture was stirred at 20 °C for 1.5 hours. LCMS showed most of starting material remained. Then 2,2,2-trifluoroacetaldehyde (56.4 mg, 0.431 mmol, 75% purity) was added to the mixture, followed by NaBHsCN (33.9 mg, 0.539 mmol). The resulting mixture was stirred at 20 °C for another 2 hours. LCMS showed the starting materials were consumed and the desired compound was detected. The reaction mixture was concentrated in vacuum to remove the organic solvent. The resulting mixture was diluted with water (40 mL), basified to pH=9 by saturated Na2CO3aqueous solution and extracted with EtOAc (40 mL * 3). The combined organic phases were washed with brine (30 mL*3), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum to give a residue, which was purified by column chromatography (SiO3. petroleum ether: ethyl acetate = 10:0 to 1: 1) and then purified by reverse-phase HPLC to afford (S)-3- (l-(2-(3-chloro-5- fhiorophenyl)acetyl)piperidin-3-yl)-l-methyl-5-((2,2,2-trifluoroethyl)amino)-lH- benzo[d]imidazol-2(3H)-one as a white solid (57.34 mg, 31.94% yield), m / z 499.3 (M+H)+(ES+); ‘H NMR (400 MHz, CD3OD) <5 7.19 - 6.90 (m, 4H), 6.71 - 6.60 (m, 1H), 6.59 - 6.52 (m, 1H), 4.65 - 4.56 (m, 1H), 4.18 - 4.00 (m, 2H), 3.93 - 3.79 (m, 4.5H), 3.44 - 3.37 (m, 0.5H), 3.34 - 3.32 (m, 3H), 3.21 - 3.13 (m, 0.5H), 2.77 - 2.67 (m, 0.5H), 2.57 - 2.40 (1H), 2.00 - 1.89 (m, 2H), 1.68 - 1.52 (m, 1H).

[0620] (S)-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-5-((2-methoxyethyl)amino)-l-methyl- l,3-dihydro-2H-benzo[d]imidazol-2-one (Compound 117):

[0621] 117

[0622] To a mixture of (S)-5-bromo-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH- benzo[d]imidazol-2(3H)-one (100 mg, 0.208 mmol), 2 -methoxy ethanamine (156.2 mg, 2.08 mmol) and K3PO4 (88.3 mg, 0.416 mmol) in DMSO (4 mL) was added L-proline (47.9 mg, 0.416 mmol) and Cui (39.6 mg, 0.208 mmol). The mixture was degassed and purged with N2 for 3 times, then heated to 90 °C and stirred for 12 hours. LCMS showed the starting materials were consumed and the desired mass was detected. The reaction mixture was poured into water (40 mL) and extracted with EtOAc (30 mL * 3). The combined organic phases were washed with brine (40 mb * 3), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC to afford (S)-3-(l-(2-(3-chloro-5-fhiorophenyl)acetyl)piperidin-3-yl)-5-((2-methoxyethyl)amino)-l- methyl-lH-benzo[d]imidazol-2(3H)-one as a yellow solid (66.31 mg, 50.24% yield), m / z 475.2 (M+H)+(ES+); 'H NMR (400 MHz, CD3OD) d 7.21 - 7.07 (m, 2H), 7.06 - 6.95 (m, 1H), 6.94 - 6.86 (m, 1H), 6.71 - 6.64 (m, 0.5H), 6.59 - 6.46 (m, 1.5H), 4.66 - 4.54 (m, 1H), 4.18 - 3.98 (m, 2H), 3.95 - 3.75 (m, 2.5H), 3.65 - 3.53 (m, 2H), 3.44 - 3.35 (m, 3.5H), 3.34 - 3.32 (m, 3H), 3.29 - 3.25 (m, 2H), 3.19 - 3.11 (m, 0.5H), 2.77 - 2.66 (m, 0.5H), 2.56 - 2.39 (m, 1H), 1.99 - 1.84 (m, 2H), 1.68 - 1.50 (m, 1H).

[0623] (S)-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-5-((2-(dimethylamino)ethyl)amino)- l-methyl-l,3-dihydro-2H-benzo[d]imidazol-2-one (Compound 118):

[0624] To a mixture of (S)-5-bromo-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH- benzo[d]imidazol-2(3H)-one (100 mg, 0.208 mmol), N',N'-dimethylethane-l,2-diamine (183.3 mg, 2.08 mmol) and K3PO4 (88.3 mg, 0.416 mmol) in DMSO (4 mb) was added L-proline (47.9 mg, 0.416 mmol) and Cui (39.6 mg, 0.208 mmol). The mixture was degassed and purged with N2 for 3 times, then heated to 90 °C and stirred for 12 hours. LCMS showed the starting materials were consumed and the desired mass was detected. The reaction mixture was poured into water (60 mb) and extracted with EtOAc (40 mL * 3). The combined organic phases were washed with brine (40 mb * 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC to give a solution. The solution was concentrated in vacuum to remove the organic solvent and basified to pH=9 by saturated Na2CC>3 aqueous solution. The mixture was extracted with DCM (40 mL * 3). The combined organic phases were washed by brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford (S)-3-(l-(2-(3-chloro-5- fluorophenyl)acetyl)piperidin-3-yl) -5-((2-(dimethylamino)ethyl)amino)-l-methyl-lH- benzo[d]imidazol-2(3H)-one as a white solid (70.04 mg, 53.08% yield), m / z 488.2 (M+H)+(ES+); ’H NMR (400MHz, CD3OD) d 7.25 - 7.06 (m, 2H), 7.06 - 6.89 (m, 2H), 6.66 - 6.47 (m, 2H), 4.66 - 4.55 (m, 1H), 4.18 - 3.99 (m, 2H), 3.96 - 3.77 (2.5H), 3.40 (t, J= 12.4Hz, 0.5H), 3.34 - 3.32 (m, 3H), 3.29 - 3.23 (m, 2H), 3.19 - 3.11 (m, 0.5H), 2.79 - 2.60 (m, 2.5H), 2.58 - 2.44 (m, 1H), 2.41 - 2.31 (d, J= 7.6 Hz, 6H), 2.01 - 1.87 (m, 2H), 1.68 - 1.53 (m, 1H).

[0625] (S)-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-5-(cyclobutylamino)-l-methyl-l,3- dihydro-2H-benzo[d]imidazol-2-one (Compound 119):

[0626] 119

[0627] To a mixture of (S)-5-bromo-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH- benzo[d]imidazol-2(3H)-one (150 mg, 0.312 mmol), cyclobutanamine (110.9 mg, 1.56 mmol) and K3PO4 (132.4 mg, 0.624 mmol) in DMSO (4 mL) was added L-proline (71.8 mg, 0.624 mmol) and Cui (59.4 mg, 0.312 mmol). The mixture was degassed and purged with N2 for 3 times, then heated to 90 °C and stirred for 12 hours. LCMS showed the starting materials were consumed and the desired mass was detected. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL * 3). The combined organic phases were washed with brine (50 mL*3), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC to afford (S)-3 -( 1 -(2-(3 -chloro-5 -fluorophenyl)acetyl)piperidin-3 -y 1) -5 - (cyclobutylamino)- 1 -methyl- 1H- benzo[d]imidazol-2(3H)-one as a yellow solid (48.67 mg, 32.19% yield), m / z 471.2 (M+H)+(ES+); ’H NMR (400MHz, CD3OD) d 7.20 - 6.95 (m, 3H), 6.94 - 6.88 (m, 1H), 6.58 - 6.42 (m, 2H), 4.65 - 4.56 (m, 1H), 4.16 - 3.99 (m, 2H), 3.94 - 3.77 (m, 3.5H), 3.41 - 3.35 (m, 0.5H), 3.33 - 3.32 (m, 3H), 3.19 - 3.13 (m, 0.5H), 2.78 - 2.65 (m, 0.5H), 2.56 - 2.35 (m, 3H), 1.98 - 1.77 (m, 6H), 1.65 - 1.52 (m, 1H).

[0628] (S)-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-5-(oxetan-3-ylamino)-l,3- dihydro-2H-benzo[d]imidazol-2-one (Compound 120):

[0629] 120

[0630] To a mixture of (S)-5-bromo-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH- benzo[d]imidazol-2(3H)-one (120 mg, 0.249 mmol), oxetan-3 -amine (91.2 mg, 1.25 mmol) and K3PO4 (105.9 mg, 0.499 mmol) in DMSO (4 mL) was added L-proline (57.4 mg, 0.499 mmol) and Cui (47.5 mg, 0.249 mmol). The mixture was degassed and purged with N2 for 3 times, then heated to 90 °C and stirred for 12 hours. LCMS showed the starting materials were consumed and the desired mass was detected. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL * 3). The combined organic phases were washed with brine (50 mL * 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC to afford (S)-3 -( 1 -(2-(3 -chloro-5 -fluorophenyl)acetyl)piperidin-3 -yl)- 1 -methyl-5 - (oxetan-3 -ylamino)- lH-benzo[d]imidazol-2(3H)-one as a yellow solid (41.07 mg, 34.44% yield), m / z 473.2 (M+H)+(ES+); 'H NMR (400MHz, CD3OD) d 7.20 - 6.95 (m, 3H), 6.95 - 6.89 (m, 1H), 6.55 - 6.45 (m, 1H), 6.39 - 6.31 (m, 1H), 5.02 - 4.96 (m, 2H), 4.68 - 4.57 (m, 2H), 4.57 - 4.52 (m, 2H), 4.16 - 4.00 (m, 2H), 3.93 - 3.80 (m, 2.5H), 3.41 - 3.32 (m, 3.5H), 3.19 - 3.32 (m, 0.5H), 2.78 - 2.66 (m, 0.5H), 2.56 - 2.39 (m, 1H), 2.00 - 1.89 (m, 2H), 1.67 - 1.53 (m, 1H).

[0631] (S)-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-5-((3-methyloxetan-3- yl)amino)-l,3-dihydro-2H-benzo[d]imidazol-2-one (Compound 121):

[0632] 121 To a mixture of (S)-5-bromo-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH- benzo[d]imidazol-2(3H)-one (100 mg, 0.208 mmol) and 3-methyloxetan-3-amine (21.7 mg, 0.249 mmol) in dioxane (4 mb) was added K2CO3 (86.2 mg, 0.624 mmol) and BrettPhos Pd G3 (18.8 mg, 0.021 mmol). The mixture was degassed and purged with N2 for 3 times and stirred at 90 °C for 12 hours. LCMS showed the starting materials were consumed and the desired mass was detected. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (40 mb * 3). The combined organic phases were washed with brine (40 mL * 2), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum to give a residue, which was purified by column chromatography (SiCL, petroleum ether : ethyl acetate = 10:0 to 0: 1) and then purified by prep-HPLC to afford (S)-3-(l-(2-(3- chloro-5- fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-5-((3-methyloxetan-3-yl)amino)-lH- benzo[d]imidazol-2(3H)-one as a white solid (28.57 mg, 27.50% yield), m / z 487.1 (M+H)+(ES+); ‘H NMR (400 MHz, CD3OD) <5 7.19 - 6.91 (m, 4H), 6.53 - 6.41 (m, 1H), 6.31 - 6.22 (m, 1H), 4.83 - 4.78 (m, 2H), 4.66 - 4.59 (m, 1H), 4.58 - 4.54 (m, 2H), 4.17 - 4.02 (m, 2H), 3.90 - 3.79 (m, 2.5H), 3.40 - 3.32 (m, 3.5H), 3.17 - 3.10 (m, 0.5H), 2.76 - 2.61 (m, 0.5H), 2.56 - 2.40 (m, 1H), 2.00 - 1.88 (m, 2H), 1.66 - 1.61 (m, 3H), 1.60 - 1.49 (m, 1H).

[0633] (S)-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-5-((l-methylazeti din-3- yl)amino)-l,3-dihydro-2H-benzo[d]imidazol-2-one (Compound 122):

[0634] To a mixture of (S)-5-bromo-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH- benzo[d]imidazol-2(3H)-one (150 mg, 0.312 mmol), 1 -methylazetidin-3 -amine (134.3 mg, 1.56 mmol) and K3PO4 (132.4 mg, 0.624 mmol) in DMSO (4 mL) was added L-proline (71.8 mg, 0.624 mmol) and Cui (59.4 mg, 0.312 mmol). The mixture was degassed and purged with N2 for 3 times, then heated to 90 °C and stirred for 12 hours. LCMS showed the starting materials were consumed and the desired mass was detected. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (40 mL*4). The combined organic phases were washed with brine (40 mL * 3), dried with anhydrous Na2SC>4, fdtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC to give a solution (50 mL). The solution was concentrated in vacuum to remove the organic solvent and basified to pH=9 by saturated Na2CO3aqueous solution. The mixture was extracted with DCM (20 mb * 3). The combined organic phases were washed by brine (40 mL), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum to afford (S)-3-(l-(2-(3-chloro-5- fluorophenyl)acetyl)piperidin-3- yl)-l-methyl-5-((l-methylazetidin-3-yl)amino)-lH-benzo[d]imidazol-2(3H)-one as a white solid (32.96 mg, 20.76% yield), m / z 486.2 (M+H)+(ES+); 'H NMR (400 MHz, CD3OD) d 7.20 - 6.96 (m, 3H), 6.95 - 6.89 (m, 1H), 6.56 - 6.46 (m, 1H), 6.44 - 6.36 (m, 1H), 4.66 - 4.56 (m, 1H), 4.16 - 4.01 (m, 3H), 3.92 - 3.80 (m, 4.5H), 3.42 - 3.32 (m, 3.5H), 3.18 - 3.12 (m, 0.5H), 3.07 - 2.97 (m, 2H), 2.76 - 2.67 (m, 0.5H), 2.58 - 2.44 (m, 1H), 2.44 - 2.39 (m, 3H), 1.99 - 1.89 (m, 2H), 1.69 - 1.52 (m, 1H).

[0635] (S)-5-(benzylamino)-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-l,3- dihydro-2H-benzo[d]imidazol-2-one (Compound 123):

[0636] 123

[0637] To a mixture of (S)-5-bromo-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH- benzo[d]imidazol-2(3H)-one (150 mg, 0.312 mmol), phenyhnethanamine (167.1 mg, 1.56 mmol) and K3PO4 (132.4 mg, 0.624 mmol) in DMSO (4 mL) was added L-proline (71.8 mg, 0.624 mmol) and Cui (59.4 mg, 0.312 mmol). The mixture was degassed and purged with N2 for 3 times, then heated to 90 °C and stirred for 12 hours. LCMS showed the starting materials were consumed and the desired mass was detected. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (30 mL * 3). The combined organic phases were washed with brine (30 mL * 3), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC to afford (S)-5-(benzylamino)-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin -3-yl)-l-methyl-lH- benzo[d]imidazol-2(3H)-one as a yellow solid (47.43 mg, 28.99% yield), m / z 507.2 (M+H)+(ES+); ’H NMR (400MHz, CD3OD) d 7.43 - 7.37 (m, 2H), 7.33 - 7.24 (m, 2H), 7.21 - 6.94 (m, 4H), 6.91 - 6.85 (m, 1H), 6.85 - 6.42 (m, 2H), 4.62 - 4.49 (m, 1H), 4.37 - 4.31 (m, 2H), 4.15 - 4.03 (m, 1.5H), 4.00 - 3.95 (m, 0.5H), 3.88 - 3.77 (m, 2H), 3.75 - 3.68 (m, 0.5H), 3.34 - 3.33(m, 3H), 3.24 - 3.17 (0.5H), 3.11 - 3.03 (m, 0.5H), 2.68 - 2.59 (m, 0.5H), 2.36 - 2.24 (m, 1H), 1.92 - 1.80 (m, 2H), 1.63 - 1.48 (m, 1H). (S)-5-(((lH-benzo[d]imidazol-2-yl)methyl)amino)-3-(l-(2-(3-chloro-5- fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-l,3-dihydro-2H-benzo[d]imidazol-2-one

[0638] (Compound 124):

[0639] 124

[0640] To a mixture of (S)-5-amino-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH- benzo[d]imidazol-2(3H)-one (100 mg, 0.239 mmol) and 2-(chloromethyl)-lH-benzo[d]imidazole (39.9 mg, 0.239 mmol) in EtOH (3 mL) was added Na2CO3(27.9 mg, 0.263 mmol). The mixture was stirred at 60 °C for 12 hours. LCMS showed the starting materials were consumed and the desired mass was detected. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (40 mL * 3). The combined organic phases were washed with brine (40 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC to give a solution (30 mL). The solution was concentrated in vacuum to remove the organic solvent, basified to pH=9 by saturated Na3CO3aqueous solution. The mixture was extracted with DCM (60 mL * 3). The combined organic phases were washed by brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford (S)-5-(((lH-benzo[d]imidazol-2-yl)methyl)amino)-3-(l- (2-(3-chloro- 5-fhiorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH-benzo[d]imidazol-2(3H)-one as a yellow solid (35.06 mg, 12.82% yield), m / z 547.2 (M+H)+(ES+); 'H NMR (400 MHz, CD3OD) d 7.55 - 7.47 (m, 2H), 7.25 - 6.87 (m, 6H), 6.57 - 6.43 (m, 2H), 4.66 - 4.61 (m, 2H), 4.59 - 4.53 (m, 0.5H), 4.45 - 4.38 (m, 0.5H), 4.14 - 4.00 (m, 1.5H), 3.87 - 3.79 (m, 1.5H), 3.71 - 3.49 (m, 1.5H), 3.30 - 3.27 (m, 3H), 3.10 - 2.98 (m, 1H), 2.66 - 2.56 (m, 0.5H), 2.22 - 2.09 (m, 1H), 1.81 - 1.71 (m, 2H), 1.56 - 1.43 (m, 1H).

[0641] (S)-5-amino-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-l,3-dihydro-2H- benzo[d]imidazol-2-one (Compound 125):

[0642]

[0643] 125

[0644] To a mixture of (S)-5-bromo-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH- benzo[d]imidazol-2(3H)-one (150 mg, 0.312 mmol) and diphenylmethanimine (67.8 mg, 0.374 mmol) in dioxane (6 mb) was added CS2CO3 (152.4 mg, 0.468 mmol), Xantphos (36.1 mg, 0.062 mmol) and Pd2(dba)s (28.5 mg, 0.031 mmol). The mixture was degassed and purged with N2 for 3 times, then heated to 100 °C and stirred for 6 hours. LCMS and TLC (petroleum ether: ethyl acetate = 1: 1) showed the reaction was completed. The mixture was cooled to 20 °C, diluted with DCM (20 mL) and fdtered. The fdtrate was concentrated in vacuum to give a residue, which was purified by column chromatography (SiC>2, petroleum ether: ethyl acetate = 10: 1 to 1: 1) and then purified by reverse-phase HPLC to afford (S)-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)- 5- ((diphenylmethylene)amino)-l-methyl-lH-benzo[d]imidazol-2(3H)-one (90 mg, 24.82% yield) as a yellow solid, m / z 581.2 (M+H)+(ES+); 'H NMR (400 MHz, CD3OD) d 7.75 - 7.67 (m, 2H), 7.55 - 7.42 (m, 3H), 7.31 - 7.18 (m, 3H), 7.21 - 7.10 (m, 4H), 7.08 - 6.97 (m, 2H), 6.78 - 6.72 (m, 1H), 6.58 (d, J = 1.6 Hz, 0.5H), 6.38 (d, J= 1.6 Hz, 0.5H), 4.57 - 4.52 (m, 0.5H), 4.43 - 4.36 (m, 0.5H), 4.07 - 3.98 (m, 1H), 3.91 - 3.72 (m, 3H), 3.62 - 3.53 (m, 0.5H), 3.33 (s, 3H), 3.08 - 2.94 (m, 1H), 2.65 - 2.56 (m, 0.5H), 2.14 - 2.02 (m, 1H), 1.88 - 1.79 (m, 1H), 1.77 - 1.63 (m, 1H), 1.55 - 1.40 (m, 1H).

[0645] (S)-5-amino-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH- benzo [d] imidazol-2(3H)-one

[0646] To a solution of (S)-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-5-((diphenyhnethylene) amino)-l-methyl-lH-benzo[d]imidazol-2(3H)-one (90 mg, 0. 154 mmol) in THF (2 mL) was added HC1 (6 N, 1 mL) at 20 °C. The mixture was stirred at 20 °C for 2 hours. LCMS showed the starting materials were consumed and the desired mass was detected. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL). The aqueous phase was adjusted to pH=9 by solid Na2CC>3. The resulting mixture was extracted with EtOAc (20 mL * 3). The combined organic phases were washed with brine (20 mL * 2), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum to give a residue, which was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 5:0 to 0: 1) and then purified by prep-HPLC to afford (S)-5-amino-3-(l-(2-(3-chloro-5- fluorophenyl)acetyl)piperidin-3-yl)-l-methyl-lH-benzo[d]imidazol-2(3H)-one as a yellow solid (35.23 mg, 54.29% yield), m / z 417.3 (M+H)+(ES+); 'H NMR (400 MHz, CD3OD) 37.22 - 6.06 (m, 2H), 7.05

[0647] - 6.95 (m, 1H), 6.93 - 6.86 (m, 1H), 6.78 - 6.53 (m, 2H), 4.66 - 4.56 (m, 1H), 4.17 - 3.99 (m, 2H), 3.93

[0648] - 3.76 (m, 2.5H), 3.42 - 3.32 (m, 3.5H), 3.20 - 3.13(m, 0.5H), 2.77 - 2.65 (m, 0.5H), 2.55 - 2.40 (m, 1H), 2.03 - 1.83 (m, 2H), 1.67 - 1.50 (m, 1H).

[0649] (S)-5-amino-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-cyclopropyl-l,3-dihydro-

[0650] 2H-benzo[d]imidazol-2-one (Compound 126):

[0651] 126

[0652] To a stirred solution of tert-butyl A'-{3-|(3S)-l-|2-(3-chloro-5-fliiorophcnyl)acctyl |pipcridin-3-yl |-2- oxo-2, 3-dihydro- 1 H- 1.3-bcnzodiazol-5- l [carbamate (70 mg, 0.14 mmol, 1 equiv.) and cyclopropyl boronic acid (14 mg, 0.17 mmol, 1.2 equiv.) in dry toluene (5 mb), Cu(OAc)2 (25 mg, 0.14 mmol, 1 equiv.) followed by Na2COs (30 mg, 0.28 mmol, 2 equiv.) and pyridine (22 mg, 0.28 mmol, 2 equiv.) were added. The reaction mixture was stirred at 70°C under oxygen balloon pressure for 8 h. After completion, the mixture was cooled, extracted with ethyl acetate, washed with water, brine, dried over anhydrous Na2SC>4 and concentrated. The crude product was purified (Flash Column Silica-CS, 4 g, 50% ethyl acetate in hexane) to afford tert-butyl A-{3-[(3S)-l-[2-(3-chloro-5- fluorophenyl)acetyl]piperidin-3 -yl] - 1 -cyclopropyl-2-oxo-2, 3 -dihydro- 1H- 1 ,3 -benzodiazol -5 - yl}carbamate as a light pink solid (60 mg, 79%, 0.110 mmol), m / z 543.0 [M+H]+

[0653] To a stirred solution of tert-butyl A-{3-|(3S)-l-|2-(3-chloro-5-fliiorophcnyl)acctyl |pipcridin-3-yl |-l- cyclopropyl-2 -oxo-2, 3-dihydro-lH-l,3-benzodiazol-5-yl}carbamate (55 mg, 0.10 mmol) in 1,4- dioxane (1 mb), 4M HC1 in dioxane (2 mb) was added. The reaction mixture was stirred at room temperature for 5 h. After completion, the reaction mixture was concentrated, washed with diethyl ether and dried to afford 5-amino-3-[(3S)-l-[2-(3-chloro-5-fluorophenyl)acetyl]piperidin-3-yl]-l- cyclopropyl-2,3-dihydro- 1H- 1 ,3-benzodiazol-2-one as a light brown solid HCl-Salt (1:1) (45 mg, 0.094 mmol, 87%). ’HNMR (400 MHz, DMSO- 6) (Rotamers) 5 9.60 (br s, 3 H), 7.29-7.10 (m, 5 H), 6.99 (d, J= 6.76 Hz, 1 H), 4.48-4.40 (m, 1 H), 4.20-4.06 (m, 2 H), 3.89-3.71 (m, 2 H), 3.21-2.80 (m, 2 H), 2.49-2.32 (m, 2 H), 1.90-1.85 (m, 2 H), 1.60-1.50 (m, 1 H), 1.10-1.02 (m, 2 H), 0.90-0.80 (m, 2 H) ppm; m / z 443.26 [M+H]+

[0654] (S)-5-amino-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-(2-hydroxyethyl)-l,3- dihydro-2H-benzo[d]imidazol-2-one (Compound 127):

[0655] 127

[0656] To a stirred solution of tert-butyl A'-{3-|(3S)- l -|2-(3-chloro-5-fliiorophcnyl)acctyl |pipcridin-3-yl |-2- oxo-2, 3-dihydro- 1 H- 1.3-bcnzodiazol-5-yl [carbamate (70 mg, 0.14 mmol, 1 equiv.) in acetonitrile (2 mL), CS2CO3 (91 mg, 0.28 mmol, 2 equiv.) and 2-iodoethyl methyl ether (31 mg, 0.17 mmol, 1.2 equiv.) were added. The reaction mixture was stirred at 80 °C for 30 minutes. After completion, the mixture was fdtered and the fdtrate was concentrated. The crude product was purified (Flash Column Silica- CS, 12 g, 50% ethyl acetate in hexane) to afford tert-butyl A-{3-[(3S)-l-[2-(3-chloro-5- fluorophenyl)acetyl]piperidin-3-yl] - 1 -(2-methoxyethyl)-2-oxo-2,3-dihydro- 1H- 1 ,3-benzodiazol-5- yl}carbamate (55 mg, 70%, 0.098 mmol) as a white sticky solid, m / z 561.4 [M+H]+

[0657] To a stirred solution of tert-butyl A-{3-[(3S)-l-[2-(3-chloro-5-fluorophenyl)acetyl]piperidin-3-yl]-l- (2-methoxyethyl)-2 -oxo-2, 3-dihydro- IH- 1.3-bcnzodiazol-5-yl [carbamate (55 mg, 0.1 mmol, 1 equiv.) in dichloromethane (1 mL), BBr, in dichloromethane (IM) (1 mL, 10 equiv.) was added at -78°C. The reaction mixture was stirred at that temperature for 1 h then allowed to warm to room temperature and stirred for 2 h. After completion, the reaction mixture was cooled to -78°C, quenched by the slow addition of methanol and concentrated. The crude product was purified by prep-HPLC to afford 5- amino-3 -[(3 S)- 1 - [2 -(3 -chloro-5 -fluorophenyl)acetyl]piperidin-3 -yl] - 1 -(2-hydroxyethyl)-2,3 -dihydro- IH- l .3-bcnzodiazol-2-onc as a white solid (26 mg, 0.058 mmol, 59%). 'H NMR (400 MHz, DMSO- 6) (Rotamers) 5 7.35-7.25 (m, 1 H), 7.21-7.06 (m, 2 H), 6.85 (d, J = 8.24 Hz, 1 H), 6.60-6.58 (m, 1 H), 6.35-6.25 (m, 1 H), 4.81 (br s, 1 H), 4.72 (br, 2 H), 4.48-4.37 (m, 1 H), 4.04-4.02 (m, 2 H), 3.88- 3.74 (m, 4 H), 3.58 (d, J= 5.16 Hz, 2 H), 3.23-3.02 (m, 2 H), 2.59-2.36 (m, 1 H), 1.90-1.80 (m, 2 H), 1.56-1.44 (m, 1 H) ppm; m / z 447.27 [M+H]+

[0658] (S)-5-amino-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-(2-methoxyethyl)-l,3- dihydro-2H-benzo[d]imidazol-2-one (Compound 128):

[0659] 128 tert-butyl JV-{3-[(3S)-l-[2-(3-chloro-5-fluorophenyl)acetyl]piperidin-3-yl]-l-(2-methoxyethyl)-2- oxo-2, 3-dihydro-LH-l,3-benzodiazol-5-yl}carbamate

[0660] To a stirred solution of tert-butyl A'-{3-|(3S)- l -|2-(3-chloro-5-fliiorophcnyl)acctyl |pipcridin-3-yl |-2- oxo-2, 3-dihydro- 1 H- 1.3-bcnzodiazol-5-yl [carbamate (70 mg, 0.14 mmol, 1 equiv.) in acetonitrile (2 mL), CS2CO3 (91 mg, 0.28 mmol, 2 equiv.) and 2-iodoethyl methyl ether (31 mg, 0.17 mmol, 1.2 equiv.) were added. The reaction mixture was stirred at 80 °C for 30 minutes. After completion, the mixture was fdtered and the fdtrate was concentrated. The crude product was purified (Flash Column Silica- CS, 4 g, 50% ethyl acetate in hexane) to afford tert-butyl A-{3-[(3S)-l-[2-(3-chloro-5- fluorophenyl)acetyl]piperidin-3-yl] - 1 -(2-methoxyethyl)-2-oxo-2,3-dihydro- 1H- 1 ,3-benzodiazol-5- yl}carbamate (52 mg, 66%, 0.093 mmol) as a white sticky solid, m / z 561.4 [M+H]+

[0661] 5-amino-3-[(3S)-l-[2-(3-chloro-5-fluorophenyl)acetyl]piperidin-3-yl]-l-(2-methoxyethyl)-2,3- dihydro- 1H- 1 ,3-benzodiazol-2-one

[0662] To a stirred solution of tert-butyl A-{3-[(3S)-l-[2-(3-chloro-5-fluorophenyl)acetyl]piperidin-3-yl]-l- (2-methoxyethyl)-2-oxo-2,3-dihydro- 1H- 1, 3 -benzodiazol -5 -yl (carbamate (48 mg, 0.09 mmol) in 1,4- dioxane (2 mL), 4M HC1 in dioxane (2 mL) was added. The reaction mixture was stirred at room temperature for 5 h. After completion, the reaction mixture was concentrated, washed with diethyl ether twice and dried to afford 5-amino-3-[(3S)-l-[2-(3-chloro-5-fluorophenyl)acetyl]piperidin-3-yl]-l-(2- mcthoxycthyl)-2.3-dihydro- IH- l .3-bcnzodiazol-2-onc as a light brown solid HCl-salt (1: 1) (37 mg, 0.074 mmol, 87%). ’H NMR (400 MHz, DMSO- 6) (Rotamers) 5 9.79 (br, 3 H), 7.37-7.26 (m, 3 H), 7.21-7.17 (m, 1 H), 7.13-7.07 (m, 1 H), 7.01 (d, J= 8.12 Hz, 1 H), 4.45-4.41 (m, 1 H), 4.22-3.98 (m, 3 H), 3.90-3.73 (m, 2 H), 3.60-3.55 (m, 2 H), 3.23-3.18 (m, 4 H), 3.10-3.04 (m, 1 H), 2.58-2.33 (m, 2 H), 1.92-1.85 (m, 2 H), 1.60-1.52 (m, 1 H) ppm; m / z 461.26 [M+H]+

[0663] (S)-5-amino-3-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-l-(2-(dimethylamino)ethyl)- l,3-dihydro-2H-benzo[d]imidazol-2-one (Compound 129):

[0664] 129 tert-butyl JV-{3-[(3S)-l-[2-(3-chloro-5-fluorophenyl)acetyl]piperidin-3-yl]-l-[2-

[0665] (dimethylamino)ethyl]-2-oxo-2,3-dihydro- 1 / 7-1, 3-benzodiazol-5-yl}carbamate

[0666] To a stirred solution of tert-butyl A'-{3-|(3S)-l-|2-(3-chloro-5-fliiorophcnyl)acctyl |pipcridin-3-yl |-2- oxo-2, 3-dihydro- 1 H- 1.3-bcnzodiazol-5-yl [carbamate (80 mg, 0.16 mmol, 1 equiv.) in acetonitrile (2 mL), CS2CO3 (155 mg, 0.48 mmol, 3 equiv.) and 2 -bromo -A. A'-dimcthylcthan- 1 -amine hydrobromide (41 mg, 0.18 mmol, 1.1 equiv.) were added. The reaction mixture was stirred at room temperature for 6 h. After completion, the mixture was filtered and the filtrate was concentrated. The crude product was purified (Flash Column Silica-CS, 4 g, 2% methanol in dichloromethane) to afford tert-butyl N-{3- [(3S)-l-[2-(3-chloro-5-fhiorophenyl)acetyl]piperidin-3-yl]-l-[2-(dimethylamino)ethyl]-2-oxo-2,3- dihydro- 1H- 1, 3 -benzodiazol -5 -yl (carbamate (60 mg, 66%, 0.105 mmol) as an off white solid, m / z 573.6 [M+H]+

[0667] 5-amino-3-[(3S)-l-[2-(3-chloro-5-fluorophenyl)acetyl]piperidin-3-yl]-l-[2- (dimethylamino)ethyl]-2,3-dihydro-LH-l,3-benzodiazol-2-one

[0668] To a stirred solution of tert-butyl A-{3-[(3S)-l-[2-(3-chloro-5-fluorophenyl)acetyl]piperidin-3-yl]-l- [2-(dimethylamino)ethyl]-2 -oxo-2, 3-dihydro-IH-l.3-bcnzodiazol-5-yl [carbamate (65 mg, 0.11 mmol) in 1,4-dioxane (1 mL), 4M HC1 in dioxane (2 mL) was added. The reaction mixture was stirred at room temperature for 5 h. After completion, the mixture was concentrated, washed with diethyl ether twice and dried to afford 5-amino-3-[(3S)-l-[2-(3-chloro-5-fluorophenyl)acetyl]piperidin-3-yl]-l-[2- (dimcthylamino)cthyl |-2.3-dihydro-IH-l.3-bcnzodiazol-2-onc as a light brown di-hydrochloride-salt (55 mg, 0.101 mmol, 89%). H NMR (400 MHz, DMSO- 6) (Rotamers) 5 10.71-10.31 (m, 4 H), 7.56- 7.51 (m, 1 H), 7.43 (d, J = 8.32 Hz, 1 H), 7.32-7.27 (m, 1 H), 7.21 (s, 1 H), 7.16-7.12 (m, 2 H), 4.51- 4.45 (m, 1 H), 4.30-4.25 (m, 3 H), 4.12-4.02 (m, 1 H), 3.90-3.76 (m, 2 H), 3.50-3.39 (m, 2 H), 3.24- 3.05 (m, 1 H), 2.85 (s, 6 H), 2.67-2.50 (m, 1 H), 2.35-2.29 (m, 1 H), 1.96-1.83 (m, 2 H), 1.61-1.53 (m, 1 H) ppm; m / z 474.33 [M+H]+

[0669] (S)-5-amino-l-(l-(2-(3-chloro-5-fluorophenyl)acetyl)piperidin-3-yl)-3-methyl-l,3-dihydro-2H- benzo [d]imidazol-2-one (Compound 130):

[0670] 130

[0671] (S)-tert-butyl 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-l- carboxylate

[0672] To a solution of tert-butyl (3S)-3-(5-bromo-2-oxo-3H-benzimidazol-l-yl)piperidine-l-carboxylate (1 g, 2.52 mmol) in DMF (10 mL) was added NaH (121.1 mg, 3.03 mmol, 60% purity) at 0°C. After being stirred for 0.25 hour, CH3I (429.8 mg, 3.03 mmol) was added and the reaction was stirred for another 0.25 hour. TLC (petroleum ether: ethyl acetate = 1: 1) indicated starting material was consumed and one new spot was formed. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (20 mL * 4). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated in vacuum to give a residue, which was purified by silica gel chromatography (SiCL, petroleum ether : ethyl acetate = 8: 1 to 1: 1) to afford (S) -tert-butyl 3-(5-bromo-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)piperidine-l-carboxylate as an off-white solid (1 g, 96.6% yield). The structure was confirmed by HSQC and NOE. m / z 410.3 (M+H)+(ES+); ’H NMR (400 MHz, DMSO-t / e) <5 7.42 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.4, 2.0 Hz, 1H), 4.19 - 4.11 (m, 1H), 4.00 - 3.94 (m, 2H), 3.30 (s, 3H), 2.90 - 2.71 (m, 1H), 2.35 - 2.22 (m, 1H), 1.85 - 1.76 (m, 2H), 1.58 - 1.44 (m, 2H), 1.40 (s, 9H)

[0673] (S)-tert-butyl 3-(5-amino-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-l- carboxylate

[0674] A mixture of (S)-tert-butyl 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)piperidine-l -carboxylate (850 mg, 2.07 mmol), K2CO3 (858.9 mg, 6.21 mmol), (2S,4S)-4- hydroxypyrrolidine-2 -carboxylic acid (54.3 mg, 0.414 mmol) and ammonium hydroxide (1.24 g, 12.43 mmol, 1.37 mL, 35% purity) in DMSO (10 mL) was added Cui (394.5 mg, 2.07 mmol). The reaction was degassed and purged with nitrogen for three times. The mixture was stirred at 100 °C under nitrogen protection for 1 hour. TLC (petroleum ether: ethyl acetate = 1: 1) indicated starting material was consumed and one new spot was formed. The mixture was poured into water (100 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed by brine (20 mL), dried over sodium sulfate, fdtered and concentrated in vacuum to give a residue, which was purified by silica chromatography (SiCK petroleum ether: ethyl acetate = 3: 1 to 1: 1) to afford (S) -tert-butyl 3-(5-amino- 3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-l-carboxylate as brown oil (610 mg, 85% yield), m / z 347.1 (M+H)+(ES+); 'H NMR (400 MHz, METHANOL-^) 5 7.06 (d, J = 8.0 Hz, 1H), 6.58 - 6.52 (m, 2H), 4.21 - 4.00 (m, 3H), 3.51 - 3.38 (m, 1H), 3.33 (s, 3H), 2.89 - 2.75 (m, 1H), 2.46 - 2.33 (m, 1H), 1.96 - 1.80 (m, 2H), 1.69 - 1.55 (m, 1H), 1.47 (s, 9H).

[0675] (S)-5-amino-3-methyl-l-(piperidin-3-yl)-lH-benzo[d]imidazol-2(3H)-one

[0676] To a solution of (S)-tert-butyl 3-(5-amino-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)piperidine-l -carboxylate (610 mg, 1.76 mmol) in MeOH (5 mL) was added HCl / MeOH (10 mL). The resulting mixture was stirred at 15 °C for 0.5 hours. TLC (DCM: MeOH = 10: 1) indicated starting material was consumed and one new spot was formed. The mixture was concentrated in vacuum to afford (S)-5-amino-3-methyl-l-(piperidin-3-yl)-lH-benzo[d]imidazol-2(3H)-one (520 mg, 92.51% yield, HC1 salt) as a brown solid. 'H NMR (400 MHz, METHANOL-^) <5 7.48 (d, J = 8.4 Hz, 1H), 7.23 - 7.17 (m, 2H), 4.76 - 4.66 (m, 1H), 3.87 - 3.76 (m, 1H), 3.56 - 3.49 (m, 1H), 3.45 (s, 3H), 3.42 - 3.36 (m, 1H), 3.27 - 3.18 (m, 1H), 2.47 - 2.36 (m, 1H), 2.14 - 1.90 (m, 3H).

[0677] Prepared as described in General Procedure 1, from (S)-5-amino-3-methyl-l-(piperidin-3-yl)-lH- benzo[d]imidazol-2(3H)-one and 2-(3-chloro-5-fluorophenyl)acetic acid, in 45% yield. ’H NMR (400 MHz, DMSO- e) <5 7.32 - 7.26 (m, 1H), 7.20 - 6.92 (m, 3H), 6.35 (d, J= 1.6 Hz, 1H), 6.29 (d, J= 8.0 Hz, 1H), 4.82 (s, 2H), 4.45 - 4.32 (m, 1H), 4.07 - 3.93 (m, 2H), 3.88 - 3.69 (m, 2.5H), 3.20 - 3.08 (m, 4H), 2.67 - 2.58 (m, 0.5H), 2.36 - 2.25 (m, 1H), 1.84 - 1.75 (m, 2H), 1.59 - 1.37 (m, 1H); m / z 417.1 (M+H)+(ES+)

[0678] (S)-5-amino-l-(l-(2-(3-fluoro-5-methylphenyl)acetyl)piperidin-3-yl)-3-methyl-l,3-dihydro-2H- benzo [d]imidazol-2-one (Compound 131):

[0679] 131

[0680] Prepared as described in General Procedure 1, from (S)-5-a...

Claims

1. CLAIMS1. A composition comprising a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient:wherein: each of X1to X4is independently selected from N, CH and CR3, at least one of X6and X7comprise a nitrogen atom such that X5, X6and X7form a structure selected from any one of Formulae 1-1, 1-2 and 1-3:Formula 1-1 : Formula I-2: Formula I-3:wherein in Formula 1-1, X5is selected from NR4, O and C(R5)(R6), wherein in Formula 1-2, X5is N, wherein in Formula 1-3, X5is NR8, represents a connection point to the rest of Formula I,R1is selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, - (optionally substituted alkylene)-(optionally substituted cycloalkyl), -(optionally substituted alkylene) -(optionally substituted heterocyclyl), -(optionally substituted alkylene) -(optionally substituted aryl), -(optionally substituted alkylene)-(optionally substituted heteroaryl), -(NH)- (optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH)-(optionallysubstituted heterocyclyl), -(NH)-(optionally substituted aryl), -(NH) -(optionally substituted heteroaryl), -(O) -(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O)- (optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), and -(O) -(optionally substituted heteroaryl), each R2is independently selected from hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino, each R3is independently selected from hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, -(NH) -(optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH) -(optionally substituted heterocyclyl), -(NH) -(optionally substituted aryl), - (NH) -(optionally substituted heteroaryl), -(O)-(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O) -(optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), -(O) -(optionally substituted heteroaryl), -(CO)-(optionally substituted alkyl), -(CO)- (optionally substituted cycloalkyl), -(CO)-(optionally substituted heterocyclyl), -(CO)- (optionally substituted alkoxy), -(CO)-(optionally substituted aryl), -(CO) -(optionally substituted heteroaryl), -(CO) -(optionally substituted amino), and -COOH,R4is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, each of R5and R6is independently selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino,R7is selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, - (NH) -(optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH)- (optionally substituted heterocyclyl), -(NH) -(optionally substituted aryl), -(NH) -(optionally substituted heteroaryl), -(O) -(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O)-(optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), -(O)- (optionally substituted heteroaryl), -(CO)-(optionally substituted alkyl), -(CO)-(optionally substituted cycloalkyl), -(CO) -(optionally substituted heterocyclyl), -(CO)-(optionally substituted alkoxy), -(CO) -(optionally substituted aryl), -(CO)-(optionally substituted heteroaryl), -(CO)-(optionally substituted amino), and -COOH,R8is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, m is an integer selected from 0 to 9, n is an integer selected from 0 to 4, and with the proviso that when X5, X6and X7form a structure according to Formula 1-3, X1is N and each of X2to X4is independently selected from CH and CR3.

2. A composition according to claim 1, wherein R1is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, -(optionally substituted alkylene) -(optionally substituted heterocyclyl), -(optionally substituted alkylene) -(optionally substituted aryl), - (optionally substituted alkylene) -(optionally substituted heteroaryl), and -(NH) -(optionally substituted aryl).

3. A composition according to claim 1 or claim 2, wherein R1is selected from optionally substituted C1-C12 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C1-C12 alkoxy, optionally substituted 5-14 membered heteroaryl, -(optionally substituted C1-C12 alkylene)-(optionally substituted 3-10 membered heterocyclyl), -(optionally substituted C1-C12 alkylene)-(optionally substituted Ce- C14 aryl), -(optionally substituted C1-C12 alkylene) -(optionally substituted 5-14 membered heteroaryl), and -(NH) -(optionally substituted Ce-Ci4 aryl).

4. A composition according to any one of claims 1 to 3, wherein R1is selected from -(optionally substituted alkylene) -(optionally substituted aryl), and -(optionally substituted alkylene)- (optionally substituted heteroaryl).

5. A composition according to any one of claims 1 to 4, wherein R1is -(optionally substituted alkylene) -(optionally substituted aryl).

6. A composition according to any one of claims 1 to 3, wherein the optionally substituted heterocyclyl group for R1is selected from optionally substituted tetrahydrothiophenyl (e.g. tetrahydrothiophenyl dioxide), and optionally substituted 2-thiaspiro[3.3]heptanyl (e.g. 2- thiaspiro[3 ,3]heptanyl 2,2-dioxide).

7. A composition according to any one of claims 1 to 3, wherein the optionally substituted heteroaryl group for R1is optionally substituted indazolyl.

8. A composition according to any one of claims 1 to 3, wherein the -(optionally substituted alkylene) -(optionally substituted heterocyclyl) group for R1is -(optionally substituted alkylene) -(optionally substituted thiazolidinyl).

9. A composition according to any one of claims 1 to 4 or 6 to 8, wherein the -(optionally substituted alkylene) -(optionally substituted heteroaryl) group for R1is selected from - (optionally substituted alkylene)-(optionally substituted thiophenyl), -(optionally substituted alkylene) -(optionally substituted indolyl), -(optionally substituted alkylene) -(optionally substituted pyridyl), -(optionally substituted alkylene)-(optionally substituted isoxazolyl), - (optionally substituted alkylene) -(optionally substituted pyrazolyl), -(optionally substituted alkylene) -(optionally substituted tetrazolyl), -(optionally substituted alkylene) -(optionally substituted imidazolyl), and -(optionally substituted alkylene) -(optionally substituted pyrimidinyl).

10. A composition according to any one of claims 1 to 9, wherein the optionally substituted aryl group of the -(optionally substituted alkylene) -(optionally substituted aryl) group for R1has the following structure:wherein * represents a connection point to the optionally substituted alkylene group, and each Rlais independently selected from halogen, cyano, alkyl, haloalkyl, and alkoxy.

11. A composition according to any one of claims 1 to 10, wherein each R2is independently selected from hydroxy, optionally substituted alkyl, and optionally substituted alkoxy.

12. A composition according to any one of claims 1 to 11, wherein each R3is independently selected from hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted amino, -(NH) -(optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH) -(optionally substituted heterocyclyl), -(CO)-(optionally substituted alkoxy), -(CO)-(optionally substituted amino), and -COOH.

13. A composition according to any one of claims 1 to 12, wherein each R3is independently optionally substituted amino.

14. A composition according to any one of claims 1 to 13, wherein R4is selected from hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl.

15. A composition according to any one of claims 1 to 14, wherein R4is optionally substituted alkyl.

16. A composition according to any one of claims 1 to 15, wherein R5is selected from hydrogen, halogen, and optionally substituted alkyl.

17. A composition according to any one of claims 1 to 16, wherein R6is selected from hydrogen, halogen, and optionally substituted alkyl.

18. A composition according to any one of claims 1 to 17, wherein R7is selected from optionally substituted alkoxy, optionally substituted amino, -(O) -(optionally substituted heterocyclyl), and -COOH.

19. A composition according to any one of claims 1 to 18, wherein R8is hydrogen.

20. A composition according to any one of claims 1 to 19, wherein X1is N.

21. A composition according to any one of claims 1 to 19, wherein X1is CH or CR3.

22. A composition according to any one of claims 1 to 21, wherein X2is N.

23. A composition according to any one of claims 1 to 21, wherein X2is CH or CR3.

24. A composition according to any one of claims 1 to 23, wherein X3is N.

25. A composition according to any one of claims 1 to 23, wherein X3is CH or CR3.

26. A composition according to any one of claims 1 to 25, wherein X4is N.

27. A composition according to any one of claims 1 to 25, wherein X4is CH or CR3.

28. A composition according to any one of claims 1 to 19, wherein X1is N, and each of X2to X4is independently selected from CH and CR3.

29. A composition according to any one of claims 1 to 19, wherein X2is N, and each of X1, X3and X4is independently selected from CH and CR3.

30. A composition according to any one of claims 1 to 19, wherein X3is N, and each of X1, X2and X4is independently selected from CH and CR3.

31. A composition according to any one of claims 1 to 19, wherein X4is N, and each of X1to X3is independently selected from CH and CR3.

32. A composition according to any one of claims 1 to 19, wherein X2and X4are N, and each of X1and X3is independently selected from CH and CR3.

33. A composition according to any one of claims 1 to 19, wherein each ofX1to X4is independently selected from CH and CR3.

34. A composition according to any one of claims 1 to 19, wherein X2is CR3, and each of X1, X3and X4is CH.

35. A composition according to any one of claims 1 to 34, wherein m is 0 or 1.

36. A composition according to any one of claims 1 to 35, wherein m is 0.

37. A composition according to any one of claims 1 to 36, wherein n is 0, 1 or 2.

38. A composition according to any one of claims 1 to 37, wherein n is 1.

39. A composition according to any one of claims 1 to 38, wherein the compound according to Formula I has a structure according to Formula la:la wherein each of X1to X7, R1to R8, m and n are as defined in any one of claims 1 to 38.

40. A composition according to any one of claims 1 to 38, wherein the compound according to Formula I has a structure according to Formula lb:wherein each of X1to X7, R1to R8, m and n are as defined in any one of claims 1 to 38.

41. A composition according to any one of claims 1 to 40, wherein the compound according to Formula I has a structure according to Formula II- 1:11-1 wherein X5is selected from NR4, O and C(R5)(R6), and each of X1to X4, R1to R6, m and n are as defined in any one of claims 1 to 40.

42. A composition according to claim 41, wherein X5is NR4.

43. A composition according to claim 41, wherein X5is O.

44. A composition according to claim 41, wherein X5is C(R5)(R6).

45. A composition according to any one of claims 1 to 40, wherein the compound according to Formula I has a structure according to Formula II-2:wherein X5is N, and each of X1to X4, R1to R3, R7, m and n are as defined in any one of claims 1 to 40.

46. A composition according to any one of claims 1 to 40, wherein the compound according to Formula I has a structure according to Formula II-3:wherein X5is NR8, and each of R1to R3, R8, m and n are as defined in any one of claims 1 to 40.

47. A dosage form comprising a composition according to any one of claims 1 to 46.

48. A compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof:I wherein each of X1to X7, R1to R8, m and n are as defined in any one of claims 1 to 46; or a composition according to any one of claims 1 to 46; or a dosage form according to claim 47; for use in the treatment of a disease modulated by RNA methyltransferase.

49. A compound for use according to claim 48; or a composition for use according to claim 48; or a dosage form for use according to claim 48; wherein the disease modulated by RNA methyltransferase is a cancer.

50. A compound for use according to claim 49; or a composition for use according to claim 49; or a dosage form for use according to claim 49; wherein the cancer is selected from liver cancer (e.g. hepatocellular carcinoma), gastric cancer, intestinal cancer, colorectal cancer, glioma (e.g. glioblastoma), breast cancer, bladder cancer (e.g. urothelial carcinoma of the bladder), prostate cancer, renal cancer (e.g. clear cell renal cell carcinoma), gall bladder carcinoma, lung cancer (e.g. lung squamous cell carcinoma), skin cancer (e.g. cutaneous melanoma), throat cancer (e.g. oesophageal squamous cell carcinoma, hypopharyngeal squamous cell carcinoma), head and neck cancer (e.g. head and neck squamous cell carcinoma), and pancreatic cancer.

51. A kit comprising a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof:wherein each of X1to X7, R1to R8, m and n are as defined in any one of claims 1 to 46; or a composition according to any one of claims 1 to 46; or a dosage form according to claim 47; and a pharmaceutically acceptable carrier or excipient, and / or instructions for use of the compound, the composition or the dosage form in the treatment of a disease modulated by RNA methyltransferase .

52. A process for manufacturing a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein the process comprises a step of coupling a compound according to Formula Int-A to a compound according to Formula Int- B:Int-A wherein each of X1to X7, R1to R8, m and n are as defined in any one of claims 1 to 46.

53. A compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof:wherein: each of X1to X4is independently selected from N, CH and CR3, at least one of X6and X7comprise a nitrogen atom such that X5, X6and X7form a structure selected from any one of Formulae 1-1, 1-2 and 1-3:Formula 1-1 : Formula 1-2: Formula I-3:wherein in Formula 1-1, X5is selected from NR4, O and C(R5)(R6), wherein in Formula 1-2, X5is N, wherein in Formula 1-3, X5is NR8, represents a connection point to the rest of Formula I,R1is selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, - (optionally substituted alkylene)-(optionally substituted cycloalkyl), -(optionally substituted alkylene) -(optionally substituted heterocyclyl), -(optionally substituted alkylene) -(optionally substituted aryl), -(optionally substituted alkylene)-(optionally substituted heteroaryl), -(NH)- (optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH)-(optionally substituted heterocyclyl), -(NH)-(optionally substituted aryl), -(NH) -(optionally substituted heteroaryl), -(O) -(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O)- (optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), and -(O) -(optionally substituted heteroaryl), each R2is independently selected from hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino, each R3is independently selected from hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, -(NH) -(optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH) -(optionally substituted heterocyclyl), -(NH) -(optionally substituted aryl), - (NH) -(optionally substituted heteroaryl), -(O)-(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O) -(optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), -(O) -(optionally substituted heteroaryl), -(CO)-(optionally substituted alkyl), -(CO)- (optionally substituted cycloalkyl), -(CO)-(optionally substituted heterocyclyl), -(CO)- (optionally substituted alkoxy), -(CO)-(optionally substituted aryl), -(CO) -(optionally substituted heteroaryl), -(CO) -(optionally substituted amino), and -COOH,R4is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, each of R5and R6is independently selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino,R7is selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, - (NH) -(optionally substituted alkyl), -(NH) -(optionally substituted cycloalkyl), -(NH)- (optionally substituted heterocyclyl), -(NH) -(optionally substituted aryl), -(NH) -(optionally substituted heteroaryl), -(O) -(optionally substituted alkyl), -(O) -(optionally substituted cycloalkyl), -(O)-(optionally substituted heterocyclyl), -(O)-(optionally substituted aryl), -(O)- (optionally substituted heteroaryl), -(CO)-(optionally substituted alkyl), -(CO)-(optionally substituted cycloalkyl), -(CO) -(optionally substituted heterocyclyl), -(CO)-(optionally substituted alkoxy), -(CO) -(optionally substituted aryl), -(CO)-(optionally substituted heteroaryl), -(CO)-(optionally substituted amino), and -COOH,R8is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, m is an integer selected from 0 to 9, n is an integer selected from 0 to 4, with the proviso that when X5, X6and X7form a structure according to Formula 1-1 and X5is NR4, X4is CH or CR3, with the proviso that when X5, X6and X7form a structure according to Formula 1-1 and X5is NR4and X2is N, when X1is CR3, R3for CR3is not optionally substituted amino, with the proviso that when X5, X6and X7form a structure according to Formula 1-2, R7is selected from optionally substituted alkoxy, optionally substituted amino, -(O)-(optionally substituted heterocyclyl), and -COOH, with the proviso that when X5, X6and X7form a structure according to Formula 1-3, X1is N and each of X2to X4is independently selected from CH and CR3, andwith the proviso that the compound is not any one of the compounds as described in Tables I, II, III, and IV.

54. A compound according to claim 53, wherein each of X1to X7, R1to R8, m and n are as defined in any one of claims 1 to 46.

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